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<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Official Journal <strong>of</strong> the European Society for Medical <strong>Oncology</strong> and<br />
the Japanese Society <strong>of</strong> Medical <strong>Oncology</strong><br />
editor-in-chief:<br />
J.-C. Soria, Villejuif, France<br />
associate editors<br />
Urogenital tumors<br />
G. Attard, Sutton, UK<br />
M. De Santis, Birmingham, UK<br />
Gastrointestinal tumors<br />
D. Arnold, Lisbon, Portugal<br />
A. Cervantes, Valencia, Spain<br />
J. Tabernero, Barcelona, Spain<br />
Breast tumors<br />
F. André, Villejuif, France<br />
C. Sotiriou, Brussels, Belgium<br />
Thoracic tumors<br />
T. Mitsudomi, Osaka, Japan<br />
J. F. Vansteenkiste, Leuven, Belgium<br />
Head and neck tumors<br />
A. T. C. Chan, Shatin, Hong Kong<br />
E. Cohen, San Diego, California, USA<br />
editors emeriti<br />
F. Cavalli, Bellinzona, Switzerland<br />
D. J. Kerr, Oxford, UK<br />
J. B. Vermorken, Edegem, Belgium<br />
Gynecological tumors<br />
B. Monk, Phoenix, Arizona, USA<br />
S. Pignata, Naples, Italy<br />
Melanoma<br />
G. Long, Sydney, Australia<br />
Hematological malignancies<br />
K. Tsukasaki, Kashiwa, Japan<br />
P. L. Zinzani, Bologna, Italy<br />
Supportive care<br />
K. Jordan, Halle, Germany<br />
Epidemiology<br />
P. B<strong>of</strong>fetta, New York, New York, USA<br />
Sarcoma and clinical pharmacology<br />
O. Mir, Villejuif, France<br />
Early drug development<br />
J.-C. Soria, Villejuif, France<br />
Preclinical and experimental science<br />
T. U. E. Helleday, Stockholm, Sweden<br />
Precision medicine<br />
C. Swanton, London, UK<br />
Bioinformatics<br />
N. McGranahan, London, UK<br />
BioTechnologies<br />
E. Mardis, St. Louis, Missouri, USA<br />
Onco-Immunology<br />
G. Coukos, Lausanne, Switzerland<br />
A. Snyder, New York, New York, USA<br />
Statistics<br />
M. Buyse, Brussels, Belgium<br />
Molecular and surgical pathology<br />
I. I. Wistuba, Houston, Texas, USA<br />
<strong>Annals</strong> <strong>of</strong> oncology online<br />
C. Ferté, Villejuif, France<br />
Industry corner: perspectives and controversies<br />
K. Dhingra, New York, New York, USA<br />
editorial board<br />
M. S. Aapro, Genolier, Switzerland<br />
Y. Ando, Nagoya, Japan<br />
P. Autier, Lyon, France<br />
H. A. Azim Jr, Marseille, France<br />
I. Barnes, Oxford, UK<br />
J. Baselga, New York, USA<br />
J. Bellmunt, Boston, Massachusetts, USA<br />
B. Besse, Villejuif, France<br />
J. Beyer, Zurich, Switzerland<br />
P. Bierman, Omaha, Nebraska, USA<br />
C. Bokemeyer, Hamburg, Germany<br />
N. Boku, Tokyo, Japan<br />
F. Bretz, Basel, Switzerland<br />
E. Bria, Verona, Italy<br />
E. F. Burgess, Charlotte, North Carolina, USA<br />
P. G. Casali, Milan, Italy<br />
F. Ciardiello, Naples, Italy<br />
A. Comandone, Turin, Italy<br />
P. G. Corrie, Cambridge, UK<br />
G. Curigliano, Milan, Italy<br />
A. Di Leo, Prato, Italy<br />
T. Dorff, Los Angeles, California, USA<br />
H. Dosaka-Akita, Sapporo, Japan<br />
E. A. Eisenhauer, Kingston, Canada<br />
A. Eniu, Cluj-Napoca, Romania<br />
T. Fenske, Milwaukee, Wisconsin, USA<br />
S. Galbraith, Cambridge, UK<br />
G. Giamas, Brighton, UK<br />
R. Glynne-Jones, Northwood, UK<br />
B.-C. Goh, Singapore, Singapore<br />
A. Goldhirsch, Milan, Italy<br />
R. Govindan, St. Louis, Missouri, USA<br />
P. Grimison, Sydney, Australia<br />
A. Grothey, Rochester, Minnesota, USA<br />
S. Halabi, Durham, North Carolina, USA<br />
D. G. Haller, Philadelphia, Pennsylvania, USA<br />
K. Hotta, Okayama, Japan<br />
R. A. Huddart, Sutton, UK<br />
I. Hyodo, Tsukuba, Japan<br />
M. Ignatiadis, Brussels, Belgium<br />
D. H. Ilson, New York, New York, USA<br />
H. Iwata, Aichi, Japan<br />
F. Janku, Houston, Texas, USA<br />
N. Katsumata, Kawasaki, Japan<br />
N. Kiyota, Kobe, Japan<br />
C. La Vecchia, Milan, Italy<br />
P. N. Jr Lara, Sacramento, California, USA<br />
S. Loi, Melbourne, Australia<br />
S. Loibl, Neu-Isenburg, Germany<br />
F. Lordick, Leipzig, Germany<br />
Y. Loriot, Villejuif, France<br />
S. Lutzker, San Francisco, California, USA<br />
T. Macarulla, Barcelona, Spain<br />
M. Martin, Madrid, Spain<br />
S. Matsui, Tokyo, Japan<br />
J. Maurel, Barcelona, Spain<br />
G. McArthur, Melbourne, Australia<br />
S. Michiels, Villejuif, France<br />
H. Minami, Kobe, Japan<br />
Y. Nishimura, Osaka-Sayama, Japan<br />
K. Nishio, Osaka-Sayama, Japan<br />
M. Ogura, Gifu, Japan<br />
A. Ohtsu, Chiba, Japan<br />
I. Okamoto, Fukuoka, Japan<br />
S. I. Ou, Orange, California, USA<br />
X. Paoletti, Paris, France<br />
C. Pezaro, Melbourne, Australia<br />
P. Pfeiffer, Odense, Denmark<br />
S. V. Porceddu, Brisbane, Australia<br />
M. R. Posner, New York, USA<br />
S. Postel-Vinay, Villejuif, France<br />
A. Psyrri, New Haven, Connecticut, USA<br />
D. Quinn, Los Angeles, California, USA<br />
S. S. Ramalingam, Atlanta, Georgia, USA<br />
M. Reck, Grosshansdorf, Germany<br />
B. Rini, Cleveland, Ohio, USA<br />
R. Rosell, Badalona, Spain<br />
A. D. Roth, Geneva, Switzerland<br />
R. Salazar, Barcelona, Spain<br />
M. Scartozzi, Ancona, Italy<br />
N. Schmitz, Hamburg, Germany<br />
H.-J. Schmoll, Halle, Germany<br />
I. Sekine, Tsukuba, Japan<br />
Q. Shi, Rochester, Minnesota, USA<br />
A. F. Sobrero, Genoa, Italy<br />
G. Sonpavde, Birmingham, Alabama, USA<br />
S. Takahashi, Tokyo, Japan<br />
M. Toi, Kyoto, Japan<br />
B. A. Van Tine, St. Louis, Missouri, USA<br />
E. Vilar, Houston, Texas, USA<br />
Y.-L. Wu, Guangzhou, China<br />
J. C.-H. Yang, Taipei, Taiwan<br />
S. Yano, Kanazawa, Japan<br />
executive editor: Lewis Rowett<br />
editorial <strong>of</strong>fice: Vanessa Marchesi, Paola Minotti Bernasconi, Giovannella Porcu, <strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong>, Via Luigi Taddei 4, CH-6962<br />
Viganello-Lugano, Switzerland<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong> is covered in C.A.B. International, Current Clinical Cancer, Current Contents/Clinical Medicine®, Current Contents/<br />
Life Sciences, Elsevier BIOBASE/Current Awareness in Biological Sciences, EMBASE/Excerpta Medica, IBIDS, Index Medicus/MEDLINE,<br />
The International Monitor in <strong>Oncology</strong>, Medical Documentation Service, Science Citation Index® and Science Citation Index Expanded.
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drug disclaimer<br />
All reasonable precautions have been taken by the authors, editors and publisher<br />
to verify drug names and doses, the results <strong>of</strong> experimental work and the<br />
clinical findings published in this journal. The opinions expressed are those <strong>of</strong><br />
the authors, and not necessarily those <strong>of</strong> the editors or publisher. The ultimate<br />
responsibility for the use and dosage <strong>of</strong> drugs mentioned in <strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
and in the interpretation <strong>of</strong> published material lies with the medical practitioner.<br />
The editors and publisher can accept no liability whatsoever in respect <strong>of</strong><br />
any claim for damages arising therefrom. Please inform the editors <strong>of</strong> any<br />
errors.<br />
notice<br />
The content <strong>of</strong> the abstracts contained in this Abstract Book is subject to an<br />
embargo.<br />
Abstracts accepted for presentation at ESMO 2016 as Poster Discussion and<br />
Poster will be published online on the ESMO website at 12:00 CEST (local<br />
Swiss time) on Wednesday, 28 September 2016.<br />
Abstracts accepted for presentation at ESMO 2016 as Pr<strong>of</strong>fered Paper (oral presentation)<br />
will be published online on the ESMO website at 12:00 CEST (local Swiss<br />
time) on Wednesday, 05 October 2016.<br />
Late-breaking abstracts will be made public at 08:15 CEST (local Swiss time)<br />
on the day <strong>of</strong> the <strong>of</strong>ficial Congress session during which they are presented.<br />
Abstracts selected for the <strong>of</strong>ficial ESMO Press Programme will be made public<br />
at the beginning <strong>of</strong> the <strong>of</strong>ficial Press Conference during which they are presented<br />
at 08:15 or 12:30 CEST (local Swiss time).<br />
disclaimer<br />
No responsibility is assumed by the organizers for any injury and/or damage to<br />
persons or property as a matter <strong>of</strong> products liability, negligence or otherwise, or<br />
from any use or operation <strong>of</strong> any methods, products, instructions or ideas contained<br />
in the material herein. Because <strong>of</strong> the rapid advances in medical sciences,<br />
we recommend that independent verification <strong>of</strong> diagnoses and drug dosages<br />
should be made.<br />
Every effort has been made to faithfully reproduce the abstracts as submitted.<br />
However, no responsibility is assumed by the organizers for any omissions or<br />
misprints.<br />
© The European Society for Medical <strong>Oncology</strong> 2016<br />
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Danvers, MA 01923.<br />
Typeset by Nova Techset Private Limited, Bengaluru & Chennai, India.<br />
Printed by Bell and Bain Ltd., Glasgow, UK.
<strong>Annals</strong> <strong>of</strong><br />
<strong>Oncology</strong><br />
Official Journal <strong>of</strong> the European Society<br />
for Medical <strong>Oncology</strong> and the Japanese<br />
Society <strong>of</strong> Medical <strong>Oncology</strong><br />
Volume 27, 2016 Supplement 6<br />
Abstract Book <strong>of</strong> the 41st ESMO Congress (ESMO 2016)<br />
7–11 October 2016, Copenhagen, Denmark<br />
Guest Editors:<br />
ESMO 2016 Congress Scientific Committee
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Official Journal <strong>of</strong> the European Society for<br />
Medical <strong>Oncology</strong> and the Japanese Society <strong>of</strong> Medical <strong>Oncology</strong><br />
Volume 27, 2016 Supplement 6<br />
Abstract Book <strong>of</strong> the 41st ESMO Congress (ESMO 2016)<br />
Copenhagen, Denmark, 7–11 October 2016<br />
About ESMO<br />
vi_vi<br />
Health economics<br />
vi351<br />
ESMO Executive Board<br />
vi_vi<br />
Immunotherapy <strong>of</strong> cancer<br />
vi359<br />
ESMO 2016 Congress Officers<br />
vi_vii<br />
Melanoma and other skin tumours<br />
vi379<br />
Acknowledgements<br />
vi_x<br />
New diagnostics<br />
vi401<br />
Submitted abstracts<br />
Basic Science<br />
Biomarkers<br />
Breast cancer, early stage<br />
Breast cancer, locally advanced and metastatic<br />
Clinical trials methodology<br />
CNS tumours<br />
Developmental therapeutics<br />
Endocrine and neuroendocrine tumours<br />
Gastrointestinal tumours, colorectal<br />
Gastrointestinal tumours, non-colorectal<br />
Genitourinary tumours, prostate<br />
Genitourinary tumours, non-prostate<br />
Gynaecological cancers<br />
Haematological Malignancies<br />
Head and neck cancer<br />
vi1<br />
vi15<br />
vi43<br />
vi68<br />
vi100<br />
vi103<br />
vi114<br />
vi136<br />
vi149<br />
vi207<br />
vi243<br />
vi266<br />
vi296<br />
vi313<br />
vi328<br />
NSCLC, early stage<br />
NSCLC, locally advanced<br />
NSCLC, metastatic<br />
Palliative care<br />
Prevention and screening<br />
Psycho-oncology<br />
Public health<br />
Sarcoma<br />
SCLC<br />
Supportive care<br />
Thoracic malignancies, other<br />
Translational research<br />
Tumour biology and pathology<br />
Late-Breaking Abstracts and deferred publication<br />
Drug index<br />
Translational research index<br />
vi407<br />
vi411<br />
vi416<br />
vi455<br />
vi462<br />
vi469<br />
vi474<br />
vi483<br />
vi493<br />
vi497<br />
vi522<br />
vi526<br />
vi545<br />
vi552<br />
vi556<br />
Note: Abstract suffixes<br />
“O” indicates a submitted abstract accepted for Pr<strong>of</strong>fered Paper (oral) presentation<br />
“PD” indicates a submitted abstract accepted for Poster Discussion<br />
“P” indicates a submitted abstract accepted for Poster Presentation<br />
“TiP” indicates a submitted abstract accepted for Poster Presentation, Trial in Progress<br />
__PR indicates a submitted abstract selected for inclusion in the ESMO Press Programme<br />
Volume 27 | Supplement 6 | October 2016
The European Society for Medical <strong>Oncology</strong> (ESMO)<br />
ESMO is the leading pr<strong>of</strong>essional organisation for medical oncology, with the overarching goal <strong>of</strong> improving outcomes for<br />
cancer patients everywhere. We are the society <strong>of</strong> reference for oncology education and information, and are committed to<br />
supporting our members to develop and advance in a fast-evolving pr<strong>of</strong>essional environment.<br />
Founded in 1975, ESMO has European roots with a global reach: we welcome oncology pr<strong>of</strong>essionals from around the<br />
world. We are a home for all oncology stakeholders, connecting pr<strong>of</strong>essionals with diverse expertise and experience,<br />
and speaking with one voice for our discipline. Our education and information resources support an integrated<br />
multi-pr<strong>of</strong>essional approach to cancer care, from a medical oncology perspective. We seek to erase boundaries in cancer<br />
care, whether between countries or specialities, and pursue our mission across oncology, worldwide.<br />
The ESMO community brings together more than 13,000 oncology pr<strong>of</strong>essionals from over 130 countries. Drawing on 40<br />
years <strong>of</strong> experience and around 500 expert committee members, ESMO serves its members and the oncology community<br />
through:<br />
• Post-graduate oncology education and training<br />
• Career development and leadership training for the next generations <strong>of</strong> oncologists<br />
• International congresses and workshops to share expertise and best practice, learn about the most up-to-date scientific<br />
advances, and connect with colleagues in related disciplines<br />
• Continuously reviewed, evidence-based standards for cancer care in Europe<br />
• Advocacy and consultation to foster a favourable environment for scientific research<br />
Cancer care is rapidly becoming more integrated and more specialised; whether their field is research, diagnosis, treatment,<br />
care, or advocacy, oncology pr<strong>of</strong>essionals need to both build their specialist knowledge and connect with the best<br />
practitioners in other disciplines worldwide. ESMO membership makes this possible.<br />
Please visit esmo.org to learn more. Across <strong>Oncology</strong>. Worldwide.<br />
ESMO Executive Board<br />
President<br />
President-Elect<br />
Past President and Membership Committee Chair<br />
Treasurer<br />
Educational Committee Chair<br />
National Representatives and Membership Committee Chair<br />
EU Policy Committee Chair<br />
Global Policy Committee Chair<br />
Guidelines Working Group Chair<br />
Press and Media Affairs Committee Chair<br />
Practising Oncologists Committee Chair<br />
Board Member<br />
Board Member<br />
Board Member<br />
Board Member<br />
Fortunato Ciardiello, Naples, Italy<br />
Josep Tabernero, Barcelona, Spain<br />
Rolf A. Stahel, Zurich, Switzerland<br />
Emile Voest, Amsterdam, The Netherlands<br />
Andrés Cervantes, Valencia, Spain<br />
Fatima Cardoso, Lisbon, Portugal<br />
Paolo G. Casali, Milan, Italy<br />
Alexandru Eniu, Cluj-Napoca, Romania<br />
George Pentheroudakis, Ioannina, Greece<br />
Solange Peters, Lausanne, Switzerland<br />
Stefan Rauh, Esch-sur-Alzette, Luxembourg<br />
Dirk Arnold, Lisbon, Portugal<br />
Alexander M. M. Eggermont, Villejuif, France<br />
Jacek Jassem, Gdansk, Poland<br />
Christoph Zielinski, Vienna, Austria
ESMO 2016 Congress Officers<br />
2016 ESMO and Congress President<br />
Fortunato Ciardiello, Naples, Italy<br />
Scientific Committee Chair<br />
Andrés Cervantes, Valencia, Spain<br />
Educational Chair<br />
Jean-Yves Douillard, Lugano, Switzerland<br />
Press Officer<br />
Solange Peters, Lausanne, Switzerland<br />
Local Officer<br />
Ulrik N. Lassen, Copenhagen, Denmark<br />
Scientific Committee<br />
Basic science and translational research<br />
Chair: Richard Marais, Manchester, UK<br />
Catherine Alix-Panabieres, Montpellier, France<br />
Anton Berns, Amsterdam, Netherlands<br />
Alberto Bardelli, Candiolo, Italy<br />
Carlos Caldas, Cambridge, UK<br />
Raffaele Califano, Manchester, UK<br />
Robert Gatenby, Tampa, FL, USA<br />
Ramaswamy Govindan, St. Louis, MO, USA<br />
David Huntsman, Vancouver, BC, Canada<br />
Clare Isacke, London, UK<br />
Joan Seoane, Barcelona, Spain<br />
Sheila Singh, Hamilton, ON, Canada<br />
Thomas Tüting, Bonn, Germany<br />
Christ<strong>of</strong> von Kalle, Heidelberg, Germany<br />
Breast cancer, early stage<br />
Chair: Marco Colleoni, Milan, Italy<br />
Hatem A. Azim, Jr., Marseille, France<br />
Jacques Bernier, Genolier, Switzerland<br />
Herve Bonnefoi, Bordeaux, France<br />
Karen Gelmon, Vancouver, BC, Canada<br />
Nadia Harbeck, Munich, Germany<br />
Guy Jerusalem, Liege, Belgium<br />
Sybille Loibl, Neu-Isenburg, Germany<br />
Aleix Prat, Barcelona, Spain<br />
Isabel T. Rubio, Barcelona, Spain<br />
Elżbieta Senkus-Konefka, Gdańsk, Poland<br />
Andrew Tutt, London, UK<br />
Giuseppe Viale, Milan, Italy<br />
Breast cancer, metastatic<br />
Chair: Robert E. Coleman, Sheffield, UK<br />
Fabrice André, Villejuif, France<br />
Fatima Cardoso, Lisbon, Portugal<br />
Pier Franco Conte, Padua, Italy<br />
Javier Cortes, Barcelona, Spain<br />
Luis Costa, Lisbon, Portugal<br />
Roger Gomis, Barcelona, Spain<br />
Nadia Harbeck, Munich, Germany<br />
Per Karlsson, Gothenburg, Sweden<br />
Sherene Loi, Melbourne, Australia<br />
Peter Schmid, London, UK<br />
David Warr, Toronto, ON, Canada<br />
Developmental therapeutics<br />
Chair: Jordi Rodón, Barcelona, Spain<br />
Udai Banerji, Sutton, UK<br />
Mark Basik, Montreal, QC, Canada<br />
Irene Braña, Barcelona, Spain<br />
Mario Campone, Saint Herblain, France<br />
Bryan Hennessy, Dublin, Ireland<br />
Chia-Chi Lin, Taipei, Taiwan<br />
Christophe Massard, Villejuif, France<br />
Paolo Nuciforo, Barcelona, Spain<br />
Christian Rolfo, Edegem, Belgium<br />
Jan Schellens, Amsterdam, Netherlands<br />
Christopher Twelves, Leeds, UK<br />
CNS tumours<br />
Chair: Alba Brandes, Bologna, Italy<br />
Carmen Balaña, Barcelona, Spain<br />
Deborah Blumenthal, Tel Aviv, Israel<br />
Michael Brada, Bebington, UK<br />
Roger Henriksson, Stockholm, Sweden<br />
Simone Niclou, Luxembourg<br />
Guido Reifenberger, Dusseldorf, Germany<br />
Marc Sanson, Paris, France<br />
Colin Watts, Cambridge, UK<br />
Michael Weller, Zurich, Switzerland<br />
Patrick Wen, Boston, MA, USA<br />
Gastrointestinal tumours, colorectal<br />
Chair: Julien Taieb, Paris, France<br />
Richard Adams, Cardiff, UK<br />
Dirk Arnold, Lisbon, Portugal<br />
Daniela Aust, Dresden, Germany<br />
Chiara Cremolini, Pisa, Italy<br />
Thomas Gruenberger, Vienna, Austria<br />
Volker Heinemann, Munich, Germany<br />
Florence Huguet, Paris, France<br />
Claus-Henning Koehne, Oldenburg, Germany<br />
Fotios Loupakis, Pisa, Italy<br />
Ramon Salazar, L’Hospitalet de Llobergat, Spain<br />
Sabine Tejpar, Leuven, Belgium<br />
Christophe Tournigand, Creteil, France
Gastrointestinal tumours, non-colorectal<br />
Chair: Florian Lordick, Leipzig, Germany<br />
Fátima Carneiro, Porto, Portugal<br />
Ian Chau, Sutton, UK<br />
Eduardo Diaz Rubio, Madrid, Spain<br />
Michel Ducreux, Villejuif, France<br />
Axel Hillmer, Mainz, Germany<br />
Yelena Janjigian, New York, NY, USA<br />
Christophe Mariette, Lille, France<br />
Per Pfeiffer, Odense, Denmark<br />
Fernando Rivera, Santander, Spain<br />
Arnaud Roth, Geneva, Switzerland<br />
Eric Van Cutsem, Leuven, Belgium<br />
Marcel Verheij, Amsterdam, Netherlands<br />
Genitourinary tumours, non-prostate<br />
Chair: Joaquim Bellmunt, Boston, MA, USA<br />
Laurence Albiges, Villejuif, France<br />
Ferran Algaba, Barcelona, Spain<br />
Aris Bamias, Athens, Greece<br />
Axel Bex, Amsterdam, Netherlands<br />
Bernard Escudier, Villejuif, France<br />
Viktor Grünwald, Hannover, Germany<br />
Christian Kollmannsberger, Vancouver, BC, Canada<br />
Antonio López-Beltran, Lisbon, Portugal<br />
Nicholas Mottet, St. Etienne, France<br />
Andrea Necchi, Milan, Italy<br />
Jack Schalken, Nijmegen, Netherlands<br />
Manuela Schmidinger, Vienna, Austria<br />
Genitourinary tumours, prostate<br />
Chair: Gerhardt Attard, Sutton, UK<br />
Himisha Beltran, New York, NY, USA<br />
Johann de Bono, London, UK<br />
Ronald de Wit, Rotterdam, Netherlands<br />
Eleni Efstathiou, Houston, TX, USA<br />
Felix Feng, Ann Arbor, MI, USA<br />
Silke Gillessen, St. Gallen, Switzerland<br />
Axel Heidenreich, Aachen, Germany<br />
Yohann Loriot, Villejuif, France<br />
David Olmos, Madrid, Spain<br />
Stephane Oudard, Paris, France<br />
Mathew Sydes, London, UK<br />
Scott Tomlins, Ann Arbor, MI, USA<br />
Gynaecological cancers<br />
Chair: Sandro Pignata, Naples, Italy<br />
Carien L. Creutzberg, Leiden, Netherlands<br />
Antonio González-Martín, Madrid, Spain<br />
Charlie Gourley, Edinburgh, UK<br />
Florence Joly, Caen, France<br />
Jonathan Ledermann, London, UK<br />
Domenica Lorusso, Milan, Italy<br />
Mansoor Mirza, Copenhagen, Denmark<br />
Andres Poveda, Valencia, Spain<br />
Isabelle Ray-Coquard, Lyon, France<br />
Cristiana Sessa, Bellinzona, Switzerland<br />
Ignace Vergote, Leuven, Belgium<br />
Haematological malignancies<br />
Chair: Christian Buske, Ulm, Germany<br />
Peter Campbell, Hinxton, UK<br />
Andrés Ferreri, Milan, Italy<br />
Ramon Garcia-Sanz, Salamanca, Spain<br />
Paolo Ghia, Milan, Italy<br />
Klaus Herfarth, Heidelberg, Germany<br />
Peter Johnson, Southampton, UK<br />
Marco Ladetto, Alessandria, Italy<br />
Steven Le Gouill, Nantes, France<br />
Armando Lopez-Guillermo, Barcelona, Spain<br />
Gert J. Ossenkoppele, Amsterdam, Netherlands<br />
Mariano Provencio, Madrid, Spain<br />
Evangelos Terpos, Athens, Greece<br />
Immunotherapy <strong>of</strong> cancer<br />
Chair: John Haanen, Amsterdam, Netherlands<br />
Philipp Beckhove, Heidelberg, Germany<br />
Mario Colombo, Milan, Italy<br />
Jérôme Galon, Paris, France<br />
Ignacio Melero, Pamplona, Spain<br />
Paul Nathan, Northwood, UK<br />
Ulf Petrausch, Zurich, Switzerland<br />
Thomas Powles, London, UK<br />
Suzy Scholl, Paris, France<br />
Inge Marie Svane, Herlev, Denmark<br />
Sjoerd van der Burg, Leiden, Netherlands<br />
Laurence Zitvogel, Villejuif, France<br />
Head and neck cancer<br />
Chair: Amanda Psyrri, Athens, Greece<br />
Ana Castro, Porto, Portugal<br />
Sandrine Faivre, Clichy, France<br />
Vincent Gregoire, Brussels, Belgium<br />
Nikolaos Kavantzas, Athens, Greece<br />
Lisa Licitra, Milan, Italy<br />
Jean-Pascal Machiels, Brussels, Belgium<br />
Marco Merlano, Cuneo, Italy<br />
Ricard Mesía, L’Hospitalet de Llobregat, Spain<br />
Piero Nicolai, Brescia, Italy<br />
Christos Perisanidis, Vienna, Austria<br />
Massimo Tommasino, Lyon, France<br />
Melanoma and other skin tumours<br />
Chair: Olivier Michielin, Lausanne, Switzerland<br />
Paolo Ascierto, Naples, Italy<br />
Boris C. Bastian, San Francisco, CA, USA<br />
Reinhard Dummer, Zurich, Switzerland<br />
Jean-Jacques Grob, Marseille, France<br />
Axel Hauschild, Kiel, Germany<br />
Christoph Hoeller, Vienna, Austria<br />
Paul Lorigan, Manchester, UK<br />
Josep Malvehy, Barcelona, Spain<br />
Caroline Robert, Villejuif, France<br />
Benoît Van den Eynde, Brussels, Belgium<br />
Jeffrey Weber, New York, NY, USA
NETs and endocrine tumours<br />
Chair: Rocio Garcia-Carbonero, Madrid, Spain<br />
Jaume Capdevila, Barcelona, Spain<br />
Michel Ducreux, Villejuif, France<br />
Massimo Falconi, Milan, Italy<br />
Dik Kwekkeboom, Rotterdam, Netherlands<br />
Kjell Öberg, Uppsala, Sweden<br />
Marianne Pavel, Berlin, Germany<br />
George Pentheroudakis, Athens, Greece<br />
Eric Raymond, Lausanne, Switzerland<br />
Guido Rindi, Rome, Italy<br />
Mercedes Robledo, Madrid, Spain<br />
Juan Valle, Manchester, UK<br />
James Yao, Houston, TX, USA<br />
NSCLC, metastatic<br />
Chair: Egbert Smit, Amsterdam, Netherlands<br />
Fabrice Barlesi, Marseille, France<br />
Fiona Blackhall, Manchester, UK<br />
Rafal Dziadziuszko, Gdansk, Poland<br />
Stephen Finn, Dublin, Ireland<br />
Keith Kerr, Aberdeen, UK<br />
Peter Meldgaard, Aarhus, Denmark<br />
Tony S.K. Mok, Hong Kong, China<br />
Silvia Novello, Orbassano, Italy<br />
Luis Paz-Ares, Madrid, Spain<br />
Solange Peters, Lausanne, Switzerland<br />
Martin Reck, Grosshansdorf, Germany<br />
Gregory J. Riely, New York, NY, USA<br />
Sarcoma<br />
Chair: Olivier Mir, Villejuif, France<br />
Stefan Bielack, Stuttgart, Germany<br />
Jean Yves Blay, Lyon, France<br />
Philippe Cassier, Lyon, France<br />
A. Paolo Dei Tos, Treviso, Italy<br />
Xavier Garcia del Muro, Barcelona, Spain<br />
Alessandro Gronchi, Milan, Italy<br />
Robin Jones, London, UK<br />
Cecile Le Pechoux, Villejuif, France<br />
Javier Martin Broto, Seville, Spain<br />
Silvia Stacchiotti, Milan, Italy<br />
Maud Toulmonde, Bordeaux, France<br />
Winette van der Graaf, London, UK<br />
Non-metastatic NSCLC and other thoracic malignancies<br />
Chair: Dirk De Ruysscher, Maastricht, Netherlands<br />
Paul Baas, Amsterdam, Netherlands<br />
Benjamin Besse, Villejuif, France<br />
Anne-Marie Dingemans, Maastricht, Netherlands<br />
Wilfried Eberhardt, Essen, Germany<br />
Pilar Garrido, Madrid, Spain<br />
Tetsuya Mitsudomi, Osaka-Sayama, Japan<br />
Sanjay Popat, London, UK<br />
Jens Benn Soerensen, Copenhagen, Denmark<br />
Esther Troost, Dresden, Germany<br />
Johan Vansteenkiste, Leuven, Belgium<br />
Giulia Veronesi, Milan, Italy<br />
Public health and health economics<br />
Chair: Rosa Giuliani, Rome, Italy<br />
Tit Albreht, Ljubljana, Slovenia<br />
Peter Boyle, Ecully, France<br />
Paolo G. Casali, Milan, Italy<br />
Jack Cuzick, London, UK<br />
Silvia de Sanjosé, L’Hospitalet de Llobregat, Spain<br />
Harry de Koning, Rotterdam, Netherlands<br />
Alex Eniu, Cluj-Napoca, Romania<br />
Valerie Lemmens, Eindhoven, Netherlands<br />
Alberto Ocana, Albacete, Spain<br />
Richard Sullivan, London, UK<br />
Andreas Ullrich, Geneva, Switzerland<br />
Supportive and palliative care<br />
Chair: Karin Jordan, Halle, Germany<br />
Matti Aapro, Genolier, Switzerland<br />
Marie Fallon, Edinburgh, UK<br />
Petra Feyer, Berlin, Germany<br />
Joern Herrstedt, Odense, Denmark<br />
Stein Kaasa, Trondheim, Norway<br />
Bernardo Rapoport, Johannesburg, South Africa<br />
Carla Ripamonti, Milan, Italy<br />
Fausto Roila, Terni, Italy<br />
Tiina Saarto, Helsinki, Finland<br />
Florian Scotté, Paris, France<br />
Florian Strasser, St. Gallen, Switzerland<br />
The European Society for Medical <strong>Oncology</strong> wishes to express its appreciation and gratitude to all <strong>of</strong> the above experts for<br />
their major effort in reviewing and selecting the content <strong>of</strong> this Abstract Book.
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong> 27 (Supplement 6): vi1–vi14, 2016<br />
doi:10.1093/annonc/mdw362<br />
basic science<br />
1O<br />
EPHA2 blockade overcomes primary and acquired resistance to<br />
anti-epidermal growth factor receptor (EGFR) therapy in<br />
metastatic colorectal cancer (mCRC)<br />
G. Martini 1 , V. Belli 2 , P.P. Vitiello 1 , T. Troiani 1 , C. Cardone 1 , S. Napolitano 1 ,<br />
V. Desiderio 3 , V. Sforza 1 , M.L. Ferrara 1 , G. Papaccio 3 , L. Mele 3 , G. Liguori 4 ,<br />
G. Botti 5 , R. Franco 6 , F. Morgillo 1 , F. Ciardiello 1 , E. Martinelli 1<br />
1 Medical <strong>Oncology</strong>, AOU Seconda Università degli Studi di Napoli (AOU-SUN),<br />
Naples, Italy, 2 Dipartimento Medico-Chirurgico di Internistica Clinica e<br />
sperimentale, AOU Seconda Università degli Studi di Napoli (AOU-SUN), Naples,<br />
Italy, 3 Istology, AOU Seconda Università degli Studi di Napoli (AOU-SUN), Naples,<br />
Italy, 4 Anatomia Patologica, Istituto Nazionale Tumori – I.R.C.C.S - Fondazione<br />
Pascale, Naples, Italy, 5 Dipartimento di anatomia patologica, Istituto Nazionale<br />
Tumori – I.R.C.C.S - Fondazione Pascale, Naples, Italy, 6 Anatomia patologica,<br />
AOU Seconda Università degli Studi di Napoli (AOU-SUN), Naples, Italy<br />
detected by ELISA or qPCR, respectively. We conducted a BioMap human cell<br />
co-culture system analysis with peripheral blood mononuclear cells, endothelial cells,<br />
and H1299 human lung cancer cells to evaluate effects <strong>of</strong> each single agent and<br />
combination treatments on Th1/Th2 immune response.<br />
Results: Combination <strong>of</strong> LEN with PD-1 mAb showed more potent inhibitory activity<br />
against tumor growth in all 3 models compared with each single agent. Notably,<br />
complete tumor regressions were detected in some mice with combination treatment in<br />
the H22 syngeneic mouse tumor model. Re-inoculation <strong>of</strong> fresh H22 cells into these<br />
cured mice was rejected. BioMap analysis showed that PD-1 mAb increased both Th1<br />
and Th2 cytokines, LEN decreased Th2 cytokines, and combination treatment<br />
increased Th1 cytokines but decreased Th2 cytokines. ELISA and qPCR analysis also<br />
showed that Th1 cytokines were increased but Th2 cytokines were decreased with<br />
combination treatments in the LL/2 and CT26 syngeneic mouse models.<br />
Conclusions: The results indicate that the combination <strong>of</strong> LEN with PD-1 mAb was<br />
more effective than single-agent treatment in multiple syngeneic tumor models and<br />
was accompanied with a potent antitumor immune response.<br />
Legal entity responsible for the study: Eisai Inc.<br />
Funding: Eisai Inc.<br />
Disclosure: Y. Kato, K. Tabata, Y. Hori, S. Tachino, Y. Funahashi, J. Matsui: Employee<br />
<strong>of</strong> Eisai Co., Ltd.X. Bao, S. Macgrath, M. Matijevici: Employee <strong>of</strong> Eisai Inc.<br />
3P<br />
Dissecting the roles <strong>of</strong> Fra proteins in lung adenocarcinoma<br />
A. Alfraidi 1 , L. Bakiri 1 , A. Ucero 1 , M. Musteanu 2 , M. Barbacid 2 , E. Wagner 1<br />
1 Genes, Development and Disease, CNIO- Spanish National Cancer Center,<br />
Madrid, Spain, 2 Molecular <strong>Oncology</strong>, CNIO- Spanish National Cancer Center,<br />
Madrid, Spain<br />
2PD<br />
Lenvatinib mesilate (LEN) enhanced antitumor activity <strong>of</strong> a<br />
PD-1 blockade agent by potentiating Th1 immune response<br />
Background: Lung cancer is a life-threatening disease with increased incidence<br />
worldwide. Most patients are diagnosed with advanced disease, and as a result, the 5 year<br />
survival rate is among the lowest in cancer. Among all lung cancer, 85% are non small<br />
lung cancer (NSCLC) subtype, which can be subdivided in lung adenocarcinoma (ADC)<br />
and squamous cell carcinoma (SCC). K-Ras mutation is the most common in NSCLC,<br />
but no drugs that target K-Ras directly or indirectly have yet been discovered. Therefore,<br />
there is a need to find a druggable target that can help in the treatment <strong>of</strong> lung cancer<br />
patients. Fos-related antigen 2 (Fra-2), a member <strong>of</strong> AP-1 transcription factors, has been<br />
shown to be activated by K-Ras signalling, as well as deregulated in many cancer types.<br />
Methods: Prognosis value <strong>of</strong> Fra-2 mRNA expression level was assessed in<br />
transcriptomic data from 1928 NSCLC patients through an online survival analysis<br />
s<strong>of</strong>tware. We generated a genetic engineered mouse model (GEMM) for Fra-2<br />
inactivation in an experimental model <strong>of</strong> lung ADC induced by K-Ras mutation (G12V)<br />
and p53 inactivation. Fra-2 and p53 inactivation, and mutant K-Ras expression, are<br />
induced simultaneously by infection with a Cre-expressing Adenovirus delivered<br />
intra-nasally. Development <strong>of</strong> lung tumours was longitudinally monitored by micro-CT.<br />
Results: Fra-2 mRNA high expression was found to be significantly correlated to poor<br />
outcome in this ADC patient cohort. Genetic inactivation <strong>of</strong> Fra-2 in this lung cancer<br />
model prolongs the survival <strong>of</strong> the mice compared with heterozygous Fra-2 by<br />
decreasing tumor incidence, number and volume.<br />
Conclusions: Our results identify a new potential therapeutic target in K-Ras mutated<br />
lung ADC.<br />
Legal entity responsible for the study: A. Alfraidi<br />
Funding: World Wide Cancer Research formerly AICR<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
abstracts<br />
Y. Kato 1 , X. Bao 2 , S. Macgrath 2 , K. Tabata 1 , Y. Hori 1 , S. Tachino 1 , M. Matijevici 2 ,<br />
Y. Funahashi 1 , J. Matsui 1<br />
1 Eisai Co., Ltd., Ibaraki, Japan, 2 Eisai, Inc, Andover, MA, USA<br />
4P<br />
Metallothionein 1H functions as a tumor suppressor in<br />
hepatocellular carcinoma<br />
Background: LEN selectively inhibits the kinase activity <strong>of</strong> VEGFR1-3, FGFR1-4, KIT,<br />
PDGFRα, and RET, which are involved in tumor angiogenesis and proliferation in<br />
several cancer types. Currently, Phase 1b/2 clinical trials <strong>of</strong> the combination <strong>of</strong> LEN<br />
and pembrolizumab (a monoclonal antibody [mAb] that blocks the interaction<br />
between PD-1 and its ligands) are ongoing for selected types <strong>of</strong> cancer including<br />
melanoma and renal cancer. In order to understand the antitumor effect and<br />
mechanism <strong>of</strong> action <strong>of</strong> the combination <strong>of</strong> LEN and PD-1 blockade treatment, we<br />
analyzed immune response in syngeneic murine tumor models.<br />
Methods: We examined antitumor activity <strong>of</strong> combination treatment <strong>of</strong> LEN (10mg/<br />
kg, qd) and anti-mouse PD-1 mAb (500 µg/mouse, twice weekly) against LL/2 murine<br />
lung carcinoma, H22 murine hepatocellular carcinoma, and CT26 murine colon cancer<br />
in syngeneic mouse models. For immune population analyses, tumor or spleen samples<br />
were analyzed by flow cytometry. The expression <strong>of</strong> soluble factors and genes was<br />
Y. Zheng 1 , L. Jiang 2 ,N.Xu 1 , C. Xiao 1 ,Y.Hu 3 , X. Wang 1 , L. Chen 4 , H. Fang 5 ,<br />
J. Zhu 6<br />
1 Department <strong>of</strong> Medical <strong>Oncology</strong>, 1st Affiliated Hospital <strong>of</strong> Zhejiang University<br />
School <strong>of</strong> Medicine, Hangzhou, China, 2 Department <strong>of</strong> Neurology, The Children’s<br />
Hospital, Zhejiang University School <strong>of</strong> Medicine, Hangzhou, China, 3 Department<br />
<strong>of</strong> Haematology, 1st Affiliated Hospital <strong>of</strong> Zhejiang University School <strong>of</strong> Medicine,<br />
Hangzhou, China, 4 Department <strong>of</strong> Medical <strong>Oncology</strong>, 1st People’s Hospital <strong>of</strong><br />
Taizhou, Taizhou, China, 5 Department <strong>of</strong> <strong>Oncology</strong> Cancer Center, Zhejiang<br />
Xiaoshan Hospital, Hangzhou, China, 6 Medical <strong>Oncology</strong>, Hangzhou Cancer<br />
Hospital, Hangzhou, China<br />
Background: Hepatocellular carcinoma (HCC) remains a major cause <strong>of</strong> cancer-related<br />
death worldwide. Metallothioneins (MTs) are low-molecular weight, cysteine-rich<br />
© European Society for Medical <strong>Oncology</strong> 2016. Published by Oxford University Press on behalf <strong>of</strong> the European Society for Medical <strong>Oncology</strong>.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com.
abstracts<br />
proteins, and classified into multiple classes. One <strong>of</strong> the MT species, MT1H, is down<br />
regulated in HCC. However, the roles <strong>of</strong> MT1H in HCC are not fully understood.<br />
Methods: The expression <strong>of</strong> MT1H in large datasets derived from TCGA databases.<br />
Hepatoma HepG2 and Hep3B cells were transfected with full length Flag-tagged<br />
MT1H. The cell growth curved was obtained through MTT assay. Invasiveness and<br />
migration ability <strong>of</strong> hepatoma cells was studied through the matrigel-coated transwell<br />
assay. HepG2-Vector and HepG2-MT1H cells were subcutaneously injected into nude<br />
mice for assessing in vivo tumorigenicity <strong>of</strong> MT1H over-expression.<br />
Results: The results from TCGA RNASeq2 data showed that MT1H is significantly<br />
down regulated in most HCC analyzed. MT1H expression level was found to be<br />
markedly decreased in all HCC tumors. Hepatoma HepG2 and Hep3B cells were<br />
transfected with full length Flag-tagged MT1H. Enforced expression <strong>of</strong> MT1H in<br />
HepG2 and Hep3B cells led to a more than 50% decrease in colony numbers as<br />
compared with control cells. The DNA synthesis capability was significantly decreased<br />
in MT1H-overexpressed hepatoma cells. Ectopic overexpression <strong>of</strong> MT1H significantly<br />
impaired the migration capability <strong>of</strong> hepatoma cells. We found that Wnt/β-catenin<br />
pathway related genes were significantly enriched in the HCC patients with low MT1H<br />
expression. Consistently, ectopic over-expression <strong>of</strong> MT1H in HCC cells significantly<br />
suppressed the mRNA level <strong>of</strong> β-catenin signaling downstream targets (c-Myc, MMP7,<br />
LEF1, and TCF4) . As expected, Wnt/β-catenin nuclear translocation was significantly<br />
attenuated in MT1H over-expressed HCC cells. To assess the effect <strong>of</strong> MT1H<br />
over-expression on tumorigenicity in vivo, we subcutaneously injected nude mice with<br />
HepG2-Vector and HepG2-MT1H cells. The tumors formed by HepG2-MT1H cells<br />
were significantly smaller than that <strong>of</strong> control cells. The average tumor weight <strong>of</strong> the<br />
MT1H- transfected cells inoculated mice was significantly decreased at day 30.<br />
Conclusions: Our findings suggest that MT1H functions as tumor suppressor in HCC<br />
mediated by Wnt/β-catenin signaling pathway.<br />
Legal entity responsible for the study: N/A<br />
Funding: Zhejiang Provincial Natural Science Fund (grant no. LY13H160007) and the<br />
Zhejiang Medicines and Health Science and Technology Project (grant no. 201348801).<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
5P<br />
AMPKalpha1 restrains fibroblasts transformation and<br />
tumorigenesis in vivo<br />
P. Song, Y. Ding, Q. Lu, M-H. Zou<br />
Center for Molecular and Translational Medicine, Georgia State University, Atlanta,<br />
GA, USA<br />
Background: Adenosine monophosphate-activated protein kinase (AMPK) is a critical<br />
metabolic sensor and redox modulator. Despite evidence linking AMPK tumor<br />
suppressor functions, the role <strong>of</strong> AMPK in chromosome instability and tumorigenesis<br />
is obscure.<br />
Methods: Murine embryo fibroblasts (MEF) were isolated from AMPK alpha1 knock<br />
out (AMPKα1-KO), AMPKα2-KO, and wild type (WT) C57BL/6J mouse embryos,<br />
and immortalized by employing standard 3T3 protocol to investigate the mechanisms<br />
<strong>of</strong> chromosomal instability and fibroblast-mediated angiogenesis. Chromatin proteins<br />
and aneuploidy were monitored in cultured MEFs by Western blot and metaphase<br />
spread. Athymic nude mice were employed to test tumorigenesis <strong>of</strong> fibroblasts in vivo.<br />
Results: Deletion <strong>of</strong> AMPKα1, but not AMPKα2, exhibited a significant reduction in<br />
centromere-specific binding proteins C (CENP-C) and elevation <strong>of</strong> Polo-like kinase 4<br />
(PLK4), a trigger <strong>of</strong> centriole biogenesis. Both CENP-C and PLK4 may be associated<br />
with the increased aneuploid (34%-66%) and micronucleus. Allograft model data<br />
demonstrated that knock out <strong>of</strong> AMPKα1 enhanced the cellular proliferation <strong>of</strong><br />
immortalized MEFs, vascularization, and tumor development in athymic nude mice in<br />
vivo. Mechanistically, it was shown that the protein level <strong>of</strong> noncanonical nuclear factor<br />
kappa B2 (NF-κB2)/p52 was elevated in AMPKα1-KO MEFs and was responsible for<br />
induction <strong>of</strong> erythropoietin (Epo) expression. Lastly, the most conclusive evidence for<br />
AMPKα1-dependent inhibition <strong>of</strong> fibroblast-mediated angiogenesis as well as tumor<br />
progression was that the allograft growth <strong>of</strong> the inoculated AMPKα1-KO MEFs was<br />
attenuated by treatment with Epo neutralization antibody.<br />
Conclusions: Taken together, these data indicate that AMPKα1 activation opposes<br />
tumor development and its loss fosters tumor progression in part by controlling<br />
chromosome stability and angiogenesis that support tumor growth.<br />
Legal entity responsible for the study: Georgia State University<br />
Funding: National Institutes <strong>of</strong> Health, American Heart Association<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
receptors (VEGFR)1–3, fibroblast growth factor receptors (FGFR) 1–4, platelet-derived<br />
growth factor receptor–α, and KIT and RET proto-oncogenes. We previously reported<br />
that LEN + EVE showed significantly greater antitumor activity in human RCC<br />
xenograft models compared with each monotherapy. LEN + EVE inhibited in vitro<br />
angiogenesis driven by VEGF and FGF in an additive and a synergistic manner,<br />
respectively. Here, we examined FGFR and VEGFR signaling pathway participation in<br />
tumor growth and angiogenesis in human RCC xenografts treated with LEN + EVE.<br />
Methods: Antitumor activity was evaluated in 2 human RCC xenograft models (A–498<br />
and Caki–1). To assess dependence <strong>of</strong> in vivo growth <strong>of</strong> RCC xenografts on FGFR<br />
signaling, nude mice with RCC xenografts were treated daily with the selective FGFR<br />
inhibitor PD173074 (50 mg/kg, orally [p.o.]). To evaluate antiangiogenic activity, mice<br />
were treated daily with LEN (10 mg/kg, p.o.), EVE (30 mg/kg, p.o.) or LEN + EVE<br />
(10 + 30 mg/kg p.o.). Microvessel density (MVD) was evaluated by<br />
immunohistochemistry using an α-CD31 antibody.<br />
Results: PD173074 inhibited in vivo growth <strong>of</strong> RCC xenografts. In the Caki-1 model,<br />
administration <strong>of</strong> LEN or EVE decreased MVD in tumor tissues, with significantly<br />
reduced MVD observed with LEN + EVE (P < 0.001 and P < 0.05), compared with EVE<br />
and LEN respectively (mean ± standard deviation [/mm 2 ]; control, 135.8 ± 26.0; LEN,<br />
65.3 ± 14.8; EVE, 89.4 ± 24.0; LEN + EVE, 38.1 ± 6.0). In the A–498 model, LEN and<br />
EVE monotherapies showed antiangiogenic and antiproliferative activity, respectively.<br />
These results demonstrate FGFR signaling pathway participation in in vivo growth <strong>of</strong><br />
RCC xenografts.<br />
Conclusions: The combined activity <strong>of</strong> LEN + EVE was therefore based on 1)<br />
enhanced inhibition <strong>of</strong> VEGF- and FGF-driven angiogenesis and 2) the combination <strong>of</strong><br />
the antiangiogenic activity <strong>of</strong> LEN and antiproliferative activity <strong>of</strong> EVE. These data<br />
demonstrate that both FGFR and VEGFR pathways are necessary for the LEN + EVE<br />
combined activity in RCC xenograft models.<br />
Legal entity responsible for the study: Eisai Co., Ltd<br />
Funding: This study was funded by Eisai Co., Ltd<br />
Disclosure: All authors are employees <strong>of</strong> Eisai Co., Ltd, Tsukuba, Ibaraki, Japan.<br />
7P<br />
Identification <strong>of</strong> novel CRC pathway genes in familial CRC<br />
M.S. Lung 1 , A. Trainer 2 , I. Campbell 1<br />
1 Research, Peter MacCallum Cancer Centre, East Melbourne, Australia, 2 Familial<br />
Cancer Centre, Peter MacCallum Cancer Centre, East Melbourne, Australia<br />
Background: The Wnt, DNA repair and bone morphogenetic protein (BMP) pathways<br />
are implicated in development <strong>of</strong> familial colorectal cancer (CRC) through inherited<br />
mutations in genes such as APC, MLH1, MSH2, MSH6, PMS2, POLE, POLD1,<br />
MUTYH, SMAD4 and BMPR1A. We hypothesised that mutations in other genes<br />
within these pathways may predispose to unexplained familial colorectal cancer, and<br />
sought rare potentially deleterious variants in genes within these pathways in a cohort<br />
<strong>of</strong> familial and/or young-onset CRC cases.<br />
Methods: We performed whole exome sequencing on constitutional DNA from 51<br />
individuals with unexplained familial or young-onset (
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Methods: H1975-AFAR and –OSIR NSCLC cell lines, harboring both the EGFR<br />
activating (L858R) and the resistant (T790M) mutations at baseline, were developed in<br />
vivo by continuos treatment with afatinib and osimertinib respectively. Both cell lines<br />
presented also the SMO V404M mutation after acquisition <strong>of</strong> resistance. These cell<br />
lines were used to test the efficacy <strong>of</strong> osimertinib or afatinib in combination with the<br />
selective SMO inhibitor, LDE225.<br />
Results: Treatment with each EGFR-TKIs in combination with LDE225 resulted in a<br />
significant inhibition <strong>of</strong> cell proliferation and a strong induction <strong>of</strong> apoptosis as compared<br />
to single agent treatment. Additionally, combined treatment significantly decreased the<br />
invasive and migratory abilities <strong>of</strong> resistant cells. The combination <strong>of</strong> osimertinib and<br />
LDE225 appeared to be the most effective in reverting resistance to EGFR-TKIs. Combined<br />
treatment caused regression <strong>of</strong> tumor growth in vivo in nude mice.<br />
Conclusions: Our study further support the role <strong>of</strong> Hedgehog pathway activation as an<br />
important mediator <strong>of</strong> resistance to EGFR targeting drugs, also in the T790M scenario.<br />
In addition, it demonstrates that addition <strong>of</strong> a hedgehog inhibitor to an EGFR-TKI in<br />
tumors, which had developed resistance to third generation inhibitors, provides<br />
meaningful responses.<br />
Legal entity responsible for the study: Second University <strong>of</strong> Naples<br />
Funding: AstraZeneca<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
9P<br />
SYM004, a novel generation anti-EGFR inhibitor, is able to<br />
overcome acquired resistance to cetuximab such as MET<br />
activation, ERBB2 amplification and EGFR mutations, in<br />
colorectal cancer models<br />
S. Napolitano 1 , V. Belli 1 , M.D. Castellone 2 , A. Parascandolo 2 , E. Martinelli 1 ,<br />
G. Martini 1 , C. Cardone 1 , F. Morgillo 1 , M. Orditura 1 , F. Ciardiello 1 , T. Troiani 1<br />
1 Medical <strong>Oncology</strong>, AOU Seconda Università degli Studi di Napoli (AOU-SUN),<br />
Naples, Italy, 2 Dipartimento di Medicina Molecolare e Biotecnologie Mediche,<br />
Azienda Ospedaliera Universitaria Policlinico Federico II-AOU Federico II, Naples,<br />
Italy<br />
Background: The anti-epidermal growth factor receptor (EGFR) monoclonal<br />
antibodies (mAbs) cetuximab and panitumumab are effective in a subset <strong>of</strong> RAS/BRAF<br />
Wild-Type (WT) metastatic colorectal cancers (mCRCs). Despite RAS-driven<br />
selection, not all patients will respond to EGFR inhibitors and the onset <strong>of</strong> secondary<br />
resistance limits their clinical benefit.<br />
Methods: We have tested, in vitro and in vivo, the effects <strong>of</strong> novel generation anti-EGFR<br />
inhibitors such as SYM004 in a panel <strong>of</strong> colorectal cancer (CRC) models with acquired<br />
resistance to cetuximab that we have generated in our laboratory. SYM004 is a 1:1 mixture<br />
<strong>of</strong> two recombinant human mouse chimeric mAbs directed against non-overlapping<br />
epitopes <strong>of</strong> the EGFR. The binding site <strong>of</strong> the two antibodies is different from cetuximab.<br />
A unique feature <strong>of</strong> SYM004 is its ability to mediate rapid EGFR internalization and<br />
subsequent degradation <strong>of</strong> internalized receptors via EGFR cross-linking.<br />
Results: SYM004 shows a potent anti-proliferative effect in cetuximab-resistant CRC<br />
cells. In particular we have already demonstrated that in cetuximab-resistant CRC cells,<br />
cell proliferation, and survival pathways are activated by MET. Interestingly<br />
overexpression <strong>of</strong> TGF-a, a specific EGFR ligand, induced formation <strong>of</strong> EGFR-MET<br />
hetero-dimers, with subsequent MET phosphorylation and activation. SYM004<br />
induces reduction on MET phosphorylation in these cell lines. SYM004 treatment<br />
determined also a significant induction <strong>of</strong> apoptosis in cetuximab-resistant CRC cells<br />
and a strong anti-proliferative activity by inhibition <strong>of</strong> phospho-MAPK and<br />
phospho-AKT in these cell lines. Moreover, in others two model <strong>of</strong> cetuximab-resistant<br />
CRC cell with HER2 amplification or EGFR S492R mutation, SYM004 is able to<br />
overcome acquired resistance to cetuximab throw inhibition <strong>of</strong> proliferation and<br />
MAPK /AKT pathways activation. The antitumor activity has been confirmed by the in<br />
vivo xenografts CRC models.<br />
Conclusions: These results suggest that the treatment with SYM004 could be a strategy<br />
for overcoming resistance to first generation <strong>of</strong> anti-EGFR therapies in CRC.<br />
Legal entity responsible for the study: Second University <strong>of</strong> Naples<br />
Funding: Symphogen<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
10P<br />
Efficacy <strong>of</strong> sequential treatment with first, second and third<br />
generation EGFR inhibitors and role <strong>of</strong> Hedgehog pathway in<br />
the acquisition <strong>of</strong> resistance in in vivo NSCLC models<br />
C.M. Della Corte 1 , F. Papaccio 1 , G. Viscardi 1 , G. Esposito 1 , M. Fasano 1 ,M.<br />
D. Castellone 2 , A. Parascandolo 2 , F. De Vita 1 , M. Orditura 1 , F. Ciardiello 1 ,<br />
F. Morgillo 1<br />
1 Medical <strong>Oncology</strong>, AOU Seconda Università degli Studi di Napoli (AOU-SUN),<br />
Naples, Italy, 2 Dipartimento di Medicina Molecolare e Biotecnologie Mediche,<br />
Azienda Ospedaliera Universitaria Policlinico Federico II-AOU Federico II, Naples,<br />
Italy<br />
reaching a substantial improvement in disease outcome. However, data on the optimal<br />
sequence <strong>of</strong> these therapies is needed.<br />
Methods: An in vivo model <strong>of</strong> acquired resistance has been obtained by treating nude<br />
mice xenografted with the human EGFR mutant (del ex19) NSCLC cell line, HCC827,<br />
with a sequence <strong>of</strong> first, second and third generation EGFR-TKI. Mice were<br />
randomized to erlotinib or gefitinib in first line treatment; resistant tumors were<br />
re-implanted in mice and randomized to afatinib +/- cetuximab. Each first and<br />
second-generation EGFR-TKI resistant tumor was again re-implanted and randomized<br />
to osimertinib or standard chemotherapy with cisplatinum-pemetrexed.<br />
Results: In the first line treatment, an initial dose-dependent decrease in tumor volume<br />
with subsequent development <strong>of</strong> acquired resistance was evidenced in the majority <strong>of</strong><br />
tumors with a response rate (RR) <strong>of</strong> 60%. In the second step, while afatinib treatment<br />
resulted in a RR <strong>of</strong> 85%, mostly represented by partial responses, the combination <strong>of</strong><br />
afatinib plus cetuximab displayed a RR <strong>of</strong> 100% (85% complete responses). In the third<br />
step, although none <strong>of</strong> resistant tumors was T790M + , treatment with osimertinib<br />
resulted in a RR <strong>of</strong> 71% (including one complete response lasted more than 10 weeks).<br />
Chemotherapy caused predominantly stable diseases lasted less than 5 weeks. Protein<br />
and gene expression analysis on protein extracts from tumors with acquired resistance<br />
showed a progressively increasing activation <strong>of</strong> the Hedgehog pathway as compared to<br />
untreated controls in the majority <strong>of</strong> samples, with higher protein level <strong>of</strong> SMO and<br />
Gli1.<br />
Conclusions: Osimertinib is effective after failure <strong>of</strong> first and second generation<br />
EGFR-TKIs, independently from the T790M presence. These experiments confirm the<br />
role <strong>of</strong> Hedgehog pathway as important mediator <strong>of</strong> resistance to EGFR inhibition.<br />
Legal entity responsible for the study: Second University <strong>of</strong> Naples<br />
Funding: AstraZeneca<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
11P<br />
abstracts<br />
Recombinant AAV gene therapy for the treatment <strong>of</strong> EGFR<br />
positive lung cancer<br />
K. Zaki 1 , L. Agundez 2 , B. Sanchez 3 , M. Linden 2 , E. Henckaerts 2 , Y. Takeuchi 4 ,<br />
M. Collins 1<br />
1 Division <strong>of</strong> Advanced Therapies, National Institute for Biological Standards and<br />
Control, Potters Bar, UK, 2 Department <strong>of</strong> Infectious Diseases, King’ College<br />
London School <strong>of</strong> Medicine, London, UK, 3 Department <strong>of</strong> Tumour Immunology,<br />
Center <strong>of</strong> Molecular Immunology, Havana, Cuba, 4 Division <strong>of</strong> Infection and<br />
Immunity, UCL - University College London, London, UK<br />
Background: Gene therapy using recombinant adeno-associated virus (rAAV)<br />
encoding monoclonal antibody (mAb) sequence injected into mice muscle has been<br />
shown to produce sustained level <strong>of</strong> serum antibody level capable <strong>of</strong> protecting animals<br />
from infectious disease in mice models. We aim to develop a protocol to achieve a<br />
therapeutic serum level <strong>of</strong> 7A7, an anti-epidermal growth factor receptor (EGFR) mAb<br />
in mouse models for the treatment <strong>of</strong> EGFR-positive lung cancer.<br />
Methods: rAAV encoding 7A7 light and heavy chains driven by tMCK, a muscle<br />
specific promoter (AAV8-7A7) was produced. AAV8-7A7 was administered<br />
intra-muscularly to mice in all studies. Serial bleeds were performed at appropriate<br />
intervals to monitor 7A7 levels. Detection <strong>of</strong> serum 7A7 was done by ELISA with<br />
human EGFR (hEGFR) antigen. In dose escalation studies, different doses <strong>of</strong><br />
AAV8-7A7 vector were administered to healthy C57Bl/6 mice. For tumour protection<br />
studies, 1x10 11 v.g. <strong>of</strong> AAV8-7A7 were administered followed by tumour inoculation 6<br />
weeks later, either subcutaneously (subcutaneous model) or intravenously (metastatic<br />
model). Human A431 luciferase tumour was inoculated in Balb/C nude mice whilst<br />
murine 3LL-D122 luciferase tumour was inoculated in C57Bl/6 mice. Tumours were<br />
monitored using caliper measurements and in vitro imaging system (IVIS).<br />
Results: ELISA using hEGFR was able to detect serum 7A7 in mice following<br />
AAV8-7A7 administration. Higher dose <strong>of</strong> viral vector results in higher dose <strong>of</strong><br />
detectable serum 7A7. In Balb/C nude mice with subcutaneous A431 luciferase<br />
tumours, smaller tumours with lower luminescence signal were observed in mice<br />
administered with AAV8-7A7 compared to mice injected with IM PBS. Bigger tumours<br />
with higher luminescence signal were observed in mice given IV 7A7 compared to<br />
mice adminstered with AAV8-7A7.<br />
Conclusions: We have developed a protocol to administer AAV8-7A7, a recombinant<br />
AAV encoding 7A7, an anti-EGFR antibody that could <strong>of</strong>fer protection against<br />
subcutaneous A431 luciferase tumours in Balb/C nude mice compared to PBS control.<br />
Similar protection experiments in both subcutaneous and metastatic Lewis lung<br />
carcinoma models using murine 3LL-D122 cells as well as in metastatic A431 xenograft<br />
model are ongoing and results will be updated.<br />
Legal entity responsible for the study: National Institute for Biological Standards and<br />
Control<br />
Funding: National Institute for Biological Standards and Control<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
Background: The management <strong>of</strong> EGFR mutant NSCLC has witnessed the<br />
development <strong>of</strong> first, second and third generation tyrosine kinase inhibitors (TKIs)<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw362 | vi3
abstracts<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
12P<br />
Reversion <strong>of</strong> mesenchymal behaviour by AZD9291 (osimertinib)<br />
in EGFR mutant NSCLC cell lines resistant to first generation<br />
EGFR tyrosine kinase inhibitors<br />
Funding: AstraZeneca<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
B. Savastano, C.M. Della Corte, F. Papaccio, V. Giuseppe, G. Esposito,<br />
M. Fasano, M. Orditura, F. De Vita, F. Ciardiello, F. Morgillo<br />
Medicina Clinica Sperimentale Magrassi Lanzara, AOU Seconda Università degli<br />
Studi di Napoli (AOU-SUN), Naples, Italy<br />
Background: Resistance to first-generation EGFR tyrosine kinase inhibitors<br />
(EGFR-TKIs) is mainly mediated by the acquisition <strong>of</strong> the EGFR secondary mutation<br />
T790M and/or by the acquisition <strong>of</strong> a mesenchymal phenotype. We explored the<br />
occurrence <strong>of</strong> epithelial to mesenchymal transition (EMT) characteristics in<br />
EGFR-TKIs resistant NSCLC models, with and without acquisition <strong>of</strong> T790M<br />
mutation, and the ability <strong>of</strong> novel generation EGFR inhibitors to revert the resistant<br />
phenotype.<br />
Methods: The following human NSCLC cell lines harboring EGFR activating<br />
mutations were used: HCC827 and PC9 NSCLC cell lines harboring EGFR activating<br />
mutation (del 746-750), the PC9-T790M (T790M+) and the HCC827-GR (T790M-)<br />
gefitinib resistant cells, and the H1975 carrying both EGFR activating and T790M<br />
mutations. The mesenchymal behavior and the effects <strong>of</strong> afatinib and osimertinib on<br />
resistant cell lines were studied both in vitro, by Western blot analysis, invasion,<br />
migration and anchorage-independent growth assays and in vivo, by metastatic assay<br />
in mice after tail vein injection with resistant cells.<br />
Results: All gefitinib resistant cell lines, H1975, HCC827GR and PC9-T790M,<br />
exhibited significant higher protein expression <strong>of</strong> mesenchymal proteins, such as<br />
vimentin, Slug and VE-Cadherin and lost <strong>of</strong> E-Cadherin, as compared to gefitinib<br />
sensitive cells, with increased ability to migrate, invade and grow in<br />
anchorage-independent manner. Treatment with afatinib, and, to a greater extent, with<br />
osimertinib, strongly inhibited proliferation, migration, invasion and anchorage<br />
independent colon forming ability <strong>of</strong> H1975 and PC9-T790M cells, while effects were<br />
similar on HCC827-GR cells in vitro. Metastasic assay in vivo confirmed the<br />
superiority <strong>of</strong> osimertinib in T790M+ models<br />
Conclusions: Collectively, these results suggest that EGFR mutant NSCLC cells<br />
resistant to first generation EGFR-TKI develop a mesenchymal phenotype,<br />
independently from the acquisition <strong>of</strong> T790M mutation. In this scenario, osimertinib is<br />
the most potent agent to overcome resistance and to revert the metastatic behavior <strong>of</strong><br />
resistant cells.<br />
Legal entity responsible for the study: Second University <strong>of</strong> Naples<br />
Funding: Second University <strong>of</strong> Naples<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
13P<br />
Efficacy <strong>of</strong> second and third generation EGFR tyrosine kinase<br />
inhibitors, alone or in combination, in T790M-mediated<br />
resistance<br />
F. Papaccio, C.M. Della Corte, G. Viscardi, G. Esposito, M. Fasano, F. De Vita,<br />
M. Orditura, F. Ciardiello, F. Morgillo<br />
Medical <strong>Oncology</strong>, AOU Seconda Università degli Studi di Napoli (AOU-SUN),<br />
Naples, Italy<br />
Background: The best first-line approach to be used in T790M+ NSCLCs has to be<br />
defined. Our aim is to test in T790M+ preclinical models the efficacy <strong>of</strong> second and<br />
third generation EGFR tyrosine kinase inhibitors (EGFR-TKIs), as single agents or in<br />
combination with cetuximab or MEK-inhibitors (MEK-i).<br />
Methods: Nude mice xenografted with the human NSCLC H1975 cell line, harboring<br />
both the EGFR activating (L858R) and resistant (T790M) mutations, were randomized<br />
to receive afatinib or osimertinib. Basing on previous literature data revealing<br />
synergism between afatinib and cetuximab and between osimertinib and the MEK-i<br />
selumetinib, other four arms <strong>of</strong> treatments with combination <strong>of</strong> afatinib/osimertinib<br />
with cetuximab or selumetinib have been included.<br />
Results: Treatment with afatinib resulted in 40% complete responses with a rapid<br />
acquisition <strong>of</strong> resistance whereas 100% complete response were reported in mice<br />
treated with osimertinib. In only 1 responding mice treated with osimertinib, tumor<br />
started to regrowth within 14 weeks. All mice treated with afatinib/osimertinib plus<br />
cetuximab or selumetinib experienced complete responses that have been lasting 16+<br />
weeks. Preliminary results from gene analysis revealed appearance <strong>of</strong> SMO gene<br />
mutation (V404M) in one tumor resistant to afatinib and in the tumor resistant to<br />
osimertinib, with a concomitant activation <strong>of</strong> the Hedgehog pathway.<br />
Conclusions: T790M+ tumors represent a subgroup <strong>of</strong> EGFR mutated NSCLC with<br />
innate resistance to first generation EGFR-TKIs. Our in vivo model <strong>of</strong> resistance<br />
demonstrated the superiority <strong>of</strong> osimertinib with respect to afatinib in this setting and<br />
a strong efficacy <strong>of</strong> experimental combinations (with cetuximab and MEK-I) as first<br />
line therapy. Moreover, we found that Hedgehog pathway is involved in mediating<br />
resistance to second- and third- generation EGFR-TKIs, suggesting new potential<br />
strategies <strong>of</strong> combination with Hedgehog inhibitors to prevent the occurrence <strong>of</strong><br />
resistance in T790M + tumors.<br />
Legal entity responsible for the study: Second University <strong>of</strong> Naples<br />
14P<br />
Inhibition <strong>of</strong> PI3K pathway improves anti HER2 treatment<br />
efficacy in a panel <strong>of</strong> HER2 positive gastric cancer cell lines<br />
V. Gambardella, M.J. Llorca-Cardeñosa, J. Castillo, N. Tarazona Llavero,<br />
M. Huerta, S. Roselló Keränen, M. Ibarolla-Villava, G. Ribas, A. Gil, A. Cervantes<br />
Dept. Medical <strong>Oncology</strong>, Biomedical Research institute INCLIVA University <strong>of</strong><br />
Valencia, Valencia, Spain<br />
Background: Gastric cancer (GC) represents a major health problem. HER2, when<br />
amplified, is the only validated druggable target. Adding trastuzumab, an anti HER2<br />
monoclonal antibody, to first line chemotherapy improves overall survival. However,<br />
many patients do not benefit <strong>of</strong> this treatment due to some undiscovered mechanisms<br />
<strong>of</strong> primary resistance. Thus, we try to identify the role <strong>of</strong> PI3K and MAPKK pathways<br />
activation in a panel <strong>of</strong> HER2 positive gastric cancer cell lines (GCCL).<br />
Methods: To evaluate primary resistance to anti HER2 treatment, we selected 3 HER2+<br />
GCCL (SNU216, NCI-N87 and OE 19), and 2 negative (AGS and SNU 484). A somatic<br />
mutational analysis was conducted, (Oncocarta panel 1.0 by MassArray Sequenom) to<br />
better characterize our panel. Microsatellite instability (MSI) by PCR was also<br />
investigated. To assess sensitivity, cells were treated with two different anti HER2 drugs,<br />
trastuzumab and lapatinib. MTT assays were performed to identify IC50. A PI3K dual<br />
mTOR inhibitor (GSK 458) and a MEK inhibitor (Pimasertib) were also tested to<br />
explore the role <strong>of</strong> PI3K and MAPKK pathways in primary resistance. Protein<br />
expression by western blot (WB) at baseline and after treatment was done. FACS<br />
technology was performed to study changes in Apoptosis and Cell Cycle.<br />
Results: Baseline WB, confirmed the overexpression <strong>of</strong> HER2 in SNU216, NCI-N87<br />
and OE19 cell lines, while AGS and SNU 484 resulted negative. Our cell lines have<br />
different mutational pr<strong>of</strong>iles. MSI was not detected. In MTT assays, our HER2+ GCCL<br />
were sensitive to anti HER2 drugs. At baseline, according with our WB evaluation,<br />
both PI3K and MAPKK pathways were activated in all cell lines studied. GSK 458 and<br />
Pimasertib were tested as single agents and in combination. An anti-proliferative effect<br />
<strong>of</strong> GSK 458 when combined with trastuzumab and lapatinib was detected. Apoptosis<br />
and Cell Cycle assays confirmed that inhibition <strong>of</strong> PI3K pathway, with GSK 458, added<br />
to anti HER2 drugs, was able to increase apoptosis and decrease the S phase <strong>of</strong> cell<br />
cycle. Inhibition <strong>of</strong> molecular targets was confirmed by post treatment WB.<br />
Conclusions: Our experiments indicate that PI3K pathway have a role in primary<br />
resistance to anti HER2 agents in GCCL.<br />
Legal entity responsible for the study: Valentina Gambardella<br />
Funding: INCLIVA Foundation<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
15P<br />
HER2 activation and epithelial-mesenchymal transition (EMT)<br />
are involved in the acquired resistance to cetuximab in<br />
combination with either regorafenib or refametinib<br />
P.P. Vitiello 1 , G. Martini 2 , V. Belli 3 , C. Cardone 4 , V. Sforza 5 , M.L. Ferrara 6 ,<br />
S. Napolitano 5 , C.M. Della Corte 1 , N. Zanaletti 3 , P. Vitale 5 , L. Pompella 5 ,<br />
F. Morgillo 7 , T. Troiani 8 , F. Ciardiello 9 , E. Martinelli 10<br />
1 UOC Oncoematologia ed 16 IV piano - Dip. Medico-Chirurgico di Internistica<br />
Clinica e Sperimentale, AOU Seconda Università degli Studi di Napoli (AOU-SUN),<br />
Naples, Italy, 2 Medical <strong>Oncology</strong>, AOU Seconda Università degli Studi di Napoli<br />
(AOU-SUN), Naples, Italy, 3 Medical <strong>Oncology</strong> P.O. Edificio 3, AOU Seconda<br />
Università degli Studi di Napoli (AOU-SUN), Naples, Italy, 4 Medicina Clinica<br />
Sperimentale Magrassi Lanzara, AOU Seconda Università degli Studi di Napoli<br />
(AOU-SUN), Naples, Italy, 5 Medical <strong>Oncology</strong>, AOU Seconda Università degli<br />
Studi di Napoli (AOU-SUN), Naples, Italy, 6 Dipartimento Medico-Chirurgico di<br />
Internistica Clinica e Sperimentale, AOU Seconda Università degli Studi di Napoli<br />
(AOU-SUN), Naples, Italy, 7 Dipartimento di Internistica F Magrassi A Lanzara, AOU<br />
Seconda Università degli Studi di Napoli (AOU-SUN), Naples, Italy, 8 Medicina<br />
Clinica Sperimentale Magrassi Lanzara, AOU Seconda Università degli Studi di<br />
Napoli (AOU-SUN), Naples, Italy, 9 Department <strong>of</strong> Experimental and Clinical<br />
Medicine and Surgery, Second University <strong>of</strong> Naples, Naples, Italy, 10 Dipt. di<br />
Internistica Clinica e Sperimentale, AOU Seconda Università degli Studi di Napoli<br />
(AOU-SUN), Naples, Italy<br />
Background: Previous studies showed that primary and acquired resistance to anti-<br />
Epidermal Growth Factor Receptor (EGFR) drugs used in colorectal cancer (CRC)<br />
could be overcome by the concomitant use <strong>of</strong> either regorafenib or MEK-inhibitors<br />
with anti-EGFR antibodies, such as cetuximab. However, little is known about the<br />
mechanisms leading to the acquired resistance to these agents used in combination.<br />
Methods: We generated CRC cell lines (HCT15 and HCT116) resistant to either a<br />
combination <strong>of</strong> cetuximab and regorafenib or cetuximab and refametinib (BAY<br />
86-9766, a selective MEK-inhibitor), after continuous exposure to the drugs for 8<br />
months. Resistant clones had an IC 50 100-fold higher than parental cells. We evaluated<br />
by Western Blot (WB) analysis and quantitative Reverse Transcriptase Polymerase<br />
Chain Reaction (qRT-PCR) the expression and activation status <strong>of</strong> a panel <strong>of</strong><br />
vi4 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
membrane receptors including HER2, EGFR, AXL, EphA2, VEGFRs, intracellular<br />
transducers <strong>of</strong> MAPK and AKT pathways and Epithelial-Mesenchymal Transition<br />
(EMT) markers such as Vimentin, E-cadherin, Snail, Slug.<br />
Results: We found different activation patterns for some <strong>of</strong> the transmembrane<br />
receptors and intracellular transducers among HCT15 and HCT116 resistant clones. In<br />
particular, HER2 protein was overexpressed and activated in both<br />
Cetuximab-Regorafenib resistant (CR-res) and Cetuximab-Refametinib resistant<br />
(CM-res) cell populations compared to the parental cell lines. Moreover, there was<br />
evidence <strong>of</strong> Epithelial-Mesenchymal Transition in the CR-res cell population,<br />
suggesting the role <strong>of</strong> this process in acquired resistance to regorafenib. Experiments to<br />
test anti-HER2 drugs in resistant cell lines, as well as Next Generation Sequencing<br />
(NGS) approaches in order to detect de novo genomic rearrangements, are currently<br />
ongoing and will be presented.<br />
Conclusions: Our in vitro preliminary data demonstrated, at least in part, that HER2<br />
protein activation and EMT might play a role in the development <strong>of</strong> acquired resistance<br />
to cetuximab in combination with either regorafenib or refametinib, suggesting a<br />
possible role <strong>of</strong> anti-HER2 therapies in this setting.<br />
Legal entity responsible for the study: Fortunato Ciardiello<br />
Funding: Associazione Italiana Ricerca sul Cancro (AIRC)<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
PD-L1 expression with EMT status in surgically resected specimens after<br />
chemotherapy from 23 patients with NSCLC.<br />
Results: Our results showed that PD-L1 gene expression was up-regulated through<br />
TGF-beta -induced EMT or the chemotherapy-induced EMT process, while that was<br />
down-regulated by EMT receptor-kinase inhibitor and through MET process.<br />
Furthermore, western blotting findings showed that PD-L1 protein changed through<br />
both EMT and MET as gene expression patterns. Analysis <strong>of</strong> clinical samples obtained<br />
from NSCLC cases revealed a significant relationship between PD-L1 expression and<br />
EMT status.<br />
Conclusions: Our results suggested that PD-L1 expression is regulated by EMT status<br />
and those immunotherapies may circumvent the chemoresistance in NSCLC.<br />
Legal entity responsible for the study: N/A<br />
Funding: KAKENHI Grants-in-Aid for Scientific Research) Grant-in-Aid for Scientific<br />
Research (C).<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
18P<br />
abstracts<br />
PD-L1 pathway activation as an escape mechanism <strong>of</strong><br />
resistance to MEK inhibitor treatment in a human colorectal<br />
cancer model<br />
16P<br />
A high-throughput RNAi screen for detection <strong>of</strong><br />
immune-checkpoint molecules that mediated to cytotoxic T<br />
lymphocytes in lung cancer<br />
S. Napolitano, B. Valentina, E. Martinelli, V. Sforza, P.P. Vitiello, F. De Vita,<br />
N. Zanaletti, P. Vitale, D. Ciardiello, F. Morgillo, F. Ciardiello, T. Troiani<br />
Medical <strong>Oncology</strong>, AOU Seconda Università degli Studi di Napoli (AOU-SUN),<br />
Naples, Italy<br />
M. Xie 1 ,Y.Gu 2<br />
1 Medical <strong>Oncology</strong>, The First Affiliated Hospital <strong>of</strong> Guangzhou Medical University,<br />
Guangzhou, China, 2 Pathology, The First Affiliated Hospital <strong>of</strong> Guangzhou Medical<br />
University, Guangzhou, China<br />
Background: The success <strong>of</strong> T cell-based cancer immunotherapy is limited by tumor’s<br />
resistance against killing by cytotoxic T lymphocytes (CTLs). Tumor-immune<br />
resistance is mediated by cell surface ligands that engage immune-inhibitory receptors<br />
on T cells. These ligands represent potent targets for therapeutic inhibition. So far, only<br />
few immune-suppressive ligands have been identified.<br />
Methods: We here describe a rapid high-throughput siRNA-based screening approach<br />
that allows a comprehensive identification <strong>of</strong> ligands on lung cancer cells that inhibit<br />
CTL-mediated tumor cell killing.<br />
Results: We demonstrate that IL6 exerts strong immune-regulatory effects on T cell<br />
responses in lung cancer. Unlike PDL1, which inhibits TCR signaling, IL6 regulates<br />
STAT3 in T cells, resulting in reduced T-helper-1 cytokine secretion and reduced<br />
cytotoxic capacity. Moreover, inhibition <strong>of</strong> IL6 expression on tumor cells facilitated<br />
immunotherapy <strong>of</strong> lung cancer by tumor-specific T cells in vivo.<br />
Conclusions: Taken together, this method allows a rapid and comprehensive<br />
determination <strong>of</strong> immune-modulatory genes in lung tumor which represent the<br />
’immune modulatome’ <strong>of</strong> lung cancer.<br />
Legal entity responsible for the study: N/A<br />
Funding: Open Fund <strong>of</strong> State Key Laboratory <strong>of</strong> Southern China <strong>Oncology</strong><br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
17P<br />
The regulation <strong>of</strong> PD-L1 in non small cell lung cancer<br />
S. Funaki, Y. Shintani, E. Fukui, T. Kawamura, T. Kimura, R. Kanzaki, M. Minami,<br />
M. Okumura<br />
Department <strong>of</strong> General Thoracic Surgery, Osaka University Graduate School <strong>of</strong><br />
Medicine, Osaka, Japan<br />
Background: In cancer immunology, the programmed cell death 1/programmed cell<br />
death 1-ligand 1 (PD-1/PD-L1) pathway plays a major role, while anti-PD-1 and<br />
anti-PD-L1 antibodies are expected to provide reliable immunotherapy when give as<br />
treatment for various types <strong>of</strong> malignancy including lung cancer. PD-L1 expression in<br />
cancer cells has been reported to be a prognostic biomarker as well as a predictive<br />
factor for the therapeutic effects <strong>of</strong> immunotherapy. However, the mechanism <strong>of</strong><br />
PD-L1 expression remains unclear. Since epithelial mesenchymal transition (EMT) is<br />
also known to have a key process in cancer progression, and also to be induced by<br />
several factors such as TGF-beta, FGF, and chemotherapy. We investigated the<br />
mechanism <strong>of</strong> PD-L1 expression as well as changes in its expression during the EMT<br />
process in non-small lung cancer (NSCLC). In addition, we examined the clinical<br />
significance <strong>of</strong> PD-L1 by analysis <strong>of</strong> clinical samples from patients with NSCLC.<br />
Methods: To reveal the relationship <strong>of</strong> PD-L1 expression with the EMT process, A549<br />
(human lung adenocarcinoma cell line) underwent EMT by treatment <strong>of</strong> TGF-beta or a<br />
chemotherapies treatment, then PD-L1 expression was evaluated using RT-PCR and<br />
western blotting assays. We also examined alterations <strong>of</strong> PD-L1 expression through a<br />
reverse-EMT process; mesenchymal-epithelial transition (MET) and EMT receptor<br />
kinase inhibitors. To elucidate the clinical significance <strong>of</strong> PD-L1 expression, we<br />
performed immunohistochemical staining analysis to evaluate the relationship <strong>of</strong><br />
Background: In patients with metastatic colorectal cancer (mCRC) who receive<br />
anti-epidermal growth factor receptor (EGFR) therapies, gene alterations that emerge<br />
at relapse converge to activate the RAS-MEK-MAPK pathway. MEK is key downstream<br />
effectors <strong>of</strong> the EGFR pathway that should be inhibited to prevent and or delay the<br />
onset <strong>of</strong> acquired resistance to anti-EGFR treatment.<br />
Methods: In order to understand the mechanism underlying MEK resistance, SW48<br />
quadruple RAS/BRAF Wild-Type (WT) colorectal cancer (CRC) cell lines were<br />
injected subcutaneously into female nude mice and treated with MEK inhibitor<br />
(MEKi). When tumors were resuming growth despite MEKi treatment, mice were<br />
sacrificed and tumors were removed, cut in several pieces and used to generate in vitro<br />
MEK-resistant cell lines (SW48-MR). To investigate the potential molecular pathways<br />
involved in MEK-resistance, mRNAs from SW48 and SW48-MR cells were extracted<br />
and assessed for global gene expression changes by microarray analysis.<br />
Results: Among the genes that were upregulated in SW48-MR versus SW48 we have<br />
identified several genes involved in the PD-L1 pathway. In particular the PD-L1 gene<br />
was up regulated approximately 10-fold in the resistant cells as compared to parental<br />
cells. Moreover, genes overexpressed in MEK-resistance tumor were functionally<br />
related in pathways involving immune cell activation, inflammation, and antigen<br />
processing and presentation. These results demonstrate an enhanced immune-reactive<br />
microenvironment in MEK-resistant tumors.<br />
Conclusions: These results suggest a strategy to potentially improve the efficacy <strong>of</strong><br />
MEK inhibition by co-treatment with other agents and provide an additional<br />
mechanism <strong>of</strong> therapeutic resistance via modulation <strong>of</strong> host immune responses.<br />
Legal entity responsible for the study: Second University <strong>of</strong> Naples<br />
Funding: AIRC<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
19P<br />
microRNA-145 promotes differentiation in human urothelial<br />
carcinoma through down-regulation <strong>of</strong> syndecan-1<br />
T. Fujii 1 , Y. Tatsumi 1 , K. Fujimoto 2 , N. Konishi 1<br />
1 Pathology, Nara Medical University, Nara, Japan, 2 Urology, Nara Medical<br />
University Hospital, Kashihara, Japan<br />
Background: A new molecular marker for carcinoma in the urinary bladder is needed<br />
as a diagnostic tool or therapeutic target. Candidate markers include microRNAs<br />
(miRNAs), which are short, low-molecular-weight RNAs 19-24 nt in length, that<br />
regulate genes associated with cell proliferation, differentiation, and development in<br />
various cancers. In this study, we investigated the molecular mechanisms by which<br />
miR-145 promotes the survival <strong>of</strong> urothelial carcinoma cells and their differentiation<br />
into multiple lineages.<br />
Methods: Cell proliferation in the human urothelial carcinoma cell lines T24 and KU7<br />
was assessed by MTS assay. Cellular senescence and apoptosis were measured by<br />
senescence-associated b-galactosidase (SA-b-gal) and a TUNEL assay, respectively.<br />
Quantitative RT-PCR was used to measure the mRNA expression levels <strong>of</strong> various<br />
genes, including syndecan-1, stem cell factors, and markers <strong>of</strong> squamous, glandular, or<br />
neuroendocrine differentiation. The expression <strong>of</strong> miR-145 in urothelial carcinoma<br />
tissues from patients that were not undergoing chemotherapy or Bacillus<br />
Calmette-Guerin treatment was detected by quantitative RT-PCR.<br />
Results: Overexpression <strong>of</strong> miR-145 induced cell senescence, and thus significantly<br />
inhibited cell proliferation in T24 and KU7 cells. Syndecan-1, a heparin sulfate<br />
proteoglycan, expression decreased, whereas the levels <strong>of</strong> stem cell markers such as<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw362 | vi5
abstracts<br />
SOX2, NANOG, OCT4, and E2F3 increased. miR-145 also up-regulated the markers <strong>of</strong><br />
squamous (p63, TP63, and CK5), glandular (MUC-1, MUC-2, and MUC-5AC), and<br />
neuroendocrine (NSE and UCHL-1) differentiation. Finally, miR-145 expression was<br />
down-regulated in high-grade urothelial carcinomas, but not in low-grade tumors.<br />
Conclusions: The results indicate that miR-145 suppresses syndecan-1 and<br />
consequently up-regulates stem cell factors to induce cell senescence and<br />
differentiation. Our data provide a new mechanism <strong>of</strong> urothelial carcinogenesis via<br />
miR-145, and show that the related molecules could contribute to the development <strong>of</strong><br />
new diagnostic or prognostic markers, as well as potential therapeutic targets.<br />
Legal entity responsible for the study: Nara Medical University School <strong>of</strong> Medicine,<br />
Nara, Japan<br />
Funding: Grant-in-Aid from the Ministry <strong>of</strong> Education, Culture, Sports, Science and<br />
Technology, Japan (26462424)<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
20P<br />
Analysis <strong>of</strong> miRNA expression pr<strong>of</strong>ile induced by zoledronic<br />
acid in breast cancer cells<br />
D. Fanale, V. Amodeo, L. Insalaco, L. Incorvaia, A. Listì, V. Calò, V. Bazan,<br />
A. Russo<br />
Department <strong>of</strong> Surgical, Oncological and Oral Sciences, Section <strong>of</strong> Medical<br />
<strong>Oncology</strong>, University <strong>of</strong> Palermo, Palermo, Italy<br />
Background: Zoledronic acid (ZOL), a third generation bisphosphonate able to<br />
significantly inhibit bone resorption, is currently used for the treatment <strong>of</strong> breast<br />
cancer patients with osteolytic bone metastases. Our previous work showed an effective<br />
anticancer role <strong>of</strong> low-dose ZOL in the inhibition <strong>of</strong> several processes, such as cell<br />
adhesion, invasion, cytoskeleton remodelling and proliferation, in MCF-7 breast cancer<br />
cell line. The main aim <strong>of</strong> our study was to investigate the molecular mechanisms and<br />
signaling pathways by which ZOL exerts its anti-tumor effects in breast cancer cells<br />
focusing our attention on miRNA expression pr<strong>of</strong>ile.<br />
Methods: Using a TaqMan Low Density Array A human microRNA microarray<br />
analysis, the expression pr<strong>of</strong>ile <strong>of</strong> 377 miRNAs was analyzed in MCF7 cells treated for<br />
24 h with 10 µM ZOL with respect to untreated cells. In addition, the expression <strong>of</strong><br />
miRNAs specifically induced by ZOL was analyzed in MCF-7, MDA-MB-231 and<br />
SkBr3 cells using Real-time PCR analyses.<br />
Results: A subset <strong>of</strong> miRNAs was shown to be differentially expressed following the<br />
low-dose ZOL treatment, and several cancer-related pathways, including PI3/Akt,<br />
MAPK, Wnt, Jak-STAT, TGF-β, and mTOR signaling, were predicted as potential<br />
targets <strong>of</strong> these deregulated miRNAs, using the DIANA tool mirPath s<strong>of</strong>tware. In<br />
particular, a set <strong>of</strong> 54 miRNAs resulted significantly altered after ZOL exposure, with a<br />
group <strong>of</strong> them being up- or down-regulated, and others induced or silenced by<br />
treatment. Most <strong>of</strong> these miRNAs are unexamined in breast cancer cells. These data are<br />
perfectly in agreement with the recent results reported in literature regarding some<br />
miRNAs involved in proliferation, bone metastasis development, invasion and therapy<br />
resistance in breast cancer.<br />
Conclusions: This work establishes, for the first time, a link between anticancer effects<br />
<strong>of</strong> ZOL and miRNA expression changes, suggesting the involvement <strong>of</strong> some miRNAs<br />
in molecular pathways mediating ZOL activity in breast cancer.<br />
Legal entity responsible for the study: University <strong>of</strong> Palermo<br />
Funding: Department <strong>of</strong> Surgical, Oncological and Oral Sciences <strong>of</strong> Palermo<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
21P<br />
MiR-340 inhibits breast cancer cell progression by revering<br />
EZH2 mediated miRNAs dysregulated expression<br />
Z. Shi, J. Zhang<br />
Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin,<br />
China<br />
Background: The anti-tumor activity <strong>of</strong> miR-340 has been recently characterized in<br />
breast tumor cells. However, the mechanisms underlying miR-340 induced cell growth<br />
and invasion in triple-negative breast cancer (TNBC) have not been well elucidated.<br />
Methods: In this study, we found that miR-340 expression was negative correlated with<br />
EZH2 expression in TNBC sample tissues and cell lines. Subsequent luciferase reporter<br />
assay confirmed that EZH2 (Enhancer <strong>of</strong> zeste homolog 2) was a novel molecule target<br />
<strong>of</strong> miR-340. Upregulated MiR-340 expression levels by mimics transfection<br />
significantly inhibited the MDA-MB-231 and MDA-MB-468 breast cancer cells<br />
proliferation, invasion and migration activity, and also induced more cell apoptosis.<br />
Meanwhile, miR-340 upregulation inhibited the tumor growth in an orthotopic<br />
MDA-MB-231 breast cancer mouse models. Furthermore, we found the reduced EZH2<br />
expression by miR-340 mimics transfection also decreased the DNMT1, H3K27me3,<br />
β-catenin and P-STAT3 expressions, which ultimately resulted in the blockage <strong>of</strong><br />
miR-21 activity and the induction <strong>of</strong> miR-200a/b expressions.<br />
Results: our results identified miR-340 as a tumor suppressor in TNBC, moreover, an<br />
EZH2 medicated regulatory loop was also established. Post-transcriptional suppression<br />
<strong>of</strong> EZH2 expression not only blocked STAT3 mediated miR-21 trans-activation, but<br />
also reversed the miR200a/b silencing by reducing DNMT1 and H3K27me3<br />
expression.<br />
Conclusions: MiR-21 inhibition and miR-200a/b expression trigged by miR-340<br />
cooperated in the TNBC progression.<br />
Legal entity responsible for the study: N/A<br />
Funding: China National Natural Scientific Fund (81502306),Tianjin Medical<br />
University Research Project (2014KYQ08)<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
22P<br />
microRNA-331-3p inhibits cell proliferation and E7 expression<br />
by targeting NRP2 in cervical cancer<br />
T. Fujii, Y. Tatsumi, N. Konishi<br />
Pathology, Nara Medical University, Nara, Japan<br />
Background: Aberrant expression <strong>of</strong> microRNAs (miRNAs) is involved in the<br />
development and progression <strong>of</strong> various types <strong>of</strong> cancers. In this study, we investigated<br />
the role <strong>of</strong> miR-331-3p in cell proliferation and keratinocyte differentiation in uterine<br />
cervical cancer cells. Moreover, we evaluated whether neuropilin 2 (NRP2) which are<br />
putative target molecules <strong>of</strong> miR-331-3p regulated the human papillomavirus (HPV)<br />
-related oncoproteins E6 and E7.<br />
Methods: Cell proliferation in the human cervical cancer cell lines SKG-II and HeLa was<br />
assessed using the MTS assay. A functional assay for cell growth was performed using cell<br />
viability and cell cycle analysis. Cellular apoptosis was measured using a TUNEL assay.<br />
Quantitative RT-PCR was used to measure the mRNA expression <strong>of</strong> the E6, E7, NRP2,<br />
p63, and involucrin (IVL) genes and anti-apoptosis markers bcl2, bclXL, and BAX.<br />
Results: Overexpression <strong>of</strong> miR-331-3p inhibited cell proliferation, and induced G2/M<br />
phase arrest and apoptosis in SKG-II cells. The luciferase reporter assay <strong>of</strong> the NRP2<br />
3¢-untranslated region revealed direct regulation <strong>of</strong> NRP2 by miR-331-3p. Gene<br />
expression analyses using quantitative RT-PCR in both SKG-II and HeLa cells<br />
overexpressing miR-331-3p or suppressing NRP2 revealed down-regulation <strong>of</strong> E6, E7,<br />
and p63 mRNA and up-regulation <strong>of</strong> IVL mRNA. We showed that miR-331-3p and<br />
NRP2 were key effectors in cell proliferation by regulating the cell cycle and expression<br />
<strong>of</strong> E6 and E7, and keratinocyte differentiation by down-regulating p63 and<br />
up-regulating IVL.<br />
Conclusions: Our findings suggest that miR-331-3p has an important role in<br />
regulating cervical cancer cell proliferation, and overexpression <strong>of</strong> miR-331-3p through<br />
suppression <strong>of</strong> NRP2 may contribute to keratinocyte differentiation and may have<br />
anti-cancer effects. Our future studies will examine whether miR-331-3p and its target,<br />
NRP2, are useful clinical diagnostic and/or prognostic markers for histological and<br />
cytological examination using tissue specimens and liquid-based cytology in the<br />
screening and diagnosis <strong>of</strong> cervical cancer.<br />
Legal entity responsible for the study: Nara Medical University School <strong>of</strong> Medicine,<br />
Nara, Japan<br />
Funding: Grant-in-Aid from the Ministry <strong>of</strong> Education, Culture, Sports, Science and<br />
Technology, Japan (26462424)<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
23P<br />
Radioresistance genes in head and neck cancer<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
A.O. Naghavi 1 , Y. Kim 2 , J. Caudell 1<br />
1 Radiation <strong>Oncology</strong>, H. Lee M<strong>of</strong>fitt Cancer Center University <strong>of</strong> South Florida,<br />
Tampa, FL, USA, 2 Biostatistics, H. Lee M<strong>of</strong>fitt Cancer Center University <strong>of</strong> South<br />
Florida, Tampa, FL, USA<br />
Background: Radiotherapy (RT) is integral in the treatment <strong>of</strong> head and neck cancer<br />
(HNC). Tumors have varying response to RT. Quantifying gene expression and<br />
correlating it with outcome can identify genes that influence a tumor’s response to<br />
radiation. Our goal is to identify the genes predictive <strong>of</strong> locoregional recurrence (LRR)<br />
in HNC patients treated with RT.<br />
Methods: Patient data was abstracted from a prospectively maintained institutional<br />
Total Cancer Care (TCC) database and chart review. All microarray chips were<br />
normalized using iterative rank-order normalization method. A supervised Gene Set<br />
Enrichment Analysis (GSEA) was performed to determine whether a priori defined<br />
gene pathways shows statistically significant, concordant differences between groups <strong>of</strong><br />
samples obtained before and after radiation therapy. 50 well-annotated hallmark gene<br />
sets were obtained from Molecular signatures database v.5.1 for GSEA analysis. Linear<br />
Models for Microarray Data (LIMMA) was used to identify individual genes with<br />
differential expression between the two groups. To explore survival-associated genes,<br />
Cox proportional hazard regression analysis was performed with time to local-regional<br />
recurrence data <strong>of</strong> patients who underwent radiotherapy. Further, Spearman’s rank<br />
correlation was calculated between expression and survival fraction after 2Gy RT (SF2)<br />
<strong>of</strong> cancer cell lines in NCI-60 panel. Two-sided false discovery rate (FDR) adjusted<br />
p-value less than 0.05 is considered statistically significant.<br />
Results: A total <strong>of</strong> 108 patients were analyzed, <strong>of</strong> which 49 (45%) were sampled prior<br />
to and 59 (55%) after receiving RT. There were a total <strong>of</strong> 48 (44%) LRRs. Thirty eight<br />
genes were identified in common with a differential expression in NCI 60, prior receipt<br />
vi6 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
<strong>of</strong> RT, and cox regression analysis <strong>of</strong> LRR. Upregulation <strong>of</strong> 26 genes were associated<br />
with LRR, the majority <strong>of</strong> which (22/26; 85%) were significantly elevated in the samples<br />
that were previously radiated. Downregulation <strong>of</strong> 12 genes were associated with LRR, <strong>of</strong><br />
which 8 (67%) were significantly lower in samples that were previously radiated.<br />
Conclusions: We identify a number <strong>of</strong> genes with alteration in expression, which may<br />
be associated with resistance to radiotherapy in HNC. Further validation is necessary in<br />
other patient cohorts as well as in vitro studies.<br />
Legal entity responsible for the study: Jimmy J. Caudell<br />
Funding: M<strong>of</strong>fitt Cancer Center<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
24P<br />
Cardiotoxic effects <strong>of</strong> the novel anti-ErbB2 agent ado<br />
trastuzumab emtansine<br />
R.V. Iaffaioli 1 , C. Coppola 2 , G. Piscopo 2 , G. Riccio 2 , A. Rienzo 2 , C. Maurea 2 ,<br />
A. Barbieri 3 , C. De Lorenzo 4 , N. Maurea 2<br />
1 Dipartimento di Oncologia Addominale, Istituto Nazionale Tumori – I.R.C.C.S -<br />
Fondazione Pascale, Naples, Italy, 2 Cardiology, Istituto Nazionale Tumori – I.R.C.<br />
C.S - Fondazione Pascale, Naples, Italy, 3 Animal Facility, Istituto Nazionale Tumori<br />
– I.R.C.C.S - Fondazione Pascale, Naples, Italy, 4 Department <strong>of</strong> Molecular<br />
Medicine and Medical Biotechnology, University ‘Federico II’, Naples, Italy<br />
Background: Ado trastuzumab emtansine (TDM1) is a novel antibody–drug conjugate<br />
consisting <strong>of</strong> trastuzumab (TRAS) covalently linked to the highly potent microtubule<br />
inhibitory agent DM1 via a stable thioether linker. TDM1 is used in metastatic ErbB2<br />
positive breast cancer patients, previously treated with TRAS and taxane. Although the<br />
potential cardiotoxic effects <strong>of</strong> T-DM1 have not yet been fully elucidated, they can include<br />
all the mechanisms <strong>of</strong> TRAS-related cardiotoxicity, such as blockade <strong>of</strong> ErbB2,PI3K-Akt<br />
and MAPK pathways. Furthermore, since TDM1 is also used in combination with other<br />
anti-ErbB2 agents, the risk <strong>of</strong> cardiotoxic side effects could be further increased. Here, we<br />
aim to assess the cardiotoxic side effects <strong>of</strong> TDM1 in vitro and in vivo.<br />
Methods: To evaluate the cardiotoxic effects <strong>of</strong> TDM1 in vitro, human fetal<br />
cardiomyocytes (HFC) and cardiomyoblasts (H9C2) were treated, for 3 days, in the<br />
absence or in the presence <strong>of</strong> increasing concentrations <strong>of</strong> TDM1 and TRAS.<br />
Moreover, to assess the cardiac function in vivo, C57/BL6 mice, 2-4 months old, were<br />
daily treated with TDM1 (44.4 mg/kg/day). At day 0 and after 7 days, fractional<br />
shortening (FS) and ejection fraction (EF) were measured, by M/B mode<br />
echocardiography, and radial and longitudinal strain (RS and LS) were evaluated using<br />
2D speckle-stracking.<br />
Results: TDM1 shows a higher toxicity on HFC and H9C2 cells with respect to TRAS.<br />
TDM1 clearly causes more marked changes in HFC cell morphology, cells, that indeed<br />
lost their typical features to assume distorted forms (rounded-shape). In in vivo studies:<br />
after 7 days with TDM1, FS decreased to 53.6 ± 0.9 %, versus 61.0 ± 0.8 % (sham),<br />
(p < 0.01), and EF decreased to 85.5 ± 3.5 % versus 91.0 ± 0.8% (sham), (p < 0.01), RS<br />
decreased to 42.2 ± 10.1 % versus 20.92 ± 3.2 % (sham), (p < 0.01), LS decreased to<br />
-23.6 ± 6.7 % versus -15.5 ± 2.8 % (sham), (p < 0.01).<br />
Conclusions: Here we show for the first time the cardiotoxic effects <strong>of</strong> TDM1, both in<br />
in vitro, and in vivo models.<br />
Legal entity responsible for the study: N/A<br />
Funding: Fondi di Ricerca Corrente destinati all’ Istituto Nazionale Tumori Pascale -<br />
Napoli<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
25P<br />
Ranolazine partially blunts ado trastuzumab emtansine related<br />
cardiotoxicity<br />
N. Maurea 1 , C. Coppola 1 , G. Piscopo 1 , G. Riccio 1 , A. Rienzo 1 , C. Maurea 1 ,<br />
A. Barbieri 2 , C. De Lorenzo 3 , R.V. Iaffaioli 4<br />
1 Cardiology, Istituto Nazionale Tumori – I.R.C.C.S - Fondazione Pascale, Naples,<br />
Italy, 2 Animal Facility, Istituto Nazionale Tumori – I.R.C.C.S - Fondazione Pascale,<br />
Naples, Italy, 3 Department <strong>of</strong> Molecular Medicine and Medical Biotechnology,<br />
University ‘Federico II’, Naples, Italy, 4 Abdominal <strong>Oncology</strong>, Istituto Nazionale<br />
Tumori – I.R.C.C.S - Fondazione Pascale, Naples, Italy<br />
Background: Ado trastuzumab emtansine (TDM1) is a novel antibody–drug conjugate<br />
consisting <strong>of</strong> trastuzumab (TRAS) covalently linked to the highly potent microtubule<br />
inhibitory agent DM1 via a stable thioether linker. TDM1 is used in metastatic ErbB2<br />
positive breast cancer patients. Although, the potential cardiotoxic effects <strong>of</strong> TDM1<br />
have not yet been fully elucidated, they can include all the mechanisms <strong>of</strong><br />
TRAS-related cardiotoxicity, such as changes in Ca 2+ regulation. Here, we aim to<br />
elucidate whether Ranolazine (RAN), administered after TDM1 treatment, blunts or<br />
not cardiotoxicity in vivo and in vitro.<br />
Methods: In vitro, human fetal cardiomyocytes (HFC) were treated with TDM1 for 3<br />
days and then treated in the absence or presence <strong>of</strong> RAN for 3 days. Cell viability was<br />
assessed by cell counting and MTT assay. To evaluate cardiac function in vivo, C57/<br />
BL6 mice, 2-4 months old, were daily treated with TDM1 (44.4 mg/kg/day). At day 0<br />
and after 7 days, fractional shortening (FS) and ejection fraction (EF) were measured,<br />
by M/B mode echocardiography, and radial and longitudinal strain (RS and LS) were<br />
evaluated using 2D speckle-stracking. These measurements were repeated after 5 days<br />
<strong>of</strong> RAN treatment (305 mg/Kg/day), started at the end <strong>of</strong> TDM1 treatment.<br />
Results: RAN reduces TDM1 toxicity in HFC, as evidenced by the higher percentage <strong>of</strong><br />
viable cells treated with TDM1+ RAN with respect to the cells treated with TDM1<br />
alone (p < 0.01). In in vivo studies: after 7 days with TDM1 administration, FS<br />
decreased to 53.6 ± 0.9 %, versus 61.0 ± 0.8 % (sham), (p < 0.01), and EF decreased to<br />
85.5 ± 3.5 % versus 91.0 ± 0.8% (sham), (p < 0.01). Moreover, RS decreased by<br />
42.2 ± 10.1 % versus 20.92 ± 3.2 % (sham), (p < 0.01) and LS decreased by -23.6 ± 6.7 %<br />
versus -15.5 ± 2.8 % (sham), (p < 0.01). In mice treated with TDM1 and, successively<br />
treated with RAN for 5 days, the indices <strong>of</strong> cardiac function partially recovered: FS<br />
58 ± 2.4 % (p < 0.05), EF 88.8 ± 1.7 %, (p < 0.05), LS -17.3 ± 3.7 % (p < 0.05), whereas<br />
the alteration <strong>of</strong> RS persists even after treatment with RAN (35.7 ± 8.2 %, p > 0.05).<br />
Conclusions: Here we show that in vivo RAN post-treatment reduces cardiotoxic<br />
effects due to TDM1, as demonstrated by the recovery <strong>of</strong> FS, EF and LS values. As<br />
expected, RAN increases cell viability <strong>of</strong> HFC treated with TDM1.<br />
Legal entity responsible for the study: N/A<br />
Funding: Fondi di Ricerca Corrente destinati all’ Istituto Nazionale Tumori Pascale -<br />
Napoli<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
26P<br />
Role <strong>of</strong> the Hedgehog pathway in preventing occurrence <strong>of</strong><br />
resistance to first, second, third generation EGFR-TKIs in first<br />
line therapy <strong>of</strong> NSCLC models with EGFR activating mutations<br />
G. Viscardi, C.M. Della Corte, F. Papaccio, G. Esposito, M. Fasano, E. Martinelli,<br />
T. Troiani, F. Ciardiello, F. Morgillo<br />
Oncologia Medica, AOU Seconda Università degli Studi di Napoli (AOU-SUN),<br />
Naples, Italy<br />
Background: NSCLC patients with EGFR activating mutations can be treated with<br />
different lines <strong>of</strong> EGFR tyrosine kinase inhibitors (EGFR-TKIs), and it is still unknown<br />
which is the best EGFR-TKIs in first line. This work investigates the best choice <strong>of</strong><br />
treatment in the first line setting in EGFR mutant NSCLC models.<br />
Methods: The in vivo model <strong>of</strong> sensitivity is represented by nude mice xenografted<br />
with human cancer NSCLC cell lines harboring the EGFR activating mutation (del<br />
ex19) HCC827, which is known to not develop T790M. Mice have been randomized to<br />
receive first line therapy with a first generation EGFR-TKIs (gefitinib), second<br />
generation EGFR-TKIs (afatinib) or third generation EGFR-TKIs (osimertinib).<br />
Additionally treatments were continued until occurrence <strong>of</strong> resistance in order to<br />
obtain new in vivo models <strong>of</strong> resistance to each generation <strong>of</strong> TKIs. Each resistant<br />
tumor has been collected and analyzed for gtene and protein expression.<br />
Results: According to RECIST criteria, a dose-dependent decrease in tumor volume <strong>of</strong><br />
almost all mice treated with each inhibitor was evident after 14 weeks <strong>of</strong> treatment.<br />
Response rates were similar among inhibitors. Western blot analysis on protein extract<br />
from tumors resistant to afatinib and to osimertinib showed increased levels <strong>of</strong><br />
Hedgehog related proteins as compared to untreated controls. Preliminary results from<br />
gene analysis revealed appearance <strong>of</strong> SMO mutation (V404M) in one tumor resistant<br />
to osimertinib, with an allelic frequency <strong>of</strong> 50%, comparing to baseline.<br />
Conclusions: These data demonstrate that, in cell models not developing<br />
T790M-mediated resistance, first, second and third generation EGFR-TKIs are<br />
equivalent in terms <strong>of</strong> tumor response. In such models, Hedgehog pathway activation<br />
plays an important role as mediator <strong>of</strong> first line EGFR-TKIs treatment suggesting new<br />
strategy <strong>of</strong> combination <strong>of</strong> Hedgehog inhibitors with EGFR-TKIs in first line to prevent<br />
the occurrence <strong>of</strong> resistance.<br />
Legal entity responsible for the study: Seconda Università degli Studi di Napoli<br />
Funding: AstraZeneca<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
27P<br />
abstracts<br />
Hypoxia inducible factor prolyl hydroxylase 2 (PHD2) is a direct<br />
regulator <strong>of</strong> epidermal growth factor receptor (EGFR) signaling<br />
in breast cancer<br />
N. Kozlova 1 , M. Wottawa 2 , D.M. Katschinski 2 , G. Kristiansen 3 , T. Kietzmann 1<br />
1 Biochemistry and Molecular Medicine, University <strong>of</strong> Oulu and Biocenter Oulu,<br />
Oulu, Finland, 2 Cardiovascular Physiology, University Medical Center Göttingen,<br />
Göttingen, Germany, 3 Institute <strong>of</strong> Pathology, Universitätsklinikum Bonn, Bonn,<br />
Germany<br />
Background: Clinical studies indicate that the family <strong>of</strong> epidermal growth factor<br />
receptors (EGFR/ERBB) has important roles in the progression <strong>of</strong> breast cancer.<br />
Accordingly, many EGFR/ERBB inhibitors are used as drugs for the treatment <strong>of</strong> this<br />
disease. However, hypoxia in solid tumors is believed to contribute to resistance to<br />
EGFR/ERBB targeted therapies. A positive correlation exists between the activation <strong>of</strong><br />
EGFR and the synthesis <strong>of</strong> hypoxia-inducible factor-1 alpha (HIF-1 alpha), a key<br />
regulator <strong>of</strong> the hypoxic response. Our preliminary results indicate, that the main<br />
player <strong>of</strong> hydroxylation-driven HIF-1 alpha degradation prolyl hydroxylase 2 (PHD2)<br />
greatly contributes to the stability and signaling <strong>of</strong> EGFR.<br />
Methods: To characterize the relationships between PHD2 and EGFR in vivo we have<br />
analyzed the biopsies from breast cancer patients. To further understand the<br />
connection between these proteins on a molecular level, we have established<br />
MDA-MB-231 breast cancer cell line with a stable knockdown <strong>of</strong> PHD2. EGFR levels<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw362 | vi7
abstracts<br />
were checked on the mRNA and protein level by qPCR and Western blot; possible<br />
alterations in the EGFR signaling in the established cell line were checked by EGF<br />
stimulation followed by the measurement <strong>of</strong> the EGFR and kinases phosphorylation.<br />
Proteasomal, lysosomal degradation <strong>of</strong> EGFR and half-life <strong>of</strong> the receptor were assessed<br />
by treatment <strong>of</strong> cells with corresponding inhibitors. Functional assays, examining<br />
cellular proliferation and migration complemented the above-mentioned experiments.<br />
Results: Our study is the first to describe the relations between PHD2 and EGFR in<br />
both preclinical and clinical models <strong>of</strong> breast cancer. We identify PHD2 as a novel<br />
contributor to EGFR signaling in breast cancer by showing its direct participation in<br />
the regulation <strong>of</strong> EGFR stability.<br />
Conclusions: Since the search for novel signaling interplays is a prerequisite for the<br />
development <strong>of</strong> better treatment options <strong>of</strong> breast cancer, we believe that this novel<br />
finding is <strong>of</strong> potential value for clinicians and medical researchers.<br />
Legal entity responsible for the study: University <strong>of</strong> Oulu<br />
Funding: FEBS, Finnish Center <strong>of</strong> International Mobility (CIMO), European<br />
Association for Cancer Research (EACR), Biocenter Oulu, University <strong>of</strong> Oulu, Jane and<br />
Aatos Erkko Foundation, Finnish Academy <strong>of</strong> Sciences, the Sigrid Juselius Foundation.<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
28P<br />
The resistance mechanism <strong>of</strong> FGFR2 amplified gastric cancer<br />
cells against AZD4547, a fibroblast growth factor receptor<br />
inhibitor<br />
S.Y. Lee, Y. Jeong, Y. Na, J.L. Kim, D.H. Lee, S.C. Oh<br />
<strong>Oncology</strong>/Hematology, Korea University Guro Hospital, Seoul, Republic <strong>of</strong> Korea<br />
Background: The fibroblast growth factor- fibroblast growth factor receptor<br />
(FGF-FGFR) signaling pathway plays a role in cell proliferation, migration, survival,<br />
and angiogenesis. Because approximately 10% <strong>of</strong> gastric cancers show amplification <strong>of</strong><br />
FGFR2, inhibition <strong>of</strong> FGFR2 activation has been regarded as one <strong>of</strong> therapeutic targets.<br />
AZD4547, a selective inhibitor <strong>of</strong> the FGFR1-3 tyrosine kinases, was developed to<br />
inhibit FGFR signaling, however, its efficacy is limited by emergency <strong>of</strong> the acquired<br />
resistance. We tried to clarify a resistance mechanism against the FGFR inhibitor.<br />
Methods: The cell line resistant against the AZD4547 was established using SNU-16<br />
(SNU16R), a FGFR2 amplified gastric cancer cell line, by culturing with increasing<br />
concentration <strong>of</strong> the AZD4547. The expression level <strong>of</strong> FGFR or phosphorylated FGFR<br />
(pFGFR) and downstream signaling molecules was determined by Western blot. Cell<br />
viability was measured with MTT assay. Relative level <strong>of</strong> tyrosine phosphorylation <strong>of</strong><br />
receptor tyrosine kinases (RTKs) was evaluated with proteome pr<strong>of</strong>iler TM array by<br />
human phosphor-RTK kit (R&D Systems).<br />
Results: Loss <strong>of</strong> expression <strong>of</strong> FGFR2 and pFGFR2 was confirmed in the SNU16R cell<br />
line by Western blotting. The viability <strong>of</strong> SNU16R cell line was shown to be increased<br />
than that <strong>of</strong> the parent cell line after incubation with AZD 4547. Change <strong>of</strong> the FGFR2<br />
downstream signaling pathways was addressed, and upregulated expression level <strong>of</strong><br />
phosphorylated mammalian target <strong>of</strong> rapamycin (mTOR) was found. Overexpression<br />
<strong>of</strong> downstream targets <strong>of</strong> mTOR, such as phosphorylated 4E-BP1 and S6K was also<br />
confirmed. The SNU15R and parent SNU16 cell lines were incubated with everolimus<br />
or AZD 4547, and inhibition <strong>of</strong> activated mTOR was observed with everolimus but not<br />
with AZD 4547 by Western blotting and MTT assay. Because PI3K and Akt were not<br />
activated, an alternative signaling pathway was sought and the phosphorylated level <strong>of</strong><br />
EphB3 was found to be elevated.<br />
Conclusions: Activation <strong>of</strong> mTOR is one <strong>of</strong> mechanisms <strong>of</strong> acquiring resistance<br />
against AZD 4547 in FGFR2 amplified gastric cancer cells. Targeting mTOR could<br />
overcome the resistance by inhibition <strong>of</strong> activation <strong>of</strong> mTOR.<br />
Legal entity responsible for the study: Korea University Guro Hospital<br />
Funding: AstraZeneca<br />
Disclosure: S.Y. Lee, Y. Jeong, Y. Na, J.L. Kim, D.H. Lee, S.C. Oh: This research was<br />
funded by AstraZeneca. All experiments were performed independently from AstraZeneca.<br />
29P<br />
Anticancer activity <strong>of</strong> the mTOR inhibitor (everolimus) and dual<br />
mTORC1/mTORC2 Inhibitor (AZD2014) on mouse lymphocytic<br />
leukemia both in vitro and in vivo<br />
Y-C. Su 1 , H-F. Liao 2 , C-C. Yu 3 , Y-C. Lin 2<br />
1 Division <strong>of</strong> Hematology-<strong>Oncology</strong>, Department <strong>of</strong> Internal Medicine, E-DA<br />
Hospital, Kaohsiung, Taiwan, 2 Department <strong>of</strong> Biochemical Science and<br />
Technology, National Chiayi University, Chiayi, Taiwan, 3 Department <strong>of</strong> Medical<br />
Research, Dalin Buddhist Tzu Chi General Hospital, Chiayi, Taiwan<br />
Background: The mammalian target <strong>of</strong> rapamycin (mTOR) controls cell growth and<br />
enlargement and has been found to be aberrant in a wide variety <strong>of</strong> malignancies.<br />
Allosteric mTOR inhibitors, which inhibit mTORC1 but not mTORC2, result in<br />
feedback activation <strong>of</strong> AKT signaling, which can attenuate their antitumor activity.<br />
AZD2014 is a second generation mTOR inhibitor that blocks activation <strong>of</strong> both<br />
mTORC1 and mTORC2, and activates apoptosis in cancer cells without activation <strong>of</strong><br />
AKT signaling. Here, we investigated the therapeutic efficacy <strong>of</strong> everolimus and<br />
AZD2014 in lymphocytic leukemia cell line (L1210) and mouse xenograft model.<br />
Methods: Cytotoxicity effect <strong>of</strong> AZD2014 and everolimus in L1210 cells was assessed<br />
after 24 and 48 h by using cell viability assays, clonogenic survival assays, and cell cycle<br />
analyses. Cell cycle, mTOR signal transduction pathway and the relative regulatory<br />
molecules were examined in mTOR inhibitor-treated L1210 cells by western blotting to<br />
detect protein expression. Then, the in vivo anti-leukemic effect <strong>of</strong> AZD2014 was<br />
assessed in L1210 cell-transplanted DBA/2 mice.<br />
Results: AZD2014 significantly inhibited L1210 cell proliferation with an IC50 <strong>of</strong><br />
100nM. In contrast, everolimus was a poor growth inhibitor <strong>of</strong> L1210 cells<br />
(IC50 > 200nM). Treatment with AZD2014 was more effective than RAD001 to<br />
down-regulate the levels <strong>of</strong> mTORC1 downstream effectors, including S6K1, 4EBP1,<br />
eIF4E and a significant decrease in protein levels <strong>of</strong> rictor, a component <strong>of</strong> mTORC2<br />
protein.We also observed inhibition <strong>of</strong> mTORincreased G1 arrest by reducing cyclin<br />
D1 and CDK4 levels, which augmented growth-inhibitory effect <strong>of</strong> L1210 cells. In vivo,<br />
AZD2014 oral administration significantly inhibited the growth <strong>of</strong> L1210 cell xenograft<br />
in DBA/2 mice, and the mice survival was dramatically improved.<br />
Conclusions: These data indicate that AZD2014 may be a better therapeutic agent<br />
than mTORC1 inhibitors to enhance the antitumor activity <strong>of</strong> lymphocytic leukemia<br />
both in vitro and under xenograft model in vivo conditions. Antitumor activity <strong>of</strong><br />
AZD2014 was inhibited <strong>of</strong> both mTORC1 and mTORC2 activity and cell cycle arrest,<br />
leading to lymphocytic leukemia growth inhibition.<br />
Legal entity responsible for the study: N/A<br />
Funding: Without funding from a pharma, biotech, or other commercial company.<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
30P<br />
Transforming growth factor beta receptor (TGFβR) pathway is<br />
involved in ligand independent transactivation <strong>of</strong> AXL receptor<br />
in colorectal cancer (CRC) cell lines<br />
E. Franzese, G. Martini, C. Cardone, T. Troiani, V. Sforza, M.L. Ferrara, V. Belli, P.<br />
P. Vitiello, S. Napolitano, N. Zanaletti, P. Vitale, F. De Vita, M. Orditura, F. Morgillo,<br />
F. Ciardiello, E. Martinelli<br />
Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale, AOU<br />
Seconda Università degli Studi di Napoli (AOU-SUN), Naples, Italy<br />
Background: It has been described that AXL,a tyrosine kinase receptor, can be<br />
activated through different mechanisms: GAS6-ligand dependent dimerization and<br />
ligand-independent activation. As we previously demonstrated the absence <strong>of</strong> GAS6 in<br />
a panel <strong>of</strong> CRC cell lines, we tried to investigate the possible mechanisms <strong>of</strong> AXL<br />
activation in our in vitro CRC model.<br />
Methods: We used a panel <strong>of</strong> CRC cell lines (HCT116, SW480, SW620 and LOVO).<br />
Expression and activation <strong>of</strong> AXL and its ligand GAS6 were analyzed by Western Blot<br />
(WB) and real time-PCR (RTPCR). We generated, in our laboratory, stable<br />
(shRNA)-sh-AXL LOVO cells clones (shAXL clone 1, shAXL clone3 and shAXL clone<br />
5) to evaluate the effect <strong>of</strong> AXL specific knockdown. GAS6, TGF-β1 levels were<br />
measured by ELISA assay.<br />
Results: TGF-β1 was detected at variable levels in AXL expressing CRC cell lines<br />
(HCT116, SW480, SW620 and LOVO). We stimulated CRC cells with TGF-β1finding<br />
increased levels <strong>of</strong> pAXL, pAKT and pMAPK by WB. To reveal how TGF-β1 actives AXL<br />
we measured the mRNA levels <strong>of</strong> AXL or GAS6 by RT-PCR after TGF-β1 24h stimuli. No<br />
fold mRNA increased was observed, suggesting a different interaction between AXL and<br />
TGFβ pathway. To further correlate TGFβR pathway with AXL transactivation, we<br />
stimulated LOVO cell line, shAXL clone1, 3 and 5 with TGF-β1 for 24 hrs. An increased<br />
activation <strong>of</strong> p38MAPK in LOVO cells was demonstrated, accompanied by no change in<br />
shAXL clones, suggesting that, at least in our model, the downstream protein p38 MAPK is<br />
strictly correlated with AXL transactivation stimulated by TGF-β1. Further experiments<br />
with p38MAPK inhibitor are currently ongoing.<br />
Conclusions: Our findings suggested a relationship between TGF-b1, p38 MAPK and<br />
AXL as a possible mechanism <strong>of</strong> AXL independent ligand activation. Further<br />
investigations are ongoing.<br />
Legal entity responsible for the study: Second University <strong>of</strong> Naples<br />
Funding: Second University <strong>of</strong> Naples<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
31P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Taselisib enhances effects <strong>of</strong> anti-microtubule chemotherapic<br />
agents in phosphatidylinositol 3-kinase (PI3Kα) mutant breast<br />
cancer cell lines<br />
A. Diana, F. Morgillo, C.M. Della Corte, C. Di Mauro, V. Ciaramella, F. De Vita,<br />
F. Ciardiello, M. Orditura<br />
Medicina Clinica Sperimentale Magrassi Lanzara, AOU Seconda Università degli<br />
Studi di Napoli (AOU-SUN), Naples, Italy<br />
Background: 30-50% <strong>of</strong> breast cancer are characterized by activating mutations <strong>of</strong><br />
PI3Kα, and higher activity <strong>of</strong> this pathway is <strong>of</strong>ten associated with resistance to<br />
conventional therapies. Thus, selective PI3K inhibitors could represent a novel option<br />
to prevent treatment resistance, including chemotherapy. Several trials are evaluating<br />
the efficacy <strong>of</strong> Taselisib, a novel selective inhibitor <strong>of</strong> mutant PI3Kα, in combination<br />
with hormonal therapy (NCT02340221, NCT02273973, NCT01296555) or taxanes<br />
vi8 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
(NCT01862081) in breast cancer. In preclinical studies, taselisib is active in mutant<br />
PI3Kα xenograft models <strong>of</strong> uterine serous carcinoma and radiosensitizes PI3Kα<br />
mutant head and neck squamous carcinomas.<br />
Methods: We evaluated the effect <strong>of</strong> single agent and combination treatment with<br />
different anti-microtubule chemotherapic agents (vinorelbine, taxanes, and eribulin) or<br />
taselisib on cell proliferation by MTT (3,(4,5-dimethylthiazol-2)2,5 difeniltetrazolium<br />
bromide) assay and on cell survival by apoptosis flow-cytometry analysis. We used five<br />
breast cancer cell models: MDA-MB231 (PI3Kα mutation -) and four PI3Kα<br />
mutation + with different biological pr<strong>of</strong>ile (BT474, HER2+ and HR + ; KPL-4, HER2+<br />
HR-; SUM159, TN; MCF7, HR+ HER2-).<br />
Results: A significant activity <strong>of</strong> vinorelbin or eribulin plus taselisib was observed in<br />
PI3Kα mutant cell lines, in both HER2 and HR +/-, in terms <strong>of</strong> anti-proliferative<br />
effects. In addition, taselisib increased the pro-apoptotic effect <strong>of</strong> eribulin, more than<br />
vinorelbin.Combination with taxanes (paclitaxel) resulted less effective. Furthermore,<br />
the effects <strong>of</strong> combination <strong>of</strong> vinorelbin/eribulin plus taselisib were accompanied by<br />
inhibition <strong>of</strong> PI3K related intracellular proteins (phospho-AKT, AKT, phospho-S6, S6)<br />
and phospho-MAPK signaling.<br />
Conclusions: Further investigations are needed to evaluate the combination <strong>of</strong><br />
anti-microtubule agents and taselisib in breast cancer harbouring alterations <strong>of</strong> PI3Kα.<br />
Legal entity responsible for the study: Department <strong>of</strong> Clinical and Experimental<br />
Medicine ‘F. Magrassi’, Second University <strong>of</strong> Naples<br />
Funding: Department <strong>of</strong> Clinical and Experimental Medicine ‘F. Magrassi’, Second<br />
University <strong>of</strong> Naples<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
abstracts<br />
vivo human tumormodels with activated Akt signaling, exhibiting a specific activity on<br />
mutant Akt1. Two ongoing trials are evaluating the efficacy <strong>of</strong> ipatasertib in<br />
combination with paclitaxel in neoadjuvant (NCT02301988) or in first line<br />
(NCT02162719) therapy in triple negative breast cancer patients. We investigated the<br />
role <strong>of</strong> ipatasertib in combination with anti-microtubule agents vinorelbine, taxanes,<br />
and eribulin in breast cancer cell lines.<br />
Methods: The efficacy <strong>of</strong> combined treatment <strong>of</strong> Ipatasertib (GDC-0068) plus<br />
vinorelbine/taxanes/eribulin was evaluated in in vitro models <strong>of</strong> all breast cancer<br />
subtypes (HR and HER2 +/-, Akt wild-type/mutant). We assayed cell proliferation by<br />
using MTT (3,(4,5-dimethylthiazol-2)2,5 difeniltetrazolium bromide) and apoptosis by<br />
flow-cytometry analysis. The effect on the activation status <strong>of</strong> proteins downstream <strong>of</strong><br />
Akt (phospho-S6, S6, phosphor-4EBP1, 4EBP1) and on other intracellular pathways<br />
(phospho-MAPK, MAPK, phosphor-MEK, MEK, cleaved PARP, caspase 3, Bcl-2) was<br />
analyzed by Western Blot analysis.<br />
Results: A significant synergism <strong>of</strong> ipatasertib and chemotherapy in terms <strong>of</strong><br />
anti-proliferative and pro-apoptotic effect was registered, irrespective <strong>of</strong> HR expression,<br />
HER2, and PI3KCA mutational status. These effects were accompanied by inhibition <strong>of</strong><br />
Akt and MAPK pathways and activation <strong>of</strong> pro-apoptotic proteins, such as cleaved<br />
PARP and caspase 3.<br />
Conclusions: Targeting downstream signaling by blocking Akt with ipatasertib could<br />
represent a new strategy to enhance chemotherapy effects in breast cancer models.<br />
Legal entity responsible for the study: Second University <strong>of</strong> Naples<br />
Funding: Genentech<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
32P<br />
AXL activation can promote resistance to MEK inhibition in a<br />
model <strong>of</strong> colorectal cancer (CRC)<br />
34P<br />
Co-expression <strong>of</strong> HGFR and CD133 cancer stem cell marker in<br />
subepithelial cells <strong>of</strong> chronically active ulcerative colitis<br />
G. Martini 1 , V. Belli 2 , P.P. Vitiello 1 , T. Troiani 1 , C. Cardone 1 , S. Napolitano 1 ,<br />
V. Sforza 1 , M.L. Ferrara 1 , F. Morgillo 1 , D. Ciardiello 1 , E.F. Giunta 1 , F. Ciardiello 1 ,<br />
E. Martinelli 1<br />
1 Medical <strong>Oncology</strong>, AOU Seconda Università degli Studi di Napoli (AOU-SUN),<br />
Naples, Italy, 2 Medical <strong>Oncology</strong> P.O. Edificio 3, AOU Seconda Università degli<br />
Studi di Napoli (AOU-SUN), Naples, Italy<br />
Background: In metastatic colorectal cancer (mCRC) the presence <strong>of</strong> intrinsic and the<br />
development <strong>of</strong> acquired resistance to target therapy represent the most unsolved<br />
problems in the treatment <strong>of</strong> patients. The RAS/RAF/MEK/MAPK signalling pathway<br />
plays central roles in the intracellular transduction <strong>of</strong> proliferative signals from<br />
activated cell membrane growth factor receptors to the nucleus in cancer cells. MEK<br />
activation is an important convergence point involved in the development <strong>of</strong> drug<br />
resistance in mCRC setting. AXL, a tyrosine kinase receptor, plays important roles for<br />
cancer progression, invasion, metastasis and drug resistance. We did this preclinical<br />
study to evaluate a possible mechanism <strong>of</strong> MEK acquired resistance.<br />
Methods: CRC (HCT116 and LOVO) cell lines were used. We generated in vitro<br />
HCT116 and LOVO cell lines resistant to the MEK inhibitor refametinib. Expression<br />
and activation <strong>of</strong> intracellular pathway were analysed by Western Blot (WB). The effect<br />
<strong>of</strong> foretinib, R428 and S49076 (AXL inhibitors) were evaluated by MTT assay. Cell<br />
cycle and apoptosis were analysed by flow cytometry. Chambers <strong>of</strong> transwell were used<br />
to evaluate the migratory capacity.<br />
Results: We generated, HCT116 and LOVO clones (MEK-R) resistant to refametinib<br />
after continuous one-year drug exposure. MEK-R CRC cells have an IC 50 value 50 and<br />
100 times higher than parental cells, respectively. We found in the resistant clones a<br />
strong activation <strong>of</strong> pAXL and its downstream pathway (in particular pAKT).<br />
Treatment <strong>of</strong> resistant clones with the different concentrations <strong>of</strong> AXL inhibitors was<br />
able to reduce cell viability accompanied by a marked deregulation <strong>of</strong> activation <strong>of</strong><br />
AXL, AKT and MAPK. Further experiments on cell cycle, apoptosis and migration are<br />
still ongoing and will be presented.<br />
Conclusions: Our in vitro preliminary data demonstrate AXL activation as a potential<br />
mechanism <strong>of</strong> resistance to MEK inhibition, and suggest a treatment with AXL<br />
inhibitors as a clinical strategy to possibly prevent this mechanism <strong>of</strong> resistance in CRC.<br />
Legal entity responsible for the study: Second University <strong>of</strong> Naples<br />
Funding: AIRC<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
F. Sipos, Z. Tulassay, G. Műzes<br />
2nd Department <strong>of</strong> Medicine, Semmelweis University, Budapest, Hungary<br />
Background: Chronic, longstandig inflammation is known to be a hallmark <strong>of</strong> cancer.<br />
Colorectal cancer risk is elevated in longstanding ulcerative colitis (UC). Previously, we<br />
found that in active, newly diagnosed UC HGFR+ circulating and subepithelial cells<br />
display an expression pr<strong>of</strong>ile characteristics for mesenchymal-epitehlial transition. The<br />
aim <strong>of</strong> this study was to characterize the regeneration-associated stem cell-related<br />
phenotype <strong>of</strong> hepatocyte-derived growth factor receptor (HGFR)-expressing cells in<br />
longstanding, chronically active UC.<br />
Methods: Forty matched peripheral blood and colonic biopsy samples from 20 patients<br />
with chronically active UC and 20 healthy controls were collected. After preparing<br />
tissue microarrays and blood smears HGFR, CDX2, CD133 and Musashi-1<br />
conventional and double fluorescent immunolabelings were performed, then the<br />
samples were digitalized. For semiquantitative counting <strong>of</strong> immunopositive lamina<br />
propria (LP) and blood cells were counted, then mean ± SD were determined. Using<br />
laser microdissection subepithelial cells from the lamina propria were collected. Gene<br />
expression analysis <strong>of</strong> HGFR, CD133, CDX2, Lgr5, Musashi-1 and CK20 were<br />
performed in all samples by using real-time RT-PCR.<br />
Results: Higher number <strong>of</strong> HGFR (blood: 7.4 ± 1.3 vs 28.4 ± 2.23; LP: 2.4 ± 0.7 vs<br />
8.15 ± 0.59; P < 0.05), CDX2 (blood: 0 vs 0.9 ± 0.68; LP: 0.7 ± 0.44 vs 2.02 ± 0.76;<br />
P < 0.05), CD133 (blood: 2.3 ± 0.98 vs 9.72 ± 1.57; LP: 12.1 ± 0.55 vs 31.14 ± 2.15;<br />
P < 0.05) and Musashi-1 (blood and LP: 0 vs scattered) positive cells were detected in<br />
blood and LP <strong>of</strong> UC samples as compared to controls. HGFR/CDX2 (blood: 0 vs<br />
scattered; LP: 0.8 ± 0.2 vs 0.98 ± 0.38, n.s.) and Musashi-1/CDX2 (blood and LP: 0 vs<br />
scattered) co-expressions were found rarely in blood and LP <strong>of</strong> UC samples. HGFR/<br />
CD133 (2.3 ± 0.46) and CD133/CDX2 (scattered) co-expressions appeared only in UC<br />
LP samples.<br />
Conclusions: In chronically active UC, the portion <strong>of</strong> circulating and subeithelial<br />
HGFR-expressing cells decreased, indicating a lower activity <strong>of</strong> mucosal regeneration<br />
by mesenchymal-epithelial transition. However, the higher number <strong>of</strong> HGFR/CD133<br />
double positive cells may indicate the involvement <strong>of</strong> CD133 expression in<br />
colitis-associated carcinogenesis.<br />
Legal entity responsible for the study: Ferenc Sipos<br />
Funding: Hungarian Scientific Research Fund (OTKA-K111743 grant)<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
33P<br />
Ipatasertib (GDC-0068), a novel Akt inhibitor, synergizes with<br />
anti-microtubule chemotherapic agents in human breast<br />
cancer cell lines<br />
35P<br />
Association between polymorphisms in the leptin promoter and<br />
leptin receptor genes and cancer in a mediterranean<br />
population <strong>of</strong> the PREDIMED study<br />
C.M. Della Corte 1 , M. Orditura 1 , A. Diana 1 , C. Di Mauro 2 , V. Ciaramella 1 ,F.De<br />
Vita 1 , F. Ciardiello 1 , F. Morgillo 1<br />
1 Medical <strong>Oncology</strong>, AOU Seconda Università degli Studi di Napoli (AOU-SUN),<br />
Naples, Italy, 2 <strong>Oncology</strong>, Azienda Ospedaliera Universitaria Policlinico Federico<br />
II-AOU Federico II, Naples, Italy<br />
Background: Targeting PI3K/Akt/mTOR signaling in cancer is an attractive<br />
therapeutic option, and particular the block <strong>of</strong> Akt can inhibit tumor growth.<br />
Ipatasertib (GDC-0068) is a potent inhibitor <strong>of</strong> all three Akt is<strong>of</strong>orms in in vitro and in<br />
J.B. Ramirez Sabio 1 , J.V. Sorlí 2 , C. Ortega-Azorín 2 , P. Carrasco 3 , O. Portolés 2 ,E.<br />
M. Asensio 3 , D. Corella 2<br />
1 Servicio de Oncologia Medica, Hospital de Sagunt, Sagunt, Spain, 2 Preventive<br />
Medicine and Public Health, Universitat de València, Valencia, Spain, 3 Preventive<br />
Medicine and Public Health, CIBER Fisiopatología de la Obesidad y Nutrición,<br />
Valencia, Spain<br />
Background: Leptin is a hormone produced mainly by the adipose tissue and related<br />
in the regulation <strong>of</strong> food intake and energy balance. Elevated leptin levels and obesity<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw362 | vi9
abstracts<br />
has been shown to increase breast cancer risk in postmenopausal women. Our<br />
objective has been to estimate the risk <strong>of</strong> cancer arising from the common<br />
polymorphism within the 5’ unstranslated region <strong>of</strong> the leptin gene (-2,548G/A) and<br />
Q223R polymorphisms in the LEPR gen, which has been associated with leptin levels,<br />
in a Mediterranean population.<br />
Methods: The PREDIMED Study is a multi-center, randomized trial aimed at<br />
assessing the effects <strong>of</strong> the Mediterranean Diet on cardiovascular primary prevention.<br />
We analyzed 1108 participants (404 men and 704 women) high cardiovascular risk<br />
subjects (67 ± 6 years) were selected from a Spanish Mediterranean population.<br />
Demographic, clinical, biochemical, anthropometric, genetic and life-style variables<br />
were obtained.<br />
Results: 84 (7.6%) <strong>of</strong> the 1108 participants suffered from cancer after a median follow<br />
up <strong>of</strong> 4.8 years. The group <strong>of</strong> cancer patients showed 42.9% <strong>of</strong> current or former<br />
smokers versus 33.9% in the non cancer participants group (p = 0.003). Prevalence <strong>of</strong><br />
the -2,548G/A genotypes were: 21.4% GG, 49.7% GA, 28.9% AA (allele frequencies,<br />
G = 0.463 and A = 0.537) and <strong>of</strong> the Q223R genotypes were: 13.6% QQ, 47.7% QR,<br />
38.7% RR (allele frequencies, Q = 0.375 and R = 0.625). Interestingly, we found a<br />
consistent association <strong>of</strong> the SNP in the leptin gene with lower cancer risk. The lower<br />
risk <strong>of</strong> cancer associated with the A allele remained significant (OR = 2.21; 95% CI,<br />
1.04-4.72) after adjustment for gender, age and tobacco smoking.<br />
Conclusions: The allele A in the polymorphism -2,548G/A <strong>of</strong> the leptin gene is<br />
associated with lower cancer risk in this Mediterranean population.<br />
Clinical trial identification: ISRCTN.org Identifier: ISRCTN35739639<br />
Legal entity responsible for the study: Universitat de València<br />
Funding: Instituto de Salud Carlos III, Ministerio de Sanidad y Consumo<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
36P<br />
Radiotherapy-induced apoptotic tumor cells stimulate<br />
proliferation <strong>of</strong> living tumor cells via caspase 3/7–PKCδ–Akt/<br />
p38 MAPK pathway<br />
J. Cheng 1 , L. Tian 2 , Q. Huang 1<br />
1 The Comprehensive Cancer Center and Shanghai Key Laboratory for Pancreatic<br />
Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School <strong>of</strong><br />
Medicine, Shanghai, China, 2 Institute <strong>of</strong> Translational Medicine, Shanghai General<br />
Hospital, Shanghai Jiao Tong University School <strong>of</strong> Medicine, Shanghai, China<br />
Background: Our previous studies demonstrated that radiotherapy-induced apoptotic<br />
cells significantly stimulate the proliferation <strong>of</strong> surviving tumor cells through the<br />
caspase 3-iPLA 2 -AA-PGE 2 pathway. However, the molecular events involved in this<br />
stimulation seem to involve in different pathways. This study seeks to investigate the<br />
molecular mechanisms involved in the stimulatory role <strong>of</strong> apoptotic human pancreatic<br />
(Panc1) and colonic cancer (HT29) cells in vitro.<br />
Methods: Apoptotic Panc1 and HT29 cells were produced as feeders by 10Gy X-ray<br />
radiation. Caspase 3, 7, PKCδ, Akt, p38 MAPK and JNK1/2 activation was detected by<br />
Western blot. Panc1 and HT29 cells stably transduced by firefly luciferase and green<br />
fluorescent protein fusion gene (Panc1-Fluc and HT29-Fluc) were used as reporter.<br />
Living Panc1-Fluc and HT29-Fluc cells proliferation on radiated Panc1 and HT29 cells<br />
were evaluated by luciferase activity using bioluminescence imaging.<br />
Results: The presence <strong>of</strong> apoptotic Panc1 and HT29 cells significantly stimulated the<br />
proliferation <strong>of</strong> living Panc1-Fluc and HT29-Fluc cells. These apoptotic tumor cells<br />
showed significantly increased caspase 3 and 7 as well as PKCδ activity. However,<br />
significant decrease <strong>of</strong> the stimulation effect on living Panc1-Fluc and HT29-Fluc cells<br />
was observed when apoptotic Panc1 and HT29 cells stably transduced by either<br />
dominant-negative caspase 3, caspase 7 or PKCδ were used as feeders instead; and pan<br />
PKC inhibitor and specific PKCδ inhibitor significantly inhibited the stimulatory effect<br />
<strong>of</strong> apoptotic Panc1 and HT29 cells. Additionally, significantly increased<br />
phosphorylation <strong>of</strong> Akt, p38 MAPK and JNK1/2 were observed in the irradiated Panc1<br />
and HT29 cells. Interestedly, dominant-negative PKCδ was resistant to the cleavage<br />
and activation by caspase 3 or 7 and the expression <strong>of</strong> dominant-negative PKCδ<br />
attenuated radiation induced Akt phosphorylation in both Panc1 and HT29 cells,<br />
attenuated p38 MAPK activation in Panc1 cells.<br />
Conclusions: Apoptotic tumor cells can significantly stimulate the proliferation <strong>of</strong><br />
living tumor cells through the caspase 3/7-PKCδ-Akt/p38 MAPK pathway after<br />
radiotherapy.<br />
Legal entity responsible for the study: Qian Huang, Shanghai General Hospital,<br />
Shanghai Jiao Tong University School <strong>of</strong> Medicine<br />
Funding: National Natural Science Foundation (81120108017, 81172030) and<br />
National Basic Research Program <strong>of</strong> China (2010CB529902)<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
37P<br />
Association <strong>of</strong> IFNg production and NK cytotoxicity in PBL <strong>of</strong><br />
breast cancer patients<br />
S.S. Radenkovic 1 , V. Jurisic 2 , R. Dzodic 3 , G. Konjevic 4<br />
1 Department <strong>of</strong> Radiation <strong>Oncology</strong> and Diagnostics, Institute <strong>of</strong> <strong>Oncology</strong> and<br />
Radiology <strong>of</strong> Serbia, Belgrade, Serbia, 2 Department <strong>of</strong> Pathophysiology, School <strong>of</strong><br />
Medicine University <strong>of</strong> Kraguje, Kragujevac, Serbia, 3 Department <strong>of</strong> Surgical<br />
<strong>Oncology</strong>, Institute <strong>of</strong> <strong>Oncology</strong> and Radiology <strong>of</strong> Serbia, Belgrade, Serbia,<br />
4 Department <strong>of</strong> Experimental Research, Institute <strong>of</strong> <strong>Oncology</strong> and Radiology <strong>of</strong><br />
Serbia, Belgrade, Serbia<br />
Background: New insights revealed a critical role for endogenously produced IFNγ in<br />
promoting host responses to tumors. In this sense, molecular mechanisms underlying<br />
immune dysfunction that include the role <strong>of</strong> IFNγ in immune responses are not clearly<br />
defined in breast cancer.<br />
Methods: PBL <strong>of</strong> breast cancer patients and healthy controls were analyzed for IFNγ<br />
expression and NK cell activity using flow cytometry and 51Cr-release assay,<br />
respectively.<br />
Results: Patients in early clinical stage <strong>of</strong> breast cancer had significantly decreased NK<br />
cell cytotoxicity compared to controls. However, patients with advanced clinical stage<br />
had significantly decreased NK cell cytotoxicity compared to early breast cancer<br />
patients and controls. Positive correlation was shown between intracellular level <strong>of</strong><br />
IFNγ in PBL and NK cell activity in both healthy controls and all investigated patients.<br />
However, in patients with advanced disease stages positive correlation between<br />
intracellular IFNγ level in PBL and NK cell activity was found, while there was no<br />
correlation between the IFNγ level in PBL and NK cell activity in patients in early<br />
disease stage. IL-2 increased NK cell cytotoxicity in breast cancer patients and control.<br />
Furthermore, IFNα showed this effect also in patients and controls.<br />
Conclusions: In this study we show that, in breast cancer patients, lower IFNγ level and<br />
reduced NK cell cytotoxicity, important in the control <strong>of</strong> tumor growth, are associated<br />
with tumor progression. These results indicate that IFNγ level and NK cell cytotoxicity<br />
may represent possible targets in designing new therapeutic agents in this disease.<br />
Legal entity responsible for the study: National Projects funded by Ministry <strong>of</strong><br />
Science Government <strong>of</strong> Serbia<br />
Funding: Ministry <strong>of</strong> Science<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
38P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Antitumor immunity against hCGb induced by a tumor cell<br />
vaccine modified with a fusion gene <strong>of</strong> hCGb and polyarginines<br />
Y. Zhang 1 ,C.Su 2 , Y-S. Wang 1 ,Y.Lu 1 , Y-Q. Wei 1<br />
1 Thoracic <strong>Oncology</strong>, Cancer Center and State Key Laboratory <strong>of</strong> Biotherapy, West<br />
China Hospital, West China Medical School, Sichuan University, Chengdu, China,<br />
2 State Key Laboratory <strong>of</strong> Biotherapy, West China Hospital, Sichuan University,<br />
Chengdu, China<br />
Background: Human chorionic gonadotropin β (hCGβ) is a kind <strong>of</strong> pregnancy<br />
hormones, moreover, it is a tumor-associated antigen ectopically expressed on a variety<br />
<strong>of</strong> human non-trophoblastic tumors such as pancreatic cancer, bladder cancer and<br />
lung cancer. Therefore, hCGβ is considered as an ideal target antigen. However, as a<br />
self-antigen, hCGβ is tolerated by the immune system and immune response is hardly<br />
induced. 9-mer <strong>of</strong> L-arginine (Arg9), a type <strong>of</strong> cell penetrating peptide, can play an<br />
important role in the translocation process.<br />
Methods: Firstly, we designed and constructed two eukaryotic expressing plasmids<br />
including pCDNA3.1-hCGβ-Arg9 (phCGβ-Arg9) and pCDNA3.1-hCGβ (phCGβ).<br />
Secondly, B16.E5, a B16 cell line expressing hCGβ, was acquired by transfected<br />
B16-F10 cells with phCGβ and selected with G418. Meanwhile we constructed<br />
hCGβ-Arg9 gene modified tumor cell vaccine by transient transfection <strong>of</strong> phCGβ-Arg9<br />
into B16-F10 cells with liposome. Finally, we took the prophylactic vaccination<br />
experiment in vivo to investigate the protective efficacy and the immune mechanisms.<br />
Results: The transfectant with highest expression <strong>of</strong> hCGβ was screened and named<br />
B16.E5 as a tumor model in this experiment. The results <strong>of</strong> protective experiment<br />
demonstrated 60% mice <strong>of</strong> hCGβ-Arg9 group were protected from the challenge <strong>of</strong> B16.<br />
E5 cells. Moreover, survival benefit was also observed in mice vaccinated with the<br />
hCGβ-Arg9 tumor vaccine (48.4 ± 4.9 days) compared with controls. Then, the<br />
experiments for immune mechanism were conducted, including T lymphocytes adoptive<br />
transfer experiment, CTL-mediated cytotoxicity analysis, hCGβ antibody tests <strong>of</strong> serum<br />
after vaccination and serum transfer analysis. All <strong>of</strong> these suggested cellular immunity,<br />
rather than humoral immunity, may play the major role in the antitumor activity.<br />
Conclusions: We designed and constructed the tumor cell vaccine modified with<br />
hCGβ-Arg9 gene and demonstrated that this vaccine can induce cellular immunity,<br />
through which the vaccine can play protective efficacy in animal experiments. Our<br />
work may contribute to designing novel generation <strong>of</strong> tumor vaccines.<br />
Legal entity responsible for the study: Department <strong>of</strong> Thoracic <strong>Oncology</strong>, Cancer<br />
Center, State Key Laboratory <strong>of</strong> Biotherapy, West China Hospital, West China Medical<br />
School, Sichuan University, Chengdu, Sichuan, China<br />
Funding: National Natural Science Funds <strong>of</strong> China (81402561)<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
vi10 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
39P<br />
IL-6 induces and releasing <strong>of</strong> MMP-9 in murine bone marrow<br />
neutrophils by activating STAT3 pathway<br />
X. Wu, B. Yan<br />
Gynecological <strong>Oncology</strong>, Hubei Maternity and Child Health Hospital, Wuhan,<br />
China<br />
Background: To investigate the production and release <strong>of</strong> murine bone marrow<br />
neutrophil MMP-9 and its mechanism <strong>of</strong> activation.<br />
Methods: Murine bone marrow neutrophils were separated and cultured in vitro and<br />
randomly divided into four groups: control group, IL-6 50ng/ml stimulation group,<br />
IL-6 50ng/ml + DMSO group and IL-6 50ng/ml + STAT3 inhibitor VIII 50 µM group.<br />
RT-PCR method was used to evaluate the mRNA level <strong>of</strong> intracellular MMP-9 <strong>of</strong><br />
neutrophils. Gelatin zymography was performed to detect the activity <strong>of</strong> MMP-9<br />
released from neutrophils. Western blot was applied to test the phosphorylation levels<br />
<strong>of</strong> STAT3 pathway in neutrophils.<br />
Results: Compared with the control group, the administration <strong>of</strong> IL-6 enhanced the<br />
mRNA expression <strong>of</strong> MMP-9 (P = 0.0050); the activity <strong>of</strong> MMP-9 released from<br />
neutrophils was elevated (P = 0.0087) and the p-STAT3 levels in neutrophils was also<br />
increased (P =0.089). After the STAT3 inhibitor VIII was added, the mRNA expression<br />
<strong>of</strong> MMP-9, the activities <strong>of</strong> MMP-9 in the supernatant and the p-STAT3 levels in<br />
neutrophils were decreased significantly compared with those in the IL-6 group<br />
(P = 0.0067, 0.048 and 0.098, respectively).<br />
Conclusions: IL-6 induces the production and releasing <strong>of</strong> MMP-9 in neutrophils and<br />
the effect may be induced by the activation <strong>of</strong> STAT3 pathway.<br />
Legal entity responsible for the study: Hubei Maternity and Child Health Hospital<br />
Funding: Hubei Maternity and Child Health Hospital<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
40P<br />
Macrophage migration inhibitory factor (MIF) involvement in<br />
breast cancer cells metabolism: A 1H-NMR spectroscopy<br />
evaluation<br />
V. Richard 1 , R. Conotte 2 , N. Kindt 3 , S. Saussez 3 , J-M. Colet 2<br />
1 Medical <strong>Oncology</strong>, Hospital Ambroise Pare, Mons, Belgium, 2 Laboratory <strong>of</strong><br />
Human Biology and Toxicology, UMONS, Mons, Belgium, 3 Laboratory <strong>of</strong> Anatomy<br />
and Cellular Biology, UMONS, Mons, Belgium<br />
Background: The shift in cellular metabolism, also called Warburg effect, is an<br />
emerging hallmark <strong>of</strong> cancer cells (CC) orchestrated by oncogenic proteins. MIF, a<br />
pleiotropic cytokine, is involved in CC proliferation and multiple aspects <strong>of</strong><br />
carcinogenesis but little is known about its possible role in cellular metabolic activities.<br />
Using MIF knockdown (KD) technique and 1 H-RMN spectroscopy, we evaluated the<br />
influence <strong>of</strong> MIF on MDA-MB-231 and MCF-7cells.<br />
Methods: MIF KD cells were obtained by lentiviral transduction. MDA-MB-231 MIF<br />
sc/KD and MCF-7 MIF sc/KD cells were scrapped and quenched using methanol. The<br />
solution containing the quenched cells was pipetted for intracellular metabolites<br />
extraction (methanol, chlor<strong>of</strong>orm and water extraction procedure). Only the aqueous<br />
phase was used. Each sample was reconstituted in phosphate buffer mixed with TSP.<br />
After acquisition on a Bruker Avance spectrometer at 500 MHz, NMR spectra are<br />
integrated in 0.04ppm subregion (binning). Multivariate analysis (Partial Least Square<br />
Discriminate Analysis [PLS-DA]) was performed on the integrated data (SIMCA P + ,<br />
MKS Data Analytics Solutions).<br />
Results: PLS-DA analysis <strong>of</strong> NMR data clearly separate the MDA-MB-231 from<br />
MCF-7 cells (ANOVA, p < 0.01). MDA-MB-231 cells show significant lower levels <strong>of</strong><br />
intracellular glutamine, glutamate, alanine, valine, leucine, isoleucine, glucose, glycine<br />
and higher levels <strong>of</strong> lactate and myoinositol as compared to MCF-7 (Wilcox test, p<br />
abstracts<br />
43P<br />
Oncoguide system - A computerized self-learning interactive<br />
assistance system for the diagnosis and treatment <strong>of</strong> CML /<br />
MPN and MDS<br />
D. Hempel 1 , Y. Fischer 2<br />
1 Institute <strong>of</strong> Clinical Hematology/<strong>Oncology</strong>, Steinbeishochschule Berlin,<br />
Donauwoerth, Germany, 2 IOSB, Fraunh<strong>of</strong>er Institut, Karlsruhe, Germany<br />
Background: Clinical practice guidelines (CPG) represent the current state <strong>of</strong> research.<br />
Usually they were passive disseminations (e.g. via print media), but this doesn’t assist<br />
the physician in the adaptation <strong>of</strong> CPG into the daily diagnostic and treatment<br />
algorithm to the given boundary conditions (patient, equipment, medical experience).<br />
The project aims to develop and implement a computerized interactive assistance<br />
system for the diagnosis and treatment <strong>of</strong> CML / MPN and MDS.<br />
Methods: To create the system experts from the medical and the technical domains<br />
were necessary. They developed a CPG model in the form <strong>of</strong> a Unified Modeling<br />
Language (UML) activity followed by translation <strong>of</strong> UML activities into Bayesian nets.<br />
The future system is planned to be self-learning by weighing the decision criteria. The<br />
knowledge-based system is implemented as a client-server architecture. The server acts<br />
as a central data storage in the form <strong>of</strong> a database. As a client, for example, Internet<br />
browsers can be used. The knowledge <strong>of</strong> guidelines and interviews with experts have to<br />
be formalized in an appropriate manner. There are approaches based on an ontological<br />
or logic-based modeling. The underlying methodology is based on approaches from<br />
artificial intelligence, such as the Bayesian inference or machine learning methods.<br />
Results: On the client’s side the system suggests the user appropriate decisions for the<br />
diagnosis and further treatment <strong>of</strong> diseases. The user is navigated through the complex<br />
recommendations <strong>of</strong> current guidelines and decision trees <strong>of</strong> the CML/MPN and MDS,<br />
similar to a car navigation system. In contrast to common print media the system<br />
actively supports the physician in the adaptation <strong>of</strong> CPG into the daily diagnostic and<br />
treatment algorithm to the given boundary conditions (patient, equipment, medical<br />
experience) and has self learning components.<br />
Conclusions: The presented computerized interactive assistance system could help to<br />
increase the accuracy <strong>of</strong> diagnosis, treatment and follow up <strong>of</strong> CML/MPN and MDS.<br />
Legal entity responsible for the study: Steinbeishochschule Berlin, Institute <strong>of</strong> Clinical<br />
Hematology/<strong>Oncology</strong><br />
Funding: Celgene, Novartis<br />
Disclosure: D. Hempel: Supported by a grant <strong>of</strong> Celegene and Novartis.All other<br />
authors have declared no conflicts <strong>of</strong> interest.<br />
44P<br />
Genomic pr<strong>of</strong>ile <strong>of</strong> Li-Fraumeni syndrome patients with<br />
adrenocortical carcinoma in childhood<br />
F. Fortes 1 , L. Canto 2 , H. Kuasne 2 , F. Marchi 2 , P. Miranda 2 , K. Andrade 1 ,<br />
K. Santiago 1 , S. Rogatto 3 , M.I. Achatz 1<br />
1 Oncogenetics, A. C. Camargo Cancer Center, Sao Paulo, Brazil, 2 Neogene,<br />
A. C. Camargo Cancer Center, Sao Paulo, Brazil, 3 Clinical Genetics, Vejle Hospital<br />
Sygehus Lillebaelt, Vejle Sygehus, Vejle, Denmark<br />
Background: Li-Fraumeni syndrome (LFS) is cancer predisposition disorder with a<br />
high risk <strong>of</strong> having tumors at an early age and multiple primary tumors. LFS is an<br />
autosomal dominant disease and germline TP53 mutations were recognized as the<br />
main molecular mechanism responsible for the syndrome. LFS is present in 0.3% <strong>of</strong> the<br />
South and Southeastern Brazilian population due to the occurrence <strong>of</strong> a founder<br />
mutation, the p.R337H TP53. This mutation was initially described as tumor specific,<br />
predisposing to pediatric adrenocortical carcinoma (ADR). ADR is a rare neoplasm<br />
worldwide, but pediatric ADR is 10-15 times more incident in South and Southeast <strong>of</strong><br />
Brazil, a fact possibly linked to the presence <strong>of</strong> the p.R337H mutation. To date, the<br />
factors that lead to the development <strong>of</strong> ADR in some children while others remain<br />
asymptomatic have not been elucidated and only the presence <strong>of</strong> the mutation may not<br />
be sufficient for tumor appearance.<br />
Methods: Therefore, the aim <strong>of</strong> this study was to evaluate copy number alterations<br />
(CNA) <strong>of</strong> positive ADR patients (N = 3) or negative (N = 1) for p.R337H mutation.<br />
Analysis <strong>of</strong> gains and losses were evaluated by CytoScan HD Array (Affymetrix, Santa<br />
Clara, CA, EUA).<br />
Results: In total, 341 alterations were identified (260 gains, 55 losses and 26 LOH),<br />
with an average number <strong>of</strong> 60 alterations in positive cases, while the negative case<br />
carried 156 alterations. Among the alterations identified in the positive cases, five <strong>of</strong><br />
them were recurrent in all samples and involved 5p15.33, 12p13.33, 13q11, 15q11.2<br />
and 19p13.3 regions. Despite the small set <strong>of</strong> samples, it is evident that positive cases<br />
have fewer alterations compared to negative cases.<br />
Conclusions: The apparent higher chromosome instability in negative cases<br />
corroborates our previous results in which the presence <strong>of</strong> p.R337H mutation provides<br />
a protective effect in patients with ADR. However, this is a preliminary study and our<br />
hypothesis may be confirmed when new investigation in a larger number <strong>of</strong> samples<br />
are completed.<br />
Legal entity responsible for the study: Maria Isabel Achatz<br />
Funding: Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
45P<br />
Proteomics-based system biology analyses unravel a functional<br />
structure with prognostic value<br />
G. De Velasco 1 , L. Trilla-Fuertes 2 , A. Gámez-Pozo 2 , M. Urbanowicz 3 ,<br />
G. Ruiz-Ares 1 , J.M. Sepulveda 1 , R. Manneh 1 , B. Homet 1 , I. Otero 1 , P. Celiz 1 ,<br />
F. Villacampa 4 , L. Paz-Ares 1 , J. Fresno Vara 2 , D. Castellano 1<br />
1 Medical <strong>Oncology</strong>, Hospital Universitario Doce de Octubre, Madrid, Spain,<br />
2 Molecular <strong>Oncology</strong> and Pathology Lab, Instituto de Investigación Hospital<br />
Universitario La Paz, Madrid, Spain, 3 Pathology, Hospital Universitario Doce de<br />
Octubre, Madrid, Spain, 4 Urology, Hospital Universitario Doce de Octubre,<br />
Madrid, Spain<br />
Background: Urothelial cancer has been traditionally classified based on histology<br />
features. Recently, some works have proposed a molecular classification <strong>of</strong><br />
muscle-invasive urothelial carcinoma (MIUC) into basal and luminal subtypes. We<br />
aimed to define molecular subtypes <strong>of</strong> MIUC and evaluate the status <strong>of</strong> several<br />
biological processes in the tumor tissue and address its clinical value.<br />
Methods: Tissue samples were obtained from 57 pts who underwent curative surgical<br />
resection at “Universitary Hospital 12 Octubre” between 2006/12. We analyzed the<br />
proteome applying a high-throughput proteomics approach to routinely archive FFPE<br />
tumor tissue. Tryptic digests were analyzed by mass spectrometry for protein<br />
identification using a Q-Exactive mass spectrometer. Subgroups were defined by<br />
hierarchical clustering and random forest. Functional structure was developed using<br />
probabilistic graphical models with local minimum Bayesian Information Criterion<br />
and Gene Ontology Analysis. Data analysis was done using MeV, BRBArray Tools, R<br />
and Cytoscape s<strong>of</strong>tware suites and Uniprot (http://www.uniprot.org/) and DAVID<br />
(http://david.abcc.ncifcrf.gov) webtools.<br />
Results: We identified two different molecular subgroups with differential prognosis.<br />
Systems biology analyses showed that wide protein expression assessment allows<br />
building a functional structure where several nodes with defined biological activity were<br />
defined. Activity measurement for each node showed differences between two subtypes<br />
in metabolism, focal adhesion, RNA and splicing nodes. Subtypes defined by protein<br />
expression are comparable to basal and luminal subtypes defined by gene expression.<br />
Moreover, the focal adhesion node has prognostic value in the whole population, and<br />
this prognostic information is independent from a predefined prognostic signature<br />
(submitted Abstract: Proteomics pr<strong>of</strong>ile pr<strong>of</strong>iling predicts poor prognosis in patients<br />
with muscle invasive urothelial carcinoma).<br />
Conclusions: Protein data analysis using random forest showed subgroups matching<br />
with basal and luminal subtypes obtained by hierarchical cluster analysis. Importantly,<br />
we were able to establish different nodes according to biological functions, with<br />
diagnostic and prognostic value.<br />
Legal entity responsible for the study: Research Institute i + 12<br />
Funding: Fundacion Mutual Madrilen.<br />
Disclosure: G. De Velasco: Advisory board for Pfizer. No Conflict <strong>of</strong> interest with the<br />
abstract submitted.All other authors have declared no conflicts <strong>of</strong> interest.<br />
46P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Effect <strong>of</strong> newly synthesized progesteron derivatives on<br />
apoptotic and metastatic pathway in MCF-7 breast cancer cells<br />
S. Yahya 1 , M. Abdelhalim 1 , G. Elsayed 1 , A. Othman 2<br />
1 Hormones, National Research Centre, Cairo, Egypt, 2 Chemistry, Cairo University,<br />
Cairo, Egypt<br />
Backgroun: Breast cancer is the second leading cause <strong>of</strong> mortality among women<br />
worldwide. Anticancer agents consisting <strong>of</strong> hybrid molecules are used to improve<br />
efficacy and reduce drug resistance. Alteration <strong>of</strong> different genes is involved in the<br />
development <strong>of</strong> cancer. Consequently, novel anticancer drugs with increased selectivity<br />
and specificity are required to overcome limitation <strong>of</strong> current drugs. A variety <strong>of</strong><br />
synthetic steroid derivatives have been contrived, most these derivatives can interact<br />
with the steroid receptors because <strong>of</strong> a similarity <strong>of</strong> shape. Also, the investigation <strong>of</strong><br />
modified steroid derivatives condensed with various heterocyclic rings has a great<br />
attention. Impaired apoptosis and metastasis are critical in cancer development and is<br />
a major barrier to effective treatment.<br />
Methods: Several progesterone derivatives were synthesized. The structure <strong>of</strong> the newly<br />
derivatives was elucidated and confirmed using the analytical and spectral data. The<br />
newly synthesized progesterone derivatives, compounds 1, 2, 3, 4, 5, 6, and 7were tested<br />
for their cytotoxic effects against human breast cancer cells (MCF-7) using neutral red<br />
uptake assay. Using QRT-PCR (Quantitative real time-polymerase chain reaction), the<br />
expression levels <strong>of</strong> P53, P21, Cdc2, Bcl-2, Survivin, CCND1, VEGF, HIF-1α, FGF-1,<br />
MMP-2, MMP-9, Ang-1 and Ang-2 genes were investigated.<br />
Results: All tested compounds showed low IC50 values that were comparable to that <strong>of</strong><br />
tamoxifen. The most active compounds against MCF-7 cancer cell line was in the<br />
descending order <strong>of</strong> 5 >1> 2 >6> 4 > 7 > 3. The study revealed that all newly<br />
synthesized compounds down-regulated the expression levels <strong>of</strong> BCL-2, surviving,<br />
VEGF, Ang-2 and MMp-9. Compound 2-7 down regulated CCND1 gene expression,<br />
nevertheless, this was only significant in case <strong>of</strong> compounds 2, 3, and 6. However, P53<br />
were up-regulated by compounds 3. Moreover, compound 1 significantly down<br />
regulated MMP-2. Compoun 3 and 7 significantly down regulated FGF-1.<br />
vi12 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Conclusions: This study introduced promising pro-apoptotic and anti-metastatic<br />
anticancer agents acting through the regulation <strong>of</strong> key regulators <strong>of</strong> apoptosis, cell cycle<br />
and metastasis related genes.<br />
Legal entity responsible for the study: STDF<br />
Funding: STDF<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
47P<br />
A potential natural inhibitor in the autocrine regulation among<br />
ovarian stromal cell population & its translational implications<br />
D. Ye 1 , E.R. Smith 1 ,S.O’Toole 2 , J.J. O’Leary 3 , B. Hennessy 4 , X.X. Xu 1<br />
1 Cell Biology, University <strong>of</strong> Miami Sylvester Comprehensive Cancer Center, Miami,<br />
FL, USA, 2 Obstetrics and Gynaecology, Trinity College Dublin, Dublin, Ireland,<br />
3 Histopathology, Trinity College Dublin, Dublin, Ireland, 4 Medical <strong>Oncology</strong>, Royal<br />
College <strong>of</strong> Surgeons in Ireland, Dublin, Ireland<br />
Background: The ovarian microenvironment is influential on ovarian cancer<br />
progression and metastases as it <strong>of</strong>fers a rich niche <strong>of</strong> pro inflammatory markers<br />
potentiating angiogenesis, growth and tumour progression. We sought to investigate<br />
the malleable nature <strong>of</strong> stromal cells analyzing the paracrine communication with<br />
granulosa cells and its autocrine regulation in stromal cells using conditioned medium<br />
studies.<br />
Methods: Primary stromal cells were cultured from wild type mice C57BL/6J. Cultured<br />
stromal cells were treated with conditioned media from stromal cells (CMSC),<br />
conditioned media <strong>of</strong> preantral granulosa cells (CMPAGC), conditioned media <strong>of</strong> pre<br />
ovulatory granulosa cells (CMPOGC) and conditioned media <strong>of</strong> ovarian explants<br />
(CMOE). The treatment effects on cell proliferation were analyzed with WST 1 assay.<br />
Western blot on stromal cell lysates was performed for analyzing its treatment<br />
responses to conditioned media CMSC, CMPAGC, CMPOGC, CMOE assessing<br />
pERK, pAKT, NFKB, GP130 activity.<br />
Results: The control group exhibits a gradual increase in cell proliferation in stromal<br />
cells over a 96 hour time course. The CMPOGC & CMPAGC enhances cell growth in<br />
stromal cells. In the absence <strong>of</strong> granulosa cells, CMSC substantially inhibits the growth<br />
<strong>of</strong> the stromal cell population. Western blot analysis <strong>of</strong> stromal cells treated with CMSC<br />
showed a down regulation <strong>of</strong> GP130 receptor, a reduction in pAKT, pERK and NFKB<br />
signaling, in comparison to treatment control groups.<br />
Conclusions: Stromal cells produce a non-inflammatory mediator that suppresses cell<br />
growth in the stromal cell population in an autocrine fashion. The tumour<br />
microenvironment is a potential source in promoting tumour progression and<br />
metastases. Comparisons are needed with stromal cells cultivated from tumour<br />
samples. This highlights the need to identify the mediators in CMSC, in pursuit <strong>of</strong> a<br />
drug analogue discovery <strong>of</strong> a stromal cell inhibitor. This may be a novel targeted<br />
therapy in ovarian cancer treatment.<br />
Legal entity responsible for the study: N/A<br />
Funding: University <strong>of</strong> Miami, Bridge grant<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
48P<br />
Gender differences in functional activity <strong>of</strong> the thyroid gland in<br />
C57BL/6 mice in dynamics <strong>of</strong> transplantable В16/F10<br />
melanoma growth<br />
L. Vladimirova 1 , V. Bandovkina 2 , E. Franciyans 2 , O. Kit 3 , N. Cheryarina 2 ,<br />
I. Kaplieva 3 , E. Islamova 3 , A. Salatova 3 , L. Sergostyants 3 , M. Cherkes 3<br />
1 Department <strong>of</strong> Chemotherapy, Rostov Research Institute <strong>of</strong> <strong>Oncology</strong>,<br />
Rostov-on-Don, Russian Federation, 2 Department <strong>of</strong> Biochemistry, Rostov<br />
Research Institute <strong>of</strong> <strong>Oncology</strong>, Rostov-on-Don, Russian Federation, 3 Department<br />
<strong>of</strong> Surgical, Rostov Research Institute <strong>of</strong> <strong>Oncology</strong>, Rostov-on-Don, Russian<br />
Federation<br />
Background: Thyroid hormones stimulate metabolism practically in all cells providing<br />
all vital body functions. Influence <strong>of</strong> melanoma growth on the thyroid gland is poorly<br />
studied. The purpose <strong>of</strong> the study was to determine hormonal changes in the thyroid<br />
gland in dynamics <strong>of</strong> transplantable В16/F10 melanoma growth in male and female<br />
mice.<br />
Methods: The study included male and female С57ВL/6 mice (n = 80) bearing<br />
subcutaneously В16/F10 melanoma. Levels <strong>of</strong> TSH, total T3 and T4 and free FT3 and<br />
FT4 were determined by the radioisotope method in the thyroid gland tissue in weeks<br />
1-4 <strong>of</strong> melanoma growth.<br />
Results: Activation <strong>of</strong> thyroid gland was observed 1 week after melanoma<br />
transplantation: T4 increased by 1.3 times and Т3 and FТ3 by 1.6 times in females, FТ3<br />
and FТ4 by 2.1 and 1.7 times in males. 2.1 times decrease in pituitary TSH was noted<br />
in females only. Gender differences were found 2 weeks after: while T4 level in females<br />
was unchanged, free forms <strong>of</strong> the hormone and total T3 decreased by 1.7-4 times, and<br />
TSH level was still low. In males T4 decreased by 37 times, Т3 by 26.7 times and FТ3<br />
and FТ4 by 1.8 and 1.3 times, respectively, while TSH increased by 1.5 times. T4 and<br />
T3 content in females was normal by the 3 rd -4 th weeks <strong>of</strong> the experiment, while FT4<br />
and FT3 decreased by 4.5 times; TSH level remained 1.4 times lower than the norm.<br />
Males showed decrease in levels <strong>of</strong> both total (by 1.5 times) and free (by 3.3 times)<br />
forms with normal TSH content. Significance <strong>of</strong> the revealed characteristics <strong>of</strong><br />
melanoma development was proved as correction <strong>of</strong> the status in females was possible<br />
using 1,3-diethylbenzimidazole triiodide. As a result, life span increased by 30%,<br />
complete tumor resorption and recovery with preservation <strong>of</strong> reproductive function<br />
were observed in several cases. Pr<strong>of</strong>ound thyroid hyp<strong>of</strong>unction could not be corrected<br />
in males.<br />
Conclusions: Gender differences were revealed in thyroid gland functioning in<br />
dynamics <strong>of</strong> melanoma development which included pr<strong>of</strong>ound thyroid hyp<strong>of</strong>unction<br />
with the loss <strong>of</strong> control by the pituitary gland in males and normal production <strong>of</strong> total<br />
forms with a decrease <strong>of</strong> free forms <strong>of</strong> the hormone in females. These differences can be<br />
taken into account in personalized concomitant treatment.<br />
Legal entity responsible for the study: Rostov Research Institute <strong>of</strong> <strong>Oncology</strong><br />
Funding: Ministry <strong>of</strong> Health <strong>of</strong> the Russian Federation<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
49P<br />
Fused toes homolog (FTS) can be a target for Notch-mediated<br />
cancer stem cell survival in cervical cancer<br />
W-Y. Park 1 , P.D. Subramaniana 1 , J-R. Yu 2<br />
1 Radiation <strong>Oncology</strong>, Chungbuk National University, Cheongju, Republic <strong>of</strong> Korea,<br />
2 Environmental and Tropical Medicine, Konkuk University, Chungju, Republic <strong>of</strong><br />
Korea<br />
Background: Cancer stem-like cells (CSCs) can be a cause <strong>of</strong> resistance to chemo/<br />
radiotherapy. Notch pathway plays a vital role in maintenance <strong>of</strong> cancer stemness and<br />
its activation leads to disease progression and metastasis. FTS gene was initially<br />
identified as one <strong>of</strong> six genes deleted in a mouse mutant called Fused Toes, due to<br />
defects in limb development, and referred as FT1/FTS. However, the function <strong>of</strong> FTS<br />
has not been elucidated well in human. We previously reported that FTS plays an<br />
essential role in nuclear phosphorylation <strong>of</strong> EGFR and repair <strong>of</strong> DNA damage, and<br />
epithelial-mesenchymal transition. In this study, we evaluated the role <strong>of</strong> FTS in Notch<br />
and its downstream proteins.<br />
Methods: Human cervical carcinoma cell lines (ME180, HeLa, SiHa, CasKi) were used.<br />
Spheroids were made from singel cell suspension. Silencing <strong>of</strong> FTS was attained with<br />
siRNA. Western blot analysis was done to measure protein expression.<br />
Immunoprecipitation was done to see the protein interactions. Immun<strong>of</strong>luorescence<br />
was done to see the intracelluar localization <strong>of</strong> the proteins.<br />
Results: Protein expression <strong>of</strong> Notch 1 and Notch 2 was increased by ionizing radiation<br />
(IR) in the four cervical cancer cell lines tested. Also the protein expression <strong>of</strong> cleaved<br />
Notch1 and Hes1 was increased by IR and it was reduced by FTS-silencing.<br />
Imunoprecipation showed FTS bound to Notch1. Expression <strong>of</strong> Notch, γ-secretase<br />
complex and its downstream Hes-1 was increased by IR and it was blocked by<br />
FTS-silencing. Furthermore, spheroid formation ability and cancer stem cell markers<br />
Nanog, Oct-4A, Sox2 were reduced by FTS-silencing.<br />
Conclusions: Notch-mediated stem cell survival is regulated by FTS in cervical cancer<br />
cells. FTS can be a treatment target for Notch-mediated stem cell survival in cervical<br />
cancer.<br />
Legal entity responsible for the study: Woo-Yoon Park<br />
Funding: National Research Foundation <strong>of</strong> Korea<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
50P<br />
abstracts<br />
Functional role <strong>of</strong> 4F2hc in pancreatic ductal adenocarcinoma<br />
D. Bianconi 1 , M. Herac 2 , A. Gleiss 3 , M. Unseld 1 , R. Weigl 1 , M. Schindl 4 ,<br />
W. Scheithauer 1 , C. Zielinski 1 , G. Prager 1<br />
1 Internal Medicine I, <strong>Oncology</strong>, Vienna General Hospital (AKH) - Medizinische<br />
Universität Wien, Vienna, Austria, 2 Klinisches Institut für Pathologie, Vienna General<br />
Hospital (AKH) - Medizinische Universität Wien, Vienna, Austria, 3 Institut für<br />
Klinische Biometrie, CeMSIIS, Vienna General Hospital (AKH) - Medizinische<br />
Universität Wien, Vienna, Austria, 4 Universitätsklinik für Chirurgie, Vienna General<br />
Hospital (AKH) - Medizinische Universität Wien, Vienna, Austria<br />
Background: Pancreatic ductal adenocarcinoma (PDAC) represents one <strong>of</strong> the most<br />
aggressive cancers with limited prognosis. With less than 5 % five-year-overall survival,<br />
the characterization <strong>of</strong> new therapeutic targets is urgently needed. 4F2hc is a cell<br />
surface-antigen overexpressed in some tumor cells and therefore, it represents a<br />
promising novel therapeutic target. In the current study, we investigated the functional<br />
role <strong>of</strong> 4F2hc in PDAC.<br />
Methods: 4F2hc protein expression level was analyzed in human pancreatic cancer<br />
tissue (222 cases) and matched adjacent tissue (141 cases) via immunohistochemistry<br />
(IHC). Additionally, pancreatic cancer cells were isolated from fresh human tumor<br />
tissue and 4F2hc+ cells were phenotypically analyzed via flow cytometry. To<br />
characterize the functional role <strong>of</strong> 4F2hc in PDAC, 4F2hc was downregulated in<br />
pancreatic cancer cell lines by lentiviral transduction and in vitro experiments were<br />
performed.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw362 | vi13
abstracts<br />
Results: Using IHC, we demonstrated that 4F2hc is aberrantly expressed in PDAC and<br />
matched adjacent tissue. However, there was no significant difference in 4F2hc<br />
expression in the different grades and stages. Although Kaplan-Meier survival curves<br />
and Cox analyses did not revealed a significant association between 4F2hc expression<br />
and OS, we observed a trend that suggests an association between absence <strong>of</strong> 4F2hc<br />
expression and prolonged survival. Additionally, our results showed that 4F2hc+ cells<br />
isolated from fresh tumor tissue co-expressed other known markers <strong>of</strong> PDAC such as<br />
MUC4 and MUC1.To determine the role <strong>of</strong> 4F2hc in PDAC, cell behavior between<br />
4F2hc+ cells and 4F2hc low expressing cells was compared. We found that 4F2hc<br />
downregulation significantly inhibited tumorsphere formation and cell proliferation by<br />
arresting cell cycle.<br />
Conclusions: Herein, we demonstrated that 4F2hc is overexpressed in resected tumor<br />
tissue as well as in matched adjacent tissue <strong>of</strong> patients with pancreatic cancer.<br />
Moreover, our data suggests that 4F2hc expression increases tumorigenesis by<br />
enhancing cell proliferation and promoting anchorage-independent growth in vitro.<br />
Although further studies are needed, our results suggest that 4F2hc might be a novel<br />
therapeutic target <strong>of</strong> PDAC.<br />
Legal entity responsible for the study: Medical University <strong>of</strong> Vienna<br />
Funding: Medical University <strong>of</strong> Vienna<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
51P<br />
Marine-derived bioactive compound MB-E5 as a cytotoxic<br />
agent in glioblastoma cell lines<br />
S.Y. Cheng 1 , W-F. Chen 2 , P-J. Sung 3 , Z-H. Wen 4<br />
1 Doctoral Digress Program in Marine Biotechnoogy, National Sun Yat-sen<br />
University, Kaohsiung, Taiwan, 2 Department <strong>of</strong> Neurosurgery, Chang Gung<br />
Memorial Hospital-Kaohsiung, Kaohsiung, Taiwan, 3 Graduate Institute <strong>of</strong> Marine<br />
Biology, National Dong Hwa University, Pingtung, Taiwan, 4 Department <strong>of</strong> Marine<br />
Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung,<br />
Taiwan<br />
Background: Glioblastoma multiforme (GBM) is the most common primary central<br />
nervous system tumor. Even with standard and aggressive treatment strategies the<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
5-year survival rate is less than 30%. Also, previous results reveal that glutathione<br />
S-transferase M3 (GSTM3) is highly expressed in brain tissue and represents the<br />
predominant activity <strong>of</strong> GSTs, a group <strong>of</strong> enzymes that mainly facilitates detoxification,<br />
in the human brain. The compound studied here, ME-E5, is extracted from cultured<br />
Vibrio psychroerythrus, a marine bacterial species.<br />
Methods: In this study, the cytotoxic activity <strong>of</strong> MB-E5 in U87MG and GBM8401<br />
glioblastoma cell lines were investigated using MTT assay and TUNEL assay. Tumor<br />
sphere assay were performed to determine the impact <strong>of</strong> MB-E5 on in vitro neuron<br />
cancer stem cell growth. Immun<strong>of</strong>luorescence assay and western blotting were used to<br />
evaluate the level <strong>of</strong> autophagy-related proteins and the PI3K/Akt pathway. gstm3 gene<br />
expression levels were measured in TMZ-resistant glioblastoma cell line by<br />
semi-quantitative polymerase chain reaction (PCR).<br />
Results: MTT assays show that MB-E5 exhibits higher cytotoxic activity than<br />
Temozolomide (TMZ), a first-line drug in the treatment <strong>of</strong> gliomas, in GBM cell lines.<br />
Neurosphere formation is significantly reduced at low MB-E5 levels. TUNEL assay and<br />
western blot analysis show that MB-E5 induces apoptosis and reduces glioblastoma cell<br />
survival rate by inhibiting the PI3K/AKT/mTOR signaling pathway. Also,<br />
immun<strong>of</strong>luorescence assay and western blotting results indicate that MB-E5 promotes<br />
the expression <strong>of</strong> autophagy marker LC3-II. Furthermore, MB-E5 demonstrates higher<br />
cytotoxicity against TMZ resistant-GBM8401 cells. The results <strong>of</strong> semi-quantitative<br />
PCR indicate a decrease in the expression <strong>of</strong> gstm3 after 3 days <strong>of</strong> 200 µM TMZ<br />
treatment, but the expression level recovers after 15 days <strong>of</strong> continuous TMZ treatment<br />
in the survival population <strong>of</strong> GBM cell lines. Moreover, GSTM3 mRNA expression is<br />
reduced after MB-E5 treatment.<br />
Conclusions: These results suggest that the marine-derived bioactive compound<br />
MB-E5 may be effective as a cancer therapeutic agent in glioblastoma. We also theorize<br />
that MB-E5 may reduce gstm3, which could play a key role in TMZ-resistant<br />
glioblastoma cells.<br />
Legal entity responsible for the study: Doctoral Degree Program in Marine<br />
Biotechnology, National Sun Yat-sen University, Taiwan<br />
Funding: Kaohsiung Chang Gung Memorial Hospital and Chang Gung University<br />
College <strong>of</strong> Medicine, Kaohsiung, Taiwan<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
vi14 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong> 27 (Supplement 6): vi15–vi42, 2016<br />
doi:10.1093/annonc/mdw363<br />
biomarkers<br />
52O<br />
Assessment and comparison <strong>of</strong> tumor mutational burden and<br />
microsatellite instability status in >40,000 cancer genomes<br />
G.M. Frampton 1 , D.A. Fabrizio 1 , Z.R. Chalmers 1 , J.X. Sun 1 , V.A. Miller 2 ,<br />
P.J. Stephens 1<br />
1 Research and Development, Foundation Medicine, Cambridge, MA, USA,<br />
2 Medical Affairs, Foundation Medicine, Cambridge, MA, USA<br />
Methods: Within the AngioPredict project tumor tissue samples from 182 mCRC<br />
patients treated with chemotherapy alone or chemotherapy plus BeV were<br />
retrospectively collected. The overall median progression-free survival (PFS) was 217<br />
days. A second series <strong>of</strong> 103 patients who were treated with chemotherapy and BeV in<br />
the context <strong>of</strong> the CAIRO2 trial were included for validation purposes. Copy number<br />
data, obtained by next generation sequencing (NGS), were analyzed using a routine<br />
pipeline, generating regions called for gains or losses. A log-rank test using 10.000<br />
permutations was performed to calculate the significance <strong>of</strong> DNA copy number<br />
correlations to PFS in each study arm. Then Kaplan-Meijer analysis was performed for<br />
individual candidate regions.<br />
Results: Out <strong>of</strong> 182 patients in the AngioPredict cohort, after quality assurance checks<br />
157 cases remained for downstream analysis. Out <strong>of</strong> these 157 patients, 113 patients<br />
were treated with chemotherapy in combination with BeV and 44 were treated with<br />
chemotherapy alone (non-BeV). Frequency plots for copy number alterations matched<br />
with CRC pr<strong>of</strong>iles known from literature. Log-rank test revealed significant<br />
associations between copy number alterations and PFS in the BeV group (P = 0.002),<br />
but not in the non-BeV group. The predictive value <strong>of</strong> loss at chromosome<br />
18q12.1-18q21.32 was confirmed in the CAIRO2 validation set.<br />
Conclusions: NGS copy number sequencing revealed that loss <strong>of</strong> chromosome<br />
18q12.1-18q21.32 is associated with prolonged PFS in patients treated with<br />
chemotherapy plus BeV and may serve as a candidate biomarker for response to BeV.<br />
Further studies are needed to confirm these results. The AngioPredict project was<br />
funded by the European Commission Framework Programme Seven (FP7) initiative<br />
under contract No. 278981 ‘AngioPredict’ (www. angiopredict.com).<br />
Legal entity responsible for the study: VU University Medical Center<br />
Funding: European Commission Framework Programme Seven (FP7) initiative under<br />
contract No. 278981 ‘AngioPredict’<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
54PD<br />
Multidisciplinary molecular tumour board: a tool to improve<br />
clinical practice and selection accrual for clinical trials in<br />
cancer patients<br />
C.D. Rolfo 1 , A. Machado Coelho 2 , P. Van Dam 3 , A. Dendooven 4 ,C.Weyn 4 ,<br />
M. Rasschaert 2 , L. Van Houten 2 , B.X. Trinh 3 , J. Van Meerbeeck 3 , P. Pauwels 4 ,<br />
M. Peeters 5<br />
1 Phase I - Early Clinical Trials Unit & Center for Oncological Research <strong>of</strong> Antwerp<br />
(CORE), Antwerp University Hospital, Edegem, Belgium, 2 Phase I - Early Clinical<br />
Trials Unit, <strong>Oncology</strong> Department, U.Z.A. University Hospital Antwerp, Edegem,<br />
Belgium, 3 Multidisciplinary <strong>Oncology</strong> Center, U.Z.A. University Hospital Antwerp,<br />
Edegem, Belgium, 4 Molecular Pathology Department, U.Z.A. University Hospital<br />
Antwerp, Edegem, Belgium, 5 Department <strong>of</strong> <strong>Oncology</strong>, U.Z.A. University Hospital<br />
Antwerp, Edegem, Belgium<br />
abstracts<br />
53PD<br />
Copy number alterations as predictive biomarkers for<br />
response to bevacizumab in metastatic colorectal cancer<br />
N.C. van Grieken 1 , M. Cordes 1 , H.M. Verheul 2 , M. Neerincx 2 , C. Punt 3 ,<br />
M. Koopman 4 , G.A. Meijer 5 , V. Murphy 6 , A. Barat 7 , J. Betge 8 , M. Ebert 8 ,<br />
T. Gaiser 9 , B. Fender 10 , R. Klinger 11 , S. Das 12 , D. Smeets 13 ,D.O’Connor 12 ,<br />
D. Lambrechts 13 , A.T. Byrne 7 , B. Ylstra 1<br />
1 Department <strong>of</strong> Pathology, VU University Medical Center, Amsterdam,<br />
Netherlands, 2 Department <strong>of</strong> Medical <strong>Oncology</strong>, VU University Medical Center,<br />
Amsterdam, Netherlands, 3 Medical <strong>Oncology</strong>, Academic Medical Center,<br />
University <strong>of</strong> Amsterdam, Amsterdam, Netherlands, 4 Medical <strong>Oncology</strong>, University<br />
Medical Center Utrecht, Utrecht, Netherlands, 5 Department <strong>of</strong> Pathology, Het<br />
Nederlands Kanker Instituut Antoni van Leeuwenhoek (NKI-AVL), Amsterdam,<br />
Netherlands, 6 Clinical Research, Irish Clinical <strong>Oncology</strong> Research Group ICORG,<br />
Dublin, Ireland, 7 Department <strong>of</strong> Physiology & Medical Physics, Royal College <strong>of</strong><br />
Surgeons in Ireland, Dublin, Ireland, 8 Department <strong>of</strong> Medicine II,<br />
Universitätsklinikum Mannheim, Mannheim, Germany, 9 Institute <strong>of</strong> Pathology,<br />
Universitätsklinikum Mannheim, Mannheim, Germany, 10 Research and<br />
Development Department, OncoMark Limited, Dublin, Ireland, 11 UCD Conway<br />
Institute, University College Dublin, Dublin, Ireland, 12 Department <strong>of</strong> Molecular &<br />
Cellular Therapeutics, Royal College <strong>of</strong> Surgeons in Ireland, Dublin, Ireland,<br />
13 Vesalius Research Center, VIB and KU, Leuven, Belgium<br />
Background: Bevacizumab (BeV) is an angiogenesis inhibitor that is currently used in<br />
patients with metastatic colorectal cancer (mCRC). However, response on treatment is<br />
variable and predictive biomarkers are urgently needed. The aim <strong>of</strong> this study was to<br />
identify copy number alterations that are associated with response to bevacizumab.<br />
Background: Personalized medicine, based on the discovery <strong>of</strong> druggable targets<br />
through Next-Generation Sequencing (NGS) and other molecular pr<strong>of</strong>iling techniques,<br />
is changing the clinical practice in <strong>Oncology</strong>. In this setting, Molecular Tumour Board<br />
(MTB) became a crucial multidisciplinary tool for results interpretation in order to<br />
better select the treatment for our patients, including the inclusion in clinical trials.<br />
Methods: We analysed, retrospectively, a cohort <strong>of</strong> patients with several advanced solid<br />
tumours and no candidate for standard treatment consulted in Phase I – Early Clinical<br />
Trials Unit <strong>of</strong> the Antwerp University Hospital with molecular pr<strong>of</strong>ile (MP) that were<br />
discussed in the MTB. Patients with in house and commercial NGS platforms were<br />
included. A subgroup <strong>of</strong> those patients were analysed also based in immunochemistry<br />
(IHC) and/or in situ hybridization (ISH).<br />
Results: In this study, 141 tissue samples <strong>of</strong> 133 national and international patients<br />
were included. The median age was 59 years old (18 – 85). The majority <strong>of</strong> the patients<br />
were women (56%). A total <strong>of</strong> 75.9% samples (n = 107) had genomic alterations with<br />
an average <strong>of</strong> 3.44 alterations; <strong>of</strong> which 80.4% (n = 86) correspond to gene mutations in<br />
the NGS panel. About 58.1% (n = 50) had more than one mutated gene. TP53 (32%),<br />
KRAS (13%), PIK3CA (8%) and APC (7%) were the more frequent mutated genes. In<br />
the subgroup analysis <strong>of</strong> patients with additional MP information (IHC = X: CISH = 4:<br />
FISH = 6) the more common alterations were: TOPO1 (9%), TOP2A (9%), MGMT<br />
(8%) and PTEN (8%). By primary tumour site, lung (14.9%), colon (12.1%), pancreas<br />
(9.2%) and breast (7.8%) were the most frequent. In 55% (n = 78) <strong>of</strong> the cases MTB<br />
suggested treatment: 70.5% (n = 55) matched therapy and 29.5% (n = 23) non-matched<br />
therapy. Almost 37% (n = 29) were included in clinical trials and 6.4% (n = 5) with<br />
compassionate use.<br />
Conclusions: With Multidisciplinary MTB a considerable number <strong>of</strong> patients with<br />
advanced cancer could be <strong>of</strong>fered targeted therapy or clinical trials based on molecular<br />
pr<strong>of</strong>iling. National programs for reimbursement and access to suitable target drugs and<br />
clinical trials are crucial to guarantee a step forward in cancer treatment.<br />
© European Society for Medical <strong>Oncology</strong> 2016. Published by Oxford University Press on behalf <strong>of</strong> the European Society for Medical <strong>Oncology</strong>.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com.
abstracts<br />
Legal entity responsible for the study: N/A<br />
Funding: Antwerp University Hospital- UZA - <strong>Oncology</strong> Department<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
55PD<br />
Vemurafenib (VM) in non-melanoma V600 and non-V600 BRAF<br />
mutated cancers: first results <strong>of</strong> the ACSE trial<br />
J-Y. Blay 1 , J. Mazieres 2 , D. Perol 3 , F. Barlesi 4 , D. Moro-Sibilot 5 , G. Quere 6 ,<br />
J. Tredaniel 7 , X. Troussard 8 , S. Leboulleux 9 , D. Malka 10 , A. Flechon 1 ,<br />
C. Linassier 11 , I.L. Ray-Coquard 12 , B. Arnulf 13 , I. Bieche 14 , G. Ferretti 15 ,<br />
F. Nowak 16 , M. Jimenez 17 , N. Hoog-Labouret 16 , A. Buzyn 16<br />
1 Medical <strong>Oncology</strong>, Centre Léon Bérard, Lyon, France, 2 Thoracic <strong>Oncology</strong>, CHU<br />
Toulouse, Hôpital de Larrey, Toulouse, France, 3 Direction de la Recherche Clinique<br />
et de l’Innovation, Centre Léon Bérard, Lyon, France, 4 Multidisciplinary <strong>Oncology</strong><br />
& Therapeutic Innovation, Hopital Nord, Marseille, France, 5 Thoracic <strong>Oncology</strong>,<br />
CHU Grenoble - Hopital Michallon, La Tronche, France, 6 ICH, C.H.U. Brest -<br />
Hôpital Morvan, Brest, France, 7 Service de Pneumologie, Hopital St. Joseph,<br />
Paris, France, 8 Service <strong>of</strong> Hematology, CHU de Caen, Caen, France, 9 Nuclear<br />
Medicine and Endocrine <strong>Oncology</strong>, Institut de Cancérologie Gustave Roussy,<br />
Villejuif, France, 10 Digestive <strong>Oncology</strong>, Institut de Cancérologie Gustave Roussy,<br />
Villejuif, France, 11 Medical <strong>Oncology</strong>, CHRU Bretonneau, Tours, France,<br />
12 Medecine, Centre Léon Bérard, Lyon, France, 13 Medical <strong>Oncology</strong>, Hôpital<br />
St. Louis, Paris, France, 14 Pharmacogenomic, Institut Curie, Paris, France,<br />
15 Radiology, CHU Grenoble - Hopital Michallon, La Tronche, France, 16 Research<br />
and Innovation, Institut National du Cancer, Boulogne-Billancourt, France, 17 R&D,<br />
Unicancer, Paris, France<br />
Background: BRAF mutations (mut) are observed in several cancer histotypes at low<br />
frequency (
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Conclusions: RAS and BRAF mutational analysis improved prediction <strong>of</strong> response to<br />
anti-EGFR therapy. Additionally, dPCR with a threshold <strong>of</strong> 1% outperformed the other<br />
platforms in first-line setting.<br />
Legal entity responsible for the study: Spanish Cooperative Group for Digestive<br />
Tumour Therapy<br />
Funding: F. H<strong>of</strong>fmann-La Roche LTD<br />
Disclosure: P. García Alfonso: Advisory role: Roche, Merck, Amgen, San<strong>of</strong>i, Lilly and<br />
Bayer. M. Valladares-Ayerbes: Consultant or advisory role: Amgen. Honoraria: Roche,<br />
Merck, San<strong>of</strong>i. E. Aranda: Advisory role from Amgen, Bayer, Celgene, Merck, Roche<br />
and San<strong>of</strong>i. R. Salazar: Research funding: Roche Pharma, Roche Diagnostics. All other<br />
authors have declared no conflicts <strong>of</strong> interest.<br />
57PD<br />
MHC class II in lung cancer<br />
Y. He 1 , L. Rozeboom 2 , R. Dziadziuszko 3 , C.J. Rivard 2 , K. Ellison 2 ,H.Yu 2 ,<br />
C. Zhou 1 , F. Hirsch 2<br />
1 Medical <strong>Oncology</strong>, Shanghai Pulmonary Hospital, Tongji University, Shanghai,<br />
China, 2 Medical <strong>Oncology</strong>, University <strong>of</strong> Colorado Denver, Denver, CO, USA,<br />
3 <strong>Oncology</strong> and Radiotherapy, Medical University <strong>of</strong> Gdansk, Gdansk, Poland<br />
Background: Immunotherapy is a recent hotspot in lung cancer research. The ability<br />
<strong>of</strong> the immune system to recognize tumor cells as foreign is restricted through the<br />
expression <strong>of</strong> certain cell-surface molecules such as the major histocompatibility<br />
complex (MHC) molecules. The alteration in MHC class II antigens is an event that<br />
occurs frequently on primary and metastatic cancer. Therefore, we described the<br />
expression <strong>of</strong> MHC class II in lung cancer cell lines and patient tissues.<br />
Methods: We studied MHC II (DP, DQ, DR) (CR3/43, Abcam) protein expression in<br />
55 non-small cell lung cancer (NSCLC) cell lines, 42 small cell lung cancer (SCLC) cell<br />
lines and 278 lung cancer patient tissues by immunohistochemistry (IHC).<br />
Results: Seven (12.7%) NSCLC cell lines were positive for MHC class II. No SCLC cell<br />
lines were found to be MHC II positive. MHC class II was detected in 139 lung cancer<br />
samples from the Hirsch Lab. Twenty-one (31.3%) samples stained positive for MHC<br />
class II on tumor cells, and 38 (56.7%) had positive MHC class II expression on tumor<br />
infiltration lymphocytes (TILs) in NSCLC. There was no positive MHC class II staining<br />
on SCLC tumor cells. MHC class II on TILs in SCLC was significant lower than MHC<br />
II on TILs in NSCLC (P < 0.001). MHC class II was detected in 139 NSCLC tumor<br />
tissues from Medical University <strong>of</strong> Gdansk. Forty-two samples (30.2%) stained positive<br />
for MHC class II on tumor cells, and 55 (39.6%) had positive MHC class II expression<br />
on TILs in NSCLC. MHC class II on tumor cells was expressed less in<br />
non-adenocarcinoma compared to adenocarcinoma (P = 0.002). MHC class II on TILs<br />
had higher expression in stage I and II compared to stage III and IV NSCLC<br />
(P = 0.027). High expression <strong>of</strong> MHC class II on tumor cells was correlated with high<br />
expression <strong>of</strong> MHC class II on TILs (P = 0.023). Positive staining <strong>of</strong> MHC class II on<br />
TILs had longer RFS and OS than patients who were MHC class II negative on TILs<br />
(1.05 years 95% CI 0.57-1.55 vs. 2.98 years 95% CI 1.63-4.33, P = 0.028) (1.39 years,<br />
95% CI 0.63-2.15 vs. 3.23 years 95% CI 2.62-3.84, P = 0.014).<br />
Conclusions: MHC class II was expressed in both NSCLC cell lines and tissues.<br />
However, MHC class II was absent in SCLC cell lines and tissue tumor cells. Loss <strong>of</strong><br />
expression <strong>of</strong> MHC II on SCLC tumor cells may be a means <strong>of</strong> escaping anti-cancer<br />
immunity. MHC class II expression on TILs was correlated with good prognosis in<br />
NSCLC patients.<br />
Clinical trial identification: N/A<br />
Legal entity responsible for the study: Yayi He<br />
Funding: This project was supported by IASLC Young Investigator Award, the Pia and<br />
Fred R. Hirsch Endowed Chair at the University <strong>of</strong> Colorado, and Young Program <strong>of</strong><br />
Shanghai Health Bureau.<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
58PD<br />
Th1 epitopes as potential biomarkers for ipilimumab<br />
treatment<br />
J.P. Marquez 1 , E. Ramos 2 , D.R. Herendeen 2 , K. Quayle 2 , M.L. Verburg 2 ,<br />
A. Suplee-Rivera 2 , S. Carrillo 2 , J.A. Matute-Briseno 2 , R. Soto-Soto 2 ,<br />
A. Camacho-Hernandez 2 , P.A. Lucero-Diaz 2<br />
1 <strong>Oncology</strong>, Tumor Vaccine Group University <strong>of</strong> Washington, Seattle, WA, USA,<br />
2 Immuno-<strong>Oncology</strong>, Centro De Investigacion Del Cancer En Sonora, Sonora,<br />
Mexico<br />
Background: Ipilimumab may unleash T cells in many tumors and effectively be<br />
combined with multi-antigen vaccines. The unleashed T cells could be detrimental if<br />
they are the wrong phenotype such as Th2. Th1 peptides from 4 proteins associated<br />
with bad prognosis were designed to assess the IFN-gamma production in presence<br />
and absence <strong>of</strong> ipilimumab. Then we prepared a pilot protocol with low dose <strong>of</strong><br />
ipilimumab to treat patients suffering from several malignancies. We found that<br />
patients with pre-existing Th1 immune response from four overexpressed proteins had<br />
better clinical outcomes after treatment.<br />
Methods: Naïve patients stage IV (n = 39) including ovarian (n = 10), triple negative<br />
breast cancer (TNBC; n = 8), multiple myeloma (MM; n = 5), colorectal (CRC; n = 10)<br />
and pancreatic cancer (n = 6) patients were studied. IFN-gamma and IL-10 ELISPOT<br />
assay was performed using 13 Th1 epitopes. Patients with predominant either Th1<br />
(n = 11) and Th2 (n = 28) response were grouped and treated with 25-50 mg <strong>of</strong> total<br />
ipilimumab weekly for three weeks before starting standard <strong>of</strong> care treatment. Th1<br />
epitopes from EGFR (4), Bcl-2 (3), Survivin (3) and Sox2 (3) were used for ELISPOT<br />
studies.<br />
Results: Th1 peptide-specific immune responses against at least one Th1 epitope <strong>of</strong><br />
each protein had better clinical responses with ipilimumab treatment in comparison<br />
with the Th2 patients (p = 0.001). Th1 responders pre-treated with ipilimumab before<br />
standard <strong>of</strong> care treatment had overall survival (OS) <strong>of</strong> 2 yrs for ovarian, 2.3 years for<br />
CRC, 1.8 years for MM, 2.6 years for TNBC and 8 months for pancreatic cancer. The<br />
Th2 responders had OS <strong>of</strong> less than 6 months in average.<br />
Conclusions: Patients with pre-existing Th1 response had a better prognosis and better<br />
overall survival in comparison with Th2. This could explain why pseudoprogressions<br />
seen in patients treated with checkpoint inhibitors could be in fact progression disease<br />
due to the unleash <strong>of</strong> Th2 cells, which are associated in the majority <strong>of</strong> the tumors with<br />
bad prognosis and tumor progression. Antigen-specific immune response against Th1<br />
epitopes from four bad prognosis proteins may serve as biomarker to treat multiple<br />
tumors with ipilimumab.<br />
Legal entity responsible for the study: Centro De Investigacion Del Cancer En Sonora<br />
Funding: Centro De Investigacion Del Cancer En Sonora<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
59P<br />
abstracts<br />
Genomic alterations in circulating tumor DNA (ctDNA) are<br />
associated with clinical outcomes in treatment-naive<br />
metastatic castration-resistant prostate cancer (mCRPC)<br />
patients commencing androgen receptor (AR)-targeted therapy<br />
A.W. Wyatt 1 , M. Annala 2 , K. Beja 1 , S. Parimi 3 , G. Vandekerkhove 1 , E. Warner 1 ,<br />
M. Zulfiqar 4 , D. Finch 5 , C. Oja 6 , J. Vergidis 7 , M. Nykter 2 , M.E. Gleave 1 , K. Chi 3<br />
1 Vancouver Prostate Centre, University <strong>of</strong> British Columbia, Vancouver, BC,<br />
Canada, 2 Institute <strong>of</strong> Biosciences and Medical Technology, University <strong>of</strong> Tampere,<br />
Tampere, Finland, 3 Medical <strong>Oncology</strong>, British Columbia Cancer Agency,<br />
Vancouver, BC, Canada, 4 Abbotsford Centre, British Columbia Cancer Agency,<br />
Abbotsford, BC, Canada, 5 Centre for the Southern Interior, British Columbia<br />
Cancer Agency, Kelowna, BC, Canada, 6 Fraser Valley Cancer Centre, British<br />
Columbia Cancer Agency, Surrey, BC, Canada, 7 Vancouver Island Centre, British<br />
Columbia Cancer Agency, Victoria, BC, Canada<br />
Background: There are no established genomic biomarkers to predict response to the<br />
AR-targeted therapies enzalutamide and abiraterone, partly due to the impracticality <strong>of</strong><br />
sampling tissue in a bone-predominant metastatic disease. Cell-free DNA (cfDNA) is a<br />
promising “liquid biopsy” approach to genomic characterization <strong>of</strong> mCRPC.<br />
Methods: We performed deep targeted sequencing <strong>of</strong> 72 mCRPC-related genes in<br />
baseline cfDNA from 62 chemotherapy-naïve mCRPC patients enrolled in an ongoing<br />
randomized phase II trial <strong>of</strong> abiraterone vs enzalutamide (NCT02125357). Genomic<br />
alterations in cfDNA were examined for association with clinical variables including<br />
time on treatment.<br />
Results: Evidence for ctDNA was detected in 38 <strong>of</strong> 62 (61.3%) cfDNA samples at<br />
baseline with 27 samples harbouring ≥1 mutation(s) with an allele fraction above 1%,<br />
and 28 samples containing copy number alterations affecting at ≥2 genes. Patients with<br />
confirmed ctDNA displayed a trend towards higher cfDNA yield (p = 0.07), higher<br />
baseline PSA (p = 0.14), and shorter time on treatment (p = 0.12). AR amplification<br />
was found in 17 patients and associated with shorter time on treatment (median 200 vs<br />
420 days, p = 3.5 x 10 −4 ). AR mutations were found in 6 patients, exhibited mutual<br />
exclusivity with amplifications, and correlated with prior non-steroidal anti-androgen<br />
therapy. TP53 and BRCA2 inactivating alterations were detected in 17 and 9 patients<br />
respectively and were associated with shorter time on treatment (median 236 vs 420<br />
days, p = 1.1 x 10 −4 ; median 120 vs 342 days, p = 5.6 x 10 −5 , respectively). The<br />
associations for AR, TP53 and BRCA2 remained significant after adjusting for patient<br />
age, baseline PSA and ctDNA presence (p < 0.005).<br />
Conclusions: In this preliminary analysis, the majority <strong>of</strong> patients with<br />
treatment-naïve mCRPC had detectable ctDNA and the presence <strong>of</strong> certain genomic<br />
aberrations was associated with shorter duration <strong>of</strong> therapy with abiraterone or<br />
enzalutamide. CtDNA holds great potential as a minimally-invasive biomarker to<br />
identify chemotherapy-naïve mCRPC patients that have poor therapeutic outcomes.<br />
Clinical trial identification: NCT02125357<br />
Legal entity responsible for the study: Dr. Alexander Wyatt and Dr. Kim Chi<br />
Funding: Research grants from the Canadian Cancer Society and Prostate Cancer<br />
Canada; Academic support from the BC Cancer Foundation and the Vancouver<br />
Prostate Centre (UBC); Industry grants from Janssen and Astellas.<br />
Disclosure: S. Parimi: Honoraria from Astellas for a journal club presentation<br />
(February 2016) and an advertisement board sponsored by Janssen (April<br />
2016). D. Finch: Has received honoraria for participation on an ad boards for Janssen<br />
and Astellas. Was a PI on the enzalutamide Affirm clinical trial. J. Vergidis: Has<br />
received honoraria from Astellas and am a member <strong>of</strong> an advisory board also for<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw363 | vi17
abstracts<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Astellas. K. Chi: Has received honorarium and research funding from Janssen and<br />
Astellas. All other authors have declared no conflicts <strong>of</strong> interest.<br />
61P<br />
Frequency and abundance <strong>of</strong> plasma T790M mutation<br />
associated with failure patterns <strong>of</strong> EGFR-mutant NSCLC<br />
treated with tyrosine kinase inhibitors<br />
60P<br />
Circulating free tumour-derived DNA (ctDNA) to detect EGFR<br />
mutation in patients (pts) with advanced NSCLC (aNSCLC):<br />
French subset analysis <strong>of</strong> the ASSESS study<br />
M.G. Denis 1 , M.P. Lafourcade 2 , G. Le Garff 3 , C. Dayen 4 , L. Falchero 5 , P. Thomas 6 ,<br />
C. Locher 7 , G. Fraboulet 8 , G. Oliviero 9 , M. Licour 10 , N. Normanno 11 , M. Reck 12 ,<br />
O. Molinier 13<br />
1 Department <strong>of</strong> Biochemistry, CHU de Nantes, Nantes, France, 2 Department <strong>of</strong><br />
Pneumology, CH d’Angoulême, Angouleme, France, 3 Department <strong>of</strong><br />
Pneumology, Hopital Yves Le Foll, St. Brieuc, France, 4 Department <strong>of</strong><br />
Pneumology, Centre Hospitalier St. Quentin, St Quentin, France, 5 Pneumologie et<br />
Cancérologie Thoracique, CH Villefranche-Sur-Saône, Villefranche-sur-Saône<br />
Cedex, France, 6 Department <strong>of</strong> Pneumology, CHI Alpes du Sud - Site de Gap,<br />
Gap, France, 7 Department <strong>of</strong> Pneumology, Centre Hospitalier Général Meaux,<br />
Meaux, France, 8 Department <strong>of</strong> <strong>Oncology</strong>, Hopital René Dubos, Pontoise, France,<br />
9 Department <strong>of</strong> Pneumology, CH de Longjumeau, Longjumeau, France,<br />
10 Department <strong>of</strong> Epidemiology and Biometry, AstraZeneca, Courbevoie, France,<br />
11 Cell Biology and Biotherapy Unit, Istituto Nazionale Tumori – I.R.C.C.S -<br />
Fondazione Pascale, Naples, Italy, 12 Department <strong>of</strong> Thoracic <strong>Oncology</strong>,<br />
LungenClinic Grosshansdorf GmbH, Grosshansdorf, Germany, 13 Centre de<br />
Coordination en Cancérologie, Centre Hospitalier Du Mans, Le Mans, France<br />
Background: ASSESS (non-interventional diagnostic study NCT01785888) assessed<br />
the concordance <strong>of</strong> EGFR mutation status in tumour samples and plasma ctDNA in<br />
pts with aNSCLC in Europe and Japan. Subset data for pts from France are presented.<br />
Methods: Pts: stage IIIA/B/IV chemo-/TKI-naïve NSCLC. Primary endpoint: EGFR<br />
mutation status concordance between matched plasma and tumour samples. Tumour<br />
testing was performed locally as per local practice; plasma testing was centralised.<br />
ctDNA was extracted using the PureLink Virus Kit on an iPrep Purification Instrument<br />
(Life Technologies) and EGFR mutations detected via the approved Therascreen EGFR<br />
RGQ kit (Qiagen).<br />
Results: Of 1311 enrolled pts, 145 were from France (mean age 64 years, 64% male,<br />
83% ever-smokers). Most samples were collected from primary tumours (81%);<br />
collection was mostly via bronchoscopy (38%) and image-guided core biopsy (19%). Of<br />
130 pts with available tissue, 126 were evaluable for EGFR; activating mutations were<br />
found in 13 (EGFR mutation frequency 10%). 10 pts tested positive for EGFR<br />
mutations in plasma (EGFR mutation frequency 7%). Mutation rate was significantly<br />
higher in never- vs ever-smokers (stepwise logistic regression: tumour p < 0.0001;<br />
plasma p = 0.0008). Mutation status concordance could be determined for 126 (95.2%)<br />
pts. Sensitivity <strong>of</strong> plasma testing was 61.5%. Of the 113 pts EGFR mutation-negative in<br />
tissue, one tested plasma-positive; reanalysis via 2 different techniques confirmed the<br />
presence <strong>of</strong> L858R, indicating a tissue false-negative result, and not a plasma<br />
false-positive. Sensitivity was thus adjusted to 64.3% (9/14) and specificity to 100%<br />
(112/112). One pt with a non-contributive tissue test (bone metastasis) was<br />
plasma-positive.<br />
Conclusions: These real-world data confirm ctDNA as a powerful alternative sample<br />
for EGFR mutation analysis in aNSCLC.<br />
Table: 60P Matched tissue/cytology samples (N = 126)<br />
Unadjusted parameters n/N % Exact 95% confidence interval<br />
Concordance 120/126 95.2 89.9, 98.2<br />
Sensitivity 8/13 61.5 31.6, 86.1<br />
Specificity 112/113 99.1 95.2, 100.0<br />
Positive-predictive value 8/9 88.9 51.8, 99.7<br />
Negative-predictive value 112/117 95.7 90.3, 98.6<br />
Clinical trial identification: NCT01785888<br />
Legal entity responsible for the study: AstraZeneca<br />
Funding: AstraZeneca<br />
Disclosure: M.G. Denis: Grants/Research support/consultant: AstraZeneca, Qiagen,<br />
Roche Pharma, and Boehringer Ingelheim. G. Le Garff: Clin. Trial: Lilly, Roche,<br />
AstraZeneca. All financial contributions except MUTACT study (AZ) paid by clinical<br />
research unit. Board: Novartis. Inv. to Congress: AZ (
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
acquired resistance to EGFR TKIs, all <strong>of</strong> them had activating EGFR mutations in liquid<br />
biopsies (31 L858R, 22 bp deletions in exon 19, 1 G719X; 39 women, 15 males)<br />
Results: Using the iPlex assay, we have identified 36% (18/54) <strong>of</strong> T790M. Using<br />
UltraSEEK on the same cfDNA samples 50% (27/54) were positive for T790M,<br />
increasing by 33% the detection <strong>of</strong> somatic EGFR T790M in cfDNA samples.<br />
Conclusions: The MassARRAY System with UltraSEEK detects 50% T790M in cfDNA<br />
samples concomitantly with EGFR activating mutations in patients whose tumors had<br />
developed resistance to EGFR TKIs and could benefit from Osimertinib.<br />
Legal entity responsible for the study: APHP, Oncogenetics and Biochemistry<br />
department Hop Paul Brousse Villejuif<br />
Funding: APHP, Oncogenetics and Biochemistry department Hop Paul Brousse<br />
Villejuif<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
63P<br />
Liquid biopsy testing in routine clinical management <strong>of</strong><br />
advanced non-small cell lung cancer: clinical validation in a<br />
single biopathology laboratory<br />
A.T. Falk 1 , M. Ilié 2 , E. Long 2 , V. Tanga 2 , V. Lespinet 2 , O. Bordone 2 , M. Allegra 2 ,<br />
C. Ribeyre 2 , J. Otto 3 , M. Poudenx 3 , C-H. Marquette 4 , V. H<strong>of</strong>man 2 , P. H<strong>of</strong>man 2<br />
1 Radiation Therapy, Centre Antoine Lacassagne, Nice, France, 2 Laboratory <strong>of</strong><br />
Clinical and Experimental Pathology / Liquid Biopsy Laboratory, Pasteur Hospital,<br />
Nice, France, 3 Medical <strong>Oncology</strong>, Centre Antoine Lacassagne, Nice, France,<br />
4 Pneumology, Pasteur Hospital, Nice, France<br />
Background: Molecular pr<strong>of</strong>iling <strong>of</strong> cell-free circulating tumor DNA (ctDNA) in<br />
patients with advanced NSCLC has become a powerful diagnostic approach for<br />
targeted therapy selection and monitoring response. We carried out clinical validation<br />
<strong>of</strong> ctDNA testing as liquid biopsy in patients with advanced NSCLC in<br />
ISO15189-accredited biopathology laboratory.<br />
Methods: We performed (i) pre-analytic and analytic validation in comparison with<br />
tumor tissue from 270 NSCLC patients; (ii) real-time evaluation <strong>of</strong> ctDNA analysis for<br />
EGFR mutations before anti-EGFR therapy in 16 patients, and (iii) the study <strong>of</strong><br />
resistance mutations in 34 refractory patients under treatment. For blood collection,<br />
EDTA and Cell-Free DNA BCT tubes (Streck) were used. ctDNA was extracted from<br />
plasma using the QIAamp Circulating Nucleic Acid Kit (Qiagen). ctDNA mutation<br />
status was assessed using (i) the Therascreen EGFR RGQ PCR kit (Qiagen), and (ii)<br />
NGS assay interrogating >1800 mutation hotspots in 22 cancer-associated genes using<br />
the Oncomine Solid Tumor DNA panel and Ion PGM sequencer (ThermoFisher).<br />
Results: The analytic validation demonstrated 70% sensitivity and 98% specificity for<br />
the EGFR RGQ kit with limit-<strong>of</strong>-detection »5%. 43% <strong>of</strong> samples were found mutant by<br />
tumor tissue analysis while 57% were found mutant by ctDNA NGS analysis, with<br />
limit-<strong>of</strong>-detection »1%. ctDNA yield was not affected by storage in Streck BCT tubes<br />
for up to 3 days. Real-time longitudinal ctDNA analysis showed that among 18% <strong>of</strong><br />
initially EGFR mutated patients, 33% acquire T790M resistance mutation during<br />
treatment. 74% <strong>of</strong> patients had at least one somatic alteration detected by NGS assay,<br />
with druggable alterations in various genes (e.g. MET, FGFR3). Mean turnaround time<br />
was 13 [4-22] days for tumor tissue and 6 [1-11] days for ctDNA analyses. Mean<br />
turnaround time was 12.5 [4-23] days for tumor tissue and 4.68 [1-15] days for EGFR<br />
ctDNA analysis.<br />
Conclusions: When tissue biopsy is contra-indicated or <strong>of</strong> insufficient quantity,<br />
rigorously validated ctDNA assays is an alternative approach for tumor tissue<br />
molecular analysis and may enable longitudinal examination <strong>of</strong> molecular pr<strong>of</strong>iling in<br />
advanced NSCLC patients.<br />
Legal entity responsible for the study: CHU Nice, France<br />
Funding: CHU Nice, France<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
64P<br />
Circulating cell-free DNA can predict relapse after resection <strong>of</strong><br />
metastatic liver tumors from colorectal cancer<br />
T. Iwai 1 , T. Yamada 1 , G. Takahashi 1 , S. Matsumoto 2 , M. Koizumi 1 , S. Shinji 1 ,<br />
A. Matsuda 2 , Y. Yokoyama 1 , K. Hara 1 , K. Takeda 1 , M. Nakayama 3 , S. Kitano 3 ,<br />
K. Ohta 1 , E. Uchida 1<br />
1 Surgery, Nippon Medical School Main Hospital, Tokyo, Japan, 2 Surgery, Nippon<br />
Medical School Chiba-sokusou Hospital, Chiba, Japan, 3 Toppan Technical<br />
Institute, Toppan Printing Co. Ltd, Saitama, Japan<br />
known to reflect the degree <strong>of</strong> physical damage. We thus developed a new biomarker,<br />
ccfDNA long fragment/β-globin Ratio (cLBR), which is calculated by LINE-1 297-bp/<br />
β-globin. In this study, we evaluate the clinical use <strong>of</strong> cLBR for prediction <strong>of</strong> early<br />
relapse after resection <strong>of</strong> metastatic liver tumors from CRC.<br />
Methods: We enrolled 29 patients who had undergone resections <strong>of</strong> metastatic liver<br />
tumors from primary CRC. Peripheral blood was collected before and 1-month after<br />
surgery. We extracted ccfDNA from 1 mL plasma using the QIAamp Circulating<br />
Nucleic Acid Kit (Qiagen). We measured LINE-1 297-bp and β-globin in ccfDNA<br />
using real time PCR, and calculated cLBR. Additionally, in patients with KRAS<br />
mutations, we measured ccfDNA KRAS copy number using digital PCR. The Ethics<br />
Review Committee <strong>of</strong> our institution approved the study, and each patient provided<br />
written informed consent.<br />
Results: Of the 29 patients, we completed 1-year follow-up for 18 patients. Of these 18,<br />
relapse was detected in 8 and no signs <strong>of</strong> relapse were detected in the other 10. In all 8<br />
patients which relapse was detected, cLBR 1-month after surgery increased. Conversely<br />
in the 10 patients without relapse, cLBR 1-month after surgery decreased. On the other<br />
hand, in patients with KRAS mutation, the change in KRAS mutation copy number<br />
did not associate with relapse.<br />
Conclusions: cLBR can be a useful predictor <strong>of</strong> early relapse in patients after resection<br />
<strong>of</strong> metastatic liver tumors.<br />
Legal entity responsible for the study: Nippon Medical School<br />
Funding: Research funding <strong>of</strong> Department <strong>of</strong> Digestive Surgery, Nippon Medical<br />
School<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
65P<br />
abstracts<br />
Correlation <strong>of</strong> circulating tumor cells with myeloid-derived<br />
suppressive cells in the peripheral blood <strong>of</strong> patients with<br />
advanced small cell lung cancer<br />
I. Messaritakis, A. Koutoulaki, D. Aggouraki, E.K. Vetsika, E. Politaki, S. Apostolaki,<br />
V. Georgoulias, A. Kotsakis<br />
Laboratory <strong>of</strong> Translational <strong>Oncology</strong>, School <strong>of</strong> Medicine, University <strong>of</strong> Crete,<br />
Heraklion, Greece<br />
Background: The accumulation <strong>of</strong> Myeloid-derived Suppressor Cells (MDSCs) and the<br />
Circulating Tumor Cells (CTCs) have been proposed as negative prognostic biomarkers<br />
in several tumors, including SCLC. However, no studies have shown a correlation <strong>of</strong><br />
the MDSCs with CTCs in SCLC patients. We aimed to investigate the clinical relevance<br />
<strong>of</strong> CTCs and MDSCs in progressing patients with advanced SCLC.<br />
Methods: Peripheral blood was obtained from 32 SCLC patients at the time <strong>of</strong><br />
progression after 1 st line chemotherapy and 31 healthy controls (HC). Immune cells<br />
were determined using flow cytometry and CTCs were detected using both the<br />
CellSearch System (CS) and immun<strong>of</strong>luorescence double staining <strong>of</strong> PBMCs with<br />
anti-TTF1 and/or anti-CD56 and anti-CD45 antibodies (IF). The median percentage<br />
<strong>of</strong> patients MDSCs at baseline was used to characterize MDSCs as high or low. For the<br />
CTCs detection using the CS and IF, the cut-<strong>of</strong>f values were ≥5 and ≥1 CTCs,<br />
respectively.<br />
Results: The percentage <strong>of</strong> naïve CD4 + T cells was decreased in patients vs NC at<br />
baseline. The whole population <strong>of</strong> MDSCs (CD33 + Lin − HLA-DR −/low ), as well as the<br />
granulocytic (G)-(CD15 + CD14 − CD33 + CD11b + ) and the monocytic (M)-MDSCs<br />
(CD14 + CD15 + CD33 + CD11b + Lin − HLA-DR −/low ) were significantly increased in<br />
patients (p < 0.0001). Only M-MDSCs levels were significantly correlated with TTF1 +<br />
(p
abstracts<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
66P<br />
The development <strong>of</strong> a narrow target gene panel makes next<br />
generation sequencing effective for circulating free DNA<br />
analysis<br />
U. Malapelle 1 ,C.Mayo 2 , D. Rocco 3 , M. Garzon 2 , P. Pisapia 1 , R. Sgariglia 1 ,C.De<br />
Luca 1 , N.J. Ariza 2 ,F.Pepe 1 , D.M. Espinosa 4 , A.M. Bueno 4 , M. González-Cao 4 ,<br />
N. Karachaliou 4 , S. Viteri 4 , M.A. Molina Vila 2 , R. Rosell 4 , G. Troncone 1<br />
1 Public Health, Azienda Ospedaliera Universitaria Policlinico Federico II-AOU<br />
Federico II, Naples, Italy, 2 Laboratory <strong>of</strong> Cellular and Molecular Biology, Pangaea<br />
Biotech SL, IOR Quirón-Dexeus University Institute, Barcelona, Spain, 3 <strong>Oncology</strong>,<br />
Azienda Ospedaliera Dei Colli-Monaldi, Naples, Italy, 4 Medical <strong>Oncology</strong> Service,<br />
Instituto Oncológico Dr Rosell (IOR), Hospital Universitario Quirón-Dexeus,<br />
Barcelona, Spain<br />
Background: Since tissue is not always available, biomarkers testing, can be performed<br />
on circulating free DNA (cfDNA). Compared to real time PCR, next-generation<br />
sequencing (NGS), covers also less common and novel variants. To increase sensitivity<br />
NGS can be narrowed to target a limited number <strong>of</strong> actionable genes. This strategy,<br />
known as ultra-deep sequencing, requires a careful validation. Here we validated a<br />
narrowed gene panel to produce a DNA library covering 568 actionable mutations in<br />
six gene (EGFR, KRAS, NRAS, BRAF, cKIT and PDGFRα) involved in non small cell<br />
lung cancer, gastrointestinal stromal tumor, metastatic colo rectal carcinoma and<br />
melanoma (SiRe).<br />
Methods: This study had a retrospective and prospective design. After in – vitro studies on<br />
cell lines aimed to assess the assay analytical performance, cfDNA from a retrospective<br />
series <strong>of</strong> cases including, lung (n = 51) and colon (n = 3) neoplasms and melanoma (n = 9)<br />
previously well characterized on both tissue and matched cfDNA was employed to validate<br />
the SiRe panel; then, blood samples prospectically collected from NSCLC patients (n = 87)<br />
were tested to assess this panel performance in daily clinical practice.<br />
Results: On cell lines, the SiRe had high intra – and inter – run reproducibility with<br />
0.2% lower limit <strong>of</strong> mutation detection. In the retrospective series <strong>of</strong> cfDNA, a total <strong>of</strong> 54<br />
mutations were detected by SiRe showing 100% specificity, confirming 39 EGFR, 9<br />
KRAS, 1 NRAS, 5 BRAF mutations previously detected on matched tissue. Noteworthy,<br />
in 4 cases SiRe detected mutations that had been missed on cfDNA by real time PCR. On<br />
prospectically collected cfDNA, SiRe detected in 4/46 patients, without baseline tissue<br />
availability, activating EGFR mutation; at the time <strong>of</strong> tumor progression following the<br />
treatment with gefitinib, erlotinib and afatinib SiRe detected T790M in 30% (9/30). On<br />
the overall, the SiRe panel showed a sensibility <strong>of</strong> 93.4% and specificity <strong>of</strong> 100%.<br />
Conclusions: The SiRe panel is an effective tool enabling a cost - effective<br />
implementation <strong>of</strong> NGS for cfDNA mutational pr<strong>of</strong>iling in molecular pathology<br />
practice<br />
Legal entity responsible for the study: University <strong>of</strong> Naples Federico II, Department<br />
<strong>of</strong> Public Health<br />
Funding: University <strong>of</strong> Naples Federico II, Department <strong>of</strong> Public Health.<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
68P<br />
Comparison <strong>of</strong> methods for circulating cell-free DNA isolation<br />
using blood from cancer patients. Impact on biomarker testing<br />
A. Romero, I. Nieto-Alcolado, C. Jiménez-Sánchez, V. Calvo de Juan, L. Gutierrez,<br />
M. Palka Kotlowska, M. Provencio, M. Torrente<br />
Medical <strong>Oncology</strong>, Hospital Universitario Puerta de Hierro Majadahond,<br />
Majadahonda, Spain<br />
Background: The implementation <strong>of</strong> liquid biopsy for biomarker testing and response<br />
to treatment monitoring requires the development <strong>of</strong> automated methods for<br />
circulating free DNA (cfDNA) isolation. Nevertheless, the extraction stage is critical to<br />
ensure reliable results.<br />
Methods: The present study compares the MagNA Pure Compact Nucleic Acid<br />
Isolation (MPC) Kit I and Maxwell® RSC ccfDNA Plasma Kit (MR) and the later with<br />
QIAamp Circulating Nucleid Acid (QCNA) kit using 57 serum samples from cancer<br />
patients treated at the Medical <strong>Oncology</strong> Department at Puerta de Hierro Teaching<br />
Hospital in Madrid, Spain.<br />
Results: Firstly, we observed that MPC method significantly extracted less cfDNA than<br />
MR (P < 0.0001). However, there were no significant differences in extraction yields <strong>of</strong><br />
QCNA and MR kits. cfDNA isolation yield was also associated with tumor stage but<br />
not with tumor location. Secondly, an oligonucleosomal DNA ladder pattern was<br />
observed in 88% <strong>of</strong> the samples and significant differences in the recovery <strong>of</strong> mono, diand<br />
trinucleosomes DNA fragments were observed between MPC and MR<br />
methodologies. Finally, tumor mutation quantification on cfDNA was performed on 38<br />
paired samples using digital PCR. Mutant allele fractions between paired samples were<br />
not significantly different.<br />
Conclusions: Methods for isolation <strong>of</strong> cfDNA can affect DNA yield and molecular<br />
weight fractions recovery. These observations should be taken into account for cfDNA<br />
analysis in routine clinical practice in cancer patients.<br />
Legal entity responsible for the study: Hospital Puerta de Hierro Mjadahonda<br />
Funding: Instituto de Salud Carlos III<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
69P<br />
External quality assessment <strong>of</strong> EGFR testing in circulating DNA:<br />
a french pilot study<br />
M.G. Denis 1 , I. Rouquette 2 , A. Morel 3 , C. Villalva 4 , A. Lespagnol 5 , C. Caumont 6 ,<br />
P. Gueguen 7 , K. Durand 8 , C. Collin 9<br />
1 Biochemistry, CHU de Nantes, Nantes, France, 2 Pathology, Institut Universitaire<br />
du Cancer -Toulouse- Oncopole, Toulouse, France, 3 Oncopharmacologie, Centre<br />
Paul Papin, Angers, France, 4 Oncologie Biologique, CHU Poitiers, Jean Bernard<br />
Hôpital, Poitiers, France, 5 Genetique, CHU de Pontchaillou, Rennes, France,<br />
6 Biologie des Tumeurs, CHU Hôpital Haut-Lévêque, Bordeaux, France,<br />
7 Génétique, C.H.U. Brest - Hôpital Morvan, Brest, France, 8 Centre Recherche<br />
Biologie, CHU Hôpital Haut-Lévêque, Limoges, France, 9 Biochimie, CHU Hôpital<br />
Trousseau, Tours, France<br />
Background: Tissue testing for NSCLC patients is routinely performed in France in the<br />
regional platforms certified by the French National Cancer Institute (INCa). All<br />
laboratories participate in an annual EQA scheme for tissue testing, but there is no<br />
EQA for circulating tumor DNA testing. Therefore, we set up a pilot study to assess<br />
quality testing in western France.<br />
Methods: Artificial samples were prepared by supplementing normal plasma<br />
(Clinisciences) with DNA extracted from control FFPE sections (Horizon Diagnostics)<br />
or plasma from NSCLC patients. Aliquots (2 ml) <strong>of</strong> 8 different samples were sent in<br />
dry ice. DNA extraction and EGFR testing (exon 19 deletions, L858R, G719X and<br />
T790M mutations) were performed according to local practice. Data were collected and<br />
compared to the expected results.<br />
Results: We collected 10 complete sets <strong>of</strong> data from 9 labs. DNA was extracted from 1<br />
ml (n = 4) or 2ml (n = 6) using the QIAmp circulating DNA kit (Qiagen; n = 3), the<br />
Maxwell system (Promega; n = 4) or the cfDNA sample prep (Roche; n = 3). Mutation<br />
testing was performed by NGS (n = 3), using the COBAS EGFRv2 (Roche; n = 3) or the<br />
Therascreen EGFR RGQ kit (Qiagen; n = 2), using droplet digital PCR (BioRad; n = 1)<br />
or pyrosequencing (Qiagen; n = 1). A single false positive result was observed (T790M<br />
detected by NGS). The sensitivity (number <strong>of</strong> mutations detected / number <strong>of</strong><br />
mutations present in the set <strong>of</strong> samples) and the number <strong>of</strong> correct genotypes are<br />
presented on the table. This pilot study suggested that, under the specific conditions <strong>of</strong><br />
this scheme, the COBAS kit was the most sensitive approach.<br />
Table: 69P<br />
Lab N° Sensitivity Correct genotypes<br />
NGS 3 66.7% (6/9) 62.5% (5/8)<br />
5 66.7% (6/9) 62.5% (5/8)<br />
7 77.8%(7/9) 62.5% (5/8)<br />
COBAS EGFR v2 1 88.9% (8/9) 87.5% (7/8)<br />
2 88.9% (8/9) 87.5% (7/8)<br />
6 88.9% (8/9) 87.5% (7/8)<br />
Therascreen RGQ v2 1 66.7% (6/9) 62.5% (5/8)<br />
8 55.6% (5/9) 50.0% (4/8)<br />
ddPCR 4 55.6% (5/9) 62.5% (5/8)<br />
Pyrosequencing 9 22.2% (2/9) 25.0% (4/8)<br />
Conclusions: This pilot EQA allowed each lab to evaluate its practice and could be<br />
used to improve their process. These information will be important for labs that have<br />
not yet decided which technique to use for ctDNA testing. Samples were relatively<br />
simple to prepare and it will be easy to scale-up this process. A similar approach using<br />
other genes (BRAF, KRAS and NRAS) will also be developed. Supported by a grant<br />
from Astra Zeneca.<br />
Legal entity responsible for the study: N/A<br />
Funding: Astra Zeneca<br />
Disclosure: M.G. Denis: Advisory board Qiagen. All other authors have declared no<br />
conflicts <strong>of</strong> interest.<br />
70P<br />
Diagnostic performance <strong>of</strong> liquid biopsy for pancreatic solid<br />
lesion as alternative to endoscopic ultrasound-guided fine<br />
needle aspiration (EUS-FNA)<br />
D. Sefrioui 1 , F. Blanchard 2 , P. Basile 1 , E. Toure 2 , C. Dolfus 2 , L. Beaussire 3 ,<br />
N. Vasseur 3 , A. Perdrix 4 , A. Gangl<strong>of</strong>f 1 , L. Schwarz 5 , F. Clatot 4 , J-J. Tuech 5 ,<br />
J-C. Sabourin 2 , T. Frebourg 6 , P. Michel 1 , F. Di Fiore 4<br />
1 Department <strong>of</strong> Hepato-Gastroenterology, IRON (equipe de recherche onco<br />
normande) within INSERM unit U1079., Rouen, France, 2 Department <strong>of</strong><br />
Pathology, Rouen University Hospital, Rouen, France, 3 Institute for Biomedical<br />
Research and Innovation, Inserm U1079, University <strong>of</strong> Rouen, Rouen, France,<br />
4 Medical <strong>Oncology</strong>, Centre Henri Becquerel, Rouen, France, 5 Department <strong>of</strong><br />
Surgery, Rouen University Hospital, Rouen, France, 6 Department <strong>of</strong> Genetics,<br />
Rouen University Hospital, Rouen, France<br />
Background: EUS-FNA is considered as the reference procedure for the diagnosis <strong>of</strong><br />
solid pancreatic tumor. Liquid biopsy (CA19.9, circulating tumor cells (CTCs) and<br />
vi20 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
circulating tumor DNA (ctDNA)) is an attractive alternative approach. We previously<br />
reported that the detection <strong>of</strong> CTCs had a diagnostic accuracy <strong>of</strong> 70% for pancreatic<br />
adenocarcinoma (PA) (Am J Gastroenterol 2013;108:152-155). The aim was to evaluate<br />
the diagnostic performance <strong>of</strong> each <strong>of</strong> these biomarkers (alone or combined) in an<br />
extended series <strong>of</strong> patients with pancreatic solid tumor.<br />
Methods: From 01/2011 to 03/2014, all patients with pancreatic solid tumors<br />
diagnosed on CT-scan and referred for a EUS-FNA were included. For each patient, 1<br />
EDTA tube (CTC) and 1 heparinized plasma tube (CA19.9) were systematically<br />
collected before EUS-FNA. CTCs isolation was performed using the Screencell® Cyto<br />
filtration. CTCs were characterized by an experienced cytopathologist blinded to the<br />
histological diagnosis. CtDNA extraction was performed on the remaining heparinised<br />
plasma sample if available. CtDNA was analysed with QX200 TM Droplet Digital TM<br />
PCR System (ddPCR) and a multiplex assay allowing screening in a same sample for<br />
multiple (n = 7) KRAS mutations (c.34G > A, c.34G > C, c.34G > T, c.35G > A,<br />
c.35G > C, c.35G > T and c.38G > A).<br />
Results: A total <strong>of</strong> 68 patients were included (58 with a malignancy tumor (52 PA and<br />
6 other malignant tumors) and 10 with benign lesion. The stage at diagnosis for PA<br />
was localized, locally advanced and metastatic in 13, 17 and 22 patients respectively.<br />
Sensitivity (Se) <strong>of</strong> EUS-FNA performed at inclusion for the PA diagnosis was 65%. Se<br />
<strong>of</strong> CTCs, ctDNA and CA19.9 was 64%, 63% and 79% respectively. Se <strong>of</strong> each marker<br />
increased proportionally with stage (i.e. Se (metastatic PA) = 77%, 85% and 80% for<br />
CTCs, ctDNA and CA19.9). Specificity (Spe) <strong>of</strong> these biomarkers was 81%, 75% and<br />
93% respectively. All 3 biomarkers were available for 51 patients. Positivity <strong>of</strong> at least 2<br />
on 3 was associated with a Se <strong>of</strong> 77% and a Spe <strong>of</strong> 91%.<br />
Conclusions: Our results confirm that CA19.9 alone or in combination with CTCs<br />
and/or ctDNA represents a non-invasive and effective method as an alternative to<br />
EUS-FNA for PA diagnosis.<br />
Legal entity responsible for the study: CHU Rouen<br />
Funding: Association de Cancerologie Digestive de h^Haute Normandie<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
71P<br />
Prospective analysis <strong>of</strong> CEA, CA19.9, circulating DNA (cDNA)<br />
and circulating tumor cells (CTC) in patients (pts) treated for a<br />
metastatic colorectal cancer (mCRC)_Results <strong>of</strong> COCA-COLON<br />
study<br />
D. Sefrioui 1 , N. Vasseur 2 , E. Toure 3 , F. Blanchard 3 , J. Delacour 2 , C. Thill 4 ,<br />
L. Beaussire 2 , A. Gillibert 4 , F. Ziegler 5 , A. Gangl<strong>of</strong>f 1 , K. Bouhier-Leporrier 6 ,<br />
A-C. Lefebvre 6 , A. Parzy 7 , M-P. Gallais 7 , F. Clatot 8 , A. Perdrix 9 , J-C. Sabourin 3 ,<br />
T. Frebourg 10 , P. Michel 1 , F. Di Fiore 8<br />
1 Department <strong>of</strong> Hepato-Gastroenterology, IRON (equipe de recherche onco<br />
normande) within INSERM unit U1079., Rouen, France, 2 Institute for Biomedical<br />
Research and Innovation, Inserm U1079, University <strong>of</strong> Rouen, Rouen, France,<br />
3 Department <strong>of</strong> Pathology, Rouen University Hospital, Rouen, France,<br />
4 Department <strong>of</strong> Statistics, CHU Hôpitaux de Rouen-Charles Nicolle, Rouen,<br />
France, 5 Institute <strong>of</strong> Clinical Biology, INSERM UMR 1073, CHU Hôpitaux de<br />
Rouen-Charles Nicolle, Rouen, France, 6 Department <strong>of</strong> Hepato-Gastroenterology,<br />
CHU de Caen, Caen, France, 7 Department <strong>of</strong> Hepato-Gastro-Enterology, Centre<br />
Francois Baclesse, Caen, France, 8 Department <strong>of</strong> Medical <strong>Oncology</strong>, Centre<br />
Henri Becquerel, Rouen, France, 9 Seine Maritime, Centre Henri Becquerel, Rouen,<br />
France, 10 Department <strong>of</strong> Genetics, Rouen University Hospital, Rouen, France<br />
Background: CEA, CA19.9, cDNA and CTC have been reported as useful circulating<br />
markers in mCRC pts treated with chemotherapy (CT)-based regimen. We previously<br />
reported that CEA kinetic (threshold 0.05) was associated witht outcome<br />
[Iwanicki-Caron et al, J Clin Oncol 2008;26:3681-6]. We designed a prospective<br />
muticentric trial for CEA kinetic validation and to evaluate CA19.9, cDNA and CTC<br />
kinetics.<br />
Methods: mCRC pts, PS 0-2, with CEA ≥ 5 µg/L or CA19.9 ≥ 30UI/mL, and who<br />
started a CT regimen were included. Plasma were collected taken from baseline (T0) to<br />
the fourth cycle for CEA and CA19.9 and at T0 and 6 weeks (W6) for cDNA and CTC<br />
kinetics. Cell-free DNA (cfDNA) was quantified by fluorimetric method, circulating<br />
tumour DNA (ctDNA) by Digital PCR and CTC (CTC+ vs CTC-) by ScreenCell (R)<br />
method. Primary endpoint was 3-months evaluation (control disease (CD) (response/<br />
stable) vs progressive disease (PD))) (RECIST 1.1) according to CEA kinetic.<br />
Secondary endpoints were progression-free survival (PFS) and overall survival (OS)<br />
according to baseline T0 median values (high vs low) <strong>of</strong> CEA, CA19.9, cfDNA, ctDNA,<br />
and CTC +/- and kinetics.<br />
Results: A total <strong>of</strong> 200 mCRC pts were included with a median follow-up <strong>of</strong> 12 months<br />
(m) (range 1-41). Median CEA, CA19.9, cfDNA and ctDNA were 96 µg/L, 88 UI/mL,<br />
24.2 ng/mL and 15.2% respectively. CtDNA was detected in 90% at T0 from the 95<br />
KRAS/BRAF mutated tumours. A total <strong>of</strong> 54.7% were CTC+ at T0. CEA kinetic (≤0.05<br />
threshold) was associated with response CD (90 vs 52%, p < 0.0001), PFS (8 vs 3 m;<br />
Hazard ratio (HR) 0.5, p < 0.0001) and OS (16 vs 12.5m, HR 0.62, p = 0.021). Among<br />
other tested kinetics, CA19.9 Kinetic (≥-0.12) was associated with PFS (9 vs 5 m; HR<br />
1.5, p = 0.043) without impact on OS. In multivariate analysis model taking account<br />
variable tested at baseline, median CA19.9 (ORa 3.81) and median ctDNA (ORa 3.48)<br />
were independent factor <strong>of</strong> PD while only median ctDNA was independent factor <strong>of</strong><br />
PFS (ORa 2.3) and OS (ORa 2.1).<br />
Conclusions: This prospective study confirmed that CEA kinetic is clinically relevant<br />
to monitor CT in mCRC. Results also highlight that CA19.9, cfDNA and ctDNA are<br />
also associated with outcome.<br />
Clinical trial identification: Protocol : 2009/170/HP Clinical trial number :<br />
NCT01212510<br />
Legal entity responsible for the study: CHU Rouen<br />
Funding: Amgen, Roche and Merck (pharma) Fondation Pierre Durand et<br />
Marie-Therese Chevalier<br />
Disclosure: D. Sefrioui, P. Michel, F. Di Fiore: Industrial partnership with Merck,<br />
Amgen and Roche. All other authors have declared no conflicts <strong>of</strong> interest.<br />
72P<br />
Survivin gene expression in the primary tumor and circulating<br />
tumor cells – a new biomarker <strong>of</strong> tumor progression <strong>of</strong> breast<br />
cancer<br />
Y. Shliakhtunou<br />
<strong>Oncology</strong>, Vitebsk State Medical University, Vitebsk, Belarus<br />
Background: Breast cancer is a leading cause <strong>of</strong> morbidity and mortality <strong>of</strong> the female<br />
population from malignant tumors. Distant metastases are the main cause <strong>of</strong> death <strong>of</strong><br />
patients, a substrate for the development <strong>of</strong> which are circulating tumor cells (CTCs).<br />
However, the search for these cells alone is not sufficient to provide full information<br />
about the nature and course <strong>of</strong> tumor in a single patient. Determination <strong>of</strong> the<br />
expression <strong>of</strong> tumor-genes responsible for the different processes <strong>of</strong> tumor progression<br />
allows a more complete picture. Such genes include the gene survivin (BIRC5) family<br />
<strong>of</strong> inhibitors <strong>of</strong> apoptosis (IAP).<br />
Methods: Using real-time PCR we investigated the expression <strong>of</strong> the survivin gene in<br />
36 samples <strong>of</strong> primary invasive ductal carcinoma <strong>of</strong> the breast, 10 samples <strong>of</strong> benign<br />
tumors - fibroadenoma <strong>of</strong> the breast, as well as 36 samples <strong>of</strong> peripheral blood <strong>of</strong><br />
patients with breast cancer at various stages <strong>of</strong> tumor and stage specific treatment, and<br />
10 healthy people as controls.<br />
Results: In primary breast carcinoma we determined a high expression <strong>of</strong> survivin gene<br />
in all 36 samples with the average value (M ± m) 1.58 ± 0.31 (min – 1.19; max – 4.41).<br />
The highest figures were found in tumors <strong>of</strong> medium and high grade (G II-III) with<br />
lymphovenous invasion (LVSI +). In 2 <strong>of</strong> 3 samples <strong>of</strong> benign tumor expression <strong>of</strong><br />
survivin was not found, and one was 0.015. In CTCs, isolated from peripheral blood <strong>of</strong><br />
breast cancer patients, all 36 samples as determined by the gene expression <strong>of</strong> survivin<br />
with an average value (M ± m) 1.10 ± 0.19 (min – 0.36; max – 3.79). The level <strong>of</strong><br />
expression <strong>of</strong> the control samples did not exceed 0.003. It should be noted that the<br />
maximum volume <strong>of</strong> expression was obtained in samples <strong>of</strong> tumor patients with stage<br />
N +, and especially M1, on TNM classification. Any legitimate expression <strong>of</strong> survivin,<br />
depending on the size <strong>of</strong> the tumor had been received. In patients, receiving<br />
chemotherapy average expression <strong>of</strong> survivin gene was obswerved, but it never<br />
approached the indicators <strong>of</strong> control.<br />
Conclusions: Determination <strong>of</strong> expression <strong>of</strong> the survivin gene in primary tumor and<br />
in CTCs may be one <strong>of</strong> the most promising markers <strong>of</strong> tumor progression and for<br />
monitoring <strong>of</strong> breast cancer therapy.<br />
Legal entity responsible for the study: Vitebsk State Order <strong>of</strong> Peoples’ Friendship<br />
Medical University<br />
Funding: Belarusian Republican Foundation for Fundamental Research<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
73P<br />
abstracts<br />
Evaluation <strong>of</strong> PD-1 and PD-L1 expression on CTCs isolated from<br />
non-small cell lung cancer (NSCLC) tumor patients<br />
G. Kallergi 1 , D. Aggouraki 1 , P. Katsarlinos 1 , E.K. Vetsika 1 , E. Lagoudaki 2 ,<br />
F. Koinis 1 , A. Koutsopoulos 2 , V. Georgoulias 1 , A. Kotsakis 1<br />
1 Laboratory <strong>of</strong> Translational <strong>Oncology</strong>, School <strong>of</strong> Medicine, University <strong>of</strong> Crete,<br />
Heraklion, Greece, 2 Department <strong>of</strong> Pathology, University Hospital <strong>of</strong> Heraklion,<br />
Heraklion, Greece<br />
Background: Lung cancer is the most common cause <strong>of</strong> cancer related death<br />
worldwide. Circulating tumour cells (CTCs) allows the assessment <strong>of</strong> tumor changes<br />
over time. Tumor cells may escape from the immune system through, among others,<br />
the PD-1/PD-L1 interaction between tumor cells and immune system which results to<br />
immunosuppression. The expression <strong>of</strong> PD-1/PD-L1 on CTCs isolated from NSCLC<br />
patients was investigated.<br />
Methods: CTCs were isolated, based on their size, using the ISET platform from 30<br />
chemo-naïve patients with stage IV NSCLC before chemotherapy and after the 3 rd<br />
cycle. CTCs were detected after staining with Giemsa, as well as after<br />
immun<strong>of</strong>luorescence double staining with Cytokeratin (A45-B/B3)/PD-1 and<br />
Cytokeratin (CK)//PD-L1 antibodies and analysis with the ARIOL system. Spiking<br />
experiments using the NSCLC H460, H1299, HCC827 and SKMES cell lines in normal<br />
blood were used to evaluate the detection method.<br />
Results: Twenty five and 12 out <strong>of</strong> 30 patients’ samples were evaluable for analysis at<br />
baseline and after the 3 rd cycle, respectively. CTCs could be detected in 56% (14/25)<br />
and 85.7% (10/12) patients at baseline and after the 3 rd cycle <strong>of</strong> chemotherapy,<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw363 | vi21
abstracts<br />
respectively. Giemsa staining revealed tumor cells in 60% (15/25) at baseline and in<br />
67% (8/12) after 3 rd cycle. PD-1 expression was observed in 71.4% (10/14) and 10% (1/<br />
10) (p = 0.044) <strong>of</strong> the CTC-positive patients at baseline and after the 3 rd , respectively.<br />
Conversely, PD-L1 was observed in 42,9% (6/14) and 50% (5/10) (p = 0.311) <strong>of</strong> the<br />
CTC-positive patients at baseline and after the 3 rd cycle. Among the total number <strong>of</strong><br />
detected CTCs, 47.8% were PD-1-positive at baseline and 30% after the 3 rd cycle<br />
whereas, 35.7% and 50% at baseline and after the 3 rd cycle, respectively, were<br />
PD-L1-positive.<br />
Conclusions: PD-1- and PD-L1 positive CTCs can be observed during the treatment <strong>of</strong><br />
metastatic NSCLC, suggesting that they can be used as a potential biomarker to<br />
monitor the expression <strong>of</strong> PD-L1 on tumor cells during the clinical phases <strong>of</strong> the<br />
disease and understand the mechanisms <strong>of</strong> tumor immune escape.<br />
Legal entity responsible for the study: N/A<br />
Funding: Laboratory <strong>of</strong> Translational <strong>Oncology</strong>, School <strong>of</strong> Medicine, University <strong>of</strong> Crete<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
Methods: Peripheral blood was collected from 124 pts with diverse staging and<br />
histology at three clinical sites prior to diagnostic biopsy, with some having follow-up<br />
draws. All nucleated cells were plated onto glass slides and circulating cells <strong>of</strong> interest<br />
identified by immun<strong>of</strong>luorescence and morphological features. Prognostic capacity <strong>of</strong><br />
PD-L1(+) cells (CK + /-, CD45-, PD-L1 + , malignant nuclear morphology) were<br />
assessed with Kaplan-Meier and Cox Proportional Hazard (PH) models.<br />
Results:<br />
Table: 75P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
AJCC Stage n = 124 Baseline n = 27 Follow-Up<br />
I 53 7<br />
II 18 4<br />
III 30 8<br />
IV 22 8<br />
74P<br />
The level <strong>of</strong> soluble programmed death ligand-1 in lung cancer:<br />
An exploratory biomarker study<br />
R. Geng 1 ,L.Pan 1 , S. Guo 2 , X.J. Jing 3 , F.F. Shen 1 , J.J. Xu 1 , X. Zhang 1 ,<br />
D.X. Zhang 4 , X. Song 1<br />
1 Department <strong>of</strong> Pulmonary <strong>Oncology</strong>, Shanxi Tumor Hospital, Taiyuan, China,<br />
2 Department <strong>of</strong> Molecular Biology, Shanxi Tumor Hospital, Taiyuan, China,<br />
3 Department <strong>of</strong> Etiology and Tumor, Shanxi Tumor Hospital, Taiyuan, China,<br />
4 School <strong>of</strong> Medicine and Public Health, Newcastle Private <strong>Oncology</strong> Centre,<br />
Newcastle, Australia<br />
Background: A new approach to immunotherapy based on programmed death 1<br />
(PD-1) and programmed death ligand-1 (PD-L1) pathway represents a remarkable<br />
innovation in lung cancer treatment. There is growing evidence that lung cancer cells<br />
exploit the PD-L1 to cause local immune-suppression. The aim <strong>of</strong> this prospective<br />
study was to investigate the prevalence and prognostic roles <strong>of</strong> soluble PD-L1(sPD-L1 )<br />
protein in the blood <strong>of</strong> patients with lung cancer.<br />
Methods: A total <strong>of</strong> 159 patients with lung cancer who were diagnosed by<br />
histopathology or cytopathology between July 2013 to October 2015 were enrolled.<br />
Blood samples plasma were collected at the time <strong>of</strong> diagnosis. 85 samples <strong>of</strong> healthy<br />
subjects matching in sex and age from the Health care Center <strong>of</strong> the hospital were also<br />
studied as control. The level <strong>of</strong> sPD-L1 protein in the blood was measured using an<br />
enzyme-linked immunosorbentassay (ELISA). 64 cases <strong>of</strong> lung cancer patients who<br />
were treated with platinum based chemotherapy for 4-6 cycles were followed up. The<br />
median follow-up duration since the time <strong>of</strong> diagnosis was 18.6 months (range, 4-26.6<br />
months). The associations between the level <strong>of</strong> sPD-L1 expression and<br />
clinicopathologic features and prognosis were statistically analyzed.<br />
Results: Expression <strong>of</strong> sPD-L1 in lung cancer patients was significantly up-regulated<br />
compared with health people( P < 0.001). A cut-<strong>of</strong>f value <strong>of</strong> 2.37ng/ml was<br />
distinguished in patients according to Receiver operating characteristic curve(ROC).<br />
The expression <strong>of</strong> sPD-L1 was associated with abdominal organ metastasis (P = 0.015).<br />
A high sPD-L1 expression had a worse prognosis than a low expression in patients<br />
(13.4 months vs 19.8 months, P = 0.001).<br />
Conclusions: Our results indicated that plasma sPD-L1 protein was elevated in lung<br />
cancer patients and was associated with a poor prognosis. Plasma sPD-L1 protein is a<br />
potent predicting biomarker in lung cancer and may may play a pivotal role in tumor<br />
immune evasion.<br />
Legal entity responsible for the study: N/A<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
75P<br />
PD-L1 expression on circulating CD45(-) cells is an<br />
independent prognostic factor for overall survival (OS) in<br />
patients (Pts) across all stages <strong>of</strong> treatment-naïve lung cancer<br />
in a prospective, multicenter study<br />
R. Graf 1 ,D.Lu 1 , R. Krupa 1 , J. Louw 1 , L. Dugan 1 , A. Jendrisak 1 ,S.Orr 1 ,<br />
K. Bethel 1 ,Y.Wang 1 , M. Suraneni 1 , M. Landers 1 , D. B<strong>of</strong>fa 2 , J. Nieva 3 ,<br />
L. Bazhenova 4 , M. Salazar 2 , S. Makani 4 , M. Magana 4 , R. Dittamore 1<br />
1 Translational Research, Epic Sciences, Inc, San Diego, CA, USA, 2 Surgery:<br />
Thoracic Surgery, Yale New Haven Health System, New Haven, CT, USA,<br />
3 Department <strong>of</strong> Medicine, University <strong>of</strong> Southern California Norris Comprehensive<br />
Cancer Center, Los Angeles, CA, USA, 4 Department <strong>of</strong> Medicine, Moores Cancer<br />
Center, San Diego, CA, USA<br />
Background: Biopsies are currently utilized for pr<strong>of</strong>iling (histologic, molecular) <strong>of</strong> lung<br />
cancer prior to treatment. Pr<strong>of</strong>iling tumors from circulating markers could avoid<br />
invasive procedures and enable more frequent, kinetic disease monitoring. PD-L1<br />
expression on lung cancer biopsy correlates with efficacy <strong>of</strong> immune checkpoint<br />
inhibitors. Using the Epic Sciences PD-L1 assay, we sought to correlate patient<br />
outcome with PD-L1(+) circulating CD45(-) cells, prior to its evaluation as a predictive<br />
biomarker for immune checkpoint inhibitors.<br />
When detected, PD-L1 subcellular localization was primarily membranous. Pts with >1<br />
PD-L1(+) cell/mL in baseline samples had worse overall survival (OS) (n = 22/124,<br />
mOS: 17.2 months vs. not reached, HR = 3.22, p = 0.0015) and follow-up (n = 5/22<br />
mOS = 2.1 months vs. not reached, HR = 4.25, p = 0.0302). High baseline PD-L1(+)<br />
cell burden was additive and independent to AJCC staging in Cox PH models<br />
(HR = 2.32, p = 0.0447). Single-cell sequencing is underway.<br />
Conclusions: In a multicenter cohort, circulating PD-L1(+)/CD45(-) cell burden<br />
predicted worse OS in pre-biopsy and follow-up lung cancer blood samples. This<br />
warrants prospective investigation as a predictive biomarker to PD-1 axis immune<br />
checkpoint inhibitors.<br />
Clinical trial identification: HHSN261201200049C<br />
Legal entity responsible for the study: National Cancer Institute, Epic Sciences<br />
Funding: National Cancer Institute, Epic Sciences<br />
Disclosure: R. Graf, D. Lu, R. Krupa, J. Louw, L. Dugan, A. Jendrisak, S. Orr, K. Bethel,<br />
Y. Wang, M. Landers, R. Dittamore: Epic Sciences Employee. All other authors have<br />
declared no conflicts <strong>of</strong> interest.<br />
76P<br />
Molecular characterization <strong>of</strong> PDL1 status <strong>of</strong> circulating tumor<br />
cells (CTCs) isolated with a novel label-free inertial micr<strong>of</strong>luidic<br />
system from patients (pts) with advanced cancers<br />
J. Fraser-Fish 1 , Z. Ahmad 1 , R. Kumar 2 , B. Ebbs 1 , G. Fowler 1 , P. Flohr 1 ,<br />
M. Crespo 1 , M. Ahmed 2 , S. Popat 2 , J. Bhosle 2 , U. Banerji 3 ,M.O’Brien 2 , J.S. de<br />
Bono 3 , T.A. Yap 3<br />
1 Cancer Biomarkers Laboratory, The Institute <strong>of</strong> Cancer Research, London, UK,<br />
2 Lung Cancer Unit, Royal Marsden Hospital NHS Foundation Trust, London, UK,<br />
3 Drug Development Unit, Royal Marsden Hospital and Division <strong>of</strong> Clinical Studies,<br />
The Institute <strong>of</strong> Cancer Research, London, UK<br />
Background: The ClearCell® FX system (FX) is a novel label-free inertial micr<strong>of</strong>luidic<br />
CTC isolation platform, in contrast to the EpCAM-based CELLSEARCH® system (CS).<br />
We hypothesise that label-free CTC capture will lead to more accurate assessment <strong>of</strong><br />
CTCs, including PD-L1 expression, and capture CTCs that have undergone<br />
epithelial-mesenchymal transition, which is prevalent in advanced cancers.<br />
Methods: CellTracker TM labelled EpCAM-high and EpCAM-low cell lines were spiked<br />
into healthy volunteer (HV) blood, prior to recovery on FX or CS platforms for initial<br />
validation studies. Blood samples were then obtained from pts with advanced<br />
non-small cell lung (NSCLC), prostate, ovarian, rectal and breast cancers for CTC<br />
isolation on FX and CS. CTCs captured on FX were assessed with 5-color<br />
immun<strong>of</strong>luorescence (IF) (CK, CD45, DAPI, PD-L1, as well as TTF-1 [lung<br />
adenocarcinoma], androgen receptor [AR; prostate cancer] or EpCAM [other<br />
cancers]). HV blood samples were assessed on FX and CS as controls.<br />
Results: FX and CS captured similar counts in EpCAM-high cell lines (FX 67% ± 11 vs<br />
CS 74% ± 10 [p = 0.11]). In contrast, higher cell counts were seen with EpCAM-low<br />
cell lines with FX vs CS [62% ± 8 vs 32% ± 9 [p < 0.0001]). Of 36 pts, CTC counts were<br />
higher with FX vs CS in 31 (86%) pts: 19/21 NSCLC, 7/10 prostate, 3/3 ovarian, 1/1<br />
rectal and 1/1 breast cancer pts. No CTCs were detected in HV blood (N = 10) on FX<br />
and CS. 19/19 NSCLC, 8/9 prostate, 3/3 ovarian, 1/1 rectal and 1/1 breast cancer pts<br />
had ≥1 PD-L1+ CTCs. Heterogeneity in PD-L1 expression was observed. While 19/20<br />
NSCLC pts had ≥1 PD-L1+ TTF-1+ CTCs, only 10 <strong>of</strong> these 19 pts had 100% PD-L1+<br />
TTF-1+ CTCs. 5/10 prostate cancer pts had ≥1 PD-L1+ AR+ CTCs, but only 4 <strong>of</strong> these<br />
5 pts had 100% PD-L1+ AR+ CTCs. All 3 ovarian cancer pts had ≥1 PD-L1+ EpCAM<br />
+ CTCs, with no PD-L1- EpCAM+ CTCs detected. 1/1 rectal and 1/1 breast cancer pts<br />
had 100% PD-L1+ EpCAM+ CTCs.<br />
Conclusions: Higher CTC counts were isolated with FX vs CS in 86% <strong>of</strong> pts. CTC<br />
PD-L1 heterogeneity was observed and may in part explain differences in antitumor<br />
responses to PD-1/PD-L1 inhibitors. Clinical qualification <strong>of</strong> this 5-color IF PD-L1<br />
CTC assay is ongoing in a PD-1 inhibitor NSCLC trial.<br />
Clinical trial identification: CCR-2472 study opened 2nd August 2004 CCR-3171<br />
study opened 22nd May 2009<br />
vi22 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Legal entity responsible for the study: The Institute <strong>of</strong> Cancer Research. The Royal<br />
Marsden Hospital<br />
Funding: ClearBridge Biomedics<br />
Disclosure: T.A. Yap: Funding for this research project is provided by ClearBridge<br />
Biomedics. All other authors have declared no conflicts <strong>of</strong> interest.<br />
77P<br />
Tumor mutation load assessed by FoundationOne (FM1) is<br />
associated with improved efficacy <strong>of</strong> atezolizumab (atezo) in<br />
patients with advanced NSCLC<br />
M. Kowanetz 1 ,W.Zou 2 , D.S. Shames 3 , C. Cummings 3 , N. Rizvi 4 , A.I. Spira 5 ,G.<br />
M. Frampton 6 , V. Leveque 3 , S. Flynn 7 , S. Mocci 8 , G. Shankar 8 , R. Funke 9 ,<br />
M. Ballinger 10 , D. Waterkamp 11 , A. Sandler 11 , G. Hampton 3 , L. Amler 3 ,P.<br />
S. Hegde 3 , M. Hellmann 12<br />
1 <strong>Oncology</strong> Biomarker Development, Genentech, Inc., South San Francisco, CA,<br />
USA, 2 Biostatistics, Genentech, Inc., South San Francisco, CA, USA, 3 <strong>Oncology</strong><br />
Biomarker Department, Genentech, Inc., South San Francisco, CA, USA, 4 Division<br />
<strong>of</strong> Hematology/<strong>Oncology</strong>, Columbia University, New York, NY, USA, 5 US<br />
<strong>Oncology</strong> Research, Virginia Cancer Specialists Research Institute, Fairfax, VA,<br />
USA, 6 Research & Development, Foundation Medicine, Inc., Cambridge, MA,<br />
USA, 7 PDG <strong>Oncology</strong> Sample Management, Genentech, Inc., South<br />
San Francisco, CA, USA, 8 PDO, Genentech, Inc., South San Francisco, CA, USA,<br />
9 Genentech, Inc., South San Francisco, CA, USA, 10 Product Development,<br />
<strong>Oncology</strong>, Genentech, Inc., South San Francisco, CA, USA, 11 Product<br />
Development <strong>Oncology</strong>, Genentech, Inc., South San Francisco, CA, USA,<br />
12 <strong>Oncology</strong>, Memorial Sloan Kettering Cancer Center, New York, NY, USA<br />
Background: In patients (pts) with NSCLC, the efficacy <strong>of</strong> atezo (anti-PDL1) correlates<br />
with PD-L1 expression on tumor cells (TC) and tumor-infiltrating immune cells (IC).<br />
We further examined the association between tumor mutation load (ML) and efficacy<br />
<strong>of</strong> atezo in pts with NSCLC.<br />
Methods: Pretreatment tumor specimens from 454 2L+ NSCLC pts treated on three Ph<br />
2 trials <strong>of</strong> atezo monotherapy (POPLAR, a trial comparing atezo vs docetaxel (doc);<br />
BIRCH and FIR, single-arm studies in PD-L1–selected pts) were available for targeted<br />
genetic sequencing using the FM1 panel <strong>of</strong> 315 cancer-related genes. ML was<br />
quantified for each sample and efficacy was assessed in groups defined by 75th (high),<br />
50th (median) and 25th (low) percentile <strong>of</strong> the study-specific ML. TIL infiltration was<br />
assessed by H&E staining. Teff gene expression was assessed with iChip. Atezo efficacy<br />
was examined at the following data cut<strong>of</strong>fs: POPLAR, May 8, 2015; BIRCH, May 28,<br />
2015; FIR, Jan 7, 2015.<br />
Results: Across all samples, the median ML was 9.9/MB (range 0-444.1, 25 th -75 th<br />
percentile 6.3-16.6). OS, PFS and ORR were improved in pts with increased ML treated<br />
with atezo in both unselected pts (POPLAR) and PD-L1–selected pts (BIRCH, FIR; see<br />
Table). ML appeared to predict atezo efficacy independently <strong>of</strong> PD-L1 status. ML was<br />
not associated with efficacy in pts treated with doc in POPLAR. Associations <strong>of</strong> ML<br />
with PD-L1 expression on TC and IC, TIL infiltration and Teff gene expression will be<br />
presented.<br />
Conclusions: We demonstrated for the first time that increased tumor ML assessed by<br />
the FM1 targeted sequencing panel is associated with improved outcomes with atezo in<br />
2L+ NSCLC. The association between ML and atezo efficacy was seen in both<br />
unselected and PD-L1-selected NSCLC pts. ML did not appear to be prognostic in pts<br />
treated with doc. Therefore, in addition to PD-L1, ML by FM1 may be an independent<br />
predictor <strong>of</strong> improved responsiveness to atezo in 2L+ NSCLC.<br />
Funding: F. H<strong>of</strong>fmann-La Roche Ltd<br />
Disclosure: M. Kowanetz, A. Sandler, G. Hampton, L. Amler, P.S. Hegde, D.S. Shames,<br />
C. Cummings, V. Leveque, S. Flynn, S. Mocci, G. Shankar, D. Waterkamp: Genentech<br />
employee. W. Zou: Roche employee, Roche research funding. N. Rizvi: Consulting:<br />
Merck, AZ, Roche, Novartis, Lilly Co-founder and shareholder: Gritstone <strong>Oncology</strong>. A.<br />
I. Spira: Roche funded clinical trial. G.M. Frampton: Foundation Medicine employee<br />
and Shareholder. R. Funke: Genentech employee with stocks. M. Ballinger: Genentech<br />
employee and stock. M. Hellmann: Consultancy: Genentech, Merck, AZ, BMS, Neon<br />
Research support: Genentech, BMS.<br />
78P<br />
abstracts<br />
PD-L1 expression assessment in Non-Small-Cell Lung Cancer<br />
shows stability on Ventana’s XT Benchmark platform –<br />
“Harmonization study”<br />
T. Neuman 1 , G. Vainer 2<br />
1 Pathology, Hadassah Ein Kerem, Jerusalem, Israel, 2 Pathology, Tel Aviv Sourasky<br />
Medical Center-(Ichilov), Tel Aviv, Israel<br />
Background: Pembrolizumab is a monoclonal antibody against programmed cell<br />
death 1 (CD279; PD-1), recently approved by the FDA as a 2nd line therapy in NSCLC<br />
with a companion diagnostic (PD-L1 22C3, Dako). Today, the only validated IHC<br />
platform for PD-L1 detection is the Link-48 platform (Dako), which lowers the<br />
availability <strong>of</strong> the test. Ventana’s benchmark XT platform is a widespread IHC<br />
platform. However, data about its reliability and reproducibility using the 22C3<br />
antibody is lacking.<br />
Methods: A comprehensive calibration <strong>of</strong> the 22C3 PD-L1 staining on the Benchmark<br />
XT platform (Ventana) was performed by combining the FDA-approved, pre-diluted<br />
22C3 anti PD-L1 primary antibody (Dako) with two <strong>of</strong> Ventana’s DAB detection<br />
systems, UltraView and OptiView. After receiving a comparable IHC pattern, 41<br />
NSCLC random cases were independently evaluated by 2 expert pathologists for PD-L1<br />
protein expression, using both platforms, defining the tumor proportion score (TPS):<br />
the percentage <strong>of</strong> tumor cells showing complete or partial membrane staining. Each<br />
case was classified as PD-L1 negative, weakly positive, or strongly positive (
abstracts<br />
mutation in the splice site 1941 + 1G > A for the transcriptional adaptor zinc finger<br />
2. Additional mutations are described in the Table below.<br />
81P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
PD-L1 expression and tumor immune-cell infiltration in<br />
non-small cell lung cancer from HIV-infected patients<br />
Table: 79P<br />
1# 2# 3#<br />
CDKN2A/B loss S12*<br />
CREBBP R1443fs*10 E649fs*5 splice site 1941 + 1G > A<br />
EGFR amplification (amp)<br />
NCOR1 Q1993*<br />
TP53 S241C K320fs*25 S215R<br />
CCND1 amp<br />
ERBB2<br />
G292R<br />
FGF19<br />
amp<br />
MLL2<br />
P1038fs*18<br />
NOTCH3 S1871*<br />
CCND3<br />
amp<br />
CCNE1<br />
amp<br />
LRP1B<br />
truncation<br />
MAP3K13<br />
deletion<br />
PIK3CA<br />
E542K<br />
Conclusions: Present genomic analyses revealed CREBBP alterations in extreme<br />
responders to PD1 inhibition independently by the tumor type. CREBBP is<br />
ubiquitously expressed and it is known to play many different roles in immune<br />
response. Functionally, the described mutations could impair histone acetylation and<br />
transcriptional regulation <strong>of</strong> CREBBP targets. This association deserves validation in a<br />
wider anti-PD1 treated cohort <strong>of</strong> pts but it suggests that CREBBP mutations could have<br />
a potential role as predictive biomarker for immunological treatments.<br />
Legal entity responsible for the study: START MAdrid-CIOCC<br />
Funding: START Madrid-CIOCC<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
80P<br />
Dynamics <strong>of</strong> neutrophil to lymphocyte ratio (NLR) predict<br />
effectiveness <strong>of</strong> PD1/PDL1 inhibition<br />
M. Moschetta 1 , B. Kasenda 2 , G. Mak 1 , M. Voskoboynik 1 , N. Martynyuk 1 , S. Rafii 1 ,<br />
V. Formica 3 , H-T. Arkenau 1<br />
1 Drug Development Unit, Sarah Cannon Research Institute UK, London, UK,<br />
2 Department for Haematology/<strong>Oncology</strong>, Klinikum Stuttgart - Katharinenhospital<br />
Klinik f. Onkologie, Stuttgart, Germany, 3 Medical <strong>Oncology</strong> Unit, Internal Medicine<br />
Department, Policlinico Tor Vergata, Rome, Italy<br />
Background: Baseline neutrophil/lymphocyte ratio (NLR) has repeatedly been<br />
associated with progression free (PFS) and overall survival (OS) <strong>of</strong> patients with<br />
advanced cancer. We explored whether changes in NLR can predict PFS <strong>of</strong> advanced<br />
cancer patients (pts) enrolled into Phase-1 (Ph-1) trials and treated with anti-PD1/<br />
PDL1 inhibitors.<br />
Methods: Stage IV cancer patients enrolled into Ph-1 trials between September 2013<br />
and May 2016, and treated with an anti-PD1/PDL1 checkpoint inhibitors were<br />
included in this study. NLR was calculated at baseline, before starting treatment (cycle<br />
1 day 1), and after 2 cycles (cycle 3 day 1) <strong>of</strong> treatment. Royal Marsden Prognostic<br />
Score (RMPS) was calculated at baseline for all patients enrolled. Kaplan-Meier<br />
estimation and Cox regression analyses with a random effect for tumour entity (to<br />
account for heterogeneity between tumour types) were used to assess the impact <strong>of</strong><br />
NLR changes on PFS. Pts who were not able to receive at least 2 cycles <strong>of</strong> treatment<br />
were excluded to avoid guarantee time bias.<br />
Results: Of 67 pts treated, 12 were excluded because not receiving 2 full cycles <strong>of</strong><br />
anti-PD1/PDL1 treatment. In total 55 pts were eligible (median age <strong>of</strong> 61 years, PS 0/<br />
1 = 65.5% / 34.5%, female = 34.5%). Tumour types were non-small cell lung cancers<br />
(n = 18, 32.7%), renal cell (n = 8, 14.5%), upper gastrointestinal (n = 10, 18.2%), breast<br />
(n = 7, 12.7%), urothelial (n = 8, 14.5%), colorectal (n = 2, 3.6%), ovarian (n = 1, 1.8%),<br />
and small bowel cancers (n = 1, 1.8%). Before trial enrolment pts received a median <strong>of</strong><br />
1 treatment line (range 1-6), and presented with a median number <strong>of</strong> 2 metastatic sites<br />
(range 0-4). 24 (43.6%) patients had a RMPS <strong>of</strong> 1 or higher. 26 (47.3%) patients<br />
received an anti-PDL1 monoclonal antibody (MAb) and 29 (52.7%) an anti-PD1 MAb.<br />
Patients with increasing NLR between baseline and 2 cycles had a significantly shorter<br />
PFS in univariate analysis (HR 1.63, 95% CI 1.27 – 2.11, p < 0.001), and this effect was<br />
still observed when adjusting for baseline RMPS in multivariable analysis (HR 1.63,<br />
95% CI 1.23 – 2.15, p = 0.001).<br />
Conclusions: Changes in the NLR (as continuous variable) after 2 cycles <strong>of</strong> treatment<br />
with anti-PD1/PDL1 treatment independently predict PFS in patients with multiple<br />
types <strong>of</strong> advanced cancer.<br />
Legal entity responsible for the study: Sarah Cannon Research Institute UK<br />
Funding: Sarah Cannon Research Institute UK<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
M. Wislez 1 , C. Domblides 1 , M. Antoine 2 , C. Hamard 1 , N. Rabbe 3 , A. Rodenas 2 ,<br />
T. Vieira 1 , P. Créquit 1 , J. Cadranel 1 , A. Lavolé 1<br />
1 Pneumology, APHP, CancerEst, Tenon University Hospital, Paris, France,<br />
2 Pathology, APHP, CancerEst, Tenon University Hospital, Paris, France,<br />
3 Sorbonne Universités, UPMC Univ. Paris 06, GRC n°04, Theranoscan, APHP,<br />
CancerEst, Tenon University Hospital, Paris, France<br />
Background: Immunotherapies targeting the programmed cell death protein 1 (PD-1)<br />
to PD ligand 1 (PD-L1) checkpoint have improved prognosis in non-small cell lung<br />
cancer (NSCLC). PD-1/PD-L1 status has not been investigated in human<br />
immunodeficiency virus (HIV)-positive patients. This study sought to assess PD-L1<br />
status and tumor immune-cell infiltration in NSCLC in HIV patients.<br />
Methods: Consecutive HIV patients treated for NSCLC between 1996 and 2014 at<br />
Tenon hospital (Paris, France) were enrolled. PD-L1 tumor expression was assessed<br />
using immunohistochemistry (2 antibodies: L. Chen, clone 5H1 and Cell Signaling,<br />
clone E1L3N). Tumor immune cell infiltration was assessed for CD3 (SP7), CD4 (1F6),<br />
CD8 (C8/144b), CD20 (L26), CD163 (10D6) and MPO (59A5). The percentage <strong>of</strong><br />
PD-L1- and immune-positive cells was ≥5%. The score used is the product <strong>of</strong> intensity<br />
(0, 1, 2 or 3) by positive cell percentage. The PD-L1 score was considered positive if >5.<br />
PD-L1 status and immune-cell infiltration results were compared to those <strong>of</strong> 54<br />
NSCLCs from unknown HIV status patients.<br />
Results: In total, 34 HIV-positive patients were evaluated: predominantly men (88.2%)<br />
with a median age <strong>of</strong> 51.1 years and adenocarcinomas (76.5%) with 38.2% stage IV.<br />
The median blood CD4 count was 480/µL (86-1120) and 64% exhibited undetectable<br />
viral load. The PD-L1 score was higher in HIV-positive patients (E1L3N clone: 0<br />
[0-150] vs. 0 [0-26.7], p = 0.047; 5H1 clone: 0 [0-120] vs.0 [0-26.7] p = 0.66<br />
respectively) whereas PD-L1 expression frequency did not differ between HIV-positive<br />
and HIV-undetermined patients (18.7% vs. 9.3% using E1L3N and 10% vs. 5.6% using<br />
5H1, respectively). There was significantly greater CD8, CD20, and CD163 infiltration<br />
in the HIV-positive patients (Table).<br />
HIV-positive<br />
(n = 22)<br />
Table: 81P<br />
HIV-undetermined<br />
(n = 54)<br />
p-value<br />
Median Range Median Range<br />
CD3 40 0-150 50 5-150 0.74<br />
CD4 20 0-120 26.7 0-60 0.76<br />
CD8 90 15-120 40 0-100
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
associated with IHC test, primary tumor site and histological type. In multivariate<br />
analysis, IHC test and histological type remained significant (respectively p= 0.001 and<br />
0.008). Atezolizumab companion test (SP142) was associated with low PD-L1<br />
expression; while squamous cell carcinoma and urothelial carcinoma were associated<br />
with high expression. Among metastatic patients, samples from liver metastasis showed<br />
a trend for lower PD-L1 expression. There was no significant relationship with<br />
sampling method (biopsy or surgical resection), histological analysis place (private or<br />
academic), sample size, age or cellularity, or sample location (primary or metastatic<br />
site). There was no difference between samples acquired before or after some anticancer<br />
treatment.<br />
Conclusions: This study identified that IHC test and histological type were associated<br />
with PD-L1 status, which need to be further investigated. The trend for lower PD-L1<br />
expression in liver metastasis sample needs to be confirmed and compared with clinical<br />
response data.<br />
Legal entity responsible for the study: Gustave Roussy Cancer Campus<br />
Funding: Gustave Roussy Cancer Campus<br />
Disclosure: C. Massard: Honoraria from Genentech, Celgene, MedImmune. J-C. Soria:<br />
Consultancy fees from MSD, AstraZeneca, Roche-Genentech. All other authors have<br />
declared no conflicts <strong>of</strong> interest.<br />
83P<br />
Predictive/prognostic value <strong>of</strong> circulating regulatory T cell<br />
subset in untreated non-small lung cancer patients<br />
E.K. Vetsika 1 , F. Koinis 1 , A. Katsarou 1 , M. Gioulbasani 1 , D. Aggouraki 1 ,<br />
N. Kentepozidis 2 , V. Georgoulias 1 , A. Kotsakis 1<br />
1 Laboratory <strong>of</strong> Translational <strong>Oncology</strong>, School <strong>of</strong> Medicine, University <strong>of</strong> Crete,<br />
Heraklion, Greece, 2 Department <strong>of</strong> Medical <strong>Oncology</strong>, 251 Air Force General<br />
Hospital, Athens, Greece<br />
Background: Regulatory T-cells (Treg) are highly heterogeneous populations with<br />
immune suppressive properties and their role in NSCLC is unknown. The frequency<br />
and functionality <strong>of</strong> the different Treg subtypes in the peripheral blood (PB) <strong>of</strong> NSCLC<br />
patients, as well as their correlation with the patients’ clinical outcome was investigated.<br />
Methods: PB from 156 chemotherapy-naive patients with stage III/IV NSCLC and 31<br />
healthy donors (HD) was analyzed with flow cytometry for the presence <strong>of</strong> the<br />
different CD4 + Treg subsets [naïve: CD25 high CD127 −/low CD152 − FoxP3 low CD45RO − ,<br />
effector: CD25 high CD127 −/low CD152 + FoxP3 low CD45RO + and terminal effector:<br />
CD25 high CD127 − CD152 + FoxP3 + CD45RO + ]. Their functionality was tested based on<br />
TGF-β and IL-10 production. The patients’ clinical outcome (PFS and OS) was<br />
correlated with the frequency <strong>of</strong> Treg subtypes (high vs low expression, according to<br />
their percentage > 90% percentile <strong>of</strong> the HD).<br />
Results: All CD4 + Treg subsets exhibited a highly suppressive activity as revealed by<br />
their TGF-β and IL-10 production. The percentages <strong>of</strong> naïve Tregs were increased in<br />
patients compared to HD (p = 0.02) and were associated with poor clinical outcome.<br />
Effector Tregs did not associated with response to treatment; Higher levels <strong>of</strong> Terminal<br />
effector Tregs were correlated with improved clinical response (p= 0.04). Normal levels<br />
<strong>of</strong> naïve and effector Treg, at baseline, were associated with longer PFS and OS<br />
compared to those with high levels (p= 0.03 and p = 0.02; p= 0.03 and p= 0.03,<br />
respectively). In contrast, high frequency <strong>of</strong> the terminal effector Treg, at baseline, was<br />
correlated with longer PFS (p = 0.03) and OS (p = 0.04) compared to low frequency.<br />
Conclusions: It is demonstrated, for the first time, that particular CD4 + Treg subtypes are<br />
increased in NSCLC patients and are associated to the clinical outcome. Their depletion or<br />
blocking their migration to the tumour site may be an effective therapeutic strategy.<br />
Legal entity responsible for the study: N/A<br />
Funding: Laboratory <strong>of</strong> Translational <strong>Oncology</strong>, School <strong>of</strong> Medicine, University <strong>of</strong> Crete<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
84P<br />
Prognostic and predictive value <strong>of</strong> tumor-infiltrating<br />
lymphocytes (TILs) in triple-negative breast cancers (TNBC)<br />
treated with neoadjuvant chemotherapy (NAC)<br />
C. Herrero-Vicent 1 , A. Guerrero 1 , J. Gavilá 1 , F. Gozalbo 2 , S. Blanch 1 ,<br />
A. Hernández 1 , S. Sandiego 1 , A. Calatrava 2 , V. Guillem 1 ,A.Ruiz 1<br />
1 Medical <strong>Oncology</strong>, Fundación Instituto Valenciano de Oncología, Valencia, Spain,<br />
2 Pathology, Fundación Instituto Valenciano de Oncología, Valencia, Spain<br />
Background: Recent clinical studies have evaluated TILs in TNBC patients(pts) with<br />
different methodological approaches. The aim is to analyse the predictive and<br />
prognostic value <strong>of</strong> TIL following the recommendations for TILs Evaluations in Breast<br />
Cancer(BC) by an International TIL Working Group.<br />
Methods: Using our BC database with 756 pts, we identified 164 TNBC treated with<br />
NAC between 1998-2015. Evaluation <strong>of</strong> TILs was following a standardized<br />
methodology for visual assessment on hematoxylin-eosin sections and TILs were<br />
quantitated in deciles. We categorized lymphocyte-predominant BC (LPBC) cut<strong>of</strong>f<br />
according to a receiver operating characteristic (ROC) curve. The primary endpoint<br />
was predictive value <strong>of</strong> TILs to NAC and secondary endpoint was disease-free survival<br />
(DFS). Kaplan-Meier curves were used to summarize DFS, and curves were compared<br />
with a log-rank test. Univariate and multivariate Cox models were used to generate<br />
hazard ratios (HR) for determining associations between variables and DFS.<br />
Results: We categorized LPBC as the involving > 40% TIL stroma. Pts were divided in<br />
subgroups:58 pts (35.4%) with LPBC and 106 pts (64.6%) non-LPBC. Main pts’<br />
characteristics are listed in Table 1. We identify different pathological complete<br />
response (pCR) to anthracycline and taxane-based NAC; LPBC 88% pCR vs<br />
non-LPBC 9% pCR, p = 0.001. At a median follow-up <strong>of</strong> 78 months, LPBC was<br />
associated with better DFS; the 3-year Kaplan-Meier estimates for DFS were 2 % and<br />
30% in LPBC and non-LPBC, respectively p = 0.01. Univariate and multivariate<br />
analysis confirmed TIL to be an independent prognostic marker <strong>of</strong> DFS.<br />
Table: 84P Patient’s characteristics<br />
Variable<br />
TILs level<br />
HIGH<br />
LOW<br />
50 50 (86%) 90 (85%) p.270<br />
NAC<br />
Anthracycline + taxane 47 (81%) 98 (92%) p.570<br />
pCR (ypT0/is, ypN0) 51 (88%) 10 (9%) p.001<br />
ResidualTumor<br />
Multifocal 4 (7%) 24 (22%) p.001<br />
Conservative surgery 39 (67%) 43 (41%) p.001<br />
Adjuvant Radiotherapy 51 (88%) 93 (88%) p.754<br />
AC 12 (21%) 47(44%) p.078<br />
Conclusions: TIL evaluation in TNBC pts could be included in the standard<br />
histopathological practise to identify two subgroups; LPBC with high pCR response to<br />
NAC and non-LPBC with worse prognosis. While our findings may not change<br />
current NAC options, it is a clinically relevant finding as TIL could be useful as an<br />
adjustment factor in future studies.<br />
Legal entity responsible for the study: N/A<br />
Funding: Fundación Colegio de Médico de Valencia<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
85P<br />
Correlation <strong>of</strong> intratumoral CD8(+) T-cells, neutrophils and<br />
eosinophils frequency with morphological characteristics and<br />
clinical outcome <strong>of</strong> gastrointestinal adenocarcinomas<br />
N. Beliak 1 , S. Kutukova 1 , G. Manikhas 2 , G. Raskin 3<br />
1 Chemotherapy, City Clinical <strong>Oncology</strong> Dispensary, Saint Petersburg, Russian<br />
Federation, 2 City Clinical <strong>Oncology</strong> Dispensary, Saint Petersburg, Russian<br />
Federation, 3 Pathology, Russian Scientific Center <strong>of</strong> Radiology and Surgical<br />
Technology, Saint Petersburg, Russian Federation<br />
Background: The purpose <strong>of</strong> our study was to investigate some correlation between<br />
tumor and microenvironment infiltration <strong>of</strong> CD8(+) T-cells, eosinophils and<br />
neutrophils, clinical parameters, treatment options and OS in our patient cohort.<br />
Methods: In the prospective study we analyzed cards and tumor samples <strong>of</strong> 15 patients<br />
with colorectal and gastric cancer: 6 patients with gastric cancer: 2pp. - stage II; 4pp. -<br />
stage IV; 9 patients with CRC: 5pp. - stage III, 4pp. - stage IV. All patients were treated<br />
under the standard clinical complex protocol. All patients were under our supervision<br />
from 2013 to 2015. We studied clinical stage, level <strong>of</strong> expression <strong>of</strong> CD8(+) T-cells,<br />
eosinophils and neutrophils in the tumor and microenvironment.<br />
Results: The frequency <strong>of</strong> neutrophils in microenvironment varied from 0 to 1000<br />
cells/mm2 (median 55.5 cells, 95% CI from 20.55 to 703.61). The frequency <strong>of</strong><br />
eosinophils varied from 0 to 32 cells/mm2 (median 10 cells, 95% CI from 5.38 to<br />
26.78). Expression <strong>of</strong> CD8(+) T-cells varied from 26 to 624 cells/mm2 (median 241.5<br />
cells, 95% CI from 117.30 to 379.05). Neutrophil frequency had an inversely correlation<br />
with regional lymph nodes (r= -0.84, 95% CI from -0.97 to -0.34, p = 0,0087).<br />
Expression <strong>of</strong> CD8(+) T-cells had inverse correlation with tumor differentiation (r=<br />
-0.60, 95% CI from -0.89 to 0.05, p = 0.0682). OS was 27 month (95% CI from 18,00<br />
month, all patients alive on Dec,2015). Cox’s regression showed dependence <strong>of</strong> OS on<br />
the frequency <strong>of</strong> CD8(+) T-cells: p = 0.56, 95% CI <strong>of</strong> Exp(b) from 0.99 to 1.00); from<br />
eosinophils frequency - p = 0,24, 95% CI <strong>of</strong> Exp(b) from 0.97 to 1.13); from neutrophils<br />
frequency - p = 0,89, 95% CI <strong>of</strong> Exp(b) from 0.99 to 1.00).<br />
Conclusions: Definition <strong>of</strong> intratumoral expression <strong>of</strong> CD8(+) T-cells and infiltration<br />
<strong>of</strong> eosinophils and neutrophils could be informative prognostic factors for patient with<br />
gastrointestinal adenocarcinomas.<br />
Legal entity responsible for the study: Kutukova Svetlana<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw363 | vi25
abstracts<br />
86P<br />
Serum interleukin-6 as a prognostic biomarker for survival in<br />
patients with unresectable pancreatic cancer<br />
I. Chen 1 , C. Dehlendorff 2 , B.V. Jensen 1 , P. Pfeiffer 3 , S.E. Nielsen 1 , N.H. Holländer 4 ,<br />
M.K. Yilmaz 5 , J. Johansen 1<br />
1 <strong>Oncology</strong>, Herlev and Gent<strong>of</strong>te Hospital, Herlev, Denmark, 2 Research Center,<br />
Danish Cancer Society Institute <strong>of</strong> Cancer Biology, Copenhagen, Denmark,<br />
3 Department <strong>of</strong> <strong>Oncology</strong>, Odense University Hospital, Odense, Denmark,<br />
4 <strong>Oncology</strong>, Zealand University Hospital, Naestved, Denmark, 5 Department <strong>of</strong><br />
<strong>Oncology</strong>, Aalborg University Hospital, Aalborg, Denmark<br />
Background: Patients with pancreatic cancer (PC) have the highest mortality rate <strong>of</strong> all<br />
major cancers. Interleukin-6 (IL-6) is produced by PC cells and macrophages, regulates<br />
inflammation and plays an important role in cachexia. The aim <strong>of</strong> this biomarker study<br />
was to determine the clinical utility <strong>of</strong> serum IL-6 as a prognostic factor. We further<br />
explored age, sex, CA 19.9, PS, stage and chemotherapy type as predictors <strong>of</strong> outcome<br />
in patients receiving palliative chemotherapy.<br />
Methods: 452 patients with unresectable PC (M/F: 242/210; median age 67.5 (IQR<br />
61.8, 73.0); ECOG Performance Status (PS) <strong>of</strong> 0/1/2: 150/247/55; locally advanced<br />
disease/metastatic: 97/355; treated with gemcitabine n = 337, FOLFIRINOX n= 83,<br />
gemcitabine and nab-Paclitaxel n = 14 or capecitabine-containing regimens n = 18)<br />
were included in the BIOPAC study from five hospitals in Denmark (2008-2016).<br />
Pretreatment and longitudinal serum CA 19.9 (Siemens) and IL-6 were determined<br />
(ELISA, R&D Systems).<br />
Results: Patients were grouped into quartiles according to baseline IL-6 values (0.8 to<br />
3.2, 3.2 to 6.4, 6.4 to 14, and ≥14 pg/ml) and CA 19.9 values (1 to 119, 119 to 992, 992<br />
to 7280, and 7280 to 687.000 U/ml. On univariate analysis, IL-6 ≥6.4 pg/ml, CA 19.9,<br />
PS, stage, chemotherapy type were identified as significant risk factors for overall<br />
survival (OS). Hazard ratio (HR) in quartiles with lowest quartile as reference were 1.20<br />
(95% confidence interval (CI), 0.91–1.57; P = 0.19), 1.87 (95% CI, 1.43–2.46;<br />
P < 0.001), and 2.81 (95% CI, 2.14–3.70; P < 0.001), for IL-6 groups 2–4, respectively.<br />
Multivariate cox analysis showed that apart from age and sex all variables were<br />
independently associated with short OS. The hazard rate <strong>of</strong> death for patients with<br />
IL-6 ≥ 14 pg/ml was 2.23 times as high as those with IL-6
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
89P Table: (CR/PR = complete/partial response; HR = hazard ratio)<br />
n patients (R/L) OS(m) PFS(m) CR + PR(%)<br />
Right left right left right left<br />
PRIME (1st line)<br />
Pmab-FOLFOX 26/156 22.5 (8.1-30.8) 32.5 (27.5-37.6) 8.9 (5.5-11.3) 12.9 (10.0-14.9) 52.0 70.3<br />
FOLFOX 32/148 21.5 (10.8-26.0) 23.6 (18.2-27.7) 7.3 (4.2-11.1) 9.3 (7.7-10.8) 41.2 54.8<br />
HR 0.94 (0.53-1.67) 0.67 (0.56-0.859) 0.71 (0.4-1.27) 0.69 (0.54-0.88)<br />
PEAK (1st line)<br />
Pmab-FOLFOX 13/52 22.5 (8.4-36.9) 43.4 (34.2-63.0) 10.3 (6.1-11.6) 14.6 (11.6-18.1) 69.2 63.5<br />
Beva FOLFOX 13/53 23.3 (6.0-29.0) 32.0 (26.9-48.5) 12.6 (1.8-18.4) 11.5 (9.3-13.0) 46.2 58.5<br />
HR 0.63 (0.26-1.54) 0.77 (0.46-1.28) 0.88 (0.39-2.02) 0.67 (0.44-1.02)<br />
181 (2nd line)<br />
Pmab-FOLFIRI 22/143 11.9 (6.4-16.0) 20.1 (16.6-21.7) 6.8 (3.7-10.3) 8.0 (7.3-9.3) 19 50.7<br />
FOLFIRI 26/144 10.9 (6.7-13.0) 16.9 (15.1-22.2) 3.7 (2.0-5.9) 6.6 (5.3-7.4) 3.8 13.5<br />
HR 0.84 (0.46-1.54) 0.97 (0.76-1.26) 0.62 (0.34-1.13) 0.89 (0.69-1.13)<br />
the association between tumor location and anticancer treatment efficacy in mCRC<br />
patients with a RAS/BRAF WT primary tumor.<br />
Methods: Data from three Amgen-sponsored clinical trials were analyzed for treatment<br />
outcomes in relation to location <strong>of</strong> the primary tumor. All studies were randomized: a<br />
first-line phase 3 (PRIME; NCT00364013), a first-line phase 2 (PEAK; NCT00819780)<br />
and a second-line phase 3 (181; NCT00339183) study. In order to have a biomarker<br />
refined patient population, only RAS/BRAF WT cases were included. Information on<br />
tumor location (left/right colon) was obtained from the free-text surgery descriptions<br />
and from the original pathology reports. Primary tumors located in the caecum to<br />
transverse colon were coded as right-sided and tumors located from the splenic flexure<br />
to rectum were coded as left-sided.<br />
Results: Tumor location ascertainment rate was greater than 80%. Between 80%<br />
and 85% <strong>of</strong> cases are left sided. Results for overall survival (OS), progression-free<br />
survival (PFS) and overall response rate (ORR) for each treatment arm in the 3<br />
studies are summarized in table 1. Patients with right-sided tumors did worse for<br />
all parameters compared to left sided. Panitumumab provided better outcomes<br />
than the comparator on the left side. On the right side, the small number <strong>of</strong><br />
patients does not allow drawing definitive conclusions, but a lack <strong>of</strong> efficacy <strong>of</strong><br />
panitumumab was not confirmed, contradicting previous reports on the impact <strong>of</strong><br />
tumor sidedness.<br />
Conclusions: The result <strong>of</strong> these retrospective analyses on a homogenous RAS/BRAF<br />
WT subpopulation confirms that primary CRC arising on the right side is associated<br />
with poor prognosis regardless <strong>of</strong> treatment received. Moreover, panitumumab plus<br />
chemotherapy provide a benefit over chemotherapy with or without bevacizumab in<br />
left-sided tumors. No final conclusions can be drawn on the optimal treatment in<br />
patients with right-sided primary tumors.<br />
Legal entity responsible for the study: Amgen Ltd<br />
Funding: Amgen Ltd<br />
Disclosure: A. Toler: Amgen contractor. G. Kafatos: Amgen Ltd employee and<br />
company stock owner. K. Lowe: Amgen, Inc employee and stock owner. G. Demonty:<br />
employee <strong>of</strong> Amgen. M. Peeters: Research grant, Advisor and speaker Amgen. All other<br />
authors have declared no conflicts <strong>of</strong> interest.<br />
90P<br />
The prognostic impact <strong>of</strong> RAS and RAF serum mutations in<br />
localized colon cancer<br />
C.B. Thomsen, A.L. Appelt, R.F. Andersen, J. Lindebjerg, L.H. Jensen,<br />
A. Jakobsen<br />
<strong>Oncology</strong>, Danish Colorectal Cancer Center South, Vejle, Denmark<br />
Background: The prognostic impact <strong>of</strong> RAS/RAF mutations in localised colon cancer<br />
needs clarification. Based on analysis <strong>of</strong> tumour specific DNA this study aimed at<br />
elucidating the prognostic impact <strong>of</strong> mutational status in serum using an extended<br />
panel <strong>of</strong> mutations.<br />
Methods: Stage I-III curatively resected colon adenocarcinoma patients (n = 294) were<br />
retrospectively included. Mutations and mismatch repair (MMR) status in tumor were<br />
determined at time <strong>of</strong> operation. The status (categorical) <strong>of</strong> mutated ctDNA in<br />
preoperative serum samples was obtained for patients with tissue mutations. Analyses<br />
were performed with droplet digital PCR technology. Hazard ratio (HR) for the<br />
association between mutation status and survival was estimated in multivariate analysis<br />
taking known prognostic factors into account. Primary endpoints were overall survival<br />
(OS) and disease free survival (DFS) and median follow-up was 3.9 and 3.0 years,<br />
respectively.<br />
Results: Mutational status in tumor alone (n = 189) had no prognostic impact<br />
(p = 0.22). Patients with RAS mutated DNA in both tumor and serum (n = 36) had a<br />
significantly worse prognosis, OS (HR= 2.30, 95% CI 1.27-4.15, p = 0.0057) and DFS<br />
(HR = 2.18, 95% CI 1.26-3.77, p = 0.0053). BRAF mutated DNA in serum and<br />
pr<strong>of</strong>icient MMR (pMMR) protein in tumor (n = 14) also reflected significantly worse<br />
survival, OS (HR= 3.45, 95%CI 1.52-7.85, p = 0.0032) and DFS (HR= 3.61, 95%CI<br />
1.70-7.67, p = 0.0008). Mutational load had significant prognostic impact as well.<br />
Table: 90P<br />
OS HR (95%CI) DFS HR (95%CI)<br />
RAS mutation in serum 2.30 (1.27-4.15) 2.18 (1.26-3.77)<br />
BRAF mutation in serum and 3.45 (1.52-7.85) 3.61 (1.70-7.67)<br />
pMMR protein in tumor<br />
Stage I >< II I >< III 1.13 (0.50-2.59) 1.33<br />
(0.56-3.16)<br />
1.16 (0.54-2.50) 1.28<br />
(0.57-2.89)<br />
Differentiation High >< Low<br />
High >< Mucinous<br />
0.99 (0.43-2.31) 1.41<br />
(0.59-3.38)<br />
0.91 (0.42-1.99) 1.17<br />
(0.50-2.72)<br />
Neural or vascular involvement 1.48 (0.84-2.59) 1.58 (0.94-2.66)<br />
Perforation <strong>of</strong> the peritoneum 2.10 (1.09-4.04) 1.87 (1.02-3.45)<br />
Conclusions: Mutational status in tumor did not demonstrate any prognostic impact.<br />
RAS mutations in serum, and BRAF mutation in serum combined with pMMR in<br />
tumor were both strong independent prognostic factors.<br />
Clinical trial identification: S-20140178<br />
Legal entity responsible for the study: Danish Colorectal Cancer Center South<br />
Funding: Danish Colorectal Cancer Center South<br />
Disclosure: C.B. Thomsen: During the last 2 years some travel and accommodation<br />
expenses has been paid by Roche. L.H. Jensen: During the last 2 years some travel and<br />
accommodation expenses has been paid by Roche, Amgen, Bayer. Honoraria has been<br />
given by Astra Zeneca. All other authors have declared no conflicts <strong>of</strong> interest.<br />
91P<br />
Implications <strong>of</strong> key differences across 12 KRAS mutation<br />
detection technologies and their relevance in clinical practice<br />
J.L. Sherwood 1 , A. Rettino 2 , H. Brown 1 , A. Schreieck 3 , B. Claes 4 , G. Clark 5 ,<br />
B. Agrawal 6 , R. Chaston 7 , P. Choppa 8 , A.O.H. Nygren 9 , A. Kohlman 1<br />
1 IMED Biotech Unit: Personalised Healthcare & Biomarkers, AstraZeneca,<br />
Cambridge, UK, 2 West Midlands Regional Genetics Laboratory, Birmingham<br />
Women’s NHS Foundation Trust, Birmingham, UK, 3 R&D, IMGM Laboratories<br />
GmbH, Martinsried, Germany, 4 R&D, Biocartis NV, Mechelen, Belgium, 5 Medical<br />
Genetics, University <strong>of</strong> Cambridge, Cambridge, UK, 6 Vela Diagnostics Pte Ltd,<br />
Singapore, 7 R&D, Leica Biosystems, Newcastle Upon Tyne, UK, 8 Clinical<br />
Sequencing Division, Thermo Fisher Scientific, West Sacramento, CA, USA, 9 R&D,<br />
Agena Bioscience, San Diego, CA, USA<br />
Background: This study assessed, for the first time, KRAS mutation detection and<br />
functional characteristics across 12 distinct platforms and chemistries available in<br />
clinical practice.<br />
Methods: 5 distinct KRAS-mutant cell lines (MIA PACA-2, PANC-1, MDA-MB231,<br />
SW620 and NCI-H460) were obtained from AstraZeneca, Alderley Park Cell Bank, and<br />
5 clinically relevant KRAS mutations were studied: p.G12C, p.G12D and p.G12V, p.<br />
G13D and p.Q61H. 50 cell line admixtures with low (50 and 100) mutant KRAS allele<br />
copies at 20, 10, 5, 1 and 0.5% frequency were analysed using qPCR (n = 3), digital PCR<br />
(n = 1), capillary sequencing (n = 1), NGS (n = 5) and MALDI-TOF (n = 2) assays.<br />
Results: Important performance differences were revealed which could impact patient<br />
treatment decisions, particularly sensitivity, regulatory status (e.g. CE-IVD) and<br />
turnaround time. Only 384/672 data points across all 12 methods were identified correctly.<br />
Successful genotyping <strong>of</strong> admixtures ranged from 0% (Sanger sequencing) to 100% (NGS).<br />
4/5 NGS platforms reported similar allelic frequency for each sample. Of these, one was<br />
able to detect mutations down to a frequency <strong>of</strong> 0.1% and correctly identify all 56 samples<br />
(Oncomine Focus Assay, Thermo Fisher Scientific). A qPCR near impact device<br />
Volume 27 | Supplement 6 | 2016<br />
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abstracts<br />
(Idylla, Biocartis) and MALDI-TOF (UltraSEEK, Agena Bioscience) accurately<br />
identified 96% (all 100 copies & 23/25 50 copies input) and 93% (23/25 100 copies & 23/<br />
25 50 copies input) <strong>of</strong> samples, respectively. Conversely, the digital PCR assay (KRAS<br />
PrimePCR ddPCR,Bio-RadLaboratories,Inc.)wasnon-specific,identifyingthe<br />
wrong mutation in 8 different mutation/allele frequency combinations. Turnaround time<br />
from clinical sample to result ranged from ∼2 hours (Idylla CE-IVD) to 1 day (cobas®<br />
CE-IVD) to >1 week for most NGS assays, while the level <strong>of</strong> required laboratory expertise<br />
ranged from minimal (Idylla CE-IVD) to high (NGS platforms).<br />
Conclusions: This comprehensive parallel assessment used high molecular weight<br />
cell-line DNA as a model to address key questions for a clinical laboratory when<br />
implementing routine KRAS testing. As most <strong>of</strong> the technologies are available for other<br />
molecular biomarkers, results may be informative for other diagnostic functions.<br />
Legal entity responsible for the study: AstraZeneca<br />
Funding: AstraZeneca<br />
Disclosure: J.L. Sherwood, H. Brown, A. Kohlman: Employee <strong>of</strong> and shareholder in<br />
AstraZeneca London. A. Schreieck: institution received financial support for molecular<br />
analysis from AstraZeneca. B. Claes: Reports a patent pending for isolation <strong>of</strong> nucleic<br />
acids. B. Agrawal: Employee <strong>of</strong> Vela Diagnostics.A.O.H. Nygren: Employee <strong>of</strong> and<br />
shareholder in Agena Bioscience. All other authors have declared no conflicts <strong>of</strong> interest.<br />
92P<br />
Impact <strong>of</strong> Kras mutant subtypes on PD-L1 expression in lung<br />
adenocarcinoma<br />
A.T. Falk 1 , N. Yazbeck 1 , L. Thon 1 , N. Guibert 2 , V. H<strong>of</strong>man 3 , K. Zahaf 3 , V. Lespinet 3 ,<br />
O. Bordone 4 ,V.Tanga 4 , K. Washetine 4 , C. Cohen 5 , N. Venissac 5 , J. Mouroux 5 ,<br />
C-H. Marquette 6 , P. Brest 1 , M. Ilié 7 , P. H<strong>of</strong>man 7<br />
1 INSERM U1081/UMR CNRS 7284, Team 3, Institute for Research on Cancer and<br />
Ageing, Nice, France, 2 Thoracic <strong>Oncology</strong>, CHU Toulouse, Hôpital de Larrey,<br />
Toulouse, France, 3 Laboratory <strong>of</strong> Clinical and Experimental Pathology / Liquid<br />
Biopsy Laboratory, Pasteur Hospital, Nice, France, 4 Hospital-Integrated Biobank<br />
(BB-0033-00025), Pasteur Hospital, Nice, France, 5 Department <strong>of</strong> Thoracic<br />
Surgery, Pasteur Hospital, Nice, France, 6 Department <strong>of</strong> Pneumology, Pasteur<br />
Hospital, Nice, France, 7 INSERM U1081/UMR CNRS 7284, Team 3, Institute for<br />
Research on Cancer and Ageing, Nice, France<br />
Background: Clinical responses to immune checkpoint blockade by anti-PD-1/PD-L1<br />
monoclonal antibodies in non-small-cell lung cancer (NSCLC) may be associated with<br />
PD-L1 expression. This study was undertaken to determine the expression pr<strong>of</strong>ile <strong>of</strong><br />
PD-L1 in patients with Kras-mutant lung adenocarcinoma (LUAD) and to investigate<br />
the activation <strong>of</strong> Kras codon subtypes as a mechanism <strong>of</strong> PD-L1 regulation.<br />
Methods: PD-L1 expression was evaluated by IHC (SP142 clone, Ventana) on 117<br />
LUAD (Kras WT , n = 51; Kras mut , n = 66). Stable cell lines were generated by<br />
transfection <strong>of</strong> Kras-G12D, G12V, G12C and WT plasmids into Beas2B bronchial cells.<br />
Results: IHC analysis showed higher expression <strong>of</strong> PD-L1 in both tumor and immune<br />
cells in Kras-mutant LUAD compared with Kras WT tumors (37% vs. 18%; P = 0.005).<br />
Kras-mutant PD-L1 + tumors had increased CD66b + neutrophil infiltrates and lower CD8 +<br />
T-cell content than PD-L1 − tumors. In vitro, mutant Kras led to significantly higher<br />
cell-surface PD-L1 expression and PD-L1 transcripts, notably in Kras G12C and Kras G12V<br />
cells, suggesting PD-L1 transcriptional regulation. There was differential activation <strong>of</strong><br />
NF-kB, ERK and Pi3k/Akt pathways between Kras-mutant subtypes. In addition, PD-L1<br />
was upregulated 3-fold by stimulation with IFNγ, independently <strong>of</strong> the Kras codon<br />
subtypes. Instead, hypoxia significantly increased PD-L1 expression in Kras G12C and<br />
Kras G12D cells. Co-culture experiments with human PBMCs from healthy patients were<br />
performed to determine the functional effect <strong>of</strong> altered PD-L1 expression. Increased PD-L1<br />
expression by tumor cells induced by Kras mutations led to decreased PBMCs proliferation<br />
and increased apoptosis. An anti-PD-L1 checkpoint inhibitor is currently being tested as<br />
single agent or in combination with ERK or PI3K inhibitors in our Kras cell models.<br />
Conclusions: PD-L1 is expressed in 37% <strong>of</strong> Kras mutant LUAD, suggesting PD-L1 as a<br />
therapeutic target in this subset. According to the Kras mutation subtype, potential<br />
drugs targeting the NF-kB, ERK or Pi3k/Akt pathways may additionally increase the<br />
antitumor adaptive immune responses.<br />
Legal entity responsible for the study: N/A<br />
Funding: Pasteur Hospital, Nice<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
93P<br />
KRAS status and HER2 targeted treatment in advanced gastric<br />
cancer<br />
E. Shinozaki, H. Osumi, K. Chin, D. Takahari, M. Ogura, T. Ichimura,<br />
T. Matsushima, T. Wakatsuki, I. Nakayama, K. Yamaguchi<br />
Department <strong>of</strong> GI <strong>Oncology</strong>, Cancer Institute Hospital <strong>of</strong> JFCR, Tokyo, Japan<br />
Background: Trastuzumab targeted on HER2 has been shown to confer overall<br />
survival benefit adding to fluoropyrimidine (Fp) plus CDDP in HER2-positive<br />
advanced gastric cancer (AGC). HER2 is known to make the formation <strong>of</strong> heterodimer<br />
with EGFR(HER1), HER3 and HER4. HER2 containing heterodimer activates the<br />
common downstream <strong>of</strong> HER family such as MAPK pathway via RAS. RAS and BRAF<br />
status has been established as predictive biomarkers for anti EGFR treatment in<br />
metastatic colorectal cancer. However it remains unclear that the implications for these<br />
status and HER2 targeted treatment in AGC. In this study we attempted to assess the<br />
relationship with the efficacy <strong>of</strong> trastuzumab including treatment and mutational status<br />
<strong>of</strong> HER family signaling pathway.<br />
Methods: Out <strong>of</strong> 100 patients received Fp plus CDDP with trastuzumab as 1st-line<br />
between March 2011 and November 2015, total 77 patients with sufficient specimen for<br />
DNA extraction were enrolled in this analysis. Multiplex genotyping <strong>of</strong> HER family<br />
common downstream was performed on archival samples using Luminex Assay<br />
(MEBGEN and GENOSEARCH Mu-PACK, MBL) for KRAS and NRAS including<br />
exon 2, 3 and 4, PIK3CA and BRAF. Tumor response was re-assessed by the<br />
investigator retrospectively by RECIST1.1.<br />
Results: KRAS mutation <strong>of</strong> exon2 was detected in only 6 patients <strong>of</strong> 77 patients (7.8<br />
%). No mutations were found in NRAS, PIK3CA and BRAF in this HER2 positive<br />
AGC series. An overall RR and the disease control rate (DCR) in KRAS wild type (WT)<br />
vs. mutant type (MT) were following, RR; 66.2% vs. 16.7%, DCR; 87.3% vs. 66.7%,<br />
respectively (CR2/0, PR 45/1, SD 15/3, PD 9/2). The median PFS and OS in KRAS WT<br />
vs. MT were as followed, 8.9 months (m) vs. 3.6 m and 20.8 m vs. 10.3 m, respectively.<br />
KRAS MT showed extremely shorter PFS and OS compared with KRAS WT<br />
(P = 0.00008 and 0.0008).<br />
Conclusions: Our data suggested HER2-positive AGC harbored KRAS mutation at the<br />
low frequency. KRAS mutation might predict poor prognosis as receiving HER2<br />
targeted treatment. Further investigation was warranted to confirm the predictive value<br />
<strong>of</strong> KRAS status in HER2-positive AGC treated with trastuzumab to fluoropyrimidine<br />
plus CDDP. We will present additional analysis <strong>of</strong> KRAS amplification in this cohort at<br />
the convention.<br />
Legal entity responsible for the study: N/A<br />
Funding: Japanese Foundation for Cancer Research<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
94P An extended KRAS mutation test for the detection <strong>of</strong> 28<br />
common mutations in FFPET and plasma specimens<br />
J. Li 1 , C. Hoeppner 2 , S. Gan 1 , A. Blair 1 , K. Min 1 , A. Sims 2 , A. Tietz 2 , M. Vinas 2 ,<br />
T.T. Rehage 2 , K. Malhotra 2 , H. Halait 2 , V. Brophy 1<br />
1 Genomics and <strong>Oncology</strong>, Roche Molecular Systems, Pleasanton, CA, USA,<br />
2 Assay Development, Roche Molecular Systems, Pleasanton, CA, USA<br />
Background: The KRAS oncogene is frequently mutated in human cancers. In<br />
addition to KRAS codons 12, 13, 61 hotspot mutations, recent clinical trial data<br />
revealed that mutations in KRAS codons 59, 117, 146 also predict poor response to<br />
anti-epidermal growth factor receptor (EGFR) therapy in patients with metastatic<br />
colorectal cancer (mCRC). Detection <strong>of</strong> an extended set <strong>of</strong> KRAS mutations in<br />
colorectal cancer tissues is now accepted clinical practice.<br />
Methods: The KRAS Mutation Test v2 (Life Science Research, LSR) is a real-time PCR<br />
assay, which detects 28 mutations in codons 12, 13, 59, 61, 117 and 146 <strong>of</strong> the KRAS<br />
gene in DNA derived from formalin-fixed, paraffin-embedded tissue (FFPET) as well<br />
as plasma specimens. Mutations are detected by allele-specific amplification in three<br />
multiplex PCR reactions on the cobas z 480 analyzer. LOD studies were performed<br />
using contrived tissue and plasma samples. For method correlation, 301 FFPET<br />
specimens and 636 plasma specimens were tested with the KRAS Mutation Test v2<br />
(LSR) and MiSeq (Illumina) sequencing as the reference method.<br />
Results: Using preliminary analysis parameters, the KRAS test has shown it can detect<br />
at least 1% mutant sequence in a background <strong>of</strong> wild-type DNA for tissue, and at least<br />
100 mutant sequence copies per mL for plasma in the LOD studies. Preliminary<br />
method correlation results revealed >98% overall concordance for tumor FFPET and<br />
>90% overall concordance for cell-free DNA samples with MiSeq reference data. Final<br />
results will be presented.<br />
Conclusions: The KRAS Mutation Test v2 (LSR) demonstrated strong initial analytical<br />
performance for the detection <strong>of</strong> 28 KRAS mutations. It is a sensitive, robust and reliable<br />
assay with a quick turnaround time which can be used on both tissue and liquid biopsies.<br />
Legal entity responsible for the study: Roche Molecular Systems<br />
Funding: Roche Molecular Systems<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
95P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Plasma YKL-40 as a biomarker for poor prognosis in patients<br />
with metastatic colorectal cancer treated with 3. line<br />
cetuximab and irinotecan<br />
B.V. Jensen 1 , K-L.G. Spindler 2 , I.J. Christensen 3 , J.V. Schou 4 , D.L. Nielsen 1 ,<br />
A. Jakobsen 5 , E. Høgdall 3 , P. Pfeiffer 6 , M.K. Yilmaz 7 , J. Johansen 1<br />
1 Department <strong>of</strong> <strong>Oncology</strong>, Herlev and Gent<strong>of</strong>te Hospital, Herlev, Denmark,<br />
2 <strong>Oncology</strong>, Aarhus University Hospital, Aarhus, Denmark, 3 Department <strong>of</strong><br />
Pathology, Herlev and Gent<strong>of</strong>te Hospital, Herlev, Denmark, 4 Department <strong>of</strong><br />
<strong>Oncology</strong>, Herlev and Gent<strong>of</strong>te Hospital, Copenhagen, Denmark, 5 <strong>Oncology</strong>, Vejle<br />
Hospital Sygehus Lillebaelt, Vejle Sygehus, Vejle, Denmark, 6 Department <strong>of</strong><br />
<strong>Oncology</strong>, Odense University Hospital, Odense, Denmark, 7 Department <strong>of</strong><br />
<strong>Oncology</strong>, Aalborg University Hospital, Aalborg, Denmark<br />
Background: YKL-40 (CHI3L1) plays a major role in inflammation and angiogenesis.<br />
In patients with metastatic colorectal cancer (mCRC) we wanted to test if high<br />
pretreatment levels <strong>of</strong> plasma YKL-40 and change <strong>of</strong> YKL-40 during therapy with<br />
vi28 | abstracts Volume 27 | Supplement 6 | 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
cetuximab and irinotecan was independent <strong>of</strong> KRAS mutation status and associated<br />
with progression free (PFS) and overall survival (OS).<br />
Methods: Two independent studies <strong>of</strong> 162 patients and 98 patients (Study I and II)<br />
with mCRC resistant to 5-FU, oxaliplatin and irinotecan treated with cetuximab and<br />
irinotecan without knowledge <strong>of</strong> their KRAS mutation status were performed in<br />
Denmark between 2006 and 2008. Plasma YKL-40 was determined by ELISA. Seven<br />
mutations in the KRAS oncogene were determined by the DxS TheraScreen kit.<br />
Results: In both studies a high pretreatment plasmaYKL-40 (log transformed<br />
continuous variable) was significantly associated to short overall survival (OS)<br />
independent <strong>of</strong> KRAS mutation status (Study I: HR = 1.17, 95% CI 1.04-1.30,<br />
P = 0.009; interaction between KRAS and YKL-40 P = 0.75; Study II: HR = 1.34, 95%<br />
CI 1.12-1.59, P = 0.0001; interaction between KRAS and YKL-40 p = 0.85).<br />
Multivariate Cox analysis including YKL-40, age, sex, performance status (PS), number<br />
<strong>of</strong> metastatic sites and KRAS mutation status demonstrated that elevated pretreatment<br />
plasma YKL-40 was an independent biomarker <strong>of</strong> OS (Study I: HR = 1.53, 95% CI<br />
1.10-2.13, P = 0.013; Study II: HR = 2.89, 1.84-4.53, P < 0.0001). During treatment high<br />
YKL-40 ratio (YKL-40 at different time points compared to pretreatment level) was<br />
associated with short PFS (HR = 1.30, 95% CI 1.10-1.54, P = 0.002) and OS (1.38, 95%<br />
CI 1.17-1.63, P = 0.0002). Log transformed plasma YKL-40 during therapy adjusted for<br />
study and KRAS mutation status was also associated with PFS (HR = 1.11, 95% CI<br />
1.04-1.20, P = 0.002) and OS (HR = 1.23, 95% CI 1.14-1.33, P < 0.0001).<br />
Conclusions: In two independent studies plasma YKL-40 before and during treatment<br />
<strong>of</strong> patients with mCRC with cetuximab and irinotecan was a strong independent<br />
biomarker <strong>of</strong> PFS and OS independent <strong>of</strong> KRAS mutation status.<br />
Clinical trial identification: EudraCT number 2006-001-961-40<br />
Legal entity responsible for the study: Department <strong>of</strong> <strong>Oncology</strong>, Herlev and Gent<strong>of</strong>te<br />
Hospital, University <strong>of</strong> Copenhagen<br />
Funding: Department <strong>of</strong> <strong>Oncology</strong>, Herlev and Gent<strong>of</strong>te Hospital, University <strong>of</strong><br />
Copenhagen<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
96P<br />
Whole exome sequencing (WES) and RNA sequencing<br />
(RNA-seq) in routine clinical practice for colorectal cancer<br />
(CRC) and non-small cell lung cancer (NSCLC) patients (pts)<br />
G. Perkins 1 , E. Fabre 2 , V. Fallet 3 , H. Blons 4 , N. Pecuchet 2 , V. Gounant 5 ,<br />
L. Gibault 6 , E. Michel-Jeljeli 7 , M. Antoine 8 , E. Roux 9 , M. Wislez 3 , D. Le Corre 10 ,<br />
K. Leroy 11 , R. Lacave 12 , J. Taieb 1 , J. Cadranel 3 , P. Laurent-Puig 4<br />
1 GI <strong>Oncology</strong>, Hopital European George Pompidou, Paris, France, 2 Medical<br />
<strong>Oncology</strong>, Hopital European George Pompidou, Paris, France, 3 Pneumology,<br />
APHP, CancerEst, Tenon University Hospital, Paris, France, 4 Biology, Hopital<br />
European George Pompidou, Paris, France, 5 Thoracic <strong>Oncology</strong>, Hopital Bichat<br />
Claude Bernard, Paris, France, 6 Pathology, Hopital Europeen Georges, Paris,<br />
France, 7 Pathology and PRB-HEGP, Hopital Europeen Georges, Paris, France,<br />
8 Pathology, APHP, CancerEst, Tenon University Hospital, Paris, France,<br />
9 Tumorothèque HUEP «TumeurEst», APHP, CancerEst, Tenon University Hospital,<br />
Paris, France, 10 INSERM 1147, Paris Descartes University, Paris, France,<br />
11 Genetic and Molecular Biology, Hôpital Cochin, Paris, France, 12 Tumors<br />
Genomics Unit, APHP, CancerEst, Tenon University Hospital, Paris, France<br />
Background: Precision medicine is a promising approach to select effective treatments<br />
for cancer pts. Here we report the use <strong>of</strong> WES and RNA-seq analysis in routine clinical<br />
practice, to select targeted therapies (TT) for pretreated metastatic cancer pts.<br />
Methods: CRC and NSCLC pts without druggable genetic alterations were selected<br />
during a multidisciplinary medical board. Fresh frozen (FF) and/or formalin-fixed<br />
paraffin embedded (FFPE) tissue <strong>of</strong> the primary and/or metastasis tumors were<br />
collected. Re-biopsy was performed when possible. Blood was drawn for comparative<br />
germline analysis. WES was performed on tumor/germline DNA, and RNA-seq on FF<br />
tumor RNA. Pts were systematically referred for genetic counseling and written<br />
informed consent was recorded. Results were reviewed during a second medical board,<br />
to identify molecular alterations and propose a relevant TT.<br />
Results: Between 09/2014 and 4/2016, 35 pts were selected; 1 pt refused WES analysis.<br />
34 pts (13 CRC, 21 NSCLC) had WES and/or RNA-seq <strong>of</strong> their tumor; 1 pt refused to<br />
be informed <strong>of</strong> incidental germline mutations. The median age was 49 years (27-74). 8<br />
pts had undergone a tumor re-biopsy. 45 tumor tissues (17 primary/28 metastatic) and<br />
30 germline samples were tested. Germline mutations (BRCA2, STK11, MEN1,<br />
COL3A1, MYBPC3) were found in 5 pts. An average <strong>of</strong> 1.3 tumors (1-3) by pt was<br />
tested. WES was done on 37 FF and 4 FFPE tissues; 1 analysis failed because <strong>of</strong> low<br />
tumor cellularity. RNA-seq was done on 34 FF tissues. The median analysis<br />
turnaround was 21.5 days (8-92). Potential driver alterations were found in 27 pts, most<br />
frequently in HER/RAS/MAPK (n = 14), PTEN/PI3K/AKT (n = 6), STK11 (n = 4)<br />
pathways. Gene alterations were identified in chromatin organization (ARID1A/<br />
ARID2/EZH2, n = 8), cell cycle checkpoint signaling (ATR/ATRX/ATM, n = 4), and<br />
DNA repair (BRCA1/BRCA2, n = 4) pathways. Therapy could be personalized in 13<br />
pts, <strong>of</strong> whom 7 were included in a clinical trial.<br />
Conclusions: These results are encouraging on the feasibility <strong>of</strong> WES and RNA-seq<br />
analysis in routine clinical basis, in order to select dedicated TT in pretreated pts.<br />
Legal entity responsible for the study: Pierre Laurent-Puig<br />
Funding: Canceropole Ile de France<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
97P<br />
Chitinase activity can predict liver metastases in colorectal<br />
cancer in blood<br />
Z. Song<br />
Department <strong>of</strong> Colorectal Surgery, Sir Run Run Shaw Hospital, Zhejiang University,<br />
Hangzhou, China<br />
Background: DNA damage accumulation and telomere dysfunction is associated with<br />
the development <strong>of</strong> cancer. However, we do not know the exact role <strong>of</strong> DNA damage<br />
and telomere dysfunction in metastases <strong>of</strong> colorectal cancer. We have previously<br />
identified biomarkers for DNA damage and telomere dysfunction. In this study we<br />
evaluated the role <strong>of</strong> chitinase activity (one <strong>of</strong> the biomarkers) in blood in predicting<br />
liver metastases <strong>of</strong> colorectal cancer.<br />
Methods: The levels <strong>of</strong> chitinase activity were examined in 400 colorectal cancer<br />
patients, including 53 synchronous liver metastases in peripheral blood. 347 colorectal<br />
cancer patients’ peripheral blood activities were measured before resection <strong>of</strong> the<br />
cancer. The clinical parameters were collected, and the patients were prospectively<br />
followed up.<br />
Results: The average age <strong>of</strong> the cancer patient was 65 years old, the chitinase activity<br />
was significantly over-expressed in synchronous liver metastases when compared with<br />
colorectal cancer patients who had no metastases. During the follow up in 347<br />
colorectal cancer patients, higher expression <strong>of</strong> chitinase activity, higher risk <strong>of</strong> liver<br />
metastases, both univariate Cox analysis (HR6.0) and multivariate Cox analysis(HR<br />
5.3) showed chitinase has high predictive value for liver metastases after resection <strong>of</strong><br />
the primary colorectal cancer. Kaplan-Meier analysis shows the chitinase activity has<br />
significant correlation to survival in colorectal cancer patients. The metastasis ratio<br />
between two groups in non-synchronic colorectal metastasis patients.<br />
Table: 97P<br />
Group One year Three years Five years<br />
Low chitinase activity 4.7% (10/211) 9.5% (20/211) 10.4% (22/211)<br />
High chitinase activity 10.4% (12/115) 16.5% (19/115) 22.6% (26/115)<br />
*Cut-<strong>of</strong>f value = 22.8026<br />
Conclusions: Taken together, the findings in this study provide experimental evidence<br />
that chitinase activity is a potentially predictive biomarker for liver metastases in<br />
colorectal cancer.<br />
Legal entity responsible for the study: N/A<br />
Funding: National Natural Science Foundation <strong>of</strong> China (NSFC)<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
98P<br />
Genetic variations in the VEGF pathway as prognostic factors in<br />
stages II and III colon cancer<br />
A.C. Virgili Manrique 1 , P. Riera Armengol 2 , J. Salazar Blanco 2 , M. Tobeña 1 ,A.<br />
Sebio Garcia 1 , M. Martín Richard 1 , E. del Rio Conde 2 , N. Dueñas Cid 1 ,A.<br />
Vethencourt Casado 1 , A. Barba Joaquín 1 , M. Andrés Granyo 1 , D. Paez 1<br />
1 Medical <strong>Oncology</strong>, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain,<br />
2 Genetics, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain<br />
Background: It is well known that angiogenesis plays an important role in progression<br />
and metastasis in solid tumours. We hypothesized whether genetic variations involved<br />
in this pathway may impact in stages II-III colon cancer prognosis.<br />
Methods: We retrospectively revised 232 stage II and III colon cancer patients<br />
diagnosed between 2009 and 2014 in our institution. DNA was extracted from EDTA<br />
blood samples. A total <strong>of</strong> 27 single-nucleotide polymorphisms (SNPs) in 12 genes in<br />
the VEGF-dependent angiogenesis process were genotyped using a dynamic array on<br />
the BioMark system.<br />
Results: The median age <strong>of</strong> the patients was 68.1 years (range 31-94) and 53.9% were<br />
men. One-hundred twenty-six patients were diagnosed at stage II and 106 at stage III.<br />
With a median follow-up <strong>of</strong> 37.1 months (range 9.3-91.5 months) 23.6% <strong>of</strong> patients<br />
with stage II and 30.5% with stage III relapsed. Median overall survival (OS) was 78.9<br />
and 54.5 months for patients with stages II and III, respectively. Among the<br />
clinicopathological risk factors analysed, in the multivariate analysis, N2 (metastasis in<br />
4 or more regional lymph nodes) was significantly associated with worse recurrence<br />
free survival (RFS) (HR: 2.56; 95% CI 1.05-6.2; adjusted p = 0.038) and OS (HR: 3.18;<br />
95% CI 1.05-9.6; adjusted p = 0.04); and stage was also associated with worse OS (HR:<br />
3.47; 95% CI 1.2-9.9; adjusted p = 0.019). Regarding the genetic variants analysed, in<br />
the univariate analysis, 5 polymorphisms in 4 genes (VEGFA rs1570360 A/G and<br />
rs2010963 C/G, VEGFR2 rs1551641 G/A, KRAS rs12813351 C/T and MAP2K6<br />
rs2716191 C/T) were significantly associated with prognosis. In the multivariate<br />
analysis, patients homozygous for the variant allele <strong>of</strong> MAP2K6 rs2716191 C/T,<br />
showed significant worse prognosis in terms <strong>of</strong> RFS (HR: 1.98; 95% CI: 1.03-3.83;<br />
adjusted p = 0.041) and OS (HR: 3.38; 95% CI: 1.49-7.72; adjusted p = 0.004). Patients<br />
homozygous for the variant allele <strong>of</strong> VEGFA rs2010963 C/G showed worse OS (HR:<br />
6.36; 95%CI 1.2-32.6; adjusted p = 0.027).<br />
Volume 27 | Supplement 6 | 2016<br />
doi:10.1093/annonc/mdw363 | vi29
abstracts<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Conclusions: This study provides evidence that functional germline polymorphisms in<br />
the VEGF pathway may be helpful as prognostic biomarkers in colon cancer.<br />
Legal entity responsible for the study: Hospital de la Santa Creu i Sant Pau (Barcelona)<br />
Funding: Hospital de la Santa Creu i Sant Pau (Barcelona)<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
99P<br />
Clinical characteristics in colorectal cancer harboring BRAF<br />
V600E and non-V600E mutations<br />
E. Shinozaki 1 , Y. Miki 2 , M. Ueno 3 , M. Igarashi 4 , K. Chin 1 , D. Takahari 1 , M. Ogura 1 ,<br />
T. Ichimura 1 , I. Nakayama 1 , H. Osumi 1 , T. Wakatsuki 1 , T. Matsushima 1 ,<br />
K. Yamaguchi 1<br />
1 Department <strong>of</strong> GI <strong>Oncology</strong>, Cancer Institute Hospital <strong>of</strong> JFCR, Tokyo, Japan,<br />
2 Lab <strong>of</strong> Genetic Diagnosis, Cancer Institute Hospital <strong>of</strong> JFCR, Tokyo, Japan,<br />
3 Department <strong>of</strong> Gastroenterological Surgery, Cancer Institute Hospital <strong>of</strong> JFCR,<br />
Tokyo, Japan, 4 Department <strong>of</strong> Gastroenterology, Cancer Institute Hospital <strong>of</strong><br />
JFCR, Tokyo, Japan<br />
Background: BRAF V600E mutation (MT) in metastatic colorectal cancer (CRC) has<br />
been known thoroughly as a prognostic biomarker, and as a negative predictive<br />
biomarker for anti-EGFR treatment. On the other hand, the feature <strong>of</strong> BRAF MTs<br />
other than BRAF V600E still remains unclear. This study aimed to reveal the clinical<br />
characteristics <strong>of</strong> BRAF non-V600E MTs compared with the EGFR signaling pathway<br />
MTs status including BRAF V600E MT.<br />
Methods: Consecutive patients from June 2012 to November 2013 were enrolled in this<br />
study. Multiplex genotyping <strong>of</strong> EGFR signaling pathway was performed on archival<br />
samples using Luminex Assay (MABGEN, GENOSEARCH Mu-PACK and<br />
GENOSEARCH BRAF, MBL) for BRAF V600E / BRAF non-V600E , KRAS including exon<br />
2, 3 and 4, NRAS, and PIK3CA. We analyzed the correlation among MTs pr<strong>of</strong>ile,<br />
clinical data and location <strong>of</strong> CRC.<br />
Results: A total <strong>of</strong> 824 CRC patients was analyzed; consisted <strong>of</strong> 374 females and 450<br />
males, 147, 200, 263 and 214 in stage I, II, III and IV or recurrent CRC, respectively.<br />
The incidence <strong>of</strong> MTs were as followings; BRAF V600E / BRAF non-V600E , KRAS<br />
including exon 2, 3 and 4, NRAS and PIK3CA were 5.3% / 1.7%, 41.5%, 3.3% and<br />
9.7%, respectively. The relationship among main characteristics and mutational status<br />
showed in table below. Although RAS and BRAF V600E MTs were in a mutually<br />
exclusive manner, one case <strong>of</strong> co-mutation with KRAS A146T MT was observed in<br />
BRAF non-V600E cases. In both BRAF V600E MT and BRAF non-V600E MT, four cases were<br />
having co-mutation with PIK3CA MTs.<br />
female/<br />
male<br />
n = 374/<br />
450<br />
Table: 99P<br />
right/ left +rectum*<br />
n = 235/ 589<br />
(335 + 254)<br />
por/<br />
others**<br />
n = 47/<br />
777<br />
stage I/ II/ III/<br />
IV + rec***<br />
n = 147/ 200/<br />
263/ 214<br />
BRAF V600E n = 44 24/ 20 33/ 11 (8 + 3) 9/ 35 7/ 11/ 9/ 17<br />
BRAF non-V600E n = 14 7/ 7 3/ 11 (4 + 7) 1/ 13 4/ 4/ 3/ 3<br />
KRAS exon2 n = 307 153/ 154 116/191(89 + 102) 9/ 298 52/ 76/ 102/ 65<br />
KRAS exon3,4 n = 35 17/ 18 4/ 31 (16 + 15) 2/ 33 6/ 6/ 17/ 5<br />
NRAS n = 27 13/ 14 2/ 25 (11 + 14) 0/ 27 2/ 7/ 8/ 9<br />
PIK3CA n = 80 32/ 48 38/ 42 (17 + 25) 2/ 78 15/ 25/ 23/ 17<br />
Abbreviation; *right/ left-sided colon; ** poorly differentiate; *** recurrence<br />
Conclusions: In this analysis BRAF non-V600E MTs were identified as a rare fraction and<br />
had no specific character revealed in contrast to the BRAF V600E MT, which was more<br />
frequent in right-sided primary, female and poorly differentiated histology. Further<br />
more large-scale investigation in this rare fraction <strong>of</strong> BRAF non-V600E MTs will be<br />
necessary to clarify its clinical meaning for precision medicine.<br />
Legal entity responsible for the study: N/A.<br />
Funding: Japanese Foundation for Cancer Research<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
100P<br />
5-fluorouracil degradation rate as a predictive toxicity<br />
biomarker in early stage gastrointestinal cancer<br />
M. Roberto 1 , A. Romiti 1 , A. Botticelli 2 , F.R. Di Pietro 1 , L. Lionetto 3 , G. Gentile 3 ,<br />
F. Mazzuca 1 , R. Falcone 1 , M. Occhipinti 1 , S. Macrini 1 , E. Anselmi 1 , A. Petremolo 1 ,<br />
C.E. Onesti 1 , M. Simmaco 3 , P. Marchetti 1<br />
1 Clinical and Molecular Medicine, Azienda Ospedaliera St. Andrea - Roma, Rome,<br />
Italy, 2 Medical <strong>Oncology</strong>, Azienda Ospedaliera St. Andrea - Roma, Rome, Italy,<br />
3 NESMOS, Sapienza University, Rome, Italy<br />
Background: Prediction and early management <strong>of</strong> severe toxicity might avoid both<br />
therapy’s interruption and the benefit loss <strong>of</strong> adjuvant chemotherapy. However,<br />
predictive toxicity biomarkers are not yet available. The aim <strong>of</strong> this study was to<br />
investigate whether polymorphisms <strong>of</strong> different genes involved in fluoropyrimidine<br />
metabolism and 5-fluorouracil (5-FU) degradation rate were associated with clinical<br />
outcome <strong>of</strong> oral fluoropyrimidine-based adjuvant chemotherapy in patients with early<br />
stage GI cancer.<br />
Methods: Genotyping <strong>of</strong> DPYD IVS14 IVS 14 + 1 G > A, MTHFR C677T and A1298C<br />
SNPs were performed by pyro-sequencing technology. PCR analysis was used for<br />
genotyping TYMS-TSER. Using PBMC cells, we also evaluated the 5-FU degradation<br />
rate, which determines the amount <strong>of</strong> drug consumed by cells in a time unit. Patients<br />
were categorized in two groups according to their value <strong>of</strong> 5-FU degradation rate:<br />
below the 5th centile (poor metabolism - PM) or above the 95th centile (ultra-rapid<br />
metabolism - UM) and within 5-95th centile (0.85-2.2 ng/ml/10 6 cells/min).<br />
Results: One hundred forty-two patients with early stage colon (39%), rectal (28%),<br />
stomach (20%) and pancreatic (13%) cancer, treated with 5FU-based adjuvant<br />
monochemotherapy, were included in this retrospective analysis. Forty-three per cent <strong>of</strong><br />
patients had a lymphnode-positive disease, and 37% received concomitant radiotherapy.<br />
Most <strong>of</strong> patients had an ECOG PS = 0-1. Seventy-four and 20% <strong>of</strong> the patients suffered<br />
from at least one G1-4 and G3-4 adverse events (12 hematologic, 24 GI, 12 HFS),<br />
respectively. Sixteen (11%) patients resulted abnormal 5-FU metabolizers. At a<br />
multivariate logistic regression analysis, an altered 5-FU degradation rate (2.10)<br />
resulted significantly associated with both G1-4 hematologic (OR = 2.99, 95% CI 0.98-9.12,<br />
P = 0.05) and all grade 3-4 adverse events (OR = 4.39, 95% CI 1.40-13.80, P = 0.01). No<br />
correlation was reported between toxicity and each tested gene polymorphism.<br />
Conclusions: Our study showed a statistically significant association between 5-FU<br />
degradation rate and both G1-4 hematologic and all G3-4 toxicities. Therefore, the<br />
5FU-degradation rate may be considered as a putative, predictive biomarker <strong>of</strong><br />
fluoropyrimidine-related toxicity.<br />
Legal entity responsible for the study: N/A<br />
Funding: Self-funded<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
101P<br />
Predictive value <strong>of</strong> vascular endothelial growth factor A<br />
(VEGF-A) for bevacizumab-based treatments across advanced<br />
cancers: a meta-analysis based on eight phase III randomized<br />
control trials involving 4,523 patients<br />
S. Tang, Y. Zhang, W. Liang, J. He<br />
Department <strong>of</strong> Thoracic <strong>Oncology</strong>, The 1st Affiliated Hospital <strong>of</strong> Guangzhou<br />
Medical University, Guangzhou, China<br />
Background: Bevacizumab, a monoclonal antibody against vascular endothelial growth<br />
factor (VEGF), has been shown to be beneficial for patients with advanced cancer in<br />
phase III randomized control trials which had associated biomarker analyses. We aim<br />
to evaluate the predictive value <strong>of</strong> circulating VEGF-A on patient survival in these<br />
studies.<br />
Methods: PubMed was searched for eligible trials from the date <strong>of</strong> inception to 31st<br />
December, 2015. Based on the median circulating level <strong>of</strong> VEGF-A in each trial, we<br />
conducted a meta-analysis with random-effect model to estimate the treatment effects<br />
between bevacizumab-based treatments and treatments without bevacizumab on<br />
progression-free survival (PFS) and overall survival (OS). Interaction test was used to<br />
examine the predictive value.<br />
Results: Eight studies were included, involving 4,523 patients analyzed with VEGF-A<br />
level. Patients following bevacizumab-based treatments had significantly prolonged<br />
PFS regardless <strong>of</strong> VEGF-A level (high:HR = 0.70 [95 % CI 0.63-0.77], P < 0.001, I2=<br />
0%; low: HR = 0.78 [0.70-0.87], P < 0.001, I2= 3%). No significant interaction effect was<br />
observed (Chi 2 = 5.15, P = 0.12). Although significant benefit on OS was exclusively<br />
shown in patients with higher VEGF-A level (high: HR = 0.83 [0.73-0.95], P = 0.005,<br />
I2= 0%; low: HR = 0.96 [0.83-1.10], P = 0.55, I2= 4%) but there was still no interaction<br />
effect between stratified groups (Chi 2 = 5.15, P = 0.14). Subgroup analysis revealed<br />
potential VEGF-A subgroup differences in patients with breast cancer and gastric<br />
cancer but not lung cancer and colorectal cancer. However, tumor type was not a<br />
source <strong>of</strong> heterogeneity during synthesis on PFS or OS.<br />
Conclusions: There is still insufficient evidence to support the use <strong>of</strong> VEGF-A as a<br />
predictive biomarker for bevacizumab-based treatment in advanced cancers.<br />
Legal entity responsible for the study: N/A<br />
Funding: The First Affiliated Hospital <strong>of</strong> Guangzhou Medical University<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
102P<br />
Large scale DFNA5 methylation and expression analysis in<br />
primary breast adenocarcinoma using data from the Cancer<br />
Genome Atlas<br />
L. Croes 1 , M. Beyens 1 , E. Franssen 2 , A. Goepfert 1 , M. Peeters 3 , P. Pauwels 4 ,<br />
G. Van Camp 2 , K. Op De Beeck 1<br />
1 <strong>Oncology</strong> - Medical Genetics, University <strong>of</strong> Antwerp-Campus Drie Eiken,<br />
Antwerp, Belgium, 2 Medical Genetics, University <strong>of</strong> Antwerp-Campus Drie Eiken,<br />
Antwerp, Belgium, 3 Department <strong>of</strong> <strong>Oncology</strong>, University Hospital Antwerp,<br />
Edegem, Belgium, 4 Department <strong>of</strong> Molecular Pathology, University Hospital<br />
Antwerp, Edegem, Belgium<br />
Background: Methylation <strong>of</strong> promotor CpG islands is frequently associated with<br />
transcriptional silencing and may serve as a mechanism to inactivate tumor suppressor<br />
vi30 | abstracts Volume 27 | Supplement 6 | 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
genes in breast cancer. We hypothesize that DFNA5 promotor methylation may be a<br />
valuable epigenetic biomarker, based upon strong indications for its role as tumor<br />
suppressor gene, its function in programmed cell death and its potential role as<br />
biomarker in cancer.<br />
Methods: In this study we analyzed DFNA5 methylation in a high number <strong>of</strong> samples<br />
using publicly available data from TCGA. Infinium HumanMethylation450k data,<br />
covering 22 different CpGs in the DFNA5 gene, from 668 female breast<br />
adenocarcinoma samples and 79 paired normal breast samples were obtained. Agilent<br />
244K Custom Gene Expression data were obtained for 476 female breast<br />
adenocarcinoma samples and 55 paired normal breast samples.<br />
Results: A significant difference in DFNA5 methylation (N = 79) between primary<br />
tumor and paired normal breast samples was found for all 22 CpGs (p < 0,001). This<br />
was also the case for DFNA5 expression (N = 55; p < 0,0001). Furthermore, a<br />
significant higher DFNA5 methylation was found in lobular compared to ductal<br />
adenocarcinoma in 11 out <strong>of</strong> 22 CpGs (p < 0,05). The same is true for DFNA5<br />
expression (p < 0,01). Next, a physical map was constructed to correlate the<br />
chromosomal location <strong>of</strong> the 22 CpGs with the average methylation values <strong>of</strong> the<br />
different subgroups (normal vs. tumor). A clear clustering <strong>of</strong> the methylation values at<br />
the different positions was observed. The methylation values <strong>of</strong> the first 6 CpGs,<br />
located in the gene body, were always higher in the normal samples compared to the<br />
tumor samples. In contrast, for CpG7 till CpG20, located in the gene promotor region,<br />
the average methylation values <strong>of</strong> the normal samples were always lower than the<br />
tumor samples. For CpG21 and CpG22 methylation values were again higher in<br />
normal samples. Finally, we showed that ER state is associated with DFNA5<br />
methylation in 18 CpGs (p < 0,05).<br />
Conclusions: These preliminary data suggest a promising role <strong>of</strong> DFNA5 in breast<br />
cancer. In addition, this analysis shows the power <strong>of</strong> initiatives such as TCGA, providing<br />
data for large sample numbers, for the analysis <strong>of</strong> individual genes involved in cancer.<br />
Legal entity responsible for the study: University <strong>of</strong> Antwerp<br />
Funding: FWO, University <strong>of</strong> Antwerp<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
103P<br />
Evaluation <strong>of</strong> the conversion rate in Ki-67, estrogen receptor<br />
(ER), progesterone receptor (PR) and HER2 between primary<br />
breast cancer and relapse and their value as a prognostic<br />
factor<br />
I. Blancas López-Barajas 1 , A. Muñoz 2 , M. Legerén 1 , F. Galvez 1 , R. González 1 ,<br />
J.M. Jurado 1 , C.J. Rodriguez 1 , M. Delgado 1 , B. Gonzalez Astorga 1 , M. Yélamos 1 ,<br />
S. Sequero 1 , V. Chacon 1<br />
1 <strong>Oncology</strong>, Hospital Clinico San Cecilio, Granada, Spain, 2 Medicina, Facultad de<br />
Medicina, Universidad de Granada, Granada, Spain<br />
Background: The aims are to asses the different expression <strong>of</strong> ER, PR, HER2 and Ki-67<br />
between primary tumor and the recurrence and theirs prognostic consequences.<br />
Methods: Observational retrospective unicentric study <strong>of</strong> 45 breast cancer patients. We<br />
have two different populations: patients who have a local and complete resected relapse<br />
(LR) and patients with a metastatic biopsied disease (MD).The changes in ER, PR,<br />
HER2 and Ki-67 between the pathologist report <strong>of</strong> primary tumor and the biopsy <strong>of</strong><br />
the relapse have been analyzed. We studied ER, PR, HER2 and Ki-67 determined in the<br />
relapse as prognostic factor for relapse free survival (RFS) and overall survival (OS) in<br />
the LR group, and for progression-free survival (PFS) and OS in MD group.<br />
Results: The conversion rate <strong>of</strong> 34,8% for Ki-67 (p = 0,046), 20% for ER (p = 0,001),<br />
20% for PR (p < 0,001), and 15,6% for HER2 (p < 0,001). In LR group we have not<br />
found statistical differences in RFS according to ER, PR, HER2, either Ki-67; the mean<br />
for Ki-67≥ 14% 27,1 months (m) (IC95% 19,6-36,2) vs Ki-67 < 14% 69,5m (IC95%<br />
0,0-145,0) (p = 0,262). In MD group we have not found statistical differences in PFS<br />
according to ER, PR, HER2, either Ki-67; the mean for Ki-67≥ 14% 18,2m (IC95%<br />
10,3-26,0) vs Ki-67 < 14% 53,0m (IC95% 13,4-92,7) (p = 0,272). In the LR group, the<br />
OS mean for: ER+ 178,6m (IC95% 154,7-202,4) vs ER- 72m (IC95% 17,7-126,3)<br />
(p = 0,001); PR+ 173,4m (IC95% 143,8-203,0) vs PR- 102,4m (IC 95% 67,8-137,0)<br />
(p = 0,248); HER2- 162,3m (IC95% 127,0-197,6) vs HER2+ 146,5m (IC95%<br />
76,5-216,5) (p = 0,633); in Ki-67 no statistical differences have been observed<br />
(p = 0,144). In the MD group, OS mean for: ER+ 137,7m (IC95% 105,9-169,5) vs ER-<br />
43,1 m (IC95% 8,3-77,9) (p = 0,043); PR + 144,6m (IC95% 108,1-181,0) vs PR- 70m<br />
(IC 95% 27,3-112,8) (p = 0,027); HER2- 127,2m (IC95% 90,7-163,7) vs HER2+ 110m<br />
(IC95% 5,454-157,0) (p = 0,921); Ki-67 ≥ 14% 94m (IC95% 37,7-150,5) vs<br />
Ki-67 < 14% 147,3m (IC95% 85,6-209,0) (p = 0,411).<br />
Conclusions: We observed a significative conversion rate in Ki-67, ER, PR and HER2<br />
between primary breast cancer and relapse. We saw that ER- in the local relapse or<br />
metastasis, as well as a PR- in the metastasis were associated with a worse prognosis.<br />
Legal entity responsible for the study: Hospital Clinico San Cecilio Granada<br />
Funding: Hospital Clinico San Cecilio Granada<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
104P<br />
Evaluation <strong>of</strong> the association <strong>of</strong> HER family members with<br />
efficacy <strong>of</strong> trastuzumab therapy in metastatic breast cancer<br />
A. Koutras 1 , V. Kotoula 1 , G. Kouvatseas 2 , C. Christodoulou 1 , D. Pectasides 1 ,<br />
A. Batistatou 1 , M. Bobos 1 , E. Tsolaki 1 , K. Papadopoulou 1 , G. Pentheroudakis 1 ,<br />
P. Papakostas 1 , S. Pervana 1 , K. Petraki 1 , S. Chrisafi 1 , E. Razis 1 , A. Psyrri 1 ,<br />
D. Bafaloukos 1 , K.T. Kalogeras 1 , H.P. Kal<strong>of</strong>onos 1 , G. Fountzilas 1<br />
1 Data Office, Hellenic Cooperative <strong>Oncology</strong> Group (HeCOG), Athens, Greece,<br />
2 Biostatistics, Health Data Specialists Ltd, Athens, Greece<br />
Background: In the current study, we performed a complete analysis <strong>of</strong> gene<br />
amplification, copy-number variations (CNV), transcriptional pr<strong>of</strong>iling and protein<br />
expression <strong>of</strong> all four HER family receptors, in a series <strong>of</strong> patients with metastatic<br />
breast cancer (MBC), treated with trastuzumab-based regimens. In addition, our<br />
analysis included the evaluation <strong>of</strong> several other factors, such as PTEN and mTOR<br />
protein expression by immunohistochemistry (IHC) and PIK3CA mutations.<br />
Methods: Formalin-fixed paraffin-embedded tumor tissue samples were collected from<br />
229 patients, considered to be HER2-positive when assessed at the local laboratories.<br />
Central review <strong>of</strong> HER2 status by fluorescence in situ hybridization and/or IHC<br />
revealed that <strong>of</strong> the 229 patients, only 139 (61%) were truly HER2-positive.<br />
Results: In the multivariate analysis, HER3 gene amplification (using the 75 th percentile<br />
as a cut-<strong>of</strong>f point) (HR = 0.50, 95% CI 0.27-0.93, p = 0.027), HER3 mRNA expression<br />
(75 th percentile as a cut-<strong>of</strong>f point) (HR = 0.47, 95% CI 0.22-1.01, p = 0.052) and PTEN<br />
protein expression (HR = 0.60, 95% CI 0.37-0.98, p = 0.042) retained their favorable<br />
prognostic significance for OS in the HER2-positive subgroup. In HER2-negative<br />
patients, none <strong>of</strong> the significant factors that were identified in the univariate analysis<br />
retained prognostic ability for OS. Moreover, wild-type PIK3CA was found to be an<br />
independent favorable prognostic factor for TTP in the HER2-positive patients<br />
(HR = 0.53, 95% CI 0.27-1.02, p = 0.059). In addition, EGFR CNVs (HR = 4.89, 95% CI<br />
1.23-19.36, p = 0.024), HER3 gene amplification (using the median value as a cut-<strong>of</strong>f<br />
point) (HR = 0.41, 95% CI 0.16-1.06, p = 0.067), HER3 protein expression (HR = 0.15,<br />
95% CI 0.04-0.52, p = 0.003) and mTOR protein expression (HR = 0.33, 95% CI<br />
0.13-0.84, p = 0.02) independently affected TTP in the HER2-negative subgroup.<br />
Conclusions: The present study suggests that EGFR is a negative, whereas HER3 is a<br />
positive prognostic factor in patients with MBC. Since the above associations were not<br />
restricted to HER2-positive patients only, a definitive predictive value for trastuzumab<br />
treatment is not documented. Given the retrospective nature <strong>of</strong> the current analysis,<br />
our findings should be considered as hypothesis generating.<br />
Legal entity responsible for the study: Hellenic Cooperative <strong>Oncology</strong> Group<br />
Funding: Roche Hellas S.A.<br />
Disclosure: G. Fountzilas: Advisory Board: Roche Hellas S.A. All other authors have<br />
declared no conflicts <strong>of</strong> interest.<br />
105P<br />
abstracts<br />
Pathology <strong>of</strong> BRCA1- and BRCA2-associated breast cancers:<br />
known and less known connections<br />
F. Fostira 1 , E. Fountzila 2 , A. Vagena 1 , P. Apostolou 1 , I. Konstanta 1 ,<br />
C. Papadimitriou 2 , E. Razis 2 , C. Christodoulou 2 , E. Timotheadou 2 , V. Mollaki 1 ,<br />
M. Papamentzelopoulou 1 , I.S. Vlachos 1 , D. Yannoukakos 1 , I. Konstantopoulou 1<br />
1 Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific<br />
Research ‘Demokritos’, Athens, Greece, 2 Data Office, Hellenic Cooperative<br />
<strong>Oncology</strong> Group (HeCOG), Athens, Greece<br />
Background: BRCA1 and BRCA2 mutation carriers face an elevated lifetime risk for<br />
breast and ovarian cancer diagnosis. BRCA-related tumors display characteristic<br />
pathological features, with the BRCA1-associated being predominantly triple-negative.<br />
On the contrary, BRCA2-associated tumors are more commonly found to be estrogen/<br />
progesterone receptor (ER/PgR)-positive. The incidence <strong>of</strong> BRCA1 and BRCA2<br />
deleterious mutations in HER2-positive breast cancers, as well as the incidence <strong>of</strong><br />
BRCA2 deleterious mutations in triple-negative breast cancer cases has not been<br />
investigated in depth. Our aim was to explore the clinicopathological characteristics <strong>of</strong><br />
breast cancers in BRCA mutation carriers in a Greek population.<br />
Methods: Patients diagnosed with breast cancer between 1999 and 2016 were tested for<br />
BRCA1 and BRCA2 mutations, either by Sanger sequencing or by next generation<br />
sequencing using the Trusight Cancer 94-gene panel. A retrospective review <strong>of</strong> the<br />
medical records was conducted to retrieve patient demographics and tumor<br />
histopathological characteristics.<br />
Results: Out <strong>of</strong> 2096 high-risk breast cancer families tested, we identified 303 BRCA1<br />
and 88 BRCA2 carriers (18.7%). Mean age <strong>of</strong> breast cancer diagnosis for BRCA1 and<br />
BRCA2 carriers was 40.0 years (range 19-74) and 42.8 years (range 25-71), respectively.<br />
Information on clinicopathological characteristics (including ER/PgR and HER2<br />
status) was available for 282 (72%) <strong>of</strong> the 391 mutation carrier patients. Tumor<br />
histological subtypes in BRCA1 carriers were predominantly ductal (79%) and<br />
medullary (10%), while in BRCA2 carriers these were more frequently ductal (74%)<br />
and lobular (15%). Interestingly, 20% <strong>of</strong> the BRCA2 tumors were triple-negative, in<br />
contrast to the expected, significantly higher proportion (75%) observed in BRCA1<br />
carriers (chi-square, p < 0.001). Moreover, a significantly higher percentage <strong>of</strong> BRCA2<br />
tumors were HER2-positive compared to BRCA1 tumors (24% vs 4.7%, p < 0.001).<br />
Conclusions: These data confirm established observations in the pathology <strong>of</strong><br />
BRCA-related tumors, but provide further insight on the association <strong>of</strong> rare histological<br />
and immunohistochemical entities with loss-<strong>of</strong>-function mutations in these genes,<br />
which can be clinically important.<br />
Volume 27 | Supplement 6 | 2016<br />
doi:10.1093/annonc/mdw363 | vi31
abstracts<br />
Legal entity responsible for the study: Hellenic Cooperative <strong>Oncology</strong> Group,<br />
INRASTES-National Centre for Scientific Research "Demokritos"<br />
Funding: Hellenic Cooperative <strong>Oncology</strong> Group, INRASTES-National Centre for<br />
Scientific Research "Demokritos"<br />
Disclosure: F. Fostira: Advisory Board - Astra Zeneca. All other authors have declared<br />
no conflicts <strong>of</strong> interest.<br />
106P<br />
Identification <strong>of</strong> breast cancer associated altered DNA<br />
methylation in peripheral blood using MALDI-TOF mass<br />
spectrometry<br />
R. Yang 1 , B. Burwinkel 2<br />
1 MammaScreen Group, University Hospital <strong>of</strong> Heidelberg, Heidelberg, Germany,<br />
2 Molecular Biology, University Hospital Heidelberg, Heidelberg, Germany<br />
Background: Breast cancer (BC) is the leading cause <strong>of</strong> cancer-related mortality in<br />
women worldwide. Changes in DNA methylation in peripheral blood could be<br />
associated with malignancy at early stage. However, the BC-associated DNA<br />
methylation signatures in peripheral blood were largely unknown.<br />
Methods: Illumina 27K Methylation Array and Illumina 450K Methylation Array for<br />
the discovery <strong>of</strong> BC-related aberrant methylation sites in peripheral blood. The top<br />
hints were selected and validated using the MALDI-TOF Mass Spectrometry<br />
(MassARRAY, Agena Bioscience, Inc.) in two independent case-control studies with<br />
subjects from different centers. Gene expression levels were measured by real-time PCR<br />
and correlated with methylation. The clustering <strong>of</strong> samples by multiple CpG sites from<br />
a total <strong>of</strong> eight genes was realized by logistic regression. Receiver operating<br />
characteristic curve analyses was used to determine the discriminatory power.<br />
Results: The methylation <strong>of</strong> an eight-gene-panel in peripheral blood cells was<br />
significantly correlated with BC, and showed outstanding discriminatory power for<br />
distinguishing BC cases from non-cancer controls (first validation round with 270<br />
familial BC case and 251 non-cancer controls: AUC = 0.94, 95% C.I. 0.92-0.96; second<br />
validation round with 189 sporadic BC case and 189 non-cancer controls: AUC = 0.93,<br />
95% C.I. 0.91-0.96). This panel also shows robust power for the breast cancer at early<br />
stage (in the second validation round 101 stage 0&I sporadic BC case vs. 189<br />
non-cancer controls: AUC = 0.93, 95% C.I. 0.90-0.96). In addition, these blood-based<br />
DNA methylation signatures were similar among BC patients with differential clinical<br />
characteristics regardless <strong>of</strong> stage, receptor status and menopause status. The<br />
expression <strong>of</strong> four genes were also analysed in the leucocytes from 72 subjects and<br />
showed inversely correlation with the methylation levels (p < 0.05).<br />
Conclusions: This study reveals a strong association between decreased methylation <strong>of</strong><br />
genes in peripheral blood and BC, and provides a promising blood-based marker panel<br />
for the detection <strong>of</strong> early BC.<br />
Legal entity responsible for the study: University Hospital <strong>of</strong> Heidelberg<br />
Funding: This work was supported by the Dietmar-Hopp Foundation, University<br />
Hospital <strong>of</strong> Heidelberg, Helmholtz Society and the German Cancer Research Center<br />
(DKFZ). The familial BC samples were collected within a project funded by the<br />
Deutsche Krebshilfe (Grant number: 107054).<br />
Disclosure: R. Yang, B. Burwinkel: Inventors <strong>of</strong> a provisional patent application<br />
relating to the subject matter <strong>of</strong> this manuscript and therefore declare a potential<br />
conflict <strong>of</strong> interests.<br />
107P<br />
Evaluation <strong>of</strong> RAD50 as a prognostic marker <strong>of</strong> survival in<br />
breast cancer patients<br />
K.V. Havrysh 1 , V.V. Filonenko 1 , I.G. Serebriiskii 2 , R.G. Kiyamova 3<br />
1 Cell Signalling, Institute <strong>of</strong> Molecular Biology and Genetics <strong>of</strong> National Academy <strong>of</strong><br />
Sciences <strong>of</strong> Ukraine, Kyiv, Ukraine, 2 Molecular Therapeutics, Fox Chase Cancer<br />
Center, Philadelphia, PA, USA, 3 Institute <strong>of</strong> Fundamental Medicine and Biology,<br />
Kazan Federal University, Kazan, Russian Federation<br />
Background: Breast cancer (BC) is common and aggressive malignancy. Resistance to<br />
drugs <strong>of</strong>ten develops and is not fully understood. One <strong>of</strong> the possible reasons <strong>of</strong> this is<br />
increased activity <strong>of</strong> the DNA repair system in cancer cells. Since molecular disruption<br />
<strong>of</strong> RAD50, which implicated in DNA double-break repair, sensitizes breast tumor cells<br />
to cisplatin-based chemotherapy in cell culture, one may be hypothesized that level <strong>of</strong><br />
RAD50 gene expression in breast tumors could be considered as a potential predictive<br />
and prognostic marker <strong>of</strong> BC. The aim <strong>of</strong> this investigation was to examine the impact<br />
<strong>of</strong> RAD50 gene features (level <strong>of</strong> expression and Copy Number Alteration (CNA)) on<br />
survival <strong>of</strong> BC patients taking into account their clinical characteristics: stage <strong>of</strong> disease<br />
and molecular subtype <strong>of</strong> tumors.<br />
Methods: Data on the clinical behavior, RAD50 gene expression (RNA-Seq (V2)) and<br />
CNA (deletion, gain, amplification) <strong>of</strong> the BC patients were obtained from three<br />
independent studies (TCGA, Provisional (n = 1105); TCGA, Cell 2015 (n = 1105);<br />
TCGA, Nature 2012(n = 825) using the cBioPortal (www.cbioportal.org/). Cases with<br />
absence <strong>of</strong> necessary data were excluded, leading to data sets from 2359 to 1220<br />
samples. Testing intergroup differences (ANOVA, Tukey’s HSD, Wilcoxon tests and<br />
Spearman’s correlation) and analysis <strong>of</strong> BC patients’ survival (Kaplan-Meier and<br />
Log-rank test) were performed using RStudio.<br />
Results: A pairwise comparison groups <strong>of</strong> BC patients showed that level <strong>of</strong> RAD50<br />
gene expression fluctuates significantly in breast tumors <strong>of</strong> various molecular subtypes<br />
(except pair <strong>of</strong> Luminal A and B), between patients on 1 st and 2 nd stages <strong>of</strong> disease and<br />
patients with different CNA. The patients with high level <strong>of</strong> RAD50 gene expression<br />
had significantly reduced overall survival in comparison with the patients that had low<br />
level <strong>of</strong> RAD50 gene expression only among patients with CNA. Correlation analysis <strong>of</strong><br />
CNA and level <strong>of</strong> RAD50 gene expression has shown that high level <strong>of</strong> RAD50 gene<br />
expression bonded with gain and amplification <strong>of</strong> RAD50 gene.<br />
Conclusions: Our finding allows us to consider the gain and amplification <strong>of</strong> RAD50<br />
gene as traits which are associated with poor survival <strong>of</strong> BC patients and RAD50 as<br />
potential prognostic marker <strong>of</strong> BC.<br />
Legal entity responsible for the study: Kiyamova Ramziya Gallyamovna<br />
Funding: Russian Science Foundation (project 15–15–20032)<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
108P<br />
HER2 based expression subpopulations in TNBC: pathological<br />
aspects and clinical significance<br />
S.M. Ilie 1 , C. Desauw 2 , M. Hebbar 3<br />
1 Medical <strong>Oncology</strong>, University <strong>of</strong> Medicine and Pharmacy "Carol Davila",<br />
Bucharest, Romania, 2 Medical <strong>Oncology</strong>, C.H.U. Claude Huriez, Lille, France,<br />
3 Oncologie médicale, C.H.U. Claude Huriez, Lille, France<br />
Background: Triple negative breast cancer (TNBC) is defined as hormone receptors<br />
less than 1% and human epithelial growth factor receptor 2 (HER2) negative by<br />
immun<strong>of</strong>luorescence. HER2 negative tumors can express an intracellular domain and<br />
present a HER2 positive phenotype. Before Trastuzumab era, the prognostic was worse<br />
in HER2 over expressed early breast cancer than in triple negative counterpart.<br />
Methods: We conducted a retrospective analysis in order to explore the clinical<br />
significance <strong>of</strong> different degrees <strong>of</strong> tumor HER2 immunohistochemistry expression: 0,<br />
1 or 2 inside triple breast cancer population.<br />
Results: We analysed data from 440 early stage breast cancer patients, primary treated<br />
by surgery, addressed to the Department <strong>of</strong> Medical <strong>Oncology</strong> <strong>of</strong> University Hospital<br />
<strong>of</strong> Lille France, for adjuvant chemotherapy, between January 2010 and April 2013. 47<br />
patients (10, 6%) had triple negative phenotype, 67pts (15,2%) HER2 positive, 326 pts<br />
(74, 1%) luminal. The mean age was 47 years, 19 %( 9pts) and deleterious BRCA1 or<br />
BRCA2 mutations were found in 10 pts (21%). The patients were more likely to have<br />
stage IIA 48 %( 23pts), invasive ductal carcinoma 74 %( 35pts), the surgery was<br />
conservatory in 28 pts(59,5pts)and the majority, 44pts (93%) was anthracycline<br />
exposed. The distribution <strong>of</strong> HER2 score among TN patients were as follows: 62%<br />
(29pts) negative, 27,6 %( 13pts) one plus, 10,4 %( 5pts) two plus and negative for in<br />
situ hybridization. HER 2 positivity correlated with pT (p = 0, 05), Ki67 (p = 0, 06) and<br />
tumor grade (p = 0, 08). Pathologic stage pT, Ki67, and HER2 score were associated<br />
with relapse (p < 0, 05). For a median follow up <strong>of</strong> 38 months (range 24 to 52mo), 8pts<br />
(17%) experienced recurrence: loco regional in three cases and distant metastasis in<br />
5pts (10%). The median event free survival (EFS) was 29, 8 months (range 7 to 76 mo)<br />
and the median PFS <strong>of</strong> 11,3months. Median EFS was shorter in HER2+ score (29,8mo)<br />
respectively in HER2 positive (29,2mo) population than in triple negative HER2<br />
negative (31,8mo), without reaching the significance (P = 0, 9).<br />
Conclusions: The proportion <strong>of</strong> HER2 positivity inside TNBC population is valuable.<br />
The HER2 score 2 correlates with prognostic negative tumor features and associates<br />
with poor outcome in our analysis.<br />
Legal entity responsible for the study: University Hospital <strong>of</strong> Lille France<br />
Funding: University Hospital <strong>of</strong> Lille France<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
109P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Genetic influence <strong>of</strong> EGFR-PI3K-mTOR pathway and other loci<br />
in triple-negative breast cancer<br />
C. Cabrera 1 , M.J. Arranz 2 , M.L. Surralles Calnge 3 , A. Salas 3 , X. Tarroch 3 ,<br />
L. Ibañez 2 , A. Garcia 4 , S. Gonzalez Jimenez 1 , M. Campayo 1 , L. Cirera 1<br />
1 <strong>Oncology</strong> and Hematology Department, Hospital Univeristari Mutua Terrassa,<br />
Terrassa, Spain, 2 Fundacio Docència i Recerca Mútua Terrassa, Hospital<br />
Univeristari Mutua Terrassa, Terrassa, Spain, 3 Pathology Department, Hospital<br />
Univeristari Mutua Terrassa, Terrassa, Spain, 4 Gynecology and Obstretics<br />
Department, Hospital Univeristari Mutua Terrassa, Terrassa, Spain<br />
Background: Breast cancer (BC) is the most frequent cancer in women. About 15% <strong>of</strong> all<br />
cases account for the most aggressive subtype: triple negative breast cancer (TNBC). TNBC<br />
biological heterogeneity has been explained in both gene expression pr<strong>of</strong>ile studies and<br />
genome wide association studies (GWAS). Our study explores the role <strong>of</strong> single nucleotide<br />
polymorphisms (SNP) in TNBC. We hypothesized that new loci can confer risk and<br />
prognosis <strong>of</strong> TNBC, given its well-known tendency to genetic aberrations.<br />
Methods: In this retrospective study, we genotyped a group <strong>of</strong> SNP in 111<br />
paraffin-embedded tumor samples <strong>of</strong> patients diagnosed with TNBC (cases) and in 176<br />
blood samples <strong>of</strong> healthy donors (controls). The SNP were selected from 5 genes<br />
(MAP3K1, PI3K, TERT, EGFR, and mTOR) known for their implication in TNBC and<br />
other types <strong>of</strong> cancer.<br />
Results: Univariate analysis with chi-square test comparing genotypic frequencies<br />
between cases and controls confirmed statistical significance in EGFR rs4947986 (p=<br />
0.001) and TERT rs2736100 (p=
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
These results in EGFR and TERT have not been described elsewhere in the literature.<br />
Likewise, our study also indicates the existence <strong>of</strong> similar associations that influence the<br />
risk <strong>of</strong> developing TNBC in EGFR rs712829 (p = 0.04), MAP3K1 rs889312 (p = 0.016),<br />
PI3K rs2699887 (p = 0.011) and PI3K rs2699905 (p = 0.011). A strong trend towards<br />
risk <strong>of</strong> TNBC was detected (p = 0.053) in mTOR rs2295080.<br />
Conclusions: Our study found no prognostic significance <strong>of</strong> SNP for disease free<br />
survival (DFS) or overall survival (OS) in the multivariate analyses including TNM<br />
stage, axillary status, treatment (chemotherapy and/or radiotherapy) and age.Our<br />
findings not only confirm the genetic influence <strong>of</strong> molecular pathways in EGFR, PI3K,<br />
mTOR and MAP3K1 but also reveal new loci for development <strong>of</strong> TNBC.Having<br />
recognized new TERT and EGFR mutations in our cohort encourages us to keep<br />
unveiling plausible new pathways on carcinogenesis and treatment targets for TNBC.<br />
However, more translational studies are mandatory.<br />
Legal entity responsible for the study: Hospital Universitari Mutua<br />
Terrassa-<strong>Oncology</strong> and Hematology Department<br />
Funding: Hospital Universitari Mutua Terrassa<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
110P<br />
Biomarkers for afatinib and dasatinib treatment in triple<br />
negative breast cancer<br />
A. Canonici 1 , M.F.K. Ibrahim 1 , K. Fanning 1 , M. Cremona 2 , C. Morgan 2 ,<br />
B. Hennessy 2 , F. Solca 3 ,J.Crown 4 ,N.O’Donovan 1<br />
1 National Institute for Cellular Biotechnology, Dublin City University, Dublin, Ireland,<br />
2 Medical <strong>Oncology</strong> Lab., Dip. Molecular Medicine, Royal College <strong>of</strong> Surgeons in<br />
Ireland, Dublin, Ireland, 3 Pharmacology and Translational Research, Boehringer<br />
Ingelheim RCV GmbH & Co KG, Vienna, Austria, 4 Medical <strong>Oncology</strong>, St. Vincents<br />
University Hospital, Dublin, Ireland<br />
Background: Triple negative breast cancer (TNBC) lacks expression <strong>of</strong> hormone<br />
receptors and amplification <strong>of</strong> HER2. There are currently no approved targeted<br />
therapies. EGFR is frequently overexpressed in TNBC and may be a rationale target.<br />
The activity <strong>of</strong> afatinib, an irreversible pan-HER TKI, was assessed alone and in<br />
combination with inhibitors <strong>of</strong> other promising targets for TNBC.<br />
Methods: Sensitivity to afatinib and other targeted therapies was assessed using<br />
proliferation assays. IC 50 and CI values were determined using CalcuSyn. Statistical<br />
analyses were performed on StatView s<strong>of</strong>tware. Proteomic pr<strong>of</strong>iling was performed by<br />
Reverse Phase Protein Array (RPPA).<br />
Results: As previously shown (Ibrahim et al, ASCO 2014), the IC 50 values for afatinib<br />
in 14 TNBC cell lines ranged from 0.007-5.0 µM. 3 <strong>of</strong> the 7 basal-like cell lines were<br />
sensitive to afatinib (IC 50 < 80 nM) whereas none <strong>of</strong> the non-basal like cell lines were<br />
sensitive, although this difference did not achieve statistical significance (p = 0.07).<br />
Based on the RPPA data, sensitivity to afatinib correlated with higher levels <strong>of</strong> pSrc<br />
(Y416) (p = 0.02, r = -0.645). Addition <strong>of</strong> afatinib enhanced response to 6 <strong>of</strong> the 8<br />
targeted therapies tested. The combination <strong>of</strong> afatinib with dasatinib showed strong<br />
anti-proliferative activity and was further investigated. The afatinib/dasatinib<br />
combination was synergistic in 10 <strong>of</strong> the 14 cell lines. Low levels <strong>of</strong> Bcl2 were predictive<br />
<strong>of</strong> a synergistic response to the afatinib/dasatinib combination (p = 0.05, r = 0.541).<br />
The phosphorylation <strong>of</strong> 5 proteins, including EGFR (Y1068), HER2 (Y1248) and Src<br />
(Y527), was significantly decreased following afatinib/dasatinib treatment. In BT20<br />
cells, which show the strongest synergistic response to the combined treatment,<br />
phosphorylation <strong>of</strong> both ERK1/2 (T202/Y204) and Akt (S473/T308) was significantly<br />
reduced following treatment.<br />
Conclusions: Afatinib in combination with dasatinib may have activity in TNBC. Bcl2<br />
may be a predictive biomarker to identify patients who are more likely to benefit from<br />
this combination. RPPA results suggest that efficient inhibition <strong>of</strong> both ERK and Akt<br />
signalling may contribute to the synergistic anti-proliferative effects <strong>of</strong> afatinib<br />
combined with dasatinib.<br />
Legal entity responsible for the study: Dublin City University<br />
Funding: Boehringer Ingelheim<br />
Disclosure: A. Canonici, N. O’Donovan: Received research funding from Boehringer<br />
Ingelheim. F. Solca: Eployee <strong>of</strong> Boehringer Ingelheim. J. Crown: Received research<br />
funding from Boehringer Ingelheim; and travel, accommodation and expenses from<br />
Bristol-Myers Squibb. All other authors have declared no conflicts <strong>of</strong> interest.<br />
111P<br />
The prognostic impact <strong>of</strong>PI3K/AKT/mTORpathway aberrations<br />
on luminal breast cancer patients<br />
L. Kassem 1 , T. Bachelot 2 , I. Treilleux 3 , C. Zhang 3 , M. Le Romancer 4<br />
1 Clinical <strong>Oncology</strong>, Cairo University, Cairo, Egypt, 2 Service Oncologie Medicale,<br />
Centre Léon Bérard, Lyon, France, 3 Département de Biopathologie, Centre Léon<br />
Bérard, Lyon, France, 4 University <strong>of</strong> Lyon, Centre de Recherche en Cancérologie,<br />
Centre Léon Bérard, Lyon, France<br />
Background: The exact role <strong>of</strong> the dysregulation <strong>of</strong> the PI3K/AKT/mTOR pathway<br />
components is not clearly understood. In this study, we aimed to clarify the<br />
correlations between each <strong>of</strong> the pathway components with the presentation and<br />
outcome <strong>of</strong> estrogen receptor (ER) positive, human epidermal growth factor receptor 2<br />
(HER2) negative breast cancer.<br />
Methods: Immunohistochemistry (IHC) was performed on TMA blocks prepared<br />
from samples <strong>of</strong> 352 luminal breast cancer patients (ER + /HER2-) who presented for<br />
adjuvant treatment to CLB between January 2001 to December 2003. Another<br />
validation cohort <strong>of</strong> 160 patients (from 1999 to 2000) was used to confirm the findings.<br />
Patients were followed for a median <strong>of</strong> 9.2 years (Range: 0.2-13.7 years).<br />
Results: Median age at diagnosis was 58.3y. Tumors were larger than 2 cm in 36.4% <strong>of</strong><br />
the cases and 58.5% had axillary LN deposits. Among the whole cohort, 329 patients<br />
were assessable for Nuclear LKB1, 331 for cytoplasmic LKB1, 329 for nuclear pAKT,<br />
330 for cytoplasmic pAKT, 335 for p70-pS6RP, 335 for p4E-BP1, 319 for p85-pS6K,<br />
339 for p70-pS6K and 332 for cytoplasmic IGF1. Nuclear LKB1, cytoplasmic LKB1,<br />
nuclear pAKT, cytoplasmic pAKT, p4EBP1, p70-S6RP, p70-pS6K, p85-pS6K and<br />
cytoplasmic IGF1 expression was high in 48%, 36%, 55.9%, 19.1%, 43.9%, 22.7%,<br />
71.4%, 27.3 and 55.1% respectively.Nuclear pAKT high expression, but not cytoplasmic<br />
pAKT expression, was associated with better disease free survival (DFS) (HR = 0.53;<br />
95%CI:0.36-0.79; p = 0.002), OS (HR = 0.48; 95%CI: 0.31-0.75; p = 0.001), smaller<br />
tumors (p = 0.002), lower lymph node involvement (p = 0.007) and lower pathological<br />
grade. This was confirmed in an independent patient cohort. In contrast, p85-pS6K<br />
was associated with poorer DFS (HR = 1.65; 95%CI: 1.08-2.50; p = 0.02) and OS<br />
(HR = 1.85; 95%CI: 1.09-3.13; p = 0.022). Neither p4E-BP1 nor p70-pS6K expression<br />
showed any prognostic significance. In the multivariate analysis, p85-pS6K was the<br />
only independent for poorer DFS (HR = 1.81; 95%CI: 1.18-2.97; p = 0.007) & OS<br />
(HR = 2.07; 95%CI: 1.20-3.38; p = 0.009).<br />
Conclusions: Higher nuclear pAKT is associated with better prognosis while the<br />
downstream markers <strong>of</strong> mTOR activation as p85-pS6K are associated with poorer<br />
prognosis.<br />
Legal entity responsible for the study: Centre Leon Berard<br />
Funding: Centre Leon Berard<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
112P<br />
abstracts<br />
3-biomarker HRD score versus individual biomarker (LOH, TAI,<br />
LST) scores in platinum treated serous ovarian cancer (SOC)<br />
J. Lanchbury 1 , K. Timms 1 , J. Reid 1 , E. Stronach 2 , A. Gutin 1 , T. Krivak 3 ,<br />
B. Hennessy 4 , J. Paul 2 ,R.Brown 2 , R. Nix 1 , Z. Sangale 1 , E. Hughes 1 , V. Abkevich 1 ,<br />
G.B. Mills 5<br />
1 Clinical Research, Myriad Genetics Inc, Salt Lake City, UT, USA, 2 Surgical<br />
<strong>Oncology</strong>, Imperial College London-South Kensington Campus, London, UK,<br />
3 Gynecologic <strong>Oncology</strong>, Western Pennsylvania Hospital, Pittsburgh, PA, USA,<br />
4 Medical <strong>Oncology</strong>, MD Anderson Cancer Center, Houston, TX, USA, 5 Systems<br />
Biology, MD Anderson Cancer Center, Houston, TX, USA<br />
Background: Previous studies have shown that tumors with defects in the homologous<br />
recombination (HR) pathway show improved response to DNA-damaging agents. To<br />
identify tumors likely to benefit from these therapies, we developed a 3-biomarker HR<br />
deficiency (HRD) score that is the sum <strong>of</strong> three independent measures <strong>of</strong> HRD (loss <strong>of</strong><br />
heterozygosity (LOH), telomeric-allelic imbalance (TAI), large-scale state transitions<br />
(LST)). Previous studies have shown that the HRD score is a better prognostic marker<br />
<strong>of</strong> PFS and OS relative to the individual scores in platinum treated SOC. Here we<br />
evaluate the correlation between, and specificity <strong>of</strong>, the 3-biomarker HRD and<br />
individual scores to quantify potential false positive and negative results.<br />
Methods: An HRD threshold (≥42) was developed in a training cohort <strong>of</strong> ovarian and<br />
breast tumors using a cut-<strong>of</strong>f <strong>of</strong> 95% sensitivity to detect BRCA1/2 deficient tumors. A<br />
threshold for each HRD component was determined using the same cohort and<br />
method (LOH ≥8, TAI ≥10, LST ≥18). The correlation between the dichotomized<br />
scores (high, low), and specificity for classifying tumors as BRCA1/2 deficient, for the<br />
HRD score and component scores was retrospectively evaluated in 859 SOC tumors.<br />
Results: The correlation between the HRD score and the LOH score was 0.872. There<br />
were 126 discordant scores, including 102 cases with high LOH scores and low HRD<br />
scores. These represent potential false positives based on LOH alone. Similarly, 24<br />
samples with low LOH scores had high HRD scores (potential false negatives). Similar<br />
behavior was observed for TAI (correlation coefficient 0.905, 95 discordant scores) and<br />
LST (correlation coefficient 0.941, 88 discordant scores). Specificity was highest for the<br />
HRD score in both the training and test cohorts (0.897 and 0.796) compared to any <strong>of</strong><br />
the component scores (LOH: 0.624 and 0.668; TAI: 0.766 and 0.690; LST: 0.759 and<br />
0.672).<br />
Conclusions: Here we show that the use <strong>of</strong> a single HRD biomarker may misinform<br />
treatment decisions in SOC relative to the combined 3-biomarker score. The combined<br />
HRD assay, which has been validated on FFPE SOC tumor tissue, warrants evaluation<br />
in a prospective study sample set in a rigorously validated laboratory.<br />
Legal entity responsible for the study: N/A<br />
Funding: Myriad Genetics, Inc<br />
Disclosure: J. Lanchbury: Myriad Employee compensated with salary and stock<br />
options. K. Timms: Myriad Genetics Employee – Receive salary and stock<br />
options. J. Reid, A. Gutin, V. Abkevich R. Nix, Z. Sangale: Myriad Employee – Salary<br />
and stock options. All other authors have declared no conflicts <strong>of</strong> interest.<br />
Volume 27 | Supplement 6 | 2016<br />
doi:10.1093/annonc/mdw363 | vi33
abstracts<br />
113P<br />
Characteristics <strong>of</strong> homologous recombination deficiency<br />
(HRD) in paired primary and recurrent high-grade serous<br />
ovarian cancer (HGSOC)<br />
J. Patel 1 , J. Sehouli 2 , K. Timms 3 , C. Solimeno 3 , J. Reid 3 , J. Lanchbury 3 , I. Braicu 2 ,<br />
S. Darb-Esfahani 2 , M. Ganapathi 1 , R. Ganapathi 1<br />
1 Pharmacology, Levine Cancer Institute, Charlotte, NC, USA, 2 Department <strong>of</strong><br />
Gynecology, Charité / University Hospital Berlin, Berlin, Germany, 3 Clinical<br />
Research, Myriad Genetics Inc, Salt Lake City, UT, USA<br />
Background: Recently, a 3-biomarker homologous recombination deficiency (HRD)<br />
score has been shown to predict response to DNA damaging therapies in patients with<br />
HGSOC, where patients with a high HRD score (≥42) and/or BRCA1/2 mutation show<br />
improved response. In order to evaluate whether changes in tumor biology can impact<br />
the prognostic value <strong>of</strong> this HRD score, we investigated the characteristics <strong>of</strong> HRD in<br />
paired primary and recurrent HGSOC specimens.<br />
Methods: HRD scores were evaluated in paired primary and recurrent specimens <strong>of</strong><br />
HGSOC from 55 patients treated with adjuvant carboplatin and paclitaxel. BRCA1/2<br />
mutation and BRCA1 methylation (including loss <strong>of</strong> heterozygosity (LOH) status), and<br />
HRD scores were characterized using tumor DNA-based assays.<br />
Results: Here we present the results <strong>of</strong> the initial analysis performed for the first 25<br />
patients. Data for 19 complete primary-recurrent pairs were available for comparative<br />
analysis (7/50 samples failed HRD analysis). BRCA mutations were detected in 12% (3/<br />
25) <strong>of</strong> tumors, all <strong>of</strong> which occurred in BRCA1 and contained LOH at BRCA1. There<br />
was no mutation reversion in recurrent samples. Overall, 9 primary-recurrent pairs had<br />
high HRD scores, including all 3 mutant pairs. There was a high degree <strong>of</strong> correlation<br />
for all HRD scores in primary and recurrent samples (Pearson correlation coefficient<br />
0.953). Scores for recurrent tumor samples were somewhat more likely to be higher<br />
than in the primary (mean = 2.6), but the difference was not significant<br />
(p-value = 0.11). The complete analysis will include data from paired primary and<br />
recurrent tumors from an additional 30 patients. This will allow more thorough<br />
investigation <strong>of</strong> how changes in the genomic pr<strong>of</strong>ile <strong>of</strong> primary and recurrent tumors<br />
may impact the HRD score.<br />
Conclusions: Here we show that the 3-biomarker HRD score was not impacted by<br />
changes in the genomic pr<strong>of</strong>ile <strong>of</strong> paired primary and recurrent tumor samples. This<br />
suggests that that testing recurrent HGSOC tumors will not alter treatment strategies<br />
relative to analysis <strong>of</strong> the primary tumor. Additional analysis will reveal whether the<br />
trends observed in this initial analysis are maintained in a larger cohort.<br />
Legal entity responsible for the study: N/A<br />
Funding: Myriad Genetics<br />
Disclosure: J. Patel: Consultant, BTG; Research Funding, Myriad Genetics; Travel,<br />
accommodations. J. Sehouli, S. Darb-Esfahani, M. Ganapathi, R. Ganapathi: Research<br />
Funding, Myriad Genetics, Inc. K. Timms, C. Solimeno, J. Reid: Myriad employee,<br />
salary and stock options. J. Lanchbury: Employee <strong>of</strong> Myriad Genetics, Inc. Receives<br />
salary and stock options as compensation. I. Braicu: Research Funding, Myriad<br />
Genetics, Inc.<br />
114P<br />
Prognostic biomarkers in locally advanced cervical cancer<br />
(Cx Ca) treated with chemoradiation (CRT)<br />
Y. Kanjanapan 1 , S. Deb 2 , R. Young 3 , M. Bressel 4 , L. Mileshkin 1 , D. Rischin 1 ,<br />
M. H<strong>of</strong>man 5 , K. Narayan 6 , S. Siva 6<br />
1 Medical <strong>Oncology</strong>, Peter MacCallum Cancer Center, Melbourne, Australia,<br />
2 Anatomical Pathology, Peter MacCallum Cancer Center, Melbourne, Australia,<br />
3 Translational Research Laboratory, Peter MacCallum Cancer Center, Melbourne,<br />
Australia, 4 Centre for Biostatistics and Clinical Trials, Peter MacCallum Cancer<br />
Center, Melbourne, Australia, 5 Cancer Imaging, Peter MacCallum Cancer Center,<br />
Melbourne, Australia, 6 Radiation <strong>Oncology</strong>, Peter MacCallum Cancer Center,<br />
Melbourne, Australia<br />
Background: Definitive chemoradiation (CRT) is standard therapy for locally<br />
advanced cervical cancer (Cx Ca). However, there is a lack <strong>of</strong> biomarkers to identify<br />
patients at increased risk <strong>of</strong> relapse. Post-therapy 18 F-fluoro-deoxyglucose positron<br />
emission tomography (PET) response correlates with outcome, but cannot inform<br />
treatment planning. We tested metabolic (glucose transporter [Glut-1]), hypoxic<br />
(hypoxia inducible factor [HIF-1a] and carbonic anhydrase [CA-9]) and proliferative<br />
(Ki-67) markers for prognostic utility in Cx Ca.<br />
Methods: 60 FIGO stage Ib to IVa Cx Ca patients treated with CRT had formalin-fixed<br />
paraffin-embedded tumour tissue from pre treatment biopsies. Immunohistochemistry<br />
was performed for Glut-1, HIF-1a and CA-9, to generate a histoscore (0-12) by<br />
multiplying intensity (0 absent, 1 mild, 2 moderate and 3 intense staining) by a<br />
categorical percentage score (0 for none, 1 for 1-24%, 2 for 25-49%, 3 for 50-74% and 4<br />
for ≥75% <strong>of</strong> cells staining), for each biomarker in each tumour sample. Ki-67 was<br />
scored by percentage <strong>of</strong> positive cells amongst 1000 representative tumour cells. For<br />
each biomarker, the cohort was dichotomized and survival estimated by the<br />
Kaplan-Meier method and compared using logrank testing.<br />
Results: High Glut-1 expression was associated with inferior progression-free survival<br />
(PFS), (hazard ratio [HR] 2.8, 95% confidence interval [CI] 1.0 – 7.9, p = 0.049) and<br />
overall survival (OS), (HR 5.0, 95% CI 1.3 – 19.2, p = 0.011) on multifactor analysis<br />
adjusting for stage, node positivity, tumour volume and uterine corpus invasion. High<br />
Glut-1 correlated with increased risk <strong>of</strong> distant failure (HR 14.6, 95% CI 1.9 - 112.9,<br />
p = 0.001) but not with local failure (HR 2.1, 95% CI 0.5 - 8.9, p = 0.48). Low Glut-1<br />
was associated with higher complete metabolic response rate on post-therapy PET scan<br />
(odds ratio 3.4, 95% CI 1.0 – 12.3, p = 0.048). Ki-67 was significantly associated with<br />
PFS only (HR 1.19 per 10 units increase, 95% CI 1.01 – 1.41, p = 0.033). Biomarkers for<br />
hypoxia were not associated with outcome.<br />
Conclusions: High Glut-1 expression in pre-treatment Cx Ca biopsies is associated<br />
with worse outcome post CRT. If prospectively validated, Glut-1 may be used to select<br />
Cx Ca patients who may benefit from a more intensive treatment regimen.<br />
Legal entity responsible for the study: Division <strong>of</strong> Medical <strong>Oncology</strong>, Peter<br />
MacCallum Cancer Centre<br />
Funding: Funding for statistical support from the Division <strong>of</strong> Medical <strong>Oncology</strong>, Peter<br />
MacCallum Cancer Centre, Melbourne, Australia<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
115P<br />
The molecular landscape <strong>of</strong> genome instability in prostate<br />
cancer (PC)<br />
K. Timms 1 , J. Cuzick 2 , C. Neff 1 , J. Reid 1 , C. Solimeno 1 , Z. Sangale 1 , D. Pruss 1 ,<br />
A. Gutin 1 , J. Lanchbury 1 , S. Stone 1<br />
1 Clinical Research, Myriad Genetics Inc, Salt Lake City, UT, USA, 2 Cancer<br />
prevention, Centre for Cancer Prevention, Wolfson Institute <strong>of</strong> Preventive Medicine,<br />
Barts and The London School <strong>of</strong> Medicine, London, UK<br />
Background: Prostate cancer is a leading cause <strong>of</strong> cancer death in men. A recent study<br />
suggests that prostate tumors with defects in DNA damage repair (DDR) genes may<br />
respond to PARP inhibitor therapy. In breast and ovarian cancer a homologous<br />
recombination deficiency (HRD) score optimally defines treatment groups for DNA<br />
damaging therapy. This study investigates mutations in DDR genes and molecular<br />
signatures for HRD, microsatellite instability (MSI), and high mutation load (HML) in PC.<br />
Methods: DNA was extracted from 50 radical prostatectomies and 45 transurethral<br />
resections <strong>of</strong> the prostate, and analyzed using a next generation sequencing assay<br />
targeting 43 genes, and genomic regions used to generate HRD, HML, and MSI scores.<br />
Results: DDR genes were considered non-functional if both alleles were mutated and/<br />
or deleted. If the second allele is intact these genes were considered defective but<br />
functional. Non-functional DDR genes (CDK12, PALB2, RPA1, ATM, and BRCA2)<br />
were observed in 7 tumors. 11 tumors were observed with DDR gene defects in 8<br />
additional genes. DDR gene mutation status was significantly associated with high<br />
Gleason score (n = 84; p = 0.0028). Mean HRD scores were higher in tumors with<br />
non-functional DDR genes (n = 7) compared to non-mutant tumors (n = 49) (31.7 vs.<br />
14.6; p = 0.0039), but not in tumors with defective DDR genes (n = 11) (14.0 vs. 14.6;<br />
p = 0.92). HRD scores were associated with high Gleason score (Gleason ≤7<br />
mean = 11.3; Gleason >7 mean = 20.9; p = 0.00064). 3 MSI positive tumors were<br />
identified, all had Gleason scores >7.<br />
Conclusions: HRD scores, non-functional DDR genes (but not DDR gene defects), and<br />
MSI are all associated with higher Gleason scores in PC. A significant proportion <strong>of</strong><br />
aggressive prostate tumors carry molecular signatures associated with response to therapies<br />
targeting DDR deficiencies or to immunotherapeutics. This study demonstrates the<br />
importance <strong>of</strong> assessing both alleles when identifying prostate tumors with DDR gene<br />
mutations. In this study an HRD score <strong>of</strong> ≥20 captures three times as many potential<br />
responders to HRD-dependent therapies compared to non-functional DDR gene<br />
mutations. Further studies are required to investigate response to targeted therapies in PC.<br />
Legal entity responsible for the study: N/A<br />
Funding: Myriad Genetics<br />
Disclosure: K. Timms, C. Neff, J. Reid, C. Solimeno, D. Pruss, S. Stone, Z. Sangale,<br />
A. Gutin, J. Lanchbury: Myriad Employee, salary and stock options. J. Cuzick:<br />
Consulting/Advisory-Becton Dickinson.<br />
116P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Correlation <strong>of</strong> mutant P53 protein expression and Ki67 index<br />
with tumor response to concurrent chemoradiation in locally<br />
advanced head and neck cancer<br />
P.B. Shanmuga, K.T. Bhowmik, K. Periasamy<br />
Radiotherapy, Vardhman Mahavir Medical College & Safdarjung Hospital<br />
(VMMC-SJH), New Delhi, India<br />
Background: Concurrent chemoradiotherapy (CRT) remains mainstay <strong>of</strong> management<br />
in locally advanced head and neck squamous cell cancers. Despite advancements in<br />
treatment delivery, there is heterogeneity in treatment outcome and only marginal<br />
improvement in survival rates. This study was done to find out the correlation <strong>of</strong><br />
mutant P53 protein expression and Ki67 index with the treatment response to<br />
concurrent chemoradiotherapy.<br />
Methods: 55 patients <strong>of</strong> stage III-IVA non-nasopharyngeal head and neck squamous<br />
cell carcinoma were enrolled and the expression <strong>of</strong> mutant P53 protein and Ki67 index<br />
in the tumor were analysed. All patients were treated with concurrent<br />
chemoradiotherapy using conventional planning to a dose <strong>of</strong> 66Gy in 33 fractions and<br />
2 cycles <strong>of</strong> Inj cisplatin 100mg/m 2 as concurrent chemotherapy. The degree <strong>of</strong> mutant<br />
P53 protein expression and Ki67 index were correlated with the response to concurrent<br />
chemoradiotherapy, examined within three months <strong>of</strong> treatment completion with<br />
RECIST1.1 criteria.<br />
vi34 | abstracts Volume 27 | Supplement 6 | 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Results: It was observed that 30 patients had complete response and 25 patients had<br />
partial response to CRT. It was found that 76% <strong>of</strong> the study patients had mutant p53<br />
protein expression and 95% had Ki67 positivity. On statistical analysis it was found<br />
that the expression <strong>of</strong> mutant p53 protein and Ki67 index showed strong association<br />
with N-stage, TNM stage and tumor response following CTRT. All patients whose<br />
tumors were negative for mutant P53 protein expression and negative Ki-67 had<br />
complete response to CRT.<br />
Conclusions: Rate <strong>of</strong> mutant P53 protein expression and Ki67 were significant in<br />
predicting tumor response to CRT. With careful evaluation and molecular<br />
prognostication <strong>of</strong> all head and neck cancer, high risk patients can be identified, who<br />
tend to show partial response to CRT. This might provide a cohort <strong>of</strong> patient selection<br />
for future trials planning for targeted therapy against these molecular markers.<br />
Legal entity responsible for the study: Priya Baskaran Shanmuga<br />
Funding: VMMC and SJH hospital<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
117P<br />
Evaluation <strong>of</strong> tumor- and stromal immune marker<br />
heterogeneity in non-small cell lung cancer<br />
D. Casadevall Aguilar 1 , L. Pijuan 2 , S. Clave 2 , A. Taus 1 , A. Hernández 1 ,<br />
M. Lorenzo 2 , S. Mojal 3 , S. Menéndez 2 , J. Albanell 4 , M. Salido 4 , E. Arriola 4<br />
1 Medical <strong>Oncology</strong>, University Hospital del Mar, Barcelona, Spain, 2 Pathology,<br />
University Hospital del Mar, Barcelona, Spain, 3 Assessorament Metodològic en<br />
Investigació Biomèdica (AMIB), Institut Hospital del Mar d’Investigacions Mèdiques<br />
(IMIM), Barcelona, Spain, 4 Cancer Research Program, Institut Hospital del Mar<br />
d’Investigacions Mèdiques (IMIM), Barcelona, Spain<br />
Background: Immunotherapy is the current standard in second-line treatment for<br />
non-small cell lung cancer (NSCLC) patients. However, accurate identification <strong>of</strong> patients<br />
who benefit based on immune marker (IM) expression remains a challenge. Here, we<br />
aimed to estimate the potential impact <strong>of</strong> heterogeneity on the assessment <strong>of</strong> IM<br />
expression in both lung adenocarcinoma (ADC) and squamous-cell carcinoma (SCC).<br />
Methods: A total <strong>of</strong> 144 surgically treated NSCLC patients were included, 94 ADCs and<br />
50 SCCs. Two tumor cores per patient were incorporated into tissue microarrays (TMA).<br />
CD3 and CD8 were assessed by immunohistochemistry (IHC) and PD-L1 by IHC and<br />
FISH. Expression <strong>of</strong> IM was analyzed both in tumor cells (TC) and tumor stroma (TS). A<br />
PD-L1 positivity threshold <strong>of</strong> ≥1% was established for IHC and PDL1 gene amplification<br />
was defined as a PDL1/CEP9 ratio <strong>of</strong> ≥2. In each core, CD3 and CD8 positive cells were<br />
recorded quantitatively and the CD8/CD3 ratio was calculated. Heterogeneity <strong>of</strong> IM<br />
between corresponding tumor cores was analyzed using kappa agreement index. Finally,<br />
IM expression was correlated with clinical, pathological and molecular variables.<br />
Results: Patients’ median age was 65, 80% were male and 46% were current smokers.<br />
PD-L1 was expressed in TC and TS in 22% and 62% <strong>of</strong> cases, respectively.<br />
Amplification <strong>of</strong> PDL1 was found in 12 <strong>of</strong> cases, <strong>of</strong> which 8 (67%) were IHC PD-L1<br />
positive in TC. Heterogeneity <strong>of</strong> TC PD-L1 positivity was 8% in ADC and 6% in SCC.<br />
Regarding TS PD-L1 expression, discordance between corresponding cores was found<br />
in 19% and 34% <strong>of</strong> ADC and SCC cases, respectively. PDL1 amplification was<br />
discordant between cores in 5 <strong>of</strong> 12 (42%) cases. Per core, median CD3 and CD8<br />
positive cells were 436 and 159, respectively. Median CD8/CD3 ratio was 0.23 in ADC<br />
and 0.53 in SCC. Taking these values as cut-<strong>of</strong>f points, CD8/CD3 ratio was discordant<br />
in 22% and 10% <strong>of</strong> ADC and SCC cases, respectively. Finally, TC PD-L1 expression<br />
was correlated with CD8 infiltrate. (p < 0.05 for ADC and SCC).<br />
Conclusions: PD-L1 IHC expression appears to be more heterogeneous when assessed<br />
in the TS compared to the TC compartment, especially in SCC histology. Intra-tumor<br />
heterogeneity has to be taken into account when selecting patients for immunotherapy<br />
based on PD-L1 positivity or lymphocyte presence.<br />
Legal entity responsible for the study: University Hospital del Mar, Barcelona, Spain<br />
Funding: Medical <strong>Oncology</strong> Department, University Hospital del Mar, Barcelona, Spain<br />
Disclosure: D. Casadevall Aguilar: Is the recipient <strong>of</strong> a competitive grant "Beca FSEOM<br />
para la realización de tesis doctoral" awarded in October 2015 by the Spanish Society<br />
for Medical <strong>Oncology</strong> Foundation (Fundación SEOM). All other authors have declared<br />
no conflicts <strong>of</strong> interest.<br />
118P<br />
Hyponatremia and hypoalbuminemia as predictive factors for<br />
response to first line treatment for metastatic non-small cell<br />
lung cancer<br />
A.A. Badawy 1 , G. Khedr 1 , A. Omar 1 , S. Bae 2 , W. Arafat 1 , S. Grant 3<br />
1 Clinical <strong>Oncology</strong> and Nuclear Medicine, University <strong>of</strong> Alexandria Faculty <strong>of</strong><br />
Medicine, Alexandria, Egypt, 2 Preventive Medicine, University <strong>of</strong> Alabama at<br />
Birmingham, Birmingham, AL, USA, 3 Hematology oncology, Wake Forest<br />
University Comprehensive Cancer Center, Winston Salem, NC, USA<br />
Background: There is a great controversies in the choice <strong>of</strong> the best drug for first line<br />
treatment <strong>of</strong> metastatic non-small cell lung cancer (NSCLC); especially for those patients<br />
with no driving mutation. In this analysis we try to identify predictive factors which may<br />
help selection <strong>of</strong> first line therapy for metastatic NSCLC in big retrospective data.<br />
Methods: we conducted a retrospective analysis <strong>of</strong> patients with stage IV NSCLC<br />
receiving systemic treatment at the University <strong>of</strong> Alabama at Birmingham (UAB)<br />
comprehensive cancer center which is a NCCN member institute. Pretreatment risk<br />
factors including age, race, gender, presenting symptoms, histological feature <strong>of</strong> tumor<br />
and pretreatment laboratory values, were evaluated. These factors correlated with<br />
response to fist line therapy.<br />
Results: 409 patients received more than 10 different regimens as first line treatment in<br />
metastatic non-small-cell lung cancer. The most commonly used regimens were<br />
paclitaxel and carboplatin with or without bevacizumab; Carboplatin and pemetrexed<br />
with or without bevacizumab; pemetrexed single agent; Carboplatin and Gemcitabine;<br />
or Tyrosine kinase inhibitor. Most <strong>of</strong> patients in our series had performance status<br />
range between 0-1 More than 50 pretreatment factor were analyzed <strong>of</strong> which smoking<br />
(p = 0.049), pleural metastases or effusion (p = 0.004), abdominal metastases<br />
(p = 0.033), hypoalbuminemia (p = 0.043) and hyponatremia (p = 0.002) are<br />
associated with poor responses to first line treatment <strong>of</strong> metastatic NSCLC.<br />
Conclusions: Hypoalbuminemia, hyponatremia among other factors can help identify<br />
patients who are less likely to respond to first line therapy for treatment <strong>of</strong> metastatic<br />
NSCLC. We are finalizing mathematical model that incorporate these factors. This may<br />
help in the selection <strong>of</strong> patients for systemic therapy and may improve stratification in<br />
clinical trials.Bottom <strong>of</strong> Form<br />
Legal entity responsible for the study: UAB<br />
Funding: Ministry <strong>of</strong> Higher Education; Egypt<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
119P<br />
NGS for precision medicine in non-small cell lung cancer:<br />
Challenges and opportunities<br />
V. Mileyko 1 , M. Ivanov 1 , E. Novikova 2 , E. Telysheva 2 , P. Chernenko 3 , V. Breder 3 ,<br />
K. Laktionov 3 , A. Baranova 4<br />
1 Laboratory <strong>of</strong> Molecular Medicine, Institute <strong>of</strong> Chemical Biology and Fundamental<br />
Medicine, Novosibirsk, Russian Federation, 2 Laboratory <strong>of</strong> Molecular Biology and<br />
Cytogenetics, Russian Scientific Center <strong>of</strong> Radiology and Nuclear Medicine,<br />
Moscow, Russian Federation, 3 Department <strong>of</strong> Clinical Biotechnologies,<br />
N. N. Blokhin Russian Cancer Research Center, Moscow, Russian Federation,<br />
4 School <strong>of</strong> Systems Biology, George Mason University, Washington, DC, USA<br />
Background: Recent advances in target therapy development and precision oncology<br />
researches has led to the spreading <strong>of</strong> the use <strong>of</strong> the molecular testing. The need on broad<br />
tumor pr<strong>of</strong>iling has been met by the NGS, though several limitations remains unsolved.<br />
Methods: FFPE tissue sections were obtained from 25 patients with NSCLC (stages<br />
III-IV). DNA libraries were prepared with the Truseq Cancer Panel (Illumina). Bowtie-2<br />
with the following Varscan2, Strelka and Scalpel accompanied with the in-house<br />
s<strong>of</strong>tware as well as Somatic Variant Caller (Illumina) were used for data analysis.<br />
Results: Clinicaly-actionable mutations were identified in 13 patients (52%). Of them 8<br />
has activating EGFR mutations. Rare EGFR exon 19 insertion was identified in one<br />
patient, which may be associated with EGFR TKI sensitivity. This mutation was not<br />
detcted employing the default s<strong>of</strong>tware (Illumina Somatic Variant Caller) due to<br />
misalignment near the end <strong>of</strong> the reads and was successfully identified with custom<br />
pipeline. Another patient with EGFR G719 mutation harbored frameshift mutation in<br />
the 717th codon, which would eliminate EGFR activation by G719 mutation. In this<br />
case detection <strong>of</strong> signle G719 mutation would falsely indicate at EGFR TKI sensitivity.<br />
Despite the absense <strong>of</strong> matched normal tissues we were able to detect CNV employing<br />
bootstrapping, allowing to detect EGFR amplifications in two patients. Low prevalent<br />
mutations were enriched with the C/T and G/A changes which are known to be FFPE<br />
arefacts. Therefore, mutations with allele frequency lower 10% were not detectable in<br />
13 samples (52%). In four patients low library concentration led to the increased count<br />
<strong>of</strong> high prevalent mutations. This resulted in false positive mutations including AKT1<br />
E17K and CTNNB1 S45F, suggesting that simple mutant allele frequency cut<strong>of</strong>f can<br />
not be used to sort out FFPE artefacts.<br />
Conclusions: NGS allows to detect rare mutations associated with TKI sensitivity which<br />
<strong>of</strong>ten remain unseen using gold standard methods. Obaining low-level information it<br />
allows to exclude false positive and false negative results. Though tbioinformatic pipelines<br />
remain the major sensitivity limitating stage. We were able to perform thorough<br />
configuration complexed with internal devepments to overcome these obstacles.<br />
Legal entity responsible for the study: Vladislav Mileyko<br />
Funding: Ministry <strong>of</strong> Education and Science <strong>of</strong> the Russian Federation<br />
(RFMEFI60714X0098)<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
120P<br />
abstracts<br />
Detection <strong>of</strong> early genetic and epigenetic alterations in<br />
NSCLC by using mass spectrometry and pyrosequencing<br />
analysis<br />
D. Furlan 1 , N. Sahnane 1 , N. Rotolo 2 , F. Franzi 1 , E. Nardecchia 2 , F. Sessa 1 ,<br />
L. Dominioni 2 , A. Imperatori 2<br />
1 Department <strong>of</strong> Surgical and Morphological Sciences, Anatomic Pathology Unit,<br />
University <strong>of</strong> Insubria, Varese, Italy, 2 Department <strong>of</strong> Surgical and Morphological<br />
Sciences, Center for Thoracic Surgery, University <strong>of</strong> Insubria-Ospedale del Circolo,<br />
Varese, Italy<br />
Background: Complete surgical resection remains the best curative treatment for<br />
patients with stage I non small cell lung cancer (NSCLC), but despite tumor resection,<br />
a high proportion <strong>of</strong> patients is still at high risk for cancer related death. Thus, there is<br />
Volume 27 | Supplement 6 | 2016<br />
doi:10.1093/annonc/mdw363 | vi35
abstracts<br />
a strong need <strong>of</strong> reliable biomarkers for providing information about the molecular<br />
events that occur in early stage <strong>of</strong> NSCLC.<br />
Methods: We analyzed a ten-year series <strong>of</strong> 167 consecutive formalin fixed stage I<br />
NSCLCs. We included 67 squamous cell carcinomas (SCC) and 100 adenocarcinomas<br />
(ADC). Mutation analysis <strong>of</strong> 10 genes involved in NSCLC (EGFR, KRAS, BRAF,<br />
PIK3CA, NRAS, ALK, ERBB2, DDR2, MAP2K1 and RET) was performed by<br />
MALDI-TOF Mass Spectometry (MassARRAY, Agena Bioscience) using the Myriapod<br />
Lung Status Kit (Diatech Pharmacogenetics). Tumor LINE-1 methylation status was<br />
determined by PCR-pyrosequencing on bisulfite-treated DNA and compared with<br />
normal lung tissue.<br />
Results: In ADCs we identified 29 KRAS (29%), 17 EGFR (17%), two BRAF (2%) and<br />
one PIK3CA mutations (1%). Considering the smoking habit, we observed that all the<br />
KRAS mutations clustered in NSCLC from smoker patients. The never-smoker group<br />
only showed EGFR mutations. In SCCs, we identified four non-canonical mutations in<br />
EGFR gene (6%), and four mutation in PIK3CA (6%). NSCLC showed methylation<br />
levels ranging from 14.8% to 78.8% while normal tissue had percentages from 66% to<br />
76.4%. The mean LINE1 methylation value was significantly lower in NSCLC than in<br />
normal lung (p = 0.0025). A strong LINE-1 hypomethylation was observed in SCC<br />
compared with ADC samples (p < 0.0001). Moreover, a positive association between<br />
LINE-1 hypomethylation and smoking habit was observed (p = 0.0003).<br />
Conclusions: The mutation pattern typical <strong>of</strong> advanced disease is observed also in<br />
stage I NSCLC patients who may deserve tailored adjuvant target therapy. LINE-1<br />
hypomethylation occurs early in NSCLC and is specifically associated with smoking<br />
habit and with SCC histology. Genetic and epigenetic events represents two<br />
complementary mechanisms in cancer and the knowledge <strong>of</strong> both types <strong>of</strong> alterations<br />
in NSCLC opens the possibility <strong>of</strong> new combinations <strong>of</strong> therapeutic agents.<br />
Legal entity responsible for the study: University <strong>of</strong> Insubria<br />
Funding: University <strong>of</strong> Insubria<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
mutated breast cancer patient, the clinical efficacy <strong>of</strong> treatments targeting ERBB3<br />
mutations remain largely unknown 1 . The objective <strong>of</strong> our study was to evaluate the<br />
efficacy <strong>of</strong> approved HER3 partners’ inhibitors in the ERBB3 mutant population.<br />
Methods: We retrospectively evaluated the clinical efficacy <strong>of</strong> HER3 partner’s inhibitor<br />
in ERBB3 mutant tumors. ERBB3 mutations were detected using Targeted Gene Panel<br />
Sequencing in patients enrolled in our molecular screening program (MOSCATO 01).<br />
Results: Mutations in ERBB3 were observed in less than 2% <strong>of</strong> the cases (12 patients)<br />
in various tumor types: head and neck SCC (2), biliary tract carcinoma (2), a rectal<br />
neuroendocrine tumor, an urothelial bladder carcinoma, a clear cell adenocarcinoma <strong>of</strong><br />
the cervix, a carcinoma <strong>of</strong> unknown primary, a lung SCC, an invasive lobular breast<br />
carcinoma and a pterygoid sarcoma. Overall, 7 patients received HER3 partners’<br />
inhibitors (trastuzumab and/or lapatinib or afatinib), 4 patients received other<br />
molecularly targeted agents (mTOR, PI3K or NOTCH inhibitors) and one failed being<br />
treated. We observed 1 partial response (PR) with the association <strong>of</strong><br />
trastuzumab + lapatinib for a biliary tract carcinoma patient and 1 PR for a HNSCC<br />
patient with torisel. Out <strong>of</strong> 6 patients with stable disease (SD), the breast cancer patient<br />
had 504 days on xeloda + lapatinib association, and the lung SCC patient had 420 days<br />
on afatinib. When the mutation was located in the tyrosine kinase domain (TKD),<br />
patients were highly sensitive to HER3 partners’ inhibitors, compared to mutations out<br />
<strong>of</strong> the TKD (hazard ratio for PFS = 6.63, p value = 0.01). Conversely, poor treatment<br />
efficacy was associated with the following parameters: mutations in the extracellular<br />
domain, >2 coexisting driver alterations, and > 1 previous systemic treatment line.<br />
Conclusions: This preliminary data supports the role <strong>of</strong> ERBB3 as an oncogenic driver.<br />
Larger cohorts <strong>of</strong> patients with ERBB3 mutations will be required to further identify<br />
and validate characteristics that drive sensitivity to HER3 partners’ inhibitors.<br />
Legal entity responsible for the study: Gustave Roussy Cancer Campus<br />
Funding: Gustave Roussy Cancer Campus<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
121P<br />
Screening <strong>of</strong> significant oncogenic changes in air<br />
pollution-related lung cancer in a Xuanwei County, China<br />
123P<br />
Signal transducer and activator <strong>of</strong> transcription–3 (STAT3)<br />
expression concordance in paired primary and metastatic<br />
colorectal cancers (mCRC)<br />
M. Kanwal 1 , X. Ding 1 ,C.Yi 1 , Y. Huang 2<br />
1 Laboratory <strong>of</strong> Molecular and Experimental Pathology, Kunming Institute <strong>of</strong><br />
Zoology, Kunming, China, 2 Department <strong>of</strong> Thoracic and Cardiovascular Surgery,<br />
Yunnan Tumour Hospital (3rd Affiliated Hospital Affiliated to Kunming Medical<br />
College), Kunming, China<br />
Background: Air pollution-related lung cancer has been considered as an exacerbating<br />
public health problem worldwide, particularly in developing countries. Xuanwei and<br />
Fuyuan County in Yunnan, China, regions with severely polluted air and exceptionally<br />
high lung cancer rates, are considered as good models to study air pollution-related<br />
lung cancer. The objective <strong>of</strong> the study was to establish a simple and sensitive test to<br />
define the status <strong>of</strong> clinically significant oncogenes in air pollution-related lung cancer.<br />
Methods: This study investigated the expression and mutation <strong>of</strong> HER2, and fusion<br />
gene EML4-ALK, CD74-ROS1 prevalence in lung cancer patients by reverse<br />
transcription PCR (RT-PCR) and DNA sequencing.<br />
Results: Of the 82 patients with non-small cell lung cancer, 20.7% (17/82) exhibited<br />
HER2 up-regulation, and 1.2% (1/82) harbored HER2 insertion at exon 20. HER2<br />
overexpression was not associated with air pollution levels and smoking status; 6.1% (5/<br />
82) showed ALK gene rearrangements, two belonged to EML4-E2 + ALK-E20 and<br />
three were EML4-E13 + ALK-E20; 3.6% (3/82) carried the CD74-ROS1 fusion gene<br />
(CD74-E6 + ROS1-E34). EML4-ALK fusion was found associated with smoking or a<br />
heavily polluted region, while CD74-ROS1 fusion occurred more frequently in<br />
non-smokers and in low polluted areas.<br />
Conclusions: The screening <strong>of</strong> HER2 overexpression and EML4-ALK fusion is helpful<br />
to guide treatment <strong>of</strong> air pollution-related lung cancer; the proposed RT-PCR-based<br />
test could be a useful tool in clinical applications to screen these genetic changes.<br />
Legal entity responsible for the study: N/A<br />
Funding: Natural Science Foundation <strong>of</strong> China (grant number 81272617)<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
122P<br />
Clinical efficacy <strong>of</strong> HER3 partners’ inhibitors in ERBB3<br />
mutated cancer patients<br />
L. Verlingue 1 , C. Massard 1 , A. Hollebecque 1 , E. Castanon Alvarez 1 ,<br />
S. Postel-Vinay 1 , E. Angevin 1 , J-P. Armand 1 , S. Aspeslagh 1 , A. Varga 1 ,<br />
B. Ratislav 1 , A. Gazzah 1 , J-M. Michot 1 , L. Lacroix 2 , T. De Baere 3 , A. Marabelle 1 ,<br />
J-C. Soria 4<br />
1 Drug Development Department (DITEP), Institut Gustave Roussy, Villejuif, France,<br />
2 Laboratoire de Recherche Translationnelle et Centre de Ressources Biologiques,<br />
Institut Gustave Roussy, Villejuif, France, 3 Interventional Radiology, Institut Gustave<br />
Roussy, Villejuif, France, 4 Drug Development Department (DITEP), Gustave<br />
Roussy, University Paris-Saclay, Villejuif, France<br />
D. Yokom 1 , S. Sud 2 , H. Marginean 2 , T. Asmis 2 , D.J. Jonker 2 , G. Martel 3 ,<br />
A. Gown 4 , M. Daneshmand 5 , E.C. Marginean 5 , R. Goodwin 2<br />
1 Division <strong>of</strong> Medical <strong>Oncology</strong>, Princess Margaret Hospital, Toronto, ON, Canada,<br />
2 Division <strong>of</strong> Medical <strong>Oncology</strong>, The Ottawa Hospital Regional Cancer Centre,<br />
Ottawa, ON, Canada, 3 Department <strong>of</strong> General Surgery, The Ottawa Hospital<br />
Regional Cancer Centre, Ottawa, ON, Canada, 4 Department <strong>of</strong> Pathology,<br />
PhenoPath, PLLC, Seattle, WA, USA, 5 Department <strong>of</strong> Pathology, The Ottawa<br />
Hospital Regional Cancer Centre, Ottawa, ON, Canada<br />
Background: STAT3 is a constitutively activated transcription factor in several cancers.<br />
In patients with mCRC overexpression <strong>of</strong> STAT3 is associated with worse survival. To<br />
determine if STAT3 is a potential target for therapy and to evaluate expression through<br />
metastatic progression in mCRC the concordance <strong>of</strong> expression in primary and<br />
metastatic tumors was assessed.<br />
Methods: Patients treated at the Ottawa Hospital from 2001-2012 were retrospectively<br />
identified and included if tumor tissue was available from both the primary and a<br />
metastasis. Tissue microarrays were constructed using 2 x 2mm cores for each tumor.<br />
Nuclear phosphorylated STAT3 expression intensity by immunohistochemistry was<br />
evaluated by 2 independent pathologists as 0 (absent), 1-2 (low), or 3 (high). The<br />
primary outcome was concordance <strong>of</strong> STAT3 expression between primary and<br />
metastatic sites. Secondary outcomes included correlation <strong>of</strong> STAT3 expression with<br />
demographic and disease characteristics as well as clinical outcomes.<br />
Results: Among 38 patients identified 52% were male, median age at diagnosis was 61,<br />
and 36% <strong>of</strong> metastases were synchronous. Expression <strong>of</strong> STAT3 in primary tumors was<br />
5% high, 42% low and absent in 53% compared to 16% high, 47% low, and 37% absent<br />
in metastatic samples. Expression between paired primary and metastatic samples was<br />
concordant in 33% <strong>of</strong> patients whereas it increased in 21% and decreased in 45%. A<br />
weak correlation was observed between primary and metastatic STAT3 expression<br />
(Pearson’s correlation 0.1). After a median follow-up <strong>of</strong> 13.1 years, 30 <strong>of</strong> 35 patients<br />
included in the survival analysis died. Median survival was 4.6 years. Higher STAT3<br />
expression in primary tumors showed a trend towards worse survival (HR 1.7, 95% CI<br />
0.81-3.64, p = 0.1), while there was no prognostic correlation <strong>of</strong> STAT3 expression in<br />
metastases.<br />
Conclusions: In patients with mCRC there was low concordance <strong>of</strong> STAT3 expression<br />
in primary and metastatic tumors. STAT3 expression in the primary, but not the<br />
metastatic site, was related to survival, indicating that the prognostic value <strong>of</strong> STAT3<br />
depended on tumor sampling. These results have important implications for further<br />
research in the use <strong>of</strong> STAT3 as a biomarker in patients with mCRC.<br />
Legal entity responsible for the study: Ottawa Hospital Research Institute<br />
Funding: The Ottawa Hospital Department <strong>of</strong> Medicine<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
Background: Mutations affecting ERBB3 are rare but diffuse across cancer types.<br />
Besides the case report <strong>of</strong> an effective treatment by HER2 double blockade in an ERBB3<br />
vi36 | abstracts Volume 27 | Supplement 6 | 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
124P<br />
Tandem repeat variation in HIC1 gene predicts outcome for<br />
oxaliplatin-based chemotherapy in patients with metastatic<br />
colorectal cancer<br />
S. Okazaki 1 , F. Loupakis 2 , M. Schirripa 3 , S. Cao 4 , W. Zhang 3 , D. Yang 4 , Y. Ning 3 ,<br />
M.D. Berger 3 , Y. Miyamoto 3 , M. Suenaga 3 , R. Gopez 3 , B.B. Borelli 5 , C. Cremolini 5 ,<br />
A. Falcone 5 , S. Lonardi 2 , L. Salvatore 5 , H. Uetake 6 , T. Kawano 1 , T. Helentjaris 7 ,<br />
H-J. Lenz 3<br />
1 Gastrointestinal Surgery, Tokyo Medical and Dental University, Tokyo, Japan,<br />
2 Oncologia Medica 1, Istituto Oncologico Veneto IRCCS, Padua, Italy,<br />
3 Department <strong>of</strong> Medical <strong>Oncology</strong>, University <strong>of</strong> Southern California Norris<br />
Comprehensive Cancer Center, Los Angeles, CA, USA, 4 Department <strong>of</strong> Preventive<br />
Medicine, University <strong>of</strong> Southern California Norris Comprehensive Cancer Center,<br />
Los Angeles, CA, USA, 5 Unit <strong>of</strong> Medical <strong>Oncology</strong> 2, Azienda<br />
Ospedaliero-Universitaria Pisana, Pisa, Italy, 6 Specialized Surgeries, Tokyo<br />
Medical and Dental University, Tokyo, Japan, 7 BIO5 and Department <strong>of</strong> Plant<br />
Sciences, University <strong>of</strong> Arizona, Tucson, AZ, USA<br />
Background: HIC1 (Hypermethylated in Cancer 1) is a transcription repressor, which<br />
cooperates with several partners to suppress the expression <strong>of</strong> multiple target genes.<br />
Among HIC1 targets, SIRT1 (Sirtuin1) plays a critical role in promoting the nucleotide<br />
excision repair (NER) pathway, which is the main oxaliplatin-induced damage repair<br />
system. HIC1 expression might be influenced by the number <strong>of</strong> variations in a<br />
tandemly-repeated sequence, situated close to the promoter region. We tested the<br />
hypothesis that variable number <strong>of</strong> tandem repeat (TR) in HIC1 will be associated with<br />
outcome in metastatic colorectal cancer patients (mCRC pts) receiving 1st-line<br />
chemotherapy with oxaliplatin.<br />
Methods: This study enrolled 3 independent cohorts. Pts treated with<br />
FOLFOXIRI + bevacizumab in the phase III TRIBE study served as a training set<br />
(TRIBE-B cohort, n = 218). Pts receiving FOLFOXIRI + bevacizumab in the phase II<br />
MOMA study served as a validation set (MOMA cohort, n = 176). Pts treated without<br />
oxaliplatin (FOLFIRI + bevacizumab) in the TRIBE study served as a control set<br />
(TRIBE-A cohort, n = 215). Genomic DNA was isolated from blood samples.<br />
Variations in the number <strong>of</strong> TR were analyzed by PCR and Gel electrophoresis, and<br />
tested for the association with PFS and OS.<br />
Results: Main patients characteristics’ were the following: TRIBE-A; M/F 60/40%,<br />
median age 60, TRIBE-B; M/F 60/40%, median age 60, MOMA; M/F 57/43%, median<br />
age 61. Median follow-up times were 49.9, 48.0, and 25.3 months, respectively. Pts with<br />
number <strong>of</strong> TR ≤4or≥5 were 90/10% (TRIBE-A), 91/9% (TRIBE-B), and 95/5%<br />
(MOMA), respectively. In the training cohort, pts with TRs ≥5 showed a significantly<br />
shorter PFS compared to those with TRs ≤4 (9.5 vs. 11.6 mo, HR 1.93, P = 0.012),<br />
which retained statistical significance in multivariate analysis (HR 2.00, 95%CI:<br />
1.13-3.54, P = 0.018). This preliminary association was confirmed in the validation<br />
cohort, and pts with TRs ≥5 showed a worse PFS compared to others (7.9 vs. 9.8 mo,<br />
HR 1.85, P = 0.044). This correlation was not observed in the control cohort.<br />
Conclusions: Our findings suggest that variable number <strong>of</strong> TRs in HIC1 could be a<br />
predictive marker for oxaliplatin-containing chemotherapy in mCRC pts.<br />
Legal entity responsible for the study: University <strong>of</strong> Southern California<br />
Funding: National Institute <strong>of</strong> Health<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
125P<br />
Levels <strong>of</strong> miR-17, miR-21, miR-29a and miR-92 as recurrence<br />
markers after adjuvant chemotherapy in Nx lymph node status<br />
colon cancer patients<br />
N.V. Conev 1 , A. Konsoulova-Kirova 1 , J. Kashlov 2 , I. Tonev 3 , I. Donev 1<br />
1 Department <strong>of</strong> Medical <strong>Oncology</strong>, St. Marina University Hospital, Varna, Bulgaria,<br />
2 Department <strong>of</strong> Internal Diseases, St. Marina University Hospital, Varna, Bulgaria,<br />
3 <strong>Oncology</strong> Clinic, Complex Cancer Center, Plovdiv, Bulgaria<br />
Background: The benefit <strong>of</strong> adjuvant chemotherapy in II and III stage patients with<br />
colon cancer (CC) is determined in large-scale trials. Despite the surprisingly large<br />
number <strong>of</strong> Nx cases (less than 12 lymph nodes examined), the potential benefit <strong>of</strong><br />
adjuvant chemotherapy is not known and there are only a few biomarkers that could<br />
predict recurrence <strong>of</strong> the disease. Recent evidence suggests that microRNAs are<br />
important cancer markers.<br />
Methods: CC patients (n = 18) with Nx lymph node status, who have undergone<br />
radical surgery and have completed 5-FU based adjuvant chemotherapy were included.<br />
Serum after last cycle <strong>of</strong> adjuvant chemotherapy was obtained and patients were<br />
followed-up regularly for 1 year <strong>of</strong> follow-up. Real-time reverse transcription<br />
quantitative polymerase chain reaction was used to measure the expression levels <strong>of</strong><br />
miRNAs (miR-17, miR-21, miR-29a and miR-92), in the patients’ samples and in 7<br />
healthy individuals, as a control group.<br />
Results: Seven patients from the tested group experienced recurrence after 1 year <strong>of</strong><br />
follow-up. Within the Nx patients all miRNAs except miR-29a had significant<br />
differences in expression levels between the recurred patients vs non recurred patients<br />
groups. The area under the receiver operating characteristic curve (AUCs) used to<br />
evaluate the predictive performance <strong>of</strong> the miR-17, miR-21, miR-92 for Nx patients<br />
were 0.844, 0.948, and 0.935, respectively (p < 0.05). In patients with Nx disease only<br />
expression levels <strong>of</strong> miR-29a were not good enough to discriminate between patients<br />
with recurrence and no recurrence <strong>of</strong> the disease.<br />
Conclusions: This study suggests that the expression levels <strong>of</strong> the tested serum miR-21,<br />
miR-17 and miR-92 in Nx patients with CC who underwent radical surgery and<br />
adjuvant chemotherapy may have diagnostic value for differentiating between recurred<br />
and non-recurred patients.<br />
Legal entity responsible for the study: Ivan Donev<br />
Funding: Medical University Varna<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
126P<br />
Comprehensive analysis <strong>of</strong> histone related modifications <strong>of</strong><br />
formaldehyde fixed paraffin embedded and fresh frozen<br />
pancreatic tumor xenografts using LC-MS/MS<br />
T. Kristl 1 , M. Bauden 2 , D. Ansari 2 , R. Andersson 2 , G. Marko-Varga 3<br />
1 <strong>Oncology</strong> and Pathology, Lund University, Lund, Sweden, 2 Surgery, Lund<br />
University, Lund, Sweden, 3 Biomedical Engineering, Lund University, Lund,<br />
Sweden<br />
Background: Post translational modifications (PTMs) <strong>of</strong> histones including<br />
acetylation, methylation or ubiquitination are known to be involved in the epigenetic<br />
regulation <strong>of</strong> gene expression and thus can play an important role in tumorigenesis.<br />
Some PTMs have been linked to pancreatic cancer and are frequently studied as a<br />
potential target for cancer therapy. Tissue samples can be stored as formaldehyde fixed<br />
paraffin embedded (FFPE) blocks or fresh frozen (FF). It is however important to<br />
consider that the treatment with formaldehyde may induce a variety <strong>of</strong> chemical<br />
modifications in the proteins. The aim <strong>of</strong> this study is to evaluate whether the FFPE<br />
tissue processing induced chemical modifications on the histone proteins originating<br />
from pancreatic tumor xenografts.<br />
Methods: Tissues were obtained from human pancreatic tumor xenografts developed<br />
from inoculated human pancreatic cancer cell line, capan-1. This study comprised two<br />
sample cohorts, including nine FFPE or FF samples, respectively. Peptides obtained<br />
after protein extraction, reduction, alkylation, and digestion were separated by capillary<br />
HPLC with a 150 min 5-40% acetonitrile in 0.10 % FA gradient and identified by<br />
quadrupole-Orbitrap mass spectrometry.<br />
Results: In total sixteen individual modification sites located on lysine residues have<br />
been characterized in FFPE samples compared to five matched modification sites<br />
identified in FF samples. We speculate, based on the obtained results that only the<br />
three equivalent modifications found uniformly in both groups, identified as<br />
H1.1K55me2, H1.2K34me and H3K80me together with H3K80me2 and H3K24Ac<br />
detected only in FF samples might be <strong>of</strong> biological origin. All the remaining identified<br />
modifications occurring exclusively in FFPE material were considered as PTM artifacts<br />
resulting from processing.<br />
Conclusions: Our results indicate that FFPE tissue processing can induce chemical<br />
modifications on lysine residues <strong>of</strong> histones originating from pancreatic tumor<br />
xenografts. A current experiment about the analysis <strong>of</strong> histone related PTMs between<br />
patient and control pancreatic cancer FF tissues should contribute to the discovery <strong>of</strong><br />
novel biomarkers.<br />
Legal entity responsible for the study: Lund University Medical Faculty<br />
Funding: Lund University Medical Faculty<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
127P<br />
abstracts<br />
Immuno-histochemical assessment <strong>of</strong> hENT1 biomarker as a<br />
prognostic biomarker for patients undergoing<br />
gemcitabine-based chemotherapy for resected biliary tract<br />
cancers: A systematic review and meta-analysis<br />
N. Bird 1 , M. Elmasry 2 , M. Elniel 2 , S. Fenwick 2 , H. Malik 2<br />
1 Surgery, University Hospital Aintree, Liverpool, UK, 2 Surgical <strong>Oncology</strong>, Aintree<br />
University Hospital NHS Foundation Trust, Liverpool, UK<br />
Background: Human Equilibriative Nucleoside Transporters (hENT) are<br />
trans-membranous ubiquitous proteins which facilitate the uptake <strong>of</strong> nucleosides and<br />
nucleoside analogues, such as gemcitabine, in to the cell. Research has tentatively<br />
inferred that the expression <strong>of</strong> hENT1 transporters in resected biliary tract cancer is a<br />
prognostic biomarker for gemcitabine-based chemotherapy. The aim <strong>of</strong> this<br />
meta-analysis and systematic review is to assess if hENT1 expression, as determined by<br />
immuno-histochemistry, is a prognostic biomarker for subsequent treatment with<br />
gemcitabine-based chemotherapy.<br />
Methods: The authors systematically identified articles pertaining to hENT1<br />
immuno-histochemical analysis in resected biliary tract cancer specimens from<br />
patients who subsequently underwent gemcitabine-based chemotherapy. Eligible<br />
studies had to contain survival analysis statistics, reporting specifically Overall Survival<br />
(OS), Disease Free Survival (DFS) and Progression Free Survival (PFS) with associated<br />
Hazard Ratios (HR’s) stratified by hENT1 status. Potential sources <strong>of</strong> inter-study<br />
heterogeneity were identified and accounted for in the statistical meta-analysis by use<br />
<strong>of</strong> a Random-Effects model to produce Forest Plots.<br />
Volume 27 | Supplement 6 | 2016<br />
doi:10.1093/annonc/mdw363 | vi37
abstracts<br />
Results: Of 105 received articles, 6 were deemed suitable for review, with a total<br />
population <strong>of</strong> 283 patients underwent statistical meta-analysis.<br />
Immuno-histochemically detected hENT1 expression is found to be significantly<br />
associated with both univariate PFS (0.43[95% CI 0.31-0.69]; I 2 0%; Z Score= 5.16; p=<br />
0.00001) and univariate OS (0.50[95%CI 0.38-0.67]; I 2 0%; Z score= 4.75; p= 0.00001).<br />
Conclusions: This meta-analysis demonstrates empirical evidence that hENT1<br />
expression is a valid predictor <strong>of</strong> survival for patients undergoing gemcitabine-based<br />
chemotherapy. The hENT1 biomarker should be used to stratify patients into<br />
appropriate adjuvant chemotherapeutic regimens to improve outcomes and reduce<br />
un-necessary exposure to inefficacious treatments for patients determined to be<br />
hENT1-ve.<br />
Legal entity responsible for the study: Liverpool University and University Hospital<br />
Aintree<br />
Funding: Liverpool University Translational Medicine Department<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
128P<br />
Modulation <strong>of</strong> specificity protein 1 (SP1) is a novel therapeutic<br />
strategy for pancreatic cancer<br />
J.S. Park, Y.S. Lee, D.S. Yoon<br />
Surgery, Gangnam Severance Hospital, Yonsei University College <strong>of</strong> Medicine,<br />
Seoul, Republic <strong>of</strong> Korea<br />
Background: Pancreatic cancer is one <strong>of</strong> the most aggressive and lethal malignancies.<br />
Specificity Protein 1 (SP1) is a transcription factor regulates and promotes tumor<br />
progression. Some studies have reported SP1 promotes epithelial-mesenchymal<br />
transition (EMT) and is associated with aggressive and poor patient prognosis.<br />
However, there is a paucity <strong>of</strong> clinical evidence regarding the role <strong>of</strong> SP1 in pancreatic<br />
cancer. In this study, we aimed to confirm the function <strong>of</strong> SP1 in invasiveness <strong>of</strong><br />
pancreatic cancer cells and to evaluate the clinical impact in patients with pancreatic<br />
cancer.<br />
Methods: Between June 2002 and December 2012, 81 patients underwent radical<br />
curative resection for pancreatic cancer at Gangnam Severance Hospital, Seoul, Korea.<br />
Pancreatic cancer cell lines MIA PaCa-2, PANC-1, AsPC-1, and BxPC-3 were used for<br />
in vitro study. To evaluate the endogenous expression level <strong>of</strong> SP1, we purified the<br />
whole RNA and protein to perform the qPCR, RT-PCR and Western blot. si-SP1 was<br />
used for specifically inhibit the function <strong>of</strong> SP1. The invasive potential <strong>of</strong> pancreatic<br />
cancer cells were assessed in matrigel coated chambers.<br />
Results: Among the 81 patients, 32 (39.5%) were positive for SP1. On univariate and<br />
multivariate analyses, poor differentiation tumor and SP1-positive status were<br />
identified as independent prognostic factors for DFS. High expression <strong>of</strong> SP1 was<br />
observed and correlated with the expression <strong>of</strong> mesenchymal markers (Snail, L1CAM,<br />
Vimentin) unlike epithelial markers (CDH1). Importantly, silencing <strong>of</strong> SP1 showed<br />
markedly decrease in motility and the invasiveness <strong>of</strong> cancer cells (p < 0.001) as<br />
determined from transwell invasion and transendothelial migration assays, respectively.<br />
Conclusions: Our results demonstrated that SP1 is an independent marker for<br />
metastatic disease and death in patients with pancreatic cancer. Additionally, our in<br />
vitro study demonstrated that SP1 expression promotes EMT and the invasiveness <strong>of</strong><br />
pancreatic cancer cell lines, a finding compatible with the results <strong>of</strong> previous in vitro<br />
studies. These findings suggest that SP1 can potentially be a valuable target for the<br />
improvement <strong>of</strong> survival rates in patients with pancreatic cancer.<br />
Legal entity responsible for the study: J. Park<br />
Funding: Gangnam Severance Hospital<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
patients in stage I and II from 890 healthy individuals controls with 96% accuracy*.<br />
Furthermore, when analyzing all stages <strong>of</strong> pancreatic cancer in retrospective studies<br />
covering more than 3000 blood samples, the test accuracy is as high as 98%.<br />
*Manuscript in preparation<br />
Conclusions: IMMray PanCan-d can detect asymptomatic pancreatic cancer patients<br />
stage 1 and 2 with 96% accuracy and stage 1 to 4 with 98% accuracy.<br />
Legal entity responsible for the study: Lund University, Create Health, Dept. <strong>of</strong><br />
Immunotechnology<br />
Funding: Lund University, Create Health, Dept. <strong>of</strong> Immunotechnology<br />
Disclosure: L. Dexlin Mellby, A. Holmér: Employee at Immunovia AB. All authors<br />
have declared no conflicts <strong>of</strong> interest.<br />
130P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Novel genetic marker <strong>of</strong> diarrhea in renal cell carcinoma<br />
patients treated with sorafenib<br />
F. Innocenti 1 , A. Karabinos 1 , A. Etheridge 1 , C. Pena 2 , D. Crona 1<br />
1 Eshelman School <strong>of</strong> Pharmacy, University <strong>of</strong> North Carolina - Chapel Hill, Chapel<br />
Hill, NC, USA, 2 Clinical Pharmacology, <strong>Oncology</strong>, Bayer Healthcare<br />
Pharmaceuticals, Whippany, NJ, USA<br />
Background: Sorafenib, the first oral anti-angiogenic multikinase inhibitor, is<br />
primarily used in the treatment <strong>of</strong> advanced renal cell carcinoma (RCC), hepatocellular<br />
carcinoma, and thyroid cancer. Common toxicities experienced by patients treated<br />
with sorafenib limit its use and affect adherence to treatment, reducing sorafenib<br />
efficacy. No biomarkers are currently available to identify patients at risk <strong>of</strong> toxicity.<br />
Methods: Metastatic RCC (mRCC) patients (n = 153) treated with sorafenib, as part <strong>of</strong><br />
the TARGET study (Escudier B, N Engl J Med. 2007), were genotyped for common<br />
germline DNA variants in 56 candidate genes. Associations between 5846 variants and<br />
grade 2-4 toxicities were analyzed. Patients treated for ≤28 days were excluded.<br />
Toxicities included diarrhea, hypertension, hand-foot skin reaction, and/or rash or<br />
desquamation. For each toxicity, the worst grade event for each patient was used. After<br />
linkage disequilibrium-based pruning, 685 variants were utilized for analysis via a<br />
chi-squared test.<br />
Results: Out <strong>of</strong> 153 patients, 28 (18%) experienced grade ≥2 diarrhea. The A allele <strong>of</strong><br />
rs917881 (G > A) in the epidermal growth factor receptor (EGFR) gene was associated<br />
with an increased risk <strong>of</strong> grade ≥2 diarrhea (p = 0.00006, p = 0.04 after Bonferroni’s<br />
correction, odds ratio 3.6). The frequency <strong>of</strong> grade ≥2 diarrhea was 50% (3/6) in AA,<br />
33% (15/45) in GA, and 10% (10/102) in GG patients. The frequency <strong>of</strong> grade 3<br />
diarrhea was 8% (4/51) in patients with the A allele (AA + GA) versus 2% (2/102) in<br />
patients with the GG genotype. No other variants were significantly associated with<br />
sorafenib toxicity after Bonferroni correction.<br />
Conclusions: To our knowledge, this is the first reported study <strong>of</strong> a genetic basis <strong>of</strong><br />
sorafenib toxicity. rs917881 is a common intronic variant (17% allele frequency) in<br />
EGFR. RAF kinase, a critical component <strong>of</strong> the EGFR signaling pathway, is a known<br />
target <strong>of</strong> sorafenib. Patients with the rs917881 A allele treated with sorafenib may be at<br />
an increased risk for diarrhea as a result <strong>of</strong> decreased EGFR expression potentiated by<br />
sorafenib-induced inhibition <strong>of</strong> the RAF/MEK/Erk pathway, which regulates chloride<br />
secretion (Keely SJ, J Biol Chem. 1998). Replication analyses in additional patient<br />
cohorts and functional studies are ongoing.<br />
Clinical trial identification: NCT00073307<br />
Legal entity responsible for the study: University <strong>of</strong> North Carolina at Chapel Hill<br />
Funding: National Institutes <strong>of</strong> Health<br />
Disclosure: C. Pena: Employee <strong>of</strong> and owns stock in Bayer Healthcare<br />
Pharmaceuticals. All other authors have declared no conflicts <strong>of</strong> interest.<br />
129P<br />
Early-stage diagnosis <strong>of</strong> pancreatic cancer <strong>of</strong>fers opportunity<br />
to improve overall patient survival<br />
L. Dexlin Mellby 1 , A. Holmér 1 , C. Wingren 2 , J. Johansen 3 , S.E. Bojesen 4 ,B.<br />
G. Nordestgaards 4 , C.A. Borrebaeck 2<br />
1 Immunovia AB, Lund, Sweden, 2 Immunotechnology, Lund University, Lund,<br />
Sweden, 3 Department <strong>of</strong> <strong>Oncology</strong>, Herlev and Gent<strong>of</strong>te Hospital, Herlev,<br />
Denmark, 4 Health and Medical Sciences, University <strong>of</strong> Copenhagen, Copenhagen,<br />
Denmark<br />
Background: Pancreatic ductal adenocarcinoma (PDAC) has one <strong>of</strong> the worst survival<br />
rates with only 5% five years survival. By providing physicians with actionable<br />
information when the tumour is still resectable, the overall 5 year PDAC patient<br />
survival rate could increase from 5 % to 50- 60%. We present a summary <strong>of</strong><br />
retrospective studies performed on IMMray PanCan-d, a blood test developed for<br />
early stage diagnosis <strong>of</strong> pancreatic cancer.<br />
Methods: IMMray PanCan-d creates a biological snapshot <strong>of</strong> an individual’s<br />
immune response by analysing serum proteins that change as a sign <strong>of</strong> disease. The<br />
process to derive unique biomarker immunosignatures from an antibody microarray<br />
platform, through state <strong>of</strong> the art bioinformatics algorithms, is also presented.<br />
Results: Based on recent results from the largest retrospective study on pancreas cancer<br />
covering 1400 blood samples, we have been able to differentiate 148 asymptomatic<br />
131P<br />
Molecular pathology <strong>of</strong> the 10q23.3-26.3 chromosome region<br />
in glioblastoma<br />
E. Alekseeva 1 , A. Tanas 1 , E. Prozorenko 2 , A. Zaytsev 3 , O. Kirsanova 3 ,<br />
V. Strelnikov 1 , D. Zaletayev 4<br />
1 Federal Agency for Scientific Organizations, Federal State Budgetary Institution<br />
"Research Centre for Medical Genetics", Moscow, Russian Federation,<br />
2 N. N. Blokhin Russian Cancer Research Center, Moscow, Russian Federation,<br />
3 Moscow <strong>Oncology</strong> Research Institute, Moscow, Russian Federation, 4 IM<br />
Sechenov First Moscow State Medical University, Moscow, Russian Federation<br />
Background: Glioblastoma is the most common and aggressive primary brain tumor<br />
in adults. The most common genetic alteration in glioblastoma is the loss <strong>of</strong><br />
heterozygosity (LOH) <strong>of</strong> the chromosome 10q. However LOH merely reflects allelic<br />
imbalance in the area without detailed information on the gene copy number.<br />
Methods: We have been the first to conduct a targeted analysis <strong>of</strong> LOH at the<br />
10q23.3-26.3 chromosome region which contains candidate genes PTEN, FGFR2,<br />
MKI67 and MGMT in glioblastoma. A panel <strong>of</strong> microsatellite markers to detect LOH<br />
in the area under study, which includes 20 microsatellite polymorphisms, has been<br />
developed and characterized. In order to assess copy number alterations at the<br />
10q23.3-26.3 region in glioblastoma samples with identified LOH, we have developed a<br />
system for quantitative microsatellite analysis (QuMA). QuMA is based on<br />
vi38 | abstracts Volume 27 | Supplement 6 | 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
amplification <strong>of</strong> microsatellite loci that contain (CA)n repeats where the repeat itself is<br />
the target for hybridization by the fluorescently labeled probe. The reference pool<br />
contains primer pairs for six genomic regions located on different chromosomes in<br />
which copy number violations are not typical for glioblastoma.<br />
Results: Frequency <strong>of</strong> LOH at the 10q23.3-26.3 region evaluated in glioblastoma<br />
samples equals 62,1% (77/124). In 37,5% (24/64) <strong>of</strong> the samples only one copy <strong>of</strong><br />
10q23.3-26.3 chromosome region was found (deletion), in 25,0% (16/64) two copies<br />
were detected (acquired uniparental disomy, aUPD). In 37,5% (24/64) <strong>of</strong> the samples<br />
areas <strong>of</strong> alternation <strong>of</strong> deletion and aUPD throughout the tested region were identified.<br />
Higher frequencies <strong>of</strong> deletions were characteristic for the proximal part <strong>of</strong><br />
10q23.3-26.3 region (PTEN and FGFR2 genes), while aUPDs were more frequent in<br />
the distal part (MGMT gene). Thus, the transition from a region with deletion to a<br />
region with aUDP occurs at 10q26.1 - 10q26.2.<br />
Conclusions: Thus, we have shown that the LOH at the 10q23.3-26.3 region in<br />
glioblastoma can reflect either a deletion or an aUPD. Detailed study <strong>of</strong> copy number<br />
changes at the 10q23.3-26.3 chromosome region containing PTEN, FGFR2, MKI67<br />
and MGMT will allow to discover new targets for drugs and molecular markers <strong>of</strong><br />
disease prognosis and response to therapy.<br />
Legal entity responsible for the study: The research was supported by RFBR grant<br />
14-04-031832 mol_a<br />
Funding: Russian Foundation for Basic Research<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
132P<br />
Using diffusion-weighted MRI derived apparent diffusion<br />
coefficient as a predictive biomarker <strong>of</strong> tumor response in<br />
non-Hodgkin lymphoma<br />
S. Kharuzhyk 1 , E. Zhavrid 2 , N. Sachivko 2<br />
1 Department <strong>of</strong> Radiology, N.N. Alexandrov National Cancer Centre <strong>of</strong> Belarus,<br />
Minsk, Belarus, 2 Department <strong>of</strong> Chemotherapy, N.N. Alexandrov National Cancer<br />
Centre <strong>of</strong> Belarus, Minsk, Belarus<br />
Background: Diffusion-weighted MRI (DW-MRI) is a radiation free, non-invasive<br />
diagnostic imaging technique detecting random movement <strong>of</strong> water molecules in vivo.<br />
Extent <strong>of</strong> diffusion in fluids and tissues can be assessed quantitatively using apparent<br />
diffusion coefficient (ADC). The aim <strong>of</strong> this study was to determine usefulness <strong>of</strong><br />
DW-MRI with ADC calculation for early prediction <strong>of</strong> tumor response in patients with<br />
non-Hodgkin lymphoma (NHL).<br />
Methods: DW-MRI was performed in 26 patients (13 males and 13 females, mean age<br />
55 years, range 26-76) with NHL at baseline, after 1 cycle and at the end <strong>of</strong> induction<br />
chemotherapy. The largest not necrotic lymph node was chosen as a target lesion for<br />
serial size and ADC measurement. End <strong>of</strong> treatment tumor response was categorized as<br />
complete (CR) or non-complete using revised International Working Group criteria.<br />
Results: Target lesion ADC (mean ± SD) increased from 0.81 ± 0.33 × 10 −3 mm 2 /c at<br />
baseline to 1.16 ± 0.44 × 10 −3 mm 2 /c after 1 cycle <strong>of</strong> chemotherapy resulting in average<br />
increase <strong>of</strong> 50.3 ± 48.4%. The earliest ADC increase was noted on day 3 after start <strong>of</strong><br />
chemotherapy. Product <strong>of</strong> two perpendicular diameters <strong>of</strong> target lesion decreased from<br />
3407.7 ± 3583.7 mm 2 to 2359.2 ± 2813.2 mm 2 from baseline to after 1 cycle respectively<br />
giving average decrease <strong>of</strong> 36.4 ± 22.0%. Pre-treatment ADC was significantly lower in<br />
patients with CR than non-CR – 0.65 ± 0,15 × 10 −3 mm 2 /s and 0.94 ± 0,39 × 10 −3<br />
mm 2 /s respectively (p < 0,03). Pre-treatment ADC ≤ 0.88 × 10 −3 mm 2 /s predicted CR<br />
with a sensitivity <strong>of</strong> 100%, specificity <strong>of</strong> 50% and accuracy <strong>of</strong> 77%. ADC increase post 1<br />
cycle > 25% predicted CR with a sensitivity <strong>of</strong> 83%, specificity <strong>of</strong> 67% and an accuracy<br />
<strong>of</strong> 75%. When two parameters were combined prediction accuracy increased to 83%.<br />
Conclusions: DW-MRI with ADC calculation can be used for pretreatment and early<br />
during treatment tumor response prediction in patients with NHL. Combination <strong>of</strong><br />
pretreatment ADC and ADC change post 1 cycle <strong>of</strong> chemotherapy increases prediction<br />
accuracy.<br />
Legal entity responsible for the study: N.N. Alexandrov National Cancer Center <strong>of</strong><br />
Belarus<br />
Funding: Ministry <strong>of</strong> Health<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
133P<br />
Identification <strong>of</strong> an epigenetic biomarker predicting the<br />
response to therapy with APG101 in glioblastoma<br />
M. Thiemann 1 , C. Gieffers 1 , C. Kunz 2 , J. Sykora 1 , C. Merz 1 , H. Fricke 2 ,<br />
B. Wiestler 3 , W. Wick 4<br />
1 Protein Analytics, Apogenix AG, Heidelberg, Germany, 2 Clinical Development,<br />
Apogenix AG, Heidelberg, Germany, 3 Abteilung für Neuroradiologie, Rechts der<br />
Isar Hospital,TUM, Munich, Germany, 4 Abteilung für Neuroonkologie, University<br />
Hospital Heidelberg, Heidelberg, Germany<br />
Background: APG101, a fully human fusion protein consisting <strong>of</strong> the extracellular<br />
domain <strong>of</strong> CD95 and the Fc-domain <strong>of</strong> an IgG, has been developed by Apogenix. It<br />
was confirmed as a potent inhibitor <strong>of</strong> CD95L induced invasion <strong>of</strong> glioblastoma cells in<br />
vitro. In a randomized phase 2 study in glioblastoma patients with 1 st or 2 nd relapse the<br />
combined therapy <strong>of</strong> APG101 plus radiotherapy (RT) was found to be superior to RT<br />
alone in a clinically relevant order <strong>of</strong> magnitude in all efficacy endpoints (i.e. PFS-6,<br />
PFS and OS). At the same time APG101 exhibited an excellent safety pr<strong>of</strong>ile and was<br />
well tolerated. The presented data summarizes the identification <strong>of</strong> a predictive<br />
biomarker.<br />
Methods: To identify potential biomarkers we used available tissue sections originating<br />
from archived primary tumor <strong>of</strong> the study patients and analyzed them for the<br />
expression <strong>of</strong> CD95L as well as for the DNA methylation status.<br />
Results: A genome-wide assessment <strong>of</strong> DNA methylation identified a single CpG-site<br />
(CpG2) upstream <strong>of</strong> the CD95L-promotor that showed differential methylation<br />
between APG101 responders (PFS > 5 months) and non-responders (PFS < 2 months).<br />
Available patient DNAs were in addition analyzed by MassARRAY and<br />
Pyro-sequencing to confirm differential CpG2 methylation. Based on this data we used<br />
the median <strong>of</strong> the CpG2 methylation level as a threshold to analyze for a correlation <strong>of</strong><br />
CpG2 methylation and response to APG101 therapy. Patients showing a low level <strong>of</strong><br />
CpG2 methylation responded best to therapy with APG101 whereas patients with a<br />
high level <strong>of</strong> CpG2 methylation did not show a relevant benefit when treated with<br />
APG101 compared to the control RT-group. The analysis shows a significant survival<br />
benefit achieved in patients with low CpG2 methylation (median OS: 16.1 vs 7.7<br />
months, p = 0.038).<br />
Conclusions: The level <strong>of</strong> CpG2 methylation in the CD95L promoter in the patients’<br />
glioblastoma tissue is a prognostic biomarker predicting response to therapy with<br />
APG101. Apogenix currently develops a qPCR-based assay to quantify CpG2<br />
methylation. This assay is intended as companion diagnostic to identify patients that<br />
may respond best to APG101 treatment.<br />
Clinical trial identification: EudraCT-Number: 2009-013421-42<br />
Legal entity responsible for the study: Apogenix AG<br />
Funding: Apogenix AG<br />
Disclosure: M. Thiemann, C. Gieffers, C. Kunz, J. Sykora, C. Merz, H. Fricke:<br />
Employee <strong>of</strong> Apogenix AG. W. Wick: Commercial research grant from Boehringer<br />
Ingelheim and Roche; speaker’s bureau honoraria from Prime <strong>Oncology</strong>; and is a<br />
consultant/advisory board member for Eli Lilly and Co. and Roche. All other authors<br />
have declared no conflicts <strong>of</strong> interest.<br />
134P<br />
abstracts<br />
APO010 sensitivity in relapsed multiple myeloma patients<br />
A.J. Vangsted 1 , P.B. Jensen 2 , M.W. Madsen 2 , P. Gimsing 1 , T. Jensen 3 ,<br />
A. Hansen 3 , A. Rasmussen 2 , A. Nielsen 2 , U. Buhl 2 , H. Jandu 2 , N. Brunner 2 ,<br />
B. Pratt 2 , U.C. Frølund 4 , C. Helleberg 5 , N. Abildgaard 6 , S. Knudsen 2<br />
1 Haematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen,<br />
Denmark, 2 <strong>Oncology</strong>, <strong>Oncology</strong> Venture, Hørsholm, Denmark, 3 Biology, Medical<br />
Prognosis, Scottsdale, AZ, USA, 4 Haematology, Roskilde Hospital, Roskilde,<br />
Denmark, 5 <strong>Oncology</strong>, University Hospital Herlev, Herlev, Denmark, 6 Haematology,<br />
Odense University Hospital, Odense, Denmark<br />
Background: Multiple myeloma is the next most common hematological malignancy<br />
and represents a continuous medical challenge since all patients eventually progress<br />
despite <strong>of</strong> many new drugs approved lately. The incidence <strong>of</strong> MM is about 6 to 8 out <strong>of</strong><br />
100.000 in Western Countries. APO010 (a hexameric FAS-ligand) is an<br />
immune-oncology drug, which mimics cytotoxic T-lymphocyte signaling to induce<br />
apoptosis and could therefore be a new effective drug for MM as these cells express<br />
CD95 (FAS-receptor).<br />
Methods: Using a previously validated method by Medical Prognosis Institute A/S<br />
(MPI), we have developed an APO010 response predictor (APO010-DRP TM ), which is<br />
based on gene expression cluster obtained by comparing associations between gene<br />
expression pr<strong>of</strong>iles and growth inhibition by APO010 in a panel <strong>of</strong> cell lines. A second<br />
step has included filtering the identified gene expression pr<strong>of</strong>ile against mRNA<br />
expression from a collection <strong>of</strong> 3200 human tumors, thereby making a predictive<br />
pr<strong>of</strong>ile for APO010 responsiveness. We have initiated to screen relapse/refractory MM<br />
patients by isolating CD138 positive myeloma cells from the bone marrow and perform<br />
APO010-DRP TM in order to select the patients with the highest likelihood <strong>of</strong> benefit<br />
from APO010 treatment.<br />
Results: Using the APO010-DRP TM analysis demonstrated multiple myeloma to be<br />
sensitive to APO010 compared to most solid tumors except breast cancer, which also<br />
appeared to be sensitive. First results from multiple myeloma patient screening will be<br />
presented at ESMO 2016.<br />
Conclusions: Conclusion: Combining APO010 with DRP TM analysis will add a<br />
precision medicine element to immune-oncology treatment <strong>of</strong> multiple myeloma. This<br />
will enable us to identify patients with high likelihood <strong>of</strong> response and thereby facilitate<br />
focused future trial design and patient recruitment to achieve clinical success.<br />
Clinical trial identification: Danish Ethical Committee, Journal nr.: H15018326,<br />
Approved on 01/03/2016<br />
Legal entity responsible for the study: <strong>Oncology</strong> Venture<br />
Funding: <strong>Oncology</strong> Venture<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
Volume 27 | Supplement 6 | 2016<br />
doi:10.1093/annonc/mdw363 | vi39
abstracts<br />
135P<br />
ACE and CXCL10 as predictive biomarkers in the LEA study<br />
J. de la Haba 1 , E. Aranda Aguilar 1 , S. Morales 2 , J.A. García-Sáenz 3 , A. Guerrero 4 ,<br />
N. Martínez 5 , A. Antón 6 , M. Muñoz 7 , M. Ramos 8 , M. Gil-Gil 9 , M. Margelí 10 ,<br />
S. Servitja 11 , B. Bermejo 12 , J. Cruz 13 , A. Rodríguez Lescure 14 , M. Casas 15 ,<br />
M. Sánchez-Aragó 15 , R. Caballero 15 , E. Carrasco 15 , M. Martin 16<br />
1 Medical <strong>Oncology</strong> Dpto, University Hospital Reina S<strong>of</strong>ia, Cordoba, Spain,<br />
2 Medical <strong>Oncology</strong>, Hospital Universitario Arnau Vilanova de Lleida, Lerida, Spain,<br />
3 Medical <strong>Oncology</strong>, Hospital Clinico Universitario San Carlos, Madrid, Spain,<br />
4 Medical <strong>Oncology</strong>, Fundación Instituto Valenciano de Oncología, Valencia, Spain,<br />
5 Medical <strong>Oncology</strong>, Hospital Universitario Ramon y Cajal, Madrid, Spain, 6 Medical<br />
<strong>Oncology</strong>, Hospital Miguel Servet, Zaragoza, Spain, 7 Medical <strong>Oncology</strong>, Hospital<br />
Clinic y Provincial de Barcelona, Barcelona, Spain, 8 Medical <strong>Oncology</strong>, Fundacion<br />
Centro Oncologico de Galicia, A Coruna, Spain, 9 Medical <strong>Oncology</strong>, ICO<br />
L’Hospitalet, Barcelona, Spain, 10 Medical <strong>Oncology</strong>, Hospital Germans Trias i<br />
Pujol, Barcelona, Spain, 11 Medical <strong>Oncology</strong>, University Hospital del Mar,<br />
Barcelona, Spain, 12 Serv. Hematologia Y Oncologia Medica, Hospital Clinico<br />
Universitario de Valencia, Valencia, Spain, 13 Medical <strong>Oncology</strong>, Hospital<br />
Universitario de Canarias, Santa Cruz, Spain, 14 Medical <strong>Oncology</strong>, Hospital<br />
General Universitario de Elche, Elche, Spain, 15 GEICAM (Spanish Breast Cancer<br />
Research Group), Madrid, Spain, 16 Medical <strong>Oncology</strong>, Hospital General<br />
Universitario Gregorio Marañon, Madrid, Spain<br />
Background: LEA Study (GEICAM/2006-11/GBG51), is a randomized clinical trial<br />
comparing bevacizumab in combination with endocrine therapy (ET + B) with<br />
endocrine therapy (ET) in postmenopausal women with advanced or metastatic<br />
HR-positive/HER2-negative breast cancer (BC) with indication <strong>of</strong> hormonotherapy as<br />
first-line treatment. Patients with secondary hypertension had better progression-free<br />
survival (PFS) and overall survival (OS). We have evaluated the role <strong>of</strong> two<br />
hypertension-related biomarkers, Angiotensin-Converting Enzyme (ACE) and<br />
Small-Inducible Cytokine B10 (CXCL10) as prognostic and/or predictive biomarkers<br />
<strong>of</strong> benefit to bevacizumab in the first line metastatic disease.<br />
Methods: From 380 patients, 266 were included in 33 Spanish sites. Median age was 64<br />
years, 63.5% had measurable disease, 97.4% were metastatic at randomization, 51.5%<br />
had visceral disease and 52.6% received previous chemotherapy. PFS was 14.3 months<br />
(range 0.8-61.1), OS was 34 months (range 0.8-71.6) and 93 patients had Objective<br />
Response (OR). We analyzed 124 plasma samples collected before treatment (52 from<br />
ET and 72 from ET + B arms). Circulating levels <strong>of</strong> ACE and CXCL10 were determined<br />
by ELISA. ACE levels <strong>of</strong> 115ng/ml and 135ng/ml were pre-defined as cut<strong>of</strong>f values.<br />
CXCL10 was explored as a quantitative variable.<br />
Results: PFS was 15.1 months (range 1.4-61.1), OS was 31.1 months (range 2.8-61.1)<br />
and 40.3% had OR. OR was significantly different between treatment arms (p < 0.001)<br />
but not PFS or OS. Median ACE concentration was 130.9ng/ml (range 35.3-315.4).<br />
Low ACE (
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
138P<br />
Improved efficacy response attributed to diagnostic selection<br />
– Interim results <strong>of</strong> the phase 1 experience from<br />
ALKA-372-001<br />
J. Christiansen 1 , S. Siena 2 , E. Valtorta 3 , A. Johnson 1 , D. Murphy 1 , R. Shoemaker 1 ,<br />
J. Lamoureux 1 , D. Luo 1 , R. Patel 1 , Z. Hornby 1 , P. Multani 1 , E. Chow Maneval 1 ,<br />
M. Duca 4 , F. Debraud 4<br />
1 Diagnostics, Ignyta, Inc., San Diego, CA, USA, 2 Niguarda Cancer Center, Grande<br />
Ospedale Metropolitano Niguarda and Università degli Studi di Milano, Milan, Italy,<br />
3 Cytogenetics, Ospedale Niguarda Ca Granda, Milan, Italy, 4 <strong>Oncology</strong>,<br />
Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy<br />
Background: The ALKA-371-001 phase 1 trial was implemented to assess safety and<br />
dosing in patients with advanced solid tumors and treated with entrectnib, which<br />
targets the tyrosine kinases encoded by NTRK1, NTRK2, NTRK3, ROS1, and ALK.<br />
Being a targeted therapy, a subset <strong>of</strong> patients were enrolled based on the local<br />
assessment <strong>of</strong> gene rearrangements in the NTRK1, ROS1 or ALK genes, by FISH or<br />
IHC, during dose escalation and expansion. Retrospectively, a subset <strong>of</strong> phase 1 patient<br />
specimens were submitted for central laboratory testing using RNA based next<br />
generation sequencing (NGS) to determine status <strong>of</strong> gene rearrangements (n = 33) <strong>of</strong><br />
those, 23 were treated at, or above, the recommended phase 2 dose. Together, these<br />
clinical responses were correlated with diagnostic detection <strong>of</strong> a gene rearrangement to<br />
assess prediction <strong>of</strong> outcome based on patient selection.<br />
Methods: Two primary hospital centers performed FISH or IHC for the assessment <strong>of</strong><br />
gene rearrangements and applied consensus scoring. These results were used for<br />
patient enrollment and treated as the reference standard. For central testing, an<br />
anchored multiplex PCR NGS <strong>of</strong> sample RNA was used to assess gene rearrangements.<br />
Tumor response was determined using RECIST criteria. Statistical analyses to test<br />
correlation with outcomes was performed.<br />
Results: For patients with results from both local testing and central confirmation<br />
testing (n = 33), there is strong negative agreement (100%) yet poor positive agreement<br />
(ALK 62.5%, ROS1 40%, NTRK 0%). However, when results are correlated for n = 23<br />
study patients with the overall response rate (PR or CR), the use <strong>of</strong> central NGS testing<br />
provides a significant ORR <strong>of</strong> 66.7% (CI: 30%, 90%) vs local testing 41.7% (CI: 19%,<br />
68%).<br />
Conclusions: The current response data <strong>of</strong> the ALKA-371-001 trial demonstrates that<br />
the use <strong>of</strong> high sensitivity NGS testing is significantly predictive <strong>of</strong> overall response rate<br />
in the targeted patient population. Indicating that the predictive methods used<br />
centrally must be readily deployable to local testing laboratories to find patients beyond<br />
the clinical trial setting. The early identification <strong>of</strong> appropriate diagnostic testing at the<br />
phase 1 level improves the chances for effective trial outcomes and treatment <strong>of</strong><br />
patients.<br />
Clinical trial identification: ALKA-371-001, Phase 1 (EudraCT Number:<br />
2012-000148-88)<br />
Legal entity responsible for the study: Ignyta,Inc.<br />
Funding: Ignyta, Inc.<br />
Disclosure: J. Christiansen, A. Johnson, D. Murphy, R. Shoemaker, J. Lamoureux,<br />
D. Luo, R. Patel, Z. Hornby, P. Multani, E. Chow Maneval: Employee <strong>of</strong> Ignyta, Inc. All<br />
other authors have declared no conflicts <strong>of</strong> interest.<br />
139P<br />
Levels <strong>of</strong> endogenous anti-beta-glucan IgG antibodies (ABA)<br />
predict clinical outcomes for imprime PGG: Evidence from<br />
phase 3 PRIMUS study in patients (pts) with metastatic<br />
colorectal cancer (mCRC)<br />
M. Shum 1 , J.T. Beck 2 , J. Meyerhardt 3 , R. Patel 4 , M. Kochenderfer 5 , T. Crocenzi 6 ,<br />
M. Patchen 7 , M.A. Gargano 8 ,B.Ma 9 ,J.Lowe 8 , J.L. Iglesias 8<br />
1 <strong>Oncology</strong>, Innovative Clinical Research Institute, Whittier, CA, USA, 2 Medical<br />
<strong>Oncology</strong>, Highlands <strong>Oncology</strong> Group, Fayetteville, AR, USA, 3 Medical <strong>Oncology</strong>,<br />
Dana Farber Cancer Institute, Boston, MA, USA, 4 Medical <strong>Oncology</strong>,<br />
Comprehensive Blood and Cancer Center, Bakersfield, CA, USA, 5 Medical<br />
<strong>Oncology</strong>, Blue Ridge Cancer Care, Roanoke, VA, USA, 6 Medical <strong>Oncology</strong>,<br />
Providence Portland Medical Center, Portland, OR, USA, 7 Research, Biothera<br />
Pharmaceuticals, Eagan, MN, USA, 8 Clinical Research, Biothera Pharmaceuticals,<br />
Eagan, MN, USA, 9 Biostatistics, Biothera Pharmaceuticals, Eagan, MN, USA<br />
Background: Imprime PGG (I) is a yeast-derived beta-glucan PAMP administered<br />
systemically. It binds endogenous ABA to form immune complexes opsonized by<br />
complement, which trigger immune cell activation. Combination Ph 2 trials with<br />
monoclonal antibodies (mAbs) in over 300 cancer pts have shown increased clinical<br />
benefit, including PFS and OS, enhanced in ABA+ patients.<br />
Methods: PRIMUS was a Ph 3, open-label, multi-center randomized study <strong>of</strong><br />
cetuximab + Imprime PGG in 3 rd line K-RAS wild type mCRC pts. 217 pts were<br />
randomized 2:1 to doublet vs. singlet. Cetuximab (Erbitux®) (E) was given as per<br />
package insert and I at 4mg/kg, IV, over 2 h, weekly. Pts were treated until progression<br />
(by RECIST 1.1). Primary endpoint was OS in the Intent to Treat (ITT) population.<br />
Secondary endpoints included PFS, ORR, Time to Response (TTR), and Response<br />
Duration (RD). Translational prospective analyses included relationship <strong>of</strong> ABA levels<br />
with clinical outcomes in the evaluable population.<br />
Results: 140 pts were randomized to I + E and 77 to E. The study closed early due to<br />
low accrual. Median OS in the ITT population was 15.1 mo. for E and 10.7 mo. for<br />
I + E. (log-rank p = 0.047). Post-progression therapy was higher for E (58%) than for<br />
I + E (46%). ORR was 10% for E and 7% for I + E (p = 0.45). TTR was shorter for I + E<br />
(1.41 mo.) than for E (2.58 mo., log-rank p = 0.03). RD was longer for I + E (7.20 mo.)<br />
than for E (4.21 mo. (log rank p = 0.36). There was no difference in PFS [4.07 mo. for<br />
I + E and 4.11 mo. for E (log-rank p = 0.11)]. Correlative analysis <strong>of</strong> OS and PFS with<br />
ABA levels showed that pts with baseline IgG ABA <strong>of</strong> >35 µg/mL, when compared to<br />
those with 35 µg/<br />
mL correlated with a statistically significant increase in PFS and OS in pts receiving I+<br />
E, but not in those receiving E alone. Further validation studies <strong>of</strong> this Imprime<br />
PGG-specific biomarker and its correlation with clinical outcomes are warranted.<br />
Clinical trial identification: NCT01309126<br />
Legal entity responsible for the study: Biothera Pharmaceuticals<br />
Funding: Biothera Pharmaceuticals<br />
Disclosure: M. Patchen, M.A. Gargano, B. Ma, J. Lowe, J.L. Iglesias: Employee <strong>of</strong><br />
Biothera Pharmaceuticals and receives stock options as part <strong>of</strong> her compensation. All<br />
other authors have declared no conflicts <strong>of</strong> interest.<br />
140P<br />
abstracts<br />
Similarity-based automated evidence ranking for clinical<br />
interpretation <strong>of</strong> multigene diagnostic panels<br />
I. Petak 1 , C. Hegedus 1 , Z. Binder 1 , M. Peeters 2 , C.D. Rolfo 3 , G. Keri 4 , R. Schwab 1 ,<br />
L. Urban 5<br />
1 R&D, Oncompass Medicine Hungary, Budapest, Hungary, 2 Department <strong>of</strong><br />
<strong>Oncology</strong>, University Hospital Antwerp, Edegem, Belgium, 3 Phase I - Early Clinical<br />
Trials Unit & Center for Oncological Research <strong>of</strong> Antwerp (CORE), Antwerp<br />
University Hospital, Edegem, Belgium, 4 Medical Chemistry, Semmelweis<br />
University, Budapest, Hungary, 5 Pulmonology, Matrahaza University and Teaching<br />
Hospital, Matrahaza, Hungary<br />
Background: Precision medicine incorporates individual molecular genetic pr<strong>of</strong>iles in<br />
cancer therapeutic decisions. Establishing clinical relevance <strong>of</strong> tumour biomarkers can<br />
be limited by distinct biomarker functions in different histology types, simultaneous<br />
presence <strong>of</strong> multiple biomarkers in different combinations, long-tail distribution <strong>of</strong><br />
driver genetic alterations and the resulting limited number <strong>of</strong> similar cancer cases.<br />
Difficulty in aggregating definitive phase 3 trial data further hampers optimal delivery<br />
<strong>of</strong> tumour genomic information to the clinic especially in the case <strong>of</strong> rare mutations.<br />
These might result in conflicting evidence regarding biomarker roles and requires<br />
decision support algorithms to help cancer treatment decisions.<br />
Methods: Here we describe a novel decision support system which is capable <strong>of</strong><br />
dynamically aggregating and ranking scientific and clinical evidence to aid cancer<br />
therapeutic decisions.<br />
Results: The algorithm aggregates scientific evidence and clinical experience for an<br />
automated, adaptive ranking <strong>of</strong> anti-cancer therapies that best match with the<br />
molecular and clinical pr<strong>of</strong>ile <strong>of</strong> the individual patient and are supported by the most<br />
relevant evidences. Input is generated by cancer molecular pr<strong>of</strong>iles and clinical<br />
parameters. Outcome is represented by identification <strong>of</strong> clinically relevant tumour<br />
genomic alterations and matching drugs. Compounds are ranked based on the number<br />
and merit <strong>of</strong> scientific evidence that supports the functional relevance <strong>of</strong> identified<br />
genetic alterations (biomarker or driver evidence) and their association with drug<br />
targets (target evidence) or compounds (drug evidence). Direct association between<br />
drugs and tumour histologies are also counted. Evidence is also weighted based on<br />
similarity to the given cancer case. The algorithm is used to combine and prioritize<br />
evidences based on their relevance (clinical over preclinical, direct over indirect,<br />
registered over non-registered indications) and level. Evidences are constantly updated<br />
and accumulated.<br />
Conclusions: Incorporation <strong>of</strong> similarity based evidence ranking in classical<br />
evidence-based medicine enhances the delivery <strong>of</strong> genomically informed precision<br />
medicine.<br />
Legal entity responsible for the study: Oncompass Medicine Hungary<br />
Funding: Oncompass Medicine Hungary<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
Volume 27 | Supplement 6 | 2016<br />
doi:10.1093/annonc/mdw363 | vi41
abstracts<br />
141P<br />
Identification <strong>of</strong> baseline parameters associated with the<br />
inter-individual variability in cytidine deaminase serum activity,<br />
a key enzyme in the metabolism <strong>of</strong> pyrimidine analogue<br />
R. Cohen 1 , L-H. Preta 2 , A. Bessone 3 , C. Narjoz 3 , I. Nicolis 4 , D. Desaulle 4 ,<br />
E. Curis 4 , A. Cessot 1 , O. Huillard 1 , A. Thomas-Schoemann 2 , M. Vidal 2 ,<br />
F. Goldwasser 5 , J. Alexandre 5 , B. Blanchet 6<br />
1 Medical <strong>Oncology</strong>, Paris Descartes University, Cochin - Port Royal Hospital,<br />
AP-HP, Paris, France, 2 Laboratory <strong>of</strong> Toxicology and Pharmacology, Paris<br />
Descartes University, Cochin - Port Royal Hospital, AP-HP, Paris, France, 3 Service<br />
de Biochimie, Hopital European George Pompidou, Paris, France, 4 Laboratoire de<br />
Biomathématiques et Informatique, Département de Santé Publique et<br />
Biostatistiques, EA 4064, Faculté de Pharmacie Université Paris Descartes, Paris,<br />
France, 5 Department <strong>of</strong> Medical <strong>Oncology</strong>, Cochin Hospital, Paris Descartes<br />
University, APHP, CARPEM, CERTIM, Hôpital Cochin, Paris, France, 6 Laboratory<br />
<strong>of</strong> Toxicology and Pharmacology, Immunomodulatory Therapies Multidisciplinary<br />
Study Group (CERTIM), Paris Descartes University, Cochin - Port Royal Hospital,<br />
AP-HP, Paris, France<br />
Background: Cytidine deaminase (CDA) catabolizes gemcitabine and cytosine<br />
arabinoside and its serum activity (CDA-A) has been associated with efficacy and<br />
toxicity <strong>of</strong> both treatments. CDA is mainly produced by hepatocytes and neutrophils.<br />
Our objective was to identify pretreatment patients (pts) characteristics that may<br />
contribute to the large inter-individual variability in CDA-A.<br />
Methods: From December 2014 to November 2015, all consecutive pts were<br />
prospectively included into this single-center study. CDA-A in serum was assayed<br />
using a standardized spectrophotometric method. Biological, clinical characteristics<br />
and 5 common single nucleotide polymorphisms in the CDA gene (-451g > a, -92a > g,<br />
-33delc, 79a > c, 435t > c) were analyzed according to pretreatment CDA-A. Written<br />
consent was obtained from all patients. Univariate and multivariate statistical analysis<br />
were performed on log-transformed CDA-A with significance level <strong>of</strong> 0.05.<br />
Results: 275 pts (male: 61%) were analyzed. Median age was 66.2 years. Main primary<br />
tumor locations were lung (19%), prostate (11%) and urinary tract (10%). Median<br />
CDA-A was 4.08 u/mg protein (range 1.53-15.49). The inter-individual variability in<br />
CDA-A was large (43%). 49 pts (18%) had high CDA-A (> 6 U/mg). In univariate<br />
analysis, high CDA-A was associated with absolute neutrophil count (ANC) (p < 10 −16 ),<br />
C-reactive protein level (p = 10 −7 ), malnutrition (p = .014), altered ECOG performance<br />
status (p = .0003) and -33delC genotype (p = .0152). In multivariate analysis, only ANC<br />
was independently associated with CDA-A (p < 10 −9 ). Finally, this correlation between<br />
CDA-A and ANC (Pearson coefficient >0.5) was also observed over the treatment course<br />
with gemcitabine (at least 3 sampling occasions per patient; n = 6).<br />
Conclusions: Our results show for the first time an association between the<br />
pretherapeutic number <strong>of</strong> neutrophils and CDA activity, suggesting a CDA release<br />
from neutrophils. However, it explains only a small part <strong>of</strong> inter-individual variability<br />
in CDA-A. Therefore, CDA-A assessment in serum remains <strong>of</strong> interest to identify pts<br />
with high risk <strong>of</strong> toxicity or low efficacy under pyrimidine analogues.<br />
Legal entity responsible for the study: Paris Descartes University, Cochin - Port Royal<br />
Hospital, AP-HP<br />
Funding: None<br />
Disclosure: F. Goldwasser: Honoraria: Fresenius Kabi, Boehringer Ingelheim, Bayer,<br />
Pfizer Consulting or Advisory Role: Fresenius Kabi, Bayer. Travel, accomodation:<br />
Bayer, Novartis, AsrtaZeneca, Roche Glycart. All other authors have declared no<br />
conflicts <strong>of</strong> interest.<br />
142P<br />
Development <strong>of</strong> an ELISA to detect tumor-associated antigen<br />
tNASP in urine<br />
O. Alekseev 1 , J. Vaughn 2 , B. Taylor 2 , L. Barba 2 , J. Greiner 2 , C. Dickson 2 ,<br />
C. Anderson 2 , J. Fullmer 2 , Z. Vaskalis 3<br />
1 Physiology and Pathophysiology, Campbell University, Buies Creek, NC, USA,<br />
2 Campbell University, Buies Creek, NC, USA, 3 School <strong>of</strong> Osteopathic Medicine,<br />
Campbell University, Buies Creek, NC, USA<br />
Background: Tumor-associated antigens (TAAs) are proteins that elicit a humoral<br />
immune response when their expression is elevated in tumor progression. tNASP is<br />
one <strong>of</strong> two splice variants <strong>of</strong> Nuclear Autoantigenic Sperm Protein. In addition to its<br />
normal testicular expression, it is also aberrantly expressed in cancer cells. We have<br />
previously demonstrated that immunohistochemical detection <strong>of</strong> tNASP has high<br />
diagnostic sensitivity and specificity in ovarian cancer. We have discovered that tNASP<br />
is also aberrantly expressed in prostate cancer cells and tissues. In the current study, we<br />
developed an ELISA to detect specific anti-tNASP serum antibodies as well as tNASP<br />
protein in urine for early diagnosis <strong>of</strong> prostate cancer.<br />
Methods: tNASP protein expression was assayed by immunohistochemistry (IHC) in<br />
prostate cancer biopsy samples from different disease stages, using affinity-purified goat<br />
anti-tNASP serum, which specifically recognizes only tNASP protein. A recombinant<br />
tNASP-specific fragment was used as bait to produce a standard curve for detection <strong>of</strong><br />
anti-tNASP antibodies by ELISA. Serum and urine samples from patients with prostate<br />
cancer, and otherwise healthy control patients, were obtained from the Tissue<br />
Procurement Facility <strong>of</strong> the University <strong>of</strong> North Carolina at Chapel Hill, Roswell Park<br />
Cancer Institute, and Fox Chase Cancer Center. Correlation between serum<br />
anti-tNASP antibody levels, urine tNASP protein level and Prostate Specific Antigen<br />
(PSA) was analyzed by Spearman’s coefficient.<br />
Results: ELISA measurements demonstrated a significant increase in tNASP protein<br />
levels in the urine <strong>of</strong> prostate cancer patients, as compared to control group urine.<br />
Spearman’s rank correlation demonstrated that the concentration <strong>of</strong> anti-tNASP<br />
antibodies and tNASP levels in urine co-varied with PSA levels. Urine tNASP protein<br />
was detected by ELISA with anti t-NASP antibody as bait, whereas anti-tNASP<br />
antibodies were not detected in urine samples.<br />
Conclusions: Combined detection <strong>of</strong> serum anti-tNASP antibody and urine tNASP<br />
protein could be used for diagnosis <strong>of</strong> prostate cancer and has the potential to improve<br />
early diagnostic confidence.<br />
Legal entity responsible for the study: This study was supported by Campbell<br />
University School <strong>of</strong> Osteopathic Medicine, North Carolina, 27506, USA. Associate<br />
Pr<strong>of</strong>essor Oleg Alekseev, MD, PhD is a principal investigator on this project.<br />
Funding: This study was funded by School <strong>of</strong> Osteopathic Medicine <strong>of</strong> the Campbell<br />
University (CUSOM). Principal investigator Dr. Oleg Alekseev is a full-time faculty in<br />
CUSOM and research activity is his duty along with teaching.<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
143TiP<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
A biomarker-guided first-in-human trial <strong>of</strong> subcutaneous<br />
ALM201 in patients with solid tumours<br />
A. El-Helali 1 , R. Plummer 2 , G. Jayson 3 , V. Coyle 1 , C. Rogers 3 ,M.D’Arcangelo 2 ,D.<br />
M. Graham 1 ,Y.Drew 2 , A. Clamp 3 , J. McCann 4 , A. McCavigan 5 , L. Knight 5 ,<br />
N. McCabe 5 , K. Keating 5 ,R.Dyer 6 , T. Harrison 6 , P. Harkin 5 , T. Robson 7 ,<br />
R. Kennedy 1 , R. Wilson 1<br />
1 Centre for Cancer Research and Cell Biology, Queen’s University Belfast, Belfast,<br />
UK, 2 Medical <strong>Oncology</strong>, Sir Bobby Robson Cancer Trials Research Centre,<br />
Northern Centre for Cancer Care, Newcastle upon Tyne, UK, 3 Medical <strong>Oncology</strong>,<br />
The Christie NHS Foundation Trust, Manchester, UK, 4 Cancer Research Forum,<br />
Northern Ireland Cancer Research Consumers Forum, Belfast, UK, 5 Almac<br />
Diagnostics, Almac Group, Craigavon, UK, 6 Almac Discovery, Almac Group,<br />
Craigavon, UK, 7 School <strong>of</strong> Pharmacy, Queen’s University Belfast, Belfast, UK<br />
Background: ALM201 is a 23-amino acid peptide derived from FKPB-L, a human<br />
endogenous protein with inherent anti-angiogenic activity. ALM201 is active after<br />
internalisation via CD44 into the cell, where it binds to tubulin and prevents<br />
microtubule formation. Preclinical studies have demonstrated that ALM201 is a potent<br />
inhibitor <strong>of</strong> migration, invasion and new blood vessel formation but has no effects on<br />
cell cycle or proliferation. It was very well tolerated in pre-clinical toxicology studies.<br />
High grade serous ovarian cancer (HGSOC) is a disease <strong>of</strong> clinical unmet need, and the<br />
role <strong>of</strong> anti-angiogenics in HGSOC remains a critical area <strong>of</strong> investigation. The 63-gene<br />
AADx biomarker (Gourley et al, ASCO 2014) identifies a sub-group <strong>of</strong> HGSOC with<br />
significant up-regulation <strong>of</strong> angiogenic genes and a worse outcome from conventional<br />
platinum-based chemotherapy. In our trial, we wish to investigate ALM201 in this<br />
AADx-selected “Angiogenic” HGSOC population.<br />
Trial design: This phase I trial employs an accelerated dose-escalation design with<br />
single patient cohorts, later moving to a standard 3 + 3 design, and will explore 6 dose<br />
levels. Patients will have histologically confirmed advanced solid tumours, in which use<br />
<strong>of</strong> an antiangiogenic is reasonable. The dose expansion cohort will recruit 36 patients<br />
and treat them with the recommended phase II dose (RP2D). They will have relapsed<br />
advanced HGSOC with a tumour classified as angiogenic by the AADx signature. This<br />
companion diagnostic will utilise a pre-enrolment FFPE tumour sample. Patients will<br />
receive ALM201 once daily as a subcutaneous injection on days 1-5, 8-12, and 15-19<br />
every 21 days. The primary objectives are to determine the safety, tolerability and<br />
RP2D <strong>of</strong> ALM201. Secondary objectives are to determine the pharmacokinetic pr<strong>of</strong>ile<br />
and preliminary antitumor activity <strong>of</strong> ALM201 overall and in the biomarker-selected<br />
HGSOC population. Exploratory objectives are to assess relevant tumour biomarkers<br />
and the pharmacodynamic activity <strong>of</strong> ALM201. This trial commenced recruitment in<br />
July 2015, with 10 patients currently enrolled across the first 6 dose levels.<br />
Clinical trial identification: EudraCT No: 2014-001175-31<br />
Legal entity responsible for the study: Almac Discovery<br />
Funding: Almac Discovery<br />
Disclosure: V. Coyle: Research funding and site PI: Onyx/Amgen. Travel and<br />
accommodation expense covered by san<strong>of</strong>i and BM. C. Rogers: consulting/advisory<br />
role for AstraZeneca. Y. Drew: Honoraria: AstraZeneca and Clovis <strong>Oncology</strong>.<br />
Consulting and advisory role: AstraZeneca and Clovis <strong>Oncology</strong>. A. Clamp: Consulting<br />
and advisory role: Astra Zeneca. Speakers Bureau: Astra Zeneca and Roche. Research<br />
funding: Astra Zeneca, Clovis <strong>Oncology</strong>, Array Biopharma, AB bioscience and<br />
Amgen. A. McCavigan: Employee <strong>of</strong> Almac Diagnostics. L. Knight: Employee <strong>of</strong> Almac<br />
group. N. McCabe: Employee <strong>of</strong> Almac group. Research funding from ALmac<br />
group. K. Keating: Employed by Almac diagnostics. Research funded by Almac<br />
Diagnostics. Hold patent and royalties in ALmac diagnostics. Travel and expenses<br />
covered by Almac Diagnostics. R. Dyer: Almac discovery employee, holds patent/<br />
royalties through Almac Discovery. Travel/accommodation expenses covered by Almac<br />
Discovery. T. Harrison: Employee <strong>of</strong> Almac Discovery, research funded by Almac<br />
Discovery. P. Harkin: Employment: Almac Diagnostics. Research funded by Almac<br />
Diagnostics. Patent and royalties held and received by Almac Diagnostics. T. Robson:<br />
Research funding: Almac Discovery. Patent/royalties held with Almac<br />
Discovery. R. Kennedy: Employee <strong>of</strong> Almac Diagnostics. Patent and royalties held with<br />
Almac Diagnostics. R. Wilson: Honoraria, Advisory roles and travel expenses from<br />
San<strong>of</strong>i, Merck Serono, Amgen and Sirtex. All other authors have declared no conflicts<br />
<strong>of</strong> interest.<br />
vi42 | abstracts Volume 27 | Supplement 6 | 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong> 27 (Supplement 6): vi43–vi67, 2016<br />
doi:10.1093/annonc/mdw364<br />
breast cancer, early stage<br />
145O<br />
Prognostic role for derived neutrophil-to-lymphocyte ratio in<br />
early breast cancer<br />
144O<br />
Superimposable outcomes for sequential and concomitant<br />
administration <strong>of</strong> adjuvant trastuzumab in HER2-positive<br />
breast cancer: Results from the SIGNAL/PHARE prospective<br />
cohort<br />
X. Pivot 1 , J-Y. Pierga 2 , S. Delaloge 3 , P. Fumoleau 4 , H. Bonnefoi 5 , T. Bachelot 6 ,<br />
C. Jouannaud 7 , H. Bourgeois 8 , M. Rios 9 , P. Soulie 10 , J.P. Jacquin 11 ,<br />
S. Lavau-Denes 12 , P. Kerbrat 13 , C. Faure Mercier 14 , I. Pauporte 14 , J. Gligorov 15 ,<br />
E. Curtit 1 , J. Henriques 16 , S. Paget-Bailly 16 , G. Romieu 17<br />
1 <strong>Oncology</strong>, CHU Besançon, Hôpital Jean Minjoz, Besançon, France, 2 Medical<br />
<strong>Oncology</strong>, Institut Curie, Paris, France, 3 Dept. <strong>of</strong> Medicine, Institut Gustave<br />
Roussy, Villejuif, France, 4 <strong>Oncology</strong>, Centre Georges-François Leclerc (Dijon),<br />
Dijon, France, 5 <strong>Oncology</strong>, Institut Bergonié Unicancer, Bordeaux, France,<br />
6 <strong>Oncology</strong>, Centre Leon Berrard, Lyon, France, 7 <strong>Oncology</strong>, Institut Jean Godinot,<br />
Reims, France, 8 <strong>Oncology</strong>, Clinique Victor Hugo Le Mans, Le Mans, France,<br />
9 <strong>Oncology</strong>, Institut de Cancérologie de Lorraine - Alexis Vautrin, Vandoeuvre Les<br />
Nancy, France, 10 <strong>Oncology</strong>, Centre Paul Papin, Angers, France, 11 <strong>Oncology</strong>,<br />
Institut Lucien Neuwirth, Saint Priest en Jarred, France, 12 <strong>Oncology</strong>, CHU Limoges<br />
- Hopital du Cluzeau, Limoges, France, 13 <strong>Oncology</strong>, Centre Eugene - Marquis,<br />
Rennes, France, 14 Research, Institut National du Cancer, Boulogne-Billancourt,<br />
France, 15 Oncologie Medicale, APHP, CancerEst, Tenon University Hospital, Paris,<br />
France, 16 Biostatistic, CHU Besançon, Hôpital Jean Minjoz, Besançon, France,<br />
17 <strong>Oncology</strong>, ICM Regional Cancer Institute <strong>of</strong> Montpellier, Montpellier, France<br />
A. Ocana Fernandez 1 , A.J. Templeton 2 , M. Casas 3 , M. Sánchez-Aragó 4 ,<br />
R. Caballero 4 , A. Rodríguez Lescure 5 , A. Ruiz 6 , E. Alba 7 , L. Calvo 8 ,M.Ruiz 9 ,<br />
A. Santaballa 10 , C. Rodríguez 11 , C. Crespo 12 , M. Ramos 13 , J.M. Gracia Marco 14 ,<br />
A. Lluch-Hernandez 15 , I. Alvarez 16 , E. Carrasco 17 , E. Amir 18 , M. Martin 19<br />
1 Research Unit and Medical <strong>Oncology</strong>, Albacete University Hospital, Albacete,<br />
Spain, 2 Klinik für Onkologie, St. Claraspital, Basel, Switzerland, 3 Statistics,<br />
GEICAM (Spanish Breast Cancer Research Group), Madrid, Spain, 4 Translational<br />
Research, GEICAM (Spanish Breast Cancer Research Group), Madrid, Spain,<br />
5 Medical <strong>Oncology</strong>, Hospital General Universitario de Elche, Elche, Spain,<br />
6 Medical <strong>Oncology</strong>, Fundación Instituto Valenciano de Oncología, Valencia, Spain,<br />
7 Hospital Universitario Regional y Virgen de la Victoria, Instituto de Investigacion<br />
Biomedica de Malaga (IBIMA), Malaga, Spain, 8 Medical <strong>Oncology</strong>, 7Complejo<br />
Hospitalario Juan Canalejo, A Coruna, Spain, 9 Medical <strong>Oncology</strong>, Hospital<br />
Universitario Virgen del Rocio, Sevilla, Spain, 10 Medical <strong>Oncology</strong>, Hospital<br />
Universitari i Politècnic La Fe, Valencia, Spain, 11 Medical <strong>Oncology</strong>, Clínico de<br />
Salamanca Hospital, Salamanca, Spain, 12 Medical <strong>Oncology</strong>, Hospital<br />
Universitario Ramon y Cajal, Madrid, Spain, 13 Medical <strong>Oncology</strong>, Centro<br />
Oncologico de Galicia, A Coruna, Spain, 14 Medical <strong>Oncology</strong>, Hospital de<br />
Cabueñes, Gijon, Spain, 15 Serv. Hematologia y Oncologia Medica, Hospital<br />
Clinico Universitario de Valencia, Valencia, Spain, 16 Medical <strong>Oncology</strong> Dept.,<br />
Hospital Donostia, San Sebastian, Spain, 17 GEICAM (Spanish Breast Cancer<br />
Research Group), Madrid, Spain, 18 Medical <strong>Oncology</strong>, Princess Margaret<br />
Hospital, Toronto, ON, Canada, 19 Medical <strong>Oncology</strong>, Canada17Instituto de<br />
Investigación Sanitaria Gregorio Marañón, Madrid, Spain<br />
abstracts<br />
© European Society for Medical <strong>Oncology</strong> 2016. Published by Oxford University Press on behalf <strong>of</strong> the European Society for Medical <strong>Oncology</strong>.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com.
abstracts<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
146O<br />
Outcome disparities by age and 21-gene recurrence score®<br />
(RS) result in hormone receptor positive (HR+) breast cancer<br />
(BC)<br />
S. Shak 1 , D.P. Miller 1 , N. Howlader 2 , N. Gliner 1 ,W.Howe 3 , N. Schussler 3 ,<br />
K. Cronin 2 , F.L. Baehner 1 , L. Penberthy 2 , V.I. Petkov 2<br />
1 Translational Sciences, Genomic Health, Inc., Redwood City, CA, USA, 2 Division<br />
<strong>of</strong> Cancer Control and Population Sciences, National Cancer Institute, Rockville,<br />
MD, USA, 3 Analytic Services & Data Management, Information Management<br />
Systems, Inc., Calverton, MD, USA<br />
147PD<br />
First prospectively-designed outcome study in estrogen<br />
receptor (ER)+ breast cancer (BC) patients (pts) with N1mi or<br />
1-3 positive nodes in whom treatment decisions in clinical<br />
practice incorporated the 21-gene recurrence score (RS)<br />
result<br />
S.M. Stemmer 1 , M. Steiner 2 , S. Rizel 3 , D. Geffen 4 , B. Nisenbaum 5 , T. Peretz 6 ,<br />
L. Soussan-Gutman 7 , A. Bareket-Samish 8 , K. Isaacs 9 , O. Rosengarten 10 ,<br />
G. Fried 11 , C. Svedman 12 , S. Shak 12 , N. Liebermann 13 , N. Ben-Baruch 14<br />
1 David<strong>of</strong>f Cancer Center, Rabin Medical Center and Sackler Faculty <strong>of</strong> Medicine,<br />
Tel Aviv University, Petach Tikva, Israel, 2 <strong>Oncology</strong> Dept., LIN Medical Center,<br />
Haifa, Israel, 3 David<strong>of</strong>f Center, Rabin Medical Center, Petach Tikva, Israel,<br />
4 <strong>Oncology</strong>, Soroka University Medical Center, Beer Sheva, Israel, 5 <strong>Oncology</strong>, Meir<br />
Medical Center, Kfar Saba, Israel, 6 Sharett Institute <strong>of</strong> <strong>Oncology</strong>, Hadassah<br />
Hebrew University Medical Center, Jerusalem, Israel, 7 Oncotest Division, Teva<br />
Pharmaceutical Industries, Ltd, Shoham, Israel, 8 <strong>Oncology</strong>, BioInsight Ltd, Zichron<br />
Yaakov, Israel, 9 <strong>Oncology</strong>, Ha’emek Medical Center, Afula, Israel, 10 <strong>Oncology</strong>,<br />
Shaare Zedek Medical Center, Jerusalem, Israel, 11 <strong>Oncology</strong>, Rambam Health<br />
Care Campus, Haifa, Israel, 12 Research and Development, Genomic Health Inc,<br />
Redwood City, CA, USA, 13 Community Division, Clalit Health Services, Tel Aviv,<br />
Israel, 14 <strong>Oncology</strong> department, Kaplan Medical Center, Rehovot, Israel<br />
Background: Recent outcome data including those from the prospective TAILORx trial<br />
strongly confirmed the RS role in node negative (N0) ER+ BC. The prospective WSG<br />
PlanB study showed excellent outcomes in high-risk N0 and node-positive (N+) pts<br />
with RS ≤ 11 and no adjuvant chemotherapy (CT). Physicians are increasingly using<br />
the RS for treatment decisions in N+ BC. We evaluated treatment and clinical<br />
outcomes in N+ pts undergoing RS testing through Clalit Health Services (CHS).<br />
Methods: Medical records <strong>of</strong> all CHS pts with N+ ER+ HER2- BC who were tested<br />
between 1/2008 and 12/2011 were reviewed to verify treatment given and recurrence/<br />
death status. Interim results are presented herein. Final cohort results (>700 pts) will be<br />
presented at the meeting.<br />
Results: The current analysis includes 627 pts. Median age, 61 (34-87) yrs; 270 (43%)<br />
were N1mi, whereas 231 (37%) and 126 (20%) had 1 and 2-3, positive nodes,<br />
respectively. Grade 1 (15%), 2 (53%), 3 (16%), N/A (16%); histology, IDC (82%),<br />
lobular (12%), other (6%). With a median follow-up <strong>of</strong> 5.7 yrs, proportion <strong>of</strong> patients<br />
with distant recurrence (DR)/BC death by Paik et al and TAILORx RS categorization<br />
and by nodal status are presented in the Table. As pts were not randomized to<br />
treatment, analysis <strong>of</strong> DR/BC death by CT use is only exploratory: within the RS 18-30<br />
group, CT-untreated pts (60%) had DR rate and BC death rate <strong>of</strong> 9.6% and 3.7%,<br />
respectively, whereas in CT-treated pts (40%) these rates were 2.2% and 1.1%; within<br />
the RS 11-25 group, CT-untreated pts (82%) had DR rate and BC death rate <strong>of</strong> 4.1%<br />
and 1.2%, respectively, whereas in CT-treated pts (18%) these rates were 2.7% and 0%.<br />
Table: 147PD<br />
CT use, % DR rate, % BC death rate, %<br />
Paik et al RS categorization<br />
RS < 18<br />
N1mi (n = 146) 5 0.7 0.7<br />
1 positive node (n = 128) 10 4.7 0.0<br />
2-3 positive nodes (n = 65) 8 6.2 3.1<br />
Total (n = 339) 7 3.2 0.9<br />
RS: 18-30<br />
N1mi (n = 93) 37 10.8 3.2<br />
1 positive node (n = 81) 47 3.7 2.5<br />
2-3 positive nodes (n = 53) 38 3.8 1.9<br />
Total (n = 227) 40 6.6 2.6<br />
RS ≥ 31<br />
N1mi (n = 31) 97 19.4 16.1<br />
1 positive node (n = 22) 86 18.2 13.6<br />
2-3 positive nodes (n = 8) 75 0.0 0.0<br />
Total (n = 61) 90 16.4 13.1<br />
TAILORx RS categorization<br />
RS < 11<br />
N1mi (n = 45) 4 2.2 2.2<br />
1 positive node (n = 37) 14 5.4 0.0<br />
2-3 positive nodes (n = 20) 0 10.0 5.0<br />
Total (n = 102) 7 4.9 2.0<br />
RS: 11-25<br />
N1mi (n = 169) 14 4.1 1.2<br />
1 positive node (n = 152) 20 3.3 0.0<br />
2-3 positive nodes (n = 90) 22 4.4 2.2<br />
Total (n = 411) 18 3.9 1.0<br />
RS > 25<br />
N1mi (n = 56) 82 16.1 10.7<br />
1 positive node (n = 42) 83 14.3 11.9<br />
2-3 positive nodes (n = 16) 69 0.0 0.0<br />
Total (n = 114) 81 13.2 9.6<br />
vi44 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
Conclusions: CT use was aligned with the RS results. Pts with N1mi or 1-3 positive<br />
nodes and RS ≤ 25 had very good outcomes, even when selected for endocrine therapy<br />
alone. Updated data will be presented at the meeting.<br />
Clinical trial identification: Trial protocol number: 0075-14-COM<br />
Legal entity responsible for the study: Dr. Stemmer is the sponsor-investigator<br />
responsible for all aspects <strong>of</strong> the study including design and conduct <strong>of</strong> the study,<br />
collection, analysis and interpretation <strong>of</strong> the data, and preparation <strong>of</strong> the manuscript.<br />
Funding: Funded through grant from Teva Pharmaceuticals Ltd.<br />
Disclosure: S.M. Stemmer: Received grant funding from Teva and travel expenses from<br />
Genomic Health. L. Soussan-Gutman: Teva employee. Holds stock options for Teva<br />
Pharmaceuticals Ltd. A. Bareket-Samish: Consultant for Teva Pharmaceutical<br />
Industries and Genomic Health, Inc. O. Rosengarten: Received payments for lectures<br />
and grants for traveling from Teva Pharmaceuticals. C. Svedman, S. Shak: Genomic<br />
Health employee. Holds stock options for Genomic Health. N. Ben-Baruch: Serves on<br />
Genomic Health’s speakers bureau. All other authors have declared no conflicts <strong>of</strong><br />
interest.<br />
148PD<br />
Analysis <strong>of</strong> Oncotype DX recurrence score and its clinical<br />
implications in invasive lobular carcinomas <strong>of</strong> the breast<br />
C.I. Truica 1 , J. Felts 2 , B. Han 3 , J. Zhu 1<br />
1 Cancer Institute, Penn State Hershey Medical Center, Hershey, PA, USA,<br />
2 College <strong>of</strong> Medicine, Penn State University, Penn State College <strong>of</strong> Medicine,<br />
Hershey, PA, USA, 3 Pathology, Penn State Hershey Medical Center, Hershey, PA,<br />
USA<br />
Background: The Oncotype DX breast cancer assay is increasingly being used to guide<br />
treatment decisions for patients with early stage, hormone-positive, Her-2 negative<br />
breast cancer, regardless <strong>of</strong> the histologic subtype. The utility <strong>of</strong> the Oncotype DX in<br />
decision making for treatment <strong>of</strong> invasive lobular carcinoma (ILC) has not been<br />
investigated.<br />
Methods: We performed a retrospective analysis <strong>of</strong> early stage breast cancer patients<br />
treated at Penn State Cancer Institute from 2001 to 2011 and identified 102 patients<br />
with ILC. We evaluated the clinicopathological features and compared the Recurrence<br />
Score (RS) distribution in this population to that reported by Genomic Heath for the<br />
ductal histology (Kruskal-Wallis test). Median follow-up was 4.5 years<br />
Results: We found that the RS distribution for ILC differed significantly from that<br />
reported by Genomic Health (P < 0.0001). The vast majority <strong>of</strong> patients (97.8%) have<br />
low/intermediate RS and only 2.2% high RS whereas the RS distribution reported by<br />
Genomic Health is 54.2% for low RS, 20.6% for intermediate and 25.2% high RS. We<br />
also found a statistically significant difference in the RS distribution between pure ILC<br />
and pleomorphic ILC (P = 0.027). When using RS <strong>of</strong> 25 as cut<strong>of</strong>f for chemotherapy<br />
recommendation, 93.3% <strong>of</strong> ILC patients have RS ≤ 25 and would not be candidates for<br />
adjuvant chemotherapy. Most tumors were T1-T2 (93.5%) and 6.5% were T3. Most<br />
tumors (64.4%) were node negative, 21% had 1-3 lymph nodes positive and 14.4% had<br />
N2/N3 disease. All the pure ILC tumors were hormone positive and only one<br />
pleomorphic ILC tumor was HR negative. 5.8 % tumors were Her 2 +. The 5 yr.<br />
Disease free survival (DFS) for the entire cohort was 84.9% and 5 yr. overall survival<br />
(OS) was 91.4%. OS varies significantly by histologic subtype with 5 yr. OS being 100%<br />
for pleomorphic ILC, 92% for pure ILC and 73% for mixed subtypes.<br />
Conclusions: The Oncotype DX RS distribution in invasive lobular carcinoma is<br />
unique, differing significantly from that in invasive ductal carcinoma. Majority <strong>of</strong><br />
patients (97.8%) have low/intermediate RS and 93.3% have RS ≤ 25 and would not be<br />
candidates for adjuvant chemotherapy. The clinical usefulness and cost-effectiveness <strong>of</strong><br />
the Oncotype DX in guiding treatment for ILC should be further investigated.<br />
Legal entity responsible for the study: Jesse Felts Cristina Truica<br />
Funding: Pink Zone and Lady Lion Basketball Breast Cancer Research Endowment<br />
and the Federal US Work Study program<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
149PD<br />
Prognostic impact <strong>of</strong> proliferation for resected early stage<br />
breast cancer according to histology: Cut-<strong>of</strong>f analysis <strong>of</strong> Ki67<br />
in 859 patients with pure invasive lobular and ductal breast<br />
carcinoma (ILC/IDC)<br />
L. Carbognin 1 , I. Sperduti 2 , M.V. Dieci 3 , I. Zampiva 1 , G. Griguolo 3 , S. Pilotto 1 ,<br />
V. Guarneri 3 , M. Brunelli 4 , R. Nortilli 1 , E. Manfrin 4 , E. Fiorio 1 , V. Parolin 1 , E. Filippi 1 ,<br />
F. Pellini 5 , F. Bonetti 4 , G.P. Pollini 5 , P.F. Conte 3 , G. Tortora 4 , E. Bria 1<br />
1 Medical <strong>Oncology</strong>, AOU Integrata Verona "Borgo Roma", Verona, Italy,<br />
2 Biostatistics Unit, Istituto Regina Elena, Rome, Italy, 3 Department <strong>of</strong> Surgery,<br />
<strong>Oncology</strong> and Gastroenterology, University <strong>of</strong> Padova, Istituto Oncologico Veneto<br />
IRCCS, Padua, Italy, 4 Pathology and Diagnostics, Azienda Ospedaliera<br />
Universitaria Integrata Verona-"Borgo Roma", Verona, Italy, 5 Breast Unit, AOU<br />
Integrata Verona "Borgo Roma", Verona, Italy<br />
validated. Thus, the aim <strong>of</strong> this analysis was to investigate the prognostic potential <strong>of</strong><br />
Ki67 in a multi-center series <strong>of</strong> patients (pts) affected by early stage pure ILC<br />
comparing with IDC.<br />
Methods: Clinicalpathological data <strong>of</strong> consecutive pts affected by pure ILC and IDC,<br />
referring to 2 institutions, were correlated with overall survival and disease-free survival<br />
(OS/DFS) using a Cox model. The maximally selected Log-Rank statistics (MSLRS)<br />
analysis was applied to the Ki67 continuous variable to estimate the appropriate cut-<strong>of</strong>f<br />
according to histology.<br />
Results: Data from 457 ILC and 402 IDC pts were gathered (median age 61/59 years<br />
[yrs]). At a median follow-up <strong>of</strong> 75 months, 10-yrs OS and DFS for ILC and IDC were<br />
81.7%/83.4%, and 71.4%/76.2%, respectively. The MSLRS analysis identified 4% and<br />
18% as optimal Ki67 cut-<strong>of</strong>fs for OS for ILC and IDC, respectively. At the multivariate<br />
analysis Ki67, Performance Status (PS), nodal status (N), and TNM-tumor-size<br />
(T-size) were independent predictors for OS in ILC pts. Ki67 highly replicated at the<br />
internal cross-validation analysis. For IDC pts, PS, age, estrogen receptor expression<br />
and T-size were independent predictors for OS. With regard to DFS, the MSLRS<br />
analysis identified 4% and 14% as optimal KI67 cut-<strong>of</strong>fs for ILC and IDC, respectively.<br />
PS and N were independent predictors for ILC, while PS, age, grading and T-size were<br />
predictors for IDC. Log-rank analysis is shown in the table:<br />
Table: 149PD<br />
Histotype Ki67 5-yrs OS (%) 10-yrs OS (%) Log-Rank<br />
ILC ≤ 4% 96.9 89.9 p = 0.008<br />
>4% 90.1 77.2<br />
IDC ≤ 18% 97.4 95.8 p = 0.002<br />
> 18% 93.6 62.6<br />
5-yrs DFS (%) 10-yrs DFS (%)<br />
ILC ≤ 4% 88.2 79.4 p = 0.03<br />
>4% 81.1 69.2<br />
IDC ≤ 14% 96.0 87.0 p = 0.002<br />
> 14% 89.2 61.8<br />
Conclusions: Despite the retrospective and exploratory nature <strong>of</strong> the study, the<br />
prognostic relevance <strong>of</strong> Ki67 (as well as its optimal cut-<strong>of</strong>f) seems to significantly differ<br />
according to histology. In particular, a very low cut-<strong>of</strong>f <strong>of</strong> Ki67 (4%) may significantly<br />
discriminate the prognosis <strong>of</strong> pts with ILC.<br />
Legal entity responsible for the study: University <strong>of</strong> Verona, Verona<br />
Funding: University <strong>of</strong> Verona, Verona<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
150PD<br />
Breast cancer-specific survival in >4,600 patients with lymph<br />
node-positive (LN+) hormone receptor-positive (HR+)<br />
invasive breast cancer (BC) and 21-gene recurrence score®<br />
(RS) results in the SEER registries<br />
D.P. Miller 1 , M. Roberts 2 , V.I. Petkov 3 , S. Shak 1 , N. Howlader 3 , K. Cronin 3 ,<br />
L. Penberthy 3<br />
1 Translational Sciences, Genomic Health, Inc., Redwood City, CA, USA, 2 Division<br />
<strong>of</strong> Cancer Prevention, National Cancer Institute, Rockville, MD, USA, 3 Division <strong>of</strong><br />
Cancer Control and Population Sciences, National Cancer Institute, Rockville, MD,<br />
USA<br />
Background: The 21-gene RS assay has been shown to predict BC recurrence and<br />
adjuvant chemotherapy benefit in LN + , HR + , HER2-negative BC. We assessed<br />
5-year BC-specific survival (BCSS) in LN+ patients with 21-gene RS results in the<br />
SEER registries, a cancer surveillance program that covers 30% <strong>of</strong> the US population.<br />
Methods: All SEER BC cases diagnosed 2004-2012 were linked to 21-gene assays<br />
performed by the Genomic Health Clinical Laboratory. The analysis was restricted to<br />
single primary invasive BC, LN + , no distant metastases, HR+ (per SEER),<br />
HER2-negative (per RT-PCR). Using the actuarial method in SEER*Stat, BCSS was<br />
assessed for those who were diagnosed 2004-2011 with survival follow-up through<br />
2012, by RS category and by number <strong>of</strong> positive nodes.<br />
Results: The proportion <strong>of</strong> women with LN + , HR+ BC who had RS results (n = 7695)<br />
increased over time between 2004 (0.3%, n = 33) and 2012 (13.8%, n = 2010), and was<br />
lower with increasing nodal involvement, from micrometastases only (36.0%, n = 792)<br />
to 4+ nodes (2.6%, n = 81) in 2012. BCSS differed significantly by both RS category<br />
(log-rank p < 0.001) and number <strong>of</strong> positive nodes (p < 0.001). Five-year BCSS<br />
outcomes for those with RS
abstracts<br />
#<strong>of</strong><br />
positive LN<br />
Micromets<br />
Table: 150PD<br />
RS
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
Legal entity responsible for the study: The University <strong>of</strong> Texas MD Anderson Cancer<br />
Center<br />
Funding: MD Anderson Moonshot, Wolff-Toomim Fund. Drug only was provided by<br />
Biomarin and then Medivation once the drug was purchased by Medivation<br />
Disclosure: J.K. Litton: I currently have research funding from Medivation, Genentech,<br />
Novartis and formerly from Biomarin; as the Principal Investigator <strong>of</strong> ongoing trials at<br />
my institution. No personal compensation.All other authors have declared no conflicts<br />
<strong>of</strong> interest.<br />
154PD<br />
Gestational breast cancer: distinctive molecular and<br />
clinico-epidemiological features. GEICAM/2012-03 study<br />
J. de la Haba 1 , A. Ruiz 2 , M. Pollan 3 ,A.Prat 4 ,F.Rojo 5 , M. Martin 6 , E. Alba Conejo 7 ,<br />
J.A. Perez-Fidalgo 8 , J. Gavilá 9 , C. Morales 10 , B. Navarro 11 ,<br />
A. Hernández-Blanquisett 2 , I. Porras 10 , A. Rodriguez-Lescure 12 ,<br />
B. Jiménez-Rodríguez 13 , N. Martín 14 , L. Pérez-Ramos 15 , R. Caballero 16 ,<br />
E. Carrasco 17 , A. Lluch-Hernandez 18<br />
1 Medical <strong>Oncology</strong>, Hospital Universitario Reina S<strong>of</strong>ía, Cordoba, Spain, 2 Medical<br />
<strong>Oncology</strong>, Fundación Instituto Valenciano de Oncología, Valencia, Spain, 3 Cancer<br />
Epidemiology, Instituto de Salud Carlos III (ISCIII), Madrid, Spain, 4 Translational<br />
Genomics Group, Vall d’Hebron Institute <strong>of</strong> <strong>Oncology</strong> (VHIO),, Barcelona, Spain,<br />
5 Pathology Department, University Hospital "Fundacion Jimenez Diaz", Madrid,<br />
Spain, 6 Medical <strong>Oncology</strong>, 6Instituto de Investigación Sanitaria Gregorio Marañón,<br />
Madrid, Madrid, Spain, 7 Medical <strong>Oncology</strong>, Hospital Universitario Regional y<br />
Virgen de la Victoria. IBIMA, Malaga, Spain, 8 <strong>Oncology</strong>, Hospital Clinico<br />
Universitario de Valencia. Instituto de Investigación Sanitaria (INCLIVA), Valencia,<br />
Spain, 9 Medical <strong>Oncology</strong>, Fundación Instituto Valenciano de Oncología, Valencia,<br />
Spain, 10 Medical <strong>Oncology</strong>, University Hospital Reina S<strong>of</strong>ia (Andalussian Health<br />
Service), IMIBIC, Cordoba, Spain, 11 Medical <strong>Oncology</strong>, 8Hospital Clinico<br />
Universitario de Valencia. Instituto de Investigación Sanitaria (INCLIVA), Valencia,<br />
Spain, 12 Medical <strong>Oncology</strong>, Hospital General Universitario de Elche, Elche, Spain,<br />
13 Hospital Universitario Regional y Virgen de la Victoria, Instituto de Investigacion<br />
Biomedica de Malaga (IBIMA), Malaga, Spain, 14 Translational Research, GEICAM<br />
Spanish Breast Cancer Group, Madrid, Spain, 15 Statistics, GEICAM Spanish<br />
Breast Cancer Group, Madrid, Spain, 16 Translational Research, GEICAM (Spanish<br />
Breast Cancer Research Group), Madrid, Spain, 17 GEICAM (Spanish Breast<br />
Cancer Research Group), Madrid, Spain, 18 Serv. Hematologia Y Oncologia<br />
Medica, 11Hospital Clínico Universitario de Valencia. INCLIVA Instituto de<br />
Investigación Sanitaria- Universitat de València, Valencia, Spain<br />
Background: Incidence <strong>of</strong> gestational breast cancer (GBC) (during pregnancy,<br />
lactation or first year postpartum) ranges from 6-15% <strong>of</strong> BC in the 20-44 subgroup age.<br />
GBC is associated with positive nodes, negative hormonal receptors (HR), triple<br />
negative and high grade tumors but little is known at molecular level. We explore<br />
specific genomic pr<strong>of</strong>iles and clinico-epidemiological features <strong>of</strong> GBC.<br />
Methods: Expression <strong>of</strong> 105 genes was assessed in 50 evaluable tumors from 70 GBC<br />
Spanish patients using nCounter platform. The following signatures were assessed: 1)<br />
Intrinsic subtypes; 2) Proliferation (P) and Risk <strong>of</strong> Recurrence (ROR) scores; 3)<br />
Claudin-low and 4) Chemo-Endocrine Sensitivity Predictor (CESP). Genomic pr<strong>of</strong>ile<br />
and clinico-epidemiological data were compared to equivalent nonGBC cohorts from<br />
GEICAM/9906 (n = 293) (NCT00129922), Málaga (n = 96) (Cancer Res, 2016 76; P3<br />
07 15) and Alamo III project (n = 1473).<br />
Results: Out <strong>of</strong> the 70 patients, 43% were diagnosed during pregnancy and 57%<br />
postpartum. The table reports patient and tumor characteristics:<br />
Table: 154PD<br />
n (%) GBC Alamo III 9906 Málaga<br />
Mean age at diagnosis 35 37 37 37<br />
Negative HR 30 (43) 330 (24) 33 (16) 27 (28)<br />
T2-T4 51 (76) 787 (56) 176 (60) 84 (92)<br />
Grade 3 38 (63) 479 (40) 121 (44) 38 (47)<br />
Ki67 (≥20%) 33 (89) 209 (61) 46 (22) 60 (64)<br />
Family history <strong>of</strong> BC 32 (47) 296 (25) - -<br />
Mean age at first partum 31 26 - -<br />
Intrinsic subtypes in GBC were 44% Basal-like, 22% Her2-enriched, 20% Luminal B<br />
and 14% Luminal A; no Claudin-low tumors were identified. Basal-like phenotype was<br />
enriched (44% vs 14%, p < 0.01) and Luminal A was less prevalent (14% vs 28%,<br />
p = 0.02) in GBC compared to GEICAM/9906 and Málaga combined dataset.<br />
Moreover, GBC showed a lower CESP score (-0.49 vs 0.04) and higher prevalence <strong>of</strong><br />
ROR-P high risk group (62% vs 41%) than nonGBC cohorts (p ≤ 0.01). Luminal B<br />
GBC cases were younger at first partum than Luminal A and Her2 (p = 0.02).<br />
Compared to Alamo III, GBC had worse disease free (68% vs 77%, p = 0.01) and<br />
overall survival at 5 years (78% vs 91%, p < 0.01).<br />
Conclusions: GBC differential biology is suggested by higher Basal-like and lower<br />
Luminal A rates, and absence <strong>of</strong> Claudin-low phenotype, correlating with worse<br />
survival and a more aggressive clinico-pathological pr<strong>of</strong>ile confirmed by a higher<br />
ROR-P high rate and lower CESP score.<br />
Legal entity responsible for the study: GEICAM Spanish Breast Cancer Group<br />
Funding: Sociedad Española de Oncologia Medica (SEOM): Grant “SEOM Buckler”,<br />
Fundacion BBVA: Solidarity project: “BBVA Solidarity Territories“ Donations from<br />
two Associations <strong>of</strong> Breast Cancer Patients “Rosae” and “Santa Agueda”<br />
Disclosure: A. Prat: Consulting Fees (advisory boards) Nanostring Technologies. All<br />
other authors have declared no conflicts <strong>of</strong> interest.<br />
156P<br />
Changes in breast cancer incidence may be attributed to<br />
implementation <strong>of</strong> all-national dispensarization:<br />
a population-based study from North-West Russia<br />
L. Bakare, M. Valkov<br />
Department <strong>of</strong> Radiology, Radiotherapy and Clinical <strong>Oncology</strong>, Northern State<br />
Medical University, Arkhangelsk, Russian Federation<br />
Background: Breast cancer (BC) is the most common cancer pathology among women<br />
worldwide and leading cause <strong>of</strong> death in the developed and less developed countries.<br />
Consequently, there were two projects implemented in 2006 (National project<br />
“Health”) and in 2013 (Law <strong>of</strong> All-national dispensarization) focusing on improvement<br />
in health care delivery in Russia. The aim <strong>of</strong> study is to evaluate the effects <strong>of</strong> the<br />
projects on incidence and stage proportion in breast cancer.<br />
Methods: In this retrospective population-based study, we analyzed data from the<br />
Arkhangelsk regional Cancer Registry over the period 2000-2014. The variables for the<br />
analysis included female gender only, date <strong>of</strong> birth, date <strong>of</strong> diagnosis, and stage<br />
according to the TNM 7 classification. Age-standardized rates per 100,000<br />
person-years were calculated, using the direct method <strong>of</strong> standardization to the world<br />
population. The Joinpoint Regression Analysis program, version 4.2.0.2, was used to<br />
calculate trends <strong>of</strong> BC incidence and Stage proportions.<br />
Results: Over the period <strong>of</strong> study, 5842 cases <strong>of</strong> breast cancer were recorded in the<br />
Arkhangelsk Regional Cancer Registry. The incidence <strong>of</strong> breast cancer has been<br />
increasing over the period from 35 to 48 cases per 100 000 between 2000 and 2014 with<br />
annual percentage change (APC) varying from 0.9% during a period 2000-2006 and<br />
3.9% in 2007-2014. The proportion <strong>of</strong> Stage 1 varied from 9% to 21% between 2000<br />
and 2014. In JoinPoint regression a significant growth <strong>of</strong> Stage 1 proportion was<br />
observed over the period 2011-2015 with APC 15.7%.<br />
Conclusions: Over the past 15 years there has been a steady increase in breast cancer<br />
incidence in the Arkhangelsk region. Taking in account a significant growth <strong>of</strong> Stage 1<br />
BC over the latter 4 years, this increase is at least partially explained by better earlier<br />
diagnosis after the implementation the All-national dispensarization in Russia. The<br />
National project “Health” is less possible responsible for the increased incidence.<br />
Legal entity responsible for the study: N/A<br />
Funding: Northern State Medical University<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
157P<br />
Accuracy and adequacy <strong>of</strong> pre-operative bracketing for<br />
therapeutic excision <strong>of</strong> non-palpable malignant breast lesions<br />
S. Zeeshan, S.M. Khan<br />
Surgery, The Aga Khan University Hospital, Karachi, Pakistan<br />
Background: Bracketing comprises <strong>of</strong> using two or more needles for localization <strong>of</strong><br />
boundaries <strong>of</strong> an impalpable breast lesion. The tissue around the wires is excised and<br />
sent for histopathology. Objectives: To determine the accuracy & adequacy <strong>of</strong><br />
pre-operative bracketing for therapeutic excision <strong>of</strong> non-palpable malignant breast<br />
lesions and in achieving tumor free margins.<br />
Methods: Retrospective review <strong>of</strong> mammograms & pathology reports <strong>of</strong> patients who<br />
underwent bracketing for malignant breast lesions at AKUH from January 2004 to<br />
April 2016. All cases <strong>of</strong> clinically non-palpable primary malignant breast lesions<br />
requiring therapeutic excision and with complete clinical response to Neoadjuvant<br />
therapy targeted for breast conservation were included whereas those with benign<br />
pathology were excluded.<br />
Results: 76 patients with mean age <strong>of</strong> 48.09 years (range 25 - 81 years) underwent<br />
bracketing for excision <strong>of</strong> both benign and malignant breast lesions. 62 patients<br />
underwent breast conservation surgery for a pre-operative diagnosis <strong>of</strong> IDC (n = 56),<br />
ILC (n = 3), DCIS (n = 2) and metaplastic carcinoma (n = 1) with the help <strong>of</strong><br />
bracketing. 85.5% (n = 53) received neo-adjuvant chemotherapy to reduce the size <strong>of</strong><br />
lump. 93.5% (n = 58) underwent stereotactic wire localization, 4.8% (n = 3) underwent<br />
sonographic localization whereas 1.6% (n = 1) was localized with the help <strong>of</strong> both<br />
mammogram and ultrasound. Presence <strong>of</strong> radiopaque marker within the excised<br />
specimen and grossly adequate margins around the lesion guided the surgeon to decide<br />
about further margin excision. 95.2% (n = 59) had negative margins <strong>of</strong> the breast lump<br />
and 2 out <strong>of</strong> 62 patients (3.2%) had close margins (DCIS at 0.1cm from closest<br />
margin). 1.6% (n = 1) patient had invasive tumor at the margin. None <strong>of</strong> the re-excised<br />
tissue in 2 patients with close margins showed any evidence <strong>of</strong> tumor in the final<br />
histopathology report except the patient with positive margin who underwent second<br />
procedure <strong>of</strong> margin excision followed by mastectomy<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw364 | vi47
abstracts<br />
Conclusions: Our study showed that bracketing wire localization is a beneficial<br />
procedure in terms <strong>of</strong> achieving clear histologic margins in breast conservation surgery<br />
without significant increase in the rate <strong>of</strong> re-excision<br />
Legal entity responsible for the study: The Aga Khan University and Hospital<br />
Funding: The Aga Khan University Hospital<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
158P<br />
Ultrasound-guided core needle biopsy could replace sentinel<br />
lymph nodes biopsy for patients with suspicious node positive<br />
breast cancer<br />
R. Nakamura 1 , N. Yamamoto 1 , K. Fujisaki 1 , R. Teranaka 1 , T. Miyaki 2 , D. Ikebe 3<br />
1 Breast surgery, Chiba Cancer Center Hospital, Chiba, Japan, 2 Breast oncology,<br />
Chiba Cancer Center Hospital, Chiba, Japan, 3 Diagnositic pathology, Chiba<br />
Cancer Center Hospital, Chiba, Japan<br />
Background: The Z0011 trial indicated that the information achieved by axillary<br />
dissecting lymph nodes (Ax LNs) does not change the prognosis <strong>of</strong> the disease for<br />
patients with clinical node negative breast cancer. Several clinical trials conduct the<br />
need for SNB in cases with negative ultrasound-guided (US) fine needle aspiration<br />
cytology (FNA) <strong>of</strong> the suspicious LNs. The aim <strong>of</strong> this study was to evaluate the<br />
reliability <strong>of</strong> CNB to detect positive LN compared to that <strong>of</strong> FNA.<br />
Methods: A total <strong>of</strong> 1465 consecutive patients (pts) with breast cancer were<br />
prospectively identified at our institution between March, 2012 and April, 2016. The<br />
inclusion criteria <strong>of</strong> both FNA(21G) and CNB(16G) was cortical thickness greater than<br />
3 mm or abnormal morphologic characteristics. Patients with biopsy-proved metastasis<br />
underwent Ax, and those with a negative FNA or CNB underwent SNB. If the SNB was<br />
positive, Ax was performed. Diagnostic accuracy was calculated for FNA and CNB.<br />
Results: The number <strong>of</strong> negative US <strong>of</strong> LNs was 744 pts, 440 FNA and 212 CNB were<br />
performed for suspicious LNs. Sensitivity, specificity, PPV, NPV, and accuracy were<br />
83%, 99%, 97%, 88%, and 91% in FNA, and 93%, 99%, 99%, 97% and 97% in CNB,<br />
respectively. SNB was performed in 141 <strong>of</strong> 212 CNB and 254 <strong>of</strong> 463 FNA. 141CNB<br />
(T1;83,T2;52,T3;9 pts) treated with SNB were compared to 254 FNA (T1;127, T2;116,<br />
T3;11 pts) regarding the number <strong>of</strong> LNs metastasis. The number <strong>of</strong> positive SLNs and<br />
positive LNs more than 3 was 5 (4%), 0(0%) in CNB, and 35(14%), 15(6%) in FNA,<br />
respectively.<br />
Conclusions: CNB is a reliable method for the preoperative diagnosis <strong>of</strong> LNs<br />
metastasis. If CNB shows negative LNs, SNB might be safely omitted for patients with<br />
breast cancer.<br />
Clinical trial identification: none<br />
Legal entity responsible for the study: N/A<br />
Funding: Chiba Cancer Center<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
159P<br />
Endoscopy-assisted breast surgery for breast cancer: updated<br />
results from study conducted by the Taiwan Endoscopic<br />
Breast Surgery Cooperative Group<br />
Y-L. Kuo 1 , H-W. Lai 2 , C-S. Hung 3<br />
1 Surgery, National Cheng Kung University, Tainan, Taiwan, 2 Surgery, Changhua<br />
Christian Hospital, Changhua City, Taiwan, 3 Surgery, Taipei Medical Unversity<br />
Hospital, Taipei, Taiwan<br />
Background: Endoscopy-assisted breast surgery (EABS) performed through minimal<br />
axillary and/or peri- areolar incisions is a possible alternative to open surgery for<br />
certain patients with breast cancer. In this study, we report the early results <strong>of</strong> an EABS<br />
program in Taiwan.<br />
Methods: The medical records <strong>of</strong> patients who underwent EABS for breast cancer<br />
during the period May 2009 to December 2015 were collected from the Taiwan<br />
Endoscopic Breast Surgery Cooperative Group database. Data on clinicopathologic<br />
characteristics, type <strong>of</strong> surgery, method <strong>of</strong> breast reconstruction, complications and<br />
recurrence were analyzed to determine the effectiveness and oncologic safety <strong>of</strong> EABS<br />
in Taiwan.<br />
Results: A total <strong>of</strong> 345 EABS procedures were performed in 320 patients with breast<br />
cancer, including 25 (7.2%) patients with bilateral disease. The number <strong>of</strong> breast cancer<br />
patients who underwent EABS increased initially from 2009 to 2012 and then stabilized<br />
during the period 2012–2015. The most commonly performed EABS was<br />
endoscopy-assisted total mastectomy (EATM) (85.8%) followed by endoscopy-assisted<br />
partial mastectomy (EAPM) (14.2%). Approximately 76% <strong>of</strong> the EATM procedures<br />
involved breast reconstruction, with the most common types <strong>of</strong> reconstruction being<br />
implant insertion and autologous pedicled TRAM flap surgery. During the seven-year<br />
study period, there was an increasing trend in the performance <strong>of</strong> EABS for the<br />
management <strong>of</strong> breast cancer when total mastectomy was indicated. The positive<br />
surgical margin rate was 1.4 %. Overall, the rate <strong>of</strong> complications associated with EABS<br />
was 13.2 % and all were minor and wound-related. During a median follow-up <strong>of</strong> 31.7<br />
(4.2–75.6) months, there were 3 (1%) cases <strong>of</strong> local recurrence, 5 (1.4%) case <strong>of</strong> distant<br />
metastasis and 2 (0.5%) death.<br />
Conclusions: The updated results from the EABS program in Taiwan show that EABS<br />
is a safe procedure and results in acceptable cosmetic outcome. These findings could<br />
provide an alternative in surgical technique for certain breast cancer patients.<br />
Clinical trial identification: IRB No.: 141224<br />
Legal entity responsible for the study: National Cheng Kung University<br />
Funding: Funding from Ministry <strong>of</strong> Science and Technology, ROC (Nr.<br />
104-2314-B-371 -006 -MY3)<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
160P<br />
The role <strong>of</strong> preoperative breast magnetic resonance (MR)<br />
imaging for surgical decision in patients with triple-negative<br />
breast cancer<br />
T.J. Kwon 1 , H.Y. Park 1 , J.H. Jung 1 , W.W. Kim 1 , S.O. Hwang 1 , Y.S. Chae 2 ,S.<br />
J. Lee 2 , J-Y. Park 3 , J.H. Chung 1 , J. Lee 1<br />
1 Department <strong>of</strong> Surgery, Kyungpook National University School <strong>of</strong> Medicine,<br />
Daegu, Republic <strong>of</strong> Korea, 2 Department <strong>of</strong> Hematology/<strong>Oncology</strong>, Kyungpook<br />
National University School <strong>of</strong> Medicine, Daegu, Republic <strong>of</strong> Korea, 3 Department <strong>of</strong><br />
Pathology, Kyungpook National University School <strong>of</strong> Medicine, Daegu, Republic <strong>of</strong><br />
Korea<br />
Background: Several reliable randomized studies do not recommend routine<br />
preoperative breast MR imaging for patients with breast cancer. However, because the<br />
principle <strong>of</strong> MR imaging is based on the dynamics <strong>of</strong> contrast enhancement, a specific<br />
biologic subgroup <strong>of</strong> tumors should sensitively respond to the imaging process.<br />
Methods: From 2008 to 2013, 918 eligible patients with breast cancer underwent breast<br />
surgery and were divided into two groups based on preoperative breast MR findings:<br />
patients in whom the surgical plan was changed and those in whom the surgical plan<br />
remained unchanged. We investigated the changing patterns <strong>of</strong> breast surgery based on<br />
routine mammography, ultrasound, and preoperative breast magnetic resonance (MR)<br />
findings and analyzed the association between additional suspicious lesions on breast<br />
MR imaging and clinicopathologic factors.<br />
Results: Additional suspicious breast lesions were detected on preoperative MR<br />
imaging in 104 cases (11.3%), and the surgical strategy was changed as the final<br />
decision in 97 cases (10.6%). There was no difference between oncologic results<br />
between two groups. However, the triple-negative breast cancer (TNBC) was<br />
significantly associated with changing <strong>of</strong> the surgical strategy based on breast MR<br />
findings (P = 0.048).<br />
Conclusions: Additional preoperative breast MR imaging may be helpful in surgical<br />
decision for patients with TNBC.<br />
Legal entity responsible for the study: Department <strong>of</strong> Surgery, Kyungpook National<br />
University School <strong>of</strong> Medicine<br />
Funding: Department <strong>of</strong> Surgery, Kyungpook National University School <strong>of</strong> Medicine<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
161P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
What decides breast conservation versus mastectomy in the<br />
background <strong>of</strong> diverse sociocultural environment, an Indian<br />
study<br />
P.P.P. Bapsy 1 , P. Maurya 1 , S. Dhande 2 ,L.K 1 , A. Kamath 1 , C. Mudlapur 1 ,S.<br />
S. Holla 1 , C. Patil 2<br />
1 Medical <strong>Oncology</strong>, Apollo Hospitals Bangalore, Bangalore, India, 2 Medical<br />
<strong>Oncology</strong>, Apollo Hospitals Bangalore, Bangalore, India<br />
Background: Breast cancer is the most common cancer in Indian females, about a<br />
third being operable. The reason for low rates <strong>of</strong> BCS in early breast cancer (EBC) is<br />
multifactorial inspite <strong>of</strong> results from SABCS 2015 which revealed better survival in BCS<br />
patients than in mastectomy group. India is a culturally rich, multilinguistic and<br />
diverse nation, with many communities which live in their respective social structures,<br />
contributing to low rates <strong>of</strong> BCS. Understanding these multidimensional psychosocial,<br />
and cultural factors are essential for providing comprehensive and appropriate cancer<br />
care. Our objective was to look at factors that influence the type <strong>of</strong> surgery in EBC in<br />
our diverse cultural and socioeconomic background and to improvise.<br />
Methods: 153 EBC pateints at Apollo hospitals from Jan 2014 to June 2015, were<br />
interviewed regarding various factors which influence the surgical decision. The<br />
questionnaire included literacy, economic status, single or joint family, rural or urban,<br />
deciding factor- patient preference, family and surgeon, psychological impact interms<br />
<strong>of</strong> anxiety or depression and fear <strong>of</strong> tumour recurrence.<br />
Results: Of the total 153 EBC patients, 36% (55) had BCS and rest (98) 64% had MRM.<br />
BCS group had more urban population (64 %) than in mastectomy group (56%). BCS<br />
group had higher education level (66% graduates) as opposed to patients undergoing<br />
MRM (23% graduates). Higher proportion <strong>of</strong> younger women was observed in the BCS<br />
(69%)group as opposed to mastectomy group (33%). Surgeon seemed to play a major<br />
role in making MRM decision (67%) as compared to BCS (11%) in contrast to western<br />
scenario where patient has a major role in decision making. BCS group had significant<br />
patient involvement (39%) in decision making as compared to 10% in MRM group.<br />
vi48 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
Fear <strong>of</strong> tumour recurrence (81% vs 38%) and post mastectomy depression (91% vs<br />
58%) was higher in the mastectomy group as compared to BCS group.<br />
Conclusions: Surgical decision in EBC patients is influenced by varying<br />
socio-demographic characteristics that results in disparities in cancer care and health<br />
outcomes. Health care providers need to be attentive to the varied socio- cultural<br />
factors. Optimizing patient involvement in the surgical decision making <strong>of</strong> EBC is the<br />
need <strong>of</strong> the hour.<br />
Legal entity responsible for the study: N/A<br />
Funding: Apollo Hospitals Bangalore<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
162P<br />
Menopausal status on tumour biology in early breast cancer<br />
O. Ayodele 1 , I. Ali 1 , A. Konenko 1 , L. Duggan 1 ,N.O’Mara 1 , R. Rahman 2 , Y. Ged 1 ,<br />
P. Calvert 1 , A. Horgan 1 ,M.O’Connor 1<br />
1 Medical <strong>Oncology</strong>, University Hospital Waterford, Waterford, Ireland, 2 Medical<br />
<strong>Oncology</strong>, St Vincents University Hospital, Dublin, Ireland<br />
Background: Breast cancer (BC) is primarily a disease <strong>of</strong> older or post menopausal<br />
women. It has been suggested that BC arising in young women is a unique biological<br />
subset characterized by less hormone sensitivity and higher HER2 (epidermal growth<br />
factor receptor) expression. This study was performed to compare the tumour biology<br />
between pre menopausal (PrM) and post menopausal (PoM) women.<br />
Methods: New diagnosis <strong>of</strong> early BC from 2011-2015 in the South East Cancer Centre<br />
were included. The patients were divided into PrM (20 to 50 mm (OR 0.32; 95% CI: 0.16-0.67).<br />
Conclusions: Our analysis seems to exclude significant relation between Ki67 and<br />
ALNM, while T-size and ALNM were confirmed to be highly related in all BCs but TN.<br />
Given these data it is appropriate to discuss if axillary surgery may be redundant in<br />
cases with exceptionally good prognosis and in pts with poor prognosis that will be<br />
<strong>of</strong>fered systemic therapy and radiotherapy anyway. Hence BC pts aged > 50 with small<br />
tumors and low Ki67 and most TN pts represent ideal candidates for current clinical<br />
trials evaluating the potential for eliminating axillary surgery and sentinel node biopsy.<br />
Legal entity responsible for the study: Fondazione IRCCS Istituto Nazionale dei<br />
Tumori, Milan, Italy<br />
Funding: Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
164P<br />
The prognostic performance <strong>of</strong> Adjuvant! Online and<br />
Nottingham Prognostic Index in young breast cancer patients:<br />
an international multicentre hospital-based retrospective<br />
cohort study<br />
M. Lambertini 1 , A.C. Pinto 2 , L. Ameye 3 , L. Jongen 4 , L. Del Mastro 5 , F. Puglisi 6 ,<br />
F. Poggio 1 , M. Bonotto 7 , G. Floris 8 , K. van Asten 4 , H. Wildiers 4 , P. Neven 4 ,E.de<br />
Azambuja 9 , M. Paesmans 3 , H.A. Azim, Jr. 10<br />
1 Department <strong>of</strong> Medical <strong>Oncology</strong>, U.O. Oncologia Medica 2, IRCCS AOU San<br />
Martino - IST-Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy,<br />
2 Department <strong>of</strong> Medicine, Institute Jules Bordet, Brussels, Belgium, 3 Data Centre,<br />
Institute Jules Bordet, Brussels, Belgium, 4 Department <strong>of</strong> <strong>Oncology</strong>, University<br />
Hospitals Leuven - Campus Gasthuisberg, Leuven, Belgium, 5 Medical <strong>Oncology</strong>,<br />
IRCCS AOU San Martino - IST-Istituto Nazionale per la Ricerca sul Cancro, Genoa,<br />
Italy, 6 Department <strong>of</strong> Medical and Biological Sciences, University <strong>of</strong> Udine, Udine,<br />
Italy, 7 Department <strong>of</strong> Medical <strong>Oncology</strong>, AOU Santa Maria della Misericordia,<br />
Udine, Italy, 8 Department <strong>of</strong> Imaging and Pathology, University Hospitals Leuven -<br />
Campus Gasthuisberg, Leuven, Belgium, 9 Medical <strong>Oncology</strong>, Institute Jules<br />
Bordet, Brussels, Belgium, 10 Medical <strong>Oncology</strong>, Institut Jules Bordet, Brussels,<br />
Belgium<br />
Background: Adjuvant! Online (AOL) and Nottingham Prognostic Index (NPI) are<br />
prognostic tools that are widely used to aid treatment decision-making. Although<br />
performing globally well, their performance is unclear in populations other than those<br />
used in their validation studies and particularly in specific subgroups such as<br />
women ≤ 40 years. The present study aimed to evaluate for the first time the prognostic<br />
performance <strong>of</strong> AOL and NPI in young early breast cancer patients.<br />
Methods: This is a multicentre hospital-based retrospective cohort study including<br />
young (≤ 40 years) and older (55-60 years) breast cancer patients treated from January<br />
2000 until December 2004 at 4 large Belgian and Italian institutions. Predicted 10-year<br />
overall survival (OS) and disease-free survival (DFS) using AOL and 10-year OS using<br />
NPI were calculated for every patient. To assess calibration, the trimmed mean <strong>of</strong> the<br />
predicted 10-year outcomes was compared to the observed (Kaplan-Meier estimate at<br />
10 years) 10-year rates by using one-sample t-test. Discriminatory accuracy was<br />
assessed by calculating the area under the receiver-operator characteristic curve and the<br />
corresponding 95% confidence intervals for 10-year predicted OS and DFS. Vital status<br />
was cross-checked with the national registries in Belgium and Italy.<br />
Results: A total <strong>of</strong> 1,283 patients were included (376 in the young and 907 in the older<br />
cohorts, respectively). AOL accurately predicted 10-year OS (absolute difference: 0.66%;<br />
p = 0.37) in the young cohort, but overestimated 10-year DFS by 7.66% (p = 0.003). In<br />
the older cohort, AOL significantly underestimated both 10-year OS and DFS, by 7.20%<br />
(p < 0.001) and 3.12% (p = 0.04), respectively. NPI significantly underestimated 10-year<br />
OS in both the young (8.46%; p < 0.001) and the older (4.04%; p < 0.001) cohorts. AOL<br />
and NPI had comparable discriminatory accuracy in predicting both OS and DFS.<br />
Conclusions: In young breast cancer patients, AOL is a reliable tool in predicting OS at<br />
10 years but not DFS, while the calibration performance <strong>of</strong> NPI is suboptimal. In<br />
patients aged 55-60 years, the role <strong>of</strong> AOL and NPI deserves further investigations.<br />
Legal entity responsible for the study: N/A<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw364 | vi49
abstracts<br />
165P<br />
Tumor lymphocyte infiltrations decrease the risk <strong>of</strong> late<br />
relapse in breast cancer patients<br />
C. Grasic Kuhar, B. Zakotnik<br />
Dept. <strong>of</strong> Medical <strong>Oncology</strong>, Institute <strong>of</strong> <strong>Oncology</strong> Ljubljana, Ljubljana, Slovenia<br />
Background: Tumor lymphocyte infiltrations (TLI) seem to be a prognostic factor for<br />
survival in hormone receptor negative breast cancer (i.e. triple negative and HER2<br />
positive). The majority <strong>of</strong> breast cancer patients relapse early in the first five years after<br />
diagnosis. The impact <strong>of</strong> TLI on late relapses in breast cancer patients is unknown.<br />
Methods: Data <strong>of</strong> patients with early breast cancer treated in years 1984-1988 at the<br />
Institute <strong>of</strong> <strong>Oncology</strong> Ljubljana, Slovenia, were analysed retrospectively from patient’s<br />
charts. We evaluated the prognostic value <strong>of</strong> TLI on late relapses (>5 years after<br />
diagnosis).<br />
Results: In 1034 patients (median age 57 years, 61% postmenopausal) primary<br />
treatment was surgical by modified radical mastectomy (87%) or breast conserving<br />
surgery (13%). All had axillary dissection and 12% adjuvant radiation. 47% were node<br />
negative, 51% size <strong>of</strong> tumor 2-5 cm, 40% grade II and 21% grade III, 15% had<br />
lymphovascular invasion (LVI) and 42% TLI, 50% positive estrogen receptors (ER),<br />
30% positive progesterone receptors (PR). HER2 status was unknown. 30% <strong>of</strong> patients<br />
received adjuvant chemotherapy (CMF schedule), 16% adjuvant hormonal therapy<br />
with tamoxifen, and 3% both chemo- and hormonal therapy. 516 (50%) <strong>of</strong> patient<br />
relapsed during the whole follow-up time (median follow-up time was 26.5 years). At 5<br />
years 595 patients were alive and relapse-free, 150 (14.5%) patients relapsed after 5<br />
years after diagnosis. In univariate analysis TLI (HR 0.56; 95% CI 0.40-0.78), nodal<br />
stage (HR 1.39; 95% CI 1.14-1.69) and PR (HR 1.78; 95% CI 1.25-2.54) were found as<br />
prognostic factors for relapse. ER (HR 1.39; 95% CI 0.99-1.95) and LVI (HR 1.63; 95%<br />
CI 0.97-2.73) were nearly statistically significant. In multivariate Cox analysis a<br />
favourable prognostic factor for relapse was TLI (HR 0.58; 95% CI 0.40-0.84; p = 0.004)<br />
and two unfavourable prognostic factors were positive PR (HR 1.65; 95% CI 1.14-2.39;<br />
p = 0.007) and nodal stage (HR 1.43; 95% CI 1.13-1.80; p = 0.03).<br />
Conclusions: Our data indicate that TLI could decrease the risk <strong>of</strong> late relapse in breast<br />
cancer patients indicating the significance <strong>of</strong> immune response mechanisms as a<br />
potential therapeutic target in breast cancer. Prospective studies to test this hypothesis<br />
are needed.<br />
Clinical trial identification: National Medical Ethics Comittee at Ministry <strong>of</strong> Health,<br />
Republic <strong>of</strong> Slovenia, Number 121/07/02<br />
Legal entity responsible for the study: Institutional ethics commitee, Institutional<br />
review board<br />
Funding: None<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
166P<br />
The let-7/Lin28 can be an early detection marker <strong>of</strong> anti-HER2<br />
containing therapy sensitivity in HER2 positive breast cancer<br />
H. Takuwa, F. Sato, J. Itou, M. Toi<br />
Breast surgery, Kyoto University-Graduate School <strong>of</strong> Medicine, Kyoto, Japan<br />
Background: Anti-Human epidermal growth factor receptor (HER) 2 therapy,<br />
trastuzumab for HER2 positive breast cancer patients improved their prognoses<br />
dramatically. However, there are some potentially trastuzumab-resistant breast cancer<br />
even in trastuzumab-naïve patients. Therefore, understanding <strong>of</strong> the molecular<br />
mechanism <strong>of</strong> trastuzumab resistance is strongly demanded. In this study, we<br />
hypothesized that micro RNA (miRNA) play important roles in trastuzumab<br />
treatment.<br />
Methods: We performed comprehensive microRNA expression pr<strong>of</strong>iling <strong>of</strong><br />
pre-treatment biopsy specimens in 83 HER2-positive breast cancer patients who<br />
underwent preoperative trastuzumab-chemo combined therapy. Then, let-7 family<br />
expression in cancer cells was elevated in non-pCR cases compared to pCR cases. Thus,<br />
we tried to elucidate molecular mechanisms associated with trastuzumab sensitivity<br />
and let-7 expression. We investigated their function in HER2-positive human breast<br />
cancer cell lines, trastuzumab-sensitive and -resistant. These two cell lines were used<br />
for gain/loss <strong>of</strong> function experiments. We also attempted to prove their correlations<br />
between serum let-7 change extracted from exosome and therapeutic effect using<br />
another 6 patients’ blood sample.<br />
Results: The expression <strong>of</strong> let-7 family is regulated by LIN28 because it forms a double<br />
negative feedback loop with let-7. Let-7/LIN28 expression was down/up-regulated in<br />
BT474 (sensitive) cells by trastuzumab exposure, respectively, whereas the let-7/LIN28<br />
expression was up/down-regulated in JIMT-1 (resistant) cells. Exogenous<br />
overexpression <strong>of</strong> let-7 in BT474 cell decreased trastuzumab sensitivity from 50% to<br />
40% 6-day exposure <strong>of</strong> trastuzumab. Conversely, let-7-down-regulated JIMT-1 cells<br />
had down-regulated expression <strong>of</strong> let-7 family and recovered trastuzumab sensitivity<br />
from 0% to 20% (>2ug/mL).<br />
Conclusions: The let-7/LIN28 regulatory circuit may have an important role in<br />
molecular mechanisms <strong>of</strong> trastuzumab-chemo therapy for HER2-positive breast<br />
cancer. Early assessment <strong>of</strong> this let-7/LIN28 response after treatment start might<br />
predict treatment outcome. We believe that modulation <strong>of</strong> this regulatory circuit might<br />
sensitize trastuzumab-resistant breast cancer cells.<br />
Legal entity responsible for the study: N/A<br />
Funding: Chugai, Scientific research grant<br />
Disclosure: M. Toi: Chugai Scientific research grantAll other authors have declared no<br />
conflicts <strong>of</strong> interest.<br />
167P<br />
Clinicopathological characteristics and BRCA1/2 mutation<br />
rate in male breast cancer: a retrospective case series by the<br />
Hellenic Society <strong>of</strong> Medical <strong>Oncology</strong><br />
G. Lypas, D. Tryfonopoulos, E. Saloustros, P. Zacharopoulou, L. Florentin,<br />
A. Apessos, E. Kabletsas, E. Prinarakis, V. Barbounis, G. Fountzilas, D. Mavroudis,<br />
V. Georgoulias<br />
Male Breast Cancer Working Group, Hellenic Society <strong>of</strong> Medical <strong>Oncology</strong>,<br />
Athens, Greece<br />
Background: Due to its rarity, male breast cancer (MBC) remains an inadequately<br />
characterized disease. Germline mutations in the BRCA1/2 genes are considered the<br />
most significant risk factor for MBC development.<br />
Methods: We retrospectively analyzed the clinicopathological characteristics, treatment<br />
patterns, and the BRCA1/2 germline mutation rate <strong>of</strong> BC patients (pts) treated from<br />
1995 to 2014. Pts who were still alive were identified and were invited for genetic<br />
counseling and testing. The study was coordinated by the University <strong>of</strong> Crete School <strong>of</strong><br />
Medicine.<br />
Results: A total <strong>of</strong> 166 pts were identified through their medical records. Median age at<br />
diagnosis was 64. Family history <strong>of</strong> either FBC or ovarian cancer was positive in 19,9%<br />
while 9% had a personal history <strong>of</strong> gynecomastia. Histology was <strong>of</strong> Ductal Invasive type<br />
in 84% <strong>of</strong> the pts. Node positive locally advanced disease was diagnosed at 30% <strong>of</strong> pts,<br />
while 18% were metastatic at presentation. ER and/or PR-positive, HER2-negative was<br />
the predominant subtype (78.4%), followed by triple-positive (18.1%) and only in few<br />
pts triple-negative subtype (3.4%). Histologic grade distribution was: gr. I in 5.4%, gr. II<br />
in 53.4% and gr III in 41%. All 99 patients who received genetic counselling consented<br />
to BRCA1/2 genetic testing. Overall BRCA1/2 deleterious mutation rate was 6 % (5%<br />
BRCA2 and 1% BRCA1), while 3 pts (3%) carried a VUS. Most pts (80%) underwent<br />
modified radical mastectomy, 41% <strong>of</strong> which received adjuvant radiotherapy. Adjuvant<br />
systemic therapy was administered to 71.6% (10% had chemotherapy only, 27%<br />
hormonotherapy only and 63% both). Metastatic disease was treated with at least 1 line<br />
<strong>of</strong> systemic therapy in 31.9% <strong>of</strong> pts (chemotherapy in 60% <strong>of</strong> them), 60% <strong>of</strong> which<br />
proceeded to subsequent lines.<br />
Conclusions: In one <strong>of</strong> the largest national cohorts <strong>of</strong> MBC pts reported yet, we<br />
confirmed similar biological patterns to post-menopausal FBC. BRCA1/2 germline<br />
mutation rate is comparable to other European populations. Male Breast Cancer<br />
Working Group <strong>of</strong> the Hellenic Society <strong>of</strong> Medical <strong>Oncology</strong> Koumarianou A.,<br />
Bournakis E., Boutis A., Diamantopoulos N., Katsaounis P., Korantzis I., Lianos E.,<br />
Tsoukalas N., Bakogeorgos M., Kalampaliki T.<br />
Legal entity responsible for the study: N/A<br />
Funding: NSRF (National Strategic Reference Framework), Hellenic Ministry for<br />
Health and Social Solidarity<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
168P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Triple-negative breast cancer and BRCA mutation: looking at<br />
the future<br />
Z. Ballatore, M. Pistelli, R. Bracci, F. Bianchi, E. Maccaroni, L. Belvederesi,<br />
C. Brugiati, S. Pagliaretta, M. De Lisa, A. Della Mora, L. Cantini, L. Bastianelli,<br />
A. Pagliacci, N. Battelli, R. Berardi<br />
1. Clinica di Oncologia Medica e Centro Regionale di Genetica Oncologica, AOU<br />
Ospedali Riuniti Ancona Università Politecnica delle Marche, Ancona, Italy<br />
Background: More than 75% <strong>of</strong> breast carcinomas that develop in BRCA mutation<br />
carriers (BRCA+) are triple-negative breast cancer (TNBC). Despite higher prevalence,<br />
it is controversial whether BRCA+ have lower survival. The aim <strong>of</strong> this study was to<br />
compare disease free survival (DFS) and overall survival (OS) in TNBC patients with<br />
and without deleterious BRCA1/2 mutations.<br />
Methods: A total <strong>of</strong> 116 women with TNBC referred to our Institution for genetic<br />
counseling and underwent BRCA genetic testing between 2002 and 2015, 13 patients<br />
with a BRCA variant <strong>of</strong> uncertain significance (VUS) were excluded. Associations<br />
between clinical features and outcomes were evaluated using univariate and<br />
multivariate Cox analysis.<br />
Results: Overall, 103 women were included, 55 (47%) were BRCA+ (BRCA1 n = 48,<br />
BRCA2 n = 7) and 48 cases wild-type (BRCA-). Recurrent mutations were: 2 frameshift<br />
mutations in exon 11 in 5 cases with 3901delT and 4 with 962del4 Stop 297<br />
respectively. Six patients presented exon 5 frameshift mutation (300T > G) and 5<br />
women presented large genomic rearrangement (Del 1 and 2). Median age was 42<br />
years in BRCA+ and 48 years in BRCA-. The two patient groups were comparable for<br />
prognostic factors. Median follow-up was 6.2 years (range 0.5-22.8), the 5-year RFS<br />
rates were 79% and 72% (P = 0.12) in BRCA+ and BRCA- and 5-year OS rates was 83%<br />
in both groups. No significant prognostic difference was evidenced in DFS (p = 0.54)<br />
vi50 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
and OS (p = 0.24). A better DFS was associated to early stage and absence <strong>of</strong><br />
lymphovascular invasion; these findings were confirmed to multivariate analysis<br />
(p = 0.01, HR 3.02 CI 1.28-7.11 and p = 0.02, HR 3.01 CI 1.23-7.38). The OS was<br />
correlated only to early stage (p = 0.04, HR 0.33 CI 0.09-0.96).<br />
Conclusions: Given the 47% prevalence <strong>of</strong> deleterious BRCA1 mutations, referral for<br />
genetic testing should be considered in TNBC. The 4 detected deleterious BRCA1<br />
mutations seem recurrent in our Country. TNBC prognosis is similar between BRCA+<br />
and sporadic disease. These findings parallel previous literature data showing limited<br />
clinical impact <strong>of</strong> BRCA status as a whole in TNBC survival. Study limitation include<br />
small number <strong>of</strong> events which may have reduced statistical power. Further studies are<br />
required to find prognostic/predictive factors in order to guide therapy in TNBC BRCA<br />
positive and negative.<br />
Legal entity responsible for the study: N/A<br />
Funding: Clinica di Oncologia Medica e Centro Regionale di Genetica Oncologica,<br />
Università Politecnica delle Marche e AOU Ospedali Riuniti Ancona<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
169P<br />
BRCA mutations and IGF-R1 expression in modulating<br />
sensitivity to trastuzumab in HER2-positive breast cancer<br />
M. Pistelli 1 , A. Santinelli 2 , M. Santoni 1 , F. Piva 1 , F. Bianchi 1 , L. Belvederesi 1 ,<br />
T. Biscotti 1 , M. De Lisa 1 , Z. Ballatore 1 , G. Occhipinti 1 , A. Pagliacci 1 , E. Maccaroni 1 ,<br />
R. Bracci 1 , N. Battelli 1 , L. Cantini 1 , L. Bastianelli 1 , R. Berardi 1 , S. Cascinu 3<br />
1 <strong>Oncology</strong>, AOU Ospedali Riuniti Ancona Università Politecnica delle Marche,<br />
Ancona, Italy, 2 Pathology, AOU Ospedali Riuniti Ancona Università Politecnica<br />
delle Marche, Ancona, Italy, 3 Department <strong>of</strong> <strong>Oncology</strong> and Haematology,<br />
University <strong>of</strong> Modena and Reggio Emilia, Modena, Italy<br />
Background: HER2 amplification is uncommon BRCA1/2 mutated breast cancer. We<br />
aimed to assess the relevance <strong>of</strong> both BRCA mutations and the expression <strong>of</strong><br />
insulin-like growth factor receptor-1β (IGF-R1β) in patients with HER2-positive BC<br />
who met clinical criteria for BRCA testing treated with Trastuzumab for early/<br />
metastatic disease. Furthermore, we investigated by pathway reconstruction analysis the<br />
relationship among HER2 overexpression, BRCA and IGF-1R expression.<br />
Methods: We analyzed data from 35 patients treated with adjuvant/neoadj<br />
Trastuzumab (82.9%) or after development <strong>of</strong> metastasis (17.1%). We performed<br />
immunochemistry for HER2, ER/PR, Ki67 and IGF-R1β. Bioinformatic analysis was<br />
carried out to identify any correlation among HER2 overexpression, BRCA mutations<br />
and IGF-1Rβ expression.<br />
Results: 19 tumors (54%) presented BRCA mutations: 11(57.9%) were pathogenic.<br />
Median IGF-1Rβ IHC score was 80 (range 0-285). IGF1Rβ IHC score above median<br />
was found in 78.6% (10/14) <strong>of</strong> BRCA mutated and 26.7% (4/15) <strong>of</strong> BRCA not-mutated<br />
patients (p = 0.027). mPFS was 15.1 months in the overall population and 9.7months<br />
in patients harboring BRCA mutations. mDFS was 60.3 months in HER2 + BRCA<br />
mutated tumors, whilst was not reached in HER2 + BRCA not-mutated ones<br />
(p = 0.018). Interestingly, a trend toward a longer DFS was noted in HER2 + BRCA2 vs<br />
BRCA1 mutated patients. As for IGF-R1β score, mDFS was 92.4 months in patients<br />
with IGF-R1β + tumors treated with adjuvant and/or neoadjuvant Trastuzumab and<br />
was not reached those with IGF-R1β − tumors (p = 0.234). Reconstructed pathway<br />
showed that BRCA1 mutations lead to IGF-1R overexpression and to increased<br />
phosphorylation <strong>of</strong> AKT and, as a consequence, <strong>of</strong> the transcription factor Y box<br />
binding protein 1. YB-1 translocates into the nucleus to bind HER2 promoter, leading<br />
to HER2 overexpression, and increases the expression <strong>of</strong> EGFR.<br />
Conclusions: Our results support that sensitivity to Trastuzumab seems to be<br />
associated with BRCA mutational status and to IGF-1R expression in a subset <strong>of</strong> HER2<br />
positive BC patients.<br />
Legal entity responsible for the study: N/A<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
170P<br />
Germline BRCA screening in breast cancer patients in Tatar<br />
women population<br />
E. Shagimardanova 1 , L. Shigapova 1 , O. Gusev 1 , A. Nikitin 2 , M. Druzhkov 3 ,<br />
R. Enikeev 3 , M. Gordiev 4<br />
1 Institute <strong>of</strong> Fundamental Medicine and Biology, Kazan Volga Redion Federal<br />
University, Kazan, Russian Federation, 2 Genetic Laboratory, Federal Research and<br />
Clinical Center, FMBA, Moscow, Russian Federation, 3 Chemotherapy, Kazan<br />
Clinical <strong>Oncology</strong> Center, Kazan, Russian Federation, 4 Molecular genetics, Kazan<br />
Clinical <strong>Oncology</strong> Center, Kazan, Russian Federation<br />
Background: Breast cancer is the most common cancer among women in Russia. In<br />
2014 61 308 breast cancer cases were diagnosed in Russia, including 1577 cases in the<br />
Republic <strong>of</strong> Tatarstan region. Among them nearly 10% has familiar history breast or<br />
ovarian cancer. The number <strong>of</strong> founder BRCA1 and 2 mutations are known to be<br />
responsible for hereditary breast cancer. It is also known that the frequency <strong>of</strong><br />
occurrence <strong>of</strong> certain founder mutations varies in different countries and nationalities.<br />
It was previously reported that frequent for Slavic population BRCA mutation is not<br />
found in Tatar women with hereditary breast cancer. We screened BRCA genes <strong>of</strong> 24<br />
Tatar women with breast cancer for presence alternative founder mutations.<br />
Methods: The DNA was isolated from patients’ blood using NucleoSpin Tissue kit<br />
(Macherey Nagel) in accordance with manufacturer instructions. 400 nanogram <strong>of</strong><br />
DNA was sheared by sonication using a Q800R2 instrument (Q-Sonica). Further steps<br />
<strong>of</strong> library preparation were performed using a KAPA Library preparation kit<br />
(Kapabiosystems) followed by targeted gene enrichment by NimbleGen SeqCap EZ<br />
Choice (Roche) according to the manufacturer’s instructions. The library was<br />
sequenced using an Illumina MiSeq instrument with read length 249 bp from each end<br />
<strong>of</strong> the fragment.<br />
Results: Three previously reported BRCA1 pathogenic mutations, c.5161C > T,<br />
c. 5382insC and 300T > G and one BRCA2 pathogenic mutation c.468dup were<br />
observed in 4 patients (16,7%). Additionally, novel variant BRCA2 c7544C > T was<br />
predicted to be pathogenic in silico. Only two <strong>of</strong> the observed mutations is included in<br />
routine BRCA testing in Russia (185delAG, 4153delA, 5382insC, 3819delGTAAA,<br />
3875delGTCT, 300T > G, (Cys61Gly), 2080delA, 6174delT) and usage <strong>of</strong> standard<br />
real-time PCR kits would cause false negative results.<br />
Conclusions: The study demonstrated that breast cancer individuals in Tatar ethnos<br />
possess different founder mutations from Slavic Russian population in BRCA genes.<br />
Thus, current genetic testing protocol for Russian BRCA1 founder mutation is not<br />
enough sensitive for clinical use and nationality has to be taken into account.<br />
Legal entity responsible for the study: N/A<br />
Funding: Kazan (Volga Region) Federal university Kazan Clinical <strong>Oncology</strong> Center<br />
Federal Research and Clinical Center, FMBA<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
171P<br />
Transcriptomic stratification <strong>of</strong> breast carcinomas with<br />
double-equivocal HER2 status<br />
C. Marchio 1 , P. Dell’Orto 2 , L. Annaratone 1 , N. Rangel 1 , A. Özgüzer 3 , L. Verdun Di<br />
Cantogno 4 , A. Sapino 3 , G. Viale 2<br />
1 Department <strong>of</strong> Medical Sciences, Università degli Studi di Torino, Turin, Italy,<br />
2 Pathology, University <strong>of</strong> Milan, European Institute <strong>of</strong> <strong>Oncology</strong>, Milan, Italy,<br />
3 Pathology Unit, Istituto di Candiolo-IRCCS-Fondazione Piemontese per la Ricerca<br />
sul Cancro-Onlus, Candiolo, Italy, 4 Pathology Unit, Città della Saluta e della<br />
Scienza - Torino, Turin, Italy<br />
Background: The evaluation <strong>of</strong> HER2 overexpression and amplification in breast<br />
cancer (BC) provides a validated predictor <strong>of</strong> response to anti-HER2 agents. However,<br />
the algorithm based on immunohistochemistry (IHC) and in situ hybridization (ISH)<br />
still identifies a category <strong>of</strong> carcinomas that remain equivocal after ISH testing (“double<br />
equivocal” carcinomas). These carcinomas represent a real challenge for oncologists,<br />
who have to face the dilemma “to treat or not to treat”. The ASCO/CAP guidelines<br />
stress the need for data defining their biology and clinical behavior. Our aim was to<br />
stratify double-equivocal BCs by using transcriptomics.<br />
Methods: We retrieved a series <strong>of</strong> 28 formalin fixed paraffin embedded<br />
double-equivocal BCs, i.e. showing HER2/CEP17 ratio < 2 and HER2 copy number 4-6<br />
according to the ASCO/CAP 2013 guidelines. RNA was extracted following<br />
mesodissection and subjected to Prosigna assay (nCounter/Nanostring technology),<br />
which assigns the molecular subgroup and provides a prediction <strong>of</strong> risk <strong>of</strong> recurrence<br />
(ROR).<br />
Results: All cases were estrogen receptor positive and 68% showed progesterone<br />
receptor expression in more than 20% <strong>of</strong> tumor cells. The large majority <strong>of</strong> double<br />
equivocal BCs were classified by Prosigna as pertaining to the Luminal B molecular<br />
subgroup (23/28, 82%); three cases (11%) were classified as Luminal A and two cases<br />
(7%) as HER2-enriched. These carcinomas frequently (23/28, 82%) showed a high risk<br />
<strong>of</strong> recurrence (ROR) even when the analysis was restricted to node negative BCs<br />
showing a tumor size
abstracts<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
the most prevalent cancer in female population, which would combine<br />
non-invasiveness with high-precision performance. Since mammary glands do not<br />
produce any specific molecular markers, we studied several molecular biomarkers that<br />
are involved in immunoregulation. One <strong>of</strong> such molecules are caspases, a family <strong>of</strong><br />
intracellular enzymes that can play protective role in tumorigenesis by inducing<br />
apoptotic cell death in lymphocytes.<br />
Methods: Activity <strong>of</strong> aspases-3, -6, -8, and -9 was assessed in the peripheral blood<br />
lymphocytes in patients at different breast cancer stage <strong>of</strong> breast benign disease (BBD)<br />
and healthy controls. The caspase activity was measured using fluorogenic substrate<br />
while cellular apoptosis was evaluated by means <strong>of</strong> cyt<strong>of</strong>luorometric assay. In addition,<br />
the ratio <strong>of</strong> T-cell subsets was compared using antibodies to CD3, CD4, CD8, CD16,<br />
CD20, CD25, CD95 antigens. Discriminant function analysis and artificial neuronal<br />
networks (ANNs) method were used to create test-system.<br />
Results: We obtained statistically significant data in all groups <strong>of</strong> 138 analyzed samples.<br />
Discriminant analysis revealed significance for all 11 biomarkers. Using the<br />
biomarkers, we were able to differentiate correctly 100% <strong>of</strong> cases without pathology,<br />
87% – BBD, I breast cancer stage – 90%, II stage – 100% and III stage – 100%. By<br />
introducing permutation in expanded to 3464 samples size, we were able to increase<br />
the sensitivity <strong>of</strong> the test system that is 100% control samples, 97% – BDD, 92% - stage<br />
I <strong>of</strong> breast cancer, 99% - stage II, 100% - stage III. On the basis <strong>of</strong> ANNs analysis<br />
s<strong>of</strong>tware was developed in R-statistics. Network produced 100% correct result both on<br />
the original selection and on the artificially increased.<br />
Conclusions: Studies have shown that combining <strong>of</strong> biomarkers with the used<br />
algorithms can be successfully used to differentiate pathological blood from controls,<br />
classify breast cancer by the stage and separate benign and malignancy breast tumors.<br />
Further, the diagnostic system must be blindly tested with new clinical data.<br />
Legal entity responsible for the study: Petrozavodsk State University<br />
Funding: The Ministry <strong>of</strong> Education and Science <strong>of</strong> Russia, grant No 2014/154 – 1713.<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
173P<br />
Expression <strong>of</strong> androgen receptors in primary breast cancer<br />
A. Ghannam 1 , S. Galal 2 , M. Ellity 2<br />
1 Clinical <strong>Oncology</strong> Department, Tanta University-Faculty <strong>of</strong> Medicine, Tanta,<br />
Egypt, 2 Pathology, Tanta University Hospital, Tanta, Egypt<br />
Background: The objective <strong>of</strong> the study was to evaluate the prognostic effect <strong>of</strong><br />
androgen receptor (AR) in breast cancers.<br />
Methods: We investigated immunohistochemical AR expression from paraffin blocks<br />
<strong>of</strong> one hundred patients between 2007 and 2011, and analyzed demographics and<br />
outcomes using univariet analyses. Tumors with ≥10% nuclear-stained cells were<br />
considered positive for AR.<br />
Results: AR was expressed in 62% <strong>of</strong> patients. AR was significantly related to older age<br />
at diagnosis, smaller tumor size, histological type, higher positivity <strong>of</strong> hormone<br />
receptors and the administration <strong>of</strong> systemic treatment. In estrogen receptor<br />
(ER)-negative tumors, AR was distinctively associated with histological type and<br />
progesterone receptors unexpression. With a mean follow-up <strong>of</strong> 35.72 months, AR<br />
expression was a significant prognostic factor for DFS and OS in all patients. The<br />
3-year DFS and OS <strong>of</strong> patients with AR-positive tumor were 87.1% and 90.73%,<br />
respectively. The 3-year DFS and OS <strong>of</strong> those with AR-negative tumor were 66.32%<br />
and 84.21%, respectively. AR expression was positively associated with survival<br />
outcomes in all patients.<br />
Conclusions: AR is significantly associated with favorable features in breast cancers<br />
and related to better outcomes in ER-positive not in ER-negative tumors. These results<br />
suggest that AR could be an additional marker for endocrine responsiveness in<br />
ER-positive tumors and a candidate for therapeutic targeting <strong>of</strong> ER-negative tumors.<br />
Legal entity responsible for the study: Tanta University<br />
Funding: Tanta Facultiy <strong>of</strong> Medicine<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
174P<br />
Immunohistochemical status <strong>of</strong> p53 as prognostic factor in<br />
patients with node negative triple-negative breast cancer<br />
S.Y. Bae, J.E. Lee, S.K. Lee, S.J. Nam<br />
Department <strong>of</strong> Surgery, Samsung Medical Center Sungkyunkwan University<br />
School <strong>of</strong> Medicine, Seoul, Republic <strong>of</strong> Korea<br />
Background: TP53 mutations are the most common genomic alteration in TNBC,<br />
translation <strong>of</strong> p53 into the clinical setting is particularly pertinent in TNBC, with p53<br />
mutations reported in over 60–88% <strong>of</strong> TNBC or BLBCs, compared with only 13–26%<br />
<strong>of</strong> luminal breast cancers. However, despite the high incidence <strong>of</strong> genetic alterations in<br />
breast cancer, there is no consensus about the clinical application <strong>of</strong> p53 to<br />
management breast cancer.<br />
Methods: We retrospectively reviewed the clinicopathologic records <strong>of</strong> patients<br />
diagnosed with surgically treated invasive breast cancer at Samsung Medical Center<br />
between Jan. 2003 and Apr. 2013. During these periods, 7739 patients with complete<br />
pathologic data, including tumor size, nuclear grade, multiple tumors, the presence <strong>of</strong><br />
lymphovascular invasion (LVI), TNM stage, and the expression <strong>of</strong> estrogen receptor<br />
(ER), progesterone receptor (PR) and HER2, Ki-67 and p53 were included in the<br />
analysis.<br />
Results: Median follow-up duration <strong>of</strong> patients was 57 months (4-140 months).<br />
Median age <strong>of</strong> patients was 48 years (21-78 years) Of total 1129 patients, 732 patients<br />
(64.8%) had no LN metastasis and 397 patients had LN metastasis. In TNBC patients<br />
without LN metastasis, p53+ tumors had shown higher nuclear grade than p53-<br />
tumors (87.2% vs.81.5%, P = 0.034). And, p53+ tumors had shown higher EGFR<br />
expression than p53- tumors (90.7% vs. 84.8%, P = 0.039). With multivariate analysis,<br />
p53 expression (p53+) had shown significantly better OS than patients without p53<br />
expression (p53-) (p53+ VS. p53-; HR 2.8, 95% confidence interval: 1.1-7.1, P = 0.022)<br />
. However, in patients with LN metastasis, p53+ expression was not associated with<br />
DFS, However, in TNBC patients with LN metastasis, there was no difference <strong>of</strong><br />
clinicopathologic characteristics between p53+ tumors and p53- tumors. And, there<br />
was no association with survival, neither DFS nor OS.<br />
Conclusions: Conclusively, in TNBC, p53 expression was associated with better OS in<br />
patients with node-negative, not in patients with node-metastasis. These results suggest<br />
that p53 expression could be a favorable prognostic factor in early TNBC.<br />
Legal entity responsible for the study: N/A<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
175P<br />
First prospective multicenter Italian study on the impact <strong>of</strong> the<br />
21-gene recurrence score® (RS) in adjuvant clinical decisions<br />
for ER + /HER2- early breast cancer patients<br />
M.V. Dieci 1 , V. Guarneri 1 , M. Mion 2 , G. Tortora 3 , P. Morandi 4 , S. Gori 5 , L. Merlini 6 ,<br />
C. Oliani 7 , F. Pasini 8 , G. Bonciarelli 9 , E. Orvieto 10 , P. Del Bianco 11 , G.L. De Salvo 11 ,<br />
P.F. Conte 1<br />
1 Department <strong>of</strong> Surgery, <strong>Oncology</strong> and Gastroenterology, University <strong>of</strong> Padova,<br />
Istituto Oncologico Veneto IRCCS, Padua, Italy, 2 Medical <strong>Oncology</strong>, Ospedale<br />
Civile, Camposampiero, Italy, 3 Medical <strong>Oncology</strong>, AOU Integrata Verona "Borgo<br />
Roma", Verona, Italy, 4 <strong>Oncology</strong>, Ospedale dell’Angelo di Mestre, Venezia-Mestre,<br />
Italy, 5 Medical <strong>Oncology</strong> department, Ospedale S.Cuore, Negrar, Italy, 6 Medical<br />
<strong>Oncology</strong>, Ospedale San Bortolo, Vicenza, Italy, 7 Medical <strong>Oncology</strong>, Ospedale di<br />
Montecchio Maggiore, Montecchio Maggiore, Italy, 8 Medical <strong>Oncology</strong>, Ospedale<br />
S. Maria della Misericordia Azienda Sanitaria Local 18 Rovigo, Rovigo, Italy,<br />
9 Medical <strong>Oncology</strong>, Presidio Ospedaliero ULSS 17, Monselice (PD), Italy,<br />
10 Pathology, Azienda Ospedaliera di Padova Università, Padua, Italy, 11 UOS<br />
Sperimentazioni Cliniche, Biostatistica, Istituto Oncologico Veneto IRCCS, Padua,<br />
Italy<br />
Background: The Breast-DX Italy study evaluates the impact <strong>of</strong> the 21-gene RS on<br />
adjuvant clinical decisions in a prospective Italian cohort <strong>of</strong> early breast cancer<br />
patients.<br />
Methods: The study planned to enroll, in 9 centers <strong>of</strong> the Veneto Region, 250<br />
consecutive patients with ER + , HER2-, T1 to T3 early breast cancer and 0 to 3 positive<br />
axillary nodes. Patients met protocol-defined criteria for “intermediate risk” based on<br />
clinicopathological features. Pre-RS and post-RS physicians’ treatment<br />
recommendations and the type <strong>of</strong> therapy actually received by the patient were<br />
collected. Here, we present the results for the N0 patients cohort.<br />
Results: From November 2014 to February 2016, 124 N0 patients were enrolled (66%<br />
at hub and 34% at spoke centers). The majority had PgR-positive (89%), G2 (69%) and<br />
pT1c (69%) tumors. Median age was 56 years, median Ki67 was 23% (range 5-70%).<br />
The distribution <strong>of</strong> RS was: 30 (6%). Pre-RS physician’s<br />
recommendation was hormonal treatment (HT) without chemotherapy (CT) for 61%<br />
<strong>of</strong> the patients (similar in hub/spoke centers). The post-RS recommendation differed<br />
from the pre-RS recommendation for 15 patients (12%; 10/15 changed from CT + HT<br />
to HT). The received treatment differed from the pre-RS recommendation in 19 cases<br />
(15%; 16/19 changed from CT + HT to HT: 11 with low and 5 with intermediate RS).<br />
The change was more frequent in hub centers (Table 1). Overall, 13 CT treatments<br />
were spared, being 47 the patients with pre-RS indication to CT and 34 the patients<br />
who actually received it (McNemar’s p = 0.006). Physicians confirmed the RS provided<br />
additional information and influenced their decision in 63% and 32% <strong>of</strong> the cases,<br />
respectively.<br />
Change: Pre-RS<br />
recommendation to received<br />
treatment<br />
Table: 175P<br />
Hub centers<br />
(n = 2)<br />
Spoke<br />
centers<br />
(n = 7)<br />
No change; n (%) 67 (64%) 37 (36%) 104<br />
Any change; n (%) 15 (79%) 4 (21%) 19<br />
HT to CT + HT; n 2 1 3<br />
CT + HT to HT; n 13 3 16<br />
Total (n = 123;<br />
missing data: 1<br />
patient)<br />
Conclusions: Although a majority <strong>of</strong> patients had a pre-RS recommendation for HT<br />
alone, the use <strong>of</strong> the 21-gene RS further contributed in sparing CT administration,<br />
vi52 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
more so for patients enrolled at hub centers, decreasing the use <strong>of</strong> CT from 38% to 28%<br />
<strong>of</strong> patients.<br />
Legal entity responsible for the study: Istituto Oncologico Veneto IRCCS<br />
Funding: The sponsor <strong>of</strong> the study is the Istituto Oncologico Veneto IRCCS in Padua.<br />
The study was selected in the context <strong>of</strong> the Regione Veneto call “Chiamata –<br />
nell’ambito di collaborazioni pubblico-private – alla presentazione di progetti di<br />
ricerca, innovazione e formazione in sanità. Anno 2013”. A research grant by Genomic<br />
Health supported in part the study.<br />
Disclosure: M.V. Dieci: Consulting activity (Genomic Health). P.F. Conte: Research<br />
grant (Genomic Health). All other authors have declared no conflicts <strong>of</strong> interest.<br />
176P<br />
Famosa: Evaluation <strong>of</strong> a multigene panel in patients with<br />
suspected HBOC<br />
E. Adrover 1 , I. Esteban 2 , G. Llort 3 , S. Servitja 4 , S. Martinez Peralta 5 , I. Garau 6 ,J.<br />
M. Cano 7 , R. Serrano 8 , M.J. Juan Fita 9 , A. Casas 10 , B. Graña 11 , A. Teulé 12 ,<br />
A. Marquez 13 , J.E. Ales Martínez 14 , A. Antón 15 , J. Brunet 16 , F. Balaguer 17 ,<br />
S. Gonzalez 18 , J. Balmaña 2 , C. Alonso 19<br />
1 <strong>Oncology</strong> Department, Complejo Hospitalario Universitario de Albacete,<br />
Albacete, Spain, 2 <strong>Oncology</strong> Department, Vall d’Hebron University Hospital Institut<br />
d’Oncologia, Barcelona, Spain, 3 <strong>Oncology</strong> Department, Hospital de Sabadell<br />
Corporacis Parc Tauli, Sabadell, Spain, 4 <strong>Oncology</strong> Department, University Hospital<br />
del Mar, Barcelona, Spain, 5 <strong>Oncology</strong> Department, Hospital de Mataro Consorcio<br />
Sanitario del Maresme, Mataro, Spain, 6 <strong>Oncology</strong> Department, Hospital Son<br />
Llatzer, Palma de Mallorca, Spain, 7 <strong>Oncology</strong> Department, Hospital General<br />
Ciudad Real, Ciudad Real, Spain, 8 <strong>Oncology</strong> Department, University Hospital<br />
Reina S<strong>of</strong>ia, Cordoba, Spain, 9 <strong>Oncology</strong> Department, Fundación Instituto<br />
Valenciano de Oncología, Valencia, Spain, 10 <strong>Oncology</strong> Department, Hospital<br />
Universitario Virgen del Rocio, Sevilla, Spain, 11 <strong>Oncology</strong> Department, Hospital<br />
Abente y Lago, A Coruna, Spain, 12 <strong>Oncology</strong> Department, Institut Catala de<br />
Oncologia, L’Hospitalet de Llobregat, Barcelona, Spain, 13 <strong>Oncology</strong> Department,<br />
Hospital Universitario Virgen de la Victoria, Malaga, Spain, 14 <strong>Oncology</strong><br />
Department, Hospital Nuestra Señora de Sonsoles, Ávila, Spain, 15 <strong>Oncology</strong><br />
Department, Hospital Miguel Servet, Zaragoza, Spain, 16 <strong>Oncology</strong> Department,<br />
Catalan Institute <strong>of</strong> <strong>Oncology</strong> (ICO)-Hospital Universitari Josep Trueta, Girona,<br />
Spain, 17 Gastroenterology, Hospital Clinic y Provincial de Barcelona, Barcelona,<br />
Spain, 18 <strong>Oncology</strong> Department, Hospital San Pedro de Alcántara, Cáceres, Spain,<br />
19 <strong>Oncology</strong> Department, Hospital Universitario de La Princesa, Madrid, Spain<br />
Background: Objectives: Characterize 1) the frequency <strong>of</strong> mutations in patients with<br />
clinical criteria for HBOC using a 25-gene panel in a Spanish population (FAMOSA<br />
study). 2) The psychological impact <strong>of</strong> these tests and patient’s counseling preferences.<br />
Methods: Patients with breast or ovarian cancer who met the NCCN criteria for<br />
genetic testing with a) prior testing for BRCA genes with NO mutation identified; or b)<br />
recently diagnosed (90% <strong>of</strong> physicians indicating that it<br />
influenced their treatment decision. The total budget impact <strong>of</strong> usage <strong>of</strong> the 21-gene<br />
assay in the Czech Republic is expected to be almost $282,851 per year in 2020, with<br />
part <strong>of</strong> the assay reimbursement cost compensated for by reduced CT usage. Further<br />
health economic studies are warranted to evaluate cost effectiveness.<br />
Legal entity responsible for the study: Masaryk Memorial Cancer Institute, Brno,<br />
Czech Republic<br />
Funding: Masaryk Memorial Cancer Institute<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
178P<br />
abstracts<br />
Assessment <strong>of</strong> the prognostic role <strong>of</strong> a 94-single nucleotide<br />
polymorphisms risk score in early breast cancer in the<br />
SIGNAL/PHARE prospective cohort: no correlation with<br />
clinico-pathological characteristics and outcomes<br />
E. Curtit 1 , X. Pivot 1 , J. Henriques 1 , S. Paget-Bailly 1 , P. Fumoleau 2 , M. Rios 3 ,<br />
H. Bonnefoi 4 , P. Soulie 5 , C. Jouannaud 6 , H. Bourgeois 7 , J-Y. Pierga 8 , I. Tennevet 9 ,<br />
V. Trillet-Lenoir 10 , P. Kerbrat 11 , T. Petit 12 , T. Bachelot 13 , J-F. Deleuze 14 ,<br />
I. Pauporte 15 , G. Romieu 16 ,D.Cox 17<br />
1 <strong>Oncology</strong>, CHU Besançon, Hôpital Jean Minjoz, Besançon, France, 2 <strong>Oncology</strong>,<br />
Centre Georges-François Leclerc (Dijon), Dijon, France, 3 <strong>Oncology</strong>, Institut de<br />
Cancérologie de Lorraine - Alexis Vautrin, Vandoeuvre Les Nancy, France,<br />
4 <strong>Oncology</strong>, Institute Bergonié, Bordeaux, France, 5 <strong>Oncology</strong>, Centre Paul Papin,<br />
Angers, France, 6 <strong>Oncology</strong>, Institut Jean Godinot, Reims, France, 7 <strong>Oncology</strong>,<br />
Clinique Victor Hugo Le Mans, Le Mans, France, 8 Medical <strong>Oncology</strong>, Institut Curie,<br />
Paris, France, 9 <strong>Oncology</strong>, Centre Henri Becquerel, Rouen, France, 10 <strong>Oncology</strong>,<br />
Centre Hospitalier Lyon Sud, Lyon, France, 11 <strong>Oncology</strong>, Centre Eugene - Marquis,<br />
Rennes, France, 12 <strong>Oncology</strong>, Centre Paul Strauss Centre de Lutte Contre le<br />
Cancer, Strasbourg, France, 13 <strong>Oncology</strong>, Centre Léon Bérard, Lyon, France,<br />
14 CEPH, CEPH, Paris, France, 15 Research, Institut National du Cancer,<br />
Boulogne-Billancourt, France, 16 <strong>Oncology</strong>, ICM, Montpellier, France, 17 SCL -<br />
INSERM, Centre Léon Bérard, Lyon, France<br />
Background: Genome Wide Association Studies (GWAS) have to date identified 94<br />
genetic variants (Single Nucleotide Polymorphisms – SNPs) associated with risk <strong>of</strong><br />
developing breast cancer. A score based on the combined effect <strong>of</strong> the 94 risk alleles can<br />
be calculated to measure the global risk <strong>of</strong> breast cancer. We aimed to test the<br />
hypothesis that the 94-SNP-based risk score is associated with clinico-pathological<br />
characteristics, breast cancer subtypes and outcomes in early breast cancer.<br />
Methods: A 94-SNP risk score was calculated in 8703 patients in the PHARE and<br />
SIGNAL prospective case-cohort. Clinical data and outcomes were prospectively<br />
registered. Genotyping was obtained from a GWAS study. A two-staged genotyping<br />
strategy was carried out.<br />
Results: The median 94-SNP risk score in 8703 breast cancer patients with early breast<br />
cancer was 77.5 (ranges: 58.1 – 97.6). The risk score was not associated with usual<br />
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abstracts<br />
prognostic and predictive factors (age, TNM status, Scarff-Bloom-Richardson grade,<br />
inflammatory feature, estrogen receptor status, progesterone receptor status, HER2<br />
status) and did not correlate with breast cancer subtypes. 94-SNP risk score did not<br />
predict outcomes represented by overall survival and disease free survival.<br />
Conclusions: In a prospective cohort <strong>of</strong> 8703 patients, a risk score based on 94 SNPs<br />
was not associated with breast cancer characteristics, cancer subtypes or patient’s<br />
outcomes. If we hypothesize that prognosis and subtypes <strong>of</strong> breast cancer are<br />
determined by constitutive genetic factors, variants associated with breast cancer<br />
subtypes and prognosis should be different from variants involved in the risk <strong>of</strong><br />
developing a breast cancer.<br />
Clinical trial identification: SIGNAL / PHARE (NCT00381901 – RECF1098).<br />
Legal entity responsible for the study: Xavier Pivot - Institut National du Cancer -<br />
France<br />
Funding: INCa<br />
Disclosure: X. Pivot: XP received honorarium from Roche, Eisai. All other authors<br />
have declared no conflicts <strong>of</strong> interest.<br />
179P<br />
A nomogram for predicting the Oncotype DX recurrence score<br />
in women with T1-3N0-1miM0 hormone receptor-positive,<br />
human epidermal growth factor-2 (HER2)-negative breast<br />
cancer<br />
S. Lee<br />
Surgery, Asan Medical Center, University <strong>of</strong> Ulsan College <strong>of</strong> Medicine, Seoul,<br />
Republic <strong>of</strong> Korea<br />
Background: The aims <strong>of</strong> this preliminary study were to evaluate the association<br />
between the Oncotype DX (ODX) recurrence scores and traditional prognostic factors<br />
and to develop a nomogram that predict a subgroup <strong>of</strong> patients with low ODX<br />
recurrence scores (≤25), in whom addition <strong>of</strong> chemotherapy can be avoided.<br />
Methods: Clinicopathological and immunohistochemical variables from a series <strong>of</strong> 396<br />
T1-3N0-1miM0 hormone receptor-positive, human epidermal growth factor-2<br />
(HER2)-negative breast cancer patients with available ODX test results at Asan Medical<br />
Center from 2010 to 2015 were retrospectively retrieved and analyzed. One hundred<br />
eight (27%) had positive axillary lymph node micrometastases, and 333 (84%) had<br />
ODX recurrence scores <strong>of</strong> ≤25. Logistic regression was performed to build a<br />
nomogram for predicting a low-risk subgroup <strong>of</strong> the ODX assay. The cut<strong>of</strong>f value <strong>of</strong><br />
ODX recurrence scores for the low-risk subgroup was set at 25, which is used in the<br />
ongoing Oncotype DX phase 3 TAILORx trial.<br />
Results: Multivariate analysis revealed that estrogen receptor (ER) score, progesterone<br />
receptor (PR) score, lymphovascular invasion (LVI), nuclear grade, and Ki-67 had<br />
statistically significant association with the low-risk subgroup (all p values < 0.001).<br />
With these variables, we developed a nomogram to predict the low-risk subgroup with<br />
the ODX recurrence scores <strong>of</strong> ≤25. The area under the ROC curve was 0.90 (95% CI,<br />
0.85-0.96).<br />
Conclusions: Low ODX recurrence score subgroup can be predicted by a nomogram<br />
incorporating five traditional prognostic factors: ER, PR, LVI, nuclear grade, and Ki-67.<br />
An independent prospective validation for the present nomogram is underway to<br />
confirm its accuracy.<br />
Legal entity responsible for the study: Saebyul Lee<br />
Funding: Asan Medical Center<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
180P<br />
Use <strong>of</strong> Oncotype DX Recurrence Score® (RS) reduces<br />
chemotherapy (CT) beyond treatment decisions using<br />
Ki67-based determinations <strong>of</strong> luminal A and B breast cancer<br />
subtypes: a retrospective study in the Spanish population<br />
L. Garcia-Estevez, E. Hernandez, D. Acosta, F. Lopez-Rios, M. Prieto Pozuelo,<br />
I. Calvo<br />
Medical <strong>Oncology</strong> Service, Hospital Madrid Norte San Chinarro Centro Integral<br />
Oncologico Clara Campal, Madrid, Spain<br />
Background: St Gallen guidelines recommend the use <strong>of</strong> Ki67 by IHC as a surrogate<br />
marker for luminal A and B breast cancer (BC) subtypes, such that patients (pts) with<br />
luminal B (≥ 14%) subtypes should be considered for adjuvant CT. Oncotype DX RS is<br />
a predictor <strong>of</strong> CT benefit. The aim <strong>of</strong> this study is to assess the distribution <strong>of</strong> the RS in<br />
luminal A and B BC subtypes as defined by Ki67 and to assess treatment changes based<br />
on RS.<br />
Methods: Data were collected from 210 pts with invasive breast cancer for which<br />
Oncotype DX results and pathology data were available. Estrogen (ER) and<br />
progesterone (PR) receptor was assessed by immunostaining (cut-<strong>of</strong>f 10% nuclear<br />
staining). Ki67 was assessed by IHC [high (≥14%) and low (
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Methods: We examined 76 patients (75 women and one man) with BBC, 52<br />
concurrent and 24 metachronous. Paraffin tumors (n = 155) with informative targeted<br />
NGS data were histologically reviewed and subtyped with immunohistochemistry<br />
(IHC). In a patient subset, peripheral blood genotypes were obtained with the same<br />
panel and/or upon testing for cancer predisposing genes (germline testing). We<br />
analyzed coding mutations (amino acid changing, minor allele frequency 2-5 cm in<br />
45% and >5cm in 8%. Tumors were grade 1 in 22%, grade 2 in 58% and grade 3 in 20%.<br />
RS was low ( 0.05 respectively).<br />
Conclusions: The level <strong>of</strong> expression <strong>of</strong> HER2 determined by IHC ( ++ with<br />
positive-FISH versus +++) did not impact OS and DFS <strong>of</strong> patients in HER2-positive<br />
early breast cancer treated by trastuzumab.<br />
Clinical trial identification: NCT00381901 – RECF1098<br />
Legal entity responsible for the study: INCa: Institut National du cancer (France)<br />
Funding: INCa<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
185P<br />
abstracts<br />
Younger age as a prognostic indicator in breast cancer:<br />
Correlation between clinical-pathologic factors and miRNAs<br />
and long-term follow-up<br />
M.T.M. Martinez 1 , M. PeÑa-Chilet 1 , S.S. Oltra 1 , J.A. Perez-Fidalgo 1 , E. Alonso 2 ,<br />
O. Burgues 2 , I. Chirivella Gonzalez 1 , B. Bermejo 1 , A. Lluch-Hernandez 1 , G. Ribas 1<br />
1 Departamento de hematologia y Oncologia medica, Hospital Clinico Universitario<br />
de Valencia, Valencia, Spain, 2 Pathology Unit, Hospital Clinico Universitario de<br />
Valencia, Valencia, Spain<br />
Background: Breast cancer (BC) in very young patients (≤ 35 years) (BCVY) is an<br />
uncommon disease and when it occurs it usually has aggressive biological<br />
characteristics. The objective <strong>of</strong> this study was to evaluate the relevance <strong>of</strong><br />
clinical-pathologic factors and prognosis in BCVY cancer patients versus a cohort <strong>of</strong><br />
older counterparts.<br />
Methods: 258 patients (Group I) diagnosed <strong>of</strong> BCVY retrospectively analyzed in our<br />
hospital between 1998 to 2014 and relate to 101 patients over 45 years with BC (Group<br />
II). All data related to clinical, pathological features were obtained from medical<br />
records, and we used chi-squared to compare them. In addition, we correlate any<br />
clinic-pathological factors with the expression <strong>of</strong> miRNAs (previously published by<br />
our group Peña-chilet et al. 2014).<br />
Results: T stage, histological grade, c-erbB2 expression and ER status did not differ<br />
significantly between the two age groups. BVCY patients had a greater probability <strong>of</strong><br />
recurrence and death at all periods (45% have presented a relapse <strong>of</strong> BC compared to<br />
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<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
21% <strong>of</strong> group II). The BCVY group showed worse prognosis among lymph<br />
node-positive patients (p= 0.02). The status <strong>of</strong> lymph nodes post-surgery seems to be<br />
the only factor related to BCVY patients. In group I, we objectify also a statistically<br />
significant relationship between axillary involvement, IHQ HER2 positive subtype and<br />
disease relapse (p = 0.03). We also observed a lower time between diagnosis and first<br />
relapse with a more likelihood to die from the disease to BCVY (p = 0.002). Finally,<br />
from our panel <strong>of</strong> deregulated miRNAs (miR-30c, miR-125a, miR-17, miR-92b,<br />
miR-139 and miR-663) we are able to associate repressed miR-30 with more aggressive<br />
BCVY with lower overall survival and with axillary metastases.<br />
Conclusions: Patient age and axillary lymph nodes post-surgery are the independent<br />
and significant predictors <strong>of</strong> distant disease-free survival, local recurrence-free survival,<br />
and overall survival. HER2 subtype and repressed miR-30 relates to poor prognosis in<br />
lymph node-positive young patients. The risk factor grouping provides a useful index<br />
to evaluate the risk <strong>of</strong> BCVY to identify subgroups <strong>of</strong> patients with better prognosis.<br />
Legal entity responsible for the study: N/A<br />
Funding: INCLIVA<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
186P<br />
P53 and ERCC1 gene polymorphisms can predict the<br />
recurence risk <strong>of</strong> breast cancer<br />
T. Kus, G. Aktas, M.E. Kalender, A. Sevinc, C. Camci<br />
Medical <strong>Oncology</strong>, University <strong>of</strong> Gaziantep, Kilis way <strong>Oncology</strong> Hospital,<br />
Gaziantep, Turkey<br />
Background: Genetic variations, molecular and histopathological features, age and<br />
stage predict the recurrence risk <strong>of</strong> breast cancer patients. Gene polymorphisms<br />
encoding the enzymes involved in transport and metabolism <strong>of</strong> drugs, DNA repair or<br />
drug pharmacodynamics may predict the treatment response or chemotherapy<br />
resistence. In this context, we aimed to investigate the association <strong>of</strong> single nucleotide<br />
polymoprhisms in NQO1, CYP3A4, ERCC1, ERCC2, FGFR4, TP53, ERBB2, ABCB1<br />
and 5-years reccurent rate.<br />
Methods: Operated breast cancer patients followed in Gaziantep University <strong>Oncology</strong><br />
Hospital between June 2004 and June 2011 were analyzed retrospectively.<br />
Clinicopathologic variables and administered treatment schemes were noted. Blood<br />
samples were taken and genomic DNA was extracted. ’’ Genotyping the Fluidigm<br />
Digital Array’’ was performed and ’’genomic DNA a 96.96 dynamic array on the<br />
BioMark HD system’’ was used for evaluation. Relations <strong>of</strong> these parameters with<br />
5-year recurrence risk were analyzed with univariate and multivariate regression<br />
models.<br />
Results: 286 patients were included in this study. According to tumor size, recurrence<br />
rates <strong>of</strong> T1/T2/T3 and T4 patients were 17.1%/17.2%/34.5% and 18.2% respectively<br />
(p = 0.045). According to lymph node status, recurrence rates <strong>of</strong> N0/N1/N2 and N3<br />
patients were 12%/13.4%/32.6% and 51.4% respectively (p < 0.001). The relation <strong>of</strong><br />
tumor size (T), Her-2 status, p53 and ABCB1 gene mutations with recurrence in<br />
patients with node positive disease was evaluated in multivariate analysis. Accordingly,<br />
both P53 (p= 0.021) and ERCC1 genes (p = 0.027) was found to be related with<br />
recurrence risk.<br />
Table: 186P Gene polymorphisms<br />
Gene N SNP Genotype P value OR; 95%Cl<br />
CYP3A4* 261 rs2740574 GG vs AA and AG 0.239 1.515; 0.567- 4.052<br />
NQO1 280 rs1800566 AA vs. AG andGG 0.731 0.696; 0.328-1.474<br />
ABCB1* 255 rs1045642 CC and CT vs TT 0.916 0.958; 0.426-2.152<br />
ERCC1 272 rs3212935 AA and AG vs GG 0.031 3.630; 1.051-12.537<br />
ERCC2 212 rs13181 AA vs AC and CC 0.708 1.184; 0.490-2.864<br />
ERBB2** 61 rs1136201 AA vs AG and GG 0.025 4.278; 1.147-15.952<br />
P53 239 rs1042522 CC vs. GC and GG 0.040 2.573; 1.022-6.475<br />
FDGFR 247 rs351855 AA vs AG and GG 0.342 0.696; 0.328-1.474<br />
* Only for the patients who received antracycline and taxane based treatment. ** Only<br />
for the patients who received anti Her-2 treatment. SNP: single nucleotide<br />
polymorphism, OR: odds ratio<br />
Conclusions: ERCC1 and p53 genes can predict the 5-year recurrence risk <strong>of</strong> lymph<br />
node positive breast cancer patients.<br />
Legal entity responsible for the study: Tulay Kus<br />
Funding: None<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
187P<br />
Luminal androgen receptor role and pathological complete<br />
response rate to neoadjuvant chemotherapy in triple negative<br />
breast cancer<br />
M.R. Chica-Parrado 1 , A. Santonja 1 , A. Lluch-Hernandez 2 , J. Albanell 3 ,<br />
A. Sanchez-Muñoz 1 , I. Chacón 4 , L. Calvo 5 , P. Sanchez-Rovira 6 , J. De la Haba 7 ,<br />
L. Vicioso 1 , M. Martin 4 , A. Plazaola 8 ,A.Prat 4 , N. Ribelles 1 , M. Sánchez-Aragó 4 ,J.<br />
M. Jerez 1 , M.J. Escudero 4 , R. Caballero 4 , E. Carrasco 7 , E. Alba Conejo 1<br />
1 Translational oncology, Biomedical Research Institute <strong>of</strong> Malaga (IBIMA), Malaga,<br />
Spain, 2 Serv. Hematologia Y Oncologia Medica, Hospital Clinico Universitario de<br />
Valencia, Valencia, Spain, 3 Cancer Research Program, Institut Hospital del Mar<br />
d’Investigacions Mèdiques (IMIM), Barcelona, Spain, 4 Translational Research,<br />
GEICAM (Spanish Breast Cancer Research Group), Madrid, Spain, 5 Medical<br />
<strong>Oncology</strong>, University Hospital Complex <strong>of</strong> A Coruña, A Coruna, Spain, 6 Medical<br />
<strong>Oncology</strong>, Complejo Hospitalario de Jaen Universidad de Jaen, Jaen, Spain,<br />
7 GEICAM (Spanish Breast Cancer Research Group), Madrid, Spain, 8 Medical<br />
<strong>Oncology</strong> Dept., Onkologikoa-Kutxaren Instituto Onkologikoa, San Sebastian,<br />
Spain<br />
Background: Triple negative breast cancer (TNBC) is a heterogeneous disease with<br />
distinct molecular subtypes. A luminal androgen receptor subgroup dependent on AR<br />
expression has been recently defined in a gene-expression study by Lehmann et al. We<br />
aimed to explore the clinical relevance <strong>of</strong> this AR dependent subtype in TNBC<br />
determining differences in response to neoadjuvant chemotherapy.<br />
Methods: In a population <strong>of</strong> 116 patients (39 [34%] from GEICAM/2006-03 trial)<br />
treated with neoadjuvant anthracyclines and taxanes + /-carboplatin, tumor DNA was<br />
obtained from FFPE pre-treatment tumor biopsies. Lehmann subtypes were<br />
determined by gene expression pr<strong>of</strong>iling with HTA2.0 arrays (Illumina) and the<br />
classification tool TNBCtype. Breast cancer intrinsic subtypes according to PAM50 test<br />
were also determined with an nCounter Analysis System (Nanostring Technologies).<br />
The association <strong>of</strong> the different subtypes with pathologic complete response (pCR) was<br />
explored using Fisher’s exact test and logistic regression.<br />
Results: The global rate pCR <strong>of</strong> TNBC patients was 38.8%, and it was unevenly<br />
distributed within Lehmann’s subtypes. Basal-like subtypes had the highest rates<br />
(BL1 = 53%, BL2 = 46%) and the luminal-androgen receptor (LAR) the lowest (14%).<br />
As it has been previously described that MSL is enriched in normal tissue, we<br />
performed this analysis with and without MSL subgroup, obtaining a significant<br />
association between LAR subtypes and pCR when MSL was excluded (p = 0.35 and<br />
p = 0.045, respectively). Most patients were classified as basal-like according to PAM50<br />
except those included in LAR subtype that were also HER2-enriched (33.3%) and<br />
Luminal A (11.1%).<br />
Conclusions: Our results suggest that there is a high genetic diversity within TNBC,<br />
mainly due to a luminal androgen receptor subtype that includes an elevated<br />
percentage <strong>of</strong> non-basal-like tumors. The LAR subtype is associated with a lower rate<br />
<strong>of</strong> pCR probably because almost half <strong>of</strong> them don’t have basal-like characteristics<br />
(HER2 without anti-HER2 therapy and Luminal). Taking into account this specific<br />
subtype it could be necessary to use a new TNBC classification.<br />
Legal entity responsible for the study: FIMABIS-GEICAM<br />
Funding: FIMABIS<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
188P<br />
Intrinsic subtype and response to neoadjuvant chemotherapy<br />
with carboplatin and docetaxel (TCb) in triple-negative breast<br />
cancer (TNBC)<br />
I. Echavarria Diaz-Guardamino 1 , S. Lopez-Tarruella 2 , J.A. García-Sáenz 3 ,H.<br />
Gomez Moreno 4 , F. Moreno 3 , Y. Jerez 2 , H. Fuentes 4 , I. Marquez-Rodas 2 ,<br />
M. Cebollero 5 , M. Del Monte-Millan 2 , A. Picornell 2 , T. Massarrah 1 , A. Barnadas 6 ,<br />
A. Prat 7 , A. Ballesteros García 8 , R. Colomer Bosch 8 , B. Pelaez 9 ,<br />
M. González-Rivera 2 , C.M. Perou 10 , M. Martin 2<br />
1 Medical <strong>Oncology</strong>, Hospital General Universitario Gregorio Marañon, Madrid,<br />
Spain, 2 Medical <strong>Oncology</strong>, Instituto de Investigación Sanitaria Gregorio Marañón<br />
(IiSGM), Madrid, Spain, 3 Medical <strong>Oncology</strong>, Hospital Clinico Universitario San<br />
Carlos, Madrid, Spain, 4 Medicina Oncologica, Instituto Nacional de Enfermedades<br />
Neoplasicas - INEN, Lima, Peru, 5 Pathology, Hospital General Universitario<br />
Gregorio Marañon, Madrid, Spain, 6 Medical <strong>Oncology</strong>, Hospital de la Santa Creu i<br />
Sant Pau, Barcelona, Spain, 7 Medical <strong>Oncology</strong>, Vall d’Hebron Institute <strong>of</strong><br />
<strong>Oncology</strong> (VHIO),, Barcelona, Spain, 8 Medical <strong>Oncology</strong>, Hospital Universitario de<br />
La Princesa, Madrid, Spain, 9 Medical <strong>Oncology</strong>, Hospital clinico de Valladolid,<br />
Valladolid, Spain, 10 Department <strong>of</strong> Genetics, Lineberger Comprehensive Cancer<br />
Center University <strong>of</strong> North Carolina, Chapel Hill, NC, USA<br />
Background: Triple-negative breast cancer (TNBC), while sensitive to chemotherapy,<br />
remains a challenge due to its differential response to treatment and poor prognosis. In<br />
a population <strong>of</strong> TNBC patients treated with NACT with docetaxel plus carboplatin<br />
(TCb), we evaluated the predictive value <strong>of</strong> the intrinsic subtype by PAM50.<br />
Methods: Pathological response was defined by RCB (residual cancer burden) method,<br />
with pathological complete response (pCR) considered as lack <strong>of</strong> invasive tumor in<br />
breast plus axilla (ypT0/isypN0). Intrinsic subtype was determined by PAM50 gene<br />
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expression assay using the nCounter platform (nanoString Technologies Inc; Seattle,<br />
USA). Association between RCB and subtypes was assessed on R s<strong>of</strong>tware.<br />
Results: 121 consecutive patients received NACT with TCb in a prospective<br />
multicenter trial, 95 were available for the PAM50 analysis. Overall, the distribution <strong>of</strong><br />
responses was: pCR 44%, class I 13%, class II 31%, and class III 14%. The majority <strong>of</strong><br />
the tumors were basal-like (BL) (83%), followed by HER2E (13%), normal-like (3%)<br />
and luminal B (1%). A clear difference between the intrinsic subtypes with regard to<br />
RCB distribution was found (p = 0.009, Table 1). BL tumors had a significantly better<br />
response to TCb: 51 % achieved pCRvs 13% <strong>of</strong> non-BL tumors (p = 0.0055).<br />
Multivariate analyses including tumor size and nodal status confirmed the significance<br />
<strong>of</strong> intrinsic subtype for the prediction <strong>of</strong> response. Concordantly, resistance to TCb was<br />
more frequent in non-BL tumors (38% RCB-II, 31% RCB-III) as compared to BL (29 %<br />
and 10%).<br />
Table: 188P RCB distribution across subtypes (Symmans et al, JCO<br />
2007)<br />
% All (n = 95) Basal-like (n = 79) Non-Basal (n = 16)<br />
pCR 44.2 50.6 12.5<br />
RCB I 11.6 10.1 18.8<br />
RCB II 30.5 29.1 37.5<br />
RCB III 13.7 10.1 31.2<br />
Conclusions: TCb was shown to be an effective NACT regimen for TNBC with a pCR<br />
rate <strong>of</strong> 44%. Intrinsic subtype by PAM50 helps predict response to NACT with TCb,<br />
with BL TNBC associated with significant better outcomes as compared to non-BL<br />
TNBC (pCR rates <strong>of</strong> 51 % vs 13% respectively, p 0.0051), although better predictors <strong>of</strong><br />
response are still needed.<br />
Clinical trial identification: NCT01560663<br />
Legal entity responsible for the study: Instituto de Investigacion Sanitaria Gregorio<br />
Marañon, Universidad Complutense, Madrid<br />
Funding: This work was partially supported by the Ministry <strong>of</strong> Economy and<br />
Competitiveness ISCIII-FIS grants PI12/02684, and RD12/0036/0076, co-financed by<br />
ERDF (FEDER) Funds from the European Commission, “A way <strong>of</strong> making Europe”.<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
189P<br />
Breast cancer prognosis after neoadjuvant chemotherapy for<br />
breast cancers: molecular downstaging, proliferation, and<br />
endocrine sensitivity importance<br />
M-A. Benderra 1 , S. Richard 1 , M. Antoine 2 , D. Buob 2 , S. Zilberman 3 , A. Esteso 1 ,J.<br />
P. Lotz 1 , K. Kerrou 4 , J. Gligorov 1<br />
1 Medical <strong>Oncology</strong>, APHP, CancerEst, Tenon University Hospital, Paris, France,<br />
2 Pathology, APHP, CancerEst, Tenon University Hospital, Paris, France,<br />
3 Gynaecology, APHP, CancerEst, Tenon University Hospital, Paris, France,<br />
4 Nuclear Medicine, APHP, CancerEst, Tenon University Hospital, Paris, France<br />
Background: Pathological complete response (pCR) after neoadjuvant chemotherapy<br />
(NAC) is a questionable prognostic factor for all breast cancer (BC) subtypes. We<br />
assessed the importance <strong>of</strong> other clinical and pathological parameters as prognostic<br />
factors after NAC.<br />
Methods: From 2005 to 2014, 236 non metastatic BC patients were consecutively<br />
treated in our institution with the same NAC combining sequentially<br />
anthracyclines-cyclophosphamide followed by taxanes (trastuzumab was added in<br />
HER2 positive population). All the data concerning patient population, initial tumor<br />
stage, pathological characteristics on biopsy, as also after surgery were collected.<br />
Pathological analysis was centralized. pCR was defined according to UICC criteria,<br />
disease free survival (DFS) was calculated since the day <strong>of</strong> first surgery. Analyses<br />
employed logistic regression and Cox proportional hazard models.<br />
Results: Of 236 patients, 140 (59%) were ER positive, 44 (19%) were triple negative and<br />
52 (22%) were Her2 positive. The overall pCR rate was 26.3%. We found that High<br />
Ki67, low PgR and low ER are associated with a pCR. In the group <strong>of</strong> ER positive<br />
population, a cut-<strong>of</strong>f <strong>of</strong> Ki67 at 30% was associated in a multivariate analysis with the<br />
probability <strong>of</strong> pCR (> 30% versus 30% - odds ratio= 3.09, IC 95% = 1.13-8.91, p=<br />
0.028) as well as ER 90% (>90% vs 90% - OR = 0.24, IC 95% = 0.07-0.68, p = 0.007).<br />
The association <strong>of</strong> these two factors gave a pCR with an odds ratio <strong>of</strong> 7.8 (p = 0.0015).<br />
Even if pCR was not achieved, we found a molecular down-staging particularly among<br />
the luminal B population (defined by IHC criteria) (58.1% change into luminal A).<br />
Among patients that did not achieve pCR, several parameters are associated with better<br />
survival after surgery. In multivariate analysis, the clinical stage and the decrease <strong>of</strong> the<br />
Ki67 (defined by (final Ki67-initial Ki67)/initial Ki67) are associated with a reduced<br />
risk <strong>of</strong> disease relapse (hazard ratio = 2.93, IC 95% = 1.19-7.24, p = 0.02).<br />
Conclusions: Our data suggest that particularly in HR positive population,<br />
pathological characteristics <strong>of</strong> residual tumor (ER, PgR, Ki67) might be very<br />
informative for clinical outcome <strong>of</strong> patient that did not achieve pCR after NAC.<br />
Legal entity responsible for the study: N/A<br />
Funding: None<br />
Disclosure: J. Gligorov: Consulting or advisory role: Eisai, Roche/Genentech, Novartis,<br />
Teva, Prizer Honoraria: Eisai, Roche/Genentech, Novartis, Teva, Genomic Health,<br />
Prizer Speaker’s bureau: Eisai, Roche/GenentechAll other authors have declared no<br />
conflicts <strong>of</strong> interest.<br />
190P<br />
Measurement <strong>of</strong> molecular biomarkers to predict tumor<br />
response in estrogen receptor positive breast cancer after<br />
dose-dense (biweekly) paclitaxel/carboplatin neoadjuvant<br />
chemotherapy<br />
K. Wang 1 , T. Zhu 2 , C. Yang 2 , Y. Zhang 2 , L. Zhang 2<br />
1 The second department <strong>of</strong> breast cancer, Guangdong General Hospital,<br />
Guangzhou, China, 2 The Second Department <strong>of</strong> Breast Cancer, Guangdong<br />
General Hospital, Guangzhou, China<br />
Background: Dose-dense (biweekly) paclitaxel/carboplatin(PC) as neoadjuvant<br />
Chemotherapy (NCT) for operable breast cancer is feasible and efficient. This study<br />
was to analysis the relationship between the molecular biomarkers and tumor response<br />
in estrogen receptor(ER) positive breast cancer.<br />
Methods: 84 ER-positive breast cancer patients treated with Dose-dense (biweekly)<br />
paclitaxel/carboplatin NCT were analyzed for expression <strong>of</strong> progesrone receptor (PgR),<br />
Tau, ki67, HER2, Bcl-2 by immunohistochemistry (IHC), these data were used to test<br />
whether these biomarkers can predict tumor response. The primary endpoint was a<br />
pathologically complete response (pCR). The second endpoint was the change in<br />
tumor size between pre and post NCT.<br />
Results: Univariate analysis showed that HER2 positive (53.85% vs 8.62%, p < 0.01,Tau<br />
negative (40.91% vs 16.13%,p = 0.017, BCL-2 negative (48.15% vs 10.53%, p < 0.01)<br />
expression were associated with higher pCR rate. Multivariate analysis revealed that<br />
HER2 (OR: 8.116; 95%CI: 1.931-34.115; p = 0.04), BCL-2(OR: 0.176; 95%CI:<br />
0.041-0.746; p = 0.018) were independent pCR predictive biomarkers. Tumor size was<br />
significant reduced in HER2 positive (p = 0.001, high-level ki67 (p = 0.007, Tau<br />
negative (p = 0.002, BCL-2 negative (p = 0.008) breast cancer.<br />
Conclusions: This study investigates the value <strong>of</strong> traditional biological markers, Bcl-2<br />
and Tau in ER-positive patients treated with dose-dense (biweekly) paclitaxel/<br />
carboplatin NCT.<br />
Clinical trial identification: NCT02059876<br />
Legal entity responsible for the study: N/A<br />
Funding: Guangdong General Hospital<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
191P<br />
Effect <strong>of</strong> body mass index (BMI) on response to neoadjuvant<br />
therapy in human epidermal growth factor receptor 2 (HER2)<br />
positive breast cancer (BC): Analysis from NeoALLTO trial<br />
G. Galli 1 , I. Bradbury 2 , S. Cinieri 3 , D. Agbor-Tarh 2 , F.G.M. De Braud 1 , J. Baselga 4 ,<br />
J. Huober 5 , D. Fumagalli 6 , S. Sarp 7 , M. Piccart 8 , E. de Azambuja 9 , S. Di Cosimo 1<br />
1 <strong>Oncology</strong> Department, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan,<br />
Italy, 2 Statistics, Frontier Science, Kincraig, UK, 3 U.O.C. Oncologia, Ospedale<br />
A. Perrino, Brindisi, Italy, 4 Department <strong>of</strong> Hematology & <strong>Oncology</strong>, Memorial Sloan<br />
Kettering Cancer Center, New York, NY, USA, 5 Gynecology, Ulm Medical<br />
University, Ulm, Germany, 6 Breast Cancer Translational Research Laboratory,<br />
Institute Jules Bordet, Brussels, Belgium, 7 Novartis <strong>Oncology</strong>, Novartis Pharma<br />
AG, Basel, Switzerland, 8 Medicine Department, Institute Jules Bordet, Brussels,<br />
Belgium, 9 Medical <strong>Oncology</strong>, Institute Jules Bordet, Brussels, Belgium<br />
Background: Obesity is a risk factor for the development <strong>of</strong> BC in postmenopausal<br />
women and has been linked to increased risk <strong>of</strong> recurrence and death in BC patients<br />
(pts). Herein, we aimed to investigate the prognostic and predictive role <strong>of</strong> obesity in<br />
HER2 positive BC pts treated with neoadjuvant anti-HER2 therapies.<br />
Methods: NeoALTTO enrolled 455 women with invasive HER2 positive BC and<br />
compared rates <strong>of</strong> pathologic complete response (pCR) to neoadjuvant lapatinib,<br />
trastuzumab or their combination given alone for 6 weeks and then combined with<br />
weekly paclitaxel. In the present analysis, pts’ outcomes in terms <strong>of</strong> event free survival<br />
(EFS), overall survival (OS) and pCR rates were evaluated according to hormone<br />
receptor (HR) status and BMI. We used the World Health Organisation (WHO)<br />
classification for BMI categories.<br />
Results: 14 pts (3.1%) were underweight (BMI 30.0 kg/m2). The impact <strong>of</strong> BMI on<br />
pCR rate was studied by collapsing BMI into two groups, above and below 25 kg/m2.<br />
There were no apparent effects <strong>of</strong> BMI when an effect independent <strong>of</strong> HR status was<br />
fitted [odds ratio (OR) for effect <strong>of</strong> normal BMI relative to high 1.12, 95% confidence<br />
interval (CI) 0.72-1.79]. However, there was a significant interaction between BMI and<br />
HR status (p 0.036). In the interaction model, a modest effect <strong>of</strong> BMI was seen in HR<br />
positive pts (OR 2.02, 95% CI 1.04-3.92), whereas in HR negative pts there were no<br />
apparent effects (OR 0.79, 95% CI 0.45-1.39). BMI did not predict either EFS or OS in<br />
any treatment arms or HR subgroups, but NeoALLTO was not powered for these<br />
endpoints.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw364 | vi57
abstracts<br />
Conclusions: The present study found no significant impact <strong>of</strong> BMI in response to<br />
neoadjuvant therapy in the whole HER2 positive population. However, a significant<br />
correlation was seen in pts with HR positive tumours. Our data potentially pave the<br />
way to future research in developing combined therapeutic strategies for HER2 positive<br />
luminal BC, with the intent <strong>of</strong> obtaining a complete blockade <strong>of</strong> the driving growth<br />
factor signals via both HER2 and HRs.<br />
Clinical trial identification: NCT00553358<br />
Legal entity responsible for the study: Fondazione IRCCS Istituto Nazionale dei<br />
Tumori<br />
Funding: None<br />
Disclosure: I. Bradbury: Ian Bradbury’s institution has received funding from<br />
GlaxoSmithKline and Roche.J. Baselga: Honoraria received from Roche.S. Sarp:<br />
Novartis AG.M. Piccart: Honoraria received from GlaxoSmithKline and Roche,<br />
research funding to Institution from GlaxoSmithKline.E. de Azambuja: Advisory board<br />
and travelling grant from GlaxoSmithKline, speaker for Roche.S. Di Cosimo: Speaker<br />
for GlaxoSmithKline.All other authors have declared no conflicts <strong>of</strong> interest.<br />
192P<br />
Effect <strong>of</strong> body mass index on pharmacokinetics <strong>of</strong> paclitaxel in<br />
women with early breast cancer<br />
V. Gota 1 , A. Bonda 2 , A. Karanam 1 , B. Shriyan 1 , M. Gurjar 1 , A. Patil 1 , A. Singh 2 ,<br />
M. Nookala 1 , S. Gupta 2<br />
1 Clinical Pharmacology, Tata Memorial Hospital Centre, Mumbai, India,<br />
2 Department <strong>of</strong> Medical <strong>Oncology</strong>, Tata Memorial Hospital Centre, Mumbai, India<br />
Background: It is common practice to dose paclitaxel according to body surface area<br />
(BSA) in women with early breast cancer (EBC). However, there is scant information<br />
on actual drug exposure in overweight/obese women and whether actual or modified<br />
weight should be used in calculating BSA. The present study evaluates effect <strong>of</strong> Body<br />
Mass Index (BMI) on pharmacokinetic (PK) pr<strong>of</strong>ile <strong>of</strong> paclitaxel.<br />
Methods: EBC patients in two BMI groups (normal, 18-24.9 kg/m 2 and overweight/<br />
obese, ≥25 kg/m 2 , respectively) were enrolled. All patients received single agent<br />
paclitaxel at 175 mg/m 2 q3weeks. The two groups were matched for age, albumin and<br />
bilirubin levels using a minimization technique. Sparse PK sampling was performed at<br />
7 time points from time 0 until 24 hours <strong>of</strong> starting paclitaxel infusion in cycle<br />
1. Paclitaxel concentration was measured using a validated LCMS/MS method. PK data<br />
was modeled using WinNonlin s<strong>of</strong>tware and PK parameters were compared using<br />
Student’s t test. Covariate effect on paclitaxel PK was evaluated by population PK<br />
analysis using NONMEM s<strong>of</strong>tware.<br />
Results: Thirty-six patients (18 in each group) were enrolled with mean BMI <strong>of</strong><br />
21.5 ± 2.0 and 28.2 ± 2.3 kg/m 2 , mean BSA <strong>of</strong> 1.43 ± 0.11 and 1.69 ± 0.14 and mean<br />
paclitaxel dose <strong>of</strong> 250 ± 18 and 293 ± 20 mg, in normal and overweight/obese groups,<br />
respectively. The two groups were comparable with respect to serum albumin,<br />
bilirubin, hemoglobin and performance status. PK data was well described by a<br />
two-compartment nonlinear clearance model. Normal and overweight/obese groups<br />
had comparable AUC0-∞ (26 ± 14 vs. 24 ± 13 µg/ml*hr, p = 0.657), C max (7.6 ± 4 vs.<br />
6.6 ± 3 µg/ml, p = 0.363), volume <strong>of</strong> distribution (69 ± 47 vs. 68 ± 34 L/m 2 , p = 0.938)<br />
and clearance (8.9 ± 4.8 vs. 9.7 ± 5.4 L/hr/m 2 , p = 0.637), respectively. Population PK<br />
analysis showed a significant positive correlation between BMI and paclitaxel clearance<br />
while no other covariate was significant. There was no significant difference in toxicity<br />
between the two groups.<br />
Conclusions: There is no significant difference in paclitaxel exposure between normal<br />
and overweight/obese women with EBC when dosed according to BSA that is<br />
calculated using actual body weight. The latter should be used when calculating<br />
paclitaxel dose in overweight/obese patients.<br />
Clinical trial identification: Clinical trial registry <strong>of</strong> India Identifier: CTRI/2015/09/<br />
006193<br />
Legal entity responsible for the study: Tata Memorial Centre, Mumbai<br />
Funding: The study was funded by Tata Memorial Centre, Mumbai, through the<br />
intramural funds<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
193P<br />
Effect <strong>of</strong> body mass index in the outcome <strong>of</strong> stage I-III triple<br />
negative breast cancer<br />
M.A. Sendur 1 , S. Aksoy 2 , N. Ozdemir 1 , O. Yazici 3 , N. Zengin 3 , K. Altundag 2<br />
1 Department <strong>of</strong> Medical <strong>Oncology</strong>, YıldırımBeyazıt University, Faculty <strong>of</strong> Medicine,<br />
Ankara, Turkey, 2 Department <strong>of</strong> Medical <strong>Oncology</strong>, Hacettepe University Faculty <strong>of</strong><br />
Medicine, Ankara, Turkey, 3 Medical <strong>Oncology</strong>, Ankara Numune Education and<br />
Research Hospital, Ankara, Turkey<br />
Background: Breast cancer classified mostly into 4 major molecular subtypes based on<br />
the expression <strong>of</strong> receptors for estrogen (ER), progesterone (PR), and human epidermal<br />
growth factor (HER-2) and ki-67 staining. Triple-negative breast cancer (TNBC) refers<br />
to a subgroup <strong>of</strong> patients with no expression <strong>of</strong> ER, PR or HER-2, and accounts for<br />
10-20% <strong>of</strong> all newly diagnosed breast cancer cases. Although obesity is known to be an<br />
important risk factor for development <strong>of</strong> breast cancer and affects the prognosis<br />
unfavorably especially in luminal type tumors the effect <strong>of</strong> obesity in TNBC was not<br />
known exactly. In this trial we aimed to investigate the effect <strong>of</strong> body mass index (BMI)<br />
on the outcome <strong>of</strong> TNBC.<br />
Methods: Between 1998-2015 years from 4584 patients with invasive breast cancer<br />
patients who had non-metastatic TNBC with baseline BMI at the time <strong>of</strong> diagnosis<br />
were enrolled to this study (n = 371). Patient’s demographics, including survival data<br />
and tumor characteristics were obtained from medical charts. Patients with BMI<br />
ranging between 18.5 and 24.9 kg/m 2 were considered as normal weight patients (Arm<br />
A, n = 122), and patients with a BMI ranging ≥ 25 kg/m 2 were grouped as overweight<br />
and obese patients (Arm B, n = 249). Kaplan–Meier survival analysis was carried out<br />
for disease free survival (DFS) and overall survival (OS).<br />
Results: The median follow up <strong>of</strong> patients was 44.1 months. Median age <strong>of</strong> patients<br />
was 43 (23-81) and 49 (20-82) in group A and B, respectively (P < 0.001). There were<br />
no apparent differences in histological type, grade, axillary lymph node involvement,<br />
extracapsular extension, perineural invasion, lymphovascular invasion, menopausal<br />
status, Treatment patterns such as chemothearpy and radiotherapy were similar. But<br />
significantly TNM stage 3 was seen significantly higher in Group B patients (26.9% vs<br />
15.8%, P = 0.01). In Group A, 5-year diseases free survival (DFS) rate was 89.3%<br />
whereas it was 75.0% in Group B (P = 0.05). In Group A, 5-year overall survival (OS)<br />
rate was 93.0% whereas it was 81.0% in Group B (P = 0.01).<br />
Conclusions: In our study, like luminal A and B tumors, obesity is associated with<br />
poorer DFS and OS in stage 1-3 TNBC patients.<br />
Legal entity responsible for the study: N/A<br />
Funding: None<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
194P<br />
Body mass index as a prognostic factor in operable breast<br />
cancer patients treated with adjuvant anthracyclines with or<br />
without taxanes<br />
W. El-Sadda, M. El-Ibrashi, I. Abdel-Halim<br />
Clinical <strong>Oncology</strong> and Nuclear Medicine, Mansoura University Hospital School <strong>of</strong><br />
Medicine, Mansoura, Egypt<br />
Background: Breast cancer is the most frequent invasive tumor in women. Obesity is a<br />
risk factor for several types <strong>of</strong> cancer, including breast cancer. Obesity is an unfavorable<br />
prognostic factor in breast cancer regardless <strong>of</strong> menopausal status and treatment<br />
protocol. The aim <strong>of</strong> the study was to assess the effect <strong>of</strong> obesity on prognosis in<br />
operable breast cancer patients according to pathologic subtypes.<br />
Methods: A retrospective analysis <strong>of</strong> 500 operable breast cancer patients received<br />
adjuvant anthracyclines with or without taxanes enrolled in the period between Sep<br />
2011 and Sep 2013, the primary end point was to assess the prognostic effect <strong>of</strong> body<br />
mass index (BMI) on disease recurrence, breast cancer mortality (BCM), and overall<br />
mortality (OM). The secondary end point was to detect the difference by breast cancer<br />
pathologic subtypes (ER, PR positive/HER2 positive, ER, PR positive/HER2 negative,<br />
ER, PR negative/HER2 positive, and triple negative)<br />
Results: Analyses were adjusted for age, tumor size, grade, nodal status, menopausal<br />
status, hormone receptors and HER2 receptor status, surgery and chemotherapy<br />
regimen. Obese patients (BMI = 30-39.9 kg/m 2 ) had similar prognosis as that <strong>of</strong><br />
normal weight patients (BMI
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
calculated by the formula: body weight (kg)/height (m2). SPSS was used for statistical<br />
Analysis, tests used are analysis <strong>of</strong> variance, comparison <strong>of</strong> mediums, and test Khi-two.<br />
Results: 481 patients were eligible. Medium <strong>of</strong> age was 48.9 years. 21.7% <strong>of</strong> tumors<br />
were HER2, 17.7% Triple negative and 60.6% luminal. The tumors were: T1 = 21.9%,<br />
T2 = 47.9% T3 = 11.7%, T4 = 12.7% Tx = 5.6%. For stages: I : 11.9%, IIA = 24.4%,<br />
IIB = 20.4%, IIIA = 15.8%, IIIB = 10.2%, IIIC = 10%, IV = 7.3%. The tumors grading:<br />
Grade 1 : 8.7%, Grade 2 : 57.9%, Grade 3 : 33.6% all correlation between BMI and other<br />
parameters and was negative even in triple negative cancers.<br />
Table: 195P<br />
BMI Pr<strong>of</strong>ile<br />
Underweight 1%<br />
Normal 26.5%<br />
Overweight 35.0%<br />
Obesity moderate 26.7%<br />
Severe obesity 8.5%<br />
Morbid obesity 2.3%<br />
Statistical correlation between BMI and:<br />
Tumor stage for all subtypes p = 0.29<br />
Tumor size p = 0.096<br />
Tumor stage for luminal cancers p = 0.48<br />
Tumor stage for HER2 + cencers p = 0.33<br />
Tumor stage for triple negative cancers p = 0.23<br />
Expression estrogen hormone receptors p = 0.35<br />
Expression progesterone hormone receptors p = 0.13<br />
Expression HER2 p = 0.30<br />
Conclusions: Our study suggests that there is no correlation between BMI and tumor<br />
stage regardless <strong>of</strong> the biological subtypes. Others studies are needed to confirm our<br />
results.<br />
Legal entity responsible for the study: National Institute <strong>of</strong> <strong>Oncology</strong> Rabat Morocco<br />
Funding: National Institute <strong>of</strong> <strong>Oncology</strong> Rabat Morocco<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
196P<br />
Efficacy <strong>of</strong> statin usage before diagnosis on<br />
clinico-pathological characteristics and outcome <strong>of</strong> invasive<br />
breast cancer<br />
M.A. Sendur 1 , S. Aksoy 2 , N. Ozdemir 1 , O. Yazici 3 , B. Yalçın 1 , N. Zengin 1 ,<br />
K. Altundag 2<br />
1 Department <strong>of</strong> Medical <strong>Oncology</strong>, YıldırımBeyazıt University, Faculty <strong>of</strong> Medicine,<br />
Ankara, Turkey, 2 Department <strong>of</strong> Medical <strong>Oncology</strong>, Hacettepe University Faculty <strong>of</strong><br />
Medicine, Ankara, Turkey, 3 Medical <strong>Oncology</strong>, Ankara Numune Education and<br />
Research Hospital, Ankara, Turkey<br />
Background: In vitro studies showed that statins have antiproliferative, antiapoptotic,<br />
antiangiogenetic and immunomodulatory effect which prevent cancer growth. As a<br />
result <strong>of</strong> the published studies and meta-analyses, there were contradictory results with<br />
statin use on breast cancer risk, but the effect on clinical and pathological properties <strong>of</strong><br />
breast cancer with statin use was not known exactly. In this study, we aimed to<br />
investigate retrospectively the effect <strong>of</strong> statin usage on clinico-pathological<br />
characteristics and recurrence risk <strong>of</strong> patients with invasive breast cancer.<br />
Methods: Between 1998-2015 years from 4584 patients with invasive breast cancer<br />
patients who were taking statins at the time <strong>of</strong> diagnosis were enrolled as statin users<br />
(n = 164), where the patients matched with the same age who were not taking statin<br />
were included as a control group (n = 676). A total <strong>of</strong> 840 patients were included in this<br />
study.<br />
Results: The median follow up <strong>of</strong> patients was 73 months. Median age <strong>of</strong> both statin<br />
users and nonusers was 55 (36-86). There were no apparent differences in histological<br />
type, grade, axillary lymph node involvement, extracapsular extension, perineural<br />
invasion, lymphovascular invasion, menopausal status, HER2 positivity and hormonal<br />
receptor status between both groups. Treatment patterns such as hormonal treatment,<br />
chemothearpy and radiotherapy were similar. But non-significantly TNM stage 3-4<br />
were seen lower in statin users group (26.4% vs 36.4%, P = 0. 09). In patients with statin<br />
users 5-year diseases free survival (DFS) rate was 85.1% whereas it was 74.7% and in<br />
nonusers (P = 0.02). The median estimated DFS was 221 months in statin users,<br />
whereas 175 months in nonusers. In patients with statin users 5-year overall survival<br />
(OS) rate was 92.3% whereas it was 84.6% in nonusers (P = 0.01).<br />
Conclusions: Despite no clinicopathological difference between two treatment arms,<br />
statin usage improved both DFS and OS significantly. Thus our evidence suggests an<br />
alternative pathway for targeted therapy in breast cancer.<br />
Legal entity responsible for the study: N/A<br />
Funding: None<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
197P<br />
Effect <strong>of</strong> using different antihypertensive drugs on<br />
demographic and clinico-pathological characteristics <strong>of</strong><br />
breast cancer<br />
M.A. Sendur 1 , S. Aksoy 2 , N. Ozdemir 1 , O. Yazici 3 , M.B. Akıncı 1 , D.S. Dede 1 ,<br />
B. Yalçın 1 , N. Zengin 1 , K. Altundag 2<br />
1 Department <strong>of</strong> Medical <strong>Oncology</strong>, YıldırımBeyazıt University, Faculty <strong>of</strong> Medicine,<br />
Ankara, Turkey, 2 Department <strong>of</strong> Medical <strong>Oncology</strong>, Hacettepe University Faculty <strong>of</strong><br />
Medicine, Ankara, Turkey, 3 Medical <strong>Oncology</strong>, Ankara Numune Education and<br />
Research Hospital, Ankara, Turkey<br />
Background: There is limited data about the association <strong>of</strong> breast cancer and with a<br />
selective anti-HT usage. Thus, we aimed to investigate relationship between anti-HT<br />
usage and clinico-pathological properties <strong>of</strong> breast cancer.<br />
Methods: Breast cancer patients from 1998 to 2015 were retrospectively analyzed.<br />
Patients who were taking oral antihypertensive drugs more than 12 months at the time<br />
<strong>of</strong> breast cancer diagnosis were enrolled as anti-HT users (n = 923), where the patients<br />
matched with the same age who were not taking oral anti-HT were included as a<br />
control group (n = 923).<br />
Results: A total <strong>of</strong> 1946 patients with breast cancer were included in this study. 923<br />
patients received an oral anti-HT treatment more than 1 year at the time <strong>of</strong> breast<br />
cancer diagnosis, and 923 patients were considered as non-users. The median<br />
follow-up <strong>of</strong> patients was 57 months. Median age <strong>of</strong> both group were 57 (23-89). There<br />
were no apparent differences in histological type, terms <strong>of</strong> baseline tumor size, grade,<br />
axillary lymph node involvement, extracapsular extension, lymphovascular invasion,<br />
type <strong>of</strong> surgery, menopausal status and hormonal receptor status between both groups.<br />
In hypertensive group the history <strong>of</strong> obesity, hyperlipidemia and diabetes were<br />
significantly higher than control group. But perineural invasion positivity and HER2<br />
expression was significantly lower in patients with anti-HT users group (PNI; 12.9% vs<br />
8.8%, P = 0.009, HER2 positivity; 19.5% vs 15.3%, P = 0.02). Significantly lower<br />
incidence <strong>of</strong> T3-T4 tumor and TNM stage were seen in patients with anti-HT users<br />
group compared to nonusers. (Stage 3-4; 31.6% vs 33.8%, P = 0.04). In survival<br />
analysis, in oral anti-HT users 5-year DFS rate was 80.3%, whereas it was 75.4% in<br />
non-users (P = 0.14). Median OS could not be obtained due to low events in both<br />
groups but 5-year survival rate in oral anti-HT users was 89.6%, whereas in non-users<br />
it was 86.3% (P = 0.01). In oral anti-HT group there was no effect on recurrence and<br />
survival between different anti-HT treatments.<br />
Conclusions: In our study, despite higher body mass index and higher incidence <strong>of</strong><br />
comorbidities in patients with oral anti-HT users, a trend <strong>of</strong> improvement was<br />
observed in terms <strong>of</strong> DFS and significantly improvement in OS was observed.<br />
Legal entity responsible for the study: N/A<br />
Funding: None<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
198P<br />
Effect <strong>of</strong> using different antidiabetic drugs on demographic<br />
and clinico-pathological characteristics <strong>of</strong> breast cancer<br />
M.A. Sendur 1 , S. Aksoy 2 , O. Yazici 3 , N. Ozdemir 1 , D.S. Dede 1 , M.B. Akıncı 1 ,<br />
B. Yalçın 1 , N. Zengin 1 , K. Altundag 2<br />
1 Department <strong>of</strong> Medical <strong>Oncology</strong>, YıldırımBeyazıt University, Faculty <strong>of</strong> Medicine,<br />
Ankara, Turkey, 2 Department <strong>of</strong> Medical <strong>Oncology</strong>, Hacettepe University Faculty <strong>of</strong><br />
Medicine, Ankara, Turkey, 3 Medical <strong>Oncology</strong>, Ankara Numune Education and<br />
Research Hospital, Ankara, Turkey<br />
Background: Approximately 20 % <strong>of</strong> patients diagnosed with breast cancer have also<br />
diabetes mellitus as a comorbid condition. There is growing evidence that the use <strong>of</strong><br />
metformin in diabetic patients was associated with lower risks <strong>of</strong> cancer. In this study,<br />
we aimed to investigate retrospectively the demographic and clinicopathological<br />
characteristics <strong>of</strong> patients with different antidiabetics (AD) users at the time <strong>of</strong> breast<br />
cancer diagnosis.<br />
Methods: From 3890 breast cancer patients who were taking AD drugs more than 12<br />
months at the time <strong>of</strong> breast cancer diagnosis were enrolled (n = 378). Patients were<br />
classified as Group 1 if they treated only with metformin, Group 2; another oral AD,<br />
Group 3; oral AD combination, Group 4; insulin plus oral AD and Group 5; if they<br />
treated with insulin only.<br />
Results: Median age <strong>of</strong> 378 patients diagnosed with breast cancer and diabetes was 58<br />
(23-92). The median follow-up <strong>of</strong> patients was 47 months. There were 128 patients (%<br />
38.8) in Group 1, 106 patients (%32.1) in Group 2, 13 patients (%3.9) in Group 3, 27<br />
patients (%8.2) in Group 4 and 56 patients (%17.0) in Group 5. The 5 groups were<br />
well-balanced and there were no apparent differences in histological type, terms <strong>of</strong><br />
baseline tumor size, grade, axillary lymph node involvement, extracapsular extension,<br />
perineural invasion, lymphovascular invasion, type <strong>of</strong> surgery, menopausal status,<br />
HER2 positivity and hormonal receptor status between 5 groups. Both estrogen and<br />
progesteron receptor positivity were same between 5 groups. Treatment patterns such<br />
as hormonal treatment, chemothearpy and radiotherapy were also similar. Similarly,<br />
distribution <strong>of</strong> TNM stages were same between groups. 5-year DFS rates were 81.9%,<br />
77.3%, 79.3%, 72.5% and 61.9% in Groups 1-5, respectively (P = 0.06). 5-year OS rates<br />
were 89.3%, 92.5%, 92.9%, 81.8% ve 67.7% in Groups 1-5, respectively. (P = 0. 002).<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw364 | vi59
abstracts<br />
Conclusions: In our study, patients treated with insülin alone or combination have<br />
significantly worse OS and borderline significant worse DFS compared to diabetic<br />
breast cancer patients treated with oral AD medications. The insulin-sensitizing effect<br />
<strong>of</strong> metformin may play a major role in its anticancer activity. B<br />
Legal entity responsible for the study: N/A<br />
Funding: None<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
199P<br />
Impact <strong>of</strong> vitamin D3 replacement therapy on clinical<br />
outcomes and survival rates in patients with early stage breast<br />
cancer<br />
O. Yazici 1 , S. Aksoy 2 , M.A. Sendur 3 , N. Ozdemir 1 , N. Zengin 1 , K. Altundag 2<br />
1 Medical <strong>Oncology</strong>, Ankara Numune Education and Research Hospital, Ankara,<br />
Turkey, 2 Department <strong>of</strong> Medical <strong>Oncology</strong>, Hacettepe University Faculty <strong>of</strong><br />
Medicine, Ankara, Turkey, 3 Department <strong>of</strong> Medical <strong>Oncology</strong>, Ankara Ataturk<br />
Research and Teaching Hospital, Ankara, Turkey<br />
Background: In literature some studies suggested that in patients having solid<br />
malignancies poor prognosis is associated with vitamin D3 deficiency and replacement<br />
<strong>of</strong> vitamin D3 might have positive impact on prognosis. However, some <strong>of</strong> the results<br />
<strong>of</strong> the studies were against this suggestion. Therefore, in the current study we aimed to<br />
compare the clinical, pathological features and survival rates in patients with early<br />
breast cancer having regular vitamin D3 replacement or not.<br />
Methods: In between October 2002 and October 2015, patients with early stage breast<br />
cancer were included in study population. The patients were divided into two groups<br />
according to their regular vitamin D3 replacement status. Vitamin D3 doses that the<br />
patients were receiving were calculated to increase the levels beyond 20 ng/mL (50<br />
nmol/L). The patients with metastasis/relapse or second primary cancers were<br />
excluded.<br />
Results: In vitamin D3 and non-vitamin D3 group 92 and 2864 patients were included.<br />
Median follow up time was 60 (min:1- max:420) months. Mean age at time <strong>of</strong><br />
diagnosis, rate <strong>of</strong> patients with postmenopause, T1 tumor and breast conserving<br />
surgery was significantly higher in vitamin D3 replacement group compared with<br />
non-vitamin D3 group (p < 0.05) (Table 1). Disease free survival rate was similar in<br />
both patients group. In vitamin D3 replacement and non-vitamin D3 group overall<br />
survival rates in 1st, 3rd and 5th year was in order 98% vs 99%; 96% vs 96%; 95% vs<br />
92%; the difference was not significant (p = 0.16)<br />
Conclusions: Regular vitamin D3 replacement therapy did not have effect on prognosis<br />
<strong>of</strong> patients with early breast cancer. Most <strong>of</strong> the postmenopausal and older aged<br />
patients with early breast cancer received vitamin D3 replacement most probably due<br />
to higher rate <strong>of</strong> osteoporosis in this aged patient group.<br />
Table: 199P Clinical and pathological features <strong>of</strong> early breast cancer<br />
patients in vitamin D and non-vitamin D group<br />
Regular Vitamin D<br />
Replacement Group<br />
(n = 92) (%)<br />
Non-Vitamin D<br />
Group (n = 2864)<br />
(%)<br />
Mean Age 59 ± 11 49 ± 13 0.001<br />
Invasive Histopathological 75 5.4 19.6 70 5 25 0.77<br />
Subtype Dutal Lobular Other<br />
Grade 1 2 3 21 45.2 33.9 13 44.9 42.1 0.14<br />
Body Mass Index 0-25 kg/m 2 34.7 37.3 28 35.4 36.6 28.1 0.98<br />
25-29.9 kg/m 2 ≥30 kg/m 2<br />
Menapausal Status<br />
22.8 8.7 68.5 49.8 7.1 43.1 0.001<br />
Premenopausal<br />
Perimenopausal<br />
Postmenopausal<br />
Breast Surgery Mastectomy 52.2 46.4 65.7 33.8 0.04<br />
Breast Conserving<br />
Estrogen Receptor Positive 83.3 16.7 75.2 24.8 0.11<br />
Negative<br />
Progesterone Receptor Positive 77.8 22.2 71.4 28.6 0.23<br />
Negative<br />
Her-2 Status Positive Negative 13.3 86.7 19.4 80.6 0.18<br />
TNM Tumor Stage T1 T2 T3 T4 55.6 31.9 9.7 2.8 34.8 48.8 13.6 2.8 0.004<br />
TNM Nodal Stage N0 N1 N2 N3 54.1 29.7 8.1 5.4 46 27.3 12.5 9.5 0.37<br />
Legal entity responsible for the study: Ankara Numune Education and Research<br />
Hospital<br />
Funding: None<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
p<br />
200P<br />
Metformin anti-proliferative effect on a cohort <strong>of</strong> non-diabetic<br />
breast cancer patients<br />
S. Sadighi 1 , M. Saberian 1 , M. Nagafi 2 , I. Jahanzad 3 , R. Omranipoor 2 , B. Behrouzi 4<br />
1 Medical <strong>Oncology</strong>-Hematology, Cancer Institute <strong>of</strong> Iran, Tehran, Iran, 2 Surgery,<br />
Cancer Institute <strong>of</strong> Iran, Tehran, Iran, 3 Pathology, Cancer Institute <strong>of</strong> Iran, Tehran,<br />
Iran, 4 St George Campus, Faculty <strong>of</strong> Art and Sciences, Toronto, ON, Canada<br />
Background: Whereas the preoperative period is increasingly popular for the clinical<br />
investigation <strong>of</strong> new biological agents and also establishment <strong>of</strong> Ki67 as an<br />
intermediate proliferative marker <strong>of</strong> treatment benefit,<br />
Methods: we design a prospective randomized controlled study about metformin<br />
efficacy in the window time between biopsy and definite surgery. Our primary<br />
endpoint was changes <strong>of</strong> Ki67. Patients neither had indication <strong>of</strong> neoadjuvant<br />
chemotherapy, nor involved with diabetes mellitus. They followed during the time<br />
period <strong>of</strong> biopsy and definitive surgery. Metformin (1500mg/day) was prescribed to<br />
intervention group from pathology report to the night before surgery. Control group<br />
were patients with the same inclusion criteria who did not receive any drug.<br />
Results: From 50 patients enrolled 5 excluded. Four before using any pills and one in<br />
the first day <strong>of</strong> taking metformin; 25 had been received metformin for median time <strong>of</strong><br />
2.8 weeks. Controlled group included 20 patients who followed in the window time.<br />
There were no statistically significant differences between two groups regarding<br />
baseline clinical and tumor characteristics such as age, stage, grade, Er, Pgr, HER2<br />
status, time and type <strong>of</strong> surgery. However, immunohistochemistry study showed<br />
decrease <strong>of</strong> median KI67 from 35.14 to 29.6 in the intervention group and increase<br />
from 24.5 to 30.6 in the control group. Both <strong>of</strong> these results were statistically<br />
significant. Although mild gastrointestinal symptoms were seen in 30% <strong>of</strong> cases,<br />
generally patients tolerated metformin very well. There was a correlation between<br />
metabolic factor <strong>of</strong> HOMA score and changes in KI67.<br />
Conclusions: In the present study metformin prescription in the short period <strong>of</strong> time<br />
between biopsy and definite surgery had shown inhibition <strong>of</strong> breast cancer cell growth.<br />
We found relationship between metformin anti-proliferative effect and glucose and<br />
insulin metabolism.<br />
Clinical trial identification: code number in Research Deputy <strong>of</strong> Tehran University is<br />
92-03-51-24050<br />
Legal entity responsible for the study: Research Deputy <strong>of</strong> Tehran U Medical Sciences<br />
Funding: Research Deputy <strong>of</strong> Tehran U Medical Sciences<br />
Disclosure: B. Behrouzi: I declare there is no conflict <strong>of</strong> interest about this research. All<br />
other authors have declared no conflicts <strong>of</strong> interest.<br />
201P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Dyslipidaemias after adjuvant chemotherapy in young Chinese<br />
breast cancer patients<br />
W. Yeo 1 ,F.Mo 1 , J. Suen 2 , H. Loong 1 , E. Pang 1 , C. Yip 1 , G.S. Liem 1<br />
1 Clinical <strong>Oncology</strong>, The Chinese University <strong>of</strong> Hong Kong, Shatin, Hong Kong,<br />
China, 2 Clinical <strong>Oncology</strong>, Prince <strong>of</strong> Wales Hospital, Shatin, Hong Kong, China<br />
Background: Adjuvant chemotherapy improves outcome <strong>of</strong> patients with early breast<br />
cancer. However, chemotherapy may be associated with long term toxicities, there is<br />
limited data on the incidence <strong>of</strong> dyslipidaemias after adjuvant chemotherapy. In this<br />
prospective cross-sectional study, the objectives were to determine the incidence <strong>of</strong><br />
dyslipidaemias and the associated factors among young premenopausal Chinese breast<br />
cancer patients after adjuvant chemotherapy.<br />
Methods: Eligibility criteria include Chinese breast cancer patients <strong>of</strong> stage I-III,<br />
younger than 45 years at diagnosis, having received adjuvant chemotherapy, within<br />
3-10 years after the diagnosis <strong>of</strong> breast cancer. Patients’ characteristics, anti-cancer<br />
treatments, body weight and height at the time <strong>of</strong> breast cancer diagnosis (i.e. prior to<br />
chemotherapy) were collected. At study entry, patients had body weight and fasting<br />
blood lipids determined; incidence <strong>of</strong> chemotherapy-related amenorrhea (CRA) and<br />
menopause were determined based on detailed menstrual history. Dyslipidaemia was<br />
defined according to US National Cholesterol Education Program. Analysis was<br />
conducted to identify factors associated with dyslipidaemias.<br />
Results: 280 patients were studied; the median time from breast cancer diagnosis<br />
was 5.0 years. 91.1% developed CRA; 48.9% had become menopausal and 10% were<br />
peri-menopausal. At the time <strong>of</strong> study entry, the mean weight gain was 1.8 kg;<br />
63.2% had gained weight by >2%; 52.1% were overweight/obese. Abnormal<br />
total-cholesterol, LDL-cholesterol, HDL-cholesterol and triglyceride levels occurred<br />
34.3%, 56.1%, 6.6% and 22.9% respectively. Increase in BMI categories to<br />
overweight/obese and older age were associated with hypercholesterolaemia.<br />
Tamoxifen was associated with reduced risk, while older age, corticosteroid<br />
premedication and having increase in BMI categories were associated with<br />
increased risk <strong>of</strong> abnormal LDL-cholesterol.<br />
Conclusions: At a median <strong>of</strong> 5 years after breast cancer diagnosis and adjuvant<br />
chemotherapy, dyslipidaemias were frequent. Clinicians need to increase awareness <strong>of</strong><br />
this aspect and interventional studies including lifestyle modifications are warranted to<br />
optimize long-term care for these patients.<br />
Legal entity responsible for the study: Chinese University <strong>of</strong> Hong Kong<br />
vi60 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Funding: Hong Kong Cancer Fund and Madam Diana Hon Fun Kong Donation for<br />
Cancer Research<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
202P<br />
Influence <strong>of</strong> adjuvant chemotherapy on anti-müllerian<br />
hormone (AMH) level in patients younger than 35 years treated<br />
for an early breast cancer (EBC)<br />
M. Saint-Ghislain 1 , F. Clatot 1 , M. Degrémont 2 , M. Leheurteur 1 , M. David 2 ,<br />
C. Veyret 1 , F. Di Fiore 1 , A. Perdrix 2<br />
1 Medical <strong>Oncology</strong>, Centre Henri Becquerel, Rouen, France, 2 Biopathology,<br />
Centre Henri Becquerel, Rouen, France<br />
Background: The overall negative influence <strong>of</strong> chemotherapy on ovarian reserve is well<br />
established. Since few years, AMH is used as a fertility marker, both in assisted<br />
reproductive technology and oncology. Surprisingly, if young patients are the most ones<br />
concerned with fertility questions, the specific impact <strong>of</strong> adjuvant chemotherapy for EBC<br />
in this population is unknown. In this context, we analysed AMH in patients ≤ 35 years<br />
presenting an EBC, before any treatment, at 1, 3 and 5 years after diagnosis.<br />
Methods: This is a monocentric retrospective study. Patients aged ≤35 years treated for<br />
EBC between 2008 and 2014, with frozen heparined plasma samples before and after<br />
chemotherapy exposure and with a written consent for research use were included. All<br />
analysis were performed simultaneously with Elecsys® AMH assay (Roche Diagnostics).<br />
Statistics were performed using Mann-Whitney or Wilcoxon tests.<br />
Results: Fifty-four patients were included, 23 (43%) had a triple negative and 29 (54%)<br />
a hormonal positive receptors tumor. Median age at diagnosis was 31.5 years (range<br />
22-35). Median AMH before treatment was 2.12 ng/mL (range 0.33-17.5) and dropped<br />
to 0.13 ng/mL (0.01-6.1, p < 0.0001) after a median delay <strong>of</strong> 387 days from diagnosis. A<br />
slight increase <strong>of</strong> the median AMH to 0.30 ng/mL (0.01-3.28) was observed after 2<br />
more years <strong>of</strong> survey (p = 0.007 between 1 and 3 years AMH). No additional AMH<br />
recovery was observed 5 years after the diagnosis in comparison to 3 years (n = 11).<br />
Considering the median <strong>of</strong> age, AMH was not different in younger compared to older<br />
patients before or after treatment (1, 3 or 5 years). For the whole population, the use <strong>of</strong><br />
adjuvant hormonal therapy did not modify post-treatment AMH. In contrast, the post<br />
treatment median AMH was significantly lower after a 3FEC-3TXT (n = 45, 83%) than<br />
after a 6FEC (n = 9, 17%) chemotherapy based regimen (0.09 and 0.38 ng/mL<br />
respectively, p = 0.01).<br />
Conclusions: Despite a normal ovarian reserve before treatment, AMH decreases<br />
deeply 1 year after diagnosis, whatever the age <strong>of</strong> the patient. A slight recovery can be<br />
observed 3 years after diagnosis, without ranging the normal expected values for the<br />
age. Use <strong>of</strong> taxanes seems to increase gonadotoxicity.<br />
Legal entity responsible for the study: Centre Henri Becquerel<br />
Funding: Centre Henri Becquerel, Department <strong>of</strong> Biopathology<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
203P<br />
Follow-up <strong>of</strong> chemotherapy induced changes in anti-Mullerian<br />
hormone, antral follicle number and ovary volume in<br />
premenopausal breast cancer patients<br />
F. Elbuken 1 , C. Ordu 2 , D. Sarsenov 3 , S. Ilgun 4 , K. Pilanci 5 , Z. Erdogan 6 ,<br />
F. Agacayak 7 , G. Alco 8 , A. Ozturk 9 ,Y.Eralp 10 , B. Baysal 11 , V. Ozmen 12<br />
1 Radiology, Ozel Gayrettepe Florence Nightingale Hospital, Istanbul, Turkey,<br />
2 Medical <strong>Oncology</strong>, Ozel Gayrettepe Florence Nightingale Hospital, Istanbul,<br />
Turkey, 3 General surgery, Istanbul Florence Nightingale Hospital, Istanbul, Turkey,<br />
4 General surgery, Taksim Egitim Arastirma Hastanesi, Istanbul, Turkey, 5 Medical<br />
<strong>Oncology</strong>, Haseki Education & Research Hopital, Istanbul, Turkey, 6 Physical<br />
Therapy and Rehabilitation, Istanbul Bilim University-Shisane Campus, Istanbul,<br />
Turkey, 7 Radiology, Istanbul Florence Nightingale Hospital, Istanbul, Turkey,<br />
8 Radiation Therapy, Ozel Gayrettepe Florence Nightingale Hospital, Istanbul, Turkey,<br />
9 General surgery, Biruni University Medical Faculty, Istanbul, Turkey, 10 Medical<br />
<strong>Oncology</strong>, Istanbul University Medical Faculty, Istanbul, Turkey, 11 ObGyn, Istanbul<br />
Florence Nightingale Hospital, Istanbul, Turkey, 12 General surgery, Istanbul<br />
University Medical Faculty, Istanbul, Turkey<br />
Background: Ovarian functions in premenopausal breast cancer patients are frequently<br />
affected due to the applied chemotherapy regimen. In this study, we aimed to evaluate the<br />
ovarian functions after chemotherapy by assessing the AMH, the number <strong>of</strong> antral follicle<br />
and the volume <strong>of</strong> ovaries in the premenopausal patients with breast cancer.<br />
Methods: Fifty-one premenopausal operable breast cancer patients who were given<br />
adjuvant and neoadjuvant chemotherapy were included in our study. We planned to<br />
evaluate the change <strong>of</strong> serum AMH levels throughout the timeline <strong>of</strong> the study and<br />
ovarian volume-antral follicle numbers measured by transvaginal ultrasonography.<br />
First measurements were performed before chemotherapy and repeated in every<br />
following 3 months for one-year follow-up period.<br />
Results: Interim third month and initial results <strong>of</strong> 31 patients were evaluated. Median<br />
age: 39 (range: 23-48). The results <strong>of</strong> 31 patients’ 3 rd AMH results and the<br />
measurements <strong>of</strong> ovarian volumes and antral follicle numbers <strong>of</strong> 28 patients were<br />
recorded prospectively from database. Initial AMH levels and 3 rd follow-up AMH<br />
levels were compared revealing statistically significant decrease (p = 0.000). When preand<br />
post-chemotherapy measurements were compared right and left ovary volumes<br />
and antral follicle numbers demonstrated statistically significant decrease after<br />
chemotherapy (p = 0.000).<br />
Conclusions: Preliminary data <strong>of</strong> this study showed that 3 rd month AMH levels, antral<br />
follicle numbers and ovarian volumes were significantly lower in contrast to<br />
pretreatment measurements. By the end <strong>of</strong> study period we aimed to evaluate the<br />
effects <strong>of</strong> different chemotherapy regimens on ovarian function and predictive strength<br />
<strong>of</strong> utilized markers for evaluation <strong>of</strong> ovarian function.<br />
Legal entity responsible for the study: Istanbul Bilim University Medical Faculty<br />
Funding: None<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
204P<br />
Dual block versus single agent trastuzumab plus<br />
chemotherapy as neoadjuvant treatment <strong>of</strong> HER2-positive<br />
breast cancer: a meta-analysis <strong>of</strong> randomized trials<br />
M. Clavarezza 1 , M. Puntoni 2 , A. Gennari 1 , L. Paleari 1 , N. Provinciali 1 ,M.D’Amico 1 ,<br />
A. Decensi 1<br />
1 <strong>Oncology</strong> Unit, Ospedali Galliera, Genoa, Italy, 2 Clinical Trial and Biostatistical<br />
Unit, Scientific Direction, Ospedali Galliera, Genoa, Italy<br />
Background: (Neo)adjuvant chemotherapy plus trastuzumab reduces death risk in<br />
HER2-positive breast cancer. Randomized trials assessed HER2 dual block in the<br />
neoadjuvant setting using pathological complete response (pCR) as the outcome<br />
measure. We conducted a meta-analysis <strong>of</strong> randomized trials testing neoadjuvant dual<br />
block versus trastuzumab alone.<br />
Methods: Trials were identified by Medline (PUBMED), ISI Web <strong>of</strong> Science (Science<br />
Citation Index Expanded), Embase, Cochrane library and a reference lists <strong>of</strong> published<br />
studies, review articles, editorials and by hand-searched reports from major cancer<br />
meeting reports.<br />
Results: 8 randomized trials with 1453 patients were identified, 598 (43.6%) were<br />
hormone receptors negative, 774 (56.4%) hormone receptors positive, 832 (57.2%)<br />
received taxanes alone and 621 (42.8%) anthracyclines plus taxanes or the<br />
docetaxel-carboplatin regimen. Dual block was associated with a significant 14%<br />
absolute improvement in pCR rate compared to single agent trastuzumab (Summary<br />
Risk Difference SRD 0.14, 95%CI: 0.09 to 0.19). Interaction test by type <strong>of</strong><br />
chemotherapy was not significant (taxanes-alone: SRD 0.16, 95%CI: 0.10-0.23;<br />
polychemotherapy: SRD 0.10, 95%CI: 0.03-0.18; p-interaction 0.298), while it was<br />
significant by hormone receptors status (hormone receptors negative: SRD 0.19, 95%<br />
CI: 0.12-027; hormone receptors positive: SRD 0.07, 95%CI: 0.01-0.14; p-interaction<br />
0.037). The activity was greater in hormone receptors negative treated with taxanes<br />
alone (SRD 0.25, 95%CI: 0.15 to 0.34), compared to hormone receptors positive or<br />
hormone receptors negative disease treated with polychemotherapy (SRD 0.08, 95%CI:<br />
0.02 to 0.14; p-interaction 0.012).<br />
Table: 204P<br />
Trastuzumab plus<br />
Lapatinib (Clin Cancer<br />
Res 2016)<br />
abstracts<br />
Trastuzumab plus<br />
Lapatinib or Pertuzumab<br />
or Neratinib<br />
number <strong>of</strong> trials 6 8<br />
number <strong>of</strong> patients 1155 1453<br />
% hormone receptors negative 41.8% 43.6%<br />
% taxane-alone 46.2% 57.2%<br />
ΔpCR overall<br />
+13% (95%CI: +14% (95%CI: 0.09-0.19)<br />
0.08-0.19)<br />
p-interaction by type <strong>of</strong> 0.336 0.298<br />
chemotherapy<br />
p-interaction by hormone 0.157 0.037<br />
receptors status<br />
p-interaction by taxane-alone<br />
and hormone receptors<br />
status versus others<br />
0.050 0.012<br />
Conclusions: Based on ΔpCR data, the HER2 dual block plus chemotherapy is a very<br />
active treatment only in HER2-positive, hormone receptors negative breast cancer<br />
treated with taxane monochemotherapy.<br />
Legal entity responsible for the study: E.O. Ospedali Galliera - Genoa<br />
Funding: This meta-analysis was partially supported by AIRC (Associazione Italiana<br />
Ricerca Cancro)<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw364 | vi61
abstracts<br />
205P<br />
Individual approach to the planning <strong>of</strong> neoadjuvant<br />
chemotherapy (NAC) in patients with luminal B breast cancer<br />
P. Kazantseva 1 , E. Slonimskaya 1 , N. Litviakov 2 , M. Tsyganov 2<br />
1 Department <strong>of</strong> General <strong>Oncology</strong>, Tomsk Cancer Research Institute RAMS,<br />
Tomsk, Russian Federation, 2 Laboratory <strong>of</strong> Oncovirology, Tomsk Cancer Research<br />
Institute RAMS, Tomsk, Russian Federation<br />
Background: Breast cancer is a leading cause <strong>of</strong> death in women worldwide.<br />
Neoadjuvant chemotherapy (NAC) is one <strong>of</strong> the treatment options for locally advanced<br />
breast cancer patients. Currently, there are no clinically useful predictive markers <strong>of</strong><br />
response to NAC. We previously identified the chromosome regions in which copy<br />
number variations (CNVs) were correlated with response to NAC. Several studies have<br />
shown associations between drug effects and gene expression levels and specific<br />
mutations.<br />
Methods: The criteria for inclusion in the study were as follows: luminal B breast<br />
cancer and clinical stage II or III disease. The study group consisted <strong>of</strong> 36 patients and<br />
the control group comprised 71 patients. The tissue samples were obtained with a<br />
biopsy prior to NAC. CNVs in biopsy specimens were tested using the high-density<br />
microarray platform. The expression levels <strong>of</strong> TYMS and Top2a were determined by<br />
PCR. Depending on the molecular and genetic characteristics <strong>of</strong> the tumor, patients<br />
began treatment with NAC: docetaxel or FAC (fluorouracil, adriamycin,<br />
сyclophosphamide) or CAX (сyclophosphamide, adriamycin, capecitabine) or CP<br />
(сyclophosphamide, cisplatin) or AD (adriamycin, docetaxel) or surgery. All patients<br />
in the control group received NAC followed by surgery. Response to NAC was assessed<br />
by means <strong>of</strong> International Union Against Cancer criteria.<br />
Results: Based on the findings <strong>of</strong> previous studies and literature data, we had developed<br />
an algorithm <strong>of</strong> personalized treatment with NAC for breast cancer patients. Patients<br />
having CNV markers <strong>of</strong> response to NAC (deletions in АВСВ1, АВСB3, ABCC1,<br />
ABCG2, АВСС5, АВСВ7, deletions in 18р11.1 – 32; 11q21 – 25 and amplification<br />
in1q21.3-44) began treatment with NAC. The choice <strong>of</strong> the NAC regimen depended on<br />
the Тор2а amplification, deletions in BRCA1 and TUBB3, expression level <strong>of</strong> Top2a<br />
and TYMS. Of the 36 patients, 26 had markers <strong>of</strong> response to NAC and began<br />
treatment with NAC. Partial and complete response rate was 88.5 % in the study group<br />
and 53.8% in the control group (p = 0.002).<br />
Conclusions: The CNVs mentioned above could be considered as new markers <strong>of</strong><br />
NAC response. The developed algorithm can be used for personalized treatment <strong>of</strong><br />
breast cancer patients.<br />
Legal entity responsible for the study: P. Kazantseva<br />
Funding: Tomsk Cancer Research Institute, Tomsk, Russian Federation<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
206P<br />
Bevacizumab plus dose-dense neoadjuvant FEC followed by<br />
docetaxel chemotherapy in patients with HER2-negative<br />
breast cancer: a multicentre, phase 2 study by the Hellenic<br />
<strong>Oncology</strong> Research Group<br />
E. Saloustros, I. Boukovinas, K. Kalbakis, P. Katsaounis, A. Ardavanis,<br />
L. Vamvakas, K. Papazisis, E. Prinarakis, T. Skaltsi, V. Georgoulias, D. Mavroudis<br />
Medical <strong>Oncology</strong>, Hellenic <strong>Oncology</strong> Research Group (HORG), Athens, Greece<br />
Background: Addition <strong>of</strong> bevacizumab to standard chemotherapy in the neoadjuvant<br />
setting improves the proportion <strong>of</strong> patients with HER2-negative breast cancer who<br />
achieve pathological complete response. We aimed to assess the addition <strong>of</strong><br />
bevacizumab to dose-dense neoadjuvant chemotherapy.<br />
Methods: We enrolled women with operable HER2-negative breast cancer (T1c-T4<br />
and N0-3). Patients underwent treatment every 2 weeks (with pegfilgrastim support) <strong>of</strong><br />
fluorouracil (500 mg/m 2 ), epirubicin (75 mg/m 2 ), cyclophosphamide (500 mg/m 2 ),<br />
and bevacizumab (10 mg/kg) for 4 cycles followed by docetaxel (75 mg/m 2 )and<br />
bevacizumab for 4 cycles. After surgery, patients received adjuvant radiotherapy, and<br />
hormone therapy (if indicated). The primary endpoint was pathological complete<br />
response in breast and the axilla, and safety <strong>of</strong> the combination. A two-stage trial<br />
design was planned with 15 and 33 patients to enroll, respectively. The trial was<br />
terminated early due to slow accrual and follow-up is ongoing.<br />
Results: Between Oct, 2011, and Apr, 2015, we enrolled 34 patients, <strong>of</strong> whom 3 didn’t<br />
undergo surgery, leaving 31 patients in the primary endpoint analysis. After<br />
neoadjuvant therapy, 5 (16.1%) <strong>of</strong> 31 patients achieved a pathological complete<br />
response according to centralized review. No patient discontinued treatment due to<br />
adverse events. The most frequent grade 3–4 toxicities were neutropenia (23.5%),<br />
nausea and vomiting (5,8%), and febrile neutropenia (2,9%). Only one patient<br />
developed grade III bevacizumab-related toxicity (hypertention). One patient died <strong>of</strong><br />
pneumonia after cycle 8 and before surgery, which was thought to be unrelated to<br />
bevacizumab. After 25,2 months <strong>of</strong> median follow-up (range: 2,3-43,3) five patients<br />
experienced a disease relapse (16,1%).<br />
Conclusions: Our results seem to indicate that the addition <strong>of</strong> bevacizumab to<br />
dose-dense neoadjuvant chemotherapy with FEC and docetaxel, although safe and<br />
feasible, does not provide clinical benefit to patients with non-metastatic<br />
HER2-negative breast cancer. Translational research to identify patients who might<br />
benefit from bevacizumab is needed.<br />
Clinical trial identification: NCT01985841<br />
Legal entity responsible for the study: N/A<br />
Funding: Hellenic <strong>Oncology</strong> Research Group (HORG)<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
207P<br />
Survival impact <strong>of</strong> adjuvant chemotherapy in screening breast<br />
cancer<br />
I. Zarcos Pedrinaci 1 , A. Romero 2 , J. Louro 2 , M. Banqué 2 , M. Vernet 3 , L. Serrano 4 ,<br />
R. Funez 5 , F. Medina 6 , D. Perez 7 , A. Rueda 8 , M. Sala 2 , M. Redondo 9<br />
1 Medical <strong>Oncology</strong>, A.S Hospital Costa del Sol, Malaga, Spain, 2 Epidemiology,<br />
University Hospital del Mar, Barcelona, Spain, 3 Surgery, University Hospital del<br />
Mar, Barcelona, Spain, 4 Pathology, University Hospital del Mar, Barcelona, Spain,<br />
5 Pathology, A.S Hospital Costa del Sol, Malaga, Spain, 6 Surgery, A.S Hospital<br />
Costa del Sol, Malaga, Spain, 7 <strong>Oncology</strong>, A.S Hospital Costa del Sol, Malaga,<br />
Spain, 8 Medical <strong>Oncology</strong>, Hospital Costa del Sol, Malaga, Spain, 9 Research Unit,<br />
A.S Hospital Costa del Sol, Malaga, Spain<br />
Background: Breast cancers (BC) detected by mammographic screening have shown to<br />
have better prognosis than symptomatic ones. The benefit <strong>of</strong> adjuvant chemotherapy<br />
(CT) in some localized BC is controversial, as it has potential side effects. The objective<br />
<strong>of</strong> this study is to analyze survival differences <strong>of</strong> adjuvant CT among screening BC.<br />
Methods: This is a cohort study with 1.248 breast cancers included from 4 screening<br />
national programs, between 2000-2006. Follow-up was ended in 2014. Risk <strong>of</strong> death<br />
was estimated through Cox analysis. Hazard Ratio was adjusted by chemotherapy<br />
groups (with or without CT) and stage.<br />
Results: Two hundred sixty six prevalent cases were diagnosed (41,7% with CT), 633<br />
Incident (40,9% with CT), and 349 interval carcinomas (59,6% with CT). After a<br />
median follow-up <strong>of</strong> 102 months deaths were 22.1% for Interval, 10.4% for Incident<br />
and 7,9% for prevalent carcinomas. Prevalent and Incident carcinomas who did not<br />
receive CT had no differences in death risk with respect to those who received CT<br />
adjusting by the stage. However, comparing to Prevalent carcinomas without CT,<br />
Interval carcinomas have shown an increase risk <strong>of</strong> death more pronounced when CT<br />
is not administered (Table).<br />
Table: 207P Risk <strong>of</strong> death was estimated through Cox analysis. **<br />
Hazard Ratio adjusted by chemotherapy groups (with or without CT)<br />
and stage<br />
Death Risk<br />
HR<br />
aHR**<br />
Screening BC group<br />
Prevalent<br />
Ref<br />
Incident 1,42 (0,87-2,34)<br />
Interval 3,5 (2,15-5,7)<br />
Group + CT<br />
Prevalent without CT Ref Ref<br />
Prevalent with CT 0,54 (0,22-1,34) 1,72 (0,66-4,47)<br />
Incident with CT 1,34 (0,67-2,67) 2,12 (0,92-4,89)<br />
Incident without CT 0,91 (0,45-1,82) 1,82 (0,79-4,17)<br />
Interval with CT 2,44 (1,25-4,75) 3,14 (1,37-7,17)<br />
Interval without CT 3,3 (1,66-6,56) 3,69 (1,56-8,74)<br />
Conclusions: Interval carcinoma is a screen-detected tumor with a worse prognosis<br />
compared to Incident and prevalent carcinomas. Adjuvant CT did not modify survival<br />
in Prevalent and incident carcinomas. Therefore, the detection methods should be<br />
taken into account before administering adjuvant CT.<br />
Legal entity responsible for the study: Red de Investigación en Servicios de Salud en<br />
Enfermedades Crónicas (REDISSEC)<br />
Funding: Red de Investigación en Servicios de Salud en Enfermedades Crónicas<br />
(REDISSEC)<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
208P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Delayed initiation <strong>of</strong> HER2-targeted therapy (HER2Tx) is<br />
associated with a higher risk <strong>of</strong> relapse for early stage (ES)<br />
HER2-positive (HER2+) breast cancer (BrCa)<br />
G. Gullo 1 , R. Bose 1 , N. Walsh 2 , M. Maltese 1 , D. Fennelly 1 , J. Walshe 1 , J. Ballot 3 ,<br />
J. Crown 1<br />
1 Medical <strong>Oncology</strong>, St Vincents University Hospital, Dublin, Ireland, 2 National<br />
Institute for Cellular Biotechnology, Dublin City University, Dublin, Ireland, 3 Medical<br />
<strong>Oncology</strong>, Cancer Clinical Research Trust, Dublin, Ireland<br />
Background: The prognosis <strong>of</strong> HER2+ ESBrCa has improved since the addition <strong>of</strong><br />
trastuzumab (H) to chemotherapy (CRx). Several H/CRx regimens have been validated<br />
vi62 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
in random assignment trials. Some include delayed H, either at the completion <strong>of</strong> CRx<br />
(as per HERA) or, with taxanes (T) after cycles <strong>of</strong> non-H containing CRx with<br />
anthracycline (A) and cyclophosphamide (C) (e.g. AC-TH). Conversely, in the BCIRG<br />
TCH program (C = carboplatin), H is administered from day 1.<br />
Methods: We conducted a retrospective analysis <strong>of</strong> our database <strong>of</strong> all pts with HER2+<br />
ESBrCa (stages I-III) who received H. The date <strong>of</strong> first biopsy (Bx) was recorded as the<br />
initial diagnosis (Dx). The primary endpoint was relapse-free survival (RFS), i.e. time<br />
from start <strong>of</strong> H to the date <strong>of</strong> relapse.<br />
Results: We identified 592 pts treated between September 2001 and March 2013 and<br />
performed outcome analyses on 452 pts with a minimum <strong>of</strong> 36 months <strong>of</strong> follow up<br />
(FU). Pts characteristics: Neoadjuvant (NeoA) 95/Adjuvant (Adj) 357, N+ 233 (52%)/<br />
N-211 (47%)/unknown = 8 (1%), ER+ 282 (62%)/ER- 167 (37%)/unknown 3. Therapy<br />
administered: TCH 251 (56%)/AC-TH 84 (19%)/ other taxane-based + H 37 (8%)/<br />
sequential H 13 (3%)/single-agent H/unknown 18 (4%). Median FU is 70.1 months<br />
(range 5.5-169.6). The median time from BrCa Dx to first H is 11.9 weeks. Overall RFS<br />
rate is 90.5%. The relative risk <strong>of</strong> relapse for pts starting H > 12 weeks from Dx is<br />
significantly increased with an HR 2.55 (95%CI 1.3-4.98 p = 0.006). This effect is<br />
particularly evident in pts with ER negative (p = 0.0069), node positive (p = 0.0197), and<br />
age
abstracts<br />
event (AE) pr<strong>of</strong>ile in the EBC population is shown in the table. The most common<br />
grade 3–4 serious AE (SAE) was decreased ejection fraction (3 patients, all grade 3).<br />
Table: 210P<br />
Patients, n (%) Overall EBC population N = 719<br />
AE 588 (82)<br />
Grade 1 533 (74)<br />
Grade 2 344 (48)<br />
Grade 3 103 (14)<br />
Grade 4 18 (3)<br />
AE leading to discontinuation 33 (5)<br />
SAE 52 (7)<br />
Grade 1 0<br />
Grade 2 18 (3)<br />
Grade 3 24 (3)<br />
Grade 4 13 (2)<br />
Injection-site reaction 105 (15)<br />
Grade 1 91 (13)<br />
Grade 2 14 (2)<br />
Grade 3 1 (
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
deleterious effect on QoL and fatigue in BC pts, no data are available on experience <strong>of</strong><br />
BC pts during this additional one-year treatment period by Trastuzumab. This<br />
case-control study assessed fatigue and QoL during and after Trastuzumab treatment<br />
as compared to age-matched BC pts receiving the same CT without Trastuzumab.<br />
Methods: 70 pts were included (35 pts in each group) on day 1 <strong>of</strong> last cycle <strong>of</strong> CT (first<br />
day <strong>of</strong> Trastuzumab for case group). The primary endpoint was severe fatigue<br />
(FACIT-F < 37) at 9 months (mo) post CT. QoL (Fact-G, Fact-B), fatigue (FACIT-F)<br />
and anxiety/depression (HADS) were assessed at 3, 6, 9, 15 mo post CT.<br />
Results: No statistically significant differences were noted at baseline between groups:<br />
age (48 ± 10 y); marital status (87%); surgery (mastectomy, 42%); CT (all pts received<br />
complete FEC100-Docetaxel treatment except one pt who received only 1 cycle <strong>of</strong><br />
Docetaxel; dose reduction for 12 pts); radiotherapy (84%); hormonotherapy (69%);<br />
anxiety (41%); depression (23%); severe fatigue at baseline (66%). At 9 mo post CT,<br />
proportion <strong>of</strong> pts with severe fatigue (39%) did not statistically significantly differ<br />
between groups and a significant reduction <strong>of</strong> severe fatigue from baseline was noted<br />
(p < 0.0001). QoL and severe fatigue did not differ between groups over time.<br />
Conclusions: Trastuzumab treatment was not shown to have a deleterious impact on<br />
fatigue and QoL in adjuvant setting as compared to CT with no indication to<br />
Trastuzumab treatment. CT-induced fatigue appears to improve similarly between<br />
women receiving or not Trastuzumab, despite a one-year longer duration <strong>of</strong> treatment.<br />
Clinical trial identification: Clinical trial information: NCT01400438<br />
Legal entity responsible for the study: N/A<br />
Funding: Ligue contre le Cancer and Association “Le Cancer du Sein, Parlons-En !”,c/<br />
o Estée Lauder - Prix Ruban Rose<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
213P<br />
Age alone or Charlson comorbidity index – what guides<br />
anticancer treatment choice in newly diagnosed,<br />
non-metastatic breast cancer in the real life setting?<br />
A. Badora-Rybicka, E. Nowara, D. Starzyczny-Słota<br />
The Medical and Experimental <strong>Oncology</strong> Department, Maria Sklodowska Curie<br />
MSC Memorial Cancer Institute in Gliwice, Gliwice, Poland<br />
Background: Breast cancer is the the most common malignancy in woman and its<br />
frequency increases with age. The aim <strong>of</strong> the study was to asses if age itself impacts<br />
treatment choice in non-metastatic breast cancer patients and is associated with<br />
increased treatment toxicity in a real life observational setting. We also investigated<br />
whether Charlson comorbidity index values were correlated with PFS and OS.<br />
Methods: We conducted a retrospective analysis <strong>of</strong> medical records <strong>of</strong> 730 patients<br />
with newly diagnosed, non-metastatic breast cancer, treated in Maria<br />
Skłodowska-Curie Memorial Cancer Center and Institute <strong>of</strong> <strong>Oncology</strong>, Gliwice Branch<br />
between 2007 and 2013. This analysis is preliminary, since the data collection is not<br />
completed yet. 244 patients were above 65 years old and 147 – above 70 years old.<br />
Variables included in uni- and multivariate analysis were: age, ECOG-PS, clinical stage<br />
<strong>of</strong> the disease, subtype <strong>of</strong> breast cancer (according to St Gallen 2015 classification).<br />
Results: Older patients or in poor ECOG-PS were less likely to receive preoperative<br />
chemotherapy (p = 0.0073 and p < 0.001, respectively) or undergo surgery (p = 0.01<br />
and p < 0.001, respectively). Older age (p < 0.0001) and luminal subtype <strong>of</strong> breast<br />
cancer (p < 0.0001) were associated with lower chance <strong>of</strong> adjuvant chemotherapy. In<br />
older patients (p < 0.0001) with poor PS (p = 0.04) hormonotherapy as the only<br />
treatment method was chosen significantly more common. Older patients were more<br />
likely to experience hematological toxicities (p = 0.03), including grade 3-4 toxicities<br />
(p = 0.04), after chemotherapy. Nausea and vomiting were significantly less common<br />
among older patients receiving chemotherapy (p = 0.03). The independent prognostic<br />
factor for shorter PFS was advanced pathological stage (p = 0.002) and for shorter OS –<br />
patients age (p = 0.02) and HER2 overexpression (p = 0.006). Higher Charlson<br />
comorbidity index was significantly correlated with shorter PFS (p < 0.0001) and OS<br />
(p < 0.0001), independent <strong>of</strong> patients age.<br />
Conclusions: According to this preliminary analysis, older breast cancer patients are<br />
less likely to receive chemotherapy or undergo surgery. Charlson comorbidity index<br />
was strongly correlated with shorter PFS and OS.<br />
Legal entity responsible for the study: Maria Skłodowska-Curie Memorial Cancer<br />
Center and Institute <strong>of</strong> <strong>Oncology</strong>, Gliwice Branch. Poland<br />
Funding: Maria Skłodowska-Curie Memorial Cancer Center and Institute <strong>of</strong><br />
<strong>Oncology</strong>, Gliwice Branch. Poland<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
214P<br />
Effect <strong>of</strong> polypharmacy on treatment preferences and<br />
outcome in older breast cancer patients<br />
M.A. Sendur 1 ,K.Sılay 2 , S. Aksoy 3 , S. Özbek 4 , N. Ozdemir 1 , K. Altundag 3<br />
1 Department <strong>of</strong> Medical <strong>Oncology</strong>, YıldırımBeyazıt University, Faculty <strong>of</strong> Medicine,<br />
Ankara, Turkey, 2 Department <strong>of</strong> Geriatric Medicine, YıldırımBeyazıt University,<br />
Faculty <strong>of</strong> Medicine, Ankara, Turkey, 3 Department <strong>of</strong> Medical <strong>Oncology</strong>, Hacettepe<br />
University Faculty <strong>of</strong> Medicine, Ankara, Turkey, 4 Department <strong>of</strong> Internal Medicine,<br />
YıldırımBeyazıt University, Faculty <strong>of</strong> Medicine, Ankara, Turkey<br />
Background: In older cancer patients, polypharmacy is at least as common as it is in<br />
individuals <strong>of</strong> the same age without cancer. However, information related to<br />
polypharmacy in older cancer patients is limited. The aim <strong>of</strong> this study is to evaluate<br />
the prevalence <strong>of</strong> polypharmacy in older breast cancer patients at the time <strong>of</strong> diagnosis<br />
and its association with treatment preferences and disease outcome.<br />
Methods: A total <strong>of</strong> 418 breast cancer patients who were 65 and older at the time <strong>of</strong><br />
diagnosis between 2001 and 2014 were retrospectively analyzed. Polypharmacy has<br />
been defined according to the number <strong>of</strong> drugs that an individual takes or to the risk <strong>of</strong><br />
at least one severe drug interaction. Patients were considered as polypharmacy (Arm A,<br />
n = 84) and non-polypharmacy group (Arm B, n = 334). Kaplan–Meier survival<br />
analysis was carried out for disease free survival (DFS) and overall survival (OS).<br />
Two-sided P values <strong>of</strong> 0.05). COX proportional hazard<br />
regression model indicated that chemotherapy did not have significant correlation with<br />
DFS (hazard ratio, HR = 0.371, p > 0.05); while it might be a protective factor on OS<br />
(HR = 0.108, p = 0.030), which appeared a high consistency with poor-prognosis<br />
factors such as histological grade, HR, HER2 and Ki67. The stratified analysis showed<br />
that MBC with positive lymph node and high histological grade have benefited from<br />
chemotherapy.<br />
Conclusions: The utility <strong>of</strong> chemotherapy should be considered in the high-risk level<br />
<strong>of</strong> recurrence/metastasis in MBC.<br />
Legal entity responsible for the study: Zhejiang Cancer Hospital<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw364 | vi65
abstracts<br />
Funding: Zhejiang Cancer Hospital<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
216P<br />
The impact <strong>of</strong> delay in adjuvant radiotherapy in the combined<br />
modality treatment <strong>of</strong> early stage breast cancer: single<br />
institutional experience<br />
M. Ezz El Din, D. Abd El Ghany<br />
Clinical <strong>Oncology</strong>, Ain Shams University Faculty <strong>of</strong> Medicine, Cairo, Egypt<br />
Background: To study how the timing <strong>of</strong> radiation influences local control,<br />
disease-free survival (DFS) and overall survival (OS) in patients being treated with<br />
chemotherapy and radiation for early stage carcinoma <strong>of</strong> the breast.<br />
Methods: In this retrospective study the medical records <strong>of</strong> patients who received<br />
adjuvant chemotherapy and radiotherapy (RT) for early stage breast cancer (I- II) after<br />
definitive surgery at the department <strong>of</strong> Clinical <strong>Oncology</strong>, Ain Shams University<br />
Hospitals were collected and reviewed.<br />
Results: Between 2007 and 2009, 118 patients were collected and included for analysis.<br />
Patients were divided into 2 groups: Group A consisted <strong>of</strong> 56 patients that started<br />
adjuvant RT < 6 months after surgery and group B included 62 patients who had RT<br />
delay ≥ 6 months. Both groups were matched demographically. Comparisons <strong>of</strong> local<br />
control, overall survival and disease-free survival between group A and group B<br />
patients all favored group A. At 5-years the local control rates were 88% vs 72%<br />
(p = 0.001), OS rates were 90% vs 78 % (p = 0.01), while DFS rates were 86% vs 64%<br />
(p= 0.01). Analysis <strong>of</strong> other prognostic factors; age, tumour size, lymph node status,<br />
grade, HER2 status, type <strong>of</strong> surgery (modified radical mastectomy vs breast conserving<br />
surgery), chemotherapy regimen and local radiotherapy received were analyzed. Larger<br />
tumor size >2 and lymph node positive disease predicted for worse DFS (p = 0.05) and<br />
OS (p = 0.006).<br />
Conclusions: In patients requiring chemotherapy and radiation treatments for early<br />
stage breast cancer, a delay in the initiation <strong>of</strong> radiation for a period exceeding 6<br />
months from diagnosis resulted in a higher local failure rate. Furthermore, this higher<br />
local failure rate was associated with an increased rate <strong>of</strong> distant metastases and a<br />
reduced overall survival rate.<br />
Legal entity responsible for the study: Ain Shams University<br />
Funding: Ain Shams University<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
217P<br />
Concurrent paclitaxel and radiotherapy for node positive<br />
breast cancer<br />
M.A.R. Kassem 1 , A.A. Hassan 1 , N.Y. Ibrahim 2 , A.A.M. Toeama 3<br />
1 <strong>Oncology</strong>, Kasr Al-Aini Ctr <strong>of</strong> Clin <strong>Oncology</strong> and Nuclear Medicine(NEMROCK),<br />
Cairo Univ, Cairo, Egypt, 2 <strong>Oncology</strong>, Faculty <strong>of</strong> Medicine Kasr Al Ainy - Cairo<br />
University, Cairo, Egypt, 3 <strong>Oncology</strong>, Assuit University, Cairo, Egypt<br />
Background: Concurrent chemo-radiotherapy in breast cancer (BC) may yield better<br />
local control with minimal toxicity in node positive patients. The feasibility <strong>of</strong><br />
paclitaxel with radiotherapy was assessed for tolerability, cosmetic outcome as well as<br />
local control<br />
Methods: All female BC with stage II-III were included in the study. Adjuvant<br />
chemotherapy was 4 cycles AC (Doxorubicin 60mg/m2+ cyclophosphamide 600mg/<br />
m2) followed by 4cycles <strong>of</strong> Paclitaxel 60mg/m2 weekly for 12 weeks concurrent with<br />
3D Conformal radiotherapy in a dose <strong>of</strong> 45Gy/20ttt/4wks to the whole breast and<br />
supraclavicular nodal region. Boost <strong>of</strong> 10Gy/5ttt was given to the tumor bed in<br />
conservative cases. Evaluation <strong>of</strong> lung function was done by carbon monoxide<br />
diffusion. Radiotherapy toxicity and breast cosmesis were assessed by the RTOG and<br />
Harvard criteria respectively. The cosmesis was assessed and scored at the beginning &<br />
end <strong>of</strong> RT and every 6 months thereafter. This was done by patient (subjective score)<br />
and physician (objective score) by comparing it with the contralateral untreated breast.<br />
Results: There were 40 patients, 50% underwent modified radical mastectomy and the<br />
other half had conservative surgery. The mean age was 50 years (31-70). With<br />
24months follow up, the overall survival was 92% with no local relapse or radiation<br />
pneumonitis. There was no significant change in carbon monoxide diffusion after<br />
radiotherapy (p: 0.55). There was 15% delay in radiotherapy mainly due to acute GIII<br />
skin toxicity 7.5% followed equally by mucositis, tender erythema and wound gap. In<br />
only one patient, acute cosmesis and grade III skin toxicity was related to the volume <strong>of</strong><br />
irradiated breast tissue. At the last follow up, the majority <strong>of</strong> patients declared excellent<br />
score in 62.5%, good in 20%, fair in 10% and poor in 7.5%. Subjective patient’s<br />
satisfaction for the shape, color &size <strong>of</strong> the treated breast was 93%.<br />
Conclusions: In conclusion, concurrent chemo-radiotherapy with weekly paclitaxel<br />
minimized the treatment duration with acceptable tolerance, cosmesis and good local<br />
control<br />
Legal entity responsible for the study: Kasr Alainy Center <strong>of</strong> <strong>Oncology</strong> and Nuclear<br />
Medicine<br />
Funding: Kasr Alainy Center <strong>of</strong> <strong>Oncology</strong> and Nuclear Medicine<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
218P<br />
Outcomes for radiation associated angiosarcoma <strong>of</strong> the breast<br />
J. Joseph, E. Thomas, S. Kumar<br />
<strong>Oncology</strong>, The Leeds Teaching Hospital NHS Trust St. James University Hospital,<br />
Leeds, UK<br />
Background: Angiosarcoma is a rare late effect <strong>of</strong> radiotherapy following early breast<br />
cancer treatment. This study looked at the management and outcomes for radiation<br />
associated angiosarcoma at our Cancer centre serving a population <strong>of</strong> 2.5 million<br />
Methods: All patients diagnosed with breast angiosarcoma from Jan 1997- March 2016<br />
were identified from electronic medical records. 41patients were identified. 5 patients<br />
had primary angiosarcoma and were excluded. 36 had prior adjuvant radiotherapy for<br />
breast cancer and formed the study cohort. All patients were discussed by the central<br />
Sarcoma multidisciplinary team for pathology review and management planning.<br />
Patient demographics, breast cancer treatment, radiotherapy details, date <strong>of</strong> diagnosis<br />
<strong>of</strong> radiation associated angiosarcoma(RAS) and surgical treatment details and<br />
pathological parameters <strong>of</strong> RAS including grade, size and margin information was<br />
collated. Date <strong>of</strong> recurrence and date <strong>of</strong> death were collected. Excel spreadsheet and<br />
SPSS were used to analyse the data.<br />
Results: Median follow up was 5 years (Range 0.2-18 years). Median age at diagnosis<br />
was 70 years (Range 37-85). 32 patients had wide excision and 4 mastectomy for breast<br />
cancer. All had whole breast radiotherapy -40 Gray in 15 fractions and 7 had additional<br />
breast boost radiation to tumour bed. Median time from radiotherapy to developing<br />
angiosarcoma was 7 years (Range 2 - 17). 32 patients had surgery for RAS with radical<br />
intent. 18 had clear (>10mm) and 10 patients had close margins(
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Funding: Clovis <strong>Oncology</strong> Inc. This study has been endorsed by Cancer Research UK<br />
(CRUK/12/034)<br />
Disclosure: N. Turner: The Chief Investigator has received advisory board honoraria<br />
from Clovis <strong>Oncology</strong> Inc.All other authors have declared no conflicts <strong>of</strong> interest.<br />
220TiP<br />
Improving outcomes in triple-negative breast cancer (TNBC)<br />
using molecular characterization and diagnostic imaging to<br />
identify and treat chemo-insensitive disease<br />
S.L. Moulder 1 , J.K. Litton 1 , E. Mittendorf 2 ,W.Yang 3 , N. Ueno 4 , K.R. Hess 5 ,<br />
V. Valero 4 , R.K. Murthy 1 , N. Ibrahim 1 , B. Lim 1 , B.K. Arun 1 , A. Thompson 2 ,<br />
H. Piwnica-Worms 6 , D. Tripathy 7 , W.F. Symmans 8<br />
1 Breast Medical <strong>Oncology</strong>, MD Anderson Cancer Center, Houston, TX, USA,<br />
2 Department <strong>of</strong> Surgery, MD Anderson Cancer Center, Houston, TX, USA,<br />
3 Diagnostic Imaging, MD Anderson Cancer Center, Houston, TX, USA, 4 Breast<br />
Medical <strong>Oncology</strong>, MD Anderson Cancer Center, Houston, TX, USA,<br />
5 Biostatistics, MD Anderson Cancer Center, Houston, TX, USA, 6 MD Anderson<br />
Cancer Center, Houston, TX, USA, 7 Department <strong>of</strong> Breast Medical <strong>Oncology</strong>, MD<br />
Anderson Cancer Center, Houston, TX, USA, 8 Molecular Diagnostics, MD<br />
Anderson Cancer Center, Houston, TX, USA<br />
Background: TNBC treated using neoadjuvant chemotherapy (NACT) has a varied<br />
prognosis with 50% <strong>of</strong> patients (pts) having excellent response to treatment (pCR/<br />
RCB-I) and excellent prognosis, while 50% have marked residual disease (RCB-II-III)<br />
and significantly worse prognosis. Lack <strong>of</strong> response to an initial NACT regimen also<br />
indicates a low chance (5%) <strong>of</strong> achieving pCR with subsequent chemotherapy, even if<br />
drugs are changed.<br />
Trial design: This randomized study will determine the impact <strong>of</strong> predicting<br />
chemosensitivity to NACT using molecular characterization combined with diagnostic<br />
imaging and determine if <strong>of</strong>fering a clinical trial <strong>of</strong> selected targeted therapy will<br />
impact outcomes (as measured by pCR and RCB) in predicted chemo-insensitive<br />
disease. The algorithm uses a pre-defined genomic signature (JAMA,<br />
2011;305:1873-81) and response to an intitial course <strong>of</strong> anthracycline based NACT to<br />
determine predicted sensitivity to chemotherapy. Pts undergo biopsy <strong>of</strong> the primary<br />
tumor prior to NACT and are randomized 2:1 to know the molecular testing results<br />
versus not (control). For the second phase <strong>of</strong> neoadjuvant therapy, pts who fit<br />
molecular/imaging criteria for chemo-insensitive disease after AC are <strong>of</strong>fered a clinical<br />
trial based upon comprehensive molecular pr<strong>of</strong>iling (if known) or based upon<br />
physician/patient choice if randomized to the control arm. Pts with chemo-sensitive<br />
disease continue with taxane based NACT. Success is defined as improvement in the<br />
rate <strong>of</strong> excellent pathologic response (pCR/RCB-I) from 50%– > 64% using the<br />
platform. A maximum <strong>of</strong> 360 pts will be randomized using a group sequential design<br />
with one-sided O’Brien-Fleming boundaries, with up to two equally spaced binding<br />
interim tests for both futility and superiority and one final test, having an overall Type I<br />
error .05 and power .80 to detect a response rate improvement from a null rate <strong>of</strong> .50 to<br />
a target value <strong>of</strong> .642.<br />
Clinical trial identification: ClinicalTrials.gov Identifier: NCT02276443 (10/21/2014)<br />
Legal entity responsible for the study: MD Anderson<br />
Funding: MD Anderson Moon Shot Program<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
221TiP<br />
abstracts<br />
A randomized phase II study to investigate the addition <strong>of</strong><br />
PD-L1 antibody MEDI4673 (durvalumab) to a<br />
taxane-anthracycline containing chemotherapy in triple<br />
negative breast cancer (GeparNuevo)<br />
S. Loibl 1 , A. Schneeweiss 2 , N. Burchardi 3 , J-U. Blohmer 4 , C. Hanusch 5 ,S.<br />
D. Costa 6 , J. Huober 7 , C. Jackisch 8 , G. von Minckwitz 9 , S. Kümmel 10 ,<br />
S. Paepke 11 , C. Denkart 12 , M. Untch 13<br />
1 Medicine and Research, German Breast Group, Neu-Isenburg, Germany,<br />
2 National Center for Tumor Diseases, University Hospital, Heidelberg, Germany,<br />
3 Medicine and Research, German Breast Group (GBG) Forschungs GmbH,<br />
Neu-Isenburg, Germany, 4 Brustzentrum, Charite Berlin Mitte, Berlin, Germany,<br />
5 Frauenklinik, Rotkreuzklinikum München, Munich, Germany,<br />
6 Universitätsfrauenklinik Magdeburg, Otto-von Guericke-Universität, Magdeburg,<br />
Germany, 7 Gynecology, Ulm Medical University, Ulm, Germany, 8 Frauenklinik,<br />
Sana Klinikum Offenbach, Offenbach, Germany, 9 Department <strong>of</strong> Medical<br />
<strong>Oncology</strong>, German Breast Group, Neu-Isenburg, Germany, 10 Frauenklinik, Kliniken<br />
Essen Mitte Evang. Huyssens-Stiftung, Essen, Germany, 11 Frauenklinik,<br />
Technische Universität München, Munich, Germany, 12 Institute <strong>of</strong> Pathology,<br />
Charite Berlin Mitte, Berlin, Germany, 13 Frauenklinik, Helios Klinikum Berlin Buch,<br />
Berlin, Germany<br />
Background: Chemotherapy (CT) is the only treatment option in triple negative breast<br />
cancer (TNBC) since so far no targeted agents are available. High amounts <strong>of</strong> tumor<br />
infiltrating lymphocytes (TILs) in TNBC are associated with higher treatment response<br />
and better outcome. Immunotherapy alone or in combination might be used to<br />
increase pathological complete response (pCR, ypT0 ypN0). Adding an anti-PD-L1<br />
checkpoint inhibitor (Durvalumab) to standard CT might be a valid option.<br />
Trial design: GeparNuevo will randomize patients to Durvalumab 1500 mg i.v. or<br />
placebo every 4 weeks. Monotherapy (750 mg i.v.) is given for the first 2 weeks<br />
(window phase), followed by a biopsy and Durvalumab/placebo plus nab-paclitaxel<br />
(nP) 125 mg/m 2 weekly for 12 weeks followed by Durvalumab/placebo plus epirubicin/<br />
cyclophosphamide every 2 weeks for 4 cycles. Randomization will be stratified by TILs.<br />
Patients with primary cT1b-cT4a-d disease, centrally confirmed TNBC, and Ki-67 and<br />
TILs status on core biopsy can be included. Stromal TILs will be evaluated as no<br />
(≤10%) vs intermediate (11-59%) immune infiltrate vs lymphocyte predominant breast<br />
cancer (≥60%). PD-L1 status, immune markers and other predefined biomarkers will<br />
be prospectively assessed. Primary objective is to compare pCR rates. Secondary<br />
objectives are pCR rates in stratified subpopulations and according to other definitions;<br />
response rates; breast conservation rate; toxicity and compliance; quality <strong>of</strong> life; and<br />
survival. Change in TILs, Ki67 and other biomarkers before CT, after the window<br />
phase and after CT will be correlated with outcome. Six safety interim analyses<br />
focusing especially on immune-mediated adverse events are planned. It is planned to<br />
recruit 174 patients into this phase II trial. Recruitment has started in QII/2016 and is<br />
planned for 18 months in 30 sites in Germany.<br />
Legal entity responsible for the study: German Breast Group<br />
Funding: AstraZeneca<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw364 | vi67
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong> 27 (Supplement 6): vi68–vi99, 2016<br />
doi:10.1093/annonc/mdw365<br />
breast cancer, locally advanced and<br />
metastatic<br />
222O<br />
BOLERO-4: Phase 2 trial <strong>of</strong> first-line everolimus (EVE) plus<br />
letrozole (LET) in estrogen receptor–positive (ER+), human<br />
epidermal growth factor receptor 2–negative (HER2−)<br />
advanced breast cancer (BC)<br />
M. Royce 1 , C. Villanueva 2 , M. Ozguroglu 3 , T. Bachelot 4 , S. Azevedo 5 , F. Melo<br />
Cruz 6 , R. Hegg 7 , M. Debled 8 , W.J. Gradishar 9 , C. Manlius 10 , A. Ridolfi 11 , J. Lin 12 ,<br />
F. Ringeisen 13 , F. Cardoso 14<br />
1 Department <strong>of</strong> Internal Medicine, University <strong>of</strong> New Mexico, Albuquerque, NM,<br />
USA, 2 Department <strong>of</strong> Medical <strong>Oncology</strong>, CHU Besançon, Hôpital Jean Minjoz,<br />
Besançon, France, 3 Medical <strong>Oncology</strong>, Istanbul University Institute <strong>of</strong> <strong>Oncology</strong>,<br />
Istanbul, Turkey, 4 Service Oncologie Medicale, Centre Léon Bérard, Lyon, France,<br />
5 <strong>Oncology</strong>, Hospital de Clinicas de Porto Alegre Universidade Federal Do Rs,<br />
Porto Alegre, Brazil, 6 <strong>Oncology</strong>, Instituto Brasileiro de Controle do Cancer, Sao<br />
Paulo, Brazil, 7 Department <strong>of</strong> Medicine, Hospital Perola Byington, Sao Paulo,<br />
Brazil, 8 Medical <strong>Oncology</strong>, Institute Bergonié, Bordeaux, France, 9 Hematology/<br />
<strong>Oncology</strong>, Northwestern University Feinberg School <strong>of</strong> Medicine, Chicago, IL,<br />
USA, 10 <strong>Oncology</strong>, Novartis Pharma AG, Basel, Switzerland, 11 <strong>Oncology</strong>, Novartis<br />
Pharma S.A.S., Rueil-Malmaison, France, 12 <strong>Oncology</strong>, Novartis Pharmaceuticals<br />
Corporation, East Hanover, NJ, USA, 13 <strong>Oncology</strong>, Novartis Pharma, Basel,<br />
Switzerland, 14 Breast Unit, Champalimaud Clinical Centre, Lisbon, Portugal<br />
223O<br />
Anti-tumor activity <strong>of</strong> PM01183 (lurbinectedin) in BRCA1/<br />
2-associated metastatic breast cancer patients: results <strong>of</strong> a<br />
single-agent phase II trial<br />
J. Balmaña 1 , C. Cruz 1 , B.K. Arun 2 , M. Telli 3 , J. Garber 4 , S. Domchek 5 ,C.<br />
M. Fernandez 6 , C. Kahatt 6 , S. Szyldergemajn 6 , A. Soto-Matos 6 , A. Perez de<br />
la Haza 6 , J.A. Perez Fidalgo 7 , A. Lluch-Hernandez 7 , S. Antolin 8 , N.M. Tung 9 ,L.<br />
T. Vahdat 10 , R. Lopez 11 , S.J.J. Isak<strong>of</strong>f 12<br />
1 Medical <strong>Oncology</strong>, Hospital Vall d’Hebron and Vall d’Hebron Institute <strong>of</strong><br />
<strong>Oncology</strong>, Barcelona, Spain, 2 Breast Medical <strong>Oncology</strong>, MD Anderson Cancer<br />
Center, Houston, TX, USA, 3 Medical <strong>Oncology</strong>, Stanford University Medical<br />
Center, Stanford, CA, USA, 4 Medical <strong>Oncology</strong>, Dana Farber Cancer Institute,<br />
Boston, MA, USA, 5 Medical <strong>Oncology</strong>, Hospital <strong>of</strong> the University <strong>of</strong> Pennsylvania,<br />
Philadelphia, PA, USA, 6 Clinical Development, PharmaMar SA, Colmenar Viejo,<br />
Spain, 7 Medical <strong>Oncology</strong>, Hospital Clinico Universitario de Valencia, Valencia,<br />
Spain, 8 Medical <strong>Oncology</strong>, Complejo Universitario Hospitalario La Coruña, A<br />
Coruna, Spain, 9 Medical <strong>Oncology</strong>, Beth Israel Deaconess Medical Center,<br />
Boston, MA, USA, 10 Medical <strong>Oncology</strong>, Weill Cornell Medicine, New York, NY,<br />
USA, 11 Medical <strong>Oncology</strong>, Complejo Hospitalario Universitario de Santiago de<br />
Compostela, Santiago De Compostela, Spain, 12 Medical <strong>Oncology</strong>,<br />
Massachusetts General Hospital, Boston, MA, USA<br />
abstracts<br />
© European Society for Medical <strong>Oncology</strong> 2016. Published by Oxford University Press on behalf <strong>of</strong> the European Society for Medical <strong>Oncology</strong>.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com.
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
224PD<br />
Efficacy and safety <strong>of</strong> BCD-022, trastuzumab biosimilar<br />
candidate, compared to herceptin: Results <strong>of</strong> international<br />
multicenter randomized double blind study in patients with<br />
HER2+ mBC<br />
M. Shustova 1 , O. Burdaeva 2 , S. Alexeev 3 , K. Shelepen 4 , A. Khorinko 5 ,<br />
G. Mukhametshina 6 , L. Sheveleva 7 , R. Ivanov 1<br />
1 Medical Department, JSC "BIOCAD", St. Petersburg, Russian Federation,<br />
2 Chemotherapy Department, Arkhangelsk Regional Clinical <strong>Oncology</strong> Dispensary,<br />
Arkhangelsk, Russian Federation, 3 Therapeutic <strong>Oncology</strong>, N.N.Petrov Research<br />
Inst. <strong>of</strong> <strong>Oncology</strong>, St. Petersburg, Russian Federation, 4 <strong>Oncology</strong> Department,<br />
Brest Regional Oncologic Dispensary, Brest, Belarus, 5 Chemotherapy<br />
Department, Perm Regional Oncological Dispensary, Perm, Russian Federation,<br />
6 Chemotherapy Department, Kazan Clinical <strong>Oncology</strong> Center, Kazan, Russian<br />
Federation, 7 Chemotherapy Department, Volgograd Regional Oncologic<br />
Dispensary, Volgograd, Russian Federation<br />
Background: BCD-022 demonstrated equivalence to Herceptin in a comprehensive<br />
comparability physicochemical, non-clinical PK and PD studies, as well as phase I PK<br />
clinical study in patients with HER2+ mBC.<br />
Methods: 126 patients with HER2-positive metastatic BC were randomly assigned into<br />
2 groups at a ratio <strong>of</strong> 1:1 to receive BCD-022 or Herceptin at a loading dose <strong>of</strong> 8 mg/kg<br />
and then in maintenance dose <strong>of</strong> 6 mg/kg in combination with paclitaxel (175 mg/m 2 )<br />
every 3 weeks up to 6 cycles <strong>of</strong> therapy or until progression or unbearable toxicity.<br />
Results: ORR (primary endpoint) in both groups had no statistically significant<br />
differences: 53.57% (95% CI 40.70 – 65.98%) in BCD-022 group and 53.70% (95% CI<br />
40.60 – 66.31%) in Herceptin group. The lower limit <strong>of</strong> 95% CI for ORR difference<br />
between the groups (-19.83%) did not exceed the non-inferiority margin, hence<br />
BCD-022 is non-inferior to Herceptin. There were also no differences between the<br />
groups for all other efficacy parameters: CR (5.36 vs 3.70%), PR (48.21 vs 50.00%), SD<br />
(25.00 vs 25.93%) and progression rate (21.43 vs 20.37%) in BCD-022 and Herceptin<br />
group, respectively. AEs pr<strong>of</strong>iles <strong>of</strong> BCD-022 and Herceptin were equivalent. Rate <strong>of</strong> all<br />
observed AEs including severe AEs had no statistically significant difference between<br />
the groups. Most AEs were associated with chemotherapy: neutropenia (73.02 vs<br />
73,77%), anemia (82.54 vs 77.05%), leukopenia (73.02 vs 68.85%), lymphopenia (69.84<br />
vs. 65.57%), thrombocytopenia (17.46 vs 29.51%), hyperglycemia (57.14 vs 70.49%),<br />
ALP increase (38.68 vs 42.62%), AST increase (42.86 vs 42.62%), ALT increase (33.33<br />
vs 40.98%), alopecia (33.33 vs 34.43%), arthralgia (17.46 vs 18.03%) etc. Cardiovascular<br />
events specific for trastuzumab included: tachycardia (34.92 vs 19.67%), arterial<br />
hypertension (20.63 vs 18.03%), atrial fibrillation (0 vs 3.28%), extrasystoles (0% vs<br />
1.64%), CAD gr.1 (1.59 vs 0%) and aggravated myocardiodystrophy (1.59 vs 0%).<br />
Binding antibodies with neutralizing activity were detected only in 1 patient in each<br />
group that indicated to low immunogenic potential <strong>of</strong> both drugs.<br />
Conclusions: BCD-022 demonstrated non-inferiority to Herceptin in patients with<br />
HER2+ mBC.<br />
Clinical trial identification: NCT01764022<br />
Legal entity responsible for the study: JSC "BIOCAD"<br />
Funding: JSC "BIOCAD"<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
225PD<br />
Impact <strong>of</strong> palbociclib plus letrozole on health related quality<br />
<strong>of</strong> life (HRQOL) compared with letrozole alone in treatment<br />
naïve postmenopausal patients with ER+ HER2- metastatic<br />
breast cancer (MBC): results from PALOMA-2<br />
H. Rugo 1 , V. Dieras 2 , K.A. Gelmon 3 , R. Finn 4 , D. Slamon 5 , M. Miguel 6 , P. Neven 7 ,<br />
J. Ettl 8 , Y. Shparyk 9 , A. Mori 10 , D.R. Lu 11 , H. Bhattacharyya 12 , C.H. Bartlett 13 ,<br />
S. Iyer 14 , S. Johnston 15 , N. Harbeck 16<br />
1 Medicine, UCSF Helen Diller Family Comprehensive Cancer Center,<br />
San Francisco, CA, USA, 2 Department <strong>of</strong> Medical <strong>Oncology</strong>, Institut Curie, Paris,<br />
France, 3 Medical <strong>Oncology</strong>, British Columbia Cancer Agency, Vancouver, BC,<br />
Canada, 4 Medical <strong>Oncology</strong>, UCLA - School <strong>of</strong> Medicine, Los Angeles, CA, USA,<br />
5 Hematology/<strong>Oncology</strong>, UCLA Medical Center, Santa Monica, Santa Monica, CA,<br />
USA, 6 Medical <strong>Oncology</strong> Service, Hospital General Universitario Gregorio<br />
Marañon, Madrid, Spain, 7 <strong>Oncology</strong>, University Hospitals Leuven - Campus<br />
Gasthuisberg, Leuven, Belgium, 8 <strong>Oncology</strong>, Technische Universität München,<br />
Munich, Germany, 9 Department <strong>of</strong> Chemotherapy, Lviv State Regional Treatment<br />
and Diagnostics <strong>Oncology</strong> Center, Lviv, Ukraine, 10 Clinical Development, Pfizer,<br />
Milan, Italy, 11 Biostatistics, Pfizer, La Jolla, CA, USA, 12 Statistics, Pfizer,Inc,<br />
New York, NY, USA, 13 Global Medical, Pfizer,Inc, New York, NY, USA, 14 Global<br />
Outcomes & Evidence, Pfizer, Inc, New York, NY, USA, 15 Medical <strong>Oncology</strong>, Royal<br />
Marsden Hospital NHS Foundation Trust, London, UK, 16 Breast Center, University<br />
<strong>of</strong> Munich, Munich, Germany<br />
Background: Palbociclib plus letrozole significantly improved progression free survival<br />
(PFS) compared to letrozole alone in the phase III PALOMA-2 trial. QOL is a critical<br />
consideration when adding targeted agents to hormone therapy in metastatic breast<br />
cancer (MBC). We compared patient reported HRQOL in treatment naïve<br />
postmenopausal patients with ER + , HER2- MBC in PALOMA-2 (Pfizer:<br />
NCT01740427).<br />
Methods: PALOMA-2 randomized patients 2:1 to palbociclib + letrozole (N= 444) or<br />
placebo + letrozole (N= 222). Patient reported outcomes were assessed at baseline, day<br />
1 <strong>of</strong> cycle 2, 3 and day 1 <strong>of</strong> every other cycle from cycle 5 until end <strong>of</strong> treatment using<br />
the Functional Assessment <strong>of</strong> Cancer Therapy – Breast (FACT-B) questionnaire.<br />
FACT-B includes FACT-General (FACT-G) and BC-specific subscale (BCS). FACT-B<br />
produces five subscale scores: physical well-being (PWB), social/family well-being<br />
(SWB), emotional well-being (EWB), functional wellbeing (FWB), and a BC subscale<br />
(BCS), used to derive overall FACT-B, FACT-G, and Trial Outcome Index (TOI)<br />
scores. A higher score indicates a better QOL. Repeated measures mixed-effects<br />
analyses were performed to compare between treatments change from baseline in each<br />
subscale and FACT-B scores, controlling for baseline.<br />
Results: Baseline scores were comparable between the two treatment arms for FACT-B<br />
(102 vs 103), FACT- G, TOI and each <strong>of</strong> the subscale scores. There were no significant<br />
differences between the treatment groups in change from baseline scores for PWB (-0.5<br />
vs. -0.3; p= 0.414), SWB (-0.6 vs -0.7; p = 0.762), EWB (0.7 vs 0.5;p = 0.538) and FWB<br />
(0.2 vs 0.3;p = 0.707). Overall change from baseline scores was comparable for the BCS<br />
(0.19 vs 0.83; p =0.055), Trial Outcome Index (-0.1 vs 0.71; p= 0.325), FACT- G (-0.39<br />
vs -0.53; p = 0.882) and FACT-B (-0.11 vs 0.22; p = 0.782) scores.<br />
Conclusions: The addition <strong>of</strong> palbociclib to letrozole maintains HRQOL in treatment<br />
naïve postmenopausal patients with ER+ HER2- MBC and showed no significant<br />
difference compared to letrozole alone. This data adds favorably to the significant<br />
improvement in PFS seen in PALOMA-2.<br />
Clinical trial identification: Pfizer: NCT01740427<br />
Legal entity responsible for the study: Pfizer, Inc<br />
Funding: Pfizer, Inc<br />
Disclosure: H. Rugo: Institution receives research funding from Pfizer, Novartis,<br />
Lilly. V. Dieras: Consultant/Advisory role -Roche, Pfizer, Novartis Speaker’s<br />
Bureau-Roche, Pfizer, Novartis. R. Finn: Consultant/Advisory role -Pfizer, Bayer,<br />
Novartis, Bristol Myers Squibb Institution receives research funding from Pfizer.D.<br />
Slamon: Stock Ownership; Travel Accommodations or Expenses -PFizer Leadership;<br />
Stock Ownership; Travel Accommodations or Expenses- BioMarin. M. Miguel:<br />
Honraria - Amgen, Novartis Consultant/Advisory Role -Celgene; Novartis; Pfizer;<br />
Roche Pharma AG Research funding – Novartis.J. Ettl: Consulting or Advisory Role;<br />
Travel Accommodations or Expenses - Pfizer, Roche, GSK, Teva, Novartis. A. Mori, D.<br />
R. Lu, H. Bhattacharyya, C.H. Bartlett, S. Iyer: Pfizer employee and stockholderS.<br />
Johnston: Research Funding - Pfizer Consultant/Advisory Board - Astra Zeneca,<br />
Roche/Genetech, Novartis, Puma. N. Harbeck: Honararia-Amgen; Celgene,<br />
NanoString Technologies, Novartis; Pfizer, Roche.Consultant/Advisory Role<br />
-AstraZeneca, Celgene, Genomic Health, Novartis, Roche/Genentech, Sandoz, Wilex.<br />
Research Funding -Boehringer Ingelheim, Novartis, Pfizer, Roche/Genentech. All other<br />
authors have declared no conflicts <strong>of</strong> interest.<br />
226PD<br />
abstracts<br />
First line hormone therapy vs chemotherapy for HR+ HER2-<br />
metastatic breast cancer in the phase III STIC CTC trial:<br />
clinical choice and validity <strong>of</strong> CTC count<br />
F-C. Bidard 1 , E. Brain 1 , W. Jacot 2 , T. Bachelot 3 , S. Ladoire 4 , H. Bourgeois 5 ,<br />
A. Gonçalves 6 , H. Naman 7 , J. Gligorov 8 , F. Dalenc 9 , C. Levy 10 , M. Espie 11 ,<br />
J-M. Ferrero 12 , E. Luporsi 13 , M-P. Sablin 1 , C. Dubot 1 , M. Chevrier 14 , F. Berger 14 ,<br />
C. Alix-Panabieres 15 , J-Y. Pierga 1<br />
1 Medical <strong>Oncology</strong>, Institut Curie, Paris, France, 2 Department <strong>of</strong> Medical<br />
<strong>Oncology</strong>, Institut du Cancer de Montpellier (ICM), Montpellier, France, 3 Service<br />
Oncologie Medicale, Centre Léon Bérard, Lyon, France, 4 Medical <strong>Oncology</strong>,<br />
Centre Georges-François Leclerc (Dijon), Dijon, France, 5 <strong>Oncology</strong>, Clinique Victor<br />
Hugo Le Mans, Le Mans, France, 6 Oncologie Médicale, Institute Paoli Calmettes,<br />
Marseille, France, 7 Department <strong>of</strong> Medical <strong>Oncology</strong>, Centre azuréen de<br />
Cancérologie, Mougins, France, 8 Medical <strong>Oncology</strong>, APHP, CancerEst, Tenon<br />
University Hospital, Paris, France, 9 Medical <strong>Oncology</strong>, Institut Universitaire du<br />
Cancer -Toulouse- Oncopole, Toulouse, France, 10 <strong>Oncology</strong>, Centre Francois<br />
Baclesse, Caen, France, 11 Medical <strong>Oncology</strong>, Assistance Publique - Hopitaux De<br />
Paris, Paris, France, 12 Medical <strong>Oncology</strong>, Centre Antoine Lacassagne, Nice,<br />
France, 13 Medical <strong>Oncology</strong>, Institut de Cancérologie de Lorraine - Alexis Vautrin,<br />
Vandoeuvre Les Nancy, France, 14 Biostatistics, Institut Curie, Paris, France,<br />
15 Laboratory <strong>of</strong> Rare Human Circulating Tumor Cells, University Medical Center <strong>of</strong><br />
Montpellier, Montpellier, France<br />
Background: In patients (pts) diagnosed with HR+ HER2- metastatic BC the choice<br />
between by front-line hormone therapy (HT, favored option) or chemotherapy (CT) is<br />
based on prognostic factors that are overpassed by CTC count. The STIC CTC trial is a<br />
large multicentric phase III randomized trial comparing two strategies to choose the<br />
front-line treatment type: decision by clinician vs by CTC levels.<br />
Methods: Clinical/pathological characteristics were registered at time <strong>of</strong> inclusion,<br />
together with the a priori treatment preferred by clinicians (HT or CT). CTC count was<br />
then performed by CellSearch® and pts were randomized between a priori treatment<br />
and CTC-driven treatment (HT if = 3<br />
metastatic sites (34%), lymphocytopenia (39%). HT was the a priori treatment for 371<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw365 | vi69
abstracts<br />
pts (70%) and CT for 159 pts (30%). Characteristics independently associated with the<br />
a priori choice were: age (p = 0.01), center (p < 0.001), prior (neo)adjuvant<br />
chemotherapy (HR = 0.47 favoring CT; p = 0.02), elevated SGOT (HR = 0.41;<br />
p < 0.001), liver (HR = 0.45; p = 0.005) & bone-only (HR = 3.16 favoring HT; p10y disease-free interval (HR = 3.45; p = 0.003). 205 patients (39%) had<br />
elevated CTC count (≥5 CTC/7.5ml). In MCA, the two first axes were CTC count and<br />
prior chemotherapy for early BC, the other clinical and pathological factors being<br />
distributed accordingly. Among the 263 pts randomized to the CTC-driven decision<br />
arm, a priori HT (186 pts, 71%) was confirmed in 122 pts (68%) and switched to CT in<br />
58 pts (32%); a priori CT (77 pts, 29%) was confirmed in 35 pts only (49%) and<br />
switched to HT in 37 pts (51%).<br />
Conclusions: In the absence <strong>of</strong> any predictive factor, treatment decision is influenced<br />
by numerous prognostic factors, among which CTC count appears to play a central<br />
role. Patients are followed up to compare the outcome <strong>of</strong> CTC-driven decision vs a<br />
priori clinical decision.<br />
Clinical trial identification: NCT01710605<br />
Legal entity responsible for the study: Institut Curie<br />
Funding: INCa<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
227PD<br />
Everolimus use in breast cancer patients:<br />
a population-based study<br />
M. Chavez-Macgregor, D. Zhigang, M. Sharma, S.H. Giordano<br />
Health Services Research, MD Anderson Cancer Center, Houston, TX, USA<br />
Background: Everolimus in an mTOR inhibitor that is approved to be use in<br />
combination with exemestane for the treatment <strong>of</strong> postmenopausal patients with<br />
hormone receptor positive metastatic breast cancer. In this study we evaluate the<br />
patterns <strong>of</strong> care and complications associated with the use <strong>of</strong> this medication.<br />
Methods: Breast cancer patients treated with everolimus between 2009-2014 were<br />
identified in the MarketScan database, a nationwide, employment-based database that<br />
includes claim data <strong>of</strong> employees and its dependents. The everolimus treatment pattern<br />
was evaluated. The frequency <strong>of</strong> toxicities as well as associated emergency room (ER)<br />
visits and hospitalizations between the first claim and 30 days after the last claim for<br />
everlimus were identified. Descriptive statistics were used.<br />
Results: In all, 2949 everolimus-treated breast cancer patients were identified; the<br />
median age was 60 years old. The median <strong>of</strong> cumulative days <strong>of</strong> supply was 112 days, at<br />
the time <strong>of</strong> the first claim the initial prescribed dose was 10mg in 76.9% <strong>of</strong> the patients;<br />
2.7% received a dose <strong>of</strong> 7.5mg; 17.8% 5mg and 2.6% received a 2.5mg prescription.<br />
Compared to the initial dose, 77.3% <strong>of</strong> the patients maintained the same dose, 16.7%<br />
decreased it and 6% increased it. A total <strong>of</strong> 1488 patients (50.5%) had claims associated<br />
with known everolimus-related toxicities; nausea, vomiting and electrolyte imbalances<br />
were identified in 31.7% <strong>of</strong> the patients, 17.9% had metabolic toxicities, 11.9%<br />
hematological toxicities, 5.1% stomatitis, 4.7% rash and 0.4% had a claim for<br />
pneumonitis. A total <strong>of</strong> 644 patients (21.8%) were hospitalized or had an ER visit<br />
associated with the toxicities above.<br />
Conclusions: Half <strong>of</strong> the patients receiving everolimus had a claim for a known<br />
everolimus-related toxicity and 21.8% were hospitalized or visited the ER while on<br />
everolimus for a toxicity. We cannot rule out that symptoms that lead to the<br />
hospitalizations/ER visit were not related to the breast cancer or to other causes, but<br />
this data provides real world information <strong>of</strong> the toxicities associated with everolimus<br />
treatment. The pattern <strong>of</strong> toxicities differs from what has been reported in clinical<br />
trials, it is possible that only serious toxicities are associated with a claim.<br />
Legal entity responsible for the study: The University <strong>of</strong> Texas MD Anderson Cancer<br />
Center<br />
Funding: Susan G. Komen, The Duncan Family Institute, CIPRIT<br />
Disclosure: M. Chavez-Macgregor: I have received research support form Novartis<br />
(institutional). I have served as a Consultant for Pfizer and Roche. All other authors<br />
have declared no conflicts <strong>of</strong> interest.<br />
228PD<br />
BRAF genomic alterations in breast cancer<br />
J. Albanell 1 , J.A. Elvin 2 , J. Suh 2 , J-A. Vergilio 2 , I. Phuong Le 3 , V. Kaklamani 3 ,<br />
S. Ali 2 , V. Miller 4 , P. Stephens 5 , L.M. Gay 2 , J.S. Ross 6<br />
1 Cancer Research Program, Institut Hospital del Mar d’Investigacions Mèdiques<br />
(IMIM), Barcelona, Spain, 2 Pathology, Foundation Medicine, Inc., Cambridge, MA,<br />
USA, 3 Health Science Center, University <strong>of</strong> Texas Health Science Center San<br />
Antonio, San Antonio, TX, USA, 4 Clinical Development, Foundation Medicine, Inc.,<br />
Cambridge, MA, USA, 5 Clinical Genomics, Foundation Medicine, Inc., Cambridge,<br />
MA, USA, 6 Pathology, Albany Medical Center, Albany, NY, USA<br />
Background: Targeting BRAF genomic alterations (GA) in non-melanoma cancer<br />
patients is well-established, but BRAF targeting for treating metastatic breast cancer<br />
(mBC) remains under investigation.<br />
Methods: DNA was extracted from 40 microns <strong>of</strong> FFPE sections <strong>of</strong> 7850 tumors, and<br />
comprehensive genomic pr<strong>of</strong>iling (CGP) was performed on hybridization-captured,<br />
adaptor ligation based libraries to a mean coverage depth <strong>of</strong> 579X for up to 315<br />
cancer-related genes plus 37 introns from 14 genes frequently rearranged in cancer.<br />
Genomic alterations (GA) included base substitutions (sub), indels, copy number<br />
alterations (CNA) and fusions/rearrangements.<br />
Results: A total <strong>of</strong> 83 (1.1%) cases <strong>of</strong> BRAF-altered BC were identified. The mean age<br />
<strong>of</strong> the 83 patients was 57 years (range 32 to 84 years). The primary tumor was used for<br />
CGP in 29 (34.9%) cases and from metastatic sites including lymph nodes, liver, bone,<br />
lung, brain adrenal and s<strong>of</strong>t tissue in 54 (65.1%). Of these 83 tumors, there were 39<br />
ductal, 1 inflammatory, 3 metaplastic, 2 lobular and 38 NOS mBC. BRAF GA that may<br />
lead to aberrant MAPK signaling included amplifications (51.8%), V600E sub (15.7%),<br />
K601E sub (3.6%), other missense sub (21.6%), and fusions (6.0%); 3 additional<br />
mutations are uncharacterized for their effect on BRAF signaling activity (3.6%). The<br />
identified fusions were KIAA1549-BRAF (2), AGK-BRAF (1), FCHSD2-BRAF (1), and<br />
KLHDC10-BRAF (1). There was a statistically significant reduction in ERBB2<br />
mutations in tumors harboring a BRAF GA (amplification or sub)(p = 0.011). Of the<br />
cases harboring BRAF GA, 38.6% were TNBC, 21.7% HR + /HER2-, 2.4% HR-/<br />
HER2 + , 2.4% HR + /HER2 + , and 30.1% status unknown. Targetable genes more<br />
commonly amplified in tumors with BRAF GA, compared to BRAF WT breast cancer,<br />
include CDK6 (p = 0.001), HGF (p < 0.001) and MET (p < 0.001).<br />
Conclusions: BRAF GA are uncommon in BC, identified in 1.1% <strong>of</strong> cases, but include<br />
targetable base substitutions and rare fusions. BRAF GA in mBC appear to be more<br />
common in HER2-negative and TNBC mBC, and there is a significant decrease in<br />
ERBB2 mutation in tumors with BRAF GA. Targetable genes co-altered with BRAF in<br />
BC include CDK6, HGF and MET. Further study <strong>of</strong> BRAF alterations in BC appears<br />
warranted.<br />
Legal entity responsible for the study: Foundation Medicine, Inc.<br />
Funding: Foundation Medicine, Inc.<br />
Disclosure: J.A. Elvin, J. Suh, J-A. Vergilio, S. Ali, V. Miller, P. Stephens, L.M. Gay, J.S.<br />
Ross: Employee <strong>of</strong> and stockholder in Foundation Medicine, Inc. All other authors<br />
have declared no conflicts <strong>of</strong> interest.<br />
229PD<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Comprehensive genomic pr<strong>of</strong>iling <strong>of</strong> 8,654 breast carcinoma<br />
reveals therapeutically targetable molecular subtypes<br />
beyond those defined by hormone-receptor expression<br />
J.S. Ross 1 , L.M. Gay 2 , J.A. Elvin 2 , J. Suh 2 , J-A. Vergilio 2 , S. Ramkissoon 2 , S. Ali 3 ,<br />
V.A. Miller 4 , P.J. Stephens 5<br />
1 Pathology, Albany Medical Center, Albany, NY, USA, 2 Pathology, Foundation<br />
Medicine, Inc., Cambridge, MA, USA, 3 Clinical Development, Foundation<br />
Medicine, Inc., Cambridge, MA, USA, 4 Clinical Development, Foundation<br />
Medicine, Inc., Cambridge, MA, USA, 5 Clinical Genomics, Foundation Medicine,<br />
Inc., Cambridge, MA, USA<br />
Background: Breast carcinomas (BC) are commonly classified into 4 subtypes based<br />
on hormone receptor expression: basal, luminal A, luminal B, and HER2<br />
overexpressed. Comprehensive genomic pr<strong>of</strong>iling (CGP) can reveal targetable genomic<br />
alterations (GA) and redefine BC classification into therapeutically relevant subtypes.<br />
Methods: DNA was extracted from 40 µm <strong>of</strong> FFPE sections for 8654 consecutive BCs.<br />
CGP was performed on hybridization-captured, adaptor ligation-based libraries (mean<br />
coverage >500X) for up to 315 cancer-related genes. Total mutational burden (TMB)<br />
was determined on 1.2 Mbp <strong>of</strong> sequenced DNA. Clinically relevant GA (CRGA) are<br />
GA linked to drugs on the market or under evaluation in clinical trials.<br />
Immunotherapy (IO) sensitivity is defined as TMB >20 mut/Mbp or mutation <strong>of</strong><br />
specific DNA repair pathways. Homologous recombination (HR) deficiency is defined<br />
as mutation <strong>of</strong> the BRCA genes, other genes in the FANC complex, or DNA repair<br />
genes that have been shown to confer sensitivity to PARP inhibitors.<br />
Results: Several distinct pathways are altered in BC, and these pathways are targetable<br />
with therapies that are FDA approved for oncology indications. Rare mutations can<br />
also be found in targetable kinases such as RET, ROS1, and RAF. 6959 (80.4%) tumors<br />
harbor a GA in at least one pathway, and 2697 (31.2%) BC harbor alterations in just<br />
one pathway (unique cases). Only 9.8% <strong>of</strong> BC would be HER2-positive by IHC.<br />
Conclusions: CGP can identify CRGA that can stratify tumors by predicted sensitivity<br />
to a variety <strong>of</strong> therapies, including HER2- or mTOR-targeted therapies,<br />
immunotherapies, and other kinase inhibitors. 80% <strong>of</strong> BC harbor targetable GA, and<br />
30% <strong>of</strong> samples harbor mutations in only one pathway. Many GA would not be<br />
identified by IHC or hotspot testing, but can be detected by next-generation<br />
sequencing. CGP is a powerful tool for guiding treatment across therapeutically<br />
distinct, but targetable, pathways.<br />
Legal entity responsible for the study: Foundation Medicine, Inc.<br />
Funding: Foundation Medicine, Inc.<br />
Disclosure: J.S. Ross: Foundation Medicine, Inc. (compensated), Research Support:<br />
Foundation Medicine, Inc. (un-compensated), Stock Ownership: Foundation<br />
Medicine, Inc. (compensated). L.M. Gay, J.A. Elvin, J. Suh, J-A. Vergilio,<br />
S. Ramkissoon, S. Ali: Employee <strong>of</strong> and stockholder in Foundation Medicine, Inc. V.A.<br />
Miller, P.J. Stephens: Employee <strong>of</strong>, stockholder in, and holds a leadership position for<br />
Foundation Medicine, Inc.<br />
vi70 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
ERBB pathway<br />
Hormone therapy<br />
resistant (ESR1<br />
mut)<br />
HR<br />
deficient<br />
Table: 229PD<br />
IO sensitive<br />
PI3K/AKT/<br />
mTOR pathway<br />
FGFR<br />
pathway<br />
CDK<br />
pathway<br />
Total Cases 1294 796 1266 419 4375 2650 2685 424<br />
% Total Cases 15% 9% 15% 5% 51% 31% 31% 5%<br />
Unique Cases 274 109 309 48 1442 226 231 58<br />
% Unique Cases 3% 1% 4% 1% 17% 3% 3% 1%<br />
Therapies<br />
Trastuzumab,<br />
Pertuzumab,<br />
Afatinib, Lapatinib,<br />
Neratinib<br />
Fulvestrant,<br />
Tamoxifen<br />
Olaparib<br />
Pembrolizumab,<br />
Nivolumab,<br />
Atezolizumab,<br />
Ipilumumab<br />
Everolimus,<br />
Temsirolimus<br />
Pazopanib,<br />
Ponatinb<br />
Palbociclib<br />
Other kinases<br />
Sorafenib,<br />
Regorafenib,<br />
Dabrafenib,<br />
Vemurafenib,<br />
Crizotinib,<br />
Cabozantinib,<br />
Sunitinib<br />
230PD<br />
Phase II randomised clinical study <strong>of</strong> metformin plus<br />
chemotherapy vs chemotherapy alone in HER2 negative<br />
metastatic breast cancer: final results <strong>of</strong> the MYME trial<br />
231PD A phase II study <strong>of</strong> the cell cycle checkpoint kinases 1 and 2<br />
(CHK1/2) inhibitor (LY2606368; prexasertib) in sporadic<br />
triple negative breast cancer (TNBC)<br />
A. Gennari 1 , O. Nanni 2 , A. Rocca 3 , A. De Censi 1 , A. Fieschi 4 , A. Bologna 5 ,<br />
L. Gianni 6 , F. Rosetti 7 , L. Amaducci 8 , L. Cavanna 9 ,F.Foca 2 , S. Sarti 3 , P. Serra 2 ,<br />
L. Valmorri 2 , D. Corradengo 1 , G. Antonucci 10 , P. Bruzzi 11 , D. Amadori 3<br />
1 Medical <strong>Oncology</strong>, Ospedali Galliera, Genoa, Italy, 2 Biostatistics, Istituto Tumori<br />
della Romagna I.R.S.T., Meldola, Italy, 3 Medical <strong>Oncology</strong>, Istituto Tumori della<br />
Romagna I.R.S.T., Meldola, Italy, 4 Medical <strong>Oncology</strong>, Centro di Riferimento<br />
Oncologico, Aviano, Italy, 5 Medical <strong>Oncology</strong>, Azienda Ospedaliera Arcispedale<br />
Santa Maria Nuova - IRCCS, Reggio Emilia, Italy, 6 Medical <strong>Oncology</strong>, Ospedale<br />
Infermi, Rimini, Italy, 7 Medical <strong>Oncology</strong>, Unita Locale Socio Sanitaria 13 P.O<br />
Mirano, Mirano, Italy, 8 Medical <strong>Oncology</strong>, Ospedale degli Infermi, Faenza, Italy,<br />
9 Medical <strong>Oncology</strong>, Azienda Ospedaliera Piacenza, Piacenza, Italy, 10 Internal<br />
Medicine, Ospedali Galliera, Genoa, Italy, 11 Epidemiology and Biostatistics, IRCCS<br />
AOU San Martino - IST-Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy<br />
Background: The potential antitumor effect <strong>of</strong> metformin (M) in breast cancer is being<br />
explored by several clinical studies, in early disease. In this phase II randomised study,<br />
we compare the efficacy <strong>of</strong> M plus first line chemotherapy (CT) versus CT in metastatic<br />
breast cancer (MBC).<br />
Methods: 126 non-diabetic women (ITT 122) with stage IV, HER2 negative BC,<br />
untreated with CT, were randomized to Arm A: AC (non-pegylated liposomal<br />
doxorubicin 60 mg/m2 + cycl<strong>of</strong>osfamide 600mg/m2, x 8 Q21 + metformin 2,000 mg<br />
pos daily until progression) vs Arm B: AC. The primary endpoint was progression free<br />
survival (PFS); 98 PFS events were required for 80% power. Secondary endpoints were<br />
overall survival (OS), safety and outcome by insulin resistance status (HOMA Index<br />
≥2.5).<br />
Results: 122 patients are evaluable for primary endpoint. HOMA Index was > 2.5 in 57<br />
patients (46.7%). At 39.6 months’ median follow-up (range 1-71 months), 111 PFS<br />
events and 70 deaths had been observed. Median PFS was 9.4 months (95%CI 7.8-10.4)<br />
in Arm A (CT + M) and 10.1 (95%CI 7.7-11.5) in Arm B (CT), p= 0.61. 12 month PFS<br />
rate was 28.6% (95%CI: 17.4%-40.8%) in Arm A vs 37.1% (95%CI: 25.2%-49.0%) in<br />
Arm B. Overall, median PFS was 10.7 months (95%CI 9.6-12.8) in patients with<br />
HOMA Index
abstracts<br />
Methods: Eighty-five patients with stage IV breast cancer who met the eligibility<br />
criteria were enrolled in the study. Before starting a new treatment, all patients<br />
underwent full imaging studies and blood sampling for CTC enumeration. Patients<br />
with < 5 CTC/7.5 ml blood detected at baseline had no further CTC count. Patients<br />
with ≥ 5 CTCs /7.5 ml blood had another blood sampling for estimation <strong>of</strong> CTC before<br />
the 2 nd cycle (C2). Radiological assessment <strong>of</strong> disease status was done every 9 to 12<br />
weeks. Disease response was assessed according to the Response Evaluation Criteria In<br />
Solid Tumors (RECIST).<br />
Results: At baseline, 44 (51.8%) <strong>of</strong> the 85 eligible patients did not have increased CTC<br />
levels. Of the other 41 patients with ≥ 5 CTCs /7.5 ml blood, only 38 patients had<br />
CTCs evaluation at first follow-up before 2 nd cycle (CTC FU ) that showed 25 (65.8 %)<br />
patients had < 5 CTC/7.5 ml blood and 13 (34.2%) patients had ≥ 5 CTCs /7.5 ml<br />
blood. Seventy-five patients (75/85, 88.2 %) underwent radiological restaging.<br />
According to RECIST, 36 (48%) patients were scored as having a partial response, 19<br />
(25.3%) as having stable disease, and 20 (26.7%) as having progressive disease.<br />
Radiologic response was concordant with follow-up CTC levels in 76.5% <strong>of</strong> cases.<br />
Survival <strong>of</strong> our patients depended significantly on both the results <strong>of</strong> CTC evaluation<br />
and radiological response. The median follow-up was 18.0 [1–60] months.<br />
Conclusions: This study supports the significance <strong>of</strong> elevated CTCs before C2 in MBC<br />
patients starting a new line <strong>of</strong> chemotherapy as an early predictive marker <strong>of</strong> disease<br />
progression, thus, monitoring treatment benefit. It confirmed the independent<br />
prognostic significance <strong>of</strong> CTCs.<br />
Legal entity responsible for the study: The Ethics Committee <strong>of</strong> the Faculty <strong>of</strong><br />
Medicine, Assiut University<br />
Funding: Assiut University Hospitals<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
233P<br />
Intratumoral heterogeneity <strong>of</strong> HER2 expression is relevant to<br />
breast cancer malignancy<br />
M. Hosonaga 1 , Y. Arima 2 ,E.Sato 3 , K. Yamada 1 , H. Kaise 1 ,Y.Kawai 1 ,<br />
S. Teraoka 1 ,H.Saya 2 , T. Ishikawa 1<br />
1 Breast Surgical <strong>Oncology</strong>, Tokyo Medical University Hospital, Tokyo, Japan,<br />
2 Division <strong>of</strong> Gene Regulation, Institute for Advanced Medical Research, Keio<br />
University School <strong>of</strong> Medicine, Tokyo, Japan, 3 Pathology, Tokyo Medical University<br />
Hospital, Tokyo, Japan<br />
Background: Tumor diversity may cause therapeutic resistance and HER2<br />
heterogeneity have been reported to associate with poor prognosis in esophageal<br />
adenocarcinomas. We focused on the correlation between HER2 heterogeneity and<br />
prognosis in breast cancer.<br />
Methods: To determine the characteristics <strong>of</strong> heterogeneous overexpression <strong>of</strong> HER2<br />
in breast cancer, we established two types <strong>of</strong> HER2-expressing cells, HER2-60 contains<br />
63.2% <strong>of</strong> HER2-positive cells, and HER2-90 contains 92.4%, by introducing the HER2<br />
gene into a human triple-negative breast cancer cell line, MDA-MB 231. We also<br />
investigated correlation between HER2 heterogeneity and tumor malignancy in human<br />
breast cancer specimens.<br />
Results: When we inoculate the HER2-60 into the mammary fat pads <strong>of</strong> nude mice,<br />
heterogeneous HER2-expressing tumors developed, while HER2-90 consists mostly <strong>of</strong><br />
HER2-expressed cells, and developed monotonous HER2-expressing tumors. We<br />
found that HER2-60 mice showed shorter survivals than HER2-90 mice, the median<br />
survival days after intracardiac injections were 24 (n = 22) and 30 (n = 13), respectively.<br />
Next we investigated the correlation between HER2 expression and prognosis in<br />
human breast cancer. There were 73 HER2-positive breast cancer patients who received<br />
neoadjuvant chemotherapy with trastuzumab and underwent surgery between January<br />
2004 and December 2010 in our hospital. Fifty-five patients showed HER2 3+ by<br />
immunohistochemistry and 18 patients showed HER2 2+ and FISH-positive. HER2 2+<br />
patients were divided into 2 groups by the staining pattern, overall and partially stained<br />
cases. We defined as HER2 monotonous-type (HER2 mono) and HER2<br />
heterogeneous-type (HER2 hetero), respectively At the median follow-up <strong>of</strong> 69.1<br />
months, recurrent diseases were found in 25% (14/55) in HER2 3+ cases, and 30% (3/<br />
10) in HER2 hetero cases, while no recurrence was found in HER2 mono cases.<br />
Conclusions: Intratumoral HER2 heterogeneity is associated with aggressive breast<br />
cancers. Additional therapy should be considered for HER2 hetero breast cancers<br />
because HER2-positive breast cancers are all treated with chemotherapy with<br />
trastuzumab.<br />
Legal entity responsible for the study: N/A<br />
Funding: Grants-in-Aid for Scientific Research<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
234P<br />
Faster turnaround time for circulating tumor cell results by<br />
CTC rating <strong>of</strong> hotspots<br />
M.T. Nielsen 1 , H. Stender 1 , T. Glückstadt 1 , J. Kraan 2 , J. Smith 3 , T. Hillig 4 ,<br />
G. Sölétormos 4<br />
1 CTC Center <strong>of</strong> Excellence, CytoTrack, Lyngby, Denmark, 2 Department <strong>of</strong> Medical<br />
<strong>Oncology</strong>, Erasmus University Medical Center, Rotterdam, Netherlands, 3 Faculty<br />
<strong>of</strong> Health and Technology, Metropolitan University College, Copenhagen,<br />
Denmark, 4 Department <strong>of</strong> Clinical Biochemstry, CTC Center <strong>of</strong> Excellence, Hillerod<br />
Hospital, Hillerod, Denmark<br />
Background: Detection and enumeration <strong>of</strong> circulating tumor cells (CTC) in patients<br />
with metastatic cancer <strong>of</strong>fers important prognostic information and may assist in<br />
patient management and therapy. CTC are cytokeratin-positive, CD45-negative<br />
nucleated >4 um diameter cells where identification with current methods relies on<br />
automated scanning for presumptive identification as hotspots followed by final<br />
identification by manual review <strong>of</strong> images <strong>of</strong> each hotspot randomly presented to the<br />
operator. Often hundreds to thousands <strong>of</strong> images are manually reviewed making the<br />
process time-consuming and laborious. As an alternative to random review <strong>of</strong> images<br />
<strong>of</strong> hotspots a concept for CTC rating <strong>of</strong> hotspots based on the scanning measurement<br />
to determine their likelihood <strong>of</strong> being CTC has been developed and in this study<br />
validated on clinical specimens.<br />
Methods: 29 blood samples from metastatic breast cancer patients (Erasmus Medical<br />
Ctr, Rotterdam, NL) were analyzed using the CytoTrack system. CTC were identified<br />
by random manual review <strong>of</strong> each hotspot. Subsequently, the CTC rating concept was<br />
applied and the number <strong>of</strong> CTC present among the CTC rated hotspots was<br />
determined.<br />
Results: 29 blood samples had a total <strong>of</strong> 21129 hotspots ranging from 93 - 2246 per<br />
sample. 15 <strong>of</strong> 29 samples contained CTC ranging from 1 - 104 CTC per sample. Of the<br />
15 CTC-positive samples, 100% had CTC among the CTC rated hotspots ranging from<br />
50 - 100% <strong>of</strong> the total number <strong>of</strong> CTC. In summary, the negative predictive value <strong>of</strong><br />
CTC rating is 100% whereas the presence <strong>of</strong> CTC correlates with 81% (50-100%) <strong>of</strong> the<br />
total number <strong>of</strong> CTC. In the present study CTC rating <strong>of</strong> hotspots could avoid imaging<br />
<strong>of</strong> a total <strong>of</strong> 14224 hotspots ranging from 43 - 2000 hotspots per sample.<br />
Conclusions: The high negative predictive value using CTC rating <strong>of</strong> hotspots <strong>of</strong>fers<br />
the potential for 67% (14224/21129) reduction in the number <strong>of</strong> images to be reviewed<br />
to determine the presence or absence <strong>of</strong> CTC. For samples with the presence <strong>of</strong> at least<br />
1 CTC the remaining images may optionally be reviewed to detect all CTC in the<br />
sample.<br />
Legal entity responsible for the study: CytoTrack<br />
Funding: CytoTrack<br />
Disclosure: M.T. Nielsen, H. Stender, T. Glückstadt: Employed by CytoTrack. All other<br />
authors have declared no conflicts <strong>of</strong> interest.<br />
235P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Phase II trial evaluating the combination <strong>of</strong> eribulin (E)+<br />
bevacizumab (BEV) as first line chemotherapy in patients with<br />
metastatic Her2-negative breast cancer (MBC): a GINECO<br />
group study<br />
A-C. Hardy-Bessard 1 , F. Brocard 2 , M. Leheurteur 3 , A. Melis 4 , J. Dauba 5 ,<br />
A. Lortholary 6 ,B.You 7 , E. Guardiola 8 , J. Grenier 9 , J. Martin-Babau 10 , J. Meunier 11 ,<br />
P. Follana 12 , A-M. Savoye 13 , A. Mercier-Blas 14 , A. Marti 15 , R. Despax 16 ,<br />
N. Barbier 17 , N. Gane 18 , P. Ardisson 19 , C. Segura-Djezzar 20<br />
1 Oncologie Médicale, Centre CARIO - HPCA, Plerin-sur-Mer, France, 2 Oncologie<br />
Médicale, ORACLE - Centre d’Oncologie de Gentilly, Nancy, France, 3 Oncologie<br />
Médicale, Centre Henri Becquerel, Rouen, France, 4 Oncologie Médicale, Hôpital<br />
Privé Sainte-Marie, Chalon-sur-Saône, France, 5 Oncologie Médicale, Hôpital de<br />
Mont-de-Marsan, Mont De Marsan, France, 6 Oncologie, Centre Catherine de<br />
Sienne, Nantes, France, 7 Oncologie Médicale, Centre Hospitalier Lyon Sud, Pierre<br />
Bénite, France, 8 Oncologie Médicale, CH de la Dracénie-Draguignan, Draguignan,<br />
France, 9 Cancérologie Clinique, Institut Ste Catherine, Avignon, France, 10 Institut<br />
de Cancérologie et d’Hématologie, C.H.U. Brest - Hôpital Morvan, Brest, France,<br />
11 Oncologie Médicale, C.H.R. Orleans - La Source, Orleans, France, 12 Oncologie<br />
Médicale, Centre Antoine Lacassagne, Nice, France, 13 Service Rubis - Oncologie<br />
Médicale, Institut Jean Godinot, Reims, France, 14 Oncologie Médicale, Centre<br />
Hospitalier Privé de Saint-Grégoire, Saint-Grégoire, France, 15 Service Oncologie,<br />
CH Auxerre, Auxerre, France, 16 Oncologie - Hématologie, Clinique Pasteur -<br />
ONCOSUD, Toulouse, France, 17 Oncologie Médicale, Centre Catalan d’Oncologie<br />
Clinique St. Pierre, Perpignan, France, 18 Service de Biostatistique, Arcagy-Gineco,<br />
Paris, France, 19 Service de Chimiothérapie, Clinique de la Sauvegarde, Lyon,<br />
France, 20 Oncologie Médicale, Centre Francois Baclesse, Caen, France<br />
Background: Phase III combination <strong>of</strong> chemotherapy with BEV versus chemotherapy<br />
alone in first line MBC showed a benefit in favour <strong>of</strong> the combination in terms <strong>of</strong> PFS.<br />
Moreover, paclitaxel + BEV is a standard <strong>of</strong> care in Europe, and the main toxicity is<br />
sensory neuropathy (23.5 % <strong>of</strong> grade >= 3). The efficacy <strong>of</strong> E is well established in MBC<br />
pre-treated with taxanes and anthracyclines with a favourable safety pr<strong>of</strong>ile. Therefore,<br />
our group initiated a study to assess the efficacy and safety <strong>of</strong> E + BEV combination in<br />
first-line MBC.<br />
vi72 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Methods: In this prospective, open-label, phase II study, patients with histologically<br />
confirmed HER2-negative MBC received as initial chemotherapy E every 3 weeks 1.23<br />
mg/m 2 on day 1 and day 8 for 6 cycles or more with BEV 15 mg/kg on day 1, until<br />
progression. The primary end point was non-progression rate at 1 year. Secondary end<br />
points were progression free survival (PFS) and safety.<br />
Results: Of the 62 patients enrolled, 61 received the treatment. Median age was 59, 16%<br />
were triple negative, 30% had 3 metastatic sites or more. 71% <strong>of</strong> patients received prior<br />
chemotherapy, as adjuvant or neo-adjuvant treatment and 36% received<br />
hormonotherapy for MBC before enrolment. Median number <strong>of</strong> E cycles was 6 and 9<br />
for BEV. The non-progression rate at 1 year was 32% (95% CI: 20%-43%), overall<br />
response rate (ORR) was 46%, and PFS was 8.3 months (95%CI: 7-9.6 months). Grade<br />
3 or 4 neutropenia was observed in 26% patients only. Grade 3 HTA and thrombosis<br />
were observed in 39% and 8% <strong>of</strong> patients respectively. Grade 3 or 4 neuropathy<br />
occurred in 11% <strong>of</strong> patients. Other non-haematological adverse events were mild in<br />
severity.<br />
Conclusions: This trial shows that E plus BEV has antitumor activity similar to<br />
paclitaxel plus BEV as first line chemotherapy in MBC, with an acceptable safety<br />
pr<strong>of</strong>ile, notably a lower rate <strong>of</strong> neuropathy than expected with paclitaxel. This<br />
combination might be beneficial for patients with HER2-negative MBC what should be<br />
confirmed by further comparative study.<br />
Clinical trial identification: NCT01341407<br />
Legal entity responsible for the study: ARCAGY-GINECO<br />
Funding: Eisai<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
236P<br />
Efficacy and safety <strong>of</strong> nab-paclitaxel in patients with<br />
metastatic breast cancer: final results <strong>of</strong> the<br />
non-interventional study NABUCCO<br />
K. Potth<strong>of</strong>f 1 , A. Nusch 2 , U. Söling 3 , R. Hansen 4 , C. Salat 5 , S. Grebhardt 6 ,<br />
N. Marschner 7<br />
1 Medical Department, IOMEDICO AG, Freiburg, Germany, 2 Hämatologie und<br />
internistische Onkologie, Krebszentrum Ratingen, Ratingen, Germany, 3 Innere<br />
Medizin, Hämatologie und Internistische Onkologie, Onkologische<br />
Gemeinschaftspraxis, Kassel, Germany, 4 Hämatologie und Onkologie,<br />
Onkologische Schwerpunktpraxis Dres. Hansen & Reeb, Kaiserslautern, Germany,<br />
5 Innere Medizin, Hämatologie und internistische Onkologie, Hämato-Onkologische<br />
Schwerpunktpraxis, Munich, Germany, 6 Clinical Operations, IOMEDICO AG,<br />
Freiburg, Germany, 7 Internal Medicine / Hematology, Praxis für Interdisziplinaere<br />
Onkologie, Freiburg, Germany<br />
Background: One <strong>of</strong> the most effective chemotherapies for metastatic breast cancer<br />
(MBC) is nab-paclitaxel (nab-P) which is approved for the treatment <strong>of</strong> MBC after<br />
failure <strong>of</strong> 1st-line therapy and when anthracyclines are not indicated.Randomized<br />
clinical trials have shown high efficacy and acceptable toxicity. Real world data <strong>of</strong> nab-P<br />
in MBC, however, are still limited.<br />
Methods: The prospective multicenter non-interventional study NABUCCO was<br />
designed to collect data on the routine treatment <strong>of</strong> 700 patients (pts) with MBC in<br />
approximately 100 sites across Germany. Primary objective was the time to tumor<br />
progression (TTP), secondary objectives were overall response rate (ORR), overall<br />
survival (OS), the dosage scheme <strong>of</strong> nab-P, time on treatment, safety parameters and<br />
quality <strong>of</strong> life. Descriptive statistics were used to analyze the data. TTP and OS were<br />
calculated using the Kaplan-Meier method.<br />
Results: Between 4/2012 and 4/2015 705 pts with MBC at 128 sites had been enrolled.<br />
697 pts were evaluable with a median follow-up <strong>of</strong> 17.7 months. Baseline<br />
characteristics: Median age 62.3 years (range 29.2-89.3), age ≥ 65 years n = 291<br />
(41.8%), ECOG PS ≥ 2 n = 49 (7.0%), prior taxanes 419 pts (60.1%). Pts were treated at<br />
the physician’s discretion. The application mode <strong>of</strong> nab-P was as follows: 260 mg/m 2<br />
q3w (n = 153, 22.0%), ≥ 15% reduced dose q3w (n = 37, 5.3%), 150 mg/m 2 d1, d8, d15<br />
q4w (n = 54, 7.7%), ≥ 15% reduced dose d1, d8, d15 q4w (n = 219, 31.4%), 100-125<br />
mg/m2 d1,8,15 q3w (n = 90, 12.9%) and other (n = 144, 20.7%).<br />
Table: 236P Summary <strong>of</strong> effectiveness analyses by treatment line<br />
Legal entity responsible for the study: Ethikkommission der Landesärztekammer<br />
Baden-Württemberg<br />
Funding: Celgene GmbH<br />
Disclosure: N. Marschner: Employment or Leadership Position: iOMEDICO AG;<br />
Sponsored research: Grant by Celgene GmbH; Other Financial Relationships:<br />
Remuneration for presentation and compensation for travel expenses. All other authors<br />
have declared no conflicts <strong>of</strong> interest.<br />
237P<br />
Real-world effectiveness and safety <strong>of</strong> first-line bevacizumab<br />
(BEV) + paclitaxel (PAC) in >2000 patients (pts) with<br />
HER2-negative metastatic breast cancer (mBC)<br />
V. Mueller 1 , M. Dank 2 , S. de Ducla 3 , L. Mitchell 4 , A. Schneeweiss 5<br />
1 Department <strong>of</strong> Gynecology, University Medical Center Hamburg-Eppendorf,<br />
Hamburg, Germany, 2 <strong>Oncology</strong> Division, Semmelweis University Cancer Center,<br />
Budapest, Hungary, 3 Pharma Development Medical Affairs, F. H<strong>of</strong>fmann-La Roche<br />
Ltd, Basel, Switzerland, 4 Pharma Development Medical Affairs Biometrics,<br />
F. H<strong>of</strong>fmann-La Roche Ltd, Basel, Switzerland, 5 Division Gynecologic <strong>Oncology</strong>,<br />
National Center for Tumor Diseases, University Hospital, Heidelberg, Germany<br />
Background: Real-world data exploring effectiveness <strong>of</strong> treatments following<br />
demonstrated efficacy in phase III trials are becoming increasingly important,<br />
especially for regulatory bodies and payers. Pooling outcome and adverse-event (AE)<br />
data from non-interventional studies enables more accurate estimation <strong>of</strong> real-world<br />
effectiveness and safety in clinically important subgroups.<br />
Methods: Individual pt data from pts receiving first-line BEV + PAC with no<br />
additional chemotherapy agent for HER2-negative mBC in three non-interventional<br />
studies (ML21165 [Germany], AVANTI [Germany] and AVAREG [Hungary]) were<br />
extracted and pooled. Progression-free survival (PFS) and overall survival (OS) were<br />
estimated in the BEV + PAC population and subgroups <strong>of</strong> clinical interest by<br />
Kaplan-Meier methodology. Safety was analysed descriptively.<br />
Results: The analysis population included 2135 pts. The median duration <strong>of</strong> follow-up<br />
was 13.1 (range
abstracts<br />
LM is a full-time employee <strong>of</strong> Roche with all conditions/benefits under Roche’s<br />
contract. A. Schneeweiss: AS has received honoraria from Roche and Celgene for<br />
several talks and research funding from Celgene. All other authors have declared no<br />
conflicts <strong>of</strong> interest.<br />
238P<br />
MERIBEL study: Single-agent eribulin as first-line therapy for<br />
taxane-resistant HER2[-] metastatic breast cancer (MBC)<br />
patients (pts)<br />
V. Ortega 1 , J. Lao 2 , I. Garau 3 , N. Afonso 4 , L. Calvo 5 , Y. Fernández 6 ,<br />
M. Martinez-Garcia 7 , E. Blanco 8 , P. Zamora 9 , M. García 10 , J.J. Illarramendi 11 ,<br />
C. Rodríguez 12 , E. Aguirre 13 , J. Pérez 14 , J. Cortes Castan 15 , A. Llombart-Cussac 16<br />
1 Medical <strong>Oncology</strong>, Vall d’Hebron University Hospital Institut d’Oncologia,<br />
Barcelona, Spain, 2 Medical <strong>Oncology</strong>, Hospital Miguel Servet, Zaragoza, Spain,<br />
3 Medical <strong>Oncology</strong>, Hospital Son Llatzer, Palma de Mallorca, Spain, 4 Medical<br />
<strong>Oncology</strong>, CUF Porto Hospital, Porto, Portugal, 5 Medical <strong>Oncology</strong>, University<br />
Hospital Complex <strong>of</strong> A Coruña, A Coruna, Spain, 6 Medical <strong>Oncology</strong>, Central de<br />
Asturias University Hospital, Oviedo, Spain, 7 Department <strong>of</strong> Medical <strong>Oncology</strong>,<br />
University Hospital del Mar, Barcelona, Spain, 8 Medical <strong>Oncology</strong>, Hospital Infanta<br />
Cristina, Badajoz, Spain, 9 Medical <strong>Oncology</strong>, La Paz University Hospital, Madrid,<br />
Spain, 10 Medical <strong>Oncology</strong>, Insular de Las Palmas University Hospital, Las<br />
Palmas, Spain, 11 Medical <strong>Oncology</strong>, General de Navarra University Hospital,<br />
Pamplona, Spain, 12 Medical <strong>Oncology</strong>, Clínico de Salamanca Hospital,<br />
Salamanca, Spain, 13 Scientific Department, Medica Scientia Innovation Research,<br />
Barcelona, Spain, 14 Medical <strong>Oncology</strong>, Institute <strong>of</strong> <strong>Oncology</strong> Baselga Quiron<br />
Hospital; Medica Scientia Innovation Research MEDSIR ARO, Barcelona, Spain,<br />
15 Medical <strong>Oncology</strong>, Ramon y Cajal University Hospital, Madrid and Vall d’Hebron<br />
Institute <strong>of</strong> <strong>Oncology</strong> (VHIO), Barcelona, Barcelona, Spain, 16 Medical <strong>Oncology</strong>,<br />
Hospital Arnau de Vilanova, Valencia, Spain<br />
Background: Eribulin improved overall survival (OS) in ≥3 line treatment <strong>of</strong> MBC pts.<br />
In a large retrospective study, short disease-free interval (DFI) and prior taxane therapy<br />
have been associated with worse OS in pts receiving first-line chemotherapy for HER2<br />
[-] MBC. The aim <strong>of</strong> MERIBEL trial is to evaluate the efficacy and safety <strong>of</strong> eribulin as<br />
first-line therapy for HER2[-] MBC pts with these poor prognostic factors.<br />
Methods: Phase II, multicenter, single arm, trial. Eribulin (1.23 mg/m 2 ) as single-agent<br />
was administered on days 1 and 8 <strong>of</strong> 21 day cycles until progression or unacceptable<br />
toxicity. Principal selection criteria: (1) HER2[-] pts without prior chemotherapy for<br />
MBC; (2) prior taxane therapy (≥4 cycles) for early BC; (3) less than 36 months* (mo)<br />
between the last taxane cycle and relapse; (4) RECIST v1.1 evaluable disease; (5) no<br />
symptomatic brain involvement. (*) Amendment to 48 mo. Primary outcome was time<br />
to progression (TTP). Secondary endpoints included OS, progression-free survival<br />
(PFS), objective response rate (ORR), clinical benefit rate (CBR) and toxicity. We<br />
included 53 women from 61 pts recruited between SEP/2013 to MAR/2015 across 12<br />
sites and 2 countries.<br />
Results: Median age 51 years [range 23-83]; 50.9% were ECOG 0; 45.3% were<br />
triple-negative; 84.9% received prior anthracyclines. Median DFI was 15.7 mo<br />
[0.1-46.5]; and 52.8% had visceral metastases (11.3% with ≥3 involved organ sites).<br />
Median follow-up was 12.7 mo [0.2 – 30.5]. Median TTP was 4.1 mo [95%CI 2.2-6],<br />
median PFS was 4.3 mo [2.2-6.5], and median OS has not been reached yet. The 1-year<br />
TTP, PFS and OS rates were 16.2%, 24.3%, and 65.9%, respectively. The ORR was<br />
20.8% and CBR, 26.4%. Eribulin all grades and 3/4 adverse events (AEs) were reported<br />
in 96.2% and 71.7% <strong>of</strong> the pts, respectively. The most common grade 3/4 AEs were<br />
neutropenia (28.3%), leukopenia (17%), peripheral neuropathy (5.7%) and asthenia<br />
(5.7%). One patient experienced febrile neutropenia. Percentages <strong>of</strong> pts with AEs<br />
leading to treatment discontinuation, reduction, or delay were 15.1%, 9.4%, and 26.4%,<br />
respectively.<br />
Conclusions: Eribulin is effective and safe as first-line therapy for aggressive<br />
taxane-resistant HER2[-] MBC pts.<br />
Clinical trial identification: EudraCT: 2012-004463-41<br />
Legal entity responsible for the study: Medica Scientia Innovation Research -<br />
MEDSIR ARO<br />
Funding: Eisai<br />
Disclosure: J. Cortes Castan: Javier Cortés has been member on advisory boards <strong>of</strong><br />
Roche, Celgene, AstraZeneca and Celestial and has received honoraria from Roche,<br />
Novartis and Eisai.A. Llombart-Cussac: Antonio Llombart-Cussac has received<br />
honoraria for lectures and advisory boards from Roche, GlaxoSmithKline, Novartis,<br />
Celgene, Eisai and AstraZeneca and research funding from GlaxoSmithKline, San<strong>of</strong>i<br />
and Puma BiotechnologyAll other authors have declared no conflicts <strong>of</strong> interest.<br />
239P<br />
Capecitabine in combination with bendamustine in pretreated<br />
women with HER2-negative metastatic breast cancer:<br />
Updated safety results <strong>of</strong> a phase II trial (AGMT MBC-6)<br />
G. Rinnerthaler 1 , S.P. Gampenrieder 1 , D. Voskova 2 , A. Petzer 3 , M. Hubalek 4 ,<br />
E. Petru 5 , B. Hartmann 6 , J. Andel 7 , M. Balic 8 , T. Melchardt 1 , B. Mlineritsch 1 ,<br />
R. Greil 1<br />
1 IIIrd Medical Department, Salzburg Cancer Research Institute with Laboratory <strong>of</strong><br />
Immunological and Molecular Cancer Research and Center for Clinical Cancer and<br />
Immunology Trials, Cancer Cluster Salzburg, Paracelsus University Hospital<br />
Salzburg, Salzburg, Austria, 2 3rd Medical Department, Kepler University Hospital,<br />
Linz, Austria, 3 Internal Department I for Medical <strong>Oncology</strong> and Hematology,<br />
Barmherzige Schwestern Hospital Linz, Linz, Austria, 4 Department <strong>of</strong> Obstetrics<br />
and Gynaecology, Innsbruck Medical University, Innsbruck, Austria, 5 Department<br />
<strong>of</strong> Obstetrics and Gynaecology, Medical University Graz, Graz, Austria, 6 Medical<br />
Department E, General Hospital Feldkirch, Feldkirch, Austria, 7 2nd Medical<br />
Department, County Hospital Steyr, Steyr, Austria, 8 Division <strong>of</strong> <strong>Oncology</strong>, Medical<br />
University Graz, Graz, Austria<br />
Background: Capecitabine is a well-established treatment option in HER2-negative<br />
advanced breast cancer (ABC) patients. Bendamustine is a generally well tolerated<br />
cytotoxic drug. Since bendamustine has already shown anticancer activity in ABC we<br />
evaluated the efficacy and tolerability <strong>of</strong> bendamustine in combination with<br />
capecitabine in 40 pretreated patients with ABC.<br />
Methods: MBC-6 is a non-randomized, multicenter, open-label, single-arm phase II<br />
study in patients with HER2-negative ABC (ClinicalTrials.gov identifier:<br />
NCT01891227). All patients were pretreated with anthracyclines and/or taxans and<br />
measurable disease according to RECIST 1.1. had to be present at baseline. Eligible<br />
patients received 1000 mg/m 2 capecitabine twice daily on days 1 to 14 in combination<br />
with 80 mg/m 2 bendamustine on day 1 and 8 <strong>of</strong> a 3-week cycle. After a maximum <strong>of</strong><br />
eight cycles, capecitabine was continued as single drug therapy until disease<br />
progression or unacceptable toxicity. Efficacy results have been presented at the ASCO<br />
Annual Meeting 2016, Abstr 1032. Here we report the updated safety analysis.<br />
Results: From September 2013 to May 2015, 40 patients were recruited in 8 Austrian<br />
centers. At data cut-<strong>of</strong>f on 05/02/16 overall 37 <strong>of</strong> 40 patients had discontinued<br />
treatment: 25 (68%) due to progressive disease, 4 (11%) because <strong>of</strong> adverse events<br />
(AEs), 7 (18%) on their own or investigator decision and 1 (3%) due to protocol<br />
violation. Twelve patients (30%) experienced at least one drug related<br />
non-hematological AE ≥ grade 3 during combination treatment (2 infections, 1<br />
erysipelas, 5 fatigue, 4 thromboembolic events, 2 diarrhea, 1 nausea, 1 emesis, 1<br />
constipation, 1 syncope, 1 polyneuropathy, 1 stomatitis, 1 hand-foot syndrome, each<br />
grade 3) and further 6 patients (15%) during capecitabine maintainance (3 infections, 3<br />
diarrhea, and 4 hand-foot syndroms, each grade 3). Three grade 4 hematological AEs<br />
(neutropenias) were observed. One patient died as a result <strong>of</strong> restrictive<br />
cardiomyopathy, where a relationship to capecitabine cannot be excluded, but seems<br />
unlikely.<br />
Conclusions: The combination <strong>of</strong> capecitabine and bendamustine has a moderate<br />
toxicity pr<strong>of</strong>ile. Final study results are awaited later in 2016.<br />
Clinical trial identification: ClinicalTrials.gov identifier: NCT01891227<br />
Legal entity responsible for the study: AGMT (Arbeitsgemeinschaft medikamentöse<br />
Tumortherapie - Study Group <strong>of</strong> Medical Tumour Therapy) Wolfsgartenweg 31 5026<br />
Salzburg, Austria<br />
Funding: This research was supported in part by a Research Grant from<br />
Mundipharma®<br />
Disclosure: A. Petzer: Conflicts <strong>of</strong> Interest with Mundipharma®: Fees for non-CME<br />
services received directly from commercial interest or their agents and Traveler<br />
Grants. E. Petru, R. Greil: Conflicts <strong>of</strong> Interest with Mundipharma®: Fees for non-CME<br />
services received directly from commercial interest or their agents.J. Andel: Conflicts <strong>of</strong><br />
Interest with Mundipharma®: Consultant or Advisory Role. M. Balic: Conflicts <strong>of</strong><br />
Interest with Mundipharma®: Consultant or Advisory Role and Traveler<br />
Grants. B. Mlineritsch: Conflicts <strong>of</strong> Interest with Mundipharma®: Consultant or<br />
Advisory Role, and Fees for non-CME services received directly from commercial<br />
interest or their agents. All other authors have declared no conflicts <strong>of</strong> interest.<br />
240P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Capecitabine monotherapy in patients aged 70 years and<br />
older with metastatic breast cancer (MBC)<br />
D. Okonji, K. Mohammed, S. Redana, A. Ring, S. Johnston<br />
Medical <strong>Oncology</strong>, Royal Marsden Hospital NHS Foundation Trust, London, UK<br />
Background: Capecitabine monotherapy is associated with a clinical benefit rate<br />
(CBR) <strong>of</strong> 60% and a median time to progression (TTP) <strong>of</strong> 4 months in patients ≥65<br />
years (yrs) with MBC. However, 30% require a dose reduction (DR) due to toxicity. At<br />
the Royal Marsden Hospital, the starting dose and schedule for capecitabine is<br />
2000mg/m 2 on days 1-14, every 3 weeks. Older patients (pts), with a poor performance<br />
status (PS), comorbidities and/or moderate to severe renal impairment may start with a<br />
further DR. If early CTCAE grade ≥2 toxicity occurs, a switch from 3-weekly to a<br />
week-on-week-<strong>of</strong>f (WOWO) schedule is used to improve tolerance.<br />
vi74 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Methods: To evaluate toxicity and efficacy <strong>of</strong> capecitabine monotherapy in pts ≥70 yrs<br />
diagnosed with MBC. Primary endpoint- toxicity. Secondary endpoints- CBR, TTP &<br />
Overall Survival (OS).<br />
Results: From October 2013-October 2015, 77pts ≥70yrs retrospectively identified<br />
from the RMH Pharmacy Data Base received capecitabine monotherapy for MBC.<br />
Capecitabine was 1 st line therapy in 65 pts (84%), with 43 & 34 receiving 2000mg/m 2 &<br />
abstracts<br />
unknown. In 14 patients MBC was present at time <strong>of</strong> primary diagnosis. Prior<br />
treatment consisted <strong>of</strong> adjuvant endocrine treatment (17/35 HR+ patients), adjuvant<br />
CT (n = 7) and palliative hormonal treatment (29/35 HR+ patients). Most patients<br />
(n = 42) received single agent CT, consisting <strong>of</strong> capecitabine (n = 15), adriamycine<br />
(n = 10), paclitaxel (n = 8), vinorelbine (n = 4) or 5-fluorouracil (n = 3). Combination<br />
CT was given to 11 patients. A total <strong>of</strong> 28 patients (52%) had clinical benefit (defined<br />
as >6 months progression-free survival(PFS)). Median PFS and median overall survival<br />
(OS), analyzed according to Kaplan-Meier, from start <strong>of</strong> palliative CT were 6.8 months<br />
(95% Confidence Interval (CI) 4.8 - 8.8) and 14.4 months (95% CI 10.3 - 18.6),<br />
respectively. PFS and OS did not differ significantly between single agent or<br />
combination CT (p > .05). CT was stopped because <strong>of</strong> PD or toxicity in 32 and 13<br />
patients (62% and 25%), respectively.<br />
Conclusions: Even in very elderly MBC patients, palliative chemotherapy may have<br />
clinical benefit in selected patients aged 75+. Single agent CT seems feasible and<br />
effective, but 25% <strong>of</strong> patients discontinued CT due to toxicity.<br />
Clinical trial identification: N.A.<br />
Legal entity responsible for the study: Netherlands Cancer Institute - Antoni Van<br />
Leeuwenhoek<br />
Funding: Netherlands Cancer Institute - Antoni Van Leeuwenhoek<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
244P<br />
Eribulin mesylate may improve the sensitivity <strong>of</strong> endocrine<br />
therapy in metastatic breast cancer<br />
K. Kobayashi 1 ,Y.Ito 1 , T. Shibayama 1 , I. Fukada 1 , N. Ishizuka 2 , R. Horii 3 ,<br />
S. Takahashi 4 , F. Akiyama 5 ,T.Iwase 6 , S. Ohno 7<br />
1 Breast Medical <strong>Oncology</strong>, Cancer Institute Hospital <strong>of</strong> JFCR, Tokyo, Japan,<br />
2 Clinical trial department, Cancer Institute Hospital <strong>of</strong> JFCR, Tokyo, Japan,<br />
3 Pathology, Cancer Institute Hospital <strong>of</strong> JFCR, Tokyo, Japan, 4 Medical <strong>Oncology</strong>,<br />
Cancer Institute Hospital <strong>of</strong> JFCR, Tokyo, Japan, 5 Pathology, Japanese<br />
Foundation for Cancer Research, Tokyo, Japan, 6 Breast surgical <strong>Oncology</strong>,<br />
Cancer Institute Hospital <strong>of</strong> JFCR, Tokyo, Japan, 7 Breast center, Cancer Institute<br />
Hospital <strong>of</strong> JFCR, Tokyo, Japan<br />
Background: Eribulin mesylate (ERI) is a microtubule dynamics inhibitor that has<br />
been demonstrated to prolong overall survival in metastatic breast cancer . Recently,<br />
ERI has shown to reduce the abnormality <strong>of</strong> the tumor microenvironment. Endocrine<br />
therapy has been reported to be ineffective under hypoxic conditions; however,<br />
improved oxygenation <strong>of</strong> the peritumoral area due to ERI may increase the sensitivity<br />
<strong>of</strong> endocrine therapy. Generally, the efficacy <strong>of</strong> endocrine therapy at late-line treatment<br />
is inferior to that <strong>of</strong> endocrine therapy at early-line. Hence, we hypothesized that<br />
endocrine therapy following ERI administration might be more effective.<br />
Methods: Since the approval <strong>of</strong> ERI in Japan, 178 patients with metastatic breast<br />
cancer received ERI from August 2011 to October 2014 at the Cancer Institute<br />
Hospital. Of those, we assessed the time to treatment failure (TTF) <strong>of</strong> endocrine<br />
therapies provided to 25 postmenopausal patients in whom at least two endocrine<br />
therapies had been performed before ERI and at least one endocrine therapy after ERI.<br />
We retrospectively analyzed the effectiveness <strong>of</strong> the endocrine therapies on the basis <strong>of</strong><br />
intraindividual changes.<br />
Results: In these 25 cases, TTF <strong>of</strong> endocrine therapy before ERI administration (N-1)<br />
was longer in 6 cases (24%) compared with that <strong>of</strong> N-2, which is another endocrine<br />
therapy before N-1. In contrast, TTF <strong>of</strong> endocrine therapy after ERI administration (N)<br />
was found to be longer than that <strong>of</strong> N-1 in 16 cases (64%).Thus, the ratio that the TTF<br />
<strong>of</strong> late endocrine therapy was longer than that <strong>of</strong> early endocrine therapy was<br />
significantly higher (p = 0.018) when the ERI administration was inserted between<br />
endocrine therapies.<br />
Conclusions: In the present study, ERI administration between two endocrine<br />
therapies prolonged the TTF in majority <strong>of</strong> the cases, and ERI might improve the<br />
sensitivity <strong>of</strong> endocrine therapy.<br />
Legal entity responsible for the study: Kokoro Kobayashi<br />
Funding: Cancer institute hospital <strong>of</strong> JFCR<br />
Disclosure: Y. Ito: Research grants from Novartis, Chugai,and Parexel. N. Ishizuka:<br />
Former employee <strong>of</strong> San<strong>of</strong>i Honorarium from Eli Lilly. S. Takahashi: Honorarium<br />
from Eisai. S. Ohno: Honoraria from Chugai and AstraZeneca. All other authors have<br />
declared no conflicts <strong>of</strong> interest.<br />
245P<br />
Maintenance metronomic chemotherapy combined with<br />
conventional treatment for metastatic breast cancer patients<br />
S.F. El Zawawy 1 , G. Khedr 1 , B. Elsabaa 2<br />
1 Clinical oncology, Alexandria University, Alexandria, Egypt, 2 Pathology, Alexandria<br />
University, Alexandria, Egypt<br />
Background: The treatment duration for metastatic breast cancer patients remains a<br />
controversial issue, with no overall survival benefit for continuous chemotherapy with<br />
increased toxicity. This study was carried out to evaluate the benefit <strong>of</strong> adding<br />
metronomic chemotherapy to conventional treatment regarding progression free<br />
survival, response rate and toxicity.<br />
Methods: Patients received first line treatment for their metastatic disease either<br />
chemotherapy followed by maintenance metronomic chemotherapy with or without<br />
hormonal therapy or primarily treated with hormonal therapy concomitant with<br />
metronomic chemotherapy. Metronomic chemotherapy consists <strong>of</strong> cyclophosphamide<br />
50 mg tablet daily and methotrexate 2.5mg twice daily on days 2 and 5 weekly,<br />
continued until disease progression or development <strong>of</strong> unacceptable toxicity. Her2 +ve<br />
patients didn’t receive trastuzumab.<br />
Results: After median follow up <strong>of</strong> 24 months (range: 9 months – 30 months), 40<br />
patients were assessed, the progression free survival was 42.5 % and the median time to<br />
disease progression was 10.6 months. The overall clinical benefit (CR + PR + SD) was<br />
42.5 % with no G3/4 toxicities encountered for metronomic therapy. Only G1/2<br />
leucopenia (40%), G1/2 gasteritis (62.5%), one patient developed grade 3 increased<br />
transaminases and resume treatment with 50% dose reduction. The median time to<br />
disease progression was 13.5 months for ER +ve, Her2-ve compared to 8.5 months for<br />
ER + ve, Her2 + ve, 8 months for ER-ve,Her2 + ve and 8 months for triple negative. The<br />
difference was statistically significant (P value = .018). Univariate and multivariate<br />
analysis found that ER –ve, Her2 +ve and the presence <strong>of</strong> visceral metastasis are the<br />
most significant negative prognostic factors for time to disease progression whereas<br />
patients with bone only metastasis and ER + ve, HER2 neu –ve have the best outcome.<br />
Conclusions: Maintenance metronomic cyclophosphamide and methotrexate<br />
demonstrated efficacy and provided durable disease stabilization especially for ER<br />
positive patients. The low costs and minimal toxicity support its use as an additional<br />
therapeutic tool.<br />
Clinical trial identification: 1/29 26/1/2014<br />
Legal entity responsible for the study: Ethics committee, Alexandria University<br />
Funding: Ayady AlMostakbal <strong>Oncology</strong> Center (AAOC)<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
246P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Single arm, multicentre, non-randomized open-label trial to<br />
evaluate the safety <strong>of</strong> eribulin in third line chemotherapy in<br />
patients with HER2-negative metastatic or locally advanced<br />
breast cancer previously treated with anthracyclines and<br />
taxanes: Onsite study (ONCOSUR 2012-02)<br />
L.M. Manso Sánchez 1 , F. Moreno Antón 2 , Y. Izarzugaza Perón 3 , J.I.<br />
Delgado Mingorance 4 , P. Borrega 5 , M.J. Echarri González 6 , N. Martínez 7 ,A.<br />
López González 8 , C. Olier 9 , A. Ballesteros García 10 , I. Chacón 11 , E. Ciruelos 1 ,J.<br />
A. García-Sáenz 2 , L. Paz-Ares 1<br />
1 <strong>Oncology</strong>, University Hospital 12 De Octubre, Madrid, Spain, 2 Medical <strong>Oncology</strong>,<br />
Hospital Clinico Universitario San Carlos, Madrid, Spain, 3 Medical <strong>Oncology</strong>,<br />
University Hospital "Fundacion Jimenez Diaz", Madrid, Spain, 4 Medical <strong>Oncology</strong>,<br />
Hospital Infanta Cristina, Badajoz, Spain, 5 Medical <strong>Oncology</strong>, Hospital San Pedro<br />
de Alcántara, Cáceres, Spain, 6 Medical <strong>Oncology</strong>, Hospital Severo Ochoa,<br />
Leganes, Spain, 7 Medical <strong>Oncology</strong>, Hospital Universitario Ramon y Cajal, Madrid,<br />
Spain, 8 Medical <strong>Oncology</strong>, University Hospital <strong>of</strong> León, Leon, Spain, 9 Medical<br />
<strong>Oncology</strong>, HUFA Hospital Universitario Fundacion Alcorcon, Alcorcon, Spain,<br />
10 Medical <strong>Oncology</strong>, Hospital Universitario de La Princesa, Madrid, Spain,<br />
11 Medical <strong>Oncology</strong>, Hospital Virgen de la Salud, Toledo, Spain<br />
Background: Eribulin monotherapy is indicated for the treatment <strong>of</strong> patients with<br />
locally advanced or metastatic breast cancer who have progressed after at least one<br />
chemotherapy regimen for advanced disease. In an updated analysis <strong>of</strong> the EMBRACE<br />
study, survival improved in patients with 2-3 previous regimens (13.3 months vs 10.7<br />
months HR 0.77, P = .039).<br />
Methods: Patients received eribulin (1.23 mg/m 2 on days 1 and 8 <strong>of</strong> every 21-day cycle)<br />
as third-line therapy until progression, unacceptable toxicity or withdrawal. The<br />
primary endpoint was safety, and secondary endpoints included objective response<br />
rate, clinical benefit, 1-year overall survival and progression free survival (PFS) rates,<br />
and circulating tumour cell levels (EudraCT number 2013-001416-30).<br />
Results: Out <strong>of</strong> 59 eligible women (mean age 57.7), 58 (98.3%) had received previous<br />
taxanes and/or anthracyclines. Nearly all (98.3%) had HER2-negative tumors, 72%<br />
were positive for estrogens, 21% were triple negative; 64.4% had liver metastasis and<br />
57.6% bone metastasis. Grade 3 or 4 hematologic adverse events were febrile<br />
neutropenia (N = 3; 5%) and neutropenia (n = 2; 3%). The most common<br />
non-hematologic adverse events were grade 1-2 asthenia (n = 2; 3%), grade 1-2<br />
constipation (n = 2; 3%) and grade 1-2 skin rash (n = 1; 1%). Mean number <strong>of</strong><br />
administered cycles was 6.9 ± 5.4. Follow-up was performed in 52 patients, with 19.2%<br />
(n = 10) partial response, 42.3% (n = 22) stable disease, and 38% (n = 20) progressive<br />
disease. Clinical benefit was achieved in 32 patients (61.5%). Median PFS was 5.13<br />
months (95% CI 3.23, 8.90). After one year, 47 patients were still alive (81.03%).<br />
Conclusions: Treatment with eribulin in third line chemotherapy for locally advanced<br />
or metastatic breast cancer is effective and minimally toxic, presenting a high clinical<br />
benefit rate.<br />
Clinical trial identification: EudraCT number 2013-001416-30<br />
Legal entity responsible for the study: Fundación Oncosur<br />
Funding: Experior<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
vi76 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
247P<br />
Safety and efficacy <strong>of</strong> eribulin plus trastuzumab in pretreated<br />
HER2-positive advanced breast cancer (ABC) patients. An<br />
Italian multicenter experience<br />
E.S. Lutrino 1 , L. Orlando 1 , G. Giordano 2 , C. Zamagni 3 , C. Caliolo 1 , A. Febbraro 4 ,<br />
M. Giampaglia 5 , G. Dima 6 , A. Quaranta 1 , C. Scavelli 7 , D. Bilancia 5 , G. Filippelli 6 ,<br />
C. Fontanella 8 , P. Schiavone 1 , P. Fedele 1 , M. Enrica 1 , D. Rubino 3 , S. Cinieri 1<br />
1 Medical <strong>Oncology</strong>, Ospedale A. Perrino, Brindisi, Italy, 2 Oncologia, Ospedale<br />
"Sacro Cuore di Gesù" Fatebenefratelli, Benevento, Italy, 3 Oncologia Medica<br />
"Addarii", Policlinico S. Orsola-Malpighi-"F.Addarii", Bologna, Italy, 4 Medical<br />
<strong>Oncology</strong>, Ospedale "Sacro Cuore di Gesù" Fatebenefratelli, Benevento, Italy,<br />
5 Oncologia, Azienda ospedaliera Regionale S. Carlo di Potenza, Potenza, Italy,<br />
6 Oncologia, Ospedale S.Francesco, Paola, Italy, 7 Oncologia, Ospedale "Sacro<br />
Cuore di Gesù" Fatebenefratelli, Gallipoli, Italy, 8 Medical <strong>Oncology</strong>, AOU Santa<br />
Maria della Misericordia, Udine, Italy<br />
Background: Data on the combination <strong>of</strong> eribulin and trastuzumab (E/T) are limited,<br />
although recent analyses demonstrated safety and efficay for its use. The aim <strong>of</strong> this<br />
observational, retrospective, multicenter study was to examine the tolerability and the<br />
clinical activity <strong>of</strong> eribulin plus trastuzumab in the treatment <strong>of</strong> HER2 positive ABC.<br />
Methods: Patients (pts) treated with eribulin mesylate (1.23 mg/m 2 on days 1 and 8 <strong>of</strong><br />
a 21-day cycle) plus standard dosing <strong>of</strong> trastuzumab (16 pts received 3-week schedule:<br />
8 mg/kg load, 6 mg/kg q 3 weeks; 8 pts received weekly schedule: 4 mg/kg load, 2 mg/<br />
kg q week) in 6 Italian oncology units were include. Data on response rate (RR), overall<br />
survival (OS) and safety were reported.<br />
Results: Between October 2012 and November 2015 twenty four pts with<br />
HER2-positive ABC were included. Median age was 57 years (32 to 74). All patients<br />
were heavily pretreated: the median number <strong>of</strong> prior chemotherapy (CT) regimens for<br />
MBC was 3 (range 2-9). ECOG PS pre-E/T treatment was 0-1 in 75%. The median<br />
number <strong>of</strong> cycles with E/T was 11,5 (range 2-26). Complete response (CR) was<br />
achieved in 1 pts (4,2%), 9 pts (37,5%) achieved partial response (PR), 9 pts (37,5%)<br />
had stable disease (SD), and 5 pts (20,8%) had progressive disease (PD). Median OS<br />
was 7,7 months (range 2,8-30,5). Comorbidities at study entry were cardiovascular<br />
(including hypertension), 54.2%; diabetes, 8.3%; other diseases, 16.7%. Neutropenia<br />
was the most common clinical grade 3/4 adverse event (25%); one case (4,2%) <strong>of</strong> febrile<br />
neutropenia was observed. Main grade 3/4 non hematological toxicities were fatigue<br />
(4,2%), peripheral neuropathy (4,2%) and nausea (4,2%). Alopecia was observed in<br />
more than half <strong>of</strong> pts (66,7%). Dose reduction was applied in 6 pts (25%); three pts<br />
(12,5%) interrupted the treatment prematurely.<br />
Conclusions: Tolerability and efficacy <strong>of</strong> E/T combination schedule are encouraging .<br />
The results <strong>of</strong> this study indicated that this combination might be considered for future<br />
prospective study.<br />
Legal entity responsible for the study: Saverio Cinieri<br />
Funding: Medical <strong>Oncology</strong> Group Ospedale Perrino Brindisi<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
248P<br />
CASCADE study: pronounced decline in treatment efficacy<br />
through the metastatic life <strong>of</strong> breast cancer patients<br />
L. De Paz Arias 1 , P. García Teijido 2 , S. Servitja 3 , A. Santaballa 4 , J. García 5 ,Y.<br />
Plata Fernández 6 , I. Garau 7 , J. Florian 8 , I. Chacón 9 , J. de la Haba 10 , P. Zamora 11 ,<br />
L. Orcajo Rincon 12 , J. Rodríguez-Villanueva 12 , M.Á. Seguí 13 , E. Martínez 14<br />
1 Medical <strong>Oncology</strong>, Complejo Hospitalario Universitario de Ferrol, Ferrol, Spain,<br />
2 Medical <strong>Oncology</strong>, Hospital San Agustín de Aviles, Avilés, Spain, 3 Medical<br />
<strong>Oncology</strong>, University Hospital del Mar, Barcelona, Spain, 4 Medical <strong>Oncology</strong>,<br />
Hospital Universitari i Politècnic La Fe, Valencia, Spain, 5 Medical <strong>Oncology</strong>,<br />
Complejo Hospitalario Universitario de Orense, Ourense, Spain, 6 Medical<br />
<strong>Oncology</strong>, Complejo Hospitalario de Jaén, Jaén, Spain, 7 Medical <strong>Oncology</strong>,<br />
Hospital Son Llatzer, Palma de Mallorca, Spain, 8 Medical <strong>Oncology</strong>, Hospital de<br />
Barbastro, Barbastro, Spain, 9 Medical <strong>Oncology</strong>, Hospital Virgen de la Salud,<br />
Toledo, Spain, 10 Medical <strong>Oncology</strong>, Hospital Universitario Reina S<strong>of</strong>ía, Cordoba,<br />
Spain, 11 Medical <strong>Oncology</strong>, Hospital Universitario La Paz, Madrid, Spain,<br />
12 Medical <strong>Oncology</strong>, Eisai Pharmaceuticals SA., Madrid, Spain, 13 Medical<br />
<strong>Oncology</strong>, Hospital de Sabadell Corporacis Parc Tauli, Sabadell, Spain, 14 Medical<br />
<strong>Oncology</strong>, Hospital Provincial Castellon, Castellon, Spain<br />
Background: There is scarce information regarding the actual clinical benefit current<br />
therapies have on the general population and per tumour immunotype in advanced<br />
and/or metastatic breast cancer (LA/MBC). In this regard, analysis <strong>of</strong> the response<br />
elicited per line <strong>of</strong> treatment by a given pharmacological strategy will better guide the<br />
decision-making process, thus prioritizing most active drugs in earlier lines where they<br />
might have more chances <strong>of</strong> securing a long-lasting survival impact.<br />
Methods: 13 Spanish public hospitals serving nearly 5’000’000 inhabitants (>10% <strong>of</strong><br />
the national population) were selected. 443 patients diagnosed <strong>of</strong> LA/MBC from 01/<br />
2007 to 12/2008 were followed until death, lost to follow-up, or until December 2013.<br />
Objective response rates (ORR) and clinical benefit rates (CBR) were analysed<br />
throughout all treatment lines and per tumour immunotype. Data collected included<br />
demographical, pathological, diagnostic, and therapeutic information for each line <strong>of</strong><br />
treatment during this time. Descriptive statistics were applied (Methods have been<br />
previously described in ESMO Congress 2015 Poster no. 1882).<br />
Results: Important differences in both efficacy variables were seen according to<br />
treatment line and tumour immunotype. First line ORR and CBR were similar in all<br />
groups. As <strong>of</strong> the third line, however, objective responses in Triple-negative were<br />
minimal while still averaging 20% (range: 10.6% - 29.6%) for all other tumour types.<br />
HER2+ subgroups showed the overall greatest and most sustained responses (Table 1).<br />
Immunotype<br />
HER2-/HR+<br />
N = 187<br />
Triple-negative<br />
N=67<br />
HER2 + /HR+<br />
N=72<br />
HER2 + /HR-<br />
N=53<br />
Response<br />
(%)<br />
Table: 248P<br />
1L 2L 3L 4L 5L 6L 7L 8L<br />
ORR 40.6 10.7 21.8 11.8 8.9 14.3 10.6 16.7<br />
CBR 72.4 56.4 50.9 46.0 31.1 39.3 36.9 33.4<br />
ORR 40.3 17.7 0.0 4.5 0.0 0.0 0.0 0.0<br />
CBR 53.2 44.4 26.7 22.7 25.0 33.3 0.0 0.0<br />
ORR 37.9 41.3 24.3 29.6 15.8 26.7 11.1 14.3<br />
CBR 75.8 65.2 59.4 55.5 57.9 66.7 44.4 28.6<br />
ORR 49.1 38.2 30.8 20.0 0.0 16.7 0.0 0.0<br />
CBR 68.7 73.5 69.3 55.0 30.0 33.4 0.0 33.3<br />
ORR= complete + partial response rate. CBR= complete + partial<br />
response + disease stabilization rate.<br />
Conclusions: There is a rapid and progressive reduction <strong>of</strong> treatment efficacy in LA/<br />
MBC, especially in those patients who do not have or have lost the benefits <strong>of</strong> hormone<br />
and anti-HER2 targeted therapies. Therefore, introduction <strong>of</strong> the most active agents<br />
should not be delayed until very late lines <strong>of</strong> treatment.<br />
Clinical trial identification: EIS-ERI-2013-01<br />
Legal entity responsible for the study: Eisai Pharmaceuticals SA.<br />
Funding: Eisai Pharmaceuticals SA.<br />
Disclosure: L. Orcajo Rincon, J. Rodríguez-Villanueva: Eisai Pharmaceuticals<br />
Employee.All other authors have declared no conflicts <strong>of</strong> interest.<br />
249P<br />
Focalized treatment strategy for patients with 1 to 5 breast<br />
cancer brain metastasis: a retrospective study <strong>of</strong> 70 patients<br />
treated with surgery or stereotactic radiosurgery<br />
L. Eberst 1 , M. Morelle 1 , M-P. Sunyach 2 , E. Jouanneau 3 , P. Heudel 1 , O. Tredan 1 ,<br />
R. Tanguy 2 , I.L. Ray-Coquard 1 , T. Bachelot 1<br />
1 Medecine, Centre Léon Bérard, Lyon, France, 2 Radiotherapy, Centre Léon<br />
Bérard, Lyon, France, 3 Neurosurgery, Hôpital Louis Pradel-Hospices Civils de<br />
Lyon, Bron, France<br />
Background: Systemic treatment for metastatic breast cancer (MBC) has improved,<br />
allowing better control <strong>of</strong> extracranial disease, and longer survival. As a consequence,<br />
incidence <strong>of</strong> brain metastasis (BM) increases. Focalized treatment with surgical<br />
excision or stereotactic radiosurgery (SRS) should be considered for patients with a low<br />
number <strong>of</strong> BM.<br />
Methods: We identified all MBC patients undergoing focalized treatment by surgery or<br />
SRS, for 1 to 5 BM in our institution, between January 2008 and January 2015, with the<br />
aim <strong>of</strong> describing their outcome.<br />
Results: 70 patients were identified: 39 treated with surgery for 1 to 2 BM, 29 treated<br />
with SRS for 1 to 5 BM, and 2 patients treated with both modalities for 2 to 3 BM. After<br />
a median follow-up <strong>of</strong> 49 months, 55% <strong>of</strong> patients (38 among 69) had brain recurrence.<br />
From focalized treatment <strong>of</strong> BM, recurrence-free survival (RFS) was 20 months for the<br />
whole cohort (n = 69, [11-26]). From BM diagnosis, median OS was 37 months<br />
(n = 70, 95%CI[20-52]) for the whole cohort, with significant differences according to<br />
tumor subtypes (p = 0.008, log-rank test, see table below). In multivariate analysis, HR<br />
positivity (HR à 0,39 [0,16-0,93], p = 0.033), and extracranial disease control (HR à<br />
0,15 [0,06-0,39], p < 0.001), were associated with significant better outcome. At the<br />
time <strong>of</strong> analysis, 41 patients among 70 (56%) had died, including 23 from isolated<br />
neurologic cause. Nine patients died from leptomeningeal evolution. Eight patients<br />
developed severe neurologic symptoms, leading to death for 7 <strong>of</strong> them. Seven patients<br />
among these 8 had previous whole-brain radiation therapy (WBRT).<br />
Table: 249P<br />
HR-positive HR-positive HR-negative HR-negative Total p<br />
HER2-<br />
negative<br />
HER2-<br />
positive<br />
HER2-positive HER2-negative<br />
abstracts<br />
N 14 22 19 15 70<br />
Brain recurrence-free 35 [8;NR] 14 [9;24] 14 [6;NR] 13 [5;NR] 20 [11;26] 0,266<br />
survival [95%CI]<br />
OS - from metastatic 88 [20;151] 62 [43;NR] 87 [43;90] 17 [6;86] 70 [52;87] 0,001<br />
phase [95%CI]<br />
OS - from diagnosis<br />
<strong>of</strong> BM [95%CI]<br />
24 [14;53] 43 [31;NR] 40 [15;73] 13 [6;37] 37 [20;52] 0,008<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw365 | vi77
abstracts<br />
Conclusions: Patients with a low number <strong>of</strong> BM from MBC who had aggressive<br />
treatment with surgery or SRS have a favorable outcome. WBRT use should be delayed<br />
as much as possible, to avoid neurocognitive sequelae.<br />
Legal entity responsible for the study: Centre Leon Berard<br />
Funding: Centre Leon Berard<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
250P<br />
Relationship between progression-free survival and overall<br />
survival in advanced breast cancer: a novel approach using<br />
first-line treatment data for fulvestrant 500 mg and<br />
anastrozole<br />
M. Ouwens 1 , L.M. Grinsted 2 , C. Telford 3<br />
1 Global Medicines Development, AstraZeneca R&D, Molndal, Sweden, 2 Global<br />
Medicines Development, AstraZeneca, Cambridge, UK, 3 Global Payer Evidence<br />
Pricing, AstraZeneca, Gaithersburg, MD, USA<br />
Background: Overall survival (OS) is considered the gold standard for clinical benefit<br />
in oncology trials, but mature data are <strong>of</strong>ten unavailable. A relationship between<br />
progression-free survival (PFS) and OS in advanced cancer, including breast cancer<br />
(BC), is known: FDA (2007) suggests PFS may be a surrogate for OS; a NICE DSU<br />
report (Davis et al 2012) presents evidence <strong>of</strong> a relationship between PFS and OS in<br />
BC. This analysis further examined the relationship between PFS and OS with a view <strong>of</strong><br />
using PFS as a predictor <strong>of</strong> OS using data from the Phase II FIRST study (n = 205;<br />
NCT00274469) <strong>of</strong> fulvestrant 500 mg vs. anastrozole as first-line treatment in<br />
hormone-receptor positive advanced BC.<br />
Methods: In the interests <strong>of</strong> homogeneity, the relationship between PFS and OS was<br />
evaluated in endocrine-naïve patients in the FIRST study (n = 73 [72%] fulvestrant;<br />
n = 80 [78%] anastrozole) by substituting the linear expression into each other and<br />
using Weibull parametric fits and linear regression. PFS and OS data from a study <strong>of</strong><br />
anastrozole in a similar population (Nabholtz et al 2000, 2003) were applied to validate<br />
the Weibull and linear regression model.<br />
Results: Using log cumulative hazard plots, a linear trend was shown for PFS and OS.<br />
From the Weibull model, relationships between OS and PFS were derived: for given S,<br />
number surviving, fulvestrant ln time_OS(S) = 0.82 + 0.80 ln time_PFS(S); and<br />
anastrozole ln time_OS(S) = 0.97 + 0.79 ln time_PFS(S). Based on linear regression <strong>of</strong><br />
part <strong>of</strong> the PFS and OS curve (driven by apparent deviation from a linear relationship),<br />
the following relationships were derived: fulvestrant ln time_OS(S) = 0.77 + 0.63 ln<br />
time_PFS(S); and anastrozole ln time_OS(S) = 0.95 + 0.67 ln time_PFS(S). In all<br />
equations, time = days/1000. Applying both models to other clinical data for<br />
anastrozole showed a good fit and thus extends this relationship beyond the FIRST<br />
study.<br />
Conclusions: This analysis shows a novel, validated approach by which the<br />
relationship between PFS and OS in patients receiving first-line treatment with<br />
fulvestrant or anastrozole can be modelled. These results add to the acceptance <strong>of</strong> PFS<br />
as a predictor <strong>of</strong> OS in this setting.<br />
Clinical trial identification: NCT00274469<br />
Legal entity responsible for the study: AstraZeneca<br />
Funding: AstraZeneca<br />
Disclosure: M. Ouwens, L.M. Grinsted, C. Telford: Employment, stock or other<br />
ownership - AstraZeneca<br />
251P<br />
Clinical decision making in patients with metastatic breast<br />
sancer in the United Kingdom (UK) and Italy<br />
L. Ferrari 1 , L. Gerratana 1 ,M.Jove 2 , M. Bonotto 1 , M. Cinausero 1 , C. Twelves 2 ,<br />
F. Puglisi 1<br />
1 Department <strong>of</strong> <strong>Oncology</strong>, University and General Hospital, Udine, Italy, 2 Leeds<br />
Institute <strong>of</strong> cancer and Pathology, St James’s University Hospital, Leeds, UK<br />
Background: Several treatment options are available for metastatic breast cancer<br />
(MBC), but guidelines may not specify, for example, the nature, number and sequence<br />
to be used. The aim <strong>of</strong> this study was to compare treatment strategies between two<br />
oncology Centers in the UK and Italy.<br />
Methods: We retrospectively collected disease characteristics, demographic and<br />
treatment data <strong>of</strong> 228 consecutive patients (pts) diagnosed with MBC at the University<br />
Hospitals <strong>of</strong> Leeds (UK) and Udine (Italy) between January 2012 and December 2013<br />
who received at least one line <strong>of</strong> therapy. The cohorts were compared using Chi square<br />
test or Fisher exact test as appropriate. Overall Survival (OS) was analyzed by log-rank<br />
test.<br />
Results: We identified 120 UK and 108 Italian pts; median follow-up from the<br />
diagnosis <strong>of</strong> MBC was 41 and 38 months, respectively. The UK and Italian patients<br />
were similar with respect to clinical and pathological characteristics. Median age was 64<br />
years; hormone receptor (HR) +ve rates were 88% vs. 80 % for the UK and Italian pts,<br />
respectively while 26% and 24% <strong>of</strong> pts respectively were classified as HER2 +ve. When<br />
diagnosed with MBC, visceral metastases were present in 54% vs. 47% <strong>of</strong> the UK and<br />
Italian pts, respectively. Fifty-one percent <strong>of</strong> UK pts and 43% <strong>of</strong> Italian pts underwent<br />
biopsy before first line treatment for MBC. The number <strong>of</strong> systemic treatment lines was<br />
the same for the two Centers (median 2; range 1-7). Analyzing first line treatment, a<br />
similar proportion <strong>of</strong> UK and Italian pts with HR +ve /HER2 -ve disease received<br />
endocrine therapy (55% vs. 49%) and chemotherapy (45% vs. 51%); the presence <strong>of</strong><br />
visceral metastases increased the likelihood <strong>of</strong> chemotherapy being preferred as first<br />
line therapy in the UK but not Italy (64% vs 52%, respectively). As <strong>of</strong> December 2015,<br />
63% and 56% <strong>of</strong> pts from Leeds and Udine, respectively had died. The median OS was<br />
28 vs 27 months for the UK and Italian pts, respectively. No significant differences<br />
were observed in the time between the start <strong>of</strong> the final line <strong>of</strong> systemic therapy and<br />
death (7 vs. 8 month in UK and Italian pts, respectively).<br />
Conclusions: So far, we have not identified significant differences in the management<br />
<strong>of</strong> MBC pts between the two Centers or in OS outcomes between English and Italian<br />
pts. More detailed analyses are ongoing.<br />
Legal entity responsible for the study: University <strong>of</strong> Udine<br />
Funding: University <strong>of</strong> Udine<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
252P<br />
Long lasting survival (LLS) after removal <strong>of</strong> primary tumor (PT)<br />
in metastatic breast cancer (MBC). Impact <strong>of</strong> age on outcome<br />
J.A. Perez Fidalgo 1 , A. Caballero 2 , J.M. Cejalvo 1 , O. Burgues 3 , C. Hernando 1 ,<br />
P. Tolosa 1 , A. Iranzo 1 , B. Bermejo 1 , J.B. Ramirez Sabio 4 , A. Magro 5 ,<br />
A. Lluch-Hernandez 1<br />
1 <strong>Oncology</strong> and Hematology, Hospital Clinico Universitario de Valencia, Valencia,<br />
Spain, 2 Department <strong>of</strong> Surgery, Senology, Hospital Clinico Universitario de<br />
Valencia, Valencia, Spain, 3 Pathology Department, Hospital Clinico Universitario de<br />
Valencia, Valencia, Spain, 4 Servicio de Oncologia Medica, Hospital de Sagunt,<br />
Sagunt, Spain, 5 Medical <strong>Oncology</strong>, Hospital Francesc de Borja, Gandia, Spain<br />
Background: Retrospective evidence suggest an impact <strong>of</strong> the local control on survival<br />
in patients with MBC. A potential cause is the presence <strong>of</strong> LLS after PT removal. The<br />
aim was to assess the proportion <strong>of</strong> LLS after PT removal versus no surgery and the<br />
impact <strong>of</strong> age.<br />
Methods: A retrospective study was performed between February 1982 and September<br />
2005 in our institution. In order to minimize selection bias patients > 80y, with median<br />
follow-up 2 were excluded. An univariate and<br />
multivariate analysis <strong>of</strong> surgery and other prognostic variables was performed. Overall<br />
survival (OS) was calculated with Kaplan-Meier (KM). Probability <strong>of</strong> LLS was<br />
considered for patients with survival >120 months. Analyses were performed for the<br />
whole series, 65 years old cohorts.<br />
Results: 192 pts with MBC at diagnosis were recruited, <strong>of</strong> whom 112 underwent<br />
excision <strong>of</strong> the PT (Surgery group) and 80 pts did not received local therapy<br />
(Non-surgery group). Median age was 56 (48-65) for Surgery and 59 (51-70) for<br />
Non-surgery group. Operated patients were more likely to have only 1 site <strong>of</strong><br />
metastasis. In the univariate analysis removal <strong>of</strong> PT, ER, PR, PS and number <strong>of</strong><br />
metastatic sites were significantly related with OS. However only removal <strong>of</strong> PT and ER<br />
remained as independent prognostic factors in the multivariate analysis. With a<br />
median follow-up <strong>of</strong> 67.7 months, OS was significantly superior in Surgery group (40.7<br />
vs 22 months, p < 0.001). Proportion <strong>of</strong> LLS was 16.7% vs 4.4% in surgery vs<br />
non-surgery group. KM for OS in the subgroup <strong>of</strong> < 65 showed similar results with<br />
median <strong>of</strong> 40.7 vs 22.0 months (p < 0.001) and LLS <strong>of</strong> 19.9% vs 2.1%. In this group<br />
removal <strong>of</strong> PT, ER and bone-disease only were significant in multivariate analysis. Of<br />
note in >65 years surgery had no benefit in OS (log rank p = 0.340) and LLS <strong>of</strong> 14.0%<br />
vs 8.1% in surgery vs non-surgery group. In this group Charlson score was a significant<br />
prognostic factor for survival in this cohort.<br />
Conclusions: Surgical excision <strong>of</strong> PT in younger patients with ER+ and small number<br />
<strong>of</strong> metastatic sites seems to have an impact in achieving an important proportion <strong>of</strong><br />
LLS . No benefit in >65 years was seen.<br />
Legal entity responsible for the study: Instituto de Investigacion Clinico Valencia<br />
(INCLIVA) Hospital Clinico Universitario Valencia<br />
Funding: Instituto de Investigacion Clinico Valencia (INCLIVA) Hospital Clinico<br />
Universitario Valencia<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
253P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
The difference in prognostic outcomes between de novo stage<br />
IV and recurrent metastatic patients with hormone<br />
receptor-positive, HER2-negative breast cancer:<br />
a single-center study<br />
J. Yamamura 1 , S. Kamigaki 1 , M. Tsujie 2 , J. Fujita 2 , H. Osato 2<br />
1 Surgery, Breast <strong>Oncology</strong>, Sakai City Medical Center, Sakai, Japan, 2 Surgery,<br />
Sakai City Medical Center, Sakai, Osaka, Japan<br />
Background: The difference in prognostic outcomes between de novo stage IV and<br />
recurrent metastatic breast cancer is still unclear, and these patients have <strong>of</strong>ten been<br />
treated with the same treatment strategies. The objective <strong>of</strong> this retrospective<br />
single-center study was to compare prognostic outcomes between these patients, in<br />
vi78 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
particular patients with hormone receptor-positive (HR+), HER2-negative (HER2-)<br />
metastatic breast cancer. This analysis may help us to interpret results from current<br />
clinical research and propose future studies.<br />
Methods: This is a chart review study <strong>of</strong> de novo stage IV and recurrent metastatic<br />
patients with HR + /HER2- breast cancer, who were treated between January 2000 and<br />
December 2015 in Sakai City Medical Center, Japan. We used the Kaplan-Meier<br />
method to estimate overall survival <strong>of</strong> the two groups. The Cox proportional hazards<br />
model was used to examine the prognostic evaluation between the groups by using two<br />
prognostic indicators: disease-free interval (DFI) and interval from the end <strong>of</strong> adjuvant<br />
treatment to the first recurrence (AFI).<br />
Results: We studied 145 patients, including 52 de novo stage IV and 93 recurrent<br />
metastatic patients with HR + /HER2- breast cancer. There was no significant<br />
difference in prognosis between the groups. However recurrent patients with DFI < 2<br />
years were found to have significantly poorer prognosis compared with recurrent<br />
patients with DFI ≧ 2 years (hazard ratio (HR):2.108, 95%CI:1.146-3.876, p = 0.016),<br />
and de novo stage IV patients (HR:2.843, 95%CI:1.473-5.489, p = 0.002). Similarly,<br />
recurrent patients with AFI < 1 year had significant poorer prognosis compared with de<br />
novo stage IV patients (HR:1.330, 95%CI:1.034-1.711, p = 0.026).<br />
Conclusions: De novo stage IV breast cancer had better prognosis due to therapy-naive<br />
or less resistant metastatic disease compared with recurrent patients with DFI < 2 years<br />
or AFI < 1 year, who were likely to have an insufficient or non-carry-over effect <strong>of</strong><br />
adjuvant treatment. If future efforts are conducted with a larger spectrum <strong>of</strong> patients<br />
and treatment analysis, results might be more conclusive.<br />
Legal entity responsible for the study: Sakai City Hospital Orgaization<br />
Funding: Sakai City Hospital Orgaization<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
254P<br />
Hemoglobin level trajectories in early treatment period related<br />
to survival outcomes in patients <strong>of</strong> breast cancer<br />
H-E. Tzeng 1 , C-L. Lee 2<br />
1 Division <strong>of</strong> Hematology and Medical <strong>Oncology</strong>, Taichung Veterans General<br />
Hospital, Taichung, Taiwan, 2 Division <strong>of</strong> Endocrinology and Metabolism, Taichung<br />
Veterans General Hospital, Taichung, Taiwan<br />
Background: Anemia has been reported between 2% to 78% incidence rates in patients<br />
with solid tumors .The hemoglobin level has been reported related to treatment<br />
outcomes and survival in patients with various cancers. However,a longer term<br />
perspective including after treatment for the effects <strong>of</strong> Hb in survival analysis is still<br />
unknown. Therefore, the aims <strong>of</strong> this study were (1) to identify subgroups <strong>of</strong> cases with<br />
similar trajectories in Hb levels through different breast cancer stages; (2) to determine<br />
the independent association <strong>of</strong> Hb level trajectories in a definite treatment time interval<br />
with long term survival; and (3) to assess the survival in different cancer stage with Hb<br />
trajectories.<br />
Methods: Data source The VGHTC Cancer Registry, a population-based cancer<br />
registry established in 1983, was approved by Taiwan Cancer Registry Database. Stastics<br />
Group-based trajectory with latent class model was used to identify distinct trajectories<br />
<strong>of</strong> hemoglobin (Hb).These models were fit using SAS ProcTraj procedure. Model fit<br />
was assessed using the Bayesian Information Criterion (BIC) and censored normal<br />
model was appropriate for continuous outcomes. Differences in clinical variables<br />
between Hb trajectories were tested with one-way analysis <strong>of</strong> variance (ANOVA) for<br />
continuous variables, and with the chi-square test for categorical variables. Survival<br />
curve was plotted by Kaplan-Meier method according by different Hb trajectory<br />
groups.<br />
Results: Overall, 2622 patients were enrolled and 327 patients died during follow up.<br />
We identified 5 distinct Hb trajectories: Persisted anemia (4.3%), Improved anemia<br />
(3.5%), Mild anemia (16.8%), Low normal Hb (54.9%), and normal Hb (20.5%; ).<br />
Compared with the Persisted-anemia group, trajectories with elevated Hb levels had<br />
better performance <strong>of</strong> 10 year survival.<br />
Conclusions: Hb level trajectories in breast cancer treatment vary, and improved Hb<br />
level trajectory was associated with better 10-year survival. The first 12 months<br />
treatment trajectories in Hb level provide more accurate prediction in 10- year survival<br />
in breast cancer patients.<br />
Clinical trial identification: TCVGH-1055701E<br />
Legal entity responsible for the study: Taichung Veterans General Hospital, Taiwan<br />
Funding: his study was conducted and supported by the Taichung Veterans General<br />
Hospital, Taiwan (TCVGH-1055701E)<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
255P<br />
Patient-specific circulating tumor DNA detection during<br />
neoadjuvant chemotherapy in triple negative breast cancer<br />
J-Y. Pierga 1 , F. Riva 2 , A. Houy 3 , A. Saliou 4 , J. Madic 4 , A. Rampanou 4 , C. Hego 4 ,<br />
M. Milder 5 , P. Cottu 1 , M-P. Sablin 1 , A. Vincent-Salomon 6 , O. Lantz 5 , M-H. Stern 3 ,<br />
C. Proudhon 4 , F-C. Bidard 1<br />
1 Medical <strong>Oncology</strong>, Institut Curie, Paris, France, 2 Circulating Biomarkers Lab<br />
SIRIC, Institut Curie, Paris, France, 3 INSERM U830, Institut Curie, Paris, France,<br />
4 Circulating Biomarkers Lab, Institut Curie, Paris, France, 5 INSERM U932, Institut<br />
Curie, Paris, France, 6 Biopathology, Institut Curie, Paris, France<br />
Background: Pro<strong>of</strong>-<strong>of</strong>-concept studies also suggested the use <strong>of</strong> ctDNA levels as a<br />
dynamic biomarker reflecting the tumor response to therapy in metastatic breast<br />
cancer patients. We previously reported that TP53 mutations can be detected in the<br />
plasma <strong>of</strong> most metastatic Triple Negative Breast Cancer (TNBC) patients. Yet, few<br />
data about ctDNA levels and changes during neoadjuvant chemotherapy (NCT) are<br />
available for localized breast cancer. We investigated whether circulating tumor DNA<br />
(ctDNA) detection can reflect the tumor response to NCT and detect minimal residual<br />
disease after surgery non-metastatic TNBC patients.<br />
Methods: 10 ml <strong>of</strong> plasma were collected at 4 time points: before NCT; after 1 cycle;<br />
before surgery; after surgery. Customized ddPCR assays were used to track TP53<br />
mutations previously characterized in tumor tissue by massively parallel sequencing<br />
(MPS).<br />
Results: Forty-six patients with non-metastatic TNBC were enrolled. TP53 mutations<br />
were identified in 40 <strong>of</strong> them. Customized ddPCR probes were validated for 38<br />
patients, with excellent correlation with MPS (r = 0.99), specificity (≥2 droplets/assay)<br />
and sensitivity (at least 0.1%). At baseline, ctDNA was detected in 27/36 patients<br />
(75%). Its detection was associated with mitotic index (p = 0.003), tumor grade<br />
(p = 0.003) and stage (p = 0.03). During treatment, we observed a drop <strong>of</strong> ctDNA levels<br />
in all patients but one. No patient had detectable ctDNA after surgery. The patient with<br />
rising ctDNA levels experienced tumor progression during NCT. Pathological<br />
complete response (16/38 patients) was not correlated with ctDNA detection at any<br />
time point. ctDNA positivity after one cycle <strong>of</strong> NCT was correlated with shorter<br />
disease-free (p < 0.001) and overall (p = 0.006) survival.<br />
Conclusions: Customized ctDNA detection by ddPCR achieved a 75% detection rate at<br />
baseline. During NCT, ctDNA levels decreased quickly and minimal residual disease<br />
was not detected after surgery. However, a slow decrease <strong>of</strong> ctDNA level during NCT<br />
was strongly associated with shorter survival. If confirmed by further prospective<br />
studies, ctDNA may become a clinically valuable prognostic tool to manage TNBC<br />
patients treated by NCT.<br />
Clinical trial identification: NCT02220556<br />
Legal entity responsible for the study: Institut Curie<br />
Funding: ITMO Santé Publique and SIRIC Institut Curie<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
256P<br />
abstracts<br />
Correlation between severe infection and breast cancer<br />
metastases in the EORTC 10994/BIG 1-00 trial: Investigating<br />
innate immunity as a tumor suppressor in breast cancer<br />
N. Touati 1 , K. Tryfonidis 2 , F. Caramia 3 , H. Bonnefoi 4 , D. Cameron 5 , L. Slaets 1 ,B.<br />
S. Parker 6 , S. Loi 7<br />
1 Biostatistics department, EORTC Headquarters, Brussels, Belgium, 2 Medical<br />
Department, EORTC Headquarters, Brussels, Belgium, 3 Division <strong>of</strong> Cancer<br />
Research, Peter MacCallum Cancer Centre, East Melbourne, Australia,<br />
4 Department <strong>of</strong> Medical <strong>Oncology</strong>, Institut Bergonié (University <strong>of</strong> Bordeaux),<br />
Bordeaux, France, 5 <strong>Oncology</strong>, Edinburgh Cancer Centre Western General<br />
Hospital, Edinburgh, UK, 6 Department <strong>of</strong> Biochemistry and Genetics, La Trobe<br />
University, Melbourne, Australia, 7 Division <strong>of</strong> Cancer Medicine, Peter MacCallum<br />
Cancer Centre, East Melbourne, Australia<br />
Background: Breast cancer cells that express an innate immune signature regulated by<br />
interferon regulatory factor 7 (IRF7) have reduced bone metastatic capacity (Bidwell<br />
et al, Nat Med 2012). However, viral or bacterial infections can restore this IFN<br />
signature and activate an anti-tumor immune response. Objectives <strong>of</strong> the study were to<br />
evaluate if the occurrence <strong>of</strong> “severe infection” could be a clinical surrogate <strong>of</strong> this<br />
phenomenon and/or if the presence <strong>of</strong> high levels <strong>of</strong> an IRF7 signature during<br />
neoadjuvant chemotherapy (NACT) was associated with a reduced distant relapse risk,<br />
specifically <strong>of</strong> bony metastases.<br />
Methods: Clinical data <strong>of</strong> the EORTC 10994/BIG 1-00 phase III trial were used which<br />
evaluated NACT in 1856 early-stage breast cancers. “Severe infection” was defined as<br />
febrile neutropenia or other infective adverse events (grade 3-4) during NACT. The<br />
IRF7 signature was calculated from gene expression data available for 160 patients. Cox<br />
models for distant relapse free interval (DRFI) investigated the effect <strong>of</strong> the severe<br />
infection (landmark approach) and IRF7. Fine & Gray models studied the secondary<br />
endpoint <strong>of</strong> bone metastases as first distant relapse.<br />
Results: No major associations were observed between the occurrence <strong>of</strong> a severe<br />
infection during NACT and baseline patient and tumor characteristics. Median<br />
follow-up was 4.8 years. No significant association between severe infection and DFRI<br />
was observed (HR = 0.99, 90% CI = 0.81-1.20, N = 1615). For IRF7 (N = 160), a trend<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw365 | vi79
abstracts<br />
towards an association with DRFI was observed (HR = 0.89 for a 50-unit increase, 90%<br />
CI = 0.78-1.02, 1-sided p = 0.081). However higher levels <strong>of</strong> the IRF7 signature were<br />
significantly associated with a decreased bone metastases risk: HR = 0.76 for a 50-unit<br />
increase, (95% CI, 0.62-0.94, p = 0.012).<br />
Conclusions: The occurrence <strong>of</strong> a severe infection during NACT was not associated<br />
with decreased DRFI. High expression <strong>of</strong> the IRF7 signature was significantly<br />
associated with reduced risk <strong>of</strong> bone relapse supporting preclinical evidence that tumor<br />
intrinsic innate immunity is crucial for bone metastases prevention. This may be useful<br />
for guiding future adjuvant bisphosphonate/denosumab use.<br />
Clinical trial identification: NCT00017095<br />
Legal entity responsible for the study: EORTC<br />
Funding: Cancer Research Fund and EORTC Breast Cancer Group<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
257P<br />
Breast-GPA and type <strong>of</strong> treatment predictors <strong>of</strong> survival in<br />
brain metastasis patients<br />
J.L. Linares 1 , A. Stradella 1 , S. Pernas 1 , A. Ortega 1 , M. Galdeano 2 , A. Lucas 2 ,<br />
M. Macia 2 , N. Vidal 3 , I. Morilla 1 , R. Sabela 1 , C. Falo 1 , R. Velasco 4 , M. Gil-Gil 1<br />
1 Medical <strong>Oncology</strong>, Institut Català d’Oncologia Hospital Duran i Reynals,<br />
Barcelona, Spain, 2 Radiation <strong>Oncology</strong>, Institut Català d’Oncologia Hospital Duran<br />
i Reynals, Barcelona, Spain, 3 Pathology, Bellvitge University Hospital, Barcelona,<br />
Spain, 4 Neurology, Bellvitge University Hospital, Barcelona, Spain<br />
Background: Brain metastases (BM) occur in 15-30% <strong>of</strong> patients with metastatic breast<br />
cancer (MBC). In spite <strong>of</strong> improvements in the treatment, the development <strong>of</strong> BM is<br />
still being a major limitation <strong>of</strong> life expectancy and quality <strong>of</strong> life for many patients (P).<br />
Methods: Ambispective analysis <strong>of</strong> MBC patients who developed single or multiple<br />
BM and were treated in a single cancer comprehensive center. Identification <strong>of</strong> patients<br />
and updates <strong>of</strong> follow up were performed through Radiation <strong>Oncology</strong> department<br />
registries and Pathology Records. Breast Graded Prognostic Assessment (GPA) was<br />
calculated according to Sperduto GPA (2012).<br />
Results: From 2007 to 2014, 133 patients were identified; 30(22.6%) were diagnosed at<br />
de novo IV stage. Median age at BM diagnosis 52.3 years (29.7-81); 53 (39.8%) were<br />
luminal (LT), 42 (31.6%) HER2 positive (Her2), 31 (23.3%) triple negative (TN) and 7<br />
cases unknown. Median PFS was 28m and median time to BM after cancer diagnosis<br />
(TBM) was 41 m (71m in LT, 26m in Her-2 and 20 m in TN (p < 0.001). Her2 showed<br />
more incidence <strong>of</strong> BM as first relapsed (17.5%) than others subtypes (11.1 % LT and<br />
13.5% TN p = 0.002). 45 P (33.8%) had a solitary BM, 50 (36.7%) had 2-3 lesions and<br />
35 (26.3%) more than 3, and 3 unknown. No correlation between number <strong>of</strong> lesions<br />
and histological subtypes was found. Breast-GPA: (0-1): 12%, (1.5-2): 26.3%, (2.5-3):<br />
24.6% and (3.5-4): 25.6%. 18% were treated with stereotactic radiosurgery (SRS), 21%<br />
surgery (S) and 76% WBRT. Median survival after BM (BMS) was 12 m (7-17). BMS<br />
according GPA was (0-1) 8m, (1.5-2) 6m, (2.5-3) 19m and (3.5-4) 30m (p = 0.001).<br />
BMS according number <strong>of</strong> BM: 1 lesion 21m (8.9-33), 2-3 lesions 10 m (5.7-14) and >3<br />
lesions 8 m (5-11) and according subtypes LT 11 m (4-18),TN 8m (4.5-11.5) and Her2<br />
26m (7-45). Local treatment with SRS and S prolonged BMS (28 vs 8 m p= 0.001) as<br />
well as the administration <strong>of</strong> chemotherapy (29 vs 10 m p = 0.032). Significant<br />
prognostic factors by multivariate Cox regression were GPA (HR 0.7 CI 0.55-0.91<br />
p = 0.008) and number <strong>of</strong> lesions (HR 1.3 CI 1.03-1.79 p = 0.027).<br />
Conclusions: Breast-GPA, number <strong>of</strong> lesions and type <strong>of</strong> treatment are the most<br />
important prognosis factors for MBC patients with BM. Multidisciplinary treatment<br />
should be decided according to these factors.<br />
Legal entity responsible for the study: Jenniffer Linares Aceituno<br />
Funding: Catalan Institute <strong>of</strong> <strong>Oncology</strong><br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
258P<br />
Impact <strong>of</strong> the biological subtype on the risk <strong>of</strong> developing<br />
brain metastasis in Egyptian breast cancer patients<br />
L. Kassem 1 , R. Abdel-Malek 1 , D. Abd El Moneim 2 , M. Ismail 2 , H.A. Azim 3<br />
1 Clinical <strong>Oncology</strong>, Cairo University, Cairo, Egypt, 2 Medical <strong>Oncology</strong>, Cairo<br />
<strong>Oncology</strong> Center (Cairocure), Cairo, Egypt, 3 Clinical <strong>Oncology</strong> Department, Cairo<br />
University, Cairo, Egypt<br />
Background: We aimed at investigating the impact <strong>of</strong> the biological subtype <strong>of</strong> breast<br />
cancer on the risk <strong>of</strong> developing brain metastasis and the outcome <strong>of</strong> Egyptian patients<br />
with brain metastasis.<br />
Methods: We retrospectively reviewed the clinical records <strong>of</strong> 2193 consecutive women<br />
(1947 with localized disease and 246 with metastatic disease at presentation) diagnosed<br />
with breast cancer between January 1999 and December 2010. We explored the<br />
relationship between the clinico-pathological factors (including the biological<br />
subtypes) and the incidence <strong>of</strong> brain metastasis, Brain metastasis free survival (BMFS),<br />
and the Brain metastasis specific survival (BMSS).<br />
Results: Median follow up period for the whole cohort was 43.5 months (IQR 26-74<br />
months); 160 patients (7.3%) developed brain metastasis. Among the individual<br />
clinico-pathological parameters, larger tumors (p = 0.006), axillary LN positivity<br />
(p < 0.001), high grade (p = 0.006) and HER2 positivity (p < 0.001) were associated<br />
with higher incidence <strong>of</strong> brain metastasis. By Kaplan Meier model, and in those<br />
presenting with localized disease, the HER2-rich subtype was associated with the<br />
poorest BMFS (8y BMFS: 77.6%) followed by Triple negative and Luminal B diseases<br />
(8y BMFS: 80.9% and 81.3%) with the longest BMFS in the Luminal A subtype (8y<br />
BMFS: 88.2%; p for trend: 0.002). In the multivariate model, only 3 factors remained<br />
independent predictors for developing brain metastasis; tumors larger than 2 cm<br />
(HR = 3.60;95%CI: 1.54-8.38; p = 0.003), axillary LN metastasis (HR = 4.03; 95%CI:<br />
1.91-8.52; p < 0.001) and HER2-rich subtype (HR = 1.85; 95%CI: 0.99-3.45; p = 0.051).<br />
Regarding the outcome <strong>of</strong> the 160 patients with brain metastasis, BMSS was highest in<br />
the Luminal A patients (Median: 31.3m) followed by Luminal B (Median: 8.3m) with<br />
poorest BMSS among HER2 rich and triple negative patients (median 7.9m and 7.6m<br />
respectively; p for trend: 0.024).<br />
Conclusions: Breast cancer biological subtype plays a pivotal role in predicting the<br />
pattern <strong>of</strong> failure <strong>of</strong> patients presenting with localized disease and the subsequent<br />
outcome after brain metastasis in addition to the classical prognostic factors.<br />
Legal entity responsible for the study: Cairo <strong>Oncology</strong> Center<br />
Funding: None<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
259P<br />
Site <strong>of</strong> first recurrence <strong>of</strong> breast cancer after adjuvant therapy:<br />
Clinical aspects and outcome analysis<br />
N. Mejri 1 , S. Labidi 1 , M. Afrit 2 , H. El Benna 1 , H. Boussen 1<br />
1 Medical <strong>Oncology</strong>, Abderrahmen Mami Hospital, Ariana, Tunisia, 2 Medical<br />
<strong>Oncology</strong>, Abderrahmen Mami Hospital, Ariana, Tunisia<br />
Background: The objective <strong>of</strong> this retrospective study was to characterize the sites <strong>of</strong><br />
first relapse in a cohort <strong>of</strong> Tunisian patients with metastatic breast cancer relapsing<br />
after adjuvant therapy and to report survival results.<br />
Methods: Among 1400 early breast cancer patients treated from 2000 to 2010, 324<br />
(23%) relapses were divided into 4 groups according to first site <strong>of</strong> appearance:<br />
A-locoregional alone (breast and lymph nodes), B-Bone alone, C-Brain alone and<br />
D-other sites. Controlateral breast cancer was excluded. Clinico-pathological aspects<br />
and initial therapy were studied for each group. Survival results were reported.<br />
Results: In group A, 12 patients had local recurrence (8 after breast-conserving<br />
surgery), 37 patients had nodal recurrence (23 axillary, 14 sub-clavicular and 11 had<br />
both). Nine patients had surgical resection, 19 had radiation therapy and all patients<br />
received chemotherapy. In group B, 35 patients had palliative radiation, 50 had<br />
chemotherapy, bisphosphonates were available for 67 patients. In group C, we observed<br />
4 cases <strong>of</strong> meningeal carcinomatosis, one case was operated, and all other cases had<br />
whole brain radiation. In group D, metastases were: liver (43), lung (32), pleural (27),<br />
peritoneal (12), gastric (3) and other (32). Seven patients had initial endocrine therapy,<br />
3 patients had metastasectomy (2 liver, 1 lung) and the remaining had chemotherapy.<br />
Table: 259P Patient characteristics according to site <strong>of</strong> recurrence<br />
groups<br />
An=60<br />
(18%)<br />
Bn=92<br />
(29%)<br />
Cn=23<br />
(7%)<br />
D n = 149<br />
(46%)<br />
Median age 47 48 44 48<br />
Body mass index ≥ 35 24 (40%) 17 (18%) 7 (30%) 44 (29%)<br />
Premenopaused 34 (56%) 54 (58%) 15 (65%) 89 (60%)<br />
Age < 35 11 (18%) 8 (8%) 4 (17%) 15 (10%)<br />
Tumor size (mm) 27 33 45 37<br />
SBR II-III 44 (75%) 64 (78%) 20 (86%) 109 (73%)<br />
p N + 37 (61%) 62 (70%) 16 (70%) 96 (63%)<br />
Immunohistochemistry (available<br />
data) -HR + ,HER2- -HER2<br />
amplified -Triple negative<br />
55 22 (40%)<br />
19 (34%)<br />
14 (25%)<br />
79 39 (50%)<br />
29 (37%)<br />
11 (14%)<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
20 3 (15%)<br />
9<br />
(45%)<br />
8<br />
(40%)<br />
Time to relapse (months) 60 54 33 40<br />
Median survival (months) 43 39 10 22<br />
2 years survival (%) 79 72 0 50<br />
139 55<br />
(39%) 39<br />
(28%) 45<br />
(32%)<br />
Overall survival at 2 years was 49% (median <strong>of</strong> 37 months) after median follow-up <strong>of</strong><br />
67 months. Site <strong>of</strong> initial recurrence favoring loco-regional and bone locations<br />
(p < 0.0001) and time to relapse (p = 0.006) were important determinants for<br />
predicting survival from the time <strong>of</strong> initial recurrence.<br />
Conclusions: In Tunisia, patterns <strong>of</strong> relapse according to first site <strong>of</strong> appearance are<br />
similar to results reported in the literature, being characterized by young age, large<br />
tumor size and aggressive histological features.<br />
Legal entity responsible for the study: N/A<br />
Funding: None<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
vi80 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
260P<br />
Impact <strong>of</strong> palbociclib plus fulvestrant on patient reported<br />
general health status compared with fulvestrant alone in HR + ,<br />
HER2- metastatic breast cancer<br />
261P<br />
Phase I/II trial <strong>of</strong> palbociclib in combination with bicalutamide<br />
for the treatment <strong>of</strong> androgen receptor (AR)(+) metastatic<br />
breast cancer (MBC): Pharmacokinetics (PK)<br />
S. Loibl 1 , A. Demichele 2 , N.M. Turner 3 , M. Crist<strong>of</strong>anilli 4 , S. Loi 5 , S. Verma 6 ,<br />
H. Bhattacharyya 7 ,Z.Ke 8 , C. Giorgetti 9 , C.H. Bartlett 10 ,S.Iyer 11 , M. Colleoni 12 ,<br />
N. Masuda 13 , S-A. Im 14 , N. Harbeck 15<br />
1 Medicine and Research, German Breast Group (GBG) Forschungs GmbH,<br />
Neu-Isenburg, Germany, 2 Medicine, University <strong>of</strong> Pennsylvania-Perelman Center<br />
for Advanced Medicine, Philadelphia, PA, USA, 3 Molecular <strong>Oncology</strong>, Royal<br />
Marsden Hospital NHS Foundation Trust, London, UK, 4 Feinberg School <strong>of</strong><br />
medicine, Robert. H. Lurie Cancer Center <strong>of</strong> Northwestern University, Chicago, IL,<br />
USA, 5 Division <strong>of</strong> Cancer Medicine, Peter MacCallum Cancer Centre, East<br />
Melbourne, Australia, 6 Tom Baker Cancer Centre, Department <strong>of</strong> <strong>Oncology</strong>,<br />
University <strong>of</strong> Calgary, Calgary, AB, Canada, 7 Statistics, Pfizer,Inc, New York, NY,<br />
USA, 8 Biostatistics, Pfizer, Inc, La Jolla, CA, USA, 9 Clinical Development, Pfizer,<br />
Inc, Milan, Italy, 10 Global Medical, Pfizer,Inc, New York, NY, USA, 11 Global<br />
Outcomes & Evidence, Pfizer, Inc, New York, NY, USA, 12 Medical <strong>Oncology</strong>,<br />
European Institute <strong>of</strong> <strong>Oncology</strong> (EIO), Milan, Italy, 13 Surgery, National Hospital<br />
Organization Osaka National Hospital, Osaka, Japan, 14 Internal Medicine, Seoul<br />
National University Hospital, Seoul, Republic <strong>of</strong> Korea, 15 Breast Center, University<br />
<strong>of</strong> Munich, Munich, Germany<br />
Background: The present analyses compares patient reported general health status<br />
between palbociclib plus fulvestrant and fulvestrant alone in HR + , HER2- metastatic<br />
breast cancer.<br />
Methods: Patients in PALOMA -3 study (NCT 01942135; Turner et al. NEJM 2016)<br />
were randomized to palbociclib plus fulvestrant (n= 347) or placebo plus fulvestrant<br />
(n= 174). Patient-reported outcomes were assessed at baseline, on day 1 <strong>of</strong> each cycle<br />
until cycle 4 and every alternate cycle from cycle 6 until end <strong>of</strong> treatment using EQ-5D,<br />
a standardized measure <strong>of</strong> health status that consists <strong>of</strong> a descriptive system comprising<br />
5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/<br />
depression rated at 3 levels (no, some, or extreme problems) and a single index score<br />
for health status (range 0 [dead] to 1 [full health]) calculated using a standard<br />
algorithm. In addition, a visual analog scale (VAS) measured self-rated health status<br />
from ‘0’ (worst imaginable) to ‘100’ (best imaginable). Repeated measures mixed-effects<br />
analyses were performed to compare overall index and VAS scores between treatments,<br />
controlling for baseline.<br />
Results: Completion rates at baseline were ≥85% in each group. The mean (SD) scores<br />
at baseline were comparable between palbociclib plus fulvestrant and fulvestrant alone<br />
for the VAS (72.9 [17.22] vs 70.3 [19.87]) and the EQ-5D index scores (0.73 [0.23]) vs<br />
(0.71 [0.23]). General health status assessed by VAS was found to be maintained from<br />
baseline and no significant difference in overall EQ-5D VAS scores was observed<br />
between the treatment arms. The proportion <strong>of</strong> patients reporting the presence <strong>of</strong> a<br />
problem at baseline was similar for palbociclib plus fulvestrant and fulvestrant,<br />
respectively: mobility (28% vs 32%), self-care (9% vs 9%), usual activities (38% vs 45%),<br />
pain (67% vs 67%), and anxiety/depression (52% vs 61%). The overall mean EQ-5D<br />
index scores on treatment was significantly greater (p < 0.05) for palbociclib plus<br />
fulvestrant (0.74) compared with fulvestrant alone (0.69).<br />
Conclusions: Addition <strong>of</strong> palbociclib to fulvestrant was associated with significantly<br />
higher on treatment EQ-5D index scores compared to fulvestrant alone.<br />
Clinical trial identification: NCT01942135<br />
Legal entity responsible for the study: Pfizer<br />
Funding: Pfizer, Inc<br />
Disclosure: S. Loibl: Research and funding and honoraria to institution from<br />
GlaxoSmithKline; Novartis; Roche Pharma AG; Pfizer;Celgene, Amgen, and most<br />
other pharmaceutical companies. A. Demichele: Participant on Advisory Board<br />
sponsored by Pfizer. N.M. Turner: Consultant/ Advisory role and receives honoraria<br />
from AstraZeneca; Pfizer; Roche Pharma AG. M. Crist<strong>of</strong>anilli: honoraria - Agendia;<br />
Cynvenio Biosystems; Dompé Farmaceutici Consulting/Advisory role-Cynvenio<br />
Biosystems; Dompé Farmaceutici; Newomics Speaker’s bureau- Agendia; NanoString<br />
Technologies. S. Loi: Affiliated Institute receives research funding from<br />
PharmaSea. S. Verma: Advisory Board Panel Member for Pfizer, Roche, AZ, Novartis,<br />
Amgen, Eisai,BMS, Eli Liily and Merck. H. Bhattacharyya: Pfizer employee and<br />
stockholder.Z. Ke, C. Giorgetti, C.H. Bartlett: Pfizer Employee and Stockholder. S. Iyer:<br />
Employee and shareholder/stock options owner <strong>of</strong> Pfizer, Inc .M. Colleoni: Honararia -<br />
Novartis Advisory Role - Boehringer, Astra Zeneca, Pierre Fabre, Pfizer. N. Masuda:<br />
Personal Fees, Honararia; Research funding -Chugai, Astra zeneca, kyowa krin<br />
Research funding- Pfizer, Novartis, Eli Lilly. S-A. Im: Grant - Astra Zeneca Advisory<br />
Role- AZ, Roche, Novartis. N. Harbeck: Honoraria -Amgen; Celgene; NanoString<br />
Technologies; Novartis; Pfizer; Roche Consulting/Advosory role -AstraZeneca;<br />
Celgene; Genomic Health; Novartis; Roche/Genentech; Sandoz; Wilex Research<br />
funding -Boehringer Ingelheim; Novartis; Pfizer;<br />
A. Gucalp 1 , A. Corben 1 , S. Patil 1 , L.A. Boyle 1 , C. Hudis 2 , T.A. Traina 1<br />
1 Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA,<br />
2 Department <strong>of</strong> Medicine, Memorial Sloan-Kettering Cancer Center, New York,<br />
NY, USA<br />
Background: Emerging evidence demonstrates that the androgen-signaling pathway<br />
plays a role in BC pathogenesis and may be a valuable therapeutic target. In<br />
TBCRC011, bicalutamide (B) in patients (pts) with AR + /ER/PR- MBC was<br />
well-tolerated and demonstrated a clinical benefit rate <strong>of</strong> 19% in this population<br />
(Gucalp et al. CCR 2013). Palbociclib (P) is a competitive inhibitor <strong>of</strong> CDK4/6 and has<br />
been shown to reduce growth <strong>of</strong> AR + ER/PR- MDA-MB-453 BC cells. In<br />
postmenopausal pts with luminal ER+ MBC the addition <strong>of</strong> P to letrozole significantly<br />
improved median progression-free survival (PFS) in comparison to letrozole alone.<br />
Given the luminal signature <strong>of</strong> AR+ triple negative BC (TNBC) and the presence <strong>of</strong><br />
intact Rb in this ER(-) subtype, we are testing the efficacy <strong>of</strong> B + P in pts with<br />
metastatic AR+ TNBC. This Phase I study is evaluating the safety and PK <strong>of</strong> this drug<br />
combination and will establish the recommended phase II dose for further study.<br />
NCT02605486.<br />
Methods: Pts with AR+ (IHC ≥ 1%)/ER any/HER2(-) MBC on central review at MSK<br />
were eligible if met following criteria: ECOG ≤2, postmenopausal, no limit to prior<br />
regimens. Pts with ER+ BC must have had 1 prior endocrine therapy. Treatment (tx): B<br />
100 mg orally daily and P 100 mg orally daily 3 weeks on 1 week <strong>of</strong>f for the 1 st<br />
dose-escalation cohort (DLT period = 28 days). Pts are evaluated for toxicity every 2-4<br />
weeks and for response every 8 weeks. Ph I standard 3 + 3 design with 3 dose<br />
escalations. Plasma for PK was collected throughout the study.<br />
Results: As <strong>of</strong> 5/11/16, 7 pts with AR+ MBC are enrolled. Accrual is complete to the<br />
second dose escalation cohort and the final cohort <strong>of</strong> B 150mg + P 125 mg is enrolling<br />
as <strong>of</strong> May 2016. Tx has been well tolerated: the only related Grade 3 AE was<br />
neutropenia in 1 pt. No related Grade 4 or 5 AEs were observed. One SAE <strong>of</strong> Grade 3<br />
anemia, Grade 4 hypercalcemia was related to disease progression. PK analysis is<br />
ongoing.<br />
Conclusions: The combination <strong>of</strong> palbociclib and bicalutamide has been well tolerated<br />
with no unexpected toxicity observed. Updated safety and PK data will be presented.<br />
Clinical trial identification: NCT02605486<br />
Legal entity responsible for the study: MSKCC<br />
Funding: Pfizer<br />
Disclosure: A. Gucalp, T.A. Traina: Research support from Medivation, Astellas, Pfizer<br />
and InnocrinAll other authors have declared no conflicts <strong>of</strong> interest.<br />
262P<br />
The influence <strong>of</strong> old age on everolimus exposure in patients<br />
with cancer<br />
A.E.C.A.B. Willemsen 1 , C. van Herpen 1 , T.C. Schneider 2 ,D.deWit 3 , E. Kapiteijn 2 ,<br />
N.P. van Erp 4<br />
1 Medical <strong>Oncology</strong>, Radboud University Medical Centre Nijmegen, Nijmegen,<br />
Netherlands, 2 Clinical <strong>Oncology</strong>, Leiden University Medical Center (LUMC),<br />
Leiden, Netherlands, 3 Clinical Pharmacy and Toxicology, Leiden University<br />
Medical Center (LUMC), Leiden, Netherlands, 4 Pharmacy, Radboud University<br />
Medical Centre Nijmegen, Nijmegen, Netherlands<br />
Background: When starting treatment with everolimus in elderly cancer patients (pts),<br />
clinicians are <strong>of</strong>ten concerned about everolimus related toxicity. Elderly pts frequently<br />
have comorbidities and are considered more fragile. Therefore, upfront dose reduction<br />
<strong>of</strong> everolimus to prevent toxicity is applied more readily in elderly pts. However, very<br />
limited data are available on the pharmacokinetics (PK) in elderly pts and therefore,<br />
the influence <strong>of</strong> age on everolimus PK in cancer pts is yet unknown. The objective <strong>of</strong><br />
this study was to determine the effect <strong>of</strong> age on everolimus PK.<br />
Methods: In two PK studies in pts with either metastatic breast cancer or advanced<br />
thyroid cancer treated with everolimus 10mg OD, everolimus PK was compared<br />
between elderly pts (age ≥ 70 years ) and control pts (age < 70 years). Blood samples<br />
were collected at steady-state PK, after 2 weeks <strong>of</strong> therapy. Blood was collected for PK<br />
assessment at 0, 1, 2, and 3 hours or at 0, 1, 2, 3, 5 and 8 hours after everolimus intake.<br />
Whole blood concentrations were measured. Plasma concentrations were calculated by<br />
correcting for the individual hematocrit. Area under the concentration time curves<br />
over 24 hours after dosing (AUC 0-24h ), were calculated by using a two compartment<br />
population PK model with first order absorption using Nonlinear Mixed Effect<br />
modeling (NONMEM v7.2). Dose changes for each patient were recorded. Statistical<br />
analysis was done with SPSS, using an unpaired t-test.<br />
Results: 19 elderly and 56 control pts were included. Comparative PK data are shown<br />
in table 1. Everolimus exposure in both whole blood and plasma did not differ<br />
significantly between the two groups. Dose reductions or discontinuations due to<br />
toxicity occurred in 42% <strong>of</strong> elderly and 40% <strong>of</strong> control pts (p = .73). Table: results.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw365 | vi81
abstracts<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Table: 262P<br />
Parameter Control (n = 56);<br />
mean (range; SD)<br />
Elderly (n = 19);<br />
mean (range; SD)<br />
Age (years) 57.5 (37-69) 73.4 (70-80)<br />
Whole blood AUC 0-24 580.0 (223.1) 507.9 (182.3) .208<br />
Plasma AUC 0-24 209.1 (79.3) 190.0 (66.3) .349<br />
AUC0–24 = area under concentration–time curve from zero to 24 hours,<br />
µg*h/L<br />
Conclusions: Everolimus PK is not affected by older age. Upfront dose adjustment,<br />
such as frequently considered in elderly pts, is not supported by PK and clinical data<br />
and needs to be reconsidered.<br />
Clinical trial identification: NCT01948960 AND NCT01118065<br />
Legal entity responsible for the study: Radboud University Medical Center<br />
Funding: Novartis<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
263P<br />
Predictors <strong>of</strong> effectiveness <strong>of</strong> the use <strong>of</strong> steroidal aromatase<br />
inhibitors after progression on non-steroidal aromatase<br />
inhibitors in advanced breast cancer patients<br />
M.M. Ulrich de Menezes Pereira dos Santos, C. Cardoso, M. Sousa, S. Esteves,<br />
M. Brito, A. Moreira<br />
<strong>Oncology</strong>, IPO LFG, Lisbon, Portugal<br />
Background: Clinical evidence suggests that steroid aromatase inhibitors (SAI) lack<br />
cross resistance with non-steroid aromatase inhibitors (nSAI). Therefore, the use <strong>of</strong><br />
SAI in advanced breast cancer (ABC) patients (pts) after disease progression on nSAI<br />
has been considered a reasonable option in several centers. Our aim is to confirm the<br />
effectiveness <strong>of</strong> using this strategy in ABC and identify predictors <strong>of</strong> response.<br />
Methods: Retrospective analysis <strong>of</strong> a cohort <strong>of</strong> consecutive ABC female<br />
postmenopausal hormone receptor patients treated in a single cancer center with SAI<br />
(exemestane) after progression with nSAI (letrozol or anastrozole), between 2009 and<br />
2013. Effectiveness outcomes were time to progression (TTP) and clinical benefit (CB),<br />
defined as complete response or partial response or stable disease for more than 6<br />
months. We used logistic and Cox regression models.<br />
Results: 160 ABC pts were identified, with a median age <strong>of</strong> 60 (range 32-87). In 74%<br />
pts estrogen receptor was high (≥75%) and in 16% HER2 was overexpressed. Visceral<br />
disease was present in 25% pts and 67% had been previously treated with adjuvant<br />
endocrine therapy. In ABC, 57% were initially treated with nSAI. The average number<br />
<strong>of</strong> therapeutic lines until exemestane was 2.3 (1-8) and 33% were treated with<br />
exemestane immediately after progression under nSAI. The exemestane CB rate was<br />
64%. In univariable analysis, the factors associated with CB were visceral disease<br />
(p = 0.047), previous CB to nSAI (p = 0.047) and number <strong>of</strong> treatment lines between<br />
nSAI and exemestane (p = 0.011). In multivariable analysis, visceral disease and CB to<br />
nSAI were the only independent factors significantly associated with CB to exemestane<br />
(OR 0.38 and 2.15, respectively). Median TTP was 7.8m (95%CI 6.8-9.2). In<br />
multivariable analysis, visceral disease and the number <strong>of</strong> treatments between AI were<br />
the only independent factors significantly associated with TTP (HR 1.35 and 1.56,<br />
respectively).<br />
Conclusions: The use <strong>of</strong> exemestane after progression on nSAI seems to be a valid<br />
option, especially in ABC patients with non-visceral disease, few treatment lines<br />
between nSAI and SAI and with previous CB to nSAI.<br />
Legal entity responsible for the study: IPO Lisboa<br />
Funding: IPO Lisboa<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
264P<br />
Patterns <strong>of</strong> treatment and outcome <strong>of</strong> fulvestrant 500mg in<br />
postmenopausal women with hormone-positive (HR<br />
+)/Her2-negative (HER2-) metastatic breast cancer (MBC):<br />
a real life multicenter Italian experience<br />
R. Palumbo 1 , A. Ferzi 2 , A. Gambaro 3 , F. Sottotetti 4 , L. Licata 1 , C. Teragni 1 ,<br />
B. Tagliaferri 1 , E. Pozzi 1 , A. Bernardo 1<br />
1 USD Oncologia, Fondazione S. Maugeri IRCCS, Pavia, Italy, 2 Medical <strong>Oncology</strong>,<br />
Ospedale Civile di Legnano, Legnano, Italy, 3 Medical <strong>Oncology</strong>, Ospedale Luigi<br />
Sacco, Milan, Italy, 4 Oncologia Medica, IRCCS Fondazione Salvatore Maugeri,<br />
Pavia, Italy<br />
Background: Fulvestrant 500 mg (F500) is a well-established therapeutic option for<br />
HR + /HER2- MBC postmenopausal patients (pts) who had previously progressed on<br />
hormonal therapy. Available data on F500 use in routine clinical practice are lacking.<br />
P<br />
This retrospective multicenter observational study was conducted to describe the<br />
patterns <strong>of</strong> treatment and outcome <strong>of</strong> F500 in the real life setting,<br />
Methods: Data <strong>of</strong> postmenopausal HR + /HER2- MBC pts who received F500 from<br />
January 2011 to December 2014 were collected from institutional databases <strong>of</strong> 4 Italian<br />
Centers. The primary study aim was to analyze progression-free survival (PFS) and<br />
Clinical Benefit Rate (CBR: complete response [CR] + partial response [PR] + stable<br />
disease [SD] > 24 weeks); secondary endpoints included overall survival (OS) and<br />
safety pr<strong>of</strong>ile.<br />
Results: 490 pts were included in the study, 480 were evaluable. F500/month was given<br />
as 1 st up to 7 th treatment line: 1 st line in 24% <strong>of</strong> pts, 2 nd line in 35%, >3 rd in 41%. 306<br />
pts received the drug upon progression <strong>of</strong> disease (PD) on prior endocrine treatment,<br />
92 and 68 as maintenance therapy following 1 st or 2 nd line chemotherapy, respectively;<br />
21% <strong>of</strong> pts had de novo metastatic disease. Median age: 66 years (range 56-81); visceral<br />
metastases: 32%; ECOG PS = 1: 62%. Median <strong>of</strong> cycles administered: 14 (range 6-28).<br />
At a median follow-up <strong>of</strong> 18 months (range 6-38) median PFS was 11.6 months (range<br />
8.1-16.2: 12.5 in 1 st line, 11.4 in 2 nd line, 9.2 in >3 lines), CBR was 68.6% (8.8% CR,<br />
21.6 PR, 38,2 SD> 24 weeks). No differences in CBR (67.8% vs 69.1%) and PFS (11.5 vs<br />
11.6 months) were observed between pts receiving F500 as maintenance therapy and<br />
those treated at PD on prior therapy. Median OS was 44.2 months (range 35-NR).<br />
More frequent toxicities did not exceed grade 1 NCI-CTC: local injection site pain<br />
(11.2%), joint disorders (6.2%), hot flushes (4.9%).<br />
Conclusions: Our real word experience confirm that F500 can safely be <strong>of</strong>fered to most<br />
women with HR + /HER2- MBC, with interesting expectations <strong>of</strong> PFS and CBR and<br />
good safety pr<strong>of</strong>ile, producing similar outcomes as both upon PD treatment and<br />
maintenance therapy.<br />
Legal entity responsible for the study: Raffaella Palumbo<br />
Funding: IRCCS Fondazione S. Maugeri<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
265P<br />
Fulvestrant (FUL) 500 milligrams as endocrine therapy (ET) for<br />
hormone sensitive advanced breast cancer patients. The<br />
Ful500 prospective observational trial<br />
L. Moscetti 1 , M.A. Fabbri 2 , P. Vici 3 , C. Natoli 4 , T. Gamucci 5 , I. Sperduti 6 , L. Pizzuti 3 ,<br />
L. Iezzi 4 , E. Iattoni 1 , C.L. Roma 7 , A. Vaccaro 5 ,G.D’Auria 2 , M. Mauri 7 , E. Ruggeri 2<br />
1 <strong>Oncology</strong> and Hematology, Azienda Ospedaliero - Universitaria Policlinico di<br />
Modena, Modena, Italy, 2 Medical <strong>Oncology</strong> Department, Ospedale Belcolle, ASL<br />
di Viterbo <strong>Oncology</strong> Unit, Viterbo, Italy, 3 Division <strong>of</strong> Medical <strong>Oncology</strong> B, Istituto<br />
Regina Elena, Rome, Italy, 4 Department <strong>of</strong> Medical, Oral and Biotechnological<br />
Sciences, Experimental and Clinical Sciences, University G D’Annunzio, Chieti,<br />
Italy, 5 Oncologia Medica, Ospedale SS Trinità, Sora, Italy, 6 Biostatistic Unit, Istituto<br />
Regina Elena, Rome, Italy, 7 <strong>Oncology</strong> and Hematology, S Giovanni Addolorata,<br />
Rome, Italy<br />
Background: FUL represents a ET option for pts whose endocrine sensitive locally or<br />
advanced breast cancer (LABC) has progressed after an antiestrogen. The 500 mg<br />
monthly represents the actual standard dose showing a disease control rate <strong>of</strong> 45%-72%<br />
and a progression free survival (PFS) ranging from 6.5 to 23 months (mo) depending<br />
on treatment line. To evaluate the efficacy <strong>of</strong> FUL in unselected LABC pts we<br />
performed an observational prospective trial.<br />
Methods: Eligible pts were women with LABC suitable for ET and who received<br />
previous treatment with either an antiestrogen or an aromatase inhibitor (AI) as a<br />
first-line therapy, or relapsing while on or within 1 year from completion <strong>of</strong> adjuvant<br />
ET. Primary end point was the clinical benefit rate (CBR), defined as complete<br />
response (CR) or partial response (PR) plus stable disease (SD) lasting >24 weeks.<br />
Secondary end points were overall survival (OS), PFS and tolerability.<br />
Results: 163 consecutive eligible pts were enrolled. Pts characteristics: median age 68<br />
ys, PS 0/1 in 95% <strong>of</strong> pts, adjuvant ET administered in 75% <strong>of</strong> pts, 55% <strong>of</strong> pts had<br />
received first-line ET (11 tamoxifen, 78 AIs), 44% had visceral disease, 30% had bone<br />
disease, 52% <strong>of</strong> pts had more than one site <strong>of</strong> disease. Overall, CBR was reached in 59%<br />
<strong>of</strong> pts (CR + PR + SD, 95%CI 51-66). Median PFS was 7 mo (95%CI 6-8), median OS<br />
was 35 mo (95%CI 24-46). Analysis <strong>of</strong> safety did not show any relevant toxicity, no<br />
serious adverse event has been observed. In the multivariate analysis, visceral<br />
involvement showed to be prognostic factor for PFS (HR 1.60 95%CI 1.13-2.27, p<br />
0.008), whereas previous ET in advanced setting (HR 2.11, 95%CI 1,27-3.29, p 0.004)<br />
and >1 site <strong>of</strong> metastases (HR 2.53 95%CI 1.54-4.22, p 50% (OR 3.49 95%CI 1.30-9.38, p 0.01), 1<br />
site <strong>of</strong> metastases (OR 2.21 95%CI 1.08-4.50, p 0.03) and no previous ET for advanced<br />
disease (OR 2.24 95%CI 1.1-4.58, p 0.03) were predictive factors for CBR.<br />
Conclusions: In this observational prospective trial, FUL showed to be a safe and active<br />
treatment and confirm the efficacy <strong>of</strong> the 500 mg dose. Treatment was very well<br />
tolerated. As expected, pts who had received first-line ET have a worse outcome and a<br />
reduced CBR.<br />
Clinical trial identification: AUSL Viterbo Ethical committe approval for prospective<br />
observational trial nr 16889 CE 320/12, April 6 2012<br />
Legal entity responsible for the study: Luca Moscetti<br />
Funding: AUSL Viterbo<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
vi82 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
266P<br />
Is the overall survival after hormone therapy for<br />
hormone-receptor-positive, HER2-negative metastatic breast<br />
cancer still better than for triple-negative metastatic breast<br />
cancer?<br />
J. Watanabe 1 , T. Hayashi 2 ,Y.Tadokoro 2 , S. Nishimura 2 , K. Takahashi 2<br />
1 Breast oncology, Shizuoka Cancer Center, Shizuoka, Japan, 2 Breast surgery,<br />
Shizuoka Cancer Center, Shizuoka, Japan<br />
Background: Hormone-receptor-positive (HR+) HER2-negative (HER2-) metastatic<br />
breast cancer (MBC), i.e. luminal-type MBC, is known to have a better prognosis than<br />
triple-negative MBC (TNMBC). However, if HR + HER2-MBC patients (pts) are<br />
diagnosed to be resistant to hormone therapy (HTx), they must undergo chemotherapy<br />
(CTx), just like TNMBC pts. To our knowledge, however, the overall survival (OS) after<br />
HTx (the OS derived from CTx) has not been well discussed.<br />
Methods: We herein reviewed our medical records from 2002 to the present to assess<br />
the OS beyond HTx and identify the prognostic factors in HR + HER2-MBC pts.<br />
Statistical analyses were performed using the Kaplan-Meyer method and a multivariate<br />
COX regression analysis.<br />
Results: We identified 344 HR + HER2-MBC pts from our medical records, and 286<br />
(207 recurrent [rBC], 79 advanced [aBC]) underwent CTx. Among those 286 pts, 239<br />
(83.6%) received at least 1 or more HTx sessions prior to CTx, while the other 47<br />
(16.4%) received CTx as their initial systemic therapy. We also extracted 95 (69 rBC, 26<br />
aBC) TNMBC pts from the records as a control group. The median OS for the 286 pts<br />
from the diagnosis <strong>of</strong> MBC was 1395.0 days (95% confidence interval [CI]<br />
500.0-3942.0), which was superior to that <strong>of</strong> TNMBC pts (777.0 days, 95%CI<br />
238.0-1784.0, p < 0.001, log-rank). The median OS from the initiation <strong>of</strong> CTx was<br />
972.0 days (95%CI 294.0-2285.0) in HR + HER2-MBC pts, which was significantly<br />
(p < 0.01, log-rank) better than that in TNMBC pts. However, when limited to rBC pts,<br />
who comprise the majority <strong>of</strong> ER + HER2-MBC pts, the OS from the initiation <strong>of</strong> CTx<br />
was almost the same as that <strong>of</strong> TNrBC pts (median 932.0 and 866.0, respectively,<br />
p = NS). Multivariate analyses further revealed that rBC pts who had a disease-free<br />
interval (DFI) <strong>of</strong> less than 24 months or pts who had bone lesions at the initiation <strong>of</strong><br />
CTx showed a significantly poorer prognosis than those who had a longer DFI or no<br />
bone lesions (hazard ratio <strong>of</strong> 1.50 [95%CI 1.01-2.23] and 1.57 [1.02-2.40], respectively).<br />
Conclusions: Our single-institution retrospective analysis with some limitations found<br />
that the OS after HTx in recurrent HR + HER2-BC pts was almost identical to that <strong>of</strong><br />
recurrent TNBC pts.<br />
Legal entity responsible for the study: Junichiro Watanabe<br />
Funding: None<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
267P<br />
Survival pattern <strong>of</strong> negative lymph node non-metastatic breast<br />
cancer females in the United States with radiotherapy<br />
treatment according to estrogen and progesterone receptors<br />
status<br />
A. Meshref 1 , M. Mousa 1 , M. Ramadan 2 , M.Y. Haggag 1<br />
1 Faculty <strong>of</strong> Medicine, Suez Canal University, Ismailia, Egypt, 2 Faculty <strong>of</strong> Pharmacy,<br />
Suez Canal University, Ismailia, Egypt<br />
Background: Estrogen and progesterone receptors have important role in management<br />
<strong>of</strong> breast cancer. Our study aim to evaluate the effect <strong>of</strong> radiotherapy with different<br />
estrogen and progesterone receptors status.<br />
Methods: SEER database used to obtain patient data. All 18 SEER registries were used<br />
to estimate five-year relative survival rates <strong>of</strong> non-metastatic breast cancer cases with<br />
negative lymph node infiltration patient who received radiotherapy (RT) between 1998<br />
and 2007 by Kaplan-Meir method. We compared relative survival rates among groups<br />
<strong>of</strong> patients categorized by estrogen and progesterone receptors status.<br />
Results: 200535 patient who met selection criteria in SEER database was divided into 9<br />
groups depending on estrogen (ER) and progesterone (PR) receptor status ]positive<br />
(+), negative (-) or borderline (b)[. The result showed that there was significant<br />
difference in five-years relative survival rate in patient who received RT comparing with<br />
patient who didn’t receive RT in ER+ & PR+ ]100% & 98.5% (95% CI:98.1-98.8)<br />
respectively[ (P value >0.001), ER+ & PR- ]100% & 95.1% (95% CI:94.2-95.8)<br />
respectively[ (P value >0.001), ER- & PR+ ]97.6% (95% CI:95.6-98.7) & 92% (95%<br />
CI:89.7-93.8) respectively[ (P value >0.001), ER- & PR- ]93.8% (95% CI:93.3-94.2) &<br />
91.5% (95% CI:87.5-88.7) respectively[ (P value >0.001), ERb & PR- ]97.5% (95%<br />
CI:79.5-99.7) & 90.4% (95% CI:78.8-95.8) respectively[ (P value =0.028) & ERb & PRb<br />
]98.5% (95% CI:31.6-100) & 84% (95% CI:73.2-90.7) respectively[ (P value =0.003)<br />
groups. The study showed that ER+ status has 100% five years relative survival rate with<br />
all PR receptor status.<br />
Conclusions: RT is highly recommended in patient with ER+ regardless the status <strong>of</strong><br />
PR receptor status. Also it is recommended in previous sub group which showed<br />
significant difference between patients who received RT comparing with patients who<br />
didn’t receive RT.<br />
Legal entity responsible for the study: The Surveillance, Epidemiology, and End<br />
Results (SEER) Program <strong>of</strong> the National Cancer Institute<br />
Funding: None<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
268P<br />
Survival patterns <strong>of</strong> high-grade breast cancer patients in the<br />
United States<br />
M. Mousa, A. Meshref, M. Ramadan, M.Y. Haggag<br />
Faculty <strong>of</strong> Medicine, Suez Canal University, Ismailia, Egypt<br />
Background: Our study aimed at evaluation <strong>of</strong> relative survival rates <strong>of</strong> patients with<br />
high-grade breast in the United States diagnosed in 2010 using the Surveillance,<br />
Epidemiology, and End Results (SEER) Registry.<br />
Methods: We used Kaplan-Meir method to analyze the 2-year relative survival rates <strong>of</strong><br />
14283 Bloom-Richardson grade III breast cancer patients using SEER*Stat Program.<br />
We used Z-test to compare relative survival rates among patients’ groups categorized<br />
by radiation therapy status, age groups, race, site, histology, Her2/Hormone Receptors<br />
(HR) status, and laterality using Z–test. We used Kaplan-Meir method to analyze the<br />
2-year relative survival rates <strong>of</strong> 14283 Bloom-Richardson grade III breast cancer<br />
patients using SEER*Stat Program. We used Z-test to compare relative survival rates<br />
among patients’ groups categorized by radiation therapy status, age groups, race, site,<br />
histology, Her2/Hormone Receptors (HR) status, and laterality using Z–test.<br />
Results: There was a statistically significant increase in the 2-year relative survival rate<br />
for patients who received radiation therapy (96.8 ± 0.3%) in comparison to patients<br />
who did not receive it (89.3 ± 0.4%, P < 0.001). We also found a significant increase in<br />
the 2-year relative survival rate for age group
abstracts<br />
Conclusions: In our study, CNS progression on T-DM1 was more common than<br />
previously reported and survival for patients who developed CNS disease was shorter<br />
than expected. If confirmed by other studies, our results suggest that surveillance CNS<br />
imaging may be required for patients on T-DM1 therapy.<br />
Legal entity responsible for the study: The Royal Marsden NHS Foundation Trust<br />
Funding: The Royal Marsden NHS Foundation Trust<br />
Disclosure: N.M. Turner: I have received advisory board honoraria from<br />
Roche. S. Johnston: I have received consultancy advisory board fees from Roche<br />
Genentech. S. Stanway: I’ve received payment for advisory boards for Roche and for<br />
Clinigen in the last year. All other authors have declared no conflicts <strong>of</strong> interest.<br />
270P<br />
Phase II study <strong>of</strong> gemcitabine, trastuzumab, and pertuzumab<br />
for HER2-positive metastatic breast cancer after prior<br />
pertuzumab-based therapy<br />
N.M. Iyengar 1 , L. Smyth 1 , D. Lake 1 , A. Gucalp 1 , J. Singh 1 , T.A. Traina 1 ,<br />
P. Defusco 1 , M.N. Dickler 1 , M. Fornier 1 , S. Goldfarb 1 , K. Jhaveri 1 , A. Latif 1 ,<br />
S. Modi 1 , T. Troso-Sandoval 1 , G. Ulaner 2 , M. Jochelson 2 , J. Baselga 1 , L. Norton 1 ,<br />
C. Hudis 1 , C. Dang 1<br />
1 Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA,<br />
2 Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA<br />
Background: The combination <strong>of</strong> taxanes with trastuzumab (H) and pertuzumab (P)<br />
for first line treatment <strong>of</strong> HER2-positive metastatic breast cancer (MBC) is associated<br />
with improved progression-free survival (PFS) and overall survival (OS). Treatment per<br />
physician’s choice with anti-HER2 therapy after second line therapy is associated with<br />
a median PFS <strong>of</strong> 3 months. While continued use <strong>of</strong> H in therapeutic combinations<br />
after progression on H-based therapy is common, the efficacy <strong>of</strong> continuing HP-based<br />
treatment after progression on P-based therapy is unknown.<br />
Methods: This is a single arm phase II trial <strong>of</strong> gemcitabine (G) with HP. Eligible<br />
patients had HER2-positive (IHC 3+ or FISH > 2.0) MBC with prior HP-based<br />
treatment and ≤ 3 prior chemotherapies. Patients received G (1200 mg/m 2 )ondays1<br />
and 8 <strong>of</strong> a q 3 week (w) cycle, and H (8 mg/kg load → 6 mg/kg) and P (840 mg load →<br />
420 mg) q3w. The primary endpoint is PFS at 3 months. Secondary endpoints include<br />
OS, safety and tolerability. An exploratory endpoint is to compare PFS by RECIST<br />
criteria versus 18-F FDG-PET response criteria. Using a Simon optimal 2-stage design,<br />
21 patients were enrolled in stage 1. The successful 3-month PFS rate for stage 1 was set<br />
at 57% to allow accrual to stage 2 for a total <strong>of</strong> 45 patients. The study therapy will be<br />
considered successful if at least 27/45 (60%) patients are progression free at 3 months.<br />
Results: As <strong>of</strong> April 11, 2016, 22 patients are enrolled; 17 are evaluable at 3 months and<br />
5 have not had 3-month evaluation. At 3 months, 12/17 (71%) are progression free (1<br />
CR, 4 PR, 7 SD); 5 patients have progressed. The 3 month-PFS results for evaluable<br />
patients will be updated. There are no cardiac or febrile neutropenic events to date. 5<br />
patients required G dose reduction (4 due to grade 3 neutropenia and 1 due to grade 3<br />
vomiting) and the study was amended to lower initial G dose to 1000 mg/m 2 .<br />
Conclusions: The preliminary 3 month-PFS is 71% in evaluable patients, and updated<br />
data will be presented. These findings suggest clinical benefit when P is continued<br />
beyond progression.<br />
Clinical trial identification: NCT02252887 September 26, 2014<br />
Legal entity responsible for the study: Memorial Sloan Kettering Cancer Center<br />
Funding: Genentech/Roche<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
271P<br />
HER2 positive breast cancer with central nervous system<br />
metastases: Pathological features and clinical outcome<br />
G. Masci 1 , L. Santarpia 2 , G. Bottai 2 , L. Giordano 3 , M. Zuradelli 1 , R. Torrisi 1 ,L.Di<br />
Tommaso 4 , A. Sagona 5 , V. Errico 5 , W. Gatzemeier 5 , A. Testori 5 , P. Navarria 6 ,<br />
L. Bello 7 , C. Tinterri 5 , M. Scorsetti 6 , A. Santoro 1<br />
1 Medical <strong>Oncology</strong> and Hematology, Istituto Clinico Humanitas, Rozzano, Italy,<br />
2 <strong>Oncology</strong> Experimental Therapeutics Unit, Istituto Clinico Humanitas, Rozzano,<br />
Italy, 3 Biostatistic Unit, Istituto Clinico Humanitas, Rozzano, Italy, 4 Pathology,<br />
Istituto Clinico Humanitas, Rozzano, Italy, 5 Breast Unit, Istituto Clinico Humanitas,<br />
Rozzano, Italy, 6 Radiotherapy Unit, Istituto Clinico Humanitas, Rozzano, Italy,<br />
7 Neurosurgery, Istituto Clinico Humanitas, Rozzano, Italy<br />
Background: Since the introduction <strong>of</strong> trastuzumab-containing therapies, patients<br />
with HER2+ breast cancers (BC) are experiencing longer progression-free (PFS) and<br />
overall survival (OS). However, the increasing life expectancy is associated with an<br />
increased incidence <strong>of</strong> central nervous system (CNS) metastases. Objective <strong>of</strong> the study<br />
is the identification <strong>of</strong> potential clinico-pathological features associated with CNS<br />
metastases compared to patients who develop extracranial metastases in HER2+<br />
patients.<br />
Methods: We respectively analyzed 232 metastatic HER2+ BC patients (ER + /<br />
HER2 + , n = 126; ER-/HER2 + , n = 89). OS was estimated by the Kaplan Meier<br />
method and differences between groups were assessed by the log-rank test. The<br />
incidence <strong>of</strong> CNS metastases was considered as a time depend variable. Cox<br />
proportional Hazard model was used to estimate Hazard ratio (HR) with 95%<br />
confidence intervals (CI). Statistical significance was set at 0.05.<br />
Results: We identified 90 HER2+ patients with CNS and 142 patients with different<br />
types <strong>of</strong> metastases. The patients with CNS metastases were younger at the diagnosis<br />
(p = 0.015). There was a trend for an increase <strong>of</strong> CNS metastases in patients with<br />
hormone receptor negativity. The median follow-up for the entire cohort was 64.1<br />
months. The median OS was 38.9 months for the entire cohort, 31.6 for patients with<br />
CNS metastases, and 44.7 for patients with other metastases (p = 0.005). Patients who<br />
received hormonal therapy/adjuvant chemotherapy had a favorable outcome<br />
(p < 0.001). In multivariate analysis the presence <strong>of</strong> CNS metastases increased the risk<br />
<strong>of</strong> death <strong>of</strong> 4.2 times (CI 95% 3.0-5.9, p < 0.001). The median OS <strong>of</strong> patients with a<br />
single CNS lesion was 118 vs 31 months <strong>of</strong> those with multiple lesions (p = 0.002).<br />
Moreover, we found a statistically significant decrease in OS as the number <strong>of</strong> CNS<br />
lesions increase (HR 1.3, CI 95% 1.2-1.8, p = 0.01), independently from the treatment<br />
received.<br />
Conclusions: HER2+ patients with multiple CNS lesions had a poor prognosis<br />
regardless <strong>of</strong> the pathological features and therapeutic approach. Current<br />
targeted-therapies are unlikely to be active against brain metastases and novel<br />
biological agents are urgently needed.<br />
Legal entity responsible for the study: Humanitas Clinical and Research Center<br />
Funding: Humanitas Clinical and Research Center<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
272P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Clinical and molecular analysis <strong>of</strong> long-term HER2 positive<br />
metastatic breast cancer survivors<br />
C. Omarini 1 , C. Caprera 2 , S. Manfredini 2 , F. Caggia 1 , G. Guaitoli 1 , M.E. Filieri 1 ,S.<br />
R. Bettelli 2 , L. Moscetti 3 , S. Kaleci 4 , A.V. Tamma 1 , S. Cascinu 1 , F. Piacentini 1<br />
1 Department <strong>of</strong> Medical and Surgical Sciences for Children & Adults, Azienda<br />
Ospedaliero - Universitaria Policlinico di Modena, Modena, Italy, 2 Molecular<br />
Pathology Lab - Modena, Azienda Ospedaliero - Universitaria Policlinico di<br />
Modena, Modena, Italy, 3 Oncological Day Hospital, Azienda Ospedaliero -<br />
Universitaria Policlinico di Modena, Modena, Italy, 4 Dipartimento di Medicina<br />
Diagnostica,, Azienda Ospedaliero - Universitaria Policlinico di Modena, Modena,<br />
Italy<br />
Background: Several multigene tests have been developed in Metastatic Breast Cancer<br />
(MBC) disease, in order to identify predictive factors correlated to clinical outcomes.<br />
The purpose <strong>of</strong> this study is to investigate the clinico-pathological and molecular<br />
characteristics that could differentiate long term responders from patients experiencing<br />
early progression during anti-HER2 treatments.<br />
Methods: A total <strong>of</strong> 34 HER2 positive MBC patients were included: 20 patients with a<br />
time to progression longer than 3 years in Long Responders group (LR) and 14 patients<br />
with a progression disease within one year <strong>of</strong> anti-HER2 therapy in Poor Responders<br />
group (PR). Tumor characteristics and treatment information were collected. The<br />
expression <strong>of</strong> 770 genes and 13 molecular pathways were evaluated using Nanostring<br />
PanCancer pathway panel performed on BC formalin-fixed paraffin-embedded tissues<br />
from diagnostic core biopsy or surgical resection.<br />
Results: Baseline patients and tumor characteristics were similar between the two<br />
groups, although PR patients were more likely to have CNS spread and more metastatic<br />
burden <strong>of</strong> disease compared to LR (29% vs. 0, p = 0.02 and 57% vs. 20%, p = 0.04,<br />
respectively). Gene expression analysis identified 30 genes with significantly different<br />
expression in the two cohorts; five <strong>of</strong> these were driver genes (BRCA1, PDGFRA, AR,<br />
PHF6 and MSH2). The majority <strong>of</strong> these genes were over-expressed, mainly in LR<br />
patients, and encoded growth factors, pro- or anti-inflammatory interleukins and DNA<br />
repair factors. Only four genes were down-regulated, all in PR group (TNFSF10,<br />
CACNG1, IL20RB and BRCA1). Most <strong>of</strong> these genes were involved in MAPK and<br />
PI3K pathways (9 and 8, respectively). MAPK pathway was differently expressed<br />
between LR and PR (p = 0.05). Even if not statistically significant but clinically<br />
relevant, PI3K was the only pathway overexpressed in PR patients (median expression<br />
LR: 1441 ± 485 vs 1759 ± 762 in PR group; p= 0.1).<br />
Conclusions: Whole genome expression analysis comparing LR vs. PR identified a<br />
group <strong>of</strong> genes that may predict more favourable long-term outcomes. Up-regulation <strong>of</strong><br />
MAPK and down-regulation <strong>of</strong> PI3K pathways could be a positive predictive factors.<br />
Further clinical implications are warranted.<br />
Legal entity responsible for the study: Modena University<br />
Funding: Progetto Ricerca Finalizzata 2009<br />
Disclosure: S. Cascinu: Roche and AstraZeneca. All other authors have declared no<br />
conflicts <strong>of</strong> interest.<br />
vi84 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
273P<br />
A randomized phase II study to determine the efficacy and<br />
tolerability <strong>of</strong> two doses <strong>of</strong> eribulin plus lapatinib in<br />
trastuzumab pre-treated patients with Her2-positive<br />
metastatic breast cancer - E-Vita -<br />
J. Bisch<strong>of</strong>f 1 , J. Barin<strong>of</strong>f 2 , C. Mundhenke 3 , D. Bauerschlag 3 , S.D. Costa 4 , D. Herr 5 ,<br />
K. Lübe 6 , F. Marmé 7 , N. Maass 8 , G. von Minckwitz 9 , E-M. Grischke 10 , V. Müller 11 ,<br />
M. Schmidt 12 , B. Gerber 13 , S. Kümmel 14 , C. Schumacher 15 , P. Krabisch 16 ,<br />
M. Thill 2 , V. Nekljudova 17 , S. Loibl 17<br />
1 Frauenklinik, Städtisches Klinikum Dessau, Dessau, Germany, 2 Frauenklinik,<br />
Kliniken Markus-Krankenhaus, Agaplesion, Frankfurt am Main, Germany,<br />
3 Universitätsfrauenklinik Kiel, UK-SH, Campus Kiel, Kiel, Germany,<br />
4 Universitätsfrauenklinik Magdeburg, Otto-von Guericke-Universität, Magdeburg,<br />
Germany, 5 Frauenklinik, University Hospital Wuerzburg, Würzburg, Germany,<br />
6 Brustzentrum, Henriettenstiftung, Hannover, Germany, 7 Nationales Centrum für<br />
Tumorerkrankungen, University Hospital Heidelberg, Heidelberg, Germany,<br />
8 Frauenklinik, UK-SH, Campus Kiel, Kiel, Germany, 9 Department <strong>of</strong> Medical<br />
<strong>Oncology</strong>, German Breast Group, Neu-Isenburg, Germany, 10 Frauenklinik,<br />
Universitätsklinikum Tübingen, Tübingen, Germany, 11 Frauenklinik, UKE<br />
Universitätsklinikum Hamburg-Eppendorf KMTZ, Hamburg, Germany,<br />
12 Frauenklinik, Universitätsmedizin Mainz, Mainz, Germany, 13 Frauenklinik,<br />
Universitätsklinikum Rostock, Rostock, Germany, 14 Frauenklinik, Kliniken Essen<br />
Mitte Evang. Huyssens-Stiftung, Essen, Germany, 15 Brustzentrum, St. Elisabeth<br />
Krankenhaus Hohenlind, Cologne, Germany, 16 Frauenklinik, Klinikum Chemnitz<br />
gGmbH, Chemnitz, Germany, 17 Medicine and Research, German Breast Group,<br />
Neu-Isenburg, Germany<br />
Background: Lapatinib (L) in combination with capecitabine has been approved for<br />
the treatment <strong>of</strong> HER2+ advanced breast cancer (ABC) progressed after anthracycline-,<br />
taxane-, and trastuzumab (T)-containing therapies. The use is limited by overlapping<br />
toxicities. Therefore, other combinations <strong>of</strong> L with less toxic agents are needed. In the<br />
E-VITA study two schedules <strong>of</strong> Eribulin (E) in association with L have been<br />
investigated.<br />
Methods: E-VITA (NCT01534455) is a randomized phase II study to determine the<br />
efficacy and tolerability <strong>of</strong> two doses <strong>of</strong> E plus L in T pre-treated pts with HER2+ ABC.<br />
Main eligibility criteria were: ABC not suitable for surgery or radiotherapy alone;<br />
adjuvant and up to 3 chemotherapy regimen for ABC. Pts were randomized (1:1) to<br />
receive E 1.23mg/m 2 iv d1,8 q21 (E1.23) or E 1.76mg/m 2 d1 qd21 iv (E1.76) plus L<br />
1000mg os d1-21 (3w cycle). Treatment was given until disease progression or<br />
unacceptable toxicity. Primary endpoints were time to progression (TTP), safety and<br />
compliance. Secondary endpoints were response rate (RR), clinical benefit rate (CBR)<br />
and overall survival (OS). It was planned to recruit a total <strong>of</strong> 80 pts.<br />
Results: Between 2/2012 and 7/2014 43 pts were randomized (41 started treatment).<br />
The study was stopped in 7/2014 due to slow accrual. Median age was 54 yrs. Median<br />
TTP was 8.1 months (95% CI 4.8-9.4) with E1.23 vs 6.5 months (95% CI 4.6-13.4) with<br />
E1.76. No difference in OS was seen (23.1 [95% CI 12.5-35.0] vs 23.2 months [95%CI<br />
13.7-30.1]). RR was 52.4% (95% CI 31.0-73.7) vs 45.0% (95% CI 23.2-66.8). CBR was<br />
71.4% (95% CI 52.1-90.8) vs 75.0% (56.0-94.0). High grade adverse events (AEs) were<br />
more common under E1.76. Overall the most frequently grade 3-4 AEs were<br />
neutropenia (47.6% vs 70.0%), fatigue (19.0% vs 0.0%) and diarrhea (9.5% vs 5.0%). 5<br />
pts discontinued therapy due to AEs (2 in E1.23 arm and 3 in E1.76), 13 pts in both<br />
arms due to progression.<br />
Conclusions: The combination <strong>of</strong> E and L show an acceptable safety pr<strong>of</strong>ile. Due to<br />
premature study termination, no definitive conclusion on efficacy can be drawn.<br />
However, due to its lower toxicity pr<strong>of</strong>ile, the preferred regimen remains E1.23 d1,8<br />
q21.<br />
Clinical trial identification: NCT01534455<br />
Legal entity responsible for the study: German Breast Group<br />
Funding: Eisai<br />
Disclosure: G. von Minckwitz: Institution received grant from Eisai. All other authors<br />
have declared no conflicts <strong>of</strong> interest.<br />
274P<br />
abstracts<br />
Patient preference <strong>of</strong> trastuzumab administration (SC versus<br />
IV) in HER2-positive metastatic breast cancer: Results <strong>of</strong> the<br />
randomised Metaspher study<br />
X. Pivot 1 , J-P. Spano 2 , E. Marc 3 , P. Cottu 4 , C. Jouannaud 5 , V. Pottier 6 , L. Moreau 7 ,<br />
J-M. Extra 8 , A. Lortholary 9 , P. Rivera 10 , D. Spaeth 11 , H. Attar-Rabia 12 ,<br />
C. Benkamoun 12 , L. Dima-Martinez 12 , N. Esposito 13 , J. Gligorov 14<br />
1 <strong>Oncology</strong>, CHU Besançon, Hôpital Jean Minjoz, Besançon, France, 2 Medical<br />
<strong>Oncology</strong>, Pitié-Salpêtrière Hospital, Paris, France, 3 <strong>Oncology</strong>, Hôpital St. Louis,<br />
Paris, France, 4 Medical <strong>Oncology</strong>, Institut Curie, Paris, France, 5 <strong>Oncology</strong>, Institut<br />
Jean Godinot, Reims, France, 6 <strong>Oncology</strong>, Centre Léonard de Vinci, Dechy,<br />
France, 7 <strong>Oncology</strong>, Pole Sante Republique, Clermont-Ferrand, France, 8 Oncologie<br />
Médicale, Institute Paoli Calmettes, Marseille, France, 9 <strong>Oncology</strong>, Centre<br />
Catherine de Sienne, Nantes, France, 10 <strong>Oncology</strong>, Centre Claudius-Regaud,<br />
Toulouse, France, 11 <strong>Oncology</strong>, Centre d’Oncologie de Gentilly, Nancy, France,<br />
12 Clinical research, Laboratoire Roche, Boulogne-Billancourt, France, 13 Statistical<br />
research department, Laboratoire Roche, Boulogne-Billancourt, France, 14 Medical<br />
<strong>Oncology</strong> Department, Assistance Publique Hôpitaux de Paris – Tenon, Paris,<br />
France<br />
Background: HANNAH (NCT00950300) and PREFHER (NCT01401166)<br />
international, randomised studies validated the subcutaneous (SC) formulation <strong>of</strong><br />
trastuzumab as effective and safe as intravenous (IV) and highly preferred by patients<br />
in early breast cancer. The present randomized Metaspher trial (NCT 01810393)<br />
assessed patient’s preference in metastatic setting.<br />
Methods: Patients with HER2-positive metastatic breast cancer who completed a first<br />
line chemotherapy with trastuzumab (IV) and achieved a long term response lasting<br />
more than 3 years were randomised to receive 3 cycles <strong>of</strong> 600 mg fixed-dose adjuvant<br />
trastuzumab SC, followed by 3 cycles <strong>of</strong> standard IV, or the reverse sequence. Primary<br />
endpoint was overall preference for SC or IV at cycle 6, assessed by Patient Preference<br />
Questionnaire (PPQ). Secondary endpoints included healthcare pr<strong>of</strong>essional (HCP)<br />
satisfaction, assessed by questionnaire; safety and tolerability, assessed by NCI-CTCAE<br />
v4.0; quality <strong>of</strong> life assessed by QLQ C30 questionnaire. The modified-Intent-To-Treat<br />
population (m-ITT) included patients who received both routes <strong>of</strong> administration and<br />
who completed the last question <strong>of</strong> PPQ. The safety population included all enrolled<br />
patients who received at least one dose <strong>of</strong> treatment.<br />
Results: 113 patients were randomised. SC was preferred by 79/92 evaluable m-ITT<br />
patients (85.9%, 95% CI [78.8;93.0]; p < 0·001), 13 preferred IV (14.1%, 95% CI<br />
[7.0;21.3]). Among patients without preference at baseline (52/89 available data), SC<br />
was preferred by 46/52 patients (88,5%, [79.8;97.2]). HCP were most satisfied with SC<br />
(56/88 available data, 63.6%, [53.6;73.7]). On the safety population, 108 patients<br />
received SC and 111 received IV. Clinician-reported adverse events occurred in 73<br />
(67.6%) and 49 (44·1%) patients during the SC and IV periods, respectively; 7 (6.5%)<br />
and 4 (3.6%) were grade ≥ 3, 3 (2·8%) and 2 (1·8%) were serious.<br />
Conclusions: Patients preferred trastuzumab SC. The safety pr<strong>of</strong>ile was consistent with<br />
the known IV pr<strong>of</strong>ile with no safety concerns raised. Next step will assess the follow up<br />
<strong>of</strong> this cohort <strong>of</strong> long responder patient with metastatic breast cancer.<br />
Clinical trial identification: NCT 01810393<br />
Legal entity responsible for the study: Roche<br />
Funding: Roche<br />
Disclosure: X. Pivot: consultant for Roche Amgen Novartis Pierre Fabre Eisai. J-P.<br />
Spano: Consultant for Roche.E. Marc, D. Spaeth: Roche. H. Attar-Rabia,<br />
C. Benkamoun, L. Dima-Martinez, N. Esposito: Employed by Roche. J. Gligorov:<br />
Consultant for Roche, Novartis, Eisai, Pfizer, Genomic Health. All other authors have<br />
declared no conflicts <strong>of</strong> interest.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw365 | vi85
abstracts<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
275P<br />
Trastuzumab emtansine (T-DM1) in patients (pts) with human<br />
epidermal growth factor receptor 2 (HER2)-positive metastatic<br />
breast cancer (MBC): Results from a multicenter retrospective<br />
analysis<br />
L. Pizzuti 1 , I. Sperduti 2 , A. Michelotti 3 , C. Omarini 4 , T. Gamucci 5 , C. Natoli 6 ,<br />
L. D’On<strong>of</strong>rio 7 , F. Giotta 8 , C. Ficorella 9 , L. Laudadio 10 , A. Cassano 11 , P. Marchetti 12 ,<br />
V. Adamo 13 , M. Mauri 14 , A.F. Scinto 15 , G. Zampa 16 , A. Fabbri 17 , L. Mentuccia 18 ,<br />
S. Barni 19 , P. Vici 1<br />
1 Division <strong>of</strong> Medical <strong>Oncology</strong> 2, Istituto Regina Elena, Rome, Italy, 2 Biostatistics<br />
Unit, Istituto Regina Elena, Rome, Italy, 3 Polo Oncologico, Azienda Ospedaliera<br />
Universitaria S.Chiara, Pisa, Italy, 4 Department <strong>of</strong> Medical and Surgical Sciences<br />
for Children & Adults, Azienda Ospedaliero - Universitaria Policlinico di Modena,<br />
Modena, Italy, 5 Oncologia Medica, Ospedale SS Trinità, Sora, Italy, 6 Department<br />
<strong>of</strong> Medical, Oral and Biotechnological Sciences, Experimental and Clinical<br />
Sciences, University G D’Annunzio, Chieti, Italy, 7 Department <strong>of</strong> Medical<br />
<strong>Oncology</strong>, Libero Istituto Universitario Campus Bio-Medico (LIUCBM), Rome, Italy,<br />
8 Division <strong>of</strong> Medical <strong>Oncology</strong>, Istituto Tumori Giovanni Paolo II, Bari, Italy,<br />
9 Medical <strong>Oncology</strong> Unit, Ospedale Civile San Salvatore, L’Aquila, Italy, 10 Division<br />
<strong>of</strong> Medical <strong>Oncology</strong>, Renzetti Hospital, Lanciano, Italy, 11 Medicina Interna - U.O.<br />
C. di Oncologia Medica, Policlinico Universitario A. Gemelli, Rome, Italy, 12 Clinical<br />
and Molecular Medicine Department, Sapienza University, Sant’Andrea Hospital,<br />
Rome, Italy, 13 Medical <strong>Oncology</strong> Unit, Centro Oncologico Ospedale Papardo,<br />
Messina, Italy, 14 Department <strong>of</strong> <strong>Oncology</strong>, S Giovanni Addolorata, Rome, Italy,<br />
15 Medical <strong>Oncology</strong> Unit, Ospedale Fatebenefratelli - Isola Tiberina, Rome, Italy,<br />
16 <strong>Oncology</strong> Unit, Nuovo Regina Margherita Hospital, Rome, Italy, 17 Medical<br />
<strong>Oncology</strong> Department, Ospedale Belcolle, ASL di Viterbo <strong>Oncology</strong> Unit, Viterbo,<br />
Italy, 18 Medical <strong>Oncology</strong> Unit, ASL Frosinone, Frosinone, Italy, 19 Medical<br />
<strong>Oncology</strong> Unit, Azienda Ospedaliera Treviglio-Caravaggio, Treviglio, Italy<br />
Background: T-DM1 improved outcomes in pts with HER2+ MBC, but few data<br />
concerning its use in routine clinical practice are available.<br />
Methods: We retrospectively enrolled 194 HER2+ (IHC 3+ or 2+ amplified) MBC pts<br />
treated with T-DM1 in real-world practice in 20 Italian oncologic centers.<br />
Results: Baseline pts and tumors characteristics are listed in Tab 1. Median (m) follow<br />
up was 9.8 months (mo) (range,2-37), m T-DM1 treatment duration was 5 mo (range,<br />
1-30). Among 183 evaluable pts, 5.4% had a complete response and 35% a partial<br />
response, for an Overall Response Rate <strong>of</strong> 40% (95%CI, 33-47). A stable disease (SD)<br />
was recorded in 26.8% pts, with a clinical benefit (CB: response or SD lasting ≥ 6 mo)<br />
<strong>of</strong> 55% (95%CI, 47-62). No significant differences in responses have emerged according<br />
to disease sites. M Progression Free Survival (PFS) was 6 mo (95%CI, 5-7), m Overall<br />
Survival (OS) was 35 mo (95%CI, 11-59). Pts who have previously carried out ≤3 lines<br />
for MBC had improved PFS (p = 0.006). At multivariate analysis, factors related to PFS<br />
benefit were lower ECOG performance status (PS) (p < 0.0001) and HER2+ status at<br />
first diagnosis (p = 0.03), while OS benefit was related with lower ECOG PS (p = 0.01),<br />
absence <strong>of</strong> brain metastases (p = 0.08), other than ductal histology (p = 0.04) and CB<br />
(p < 0.0001). Central nervous system (CNS) progression occurred in 10.4% <strong>of</strong> the pts<br />
without CNS metastases, and in 29.1% <strong>of</strong> the pts with CNS metastases at baseline. Pts<br />
with CNS metastases at baseline have a m PFS similar to that observed in the general<br />
population, whereas m OS was shorter (16 mo, C.I. 95%, 12-21). Toxicity was<br />
manageable, with grade ≥3 adverse events reported in 5.6% <strong>of</strong> pts, most commonly<br />
thrombocytopenia and fatigue. Cardiac dysfunction was reported in 2 pts (1%).<br />
Table: 275P<br />
Characteristics N (%)<br />
Age Median (range) 56 (34-82)<br />
Hystology Ductal Lobular Other 173 (89.2) 11 (5.7) 10 (5.1)<br />
Grading G2 G3 Unknown (Uk) 55 (28.4) 124 (63.9) 15 (7.7)<br />
Metastatic at diagnosis Yes No 47 (24.2) 147 (75.8)<br />
HER2+ at diagnosis Yes No Uk 157 (80.9) 25 (12.9) 12 (6.2)<br />
ECOG PS 0 1 2 3 Uk 97 (50) 63 (32.5) 9 (4.6) 1 (0.5) 24 (12.4)<br />
Previous regimen for MBC 0 1 2 ≥3 10 (5.2) 40 (20.6) 47 (24.2) 97 (50)<br />
276P<br />
Electrochemotherapy for breast cancer - results from the<br />
INSPECT database<br />
L.W. Matthiessen 1 , M. Keshtgar 2 , C. Kunte 3 , E-M. Grischke 4 , J. Odili 5 , T. Muir 6 ,<br />
P. Curatolo 7 , D. Mowatt 8 , J. Clover 9 , S.H. Liew 10 , H.F. Hansen 1 , J. Newby 11 ,<br />
V. Letulé 3 , E. Stauss 4 , A.C. Humphreys 12 , S. Banerjee 13 , A. Klein 14 , F. de Terlizzi 15 ,<br />
J. Gehl 1<br />
1 Department <strong>of</strong> <strong>Oncology</strong>, Copenhagen University Hospital Herlev and Gent<strong>of</strong>te,<br />
Herlev, Denmark, 2 Department <strong>of</strong> Plastic Surgery, Royal Free London NHS<br />
foundation trust, London, UK, 3 Department <strong>of</strong> Dermatology and Allergology,<br />
Ludwig Maximilians University, Munich, Germany, 4 Department <strong>of</strong> <strong>Oncology</strong>,<br />
Universitet Frauenklinik Tübingen, Tübingen, Germany, 5 Department <strong>of</strong> Plastic<br />
Surgery, St George’s Hospital NHS Trust, London, UK, 6 Department <strong>of</strong> Plastic<br />
Surgery, The James Cook University Hospital, Middlesbrough, UK, 7 Department<br />
<strong>of</strong> Internal Medicine and Medical Specialties, Sapienza – Università di Roma,<br />
Rome, Italy, 8 Department <strong>of</strong> Plastic Surgery, The Christie NHS Foundation Trust,<br />
Manchester, UK, 9 Department <strong>of</strong> Plastic Surgery, Cork University Hospital, Cork,<br />
Ireland, 10 Department <strong>of</strong> Plastic Surgery, Liverpool Hospital, Liverpool, UK,<br />
11 Department <strong>of</strong> <strong>Oncology</strong>, Royal Free London NHS foundation trust, London, UK,<br />
12 Department <strong>of</strong> <strong>Oncology</strong>, The James Cook University Hospital, Middlesbrough,<br />
UK, 13 Division <strong>of</strong> Surgery and interventional Science, Royal Free London NHS<br />
foundation trust, London, UK, 14 Department <strong>of</strong> Dermatologic surgery and<br />
Dermatology, Artemed Fachklinik, Munich, Germany, 15 Scientific & Medical<br />
Department, IGEA, Carpi, Italy<br />
Background: Cutaneous recurrence from breast cancer can pose a clinical challenge. It<br />
may be the only disease site, or be part <strong>of</strong> disseminated disease, and <strong>of</strong>ten pr<strong>of</strong>oundly<br />
impacts quality <strong>of</strong> life. Electrochemotherapy is a palliative treatment for cutaneous<br />
metastases. Using electric pulses to locally permeabilize tumor cells, bleomycin<br />
cytotoxicity is significantly increased. Collaborating in the International Network for<br />
sharing Practice on ElectroChemoTherapy (INSPECT), we consecutively and<br />
prospectively accrued data on patients treated with electrochemotherapy for skin<br />
metastases <strong>of</strong> breast cancer.<br />
Methods: Patients with cutaneous metastases were treated with electrochemotherapy at<br />
10 European centers. Treatment data and results were entered into the INSPECT<br />
database. Patients were treated with either local injection (1000 IU/ml intratumoral<br />
injection) or systemic infusion (15.000 IU/m2) <strong>of</strong> bleomycin, and under either local or<br />
general anesthesia, depending on tumor size. Pulse sequences (8 pulses <strong>of</strong> 0.1 ms) were<br />
sequentially applied to the tumor area, using an electroporation system with needle or<br />
plate electrodes (IGEA, Italy).<br />
Results: 104 patients were included. Median age was 65 years. Patients had previous<br />
received chemotherapy (87%), radiotherapy (83%), endocrine therapy (46%) and<br />
HER2 targeted therapy (20%). Primary location was the chest (87%), median diameter<br />
<strong>of</strong> the cutaneous metastases being 26 mm (range 1 mm to 550 mm). 75 patients were<br />
available for response evaluation after 2 months. Complete response was observed in 38<br />
(51%) patients, partial response in 13 (17%), stable disease in 14 (19%), and progressive<br />
disease in 5 (9%), 3 patients were not evaluable. Common side effects were ulceration,<br />
long lasting hyperpigmentation, and slight increase in pain. No serious adverse events<br />
were observed.<br />
Conclusions: Electrochemotherapy showed high response rates, particularly in smaller<br />
metastases. Electrochemotherapy has high response rates seen after a single treatment,<br />
with few side effects and can be used as an adjunct to systemic therapies as well as a<br />
sole treatment. We therefore highly recommend to consider electrochemotherapy for<br />
patients with cutaneous metastases, where radiotherapy and surgery is not an option.<br />
Legal entity responsible for the study: Each center participating in the study are<br />
responsible for governance and running <strong>of</strong> the study, and are legally responsible for the<br />
study at their own institution. Coordination was performed by investigators at one<br />
center elected by the International Network <strong>of</strong> Sharing Practices <strong>of</strong><br />
Electrochemotherapy, which is a collaboration <strong>of</strong> between clinicians and centers<br />
performing electrochemotherapy.<br />
Funding: The study is funded by each center. IGEA, Carpi, Italy is funding and<br />
maintaining the database, where the INSPECT members upload data.<br />
Disclosure: F. de Terlizzi: Employee in IGEA, Carpi, Italy. All other authors have<br />
declared no conflicts <strong>of</strong> interest.<br />
Conclusions: In this real-world setting <strong>of</strong> heterogeneous HER2+ MBC pts, efficacy <strong>of</strong><br />
T-DM1 was comparable with that reported in phase II-III studies, without new safety<br />
issues.<br />
Legal entity responsible for the study: Patrizia Vici<br />
Funding: None<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
vi86 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
277P<br />
Phase 1b/2 safety and efficacy <strong>of</strong> TAK-228 (MLN0128), plus<br />
exemestane (E) or fulvestrant (F) in postmenopausal women<br />
with ER + /HER2- metastatic breast cancer (MBC)<br />
J. Diamond 1 , V.F. Borges 1 , P. Kabos 2 , E. Krill-Jackson 3 , R. Graham 4 , A. H<strong>of</strong>fman 5 ,<br />
B. Lim 6 , D.A. Richards 7 , M.A. Salkeni 8 , S. Wilks 9 , C. Patel 10 , R. Neuwirth 11 ,<br />
M. Kneissl 12 , F. Zohren 13<br />
1 Medical <strong>Oncology</strong>, University <strong>of</strong> Colorado Cancer Center, Aurora, CO, USA,<br />
2 Medicine, University <strong>of</strong> Colorado Cancer Center, Aurora, CO, USA, 3 TBC, Mount<br />
Sinai Medical Center, Miami Beach, FL, USA, 4 Hematology and <strong>Oncology</strong>,<br />
UT-Erlanger Medical Center, Chattanooga, TN, USA, 5 Medical <strong>Oncology</strong>,<br />
Eastchester Center for Cancer Care / BRANY, Bronx, NY, USA, 6 Department <strong>of</strong><br />
Breast Medical <strong>Oncology</strong>, MD Anderson Cancer Center, Houston, TX, USA,<br />
7 TBD, Texas <strong>Oncology</strong> – Tyler, Tyler, TX, USA, 8 Department <strong>of</strong> Medicine, Section<br />
<strong>of</strong> Hematology/<strong>Oncology</strong>, West Virginia University, Morgantown, WV, USA, 9 TBD,<br />
Cancer Care Network <strong>of</strong> South Texas – SAT&BC, San Antonio, TX, USA, 10 Clinical<br />
Pharmacology, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary <strong>of</strong><br />
Takeda Pharmaceutical Company Limited, Cambridge, MA, USA, 11 Statistics,<br />
Millennium Pharmaceuticals, Inc., a wholly owned subsidiary <strong>of</strong> Takeda<br />
Pharmaceutical Company Limited, Cambridge, MA, USA, 12 <strong>Oncology</strong> Clinical<br />
Research, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary <strong>of</strong> Takeda<br />
Pharmaceutical Company Limited, Cambridge, MA, USA, 13 Early Clinical<br />
Research & Development, <strong>Oncology</strong> Therapeutic Area Unit, Millennium<br />
Pharmaceuticals, Inc., a wholly owned subsidiary <strong>of</strong> Takeda Pharmaceutical<br />
Company Limited, Cambridge, MA, USA<br />
Background: TAK-228, an investigational, oral, highly selective, ATP-competitive<br />
inhibitor <strong>of</strong> TORC1/2, may mitigate feedback activation within the PI3K/AKT/mTOR<br />
pathway. This represents a potential cause <strong>of</strong> resistance to TORC1 selective inhibitors.<br />
Thus TORC1/2 inhibition may restore sensitivity to endocrine therapies in patients<br />
(pts) who have progressed on such agents plus everolimus. We report the<br />
recommended phase 2 dose (RP2D), safety, pharmacokinetics (PK), and preliminary<br />
efficacy <strong>of</strong> TAK-228 + E or F.<br />
Methods: Postmenopausal (≥1 y) women ≥18 y with advanced or MBC following<br />
everolimus + E or F were eligible. Phase 1b: part 1, unmilled TAK-228 5 mg<br />
continuously once-daily (QD) + E 25 mg QD or F 500 mg monthly; part 2, milled<br />
TAK-228 3 or 4 mg QD + E or F. Modified 3 + 3 dose escalation rules were applied, and<br />
pts were treated until disease progression.<br />
Results: N = 24 were enrolled into phase 1b (median age 58.5 y [33–75]; median prior<br />
lines <strong>of</strong> therapy/chemotherapy 5 [1–10]/1 [0–2]). In part 1 (n = 12), pts received 5 mg<br />
unmilled TAK-228 QD + E or F (each n = 6). No dose-limiting toxicities (DLT) were<br />
seen, with no apparent differences in tolerability between the two groups. In part 2<br />
(n = 12), 6 pts received 3 mg milled TAK-228 QD and no DLTs were seen. Another 6<br />
pts received 4 mg milled TAK-228 QD; 1 pt treated with TAK-228 + E had DLTs <strong>of</strong><br />
grade 3 nausea and diarrhea. The most common grade ≥3 drug-related adverse events<br />
(≥2 pts) were: diarrhea (13%) and increased ALT, fatigue, hyperglycemia, nausea, rash<br />
and stomatitis (each 8%). PK data suggest there was a dose related increase in total<br />
systemic exposure from 3 to 5 mg TAK-228, with no readily apparent difference<br />
between milled and unmilled TAK-228. Five pts (21%) had an overall response (1<br />
complete response [CR], 4 partial responses [PRs]), and 12 (50%) had stable disease<br />
(SD). The overall response rate was 21% (7% E vs 44% F) and the disease control rate<br />
(CR + PR + SD) was 71% (60% E vs 89% F). The median duration <strong>of</strong> clinical benefit<br />
was 6 mos for TAK-228 + E vs 10 mos for TAK-228 + F.<br />
Conclusions: Safety was established for milled TAK-228 at the RP2D <strong>of</strong> 4 mg QD + E<br />
or F. The encouraging preliminary efficacy warrants further evaluation in the phase 2<br />
portion.<br />
Clinical trial identification: NCT02049957 (Clinical Trial Protocol C31001<br />
Amendment 4; October 22, 2015)<br />
Legal entity responsible for the study: Millennium Pharmaceuticals, Inc.<br />
Funding: Millennium Pharmaceuticals Inc., a wholly owned subsidiary <strong>of</strong> Takeda<br />
Pharmaceutical Company Limited<br />
Disclosure: C. Patel: Employment: Millennium Pharmaceuticals, Inc., a wholly owned<br />
subsidiary <strong>of</strong> Takeda Pharmaceutical Company Limited; Stock ownership: Takeda<br />
Pharmaceutical Company Limited.R. Neuwirth: Employment: Millennium<br />
Pharmaceuticals, Inc., a wholly owned subsidiary <strong>of</strong> Takeda Pharmaceutical Company<br />
Limited. M. Kneissl: Employment: Millennium Pharmaceuticals, Inc., a wholly owned<br />
subsidiary <strong>of</strong> Takeda Pharmaceutical Company Limited. F. Zohren: Employment:<br />
Millennium Pharmaceuticals, Inc., a wholly owned subsidiary <strong>of</strong> Takeda<br />
Pharmaceutical Company Limited; Stock ownership: Millennium Pharmaceuticals,<br />
Inc., a wholly owned subsidiary <strong>of</strong> Takeda Pharmaceutical Company Limited. All other<br />
authors have declared no conflicts <strong>of</strong> interest.<br />
278P<br />
Cutaneous responses in Her-2+ metastatic breast cancer<br />
(MBC) on phase 1b study <strong>of</strong> ONT-380, an oral HER2-specific<br />
inhibitor in combination with capecitabine (C) and/or<br />
trastuzumab (T) in third line or later treatment<br />
A.K. Conlin 1 , V.F. Borges 2 , N.M. Moxon 1 , L.N. Walker 3 , S.L. Moulder 4<br />
1 Medical <strong>Oncology</strong>, Providence Cancer Center, Portland, OR, USA, 2 Medical<br />
<strong>Oncology</strong>, University <strong>of</strong> Colorado Cancer Center Anschutz Cancer Pavilion,<br />
Aurora, CO, USA, 3 Medical <strong>Oncology</strong>, Oncothyreon Inc, Seattle, WA, USA,<br />
4 Medical <strong>Oncology</strong>, MD Anderson Cancer Center, Houston, TX, USA<br />
Background: Cutaneous metastases in breast cancer are a common and very morbid<br />
development in women with metastatic breast cancer (MBC). Skin metastases have<br />
been estimated to develop in 24% <strong>of</strong> patients with MBC, maybe even higher if Her2<br />
overexpressing. It has been hypothesized that skin may represent a sanctuary site, like<br />
CNS, for Her2+ patients (pts). Case reports <strong>of</strong> patients developing skin only<br />
progression on anti-Her-2 antibody therapy have been reported.<br />
Methods: This phase 1 study <strong>of</strong> ONT-380, a potent, oral selective small molecule<br />
inhibitor <strong>of</strong> HER2, dosed in 2 cohorts <strong>of</strong> 350mg PO BID (8 pts) and 300mg PO BID<br />
(52 pts) given with either C (1000mg/m 2 PO BID 14 days <strong>of</strong> 21-day-cycle) or T (8mg/<br />
kg IV load; then 6mg/kg IV once every 21 days) or the triplet was conducted in women<br />
with Her2+ MBC previously treated with trastuzumab and T-DM1. Prior lapatinib,<br />
neratinib, and pertuzumab were allowed. Tumor response was assessed by RECIST 1.1.<br />
Sixty patients were treated on study and 27 received the triplet <strong>of</strong> ONT-380 with C and<br />
T. Eight patients had skin noted as a site <strong>of</strong> disease.<br />
Results: Skin was a measurable site <strong>of</strong> disease in 6 women and non-measurable site in<br />
2 women. In all 8 women there were clinical responses in the skin with ONT-380 and<br />
C (2 pts), ONT-380 with T (1 pt) or ONT-380 with C plus T (5 pts). Two women had<br />
complete response <strong>of</strong> their skin disease, 3 had partial response (PR) and 3 had<br />
regressions that did not meet criteria for PR. All but one woman had prior lapatinib<br />
therapy and all but one woman had prior radiation to the skin and chest wall. Median<br />
time on therapy was 8.5 cycles (5-13 range). One patient is still on study.<br />
Conclusions: We report on 8 patients with significant response in skin as a disease site<br />
while on ONT-380 with either C or T or the combination. ONT-380 shows evidence <strong>of</strong><br />
efficacy in cutaneous metastases, a common and difficult site <strong>of</strong> disease to control for<br />
women with Her2+ MBC.<br />
Clinical trial identification: NCT02025192<br />
Legal entity responsible for the study: Oncothyreon Inc.<br />
Funding: Oncothyreon Inc.<br />
Disclosure: L.N. Walker: I am an employee <strong>of</strong> Oncothyreon, Inc.S.L. Moulder: My only<br />
disclosures are to be a non-compensated advisor to Oncothyreon and to have received<br />
funding to support the clinical trial including effort as PI.All other authors have<br />
declared no conflicts <strong>of</strong> interest.<br />
279P<br />
abstracts<br />
Phase I/II pharmacokinetics/pharmacodynamics study <strong>of</strong><br />
irinotecan and S-1 for recurrent/metastatic breast cancer in<br />
patients with select UGT1A1 genotypes (the JBCRG-M01<br />
study)<br />
S. Saji 1 , H. Ishiguro 2 , S. Nomura 3 ,H.Iwata 4 , S. Tanaka 5 , T. Ueno 6 , M. Onoue 7 ,<br />
T. Yamanaka 8 , Y. Sasaki 9 ,M.Toi 5<br />
1 Department <strong>of</strong> Medical <strong>Oncology</strong>, Fukushima Medical University, Fukushima,<br />
Japan, 2 Department <strong>of</strong> Target Therapy <strong>Oncology</strong>, Kyoto University-Graduate<br />
school <strong>of</strong> medicine, Kyoto, Japan, 3 Biostatistics Division, Center for Research<br />
Administration and Support, National Cancer Center Hospital East, Kashiwa,<br />
Japan, 4 Department <strong>of</strong> Breast <strong>Oncology</strong>, Aichi Cancer Center Hospital, Nagoya,<br />
Japan, 5 Department <strong>of</strong> Breast Surgery, Kyoto University-Graduate school <strong>of</strong><br />
medicine, Kyoto, Japan, 6 Department <strong>of</strong> Breast Surgery, Kyorin university<br />
Hospital, Mitaka, Japan, 7 Department <strong>of</strong> Pharmacy, Kitano Hospital, Osaka,<br />
Japan, 8 Department <strong>of</strong> Biostatistics, Yokohama City University, Yokohama, Japan,<br />
9 Division <strong>of</strong> Medical <strong>Oncology</strong>, Showa University, School <strong>of</strong> Medicine, Tokyo,<br />
Japan<br />
Background: S-1 (combination <strong>of</strong> tegafur, gimeracil, and oteracil) and irinotecan<br />
(CPT) have different mechanisms <strong>of</strong> action. Combined therapy <strong>of</strong> S-1 and CPT is an<br />
attractive option for anthracycline and taxane-refractory breast cancer.<br />
Methods: Patients with advanced HER2-negative breast cancer previously treated with<br />
anthracycline and taxane and with measurable lesions were eligible for the trial. Those<br />
with brain metastases and homozygous for UGT1A1*6 or *28 or compound<br />
heterozygous (*6/*28) were excluded. A 3 + 3 dose escalation design was used in phase<br />
I (Level 1: CPT 80 mg/m 2 on days 1 and 8, and S-1 80 mg/m 2 on days 1-14, every 3<br />
weeks; Level 2: CPT 100 mg/m 2 and S-1 80 mg/m 2 ). The objectives were to determine<br />
the recommended dose (RD) for the phase II (primary for phase I) study, response rate<br />
(RR, primary for phase II), progression-free survival (PFS), and safety in relation to<br />
UGT1A1. Pharmacokinetics (PK) <strong>of</strong> CPT and circulating endothelial cells (CEC) as<br />
pharmacodynamics (PD) <strong>of</strong> S-1 were analysed.<br />
Results: Thirty-seven patients (13 for phase I, 24 for phase II) were enrolled. One<br />
patient at level 1 developed grade (G) 3 non-haematological toxicity and another at<br />
level 2 developed G4 neutropenia; therefore, level 2 was used as the RD. Common<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw365 | vi87
abstracts<br />
adverse events and their rates in the UGT1A1 wt/wt and wt/*6 or *28 heterozygous<br />
groups were diarrhoea, 25% and 46%; vomiting, 17% and 9%; anorexia, 25% and 9%;<br />
and fatigue, 25% and 9% respectively. As shown in Table 1 and supported by PK data,<br />
PFS seemed better for the UGT1A1 wt/*6 or *28 group compared to that for the wt/wt<br />
group. There also seemed to be an association between clinical benefit and suppression<br />
<strong>of</strong> CD34+ CEC by S-1 (Wilcoxon p = 0.047).<br />
Table: 279P Efficacy results <strong>of</strong> Level 2 patients (n = 29, 6 for phase I<br />
and 23 for phase II)<br />
Wild/Wild<br />
(n = 15)<br />
Wild/*6 or *28<br />
(n = 14)<br />
Response Rate 1 (7%) 3 (21%) -<br />
Clinical Benefit Rate 4 (27%) 5 (36%) -<br />
Median PFS<br />
(month)<br />
8.3 12.3 HR = 0.47<br />
(p = 0.0600)<br />
Median OS (month) 17.4 23.1 HR = 0.74<br />
(p = 0.5607)<br />
Conclusions: A combination <strong>of</strong> CPT and S-1 is effective in patients having recurrent/<br />
metastatic breast cancer, and further study <strong>of</strong> the underlying pharmacogenomics/PK/<br />
PD is warranted.<br />
Clinical trial identification: UMIN 000000517<br />
Legal entity responsible for the study: Masakazu Toi<br />
Funding: JBCRG, ACRO<br />
Disclosure: S. Saji: Lecture fee from Taiho Pharmaceutical Co. Ltd. S. Nomura:<br />
Receiving personal fees from Japan Breast Cancer Research Group.Y. Sasaki: Financial<br />
interest with Taiho Pharmaceutical Co. Ltd.All other authors have declared no conflicts<br />
<strong>of</strong> interest.<br />
280P<br />
Phase Ib/II open-label study <strong>of</strong> Ad-RTS-hIL-12 + veledimex<br />
gene therapy in chemotherapy-responsive locally advanced or<br />
metastatic breast cancer patients<br />
H. McArthur 1 , D. Page 1 , T. Proverbs-Singh 1 , S. Solomon 1 , C. Hudis 1 , L. Norton 1 ,<br />
S. Patil 1 , M. Henrich 1 , D. Halpenny 1 , J. Erinjeri 1 , J. Yuan 1 , P. Wong 1 , C.A. Jones 2 ,<br />
M. Escudero 2 , H. Cai 2 , J. Zhou 2 , Y. Yang 2 , J.A. Barrett 2 , F. Lebel 2<br />
1 Department <strong>of</strong> Medicine, Memorial Sloan-Kettering Cancer Center, New York,<br />
NY, USA, 2 Research & Development, ZIOPHARM <strong>Oncology</strong>, Inc., Boston, MA,<br />
USA<br />
Background: Ad-RTS-hIL-12 (Ad) is a novel gene therapy candidate expressing IL-12<br />
under the control <strong>of</strong> an orally administered activator ligand, veledimex (V), through<br />
the proprietary RheoSwitch Therapeutic System® (RTS®) gene switch. Ad + V controls<br />
local IL-12 expression and stimulates anti-cancer T cell immune response.<br />
Methods: Patients with stable or responsive disease to 1st or 2 nd line chemotherapy<br />
were injected intratumorally with Ad 1 x10 12 vp and received up to 7 daily V doses.<br />
The primary endpoint is safety and tolerability. Secondary endpoints including 12 week<br />
(wk) progression rate and comparison <strong>of</strong> responses by Immune-Related Response<br />
Criteria (irRC) vs. RECIST.<br />
Results: As <strong>of</strong> April 28, 2016, 8 subjects (7 HER2-, 1 HER2+) have been treated (33-63<br />
yo): 6 have completed 6wk and 3 have completed 12 wk imaging. At 12wks, 1 achieved<br />
a partial response that was durable until wk 18, 1 maintained stable disease until wk 35,<br />
and 1 had progression per irRC. Tumor levels showed increased and persisting<br />
elevation <strong>of</strong> IFNγ (51 @ baseline vs. 183 pg/g @ 6 wks), demonstrating sustained<br />
activation <strong>of</strong> immune system in the tumor microenvironment. Plasma cytokines were<br />
assessed at baseline, day (D) 1, D3, D8, Wk 6 and 12. IL-12 plasma level increased<br />
peaking at D3 with a median value <strong>of</strong> 5 pg/ml and downstream IFNγ at 1549 pg/ml.<br />
Concomitant increases in IL-10 & IL-6 were observed. Plasma (median) levels TNFα<br />
significantly increased from 1 pg/ml (baseline) to 5 pg/ml at D3-8. Plasma cytokines<br />
returned to baseline after discontinuation <strong>of</strong> V. Immunohistochemistry (IHC) and flow<br />
cytometry correlates are underway. Expected treatment-related AEs (TRAE) were<br />
reported in all subjects. There were related grade 3 events in 3 subjects, including 2<br />
AST/ALT increased (1 SAE), 1 fatigue (SAE) and 1 leukopenia. All related SAEs and<br />
grade 3 AEs resolved with discontinuance <strong>of</strong> V.<br />
Conclusions: Intratumoral regulated IL-12 expression using AD + V in locally<br />
advanced or metastatic breast cancer patients was associated with expected toxicities<br />
that resolved with discontinuance <strong>of</strong> V. Clinical and biologic activity have been<br />
observed, warranting continued investigation.<br />
Clinical trial identification: NIH RAC 1407-1335<br />
Legal entity responsible for the study: ZIOPHARM <strong>Oncology</strong>, Inc.<br />
Funding: ZIOPHARM <strong>Oncology</strong>, Inc.<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
281P<br />
A phase I study <strong>of</strong> sonidegib (S) in combination with docetaxel<br />
(D) in patients (pts) with triple negative (TN) advanced breast<br />
cancer (ABC): GEICAM/2012-12 (EDALINE study)<br />
M. Martín 1 , M. Ruiz-Borrego 2 , J.M. Trigo Perez 3 , S. Antolín 4 , J.A. García-Sáenz 5 ,<br />
J. Corral 6 , Y. Jerez 7 , A. Urruticoechea 8 , H. Colom 9 , N. Gonzalo 10 , C. Muñoz 10 ,<br />
J. Cuevas 2 , C. del Monte 11 , L. Pérez-Ramos 12 , R. Caro 13 , A. Blach 14 , S. Benito 11 ,<br />
S. Bezares Montes 15 , E. Carrasco 16 ,F.Rojo 17<br />
1 Department <strong>of</strong> Medical <strong>Oncology</strong>, Instituto de Investigación Sanitaria Gregorio<br />
Marañón, Universidad Complutense de Madrid, Madrid, Spain, 2 Dept <strong>of</strong><br />
<strong>Oncology</strong>, Hospital Universitario Virgen del Rocio, Sevilla, Spain, 3 Medical<br />
<strong>Oncology</strong>, Hospital Universitario Virgen de la Victoria, Malaga, Spain, 4 Medical<br />
<strong>Oncology</strong>, Hospital Universitario a Coruna - a Corunac, A Coruna, Spain, 5 Medical<br />
<strong>Oncology</strong>, Hospital Clinico Universitario San Carlos, Madrid, Spain, 6 Medical<br />
<strong>Oncology</strong>, Hospital Universitario Virgen del Rocio, Sevilla, Spain, 7 Medical<br />
<strong>Oncology</strong>, Hospital General Universitario Gregorio Marañon, Madrid, Spain,<br />
8 Medical <strong>Oncology</strong>, Onkologikoa-Kutxaren Instituto Onkologikoa, San Sebastian,<br />
Spain, 9 Faculty <strong>of</strong> Pharmacy, Universitat de Barcelona, Barcelona, Spain,<br />
10 Pharmacinetics Lab, Institut Català d’Oncologia Hospital Duran i Reynals,<br />
Barcelona, Spain, 11 Clinical Operations, GEICAM Spanish Breast Cancer Group,<br />
Madrid, Spain, 12 Statistics, GEICAM Spanish Breast Cancer Group, Madrid,<br />
Spain, 13 Data Management, GEICAM Spanish Breast Cancer Group, Madrid,<br />
Spain, 14 Translational Research, GEICAM Spanish Breast Cancer Group, Madrid,<br />
Spain, 15 Medical Lead, GEICAM Spanish Breast Cancer Group, Madrid, Spain,<br />
16 GEICAM (Spanish Breast Cancer Research Group), Madrid, Spain, 17 Pathology<br />
Department, University Hospital "Fundacion Jimenez Diaz", Madrid, Spain<br />
Background: S is a potent and selective oral inhibitor <strong>of</strong> Smo, a key component <strong>of</strong> the<br />
hedgehog (Hh) signaling pathway. Up-regulation <strong>of</strong> the Hh pathway is implicated in<br />
the genesis <strong>of</strong> a wide range <strong>of</strong> tumors including TN breast cancer. Here we report a<br />
phase I study exploring the combination <strong>of</strong> S with D in TN ABC pts to identify the<br />
Maximum Tolerated Dose (MTD) and Recommended Phase II Dose (RP2D)<br />
(ClinicalTrials.gov Identifier: NCT02027376).<br />
Methods: Pts with ≤3 prior chemotherapy regimens for ABC were included.<br />
Treatment consisted <strong>of</strong> 21-day cycles (cy) <strong>of</strong> D 75mg/m 2 on day 1, and increasing doses<br />
<strong>of</strong> S given once daily (QD). A standard 3 + 3 design was followed including 3 dose<br />
levels (DL) for S: DL1 400mg, DL2 600mg and DL3 800mg. The primary objective was<br />
to define the MTD and RP2D <strong>of</strong> the combination, based on dose-limiting toxicities<br />
(DLT) in the first 2 cy; secondary objectives included the evaluation <strong>of</strong> safety, changes<br />
on QTc, efficacy, and pharmacokinetics (PK).<br />
Results: 12 pts were included (5 at DL1, 4 at DL2 and 3 at DL3); 3 pts were replaced<br />
due to early progressive disease (PD). Median age was 49.5 years (26–76). Pts received<br />
a median <strong>of</strong> 2 cy (2–4) at DL1, 2 cy (1–3) at DL2 and 8 cy (6–9) at DL3. No DLTs were<br />
observed in any DL. DL3 was the MTD, and toxicities grade (G) 3, none G4, in all cy<br />
included neutropenia (NP) 66.7%, CPK increase, leukopenia, and paresthesia 33.3%<br />
each; 1 event <strong>of</strong> NP and the event <strong>of</strong> CPK increase caused S dose reduction. 2 pts had<br />
G1 QTc prolongation. The mean relative dose intensity <strong>of</strong> S and D were 99.3% (94.1–<br />
100.8) and 100% (98.9-102.4), respectively. 11 pts discontinued study treatment due to<br />
PD and 1 pt by Investigator’s criterion (on complete response at DL3). The objective<br />
response rate (n = 10) was 10% (95% CI 0.3-44.5). Median time to progression (n = 12)<br />
was 42.5 days (95% CI 29-155), being <strong>of</strong> 188 days at DL3. When co-administrated S<br />
and D, there was a trend to lower S trough concentrations, but could not be proved to<br />
be statistically significant and D clearance was similar on day 1 <strong>of</strong> Cycles 1 and 2.<br />
Conclusions: S can be safely combined with D. Co-administration <strong>of</strong> S and D seems<br />
not to have PK interaction. S 800mg QD and D 75mg/m 2 was declared as the RP2D.<br />
Clinical trial identification: Nº EudraCT: 2013-001750-96<br />
Legal entity responsible for the study: GEICAM (Spanish Breast Cancer Group)<br />
Funding: Novartis Farmaceutica S.A.<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
282P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
A new oral dihydroxysterol (24-ethyl-cholestane-<br />
3β,5α,6α-triol) showing activity in the treatment <strong>of</strong> advanced<br />
and metastatic breast cancer<br />
N. Habib, H.E. Daaboul, G. Hage, A. Jabbour, H. Zeitouni, N. Kassem, R. Khalifeh<br />
<strong>Oncology</strong>, Nabil Habib Institution, Beirut, Lebanon<br />
Background: Hydroxysterols are oxygenated derivatives <strong>of</strong> cholesterol. They have nuclear<br />
receptors and have been ascribed a number <strong>of</strong> important roles in connection with<br />
cholesterol turnover, atherosclerosis, apoptosis, and necrosis. Hydroxysterols have also<br />
been shown to have antitumor effects in experimental tumor models. (24-ethyl-cholestane-<br />
3β,5α,6α-triol) is a new oral hydroxysterol. The introduction <strong>of</strong> additional hydroxyl groups<br />
to the cholesterol skeleton facilitates the flux <strong>of</strong> hydroxysterols across the blood brain<br />
barrier. Most <strong>of</strong> these derivatives have been shown to be very toxic. Our compound<br />
(24-ethyl-cholestane- 3β,5α,6α-triol) is the first dihydroxysterol to have reached the clinical<br />
level. It is also one <strong>of</strong> the rare ones to be safe and non toxic.<br />
Methods: We have treated with this new compound 21 patients suffering from advanced<br />
breast cancer. The median age was 55 years. Eighteen patients had stage IV and three<br />
stage III. All had received at least one line <strong>of</strong> chemotherapy (some received more than 4<br />
vi88 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
lines <strong>of</strong> therapy) and all except 3 previous radiotherapy. Nine patients had a PS: 1, eight<br />
had a PS: 2 and four had a PS: 3. Eighty percent were symptomatic and sixty five percent<br />
were taking pain killers. Patients received daily 10 mg/Kg <strong>of</strong> oral (24-ethyl-cholestane-<br />
3β,5α,6α-triol) divided in 3 equal doses, until disease progression.<br />
Results: Two patients exhibited a complete remission (CR). Nine patients had a partial<br />
response (PR), five patients had a stable disease (NC) and five patients had a disease<br />
progression (PD). The median duration <strong>of</strong> response was 11 months and 6 patients are<br />
still under treatment. One patient with lepto-meningeal involvement is still alive and<br />
under treatment after 49 months. No toxicity was observed so ever. Eighty percent <strong>of</strong><br />
symptomatic patients had a remarkable symptom control.<br />
Conclusions: These encouraging results make this new and safe drug a good candidate<br />
for further clinical trials either alone or in association with other drugs in advanced<br />
breast cancer.<br />
Legal entity responsible for the study: Nabil Habib Institute, Beirut, Lebanon.<br />
Funding: Nabil Habib Institute, Beirut, Lebanon.<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
283P<br />
Satisfaction with cancer treatments in HR + /HER2- metastatic<br />
breast cancer patients in a real world setting<br />
J. de Courcy 1 , R. Wood 1 , D. Mitra 2 , S. Iyer 2<br />
1 Adelphi Real World, Adelphi Group Ltd., Bollington, UK, 2 Global Outcomes and<br />
Evidence, Pfizer Inc., New York, NY, USA<br />
Background: To assess patient reported cancer treatment satisfaction in HR + /HER2-<br />
metastatic breast cancer (MBC).<br />
Methods: Physicians were recruited into the Disease Specific Program (DSP) across 5<br />
EU countries (UK, FR, DE, ES, IT) and the US. Patients (N = 739) completed<br />
self-reported questionnaires which included the Cancer Therapy Satisfaction<br />
Questionnaire (CTSQ); this assesses 3 domains, Expectations <strong>of</strong> Therapy (ET), Feelings<br />
about Side Effects (FSE) and Satisfaction with Therapy (SWT). Each domain is scored<br />
from 0-100 with a higher score associated with the best outcome. Results are reported<br />
for the overall cohort, by current therapy and by metastatic sites. Significance was<br />
assessed using Mann-Whitney U and Kruskal-Wallis tests.<br />
Results: A total <strong>of</strong> 611 MBC patients completed the questionnaire; mean age (SD) 66.3<br />
(10.3). Most patients received either chemotherapy w/o endocrine therapy (46.2%) or<br />
endocrine therapy w/o chemotherapy (48.8%). 5.1% received both or neither. Mean<br />
scores (SD) for ET, FSE and SWT were 60.6 (21.0), 54.9 (17.5) and 69.4 (15.4)<br />
respectively. Domain scores are stratified by current therapy and metastatic sites in<br />
Table 1. ET scores did not vary by either stratification. Significantly worse scores were<br />
reported in the chemotherapy group for the FSE and SWT domains, while bone and<br />
visceral metastases patients reported worse FSE outcomes. When stratified by therapy,<br />
patients with bone and visceral metastases scored lower on most domains compared to<br />
other metastases groups (not significant).<br />
CURRENT THERAPY<br />
Endocrine<br />
(n = 298)<br />
Chemotherapy<br />
(n = 282)<br />
Table: 283P<br />
METASTATIC SITES (± lymph nodes)<br />
Bone not<br />
visceral<br />
(n = 195)<br />
Visceral not<br />
bone<br />
(n = 242)<br />
Bone &<br />
visceral<br />
(n = 110)<br />
ET 61.2 (21.1) 61.4 (18.8) 62.6 (20.0) 59.2 (21.9) 57.2 (19.8)<br />
FSE 59.7 (18.4) 50.9 (14.8)* 57.7 (17.3) 53.2 (17.2) 49.5 (15.9)*<br />
SWT 71.6 (15.6) 68.2 (14.0)* 70.9 (14.0) 68.7 (15.7) 65.7 (16.2)<br />
* P < 0.05 Visceral = brain, liver, lung, pancreas<br />
Conclusions: Therapy expectations do not differ by therapy type or metastatic sites.<br />
Patients on chemotherapy appear less satisfied with their treatment and feel worse<br />
about their side effects than patients on endocrine therapy. Presence <strong>of</strong> bone and<br />
visceral metastases is associated with worse feelings about side effects.<br />
Legal entity responsible for the study: Adelphi Real World<br />
Funding: Pfizer<br />
Disclosure: J. de Courcy, R. Wood: Adelphi Real World produces research which is<br />
funded by pharmaceutical companies. D. Mitra, S. Iyer: Employee <strong>of</strong> Pfizer, Inc. and<br />
owns Pfizer stock<br />
284P<br />
Patient reported pain severity and interference in HR + /HER2-<br />
advanced/metastatic breast cancer in real world settings<br />
R. Wood 1 , J. de Courcy 1 , D. Mitra 2 ,S.Iyer 2<br />
1 Adelphi Real World, Adelphi Group Ltd., Bollington, UK, 2 Global Outcomes and<br />
Evidence, Pfizer Inc., New York, NY, USA<br />
Background: To assess patient reported pain severity and pain interference in HR + /<br />
HER2- advanced/metastatic breast cancer (ABC/MBC) across multiple countries in a<br />
real world setting.<br />
Methods: Physicians across 5 major EU countries and the US participated in a<br />
cross-sectional study <strong>of</strong> over 2000 patients with HR + /HER2- ABC/MBC. A subset <strong>of</strong><br />
patients (N = 739) completed validated questionnaires, including the Brief Pain<br />
Inventory (BPI), used to assess the severity and impact <strong>of</strong> pain on daily functions. Pain<br />
severity is reported at its worst on a 0-10 scale, while average pain severity is a mean <strong>of</strong><br />
4 items on a 0-10 scale (worst & least in past 24 hours, average and current pain). On<br />
both scales a higher score implies greater pain. Interference is a mean <strong>of</strong> 7 items on a<br />
0-10 scale with higher scores implying greater pain interference. Mean scores are<br />
reported for the overall cohort and by sites <strong>of</strong> metastases and compared using<br />
Mann-Whitney U and Kruskal-Wallis tests.<br />
Results: Mean (SD) scores for worst pain was 3.1 (2.4), average pain was 2.4 (1.9), and<br />
pain interference was 2.8 (2.2). The subgroup with bone and visceral metastases had<br />
significantly higher (p < 0.05) average pain severity [3.0 (1.9)], compared to those with<br />
bone disease (no visceral metastases) [2.5 (1.9)] and those with visceral (no bone)<br />
disease [2.2 (1.9)]. Pain interference was significantly higher (p < 0.05) for those with<br />
both bone and visceral metastases (3.4 [2.2]) followed by bone disease (2.9 [2.1]) and<br />
visceral disease (2.6 [2.2]). In a subset <strong>of</strong> patients receiving chemotherapy at the time <strong>of</strong><br />
completion <strong>of</strong> the BPI, worst pain was significantly (p < 0.05) higher in patients with<br />
both metastases [3.8 (2.4)], compared to those with bone metastases [3.4 (2.3)] and<br />
those with visceral metastases [2.8 (2.3)]. No significant difference in pain interference<br />
scores were observed by type <strong>of</strong> metastatic site within the subset <strong>of</strong> patients treated with<br />
chemotherapy.<br />
Conclusions: Low to moderate levels <strong>of</strong> pain severity and pain interference scores<br />
observed in advanced/metastatic breast cancer patients in the real world, which vary<br />
significantly by extent and site <strong>of</strong> metastases.<br />
Legal entity responsible for the study: Adelphi Real World<br />
Funding: Pfizer<br />
Disclosure: R. Wood, J. de Courcy: Adelphi Real World produce research that is<br />
funded by pharmaceutical companies. D. Mitra, S. Iyer: Employee <strong>of</strong> Pfizer, Inc. and<br />
owns Pfizer stock.<br />
285P<br />
Association <strong>of</strong> age and body mass index with<br />
paclitaxel-induced peripheral neuropathy in patients with<br />
breast cancer<br />
Z. Ghoreishi 1 , A. Esfahani 2 , S. Keshavarz 3<br />
1 Nutrition Research Center, Tabriz University <strong>of</strong> Medical Sciences, Tabriz, Iran,<br />
2 Hematology and <strong>Oncology</strong> Research Center, Tabriz University <strong>of</strong> Medical<br />
Sciences, Tabriz, Iran, 3 School <strong>of</strong> Nutritional Sciences and Dietetics, Tehran<br />
University <strong>of</strong> Medical Sciences, Tehran, Iran<br />
Background: Peripheral neuropathy is one <strong>of</strong> the most common dose-limiting side<br />
effects <strong>of</strong> paclitaxel in patients with breast cancer. This study investigated the<br />
association <strong>of</strong> age and body mass index (BMI) with incidence and severity <strong>of</strong><br />
pacitaxel-induced peripheral neuropathy (PIPN) in these patients.<br />
Methods: Analyzed data belonged to a randomized double-blind placebo controlled<br />
trial (ID registrationat ClinicalTrials.gov: NCT01049295) in which the effect <strong>of</strong> n-3<br />
polyunsaturated fats (PUFAs) on PIPN in patients with breast cancer was examined.<br />
Logistic regression analysis (estimation odds ratio) and ordinal regression analysis were<br />
used for finding the association <strong>of</strong> age and BMI with incidence and severity <strong>of</strong> PIPN<br />
(adjusting for intervention effect) respectively.<br />
Results: Age was associated with PIPN in 57 patients with breast cancer (mean age and<br />
BMI: 45.97± 10.75 and 45.16± 8.93, respectively) such that for every one-year increase<br />
in age, incidence and severity will increase 8% and 7% respectively (OR = 1.08, .95%<br />
CI = (1.01 to 1.14), p = 0.015) and B= .07, 0.95% CI = 0.02 to 0.11), p = 0.010, adjusting<br />
for intervention effect). Also BMI had a positive association with PIPN, so that a 1 kg/<br />
m 2 increase in BMI, leads to an increase <strong>of</strong> incidence and severity by 7% and 8%,<br />
respectively(OR = 1.07, .95% CI = (1.00 to 1.15), p = 0.041) and B= .08, 0.95% CI = 0.02<br />
to 0.14), p = 0.012, adjusting for intervention effect).<br />
Conclusions: Older age and higher BMI were associated with greater incidence and<br />
severity <strong>of</strong> PIPN in patients with breast cancer.<br />
Clinical trial identification: ClinicalTrials.gov NCT01049295)<br />
Legal entity responsible for the study: Tehran University <strong>of</strong> Medical Sciences, Tehran,<br />
Iran<br />
Funding: Tehran University <strong>of</strong> Medical Sciences, Tehran, Iran<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw365 | vi89
abstracts<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
286P<br />
First-line cobimetinib (C) + paclitaxel (P) in patients (pts) with<br />
advanced triple-negative breast cancer (TNBC): Updated<br />
results and tumoral immune cell infiltration data from the<br />
phase 2 COLET study<br />
D.W. Miles 1 , S-B. Kim 2 ,T.Velu 3 , J.A. García-Saenz 4 , E. Tan-Chiu 5 , J.H. Sohn 6 ,<br />
L. Dirix 7 ,J.Vaňásek 8 , M.V. Borms 9 , J.I. Delgado Mingorance 10 , M-C. Liu 11 ,M.<br />
M. Moezi 12 , M.F. Kozl<strong>of</strong>f 13 , J.A. Sparano 14 ,N.Xu 15 ,Y.Yan 16 , M.J. Wongchenko 16 ,<br />
B. Simmons 17 , V. McNally 18 , A. Brufsky 19<br />
1 Medical <strong>Oncology</strong>, Mount Vernon Cancer Centre, Northwood, UK, 2 <strong>Oncology</strong>,<br />
Severance Hospital, Yonsei University Health System, Seoul, Republic <strong>of</strong> Korea,<br />
3 <strong>Oncology</strong>, Chirec Cancer Institute CHIREC, Brussels, Belgium, 4 Medical<br />
<strong>Oncology</strong>, Hospital Clinico San Marcos, Madrid, Spain, 5 Florida Cancer Research<br />
Institute, Plantation, FL, USA, 6 Medical <strong>Oncology</strong>, Yonsei Severance Hospital<br />
Cancer Center, Seoul, Republic <strong>of</strong> Korea, 7 Cancer Center, Sint-Augustinuskliniek,<br />
Antwerp, Belgium, 8 Radiation <strong>Oncology</strong>, Multiscan, s.r.o., Pardubice, Czech<br />
Republic, 9 Medical <strong>Oncology</strong>, AZ Groeninge Hospital, Kortrijk, Belgium, 10 Medical<br />
<strong>Oncology</strong>/CICAB Clinical Research Center, Hospital Infanta Cristina, Badajoz,<br />
Spain, 11 Hemato-oncology, Koo Foundation Sun Yat Sen Cancer Center, Taipei,<br />
Taiwan, 12 Clinical Research, Cancer Specialists <strong>of</strong> North Florida, Jacksonville, FL,<br />
USA, 13 Medicine in <strong>Oncology</strong>/Hematology, Ingalls Memorial Hospital, Harvey, IL,<br />
USA, 14 <strong>Oncology</strong>, Montefiore Medical Center Albert Einstein College <strong>of</strong> Medicine,<br />
Bronx, NY, USA, 15 PD Biostatistics, Genentech, Inc., South San Francisco, CA,<br />
USA, 16 <strong>Oncology</strong> Biomarker Development, Genentech, Inc., South San Francisco,<br />
CA, USA, 17 Product Development <strong>Oncology</strong>, Genentech, Inc., South<br />
San Francisco, CA, USA, 18 PDC, Roche Products Ltd., Welwyn Garden City, UK,<br />
19 Division <strong>of</strong> Hematology-<strong>Oncology</strong>, University <strong>of</strong> Pittsburgh, Pittsburgh, PA, USA<br />
Background: Resistance to standard taxane-based chemotherapy is common in TNBC.<br />
Preclinical data suggest that MEK inhibition may overcome taxane resistance and<br />
enhance antitumor immune response. The safety and efficacy <strong>of</strong> combining C, a highly<br />
selective MEK inhibitor, with P was explored in pts with metastatic/locally advanced<br />
TNBC and no prior systemic therapy for metastatic disease.<br />
Methods: The COLET study (NCT02322814; EudraCT number, 2014-002230-32)<br />
consisted <strong>of</strong> a safety run-in (n ≈ 12) followed by a blinded 1:1 randomized stage<br />
(n ≈ 100 pts) to C + P or placebo (PBO) + P. Pts were treated with P 80 mg/m 2 on days<br />
1, 8, and 15 and C/PBO 60 mg/d on days 3-23 <strong>of</strong> each 28-d cycle. Gene expression and<br />
CD8 T-cell infiltration were measured by RNA-Seq and immunohistochemistry,<br />
respectively.<br />
Results: Sixteen women (median age, 55.5 years) were enrolled in the safety stage. At<br />
data snapshot (April 22, 2016), all 16 pts had received ≥1 dose <strong>of</strong> study treatment.<br />
Median time on treatment was 116 d (range, 7-336) for C and 84 d (range, 0-351) for<br />
P. 94% <strong>of</strong> pts had ≥1 adverse event (AE); most were grade 1/2 (Table). Ten pts (63%)<br />
had grade 3 AEs; there were no grade 4-5 AEs. Preliminary efficacy data from safety<br />
run-in included unconfirmed partial response (n = 8, 6 confirmed), stable disease<br />
(n = 4), and progressive disease (n = 2); 2 pts had not completed a tumor assessment.<br />
To date, matched pre- and post-treatment biopsies have been tested for 2 pts and<br />
demonstrate an increase in CD8 T-cell infiltration and PD-L1 expression with<br />
treatment in the basal subtype.<br />
Table: 286P Most common (any grade ≥ 20%) AEs<br />
Treatment-emergent AEs C + P (safety run-in stage), N = 16<br />
All grades<br />
Grade ≥3<br />
Diarrhea 10 (63) 1 (6)<br />
Rash 8 (50) 0<br />
Nausea 7 (44) 0<br />
Blood CPK level increase 5 (31) 1 (6)<br />
Alopecia 5 (31) 0<br />
Stomatitis 4 (25) 2 (13)<br />
Asthenia 4 (25) 1 (6)<br />
Constipation 4 (25) 0<br />
Dyspnea 4 (25) 0<br />
Peripheral edema 4 (25) 0<br />
Pyrexia 4 (25) 0<br />
Vomiting 4 (25) 0<br />
Abbreviations: AEs, adverse events; C, cobimetinib; CPK, creatinine<br />
phosphokinase; P, paclitaxel.<br />
Conclusions: This is the first study to evaluate C + P in TNBC. The safety pr<strong>of</strong>ile <strong>of</strong><br />
C + P is consistent with that <strong>of</strong> known safety pr<strong>of</strong>iles. Initial data are consistent with<br />
previous reports on the immunomodulatory effects <strong>of</strong> MEK inhibition. Efficacy and<br />
safety will be further evaluated in the ongoing randomized stage.<br />
Clinical trial identification: ClinicalTrials.gov ID NCT02322814; EudraCT number,<br />
2014-002230-32<br />
Legal entity responsible for the study: F. H<strong>of</strong>fmann-La Roche, Ltd.<br />
Funding: This study was funded by F. H<strong>of</strong>fmann-La Roche, Ltd.<br />
Disclosure: D.W. Miles: Advisory Board, Honoraria, Investigator: Roche/Genentech.<br />
M.V. Borms: Consultant, grants: Roche. M-C. Liu: Consulting or Advisory Role: Roche,<br />
Pfizer. M.M. Moezi: Advisory Board: Millennium and BMS; Board <strong>of</strong> Directors:<br />
Cancer Specialists <strong>of</strong> North Florida; Investigator: Genentech and BMS; Speaker:<br />
Novartis, Millennium, BMS, and Pfizer. M.F. Kozl<strong>of</strong>f: Advisory Board, Consultant,<br />
Investigator: Genentech/Roche; Speaker: Genentech. J.A. Sparano: Advisory Board:<br />
Genentech/Roche, Merrimack, AstraZeneca, Celgene, and Pfizer; Consultant: Metastat<br />
and Prescient Therapeutics; Research: Genentech/Roche, Takeda, Novartis, Merrimack,<br />
and Mediummune; Ownership Interest, Stock Options: Metastat. N. Xu: Employment,<br />
stock or other ownership: Roche. Y. Yan: Employment, stock or other ownership,<br />
patents, royalties, other intellectual property, travel, accommodations, expenses:<br />
Genentech/Roche. M.J. Wongchenko: Employment: Genentech; Stock or Other<br />
Ownership: Roche, ARIAD Pharmaceuticals. B. Simmons, V. McNally: Employment,<br />
stock or other ownership: Genentech.A. Brufsky: Advisory board, honoraria,<br />
corporate-sponsored research: Genentech. All other authors have declared no conflicts<br />
<strong>of</strong> interest.<br />
287P<br />
Mutation screening and clinical evaluation <strong>of</strong> multiple-gene<br />
sequencing for triple negative breast cancer<br />
J. Zhang, R. Guo, S. Zhang, Y. Hu, J. Liu, J. Bai<br />
Department III <strong>of</strong> breast surgery, Tianjin Medical University Cancer Institute and<br />
Hospital, Tianjin, China<br />
Background: Triple negative breast cancers (TNBCs) were proved to be a<br />
heterogeneous disease with a wide spectrum <strong>of</strong> genomic alterations. TNBC is<br />
associated with early recurrence <strong>of</strong> disease and poor outcome. Recently next generation<br />
sequencing (NGS) is entering practice, whether multiple-gene changes have some<br />
relevance with TNBC, whether predict heterogeneity, prognostic or chemo-sensitivity<br />
<strong>of</strong> TNBC patients are worthy to be explored.<br />
Methods: 170 TNBC patients were invited to donate a research blood sample,<br />
including 100 patients unselected for family history <strong>of</strong> breast cancer and 70 patients<br />
with neo-adjuvant chemotherapy. For each patient, genomic DNA was extracted from<br />
peripheral-blood samples. NGS were used to sequence 115 genes that had cancer risk<br />
associations. Medical records were collected and patients were followed up.<br />
Results: Overall, 36 deleterious mutations were identified in 34 patients (20%). Of<br />
these, 9.4% had pathogenic mutations in the BRCA1 (5.9%) and BRCA2 (3.5%) genes<br />
in 170 patients. Twenty pathogenic variants were detected in other genes except for<br />
BRCA1/2 mutations, for a prevalence <strong>of</strong> 11.8%. The affected genes were PALB2(2.9%),<br />
ATM(1.8%), MUTYH(1.8%), BRIP1, CHEK2, GALNT12, HMMR, MSR1, NTRK1,<br />
RAD50, SDHC, VHL (0.6%one women).A total <strong>of</strong> 354 variants <strong>of</strong> uncertain<br />
significance(VUS) were identified in 115 genes among 170 participants.Participants<br />
carried an average <strong>of</strong> 1.6 VUS among 49 genes. Multiple-gene analysis suggests that<br />
TNBC patient with a pathogenic germline gene mutation and (or) has multiple-gene<br />
mutations has a poor outcome, however, neo-adjuvant chemotherapy is more<br />
sensitivity in these patients.<br />
Conclusions: Pathogenic mutations associated with cancer or DNA repair pathways<br />
are present at high frequency in patients with TNBC unselected for family history <strong>of</strong><br />
cancer. VUS is prevalent in TNBCs. TNBC patients with a high level <strong>of</strong> genomic<br />
instability have a relatively poor prognosis, however, sensitive to chemotherapy. Since<br />
then, additional studies are required to determine whether neo-adjuvant chemotherapy<br />
can improve survival <strong>of</strong> this group <strong>of</strong> TNBCs. These results suggest that multiple-gene<br />
sequencing may benefit TNBC patients.<br />
Legal entity responsible for the study: Jin Zhang<br />
Funding: National Science and Technology Support Program(No. 2015BAI12B15)<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
288P<br />
Effect <strong>of</strong> ABCB1 gene polymorphisms C3435T and C1236T on<br />
tumour response and plasma levels <strong>of</strong> docetaxel in<br />
locally-advanced breast cancer patients <strong>of</strong> South India<br />
receiving neo-adjuvant chemotherapy<br />
R. Priyadarshini 1 , S. Kayal 2 ,R.A 3 , D.G. Shewade 1<br />
1 Pharmacology, Regional Cancer Centre, Jawaharlal Institute <strong>of</strong> Postgraduate<br />
Medical Education & Research, Puducherry, India, 2 Dept. Of Medical <strong>Oncology</strong>,<br />
Regional Cancer Centre, JIPMER Jawaharlal Institute Postgraduate & Medical<br />
Research, Puducherry, India, 3 Radio-diagnosis, Regional Cancer Centre,<br />
Jawaharlal Institute <strong>of</strong> Postgraduate Medical Education & Research, Puducherry,<br />
India<br />
Background: Variable response to docetaxel, which is given in locally-advanced breast<br />
cancer (LABC) patients as a part <strong>of</strong> neo-adjuvant chemotherapy (NACT), had been<br />
reported. This altered response could be due to polymorphisms in the gene (ABCB1)<br />
coding for the efflux transporter ABCB1 (MDR1). Objectives: · To evaluate the effect<br />
<strong>of</strong> single nucleotide polymorphisms (SNPs) C3435T (rs1045642) and C1236T<br />
(rs1128503) in ABCB1 gene on the tumor response in LABC patients <strong>of</strong> South India<br />
vi90 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
receiving docetaxel as NACT. · To determine the effect <strong>of</strong> these SNPs on plasma levels<br />
<strong>of</strong> docetaxel.<br />
Methods: Tumour response to docetaxel was evaluated in 129 LABC patients, out <strong>of</strong><br />
which plasma levels <strong>of</strong> docetaxel were estimated in 74. Blood samples were collected at<br />
the end <strong>of</strong> infusion and 1 hour later. DNA was extracted by ‘phenol-chlor<strong>of</strong>orm<br />
extraction method’ from the leucocytes. Genotyping was performed with RT-PCR<br />
System. Tumor response was assessed by RECIST criteria. Plasma levels <strong>of</strong> docetaxel<br />
were estimated by LCMS/MS.<br />
Results: Patients with “CT/TT” genotypes (response rate: 66%) <strong>of</strong> ABCB1 gene<br />
(C1236T) showed better tumor response than those with “CC” genotype (response<br />
rate: 13%) [OR = 2.94 (CI: 1.15 - 7.52); p = 0.032]. The superior response in “CT/TT”<br />
genotypes can be attributed to the presence <strong>of</strong> “T” allele causing altered function <strong>of</strong><br />
ABCB1 gene coding for MDR1 transporter. Plasma levels <strong>of</strong> docetaxel were also in line<br />
with the tumor response in “CT/TT” genotypes <strong>of</strong> ABCB1 gene (C1236T). Mean <strong>of</strong> the<br />
plasma concentration ratios (C 0 /C 1 ) <strong>of</strong> docetaxel in “CT/TT” genotypes (13.49 ± 6.48<br />
ng/mL) were significantly higher than those <strong>of</strong> the “CC” genotype (8.19 ± 3.10 ng/mL)<br />
[p = 0.003]. In contrast, the genotypes <strong>of</strong> C3435T in ABCB1 gene were not found to<br />
significantly influence the tumor response or the plasma levels <strong>of</strong> docetaxel.<br />
Conclusions: These results suggest that ABCB1 C1236T polymorphism could<br />
significantly influence the treatment response to docetaxel and the plasma levels <strong>of</strong><br />
docetaxel. Hence, our study emphasizes the importance <strong>of</strong> ABCB1 genotyping for<br />
individualization <strong>of</strong> docetaxel pharmacotherapy in breast cancer patients.<br />
Legal entity responsible for the study: Jawaharlal Institute <strong>of</strong> Postgraduate Medical<br />
Education & Research (JIPMER), Puducherry<br />
Funding: Jawaharlal Institute <strong>of</strong> Postgraduate Medical Education & Research<br />
(JIPMER), Puducherry<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
289P<br />
Prognostic significance <strong>of</strong> immunohistochemical subtyping<br />
and PAM50 intrinsic subtypes in male breast cancer (MaBC)<br />
M. Alvarez 1 , A. Sanchez-Muñoz 2 , A. Santonja 2 , Y. Plata Fernández 3 , J. Miramón 4 ,<br />
I. Zarcos Pedrinaci 5 , C. Llacer 6 , V. de Luque 7 , M.J. Lozano León 1 , J.M. Jerez 1 ,L.<br />
Pérez Villa 1 , R. Lavado 2 , C. Ramirez 8 , A. Jiménez 9 , I. Rodrigo 6 , E. García 10 ,<br />
L. Vicioso 1 , E. Alba Conejo 2<br />
1 Pathology, Biomedical Research Institute <strong>of</strong> Málaga (IBIMA), Malaga, Spain,<br />
2 Medical <strong>Oncology</strong>, Biomedical Research Institute <strong>of</strong> Málaga (IBIMA), Malaga,<br />
Spain, 3 <strong>Oncology</strong>, Complejo Hospitalario de Jaen Universidad de Jaen, Jaen,<br />
Spain, 4 Medical <strong>Oncology</strong>, Hospital de la Serrania, Ronda (Málaga), Spain,<br />
5 <strong>Oncology</strong>, A.S Hospital Costa del Sol, Malaga, Spain, 6 Servicio de Oncología<br />
médica, Hospital Regional Universitario Carlos Haya, Malaga, Spain, 7 Medical<br />
<strong>Oncology</strong>, Iomedical Research Institute <strong>of</strong> Malaga (IBIMA)-Hospital Universitario<br />
Regional y Virgen de la Victoria, Malaga, Malaga, Spain, 8 Pathology Department,<br />
Complejo Hospitalario de Jaen Universidad de Jaen, Jaen, Spain, 9 Pathology<br />
Department, Hospital Regional Universitario Carlos Haya, Malaga, Spain,<br />
10 Pathology Department, Hospital de la Serrania, Ronda (Málaga), Spain<br />
Background: Substantial controversy exists about the prognostic role <strong>of</strong> molecular<br />
tumor subtypes in MaBC. It is mainly classified as a luminal disease, but survival<br />
differences between Luminal A and B are not clarified. The aim <strong>of</strong> this study was to<br />
assess the molecular subtype pr<strong>of</strong>iles <strong>of</strong> MaBC, and subsequently the clinical outcome,<br />
using two different approaches: mmunochemistry and the gene-expression pr<strong>of</strong>ile<br />
PAM50.<br />
Methods: A total <strong>of</strong> 69 cases <strong>of</strong> invasive MaBC, were examined using an<br />
immunohistochemical standard staining for estrogen receptor (ER), progesterone<br />
receptor (PR), androgen receptor (AR), human epidermal growth factor receptor 2<br />
(HER2), cytokeratin 5/6 (CK5/6), epidermal growth factor receptor (EGFR) and Ki-67.<br />
Immunohistochemical subtypes were classified according to Cheang et al. (2009).<br />
Gene-expression pr<strong>of</strong>iling was performed on a research-use-only (RUO) nCounter<br />
Analysis System using the RUO PAM50 assay analyzed with the Prosigna® algorithm.<br />
The Kaplan-Meier method was used to estimate Overall Survival (OS).<br />
Results: Patients had a median age <strong>of</strong> 63 (range 23-92). The mean and median OS were<br />
184 and 156 months, respectively. At diagnosis, patients were mainly stage I (27.5%)<br />
and II (40.6%). When subtyping by IHQ and PAM50, the majority <strong>of</strong> samples were<br />
luminal B (49.3% and 59.7%, respectively) followed by luminal A (44.3% and 29.9%).<br />
Only 5.8% by IHQ and 10.4% by PAM50 were non-luminal (1 basal-like, 2 non-basal<br />
triple negative and 1 Her2-enriched by IHQ and 7 Her2-enriched by PAM50). We<br />
found a strong association between both IHQ and PAM50 classifications<br />
(p-value = 0.007). There were no significant differences in OS between luminal A and<br />
luminal B subtypes, neither by immunohistochemistry (p = 0.22) nor in PAM50<br />
subtypes (p = 0.89). However, Her2-enriched patients by PAM50 showed significant<br />
worse prognosis (p = 0.009).<br />
Conclusions: The most common subtypes in our MaBC cohort were luminal B<br />
followed by luminal A. No differences were found between these tumor subtypes in<br />
terms <strong>of</strong> patient outcome. However, Her2-enriched patients by PAM50 showed worse<br />
prognosis. Further research with larger cohorts is needed to unveil the real role <strong>of</strong> the<br />
different subtypes in MaBC.<br />
Legal entity responsible for the study: Biomedical Research Institute <strong>of</strong> Malaga<br />
(IBIMA)-Hospital Universitario Regional y Virgen de la Victoria, Malaga (Spain)<br />
Funding: FIMABIS<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
290P<br />
Anthracycline mediated cardiotoxicity: Detection <strong>of</strong> miRNA<br />
based early biomarkers for the prediction <strong>of</strong> myocardial injury.<br />
Hecatos study<br />
C. Salvador Coloma 1 , P. Sepúlveda 2 , A. Hernandiz 2 , S. Tejedor 2 , L. Palomar 1 ,<br />
A. Ruiz 3 , V. Miro 4 , H. De la Cueva 1 , I. Ontoria-Oviedo 2 , A. Salvador 4 , V. Castel 5 ,<br />
A. Santaballa 1<br />
1 Medical <strong>Oncology</strong>, Hospital Universitari i Politècnic La Fe, Valencia, Spain,<br />
2 Regenerative Medicine and Heart Transplantation Unit, Instituto de Investigación<br />
sanitaria La Fe, Hospital Universitari i Politècnic La Fe, Valencia, Spain, 3 Medical<br />
<strong>Oncology</strong>, Fundación Instituto Valenciano de Oncología, Valencia, Spain,<br />
4 Cardiology, Hospital Universitari i Politècnic La Fe, Valencia, Spain, 5 <strong>Oncology</strong>,<br />
Hospital Universitari i Politècnic La Fe, Valencia, Spain<br />
Background: An improvement in the diagnosis and treatment <strong>of</strong> cancer has been<br />
shown in recent years with a significant increase in survival. Systemic therapies have an<br />
impact on reducing the risk for recurrence and mortality. However, there are potential<br />
long-term sequel like cardiac toxicity which could be a long-term determinant <strong>of</strong><br />
quality <strong>of</strong> life. The principal aim is to identified predictive biomarkers related to acute<br />
and later cardiotoxic. HeCaTos Study<br />
Methods: Multicenter, prospective, observational study. 400 patients diagnosed with<br />
breast cancer, lymphoma or leukemia treated with adjuvant chemotherapy (CT)<br />
(antracyclines) and 10 years <strong>of</strong> follow-up. There were analysed 97 patients with breast<br />
cancer treated with adjuvant therapies. A selected group <strong>of</strong> 25 patients was use to<br />
analyze variations in miRNA expression levels using qPCR. Cardiotoxicity was defined<br />
by left ventricular ejection fraction (LVEF) reduction >5% with LVEF < 55% and<br />
symptoms <strong>of</strong> heart failure or LVEF reduction > 10% with LVEFT < 55% in<br />
asymptomatic<br />
Results: Table 1 describes patient characteristics. LVEF and longitudinal strain are the<br />
most reliable indicators <strong>of</strong> drug induced cardiotoxicity. There was a decrease in LVEF<br />
(10% in 6,3% patients. Longitudinal strain was affected<br />
in 18% <strong>of</strong> patients and Troponin T was pathological in 29% <strong>of</strong> cases. We found a<br />
correlation among the decrease in LVEF and miRNA-208 associated with congestive<br />
heart failure (P < 0.02).<br />
Table: 290P Clinical characteristics<br />
Characteristics<br />
Results<br />
Female/Male 97/0<br />
Age 54 + /-13<br />
Hypertension 28.7%<br />
Diabetes 10.3%<br />
Dyslipidemia 21.8%<br />
Smoking 22.9%<br />
Sedentary lifestyle 0%<br />
Cardiovascular disease 0%<br />
Family history <strong>of</strong> cardiovascular disease 0%<br />
Conclusions: Decrease in LVEF, related to adjuvant CT, is correlated with an increase<br />
<strong>of</strong> congestive heart failure associated miRNA. Also, there was an increase <strong>of</strong> troponin<br />
levels after last CT cycle and variations in miRNA expression levels. Among them we<br />
found a strong correlation between the decrease in LVEF and the increase in miRNA<br />
208 levels in serum <strong>of</strong> patients during CT. Further studies must be performed to<br />
evaluate the impact <strong>of</strong> these observations in the cardiotoxic process.<br />
Legal entity responsible for the study: Hospital Universitario y Politécnico La Fe.<br />
Funding: Supported by EC grant FP7-HEALTH-2013-INNOVATION-1. C<strong>of</strong>unded by<br />
FEDER “una manera de hacer Europa"<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
291P<br />
Prognostic significance <strong>of</strong> the derived neutrophil-lymphocyte<br />
ratio in non-metastatic breast cancer: An institutional analysis<br />
from a tertiary care center in India<br />
C.K. Das 1 , A. Gogia 1 , S. Deo 2 , N.K. Shukla 2 , S. Mathur 3 , V. Sreenivas 4 ,<br />
D. Sharma 5<br />
1 Medical <strong>Oncology</strong>, All India Institute <strong>of</strong> Medical Sciences, New Delhi, India,<br />
2 Surgical oncology, Institute <strong>of</strong> Rotary cancer Institute(IRCH), All India Institute <strong>of</strong><br />
Medical Sciences, New Delhi, India, 3 Pathology, All India Institute <strong>of</strong> Medical<br />
Sciences, New Delhi, India, 4 Biostatistics, All India Institute <strong>of</strong> Medical Sciences,<br />
New Delhi, India, 5 Radiation <strong>Oncology</strong>, All India Institute <strong>of</strong> Medical Sciences, New<br />
Delhi, India<br />
Background: The prognostic value <strong>of</strong> cancer-associated inflammatory response has<br />
been evaluated in various solid malignancies.Derived Neutrophil to lymphocyte ratio<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw365 | vi91
abstracts<br />
(dNLR) is easily accessible and simple prognostic parameter <strong>of</strong> systemic inflammation<br />
associated with breast cancer. Data regarding the dNLR in breast cancer are limited in<br />
India. We assessed dNLR as a prognostic marker in patients with non-metastatic breast<br />
cancer treated at a tertiary care institute in North India<br />
Methods: We retrospectively evaluated the impact <strong>of</strong> baseline peripheral neutrophil<br />
and lymphocyte counts on survival, and investigated the correlation between<br />
inflammatory biomarkers and clinico-pathological factors in 497 consecutively treated<br />
non-metastatic breast cancer patients between 2011-2014.<br />
Results:<br />
Table: 291P Baseline characeristics N = 497<br />
Parameters<br />
Results<br />
Age in years 47.7(23-85)<br />
Presenting symptoms<br />
Lump > pain > ulcer > bleeding<br />
Duration <strong>of</strong> symptoms in month 7.8 (1-72)<br />
Stage I 18(4%), II 228(46%), III 251(50%)<br />
Histology Ductal 485(97.5%),Lobular 7(1.5%),Metaplastic 5(1%)<br />
Receptor Status ER + /PR + HER2- 209(42%), ER + /PR+ HER2 + ++ 85<br />
(17%), ER-PR-HER2 + ++ 71(14%), TNBC 132<br />
(27%)<br />
Hemoglobin in gm% 11.42(7-16)<br />
Total Leukocyte count in mm3 7369 (2450-21900)<br />
Absolute Neutrophil Count in 4506 (1100-19800)<br />
mm3<br />
Elevated dNLR 142(28.6%)<br />
Neoadjuvant Therapy 115(27.5%)<br />
Out <strong>of</strong> the 497 patients,with a median follow up <strong>of</strong> 33.5 months, the median disease<br />
free survival (DFS) was 33.1 months and 3-year estimated overall survival (OS) was<br />
90%. Receiver operating curve (ROC) analysis showed a cut<strong>of</strong>f <strong>of</strong> 2 to be sensitive<br />
(60%) and specific (73.7%) with coefficient <strong>of</strong> 0.76. Pre-therapy high dNLR was<br />
independently associated with tendency to poor PFS (HR 0.7, 95%CI 0.4-1.04, p=<br />
0.085) and reduced OS (HR <strong>of</strong> 3.8, 95% CI = 1.9–7.6, p< 0.001).On multivariate<br />
analysis, following factors were associated with inferior survival: elevated dNLR (HR<br />
0.8,p = 0.049, 95% CI1.65-0.04), nodal disease(HR 0.09,p = 0.028, 95%CI 0.009-0.17),<br />
presenting duration >6 months (HR 0.04,p-0.014, 95%CI 0.008-0.72) and TNBC<br />
subgroups (HR1.5, p < 0.001, 95%CI 1.2-1.9).<br />
Conclusions: In patients with breast cancer, inflammatory biomarker like elevated<br />
dNLR is strongly associated with poor overall survival.It can be utilized as a readily<br />
available and reproducible prognostic factor for patients with non-metastatic breast<br />
cancer across subgroups and its integration into patient evaluation is relevant in<br />
resource limited countries like India.<br />
Legal entity responsible for the study: Ethics Committee, All India Institute <strong>of</strong><br />
Medical Science<br />
Funding: All India Institute <strong>of</strong> Medical Science, New Delhi<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
292P<br />
Clinical implication <strong>of</strong> PIK3CA activating mutation in<br />
ER + HER2+ breast cancer: Based upon explorative mutational<br />
analysis <strong>of</strong> Neo-ALL-IN study<br />
J.H. Park 1 , D-H. Kim 2 , J-H. Ahn 1 , J.E. Kim 3 , K.H. Jung 4 , G. Gong 5 , S-H. Ahn 6 ,H.<br />
J. Lee 5 , B-H. Son 6 , H-H. Kim 7 , H.J. Shin 7 , D-H. Moon 8 , S-M. Ahn 2 , S-B. Kim 9<br />
1 <strong>Oncology</strong>, Asan Medical Center, University <strong>of</strong> Ulsan College <strong>of</strong> Medicine, Seoul,<br />
Republic <strong>of</strong> Korea, 2 Center for cancer genome discovery, Asan Medical Center,<br />
University <strong>of</strong> Ulsan College <strong>of</strong> Medicine, Seoul, Republic <strong>of</strong> Korea, 3 Department <strong>of</strong><br />
oncology, Asan Medical Center, University <strong>of</strong> Ulsan College <strong>of</strong> Medicine, Seoul,<br />
Republic <strong>of</strong> Korea, 4 Department <strong>of</strong> <strong>Oncology</strong>, Asan Medical Center, University <strong>of</strong><br />
Ulsan College <strong>of</strong> Medicine, Seoul, Republic <strong>of</strong> Korea, 5 Department <strong>of</strong> Pathology,<br />
Asan Medical Center, University <strong>of</strong> Ulsan College <strong>of</strong> Medicine, Seoul, Republic <strong>of</strong><br />
Korea, 6 Department <strong>of</strong> Sugery, Asan Medical Center, University <strong>of</strong> Ulsan College<br />
<strong>of</strong> Medicine, Seoul, Republic <strong>of</strong> Korea, 7 Department <strong>of</strong> Radiology, Asan Medical<br />
Center, University <strong>of</strong> Ulsan College <strong>of</strong> Medicine, Seoul, Republic <strong>of</strong> Korea,<br />
8 Nuclear medicine, Asan Medical Center, University <strong>of</strong> Ulsan College <strong>of</strong> Medicine,<br />
Seoul, Republic <strong>of</strong> Korea, 9 Department <strong>of</strong> <strong>Oncology</strong>, Asan Medical Center,<br />
University <strong>of</strong> Ulsan College <strong>of</strong> Medicine, Seoul, South Korea, Seoul, South Africa<br />
Background: Both ER + HER2+ breast cancer presents a heterogeneous biology, which<br />
is yet to be explored. Thus, using the cohort <strong>of</strong> our previous phase II study, we<br />
investigated their somatic mutation pr<strong>of</strong>ile to find out the frequency and clinical<br />
implication.<br />
Methods: Formalin-fixed paraffin-embedded (FFPE) tissue from 21 postmenopausal<br />
ER + HER2+ breast cancer patients were obtained from Asan Medical Center. The<br />
samples were sequenced by targeted capture sequencing with NGDx (coding sequence<br />
<strong>of</strong> 585 cancer-related genes + selected introns from 57 genes). Sequenced data were<br />
mapped to the reference human genome (hg19) using the Burrows-Wheeler Aligner,<br />
and were processed using publicly available Picard and the Genome Analysis Toolkit.<br />
Single nucleotide variant calls from MuTect were filtered against the dbSNP database<br />
to enrich for somatic mutations. Copy number alterations were detected by G + C<br />
normalization <strong>of</strong> read depth <strong>of</strong> coverage.<br />
Results:<br />
Table: 292P<br />
Gene mutation ER + HER2+ breast cancer in TCGA Neo ALL- IN<br />
PIK3CA 38.1% 66.7%<br />
AA change/frequency<br />
AA change/<br />
frequency<br />
Exon 9 (helical<br />
domain)<br />
E542K: 11% E545K: 16% Q546K: 1%<br />
Q546P:
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
significant benefit in terms <strong>of</strong> pCR. More patients in the AC group experienced<br />
cardiovascular events than in the MCH group.<br />
Clinical trial identification: C19562/2037/BC/EU<br />
Legal entity responsible for the study: This is a company-sponsored study: Teva<br />
Branded Pharmaceutical Products R&D, Inc. Sponsor’s Responsible Medical Officer<br />
Richard Malamut, MD<br />
Funding: Teva Branded Pharmaceutical Products R&D, Inc.<br />
Disclosure: S. Paepke: Honoraria from Teva. All other authors have declared no<br />
conflicts <strong>of</strong> interest.<br />
294P<br />
Neoadjuvant chemotherapy carboplatin – taxane response in<br />
locally advanced triple negative breast cancer patients in<br />
relation to molecular biomarkers<br />
L.M. Sad 1 , S. Younis 1 , M. Abd El Hak 2<br />
1 <strong>Oncology</strong>, Tanta University Hospital, Tanta, Egypt, 2 PATHOLOGY, Tanta<br />
University Hospital, Tanta, Egypt<br />
Background: Breast cancer is a heterogeneous disease with different clinical behavior.<br />
The molecular classification <strong>of</strong> breast cancer differentiates, at least, three subgroups <strong>of</strong><br />
tumors: the luminal subtype with cells expressing estrogen receptors and ER-related<br />
genes; the human epidermal growth factor receptor 2 (HER2)-overexpressing subtype;<br />
and the basal-like subtype associated with the expression <strong>of</strong> basal cell markers.<br />
Targeted therapies for TNBC are not completely validated and the main treatment for<br />
this group <strong>of</strong> tumors is the use <strong>of</strong> chemotherapy, including platinum as single agent or<br />
in combination with other chemotherapy agents.<br />
Methods: From June 2010 to November 2011, 149 locally advanced triple negative<br />
breast cancer patients in the oncology department, Tanta University, were assigned to<br />
receive four cycles <strong>of</strong> PCb with dose <strong>of</strong> paclitaxel 80 mg/m2 and carboplatin AUC 2,<br />
given day 1, 8 and 15 <strong>of</strong> every 4 weeks. Immunohistochemistry <strong>of</strong> the following<br />
molecular markers: the estrogen receptor, progesterone receptor, HER2, p53, and Ki67.<br />
For ERCC1, grading was (0: no expression, 1: weak expression, 2: moderate expression,<br />
3: strong expression). Operable disease should be subjected to surgery within 4 weeks<br />
from the last chemotherapy cycle. An additional two cycles <strong>of</strong> weekly PCb were<br />
delivered after surgery in patients who achieved pCR. Four cycles PCb could be<br />
administrated after surgery in patients showing response at pathologic assessment.<br />
Results: Ninety patients (60.4%) showed negative ERCC1 expression. Negative ERCC1<br />
expression was associated with higher pathological CR (71.1%) than positive ERCC1<br />
(15.3%) to PCB (P = 0.001). Five year OS was better in negative ERCC1 versus positive<br />
ERCC1 (92.1 % versus 51.4% respectively, p value 0.001). Five year DFS was better in<br />
negative ERCC1 versus positive ERCC1 (69,6 % versus 64.2% respectively, p value<br />
0.001). In multivariate analysis ERCC1 maintained statistical siginficance as regard OS<br />
& DFS.<br />
Conclusions: In conclusion, the expression <strong>of</strong> this ERCC1 protein is lower in TNBC<br />
and associated with high pathologic complete response to carboplatin-taxol with better<br />
overall survival and DFS. ERCC1 and other pathological markers may be used to define<br />
better treatment lines for locally advanced triple negative breast cancer.<br />
Legal entity responsible for the study: Tanta University Hospital, <strong>Oncology</strong><br />
Department<br />
Funding: The authors <strong>of</strong> the study<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
295P<br />
Neoadjuvant chemotherapy use in breast cancer patients in<br />
the Nethelands: an expert opinion on current practice<br />
P. Spronk 1 , K. de Ligt 2 , A. van Bommel 1 , S. Siesling 2 , M-J. Vrancken Peeters 3 ,<br />
C. Smorenburg 4<br />
1 Surgical oncology, Leiden University Medical Center (LUMC), Leiden,<br />
Netherlands, 2 Epidemiology, Comprehensive Cancer Centre the Netherlands<br />
(IKNL), Utrecht, Netherlands, 3 Surgical oncology, Het Nederlands Kanker Instituut<br />
Antoni van Leeuwenhoek (NKI-AVL), Amsterdam, Netherlands, 4 Medical<br />
<strong>Oncology</strong>, Het Nederlands Kanker Instituut Antoni van Leeuwenhoek (NKI-AVL),<br />
Amsterdam, Netherlands<br />
Background: According to the national guidelines, neoadjuvant chemotherapy (NAC)<br />
is indicated for patients with locally advanced breast cancer (LABC). Furthermore,<br />
NAC is increasingly being used for downsizing the tumour in order to enable breast<br />
conservation therapy (BST). Despite these common believes, a large variation between<br />
the 92 Dutch hospitals is observed in the use <strong>of</strong> NAC according to the national<br />
NABON Breast Cancer Audit (NBCA), suggesting non-uniform practice patterns. The<br />
aim <strong>of</strong> the present study is to examine reasons for this variation by investigating the<br />
pattern <strong>of</strong> recommendation <strong>of</strong> NAC in daily practice, among surgical- and medical<br />
oncologists.<br />
Methods: All surgeons and medical oncologists participating in breast cancer care in<br />
the 92 hospitals in the Netherlands were provided with a 20-question survey.<br />
Descriptive statistical analysis was conducted and univariate analysis was performed.<br />
Results: Questionnaires were sent to 580 specialists and 140 (24%) responded; with a<br />
surgeon/medical-oncologist ratio <strong>of</strong> 50:50. LABC was the most <strong>of</strong>ten selected reason<br />
for recommending NAC (94%), followed by tumor downsizing to provide BST (87%)<br />
and a strong indication for adjuvant chemotherapy (64%). Another common reason<br />
mentioned was the time span for testing on hereditary breast cancer (34%) that could<br />
be created. The most important concern for recommending NAC was the performance<br />
status (64%). Age did not play a very large role against recommending NAC (23%). Of<br />
all the respondents, 54% reported that patients where chemotherapy is recommended<br />
are not always informed about the option <strong>of</strong> NAC. Subanalysis for the type <strong>of</strong> hospital<br />
(academic vs teaching vs general) where the questioned specialist worked, did not play<br />
any significant role in the reason(s) to decide for NAC.<br />
Conclusions: According to the national NABON Breast Cancer Audit (NBCA) there is<br />
a large variation in the use <strong>of</strong> NAC. The results <strong>of</strong> the survey give interesting insights,<br />
but could not define specific factors influencing this variation. A discrepancy is seen<br />
between the expert opinion and the actual implementation <strong>of</strong> NAC.<br />
Legal entity responsible for the study: N/A<br />
Funding: grant from the KWF (Dutch Cancer Society (DCS))<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
296P<br />
abstracts<br />
Evaluation <strong>of</strong> neoadjuvant weekly nanoparticle albumin-bound<br />
paclitaxel for HER2-negative breast cancer<br />
A. Nagayama 1 , A. Matsui 1 , A. Tachibana 2 , N. Suzuki 3 , M. Hirata 4 , Y. Oishi 5 ,<br />
Y. Hamaguchi 6 , Y. Murata 7 , Y. Okamoto 8<br />
1 Surgery, National Hospital Organization,Tokyo Medical Center, Tokyo, Japan,<br />
2 Breast Surgery, Kanto Central Hospital <strong>of</strong> the Mutual Aid Association <strong>of</strong> Public<br />
School Teachers, Tokyo, Japan, 3 Breast Surgery, Omori Red Cross Hospital,<br />
Tokyo, Japan, 4 Breast Surgery, JR Tokyo General Hospital, Tokyo, Japan, 5 Breast<br />
Surgery, Nissan Tamagawa Hospital, Tokyo, Japan, 6 Breast Surgery,<br />
Futakotamagawa Breast Clinic, Tokyo, Japan, 7 Pathology, National Hospital<br />
Organization,Tokyo Medical Center, Tokyo, Japan, 8 Breast Surgery, Toho<br />
University Medical Center Ohashi Hospital, Tokyo, Japan<br />
Background: Taxanes have been established as one <strong>of</strong> the key drugs for breast cancer.<br />
In order to maximize its benefit, reliable prediction <strong>of</strong> the response is needed especially<br />
in the neoadjuvant setting. The aim <strong>of</strong> this study is to evaluate the efficacy and safety <strong>of</strong><br />
neoadjuvant weekly nanoparticle albumin-bound paclitaxel (nab-PTX) for<br />
HER2-negative breast cancer and to explore the predictive factors.<br />
Methods: Patients with Stage II to IV HER2-negative breast cancer received 12 cycles<br />
<strong>of</strong> weekly nab-PTX 100 mg/m 2 as the first line treatment and response was assessed by<br />
imaging studies. Correlations between tumor response in the breast after nab-PTX<br />
regimen and positivity <strong>of</strong> ER, PgR, HER2, Ki67, Tau, FOXA1 and androgen receptor<br />
(AR) by immunohistochemistry (IHC) and mRNA expression <strong>of</strong> TS, DPD, SPARC,<br />
Tubulinβ3, Ki67, MDR1 and TOPO IIα were evaluated. Correlations were investigated<br />
using the Spearman test and Mann-Whitney test.<br />
Results: From December 2012 to December 2014, we enrolled 66 patients, <strong>of</strong> whom 57<br />
patients completed 12 cycles <strong>of</strong> nab-PTX treatment. The dose <strong>of</strong> nab-PTX was reduced<br />
20% in one patient. Among all, 55 patients (83.3%) had hormone receptor-positive<br />
tumors and 11 patients (16.7%) had triple negative tumors. The response rate in the<br />
breast after nab-PTX regimen was 59.1% (95% CI, 47.2% to 71.0%); 63.6% in hormone<br />
receptor-positive tumor and 36.4% in triple negative tumor respectively (p = 0.090).<br />
The pathological complete response at the time <strong>of</strong> surgery was 15% (95% CI, 6.1% to<br />
24.4%). Toxicity analysis showed that the incidence <strong>of</strong> grade 2 peripheral sensory<br />
neuropathy was 38 (57.6%), grade 2 or grade 3 leukocytopenia was 29 (43.9%), grade 2<br />
or grade 3 neutropenia was 20 (30.4%) and grade 2 or grade 3 liver dysfunction was 5<br />
(7.5%). Younger age, high Ki67 and low AR in IHC showed a statistically significantly<br />
higher tumor reduction rates in the breast. Low SPARC and high TOPO IIα in mRNA<br />
levels showed statistically significantly higher tumor reduction rates in the breast.<br />
Conclusions: Weekly nab-PTX in the neoadjuvant setting was well tolerated, especially<br />
in the peripheral sensory neuropathy pr<strong>of</strong>ile. Biomarker analysis suggested that high<br />
Ki67, low AR in IHC, low SPARC and high TOPO IIα in mRNA levels predict<br />
responses <strong>of</strong> weekly nab-PTX.<br />
Clinical trial identification: UMIN000009526<br />
Legal entity responsible for the study: Toho University Medical Center Ohashi<br />
Hospital<br />
Funding: National Hospital Organization and Taiho Pharmaceutical Co.<br />
Disclosure: A. Nagayama: owns stock options <strong>of</strong> Chugai, Inc.A. Matsui: received from<br />
research grants from Taiho, Takeda, Chugai, Eisai and Daiichi-Sankyo. received lecture<br />
fees Taiho, Eisai, Kyowa-Kirin, Chugai and Daiichi-Sankyo.Y. Okamoto: received<br />
research funding from Taiho and lecture fees from Eisai, Taiho, Chugai, Kyowa-Kirin,<br />
Takeda, Daiichi-Sankyo, AstraZeneca and Novartis.All other authors have declared no<br />
conflicts <strong>of</strong> interest.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw365 | vi93
abstracts<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
297P<br />
High-dose chemotherapy for inflammatory breast cancer:<br />
impact <strong>of</strong> immunohistochemical status on survival outcome<br />
299P<br />
The clonal evolution <strong>of</strong> a breast tumor during neoadjuvant<br />
chemotherapy and metastasis<br />
L. Boudin 1 , C. Chabannon 2 , R. Sabatier 3 , F. Bertucci 3 , P. Sfumato 4 , C. Tarpin 3 ,<br />
M. Provansal 3 , G. Houvenaegel 5 , E. Lambaudie 5 , A. Tallet 6 , R. Michel 6 ,<br />
E. Charafe-Jauffret 7 , B. Calmels 2 , C. Lemarie 2 , B. Jean-Marie 4 , J-M. Extra 3 ,<br />
P. Viens 3 , A. Gonçalves 3<br />
1 Oncologie Médicale, Hôpital d’Instruction des Armées (HIA) Ste Anne, Toulon,<br />
France, 2 Centre de Therapie Cellulaire, Institute Paoli Calmettes, Marseille, France,<br />
3 Oncologie Médicale, Institute Paoli Calmettes, Marseille, France, 4 Biostatistiques,<br />
Institute Paoli Calmettes, Marseille, France, 5 Chirurgie Oncologique, Institute Paoli<br />
Calmettes, Marseille, France, 6 Radiothérapie, Institute Paoli Calmettes, Marseille,<br />
France, 7 Biopathologie, Institute Paoli Calmettes, Marseille, France<br />
Background: Studies examining high-dose chemotherapy with autologous<br />
hematopoietic stem cell transplantation (HDC-AHSCT) strategies in inflammatory<br />
breast cancer (IBC), showed encouraging results in terms <strong>of</strong> disease-free survival<br />
(DFS), and overall survival (OS). The lack <strong>of</strong> data regarding HER2 status in all <strong>of</strong> these<br />
studies prevented any prognostic analysis involving breast cancer subtypes.<br />
Methods: All consecutive female patients treated for IBC with HDC and AHSCT at<br />
Institut Paoli-Calmettes between 2003 and 2012 were included. Since 2005,<br />
trastuzumab was included in initial treatment. Patient, tumor and treatment<br />
characteristics were collected. Patients were categorized in three subtypes based on<br />
hormonal receptor (HR) and HER2 status <strong>of</strong> the primary tumor: Luminal, (HR + /<br />
HER2-), HER2 (HER2 + , any HR), and triple negative (TN) (HER2- and HR-). The<br />
main objective was the analysis <strong>of</strong> OS according to the IHC subtypes.<br />
Results: Sixty seven patients were included. Eleven patients received trastuzumab.<br />
Median follow up was 80.04 months (95% CI 73.2-88.08). Five-year OS and DFS for<br />
the whole population patients were 74% (95% CI 61-83) and 65 % (95% CI 52-75),<br />
respectively. OS differed across subtypes (p = 0.057) : HER2 subgroup appeared to have<br />
the best prognosis with a 5-year OS <strong>of</strong> 89% (95% CI 64-97) compared to 57% (95% CI<br />
33-76) for the TN subgroup (HR 5.38, 95% CI 1.14-25.44; p = 0.034).<br />
Conclusions: In IBC patients receiving HDC-AHSCT, OS favorably compares with<br />
data available in the literature on similar groups <strong>of</strong> patients. TN patients carried the<br />
least favourable OS and HER2 patients, half <strong>of</strong> them also receiving trastuzumab, had<br />
the best outcome. These findings provide additional information and options for<br />
patients with IBC and who could potentially benefit <strong>of</strong> HDC-AHSCT.<br />
Legal entity responsible for the study: Institut Paoli Calmettes<br />
Funding: SIRIC program (INCa-DGOS-Inserm 6038).<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
298P<br />
Survival patterns <strong>of</strong> T2 & T3 breast cancer according to<br />
different modalities <strong>of</strong> treatment in the United States<br />
M. Ramadan, A. Meshref, M. Mousa<br />
Faculty <strong>of</strong> Pharmacy, Suez Canal University, Ismailia, Egypt<br />
Background: The study aim to detect five years relative survival rate <strong>of</strong> T2 & 3 stage <strong>of</strong><br />
breast cancer with radiotherapy (RT) and surgical treatment<br />
Methods: The patient data was obtained from SEER database using all 18 SEER<br />
registries. We included patient who diagnosed with breast cancer between 1998 & 2007<br />
with T2 & 3 stage according to breast-Adjusted American Joint Committee on Cancer<br />
6th edition for 1998. Five years relative survival rates <strong>of</strong> patients with different<br />
modalities <strong>of</strong> treatment calculated and compared among groups <strong>of</strong> patients categorized<br />
by T stage.<br />
Results: 117498 patient included depending on selection criteria from SEER database.<br />
The result showed that there is significant difference (P value >0.001) in five years<br />
relative survival rate in T2 stage between patient who not received neither RT nor<br />
surgery 53.6% (95%CI:50.5-56.6) comparing with patient who received RT only 86.4%<br />
(95%CI:79.8-90.9). Also there is significant difference (P value =0.029) in five years<br />
relative survival rate in T3 stage between patient who not received neither RT nor<br />
surgery 46.5% (95%CI:41.6-51.2) comparing with patient who received RT only 55.9%<br />
(95%CI:44.7-65.6). Also there is significant difference (P value >0.001) in five years<br />
relative survival rate in T2 stage between patient who received surgical intervention<br />
only 86.6% (95%CI:86.2-87) comparing with patient who received RT combined with<br />
surgical intervention 90.5% (95%CI:90.1-90.8). Also there is significant difference (P<br />
value >0.001) in five years relative survival rate in T3 stage between patient who<br />
received surgical intervention only 70.9% (95%CI:69.6-72.1) comparing with patient<br />
who received RT combined with surgical intervention 82.1% (95%CI:81.1-83).<br />
Conclusions: RT has high five years relative survival rate with T2 &3 stage in breast<br />
cancer patient. Also RT combined with surgical intervention has better five years<br />
relative survival rate with T2&3 stage <strong>of</strong> breast cancer than surgical intervention only.<br />
Legal entity responsible for the study: Mohammed Ramadan<br />
Funding: Mohammed Ramadan<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
N.V. Litviakov 1 , N. Cherdyntseva 2 , M.K. Ibragimova 1 , M. Tsyganov 3 ,A.<br />
V. Doroshenko 4 , P. Kazantseva 4 , J. Kzhyshkowska 5 , E. Slonimskaya 4<br />
1 Laboratory <strong>of</strong> Oncovirology, Tomsk Cancer Research Institute, Tomsk, Russian<br />
Federation, 2 Laboratory <strong>of</strong> Molecular <strong>Oncology</strong> and Immunology, Tomsk Cancer<br />
Research Institute, Tomsk, Russian Federation, 3 Laboratory <strong>of</strong> cell and molecular<br />
biomedicine, National Research Tomsk State University, Tomsk, Russian<br />
Federation, 4 Department <strong>of</strong> General <strong>Oncology</strong>, Tomsk Cancer Research Institute,<br />
Tomsk, Russian Federation, 5 Department <strong>of</strong> Innate Immunity and Tolerance,<br />
University <strong>of</strong> Heidelberg, Heidelberg, Germany<br />
Background: In the present study we have examined the cytogenetic landscape (CNV<br />
– Copy Number Variation) <strong>of</strong> breast cancer prior to and following neoadjuvant<br />
therapy (NAC) and the associated tumor landscape alteration with chemotherapy<br />
efficiency as well as metastasis-free survival.<br />
Methods: Breast cancer patients (n = 30) with stage IIA to IIIB received four cycles <strong>of</strong><br />
systemic anthracycline-based NAC. To study CNVs in pre- and post-NAC tumor<br />
tissues microarray analysis was performed using the Affymetrix (USA) CytoScan HD<br />
Array.<br />
Results: The obtained data indicate a direct correlation between CNV frequency<br />
alteration during NAC and tumor response to therapy (R = 0.71, p = 0.000011). We<br />
showed that the number <strong>of</strong> cytobands bearing mosaic CNV was decreased after<br />
chemotherapy in 43% patients (13/30). The analysis <strong>of</strong> all CNV, including<br />
amplifications and deletions demonstrated that NAC do not influence CNV frequency<br />
in 27% <strong>of</strong> patients (8/30). For 30% (9/30) <strong>of</strong> patients the appearance <strong>of</strong> new CNV was<br />
detected after chemotherapy. The origin <strong>of</strong> new clones with amplifications was revealed<br />
in 6 cases <strong>of</strong> 9. The new clones with amplifications in such loci as 5p, 6p, 7q, 8q, 9p,<br />
10p, 10q22.1, 13q, 16p, 19p were detected. All these patients demonstrated distant<br />
metastasis where in 5 cases metastases were manifested within 2 years <strong>of</strong> follow up,<br />
excluding 1 patient surviving more than 4 years without metastases. All other patients<br />
(n = 24) who have not acquired the new tumor clones with Gain function after NAC<br />
did not manifest distant metastasis in 5-year follow-up (Kaplan-Meier, p = 0.00000<br />
Log-rank test). In accordance with these findings amplified tumor clones (loci 5p, 6p,<br />
7q, 8q, 9p, 10p, 10q22.1, 13q, 16p, 19p) could be considered as potential metastatic<br />
clones (named as seeds) which are able to go out from primary tumor sites in blood<br />
vessels with subsequent penetration to distant metastatic sites and in the case that<br />
prometastatic conditions exist in the microevironment they are able to give rise to<br />
metastases.<br />
Conclusions: Our study results demonstrate that the clonal evolution <strong>of</strong> tumors under<br />
the exposure to NAC can stimulate tumor metastatic potential. Data obtained dictate a<br />
very intelligent approach to treatment with NAC to avoid metastasis stimulation.<br />
Legal entity responsible for the study: Tomsk Cancer Research Institute<br />
Funding: Russian Foundation for Basic Research (project 15-04-03091)and Tomsk<br />
State University Competitiveness Improvement Program<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
300P<br />
Predictive factors for nonsentinel lymph node metastasis in<br />
patients with positive sentinel lymph nodes after neoadjuvant<br />
chemotherapy<br />
J.M. Ryu, S.J. Nam, J.E. Lee, J. Yu, S.K. Lee, S.Y. Bae, H-J. Paik, S. Park<br />
Surgery, Samsung Medical Center Sungkyunkwan University School <strong>of</strong> Medicine,<br />
Seoul, Republic <strong>of</strong> Korea<br />
Background: Axillary lymph node (ALN) status is an important prognostic factor for<br />
breast cancer patients. With increasing numbers <strong>of</strong> patients undergoing neoadjuvant<br />
chemotherapy (NAC), issues concerning sentinel lymph node biopsy (SLNB) after<br />
NAC have emerged. We analyzed clinicopathological features and developed a<br />
nomogram to predict the possibility <strong>of</strong> nonsentinel lymph node (NSLN) metastases in<br />
patients with positive SLNs after NAC.<br />
Methods: A retrospective chart review was performed for 141 patients who were<br />
clinically ALN positive at presentation, had a positive SLN after NAC on subsequent<br />
SLNB, and underwent axillary lymph node dissection (ALND) between 2008 and 2014.<br />
Results: On univariate analysis, SLN metastasis size, clinical ALN status after NAC,<br />
lymphovascular invasion (LVI), number <strong>of</strong> positive SLNs, number <strong>of</strong> negative SLNs,<br />
and pathologic T stage were significantly associated with likelihood <strong>of</strong> NSLN<br />
metastases (P < 0.05). On multivariate stepwise logistic regression analysis, pathologic<br />
T stage, SLN metastasis size, LVI, and number <strong>of</strong> positive SLN metastases were<br />
independent predictors for NSLN metastases (P < 0.05). The NAC nomogram was<br />
based on these four variables. A receiver operating characteristic curve was plotted and<br />
the area under the curve (AUC) was 0.791 for the NAC nomogram. In internal<br />
validation <strong>of</strong> performance, the AUC was 0.801 and 0.760. The nomogram was<br />
validated in an external patient cohort with AUC <strong>of</strong> 0.705.<br />
Conclusions: The NAC nomogram was developed to predict the likelihood <strong>of</strong><br />
additional positive NSLNs because this information may help dictate appropriate<br />
axillary surgery in the future as we strive to safely minimize axillary morbidity.<br />
Legal entity responsible for the study: N/A<br />
vi94 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Funding: This research was supported by a grant <strong>of</strong> the Korea Health Technology<br />
R&D Project through the Korea Health Industry Development Institute (KHIDI),<br />
funded by the Ministry <strong>of</strong> Health & Welfare, Republic <strong>of</strong> Korea. (HI14C3418)<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
301P<br />
A multicenter study <strong>of</strong> the impact <strong>of</strong> body mass index (BMI) on<br />
the incidence <strong>of</strong> pathologic complete response (pCR) among<br />
Saudi patients with locally advanced breast cancer (LABC)<br />
post neoadjuvant chemotherapy (NCth)<br />
A.M. Abdelwarith, K. Alsaleh, N. Abdelaziz, A. Ali, S. Elsamany, A. Rasmy,<br />
O. Elfarargy, S. Husain, A. Rikabi<br />
Medicine, King Khalid University Hospital King Saud University, Riyadh, Saudi<br />
Arabia<br />
Background: Obesity was reported as a poor prognostic factor for breast cancer. There<br />
is growing evidence <strong>of</strong> increasing prevalence <strong>of</strong> obesity among Saudi women (>44%).<br />
Since the prognostic significance <strong>of</strong> obesity was not studied in Saudi patients with<br />
breast cancer the aim <strong>of</strong> this study was to evaluate the impact <strong>of</strong> BMI on pCR in LABC<br />
patients post NCth.<br />
Methods: Between May 2005 and July 2010, 246 consecutive patients with LABC from<br />
three tertiary care centers, (KKHUH– Riyadh, KAH / Mekka and KFSH/ Dammam,<br />
were included in this study. All patients have received NCth (Anthracycline<br />
based + Taxane based combination chemotherapy). Patients were categorized as<br />
normal (BMI < 25 kg/m2), overweight (BMI <strong>of</strong> 25 to < 30 kg/m2) and obese (BMI >30<br />
kg/m2). pCR was defined as no invasive cancer in the breast or axillary tissue.<br />
Univariate and multivariate analysis were used to evaluate the statistical associations<br />
between, pCR and BMI with respect to the other previously established prognostic<br />
factors.<br />
Results: The median age was 50y (range 24-68), Molecular subtypes were as follows:<br />
luminal A 23.2%, luminal B 45.1%, triple negative 16.7%, Her-2 neu positive 15%.<br />
Eighty six (35 %) were stage II and 160 (65 %) were stage III. Intermediate and high<br />
grade malignancy were found in 52% and 44.3% <strong>of</strong> the patients respectively. Positive<br />
lymphovascular invasion was detected in 41.5% Obese patients constitutes 55.7% <strong>of</strong><br />
our cohort Pathologic complete response was achieved in 62 patients (25.2%). In<br />
Univariate analysis LVI and overweight /obesity were negatively correlated with pCR<br />
(P= 0.037 and 0.000 respectively) while tumor grade was positively correlated<br />
(P = 0.008). In multivariate analysis, Overweight/ obesity was the only significant<br />
independent factor correlating with pCR (P = 0.000).<br />
Conclusions: In this study, overweight / obesity (which represent more than half <strong>of</strong> the<br />
patients =55.7%) had a negative impact on pCR in Saudi patients with LABC treated<br />
with NCth. This poorer outcome in overweight / obese patients necessitates further<br />
prospective studies <strong>of</strong> this risk factor in order to optimize the care <strong>of</strong> this group <strong>of</strong><br />
patients.<br />
Legal entity responsible for the study: King Khalid University Hospital<br />
Funding: King Khalid University Hospital<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
302P<br />
Metformin in neoadjuvant systemic treatment in breast cancer<br />
patients with metabolic syndrome<br />
R. Liubota 1 , A. Zotov 1 , R. Vereshchako 1 , V. Cheshuk 1 , N. Anikusko 2 , I. Liubota 3<br />
1 Department <strong>of</strong> <strong>Oncology</strong>, O.O Bogomolets National Medical University Kiev, Kiev,<br />
Ukraine, 2 Surgery, Kyiv City Clinical Oncological Centre, Kiev, Ukraine,<br />
3 Dispensary, Kyiv City Clinical Oncological Centre, Kiev, Ukraine<br />
Background: The aim <strong>of</strong> this prospective randomized trial was investigate the<br />
influence <strong>of</strong> metformin on the effectiveness <strong>of</strong> neoadjuvant systemic anticancer therapy<br />
(NAST) breast cancer in patients with metabolic syndrome (MS).<br />
Methods: The study included 54 patients (aged 46 to 77 years) who received<br />
neoadjuvant systemic treatment for stage II-III breast cancer, in the clinic <strong>of</strong> oncology<br />
National medical university named after O.O. Bogomolets based in Kiev municipal<br />
clinical oncological centre between 2010-2014. All patients was diagnosed MS<br />
according to the IDF criteria and were compared by 2 groups group 1 included 36<br />
patients with MS and BC who did not take metformin during NAST, and group 2 - 18<br />
metabolic syndrome patients with breast cancer taking metformin with NAST. Clinical<br />
and pathological response rates were compared between the two groups using the<br />
fourfold tables analysis method.<br />
Results: Clinical complete response (CR) was identified in 6%patients from group 1<br />
and in 28% patients from group 2. Clinical benefit response <strong>of</strong> treatment (CR + PR)<br />
was achieved in 67% <strong>of</strong> patients treated with metformin compared to 25% patients<br />
from group 1. In 53% <strong>of</strong> patients who were not taking metformin was observed stabile<br />
disease (SD). The rate <strong>of</strong> pathological complete response (pCR) was 31% in the<br />
metformin group and 6% in the nonmetformin group.<br />
Conclusions: Appointment metformin and neoadjuvant systemic anticancer therapy<br />
breast cancer patients with metabolic syndrome have a higher clinical and pathological<br />
CR rate and clinical benefit response <strong>of</strong> treatment than BC patient with MS not<br />
receiving metformin. This study demonstrated the potential <strong>of</strong> metformin as an<br />
antitumor agent in breast cancer patients with metabolic syndrome.<br />
Legal entity responsible for the study: Liubota Roman<br />
Funding: NMU named after O.O. Bogomolets<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
303P<br />
Metformin and response to neoadjuvant chemotherapy in<br />
patients with breast cancer<br />
M. Ghareeb 1 , H. Naser 2 , M. El-Gammal 2 , A. Zeeneldin 2 , A. Bahnacy 3 , H. Khaled 2<br />
1 Medical <strong>Oncology</strong>, National Cancer Institute, Cairo, Egypt, 2 Medical <strong>Oncology</strong>,<br />
National Cancer Institute, Cairo, Egypt, 3 Pathology, National Cancer Institute,<br />
Cairo, Egypt<br />
Background: Breast cancer is the most frequently diagnosed malignancy and is a<br />
leading cause <strong>of</strong> cancer death in women worldwide. Neoadjuvant chemotherapy for<br />
breast cancer has been established as an effective therapeutic approach for advanced<br />
non metastatic-breast cancer. Metformin, an oral hypoglycemic drug with<br />
well-established side effect and safety pr<strong>of</strong>iles, has been widely studied for its<br />
anti-tumor activities in a number <strong>of</strong> cancers, including breast cancer.<br />
Methods: This study included 76 female non-diabetic patients with IDC who were<br />
eligible for neoadjuvant chemotherapy. They underwent clinical examination, bilateral<br />
mammography and ultrasound, and other standard radiologic modalities and they<br />
received anthracycline-based regimen (with or without Taxanes according to clinical<br />
response) with metformin 500mg, twice daily till time <strong>of</strong> surgery. After surgery,<br />
pathological response (by both Miller and Satell<strong>of</strong> grading systems) and RNA<br />
expression levels <strong>of</strong> p53 pathway, and the PI3K/AKT/m-TOR pathway were done on<br />
tissues<br />
Results: The mean age was 44.3 years. The mean BMI was 32.8 Kg/m 2 and 37.3 Kg/m 2<br />
in good responders and poor responders respectively (p value 0.042). Grade III<br />
pathology, Her2overexpression, T2-3 tumor, stage II and smaller mammographic<br />
tumor size were predictors <strong>of</strong> better pathological response. Obese patients had better<br />
DFS than normal-overweight group <strong>of</strong> patients (p value 0.001). Significant<br />
overexpression <strong>of</strong> AMPK, LKB1, TSC1/2, OCT1, PKA, APAF1, P53, P21, RPRM.,<br />
PIDD,FADD and CHEK1/2 and reduced expression <strong>of</strong> m-TOR, CYCLIN D-1,VEGF,<br />
CDK-4, CDK-1,IGF, NFKB and AKT among responders suggesting action <strong>of</strong><br />
metformin can be through AMPK activation and subsequent stimulation <strong>of</strong> p53,<br />
inhibition <strong>of</strong> mTOR, reduced expression <strong>of</strong> IGF1, stimulation <strong>of</strong> apoptotic pathways<br />
Conclusions: Obese group <strong>of</strong> patients had significantly better DFS when compared to<br />
normal-overweight group <strong>of</strong> patients, this could be explained by adding Metformin to<br />
neoadjuvant chemotherapy but further studies with larger number <strong>of</strong> patients and<br />
longer follow up is warranted. Also further efforts are needed for establishing<br />
antineoplastic molecular pathway for metformin<br />
Legal entity responsible for the study: National Cancer Institute, Egypt<br />
Funding: National Cancer Institute, Egypt<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
304P<br />
abstracts<br />
Prognostic factors after neoadjuvant chemotherapy in breast<br />
cancer: Surgery type as a new prognostic factor<br />
M. Fujihara, T. Kin, Y. Yoshimura, Y. Kajiwara, M. Ito, K. Abe, Y. Sakata, K. Hiraki,<br />
S. Ohtani<br />
Naka-ku, Hiroshima City Hospital, Hiroshima, Japan<br />
Background: Pathological complete response (pCR) after neoadjuvant chemotherapy<br />
(NAC) is not necessarily linked to long-term survival. Response to chemotherapy and<br />
outcomes after NAC differ among breast cancer subtypes, so we analyzed prognostic<br />
factors by subtype.<br />
Methods: We retrospectively analyzed 451 patients treated with anthracycline and<br />
taxane-based NAC between 2007 and 2015. Trastuzumab was added for human<br />
epidermal growth factor receptor (HER)-2-positive breast cancer. pCR was defined as<br />
no residual invasive breast carcinoma; noninvasive residuals and infiltrated lymph<br />
nodes were allowed. Kaplan–Meier and multivariate cox regression analyses were used<br />
to evaluate disease-free interval (DFI) and DFI prognostic values, respectively.<br />
Results: Median follow-up was 43 months; median age was 56 (range, 23–88) years.<br />
pCR rate was 26.2% (118/451) in all cases: 0% (0/82), luminal A; 10.9% (14/128),<br />
luminal B HER2(−); 43.1% (31/71), luminal B HER2(+); 59.4% (38/64), HER2; and<br />
34% (36/106), triple negative (TN). For all subtypes, patients who achieved pCR had a<br />
non-significantly higher DFI. Multivariate cox regression showed these associations<br />
with DFI: surgery type and Ki-67 > 30% after NAC for all cases and luminal B HER2<br />
(-); ypN (lymph node status after NAC), luminal B HER2(+); ypN and menopausal<br />
status, HER2; and age, surgery type, and clinical lymph node status, TN. Kaplan–Meier<br />
analysis showed that surgery type was strongly associated with DFI after NAC.<br />
Mastectomy patients had significantly poorer prognosis than partial mastectomy<br />
patients for all subtypes except HER2. For all cases, the median DFI in mastectomy<br />
patients was 73 months, but DFI was not reached in partial mastectomy patients<br />
(p < 0.0001). Compared with partial mastectomy patients, mastectomy patients had<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw365 | vi95
abstracts<br />
more advanced disease in terms <strong>of</strong> tumor size, lymph node status, and stage and<br />
showed lesser clinical and pathological responses to NAC and effects on ypN.<br />
Furthermore, first recurrences in mastectomy patients were <strong>of</strong>ten distant metastases,<br />
leading to poor prognosis.<br />
Conclusions: Prognostic factors after NAC differ among subtypes. Surgery type was<br />
strongly associated with outcomes after NAC, so it could be an independent prognostic<br />
factor.<br />
Legal entity responsible for the study: N/A<br />
Funding: Hiroshima City Hiroshima Citizens Hospital<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
305P<br />
Association between physical activity, psychological mood<br />
pr<strong>of</strong>ile and self-esteem among breast cancer survivors<br />
M.V. Karamouzis 1 , E. Patsou 2 , G. Alexias 2 , F. Anagnostopoulos 2<br />
1 Department <strong>of</strong> Biological Chemistry, National and Kapodistrian University <strong>of</strong><br />
Athens, Athens, Greece, 2 Panteion University Of Social and Political Sciences,<br />
University <strong>of</strong> Athens, Athens, Greece<br />
Background: Physical activity is defined as any bodily movement that is performed on<br />
a repeated basis with the intention <strong>of</strong> improving health or performance. Research<br />
demonstrates beneficial effects <strong>of</strong> Physical Activity (PA) and exercise among breast<br />
cancer survivors before and after treatment on phychological outcomes, mood pr<strong>of</strong>ile<br />
and self-esteem.<br />
Methods: The aim <strong>of</strong> the study was to investigate the relationship between Physical<br />
Activity, Psychological Mood Pr<strong>of</strong>ile and self-esteem among breats cancer survivors.<br />
The participants were 115 Greek women aged between 18-65 (M = 51,97, SD = 8.36),<br />
who had been diagnosed with breast cancer and finished oncology treatment or<br />
hormone therapy for stage I-IIIa cancer for at least one and a half year ago. The Greek<br />
version <strong>of</strong> POMS, SES, SDS, and IPAQ questionnaires were given to alla participants.<br />
SPSS 22 package was used for the statistic analysis.<br />
Results: The results indicated that inactive women experienced higher levels <strong>of</strong> tension<br />
(t = 2.05, p < .01), higher levels <strong>of</strong> depression (t = 2.51, p < .01) and less self-esteem<br />
(t = 2.11, p < .01) than active women which were statistically significant. Additionally,<br />
they experienced more heightened feelings <strong>of</strong> anger (t = -1.11, p < .01), fatigue<br />
(t = -1.58, p < .01), confusion (t = -1.08, p < .01), stait-anxiety (t = -1.46, p < .01) and<br />
lower vigour (t = 1.12, p < .01).<br />
Conclusions: Based on the results it can be concluded that women who exercised<br />
acquired psychological benefits. More specifically, Physical Activity is associated with<br />
better mood state and self-esteem among breast cancer survivors.<br />
Legal entity responsible for the study: Patsou Efrossini-Panteion University <strong>of</strong> Social<br />
and Political Sciences <strong>of</strong> Greece<br />
Funding: Panteion University <strong>of</strong> Social and Politcal Sciences<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
306P<br />
Contrast-enhanced ultrasound features <strong>of</strong> triple-negative<br />
breast cancer<br />
Y. Zhang, M. Chen<br />
Ultrasonography, Shanghai Ruijin Hospital, Shanghai Jiao Tong University, College<br />
<strong>of</strong> Medicine, Shanghai, China<br />
Background: It is important for triple-negative breast cancer(TNBC) to be detected<br />
early for its potential to be aggressive. The purpose <strong>of</strong> this study was to evaluate the<br />
ultrasound and contrast-enhanced ultrasound features <strong>of</strong> TNBC,and to explore<br />
symptoms for the diagnosis <strong>of</strong> TNBC.<br />
Methods: The study retrospectively reviewed 290 patients with postoperative pathology<br />
results in our hospital,including 45 cases <strong>of</strong> TNBC and 255 case <strong>of</strong> non-triple-negative<br />
breast cancer(NTNBC),one fifth <strong>of</strong> NTNBC(51case)were randomly selected as the<br />
control group.Qualitative and quantitative analysis were carried out between TNBC<br />
and NTNBC group.<br />
Results: There are larger percentage for TNBC group to have round or oval shapes<br />
(37.8%) circumscribed margins(35.6%),no posterior features(75.6%),no calcifications<br />
(71.1%),rich vascularities(80.0%) than that <strong>of</strong> NTNBC group<br />
(9.8%,11.8%,54.9%,39.2%,60.8%). In qualitative analysis, there are larger percentage for<br />
enhancement patterns <strong>of</strong> TNBC group to have well defined margins(66.7%) and<br />
hyper-enhancement perfusion(73.3%)than that <strong>of</strong> NTNBC group (31.4%,33.3%).In<br />
quantitative analysis,the whole mass and the spot with the strongest perfusion <strong>of</strong><br />
TNBC group tended to show higher peak intensity(Peak) than that <strong>of</strong> NTNBC group,<br />
the spot with the strongest perfusion <strong>of</strong> TNBC group tended to show lower sharpness<br />
than that <strong>of</strong> NTNBC group.All the parameters above have significant difference<br />
between two group(P < 0.05).<br />
Conclusions: Triple-negative breast cancer have some symptoms beneficial to its<br />
preoperative diagnosis in contrast-enhanced ultrasound.<br />
Clinical trial identification: NIH<br />
Legal entity responsible for the study: N/A<br />
Funding: I declare that the study presented in the abstract which I am submitting has<br />
received funding from the national clinical key specialty construction projects <strong>of</strong> China.<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
307P<br />
Contrast-enhanced ultrasound for evaluating the response <strong>of</strong><br />
breast cancer to neoadjuvant chemotherapy: Time-intensity<br />
curve analysis and texture analysis<br />
C. Yuan 1 , L. Tang 1 , Q. Zhang 2 ,W.Jia 1 , M. Chen 1<br />
1 Ultrasound, Shanghai Ruijin Hospital, Shanghai Jiao Tong University, College <strong>of</strong><br />
Medicine, Shanghai, China, 2 Institute <strong>of</strong> Biomedical Engineering, Institute <strong>of</strong><br />
Biomedical Engineering, Shanghai University, Shanghai, China<br />
Background: The purpose <strong>of</strong> this study was to investigate the features and<br />
performance <strong>of</strong> contrast-enhanced ultrasound (CEUS) in evaluating the response <strong>of</strong><br />
breast cancer to neoadjuvant chemotherapy (NAC) using time-intensity curve (TIC)<br />
analysis and texture analysis (TA) and the MATLAB programme for quantification.<br />
Methods: The study included 21 breast cancer patients who were treated with NAC<br />
between January 2011 and July 2015. All <strong>of</strong> the patients received at least four cycles <strong>of</strong><br />
chemotherapy, and CEUS data were available both before and after the NAC. Using the<br />
MATLAB program, both quantitative TIC analysis and TA were performed on the<br />
CEUS images before and after NAC. Additionally, after NAC, the pathologic breast<br />
tumour responses were assessed using the Miller and Payne system. Grades 1–3were<br />
categorized as the non-response group, and grades 4-5 were categorized as the response<br />
group. The performances <strong>of</strong> the two quantitative analyses were compared between the<br />
non-response and response groups.<br />
Results: For these 21 patients, the TIC analysis identified two parameters, i.e., BI-BIr<br />
(p = 0.025) and AUT-AUTr (p = 0.011), that exhibited significant differences between<br />
the subjects after NAC, which indicated that the intensity decreased after treatment.<br />
The texture analysis revealed that four parameters (Contrast, Entropy, Energy and<br />
Homogeneity) exhibited significant differences (p < 0.05), and the tumours tended to<br />
be more heterogeneous after treatment. Moreover, after NAC, there were 14 cases <strong>of</strong><br />
non-responders and 7 cases <strong>of</strong> responders. The areas under the receiver operating<br />
characteristic curves <strong>of</strong> the above parameters, i.e., Contrast, Entropy, Energy,<br />
Homogeneity, BI-BIr and AUT-AUTr, were 0.709, 0.699, 0.684, 0.770, 0.577 and 0.561,<br />
respectively, for the differentiation <strong>of</strong> the responders from the non-responders.<br />
Conclusions: This study demonstrated that quantitative analysis <strong>of</strong> the features<br />
computed from breast CEUS images is a promising tool for evaluating the responses <strong>of</strong><br />
breast cancers to NAC.<br />
Legal entity responsible for the study: Man Chen, MD & PhD Department <strong>of</strong><br />
Ultrasound, Ruijin Hospital, School <strong>of</strong> Medicine, Shanghai Jiaotong University<br />
Funding: National Natural Science Foundation <strong>of</strong> China (grant number 81470079,<br />
81172078)<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
308P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
The effectiveness <strong>of</strong> neoadjuvant chemotherapy with<br />
recombinant tumor necrosis factor-thymosin-a1in locally<br />
advanced breast cancer and effect on tumor angiogenesis<br />
L. Vladimirova 1 , N. Podzorova 1 , E. Nepomnyaschaya 2 , I. Novikova 3 , E. Ulyanova 3 ,<br />
G. Zakora 3 , E. Bondarenko 3<br />
1 Department <strong>of</strong> antitumor drug therapy, Rostov Research <strong>Oncology</strong> Institute,<br />
Rostov-on-Don, Russian Federation, 2 Department <strong>of</strong> patology, Rostov Research<br />
<strong>Oncology</strong> Institute, Rostov-on-Don, Russian Federation, 3 Laboratory <strong>of</strong><br />
Immunophenotyping <strong>of</strong> Tumors, Rostov Research Institute <strong>of</strong> <strong>Oncology</strong>,<br />
Rostov-on-Don, Russian Federation<br />
Background: The little is known about the influence <strong>of</strong> recombinant hybrid protein <strong>of</strong><br />
tumor necrosis factor-alpha-thymosin-alpha1 (TNF-T) on angiogenesis in breast<br />
cancer (ВС). The aim <strong>of</strong> the study was to investigate markers <strong>of</strong> angiogenesis and<br />
vascular proliferation in the tumor and to evaluate the efficacy <strong>of</strong> TNF-T in the<br />
neoadjuvant treatment <strong>of</strong> locally advanced breast cancer (LABC).<br />
Methods: Eligibility criteria included LABC <strong>of</strong> IIB-IIIB stages, ECOG ≤ 1, adequate<br />
kidney, liver and bone marrow function, no brain metastases. TNF-T 200000 IU was<br />
used peritumorally (injected around the tumor) on D1-5 (30 min before cytostatics<br />
injection), combined with standard FAC or PA regimens. The factors <strong>of</strong> angiogenesis<br />
CD31 and CD34 were studied in trephine-biopsy specimens before treatment and in<br />
postsurgical biopsies <strong>of</strong> the tumor after TNF-T courses.<br />
Results: 82 women were recruited between April 2012 – October 2013 (mean age<br />
53.3 ± 1.1 years). Group A (30 pts) received TNF-T combined to PA (17) and FAC (13)<br />
up to 6 courses. Group B (52pts) received standard PA (31) and FAC (21). Tumor<br />
response (TR) in Group A was 80% and in Group B 71.9% (p < 0.05), including CR<br />
15% and 6.25%, correspondingly (p < 0.05). The number <strong>of</strong> vessels <strong>of</strong> the<br />
microcirculation in sight was for CD31: 5,9 ± 0,34 before treatment and 2,24 ± 0,35<br />
after treatment (p < 0.05); CD34: 6.88 ± 1.07 and 2,75 ± 0,72, respectively (p < 0.05).<br />
The VEGF level in the main group decreased from 0,62 ± 0,11 to 0,11 ± 0,07(p < 0.05).<br />
The level <strong>of</strong> EGFR in the main group decreased from 0,87 ± 0,13 to 0,18 ± 0,05<br />
(p < 0.05). All patients in Group A were operated successfully, no postoperative<br />
vi96 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
complications connected with TNF-T use were observed. By the time <strong>of</strong> abstract<br />
submission OS in Group A was 35.6 ± 1.2mos, in Group B was 34.1 ± 1.1mos; EFS in<br />
Group A was 33.5 ± 1.1mos, in Group B was 28.7 ± 1.2mos (p < 0.05). Three-year EFS<br />
in group A is 20% higher than in group B (83% and 63% respectively, log-rank test<br />
p = 0,04778).<br />
Conclusions: TNF-T injected peritumorally allows to increase the antitumor activity <strong>of</strong><br />
cytostatics (CR) which is <strong>of</strong> great importance for survival in LABC. The data acquired<br />
in the biopsies show that the recombinant protein <strong>of</strong> TNF-T has the suppressive effect<br />
on angiogenesis.<br />
Legal entity responsible for the study: Rostov Institute <strong>of</strong> <strong>Oncology</strong><br />
Funding: Rostov Institute <strong>of</strong> <strong>Oncology</strong><br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
309TiP<br />
METRIC: A randomized international study <strong>of</strong> the antibody<br />
drug conjugate (ADC) glembatumumab vedotin (GV,<br />
CDX-011) in patients (pts) with metastatic gpNMB<br />
overexpressing triple-negative breast cancer (TNBC)<br />
P. Schmid 1 , M. Melisko 2 , D.A. Yardley 3 , K. Blackwell 4 , A. Forero 5 , G. Ouellette 6 ,<br />
Y. He 7 , R.G. Bagley 8 , J. Zhang 8 , L.T. Vahdat 9<br />
1 Centre for Experimental Cancer Medicine, Barts Cancer Institute-Queen Mary<br />
University <strong>of</strong> London, London, UK, 2 Department <strong>of</strong> Medicine, UCSF Helen Diller<br />
Family Comprehensive Cancer Center, San Francisco, CA, USA, 3 Breast Cancer<br />
Research Program, Sarah Cannon Research Institute/Tennessee <strong>Oncology</strong>, PLLC,<br />
Nashville, TN, USA, 4 Department <strong>of</strong> Medicine, Duke University Medical Center,<br />
Durham, NC, USA, 5 Department <strong>of</strong> Medicine, University <strong>of</strong> Alabama at<br />
Birmingham, Birmingham, AL, USA, 6 Clinical Operations, Celldex Therapeutics,<br />
Inc., Hampton, NJ, USA, 7 Biostatistics, Celldex Therapeutics, Inc., Hampton, NJ,<br />
USA, 8 Clinical Science, Celldex Therapeutics, Inc., Hampton, NJ, USA, 9 Breast<br />
Cancer Research Program, Weill Cornell Medicine, New York, NY, USA<br />
Background: Glycoprotein NMB (gpNMB) is an internalizable transmembrane<br />
protein overexpressed in ∼20% <strong>of</strong> breast cancer (BC) including ∼40% <strong>of</strong> TNBC.<br />
gpNMB is a poor prognostic marker in BC (Rose CCR 2010) and implicated in tumor<br />
invasion, metastasis, and angiogenesis. GV is a novel ADC delivering the potent<br />
cytotoxin MMAE to gpNMB expressing cancer cells. In a Phase 1/2 study and in the<br />
Phase 2 EMERGE study, GV was well tolerated and demonstrated promising activity,<br />
particularly in TNBC and/or gpNMB overexpressing (≥25% tumor cells; gpNMB+)<br />
BC. GV toxicity included rash, neutropenia and neuropathy (primarily grade 1 and 2).<br />
In EMERGE subset analyses, objective response rate (ORR) for GV vs. investigator’s<br />
choice chemotherapy = 30% (7/23) vs. 9% (1/11) in gpNMB+ BC; 18% (5/28) vs. 0%<br />
(0/11) in TNBC; and 40% (4/10) vs. 0% (0/6) in gpNMB+ TNBC. Improvements in<br />
PFS (hazard ratio (HR) = 0.11; 95% CI, 0.02 to 0.57) and OS (HR = 0.14; 95% CI, 0.03<br />
to 0.59) were also apparent in gpNMB+ TNBC.<br />
Trial design: The METRIC Trial (NCT#01997333) is an ongoing international, 2-arm<br />
Phase 2, registrational, TNBC study open in the USA, Canada, Australia, Spain and UK<br />
with sites planned in France, Germany and Italy. Pts are randomized 2:1 to GV (1.88<br />
mg/kg IV q3w) or capecitabine (2,500 mg/m 2 PO d1-14 q3w) until progression or<br />
intolerance. Eligibility Criteria Key eligibility criteria: ≥25% tumor epithelium<br />
gpNMB+ by central IHC screening; estrogen and progesterone receptors
abstracts<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
311TiP<br />
A phase III study <strong>of</strong> alpelisib and fulvestrant in men and<br />
postmenopausal women with hormone receptor-positive (HR<br />
+), human epidermal growth factor receptor 2-negative<br />
(HER2–) advanced breast cancer (BC) progressing on or after<br />
aromatase inhibitor (AI) therapy (SOLAR-1)<br />
312TiP<br />
A phase 2 randomized, double-blinded, controlled study <strong>of</strong><br />
ONT-380 vs. placebo in combination with capecitabine (C)<br />
and trastuzumab (T) in patients with pretreated HER2+<br />
unresectable locally advanced or metastatic breast<br />
carcinoma (MBC)<br />
F. André 1 , B. Kaufman 2 , D. Juric 3 , E. Ciruelos 4 ,H.Iwata 5 , I.A. Mayer 6 ,P.Conte 7 ,<br />
H.S. Rugo 8 , S. Loibl 9 , G. Rubovszky 10 , H. Tesch 11 , K. Inoue 12 , Y-S. Lu 13 ,<br />
L. Ryvo 14 , A-S. Longin 15 , D. Mills 16 , C. Wilke 16 , C. Germa 17 , M. Campone 18<br />
1 Breast Cancer Unit, Department <strong>of</strong> Medical <strong>Oncology</strong>, Institut Gustave Roussy,<br />
Villejuif, France, 2 Breast Cancer Unit, The Chaim Sheba Medical Center,<br />
Ramat-Gan, Israel, 3 Termeer Center for Targeted Therapies, Massachusetts<br />
General Hospital, Boston, MA, USA, 4 Medical <strong>Oncology</strong> Department, University<br />
Hospital 12 De Octubre, Madrid, Spain, 5 Department <strong>of</strong> Breast <strong>Oncology</strong>, Aichi<br />
Cancer Center Hospital, Nagoya, Japan, 6 Department <strong>of</strong> Medicine, Vanderbilt<br />
Ingram Cancer Center, Nashville, TN, USA, 7 University <strong>of</strong> Padova, Istituto<br />
Oncologico Veneto IRCCS, Padua, Italy, 8 Medicine (Hematology/<strong>Oncology</strong>),<br />
University <strong>of</strong> California San Francisco Comprehensive Cancer Center,<br />
San Francisco, CA, USA, 9 Medicine and Research, German Breast Group,<br />
Neu-Isenburg, Germany, 10 Internal Medicine-<strong>Oncology</strong> Division "B" and Clinical<br />
Pharmacology Department, National Institute <strong>of</strong> <strong>Oncology</strong>, Budapest, Hungary,<br />
11 Department <strong>of</strong> <strong>Oncology</strong>, Centrum für Hämatologie und Onkologie Bethanien,<br />
Frankfurt am Main, Germany, 12 Division <strong>of</strong> Breast <strong>Oncology</strong>, Saitama Cancer<br />
Center, Saitama, Japan, 13 Department <strong>of</strong> <strong>Oncology</strong>, National Taiwan University<br />
Hospital, Taipei, Taiwan, 14 Division <strong>of</strong> <strong>Oncology</strong>, Tel Aviv Sourasky Medical<br />
Center-(Ichilov), Tel Aviv, Israel, 15 Novartis Pharma S.A.S, Novartis Pharma S.A.S,<br />
Paris, France, 16 Novartis Pharma AG, Novartis Pharma AG, Basel, Switzerland,<br />
17 Novartis Pharmaceuticals Corporation, Novartis Pharmaceuticals Corporation,<br />
East Hanover, NJ, USA, 18 Medical <strong>Oncology</strong>, Institut de Cancérologie de l’Ouest<br />
Site Centre René Gauducheau, Saint Herblain, France<br />
Background: The phosphatidylinositol 3-kinase (PI3K)/mammalian target <strong>of</strong><br />
rapamycin (mTOR) pathway is <strong>of</strong>ten dysregulated in HR+ BC and is associated with<br />
resistance to endocrine therapy (ET). Alpelisib (BYL719; PI3Kα-specific inhibitor) and<br />
fulvestrant showed signs <strong>of</strong> antitumor activity in patients (pts) with estrogen<br />
receptor-positive (ER+), HER2– advanced BC (phase I), especially in PIK3CA-altered<br />
tumors (Janku et al. SABCS 2014, PD5-5).<br />
Trial design: SOLAR-1 (NCT02437318) is a phase III, randomized, double-blind study<br />
in men and postmenopausal women with HR + , HER2– advanced BC. Pts are assigned<br />
to 1 <strong>of</strong> 2 cohorts based on PIK3CA tumor status (mutant vs non-mutant), and<br />
randomized 1:1 to oral alpelisib/placebo (300 mg once daily) and intramuscular<br />
fulvestrant (500 mg on Day 1 and 15 <strong>of</strong> Cycle 1; Day 1 <strong>of</strong> Cycles ≥2 [28-day cycles])<br />
until disease progression or discontinuation. Randomization is stratified by presence <strong>of</strong><br />
liver and/or lung metastases and prior CDK4/6 inhibitor therapy. Key inclusion<br />
criteria: recurrence or progression on or after AI therapy, ≥1 measurable lesion<br />
(RECIST v1.1) or predominantly lytic bone lesion, and ECOG performance status ≤1.<br />
Key exclusion criteria: symptomatic visceral disease or disease burden precluding ET,<br />
acute pancreatitis ≤1 year prior to screening or history <strong>of</strong> chronic pancreatitis, and<br />
prior therapy with fulvestrant, chemotherapy (except [neo]adjuvant), or PI3K/AKT/<br />
mTOR inhibitors. The primary and key secondary endpoints are progression-free<br />
survival (PFS; RECIST v1.1; local assessment) and overall survival (OS), respectively, in<br />
the PIK3CA-mutant cohort. Other secondary endpoints include PFS and OS in the<br />
PIK3CA non-mutant cohort, PFS (Blinded Independent Central Review; RECIST<br />
v1.1), the association between PFS and baseline PIK3CA status in circulating tumor<br />
DNA, overall response rate, clinical benefit rate, safety, and pharmacokinetics. The<br />
primary endpoint will be analyzed by a stratified log-rank test at one-sided 2% level <strong>of</strong><br />
significance. Recruitment <strong>of</strong> the planned 560 pts is ongoing.<br />
Clinical trial identification: SOLAR-1/NCT02437318<br />
Legal entity responsible for the study: Novartis Pharmaceuticals Corporation<br />
Funding: Novartis Pharmaceuticals Corporation<br />
Disclosure: F. André: Research support: Novartis. B. Kaufman: Has served in advisory<br />
boards for Novartis, AstraZeneca, and Roche. D. Juric: Research funding from Novartis,<br />
and has served in a consulting/advisory role for Novartis, EMD Serono, Eisai, BIND<br />
Therapeutics, and Natera.I.A. Mayer: Research funding, advisory board:<br />
Novartis. P. Conte: Speaker and Advisory Boards for: novartis, roche, eli-lilly, celgene,<br />
astra-zeneca, obi Research Grants from: Novartis, Roche, Merck-serono. H.S. Rugo: I do<br />
not receive funding personally. Funding is provided to my institution for the conduct <strong>of</strong><br />
clinical trials sponsored by Novartis. S. Loibl: My institution has received research<br />
funding and honoraria from the majority <strong>of</strong> pharmaceutical companies i.e. but not<br />
limited to Novartis, Pfizer, Amgen, Roche, AZ, Celgene. H. Tesch: Consulting activities:<br />
Novartis, Roche, Pfizer Fees: Novartis, Roche, Pfizer. A-S. Longin: Employment,<br />
leadership, Research funding and travel/accommodation/expenses: Novartis. D. Mills: I<br />
own stock in Novartis Pharma AG. C. Wilke: Employee <strong>of</strong> Novartis AG, sponsor <strong>of</strong> the<br />
study. C. Germa: Employment and stock ownership: Novartis.M. Campone: Novartis:<br />
advisory board greant speaker bureau Menarini: advisory board Astra Zeneca: advisory<br />
board speaker bureau Pfizer: advisory board speaker bureau Roche: Advisory board. All<br />
other authors have declared no conflicts <strong>of</strong> interest.<br />
G. Curigliano 1 , S. Loibl 2 , V. Müller 3 , X. Pivot 4 , A. Wardley 5 , D. Cameron 6<br />
1 Drug Development, Istituto Europeo di Oncologia, Milan, Italy, 2 Medicine and<br />
Research, German Breast Group, Neu-Isenburg, Germany, 3 Department <strong>of</strong><br />
Gynecology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany,<br />
4 Service Oncologie Medicale, CHU Besançon, Hôpital Jean Minjoz, Besançon,<br />
France, 5 Medical <strong>Oncology</strong>, The Christie NHS Foundation Trust, Manchester, UK,<br />
6 <strong>Oncology</strong>, Edinburgh Cancer Centre Western General Hospital, Edinburgh, UK<br />
Background: ONT-380 is a highly selective small molecule inhibitor <strong>of</strong> HER2 kinase<br />
with nanomolar potency. Unlike dual HER2/EGFR agents, it does not inhibit EGFR at<br />
clinically relevant concentrations, decreasing the potential for EGFR-related toxicities<br />
(severe skin rash and diarrhea). In preclinical studies, ONT-380 demonstrated<br />
synergistic activity with T, and was active in HER2+ models <strong>of</strong> brain metastases (mets).<br />
In a Phase 1b study, ONT-380 was combined with C and T in pts with HER2+ MBC<br />
previously treated with trastuzumab emtansine (T-DM1) and T. Objective response<br />
rate (ORR) was 13/ 24 (54%) in pts with measurable disease treated with<br />
ONT-380 + C + T (including 10 pts with brain mets). The combination was well<br />
tolerated, with low rates <strong>of</strong> Gr 3 diarrhea at the recommended dose (300 mg PO BID,<br />
equivalent to the single agent MTD). Based on these data, ONT-380 is now being<br />
evaluated in a Phase 2 study in combination with C and T.<br />
Trial design: The primary study objective is to assess the effect <strong>of</strong> ONT-380 vs placebo<br />
given with C + T on progression-free survival (PFS) based on independent central<br />
review. Additional secondary objectives include CNS PFS, non-CNS PFS, time to CNS<br />
progression, ORR, duration <strong>of</strong> response, clinical benefit rate, and safety. The study<br />
population includes adult pts with progressive HER2+ locally advanced or MBC who<br />
have had prior treatment with a taxane, T, pertuzumab and T–DM1 but not C or<br />
lapatinib. Pts with brain mets, including untreated or progressive mets, may be<br />
enrolled. 180 pts will be enrolled in North America and Europe. Pts will receive C<br />
(1000 mg/mg 2 PO BID for 14 days <strong>of</strong> a 21-day cycle) and T (8 mg/kg IV loading dose;<br />
6 mg/kg IV once every 21 days), and will be randomized in a 2:1 ratio to receive ONT–<br />
380 300 mg PO BID or placebo. Pts with isolated CNS progression may continue on<br />
study treatment after undergoing local CNS therapy. An independent Data Monitoring<br />
Committee will monitor pt safety.<br />
Clinical trial identification: ONT-380-206<br />
Legal entity responsible for the study: Oncothyreon Inc.<br />
Funding: Oncothyreon Inc.<br />
Disclosure: G. Curigliano: ESMO Faculty and ESMO Multi-Committee member.<br />
Please refer to the declaration uploaded previously. All other authors have declared no<br />
conflicts <strong>of</strong> interest.<br />
313TiP<br />
SANDPIPER: Phase III study <strong>of</strong> the PI3-kinase (PI3K) inhibitor<br />
taselisib (GDC-0032) plus fulvestrant in patients (pts) with<br />
oestrogen receptor (ER)-positive, HER2-negative locally<br />
advanced or metastatic breast cancer (BC) enriched for pts<br />
with PIK3CA-mutant tumours<br />
J. Baselga 1 , J. Cortes Castan 2 , M. De Laurentiis 3 , V. Dieras 4 , N. Harbeck 5 ,<br />
J. Hsu 6 , H. Jin 7 , F. Schimmoller 6 , T.R. Wilson 8 , Y-H. Im 9 , W. Jacot 10 , I.E. Krop 11 ,<br />
S. Verma 12<br />
1 Human <strong>Oncology</strong> and Pathogenesis Program (HOPP); Department <strong>of</strong> Medicine,<br />
Memorial Sloan Kettering Cancer Center, Memorial Hospital, New York, NY, USA,<br />
2 Department <strong>of</strong> Medical <strong>Oncology</strong>, Vall d’Hebron Institute <strong>of</strong> <strong>Oncology</strong> (VHIO),<br />
Barcelona, ES, and Ramón y Cajal University Hospital, Madrid, Spain, 3 Breast<br />
<strong>Oncology</strong> Department, Istituto Nazionale Tumori Fondazione G. Pascale, Naples,<br />
Italy, 4 Department <strong>of</strong> Medical <strong>Oncology</strong>, Institut Curie, Paris, France, 5 Breast<br />
Cancer Center, University <strong>of</strong> Munich, Munich, Germany, 6 Product Development<br />
<strong>Oncology</strong>, Genentech Inc, San Francisco, CA, USA, 7 Department <strong>of</strong> <strong>Oncology</strong>,<br />
Genentech Inc, San Francisco, CA, USA, 8 <strong>Oncology</strong> Biomarker Department,<br />
Genentech Inc, San Francisco, CA, USA, 9 Department <strong>of</strong> Medicine, Samsung<br />
Medical Center, Seoul, Republic <strong>of</strong> Korea, 10 Department <strong>of</strong> Medical <strong>Oncology</strong>,<br />
Institut du Cancer de Montpellier (ICM), Montpellier, France, 11 Department <strong>of</strong><br />
Medical <strong>Oncology</strong>, Dana Farber Cancer Institute, Boston, MA, USA, 12 Tom Baker<br />
Cancer Centre, Department <strong>of</strong> <strong>Oncology</strong>, University <strong>of</strong> Calgary, Calgary, AB,<br />
Canada<br />
Background: The PI3K signalling pathway is one <strong>of</strong> the most dysregulated in BC. The<br />
alpha (α) is<strong>of</strong>orm <strong>of</strong> the catalytic subunit <strong>of</strong> PI3K, encoded by PIK3CA, is mutated in<br />
∼40% <strong>of</strong> ER-positive, HER2-negative breast tumours. Mutations in PIK3CA promote<br />
tumour growth and proliferation and can mediate resistance to endocrine therapies.<br />
The potent and selective PI3K inhibitor, taselisib, displays greater selectivity for mutant<br />
PI3Kα compared with wild-type PI3Kα, and has demonstrated enhanced activity in<br />
PIK3CA-mutant BC cell lines. In pts with PIK3CA-mutant BC, confirmed partial<br />
responses were reported following treatment with either single-agent taselisib or<br />
taselisib in combination with fulvestrant.<br />
vi98 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Trial design: SANDPIPER is a double-blind, placebo-controlled, randomised, phase<br />
III study that aims to examine taselisib in combination with fulvestrant in<br />
postmenopausal women with ER-positive, HER2-negative, PIK3CA-mutant locally<br />
advanced or metastatic BC. Pts with disease recurrence or progression during or after<br />
aromatase inhibitor treatment will be randomised 2:1 to receive either taselisib (4 mg<br />
qd) or placebo in combination with fulvestrant (500 mg intramuscular on Days 1 and<br />
15 <strong>of</strong> Cycle 1, and on Day 1 <strong>of</strong> each subsequent 28-day cycle). Pts require a valid<br />
PIK3CA-mutation test result from tumour tissue via central assessment prior to<br />
enrolment, as SANDPIPER enriches for pts with PIK3CA-mutant tumours (these pts<br />
will be randomised separately from those with non-mutant tumours). Randomisation<br />
will be stratified by visceral disease, endocrine sensitivity and geographical region. The<br />
primary efficacy endpoint is investigator-assessed progression-free survival in pts with<br />
PIK3CA-mutant tumours. Other endpoints include overall survival, objective response<br />
rate, clinical benefit rate, duration <strong>of</strong> objective response, safety, pharmacokinetics and<br />
patient-reported outcomes. Enrolment <strong>of</strong> 600 pts is planned and recruitment is<br />
ongoing; >200 pts have been enrolled into the study (NCT02340221).<br />
Clinical trial identification: Trial protocol number: GO29058 clinicaltrials.gov:<br />
NCT02340221<br />
Legal entity responsible for the study: F. H<strong>of</strong>fmann-La Roche/Genentech<br />
Funding: F. H<strong>of</strong>fmann-La Roche/Genentech<br />
Disclosure: J. Cortes Castan: Membership <strong>of</strong> an advisory board: Roche, Celgene. Other<br />
substantive relationships: Honoraria for speaking lectures - Roche, Celgene, Eisai,<br />
Novartis. Institutional Financial Interest / Financial support for Clinical trials &<br />
research – Roche. M. De Laurentiis: Membership <strong>of</strong> an advisory board (companies):<br />
Roche, Novartis, Celgene, Pfizer, Eisai. V. Dieras: Membership <strong>of</strong> an advisory board<br />
(companies): Roche, Novartis, Pfizer Other substantive relationships (companies):<br />
travel grants - Roche, Novartis, Pfizer. N. Harbeck: Other substantive relationships<br />
(companies): consulting & lectures with honoraria – Roche. J. Hsu, H. Jin, T.R. Wilson:<br />
Stock ownership (companies): Roche Other substantive relationships (companies):<br />
employed by Genentech. F. Schimmoller: Stock ownership (companies): Roche,<br />
Exelixis, Merck, Teva Other substantive relationships (companies): Employment -<br />
Genentech, Exelixis. Patents/royalties/intellectual property – Exelixis. W. Jacot:<br />
Membership <strong>of</strong> an advisory board (companies): Pfizer. I.E. Krop: Corporate-sponsored<br />
research (companies): Genentech. S. Verma: Membership <strong>of</strong> an advisory board<br />
(companies): Amgen, Astra Zeneca, BI, Novartis, Pfizer, Roche, Spectrum Health<br />
Other substantive relationships (companies): Medical Director and Co-Founder,<br />
<strong>Oncology</strong>Education.com. All other authors have declared no conflicts <strong>of</strong> interest.<br />
314TiP<br />
monarcHER: A phase 2 randomized open-label study <strong>of</strong><br />
abemaciclib plus trastuzumab (T) with or without fulvestrant<br />
(F) compared to standard-<strong>of</strong>-care chemotherapy <strong>of</strong><br />
physician’s choice plus T in women with HR + , HER2+<br />
advanced breast cancer<br />
S.M. Tolaney 1 , N. Bourayou 2 , S. Goel 1 , T. Forrester 3 , F. André 4<br />
1 Breast <strong>Oncology</strong> Center, Dana-Farber Cancer Institute, Boston, MA, USA,<br />
2 Medical <strong>Oncology</strong>, Eli Lilly and Company, Paris, France, 3 Statistics-<strong>Oncology</strong>, Eli<br />
Lilly and Company, Indianapolis, IN, USA, 4 Breast Cancer Unit, Department <strong>of</strong><br />
Medical <strong>Oncology</strong>, Institut Gustave Roussy, Villejuif, France<br />
Background: Preclinical data strongly suggest a crosstalk between HER2 signaling and<br />
the cyclin D/CDK4 signaling pathway in HER2-positive breast cancer cells. Transgenic<br />
mouse models, cell line-based studies, and clinical specimens suggest cyclin D/CDK4<br />
mediate resistance to HER2-directed therapy, and CDK4 & CDK6 inhibitors may<br />
re-sensitize resistant tumors to HER2 blockade. Abemaciclib, a selective CDK4 &<br />
CDK6 inhibitor, demonstrated durable single-agent activity in women with HR+<br />
advanced breast cancer (ABC) (both HER2+ and HER2-) and an acceptable safety<br />
pr<strong>of</strong>ile (both as a single agent and combined with F or T).<br />
Trial design: monarcHER, is a randomized, 3-arm, open-label Phase 2 study that aims<br />
to enroll 225 postmenopausal patients with HR + , HER2+ ABC with prior exposure to<br />
≥2 HER2-directed therapies for ABC and prior exposure to T-DM1 and a taxane in<br />
any disease setting. Patients may have received other HER2-directed therapy in any<br />
disease setting and must not have received F or any CDK4 & CDK6 inhibitor. The<br />
study excludes patients with ECOG PS ≥2; LVEF
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong> 27 (Supplement 6): vi100–vi102, 2016<br />
doi:10.1093/annonc/mdw366<br />
abstracts<br />
clinical trials methodology<br />
316P<br />
Comparison <strong>of</strong> assessments by blinded independent central<br />
reviewers and local investigators: An analysis <strong>of</strong> phase III<br />
randomized control trials on solid cancers (2010-2015)<br />
W. Liang, J. Zhang, Q. He, S. Tang, Y. Zhang, J. He<br />
Department <strong>of</strong> Thoracic <strong>Oncology</strong>, The 1st Affiliated Hospital <strong>of</strong> Guangzhou<br />
Medical University, Guangzhou, China<br />
Background: Accurate and unbiased assessment <strong>of</strong> tumor response or progression is<br />
crucial in randomized control trials. Blind independent central reviews are usually used<br />
as a supplemental or monitor to local investigator assessment but are costly. It is worth<br />
determining the value <strong>of</strong> central assessment.<br />
Methods: We compared central and local assessments by study-level pooling analysis<br />
and correlation analysis, primarily through investigating treatment effects <strong>of</strong> objective<br />
response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and<br />
time-to-progression (TTP). Evaluation for response between two assessments was also<br />
compared. Eligible trials were phase III RCTs <strong>of</strong> anti-cancer drugs for non-hematologic<br />
solid tumors, searched in PubMed between the dates <strong>of</strong> Jan 1, 2010 to Jun 24, 2015.<br />
Results: Of 61 included trials involving 37,396 patients, 10 (16%) trials were with<br />
different statistical conclusion regarding primary or secondary endpoints between two<br />
assessments. However, pooling analysis found no significant difference when<br />
comparing estimates <strong>of</strong> treatment effects between two assessments, pooled odds ratios<br />
(OR) <strong>of</strong> ORR, DCR, PFS and TTP was 1.03 [95% CI 0.98-1.09], 0.96 [0.90-1.03], 1.01<br />
[0.99-1.03] and 1.04 [0.95-1.14], respectively. This concordant outcome could be found<br />
regardless <strong>of</strong> mask (open/blind), region (global/intercontinental), tumor type, study<br />
design (superiority/non-inferiority), criteria <strong>of</strong> tumor assessment (RECIST/WHO).<br />
Correlation analysis also indicated their concordance on treatment effects (ORR, DCR,<br />
PFS: r > 0.80, p < 0.01; TTP: r = 0.896, p = 0.293). Synthesis for response evaluation<br />
indicated central ORR and DCR were numerically higher than those <strong>of</strong> the local in<br />
both experimental arms and control arms, without evaluation bias (ORR: OR = 1.02<br />
[0.97-1.08]; DCR: OR = 0.96 [0.90-1.03]).<br />
Conclusions: Central assessment remains an irreplaceable method but the necessity to<br />
apply it in a complete-case fashion should be questioned regarding efficiency, especially<br />
in trials with double-blind design. A modified strategy, such as sampling central<br />
assessment, warrants further evaluation.<br />
Legal entity responsible for the study: N/A<br />
Funding: The First Affiliated Hospital <strong>of</strong> Guangzhou Medical University<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
ESMO preliminary<br />
magnitude <strong>of</strong><br />
clinical benefit<br />
grade<br />
ASCO criteria for<br />
clinical benefit<br />
(% improvement<br />
in outcome)<br />
Table: 317P<br />
Primary<br />
outcome <strong>of</strong><br />
OS N = 102<br />
(50%)<br />
Primary<br />
outcome <strong>of</strong><br />
PFS or TTP<br />
N = 94 (46%)<br />
Total number<br />
<strong>of</strong> trials that<br />
meet criteria<br />
N = 203<br />
(100%)<br />
1 Least benefit 9 (4%) 79 (39%) 88 (43%)<br />
2 81 (40%) 0 (0%) 81 (40%)<br />
3 1 (0.5%) 13 (6%) 14 (7%)<br />
4 Most benefit 7 (3%) N/A 7 (3%)<br />
1(>0– 24%) 0 (0%) 0 (0%) 0 (0%)<br />
Least benefit<br />
2 (25 – 49%) 87 (43%) 65 (32%) 152 (75%)<br />
3 (50 – 75%) 11 (5%) 25 (12%) 36 (18%)<br />
4 (76 – 100%) 0 (0%) 2 (1%) 2 (1%)<br />
5 (>100%) Most<br />
benefit<br />
0 (0%) 0 (0%) 0 (0%)<br />
Conclusions: Only 69% <strong>of</strong> these phase 3 trials included sufficient information to<br />
determine both the relative and absolute effects sizes hypothesized. The majority <strong>of</strong><br />
trials were powered to show magnitudes <strong>of</strong> clinical benefit rated modest by the ESMO<br />
and ASCO frameworks. Trial protocols and reports should specify both the relative and<br />
absolute benefits hypothesized.<br />
Legal entity responsible for the study: The University <strong>of</strong> Sydney<br />
Funding: Cancer Australia, Cancer Institute New South Wales, NHMRC Clinical<br />
Trials Centre Postgraduate PhD Scholarship, Sydney Catalyst PhD Top Up<br />
Scholarship, Goldman Sachs New Zealand Clinical Fellowship Award<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
318P<br />
Comparison <strong>of</strong> the EORTC criteria and PERCIST in solid<br />
tumors<br />
J.H. Kim 1 , S.H. Park 2 , S.N. Yoon 3<br />
1 Hemato-<strong>Oncology</strong>, Kangnam Sacred-Heart Hospital, Seoul, Republic <strong>of</strong> Korea,<br />
2 Gynecology, Kangnam Sacred-Heart Hospital, Seoul, Republic <strong>of</strong> Korea,<br />
3 Surgery, Kangnam Sacred-Heart Hospital, Seoul, Republic <strong>of</strong> Korea<br />
317P<br />
Valuing the effect sizes hypothesized in phase 3 trials<br />
published from 2005 to 2015<br />
N. Lawrence, F. Roncolato, M. Stockler<br />
Medical <strong>Oncology</strong>, NHMRC Clinical Trials Centre, Sydney, Australia<br />
Background: We sought to determine the effect sizes hypothesized (ESH) for phase 3<br />
trials <strong>of</strong> targeted therapies, and to compare them against frameworks for assessing the<br />
magnitude <strong>of</strong> benefit from anti-cancer treatments recently proposed by ESMO (Cherny<br />
et al Ann Onc 2015), and ASCO (Schnipper et al JCO 2015), and against<br />
recommendations for designing phase 3 trials (Ellis et al JCO 2014).<br />
Methods: We searched Medline from 2005-15 for phase 3 trials <strong>of</strong> targeted therapies,<br />
including immunotherapies, in metastatic solid organ malignancies, designed with a<br />
superiority hypothesis. For each trial’s primary endpoint, we determined the ESH in<br />
relative terms (typically a hazard ratio [HR]), and in absolute terms (typically a<br />
difference in median survival times or rates). The hypothesised effect size was assigned<br />
a clinical benefit score according to the ESMO and the ASCO frameworks for valuing<br />
the results <strong>of</strong> phase 3 trials, with scores <strong>of</strong> 1 or 2 indicating modest benefits, and higher<br />
scores indicating larger benefits.<br />
Results: Sufficient information was available to determine both the relative and<br />
absolute ESH in 141 <strong>of</strong> the 203 included trials (69%), only the relative ESH in 53<br />
(26%), only the absolute ESH in 0, and neither relative nor absolute ESH in 9 (4%). The<br />
2014 ASCO recommendation that phase 3 trials should be designed with a HR ≤ 0.8<br />
was met by the majority <strong>of</strong> trials (98/102, 96%) with a primary outcome <strong>of</strong> overall<br />
survival. The majority <strong>of</strong> these phase 3 trials had hypothesized effect sizes that were<br />
judged to reflect modest clinical benefits by both frameworks: ESMO 169/203 trials,<br />
83% and ASCO 152/203 trials, 75% (see table).<br />
Background: There are two sets <strong>of</strong> criteria using PET to monitor metabolic changes to<br />
anti-cancer treatment: the criteria developed by the European Organization for<br />
Research and Treatment <strong>of</strong> Cancer (EORTC criteria) and the PET Response Criteria in<br />
Solid Tumors (PERCIST). We conducted this pooled study to investigate the strength<br />
<strong>of</strong> agreement between the EORTC criteria and PERCIST in the assessment <strong>of</strong> tumor<br />
response.<br />
Methods: We searched for all relevant studies written in English through the following<br />
searching strategy. A systematic literature search <strong>of</strong> MEDLINE, PUBMED, and<br />
EMBASE from 2009 when the PERCIST criteria were proposed to January 2016 was<br />
carried out to find articles including the following terms in their title, abstract, or key<br />
words; ‘tumor response’, ‘EORTC criteria’,or‘PERCIST.’ We used the ‘related articles’<br />
feature <strong>of</strong> the PUBMED to identify the related articles. Articles were considered for<br />
inclusion in this pooled study if they compared tumor responses by the EORTC criteria<br />
and PERCIST.<br />
Results: There were six articles with the data on the comparison <strong>of</strong> the EORTC criteria<br />
and PERCIST. A total <strong>of</strong> 348 patients were collected; 190 (54.6%) with breast cancer, 81<br />
with colorectal cancer, 45 with lung cancer, 14 with basal cell carcinoma in the skin, 12<br />
with stomach cancer, and 6 with head and neck cancer. The agreement <strong>of</strong> tumor<br />
response between the EORTC criteria and PERCIST was excellent (k = 0.946). Of 348<br />
patients, only 12 (3.4%) showed disagreement between two criteria in the assessment <strong>of</strong><br />
tumor response. The shift <strong>of</strong> tumor response between two criteria occurred mostly in<br />
patients with PMR and SMD. The estimated overall response rates were not<br />
significantly different between two criteria (72.7% byEORTC vs. 73.6% by PERCIST).<br />
Conclusions: In conclusion, this pooled study demonstrates that the EORTC criteria<br />
and PERCIST showed almost perfect concordance in the assessment <strong>of</strong> tumor response<br />
in patients with solid tumors. However, it is still necessary to investigate potential<br />
differences between the two criteria in studies with larger homogeneous patients’<br />
cohort to elucidate if the criteria can be used interchangeably in clinical practice.<br />
© European Society for Medical <strong>Oncology</strong> 2016. Published by Oxford University Press on behalf <strong>of</strong> the European Society for Medical <strong>Oncology</strong>.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com.
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Legal entity responsible for the study: N/A<br />
Funding: Hallym Medical Center<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
319P<br />
Selective registration <strong>of</strong> non-primary endpoints in randomized<br />
clinical trials in oncology: a comparison <strong>of</strong> endpoint reporting<br />
between clinical trial protocols and US national clinical trial<br />
registration<br />
V. Serpas 1 , D. Halperin 2 , K. Raghav 2 , M.J. Overman 2<br />
1 Internal Medicine Residency, MD Anderson Cancer Center, Houston, TX, USA,<br />
2 Gastrointestinal Medical <strong>Oncology</strong>, MD Anderson Cancer Center, Houston, TX,<br />
USA<br />
Background: Randomized clinical trials represent the cornerstone <strong>of</strong> evidence-based<br />
medicine. Despite the implementation <strong>of</strong> clinical trial registration, the completeness <strong>of</strong><br />
such reporting has not been well studied.<br />
Methods: We analyzed oncology-based randomized clinical trials (RCTs) conducted in<br />
2012 in the Journal <strong>of</strong> Clinical <strong>Oncology</strong>, New England Journal <strong>of</strong> Medicine, and The<br />
Lancet. The primary endpoints and non-primary endpoints from each clinical trial<br />
protocol (a required supplement for publication in these journals) and the<br />
corresponding listing on the US national clinical trial registry (clinicaltrials.gov) were<br />
collected. Secondary, exploratory, correlative, and translational end points were<br />
considered non-primary end points. Registry/protocol discrepancies were then<br />
quantitatively and qualitatively evaluated.<br />
Results: Out <strong>of</strong> the 58 RCTs, primary endpoint registry/protocol discrepancies<br />
occurred in only 2 trials (3%). However, registry/protocol discrepancies in<br />
non-primary endpoints occurred in 46 trials (79%). Of these 46 trials, 39 (85%) had<br />
non-primary endpoints found in the protocol but not in the registry. Of these 39 trials,<br />
10 discrepancies related to exploratory or translational endpoints missing from the<br />
registry, and 6 related to the endpoint <strong>of</strong> safety missing from the registry. Of the 46<br />
trials with non-primary endpoint registry/protocol discrepancies, 20 (43%) had<br />
non-primary endpoints found in the registry that were not found in the protocol. 18 <strong>of</strong><br />
these 20 trials had de novo endpoints not listed anywhere in the protocol and 2 had<br />
endpoints listed in the protocol but not within the respective objective/endpoint<br />
section. Registry/protocol discrepancies regarding time-to-event endpoints occurred in<br />
12 trials (21%), with 10 related to omission <strong>of</strong> such endpoints from the registry.<br />
Conclusions: The clinical trial registry is intended to serve as a transparent public<br />
database <strong>of</strong> clinical trials. However, according to our research, the majority <strong>of</strong> RCTs in<br />
high-impact journals demonstrate registry/protocol discrepancies in the listing <strong>of</strong><br />
non-primary endpoints.<br />
Legal entity responsible for the study: Victoria Serpas<br />
Funding: MD Anderson Cancer Center<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
320P<br />
Systematic review <strong>of</strong> adverse events reporting in clinical trials<br />
leading to approval <strong>of</strong> targeted therapy and immunotherapy<br />
P. Bossi 1 , L. Botta 2 , P. Bironzo 3 , C. Sonetto 3 , G. Musettini 4 , A. Sbrana 4 ,V.Di<br />
Giannantonio 1 , L. Locati 1 , M. Di Maio 5 , A. Antonuzzo 4<br />
1 Head & Neck Unit, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy,<br />
2 Evaluative Epidemiology, Preventive and Predictive Medicine, Fondazione IRCCS<br />
- Istituto Nazionale dei Tumori, Milan, Italy, 3 Medical <strong>Oncology</strong>, Azienda<br />
Ospedaliero-Universitaria ASOU San Luigi Gonzaga, Orbassano, Italy, 4 Medical<br />
<strong>Oncology</strong>, Azienda Ospedaliera Universitaria S.Chiara, Pisa, Italy, 5 Medical<br />
<strong>Oncology</strong>, Università di Torino, Ospedale Mauriziano, Turin, Italy<br />
Background: Reporting toxicities <strong>of</strong> targeted therapies (TTs) and immunotherapy in<br />
oncology requires care in respect to way <strong>of</strong> measurement, duration <strong>of</strong> adverse events<br />
(AEs) and impact on treatment dose intensity.New drugs are approved by regulatory<br />
agencies on the basis <strong>of</strong> the safety and efficacy results deriving from pivotal trials, but<br />
the impact on broader use is <strong>of</strong>ten misunderstood.<br />
Methods: We identified the TTs and immunotherapies approved by FDA for solid<br />
malignancies in adult patients from 2000 to Oct 2015. The trials which led to this<br />
indication were retrieved from the FDA website.Publications were reviewed according<br />
to a 24-point score based on the Consolidated Standards <strong>of</strong> Reporting Trials<br />
(CONSORT) guidance.<br />
Results: We identified 81 trials, mainly performed in colorectal, lung, breast cancer and<br />
melanoma, globally involving more than 45.000 patients. The experimental drug was<br />
studied as single agent in 51% <strong>of</strong> the cases and associated with chemotherapy in 32%;<br />
setting <strong>of</strong> trials was mainly the treatment <strong>of</strong> advanced disease (95% <strong>of</strong> the trials).When<br />
specified, the median rate <strong>of</strong> elderly population (> 65 years) who were treated was 37%.<br />
The items that reported the higher proportion <strong>of</strong> trials with a low score in AEs<br />
description are the following: reporting recurrent and late toxicities and duration <strong>of</strong> the<br />
AEs (in more than 90% <strong>of</strong> the trials); description <strong>of</strong> time <strong>of</strong> occurrence (86% <strong>of</strong> the<br />
trials) and indication <strong>of</strong> all AEs, instead <strong>of</strong> only those occurred with a frequency above<br />
a fixed threshold (75% <strong>of</strong> the trials) Limitations in methods for presenting AEs, in<br />
description <strong>of</strong> the toxicities leading to therapy withdrawal and in follow up interval<br />
assessment were present in more than 50% <strong>of</strong> the analysed papers. Dose reductions due<br />
to AEs were not reported in 1 out <strong>of</strong> 3 trials.<br />
Conclusions: Suboptimal reporting <strong>of</strong> AEs in trials leading to approval <strong>of</strong> TTs and<br />
immunotherapy was shown. Improving AEs caption and description should be a<br />
priority in ongoing trials as well as post-marketing safety analysis. This is particularly<br />
true for AEs <strong>of</strong> new drugs, frequently mild or moderate in severity but potentially<br />
longer in duration and recurrent, with a clear impact on patients’ quality <strong>of</strong> life.<br />
Legal entity responsible for the study: Fondazione IRCCS Istituto Nazionale Tumori,<br />
Milan, Italy<br />
Funding: None<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
321P<br />
The new European Clinical Trial Regulation: Perception and<br />
expectations in Italy<br />
C. Cagnazzo 1 , S. Campora 2 , F. Arizio 3 , E. Marchesi 4<br />
1 Oncologia Medica 1, Istituto di Candiolo-IRCCS-Fondazione Piemontese per la<br />
Ricerca sul Cancro-Onlus, Candiolo, Italy, 2 Medicina Nucleare, Ente Ospedaliero<br />
Ospedali Galliera, Genoa, Italy, 3 Oncologia Polmonare, Azienda<br />
Ospedaliero-Universitaria ASOU San Luigi Gonzaga, Orbassano, Italy, 4 Clinical<br />
Trial Unit, Italian Sarcoma Group, Bologna, Italy<br />
Background: In the last decade Europe has faced a sharp slowdown in Clinical<br />
Research (CR) mainly due to European Directive 2001/20/CE application.<br />
Consequently the European Commission enacted the EU Regulation 536/2014 (ER)<br />
that is expected to become effective only in 2018, due to delays in the portal<br />
development. To investigate the ER perception and knowledge <strong>of</strong> the Italian<br />
pr<strong>of</strong>essionals, two online surveys, addressed to Clinical Research Coordinators (CRCs)<br />
and Clinical Investigators (CIs), were conducted.<br />
Methods: Two anonymous web-based surveys, both consisting <strong>of</strong> 17 questions, have<br />
been used.<br />
Results: The 62.5% and 58.9% <strong>of</strong> the contacted CIs and CRCs respectively answered to<br />
the survey: 12% <strong>of</strong> the CIs have a fully knowledge <strong>of</strong> the incoming ER while many are<br />
only partially (64%) or not (24%) informed. 80.4% <strong>of</strong> CRCs demonstrate a complete<br />
knowledge and are already trained. Amongst the evaluated topics, the need <strong>of</strong> a<br />
Reporting Member State in the first stage <strong>of</strong> the evaluation process is considered as<br />
positive by 74% <strong>of</strong> the CIs and almost all (90%) believe that this procedure will reduce<br />
the approval time. With regards to newly imposed transparency standards, 86% <strong>of</strong> the<br />
CIs would welcome the publication <strong>of</strong> trial results, while 14% believes that this<br />
obligation should only apply to pr<strong>of</strong>it trials. Overall 70% <strong>of</strong> CIs state that staff site’s<br />
facilities already met all <strong>of</strong> the ER imposed qualification. The 50% <strong>of</strong> CIs foresee that<br />
the ER will promote independent CR while 42% supposes that it will essentially affect<br />
the pr<strong>of</strong>it trials. Even though 71.4% <strong>of</strong> CRCs do not have a definite opinion on ER,<br />
85.7% is convinced that it will have a direct impact on their job.<br />
Conclusions: The ER is a turning point for European CR: it is designed to ensure faster<br />
procedures, with positive effects both on timing and overall costs and it will require a<br />
rigorous methodology and an increased quality. The surveys highlighted different<br />
opinions among CIs and CRCs on Italian ability to rise to this challenge: while CIs<br />
believe that the centers already met the imposed requirements with only an initial<br />
period <strong>of</strong> transition, CRCs are less optimistic. This process will involve big efforts and<br />
resources, but the payback is the opportunity to be on board <strong>of</strong> innovative treatments<br />
for the Italian patients.<br />
Legal entity responsible for the study: Institute for Cancer Research and Treatment,<br />
Candiolo (TO) - Italy<br />
Funding: None<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
322P<br />
abstracts<br />
Re-treatments after gamma knife radiosurgery for metastatic<br />
brain disease<br />
D.M. Ten Berge 1 , Z. Sadik 2 , G.N. Beute 2 , S. Leenstra 2 , B. van der Pol 2 , J.H.<br />
B. Verheul 2 , P.E.J. Hanssens 3<br />
1 Radiology, St. Elisabeth Hospital, Tilburg, Netherlands, 2 Neurosurgery,<br />
St. Elisabeth Hospital, Tilburg, Netherlands, 3 Gamma Knife center Tilburg,<br />
St. Elisabeth Hospital, Tilburg, Netherlands<br />
Background: Gamma Knife radiosurgery (GKR) has become a first-line treatment<br />
option for brain metastases resulting in high local tumor control. As systemic therapies<br />
improve and survival prolongs, local recurrences and new brain metastases are more<br />
likely to occur following GKR, with may increase the need for secondary treatments. In<br />
this report we evaluated the number <strong>of</strong> patients receiving re-treatments, the timing and<br />
kind <strong>of</strong> re-treatments, as well as the survival after treatment <strong>of</strong> local recurrences and<br />
new brain metastases in a group <strong>of</strong> patients initially treated with GKR alone.<br />
Methods: We performed a retrospective analysis <strong>of</strong> 806 patients with histologically<br />
confirmed metastatic cancer, <strong>of</strong> all primary origins, who underwent GKR in our center<br />
between January 2009 and December 2014. All the brain metastases that were visible<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw366 | vi101
abstracts<br />
on the high resolution triple dosed gadolinium planning MR imaging (n = 2180) were<br />
treated. In all cases, a dose <strong>of</strong> 18-25 Gy was prescribed to the isodose covering 99-100%<br />
<strong>of</strong> the tumor volume. All patients had a Karn<strong>of</strong>ski index ≥70 and had no prior<br />
treatment to the brain.<br />
Results: A median survival <strong>of</strong> 6 months (95%CI: 5.3-6.7) was found in the studied<br />
population (n = 806; 51% male; mean age 63 years). Per patient a median <strong>of</strong> two brain<br />
metastases were treated at first GKR (Range 1-15). Retreatment was given to 289<br />
patients (36%) out <strong>of</strong> whom 69% received GKR as the second treatment, 14% received<br />
whole brain radiotherapy (WBRT), 12% underwent resection and 5% received other<br />
re-treatments. Patients receiving re-treatment had a median survival <strong>of</strong> 13 months<br />
(95%CI: 11.3-14.7) versus patients not receiving re-treatment with a median survival <strong>of</strong><br />
4 months (95%CI: 3.6-4.4). The median interval between the first GKR and the second<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
treatment was 6 months. Out <strong>of</strong> the deceased patients most died within the first 3<br />
months (35%). Most patients died due to their extracranial disease (61-66%).<br />
Conclusions: About one third <strong>of</strong> patients treated with GKR for brain metastases in our<br />
center received a secondary treatment to the brain along the course <strong>of</strong> their disease.<br />
Repeat GKR was given to the majority <strong>of</strong> these patients. Re-treatment <strong>of</strong> new brain<br />
metastases or local recurrence appeared to be an effective therapy as most patients died<br />
due to extracranial disease.<br />
Legal entity responsible for the study: Dr. Hannsens, Gamma Knife Center Tilburg<br />
Funding: Gamma knife center Tilburg<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
vi102 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong> 27 (Supplement 6): vi103–vi113, 2016<br />
doi:10.1093/annonc/mdw367<br />
CNS tumours<br />
323O<br />
Clinical risk or molecular risk: What matters in low grade<br />
gliomas? A study from the Gruppo Italiano Cooperativo di<br />
Neuro-Oncologia (GICNO)<br />
E. Franceschi 1 , D. De Biase 2 , A. Paccapelo 1 , M. Reni 3 , A. Mura 1 , G. Tallini 2 ,<br />
C. Bortolotti 4 , L. Volpin 5 , G. Marucci 6 , L. Cirillo 7 , A. Pession 2 , C. Ghimenton 8 ,<br />
R. Poggi 1 , S. Bartolini 1 , L. Albini Riccioli 7 , A. Tosoni 1 , C. Degli Esposti 9 ,<br />
D. Danieli 10 , G. Genestreti 1 , A.A. Brandes 1<br />
1 Medical <strong>Oncology</strong>, Bellaria - Maggiore Hospitals, Azienda USL - IRCCS Institute<br />
<strong>of</strong> Neurological Sciences, Bologna, Italy, 2 Department <strong>of</strong> Biomedical and<br />
NeuroMotor Sciences (DiBiNeM), Section <strong>of</strong> Pathology, M. Malpighi, Bellaria<br />
Hospital, University <strong>of</strong> Bologna, Bologna, Italy, 3 Medical <strong>Oncology</strong>, IRCCS San<br />
Raffaele, Milan, Italy, 4 Neurosurgery, IRCCS, Istituto delle Scienze Neurologiche di<br />
Bologna, Ospedale Bellaria, Bologna, Italy, 5 Department <strong>of</strong> Neuroscience and<br />
Neurosurgery, Ospedale San Bortolo, Vicenza, Italy, 6 Section <strong>of</strong> Pathology,<br />
M. Malpighi, Bellaria Hospital, Bologna, Italy, 7 IRCCS Institute <strong>of</strong> Neurological<br />
Sciences, Unit <strong>of</strong> Neuroradiology, Ospedale Bellaria, Bologna, Italy, 8 Pathology<br />
Department, Azienda Ospedaliera Universitaria Integrata Verona-"Borgo Trento",<br />
Verona, Italy, 9 Radiotherapy, Bellaria - Maggiore Hospitals, Azienda USL - IRCCS<br />
Institute <strong>of</strong> Neurological Sciences, Bologna, Italy, 10 Department <strong>of</strong> Pathology,<br />
Ospedale San Bortolo, Vicenza, Italy<br />
324O<br />
ANG1005, a novel peptide-paclitaxel conjugate crosses the<br />
BBB and shows activity in patients with recurrent CNS<br />
metastasis from breast cancer, results from a phase II clinical<br />
study<br />
S-C. Tang 1 , P. Kumthekar 2 , A.J. Brenner 3 , S. Kesari 4 , D. Piccioni 5 , C.K. Anders 6 ,<br />
J.A. Carillo 7 , P. Chalasani 8 , P. Kabos 9 , S.L. Puhalla 10 , A. Garcia 11 , K. Tkaczuk 12 ,<br />
M.S. Ahluwalia 13 , N. Lakhani 14 , N. Ibrahim 15<br />
1 Georgia Regents University Cancer Center, Augusta University, Augusta, GA,<br />
USA, 2 Neurology, Northwestern University, Chicago, IL, USA, 3 Hematology/<br />
<strong>Oncology</strong>, The University <strong>of</strong> Texas Health Science Center at San Antonio, San<br />
Antonio, TX, USA, 4 Neuro-<strong>Oncology</strong>, John Wayne Cancer Institute, Santa Monica,<br />
CA, USA, 5 Moores Cancer Center, University <strong>of</strong> California in San Diego, San<br />
Diego, CA, USA, 6 Division <strong>of</strong> Hematology <strong>Oncology</strong>, University <strong>of</strong> North Carolina -<br />
Chapel Hill, Chapel Hill, NC, USA, 7 Neuro-<strong>Oncology</strong>, UC Irvine School <strong>of</strong><br />
Medicine, Orange, CA, USA, 8 UACC North Campus Clinic, University <strong>of</strong> Arizona<br />
Cancer Center, Tucson, AZ, USA, 9 University <strong>of</strong> Colorado Cancer Center,<br />
University <strong>of</strong> Colorado Denver, Aurora, CO, USA, 10 Medicine, Magee-Womens<br />
Hospital <strong>of</strong> UPMC, Pittsburgh, PA, USA, 11 Division <strong>of</strong> Medical <strong>Oncology</strong>,<br />
University <strong>of</strong> Southern California Norris Comprehensive Cancer Center, Los<br />
Angeles, CA, USA, 12 Division <strong>of</strong> Medical <strong>Oncology</strong>, University <strong>of</strong> Maryland<br />
Greenebaum Cancer Center, Baltimore, MD, USA, 13 Cleveland Clinic Lerner<br />
College <strong>of</strong> Medicine, Cleveland Clinic, Cleveland, OH, USA, 14 Clinical Research,<br />
START Midwest/Cancer & Hematology Centers <strong>of</strong> Western Michigan, PC, Grand<br />
Rapids, MI, USA, 15 Breast Medical <strong>Oncology</strong>, MD Anderson Cancer Center,<br />
Houston, TX, USA<br />
abstracts<br />
© European Society for Medical <strong>Oncology</strong> 2016. Published by Oxford University Press on behalf <strong>of</strong> the European Society for Medical <strong>Oncology</strong>.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com.
abstracts<br />
325O<br />
Routine molecular subgrouping <strong>of</strong> medulloblastoma: Bridging<br />
the divide between research and the clinic using low-cost,<br />
mass spectrometry-based DNA methylomics<br />
E. Schwalbe 1 , D. Hicks 1 , G. Rafiee 1 , M. Bashton 1 , H. Gohlke 2 , A. Enshaei 1 ,<br />
S. Potluri 1 , J. Matthiesen 1 , M. Mather 1 , P. Taleongpong 1 , R. Chaston 3 , S. Crosier 1 ,<br />
A. Smith 1 , D. Williamson 1 , S. Bailey 1 , S. Clifford 1<br />
1 Paediatric Neuro<strong>Oncology</strong>, Northern Institute for Cancer Research University <strong>of</strong><br />
Newcastle, Newcastle Upon Tyne, UK, 2 Agena BioScience, Agena, Hamburg,<br />
Germany, 3 Genetic Diagnostics, NewGene, Newcastle Upon Tyne, UK<br />
326PD<br />
Efficacy <strong>of</strong> a novel antibody-drug conjugate (ADC), ABT-414,<br />
with temozolomide (TMZ) in recurrent glioblastoma (rGBM)<br />
A.B. Lassman 1 , M. van den Bent 2 , H.K. Gan 3 , D.A. Reardon 4 , P. Kumthekar 5 ,<br />
N. Butowski 6 , Z. Lwin 7 , T. Mikkelsen 8 , L.B. Nabors 9 , K.P. Papadopoulos 10 ,<br />
M. Penas-Prado 11 , J. Simes 12 , H. Wheeler 13 , E. Gomez 14 , H-J. Lee 14 ,<br />
L. Roberts-Rapp 14 , H. Xiong 14 , E. Bain 14 , K. Holen 14 , R. Merrell 15<br />
1 Department <strong>of</strong> Neurology & Herbert Irving Comprehensive Cancer Center,<br />
Columbia University, New York, NY, USA, 2 Department <strong>of</strong> Neuro-<strong>Oncology</strong>,<br />
Erasmus MC Cancer Institute, Rotterdam, Netherlands, 3 Department <strong>of</strong> Medical<br />
<strong>Oncology</strong>, Austin Health and Olivia Newton-John Cancer Research Institute,<br />
Melbourne, Australia, 4 Center for Neuro-<strong>Oncology</strong>, Dana-Farber Cancer Institute,<br />
Boston, MA, USA, 5 Department <strong>of</strong> Neurology, Northwestern University, Chicago,<br />
IL, USA, 6 Department <strong>of</strong> Neurological Surgery, University <strong>of</strong> California<br />
San Francisco, San Francisco, CA, USA, 7 Department <strong>of</strong> Medical <strong>Oncology</strong>,<br />
University <strong>of</strong> Queensland School <strong>of</strong> Medicine, Brisbane, Australia, 8 Neurosurgery<br />
and Neuroscience Research, Henry Ford Health System, Detroit, MI, USA,<br />
9 Department <strong>of</strong> Neurobiology, University <strong>of</strong> Alabama at Birmingham, Birmingham,<br />
AL, USA, 10 Department <strong>of</strong> Clinical Research, South Texas Accelerated Research<br />
Therapeutics (START), San Antonio, TX, USA, 11 Department <strong>of</strong> Neuro-<strong>Oncology</strong>,<br />
MD Anderson Cancer Center, Houston, TX, USA, 12 NHMRC Clinical Trials Centre,<br />
University <strong>of</strong> Sydney, Sydney, Australia, 13 Medical <strong>Oncology</strong>, Royal North Shore<br />
Hospital, Sydney, Australia, 14 Global Pharmaceutical R&D, AbbVie, North<br />
Chicago, IL, USA, 15 Department <strong>of</strong> Neurology, NorthShore University<br />
HealthSystem, Evanston, IL, USA<br />
Background: ABT-414 is a first-in-class ADC that selectively targets EGFR<br />
amplification (amp) to deliver a potent microtubule cytotoxin (monomethyl auristatin<br />
F) inside the tumor cells. Almost 50% <strong>of</strong> GBMs harbor EGFR amp. ABT-414<br />
monotherapy has shown preliminary efficacy in EGFR amp rGBM. Here we report<br />
safety and efficacy <strong>of</strong> ABT-414 + TMZ in EGFR amp rGBM at the recommended phase<br />
2 dose.<br />
Methods: Adults with rGBM harboring centrally-confirmed EGFR amp, adequate<br />
end-organ function, and KPS >70 were eligible. To isolate the effects <strong>of</strong> ABT-414 from<br />
TMZ, all patients (pt)s were TMZ refractory, defined as a recurrent/progressive disease<br />
3<br />
(n = 1) prior therapies. The most common adverse events (AE)s (≥25% pts) were<br />
blurred vision (53%), photophobia (34%), headache (34%), fatigue (31%) and<br />
constipation (25%). Grade 3/4 AEs included (>1 pt) keratitis (16%), ataxia, decreased<br />
platelet count, hemiparesis and thrombocytopenia (6% each). Seizure was the most<br />
common serious AE, occurring in 13% pts. Neurologic AEs were generally attributed to<br />
the underlying tumor. No dose-limiting toxicities were observed. Best radiographic<br />
responses in 31 pts with available imaging data were: 3 (10%) partial responses (PR), 18<br />
(58%) stable disease (SD), and 10 (32%) progressive disease (PD). Pts with PD were<br />
allowed a repeat resection as clinically indicated. Four <strong>of</strong> them were found to have all or<br />
mainly treatment effect rather than active recurrence on histologic analysis; the<br />
progression-free survival (PFS), response, and 6 month-PFS rates will be updated after<br />
clarifying their outcomes.<br />
Conclusions: In this TMZ refractory population, ABT-414 demonstrated 10% PR and<br />
58% SD rates, although histology <strong>of</strong> tissue resected for presumed recurrence remains to<br />
be clarified, which may increase rate <strong>of</strong> disease control. No new safety events were<br />
observed and ocular toxicity was the most common AE. A global, randomized trial <strong>of</strong><br />
ABT-414 alone or with TMZ, vs. TMZ or lomustine, is underway in rGBM<br />
(NCT02343406).<br />
Clinical trial identification: NCT01800695<br />
Legal entity responsible for the study: AbbVie, Inc.<br />
Funding: AbbVie, Inc.<br />
Disclosure: A.B. Lassman: Comp./Res.Support:VBI Vaccines, SapienceTh.,<br />
CorticeBioSci., Oxigene, prIMEOnc., AbbVie, Genentech, Regeneron, Amgen,<br />
Novartis, Karyopharm, Celldex, NWBiotherapeutics, Plexxicon, Pfizer, Agenus,<br />
Medimmune, BoehringerIngelheim, Angiochem, Novocure, Stemline, E-Th.,<br />
Millennium. M. van den Bent: Received honoraria from Roche, Abbvie, Celldex,<br />
Novocure, Merck Ag, Cavion, Actelion, BMS, Blue Earth Diagnostics; received research<br />
funding from AbbVie and Roche. H.K. Gan: Has an investigator-initiated study with<br />
AbbVie; received travel support and research funding from AbbVie; received honoraria<br />
from AbbVie, Pfizer and Merck Serono; affiliated with the Ludwig Institute for Cancer<br />
Research. D.A. Reardon: Received honoraria/consulting/advisory role: Abbvie, BMS,<br />
Cavion, Celldex, Inovio, Merck, Novartis, Roche/Genentech, Amgen, Novocure,<br />
Oxigene, Regeneron, Stemline Therapeutics; speakers’ bureau: Roche, Merck; research<br />
funding: Incyte, Midatech, Celldex. P. Kumthekar: Received Honoraria for advisory<br />
role with AbbVie within the last 12 months. N. Butowski: Received honoraria from and<br />
has a consulting or advisory role with, Roche/Genentech, Medicenna, VBL<br />
Therapeutics, Omniox, Celldex; is involved in speakers’ bureaus with Roche and<br />
Merck; received research funding Insys. L.B. Nabors: Serve on a Scientific Advisory<br />
Board for Cavion. K.P. Papadopoulos: Received research funding from AbbVie,<br />
MedImmune, Daiichi Sankyo, GlaxoSmithKline, Onyx, San<strong>of</strong>i, Novartis. J. Simes:<br />
Employed at an institute that received funding for the trial; also received co‐funding for<br />
an investigator‐initiated trial from AbbVie. E. Gomez, H-J. Lee, L. Roberts-Rapp,<br />
H. Xiong, E. Bain, K. Holen: Employed by AbbVie and may own AbbVie<br />
stock. R. Merrell: Advisory Board for AbbVie. All other authors have declared no<br />
conflicts <strong>of</strong> interest.<br />
327PD<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
PD-L1 and IL17 expression in tumor infiltrating lymphocytes<br />
are opposite prognostic factors in glioblastoma<br />
E. Bronsart 1 , V. Derangere 2 , M. Boone 1 , B. Chauffert 1 , F. Ghiringhelli 2<br />
1 Oncologie, CHU Amiens-Picardie Site Nord, Amiens, France, 2 Oncologie, Centre<br />
Georges-François Leclerc (Dijon), Dijon, France<br />
Background: Glioblastoma (GB) is the most frequent malignant primary brain tumor.<br />
Median overall survival (OS) is only 15 months despite recent progress with the<br />
association <strong>of</strong> temozolomide and radiotherapy. Tumor infiltrating lymphocytes (TIL)<br />
are present in GB stroma but their influence on prognosis is not clearly defined. The<br />
purpose <strong>of</strong> this retrospective study was to explore the prognostic value in GB <strong>of</strong> tumor<br />
infiltration by IL17 (interleukin 17), CD45 and PD-L1 (programmed death ligand 1)<br />
expressing lymphocytes.<br />
Methods: All included patients had surgery followed by radiotherapy and<br />
temozolomide (Stupp’s regimen). IL-17, CD45 and PD-L1 were assessed by<br />
immunohistochemistry in a cohort <strong>of</strong> 77 GBM. Number <strong>of</strong> positive cells were count in<br />
a X40 field. We used the s<strong>of</strong>tware cut<strong>of</strong>f finder to determine the optimal cut <strong>of</strong>f to<br />
separate patients with high or low infiltrate. Logrank analysis and Cox proportional<br />
hazard models were used to determine overall survival factors in function <strong>of</strong> type and<br />
number <strong>of</strong> TIL.<br />
Results: In univariate analysis, high number <strong>of</strong> IL17 expressing cells was correlated<br />
with poor OS (HR = 1.7 IC[1.1-1.19]p = 0.03). High PD-L1 infiltration was correlated<br />
with a better prognosis (OS : 15.3 months if PD-L1 1%;<br />
p = 0.05). IN contrast CD45 is no associated with outcome. In multivariate analysis,<br />
high PD-L1 infiltration remain independent factor was associated with a better survival<br />
(HR = 0.4 IC95 [0.2-0.8] p = 0.016) and high IL17 infiltration <strong>of</strong> poor survival (<br />
HR = 2.6 IC95 [1.4-5.3] p = 0.03).<br />
vi104 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Conclusions: This study underline that PDL1 infiltrate and IL-17 are associated with<br />
outcome in a cohort <strong>of</strong> 77 patients with GBM that received an optimal treatment with<br />
surgery and radiochemotherapy. Such data support rational to test PD-L1 and IL17<br />
targeted immunotherapy in GBM.<br />
Legal entity responsible for the study: Centre Georges Francçois Leclerc, Dijon, CHU<br />
Amiens<br />
Funding: CHU Amiens<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
328PD<br />
Effectiveness <strong>of</strong> antiangiogenic drugs (ADs) in glioblastoma<br />
(GBM) patients (PTS): a metanalysis <strong>of</strong> randomized clinical<br />
trials (RCTs)<br />
G. Lombardi, L. Bellu, A. Pambuku, V. Zagonel<br />
U.O.C. Oncologia Medica 1, Veneto Institute <strong>of</strong> <strong>Oncology</strong>- IRCCS, Padua, Italy<br />
Background: GBMs are highly vascularized tumors and various ADs have been<br />
investigated in clinical trials showing unclear results. We performed this metanalysis to<br />
evaluate the effectiveness <strong>of</strong> ADs, in terms <strong>of</strong> progression-free survival (PFS) and<br />
overall survival (OS), as first or second-line therapy and their association with<br />
chemotherapy in GBM PTS.<br />
Methods: The authors searched relevant published and unpublished RCTs analyzing<br />
ADs versus chemotherapy in GBM PTS from 2000 to January 2016 in MEDLINE,<br />
WEB <strong>of</strong> SCIENCE, ASCO, ESMO and SNO databases.<br />
Results: Sixteen RCTs (9 with bevacizumab, 2 cilengitide, 1 enzastaurin, 1 dasatinib, 1<br />
vandetanib, 1 temsirolimus, 1 cediranib) were identified including 4566 PTS. All trials<br />
showed no improvement in OS with a pooled HR <strong>of</strong> 1.02 (95% CI 0.93-1.1; p = 0.7).<br />
The use <strong>of</strong> bevacizumab (BEV) did not improve OS; indeed, the pooled HR for OS for<br />
BEV studies (9 studies, 2752 PTS) was 0.98 (95% CI 0.89-1.08; p = 0.7); 6 RCTs (2084<br />
PTS) analyzed BEV as first-line and the pooled HR for OS was 1.02 (95% CI 0.88-1.19;<br />
p = 0.8); 3 RCTs studied BEV as second-line therapy and the pooled HR for OS was<br />
0.95 (95% CI 0.77-1.17; p = 0.6). No improvement <strong>of</strong> OS was shown when BEV was<br />
associated with chemotherapy (2588 PTS) with a pooled HR <strong>of</strong> 0.99 (95% CI 0.88-1.11;<br />
p = 0.8). Seven RCTs with a different AD demonstrating no improvement <strong>of</strong> OS versus<br />
standard treatment with a pooled HR <strong>of</strong> 1.05 (95% CI 0.89-1.23; p = 0.5). 14 RCTs<br />
(4349 PTS) were analyzed for PFS and the use <strong>of</strong> ADs showed a statistically longer PFS<br />
with a pooled HR <strong>of</strong> 0.73 (95% CI 0.62-0.86;p < 0.01); However, among ADs, only<br />
bevacizumab (2752 PTS) demonstrated an improvement <strong>of</strong> PFS; indeed, the pooled HR<br />
for PFS for BEV studies was significant at HR = 0.6 (95% CI 0.5-0.7; p < 0.01), both<br />
alone (HR = 0.6; CI 95% 0.44-0.82; p < 0.01) or in combination to CT (HR = 0.6; 95%<br />
CI 0.4-0.7;p < 0.01), both as first-line treatment (HR = 0.65; 95% CI 0.52-0.83; p < 0.01)<br />
or in recurrent disease (HR = 0.51; 95% CI 0.43-0.61; p < 0.01).<br />
Conclusions: ADs did not improve OS in GBM PTS, both as first or second-line<br />
treatment. Among ADs, only BEV demonstrated a PFS benefit both as single agent or<br />
in combination with chemotherapy, both as first or second-line treatment.<br />
Legal entity responsible for the study: IOV<br />
Funding: None<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
329PD<br />
Survival <strong>of</strong> patients with synchronous and metachronous<br />
breast cancer and meningioma<br />
C.G. Ribeiro 1 , L. Mascarenhas 2 , J.P. Lavrador 3 , A. Peralta 4 , M. Valente 5<br />
1 Dept. <strong>of</strong> <strong>Oncology</strong>, Centro Hospitalar Lisboa Central-CHLC-Hospital São Jose,<br />
Lisbon, Portugal, 2 Pathology, Centro Hospitalar Lisboa Central-CHLC-Hospital<br />
São Jose, Lisbon, Portugal, 3 Neurosurgery, Centro Hospitalar Lisboa Norte -<br />
Hospital Sta Maria (HSM-CHLN), Lisbon, Portugal, 4 Public Health, Public Health,<br />
Lisbon, Portugal, 5 Pediatrics, John Radcliffe Hospital University <strong>of</strong> Oxford, Oxford,<br />
UK<br />
Background: The prognostic relevance <strong>of</strong> the association between Breast Cancer (BC)<br />
and Meningioma (M) is still unknown. Therefore, our aim was to evaluate the survival<br />
impact <strong>of</strong> tumor exposure sequence - synchronous or metachronous - in patients with<br />
these tumors.<br />
Methods: Patients were divided in three groups according to the exposurevariable –<br />
sequence <strong>of</strong> tumors: M before BC (M → BC), synchronous BC and M (BC + M) and BC<br />
before M (BC → M). Only patients exclusively with both these tumors were included.<br />
The SEER database was used. Demographic variables, meningioma variables (site, grade<br />
and treatment) and breast cancer variables (grade, stage, hormonal receptor status and<br />
treatment) were collected and the primary outcome was oncological survival.<br />
Results: A total <strong>of</strong> 1715 patients were followed for a median follow-up <strong>of</strong> 84 months.<br />
The BC + M group had the shortest survival (median <strong>of</strong> 32 months) and BC → M the<br />
longest (median <strong>of</strong> 110 months). The unadjusted analysis revealed BC + M group as<br />
statistically related to the shortest survival (HR 3.13, 95%[CI] [1.62-6.04]). The<br />
adjusted analysis confirmed that the BC + M group as the one with worst prognosis<br />
(HR 3.11, 95%[CI] [1.58-6.19]), with no statistical difference between the<br />
metachronous tumors . Increasing age (HR:1.13, 95%CI: 1.11-1.15, p < 0.005) and<br />
grade III meningioma (HR:4.51, 95%CI:1.90-10.69, p0.05) and breast<br />
cancer…Grade III meningioma and receptor hormonal status influenced synchronous<br />
tumors(p > 0.05) but have no influence on metachronous tumors survival (p < 0.05) on<br />
stratified analysis.<br />
Conclusions: Synchronous BC and M were associated with lower survival, when<br />
compared with metachronous tumors. Increasing age had a negative influence on<br />
patients’ survival. Grade III meningioma and hormonal receptor status only influenced<br />
synchronous tumors oncological survival.<br />
Legal entity responsible for the study: Clinical Scholars Research Training Program,<br />
Harvard Medical School Portugal<br />
Funding: None<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
330PD<br />
Temporal muscle thickness (TMT) is an independent<br />
prognostic parameter in patients with newly diagnosed brain<br />
metastases (BM) <strong>of</strong> breast cancer (BC)<br />
A.S. Bergh<strong>of</strong>f 1 , J. Furtner 2 , G. Widhalm 3 , B. Gatterbauer 3 , U. Dieckmann 4 ,<br />
P. Birner 5 , R. Bartsch 1 , C. Zielinski 1 , V. Schöpf 6 , M. Preusser 1<br />
1 Department <strong>of</strong> Medicine1, Medizinische Universitaet Wien (Medical University <strong>of</strong><br />
Vienna), Vienna, Austria, 2 Department <strong>of</strong> Biomedical Imaging and Image-guided<br />
Therapy, Medizinische Universitaet Wien (Medical University <strong>of</strong> Vienna), Vienna,<br />
Austria, 3 Department <strong>of</strong> Neurosurgery, Medizinische Universitaet Wien (Medical<br />
University <strong>of</strong> Vienna), Vienna, Austria, 4 Department <strong>of</strong> Radiotherapy, Medizinische<br />
Universitaet Wien (Medical University <strong>of</strong> Vienna), Vienna, Austria, 5 Department <strong>of</strong><br />
Pathology, Medizinische Universitaet Wien (Medical University <strong>of</strong> Vienna), Vienna,<br />
Austria, 6 Institute <strong>of</strong> Psychology, Medical University Graz, Graz, Austria<br />
Background: Sarcopenia has been described as objectively measurable parameter<br />
indicating frailty and adverse prognosis in several cancer types. We thus hypothesized<br />
that TMT may serve as surrogate marker <strong>of</strong> frailty.<br />
Methods: 189 BC patients (luminal A: 45/189 (23.8%); HER2: 75/189 (39.7%); triple<br />
negative: 35/189 (18.5%); unknown subtype: 34/189 (18.0%), all female with a median<br />
age <strong>of</strong> 54 years (range 30-85) and newly diagnosed BM were identified from a BM<br />
database. Clinical characteristics including survival times were retrieved from chart<br />
review. Diagnosis specific graded prognostic assessment (DS-GPA) was calculated<br />
based on clinical characteristics. Baseline TMT at diagnosis <strong>of</strong> BM was measured in<br />
MRI (axial plane <strong>of</strong> isovoxel (1x1x1mm), T1 – weighted images) at diagnosis <strong>of</strong> BM.<br />
Results: Median TMT was 5.4 mm (range 1.65 – 10.50 mm) and showed no<br />
correlation with age (correlation coefficient -0.341; p < 0.001 or Karn<strong>of</strong>sky<br />
performance status (correlation coefficient 0.213; p = 0.003), as well as no difference in<br />
dependence <strong>of</strong> cortisone treatment (p = 0.994) at BM diagnosis. Survival analysis using<br />
a Cox regression model was performed using baseline TMT diameters to predict<br />
survival time (HR 0.810; 95% CI 0.735-0.892; p < 0.001). Patients with a higher<br />
baseline TMT presented with an improved survival prognosis. In detail, risk <strong>of</strong> death<br />
was reduced by 19% with every additional millimeter <strong>of</strong> baseline TMT. Further analysis<br />
was performed by the means <strong>of</strong> a Cox regression model including TMT and DS-GPA<br />
as covariates (TMT: HR 0.790; 96% CI 0.703-0.889; p < 0.001; DS-GPA: HR 1.426; 95%<br />
CI 1.154-1.762; p = 0.001). In the multivariate model TMT prediction <strong>of</strong> survival was<br />
nearly unchanged with a reduced risk <strong>of</strong> death <strong>of</strong> 21 % with every additional millimeter<br />
<strong>of</strong> baseline TMT.<br />
Conclusions: TMT, which can serve as a surrogate parameter <strong>of</strong> sarcopenia, is an<br />
independent predictor <strong>of</strong> survival in patients with newly diagnosed BC BM. TMT is<br />
easily and reproducibly assessable in routine MR images and may help to better define<br />
frail patient populations and may thus facilitate patient management by supporting<br />
patient selection for therapeutic measures or clinical trials.<br />
Legal entity responsible for the study: Medical University <strong>of</strong> Vienna<br />
Funding: Medical University <strong>of</strong> Vienna<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
331PD<br />
abstracts<br />
Phase I/II study <strong>of</strong> single agent ibrutinib in recurrent/<br />
refractory primary (PCNSL) and secondary CNS lymphoma<br />
(SCNSL)<br />
C. Grommes, I. Gavrilovic, T. Kaley, C. Nolan, A. Omuro, J. Wolfe, E. Pentsova,<br />
V. Hatzoglou, I.K. Mellingh<strong>of</strong>f, L. Deangelis<br />
Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, USA<br />
Background: PCNSL is an aggressive primary brain tumor. Outcome and treatment<br />
options are poor for recurrent/refractory (r/r) disease. Response rates (ORR) range<br />
between 30-60% with a progression free survival (PFS) <strong>of</strong> 2-5 months. Ibrutinib has<br />
shown promising clinical response in some B-cell malignancies. This trial investigates<br />
Ibrutinib in patients with r/r PCNSL and SCNSL.<br />
Methods: Eligible patients had r/r PCNSL or SCNSL, age ≥ 18, ECOG ≤ 2, normal<br />
end-organ function, and unrestricted number <strong>of</strong> CNS directed prior therapies. In<br />
patients with SCNSL disease, systemic disease needed to be absent.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw367 | vi105
abstracts<br />
Results: Twenty patients were enrolled (3 at 560 mg; 17 at 840 mg). Median age was 69<br />
(range 21-85); 12 were women. Median ECOG was 1 (0: 2, 1: 12, 2: 6). 65% had PCNSL<br />
and 35% SCNSL; 70% had recurrent disease. Eleven had parenchymal disease, 3<br />
isolated cerebrospinal fluid (CSF) involvement and 6 both. The median prior CNS<br />
directed therapy was 2; all methotrexate regimens. Despite clinical and radiographic<br />
response, 2 patients withdrew and 1 stopped due to toxicity (fungal infection). Four<br />
grade 4 toxicities were observed in 4 patients (lymphopenia (2), sepsis (1), neutropenia<br />
(1)). Ten patients developed grade 3 toxicities, including lymphopenia in 3 patients,<br />
thrombocytopenia in 2, hyperglycemia in 2, lung infection in 2, neutropenia in 1,<br />
urinary tract infection in 1, colitis in 1, and fungal encephalitis in 1. The most common<br />
toxicities were hyperglycemia, anemia, and thrombocytopenia. After a median<br />
follow-up <strong>of</strong> 147 days, 16/20 patients were evaluated for response: 4 CR (3 in CSF; 1 in<br />
the parenchyma), 9 PR, and 3 PD; 65% (13/20) ORR. In 3 patients response has not<br />
been confirmed in a 2nd assessment. The median PFS is 5.5 months (longest: 13.2<br />
months). The mean Ibrutinib concentration in the CSF at day 1 and 29 was 1.75 ng/mL<br />
(3.97 nM) and 2.51 ng/mL (5.6 nM). The CSF Ibrutinib concentrations reached in<br />
patients is above the IC50 (1nM) required in vitro to reduce growth <strong>of</strong> lymphoma cells.<br />
Molecular testing is in process to associate genomic alterations and outcome.<br />
Conclusions: Patients with CNS lymphoma tolerate Ibrutinib with manageable<br />
toxicities. Ibrutinib might be a therapeutic alternative that should be further<br />
investigated in r/r CNS lymphoma patients.<br />
Clinical trial identification: NCT02315326<br />
Legal entity responsible for the study: Memorial Sloan Kettering Cancer Center<br />
Funding: Pharmacyclics<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
332P<br />
The pharmacokinetics <strong>of</strong> methotrexate with and without<br />
rituximab in the treatment <strong>of</strong> primary central nervous system<br />
lymphoma (PCNSL)<br />
F.R. Rawat 1 , A. Nolan 1 , S.Y. Teo 1 , M. Triggs 2 , G. Carroll 2 , S. Picardo 3 ,N.<br />
M. Keegan 3 , V. Mallett 3 , I. Ismail 3 , B. Hennessy 3 , W. Grogan 3 , O. Breathnach 3 ,<br />
P. Morris 3<br />
1 Department <strong>of</strong> Medical <strong>Oncology</strong>, Royal College <strong>of</strong> Surgeons in Ireland, Dublin,<br />
Ireland, 2 Department <strong>of</strong> Pharmacy and Cancer Clinical Trials and Research Unit,<br />
Beaumont Hospital, Dublin, Ireland, 3 Cancer Clinical Trials and Research Unit,<br />
Beaumont Hospital, Dublin, Ireland<br />
Background: PCNSL is a rare B-cell lymphoma. Most chemotherapy regimens are<br />
methotrexate (MTX) - based, but recently have included Rituximab (R). MTX<br />
pharmacokinetics (PKs) are highly variable and may correlate with patient (pt)<br />
outcome. However, the effect <strong>of</strong> R on MTX PKs has not been well characterised. We<br />
aimed to compare MTX PKs in pts treated with and without R.<br />
Methods: We conducted a retrospective study <strong>of</strong> the PCNSL database at the National<br />
Neuro-<strong>Oncology</strong> Centre in Dublin, Irleland. Pts received MTX (3.5g/m 2 )/<br />
Procarbazine/Vincristine (MTX group), or MTX/Procarbazine/<br />
Vincristine + Rituximab (R-MTX). From written and electronic medical records, the<br />
following data were collected: pt demographics, creatinine clearance (CrCl), MTX dose<br />
and MTX levels.<br />
Results: From 2010 to 2015, 24 pts (14 men, 10 women) with median age <strong>of</strong> 67 (range<br />
20-76) were included. Baseline characteristics were similar between pts who received<br />
R-MTX (n = 10) and MTX (n = 14); median (range) age 62 (20-73) vs. 68 (41-76),<br />
weight 82.5kg (61-133) vs. 78.5 (52-92.3), CrCl 123.3mls/min (53.2-214.1) vs. 108.3<br />
(46.5-227.5), total MTX dose g/m 2 7.0 (1.7-7.7) vs. 6.35 (5.3-7.1). In cycle 1, MTX<br />
clearance appeared to be prolonged in the R-MTX group (Table 1). Of note, mean<br />
MTX levels at 48hrs appeared similar in pts who received R-MTX (0.388) vs MTX<br />
(0.376). However, at 144hrs mean MTX levels appeared higher in pts who received<br />
R-MTX (0.147) vs. MTX (0.09). This difference in MTX levels was not apparent in<br />
subsequent cycles, possibly due to the confounding effects <strong>of</strong> MTX dose reductions;<br />
escalation in folinic acid and changes in CrCl. Correlation <strong>of</strong> MTX PKs with survival is<br />
ongoing. Table 1: Mean MTX Level Over Time<br />
Table: 332P<br />
Hours 48 72 96 120 144 168 192 216<br />
R-MTX 0.388 ± 0.56 0.115 ± 0.15 0.132 ± 0.12 0.167 ± 0.09 0.147 ± 0.1 0.113 ± 0.08 0.145 ± 0.11 0.105 ± 0.08<br />
MTX 0.376 ± 0.46 0.164 ± 0.25 0.126 ± 0.07 0.12 ± 0.07 0.09 ± 0.03 0.08 ± 0.03 0.06 ± 0 0.05 ± 0<br />
Values = mean ± SD.<br />
Conclusions: This retrospective study in this rare cancer suggests that R may prolong<br />
MTX clearance. This may have implications for optimum MTX dosing and prognosis.<br />
Legal entity responsible for the study: Cancer Clinical Trials and Research Unit,<br />
Beaumont Hospital, Dublin, Ireland.<br />
Funding: Cancer Clinical Trials and Research Unit, Beaumont Hospital, Dublin,<br />
Ireland.<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
333P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
IMRT and temozolomide for grade III glioma: Clinical and<br />
prognostic factors<br />
T. Basu, T. Kataria, S. Goyal, D. Gupta, A. Abhishek, S.S. Bisht<br />
Radiation <strong>Oncology</strong>, Medanta Cancer Institute, Medanta The Medicity, Gurgaon,<br />
India<br />
Background: To evaluate grade III gliomas treated in the era <strong>of</strong> IMRT and concurrent<br />
plus adjuvant Temozolomide (TMZ) with early clinical outcome and prognostic<br />
factors with quality <strong>of</strong> life.<br />
Methods: 53 patients with anaplastic oligodendroglioma(25), anaplastic astrocytoma<br />
(18) and anaplastic oligoastrocytoma(10) treated with IMRT and concurrent (95%)<br />
and adjuvant TMZ (90%) were analyzed. 1p19q co-deletion data was available for 13<br />
patients. 80% had KPS at least 90 with 30% seizure at presentation. Postoperative MRI<br />
was available in 65% cases and IMRT dose was 60 Gy in 30 fractions. First post<br />
treatment imaging was performed at 1 month and then at 3 months and 6 months post<br />
IMRT and then every 3 months. EORTC quality <strong>of</strong> life scale C35 and BN 20 was<br />
administered before starting IMRT, at completion and then at each follow up.<br />
Kaplan-Meier analysis was used to estimate disease free survival (DFS), overall survival<br />
(OS) and analysis was done using SPSS version 18.0<br />
Results: The median follow-up was 25 months with 2 year DFS and OS were 75% and<br />
88%. Patients tolerated treatment well with only 5% symptomatic CNS and 8%<br />
symptomatic hematological toxicities. 95% completed concurrent TMZ schedule. At 1 st<br />
evaluation, 30.4% had complete response, at 3 months 40% and at 6 months 43%. At 6<br />
months only 4 % had progressive disease. Llast follow up 46/53 patients were evaluable<br />
with 8 deaths and 55% having stable to complete response. On univariate analysis for<br />
DFS, KPS at presentation > 90 (p = 0.001) and response at 6 months (p = 0.02) were<br />
significant and for OS KPS at presentation (p = 0.004) alone. Gross total resection, no<br />
residual at postoperative MRI, upto 6 cycles <strong>of</strong> adjuvant TMZ, complete response at 6<br />
months were favorable in terms <strong>of</strong> both DFS and OS. Histopathological types were not<br />
significant for DFS and OS and only 3 patients were 1p19q co-deletion positive.<br />
Quality <strong>of</strong> life scales suggested decline in mood, cognition, fatigue and toilet control<br />
initially and improvement beyond 3 months. There were no significant late effects till<br />
last follow up.<br />
Conclusions: IIMRT with TMZ among grade III glioma patients resulted in minimum<br />
treatment related toxicities and better quality <strong>of</strong> life with encouraging results. Proper<br />
case selection with future molecular prognostic markers will determine most favorable<br />
groups.<br />
Legal entity responsible for the study: Medanta The Medicity, Gurgaon<br />
Funding: Medanta The Medicity, Gurgaon<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
334P Treatment outcome in medulloblastoma with the POG 9031<br />
protocol : a single institution review<br />
A. Philip 1 , V. Munirathnam 1 , K. Pavithran 1 , J. Wesley M 1 , D. Poorna 2 ,D.M 2 ,<br />
R. Pillai 1<br />
1 Medical <strong>Oncology</strong>, Amrita institute <strong>of</strong> medical sciences, Cochin, India, 2 Radiation<br />
<strong>Oncology</strong>, Amrita Instittue <strong>of</strong> Medical sciences, Cochin, India<br />
Background: The aim <strong>of</strong> the present study was to identify the various<br />
clinicopathological features and treatment outcome <strong>of</strong> cases <strong>of</strong> medulloblastoma who<br />
had received concurrent Chemoradiotherapy post operatively and treated as per the<br />
POG 9031 protocol at a tertiary care centre.<br />
Methods: Medical records were reviewed to identify patients <strong>of</strong> Medulloblastoma who<br />
were treated between January 2005 and January 2015 at our centre. Data was gathered<br />
on demographics, clinical presentation, tumor characteristics, chemotherapy &<br />
radiotherapy protocols, adverse events and survival. The Chang-Harisiadis system was<br />
used for staging. Patients were classified as either poor risk (T3b-4, M1 or > 1.5<br />
cm 2 residual tumor) or standard risk disease (T1-3a, M0 and
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Legal entity responsible for the study: Amrita Institute <strong>of</strong> Medical sciences<br />
Funding: Amrita Institute <strong>of</strong> Medical Sciences<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
335P<br />
Phase II study <strong>of</strong> single agent buparlisib in recurrent/<br />
refractory primary (PCNSL) and secondary CNS lymphoma<br />
(SCNSL)<br />
C. Grommes, E. Pentsova, C. Nolan, J. Wolfe, I.K. Mellingh<strong>of</strong>f, L. Deangelis<br />
Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, USA<br />
Background: PCNSL is an aggressive primary brain tumor. Outcome and treatment<br />
options are poor for patients with recurrent/refractory disease. Response rates range<br />
between 30-60% with a progression free survival (PFS) <strong>of</strong> 2-6 months. PI3K inhibition,<br />
particular <strong>of</strong> the delta is<strong>of</strong>orm, has shown promising clinical response in some B-cell<br />
malignancies. This phase II trial investigates the pan-PI3K inhibitor Buparlisib in<br />
patients with recurrent/refractory (r/r) PCNSL and SCNSL.<br />
Methods: Eligible patients had r/r PCNSL/SCNSL, age ≥ 18, KPS ≥ 50, normal<br />
end-organ function, and unrestricted number <strong>of</strong> prior therapies. In patients with<br />
SCNSL, systemic disease needed to be absent. Enrolled patients received Buparlisib<br />
100 mg daily. The trial was closed prematurely due to limited clinical response.<br />
Results: Four patients were enrolled at age 55, 60, 68, and 79 with a KPS <strong>of</strong> 90, 100, 90<br />
and 60, respectively. Three were men; 50% had PCNSL. All had parenchymal disease.<br />
Median prior CNS directed treatment was 2 (range 1-3); all methotrexate regimens.<br />
Two grade 4 toxicities (lymphopenia and neutropenia) were observed that resolved<br />
after drug was held. The most common toxicities observed were hyperglycemia,<br />
thrombocytopenia, and lymphopenia. The overall response rate was 25% with one<br />
partial response. This patient developed psychiatric symptoms within 8 weeks <strong>of</strong><br />
treatment and drug was discontinued. Three patients developed neurologic symptoms<br />
at a median <strong>of</strong> 37 days after trial drug initiation. All were found to have disease<br />
progression. The median progression free survival was 39 days with a median overall<br />
survival <strong>of</strong> 196 days. Buparlisib concentrations were assessed on day 15 <strong>of</strong> drug<br />
treatment in plasma and CSF 2h after drug dosing. Mean plasma concentration was<br />
1104ng/ml (range: 844-1610); mean CSF concentration 139.5ng/ml (82.9-205). CSF<br />
concentration in the trial population (340nM; range 202-499) was below the IC50<br />
observed to induce cell death in lymphoma cells in vitro (>500nM).<br />
Conclusions: Patients with CNS lymphoma tolerate drug with acceptable toxicities.<br />
Treatment did not result in clinical response possibly due to CNS concentrations below<br />
a meaningful IC50. Buparlisib might also not have single agent activity in this disease.<br />
Clinical trial identification: NCT02301364<br />
Legal entity responsible for the study: Memorial Sloan Kettering Cancer Center<br />
Funding: Novartis<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
336P<br />
Case report <strong>of</strong> the effective use <strong>of</strong> BRAF inhibitor vemurafenib<br />
in a patient with relapse <strong>of</strong> pleomorphic xanthoastrocytoma<br />
D.R. Naskhletashvili<br />
Neurooncology, N. N. Blokhin Russian Cancer Research Center, Moscow,<br />
Russian Federation<br />
Background: Pleomorphic xanthoastrocytoma is a rare tumor <strong>of</strong> the brain. It is<br />
approximately 1% <strong>of</strong> the astocytomas <strong>of</strong> the brain. In some cases, the tumor is<br />
well-demarcated and slow-growing with a favorable prognosis. At the same time<br />
reported cases <strong>of</strong> its malignant transformation with a poor prognosis. Most <strong>of</strong>ten this<br />
tumor occurs in a young age and manifest with epileptic syndrome. The main<br />
treatment is surgical. According to the literature, 30-40% <strong>of</strong> patients with pleomorphic<br />
xanthoastrocytoma detected mutation <strong>of</strong> V600E BRAF was.<br />
Methods: The patient 25 years old in January 2011 revealed a tumor <strong>of</strong> the left occipital<br />
lobe <strong>of</strong> the brain. 22 Jan 2011 completed the removal <strong>of</strong> a brain tumor.<br />
Morphologically diagnosed as a pleomorphic xanthoastrocytoma with signs <strong>of</strong><br />
anaplasia grade 3, Ki-67 – 15%. In the postoperative, in February-April 2012,<br />
conducted a course <strong>of</strong> radiation therapy to the left occipital lobe <strong>of</strong> the brain with total<br />
focal dose 60 Gy. In September 2014 after 2 years and 8 months after the operation<br />
revealed a relapse <strong>of</strong> a brain tumor. 25 Sep 2014 made the removal <strong>of</strong> the recurrence <strong>of</strong><br />
a brain tumor. Morphologically diagnosed as a pleomorphic xanthoastrocytoma with<br />
signs <strong>of</strong> anaplasia grade 4, Ki-67 > 20%. Carried out a genetic examination <strong>of</strong> the<br />
tumor. Revealed no methylation <strong>of</strong> the MGMT gene in the tumor. The identified<br />
mutation V600E BRAF in the tumor.<br />
Results: In December 2014 marked the progression <strong>of</strong> the disease. Revealed continued<br />
tumor growth in the brain. The size <strong>of</strong> the recurrent tumor 4 x 3 cm. From December<br />
2014 we started the targeted therapy with Vemurafenib. Achieved partial regression <strong>of</strong><br />
the tumor in the brain. The size <strong>of</strong> residual tumors currently, less than 1 cm. Therapy<br />
with Vemurafenib lasts 1 year and 6 months.<br />
Conclusions: Thus, the presence <strong>of</strong> the V600E BRAF mutation is another target for<br />
effective treatment <strong>of</strong> recurrences <strong>of</strong> pleomorphic xanthoastrocytoma. Further studies<br />
are needed for the study <strong>of</strong> BRAF inhibitors in patients with pleomorphic<br />
xanthoastrocytoma.<br />
Legal entity responsible for the study: Russian N.N.Blokhin Cancer Research Center<br />
Funding: Russian N.N.Blokhin Cancer Research Center<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
337P<br />
MGMT promoter methylation status in glioblastoma (GBM)<br />
patients: a quantitative pyrosequencing approach and its<br />
prognostic role<br />
A. Pambuku 1 , G. Lombardi 1 , R. Bertorelle 2 , L. Bellu 1 , P. Fiduccia 2 , M. Gardiman 3 ,<br />
A. Della Puppa 4 , F. Berti 5 ,D.D’Avella 6 , V. Zagonel 1<br />
1 Department <strong>of</strong> Clinical and Experimental <strong>Oncology</strong>, Medical <strong>Oncology</strong> 1, Veneto<br />
Institute <strong>of</strong> <strong>Oncology</strong>, Padua, Italy, 2 Department <strong>of</strong> Clinical and Experimental<br />
<strong>Oncology</strong>, Clinical Trials and Biostatistics Unit and Molecular Immunology and<br />
<strong>Oncology</strong> Unit, Istituto Oncologico Veneto IRCCS, Padua, Italy, 3 Deaprtment <strong>of</strong><br />
Pathology, Azienda Ospedaliera Padova, Padua, Italy, 4 Neurosurgery Department,<br />
Azienda Ospedaliera Padova, Padua, Italy, 5 Radiotherapy, Veneto Institute <strong>of</strong><br />
<strong>Oncology</strong>, Padua, Italy, 6 Neurosurgery Department, University <strong>of</strong> Padova, Padua,<br />
Italy<br />
Background: MGMT gene promoter methylation status is acknowledged as a<br />
prognostic factor and predictive marker for temozolomide (TMZ) treatment. Although<br />
MGMT status determined by pyrosequencing was showed to correlate with progression<br />
free survival (PFS) and overall survival (OS), it is still unclear a cut-<strong>of</strong>f value that<br />
discriminates between methylated and unmethylated patient (pts) and its correlation<br />
with the patient clinical outcome.<br />
Methods: We analyzed the tissue samples from 128 PTS diagnosed with GBM from<br />
November 2009 to December 2015. All PTS underwent treatment with RT + TMZ and<br />
had an ECOG-PS 0-2. Methylation percentage for each sample was obtained by<br />
calculating the average methylation <strong>of</strong> all 10CpG sites (75-84) <strong>of</strong> MGMT promoter by<br />
pyrosequencing analysis. PTS with 0-6% <strong>of</strong> methylation were classified as<br />
unmethylated (UM), PTS with 7-24% as low methylated (LM) and PTS with ≥ 25% as<br />
high methylated (HM). 25% was the median value <strong>of</strong> methylation <strong>of</strong> our PTS having<br />
>6% <strong>of</strong> methylation.<br />
Results: Median age was 60 yrs (range 25-84), 60.9% were male, 74.2% had an ECOG<br />
PS 0-1, 50.8% underwent radical surgery, 85 PTS were dead at the time <strong>of</strong> analysis. 75<br />
PTS (58.6%) were UM, 26 PTS (20,3%) were LM and 27 PTS (21,1%) were HM. On<br />
univariate analysis HM, LM and UM showed a PFS <strong>of</strong> 15.8, 10 and 9.1 ms, respectively<br />
(p = 0.1). OS was 38.7, 21 and 18.8ms (p= 0.06). On multivariate analysis UM and LM<br />
PTS had a statistically lower PFS vs HM PTS (HR = 2.57; p = 0.001; HR= 2.5; p = 0.007,<br />
respectively) and statistically lower OS (HR = 3.47; p < 0.001; HR = 2.63; p = 0.016;<br />
respectively). No significant difference was showed between UM and LM PTS in terms<br />
<strong>of</strong> PFS and OS, both on univariate and multivariate analyses.<br />
Conclusions: MGMT promoter methylation status determined by pyrosequencing<br />
analysis may correlate to PFS and OS. We found a cut-<strong>of</strong>f <strong>of</strong> 25% <strong>of</strong> methylation which<br />
determined two sub-groups <strong>of</strong> PTS having different clinical outcome; in particular,<br />
HM PTS had a significant longer PFS and OS.<br />
Legal entity responsible for the study: IOV<br />
Funding: None<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
338P<br />
abstracts<br />
MGMT methylated (Met) patients (p) with glioblastoma (GBM)<br />
have a better prognosis with an earlier response (ER) than<br />
those who have a late response or pseudoprogression (LR/<br />
PsP). Results <strong>of</strong> the Gliocat study<br />
A. Estival 1 , E. Pineda 2 , M. Martinez-Garcia 3 , J. Marruecos 4 , C. Mesía 5 , A. Lucas 6 ,<br />
M. Macia 6 , M. Gil 5 , O. Gallego 7 , E. Verger 8 , S. Del Barco 4 , R. Fuentes 4 , J. Craven 7 ,<br />
N. García 1 , S. Villà 9 , J.M. Velarde 1 , C. Carrato 10 , T. Ribalta 11 , O. Arpi 12 , C. Balana 1<br />
1 Medical <strong>Oncology</strong>, Catalan Institute <strong>of</strong> <strong>Oncology</strong> (ICO Badalona), Hospital<br />
Germans Trias i Pujol, Badalona, Spain, 2 Medical <strong>Oncology</strong>, Hospital Clinic y<br />
Provincial de Barcelona, Barcelona, Spain, 3 Department <strong>of</strong> Medical <strong>Oncology</strong>,<br />
University Hospital del Mar, Barcelona, Spain, 4 Medical <strong>Oncology</strong>, Catalan<br />
Institute <strong>of</strong> <strong>Oncology</strong> (ICO)-Hospital Universitari Josep Trueta, Girona, Spain,<br />
5 Medical <strong>Oncology</strong>, Institut Catala de Oncologia, L’Hospitalet de Llobregat,<br />
Barcelona, Spain, 6 Radiation <strong>Oncology</strong>, Institut Català d’Oncologia Hospital Duran<br />
i Reynals, Barcelona, Spain, 7 Medical <strong>Oncology</strong>, Hospital de la Santa Creu i Sant<br />
Pau, Barcelona, Spain, 8 Radiotherapy, Hospital Clinic y Provincial de Barcelona,<br />
Barcelona, Spain, 9 Radiation <strong>Oncology</strong>, Catalan Institute <strong>of</strong> <strong>Oncology</strong> (ICO<br />
Badalona), Hospital Germans Trias i Pujol, Badalona, Spain, 10 Pathology, Hospital<br />
universitari germans trias i pujol, Badalona, Spain, 11 Pathology, Hospital Clinic y<br />
Provincial de Barcelona, Barcelona, Spain, 12 Cancer Research program IMIM,<br />
University Hospital del Mar, Barcelona, Spain<br />
Background: LR/PsP is more frequent in Met patients than in UnMet ones and it is<br />
considered an expression <strong>of</strong> therapeutic efficacy due to the combination with<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw367 | vi107
abstracts<br />
temozolomide and radiotherapy (TMZ&RT) <strong>of</strong> the Stupp’s scheme. Our aim was to<br />
figure out if an ER at first evaluation (no PsP) was better or worse than a LR/PsP.<br />
Methods: From the GLIOCAT study data base (432p) we identified those patients who<br />
had the first disease assessment within 60 days after the last day <strong>of</strong> concurrent<br />
TMZ&RT having further evaluations at 3/6 months or until progression while<br />
continuing on adjuvant TMZ treatment (256p). We defined ER as those patients<br />
without progression at first evaluation, and LR/ PsP as those that progressed at first<br />
evaluation but improved or maintained stable disease at subsequent evaluations.<br />
Results: At first evaluation 128/256 (50%) p had an ER and 128/256 (50%) were at<br />
suspected progression (P); 56 <strong>of</strong> them improved at second and 4 at third evaluation (so<br />
60 patients (23.5%) were considered as LR/PsP and 68 p (26.5%) were real P. PsP/LR<br />
was seen for any kind <strong>of</strong> initial surgery (0.12) and was more frequently seen in Met p<br />
(66%) than in unMet ones (34%). Conversely Met p had less real progressions (37.7%)<br />
than unMet p (62.3%) p = 0.01. All IDH1 mutated p (9) had ER (7) or PsP/LR (2) to<br />
treatment. Median Overall Survival (OS) was not different for patients with LR/PsP<br />
(17.9m) than those with ER (19.7); P = 0.48. (OS was only 12.3m for P patients).<br />
Nevertheless, Met p lived longer if they had ER (N = 45: 30.9m) than if they had LR/<br />
PsP (N = 33: 17.9m); P = 0.59. This held not true for unMet p: ER (N = 53: 18.0m) vs<br />
LR/PsP (N = 17: 17.9m); P = 0.44.<br />
Conclusions: Although differences were not significant, our results suggest that LR/PsP<br />
does not increase survival and that it is a deleterious effect especially for Met p where it<br />
is more frequently observed. This should be explored in a larger series.<br />
Legal entity responsible for the study: N/A<br />
Funding: Marató TV3<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
339P<br />
First steps in the definition <strong>of</strong> a prognostic score based on<br />
MGMT methylation status in patients with glioblastoma<br />
E. De Carlo 1 , L. Gurrieri 2 , G. De Maglio 3 , L. Gerratana 1 , V. Buoro 1 , S. Rizzato 1 ,<br />
M. Isola 4 ,M.Skrap 5 , G. Fasola 1 , F. Puglisi 1 , S. Pizzolitto 3<br />
1 Department <strong>of</strong> <strong>Oncology</strong>, University Hospital <strong>of</strong> Udine, Udine, Italy, 2 Department<br />
<strong>of</strong> <strong>Oncology</strong>, Ospedale dell’Angelo, Mestre, Italy, 3 Department <strong>of</strong> Pathology,<br />
University Hospital <strong>of</strong> Udine, Udine, Italy, 4 Department <strong>of</strong> Medical and Biological<br />
Sciences, University <strong>of</strong> Udine, Udine, Italy, 5 Department <strong>of</strong> Neurosurgery,<br />
University Hospital <strong>of</strong> Udine, Udine, Italy<br />
Background: Epigenetic variations in the O6-methylguanine-methyltransferase (MGMT)<br />
gene had been widely associated with a favorable impact on survival in patients (pts)<br />
affected by glioblastoma (GBM). MGMT includes 98 CpG islands (CpGi) and patterns <strong>of</strong><br />
methylation are rather heterogeneous. Aim <strong>of</strong> this study is to explore a scoring system<br />
based on the gene promoter methylation in order to predict pts’ prognosis.<br />
Methods: The study analyzed a series <strong>of</strong> 121 pts with GBM treated at the University<br />
Hospital <strong>of</strong> Udine between 2008 and 2014. The methylation level <strong>of</strong> CpGi from 74 to 83<br />
was analyzed through pyrosequencing. In accordance to previous literature, each island<br />
was assigned with 1 point if the corresponding methylation level was higher than 9%.<br />
The sum consisted in a score that went from 0 (all CpGi < 9%) to 10 (all CpGi >= 9%). A<br />
training set <strong>of</strong> 75 pts was randomly generated. A threshold capable to detect a favorable<br />
outcome (OS > 24 months) was identified by ROC analysis. The prognostic impact was<br />
explored through Cox regression. The results were verified on a validation set <strong>of</strong> 46 pts.<br />
Results: Median OS was 14 months. Among the total population 35% <strong>of</strong> the pts had a<br />
score <strong>of</strong> 0, while 29% had a score <strong>of</strong> 10. The score’s prognostic impact was confirmed also<br />
by comparison with the methylation mean and median through stepwise Cox regression<br />
(P= 0.0002). The threshold identified was 6 (AUC 0.74). On univariate analysis, a score > 6<br />
was associated with a favorable prognosis both in the training and in the validation set (HR<br />
0.42, 95%CI 0.23-0.77, P= 0.0046; HR 0.37, 95%CI 0.18-0.77, P = 0.0078; respectively). The<br />
result was maintained also in multivariate analysis <strong>of</strong> the whole population (HR 0.43, 95%<br />
CI 0.27-0.67, P = 0.0002) when corrected for age (>70 vs ≤ 70 years HR 2.19, 95%CI<br />
1.30-3.69, P = 0.0032) and ECOG performance status (0-1 vs 2-3 HR 2.20, 95%CI<br />
1.36-3.54, P = 0.0012). Similar results were observed also in terms <strong>of</strong> PFS.<br />
Conclusions: The present study explored a novel scoring system capable to take into<br />
consideration the methylation status <strong>of</strong> single CpGi. Since the limited prognostic<br />
significance <strong>of</strong> each CpGi, combining the information from multiple CpGi is crucial in<br />
order to better predict prognosis in GBM patients.<br />
Legal entity responsible for the study: University Hospital <strong>of</strong> Udine<br />
Funding: None<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
340P<br />
The study <strong>of</strong> MIB-1 LI and CD-34 as a marker <strong>of</strong> proliferative<br />
activity and angiogenesis in different grades <strong>of</strong> meningioma<br />
H.R. Bohra<br />
Pathology, All India Institute Of Medical Sciences(AIIMS), Jodhpur, India<br />
Background: Meningiomas comprise 24-30% <strong>of</strong> all tumours occurring in the central<br />
nervous system. Conventional morphologic criteria as studied in routine Hematoxylin<br />
and Eosin stained sections ( H and E) may not be accurate in grading and assessing<br />
prognosis in small stereotactic biopsy specimens. Thus, the need for objective methods<br />
for assessing tumour biology. Prolifereative index using MIB -1 labelling index is<br />
helpful in grading and prognosis <strong>of</strong> tumours. Angiogenesis is a key event in the spread<br />
<strong>of</strong> tumours and denotes a poor prognosis. Intratumoral microvessel density (MVD)<br />
helps in quantification <strong>of</strong> angiogenesis.<br />
Methods: Paraffin blocks <strong>of</strong> 30 surgically resected cases, 10 each <strong>of</strong> Grade I, II and III<br />
meningiomas were reviewed. Tumours were graded and subtyped as per WHO criteria.<br />
Immunohistochemical staining was done for proliferative index with Ki-67 and for<br />
angiogenesis with CD 34 antibodies. Statistical analysis was performed using Mann –<br />
Whitney U test. p value <strong>of</strong> < 0.05 was considered significant.<br />
Results: The male to female ratio overall was 1:1.The age <strong>of</strong> the patients ranged from<br />
18-81 years. 73% <strong>of</strong> patients had raised intracranial pressure and 18.4% <strong>of</strong> patients<br />
presented with seizures. The mean +/- SD MIB-1 LI was 1.14 +/-0.84, 8.94 + /-2.73 and<br />
35.62 +/-4.44 in grade I, II and III tumours respectively which was statistically<br />
significant. (p< 0.01). The mean +/- SD MVD was 49.67 +/- 22.35, 41.37 + /-7.45 and<br />
47.86 +/- 10.77 respectively in grade I, II and III tumours respectively. was statistically<br />
non significant ( p > 0.05).<br />
Conclusions: MIB-1 LI is an important complementary tool to accurately grade<br />
meningothelial tumours and assess tumour biology. Specific cycling endothelial markers<br />
along with CD 34 MVD could be used to assess the prognosis <strong>of</strong> these tumours.<br />
Legal entity responsible for the study: National Board <strong>of</strong> Examinations, New Delhi.<br />
Base Hospital, Delhi Cantt, New Delhi.<br />
Funding: Base Hospital Delhi Cantt, New Delhi.<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
341P<br />
Clinical correlation <strong>of</strong> cancer stem cells in low and high grade<br />
glioma <strong>of</strong> North Indian population<br />
D. Mohania 1 , R. Acharya 2 , S.K. Kalra 2 , K. Jain 1 , D. Tripathi 1 , S. Chandel 1 ,<br />
S. Mohania 1 , K. Choudhury 1 , S. Jain 3 , S. Bhalla 3<br />
1 Department <strong>of</strong> Research, Sir Ganga Ram Hospital, Delhi, India, 2 Department <strong>of</strong><br />
Neurosurgery, Sir Ganga Ram Hospital, Delhi, India, 3 Department <strong>of</strong> Pathology, Sir<br />
Ganga Ram Hospital, Delhi, India<br />
Background: Cancer stem cells (CSCs) are resistant to radiation and chemotherapy,<br />
and are most likely cause <strong>of</strong> cancer recurrence in glioma. Therefore, we aimed at<br />
pr<strong>of</strong>iling <strong>of</strong> different CSCs in low and high grade astrocytoma; and their clinical<br />
correlation with histopathological parameters, survival and clinical outcome.<br />
Methods: The expression <strong>of</strong> various CSC markers was compared between tumor<br />
tissues and neurospheres derived from low and high grade glioma using RT-PCR, flow<br />
cytometry and immunohistochemical staining.<br />
Results: CD44, CD44v6, Nestin and EpCAM mRNA expression levels were<br />
upregulated in PA patients. All newly diagnosed DA patients showed upregulation <strong>of</strong><br />
mRNA expressions <strong>of</strong> Nestin, CD44, CD44v6, Musashi-1, Bmi-1, Nanog, Sox-2 and<br />
Oct4. Almost 50% <strong>of</strong> the patients enrolled in newly diagnosed DA patients showed<br />
upregulation <strong>of</strong> mRNA expression levels <strong>of</strong> CD133 and EpCAM. Expression levels <strong>of</strong><br />
CD90 mRNA was absent in all newly diagnosed DA. The expression levels <strong>of</strong> various<br />
CSCs in newly diagnosed cases <strong>of</strong> GBM patients were significantly higher than AA<br />
patients except for EpCAM and Oct-4. Interestingly, embryonic stem cells markers<br />
such as Oct4 and Nanog mRNA expression levels were significantly higher in follow up<br />
cases <strong>of</strong> GBM in comparison to newly diagnosed cases. One recurrent case <strong>of</strong> GBM<br />
showed upregulation <strong>of</strong> mRNA levels <strong>of</strong> Nestin, CD44, CD44v6, Bmi-1, EpCAM and<br />
Sox-2 when compared to non-neoplastic brain tissues. Furthermore, CD133, CD90,<br />
Oct4 and Nanog showed no mRNA expression. These results showed a positive<br />
concordance between mRNA expression <strong>of</strong> CD133, CD44, CD90, Nestin, Musashi-1,<br />
BMI-1 and SOX-2 with the immunohistochemical as well as flow cytometry analysis. A<br />
significant correlation (P < 0.05) was observed between the median fold change <strong>of</strong><br />
Nestin, SOX-2 and MGMT in terms <strong>of</strong> survival status in low and high grade glioma.<br />
Furthermore, we also observed significant correlation with the expression levels <strong>of</strong><br />
Indoleamine 2, 3-dioxygenease (IDO) and O6-methylguanine-DNA-methytransferease<br />
(MGMT) in various grades <strong>of</strong> astrocytoma.<br />
Conclusions: The study gives an important insight <strong>of</strong> CSC signature genes which<br />
correlates with clinical outcome and demonstrates the clinical relevance <strong>of</strong> CSCs in low<br />
grade and high grade astrocytoma.<br />
Legal entity responsible for the study: Sir Ganga Ram Hospital, New Delhi<br />
Funding: Department <strong>of</strong> Science and Technology (DST), Government <strong>of</strong> India, New<br />
Delhi<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
342P<br />
Analysis <strong>of</strong> EGFRvIII and EGFR overexpression in glioma and<br />
its prognostic significance<br />
V. Munirathnam, A. Philip, B. R, S. Km, K. Pavithran, J. Wesley M<br />
Medical <strong>Oncology</strong>, Amrita institute <strong>of</strong> medical sciences, Cochin, India<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Background: The clinical significance <strong>of</strong> EGFRvIII and EGFR wild type expression in<br />
glioblastoma multiforme (GBM) with correlation to clinical outcome have not been<br />
vi108 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
consistent. We sought to evaluate the clinical significance <strong>of</strong> EGFRvIII status and the<br />
EGFR overexpression in GBM among the Indian population, where potential targeted<br />
therapy may be the only hope.<br />
Methods: A single centre, non-randomized, retrospective study with a prospective arm<br />
was done. All patients were treated at the Amrita Institute Of Medical Sciences, Kochi<br />
between Jan 2014 and August 2015. 40 patients were included; being the first <strong>of</strong> its kind<br />
in the Indian context the study was undertaken as a pilot.<br />
Results: Results show expression <strong>of</strong> EGFRvIII had no correlation with the clinical<br />
outcome, OS 17.5 months vs 16.7 months (p = 0.920), PFS 11months vs 8.8months<br />
(p = 0.520). However a significant number <strong>of</strong> patients expressed EGFRvIII (58%).<br />
Surprisingly, the majority <strong>of</strong> patients expressed the EGFR wild type, and EGFR exon 19<br />
(57%) over-expression had a significantly negative impact on the clinical outcome, with<br />
an OS <strong>of</strong> 7.3 months vs 15.4 months and PFS 7.3months vs 13months (p = 0.001).<br />
Conclusions: We found that a high percentage <strong>of</strong> GBM exhibit EGFR overexpression<br />
and amplification, as did a significant proportion expressing EGFRvIII. Our results<br />
represent a step forward for the identification <strong>of</strong> GBM patients in the Indian scenario<br />
who could respond to specific therapies targeting EGFR. This requires confirmation in<br />
independent larger data sets.<br />
Legal entity responsible for the study: Amrita Institute <strong>of</strong> Medical Sciences<br />
Funding: Amrita Institute <strong>of</strong> Medical Sciences<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
OA and GBM respectively if wild type TERT, while if mutated 14, 20 and 8 months.<br />
TERT and ATRX seem to be mutually exclusive as there were only 2% coincidences.<br />
Table: 344P<br />
Wild type TERT<br />
Mutated TERT<br />
Median PFS Range Median PFS Range<br />
Astrocytoma 37.6 124 14.2 120<br />
Glioblastoma 7.1 37 8.8 42<br />
Oligoastrocytoma 19.3 73 82.7 0<br />
Oligodendroglioma 33.1 34 20.7 98<br />
Conclusions: TERT mutations are determinant prognostic factors in glioma biology <strong>of</strong><br />
both high and low grade.<br />
Legal entity responsible for the study: Hospital Universitario 12 de Octubre:<br />
Multidisciplinar Neurooncology Unit<br />
Funding: Hospital Universitario 12 de Octubre: Multidisciplinar Neurooncology Unit<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
343P<br />
The role <strong>of</strong> ABO blood groups in glial neoplasia<br />
A. Alkan 1 ,G.Yazıcı 2 , M. Cengiz 2 ,İ . Çelik 3 , A. Kars 3 , F. Zorlu 2<br />
1 Medical <strong>Oncology</strong>, Ankara University Medical School-Cebeci Hastaneleri Tıbbi<br />
Onkoloji, Ankara, Turkey, 2 Radiation <strong>Oncology</strong>, Hacettepe University Faculty <strong>of</strong><br />
Medicine, Ankara, Turkey, 3 Medical <strong>Oncology</strong>, Hacettepe University Faculty <strong>of</strong><br />
Medicine, Ankara, Turkey<br />
Background: There are numerous diseases that are claimed to have a correlation with<br />
ABO blood groups. The association with malignancy, especially with exocrine pancreas<br />
malignancy, has been documented. Analysis on distribution <strong>of</strong> blood groups in<br />
primary brain tumors and clinical value has revealed conflicting results. Here we aimed<br />
to evaluate the association between blood groups and glial neoplasia.<br />
Methods: Patients admitted between 2000–2013 and had a diagnosis <strong>of</strong> glial neoplasia<br />
were evaluated. Documented blood groups were analyzed and compared with the<br />
National blood group data obtained from Turkish Red Crescent Society. The<br />
prognostic significance <strong>of</strong> ABO blood groups was analyzed within glioblastoma<br />
multiforme (GBM), anaplastic astrocytoma and grade 1-2 astrocytoma.<br />
Results: 759 patients with a diagnosis <strong>of</strong> glial neoplasia were evaluated. Distribution <strong>of</strong><br />
ABO blood groups in the different grades <strong>of</strong> glial neoplasia was similar with the<br />
national blood group frequencies. There was no statistically significant difference<br />
between all grades <strong>of</strong> glial neoplasia and healthy control patients. Median overall<br />
survival (mOS) <strong>of</strong> GBM patients are 12.9, 13.4, 5.7, 12.8 months in A, B, AB, and O<br />
blood groups, respectively (p = 0.46). mOS <strong>of</strong> anaplastic astrocytoma patients are 24.4,<br />
47.2, 37.8, 29.2, 25.7 months, respectively (p = 0.96). mOS in grade1-2 astrocytoma in<br />
different blood groups are similar (p = 0.80).<br />
Conclusions: In our small patient group, when compared with general population,<br />
there seems to be no association between frequencies <strong>of</strong> ABO blood groups and glial<br />
neoplasia. The ABO blood groups have no prognostic impact on glial neoplasia.<br />
Legal entity responsible for the study: N/A<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
344P<br />
TERT as a prognostic factor for gliomas progression-free<br />
survival (PFS)<br />
M.P. Solis Hernandez 1 , L. Faez 1 , D. Cantero 2 , A. Hernandez Lain 2 ,P.<br />
Sanchez Gomez 2 , Y. Ruano 2 , M.D.M. Galera 3 , J.M. Sepúlveda Sánchez 3<br />
1 Medical <strong>Oncology</strong>, Hospital Universitario Central de Asturias, Oviedo, Spain,<br />
2 Multidisciplinar Neurooncology Unit, University Hospital 12 De Octubre, Madrid,<br />
Spain, 3 Medical <strong>Oncology</strong>, University Hospital 12 De Octubre, Madrid, Spain<br />
Background: High frequencies <strong>of</strong> TERT promoter mutations have been described in<br />
gliomas. This underlies telomere maintenance upregulating telomerases. The mutation<br />
rate is higher in glioblastomas (GBM).<br />
Methods: Observational and retrospective analysis <strong>of</strong> 100 patients with different<br />
histological types <strong>of</strong> gliomas. TERT mutations were determined by RT-PCR in brain<br />
tumor samples obtained from paraffin-embedded tissue. Survival analysis was<br />
performed with Kaplan-Meier curves compared by Log-Rank test.<br />
Results: There were included 52% GBM, oligodendrogliomas (OO) 12% and<br />
astrocytomas (AA) 29% each, and oligoastrocytomas (OA) 7%. The highest rate <strong>of</strong><br />
TERT mutation was achieved in the OO group (66.7%) followed by GBM (55.8%) and<br />
AA (27.6%). From the 46% patients with TERT mutation: GBM 63%, OO and AA each<br />
17.4%. Median relapse/progression free survival was 37, 33 and 7 months for AA, OO,<br />
345P<br />
Concomitant chemoradiation (Ch-RT) in elderly newly<br />
diagnosed glioblastoma (GB) patients. Updated clinical<br />
outcome and molecular characteristics from the GLIOCAT<br />
study<br />
M. Martinez-Garcia 1 , E. Pineda 2 , S. Del Barco 3 , A. Estival 4 , E. Verger 5 ,<br />
J. Marruecos 6 , O. Gallego 7 , M. Gil 8 , R. Fuentes 6 , J. Craven-Bartle Lamote de<br />
Grigno 9 , A. Lucas 10 , M. Macia 10 , C. Mesía 8 , J.M. Velarde 4 , N. García 4 , S. Villà 11 ,<br />
C. Balana 4<br />
1 Department <strong>of</strong> Medical <strong>Oncology</strong>, University Hospital del Mar, Barcelona, Spain,<br />
2 Medical <strong>Oncology</strong>, Hospital Clinic y Provincial de Barcelona, Barcelona, Spain,<br />
3 Medical <strong>Oncology</strong>, Catalan Institute <strong>of</strong> <strong>Oncology</strong> (ICO)-Hospital Universitari Josep<br />
Trueta, Girona, Spain, 4 Medical <strong>Oncology</strong>, Catalan Institute <strong>of</strong> <strong>Oncology</strong> (ICO<br />
Badalona), Hospital Germans Trias i Pujol, Badalona, Spain, 5 Radiotherapy,<br />
Hospital Clinic y Provincial de Barcelona, Barcelona, Spain, 6 Radiation oncology,<br />
Catalan Institute <strong>of</strong> <strong>Oncology</strong> (ICO)-Hospital Universitari Josep Trueta, Girona,<br />
Spain, 7 Medical <strong>Oncology</strong>, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain,<br />
8 Medical <strong>Oncology</strong>, Institut Catala de Oncologia, L’Hospitalet de Llobregat,<br />
Barcelona, Spain, 9 Departament <strong>of</strong> Radiation <strong>Oncology</strong>, Hospital de la Santa Creu<br />
i Sant Pau, Barcelona, Spain, 10 Radiation <strong>Oncology</strong>, Institut Català d’Oncologia<br />
Hospital Duran i Reynals, Barcelona, Spain, 11 Radiation <strong>Oncology</strong>, Catalan<br />
Institute <strong>of</strong> <strong>Oncology</strong> (ICO Badalona), Hospital Germans Trias i Pujol, Badalona,<br />
Spain<br />
Background: GB incidence is growing in elderly patients (pts), and approximately 50%<br />
<strong>of</strong> GB pts are over 65 years old. There is no standard treatment for newly diagnosed GB<br />
elderly patients. Elderly population is lacking <strong>of</strong> known molecular prognostic factors.<br />
Methods: We report a multicenter study <strong>of</strong> newly diagnosed GB treated with Ch-RT<br />
(Stupp regimen). In this substudy we analysed outcome and prognostic factors<br />
in > 65y. Baseline characteristics and preliminary survival results will be presented at<br />
2016 ASCO meeting, abstract 2045. We report the final survival and new data<br />
regarding pseudoprogression and molecular analysis.<br />
Results: Between 2005 to 2014, 148 pts over 65y were enrolled. There were 117 (79%)<br />
>65-75y and 31 (21%) >75y with a median age <strong>of</strong> 72y. 19 pts (14.7%)presented<br />
pseudoprogression(psPD) in >65y, comparing to 42 (17.6%) in younger population<br />
(p = 0.47). MGMT methylation status was studied in 116 pts <strong>of</strong> which 65 (56%) were<br />
methylated vs 87 (40.3%) in ≤65y (p = 0.006). IDH1 status was studied in 82 pts >65y,<br />
none <strong>of</strong> them presented mutated IDH1vs 10 (5.6%) in younger pts(p = 0.029). Median<br />
follow up was 13.5 months (mo). In the global population median progression-free<br />
survival (mPFS) and overall survival (mOS) were 8 mo(95% CI, 7.49-8.5) and 14 mo<br />
(95% CI, 12.74-15.25) respectively, compared to 7 mo(95% CI, 6.09-7.9) and 10 mo<br />
(95% CI, 7.97-12.02) in >65y (p = 0.020 and p< 0.000). mOS in elderly pts presenting<br />
pseudoprogression was 16mo (95% CI, 13.23-18.76) vs 9 mo (95% CI 7.29-10.7)<br />
without it (p = 0.022). Pts with methylated MGMT had a higher incidende <strong>of</strong> psPD<br />
(p = 0.05). For elderly pts on multivariate analysis, gross total resection and<br />
pseudprogression but not KPS or MGMT were independent predictors <strong>of</strong> OS and PFS.<br />
Conclusions: We confirmed that PFS and OS were poorer in >65y. There were no<br />
differences in the rates <strong>of</strong> pseudoprogression and MGMT methylation in the elderly<br />
population comparing to younger pts. Pseudoprogression had significant impact in OS.<br />
None <strong>of</strong> the elderly pts studied presented IDH1 mutation. For elderly patients, type <strong>of</strong><br />
resection and pseudoprogression were the more relevant prognostic factors in newly<br />
diagnosed GB treated with the Stupp regimen.<br />
Clinical trial identification: This work has been supported by the Marato Project:<br />
665/C/2013<br />
Legal entity responsible for the study: IGTP, IDIBELL, Fundacio Parc Salut Mar<br />
Funding: Marato Project: 665/C/2013<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw367 | vi109
abstracts<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
346P<br />
A prospective analysis <strong>of</strong> quality <strong>of</strong> life (QoL), cognitive<br />
functions (CF) and psychological status (PSY) in glioblastoma<br />
(GBM) patients (PTS) treated with RT and temozolomide (TMZ)<br />
E. Bergo 1 , G. Lombardi 1 , P. Del Bianco 2 , F. Berti 3 , L. Bellu 1 , A. Pambuku 1 ,<br />
V. Zagonel 1<br />
1 Department <strong>of</strong> Clinical and Experimental <strong>Oncology</strong>, Medical <strong>Oncology</strong> 1, Veneto<br />
Institute <strong>of</strong> <strong>Oncology</strong> - IRCCS, Padua, Italy, 2 Clinical Trials and Biostatistics Unit,<br />
and Molecular Immunology and <strong>Oncology</strong> Unit, Veneto Institute <strong>of</strong> <strong>Oncology</strong> -<br />
IRCCS, Padua, Italy, 3 Radiation Therapy and Nuclear Medicine Unit, Veneto<br />
Institute <strong>of</strong> <strong>Oncology</strong> - IRCCS, Padua, Italy<br />
Background: GBM PTS can show changes in CF during the treatment which can affect<br />
their daily lives. We analyzed QoL, PSY and CF in these PTS treated with RT plus<br />
TMZ.<br />
Methods: PTS with newly histologically diagnosed GBM treated with RT and TMZ as<br />
first-line therapy and KPS ≥ 60 were enrolled. We assessed QoL using EORTC<br />
QLQ-C30 and BN20. CF were evaluated with MMSE, and PSY with HADS test.<br />
Evaluations were performed at each radiological assessment: T0 (before treatment), T1<br />
(1 month after RT + TMZ), T2 (6 ms from T0), T3 (9 ms from T0) and T4 (12 ms<br />
from T0). A repeated-measure linear mixed-model was used to estimate group<br />
differences over time and χ2 test for compare mean values at each time.<br />
Results: we enrolled 112 PTS, median age was 59; 69 PTS were male and 36 PTS aged<br />
≥65. All PTS were treated with TMZ until disease progression. Role functioning (RF)<br />
statistically improved over time in female (p = 0.02) and PTS
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
349P<br />
Anaplastic astrocytoma (AA) and glioblastoma (GBM):<br />
a real-life experience in Padua Neuro-<strong>Oncology</strong> Center<br />
G. Lombardi 1 , A. Pambuku 1 , L. Bellu 1 , P. Fiduccia 2 , A. Della Puppa 3 ,<br />
M. Gardiman 4 , F. Berti 5 ,D.D’Avella 6 , V. Zagonel 1<br />
1 Department <strong>of</strong> Clinical and Experimental <strong>Oncology</strong>, Medical <strong>Oncology</strong> 1, Veneto<br />
Institute <strong>of</strong> <strong>Oncology</strong>, Padua, Italy, 2 Department <strong>of</strong> Clinical and Experimental<br />
<strong>Oncology</strong>, Veneto Institute <strong>of</strong> <strong>Oncology</strong>, Padua, Italy, 3 Neurosurgery Department,<br />
Azienda Ospedaliera Padova, Padua, Italy, 4 Deaprtment <strong>of</strong> Pathology, Azienda<br />
Ospedaliera Padova, Padua, Italy, 5 Radiotherapy, Veneto Institute <strong>of</strong> <strong>Oncology</strong>,<br />
Padua, Italy, 6 Neurosurgery Department, University <strong>of</strong> Padova, Padua, Italy<br />
Background: Various prospective clinical trials on high-grade gliomas were performed<br />
in the last years but patient (PTS) characteristics and outcome may be different in real<br />
clinical practice. We performed a retrospective analysis to evaluate the real-life<br />
experience in Padua Neuro-<strong>Oncology</strong> center.<br />
Methods: Retrospectively, we reviewed the medical records <strong>of</strong> PTS admitted to our<br />
observation from June 2010 to June 2015 with a diagnosis <strong>of</strong> AA or GBM. We analyzed<br />
clinical outcome with prognostic factors<br />
Results: We analyzed 592 PTS with a diagnosis <strong>of</strong> CNS primary tumor. Among these,<br />
we enrolled 395 PTS: 33 (8.4%) with a histological diagnosis <strong>of</strong> AA, 293 (74%) with a<br />
histological diagnosis <strong>of</strong> GBM and 69 (17.4%) with a radiological diagnosis <strong>of</strong> GBM. At<br />
diagnosis, median age was 63.2 (range 24-88), 61.8% were male; 80% <strong>of</strong> PTS had an<br />
ECOG PS 0-2. Among PTS who underwent surgery, 48% had a radical surgery; 279<br />
PTS (70.6%) performed RT in association to chemotherapy. 17% <strong>of</strong> PTS performed a<br />
second surgery at relapse and 45% a second-line treatment. MGMT was analyzed in all<br />
PTS who underwent surgery: it was methylated in 38.7% <strong>of</strong> PTS, IDH1 was mutated in<br />
6%. GBM PTS with ECOG PS 0-2 and >2 had a median OS <strong>of</strong> 21.1 and 7.2 ms,<br />
respectively. GBM PTS with met and unmet MGMT had a mOS <strong>of</strong> 22.7 and 13.7 ms<br />
(p = 0.005). AA PTS with met and unmet MGMT had a mOS <strong>of</strong> 29.5 and 16.6 ms<br />
(p = 0.03). Considering all high-grade gliomas, PTS with met MGMT + mutIDH1<br />
reported a mOS <strong>of</strong> 23.1ms, PTS with metMGMT + wtIDH1 had a mOS <strong>of</strong> 20.9 ms and<br />
PTS with unmetMGMT + wtIDH1 showed a mOS <strong>of</strong> 12.6ms (p < 0.001). On<br />
multivariate analysis, ECOG PS 0-2 (HR = 0.6), radical surgery (HR = 0.7), methylated<br />
MGMT (HR = 0.5) and PTS receiving a second-line chemoterapy (HR = 0.7) were<br />
positive prognostic factors in terms <strong>of</strong> OS<br />
Conclusions: In our real-life experience most PTS underwent surgery, performed a<br />
radiation therapy in association to chemotherapy and nearly half <strong>of</strong> PTS performed a<br />
second-line chemotherapy, although a subset <strong>of</strong> PTS had a poor performance status.<br />
However, we reported a good clinical outcome demonstrating the importance <strong>of</strong><br />
molecular characterization in these PTS. Type <strong>of</strong> surgery, ECOG PS, MGMT<br />
methylation and lines <strong>of</strong> chemotherapy were independent prognostic factors<br />
Legal entity responsible for the study: IOV<br />
Funding: None<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
350P<br />
Extended adjuvant temozolamide as prognostic factor <strong>of</strong><br />
longer overall and progression-free survival in glioblastoma<br />
multiforme<br />
S.C. Póvoa 1 , N. Tavares 1 , M.J. Ribeiro 1 , D. Azevedo 1 , A. Coelho 1 , A. Fernandes 1 ,<br />
A. Costa 1 , C. Caeiro 1 , B. Carvalho 2 , P. Linhares 2 , L. Osório 3 , L. Castro 4 ,<br />
J. Fonseca 5 , M. Damasceno 1<br />
1 Medical <strong>Oncology</strong> Department, Hospital de S. João, Porto, Portugal,<br />
2 Neurosurgical Department, Hospital de S. João, Porto, Portugal, 3 Radiation<br />
<strong>Oncology</strong> Department, Hospital de S. João, Porto, Portugal, 4 Pathology<br />
Department, Hospital de S. João, Porto, Portugal, 5 Neuroradiology Department,<br />
Hospital de S. João, Porto, Portugal<br />
Background: Glioblastoma multiforme (GBM), the most common malignant primary<br />
central nervous system tumour, has significant morbi-mortality. The aim is to<br />
determine prognostic factors (PF) <strong>of</strong> overall survival (OS) and progression-free survival<br />
(PFS) in patients treated with Stupp protocol.<br />
Methods: Retrospective analysis <strong>of</strong> GBM patients ≥18 years, diagnosed from March<br />
2004 to December 2014, treated with radiotherapy (RT) plus concomitant and<br />
adjuvant temozolomide (aTMZ). OS and PFS were assessed by Kaplan-Meier method<br />
and multivariate analysis (MA) was performed using Cox regression.<br />
Results: A total <strong>of</strong> 213 patients completed concomitant TMZ-RT and were included in<br />
final analysis. Majority were males (n = 134), with median age <strong>of</strong> 61 years old (24-84)<br />
and 43.1% ECOG performance status 0. Gross total resection (GTR) was possible in<br />
46.9%, partial resection in 33.3% and stereotactic biopsy (SB) in 19.7%. 197 patients<br />
proceeded to aTMZ: 107 suspended 6 cycles (p < 0.001). In MA,<br />
ECOG 0 (p = 0.011), imagiologic response (p = 0.001) and 2 nd line CT (p = 0.046)<br />
were prognostic <strong>of</strong> better OS. Also, aTMZ >12 cycles (p < 0.001, OS and PFS) and<br />
aTMZ 7-12 (p = 0.001, OS; p < 001, PFS) vs. 6 had longer OS and PFS. Analysing only<br />
patients who did 6 cycles <strong>of</strong> programmed aTMZ or extended until progression: aTMZ<br />
>12 cycles was associated with longer OS (vs. 6, p = 0.04; vs. 7-12, p = 0.037) without<br />
impact on PFS. In MA only aTMZ >12 cycles had positive impact on OS (p = 0.032,<br />
HR 0.34, CI 95%, 0.13-0.91).<br />
Conclusions: Our results suggest an OS and PFS benefit <strong>of</strong> extended aTMZ beyond<br />
standard 6 cycles, with stronger impact in OS with >12 cycles. The retrospective study<br />
design limits conclusions and further validation is necessary in prospective randomized<br />
studies.<br />
Legal entity responsible for the study: N/A<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
351P<br />
Brain metastases in NSCLC patients in the era <strong>of</strong> precision<br />
medicine<br />
S. Mpima 1 , C. Anger 1 , L. Mitr<strong>of</strong>an 2<br />
1 Global <strong>Oncology</strong>, IMS Health, London, UK, 2 Global <strong>Oncology</strong>, IMS Health, La<br />
Defence, France<br />
Background: The frequent occurrence <strong>of</strong> brain metastases (BM) in patients with<br />
advanced NSCLC represents a significant obstacle to long-term survival. The<br />
development <strong>of</strong> targeted therapies (TTs) in NSCLC along with compelling evidence<br />
suggesting that EGFR overexpansion might play a role in cancer metastasis mechanism<br />
to the brain makes their usage a very appealing substitution approach to available<br />
treatment options in neurooncology. However, the literature describing effects <strong>of</strong> TTs<br />
on brain lesions and microenvironment remains sparse. In addition, initial clinical<br />
developments <strong>of</strong> systemic treatments in NSCLC exclude patients with active BM. Using<br />
real world data, we are able to pr<strong>of</strong>ile patients with BM from NSCLC including full<br />
molecular pr<strong>of</strong>ile along with the effects <strong>of</strong> the EGFR Inhibitors.<br />
Methods: This study used IMS <strong>Oncology</strong> Analyzer, a syndicated, retrospective,<br />
longitudinal cancer treatment database, collecting anonymized patient-level oncology<br />
data in EU5, projected to national level. Data collected between 2006 - 2015 was used<br />
to pr<strong>of</strong>ile BM patients and treatment effects with a special emphasis on anti EGFR<br />
therapies.<br />
Results: Of the currently 607,437 treated population with BM, lung cancer accounts for<br />
50%, followed by breast (14%), and melanoma (11%). NSCLC alone accounts for 34%<br />
from the entire currently treated population. 77% <strong>of</strong> the NSCLC with BM is<br />
non-squamous and 11% is EGFR mutated; mode age is between 61-65 years. 69 % <strong>of</strong><br />
the studied population previously treated with EGFR inhibitors [erlotinib (ERL),<br />
gefitinib (GFT)], discontinued their therapy due to distant and/or local progression<br />
after on average 6.3 months while in patients with no BM it was on average 7.1 months.<br />
10% <strong>of</strong> these patients were retreated with an EGFR inhibitor, either reversible (ERL,<br />
GFT) or irreversible (afatinib-based regimens, osimertinib). The remaining, received<br />
pemetrexed (28%), platinum-based therapies (9%), and chemotherapy alone (50%).<br />
Conclusions: The usage <strong>of</strong> reversible EGFR inhibitors in BM patients from NSCLC has<br />
limited benefit and chemotherapy remains the treatment <strong>of</strong> choice after TTs failure.<br />
TTs which can penetrate the Blood-Brain Barrier today <strong>of</strong>fer a new treatment option<br />
for BM patients, but further stratification <strong>of</strong> this patient segment is mandatory to drive<br />
clinical innovation.<br />
Legal entity responsible for the study: IMS Health<br />
Funding: IMS Health<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
352P<br />
abstracts<br />
Functional status <strong>of</strong> central nervous system in intensive<br />
radiotherapy for brain metastases<br />
M. Zinkovich 1 , O. Kit 2 , T. Protasova 3 , A. Pushkin 3 , Y. Arapova 3 , E. Korobeynikova 3 ,<br />
A. Shikhlyarova 3 , L. Vladimirova 4<br />
1 Department <strong>of</strong> Radiology, Rostov Research Institute <strong>of</strong> <strong>Oncology</strong>,<br />
Rostov-on-Don, Russian Federation, 2 Surgical Department, Rostov Research<br />
Institute <strong>of</strong> <strong>Oncology</strong>, Rostov-on-Don, Russian Federation, 3 Experimental<br />
Laboratory Center, Rostov Research Institute <strong>of</strong> <strong>Oncology</strong>, Rostov-on-Don,<br />
Russian Federation, 4 Department <strong>of</strong> Chemotherapy, Rostov Research Institute <strong>of</strong><br />
<strong>Oncology</strong>, Rostov-on-Don, Russian Federation<br />
Background: Combined treatment including whole brain irradiation (WBI) with<br />
additional boost has shown its advantages concerning overall survival <strong>of</strong> patients with<br />
solitary brain metastasis (SBM). However, the literature data on neurotoxicity and<br />
safety <strong>of</strong> additional local irradiation are ambiguous. The purpose <strong>of</strong> the study was to<br />
compare electrophysiological parameters <strong>of</strong> the functional state <strong>of</strong> the brain after WBI<br />
and WBI with additional boost to the bed <strong>of</strong> removed metastatic foci.<br />
Methods: The study included 16 patients <strong>of</strong> each gender with SBM after the treatment<br />
<strong>of</strong> primary tumors. Parameters <strong>of</strong> EEG and electrical conductivity (EC) <strong>of</strong> auricular<br />
points (AP) were studied in two groups <strong>of</strong> patients receiving irradiation 3-4 weeks after<br />
metastasis removal: the control group (WBI) and the main one (WBI + boost). EEG<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw367 | vi111
abstracts<br />
was recorded monopolarly using Encephalan EEG-19/26, Russia (26 channels) from 19<br />
electrodes according to the international 10–20 system. Power spectrum values before<br />
and after radiation therapy (RT) were compared using MANOVA. ECAP were studied<br />
using DiaDENS PC medical diagnostic system at the same RT stages.<br />
Results: The main group showed increased power values <strong>of</strong> θ range by 6-9% (р < 0.05),<br />
compared with the initial values, at Ϝ 3 , Р Z , С 3 after RT, as well as decreased α values by<br />
10-13% (р < 0.05) at О 2 , Т 4 . Analysis <strong>of</strong> EC in AP <strong>of</strong> the nervous system demonstrated<br />
primary transition to the hyp<strong>of</strong>unction during RT, which was more marked in the<br />
main group: in AP associated to the cerebral cortex, dynamics <strong>of</strong> decrease <strong>of</strong> functional<br />
activity in the structure was noted 2.4 times more <strong>of</strong>ten than in WBI.<br />
Conclusions: EEG and electroacupuncture parameters showed the decrease in CNS<br />
functional activity during increased radiation exposure due to the additional boost. The<br />
data suggest the need for development <strong>of</strong> bioadaptive effects weakening the damaging<br />
effects <strong>of</strong> adjuvant RT in patients with brain metastasis.<br />
Legal entity responsible for the study: Rostov Research Institute <strong>of</strong> <strong>Oncology</strong><br />
Funding: Ministry <strong>of</strong> Health <strong>of</strong> the Russian Federation<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
353P<br />
Metformin as an adjuvant anticancer therapy in the treatment<br />
<strong>of</strong> high grade glioma<br />
D.Q. Chong 1 , C.K. Tham 1 , W.H. Ng 2 , L-L. Kwok 3 , E. Aliwarga 4 , Y.L. Kok 4 , P.Y.<br />
P. Lam 4<br />
1 Medical <strong>Oncology</strong>, National Cancer Center, Singapore, 2 Neurosurgery, National<br />
Neuroscience Institute, Singapore, 3 CTE - Clinical Trials Office, National Cancer<br />
Center, Singapore, 4 Division <strong>of</strong> Cellular and Molecular Research, Laboratory <strong>of</strong><br />
Cancer Gene Therapy, National Cancer Center, Singapore<br />
Background: Despite standard treatment with surgery, temozolomide (TMZ) and<br />
radiotherapy, the prognosis <strong>of</strong> high-grade glioma (HGG) remains dismal. Metformin,<br />
an anti-diabetic drug has demonstrated anti-tumor effects in gliomas. Interestingly, a<br />
recent transcriptomic analysis study showed that interleukin 13 receptor alpha 2<br />
(IL-13Rα2) is highly upregulated in patients with diabetic nephropathy. IL-13Rα2is<br />
also commonly overexpressed in HGG. However, the effect <strong>of</strong> metformin on<br />
IL-13Rα2-expressing glioma cells is currently unknown. Hence, we aim to evaluate the<br />
combined treatment <strong>of</strong> TMZ and metformin in a series <strong>of</strong> human glioma cells with<br />
IL-13Rα2, and other commonly found genetic aberrations for translational purpose.<br />
Methods: A series <strong>of</strong> human glioma cell lines were treated with TMZ, metformin and a<br />
combination <strong>of</strong> TMZ and metformin. Cell viability was determined with CCK-8 assay.<br />
The effect <strong>of</strong> these treatments on key glioma-associated signalling pathways, such as<br />
phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mTOR were investigated by<br />
immunoblot analysis. Findings were validated through loss-<strong>of</strong>-function assays.<br />
Results: IL-13Rα2 positive glioma cells were resistant to metformin in a<br />
dose-dependent manner. The combination <strong>of</strong> TMZ and metformin markedly<br />
enhanced adenosine monophosphate-activated protein kinase (AMPK) activation in<br />
IL-13Rα2-positive glioma cells, compared to IL-13Rα2-null glioma cells. Furthermore,<br />
in the combined treatment group, metformin effectively inhibited Akt and mTOR<br />
activation induced by TMZ. There was no significant reduction in mTOR and S6K<br />
phosphorylation in the combined versus metformin group.<br />
Conclusions: Metformin sensitizes TMZ-resistant cells to increased cell death. The<br />
overexpression <strong>of</strong> IL-13Rα2 in glioma cells could confer resistance against metformin<br />
through the enhanced activation <strong>of</strong> AMPK and Akt pathways. Elucidation <strong>of</strong> how<br />
IL-13Rα2 confers resistance against metformin is important in the potential<br />
application <strong>of</strong> metformin in patients with high-grade glioma.<br />
Legal entity responsible for the study: Dawn Chong<br />
Funding: National Medical Research Council<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
354P<br />
Phase II study <strong>of</strong> atorvastatin in combination with radiotherapy<br />
and temozolomide In patients with glioblastoma (ART): interim<br />
analysis report<br />
A.K. Altwairgi 1 , W. Alghareeb 1 , F. Alnajjar 1 , E. Alsaeed 1 , A. Balbaid 1 , H. Alhussain 1 ,<br />
S. Aldanan 1 ,Y.Orz 2 , A. Lari 2 , A. Alsharm 1<br />
1 Comprehensive cancer center, King Fahad Medical City, Riyadh, Saudi Arabia,<br />
2 National Neuroscience Institute, King Fahad Medical City, Riyadh, Saudi Arabia<br />
Background: Glioblastoma (GBM) is the commonest primary brain tumor in adult<br />
and it carries the worst prognosis. Atorvastatin is an inhibitor <strong>of</strong> HMG-CoA reductase,<br />
a rate limiting enzyme in the mevalonate pathway. Preclinical studies demonstrate<br />
encouraging anticancer activity <strong>of</strong> statins.<br />
Methods: In this open-label, prospective, single-arm, phase II study, eligible patients<br />
received oral Atorvastatin (40 mg/d for 3 weeks and 80 mg/d thereafter) in<br />
combination with standard therapy comprising radiotherapy (60 Gy/30 fractions) and<br />
TMZ (75 mg/m 2 /d) in the 6-wk concurrent phase, then with TMZ (150-200 mg/m 2 /d<br />
on days 1-5 for 6 cycles). The primary endpoint is progression free survival (PFS) at 6<br />
months. A minimum <strong>of</strong> 80% power required at least 32 eligible patients with planned<br />
interim analysis after the first 15 evaluable patients.<br />
Results: From January 2014, 20 <strong>of</strong> 32 planned patients have received therapy and the<br />
first 15 evaluable patients were included in this planned interim analysis. Median age<br />
was 48 (20-69); 28% were ≥ 60 years <strong>of</strong> age and 61% were male. 95% <strong>of</strong> patients<br />
underwent resection and 5% had biopsy only. Patients had median and minimum<br />
follow-up <strong>of</strong> 11.6 months and 6 months, respectively. PFS-6 rate was 67% with median<br />
PFS <strong>of</strong> 9.1 months. Median overall survival has not yet been reached to date. Grades 3<br />
and 4 hematological adverse events occurred in 33% <strong>of</strong> patients. Three patient died due<br />
to disease progression.<br />
Conclusions: This is the first clinical trial investigating statins in combination with<br />
standard therapy (RT and TMZ) in newly diagnosed GBM patients. Planned interim<br />
analysis appears promising and it met criteria for continued accrual.To date, the<br />
treatment was safe in this patient population. clinical trial information: NCT02029573<br />
Clinical trial identification: NCT02029573<br />
Legal entity responsible for the study: Ministry <strong>of</strong> Health, Saudi Arabia<br />
Funding: King Fahad Medical City<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
355TiP<br />
METIS: A phase III study <strong>of</strong> radiosurgery with TTFields for<br />
1-10 brain metastases from NSCLC<br />
M.P. Mehta 1 , V. Gondi 2 , P.D. Brown 3<br />
1 Radiation <strong>Oncology</strong>, University <strong>of</strong> Maryland School <strong>of</strong> Medicine, Baltimore, MD,<br />
USA, 2 Radiation <strong>Oncology</strong>, Northwestern Medicine Cancer Center, Chicago, IL,<br />
USA, 3 Radiation <strong>Oncology</strong>, MD Anderson Cancer Center, Houston, TX, USA<br />
Background: Tumor Treating Fields (TTFields) are a novel, non-invasive regional<br />
anti-mitotic treatment modality, based on low intensity alternating electric fields.<br />
Efficacy <strong>of</strong> TTFields in non-small cell lung cancer (NSCLC) has been demonstrated in<br />
multiple in vitro and in vivo models, and in a phase I/II clinical study. TTFields<br />
treatment to the brain was shown to be safe and effective in glioblastoma patients.<br />
Trial design: 270 patients with 1-10 brain metastases (BM) from NSCLC will be<br />
randomized in a ratio <strong>of</strong> 1:1 to receive stereotactic radio surgery (SRS) followed by<br />
either TTFields or supportive care alone. Patients are followed-up every two months<br />
until 2 nd cerebral progression. Patients in the control arm may cross over to receive<br />
TTFields at the time <strong>of</strong> 1 st cerebral progression. Objectives: To test the efficacy, safety<br />
and neurocognitive outcomes <strong>of</strong> TTFields in this patient population. Endpoints: Time<br />
to 1 st cerebral progression (primary); time to neurocognitive failure based on the<br />
following tests: HVLT, COWAT and TMT; overall survival; radiological response rate;<br />
quality <strong>of</strong> life; adverse events severity and frequency (secondary). Treatment:<br />
Continuous TTFields at 150 kHz will be applied to the brain within 7 days <strong>of</strong> SRS. The<br />
treatment system is a portable medical device allowing normal daily life activities. The<br />
device delivers TTFields to the brain using 4 Transducer Arrays, which may be covered<br />
by a wig or a hat for cosmetic reasons. Patients will receive the best standard <strong>of</strong> care for<br />
their systemic disease. Statistical Considerations: This is a prospective, randomized,<br />
multicenter study for 270 patients. The trial is designed to detect an increase in the<br />
time to cerebral progression from 7.7 to 13.4 months (hazard ratio 0.57). This sample<br />
size assessment takes into consideration a competing risk (death prior to cerebral<br />
progression) <strong>of</strong> 0.08252 per month in both treatment arms. The competing risk is<br />
based on a predicted median overall survival <strong>of</strong> 8.4 months mainly due to systemic<br />
disease progression. The trial has 80% power at a two sided alpha <strong>of</strong> 0.05. The sample<br />
size was calculated using a log-rank test (based on Lakatos 1988 and 2002).<br />
Legal entity responsible for the study: FDA<br />
Funding: Novocure Ltd.<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
356TiP<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
A randomized phase 2, single-blind study <strong>of</strong> temozolomide<br />
(TMZ) and radiotherapy (RT) combined with nivolumab or<br />
placebo (PBO) in newly diagnosed adult patients (pts) with<br />
tumor O6-methylguanine DNA methyltransferase<br />
(MGMT)-methylated glioblastoma (GBM)—CheckMate-548<br />
M. Weller 1 , G. Vlahovic 2 , M. Khasraw 3 , A.A. Brandes 4 , R. Zwirtes 5 , K. Tatsuoka 6 ,<br />
A.F. Carpentier 7 , D.A. Reardon 8 , M. van den Bent 9<br />
1 Department <strong>of</strong> Neurology, University Hospital Zurich, Zurich, Switzerland, 2 Brain<br />
Tumor Immunotherapy Clinical Research, Duke University Medical Center,<br />
Durham, NC, USA, 3 Sydney Medical School, University <strong>of</strong> Sydney, Sydney,<br />
Australia, 4 Medical <strong>Oncology</strong> Dept, AUSL BOLOGNA-Italy, Bologna, Italy,<br />
5 Medical Monitor, Bristol-Myers Squibb, Princeton, NJ, USA, 6 Biostatistics,<br />
Bristol-Myers Squibb, Princeton, NJ, USA, 7 Assistance Publique-Hôpitaux de<br />
Paris, Service de Neurologie, Hôpital Avicenne, Bobigny, France, 8 Center for<br />
Neuro-<strong>Oncology</strong>, Dana-Farber Cancer Institute, Boston, MA, USA,<br />
9 Neuro-<strong>Oncology</strong>, Erasmus MC Daniel den Hoed Cancer Center, Rotterdam,<br />
Netherlands<br />
Background: GBM, the most common adult primary brain tumor, has an aggressive<br />
clinical course and a poor prognosis. Approximately 40% <strong>of</strong> pts with GBM have<br />
tumors with a methylated MGMT gene promoter, which is associated with DNA<br />
repair. In these pts, TMZ may induce DNA damage and cell death due to silencing <strong>of</strong><br />
vi112 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
the MGMT promoter, a mechanism potentially augmented by combination with<br />
checkpoint inhibitors. Nivolumab, a fully human IgG4 monoclonal antibody to the<br />
programmed death-1 receptor, has demonstrated overall survival (OS) benefit in the<br />
treatment <strong>of</strong> metastatic melanoma, non-small cell lung cancer, and advanced renal cell<br />
carcinoma. CheckMate-548 (NCT02667587) is a phase 2, randomized, single-blind<br />
study evaluating the efficacy and safety <strong>of</strong> TMZ/RT —> TMZ with nivolumab or PBO<br />
in pts with newly diagnosed MGMT-methylated GBM. In a companion phase 3 trial<br />
(CheckMate-498; NCT02617589), eligible pts with MGMT-unmethylated tumors<br />
(N = 550) will be randomized to receive nivolumab + RT followed by nivolumab, or<br />
TMZ/RT —> TMZ, with OS as the primary endpoint.<br />
Trial design: Eligibility criteria include newly diagnosed, histologically confirmed<br />
supratentorial GBM in pts aged ≥18 years with Karn<strong>of</strong>sky performance status ≥70,<br />
and a tumor test result that shows a MGMT methylated, partially methylated, or<br />
indeterminate methylation type. Pts previously treated for GBM other than by<br />
resection and those with recurrent or secondary GBM are ineligible. Approximately<br />
320 pts, stratified by partial or complete resection, will be randomized 1:1 to receive<br />
TMZ/RT —> TMZ in combination with nivolumab or PBO. Treatment will continue<br />
until disease progression or unacceptable toxicity. The primary objective is OS in pts<br />
treated with TMZ/RT —> TMZ and nivolumab versus TMZ/RT —> TMZ and PBO;<br />
the secondary objective is progression-free survival. Select exploratory objectives<br />
include safety, biomarker analyses, and neurocognitive outcomes. In the follow-up<br />
period, safety and tolerability, tumor progression, and survival will be evaluated.<br />
abstracts<br />
Legal entity responsible for the study: Bristol-Myers Squibb<br />
Funding: Bristol-Myers Squibb<br />
Disclosure: M. Weller: Has received research funding and/or honoraria from Celldex,<br />
ICT, Isarna, Magforce, MSD, Merck SG, Novocure, Northwestern Bio, Pfizer, Roche,<br />
Teva, Acceleron Pharma, Bayer. G. Vlahovic: Received research funding, honoraria,<br />
provided consulting or advisory services, or had travel, accommodations, or other<br />
expenses paid or reimbursed by Genentech, Pfizer, Hospira, or Bristol-Meyers Squibb.<br />
A.A. Brandes: Has had travel, accommodations, or other expenses paid or reimbursed<br />
by RocheR. Zwirtes: Is an employee <strong>of</strong> Bristol-Myers Squibb who sponsored this<br />
study. K. Tatsuoka: Is an employee <strong>of</strong> Bristol-Myers Squibb who sponsored this study,<br />
and has patents, royalties, or other intellectual property interests related to<br />
GlaxoSmithKline. A.F. Carpentier: Has provided consulting services for Bristol-Myers<br />
Squibb. D.A. Reardon: Received research funding, honoraria, or provided consulting<br />
for Cavion, Genentech/Roche, Merck, Momenta, Novartis, Novocure, Regeron,<br />
Stemline Ther, BMS, Inovio, Juno Ther, Celldex, Oxigene, Celldex, Incyte, Midatech,<br />
Monteris Medical, Abbvie. M. van den Bent: Provided consulting or advisory services,<br />
or received research funding from Cavion, Roche, Merck, Serono, Actelion, Abbvie,<br />
Celldex, Amgen, Blue Earth Diagnostics, Novocure, Novartis, and Bristol-Myers<br />
Squibb. All other authors have declared no conflicts <strong>of</strong> interest.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw367 | vi113
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong> 27 (Supplement 6): vi114–vi135, 2016<br />
doi:10.1093/annonc/mdw368<br />
developmental therapeutics<br />
357O<br />
A phase I study evaluating DLYE5953A, an antibody-drug<br />
conjugate targeting the tumor-associated antigen lymphocyte<br />
antigen 6 complex locus E (Ly6E), in patients (Pts) with solid<br />
tumors<br />
S. Modi 1 , J.P. Eder 2 , P. Lorusso 2 , C. Weekes 3 , S. Chandarlapaty 4 , S.M. Tolaney 5 ,<br />
J. McLaughlin 2 , D.R. Camidge 6 , C-W. Chang 7 , D. Nazzal 7 , S-C. Chen 7 ,<br />
E. Schuth 7 , F. Brunstein 7 , W. Darbonne 7 , W. Flanagan 7 , A. Ungewickell 7 ,<br />
G. Shapiro 8<br />
1 Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA, 2 Yale<br />
School <strong>of</strong> Medicine, Yale Cancer Center, New Haven, CT, USA, 3 Department <strong>of</strong><br />
Medicine, University <strong>of</strong> Colorado Cancer Center Anschutz Cancer Pavilion, Aurora,<br />
CO, USA, 4 Human <strong>Oncology</strong> & Pathogenesis Program, Memorial Sloan Kettering<br />
Cancer Center, New York, NY, USA, 5 Breast <strong>Oncology</strong> Center, Dana-Farber<br />
Cancer Institute, Boston, MA, USA, 6 Cancer Center, University <strong>of</strong> Colorado,<br />
Aurora, CO, USA, 7 Early Development, Genentech, Inc., South San Francisco, CA,<br />
USA, 8 Early Drug Development Centre, Dana-Farber Cancer Institute, Boston, MA,<br />
USA<br />
358O<br />
89Zr-labeled CEA-targeted IL-2 variant immunocytokine in<br />
patients with solid tumors: CEA-mediated tumor<br />
accumulation in a dose-dependent manner and role <strong>of</strong> IL-2<br />
receptor-binding<br />
C.W. Menke-van der Houven van Oordt 1 , E. van Brummelen 2 ,T.Nayak 3 ,<br />
M. Huisman 4 , L. de Wit- van der Veen 5 , E. Mulder 4 , O. Hoekstra 4 , M. Stokkel 5 ,G.<br />
A. van Dongen 4 , H.M. Verheul 1 , M. Feilke 6 , C. Guizani 3 , E. Guarin 3 , S. Evers 7 ,<br />
J. Saro 7 , J.H.M. Schellens 2<br />
1 Medical <strong>Oncology</strong>, Vrije University Medical Centre (VUMC), Amsterdam,<br />
Netherlands, 2 Clinical Pharmacology, The Netherlands Cancer Institute Antoni van<br />
Leeuwenhoek Hospital, Amsterdam, Netherlands, 3 Roche Pharma Research and<br />
Early Development, Roche Innovation Centre, Basel, Switzerland, 4 Nuclear<br />
Medicine and Radiology, Vrije University Medical Centre (VUMC), Amsterdam,<br />
Netherlands, 5 Nuclear Medicine, The Netherlands Cancer Institute Antoni van<br />
Leeuwenhoek Hospital, Amsterdam, Netherlands, 6 Roche Pharma Research and<br />
Early Development, Roche Innovation Centre, Prentsberg, Germany, 7 Roche<br />
Pharma Research and Early Development, Roche Innovation Centre, Zürich,<br />
Switzerland<br />
abstracts<br />
© European Society for Medical <strong>Oncology</strong> 2016. Published by Oxford University Press on behalf <strong>of</strong> the European Society for Medical <strong>Oncology</strong>.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com.
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
359O<br />
First-in-human study <strong>of</strong> AC0010, a novel irreversible,<br />
mutant-selective EGFR inhibitor in patients with 1st<br />
generation EGFR TKI-resistant non-small cell lung cancer<br />
(NSCLC)<br />
L. Zhang 1 , H. Zhao 2 ,B.Hu 3 , J. Jiang 3 , X. Zheng 3 , Y. Zhang 2 ,Y.Ma 2 ,J.Ge 2 ,<br />
B. Zou 1 , X. Fang 4 ,W.Xu 4 ,X.Xu 5<br />
1 State Key Laboratory <strong>of</strong> <strong>Oncology</strong> in South China, Sun Yat-sen University Cancer<br />
Center, Guangzhou, China, 2 Clinical trial center, Cancer Centre Sun Yat-Sen<br />
University, Guangzhou, China, 3 Clinical Pharmacology Research Center, Peking<br />
Union Medical College Hospital, Beijing, China, 4 ACEA Biosciences Inc., ACEA<br />
Pharmaceutical Research, Hangzhou, China, 5 ACEA Pharmaceutical Research,<br />
ACEA Biosciences Inc., San Diego, CA, USA<br />
abstracts<br />
microangiopathy (1pt each). The only grade 3 AE occurring in >10% <strong>of</strong> pts was<br />
hypertension (33%). The most frequent AEs, irrespective <strong>of</strong> relation to study drug, were<br />
hypertension (63% <strong>of</strong> pts), diarrhea (46%), fatigue (46%), cough (33%), nausea (29%),<br />
proteinuria, anorexia, and vomiting (25% each). Pharmacokinetic analyses show<br />
dose-dependent AUC and Cmax increases and sustained exposure over multiple cycles<br />
with a mean half-life <strong>of</strong> 12 days. Signs <strong>of</strong> clinical activity were observed. Two patients<br />
showed significant reductions in tumor volume (1 confirmed as partial response). In<br />
addition, prolonged stable disease was seen in 4 patients (between 22 and 60 weeks).<br />
Conclusions: MP0250 showed a favorable PK pr<strong>of</strong>ile and is well tolerated with most<br />
AEs being consistent with pr<strong>of</strong>ound inhibition <strong>of</strong> the VEGF pathway. Signs <strong>of</strong> clinical<br />
activity were seen. Expansion cohorts are planned and ongoing. Phase 2 studies in<br />
selected oncology indications including multiple myeloma are planned.<br />
Clinical trial identification: MP0250-CP101<br />
Legal entity responsible for the study: Molecular Partners<br />
Funding: Molecular Partners<br />
Disclosure: M.R. Middleton: Consultant and/or Research support: Abbvie, Amgen,<br />
AZ, BMS, Clovis, Eisai, GSK, Immucore, Lilly, Merck, Millenium, Novartis,<br />
Physiomics, Rigontec, Roche, Molecular Partners, Pfizer, Vertex (all to<br />
institution). J. Rodón: Novartis; Eli Lilly; Servier; Leti Pharma. C. Zitt, D. Feurstein,<br />
S. Schreiner, D. Turner, K. Dawson, K. Tadjalli-Mehr, E. vom Baur, M. Stumpp,<br />
A. Harstrick: Molecular Partners stock. A. Omlin: Travel support; Bayer; Travel<br />
support; San<strong>of</strong>i; Janssen; Travel support; Astellas; Pfizer; AstraZeneca; Teva. Research<br />
support: Janssen, Teva. All other authors have declared no conflicts <strong>of</strong> interest.<br />
362PD<br />
TAX-TORC: An investigator initiated phase I study combining<br />
the dual mTORC1/2 inhibitor AZD2014 in combination with<br />
weekly paclitaxel in high-grade serous ovarian cancer<br />
U. Banerji 1 , B. Basu 2 , J.F. Spicer 3 , R. Wilson 4 , E. Hall 1 , R. Sundar 1 , S. Kumar 2 ,<br />
Y. Wu 3 , V. Coyle 4 , S. Carreira 1 , M. Parmar 1 , J.C. Dawes 1 , S. Banerjee 1 , J.S. de<br />
Bono 1<br />
1 Drug Development Unit, Institute <strong>of</strong> Cancer Research ICR, London, UK,<br />
2 <strong>Oncology</strong>, Addenbrooke’s Hospital University <strong>of</strong> Cambridge Hospitals,<br />
Cambridge, UK, 3 Department <strong>of</strong> Medical <strong>Oncology</strong>, King’s College London Guy’s<br />
Hospital, London, UK, 4 Centre for Cancer Research and Cell Biology, Queen’s<br />
University Belfast, Belfast, UK<br />
361PD<br />
Interim results from the completed first-in-human phase I<br />
dose escalation study evaluating MP0250, a multi-DARPin®<br />
blocking HGF and VEGF, in patients with advanced solid<br />
tumors<br />
M.R. Middleton 1 , A. Azaro 2 , S. Kumar 3 , P. Niedermann 4 , J. Rodón 2 ,K.<br />
H. Herbschleb 1 , J. Steiner 5 , C. Zitt 6 , D. Feurstein 6 , S. Schreiner 6 , D. Turner 6 ,<br />
K. Dawson 6 , K. Tadjalli-Mehr 6 , E. vom Baur 6 , M. Stumpp 6 , A. Harstrick 6 , R. Baird 3 ,<br />
A. Omlin 4<br />
1 Cancer and Haematology Centre, Churchill Hospital, Oxford, UK, 2 Institute <strong>of</strong><br />
<strong>Oncology</strong>, Vall d’Hebron University Hospital Institut d’Oncologia, Barcelona,<br />
Spain, 3 Breast Cancer Research Unit, Addenbrooke’s Hospital University <strong>of</strong><br />
Cambridge Hospitals, Cambridge, UK, 4 Klinik für Onkologie und Hämatologie,<br />
Kantonsspital St. Gallen, St. Gallen, Switzerland, 5 Consulting, Oxford Therapeutics<br />
Consulting Ltd, Crowthorne, UK, 6 R&D, Molecular Partners, Zürich, Switzerland<br />
Background: The VEGF/VEGFR and HGF/cMet pathways are implicated in tumor<br />
survival, growth, angiogenesis, invasion and metastasis. DARPins® (designed ankyrin<br />
repeat proteins) are small proteins that can be engineered to bind to specific targets<br />
with high specificity and affinity. MP0250 is a first-in-class, tri-specific multi-DARPin®<br />
neutralizing VEGF and HGF as well as binding to human serum albumin to increase<br />
plasma half-life and potentially enhance tumor penetration.<br />
Methods: A phase I, open-label, multi-center study with completed dose escalation.<br />
Eligibility: patients with advanced solid tumors. Design: 3 + 3 dose escalation cohorts<br />
receiving intravenous MP0250 every 2 weeks.<br />
Results: A total <strong>of</strong> 24 patients have been enrolled in 5 cohorts: 0.5 (n = 3), 1.5 (n = 3), 4<br />
(n = 6), 8 (n = 7), or 12 mg/kg (n = 5) MP0250. The maximum tolerated dose was<br />
determined as 8 mg/kg. At 12mg/kg, 2 DLTs were observed in line with expected<br />
anti-VEGF activity: a grade 3 (CTC v4.03) GI hemorrhage and a grade 3 nephrotic<br />
syndrome plus grade 3 hypertension. Other AEs <strong>of</strong> special interest were: grade 3<br />
pulmonary embolism (2pts), grade 3 left ventricular failure, grade 4 thrombotic<br />
Background: We previously evaluated the tolerability <strong>of</strong> AZD2014 administered with<br />
weekly paclitaxel in 2 intermittent schedules. Based on the preliminary activity and<br />
preclinical data, we aimed to confirm tolerability in high-grade serous ovarian cancer<br />
(HGSOC), document preliminary efficacy and evaluate biomarkers <strong>of</strong> resistance and<br />
sensitivity.<br />
Methods: Patients with HGSOC were treated with oral AZD2014 (50mg BD) for 3 days<br />
on/4 days <strong>of</strong>f with weekly paclitaxel (80mg/m 2 ) for 6 weeks <strong>of</strong> a 7 week cycle. Archival<br />
tumour samples are being assessed by targeted next-generation sequencing to identify<br />
potential biomarkers <strong>of</strong> sensitivity and resistance. Circulating plasma DNA<br />
assessments are being performed at baseline, at the end <strong>of</strong> cycle 1, at maximum<br />
response and at relapse.<br />
Results: Currently 20/25 patients have been recruited with a median age <strong>of</strong> 67 years.<br />
The median number <strong>of</strong> previous treatments is 3 and 18/20 patients (90%) were<br />
platinum resistant or refractory prior to trial entry. Nineteen <strong>of</strong> the twenty patients<br />
(95%) received prior paclitaxel, <strong>of</strong> whom 3/20 (15%) received weekly paclitaxel. All 20<br />
patients were assessed for toxicity; the most common grade 3-4 toxicities seen were<br />
vomiting (3/20), diarrhoea (2/20) and respiratory infections (2/20). There were 2 cases<br />
<strong>of</strong> pneumonitis (grades 1 and 3) and one case <strong>of</strong> bowel perforation which occurred at<br />
the site <strong>of</strong> metastatic infiltration, in the context <strong>of</strong> a rapidly reducing CA125 response.<br />
Twelve patients were evaluable for RECIST response at the end <strong>of</strong> cycle 1, after 6 weeks<br />
<strong>of</strong> combination therapy, 7/12 (58%) showed a partial response. Of 14 patients with<br />
evaluable CA125, 10 (71%) had a 50% reduction in baseline values. Of the patients that<br />
had previously received weekly paclitaxel, 2/3 (67%) had a CA125 response <strong>of</strong> greater<br />
than 50%. Biomarker analysis will be presented as the trial data matures.<br />
Conclusions: The combination <strong>of</strong> the AZD2014 and paclitaxel is tolerable in patients<br />
with HGSOC. This schedule has shown promising preliminary efficacy in a population<br />
<strong>of</strong> patients pre-treated with a paclitaxel-containing regimen.<br />
Clinical trial identification: EudraCT#2012-003896-20<br />
Legal entity responsible for the study: Institute <strong>of</strong> Cancer Research and Royal<br />
Marsden NHS Foundation Trust<br />
Funding: ECMC and AstraZeneca<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw368 | vi115
abstracts<br />
363PD<br />
Molecular imaging <strong>of</strong> PgP/BCRP inhibition at the blood brain<br />
barrier using elacridar and [11C]erlotinib PET<br />
R.B. Verheijen 1 , M. Yaqub 2 , E. Sawicki 1 , O. van Tellingen 3 , A.A. Lammertsma 2 ,<br />
B. Nuijen 1 , J.H.M. Schellens 4 , J.H. Beijnen 1 , A.D.R. Huitema 1 , N.H. Hendrikse 2 ,<br />
N. Steeghs 4<br />
1 Department <strong>of</strong> Pharmacy and Pharmacology, The Netherlands Cancer Institute<br />
Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands, 2 Department <strong>of</strong><br />
Radiology & Nuclear Medicine, Vrije University Medical Centre (VUMC),<br />
Amsterdam, Netherlands, 3 Department <strong>of</strong> Bio-Pharmacology/ Mouse Cancer<br />
Clinic, The Netherlands Cancer Institute Antoni van Leeuwenhoek Hospital,<br />
Amsterdam, Netherlands, 4 Department <strong>of</strong> Medical <strong>Oncology</strong> & Clinical<br />
Pharmacology, The Netherlands Cancer Institute Antoni van Leeuwenhoek<br />
Hospital, Amsterdam, Netherlands<br />
Background: Drug transporters such as PgP and BCRP limit the exposure <strong>of</strong> several<br />
drugs to the brain. This study investigated the effect <strong>of</strong> the PgP/BCRP inhibitor<br />
elacridar at the blood brain barrier <strong>of</strong> mice and cancer patients using the PET tracer<br />
[ 11 C]erlotinib.<br />
Methods: Elacridar (10, 25, 50 mg/kg) and cold erlotinib (20 mg/kg) were<br />
administered orally to wild type (WT) mice (n = 4 per group). Erlotinib was measured<br />
in blood and the brain ex vivo using LC-MS/MS. In addition, brain uptake was assessed<br />
using [ 11 C]erlotinib (SA > 18.5 GBq/µmol, 10 MBq) time-activity curves (TAC) and ex<br />
vivo scintillation counting in WT (n = 2) and PgP/BCRP knockout (KO) mice (n = 2).<br />
Six patients underwent [ 11 C]erlotinib PET before and after an oral dose <strong>of</strong> 1000 mg<br />
elacridar. Uptake <strong>of</strong> [ 11 C]erlotinib (SA > 18.5 GBq/µmol, 370 MBq) in the brain was<br />
quantified by pharmacokinetic modeling using volume <strong>of</strong> distribution (V T ) as the<br />
outcome parameter. V T is defined as activity in the brain/activity in plasma and was<br />
estimated using the two tissue reversible metabolite corrected plasma input curve.<br />
[ 15 O]H 2 O (800 MBq) scans were used to measure cerebral blood flow (CBF). Elacridar<br />
plasma concentrations were measured at the start and end <strong>of</strong> each scan.<br />
Results: Brain uptake <strong>of</strong> [ 11 C]erlotinib was higher in PgP/BCRP KO mice than in WT<br />
mice, both as TAC and ex vivo as % <strong>of</strong> injected dose/gram tissue (2.6-fold, p = 0.01). In<br />
WT mice, elacridar concentrations <strong>of</strong> ≥200 ng/mL resulted in increased brain<br />
concentration <strong>of</strong> erlotinib, achieving levels similar to KO mice, without affecting<br />
erlotinib plasma concentration. In patients, V T <strong>of</strong> [ 11 C]erlotinib did not increase after<br />
intake <strong>of</strong> elacridar (0.236 ± 0.11 versus 0.205 ± 0.07, mean ±SD, p = 0.43). [ 15 O]H 2 O<br />
PET showed no significant changes in CBF. Elacridar exposure in patients was<br />
340 ± 192 ng/mL (mean ±SD).<br />
Conclusions: When PgP/BCRP was disabled in mice, brain uptake <strong>of</strong> erlotinib<br />
increased both at a tracer and pharmacological dose. In patients, brain uptake <strong>of</strong> [ 11 C]<br />
erlotinib was not higher after administration <strong>of</strong> elacridar. The discrepancy between the<br />
preclinical and clinical results may be due to interspecies differences in abundance,<br />
activity and specificity <strong>of</strong> drug transporters in the mouse and human brain.<br />
Clinical trial identification: Netherlands Trial Registry number: NTR4780 EUdraCT<br />
clinical trial database: 2014-000281-21<br />
Legal entity responsible for the study: Netherlands Cancer Institute<br />
Funding: Netherlands Cancer Institute<br />
Disclosure: O. van Tellingen: Received research funding from Alion Pharmaceuticals<br />
(paid to institute). Is co-inventor <strong>of</strong> patent US20140235631A1. A.A. Lammertsma:<br />
Received research funding from Avid (paid to institute), recieved travel expenses and<br />
accommodation for a meeting co-sponsored by Philips. J.H. Beijnen: Owns stock in<br />
Modra Pharmaceuticals Holding, owns a patent on oral taxane<br />
formulations. N. Steeghs: Received research funding from Pfizer, GlaxoSmithKline,<br />
Novartis, Bayer, Boehringer Ingelheim and Roche. All other authors have declared no<br />
conflicts <strong>of</strong> interest.<br />
364PD<br />
Anti-tumor activity <strong>of</strong> PEGylated human IL-10 (AM0010) in<br />
renal cancer alone and in combination with anti-PD1<br />
A. Naing 1 , K.P. Papadopoulos 2 , K.A. Autio 3 , P.A. Ott 4 , M.R. Patel 5 , D.J. Wong 2 ,<br />
G. Falchook 6 , S. Pant 1 , M. Whiteside 2 , D. Rasco 7 , A. Patnaik 8 , J.C. Bendell 9 ,T.<br />
M. Bauer 10 , R.R. Colen 1 , D. Hong 1 , P. Van Vlasselaer 2 , G.L. Brown 2 , M. Oft 2 ,<br />
N. Tannir 1 , J.R. Infante 11<br />
1 Investigational Cancer Therapeutics, MD Anderson Cancer Center, Houston, TX,<br />
USA, 2 Clinical Operations, ARMO Biosciences, Redwood City, CA, USA, 3 Medical<br />
<strong>Oncology</strong>, Memorial Sloan-Kettering Cancer Center, New York, NY, USA,<br />
4 Medical <strong>Oncology</strong>, Dana-Farber Cancer Institute, Boston, MA, USA, 5 Drug<br />
Development Unit, Florida Cancer Specialists/Sarah Cannon Research Institute,<br />
Sarasota, FL, USA, 6 Drug Development, Sarah Cannon Research Institute,<br />
Denver, CO, USA, 7 START, South Texas Accelerated Research Therapeutics<br />
(START), San Antonio, TX, USA, 8 Medical <strong>Oncology</strong>, South Texas Accelerated<br />
Research Therapeutics (START), San Antonio, TX, USA, 9 GI <strong>Oncology</strong> Research,<br />
Sarah Cannon Research Institute, Nashville, TN, USA, 10 Drug Development, Sarah<br />
Cannon Research Institute/Tennessee <strong>Oncology</strong>, Nashville, TN, USA,<br />
11 Department <strong>of</strong> Medicine, Tennessee <strong>Oncology</strong>, PLLC, Nashville, TN, USA<br />
Background: IL-10 is regarded as an anti-inflammatory cytokine but it is also essential<br />
for the cytotoxicity and proliferation <strong>of</strong> antigen-activated CD8 T cells. Activation <strong>of</strong> the<br />
T cell receptor induces the expression <strong>of</strong> IL-10 receptors and PD-1 on CD8 T cells.<br />
This provides the mechanistic rationale for combining AM0010 and anti-PD1 for the<br />
treatment <strong>of</strong> cancer pts. Tolerability and anti-tumor activity <strong>of</strong> AM0010 alone and in<br />
combination with chemotherapies or immune checkpoint inhibitors was explored in a<br />
multi-basket phase 1 clinical trial.<br />
Methods: Pts with advanced renal cell cancer (RCC) were treated with AM0010 alone<br />
(daily SC) or in combination with pembrolizumab (q3wk IV). Tumor responses were<br />
monitored following irRC. Immune responses were measured by analysis <strong>of</strong> serum<br />
cytokines, activation <strong>of</strong> blood derived T cells, peripheral T cell clonality.<br />
Results: Nineteen pts. with RCC (15 evaluable), were treated with AMO010 alone (20<br />
mg/kg) and eight were treated in combination with pembrolizumab (2mg/kg). Both<br />
regimens were tolerated well (observation period 15 months). All TrAEs were transient<br />
and TrAEs leading to study discontinuation were not observed. There was no colitis,<br />
pneumonitis, or endocrine disruptions. G3/4 TrAEs in monotherapy included anemia<br />
(9), hypertriglyceridemia (3), thrombocytopenia (2), ALT/AST increase (2) and fatigue<br />
(2). AM0010 combination with Pembrolizumab did not increase TrAEs. Objective<br />
responses (PR/CR) were observed in 4 <strong>of</strong> 15 evaluable RCC pts. in monotherapy (27%)<br />
and in 4 <strong>of</strong> 8 patients in AM0010 /pembrolizumab (50%). Progression free survival<br />
(PFS) was 3 and 9.4 months, respectively. AM0010 alone and in combination with<br />
anti-PD1 increased Th1 cytokines (IL-18, IFNg, IL-7) as well as the number and<br />
proliferation <strong>of</strong> PD1+ activated CD8 T cells while decreasing the proliferation <strong>of</strong> FoxP3<br />
+ Tregs and TGFb in the blood. AM0010 / anti-PD1 induced de-novo oligoclonal<br />
expansion <strong>of</strong> T cell clones in the blood without affecting total lymphocyte counts.<br />
Conclusions: AM0010 alone or in combination with anti-PD1 is well-tolerated. The<br />
clinical activity and the observed CD8 T cell activation encourages the continued<br />
exploration <strong>of</strong> AM0010 in combination with anti-PD1.<br />
Clinical trial identification: Clinicaltrials.gov NCT02009449<br />
Legal entity responsible for the study: ARMO Bioscience - Martin Oft<br />
Funding: ARMO Biosciences<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
365PD<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Anti-oxidized macrophage migration inhibitory factor (oxMIF)<br />
antibody imalumab (BAX69) in advanced solid tumors: Final<br />
results <strong>of</strong> first-in-human phase 1 study<br />
D. Mahalingam 1 , M.R. Patel 2 , J.C. Sachdev 3 , L.L. Hart 4 , N. Halama 5 ,R.<br />
K. Ramanathan 6 , J. Sarantopoulos 7 , X. Liu 8 , S. Yazji 8 , D. Jäger 5 , M. Yoon 8 ,G.<br />
Ç. Manzur 8 , D. Adib 8 , R. Kerschbaumer 9 , A. Tsimberidou 10<br />
1 Hematology/oncology, Cancer Therapy Research Center, San Antonio, TX, USA,<br />
2 Sarah Cannon Research Institute, Florida Cancer Specialists, Sarasota, FL, USA,<br />
3 <strong>Oncology</strong>, HonorHealth Research Institute, Scottsdale, AZ, USA, 4 Hematology/<br />
oncology, Florida Cancer Specialists, Ft. Myers, FL, USA, 5 <strong>Oncology</strong>, National<br />
Center for Tumor Diseases, Heidelberg, Germany, 6 Hematology/oncology, Mayo<br />
Clinic Cancer Center, Scottsdale, AZ, USA, 7 <strong>Oncology</strong>, Institute for Drug<br />
Development Cancer Therapy Research Center, San Antonio, TX, USA, 8 Clinical,<br />
Baxalta, Cambridge, MA, USA, 9 Clinical, Baxalta Innovations GmbH, Vienna,<br />
Austria, 10 Investigational Cancer Therapeutics, MD Anderson Cancer Center,<br />
Houston, TX, USA<br />
Background: MIF is a pleiotropic cytokine involved in tumor cell proliferation,<br />
angiogenesis, and inflammation. oxMIF is the pathogenic is<strong>of</strong>orm found in tumor and<br />
its stroma. Imalumab is a novel recombinant, fully human, monoclonal antibody that<br />
targets oxMIF, with antitumor activity.<br />
Methods: Dose escalation study (3 + 3 design). Primary endpoint was maximum<br />
tolerated dose (MTD). Secondary endpoints were antitumor activity, safety,<br />
pharmacokinetics (PK), and pharmacodynamics (PD). Patients (pts), previously<br />
treated with other agents, received intravenous (IV) imalumab [28-d cycles; 2 dose<br />
schedules]: biweekly in all solid tumors (Q2W); weekly in metastatic colorectal cancer<br />
(mCRC), metastatic ovarian cancer (OvCa), and metastatic non-small cell lung cancer<br />
(NSCLC) (QW).<br />
Results: 50 pts dosed on the trial: 19 (Q2W) in 6 cohorts (1, 3, 10, 25, 37.5, and 50 mg/<br />
kg), and 31 (QW) in 2 cohorts (10 and 25 mg/kg) including expansion (10 mg/kg) into<br />
mCRC, OvCa, and NSCLC. Dose escalation was stopped at 50 mg/kg (Q2W) and 25<br />
mg/kg (QW). MTD was not reached. One mCRC pt reported dose-limiting toxicities:<br />
hypersensitivity pneumonitis (Q2W; 50 mg/kg) at grade 3. One NSCLC pt had grade 3<br />
treatment-related AEs (TRAE): constipation, nausea, and vomiting. Grade 2 TRAEs<br />
included: fatigue (n = 2), diarrhea (n = 1), peripheral edema (n = 1), infusion reaction<br />
(n = 1), and urticaria (n = 1). Stable disease (SD) ≥4 mo was seen in 8 pts, including 1<br />
pt with NSCLC who achieved SD for 12.6 mo and 1 with OvCa ongoing beyond 10 mo.<br />
In DS2, pre- and on-therapy tumor biopsies showed tissue penetration <strong>of</strong> imalumab<br />
resulting in target saturation in all biopsy-evaluable patients in all 3 tumor types.<br />
Biopsies revealed regulation <strong>of</strong> PI3K-AKT-mTOR downstream signaling, TNF-α<br />
signaling, anti-inflammatory cytokines (IL-1 and IL-10), and apoptosis. Based on<br />
clinical PK and PD study, 10 mg/kg weekly was considered a biologically active dose<br />
and sufficient to reach ≥95% target binding by the end <strong>of</strong> first cycle.<br />
Conclusions: Imalumab 10 mg/kg IV weekly was well tolerated and showed<br />
single-agent antitumor activity in these pts.<br />
Clinical trial identification: NCT01765790<br />
Legal entity responsible for the study: Baxalta<br />
vi116 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Funding: Baxalta<br />
Disclosure: D. Mahalingam: Participated in Ad Boards: Baxter, Genspera, Dendreon,<br />
San<strong>of</strong>i, Celgene. X. Liu, S. Yazji, M. Yoon, G.Ç. Manzur, D. Adib: Employee <strong>of</strong><br />
Baxalta. R. Kerschbaumer: Employee <strong>of</strong> Celgene A. Tsimberidou: Grants/Research<br />
Support Recipient: Onyx, EMD Serono, Baxter, Foundation Medicine All other authors<br />
have declared no conflicts <strong>of</strong> interest.<br />
366PD<br />
A phase I, open-label, multi-center, dose escalation study <strong>of</strong><br />
oral NVP-CGM097, a p53/HDM2-protein-protein interaction<br />
inhibitor, in adult patients with selected advanced solid<br />
tumors<br />
S. Bauer 1 , G. Demetri 2 , S. Jeay 3 , R. Dummer 4 , N. Guerreiro 3 , D.S. Tan 5 ,<br />
A. Kumar 6 , C. Meille 3 , L. Van Bree 3 , E. Halilovic 7 , J.U. Wuerthner 3 , P. Cassier 8<br />
1 Internal Medicine, Universitätsklinikum Essen, Essen, Germany, 2 Ludwig Center,<br />
Dana-Farber Cancer Institute, Boston, MA, USA, 3 Novartis Pharma AG, Basel,<br />
Switzerland, 4 University Hospital Zürich, Zürich, Switzerland, 5 National Cancer<br />
Center, Singapore, 6 Novartis Healthcare Pvt. Ltd., Hyderabad, India, 7 Novartis<br />
Institutes for BioMedical Research, Cambridge, MA, USA, 8 Centre Léon Bérard,<br />
Lyon, France<br />
Background: p53 is one <strong>of</strong> the most frequently inactivated proteins in human cancer,<br />
either through direct mutation <strong>of</strong> the TP53 gene or via suppressive mechanisms such<br />
as overexpression <strong>of</strong> HDM2. NVP-CGM097 is a potent and specific inhibitor <strong>of</strong> the<br />
HDM2/p53 interaction and has been shown to restore p53 function in preclinical<br />
models.<br />
Methods: This is a multi-center, open-label Phase 1, first in human study, enrolling<br />
patients (pts) with p53WT solid tumors. The primary objective is to determine the<br />
maximum tolerated dose (MTD); secondary objectives are to assess safety, tolerability,<br />
pharmacokinetics (PK), pharmacodynamics and preliminary antitumor activity.<br />
NVP-CGM097 was administered orally, initially in a continuous regimen three times<br />
weekly (3QW) in a 28-day cycle, and subsequently on an alternative regimen <strong>of</strong> 3QW<br />
in a two weeks on/ one week <strong>of</strong>f 21-day cycle. Dosing started at 10 mg 3QW and<br />
escalation was guided by a Bayesian logistic regression model to determine the MTD.<br />
Peripheral blood was collected for PK at multiple time points during the first 24 hours<br />
and after multiple dosing, and plasma GDF-15 levels were assessed at pre- and<br />
post-treatment on day 1.<br />
Results: 48 pts received at least one dose <strong>of</strong> NVP-CGM097. Post cycle 1 adverse event<br />
data suggested that the continuous regimen (31 pts, dose range 10-400 mg, 2 pts<br />
ongoing) was not tolerated due to delayed grade 3/4 thrombocytopenia and/or<br />
neutropenia. The switch to the pre-defined alternative dosing regimen allowed<br />
escalation to higher doses (17 pts, dose range 300-700 mg, 5 pts ongoing). Best overall<br />
responses were: 1 partial response (melanoma) 2.1%; 21 stable diseases (SD), 43.8%.<br />
Pts achieving SD had median duration <strong>of</strong> exposure <strong>of</strong> 24.14 weeks (wks) (range:<br />
7.7-86.7 wks, ongoing pts censored at data cut<strong>of</strong>f date). 12 pts (25%) had duration <strong>of</strong><br />
exposure <strong>of</strong> more than 24 wks. p53 pathway activation by NVP-CGM097 was<br />
demonstrated in pts by induction <strong>of</strong> its downstream target GDF-15 in serum and<br />
plasma.<br />
Conclusions: NVP-CGM097 single agent shows clinical activity (disease control) in<br />
pts with solid tumors as demonstrated for pts who remained on study more than 24<br />
wks. 7 pts (14.6%) are still on treatment and dose escalation is ongoing.<br />
Clinical trial identification: NCT01760525 First received January 2, 2013<br />
Legal entity responsible for the study: Novartis Pharma AG<br />
Funding: Novartis Pharma AG<br />
Disclosure: S. Bauer: Research support: Novartis, Blueprint Medicines, Ariad<br />
Consultant: GSK, Novartis, Pfizer, Bayer, Fresenius, Lilly, Blueprint Medicines<br />
Honoraria (CME): Pharmamar, GSK, Pfizer, Bayer Travel support: Pharmamar,<br />
Bayer. G. Demetri: The following interactions with NOVARTIS are noted as study<br />
sponsor: 1. Consultant, consulting fees, 2. Patent on imatinib licensed to Novartis from<br />
Dana-Farber 3. Research support to Dana-Farber for clinical trial. S. Jeay: I am an<br />
employee and stockholder <strong>of</strong> Novartis A.G. R. Dummer: Research funding from<br />
Novartis, Merck Sharp & Dhome (MSD), Bristol-Myers Squibb (BMS), Roche,<br />
GlaxoSmithKline (GSK) and has a consultant or advisory board relationship with<br />
Novartis, MSD, BMS, Roche, GlaxoSmithKline, Amgen outside the submitted<br />
work. N. Guerreiro, E. Halilovic: Novartis employee and stock owner. D.S. Tan:<br />
Consulting or advisory fees from Novartis, Bayer, Boehringer Ingelheim and Eisai;<br />
honoraria from Novartis and Pfizer; research funding from Novartis, Bayer and GSK;<br />
and expense reimbursements from Novartis and MERCK, outside the submitted work.<br />
A. Kumar, C. Meille, L. Van Bree: Novartis employee. J.U. Wuerthner: Employee <strong>of</strong><br />
Novartis and has stock ownership <strong>of</strong> Novartis. P. Cassier: Received honoraria and<br />
research funding from Novartis, Roche, BluePrint and Amgen, as well as research<br />
funding from Eli Lilly, Celgene, AstraZeneca, GlaxoSmithKline, Merck Sharp Dohme,<br />
Merck Serono.<br />
367PD<br />
Phase 1b study <strong>of</strong> WNT inhibitor ipafricept (IPA, decoy<br />
receptor for WNT ligands) with nab-paclitaxel (Nab-P) and<br />
gemcitabine (G) in patients (pts) with previously untreated<br />
stage IV pancreatic cancer (PC)<br />
C. Weekes 1 , J. Berlin 2 , H-J. Lenz 3 ,B.O’Neil 4 , W. Messersmith 1 , S. Cohen 5 ,<br />
C. Dendinger 5 , S. Shahda 4 , A. Kapoun 6 , C. Zhang 6 , R. Jenner 6 , F. Cattaruzza 6 ,<br />
L. Xu 6 , J. Dupont 6 , R. Brachmann 6 , S. Uttamsingh 6 , A. Farooki 7 , E. Dotan 5<br />
1 Medicine/Medical <strong>Oncology</strong>, University <strong>of</strong> Colorado Cancer Center Anschutz<br />
Cancer Pavilion, Aurora, CO, USA, 2 Gastrointestinal Cancer Research, Medical<br />
Hematology/<strong>Oncology</strong>, Vanderbilt Ingram Cancer Center, Nashville, TN, USA,<br />
3 Division <strong>of</strong> Medical <strong>Oncology</strong>, University <strong>of</strong> Southern California Norris<br />
Comprehensive Cancer Center, Los Angeles, CA, USA, 4 <strong>Oncology</strong>, Indiana<br />
University Simon Cancer Center, Indianapolis, IN, USA, 5 Medicine/Medical<br />
<strong>Oncology</strong>, Fox Chase Cancer Center, Philadelphia, PA, USA, 6 Clinical Research,<br />
OncoMed Pharmaceuticals, Redwood, CA, USA, 7 Medicine/Medical <strong>Oncology</strong>,<br />
Memorial Sloan-Kettering Cancer Center, New York, NY, USA<br />
Background: The first-in-class recombinant fusion protein IPA blocks WNT signaling<br />
by binding WNT ligands. IPA, with Nab-P and G, caused tumor regression in<br />
pt-derived PC xenografts. In Phase (P) 1a, IPA was tolerated well with dysgeusia,<br />
fatigue, muscle spasms and anorexia as most common adverse events (AEs). Based on<br />
vantictumab (VAN, 2 nd Wnt inhibitor) data, serum bone turnover markers and/or loss<br />
<strong>of</strong> bone density were used to trigger zoledronic acid (ZA). Target modulation was<br />
observed in hair follicles at ≥2.5 mg/kg every 3 weeks (q3w).<br />
Methods: Dose escalation started with intravenous IPA q2w with a standard 3 + 3<br />
design and was then pursued for q4w with 6-pt cohorts (baseline ZA, if indicated,<br />
increased monitoring & more sensitive ZA triggers). The change was made after<br />
fragility fractures in (mainly) VAN and IPA P1 studies. Nab-P at 125 mg/m 2 and G at<br />
1000 mg/m 2 were given on Days 1, 8 and 15 <strong>of</strong> 28-day cycles. Objectives were<br />
determination <strong>of</strong> safety, maximum tolerated dose, recommended P2 dose,<br />
pharmacokinetics (PK), immunogenicity, pharmacodynamics, predictive biomarkers<br />
and efficacy.<br />
Results: To date, 19 pts have been treated; in 1 q2w cohort (5 pts, 3.5 mg/kg) and 2<br />
q4w cohorts (14 pts, 3 & 5 mg/kg, revised safety plan). IPA has a PK half-life <strong>of</strong> 4 days<br />
(not significantly changed by Nab-P/G) and a low immunogenicity rate. IPA-related<br />
AEs ≥20% were fatigue, nausea, dysgeusia, vomiting, decreased appetite, alopecia and<br />
pyrexia. Only related G ≥ 3 AEs were 2 aspartate aminotransferase increased, and 1<br />
each <strong>of</strong> nausea, maculopapular rash, vomiting and white blood cell count decreased (all<br />
G3). No dose limiting toxicities or fragility fractures were observed. ZA was given at<br />
baseline or on study for 6 <strong>of</strong> 14 (43%) pts. Of 14 evaluable pts, 4 (29%) had a partial<br />
response and 7 (50%) stable disease. Median progression free survival (PFS) was 3.9<br />
months, 95% CI [1.7, 7.5] (7/19 with PFS events).<br />
Conclusions: IPA can be safely administered in combination with Nab-P and G in pts<br />
with stage IV PC. No fragility fractures were observed. Updated results, including<br />
biomarker analysis in pt tumors, with PFS and overall survival, will be presented.<br />
Clinical trial identification: NCT02050178<br />
Legal entity responsible for the study: Rainer Brachmann<br />
Funding: Onco med Pharmaceuticals<br />
Disclosure: C. Weekes: Research Funding from OncoMed Research Funding from<br />
Celgene Research Funding From Bayer. J. Berlin: Celgene Advisory Board; OncoMed<br />
Research Support. H-J. Lenz: Bayer - Advisory Board and Lectures. W. Messersmith:<br />
Research Funding OncoMed. S. Cohen: Celgene Advisory Board Bayer Advisory<br />
Board. C. Dendinger: Celgene: Research Funding, Advisory Board Bayer:Research<br />
Funding, Advisory Board OncoMed:Research Funding, Advisory Board. A. Kapoun,<br />
C. Zhang, R. Jenner, F. Cattaruzza, L. Xu, J. Dupont, R. Brachmann, S. Uttamsingh:<br />
OncoMed employee. A. Farooki: Bayer Advisory Board. All other authors have<br />
declared no conflicts <strong>of</strong> interest.<br />
368P<br />
abstracts<br />
Suppression <strong>of</strong> oncogene transcription - PNA as targeted<br />
cancer therapy for BRAF-V600E mutant melanoma<br />
J.H. Rothman, O. Surriga, G. Ambrosini, S. Vasudeva, G.K. Schwartz<br />
Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer<br />
Center, New York, NY, USA<br />
Background: Our aim is to target tumor cells specifically by directly suppressing their<br />
oncogenes with peptide nucleic acid (PNA) oligonucleotide analogues. These bind to<br />
DNA over 1000-fold more avidly than its native complement and when conjugated to<br />
delivery peptides can be made nuclear and cell membrane permeable. We have<br />
employed these PNA oligomers to target BRAF V600E in a sequence-specific<br />
complementary manner in order to disrupt transcription.<br />
Methods: For these studies, we have employed a novel delivery peptide conjugated to<br />
PNA modified to increase both cellular delivery and stability towards its target. We<br />
have assessed its ability to obstruct BRAF V600E transcription specifically in variety <strong>of</strong><br />
cell lines by monitoring suppression <strong>of</strong> cell proliferation, BRAF V600E protein<br />
expression, and mRNA transcription. Tumor reduction was assessed through xenograft<br />
mouse models.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw368 | vi117
abstracts<br />
Results: Our results indicate that exposure <strong>of</strong> the melanoma cell lines to a modified<br />
PNA-peptide conjugate selective for BRAF V600E results in a<br />
concentration-dependent inhibition <strong>of</strong> cell growth that is specific for the BRAF V600E<br />
mutant melanoma cell lines with an IC50 range <strong>of</strong> 250 to 500 nM. Moreover, there is<br />
no inhibition <strong>of</strong> BRAF WT cell growth at these concentrations. This is associated with<br />
suppression <strong>of</strong> BRAF V600E protein over time. Furthermore, BRAF V600E protein<br />
expression was suppressed for up to 6 days following initial exposure proving its<br />
durability <strong>of</strong> inhibition. Exposure to this modified PNA-peptide down-regulates BRAF<br />
V600E mRNA transcription exclusively in the mutant cell lines. Live cell imaging <strong>of</strong><br />
BRAF V600E mutant cells indicates localization <strong>of</strong> fluorescein-labeled PNA-delivery<br />
peptide conjugates to the nucleus within 3 hours <strong>of</strong> treatment. Xenograft mouse studies<br />
show reversal <strong>of</strong> tumor burden after four doses continuing for days following the last<br />
dose with a maximum tolerated dose to at least 50mg/kg.<br />
Conclusions: Our results indicate that these PNA-peptide derivatives could represent a<br />
novel and promising new therapy for patients with BRAF V600E mutant melanoma,<br />
and this technology could be applied to a multitude <strong>of</strong> other cancers either with<br />
specific translocations or mutations differing from wild-type cells even by only a single<br />
base pair.<br />
Legal entity responsible for the study: Memorial Sloan Kettering Cancer Center<br />
Funding: Memorial Sloan Kettering Cancer Center<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
369P<br />
Impact <strong>of</strong> tumor heregulin mRNA expression on outcome <strong>of</strong><br />
patients with advanced/metastatic squamous NSCLC treated<br />
with lumretuzumab, a glycoengineered monoclonal antibody<br />
targeting HER3, in combination with erlotinib<br />
D. Meulendijks 1 , U. Lassen 2 , A. Cervantes 3 , J-Y. Han 4 , A. Calles 5 , E. Felip 6 ,<br />
S-W. Kim 7 , J.H.M. Schellens 1 , A. Taus 8 , M. Sorensen 2 , T. Fleitas 3 ,<br />
B. Bossenmaier 9 , F. Michielin 10 , C. Adessi 10 , G. Meneses-Lorente 11 , M. Ceppi 9 ,<br />
I. James 12 , W. Jacob 9 , M. Weisser 9 , M. Martinez-Garcia 8<br />
1 Clinical Pharmacology & Medical <strong>Oncology</strong>, The Netherlands Cancer Institute,<br />
Amsterdam, Netherlands, 2 Department <strong>of</strong> <strong>Oncology</strong>, Rigshospitalet, Copenhagen<br />
University Hospital, Copenhagen, Denmark, 3 Serv. Hematologia Y Oncologia<br />
Medica, Institute <strong>of</strong> Health Research INCLIVA, University <strong>of</strong> Valencia, Valencia,<br />
Spain, 4 Center for Lung Cancer, National Cancer Center, Goyang, Republic <strong>of</strong><br />
Korea, 5 Centro Integral Oncológico Clara Campal, START-Madrid, Madrid, Spain,<br />
6 Oncologia Médica, Vall d’Hebron University Hospital Institut d’Oncologia,<br />
Barcelona, Spain, 7 Lung Cancer Center, Asan Medical Center, Seoul, Republic <strong>of</strong><br />
Korea, 8 Department <strong>of</strong> Medical <strong>Oncology</strong>, University Hospital del Mar, Barcelona,<br />
Spain, 9 Roche Innovation Center Munich, Pharma Research and Early<br />
Development, Penzberg, Germany, 10 Roche Innovation Center Basel, Pharma<br />
Research and Early Development, Basel, Switzerland, 11 Roche Innovation Center<br />
Welwyn, Pharma Research and Early Development, Welwyn, UK, 12 A4P,<br />
Consulting Ltd, Sandwich, UK<br />
Background: Preclinical data suggest that high mRNA expression levels <strong>of</strong> heregulin<br />
(HRG) are associated with anti-tumor activity <strong>of</strong> HER3-targeted therapy. In addition,<br />
studies have shown that HRG mRNA is more highly expressed in squamous (sq)<br />
NSCLC compared to non-sq NSCLC. The aim <strong>of</strong> this study was to evaluate the safety<br />
and efficacy <strong>of</strong> lumretuzumab in combination with erlotinib in sqNSCLC patients and<br />
evaluate the impact <strong>of</strong> tumor HRG mRNA expression levels as potential biomarker.<br />
Methods: Thirty-two patients (pts) with advanced or metastatic sqNSCLC with<br />
centrally confirmed tumor HER3 protein expression were studied in a dedicated phase<br />
Ib expansion cohort. HRG expression levels were assessed by RT-PCR from<br />
pretratment formalin-fixed paraffin-embedded tumor samples. Lumretuzumab (800<br />
mg i.v.) was administered on a q2w regimen in combination with erlotinib (150 mg/<br />
day p.o.).<br />
Results: Median age was 66 years, pts had received a median <strong>of</strong> 2 prior lines <strong>of</strong> therapy,<br />
and 22% had previously received an EGFR inhibitor. In line with a previous report<br />
(Lassen et al., Ann Oncol 25; suppl. 4: iv147, 2014), diarrhea (78%) and rash (62%)<br />
were the most frequently reported adverse events. Overall, 2 pts (6%) achieved a<br />
confirmed PR with a duration <strong>of</strong> response <strong>of</strong> 3.8 and 4.9 months, respectively. The<br />
overall disease control rate (DCR) was 59% and median PFS was 2.0 months. In tumors<br />
expressing higher levels <strong>of</strong> HRG mRNA (n = 12), defined as expression levels above the<br />
median <strong>of</strong> an in-house sqNSCLC tumor bank (n = 150 samples), ORR and DCR were<br />
8% and 75%, respectively. PFS and duration <strong>of</strong> response were 2.9 and 3.8 months,<br />
respectively. Assessment <strong>of</strong> alternative cut-<strong>of</strong>f values or assays (IHC or ISH) did not<br />
significantly change the efficacy results.<br />
Conclusions: Lumretuzumab in combination with erlotinib demonstrated modest<br />
clinical efficacy in sqNSCLC. Higher expression levels <strong>of</strong> HRG were associated with<br />
numerically higher rates <strong>of</strong> disease stabilization. However, ORR was low and duration<br />
<strong>of</strong> response and stable disease was relatively short, questioning the utility <strong>of</strong> tumor<br />
HRG mRNA as a clinically meaningful and robust biomarker for HER3 targeted<br />
therapy in sqNSCLC.<br />
Clinical trial identification: NCT01482377<br />
Legal entity responsible for the study: Roche Pharma Research and Early<br />
Development<br />
Funding: Roche Pharma Research and Early Development<br />
Disclosure: U. Lassen: Research funding from Roche.A. Cervantes: Consulting and<br />
Advisory role for Roche Speakers bureau for Roche. J-Y. Han: Consulting and Advisory<br />
role for BMS, Astra Zeneca, Boehringer Ingelheim Speakers bureau for Astra Zeneca<br />
Research funding from BMS, Roche, Astra Zeneca. E. Felip: Consulting and Advisory<br />
role for Boeheringer Ingelheim, MSD, Eli Lilly, Roche, Pfizer, Novartis, BMS, Celgene.<br />
Honoraria from Boeheringer Ingelheim, MSD, Eli Lilly, Roche, Pfizer, Novartis, BMS,<br />
Celgene. Speakers bureau for BMS, Novartis, Roche.M. Sorensen: Travel expenses from<br />
Roche. T. Fleitas: Family member employed by MSD. B. Bossenmaier, F. Michielin,<br />
C. Adessi: Employee <strong>of</strong> Roche. G. Meneses-Lorente, M. Ceppi: Employee <strong>of</strong> Roche and<br />
stock ownership. I. James: Employee <strong>of</strong> Roche and A4P. W. Jacob, M. Weisser:<br />
Employee <strong>of</strong> Roche Stock ownership.All other authors have declared no conflicts <strong>of</strong><br />
interest.<br />
370P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Phase 1 study <strong>of</strong> ODM-203, a selective dual FGFR/VEGFR<br />
inhibitor, in patients with advanced solid tumours<br />
J. Rodón 1 , K. Peltola 2 , A. Azaro 1 , E. Castanon Alvarez 3 , C. Garratt 4 , H. Leskinen 5 ,<br />
H. Bjorklund 6 , A. Ruck 4 , C. Massard 3 , P. Bono 2<br />
1 Medical <strong>Oncology</strong>, Vall d’Hebron University Hospital Institut d’Oncologia,<br />
Barcelona, Spain, 2 Comprehensive Cancer Center, HUCH Helsinki University<br />
Central Hospital, Helsinki, Finland, 3 Drug Development Department (DITEP),<br />
Institut Gustave Roussy, Villejuif, France, 4 <strong>Oncology</strong> and Critical Care, Orion<br />
Pharma, Nottingham, UK, 5 Drug Safety, Orion Pharma, Helsinki, Finland, 6 Drug<br />
Metabolism, Orion Pharma, Turku, Finland<br />
Background: Inhibitors <strong>of</strong> fibroblast growth factor receptors (FGFR) are being<br />
developed for treatment <strong>of</strong> solid tumours with FGFR genetic alterations. ODM-203 is a<br />
small molecule with balanced inhibitory effects on both FGFR 1-4 and VEGFR 1-3<br />
subtypes. We present updated results from the first-in-man study.<br />
Methods: ODM-203 was evaluated in an open 3 + 3 dose escalation design to identify<br />
the maximum tolerated dose (MTD), dosed daily in a 4 week cycle. Subsequent cohorts<br />
are evaluating the optimal dose and alternative dosing schedules. Pharmacokinetics<br />
and safety variables were closely monitored during the first 4 weeks with tumour<br />
response according to RECIST recorded every 8 weeks on treatment. Patients<br />
continued ODM-203 treatment until disease progression or dose limiting toxicity<br />
(DLT).<br />
Results: 31 patients (median age 54, range 28-80 years) with advanced solid tumours<br />
received ODM-203 treatment in doses between 50-800mg once/day during the dose<br />
escalation phase. Patients had various primary tumours, some having FGFR<br />
alterations. One cholangiocarcinoma patient with FGFR2 fusion has been treated for<br />
more than 1 year. One DLT (corneal keratopathy) was recorded at 800mg/day but<br />
MTD was not identified. A single grade 4 AE (lipase increase) was reported. Most AE’s<br />
reported were grade 1-2, the most common ones being increased bilirubin (61%),<br />
diarrhoea (36%), alopecia (29%), jaundice (26%), increased phosphate (26%),<br />
stomatitis (23%) and epistaxis (19%). Increased bilirubin was due to UGT1A1<br />
inhibition by ODM-203 and resolved in all cases upon dose reduction/interruption.<br />
Plasma ODM-203 exposure was variable. There were 3 partial responses (RCC, ovarian<br />
and FGFR mutated salivary gland cancer) and 5 further patients achieved target lesion<br />
reduction. In addition, 4 patients had disease stabilisation <strong>of</strong> at least 24wk. Further<br />
follow-up and results <strong>of</strong> ongoing dose schedule evaluation will also be presented.<br />
Conclusions: In ODM-203 treated patients there was preliminary evidence <strong>of</strong><br />
promising anti-tumour activity although FGFR-aberrant tumours were not preselected.<br />
ODM-203 elicited on-target adverse effects in addition to bilirubin changes. An<br />
expansion study in patients with FGFR-aberrant or VEGFR sensitive tumours is<br />
ongoing.<br />
Clinical trial identification: NCT02264418<br />
Legal entity responsible for the study: Orion Corporation, Orion Pharma<br />
Funding: Orion Corporation, Orion Pharma<br />
Disclosure: J. Rodón: Consulting/Advisory role: Novartis, Lilly/ImClone, Servier. K.<br />
Peltola: Employment: Orion Corporation. Stock: Faron Pharmaceuticals. Consulting/<br />
honoraria: Lilly, San<strong>of</strong>i, Novartis, Baxalter, Bristol Myers Squibb, Pfizer. C. Garratt,<br />
H. Leskinen, H. Bjorklund, A. Ruck: Employee <strong>of</strong> Orion Pharma. P. Bono: Honoraria:<br />
MSD, Orion Pharma, Novartis, Bristol Myers Squibb, Pfizer. Research funding:<br />
Novartis. All other authors have declared no conflicts <strong>of</strong> interest.<br />
vi118 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
371P<br />
First-in-human phase 1, dose-escalation and -expansion study<br />
<strong>of</strong> ABBV-399, an antibody-drug conjugate (ADC) targeting<br />
c-Met, in patients (pts) with advanced solid tumors<br />
E. Angevin 1 , K. Kelly 2 , R. Heist 3 , D. Morgensztern 4 , C. Weekes 5 , T.M. Bauer 6 ,R.<br />
K. Ramanathan 7 , J. Nemunaitis 8 ,X.Fan 9 , O. Olyaie 9 , A. Parikh 9 , E. Reilly 10 ,<br />
D. Afar 9 , L. Naumovski 9 , J. Strickler 11<br />
1 Early Drug Development Department, Gustave Roussy, Villejuif Cedex, France,<br />
2 Internal Medicine, UC Davis Comprehensive Cancer Center, Sacramento, CA,<br />
USA, 3 Children Cancer Center, Massachusetts General Hospital, Boston, MA,<br />
USA, 4 <strong>Oncology</strong>, Washington University School <strong>of</strong> Medicine, St. Louis, MO, USA,<br />
5 Department <strong>of</strong> Medicine, University <strong>of</strong> Colorado Cancer Center Anschutz Cancer<br />
Pavilion, Aurora, CO, USA, 6 Drug Development Unit, Sarah Cannon Research<br />
Institute/Tennessee <strong>Oncology</strong>, Nashville, TN, USA, 7 Hematology/<strong>Oncology</strong>, Mayo<br />
Clinic Cancer Center, Phoenix, AZ, USA, 8 <strong>Oncology</strong>, Mary Crowley Cancer<br />
Research Center, Dallas, TX, USA, 9 Biotherapeutics, AbbVie, Redwood City, CA,<br />
USA, 10 <strong>Oncology</strong>, AbbVie, Inc., North Chicago, IL, USA, 11 Department <strong>of</strong><br />
Medicine, Duke University Medical Center, Durham, NC, USA<br />
Background: The c-Met receptor is overexpressed in multiple tumors. ABBV-399 is a<br />
first-in-class ADC composed <strong>of</strong> ABT-700, a previously described anti–c-Met antibody,<br />
conjugated to monomethyl auristatin E (a microtubule inhibitor). Preclinical data<br />
support ADC ABBV-399 as a unique strategy to deliver a potent cytotoxin directly to<br />
c-Met+ tumor cells (∼30-50% <strong>of</strong> tumors overexpress c-Met).<br />
Methods: In a 3 + 3 dose-escalation design, ABBV-399 was administered at doses<br />
ranging from 0.15 to 3.3 mg/kg once every 21 days to pts with metastatic solid tumors<br />
(NCT02099058). ABBV-399 was then studied in a dose-expansion cohort in pts with<br />
c-Met+ (immunohistochemistry [IHC] H-score ≥150) non-small cell lung cancer<br />
(NSCLC). Overexpression <strong>of</strong> c-Met was assessed by an IHC assay utilizing the SP44<br />
antibody (Ventana; Tucson, AZ, USA).<br />
Results: As <strong>of</strong> March 31, 2016, 48 pts received at least 1 dose <strong>of</strong> ABBV-399.<br />
Approximately dose-proportional increases <strong>of</strong> area under the curve for ABBV-399 and<br />
total antibody were observed after single-dose administration. Half-lives for ABBV-399<br />
and total antibody were approximately 2 to 4 days. Dose-limiting toxicity <strong>of</strong> febrile<br />
neutropenia occurred in 1 pt at 3 mg/kg and 1 pt (with septic shock) at 3.3 mg/kg. A<br />
dose <strong>of</strong> 2.7 mg/kg was chosen for dose expansion based primarily on safety and<br />
tolerability. There were no treatment-related deaths. Treatment-related adverse events<br />
occurring in ≥10% <strong>of</strong> pts (including all dose levels and all grades) were fatigue (22.9%),<br />
nausea (20.8%), neuropathy (14.6%), decreased appetite (12.5%), vomiting (12.5%),<br />
and hypoalbuminemia (10.4%). Three <strong>of</strong> 16 (18.8%) ABBV-399–treated c-Met+<br />
NSCLC pts had a partial response with duration <strong>of</strong> response 1 + , 3, and 4.5 mo. At<br />
week 12, 6 <strong>of</strong> 16 (37.5%) had disease control. There were no responses among pts with<br />
c-Met–negative tumors.<br />
Conclusions: ABBV-399 is well tolerated at a dose <strong>of</strong> 2.7 mg/kg every 21 days and has<br />
demonstrated promising antitumor activity in pts with cMet+ NSCLC. Assessment <strong>of</strong><br />
antitumor activity and safety <strong>of</strong> ABBV-399 in c-Met+ pts will continue as<br />
monotherapy and in combination with standard <strong>of</strong> care.<br />
Clinical trial identification: NCT02099058<br />
Legal entity responsible for the study: AbbVie, Inc.<br />
Funding: AbbVie, Inc.<br />
Disclosure: D. Morgensztern: Speaker: Genentech, Boehringer Ingelheim; consultant:<br />
Genentech, Celgene, Heat Biologics, Bristol-Myers Squibb. R.K. Ramanathan,<br />
J. Strickler: Research funding from AbbVie. X. Fan, O. Olyaie, A. Parikh, E. Reilly,<br />
D. Afar, L. Naumovski: Employed by AbbVie and may own stock. All other authors<br />
have declared no conflicts <strong>of</strong> interest.<br />
372P<br />
A phase Ib study <strong>of</strong> lumretuzumab, a glycoengineered<br />
monoclonal antibody targeting HER3, in combination with<br />
carboplatin and paclitaxel as 1st-line treatment in patients<br />
with squamous non-small cell lung cancer<br />
J.M. Cejalvo 1 , T. Fleitas 2 , E. Felip 3 , A. Navarro Mendivil 3 , M. Martinez-Garcia 4 ,<br />
A. Taus 4 , N. Leighl 5 , U. Lassen 6 , M. Mau Soerensen 6 , C. Adessi 7 , F. Michielin 7 ,<br />
W. Jacob 8 , I. James 9 , M. Ceppi 8 , M. Weisser 8 , A. Cervantes 10<br />
1 <strong>Oncology</strong> and Hematology, Hospital Clinico Universitario de Valencia, Valencia,<br />
Spain, 2 Clinical <strong>Oncology</strong>, Hospital Clinico Universitario de Valencia, Valencia,<br />
Spain, 3 Medical <strong>Oncology</strong>, Vall d’Hebron University Hospital Institut d’Oncologia,<br />
Barcelona, Spain, 4 Department <strong>of</strong> Medical <strong>Oncology</strong>, University Hospital del Mar,<br />
Barcelona, Spain, 5 Medical <strong>Oncology</strong>, Princess Margaret Hospital, Toronto, ON,<br />
Canada, 6 Department <strong>of</strong> <strong>Oncology</strong>, Rigshospitalet, Copenhagen University<br />
Hospital, Copenhagen, Denmark, 7 Roche Innovation Center Basel, Pharma<br />
Research and Early Development, Basel, Switzerland, 8 Roche Innovation Center<br />
Munich, Pharma Research and Early Development, Penzberg, Germany,<br />
9 Consulting Services, A4P Consulting Ltd, Sandwich, UK, 10 Medical <strong>Oncology</strong>,<br />
Hospital Clinico Universitario de Valencia, Valencia, Spain<br />
Background: Preclinical data suggest that high mRNA expression levels <strong>of</strong> heregulin<br />
(HRG) could predict anti-tumor activity <strong>of</strong> lumretuzumab, an anti-HER3 antibody.<br />
HRG mRNA is more highly expressed in squamous (sq)NSCLC compared to<br />
non-sqNSCLC.<br />
Methods: This was an open-label, multicenter phase Ib study in patients (pts) with<br />
advanced or metastatic sqNSCLC who have not received prior chemotherapy or<br />
targeted therapy for NSCLC. Lumretuzumab (800 mg) was administered in<br />
combination with carboplatin (AUC 6 mg/mL x min) and paclitaxel (200 mg/m 2 )ona<br />
q3w schedule. The primary objectives were to evaluate safety and efficacy and an<br />
exploratory objective was to correlate tumor HRG mRNA expression to clinical activity.<br />
HRG mRNA expression levels were assessed by RT-PCR in archival formalin-fixed<br />
paraffin-embedded tumor samples. To distinguish high vs low HRG gene expression<br />
levels, the median gene expression level <strong>of</strong> sqNSCLC tumor samples from an internal<br />
tumor bank (n = 150) was used as an exploratory cut-<strong>of</strong>f.<br />
Results: Twelve pts were enrolled (median age 66.5 years, 10 pts male). The most<br />
frequently reported adverse events (AEs) (in >2 pts) were diarrhea (9 pts), asthenia (8<br />
pts), neurotoxicity (5 pts), nausea and infusion-related reaction (4 pts each). Grade ≥3<br />
AEs were only reported for single pts except for anemia which was reported for two pts.<br />
Overall, three pts achieved a partial response (25%) and 8 pts achieved stable disease<br />
(67%). High HRG mRNA expression levels were found in 7 pts (58%). All three<br />
responding pts showed high HRG mRNA expression levels. The duration <strong>of</strong> responses<br />
were 2.8, 6.0, and 6.2 months.<br />
Conclusions: Lumretuzumab in combination with carboplatin and paclitaxel was safe<br />
and well tolerated. While all 3 responding pts had tumors with high HRG mRNA<br />
expression levels, the addition <strong>of</strong> lumretuzumab to platinum-based therapy was not<br />
associated with a clear signal <strong>of</strong> higher clinical activity than what would have been<br />
expected with platinum-based therapy alone.<br />
Clinical trial identification: NCT02204345 First received: July 24, 2014<br />
Legal entity responsible for the study: Fa. H<strong>of</strong>fmann-La Roche<br />
Funding: Fa. H<strong>of</strong>fmann-La Roche<br />
Disclosure: E. Felip: Consulting fees from: Eli Lilly, Pfizer, Roche, Boehringer<br />
Ingelheim, MSD Lecture fees from: Astra Zeneca, BMS, Novartis. C. Adessi,<br />
F. Michielin, I. James, M. Ceppi, M. Weisser: Sponsor employee. W. Jacob: Sponsor<br />
employee Sponsor stock owner. A. Cervantes: Consulting fees from: Merck Serono,<br />
Amgen, Servier, Roche, Lilly, Novartis Research support from: Merck Serono, Amgen,<br />
Servier, Lilly, Novartis, MSD, Roche, Genentech. All other authors have declared no<br />
conflicts <strong>of</strong> interest.<br />
373P<br />
abstracts<br />
A phase II study <strong>of</strong> apatinib, a highly selective inhibitor <strong>of</strong><br />
VEGFR-2, in patients with metastatic solid tumors without<br />
standard treatment options<br />
Y-K. Kang 1 , M-H. Ryu 1 , S.R. Park 1 , Y.S. Hong 1 , C-M. Choi 1 , T.W. Kim 1 ,<br />
B-Y. Ryoo 1 , J.E. Kim 1 , S-W. Kim 1 , J.R. Weis 2 , G. Gilcrease 2 , C. Davidson 2 ,<br />
R. Kingsford 2 , J. Collett 2 , N. Orgain 2 , S.R. Kim 3 , C.H. Park 4 , A. McGinn 4 ,<br />
S. Sharma 2<br />
1 Department <strong>of</strong> <strong>Oncology</strong>, Asan Medical Center, University <strong>of</strong> Ulsan College <strong>of</strong><br />
Medicine, Seoul, Republic <strong>of</strong> Korea, 2 <strong>Oncology</strong>, Huntsman Cancer Institute, Salt<br />
Lake City, UT, USA, 3 Clinical Research, Bukwang Pharm. Co. Ltd., Seoul, Republic<br />
<strong>of</strong> Korea, 4 Clinical Research, LSK BioPharma, Salt Lake City, UT, USA<br />
Background: VEGFR-2 signaling has a pivotal role in tumor angiogenesis. Apatinib<br />
(YN968D1) is a highly selective tyrosine kinase inhibitor <strong>of</strong> VEGFR-2. A previous<br />
phase I study <strong>of</strong> continuous daily dosing <strong>of</strong> apatinib in solid tumors identified 850 mg<br />
per day as the recommended dose (Sharma et al., 2015 ASCO). This study was a phase<br />
II trial evaluating the preliminary efficacy and safety <strong>of</strong> apatinib in advanced solid<br />
tumors.<br />
Methods: In Korea and the US, 30 patients (pts) with metastatic GC (n = 15), CRC<br />
(n = 9), NSCLC (n = 3), NET (n = 2) or mesothelioma (n = 1) who failed standard<br />
chemotherapy received apatinib 850 mg p.o. q.d. until disease progression or<br />
unacceptable toxicity. Other key eligibility criteria included presence <strong>of</strong> measurable<br />
lesions and an ECOG performance status ≤2.<br />
Results: Among the 30 pts, 21 pts (70.0%) were male, and the median age was 56.5<br />
years (range, 32–82). Twenty-three pts (76.7%) were Asian, and the remaining 7 pts<br />
(23.3%) were Caucasian. In 28 evaluable pts, partial response (PR) was noted in 3 pts<br />
(10.7%, 1 GC, 1 NSCLC, and 1 NET), and stable disease (SD) in 23 pts (82.1%) with a<br />
disease control rate (DCR) <strong>of</strong> 92.9% at 8 weeks. All 15 GC pts were evaluable with 1 PR<br />
(6.7%), 12 SD (80.0%), and 2 cases <strong>of</strong> progressive disease (PD) (13.3%), resulting in a<br />
DCR <strong>of</strong> 86.7%. Grade ≥ 3 adverse events observed in more than 5% <strong>of</strong> pts included<br />
hypertension (n = 7), increased blood bilirubin (n = 4), hypokalemia (n = 3) and<br />
hand-foot skin reaction (HFSR) (n = 2). Toxicities were generally well tolerated, and<br />
there was no toxicity-related death.<br />
Conclusions: Apatinib showed a promising anti-tumor activity in advanced solid<br />
tumors after failure <strong>of</strong> standard treatment, and was well tolerated with manageable<br />
toxicity pr<strong>of</strong>iles. The results <strong>of</strong> this study support further investigation <strong>of</strong> apatinib in<br />
solid tumors, especially in gastric cancer in which efficacy and safety <strong>of</strong> apatinib has<br />
been reported in a Chinese phase 3 study.<br />
Clinical trial identification: NCT01497704<br />
Legal entity responsible for the study: LSK BioPharma, Bukwang Pharm. Co. Ltd<br />
Funding: LSK BioPharma, Bukwang Pharm. Co. Ltd<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw368 | vi119
abstracts<br />
Disclosure: Y-K. Kang: I have a research grant from Daehwa and am a Consultant (or<br />
on the advisory board) for Novartis, Roche, Ono, BMS, Daehwa.M-H. Ryu: Stock:<br />
Novartis, Bayer, Lilly, San<strong>of</strong>i, Taiho, Pfizer. Consulting: Novartis, Bayer, Lilly, San<strong>of</strong>i,<br />
Taiho, Pfizer. Research funding: Novartis. S.R. Park: Consulting to Bukwang Pharm. T.<br />
W. Kim: Honoraria from Amgen, and Lilly. Institutional funding from Merck Serono,<br />
Bayer and Roche Glycart. C. Davidson: Stock in Salarius Pharmaceuticals and<br />
honoraria from Novartis. S.R. Kim: Stock or ownership in Bukwang Pharm. C.H. Park,<br />
A. McGinn: Stock ownership in LSK BioPharma. S. Sharma: Stock: Beta Cat Pharm,<br />
Salarius Pharm and ConverGene. Funding from: Novartis, Spectrum, GSK, Blend<br />
therapeutics, Foundation Medicine, Guardant Health. All other authors have declared<br />
no conflicts <strong>of</strong> interest.<br />
374P<br />
Phase I dose escalation (esc) trial <strong>of</strong> weekly intravenous (i.v.)<br />
BI 836845 in Japanese patients (pts) with advanced solid<br />
tumors<br />
T. Doi 1 , K. Shitara 2 , Y. Naito 1 , Y. Kuboki 1 , T. Kojima 2 , A. Hosono 3 , T. Yoshino 2 ,<br />
H. Kawamoto 4 , Y. Tadayasu 5 , H. Ugai 6 , Y. Takeuchi 7 , T. Bogenrieder 8 ,K.Yoh 1<br />
1 Department <strong>of</strong> Experimental Therapeutics, National Cancer Center Hospital East,<br />
Kashiwa, Japan, 2 Department <strong>of</strong> Gastrointestinal <strong>Oncology</strong>, National Cancer<br />
Center Hospital East, Kashiwa, Japan, 3 Rare Cancer Center, National Cancer<br />
Center Hospital East, Kashiwa, Japan, 4 Division <strong>of</strong> Pediatric <strong>Oncology</strong>, National<br />
Cancer Center Hospital East, Kashiwa, Japan, 5 Clinical PK/PD Group, Nippon<br />
Boehringer Ingelheim Co., Ltd., Kobe, Japan, 6 Biostatistics and Data Sciences<br />
Japan, Nippon Boehringer Ingelheim Co., Ltd, Tokyo, Japan, 7 Clinical Trial<br />
Management Department, Nippon Boehringer Ingelheim Co., Ltd, Tokyo, Japan,<br />
8 Clinical Development and Medical Affairs, Boehringer Ingelheim Pharma GmbH &<br />
Co. KG, Vienna, Austria<br />
Background: BI 836845 is an insulin-like growth factor (IGF) ligand-neutralizing<br />
humanized antibody that binds to IGF-1/IGF-2 ligands. This Phase I trial<br />
(NCT02145741) evaluated the maximum tolerated dose (MTD), safety,<br />
pharmacokinetics (PK), pharmacodynamics (PD), and activity <strong>of</strong> BI 836845.<br />
Methods: Japanese pts with advanced tumors were recruited in a 3 + 3 dose esc design.<br />
BI 836845 was administered weekly i.v. (21-day cycles). Pts with IGF-driven tumors<br />
were recruited in an expansion (exp) cohort.<br />
Results: In the esc part, 15 pts (60% male; median age 67 years, range 46–74; Eastern<br />
Cooperative <strong>Oncology</strong> Group performance status 0/1 in 67%/33% <strong>of</strong> pts) received BI<br />
836845 across 3 doses: 750 mg (6); 1000 mg (3); and 1400 mg (6). Tumor types<br />
included esophageal (3), stomach (3), adrenal (2), colorectal (2), and non-small cell<br />
lung (2). No dose-limiting toxicities were observed; MTD was not reached. A relevant<br />
biological dose was selected at 1000 mg weekly i.v. based on previous safety, efficacy,<br />
and PK/PD data. In the exp part, 6 pts (median age 38 years, range 32–71) received BI<br />
836845 at 1000 mg. Tumor types included sarcoma (2) and desmoid (2). In total, 11/21<br />
pts (52%) had drug-related adverse events (AEs); those in ≥10% pts were fatigue (19%),<br />
neutropenia (19%), diarrhea (14%) and white blood cell count decreased (14%). No pt<br />
had a dose reduction or discontinued due to AEs. No relevant deviations from dose<br />
linearity <strong>of</strong> BI 836845 exposure were observed in the PK analysis (esc part). 5/15 pts<br />
(33%) in the esc part had stable disease (SD; mean duration 95 days). In the exp part, 1/<br />
6 pts (17%; desmoid tumor) had a partial response and 2/6 pts (33%) had SD (disease<br />
control rate 50%, mean duration 102 days).<br />
Conclusions: These findings were similar to those <strong>of</strong> previous Phase I studies <strong>of</strong> weekly<br />
i.v. BI 836845 in Caucasian or other Asian patients.<br />
Clinical trial identification: Clinical trial registration: NCT02145741<br />
Legal entity responsible for the study: Boehringer Ingelheim<br />
Funding: This study has received funding from Boehringer Ingelheim.<br />
Disclosure: T. Doi: Membership on advisory board or board <strong>of</strong> directors (Boehringer<br />
Ingelheim); corporate sponsored research (Boehringer Ingelheim). T. Kojima: Research<br />
funding (Merk Serono). T. Yoshino: Corporate-sponsored research (GlaxoSmithKline,<br />
Boehringer Ingleheim GmbH). Y. Tadayasu, H. Ugai, Y. Takeuchi: Employment<br />
(Nippon Boehringer Ingelheim). T. Bogenrieder: Employment (Boehringer Ingelheim).<br />
All other authors have declared no conflicts <strong>of</strong> interest.<br />
375P<br />
A phase Ib dose-finding study <strong>of</strong> alpelisib (ALP; BYL719) and<br />
paclitaxel (PTX) in advanced solid tumors (aST)<br />
J. Rodón 1 , G. Curigliano 2 , J-P. Delord 3 , W. Harb 4 , A. Azaro 1 , V. Donnet 5 , Y. Han 6 ,<br />
L. Blumenstein 7 , C. Wilke 7 , J.T. Beck 8<br />
1 Medical <strong>Oncology</strong>, Vall d’Hebron University Hospital Institut d’Oncologia,<br />
Barcelona, Spain, 2 Drug Development, European Institute <strong>of</strong> <strong>Oncology</strong> (IEO),<br />
Milan, Italy, 3 <strong>Oncology</strong>, Institut Claudius Régaud, Toulouse, France, 4 Unity<br />
Campus, Horizon <strong>Oncology</strong> Center, Lafayette, IN, USA, 5 <strong>Oncology</strong> Global<br />
Development, Novartis Pharma S.A.S, Paris, France, 6 Biostatistics, Novartis<br />
Pharmaceuticals Corporation, East Hanover, NJ, USA, 7 <strong>Oncology</strong> Global<br />
Development, Novartis Pharma AG, Basel, Switzerland, 8 <strong>Oncology</strong>, Highlands<br />
<strong>Oncology</strong> Group, Lafayetteville, AZ, USA<br />
Background: Aberrant activation <strong>of</strong> the phosphatidylinositol 3-kinase (PI3K)/<br />
mammalian target <strong>of</strong> rapamycin pathway due to alterations in PIK3CA (encoding<br />
PI3Kα) frequently occurs in aST. We report safety findings from an ongoing, phase Ib<br />
dose-escalation study <strong>of</strong> ALP (PI3Kα inhibitor) + PTX (NCT02051751).<br />
Methods: Patients (pts) aged ≥18 years with aST (not amenable to resection/<br />
progressed on standard therapy), ECOG performance status ≤2, adequate bone<br />
marrow/organ function, and no prior treatment with PI3K or AKT inhibitors were<br />
recruited. The primary objective was to determine the maximum tolerated dose (MTD)<br />
and/or recommended Phase II dose <strong>of</strong> ALP + PTX based on dose-limiting toxicities<br />
(DLTs) in Cycle 1. Dose escalation <strong>of</strong> ALP was guided by an adaptive Bayesian logistic<br />
regression model with escalation with overdose control principle.<br />
Results: As <strong>of</strong> Dec 7, 2015, 19 pts received oral ALP (300 mg [n = 6], 250 mg [n = 4], or<br />
150 mg [n = 9] once daily [QD]) and IV PTX (80 mg/m 2 once weekly [QW]). The<br />
most common primary sites <strong>of</strong> cancer were breast (n = 5) and rectum (n = 3).<br />
Treatment was discontinued in 18/19 pts due to disease progression (n = 12, 63%), pt<br />
decision (n = 3, 16%), adverse events (AEs; n = 2, 11%; 1 pt for grade [G]3 dehydration,<br />
G3 hyperglycemia, and G3 acute kidney injury; 1 pt for G4 neutropenia and G4<br />
γ-glutamyltransferase increase), and physician decision (n = 1, 5%). DLTs occurred in<br />
5/12 pts in the dose-determining set: 1/1 (100%) pt at 300 mg QD, 2/3 (67%) pts at<br />
250 mg QD, and 2/8 (25%) pts at 150 mg QD. Six DLTs were reported: G2<br />
hyperglycemia (n = 3), G4 hyperglycemia, G4 leukopenia, and G3 acute kidney injury<br />
(each n = 1). The MTD <strong>of</strong> ALP + PTX (80 mg/m 2 QW) was declared as 150 mg QD.<br />
All 19 pts had ≥1 treatment-emergent AE. Grade 3/4 AEs occurred in 11 (58%) pts, the<br />
most frequent being hyperglycemia (n = 6, 32%), diarrhea, anemia, lymphopenia,<br />
neutropenia, and leukopenia (each n = 2, 11%).<br />
Conclusions: In pts with aST, the MTD <strong>of</strong> ALP + PTX (80 mg/m 2 QW) was 150 mg<br />
QD. Due to the challenging safety pr<strong>of</strong>ile <strong>of</strong> the combination and lack <strong>of</strong> available data<br />
confirming the pharmacodynamics and/or clinical activity <strong>of</strong> ALP at 150 mg QD,<br />
planned dose expansion in pts with breast cancer and head and neck squamous cell<br />
carcinoma will not go forward.<br />
Clinical trial identification: NCT02051751<br />
Legal entity responsible for the study: Novartis<br />
Funding: Novartis<br />
Disclosure: J. Rodón: Advisory board for Novartis, Lily, Servier, Leti, Oncompass,<br />
Orion Pharma. V. Donnet: Novartis Full-time Employee. Y. Han: I am an employee at<br />
Novartis and receive a salary from Novartis. L. Blumenstein: I hereby confirm to be a<br />
Novartis Pharma AG employee with stock ownership. C. Wilke: Employee <strong>of</strong> Novartis<br />
AG, sponsor <strong>of</strong> the study. All other authors have declared no conflicts <strong>of</strong> interest.<br />
376P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Pharmacokinetics (PK) and pharmacogenetics (PG) <strong>of</strong> the<br />
MEK1/2 inhibitor, selumetinib, in Asian and Western healthy<br />
subjects: a pooled analysis<br />
A. Dymond 1 , C. Elks 2 , P. Martin 3 , D. Carlile 4 , G. Mariani 5 , S. Lovick 6 , Y. Huang 7 ,<br />
U. Lorch 8 , H. Brown 2 ,K.So 5<br />
1 Quantitative Clinical Pharmacology, AstraZeneca, Macclesfield, UK,<br />
2 Personalised Healthcare & Biomarkers, AstraZeneca, Cambridge, UK, 3 IMED,<br />
AstraZeneca, Macclesfield, UK, 4 Quantitative Clinical Pharmacology, AstraZeneca,<br />
Cambridge, UK, 5 Global Medicines Development, AstraZeneca, Cambridge, UK,<br />
6 Biometrics and Information Sciences, AstraZeneca, Macclesfield, UK, 7 Global<br />
Medicines Development, Biometrics & Information Sciences, AstraZeneca,<br />
Gaithersburg, MD, USA, 8 St. George’s University <strong>of</strong> London, Richmond<br />
Pharmacology, London, UK<br />
Background: Selumetinib (AZD6244, ARRY-142886) is an oral, potent and highly<br />
selective, allosteric MEK1/2 inhibitor with a short half-life. PK <strong>of</strong> selumetinib may be<br />
influenced by ethnicity and genetic differences in metabolising enzymes and<br />
transporter proteins.<br />
Methods: Pooled PK data from ten Phase I, single-dose studies <strong>of</strong> selumetinib (25, 35,<br />
50 and 75 mg) in healthy Asian subjects (Japanese [JPN], non-Japanese Asian [NJA],<br />
or Indian [IND]) and Western subjects (white or black) were analysed. PK parameters<br />
were derived using non compartmental methods and statistical comparisons<br />
performed by ANOVA stepwise model fitting. Variants in the cytochrome P450<br />
enzyme CYP2C19 and the transporters UGT1A1 and ABCG2 were assessed across<br />
ethnic groups: white (n = 24), black (n = 21) and Asian (n = 42), using PG data from<br />
vi120 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
Table: 376P<br />
Parameter<br />
Dose-normalised<br />
AUC*<br />
C max<br />
Geometric least squares mean Difference † 95% CI Geometric least squares mean Difference † 95% CI<br />
All Asian (n = 72) vs. Western (n = 236) 4.284 vs. 3.982 1.353 1.246, 1.469 3.205 vs. 2.877 1.388 1.235, 1.560<br />
Black (n = 87) vs. white (n = 149) 3.989 vs. 3.975 1.014 0.951, 1.081 2.847 vs. 2.907 0.942 0.860, 1.032<br />
JPN (n = 27) vs. white (n = 149) 4.384 vs. 3.975 1.505 1.354, 1.673 3.280 vs. 2.907 1.453 1.251, 1.687<br />
NJA (n = 36) vs. white (n = 149) 4.292 vs. 3.975 1.373 1.244, 1.516 3.088 vs. 2.907 1.198 1.042, 1.377<br />
IND (n = 9) vs. white (n = 149) 4.177 vs. 3.975 1.223 1.034, 1.447 3.247 vs. 2.907 1.405 1.108, 1.781<br />
*Western, n = 235; white, n = 148; † Point estimate: adjusted ratio <strong>of</strong> geometric means; for each comparison, a value above one implies an increase in exposure vs. the<br />
comparator. Data derived from the following studies: NCT01635023, NCT01974349, NCT02056392, NCT02322749, NCT02238782, NCT02063204, NCT02063230,<br />
NCT02093728, NCT02046850, NCT01960374.<br />
three <strong>of</strong> these studies and standard genotyping methods. Associations with PK were<br />
analysed using linear regression.<br />
Results: Compared with Western subjects, dose-normalised AUC and Cmax were 35%<br />
and 39% higher respectively in Asian subjects, adjusting for baseline bodyweight<br />
(Table 1). Exposure was similar among Western subjects. Geomeans for<br />
dose-normalised AUC and Cmax ranged from 2% to 18% greater for NJA and IND<br />
compared with JPN, indicating exposures are similar across Asian populations. Genetic<br />
analysis showed that allele frequencies <strong>of</strong> variants in CYP2C19, UGT1A1 and ABCG2<br />
varied between ethnic groups. The genetic variants CYP2C19*2, CYP2C19*3,<br />
CYP2C19*17, UGT1A1*6, UGT1A1*26, and ABCG2 421C > A, did not show any clear<br />
associations with selumetinib exposure after correction for multiple testing.<br />
Conclusions: Selumetinib exposure was greater in Asian than Western subjects.<br />
Although allele frequencies differed between populations, there did not appear to be<br />
any associations between the genetic variants analysed and selumetinib exposure. Data<br />
provide valuable insight for the use <strong>of</strong> selumetinib in Asian populations.<br />
Clinical trial identification: NCT01635023, NCT01974349, NCT02056392,<br />
NCT02322749, NCT02238782, NCT02063204, NCT02063230, NCT02093728,<br />
NCT02046850, NCT01960374<br />
Legal entity responsible for the study: AstraZeneca<br />
Funding: AstraZeneca<br />
Disclosure: A. Dymond, S. Lovick, H. Brown: Employee <strong>of</strong> and shareholder in<br />
AstraZeneca. C. Elks, D. Carlile, G. Mariani, Y. Huang, K. So: Employee <strong>of</strong><br />
AstraZeneca. P. Martin: Previous employee <strong>of</strong>, and current shareholder in,<br />
AstraZeneca. U. Lorch: Employee <strong>of</strong> Richmond Pharmacology, which was paid to<br />
perform trial EudraCT 2013-0003203-19 on behalf <strong>of</strong> AstraZeneca.<br />
377P<br />
Phase 1 study <strong>of</strong> investigational oral mTORC1/2 inhibitor<br />
TAK-228 (MLN0128): Tolerability and food effects <strong>of</strong> a milled<br />
formulation in patients (pts) with advanced solid tumors<br />
K.N. Moore 1 , T.M. Bauer 2 , G. Falchook 3 , C. Patel 4 , R. Neuwirth 5 , A. Enke 6 ,<br />
F. Zohren 7 , M.R. Patel 8<br />
1 Department <strong>of</strong> Obstetrics & Gynecology, University <strong>of</strong> Oklahoma, Oklahoma City,<br />
OK, USA, 2 Drug Development Unit, Sarah Cannon Research Institute/Tennessee<br />
<strong>Oncology</strong>, Nashville, TN, USA, 3 Drug Development, Sarah Cannon Research<br />
Institute at HealthONE, Denver, CO, USA, 4 Clinical Pharmacology, Millennium<br />
Pharmaceuticals, Inc., a wholly owned subsidiary <strong>of</strong> Takeda Pharmaceutical<br />
Company Limited, Cambridge, MA, USA, 5 Global Statistics, Millennium<br />
Pharmaceuticals, Inc., a wholly owned subsidiary <strong>of</strong> Takeda Pharmaceutical<br />
Company Limited, Cambridge, MA, USA, 6 <strong>Oncology</strong> Clinical Research, Millennium<br />
Pharmaceuticals, Inc., a wholly owned subsidiary <strong>of</strong> Takeda Pharmaceutical<br />
Company Limited, Cambridge, MA, USA, 7 Early Clinical Research & Development,<br />
<strong>Oncology</strong> Therapeutic Area Unit, Millennium Pharmaceuticals, Inc., a wholly<br />
owned subsidiary <strong>of</strong> Takeda Pharmaceutical Company Limited, Cambridge, MA,<br />
USA, 8 Drug Development Unit, Florida Cancer Specialists/Sarah Cannon<br />
Research Institute, Sarasota, FL, USA<br />
Background: The mTOR signaling pathway is frequently dysregulated in human<br />
cancers. TAK-228 is an investigational, orally available, highly selective mTOR<br />
inhibitor. Larger scale manufacturing <strong>of</strong> TAK-228 required a formulation change from<br />
unmilled to milled drug substance. Here we present safety, tolerability, and preliminary<br />
efficacy, as well as pharmacokinetics (PK) under fed and fasted conditions, <strong>of</strong> milled<br />
TAK-228.<br />
Methods: Escalation cohorts <strong>of</strong> eligible pts (aged ≥18 y with advanced nonhematologic<br />
malignancies) were concurrently enrolled into 3 arms: once daily (QD), once weekly<br />
(QW), and three days each week plus weekly paclitaxel 80 mg/m 2 (QDx3QW + P).<br />
Starting doses <strong>of</strong> milled TAK-228 were 4 mg QD, 20 mg QW and 6 mg QDx3QW + P,<br />
representing a one-dose-level reduction compared to the previously established<br />
recommended phase 2 doses <strong>of</strong> unmilled TAK-228. The effect <strong>of</strong> food on milled<br />
Dose limiting toxicity<br />
(DLT)-evaluable<br />
population, n<br />
DLTs<br />
Single-agent QD Arm TAK-228 QD (N = 19) 3 mg<br />
(n = 11) / 4 mg (n = 8)<br />
Table: 377P<br />
Single-agent QW Arm TAK-228<br />
QW (N = 20) 20 mg (n = 7) / 30<br />
mg (n = 13)<br />
10 / 6 6 / 13 12 / 6<br />
1 pt at 3 mg (Grade [Gr] 3 thrombocytopenia); 3 pts<br />
at 4 mg (Gr 3 fatigue; Gr 3 fatigue, rash, decreased<br />
appetite; Gr 3 rash)<br />
1 pt at 30 mg (Gr 3 drug<br />
reaction)<br />
Combination Arm TAK-228 QDx3QW + P<br />
(N = 22) 6 mg (n = 15) / 4 mg (n = 7)<br />
1 pt at 6 mg (Gr 3 fatigue, dehydration)<br />
Maximum tolerated dose 3 mg QD 30 mg QW 6 mg QDx3QW + P<br />
(MTD)<br />
Safety population, n 17 20 22<br />
Treatment-related adverse<br />
events (>20% all grades)<br />
Fatigue (47%), pruritus (41%), rash (41%), decreased<br />
appetite (24%), diarrhea (24%), nausea (24%)<br />
Nausea (45%), vomiting (45%),<br />
fatigue (35%), diarrhea (30%)<br />
Response, n (tumor type)<br />
2 partial responses (PR) (kidney, uterus); 4 stable<br />
disease (SD) >90 d (2 fallopian tube, colon, ovary)<br />
2 SD >90 d (head/neck, gall<br />
bladder)<br />
Diarrhea (64%), decreased appetite (41%),<br />
fatigue (41%), nausea (36%), vomiting (32%),<br />
stomatitis (27%), asthenia (23%)<br />
1 complete response (breast); 2 PR (urinary<br />
bladder, uterus); 3 SD >90 d (rectal, ovary,<br />
stomach)<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw368 | vi121
abstracts<br />
TAK-228 PK was evaluated in 14 <strong>of</strong> 16 pts in the QD arm enrolled into a designated<br />
PK run-in cohort; the PK <strong>of</strong> milled TAK-228 was assessed in all pts.<br />
Results: At data cut-<strong>of</strong>f (March 11, 2016), 61 pts (median age 64 y [28–88]) were<br />
enrolled and formed the safety-population, n = 58 the response-population, and n = 53<br />
the PK-population. The safety and preliminary efficacy results are presented (Table).<br />
Preliminary PK comparisons <strong>of</strong> 4 mg milled TAK-228 QD under fed (n = 14) and<br />
fasted (n = 13) conditions reported a clinically meaningful 38% reduction in C max and<br />
a delay in absorption with food (median T max 6 h [fed] vs 2 h [fasted]), with no<br />
meaningful change in total AUC.<br />
Conclusions: Safety was established for milled TAK-228 at the MTDs <strong>of</strong> 3 mg QD, 30<br />
mg QW and 6 mg QDx3QW + P, lower doses than the MTDs identified for unmilled<br />
TAK-228. PK data suggest that a relevant food effect might be attributable for the<br />
observed difference in tolerability. Preliminary efficacy seen with milled TAK-228 is<br />
encouraging.<br />
Clinical trial identification: NCT02412722 (Clinical Trial Protocol MLN0128-1004<br />
Amendment 2, 14 May 2015)<br />
Legal entity responsible for the study: Millennium Pharmaceuticals, Inc.<br />
Funding: Millennium Pharmaceuticals Inc., a wholly owned subsidiary <strong>of</strong> Takeda<br />
Pharmaceutical Company Limited<br />
Disclosure: K.N. Moore: Advisory boards/honoraria: Advaxis, AstraZeneca, Amgen,<br />
Clovis, Immunogen, Merrimack, VBL Therapeutics. G. Falchook: Corporate-sponsored<br />
research: Millennium Pharmaceuticals, Inc. (research funding for clinical trials; travel<br />
reimbursement to present trial results at ESGO 2013). C. Patel, F. Zohren:<br />
Employment: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary <strong>of</strong> Takeda<br />
Pharmaceutical Company Limited; Stock ownership: Takeda Pharmaceutical Company<br />
Limited. R. Neuwirth, A. Enke: Employment: Millennium Pharmaceuticals, Inc., a<br />
wholly owned subsidiary <strong>of</strong> Takeda Pharmaceutical Company Limited. All other<br />
authors have declared no conflicts <strong>of</strong> interest.<br />
378P<br />
Determination <strong>of</strong> recommended phase II dose <strong>of</strong> ABTL0812, a<br />
novel regulator <strong>of</strong> Akt/mTOR axis, by<br />
pharmacokinetic-pharmacodynamic modelling<br />
J. Alfon 1 , L. Vidal 2 , L. Gaba 2 , I. Victoria 2 , M. Gil 3 , B. Laquente 3 , M. Brunet 2 ,<br />
H. Colom 4 , J. Ramis 5 , H. Perez-Montoyo 1 , M. Cortal 1 , M. Gomez-Ferreria 1 ,<br />
P. Muñoz 1 ,T.Erazo 6 , J.M. Lizcano 6 , C. Domenech 1 , P. Gascon 2<br />
1 R&D, Ability Pharmaceuticals SL, Cerdanyola, Spain, 2 IntherUnit, Hospital Clinic y<br />
Provincial de Barcelona, Barcelona, Spain, 3 Medical <strong>Oncology</strong>, Institut Català<br />
d’Oncologia Hospital Duran i Reynals, Barcelona, Spain, 4 Faculty <strong>of</strong> Pharmacy,<br />
Universitat de Barcelona, Barcelona, Spain, 5 R&D, ADMEservices, Barcelona,<br />
Spain, 6 Protein Kinases Laboratory, Universitat Autonoma de Barcelona,<br />
Barcelona, Spain<br />
Background: ABTL0812 is an anticancer agent in clinical development with a novel<br />
mechanism <strong>of</strong> action. It inhibits the Akt/mTOR axis after binding to PPARs and<br />
subsequent induction <strong>of</strong> TRIB3, a pseudokinase that acts as a negative regulator <strong>of</strong> Akt.<br />
Preclinical studies have shown high efficacy in different tumor types including NSCLC,<br />
endometrial cancer, pancreatic cancer and neuroblastoma. ABTL0812 exhibits, efficacy in<br />
resistant models and synergy with chemotherapy while maintaining extremely low toxicity.<br />
Methods: A phase Ib clinical trial with a 3 + 3 escalation design and an expansion<br />
phase was performed in patients with advanced solid tumors. Safety and tolerability<br />
were the main objectives <strong>of</strong> the trial. ABTL0812 pharmacokinetics (PK) was<br />
determined and the ratio between phosphorylated Akt and total Akt (pAkt/Akt) levels<br />
in platelets was used as pharmacodynamic (PD) biomarker. Preliminary antitumor<br />
activity was evaluated by RECIST 1.1 criteria.<br />
Results: In the dose-escalation phase, 15 patients received 500 mg qd, 1000 mg qd,<br />
1000 mg bid and 2000 mg bid. Other 14 patients were included in the expansion part<br />
at a dose <strong>of</strong> 1300 mg tid. No dose-limiting toxicities were detected. Most AEs were<br />
grade 1-2, and only one patient had drug-related grade 3-4 AEs. Several long-term<br />
disease stabilizations were observed, including one patient with cholangiocarcinoma<br />
(≥68 weeks), one with endometrial cancer (60 weeks) and three with colorectal cancer<br />
(22-28 weeks). Linear pharmacokinetics was described after multiple daily dosing, as<br />
well as dose-dependent inhibition <strong>of</strong> pAkt/Akt. A PK/PD Inhibitory Effect Emax<br />
model was performed and it was found that at least bid administration was required to<br />
have sustained inhibition <strong>of</strong> the biomarker >50%. In addition, it was shown that 1300<br />
mg tid achieved pAkt/Akt inhibition in the range 74.7-95.5%, confirming that this dose<br />
induced the highest inhibition <strong>of</strong> the pathway.<br />
Conclusions: Phase Ib clinical trial results have shown a high safety pr<strong>of</strong>ile and signs <strong>of</strong><br />
efficacy. PK has been described and concentration-dependent inhibition <strong>of</strong> a surrogate<br />
biomarker has been demonstrated. RP2D was established at 1300 mg tid based on a<br />
PK/PD analysis using the ratio <strong>of</strong> pAkt/Akt in platelets as a surrogate biomarker.<br />
Clinical trial identification: Eudra CT 2013-001293-17; Clinicaltrials.gov<br />
NCT02201823<br />
Legal entity responsible for the study: Hospital Clinic i Provincial de Barcelona<br />
Institut Català d’Oncologia<br />
Funding: Ability Pharmaceuticals SL<br />
Disclosure: J. Alfon, H. Perez-Montoyo, M. Cortal, M. Gomez-Ferreria: I am employee<br />
<strong>of</strong> ABTL0812, sponsor <strong>of</strong> the clinical trial. P. Muñoz: Employee <strong>of</strong> Ability Pharma. T.<br />
Erazo: Participates in a corporate-sponsored research. J.M. Lizcano, P. Gascon:<br />
Participates in a corporate-sponsored research Member <strong>of</strong> Advisory Board C.<br />
Domenech: I am employee <strong>of</strong> ABTL0812, sponsor <strong>of</strong> the clinical trial I hold stock<br />
ownership in Ability Pharma. All other authors have declared no conflicts <strong>of</strong> interest.<br />
379P<br />
Phase II studies <strong>of</strong> AZD1775, a WEE1 kinase inhibitor, and<br />
chemotherapy in non-small-cell lung cancer (NSCLC): Lead-in<br />
cohort results<br />
D.R. Spigel 1 , S. Dakhil 2 , J.T. Beck 3 , A. Sadiq 4 , S. Menon 5 , C.D. Webb 6 , F.Y. Tsai 7 ,<br />
M. Johnson 1 , S.F. Jones 8 , C. Greenlees 9 , D.M. Stults 8 , D. Strickland 8 , C. Cook 10 ,<br />
G.M. Mugundu 10 , N.M. Laing 10 , T. French 11 , H.A. Burris 1<br />
1 <strong>Oncology</strong>, Sarah Cannon Research Institute/Tennessee <strong>Oncology</strong>, PLLC,<br />
Nashville, TN, USA, 2 Hematology, Cancer Center <strong>of</strong> Kansas, Wichita, KS, USA,<br />
3 Hematology, Highlands <strong>Oncology</strong> Group, Lafayetteville, AZ, USA, 4 <strong>Oncology</strong>,<br />
Fort Wayne Medical <strong>Oncology</strong> and Hematology, Fort Wayne, AR, USA, 5 <strong>Oncology</strong>,<br />
Medical College <strong>of</strong> Wisconsin, Milwaukee, WI, USA, 6 <strong>Oncology</strong>, Baptist Health<br />
Louisville, Louisville, KY, USA, 7 <strong>Oncology</strong>, Pinnacle <strong>Oncology</strong> Hematology,<br />
Scottsdale, AZ, USA, 8 <strong>Oncology</strong>, Sarah Cannon Research Institute, Nashville, TN,<br />
USA, 9 <strong>Oncology</strong>, Sarah Cannon Research Institute, London, UK, 10 <strong>Oncology</strong>,<br />
AstraZeneca, Boston, MA, USA, 11 <strong>Oncology</strong>, AstraZeneca, Cambridge, UK<br />
Background: Tumors with G1/S checkpoint deficiencies (e.g. TP53 mutations) rely on<br />
WEE1 kinase activity to arrest cell cycle progression at the G2 checkpoint, allowing for<br />
DNA repair before entry into mitosis. In preclinical models, WEE1 inhibition leads to<br />
mitotic catastrophe and cell death when combined with inhibitors <strong>of</strong> DNA damage<br />
response pathways. AZD1775 is a highly selective small molecule WEE1 inhibitor in<br />
development for the treatment (tx) <strong>of</strong> advanced solid tumors. Here, we report results<br />
from lead-in portions <strong>of</strong> two Phase 2 studies: carboplatin (C)/pemetrexed<br />
(P) + AZD1775 v. C/P in 1st-line metastatic non-squamous (NS) NSCLC<br />
(NCT02087241); and docetaxel (D) + AZD1775 v. D in recurrent NSCLC<br />
(NCT02087176).<br />
Methods: Both lead-in portions were designed to assess early safety and efficacy<br />
(response rate (RR) per RECIST 1.1). Tumor specimens were tested retrospectively for<br />
TP53 mutations using Next-Generation Sequencing. Patients (pts) with TP53-mutated<br />
(TP53+) and wild-type tumors were eligible. 1 st -line metastatic tx: C AUC 6 + P<br />
500mg/m 2 IV day (d) 1, every 21d; recurrent tx: D 75mg/m 2 IV<br />
d1 + granulocyte-colony stimulating factor 6mg SC d4 every 21d. All pts received<br />
AZD1775 225mg PO BID d1-3 x 5 doses. After a planned safety analysis <strong>of</strong> the 1st-line<br />
trial, dose and schedule were modified to reduce toxicity.<br />
Results: Data are presented in the table. Both studies were closed early owing to<br />
prioritization <strong>of</strong> other ongoing monotherapy and combination development programs,<br />
including strategies to optimize pt selection based on emerging genomic data. This<br />
limited the assessment <strong>of</strong> efficacy. One 1st-line pt (TP53 status unknown) remains on<br />
maintenance tx (Cycle 19) with AZD1775 and P.<br />
Table: 379P<br />
First-line Group (N = 14)<br />
Recurrent Group<br />
(N = 32)<br />
Patient Characteristics<br />
Median Age 63 years 62 years<br />
TP53 + , n (%) 4 (29) 17 (53)<br />
Male, n (%) 6 (43) 19 (59)<br />
Response Rate<br />
Partial Response (PR),<br />
n (%)<br />
4 (29) including 1 pt on AZD1775 alone<br />
for 1 year and 1 pt on AZD1775 and<br />
pemetrexed for over 1 year<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
3 (9)<br />
TP53+ pts with PR 1 pt, 1/4 total (25) 3 pts, 3/17 total (18)<br />
Stable Disease, n (%) 6 (43) 21 (66)<br />
TP53+ pts with SD 3 pts, 3/4 total (75) 10 pts, 10/17 total<br />
(59)<br />
Progressive Disease, n 1 (7) 1 (7)<br />
(%)<br />
TP53+ pts with PD 0 1 pt, 1/17 total (6)<br />
Not Evaluable, n 3 pts 5 pts<br />
Most Common Grade Neutropenia (36%) Neutropenia (28%)<br />
3/4 Toxicities (><br />
10%)<br />
Diarrhea (36%)<br />
Thrombocytopenia<br />
(28%)<br />
Thrombocytopenia (29%) Leukopenia (22%)<br />
Nausea (14%)<br />
Abdominal Pain<br />
(13%)<br />
Vomiting (14%) Diarrhea (13%)<br />
Anemia (14%) Asthenia (13%)<br />
Atrial Fibrillation (14%) Fatigue (13%)<br />
Febrile Neutropenia (14%)<br />
Hypokalemia (14%)<br />
Conclusions: Toxicities included myelosuppression and diarrhea. AZD1775<br />
development is ongoing across multiple tumor settings as monotherapy, in<br />
combination with olaparib, and in biomarker-specific cohorts.<br />
vi122 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Clinical trial identification: NCT02087241 NCT02087176<br />
Legal entity responsible for the study: Sarah Cannon Research Institute<br />
Funding: AstraZeneca<br />
Disclosure: D.R. Spigel: AstraZeneca-Travel funding. A. Sadiq:<br />
AstraZeneca-honoraria. C. Cook, G.M. Mugundu, N.M. Laing, T. French:<br />
AstraZeneca-employee and stock owner. All other authors have declared no conflicts <strong>of</strong><br />
interest.<br />
380P<br />
Modeling <strong>of</strong> pharmacokinetics, thrombocytopenia, plasma<br />
GDF-15 levels and tumor kinetics in response to treatment<br />
with the p53-HDM2 protein-protein interaction inhibitor<br />
NVP-CGM097<br />
C. Meille 1 , N. Guerreiro 1 , S. Bauer 2 , P. Cassier 3 , G. Demetri 4 , R. Dummer 5 ,D.<br />
S. Tan 6 , L. Van Bree 1 , T. Ramkumar 7 , E. Halilovic 7 , S. Jeay 1 , A. Jullion 1 ,<br />
F. Hourcade-Potelleret 1 , J.U. Wuerthner 1<br />
1 Novartis Pharma AG, Basel, Switzerland, 2 West German Cancer Centre, Essen,<br />
Germany, 3 Centre Léon Bérard, Lyon, France, 4 Dana-Farber Cancer Institute,<br />
Boston, MA, USA, 5 University Hospital Zürich, Zürich, Switzerland, 6 National<br />
Cancer Center, Singapore, 7 Novartis Institutes for BioMedical Research,<br />
Cambridge, MA, USA<br />
Background: NVP-CGM097 is a selective p53-HDM2 protein-protein interaction<br />
inhibitor currently in Phase I clinical development for the treatment <strong>of</strong> patients with<br />
p53 wild type malignancies. Delayed thrombocytopenia is the primary dose limiting<br />
toxicity reported upon NVP-CGM097 treatment. Anticipation <strong>of</strong> the onset and<br />
severity <strong>of</strong> thrombocytopenia is critical for improved patient outcome. The aim <strong>of</strong> this<br />
work was to develop mechanism-based pharmacokinetic-pharmacodynamic (PK-PD)<br />
models to provide an integrated quantitative understanding <strong>of</strong> safety and efficacy<br />
pr<strong>of</strong>iles.<br />
Methods: Population PK, PK/PD models <strong>of</strong> thrombocytopenia and the cytokine<br />
Growth Differentiation Factor 15 (GDF-15, as a marker for p53 pathway activation),<br />
and a kinetic (K)/PD model <strong>of</strong> tumor size was developed based on data from 48 solid<br />
tumor patients collected from the first-in-human Phase I study (NCT01760525)<br />
conducted with orally administered NVP-CGM097.<br />
Results: The PK/PD model for thrombocytopenia was derived from Friberg et al.<br />
(2002) 1 with an additional feedback mechanism and implementation <strong>of</strong> platelet (PLT)<br />
transfusion events. The model accurately reproduced the PLT time course after<br />
NVP-CGM097 administration, as well as the impact <strong>of</strong> drug on GDF-15 levels. An<br />
association between individual model-estimated drug potency on PLTs and drug<br />
potency on plasma GDF-15 levels was investigated as a descriptor <strong>of</strong> PLT change in<br />
addition to drug exposure, raising the possibility to use GDF-15 induction as a<br />
prospective marker for delayed thrombocytopenia. A kinetic (K)/PD efficacy model<br />
was also developed for the same patient population to describe tumor size as a function<br />
<strong>of</strong> dose. Large variability was seen in the tumor growth parameter while moderate<br />
variability was observed for drug potency on tumor size.<br />
Conclusions: This work further supports the use <strong>of</strong> such approaches for the clinical<br />
development <strong>of</strong> HDM2 inhibitors, and explores the feasibility <strong>of</strong> utilizing these<br />
approaches as a rational tool for tailoring regimens and doses for individual patients at<br />
risk for thrombocytopenia while maximizing patient benefit. References 1. Friberg LE,<br />
et al. J Clin Oncol 2002;20:4713–4721.<br />
Legal entity responsible for the study: Novartis Pharma AG<br />
Funding: Novartis Pharma AG<br />
Disclosure: C. Meille, L. Van Bree, A. Jullion: Novartis employee. N. Guerreiro:<br />
Novartis employee and stock owner. S. Bauer: Research support: Novartis, Blueprint<br />
Medicines, Ariad Consultant: GSK, Novartis, Pfizer, Bayer, Fresenius, Lilly, Blueprint<br />
Medicines Honoraria (CME): Pharmamar, GSK, Pfizer, Bayer Travel support:<br />
Pharmamar, Bayer. P. Cassier: Received honoraria and research funding from Novartis,<br />
Roche, BluePrint and Amgen, as well as research funding from Eli Lilly, Celgene,<br />
AstraZeneca, GlaxoSmithKline, Merck Sharp Dohme, Merck Serono. G. Demetri: With<br />
Novartis as study sponsor: 1. Consultant, consulting fees, 2. Patent on imatinib licensed<br />
to Novartis from Dana-Farber 3. Research support to Dana-Farber for clinical trial. R.<br />
Dummer: Research funding: Novartis, Merck Sharp & Dhome (MSD), Bristol-Myers<br />
Squibb (BMS), Roche, GlaxoSmithKline (GSK); and has a consultant/advisory board<br />
relationship with Novartis, MSD, BMS, Roche, GSK, Amgen outside the submitted<br />
work. D.S. Tan: Consulting or advisory fees from Novartis, Bayer, Boehringer<br />
Ingelheim and Eisai; honoraria from Novartis and Pfizer; research funding from<br />
Novartis, Bayer and GSK; and expense reimbursements from Novartis and MERCK,<br />
outside the submitted work. T. Ramkumar: Employee <strong>of</strong> Novartis Pharmaceuticals<br />
Corporation. E. Halilovic: Novartis employee and Novartis stock owner. S. Jeay:<br />
Employee and stockholder <strong>of</strong> Novartis A.G. F. Hourcade-Potelleret: Employee <strong>of</strong><br />
Novartis AG J.U. Wuerthner: Employee <strong>of</strong> Novartis and has stock ownership <strong>of</strong><br />
Novartis.<br />
381P<br />
A phase I, open-label, study <strong>of</strong> GSK2879552, a lysine-specific<br />
demethylase 1 (LSD1) inhibitor, in patients with relapsed/<br />
refractory small cell lung carcinoma (SCLC)<br />
V. Moreno 1 , T.M. Bauer 2 , J. Infante 3 , R. Govindan 4 , B. Besse 5 , E. Bertino 6 ,A.<br />
Martinez Marti 7 , T. Piontek 8 , A. Dhar 9<br />
1 Medical <strong>Oncology</strong>, START Madrid-FJD, Fundación Jiménez Díaz Hospital,<br />
Madrid, Spain, 2 Drug Development Unit, Sarah Cannon Research Institute/<br />
Tennessee <strong>Oncology</strong>, Nashville, TN, USA, 3 Other, Sarah Cannon Research<br />
Institute, Nashville, TN, USA, 4 Medical <strong>Oncology</strong>, Washington University School <strong>of</strong><br />
Medicine, St. Louis, MO, USA, 5 Departement <strong>of</strong> Medicine, Institut Gustave<br />
Roussy, Villejuif, France, 6 Department <strong>of</strong> Internal Medicine, Division <strong>of</strong> Medical<br />
<strong>Oncology</strong>, Ohio State Univ Medical Center, Columbus, OH, USA, 7 Medical<br />
<strong>Oncology</strong>, Vall d’Hebron University Hospital Institut d’Oncologia, Barcelona,<br />
Spain, 8 RD Projects Clinical Platforms & Sciences, GlaxoSmithKline, Collegeville,<br />
PA, USA, 9 Onocolgy R&D, GlaxoSmithKline, Collegeville, PA, USA<br />
Background: SCLC is initially responsive to chemotherapy; however, patients<br />
ultimately relapse. Response to second-line therapy is poor with an overall survival <strong>of</strong><br />
abstracts<br />
Results: In vitro, inhibition <strong>of</strong> DNA-PK by VX-984 had potent cytotoxic activity in<br />
combination with doxorubicin and etoposide in established cancer cell lines and in<br />
primary tumor explants from ovarian and endometrial cancers (doxorubicin) and<br />
small cell lung cancer (etoposide). Bliss synergy scores <strong>of</strong> ≤23% (strong synergy) were<br />
observed for doxorubicin and etoposide in the presence <strong>of</strong> VX-984. Further, the<br />
activity observed with VX-984 was associated with enhanced DNA damage as<br />
measured by phosphorylated Kruppel-associated protein (pKAP1) and phosphorylated<br />
histone H2AX (gamma-H2AX), consistent with failed DSB repair. In vivo, VX-984<br />
significantly enhanced the efficacy <strong>of</strong> pegylated liposomal doxorubicin (PLD) in an<br />
ovarian cancer patient-derived xenograft model as well as in cancer cell line xenograft<br />
models.<br />
Conclusions: These data provide evidence that inhibition <strong>of</strong> DNA-PK by VX-984<br />
enhances the efficacy <strong>of</strong> DSB-inducing agents in preclinical models and support the use<br />
<strong>of</strong> VX-984 in combination with agents such as PLD for the treatment <strong>of</strong> ovarian and<br />
endometrial cancers. VX-984 is currently in a Phase 1 clinical trial in combination with<br />
PLD.<br />
Legal entity responsible for the study: Vertex Pharmaceuticals Incorporated<br />
Funding: Vertex Pharmaceuticals Incorporated<br />
Disclosure: D. Boucher, S. Hillier, D. Newsome, Y. Wang, D. Takemoto, Y. Gu,<br />
W. Markland, R. Hoover, R. Arimoto, J. Maxwell, S.Z. Fields, P. Charifson, M.S.<br />
Penney, K. Tanner: Is an employee <strong>of</strong> Vertex Pharmaceuticals Incorporated and may<br />
own stock or stock options in that company.<br />
383P<br />
RAS/AKT pathway mutations as predictive biomarkers in<br />
patients with colorectal cancer treated with the exportin 1<br />
(XPO1) inhibitor selinexor (SEL) – inhibition <strong>of</strong><br />
nuclear-cytoplasmic translocation <strong>of</strong> p27 as a mechanism <strong>of</strong><br />
anti-tumour activity<br />
V.Y.M. Heong 1 ,P.Koe 1 , W.P. Yong 2 , R. Soo 3 , C.E. Chee 1 , A. Wong 2 , Y.L. Thian 2 ,<br />
R. Sundar 4 , J.S. Ho 2 , A. Gopinathan 2 , S.C. Lee 2 , B.C. Goh 2 ,D.Tan 2<br />
1 <strong>Oncology</strong>, The Cancer Institute National University Hospital, Singapore,<br />
2 Haematology-<strong>Oncology</strong>, National University Hospital, Singapore, 3 Cancer<br />
Institute, National University Cancer Institute, Singapore, 4 Medical <strong>Oncology</strong>,<br />
National University Cancer Institute, Singapore<br />
Background: Localization <strong>of</strong> p27 within a cell determines its function. Cytoplasmic<br />
sequestration <strong>of</strong> p27 promotes oncogenic activity while its nuclear retention inhibits<br />
tumorigenesis. RAS activation in tumours indirectly causes cytoplasmic sequestration<br />
<strong>of</strong> p27 via the activation <strong>of</strong> its effectors PI3K/AKT and Raf1/MEK/ERK pathway. SEL is<br />
a potent XPO1inhibitor that forces nuclear retention <strong>of</strong> multiple proteins including<br />
p27 resulting in tumour cell death.<br />
Methods: SEL was administered orally to patients with advanced solid cancers in a<br />
phase I dose escalation study. Response was evaluated every two cycles (RECIST v1.1).<br />
Nuclear-cytoplasmic localisation <strong>of</strong> p27 in RAS and/ or AKT pathway activated<br />
tumours from tumour biopsies pre and post SEL were determined together with<br />
nuclear retention <strong>of</strong> other XPO1 cargo proteins, proliferative and apoptotic markers.<br />
Results: Outcomes <strong>of</strong> 18 advanced colorectal cancer (CRC) patients with known RAS<br />
and AKT pathway mutational status (12M/6F; median age 59.5; ECOG PS 0/1: 9/9),<br />
who received at least 8 weeks <strong>of</strong> SEL were analysed. 50% (n = 9) had an activating<br />
mutation in the RAS pathway (KRAS/NRAS/BRAF: 7/1/1); 16.7%(n = 3) in the PI3K/<br />
AKT pathway (PI3K/AKT/PTEN loss: 1/1/1); 11.1% (n = 2) in both and 44.4%(n = 8)<br />
did not harbour mutations in either (WT). Median PFS for patients with a mutation in<br />
either pathway compared to WT patients were 78 days vs 50days, respectively;(p<br />
value = 0.129). 40% (n = 4) CRC patients with RAS/AKT pathway mutation achieved a<br />
disease control rate (DCR) <strong>of</strong> > 3 mths compared to 12.5% <strong>of</strong> CRC WT patients.<br />
Analysis <strong>of</strong> pre and post SEL treated biopsy samples confirmed increased nuclear<br />
retention <strong>of</strong> p27 in the KRAS/AKT mutant tumours with DCR > 3mths.<br />
Conclusions: RAS and AKT pathway activated CRC appear to have a longer PFS with<br />
an increased number <strong>of</strong> patients achieving DCR <strong>of</strong> >3 months compared to WT<br />
tumours. Cytoplasmic translocation <strong>of</strong> p27 could be a key oncogenic mechanism in<br />
RAS and/or AKT pathway activated tumours and can be targeted by inhibition <strong>of</strong><br />
XPO1<br />
Legal entity responsible for the study: National University Hospital, Singapore<br />
Funding: tudy support: Karyopharm Therapeutics Inc. and National Medical Research<br />
Council<br />
Disclosure: D. Tan: Advisory board - Astra Zeneca. All other authors have declared no<br />
conflicts <strong>of</strong> interest.<br />
384P<br />
Initial first-in-human phase 1 results <strong>of</strong> PTC596, a novel small<br />
molecule that targets cancer stem cells (CSCs) by reducing<br />
BMI1 protein levels<br />
G. Shapiro 1 , J. Infante 2 , T.M. Bauer 3 , A. Prawira 4 , P. Bedard 5 , O. Laskin 6 ,<br />
M. Weetall 7 , J. Baird 8 ,E.O’Mara 6 , R. Spiegel 9<br />
1 <strong>Oncology</strong>, Dana Farber Cancer Institute, Boston, MA, USA, 2 Other, Sarah<br />
Cannon Research Institute, Nashville, TN, USA, 3 Drug Development Unit, Sarah<br />
Cannon Research Institute/Tennessee <strong>Oncology</strong>, Nashville, TN, USA,<br />
4 Department <strong>of</strong> Medical <strong>Oncology</strong> and Hematology, Princess Margaret Hospital,<br />
Toronto, ON, Canada, 5 Medical <strong>Oncology</strong>, Princess Margaret Hospital, Toronto,<br />
ON, Canada, 6 Clinical, PTC Therapeutics, South Plainfield, NJ, USA,<br />
7 Pharmacology, PTC Therapeutics, Inc., South Plainfield, NJ, USA, 8 Clinical, PTC<br />
Therapeutics, inc., South Plainfield, NJ, USA, 9 Clinical, PTC Therapeutics, Inc.,<br />
South Plainfield, NJ, USA<br />
Background: PTC596 is a novel, oral investigational drug that reduces the levels <strong>of</strong><br />
BMI1, a protein that is required for CSC survival. PTC596 reduced the number <strong>of</strong><br />
CSCs in preclinical models and reduced growth <strong>of</strong> tumor xenografts in mouse models.<br />
The primary objectives <strong>of</strong> this first in human trial are to determine the safety,<br />
dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and<br />
pharmacokinetics (PK). Secondary objectives will include an initial assessment <strong>of</strong><br />
biological efficacy and pharmacodynamic changes and to evaluate anti-tumor activity.<br />
Methods: A phase I multi-center study comprising 2 stages is being conducted in<br />
patients with advanced solid tumors. PTC596 is administered in 4 week cycles using<br />
body-weight-adjusted twice-per-week (biw) oral capsule dosing. Stage 1 is an escalation<br />
using a modified 3 + 3 design. Anti-tumor activity is assessed by RECIST 1.1.<br />
Expansion cohorts are being enrolled to obtain pre- and post-treatment tumor biopsies<br />
for markers <strong>of</strong> target engagement. In stage 2, up to 40 patients with a limited number<br />
<strong>of</strong> tumor types will be enrolled at the MTD. Patients who appear to be deriving benefit<br />
may stay on PTC596.<br />
Results: To date, 19 patients have been enrolled at doses <strong>of</strong> 0.65, 1.3, 2.6, 5.2, and 10<br />
mg/kg. No DLTs or drug related grade 2 toxicities were observed in the first 4 cohorts.<br />
Grade 1 Nausea and vomiting were seen at these lower doses. Though a protocol<br />
defined MTD was not obtained, the dose <strong>of</strong> 10 mg/kg was deemed intolerable due to<br />
Grade 4 neutropenia and thrombocytopenia (n = 1 patient) and intolerable Grade 2<br />
nausea, vomiting, and diarrhea. An intermediate dose <strong>of</strong> 7 mg/kg is currently being<br />
evaluated. Plasma concentrations <strong>of</strong> PTC596 increased in a dose-proportional manner.<br />
Though no objective responses have been observed to date, plasma concentrations at<br />
doses ≥2.6 mg/kg biw exceed those demonstrated to be efficacious in mouse xenograft<br />
models.<br />
Conclusions: PTC596, a first-in-class oral small molecule that lowers the levels <strong>of</strong><br />
BMI1, is generally well tolerated as a monotherapy at doses that achieve preclinical<br />
target plasma concentrations. Doses
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Results: As <strong>of</strong> May 2016, 24 subjects were enrolled (11 Females, 13 males). No dose<br />
limiting toxicities or treatment related SAEs were reported. Seven subjects experienced<br />
stable disease (breast, neuroendocrine, paraganglioma, head/neck and colorectal<br />
cancers); 3 subjects received treatment for > 1 year. The most common side effects were<br />
grade 1 related adverse events: nausea, vomiting and fatigue; no grade 2 related events<br />
were reported. RX–5902 was orally bioavailable with median T max <strong>of</strong> 2 hours and<br />
half-life <strong>of</strong> 12 hours. Doses were successfully escalated to 300 mgs daily for 5 days, with<br />
a 3 weeks on, 1 week <strong>of</strong>f schedule. Daily doses <strong>of</strong> 300-400 mgs daily for 28 days are<br />
being tested.<br />
Conclusions: RX-5902 is safe and well tolerated at the doses and schedules tested.<br />
Early anti-tumor activity was observed in patients with breast, neuroendocrine,<br />
paraganglioma, squamous cell cervical and colorectal cancers. Final results from the<br />
phase 1 and data on the first stage <strong>of</strong> the Phase 2a in patients with TNBC and advanced<br />
OC will be presented.<br />
Clinical trial identification: NCT02003092<br />
Legal entity responsible for the study: Rexahn Pharmaceuticals, Inc<br />
Funding: Rexahn Pharmaceuticals, Inc<br />
Disclosure: C. Peterson, R. Mazhari, E. Benaim: Employee <strong>of</strong> Rexahn Pharmaceuticals,<br />
Inc. All other authors have declared no conflicts <strong>of</strong> interest.<br />
386P<br />
PISARRO: A EUTROC phase 1b study <strong>of</strong> APR-246 with<br />
carboplatin (C) and pegylated liposomal doxorubicin (PLD) in<br />
relapsed platinum-sensitive high grade serous ovarian cancer<br />
(HGSOC)<br />
B. Basu 1 , C. Gourley 2 , H. Gabra 3 , I.B. Vergote 4 , J.D. Brenton 5 , L. Abrahmsen 6 ,<br />
A. Smith 7 , M. Von Euler 6 , J.A. Green 8<br />
1 <strong>Oncology</strong>, University <strong>of</strong> Cambridge, Cambridge, UK, 2 MRC IGMM, University <strong>of</strong><br />
Edinburgh, Edinburgh, UK, 3 Cancer and Surgery, Imperial College London -<br />
Hammersmith Hospital, London, UK, 4 Obstetrics & Gynaecology, University<br />
Hospitals Leuven - Campus Gasthuisberg, Leuven, Belgium, 5 Cancer Research<br />
UK Cambridge Institute, University <strong>of</strong> Cambridge, Cambridge, UK, 6 <strong>Oncology</strong>,<br />
Aprea AB, Solna, Sweden, 7 <strong>Oncology</strong>, Theradex (Europe) Ltd, Crawley, UK,<br />
8 Molecular and Clinical Cancer Medicine, University <strong>of</strong> Liverpool, Liverpool, UK<br />
Background: TP53 mutations are ubiquitous in HGSOC. APR-246 stabilises mutant<br />
p53 into wild-type conformation and through its active moiety MQ, also depletes<br />
glutathione and inhibits thioredoxin reductase. These mechanisms <strong>of</strong> action potentiate<br />
chemosensitivity <strong>of</strong> cancer cells. This study aimed to establish the recommended phase<br />
II dose (RPTD) <strong>of</strong> APR-246 in combination with C and PLD.<br />
Methods: A 3 + 3 dose escalation study <strong>of</strong> APR-246 (35, 50 and 67.5mg/kg IV on days<br />
1-4) in combination with C AUC5 and PLD 30mg/m2 given on day 4 in a 28-day<br />
schedule. Eligible patients had platinum sensitive relapsed HGSOC with archival<br />
tumour specimens demonstrating cytoplasmic mutant p53 staining. Following<br />
recruitment to the three dose cohorts (3 + 6 + 6) further patients were included in dose<br />
level (DL) 1 and DL3 cohorts to evaluate possible dose dependency <strong>of</strong> safety and<br />
efficacy. CA-125 was tested at each cycle, and CT scans performed every two cycles.<br />
Results: All 3 dose escalation cohorts have completed recruitment with expansion <strong>of</strong><br />
DL2 (due to one dose limiting toxicity (DLT) <strong>of</strong> ruptured diverticulum) and DL3<br />
(RPTD). No dose dependent signals in activity or toxicity were established. The main<br />
toxicity attributable to APR-246 was dizziness in 20 out <strong>of</strong> 28 patients (71%; 18 grade<br />
1/2, 2 grade 3). There were no pharmacokinetic interactions between APR-246 and C/<br />
PLD. To date, <strong>of</strong> 17 patients evaluable for CA125 response (GCIG Intergroup criteria)<br />
after at least 2 cycles, 14 showed response. Nine <strong>of</strong> these responders were previously<br />
partially platinum sensitive, <strong>of</strong> whom 8 out <strong>of</strong> 9 were treated at DL3. Of 18 patients<br />
evaluable for radiological response, 3 had a CR (2 confirmed), 11 had a PR, 4 had SD<br />
and 0 had PD. Overall response rate (GCIG or RECIST) was 18/23 (78%).<br />
Conclusions: APR-246 at a dose <strong>of</strong> 67.5mg/kg in combination with C and PLD has<br />
been selected as RPTD. Efficacy data for the combination regimen in the phase 1b<br />
study is encouraging and a multi-centre randomised phase II study is being opened in<br />
2016. Updated efficacy and translational data will be presented.<br />
Clinical trial identification: ClinicalTrials.gov Identifier: NCT02098343<br />
Legal entity responsible for the study: N/A<br />
Funding: Aprea AB<br />
Disclosure: B. Basu: Advisory Boards: Baxter Healthcare, Nordic Pharma Research<br />
funding: Celgene Ltd Travel, Accommodations, Expenses: Bayer, Novartis. C. Gourley:<br />
Honoraria- AZ; Boehringer Ingelheim (BI); MSD; Roche/Genentech (R/G)<br />
Consulting- AZ;BI; GSK; R/G Research Funding- AZ(Inst); GSK(Inst); Incyte (Inst)<br />
Patents- anti-angiogenic therapy gene expression signature (Inst) Travel, Expenses - BI;<br />
R/G. H. Gabra: Honoraria - GlaxoSmithKline Consulting or Advisory Role - Aeterna<br />
Zentaris; Morphotek Speakers’ Bureau - Caris Life Sciences Research Funding –<br />
GlaxoSmithKline. I.B. Vergote: Consulting role for Roche Pharma AG and Oasmia<br />
Pharmaceuticals AB (Inst) Research funding Roche Pharma AG. J.D. Brenton: Stock<br />
and Other Ownership Interests - Inivata Consulting or Advisory Role - Inivata Patents,<br />
Royalties, Other Intellectual Property - TAm-Seq v2 method for ctDNA estimation<br />
Travel, Accommodations, Expenses - Aprea AB; Clovis <strong>Oncology</strong>. L. Abrahmsen,<br />
M. Von Euler: Employee <strong>of</strong> Aprea AB. A. Smith: Employee <strong>of</strong> Theradex. J.A. Green:<br />
Debiopharm advisory board.<br />
387P<br />
Phase I dose <strong>of</strong> oral quisinostat, in combination with<br />
gemcitabine (G) and cisplatin (Cis) or paclitaxel (P) and<br />
carboplatin (Carbo) in patients (pts) with non-small cell lung<br />
cancer or ovarian cancer (OC)<br />
M. Fedyanin 1 , S. Tjulandin 2 , S. Cheporov 3 , V. Vladimirov 4 , V. Moiseenko 5 ,<br />
S. Orlov 6 , G. Manikhas 7 , A. Cakana 8 , V. Azarova 9 , O. Karavaeva 9 , N. Vostokova 9 ,<br />
S. Baranovskiy 9<br />
1 Clinical pharmacology and chemotherapy, Russian <strong>Oncology</strong> Research Center<br />
named after Blokhin N.N., Moscow, Russian Federation, 2 Clinical Pharmacology<br />
and Chemotherapy, N. N. Blokhin Russian Cancer Research Center, Moscow,<br />
Russian Federation, 3 Chemotherapy, State "Regional Clinical <strong>Oncology</strong> Hospital"<br />
health care institution <strong>of</strong> Yaroslavl region, Yaroslavl, Russian Federation,<br />
4 Chemotherapy Outpatient departament, Pyatigorsk Affiliate <strong>of</strong> Stavropol Regional<br />
<strong>Oncology</strong> Center, Pyatigorsk, Russian Federation, 5 Chemotherapy, GBUZ<br />
Saint-Petersburg clinical scientific and practical center special kinds <strong>of</strong> medical<br />
care (oncology), Saint Petersburg, Russian Federation, 6 BioEq, LLC, Saint<br />
Petersburg, Russian Federation, 7 Department <strong>of</strong> Gynaecological <strong>Oncology</strong>,<br />
Saint-Petersburg State Budget institution Healthcare Municipal Clinical <strong>Oncology</strong><br />
Dispensary, Saint Petersburg, Russian Federation, 8 Janssen Pharmaceutica N.V.,<br />
Janssen Pharmaceutica N.V., High Wycombe, UK, 9 IPHARMA, LLC, Moscow,<br />
Russian Federation<br />
Background: The mechanism <strong>of</strong> action <strong>of</strong> quisinostat (Q) includes protein acetylation,<br />
leading to re-activation <strong>of</strong> tumor suppressor genes and restoration <strong>of</strong> tumor sensitivity<br />
to chemotherapy<br />
Methods: The primary endpoint was to identify the maximum tolerated dose (MTD)<br />
<strong>of</strong> Q. Secondary endpoints included safety, overall response rate, and pharmacokinetics<br />
parameters. Q was administered orally at escalated doses (8, 10 and 12 mg); 3 week<br />
cycle on Days 1, 3, 5, 7, 9, 11. In the 1st arm NSCLC pts received Q with G (1000 mg/<br />
m 2 ) on Day 7 and 14 and Cis (75 mg/m 2 ) on Day 7 <strong>of</strong> each cycle, for 2nd line. If Q was<br />
deemed tolerable at 12 mg, another dosage cohort was to have been started: Q (12 mg)<br />
with G (1250 mg/m 2 ) on Days 7 and 14 and Cis (75 mg/m 2 ) on Day 7 <strong>of</strong> each cycle for<br />
1st line NSCLC. In the 2nd arm pts received Q with P (175 mg/m 2 ) and Carbo (AUC5)<br />
on Day 7 <strong>of</strong> each cycle, in 2nd or subsequent lines for pts with NSCLC or OC. Dose<br />
escalation was according to the “3+3” dose-limiting toxicity (DLT) algorithm. After<br />
definition <strong>of</strong> MTD, additional pts were to have been included<br />
Results: 51 pts (QGCis – 28 pts, QPCarbo – 23 pts; NCSLC – 33 pts, OC – 18 pts) were<br />
enrolled: 49% male; median age = 59.6 (range 40-74) years. There were no DLTs. Q was<br />
tolerated to the maximum dose <strong>of</strong> 12 mg chosen for this study, and therefore there<br />
were MTD criteria never met; Q at 12 mg in combo was chosen and is dose<br />
recommended for Phase 2 development. The most common adverse events (AE) were<br />
neutropenia - 56% and 57%, thrombocytopenia - 39% and 75%, anemia - 35% and<br />
64% for group <strong>of</strong> QPCarbo and QGCis, respectively. Any serious AE were revealed in<br />
21.6% pts, Q related serious AE – in 13.7%, AE ¾ grades – in 64.7%, and 23.5% pts<br />
discontinued therapy due to AE. 46 pts were evaluable for response, with responses<br />
observed in 8 (17%): 8 PRs (NSCLC: 2/30 pts, 6.7%; OC: 6/16 pts, 37.5%). Most pts<br />
with OC with partial response had platinum resistance relapses<br />
Conclusions: On successfully completing the trial, the recommended dose <strong>of</strong> Q for<br />
phase 2 study is 12 mg in combination with G 1250 mg/m 2 ) and Cis (75 mg/m 2 )orP<br />
(175 mg/m 2 ) and Carbo (AUC5). The combination QPCarbo showed activity in the<br />
treatment <strong>of</strong> pts with platinum resistant OC<br />
Clinical trial identification: NCT02728492<br />
Legal entity responsible for the study: N/A<br />
Funding: NewVac<br />
Disclosure: M. Fedyanin: consultant <strong>of</strong> NewVac. S. Orlov: Employment - BioEq,<br />
LLC. A. Cakana: Employment - Janssen Pharmaceutica N.V. V. Azarova, O. Karavaeva,<br />
N. Vostokova: Employment - IPHARMA, LLC S. Baranovskiy: Employment –<br />
NewVac. All other authors have declared no conflicts <strong>of</strong> interest.<br />
388P<br />
abstracts<br />
A first-in-human (FIH) phase I/II, dose escalation,<br />
pharmacokinetic (PK) study to assess the safety and<br />
tolerability <strong>of</strong> VAL-201 in patients with advanced prostate<br />
cancer (APC) and other advanced solid tumours<br />
R.S. Kristeleit 1 , R.E. Miller 2 , L.E. Sellers 3 , N.F. Brown 2 , P. Gougis 2 , A. Boyd 4 ,<br />
G. Morris 5 , H. Payne 3 , S. Hughes 6 , M. Forster 1 , M. Linch 3<br />
1 Cancer Institute, UCL - University College London, London, UK, 2 UCLH/NIHR<br />
Clinical Research Facility, University College London Hospital, London, UK,<br />
3 <strong>Oncology</strong>, University College London Hospital, London, UK, 4 Boyd, Consulting,<br />
London, UK, 5 COO, ValiRx, London, UK, 6 <strong>Oncology</strong>, Guy’s and St. Thomas’<br />
Hospital NHS Trust, London, UK<br />
Background: Most patients with advanced prostate cancer treated with androgen<br />
deprivation therapy experience side effects <strong>of</strong> castration and eventually relapse.<br />
VAL-201 is a synthetic decapeptide that inhibits interaction <strong>of</strong> the androgen and<br />
oestradiol receptors with Src tyrosine kinase, disrupting steroid or epithelial growth<br />
factor dependent DNA synthesis. The aims <strong>of</strong> this FIH study are to assess safety,<br />
tolerability, PK and activity <strong>of</strong> VAL-201 in patients with APC.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw368 | vi125
abstracts<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Table: 388P<br />
Patient # Dose cohort Age ECOG PS days on trial Disease status Castrate sensitivity PSA doubling pre-trial (months)** PSA doubling on trial (months)<br />
>101-001 0.5mg/kg 71 0 191 locally advanced resistant 2.8 7.5<br />
101-003 1.0mg/kg 63 0 126 locally advanced sensitive 13.3 6.1<br />
101-005 2.0mg/kg 79 1 85 metastatic resistant 1.6 2.2<br />
101-006 2.0mg/kg 70 0 55 metastatic sensitive 1.9 1.6<br />
101-007 2.0mg/kg 81 0 64 locally advanced sensitive 12.5 8.2<br />
101-008 4.0mg/kg 68 1 55* metastatic resistant 2.9 -2.2<br />
101-009 4.0mg/kg 82 0 40* locally advanced sensitive 2.9 -97.5<br />
101-010 4.0mg/kg 84 0 -7* locally advanced sensitive 6 NA<br />
*continues on study **minimum <strong>of</strong> three months<br />
Methods: An accelerated titration, open label, dose-escalating design has been used to<br />
identify a maximum tolerated/administered dose (MTD/MAD). VAL-201 is given<br />
subcutaneously on Days 1, 8, 15, q21. The starting dose was 0.5 mg/kg. Expansion to a<br />
3 + 3 design was planned to occur at dose level (DL) 3. Dose limiting toxicity (DLT)<br />
was assessed during Cycle 1 and safety evaluations were conducted weekly.<br />
Results: Eight patients have been recruited to 4 DLs (0.5mg/kg n = 1; 1.0mg/kg n = 1;<br />
2.0mg/kg n = 3; 4.0mg/kg n = 3). Patient demographics are in Table 1. The final<br />
planned escalation will be 5.0mg/kg, the maximum feasible single dose which may be<br />
administered. No DLT has occurred to date. The only drug-related adverse event (AE)<br />
observed has been Grade 1 injection site reaction. Median duration on trial is currently<br />
85 days. Early signs <strong>of</strong> clinical activity have been observed with prolonged PSA<br />
doubling time (n = 2), stabilisation <strong>of</strong> PSA (n = 1) and >50% decrease in PSA (n = 1,<br />
Table).<br />
Conclusions: VAL-201 is very well-tolerated with early signs <strong>of</strong> clinical activity in<br />
advanced prostate cancer. No DLT has been observed. The MTD/MAD has not yet<br />
been identified and the study continues. Expansion to other tumour types is planned.<br />
PK data analysis is ongoing and will be presented.<br />
Clinical trial identification: NCT02280317<br />
Legal entity responsible for the study: N/A<br />
Funding: ValiRx, Inc<br />
Disclosure: A. Boyd: Is employed as a Consultant by ValiRx as a medical monitor for<br />
the trial. G. Morris: Employee <strong>of</strong> ValiRx.All other authors have declared no conflicts <strong>of</strong><br />
interest.<br />
389P<br />
Biomarker and clinical activity <strong>of</strong> CPI-444, a novel small<br />
molecule inhibitor <strong>of</strong> A2A receptor (A2AR), in a Ph1b study in<br />
advanced cancers<br />
I. McCaffery 1 , G. Laport 2 , A. Hotson 1 , S. Willingham 1 , A. Patnaik 3 , M. Beeram 3 ,<br />
R. Miller 2<br />
1 Translational Sciences, Corvus Pharmaceuticals, Burlingame, CA, USA, 2 Clinical<br />
Development, Corvus Pharmaceuticals, Burlingame, CA, USA, 3 The START<br />
Center for Cancer Care, South Texas Accelerated Research Therapeutics (START),<br />
San Antonio, TX, USA<br />
Background: Adenosine is immunosuppressive and is produced at high concentrations<br />
in tumors by both CD73 and direct release from tumor cells. Adenosine activates<br />
A2AR, an immune checkpoint that leads to direct suppression <strong>of</strong> effector T cells and<br />
stimulation <strong>of</strong> regulatory T cells. CPI-444 is an oral, selective A2AR inhibitor that has<br />
been well tolerated in Ph 1 and 2 studies in non-oncology indications. CPI-444 shows<br />
activity in multiple preclinical tumor models as a single agent and synergistic efficacy<br />
when given in combination with other checkpoint inhibitors, including anti-PD-L1.<br />
Methods: CPI-444, with or without the investigational agent atezolizumab<br />
(anti-PD-L1), is being studied in an ongoing Ph1b trial in solid tumor patients (pts).<br />
Pts with either lung, melanoma, triple negative breast, bladder, colorectal, renal, or<br />
head and neck cancers are treated at various doses <strong>of</strong> either single agent CPI-444 or<br />
combined with atezolizumab. After a dose selection stage, pts are treated in 10 disease<br />
specific cohorts (5 single agent and 5 combination). Cohorts may be expanded based<br />
on response criteria: complete response, partial response or stable disease (SD).<br />
Biomarkers are evaluated including immune cells by flow cytometry in peripheral<br />
blood and pre/post treatment tumor biopsies as well as adenosine pathway modulation<br />
by immunohistochemistry and gene expression.<br />
Results: In 7 pts treated to date, CPI-444 has been well tolerated with no Grade 3 or 4<br />
treatment related adverse events. 2 pts (1 combination and 1 single agent) have reached<br />
the first efficacy assessment by CT and both demonstrated SD (unconfirmed at 2<br />
months); these 2 pts, and 4 others who have not yet reached efficacy evaluation, remain<br />
on treatment. In the two pts with SD, peripheral blood showed increases in<br />
PD-1 + CD8+ cells (1.7 and 2.4 fold compared to baseline). This is consistent with<br />
preclinical models and reflect effector T cell activation, similar to reports by others in<br />
patients treated with anti-PD-L1.<br />
Conclusions: CPI-444 is well tolerated and demonstrates biological activity indicating<br />
activation <strong>of</strong> T cell immunity. This is the first demonstration <strong>of</strong> treatment-associated<br />
immune modulation in cancer patients receiving an adenosine antagonist.<br />
Clinical trial identification: ClinicalTrials.gov Identifier:NCT02655822 Phase 1/1b<br />
Study to Evaluate the Safety and Tolerability <strong>of</strong> CPI-444 Alone and in Combination<br />
With Atezolizumab in Advanced Cancers<br />
Legal entity responsible for the study: Corvus Pharmaceuticals<br />
Funding: Corvus Pharmaceuticals<br />
Disclosure: I. McCaffery, G. Laport, A. Hotson, S. Willingham: Employee and<br />
stockholder <strong>of</strong> Corvus Pharmaceuticals A. Patnaik, M. Beeram: Research support to<br />
institution from Corvus Pharmaceuticals R. Miller: Employee, Director and<br />
Stockholder <strong>of</strong> Corvus Pharmaceuticals<br />
390P<br />
Identification <strong>of</strong> new prognostic factors in phase I patients<br />
treated by immunotherapy<br />
F. Bigot 1 , E. Castanon Alvarez 1 , A. Hollebecque 1 , A. Carmona 2 , S. Postel-Vinay 1 ,<br />
E. Angevin 1 , J-P. Armand 1 , V. Ribrag 1 , S. Aspeslagh 1 , A. Varga 1 , R. Bahleda 1 ,<br />
A. Gazzah 1 , C. Bonnet 1 , J-M. Michot 1 , A. Marabelle 1 , J-C. Soria 1 , C. Massard 1<br />
1 Department <strong>of</strong> Medicine DITEP, Institut Gustave Roussy, Villejuif, France,<br />
2 Medical <strong>Oncology</strong>, Hospital Universitario Morales Meseguer, Murcia, Spain<br />
Background: Evaluation <strong>of</strong> patient’s life expectancy is crucial to select patient who may<br />
benefit from phase I studies. The Royal Marsden Hospital score (RMH) established a<br />
prognostic tool validated in prospective studies and based on 3 objectives variables:<br />
number <strong>of</strong> metastatic sites, LDH and serum albumin. Nevertheless, it remains unclear<br />
if those factors could be extended to immunotherapy phase I trials.<br />
Methods: A retrospective analysis <strong>of</strong> risk factors <strong>of</strong> early death for patients enrolled<br />
into immune checkpoint inhibitor phase I trials in our institution was conducted.<br />
Demographic and biological characteristics (age, gender, number <strong>of</strong> metastatic site,<br />
LDH, albumin, neutrophil count, lymphocyte count, neutrophil-to-lymphocyte ratio,<br />
hemoglobin, platelet count) were analyzed with univariate and multivariable analysis<br />
for overall survival.<br />
Results: 155 patients (Male: 83; Median age was 59 (22-88)) treated with an<br />
experimental immunotherapy between March 2012 and January 2016 were analyzed.<br />
The most frequent tumor types were non-small cell lung cancer (16.7%), head and<br />
neck cancer (12.2%), urothelial cancer (10.3%), renal cancer (9%), breast cancer (7.7<br />
%), cervical cancer (6.4%). In the multivariable model, Albumin (HR: 1.7; 95%CI<br />
1.06-2.9) and LDH (HR: 1.9; 95%CI 1.2-3.2) remained statistical significant;<br />
nevertheless the number <strong>of</strong> metastases had no impact on the patients treated with<br />
immunotherapy (HR: 0.8; 95%CI 0.5-1.3). Interestingly, a higher<br />
neutrophil-to-lymphocyte ratio (NLR) was associated with a worse prognosis<br />
(HR = 1.8; 95%CI 1.1-3). We generated a new score with albumin (upper normal limit = +1) and NLR (>6 =+ 1). We performed a Harrell c-index for<br />
evaluating the suitability <strong>of</strong> this new score (c index = 0.70; 95%CI 0.64-0.77) which was<br />
slightly higher than the c-index for RMH score in our series (0.65; 95% CI 0.58-0.72).<br />
Conclusions: Our study points that the addition <strong>of</strong> NLR to classical prognostic<br />
variables such as albumin and LDH, may predict better the overall survival <strong>of</strong> patients<br />
that are treated with immunotherapy. The number <strong>of</strong> metastasis has no prognostic<br />
value in our series. Although this score needs an external validation, this is a valuable<br />
tool to make a better selection <strong>of</strong> patients for phase 1 immunotherapy trials.<br />
Legal entity responsible for the study: Christophe Massard<br />
Funding: Institut Gustave Roussy<br />
Disclosure: J-C. Soria: Personal fees AstraZeneca, Astex, Covagen, Clovis, GSK,<br />
Gammamabs, Lilly, MSD, Mission Therapeutics, Merus, Pfizer, Pierre Fabre,<br />
Roche-Genentech, San<strong>of</strong>i, Servier, Takeda. All other authors have declared no conflicts<br />
<strong>of</strong> interest.<br />
vi126 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
Table: 391P<br />
Cohort<br />
n=pts<br />
DLT (%) ORR (95%<br />
CI)<br />
A (n = 37/32) Myelo suppression (5%) 40% (24-59) 4.2 (1.2-12.7+) NSCLC (16); SCLC<br />
(14), Breast (22);<br />
Endometrial (35),<br />
EOC (8) Other (5);<br />
B (n = 12/10)<br />
Myelo suppression<br />
(17%) Colonic<br />
Perforation (8%)<br />
DOR months Tumor Type (%) CTC ARs G1-2 % CTC ARs G3 % CTC ARs G4 (%) Prior<br />
Taxanes<br />
50% (19-81) 6.2 (2.4-10.9+) EOC (42) Nonsquamous<br />
NSCLC<br />
(58)<br />
Anemia Fatigue Nausea<br />
Vomiting Diarrhea<br />
PSN<br />
Anemia Fatigue Nausea<br />
Diarrhea Vomiting<br />
PSN<br />
72 57 51 43<br />
22 35<br />
92 58 42 33<br />
17 17<br />
Neutropenia Anemia<br />
ALT ↑ FN<br />
Thrombopenia<br />
Fatigue Rash<br />
Nausea Vomiting<br />
Neutropenia FN<br />
Anemia Fatigue<br />
Sepsis Colonic<br />
fistula<br />
28 22 11 3 3<br />
3333<br />
Prior<br />
Bev<br />
Neutropenia (28) 57% 14%<br />
33 17 8 8 8 8 Neutropenia (25)<br />
Colonic perforation<br />
(8)<br />
67% 25%<br />
CI, confidence interval; CTCAE (v4.03), common toxicity criteria adverse reactions (related/unknown); EOC, epithelial ovarian cancer; G. grade; DOR; duration <strong>of</strong><br />
response; NSCLC; non-small cell lung cancer; ORR, overall response rate; PSN; neurotoxicity; FN: febrile neutropenia<br />
391P<br />
Lurbinectedin (PM01183) plus paclitaxel (P), recommended<br />
dose (RD) expansion results with or without the addition <strong>of</strong><br />
bevacizumab (Bev) in patients (pts) with selected solid tumors<br />
A. Drilon 1 , E. Garralda 2 , A. Stathis 3 , S. Szyldergemajn 4 , D. Hyman 1 , V. Boni 2 ,<br />
G. Griguolo 3 , E. Jimenez Martinez 4 , V. Makker 1 , L. Canziani 3 ,C.<br />
Fernandez Teruel 4 , A. Soto-Matos 4 , C. Sessa 3 , E. Calvo 2<br />
1 <strong>Oncology</strong>, Memorial Sloan Kettering Cancer Center, New York, NY, USA,<br />
2 <strong>Oncology</strong>, START-Madrid, Madrid, Spain, 3 <strong>Oncology</strong>, IOSI-Ospedale San<br />
Giovanni, Bellinzona, Switzerland, 4 Clinical, PharmaMar, Colmenar Viejo, Spain<br />
Background: The identified RD <strong>of</strong> PM01183 + P is PM01183 2.2 mg/m 2 on Day (D)<br />
1 + P 80 mg/m 2 D1&8 q3w. We provide updated results after RD expansion (A), and<br />
after Bev 15 mg/kg addition on D1 (B).<br />
Methods: RECIST v1.1 evaluable pts ≤ 75 years (y) old, with ECOG PS 0-1, adequate<br />
organ function and ≤ 3 prior advanced lines were eligible. Prior taxanes were allowed if<br />
last dosed ≥ 3 months prior; prior weekly P or NAB-P were excluded. P was<br />
discontinued after 18 weeks and pts continued on PM01183 alone (A) or plus Bev (B).<br />
Pharmacokinetics (PK) was assessed in C1.<br />
Results: As <strong>of</strong> April 2016, 37/12 pts were treated (cohort A/B, accordingly); 2/37 and 3/<br />
12 experienced a dose-limiting toxicity (DLT) in Cycle 1, respectively. 32/10 were<br />
evaluable for efficacy. PK results were in line with published data.<br />
Conclusions: At the RD, PM01183/P has an acceptable safety pr<strong>of</strong>ile and remarkable<br />
antitumor activity, even in pts previously exposed to taxanes/Bev. CSFs prophylaxis<br />
was not required at the RD. Neurotoxicity was not dose-limiting. The addition <strong>of</strong> Bev<br />
to PM01183/P RD was feasible but it seems more pts might experience DLTs in C1. No<br />
Drug-Drug Interactions were observed.<br />
Clinical trial identification: NCT01831089<br />
Legal entity responsible for the study: PharmaMar<br />
Funding: PharmaMar<br />
Disclosure: S. Szyldergemajn, E. Jimenez Martinez, C. Fernandez Teruel, A. Soto-Matos:<br />
PharmaMar employee and stock ownership. D. Hyman: Consulting ATARA. E. Calvo:<br />
Consultan or Adviso: Astellas Ph, GlaxoSm, Janssen-Ci, Lilly, Novartis, Pfizer,<br />
PharmaMar, Roche/Ge, San<strong>of</strong>i Research Funding: All previous plus: Eisai, Merck Ser,<br />
Merck Sp & D, Millennium, OncoMed, Psi Oxus, Spectrum Ph Honoraria: Astellas Ph,<br />
Novartis. All other authors have declared no conflicts <strong>of</strong> interest.<br />
392P Lurbinectedin (PM01183) administered once (D1) every 3<br />
weeks (q3w) in combination with capecitabine (XEL) in<br />
patients (pts) with metastatic breast (MBC), colorectal (CRC)<br />
or pancreatic (PaC) cancer<br />
T. Sauri 1 , A. Awada 2 , E. Calvo 3 , V. Moreno 4 , S. Szyldergemajn 5 , E. Elez 1 ,<br />
P. Barthelemy 2 , V. Boni 3 , B. Doger 4 , C. Fernandez Teruel 5 , A. Soto-Matos 5 ,<br />
J. Tabernero 1 , P. Aftimos 2<br />
1 Medical <strong>Oncology</strong>, Vall d’Hebron University Hospital Institut d’Oncologia,<br />
Barcelona, Spain, 2 Medical <strong>Oncology</strong>, Institut Jules Bordet, Brussels, Belgium,<br />
3 <strong>Oncology</strong>, START Madrid-CIOCC, Centro Integral Oncológico Clara Campal,<br />
Madrid, Spain, 4 Medical <strong>Oncology</strong>, START Madrid-FJD, Fundación Jiménez Díaz<br />
Hospital, Madrid, Spain, 5 Clinical, PharmaMar, Colmenar Viejo, Spain<br />
Background: PM01183 is a new anticancer drug. Single agent efficacy is reported in<br />
MBC and in ovarian cancer, myelosuppression being a dose-limiting toxicity (DLT) in<br />
phase I studies. A recommended dose (RD) for PM01183 given on D 1 and 8 with XEL<br />
was previously defined. We explored a simplified schedule where PM01183 is given on<br />
D1 q3wk only.<br />
Methods: Adult MBC, CRC or PaC pts, ≤ 75 years (y) old, with ECOG PS 0-1,<br />
adequate major organ function and 20% but
abstracts<br />
Conclusions: MTD for CRLX101 QW monotherapy is 15 mg/m 2 , representing a 100%<br />
increase in dose intensity over the QOW MTD. In arm 2, either 12 mg/m 2 QW or 15<br />
mg/m 2 for 3 <strong>of</strong> 4 weeks in combination with bev QOW could be the MTD. No new<br />
safety concerns were observed except an increase in cystitis in arm 2 for which urine<br />
alkalization was implemented to mitigate the risk. PRs were observed in 3 pts. This<br />
more dose-intensive CRLX101 schedule will be tested in future combination studies.<br />
Clinical trial identification: NCT02648711 (NIH)<br />
Legal entity responsible for the study: Cerulean Pharma, Inc.<br />
Funding: Cerulean Pharma Inc.<br />
Disclosure: N. Lakhani: Non-financial support from Cerulean, during the conduct <strong>of</strong><br />
the study; non-financial support from Cerulean, Merck,Pfizer, Abbvie,ArQule Pharma,<br />
Regeneron Pharma,Novartis, BMS, Foundation Medicine, LAM Therapeutics, Pronai<br />
outside the submitted work.A. Senderowicz, K. Caliri, T. Crowell, H. Wang: Employee<br />
at Cerulean Pharma Inc.A. Tolcher: Received fees: Bind Therapeutics, Blend<br />
Therapeutics, Celator, Decerna, Janssen, Merus, Nanobiotix, Pharmacyclics, Pierre<br />
Fabre Medicament, Symphogen, Valent Tech, Heron, J&J, Asana Biosciences, Akebia,<br />
Genmab, Mersana, Endocyte, Proximagan, Upsher-Smith.All other authors have<br />
declared no conflicts <strong>of</strong> interest.<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Conclusions: CRLX101 exhibits high retention <strong>of</strong> drug in plasma, slow clearance and<br />
controlled slow release <strong>of</strong> CPT from the polymer. The PK data support QW dosing <strong>of</strong><br />
CRLX101 at 15 mg/m 2 , which represents a 100% increase in dose intensity when<br />
compared to QOW dosing <strong>of</strong> CRLX101 in other phase 2 trials. This more<br />
dose-intensive CRLX101 schedule will be tested in future combination studies.<br />
Clinical trial identification: NCT02648711 (NIH)<br />
Legal entity responsible for the study: Cerulean Pharma, Inc<br />
Funding: Cerulean Pharma, Inc<br />
Disclosure: H. Wang, K. Caliri, T. Crowell, A. Senderowicz: Employee at Cerulean<br />
Pharma Inc. W. Zamboni: Personal fees from Cerulean Pharma, during the conduct <strong>of</strong><br />
the study; personal fees from Cerulean Pharma, outside the submitted work.A. Tolcher:<br />
Received fees: Bind Therapeutics, Blend Therapeutics, Celator, Decerna, Janssen,<br />
Merus, Nanobiotix, Pharmacyclics, Pierre Fabre Medicament, Symphogen, Valent<br />
Tech, Heron, J&J, Asana Biosciences, Akebia, Genmab, Mersana, Endocyte,<br />
Proximagan, Upsher-Smith. N. Lakhani: Non-financial support from Cerulean, during<br />
the conduct <strong>of</strong> the study; non-financial support from Cerulean, Merck, Pfizer, Abbvie,<br />
ArQule Pharma, Regeneron Pharma, Novartis, BMS, Foundation Medicine, LAM<br />
Therapeutics, Pronai outside the submitted work.<br />
394P<br />
Pharmacokinetics (PK) <strong>of</strong> CRLX101 administered weekly in<br />
patients (pts) with advanced solid tumors<br />
H. Wang 1 , W. Zamboni 2 , A. Tolcher 3 , N. Lakhani 4 , S.A. Piha-Paul 5 , K. Caliri 6 ,<br />
T. Crowell 6 , A. Senderowicz 6<br />
1 Research, Cerulean Pharma, Inc., Waltham, MA, USA, 2 UNC Lineberger<br />
Comprehensive Cancer Center, UNC Eshelman School <strong>of</strong> Pharmacy, Carolina<br />
Center for Cancer Nanotechnology Excellence, Chapel Hill, NC, USA, 3 Clinical<br />
Research, START - South Texas Accelerated Research Therapeutics, LLC, San<br />
Antonio, TX, USA, 4 Clinical Research, START Midwest/Cancer & Hematology<br />
Centers <strong>of</strong> Western Michigan, PC, Grand Rapids, MI, USA, 5 Investigational Cancer<br />
Therapeutics, The University <strong>of</strong> Texas MD Anderson Cancer Center, Houston, TX,<br />
USA, 6 Clinical Operations, Cerulean Pharma, Inc., Waltham, MA, USA<br />
Background: CRLX101 is a novel investigational nanoparticle-drug conjugate (NDC)<br />
containing the payload camptothecin (CPT) covalently conjugated to a<br />
cyclodextrin-polyethylene glycol co-polymer that is 10-30 nm in diameter. The PK <strong>of</strong><br />
NDCs depends on the polymer until the active-drug payload is released. It is important<br />
to characterize the PK <strong>of</strong> the conjugated CPT and the active released CPT. The<br />
maximum tolerated dose (MTD) <strong>of</strong> CRLX101 from the first-in-human study is 15 mg/<br />
m 2 biweekly (QOW; Weiss, 2013. Invest New Drugs. 31:986), which is being used<br />
clinically in several tumor types (Keefe et al., 2015. JCO. 15:4543; Krasner, 2016.<br />
AACR. CT090). This study evaluated the PK <strong>of</strong> a more intensive weekly (QW) dosing<br />
schedule <strong>of</strong> CRLX101.<br />
Methods: CRLX101 was administered QW at 12 and 15 mg/m 2 intravenously over 1-2<br />
h, representing an equivalent mg dose <strong>of</strong> CPT. PK assessment was performed at weeks<br />
1, 3 and 7. Plasma samples were processed to measure total and released CPT by an<br />
LC-MS/MS assay. The concentration <strong>of</strong> conjugated CPT was calculated as total CPT<br />
minus released CPT. Area under concentration vs time curves (AUC 0-168h ) in plasma<br />
were estimated.<br />
Results: PK results are included in the Table. In plasma, >90% <strong>of</strong> the total CPT<br />
remains as the conjugated form. The interpatient variability in the exposure <strong>of</strong><br />
conjugated CPT is lower compared to many other liposomal anticancer agents (Schell<br />
et al., 2014. Nanomedicine. 10:109). The variability <strong>of</strong> the released CPT is greater than<br />
for conjugated CPT. The plasma exposure <strong>of</strong> conjugated and released CPT is consistent<br />
from week 1 to 7, suggesting no accumulation after multiple weekly doses.<br />
Table: 394P Summary <strong>of</strong> conjugated and released CPT exposures on<br />
weeks 1, 3 and 7 after weekly administration <strong>of</strong> CRLX101<br />
AUC0-168h (µg/mL·h) 12 mg/m 2 n=7<br />
Mean ± SD<br />
15 mg/m 2 n= 8<br />
Mean ± SD<br />
Week 1 Conjugated CPT 211.2 ± 123.0 (n = 7) 221.8 ± 33.6 (n = 5)<br />
Released CPT 16.2 ± 10.6 (n = 7) 18.1 ± 10.6 (n = 5)<br />
Ratio released CPT to conjugated 0.07 ± 0.02 (n = 7) 0.08 ± 0.04 (n = 5)<br />
CPT<br />
Week 3 Conjugated CPT 181.9 ± 28.6 (n = 5) 217.1 ± 46.3 (n = 5)<br />
Released CPT 15.5 ± 5.4 (n = 5) 20.3 ± 11.6 (n = 5)<br />
Ratio released CPT to conjugated 0.08 ± 0.02 (n = 5) 0.09 ± 0.06 (n = 5)<br />
CPT<br />
Ratio conjugated CPT week 3 to 1.10 ± 0.14 (n = 5) 1.03 ± 0.14 (n = 4)<br />
week 1<br />
Ratio released CPT week 3 to 1.19 ± 0.30 (n = 5) 1.13 ± 0.13 (n = 4)<br />
week 1<br />
Week 7 Conjugated CPT 188.3 ± 35.7 (n = 2) 219.5 (n = 1)<br />
Released CPT 19.5 ± 0.3 (n = 2) 14.4 (n = 1)<br />
Ratio released CPT to conjugated 0.11 ± 0.02 (n = 2) 0.06 (n = 1)<br />
CPT<br />
Ratio conjugated CPT week 7 to 0.96 ± 0.16 (n = 2) 1.12 (n = 1)<br />
week 1<br />
Ratio released CPT week 7 to<br />
week 1<br />
1.17 ± 0.16 (n = 2) 2.23 (n = 1)<br />
395P<br />
Phase 1 dose-escalation study <strong>of</strong> the folic acid-tubulysin<br />
small-molecule drug conjugate (SMDC) folate-tubulysin<br />
EC1456: Study update<br />
J.C. Sachdev 1 , M. Edelman 2 , W. Harb 3 , A. Armour 4 , D. Wang 5 , A.N. Starodub 6<br />
1 <strong>Oncology</strong>, HonorHealth Research Institute, Scottsdale, AZ, USA, 2 Cancer<br />
Center, University <strong>of</strong> Maryland Greenebaum Cancer Center, Baltimore, MD, USA,<br />
3 Unity Campus, Horizon <strong>Oncology</strong> Center, Lafayette, IN, USA, 4 Clinical, Endocyte,<br />
Inc, Indianapolis, IN, USA, 5 <strong>Oncology</strong>/Hematology, Henry Ford Hospital, Detroit,<br />
MI, USA, 6 <strong>Oncology</strong>/Hematology, IU Goshen Center for Cancer Care, Goshen, IN,<br />
USA<br />
Background: The folate receptor (FR) is highly expressed in certain cancers such as<br />
adenocarcinoma-NSCLC, but is expressed at low levels in most normal tissues. FR<br />
constitutively cycles from the plasma membrane surface to the cytoplasm. In vitro and<br />
in vivo studies show the average FR recycling time to be about 18 hours. EC1456 is a<br />
potent second generation small molecule drug conjugate (SMDC) <strong>of</strong> folic acid and the<br />
cytotoxic tubulysin B hydrazide (TubBH). EC1456 targets FR-expressing (FR + ) cancers<br />
for intracellular delivery <strong>of</strong> TubBH which inhibits tubulin polymerization in tumors.<br />
Methods: The primary objective is to determine the MTD <strong>of</strong> EC1456 and optimize the<br />
dosing schedule. Key inclusion criteria: age ≥18 years, ECOG PS 0–1, and adequate<br />
end-organ function. Dose escalation follows the “3+3” protocol for all schedules.<br />
Patients are scanned using the diagnostic imaging agent 99m Tc-EC20, however a<br />
positive scan is not required for enrollment.<br />
Results: In an unselected population, 55 patients (pts) are evaluable for cycle 1 toxicity.<br />
The median age is 69.5 (range: 39-88); 36 patients are female. Toxicities are primarily<br />
Grade (Gr) 1 and 2. Common adverse events (AE) are gastrointestinal, general fatigue,<br />
and metabolic changes. Two DLT’s have been observed: Gr 3 infusion reaction (4.5<br />
mg/m 2 D 1, 8) and G3 headache (10.0 mg/m 2 D 1, 8). Drug safety is summarized in the<br />
table below. Durable stable disease <strong>of</strong> 12 wks or longer has been observed in 10 pts.<br />
Table: 395P<br />
BIW (n = 29) BIW (n = 29) QW (n = 26) QW (n = 26)<br />
All AEs TRAE All AEs TRAE<br />
AE 28 (96.6%) 21 (72.4%) 26 (100.0%) 20 (76.9%)<br />
SAE 9 (31.0%) 1 (3.4%) 12 (46.2%) 3 (11.5%)<br />
Gr 3/4 AE 16 (55.2%) 5 (17.2%) 13 (50.0%) 4 (15.4%)<br />
Dose Reduction 1 (3.4%) 1 (3.4%) 1 (3.8%) 1 (3.8%)<br />
Discontinuation 0 (0.0%) 0 (0.0%) 2 (7.7%) 2 (7.7%)<br />
Conclusions: To date, all EC1456 schedules have been well tolerated. Dose escalation is<br />
ongoing. Anti-tumor activity <strong>of</strong> EC1456 is suggested by durable stable disease. Updated<br />
pharmacokinetic, safety, and efficacy analyses will be available for the conference.<br />
Clinical trial identification: NCT01999738<br />
Legal entity responsible for the study: Sponsor is Endocyte, Inc.<br />
Funding: Endocyte, Inc.<br />
Disclosure: A. Armour: Employee <strong>of</strong> Endocyte, Inc. All other authors have declared no<br />
conflicts <strong>of</strong> interest.<br />
vi128 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
396P<br />
RX-3117, an oral antimetabolite to treat advanced solid<br />
tumors (ST): Phase 1 and ongoing phase 2a results<br />
D. Rasco 1 , C. Peterson 2 , R. Mazhari 3 , E. Benaim 4 , J. Merchan 5<br />
1 START, South Texas Accelerated Research Therapeutics (START), San Antonio,<br />
TX, USA, 2 Clinical Operations, Rexahn Pharmaceuticals, Inc, Rockville, MD, USA,<br />
3 R&D, Rexahn Pharmaceuticals, Inc, Rockville, MD, USA, 4 Medical, Rexahn<br />
Pharmaceuticals, Inc, Rockville, MD, USA, 5 Medical <strong>Oncology</strong>, University <strong>of</strong> Miami<br />
Sylvester Comprehensive Cancer Center, Miami, FL, USA<br />
Background: RX–3117 is an oral small-molecule antimetabolite, cyclopentyl pyrimidyl<br />
nucleoside, that is activated by uridine cytidine kinase 2. RX–3117 shows efficacy in<br />
various xenograft models, including those <strong>of</strong> gemcitabine resistant pancreatic, bladder<br />
and colorectal cancers. Data from a Phase 1/2a clinical study <strong>of</strong> RX-3117 as a single<br />
agent in subjects with advanced ST are described below.<br />
Methods: The Phase 1/2a study (NCT02030067) is designed to evaluate safety,<br />
tolerability and pharmacokinetics (PK) following increasing doses and schedules <strong>of</strong><br />
RX-3117 in eligible subjects (aged ≥ 18 years) with relapsed/refractory ST. Primary<br />
objectives include safety and tolerability to determine the MTD and a recommended<br />
phase 2 dose and schedule (RP2D); secondary objectives were PK and antitumor<br />
activity. Subjects received oral RX-3117 at 3, 5 or 7 times per week for 3 weeks with 1<br />
week <strong>of</strong> rest in each 4 week cycle. Phase 2a is ongoing in patients with metastatic<br />
pancreatic or bladder cancer in a 2-stage design, where 10 patients will be treated and if<br />
2 responses are seen, 40 additional patients will be added to the corresponding arm.<br />
Results: As <strong>of</strong> May 2016, 48 subjects were enrolled (30 Females, 18 males), with 4<br />
subject enrolled in the Phase 2a portion. Sixteen subjects experienced stable disease for<br />
1 to 10 cycles; with 11 subjects treated from 82 to 276 days. A tumor burden reduction<br />
was seen in 3 subjects with pancreatic, breast and mesothelioma cancers. RX-3117 PK<br />
was dose proportional and was rapidly absorbed with a median T max <strong>of</strong> 2 to 3 hours;<br />
accumulation was minimal. The most frequent related adverse events were moderate to<br />
severe anemia, mild to moderate fatigue and nausea, mild diarrhea, vomiting, and<br />
anorexia. Dose limiting toxicity <strong>of</strong> anemia was observed at 2000 mg administered 3<br />
times per week. The RP2D is 700 mg for 5 consecutive days per week, 3 weeks on, one<br />
week <strong>of</strong>f, per each 4-week cycle.<br />
Conclusions: RX-3117 is safe and well tolerated. Early anti-tumor activity has been<br />
observed in pancreas, colorectal and mesothelioma cancers. The 2-stage Phase 2a trial<br />
for pancreatic and bladder cancers is ongoing. Final results from the phase 1 and data<br />
on the first stage <strong>of</strong> the Phase 2a will be presented.<br />
Clinical trial identification: NCT02030067<br />
Legal entity responsible for the study: Rexahn Pharmaceuticals, Inc<br />
Funding: Rexahn Pharmaceuticals, Inc<br />
Disclosure: C. Peterson, R. Mazhari, E. Benaim: Employee <strong>of</strong> Rexahn Pharmaceuticals,<br />
Inc All other authors have declared no conflicts <strong>of</strong> interest.<br />
397P<br />
Phase 1 study <strong>of</strong> sorafenib and eribulin in patients with<br />
advanced, metastatic or refractory solid tumors<br />
F. Marmé 1 , C. Gomez-Roca 2 , K. Graudenz 3 , F. Huang 4 , J. Lettieri 5 , C. Pena 4 ,<br />
Z. Trnkova 3 , J. Eucker 6<br />
1 Translationale Gynäkologische Onkologie, Universitätsklinikum Heidelberg &<br />
Nationales Centrum für Tumorerkrankungen, Heidelberg, Germany, 2 Medical<br />
<strong>Oncology</strong>, Institut Claudius Regaud, Toulouse, France, 3 Clinical Pharmacology,<br />
<strong>Oncology</strong>, Bayer Pharma AG, Berlin, Germany, 4 Clinical Pharmacology, <strong>Oncology</strong>,<br />
Bayer Healthcare Pharmaceuticals, Whippany, NJ, USA, 5 Clinical<br />
Pharmacokinetics, Pharmacodynamics, Bayer Healthcare Pharmaceuticals,<br />
Whippany, NJ, USA, 6 Onkologie und Hämatologie, Universitätsmedizin Berlin,<br />
Berlin, Germany<br />
Background: Combining sorafenib (SOR), an oral multikinase inhibitor approved for<br />
hepatocellular carcinoma, renal cell carcinoma, and differentiated thyroid carcinoma,<br />
with eribulin mesylate (ERI), a microtubule inhibitor approved for breast cancer (BC),<br />
may provide synergistic antitumor activities.<br />
Methods: This phase 1b, open label, dose escalation study evaluated safety,<br />
pharmacokinetics (PK), maximum tolerated dose/recommended phase 2 dose (MTD/<br />
RP2D), cardiac safety (QT/QTc), and preliminary efficacy <strong>of</strong> SOR + standard dose ERI<br />
(1.4 mg/kg IV on Days [D] 1 and 8 <strong>of</strong> each 21-day cycle [C]) in patients (pts) with<br />
advanced, metastatic, or refractory tumors. Starting SOR dose was 200 mg BID<br />
continuously starting on D11 <strong>of</strong> C1. SOR + ERI-related hematologic and<br />
nonhematologic dose limiting toxicities (DLT) were assessed in C2. If tolerable, SOR<br />
was escalated in new cohorts to 600 mg daily (200 mg AM/400 mg PM) and 400 mg<br />
BID. QT/QTc intervals and PK were evaluated respectively in C1 for single dose and<br />
C2 for multiple doses. Antitumor activity was assessed by RECIST v1.1. RP2D was<br />
confirmed in a MTD expansion cohort (minimum 12 pts).<br />
Results: Of 40 pts treated, 5 received SOR 200 mg BID, 8 received 600 mg/d, and 27<br />
received 400 mg BID (MTD), <strong>of</strong> whom 14 were in the expansion cohort. Of 12 cancer<br />
types reported, 62.5% <strong>of</strong> pts had BC. No DLT was reported in the 200-mg and 600-mg<br />
cohorts; 1 DLT (Grade 3 increased ALT) was reported in the 400-mg BID dose<br />
escalation cohort and 1 DLT (Grade 3 acute coronary syndrome) in the expansion<br />
cohort. Most common drug-related ≥Grade 3 TEAEs were hypophosphatemia (10%)<br />
and hypertension (10%) for SOR and neutropenia (25%) for ERI. No significant QT/<br />
QTc prolongation was observed; mean QTcF change from baseline was 11.44 ms with<br />
ERI alone and 8.25 ms with ERI + SOR. No drug interaction was observed; mean SOR<br />
AUC was 60.4 mg*h/L for SOR 400 mg BID + ERI and 56.7 mg*h/L for SOR 400 mg<br />
BID alone. Respective mean SOR C max were 6.8 and 7.7 mg/L. 8 pts had a partial<br />
response (5 confirmed, 3 unconfirmed).<br />
Conclusions: SOR 400 mg BID + standard dose ERI was well tolerated and confirmed<br />
RP2D. Toxicities were in line with known SOR and ERI safety pr<strong>of</strong>iles. Thus,<br />
SOR + ERI would be appropriate to examine in larger studies.<br />
Clinical trial identification: NCT01585870; EudraCT: 2011-005849-12<br />
Legal entity responsible for the study: N/A<br />
Funding: Pharmaceutical Division <strong>of</strong> Bayer<br />
Disclosure: F. Marmé: Honoraria (presentations and advisory boards): Roche, Novartis,<br />
Amgen, AstraZeneca, Eisai, Genomic Health, Celgene. C. Gomez-Roca: Received<br />
consulting fees from Novartis and San<strong>of</strong>i. K. Graudenz, Z. Trnkova: Employee <strong>of</strong> Bayer<br />
PharmaAG.F.Huang,J.Lettieri,C.Pena:Employee<strong>of</strong>BayerHealthCare<br />
Pharmaceuticals. J. Eucker: Consulting fees: Novartis, Amgen, Roche; Contracted research:<br />
Novartis.<br />
398P<br />
Phase Ib/II trial <strong>of</strong> NC-6004 (nanoparticle cisplatin) plus<br />
gemcitabine (G) in pts with advanced solid tumors<br />
V. Subbiah 1 , A. Combest 2 , J. Griley-Olsen 3 , N. Sharma 4 , E. Andrews 5 , I. Bobe 6 ,<br />
J. Balkissoon 7 , A. Camp 8 , A. Masada 9 , D. Reitsma 10 , L. Bazhenova 11<br />
1 Investigational Cancer Therapeutics, MD Anderson Cancer Center, Houston, TX,<br />
USA, 2 Global Product Development, PPD, Wilmington, NC, USA, 3 Hematology<br />
and <strong>Oncology</strong>, Lineberger Comprehensive Cancer Center University <strong>of</strong> North<br />
Carolina, Chapel Hill, NC, USA, 4 Hematology and <strong>Oncology</strong>, UH Case Medical<br />
Center, Cleveland, OH, USA, 5 GPD, PPD, Raleigh, NC, USA, 6 Research,<br />
NanoCarrier, Danville, VA, USA, 7 GPD, PPD, San Francisco, CA, USA,<br />
8 Biostatistics, PPD, Austin, TX, USA, 9 Research and Development, NanoCarrier,<br />
Tokyo, Japan, 10 Global Product Development, PPD, Rockville, MD, USA,<br />
11 Moores Cancer Center, University <strong>of</strong> California San Diego, La Jolla, CA, USA<br />
Background: NC-6004 is a polymeric micelle exhibiting sustained release <strong>of</strong> cisplatin<br />
(CDDP) and selective distribution to tumors, resulting in a lower plasma C max and<br />
higher AUC. Preclinical data exhibited less neuro- and nephrotoxicity with greater<br />
anti-tumor activity versus CDDP. A previous trial evaluated NC-6004 and G defining a<br />
RP2D <strong>of</strong> 90 mg/m 2 . Escalating doses <strong>of</strong> NC-6004/G were evaluated in this trial using a<br />
Bayesian NCRM.<br />
Methods: Pts with refractory solid tumors were enrolled at 4 US sites. NC-6004 at 60 -<br />
180 mg/m 2 IV was given over 1 hr on day 1 with G at 1250 mg/m 2 IV over 30 mins on<br />
day 1 and day 8 every 3 wks. Escalation <strong>of</strong> NC-6004 began with a single pt run-in,<br />
escalating by 15 mg/m 2 until a DLT occurred at 180 mg/m 2 . Cohorts <strong>of</strong> 4 pts were then<br />
enrolled at each dose predicted by the NCRM model with real time updates. The MTD<br />
was defined as the dose with the greatest posterior probability <strong>of</strong> target toxicity < 25%.<br />
Results: Among 22 pts (10 M, 12 F) enrolled, common Grade 3/4 hematologic AEs were<br />
leukopenia (67%), thrombocytopenia (55%), neutropenia (55%), lymphopenia (45%) and<br />
anemia (23%). All AEs/DLTs were manageable and resolved. Results are presented below<br />
(19/22 evaluable for response). Activity was observed in heavily pretreated pts<br />
(mean = 2.5 prior lines <strong>of</strong> therapy): tumor shrinkage in 9/19 (47%), unconfirmed PRs in<br />
3/19 (16%) in H&N and NSCLC pts (1 who failed prior anti-PD1) and SD in 12/19<br />
(63%). The MTD was 135 mg/m 2 . Of the 8 pts treated at the MTD, the average number <strong>of</strong><br />
cycles received was 7 (2-17) and none experienced neuro-, oto- or nephrotoxicity. 50% <strong>of</strong><br />
pts received a prior platinum. Of these, SD was observed in 9 (82%).<br />
Table: 398P<br />
Dose (mg/m 2 ) Best tumor shrinkage (%) DLTs<br />
60 26.3<br />
75 12.2<br />
90 -16.7<br />
105 0<br />
120 5.9<br />
135 0<br />
46.7<br />
0<br />
-45.3<br />
32.6<br />
-15.2<br />
-66.4<br />
2.6<br />
150 -3.1<br />
-3.3 Thrombocytopenia<br />
25 Thrombocytopenia<br />
-2.2<br />
165 -19.4 Nausea<br />
180 -49.1 Febrile Neutropenia<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw368 | vi129
abstracts<br />
Conclusions: The nanoparticle formulation allowed greater CDDP equivalent doses.<br />
No clinically significant neuro-, oto- or nephrotoxicity was observed. The NCRM<br />
design allowed exploration <strong>of</strong> the pharmacologic zone <strong>of</strong> interest and projected a<br />
higher MTD versus a 3 + 3. This data demonstrates promising activity and tolerability<br />
<strong>of</strong> NC-6004/G in heavily pretreated pts.<br />
Clinical trial identification: NCT02240238<br />
Legal entity responsible for the study: N/A<br />
Funding: NanoCarrier<br />
Disclosure: V. Subbiah: Research funding from NanoCarrier, no other relevant COI. A.<br />
Combest: Employed by PPD, no other COI. J. Griley-Olsen: Advisory consulting role<br />
for San<strong>of</strong>i, research funding received from GSK, Ziopharm, Kyowa Hakko Kirin, Bayer,<br />
Morphotek, Novartis, Peregrine, NanoCarrier, Genentech, Seattle Genetics,<br />
MedIummune. N. Sharma: Stock in IDRA, ICPI, Synta, Opexa, Ariad, Peregrine.<br />
Research funding from BMS, GSK, ICRM, Mirati, Novartis, IMGN, Halozyme,<br />
NanoCarrier, Astellas. I. Bobe, A. Masada: Employed by NanoCarrier. J. Balkissoon,<br />
A. Camp, D. Reitsma: Employed by PPD. L. Bazhenova: Stock in Epic Sciences.<br />
Consulting/advisory role for Heat Biologics, AstraZeneca, Pfizer, Genoptix. On<br />
speakers bureau for Genentech and Novartis. All other authors have declared no<br />
conflicts <strong>of</strong> interest.<br />
399P<br />
A phase I dose-escalation trial <strong>of</strong> bi-daily (BID) weekly oral<br />
docetaxel as ModraDoc006 in combination with ritonavir<br />
V.A. de Weger 1 , F.E. Stuurman 1 , M. Mergui-Roelvink 1 , B. Nuijen 2 , A.D.<br />
R. Huitema 2 , J.H. Beijnen 2 , J.H.M. Schellens 1 , S. Marchetti 1<br />
1 Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam,<br />
Netherlands, 2 Pharmacy & Pharmacology, The Netherlands Cancer Institute,<br />
Amsterdam, Netherlands<br />
Background: The development <strong>of</strong> an oral formulation <strong>of</strong> the anti-cancer drug<br />
docetaxel is hampered by its poor bio-availability. In (pre-)clinical studies, absorption<br />
from the gastro-intestinal tract could significantly be improved by the use <strong>of</strong> a solid<br />
dispersion formulation and the co-administration <strong>of</strong> ritonavir, an inhibitor <strong>of</strong> CYP3A4<br />
and P-glycoprotein. The primary aim <strong>of</strong> this trial was to assess the feasibility,<br />
determine the maximum tolerated dose (MTD) and the recommended phase two dose<br />
(RP2D) <strong>of</strong> the co-administration <strong>of</strong> the novel oral docetaxel formulation ModraDoc006<br />
(10 mg tablet) with 100 mg <strong>of</strong> ritonavir (/r) in a BID weekly schedule.<br />
Methods: Patients with metastatic solid tumors, ≥18 years old, and a WHO<br />
performance status ≤2 were included. ModraDoc006/r was administered BID weekly<br />
with a 7-12 hour interval. Dose-escalation was performed using a classical 3 + 3<br />
design. Pharmacokinetic sampling was performed during the first two weeks <strong>of</strong><br />
treatment up to 48 hours after study drug administration. Safety was evaluated using<br />
CTCAE v3.0. The dose-limiting toxicity (DLT) period was defined as the first four<br />
weeks <strong>of</strong> treatment. Anti-tumor activity was assessed every 6-8 weeks with a CT or<br />
MRI scan.<br />
Results: ModraDoc006/r was administered to 26 patients at three dose-levels. Seven<br />
DLTs were observed in three patients. Observed DLTs were grade 3 nausea (2x),<br />
mucositis (2x), dehydration (1x), neutropenic fever (1x) and inability to restart<br />
treatment within 3 weeks due to treatment related toxicity (1x). The most common<br />
adverse events observed were nausea, vomiting, diarrhea and fatigue, most <strong>of</strong>ten grade<br />
1-2. No hypersensitivity reactions, peripheral polyneuropathy or grade 4 neutropenia<br />
were observed. The MTD and RP2D were determined as 30/20 mg ModraDoc006/r<br />
(morning/afternoon dose) per week. The area under the plasma concentration time<br />
curve (AUC) <strong>of</strong> docetaxel at this dose was 1250 ±443 ng*h/ml. Three partial responses<br />
and six stable diseases were reported as best response to treatment.<br />
Conclusions: Oral administration <strong>of</strong> BID weekly ModraDoc006/r is feasible. The MTD<br />
and RP2D <strong>of</strong> ModraDoc006/r are 30/20 mg per week. Anti-tumor activity is promising.<br />
Clinical trial identification: NCT 01173913 (NIH register)<br />
Legal entity responsible for the study: The Netherlands Cancer Institute<br />
Funding: The Netherlands Cancer Institute<br />
Disclosure: B. Nuijen: Is holder <strong>of</strong> a patent <strong>of</strong> oral formulations <strong>of</strong> taxanes. J.H.<br />
Beijnen, J.H.M. Schellens: Is holder <strong>of</strong> a patent <strong>of</strong> oral formulations <strong>of</strong> taxanes and<br />
shareholder <strong>of</strong> Modra Pharmaceuticals, a company developing oral taxane<br />
formulations. All other authors have declared no conflicts <strong>of</strong> interest.<br />
400P<br />
Correlations for tested doses and toxicities between<br />
first-in-human trials and registration trials <strong>of</strong> FDA-approved<br />
monoclonal antibodies<br />
M. Viala 1 , M. Vinches 1 , C. Mollevi 2 , C. Gongora 3 , L. Gianni 4 , D. Tosi 1<br />
1 Medical <strong>Oncology</strong>, ICM Regional Cancer Institute <strong>of</strong> Montpellier, Montpellier,<br />
France, 2 Biometrics Unit, ICM Regional Cancer Institute <strong>of</strong> Montpellier,<br />
Montpellier, France, 3 Mechanism <strong>of</strong> resistance to cancer treatment, IRCM,<br />
Montpellier, France, 4 Medical <strong>Oncology</strong>, IRCCS San Raffaele, Milan, Italy<br />
Background: We conducted a survey (Tosi et al, J Clin Oncol 2015; Vinches et al, J<br />
Clin Oncol 2015, abstr 3040) on clinical development strategies for monoclonal<br />
antibodies (mAb) over a decade: due to mAb limited toxicity, the recommended phase<br />
II dose (RP2D) was only tentatively defined in first-in-human trials (FIHT), and the<br />
FIHT RP2D and the maximum administered doses (MAD) were infrequently used in<br />
subsequent trials. In contrast, for cancer drugs in general, FIHT results are predictive <strong>of</strong><br />
safety in registration trials (RT) and <strong>of</strong> approved drug dose (Jardim et al, Clin Cancer<br />
Res 2014).<br />
Methods: In order to determine the correlations <strong>of</strong> mAb FIHT results with safety in<br />
RT and final approved dose, we identified mAb approved as single agents by FDA on<br />
March 1, 2016. For each molecule, we performed a MEDLINE search to identify FIHT<br />
and RT, then we examined the doses tested and the toxicities observed in RT with<br />
regard to the corresponding FIHT results.<br />
Results: We retrieved 28 mAb with a FIHT, and 60 RT. The mAb indication was<br />
cancer in 11 cases (solid tumors in 8, hematological cancers in 3), immune system<br />
diseases in 13 cases and other diseases in 4 cases. In FIHT, the RP2D was determined<br />
in 5 cancer trials (vs 2 in the other trials). For mAb with the same dose calculation in<br />
FIHT and RT, the RP2D was tested in cancer RT in only 3 cases, and the MAD in 2<br />
cases (vs 1 and 2 cases respectively in the other trials). The median ratio between<br />
cancer RT dose and the corresponding MAD was 0.5 (n = 9; range: 0.2 to 2.5), versus<br />
0.67 in the other trials (n = 13; range: 0.1 to 1.2). Seven out <strong>of</strong> 11 doses tested in cancer<br />
RT were <strong>of</strong> less than 75% <strong>of</strong> the MAD, with 4 RT doses <strong>of</strong> less than 50% <strong>of</strong> the MAD.<br />
Grade 3/4 toxicities were infrequent. No statistically significant concordance for grade<br />
3/4 toxicities between RT and FIHT was observed.<br />
Conclusions: These data show a major discrepancy between RP2D and MAD <strong>of</strong> mAb<br />
FIHT when compared with doses tested in RT, and toxicities detected in mAb FIHT do<br />
not correlate with RT toxicities. As FIHT data inform only partially choices <strong>of</strong> RT<br />
doses, rational strategies for mAb dose selection in the clinical setting remain an unmet<br />
need.<br />
Legal entity responsible for the study: ICM Montpellier<br />
Funding: ICM Montpellier<br />
Disclosure: C. Gongora: Research funding from Novartis, Astellas and Janssen travel<br />
funding from Lilly. L. Gianni: Activity as consultant or advisor board member: Roche,<br />
GlaxoSmithKline, Pfizer, Boehringer Ingelheim, Celgene, Tahio Pharmaceutical,<br />
Tiziana Pharma, Synthon, AstraZeneca, Genomic Health, Merck Sharp & Dohme,<br />
Synaffix. D. Tosi: research funding from Novartis, Astellas and Janssen travel funding<br />
from Bayer, Janssen, Astellas, San<strong>of</strong>i. All other authors have declared no conflicts <strong>of</strong><br />
interest.<br />
401P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
The use <strong>of</strong> next generation sequencing (NGS) to guide patient<br />
selection for phase 1 clinical trials<br />
R.E. Miller 1 , N.F. Brown 1 , A. Speirs 2 , H.M. Shaw 1 , S. Adeleke 2 , P. Gougis 1 ,<br />
P. Bennett 3 , T. Meyer 4 , C. Swanton 5 , M. Forster 4 , R.S. Kristeleit 4<br />
1 UCLH/NIHR Clinical Research Facility, University College London Hospital,<br />
London, UK, 2 Medical <strong>Oncology</strong>, UCL - University College London, London, UK,<br />
3 Sarah Cannon-UCL Laboratories, UCL- Advanced Diagnostics Molecular<br />
Pr<strong>of</strong>iling Laboratory, London, UK, 4 Medical <strong>Oncology</strong>, University College London<br />
Cancer Institute, London, UK, 5 The Francis Crick Institute, UCL - University<br />
College London, London, UK<br />
Background: Therapeutically targeting actionable mutations in cancer may increase<br />
response rates in Phase I clinical trials. We undertook a pilot study to assess the<br />
feasibility and therapeutic benefit <strong>of</strong> incorporating NGS screening into the patient<br />
pathway for phase 1 cancer trials.<br />
Methods: NGS tumour pr<strong>of</strong>iling was performed using a 22 gene amplicon-based panel<br />
(Life Technologies Colon & Lung V2) on 117 consecutive patients (pts) referred over a<br />
13 month period for Phase I trials. BRCA1/2 analysis was performed in pts with<br />
epithelial ovarian cancer.<br />
Results: 117 pts (67% female) with a median age <strong>of</strong> 59 (range 22-78) years were<br />
included. Common tumour types were ovarian (n = 20), colorectal (n = 16), breast<br />
(n = 13), endometrial (n = 12) and lung (n = 8) cancer. NGS was successfully<br />
performed in 108 (92%) pts with a median time to results <strong>of</strong> 12 days (range 6-39). 82%<br />
<strong>of</strong> pts (89/108) had a detected variant in ≥ 1 gene with an average <strong>of</strong> 3 variants (range<br />
0-26) in 2 genes (0-10) per case. Common mutations included TP53 (69%), KRAS<br />
(14%), PIK3CA (11%) and SMAD4 (9%). BRCA1/2 mutations were present in 11<br />
(55%) ovarian cancer pts. Overall, 49 (45%) pts had ≥ 1 actionable mutation. Detected<br />
variants were reviewed in a local genomics review board to assess actionability prior to<br />
considering therapy. 53 pts were commenced on a Phase I trial; 18 (34%) were<br />
genotype directed. Median duration on trial was 73 days for pts on genotype (7-260<br />
days) or non-genotype (20-582) directed trials with 50% and 24% <strong>of</strong> allocated patients<br />
continuing on study respectively. Of pts evaluable for response (n = 47), partial<br />
response (PR), stable disease (SD) and progressive disease (PD) were observed in 50%,<br />
29% and 21% <strong>of</strong> pts on genotype directed trials and 20%, 37% and 43% <strong>of</strong> pts on<br />
non-genotype directed respectively. Excluding pts on BRCA1/2 directed trials, PR, SD<br />
and PD were observed in 33%, 33% and 33% <strong>of</strong> pts respectively in genotype-directed<br />
studies.<br />
Conclusions: NGS is feasible in real time and may affect clinical outcome in the phase<br />
1 setting. Almost half <strong>of</strong> pts had a potentially actionable mutation. Initial response rates<br />
for pts treated on genotype-driven trials are encouraging. Benefit is likely to be<br />
augmented using a broader NGS panel which is planned for future assessment.<br />
vi130 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Legal entity responsible for the study: UCLH/NIHR Clinical Research Facility<br />
Funding: UCLH/NIHR Clinical Research Facility<br />
Disclosure: P. Bennett: Employee <strong>of</strong> UCL- Advanced Diagnostics Molecular Pr<strong>of</strong>iling<br />
Laboratory, Sarah Cannon-UCL Laboratories. All other authors have declared no<br />
conflicts <strong>of</strong> interest.<br />
402P<br />
Retrospective review <strong>of</strong> new phase I clinic referrals and<br />
enrolment in the molecular screening era<br />
M.J. Rheaume, L. Wang, E. Brookes, H. Chow, A. Spreafico, A. Hansen,<br />
A. Rasak, L. Siu, P. Bedard<br />
Cancer Genomics Program, Princess Margaret Hospital, Toronto, ON, Canada<br />
Background: Phase I trials increasingly use molecular enrichment for patient selection.<br />
In 2012, we initiated a molecular screening program at Princess Margaret (PM) Cancer<br />
Centre using either a customized multi-gene hotspot panel or targeted next-generation<br />
sequencing to match patients with actionable mutations to clinical trials. Our aim was<br />
to evaluate the outcome <strong>of</strong> new patient referrals seen in the PM phase I clinic and<br />
factors associated with subsequent clinical trial enrolment.<br />
Methods: A retrospective chart analysis for consecutive PM phase I clinic new referrals<br />
from May 2012 and December 2014. Data on their demographics, prior molecular<br />
pr<strong>of</strong>iling results, medical history, and details <strong>of</strong> clinical trial participation or non-entry<br />
were recorded.<br />
Results: Of 941 new patient referrals 560 (58%) patients were <strong>of</strong>fered ≥1 clinical trials<br />
and 265 (28%) were subsequently enrolled. The most common reasons that patients<br />
were not trial candidates included poor performance status (27%), medical<br />
comorbidities (17%), other treatment preferred (16%) and ongoing systemic treatment<br />
(8%). There were 396 (42%) new referrals that had prior molecular pr<strong>of</strong>iling with no<br />
increase in the proportion <strong>of</strong> referrals with prior molecular pr<strong>of</strong>iling over time<br />
(p = 0.42). Patients with prior molecular pr<strong>of</strong>iling were younger, more heavily<br />
pre-treated with systemic therapies, with better Princess Margaret Prognostic Index<br />
(albumin < 35g/L, > 2 metastatic sites, and ECOG performance status (PS) > 0) scores,<br />
and lived closer to PM than patients who did not undergo prior molecular pr<strong>of</strong>iling (all<br />
p < 0.01). Patients with molecular pr<strong>of</strong>iling were more likely to be <strong>of</strong>fered clinical trials<br />
(68% vs 51%, p < 0.001) and subsequently enrolled (33% vs 23%, p < 0.001). In<br />
multi-variable analysis, only PS (0/1 vs 2/3), disease site (non-GI vs GI), distance to<br />
PM (
abstracts<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
– 369) ng/mL, median albumin 37 (35 – 39) g/L, median ALP 102 (72 – 178), median<br />
hemoglobin 11.9 (10.9 – 13.0) g/dL. Nineteen (20.4%) patients had a Royal Marsden<br />
Hospital Score <strong>of</strong> 2 to 3, 14 (15.1%) patients were chemo-naive and 25 (26.9%) had<br />
visceral metastases. The median number <strong>of</strong> previous treatments was 3 (range 0 - 7).<br />
Concerning efficacy, 27 (29%) pts had biological response (PSA decrease >50%) and 6<br />
<strong>of</strong> them had a very good biological response (PSA decrease >90%). Among the cohort,<br />
PFS was 3.8 months (2.96 – 4.64) and OS 21.27 months (12.6 – 29.9). Factors<br />
significantly associated with OS were RMH score (HR 1.54; 95CI 1.13 – 2.09), number<br />
<strong>of</strong> previous lines <strong>of</strong> treatment (HR 1.40; 95CI 1.12 – 1.76), and Hemoglobin (HR 0.96;<br />
95CI 0.92 – 0.99). Among patients screened for genomic characterization, 71 had<br />
CRPC and 33 (46,5%) were enrolled in phase I trials. MA were found in 49 (69%) <strong>of</strong><br />
them. Most frequent MA found were : PTEN loss (63.3%), Androgen Receptor<br />
amplification or mutation (44.9%), PI3K mutation (22.4%), FGFR and MYC mutation<br />
(16.3%). Five pts (10.2%) had BRCA alterations. Ten patients were treated with a<br />
matched targeted therapy regarding their molecular alteration.<br />
Conclusions: In our cohort <strong>of</strong> prostate cancer enriched population enrolled in phase I<br />
trials, not only RMS but the previous number <strong>of</strong> lines and hemoglobin should be taken<br />
into account to estimate OS. Moreover, targetable molecular alterations are frequently<br />
identified in advanced CRPC patients.<br />
Legal entity responsible for the study: Gustave Roussy, Université Paris-Saclay,<br />
DITEP, Villejuif, F-94805, France<br />
Funding: Gustave Roussy, Université Paris-Saclay, DITEP, Villejuif, F-94805, France<br />
Disclosure: L. Albiges: Consulting/ advisory Board : Novartis, Pfizer, Amgen, Bayer,<br />
BMS, Ceruleon, san<strong>of</strong>i (compensated - myself) Research funding : novartis, Pfizer<br />
(myself). J-C. Soria: Personal fees AstraZeneca, Astex, Covagen, Clovis, GSK,<br />
Gammamabs, Lilly, MSD, Mission Therapeutics, Merus, Pfizer, Pierre Fabre,<br />
Roche-Genentech, San<strong>of</strong>i, Servier, Takeda. All other authors have declared no conflicts<br />
<strong>of</strong> interest.<br />
406P<br />
Does dose affect tumour response in phase I oncology trials <strong>of</strong><br />
non-cytotoxic agents?<br />
J. Ghosh 1 , G. Lazaridis 2 , Z. Viney 3 , H. Verma 3 , I. Sheriff 4 ,Y.Wang 5 , H. Moller 6 ,J.<br />
F. Spicer 7 , D. Sarker 7<br />
1 Translational Cancer Medicine, King’s College London, UK & Tata Memorial<br />
Centre, Mumbai, India, London, UK, 2 Medical <strong>Oncology</strong>, Guy’s and St. Thomas’<br />
Hospital NHS Trust, London, UK, 3 Radiology, Guy’s and St. Thomas’ Hospital<br />
NHS Trust, London, UK, 4 GKT School <strong>of</strong> Medical Education, Kings College<br />
London, London, UK, 5 Primary Care and Public Health Sciences, Kings College<br />
London, London, UK, 6 Cancer Epidemiology & Poulation Health, Kings College<br />
London, London, UK, 7 Division <strong>of</strong> Cancer Studies, King’s College London & Guy’s<br />
and St Thomas’ NHS Foundation Trust, London, UK<br />
Background: Although phase I oncology trials have conventionally used the maximum<br />
tolerated dose (MTD) as the recommended dose for phase II studies (RP2D), there is<br />
conflicting data on how dose relates to response for non-cytotoxic agents. Also,<br />
patients achieving disease stabilisation have differing tumour growth rates (TGR). We<br />
retrospectively evaluated tumour response and kinetics at different dose levels in phase<br />
1 trials.<br />
Methods: All patients enrolled in phase I trials <strong>of</strong> non-cytotoxics in a single UK centre<br />
between 2007-2015 were evaluated. Patients were divided into four dose levels (60-80%, >80%) based on the percentage <strong>of</strong> the dose allocated compared to<br />
the maximum administered dose (MAD) on the trial. TGR was measured as the<br />
percentage change in tumour volume per unit time.<br />
Results: A total <strong>of</strong> 151 patients were enrolled in 12 phase I trials (8 molecularly<br />
targeted agents, 3 immunotherapy and 1 steroid synthesis inhibitor). Median age was<br />
59 years and 73% had low risk RMH score. There was no statistically significant<br />
difference in best response on treatment, progression free survival (PFS) or overall<br />
survival (OS) at different dose levels. Increased toxicity resulting in dose reduction or<br />
treatment discontinuation was seen at higher doses. However, when responders<br />
(complete or partial response, or stable disease) were analysed separately, higher doses<br />
were associated with <strong>of</strong> decreasing TGR, longer median PFS and OS (Table).<br />
Conclusions: Overall for non-cytotoxic agents there was no significant dose-response<br />
relationship but the subgroup <strong>of</strong> responding patients had longer survival at higher<br />
doses. Thus MTD should continue to be the RP2D though there is need for apriori<br />
identifying potential responders.<br />
Legal entity responsible for the study: N/A<br />
Funding: No funding was required as this was a retrospective study<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
407TiP<br />
Phase 1 study <strong>of</strong> LOXO-101, a selective TRK inhibitor, in<br />
pediatric patients with cancer<br />
T.W. Laetsch 1 , R. Nagasubramanian 2 , S.G. Dubois 3 , L. Mascarenhas 4 ,<br />
D. Hawkins 5 , N. Shukla 6 , B. Turpin 7 , S. Smith 8 , M. Reynolds 8 , S. Cruickshank 8 ,<br />
L. Donahue 9 , M.C. Cox 8 , A. Pappo 10<br />
1 Department <strong>of</strong> Pediatrics, University <strong>of</strong> Texas Southwestern Medical Center at<br />
Dallas, Dallas, TX, USA, 2 Pediatric Hematology/<strong>Oncology</strong>, Nemours Children’s<br />
Hospital, Orlando, FL, USA, 3 Dana-Farber/Boston Children’s Cancer and Blood<br />
Disorders Center, Boston Children’s Hospital, Boston, MA, USA, 4 Department <strong>of</strong><br />
<strong>Oncology</strong>, Childrens Hospital Los Angeles University <strong>of</strong> Southern California, Los<br />
Angeles, CA, USA, 5 Department <strong>of</strong> Hematology/<strong>Oncology</strong>, Seattle Children’s<br />
Hospital, Seattle, WA, USA, 6 Department <strong>of</strong> Pediatrics, Memorial Sloan Kettering<br />
Cancer Center, New York, NY, USA, 7 Department <strong>of</strong> <strong>Oncology</strong>, Cincinnati<br />
Children’s Hospital Medical Center, Cincinnati, OH, USA, 8 Clinical Development,<br />
Loxo <strong>Oncology</strong>, Inc, South San Francisco, CA, USA, 9 Clinical Operations, Loxo<br />
<strong>Oncology</strong>, Inc, Stamford, CT, USA, 10 Solid Tumor Division, St Jude Children’s<br />
Research Hospital, Memphis, TN, USA<br />
Background: Neurotrophin ligands and their receptors TRKA, TRKB, and TRKC<br />
(encoded by NTRK1, NTRK2, and NTRK3) are important for growth regulation,<br />
differentiation and survival <strong>of</strong> neurons. Translocations involving the NTRK1/2/3<br />
kinase domain, mutations involving the TRK ligand-binding site, amplifications <strong>of</strong><br />
NTRK, TRK splice variants, and autocrine/paracrine signaling have been described in<br />
diverse tumor types and may contribute to tumorigenesis. A broad range <strong>of</strong> pediatric<br />
malignancies have been found to harbor NTRK fusions, including infantile<br />
fibrosarcoma (IFS), congenital mesoblastic nephroma (CMN), secretory breast cancer,<br />
pediatric papillary thyroid cancer, pediatric gliomas and Ph-like acute lymphoblastic<br />
leukemia. Additionally, TRK protein over-expression is common in neuroblastoma.<br />
LOXO-101 is the first small-molecule selective inhibitor <strong>of</strong> TRKA, -B, and -C in<br />
clinical development and has demonstrated tumor inhibition in preclinical models and<br />
clinically meaningful responses in patients with TRK fusion cancers in an adult phase 1<br />
trial.<br />
Trial design: We have initiated an open-label, multi-center Phase I dose escalation/<br />
dose expansion study with LOXO-101 in pediatric patients with solid tumors and<br />
primary CNS tumors (NCT02637687). Patients with advanced cancer between the ages<br />
<strong>of</strong> 1 and 21 years are eligible, as well as patients as young as 1-month <strong>of</strong> age with a<br />
primary diagnosis <strong>of</strong> IFS or CMN and a documented NTRK fusion. Twice-daily oral<br />
dosing <strong>of</strong> LOXO-101 capsules is administered on a continuous 28-day schedule.<br />
LOXO-101 is available in an oral liquid formulation for patients unable to swallow<br />
capsules. PK-directed intra-subject dose escalation is permitted, with target exposures<br />
equivalent to the recommended Phase 2 dose in adults <strong>of</strong> 100 mg BID. Dose escalation<br />
utilizes a Rolling 6 design. The objective <strong>of</strong> the study is to determine the maximum<br />
tolerated dose and initial evidence <strong>of</strong> the efficacy <strong>of</strong> LOXO-101 in different tumor<br />
types. Eligibility for the dose expansion cohorts will require patient tumor samples to<br />
have documented alterations <strong>of</strong> an NTRK gene or TRK protein. Molecular<br />
abnormalities will be characterized through the analysis <strong>of</strong> archival tissue. Enrollment<br />
began in December 2015 and is ongoing.<br />
Clinical trial identification: NCT02637687<br />
Legal entity responsible for the study: Loxo <strong>Oncology</strong>, Inc.<br />
Funding: Loxo <strong>Oncology</strong>, Inc.<br />
Disclosure: S. Smith, M. Reynolds, S. Cruickshank: Paid consultant for Loxo<br />
<strong>Oncology</strong>. L. Donahue, M.C. Cox: Employee and stock holder <strong>of</strong> Loxo <strong>Oncology</strong>. All<br />
other authors have declared no conflicts <strong>of</strong> interest.<br />
Table: 406P - Response, toxicity, progression free and overall survival at different dose levels<br />
%MAD 60-80 n = 33 >80 n = 31<br />
Best Response Complete/Partial Response Stable Disease 14% 27% 12% 48% 24% 30% 23% 16% p = 0.17<br />
TGR at Best Response (Responders) 0% -14% -8% -30% p trend = 0.017<br />
Toxicity Dose Reduction Drug Discontinuation 0 0 5% 15% 21% 9% 16% 13% p = 0.017<br />
Median PFS (weeks) All Patients Responders 9 16 16 20 13 29 9 (p = 0.16) 36 (p = 0.002)<br />
Median OS (weeks) All Patients Responders 27 44 47 54 43 73 32 (p = 0.137) 108 (p = 0.24)<br />
vi132 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
408TiP<br />
CamBMT1: A pro<strong>of</strong>-<strong>of</strong>-principle phase 1b / randomised<br />
phase 2 study <strong>of</strong> afatinib penetration into brain metastases<br />
(mets) for patients undergoing neurosurgical resection, both<br />
with and without prior low-dose, targeted radiotherapy<br />
R. Baird 1 , J. Garcia-Corbacho 1 , N. Ramenatte 2 , A. Jonson 3 , S. Ahmad 4 ,<br />
D-M. Smith 5 , W. Qian 3 , S. Kumar 3 , C. Linossi 3 , T. Matys 6 ,M.Graves 6 , D. Jodrell 3 ,<br />
C. Caldas 7 ,S.Pacey 3 , G. Whitfield 8 , A. Chalmers 9 , R. Jena 4 , S. Price 10 ,<br />
S. Jefferies 4 , C. Watts 10<br />
1 Breast Cancer Research Unit, Addenbrookes Hospital Box 97, Cambridge<br />
Cancer Centre, Cambridge, UK, 2 Cambridge Clinical Trials Unit - Cancer Theme,<br />
Addenbrookes Hospital Box 279, Cambridge Cancer Centre, Cambridge, UK,<br />
3 Early Phase Clinical Trials Team, Addenbrookes Hospital Box 279, Cambridge<br />
Cancer Centre, Cambridge, UK, 4 Neuro-<strong>Oncology</strong> Team, R4, Addenbrookes<br />
Hospital Box 193, Cambridge Cancer Centre, Cambridge, UK, 5 CRUK Cambridge<br />
Institute PK/Bioanalytics Core Facility, Cambridge Cancer Centre, Cambridge, UK,<br />
6 Department <strong>of</strong> Radiology, University <strong>of</strong> Cambridge, Cambridge Cancer Centre,<br />
Cambridge, UK, 7 CRUK Cambridge Institute, Cambridge Cancer Centre,<br />
Cambridge, UK, 8 Neuro-<strong>Oncology</strong>, The Christie NHS Foundation Trust,<br />
Manchester, UK, 9 CRUK Beatson Institute, University <strong>of</strong> Glasgow, Glasgow, UK,<br />
10 Divison <strong>of</strong> Neurosurgery, Dept Clinical Neurosciences, University <strong>of</strong> Cambridge,<br />
Cambridge Cancer Centre, Cambridge, UK<br />
Background: Failure <strong>of</strong> drugs to cross the blood brain barrier (BBB) can be a major<br />
reason for treatment failure for patients with brain tumours. For most patients who<br />
don’t respond to treatment, it is not known whether this is due to inadequate drug<br />
concentrations in the tumour, or due to drug resistance. Preliminary data suggest that<br />
low-dose radiotherapy may disrupt the BBB, and could facilitate increased drug<br />
delivery into brain tumours. Afatinib is a potent, irreversible inhibitor <strong>of</strong> EGFR / HER2<br />
/ HER4 and takes approximately 8 days to achieve steady-state concentrations in cancer<br />
patients. CamBMT1 has been designed to investigate the delivery <strong>of</strong> afatinib into brain<br />
mets and whether this might be enhanced by low dose-radiotherapy.<br />
Trial design: Study population: patients with operable brain mets from breast or lung<br />
primaries for whom neurosurgical resection would be standard <strong>of</strong> care. After a phase<br />
1b safety run-in, the phase 2 part <strong>of</strong> the trial randomises patients (n = 60) into 3<br />
pre-operative arms:<br />
Table: 408TiP<br />
Arm 1: afatinib alone for 11 days, then neurosurgery on day 12<br />
Arm 2: afatinib for 11 days plus a single 2 Gy fraction on day 10, then<br />
neurosurgery on day 12<br />
Arm 3: afatinib for 11 days plus a single 4 Gy fraction on day 10, then<br />
neurosurgery on day 12<br />
The primary endpoint is to compare steady-state afatinib concentration in resected<br />
brain mets, following afatinib administered alone, or in combination with radiotherapy<br />
(2 Gy or 4 Gy). Afatinib concentrations are measured in the resected brain mets and in<br />
plasma. Secondary endpoints: safety <strong>of</strong> afatinib administration in combination with<br />
radiotherapy; and multi-sequence MRI (optional) to detect changes in perfusion,<br />
vascular density, blood-brain-barrier permeability and interstitial pressure. Exploratory<br />
endpoints: molecular pr<strong>of</strong>iling <strong>of</strong> resected brain mets, for comparison with paired<br />
primary lung and breast cancers; the study <strong>of</strong> patient-derived xenografts. CamBMT1 is<br />
a multi-centre trial now opening at additional Experimental Cancer Medicine Centres,<br />
and is funded by Cancer Research UK, the Brain Tumour Charity and<br />
Boehringer-Ingelheim.<br />
Clinical trial identification: EudraCT Number: 2013-002398-23<br />
Legal entity responsible for the study: Cambridge University Hospitals NHS<br />
Foundation Trust and the University <strong>of</strong> Cambridge<br />
Funding: Cancer Research UK The Brain Tumour Charity Boehringer-Ingelheim<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
409TiP<br />
A phase II basket study <strong>of</strong> the oral TRK inhibitor LOXO–101 in<br />
adult subjects with NTRK fusion-positive tumors<br />
A. Drilon 1 , D. Hong 2 , J. Deeken 3 , S. Smith 4 , M. Reynolds 4 , S. Cruickshank 4 ,<br />
M. Deegan 4 ,N.Ku 4 , D. Hyman 5<br />
1 Thoracic <strong>Oncology</strong> Service, Memorial Sloan Kettering Cancer Center, New York,<br />
NY, USA, 2 Investigational Cancer Therapeutics, MD Anderson Cancer Center,<br />
Houston, TX, USA, 3 Medical <strong>Oncology</strong>, Inova Cancer Center, Fairfax, VA, USA,<br />
4 Clinical Research, Loxo <strong>Oncology</strong>, Inc, Stamford, CT, USA, 5 Investigational<br />
Therapeutics, Memorial Sloan Kettering Cancer Center, New York, NY, USA<br />
Background: The TRK family <strong>of</strong> neurotrophin receptors (TRKA, TRKB, and TRKC<br />
encoded by NTRK1, NTRK2, and NTRK3 genes, respectively) and their ligands<br />
regulate growth, differentiation and survival <strong>of</strong> neurons. Fusions <strong>of</strong> NTRK genes which<br />
involve the kinase domain are oncogenic and have been identified across common<br />
tumor types. Fusions occur at a frequency <strong>of</strong>
abstracts<br />
Disclosure: I. Kiss: Has received speakers’ honoraria from Roche, Merck, and<br />
Amgen. J. Rodón: Consulting/advisory: Novartis, Eli Lilly, Servier, Orion. G. Hess:<br />
Consulting/advisory:Janssen, Novartis, Pfizer, Roche, Celgene Research funding fees:<br />
Pfizer, Roche, CTI. D. Cesic, S. Sutradhar, B. Pramanik: Employee: Novartis. All other<br />
authors have declared no conflicts <strong>of</strong> interest.<br />
411TiP<br />
First-in-human trial <strong>of</strong> 4’-thio-2’-deoxycytidine (TdCyd) in<br />
patients with advanced solid tumors<br />
G. O’Sullivan Coyne 1 , A. Chen 1 , S. Kummar 2 , J.M. Collins 3 , R.S. Meehan 1 ,<br />
M. Suto 4 , L. Rubinstein 5 , R. Kinders 6 , N. Moore 7 , R. Parchment 6 , Y. Horneffer 1 ,<br />
L. Juwara 7 , M. Difilippantonio 3 , R. Piekarz 1 , J. Doroshow 3<br />
1 Developmental Therapeutics Clinic, Division <strong>of</strong> Cancer Treatment and Diagnosis,<br />
National Cancer Institute, Bethesda, MD, USA, 2 Phase I Clinical Research, Division<br />
<strong>of</strong> <strong>Oncology</strong>, Stanford University, Palo Alto, CA, USA, 3 Division <strong>of</strong> Cancer<br />
Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA, 4 Drug<br />
Discovery Division, Southern Research Institute, Birmingham, AL, USA, 5 Biometric<br />
Research Program, National Cancer Institute, Bethesda, MD, USA, 6 Applied/<br />
Developmental Research Directorate, Frederick National Laboratory for Cancer<br />
Research, Frederick, MD, USA, 7 Clinical Monitoring Research Program, Leidos<br />
Biomedical Research, Bethesda, MD, USA<br />
Background: Methylation-mediated silencing <strong>of</strong> genes is an epigenetic mechanism<br />
implicated in tumorigenesis. Hypermethylation <strong>of</strong> cytosines at CpG sites in the<br />
regulatory sequences <strong>of</strong> tumor suppressor genes silences them in a manner akin to<br />
inactivating mutations. Agents that inhibit methylation are <strong>of</strong> clinical interest because<br />
<strong>of</strong> their potential to re-activate silenced tumor suppressor genes, and two DNA<br />
hypomethylating nucleosides have been approved by the FDA for the treatment <strong>of</strong><br />
patients (pts) with hematologic malignancies. The nucleoside analog<br />
4’-thio-2’-deoxycytidine (TdCyd, NSC764276) is a cytidine analog in which the 4’-O<br />
moiety in deoxyribose has been replaced with sulfur where it engages the active site <strong>of</strong><br />
DNA methyltransferase I (DNMT1), a maintenance methyltransferase that contributes<br />
to the hypermethylation and silencing <strong>of</strong> tumor suppressor genes. TdCyd and its active<br />
metabolites are phosphorylated and incorporated into the DNA <strong>of</strong> human cells in<br />
culture and in xenografts at rates exceeding those <strong>of</strong> the natural nucleoside or<br />
ara-analogs. Growth inhibition and tumor shrinkage were found during TdCyd dosing<br />
in several human tumour xenografts. Depletion <strong>of</strong> DNMT1 was observed also in<br />
certain xenograft models.<br />
Trial design: We are conducting an open label phase 1 first-in-human trial <strong>of</strong> TdCyd,<br />
following an accelerated titration design. TdCyd is administered PO qd x 5 days <strong>of</strong> each<br />
week for 2 weeks in 21-day cycles; the primary objective <strong>of</strong> the study is to establish its<br />
safety, tolerability, maximum tolerated dose, and recommended phase 2 dose. The<br />
secondary objectives <strong>of</strong> the study <strong>of</strong> oral TdCyd include preliminary efficacy<br />
assessment, pharmacokinetic (PK) characterization and exploratory pharmacodynamic<br />
(PD) evaluation <strong>of</strong> re-expression <strong>of</strong> select genes silenced by methylation in circulating<br />
tumor cells (CTCs). Eligibility criteria: solid tumor pts whose disease has progressed on<br />
standard therapy, ECOG ≤ 2, and normal organ function. Blood samples for PK/PD<br />
analyses and gene expression in CTCs are being evaluated. Currently, we are enrolling<br />
at DL5 in the escalation portion <strong>of</strong> the trial.<br />
Clinical trial identification: NCT02423057<br />
Legal entity responsible for the study: Division <strong>of</strong> Cancer Treatment and Diagnosis,<br />
National Cancer Institute<br />
Funding: National Cancer Institute<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
412TiP<br />
The Tailored EDVTM trial: A phase I feasibility study<br />
evaluating EGFR-targeted EDVTM nanocells as a therapy<br />
platform in patients with refractory advanced solid tumours<br />
S. Clarke 1 , S. Sidhu 2 , N. Pavlakis 1 , H. Brahmbhatt 3 , J. Macdiarmid 3<br />
1 Northern Cancer Institute, University <strong>of</strong> Sydney, Sydney, Australia, 2 Endocrine<br />
surgery unit, University <strong>of</strong> Sydney, Sydney, Australia, 3 Biotechnology, EnGeneIC,<br />
Sydney, Australia<br />
Background: EnGeneIC has developed the EDV TM -Nanocell Platform Technology<br />
(EnGeneIC Dream Vector), which is a First-in-Class Cyto-Immuno-Therapy for the<br />
treatment <strong>of</strong> solid cancers. Cytotoxic drug, siRNA or miRNA are packaged into EDV<br />
nanocells, targeted to cancer cells via antibodies and payload is delivered intracellularly<br />
following internalisation <strong>of</strong> EDVs. EDVs are also taken up by immune system cells and<br />
stimulate the adaptive immune response resulting in a two-pronged anti-tumor<br />
approach. EGFR-targeted EDVs carrying mir15/16 mimics are currently being tested<br />
in a Phase 1 trial, with objective responses and prolonged disease control seen in<br />
refractory mesothelioma patients. The hypothesis for this Tailored EDV trial is that<br />
dosing patients with EGFR- targeted EDV’s( EGFR EDVs) with a payload tailored to an<br />
individual patient’s tumour will result in enhanced anti-tumour effects, overcoming<br />
established drug resistance.<br />
Trial design: An open-label Phase I feasibility study <strong>of</strong> a single delivery agent<br />
EGFR EDVs containing clinician choice therapeutic payload(s) (cytotoxic drug, siRNA<br />
or miRNA) in subjects with advanced solid tumours who have failed standard<br />
treatments. The trial opened at the Northern Cancer Institute, Sydney, in August 2015<br />
with 5 patients being recruited to date out <strong>of</strong> a possible 25 (ANZ CTR number :<br />
ACTRN12613001249741). Eligibility criteria include EGFR expression in tumour<br />
tissue using immunohistochemistry, measurable disease by standard radiological<br />
assessment according to RECIST, ECOG 0-1, and adequate organ function. The study<br />
design allows for one dose per week via a 20 minute infusion for 8 weeks. The first dose<br />
uses 2x10 9 nanocells and subsequent doses utilize 5x10 9 nanocells. Premedication<br />
comprises dexamethasone, promethazine and paracetamol and patients are monitored<br />
for a minimum period <strong>of</strong> 3 hours. Response assessments are undertaken at 8 weeks<br />
using standard imaging and relevant tumour markers. Exploratory cytokine analysis<br />
and analysis <strong>of</strong> immune cells is included.<br />
Clinical trial identification: ANZ CTR number : ACTRN12613001249741<br />
Legal entity responsible for the study: EnGeneIC Pty Ltd<br />
Funding: EnGeneIC Pty Ltd<br />
Disclosure: S. Sidhu: I am a shareholder <strong>of</strong> EnGeneIC Pty Ltd. H. Brahmbhatt: I am a<br />
Director <strong>of</strong> EnGeneIC P/L and hold shares in that entity. J. Macdiarmid: I am a<br />
Director <strong>of</strong> EnGeneIC P/L and hold shares in it. All other authors have declared no<br />
conflicts <strong>of</strong> interest.<br />
413TiP<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
A dose-escalation study <strong>of</strong> weekly intravenous CRLX301 in<br />
patients with advanced solid tumor malignancies<br />
H. Wang 1 , B. Markman 2 , P. de Souza 3 , E.C. Dees 4 , T.C. Gangadhar 5 ,S.<br />
A. Piha-Paul 6 , W.C. Zamboni 7 , C. Murphy 8 , A. Senderowicz 8<br />
1 Research, Cerulean Pharma, Inc., Waltham, MA, USA, 2 Monash Cancer Centre,<br />
Monash Health, Melbourne, Australia, 3 Medical <strong>Oncology</strong>, Western Sydney<br />
University School <strong>of</strong> Medicine, Sydney, Australia, 4 <strong>Oncology</strong>, UNC Lineberger<br />
Comprehensive Cancer Center, Chapel Hill, NC, USA, 5 Hematology-<strong>Oncology</strong>,<br />
Abramson Cancer Center <strong>of</strong> the University <strong>of</strong> Pennsylvania, Philadelphia, PA, USA,<br />
6 Investigational Cancer Therapeutics, The University <strong>of</strong> Texas MD Anderson<br />
Cancer Center, Houston, TX, USA, 7 UNC Lineberger Comprehensive Cancer<br />
Center, UNC Eshelman School <strong>of</strong> Pharmacy, Carolina Center for Cancer<br />
Nanotechnology Excellence, Chapel Hill, NC, USA, 8 Clinical Operations, Cerulean<br />
Pharma, Inc., Waltham, MA, USA<br />
Background: Cerulean’s nanoparticle-drug conjugates (NDCs) are designed to<br />
enhance delivery <strong>of</strong> drugs to tumors while sparing healthy tissues and to gradually<br />
release drug payloads once inside tumors with the goal <strong>of</strong> improving antitumor activity<br />
and reducing systemic toxicity. CRLX301 is a novel investigational NDC containing the<br />
payload docetaxel covalently conjugated to a cyclodextrin-polyethylene glycol<br />
copolymer currently being investigated in a phase 1/2a study <strong>of</strong> patients with advanced<br />
solid tumors. The first portion <strong>of</strong> the study determined the maximum tolerated dose<br />
(MTD) for intravenous (IV) CRLX301 every 3 weeks (Q3W) to be 75 mg/m 2 and<br />
showed that CRLX301 was generally well tolerated with hints <strong>of</strong> antitumor activity and<br />
a differentiated pharmacokinetic (PK) compared to docetaxel (Wang H, ASCO 2016,<br />
Abs. 2526). This portion aims to determine the MTD for weekly administration (QW)<br />
<strong>of</strong> CRLX301.<br />
Trial design: We will enroll adults with advanced solid tumors, adequate organ<br />
function and ECOG Performance Status 0–1. Simulation modeling with the Q3W PK<br />
data suggest that total and released docetaxel will not accumulate in plasma after 9<br />
weeks <strong>of</strong> QW CRLX301 at 20, 25, 30 or 40 mg/m 2 . Also, at these doses the estimated<br />
total and released docetaxel area under the plasma drug concentration-time curves<br />
(AUCs) after the 1st, 4th and 7th doses would not exceed those observed with<br />
CRLX301 at 75 mg/m 2 Q3W. These results support a weekly starting dose between 20<br />
and 40 mg/m 2 , so 25 mg/m 2 QW (1/3 <strong>of</strong> the Q3W MTD) was selected. Escalating<br />
doses will be tested in a 3 + 3 design. The primary objective is to determine the<br />
CRLX301 QW MTD. Secondary objectives include assessments <strong>of</strong> safety, PK and<br />
antitumor activity. Serial plasma samples for PK evaluation will be collected during<br />
weeks 1, 4 and 7. Tumors will be evaluated every 8 to 9 weeks per Response Evaluation<br />
Criteria in Solid Tumors (RECIST) version 1.1. A recommended phase 2 dose will be<br />
determined for use in the phase 2a expansion in patients with specific tumor types,<br />
including taxane-naïve bladder cancer. Data from QW and Q3W studies will be<br />
evaluated to select the optimal dosing schedule for future clinical trials <strong>of</strong> CRLX301.<br />
Clinical trial identification: NCT02380677 (NIH)<br />
Legal entity responsible for the study: Cerulean Pharma, Inc.<br />
Funding: Cerulean Pharma, Inc.<br />
Disclosure: H. Wang, C. Murphy, A. Senderowicz: Employee <strong>of</strong> Cerulean Pharma Inc.<br />
B. Markman, P. de Souza: Grants from Cerulean Pharma Inc. E.C. Dees: Non-financial<br />
support and other from Cerulean, during the conduct <strong>of</strong> the study; other from Pfizer,<br />
personal fees and other from Novartis, other from Bayer, Merck, Lilly, Roche, outside<br />
the submitted work. T.C. Gangadhar: Grants from Merck, outside the submitted work<br />
W.C. Zamboni: Personal fees from Cerulean Pharma during the conduct <strong>of</strong> the study;<br />
personal fees from Cerulean Pharma, outside the submitted work. All other authors<br />
have declared no conflicts <strong>of</strong> interest.<br />
vi134 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
414TiP<br />
Agnostos precision medicine project in patients (PTS) with<br />
cancer <strong>of</strong> unknown primary (CUP)<br />
E. Geuna 1 , S. Benvenuti 2 , F. Verginelli 2 , D. Galizia 1 , S. Siena 3 , G.M. Stella 4 ,<br />
A. Gentile 2 , M. Milan 2 , A.R. Virzi’ 2 ,A.D’ambrosio 2 , P. Cassoni 5 , R. Senetta 6 ,<br />
A. Balsamo 7 , M. Spione 7 , A. Nuzzo 8 , A. Sapino 6 , S. Marsoni 7 , C. Boccaccio 2 ,P.<br />
M. Comoglio 9 , F. Montemurro 1<br />
1 Investigative Clinical <strong>Oncology</strong>, IRCCS Istituto di Candiolo, Candiolo, Italy,<br />
2 Molecular Therapeutics and Exploratory Research, Istituto di<br />
Candiolo-IRCCS-Fondazione Piemontese per la Ricerca sul Cancro-Onlus,<br />
Candiolo, Italy, 3 Niguarda Cancer Center, Grande Ospedale Metropolitano<br />
Niguarda and Università degli Studi di Milano, Milan, Italy, 4 Pneumologia,<br />
Ospedale San Matteo, Pavia, Italy, 5 Anatomia Patologica, Città della Saluta e della<br />
Scienza - Torino, Turin, Italy, 6 Anatomia Patologica, IRCCS Istituto di Candiolo,<br />
Candiolo, Italy, 7 Clinical Trials Unit - Clinical Research Office, Istituto di<br />
Candiolo-IRCCS-Fondazione Piemontese per la Ricerca sul Cancro-Onlus,<br />
Candiolo, Italy, 8 Clinical Trials Unit - Clinical Research Office, IRCCS Istituto di<br />
Candiolo, Candiolo, Italy, 9 Istituto di Candiolo-IRCCS-Fondazione Piemontese per<br />
la Ricerca sul Cancro-Onlus, Candiolo, Italy<br />
Background: CUP identifies a heterogeneous clinical and pathological syndrome<br />
characterized by absence <strong>of</strong> an identifiable site-specific tumor <strong>of</strong> origin, early metastatic<br />
dissemination and undifferentiated phenotype. Representing 3-5% <strong>of</strong> all cancers, CUPs<br />
are still an unsolved clinical problem, with elusive biology and paucity <strong>of</strong> effective<br />
therapies. No validated actionable targets and no preferred regimen have emerged so<br />
far. With 25-30% response rate (RR) and overall survival (OS) from 6 to 16 months,<br />
the current approach is largely suboptimal. The AGNOSTOS project represents a<br />
unique clinical and translational initiative aiming to improve the outlook <strong>of</strong> CUP pts<br />
through evaluation <strong>of</strong> novel chemotherapeutic regimens (AGNOSTOS TRIAL_1) and<br />
a better understanding <strong>of</strong> the complex CUP biology (AGNOSTOS TRASLATIONAL<br />
COMPANION STUDY_2).<br />
Trial design: AGNOSTOS_1 is a randomized phase II trial with a ‘Pick the Winner’<br />
design that will assess efficacy <strong>of</strong> NabPaclitaxel (NabP) in combination with either<br />
Carboplatin (C) or Gemcitabine (G) in treatment-naive CUP pts (EudraCT<br />
2014-005018-47). We plan to enroll 132 pts based on a Simon’s two-stage design.<br />
Inclusion criteria include measurable disease and adequate archived biopsy tissue for<br />
immunohistochemical and molecular pr<strong>of</strong>iles. Patients will receive NabP 125 mg/m2<br />
plus G 1000 mg/m2 or C AUC 2 on day 1 and 8 by, every 21 days. Tumor response will<br />
be assessed every 9 weeks. Primary endpoint is RR while secondary endpoints are time<br />
to progression and OS. Furthermore, AGNOSTOS_2 will perform an in-depth<br />
molecular characterization <strong>of</strong> the enrolled CUPs. Vital tissues and liquid biopsies will<br />
be collected to derive patient-derived xenografts (PDX) and circulating cancer stem<br />
cells, respectively. The comprehensive genetic analysis (by next generation sequencing)<br />
aims to pinpoint common denominators <strong>of</strong> the hypermetastatic phenotype and its<br />
molecular link with cancer stemness. Currently we have enrolled 6 pts in<br />
AGNOSTOS_1 and 31 in AGNOSTOS_2 (with 8 PDX attempted).<br />
Clinical trial identification: Clinical trial information: NCT02607202<br />
Legal entity responsible for the study: IRCCS Candiolo (ITALY)<br />
Funding: AIRC 5 x 1000; Celgene<br />
Disclosure: S. Siena: Advisory role for Amgen, Roche, Bayer, Ely Lilly, San<strong>of</strong>i, Merck.<br />
S. Marsoni: Research funding: Celgene. F. Montemurro: Speaker’s bureau member<br />
Astra Zeneca, Roche and Novartis. All other authors have declared no conflicts <strong>of</strong><br />
interest.<br />
415TiP<br />
abstracts<br />
ZUMA-3: A phase 1/2 multi-center study evaluation the<br />
safety and efficacy <strong>of</strong> KTE-C19 anti-CD19 CAR T cells in<br />
adult patients with relapsed/refractory B precursor acute<br />
lymphoblastic leukemia (R/R ALL)<br />
B. Shah 1 , J. Castro 2 , N. Gökbuget 3 , M. José Kersten 4 , T. Hagenbeek 4 ,<br />
W. Wierda 5 , G. Schiller 6 , A. Bot 7 , J.M. Rossi 7 , Y. Jiang 7 , L. Navale 7 , S. Stout 7 ,<br />
J. Aycock 7 , J. Wiezorek 7 , R. Jain 7<br />
1 Department <strong>of</strong> Hematological Malignancies, H. Lee M<strong>of</strong>fitt Cancer Center and<br />
Research Institute, Tampa, FL, USA, 2 Department <strong>of</strong> Medicine and Moores<br />
Cancer Center, University <strong>of</strong> California San Diego, La Jolla, CA, USA, 3 Department<br />
<strong>of</strong> Medicine II, Goethe University Frankfurt, Frankfurt, Germany, 4 Department <strong>of</strong><br />
Hematology, Academic Medical Center, University <strong>of</strong> Amsterdam, Amsterdam,<br />
Netherlands, 5 Department <strong>of</strong> Leukemia, The University <strong>of</strong> Texas MD Anderson<br />
Cancer Center, Houston, TX, USA, 6 N/A, UCLA Center for Health Sciences, Los<br />
Angeles, CA, USA, 7 Kite Pharma, Santa Monica, CA, USA<br />
Background: ALL has an incidence <strong>of</strong> 1.2 to 1.4 per 100,000 per year in Europe<br />
(Saltman, BMC Cancer 2015). Although 75%-90% <strong>of</strong> adult patients with ALL achieve<br />
complete remission (CR) following initial treatment, eventually most relapse. R/R ALL<br />
has a poor prognosis, with a median survival <strong>of</strong> 4-8 months (Hoelzer, Ann Oncol<br />
2016). Ongoing studies at the National Cancer Institute (NCI) using anti-CD19 CAR T<br />
cells with CD28/CD3ζ signaling domains showed durable remissions in pediatric<br />
patients with R/R ALL and adults with R/R B cell malignancies (Lee, Lancet 2015;<br />
Kochenderfer, J Clin Oncol 2015). KTE-C19 is an autologous, anti-CD19 CAR T cell<br />
therapy that uses the same construct as the NCI studies, manufactured in a streamlined<br />
6- to 8-day process. Here, we describe a phase 1/2 study evaluating KTE-C19 in adult<br />
patients with R/R ALL.<br />
Trial design: The primary objective is to evaluate efficacy <strong>of</strong> KTE-C19, assessed by<br />
overall CR rate (CR + CR with partial hematologic recovery). Key secondary objectives<br />
include duration <strong>of</strong> response, minimal residual disease-free rate, allogeneic stem cell<br />
transplant rate, OS, and safety. Exploratory objectives include pharmacokinetics,<br />
pharmacodynamics, and predictive biomarker analyses. Patients with R/R ALL will be<br />
treated with fixed-dose fludarabine and cyclophosphamide conditioning chemotherapy<br />
followed by a single infusion <strong>of</strong> KTE-C19 at a target dose <strong>of</strong> 2 × 10 6 anti-CD19 CAR T<br />
cells/kg. Phase 1 will enroll 3-12 patients with the primary objective to evaluate the<br />
safety <strong>of</strong> KTE-C19. In phase 2, approximately 50 patients will be enrolled. Eligible<br />
patients will be ≥18 years with ≥5% marrow blasts, ECOG PS 0-1, and adequate bone<br />
marrow, renal, hepatic, and cardiac function. Patients with Ph+ ALL and low-burden<br />
central nervous system disease are eligible. Patients with Burkitt lymphoma or chronic<br />
myeloid leukemia in blast crisis, extramedullary disease only, active graft-versus-host<br />
disease, or clinically significant infection are not eligible. Accrual began in December<br />
2015. The study is planned at approximately 25 sites in the US and EU. Clinical trial<br />
information: NCT02614066.<br />
Clinical trial identification: NCT02614066<br />
Legal entity responsible for the study: Kite Pharma<br />
Funding: Kite Pharma<br />
Disclosure: B. Shah: Advisory Board, Speaker Fees, Honorarium: Celgene;<br />
Honorarium: Bayer, Plexus Communications and Baxalta; Speaker Fees: Spectrum and<br />
Pharmacyclics; Research Funding: Rosetta Genomics; Advisory Board: Acetilon and<br />
Pfizer. W. Wierda: GSK research, Celgene consulting. G. Schiller: Research Funding:<br />
Novartis, Karyopharm, Astellas, Spectrum, Bluebird, Array Pharmaceutical; Honoraria,<br />
Research Funding, Speakers Bureau: Amgen and Celgene; Honoraria, Research<br />
Funding: Sunesis. A. Bot, J.M. Rossi, Y. Jiang, L. Navale, S. Stout, J. Aycock,<br />
J. Wiezorek, R. Jain: Employment with Kite Pharma. All other authors have declared<br />
no conflicts <strong>of</strong> interest.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw368 | vi135
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong> 27 (Supplement 6): vi136–vi148, 2016<br />
doi:10.1093/annonc/mdw369<br />
endocrine and neuroendocrine tumours<br />
416O<br />
Efficacy and safety <strong>of</strong> pasireotide LAR or everolimus alone, or<br />
in combination in patients with advanced carcinoids (NET) <strong>of</strong><br />
the lung/thymus: Results from the randomized, phase 2 LUNA<br />
study<br />
P. Ferolla 1 , M.P. Brizzi 2 ,T.Meyer 3 , W. Mansoor 4 , J. Mazieres 5 , C.D. Cao 6 ,<br />
H. Lena 7 , A. Berruti 8 , V. Damiano 9 , W. Buikhuisen 10 , M. Stankovic 11 , N. Singh 12 ,<br />
E. Chiodini 13 , G. Gislimberti 14 , K. Oberg 15 , E. Baudin 16<br />
1 Dept. <strong>of</strong> Medical <strong>Oncology</strong>, Multidisciplinary NET Group, Umbria Regional Cancer<br />
Network and University <strong>of</strong> Perugia, Perugia, Italy, 2 Department <strong>of</strong> <strong>Oncology</strong>,<br />
University <strong>of</strong> Torino, Torino, Italy, 3 <strong>Oncology</strong>, Royal Free Hospital and UCL,<br />
London, UK, 4 Department <strong>of</strong> Medical <strong>Oncology</strong>, The Christie NHS Foundation<br />
Trust, Manchester, UK, 5 Medical <strong>Oncology</strong>, CHU Toulouse, Hôpital de Larrey,<br />
Toulouse, France, 6 Medical <strong>Oncology</strong>, CHRU Lille, Lille, France, 7 Pneumologie,<br />
Centre Hospitalier Universitaire, Rennes, France, 8 Medical <strong>Oncology</strong>, University <strong>of</strong><br />
Brescia, Brescia, Italy, 9 Department Dip.Oncol. Endocr.Molec.Clinic, Azienda<br />
Ospedaliera Universitaria Policlinico Federico II-AOU Federico II, Napoli, Italy,<br />
10 Department <strong>of</strong> Thoracic <strong>Oncology</strong>, The Netherlands Cancer Institute,<br />
Amsterdam, Netherlands, 11 Medical affairs, Novartis Pharma Services Inc, Novi<br />
Beograd, Serbia, 12 PLS Clinical Project Mgt, Cognizant Technology Solutions,<br />
Mumbai, India, 13 Clinical, Parexel, Origgio, Italy, 14 OORE-GMO, Gislimberti,<br />
Origgio, Italy, 15 Dep <strong>of</strong> Medical Sciences, Uppsala University Hospital, Uppsala,<br />
Sweden, 16 Endocrinology, Institut Gustave Roussy, Villejuif, France<br />
417O<br />
Metformin impact on progression-free survival in diabetic<br />
patients with advanced pancreatic neuroendocrine tumors<br />
(pNET) receiving everolimus and/or somatostatin analogues.<br />
The PRIME-NET (Pancreatic multicentric, Retrospective,<br />
Italian MEtformin) study<br />
S. Pusceddu 1 , R. Marconcini 2 , F. Spada 3 , S. Massironi 4 , A. Bongiovanni 5 ,M.<br />
P. Brizzi 6 , N. Brighi 7 , A. Colao 8 , D. Giuffrida 9 , G. Delle Fave 10 , S. Cingarlini 11 ,<br />
F. Aroldi 12 , L. Antonuzzo 13 , R. Berardi 14 , L. Catena 15 , C. de divitis 16 ,<br />
P. Ermacora 17 , M. Di Maio 18 , R. Buzzoni 1 , F. de Braud 19<br />
1 Medical <strong>Oncology</strong> Department, Fondazione IRCCS - Istituto Nazionale dei<br />
Tumori, Milan, Italy, 2 U.O. Oncologia Medica 2 Universitaria, Azienda Ospedaliera<br />
Universitaria S.Chiara, Pisa, Italy, 3 Medical <strong>Oncology</strong>, Istituto Europeo di<br />
Oncologia, Milan, Italy, 4 Gastroenterology unit, IRCCS Ospedale Maggiore<br />
Policlinico, Milan, Italy, 5 Osteoncology and Rare Tumors Center, Istituto Tumori<br />
della Romagna I.R.S.T., Meldola, Italy, 6 Divison <strong>of</strong> Medical <strong>Oncology</strong>, Azienda<br />
Ospedaliero-Universitaria ASOU San Luigi Gonzaga, Orbassano, Italy, 7 Pancreas<br />
Unit, Department <strong>of</strong> Digestive System, Policlinico S. Orsola-Malpighi, Bologna,<br />
Italy, 8 Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia,<br />
Università Federico II, Naples, Italy, 9 Oncologia, Istituto Oncologico del<br />
Mediterraneo, Viagrande, Italy, 10 Digestive and Liver Disease, Azienda Ospedaliera<br />
St. Andrea - Roma, Rome, Italy, 11 Medical <strong>Oncology</strong>, Azienda Ospedaliera<br />
Universitaria Integrata AOUI, Verona, Italy, 12 <strong>Oncology</strong> Unit, Fondazione<br />
Poliambulanza, Brescia, Italy, 13 <strong>Oncology</strong>, Azienda Ospedaliera Careggi U.O.<br />
Medical <strong>Oncology</strong>, Florence, Italy, 14 Clinica di Oncologia Medica, AOU Ospedali<br />
Riuniti Ancona Università Politecnica delle Marche, Ancona, Italy, 15 <strong>Oncology</strong> unit,<br />
Istituto di Oncologia del Policlinico di Monza, Monza, Italy, 16 Department <strong>of</strong><br />
Abdominal <strong>Oncology</strong>, Istituto Nazionale Tumori – I.R.C.C.S - Fondazione Pascale,<br />
Naples, Italy, 17 <strong>Oncology</strong> Unit, Azienda Ospedaliera Universitaria-Udine Sta Maria<br />
della Misericordia, Udine, Italy, 18 Divison <strong>of</strong> Medical <strong>Oncology</strong>, Azienda<br />
Ospedaliera Mauriziano Umberto I, Turin, Italy, 19 <strong>Oncology</strong> Department -<br />
University <strong>of</strong> Milan, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy<br />
abstracts<br />
© European Society for Medical <strong>Oncology</strong> 2016. Published by Oxford University Press on behalf <strong>of</strong> the European Society for Medical <strong>Oncology</strong>.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com.
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
418O<br />
Pancreatic neuroendocrine tumour (pNET) pr<strong>of</strong>iles in the<br />
NETwork! programme: clinic–enabled genomics for<br />
genomic-enabled clinical decisions<br />
B. Lawrence 1 , C. Blenkiron 2 , K. Parker 1 , S. Fitzgerald 2 , P. Shields 2 , P. Tsai 2 ,<br />
S. James 2 , N. Poonawala 2 , M.L. Yeong 3 , N. Kramer 4 , B. Robinson 5 , S. Connor 6 ,<br />
R. Ramsaroop 7 , M. Yozu 8 , M. Elston 9 , C. Jackson 10 , R. Carroll 11 , D. Harris 5 ,<br />
M. Findlay 1 , C. Print 2<br />
1 Discipline <strong>of</strong> <strong>Oncology</strong>, University <strong>of</strong> Auckland Faculty <strong>of</strong> Medical & Health<br />
Sciences, Auckland, New Zealand, 2 Molecular Medicine and Pathology, University<br />
<strong>of</strong> Auckland Faculty <strong>of</strong> Medical & Health Sciences, Auckland, New Zealand,<br />
3 Anatomical Pathology Services, Auckland District Health Board, Auckland, New<br />
Zealand, 4 Labplus, Auckland District Health Board, Auckland, New Zealand,<br />
5 Department <strong>of</strong> Medical <strong>Oncology</strong>, Christchurch Hospital, Christchurch, New<br />
Zealand, 6 Department <strong>of</strong> Surgery, Christchurch Hospital, Christchurch, New<br />
Zealand, 7 Department <strong>of</strong> Pathology, Waitemata District Health Board, Auckland,<br />
New Zealand, 8 Department <strong>of</strong> Pathology, Counties Manukau District Health<br />
Board, Auckland, New Zealand, 9 Waikato Clinical School, University <strong>of</strong> Auckland<br />
Faculty <strong>of</strong> Medical & Health Sciences, Auckland, New Zealand, 10 Dunedin School<br />
<strong>of</strong> Medicine, Otago University, Dunedin, New Zealand, 11 Department <strong>of</strong><br />
Endocrinology, Capital and Coast District Health Board, Wellington, New Zealand<br />
420PD<br />
NETTER-1 phase III in patients with midgut neuroendocrine<br />
tumors treated with 177Lu-dotatate: Efficacy, safety, QoL<br />
results and subgroup analysis<br />
J. Strosberg 1 , E. Wolin 2 , B. Chasen 3 , M. Kulke 4 , D. Bushnell 5 , M. Caplin 6 ,<br />
R. Baum 7 , P.L. Kunz 8 , T. Hobday 9 , A. Hendifar 10 , K. Oberg 11 , M. Lopera Sierra 12 ,<br />
D. Kwekkeboom 13 , P. Ruszniewski 14 , E. Krenning 15<br />
1 <strong>Oncology</strong>, H. Lee M<strong>of</strong>fitt Cancer Center University <strong>of</strong> South Florida, Tampa, FL,<br />
USA, 2 <strong>Oncology</strong>, University <strong>of</strong> Kentucky, Lexington, KY, USA, 3 Nuclear medicine,<br />
University <strong>of</strong> Texas Health Science Center, Houston, TX, USA, 4 Medical <strong>Oncology</strong>,<br />
Dana-Farber Cancer Institute, Boston, MA, USA, 5 Division <strong>of</strong> Nuclear Medicine,<br />
University <strong>of</strong> Iowa, Iowa City, IA, USA, 6 Gastroenterology, Neuroendocrine tumour<br />
unit, Royal Free Hospital School <strong>of</strong> Medicine, London, UK, 7 Nuclear medicine,<br />
Zentralklinik Bad Berka GmbH, Bad Berka, Germany, 8 <strong>Oncology</strong>, Stanford<br />
University Medical Center, Stanford, CA, USA, 9 <strong>Oncology</strong>, Mayo Clinic, Rochester,<br />
NY, USA, 10 <strong>Oncology</strong>, Cedars-Sinai Medical Center, Los Angeles, CA, USA,<br />
11 Endocrine <strong>Oncology</strong>, University Hospital Uppsala Akademiska Sjukhuset,<br />
Uppsala, Sweden, 12 Advanced Accelerator Applications, New York, NY, USA,<br />
13 Nuclear Medicine Department, Erasmus University Medical Center, Rotterdam,<br />
Netherlands, 14 Gastroenterology, Hôpital Beaujon, Clichy, France, 15 <strong>Oncology</strong>,<br />
Erasmus University Medical Center, Rotterdam, Netherlands<br />
419O<br />
Genomic pr<strong>of</strong>ile in pulmonary neuroendocrine tumors<br />
(puNETs): the whole-exome sequencing (WES) as a strategic<br />
tool<br />
I.G. Sullivan 1 , M. Deloger 2 , L. Lacroix 3 , B. Job 4 , N. Dorvault 5 , J. Adam 6 ,<br />
A. Honore 3 , L. Gianoncelli 7 , G. Le Teuff 8 , V. de Montpreville 9 , B. Besse 1 ,<br />
J-C. Soria 1 , J-Y. Scoazec 3 , E. Baudin 10 , D. Planchard 1<br />
1 Département d’Oncologie Médicale, Gustave Roussy, Villejuif, France,<br />
2 Plateforme de bioinformatique, AMMICA, INSERM US23/CNRS UMS3655,<br />
Gustave Roussy, Villejuif, France, 3 Laboratoire de Recherche Translationnelle et<br />
Centre de Ressources Biologiques, Gustave Roussy, Villejuif, France, 4 Plateforme<br />
de bioinformatique, UMS AMMICA, Gustave Roussy, Villejuif, France, 5 INSERM -<br />
U981, Gustave Roussy, Villejuif, France, 6 Pathology, Gustave Roussy, Villejuif,<br />
France, 7 Department <strong>of</strong> Medical <strong>Oncology</strong>, Istituto Clinico Humanitas, Rozzano,<br />
Italy, 8 Service de biostatistique et d’épidémiologie, Gustave Roussy, Villejuif,<br />
France, 9 Pathology, Centre chirurgical Marie-Lannelongue, Le Plessis-Robinson,<br />
France, 10 Département de M. Nucléaire et de Cancérologie Endocrinienne,<br />
Gustave Roussy, Villejuif, France<br />
Background: Currently, there are limited therapeutic options for patients with<br />
advanced midgut neuroendocrine tumors progressing on first-line somatostatin analog<br />
therapy.<br />
Methods: NETTER-1 is the first phase III, randomized trial evaluating<br />
177 Lu-DOTA 0 -Tyr 3 -Octreotate (Lutathera®) in patients with progressive, somatostatin<br />
receptor positive midgut NETs. 230 patients were randomized to receive Lutathera 7.4<br />
GBq every 8 weeks (x4 administrations) versus Octreotide LAR 60 mg every 4 weeks.<br />
The primary endpoint was PFS (RECIST 1.1). Secondary objectives included ORR, OS,<br />
toxicity, and quality <strong>of</strong> life (QoL) based upon EORTC QLQ-C30 and QLQ-G.I.NET21<br />
questionnaires. Subgroup analysis <strong>of</strong> PFS was performed to assess impact <strong>of</strong> potential<br />
prognostic factors.<br />
Results: The centrally confirmed disease progressions or deaths were 23 in the<br />
Lutathera arm and 68 in the Octreotide LAR 60 mg arm. The median PFS was not<br />
reached for Lutathera and was 8.4 months with control, p < 0.0001, HR 0.21. At the<br />
time <strong>of</strong> the NDA/MAA submission, interim OS analysis (14 deaths in Lutathera group<br />
and 26 in control group; p = 0.0043) suggested an improvement in OS. Subgroup<br />
analyses for PFS confirmed consistent benefits <strong>of</strong> Lutathera irrespective <strong>of</strong> stratification<br />
and prognostic factors including tumor grade, age, gender, tumor marker levels, and<br />
levels <strong>of</strong> radiotracer uptake. Grade 3 or 4 neutropenia, thrombocytopenia and<br />
lymphopenia occurred in 1%, 2% and 9% <strong>of</strong> patients in Lutathera arm vs. none in<br />
controls. Health related QoL surveys indicated a moderate improvement in the global<br />
health status in the Lutathera treatment arm, demonstrating that the treatment benefit<br />
<strong>of</strong> Lutathera is not <strong>of</strong>fset by a negative impact on patient quality <strong>of</strong> life.<br />
Conclusions: The phase III NETTER-1 trial provides evidence for a clinically<br />
meaningful and statistically significant increase in PFS, and suggests an OS benefit in<br />
patients with advanced midgut NETs treated with Lutathera. Subgroup analysis<br />
demonstrates consistent benefit across prognostic factors. The Lutathera safety and<br />
QoL pr<strong>of</strong>ile was found to be favorable.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw369 | vi137
abstracts<br />
Clinical trial identification: NCT01578239<br />
Legal entity responsible for the study: Advanced Accelerator Applications<br />
Funding: Advanced Accelerator Applications<br />
Disclosure: J. Strosberg: Ipsen, Novartis, Genentech, Bayer.E. Wolin: Novartis,<br />
Advanced Accelerator Applications.B. Chasen, A. Hendifar, D. Kwekkeboom,<br />
D. Bushnell, M. Lopera Sierra: Advanced Accelerator Applications.M. Kulke: Novartis<br />
Lexicon Ipsen.M. Caplin: Novartis Pharma, Ipsen Pharma, Lexicon for advisory<br />
boards.K. Oberg: Ipsen Novartis.P. Ruszniewski: Ipsen Novartis Advanced Accelerator<br />
Applications.E. Krenning: Mallinckrodt SKF Advanced Accelerator Applications.All<br />
other authors have declared no conflicts <strong>of</strong> interest.<br />
421PD<br />
Impact <strong>of</strong> prior therapies on everolimus treatment in the<br />
subgroup <strong>of</strong> patients with advanced lung neuroendocrine<br />
tumors (NET) in the RADIANT-4 trial<br />
R. Buzzoni 1 , G.D. Fave 2 , J. Strosberg 3 ,M.Voi 4 , A. Ridolfi 5 ,<br />
L. Bubuteishvili-Pacaud 6 , F. Herbst 7 , E. Wolin 8 , N. Fazio 9<br />
1 Department <strong>of</strong> Medical <strong>Oncology</strong>, Fondazione IRCCS - Istituto Nazionale dei<br />
Tumori, Milan, Italy, 2 Medical <strong>Oncology</strong>, Azienda Ospedaliera St. Andrea - Roma,<br />
Rome, Italy, 3 Department <strong>of</strong> Medicine, M<strong>of</strong>fitt Cancer Center, Tampa, FL, USA,<br />
4 OGD OCD, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA,<br />
5 <strong>Oncology</strong>, Novartis Pharma S.A.S., Rueil-Malmaison, France, 6 Clinical Research,<br />
Novartis Pharma AG, Basel, Switzerland, 7 Medical affairs, Novartis Pharma AG,<br />
Basel, Switzerland, 8 Department <strong>of</strong> Medical <strong>Oncology</strong>, Montifiore Einstein Center<br />
for Cancer Care, Bronx, NY, USA, 9 Unit <strong>of</strong> Gastrointestinal Medical <strong>Oncology</strong> and<br />
Neuroendocrine Tumors, Istituto Europeo di Oncologia, Milan, Italy<br />
Background: Treatment paradigms in lung NET have conventionally relied on<br />
therapies such as chemotherapy, radiotherapy and somatostatin analogs (SSA)<br />
although evidence from randomized clinical trials remains limited. In the recent<br />
subgroup analysis <strong>of</strong> a large, phase 3, RADIANT-4 study everolimus (EVE), an mTOR<br />
inhibitor showed clinically meaningful 6-month improvement in PFS [EVE vs placebo<br />
(PBO): 9.2 (6.8-10.9) vs 3.6 (1.9-5.1) mos] and reduced tumor progression risk by 50%<br />
(HR, 0.50; 95% CI, 0.28-0.88) in patients with advanced, progressive, nonfunctional<br />
lung NET compared to PBO (Fazio et al. 2016 ENETS). This post-hoc analysis<br />
evaluates the impact <strong>of</strong> prior-therapies on EVE treatment in lung NET patients from<br />
the RADIANT-4 study.<br />
Methods: Patients with advanced non-functional lung or GI NET were randomized<br />
(2:1) to EVE 10 mg/d or PBO, both with best supportive care. Subgroups <strong>of</strong> patients<br />
who received SSA, chemo-, radio- or no prior therapy within the lung NET subgroup<br />
were analyzed.<br />
Results: Of the 90 patients with lung NET enrolled in the RADIANT-4 study; 63<br />
patients were randomized to the EVE arm and 27 patients to the PBO arm. Median<br />
age, 65 years; males: 52%; most pts (99%) had well-differentiated disease; Caucasian:<br />
86%; WHO PS 0/1/2: 71%/28%/1%. Prior therapies (EVE vs PBO) included: SSA<br />
(mostly for tumor growth control; 43% vs 41%), radiotherapy including peptide<br />
receptor radionuclide therapy (PRRT; 40% vs 48%), chemotherapy (40% vs 48%) and<br />
no prior therapy (14% vs 11%). Median PFS in the subgroups <strong>of</strong> patients receiving each<br />
<strong>of</strong> the prior-therapies is listed in the Table. The most common drug-related adverse<br />
events (AEs; ≥ 30% incidence in either arm for the whole lung subgroup) were<br />
stomatitis, rash and fatigue.<br />
Prior-therapies<br />
Table: 421PD<br />
EVE Median PFS,<br />
mos (95% CI)<br />
PBO Median PFS,<br />
mos (95% CI)<br />
Chemotherapy 8.5 (5.6,11.7) 2.9 (1.8,3.7)<br />
Radiotherapy* 9.2 (5.7,NE) 3.0 (1.9,5.1)<br />
SSA therapy 9.5 (6.0,11.7) 3.7 (1.0,11.2)<br />
No prior therapy 9.7 (0.9,NE) 3.6 (1.7,NE)<br />
*Includes PRRT<br />
Conclusions: EVE showed PFS benefit in patients with advanced lung NET regardless<br />
<strong>of</strong> prior-therapies, consistently with the overall RADIANT-4 study. No prior-therapy<br />
specific safety signal was seen in any <strong>of</strong> the subgroups.<br />
Clinical trial identification: NCT01524783<br />
Legal entity responsible for the study: Novartis Pharmaceuticals<br />
Funding: Novartis Pharmaceuticals<br />
Disclosure: R. Buzzoni: Grants and non-financial support from Novartis, grants from<br />
Otsuka, grants and non-financial support from Italfarmaco, non-financial support<br />
from Ipsen, during the conduct <strong>of</strong> the study.J. Strosberg: Grants and personal fees from<br />
Novartis, grants from Pfizer, personal fees from Bayer, Genentech, during the conduct<br />
<strong>of</strong> the study; personal fees from Ipsen, Lexicon, Novartis, outside the submitted work.<br />
M. Voi, A. Ridolfi, L. Bubuteishvili-Pacaud: Employment- Novartis.F. Herbst:<br />
Employment- Novartis, Stock options- Novartis.E. Wolin: Advisory Board- Advanced<br />
accelerator applications.N. Fazio: Grants, personal fees and non-financial support from<br />
Novartis, personal fees and non-financial support from Ipsen, during the conduct <strong>of</strong><br />
the study; personal fees from Italfarmaco, Ipsen, Lexicon, outside the submitted work .<br />
All other authors have declared no conflicts <strong>of</strong> interest.<br />
422PD<br />
Integrated placebo-controlled safety analysis from clinical<br />
studies <strong>of</strong> telotristat ethyl for the treatment <strong>of</strong> carcinoid<br />
syndrome<br />
M. Kulke 1 , D. Hörsch 2 , M. Caplin 3 , L. Anthony 4 , E. Bergsland 5 , K. Oberg 6 ,<br />
S. Welin 7 , R. Warner 8 , C. Lombard Bohas 9 , P.L. Kunz 10 , E. Grande 11 , J.W. Valle 12 ,<br />
P. Lapuerta 13 , P. Banks 13 , S. Jackson 14 , W. Jiang 13 , T. Biran 14 ,M.Pavel 15<br />
1 Medical <strong>Oncology</strong>, Dana-Farber Cancer Institute, Boston, MA, USA,<br />
2 Gastroenterology and Endocrinology, Center for Neuroendocrine Tumors Bad<br />
Berka, Zentralklinik Bad Berka GmbH, Bad Berka, Germany, 3 Gastroenterology<br />
and neuroendocrine tumours, Royal Free Hospital School <strong>of</strong> Medicine, London,<br />
UK, 4 Medical <strong>Oncology</strong>, University <strong>of</strong> Kentucky, Lexington, KY, USA,<br />
5 Hematology/<strong>Oncology</strong>, UCSF Helen Diller Family Comprehensive Cancer Center,<br />
San Francisco, CA, USA, 6 Dep <strong>of</strong> Medical Sciences, Uppsala University Hospital,<br />
Uppsala, Sweden, 7 Dep <strong>of</strong> Endocrine <strong>Oncology</strong>, Uppsala University Hospital,<br />
Uppsala, Sweden, 8 Gastroenterology, Mount SInai Medical College, New York,<br />
NY, USA, 9 Medical <strong>Oncology</strong>, Hopital Edouard Herriot Pav. E bis, Lyon, France,<br />
10 Medicine-<strong>Oncology</strong>, Stanford University School <strong>of</strong> Medicine, Palo Alto, CA,<br />
USA, 11 Medical <strong>Oncology</strong>, Hospital Universitario Ramon y Cajal, Madrid, Spain,<br />
12 Medical <strong>Oncology</strong>, University <strong>of</strong> Manchester / The Christie NHS Foundation<br />
Trust, Manchester, UK, 13 Medical affairs, Lexicon Pharmaceuticals, The<br />
Woodlands, TX, USA, 14 Clinical Operations, Lexicon Pharmaceuticals, Inc., The<br />
Woodlands, TX, USA, 15 Endocrinology, Charité University Medicine, Berlin,<br />
Germany<br />
Background: Telotristat etiprate (TE) is an oral tryptophan hydroxylase inhibitor in<br />
development for the treatment <strong>of</strong> carcinoid syndrome (CS). During the<br />
placebo-controlled, 12-week double-blind treatment (DBT) periods <strong>of</strong> 2 Phase 3<br />
studies, TELESTAR and TELECAST, TE significantly reduced bowel movement (BM)<br />
frequency compared to placebo.<br />
Objective: To examine the safety <strong>of</strong> TE vs placebo, a combined analysis <strong>of</strong> safety data<br />
from the DBT periods <strong>of</strong> TELESTAR and TELECAST was performed.<br />
Methods: 211 patients (pts) with CS were randomly assigned (1:1:1) to placebo or TE<br />
250 mg or 500 mg, each given 3x/day (tid). At entry, pts on stable-dose long-acting<br />
somatostatin analog (SSA) therapy had ≥4 (TELESTAR) or
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Disclosure: M. Kulke: Conflict <strong>of</strong> interest: Consulting for Lexicon Pharmaceuticals; No<br />
other relationships/conditions/circumstances that present a potential conflict <strong>of</strong><br />
interest. Dr Kulke reports other from Lexicon Pharmaceuticals, during the conduct <strong>of</strong><br />
the study.D. Hörsch: Personal fees and other from Lexicon Pharmaceuticals, Inc,<br />
grants, personal fees and other from Novartis Pharma, personal fees and other from<br />
Ipsen Pharma, personal fees and other from Pfizer Pharma, outside the submitted<br />
work.M. Caplin: Personal fees from Lexicon, personal fees from Novartis, personal fees<br />
from IPSEN, outside the submitted work.L. Anthony: Grants and personal fees from<br />
Lexicon Pharmaceuticals, Inc., during the conduct <strong>of</strong> the study.E. Bergsland: Other<br />
from Lexicon, during the conduct <strong>of</strong> the study; other from Novartis, other from Ipsen,<br />
outside the submitted work.R. Warner: Personal fees from Lexicon, personal fees from<br />
Novartis, outside the submitted work.C. Lombard Bohas: Other from Lexicon, during<br />
the conduct <strong>of</strong> the study; other from Novartis, from IPSNE, outside the submitted<br />
work.P.L. Kunz: Grants and personal fees from Lexicon Pharmaceuticals, grants and<br />
personal fees from Novartis, outside the submitted work.E. Grande: Grants from<br />
Pfizer, grants from Merck-Serono, personal fees from Lexicon, during the conduct <strong>of</strong><br />
the study.J.W. Valle: Grants and personal fees from Ipsen; grants and personal fees<br />
from Novartis; and personal fees from Pfizer, outside the submitted work.P. Lapuerta:<br />
Employee <strong>of</strong> Lexicon Pharmaceuticals during the conduct <strong>of</strong> the study. I am an<br />
employee <strong>of</strong> Lexicon Pharmaceuticals and have been compensated with salary, stock,<br />
and stock options.P. Banks: Other from Lexicon Pharmaceuticals, outside the<br />
submitted work.S. Jackson, W. Jiang: Employee <strong>of</strong> Lexicon Pharmaceuticals, Inc.T.<br />
Biran: Employee <strong>of</strong> Lexicon Pharmaceuticals and have been compensated with salary,<br />
stock, and stock options.M. Pavel: Personal fees from Lexicon, personal fees from<br />
Novartis, personal fees from Ipsen, personal fees from Pfizer, outside the submitted<br />
work.All other authors have declared no conflicts <strong>of</strong> interest.<br />
423PD<br />
Phase I, open-label, dose-escalation study <strong>of</strong> SNX-5422 plus<br />
everolimus in neuroendocrine tumors (NETs)<br />
M.E. Gutierrez 1 , G. Giaccone 2 , S.V. Liu 2 , A. Rajan 3 , U. Guha 3 , T.R. Halfdanarson 4 ,<br />
K.K. Curtis 5 , P.L. Kunz 6 , N. Gabrail 7 , J.M. Hinson 8 , E.O. Orlemans 9<br />
1 Hematology & <strong>Oncology</strong>, The John Theurer Cancer Center, Hackensack, NJ,<br />
USA, 2 Hematology & <strong>Oncology</strong>, Lombardi Cancer Center Georgetown University,<br />
Washington, DC, USA, 3 Thoracic and Gastrointestinal <strong>Oncology</strong>, Center for<br />
Cancer Research-National Cancer Institute, Bethesda, MD, USA, 4 Medicine, Mayo<br />
Clinic, Rochester, MN, USA, 5 Internal Medicine, Mayo Clinic, Scottsdale, AZ, USA,<br />
6 Medicine-<strong>Oncology</strong>, Stanford University School <strong>of</strong> Medicine, Palo Alto, CA, USA,<br />
7 Hematology, Gabrail Cancer Center, Canton, OH, USA, 8 Clinical Research,<br />
Unicorn Pharma Consulting, Nashville, TN, USA, 9 Clinical Research, Esanex, Inc.,<br />
Indianapolis, IN, USA<br />
Background: SNX-5422 is an orally bioavailable pro-drug <strong>of</strong> SNX-2112, a highly<br />
potent and selective heat shock protein 90 (Hsp90) inhibitor. In preclinical studies, the<br />
effects <strong>of</strong> SNX-2112 and EVR appear at least additive. Previously, at doses <strong>of</strong> 42-100<br />
mg/m 2 <strong>of</strong> SNX-5422 taken every other day (qod), 2 <strong>of</strong> 3 patients (pts) with refractory<br />
NETs achieved stable disease for >8 cycles. EVR, a mammalian target <strong>of</strong> rapamycin<br />
(mTOR) inhibitor, now has FDA approval for pancreatic NETs and nonfunctional<br />
gastrointestinal and pulmonary NETs.<br />
Methods: Eligible pts had unresectable gastro-entero-pancreatic or pulmonary NETs<br />
and 25<br />
cycles), 8 stable disease (57%), and 4 (29%) progressive disease as best response. Of 8<br />
pts with stable disease, 2 ongoing (1 >23 cycles), 3 study withdrawal (1 personal<br />
reasons [minor response], 2 for tolerability) and 3 progressed.<br />
Conclusions: The addition <strong>of</strong> SNX-5422 75 mg/m 2 to EVR in pts with advanced NETs<br />
warrants further study.<br />
Clinical trial identification: ClinicalTrials.gov identifier: NCT02063958<br />
Legal entity responsible for the study: Esanex, Inc.<br />
Funding: Esanex, Inc.<br />
Disclosure: S.V. Liu: Advisory boards for Genentech/Roche, Boehringer Ingelheim,<br />
Ariad, Caris Life Sciences and Biodesix.P.L. Kunz: Research funding to institution:<br />
Advanced Accelerator Applications, Esanex, Genentech, Lexicon, Merck, Oxigene.<br />
Advisor/Consultant: Ipsen, Novartis, Lexicon.J.M. Hinson: Paid consultant to Esanex,<br />
Inc.E.O. Orlemans: Employee and stockholder Esanex, Inx.All other authors have<br />
declared no conflicts <strong>of</strong> interest.<br />
424PD<br />
Prevalence <strong>of</strong> gastroenteropancreatic and lung<br />
neuroendocrine tumours in the European Union<br />
A. Bergamasco 1 , J. Dinet 2 , A. Berthon 2 , S. Gabriel 3 , G. Nayroles 2 , Y. Moride 4<br />
1 Pharmacoepidemiology, Yolarx Consultants, Paris, France, 2 HEOR, Ipsen<br />
Pharma, Boulogne-Billancourt, France, 3 Global Market Access and Pricing, Ipsen<br />
Pharma, Boulogne-Billancourt, France, 4 Faculty <strong>of</strong> Pharmacy, Université de<br />
Montreal, Montreal, QC, Canada<br />
Background: Neuroendocrine tumours (NETs) consist <strong>of</strong> a heterogeneous group <strong>of</strong><br />
neoplasms arising from a variety <strong>of</strong> neuroendocrine cell types. According to criteria <strong>of</strong><br />
the European legislation, some may be orphan indications. However, epidemiologic<br />
data on specific sub-types <strong>of</strong> NETs are scarce. This study aimed at assessing the<br />
prevalence <strong>of</strong> gastroenteropancreatic (GEP) and lung NETs in the European Union.<br />
Methods: Systematic literature reviews were conducted using Medline and Embase<br />
bibliographical databases. Search strategies combined the following concepts, using<br />
MeSH and Emtree terms: Disease <strong>of</strong> interest, epidemiologic? data (incidence or<br />
prevalence) and countries <strong>of</strong> interest. The search period covered 1st Jan 2010 to 15 Feb<br />
2016, inclusively. Pragmatic searches <strong>of</strong> web sources and conference proceedings were<br />
also conducted. Using data identified in the search, prevalence rates were estimated<br />
using the relationship between prevalence (P), incidence (I), and disease duration (D),<br />
where applicable. Size <strong>of</strong> the EU population as <strong>of</strong> 1 st January 2015 was used to estimate<br />
number <strong>of</strong> patients with GEP and lung NETs. As incidences rates and survival <strong>of</strong><br />
patients vary across countries and settings, sensitivity analyses were also performed.<br />
Results: A total <strong>of</strong> 87 and 23 sources were identified through the literature search and<br />
pragmatic search, respectively for GEP-NETs and lung NETs. Following in-depth<br />
review, 8 and 6 data sources were retained for epidemiologic data extraction on GEP<br />
and lung NETs, respectively. Considering, the highest estimated prevalence rates <strong>of</strong><br />
GEP-NETs and lung NETs (3.8 and 1.9 per 10,000, respectively), number <strong>of</strong> prevalent<br />
cases in Europe was estimated to be 195,314 and 97,657. In addition, results from the<br />
sensitivity analyses demonstrated that the prevalence rates <strong>of</strong> these conditions<br />
remained well below the threshold <strong>of</strong> 5 per 10,000 in all scenarios considered except<br />
the worst case including highest estimates <strong>of</strong> incidence rates and disease duration.<br />
Conclusions: According to these results, GEP-NETs and lung NETs could be<br />
considered separately as orphan indications according to the European legislation.<br />
Legal entity responsible for the study: Yolarx Consultants<br />
Funding: Ipsen Pharma<br />
Disclosure: A. Bergamasco, Y. Moride: Affiliated with Yolarx Consultants, which<br />
received a grant from IPSEN Pharma to conduct this research projectJ. Dinet,<br />
A. Berthon, S. Gabriel, G. Nayroles: Employee <strong>of</strong> Ispen Pharma<br />
425PD<br />
abstracts<br />
Multicentre evaluation <strong>of</strong> the role <strong>of</strong> Gallium DOTA-PET<br />
(GaPET) imaging in well differentiated bronchial carcinoids<br />
(BC): Impact on patients’ (pts) management<br />
A. Lamarca 1 , D.M. Pritchard 2 , T. Westwood 3 , G. Papaxoinis 1 , S. Vinjamuri 4 ,J.<br />
W. Valle 5 , P. Manoharan 3 , W. Mansoor 1<br />
1 Department <strong>of</strong> Medical <strong>Oncology</strong>, ENETS Centre <strong>of</strong> Excellence, The Christie NHS<br />
Foundation Trust, Manchester, UK, 2 Liverpool ENETS Centre <strong>of</strong> Excellence;<br />
Institute <strong>of</strong> Translational Medicine, University <strong>of</strong> Liverpool, Royal Liverpool and<br />
Broadgreen University Hospitals NHS Trust, Liverpool, UK, 3 Department <strong>of</strong><br />
Radiology and Nuclear Medicine, ENETS Centre <strong>of</strong> Excellence,, The Christie NHS<br />
Foundation Trust, Manchester, UK, 4 Liverpool ENETS Centre <strong>of</strong> Excellence, Royal<br />
Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK,<br />
5 Department <strong>of</strong> Medical <strong>Oncology</strong>, ENETS Centre <strong>of</strong> Excellence; Manchester<br />
Academic Health Sciences Centre, Institute <strong>of</strong> Cancer Sciences, University <strong>of</strong><br />
Manchester, The Christie NHS Foundation Trust, Manchester, UK<br />
Background: New nuclear medicine imaging techniques have improved diagnosis,<br />
staging and treatment planning for BC. GaPET is preferable to standard somatostatin<br />
receptor scintigraphy where available (ENETS guidelines); however, its role in the<br />
management <strong>of</strong> BC remains unclear.<br />
Methods: All consecutive pts diagnosed with BC from two ENETS Centres <strong>of</strong><br />
Excellence were identified retrospectively; pts with high grade tumours or lacking<br />
biopsy confirmation were excluded. Primary objective: to assess the impact <strong>of</strong> GaPET<br />
on clinical management in pts with BC.<br />
Results: Of 166 pts screened, 46 were eligible: 52% female, median age 57 years (range<br />
21-86); type <strong>of</strong> BC: DIPNECH (4%), typical (44%), atypical (35%), not reported (17%);<br />
median Ki67 and mitotic count were 3 and 1, respectively. Stage: localised (63%),<br />
locally advanced (13%) and metastatic (17%); 27 pts (59%) had curative resection; 18<br />
(39%) received palliative treatment (somatostatin analogue (12; 67%) chemotherapy (4;<br />
23%), PRRT (1; 5%), debulking surgery (1; 5%)). A total <strong>of</strong> 47 GaPETs were performed<br />
with the following rationale: BC confirmation (4; 9%), primary tumour identification<br />
(2; 4%), post-surgical assessment (19; 40%), staging (patients with known BC present<br />
at time <strong>of</strong> GaPET) (19; 40%) and consideration <strong>of</strong> Peptide Receptor Radionuclide<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw369 | vi139
abstracts<br />
Therapy (PRRT) (3; 7%). Twenty-seven (57%) scans showed evidence <strong>of</strong><br />
non-physiological uptake: median SUVmax 7.2 (range 1.42-53). Uptake rate in<br />
primary tumour, liver, lung, bone and lymph node metastases was high (80-100%).<br />
GaPET provided additional information in 37% (95%CI 22-51) <strong>of</strong> pts and impacted on<br />
management in 26% (95%-CI 12-41); 9 pts (21%) were identified to have occult sites <strong>of</strong><br />
metastases. Out <strong>of</strong> the 19 pts with post-surgical GaPET, 3 (16%) were identified distant<br />
metastases. There were no differences in the rate <strong>of</strong> practice changing GaPET results by<br />
type <strong>of</strong> BC (p-value 0.5). No factors predictive <strong>of</strong> changes in management were<br />
identified (logistic regression).<br />
Conclusions: Our results support the use <strong>of</strong> GaPET in patients with BC for planning<br />
treatment, including post-surgical assessment due to potential for identifying occult<br />
metastases.<br />
Legal entity responsible for the study: The Christie NHS Foundation Trust and Royal<br />
Liverpool and Broadgreen University Hospitals NHS Trust<br />
Funding: Dr Angela Lamarca was part-funded by the Pancreatic Cancer Research<br />
Fund and Spanish Society <strong>of</strong> Medical <strong>Oncology</strong> Fellowship Programme<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
426PD<br />
A population based analysis <strong>of</strong> outcome <strong>of</strong> chemotherapy for<br />
metastatic pulmonary large cell neuroendocrine carcinomas:<br />
does the regimen matter?<br />
J.L. Derks 1 , R.J. van Suylen 2 , E. Thunnissen 3 , M.A. Den Bakker 4 , H. Groen 5 ,<br />
E.F. Smit 6 , R.A. Damhuis 7 , E-J. Speel 8 , A-M.C. Dingemans 1<br />
1 Department <strong>of</strong> Resipratory Diseases, Maastricht University Medical Center<br />
(MUMC), Maastricht, Netherlands, 2 Pathology-DNA, Jeroen Bosch Hospital,<br />
’s-Hertogenbosch, Netherlands, 3 Department <strong>of</strong> Pathology, VU University Medical<br />
Center,, Amsterdam, Netherlands, 4 Department <strong>of</strong> Pathology, Maasstad Hospital,<br />
Rotterdam, Netherlands, 5 Department <strong>of</strong> Pulmonary Diseases, University Hospital<br />
Groningen (UMCG), Groningen, Netherlands, 6 Department <strong>of</strong> Thoracic <strong>Oncology</strong>,<br />
Netherlands Cancer Institute, Amsterdam, Netherlands, 7 Department <strong>of</strong> Research,<br />
Comprehensive Cancer Association, Utrecht, Netherlands, 8 Department <strong>of</strong><br />
Pathology, Maastricht University Medical Center (MUMC), Maastricht, Netherlands<br />
Background: It is unclear what constitutes optimal chemotherapy for metastatic<br />
pulmonary large cell neuroendocrine carcinoma (LCNEC). Expert opinion based<br />
guidelines favor platinum-etoposide, i.e. small cell lung carcinoma (SCLC) type<br />
chemotherapy treatment. However, data are lacking due to low incidence <strong>of</strong> LCNEC<br />
and changes in diagnosis after pathology revision. In a population based, pathology<br />
revised LCNEC series we compared overall survival (OS) <strong>of</strong> non-small cell lung<br />
carcinoma (NSCLC) and SCLC type chemotherapy treatment.<br />
Methods: Data <strong>of</strong> the Dutch Pathology Registry (PALGA) and Netherlands Cancer<br />
Registry were combined and searched for patients with stage IV definite LCNEC and<br />
possible LCNEC treated with chemotherapy, diagnosed between 2003-2012. In 207<br />
patients original tumor specimen slides were available for central revision blinded for<br />
clinical information. Data on clinical characteristics, chemotherapy and OS were<br />
retrieved. First-line platinum chemotherapy was clustered: 1) NSCLC type treatment<br />
including gemcitabine, docetaxel, paclitaxel and vinorelbine, 2) pemetrexed<br />
(Pem-NSCLC), and 3) SCLC type treatment including etoposide. Multivariate<br />
regression analysis included variables significant at univariate analysis and the variables<br />
gender and age.<br />
Results: 128 patients had panel-consensus definite LCNEC. 62% (N = 79) received ≥4<br />
cycles and 26% (N = 33) ≤2 cycles <strong>of</strong> chemotherapy. NSCLC type chemotherapy was<br />
administered in 46% (N = 60), Pem-NSCLC in 16% (N = 20), and SCLC type in 38%<br />
(N = 48) patients. NSCLC type chemotherapy treated patients had a median OS <strong>of</strong> 8.5<br />
[95% confidence interval (CI) 7.0-9.9] months, significantly higher than treatment<br />
with Pem-NSCLC; median 5.9 [95% CI 5.0-6.9] months (Hazard Ratio (HR) = 2.51<br />
[95% CI 1.39-4.52], p = 0.002) and SCLC; median 6.7 [95% CI 5.0-8.5] months<br />
(HR = 1.66 [1.08-2.56], p = 0.02).<br />
Conclusions: This population based analysis on outcome <strong>of</strong> chemotherapy in patients<br />
with panel-consensus LCNEC shows that NSCLC type chemotherapy treatment leads<br />
to prolonged OS when compared to SCLC and Pem-NSCLC type chemotherapy<br />
treatment.<br />
Legal entity responsible for the study: Maastricht University Medical Centre<br />
Funding: This study was supported by a grant from the Dutch Cancer Society (KWF:<br />
number 7110)<br />
Disclosure: H. Groen: Other from Lilly, GSK, Merck, Pfizer, Roche, BMS, outside the<br />
submitted work; .E-J. Speel: Other from Pfizer, other from Roche, other from Amgen,<br />
outside the submitted work; .A-M.C. Dingemans: Personal fees from Roche, BMS,<br />
Boehringer Ingelheim, Astra Zeneca, Eli Lilly, MSD, Pfizer, and Amgen, outside the<br />
submitted work;.All other authors have declared no conflicts <strong>of</strong> interest.<br />
427PD<br />
Pediatric, adolescent and young adult (PAYA) thyroid<br />
carcinoma harbors frequent and diverse targetable genomic<br />
alterations including kinase fusions<br />
P. Vanden Borre 1 , A.B. Schrock 2 , P. Anderson 3 , A.M. Heilmann 1 , O. Holmes 1 ,<br />
K. Wang 4 , S. Khan 5 , J.C. Morris 6 , S-H.I. Ou 7 , S. Waguespack 8 , P. Stephens 9 ,R.<br />
L. Erlich 1 , V. Miller 10 , J.S. Ross 11 , S. Ali 11<br />
1 Biomedical Informatics, Foundation Medicine, Inc., Cambridge, MA, USA,<br />
2 Clinical Development, Foundation Medicine, Inc., Cambridge, MA, USA,<br />
3 Pediatric Hematology <strong>Oncology</strong> and Blood and Marrow Transplantation,<br />
Cleveland Clinic Foundation, Cleveland, OH, USA, 4 Computational Biology,<br />
Foundation Medicine, Inc., Cambridge, MA, USA, 5 Department <strong>of</strong> Internal<br />
Medicine, University <strong>of</strong> Texas Southwestern Medical Center at Dallas, Dallas, TX,<br />
USA, 6 Division <strong>of</strong> Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo<br />
Clinic, Rochester, MN, USA, 7 Hematology/<strong>Oncology</strong>, Chao Family Comprehensive<br />
Cancer Center, Irvine, CA, USA, 8 The University <strong>of</strong> Texas MD Anderson Cancer<br />
Center, Department <strong>of</strong> Endocrine Neoplasia and Hormonal Disorders, Houston,<br />
TX, USA, 9 Research and Product Development, Foundation Medicine, Inc.,<br />
Cambridge, MA, USA, 10 Medical Affairs, Foundation Medicine, Inc., Cambridge,<br />
MA, USA, 11 Pathology, Foundation Medicine, Inc., Cambridge, MA, USA<br />
Background: Thyroid carcinoma in children and young adults is rare but carries the<br />
potential for morbidity and mortality. A series <strong>of</strong> advanced pediatric, adolescent and<br />
young adult (PAYA) thyroid carcinoma cases were assayed in the course <strong>of</strong> clinical care<br />
to identify genomic alterations (GAs) linked to potential benefit from targeted therapy.<br />
Methods: Hybrid-capture based comprehensive genomic pr<strong>of</strong>iling (CGP) was<br />
performed prospectively on 58 consecutively submitted PAYA thyroid carcinomas.<br />
Results: All patients were 39 years old or younger including 41 patients with papillary<br />
thyroid carcinoma (PTC) (median age: 26 years, range: 7-39 years), 3 with anaplastic<br />
thyroid carcinoma (ATC) (median age: 33 years, range 25-33 years), and 14 with<br />
medullary thyroid carcinoma (MTC) (median age: 33 years, range 15-39). 64% (37/58)<br />
<strong>of</strong> the patients were female. GAs were detected in 93% (54/58) <strong>of</strong> cases, with a mean <strong>of</strong><br />
1.4 GAs per case. Clinically relevant GAs, defined as GAs associated with at least one<br />
actively recruiting clinical trial or an FDA-approved therapy, were identified in 91%<br />
(53/58) <strong>of</strong> cases. BRAF V600E was present in 46% (19/41) <strong>of</strong> PTCs and in 1/3 ATCs.<br />
Oncogenic fusions were identified in 37% (15/41) and 33% (1/3) <strong>of</strong> PTC and ATC<br />
cases, respectively. In addition to fusions previously observed in PAYA thyroid<br />
carcinoma involving RET, NTRK1, and NTRK3, 3 ALK fusions (EML4-ALK,<br />
STRN-ALK, and GTF2IRD1-ALK) were detected in pediatric patients with PTC. In<br />
PAYA patients with MTC, RET mutation occurred in 93% (13/14) <strong>of</strong> cases, including<br />
the predominant RET M918T mutation and 3 insertion/deletions in exons 6 and 11.<br />
Two patients with MTC harboring in-frame deletions in RET exons 6 and 11<br />
experienced clinical benefit from vandetanib treatment.<br />
Conclusions: CGP identified diverse targetable genomic alterations in PAYA patients<br />
with thyroid carcinoma. 83% <strong>of</strong> PTC cases harbored either activating kinase mutations<br />
or rearrangements, including three cases with ALK fusions. Genomic alteration data<br />
and our clinical observations suggest that young patients with advanced thyroid<br />
carcinoma can <strong>of</strong>ten benefit from CGP to identify matched targeted therapies.<br />
Legal entity responsible for the study: Foundation Medicine<br />
Funding: Foundation Medicine<br />
Disclosure: P. Vanden Borre, A.B. Schrock, A.M. Heilmann, O. Holmes, K. Wang,<br />
P. Stephens, R.L. Erlich, V. Miller, J.S. Ross, S. Ali: Employee and has stock ownership<br />
in Foundation Medicine.All other authors have declared no conflicts <strong>of</strong> interest.<br />
428PD<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Damaging germline variants in TSC2 are frequently found<br />
among nonsyndromic patients with gastroenteropancreatic<br />
(GEP) neuroendocrine tumors (NETs)<br />
R.D.M. Linck 1 , P.F. Asprino 2 , F.P. Freitas 2 , F.C. Koyama 2 , P.A.F. Galante 2 ,<br />
R. Riechelmann 3 , L.F.L. Reis 2 , F.P. Costa 1 , P.M. H<strong>of</strong>f 1 , A.A. Camargo 2 ,<br />
J. Sabbaga 1<br />
1 Centro de Oncologia, Hospital Sirio Libanes, Sao Paulo, Brazil, 2 Centro de<br />
Oncologia Molecular, Hospital Sirio Libanes, Sao Paulo, Brazil, 3 Oncologia Clinica,<br />
ICESP - Instituto do Câncer do Estado de São Paulo, Sao Paulo, Brazil<br />
Background: GEP NETs are mostly sporadic neoplasms with few cases related to<br />
familial syndromes, like Multiple Endocrine Neoplasia and Von Hippel-Lindau<br />
Disease. However, epidemiological studies have demonstrated a hazard ratio <strong>of</strong> 3.6 for<br />
developing GEP NETs in healthy people with an affected first-degree relative. Germline<br />
mutation in TSC2 gene causes Tuberous Sclerosis (TS), an autosomal dominant disease<br />
with high penetrance and characterized by benign tumours throughout the body. TS is<br />
known to predispose to GEP NETs, but until now, this association has been considered<br />
weak and only based in some few case reports.<br />
Methods: Targeted Next-Generation Sequencing <strong>of</strong> the coding exons <strong>of</strong> 8 genes<br />
possibly associated with NETs (TSC2, TSC1, MEN1, VHL, NF1, RET, TP53 and<br />
FLCN) was carried out in DNA from peripheral blood <strong>of</strong> patients (pts) with GEP<br />
NETs. The functional impact <strong>of</strong> missense variants was analysed using SIFT and<br />
Polyphen2. Only variants with confirmed validation by Sanger sequencing, with<br />
vi140 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
damaging functional impact and with minor allele frequency < 0.05% were considered<br />
for the results.<br />
Results: Ninety-three pts, all phenotypically normal and with no relevant family<br />
history, were recruited. The median age at diagnosis was 52 (27-79) and 54.8% were<br />
males. The majority had grades 1 and 2 (38.7% and 41.9%, respectively) but there were<br />
18 pts with grade 3 NETs (19.4%). Pancreas was the primary site in 41 cases (44.1%)<br />
and small bowel in 33 (35.5%). Nineteen NETs (20.4%) arose in other sites. Damaging<br />
germline variants were confirmed in 10 pts (10.8%) with 7 occurring in TSC2 gene<br />
(7.5%). Other variants were in TP53 (2) and RET (1). There were no duplicate variants<br />
and 6 <strong>of</strong> them correspond to rare variants already described in the literature. Among<br />
TSC2 damaging variants, 3 occurred in conserved protein domains. There were no<br />
clear differences on age <strong>of</strong> diagnosis, primary site or tumor grade comparing pts with<br />
or without damaging variants.<br />
Conclusions: Germline TSC2 damaging variants are significantly associated to GEP<br />
NETs in phenotypically normal pts, increasing the genetic predisposition to the<br />
neoplasia and probably reflecting a new feature <strong>of</strong> TS.<br />
Legal entity responsible for the study: Hospital Sirio Libanes, Sao Paulo, SP, Br<br />
Funding: Fundacao de Amparo a Pesquisa do Estado de Sao Paulo, Sao Paulo, SP, BR<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
429P<br />
The clinicopathologic features and treatment <strong>of</strong> 607 hindgut<br />
neuroendocrine tumor (NET) patients at a single institution<br />
S.T. Kim, W. Kang, Y.S. Park, J. Park, M. Heo, H. Lee<br />
Division <strong>of</strong> Hematology-<strong>Oncology</strong>, Samsung Medical Center Sungkyunkwan<br />
University School <strong>of</strong> Medicine, Seoul, Republic <strong>of</strong> Korea<br />
Background: The clinicopathologic features <strong>of</strong> hindgut neuroendocrine tumor (NET)<br />
as well as the treatment outcomes are not well known. There are currently no published<br />
data on treatment outcomes for patients with metastatic hindgut NET. The aim <strong>of</strong> this<br />
study was to conduct a comprehensive analysis <strong>of</strong> clinicopathologic features, treatments<br />
and survival in hindgut NET patients.<br />
Methods: Among patients who were pathologically diagnosed with hindgut NET at<br />
Samsung Medical Center between March 2001 and February 2015, 607 were analyzed<br />
in this study. Hindgut NETs were defined as NETs that originated from the transverse<br />
and distal colon, rectum, and anus.<br />
Results: Primary sites included 81 colon (13.3%) and 526 rectum (86.7%). According<br />
to the WHO classification, 578 patients (95.2%) had grade 1 NETs, 17 (2.8%) grade 2<br />
NETs, and 12 (2.0%) had neuroendocrine carcinoma (NEC). Forty-two patients (6.9%)<br />
had extensive disease, while the majority (93.1%, 565 patients) only exhibited localized<br />
disease. The five- and ten-year survival rates <strong>of</strong> 565 localized NET patients were 98.1%<br />
and 95.3%, respectively. The median OS in 42 patients with extensive disease was 24.8<br />
months (95% CI, 10.7-38.8). Among 565 patients with localized disease, the majority<br />
(484 patients, 85.7%) were treated with endoscopic procedure by gastroenterologists.<br />
For 42 patients with extensive disease, 17 patients were managed by supportive care, 3<br />
by concurrent chemoradiotherapy (CCRT), and 22 by systemic therapy. Among these<br />
22 patients, 12 patients received only first-line therapy, 8 had second-line, and only 2<br />
patients had third-line therapy. As first-line chemotherapy, the most commonly used<br />
regimens were etoposide plus cisplatin (N = 7) and long acting octreotide (N = 7).<br />
During treatment courses, the most commonly used regimen was long-acting<br />
octreotide. Multivariate analysis in all 607 hindgut NETs patients suggested that the<br />
extent and the primary site <strong>of</strong> disease were significant independent prognostic factors<br />
for long term survival.<br />
Conclusions: This analysis provides useful information about the clinicopathologic<br />
features, treatments and survival outcomes for hindgut NET patients.<br />
Legal entity responsible for the study: N/A<br />
Funding: None<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
430P<br />
Neuroendocrine carcinomas <strong>of</strong> the colorectal origin - Polish<br />
experience<br />
A.D. Kolasińska-C´ wikła 1 , A. Lewczuk 2 , A. Cichocki 1 , K. Maciejkiewicz 1 ,<br />
E. Nowicka 1 , K. Roszkowska-Purska 1 , Z. Jodkiewicz 1 , M. Tenderenda 1 ,<br />
J.B. C´ wikła 3<br />
1 <strong>Oncology</strong>, MSC Memorial Cancer Centre and Institute Maria Sklodowska-Curie,<br />
Warsaw, Poland, 2 Endocrinology, Medical University <strong>of</strong> Gdansk, Gdansk, Poland,<br />
3 Department <strong>of</strong> Radiology, Faculty <strong>of</strong> Medical Sciences <strong>of</strong> the University <strong>of</strong> Warmia<br />
and Mazury, Olsztyn, Poland<br />
Background: Neuroendocrine carcinoma (NEC) <strong>of</strong> colorectal origin are in minority <strong>of</strong><br />
NEN. The aim <strong>of</strong> this retrospective study was to determine the natural history <strong>of</strong> NEC<br />
and outcomes in terms <strong>of</strong> OS (overall survival) and PFS (progression free survival),<br />
also to assess clinical, pathologic and prognostic factors <strong>of</strong> this group <strong>of</strong> cancers.<br />
Methods: All patients with NEC or mix adenoca and NEC (MANEC), confirmed in<br />
histology WHO classification 2010, were include <strong>of</strong> the study. Local ethics committee<br />
accept this retrospective review. All patient data sets were review and analysed<br />
including OS and PFS for clinical and pathological factors.<br />
Results: A total <strong>of</strong> 67 pts were include in this study, 33% <strong>of</strong> all NEN in this localisation.<br />
A female to male ratio was 1,48. There were 15 MANEC (22%) and 52 NECG3 (52%).<br />
At initial diagnosis local disease was noted in 11 subjects (16%), regional lymph nodes<br />
spread in 25 subjects (37%) and distant mts noted in 31 pts (46%). Whole large bowel<br />
was also divide on anatomical regions <strong>of</strong> primary localisation, including: caecum area<br />
19 subjects (28%), ascending, transverse and descending colon 16 subjects (24%),<br />
sigmoid 17 (25%) and rectal area 15 (22%). Median OS in whole group <strong>of</strong> pts was 18.0<br />
M, in those with local spread <strong>of</strong> disease (CS I-IIIA) OS was 77.0 M, in those with<br />
regional lymph nodes involvement (CS IIIB) 26.0 M, and in those with presence <strong>of</strong><br />
distant mts, OS was 11.0 M. Female median OS was 14.9 M compare to male 18.1<br />
M. The localisation <strong>of</strong> primary tumour provides differences in OS as follows: caecum<br />
median OS 36 M, sigmoid 11.0 M, rectal 25.0M and rest <strong>of</strong> the colon 13.0M. The<br />
median OS in patients with NEC was 16.0 M and those with MANEC was 26.0M.<br />
Factors associated with improved OS on multivariate analysis were absence <strong>of</strong><br />
metastatic disease both regional and distal and MANEC type, compare to pure<br />
NECG3.<br />
Conclusions: Colorectal NEC are relatively common, compare to other localisation <strong>of</strong><br />
NEC <strong>of</strong> GEP-NEN origin. Most <strong>of</strong> them are very aggressive cancers with poor<br />
prognosis. Patients appear to have a relatively better outcome if they present no<br />
regional and distant spread <strong>of</strong> disease. Also relatively better prognosis in terms <strong>of</strong> OS in<br />
those with rectal and caecal compare to other segments <strong>of</strong> large bowel NEN. The<br />
MANEC variant <strong>of</strong> colorectal NEC seems to be less aggressive behaviour compare to<br />
pure NEC.<br />
Legal entity responsible for the study: N/A<br />
Funding: None<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
431P<br />
Neuroendocrine neoplasms <strong>of</strong> the appendix including goblet<br />
cell carcinoids<br />
A. Kolasinska-Cwikla 1 , L. Jaskiewicz 2 , A. Lewczuk 3 , A. Cichocki 4 ,<br />
K. Roszkowska 5 , M. Tenderenda 1 , J. Cwikla 2<br />
1 <strong>Oncology</strong>, MSC Memorial Cancer Centre and Institute Maria Sklodowska-Curie,<br />
Warsaw, Poland, 2 Radiology, University <strong>of</strong> Warmia and Mazury in Olsztyn, Faculty<br />
<strong>of</strong> Medical Sciences, Olsztyn, Poland, 3 Endocrinology, Medical University <strong>of</strong><br />
Gdansk, Gdansk, Poland, 4 Surgery, MSC Memorial Cancer Centre and Institute<br />
Maria Sklodowska-Curie, Warsaw, Poland, 5 Pathology, MSC Memorial Cancer<br />
Centre and Institute Maria Sklodowska-Curie, Warsaw, Poland<br />
Background: Neuroendocrine neoplasms <strong>of</strong> the appendix are common GEP-NEN<br />
tumours. The aim <strong>of</strong> this retrospective study was review <strong>of</strong> patients records with this<br />
type <strong>of</strong> NEN, to determine natural history and outcomes base on localisation <strong>of</strong><br />
primary tumour, resection margins, initial clinical stage and cell differentiation as<br />
single institution experience.<br />
Methods: All patients with confirmed appendcieal NEN, with evaluation <strong>of</strong> resection<br />
margins, localisation <strong>of</strong> primary tumour and tumour type, based on WHO 2010<br />
classification, were included <strong>of</strong> the study. Local ethics committee accepted this<br />
retrospective review.<br />
Results: A total <strong>of</strong> 97 pts were included in this study. A female to male ratio was 1,62.<br />
There were 79 pts with NETG1 (81%), 7 pts with NETG2 (7%), and 9 in goblet cell<br />
carcinoids (GCC) (9%) and 2 pts with MANEC (2%). The resection R0 was in 63<br />
subjects in NETG1 (80%), 4 pts in NETG2 (57%) and 4 subjects with GCC (44%), no<br />
one <strong>of</strong> MANEC pts had R0. Resection R1 was noted in 13 subjects with NETG1 (16%),<br />
2 pts with NETG2 (29%), and 3 pts with GCC (33%). All MANEC pts and 2 pts GCC<br />
had R2 resection. The 5 years OS in study group was 96%. There was no difference in 5<br />
years OS between NETG1 and NETG2. There was no significant difference between 5<br />
years OS in pts with R0 98% and R1 91%. In group <strong>of</strong> MANEC and GCC 5 years<br />
survival was 85%. The distribution <strong>of</strong> localisation <strong>of</strong> primary tumour within appendix<br />
presented in table below.<br />
Table: 431P<br />
All NETG1 NETG2 MANEC GCC<br />
Top 73 (75%) 65 (67%) 6 (6%) 0 2 (2%)<br />
Middle 11 (11%) 3 (3%) 1 (1%) 1 (1%) 6 (6%)<br />
Base 9 (9%) 7 (7%) 0 1 (1%) 1 (1%)<br />
No data 3(3% 3 (3%) 0 0 0<br />
Conclusions: Appendcieal NEN had very favourable prognosis. Most <strong>of</strong> them are<br />
treated completely surgical. Even R1 resection had no significant impact on 5 years<br />
survival. Over 90% <strong>of</strong> cases are well or moderate differentiated. MANEC and GCC are<br />
very rare and represent less than 10% <strong>of</strong> all cases.<br />
Legal entity responsible for the study: Lukasz Jaskiewicz, Jaroslaw Cwikla, University<br />
<strong>of</strong> Warmia and Mazury in Olsztyn, Faculty <strong>of</strong> Medical Sciences, Department <strong>of</strong><br />
Radiology<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw369 | vi141
abstracts<br />
Funding: University <strong>of</strong> Warmia and Mazury in Olsztyn, Faculty <strong>of</strong> Medical Sciences,<br />
Department <strong>of</strong> Radiology<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
432P<br />
Prognostic validity <strong>of</strong> AJCC staging system in neuroendocrine<br />
tumors <strong>of</strong> the appendix<br />
A. Mehrvarz Sarshekeh, S. Advani, M.R. Patel, A. Dasari<br />
Gastrointestinal Medical <strong>Oncology</strong>, MD Anderson Cancer Center, Houston, TX,<br />
USA<br />
Background: Neuroendocrine tumors (NETs) are the most common appendiceal<br />
tumors and can be categorized as well-differentiated NETs (WDNETs) and mixed<br />
adenoneuroendocrine tumors (MANECs). Currently, WDNETs are classified based on<br />
the American Joint Committee on Cancer (AJCC) staging (seventh edition), first<br />
proposed in 2010 or according to the European Neuroendocrine Tumor Society staging<br />
systems (ENETS). Both systems differ slightly in the T stage. MANECs, which are more<br />
aggressive, are staged according to AJCC staging for appendiceal adenocarcinomas.<br />
However, the prognostic value <strong>of</strong> AJCC staging system in WDNETs and MANECs has<br />
not been validated.<br />
Methods: Patients (pts) diagnosed with appendiceal WDNET and MANEC (between<br />
1988-2012) in the Surveillance, Epidemiology and End Results (SEER) program were<br />
assigned stages I-IV according ENETS (WDNETs only) or AJCC 7th edition<br />
(WDNETs and MANECs). Kaplan-Meier method and univariate Cox model were used<br />
to evaluate overall survival (OS) and differences in OS across stages, respectively.<br />
Results: We identified 860 and 1173 pts with WDNET and MANEC, respectively. The<br />
10-year survival rates for WDNETs according to ENETS stages I-IV were 96%, 95%,<br />
92%, and 55%, respectively (P < 0.001, log rank). The corresponding rates for AJCC<br />
stages I-IV were 96%, 95%, 93%, and 55%, respectively (P < 0.001, log rank). Using<br />
univariate cox regression for WDNETs, only stage IV was associated with poor OS in<br />
both ENETS and AJCC (per ENET: HR = 8.27, 95%CI = 3.72-18.35, p < 0.001 and per<br />
AJCC: HR = 9.37, 95%CI = 5.11-17.19, p < 0.001). The agreement between AJCC and<br />
ENETS per weighted Cohen’s kappa coefficient was estimated to be 0.73 (95%<br />
CI = 0.70-0.76), indicating substantial agreement and moderate discrepancy. For<br />
MANEC, the number <strong>of</strong> pts with stage I-IV was 230 (19.61%), 625 (53.28%), 176<br />
(15.26%), and 139 (11.85%) respectively. By AJCC staging, median OS was 52 months,<br />
43 months, 28 months and 17 months for stage I-IV, respectively (p < 0.001, log rank).<br />
Conclusions: For WDNET, stage IV is associated with worse survival in both the AJCC<br />
and ENETS classifications. In MANEC, both stages III and IV are associated with<br />
worse survival.<br />
Legal entity responsible for the study: Dr. Amir Mehrvarz Sarshekeh, Dr. Arvind<br />
Dasari<br />
Funding: The University <strong>of</strong> Texas MD Anderson Cancer Center<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
433P<br />
Enhancer <strong>of</strong> zest homolog 2 (EZH2) expression in well and<br />
moderately differentiated pancreatic neuroendocrine tumor<br />
(pNET)<br />
R. Marconcini 1 , P. Faviana 2 , D. Campani 2 , L. Galli 1 , A. Antonuzzo 3 , C. Orlandini 1 ,<br />
A. Falcone 1 , S. Ricci 3<br />
1 U.O. Oncologia Medica 2 Universitaria, Azienda Ospedaliera Universitaria S.<br />
Chiara, Pisa, Italy, 2 U.O. Anatomia Patologica, Azienda Ospedaliera Cisanello Pisa,<br />
Pisa, Italy, 3 U.O. Oncologia Medica 1 Ospedaliera, Azienda Ospedaliera<br />
Universitaria S.Chiara, Pisa, Italy<br />
Background: Enhancer <strong>of</strong> zest homolog 2 (EZH2) is the catalytic subunit <strong>of</strong> polycomb<br />
repressive complex 2 with histone H3 methyltransferase function. EZH2 has been<br />
shown to be over-expressed in several malignant neoplasms and to be associated with<br />
aggressive behavior. Few data are currently available for NETs. EZH2 represents a<br />
potential therapeutic target and EZH2 inhibitor drugs are in development. In this<br />
study, we evaluated EZH2 expression in well differentiated G1 (Ki67
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
compared with the benign group (0.06 ± 0.18 mL vs. 0.004 ± 0.05 mL, respectively,<br />
p =
abstracts<br />
438P<br />
Efficacy <strong>of</strong> lanreotide autogel/depot (LAN) vs placebo (PBO) for<br />
symptomatic control <strong>of</strong> carcinoid syndrome (CS) in<br />
neuroendocrine tumor (NET) patients from the ELECT study<br />
E.M. Wolin 1 , G.A. Fisher, 2 , P.L. Kunz 2 , N. Liyanage 3 , S.P. Lowenthal 4 ,<br />
B. Mirakhur 4 , R.F. Pommier 5 , M. Shaheen 6 , A. Vinik 7<br />
1 <strong>Oncology</strong>, Montefiore Einstein Center for Cancer Care, New York, NY, USA,<br />
2 Stanford Cancer Center, Stanford University School <strong>of</strong> Medicine, Stanford, CA,<br />
USA, 3 Clinical Research, Ipsen, Boulogne-Billancourt, France, 4 Clinical Research,<br />
Ipsen, Basking Ridge, NJ, USA, 5 Healthcare Services, Oregon Health Science<br />
University, Portland, OR, USA, 6 Cancer Center, University <strong>of</strong> New Mexico,<br />
Albuquerque, NM, USA, 7 Neuroendocrine Unit, Eastern Virginia Medical School,<br />
Norfolk, VA, USA<br />
Background: In the 16-wk double-blind (DB) phase <strong>of</strong> ELECT, LAN significantly<br />
reduced the need for short-acting octreotide (OCT) rescue medication for symptomatic<br />
control <strong>of</strong> CS in NET patients vs PBO (primary result). Here we present posthoc data<br />
on patient-reported symptoms during DB treatment.<br />
Methods: ELECT consisted <strong>of</strong> 16-wk DB, 32-wk initial open-label, and long-term<br />
phases. Adults with histopathologically confirmed NET or NET <strong>of</strong> unknown location<br />
with liver metastases and history <strong>of</strong> CS (diarrhea and/or flushing) with/without prior<br />
somatostatin analog (SSA) use who provided informed consent were randomized to<br />
LAN 120 mg or PBO every 4 wks. Patients could administer short-acting OCT if<br />
needed and were instructed to record daily the frequency and severity <strong>of</strong> symptoms in a<br />
diary using Interactive Voice (Web) Response System for 1 month pre-randomization<br />
and throughout the DB phase. Analysis <strong>of</strong> covariance (ANCOVA) models were used<br />
for these analyses with baseline symptoms, prior SSA, and country as factors. Given the<br />
high variability <strong>of</strong> urinary 5-hydroxyindoleacetic acid (5HIAA), values were log<br />
transformed.<br />
Results: 115 patients were randomized (n = 59 LAN, n = 56 PBO). In the DB phase,<br />
percentages <strong>of</strong> days with severe or moderate/severe diarrhea and/or flushing compared<br />
to baseline were significantly reduced for LAN vs PBO (Table). The LAN group had a<br />
35% greater decrease in logarithmic 5HIAA levels at wk 12 vs PBO (relative mean ratio<br />
0.65; 95% CI: 0.40, 1.07). Treatment-emergent adverse events occurred in 53.4% <strong>of</strong><br />
patients on LAN and 59.6% <strong>of</strong> patients on PBO.<br />
Table: 438P Percentage days <strong>of</strong> diarrhea and/or flushing (ANCOVA,<br />
Intention-to-Treat Population)<br />
LAN<br />
(n = 59)<br />
PBO<br />
(n = 56)<br />
LS mean diff<br />
(LAN-PBO)<br />
(95% CI)<br />
%<br />
reduction<br />
P-value<br />
Moderate/Severe<br />
Diarrhea/<br />
Flushing<br />
LS Mean (SE), % 23.4 (3.06) 35.8 (3.12) -12.4 (-20.73, -4.07) 34.6 0.004<br />
Severe Diarrhea/<br />
Flushing<br />
LS Mean (SE), % 3.9 (1.20) 7.6 (1.23) -3.8 (-7.01, -0.52) 49.3 0.023<br />
Conclusions: The observed improvement in patient-reported symptoms supports the<br />
efficacy <strong>of</strong> LAN in CS. These findings are in concert with the previously reported<br />
primary result <strong>of</strong> less rescue medication use with LAN vs PBO.<br />
Clinical trial identification: EudraCT 2010-019066-92; NCT00774930 authors: on<br />
behalf <strong>of</strong> ELECT study investigators<br />
Legal entity responsible for the study: Ipsen Biopharmaceuticals, Inc.<br />
Funding: The study was funded by Ipsen Biopharmaceuticals, Inc.<br />
Disclosure: E.M. Wolin: Consulting or Advisory Role – Celgene; Ipsen; Novartis;<br />
Pfizer; Research Funding – Ipsen (Inst); Novartis (Inst); Pfizer (Inst).G.A. Fisher, Jr:<br />
Consulting—Ipsen; Research funding, Ipsen.P.L. Kunz: Research funding from<br />
Genentech, Merck, Advanced Accelerator Applications, Lexicon, Oxigene; Advisor for<br />
Ipsen, Novartis.N. Liyanage, S.P. Lowenthal, B. Mirakhur: Employee Ipsen<br />
Biopharmaceuticals, Inc.A. Vinik: Consulting or Advisory Role – Isis Pharmaceuticals;<br />
Merck Co., Inc.; Neurometrix; Pamlab; Pfizer; Speakers’ Bureau – Merck Co., Inc.;<br />
Pamlab; Research Funding – Daiichi Sankyo; Impeto Medical; Intarcia Therapeutics;<br />
Pfizer; Tercica; ViroMed.All other authors have declared no conflicts <strong>of</strong> interest.<br />
439P<br />
Long-term safety/tolerability <strong>of</strong> lanreotide autogel/depot<br />
(LAN) treatment for metastatic intestinal and pancreatic<br />
neuroendocrine tumours (NETs): Final results <strong>of</strong> the<br />
CLARINET open-label extension (OLE)<br />
M. Caplin 1 ,M.Pavel 2 , J.C. Cwikła 3 , A. Phan 4 , M. Raderer 5 , E. Sedlácǩová 6 ,<br />
G. Cadiot 7 , E. Wolin 8 , J. Capdevila 9 , L. Wall 10 , G. Rindi 11 , N. Liyanage 12 ,<br />
S. Braun 12 , P. Ruszniewski 13<br />
1 Neuroendocrinology, Royal Free Hospital School <strong>of</strong> Medicine, London, UK,<br />
2 Endocrinology, Charité University Medicine, Berlin, Germany, 3 Department <strong>of</strong><br />
Radiology, University <strong>of</strong> Warmia and Mazury, Olsztyn, Poland, 4 Department <strong>of</strong><br />
Gastrointestinal Medical <strong>Oncology</strong>, University <strong>of</strong> Texas MD Anderson Cancer<br />
Center, Houston, TX, USA, 5 University Department <strong>of</strong> Internal Medicine, University<br />
Hospital, Vienna, Austria, 6 Department <strong>of</strong> <strong>Oncology</strong> <strong>of</strong> the First Faculty <strong>of</strong> Medicine<br />
and General Teaching Hospital, Charles University Prague, Prague, Czech<br />
Republic, 7 <strong>Oncology</strong>, Robert Debré Hospital, Reims, France, 8 <strong>Oncology</strong>, Markey<br />
Cancer Center, Lexington, KY, USA, 9 <strong>Oncology</strong>, Vall d’Hebron University Hospital,<br />
Barcelona, Spain, 10 <strong>Oncology</strong>, Western General Hospital, Edinburgh, UK,<br />
11 <strong>Oncology</strong>, Università Cattolica del Sacro Cuore, Rome, Italy, 12 <strong>Oncology</strong>, Ipsen,<br />
Lisieux, France, 13 <strong>Oncology</strong>, Beaujon Hospital, Clichy, and Paris Diderot<br />
University, Paris, France<br />
Background: CLARINET is a landmark study that established the antitumour activity<br />
<strong>of</strong> LAN in patients with metastatic intestinal or pancreatic NETs. Here, we report final<br />
long-term safety data from the recently completed OLE.<br />
Methods: Patients were eligible to take part in the OLE if they had stable disease (with<br />
LAN or placebo [PBO]) at the end <strong>of</strong>, or progressive disease (PBO group only), during<br />
the 96-week double-blind core study. All patients received open-label LAN 120 mg by<br />
deep subcutaneous injection every 28 days.<br />
Results: In total, 89 patients were treated over the core and OLE studies (42 continued<br />
on LAN in both studies [LAN:LAN group] and 47 switched from placebo in core to<br />
LAN in OLE [PBO:LAN group]). The adverse event (AE) pr<strong>of</strong>ile <strong>of</strong> LAN treatment<br />
during both studies is summarised in the Table. The most common class <strong>of</strong> AEs on<br />
LAN:LAN across both studies was GI events (any AE, 81%; any treatment-related AE<br />
[TRAE], 43% ); among these, the most frequent were diarrhoea (any AE, 40%; any<br />
TRAE, 31%) and abdominal pain (any AE, 38%; any TRAE, 17%). On PBO:LAN in the<br />
OLE study, GI events (any AE/any TRAE) occurred in 66%/36%; with diarrhoea in<br />
32%/26% and abdominal pain in 21%/2%. Only five patients withdrew due to AEs, <strong>of</strong><br />
which only one was treatment-related. No new safety concerns were identified.<br />
Table: 439P AE pr<strong>of</strong>ile on LAN during the CLARINET core and OLE<br />
studies<br />
LAN:LAN<br />
group<br />
(n = 42)<br />
Core<br />
study<br />
LAN<br />
PBO:LAN group (n = 47)<br />
OLE<br />
study<br />
LAN<br />
Pooled<br />
both<br />
studies<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Core<br />
study<br />
PBO<br />
OLE<br />
study<br />
LAN<br />
Treatment<br />
96.9 (±1.6) 134.1 (±85.4) 234.7 (±84.9) 67.3 (±28.0) 116.1 (±95.2)<br />
exposure,<br />
weeks<br />
(mean [±SD])<br />
Any AE, n (%) 39 (93) 34 (81) 40 (95) 44 (94) 42 (89)<br />
Severe 10 (24) 12 (29) 18 (43) 13 (28) 13 (28)<br />
Moderate 19 (45) 16 (38) 17 (40) 23 (49) 22 (47)<br />
Mild 9 (21) 6 (14) 4 (10) 8 (17) 7 (15)<br />
Treatment-related 23 (55) 17 (40) 27 (64) 12 (26) 22 (47)<br />
Serious AEs, n (%) 9 (21) 11 (26) 17 (40) 12 (26) 14 (30)<br />
Treatment-related 1(2) 2(5) 3(7) 1(2) 2(4)<br />
Withdrawals due NA 2 (5) 2 (5) NA 3 (6)<br />
to AEs, n (%)<br />
Treatment-related NA 0 0 NA 1(2)<br />
NA, not applicable (no patients withdrawn from core study were entered into<br />
OLE study).<br />
Conclusions: LAN 120 mg treatment, over a period <strong>of</strong> up to >4 years, showed<br />
favourable safety/tolerability in patients with metastatic intestinal and pancreatic NETs.<br />
This supports the positive longer-term benefit–risk pr<strong>of</strong>ile <strong>of</strong> LAN as an antitumour<br />
treatment, which is consistent with previous experience from shorter-term trials.<br />
Clinical trial identification: 2-55-52030-729<br />
Legal entity responsible for the study: N/A<br />
Funding: Ipsen<br />
Disclosure: M. Caplin: Received consulting/advisory fees from Ipsen.M. Pavel:<br />
Received research funding from Novartis and consulting/advisory fees from Ipsen,<br />
Novartis, Pfizer and Lexicon.J.C. Cwikła: Received research funding from Ipsen.A.<br />
Phan: Received research funding from Ipsen, Novartis, Lexicon, San<strong>of</strong>i and Incyte;<br />
consulting/advisory fees from Ipsen and Novartis; and speaker fees from Lilly,<br />
Genentech, Celgene, Novartis and Ipsen.M. Raderer: Received honoraria from<br />
Novartis, Ipsen, Roche, Pfizer, Bayer and Celgene, and speaker fees from Novartis,<br />
Ipsen, Roche, Pfizer, Bayer and Celgene.G. Cadiot: Received research funding from<br />
Ipsen and consulting/advisory fees fromIpsen, Novartis, Keocyt.E. Wolin: Received<br />
vi144 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
research funding fromIpsen and Novartis; consulting/advisory fees from Ipsen,<br />
Novartis, Pfizer and Celgene; and honoraria from Ipsen and Novartis.J. Capdevila:<br />
Received consulting/advisory fees from Ipsen, Novartis, Pfizer.G. Rindi: Has received<br />
speaker fees from Ipsen.N. Liyanage, S. Braun: Employee <strong>of</strong> Ipsen.P. Ruszniewski:<br />
Received research funding from Ipsen and Novartis, speaker fees from Ipsen and<br />
Novartis, consulting/advisory fees from Ipsen, honoraria from Ipsen and Novartis.All<br />
other authors have declared no conflicts <strong>of</strong> interest.<br />
440P<br />
Longer term efficacy <strong>of</strong> lanreotide autogel/depot (LAN) for<br />
symptomatic treatment <strong>of</strong> carcinoid syndrome (CS) in<br />
neuroendocrine tumor (NET) patients from the ELECT open<br />
label study<br />
G.A. Fisher, Jr 1 , E. Wolin 2 , P.L. Kunz 1 , N. Liyanage 3 , B. Mirakhur 4 ,S.<br />
Pitman Lowenthal 4 , R.F. Pommier 5 , M. Shaheen 6 , A. Vinik 7<br />
1 School <strong>of</strong> Medicine, Stanford University, Stanford, CA, USA, 2 Medical <strong>Oncology</strong>,<br />
Montifiore Einstein Center for Cancer Care, Bronx, NY, USA, 3 Ipsen<br />
Biopharmaceuticals, Inc., Boulogne-Billancourt, France, 4 Ipsen Biopharmaceuticals,<br />
Inc., Basking Ridge, NJ, USA, 5 Surgical <strong>Oncology</strong>, Oregon Health Science<br />
University, Portland, OR, USA, 6 Cancer Center, University <strong>of</strong> New Mexico,<br />
Albuquerque, NM, USA, 7 Eastern Virginia Medical School, Norfolk, VA, USA<br />
Background: In ELECT, LAN significantly reduced the need for short-acting<br />
octreotide rescue medication for symptomatic control <strong>of</strong> CS in NET patients vs placebo<br />
(PBO) in the 16-wk double-blind (DB) phase (primary result). Here we compare<br />
patient-reported symptoms in the DB vs 32-wk initial open-label phase (IOL).<br />
Methods: Adults with histopathologically confirmed NET and history <strong>of</strong> CS with/without<br />
prior somatostatin analog (SSA) use were randomized to DB LAN 120 mg or PBO every 4<br />
wks for 16 wks followed by a 32-wk IOL on LAN. Patients recorded daily the frequency<br />
and severity <strong>of</strong> diarrhea and/or flushing by Interactive Voice (Web) Response System for 1<br />
month pre-randomization through IOL. Mean composite symptom scores (frequency x<br />
severity) in DB vs IOL were analyzed posthoc. Analysis <strong>of</strong> covariance models (ANCOVA)<br />
were used for these analyses with baseline symptoms, prior SSA, and country as factors.<br />
Urinary 5-hydroxyindoleacetic acid (u5HIAA) values were log transformed.<br />
Results: Of 115 randomized (n = 59 LAN, n = 56 PBO), 56 LAN- and 45 PBO-treated<br />
patients, switched to LAN, were available for IOL analysis. Among patients initially on<br />
LAN, composite diarrhea scores improved significantly from DB to IOL (mean<br />
difference 0.7, 95% CI: 0.22, 1.20; p = 0.005) and were not significantly different for<br />
flushing (mean difference -0.2, 95% CI: -1.25, 0.80) or diarrhea and flushing (mean<br />
difference 0.5, 95% CI: -0.69, 1.67). As expected, the mean difference in composite<br />
scores for diarrhea (1.1, 95% CI: 0.49, 1.65), flushing (1.1, 95% CI: 0.19, 1.93), and<br />
diarrhea / flushing (2.1, 95% CI: 0.91, 3.35) reflected significant improvement from DB<br />
to IOL for patients initially on PBO (P-values
abstracts<br />
443P<br />
Prognostic impact <strong>of</strong> the cumulative dose and dose intensity<br />
<strong>of</strong> everolimus in patients with pancreatic neuroendocrine<br />
tumors (PNETs)<br />
R. Berardi 1 , M. Torniai 1 , S. Pusceddu 2 , F. Spada 3 , T. Ibrahim 4 , C. Zichi 5 ,<br />
L. Antonuzzo 6 , P. Ferolla 7 , M. Rinzivillo 8 , N. Silvestris 9 , S. Partelli 10 , B. Ferretti 11 ,<br />
A. Bongiovanni 4 , L. Giustini 12 , F. Di Costanzo 13 , G. Delle Fave 14 , N. Fazio 15 , F.G.<br />
M. De Braud 16 , M. Falconi 10 , S. Cascinu 17<br />
1 <strong>Oncology</strong>, AOU Ospedali Riuniti Ancona Università Politecnica delle Marche,<br />
Ancona, Italy, 2 Medical <strong>Oncology</strong> Department, Fondazione IRCCS - Istituto<br />
Nazionale dei Tumori, Milan, Italy, 3 Medical <strong>Oncology</strong>, Istituto Europeo di<br />
Oncologia, Milan, Italy, 4 Osteoncology and Rare Tumors Center, Istituto Tumori<br />
della Romagna I.R.S.T., Meldola, Italy, 5 Medical <strong>Oncology</strong>, Azienda<br />
Ospedaliero-Universitaria ASOU San Luigi Gonzaga, Orbassano, Italy, 6 <strong>Oncology</strong>,<br />
Azienda Ospedaliera Careggi U.O. Medical <strong>Oncology</strong>, Florence, Italy, 7 Dept. <strong>of</strong><br />
Medical <strong>Oncology</strong>, Multidisciplinary NET Group, Umbria Regional Cancer Network<br />
and University <strong>of</strong> Perugia, Perugia, Italy, 8 Digestive and Liver Disease Unit,<br />
Sapienza University <strong>of</strong> Rome, Rome, Italy, 9 Medical <strong>Oncology</strong>, Istituto Tumori<br />
Giovanni Paolo II, Bari, Italy, 10 Pancreatic Surgery, Ospedale San Raffaele IRCCS,<br />
Milan, Italy, 11 U.O.ONCOLOGIA MEDICA, Ospedale Bartolomeo Eustachio, San<br />
Severino Marche, Italy, 12 UOC Oncologia Medica, Ospedale Augusto Murri,<br />
Fermo, Italy, 13 Dipartimento di Oncologia, Azienda Ospedaliera Careggi U.O.<br />
Medical <strong>Oncology</strong>, Florence, Italy, 14 Digestive and Liver Disease Unit, Sapienza<br />
University <strong>of</strong> Rome, Sant’Andrea Hospital, Rome, Italy, 15 Gastrointestinal and NET<br />
Unit, Istituto Europeo di Oncologia, Milano, Italy, 16 Division <strong>of</strong> <strong>Oncology</strong>,<br />
Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy, 17 Medical<br />
<strong>Oncology</strong>, Azienda Ospedaliero - Universitaria Policlinico di Modena, Modena, Italy<br />
Background: Pancreatic neuroendocrine tumors (PNETs) are still considered a rare<br />
disease, which accounts for approximately 10% <strong>of</strong> all cases <strong>of</strong> pancreatic cancer. The<br />
oral mTOR inhibitor everolimus has become an established recommended standard<br />
therapy for patients with advanced PNETs. Aim <strong>of</strong> the study is to assess if cumulative<br />
dose (CD) and dose intensity (DI) <strong>of</strong> everolimus may affect survival <strong>of</strong> advanced<br />
PNETs patients.<br />
Methods: One hundred and sixteen patients (62 males and 54 females, median age 55<br />
years) with advanced PNETs were treated with everolimus for ≥ 3 months. According<br />
to a ROC analysis, patients were stratified into two groups, with CD ≤ 3000 mg (Group<br />
A; n = 68) and CD > 3000 mg (Group B; n = 48).<br />
Results: The response rate and toxicity were comparable in the two groups. However,<br />
patients in group A experienced more dose modifications than patients in group<br />
B. Median OS was 24 months in Group A whilst in Group B it was not reached (HR:<br />
26.9; 95% CI: 11.0-76.7; p < 0.0001). Patients who maintained a DI higher than 9 mg/<br />
day experienced a significantly longer OS and experienced a trend to higher response<br />
rate.<br />
Conclusions: Overall, our study results showed that both CD and DI <strong>of</strong> everolimus<br />
play a prognostic role for patients with advanced PNETs treated with everolimus. This<br />
should prompt efforts to continue everolimus administration in responsive patients up<br />
to at least 3000 mg despite delays or temporary interruptions.<br />
Legal entity responsible for the study: Clinica di Oncologia Medica - Unversità<br />
Politecnica delle Marche - Ospedali Riuniti di Ancona<br />
Funding: Università Politecnica delle Marche<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
444P<br />
Phase II study <strong>of</strong> everolimus (EVL) and octreotide (OCT) LAR in<br />
patients with non-functioning gastrointestinal neuroendocrine<br />
tumours (GI-NETs): EVERLAR study<br />
J. Capdevila 1 , A. Teulé 2 , J. Barriuso 3 , D. Castellano 4 , C. Lopez 5 , J.L. Manzano 6 ,<br />
V. Alonso 7 , R. Garcia-Carbonero 8 , E. Dotor 9 , I. Matos 1 , A. Custodio 3 ,<br />
O. Casanovas 2 , R. Salazar 2<br />
1 Medical <strong>Oncology</strong>, Vall d’Hebron University Hospital, Barcelona, Spain, 2 Medical<br />
<strong>Oncology</strong>, Institut Català d’Oncologia Hospital Duran i Reynals, Barcelona, Spain,<br />
3 Medical <strong>Oncology</strong>, Hospital Universitario La Paz, Madrid, Spain, 4 Medical<br />
<strong>Oncology</strong>, University Hospital 12 De Octubre, Madrid, Spain, 5 Medical <strong>Oncology</strong>,<br />
Hospital Universitario Marques de Valdecilla, Santander, Spain, 6 Medical<br />
<strong>Oncology</strong>, Catalan Institute <strong>of</strong> <strong>Oncology</strong> (ICO Badalona), Hospital Germans Trias i<br />
Pujol, Badalona, Spain, 7 Medical <strong>Oncology</strong>, Hospital Miguel Servet, Zaragoza,<br />
Spain, 8 <strong>Oncology</strong>, University Hospital 12 De Octubre, Madrid, Spain, 9 Medical<br />
<strong>Oncology</strong>, Hospital de Sabadell Corporacis Parc Tauli, Sabadell, Spain<br />
Background: Anti-tumour activity <strong>of</strong> the combination <strong>of</strong> somatostatin analogues<br />
(SSA) and the mTOR inhibitor EVL in patients (pts) with NETs has been suggested<br />
but not confirmed in prospective trials.<br />
Methods: The prospective multicentre single-arm phase II EVERLAR study was<br />
conducted to explore the anti-tumour activity <strong>of</strong> EVL 10 mg/d and OCT 30 mg q28d<br />
in pts with advanced non-functioning well-differentiated GI-NETs that progressed in<br />
the last 12 months. Prior treatment with SSAs and any systemic or locoregional therapy<br />
was allowed except for mTOR inhibitors. Pts continued treatment until progression or<br />
unacceptable adverse events (AEs). Primary endpoint was progression-free survival<br />
(PFS) at 12 months; secondary endpoints included PFS by Kaplan-Meier (KM), early<br />
biochemical response (> 30% decrease at week 4), objective response rate (ORR) by<br />
RECIST v1.0, overall survival (OS), AEs, activation <strong>of</strong> mTOR pathway (insulin like<br />
growth factor 1 receptor [IGF1R] and phosphoS6 [pS6] expression).<br />
Results: Of the 44 pts enrolled (24 [54.5%] male, 32 [72.7%] ECOG PS 0), 43 were<br />
included in the ITT analyses (1 excluded due to pancreatic origin). Primary tumour<br />
location was foregut (11.6%), midgut (48.8%), hindgut (11.6%), unknown (27.9%).<br />
Prior SSA was received in 86.1% <strong>of</strong> pts. After 12 months <strong>of</strong> treatment, 62.8% (CI95%:<br />
48-77%) <strong>of</strong> pts in the ITT population had not discontinued, progressed or died.<br />
Median PFS was 11.5 months. Early biochemical response was reported in only 6 pts<br />
(14%). ORR was 4.7% and stable disease was 83.7%. Median OS was not reached after<br />
24 months <strong>of</strong> median follow-up (mean 33 months, CI95%:27.7-40 months). Dose<br />
reductions and temporary interruptions due to EVL side effects were required in 4<br />
(9%) and 20 (45.5%) pts, respectively. Most frequent AEs were low platelet count (10<br />
pts, 22.7%), anaemia (7 pts, 15.9%), hyperglycaemia (6 pts, 13.6%), hypophosphatemia<br />
(3 pts, 6.8%). No correlation was observed between IGFR1 and pS6 expression and OS<br />
(p = 0.105, Log rank Test).<br />
Conclusions: The EVL-OCT combination provided clinically relevant efficacy in<br />
non-functioning GI-NETs similar to the results <strong>of</strong> RADIANT-2 in functioning setting.<br />
Clinical trial identification: NCT01567488<br />
Legal entity responsible for the study: Spanish Task Force for Endocrine Tumors<br />
(GETNE)<br />
Funding: Novartis<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
445P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Efficacy and safety <strong>of</strong> targeted agents for treatment <strong>of</strong><br />
gastroenteropancreatic (GEP) neuroendocrine tumor (NET)<br />
H. Chae 1 ,C.Yoo 2 , K-P. Kim 2 , H-M. Chang 2 , T.W. Kim 2 , Y.S. Hong 2 , S-M. Hong 3 ,<br />
S.C. Kim 4 , B-Y. Ryoo 2<br />
1 Internal medicine, Asan Medical Center, Seoul, Republic <strong>of</strong> Korea, 2 Department<br />
<strong>of</strong> oncology, Asan Medical Center, University <strong>of</strong> Ulsan College <strong>of</strong> Medicine, Seoul,<br />
Republic <strong>of</strong> Korea, 3 Pathology, Asan Medical Center, Seoul, Republic <strong>of</strong> Korea,<br />
4 Department <strong>of</strong> surgery, Asan Medical Center, University <strong>of</strong> Ulsan College <strong>of</strong><br />
Medicine, Seoul, Republic <strong>of</strong> Korea<br />
Background: Efficacy and safety <strong>of</strong> targeted agents, such as everolimus and sunitinib,<br />
have been demonstrated in the prospective trials for patients with GEP-NET.<br />
Considering heterogeneous clinical features <strong>of</strong> NET, evaluation <strong>of</strong> real-world outcomes<br />
with these agents are necessary. We retrospectively analyze the treatment outcomes <strong>of</strong><br />
everolimus and sunitinib for patients (pts) with GEP-NET.<br />
Methods: Between Mar 2007 and Oct 2014, a total <strong>of</strong> 44 GEP-NET pts treated with<br />
everolimus or sunitinib were included. Considering distinct characteristics between<br />
pancreatic (Pan) and non-PanNETs, efficacy analysis was performed separately, while<br />
safety analysis included all pts.<br />
Results: PanNET was most common type (n = 28, 64%) and followed by hindgut NET<br />
(n = 11, 25%) and foregut NET (n = 5, 11%). Sunitinib and everolimus were given in 27<br />
(61%) and 17 (39%) pts, respectively. Among 41 pts that pathology review was<br />
available, tumor grade (G) was G1/2 in 36 (78%) and G3 in 5 (12%). Cytotoxic<br />
chemotherapy and somatostatin analogue were previously given in 16 (36%) and 18<br />
(41%) pts, respectively. In pts with PanNET, median progression-free survival (PFS)<br />
with everolimus and sunitinib was 16.6 months (95% CI, 8.0-25.1) and 8.0 months<br />
(95% CI, 0.0-17.4), and there was no significant difference between two agents<br />
(p = 0.51). For non-PanNET pts, median PFS was 14.7 months (95% CI, 2.4-27.0) with<br />
everolimus and 1.7 months (95% CI, 0.5-3.0; p = 0.001) with sunitinib; G3 tumor and<br />
prior cytotoxic chemotherapy were more common in pts with sunitinib than those<br />
with everolimus (30% vs 0%, and 70% vs 50%, respectively).Treatment was<br />
discontinued due to the adverse events in 3 pts (14%) with sunitinib and 4 (29%) with<br />
everolimus. Most common grade 3-4 toxicities were neutropenia (n = 9, 33%), anemia<br />
(5, 19%), diarrhea (3, 11%), and hand-foot syndrome (2, 7%) in pts with sunitinib<br />
(n = 27), and pneumonitis (2, 12%), and thrombocytopenia/stomatitis (1, 6%) in those<br />
with everolimus (n = 17). Tumor grade was a significant predictive factor for PFS (G1/<br />
2: median 14.7 months vs G3: 2.5 months, p = 0.002).<br />
Conclusions: Both everolimus and sunitinib were well tolerable and effective in<br />
GEP-NET pts. The activity <strong>of</strong> everolimus was seen across all GEP-NETs and consistent<br />
with previous trials.<br />
Legal entity responsible for the study: Asan Medical Center (AMC) IRB<br />
Funding: None<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
vi146 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
446P<br />
Capecitabine and streptozocin ± cisplatin for<br />
gastroenteropancreatic neuroendocrine tumours: predictors<br />
<strong>of</strong> long-term survival in the NET01 trial<br />
447P<br />
Progressing G1-G2 neuroendocrine tumors (WD NET) in<br />
treatment with capecitabine (Cp) plus somatostatin analog<br />
(SSA): a single center experience<br />
T. Meyer 1 , W. Qian 2 , J.W. Valle 3 , D. Talbot 4 , D. Cunningham 5 , N. Reed 6 , L. Wall 7 ,<br />
J. Waters 8 ,P.Ross 9 , A. Anthoney 10 , K. Sumpter 11 , N. Sarwar 12 , T. Crosby 13 ,<br />
N. Begum 2 , G. Young 2 , R. Hardy 2 , P. Corrie 14<br />
1 Department <strong>of</strong> <strong>Oncology</strong>, Royal Free London NHS Foundation Trust, London,<br />
UK, 2 Cambridge Cancer Trials Centre, Cambridge Clinical Trials Unit - Cancer<br />
Theme, Addenbrooke’s Hospital University <strong>of</strong> Cambridge Hospitals, Cambridge,<br />
UK, 3 Department <strong>of</strong> Medical <strong>Oncology</strong>, University <strong>of</strong> Manchester/The Christie NHS<br />
Foundation Trust, Manchester, UK, 4 Department <strong>of</strong> <strong>Oncology</strong>, Churchill Hospital,<br />
Oxford University Hospitals NHS Foundation Trust, Oxford, UK, 5 Department <strong>of</strong><br />
<strong>Oncology</strong>, The Institute <strong>of</strong> Cancer Research/Royal Marsden NHS Foundation<br />
Trust, Sutton, UK, 6 Beatson <strong>Oncology</strong> Centre, Gartnavel General Hospital,<br />
Glasgow, UK, 7 Edinburgh Cancer Centre, Western General Hospital, Edinburgh,<br />
UK, 8 Kent <strong>Oncology</strong> Centre, Maidstone Hospital, Kent, UK, 9 Department <strong>of</strong><br />
<strong>Oncology</strong>, Guy’s and St. Thomas’ Hospital NHS Trust, London, UK, 10 St James’s<br />
Institute <strong>of</strong> <strong>Oncology</strong>, St James’s University Hospital, Leeds, UK, 11 Northern<br />
Centre for Cancer Care, Freeman Hospital, The Newcastle upon Tyne Hospitals<br />
NHS Foundation Trust, Newcastle Upon Tyne, UK, 12 Department <strong>of</strong> <strong>Oncology</strong>,<br />
Southend University Hospitals NHS Foundation Trust, Southend, UK, 13 Velindre<br />
Cancer Centre, Velindre NHS Trust, Cardiff, UK, 14 Cambridge Cancer Centre,<br />
Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK<br />
Background: Cytotoxic chemotherapy for advanced, unresectable pancreatic and<br />
gastrointestinal foregut neuroendocrine tumours (GEPNETs) commonly comprises<br />
5-fluorouracil (FU) plus streptozocin (S). The NET01 trial, conducted in the pre-kinase<br />
inhibitor era, recruited a broad spectrum <strong>of</strong> patients (pts) to investigate whether<br />
capecitabine (Cap) was an acceptable alternative to FU, with or without adding<br />
cisplatin (Cis). At median follow up 3.4 years, objective responses (primary endpoint)<br />
were reported as similar in the 2 arms, but CapSCis was more toxic. Final<br />
progression-free survival (PFS) and overall survival (OS) (secondary endpoints) as well<br />
as outcome predictors are now reported with longer follow up.<br />
Methods: Pts with previously untreated advanced, unresectable NETs <strong>of</strong> pancreatic,<br />
gastrointestinal foregut or unknown primary site were randomised to receive<br />
three-weekly Cap 625mg/m 2 twice daily orally, S 1·0g/m 2 IV on day 1, ± Cis 70mg/m 2<br />
IV on day 1. Pts could receive the same treatment beyond 6 cycles if there was evidence<br />
<strong>of</strong> benefit. All pts were followed 12 weekly for a minimum <strong>of</strong> 5 years.<br />
Results: Of 86 (44 CapS, 42 CapSCis) pts randomised, 16% had poorly differentiated<br />
histology. With long-term median follow-up <strong>of</strong> 8 years, 83 (97%) pts have progressed/<br />
died and 69 (80%) pts have died. The estimated median PFS was 11.1 months for CapS<br />
and 9·6 months for CapSCis (HR = 0.82, 95%CI: 0.53, 1.27). Median OS was 27<br />
months for CapS and 26 months for CapSCis (HR = 0.97, 95%CI: 0.60, 1.56). Three<br />
and 5-year OS rates were 40% and 29%, with no difference between arms. Statistically<br />
significant factors predicting for OS were tumour Ki67 level, WHO grade and pt age.<br />
Addition <strong>of</strong> Cis to CapS did not appear to influence OS for high grade, poorly<br />
differentiated tumours, although numbers are small.<br />
N<br />
Overall<br />
CapS<br />
Table: 446P<br />
CapSCis<br />
Median<br />
OS (yrs)<br />
Overall<br />
CapS<br />
Age (yrs)
abstracts<br />
Disclosure: Y. Takiguchi: I received lecture fee by Nipponkayaku.All other authors<br />
have declared no conflicts <strong>of</strong> interest.<br />
449TiP<br />
Safety and efficacy <strong>of</strong> lanreotide autogel/depot (LAN) every<br />
14 days for patients with pancreatic or midgut<br />
neuroendocrine tumours (NETs) progressing on LAN every<br />
28 days: The prospective, international CLARINET FORTE<br />
study<br />
M. Pavel 1 , C. Dromain 2 , C. Massien 3 , A. Houchard 4<br />
1 Campus Virchow-Klinikum; Medizinische Klinik m. S. Hepatologie und<br />
Gastroenterologie, Charité University Medicine Berlin, Berlin, Germany, 2 Imaging,<br />
Institut Gustave Roussy, Villejuif, France, 3 International VP Medical Endocrinology,<br />
Ipsen, Boulogne-Billancourt, France, 4 Ipsen, Ipsen, Boulogne-Billancourt, France<br />
Background: The CLARINET study demonstrated the antitumor effect <strong>of</strong> lanreotide<br />
autogel/depot (LAN) vs. placebo in patients with metastatic gastroenteropancreatic<br />
neuroendocrine tumours (NETs) and reaffirmed its favourable safety pr<strong>of</strong>ile. Patients<br />
with progressive disease (PD) receiving LAN 120 mg every 28 days (standard dosing<br />
interval) are usually <strong>of</strong>fered aggressive treatments (chemotherapy, targeted therapies, or<br />
peptide receptor radionuclide therapy). The CLARINET FORTE study will investigate<br />
the safety and antitumour efficacy <strong>of</strong> a reduced dosing interval (every 14 days) <strong>of</strong> LAN<br />
120 mg in patients with pancreatic or midgut NETs, beyond progression on the<br />
standard dosing interval.<br />
Trial design: CLARINET FORTE is an international, multicentre, prospective, open<br />
label phase II study. Main eligibility criteria: adult patients with well-differentiated,<br />
metastatic or locally advanced, unresectable, functioning or non-functioning, G1/G2,<br />
pancreatic NETs (pNETs) or midgut NETs. Patients will have radiological PD, within<br />
24 months prior to enrolment, as assessed by an independent central review according<br />
to Response Evaluation Criteria In Solid Tumors (RECIST) v1.0, while receiving first<br />
line treatment with LAN 120 mg on standard dosing intervals (ECOG PS 0-2). It is<br />
planned to enrol a total <strong>of</strong> 100 patients, 50 per cohort (pNETs or midgut NETs) in a<br />
total <strong>of</strong> 30–35 sites in Europe and the USA. LAN will be administered by deep<br />
subcutaneous injection at a dose <strong>of</strong> 120 mg every 14 days up to 48 weeks or 96 weeks<br />
for the pNET or midgut NET cohorts, respectively, or until PD/death or early<br />
withdrawal due to unacceptable toxicity/tolerability. The primary endpoint is<br />
progression-free survival (PFS), based on central review according to RECIST v1.0.<br />
Secondary endpoints include overall survival, objective radiologic response rate, effect<br />
on symptoms, quality <strong>of</strong> life, LAN pharmacokinetics, and safety. Analyses will be<br />
descriptive and p-values will be provided only for exploratory purposes. As <strong>of</strong> May 9 th<br />
2016, 3 patients were enrolled in the study.<br />
Clinical trial identification: EudraCT 2014-005607-24; Clinical Trials.gov:<br />
NCT02651987.<br />
Legal entity responsible for the study: Ipsen<br />
Funding: Ipsen<br />
Disclosure: M. Pavel: Research funding from Novartis. Consulting/advisory fees from<br />
Ipsen, Novartis, Pfizer and Lexicon. C. Dromain: Consulting/advisory fees from<br />
Ipsen. C. Massien, A. Houchard: Employee <strong>of</strong> Ipsen.<br />
450TiP<br />
Safety <strong>of</strong> lanreotide 120 mg ATG in combination with<br />
metformin in patients with advanced well-differentiated<br />
gastro-intestinal (GI) or lung carcinoids. A pilot, one-arm,<br />
open-label, prospective study: The MetNET-2 trial<br />
F.G.M. De Braud 1 , R. Buzzoni 2 , L. Concas 2 , D. Femia 2 , N. Prinzi 2 , M. Milione 3 ,<br />
E. Tamborini 3 , F. Perrone 3 , G. Lo Russo 4 , C. Vernieri 2 , I. Pulice 2 , F. Piras 2 ,<br />
G. Dinoi 2 , S. Pusceddu 2<br />
1 Division <strong>of</strong> <strong>Oncology</strong>-University <strong>of</strong> Milan, Fondazione IRCCS - Istituto Nazionale dei<br />
Tumori, Milan, Italy, 2 Medical <strong>Oncology</strong> Department, Fondazione IRCCS - Istituto<br />
Nazionale dei Tumori, Milan, Italy, 3 Department <strong>of</strong> Pathology and Laboratory<br />
Medicine, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy,<br />
4 <strong>Oncology</strong> Department, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan,<br />
Italy<br />
Background: In the CLARINET trial, lanreotide (LAN) 120 mg resulted in a 53%<br />
reduction in the risk <strong>of</strong> death or disease progression, compared with placebo, in GI-NET<br />
patients. Several studies have identified diabetic patients (pts) as having increased risk for<br />
the development <strong>of</strong> cancer and have associated metformin (MET) treatment with a<br />
decrease <strong>of</strong> cancer risk. MET may have anti-proliferative activity due to its ability to<br />
decrease insulin and IGF1 levels; in addition, it promotes AMPK activation and TSC1-2/<br />
mTOR inhibition. Our retrospective experience in a large group <strong>of</strong> pancreatic NET, has<br />
suggested that MET may provide additional clinical benefit in diabetic pts receiving<br />
everolimus and/or somatostatin analogues.This study evaluates the safety <strong>of</strong> LAN 120 mg<br />
in combination with MET in pts with advanced well-differentiated GI or lung carcinoids.<br />
Trial design: Methods: Pts with advanced GI or lung carcinoids will receive a<br />
combination <strong>of</strong> LAN 120 mg/month and MET 2550 mg/day, until progression or<br />
inacceptable toxicity. Radiological progression will be assessed every 4 months. The<br />
primary objective is to evaluate the incidence <strong>of</strong> adverse events (AEs) and severe AEs<br />
(SAEs). A 1-stage Hern design will be used. The null hypothesis that the SAEs rate<br />
related to the treatment is [25%] will be tested against a one-sided alternative. 20 pts<br />
with available tissue specimens will be enrolled. The null hypothesis will be rejected if<br />
≤2 pts will experience a severe toxicity. This design yields a type I error rate <strong>of</strong> 10% and<br />
power <strong>of</strong> 85% when the true toxicity rate is ≥5%. The expression <strong>of</strong> 111 genes<br />
potentially involved in the pathways related to MET (e.g., LKB1, TP53, KRAS, IGF1R,<br />
VEGFR, PDGFR, AKT, PIK3CA, PTEN, mTOR) will be assessed by a target NGS<br />
approach. Other endpoints include TTP and RR.Results: In March 2016, the trial<br />
received institutional ethic board approval and in April 2016 the enrollment was<br />
started (EudraCT 2015-004626-34). Recruitment will be completed in April 2017.<br />
Conclusions: This study will investigate the safety <strong>of</strong> the combination <strong>of</strong> LAN 120 mg<br />
and MET and the correlation between tumor mutations and response to this therapy.<br />
Clinical trial identification: Protocol EUDRACT Number: 2015-004626-34 approved<br />
by Ethical committee <strong>of</strong> Fondazione IRCCS Istituto Tumori Milan on 8 March 2016<br />
Legal entity responsible for the study: Fondazione IRCCS Istituto Tumori Milano<br />
Funding: Fondazione IRCCS Istituto Tumori Milano<br />
Disclosure: S. Pusceddu: Ipsen, Novartis, Italfarmaco, Pfizer. All other authors have<br />
declared no conflicts <strong>of</strong> interest.<br />
451TiP<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Combined lanreotide autogel and temozolomide therapy in<br />
progressive neuroendocrine tumours: the SONNET study<br />
D. Hörsch 1 , M. Raderer 2 , H. Lahner 3 , A. Rinke 4 , T. Denecke 5 , A. Koch 6 ,<br />
A. Raspel 7 , P. H<strong>of</strong>fmanns 8 ,M.Pavel 9<br />
1 Gastroenterology and Endocrinology, Center for Neuroendocrine Tumors Bad<br />
Berka, Zentralklinik Bad Berka GmbH, Bad Berka, Germany, 2 Internal Medicine,<br />
AKH Wien, Vienna, Austria, 3 Zentrallabor – Bereich Forschung und Lehre, Klinik für<br />
Endokrinologie & St<strong>of</strong>fwechselerkrankungen, Essen, Germany, 4 Gastroenterology,<br />
<strong>Oncology</strong>, University Hospital <strong>of</strong> Marburg Klinik fuer Innere Medizin,, Marburg,<br />
Germany, 5 Charité University Medicine Berlin, Institut für Radiologie, Berlin,<br />
Germany, 6 Charité University Medicine Berlin, Institut für Neuropathologie, Berlin,<br />
Germany, 7 Medical & Regulatory Department, IPSEN Pharma GmbH, Ettlingen,<br />
Germany, 8 Therapeutic Area Endocrinology and <strong>Oncology</strong>, IPSEN Pharma GmbH,<br />
Ettlingen, Germany, 9 Campus Virchow-Klinikum; Medizinische Klinik<br />
m. S. Hepatologie und Gastroenterologie, Charité University Medicine Berlin,<br />
Berlin, Germany<br />
Background: Due to difficulty in early diagnosis, patients <strong>of</strong>ten present with<br />
gastro-enteropancreatic neuroendocrine (GEP-NET) tumours in advanced stages.<br />
Lanreotide autogel (LAN) 120mg/4 weeks has been shown to improve progression-free<br />
survival (PFS) vs. placebo in advanced, non-functioning GEP-NETs and is licensed for<br />
this indication. However, treatment options beyond LAN are limited for patients with<br />
midgut or pancreatic NETs. Temozolomide is an alkylating agent that has shown<br />
efficacy against NETs in combination with other drugs. The aim <strong>of</strong> SONNET<br />
(lanreotide [Somatuline®] in NET with temozolomide) is to evaluate the efficacy<br />
(response pr<strong>of</strong>ile) and safety <strong>of</strong> LAN 120 mg combined with temozolomide in patients<br />
with progressive GEP-NETs.<br />
Trial design: This is a phase 2, open-label, prospective, multicentre, non-comparative<br />
pilot study. To reach the statistical analysis target <strong>of</strong> 40 evaluable patients, treatment is<br />
planned for 48 patients (≥18 years) with a locally advanced, or metastatic, G1/G2,<br />
functioning or non-functioning GEP-NET, or a NET <strong>of</strong> unknown primary that is<br />
progressive according to Response Evaluation Criteria In Solid Tumors (RECIST) v1.1.<br />
SONNET consists <strong>of</strong> a screening phase (4 weeks), a combination phase (6 months),<br />
and a maintenance phase (6 months). During the combination phase, patients receive<br />
LAN 120 mg/4 weeks plus temozolomide at 150 mg/m 2 /day for 5 days in month 1,<br />
increasing to 200 mg/m 2 /day in months 2–6. At the end <strong>of</strong> the combination phase,<br />
patients showing a clinical benefit as assessed by the primary endpoint (disease control<br />
rate [complete response + partial response + stable disease], assessed centrally using<br />
RECIST v1.1) receive LAN 120 mg/4 weeks (for functioning NETs), or are randomized<br />
to receive LAN 120 mg/4 weeks or no treatment (for non-functioning NETs) for the<br />
duration <strong>of</strong> the maintenance phase. Secondary endpoints include disease control rates<br />
at the end <strong>of</strong> the maintenance phase; time to progression or death (PFS) within 12<br />
months <strong>of</strong> initiating combination treatment; time to response within the 12-month<br />
study period and safety. Recruitment will be finalized in summer 2016.<br />
Clinical trial identification: Protocol number = A-94-52030-268 EudraCT<br />
number = 2013-001697-17 Clinical Trials.gov = NCT02231762<br />
Legal entity responsible for the study: IPSEN Pharma GmbH, Germany<br />
Funding: Ipsen<br />
Disclosure: D. Hörsch: Personal fees/other from: Lexicon Pharmaceuticals, Inc.<br />
Grants/personal fees/other from: Novartis Pharma. Personal fees/other from: Ipsen<br />
Pharma. Personal fees/other from: Pfizer Pharma, outside the submitted work.<br />
M. Raderer: Advisory boards: Ipsen, Novartis, Celgene, Mundipharma, Jannsen Cilag,<br />
Roche. Honoraria/Speaker: Ipsen, Novartis, Celgene, Swedish Orphan.H. Lahner:<br />
Advisory board: Pfizer, Novartis. Consultancy fees: Pfizer, Novartis, Ipsen. Research<br />
support: Novartis. Speaker/lecturer: Pfizer, Novartis, Ipsen.A. Rinke: Advisory board<br />
meetings <strong>of</strong> Ipsen, Novartis and Pfizer.T. Denecke: Payment by Ipsen for central read<br />
<strong>of</strong> study patients.A. Raspel, P. H<strong>of</strong>fmanns: Ipsen employee.M. Pavel: Advisory board:<br />
Ipsen, Novartis, Lexicon. Consultancy fees: Ipsen, Novartis, Lexicon. Research support:<br />
Novartis, Ipsen.All other authors have declared no conflicts <strong>of</strong> interest.<br />
vi148 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong> 27 (Supplement 6): vi149–vi206, 2016<br />
doi:10.1093/annonc/mdw370<br />
gastrointestinal tumours, colorectal<br />
452O<br />
Results <strong>of</strong> a prospective randomised control 6 vs 12 trial: Is<br />
greater tumour downstaging observed on post treatment MRI<br />
if surgery is delayed to 12-weeks versus 6-weeks after<br />
completion <strong>of</strong> neoadjuvant chemoradiotherapy?<br />
J. Evans 1 , J. Bhoday 2 , B. Sizer 3 , P. Tekkis 1 , R. Swift 4 , R. Perez 5 , D. Tait 1 ,<br />
G. Brown 1<br />
1 Colorectal Surgery, Royal Marsden Hospital NHS Foundation Trust, London, UK,<br />
2 Colorectal Surgery and Radiology, Royal Marsden Hospital NHS Foundation<br />
Trust, London, UK, 3 Colorectal Surgery, Colchester Hospital University Essex<br />
County Hospital, Colchester, UK, 4 Colorectal Surgery, Croydon University<br />
Hospital, London, UK, 5 Colorectal Surgery, Ludwig Institute for Cancer research,<br />
São Paulo, Brazil<br />
454O<br />
A randomized phase III study <strong>of</strong> napabucasin [BBI608] (NAPA)<br />
vs placebo (PBO) in patients (pts) with pretreated advanced<br />
colorectal cancer (ACRC): the CCTG/AGITG CO.23 trial<br />
453O<br />
Scheduled use <strong>of</strong> CEA and CT follow-up to detect recurrence<br />
<strong>of</strong> colorectal cancer: 6-12 year results from the FACS<br />
randomised controlled trial<br />
D.J. Jonker 1 , L. Nott 2 , T. Yoshino 3 , S. Gill 4 , J. Shapiro 5 , A. Ohtsu 6 , J. Zalcberg 7 ,M.<br />
M. Vickers 1 ,A.Wei 8 ,Y.Gao 9 , N. Tebbutt 10 , B. Markman 11 , T. Esaki 12 , S. Koski 13 ,<br />
M. Hitron 9 , N.M. Magoski 14 , J. Simes 15 ,C.Li 16 ,D.Tu 17 , C.J. O’Callaghan 18<br />
1 Department <strong>of</strong> Medicine, Division <strong>of</strong> Medical <strong>Oncology</strong>, Ottawa Hospital<br />
Research Institute, University <strong>of</strong> Ottawa, Ottawa, ON, Canada, 2 Medical <strong>Oncology</strong>,<br />
Royal Hobart Hospital, Hobart, Australia, 3 Gastroenterology & Gastrointestinal<br />
<strong>Oncology</strong>, National Cancer Center Hospital East, Chiba, Japan, 4 Department <strong>of</strong><br />
Medicine, Vancouver General Hospital & HSC, British Columbia University,<br />
Vancouver, BC, Canada, 5 Department <strong>of</strong> Medicine, Cabrini Hospital, Melbourne,<br />
Australia, 6 Department <strong>of</strong> Gastroenterology and Gastrointestinal <strong>Oncology</strong>,<br />
National Cancer Center East, Kashiwa, Japan, 7 School <strong>of</strong> Public Health &<br />
Preventive Medicine, Monash University, Melbourne, Australia, 8 Division <strong>of</strong> General<br />
Surgery, Princess Margaret Cancer Centre, University <strong>of</strong> Toronto, Toronto, ON,<br />
Canada, 9 Clinical Development, Boston Biomedical Incorporated, Boston, MA,<br />
USA, 10 Medical <strong>Oncology</strong>, Austin Hospital, Heidelberg, Australia, 11 Monash<br />
Cancer Centre, Monash Health, Melbourne, Australia, 12 Gastrointestinal and<br />
Medical <strong>Oncology</strong>, National Kyushu Cancer Center, Fukuoka, Japan,<br />
13 Department <strong>of</strong> Medicine, University <strong>of</strong> Alberta Cross Cancer Institute,<br />
Edmonton, AB, Canada, 14 Canadian Cancer Trials Group, Queens University,<br />
Kingston, ON, Canada, 15 <strong>Oncology</strong>, NHMRC Clinical Trials Centre, Sydney,<br />
Australia, 16 Global <strong>Oncology</strong>, Boston Biomedical Incorporated, Boston, MA, USA,<br />
17 Department <strong>of</strong> Mathematics and Statistics, Canadian Cancer Trials Group,<br />
Queens University, Kingston, ON, Canada, 18 Department <strong>of</strong> Public Health<br />
Sciences, Canadian Cancer Trials Group, Queens University, Kingston, ON,<br />
Canada<br />
abstracts<br />
S.A. Pugh 1 , D. Mant 2 , B. Shinkins 3 , J. Mellor 4 , R. Perera 2 , J. Primrose 1<br />
1 University Surgery, University <strong>of</strong> Southampton, Southampton, UK, 2 Nuffield<br />
Department <strong>of</strong> Primary Care Health Sciences, University <strong>of</strong> Oxford, Oxford, UK,<br />
3 Academic Unit <strong>of</strong> Health Economics, University <strong>of</strong> Leeds-Institute <strong>of</strong> Health<br />
Sciences, Leeds, UK, 4 Southampton Clinical Trials Unit, University <strong>of</strong><br />
Southampton, Southampton, UK<br />
© European Society for Medical <strong>Oncology</strong> 2016. Published by Oxford University Press on behalf <strong>of</strong> the European Society for Medical <strong>Oncology</strong>.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com.
abstracts<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
455O<br />
Efficacy and circulating tumor DNA (ctDNA) analysis <strong>of</strong> the<br />
BRAF inhibitor dabrafenib (D), MEK inhibitor trametinib (T),<br />
and anti-EGFR antibody panitumumab (P) in patients (pts) with<br />
BRAF V600E–mutated (BRAFm) metastatic colorectal cancer<br />
(mCRC)<br />
R.B. Corcoran 1 , T. André 2 , T. Yoshino 3 , J.C. Bendell 4 , C.E. Atreya 5 , J.H.<br />
M. Schellens 6 , M.P. Ducreux 7 , A. McRee 8 , S. Siena 9 , G. Middleton 10 ,<br />
M. Gordon 11 , Y. Humblet 12 , K. Muro 13 , E. Elez 14 , R. Yaeger 15 , R. Sidhu 16 ,<br />
M. Squires 17 , S. Jaeger 18 , F. Rangwala 19 , E. Van Cutsem 20<br />
1 Cancer Center, Massachusetts General Hospital, Boston, MA, USA, 2 Oncologie<br />
Médicale, Hôpital Saint-Antoine, Paris, France, 3 Gastroenterology &<br />
Gastrointestinal <strong>Oncology</strong>, National Cancer Center Hospital East, Chiba, Japan,<br />
4 GI <strong>Oncology</strong> Research, Sarah Cannon Research Institute, Nashville, TN, USA,<br />
5 Helen Diller Family Comprehensive Cancer Center, University <strong>of</strong> California,<br />
San Francisco, CA, USA, 6 Clinical Pharmacology, The Netherlands Cancer<br />
Institute, Amsterdam, Netherlands, 7 Medicine, Institute Gustave Roussy, Villejuif,<br />
France, 8 GI Medical <strong>Oncology</strong>, University <strong>of</strong> North Carolina - Chapel Hill, Chapel<br />
Hill, NC, USA, 9 Ospedale Niguarda, Università degli Studi di Milano, Niguarda<br />
Cancer Center, Milan, Italy, 10 School <strong>of</strong> Cancer Sciences, University <strong>of</strong><br />
Birmingham, Birmingham, UK, 11 Division <strong>of</strong> Arizona Center for Cancer Care,<br />
Pinnacle <strong>Oncology</strong> Hematology, Scottsdale, AZ, USA, 12 Medical <strong>Oncology</strong> Dept,<br />
St-Luc University Hosptial, Brussels, Belgium, 13 Department <strong>of</strong> Clinical <strong>Oncology</strong>,<br />
Aichi Cancer Center Hospital, Nagoya, Japan, 14 Medical <strong>Oncology</strong>, Vall d’Hebron<br />
University Hospital, Barcelona, Spain, 15 Gastrointestinal <strong>Oncology</strong>, Memorial<br />
Sloan Kettering Cancer Center, New York, NY, USA, 16 Hematology/<strong>Oncology</strong>,<br />
Amgen Inc., Thousand Oaks, CA, USA, 17 Global <strong>Oncology</strong>, Novartis Pharma AG,<br />
Basel, Switzerland, 18 Biomarkers and Diagnostics Biometrics, Novartis Institute for<br />
Biomedical Research Inc., Boston, MA, USA, 19 Global <strong>Oncology</strong>, Novartis<br />
Pharmaceuticals Corporation, East Rutherford, NJ, USA, 20 Digestive <strong>Oncology</strong>,<br />
University Hospitals Leuven, Leuven, Belgium<br />
456O<br />
Circulating tumor DNA and circulating tumor cells as predictor<br />
<strong>of</strong> outcome in the PRODIGE14-ACCORD21-METHEP2 phase II<br />
trial<br />
F-C. Bidard 1 , M. Ychou 2 , J. Madic 3 , A. Saliou 3 , O. Bouché 4 , M. Rivoire 5 ,<br />
F. Ghiringhelli 6 , E. Francois 7 , R. Guimbaud 8 , L. Mineur 9 , F. Khemissa-Akouz 10 ,<br />
T. Mazard 2 , D. Moussata 11 , W. Cacheux 1 , C. Proudhon 3 , M-H. Stern 12 ,<br />
J-Y. Pierga 1 , T. Stanbury 13 , S. Thezenas 14 , P. Mariani 15<br />
1 Medical <strong>Oncology</strong>, Institut Curie, Paris, France, 2 Department <strong>of</strong> Digestive<br />
<strong>Oncology</strong>, Institut Régional du Cancer de Montpellier (ICM), Montpellier, France,<br />
3 Circulating Biomarkers Lab, Institut Curie, Paris, France, 4 Medical <strong>Oncology</strong>, CHU<br />
de Reims - Hôpital Robert Debré, Reims, France, 5 Digestive oncology, Centre<br />
Léon Bérard, Lyon, France, 6 INSERM, U866, Centre Georges-François Leclerc<br />
(Dijon), Dijon, France, 7 Service Oncologie, Centre Antoine Lacassagne, Nice,<br />
France, 8 Digestive <strong>Oncology</strong>, CHU Toulouse, Hôpital de Rangueil, Toulouse,<br />
France, 9 Radiotherapy and <strong>Oncology</strong> GI and Liver, Institut Ste Catherine, Avignon,<br />
France, 10 Gastroenterology, CH Perpignan, Hôpital Saint Jean, Perpignan, France,<br />
11 Gastroenterology, Centre Hospitalier Lyon Sud, Pierre Bénite, France, 12 INSERM<br />
U830, Institut Curie, Paris, France, 13 GI group, R&D UNICANCER, Paris, France,<br />
14 Biometrics Unit, ICM Regional Cancer Institute <strong>of</strong> Montpellier, Montpellier,<br />
France, 15 Surgical <strong>Oncology</strong>, Institut Curie, Paris, France<br />
vi150 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
458O<br />
Frequency <strong>of</strong> potentially actionable genetic alterations in<br />
EORTC SPECTAcolor<br />
457O<br />
MiR-31-3p is a predictive biomarker <strong>of</strong> cetuximab response in<br />
FIRE3 clinical trial<br />
P. Laurent-Puig 1 , M-L. Grisoni 2 , V. Heinemann 3 , K. Fontaine 2 , C. Vazart 2 ,<br />
V. Decaulne 2 , F. Rousseau 2 , B. Courtieu 2 , F. Lieabert 2 , A. Jung 4 , D. Neureiter 5 ,<br />
R. Thiébaut 2 , S. Stintzing 6<br />
1 Université Paris Descartes, Sorbonne Paris Cité, France; Department <strong>of</strong> Biology,<br />
Hôpital Européen Georges Pompidou, Paris, France; INSERM UMR-S1147,<br />
Assistance Publique - Hopitaux De Paris, Paris, France, 2 R&D, Integragen, Evry,<br />
France, 3 Medical Dept. III, Klinikum der Universität München, Munich, Germany,<br />
4 Institute <strong>of</strong> Pathology, Klinikum der Universität München, Munich, Germany,<br />
5 Pathology, Paracelsus University Hospital Salzburg, Salzburg, Austria,<br />
6 Hematology and <strong>Oncology</strong>, Ludwig Maximilians University - Grosshadern,<br />
Munich, Germany<br />
G. Folprecht 1 , P. Beer 2 , R. Salazar 3 , A. Roth 4 , D. Aust 5 , R. Salgado 6 ,<br />
P. Laurent-Puig 7 , J. Tabernero 8 , D. Arnold 9 , A. Stein 10 , V. Golfinopoulos 11 ,<br />
A. Atasoy 11 , E. Szepessy 11 , M.P. Ducreux 12 , T. Gorlia 13 , S. Tejpar 14<br />
1 Medical Department I, University Hospital Carl Gustav Carus, Dresden, Germany,<br />
2 Sanger Institute, Wellcome Trust, Cambridge, UK, 3 Medical <strong>Oncology</strong>, Catalan<br />
Institute <strong>of</strong> <strong>Oncology</strong>, ĹHospitalet, Spain, 4 Department <strong>of</strong> Medical <strong>Oncology</strong>,<br />
Hôpitaux Universitaires de Genève - HUG, Geneva, Switzerland, 5 Institute <strong>of</strong><br />
Pathology, University Hospital <strong>of</strong> the Technical University Dresden, Dresden,<br />
Germany, 6 Department <strong>of</strong> Pathology, Breast Cancer Translational research<br />
Laboratory (BCTL), Institut Jules Bordet, Antwerp, Belgium, 7 Université Paris<br />
Descarte-Bases moléculaires de la réponse aux xénobiotiques, Paris Descartes<br />
University, Paris, France, 8 Medical <strong>Oncology</strong> Department, Vall d’Hebron University<br />
Hospital and Institute <strong>of</strong> <strong>Oncology</strong> (VHIO), Barcelona, Spain, 9 Medical <strong>Oncology</strong>,<br />
Oncologia CUF, CUF Hospitals Cancer Centre, Lisbon, Portugal, 10 Medical Dpt,<br />
UKE Universitätsklinikum Hamburg-Eppendorf KMTZ, Hamburg, Germany,<br />
11 Department <strong>of</strong> Medical <strong>Oncology</strong>, European Organisation for Research and<br />
Treatment <strong>of</strong> Cancer (EORTC AISBL), Brussels, Belgium, 12 Medical Dpt, Institut de<br />
Cancérologie Gustave Roussy, Villejuif, France, 13 Department <strong>of</strong> Biostastics,<br />
European Organisation for Research and Treatment <strong>of</strong> Cancer (EORTC AISBL),<br />
Brussels, Belgium, 14 Medical Dpt, University Hospital Gasthuisberg, Leuven,<br />
Belgium<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw370 | vi151
abstracts<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
460O<br />
POLE pro<strong>of</strong>reading domain mutation defines a subset <strong>of</strong><br />
immunogenic colorectal cancers with excellent prognosis<br />
459O<br />
ERBB2 alterations a new prognostic biomarker in stage III<br />
colon cancer from a FOLFOX based adjuvant trial (PETACC8)<br />
P. Laurent-Puig 1 , R. Balogoun 1 ,A.Cayre 2 , K. Le Malicot 3 , J. Tabernero 4 , E. Mini 5 ,<br />
G. Folprecht 6 , J-L. van Laethem 7 , J. Thaler 8 , L. Nørgård Petersen 9 , E. Sanchez 10 ,<br />
J. Bridgewater 11 , S. Ellis 12 , C. Locher 13 , C. Lagorce 14 , J-F. Ramé 15 , C. Lepage 16 ,<br />
F. Penault-Llorca 2 , J. Taieb 17<br />
1 Department <strong>of</strong> Biology, Hôpital Européen Georges Pompidou; INSERM<br />
UMR-S1147, Paris Descartes University, Paris, France, 2 Department <strong>of</strong> Pathology,<br />
Centre Jean Perrin, Clermont-Ferrand, France, 3 Biostatistics, Fédération<br />
Francophone de Cancérologie Digestive (FFCD), Dijon, France, 4 Oncologia<br />
Médica, Vall d’Hebron University Hospital Institut d’Oncologia, Barcelona, Spain,<br />
5 Experimental and Clinical medicine, University <strong>of</strong> Florence, Section <strong>of</strong> Internal<br />
Medicine, Florence, Italy, 6 Medical Department I, University Hospital Carl Gustav<br />
Carus, Dresden, Germany, 7 Dept. <strong>of</strong> Gastroenterology, Erasme University<br />
Hospital-(Universite Libre de Bruxelles), Brussels, Belgium, 8 Dept. Internal<br />
Medicine IV, Klinikum Wels - Grieskirchen, Wels, Austria, 9 Department <strong>of</strong><br />
<strong>Oncology</strong>, Roskilde Hospital, Roskilde, Denmark, 10 Instituto Português de<br />
Oncologia do Porto Francisco Gentil, Instituto Portugues de Oncologia Centro do<br />
Porto(IPO-Porto), Porto, Portugal, 11 University College London, UCL - University<br />
College London, London, UK, 12 Department <strong>of</strong> Medical <strong>Oncology</strong>, Centre Catalan<br />
d’Oncologie Clinique St. Pierre, Perpignan, France, 13 Service Gastroentérologie,<br />
CH de Meaux, Meaux, France, 14 Department <strong>of</strong> Gastroenterology and GI<br />
oncology, Hopital European George Pompidou, Paris, France, 15 Department <strong>of</strong><br />
<strong>Oncology</strong>, Centre Catherine de Sienne, Nantes, France,<br />
16 Hepato-Gastroenterology Department, Dijon University Hospital and INSERM<br />
U866, Fédération Francophone de Cancérologie Digestive (FFCD), Dijon, France,<br />
17 Department <strong>of</strong> Gastroenterology and Digestive <strong>Oncology</strong>, Hopital European<br />
George Pompidou, Paris, France<br />
M.A. Glaire 1 , E. Domingo 1 , L. Vermeulen 2 , T. van Wezel 3 , G-J. Liefers 4 ,R.<br />
A. Lothe 5 , A. Nesbakkend 5 , S.A. Danielsen 5 , I. Zlobec 6 , V. Koelzer 1 , M. Berger 6 ,<br />
S. Castellví-Bel 7 , M. de Bruyn 8 , M. Novelli 9 , S. Tejpar 10 , M. Delorenzi 11 , R. Kerr 12 ,<br />
D. Kerr 12 , I. Tomlinson 1 , D.N. Church 1<br />
1 Molecular and Population Genetics Laboratory and NIHR Comprehensive<br />
Biomedical Research Centre, Wellcome Trust Centre for Molecular Genetics,<br />
Oxford, UK, 2 Center for Experimental Molecular Medicine, Academic Medical<br />
Center (AMC), Amsterdam, Netherlands, 3 Albinusdreef 2, Leiden University<br />
Medical Center (LUMC), Leiden, Netherlands, 4 Department <strong>of</strong> Surgery, Leiden<br />
University Medical Center (LUMC), Leiden, Netherlands, 5 K.G.Jebsen Colorectal<br />
Research Centre and Department <strong>of</strong> Gastrointestinal Surgery, Oslo University<br />
Hospital, Oslo, Norway, 6 Department <strong>of</strong> Medical <strong>Oncology</strong>, Universitätsspital<br />
Bern, Bern, Switzerland, 7 Gastroenterology Department, Universitat de Barcelona,<br />
Barcelona, Spain, 8 Department <strong>of</strong> Obstetrics and Gynecology, University Hospital<br />
Groningen (UMCG), Groningen, Netherlands, 9 Department <strong>of</strong> Histopathology,<br />
University College London Hospital, London, UK, 10 Department <strong>of</strong> Molecular<br />
Digestive <strong>Oncology</strong>, University Hospitals Leuven - Campus Gasthuisberg, Leuven,<br />
Belgium, 11 15Ludwig Center for Cancer Research, Ludwig Cancer Center(Division<br />
d’Onco-Immunologie Clinique) <strong>of</strong> the University <strong>of</strong> Lausanne - CHUV, Lausanne,<br />
Switzerland, 12 18Oxford Cancer Centre, The Oxford Cancer Centre, Churchill<br />
Hospital, Oxford Radcliffe Hospitals NHS Trust, Oxford, UK<br />
vi152 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
461O<br />
Adjuvant FOLFOX+ cetuximab vs FOLFOX in full RAS and<br />
BRAF wild type stage III colon cancer patients: Results from<br />
the PETACC8 trial<br />
J. Taieb 1 , K. Le Malicot 2 , R. Balogoum 3 , J. Tabernero 4 , E. Mini 5 , G. Folprecht 6 ,<br />
J-L. van Laethem 7 , J-F. Emile 8 , C. Mulot 9 , S. Fratté 10 , C-B. Levaché 11 ,<br />
L. Saban-Roche 12 , J. Thaler 13 , L. Nørgård Petersen 14 , E. Sanchez 15 ,<br />
J. Bridgewater 16 , G. Perkins 3 , C. Lepage 17 , A. Zaanan 1 , P. Laurent-Puig 3<br />
1 Department <strong>of</strong> Gastroenterology and GI oncology; Université Paris Descartes,<br />
Hopital European George Pompidou, Paris, France, 2 Biostatistics, Fédération<br />
Francophone de Cancérologie Digestive (FFCD), Dijon, France, 3 Université Paris<br />
Descartes, Sorbonne Paris Cité, France; Department <strong>of</strong> Biology, Hôpital Européen<br />
Georges Pompidou, Paris, France; INSERM UMR-S1147, Assistance Publique -<br />
Hopitaux De Paris, Paris, France, 4 Oncologia Médica, Vall d’Hebron University<br />
Hospital Institut d’Oncologia, Barcelona, Spain, 5 Section <strong>of</strong> Internal Medicine,<br />
University <strong>of</strong> Florence, Dpt <strong>of</strong> experimental and clinical medicine, Florence, Italy,<br />
6 Department <strong>of</strong> Internal Medicine I, University Hospital Carl Gustav, Dresden,<br />
Germany, 7 Dept. <strong>of</strong> Gastroenterology, Erasme University Hospital-(Universite Libre<br />
de Bruxelles), Brussels, Belgium, 8 Pathology department, Hopital Ambroise Pare,<br />
Boulogne-Billancourt, France, 9 Depatment <strong>of</strong> Biology, Hopital Européen Georges<br />
Pompidou, INSERM UMR-S1147, Assistance Publique - Hopitaux De Paris, Paris,<br />
France, 10 Department <strong>of</strong> Gastroenterology, Centre Hospitalier de<br />
Belfort-Monbéliard, Montbéliard, France, 11 Department <strong>of</strong> radiotherapy and<br />
medical oncology, Polyclinique Francheville, Périgueux, France, 12 Department <strong>of</strong><br />
medical <strong>Oncology</strong>, Institut de Cancérologie de la Loire, Saint-Priest-En-Jarez,<br />
France, 13 Dept. Internal Medicine IV, Klinikum Wels - Grieskirchen, Wels, Austria,<br />
14 Department <strong>of</strong> <strong>Oncology</strong>, Rigshospitalet, Kobenhavn, Denmark, 15 Gruppo<br />
Cooperativo do Cancro Digestivo da Associação Portuguesa de Investigação<br />
Oncológica (GCCD, APIO), - Instituto Português de Oncologia do Porto Francisco<br />
Gentil, Porto, Portugal, 16 University College London, UCL - University College<br />
London, London, UK, 17 Hepato-Gastroenterology Department, Dijon University<br />
Hospital and INSERM U866, Fédération Francophone de Cancérologie Digestive<br />
(FFCD), Dijon, France<br />
462PD<br />
Modified FOLFOXIRI (mFOLFOXIRI) plus cetuximab (cet),<br />
followed by cet or bevacizumab (bev) maintenance, in RAS/<br />
BRAF wt metastatic colorectal cancer (mCRC): The phase II<br />
randomized MACBETH trial by GONO<br />
C. Cremolini 1 , C. Antoniotti 1 , F. Loupakis 1 , F. Bergamo 2 , L. Ferrari 3 , R. Grande 4 ,<br />
G. Tonini 5 , G. Masi 1 , M. Schirripa 1 , M. Bonotto 6 , C. Soldà 2 , S. Lucchesi 7 ,<br />
D. rossini 1 , D. Corsi 8 , M. Ronzoni 9 , F.L. Rojas Llimpe 10 , G. Fontanini 11 , L. Boni 12 ,<br />
V. Zagonel 2 , A. Falcone 1<br />
1 Unit <strong>of</strong> Medical <strong>Oncology</strong> 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy,<br />
2 U.O.Oncologia Medica, Istituto Oncologico Veneto IRCCS, Padua, Italy,<br />
3 Department <strong>of</strong> <strong>Oncology</strong>, Azienda Ospedaliera Universitaria-Udine Sta Maria della<br />
Misericordia, Udine, Italy, 4 Department <strong>of</strong> <strong>Oncology</strong>, Ospedale Umberto I,<br />
Frosinone, Italy, 5 Department <strong>of</strong> <strong>Oncology</strong>, Campus Bio-Medico di Roma, Rome,<br />
Italy, 6 Department <strong>of</strong> <strong>Oncology</strong>, AOU Santa Maria della Misericordia, Udine, Italy,<br />
7 Department <strong>of</strong> <strong>Oncology</strong>, Ospedale “F. Lotti” Pontedera, Pontedera, Italy,<br />
8 Department <strong>of</strong> <strong>Oncology</strong>, Ospedale San Giovanni Calibita - Fatebenefratelli,<br />
Rome, Italy, 9 <strong>Oncology</strong> Department, IRCCS San Raffaele, Milan, Italy,<br />
10 Department <strong>of</strong> <strong>Oncology</strong>, Policlinico S. Orsola-Malpighi, Bologna, Italy, 11 U.O.<br />
Anatomia Patologica 3, Azienda Ospedaliera Universitaria S.Chiara, Pisa, Italy,<br />
12 Istituto Toscano Tumori, AOU Careggi, Florence, Italy<br />
Background: MACBETH trial aimed at evaluating the efficacy <strong>of</strong> a 4 months-induction<br />
with mFOLFOXIRI plus cet in RAS/BRAF wt mCRC patients (pts), followed by two<br />
different maintenance strategies: continuing cet or switching to bev. Although the<br />
primary endpoint, 10 months-Progression Free Rate, was not met in any treatment<br />
arm, the induction treatment was very active and the safety pr<strong>of</strong>ile was acceptable.<br />
Methods: Unresectable and untreated mCRC pts aged between 18 and 75 ys were<br />
eligible if their tumors were RAS/BRAF wt at central screening. Pts were randomized to<br />
receive up to 8 cycles <strong>of</strong> mFOLFOXIRI + cet (cet 500 mg/sqm, iri 130 mg/sqm, oxa 85<br />
mg/sqm, I-LV 200 mg/sqm, 5FU 2400 mg/sqm in 48h q2w), followed by cet (arm A)<br />
or bev (arm B) until progression (PD).<br />
Results: Between Nov 2011 and Feb 2015, 323 pts from 21 Italian centers were<br />
screened and 116 pts were included in the modified intention to treat (mITT)<br />
population (arm A/B N = 59/57). Response rate was 72% (arm A/B 68%/75%) in the<br />
mITT population and 76% in 109 evaluable pts. Early response rate was 74% (arm A/B<br />
74%/74%), and median deepness <strong>of</strong> response was 53% (arm A/B 49%/56%). Resection<br />
rate was 38% (arm A/B 46%/30%) in the mITT population and 65% (arm A/B 71%/<br />
58%) in the liver-only subgroup (N = 52, arm A/B 28/24). One-third <strong>of</strong> pts with<br />
liver-only disease who achieved resection underwent re-resection with radical intent<br />
after PD. At a median follow-up <strong>of</strong> 25.5 months, 100 pts (arm A/B 48/52) progressed.<br />
Median PFS in arm A and B was 11.2 and 9.3 months, respectively (HR: 0.78<br />
[0.52-1.18). Among patients who received at least one cycle <strong>of</strong> maintenance (arm A/B<br />
N = 36/41) median PFS was 14.0 and 10.7 months (HR: 0.63 [0.37-1.08]), and median<br />
PFS from the beginning <strong>of</strong> maintenance was 8.6 and 5.6 months (HR: 0.69 [0.40-1.17]).<br />
Conclusions: mFOLFOXIRI + cet demonstrated remarkable activity, leading to high<br />
resection rate. Re-resections were achievable after PD in a considerable subgroup <strong>of</strong> pts<br />
with liver-only disease, supporting the long-term impact <strong>of</strong> active upfront regimens.<br />
Continuing cet as maintenance until PD seems to positively affect PFS. OS results will<br />
be presented.<br />
Clinical trial identification: NCT02295930<br />
Legal entity responsible for the study: GONO (Gruppo Oncologico Nord-Ovest)<br />
Funding: GONO (Gruppo Oncologico Nord-Ovest)<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
463PD<br />
Clinical factors influencing outcome in metastatic colorectal<br />
cancer (mCRC) patients treated with fluoropyrimidine and<br />
bevacizumab (FP + Bev) maintenance treatment (Tx) vs<br />
observation: A pooled analysis <strong>of</strong> the phase 3 CAIRO3 and<br />
AIO 0207 trials<br />
K. Goey 1 , S. Elias 2 , A. Hinke 3 , M. van Oijen 4 , C. Punt 4 , S. Hegewisch Becker 5 ,<br />
D. Arnold 6 , M. Koopman 1<br />
1 Medical <strong>Oncology</strong>, University Medical Center Utrecht, Utrecht, Netherlands,<br />
2 Epidemiology, Julius Center for Health Sciences and Primary Care, University<br />
Medical Center Utrecht, Utrecht, Netherlands, 3 Epidemiology, WiSP GmbH,<br />
Langenfeld, Germany, 4 Medical <strong>Oncology</strong>, Academic Medical Center, University <strong>of</strong><br />
Amsterdam, Amsterdam, Netherlands, 5 Medical <strong>Oncology</strong>, Internal Medicine<br />
<strong>Oncology</strong> and Hematology, Hamburg, Germany, 6 Medical <strong>Oncology</strong>, Oncologia<br />
CUF, CUF Hospitals Cancer Centre, Lisbon, Portugal<br />
Background: The CAIRO3 and AIO 0207 studies showed that first-line maintenance<br />
Tx with FP + Bev vs observation after FP + oxaliplatin(Ox) + Bev induction Tx in<br />
mCRC patients is effective, while quality <strong>of</strong> life is maintained. We performed a pooled<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw370 | vi153
abstracts<br />
analysis and aimed to identify subgroups with clinical characteristics that benefit most<br />
from FP + Bev maintenance Tx.<br />
Methods: A total <strong>of</strong> 871 mCRC patients (CAIRO3: n = 557; two arms <strong>of</strong> AIO 0207:<br />
n = 314) that received FP + Bev maintenance Tx vs observation were analyzed. We<br />
analyzed whether Tx effect was modified by 12 clinical characteristics: sex; age;<br />
performance status; response to induction Tx; stage; primary tumor site and resection<br />
status; number <strong>of</strong> metastatic sites; synchronous vs metachronous mCRC; LDH at<br />
randomization; platelet count and CEA at start <strong>of</strong> induction Tx. We used mixed effects<br />
Cox models with study as random intercept and baseline covariables and treatment as<br />
fixed effects. Time to 1 st progression (PFS1), time to 2 nd progression after<br />
FP + Ox + Bev reintroduction (PFS2, primary endpoint <strong>of</strong> both studies) and overall<br />
survival (OS) were analyzed.<br />
Results: FP + Bev maintenance Tx compared to observation resulted in a highly<br />
significant benefit in PFS1 (HR 0.40 [95% CI 0.34 - 0.47]) and PFS2 (HR 0.68 [95% CI<br />
0.59 - 0.80]), which was observed in all investigated subgroups. OS results showed a<br />
marked heterogeneity between the two studies, for yet unknown reasons, and remained<br />
not significant in the pooled analysis (HR 0.90 [95% CI 0.76 – 1.05]). Patients with<br />
elevated platelet count (> 400 x 10 9 /L) at start <strong>of</strong> induction Tx had significantly more<br />
benefit from FP + Bev maintenance Tx vs observation in PFS1 (HR 0.31 [95% CI 0.23 -<br />
0.41] vs HR 0.45 [95% CI 0.37 - 0.55]) and PFS2 (HR 0.53 [95% CI 0.40 - 0.70] vs HR<br />
0.76 [95% CI 0.63 - 0.92]). Tests for interaction were p < 0.05.<br />
Conclusions: This pooled analysis confirms the benefit <strong>of</strong> FP + Bev maintenance Tx<br />
compared to observation in the first-line Tx <strong>of</strong> mCRC. This benefit was observed in all<br />
subgroups that were investigated. We identified platelet count at start <strong>of</strong> induction Tx<br />
to be a significant predictive factor for efficacy <strong>of</strong> FP + Bev maintenance Tx.<br />
Clinical trial identification: CAIRO3: registrered with ClinicalTrials.gov, number<br />
NCT00442637. Published: April 8, 2015 (Lancet) AIO 0207: registrered with<br />
ClinicalTrials.gov, number NCT00973609. Published: September 9, 2015 (Lancet<br />
Oncol)<br />
Legal entity responsible for the study: CAIRO3: Dutch Colorectal Cancer Group<br />
(DCCG); AIO 0207: Arbeitsgemeinschaft Internistische Onkologie (AIO)<br />
Funding: CAIRO3: Dutch Colorectal Cancer Group (DCCG); AIO 0207:<br />
Arbeitsgemeinschaft Internistische Onkologie (AIO)<br />
Disclosure: M. van Oijen: Research funding: Roche, Merck, Bayer, Lilly (all outside the<br />
submitted abstract). C. Punt: Advisory role: Roche, Amgen, Bayer, Nordic Pharma,<br />
Merck-Serono. S. Hegewisch Becker: Advisory role: Roche, Merck, Amgen, Lilly. D.<br />
Arnold: Advisory role: Roche, Bayer, Merck, Servier. Honoraria: San<strong>of</strong>i-Aventis,<br />
Amgen, Merck, Bayer. M. Koopman: Advisory role: Amgen, Roche, Bayer and Merck.<br />
Research funding: Roche, Merck, Bayer (all outside the submitted abstract). All other<br />
authors have declared no conflicts <strong>of</strong> interest.<br />
464PD<br />
A multi-center, randomized, double-blind phase II trial <strong>of</strong><br />
FOLFIRI + regorafenib or placebo for patients with metastatic<br />
colorectal cancer who failed one prior line <strong>of</strong><br />
oxaliplatin-containing therapy<br />
B. O’Neil 1 ,S.O’Reilly 2 , S. Kasbari 3 , R. Kim 4 , R. McDermott 5 ,D.Moore 6 ,<br />
W. Grogan 7 , A. Cohn 8 , T. Bekaii-Saab 9 , A. Ivanova 6 , O. Olowokure 10 ,<br />
N. Fernando 11 , J. McCaffrey 12 , B. El-Rayes 13 , A. Horgan 14 , T. Ryan 15 , G. Sherrill 16 ,<br />
G. Yacoub 17 , R.M. Goldberg 18 , H. San<strong>of</strong>f 19<br />
1 <strong>Oncology</strong>, Indiana University Simon Cancer Center, Indianapolis, IN, USA,<br />
2 Medical <strong>Oncology</strong>, Cork University Hospital, Cork, Ireland, 3 <strong>Oncology</strong>, SMOC,<br />
Wison, NC, USA, 4 Clinical <strong>Oncology</strong>, H. Lee M<strong>of</strong>fitt Cancer Center University <strong>of</strong><br />
South Florida, Tampa, FL, USA, 5 Dept. <strong>of</strong> Medical <strong>Oncology</strong>, AMNCH Adelaide<br />
and Meath Hospital, Dublin, Ireland, 6 Biostatistics, University <strong>of</strong> North Carolina -<br />
Chapel Hill, Chapel Hill, NC, USA, 7 Medical <strong>Oncology</strong>, Beaumont Hospital, Dublin,<br />
Ireland, 8 <strong>Oncology</strong>, Rocky Mountain Cancer Centers U.S. <strong>Oncology</strong> Network,<br />
Denver, CO, USA, 9 Hematology/<strong>Oncology</strong>, Mayo Clinic, Phoenix, AZ, USA,<br />
10 Hematology/<strong>Oncology</strong>, University <strong>of</strong> Cincinnati, Cincinnati, OH, USA,<br />
11 Hematology/<strong>Oncology</strong>, Georgia Cancer Centers, Atlanta, GA, USA, 12 Medical<br />
<strong>Oncology</strong>, Irish Clinical <strong>Oncology</strong> Research Group, Cork, Ireland, 13 <strong>Oncology</strong>,<br />
Emory University Winship Cancer Institute, Atlanta, GA, USA, 14 Medical <strong>Oncology</strong>,<br />
University Hospital Waterford, Waterford, Ireland, 15 Hematology/<strong>Oncology</strong>, NYU<br />
Langone Medical Center, New York, NY, USA, 16 Hematology/<strong>Oncology</strong>, Moses<br />
Cone Health System, Greensboro, NC, USA, 17 Hematology/<strong>Oncology</strong>, Wake<br />
Forest University Comprehensive Cancer Center, Winston Salem, NC, USA,<br />
18 Division <strong>of</strong> Medical <strong>Oncology</strong>, The Ohio State University Comprehensive Cancer<br />
Center and James Cancer Hospital, Columbus, OH, USA, 19 Hematology/<br />
<strong>Oncology</strong>, Lineberger Comprehensive Cancer Center University <strong>of</strong> North Carolina,<br />
Chapel Hill, NC, USA<br />
Background: Regorafenib (rego) is a multi-kinase inhibitor that inhibits angiogenesis<br />
(VEGFR 2/3, TIE-2), and growth and proliferation (BRAF), and is active in<br />
chemotherapy-refractory mCRC. This international investigator-initiated trial assessed<br />
the efficacy <strong>of</strong> second-line FOLFIRI +/- rego given on an intermittent dosing strategy<br />
(week on, week <strong>of</strong>f) in patients with mCRC.<br />
Methods: Patients with mCRC were recruited from 45 sites in the US and Ireland<br />
(ICORG). Key eligibility included progression on first-line OX and fluoropyrimidine,<br />
measurable disease, ECOG PS 0-1, and adequate organ function. Patients were<br />
randomized 2:1 (double blind), stratified by prior bevacizumab, to receive rego 160 mg<br />
(arm A) or placebo (arm B) on days 4-10 and 18-24 with FOLFIRI given on days 1-2<br />
and 15-16 <strong>of</strong> every 28 day cycle. Treatment was continued until progression or toxicity.<br />
The primary endpoint was PFS; secondary endpoints included RR (CR + PR) and OS.<br />
With n = 180 (120 A, 60 B) 75% event rate yielded 135 events required to achieve 90%<br />
power for a 60% improvement in PFS with a one-sided alpha <strong>of</strong> 0.1.<br />
Results: 181 patients were enrolled from 4/11 to 8/15 (120 rego, 61 placebo). Arms<br />
were balanced for age, sex, prior adjuvant, prior bev. 118 (65.2%) had prior anti-VEGF,<br />
14 (7.7%) had prior anti-EGFR in 1 st line (2 patients received both). Median PFS was<br />
6.14 mo for arm A and 5.29 mo for arm B, (HR 0.69, log-rank p = 0.02). Median OS<br />
was 13.2 mo for A and 12.0 mo for B (HR 1.06, p = 0.76). RR in evaluable pts was 32%<br />
(95% CI 23, 42) for A, 19% (95% CI 10, 32) for B, p = 0.10. RR in ITT population was<br />
27% versus 18% (p = 0.11). Grade ≥ 3 adverse events occurring in > 5% <strong>of</strong> pts (A v. B)<br />
included neutropenia (40% v. 30%), diarrhea (14% v. 5%), hypophosphatemia (14% v<br />
0), fatigue (11% v. 7%), mucositis (9% v. 10%), HTN (8% v. 2%), elevated lipase (8%<br />
v. 3%). Hand-foot syndrome grade ≥ was5%onarmAvs2%onB.<br />
Conclusions: The addition <strong>of</strong> rego on an intermittent schedule to FOLFIRI was<br />
tolerable, and resulted in a statistically significant prolongation <strong>of</strong> PFS compared to<br />
FOLFIRI alone. The study was underpowered to definitively evaluate OS, and<br />
potentially influenced by post-protocol crossover to regorafenib.<br />
Clinical trial identification: NCT01298570<br />
Legal entity responsible for the study: University <strong>of</strong> North Carolina at Chapel Hill<br />
Funding: Bayer<br />
Disclosure: B. O’Neil: Has consulted for Bayer in past 2 years and received honoraria<br />
totaling < $10,000 USD. T. Bekaii-Saab: Has consulted for Bayer. O. Olowokure: Has<br />
consulted for Bayer and participated in Bayer speaker’s bureau. B. El-Rayes: Has<br />
consulted for Bayer for honoraria. R.M. Goldberg: Consulting for Bayer. All other<br />
authors have declared no conflicts <strong>of</strong> interest.<br />
465PD<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
TERRA: a randomized, double-blind, placebo-controlled<br />
phase 3 study <strong>of</strong> TAS-102 in Asian patients with metastatic<br />
colorectal cancer<br />
T.W. Kim 1 , L. Shen 2 , J.M. Xu 3 , V. Sriuranpong 4 ,H.Pan 5 ,R.Xu 6 , S-W. Han 7 ,<br />
T. Liu 8 , Y.S. Park 9 , C. Shir 10 , Y. Bai 11 ,F.Bi 12 , J.B. Ahn 13 , S. Qin 14 ,Q.Li 15 ,C.Wu 16 ,<br />
F. Zhou 17 ,D.Ma 18 , V. Srimuninnimit 19 ,J.Li 20<br />
1 Department <strong>of</strong> <strong>Oncology</strong>, Asan Medical Center, Seoul, Republic <strong>of</strong> Korea,<br />
2 Gastrointestinal <strong>Oncology</strong>, Peking University Cancer Hospital, Beijing, China,<br />
3 Gastrointestinal <strong>Oncology</strong>, Affiliated Hospital Cancer Center, Academy <strong>of</strong> Military<br />
Medical Sciences, Beijing, China, 4 Medicine, Chulalongkorn University and The<br />
King Chulalongkorn Memorial Hospital, Bangkok, Thailand, 5 Medical <strong>Oncology</strong>, Sir<br />
Run Run Shaw Hospital, Zhejiang University School <strong>of</strong> Medicine, Hangzhou,<br />
China, 6 Medical <strong>Oncology</strong>, Cancer Centre Sun Yat-Sen University, Guangzhou,<br />
China, 7 Internal Medicine, Seoul National University Hospital, Seoul, Republic <strong>of</strong><br />
Korea, 8 Medical <strong>Oncology</strong>, Zhongshan Hospital Fudan University, Shanghai,<br />
China, 9 Medicine, Samsung Medical Center Sungkyunkwan University School <strong>of</strong><br />
Medicine, Seoul, Republic <strong>of</strong> Korea, 10 <strong>Oncology</strong>, Fujian Medical University Union<br />
Hospital, Fuzhou, China, 11 Digestive <strong>Oncology</strong>, Harbin Medical University Cancer<br />
Hospital, Harbin, China, 12 Abdomen <strong>Oncology</strong>, West China Hospital, Sichuan<br />
University, Chengdu, China, 13 Internal Medicine, Yonsei University College <strong>of</strong><br />
Medicine, Seoul, Republic <strong>of</strong> Korea, 14 Medical <strong>Oncology</strong>, No. 81 Hospital <strong>of</strong> PLA,<br />
Nanjing, China, 15 <strong>Oncology</strong>, Shanghai First People’s Hospital Affiliated Shanghai<br />
Jiaotong University, Shanghai, China, 16 <strong>Oncology</strong>, The First People’s Hospital <strong>of</strong><br />
Changzhou, Changzhou, China, 17 Medical and Radiation <strong>Oncology</strong>, Zhongnan<br />
Hospital <strong>of</strong> Wuhan University, Wuhan, China, 18 Medical <strong>Oncology</strong>, Guangdong<br />
General Hospital, Guangzhou, China, 19 Medical <strong>Oncology</strong> Division, Siriraj Hospital,<br />
Mahidol University, Bangkok, Thailand, 20 Medical <strong>Oncology</strong>, Tongji University<br />
Affiliate Tianyou Hospital, Shanghai, China<br />
Background: The RECOURSE study demonstrated that trifluridine/tipiracil<br />
hydrochloride (TAS-102) significantly improved overall survival (OS) and<br />
progression-free survival (PFS) in patients (pts) with metastatic colorectal cancer<br />
(mCRC) who had failed standard therapies. In the TERRA study, the efficacy and<br />
safety <strong>of</strong> TAS-102 were evaluated in similar Asian population with mCRC who had<br />
failed conventional cytotoxic therapies.<br />
Methods: This was a multicenter, randomized, double-blind, placebo-controlled phase<br />
3 study. Pts must have had received at least 2 prior standard regimens for mCRC,<br />
including fluoropyrimidines, oxaliplatin, and irinotecan. Prior anti-VEGF or<br />
anti-EGFR targeted therapy was not mandatory therapy. Between 16 Oct, 2013 and 15<br />
Jun, 2015, 516 pts were screened and 406 pts were enrolled. Pts were stratified by KRAS<br />
status and geographic region and were randomized in a 2:1 ratio to receive TAS-102<br />
(35 mg/m 2 BID on days 1-5 and 8-12 <strong>of</strong> each 28-day cycle) plus best supportive care<br />
(BSC) or placebo plus BSC. The primary endpoint was OS. Key secondary endpoints<br />
included PFS and safety.<br />
Results: In the primary analysis, TAS-102 demonstrated an improvement in OS versus<br />
placebo, hazard ratio ([HR] 0.79; 95% confidence interval [CI] 0.62-0.99; P = 0.035)<br />
(the median OS were 7.8 versus 7.1 months, respectively). Improvement in PFS was<br />
also observed (HR: 0.43; 95% CI 0.34-0.54, P < 0.001) for the TAS-102 group vs<br />
placebo (median PFS were 2.0 versus 1.8 months, respectively). In particular, the HRs<br />
for OS in the subgroups were 0.77 in pts with KRAS wild-type tumors and 0.83 in pts<br />
with KRAS mutated tumors. The disease control rate (DCR) was higher in the<br />
vi154 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
TAS-102 group (44.1% versus 14.6 %). Most frequent Grade ≥3 treatment-emergent<br />
adverse events (TEAEs) were neutropenia (20.3% in TAS-102, 0% in placebo), anemia<br />
(15.9%, 5.9 %) and leukopenia (4.8%, 0%).<br />
Conclusions: The TERRA study demonstrated an improvement in OS and PFS in<br />
Asian pts with mCRC who had failed conventional cytotoxic therapies. The safety<br />
pr<strong>of</strong>ile <strong>of</strong> TAS-102 was similar to that in previous studies. A data according to the pre<br />
and post-study treatments, especially targeted therapies, will be presented.<br />
Clinical trial identification: NCT01955837<br />
Legal entity responsible for the study: Taiho Pharmaceutical Co., Ltd.<br />
Funding: Taiho Pharmaceutical Co., Ltd.<br />
Disclosure: T.W. Kim: Employment, leadership, Tock, Speaker’s bureau, patients,<br />
expert testimony Travel expense: No Research fund: Roche, Merck Serono Consulting<br />
or advisory role: Bayer, Lilly All other authors have declared no conflicts <strong>of</strong> interest.<br />
466PD<br />
Sorafenib (Soraf) and irinotecan (Iri) combination for<br />
pretreated RAS-mutated metastatic colorectal cancer<br />
(mCRC) patients: a multicentre randomized phase II trial<br />
(NEXIRI 2-PRODIGE 27)<br />
E. Samalin 1 , C. de la Fouchardiere 2 , S. Thezenas 3 , V. Boige 4 , H. Senellart 5 ,<br />
R. Guimbaud 6 , J. Taieb 7 , E. Francois 8 , M-P. Galais 9 , A. Adenis 10 , A. Lievre 11 ,<br />
L. Dahan 12 , F. Di Fiore 13 , F. Boissiere 14 , E. Crapez 14 , F. Bibeau 15 ,<br />
A. Ho-Pun-Cheung 14 , S. Poujol 16 , T. Mazard 1 , M. Ychou 1<br />
1 Medical <strong>Oncology</strong>, ICM Regional Cancer Institute <strong>of</strong> Montpellier, Montpellier,<br />
France, 2 Digestive <strong>Oncology</strong>, Centre Léon Bérard, Lyon, France, 3 Biometrics Unit,<br />
ICM Regional Cancer Institute <strong>of</strong> Montpellier, Montpellier, France, 4 Digestive<br />
<strong>Oncology</strong>, Institut Gustave Roussy, Villejuif, France, 5 Digestive <strong>Oncology</strong>, Institut<br />
de Cancérologie de l’Ouest, Nantes, France, 6 Digestive <strong>Oncology</strong>, CHU Toulouse,<br />
Hôpital de Rangueil, Toulouse, France, 7 Department <strong>of</strong> Gastroenterology and<br />
Digestive <strong>Oncology</strong>, Hôpital Européen Georges Pompidou, Paris, France, 8 Service<br />
Oncologie, Centre Antoine Lacassagne, Nice, France, 9 Medical <strong>Oncology</strong>, Centre<br />
Francois Baclesse, Caen, France, 10 Service Cancérologie Digestive, Centre Oscar<br />
Lambret, Lille, France, 11 Medical <strong>Oncology</strong>, Institut Curie, St. Cloud, France,<br />
12 Medical <strong>Oncology</strong>, CHU La Timone Adultes, Marseille, France, 13 Digestive<br />
<strong>Oncology</strong> Unit, CHU Hôpitaux de Rouen-Charles Nicolle, Rouen, France,<br />
14 Translationnal Research Unit, ICM Regional Cancer Institute <strong>of</strong> Montpellier,<br />
Montpellier, France, 15 Anatomo-Pathology Department, ICM Regional Cancer<br />
Institute <strong>of</strong> Montpellier, Montpellier, France, 16 Pharmacology Department, ICM<br />
Regional Cancer Institute <strong>of</strong> Montpellier, Montpellier, France<br />
abstracts<br />
Results: We included 173 patients (age 62 years [31-82]; PS 0/1: 38/61%) between<br />
January 2012 and July 2014 in 17 French centres. Main results were (median follow-up<br />
17.5 months):<br />
Conclusions: In this randomized study, we confirmed the NEXIRI regimen efficacy for<br />
refractory mtRAS mCRC patients and the predictive value <strong>of</strong> CCND1 rs9344 which<br />
may identify patients who benefit from this combination. These results justify<br />
comparing NEXIRI to regorafenib monotherapy in CCND1 rs9344 A/A patients.<br />
Clinical trial identification: The trial was registered on clinicaltrials.gov:<br />
NCT01715441<br />
Legal entity responsible for the study: Institut régional du Cancer de Montpellier<br />
(ICM)<br />
Funding: Grant from the Bayer laboratories<br />
Disclosure: E. Samalin: Honoraria: Lilly, San<strong>of</strong>i, Amgen, Roche Consulting or<br />
Advisory Role: Amgen, San<strong>of</strong>i, Roche Research funding: Bayer (institution) Travel,<br />
Accommodations, Expenses: Novartis, Lilly, Ipsen, Roche C. de la Fouchardiere:<br />
Consulting or Advisory Role: Amgen, Lilly, Bayer, Roche Research Funding: Roche<br />
Travel, Accommodations, Expenses: Roche, Celgene, Amgen. V. Boige: Honoraria:<br />
Bayer, San<strong>of</strong>i, Merk-Serono, Daiichi Sankyo Consulting or Advisory Role: Bayer,<br />
Amgen Research Funding: Merk-Serono Travel, Accommodations, Expenses:<br />
Merk-Serono, Amgen. H. Senellart: Consulting or Advisory Role: Boehringer<br />
Ingelheim, Merck, Roche Travel, Accommodations, Expenses: Roche, Pfizer. R.<br />
Guimbaud: Consulting or Advisory Role: Ipsen Research Funding: Roche/Genentech<br />
(institution) J. Taieb: Honoraria: Merck, Amgen, Lilly, San<strong>of</strong>i, Celgene, Roche Travel,<br />
Accommodations, Expenses: Merck, Amgen, Roche. M-P. Galais: Honoraria: Roche. A.<br />
Adenis: Consulting or Advisory Role: Bayer, San<strong>of</strong>i Speaker’s Bureau: Roche/<br />
Genentech Research Funding: Bayer (Institution), San<strong>of</strong>i (Institution). A. Lievre:<br />
Honoraria: Merck Serono, San<strong>of</strong>i, Lilly, Amgen, Roche Consulting or Advisory Role:<br />
Merck Serono, San<strong>of</strong>i, Lilly, Roche Speaker’s Bureau: Celgene Travel,<br />
Accommodations, Expenses: Merck Serono, Amgen, Lilly, Roche. F. Di Fiore:<br />
Honoraria: Merck, Amgen, San<strong>of</strong>i, Bayer, Novartis, Lilly, Celgene, Roche Research<br />
Funding: Amgen (Institution), Merck (Institution), Roche (Institution). F. Bibeau:<br />
Honoraria: Amgen, Merck, San<strong>of</strong>i, Roche Consulting or Advisory Role: Amgen, San<strong>of</strong>i<br />
Research Funding: Roche (Institution) Travel, Accommodations, Expenses: Amgen,<br />
Roche T. Mazard: Honoraria: Amgen, San<strong>of</strong>i Research Funding: Roche Parma AG<br />
(Institution) Travel, Accommodations, Expenses: Amgen. M. Ychou: Honoraria: Bayer,<br />
Merck, Roche Consulting or Advisory Role: Bayer, Merck, Roche All other authors<br />
have declared no conflicts <strong>of</strong> interest.<br />
Background: Sorafenib and irinotecan combination (NEXIRI) showed promising<br />
efficacy with a 65% disease control rate (DCR) in pretreated mutated (mt) KRAS<br />
mCRC. In our previous single-arm phase II study, CCND1 rs9344 A/A polymorphism<br />
was found to be a candidate predictive biomarker (Samalin et al. 2014). Our<br />
multicentre randomized phase II trial aimed to determine the 2-month<br />
progression-free survival (2-PFS) <strong>of</strong> NEXIRI vs Iri or Soraf monotherapies in these<br />
patients after failure <strong>of</strong> all approved active drugs at the time <strong>of</strong> the study.<br />
Methods: Patients PS ≤ 1 with progressive non-resectable mtKRAS (then RAS) mCRC<br />
pretreated with irinotecan, oxaliplatin, fluoropyrimidines and bevacizumab (none with<br />
regorafenib), were randomized in 3 arms: NEXIRI (biweekly Iri IV 120, 150, 180mg/m 2<br />
at C3 combined with a fixed dose <strong>of</strong> 400mg Soraf twice daily) vs Iri (180mg/m 2 ) alone<br />
vs Soraf alone, until progression or toxicity, with cross-over to NEXIRI at progression.<br />
Primary endpoint was the 2-PFS (RECIST v1.1). Pharmacokinetic, pharmacogenetics<br />
and tissular ancillary studies were performed.<br />
Table: 466PD<br />
NEXIRI n = 57 Iri n = 56 Soraf n = 57 Cross-over n = 69<br />
Median treatment duration (months) 3 2 2.5 2<br />
Grade 3/4 toxicities (%)*<br />
Neutropenia (febrile) 16/2 (5) 6/0 (0) 0/0 (0) 1/0<br />
Diarrhea 26/0 7/0 7/0 22/0<br />
Hand-foot syndrome 17/0 0/0 16/0 7/0<br />
Hypertension 10/0 2/0 10/0 6/0<br />
2-PFS (%) $ 59 [39-66] 23 [10-33] 22 [8-30] 51 [30-54]<br />
DCR/PR (%) $ 59/4 25/0 22/0 51/1<br />
Median PFS (months) 3.7 [2.2-4.9] 1.9 [1.7-2.1] 2.1 [1.9-2.5] 3.5 [2.1-3.7]<br />
Median OS (months) CCND1 rs9344 genotype<br />
A/A<br />
A/G or G/G<br />
7.2 [5.8-9.4]<br />
19.6 [4.8-/]<br />
6.2 [4.9-9.4]<br />
3.0 [2.1-3.8]¤<br />
2.1 [1.4-/]¤<br />
3.2 [1.4-/]¤<br />
3.3 [2.5-4.2]¤<br />
3.0 [2.3-/]¤<br />
3.3 [2-4.2]¤<br />
7.9 [7.1-8.7]<br />
9.7 [7.7-12.6]<br />
7.5 [5.6-8.5]<br />
*170 patients; $ 18 (6/4/8/12) non-evaluable patients; ¤monotherapies alone, patients who did not cross. Pharmacokinetics results showed an increase <strong>of</strong> the Irinotecan<br />
plasma concentration with the addition <strong>of</strong> Sorafenib for patients in the Nexiri and cross-over arms.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw370 | vi155
abstracts<br />
467PD<br />
Preoperative chemoradiotherapy and postoperative<br />
chemotherapy with capecitabine and oxaliplatin vs.<br />
capecitabine alone in locally advanced rectal cancer: final<br />
analyses<br />
H.J. Schmoll 1 , A. Stein 2 , R.D. H<strong>of</strong>heinz 3 , T.J. Price 4 , B. Nordlinger 5 , J-F. Daisne 6 ,<br />
J-F. Daisne 6 , J. Janssens 7 , B. Brenner 8 , P. Schmidt 9 , H. Reinel 10 , S. Hollerbach 11 ,<br />
K. Caca 12 , F. Fauth 13 , J. Zalcberg 14 , S. Marreaud 15 , M. Mauer 16 , M. Lutz 17 ,E.Van<br />
Cutsem 18 , K. Haustermans 19<br />
1 Dept. Hematology/ <strong>Oncology</strong> FG 16 / U1, Martin Luther University <strong>of</strong> Halle, Halle,<br />
Germany, 2 Medical Dpt, UKE Universitätsklinikum Hamburg-Eppendorf KMTZ,<br />
Hamburg, Germany, 3 Interdisciplinary Tumorcenter, University Hospital<br />
Mannheim, Mannheim, Germany, 4 Haematology and <strong>Oncology</strong>, The Queen<br />
Elizabeth Hospital and University <strong>of</strong> Adelaide, Adelaide, Australia, 5 Surgery, Hopital<br />
Ambroise Pare, Boulogne-Billancourt, France, 6 Radiotherapy, Clinique Ste<br />
Elisabeth, Namur, Belgium, 7 Gastroenterology, AZ Turnhout - Campus Sint-Jozef,<br />
Turnhout, Belgium, 8 Institute <strong>of</strong> Hematology, Rambam Health Care Center, Haifa,<br />
Israel, 9 Private Practice, OSP Onkologische Schwerpunktpraxis, Neunkirchen,<br />
Germany, 10 Department <strong>of</strong> <strong>Oncology</strong>, Leopoldina Krankenhaus Medizinische<br />
Klinik II, Schweinfurt, Germany, 11 Gastroenterology, Allgemeines Krankenhaus<br />
Celle, Celle, Germany, 12 Department for Internal Medicine, Gastroenterology,<br />
Hemato-Onkology, Klinikum Ludwigsburg Hämatologie/Onkologie,<br />
Palliativmedizin, Ludwigsburg, Germany, 13 Private Practice, Onkologische<br />
Schwerpunktpraxis Hanau, Hanau, Germany, 14 School <strong>of</strong> Public Health &<br />
Preventive Medicine, Monash University, Melbourne, Australia, 15 EORTC<br />
Headquarters, European Organisation for research and treatment <strong>of</strong> Cancer<br />
(EORTC), Brussels, Belgium, 16 GI Group, EORTC, Brussels, Belgium, 17 Dept. for<br />
Gastroenterology, Caritasklinik St. Theresia, Saarbruecken, Germany, 18 Digestive<br />
<strong>Oncology</strong>, University Hospitals Leuven - Campus Gasthuisberg, Leuven, Belgium,<br />
19 Radiation <strong>Oncology</strong>, University Hospitals Leuven - Campus Gasthuisberg,<br />
Leuven, Belgium<br />
Background: The PETACC-6 trial investigates whether the addition <strong>of</strong> oxaliplatin to<br />
preoperative oral fluoropyrimidine-based chemoradiation (CRT) followed by<br />
postoperative adjuvant fluoropyrimidine-based chemotherapy (CT) improves<br />
disease-free survival (DFS) in locally advanced rectal cancer.<br />
Methods: Between 11/2008 and 09/2011, patients with rectal adenocarcinoma within<br />
12 cm from the anal verge, T3/4 and/or node-positive, with no evidence <strong>of</strong> metastatic<br />
disease and considered either resectable at the time <strong>of</strong> entry or expected to become<br />
resectable, were randomly assigned to receive 5 weeks <strong>of</strong> preoperative CRT with<br />
capecitabine, followed by 6 cycles <strong>of</strong> adjuvant CT with capecitabine with (arm 2) or<br />
without (arm 1) the addition <strong>of</strong> oxaliplatin before and after surgery. 440 DFS events<br />
were required to have 80% power to detect an improvement in 3-year DFS from 65%<br />
with capecitabine alone to 72% with capecitabine and oxaliplatin (HR = 0.763) using a<br />
two-sided alpha <strong>of</strong> 5% and owing for an interim analysis for early efficacy at 200 events.<br />
The primary analysis was intent-to-treat, adjusted for stratification factors (clinical T<br />
category, nodal status, distance from the tumor to the anal verge and method <strong>of</strong><br />
locoregional staging) except center.<br />
Results: 1094 patients randomized (547 each arm); 543 eligible patients (arm 1), 526<br />
(arm 2) started treatment; 67.4% completed protocol treatment in arm 1 vs. 53.8% in<br />
arm 2. Early analysis driven by the IDMC did not show a difference in 3 years in DFS<br />
and OS between both arms. The updated analysis 01/16 after a median follow-up <strong>of</strong> 52<br />
months (86-55 months) again are not showing a difference with 76,5% in Arm 1 vs.<br />
75,4% in arm 2 (HR 1,04, p = 0,744). Subgroup analysis showed superiority for DFS in<br />
nongerman participants (33%), whereas for german participants (67%) showed an<br />
inferior outcome (arm 1: HR 0,73, p= 0,061; arm 2: HR 1,35, p= 0,109), cape vs. cape/<br />
ox; 78,2% vs. 73,6% (arm1); 73,2% vs. 81,1% (arm 2). Multivariate analysis for<br />
identification <strong>of</strong> the confounding factors is ongoing and will be presented.<br />
Conclusions: PETACC-6 does not show any benefit for the addition <strong>of</strong> oxaliplatin to<br />
capecitabine in contrast to the AIO / ARO / CAO trial and the Korean trial.<br />
Clinical trial identification: NCT00766155 First received: October 2, 2008<br />
Legal entity responsible for the study: EORTC<br />
Funding: Roche<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
468PD<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Evaluation for surgical treatment options in metastatic<br />
colorectal cancer (mCRC) – a retrospective, central<br />
evaluation <strong>of</strong> FIRE-3<br />
U. Neumann 1 , T. Denecke 2 , J. Pratschke 3 , H. Lang 4 , M. Bemelmans 5 , T. Becker 6 ,<br />
M. Rentsch 7 , D. Seeh<strong>of</strong>er 8 , C.J. Bruns 9 , B. Gebauer 2 , G. Folprecht 10 ,<br />
S. Stintzing 11 , S. Held 12 , V. Heinemann 11 , D.P. Modest 11<br />
1 Department <strong>of</strong> General, Visceral and Transplantation Surgery,<br />
Universitaetsklinikum Aachen (UKA), Aachen, Germany, 2 Institute <strong>of</strong> radiology,<br />
Charité, Campus Virchow Klinikum, Berlin, Germany, 3 General, Visceral, and<br />
Transplantation Surgery, Charité, Campus Virchow Klinikum, Berlin, Germany, 4 für<br />
Allgemein-, Viszeral- und Transplantationschirurgie, Universitätsmedizin Mainz,<br />
Mainz, Germany, 5 Oncologiecentrum, Maastricht University Medical Center<br />
(MUMC), Maastricht, Netherlands, 6 für Allgemeine-, Viszeral-, Thorax-,<br />
Transplantations- und Kinderchirurgie, UK-SH, Campus Kiel, Kiel, Germany,<br />
7 Department <strong>of</strong> General, Visceral, Transplantation, Vascular and Thoracic Surgery,<br />
Klinikum der Universität München, Munich, Germany, 8 und Poliklinik für Visceral-,<br />
Transplantations-, Thorax- und Gefäßchirurgie, University <strong>of</strong> Leipzig, Leipzig,<br />
Germany, 9 Universitätsklinik für Allgemein-, Viszeral- und Gefäßchirurgie, Otto-von<br />
Guericke-Universität, Magdeburg, Germany, 10 Medical Department I, University<br />
Hospital Carl Gustav Technischen Univ.Dresden Medizinische, Dresden, Germany,<br />
11 Medical Dept. III, Klinikum der Universität München, Munich, Germany,<br />
12 ClinAssess GmbH, ClinAssess GmbH, Leverkusen, Germany<br />
Background: The integration <strong>of</strong> resections and/or ablation <strong>of</strong> metastases represent a<br />
cornerstone <strong>of</strong> multi-disciplinary treatment <strong>of</strong> mCRC, but access to this is <strong>of</strong>ten not<br />
fully evaluated.<br />
Methods: We performed a central retrospective radiographic review <strong>of</strong> tumor lesions,<br />
conducted by eight visceral surgeons and three medical oncologists, with respect to<br />
surgical treatment options (with or without local thermic ablation, body radiation, etc),<br />
in addition to systemic treatment. Evaluation was done at baseline (before study<br />
treatment) and at “best response” (in 448 patients (pts.) receiving FOLFIRI plus<br />
cetuximab (arm A, 210 pts.) or FOLFIRI plus bevacizumab (arm B, 238 pts.).<br />
Investigators were blinded for treatment arm.<br />
Results: Based on a majority vote (≥50% votes for surgical-based intervention),<br />
resection <strong>of</strong> all tumor lesions at "baseline" (before treatment) was retrospectively<br />
considered possible in 97 (21.7%) pts. (23.3% arm A, 20.2% arm B), whereas at “best<br />
response” 238 (53.1%) pts. (53.3 % arm A, 52.9% arm B) were considered candidates<br />
for surgical resections (with or without additional locoregional therapy). These<br />
recommendations compare to reported secondary resection <strong>of</strong> tumor lesions in 60<br />
(13.4%) pts. (13.8% arm A, 13.0% arm B). Additional 71 (15.8%) pts. (14.8% arm A,<br />
16,8% arm B), <strong>of</strong> those 16 pts. in combination with operation, received locoregional<br />
therapies. The reviewers recommended surgery in 58 (96.7%) <strong>of</strong> effectively operated<br />
pts. and 48 (67.7%) <strong>of</strong> pts. with locoregional treatment. Additional information,<br />
including clinical (metastatic sites) and molecular subgroups as well as scoring <strong>of</strong><br />
technical difficulties and expected clinical benefit <strong>of</strong> intended interventions, will be<br />
presented at the meeting.<br />
Conclusions: In FIRE-3, surgery is a treatment option for approximately half <strong>of</strong> the<br />
pts. The discrepancy between possible and de facto done resections highlights the need<br />
for a multi-disciplinary decision making. The inclusion <strong>of</strong> dedicated surgeons or other<br />
interventionalists in addition to medical oncologists appears as mandatory, not only<br />
before start <strong>of</strong> treatment, but also more importantly during systemic treatment on a<br />
regular and preplanned basis.<br />
Clinical trial identification: NCT00433927<br />
Legal entity responsible for the study: University <strong>of</strong> Munich<br />
Funding: Merck, Pfizer<br />
Disclosure: U. Neumann: Honoraria: Merck, Amgen, Roche Research Support: Merck.<br />
G. Folprecht: Honoraria - Merck, Roche/Genentech, Lilly, Bayer, San<strong>of</strong>i-Aventis,<br />
Baxalta, Servier, Boehringer. Study grant – Merck. S. Stintzing: Honoraria: Merck<br />
Serono, Roche/Genentech, Amgen, Bayer, san<strong>of</strong>i-aventis Consulting or Advisory Role:<br />
Merck Serono, Roche Travel, Accommodations, Expenses: Roche/Genentech, Merck<br />
Serono, san<strong>of</strong>i-aventis. V. Heinemann: Honoraria: Merck KGaA, Roche, Consulting or<br />
Advisory Role: Merck KGaA Speakers’ Bureau: Merck KGaA Research Funding: Merck<br />
KGaA (Inst), Roche (Inst), Travel, Accommodations, Expenses: Merck KGaA, Roche.<br />
D.P. Modest: Merck: research support (inst), honoraria, travel Support, advisory boards<br />
Roche: research support (inst), honoraria. All other authors have declared no conflicts<br />
<strong>of</strong> interest.<br />
vi156 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
469PD<br />
Phase III trial <strong>of</strong> 24 weeks vs. 48 weeks capecitabine<br />
adjuvant chemotherapy for patients with stage III colon<br />
cancer: Final results <strong>of</strong> JFMC37-0801<br />
S. Yamaguchi 1 , K. Kunieda 2 ,T.Sato 3 , Y. Naramoto 4 , M. Kobayashi 5 , Y. Ogata 6 ,<br />
T. Furuhata 7 , Y. Takii 8 , M. Kusunoki 9 , Y. Maehara 10 , K. Koda 11 , K. Okuno 12 ,<br />
M. Ohno 13 , H. Mishima 14 , S. Sadahiro 15 , C. Hamada 16 , J. Sakamoto 17 , S. Saji 17 ,<br />
N. Tomita 18<br />
1 Gastroenterological Surgery, Saitama Medical University International Medical<br />
Center, Hidaka, Japan, 2 Surgery, Gifu Prefectural General Medical Center, Gifu,<br />
Japan, 3 Surgery, Yamagata Prefectural Central Hospital, Yamagata, Japan,<br />
4 Surgery, Kawasaki Medical School Hospital, Okayama, Japan, 5 Human Health<br />
and Medical Sciences, Kochi Medical School Hospital Cancer Treatment Center,<br />
Kochi, Japan, 6 Cancer Center, Kurume University, Kurume, Japan, 7 Surgery,<br />
Sapporo Medical University School <strong>of</strong> Medicine, Sapporo, Japan, 8 Surgery,<br />
Niigata Cancer Center Hospital, Niigata, Japan, 9 Surgery, Mie University Graduate<br />
School <strong>of</strong> Medicine, Tsu, Japan, 10 Surgery and Science, Graduate School <strong>of</strong><br />
Medical Sciences, Kyushu University, Fukuoka, Japan, 11 Surgery, University <strong>of</strong><br />
Teikyo Teikyo University Chiba Medical Center, Ichihara, Japan, 12 Surgery, Kindai<br />
University Faculty <strong>of</strong> Medicine, Osaka, Japan, 13 Surgery, Hyogo Prefectural<br />
Kaibara Hospital, Kaibara, Japan, 14 Cancer Center, Aichi Medical University,<br />
Nagakute, Japan, 15 Surgery, Tokai University, Isehara, Japan, 16 Graduate School<br />
<strong>of</strong> Engineering, Tokyo University <strong>of</strong> Science, Tokyo, Japan, 17 Japanese<br />
Foundation for Multidisciplinary Treatment <strong>of</strong> Cancer, Tokyo, Japan, 18 Surgery,<br />
Hyogo College <strong>of</strong> Medicine, Nishinomiya, Japan<br />
Background: JFMC37-0801 study was planned to <strong>of</strong>fer superiority <strong>of</strong> 48 weeks<br />
treatment <strong>of</strong> capecitabine adjuvant chemotherapy to 24 weeks conventional treatment<br />
with respect to the primary endpoint <strong>of</strong> disease free survival (DFS) in patients with<br />
stage III colon and rectosigmoid cancer. Here, we report the final results <strong>of</strong> this study.<br />
Methods: Patients with curatively resected stage III colon and rectosigmoid cancer (PS,<br />
0 to 1; age, 20 to 79 years; no other therapy) were randomly assigned to receive<br />
capecitabine (1,250 mg/m2/day) for 14 out <strong>of</strong> 21 days for 24 weeks, 8 courses (Control<br />
(C) arm) or for 48 weeks, 16 courses (Study (S) arm). The primary endpoint was the<br />
DFS, and the secondary endpoints were overall survival (OS) and relapse free survival<br />
(RFS). Patient information was fixed in March 2016.<br />
Results: At the time <strong>of</strong> this final analysis, median follow-up was 60 months with 434<br />
DFS events out <strong>of</strong> 1304 (C: 654, S: 650) pts. The 3-year and 5-year DFS for the primary<br />
endpoint was 75.3%, 68.7% in the S arm and 70.0%, 65.3% in the C arm, respectively<br />
(p = 0.068, HR = 0.866, 95%CI: 0.717-1.046). The 5-year OS was 87.6% in the S arm<br />
and 83.2% in the C arm (p = 0.0159, HR = 0.737, 95%CI: 0.557-0.975). The 5-year RFS<br />
was 74.1% in the S arm and 69.3% in the C arm (p = 0.0207, HR = 0.808, 95%CI:<br />
0.658-0.992). Overall grade 3-4 adverse events <strong>of</strong> S arm were comparable with those <strong>of</strong><br />
C arm except increasing hand-foot syndrome.<br />
Conclusions: DFS superiority in 48 weeks treatment <strong>of</strong> capecitabine adjuvant<br />
chemotherapy was not demonstrated in patients with stage III colon cancer. However,<br />
p-values <strong>of</strong> OS and RFS comparing 48 weeks treatment with 24 weeks treatment were<br />
less than 0.025. Thus, with regard to the optimal duration <strong>of</strong> adjuvant chemotherapy<br />
for stage III colon cancer, further investigation was considered to be needed.<br />
Legal entity responsible for the study: N/A<br />
Funding: Japanese Foundation for Multidisciplinary Treatment <strong>of</strong> Cancer<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
470P<br />
Efficacy and safety <strong>of</strong> cobimetinib (cobi) and atezolizumab<br />
(atezo) in an expanded phase 1b study <strong>of</strong> microsatellite-stable<br />
(MSS) metastatic colorectal cancer (mCRC)<br />
J. Desai 1 , Y.S. Hong 2 , J.E. Kim 2 , T.W. Kim 2 , S.W. Han 3 , Y-J. Bang 3 , C.E. Chee 4 ,V.<br />
Y.M. Heong 4 , A. McRee 5 , L.Q. Chow 6 , E.L. Kwak 7 , J.R. Infante 8 , J. Wallin 9 ,M.<br />
Das Thakur 9 , G. Mwawasi 9 , P. Foster 9 , E. Cha 9 , J.C. Bendell 8<br />
1 Medical <strong>Oncology</strong>, Royal Melbourne Hospital, Melbourne, Australia, 2 Department<br />
<strong>of</strong> <strong>Oncology</strong>, Asan Medical Center, University <strong>of</strong> Ulsan College <strong>of</strong> Medicine, Seoul,<br />
Republic <strong>of</strong> Korea, 3 <strong>Oncology</strong>, Seoul National University Hospital, Seoul, Republic<br />
<strong>of</strong> Korea, 4 <strong>Oncology</strong>, The Cancer Institute National University Hospital, Singapore,<br />
5 GI Medical <strong>Oncology</strong>, University <strong>of</strong> North Carolina - Chapel Hill, Chapel Hill, NC,<br />
USA, 6 Department <strong>of</strong> Medicine, Division <strong>of</strong> Medical <strong>Oncology</strong>, University <strong>of</strong><br />
Washington, Seattle, WA, USA, 7 <strong>Oncology</strong>, Massachusetts General Hospital,<br />
Boston, MA, USA, 8 Drug Development Program, Sarah Cannon Research<br />
Institute/Tennessee <strong>Oncology</strong>, PLLC, Nashville, TN, USA, 9 <strong>Oncology</strong>, Genentech,<br />
Inc., South San Francisco, CA, USA<br />
Background: MSS colorectal cancers, which comprise the vast majority <strong>of</strong> mCRC<br />
patients (pts), appear essentially resistant to PD-L1/PD-1 blockade vs many other<br />
tumors. Since inhibition <strong>of</strong> MEK promotes T cell accumulation intratumorally and<br />
combines with anti-PDL1 pre-clinically (Ebert, Immunity 2016), the combination <strong>of</strong><br />
cobi (MEK inhibitor) and atezo (anti-PDL1) was evaluated in pts with mCRC.<br />
Methods: 44 mCRC pts were enrolled with 23 evaluable pts for efficacy, including 22<br />
KRASmt and 1 KRASwt, who failed prior lines <strong>of</strong> therapy and were not selected by<br />
PD-L1 expression. Of these 23 pts, 3 were treated with cobi during escalation (2 at 20<br />
mg; 1 at 60 mg) and 20 were treated during expansion (60 mg). Cobi was dosed PO for<br />
21 d on/7 d <strong>of</strong>f and atezo at 800 mg IV q2w. Primary endpoints were safety and<br />
tolerability. Secondary endpoints included investigator-assessed efficacy by RECIST<br />
v1.1. MSS status was confirmed centrally by mutation load pr<strong>of</strong>iling.<br />
Results: As <strong>of</strong> Feb 12, 2016, the 23 efficacy evaluable mCRC pts had a median safety<br />
follow-up <strong>of</strong> 3.78 mo (range, 1.1-15.1). None were identified as MSI-H and the<br />
majority expressed low levels <strong>of</strong> PD-L1 at baseline. The 6 mo survival rate was 72%<br />
(95% CI: 52, 93). Confirmed responses were seen in 4 pts (17%) with duration ranging<br />
from 5.4 to 11.1 mo and were ongoing in 2 pts. Activity did not correlate with PD-L1<br />
expression. All grade treatment-related AEs occurring in > 20% pts included diarrhea,<br />
fatigue, dermatitis acneiform, rash, maculopapular rash, pruritus, nausea, creatine<br />
phosphokinase increase and AST elevation, consistent with that seen for the single<br />
agents. G3-4 AEs related to either drug were seen in 8 pts (34.8%). The most common<br />
individual, related G3-4 AEs (diarrhea and rash) occurred in ≤ 2 pts (8.7%). No G5<br />
AEs occurred. Four AEs led to discontinuation <strong>of</strong> cobi. No AEs led to atezo withdrawal.<br />
Updated biomarker data including anti-tumor immune markers will be presented.<br />
Conclusions: In chemotherapy-refractory MSS mCRC where single-agent cobi and<br />
atezo have shown minimal activity, encouraging early results with the combination are<br />
observed for ORR, DOR, and 6 mo survival. Further trial follow-up is ongoing.<br />
NCT01988896<br />
Clinical trial identification: NCT01988896<br />
Legal entity responsible for the study: F. H<strong>of</strong>fmann La-Roche Ltd.<br />
Funding: F. H<strong>of</strong>fmann La-Roche Ltd.<br />
Disclosure: J.R. Infante: I have no personal financial conflicts <strong>of</strong> interest but my<br />
institution receives research funding and consulting from Genentech. J. Wallin, M. Das<br />
Thakur, G. Mwawasi, P. Foster, E. Cha: Genentech employee. All other authors have<br />
declared no conflicts <strong>of</strong> interest.<br />
471P<br />
abstracts<br />
A phase IB/II study <strong>of</strong> second-line therapy with panitumumab,<br />
irinotecan and everolimus (PIE) in metastatic colorectal<br />
cancer (mCRC) with KRAS wild type (WT)<br />
A. Townsend 1 , N. Tebbutt 2 , C. Karapetis 3 , P. Cooper 4 , N. Singhal 5 , S. Yeend 4 ,<br />
L. Pirc 4 , R. Joshi 6 , T.J. Price 1<br />
1 Haematology and <strong>Oncology</strong>, The Queen Elizabeth Hospital and University <strong>of</strong><br />
Adelaide, Adelaide, Australia, 2 Medical <strong>Oncology</strong>, Austin Hospital, Heidelberg,<br />
Australia, 3 Medical <strong>Oncology</strong>, Flinders Medical Centre and Flinders University,<br />
Adelaide, Australia, 4 Medical <strong>Oncology</strong>, Queen Elizabeth Hospital, Adelaide,<br />
Australia, 5 Medical <strong>Oncology</strong>, Royal Adelaide Hospital RAH Cancer Centre,<br />
Adelaide, Australia, 6 Medical <strong>Oncology</strong>, Elizabeth Vale, Lyell McEwin Hospital,<br />
Adelaide, Australia<br />
Background: Inhibition <strong>of</strong> mTOR in addition to EGFR may overcome upstream<br />
resistance to EGFR inhibitors in CRC. This phase II study evaluated the efficacy and<br />
safety <strong>of</strong> the combination <strong>of</strong> irinotecan, panitumumab and everolimus based on dosing<br />
established in the previously reported phase Ib study (Townsend JCO 2013 (suppl;abstr<br />
14506)).<br />
Methods: Patients with KRAS exon 2 WT mCRC following failure <strong>of</strong> fluoropyrimidine<br />
based therapy received IV irinotecan (200mg/m2), panitumumab (6mg/kg) every 2<br />
weeks, and everolimus 5mg orally alternate days throughout a 14 day cycle. The<br />
primary endpoint was response rate (RR) and secondary endpoints were safety and<br />
tolerability, progression free survival (PFS) and overall survival (OS). Survival<br />
outcomes were calculated using Kaplan-Meier method and all results analysed as<br />
intention to treat.<br />
Results: 40 patients were enrolled in the expansion phase. Median age 60 years (37-76),<br />
M/F 26/14, ECOG 0/1/2 18/21/1, neutrophil/lymphocyte ratio >3 at baseline in 53%.<br />
The median number <strong>of</strong> cycles <strong>of</strong> the PIE combination received was 5 (range 0-28<br />
cycles) and mean 8.2 cycles with 4 patients still on treatment. Grade 3 toxicities were<br />
diarrhoea 23%, mucositis 18%, rash 13%, fatigue 8%, dehydration 5%, neutropenia<br />
20%, febrile neutropenia 8%, hypomagnesemia 20% and hypokalaemia 8%. Grade 4<br />
toxicities were hypomagnesemia 5% and neutropenia 3%. The median relative dose<br />
intensity was 85%. 4 patients ceased everolimus within 30 days due to toxicity. RR was<br />
45%, stable disease 45%, and disease progression 10%. 2 patients underwent<br />
subsequent liver resection. The median PFS was 5.6 months and median OS 10.8<br />
months. The 12 month OS was 48% and 18 month OS 33%.<br />
Conclusions: This regimen has major toxicities <strong>of</strong> diarrhoea, mucositis and rash. The<br />
RR <strong>of</strong> 45% supports further study <strong>of</strong> this combination. Median OS was relatively short<br />
noting poor prognostic markers and analysis <strong>of</strong> extended RAS/BRAF is ongoing and<br />
will be presented.<br />
Clinical trial identification: NCT01139138<br />
Legal entity responsible for the study: Central Adelaide Local Health Network<br />
Funding: Amgen provided funding Novartis provided everolimus<br />
Disclosure: A. Townsend: Research funding from Amgen. N. Tebbutt: Advisory board<br />
for Amgen Research funding from Amgen and Novartis. C. Karapetis: Advisory board<br />
member for Amgen. T.J. Price: Amgen Advisory board membership. All other authors<br />
have declared no conflicts <strong>of</strong> interest.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw370 | vi157
abstracts<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
472P<br />
A multicentre phase I/II study <strong>of</strong> TAS-102 with nintedanib in<br />
patients with metastatic colorectal cancer refractory to<br />
standard therapies (N-TASK FORCE: EPOC1410); Phase I<br />
results<br />
473P<br />
Targeting FGF2 expression against chemoresistance in<br />
colorectal cancer (CRC) cell lines - a potential prognostic<br />
biomarker in patients with metastatic colorectal cancer<br />
(mCRC) treated with FUFIRI or mIrOx (FIRE1)<br />
T. Nishina 1 , Y. Kuboki 2 , E. Shinozaki 3 , S. Fukuoka 2 , T. Kajiwara 1 , K. Shitara 2 ,<br />
K. Yamaguchi 3 , Y. Komatsu 4 , S. Yuki 5 , K. Yamazaki 6 , H. Hara 7 , N. Mochizuki 8 ,<br />
M. Fukutani 9 , H. Hasegawa 9 , S. Matsuda 9 , M. Wakabayashi 9 , S. Nomura 9 ,<br />
A. Sato 9 , A. Ohtsu 2 , T. Yoshino 2<br />
1 Department <strong>of</strong> Gastrointestinal Medical <strong>Oncology</strong>, Shikoku Cancer Center,<br />
Matsuyama, Japan, 2 Department <strong>of</strong> GI oncology, National Cancer Center Hospital<br />
East, Kashiwa, Japan, 3 Department <strong>of</strong> Gastroenterology, Cancer Institute Hospital<br />
<strong>of</strong> JFCR, Tokyo, Japan, 4 Department <strong>of</strong> Cancer Chemotherapy, Hokkaido<br />
University Hospital, Sapporo, Japan, 5 Gastroenterology and Hepatology,<br />
Hokkaido University Hospital, Sapporo, Japan, 6 Division <strong>of</strong> Gastrointestinal<br />
<strong>Oncology</strong>, Shizuoka Cancer Center, Shizuoka, Japan, 7 Department <strong>of</strong><br />
Gastroenterology, Saitama Cancer Center, Saitama, Japan, 8 Department <strong>of</strong><br />
pharmacy, National Cancer Center Hospital East, Kashiwa, Japan, 9 Office <strong>of</strong><br />
Clinical Research Support, National Cancer Center Hospital East, Kashiwa, Japan<br />
Background: TAS-102 is an oral nucleoside antitumor agent, which demonstrated<br />
significant improvement in overall survival over placebo in patients (pts) with<br />
metastatic colorectal cancer (mCRC). Nintedanib is a triple angiokinase inhibitor <strong>of</strong><br />
VEGFR (1, 2, 3), PDGFR (a, β), and FGFR (1, 2, 3). A global phase III study is ongoing<br />
to compare nintedanib with placebo in pts with mCRC resistant to standard therapies.<br />
In preclinical models, the combination <strong>of</strong> TAS-102 plus nintedanib demonstrated<br />
enhanced activity against CRC compared with either drug alone (Suzuki N, et al.<br />
AACR 2016). This study investigates efficacy and safety <strong>of</strong> TAS-102 with nintedanib,<br />
and herein we present the results <strong>of</strong> the phase I part.<br />
Methods: The key eligibility criteria were pts with mCRC refractory or intolerant to<br />
fluoropyrimidine, irinotecan, oxaliplatin, anti-angiogenesis inhibitor and anti-EGFR<br />
antibody (if wild-type RAS) and without prior regorafenib. Phase I part was designed<br />
to determine the recommended phase II dose (RP2D) in a “3+3” cohort-based dose<br />
escalation design <strong>of</strong> nintedanib (150mg BID every day on level 1 and 200mg BID every<br />
day on level 2) adding to standard-dose <strong>of</strong> TAS-102.<br />
Results: Three patients were treated in level 1, and 6 pts in level 2. No dose-limiting<br />
toxicities were observed at either level. The most common grade 3 or worse<br />
treatment-associated adverse events were neutropenia (67%), anaemia (33%), and<br />
increased liver enzymes (22%; asymptomatic reversible grade 3 AST/ALT elevation<br />
without any bilirubin elevation). The disease control rate was 100%, and 8 pts (89%)<br />
showed any tumor shrinkage including one partial response. With a median follow-up<br />
<strong>of</strong> 113 days (ranging from 85 to 180 days), six patients still continued the study<br />
treatment. The relative dose intensity was 86.4% for TAS-102 and 89.8% for<br />
nintedanib. Drug–drug interaction was not indicated by pharmacokinetic analysis.<br />
Conclusions: Standard-dose <strong>of</strong> TAS-102 with nintedanib 200 mg BID was tolerable<br />
and determined as RP2D. This combination regimen had a promising antitumor<br />
activity, which will be confirmed by ongoing phase II part.<br />
Clinical trial identification: Clinical trial information: UMIN000017114. Release date:<br />
13/April/2015<br />
Legal entity responsible for the study: Declaration <strong>of</strong> Helsinki, Ministerial Ordinance<br />
on Good Clinical Practice<br />
Funding: Boehringer Ingelheim<br />
Disclosure: T. Nishina, E. Shinozaki, K. Yamaguchi: Other Substantive Relationships:<br />
(Honoraria (lecture fee) from: Taiho Pharmaceutical). Y. Komatsu:<br />
Corporate-sponsored Research: Boehringer Ingelheim GmbH Other Substantive<br />
Relationships: (Honoraria (lecture fee) from: Taiho Pharmaceutical). S. Yuki: Other<br />
Substantive Relationships:(Honoraria (lecture fee) from: Taiho Pharmaceutical, Merck<br />
Serono, Bristol-Myers Squibb, Takeda Pharmaceutical, Chugai Pharmaceutical, Bayer<br />
Yakuhin, Eli Lilly Japan). K. Yamazaki: Other Substantive Relationships: (Honoraria<br />
(lecture fee) from: Taiho Pharmaceutical). H. Hara: Other Substantive Relationships:<br />
(Honoraria (lecture fee) from: Taiho Pharmaceutical, Merck Serono, Chugai<br />
Pharmaceutical, Eli Lilly Japan, Yakult Honsha). S. Nomura: Personal fees from Japan<br />
Breast Cancer Research Group: (JBCRG), and grants from Japan Agency for Medical<br />
Research and Development: (AMED), outside the submitted work. T. Yoshino:<br />
Corporate-sponsored Research: GlaxoSmithKline K.K. and Boehringer Ingelheim<br />
GmbH All other authors have declared no conflicts <strong>of</strong> interest.<br />
A. Stahler 1 , S. Stintzing 2 , M. Urbischek 1 , D.P. Modest 2 , L. Fischer von<br />
Weikersthal 3 , J. Kumbrink 1 , V. Heinemann 2 , T. Kirchner 1 , A. Jung 1<br />
1 Institute <strong>of</strong> Pathology, Klinikum der Universität München, Munich, Germany,<br />
2 Medical Dept. III, Klinikum der Universität München, Munich, Germany,<br />
3 <strong>Oncology</strong>, Klinikum St. Marien Amberg, Amberg, Germany<br />
Background: Our aim was to evaluate fibroblast growth factor 2 (FGF2) expression in<br />
cultivated CRC cell lines exposed to 5-fluorouracil (5-FU) and validate results with<br />
clinical data from mCRC patients receiving first-line chemotherapy.<br />
Methods: 5-FU IC 50 was determined in CRC cell lines DLD1, LoVo, and HCT-15<br />
applying MTT assays. mRNA expression <strong>of</strong> FGF2 was measured by RT-qPCR with<br />
HPRT as reference gene. Threshold values were determined by minimum p-value<br />
method. FGF2 expression was knocked down by sh (short hairpin) RNA in vitro. FGF<br />
receptor (FGF-R) was inhibited using Dovitinib with DMSO as control. In vitro results<br />
were were translated on the randomized FIRE1 trial (5-FU/LV/irinotecan [FUFIRI] vs.<br />
irinotecan/oxaliplatin [mIrOx] using Nanostring technology. 187 patients were<br />
included in this analysis.<br />
Results: 48 h incubation <strong>of</strong> CRC cell lines with 5-FU showed an increase <strong>of</strong> FGF2<br />
expression [DLD1: 1.98-fold, p < 0.001; LoVo: 3.51-fold, p < 0.001; HCT-15: 1.96-fold,<br />
p = 0.002]. Knocking down FGF2 expression [loss <strong>of</strong> FGF2 expression: DLD1: 86%,<br />
p = 0.008; LoVo: 97%, p = 0.03; HCT-15: 42%, p = 0.04] correlated with a significant<br />
decrease <strong>of</strong> IC 50 for 5-FU in CRC cell lines [DLD1: 23.52 to 15.27 µM, p = 0.023; LoVo:<br />
28.96 to 15.23 µM, p < 0.001; HCT-15: 34.40 to 21.12 µM, p = 0.005]. 72 h incubation<br />
with Dovitinib led to a total growth restriction in all CRC cell lines when compared to<br />
control (DMSO). In FIRE1, high (n = 89) vs. low (n = 98) FGF2 expression was not<br />
correlated significantly with PFS [8.0 vs. 8.2 months, HR: 0.87, 95% CI: 0.65 – 1.17,<br />
p = 0.370], but with OS [17.9 vs. 23.5 months, HR: 0.70, 95% CI: 0.51 – 0.96, p = 0.025]<br />
in FUFIRI and mIrOx. Higher FGF2 expression was significantly associated with worse<br />
objective response rate [PR and CR (n = 84) vs. SD and PD (n = 21); 24.85 vs. 31.89,<br />
p = 0.049].<br />
Conclusions: FGF2 expression might reflect chemoresistance in CRC cell lines as a<br />
knockdown <strong>of</strong> FGF2 led to a decrease <strong>of</strong> IC 50 for 5-FU in vitro. In FIRE1, high FGF2<br />
expression was associated with lower response rate and overall survival significantly.<br />
Interfering the FGF2 system might be a modulator for acquired chemoresistance.<br />
Legal entity responsible for the study: Department <strong>of</strong> Medicine III, University <strong>of</strong><br />
Munich; Institute <strong>of</strong> Pathology, University <strong>of</strong> Munich<br />
Funding: Weigand-Bohnewand-Gravenhorst-Fond, University <strong>of</strong> Munich<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
474P<br />
A phase I study to determine the effect <strong>of</strong> regorafenib (REG) on<br />
the pharmacokinetics (PK) <strong>of</strong> substrates <strong>of</strong> P-glycoprotein<br />
(P-gp; digoxin) and breast cancer resistant protein (BCRP;<br />
rosuvastatin) in patients with advanced solid tumors<br />
D. Strumberg 1 , S-E. Al-Batran 2 , I. Takacs 3 , L. Géczi 4 , A. Cleton 5 , F. Huang 6 ,<br />
U. Mueller 7 , K. Graudenz 5 , Z. Trnkova 5 , I. Sturm 5<br />
1 Department <strong>of</strong> Hematology and <strong>Oncology</strong>, Ruhr-University Bochum, Bochum,<br />
Germany, 2 Institute for Clinical Research, Northwest Hospital, Frankfurt, Germany,<br />
3 1st Department <strong>of</strong> Internal Medicine, Semmelweis University, Budapest, Hungary,<br />
4 Medical <strong>Oncology</strong> and Clinical Pharmacology, National Institute <strong>of</strong> <strong>Oncology</strong>,<br />
Budapest, Hungary, 5 Clinical Pharmacology <strong>Oncology</strong>, Bayer Pharma AG, Berlin,<br />
Germany, 6 Clinical Pharmacology <strong>Oncology</strong>, Bayer HealthCare Pharmaceuticals,<br />
Whippany, NJ, USA, 7 Clinical Statistics, ClinStat GmbH, Cologne, Germany<br />
Background: REG is an oral multikinase inhibitor approved for the treatment <strong>of</strong><br />
mCRC and advanced GIST. In vitro data showed that REG has an inhibitory effect on<br />
BCRP and P-gp transporters. A study was designed to evaluate the effect <strong>of</strong> REG on the<br />
PK <strong>of</strong> digoxin (P-gp substrate) and rosuvastatin (BCRP substrate).<br />
Methods: This was an open-label, non-randomized, 2-parallel group study to compare<br />
the PK <strong>of</strong> the P-gp substrate digoxin (group A) and BRCP substrate rosuvastatin<br />
(group B) with and without REG. Oral REG 160 mg QD was administered in 28-day<br />
cycles (3 weeks on/1 week <strong>of</strong>f). On pre-cycle Day -7 and cycle 1 Day 15, patients<br />
received a single oral dose <strong>of</strong> digoxin (0.5 mg, group A) or rosuvastatin (5 mg, group<br />
B), and serial plasma samples were collected for PK analysis.<br />
Results: 42 patients were treated and 30 patients were evaluable for PK analysis (17 in<br />
group A; 13 in group B). There was no relevant change in mean AUC (0–24) and C max <strong>of</strong><br />
digoxin (
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Conclusions: REG had no effect on the PK <strong>of</strong> the P-gp substrate digoxin.<br />
Co-administration <strong>of</strong> REG with the BCRP substrate rosuvastatin resulted in a 3.8-fold<br />
increase in mean exposure (AUC) and a 4.6-fold increase in C max <strong>of</strong> rosuvastatin<br />
indicating that REG may increase the plasma concentrations <strong>of</strong> other concomitant<br />
BCRP substrates (e.g. methotrexate, fluvastatin, atorvastatin). Therefore, it is<br />
recommended to monitor patients closely for signs and symptoms <strong>of</strong> increased<br />
exposure to BCRP substrates. The safety pr<strong>of</strong>ile was consistent with the known safety<br />
pr<strong>of</strong>ile <strong>of</strong> REG.<br />
Clinical trial identification: NCT02106845<br />
Legal entity responsible for the study: Bayer<br />
Funding: Bayer<br />
Disclosure: A. Cleton: Stock ownership: AstraZeneca, Bayer, Pfizer. Other substantive<br />
relationships: Bayer (employee). F. Huang, K. Graudenz, Z. Trnkova: Other substantive<br />
relationships: Bayer (employee). U. Mueller: Advisory board: Bayer. Other substantive<br />
relationships: ClinStat GmbH (employee). I. Sturm: Stock ownership: Bayer. Other<br />
substantive relationships: Bayer (employee). All other authors have declared no<br />
conflicts <strong>of</strong> interest.<br />
476P<br />
Phase II clinical trial with axitinib as maintenance therapy in<br />
patients (p) with metastatic colorectal carcinoma (CRC)<br />
C. Gravalos 1 , A. Carrato 2 , M. Tobeña 3 , E. Grande Pulido 2 , G. Soler 4 , J. Vieitez 5 ,<br />
L. Robles 1 , M. Valladares-Ayerbes 6 , E. Polo 7 , M.L. Limon 8 , M.J. Safont 9 ,<br />
C. Lopez 10 , P. García Alfonso 11 , E. Aranda 12<br />
1 Medical <strong>Oncology</strong>, University Hospital 12 De Octubre, Madrid, Spain, 2 Medical<br />
<strong>Oncology</strong>, Hospital Universitario Ramon y Cajal, Madrid, Spain, 3 Medical<br />
<strong>Oncology</strong>, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain, 4 Medical<br />
<strong>Oncology</strong>, ICO Hospital Duran i Reynals, Hospitalet, Spain, 5 Medical <strong>Oncology</strong>,<br />
Hospital Universitario Central de Asturias, Oviedo, Spain, 6 Medical <strong>Oncology</strong>,<br />
Hospital Universitario a Coruna - a Corunac, A Coruna, Spain, 7 Medical <strong>Oncology</strong>,<br />
Hospital Miguel Servet, Zaragoza, Spain, 8 Medical <strong>Oncology</strong>, Hospital<br />
Universitario Virgen del Rocio, Sevilla, Spain, 9 Medical <strong>Oncology</strong>, Hospital General<br />
Universitario Valencia, Valencia, Spain, 10 Medical <strong>Oncology</strong>, Hospital Universitario<br />
Marques de Valdecilla, Santander, Spain, 11 Medical <strong>Oncology</strong>, Hospital General<br />
Universitario Gregorio Marañon, Madrid, Spain, 12 Medical <strong>Oncology</strong>, Reina S<strong>of</strong>ía<br />
Hospital, University <strong>of</strong> Córdoba, Maimonides Institute <strong>of</strong> Biomedical Research<br />
(IMIBIC). Spanish Cancer Network (RTICC), Instituto de Salud Carlos III,, Cordoba,<br />
Spain<br />
Background: The prognosis <strong>of</strong> advanced CRC p has improved during last years.<br />
Nevertheless, treatment options in this situation are still limited. Maintenance therapy<br />
with bevacizumab has been stablished as standard <strong>of</strong> care after bevacizumab plus<br />
fluropyrimidine based chemotherapy. Axitinib is a novel drug targeting VEGFR1, 2<br />
and 3, with contradictory results in CRC<br />
Methods: In this phase 2 randomized double blinded trial, axitinib (5 mg/bid) was<br />
compared to placebo in metastatic CRC p who had not progressed after 6-8 months <strong>of</strong><br />
first line treatment with chemotherapy with or without bevacizumab or cetuximab.<br />
The primary objective was progression-free survival (PFS) at 6 months. Secondary<br />
objectives included overall survival (OS), response rate (RR) and safety<br />
Results: A total <strong>of</strong> 49 p were included: 25 cohort A (axitinib) and 24 cohort B<br />
(placebo). Baseline characteristics were well balanced. Mean age was 66 years (Standard<br />
Deviation (SD) ±10.35); 33 (67%) were men; ECOG Performance status was 0 for 19 p<br />
and 1 for 30 p. PFS at 6 months was 40% (Confidence Interval (CI) 95% 21.28, 58.12)<br />
for cohort A and 8.33% (CI95% 1.44, 23.30) for cohort B; p-value p = 0.01. Median PFS<br />
was 4.96 months in cohort A and 3.16 months for cohort B; Hazard Ratio (HR) 0.46<br />
(0.2515, 0.8565), p = 0.0116. Median OS was 27.61 months in cohort A (CI: 14.96;<br />
38.94), and 19.99 months (CI: 12.08; 27.35) in cohort B, p = 0.3279. The study was<br />
prematurely closed due to lack <strong>of</strong> accrual; however p-value <strong>of</strong> the log-rank contrast was<br />
significant. Regarding safety, grade 3-4 treatment related toxicities were experienced by<br />
7 p (28%) in cohort A and 1 p (4%) in cohort B. The most frequent grade 3-4 treatment<br />
related toxicities were hypertension in 6% and 2%; diarrhea in 4% and 0%, asthenia in<br />
2% and 0% in cohort A and B, respectively. There were no toxic deaths<br />
Conclusions: Maintenance treatment with axitinib in advanced CRC with no<br />
progression after first line chemotherapy is associated with a significantly increased<br />
PFS when compared to placebo. Axitinib was well tolerated with few SAEs. The<br />
initially estimated sample size was not reached, but the study drug should be further<br />
studied in this setting since promising efficacy data were met<br />
Clinical trial identification: EudraCT: 2011-002384-16<br />
Legal entity responsible for the study: Spanish Cooperative Group for the Digestive<br />
Tumour Therapy<br />
Funding: Pfizer, New York, NY, USA<br />
Disclosure: A. Carrato: Consultant or advisore role: Amgen, Merck, Roche. M.<br />
Valladares-Ayerbes: Consultant or advisory role: Amgen, Bayer. C. Lopez: Consultant<br />
or advisory role Amgen, Pfizer, Celgene, San<strong>of</strong>i, Roche, Novartis, Ipsen. P. García<br />
Alfonso: Advisory role: Roche, Merck, Amgen, San<strong>of</strong>i, Lilly y Bayer. E. Aranda:<br />
advisory role from Amgen, Bayer, Celgene, Merk, Roche and San<strong>of</strong>i. All other authors<br />
have declared no conflicts <strong>of</strong> interest.<br />
477P<br />
A multicenter phase II study <strong>of</strong> preoperative concurrent<br />
chemoradiotherapy with S-1 plus irinotecan for locally<br />
advanced rectal cancer: SAMRAI-2<br />
M. Noda 1 ,T.Sato 2 , K. Hayakawa 3 , N. Tomita 1 , N. Kamikonnya 4 , S. Matoba 5 ,<br />
A. Uki 6 , H. Baba 7 , N. Oya 8 , H. Hasegawa 9 , N. Shigematu 10 , K. Hida 11 ,<br />
T. Furuhata 12 , T. Naitou 13 , M. Shimada 14 , K. Otuka 15 , Y. Higuchi 16 , Y. Sakai 11 ,<br />
M. Takeuchi 17 , M. Watanabe 2<br />
1 Surgery, Hyogo College <strong>of</strong> Medicine, Nishinomiya, Japan, 2 Surgery, Kitasato<br />
University School <strong>of</strong> Medicine, Sagamihara, Japan, 3 Radiation <strong>Oncology</strong>, Kitasato<br />
University School <strong>of</strong> Medicine, Sagamihara, Japan, 4 Radiology, Hyogo College <strong>of</strong><br />
Medicine, Nishinomiya, Japan, 5 Gastrointestinal surgery, Toranomon Hospital,<br />
Minato-ku, Japan, 6 Radiology, Toranomon Hospital, Minato-ku, Japan,<br />
7 Gastroenterological Surgery, Kumamoto University, Kumamoto, Japan,<br />
8 Radiation <strong>Oncology</strong>, Kumamoto University, Kumamoto, Japan, 9 Surgery, Keio<br />
University School <strong>of</strong> Medicine, Shjnnjyukuku, Japan, 10 Radiology, Keio University<br />
School <strong>of</strong> Medicine, Shjnnjyukuku, Japan, 11 Surgery, Kyoto University-Graduate<br />
school <strong>of</strong> medicine, Kyoto, Japan, 12 Surgery, Sapporo Medical University School<br />
<strong>of</strong> Medicine, Sapporo, Japan, 13 Surgery, Tohoku University Graduate School <strong>of</strong><br />
Medicine, Sendai, Japan, 14 Surgery, Tokushima University, Tokushima, Japan,<br />
15 Surgery, Iwate Medical University School <strong>of</strong> Medicine, Morioka, Japan,<br />
16 Surgery, Teikyo University, Itabashi, Japan, 17 Clinical Medicine, Kitasato<br />
University School <strong>of</strong> Pharmacy, Minato-ku, Japan<br />
Background: We previously conducted a phase I study <strong>of</strong> preoperative concurrent<br />
chemoradiotherapy combining S-1 and irinotecan with radiotherapy <strong>of</strong> the lesser pelvis<br />
in patients with resectable, locally advanced rectal cancer (SAMRAI-1 Trial). The<br />
maximum tolerated dose (MTD) <strong>of</strong> irinotecan was 80 mg/m 2 , and the recommended<br />
dose was 60 mg/m 2 . We thus conducted a phase II study (SAMRAI-2 Trial) to further<br />
evaluate efficacy and safety.<br />
Methods: We studied patients 20–80 years <strong>of</strong> age with a performance status <strong>of</strong> 0 or 1<br />
who had clinical stage T3 or T4, N0–N2, resectable cancer (adenocarcinoma) <strong>of</strong> the<br />
upper rectum (Ra) or lower rectum (Rb). The treatment schedule was irinotecan 60<br />
mg/m 2 on days 1, 8, 22, and 29; S-1 80 mg/day (body surface area,
abstracts<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
KRAS wildtype (KRASwt) metastatic colorectal cancer (mCRC). Pre-clinical studies<br />
have demonstrated activity <strong>of</strong> temozolomide (TMZ) in mCRC cell lines (Inno et al,<br />
World J Clin Cases 2014), and clinical phase 2 data indicate effect <strong>of</strong> TMZ in heavily<br />
pre-treated mCRC patients (Scacham-Shmueli et al, JCO 2011; Pietrantonio et al, Ann<br />
<strong>of</strong> Oncol 2014, Pietrantonio et al, Targ Oncol, 2015). The combination <strong>of</strong> TMZ and<br />
capecitabine (TMZ-Cap) have synergetic schedule-depend effect (Fine et al, ASCO<br />
2005). Therefore we initiated and completed two parallel phase II studies on the<br />
combination <strong>of</strong> TMZ-Cap in heavily pre-treated mCRC patients with KRASwt and<br />
KRASmut mCRC, respectively. Data on the combination <strong>of</strong> TMZ-Cap in KRASmut<br />
patients was recently presented (Qvortrup et al, ESMO 2015).<br />
Methods: Phase II study evaluating the combination <strong>of</strong> capecitabine (2000 mg/m 2 days<br />
1-14) with TMZ (150 mg/m 2 days 10-14) every 4 weeks in patients with refractory<br />
mCRC (EUDRACT: 2012-002327-15). The main inclusion criteria were: histologically<br />
confirmed KRASwt mCRC; PD during or after therapy with fluoropyrimidine,<br />
irinotecan, oxaliplatin, and an anti-EGFR-inhibitor; PS 0-1. The primary endpoint <strong>of</strong><br />
the study is progression free survival (PFS). Secondary endpoints were RR, OS and<br />
predictive markers. Tumor tissue and liquid biopsies has been collected to search for<br />
predictive markers (including MGMT in tumor tissue).<br />
Results: Forty patients with refractory KRASwt mCRC from 3 Danish oncological<br />
departments were included from June 2013 to October 2015. Median age was 65 years<br />
(47-77), 33% were women. No patients achieved PR, mPFS was 1.9 (1.7-3.4) months,<br />
and mOS was 7.1 (5.8-7.9) mo. Toxicity was modest, only 1 patient stopped therapy<br />
due to toxicity.<br />
Conclusions: The combination <strong>of</strong> TMZ and capecitabine is safe and has activity<br />
comparable to regorafenib and TAS-102 in patients with heavily pre-treated KRASwt<br />
mCRC. A search for predictive markers including MGMT expression is ongoing.<br />
Clinical trial identification: EUDRACT: 2012-002327-15<br />
Legal entity responsible for the study: Clinical Research Unit at department <strong>of</strong><br />
<strong>Oncology</strong> Odense University hospital<br />
Funding: Clinical Research Unit at department <strong>of</strong> <strong>Oncology</strong> Odense University<br />
Hospital<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
479P<br />
Nivolumab ± ipilimumab treatment (Tx) efficacy, safety, and<br />
biomarkers in patients (Pts) with metastatic colorectal cancer<br />
(mCRC) with and without high microsatellite instability<br />
(MSI-H): results from the CheckMate-142 study<br />
M.J. Overman 1 , S. Kopetz 2 , S. Lonardi 3 , R. McDermott 4 , F. Leone 5 , J. Leach 6 ,<br />
H-J. Lenz 7 , A. Hendlisz 8 , M. Morse 9 , P. Garcia-Alfonso 10 , J. Desai 11 , A. Hill 12 ,R.<br />
A. Moss 13 , M.V. Goldberg 13 , C-S. Lin 14 , H. Tang 13 , T. André 15<br />
1 Gastrointestinal Medical <strong>Oncology</strong>, MD Anderson Cancer Center, Houston, TX,<br />
USA, 2 Department <strong>of</strong> Gastrointestinal (GI) Medical <strong>Oncology</strong>, Division <strong>of</strong> Cancer<br />
Medicine, MD Anderson Cancer Center, Houston, TX, USA, 3 Department <strong>of</strong><br />
<strong>Oncology</strong>, Istituto Oncologico Veneto IRCCS, Padua, Italy, 4 Medical <strong>Oncology</strong>, St<br />
Vincents University Hospital, Dublin, Ireland, 5 School <strong>of</strong> Medicine, University <strong>of</strong><br />
Turin School <strong>of</strong> Medicine, Turin, Italy, 6 <strong>Oncology</strong>, Allina Health System,<br />
Minneapolis, MN, USA, 7 Division <strong>of</strong> Medical <strong>Oncology</strong>, University <strong>of</strong> Southern<br />
California Norris Comprehensive Cancer Center, Los Angeles, CA, USA, 8 Digestive<br />
Endoscopy, Institute Jules Bordet, Brussels, Belgium, 9 Cancer, Duke Cancer<br />
Institute, Durham, NC, USA, 10 Department <strong>of</strong> <strong>Oncology</strong>, Hospital General<br />
Universitario Gregorio Marañon, Madrid, Spain, 11 Royal Melbourne Hospital, The<br />
University <strong>of</strong> Melburne, Melbourne, Australia, 12 <strong>Oncology</strong>, Tasman <strong>Oncology</strong><br />
Research Pty Ltd, Southport, Australia, 13 Global Clinical Research, <strong>Oncology</strong>,<br />
Bristol-Myers Squibb, Princeton, NJ, USA, 14 Biostatistics, Bristol-Myers Squibb,<br />
Princeton, NJ, USA, 15 Oncologie médicale, Hopital St. Antoine, Paris, France<br />
Background: Globally, about 10% <strong>of</strong> new cancers each year are CRC and ∼15% <strong>of</strong><br />
these are MSI-H. Nivolumab (N), a fully human anti-PD-1 mAb, and ipilimumab (I), a<br />
humanized anti-CTLA-4 mAb, are immune checkpoint inhibitors with favorable safety<br />
and efficacy pr<strong>of</strong>iles in multiple tumor types. This phase 2 study evaluates N ± I in<br />
MSI-H and non-MSI-H pts with mCRC.<br />
Methods: MSI-H pts received N 3 mg/kg q2 wk (N3) or N 3 mg/kg + I 1 mg/kg q3 wk<br />
(N3 + I1) x 4 doses followed by N3 until disease progression (PD) or other<br />
discontinuation. Initial evaluation <strong>of</strong> N + I was also completed in non-MSI-H pts.<br />
Primary endpoint was investigator-reported ORR by RECIST 1.1. Other endpoints<br />
included safety, OS, PFS, and clinical activity in biomarker-defined subpopulations<br />
(KRAS, BRAF status, and PD-L1).<br />
Results: 70 (N3) and 30 (N3 + I1) MSI-H pts and 3 (N1 + I1), 10 (N1 + I3), and 10<br />
(N3 + I1) non-MSI-H pts were enrolled. All non-MSI-H pts and 87% (N3) and 93%<br />
(N3 + I1) <strong>of</strong> MSI-H pts had ≥2 prior regimens. 47 (67%; N3) and 18 (60%; N3 + I1)<br />
MSI-H pts remain on tx. Efficacy data for MSI-H pts are shown in the Table. Responses<br />
were also seen in non-MSI-H pts. Median (95% CI) PFS across all non-MSI-H pts was<br />
1.4 mo (1.2, 1.9). Responses were observed regardless <strong>of</strong> tumor PD-L1 expression.<br />
Treatment-related adverse events (TRAEs) occurred in 41 (59%; N3) and 25 (83%;<br />
N3 + I1) MSI-H pts; 10 (14%; N3) and 8 (27%; N3 + I1) pts had Grade 3–4 TRAEs.<br />
One pt on N3 had a Grade 5 TRAE (sudden death). Additional biomarker data<br />
including MSI assessment and influence <strong>of</strong> BRAF/KRAS mutations will be presented.<br />
Conclusions: N ± I demonstrated promising clinical activity with a favorable overall<br />
safety pr<strong>of</strong>ile in pts with mCRC, regardless <strong>of</strong> tumor PD-L1 expression. Additional<br />
biomarker analyses are ongoing.<br />
Legal entity responsible for the study: Sponsored by Bristol-Myers Squibb<br />
Funding: Sponsored by Bristol-Myers Squibb<br />
Disclosure: H-J. Lenz: Has served as a consultant/advisory board member and received<br />
travel expenses from Bayer, Merck Serono, and Roche. He has received honoraria from<br />
Bayer, Boehringer Ingelheim, Celgene, Merck Serono, and Roche. P. Garcia-Alfonso:<br />
Has served on advisory boards for Roche, Merck, San<strong>of</strong>i, Amgen, Bayer, and Lilly. A.<br />
Hill: Is employed by, owns stock in, and has received research funding from Tasman<br />
<strong>Oncology</strong> Research. He has received travel accommodations/expenses from BMS. R.A.<br />
Moss: Is employed by and owns stock in Bristol-Myers Squibb. M.V. Goldberg, C-S.<br />
Lin, H. Tang: Is an employee <strong>of</strong> Bristol-Myers Squibb. T. André: Has received<br />
honoraria from BMS and consultant fees from Roche. All other authors have declared<br />
no conflicts <strong>of</strong> interest.<br />
480P<br />
MErCuRIC1: A phase 1a study <strong>of</strong> MEK1/2 inhibitor<br />
PD-0325901 with cMET inhibitor crizotinib in patients with<br />
advanced solid tumours<br />
R. Wilson 1 , M.R. Middleton 2 , J. Houlden 2 , S. Van Schaeybroeck 3 , C.D. Rolfo 4 ,<br />
E. Elez 5 , J. Taieb 6 , T. André 7 , A. Bardelli 8 , P. Laurent-Puig 9 , J. Tabernero 10 ,<br />
M. Peeters 11 , T. Maughan 2 , C. Roberts 2 ,S.Love 2 , M. Lawler 12 , M. Salto-Tellez 12 ,<br />
M. Grayson 13 , V. Popovici 14 , F. Di Nicolantonio 8<br />
1 Centre for Cancer Research and Cell Biology, Belfast City Hospital Northern<br />
Ireland Cancer Centre, School <strong>of</strong> Medicine, Dentistry & Biomedical Science,<br />
Belfast, UK, 2 <strong>Oncology</strong> Clinical Trials Office (OCTO), Oxford Cancer and<br />
Haematology Centre, Churchill Hospital, Oxford, UK, 3 <strong>Oncology</strong>, Belfast City<br />
Hospital Northern Ireland Cancer Centre, School <strong>of</strong> Medicine, Dentistry &<br />
Biomedical Science, Belfast, UK, 4 Phase I - Early Clinical Trials Unit & Center for<br />
Oncological Research <strong>of</strong> Antwerp (CORE), Antwerp University Hospital, Edegem,<br />
Belgium, 5 Medical <strong>Oncology</strong>, Vall d’Hebron University Hospital Institut<br />
d’Oncologia, Barcelona, Spain, 6 Gastroenterology and digestive oncology, Hopital<br />
European George Pompidou, Paris, France, 7 Oncologie médicale, Hopital<br />
St. Antoine, Paris, France, 8 Dept <strong>of</strong> <strong>Oncology</strong>, IRCCs University <strong>of</strong> Turin School <strong>of</strong><br />
Medicine, Candiolo, Italy, 9 Department <strong>of</strong> Biology, Hopital European George<br />
Pompidou, Paris, France, 10 Medical <strong>Oncology</strong>, Vall d’Hebron University Hospital<br />
and Institute <strong>of</strong> <strong>Oncology</strong> (VHIO), Barcelona, Spain, 11 Department <strong>of</strong> <strong>Oncology</strong>,<br />
University Hospital Antwerp, Edegem, Belgium, 12 Centre for Cancer Research and<br />
Cell Biology, Queen’s University Belfast, Belfast, UK, 13 NI Cancer Trials Network,<br />
Belfast City Hospital Northern Ireland Cancer Centre, School <strong>of</strong> Medicine,<br />
Dentistry & Biomedical Science, Belfast, UK, 14 Institute <strong>of</strong> Biostatistics, Masaryk<br />
University Faculty <strong>of</strong> Medicine, Brno, Czech Republic<br />
Background: RAS activating mutations occur in ∼55% <strong>of</strong> metastatic (m) CRC.<br />
RASMT and >50% <strong>of</strong> RASWT mCRC patients (pts) do not benefit from anti-EGFR<br />
antibodies. c-MET is overexpressed in ∼50-60%, amplified in ∼2-3% and mutated in<br />
∼1-3% <strong>of</strong> mCRC. Preclinical data support the clinical evaluation <strong>of</strong> MEK1/2 and<br />
METi, in particular in RASMT tumours and RASWT with aberrant c-MET expression.<br />
The primary aim <strong>of</strong> the phase I study was to establish the maximum tolerated dose<br />
Table: 479P MSI-H a efficacy<br />
N3 (n = 70) N3 + I1 (n = 30)<br />
ORR, n (%) b 12 (25.5) 9 (33.3)<br />
CR PR SD PD Not determined/not reported 0 12 (25.5) 14 (29.8) 17 (36.2) 4 (8.5) 0 9 (33.3) 14 (51.9) 3 (11.1) 1 (3.7)<br />
Median DOR (95% CI), mo NR (4.2, NE) NR (NE, NE)<br />
PFS rates, % (95% CI) 6 mo 9 mo 12 mo 45.9 (29.8, 60.7) 45.9 (29.8, 60.7) 45.9 (29.8, 60.7) 66.6 (45.5, 81.1) NR NR<br />
OS rates, % (95% CI) 6 mo 9 mo 12 mo 75.0 (58.5, 85.7) 65.6 (48.0, 78.6) 65.6 (48.0, 78.6) 85.1 (65.0, 94.2) 85.1 (65.0, 94.2) NR<br />
Baseline PD-L1 expression, n (%) ≥1%
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
(MTD) and assess safety/toxicity pr<strong>of</strong>ile <strong>of</strong> PD-0325901 MEKi & crizotinib METi in<br />
pts with advanced solid tumours using NCI CTCAE V4.03.<br />
Methods: A single arm, open-label phase I trial <strong>of</strong> PD-0325901 with crizotinib was<br />
performed in pts with advanced solid tumours, measurable disease, ECOG PS 0-1 and<br />
adequate end organ function. Pts received oral PD-0325901 BD (days 1-21 every 28<br />
days) at doses <strong>of</strong> 2 - 8mg BD with oral crizotinib continuously at 250mg OD or 200mg<br />
BD, using a rolling 6 design. Crizotinib started after a 1 week lead-in with PD-0325901.<br />
Blood samples for pharmacokinetics, pERK and soluble c-MET levels and skin biopsies<br />
for pERK levels were collected.<br />
Results: Between 12/2014 and 11/2015 we enrolled 25 pts; Male (13), Female (12).<br />
Median age 63 yrs (range 36-78). MTD was defined at the highest dose; crizotinib:<br />
200mg BD continuously; PD-0325901: 8mg BD days 1-21 every 28 days. 1 <strong>of</strong> 6 patients<br />
exhibited dose-limiting toxicity (fatigue) at this dose level. The 25 pts received a total <strong>of</strong><br />
52 cycles. Drug-related adverse events were in keeping with single agent toxicity pr<strong>of</strong>iles,<br />
including rash, diarrhoea, fatigue, nausea, hypoalbuminemia and visual disturbances.<br />
Best clinical response was stable disease at the end <strong>of</strong> cycle 2, in 4/25 evaluable pts.<br />
Conclusions: MEK/METi can be given together at pharmacologically active doses.<br />
MTD for the PD-0325901/crizotinib combination was 8mg BD (days 1-21) and 200mg<br />
BD continuously in a 28 day cycle. The combination is now being explored further<br />
with an alternate MEKi before expansion into RASMT and RASWT CRC with<br />
aberrant c-MET expression. EudraCT registry number: 2014-000463-40.<br />
Clinical trial identification: EudraCT Number: 2014-000463-40<br />
Legal entity responsible for the study: University <strong>of</strong> Oxford<br />
Funding: European FP7 Grant<br />
Disclosure: M.R. Middleton: Consultant: Amgen, AZ, BMS, Eisai, GSK, Lilly, Merck,<br />
Millenium, Novartis, Physiomics, Rigontec, Roche Grant/Research support: Abbvie,<br />
Amgen, AZ, BMS, Clovis, Eisai, GSK, Immunocore, Merck, Millenium, Novartis,<br />
Pfizer, Roche, Vertex (all to institution). J. Tabernero: Consultant/Advisory role:<br />
Amgen, Bayer, Boehringer Ingelheim, Celgene, Chugai, Lilly, MSD, Merck Serono,<br />
Novartis, Roche, San<strong>of</strong>i, Symphogen, Takeda and Taiho. All other authors have<br />
declared no conflicts <strong>of</strong> interest.<br />
481P<br />
The correlation between tumor regression grade and retrieved<br />
lymph nodes status in locally advanced rectal cancer after<br />
neoadjuvant treatment: results from a prospective study<br />
J. Zhang 1 , Y. Deng 1 ,Y.Cai 1 ,H.Hu 1 , J. Ling 1 , J. Xiao 1 , P. Lan 2 , L. Wang 2 ,<br />
M. Huang 2 , L. Kang 2 ,X.Wu 2 , J. Wang 2<br />
1 Medical <strong>Oncology</strong>, The Sixth Affiliated Hospital <strong>of</strong> Sun Yat-sen University,<br />
Guangzhou, China, 2 Surgery, The Sixth Affiliated Hospital <strong>of</strong> Sun Yat-sen<br />
University, Guangzhou, China<br />
Background: A paucity <strong>of</strong> lymph nodes harvested is common in rectal cancer after<br />
neoadjuvant treatment and the significance is still uncertain. We aimed to evaluate the<br />
correlation between tumor regression grade (TRG) and retrieved lymph nodes status in<br />
patients who underwent neoadjuvant treatment followed by total mesorectal excision<br />
(TME) for locally advanced rectal cancer.<br />
Methods: From Jan 2011 to Feb 2015, complete data was available for 447 patients with<br />
rectal cancer who received neoadjuvant treatment followed by TME enrolled in<br />
FOWARC study. According to the post-operative pathologic TRG <strong>of</strong> primary lesion,<br />
patients were categorized into 4 groups, TRG 0, 1, 2 and 3.The number <strong>of</strong> harvested<br />
lymph nodes, lymph node metastasis, and extranodal tumor deposits in each group<br />
were analyzed.<br />
Results: Of the 447 patients, 77 (17.2%) patients were TRG 0, and 143 (32.0%) patients<br />
were TRG 1. Another 156 (34.9%) and 71 (15.9%) patients were TRG 2 and TRG 3,<br />
respectively. The median retrieved lymph node counts among the 4 groups were 8, 10,<br />
11 and 13, respectively. The harvested lymph node in better TRG groups was less than<br />
that <strong>of</strong> poor TRG group (p = 0.001). The lymph node metastasis rates <strong>of</strong> the 4 groups<br />
were 7.8%, 14.7%, 21.8% and 38.0%, respectively. The differences were statistically<br />
significant (p < 0.001). And the extranodal tumor deposits rates <strong>of</strong> the 4 groups were<br />
3.9%, 7.7%, 16.0% and 21.1%, respectively (p = 0.002).<br />
Items TRG 0<br />
(N = 77)<br />
Harvested lymph<br />
nodes (median)<br />
LN metastasis<br />
(n,%)<br />
Extranodal TD<br />
(n,%)<br />
Table: 481P<br />
TRG 1<br />
(N = 143)<br />
TRG 2<br />
(N = 156)<br />
TRG 3<br />
(N = 71)<br />
8 10 11 13 0.001<br />
6(7.8) 21(14.7) 34(21.8) 27(38.3) 1 at baseline or an Eastern Cooperative<br />
<strong>Oncology</strong> Group score <strong>of</strong> 1.<br />
Results: Overall 439 pts had RAS WT/BRAF WT mCRC. Progression-free (PFS) and<br />
overall survival (OS) were longer for pmab + FOLFOX4 vs FOLFOX4 in both groups<br />
(Table). Results were similar when the ECOG = 1 definition was used (Cytoreduction<br />
Group [n = 214] PFS hazard ratio [HR]: 0.77, OS HR: 0.76; Disease Control Group<br />
[n = 197] PFS HR: 0.64, OS HR: 0.68). ORR were higher for pmab + FOLFOX4<br />
compared with FOLFOX4 in both groups (Table).<br />
Table: 482P<br />
Median, months<br />
PFS OS ORR<br />
Cytoreduction<br />
Group<br />
(n = 252)<br />
Pmab + FOLFOX4 10.0 23.8 80/124 (64.5%)<br />
FOLFOX4 9.3 20.2 63/122 (51.6%)<br />
HR (95% CI) 0.73 (0.56-0.96) 0.78 (0.60-1.03)<br />
Disease Control<br />
Group<br />
(n = 172)<br />
Pmab + FOLFOX4 12.9 31.1 56/87 (64.4%)<br />
FOLFOX4 9.9 24.0 41/83 (49.4%)<br />
HR (95% CI) 0.68 (0.49-0.94) 0.62 (0.44-0.88)<br />
CI = confidence intervals<br />
abstracts<br />
Conclusions: Although the definition <strong>of</strong> tumour-related symptoms used in this study<br />
has some limitations, this exploratory analysis suggests that first-line<br />
pmab + FOLFOX4 treatment significantly improves PFS and OS vs FOLFOX4 alone in<br />
pts with RAS WT/BRAF WT mCRC who are candidates for disease control.<br />
Clinical trial identification: NCT00364013<br />
Legal entity responsible for the study: Amgen<br />
Funding: Amgen (Europe) GmbH<br />
Disclosure: J. Taieb: Honoraria/consulting/advisory role for Roche, Amgen, Merck,<br />
Lilly, San<strong>of</strong>i, Celgene, Sirtex. M. Peeters: Received research funding and acted in<br />
consultancy/advisory roles for Amgen and received research funding and participated<br />
in symposia for Merck Serono. S. Siena: Member <strong>of</strong> advisory boards or steering<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw370 | vi161
abstracts<br />
committees or principal investigator for Amgen, Bayer, Boehringer Ingelheim, Celgene,<br />
Genentech, Ignyta, Merck, Merrimack, Novartis, Pfizer, Roche and San<strong>of</strong>i Aventis. F.<br />
Rivera Herrero: Acted on advisory boards and received research funding from Amgen,<br />
San<strong>of</strong>i, Merck-Serono and Roche. R. Koukakis: Amgen Ltd employee and stockholder.<br />
G. Demonty: Amgen (Europe) GmbH employee and stockholder. J-Y. Douillard:<br />
Honoraria/consulting/advisory roles for Amgen, Bayer, Roche, Merck; Research<br />
funding from Merck Serono; Travel/accommodation/expenses from Amgen, Bayer,<br />
Roche, Merck.<br />
483P<br />
Effect <strong>of</strong> 5 years <strong>of</strong> imaging and CEA follow-up to detect<br />
recurrence <strong>of</strong> colorectal cancer - PRODIGE 13 a FFCD and<br />
Unicancer phase III trial: baseline characteristics<br />
C. Lepage 1 , J-M. Phelip 2 , L. Cany 3 , E. Maillard 4 , A. Lievre 5 , T. Chatellier 6 ,<br />
R. Faroux 7 , J-C. Duchmann 8 , M. Ben Abdelghani 9 , G. Breysacher 10 , P. Ge<strong>of</strong>froy 11 ,<br />
D. Pere-Verge 12 , A. Pelaquier 13 , D. Pillon 14 , J. Ezenfis 15 , Y. Rinaldi 16 ,<br />
A. Darut-Jouve 17 , M. Duluc 18 , A. Adenis 19 , O. Bouché 20<br />
1 Service HGE, CHU Le Bocage, INSERM U866, Dijon, France, 2 Service HGE,<br />
CHU Nord, St. Etienne, France, 3 Service Radiothérapie et Oncologie, Polyclinique<br />
Francheville, Périgueux, France, 4 Faculté de médecine, FFCD, Dijon, France,<br />
5 Service Maladies de l’Appareil Digestif, CHU de Pontchaillou, Rennes, France,<br />
6 Service d Oncologie, Clinique Mutualiste de l’Estuaire, St. Nazaire, France,<br />
7 Service d’HGE, CHD Vendee - Hopital Les Oudairies, La Roche Sur Yon, France,<br />
8 Service d’HGE, Centre Hospitalier de Compiègne, Compiegne, France, 9 Service<br />
d’Oncologie, Centre Paul Strauss Centre de Lutte contre le Cancer, Strasbourg,<br />
France, 10 Service de Médecine A, Hopitaux Civils de Colmar, Colmar, France,<br />
11 Clinique Saint Vincent, Epernay, France, 12 Service d’HGE, CH Saint-Joseph<br />
Saint-Luc, Lyon, France, 13 Service HGE, CH Montelimar, Montelimar, France,<br />
14 Service d’HGE, CH Fleyriat, Bourg En Bresse, France, 15 Unité de<br />
Chimiothérapie, CH de Longjumeau, Longjumeau, France, 16 Service d’HGE,<br />
Hôpital européen, Marseille, France, 17 Centre de Radiothérapie du Parc, Dijon,<br />
France, 18 Service d’HGE et d’Oncologie, CHU La Timone, Marseille, France,<br />
19 Service Cancérologie Digestive, Centre Oscar Lambret, Lille, France,<br />
20 Médecine Ambulatoire-Cancérologie, CHU de Reims - Hôpital Robert Debré,<br />
Reims, France<br />
Background: PRODIGE 13 is a cooperative prospective multicentre controlled phase<br />
III trial evaluating by double randomisation the impact <strong>of</strong> intensive radiological<br />
monitoring versus a standard one and CEA monitoring versus no monitoring in Stage<br />
II or III colorectal cancer. This abstract describes patient’s baseline characteristics.<br />
Methods: Recommendations for colorectal cancer, according to various scientific<br />
societies have been based on heterogeneous clinical trials, and indeed mainly on expert<br />
opinions. Differences still exist particularly concerning the imaging techniques used.<br />
The CEA dosage is also poorly evaluated. Despite their limits, recent trials suggest that<br />
survival is increased thanks to clinical monitoring combined with hepatic and<br />
pulmonary imaging and possibly CEA assay. PRODIGE 13 is a large randomised trial<br />
<strong>of</strong> monitoring strategy and will evaluate the strategies to eliminate existing doubts in<br />
1997 patients (pts) recruited in 96 centers in France and Belgium. The primary<br />
endpoint is 5-year overall survival (OS). The design with 4 arms is already described in<br />
a publication (Lepage C et al., Dig Liver Dis, 2015)<br />
Results: On the 1997 pts included between 09/2009 and 04/2015, 59% were men, 76%<br />
were less than 75 years old and OMS was 0 for more than 66% <strong>of</strong> the pts. Around 50 %<br />
were Stage II (treated or not) and 12% were previously included in a adjuvant trial<br />
(mainly IDEA). Sixteen % were rectum cancer, 44% were left colon cancer. More than<br />
90% <strong>of</strong> the cancers were well-differentiated. For the rectum primary tumor, 83% <strong>of</strong> the<br />
pts received at least one treatment (chemotherapy or radiotherapy) and it was mainly<br />
pre-operative treatment (70%). For the colon primary tumor, 60.5% <strong>of</strong> the pts received<br />
at least one treatment, mainly post-operative treatment (99%). According to EuroQol<br />
questionnaire, median Visual Analog Scale was 75 mm [range: 2-100] meaning that<br />
most <strong>of</strong> the pts felt in a good health.<br />
Conclusions: The study will show the effect <strong>of</strong> intensive follow-up versus standard<br />
follow-up in Stage II or Stage III colorectal cancer patients. The survival results <strong>of</strong> the<br />
study will be reported in 2021 (6 years after last patient randomization).<br />
Clinical trial identification: NCT00995202<br />
Legal entity responsible for the study: FFCD<br />
Funding: FFCD<br />
Disclosure: C. Lepage: has a conflict <strong>of</strong> interest with: Ipsen. J-M. Phelip: received grant/<br />
reseach support from: Amgen, Merck, Roche Glycart, is a consultant/advisor for<br />
industry from: San<strong>of</strong>i, Bayer, Lilly, Ipsen, Novartis, Merck, Amgen, Celgene, Roche<br />
Glycart. O. Bouché: received grant/reseach support from: Pierre Fabre, is a consultant/<br />
advisor for industry from: Roche, Merck Serono, Teva, is speaker bureau from :<br />
Novartis, Lilly, Amgen,Hospira, has a conflict <strong>of</strong> interest with: Amgen. All other<br />
authors have declared no conflicts <strong>of</strong> interest.<br />
484P<br />
A multicenter phase II trial to evaluate the efficacy <strong>of</strong><br />
mFOLFOX6 + cetuximab as induction chemotherapy to achieve<br />
R0 surgical resection for advanced colorectal liver metastases<br />
(NEXTO trial)<br />
K. Hasegawa 1 , A. Saiura 2 , M. Oba 1 , S. Aosasa 3 , N. Tanaka 4 , T. Takayama 5 ,<br />
Y. Hashiguchi 6 , Y. Bandai 7 , H. Sakamoto 8 , S. Yamagata 9 , N. Aoyanagi 10 ,<br />
H. Kaneko 11 , H. Koyama 12 , S. Miyagawa 13 , J. Yamamoto 3 , Y. Mise 2 ,<br />
E. Shinozaki 14 , S. Yoshida 15 , T. Watanabe 16 , N. Kokudo 1<br />
1 Hepato-Biliary-Pancreatic Surgery Division, The University <strong>of</strong> Tokyo Graduate<br />
School <strong>of</strong> Medicine, Tokyo, Japan, 2 Department <strong>of</strong> Gastrointestinal Surgery,<br />
Cancer Institute Hospital <strong>of</strong> JFCR, Tokyo, Japan, 3 Department <strong>of</strong> Surgery, National<br />
Defense Medical College, Saitama, Japan, 4 Department <strong>of</strong> Surgery, Asahi General<br />
Hospital, Chiba, Japan, 5 Department <strong>of</strong> Digestive Surgery, Nihon University<br />
School <strong>of</strong> Dentistry Medecine, Tokyo, Japan, 6 Department <strong>of</strong> Surgery, Teikyo<br />
University, Tokyo, Japan, 7 Department <strong>of</strong> Surgery, JCHO Tokyo Yamate Medical<br />
Center, Tokyo, Japan, 8 Department <strong>of</strong> Digestive Surgery, Saitama Cancer Center<br />
Hospital, Saitama, Japan, 9 Department <strong>of</strong> Surgery, JCHO Tokyo Shinjuku Medical<br />
Center, Tokyo, Japan, 10 Department <strong>of</strong> Surgery, Kohnodai Hospital, National<br />
Center for Global-Health and Medicine, Chiba, Japan, 11 Department <strong>of</strong> Surgery,<br />
Toho University Faculty <strong>of</strong> Medicine, Tokyo, Japan, 12 Department <strong>of</strong> Surgery,<br />
JCHO Tokyo Takanawa Hospital, Tokyo, Japan, 13 Department <strong>of</strong> Surgery,<br />
Shinshu University School <strong>of</strong> Medicine, Matsumoto, Japan, 14 Medical <strong>Oncology</strong>,<br />
Cancer Institute Hospital <strong>of</strong> JFCR, Tokyo, Japan, 15 Gastroenterology, University <strong>of</strong><br />
Tokyo, Tokyo, Japan, 16 Department <strong>of</strong> Surgical <strong>Oncology</strong>, The University <strong>of</strong> Tokyo<br />
Graduate School <strong>of</strong> Medicine, Tokyo, Japan<br />
Background: For colorectal liver metastasis (CRLM), surgical resection is now<br />
established as the standard treatment option. The recent advance <strong>of</strong> anti-cancer drugs<br />
including the molecular-targeted agents enables us to extend the surgical indication<br />
and improve prognosis in a case with advanced CRLM. Because mFOLFOX with<br />
cetuximab has been expected to provide early tumor shrinkage for advanced-stage<br />
CRLM with KRAS wild type, we conducted this phase II trial to prospectively evaluate<br />
the significance <strong>of</strong> the treatment strategy.<br />
Methods: Patients having advanced CRLM (tumor number > =5 and/or technically<br />
unresectbale) with KRAS wild were included to this study. First, mFOLFOX with<br />
cetuximab was induced, and surgical indication was evaluated every 4 cycles (2<br />
months). If all tumors including primary and/or metastatic colorectal carcinoma were<br />
regarded as technically resectable, we performed surgical resection after the waiting<br />
period <strong>of</strong> 1 month. If they were unresctable, we repeated the regimen within the upper<br />
limit <strong>of</strong> 12 cycles. The primary endpoint was R0 resection rate. The secondary<br />
endpoints included safety, PFS, and OS.<br />
Results: Between May 2012 and May 2015, total 50 patients were enrolled to this trial<br />
in 14 centers. The induction was not done in 2 patients, who were excluded. The<br />
median age <strong>of</strong> the 48 patients was 62.5 (range: 45 to 79) including 36 men and 12<br />
women. The median tumor number detected by CT before the induction was 12 (1 to<br />
57). Although the experimental treatment was incomplete in 15 patients, the rates <strong>of</strong><br />
complete and partial response were 0% and 63.6%, respectively. R0 and R1 resections<br />
were done with no mortality in 26 and 5 patients, respectively (R0 resection rate:<br />
54.2%), whereas surgery was abandoned in 2. Under the median follow-up <strong>of</strong> 1.5 years,<br />
the 1-year PFS was 51.7%, and 2-year OS was 71.5%.<br />
Conclusions: For advanced CRLM with KRAS wild, mFOLFOX with cetuximab<br />
induction therapy was safely done and provided the sufficient R0 resection rate. This<br />
strategy can be effective to improve prognosis, which will be evaluated by further<br />
follow-up.<br />
Clinical trial identification: UMIN Clinical Trials Registry; C000007923<br />
Legal entity responsible for the study: The Institutiona Review Board <strong>of</strong> each<br />
participating institutions<br />
Funding: Self-funding<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
485P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Impact <strong>of</strong> depth <strong>of</strong> response (DpR) on survival in patients (pts)<br />
with RAS wild-type (WT) metastatic colorectal cancer (mCRC)<br />
receiving first-line panitumumab + FOLFOX4 vs FOLFOX4<br />
S. Siena 1 , F. Rivera Herrero 2 , J-Y. Douillard 3 , J. Taieb 4 , R. Koukakis 5 ,<br />
G. Demonty 6 , M. Peeters 7<br />
1 Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda and<br />
Università degli Studi di Milano, Milan, Italy, 2 Medical <strong>Oncology</strong>, University Hospital<br />
Marques de Valdecilla, Santander, Spain, 3 Oncologie Médicale, ICO<br />
R. Gauducheau, St Herblain, France, 4 Department <strong>of</strong> Gastroenterology and<br />
Digestive <strong>Oncology</strong>, Hôpital Européen Georges Pompidou, Paris, France,<br />
5 Biostatistics, Amgen Ltd, Uxbridge, UK, 6 Medical Development - <strong>Oncology</strong>,<br />
Amgen (Europe) GmbH, Zug, Switzerland, 7 Department <strong>of</strong> <strong>Oncology</strong>, University<br />
Hospital Antwerp, Edegem, Belgium<br />
Background: DpR has been associated with overall survival (OS) in first-line trials <strong>of</strong><br />
epidermal growth factor receptor inhibitors + chemotherapy in pts with mCRC. Here<br />
vi162 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
we evaluate the impact <strong>of</strong> DpR on progression-free survival (PFS) and OS in pts with<br />
RAS WT mCRC from the PRIME trial.<br />
Methods: PRIME (NCT00364013) was a randomised, phase III trial <strong>of</strong> first-line<br />
panitumumumab + FOLFOX4 vs FOLFOX4 in pts with mCRC. DpR was calculated as<br />
the maximal % change from baseline to nadir in pts who had tumour shrinkage. In pts<br />
with tumour growth, DpR was defined as WT mCRC who had measurable disease at<br />
baseline and calculable DpR post-baseline, were included in the analysis. Median DpR<br />
was higher in pts receiving panitumumab + FOLFOX4 vs FOLFOX4 (54% vs 46%;<br />
p = 0.0149). In the simple regression model, DpR was associated with PFS (p < 0.0001)<br />
and OS (p < 0.0001) irrespective <strong>of</strong> treatment received. Overall results by DpR category<br />
are shown in the Table. DpR remained associated with PFS (p < 0.0001) and OS<br />
(p < 0.0001) in the multiple Cox regression model.<br />
DpR<br />
continuous<br />
(n = 460)<br />
Group 1<br />
DpR
abstracts<br />
Disclosure: D. Malka, J. Telliez, S. Bakiri: Roche. J-P. Metges: Roche, Merck, San<strong>of</strong>i,<br />
Bayer. J. Bennouna: Roche, Boehringer, Astra-Zeneca, MSD. F. Bonnetain: Novartis,<br />
Celgene, Roche, Merck, Amgen, Chugai. L-M. Dourthe: Roche, Novartis, Astellas. M.<br />
Ben Abdelghani, A. Radji: San<strong>of</strong>i, Ipsen. P. Laplaige: Roche, Pfizer, San<strong>of</strong>i, Genomic<br />
Health, Pierre Fabre. All other authors have declared no conflicts <strong>of</strong> interest.<br />
488P<br />
Survival after resection <strong>of</strong> colorectal cancer with synchronous<br />
metastases – a Danish population based historical cohort<br />
study<br />
A.K. Boysen 1 , A.G. Ording 2 , H.T. Sørensen 2 , D.K. Farkas 2 , K-L. Spindler 1<br />
1 <strong>Oncology</strong>, Aarhus University Hospital, Aarhus, Denmark, 2 Clinical Epidemiology,<br />
Aarhus University Hospital, Aarhus, Denmark<br />
Background: Conflicting data exist on the optimal treatment for resectable<br />
synchronous metastatic disease in liver and/or lungs in patients with colorectal cancer<br />
(CRC). We examined the long term survival <strong>of</strong> a large national cohort <strong>of</strong> patients<br />
resected for CRC and timing <strong>of</strong> treatment for synchronous metastasectomies.<br />
Methods: From 2000-2013 we included all patients from the Danish Cancer Registry<br />
and the Danish National Patient Registry recorded with CRC surgery for<br />
adenocarcinoma We also obtained data from the Danish National Patient Registry for<br />
patients operated for liver and/or lung metastases synchronously ( 1 hepatic vein or > 4 segments) and/or biological<br />
reasons (> 4 metastases, CEA > 200, synchronicity). Limited resectable extraepatic<br />
disease and in situ primary allowed. Primary endpoint: pathological response<br />
according to Rubbia-Brandt et al., with a Simon 2-stage design (first step 22 pts; target<br />
46 pts); secondary endpoints: objective response rate (ORR); R0 resection; safety;<br />
progression-free and overall survival. Pts received biweekly irinotecan (180 mg/mq)<br />
and bev (5 mg/kg) day 1, oxaliplatin (85 mg/mq) day 2 and capecitabine 1000 mg/mq<br />
day b.i.d.) days 2-6; 5 cycles pre-operatively (the last without bev) and 4<br />
post-operatively.<br />
Results: We present preliminary data on 36 pts (30 resected, 6 still awaiting). M/F: 21/<br />
15, median age 62 years (38-76), synchronous disease in 29 pts (80%), multiple nodules<br />
61% (39% ≥ 4 nodules), N+ primary tumor 50%, CEA > 200 in 4 pts (11%),<br />
extrahepatic disease 2.7%, RAS mutation in 53% and no BRAF mutations. Two-stage<br />
hepatectomy 3%, ≥ 4 segments involved 43%, > 1 hepatic veins 16%. ORR was 88%,<br />
with 3 SD and 1 PD. R0 resection in 24 (80%) pts. TRG 1-2 was observed in 9 (30%),<br />
while TRG 3 in 12 pts (40%), i.e. pathological response 70%. Grade ≥ 3 toxicities:<br />
diarrhea 2, neutropenia 2, thrombosis 2, fatigue 2, neuropathy 1. At a median follow up<br />
<strong>of</strong> 12 months, we observed 8 relapses and 2 deaths.<br />
Conclusions: COI-B regimen is a feasible perioperative chemotherapy for borderline<br />
resectable CLM. This is the first trial to select pathological response as primary<br />
endpoint with encouraging activity.<br />
Clinical trial identification: NCT2086656<br />
Legal entity responsible for the study: N/A<br />
Funding: Istituto Nazionale Tumori<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
490P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Phase 2 <strong>of</strong> intra-arterial hepatic (IAH) bevacizumab with<br />
systemic chemotherapy (CT) in second line treatment <strong>of</strong> liver<br />
metastases <strong>of</strong> colorectal cancer (LMCRC)<br />
M.P. Ducreux 1 , O. Glehen 2 , G. Tergemina-Clain 3 , D. Smith 4 , B. Lacas 5 , V. Boige 1 ,<br />
D. Malka 1 , J-P. Pignon 3 , E. Dupont-Bierre 6 , R. Guimbaud 7<br />
1 Département de Médecine, Gustave Roussy, Université Paris-Saclay, Villejuif,<br />
France, 2 Chirurgie, Centre Hospitalier Lyon-Sud, Lyon, France, 3 Service de<br />
Biostatistiques et d’Epidémiologie, Gustave Roussy, Université Paris-Saclay,<br />
Villejuif, France, 4 Digestive oncology, CHU Bordeaux Hopital St. André, Bordeaux,<br />
France, 5 Service de Biostatistique et d’Epidemiologie, Gustave Roussy, Université<br />
Paris-Saclay, Villejuif, France, 6 Département de Chirurgie Digestive, CHP<br />
Saint-Grégoire, St. Grégoire, France, 7 Digestive <strong>Oncology</strong>, CHU Toulouse, Hôpital<br />
de Rangueil, Toulouse, France<br />
Background: IAHCT is used in the treatment <strong>of</strong> LMCRC. Regarding its<br />
anti-angiogenic effect bevacizumab (B) is a good candidate for IAH treatment. This<br />
phase II evaluate IAH administration <strong>of</strong> B in second line treatment <strong>of</strong> LMCRC<br />
combined with systemic treatment. We report here the results <strong>of</strong> the planned interim<br />
analysis on toxicity plus those on efficacy as the trial closed prematurely.<br />
Methods: Inclusion criteria: patients (pts) with LMCRC after failure to a 1st line <strong>of</strong> IV<br />
CT; ECOG performance status (PS) 0 or 1; at least one liver lesion evaluable by<br />
RECIST; extra-hepatic disease acceptable when limited to one or two lung metastases<br />
or lymph nodes potentially accessible to a curative treatment. They had to receive IAH<br />
treatment with B, 7.5 mg/kg every 3 weeks, and systemic CT with capecitabine (2 g/m 2 /<br />
day (d) 14 d, followed by 7 d rest) + irinotecan (200 mg/m 2 every 21d) or oxaliplatin<br />
(130 mg/m 2 every 21 d) depending on the 1st line received.<br />
Results: Between 06:2013 and 02/2015, 10 pts from 5 centers were included: 6 men, 4<br />
women (median age 61 years); ECOG PS0 (7) and PS1 (3); limited extra-hepatic<br />
disease in 4 pts. Median duration <strong>of</strong> 1st line treatment was 6 months. IAH catheter was<br />
implanted surgically in one pt and radiologically in 9. Pts had an average <strong>of</strong> 6 cycles <strong>of</strong><br />
IAH B, 3 received oxaliplatin and 7 irinotecan concomitantly. There was one grade (G)<br />
3 allergic reaction to IAH B, one G3 abdominal pain, one G3 mucositis, one G3 nausea<br />
and one G3 vomiting events. Related to the use <strong>of</strong> B, 2 G3 thromboembolic events and<br />
3 G3 hypertension were observed. The arterial catheter has to be replaced in one pt and<br />
a thrombosis <strong>of</strong> hepatic artery was observed in a second one preventing continuation <strong>of</strong><br />
IAH treatment after one cycle. In the 9 evaluable pts, 2 had partial response (22%), 5<br />
stable disease (56%) and 2 progressive disease (22%). The median progression-free and<br />
overall survival were 5.2 months 95%CI [1.6 – 6.2] and 13.5 months [4.8 – NR].<br />
Conclusions: IAH administration <strong>of</strong> bevacizumab in pts with LMCRC seems to be<br />
feasible with no major side effect. The efficacy reported did not suggest a major effect <strong>of</strong><br />
this treatment that should rather be used in combination with IAHCT with oxaliplatin.<br />
We thank the PHRC for its financial support<br />
Clinical trial identification: ClinicalTrials.gov: NCT01677884<br />
Legal entity responsible for the study: Gustave Roussy, Villejuif, France<br />
Funding: Programme Hospitalier de Recherche Clinique<br />
Disclosure: M.P. Ducreux: Receipt <strong>of</strong> grants/research supports: Roche, Chugai, Pfizer.<br />
Receipt <strong>of</strong> honoraria or consultation fees: Roche, Celgene, Merck Serono. Amgen,<br />
Novartis, San<strong>of</strong>i, Pfizer, Lilly, Servier. Spouse: Head <strong>of</strong> Business Unit, Sandoz. V. Boige:<br />
Advisory boards: Bayer, Symposium participation: Bayer, Amgen. D. Malka:<br />
Symposium participations: Roche, Amgen, Lilly, Merck Serono, Research funding:<br />
Merck Serono, Roche, Amgen Advisory boards: Roche, Amgen. All other authors have<br />
declared no conflicts <strong>of</strong> interest.<br />
vi164 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
491P<br />
Impact <strong>of</strong> surgical resection <strong>of</strong> liver metastases on outcome <strong>of</strong><br />
patients with KRAS-wildtype exon 2 (KRAS-wt) metastatic<br />
colorectal carcinoma (mCRC) treated with a cetuximab-based<br />
first-line therapy - Interim analysis <strong>of</strong> the German<br />
non-interventional study ERBITAG<br />
U. Neumann 1 , T. Goehler 2 , C. Hering-Schubert 3 , J. Janssen 4 , S. Sahm 5 ,<br />
M. Schwittay 6 , M.O. Zahn 7 , K.G. Stenzel 8 , F. Overkamp 9<br />
1 Department <strong>of</strong> General, Visceral and Transplantation Surgery,<br />
Universitaetsklinikum Aachen (UKA), Aachen, Germany, 2 Dresden/Freiberg,<br />
Onkozentrum, Dresden, Germany, 3 Hematology/<strong>Oncology</strong>/Palliative Care,<br />
St. Georg Klinikum Eisenach, Eisenach, Germany, 4 Medical <strong>Oncology</strong><br />
Department, Gemeinschaftspraxis für Hämatologie und Onkologie, Westerstede,<br />
Germany, 5 Medizinische Klinik I, Ketteler Krankenhaus gGmbH, Offenbach,<br />
Germany, 6 Leipziger Land, Tumorzentrum, Groitzsch, Germany, 7 Onkologische<br />
Kooperation Harz, MVZ, Goslar, Germany, 8 Medical Affairs, Merck Serono GmbH,<br />
Darmstadt, Germany, 9 Studiengesellschaft, Oncologianova GmbH,<br />
Recklinghausen, Germany<br />
Background: Cetuximab in combination with irinotecan- or oxaliplatin-based<br />
chemotherapy (CT) has shown to increase amongst other efficacy parameter the R0<br />
resection rate <strong>of</strong> liver metastases (LM) <strong>of</strong> primary irresectable KRAS-wt mCRC<br />
patients (pts). The non-interventional study ERBITAG aimed to evaluate safety and<br />
efficacy <strong>of</strong> cetuximab in combination with various first-line CT regimens in pts with<br />
unresectable KRAS-wt mCRC.<br />
Methods: KRAS-wt pts on a cetuximab-based first-line treatment with written<br />
informed consent could be enrolled in this prospective, non-interventional study.<br />
Primary endpoint was ORR, secondary endpoints were amongst others PFS, OS, TTF,<br />
and resection rate <strong>of</strong> liver metastasis. Here we update the interim analysis in terms <strong>of</strong><br />
the outcome <strong>of</strong> pts according to secondary resection <strong>of</strong> LM.<br />
Results: 456 KRAS-wt mCRC pts out <strong>of</strong> 817 recruited KRAS-wt pts were evaluable for<br />
this interim analysis. Location <strong>of</strong> metastasis was liver, lung, lymph nodes, and<br />
peritoneum in 70.6%, 23.5%, 22.4%, and 17.8% <strong>of</strong> pts, respectively. 39.7% <strong>of</strong> pts had<br />
liver-limited disease (LLD). 79.2% had surgery <strong>of</strong> the primary tumor and 15.6% had a<br />
resection <strong>of</strong> metastases before enrolment. The median [range] age was 65 [27-87] yrs,<br />
ECOG performance status was 0, 1, 2, or missing in 34.4%, 49.6%, 8.8%, and 7.2% <strong>of</strong><br />
pts, respectively. Resection <strong>of</strong> LM and/or lung metastases was done in 17.3% <strong>of</strong> pts,<br />
13.4% were R0 resected. For LLD-pts resection rate and R0-rate were 29.3% and 23.8%,<br />
respectively. Intraoperative and postoperative complications were observed in 1.1% and<br />
12.4% <strong>of</strong> pts with resection <strong>of</strong> metastasis, respectively. In 4.5% <strong>of</strong> pts a revision surgery<br />
was necessary. Median PFS was 20.3 and 9.5 months for pts with and without resection<br />
<strong>of</strong> LM, respectively (p < 0.0001). Median OS was 42.0 and 18.2 months for pts with<br />
and without resection <strong>of</strong> LM, respectively (p < 0.0001). For LLD-pts median PFS was<br />
20.5 and 11.9 months and median OS 42.0 and 18.7 months for pts with and without<br />
resection <strong>of</strong> LM, respectively(p < 0.0001 each).<br />
Conclusions: Pts with resection <strong>of</strong> LM had a significant longer PFS and OS compared<br />
to pts without resection.<br />
Clinical trial identification: German Database on pei.de <strong>of</strong> non-interventional trials<br />
NIS-Nr.: 114<br />
Legal entity responsible for the study: Merck Serono GmbH, Darmstadt, Germany<br />
Funding: Merck Serono GmbH, Darmstadt, Germany<br />
Disclosure: U. Neumann: Honoraria - Amgen; Merck Serono; Roche;<br />
corporate-sponsored research - Merck Serono (Inst). C. Hering-Schubert: Honoraria -<br />
Amgen; Boehringer Ingelheim; Bristol-Myers Squibb; Celgene; Mundipharma;<br />
Novartis; Pfizer. S. Sahm: Stock ownership - Fresenius Medical Care; Merck KGaA<br />
honoraria - Fresenius Medical Care corporate-sponsored research - Merck Serono<br />
(Inst); Roche (Inst). M.O. Zahn: Honoraria - Celgene consulting or advisory role –<br />
Novartis. K.G. Stenzel: Employment - Merck Serono GmbH stock ownership - Merck<br />
KGaA. F. Overkamp: Honoraria - Merck Serono consulting or advisory role - Merck<br />
Serono. All other authors have declared no conflicts <strong>of</strong> interest.<br />
492P<br />
Selective internal radiation therapy (SIRT) in metastatic<br />
colorectal cancer (mCRC): Safety, efficacy and survival<br />
outcomes from the South Australian registry<br />
A. Ayoola 1 , S. Vantandoust 1 ,A.Roy 2 , T.J. Price 3 , M. Kitchener 4 , D. Roder 5 ,<br />
S. Quinn 6 , G. Kichenadasse 2 , C. Piantadosi 7 , R. Padbury 8 , C. Karapetis 2<br />
1 Department <strong>of</strong> Medical <strong>Oncology</strong>, Flinders Medical Center, Bedford Park,<br />
Australia, 2 Medical <strong>Oncology</strong>, Flinders Medical Centre and Flinders University,<br />
Adelaide, Australia, 3 Haematology and <strong>Oncology</strong>, The Queen Elizabeth Hospital<br />
and University <strong>of</strong> Adelaide, Adelaide, Australia, 4 Department <strong>of</strong> Nuclear Medicine,<br />
The Queen Elizabeth Hospital, Adelaide, Australia, 5 Population Health, University <strong>of</strong><br />
South Australia, Adelaide, Australia, 6 School <strong>of</strong> Medicine, Flinders University,<br />
Adelaide, Australia, 7 Flinders Center for Innovation in Cancer, Flinders University,<br />
Adelaide, Australia, 8 Department <strong>of</strong> Surgery, Flinders Medical Centre and Flinders<br />
University, Adelaide, Australia<br />
Background: Colorectal cancer remains one <strong>of</strong> the commonly diagnosed cancers. The<br />
liver is the most common site <strong>of</strong> metastatic disease and the majority <strong>of</strong> patients<br />
eventually die from cancer progression in the liver. We report on the South Australian<br />
experience <strong>of</strong> the use <strong>of</strong> liver directed treatment with SIRT and we analyze the safety<br />
and efficacy <strong>of</strong> this intervention.<br />
Methods: Data was obtained from the State-wide Metastatic Colorectal Cancer Registry<br />
which was established in 2006. Patients treated with SIRT were identified. The<br />
objectives were to determine time to progression in the liver, overall survival, response<br />
rate, acute toxicity and safety <strong>of</strong> SIRT. 55 patients (37 males; 18 Females) were treated<br />
with SIRT from 2006-2015. The median age was 67.5 years. 70% had ECOG score < 2.<br />
44 (80%) patients had liver limited disease; 11 (20%) had extra-hepatic disease. 4 (7%)<br />
patients had SIRT with first line chemotherapy; 22 (40%) had SIRT after ≥4 lines <strong>of</strong><br />
chemotherapy; 10 (18.2%) received SIRT concurrent with chemotherapy; 45 (81.8%)<br />
had SIRT alone; Only 1 patient had SIRT twice<br />
Results: The median time to hepatic progression was 3.72 (95% CI. 2.26-4.83) months;<br />
the median survival was 10.6 (95% CI. 7.73-15.32) months. Patients with liver limited<br />
disease vs extra-hepatic disease showed no difference in median survival (14.2 vs<br />
10.6months, p = 0.67). In other univariable analyses, there was no significant difference<br />
in survival according to age, ECOG, lines <strong>of</strong> chemotherapy, number <strong>of</strong> liver lesions or<br />
presence <strong>of</strong> extra-hepatic disease. The radiological response rate was 14.2%. There was<br />
no grade 3 or 4 acute toxicity. The most common short-term adverse effects were<br />
hepatic pain (18%), nausea, vomiting and back pain. Data regarding potential long<br />
term toxicity was not systemically collected.<br />
Conclusions: In this population based analysis, SIRT was mostly administered in<br />
pre-treated patients and we observed activity with an acceptable short term safety<br />
pr<strong>of</strong>ile.<br />
Legal entity responsible for the study: N/A<br />
Funding: None<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
493P<br />
abstracts<br />
Secondary resectability rates observed in a multicenter<br />
randomized phase II study <strong>of</strong> modified capecitabine/<br />
irinotecan (mXELIRI) plus bevacizumab (bev) followed by<br />
capecitabine/oxaliplatin (XELOX) plus bev or the reverse<br />
sequence in patients with metastatic colorectal cancer<br />
(mCRC)<br />
W. Scheithauer 1 , G. Prager 1 , R. Greil 2 , B. Mlineritsch 2 , R. Schaberl-Moser 3 ,<br />
A. Gerger 3 , F. Längle 4 , I. Viragos-Toth 4 , J. Andel 5 , A. Pichler 6 , M. Pecherstorfer 7 ,<br />
A. Kretschmer 8 , A. Seebacher 9 , B. Jagdt 10 , W. Eisterer 11 , P. Krippl 12<br />
1 Medicine I, Clin. Div. <strong>of</strong> <strong>Oncology</strong> and Comprehensive Cancer Center,<br />
Medizinische Universitaet Wien (Medical University <strong>of</strong> Vienna), Vienna, Austria,<br />
2 IIIrd Medical Department, Paracelsus Medical University Salzburg, Salzburg<br />
Cancer research Institute and Cancer Cluster, Paracelsus University Hospital<br />
Salzburg, Salzburg, Austria, 3 Department <strong>of</strong> Internal Medicine, Medical University<br />
Graz, Graz, Austria, 4 General Surgery, Krankenhaus Wiener Neustadt, Wiener<br />
Neustadt, Austria, 5 2nd Medical Department, County Hospital Steyr, Steyr,<br />
Austria, 6 Department <strong>of</strong> Hematology/<strong>Oncology</strong>, Landeskrankenhaus<br />
Hochsteiermark-Leoben, Leoben, Austria, 7 Karl Langsteiner University <strong>of</strong> Health<br />
Sciences, University Hospital Krems, Krems, Austria, 8 Interne Abteilung,<br />
Landesklinikum(LK) Waldviertel Waidh<strong>of</strong>en a.d.Thaya, Waidh<strong>of</strong>en a.d.Thaya,<br />
Austria, 9 3rd Medical Department, Hanusch Krankenhaus, Vienna, Austria,<br />
10 Department <strong>of</strong> Internal Medicine, Krankenhaus der Barmherzigen Schwestern<br />
Ried im Innkreis, Ried Im Innkreis, Austria, 11 Department <strong>of</strong> Hemto-<strong>Oncology</strong>,<br />
Landeskrankenhaus LKH Klagenfurt am Woerthersee, Klagenfurt, Austria,<br />
12 Internal Medicine, Landeskrankenhaus (LKH) Fuerstenfeld, Fuerstenfeld, Austria<br />
Background: Fluoropyrimidines plus irinotecan or oxaliplatin combination<br />
chemotherapy + bev represents an effective treatment option in patients (pts) with<br />
mCRC invariable <strong>of</strong> the RAS mutational status. Not in the primary focus <strong>of</strong> a<br />
sequential study treatment protocol in pts with high tumour burden, resectability<br />
becomes more and more <strong>of</strong> interest since it implicates the only potential for cure.<br />
Methods: Previously untreated mCRC pts were randomized into two different<br />
treatment arms: in Arm A pts started with mXELIRI (capecitabine [cape] 800mg/m2<br />
bid d1-14, irinotecan 200 mg/m2 iv d1) + bev 7.5 mg/kg iv d1 q3w, in Arm B treatment<br />
started with XELOX (cape 1000mg/m2 bid d1-14, oxaliplatin 130mg/m2 iv. d1) + bev<br />
7.5mg/kg iv d1 q3w. After 8 cycles, maintenance treatment (bev 7.5 mg/kg q3w ± cape<br />
1000 mg/m2 bid, days 1-14 q3w) was started until progression (PD). Upon PD, pts<br />
were crosswise treated with the regimen <strong>of</strong> the other arm for 6 cycles, again follwed by<br />
maintenance treatment until PD. We herin report the secondary resection rates noted<br />
in this trial.<br />
Results: 120 pts were randomized to Arm A (n = 58) or Arm B (n = 62). Median age<br />
(65 years), gender (68% male) and RAS mutational status were similar in both arms<br />
(33% wildtype, 38% mutated). 24 pts (20%) could be converted in a resectable stage<br />
and underwent R0 liver- (n = 16; 8 pts in both arms), lung- (n = 4, 2 pts in both arms),<br />
ovarian metastasis- (n = 2 in Arm B) and inoperable primary tumor-resection (n = 3 in<br />
Arm B) after a median <strong>of</strong> 6 months (range 4-27). 22 pts were resected during 1st-line, 2<br />
pts during 2nd-line treatment. At a median follow-up time <strong>of</strong> 10 months after<br />
secondary surgery 9 pts (2 in Arm A, 7 in Arm B) had disease recurrence. Perioperative<br />
AEs included 5 thromboembolic events (1 lethal), 3 wound healing complications, 4<br />
fistula/abscess, hyperbilirubinaemia x2 and 1 post-surgical perforation.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw370 | vi165
abstracts<br />
Conclusions: Both treatment regimens are effective and tolerable treatment options in<br />
patients with mCRC, and have resulted in secondary resectability in 20% invariable <strong>of</strong><br />
the RAS mutational status.<br />
Clinical trial identification: NCT02119026, release 01.April 2014<br />
Legal entity responsible for the study: Medicine I, Clin. Div. <strong>of</strong> <strong>Oncology</strong> and<br />
Comprehensive Cancer Center, Medizinische Universitaet Wien (Medical University <strong>of</strong><br />
Vienna),<br />
Funding: Roche Austria GmbH<br />
Disclosure: W. Scheithauer: Personal honoraries for advisory board & invited speaker<br />
activities from Roche-Austria. G. Prager: Research grant from Roche Austria<br />
(Passionate-Trial). R. Greil: By Roche: research support, honoraria, travel costs,<br />
advisory boards; non related to abstract under submission, no stock options. A. Gerger:<br />
Research grant from Roche - Passionate trial. A. Pichler: Honorarium for speech<br />
"Rectum carcinoma" Amgen, Oct 2015. All other authors have declared no conflicts <strong>of</strong><br />
interest.<br />
494P<br />
DC-beads loaded with irinotecan combined with systemic<br />
chemotherapy for pretreated liver dominant metastatic<br />
colorectal cancer: Procedure and outcomes <strong>of</strong> 49 patients<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
ED or hospital visits between Cmab + I and Pmab, adjusting for observable<br />
confounders (including age, gender, year <strong>of</strong> diagnosis, stage at presentation, duration <strong>of</strong><br />
prior treatment in 1 st and 2 nd line, previous liver resection, rural residence and income<br />
quintile) using propensity score methods.<br />
Results: 1081 pts were identified (Cmab + I: 278, Pmab: 803); median age: 60 (21.1%<br />
>age 70), 36.4% female, 36.2% rectal cancer and 60.1% stage IV at presentation. After<br />
adjusting for confounders, the use <strong>of</strong> Cmab + I as compared to Pmab alone was<br />
associated with a prolonged time to treatment discontinuation [median: 3.5 mos vs. 2.8<br />
mos, HR 0.63, 95%CI 0.53-0.75, p < 0.001]and an improved OS compared to Pmab<br />
alone [median: 8.8 mos vs. 5.9 mos, HR 0.62, 95% CI 0.53-0.73, p < 0.001]. Both had<br />
similar 14-day mortality and incidence <strong>of</strong> ED or hospital visits. Interaction tests <strong>of</strong><br />
treatment effect and age were >0.05.<br />
Conclusions: "Real world" data suggest a possible OS benefit with Cmab + I compared<br />
to Pmab alone, without an associated increase in toxicity. Pts age ≥70 appear to<br />
experience similar benefit and toxicity from combination therapy. These results suggest<br />
a need for adequately powered randomized trials to compare Cmab + I and Pmab like<br />
the ongoing ICECREAM study.<br />
Legal entity responsible for the study: N/A<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
A-L. Pointet 1 , S. Pernot 1 , O. Pellerin 2 , G. Amouyal 2 , A. Berger 3 , P. Rougier 1 ,<br />
M. Sapoval 2 , J. Taieb 1<br />
1 Digestive <strong>Oncology</strong>, Hopital European George Pompidou, Paris, France,<br />
2 Radiology, Hopital European George Pompidou, Paris, France, 3 Surgical<br />
<strong>Oncology</strong>, Hopital European George Pompidou, Paris, France<br />
496P<br />
A triplet combination with oxaliplatin/capecitabine/irinotecan<br />
(XELOXIRI) plus cetuximab (Cmab) as a first-line therapy in<br />
wild-type KRAS, metastatic colorectal cancer: a dose<br />
escalating study<br />
Background: The use <strong>of</strong> trans-arterial chemo-embolization with irinotecan drug eluted<br />
beads (DEBIRI) for liver-dominant metastatic colorectal cancer (mCRC) is usually<br />
proposed for end-stage patients as a salvage treatment without any concomitant<br />
systemic treatment. The goals <strong>of</strong> our study were to evaluate the safety and efficacy <strong>of</strong><br />
the DEBIRI procedure, in patients treated by concomitant systemic chemotherapy.<br />
Methods: Between 04/2011 and 04/2014, all consecutive ECOGPS 0-2 patients with<br />
stable or progressive liver-dominant mCRC pretreated by at least 2 previous<br />
chemotherapy lines, were referred for DEBIRI as salvage treatment. All patients<br />
received in addition systemic chemotherapy. Safety <strong>of</strong> the procedure, toxicities<br />
(NCI-CTC AE V4.02), tumor response rates (RECIST 1.1), progression-free (PFS) and<br />
overall survivals (OS), were recorded.<br />
Results: Forty-nine consecutive patients (mean age: 63 years) underwent 81 DEBIRI<br />
sessions administered in a lobar manner in the same session. All patients had<br />
previously received chemotherapy by FOLFOX and FOLFIRI and 49% with<br />
biotherapies. RAS status was mutated in 45% <strong>of</strong> cases. Patients received concomitant<br />
systemic chemotherapy (capecitabine: 26%, FOLFOX +/- bevacizumab: 51%, other<br />
23%). 35% didn’t received the second DEBIRI due to a rapid disease progression (20%)<br />
or limiting toxicity (15%). Altogether, 45 (55%) grade 3/4 arterial hypertension crises<br />
occurred during the procedure, 11 (14%) grade 3 post-embolization syndrome and 5<br />
(6%) grade 2-3 toxicities (cholecystitis, pancreatitis or non-malignant ascites) were<br />
observed. All toxicities were successfully managed. No toxic death occurred. The mean<br />
hospital stay was 4.5 days. The 3-month response and disease control rates were 15%<br />
and 75%, respectively. Tumor response was correlated with tumor involvement.<br />
Median PFS and OS were 8.1 and 21 months, respectively.<br />
Conclusions: DEBIRI plus systemic chemotherapy for pretreated liver-dominant<br />
mCRC provide promising efficacy results together with specific and severe side effects<br />
that need to be adequately managed.<br />
Legal entity responsible for the study: Julien Taieb<br />
Funding: European Hospital George Pompidou<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
495P<br />
Cetuximab (Cmab) plus irinotecan (I) versus panitumumab<br />
(Pmab) in patients with refractory metastatic colorectal cancer<br />
(mCRC) in Ontario<br />
K.J. Jerzak, C. Earle, Y-J. Ko, S. Berry, K.K. Chan<br />
Medicine, Sunnybrook Odette Cancer Center, Sunnybrook HSC, Toronto, ON,<br />
Canada<br />
Background: In the BOND trial (Cunningham et al, NEJM 2004) for refractory<br />
mCRC, the addition <strong>of</strong> I to an EGFR antibody improved tumor response rate and time<br />
to progression but not overall survival (OS). We assessed the "real world" efficacy and<br />
toxicity <strong>of</strong> combination versus monotherapy in i) all-comers and ii) older patients (pts)<br />
who are under-represented in randomized trials.<br />
Methods: In Ontario, universal public funding is available for either Cmab + I<br />
combination or Pmab monotherapy only in pts with refractory non-mutated Kras<br />
mCRC. All pts diagnosed before Dec 2012 and treated with an EGFR antibody for<br />
mCRC were identified from the Ontario drug database and linked to the Ontario<br />
Cancer Registry and other administrative databases to ascertain baseline characteristics,<br />
health services utilization and outcomes. Multivariable Cox and logistic models were<br />
constructed to compare the time to treatment discontinuation, overall survival (OS),<br />
Y. Sato 1 , H. Ohnuma 1 , M. Hirakawa 1 , S. Kikuch 1 , M. Takahashi 2 , T. Okamoto 3 ,<br />
Y. Tsuji 4 , K. Okita 5 , T. Furuhata 5 , I. Takemasa 5 , J. Kato 1<br />
1 Depertment <strong>of</strong> Medical <strong>Oncology</strong> and Hematology, Sapporo Medical University<br />
School <strong>of</strong> Medicine, Sapporo, Japan, 2 Department <strong>of</strong> Gastroenterology, Sapporo<br />
Kyoritsu Gorinbashi Hospital, Sapporo, Japan, 3 Department <strong>of</strong> Gastroenterology,<br />
Kiyota Hospital, Sapporo, Japan, 4 Department <strong>of</strong> Medical <strong>Oncology</strong>, Tonan<br />
Hospital, Sapporo, Japan, 5 Department <strong>of</strong> Surgery, Surgical <strong>Oncology</strong> and<br />
Science, Sapporo Medical University School <strong>of</strong> Medicine, Sapporo, Japan<br />
Background: We previously reported the promising activity <strong>of</strong> a triweekly oxaliplatin/<br />
capecitabine/irinotecan (XELOXIRI) plus bevacizumab regimen, which was easier to<br />
administer than FOLFOXIRI/ bevacizumab, using capecitabine, instead <strong>of</strong><br />
5-fuorouracil, in pts with metastatic colorectal cancer (mCRC)(Cancer Chemother<br />
Pharmacol 2015). In order to achieve more potent efficacy, we explored the dose<br />
limiting toxicity and feasibility <strong>of</strong> the combination XELOXIRI plus cetuximab<br />
(XELOXIRI/Cmab) in pts with KRAS wild type mCRC.<br />
Methods: Pts were eligible if they had KRAS wild-type mCRC (liver and/or other<br />
metastases), ECOG PS 0-1, were either negative or heterozygous for UGT1A1*6 or<br />
UGT1A1*28 and were not pretreated for metastatic disease. Treatment consisted <strong>of</strong><br />
oxaliplatin (100 mg/m 2 day 1), capecitabine (1700 mg/m 2 /day from day 2 to 15),<br />
irinotecan (100,120,150 mg/m 2 for dose levels 1, 2, or 3, day 1) repeated every 3 weeks<br />
and weekly cetuximab (400 mg/m 2 and, thereafter, 250 mg/m 2 , day 1). The dose <strong>of</strong><br />
irinotecan was escalated if dose limiting toxicities (DLT) were absent in the first three<br />
pts per cohort, or if
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
497P<br />
Phase II trial <strong>of</strong> panitumumab monotherapy for patients with<br />
KRAS exon2 wild type colorectal cancer after progression on<br />
cetuximab. HGCSG1101<br />
S. Yuki 1 , Y. Komatsu 2 , T. Muranaka 2 , K. Harada 2 , J. Sugiyama 3 , Y. Tsuji 3 ,<br />
T. Ando 4 , A. Hosokawa 4 , K. Hatanaka 5 , H. Naruse 5 , T. Takahata 6 ,A.Sato 6 ,<br />
Y. Kobayashi 7 , T. Miyagishima 7 , H. Okuda 8 , M. Kudo 9 , M. Nakamura 10 , H. Hisai 11 ,<br />
N. Sakamoto 1 , Y. Sakata 12<br />
1 Gastroenterology and Hepatology, Hokkaido University Hospital, Sapporo,<br />
Japan, 2 Cancer Center, Hokkaido University Hospital, Sapporo, Japan, 3 Medical<br />
<strong>Oncology</strong>, Tonan Hospital, Sapporo, Japan, 4 Gastroenterology and Hematology,<br />
Faculty <strong>of</strong> medicine, University <strong>of</strong> Toyama, Toyama, Japan, 5 Gastroenterology,<br />
Hakodate Municipal Hospital, Hakodate, Japan, 6 Medical <strong>Oncology</strong>, Hirosaki<br />
University Graduate School <strong>of</strong> Medicine, Hirosaki, Japan, 7 Medical <strong>Oncology</strong>,<br />
Kushiro Rosai Hospital, Kushiro, Japan, 8 Medical <strong>Oncology</strong>, Keiyukai Sapporo<br />
Hospital, Sapporo, Japan, 9 Gastroenterology, Sapporo Hokuyu Hospital,<br />
Sapporo, Japan, 10 Gastroenterology, Sapporo City General Hospital, Sapporo,<br />
Japan, 11 Gastroenterology, Japanese Red Cross Date Hospital, Date, Japan,<br />
12 Misawa City Hospital, Misawa, Japan<br />
Background: Both panitumumab and cetuximab known as antibody to EGFR play a<br />
key role in treatment with patients for colorectal cancer. Although the action for EGFR<br />
is considered to be similar in clinical practice, the differences between these drugs have<br />
been reported. The affinity for EGFR shows to be higher in panitumumab. And<br />
because <strong>of</strong> different subclass <strong>of</strong> antibody between panitumumab [IgG2] and cetuximab<br />
[IgG1], it has been reported that cetuximab has Antibody-dependent cellular<br />
cytotoxicity (ADCC). Some retrospective analyses have revealed that the<br />
administration <strong>of</strong> panitumumab after cetuximab demonstrate the valuable efficacy,<br />
however, the prospective study for cetuximab refractory patients have only been a few<br />
reported.<br />
Methods: HGSCG1101 is a multicenter phase II study. Eligibility includes<br />
histologically confirmed KRAS exon2 colorectal cancer, previously received oxaliplatin/<br />
irinotecan/fluoropyrimidine, and previously refractory for cetuximab. Patients<br />
intravenously received panitumumab 6 mg/kg every 14 days. The primary endpoint<br />
was 6-month progression-free survival rate (threshold 8%, expected 31%) and the<br />
secondary endpoints were safety, response rate, disease control rate, PFS and OS. We<br />
estimated that a target sample size <strong>of</strong> 28 patients.<br />
Results: Between May 2011 and April 2014, 33 pts were enrolled. Two patients were<br />
ineligible. Patients characteristics were as follows: median age 67 years (range 44-90),<br />
male: female 23:8, PS 0:1:2 17:13:1, best response for cetuximab PR:SD:PD 8:15:5.<br />
Median number <strong>of</strong> panitumumab administration was 4. The median relative dose<br />
intensity was 1.000. The main grade 3-4 AE were hypomagnesemia (9.7%) and rash<br />
acneiform/pruritus/dry skin (3.2%). 6-month progression-free survival rate was 3.3%.<br />
Response rate was 6.5% and disease control rate was 35.5%. Median progression-free<br />
survival was 1.9 months (95%C.I. 1.8-1.9 months) and median survival time was 7.8<br />
months (95%C.I. 6.7-8.9 months).<br />
Conclusions: 6-month progression-free survival rate as the primary endpoint could<br />
not be achieved in this study. We could not demonstrate the efficacy <strong>of</strong> panitumumab<br />
monotherapy for patients in refractory to treatment with cetuximab.<br />
Clinical trial identification: This trial does not have to register, such as the NIH or<br />
European equivalent. Hokkaido University Hospital IRB trial number : 010-0313<br />
Legal entity responsible for the study: Specified Nonpr<strong>of</strong>it Corporation : Hokkaido<br />
Gastrointestinal Cancer Study Group<br />
Funding: Specified Nonpr<strong>of</strong>it Corporation : Hokkaido Gastrointestinal Cancer Study<br />
Group<br />
Disclosure: S. Yuki: Honoraria: Taiho Pharmaceutical, Merck Serono, Bristol-Myers<br />
Squibb, Takeda Pharmaceutical, Chugai Pharmaceutical, Bayer Yakuhin, Eli Lilly Japan<br />
Y. Komatsu: Taiho Pharmaceutical, Yakult Honsha, Chugai Pharmaceutical, Merck<br />
Serono, Pfizer Japan, Novartis Pharma, Ono Pharmaceutical, Daiichi Sankyo, Takeda<br />
Pharmaceutical, Eli Lilly Japan, Novartis Pharma, Daiichi Sankyo, Kureha Corporation<br />
T. Takahata: Honoraria: Novartis Pharma, Kyowa Hakko Kirin, Janssen<br />
Pharmaceutical, Otsuka Pharmaceutical, Taiho Pharmaceutical, Daiichi Sankyo Y.<br />
Sakata: Honoraria: Taiho Pharmaceutical, Yakult Honsha, Chugai Pharmaceutical,<br />
Daiichi Sankyo, Takeda Pharmaceutical, Merck Serono All other authors have declared<br />
no conflicts <strong>of</strong> interest.<br />
498P<br />
The colorectal carcinoma – treatment research and treatment<br />
reality in oncology practices (Anti-VEGF or Anti-EGFR<br />
therapies)<br />
H.W. Tessen 1 , O. Rubanov 2 , A. Schlichting 3 , A. Valdix 4<br />
1 Specialized <strong>Oncology</strong> Practice, Oncological Collaboration Harz, Goslar, Germany,<br />
2 <strong>Oncology</strong>, Spezialized <strong>Oncology</strong> Practice, Hameln, Germany, 3 <strong>Oncology</strong>, RGB<br />
Onkologisches Management GmbH, Berlin, Germany, 4 <strong>Oncology</strong>, Specialized<br />
<strong>Oncology</strong> Practice, Schwerin, Germany<br />
Background: Since 2003, 124 oncology practices in Germany have been documenting<br />
disease histories for all treated tumor entities in the registry “ONCOReg”. 32,165<br />
patients have been recorded so far. Here we show the data for the colorectal carcinoma,<br />
specially focussing on the treatment with aflibercept.<br />
Methods: Since 2003, 9,301 disease histories <strong>of</strong> patients with a colorectal carcinoma<br />
have been documented, 8,687 cases there<strong>of</strong> with a total <strong>of</strong> 19,589 therapies were<br />
analysed in the registry ONCOReg. Distant metastases were present in 5,691 patients<br />
during the course <strong>of</strong> the disease. The evaluation <strong>of</strong> the data is based on the<br />
documentation <strong>of</strong> the participating practices.<br />
Results: For 5,606 patients, 14,053 palliative therapies have been documented so far.<br />
3,238 patients <strong>of</strong> them were treated with bevacizumab, 1,752 with cetuximab, 630 with<br />
panitumumab and 217 with aflibercept. The median progression-free survival in the<br />
complete registry is at 9.9 or 6.4 months for the 1st- and 2nd-line therapy, the median<br />
overall survival at 25.0 and 15.3 months. Aflibercept has been administered as first-line<br />
(2.8%), second-line (31.8%), third-line therapy (25.8%) and later. The median overall<br />
survival under the therapy with aflibercept was at 8.4 months, the median<br />
progression-free survival at 4.8 months. The survival <strong>of</strong> patients with aflibercept in the<br />
second line is at 15.1 months.1,026 (18.0%) <strong>of</strong> the patients had a secondary metastases<br />
resection.<br />
Bevacizumab<br />
n = 3,170<br />
Table: 498P Secondary metastases resection<br />
Cetuximab<br />
n = 1,715<br />
Panitumumab<br />
n = 623<br />
Aflibercept<br />
n = 217<br />
574 (18.1%) 301 (17.6%) 144 (23.1%) 69 (31.1%)<br />
Patients with a secondary metastases resection survived 50.5 months, patients without<br />
a secondary metastases resection 24.8 months (p < 0.00001). Patients who were treated<br />
with aflibercept and had received a metastases resection survived 54.5 months.<br />
Conclusions: The median overall survival <strong>of</strong> 25.0 months from the start <strong>of</strong> the 1st-line<br />
therapy reflects the targeted treatment <strong>of</strong> the colorectal carcinoma in the practices.<br />
Patients with a secondary metastases resection had a significantly prolonged overall<br />
survival.<br />
Clinical trial identification: The ONCOreg register study is listed since 04/26/2013 in<br />
the German Clinical Trials Register under the following number: DRKS00004818<br />
Legal entity responsible for the study: H-W. Tessen<br />
Funding: Medac GmbH, Onkovis, Ribosepharm Division, San<strong>of</strong>i-Aventis Deutschland<br />
GmbH<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
499P<br />
PULSE, a phase 2 study <strong>of</strong> mFOLFOX6-panitumumab (P) with<br />
biomarker stratification as first-line chemotherapy (CT), in<br />
patients (pts) with KRAS (exon 2) metastatic colorectal cancer<br />
(mCRC). A GEMCAD 09-03 study<br />
J. Maurel 1 , C. Fernández Martos 2 , M. Martín Richard 3 , V. Alonso 4 ,C.<br />
Méndez Méndez 5 , A. Salud 6 , C. Pericay 7 , J. Aparicio 8 , J. Gallego 9 , A. Carmona 10 ,<br />
E. Casado 11 , H. Manzano 12 , C. Horndler 4 , M. Rubini 13 , M. Cuatrecasas 14 ,<br />
X. García-Albéniz 15 , J. Feliu 16<br />
1 Medical <strong>Oncology</strong>, Hospital Clinic y Provincial de Barcelona, Barcelona, Spain,<br />
2 Medical <strong>Oncology</strong>, Fundación Instituto Valenciano de Oncología, Valencia, Spain,<br />
3 Medical <strong>Oncology</strong>, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain,<br />
4 Medical <strong>Oncology</strong>, Hospital Miguel Servet, Zaragoza, Spain, 5 Medical <strong>Oncology</strong>,<br />
Fundacion Centro Oncologico de Galicia, A Coruna, Spain, 6 Medical <strong>Oncology</strong>,<br />
Hospital Universitario Arnau Vilanova de Lleida, Lerida, Spain, 7 Medical <strong>Oncology</strong>,<br />
Hospital de Sabadell Corporacis Parc Tauli, Sabadell, Spain, 8 Medical <strong>Oncology</strong>,<br />
Hospital Universitari i Politècnic La Fe, Valencia, Spain, 9 Medical <strong>Oncology</strong>,<br />
Hospital General Universitario de Elche, Elche, Spain, 10 Medical <strong>Oncology</strong>,<br />
Hospital Universitario Morales Meseguer, Murcia, Spain, 11 Medical <strong>Oncology</strong>,<br />
Hospital Infanta S<strong>of</strong>ia, Madrid, Spain, 12 Medical <strong>Oncology</strong>, Hospital Universitario<br />
Son Espases, Palma de Mallorca, Spain, 13 Medical <strong>Oncology</strong>, Università di<br />
Ferrara, Ferrara, Italy, 14 Department <strong>of</strong> Pathology, Hospital Clinic y Provincial de<br />
Barcelona, Barcelona, Spain, 15 Medical <strong>Oncology</strong>, Harvard Institutes <strong>of</strong> Medicine,<br />
Boston, MA, USA, 16 Medical <strong>Oncology</strong>, Hospital Universitario La Paz, Madrid,<br />
Spain<br />
Background: Matrilysin (MMP7) can activate phospho-insulin growth factor<br />
receptor-1 (pIGF-1R) through IGFBP-3 degradation, releasing IGF-1. Co-expression <strong>of</strong><br />
MMP7 and pIGF-1R (double positivity, DP) correlates with poor prognosis in WT<br />
KRAS pts treated with anti-EGFR in second-third line therapy. We performed a<br />
prospective clinical trial in WT KRAS (exon 2) pts, treated with FOLFOX6-P in<br />
first-line CT to validate those findings. A non-planned sub-analysis in the RAS/BRAF<br />
WT subset <strong>of</strong> pts is now presented.<br />
Methods: Positive cases were defined by immunohistochemistry as those with<br />
moderate or strong intensity (++ / + ++ ) and >70% expression for both MMP7 and<br />
pIGF-1R (antibody anti-pY1316). The primary end-point was progression-free survival<br />
(PFS). Seventy-eight pts and 56 events were required to have an 80% power to detect a<br />
difference in median PFS <strong>of</strong> 6 months (m) (two-sided p < 0.05).<br />
Results: We screened 196 mCRC pts in 24 centers between Nov/2010 and Apr/2013<br />
and 60/78 pts were RAS/BRAF WT (31 non-DP and 29 DP). Median follow-up was<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw370 | vi167
abstracts<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
23m. Response rate was 81.7%, mPFS 9.6m (95%CI 7.1-14.1) and median overall<br />
survival (OS) 30.4m (95%CI 18.2-39.1).There were no differences in baseline<br />
characteristics (age, sex, liver metastases, lactate dehydrogenase (LDH) levels and<br />
performance status between both groups). There were no differences in the number <strong>of</strong><br />
CT cycles received and second-line therapies between both groups. Response rate was<br />
86.2% in non-DP and 77.4% in DP pts (p = 0.74). Median PFS (95% CI) was 9.2m<br />
(95%CI 5.2-15.2) in non-DP and 10.5m (95% CI 7.8-18.2, p = 0.16) in DP pts. Median<br />
OS was 18.2m (11.2-37.9) in non-DP pts and 39.1m (30-NE, p = 0.11) in DP pts.<br />
Adjusted HR for PFS was 0.60 (95% CI 0.31-1.14). Adjusted HR for OS was 0.51 (95%<br />
CI 0.27-0.98).<br />
Conclusions: Our study suggest that unexpectedly, co-expression <strong>of</strong> MMP7 and<br />
pIGF-1R, could be a novel strong prognostic biomarker <strong>of</strong> survival benefit, in mCRC<br />
RAS/BRAF WT pts treated in first-line with FOLFOX6-P.<br />
Clinical trial identification: EUdraCT: 2009-017331-18<br />
Legal entity responsible for the study: Grupo Español Multidisciplinar de Cáncer<br />
Digestivo (GEMCAD)<br />
Funding: Grupo Español Multidisciplinar de Cáncer Digestivo (GEMCAD)<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
500P<br />
S-1 plus oxaliplatin combined with radiation (SOX/RT) for<br />
preoperative locally advanced rectal carcinoma: final results<br />
<strong>of</strong> a phase II study (JACCRO CC-04: SHOGUN trial)<br />
H. Horie 1 , S. Matsusaka 2 , S. Ishihara 3 , K. Kondo 4 , K. Uehara 5 , M. Oguchi 6 ,<br />
K. Mur<strong>of</strong>ushi 6 , M. Ueno 7 , N. Mizunuma 8 , T. Shimbo 9 , D. Kato 6 , J. Okuda 10 ,<br />
Y. Hashiguchi 11 , M. Nakazawa 12 , E. Sunami 3 ,K.Kawai 3 , H. Yamashita 13 ,<br />
T. Okada 14 , T. Nakajima 15 , T. Watanabe 3<br />
1 Surgery, Jichi MedicalUniversity Hospital, Shimotsuke, Japan, 2 Gastroenterology,<br />
Cancer Institute Hospital <strong>of</strong> JFCR, Tokyo, Japan, 3 Department <strong>of</strong> Surgical<br />
<strong>Oncology</strong>, University <strong>of</strong> Tokyo, Tokyo, Japan, 4 Department <strong>of</strong> General &<br />
Gastroenterological Surgery, Osaka Medical College, Osaka, Japan, 5 Department<br />
<strong>of</strong> Surgical <strong>Oncology</strong>, Nagoya University, Graduate School <strong>of</strong> Medicine, Nagoya,<br />
Japan, 6 Radiation <strong>Oncology</strong> Department, Cancer Institute Hospital <strong>of</strong> JFCR,<br />
Tokyo, Japan, 7 Department <strong>of</strong> Gastroenterological Surgery, Cancer Institute<br />
Hospital <strong>of</strong> JFCR, Tokyo, Japan, 8 Department <strong>of</strong> Gastroenterology, Cancer<br />
Institute Hospital <strong>of</strong> JFCR, Tokyo, Japan, 9 Department <strong>of</strong> Radiology, Osaka<br />
Medical College, Osaka, Japan, 10 Cancer Center, Osaka Medical College<br />
Hospital, Osaka, Japan, 11 Department <strong>of</strong> Surgery, Teikyo University, Tokyo,<br />
Japan, 12 Department <strong>of</strong> Radiation <strong>Oncology</strong>, School <strong>of</strong> Medicine, Jichi Medical<br />
University, Tochigi, Japan, 13 Department <strong>of</strong> Radiology, University <strong>of</strong> Tokyo, Tokyo,<br />
Japan, 14 Department <strong>of</strong> Radiology, Nagoya University, Nagoya, Japan,<br />
15 Gastroenterology, Japan Clinical Cancer Research Organization, Tokyo, Japan<br />
Background: The study was designed to evaluate the safety and efficacy <strong>of</strong> adding<br />
oxaliplatin to preoperative chemoradiotherpy (CRT) with S-1, an oral fluoropyrimidine<br />
in patients with locally advanced rectal carcinoma (LARC). We report here final results<br />
<strong>of</strong> the study.<br />
Methods: Patients with histopathologically confirmed LARC (cT3-T4, any N) were<br />
eligible. They received oral S-1 (80 mg/m2/day on days 1-5, 8-12, 22-26, and 29-33)<br />
and infusional oxaliplatin (60 mg/m2/day on 1, 8, 22, 29) plus radiotherapy (1.8Gy/<br />
day, a total dose <strong>of</strong> 50.4 Gy in 28 fractions), with a chemotherapy gap in the third week<br />
<strong>of</strong> radiotherapy. Primary endpoint <strong>of</strong> the study was pCR rate. Secondary endpoints<br />
were R0 resection rate, down-staging rate, cumulative 3-year local recurrence rate,<br />
3-year disease free survival (DFS) and toxicity.<br />
Results: Forty five patients were enrolled at six centers in Japan. All the patients<br />
received CRT, and 44 underwent operation. The pCR rate was 27.3 % (12/44). The R0<br />
resection rate was 95.5 % (42/44). T- down-staging rate was 59.1% (26/44), and N-<br />
down-staging rate was 65.9 % (29/44): the combined pathological down-staging rate<br />
was 79.5 % (35/44). There were no grade 4 adverse events, and 11.1% <strong>of</strong> the patients<br />
had grade 3 adverse events. No patients suffered from local recurrence. Therefore,<br />
cumulative 3-year local recurrence rate was 0%. However, 13 (29.5%) patients suffered<br />
from distant metastasis and one patient suffered from a secondary cancer (esophageal<br />
cancer). Eight patients had lung metastasis, and 4 had liver metastasis. Three patients<br />
died <strong>of</strong> the metastatic disease. The 3-year DFS <strong>of</strong> the 44 patients was 67.5% (median<br />
follow up 36.3 month), and the 3-year overall survival (OS) was 93.0%. Then the<br />
patients were divided into two groups: pCR (12) and non pCR (32) groups. The 3-year<br />
DFS <strong>of</strong> each group was 91.7% and 58.1%, respectively. The 3-year OS was 100% and<br />
90.3%, respectively.<br />
Conclusions: The study showed a high pCR rate with no severe acute toxicity with<br />
good follow up results. Therefore, addition <strong>of</strong> oxaliplatin to preoperative CRT with S-1<br />
in patients with LARC might be feasible and lead to a better local control than standard<br />
treatment.<br />
Clinical trial identification: NCT01227239, Oct 18 2010<br />
Legal entity responsible for the study: Toshiaki Watanabe<br />
Funding: Taiho Pharmaceutical Co Ltd., Japan<br />
Disclosure: T. Watanabe: Membership on an advisory board: Taiho Pharmaceutical<br />
honoraria: Yakult Honsha, Taiho Pharmaceutical All other authors have declared no<br />
conflicts <strong>of</strong> interest.<br />
501P<br />
Efficacy <strong>of</strong> first-line modified FOLFOX6 with panitumumab or<br />
bevacizumab in RAS wild-type/BRAF wild-type metastatic<br />
colorectal cancer: impact <strong>of</strong> tumour symptoms and extent <strong>of</strong><br />
disease<br />
F. Rivera 1 , M. Peeters 2 , J-Y. Douillard 3 , J. Taieb 4 , R. Koukakis 5 , G. Demonty 6 ,<br />
S. Siena 7<br />
1 Department <strong>of</strong> Medical <strong>Oncology</strong>, Hospital Universitario Marques de Valdecilla,<br />
Santander, Spain, 2 Department <strong>of</strong> <strong>Oncology</strong>, University Hospital Antwerp,<br />
Edegem, Belgium, 3 Oncologie Médicale, ICO R. Gauducheau, St Herblain,<br />
France, 4 Service HGE, Hôpital Européen G.Pompidou, Paris, France,<br />
5 Biostatistics, Amgen Ltd, Uxbridge, UK, 6 Medical Development - <strong>Oncology</strong>,<br />
Amgen (Europe) GmbH, Zug, Switzerland, 7 Niguarda Cancer Center, Grande<br />
Ospedale Metropolitano Niguarda and Università degli Studi di Milano, Milan, Italy<br />
Background: In patients with previously untreated metastatic colorectal cancer<br />
(mCRC), the goal <strong>of</strong> treatment is likely to influence choice <strong>of</strong> first-line therapy, as<br />
suggested in ESMO 2016 guidelines previewed at WCGIC 2015. We conducted an<br />
exploratory analysis <strong>of</strong> the efficacy <strong>of</strong> first-line modified FOLFOX6 (mFOLFOX6) plus<br />
panitumumab or bevacizumab in patients with RAS wild-type (WT)/BRAF WT mCRC<br />
based on the aim <strong>of</strong> treatment: cytoreduction or disease control.<br />
Methods: PEAK (NCT00819780) was an open-label randomised phase II trial <strong>of</strong><br />
first-line panitumumab + mFOLFOX6 vs bevacizumab + mFOLFOX6. Using baseline<br />
characteristics, patients with RAS WT/BRAF WT mCRC were retrospectively classified<br />
into groups according to treatment goal: Cytoreduction group (liver-limited disease<br />
[LLD] and/or symptoms) or Disease-control group (asymptomatic with<br />
non-liver-limited metastases [with or without liver metastases]). Patients with an<br />
Eastern Cooperative <strong>Oncology</strong> Group (ECOG) score <strong>of</strong> 1 were considered to have<br />
tumour-related symptoms; those with ECOG 2 were excluded as they were not<br />
considered fit enough to meet ESMO criteria.<br />
Results: The analysis included 155 patients with RAS WT/BRAF WT mCRC, <strong>of</strong> whom<br />
83 were in the Cytoreduction group and 72 were in the Disease-control group. Median<br />
PFS and OS were numerically longer with panitumumab + mFOLFOX6 vs<br />
bevacizumab + mFOLFOX4 in both groups (Table).<br />
Table: 501P<br />
Median, months<br />
PFS<br />
OS<br />
Cytoreduction group (n = 83)<br />
mFOLFOX6 +<br />
Panitumumab (n = 42) 12.7 36.8<br />
Bevacizumab (n = 41) 10.6 29.0<br />
HR (95% CI) 0.66 (0.43-1.06) 0.78 (0.46-1.33)<br />
Disease-control group (n = 72)<br />
mFOLFOX6 +<br />
Panitumumab (n = 35) 13.1 46.1<br />
Bevacizumab (n = 37) 11.5 31.3<br />
HR (95% CI) 0.71 (0.43-1.18) 0.60 (0.33-1.07)<br />
Conclusions: This exploratory analysis suggests that first-line treatment with<br />
mFOLFOX6 provides longer PFS and OS when combined with panitumumab than<br />
when combined with bevacizumab in patients with RAS WT/BRAF WT mCRC<br />
whether the aim <strong>of</strong> treatment is cytoreduction or disease control. These results are<br />
consistent with data from the PRIME study presented elsewhere at this congress (Taieb<br />
et al.) using two definitions <strong>of</strong> ‘symptomatic’, based on ECOG and patient-reported<br />
outcomes.<br />
Clinical trial identification: ClinicalTrials.gov: NCT00819780<br />
Legal entity responsible for the study: Amgen<br />
Funding: Amgen<br />
Disclosure: F. Rivera: Acted on advisory boards and received research funding from<br />
Amgen, San<strong>of</strong>i, Merck-Serono and Roche. M. Peeters: Received research funding and<br />
acted in consultancy/advisory roles for Amgen and received research funding and<br />
participated in symposia for Merck Serono J-Y. Douillard: Honoraria/consulting/<br />
advisory roles for Amgen, Bayer, Roche, Merck; Research funding from Merck Serono;<br />
Travel/accommodation/ expenses from Amgen, Bayer, Roche, Merck. J. Taieb:<br />
Honoraria/consultigng/advisory role for Roche, Amgen, Merck, Lilly, San<strong>of</strong>i, Celgene,<br />
Sirtex R. Koukakis: Employee <strong>of</strong> Amgen Ltd. G. Demonty: Employee <strong>of</strong> Amgen<br />
(Europe) GmbH. S. Siena: Member <strong>of</strong> advisory boards or steering committees or<br />
principal investigator for Amgen, Bayer, Boehringer Ingelheim, Celgene, Genentech,<br />
Ignyta, Merck, Merrimack, Novartis, Pfzer, Roche, and San<strong>of</strong>iAventis.<br />
vi168 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
502P<br />
Pharmacological bioquivalence <strong>of</strong> branded and generic<br />
oxaliplatin: from preclinical assessment to clinical incidence<br />
<strong>of</strong> hypersensitivity reactions in patients with colorectal cancer<br />
C. Sonetto, C. Baratelli, M.P. Brizzi, M. Di Maio, G. Scagliotti, M. Tampellini<br />
Divison <strong>of</strong> Medical <strong>Oncology</strong>, Azienda Ospedaliero-Universitaria ASOU San Luigi<br />
Gonzaga, Orbassano, Italy<br />
Background: Generic drugs represent a relevant, potential opportunity in terms <strong>of</strong> cost<br />
savings. However, several physicians are uncomfortable with the replacement <strong>of</strong> the<br />
branded drugs with generic equivalents, indicating among several reasons their<br />
hypothetical lower tolerability.<br />
Methods: In the preclinical phase we in vitro tested the concentrations, stability and<br />
efficacy in CACO-2 cell line <strong>of</strong> branded versus two generic oxaliplatin formulations. In<br />
a second step we retrospectively collected safety and toxicity data from 427 colorectal<br />
cancer patients submitted to an oxaliplatin-based regimen between January 1994 and<br />
June 2014 at our institution. Patients were stratified according whether they received<br />
branded (BRAND group) or generic oxaliplatin (GENERIC group). Primary aim <strong>of</strong><br />
this second step was the assessment <strong>of</strong> the hypersensitivity reaction (HSR) incidence.<br />
Secondary aims were the evaluation <strong>of</strong> hematological and non-hematological toxicities<br />
and, in metastatic patients, clinical outcomes.<br />
Results: Preclinical tests did not demonstrated differences in concentration and<br />
stability in different storing conditions between branded and generic formulations.<br />
Furthermore, dose- and time-dependent anti-proliferative activities were similar.The<br />
incidence <strong>of</strong> HSRs was 12.1% in BRAND (33/273 patients) and 9.8% (15/154) in<br />
GENERIC group (p = 0.46). Occurrence <strong>of</strong> grade III-IV HSRs and severe HSRs leading<br />
to oxaliplatin discontinuation were comparable. In metastatic patients no significant<br />
difference in response rate was reported. A longer PFS was recorded in the BRAND<br />
group (14.4 vs 12.4 months, log rank p < 0.03), whereas OSs were comparable (24.9 vs<br />
26.9 months; log-rank p = 0.14).<br />
Conclusions: Tested generic and branded oxaliplatin formulations had equivalent<br />
concentrations <strong>of</strong> the active drug, and presented similar stability and in vitro efficacy.<br />
Likewise, the incidence <strong>of</strong> oxaliplatin-induced HSRs as well as toxicity pr<strong>of</strong>iles and<br />
clinical outcomes were similar. According to our data, generic oxaliplatin can be<br />
considered a safe and active alternative to the branded formulation.<br />
Legal entity responsible for the study: AOU San Luigi Gonzaga<br />
Funding: AOU San Luigi Gonzaga<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
503P<br />
A 12-week regimen with interdigitating FOLFOX/bevacizumab<br />
and pelvic chemoradiation for synchronous primary and<br />
metastatic rectal cancer. The CHROME B trial<br />
S. Ngan 1 , M. Bressel 2 , J. Chu 1 , J. McKendrick 3 , S. Chander 1 , P. Cooray 3 ,<br />
M. Jefford 4 , R. Wong 3 , M. Steel 5 , T. Leong 1 , A. Heriot 6 , M. Michael 4<br />
1 Radiation <strong>Oncology</strong>, Peter MacCallum Cancer Center, Melbourne, Australia,<br />
2 Centre for Biostatistics and Clinical Trials, Peter MacCallum Cancer Center,<br />
Melbourne, Australia, 3 Medical <strong>Oncology</strong>, Box Hill Hospital-Eastern health, Box<br />
Hill, Australia, 4 Medical <strong>Oncology</strong>, Peter MacCallum Cancer Center, Melbourne,<br />
Australia, 5 Colorectal Surgery, Box Hill Hospital-Eastern health, Box Hill, Australia,<br />
6 Surgical <strong>Oncology</strong>, Peter MacCallum Cancer Center, Melbourne, Australia<br />
Background: Chemotherapy used during chemoradiation for advanced rectal cancer is<br />
adequate for radiosensitisation but suboptimal for systemic control. The aim <strong>of</strong> this<br />
study was to assess tolerability and local/systemic control <strong>of</strong> a new regimen<br />
interdigitating intensive chemotherapy, bevacizumab (Bev) and radical radiotherapy.<br />
Methods: This was a single arm prospective trial for patients presenting with untreated<br />
synchronous symptomatic primary and metastatic rectal cancer. The treatment<br />
regimen was 12 weeks long. FOLFOX chemotherapy comprised oxaliplatin (Ox) 100<br />
mg/m 2 day 1, leucovorin 200 mg/m 2 day 1, 5-FU 400 mg/m 2 bolus day 1, then<br />
continuous infusion 2.4 g/m 2 over 46 hours was given in week 1, 6, and 11. Pelvic<br />
radiotherapy (25.2 Gy in 3 weeks in 1.8 Gy/fr with concurrent Ox 85 mg/m 2 day 1 and<br />
5-FU continuous infusion 200 mg/m 2 /day) was given in week 3-5, and week 8-10. Bev<br />
5 mg/kg was given in week 1, 3, 5, 7, 9, 11. In total patients received in 12 weeks, 3<br />
courses <strong>of</strong> FOLFOX, 50.4 Gy with Ox/5-FU, and 2-weekly Bev. All patients were staged<br />
with CT, MRI and FDG-PET before and 4 weeks after treatment.<br />
Results: Thirty patients were treated in this trial. The median age was 58 (range 36-75)<br />
years. 56.7% were male. Rectal primary MRI-stage was T2 3%, T3 73% and T4 24%.<br />
Liver metastasis was present in 80%. 33% had more than one site <strong>of</strong> metastasis. 24<br />
patients (80% [80% CI:68%-89%]) reached week 12 <strong>of</strong> the treatment. Chemotherapy<br />
dose modification was required in 63%, mainly for haematologic toxicity (neutropaenia<br />
G4 23% G3 23%, febrile neutropaenia G3 3%, thrombocytopaenia G4 3%). PET (SUV)<br />
response 4 weeks post-therapy for pelvic disease was CR + PR 100% [95%<br />
CI:88%-100%] (CR 14%), and for distant disease was CR + PR 93% [95% CI:76%-99%]<br />
(CR 41%). At 24 months, freedom from failure for pelvic and distant disease were 86%<br />
[95% CI:75%-100%] and 28% [95% CI:15%-50%] respectively. Overall survival at 24<br />
months was 67% [95% CI:52%-86%].<br />
Conclusions: It is feasible to deliver interdigitating intensive chemotherapy with<br />
bevacizumab and radiotherapy to treat primary and metastatic rectal cancer<br />
simultaneously. Favourable tumour control rates are encouraging. This treatment<br />
design warrants further investigation.<br />
Clinical trial identification: ACTRN: ACTRN12611000033943<br />
Legal entity responsible for the study: Peter MacCallum Cancer Centre<br />
Funding: Peter MacCallum Cancer Centre and Roche<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
504P<br />
Calcium gluconate and magnesium sulfate in preventing<br />
neurotoxicity in patients receiving oxaliplatin-based<br />
combination chemotherapy-capeOX<br />
I.Z. Kiladze 1 , N. Sharikadze 2 , T. Esakia 2<br />
1 Clinical <strong>Oncology</strong>, Aversi Clinic, Tbilisi, Georgia, 2 Medical <strong>Oncology</strong>,<br />
MediClubGeorgia, Tbilisi, Georgia<br />
Background: Oxaliplatin in combination with Capecitabine (CapeOX) is widely used<br />
chemotherapy regimen in the treatment <strong>of</strong> colorectal (CRC) and gastric (GC) cancer<br />
both in the adjuvant and metastatic setting. Oxaliplatin-induced peripheral neuropathy<br />
(OXA-IPN) is the major cause <strong>of</strong> treatment delay, dose reduction and cessation <strong>of</strong><br />
oxaliplatin-based therapy. Evidence regarding the role <strong>of</strong> calcium(Ca) and magnesium<br />
(Mg) prophylaxis to prevent oxaliplatin-related neurotoxicity is conflicting. This study<br />
is a prospective randomized study to evaluate the effect <strong>of</strong> Ca/Mg infusion on<br />
prevention or amelioration <strong>of</strong> oxaliplatin neuropathy in patients with CRC and GC<br />
treated with CapeOX.<br />
Methods: Patients with CRC or GC undergoing adjuvant or palliative therapy with<br />
CapeOX were randomly assigned to Ca/Mg (1g Ca gluconate+ 1g Mg sulfate pre- and<br />
post-oxaliplatin) or placebo group. 133 oxaliplatin-naive CRC/GC patients were<br />
enrolled (112 CRC, 22 GC ) who received at least one cycle <strong>of</strong> CapeOX. Patients were<br />
randomized to receive (Ca/Mg group; n = 78) or not receive (control group; n = 55) Ca<br />
gluconate and Mg sulfate infusion. The primary end point was the percentage <strong>of</strong><br />
patients with grade 2 or greater sensory neurotoxicity (sNT) at any time during or after<br />
oxaliplatin-based therapy by National Cancer Institute Common Terminology Criteria<br />
for Adverse Events (NCI CTCAE; version 3) criteria.<br />
Results: A total <strong>of</strong> 636 cycles <strong>of</strong> CapeOX were administered, median 5 and 4,5 cycles<br />
for Ca/Mg and control group respectively. Overall 82% (109) patients experienced at<br />
least Grade 1 acute sNT. Severities for control and Ca/Mg group patients, respectively<br />
were Grade 1, 33% and 41%; Grade 2, 11% and 10%; Grade3, 3% and 8%; Grade 4 2%<br />
and 0%. The incidence rates <strong>of</strong> grade 2 or worse neurotoxicity were 23% and 29% for<br />
Ca/Mg and control arms, respectively (p = 0.434)<br />
Conclusions: Calcium/Magnesium did not substantially decrease oxaliplatin-induced<br />
neurotoxicity. Our study does not support using calcium/magnesium to protect against<br />
oxaliplatin-induced sNT.<br />
Clinical trial identification: Trial has not protocol number Release date- 05.05.2016<br />
Legal entity responsible for the study: Georgian Group on Young Oncologists<br />
Funding: Georgian Group on Young Oncologists<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
505P<br />
abstracts<br />
Platinum-fluoropyrimidine (PF) and paclitaxel (PTX)-based<br />
chemotherapy (CT) in advanced anal cancer (AC)<br />
F. Sclafani 1 , F. Morano 1 , C. Baratelli 1 , E. Kalaitzaki 2 , D. Watkins 1 , N. Starling 1 ,<br />
I. Chau 1 , D. Cunningham 1 , S. Rao 1<br />
1 Medicine, The Royal Marsden NHS Foundation Trust, Sutton, UK, 2 Research &<br />
Development, The Royal Marsden NHS Foundation Trust, Sutton, UK<br />
Background: While treatment <strong>of</strong> localised AC is well established, there is paucity <strong>of</strong><br />
data to inform the management <strong>of</strong> patient (pts) with advanced tumours. Thus we have<br />
retrospectively analysed treatment pathways and outcomes <strong>of</strong> a single institution series<br />
<strong>of</strong> advanced AC pts.<br />
Methods: Inclusion criteria included epidermoid histology, inoperable locally<br />
recurrent or metastatic disease and availability <strong>of</strong> full medical records. The primary<br />
objective was overall survival (OS). Secondary objectives included objective response<br />
rate (ORR) and progression-free survival (PFS). Prognostic factors were analysed in a<br />
univariate model.<br />
Results: From 1997 to 2014, 64 pts were seen at The Royal Marsden NHS Foundation<br />
Trust who met the eligibility criteria. Pt characteristics were: females (60.9%), median<br />
age 59.2 (IQR: 52.1-66.4), history <strong>of</strong> HIV infection (7.8%), squamous histology<br />
(90.6%), metastatic disease (75%), median time to advanced disease 9.1 months (m)<br />
(IQR: 4.1-20.9), prior pelvic radiotherapy (82.8%), prior salvage surgery (15.6%). 51 pts<br />
(79.7%) received ≥1 line <strong>of</strong> systemic CT. Of these, 37% also underwent multimodality<br />
treatment including surgery, chemoradiotherapy or radi<strong>of</strong>requency ablation. PF was<br />
the most common regimen prescribed in the first-line setting (74.5%) with an ORR <strong>of</strong><br />
34.4% (95% CI: 18.6-53.2). PTX-based CT (single agent or combination therapy with<br />
carboplatin) was used in 15 pts as either front line or salvage treatment and the overall<br />
ORR was 53.3% (95% CI: 26.6-78.7). Median PFS after first- and second-line CT was<br />
5.8m (IQR: 2.8-7.6) and 3.2m (IQR: 2.5-7.1), respectively. Median OS in CT-treated pts<br />
was 15.4m (IQR: 10.0-45.2) and 13% were alive at 5 years. Age ≤65 years and liver<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw370 | vi169
abstracts<br />
metastases were predictive <strong>of</strong> better PFS (HR 0.39; 95% CI: 0.16-0.97, p = 0.04) and<br />
worse OS (HR 2.25; 95% CI: 1.25-4.03, p = 0.01), respectively.<br />
Conclusions: This is the second largest series <strong>of</strong> advanced AC ever reported. Doublet<br />
CT with PF and PTX-based CT are active regimens in this setting. Prospective clinical<br />
trials are needed to standardise treatment pathways, investigate the potential <strong>of</strong> novel<br />
therapeutics and ultimately improve the modest survival outcome <strong>of</strong> this pt population.<br />
Legal entity responsible for the study: The Royal Marsden NHS Foundation Trust<br />
Funding: The National Institute for Health Research (NIHR) Biomedical Research<br />
Centre (BRC) at the Royal Marsden NHS Foundation Trust and Institute <strong>of</strong> Cancer<br />
Research<br />
Disclosure: I. Chau: Advisory roles with Merck Serono, Roche, San<strong>of</strong>i <strong>Oncology</strong>,<br />
Bristol Myers Squibb, Eli-Lilly, Novartis, Gilead Science. Research funding from<br />
Merck-Serono, Novartis, Roche and San<strong>of</strong>i <strong>Oncology</strong>. Honoraria from Roche,<br />
San<strong>of</strong>i-<strong>Oncology</strong>, Eli-Lilly, Taiho. D. Cunningham: Research funding from: Roche,<br />
Amgen, Celgene, San<strong>of</strong>i, Merck Serono, Novartis, AstraZeneca, Bayer, Merrimack and<br />
MedImmune. All other authors have declared no conflicts <strong>of</strong> interest.<br />
506P<br />
Subgroup analysis <strong>of</strong> patients with metastatic colorectal<br />
cancer (mCRC) treated with regorafenib (REG) in the phase 3b<br />
CONSIGN trial who had progression-free survival (PFS) >4<br />
months (m)<br />
R. Garcia-Carbonero 1 , E. Van Cutsem 2 , F. Ciardiello 3 , M. Ychou 4 , J-F. Seitz 5 ,R.<br />
D. H<strong>of</strong>heinz 6 , Y. Arriaga 7 , U. Verma 7 , A. Grothey 8 , A. Miriyala 9 , J. Kalmus 10 ,<br />
C. Kappeler 11 , A. Falcone 12 , A. Zaniboni 13<br />
1 Department <strong>of</strong> Medical <strong>Oncology</strong>, Hospital Universitario Doce de Octubre,<br />
Madrid, Spain, 2 Digestive <strong>Oncology</strong>, University Hospitals Leuven, Leuven,<br />
Belgium, 3 Department <strong>of</strong> Experimental and Clinical Medicine and Surgery, Second<br />
University <strong>of</strong> Naples, Naples, Italy, 4 Department <strong>of</strong> Digestive <strong>Oncology</strong>, Institut<br />
Régional du Cancer de Montpellier (ICM), Montpellier, France, 5 Department <strong>of</strong><br />
Digestive <strong>Oncology</strong>, Aix-Marseille University, Assistance Publique Hôpitaux,<br />
Marseille, France, 6 Interdisziplinären Tumorzentrum, University Hospital<br />
Mannheim, Mannheim, Germany, 7 Division <strong>of</strong> Hematology and <strong>Oncology</strong>,<br />
University <strong>of</strong> Texas Southwestern Medical Center, Dallas, TX, USA, 8 Department<br />
<strong>of</strong> <strong>Oncology</strong>, Mayo Clinic, Rochester, MN, USA, 9 Global Pharmacovigilance and<br />
Risk Management, Bayer Pharma AG, Berlin, Germany, 10 Global Clinical<br />
Development <strong>Oncology</strong>, Ophthalmology & Neurology, Bayer Pharma AG, Berlin,<br />
Germany, 11 Clinical Statistics EU, Bayer Pharma AG, Berlin, Germany,<br />
12 Department <strong>of</strong> Medical <strong>Oncology</strong>, University <strong>of</strong> Pisa, Pisa, Italy, 13 Department <strong>of</strong><br />
<strong>Oncology</strong>, Fondazione Poliambulanza, Brescia, Italy<br />
Background: In the phase 3 randomized CORRECT trial, REG improved survival vs<br />
placebo in treatment-refractory mCRC; 19% <strong>of</strong> REG-treated patients had PFS >4 m. In<br />
the single-arm phase 3b CONSIGN trial (NCT01538680) <strong>of</strong> REG, adverse events (AEs)<br />
and PFS were consistent with phase 3 trials in mCRC. We performed a retrospective<br />
analysis <strong>of</strong> CONSIGN patients with PFS >4 m (long PFS) and ≤4 m (short PFS).<br />
Methods: Patients with treatment-refractory mCRC received REG 160 mg QD for 3 wks<br />
on/1 wk <strong>of</strong>f until disease progression, death, or unacceptable toxicity. Treatment beyond<br />
progression was at the investigator’s discretion. PFS (investigator assessed) was the time<br />
from treatment assignment to progression or death. Of 2872 patients assigned to REG, 674<br />
(23%) had long PFS and 2198 (77%) had short PFS. Descriptive statistics are reported.<br />
Results: Compared to the short PFS group, the long PFS group had a higher<br />
proportion <strong>of</strong> patients with ECOG PS 0, with no liver metastases, and ≥18 m since<br />
diagnosis <strong>of</strong> metastatic disease (Table). Long PFS patients received a median <strong>of</strong> 7 cycles<br />
(2–29); 75% ≥6 cycles; 34% ≥9 cycles. Short PFS patients received a median <strong>of</strong> 2 cycles<br />
(1–33). Dose reductions due to AEs (long PFS, short PFS) were 65%, 40%; actual mean<br />
daily doses were 136 mg, 149 mg, respectively. The most common drug-related<br />
NCI-CTCAE v4 grade ≥3 AEs (long PFS, short PFS) were hypertension (20%, 14%),<br />
hand–foot skin reaction (19%, 12%), fatigue (13%, 13%), diarrhea (8%, 4%), and<br />
hypophosphatemia (8%, 4%).<br />
Table: 506P<br />
Long PFS<br />
(n = 674)<br />
Short PFS<br />
(n = 2198)<br />
Median age, yrs (range) 62 (27–86) 62 (19–89)<br />
Age, % ≥70 yrs ≥75 yrs 19 8 23 10<br />
ECOG PS, % 0 1 58 41 44 56<br />
Liver metastases, % No Yes 32 67 20 80<br />
KRAS status, % mutant wild-type 47 49 52 43<br />
Primary site <strong>of</strong> disease, % Colon Rectum 66 28 6 64 28 8<br />
Both<br />
No. <strong>of</strong> prior regimens on or after diagnosis 22 28 50 28 27 45<br />
<strong>of</strong> metastatic disease, % 0–23≥4<br />
Time since first diagnosis <strong>of</strong> metastatic<br />
disease to treatment assignment, % 4 months) subgroup tended to have a higher<br />
proportion <strong>of</strong> patients with better performance status, with no liver involvement, and a<br />
longer time since diagnosis <strong>of</strong> metastatic disease. Higher rates <strong>of</strong> some AEs and dose<br />
reductions in the long PFS group may be related to longer treatment duration.<br />
Clinical trial identification: NCT01538680<br />
Legal entity responsible for the study: Bayer<br />
Funding: Bayer<br />
Disclosure: R. Garcia-Carbonero: Advisory board: Roche, Amgen, Merck, San<strong>of</strong>i, Lilly,<br />
Boehringer Ingelheim, Bayer, Novartis, Ipsen. E. Van Cutsem: Corporate-sponsored<br />
research: Bayer. F. Ciardiello: Advisory board: Bayer, Roche, Merck Serono, Lilly,<br />
San<strong>of</strong>i, AstraZeneca. Corporate-sponsored research: AstraZeneca, Merck Serono,<br />
Roche, Bayer. M. Ychou: Advisory board: Bayer, Roche, Merck. J-F. Seitz: Advisory<br />
board: Roche, San<strong>of</strong>i-Aventis. R.D. H<strong>of</strong>heinz: Corporate-sponsored research: Amgen,<br />
Medac, Merck, Roche, San<strong>of</strong>i. U. Verma: Advisory board: Bayer. Speakers bureau:<br />
Intramed. A. Grothey: Advisory board: Bayer Corporate-sponsored research: Bayer<br />
(institute). A. Miriyala, J. Kalmus, C. Kappeler: Stock ownership: Bayer. Other<br />
substantive relationships: Bayer (employee). A. Falcone: Advisory board: Amgen,<br />
Roche, Bayer, Lilly, San<strong>of</strong>i, Servier, Merck. Corporate-sponsored research: Roche,<br />
Amgen, Bayer, Merck, San<strong>of</strong>i. All other authors have declared no conflicts <strong>of</strong> interest.<br />
507P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
A phase 1 study evaluating the pharmacokinetics (PK) and<br />
safety <strong>of</strong> regorafenib (REG) in patients with advanced solid<br />
tumors with severe renal impairment (SRI)<br />
D.J. Renouf 1 , H.W. Hirte 2 , C.L. O’Bryant 3 , Z.J. Trnkova 4 , A. Cleton 4 , F. Huang 5 ,<br />
U. Mueller 6 , J-P. Ayoub 7 , A.C. Lockhart 8 , D.I. Quinn 9 , G.K. Dy 10 , M.B. Sawyer 11<br />
1 Division <strong>of</strong> Medical <strong>Oncology</strong>, British Columbia Cancer Agency, Vancouver, BC,<br />
Canada, 2 Division <strong>of</strong> Medical <strong>Oncology</strong>, Juravinski Cancer Centre and Escarpment<br />
Cancer Research Institute, Hamilton, ON, Canada, 3 Department <strong>of</strong> Clinical<br />
Pharmacy, University <strong>of</strong> Colorado Cancer Center, Aurora, CO, USA, 4 Clinical<br />
Pharmacology <strong>Oncology</strong>, Bayer Pharma AG, Berlin, Germany, 5 Clinical<br />
Pharmacology <strong>Oncology</strong>, Bayer HealthCare Pharmaceuticals, Whippany, NJ,<br />
USA, 6 Clinical Statistics, ClinStat GmbH, Cologne, Germany, 7 Department <strong>of</strong><br />
Medicine, Centre Hospitalier de l’Université de Montréal, Montreal, QC, Canada,<br />
8 Siteman Cancer Center, Washington University School <strong>of</strong> Medicine, St. Louis,<br />
MO, USA, 9 Norris Comprehensive Cancer Center, University <strong>of</strong> Southern<br />
California, Los Angeles, CA, USA, 10 Department <strong>of</strong> Medicine, Roswell Park Cancer<br />
Institute, Buffalo, NY, USA, 11 Department <strong>of</strong> <strong>Oncology</strong>, Cross Cancer Institute,<br />
Edmonton, AB, Canada<br />
Background: REG is an oral multikinase inhibitor used for the treatment <strong>of</strong> metastatic<br />
CRC and advanced GIST. This phase 1 study was designed to evaluate the PK and<br />
safety <strong>of</strong> REG in cancer patients with severe renal impairment (SRI; creatinine<br />
clearance [CL CR ] ≥15 to
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
ClinStat GmbH (employee). D.I. Quinn: Advisory boards: Bayer All other authors have<br />
declared no conflicts <strong>of</strong> interest.<br />
508P<br />
Cetuximab biweekly (q2w) plus mFOLFOX6 as 1st line therapy<br />
in patients (pts) with KRAS wild-type (wt) (exon 2) metastatic<br />
colorectal cancer (mCRC) – Primary endpoint and subgroup<br />
analysis <strong>of</strong> the CEBIFOX trial<br />
S. Kasper 1 , J. Meiler 1 , H. Knipp 2 , T. Höhler 3 , P. Reimer 4 , H.T. Steinmetz 5 ,<br />
W. Berger 6 , G. Linden 1 , S. Ting 7 , P. Markus 8 , A. Paul 9 , A. Dechêne 10 ,<br />
B. Schumacher 11 , K. Kostbade 1 , K. Worm 7 , K.W. Schmid 7 , T. Herold 7 ,<br />
M. Schuler 1 , T. Trarbach 12<br />
1 Medical <strong>Oncology</strong>, University Hospital Essen Westdeutsches Tumorzentrum,<br />
Essen, Germany, 2 Department <strong>of</strong> Medicine I, Alfried Krupp Krankenhaus, Essen,<br />
Germany, 3 Medizinische Klinik I, Prosper Hospital, Recklinghausen, Germany,<br />
4 Department for Hematology/<strong>Oncology</strong> and Stem Cell, Kliniken Essen Süd<br />
Evangelisches Krankenhaus Essen, Essen, Germany, 5 Medical <strong>Oncology</strong>, Praxis<br />
fuer Haematologie und Onkologie, Cologne, Germany, 6 Hematology/<strong>Oncology</strong>,<br />
Marienhospital - Onkologisches Zentrum Essen Nord, Essen, Germany, 7 Institute<br />
<strong>of</strong> pathology, University Hospital Essen Westdeutsches Tumorzentrum, Essen,<br />
Germany, 8 Department <strong>of</strong> General, Visceral and Trauma Surgery, Elisabeth<br />
Hospital Essen, Essen, Germany, 9 Department <strong>of</strong> General, Visceral and<br />
Transplantation Surgery, University Hospital Essen Westdeutsches Tumorzentrum,<br />
Essen, Germany, 10 Department <strong>of</strong> Gastroenterology and Hepatology, University<br />
Hospital Essen Westdeutsches Tumorzentrum, Essen, Germany, 11 Department <strong>of</strong><br />
Gastroenterology, Elisabeth Hospital Essen, Essen, Germany, 12 Center for Tumor<br />
Biology and Integrative Medicine, Hospital Wilhelmshaven, Wilhelmshaven,<br />
Germany<br />
Background: The multicenter, single-arm, phase II trial (Simon’s two stage design)<br />
evaluated the efficacy <strong>of</strong> mFOLFOX6 + cetuximab (500 mg/m 2 ) q2w as 1 st line therapy<br />
in KRAS wt mCRC. Final extended molecular and subgroup analyses are presented.<br />
Methods: Primary endpoint was response rate (ORR) per RECIST 1.0. In stage 1 and 2,<br />
13 and 25 responders were needed in 37 and 53 pts, respectively, to further evaluate<br />
this therapy (H 1 p > 0.55). Secondary endpoints were PFS, OS, safety, metastasectomy<br />
and quality <strong>of</strong> life (QoL). Extended molecular pr<strong>of</strong>iling was performed using<br />
NGS-based panel sequencing including NRAS, KRAS, BRAF, PIK3CA and TP53.<br />
Clinical parameters included: tumor location (left-sided LCRC), early tumor-shrinkage<br />
(ETS), depth <strong>of</strong> response (DPR), metastasectomy and inflammation markers<br />
(neutrophil/lymphocyte ratio-NLR). Differences in ORR, PFS and OS were calculated<br />
using chi-square and log rank tests. Hazard ratios were calculated by Cox regression<br />
analysis.<br />
Results: The primary endpoint was met with 57 pts enrolled (ITT) and 53 pts<br />
evaluable for response. There were 26 responders in stage 1 (70%) and 38 responders in<br />
the ITT (ORR <strong>of</strong> 67%). Median PFS and OS were 9.6 (7.4-11.7) and 29.4 (19.3-39.5)<br />
months, respectively. Secondary metastasectomy was achieved in 31.7%. Grade 3/4 AEs<br />
occurred in 52%, including leukocytopenia, rash and GI-toxicity. Molecular pr<strong>of</strong>iling<br />
could be performed in 44 pts (77%). Additional RAS or BRAF mutations were detected<br />
in 17.8% and 10.6%, respectively, with a negative impact on outcomes. TP53 mutations<br />
were detected in 62.5% without impact on outcomes. Pts with LCRC, ETS or<br />
metastasectomy had significantly prolonged OS, whereas pts with high NLR (>5) had<br />
inferior OS (all p-values
abstracts<br />
510P<br />
Phase II study <strong>of</strong> third-line cetuximab rechallenge in patients<br />
with metastatic wild-type K-RAS colorectal cancer who<br />
achieved a clinical benefit in response to first-line cetuximab<br />
plus chemotherapy (JACCRO CC-08)<br />
A. Tsuji 1 , T. Eto 2 , T. Masuishi 3 , H. Satake 4 , Y. Segawa 5 , H. Tanioka 6 , H. Hara 7 ,<br />
M. Kotaka 8 , T. Sagawa 9 , T. Watanabe 10 , M. Nakamura 11 , T. Takahashi 12 ,<br />
Y. Negoro 13 , D. Manaka 14 , H. Fujita 15 , T. Suto 16 , W. Ichikawa 17 , M. Fujii 18 ,<br />
M. Takeuchi 19 , T. Nakajima 20<br />
1 Clinical <strong>Oncology</strong>, Kagawa University Faculty <strong>of</strong> Medicine/Graduate School <strong>of</strong><br />
Medicine, Kagawa, Japan, 2 Department <strong>of</strong> Gastroenterology, Tsuchiura Kyodo<br />
General Hospital, Ibaraki, Japan, 3 Department <strong>of</strong> Clinical <strong>Oncology</strong>, Aichi Cancer<br />
Center Hospital, Aichi, Japan, 4 Department <strong>of</strong> Medical <strong>Oncology</strong>, Kobe City<br />
Medical Center General Hospital, Kobe, Japan, 5 Department <strong>of</strong> Medical<br />
<strong>Oncology</strong>, Saitama Medical University Internatl Medical Centre, Saitama, Japan,<br />
6 Department <strong>of</strong> Medical <strong>Oncology</strong>, Japan Labour Health and Welfare Organization<br />
Okayama Rosai Hospital, Okayama, Japan, 7 Department <strong>of</strong> Gastroenterology,<br />
Saitama Cancer Center, Saitama, Japan, 8 Gastrointestinal Cancer Center, Sano<br />
Hospital, Kobe, Japan, 9 Department <strong>of</strong> Gastroenterology, Hokkaido Cancer<br />
Center, Sapporo, Japan, 10 Department <strong>of</strong> Surgery, Himeji Red Cross Hospital,<br />
Himeji, Japan, 11 Aizawa comprehensive cancer center, Aizawa Hospital,<br />
Matsumoto, Japan, 12 Department <strong>of</strong> Surgical <strong>Oncology</strong>, Gifu University Hospital,<br />
Gifu, Japan, 13 Department <strong>of</strong> Gastroenterology, Kochi Health Sciences Center,<br />
Kochi, Japan, 14 Gastrointestinal Center, Department <strong>of</strong> Surgery, Kyoto-Katsura<br />
Hospital, Kyoto, Japan, 15 Department <strong>of</strong> General and Digestive Surgery,<br />
Kanazawa Medical University, Kanazawa, Japan, 16 Department <strong>of</strong><br />
Gastroenterological Surgery, Yamagata Prefectural Central Hospital, Yamagata,<br />
Japan, 17 Division <strong>of</strong> Medical <strong>Oncology</strong>, Showa University Fujigaoka Hospital,<br />
Yokohama, Japan, 18 Department <strong>of</strong> Digestive Surgery, Nihon University School <strong>of</strong><br />
Medicine, Tokyo, Japan, 19 Department <strong>of</strong> Clinical Medicine (Biostatistics), Kitasato<br />
University School <strong>of</strong> Pharmacy, Tokyo, Japan, 20 Gastroenterology, Japan Clinical<br />
Cancer Research Organization, Tokyo, Japan<br />
Background: Cetuximab rechallenge has been reported to be promising (Santini D<br />
et al. Ann Oncol 2012). We performed a multicenter phase II prospective study in<br />
Japan.<br />
Methods: The study cohort comprised patients with metastatic wild-type K-RAS<br />
colorectal cancer who achieved a clinical benefit (confirmed stable disease for at least 6<br />
months or clinical response) in response to first-line cetuximab plus chemotherapy,<br />
then had disease progression and received second-line chemotherapy, and finally had a<br />
clear new progression <strong>of</strong> disease. Patients received bi-weekly irinotecan (150 mg/m 2 )<br />
combined with cetuximab (400 mg/m 2 as an initial dose followed by 250 mg/m 2<br />
weekly). The primary endpoint was the 3-month progression-free rate. The required<br />
sample size was estimated to be at least 30 patients, assuming a 3-month<br />
progression-free rate <strong>of</strong> less than 15% as the null hypothesis versus a 3-month<br />
progression-free rate <strong>of</strong> higher than 35% as the alternative hypothesis, a power <strong>of</strong> 80%,<br />
and an alpha value <strong>of</strong> 0.05.<br />
Results: A total <strong>of</strong> 36 patients were recruited. Two patients were excluded: one met the<br />
ineligibility criteria, and the other did not receive the study treatment because <strong>of</strong> poor<br />
condition at the time scheduled for treatment. The 3-month progression-free rate <strong>of</strong><br />
44.1% (95% confidence interval: 27.4-60.8) met the primary endpoint, with a median<br />
progression-free survival time <strong>of</strong> 2.4 months and an overall survival time <strong>of</strong> 8.1<br />
months. The overall response rate and disease-control rate were 2.9% and 55.9%,<br />
respectively. The most frequent grade 3 to 4 adverse event was neutropenia (28.6%),<br />
and skin toxicities occurred in 80% <strong>of</strong> all patients, as expected.<br />
Conclusions: Third-line cetuximab rechallenge may be clinically beneficial comparable<br />
to regorafenib and TAS102, with manageable toxicity.<br />
Clinical trial identification: Trial protocol number: UMIN000010638 UMIN release<br />
date: 2013/5/7<br />
Legal entity responsible for the study: Akihito Tsuji<br />
Funding: Japan Clinical Cancer Research Organization<br />
Disclosure: A. Tsuji: Horonaria : Merck Serono, Daiichi Sankyo. H. Hara: Horonaria :<br />
Merck Serono, Yakult Honsha Research Funding : Merck Serono, Daiichi Sankyo. M.<br />
Kotaka: Horonaria : Merck Serono, Yakult Honsha. W. Ichikawa: Consulting fees :<br />
Merck Serono, Daiichi Sankyo. All other authors have declared no conflicts <strong>of</strong> interest.<br />
511P<br />
Adherence to guidelines for colorectal cancer prevention and<br />
its relationship to this cancer in the Basque country:<br />
a case-control study<br />
B. Chao-Seijo 1 , V. Ovejas-Arza 1 , I. Alegria-Lertxundi 1 , C. Aguirre 2 , L. Bujanda 3 ,F.<br />
J. Fernandez 4 , F. Polo 5 , I. Portillo 6 , M.C. Etxezarraga 7 , I. Zabalza 8 , M. Larzabal 9 ,<br />
M. M. de Pancorbo 10 , A.M. Rocandio 11 , M. Arroyo-Izaga 11<br />
1 Department <strong>of</strong> Pharmacy and Food Sciences, University <strong>of</strong> the Basque Country<br />
UPV/EHU, Vitoria, Spain, 2 Pharmacovigilance Unit, BIOMICs Research Group,<br />
Galdakao-Usansolo Hospital, Osakidetza, Galdakao, Spain, 3 Department <strong>of</strong><br />
Gastroenterology, Donostia Hospital, BioDonostia Institute, San Sebastian, Spain,<br />
4 Department <strong>of</strong> Gastroenterology, Galdakao-Usansolo Hospital, Galdakao, Spain,<br />
5 Department <strong>of</strong> Gastroenterology, Basurto Hospital, Osakidetza, Bilbao, Spain,<br />
6 Colorectal cancer screening program, Osakidetza, Bilbao, Spain, 7 Department <strong>of</strong><br />
Pathology, Basurto Hospital, Osakidetza, Bilbao, Spain, 8 Department <strong>of</strong><br />
Pathology, Galdakao-Usansolo Hospital, Osakidetza, Galdakao, Spain,<br />
9 Department <strong>of</strong> Pathology, Donostia Hospital, BioDonostia Institute, San<br />
Sebastian, Spain, 10 Department <strong>of</strong> Zoology and Cellular Biology Animal, BIOMICs<br />
Research Group, University <strong>of</strong> the Basque Country UPV/EHU, Vitoria, Spain,<br />
11 Department <strong>of</strong> Pharmacy and Food Sciences, BIOMICs Research Group,<br />
University <strong>of</strong> the Basque Country UPV/EHU, Vitoria, Spain<br />
Background: The European Prospective Investigation into Cancer and Nutrition<br />
(EPIC) has designed an index score based on recommendations for cancer prevention<br />
<strong>of</strong> the World Cancer Research Fund (WCRF) and the American Institute <strong>of</strong> Cancer<br />
Research (AICR). We aimed to investigate whether concordance with the specific<br />
guidelines for colorectal (CRC) prevention was related to this cancer in an adult<br />
population <strong>of</strong> the Basque Country.<br />
Methods: The present study included 310 cases and 310 controls randomly selected, all<br />
<strong>of</strong> them participants from the CRC screening program in the Basque Country (Spain),<br />
aged 50–69 years. At recruitment, dietary, anthropometric, and lifestyle information<br />
was collected through a questionnaire. A score was constructed based on the WCRF/<br />
AICR recommendations (2007) and the convincing evidences <strong>of</strong> association between<br />
lifestyle factors and CRC (WCRF/AICR, 2011). The recommendations used for the<br />
construction <strong>of</strong> the score were: physical activity (PA), dietary fibre, red meat and<br />
processed meat, alcoholic drinks and body fatness. The total score range was 0 to<br />
5. Higher scores indicated greater concordance with recommendations. All analysis<br />
were conducted on SPSS v. 22.0.<br />
Results: The mean score (2.7) was similar for cases and controls (Z = -0.21, P > 0.05).<br />
The scores for dietary fibre were higher in controls (0.6(0.3)) than in cases (0.5(0.3))<br />
(P = 0.013); whereas, the scores for PA were higher in cases (0.2(0.3)) than in controls<br />
(0.1(0.2)) (P < 0.001). For the rest <strong>of</strong> components no significant associations were<br />
observed with CRC: red meat and processed meat (Z = -0.63, P > 0.05), alcoholic<br />
drinks (Z = 0.00, P > 0.05) and body fatness (Z = -0.52, P > 0.05).<br />
Conclusions: The results <strong>of</strong> this study suggest that following the recommendations on<br />
dietary fibre for cancer prevention could be associated with a lower risk <strong>of</strong> CRC in this<br />
population. The differences in PA scores could be due to lifestyle changes after the<br />
diagnosis. More research is needed to elucidate the potential lifestyle risk factors for<br />
CRC and how modification <strong>of</strong> these lifestyle factors could prevent it.<br />
Legal entity responsible for the study: Dr. Marta Arroyo-Izaga<br />
Funding: Department <strong>of</strong> Health, Basque Country Government (2011111153) and<br />
Saiotek (S-PE12UNO058, a pre-doctoral grant from the Basque Government<br />
(PRE_2015_2_0084)<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
512P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Compassionate use program for trifluridine/tipiracil (TAS-102)<br />
in metastatic colorectal cancer: a real-life overview<br />
L. Salvatore 1 , M. Niger 2 , L. Bellu 3 , E. Tamburini 4 , P. Garcia-Alfonso 5 , N. Amellal 6 ,<br />
A-S. Delmas 6 , M. Wahba 7 , G. Prager 8<br />
1 U.O. Oncologia Medica 2 Universitaria, Azienda Ospedaliera Universitaria S.<br />
Chiara, Pisa, Italy, 2 Medicina Oncologica, Fondazione IRCCS - Istituto Nazionale<br />
dei Tumori, Milan, Italy, 3 Oncologia Medica 1, Istituto Oncologico Veneto IRCCS,<br />
Padua, Italy, 4 Oncologia Medica, Ospedale Infermi, Rimini, Italy, 5 Department <strong>of</strong><br />
<strong>Oncology</strong>, Hospital General Universitario Gregorio Marañon, Madrid, Spain,<br />
6 <strong>Oncology</strong> ITP, Institut de Recherches Internationales SERVIER (I.R.I.S.),<br />
Suresnes, France, 7 Medical Affairs, Taiho <strong>Oncology</strong>, Flemington, NJ, USA,<br />
8 Department <strong>of</strong> Medicine I, Vienna General Hospital (AKH) - Medizinische<br />
Universität Wien, Vienna, Austria<br />
Background: Compassionate use programs (CUPs) provide a treatment option for<br />
appropriate patients with unmet medical needs. We describe the trifluridine/tipiracil<br />
(TAS-102) CUP set up prior to marketing authorization for management <strong>of</strong> pretreated<br />
metastatic colorectal cancer (mCRC) in countries outside the USA and Japan.<br />
Methods: Registration gave mCRC patients (pts) early access to 2 cycles <strong>of</strong> treatment,<br />
renewable as necessary. Pts’ characteristics were collected at registration.<br />
Results: A total <strong>of</strong> 879 pts were registered in 21 countries by the 1st April 2016 cut<strong>of</strong>f<br />
(Argentina, Brazil, Australia, Austria, Czech Republic, Denmark, France, Germany,<br />
Hungary, Ireland, Israel, Italy, Latvia, Lithuania, Spain, The Netherlands, Portugal,<br />
vi172 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Romania, South Africa, Switzerland, and UK). Of these, 725 pts (83%) were shipped<br />
enough treatment for the first 2 cycles. Mean age was 64 years and 60% were male. Oral<br />
trifluridine/tipiracil was initiated at 35 mg/m 2 bid. Most pts had received 2, 3, or ≥4<br />
lines <strong>of</strong> prior treatment for metastatic disease (28%, 32%, and 32%, respectively); 4%<br />
had received 1 line <strong>of</strong> treatment and 4% unknown. The main reasons for not initiating<br />
treatment included cancellation <strong>of</strong> request due to worsening condition and progressive<br />
disease. 37 pts (4%) permanently discontinued treatment before the end <strong>of</strong> cycle 1 or 2<br />
due to disease progression (19 pts), death (8 pts), or other reasons (10 pts). A total <strong>of</strong><br />
184 pts (25% <strong>of</strong> pts in cycles 1or 2) went on to receive trifluridine/tipiracil for cycles 3<br />
or 4. Of those, 28 pts had a dose reduction due to neutropenia (17 pts), diarrhea (3<br />
pts), or other adverse events (8 pts; vomiting, dyspnea, creatinine increase, bowel<br />
obstruction, pleural effusion). 24 pts (3%) had treatment permanently discontinued<br />
before end <strong>of</strong> cycles 3or 4 due to progressive disease. 20 pts went on to receive<br />
treatment in cycles 5 or 6, 16 pts with no dose reduction.<br />
Conclusions: Real-world treatment and safety data are consistent with those reported<br />
in phase 3 trials <strong>of</strong> trifluridine/tipiracil in pretreated mCRC.<br />
Legal entity responsible for the study: IRIS<br />
Funding: IRIS<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
513P<br />
Pharmacokinetic and pharmacodynamic (PK/PD) analysis<br />
results from the phase 3 RECOURSE trial <strong>of</strong> trifluridine and<br />
tipiracil (TAS-102) versus placebo (pbo) in patients (pts) with<br />
refractory metastatic colorectal cancer (mCRC)<br />
T. Yoshino 1 , J. Cleary 2 , R. Mayer 2 , K. Yoshida 3 , L. Makris 4 , F. Yamashita 5 ,<br />
A. Ohtsu 1 , H-J. Lenz 6 , E. Van Cutsem 7<br />
1 Gastroenterology & Gastrointestinal <strong>Oncology</strong>, National Cancer Center Hospital<br />
East, Kashiwa, Japan, 2 Gastrointestinal Cancer, Dana-Farber Cancer Institute,<br />
Boston, MA, USA, 3 Clinical Pharmacology, Taiho <strong>Oncology</strong>, Inc., Princeton, NJ,<br />
USA, 4 Biostatistics, Stathmi Inc., New Hope, PA, USA, 5 Bioanalytics and DMPK,<br />
Taiho <strong>Oncology</strong>, Inc., Princeton, NJ, USA, 6 Division <strong>of</strong> Medical <strong>Oncology</strong>,<br />
University <strong>of</strong> Southern California Norris Comprehensive Cancer Center, Los<br />
Angeles, CA, USA, 7 Gastroenterology/Digestive <strong>Oncology</strong>, Leuven Cancer<br />
Institute, University Hosptials Leuven, Leuven, Belgium<br />
Background: The efficacy and safety <strong>of</strong> TAS-102, an oral agent that combines<br />
trifluridine and tipiracil (FTD/TPI), in pts with mCRC refractory/intolerant to standard<br />
therapies were examined in the RECOURSE trial, which showed that there was a<br />
significant improvement in overall survival (OS) and progression-free survival (PFS) for<br />
pts treated with FTD/TPI vs pbo (HR = 0.68 and 0.48 for OS and PFS, respectively; both<br />
P < 0.001). For pts at selected sites, PK, efficacy, and safety parameters were compared to<br />
explore the relation between exposure and treatment (Tx) responses.<br />
Methods: Three blood samples were collected at steady state in Cycle 1 at 1, 3, and 6<br />
hours after pts received 35 mg/m 2 <strong>of</strong> FTD/TPI or placebo in the morning. Pts were<br />
categorized into high and low exposure groups based on median AUC values for FTD<br />
(43.51 h•µg/mL) and TPI (0.65 h•µg/mL) estimated from population PK analysis.<br />
Results: 138 pts were evaluable for PK and 72 pbo pts had samples collected at ≥1time<br />
point for PK/PD analysis. There was a trend towards longer survival and median total<br />
weeks <strong>of</strong> exposure to FTD/TPI for the FTD high (n = 69) vs FTD low (n = 69) groups: 13.86<br />
and 6.14 weeks, respectively. All FTD/TPI groups had better survival outcomes than the<br />
pbo group. There were significant differences in incidence <strong>of</strong> Grade ≥3 neutropenia and<br />
dose reductions between FTD groups (Table). Rates <strong>of</strong> Grade ≥3 Tx-related adverse<br />
events (AEs) and Tx delays tended to be higher in the FTD high group. No significant<br />
differences were observed between the TPI AUC high and low groups.<br />
Conclusions: FTD/TPI pts with higher FTD AUC values were more likely to<br />
experience Grade ≥3 neutropenia and dose reductions and showed trends towards<br />
longer survival, more Grade ≥3 Tx-related AEs, and more Tx delays. Notably, all AUC<br />
groups had better survival outcomes than the pbo group.<br />
Clinical trial identification: ClinicalTrials.gov Number: NCT01607957<br />
Legal entity responsible for the study: Taiho Pharmaceutial Co., Ltd.<br />
Funding: Taiho Pharmaceutical Co., Ltd.<br />
Disclosure: T. Yoshino: received research funding from Sumitomo Dainippon Pharma<br />
Co., Ltd. R. Mayer: was a consultant/advisor to CASI Pharmaceuticals and receieved<br />
honoraria from Taiho <strong>Oncology</strong>, Inc. K. Yoshida: is an employee <strong>of</strong> Taiho <strong>Oncology</strong>,<br />
Inc. L. Makris: is an employee <strong>of</strong> Stathmi, Inc., and was a consultant/advisor to Taiho<br />
<strong>Oncology</strong>. A. Ohtsu: reports employment with Celgene and received honoraria from<br />
Taiho, Eisai, Daiichi-Sankyo, Merck Serono, and Chugai. H-J. Lenz: received research<br />
funding from Taiho. All other authors have declared no conflicts <strong>of</strong> interest.<br />
514P<br />
abstracts<br />
Role <strong>of</strong> glutamine for preventing oxaliplatin induced peripheral<br />
neuropathy (GELUPO): results <strong>of</strong> randomized open-label phase<br />
II trial<br />
O. Yazici 1 , A.P. Titiz 2 , N. Ozdemir 1 , S. Aksoy 3 , M.A. Sendur 4 , B. Arlı 2 , N. Zengin 1<br />
1 Medical <strong>Oncology</strong>, Ankara Numune Education and Research Hospital, Ankara,<br />
Turkey, 2 Neurology, Ankara Numune Education and Research Hospital, Ankara,<br />
Turkey, 3 Department <strong>of</strong> Medical <strong>Oncology</strong>, Hacettepe University Faculty <strong>of</strong><br />
Medicine, Ankara, Turkey, 4 Department <strong>of</strong> Medical <strong>Oncology</strong>, YıldırımBeyazıt<br />
University, Faculty <strong>of</strong> Medicine, Ankara, Turkey<br />
Background: Aimed to evaluate role <strong>of</strong> oral glutamine replacement for preventing<br />
neuropathy in patients with colorectal cancer receiving oxaliplatin.<br />
Methods: The patients planned to receive modified FOLFOX6 were blindly 1:1<br />
randomized to glutamine and control group. In both groups, prior to first mFOLFOX6<br />
regimen and after 8 cycles <strong>of</strong> therapy detailed neurological examination and EMG was<br />
performed.Assuming a neuropathy rate was > 30 % and 10 % in control and glutamine<br />
and it was estimated a total <strong>of</strong> 80 patients needed to be randomized to achieve 80%<br />
statistical power with a p level <strong>of</strong> 0.05 and a 10% drop-out rate. The patients with<br />
neuropathy in basal EMG, diabetes, history <strong>of</strong> neuropathy were excluded. In glutamine<br />
group all <strong>of</strong> the patients received 3x10 gr/day glutamine given before and during<br />
chemotherapy until the control EMG. The secondary end point <strong>of</strong> study was quality <strong>of</strong><br />
life evaluated by EORTC-QLQ C3O.<br />
Results: In between December 2013 and September 2015, eighty eligible patients were<br />
randomized glutamine (n = 40) and control (n = 40) group. In glutamine and control<br />
group basal and control EMG was performed in 87.5% (n = 35) and %80 (n = 32) <strong>of</strong> the<br />
patients, respectively. In between glutamine and control group after 8 cycles <strong>of</strong> therapy<br />
motor axonal and demyelinating neuropathy was detected in 8.5 % (n = 3) vs 18.7 %<br />
(n = 6) and 14.2 % (n = 5) vs 15.6 %(n = 5) <strong>of</strong> the patients and difference was not<br />
significant. In between glutamine and control group sensory axonal and demyelinating<br />
neuropathy was determined in 14.2 % (n = 5) vs 15.6 % (n = 5) and 17.1 % (n = 6) vs<br />
18.7 % (n = 6) <strong>of</strong> patients, respectively (p = 1 and p = 0.8). Following the 8 cycles <strong>of</strong><br />
therapy in control EMG there was no difference in between upper extremity and lower<br />
extremity distal latency, compound muscle action potential, motor nerve conduction<br />
velocity, F latency, compound nerve action potential and sensory nerve conduction<br />
velocity. The hematological and non-hematological toxicities were similar in between<br />
two groups. Basal and control median EORTC-QLQ scores were not different in<br />
between two groups (p = 0.46).<br />
Conclusions: In final analysis <strong>of</strong> the current open label randomized phase II trial, oral<br />
glutamine replacement therapy was ineffective to prevent oxaliplatin induced<br />
neuropathy.<br />
Clinical trial identification: ClinicalTrials.gov Identifier: NCT02024191<br />
Legal entity responsible for the study: Ankara Numune Education and Research<br />
Hospital<br />
Funding: Ankara Numune Education and Research Hospital<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
Table: 513P NA, not applicable. *Any delays that have occurred at Cycle 2 or later; denominators = number <strong>of</strong> pts who initiated Cycle 2 for each group<br />
Parameter<br />
FTD/TPI pts<br />
(n = 138)<br />
Pbo pts<br />
(n = 72)<br />
FTD high (>43.51<br />
h•µg/mL, n = 69)<br />
FTD low (≤43.51<br />
h•µg/mL, n = 69)<br />
FTD high /FTD low HR<br />
or relative risk [95%<br />
CI]<br />
FTD high /pbo HR or<br />
relative risk [95%<br />
CI]<br />
FTD low /pbo HR or<br />
relative risk [95%<br />
CI]<br />
Median OS, mo [95% CI] 8.9 [7.2, 10.2] 5.7 [4.0, 7.3] 9.2 [7.8, 11.1] 8.1 [5.3, 12.2] 0.72 [0.46, 1.11] 0.49 [0.32, 0.76] 0.60 [0.39, 0.92]<br />
Median PFS, mo [95% CI] 3.3 [1.9, 3.8] 1.8 [1.6, 1.8] 3.7 [2.1, 3.9] 2.0 [1.9, 3.9] 0.82 [0.57, 1.18] 0.26 [0.17, 0.40] 0.44 [0.29, 0.66]<br />
Grade ≥3 neutropenia, n 54 (39) 0 33 (48) 21 (30) 1.57 [1.02, 2.42] NA NA<br />
(%)<br />
Any Grade ≥3 AE, n (%) 98 (71) 38 (53) 49 (71) 49 (71) 1.00 [0.81, 1.24] 1.35 [1.03, 1.75] 1.35 [1.03, 1.75]<br />
Any Tx-related Grade ≥3 70 (51) 8 (11) 39 (57) 31 (45) 1.26 [0.90, 1.76] 5.09 [2.56, 10.09] 4.04 [2.00, 8.17]<br />
AE, n (%)<br />
Febrile neutropenia, n (%) 3 (2) 0 2 (3) 1 (1) 2.00 [0.19, 21.55] NA NA<br />
Any dose reduction, n (%) 22 (16) 0 16 (23) 6 (9) 2.67 [1.11, 6.41] NA NA<br />
Pts with ≥1 cycle<br />
initiation delay <strong>of</strong> ≥4<br />
days, n (%)*<br />
69/130 (53) 4/56 (7) 41/67 (61) 28/63 (44) 1.38 [0.98, 1.93] 8.57 [3.27, 22.45] 6.22 [2.33, 16.64]<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw370 | vi173
abstracts<br />
515P<br />
RECOURSE trial: Performance status at discontinuation in<br />
patients receiving trifluridine/tipiracil (TAS-102)<br />
E. Van Cutsem 1 , R. Garcia-Carbonero 2 , A. Pastorino 3 , A. Zaniboni 4 , A. Falcone 5 ,<br />
N. Amellal 6 , F. Benedetti 7 , R. Mayer 8 , A. Ohtsu 9 , J. Tabernero 10<br />
1 Digestive <strong>Oncology</strong>, University Hospitals Leuven - Campus Gasthuisberg,<br />
Leuven, Belgium, 2 <strong>Oncology</strong>, University Hospital 12 De Octubre, Madrid, Spain,<br />
3 Department <strong>of</strong> Medical <strong>Oncology</strong>, IRCCS AOU San Martino - IST-Istituto<br />
Nazionale per la Ricerca sul Cancro, Genoa, Italy, 4 <strong>Oncology</strong>, Fondazione<br />
Poliambulanza, Brescia, Italy, 5 Dept. <strong>of</strong> <strong>Oncology</strong>-Presidio Ospedaliero, Azienda<br />
Ospedaliera Universitaria S.Chiara, Pisa, Italy, 6 92284, Institut de Recherches<br />
Internationales SERVIER (I.R.I.S.), Suresnes, France, 7 <strong>Oncology</strong>, Taiho, Tokyo,<br />
Japan, 8 Gastrointestinal Cancer, Dana-Farber Cancer Institute, Boston, MA, USA,<br />
9 Department <strong>of</strong> Gastroenterology and Gastrointestinal <strong>Oncology</strong>, National Cancer<br />
Center Hospital East, Kashiwa, Japan, 10 Oncologia Médica, Vall d’Hebron<br />
University Hospital Institut d’Oncologia, Barcelona, Spain<br />
Background: The efficacy and safety <strong>of</strong> trifluridine/tipiracil (TAS-102) has been<br />
explored in patients with metastatic colorectal cancer (mCRC) refractory who were<br />
intolerant to standard therapies in the phase 3 RECOURSE trial. Treatment with<br />
trifluridine/tipiracil was associated with significantly improved overall and<br />
progression-free survival versus placebo. In a post hoc analysis, we compared the level<br />
<strong>of</strong> performance status (PS) at treatment discontinuation in the two arms.<br />
Methods: PS was evaluated in RECOURSE using the Eastern Cooperative <strong>Oncology</strong><br />
Group (ECOG) score. Patients included in this trial had PS = 0 or 1 at baseline. The PS<br />
at treatment discontinuation with ECOG scores 0 to 4 was compared to PS at baseline<br />
on treatment and placebo (descriptive statistics).<br />
Results: A total <strong>of</strong> 759 patients (95% <strong>of</strong> the RECOURSE population) had information<br />
on PS at treatment discontinuation. Of these, 424 (53%) had PS = 0 and 335 (42%) had<br />
PS = 1. Of the 496 trifluridine/tipiracil patients who discontinued treatment, 340 (69%)<br />
maintained the same level <strong>of</strong> PS, and only 78 (16%) had PS ≥ 2 at discontinuation<br />
(Table). Similar values were found in placebo patients, with 170/263 (65%)<br />
maintaining their PS and 50/263 (19%) with PS ≥ 2 at discontinuation.<br />
Baseline PS<br />
Table: 515P<br />
Trifluridine/tipiracil<br />
Placebo<br />
0 (n = 278) 1 (n = 218) 0 (n = 146) 1 (n = 117)<br />
PS at discontinuation<br />
0 180 (65%) 8 (4%) 86 (60%) 4 (3%)<br />
1 78 (28%) 152 (70%) 43 (30%) 80 (68%)<br />
2 13 (5%) 40 (18%) 13 (9%) 22 (19%)<br />
3 6 (2%) 17 (8%) 4 (3%) 8 (7%)<br />
4 1 (0.4%) 1 (0.5%) 0 3 (3%)<br />
Conclusions: Our results indicate that, despite expected treatment-related adverse<br />
events, the level <strong>of</strong> PS at treatment progression was maintained in patients treated with<br />
trifluridine/tipiracil.<br />
Legal entity responsible for the study: Taiho and Institut de Recherches<br />
Internationales Servier<br />
Funding: Taiho and Institut de Recherches Internationales Servier<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
516P<br />
Characteristics <strong>of</strong> patients (pts) with metastatic colorectal<br />
cancer (mCRC) treated with regorafenib (REG) who had<br />
progression-free survival (PFS) >4 months (m): Subgroup<br />
analysis <strong>of</strong> the phase 3 CORRECT trial<br />
A. Grothey 1 , A. Falcone 2 , Y. Humblet 3 , O. Bouche 4 , L. Mineur 5 , A. Adenis 6 ,<br />
J. Tabernero 7 , T. Yoshino 8 , H-J. Lenz 9 , R.M. Goldberg 10 , L. Huang 11 ,<br />
A. Wagner 12 , E. Van Cutsem 13<br />
1 Department <strong>of</strong> <strong>Oncology</strong>, Mayo Clinic, Rochester, MN, USA, 2 Department <strong>of</strong><br />
<strong>Oncology</strong>, University <strong>of</strong> Pisa, Pisa, Italy, 3 Medical <strong>Oncology</strong> Department, St-Luc<br />
University Hospital, Brussels, Belgium, 4 Digestive <strong>Oncology</strong>, Centre Hospitalier<br />
Universitaire Robert Debré, Reims, France, 5 GI and Liver Cancer Unit <strong>Oncology</strong><br />
and Radiotherapy, Institut Ste Catherine, Avignon, France, 6 Department <strong>of</strong><br />
Gastrointestinal <strong>Oncology</strong>, Centre Oscar Lambret, Lille, France, 7 Department <strong>of</strong><br />
Medical <strong>Oncology</strong>, Vall d’Hebron University Hospital and Institute <strong>of</strong> <strong>Oncology</strong>,<br />
Barcelona, Spain, 8 Department <strong>of</strong> Gastroenterology and Gastrointestinal<br />
<strong>Oncology</strong>, National Cancer Center Hospital East, Kashiwa, Japan, 9 Division <strong>of</strong><br />
Medical <strong>Oncology</strong>, USC Norris Comprehensive Cancer Center, Los Angeles, CA,<br />
USA, 10 Department <strong>of</strong> Medicine, The Ohio State University Comprehensive<br />
Cancer Center and James Cancer Hospital, Columbus, OH, USA, 11 Clinical<br />
Statistics US, Bayer HealthCare Pharmaceuticals, Whippany, NJ, USA, 12 Global<br />
Clinical Development, Bayer Pharma AG, Berlin, Germany, 13 Digestive <strong>Oncology</strong>,<br />
University Hospitals Leuven and KU Leuven, Leuven, Belgium<br />
Background: In CORRECT, REG significantly improved overall survival and PFS vs<br />
placebo in pts with treatment-refractory mCRC. We did a retrospective, exploratory<br />
subgroup analysis <strong>of</strong> REG-treated pts in CORRECT with PFS >4 m (long PFS) and ≤4<br />
m (short PFS).<br />
Methods: Pts with pretreated mCRC were randomized 2:1 to REG 160 mg or placebo<br />
QD for 3 weeks on/1 week <strong>of</strong>f until disease progression, death, or unacceptable toxicity.<br />
PFS was the time from randomization to progression or death. Of 505 pts randomized<br />
to REG, 98 (19%) had long PFS and 407 (81%) had short PFS.<br />
Results: Compared to short PFS pts, the long PFS group had a higher proportion <strong>of</strong><br />
patients with ECOG PS0, 1–2 tumor sites, and ≥18 m since diagnosis <strong>of</strong> metastatic<br />
disease (Table). Long PFS pts received a median <strong>of</strong> 6 (1–12) cycles, short PFS pts a<br />
median <strong>of</strong> 2 (1–11). Mean actual daily doses were 138.7 mg (long PFS) and 149.2 mg<br />
(short PFS). Dose modifications occurred in 91% (long PFS) and 72% (short PFS).<br />
NCI-CTCAE (v3) grade (Gr) ≥3 REG-related treatment-emergent adverse events<br />
(TEAE) occurred in 64% (long PFS) and 53% (short PFS). Most common REG-related<br />
Gr ≥3 TEAEs included (long PFS, short PFS) hand–foot skin reaction (20%, 16%),<br />
hypertension (17%, 5%), fatigue (13%, 9%), diarrhea (16%, 5%), rash/desquamation<br />
(3%, 6%), and hypophosphatemia (5%, 3%). Gr ≥3 laboratory toxicities (long PFS,<br />
short PFS) included increased bilirubin (8%, 13%), ALT (6%, 5%), and AST (5%, 6%).<br />
Although REG-related TEAEs led to a higher dose modification rate in long PFS pts<br />
(71% vs 52% for short PFS), discontinuations due to REG-related TEAEs were similar<br />
(long PFS 5%; short PFS 9%).<br />
Table: 516P<br />
Long PFS<br />
(n = 98)<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Short PFS<br />
(n = 407)<br />
Median age, yrs (range) 61 (34–82) 61 (22–82)<br />
Male, % 64 61<br />
Median body mass index, kg/m 2 25.6 24.7<br />
ECOG PS, % 0 1 63 37 50 50<br />
No. <strong>of</strong> tumor sites, % 1 2 3 ≥4 30381616 17353018<br />
KRAS status, % mutant wildtype 47 44 56 40<br />
Primary site <strong>of</strong> disease, % Colon Rectum 52 37 10 67 28 5<br />
Both<br />
No. <strong>of</strong> prior regimens on or after diagnosis <strong>of</strong> 22 22 55 28 25 47<br />
metastatic disease, % 0–23≥4<br />
Time since first diagnosis <strong>of</strong> metastatic<br />
disease to randomization, % 4 m tended to have a better performance status, fewer metastatic tumor<br />
sites, and a longer time since diagnosis <strong>of</strong> metastatic disease, compared to pts with<br />
short PFS.<br />
Clinical trial identification: NCT01103323<br />
Legal entity responsible for the study: Bayer<br />
Funding: Bayer<br />
Disclosure: A. Grothey: Advisory board: Bayer. Corporate-sponsored research: Bayer.<br />
A. Falcone: Advisory board: Amgen, Roche, Bayer, Lilly, San<strong>of</strong>i, Servier, Merck.<br />
Corporate-sponsored research: Roche, Amgen, Bayer, Merck, San<strong>of</strong>i. O. Bouche:<br />
Advisory board: Merck Serono, Roche. L. Mineur: Advisory board participation. A.<br />
Adenis: Corporate-sponsored research: Bayer, San<strong>of</strong>i Other substantive relationship:<br />
Bayer, San<strong>of</strong>i, Pfizer, Roche. J. Tabernero: Advisory board: Amgen, Bayer, Boehringer<br />
Ingelheim, Celgene, Chugai, Lilly, MSD, Merck Serono, Novartis, Roche, San<strong>of</strong>i,<br />
Symphogen, Takeda, Taiho. T. Yoshino: Corporate-sponsored research:<br />
vi174 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
GlaxoSmithKline K.K. Boehringer Ingelheim GmbH H-J. Lenz: Advisory board: Bayer.<br />
Lectures: Bayer. Clinical trial support: Bayer. R.M. Goldberg: Corporate-sponsored<br />
research: Bayer. L. Huang: Stock ownership: Bayer Other substantive relationships:<br />
Bayer (employee). A. Wagner: Other substantive relationships: Bayer (employee). E.<br />
Van Cutsem: Corporate-sponsored research: Bayer. All other authors have declared no<br />
conflicts <strong>of</strong> interest.<br />
517P<br />
TRUST: Phase II trial <strong>of</strong> induction chemotherapy (CT) with<br />
FOLFOXIRI + bevacizumab (BV) followed by<br />
chemo-radiotherapy (CRT) + BV and surgery in locally<br />
advanced rectal carcinoma (LARC)<br />
C. Vivaldi 1 , P. Buccianti 2 , G. Musettini 3 , F. Bergamo 4 , M.D. Rizzato 4 , A. Sainato 5 ,<br />
A. Martignetti 6 , S. Lucchesi 7 , M. Franceschi 2 , C. Boso 8 , F. Pasqualetti 5 ,<br />
L. Ginocchi 7 , F. Di Clemente 9 , A. Gonnelli 5 , L. Urbani 10 , S. Montrone 5 , I. Maretto 11 ,<br />
F. Sidoti 2 , A. Falcone 1 , G. Masi 1<br />
1 Oncologia Medica Universitaria, Azienda Ospedaliera Universitaria S.Chiara, Pisa,<br />
Italy, 2 U.O. Chirurgia Generale, Azienda Ospedaliero Universitaria Pisana, Pisa,<br />
Italy, 3 Medical <strong>Oncology</strong>, Azienda Ospedaliera Universitaria S.Chiara, Pisa, Italy,<br />
4 Dipartimento di Oncologia Clinica e Sperimentale, UOC Oncologia Medica 1,<br />
Istituto Oncologico Veneto IRCCS, Padua, Italy, 5 U.O. Radioterapia, Azienda<br />
Ospedaliera Universitaria S.Chiara, Pisa, Italy, 6 DH Oncologico Val d’Elsa, Azienda<br />
USL Toscana sud est, Siena, Italy, 7 Department <strong>of</strong> <strong>Oncology</strong>, Ospedale “F. Lotti”<br />
Pontedera, Pontedera, Italy, 8 UOC di Radioterapia, Istituto Oncologico Veneto<br />
IRCCS, Padua, Italy, 9 DH Oncologico Valdichiana, Azienda USL Toscana sud est,<br />
Siena, Italy, 10 U.O. Chirurgia Generale, Azienda Ospedaliera Universitaria Pisana,<br />
Pisa, Italy, 11 Dipartimento di Scienze Chirurgiche, Oncologiche e<br />
Gastroenterologiche, Clinica Chirurgica 1, Università di Padova, Padua, Italy<br />
Background: Induction CT followed by CRT is a promising strategy in LARC.<br />
FOLFOXIRI + BV is an effective treatment in metastatic colorectal cancer.<br />
Methods: This is a phase II single-arm trial. Patients (pts) with LARC at 10 cm, 56%/38%/6%. 46 pts<br />
completed induction therapy; 2 pts prematurely stopped treatment: 1 bowel perforation<br />
and sepsis resulting in death and 1 acute kidney injury recovered without sequelae.<br />
Main grade (G) 3/4 toxicities were: neutropenia (42%), febrile neutropenia (4.2%) and<br />
diarrhea (12.5%). After induction therapy 45 pts started CRT and 1 underwent surgery.<br />
After the first 13 pts, the protocol was amended and the schedule <strong>of</strong> capecitabine<br />
slightly modified (800 mg/m 2 /bid 5 days/week) due to an excessive rate <strong>of</strong> G3<br />
hand-foot syndrome (23%) and proctitis (23%). After amendment, all pts completed<br />
CRT with acceptable toxicity: no G3-4 toxicities were reported, with the exception <strong>of</strong><br />
proctitis (6.2%). After CRT 44 pts underwent surgery (1 died due to early progression<br />
after CRT): low anterior (89%) or abdomino-perineal (7%) resection. R0 resection was<br />
achieved in 98% resected pts. Early post-surgical complication rate was 32%, with a rate<br />
<strong>of</strong> 18% <strong>of</strong> anastomotic dehiscences (all solved). Pathologic complete response (pCR)<br />
rate was 36%. At a median follow up <strong>of</strong> 25.1 months, 11 pts experienced disease<br />
progression (3 local recurrences) and the estimated 2-year DFS is 78.8%.<br />
Conclusions: Induction therapy with FOLFOXIRI + BV followed by CRT + BV is<br />
feasible, but a careful patient selection is needed because <strong>of</strong> the overall safety pr<strong>of</strong>ile.<br />
Results in terms <strong>of</strong> pCR and preliminary DFS data are promising.<br />
Clinical trial identification: EUDRACT 2011-003340-45 Start Date: 2012-02-23<br />
Legal entity responsible for the study: Fondazione ARCO Onlus<br />
Funding: trial promoted by Fondazione ARCO Onlus, bevacizumab provided by Roche<br />
Disclosure: A. Falcone: Honoraria, advisory role, speakers’ bureau: Amgen, Bayer,<br />
Merck Serono, Roche, San<strong>of</strong>i, Lilly. Research funding: Amgen, Bayer, Merck Serono,<br />
Roche, San<strong>of</strong>i. G. Masi: Honoraria: Roche, Merck Serono, Amgen, Sirtex. All other<br />
authors have declared no conflicts <strong>of</strong> interest.<br />
518P<br />
Circulating tumor cells: a promising marker in predicting<br />
tumor response after preoperative chemo-radiation therapy<br />
for rectal cancer<br />
W. Sun, Z. Zhang<br />
Radiation <strong>Oncology</strong>, Fudan University Shanghai Cancer Center, Shanghai, China<br />
Background: The aim <strong>of</strong> this study was to investigate the role <strong>of</strong> circulating tumor cells<br />
(CTCs) in assessing and predicting <strong>of</strong> pathological response to preoperative CRT <strong>of</strong><br />
rectal cancer.<br />
Methods: Sixty-seven patients (average age: 55; male/female: 35/32) with T3-4 and/or<br />
N+ rectal cancer were enrolled. All patients received preoperative CRT followed by<br />
radical surgery after 6-8 weeks. Blood samples were obtained from patients before and<br />
after CRT. CTCs were detected by use <strong>of</strong> a high-performance size-based micro-fluidic<br />
device, which exploited numerous filtered micro-channels in it to enrich the large-sized<br />
target tumor cells from whole blood. The pathological results after surgery was<br />
evaluated according to tumor regression grade (TRG) classification. The association<br />
between CTC counts and the pathological tumor response was analyzed.<br />
Results: CTC counts before CRT were significantly higher than those after CRT<br />
(41.24 ± 18.45/5mL vs. 9.7 ± 8.9/5mL, P < 0.05). Based on TRG score, 67 patients were<br />
regrouped as 44 responders (TRG 3-4) and 23 non-responders (TRG 0-2). The CTC<br />
counts before CRT were not associated with tumor response. The CTC counts after<br />
CRT in responders (TRG3-4) were significantly lower than non-responders (TRG0-2)<br />
(5.93 ± 5.65/5mL vs. 16.65 ± 9.78/5mL,P < 0.05). The percentage difference <strong>of</strong> CTC<br />
counts (%CTC) between pre- and post-CRT were significantly higher in responders<br />
compared to non-responders (86.26% vs. 40.24%, P < 0.05). ROC (receiver-operating<br />
characteristics) analysis showed that %CTC was a stronger discriminator <strong>of</strong> treatment<br />
response (area under the curve <strong>of</strong> pre-, post-CRT CTC counts and %CTC: 0.38, 0.83<br />
and 0.88, respectively). Using 70.56% as the cut-<strong>of</strong>f threshold for %CTC value, a higher<br />
accuracy <strong>of</strong> 88.06%(59/67) was obtained to discriminate responders from<br />
non-responders with a sensitivity <strong>of</strong> 93.18%, a specificity <strong>of</strong> 78.26%, a positive<br />
predictive value <strong>of</strong> 89.13% and a negative predictive value <strong>of</strong> 85.71%.<br />
Conclusions: Circulating tumor cells are promising markers to predict tumor response<br />
after preoperative CRT for rectal cancer.<br />
Legal entity responsible for the study: Fudan University Shanghai Cancer Center<br />
Funding: The National Natural Science Foundation <strong>of</strong> China<br />
Disclosure: W. Sun, Z. Zhang: I identify that no financial interst in products or<br />
processes involved in their research.<br />
519P<br />
The gene expression levels <strong>of</strong> gamma-glutamyl hydrolase in<br />
tumor tissues may be a useful biomarker for proper use <strong>of</strong> S-1<br />
and tegafur-uracil /leucovorin in preoperative<br />
chemoradiotherapy in patients with rectal cancer<br />
S. Sadahiro 1 , T. Suzuki 1 , A. Tanaka 1 , K. Okada 1 , G. Saito 1 , A. Kamijo 1 , H. Nagase 2<br />
1 Surgery, Tokai University School <strong>of</strong> Medicine Isehara Campus, Isehara, Japan,<br />
2 Applied Pharmacology Labo, Taiho Pharmaceutical Co., Ltd., Tokushima, Japan<br />
Background: Preoperative chemoradiotherapy (CRT) with 5-FU-based chemotherapy<br />
is the standard <strong>of</strong> care for locally advanced rectal cancer. Both S-1 and tegafur-uracil<br />
(UFT) are 5-FU-based oral drugs. UFT is used in combination with leucovorin (LV) to<br />
enhance the effect <strong>of</strong> 5-FU. S-1 is used without LV and causes the stronger antitumor<br />
effect than UFT. We examined the association <strong>of</strong> the response to CRT with the<br />
expression levels <strong>of</strong> CRT-related genes in tumor tissues before CRT.<br />
Methods: Data <strong>of</strong> 51 patients (pts) with locally advanced rectal cancer who received<br />
preoperative CRT at a total radiation dose <strong>of</strong> 45Gy with S-1 or UFT/LV for 5 weeks<br />
were analyzed. The pathological tumor response was assessed according to the tumor<br />
regression grade (TRG) criteria. A patient with TRG 1-2 was defined as a responder.<br />
The expression levels <strong>of</strong> CRT-related 18 genes in tumor tissues were determined using<br />
a RT-PCR assay. The relationships between tumor response and the gene expression<br />
levels were analyzed. The cut<strong>of</strong>f value for gene expression <strong>of</strong> gamma-glutamyl<br />
hydrolase (GGH) was determined by the ROC curve.<br />
Results: Pathological response (TRG 1-2) and pathological complete response (pCR)<br />
was observed in 23 pts (45.1%) and 8 pts (15.7%), respectively. The expression levels <strong>of</strong><br />
methylenetetrahydr<strong>of</strong>olate dehydrogenase 1 (MTHFD1) and glycine amide<br />
phosphoribosyl synthetase (GART) were significantly higher in the pCR pts than in the<br />
non-pCR pts (p = 0.0091 and p = 0.0477). In UFT/LV group, the gene expression levels<br />
<strong>of</strong> methylenetetrahydr<strong>of</strong>olate reductase (MTHFR) and GGH were significantly lower in<br />
the responders than in non-responders (p = 0.0368 and p = 0.0379). The total<br />
pathological response rate <strong>of</strong> both high-GGH pts in S-1 group and low-GGH pts in<br />
UFT/LV group was 65.2%, and was higher than that (45.1%) in all pts.<br />
Conclusions: The expression levels <strong>of</strong> genes related to folate metabolism in tumor<br />
tissue were associated with response to preoperative CRT including S-1 or UFT/LV. In<br />
particular, the gene expression level <strong>of</strong> GGH in tumor tissues may be a useful<br />
biomarker for determining which regimen, S-1 or UFT/LV, should be used in CRT.<br />
Legal entity responsible for the study: N/A<br />
Funding: Tokai University<br />
Disclosure: H. Nagase: Is an employee <strong>of</strong> Taiho Pharmaceutical Co. Ltd. All other<br />
authors have declared no conflicts <strong>of</strong> interest.<br />
520P<br />
abstracts<br />
B cells and natural killer cells in lymph node (LN) are<br />
independent predictors <strong>of</strong> LN size, the number <strong>of</strong> retrieved<br />
LNs and survival in stage II colon cancer<br />
K. Okada, S. Sadahiro, H. Miyakita, G. Saito, A. Tanaka, T. Suzuki, A. Kamijo<br />
Surgery, Tokai University School <strong>of</strong> Medicine Isehara Campus, Isehara, Japan<br />
Background: In colon cancer, patients with many retrieved lymph nodes (LNs) have<br />
good outcomes. We previously reported that the longest diameter <strong>of</strong> retrieved LNs<br />
correlates with the number <strong>of</strong> retrieved LNs and is thus a predictor <strong>of</strong> outcomes (Int J<br />
Colorectal Dis 2015). LNs can be divided into three main regions: the cortex, the<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw370 | vi175
abstracts<br />
paracortex, and the medulla, and consist mainly <strong>of</strong> T cells, B cells, natural killer (NK)<br />
cells, and histiocytes. We studied the relations <strong>of</strong> the T-cell region, B-cell region, and<br />
the number <strong>of</strong> NK cells to the number <strong>of</strong> retrieved LNs, LN size, and outcomes.<br />
Methods: The study group comprised 320 patients with stage II colon cancer who<br />
underwent curative resection from 1991 through 2003. All operations were performed<br />
by the same team and LN dissection was performed to the origin <strong>of</strong> the feeding artery.<br />
LN with maximum long axis diameter (maximum LN) was selected in each patient and<br />
immunostained with CD3 as a T-cell marker, CD20 as a B-cell marker, and CD56 as<br />
an NK-cell marker. CD3-positive area ratio and CD20-positive area ratio were<br />
calculated using the image analyzer. The number <strong>of</strong> CD56-positive cells were counted<br />
at 6 sites and the mean number per 0.093 mm 2 was calculated.<br />
Results: The number <strong>of</strong> retrieved LNs was 14.8 ± 10.1 (mean ± SD). The mean<br />
CD3-positive area ratio was 0.39 ± 0.08. The mean CD20-positive area ratio was<br />
0.42 ± 0.10. The mean number <strong>of</strong> CD56-positive cells was 10.7 ± 9.6. Multivariate<br />
analysis showed that the diameter <strong>of</strong> the maximum LN significantly correlated with the<br />
following variables (in the order <strong>of</strong> the strongest to weakest): number <strong>of</strong> CD56-positive<br />
cells, age, tumor location, CD20-positive area ratio and sex. The number <strong>of</strong> retrieved<br />
LNs positively correlated with tumor location, age, number <strong>of</strong> CD56-positive cells, and<br />
CD20-positive area ratio. The median follow-up was 118 months. Multivariate analysis<br />
showed that age, tumor location, T stage, CD20-positive area ratio, and the number <strong>of</strong><br />
CD56-positive cells were independent prognostic factors <strong>of</strong> survival.<br />
Conclusions: B cell area ratio and the number <strong>of</strong> NK cells in maximum LNs were<br />
independent prognostic factors related to LN size, the number <strong>of</strong> retrieved LNs and<br />
survival in Stage II colon cancer.<br />
Legal entity responsible for the study: N/A<br />
Funding: Tokai University<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
521P<br />
Association between HER2 amplification and cetuximab<br />
efficacy in patients with RAS wild-type metastatic colorectal<br />
cancer<br />
J. Jeong 1 , J. Kim 2 , Y.S. Hong 1 , D. Kim 1 , J.E. Kim 1 , S.Y. Kim 1 , K-P. Kim 1 ,<br />
T.W. Kim 1<br />
1 Department <strong>of</strong> oncology, Asan Medical Center, University <strong>of</strong> Ulsan College <strong>of</strong><br />
Medicine, Seoul, Republic <strong>of</strong> Korea, 2 Department <strong>of</strong> pathology, Asan Medical<br />
Center, University <strong>of</strong> Ulsan College <strong>of</strong> Medicine, Seoul, Republic <strong>of</strong> Korea<br />
Background: Cetuximab has shown clinical benefit in patients with metastatic<br />
colorectal cancer (mCRC) harbouring wild-type RAS. HER2 amplification has been<br />
suggested as one <strong>of</strong> the resistant mechanisms <strong>of</strong> cetuximab treatment. We evaluated<br />
association between HER2 amplification and cetuximab efficacy in mCRC patients<br />
harbouring extended RAS wild-type.<br />
Methods: Between December 2003 and June 2013, we found 253 mCRC patients<br />
whose tumor harboured wild type in exon 2/3/4 both <strong>of</strong> KRAS and NRAS by high<br />
throughput sequencing (OncoMap version 4.0) and were treated with cetuximab as 2 nd<br />
or later-line. We finally included 243 mCRC cases whose HER2 status could be<br />
determined by both immunohistochemical (IHC) scoring according to HERACLES<br />
criteria and silver in-situ hybridisation (SISH). Progression-free survival (PFS) and<br />
overall survival (OS) were analysed in homogenous group (n = 149) who were<br />
progressed after oxaliplatin, irinotecan and fluoropyrimidines.<br />
Results: The median age was 55 years (range 19–76 years); 168 patients (69.1%) were<br />
male. Of the 243 RAS wild-type tumor, we observed 11 cases (4.5%) <strong>of</strong> HER2<br />
amplification (table). After the median follow-up <strong>of</strong> 13.5 months (range, 0.4–78.1),<br />
median PFS was statistically different according to the HER2 status: 3.1 months in<br />
patients harbouring HER2 amplification vs 5.7 months in those harbouring<br />
non-amplified HER2 (p = 0.013). OS was not statistically different according to the<br />
HER2 status although there was a tendency towards shorter OS in patients harbouring<br />
HER2 amplification (10.1 vs 13.5 months, p = 0.408).<br />
Table: 521P<br />
HER2 IHC (HERACLES criteria)<br />
SISH Negative Equivocal Positive Total<br />
Amplification 1 † 1 †† 9 ††† 11<br />
No amplification 229 3 0 232<br />
Total 230 4 9 243<br />
† HER2/CEP17 ratio 3.3, †† HER2/CEP17 ratio 2.7, ††† HER2/CEP17 ratio >5<br />
(all cases)<br />
Conclusions: HER2 amplification is associated with shorter PFS after cetuximab in<br />
mCRC patients harbouring extended RAS wild-type. Recent study <strong>of</strong> dual targeting <strong>of</strong><br />
EGFR and HER2 demonstrated promising result; further study is warranted for this<br />
population.<br />
Legal entity responsible for the study: Asan Medical Center<br />
Funding: None<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
522P<br />
Broad detection <strong>of</strong> alterations predicted to confer lack <strong>of</strong><br />
benefit from EGFR antibodies or sensitivity to targeted<br />
therapy in advanced colorectal cancer<br />
S.J. Klempner 1 , A. Rankin 2 , R.L. Erlich 2 , J. Sun 3 , A. Grothey 4 , M. Fakih 5 ,T.<br />
J. George, 6 , J. Lee 7 , J.S. Ross 8 , P.J. Stephens 9 , V.A. Miller 10 , S. Ali 10 ,A.<br />
B. Schrock 10<br />
1 Medical <strong>Oncology</strong>, The Angeles Clinic and Research Institute, Los Angeles, CA,<br />
USA, 2 Biomedical Informatics, Foundation Medicine, Inc., Cambridge, MA, USA,<br />
3 Biomarker Development, Foundation Medicine, Inc., Cambridge, MA, USA,<br />
4 Medical <strong>Oncology</strong>, Mayo Clinic, Rochester, USA, 5 Internal Medicine, City <strong>of</strong><br />
Hope, Duarte, CA, USA, 6 Hematology and <strong>Oncology</strong>, University <strong>of</strong> Florida College<br />
<strong>of</strong> Medicine, Gainesville, FL, USA, 7 Hematology and <strong>Oncology</strong>, Samsung Medical<br />
Center Sungkyunkwan University School <strong>of</strong> Medicine, Seoul, Republic <strong>of</strong> Korea,<br />
8 Pathology, Foundation Medicine, Inc., Cambridge, MA, USA, 9 Clinical Genomics,<br />
Foundation Medicine, Inc., Cambridge, MA, USA, 10 Clinical Development,<br />
Foundation Medicine, Inc., Cambridge, MA, USA<br />
Background: KRAS mutation represented the first genomic biomarker to predict lack<br />
<strong>of</strong> benefit from anti-EGFR antibody therapy in advanced colorectal cancer (CRC).<br />
Expanded RAS testing has further refined the treatment approach, but understanding<br />
<strong>of</strong> genomic alterations underlying primary and acquired resistance, as well as<br />
alterations predicting response to targeted therapies is limited and further study is<br />
needed.<br />
Methods: We prospectively analyzed 4,422 clinical samples from patients with<br />
advanced CRC using hybrid-capture based comprehensive genomic pr<strong>of</strong>iling (CGP) at<br />
the request <strong>of</strong> the individual treating physicians. Comparison with prior molecular<br />
testing results when available was performed to assess concordance.<br />
Results: We identified RAS/RAF pathway mutation or amplification in 62% <strong>of</strong> cases,<br />
including samples harboring KRAS mutations outside <strong>of</strong> the codon 12/13 hotspot<br />
region in 6.4% <strong>of</strong> cases. Among cases with KRAS non-codon 12/13 alterations for<br />
which prior test results were available, 79/90 (88%) were missed by focused testing. Of<br />
1,644 RAS/RAF wild-type cases analyzed by CGP, 28% harbored a genomic alteration<br />
(GA) associated with resistance to anti-EGFR therapy in advanced CRC including<br />
mutation <strong>of</strong> PIK3CA, EGFR, and ERBB2 genes. We also identified other targetable GA<br />
including novel kinase fusions, RTK amplification, activating point mutations, as well<br />
as microsatellite instability.<br />
Conclusions: Comprehensive genomic pr<strong>of</strong>iling reliably detects alterations associated<br />
with lack <strong>of</strong> benefit to anti-EGFR therapy in advanced CRC while simultaneously<br />
identifying alterations potentially important in guiding treatment. The use <strong>of</strong> CGP<br />
during the course <strong>of</strong> clinical care allows for the refined selection <strong>of</strong> appropriate targeted<br />
therapies and clinical trials, increasing the chance <strong>of</strong> clinical benefit and avoiding<br />
therapeutic futility.<br />
Legal entity responsible for the study: Foundation Medicine, Inc.<br />
Funding: Foundation Medicine, Inc.<br />
Disclosure: S.J. Klempner: Has received honoraria from Foundation Medicine. A.<br />
Rankin, R.L. Erlich, J. Sun, J.S. Ross, P.J. Stephens, V.A. Miller, S. Ali, A.B. Schrock:<br />
Employee and stock ownership in Foundation Medicine. All other authors have<br />
declared no conflicts <strong>of</strong> interest.<br />
523P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Mutational pr<strong>of</strong>iles in paired primary tumours and metastases<br />
in colorectal cancer patients: an NGS study <strong>of</strong> the Hellenic<br />
Cooperative <strong>Oncology</strong> Group<br />
G. Pentheroudakis 1 , V. Kotoula 1 , V. Kourvelos 2 , E. Charalambous 1 , V. Karavasilis 1 ,<br />
E. Giannoulatou 3 , G. Tsoulfas 1 , E. Pazarli 1 , G. Glantzounis 1 , P. Papakostas 1 ,<br />
E. Samantas 1 , D. Pectasides 1 , G. Fountzilas 1<br />
1 Data Office, Hellenic Cooperative <strong>Oncology</strong> Group (HeCOG), Athens, Greece,<br />
2 Biostatistics, Health Data Specialists, Ltd, Athens, Greece, 3 Bioinformatics, Victor<br />
Chang Cardiac Research Institute, Darlinghurst, Australia<br />
Background: Clonal heterogeneity in cancer contributes to resistance to therapy. The<br />
comparison <strong>of</strong> the genetic pr<strong>of</strong>ile <strong>of</strong> primary tumours with that <strong>of</strong> metastases will<br />
inform clinical decision-making for advanced colorectal cancer patients.<br />
Methods: Formalin-fixed paraffin-embedded colorectal adenocarcinoma from primary<br />
tumours (CRCp) and metastases (CRCm) from 82 patients managed according to<br />
HeCOG protocols were assessed. Next Generation Sequencing (Ion PROTON) was<br />
applied for mutational pr<strong>of</strong>iling <strong>of</strong> 51 cancer-related genes and 6 non-coding RNAs<br />
(444 amplicons, 48000 bases, median reading depth > 1300x). 57 patients had<br />
synchronous and 25 metachronous metastases. Intervening lines <strong>of</strong> therapy between<br />
primary tumour to resection <strong>of</strong> metastases were administered in 46 patients.<br />
Results: The most frequently mutated genes in CRCp were TP53 45%, KRAS 32%,<br />
APC 27%, IGF1R 8.5%, CDH1 8.5%, whereas in CRCm TP53 48%, APC 30%, KRAS<br />
27%, IGF1R 9.8%, PIK3CA 9.8%. Concordance rates between paired CRCp and CRCm<br />
were high (77-96%) for the commonly mutated genes. A trend for increasing<br />
vi176 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
discordance <strong>of</strong> the mutational status was observed in metachronous as compared to<br />
synchronous metastases.Higher mutational discordance was observed when therapy<br />
intervened between CRCp and CRCm. We observed co-existence <strong>of</strong> mutational<br />
discordance in genes related to several functional groups, suggesting clonal divergence<br />
affecting the genome diffusely. We will present more data on mutated allele frequencies<br />
in shared as well as in private mutations in CRCp and CRCm and analyse the impact<br />
on patient outcome.<br />
Table: 523P %Mutational discordance CRCp vs CRCm by time and<br />
exposure to therapy<br />
GENE Metachronous Synchronous Not exposed to<br />
tx<br />
p53 31 18 15 28<br />
APC 24 12 10 20<br />
KRAS 9 4 2 6<br />
IGF1R 8 4 0 10<br />
CDH1 10 8 0 14<br />
HER4 12 2 0 11<br />
SMAD4 12 4 1 11<br />
BRAF 8 2 0 6<br />
NRAS 5 2 0 4<br />
Exposed to<br />
tx<br />
Conclusions: Although a high concordance rate for frequently mutated genes was seen<br />
in CRCp versus CRCm, a trend was observed for increasing discordance with<br />
metachronous appearance <strong>of</strong> metastases and with prior exposure to antineoplastic<br />
therapy.<br />
Legal entity responsible for the study: Hellenic Cooperative <strong>Oncology</strong> Group<br />
Funding: Hellenic Cooperative <strong>Oncology</strong> Group<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
524P<br />
Phase II study to evaluate the efficacy <strong>of</strong> regorafenib in<br />
metastatic colorectal cancer patients by the assessment<br />
using FDG-PET/CT (JACCRO CC-12) metastatic colorectal<br />
cancer (JACCRO CC-12)<br />
H. Satake 1 , M. Nakamura 2 , A. Tsuji 1 , T. Sagawa 3 , F. Tamura 3 , Y. Hatachi 1 ,<br />
K. Oguchi 4 , A. Takagane 5 , T. Kaji 6 , T. Sekikawa 7 , M. Furukawa 2 , M. Kochi 8 ,<br />
W. Ichikawa 7 , M. Takeuchi 9 , M. Fujii 8 , T. Nakajima 10<br />
1 Department <strong>of</strong> Medical <strong>Oncology</strong>, Kobe City Medical Center General Hospital,<br />
Kobe, Japan, 2 Aizawa comprehensive cancer center, Aizawa Hospital,<br />
Matsumoto, Japan, 3 Department <strong>of</strong> Gastroenterology, Hokkaido Cancer Center,<br />
Sapporo, Japan, 4 Positron Imaging Center, Aizawa Hospital, Matsumoto, Japan,<br />
5 Department <strong>of</strong> Surgery, Hakodate Goryoukaku Hospital, Hakodate, Japan, 6 PET<br />
Center, Hakodate Goryoukaku Hospital, Hakodate, Japan, 7 Division <strong>of</strong> Medical<br />
<strong>Oncology</strong>, Showa University Fujigaoka Hospital, Yokohama, Japan, 8 Department<br />
<strong>of</strong> Digestive Surgery, Nihon University School <strong>of</strong> Medicine, Tokyo, Japan,<br />
9 Department <strong>of</strong> Clinical Medicine (Biostatistics), Kitasato University School <strong>of</strong><br />
Pharmacy, Tokyo, Japan, 10 Gastroenterology, Japan Clinical Cancer Research<br />
Organization, Tokyo, Japan<br />
Background: Regorafenib (REG) have been approved as salvage treatment for patients<br />
with metastatic colorectal cancer (mCRC). Tumor metabolic analysis using FDG-PET/<br />
CT has been reported to be more sensitive to predict the response <strong>of</strong> molecular<br />
targeting agents, as compared with the change <strong>of</strong> tumor burden using conventional<br />
CT. We conducted a prospective study to evaluate the efficacy <strong>of</strong> REG in mCRC<br />
patients by the assessment using FDG-PET/CT.<br />
Methods: Patients with mCRC refractory to standard chemotherapies with measurable<br />
lesions according to RECIST (Ver. 1.1) criteria, which are also assessable by FDG-PET/<br />
CT, enrolled in this study. REG was given orally in a dose <strong>of</strong> 160 mg once-daily for 3<br />
weeks, followed by 1 week <strong>of</strong> rest. After the first cycle, FDG-PET/CT was performed<br />
again to assess the chronological change in the SUV max as compared with that before<br />
the treatment. The primary endpoint is the chronological change in SUV max in the<br />
legion, <strong>of</strong> which value is highest in pretreatment FDG-PET/CT. Metabolic response<br />
and size-based response were assessed according to EORTC PET and RECIST<br />
criterion, respectively, by independent external review. We set the null and alternative<br />
hypotheses at 0% and 10%, respectively. Assuming a one-sided alpha level <strong>of</strong> 2.5% and<br />
a power <strong>of</strong> ≥90%, we estimated that 16 subjects are required and set the target sample<br />
size at 20 patients.<br />
Results: From November 2014 to March 2016, 17 <strong>of</strong> all enrolled 20 patients were<br />
evaluated for metabolic response. Six and 11 patients had SD and PD for the best<br />
overall response according to the RECIST criteria, thus the DCR was 30.0% (95% CI,<br />
11.9-54.3). As for the primary endpoint, the response rate was 5.9% (95% CI, 0.1-28.7)<br />
in all evaluable patients including one PR, 4 SD (23.5%) and 12 PD (70.6%). Based on<br />
the chronological changes <strong>of</strong> the sum <strong>of</strong> SUV max in all targeted legions up to 5, there<br />
were 5 SD (29.4%) and 12 PD (70.6%). When response was categorized into PD and<br />
non-PD (PR or SD), the metabolic response after the first cycle could predict the<br />
size-based response with a sensitivity <strong>of</strong> 83% and specificity <strong>of</strong> 100%.<br />
Conclusions: We confirmed the efficacy <strong>of</strong> REG in mCRC patients by the assessment<br />
<strong>of</strong> metabolic response using FDG-PET/CT.<br />
Clinical trial identification: UMIN000015563, Nov 01 2014<br />
Legal entity responsible for the study: Masato Nakamura<br />
Funding: Bayer<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
525P<br />
KRAS mutations in circulating tumour DNA (ctDNA) in<br />
MRI-defined, high-risk, locally-advanced rectal cancer (LARC)<br />
patients (pts) from the EXPERT-C trial<br />
F. Sclafani 1 , I. Chau 1 , D. Cunningham 1 , G. Vlachogiannis 2 , Z. Eltahir 3 , A. Lampis 2 ,<br />
C. Braconi 4 , E. Kalaitzaki 5 , D. Gonzalez De Castro 6 , A. Wotherspoon 3 ,<br />
J. Capdevila 7 , B. Glimelius 8 , A. Cervantes 9 , R. Begum 1 , H. Lote 2 , G. Mentrasti 2 ,J.<br />
C. Hahne 2 , D. Tait 1 ,G.Brown 10 , N. Valeri 11<br />
1 Medicine, The Royal Marsden NHS Foundation Trust, Sutton, UK, 2 Laboratory <strong>of</strong><br />
Gastrointestinal Cancer Biology and Genomics, Division <strong>of</strong> Molecular Pathology,<br />
The Institute <strong>of</strong> Cancer Research ICR, Sutton, UK, 3 Pathology, The Royal Marsden<br />
NHS Foundation Trust, Sutton, UK, 4 Signal Transduction and Molecular<br />
Pharmacology, The Institute <strong>of</strong> Cancer Research ICR, Sutton, UK, 5 Research &<br />
Development, The Royal Marsden NHS Foundation Trust, Sutton, UK, 6 Molecular<br />
Diagnostics, The Royal Marsden NHS Foundation Trust, Sutton, UK, 7 Medical<br />
<strong>Oncology</strong>, Vall d’Hebron University Hospital, Barcelona, Spain, 8 <strong>Oncology</strong>,<br />
Radiology and Clinical Immunology, University Hospital Uppsala Akademiska<br />
Sjukhuset, Uppsala, Sweden, 9 Medical <strong>Oncology</strong>, Biomedical Research institute<br />
INCLIVA, University <strong>of</strong> Valencia, Valencia, Spain, 10 Radiology, The Royal Marsden<br />
NHS Foundation Trust, Sutton, UK, 11 Laboratory <strong>of</strong> Gastrointestinal Cancer<br />
Biology and Genomics, Division <strong>of</strong> Molecular Pathology, The Institute <strong>of</strong> Cancer<br />
Research/Royal Marsden NHS Foundation Trust, Sutton, UK<br />
Background: Although the potential <strong>of</strong> detecting ctDNA in solid tumours has been<br />
increasingly reported, there are limited data in LARC. We sought to investigate<br />
frequency and relevance <strong>of</strong> KRAS mutations in ctDNA in a randomised phase II trial<br />
<strong>of</strong> CAPOX followed by chemoradiotherapy, surgery and adjuvant CAPOX ± cetuximab<br />
in high-risk LARC.<br />
Methods: RAS (exon 2-4) mutations were previously analysed in the biopsy and<br />
resection samples using standard sequencing techniques. ctDNA was isolated from 2<br />
ml <strong>of</strong> plasma collected prior to treatment start and analysed by digital droplet PCR.<br />
Commercially available and validated assays were used to detect KRAS mutations<br />
(G12D, G12V and G13D in all pts plus any patient-specific, additional mutation<br />
previously detected in the tissue). The sensitivity cut-<strong>of</strong>f for the assay <strong>of</strong> ctDNA was set<br />
at a lower limit <strong>of</strong> 0.02% mutant alleles.<br />
Results: 97/164 study pts (59%) were assessable for ctDNA. G12D, G12V or G13D<br />
tissue mutations were previously identified in 28 pts (7 not assessable). KRAS<br />
mutations in ctDNA in these codons were found in 13/28 (46%) and 22/62 (35%) <strong>of</strong><br />
pts who were KRAS mutant and wild type in tissue, respectively. 5/10 pts with G12A,<br />
G12C, G12S or A146T tissue mutations had the same mutation in the blood. Among<br />
38 pts with any KRAS tissue mutation, ctDNA was detected in 18 pts (47%) and<br />
associated with a higher baseline T stage (p = 0.01). However, no association was found<br />
with complete response (CR) (16.7% vs 10.0%, p = 0.65), PFS (HR 0.86, 95% CI:<br />
0.31-2.37), p = 0.77) or OS (HR 0.92, 95% CI: 0.32-2.65, p = 0.88). When tissue and<br />
ctDNA mutation data were combined to redefine the mutation status <strong>of</strong> the assessable<br />
EXPERT-C study population (n = 119; 32 RAS wild-type and 87 RAS mutant), no<br />
interaction was found between RAS status and cetuximab treatment with regards to CR<br />
(p = 0.99), PFS (p = 0.57) or OS (p = 0.98).<br />
Conclusions: In this series <strong>of</strong> high-risk LARC, KRAS mutations in ctDNA were found<br />
in up to half and one third <strong>of</strong> pts with KRAS mutant and KRAS wild-type tumours,<br />
respectively, as defined by previous tissue mutation analyses. Larger studies are needed<br />
to better address the potential role <strong>of</strong> ctDNA as a prognostic or predictive tool in<br />
LARC.<br />
Clinical trial identification: ISRCTN registration: 99828560<br />
Legal entity responsible for the study: The Royal Marsden NHS Foundation Trust<br />
and Institute <strong>of</strong> Cancer Research<br />
Funding: The NIHR Biomedical Research Centre at The Royal Marsden NHS<br />
Foundation Trust and The Institute <strong>of</strong> Cancer Research<br />
Disclosure: I. Chau: Advisory roles with Merck Serono, Roche, San<strong>of</strong>i <strong>Oncology</strong>,<br />
Bristol Myers Squibb, Eli-Lilly, Novartis, Gilead Science. Research funding from<br />
Merck-Serono, Novartis, Roche and San<strong>of</strong>i <strong>Oncology</strong>. Honoraria from Roche,<br />
San<strong>of</strong>i-<strong>Oncology</strong>, Eli-Lilly, Taiho. D. Cunningham: Research funding from: Roche,<br />
Amgen, Celgene, San<strong>of</strong>i, Merck Serono, Novartis, AstraZeneca, Bayer, Merrimack and<br />
MedImmune. A. Cervantes: Advisory roles with Merck-Serono and Roche. Research<br />
funding from Roche. Honoraria from Roche and Merck-Serono. All other authors have<br />
declared no conflicts <strong>of</strong> interest.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw370 | vi177
abstracts<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
526P<br />
Performance assessment <strong>of</strong> blood based RAS mutation<br />
testing: Concordance <strong>of</strong> results obtained from prospectively<br />
collected samples<br />
M.P. Saunders 1 , C. Cooney 1 , D. Edelstein 2 , S. Mullamitha 1 , M. Braun 1 ,<br />
S. Moghadam 1 , P. Ronga 3 , F.S. Jones 2 , A. Telaranta-Keerie 2 , R.A. Adams 4<br />
1 Clinical <strong>Oncology</strong>, The Christie NHS Foundation Trust, Manchester, UK, 2 Clinical<br />
Scientific Affairs, Sysmex Inostics, Baltimore, MD, USA, 3 Global Affairs, Merck,<br />
Darmstadt, Germany, 4 <strong>Oncology</strong>, Velindre Cancer Centre Velindre Hospital,<br />
Cardiff, UK<br />
Background: Clinical implementation <strong>of</strong> expanded RAS testing has been shown to<br />
improve the identification <strong>of</strong> mCRC patients for treatment with anti-EGFR therapy.<br />
Historically, tumour tissue has been the preferred sample type. However, emerging<br />
evidence suggest that single site tissue biopsies may not account for features <strong>of</strong> tumour<br />
molecular heterogeneity in the metastatic setting. Numerous retrospective studies<br />
support the value <strong>of</strong> blood-based RAS testing for therapy selection and monitoring.<br />
The aim <strong>of</strong> the present study was to test 100 prospectively collected samples to evaluate<br />
whether plasma testing with BEAMing is a viable alternative to standard <strong>of</strong> care<br />
tumour FFPE testing for determining RAS mutation status <strong>of</strong> mCRC patients.<br />
Methods: Peripheral blood was collected in Streck cell-free DNA BCT® tubes from an<br />
initial cohort <strong>of</strong> 43 mCRC patients that were either newly-diagnosed (72%) or<br />
presented with recurrent disease (28%). Circulating cell-free DNA was extracted and<br />
used for RAS mutation analysis using the OncoBEAM® RAS CRC assay at Sysmex<br />
Inostics. Results were then compared to those obtained by sequencing <strong>of</strong> KRAS and<br />
NRAS genes in DNA extracted from FFPE tumour tissue from the same patients.<br />
Discordant cases were re-examined with BEAMing <strong>of</strong> DNA derived from FFPE<br />
samples when available.<br />
Results: The overall agreement <strong>of</strong> plasma and tissue RAS mutation testing was 93%<br />
(40/43 patients), with positive percent agreement <strong>of</strong> 91.7% (22/24), and negative<br />
percent agreement <strong>of</strong> 94.7% (18/19). Re-examination <strong>of</strong> tissue from 1 case by<br />
BEAMing revealed a RAS mutation that matched the result obtained in plasma. RAS<br />
mutations were detected in 53.3% <strong>of</strong> plasma and 55.8% <strong>of</strong> tissue samples, respectively,<br />
similar to the expected prevalence <strong>of</strong> RAS mutations in mCRC patients.<br />
Conclusions: In this first prospective RAS mutation concordance study, a high overall<br />
agreement was observed between results obtained from tissue and plasma samples.<br />
These results are comparable to those obtained in retrospective studies. Overall, these<br />
findings indicate that RAS testing <strong>of</strong> plasma using BEAMing is a viable alternative to<br />
tissue RAS testing for determining mCRC patient eligibility for anti-EGFR therapy.<br />
Legal entity responsible for the study: The Christie<br />
Funding: Sysmex-Inostics<br />
Disclosure: D. Edelstein, F.S. Jones: Employee <strong>of</strong> Sysmex Inostics, Inc. P. Ronga:<br />
Employee <strong>of</strong> Merck KGaA, Damstadt, Germany. A. Telaranta-Keerie: Was an<br />
employee <strong>of</strong> Sysmex Inostics, Inc. All other authors have declared no conflicts <strong>of</strong><br />
interest.<br />
527P<br />
Impact <strong>of</strong> tumor epidermal growth factor receptor (EGFR)<br />
status on the outcomes <strong>of</strong> first-line FOLFOX-4 ± cetuximab in<br />
patients (pts) with RAS-wild-type (wt) metastatic colorectal<br />
cancer (mCRC) in the randomized phase 3 TAILOR trial<br />
S. Qin 1 ,J.Xu 2 , L. Wang 3 , Y. Cheng 4 , T. Liu 5 , J. Chen 6 , S.P. Eggleton 7 , J. Liu 8 ,<br />
J. Li 9<br />
1 Department <strong>of</strong> Medical <strong>Oncology</strong>, Nanjing Bayi Hospital, Nanjing, China,<br />
2 Department <strong>of</strong> Medical <strong>Oncology</strong>, 307 Hospital <strong>of</strong> PLA, Beijing, China,<br />
3 Department <strong>of</strong> Medical <strong>Oncology</strong>, Shanghai First People’s Hospital, Shanghai,<br />
China, 4 Department <strong>of</strong> Medical <strong>Oncology</strong>, Jilin Cancer Hospital, Jilin, China,<br />
5 Department <strong>of</strong> Medical <strong>Oncology</strong>, Zhongshan Hospital, Fudan University,<br />
Shanghai, China, 6 Department <strong>of</strong> Medical <strong>Oncology</strong>, Merck Serono Co., Ltd.,<br />
Beijing, China, 7 GCDC <strong>Oncology</strong>, Merck KGaA, Darmstadt, Germany,<br />
8 Department <strong>of</strong> Biostatistics, Merck Serono Co., Ltd., Beijing, China, 9 Department<br />
<strong>of</strong> Medical <strong>Oncology</strong>, Fudan University, Shanghai Cancer Center, Shanghai, China<br />
Background: Cetuximab in combination with chemotherapy (either FOLFIRI or<br />
FOLFOX) is a standard-<strong>of</strong>-care first-line treatment for pts with RAS-wt,<br />
EGFR-expressing mCRC. In this prospective subgroup analysis <strong>of</strong> the randomized<br />
phase 3 TAILOR trial, we evaluate the impact <strong>of</strong> EGFR status on the efficacy <strong>of</strong><br />
FOLFOX-4 ± cetuximab in the first-line treatment <strong>of</strong> Chinese pts with RAS-wt mCRC.<br />
Methods: TAILOR is a randomized phase 3 trial that includes a modified<br />
intention-to-treat (mITT) population <strong>of</strong> 393 Chinese pts with RAS-wt mCRC treated<br />
with FOLFOX-4 ± cetuximab. The primary endpoint <strong>of</strong> TAILOR is progression-free<br />
survival (PFS); secondary endpoints include overall survival (OS) and overall response<br />
rate (ORR). Tumor EGFR detectability was assessed in evaluable pts within the mITT<br />
population via immunohistochemistry.<br />
Results: Within the mITT population, 193 pts with RAS-wt mCRC were randomized<br />
and treated with FOLFOX-4 + cetuximab and 200 pts received FOLFOX-4. Adding<br />
cetuximab to FOLFOX-4 significantly improved median PFS (9.2 vs 7.4 mo; HR [95%<br />
CI] = 0.691 [0.536-0.891]; p = .004), preliminary assessment <strong>of</strong> median OS (20.7 vs 17.8<br />
mo; HR [95% CI] = 0.763 [0.607-0.958]; p = .020), and ORR (61.1% vs 39.5%; odds<br />
ratio [95% CI] = 2.410[1.607-3.614]; p < .001). Among 354 EGFR-evaluable pts in the<br />
mITT population, efficacy gains in PFS and ORR were independent <strong>of</strong> tumor EGFR<br />
status (Table).<br />
Conclusions: Irrespective <strong>of</strong> tumor EGFR status, the addition <strong>of</strong> cetuximab to first-line<br />
FOLFOX-4 clearly improved PFS and ORR in Chinese pts with RAS-wt mCRC. The<br />
TAILOR study data confirm cetuximab in combination with chemotherapy as a<br />
standard-<strong>of</strong>-care first-line treatment regimen for pts with RAS-wt mCRC, independent<br />
<strong>of</strong> tumor EGFR status.<br />
Clinical trial identification: EMR62202-057; NCT01228734<br />
Legal entity responsible for the study: N/A<br />
Funding: Merck KGaA, Darmstadt, Germany<br />
Disclosure: J. Chen, J. Liu: Employee <strong>of</strong> Merck Serono Co., Ltd., Beijing, China. S.P.<br />
Eggleton: Employee <strong>of</strong> Merck KGaA, Darmstadt, Germany J. Li: Research Funding<br />
from Merck and Roche. All other authors have declared no conflicts <strong>of</strong> interest.<br />
528P<br />
Tracking emerging KRAS and BRAF mutations through ccfDNA<br />
in colorectal cancers treated with EGFR blockade<br />
T. Yamada, G. Takahashi, T. Iwai, K. Takeda, M. Koizumi, S. Shinji, Y. Yokoyama,<br />
K. Hara, M. Hotta, A. Matsuda, S. Matsumoto, K. Ohta, E. Uchida<br />
Digestive Surgery, Nippon Medical School Main Hospital, Tokyo, Japan<br />
Background: Oncogenic KRAS mutations can predict lack <strong>of</strong> response by colorectal<br />
cancer (CRC) to epidermal growth factor receptor (EGFR) blockade. Although KRAS<br />
status is usually determined through primary tumor biopsies, genomic pr<strong>of</strong>iles <strong>of</strong> their<br />
metastases may differ because <strong>of</strong> intrinsic molecular heterogeneity. We used circulating<br />
cell-free DNA (ccfDNA) to genotype CRC, and then to track clonal evolution during<br />
treatment with EGFR blockade, to evaluate the utility <strong>of</strong> ccfDNA to detect KRAS and<br />
BRAF mutations before and during chemotherapy.<br />
Methods: We enrolled 55 patients with metastatic CRC, with no KRAS mutations in<br />
their primary tumors. Before starting chemotherapy, ccfDNA was purified from 1 mL<br />
serum from each patient. We detected 9 KRAS (G12A, G12R, G12D, G12C, G12S,<br />
G12V, G13D, Q61H, and Q61R) and BRAF (V600E) mutations, using the Invader<br />
method and digital PCR. Of the 55 patients, 24 were treated with systemic<br />
chemotherapy that included EGFR blockade. We extracted ccfDNA from these patients<br />
every 2–3 months until disease progression.<br />
Results: KRAS mutations in ccfDNA were detected in 5 patients before chemotherapy<br />
(9% [5/55], codon 12: 3 patients; codon 13: 2 patients). The response rate was 83% (20/<br />
24); 3 <strong>of</strong> the 4 non-responders were patients whose KRAS mutations were detected by<br />
ccfDNA before chemotherapy. The response rate <strong>of</strong> patients with no KRAS mutations<br />
in ccfDNA before chemotherapy was 95% (20/21). Of these 20 initially responsive<br />
patients, 10 (50%) acquired resistance. In 5 <strong>of</strong> these 10 patients (50%) ccfDNA detected<br />
emerging KRAS mutations. Three <strong>of</strong> these 5 patients had multiple mutations,<br />
including codon 12. Mutations in codon 61 were detected in 3 patients, but no solo<br />
codon-61 mutations were detected. BRAF mutation were also detected in 3 patients,<br />
but no solo BRAF mutations were detected.<br />
Conclusions: EGFR blockade had no beneficial effect for patients in whom ccfDNA<br />
detected KRAS mutations in the primary tumor. Emerging KRAS or BRAF mutations<br />
that were undetected before starting chemotherapy can lead to acquired resistance to<br />
EGFR blockade. However, emerging KRAS or BRAF mutations were detected in only<br />
EGFR status<br />
FOLFOX-4 + cetuximab<br />
(n = 173)<br />
Table: 527P<br />
FOLFOX-4 (n = 181)<br />
PFS, median (mo) FOLFOX-<br />
4 + cetuximab vs FOLFOX-4 (HR<br />
[95% CI])<br />
ORR, % FOLFOX-4 + cetuximab vs<br />
FOLFOX-4 (odds ratio [95% CI])<br />
# <strong>of</strong> pts # <strong>of</strong> pts<br />
Percentage <strong>of</strong> positively staining cells 0% 85 77 9.2 vs 7.9 (0.62 [0.41-0.92]) 67.1 vs 35.1 (3.77 [1.97-7.23])<br />
> 0%-10% 35 48 11.3 vs 7.4 (0.62 [0.35-1.11]) 71.4 vs 41.7 (3.50 [1.38-8.88])<br />
> 10%-20% 15 14 9.3 vs 8.1 (0.45 [0.15-1.39]) 73.3 vs 42.9 (3.67 [0.77-17.4])<br />
> 20%-35% 9 14 7.5 vs 9.2 (1.34 [0.47-3.86]) 44.4 vs 64.3 (0.44 [0.08-2.46])<br />
> 35% 29 28 7.0 vs 5.2 (0.73 [0.40-1.35]) 44.8 vs 35.7 (1.46 [0.50-4.24])<br />
vi178 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
50% <strong>of</strong> patients who acquired resistance, which implies the presence <strong>of</strong> another<br />
mechanism <strong>of</strong> acquiring resistance.<br />
Legal entity responsible for the study: Nippon Medical School<br />
Funding: research funding <strong>of</strong> Department <strong>of</strong> Digestive Surgery, Nippon Medical<br />
School<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
529P<br />
Factors associated with disconcordance <strong>of</strong> KRAS, NRAS,<br />
BRAF, PIK3CA mutation status in the primary tumor and<br />
metastases in patients (pts) with colorectal cancer (CRC)<br />
M. Fedyanin 1 , A. Stroganova 2 , A. Senderovich 2 , S. Dranko 2 , A. Tryakin 1 ,<br />
E. Polyanskaya 1 , A. Popova 1 , O. Sekhina 1 , A. Rasulov 3 , S. Gordeev 3 ,<br />
I. Sagaydak 4 , S. Tjulandin 1<br />
1 Clinical pharmacology and chemotherapy, N. N. Blokhin Russian Cancer<br />
Research Center, Moscow, Russian Federation, 2 Pathology, N. N. Blokhin Russian<br />
Cancer Research Center, Moscow, Russian Federation, 3 Oncological<br />
coloproctology, N. N. Blokhin Russian Cancer Research Center, Moscow, Russian<br />
Federation, 4 Liver and pancreatic tumors, N. N. Blokhin Russian Cancer Research<br />
Center, Moscow, Russian Federation<br />
Background: The concordance <strong>of</strong> KRAS gene mutation status between the primary<br />
and metastatic CRC is 95%. The aim <strong>of</strong> this study was to find factors associated with<br />
the disconcordance <strong>of</strong> KRAS, NRAS, BRAF, PIK3CA mutation status between the<br />
primary tumors and metastases in pts with CRC<br />
Methods: We performed DNA melting analysis with TaqMan probes and following<br />
Sanger sequencing to detect mutation hot-spots in KRAS exons 2 and 3, NRAS exons 2<br />
and 3, BRAF exon 15, PIK3CA exons 9 and 20 in 148 tumor tissues from 65 pts (65<br />
primary tumors and 83 metastases). Average age <strong>of</strong> all pts was 57 years (31-76), <strong>of</strong> male<br />
pts – 48%. The average number <strong>of</strong> metastasectomy in one pt was 1.3 (1-5). Primary<br />
tumors were located in the right, left part <strong>of</strong> colon and rectum in 10.8%, 35.4% and<br />
53.8% pts, respectively. The median time between the resection <strong>of</strong> the primary tumor<br />
and metastasectomy was 13 mon. (1-63). Most pts (88%) received chemotherapy<br />
before metastasectomy. None <strong>of</strong> the pts received anti-EGFR Mabs. Statistical analysis<br />
was performed using SPSS v.22, Inc, Chicago, IL<br />
Results: Mutations in KRAS, NRAS, PIK3CA and BRAF genes in primary tumors were<br />
detected in 43.1%, 3.1%, 13.8% and 3.1%, respectively. Discordance <strong>of</strong> mutation status<br />
<strong>of</strong> genes was identified in 29.2% <strong>of</strong> pts: 16.9% in KRAS, 3% in NRAS, 12.3% in<br />
PIK3CA and 3% BRAF status. In all cases <strong>of</strong> metastases in the brain we found the<br />
discordance in KRAS and PIK3CA mutation status (p = 0.08). Also, peritoneal<br />
metastases had discordance in KRAS status (p = 0.02). Pts with mutant RAS in<br />
primary tumor had higher chance <strong>of</strong> changed RAS status in metastases than pts with<br />
wild type RAS in primary tumors (OR 4.5, 95%CI 1.07-10.08, p = 0.04). Age, sex,<br />
number <strong>of</strong> organs with metastases, indexes T and N, tumor grade, mucinous<br />
component, adjuvant chemotherapy, radiotherapy, site <strong>of</strong> primary tumors, and other<br />
localization <strong>of</strong> metastases did not influence the discordance in mutation status<br />
Conclusions: We detected clinical significant differences in KRAS, NRAS, PIK3CA<br />
and BRAF mutation status between the primary tumors and peritoneal and brain<br />
metastases in pts with CRC. Also, in case <strong>of</strong> mutant RAS in primary tumor status <strong>of</strong><br />
RAS genes in metastases can be changed<br />
Legal entity responsible for the study: N/A<br />
Funding: Budget <strong>of</strong> clinic<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
530P<br />
Prognostic value <strong>of</strong> circulating tumor DNA in advanced<br />
colorectal cancer patients: Quantification <strong>of</strong> hypermethylated<br />
or mutant sequences using picoliter droplet digital PC<br />
A. Zaanan 1 , F. Garlan 2 , A. Didelot 2 , G. Perkins 1 , N. Siauve 3 , H. Blons 4 , J. Taieb 1 ,<br />
V. Taly 2 , P. Laurent-Puig 4<br />
1 Digestive <strong>Oncology</strong>, Hopital European George Pompidou, Paris, France,<br />
2 INSERM UMR-S1147, Paris Descartes University, Paris, France, 3 Department <strong>of</strong><br />
Medical Imaging, Hopital European George Pompidou, Paris, France,<br />
4 Department <strong>of</strong> Biology, Hopital European George Pompidou, Paris, France<br />
Background: Prognostic value <strong>of</strong> circulating tumor DNA (ctDNA) in metastatic<br />
colorectal cancer (mCRC) needs to be validated in prospective clinical studies using<br />
precise and robust procedures. In this context, picoliter-droplet digital PCR has arisen<br />
as a highly sensitive and quantitative approach <strong>of</strong>fering a broad dynamic range <strong>of</strong><br />
detection.<br />
Methods: All consecutive mCRC patients receiving chemotherapy were included in<br />
this monocentric prospective study between October 2012 and April 2015. Plasma<br />
samples were collected before the first cycle <strong>of</strong> chemotherapy, then at 14 and 28 days.<br />
For each patient, tumor DNA from biopsies was tested for the presence <strong>of</strong> KRAS,<br />
BRAF and TP53 mutations either by conventional qPCR or Next-Generation<br />
Sequencing. When no mutation was identified in the tumor, ctDNA was screened for<br />
hypermethylated sequences <strong>of</strong> WIF1 and NPY genes. CtDNA sequences (mutated or<br />
hypermethylated) were quantified (concentration, ng/mL) using picoliter-droplet<br />
digital PCR coupled to Taqman probes. Impact <strong>of</strong> ctDNA on survival and tumor<br />
response (RECIST 1.1) was analyzed using the Cox model with adjustment on age, sex<br />
and Kohne score.<br />
Results: Overall, 113 patients were included. Preliminary results are focused on 70<br />
mCRC patients treated with first-line chemotherapy (mean age: 65.7 yr [35.1-90.7];<br />
male, 58.6%). The concentration <strong>of</strong> baseline ctDNA was significantly associated with a<br />
worse overall survival (OS) (first vs third tertile: HR= 4.77, CI95% [1.0-22.2];<br />
p = 0.046). At 14 or 28 days, patients whom ctDNA concentrations remain above<br />
0.2ng/mL have a significantly worse progression free survival (PFS) (HR 7.1, CI95%<br />
[2.3-21.9]; p = 0.001). Reduction in ctDNA level at 14 or 28 days under 0.2 ng/mL was<br />
significantly associated with CT tumor responses at 8 weeks (p < 0.05).<br />
Conclusions: This study suggests that ctDNA is a significant prognostic factor in<br />
mCRC able to predict PFS and tumor response precociously. The quantifying<br />
circulating tumor DNA by picoliter-droplet digital PCR in mCRC appears to be<br />
relevant to tailor the treatment <strong>of</strong> mCRC.<br />
Clinical trial identification: ClinicalTrials.gov Identifier: NCT01983098<br />
Legal entity responsible for the study: APHP<br />
Funding: Without funding<br />
Disclosure: A. Zaanan: Has participated in consulting or/and advisory boards for<br />
Roche, Merck Serono, Amgen, San<strong>of</strong>i and Lilly. J. Taieb: Has participated in consulting<br />
or/and advisory boards for Merck, San<strong>of</strong>i, Roche Genentech, Pfizer and Amgen. P.<br />
Laurent-Puig: Has participated in consulting or/and advisory boards for San<strong>of</strong>i, Merck<br />
Serono, Amgen, Roche, Genomic Health, Myriad Genetics and Pfizer. All other<br />
authors have declared no conflicts <strong>of</strong> interest.<br />
531P<br />
abstracts<br />
Associations between dermatologic toxicity severity, patient<br />
characteristics, and efficacy among patients treated with<br />
panitumumab (Pmab) and chemotherapy<br />
T.J. Price 1 , J-Y. Douillard 2 , X. Guan 3 , C. Bohac 4 , M. Peeters 5<br />
1 Medical <strong>Oncology</strong>, Queen Elizabeth Hospital, Adelaide, Australia, 2 Medical<br />
<strong>Oncology</strong>, ICO René Gauducheau, Nantes, France, 3 Biostatistics, Amgen Inc.,<br />
Thousand Oaks, CA, USA, 4 Clinical Research, Amgen Inc., Thousand Oaks, CA,<br />
USA, 5 <strong>Oncology</strong>, Antwerp University Hospital, Edegem, Belgium<br />
Background: The identification <strong>of</strong> patient (pt) characteristics associated with<br />
dermatologic toxicity severity during treatment with anti-epidermal growth factor<br />
receptor (EGFR) monoclonal antibodies could inform treatment choices for patients<br />
with metastatic colorectal cancer.<br />
Methods: Data from the randomized, first-line, phase 3 PRIME trial <strong>of</strong><br />
pmab + FOLFOX vs FOLFOX and the randomized, second-line, phase 3 20050181 trial<br />
<strong>of</strong> pmab + FOLFIRI vs FOLFIRI were analyzed to evaluate the association <strong>of</strong><br />
dermatologic toxicity severity with pt characteristics/laboratory values and treatment<br />
outcomes. This study was supported by Amgen Inc.<br />
Results: In the pmab arms from 20050181 and PRIME, pts with grade 2–4<br />
dermatologic toxicity consistently had a trend <strong>of</strong> lower neutrophil-to-lymphocyte ratio<br />
(NLR) vs those with grade 0–1 at baseline, weeks 2–3, 4–5, 6–7, and 8–9(Table;<br />
baseline, week 8–9 shown). Carcinoembryonic antigen was elevated in pts with grade<br />
0–1 dermatologic toxicity in the pmab + FOLFOX group but reduced in grade 0–1 pts<br />
in the pmab + FOLFIRI group when each was compared with grade 2–4 dermatologic<br />
toxicity pts (Table). Among pts with progression-free survival ≥28 days, those with<br />
grade 2–4 dermatologic toxicity had improved overall survival and progression-free<br />
survival compared with pts with grade 0–1 toxicity (Table).<br />
Conclusions: This study did not clearly identify pt characteristics that are potential<br />
dermatologic toxicity biomarkers; further studies are required to understand the<br />
relationship between NLR and dermatologic toxicity severity. Increased dermatologic<br />
toxicity severity was associated with improved clinical outcomes.<br />
Clinical trial identification: NCT00364013; NCT00339183<br />
Legal entity responsible for the study: Amgen Inc.<br />
Funding: Amgen Inc.<br />
Disclosure: T.J. Price: Served as a consultant for Amgen Inc. and Merck. J-Y.<br />
Douillard: Received honoraria and travel expenses from, and served as a consultant for,<br />
Amgen Inc., Bayer, Merck and Roche Pharma AG, and received research funding from<br />
Merck Serono. X. Guan, C. Bohac: Employee <strong>of</strong>, and owns stock in, Amgen Inc. M.<br />
Peeters: Received honoraria, research funding, and travel expenses from Amgen Inc.,<br />
and has served as a consultant and on speakers bureau for Amgen Inc.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw370 | vi179
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<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Table: 531P<br />
Panitumumab + FOLFIRI<br />
Panitumumab + FOLFOX<br />
Grade 0–1 Grade 2–4 Grade 0–1 Grade 2–4<br />
Patient Characteristics, n 57 150 55 201<br />
Baseline NLR, median (IQR)* 3.7 (2.8–5.3) 3.1 (2.2–4.8) 4.2 (2.9–6.4) 3.1 (2.3–4.5)<br />
P value 0.064 0.001<br />
Week 8–9 NLR, median (IQR)* 2.9 (1.5–3.7) 2.0 (1.4–3.1) 2.1 (1.4–3.1) 1.9 (1.2–2.9)<br />
P value 0.124 0.441<br />
Basline BSA (m 2 ), mean 1.7 1.9 1.9 1.8<br />
Baseline ECOG performance status 0, % 26 58 44 64<br />
Baseline ECOG performance status 1, % 67 37 42 32<br />
Baseline CEA (µg/L), mean 220.0 422.4 848.7 466.4<br />
Alkaline phosphatase † (U/L), mean (n) 226.0 (32) 190.4 (106) 255.3 (28) 147.2 (157)<br />
Uric acid † (µmol/L), mean (n) 244.9 (29) 253.5 (94) 323.3 (28) 219.6 (137)<br />
Uric acid change from baseline † (µmol/L), mean (n) –34.1 –72.5 –1.4 –72.1<br />
Creatinine † (µmol/L), mean (n) 70.0 (32) 73.5 (105) 71.6 (29) 68.1 (162)<br />
Patients with narcotic concomitant medications, n (%) 25 (44) 73 (49) 33 (60) 101 (50)<br />
White blood cell count † (10 9 /L), mean (n) 5.5 (34) 5.9 (107) 7.9 (29) 6.1 (165)<br />
Patients with NSAID concomitant medications, n (%) 16 (28) 52 (35) 27 (49) 71 (35)<br />
Efficacy Outcomes, n 53 148 52 199<br />
Overall survival (months), median (95% CI) 10.7 (7.8–14.5) 19.4 (16.0–21.3) 15.4 (9.4–23.6) 28.7 (25.4–NE)<br />
Hazard ratio (95% CI) 0.51 (0.35–0.74) 0.45 (0.30–0.66)<br />
Progression-free survival (months), median (95% CI) 3.9 (3.5–8.6) 8.4 (7.4–9.5) 7.2 (5.3–11.0) 11.3 (9.6–12.6)<br />
Hazard ratio (95% CI) 0.83 (0.59–1.17) 0.64 (0.46–0.89)<br />
BSA, body surface area; CEA, carcinoembryonic antigen; CI, confidence interval; ECOG, Eastern Cooperative <strong>Oncology</strong> Group; IQR, interquartile range; NLR,<br />
neutrophil-to-lymphocyte ratio; NSAID, nonsteroidal anti-inflammatory drug; NE = not estimable. *From pooled local site data, platform counting bias should be<br />
considered. † Laboratory values within 7 days <strong>of</strong> worst skin toxicity.<br />
532P<br />
MicroRNA as predictive biomarker <strong>of</strong> survival for stage IIIB<br />
colon cancer patients<br />
533P<br />
Accuracy <strong>of</strong> plasma RAS mutation testing for therapy selection<br />
and monitoring <strong>of</strong> colorectal cancer patients<br />
P. Li 1 ,Q.Ou 2 , G. Chen 2 , F.S. Oduncu 1<br />
1 <strong>Oncology</strong>, Klinikum der Universität München, Munich, Germany, 2 Colorectal<br />
surgery, Cancer Centre Sun Yat-Sen University, Guangzhou, China<br />
Background: The dismal outcome <strong>of</strong> stage IIIB colon cancer highlights the need for<br />
targeted therapies on the basis <strong>of</strong> effective predictive biomarkers, such as microRNA<br />
(miRNA).<br />
Methods: Microarray was used to compare the miRNA expression pr<strong>of</strong>iles for 8 stage<br />
III B colon cancer patients with worse prognosis (metastases between 8 months and 18<br />
months) and 8 cured stage III B colon cancer patients. Quantitative real-time<br />
polymerase chain reaction (qRT-PCR) analysis <strong>of</strong> the expression <strong>of</strong> targeted miRNAs<br />
was performed on tumor tissue <strong>of</strong> 98 patients with stage IIIB B colon cancer. A<br />
predictive model for 5-year disease-free survival (DFS) and overall survival (OS) was<br />
constructed using Kaplan–Meier analysis, logistic and Cox regression.<br />
Results: miRNA-192-3p and miRNA-192-5p were down regulated in group with worse<br />
prognosis (P = 0.026 and P = 0.042 respectively). Patients with higher expression <strong>of</strong><br />
miRNA-192-5p had higher 5-year DFS (84.21%) and OS (89.47%) than those with<br />
lower targeted miRNA expression (DFS 38.8%, HR: 3.74, 95% confidence interval (CI):<br />
1.52-9.23, P: 0.04; OS 48.57%, HR: 5.01, 95%CI: 1.75-14.38, P: 0.03). Patients with<br />
higher expression MiRNA-192-3p did not statistically impact the survival in this<br />
setting (DFS 73.33%vs64.7%, HR:0.68, 95%CI: 0.31-1.52, P:0.35; OS 76.67%vs66.17%,<br />
HR: 0.62, 95% CI: 0.27-1.45, P: 0.27).<br />
Conclusions: MiRNA-192-5p is highly predictive marker for stage III B colon cancer<br />
patients. MiRNA-192-3p had no predictive value in this setting<br />
Legal entity responsible for the study: P. Li, Q. Ou, G. Chen, F.S. Oduncu<br />
Funding: Sun Yat-sen University<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
J. Vidal Barrull 1 , L. Muinelo Romay 2 , A. Dalmases 3 , A. Abalo 2 , M.C. Vela 3 ,M.<br />
Abreu Rodríguez 2 , M. Muset 3 , J. Ruiz 2 , M. Iglesias 3 , C. Blanco 2 , E. López 1 ,<br />
C. Rodríguez 2 , F.S. Jones 4 , D. Edelstein 4 , A. Lukas 5 , J. Albanell 1 , B. Bellosillo 3 ,<br />
S. Candamio 2 , C. Montagut 1 , R. López 2<br />
1 Medical <strong>Oncology</strong>, University Hospital del Mar, Barcelona, Spain, 2 Translational<br />
Medical <strong>Oncology</strong> Group, Health Research Institute <strong>of</strong> Santiago (IDIS), Complejo<br />
Hospitalario Universitario de Santiago de Compostela SERGAS, Santiago De<br />
Compostela, Spain, 3 Pathology Department, University Hospital del Mar,<br />
Barcelona, Spain, 4 Clinical Scientific Affairs, Sysmex Inostics, Baltimore, MD, USA,<br />
5 Research & Development, Sysmex Inostics, Sysmex Inostics GmbH, Hamburg,<br />
Germany<br />
Background: Tumor tissue is currently used for RAS testing in metastatic colorectal<br />
cancer (mCRC) patients, but detection <strong>of</strong> circulating tumor DNA in plasma is being<br />
actively investigated as an alternative for detection and monitoring <strong>of</strong> RAS mutations<br />
during therapy.<br />
Methods: Concordance <strong>of</strong> plasma and tissue RAS mutation was evaluated in 102 mCRC<br />
patients. RAS mutation status was also monitored in serial plasma samples from 18<br />
patients. The OncoBEAM RAS CRC assay was used to detect RAS mutations in<br />
plasma and results were compared to those obtained by standard-<strong>of</strong>-care RAS testing <strong>of</strong><br />
tissue. For discordant cases, tissue samples were re-examined with BEAMing.<br />
Results: The overall percent agreement <strong>of</strong> the two methods was 93.1% (95/102<br />
patients), with positive agreement <strong>of</strong> 95.6% (43/45) and negative agreement <strong>of</strong> 91.2%<br />
(52/57). Of the 5 plasma + /tissue − cases, 3 patients were treated with anti-EGFR<br />
therapy; 2 showed responses with loss <strong>of</strong> RAS mutations in plasma and 1 patient did<br />
not respond to therapy. In another plasma + /tissue − case, tissue BEAMing revealed a<br />
RAS mutation. This patient was treated with anti-VEGF therapy with a partial<br />
response. Longitudinal monitoring <strong>of</strong> plasma RAS status showed that <strong>of</strong> 13 patients<br />
initially treated with cetuximab, 4 showed emergence <strong>of</strong> RAS mutations at progression.<br />
In 4 other patients with basal RAS mutations treated with QT + anti-VEGF, 3 showed a<br />
significant decrease in the fraction <strong>of</strong> RAS mutant alleles. This decline mirrored<br />
responses to treatment. Interestingly, all 4 <strong>of</strong> these patients were determined to have<br />
stable disease by RECIST criteria upon CT scan.<br />
Table: 533P<br />
TISSUE RAS<br />
Positive Negative total<br />
PLASMA RAS Positive 43 5 48<br />
Negative 2 52 54<br />
Total 45 57 102<br />
vi180 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Conclusions: The high overall agreement between plasma and tissue RAS mutation<br />
status indicates that blood-based testing with OncoBEAM RAS CRC is a viable<br />
alternative to tissue testing for mCRC patients. Moreover, this study shows that<br />
BEAMing will be useful to monitor RAS mutation status in patients undergoing<br />
systemic therapy to monitor resistance and evaluate the efficacy <strong>of</strong> particular<br />
treatments.<br />
Legal entity responsible for the study: Cancer Program, IMIM-Hospital del Mar,<br />
Barcelona, Spain<br />
Funding: Cancer Program, IMIM-Hospital del Mar, Barcelona, Spain Liquid Biopsy<br />
Analysis Unit, Health Research Institute <strong>of</strong> Santiago (IDIS). Complexo Hospitalario<br />
Universitario de Santiago de Compostela, Spain<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
534P<br />
Efficacy <strong>of</strong> obesity in metastatic colorectal cancer patients<br />
treated with bevacizumab-based chemotherapy<br />
combinations: A Turkish <strong>Oncology</strong> Group Study<br />
M. Artac 1 , L. Korkmaz 2 , H. Coskun 3 , F. Dane 4 , B. Karabulut 5 , M. Karaagăç 2 ,<br />
D. Çabuk 6 , S. Karabulut 7 , F. Aykan 7 , H. Doruk 8 ,N.Avci 9 , S. Turhal 10<br />
1 Medical <strong>Oncology</strong>, Necmettin Erbakan University Meram Medical Faculty, Konya,<br />
Turkey, 2 Medical <strong>Oncology</strong>, Necmettin Erbakan University, Konya, Turkey,<br />
3 Medical <strong>Oncology</strong>, Akdeniz University Medical <strong>Oncology</strong>, Antalya, Turkey,<br />
4 Medical <strong>Oncology</strong>, Marmara University Hospital, Istanbul, Turkey, 5 Tulay Aktas<br />
<strong>Oncology</strong>, Ege University Medical School, Izmir, Turkey, 6 Medical <strong>Oncology</strong>,<br />
Kocaeli University, Kocaeli, Turkey, 7 Medical <strong>Oncology</strong>, Istanbul University Institute<br />
<strong>of</strong> <strong>Oncology</strong>, Istanbul, Turkey, 8 Medical <strong>Oncology</strong>, Acibadem Bursa Hospital,<br />
Bursa, Turkey, 9 Medical <strong>Oncology</strong>, Ali Osman Sonmez <strong>Oncology</strong> Hospital Medical<br />
<strong>Oncology</strong> & Hematology Clinic, Bursa, Turkey, 10 Medical <strong>Oncology</strong>, Anadolu<br />
Health Center, Istanbul, Turkey<br />
Background: Obesity is known as a carcinogenic factor for colorectal cancer.<br />
Interestingly, obesity is associated with increased VEGF levels. Therefore, we aimed to<br />
investigate whether obesity affects survival in metastatic colorectal cancer (mCRC)<br />
patients who treated with bevacizumab combined chemotherapies.<br />
Methods: Five hundred and sixty three patients with mCRC who received first-line<br />
chemotherapy combination with bevacizumab were studied retrospectively. Patients<br />
were grouped as obese (BMI levels > 30) and non-obese (BMI levels < 30).<br />
Progression-free survival (PFS) and overall survival (OS) were analyzed. Additionally,<br />
the efficacy <strong>of</strong> obesity was evaluated with the other prognostic factors in univariate and<br />
multivariate cox proportional hazard models.<br />
Results: The median age <strong>of</strong> all the patients was 59 years. Non-obese group had longer<br />
PFS than obese group (P = 0.030). 2-year survival rate <strong>of</strong> non-obese group was also<br />
significantly higher (P = 0.036). In the univariate cox regression analysis ECOG ≤1,<br />
male gender, and non-obesity were the positive factors for PFS (HRs: 0.46, 0.81, and<br />
0.75, respectively). In the multivariate analysis ECOG performance status was found as<br />
the most powerful prognostic factor for PFS (HR: 0.47, P < 0.001). Additionally, in<br />
Kras-wild type patients, obese group (n = 37) had longer PFS than non-obese group<br />
(n = 163), (10.1 months and 8.1 months, respectively, P = 0.010).<br />
Table: 534P Characteristics and demographics<br />
BMI < 30 BMI > 30 Total<br />
n (%) 474 (84%) 89 (16%) 563 (100%)<br />
Age (years) 58 ± 12 58 ± 10 58 ± 12<br />
ECOG ≤1>1 402 (85%) 72 (15%) 71 (80%) 18 (20%) 473 (84%) 90 (16%)<br />
Female 175(37%) 53 (60%) 228 (40%)<br />
Male 299 (63%) 36 (40%) 335 (60%)<br />
Metastases<br />
Liver 215 (46%) 38 (43%) 253 (45%)<br />
Multiple The 147 (31%) 110 (23%) 25 (28%) 26 (29%) 172 (31%) 136 (24%)<br />
other sites<br />
Treatments<br />
FI + BEV 308 (65%) 52 (58%) 360 (64%)<br />
FO + BEV 142 (30%) 33 (37%) 175 (31%)<br />
F + BEV 24 (5%) 4 (5%) 28 (5%)<br />
Kras status<br />
Wild 163 (81.5%) 37 (18.5%) 200 (100%)<br />
Mutant 157 (85.8%) 26 (14.2%) 175 (31%)<br />
Conclusions: Efficacy <strong>of</strong> bevacizumab may be lower in obese patients. Prospectively<br />
designed studies for obese patients should be done to recommend the efficacy <strong>of</strong><br />
bevacuzimab in mCRC.<br />
Legal entity responsible for the study: N/A<br />
Funding: Turkish <strong>Oncology</strong> Group (TOG)<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
535P<br />
Concordance <strong>of</strong> KRAS, NRAS and BRAF status between<br />
primary colorectal tumors and paired metastasis (mts)<br />
J. Alcaide-Garcia 1 , T. Pereda 1 , E. Perez-Ruiz 2 , F. Rivas 2 , I. Zarcos Pedrinaci 3 ,<br />
R. Villatoro 2 , D. Perez 2 , A. Rueda 4<br />
1 <strong>Oncology</strong>, Hospital Costa del Sol, Marbella, Spain, 2 Medical <strong>Oncology</strong>, Hospital<br />
Costa del Sol, Marbella, Spain, 3 <strong>Oncology</strong>, Hospital Costa del Sol, Malaga, Spain,<br />
4 Medical <strong>Oncology</strong>, Hospital Costa del Sol, Malaga, Spain<br />
Background: It is well established that patients with RAS-mutant colorectal cancer<br />
(CRC) are resistant to anti-EGFR therapies and it is suggested that BRAF mutations<br />
may also have a predictive value. However, it is not known which is the most suitable<br />
specimen for mutation testing. Although it has been postulated a high concordance <strong>of</strong><br />
KRAS status between primary tumors (pt) and liver mts, there are contradictory<br />
results. In this study we investigated the concordance <strong>of</strong> KRAS, NRAS and BRAF<br />
between pt and matched hepatic and extrahepatic mts.<br />
Methods: We examined 31 pairs <strong>of</strong> pt and mts (liver, lung, peritoneum, lymph nodes,<br />
ovary and pleura samples) <strong>of</strong> patients with CRC treated at Costa del Sol Hospital. DNA<br />
was extracted from formalin-fixed, paraffin-embedded specimens, using the DNA<br />
Tissue Kit (Qiagen). After verifying the quality <strong>of</strong> DNA, CLART CMA KRAS-BRAF<br />
Kit and Therascreen Kit or Therascreen KRAS RGQ PCR Kit, exon 15 BRAF<br />
sequencing and Therascreen Pyro Kit were employed to detect mutations in KRAS,<br />
NRAS and BRAF. To evaluate concordance differences, we used Fisher Test for<br />
independent cualitative variables, and U Mann-Whitney Test for cuantitative variables.<br />
Results: Concordance rate <strong>of</strong> KRAS, NRAS and BRAF mutational status between pt<br />
and mts <strong>of</strong> any location was 79.1% (95% Confidence Interval: CI 65.7-92.4).<br />
Table: 535P<br />
Pt-Liver mts Pt- Extrahepatic mts Pt-Any location mts<br />
KRAS 78.9% (15/19) 72.7% (8/11) 76.7% (95% CI 59.9-93.5)<br />
NRAS 66.7% (4/6) 71.4% (5/7) 71.4% (95% CI 29.0-96.3)<br />
BRAF 100% (5/5) 100% (1/1) 100% (95% CI 54.1-100)<br />
We found that discordant pairs <strong>of</strong> pt-liver mts for KRAS showed more frequently a<br />
percentage <strong>of</strong> tumor cells in pt samples
abstracts<br />
low SII and NLR,sufficient lymph node sampling (more than 12 lymph nodes<br />
dissection) may prevent unnecessary adjuvant chemotherapy in low risk patients. Their<br />
clinical utility should be validated in further studies.<br />
Legal entity responsible for the study: None<br />
Funding: None<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
537P<br />
Circulating microRNA-126 and epidermal growth factor-like<br />
domain 7 protein predict recurrence <strong>of</strong> colon cancer in<br />
patients treated with neoadjuvant chemotherapy<br />
T.F. Hansen 1 , A.L. Carlsen 2 , J.T. Tanassi 2 , N.H.H. Hegaard 2 , F.O. Larsen 3 ,<br />
F.B. Soerensen 4 , L.H. Jensen 1 , A. Jakobsen 1<br />
1 <strong>Oncology</strong>, Danish Colorectal Cancer Center South, Vejle, Denmark,<br />
2 Autoimmunology and Biomarkers, Statens Serum Institut, Copenhagen,<br />
Denmark, 3 Department <strong>of</strong> <strong>Oncology</strong>, Herlev and Gent<strong>of</strong>te Hospital, Herlev,<br />
Denmark, 4 Clinical Pathology, Danish Colorectal Cancer Center South, Vejle,<br />
Denmark<br />
Background: Neoadjuvant chemotherapy represents a new treatment approach for<br />
patients with locally advanced colon cancer. The aim <strong>of</strong> this study was to analyze the<br />
prognostic impact <strong>of</strong> circulating microRNA-126 (miRNA-126) and epidermal growth<br />
factor-like domain 7 (EGFL7) in patients with locally advanced colon cancer treated<br />
with neoadjuvant chemotherapy.<br />
Methods: All 71 patients from a phase II trial were included. Sampling <strong>of</strong> peripheral<br />
blood was carried out before initiation <strong>of</strong> neoadjuvant chemotherapy, before operation,<br />
and at the first post-operative control. The diagnostic biopsy and the resected tumour<br />
were sampled for tissue analyses. Circulating (cir-) EGFL7 was analysed in serum by<br />
enzyme-linked immunosorbent assay (ELISA) while cir-miRNA-126 was analysed by<br />
real-time qPCR based on plasma samples. The tissue expression <strong>of</strong> miRNA-126 was<br />
assessed using in situ hybridization and image guided analyses.<br />
Results: After a median follow-up <strong>of</strong> 4.0 years, disease had recurred in 14 patients. The<br />
5-year disease free survival (DFS) and overall survival (OS) rates were 80% and 85%,<br />
respectively. Overall, cir-miRNA-126 and cir-EGFL7 decreased during neoadjuvant<br />
chemotherapy. Patients with disease recurrence were characterized by a significantly<br />
lower miRNA-126 expression in the diagnostic biopsy (p = 0.049), and significantly<br />
lower levels <strong>of</strong> cir-miRNA-126 at baseline (p = 0.020), operation (p = 0.042), and<br />
control (p = 0.001), compared to patients without disease recurrence. High levels <strong>of</strong><br />
cir-EGFL7, assessed before operation, were associated with a higher recurrence rate<br />
(p = 0.019). These differences translated into significant differences in DFS and OS as<br />
well. A 5-year OS rate <strong>of</strong> 96% was demonstrated for patients with cir-miRNA-126<br />
levels above the median.<br />
Conclusions: Low levels <strong>of</strong> miRNA-126 and high levels <strong>of</strong> EGFL7 seem to correlate<br />
with disease recurrence in patients with locally advanced colon cancer treated with<br />
neoadjuvant chemotherapy. These results are in accordance with previous studies in<br />
the adjuvant and metastatic setting collectively arguing for a clinical importance <strong>of</strong><br />
these proangiogenic factors.<br />
Clinical trial identification: ClinicalTrials.gov Identifier:NCT01108107<br />
Legal entity responsible for the study: Department <strong>of</strong> <strong>Oncology</strong>, Vejle Hospital<br />
Funding: Department <strong>of</strong> <strong>Oncology</strong>, Vejle Hospital<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
538P<br />
The genomic complexity <strong>of</strong> metastatic colorectal tumors by<br />
age, gender, race, and location <strong>of</strong> primary tumor using<br />
next-generation sequencing<br />
J. Gong, M. Sy, M. Fakih<br />
Medical <strong>Oncology</strong> and Experimental Therapuetics, City <strong>of</strong> Hope, Duarte, CA, USA<br />
Background: Recent molecular pr<strong>of</strong>iling has identified a growing number <strong>of</strong> mutations<br />
that are considered targetable in metastatic colorectal cancer (mCRC). We aimed to<br />
explore the genomic complexity <strong>of</strong> metastatic colorectal tumors by patient factors such<br />
as age, gender, race, and site <strong>of</strong> primary tumor using next-generation sequencing<br />
(NGS).<br />
Methods: We conducted a retrospective study based on comprehensive genomic<br />
pr<strong>of</strong>iling <strong>of</strong> tumors from patients (pts) with predominantly mCRC at our single<br />
institution using NGS via FoundationOne. All classes <strong>of</strong> genomic alterations were<br />
identified and their frequencies analyzed according to age (
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
540P<br />
Prospective evaluation <strong>of</strong> BRAF, PI3K and PTEN as predictive<br />
and prognostic biomarkers in first-line advanced KRAS<br />
wild-type colorectal cancer treated with FOLFOX or FOLFIRI<br />
plus bi-weekly cetuximab. GEMCAD 10-02<br />
V. Alonso 1 , P. Escudero Emperador 2 , M. Mendez Urena 3 , J. Gallego 4 ,J.<br />
R. Rodriguez 5 , J. Fernández 6 , A. Salud 7 , E. Falcó 8 , H. Manzano 9 , M. Zanui 10 ,<br />
M. Gil 11 , U. Bohn Sarmiento 12 , C. Fernández Martos 13 , V. Calderero 14 ,A.<br />
I. Ferrer 15 , M. Cuatrecasas 16 ,F.Rojo 17 , J. Feliu 18 , J. Maurel 19 , X. García-Albéniz 20<br />
1 Medical <strong>Oncology</strong>, Hospital Miguel Servet, Zaragoza, Spain, 2 Medical <strong>Oncology</strong>,<br />
Hospital Clinico Universitario Lozano Blesa, Zaragoza, Spain, 3 Medical <strong>Oncology</strong>,<br />
Hospital Universitario de Móstoles, Madrid, Spain, 4 Medical <strong>Oncology</strong>, Hospital<br />
General Universitario de Elche, Elche, Spain, 5 Medical <strong>Oncology</strong>, Hospital Infanta<br />
Cristina, Madrid, Spain, 6 Medical <strong>Oncology</strong>, Hospital Mutua de Terrassa, Terrassa,<br />
Spain, 7 Medical <strong>Oncology</strong>, Hospital Universitario Arnau Vilanova de Lleida, Lerida,<br />
Spain, 8 Medical <strong>Oncology</strong>, Hospital Son Llatzer, Palma de Mallorca, Spain,<br />
9 Medical <strong>Oncology</strong>, Hospital Universitario Son Espases, Palma de Mallorca,<br />
Spain, 10 Medical <strong>Oncology</strong>, Hospital de Mataro Consorcio Sanitario del Maresme,<br />
Mataro, Spain, 11 Medical <strong>Oncology</strong>, Hospital de Sagunto, Valencia, Spain,<br />
12 Medical <strong>Oncology</strong>, Hospital de Gran Canaria Dr. Negrin, Las Palmas, Spain,<br />
13 Medical <strong>Oncology</strong>, Fundación Instituto Valenciano de Oncología, Valencia,<br />
Spain, 14 Medical <strong>Oncology</strong>, Hospital de Barbastro, Barbastro, Spain, 15 Medical<br />
<strong>Oncology</strong>, Complejo Hospitalario Universitario de Albacete, Albacete, Spain,<br />
16 Pathological Anatomy, Hospital Clinic y Provincial de Barcelona, Barcelona,<br />
Spain, 17 Pathological Anatomy, University Hospital "Fundacion Jimenez Diaz",<br />
Madrid, Spain, 18 Medical <strong>Oncology</strong>, Hospital Universitario La Paz, Madrid, Spain,<br />
19 Medical <strong>Oncology</strong>, Hospital Clinic y Provincial de Barcelona, Barcelona, Spain,<br />
20 Department <strong>of</strong> Epidemiology, T. H. Chan Harvard School <strong>of</strong> Public Health,<br />
Boston, MA, USA<br />
Background: In metastatic colorectal cancer (mCRC), mutation testing for KRAS exon<br />
2 and recently exon 2, 3 and 4 KRAS and NRAS is widely implemented to select<br />
patients, sensitive to anti-EGFR therapies, i.e. cetuximab. The added predictive value <strong>of</strong><br />
BRAF-ERK and PI3K- AKT signaling pathways remains controversial, mostly due to<br />
the retrospective nature and second-third lines studies.<br />
Methods: We conducted a biomarker-evaluation phase II trial (ClinicalTrials.gov id:<br />
NCT01276379). We included 221 KRAS exon 2 WT patients and evaluated whole<br />
KRAS and NRAS mutations by pyrosequencing, BRAF and PI3K mutations by<br />
RT-qPCR and PTEN expression by immunohistochemistry. We followed patients<br />
every 3 months with abdominopelvic CT scan and clinical examination. We analyzed<br />
progression-free survival (PFS, time from inclusion to progression or death) and<br />
overall survival (OS, time from inclusion to death) in patients with BRAF wild-type<br />
(WT) vs. BRAF mutant and in patients with increased PI3K pathway activation (PI3K<br />
mutant or loss <strong>of</strong> PTEN expression) vs. low PI3K pathway activation (PI3K WT and<br />
preserved PTEN expression).<br />
Results: BRAF mutational status was evaluable in 207 patients (20 mutated) and PI3K<br />
pathway activation status was evaluable in 193 (108 PI3K mutant or loss <strong>of</strong> PTEN<br />
expression). Patients were treated either with FOLFOX-Cetuximab (53%) or with<br />
FOLFIRI-Cetuximab (47%). Median follow-up was 24 (range 0.3-54) months. Patients<br />
had a median PFS <strong>of</strong> 11.4 (95% 9.8-13.2) months if BRAF WT and <strong>of</strong> 6.1 (3.5-8.3)<br />
months if BRAF mutant (adjusted HR = 2.00, 95% CI 1.16-3.46). Median OS for BRAF<br />
WT patients was 34.4 (95% 26.8-43.1) months and 9.7 (7.2-23.5) months for BRAF<br />
mutant patients (adjusted HR = 3.21, 95% CI 1.80-5.74). PI3K pathway activation<br />
status did not discriminate neither PFS (adjusted HR 0.83, 95% CI 0.61-1.13) nor OS<br />
(adjusted HR 1.24, 95% CI 0.80-1.91).<br />
Conclusions: BRAF mutational status is both predictive and prognostic in patients<br />
with advanced KRAS WT colorectal cancer receiving Cetuximab-containing regimes as<br />
first line <strong>of</strong> therapy. PI3K pathway activation is not associated with Cetuximab<br />
resistance.<br />
Clinical trial identification: EudraCT 2010-019236-12<br />
Legal entity responsible for the study: Grupo Español Multidisciplinar en Cáncer<br />
Digestivo (GEMCAD)<br />
Funding: Grupo Español Multidisciplinar en Cáncer Digestivo (GEMCAD)<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
541P<br />
Effects <strong>of</strong> beyond KRAS mutations on the efficacy <strong>of</strong><br />
cetuximab plus chemotherapy for patients with unresectable<br />
colorectal liver-limited metastases (BELIEF): a retrospective<br />
biomarker analysis from a Chinese trial<br />
J. Xu 1 ,L.Ren 1 ,Y.Wei 1 , P. Zheng 1 ,L.Ye 2 , Q. Feng 1 , Q. Lin 1 , D. Zhu 1 , W. Chang 1 ,<br />
M. Ji 1<br />
1 Department <strong>of</strong> General Surgery, Zhongshan Hospital, Fudan University,<br />
Shanghai, China, 2 Department <strong>of</strong> Oncological Surgery, 1st Affiliated Hospital <strong>of</strong><br />
Wenzhou Medical College, Wenzhou, China<br />
Background: To identify predictive biomarkers for the efficacy <strong>of</strong> cetuximab.<br />
Methods: 247 patients were recruited, including ITT patients <strong>of</strong> previous RCT<br />
(NCT01564810) (primary group) and a following cohort with same inclusion criteria<br />
<strong>of</strong> previous RCT (validation group). The DNA samples were sequenced for single<br />
nucleotide polymorphisms (SNPs) <strong>of</strong> biomarkers including the well-known "new" RAS<br />
(KRAS exons 3 and 4; NRAS exons 2, 3 and 4) and other 108 genes, using Ion Torrent<br />
Personal Genome Machine (PGM) sequencing. A 5% cut<strong>of</strong>f value was used to<br />
determine mutations.<br />
Results: In primary group, interaction tests between biomarker status and treatment<br />
effect were performed for objective response rate, progression-free survival and overall<br />
survival. Nine potential predictive biomarkers were identified, including FGFR3,<br />
GNAS, FLT3, NOTCH1, RBMXL3, ERBB2, MDN1, PTCH1 and LY6G6D. With RAS<br />
wild-type patients in primary group, we built a predictive model for the objective<br />
response to cetuximab plus chemotherapy with Logistic regression, employing 9<br />
identified biomarkers (wild-type vs. mutant) and treatment (cetuximab plus<br />
chemotherapy vs. chemotherapy) as variables. Our predictive model classified patients<br />
in primary group very well (AUC = 0.81, 95%CI 0.72-0.90, P < 0.001). According to<br />
Youden’s index, 0.3666 was defined as cut<strong>of</strong>f value. Patients with predictive value<br />
higher than 0.3666 had better ORR (P = 0.001), PFS (P = 0.001) and OS (P = 0.009)<br />
than that with predictive value lower than 0.3666. For RAS wild-type patients in<br />
validation group, the predictive model also performed well (AUC = 0.79, 95%CI<br />
0.71-0.87, P < 0.001). Patients with predictive value higher than 0.3666 also achieved<br />
better ORR (P = 0.04), PFS (P < 0.001). Thus, according to our model, patients with<br />
predictive value higher than 0.3666 were recommend to receive cetuximab plus<br />
chemotherapy.<br />
Conclusions: Apart from RAS mutations, several new biomarkers were firstly<br />
correlated with efficacy <strong>of</strong> cetuximab. and our predictive model including these<br />
biomarkers were useful to further tailor the administration <strong>of</strong> cetuximab, but need<br />
further validation.<br />
Clinical trial identification: N/A<br />
Legal entity responsible for the study: Zhongshan Hospital, Fudan University<br />
Funding: Merck KGaA<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
542P<br />
MicroRNA-31 overexpression is able to predict pathological<br />
response and outcome in locally advanced rectal cancer<br />
C. Carames 1 , I. Cristobal 2 , P. Minguez 2 , V. Moreno 1 , A. Leon 1 ,<br />
H. Callata-Carhuapoma 1 , J.I. Martin 1 , M. Domine 1 , R. Hernandez 1 , M. Pedregal 1 ,<br />
I. Martinez 1 , I. Moreno 1 , A. Correa 1 , F. Rojo 3 , J.M. García-Foncillas López 1<br />
1 Oncohealth Institute, University Hospital "Fundacion Jimenez Diaz", Madrid,<br />
Spain, 2 Translational <strong>Oncology</strong>-Oncohealth Institute, University Hospital<br />
"Fundacion Jimenez Diaz", Madrid, Spain, 3 Pathology, University Hospital<br />
"Fundacion Jimenez Diaz", Madrid, Spain<br />
Background: The treatment <strong>of</strong> choice for locally advanced rectal cancer is preoperative<br />
chemoradiotherapy (CRT). Despite around half <strong>of</strong> patients do not respond, suffer<br />
unnecessary toxicities and surgery delays, there are no biomarkers to guide<br />
preoperative CRT outcome. MicroRNA-31 (miR-31) has been related to acquisition <strong>of</strong><br />
5-fluorouracil resistance in rectal cancer however its potential predictive value <strong>of</strong><br />
response to preoperative CRT in locally advanced rectal cancer remains unknown.<br />
Methods: Eight-two patients diagnosed with locally advanced rectal cancer who were<br />
preoperatively treated with 5-fluorouracil based CRT were selected for this study. The<br />
miR-31 expression was quantified in formalin-fixed paraffin-embedded biopsies from<br />
this cohort previous to CRT therapy administration and the results obtained were<br />
correlated with clinical and molecular characteristics, pathological response and<br />
outcome.<br />
Results: Overexpression <strong>of</strong> miR-31 was found in 34.2% <strong>of</strong> the cases. Its overexpression<br />
significantly predicted poor pathological response (p = 0.018) and worse overall<br />
survival (OS) (p = 0.008). Multivariate analysis confirmed the clinical significance <strong>of</strong><br />
miR-31 in determining pathological response to neoadjuvant CRT as well as OS.<br />
Conclusions: miR-31 quantification emerges as a novel valuable clinical tool to predict<br />
both pathological response and outcome in locally advanced rectal cancer patients.<br />
Legal entity responsible for the study: None<br />
Funding: Fundación Jimenez Diaz<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
543P<br />
abstracts<br />
Organ preservation using contact radiotherapy for early rectal<br />
cancer: outcomes <strong>of</strong> patients treated at a single centre in the<br />
United Kingdom<br />
A.S. Dhadda 1 , A. Martin 1 , G. Solon 2 , I.A. Hunter 2<br />
1 Castle Hill Hospital, Queen’s Centre for <strong>Oncology</strong> & Haematology, Kingston Upon<br />
Hull, UK, 2 Colorectal Surgery, Castle Hill Hospital, Kingston Upon Hull, UK<br />
Background: Contact radiotherapy for early rectal cancer utilises 50KV x-rays to treat<br />
rectal cancers under direct vision as described by Papillon (1). We present data <strong>of</strong> a<br />
series <strong>of</strong> patients treated in a modern era at our centre in Hull, England, UK with<br />
prospective follow up.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw370 | vi183
abstracts<br />
Methods: All patients were treated at the Queen’s Centre for <strong>Oncology</strong>, Hull, United<br />
Kingdom between September 2011 and September 2015. Patients were worked up with<br />
biopsy, MRI <strong>of</strong> liver and pelvis, CT Chest and endorectal US. Indications for contact<br />
radiotherapy are shown in table 1. Patients were <strong>of</strong>fered either 110Gy in 4 fractions to<br />
the luminal tumour or 90Gy in 3 fractions with external beam chemo/radiotherapy to<br />
the pelvis dependent on the risk <strong>of</strong> mesorectal lymphadenopathy. Follow up consisted<br />
<strong>of</strong> 3 monthly flexible sigmoidoscopy and MRI liver/pelvis and 12 monthly CT Chest.<br />
Median follow-up was 24 months (range 1-54 months).<br />
Results: Between September 2011 and September 2015 a total <strong>of</strong> 43 patients were<br />
treated with contact radiotherapy without any surgical excision. Demographics <strong>of</strong><br />
patients are shown in table 2. Median age was 78 years (range 50-94 years). 24 patients<br />
(57%) were considered high risk for surgery. Mortality from the contact radiotherapy<br />
procedure was 0%. Functional outcomes as investigated by the Lower Anterior<br />
Resection Syndrome (LARS) score were good with 68% having no LARS and 30 % a<br />
major LARS (2). There were 5 local recurrences (12%) <strong>of</strong> which 2 received successful<br />
surgical salvage. Distant recurrences were found in 4 patients (9%). Median time to<br />
recurrence was 12 months (range 3-14 months). Disease free and overall survival<br />
curves are shown in figs 1 and 2. Local recurrence free survival was 88%, disease free<br />
survival 86% and overall survival 88% with a median follow up <strong>of</strong> 24 months.<br />
Estimated 30 day surgical mortality for this cohort with radical surgery was 12% (3).<br />
Conclusions: Contact radiotherapy for early rectal cancer is a safe, well tolerated<br />
outpatient procedure allowing organ preservation with excellent early results on<br />
oncological and functional outcomes from our centre. For elderly patients with<br />
co-morbidities and suitable rectal cancers this should be considered a standard <strong>of</strong> care.<br />
Legal entity responsible for the study: Hull & East Yorkshire NHS Trust<br />
Funding: Hull & East Yorkshire NHS Trust<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
544P<br />
Capecitabine (cape) dosing using skeletal muscle index (SMI)<br />
compared to body surface area (BSA)<br />
J. Sun 1 , A. Ilich 1 , C. Kim 2 , G. Wong 1 , S. Ghosh 1 , J. Spratlin 1 , K. Mulder 1 ,<br />
M. Danilak 1 , C. Chambers 1 ,M.Sawyer 1<br />
1 Medical <strong>Oncology</strong>, University <strong>of</strong> Alberta Cross Cancer Institute, Edmonton, AB,<br />
Canada, 2 Medical <strong>Oncology</strong>, CancerCare Manitoba MacCharles, Winnipeg, MB,<br />
Canada<br />
Background: Cape doses used to treat colorectal (CRC) and breast cancer (BC) are<br />
calculated using BSA. Cape dose is 1250 mg/m 2 in CRC and 1000 mg/m 2 in BC. Using<br />
BSA to calculate cape dose does not consider body composition. We hypothesize that<br />
differences in cape doses between CRC and BC patients (pts) is due to body<br />
composition differences between males (M) and females (F), not cancer type.<br />
Furthermore, low skeletal muscle density (SMD) is prognostic <strong>of</strong> poor survival in<br />
advanced cancers. As a secondary objective, we set out to determine if SMD was<br />
prognostic <strong>of</strong> outcomes in early stage CRC.<br />
Methods: We performed a retrospective study <strong>of</strong> all pts diagnosed with early stage<br />
CRC treated with adjuvant cape from 2008-2012. Data was collected on demographics<br />
and cape doses at cycles 1 and 3. SMI and SMD were calculated using baseline CT<br />
scans.<br />
Results: 183 pts (101 M, 82 F) were identified. F received higher starting cape doses<br />
compared to M based on SMI. Mean cape/SMI dose was 5107.4 mg/cm 2 /m 2 (SD<br />
1113.8) for F compared to 4711.9 mg/cm 2 /m 2 (SD 870.6) for M (p = 0.009). At cycle 3,<br />
F still had higher doses <strong>of</strong> 3875.1 mg/cm 2 /m 2 (SD 1663.5), but did not differ<br />
statistically from M pts at 3691.6 mg/cm 2 /m 2 (SD 1629.5) (p = 0.5). Median recurrence<br />
free survival (RFS) for low SMD pts compared to high SMD pts was 72.8 vs 76.9<br />
months (hazard ratio [HR] 1.80; p = 0.06). Patients with lower SMD were at higher risk<br />
<strong>of</strong> death (HR 2.81; p = 0.05); median overall survival was not reached.<br />
Conclusions: F received higher cape doses/SMI than M at the CRC 1250 mg/m 2 dose.<br />
After adjusting cape doses for DLTs, M and F CRC pts received the same cape dose/<br />
SMI. Our results suggest differences between CRC and BC cape dosing may be a<br />
consequence <strong>of</strong> body composition differences between M and F pts. SMI may be more<br />
useful than BSA when calculating cape doses. Our study showed low SMD was<br />
prognostic for OS probability and trended towards significance for RFS in adjuvant<br />
CRC pts.<br />
Legal entity responsible for the study: N/A<br />
Funding: N/A<br />
Disclosure: J. Spratlin: Conducted research project funded by Roche in the past 2 years.<br />
All other authors have declared no conflicts <strong>of</strong> interest.<br />
545P<br />
Geriatric assessment predicts survival and competing<br />
mortality in colorectal cancer elderly patients. Can it help in<br />
adjuvant therapy decision?<br />
M. Antonio 1 , J. Saldaña 1 , A. Carmona-Bayonas 2 , V. Navarro 3 , C. Tebe 4 ,<br />
F. Formiga 5 , R. Salazar 1 , J. Borras 6<br />
1 Medical <strong>Oncology</strong>, Institut Catala de Oncologia, L’Hospitalet de Llobregat,<br />
Barcelona, Spain, 2 Medical <strong>Oncology</strong>, Hospital Universitario Morales Meseguer,<br />
Murcia, Spain, 3 Clinical Research Unit, Institut Català d’Oncologia Hospital Duran i<br />
Reynals, Barcelona, Spain, 4 Biostatistics, IDIBELL, L’Hospitalet de Llobregat,<br />
Barcelona, Spain, 5 Internal Medicine, Bellvitge Hospital, L’Hospitalet de Llobregat,<br />
Barcelona, Spain, 6 Cancer Strategy, Institut Català d’Oncologia Hospital Duran i<br />
Reynals, Barcelona, Spain<br />
Background: The selection <strong>of</strong> elderly patients with colorectal cancer (CCR) for<br />
adjuvant therapy remains a challenge. The main critical issue is to estimate if the<br />
patient risk <strong>of</strong> dying from non-cancer-related (NCR) causes prelude cancer events.The<br />
aim <strong>of</strong> this paper is to evaluate whether an abbreviated Comprehensive Geriatric<br />
Assessment (aCGA) could predict survival and cancer mortality in high-risk resected<br />
CCR elderly patients candidates to adjuvant therapy.<br />
Methods: 195 consecutive patients aged ≥75 with high-risk stage II and III CCR were<br />
prospectively enrolled. All patients underwent aCGA, which included comorbidity,<br />
polypharmacy, functional status, geriatric syndromes, mood, cognition and social<br />
support. According to aCGA results, patients were classified as: “fit” (F), “medium fit”<br />
(MF) and “unfit” (UF) to receive standard therapy, adjusted treatment and best support<br />
care, respectively. Patients were followed-up for at least 6 months or until death, and<br />
toxicity, survival and the cause <strong>of</strong> death were recorded. A competing risk approach was<br />
used to evaluated causes <strong>of</strong> death by oncogeriatric classification.<br />
Results: 85 (44%) patients were classified as F, 56 (29%) as MF and 54 (27%) as UF.<br />
The 5-year survival rate was 74%, 52% and 27 % in the F, MF and UF, respectively. At<br />
the end <strong>of</strong> the follow-up, 61 (31%) patients had died (14 F, 16 MF and 31UF). The<br />
causes <strong>of</strong> death were cancer progression (CP), NCR, and unknown reason, in 54%, 46%<br />
and 1%, respectively; there were not toxicity-related deaths Overall population was<br />
more likely to die <strong>of</strong> CP rather than <strong>of</strong> NCR cause. However, stratifying by<br />
oncogeriatric categories, at the end <strong>of</strong> 5 year following surgery, 42% F, 52% MF and<br />
15% UF patients died because <strong>of</strong> CP, while
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
were used. Additionally, a subgroup analysis excluding patients with ECOG ≥ 2at<br />
baseline was performed.<br />
Results: Median TD (95% CI) was 5.5m (5.1-6.2) in the total safety population. In<br />
univariate analysis, ECOG > 1, which was only 14.6% <strong>of</strong> patients, and MNA were the<br />
only baseline parameters significantly associated with TD (p = 0.0006 and p = 0.0162,<br />
respectively), while G8 showed a trend (p = 0.0607). Significant correlations were<br />
observed for PFS vs. ECOG (p < 0.0001), MNA (p = 0.0001) and G8 (p = 0.0208) and<br />
for severe toxicity vs. ECOG (p < 0.0001) and G8 (p = 0.005). When lowering the G8<br />
cut-<strong>of</strong>f to 12 (i.e. median value), both TD and PFS were significantly associated with<br />
G8 (p = 0.0093 and p = 0.0002, respectively). No significant correlation was observed<br />
for fTRST. Multivariate analyses show significant correlations for ECOG vs. TD and<br />
PFS (p = 0.0047 and p < 0.0001, respectively) and for MNA versus PFS (p = 0.0007).<br />
The ECOG was no longer significant when excluding ECOG ≥ 2 patients.<br />
Conclusions: In older mCRC patients, ECOG is a strong predictive marker for<br />
treatment duration and PFS, mainly driven by patients with ECOG ≥ 2. In the large<br />
group <strong>of</strong> patients with ECOG ≤ 1, MNA is a predictive marker for PFS.<br />
Clinical trial identification: NCT01676922<br />
Legal entity responsible for the study: Roche NV/SA Belgium<br />
Funding: Roche NV/SA Belgium<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
547P<br />
Updated report: A randomized, double-blind,<br />
placebo-controlled phase II study <strong>of</strong> prophylactic<br />
dexamethasone (dex) therapy for fatigue and malaise due to<br />
regorafenib in patient (pts) with metastatic colorectal cancer<br />
(mCRC): (KSCC1402/HGCSG1402)<br />
S. Yuki 1 , Y. Komatsu 2 , H. Satake 3 , Y. Miyamoto 4 , H. Tanioka 5 , A. Tsuji 3 ,<br />
M. Asayama 6 , T. Shiraishi 7 , M. Kotaka 8 , A. Makiyama 9 , T. Kashiwada 10 ,<br />
N. Takeuchi 11 , M. Shimokawa 12 , H. Saeki 13 , E. Oki 13 ,Y.Emi 14 , H. Baba 4 ,<br />
Y. Maehara 13<br />
1 Gastroenterology and Hepatology, Hokkaido University Hospital, Sapporo,<br />
Japan, 2 Cancer Center, Hokkaido University Hospital, Sapporo, Japan, 3 Medical<br />
<strong>Oncology</strong>, Kobe City Medical Center General Hospital, Kobe, Japan,<br />
4 Gastroenterological Surgery, Graduate School <strong>of</strong> Medical Sciences, Kumamoto<br />
University, Kumamoto, Japan, 5 Medical <strong>Oncology</strong>, Okayama Rosai Hospital,<br />
Okayama, Japan, 6 Gastroenterology, Saitama Cancer Center, Saitama, Japan,<br />
7 Clinical <strong>Oncology</strong>, Matsuyama Red Cross Hospital, Matsuyama, Japan,<br />
8 Gastrointestinal Cancer Center, Sano Hospital, Kobe, Japan, 9 Hematology and<br />
<strong>Oncology</strong>, Japan Community Health care Organization Kyushu Hospital,<br />
Kitakyushu, Japan, 10 Hematology, Respiratory Medicine and <strong>Oncology</strong>, Saga<br />
University Cancer Center, Saga, Japan, 11 Medical <strong>Oncology</strong>, Ina Central Hospital,<br />
Ina, Japan, 12 Clinical Research Institute, Cancer Biostatistics Laboratory, National<br />
Kyushu Cancer Center, Fukuoka, Japan, 13 Surgery and Science, Graduate School<br />
<strong>of</strong> Medical Sciences, Kyushu University, Fukuoka, Japan, 14 Surgery, Saiseikai<br />
Fukuoka General Hospital, Fukuoka, Japan<br />
Background: Regorafenib (REG) is an oral multikinase inhibitor with survival benefit<br />
in salvage line therapy for metastatic colorectal cancer (mCRC); fatigue and malaise<br />
which are common adverse events (AEs) cause REG treatment discontinuation. Oral<br />
steroids are empirically used for treatment <strong>of</strong> cancer related fatigue, although there is<br />
only a few evidence. KSCC1402/HGCSG1402 is a phase II, randomized, double-blind,<br />
placebo-controlled study evaluating the prophylactic effects <strong>of</strong> oral dex on REG-related<br />
fatigue and malaise for pts with mCRC.<br />
Methods: Eligibility included mCRC, objective failure <strong>of</strong> standard therapy, ECOG<br />
performance status 0 or 1. ≤Grade 1 fatigue or malaise was allowed to be enrolled in<br />
this study. Pts were 1:1 randomly assigned to an oral steroids group (dex 2 mg/day, 4<br />
weeks) or a placebo (PLC) group with REG (160 mg/day, 3 weeks on/1 week <strong>of</strong>f). The<br />
protocol period was scheduled for first 28 days <strong>of</strong> REG treatment. The primary<br />
endpoint was incidence <strong>of</strong> fatigue or malaise (CTCAE ver. 4, all grades) during the<br />
protocol period. Secondary endpoints included patient-reported outcome (PRO)<br />
(CTCAE and the Brief Fatigue Inventory), AEs, relative dose intensity <strong>of</strong> REG.<br />
Response, progression free survival and overall survival were also evaluated as<br />
exploratory endpoints.<br />
Results: Between October 2014 and December 2015, 74 pts were enrolled and<br />
randomized (dex: 37, PLC: 37). Baseline characteristics were balanced between the two<br />
arms. The incidence <strong>of</strong> all grade <strong>of</strong> malaise and/or fatigue based on CTCAE for dex<br />
group was 55.6% and 58.3% for PLC group (p = 0.8119), that based on PRO CTCAE<br />
for dex was 47.2% and 58.3% for PLC (p = 0.3450). The incidence <strong>of</strong> ≥ grade 2 <strong>of</strong><br />
malaise and/or fatigue based on CTCAE for dex group was 19.4% and 38.9% for PLC<br />
group (p = 0.0695), that based on PRO for dex was 27.8% and 52.8% for PLC<br />
(p = 0.0306). The most common AE during protocol period was hand foot skin<br />
reaction in both groups (75.0 % vs. 86.1%).<br />
Conclusions: The KSCC1402/HGCSG1402 study provided promising results that<br />
improve the supportive therapy for pts with REG-related fatigue and malaise.<br />
(NCT02288078)<br />
Clinical trial identification: UMIN000015131 Release date: 2014/09/11;<br />
NCT02288078 Release date: 2014/10/28<br />
Legal entity responsible for the study: Clinical Research Support Center Kyushu<br />
Funding: Bayer Yakuhin, Ltd<br />
Disclosure: S. Yuki: Honoraria: Taiho Pharmaceutical, Merck Serono, Bristol-Myers<br />
Squibb, Takeda Pharmaceutical, Chugai Pharmaceutical, Bayer Yakuhin, Eli Lilly<br />
Japan. Y. Komatsu: Taiho Pharmaceutical, Yakult Honsha, Chugai Pharmaceutical,<br />
Merck Serono, Pfizer Japan, Novartis Pharma, Ono Pharmaceutical, Daiichi Sankyo,<br />
Takeda Pharmaceutical, Eli Lilly Japan, Novartis Pharma, Daiichi Sankyo, Kureha<br />
Corporation. E. Oki: Honoraria: Bayer Yakuhin. H. Baba: Honoraria: Bayer Yakuhin.<br />
All other authors have declared no conflicts <strong>of</strong> interest.<br />
548P<br />
Clinical activity <strong>of</strong> FOLFIRI plus cetuximab in elderly patients<br />
(pts) according to extended gene mutation status by next<br />
generation sequencing (NGS) in the CAPRI- GOIM trial<br />
E. Martinelli 1 , C. Cardone 1 , T. Troiani 1 , N. Normanno 2 , S. Pisconti 3 , R. Bordonaro 4 ,<br />
G. Francesco 5 , M. Biglietto 6 , C. Barone 7 , A.M. Rachiglio 8 , V. Montesarchio 9 ,<br />
G. Tonini 10 , S. Cinieri 11 , D. Rizzi 12 , A. Febbraro 13 , T.P. Latiano 14 , G. Modoni 15 ,<br />
C. Giuseppe 5 , E. Maiello 14 , F. Ciardiello 1<br />
1 Medical <strong>Oncology</strong>, AOU Seconda Università degli Studi di Napoli (AOU-SUN),<br />
Naples, Italy, 2 Dip. Biologia Cellulare e Bioterapie, Istituto Nazionale Tumori – I.R.C.<br />
C.S - Fondazione Pascale, Naples, Italy, 3 Medical <strong>Oncology</strong>, Ospedale Moscati,<br />
Taranto, Italy, 4 Medical <strong>Oncology</strong>, Azienda Ospedaliera ARNAS Garibaldi, Catania,<br />
Italy, 5 Medical <strong>Oncology</strong>, Istituto Tumori Giovanni Paolo II, Bari, Italy, 6 Medical<br />
<strong>Oncology</strong>, Azienda Ospedaliera di Rilievo Nazionale "Antonio Cardarelli"-AORN<br />
A. Cardarelli, Naples, Italy, 7 Medical <strong>Oncology</strong>, Università Cattolica del Sacro<br />
Cuore, Rome, Italy, 8 Laboratory <strong>of</strong> Pharmacogenomics, CROM, Istituto Nazionale<br />
Tumori “Fondazione G. Pascale”-IRCCS, Mercogliano, Italy, 9 Medical <strong>Oncology</strong>,<br />
Azienda Ospedaliera Dei Colli-Monaldi, Naples, Italy, 10 Medical <strong>Oncology</strong>,<br />
Campus Bio-Medico di Roma, Rome, Italy, 11 U.O.C. Oncologia, Ospedale<br />
A. Perrino, Brindisi, Italy, 12 GOIM, Bari, Italy, 13 Medical <strong>Oncology</strong>, Ospedale<br />
"Sacro Cuore di Gesù" Fatebenefratelli, Benevento, Italy, 14 Onco-Hematology,<br />
Ospedale Casa Sollievo della S<strong>of</strong>ferenza, San Giovanni Rotondo, Italy, 15 Medical<br />
<strong>Oncology</strong>, Ospedale Moscati, Taranto, Italy<br />
Background: The CAPRI trial, a phase II randomised trial suggested the potential role<br />
<strong>of</strong> maintaining Epidermal Growth Factor Receptor inhibition in combination with<br />
Table: 548P<br />
Age subgroups ITT Population NGS cohort KRAS,NRAS,BRAF, PIK3CA<br />
wt<br />
ORR PFS (95%CI) Safety ORR PFS (95%CI) ORR PFS (95%CI)<br />
G3-4 diarrhea G3-4 fatigue<br />
abstracts<br />
FOLFOX after first progression from cetuximab plus FOLFIRI in molecularly selected,<br />
by NGS technique, metastatic colorectal (mCRC) pts. Few data are currently available<br />
on elderly population. This subgroup analysis evaluated the efficacy and safety <strong>of</strong><br />
FOLFIRI plus cetuximab in age-defined pts subgroups.<br />
Methods: A post hoc analysis was performed in CAPRI trial pts; outcomes<br />
(Progression Free Survival [PFS], Overall Response Rate [ORR], Safety) were analysed<br />
by age groups and stratified according to molecular characterization. Three age cut-<strong>of</strong>fs<br />
were used to define elderly population (≥65 years; ≥70 years; ≥75 years).<br />
Results: 340 mCRC pts were treated in first line with FOLFIRI plus cetuximab. Among<br />
those, 154 pts were aged more than 65 years, 86 over 70, 35 over 75. NGS was<br />
performed in 182 pts. Among them, 87 pts were aged more than 65 years, 46 over 70,<br />
17 over 75. 104 <strong>of</strong> 182 pts were WT for KRAS, NRAS, BRAF, PIK3CA genes. In the<br />
quadruple WT group, 51 pts were ≥65 years; 29 were ≥70 years; 9 were ≥75 years.<br />
Median PFS was similar within the age subgroups in the intention to treat population,<br />
NGS cohort and quadruple WT pts, respectively. Likewise, ORR was not significantly<br />
different among age-subgroups in the three populations. Safety pr<strong>of</strong>ile was acceptable<br />
and similarly reported among all age-groups, with the exception <strong>of</strong> grade ≥3 diarrhea<br />
(55% vs 25% p 0.04) and neutropenia (75% vs 37% p 0.03) in pts ≥75 years and grade<br />
≥3 fatigue (31% vs 20 % p 0.01) in pts
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
is 81 years ±4, and 282 pts (80%) had primary tumor in the colon. At diagnosis, 192<br />
pts (56%) had synchronous metastatic disease and 74 pts (22%) had metachronous<br />
metastatic disease. Main metastatic sites were liver (229 pts, 65%), including liver only<br />
(134 pts, 38%). Main CT combined with Bv was FOLFOX for 127 pts (36%), FOLFIRI<br />
(102 pts, 29%), 5 FU-LV (75 pts, 21%), Xeloda monotherapy (32 pts, 9%) and other CT<br />
(15 pts, 4%). Mean treatment duration for FOLFOX was 4.71 mo ±2.99, FOLFIRI 4.72<br />
mo ±3.38, 5FU-LV 4.40 mo ±3.49, and; XELODA 3.88 mo ±3.23. At 12 mo FU,<br />
median PFS was 10.8 mo [95% CI:9.0; 12.5] with oxaliplatin-based CT (131 pts;<br />
37.3%), 9.8 mo [8.2; 11.1] with irinotecan-based CT (103 pts; 29.3%) and 7.7 mo [5.8;<br />
9.3] with 5FU-based CT (107 pts; 30.5%). Median Overall survival was 20.7 mo [18.5;<br />
-] with oxaliplatin-based CT, 19.8 mo [15.1;-] with irinotecan-based CT, and 13.7 mo<br />
[11.1; 17.5] with 5FU-based CT. AEs grade ≥ 3 occurred in 34% pts (safety population,<br />
n= 382) including 28% Bv related AEs, and 3% pts died <strong>of</strong> an AE.<br />
Conclusions: CASSIOPEE provides an overview <strong>of</strong> 1st line CTs pattern combined with<br />
Bv in elderly patients with mCRC in daily French practice. Polychemotherapy was<br />
administered in nearly 70% pts. PFS and safety results are comparable to published<br />
randomized studies.<br />
Clinical trial identification: Clinicaltrials gov NCT01555762<br />
Legal entity responsible for the study: N/A<br />
Funding: Roche<br />
Disclosure: L. Mineur: Advisory Board. P. Laplaige: Roche, Pfizer, San<strong>of</strong>i, Genomic<br />
Health, Pierre Fabre. S. Gourgou, J. Telliez, S. Gandon: Roche. All other authors have<br />
declared no conflicts <strong>of</strong> interest.<br />
552P<br />
Aflibercept plus FOLFIRI for 2nd line treatment <strong>of</strong> metastatic<br />
colorectal cancer (mCRC): Long-term safety observation from<br />
the global aflibercept safety and quality-<strong>of</strong>-life (QoL) program<br />
(ASQoP)<br />
R. Riechelmann 1 , V. Srimuninnimit 2 ,P.Kavan 3 , M. Di Bartolomeo 4 , E. Maiello 5 ,<br />
I. Cicin 6 , H. Kröning 7 , P. Garcia-Alfonso 8 , I. Chau 9 , C. Fernández-Martos 10 ,<br />
M. Ter-Ovanesov 11 , M. Peeters 12 , P. Picard 13 , R. Bordonaro 14<br />
1 Fundação Faculdade de Medicina, Faculdade de Medicina da Universidade de<br />
São Paulo, Sao Paulo, Brazil, 2 Department <strong>of</strong> Medicine, Siriraj Hospital, Mahidol<br />
University, Bangkok, Thailand, 3 Segal Cancer Centre E-715, McGill University,<br />
Montreal, QC, Canada, 4 S.C: Medicina Oncologica 1, Istituto Nazionale dei<br />
Tumori, Milan, Italy, 5 Onco-Hematology Department, IRCCS Casa Sollievo della<br />
S<strong>of</strong>ferenza, San Giovanni Rotondo, Italy, 6 Department <strong>of</strong> Medical <strong>Oncology</strong>,<br />
Trakya University, Edirne, Turkey, 7 Praxis, Schwerpunktpraxis für Hämatologie und<br />
Onkologie, Magdeburg, Germany, 8 Department <strong>of</strong> <strong>Oncology</strong>, Hospital General<br />
Universitario Gregorio Marañon, Madrid, Spain, 9 Department <strong>of</strong> Medicine, Royal<br />
Marsden NHS Foundation Trust, Sutton, UK, 10 Gastrointestinal <strong>Oncology</strong> Unit,<br />
Fundación Instituto Valenciano de Oncología, Valencia, Spain, 11 Department <strong>of</strong><br />
Oncological and Surgical, Moscow Municipal Oncological Hospital 40, Moscow,<br />
Russian Federation, 12 Department <strong>of</strong> <strong>Oncology</strong>, University <strong>of</strong> Antwerp, Antwerp,<br />
Belgium, 13 Clinical Sciences and Operations/ Biostatistics and Programming/<br />
Medical Affair and Data Mining, San<strong>of</strong>i R&D, Chilly-Mazarin, France, 14 Oncologia<br />
Medica, Azienda Ospedaliera ARNAS Garibaldi, Catania, Italy<br />
Background: The Ph 3 VELOUR study demonstrated that addition <strong>of</strong> aflibercept<br />
(ziv-aflibercept [USA]) to fixed-dose FOLFIRI improved survival outcomes & response<br />
rates in mCRC pts treated with prior oxaliplatin-based chemotherapy. The global<br />
ASQoP study (NCT01571284) is a single-arm, open-label trial in a population similar<br />
to VELOUR, evaluating QoL and safety in a closer to real-life setting. Here, we report<br />
safety data from the 5th interim analysis <strong>of</strong> ASQoP.<br />
Methods: ASQoP enrolled mCRC pts (ECOG PS 0–1) with prior oxaliplatin-based<br />
therapy, regardless <strong>of</strong> prior bevacizumab (Bev) therapy. Pts received 4 mg/kg<br />
aflibercept & FOLFIRI on d1 <strong>of</strong> a 2-wk cycle, until disease progression (PD),<br />
unacceptable toxicity, death or investigator/pt decision. Initial FOLFIRI dose &<br />
subsequent modifications were at physician’s discretion. Adverse events (AEs) were<br />
evaluated using CTCv4.03.<br />
Results: At data cut-<strong>of</strong>f (7 Mar 2016), the safety population (≥1fulltreatmentcycle)<br />
comprised 779 pts: male 59.7%; ECOG PS = 0 62.0% (VELOUR 57.0%); median age 61.0 y<br />
(VELOUR 61.0 y); age ≥65 y 39.0%; median time from diagnosis 13.4 mo; prior Bev<br />
46.2%; prior thrombovascular events/presence <strong>of</strong> CV risk factors 54.4%. In total, 774 pts<br />
discontinued treatment, mostly due to PD (52.3%) or AEs (26.7%). Among pts who<br />
discontinued treatment, the median no. <strong>of</strong> cycles was 7 (VELOUR 9 cycles); median<br />
duration <strong>of</strong> exposure was 16.6 wks (VELOUR 21.4 wks). A summary <strong>of</strong> the AEs in ASQoP<br />
and VELOUR are in the table. ASQoP is an ongoing study; these results are not final.<br />
Conclusions: Aflibercept-related toxicity was similar in ASQoP and VELOUR. The<br />
frequency <strong>of</strong> some AEs appears lower in ASQoP, which may reflect more flexible<br />
FOLFIRI dosing, or more routine in AE management. Overall, the safety pr<strong>of</strong>ile in<br />
ASQoP was consistent with the known safety pr<strong>of</strong>ile <strong>of</strong> aflibercept/FOLFIRI, with no<br />
new safety signals identified.<br />
Legal entity responsible for the study: San<strong>of</strong>i<br />
Funding: San<strong>of</strong>i<br />
Disclosure: P. Kavan: Educational grant from San<strong>of</strong>i in 2013 and 2014, not directly<br />
related to presented topic. E. Maiello: Membership on Advisory Board (last two years)<br />
for Celgene, Roche, San<strong>of</strong>i, Lilly, Amgen, Merck, Bayer. P. Garcia-Alfonso: Advisory<br />
Boards: Roche, Merck, Amgen, Lilly, San<strong>of</strong>i, Bayer. I. Chau: Advisory Boards for San<strong>of</strong>i<br />
<strong>Oncology</strong>, Eli-Lilly, Bristol Meyers Squibb, MSD, Merck Serono, Gilead. Science research<br />
funding: Janssen-Cilag, San<strong>of</strong>i <strong>Oncology</strong>, Roche, Merck-Serono, Novartis. Honorarium:<br />
Taiho, Pfizer, Amgen, Eli-Lilly, Bayer. M. Peeters: Advisory Board and speaker:<br />
San<strong>of</strong>i. P. Picard: Employee <strong>of</strong> San<strong>of</strong>i (contracted by AIXIAL). R. Bordonaro: Honoraria<br />
for participation in advisory boards and/or as a consultant and/or participation as a<br />
speaker at meetings for Novartis, H<strong>of</strong>fman-La Roche, Merck, Eli Lilly, San<strong>of</strong>i,<br />
Boheringer-Ingleheim. All other authors have declared no conflicts <strong>of</strong> interest.<br />
553P<br />
Adjuvant chemotherapy for stage III colorectal cancer in the<br />
elderly<br />
D. Brungs 1 , E. Healey 1 , J. Rose 1 , T. Tubaro 1 ,W.Ng 2 , W. Chua 3 , M. Carolan 1 ,<br />
P. de Souza 4 , M. Aghmesheh 1 , M. Ranson 5<br />
1 Medical <strong>Oncology</strong>, Wollongong Hospital, Wollongong, Australia, 2 Collaboration<br />
for Cancer Outcomes Research and Evaluation (CCORE), Ingham Institute for<br />
Applied Medical Research, University <strong>of</strong> New South Wales, Sydney, Australia,<br />
3 Medical <strong>Oncology</strong>, Liverpool Hospital, Sydney, Australia, 4 Medical <strong>Oncology</strong>,<br />
Western Sydney University School <strong>of</strong> Medicine, Liverpool, Australia, 5 Illawarra<br />
Health and Medical Research Institute, University <strong>of</strong> Wollongong, Wollongong,<br />
Australia<br />
Background: Colorectal cancer (CRC) is a common and lethal malignancy which is<br />
related to aging, with almost 40% <strong>of</strong> CRC diagnosed above 75 years in both Australia<br />
ASQoP – 5 th interim analysis<br />
Aflibercept + FOLFIRI<br />
(n = 779)<br />
Table: 552P<br />
VELOUR<br />
flibercept + FOLFIRI<br />
(n = 611)<br />
Patients (%) All grades Grade 3–4 Grade 4 All grades Grade 3–4 Grade 4<br />
Any TEAE 98.7 78.2 18.0 99.2 83.5 21.4<br />
Selected TEAEs <strong>of</strong> any grade in ≥20% <strong>of</strong> patients<br />
Diarrhoea (PT) 61.2 15.3 0.3 69.2 19.3 0.3<br />
Asthenic conditions (HLT) 57.8 13.6 0 60.4 16.9 0.8<br />
Hypertension (grouped term) 48.4 24.1 0 41.4 19.3 0.2<br />
Stomatitis and ulcerations (HLT) 43.5 10.7 0.1 54.8 13.7 0.2<br />
Infections and infestations (SOC) 31.3 11.7 2.1 46.2 12.3 1.3<br />
VEGF-associated events<br />
Venous thromboembolic events (grouped term) 6.2 4.1 0.9 9.3 7.9 4.7<br />
Arterial thromboembolic events (grouped term) 2.3 0.8 0.3 2.6 1.8 1.0<br />
Gastrointestinal perforation (grouped term) 1.4 1.4 0.6 0.5 0.5 0.3<br />
Fistula (gastrointestinal origin) (grouped term) 1.8 0.8 0 1.1 0.3 0<br />
Laboratory abnormalities<br />
Neutropenia 60.5* 30.5* 9.7* 67.8** 36.7** 13.6**<br />
Proteinuria 60.1 7.3 0.6 62.2 7.9 0.3<br />
*n = 744; **n = 603 HLT, high-level term; PT, preferred term; SOC, system organ class; TEAE, treatment-emergent adverse event<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw370 | vi187
abstracts<br />
and the United States. Adjuvant chemotherapy is a key treatment in patients with Stage<br />
III colorectal cancer, and combination chemotherapy using a fluoropyrimidine and<br />
oxaliplatin doublet (such as FOLFOX or XELOX) is the current standard <strong>of</strong> care, with a<br />
20% reduction in risk <strong>of</strong> death compared to fluoropyrimidine monotherapy. It is not<br />
clear if this benefit is seen in elderly patients in the community setting.<br />
Methods: TNM stage, chemotherapy treatment records, and overall survival data was<br />
obtained for 2923 patients with stage III colorectal cancer by linkage <strong>of</strong> New South<br />
Wales cancer registry records with data from the births, deaths and marriages registry.<br />
To determine the impact <strong>of</strong> age, two separate cox proportional hazard models were<br />
used to compare the effect <strong>of</strong> combination chemotherapy regimens on overall survival<br />
(OS) for patients 70 and older, and younger than 70. Multivariate analysis was<br />
performed using a subset <strong>of</strong> 1008 patients with more complete clinicopathologic data.<br />
Results: Patients in the 70yrs and older age group had poorer OS (5yr OS 58.8 vs<br />
76.7%, HR 0.47 95%CI 0.41 – 0.54, p
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
<strong>Oncology</strong>, Inc. P. Bebeau: Employment with Taiho <strong>Oncology</strong>, Inc. T. Yoshino:<br />
Research funding from Sumitomo Dainippon Pharma Co., Ltd. All other authors have<br />
declared no conflicts <strong>of</strong> interest.<br />
556P<br />
Evaluation <strong>of</strong> Charlson comorbidity index as predictor <strong>of</strong><br />
survival in stage II-III colorectal cancer patients treated with<br />
surgery and neoadjuvant/adjuvant chemotherapy: A single<br />
Institution observational study<br />
M. Baretti 1 , N. Personeni 1 , L. Giordano 1 , M.C. Tronconi 1 , T. Pressiani 1 ,<br />
S. Bozzarelli 1 , L. Rimassa 1 , A. Santoro 2<br />
1 Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano,<br />
Italy, 2 Humanitas Cancer Center, Humanitas Clinical and Research Center,<br />
Humanitas University, Rozzano, Italy<br />
Background: Comorbidity has a well documented detrimental effect on cancer<br />
survival, but it is difficult to disentangle its direct effect on survival from indirect effects<br />
via the influence on treatment choice. This study aimed to assess the impact <strong>of</strong><br />
comorbidity on survival in colorectal cancer (CRC) patients who underwent similarly<br />
aggressive treatment.<br />
Methods: 230 CRC patients, 68 rectal (29.6%) and 162 colon cancer (70.4%) treated<br />
with surgical resection and neoadjuvant/adjuvant chemotherapy from December 2002<br />
to December 2008 at Humanitas Cancer Center were reviewed. The key independent<br />
variable was the Charlson Comorbidity Index (CCI) score. The differences between<br />
groups for categorical data were tested by the Chi-square test. Actuarial survival curves<br />
were generated using the Kaplan–Meier method.<br />
Results: The median follow-up was <strong>of</strong> 113 months (range 8.2-145). The median age <strong>of</strong><br />
patients was 63 (range 37-78). Since all patients had a diagnosis <strong>of</strong> non-metastatic<br />
cancer, the minimum CCI score was 2. In the univariate analysis CCI score, measured<br />
as a continuous variable, was significantly associated with poorer progression-free<br />
survival (PFS) (HR 1.65, 95%CI 1.52–1.80, p < 0.001), and overall survival (OS) (HR<br />
1.55, 95%CI 1.41-1.71, p < 0.001). Patients who had a higher CCI score (>5) had a<br />
significantly poorer PFS and OS rates than did those with a CCI score <strong>of</strong> ≤5.<br />
Additionally, in the multivariate analysis, factors associated with poorer outcome were<br />
stage (stage III versus stage II, p70 years versus ≤70, p < 0.001).<br />
After adjusting for these factors we still observed a significant negative prognostic effect<br />
<strong>of</strong> CCI score on OS (adjusted HR for OS 1.59, 95%CI, 1.43–1.76, p < 0.001).<br />
Conclusions: In this retrospective study we found that a higher CCI score is associated<br />
with poorer outcome providing convincing evidence that CCI score is an important<br />
negative prognostic factor even after adjusting for other prognostic factors. Some<br />
patients with comorbidity may forego chemotherapy unnecessarily, increasing<br />
avoidable cancer mortality.<br />
Legal entity responsible for the study: Humanitas Clinical and Research Center<br />
Funding: Humanitas Clinical and Research Center<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
557P<br />
Quality <strong>of</strong> life in patients with metastatic colorectal cancer<br />
receiving maintenance therapy after first-line inductive<br />
treatment: A quality <strong>of</strong> life sub-analysis <strong>of</strong> the AIO KRK 0207<br />
phase III trial<br />
J. Quidde 1 , S. Hegewisch Becker 2 , U. Graeven 3 , C. Lerchenmueller 4 , B. Killing 5 ,<br />
R. Depenbusch 6 , C.-C. Steffens 7 , T. Lange 8 , G. Dietrich 9 , J. Stoehlmacher 10 ,<br />
A. Reinacher 11 , A. Tannapfel 12 , T. Trarbach 13 , N. Marschner 14 , H.J. Schmoll 15 ,<br />
A. Hinke 16 , S.-E. Al-Batran 17 , D. Arnold 18<br />
1 University Cancer Center Hamburg, University Hospital Hamburg, Hamburg,<br />
Germany, 2 HOPE, Internal Medicine <strong>Oncology</strong> and Hematology, Hamburg,<br />
Germany, 3 Chefarzt Privatdozent, Kliniken Maria Hilf GmbH Klinik für Haematolgie/<br />
Onkologie, Mönchengladbach, Germany, 4 Haematologie und Onkologie,<br />
Ueberoertliche Gemeinschaftspraxis, Münster, Germany, 5 Department <strong>of</strong><br />
Hematology and <strong>Oncology</strong>, Lahn-Dill-Kliniken, Wetzlar, Germany, 6 Medical<br />
<strong>Oncology</strong>, Practice for <strong>Oncology</strong>, Gütersloh, Germany, 7 Medical <strong>Oncology</strong>,<br />
Onkologische Schwerpunktpraxis Stade, Stade, Germany, 8 Department <strong>of</strong><br />
Hematology and <strong>Oncology</strong>, Asklepios-Klinik Weißenfels, Weissenfels, Germany,<br />
9 Department <strong>of</strong> Gastroenterology, Hematology and <strong>Oncology</strong>, Klinikum<br />
Bietigheim, Bietigheim, Germany, 10 Tumorgenetik, Bonn, Germany, 11 Medical<br />
Department, Ruhr University Bochum Medizinische Universitätsklinik, Bochum,<br />
Germany, 12 Department <strong>of</strong> Pathology, Ruhr University Bochum Medizinische<br />
Universitätsklinik, Bochum, Germany, 13 Medical Departement, IOMEDICO AG,<br />
Freiburg, Germany, 14 Internal Medicine / Hematology, Praxis für Interdisziplinaere<br />
Onkologie, Freiburg, Germany, 15 Dept. Hematology/ <strong>Oncology</strong> FG 16 / U1, Martin<br />
Luther University <strong>of</strong> Halle, Halle, Germany, 16 Research, WiSP GmbH, Langenfeld,<br />
Germany, 17 Medical <strong>Oncology</strong>, Nordwest-Krankenhaus, Frankfurt am Main,<br />
Germany, 18 CUF, CUF Hospitals Cancer Centre, Lisbon, Portugal<br />
Background: First-line maintenance strategies are a current matter <strong>of</strong> debate in the<br />
management <strong>of</strong> mCRC. Their impact on patient’s health related quality <strong>of</strong> life<br />
(HRQOL) has not yet been evaluated. The objective <strong>of</strong> this study was to assess whether<br />
differences in HRQOL during any active maintenance treatment compared to no<br />
maintenance treatment exist.<br />
Methods: 837 patients with mCRC were enrolled in the AIO KRK 0207 trial. 472<br />
underwent randomization after 24 weeks <strong>of</strong> induction treatment into one <strong>of</strong> the<br />
maintenance arms: FP plus Bev (arm A), Bev (arm B) or no active treatment (arm C).<br />
HRQOL were assessed every 6 weeks during induction and maintenance treatment<br />
independent from treatment stop, delay, or treatment modification (e.g. also including<br />
assessment after progression), using the EORTC QLQ-C30, QLQ-CR29. The mean<br />
value <strong>of</strong> the global quality <strong>of</strong> life dimension (GHS/QoL) <strong>of</strong> the EORTC QLQ-C30,<br />
calculated as the average <strong>of</strong> all available time points after randomization was considered<br />
as primary endpoint. Additionally, EORTC QLQ-C30 response scores were analyzed.<br />
Results: For HRQOL analysis, 413 patients were eligible (arm A: 136; arm B: 142, arm<br />
C: 135). Compliance rate with HRQOL questionnaires was 95% at time <strong>of</strong><br />
randomization and remained high during maintenance (98%, 99%, 97% and 97% at<br />
week 6, 12, 18 and 24). No significant difference in the mean GHS/QoL scores at week<br />
6, 12, 18, and 24 were observed between treatment arms. GHS/QoL scores deterioration<br />
(decrease by 10 points or more) was observed in 20.5%; 17.2 % and 20.7% <strong>of</strong> the<br />
patients, whereas an improvement <strong>of</strong> at least 10 GHS/QOL scores occurred in 36.1%;<br />
43.8% and 42.1% (arms A, B, C). Compared to PD, non-PD patients had a favorable<br />
GHS/Qol score in all arms.<br />
Conclusions: Continuation <strong>of</strong> an active maintenance treatment with FP/Bev after<br />
intensively induction treatment was neither associated with a detrimental effect on<br />
GHS/QoL scores when compared to both, less active treatment with Bev alone or no<br />
active treatment.<br />
Clinical trial identification: ClinicalTrials.gov NCT00973609<br />
Legal entity responsible for the study: Susanne Hegewisch-Becker<br />
Funding: AIO trail with foundation from Roche Pharma<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
558P<br />
Oxaliplatin and erectile dysfunction<br />
P. Dal 1 , M. Dincer 1 , B. Yildiz 1 , O. Kahraman 2 , M. Canhoroz 3 , D. Arik 4 ,<br />
B. Basȩskioğlu 5 , H. Yilmaz 6<br />
1 Medical <strong>Oncology</strong>, Eskis¸ehir Osmangazi Üniversitesi-ESOGU-Mes¸elik Kampus,<br />
Eskisehir, Turkey, 2 Eskis¸ehir Osmangazi Üniversitesi-ESOGU-Mes¸elik Kampus,<br />
Eskisehir, Turkey, 3 Medical <strong>Oncology</strong>, Acıbadem Eskisehir Hastanesii, Eskisehir,<br />
Turkey, 4 Pathology, Eskis¸ehir Osmangazi Üniversitesi-ESOGU-Mes¸elik Kampus,<br />
Eskisehir, Turkey, 5 Urology, Eskis¸ehir Osmangazi Üniversitesi-ESOGU-Mes¸elik<br />
Kampus, Eskisehir, Turkey, 6 Bioistatistics, Eskis¸ehir Osmangazi<br />
Üniversitesi-ESOGU-Mes¸elik Kampus, Eskisehir, Turkey<br />
Background: Oxaliplatin is commonly used for advanced / metastatic colorectal cancer<br />
treatment. Peripheral Neuropathy is major dose limiting side effect. It is unclear whether<br />
Oxaliplatin causes autonomic neuropathy such as erectile dysfunction or not. In this<br />
study, we assessed male sexual function in successfully treated colon cancer patients.<br />
Methods: Among male stage 2 and 3 colon cancer patients, medical records analyzed.<br />
Patients >65 years, history <strong>of</strong> pelvic surgery/radiotherapy and Erectile Dysfunction<br />
(ED), presence <strong>of</strong> stoma, cardiac and prostatic disorder were excluded.Patients had to<br />
be disease free and <strong>of</strong>f-treatment for at least 6 months. Remaining 37 patients included<br />
the study. Patients completed a survey questionnaire that consisted <strong>of</strong> demographic<br />
characteristics,risk factors for ED and the International Index Of Erectile Function (<br />
IIEF ) to assess their current level <strong>of</strong> sexual function. Peripheral neuropathy (PN) was<br />
assessed according to Common Terminology Criteria for Adverse Events (CTCAE),<br />
version 4.0. Patients designed; Group A: treated with non-Oxaliplatin chemotherapy<br />
(CT), such as Kapesitabin or 5-Fluorourasil, Group B defined as Oxaliplatin group,<br />
those treated with FOLFOX/CAPOX. IIEF score was defined as; no ED between score<br />
26-30, ED exist between the score 0-25.<br />
Table: 558P<br />
GROUP A n:17 (%<br />
45,9)<br />
abstracts<br />
GROUP B n:20 (%<br />
54,1)<br />
STAGE II III 17 (% 89,5) 0 (% 0) 2 (% 10,5) 18 (% 0,000<br />
100)<br />
BMİ 18,5-25,9 kg/m 2 25,9-30 kg/ 4 (% 40) 10 (% 6 (% 60) 9 (% 47,4) 0,700<br />
m 2 >30 kg/ m 2 52,6) 3 (% 37,5) 8 (% 100)<br />
SMOKE Never Current Ex 5 (% 50) 3 (% 37,5) 5(5%50)5(% 0,856<br />
smoker<br />
9 (% 47,4)<br />
62,5) 10 (% 52,6)<br />
ALCOHOL USE No Yes 14 (% 45,2) 3 (% 17 (% 54,8) 3 (% 50) 1,000<br />
50)<br />
DIABETES MELLİTUS No Yes 6 (% 48,5) 1 (% 25) 17 (% 51,5) 3 (% 75) 0,609<br />
HYPERTENSİON No Yes 12 (% 42,9) 5 (% 16 (% 57,1) 4 (% 0,703<br />
55,6)<br />
44,4)<br />
FSH Low Normal High 0 (% 0) 14 (% 48,3) 1 (% 100) 15 (% 0,611<br />
2 (% 40)<br />
51,7) 3 (% 60)<br />
LH Normal High 12 (% 40) 4 (% 18 (%60) 2 (% 33,3) 0,226<br />
66,7)<br />
TESTESTERON Low Normal 4 (% 80) 12 (% 1 (% 20,0) 19 (% 0,149<br />
38,7)<br />
61,3)<br />
P.NEUROPATHY Grade 0 Grade 12 (%85,7) 5 (% 2 (%14,3) 18 (78,3) 0,001<br />
1<br />
21,7)<br />
IIEF SCORE ED (-) ED (+) 11 (% 47,8) 6 (%<br />
42,9)<br />
12 (% 52,2) 8 (%<br />
57,1)<br />
0,519<br />
P<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw370 | vi189
abstracts<br />
Results: Mean age <strong>of</strong> Group A and B were 53,23 and 52,70 respectively<br />
(p:0,641). According to IIEF score, groups had some degree <strong>of</strong> ED, % 42,9 and % 57,1<br />
(IIEF score 20,38 and 17,83) respectively (p:1,000). PN according to CTCAE were %<br />
21,7 (n:5) and % 78,3 (n:18) (p:0,001), none <strong>of</strong> the patients had more than Grade 1<br />
neuropathy.<br />
Conclusions: These findings suggest that Oxaliplatin can cause peripheral neuropathy<br />
but not autonomic neuropathy such as ED. Further study and evaluation is necessary<br />
for exact decision. Therefore, the underlying pathology, either organic or psychological<br />
remains to be defined.<br />
Legal entity responsible for the study: Pinar Dal<br />
Funding: Eskişehir Osmangazi University Medical School<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
559P<br />
Patterns <strong>of</strong> venous thromboembolism risk in patients with<br />
localized colorectal cancer undergoing adjuvant<br />
chemotherapy or active surveillance<br />
J. Riedl 1 , F. Posch 1 , M. Stotz 1 , A. Bezan 1 , T. Winder 2 , R. Schaberl-Moser 1 ,<br />
M. Pichler 1 , H. Stoeger 1 , A. Gerger 1<br />
1 Clinical Division <strong>of</strong> Medical <strong>Oncology</strong>, Department <strong>of</strong> Internal Medicine, Medical<br />
University Graz, Graz, Austria, 2 Medizinische Onkologie, Universitätsspital Zürich,<br />
Zurich, Switzerland<br />
Background: The risk <strong>of</strong> cancer-associated venous thromboembolism (VTE) is highly<br />
elevated in pts w/ metastatic colorectal cancer (CRC), and in particular during<br />
antineoplastic therapy. However, patterns <strong>of</strong> VTE risk in pts w/ localized CRC are<br />
unclear. Here, we estimate the risk <strong>of</strong> VTE in CRC pts after curative surgery, and define<br />
its association with baseline risk factors, adjuvant chemotherapy (adjCTX), disease<br />
recurrence, and death.<br />
Methods: In this single-center historical cohort study, 562 pts w/ CRC (median<br />
age = 65.3 years; stages I, II, and III: n = 29, (5.2%), n = 160 (28.7%), n = 368 (66.1%);<br />
adjCTX: n = 346 (61.7%)) were included at the time <strong>of</strong> surgery and followed-up until<br />
the onset <strong>of</strong> VTE, disease recurrence, and death. The primary endpoint <strong>of</strong> this study<br />
was the cumulative incidence <strong>of</strong> objectively-confirmed, symptomatic or incidental deep<br />
vein thrombosis and/or pulmonary embolism (VTE), accounting for death as a<br />
competing risk.<br />
Results: During a median follow-up <strong>of</strong> 2.9 years, we observed 18 VTE events (3.2%),<br />
142 recurrences (25.3%), and 52 pts (9.3%) died. The 6-month, 1-year, and 5-year risk<br />
<strong>of</strong> VTE was 1.4%, 1.8%, and 3.3%, respectively. In univariable time-to-VTE regression,<br />
adjCTX was not associated with an increased risk <strong>of</strong> VTE (Subdistribution hazard<br />
ratio = 1.03, 95%CI: 0.40-2.66, p = 0.95). In multi-state analysis, the onset <strong>of</strong> disease<br />
recurrence emerged to be associated w/ an excessive increase in the risk <strong>of</strong> VTE<br />
(Transition hazard ratio (THR) = 11.8, 95%CI: 4.02-35.81, p < 0.0001). Conversely, the<br />
occurrence <strong>of</strong> VTE was associated with a 2.6-fold increase in the risk <strong>of</strong> disease<br />
recurrence (THR = 2.62, 95%CI: 1.07-6.42, p = 0.04).<br />
Conclusions: The risk <strong>of</strong> VTE in pts w/ localized CRC undergoing curative surgery is<br />
very low. Importantly, adjCTX does not appear to be a risk factor for VTE in this<br />
setting. Therefore, the role <strong>of</strong> primary thromboprophylaxis during adjCTX is likely <strong>of</strong><br />
low clinical benefit. The by far strongest determinant <strong>of</strong> VTE risk in curatively treated<br />
CRC pts turned out to be disease recurrence. Conversely, VTE emerged as a risk factor<br />
for recurrence, which indicates that VTE can be an early clinical sign for recurrent<br />
disease in this patient population.<br />
Legal entity responsible for the study: Medical University <strong>of</strong> Graz<br />
Funding: Medical University <strong>of</strong> Graz<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
560P<br />
Molecular, clinical and prognostic characterization <strong>of</strong> double<br />
KRAS/PIK3CA (dKP) mutated metastatic colorectal cancer<br />
(mCRC)<br />
J. Grasselli 1 , E. Elez 1 , G. Argiles Martinez 1 , E. Sanz-Garcia 1 , T. Macarulla 1 ,<br />
J. Capdevila 1 , M. Alsina 1 , T. Sauri 1 , C. Hierro 1 , H. Verdaguer 1 , I. Matos 1 ,<br />
A. Garcia 1 , P. Nuciforo 1 , S. Landolfi 1 , H. Garcia Palmer 1 , R. Dienstmann 2 ,<br />
A. Vivancos 3 , J. Tabernero 1<br />
1 Medical <strong>Oncology</strong>, Vall d’Hebron University Hospital Institut d’Oncologia,<br />
Barcelona, Spain, 2 <strong>Oncology</strong> Data Science, Vall d’Hebron University Hospital<br />
Institut d’Oncologia, Barcelona, Spain, 3 Genomics, Vall d’Hebron University<br />
Hospital Institut d’Oncologia, Barcelona, Spain<br />
Results: dKP mut were found in 82 cases (12.5%), RAS/BRAF/PIK3CA wild type (wt)<br />
in 38.4%, RAS mut/PIK3CA wt 38.5%, RAS/BRAF wt/PIK3CA mut 3.4% and BRAF<br />
mut 7.2%. PIK3CA mut are enriched in KRAS mut as compared to RAS wt (25% vs.<br />
9%, OR = 3.4, p < 0.001). KRAS mut in dKP were less likely <strong>of</strong> codon 13 as compared to<br />
only KRAS mut (9% vs. 19%, OR = 0.43, p = 0.07). PIK3CA codon mut distribution in<br />
dKP was different from non-dKP, less frequently <strong>of</strong> kinase domain (17% versus 26%,<br />
OR = 0.6, p = 0.4) and more likely <strong>of</strong> rare domains (9% versus 4%, OR = 2.1, p = 0.6).<br />
dKP had less co-existing TP53 mut as compared to non-dKP (31% vs. 65%, OR = 0.24,<br />
p = 0.01). Tumor site in dKP was 43% right side, 39% left and 18% rectum. Metastasis<br />
(mts) location at diagnosis was different, peritoneal disease was more frequently seen in<br />
BRAF mut and dKP as compared to others (35% and 27% vs. 15%). In multivariate<br />
model that includes number and location <strong>of</strong> mts, mts resection, tumor site and mut<br />
pr<strong>of</strong>ile, RAS mut had significantly worse time from recurrence to death (TRD) as<br />
compared to RAS/BRAF/PIK3CA wt (HR 1.4, CI95% 1.1-1.9), a similar trend was<br />
observed for dKP (HR 1.3, CI95% 0.8-2.0). In univariate model, TRD estimates <strong>of</strong> dKP<br />
were not significantly different from RAS mt (HR = 1.0, CI95% 0.7-1.3).<br />
Conclusions: The molecular features <strong>of</strong> dKP samples such as enrichment in particular<br />
KRAS/PIK3CA codons, less co-existing TP53 mut, together with their particular<br />
clinical characteristics suggest that the biology <strong>of</strong> these tumors is different from other<br />
genomically-defined groups. Nevertheless, co-occurrence <strong>of</strong> a PIK3CA mut on top <strong>of</strong><br />
RAS mut does not significantly impact survival in the metastatic setting.<br />
Legal entity responsible for the study: N/A<br />
Funding: VHIO<br />
Disclosure: J. Tabernero: Consultant/Advisory role: Amgen, Bayer, Boehringer<br />
Ingelheim, Celgene, Chugai, Lilly, MSD, Merck Serono, Novartis, Roche, San<strong>of</strong>i,<br />
Symphogen, Takeda, Taiho. All other authors have declared no conflicts <strong>of</strong> interest.<br />
561P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
CDX2 loss as a prognostic and predictive biomarker in<br />
metastatic colorectal cancer<br />
B. Zhang 1 , J. Jones 1 , A. Briggler 2 , J. Hubbard 1 , B. Kipp 3 , D. Sargent 4 , J. Dixon 4 ,<br />
A. Grothey 1<br />
1 <strong>Oncology</strong>, Mayo Clinic, Rochester, MN, USA, 2 Medicine, Mayo Clinic, Rochester,<br />
USA, 3 Pathology and Laboratory Medicine, Mayo Clinic, Rochester, USA, 4 Health<br />
Sciences Research, Mayo Clinic, Rochester, NY, USA<br />
Background: While the lack <strong>of</strong> CDX2 expression has recently been proposed as a<br />
potential biomarker for high relapse risk in patients with stage II and III colon cancer<br />
after complete surgical resection, its role in metastatic colorectal cancer (CRC) remains<br />
unclear. We conducted a retrospective analysis to characterize the clinicopathologic<br />
features <strong>of</strong> CDX2-negative metastatic CRC, and to assess the value <strong>of</strong> CDX2 loss as a<br />
potential prognostic and predictive biomarker for metastatic CRC.<br />
Methods: We identified 66 patients with CDX2-negative metastatic CRC treated at our<br />
institution between 2006 and 2016, as well as a comparison cohort consisting <strong>of</strong> 79<br />
patients with CDX2-positive metastatic CRC. Overall survival (OS) and<br />
progression-free survival (PFS) for first line systemic therapy were estimated using the<br />
Kaplan-Meier method. The associations <strong>of</strong> CDX2 expression with survival were<br />
evaluated using Cox proportional hazards regression models.<br />
Results: The prevalence <strong>of</strong> CDX2 loss in our cohort was 5.6%. Patients with<br />
CDX2-negative metastatic CRC were significantly more likely to be female (62% vs.<br />
44%, p = 0.03), have right-sided primary tumors (55% vs. 34%, p = 0.01) <strong>of</strong><br />
poorly-differentiated histology (55% vs. 24%, p = 0.0001), with distant lymph node<br />
metastasis (47% vs. 16%, p < 0.0001). The median OS for CDX2-negative and positive<br />
metastatic CRC patients were 8 months and 39 months, respectively (HR 4.04, 95% CI<br />
2.49-6.54, p < 0.0001). After adjusting for covariates that are significant in a<br />
multivariate model including age, sex, tumor grade, and the presence <strong>of</strong> BRAF<br />
mutation, the association <strong>of</strong> CDX2 loss and OS remained statistically significant (HR<br />
4.52, 95% CI 2.50-8.17, p < 0.0001). In addition, the objective response rate (29% vs.<br />
68%, p < 0.0001) and median PFS (3 vs. 10 months, HR 2.23, 95% CI 1.52-3.27,<br />
p < 0.0001) for first line chemotherapy were significantly decreased in CDX2-negative<br />
metastatic CRC patients.<br />
Conclusions: CDX2 loss in metastatic CRC is an adverse prognostic feature and a<br />
negative predictor <strong>of</strong> response to chemotherapy. These promising results warrant<br />
validation in an independent cohort. In addition, future clinical trials should be<br />
considered to evaluate the optimal treatment strategy for this aggressive histology.<br />
Legal entity responsible for the study: Mayo Clinic<br />
Funding: Minimal funding required from the Mayo Clinic Cancer Center<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
Background: Molecular screening in mCRC has demonstrated an impact in treatment<br />
selection and outcome estimation. KRAS mutations (mut) frequently coexist with<br />
PIK3CA mut. Molecular, clinical and prognostic association <strong>of</strong> the dKP group has not<br />
been studied in detail.<br />
Methods: 657 mCRC patient records that were eligible for targeted mut pr<strong>of</strong>ile were<br />
reviewed. From Jan 2010 – Jun 2014, mass spectrometry (Sequenom oncogene panel)<br />
was performed in 497 samples, and from Jul 2014 – Jul 2015, next generation<br />
sequencing (MiSeq amplicon oncogene and tumor suppressors panel) in 160.<br />
vi190 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
562P<br />
Genomic instability and early-onset colorectal cancer: a new<br />
form <strong>of</strong> classifying the disease?<br />
wild-type. Only 2 <strong>of</strong> these were less than 70 years. These patients will now be <strong>of</strong>fered<br />
genetic counselling.<br />
M. Arriba 1 , J.L. García 2 , J.M. Cano 3 , D. Rueda 4 , J. Pérez 2 , L. Brandariz 5 ,<br />
T. Fernández 5 , O.A. Nutu 5 , L. Alonso 5 , M. Urioste 6 , R. González-Sarmiento 2 ,<br />
J. Perea 5<br />
1 Digestive Cancer Research Group, Centre for Biomedical Research <strong>of</strong> 12 de<br />
Octubre University Hospital, Madrid, Spain, 2 Molecular Genetics -<br />
Oncohematology, Centro de Investigación del Cáncer-IBMCC University <strong>of</strong><br />
Salamanca-CSIC, Salamanca, Spain, 3 Department <strong>of</strong> Clinical <strong>Oncology</strong>, Hospital<br />
General Ciudad Real, Ciudad Real, Spain, 4 Molecular Biology Laboratory,<br />
University Hospital 12 De Octubre, Madrid, Spain, 5 Department <strong>of</strong> Surgery,<br />
University Hospital 12 De Octubre, Madrid, Spain, 6 Familial Cancer Clinical Unit,<br />
CNIO- Spanish National Cancer Center, Madrid, Spain<br />
Background: Early-onset colorectal cancer (EOCRC) is an uncommon entity<br />
frequently associated with poor clinical outcomes. Therefore, advances in the<br />
understanding <strong>of</strong> its molecular basis are essential for the adequate management <strong>of</strong> the<br />
patients.<br />
Methods: We used a high-resolution array comparative genomic hybridization<br />
(aCGH) platform to investigate the chromosomal instability (CIN) <strong>of</strong> 60 EOCRC (≤45<br />
years at diagnosis), and submitted the data to an unsupervised hierarchical clustering<br />
analysis in order to unveil possible associations between the CIN pr<strong>of</strong>ile and the<br />
clinical features <strong>of</strong> the tumors. We also evaluated the microsatellite instability (MSI)<br />
and CpG island methylator phenotype (CIMP) statuses with the aim <strong>of</strong> investigating a<br />
possible relationship between CIMP, MSI and CIN.<br />
Results: Based on the similarity <strong>of</strong> the copy number alterations (CNAs), the<br />
unsupervised analysis stratified samples into two main clusters (A, B) and four<br />
secondary clusters (A1, A2, B3, B4). We observed a correspondence with the molecular<br />
classification <strong>of</strong> colorectal cancer, in such a way that the CIMP-High tumors were<br />
mostly contained in A1 or A2 depending on the CIN degree (with microsatellite and<br />
chromosome stable tumors [MACS, 1-3 whole chromosomes affected] mainly included<br />
in A1 and CIN- tumors [none whole chromosome affected] mainly included in A2),<br />
and the CIMP-Low/0 tumors were mostly contained in B3 or B4 depending on the<br />
presence/absence <strong>of</strong> MSI. Interestingly, each subcluster showed some distinctive<br />
clinicopathological features. But more interestingly, the CIN <strong>of</strong> each subcluster mainly<br />
affected particular chromosomes, providing evidence <strong>of</strong> the association between the<br />
three indicators <strong>of</strong> genomic instability evaluated.<br />
Conclusions: We observed a correlation between the CIMP/MSI/CIN statuses in<br />
EOCRC which enabled us to outline an algorithm whereby tumors could be<br />
categorized according to these features. Our findings may provide a basis for a new<br />
form <strong>of</strong> classifying EOCRC according to the genomic status <strong>of</strong> the tumors.<br />
Legal entity responsible for the study: This work was funded by Projects PI10/0683,<br />
PI13/01741 and PI13/0127 from the Spanish Ministry <strong>of</strong> Health and Consumer Affairs<br />
and FEDER.<br />
Funding: This work was funded by Mari Paz Jiménez Casado Foundation.<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
563P<br />
Cascade testing following universal immunohistochemistry<br />
for mismatch repair protiens<br />
N. Karadawi 1 ,G.O’Kane 2 , D. Gallagher 3 , S. Finn 3 , C. Muldoon 4 , N. Mulligan 5<br />
1 Medical <strong>Oncology</strong>, St James’s Hospital, Dublin, Ireland, 2 Medical <strong>Oncology</strong>,<br />
Princess Margaret Hospital, Toronto, ON, Canada, 3 Cancer Molecular<br />
Diagnostics, University <strong>of</strong> Dublin Trinity College, Dublin, Ireland, 4 Histopathology<br />
Department, St James’s Hospital, Dublin, Ireland, 5 Histopathology Department,<br />
Mater Misericordiae University Hospital University College Dublin, Dublin, Ireland<br />
Background: Reflex immunohistochemistry (rIHC) to detect mismatch repair<br />
deficiency (dMMR) is a recommended screening tool for the detection <strong>of</strong> Lynch<br />
Syndrome (LS) in incident colorectal cancers (CRCs). Additional BRAF testing in<br />
tumours exhibiting MLH1 loss can help exclude sporadic cases, which do not require<br />
CGS. IHC is increasingly performed as the dMMR phenotype may be considered both<br />
a prognostic and predictive biomarker. The downstream management <strong>of</strong> dMMR<br />
results can be complex and patients are not always referred to clinical genetic services<br />
(CGS).<br />
Methods: We investigated the work-up <strong>of</strong> dMMR CRC patients detected between<br />
2005-2013 at two academic institutes. During this period centre 1 performed IHC only<br />
at physician request and centre 2 implemented rIHC in November 2008. Neither<br />
performed additional BRAF testing prior to CGS referral. Patients who did not receive<br />
a CGS referral were identified. Ethical approval was obtained and retrospective BRAF<br />
testing was performed on tissue from patients who were still alive and whose tumours<br />
exhibited loss <strong>of</strong> MLH1.<br />
Results: During the studied period, 2169 new CRC patients were reviewed. 87 (4%)<br />
<strong>of</strong> these were identified as dMMR CRCs. 39(45%) patients were referred and<br />
investigated for LS. Forty-seven patients were not referred. The characteristics <strong>of</strong> these<br />
patients are shown in table 1. 41 <strong>of</strong> 47 (87%) patients had tumours with evidence <strong>of</strong><br />
MLH1 loss, 35 <strong>of</strong> these were older than 70 years. Nineteen patients had died and BRAF<br />
testing is on-going in this cohort. 14 had a BRAFV600E mutation and 8 were<br />
Table: 563P<br />
N (47) %<br />
Median Age (yrs.) 78yrs (55-90)<br />
MMR protein loss<br />
MLH1/PMS2 41<br />
>70yrs 35<br />
≤70yrs 6<br />
MSH2/MSH6 3<br />
MSH6 2<br />
PMS2 1<br />
Conclusions: Over half <strong>of</strong> identified patients were not referred to clinical genetic<br />
services. Braf testing can enrich the appropriate patients requiring referral and thus<br />
improve the efficiency <strong>of</strong> screening. Certain patients with BRAF-wild type tumours<br />
require additional work-up.<br />
Legal entity responsible for the study: St James Hospital<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
564P<br />
Clinical significance <strong>of</strong> thymidine kinase 1 expression on<br />
TAS-102 treatment in RECOURSE phase III trial <strong>of</strong> TAS-102<br />
versus placebo for metastatic colorectal cancer<br />
K. Yamazaki 1 , T. Yoshino 2 , E. Shinozaki 3 , Y. Komatsu 4 , Y. Tsuji 5 , T. Nishina 6 ,<br />
H. Baba 7 , T. Denda 8 , N. Sugimoto 9 , A. Tsuji 10 , K. Yamaguchi 11 , T. Takayama 12 ,<br />
Y. Shimada 13 , Y. Hamamoto 14 , K. Muro 15 , M. Gotoh 16 , T. Tanase 17 , A. Ohtsu 2<br />
1 Gastrointestinal <strong>Oncology</strong> and Endoscopy, Shizuoka Cancer Center, Shizuoka,<br />
Japan, 2 Department <strong>of</strong> Gastroenterology and Gastrointestinal <strong>Oncology</strong>, National<br />
Cancer Center Hospital East, Kashiwa, Japan, 3 Department <strong>of</strong> Gastroenterology,<br />
Cancer Institute Hospital <strong>of</strong> JFCR, Tokyo, Japan, 4 Cancer Center, Hokkaido<br />
University Hospital, Sapporo, Japan, 5 Medical <strong>Oncology</strong> Dept., KKR Tonan<br />
Hospital, Sapporo, Japan, 6 Department <strong>of</strong> Gastroenterology, Shikoku Cancer<br />
Center, Matsuyama, Japan, 7 Gastroenterological Surgery, Kumamoto University,<br />
Kumamoto, Japan, 8 Gastroenterology, Chiba Cancer Center Hospital, Chiba,<br />
Japan, 9 Department <strong>of</strong> Clinical <strong>Oncology</strong>, Osaka Medical Center for Cancer and<br />
Cardiovascular Dideases, Osaka, Japan, 10 Department <strong>of</strong> Medical <strong>Oncology</strong>,<br />
Kobe City Medical Center General Hospital, Kobe, Japan, 11 Department <strong>of</strong><br />
Gastronerology, Saitama Cancer Center, Saitama, Japan, 12 Department <strong>of</strong><br />
Gastroenterology and <strong>Oncology</strong>, Tokushima University Hospital, Tokushima,<br />
Japan, 13 Department <strong>of</strong> Gastrointestinal Medical <strong>Oncology</strong>, National Cancer<br />
Center Hospital, Tokyo, Japan, 14 Department <strong>of</strong> Gastroenterology, Keio University<br />
School <strong>of</strong> Medicine, Tokyo, Japan, 15 Department <strong>of</strong> Clinical <strong>Oncology</strong>, Aichi<br />
Cancer Center Hospital, Nagoya, Japan, 16 Internal Medicine II, Osaka Medical<br />
College, Takatsuki, Japan, 17 Data Science Department, Taiho Pharmaceutical Co.,<br />
Ltd., Tokyo, Japan<br />
Background: TAS-102 is an oral nucleoside antitumor agent, consisting <strong>of</strong> trifluridine<br />
(FTD) and tipiracil hydrochloride. FTD is incorporated into DNA after<br />
phosphorylation by thymidine kinase 1 (TK1). In the RECOURSE Phase III, an overall<br />
survival (OS) benefit for TAS-102 over placebo was observed in the overall population<br />
and was consistent with that in 266 Japanese patients (pts) (TAS-102 vs. placebo; 7.8M<br />
vs 6.7M, HR = 0.77). Correlations between TK1 expression and OS, progression-free<br />
survival (PFS) and disease control rate (DCR), were investigated.<br />
Methods: Immunohistochemical analysis <strong>of</strong> TK1 expression in cytoplasm was blindly<br />
assessed. TK1 expression was divided into high or low according to the cut-<strong>of</strong>f points at<br />
each 5% increment <strong>of</strong> occupancy <strong>of</strong> positive cells previously reported (#2365, ESMO<br />
2013).<br />
Results: 179 FFPE archival tumor tissues from 183 additional consenting Japanese pts<br />
were evaluable for TK1 expression. The median OS with a high TK1 expression tends<br />
to shorter than that with a low TK1 in the placebo group, whereas TAS-102 tended to<br />
reduce the risk <strong>of</strong> death at each cut-<strong>of</strong>f point in pts with a high TK1 without a statistical<br />
significance (Table). In addition, OS benefit was more pronounced in pts with a high<br />
TK1 at cut-<strong>of</strong>f point <strong>of</strong> 10% or 15%.<br />
Conclusions: TK1 could be a negative prognostic factor <strong>of</strong> mCRC and some OS benefit<br />
for TAS-102 was observed in pts with a high TK1. Further investigation is needed to<br />
clarify the clinical significance <strong>of</strong> TK1 expression on TAS-102 treatment since this<br />
study included a small number <strong>of</strong> pts. The PFS and DCR are presented in this meeting.<br />
Clinical trial identification: JapicCTI-121918. As reference, the protocol number <strong>of</strong><br />
parental clinical study is EudraCT No: 2012-000109-66<br />
Legal entity responsible for the study: Taiho Pharmaceutical Co., Ltd.<br />
Funding: Taiho Pharmaceutical Co., Ltd.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw370 | vi191
abstracts<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Table: 564P<br />
OS at each cut-<strong>of</strong>f point TAS-102 N/Event TAS-102 Median PBO N/Event PBO Median HR (95% CI) HR p-value<br />
Cut-<strong>of</strong>f value <strong>of</strong> 5%<br />
H 103/94 9.3 37/32 6.9 0.82 (0.55, 1.24) 0.35<br />
L 22/19 9.0 17/17 9.5 1.05 (0.50, 2.20) 0.90<br />
10%<br />
H 70/63 9.9 25/21 6.9 0.71 (0.43, 1.18) 0.19<br />
L 55/50 8.1 29/28 7.9 1.08 (0.66, 1.75) 0.76<br />
15%<br />
H 45/41 8.8 18/16 7.0 0.69 (0.38, 1.25) 0.22<br />
L 80/72 9.2 36/33 7.7 0.97 (0.64, 1.49) 0.91<br />
20%<br />
H 28/27 7.1 12/11 6.8 0.91 (0.44, 1.90) 0.81<br />
L 97/86 9.8 42/38 7.9 0.88 (0.59, 1.29) 0.51<br />
25%<br />
H 14/14 6.6 9/9 6.8 0.92 (0.36, 2.31) 0.85<br />
L 111/99 9.5 45/40 7.9 0.92 (0.63, 1.33) 0.64<br />
H = High TK1; L = Low TK1; HR = Hazard Ratio; PBO = placebo; CI = Confidence Interval<br />
Disclosure: K. Yamazaki, Y. Komatsu, K. Yamaguchi: Honoraria (lecture fee) from<br />
Taiho Pharmaceutical Co., Ltd. T. Yoshino: Corporate-sponsored Research: Research<br />
funding from GlaxoSmithKline K.K., Boehringer Ingelheim GmbH. T. Tanase:<br />
Employee <strong>of</strong> Taiho Pharmaceutical Co., Ltd. Stocks <strong>of</strong> Otsuka Holdings Co., Ltd. All<br />
other authors have declared no conflicts <strong>of</strong> interest.<br />
565P<br />
The impact <strong>of</strong> mass spectrometry multigenic platform on the<br />
management <strong>of</strong> metastatic colorectal patients<br />
A. Destro 1 , C. Lo Russo 1 , P. Spaggiari 1 , S. Armenia 1 , E. Bell<strong>of</strong>iore 1 , M. Lorini 1 ,<br />
T. Brambilla 1 , M.M. Cimino 2 , A. Spinelli 3 , N. Personeni 4 , L. Rimassa 4 ,L.Di<br />
Tommaso 1 , M. Roncalli 1<br />
1 Pathology, Istituto Clinico Humanitas, Rozzano, Italy, 2 Hepatobiliary Surgery,<br />
Istituto Clinico Humanitas, Rozzano, Italy, 3 Colorectal Surgery, Istituto Clinico<br />
Humanitas, Rozzano, Italy, 4 <strong>Oncology</strong>, Istituto Clinico Humanitas, Rozzano, Italy<br />
Background: Molecular testing is becoming an important part <strong>of</strong> the diagnosis <strong>of</strong> any<br />
patient with cancer. The challenge to laboratories is to meet this need, using reliable<br />
methods and processes to ensure that patients receive a timely and accurate report on<br />
which their treatment will be based. The aim <strong>of</strong> this abstract is to analyzed the benefit<br />
<strong>of</strong> the introduction in the clinical practice <strong>of</strong> a multigenic platform on the management<br />
<strong>of</strong> metastatic colorectal cancer (CRC).<br />
Methods: DNA extraction by BiOstic Tissue DNA Isolation kit from tumor after<br />
microdissection (>20% tumoral cells). k-ras exon 2 mutations by Sanger sequencing in<br />
277 CRC, by pyrosequencing (KRAS status, Diatech Pharmacogenetics) in 538 CRC;<br />
n-ras and b-raf mutations by pyrosequencing (NRAS and BRAF status, Diatech<br />
Pharmacogenetics) only in k-ras wt CRC from 01/2014. K-ras, n-ras, b-raf and pik3ca<br />
mutations by Maldi-TOF Mass Spectrometry (MassArray Agena Bioscence) with<br />
Myriapod Colon Status (Diatech Pharmacogenetics) in 170 CRC.<br />
Results: The mutations frequencies were 41.5% k-ras by Sanger sequencing; 46.1%<br />
k-ras, 4.0% n-ras and 5.3% b-raf by pyrosequencing; 47.6% k-ras, 8.2% n-ras, 7.1%<br />
b-raf, 12.3% pik3ca by MassArray. For all genes the change <strong>of</strong> methodology has<br />
improved the diagnostic sensitivity <strong>of</strong> test. The introduction <strong>of</strong> multigenic platform<br />
allowed the simultaneous analysis <strong>of</strong> k-ras, n-ras, b-raf and pik3ca mutations in all<br />
patients with CRC, avoiding the step by step analysis approach constrained by a single<br />
gene methodology. The comparison <strong>of</strong> technical features is listed in the table.<br />
Table: 565P<br />
Sanger<br />
Pyrosequencing MassArray<br />
Sequencing**<br />
Amount <strong>of</strong> DNA 200 ng 350 ng 160 ng<br />
Contamination Likely Possible Rare<br />
Analytical Sensitivity 10-20% 5-7.5% 2.5-5% (b-raf<br />
10%)<br />
Specificity 100% 100% 100%<br />
Consumable cost/patient* 50 euro 400 euro 200 euro<br />
Hands-on time 4 h 4h 2.5 h<br />
Overall time to results from the 2.5 days 2.5 days 1 day<br />
DNA<br />
Difficulties <strong>of</strong> data<br />
Intermediate Intermediate Low<br />
interpretation<br />
CE/IVD Validation No Yes Yes<br />
* Cost determined on the basis <strong>of</strong> 5 patients/run. **Only k-ras exon 2<br />
Conclusions: The introduction in the routine diagnostics <strong>of</strong> a multigenic platform is<br />
clearly an attractive approach to increase the quality and the rapidity <strong>of</strong> molecular<br />
analysis results, that can be translate in a better clinical management <strong>of</strong> metastatic<br />
colorectal patient.<br />
Legal entity responsible for the study: Humanitas Research Hospital<br />
Funding: National Health System<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
566P<br />
A systematic review and meta-analysis <strong>of</strong> the prognostic value<br />
<strong>of</strong> total cell-free DNA quantification in metastatic colorectal<br />
cancer<br />
K.-L.G. Spindler 1 , A.K. Boysen 1 , N. Palisgaard 2 , J. Johansen 3 , J. Tabernero 4 ,P.<br />
M. Mau-Soerensen 5 , T.F. Hansen 6 , D. Sefrioui 7 , B.V. Jensen 3 , B.S. Soerensen 8 ,R.<br />
F. Andersen 9 , C. Demuth 8 , I. Brandslund 9 , A. Jakobsen 6<br />
1 <strong>Oncology</strong>, Aarhus University Hospital, Aarhus, Denmark, 2 Pathology, Roskilde<br />
Hospital, Roskilde, Denmark, 3 Department <strong>of</strong> <strong>Oncology</strong>, Herlev Hospital,<br />
Copenhagen University Hospital, Copenhagen, Denmark, 4 Universitat Autònoma<br />
de Barcelona, Vall d’Hebron University Hospital and Institute <strong>of</strong> <strong>Oncology</strong> (VHIO),<br />
Barcelona, Spain, 5 <strong>Oncology</strong>, Rigshospitalet, Copenhagen University Hospital,<br />
Copenhagen, Denmark, 6 <strong>Oncology</strong>, Danish Colorectal Cancer Center South, Vejle,<br />
Denmark, 7 Department <strong>of</strong> <strong>of</strong> Hepato-Gastroenterology, IRON (equipe de<br />
recherche onco normande) within INSERM unit U1079, Rouen, France, 8 Clinical<br />
Biochemistry, Aarhus University Hospital, Aarhus, Denmark, 9 Clinical<br />
Biochemistry, Danish Colorectal Cancer Center South, Vejle, Denmark<br />
Background: Circulating DNA is a mixture <strong>of</strong> DNA from normal and tumor cells.The<br />
majority <strong>of</strong> studies analyses the clinical potential <strong>of</strong> tumor specific mutations which are<br />
detectable in a fraction <strong>of</strong> patients. In contrast, the total cell-free DNA (cfDNA) can be<br />
analyzed in all patients and a normal upper limit provided for standardization. Studies<br />
suggest that levels <strong>of</strong> total cfDNA are higher in CRC than healthy controls and<br />
associated with a poor prognosis in metastatic disease. This indicates a strong clinical<br />
potential calling for statistical validation. The aim was to perform a systematic review<br />
and meta-analysis <strong>of</strong> the prognostic value <strong>of</strong> total cfDNA in patients with metastatic<br />
colorectal cancer (mCRC) treated with chemotherapy.<br />
Methods: A systematic literature search <strong>of</strong> PubMed and Embase was performed by two<br />
independent investigators (KGS and AKB). Eligibility criteria were; total cfDNA<br />
analysis, mCRC, prognostic value during palliative treatment. The PRISMA guidelines<br />
were followed, and meta-analysis applied on both aggregate data extraction and<br />
individual patients’ data provided by the authors when applicable. Primary endpoint<br />
was overall survival (OS).<br />
Results: A total <strong>of</strong> 11 patient cohorts were identified, including a total <strong>of</strong> 1158 patients.<br />
The majority <strong>of</strong> data were based on patients with late-line disease, but also a cohort <strong>of</strong><br />
86 patients in second-line, and study in the first-line settings, with similar results.<br />
Seven studies used qPCR methods, two BEAMing technology and two digital droplet<br />
PCR. The baseline median levels <strong>of</strong> cfDNA was similar in the presented studies, and all<br />
individual studies reported a clear prognostic value in favor <strong>of</strong> patients with lowest<br />
levels <strong>of</strong> baseline cfDNA. The meta-analysis revealed a combined estimate <strong>of</strong> favorable<br />
overall survival hazard ratio (HR) in patients with levels below the median cfDNA<br />
(HR = 2.46, 95% CI 2.17-2.75, p < 0.0001).<br />
Conclusions: The total cfDNA levels are high in patients with mCRC and bear strong<br />
prognostic information, which should be tested prospectively by using a pre-defined<br />
cut-<strong>of</strong>f value. Total cfDNA can be measured in a simple pre-treatment blood sample<br />
and potentially aid in clinical decision-making.<br />
Legal entity responsible for the study: N/A<br />
vi192 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Funding: Novo Nordisk Foundation<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
567P<br />
The differences between suspicious Lynch and sporadic<br />
dMMR colorectal cancers<br />
G. Liu, W. Huang, R. Liu, Z. Pan, P. Ding<br />
Colorectal Cancer, Cancer Centre Sun Yat-Sen University, Guangzhou, China<br />
Background: Few studies have systematically compared the difference between<br />
germline and sporadic dMMR colorectal cancers on clinical-pathological features,<br />
prognosis, lymphocytic reactions, somatic mutation frequencies and neoantigen<br />
burdens.<br />
Methods: We retrospectively collected dMMR colorectal patients identified by<br />
postoperative immunohistochemistry screening. According to genetic test or<br />
clinical-pathological criterias, patients were then grouped as suspicious Lynch or sporadic<br />
dMMR. We compared the clinico-pathologic and prognostic differences between the two<br />
groups. By evaluating the four components <strong>of</strong> lymphocytic reaction {i.e., Crohn’s-like<br />
reaction (CRO), immunoreactions in the invasive margin (IM), in the tumour stroma (TS)<br />
and cancer center (CC)} and counting CD3 + /CD4 + /CD8 + /Foxp3+ tumor-infiltrating<br />
lymphocytes, we investigated their immune response and lymphocyte subgroup<br />
differences. By whole exome sequencing and neoantigen detection pipeline, we contrasted<br />
their discrepancies on mutational frequencies and neoantigen burdens.<br />
Results: 213 <strong>of</strong> the 381 dMMR pts were grouped: 94 sporadic dMMR and 119<br />
suspicious Lynch. Sporadic dMMR patients were significantly older (P < 0.001), had<br />
more tumors proximal to splenic flexure (P < 0.001) and with poor differentiation<br />
(P = 0.003). The OS rate was higher in suspicious Lynch group (P = 0.006), after<br />
adjustment for ages and chemotherapies, the differences still remained significant<br />
(P = 0.076). The scores <strong>of</strong> CRO (P =0.013), IM (P = 0.044) and total immunoreactions<br />
(P = 0.036) <strong>of</strong> suspicious Lynch group is significantly higher. The number <strong>of</strong> CD3 + ,<br />
CD4 + , CD8+ lymphocytes in CC, CD3 + , CD4 + , FoxP3+ lymphocytes in TS,<br />
CD3 + , FoxP3+ lymphocytes in IM <strong>of</strong> suspicious Lynch patients were significantly<br />
more. There were also more somatic mutations and neoantigen burdens in suspicious<br />
Lynch group compared to sporadic dMMR group, with significant difference (357/pt vs<br />
60/pt, P = 0.015; 538/pt vs 91/pt, P = 0.049).<br />
Conclusions: There were more somatic mutations and neoantigens in suspicious<br />
Lynch patients and causing their more intense immunoreactions, which might benefit<br />
their survival.<br />
Legal entity responsible for the study: Sun Yat-sen University Cancer Center<br />
Funding: Nature Science Foundation <strong>of</strong> China (Grant number: 81101591).<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
568P<br />
BRAF mutated metastatic colorectal cancers do not always<br />
possess poor clinical outcome<br />
J.E. Kim, Y.S. Hong, K.-P. Kim, S.Y. Kim, T.W. Kim, J. Cheon<br />
Department <strong>of</strong> <strong>Oncology</strong>, Asan Medical Center, University <strong>of</strong> Ulsan College <strong>of</strong><br />
Medicine, Seoul, Republic <strong>of</strong> Korea<br />
Background: BRAF mutated (mBRAF) metastatic colorectal cancers (mCRC) are<br />
known to be related poor prognosis and low response to current chemotherapy. We<br />
investigated clinical outcomes <strong>of</strong> unselected mBRAF mCRC patients (pts) treated in<br />
real clinical practice.<br />
Methods: A total <strong>of</strong> 125 pts with mBRAF mCRC were treated between Jan 2005 and<br />
OCT 2015 at Asan Medical Center. We analyzed clinical outcomes, such as survival<br />
and progression free survival after 1 st (PFS1), 2 nd (PFS2), and 3 rd (PFS3) line palliative<br />
chemotherapy (pCT), <strong>of</strong> these pts using mCRC registry data <strong>of</strong> our center.<br />
Results: Out <strong>of</strong> 125 tumors, 121 had BRAF mutation <strong>of</strong> V600E; 3 <strong>of</strong> K6001E; 1 <strong>of</strong><br />
V600E and K600E. Median age was 59 years old and 70 (56.0%) pts were male.<br />
Primary tumor was located in right colon in 60 (48.0%) pts, left colon in 43 (34.4%)<br />
pts, and rectum in 22 (17.6%) pts. KRAS exon 2 mutation was tested in all pts; 122 had<br />
no mutation, while 3 had co-mutation <strong>of</strong> KRAS. NRAS mutation was tested in 29<br />
(23.2%) pts and known to be all wild type. Microsatellite instability (MSI) status was<br />
assessed in 86 (68.8%) pts; 10 (8.0%) were MSI and 76 (60.8%) were microsatellite<br />
stable. Median survival <strong>of</strong> all pts was 14.6 months (mos). Out <strong>of</strong> 125 pts, 115, 84, and<br />
37 pts were treated with 1 st ,2 nd , and 3 rd line pCT, respectively. Median PFS1, PFS2 and<br />
PFS3 were 5.7, 2.5 and 1.9 mos, respectively. Survival <strong>of</strong> 12 patients was longer than 30<br />
mos, which is comparable to wild type BRAF mCRC. PFS1 <strong>of</strong> these patients was longer<br />
than others with median 12 cycles <strong>of</strong> 1 st line pCT; 19.5 vs. 5.3 mos. (p < 0.0001).<br />
Conclusions: Clinical outcomes <strong>of</strong> unselected mBRAF mCRC pts treated in real<br />
clinical practice were generally similar to previous studies; short survival and PFS. But,<br />
9.6% <strong>of</strong> pts survived longer than 30 months, which is comparable survival to wild type<br />
BRAF mCRC. PFS1 <strong>of</strong> these pts was also longer than others. Further genetic analysis is<br />
warranted to define genetic features <strong>of</strong> mBRAF tumors with better prognosis.<br />
Legal entity responsible for the study: None<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
569P<br />
The location <strong>of</strong> colorectal cancer (right- vs. left-sided colon<br />
and rectum) affects the prevalence <strong>of</strong> BRAF V600E,<br />
non-V600E and PIK3CA mutations: a prospective registration<br />
study in the Aichi Cancer Network<br />
H. Taniguchi 1 , K. Uehara 2 , H. Nakayama 3 , G. Nakayama 4 , T. Takahashi 5 ,<br />
Y. Nakano 6 , H. Matsuoka 7 , S. Utsunomiya 8 , E. Sakamoto 9 , Y. Mori 10 , K. Komori 11 ,<br />
M. Tajika 12 , K. Muro 1 , Y. Yatabe 13<br />
1 Department <strong>of</strong> Clinical <strong>Oncology</strong>, Aichi Cancer Center Hospital, Nagoya, Japan,<br />
2 Department <strong>of</strong> Surgical <strong>Oncology</strong>, Nagoya University, Graduate School <strong>of</strong><br />
Medicine, Nagoya, Japan, 3 Department <strong>of</strong> Surgery, National Hospital<br />
Organization, Nagoya Medical Center, Nagoya, Japan, 4 Department <strong>of</strong><br />
Gastroenterological Surgery, Nagoya University, Graduate School <strong>of</strong> Medicine,<br />
Nagoya, Japan, 5 Department <strong>of</strong> Surgery, Tosei General Hospital, Seto, Japan,<br />
6 Department <strong>of</strong> Medical <strong>Oncology</strong>, Japanese Red Cross Nagoya First Hospital,<br />
Nagoya, Japan, 7 Surgery, Fujita Health University, Toyoake, Japan, 8 Deparment <strong>of</strong><br />
Medical <strong>Oncology</strong>, Kainan Hospital, Yatomi-shi, Japan, 9 Department <strong>of</strong> Surgery,<br />
Japanese Red Cross Nagoya Daini Hospital, Nagoya, Japan, 10 Department <strong>of</strong><br />
Gastroenterology and Metabolism, Nagoya City University, Nagoya, Japan,<br />
11 Department <strong>of</strong> Gastroenterological Surgery, Aichi Cancer Center Hospital,<br />
Nagoya, Japan, 12 Department <strong>of</strong> Endoscopy, Aichi Cancer Center Hospital,<br />
Nagoya, Japan, 13 Department <strong>of</strong> Clinical <strong>Oncology</strong>, Department <strong>of</strong> Pathology and<br />
Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya, Japan<br />
Background: Primary tumor location is an important predictive factor for KRAS/<br />
NRAS wild-type colorectal cancer treated with anti-EGFR therapy. BRAF and PIK3CA<br />
mutations are also known to affect a response in anti-EGFR therapy. However, the<br />
relationship between the prevalence <strong>of</strong> BRAF/PIK3CA mutations and the location <strong>of</strong><br />
the primary site is still unclear.<br />
Methods: We prospectively collected tumor samples and clinical data from colorectal<br />
cancer patients in 14 hospitals and investigated KRAS/NRAS/BRAF/PIK3CA gene<br />
mutations, including 33 types <strong>of</strong> BRAF non-V600E mutations, using a PCR-based<br />
multiplex kit.<br />
Results: As <strong>of</strong> April 30, 2015, a total <strong>of</strong> 545 CRC patients were enrolled, and 313<br />
patients (57%) revealed KRAS/NRAS wild-type cancer. Patient characteristics included:<br />
median age, 65 (range, 30–90); male/female, 60%/40%; clinical stage I-III/IV, 15%/<br />
85%; and location <strong>of</strong> primary site, right-sided colon/left-sided colon/rectum, 23%/30%/<br />
47%. The prevalence <strong>of</strong> BRAF V600E/BRAF non-V600E/PIK3CA mutations were<br />
10.1%, 4.7% and 5.9%, respectively. The detected BRAF non-V600E mutations were<br />
G466E, G469A, N581T, D594G, T599_V600insT, V600R, K601E and K601N. All<br />
mutations were mutually exclusive. In RAS wild-type cancer patients, BRAF/PIK3CA<br />
mutations were more frequent in female (p = 0.0029), right-sided (p = 0.0001) and<br />
peritoneal metastasis (p = 0.0016) cases and less frequent in cases presenting liver<br />
metastasis (p = 0.0041). In RAS wild-type right-sided cancers, the prevalence <strong>of</strong> BRAF<br />
V600E/ BRAF non-V600E/PIK3CA mutations were 31.7%, 8.1% and 19.2%, while in<br />
left-sided colon and rectum cancers, they were 4.6%, 2.5% and 3.6%, respectively.<br />
Conclusions: More than half <strong>of</strong> RAS wild-type right-sided colon cancer patients have<br />
BRAF/PIK3CA mutations, including BRAF non-V600E. The existence <strong>of</strong> these<br />
mutations may affect anti-EGFR efficacy between right- and left-sided colorectal<br />
cancers.<br />
Legal entity responsible for the study: N/A<br />
Funding: Aichi Cancer Network<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
570P<br />
abstracts<br />
Diagnostic value <strong>of</strong> methylation status <strong>of</strong> T-UCRs for<br />
colorectal cancer<br />
A. Kottorou 1 , A. Antonacopoulou 1 , F.-I. Dimitrakopoulos 1 , G. Diamantopoulou 2 ,<br />
T. Theodorakopoulos 2 , C. Oikonomou 3 , I. Koukourikou 3 , D. Dalla 2 , P. Karatasou 2 ,<br />
E. Katsakoulis 2 , A. Koutras 1 , T. Makatsoris 1 , M. Stavropoulos 4 , K. Thomopoulos 5 ,<br />
H. Kal<strong>of</strong>onos 1<br />
1 Clinical and Molecular <strong>Oncology</strong> Laboratory, Medical School, University <strong>of</strong> Patras,<br />
Patras, Greece, 2 Division <strong>of</strong> Gastroenterology, University Hospital Patras, Patras,<br />
Greece, 3 Division <strong>of</strong> <strong>Oncology</strong>, University Hospital Patras, Patras, Greece,<br />
4 Department <strong>of</strong> Surgery, University <strong>of</strong> Patras, Patras, Greece, 5 Division <strong>of</strong><br />
Gastroenterology, Medical School, University <strong>of</strong> Patras, Patras, Greece<br />
Background: Expression <strong>of</strong> Transcribed Ultra Conserved Regions (T-UCRs) is <strong>of</strong>ten<br />
dysregulated in various types <strong>of</strong> cancer. Regulation <strong>of</strong> T-UCR expression includes<br />
epigenetic mechanisms, and in particular CpG island methylation. Three T-UCRs<br />
(160, 283 and 346) have been found to be methylated in colon adenocarcinomas. The<br />
present study assesses the use <strong>of</strong> the T-UCR methylation status in circulating DNA as a<br />
diagnostic marker for colorectal cancer (CRC).<br />
Methods: Expression and methylation levels <strong>of</strong> T-UCRs 160, 283 and 346 were<br />
assessed in neoplastic and paired normal colonic fresh frozen tissue specimens from 75<br />
CRC patients, as well as in 5 fresh frozen adenoma tissue specimens. Methylation status<br />
<strong>of</strong> the three T-UCRs was also determined in plasma from 161 patients (56 CRC<br />
patients, 55 adenoma patients, 40 healthy subjects and 10 patients with colon<br />
inflammation or diverticulosis).<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw370 | vi193
abstracts<br />
Results: Expression levels <strong>of</strong> all three T-UCRs were lower in neoplastic tissues,<br />
compared to normal adjacent colonic tissues, but only in T-UCR 160 the difference was<br />
statistically significant (p < 0.001). Methylation levels <strong>of</strong> 160, 283 and 346 were higher<br />
in colorectal cancer tissues compared to normal adjacent tissues (p < 0.001, p = 0.029<br />
and p = 0.005 respectively). Notably, methylation levels <strong>of</strong> 160 and 346 in adenomas<br />
were higher than those in normal tissues but lower than those in cancer tissues.<br />
Methylation status <strong>of</strong> 160 in plasma differed significantly among the four different<br />
groups <strong>of</strong> patients (p = 0.024) and the difference increased when we compared<br />
methylation status in colorectal adenoma or adenocarcinoma patients with healthy<br />
subjects or patients with inflammation or diverticulosis (p = 0.007). When methylation<br />
status was used to predict if a subject has colorectal adenocarcinoma, specificity and<br />
sensitivity were 85% and 30% respectively.<br />
Conclusions: Methylation <strong>of</strong> T-UCR 160 in plasma has great specificity for CRC but<br />
low sensitivity. Alteration <strong>of</strong> the methodological approaches to improve the sensitivity<br />
could result in a promising non-invasive screening method for CRC.<br />
Legal entity responsible for the study: University <strong>of</strong> Patras<br />
Funding: University <strong>of</strong> Patras<br />
Disclosure: T. Makatsoris: Travel Pfizer, Roche, Astellas. Advisory: Roche, Boehringer.<br />
Honoraria: Roche, San<strong>of</strong>i, Merck, Amgen. H. Kal<strong>of</strong>onos: Travel: Pfizer, Roche,<br />
Novartis, Enorasis Advisory: Roche, Novartis, MSD, Genesis, Pfizer, Lilly, Leo, Amgen,<br />
Janssen, Merck, Merck Serono. Research Funding: Roche, Novartis, MSD, Genesis,<br />
Pfizer, Lilly, Bayer, Amgen, Janssen, Merck Serono. All other authors have declared no<br />
conflicts <strong>of</strong> interest.<br />
571P<br />
Clinical characteristics and outcomes <strong>of</strong> patients with<br />
metastatic colorectal cancer (CRC) harboring NRAS mutations<br />
M.I. Braghiroli, J.F. Chou, J.F. Hechtman, M. Capanu, A. Cercek, R. Yaeger<br />
Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA<br />
Background: NRAS mutations are now being identified because <strong>of</strong> extended RAS<br />
testing prior to EGFR (epidermal growth factor receptor) inhibitor therapy. The<br />
clinical implications <strong>of</strong> NRAS mutation beyond lack <strong>of</strong> response to anti-EGFR therapy<br />
and whether these tumors behave similarly to KRAS mutant (MUT) mCRC are not<br />
clear.<br />
Methods: We performed a computerized search for all cases <strong>of</strong> NRAS MUT mCRC<br />
identified at our institution under standard genotyping for anti-EGFR treatment<br />
selection from 2010 to 2016. Genotyping was performed either by a mass-spectrometry<br />
based assay (Sequenom) to detect hotspot mutations in a panel <strong>of</strong> 8 genes or (starting<br />
2014) through an exon-capture next generation sequencing assay (MSK-IMPACT) <strong>of</strong><br />
>300 cancer related genes. A comparison group consisted <strong>of</strong> all mCRC cases genotyped<br />
for RAS mutations at our institution from 2008-2012 (n = 918). All cases were reviewed<br />
for patient characteristics, treatment history, and survival.<br />
Results: We identified 87 patients with NRAS MUT mCRC (44% exon 2, 56% exon 3).<br />
Four cases had concurrent NRAS and KRAS mutations. Median age at diagnosis,<br />
gender, primary tumor site, and stage at diagnosis were similar for NRAS MUT and<br />
wild-type (WT) cases. First site <strong>of</strong> metastasis was similar to that <strong>of</strong> WT cases and<br />
included liver, lung, and peritoneum in 79%, 13%, and 10% <strong>of</strong> cases, respectively. PI3K<br />
pathway alterations consisted <strong>of</strong> less common alterations (3 mutations in C2 and 1 in<br />
helical domain <strong>of</strong> PIK3CA, 2 AKT1 mutations) and were less frequent than in KRAS<br />
MUT mCRC (p < 0.01). Survival varied by mutational status; median overall survival<br />
(OS) from metastasis was 40 months (95% CI: 23-58) for NRAS MUT, 68 months<br />
(95% CI: 58-73) for RAS WT, and 47 months (95% CI: 40-53) for KRAS MUT<br />
(p < 0.001). Compared to RAS WT mCRC, NRAS MUT and KRAS MUT had a hazard<br />
ratio (HR) <strong>of</strong> 2.0 and 1.4 for OS, respectively. Adjusting for age at metastasis, gender,<br />
primary tumor site, synchronous disease, liver-limited metastases, and metastasectomy<br />
or hepatic arterial infusion treatment in a cox proportional model assigned a HR <strong>of</strong> 1.6<br />
for NRAS MUT and 1.4 for KRAS MUT (p < 0.01).<br />
Conclusions: In this large series <strong>of</strong> NRAS MUT mCRC, we find that NRAS mutation<br />
is significantly associated with shorter OS.<br />
Legal entity responsible for the study: None<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
572P<br />
Tumor-infiltrating lymphocytes (TILs) density as prognostic<br />
determinant in stage II colorectal cancer<br />
C. Lo Nigro 1 , A. Comino 2 , D. Vivenza 1 , C. Granetto 1 , M. Ferrero 3 , L. Lattanzio 1 ,<br />
C. Varamo 1 , V. Ricci 1 , M.C. Merlano 1<br />
1 Clinical <strong>Oncology</strong>, S. Croce Teaching Hospital, Cuneo, Italy, 2 Pathology, S. Croce<br />
Teaching Hospital, Cuneo, Italy, 3 Pathology, <strong>Oncology</strong>, S. Croce Teaching<br />
Hospital, Cuneo, Italy<br />
to distinguish high and low risk stage II disease. Adjuvant chemotherapy is usually<br />
suggested in the high-risk population. Published data suggest that specific<br />
tumor-infiltrating lymphocytes (S-TILs) (CD3 + , CD8 + , CD45RO+) may represent a<br />
valuable prognostic tool to drive the decision-making process.<br />
Methods: We performed an analysis on 49 cases <strong>of</strong> CC patients underwent to adjuvant<br />
therapy, <strong>of</strong> which 34 relapsed and 15 did not. We analyzed the density <strong>of</strong> CD3 + , CD8<br />
+ and CD45RO+ (memory cells) in the surgical samples after radical surgery by IHC in<br />
the center <strong>of</strong> the tumor (CT) and in its invasive margin (IM). Measurements were<br />
recorded by image analysis as the number <strong>of</strong> positive cells per tissue surface unit in<br />
square millimeters. For each marker, we identified two grading <strong>of</strong> staining, high density<br />
(HD) or low density (LD), where the cut-<strong>of</strong>f was the median value observed. DFS and<br />
OS between HD and LD were compared by Log Rank test. This analysis was conducted<br />
to stratify patients in two cohorts: stage II (26 pts) and stage III (23 pts).<br />
Results: We limit the present report to the cumulative analysis <strong>of</strong> each cohort. In CT,<br />
HD CD3+ affects OS (p = 0.034) and HD CD45RO+ affects DFS(p = 0.002) in stage II<br />
pts. We did not observed any impact in OS nor in DFS for stage III pts. In IM, no<br />
correlation was found with OS, both in stage II and III pts, while for DFS HD CD3 + ,<br />
CD8+ and CD45RO+ showed significant benefit compared to LD (p = 0.016,<br />
p = 0.0095 and p = 0.0014 respectively) only in stage II pts.<br />
Conclusions: S-TILs (CD3 + , CD8 + , CD45RO+) might represent a valuable<br />
prognostic tool to drive the decision-making process especially for stage II CC disease.<br />
All these observations suggest a more pronounced role <strong>of</strong> S-TILs in IM compared to<br />
CT. Our results will be verified in ongoing large prospective study.<br />
Legal entity responsible for the study: M.C. Merlano<br />
Funding: ARCO Foundation<br />
Disclosure: M.C. Merlano: Consultant for Merck Serono. All other authors have<br />
declared no conflicts <strong>of</strong> interest.<br />
573P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Characterization <strong>of</strong> the immunoscore <strong>of</strong> synchronous resected<br />
primary tumor and liver colorectal cancer metastases<br />
M. van den Eynde 1 , B. Mlecnik 2 , G. Bindea 2 , J.-P. Machiels 1 , A. Jouret-Mourin 3 ,<br />
P. Baldin 3 , A. Kartheuser 4 , D. Leonard 4 , C. Remue 4 , J.-F. Gigot 4 , C. Hubert 4 ,<br />
Y. Humblet 1 , N. Haicheur 2 , F. Marliot 2 , F. Pagès 2 , J. Galon 2<br />
1 Medical <strong>Oncology</strong>, Cliniques Universitaires St. Luc, Brussels, Belgium, 2 INSERM<br />
team 15, Centre de Recherche des Cordeliers, Paris, France, 3 Pathology,<br />
Cliniques Universitaires St. Luc, Brussels, Belgium, 4 Digestive Surgery, Cliniques<br />
Universitaires St. Luc, Brussels, Belgium<br />
Background: Pooled analysis from previous trials including unresectable metastatic<br />
colorectal cancer (mCRC) patients suggests an independent survival benefit <strong>of</strong><br />
palliative primary tumor resection. Regarding the reported prognostic survival impact<br />
<strong>of</strong> Immunoscore (I) after resection <strong>of</strong> primary colorectal tumor (PCT) and liver<br />
colorectal metastases (LCM), we investigate if (I) could be different in PCT compared<br />
to LCM in a subgroup <strong>of</strong> synchronously resected mCRC patients.<br />
Methods: From a cohort <strong>of</strong> mCRC patients undergoing curative LCM resection,<br />
patients with synchronous resection <strong>of</strong> LCM and PCT were analyzed. The density <strong>of</strong><br />
CD3 (T cells) and CD8 (cytotoxic) in the core (CT) and invasive margin (IM) <strong>of</strong> all<br />
synchronous LCM and PCT was quantified with a dedicated image analysis s<strong>of</strong>tware<br />
and used to calculate the CD3/CD8 Immunoscore (I) range from 0 (I0), when low<br />
densities <strong>of</strong> both cell types are found in the CT and IM <strong>of</strong> the tumor, to 4 (I4) when<br />
high densities for both markers are found in both regions. The (I) <strong>of</strong> the PCT, the<br />
mean value <strong>of</strong> all LCM, the least and the most infiltrated LCM per patient were<br />
analyzed and compared using the Fisher’s exact test.<br />
Results: Among 161 patients with curative resection <strong>of</strong> LCM (n = 459), 29 patients (M :<br />
14, F :15 : mean 62,9 y-old) had synchronous LCM (n = 68, mean :2,34/pt) and PCT<br />
(n = 29) resection after preoperative treatment (n = 14) or not (n = 15). Low (I) I0-1-2<br />
is significantly associated with PCT compared to the mean <strong>of</strong> all, the least and the most<br />
infiltrated LCM per patient (p < 0,0002). PCT had low proportion <strong>of</strong> I3-4 (13,8%)<br />
compared to the least (41,4%, p = 0,04), the mean <strong>of</strong> all (62,1%, p = 0,0003) and the<br />
most infiltrated LCM per patient (65,5% p = 0,0001). This was not confirmed for<br />
patients with metachronous metastases (n = 15).<br />
Conclusions: In patients with synchronously resected PCT and LCM, PCT was<br />
significantly associated with a low Immunoscore compared to the LCM. This result<br />
would suggest that mCRC patients would indeed benefit from the removal <strong>of</strong> their low<br />
infiltrated PCTs, potential source <strong>of</strong> future metastases.<br />
Legal entity responsible for the study: Jerome Galon and Marc Van den Eynde<br />
Funding: INSERM team 15<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
Background: TNM, stage and key biological markers direct the choice <strong>of</strong> adjuvant<br />
chemotherapy. Stage II colon cancer (CC) is a heterogeneous disease with different<br />
clinical behavior. For this reason there is a high degree <strong>of</strong> uncertainty in<br />
recommending adjuvant chemotherapy. Pathological features are routinely employed<br />
vi194 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
574P<br />
Prognostic mRNA expression signatures in whole blood in<br />
patients with metastatic colorectal cancer treated with 3rd<br />
line cetuximab and irinotecan<br />
J.V. Schou 1 , B.V. Jensen 1 , D.L. Nielsen 1 , J.A. Palsh<strong>of</strong> 1 , E. Høgdall 2 , M.K. Yilmaz 3 ,<br />
P. Pfeiffer 4 , J. Johansen 1 , S. Rossi 5<br />
1 Department <strong>of</strong> <strong>Oncology</strong>, Herlev and Gent<strong>of</strong>te Hospital, Herlev, Denmark,<br />
2 Department <strong>of</strong> Pathology, Herlev and Gent<strong>of</strong>te Hospital, Herlev, Denmark,<br />
3 Department <strong>of</strong> <strong>Oncology</strong>, Aalborg University Hospital, Aalborg, Denmark,<br />
4 Department <strong>of</strong> <strong>Oncology</strong>, Odense University Hospital, Odense, Denmark,<br />
5 Institute <strong>of</strong> <strong>Oncology</strong> Research, <strong>Oncology</strong> Institute <strong>of</strong> Southern Switzerland,<br />
Bellinzona, Switzerland<br />
Background: Whole blood mRNA expressions have been proposed as potential useful<br />
prognostic biomarkers in patients with cancer. Few studies have evaluated circulating<br />
mRNAs in patients with metastatic colorectal cancer (mCRC). Our objective was to<br />
find prognostic mRNAs in patients with mCRC treated with 3 rd line cetuximab and<br />
irinotecan<br />
Methods: In a prospective Phase 2 study, whole blood samples were collected in<br />
PAXgene RNA tubes from 104 mCRC patients. The samples were collected before 3rd<br />
line treatment with irinotecan and cetuximab every second week. All patients had,<br />
prior to inclusion, progressed on 5FU and oxaliplatin. RNA was purified from the<br />
whole blood and hybridized to Affymetrix U133plus2 microarrays. Cox models were<br />
used and only mRNAs, adjusted with the Bonferroni method, were retained.<br />
Results: We found that eight <strong>of</strong> the tested mRNAs had a Bonferroni adjusted<br />
p-value < 0.05 and were retained for further analysis. An eight-mRNA risk index for<br />
overall survival (OS) was composed. When dichotomized in high and low risk by using<br />
the risk index’s median, a hazard ratio (HR) <strong>of</strong> 4.96 (CI 95% 3.04-8.1,<br />
p-value = 2x10 −10 ) was found. In the subgroup <strong>of</strong> KRAS wt patients a 16-gene risk<br />
index was significant for OS (HR = 5.87, CI 95% 3.08-11.2, p-value = 7x10 −7 .In<br />
multivariate analyses, adjusting for hemoglobin, white blood cells, absolute neutrophil<br />
count, platelets, age and performance status, the risk index remained significant<br />
(HR = 7.1, 95% CI 3.5-14.5 and HR = 7.7, 95% CI 2.7-20.9) for all patients and KRAS<br />
wt patients respectively.<br />
Table: 574P<br />
Index for OS Patients HR CI 95% p-value<br />
8-mRNA risk index All patients 4.96 3.04-8.1 2x10 −10<br />
16-mRNA risk index KRAS wt patients 5.87 3.08-11.2 7x10 −7<br />
Conclusions: Our results showed an eight-mRNA risk index as prognostic for OS in<br />
patients with mCRC. Thus using mRNAs in whole blood, which is non-invasive and<br />
can be repeated throughout a treatment period, has prognostic potential as a biomarker<br />
in the clinical setting if validated in the future.<br />
Legal entity responsible for the study: Herlev and Gent<strong>of</strong>te Hospital<br />
Funding: Herlev and Gent<strong>of</strong>te Hospital<br />
Disclosure: P. Pfeiffer: Research funding: Merck Serono, Roche, Taiho, Amgen. All<br />
other authors have declared no conflicts <strong>of</strong> interest.<br />
575P<br />
A transcriptomic pr<strong>of</strong>ile predicts clinical outcome in stage III<br />
colorectal cancer patients treated with adjuvant<br />
chemotherapy<br />
E. Mini 1 ,R.D’Aurizio 2 , G. Perrone 1 , A. Magi 1 , A. Lapucci 1 , R. Tassi 1 , C. Napoli 3 ,<br />
L. Picariello 4 , I. Landini 1 , M. Brugia 1 , T. Mazzei 3 , F. Tonelli 4 , S. Nobili 3<br />
1 Experimental and Clinical Medicine, University <strong>of</strong> Florence, Florence, Italy,<br />
2 LISM-IIT, National Research Council, Pisa, Italy, 3 Health Sciences, University <strong>of</strong><br />
Florence, Florence, Italy, 4 Biomedical Experimental and Clinical Sciences “Mario<br />
Serio”, University <strong>of</strong> Florence, Florence, Italy<br />
Background: 5-year overall survival <strong>of</strong> stage III colorectal cancer (CRC) patients (pts)<br />
treated with standard adjuvant (adjuv) chemotherapy (CHT) (a fluoropyrimidine, FP<br />
+/- oxaliplatin, OHP) is still unsatisfactory and highly variable (42-88%). Although in<br />
CRC single molecular biomarkers or molecular signatures predictive <strong>of</strong> adjuv CHT<br />
outcome have been identified, none <strong>of</strong> them has been validated. The goal <strong>of</strong> this study<br />
was to identify and validate molecular biomarkers predictive <strong>of</strong> response to FP-based<br />
adjuv CHT in stage III CRC pts.<br />
Methods: From a large case series <strong>of</strong> CRC pts who received adjuv CHT (a FP +/- OHP)<br />
we selected two groups with favorable (F) (no evidence <strong>of</strong> disease recurrence (DR)<br />
within 5 yrs from CHT, n = 12) or unfavorable (UNF) (evidence <strong>of</strong> DR within 3 yrs<br />
from CHT, n = 12) prognosis. We used fresh frozen CRC explants according to an IRB<br />
approved protocol. Global gene expression pr<strong>of</strong>ile was performed by Ion Proton<br />
System. Differentially expressed genes between groups were identified and some <strong>of</strong><br />
them, selected according to a preliminary candidature on the basis <strong>of</strong> literature data or<br />
their pathobiological role, were validated by RT-PCR.<br />
Results: Bioinformatic analysis identified 108 differentially expressed genes between<br />
groups (p value
abstracts<br />
multicenter data.The aim <strong>of</strong> this study is to evaluate the prognostic impact <strong>of</strong><br />
perineural invasion in rectal cancer treated with preopreraitve chemoradiotherapy.<br />
Methods: From Jan 2002 to Dec 2010, 1260 patients, with locally advanced rectal<br />
cancer treated with preopreraitve chemoradiotherapy at three institutions, were<br />
included. The median radiation dose was 5040 cGy with concurrent chemotherapy.<br />
Their medical charts were retrospectively reviewed including pathology report. Survival<br />
analysis was performed to identify the clinicopatholgic factor affecting disease-free<br />
survival (DFS) and overall survival (OS).<br />
Results: Perineural invasion was positive in 221 patients (17.5%). The patients with<br />
perineural invasion were associated with more advanced pathologic stage, less tumor<br />
regression grade, more circumferential resection involvement, more positive lymphatic<br />
invasion, and more positive venous invasion. The DFS and OS <strong>of</strong> the perineural<br />
invasion positive patients was significantly poorer than that <strong>of</strong> the perineural invasion<br />
negative patients (5-year DFS = 46.5% vs 81.1%, p < 0.001; 5-year OS = 62.5% vs 90.2%,<br />
p < 0.001). Multivariate analyses, using the Cox proportional hazards model, indicated<br />
that perineural invasion (hazard ratio [HR] = 1.95, 95% CI = 1.45-2.62, p < 0.001), age,<br />
yp stage and circumferential resection were prognostic factors for disease-free survival.<br />
Perineural invasion (HR = 1.95, 95% CI = 1.35-2.82, p < 0.001), age, gender, tumor<br />
regression grade, yp Stage, circumferential resection, venous invasion and adjuvant<br />
chemotherapy were independently significant risk factors for overall survival in<br />
multivariable analysis.<br />
Conclusions: Perineural invasion were associated with poor DFS and OS in rectal<br />
cancer patients who undergo preoperative chemoradiotherapy. These patients require<br />
careful monitoring after surgery.<br />
Legal entity responsible for the study: Ji Won Park<br />
Funding: Seoul National University Hospital<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
578P<br />
Family history <strong>of</strong> colorectal cancer (CRC) in first degree<br />
relatives and survival in patients with newly diagnosed<br />
synchronous metastatic CRC<br />
S. Ahmed 1 , S.Y.A. Kazmi 2 , M.E. Emara 3 , T. Asif 3 , R. Alvi 3 ,D.Le 3 , N. Iqbal 3 ,<br />
A. Zaidi 1 , T. Abbas 1 , K. Haider 1<br />
1 <strong>Oncology</strong>, Saskatchewan Cancer Agency, Saskatoon Cancer Center, University<br />
<strong>of</strong> Saskatchewan, Saskatoon, SK, Canada, 2 Medicine, Ziauddin Medical College,<br />
Karachi, Pakistan, 3 <strong>Oncology</strong>, Saskatoon Cancer Centre University <strong>of</strong><br />
Saskatchewan, Saskatoon, SK, Canada<br />
Background: Colorectal cancer (CRC) history in first degree relative is a known risk<br />
factor for CRC and correlates with better survival in patients with early stage CRC.<br />
However, the prognostic effect <strong>of</strong> CRC history in first degree relatives (CHFR) in newly<br />
diagnosed synchronous metastatic CRC is not well known. The current study aims to<br />
determine prognostic roles <strong>of</strong> CHFR in patients with newly diagnose metastatic CRC.<br />
Methods: A cohort <strong>of</strong> patients diagnosed with synchronous stage IV CRC during<br />
2006-2010 in the province <strong>of</strong> Saskatchewan was studied. Patients who did not have<br />
information about family history (FH) were excluded. A Cox proportional multivariate<br />
analysis was performed to assess relationship between CHFR and survival.<br />
Results: 419 eligible patients with synchronous stage IV CRC were identified, 342<br />
(81.6%) had a positive FH whereas 77 (18.4%) did not have a FH <strong>of</strong> cancer. Of 342<br />
patients with a positive FH, 106 (30.9%) had a FH <strong>of</strong> CRC and 76 (22.2%) had CHFR<br />
(father, n = 21, mother, n = 15, brother, n = 20, sister, n = 15, son n = 3, daughter,<br />
n = 2). Of 76 patients with CHFR, 69 had one, 6 had 2, and one had 3 first degree<br />
relative with the diagnosis <strong>of</strong> CRC. Thirteen (12%) <strong>of</strong> 106 patients also had a diagnosis<br />
<strong>of</strong> CRC in a grandparent. Median overall survival <strong>of</strong> patients with CHFR who received<br />
chemotherapy was 17 months (95% CI: 13.9-20.1) compared with 22 months<br />
(19.1-24.9) if they don’t have CHFR (p = 0.10). The Cox proportional multivariate<br />
model revealed following relationship between various variables and survival. Use <strong>of</strong><br />
chemotherapy, HR: 0.30 (0.22-0.39), metastasectomy, HR: 0.41 (95% CI: 0.29-0.57),<br />
age < 70 yrs, HR 0.47 (0.24-0.91), primary tumor resection, HR: 0.58 (0.46-0.73),<br />
normal WBC count, HR: 0.68 (0.52-089), ECOG performance status 0-1, HR: 0.70<br />
(0.54-0.90), stage IVa disease, HR: 0.79 (0.64-0.97), Charlson Comorbid score, HR:<br />
0.54 (0.28-1.05) and absence <strong>of</strong> CHFR 0.84 (0.64-1.09).<br />
Conclusions: Unlike early stage CRC, CHFR does not correlate with better survival in<br />
patients with newly diagnosed synchronous stage IV CRC. In fact, we noted a trend<br />
toward inferior survival in patients with CHFR.<br />
Legal entity responsible for the study: N/A<br />
Funding: Saskatchewan Cancer Agency<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
579P<br />
A nomogram for predicting overall survival (OS) in Japanese<br />
patients (pts) with advanced colorectal cancer (aCRC) treated<br />
with irinotecan (IRI)-based regimens<br />
W. Ichikawa 1 , K. Uehara 2 , K. Minamimura 3 , C. Tanaka 4 , Y. Takii 5 , H. Miyauchi 6 ,<br />
S. Sadahiro 7 , K. Shinozaki 8 , K. Fukumoto 9 , T. Otsuji 10 , T. Kambara 11 , S. Morita 12 ,<br />
Y. Ando 13 , M. Arai 14 , M. Sugihara 15 , T. Sugiyama 16 , Y. Ohashi 17 , Y. Sakata 18<br />
1 Division <strong>of</strong> Medical <strong>Oncology</strong>, Showa University School <strong>of</strong> Medicine, Tokyo,<br />
Japan, 2 Department <strong>of</strong> Surgical <strong>Oncology</strong>, Nagoya University Graduate School <strong>of</strong><br />
Medicine, Nagoya, Japan, 3 Department <strong>of</strong> Surgery, Mitsui Memorial Hospital,<br />
Tokyo, Japan, 4 Department <strong>of</strong> Surgery, Gifu Prefectural General Medical Center,<br />
Gifu, Japan, 5 Department <strong>of</strong> Surgery, Niigata Cancer Center Hospital, Niigata,<br />
Japan, 6 Department <strong>of</strong> Frontier Surgery, Chiba University Graduate School <strong>of</strong><br />
Medicine, Chiba, Japan, 7 Department <strong>of</strong> Surgery, Tokai University, Isehara, Japan,<br />
8 Division <strong>of</strong> Clinical <strong>Oncology</strong>, Hiroshima Prefectural Hospital, Hiroshima, Japan,<br />
9 Department <strong>of</strong> Surgery, Nishijin Hospital, Kyoto, Japan, 10 Department <strong>of</strong><br />
Gastroenterology, Dongo Hospital, Yamatotakada, Japan, 11 Department <strong>of</strong><br />
Surgery, Japan Mutual Aid Association <strong>of</strong> Public School Teachers Chugoku<br />
Central Hospital, Fukuyama, Japan, 12 Department <strong>of</strong> Biomedical Statistics and<br />
Bioinformatics, Kyoto University Graduate School <strong>of</strong> Medicine, Kyoto, Japan,<br />
13 Department <strong>of</strong> Clinical <strong>Oncology</strong> and Chemotherapy, Nagoya University<br />
Hospital, Nagoya, Japan, 14 Pharmacovigilance Department, Daiichi Sankyo,<br />
Tokyo, Japan, 15 Clinical Data & Biostatistics Department, Daiichi Sankyo, Tokyo,<br />
Japan, 16 Department <strong>of</strong> Obsterics and Gynecology, Iwate Medical University<br />
School <strong>of</strong> Medicine, Morioka, Japan, 17 Department <strong>of</strong> Integrated Science and<br />
Engineering for Sustainable Society, Chuo University Faculty <strong>of</strong> Science and<br />
Engineering, Tokyo, Japan, 18 Misawa City Hospital, Misawa, Japan<br />
Background: One <strong>of</strong> the standard treatments for aCRC is IRI-based regimens, which<br />
are commonly used as second line treatment in Japan. We conducted a prospective<br />
observational study to examine the correlation between UGT1A1 genotypes and the<br />
clinical outcome <strong>of</strong> IRI-based regimens in Japanese pts with aCRC (NCT 01039506).<br />
We presented previously the results <strong>of</strong> OS, the secondary endpoint (ASCO 2015, Abst<br />
No. 3525). Furthermore, We are going to present update results <strong>of</strong> OS (ASCO 2016,<br />
Abst No. 3571). We developed a nomogram for predicting survival <strong>of</strong> pts treated with<br />
second-line IRI-based regimens after first-line oxialiplatin-based treatment.<br />
Methods: From Oct 2009 to Mar 2012, 1,376 pts with histologically confirmed aCRC<br />
treated with IRI-based regimens were enrolled into the study. Among all enrolled pts,<br />
747 pts were treated with the second-line IRI-based regimens after first-line<br />
oxialiplatin-based treatment. A nomogram for predicting OS was developed using<br />
multivariable Cox proportional hazards model. The discriminative ability and<br />
predictive accuracy <strong>of</strong> the nomogram were determined by concordance index (c-index)<br />
and calibration plot. The nomogram was internally validated using bootstrap<br />
resampling.<br />
Results: The median OS was 18.5 months (95% CI, 16.8 – 20.7). The multivariable Cox<br />
proportional hazards model included age, performance status, resection <strong>of</strong> primary<br />
tumor, location <strong>of</strong> primary tumor (right vs left), tumor burden based on longitudinal<br />
diameters <strong>of</strong> target lesions according to the RECIST criteria, diabetes and white blood<br />
cell count as predictors <strong>of</strong> OS. The resulting nomogram demonstrated good<br />
discrimination and calibration in predicting OS, with a bootstrap-corrected c-index <strong>of</strong><br />
0.68. The nomogram showed good separation between risk groups stratified by tertile<br />
<strong>of</strong> the total score, with median OS <strong>of</strong> 10.1, 18.6, and 29.4 months for low, middle, and<br />
high risk groups, respectively.<br />
Conclusions: This proposed nomogram is well calibrated and internally validated.<br />
External validation is essential before implementing this nomogram in clinical practice.<br />
Clinical trial identification: NCT 01039506, first released on 23/Dec/2009. The trial<br />
protocol number is TOP009-061.<br />
Legal entity responsible for the study: Daiichi Sankyo<br />
Funding: Daiichi Sankyo<br />
Disclosure: W. Ichikawa, S. Morita, Y. Ando, T. Sugiyama, Y. Ohashi: Advisory Board<br />
members <strong>of</strong> this study. Honoraria from Daiichi Sankyo. Y. Takii: Honoraria from<br />
Daiichi Sankyo. M. Arai: Employee <strong>of</strong> Daiichi sankyo. M. Sugihara: Employee <strong>of</strong><br />
Daiichi Sankyo. Y. Sakata: Advisory Board members <strong>of</strong> this study. Honoraria from<br />
Daiichi Sankyo, Taiho Pharmaceutical, Yakult Honsya. All other authors have declared<br />
no conflicts <strong>of</strong> interest.<br />
580P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Risk factors for brain metastases in patients with metastatic<br />
colorectal cancer<br />
T.D. Christensen 1 , J.A. Palsh<strong>of</strong> 1 , F.O. Larsen 1 , E. Høgdall 2 , T.S. Poulsen 2 ,B.<br />
V. Jensen 1 , P. Pfeiffer 3 , M.K. Yilmaz 4 , I.J. Christensen 2 , D.L. Nielsen 1<br />
1 Department <strong>of</strong> <strong>Oncology</strong>, Herlev and Gent<strong>of</strong>te Hospital, Herlev, Denmark,<br />
2 Department <strong>of</strong> Pathology, Herlev and Gent<strong>of</strong>te Hospital, Herlev, Denmark,<br />
3 Department <strong>of</strong> <strong>Oncology</strong>, Institute <strong>of</strong> Clinical Research, Odense, Denmark,<br />
4 Department <strong>of</strong> <strong>Oncology</strong>, Aalborg University Hospital, Aalborg, Denmark<br />
Background: Brain metastases (BM) from colorectal cancer (CRC) are rare and usually<br />
develop late in the disease. However, it has been suggested that more patients will be<br />
diagnosed with BM from CRC due to improved diagnostics and increased survival. The<br />
vi196 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
aim <strong>of</strong> this study was to identify biological and clinical characteristics that could predict<br />
later BM development in long surviving patient with metastatic (m) CRC.<br />
Methods: We retrospectively reviewed a multicenter database and biobank<br />
encompassing consecutive patients with mCRC who all received cetuximab in<br />
combination with irinotecan as third-line treatment independently <strong>of</strong> RAS status<br />
between 2005 and 2008. We performed RAS (KRAS & NRAS), BRAF, and PIK3CA<br />
sequencing <strong>of</strong> DNA from primary tumor tissue.<br />
Results: Totally, 480 patients were included in the study. BM were diagnosed in 42<br />
patients (8.8 %) at median 29 months after mCRC diagnosis. Patient characteristics are<br />
shown in table 1. Patients with BM had a significantly longer survival from mCRC<br />
diagnosis than non-BM patients (32 months vs 28 months, p = 0.001). On univariate<br />
cox regression analysis the risk <strong>of</strong> developing BM was increased in patients with rectal<br />
cancer (Hazard ratio (HR) = 2.478, p = 0.005), metachronous metastatic disease<br />
(HR = 2.296, p = 0.013), and lung metastases at mCRC diagnosis (HR = 4.196,<br />
p < 0.0005). RAS, BRAF or PIK3CA were not associated with BM. On multivariate cox<br />
regression, only presence <strong>of</strong> lung metastases (HR = 3.534, p < 0.0005) was significantly<br />
associated with increased hazard <strong>of</strong> BM.<br />
Conclusions: The incidence <strong>of</strong> BM was 8.8 % in our cohort <strong>of</strong> long surviving patients<br />
with mCRC. Having lung metastases at mCRC diagnosis seems to be an independent<br />
risk factor for later BM development. Rectal cancer and metachronous metastatic<br />
disease were also linked to an increased risk <strong>of</strong> BM.<br />
Table: 580P Patient characteristics<br />
-BM 438 patients +BM 42 patients<br />
Median age at CRC diagnosis 60 years 58 years<br />
Rectal cancer 153 (35 %) 26 (62 %)<br />
Metachronous metastatic disease 188 (43 %) 28 (67 %)<br />
Lung metastases 130 (30 %) 26 (62 %)<br />
RAS Mut 184 (42 %) 20 (48 %)<br />
BRAF Mut 30 (7 %) 0<br />
PIK3CA Mut 58 (13 %) 7 (16 %)<br />
Legal entity responsible for the study: Troels Dreier Christensen and Dorte Lisbet<br />
Nielsen<br />
Funding: The Danish Cancer Society<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
581P<br />
Prognostic factors in patients with locally advanced rectal<br />
cancer who underwent preoperative chemoradiotherapy:<br />
Subclassification <strong>of</strong> patients with ypstage II cancer according<br />
to tumor regression grade<br />
T. Suzuki, S. Sadahiro, G. Saito, K. Okada, A. Tanaka<br />
Surgery, Tokai University School <strong>of</strong> Medicine Isehara Campus, Isehara, Japan<br />
Background: Preoperative chemoradiotherapy (CRT) is the standard <strong>of</strong> care for locally<br />
advanced rectal cancer. Patients with a marked histological response have good<br />
outcomes with low risk <strong>of</strong> local and distant recurrence. Histological response can be<br />
evaluated on the basis <strong>of</strong> T or N downstaging, and tumor regression grade (TRG).<br />
Some patients with ypStage II are evaluated to have no downstaging because <strong>of</strong> the<br />
presence <strong>of</strong> small amounts <strong>of</strong> residual cancer cells in the T3 layer even if they have a<br />
marked reduction in tumor volume and a TRG <strong>of</strong> 2. We therefore studied whether the<br />
combination <strong>of</strong> ypStage and TRG could be used as prognostic factor.<br />
Methods: We studied 191 patients with cT3/T4, Nx, or cT2, N + , M0 adenocarcinoma<br />
<strong>of</strong> the rectum who underwent surgery after CRT from 2007 to 2015. The total radiation<br />
dose was 40 or 45 Gy given in combination with oral UFT or S-1. Surgery was<br />
performed 6 to 8 weeks after the completion <strong>of</strong> radiotherapy. Survival analyses were<br />
performed according to ypStage and ypStage plus TRG.<br />
Results: Recurrence was found in 47 patients (25%). The initial site <strong>of</strong> recurrence was<br />
local in 5 patients (3%), the liver in 16 (8%), and the lung in 19 (10%). The ypStage was<br />
0 in 39 patients (20%), I in 45 (24%), II in 62 (32%), and III in 45 (24%). Downstaging<br />
was noted in 44% <strong>of</strong> the patients. The TRG was 1 in 32 patients (17%), 2 in 49 (26%), 3<br />
in 75 (39%), and 4 in 35 (18%). The median follow-up was 55 months, the 5y DFS was<br />
71%, and the 5y OS was 85%. The 5y DFS according to ypStage was 82% in 0 or I<br />
cancer and 62% in II or III cancer, and the 5y OS was 90% and 82%, respectively.<br />
Survival rates was significantly higher in ypStage 0 or I cancer than in ypStage II or III<br />
cancer (p = 0.0003 and p = 0.0465). The 5y DFS was 83% in patients with ypStage 0 or<br />
I or ypStage II cancer with a TRG <strong>of</strong> 2, as compared with 58% in other patients. The 5y<br />
OS was 92% and 79%, respectively. Survival rates were significantly higher in patients<br />
with ypStage 0 or I or ypStage II cancer with a TRG <strong>of</strong> 2 (p < 0.0001 and p = 0.0055).<br />
Conclusions: Outcomes were good even in patients with ypStage II cancer who had a<br />
TRG <strong>of</strong> 2. Combining the TRG histological response with ypStage may be a better<br />
prognostic indicator than ypStage alone.<br />
Legal entity responsible for the study: N/A<br />
Funding: Tokai University<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
582P<br />
Colorectal cancer in octogenarian patients: a single institution<br />
experience<br />
E. Inga, G. Padilla, E. Casaut, M. Gonzalez, A. Gonzalez-Haba, J.R. Rodriguez,<br />
J. Gomez-Ulla<br />
<strong>Oncology</strong>, Complejo Hospitalario Universitario de Badajoz, Badajoz, Spain<br />
Background: Colorectal cancer (CRC) is one <strong>of</strong> the most common malignancies and<br />
most <strong>of</strong>ten occurs in patients (pts) aged 65 years or older. As our population ages,<br />
elderly cancer care has become a growing challenge. However octogenarian pts are<br />
understaged, undertreated and underrepresented in scientific literature. The purpose <strong>of</strong><br />
this study was identify data <strong>of</strong> our population over 80 years<br />
Methods: We performed an institutional retrospective observational cohort study <strong>of</strong><br />
pts with CRC referred to Medical <strong>Oncology</strong> during 4 years (2012–2015), and followed<br />
until April 2016. The inclusion criteria were age >80 years old and<br />
pathologic-confirmed CRC<br />
Results: 112 pts were included in this study. Octogenarian were a 16% <strong>of</strong> all CRC pts.<br />
The median age was 84 years (range 79–94), 55% male (n = 61). The tumor was located<br />
in the rectum, left and right colon in 19%, 37% and 44% <strong>of</strong> cases. The majority (72%)<br />
were diagnosed in stage III-IV and 28% patients in stages I-II. One metastatic site was<br />
found in 69% pts, 2 sites in 21% and 10% had 3 or more; the main metastatic site was<br />
liver (56%) 44 (38%) pts underwent surgery (ST) and chemotherapy (CT) (4 pts in the<br />
neo-adjuvant setting); 22 (20%) pts only CT and 13 (12%) pts benefited from best<br />
supportive care (BSC) As first-line therapy: 70% received capecitabine (cape)<br />
monotherapy (25 in Stage III and 20 in IV), 18% oral tegafur-uracil (UFT), 8% capeox<br />
(cape and oxaliplatin) and only one patient capeox-bevacizumab. 19%(21) <strong>of</strong> pts had<br />
second-line treatment (8 cape, 6 capeox, 5 cape-irinotecan and 2 UFT); 2 pts had 3<br />
lines. 53 (47%) pts died and most at hospital (60%). Median follow-up was 19 months<br />
(mo). Median OS was 30.6 mo (95%CI 26-35) Stage IV pts had an expected survival <strong>of</strong><br />
14 mo, stage III 34 mo and stage I-II pts 44 mo with statistically significant difference.<br />
Survival is 35 mo for ST and CT group and in BSC was 16 mo (p 0.001) According to<br />
first-line therapy, cape monotherapy vs capeox, median survival was 24 and 41 mo<br />
respectively (95%CI 17–30 and 35-46) with no statistically significant difference (p<br />
0.42)<br />
Conclusions: In the present study, conventional CT had significant benefit for OS in<br />
very elderly pts with CRC. The most significant factors for OS were stage at diagnosis<br />
and treatment. Further studies are needed to determine the appropriate treatment in<br />
octogenarian pts with CRC.<br />
Legal entity responsible for the study: Elizabeth Inga Saavedra<br />
Funding: Complejo Hospitalario Universitario de Badajoz<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
583P<br />
Prognostic factor analysis for elderly patients treated for<br />
metastatic colorectal cancer in the randomized phase II trial<br />
PRODIGE 20<br />
T. Aparicio 1 , O. Bouché 2 , E. Francois 3 , E. Maillard 4 , S. Kirscher 5 , J. Taieb 6 ,<br />
P.-L. Etienne 7 , R. Faroux 8 , F. Khemissa Akouz 9 , F. El Hajbi 10 , C. Locher 11 ,<br />
Y. Rinaldi 12 , T. Lecomte 13 , S. Lavau-Denes 14 , M. Baconnier 15 , A. Oden-Gangl<strong>of</strong>f 16 ,<br />
D. Genet 17 , E. Paillaud 18 , F. Retornaz 19 , L. Bedenne 20<br />
1 Service HGE, Hôpital Avicenne - AP-HP, Bobigny, France, 2 Médecine<br />
Ambulatoire-Cancérologie, CHU Robert Debré, Reims, France, 3 Service<br />
Oncologie, Centre Antoine Lacassagne, Nice, France, 4 Faculté de médecine,<br />
FFCD, Dijon, France, 5 Institut Ste Catherine, Avignon, France, 6 Service HGE,<br />
Hôpital européen G.Pompidou, Paris, France, 7 Service Oncologie, Centre CARIO -<br />
HPCA, Plerin Sur Mer, France, 8 Service d’HGE, CHD Vendee - Hopital Les<br />
Oudairies, La Roche Sur Yon, France, 9 Service HGE, CH Saint Jean, Perpignan,<br />
France, 10 Service Cancérologie Digestive, Centre Oscar Lambret, Lille, France,<br />
11 Service Gastroentérologie, CH de Meaux, Meaux, France, 12 Service d’HGE,<br />
Hôpital européen, Marseille, France, 13 Service HGE, Hôpital Trousseau, Tours,<br />
France, 14 Service d’Oncologie, CHU Limoges - Hopital Dupuytren, Limoges,<br />
France, 15 Service HGE, CH Annecy Genevois, Pringy, France, 16 Service HGE,<br />
CHU Charles Nicolle, Rouen, France, 17 Service Oncologie, Clinique Chenieux,<br />
Limoges, France, 18 Service Médecine Interne et Gériatrie, CHU Henri Mondor,<br />
Créteil, France, 19 Hôpital Européen, Marseille, France, 20 Service HGE, CHU Le<br />
Bocage, INSERM U866, Dijon, France<br />
Background: PRODIGE 20 randomized patients (pts) aged 75+ to receive<br />
bevacizumab + chemotherapy (LV5FU2, FOLFOX, FOLFIRI, according investigators<br />
choice) or chemotherapy alone. The primary endpoint based on efficacy and safety was<br />
reached in BEV-CT. This analysis presents updated progression-free survival (PFS) and<br />
overall survival (OS), including univariate and multivariate analyses.<br />
Methods: PFS was defined as time from randomization to progression or death and OS<br />
as time from randomization to death. Prognostic factors analyzed were: treatment arm,<br />
age (≤80 vs >80), sex, rectum vs colon, primary tumor resected or not, doublet vs<br />
mono-chemotherapy, body mass index (≥21 vs
abstracts<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
questionnaire (>2 vs ≤2), fall in the 6 months previous randomization or one-leg<br />
balance, presence <strong>of</strong> anemia, albumin (>35 vs ≤35 g/L), creatinine clearance (>45 vs<br />
≤45 mL/min), CEA (>2N vs ≤2N), CA19.9 (>2N vs ≤2N) and Köhne criteria (low vs<br />
intermediate vs high). Baseline variables significant at 15% in univariate analysis were<br />
introduced in the multivariate Cox model.<br />
Results: 102 pts were randomized (51 BEV-CT, 51 CT) and 100 pts were treated:<br />
chemotherapy was LV5FU2 in 52 pts (26 BEV-CT, 26 CT) and a doublet regimen in 48<br />
pts (23 BEV-CT, 25 CT) including 23 FOLFOX and 25 FOLFIRI. The median<br />
follow-up was 20.4 months. 25 pts BEV-CT and 31 pts CT received 2 nde line<br />
chemotherapy. Multivariate analysis shows that Spitzer QoL, albumin and Köhne<br />
criteria were prognostic for OS. Spitzer QoL and Köhne criteria were also prognostic<br />
for PFS.<br />
Table: 583P<br />
CT [95% CI]<br />
BEV + CT [95% CI]<br />
Median PFS (m) 7.8 [6.6-10.2] 9.7 [8.2-12.0]<br />
12 months PFS rate 23.5% [13.0-35.8] 37.3% [24.3-50.2]<br />
Median OS (m) 19.8 [13.9-23.7] 21.7 [14.8-30.3]<br />
36 months OS rate 10.1% [3.1-22.0] 27.0% [15.7-39.7]<br />
Conclusions: Spitzer QoL and Köhne criteria are prognostic factors for OS and PFS<br />
and should be used as stratification factors in future trials in elderly pts. Pts with a<br />
prolonged OS were observed in BEV-CT.<br />
Clinical trial identification: NCT01900717<br />
Legal entity responsible for the study: CHU Dijon<br />
Funding: Programme Hospitalier de Recherche Clinique and Roche laboratory<br />
Disclosure: T. Aparicio: Roche/Genentech, San<strong>of</strong>i, Ipsen, Novartis. O. Bouché: Merck<br />
Serono, Roche, Teva, Novartis, Lilly, Amgen, Pierre Fabre. E. Francois: Roche Pharma<br />
AG, Merck Serono, Roche Pharma AG, San<strong>of</strong>i, Celgène. J. Taieb: Roche Pharma<br />
AG. R. Faroux: Merck, Amgen. C. Locher: Merck Serono, Novartis, Roche Pharma AG,<br />
San<strong>of</strong>i. S. Lavau-Denes: San<strong>of</strong>i, AstraZeneca. L. Bedenne: Merck Serono, Roche<br />
Pharma AG. All other authors have declared no conflicts <strong>of</strong> interest.<br />
584P<br />
Stratification <strong>of</strong> patients with locally advanced rectal cancer<br />
(LARC) treated with preoperative chemoradiation (ChR),<br />
according to Valentini’s nomograms (VN) and the Neoadjuvant<br />
Rectal Score (NAR). External validation in a single Institution.<br />
S. Roselló Keränen 1 , M. Frasson 2 , E. García-Granero 2 , S. Navarro 3 , S. Campos 4 ,<br />
E. Jordá 5 , P. Esclapez 2 , S. García-Botello 6 , B. Flor 2 , A. Espí 6 , A. Cervantes 1<br />
1 Medical <strong>Oncology</strong>, Hospital Clinico Universitario de Valencia, Valencia, Spain,<br />
2 Surgery, Hospital Universitari i Politècnic La Fe, Valencia, Spain, 3 Pathology,<br />
Hospital Clinico Universitario de Valencia, Valencia, Spain, 4 Radiology, Hospital<br />
Clinico Universitario de Valencia, Valencia, Spain, 5 Radiotherapy, Hospital Clinico<br />
Universitario de Valencia, Valencia, Spain, 6 Surgery, Hospital Clinico Universitario<br />
de Valencia, Valencia, Spain<br />
Background: Preoperative ChR is the standard <strong>of</strong> care for LARC. The estimation <strong>of</strong><br />
risk <strong>of</strong> locoregional (LR) or systemic recurrence (SR) or death is mainly based upon<br />
pathological and clinical features. Valentini et al. (JCO 2011) developed 3 nomograms<br />
to predict the 5-year probability <strong>of</strong> locoregional or distant control as well as overall<br />
survival (OS) with patients from 5 European randomized clinical trials. The NAR<br />
(Curr Colorectal Cancer Rep 2015) was developed after VN for OS combining the<br />
three variables (cT, ypT and ypN) with the greatest weight in the model. Both VN and<br />
NAR had an external validation.<br />
Methods: 158 consecutive patients from a single academic institution were diagnosed<br />
<strong>of</strong> LARC between 1998 and 2011 and treated with ChR followed by total mesorectal<br />
excision. Most <strong>of</strong> them received adjuvant chemotherapy (ACh). The variables used in<br />
the nomograms were sex, age, clinical stage, tumor location, radiotherapy dose,<br />
chemotherapy, surgical procedure and ypTNM stage. According to the score obtained,<br />
patients were divided in 3 groups <strong>of</strong> low (L), intermediate (I) and high (H) risk.<br />
Kaplan-Meier curves, Log-rank test and Cox regression analysis were performed.<br />
C-index was determined to assess the discrimination <strong>of</strong> the test.<br />
Results: Median follow up was 54 months. VN 5 year OS was 83%, 77% and 67% for L,<br />
I and H risk groups, respectively (p = 0,023) and the NAR Score 5 year OS was 84%,<br />
71% and 59% for L, I and H risk (p = 0,004). The c-index was 0,64 and 0,63,<br />
respectively. When the score was analyzed as a continuous variable, all 3 nomograms<br />
and the NAR had a statistically significant association with 5 year LR (HR 1,12; 95%CI<br />
1,02-1,23, p = 0,02), 5 year SR (HR 1,07; 95%CI 1,03-1,12, p = 0,001), 5 year OS in VN<br />
(HR 1,10; 95%CI 1,05-1,14, p < 0,001) and 5 year OS in NAR (HR 1,04; IC95%<br />
1,02-1,05, p < 0,001). c-index were 0,70; 0,60; 0,69 and 0,66, respectively.<br />
Conclusions: Validation <strong>of</strong> VN and the NAR in our series confirm their value to<br />
predict outcomes combining different variables in a statistical model. These predictive<br />
scores may be <strong>of</strong> interest to stratify patients according to their individual estimates <strong>of</strong><br />
risk when designing trials <strong>of</strong> ACh.<br />
Legal entity responsible for the study: Hospital Clínico Universitario de Valencia<br />
Funding: Hospital Clínico Universitario de Valencia<br />
Disclosure: A. Cervantes: Receipt <strong>of</strong> honoraria or consultation fees: Merck Serono,<br />
Roche, Amgen, Bayer, Lilly. Participation in a company sponsored speaker’s bureau:<br />
Roche, Merck Serono. All other authors have declared no conflicts <strong>of</strong> interest.<br />
585P<br />
Brain metastases (BM) in colorectal cancer (CRC): Prognostic<br />
factors and survival analysis<br />
L.P. Del Carpio Huerta 1 , M. Tobeña 1 , A.C. Virgili Manrique 1 , J. Szafranska 2 ,<br />
M. Martín-Richard 1 , D. Paez 1 , I. Espinoza 2 , A. Sebio Garcia 1 , P. Gomila Pons 1 ,<br />
M. Andrés Granyo 1 , A. Barba Joaquín 1 , N. Dueñas Cid 1 , A. Vethencourt Casado 1 ,<br />
M.S. García-Cuerva 1<br />
1 Medical <strong>Oncology</strong>, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain,<br />
2 Pathology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain<br />
Background: CRC BM are an uncommon event. Some clinical features have been<br />
associated with its occurrence but its knowledge remains limited.<br />
Methods: We retrospectively analysed CRC patients who developed BM in our center<br />
between 1997-2016. Clinical factors (age, performance status [PS], CRC location,<br />
stage), RAS/BRAF status and survival were evaluated.<br />
Results: 28 patients developed BM and their median age was 64 years (21-81). 82% <strong>of</strong> the<br />
patients had left-sided CRC and 85% had PS0-1. Median time to BM diagnosis from CRC<br />
diagnosis was 36 months (m) (1.6-97). 92% <strong>of</strong> the patients received active treatment (46%<br />
whole-brain radiotherapy [WBRT], 46% surgery [S] with or without WBRT). RAS/BRAF<br />
were analysed in 60% <strong>of</strong> cases (47% RAS mutated, 0% BRAF mutated). Median survival<br />
(MS) from BM treatment was better for patients who underwent S with or without WBRT<br />
than for those treated with WBRT alone (11.3m versus [vs] 6.7m, p = 0.03). This result<br />
remained significant in multivariate analysis (MVA) (HR 0.36; 95% confidence interval<br />
[CI] 0.14-0.94, p = 0.038). CRC location showed impact on MS from BM treatment (4.6m<br />
vs 10.7m, p = 0.017, for right- and left-sided CRC); MVA remained significant (HR 3.19;<br />
95%CI 1.12-13.6, p = 0.032). PS2 and right-sided CRC were associated with shorter time to<br />
BM diagnosis: 3.3m vs 43.8m for PS2 and PS0-1 (p < 0.001) and 9.3m vs 46.6m for rightand<br />
left-sided CRC (p = 0.003). PS2 and right-sided CRC were associated with worse<br />
overall survival (OS), too (6.8m vs 51.5, p = 0.001, for PS2 and PS0-1, respectively, and<br />
16.2m vs 53.4m, p < 0.001, for right- and left-sided CRC, respectively). Both remained<br />
significant in MVA for time to BM diagnosis (HR =10.9; 95%CI 1.74-68.29, p = 0.01;<br />
HR = 8.8; 95%CI,1.13-59.04, p = 0.025, for PS and right-sided CRC, respectively) and OS<br />
(HR = 7.6; 95%CI 1.48-39.7, p = 0.015; HR = 7.5; 95%CI 1.93-29.68, p = 0.004, for PS and<br />
right-sided CRC, respectively). None <strong>of</strong> other clinical factors nor RAS/BRAF status showed<br />
prognostic value.<br />
Conclusions: Surgical treatment <strong>of</strong> CRC with or without WBRT seems superior to<br />
WBRT in terms <strong>of</strong> survival. Right-sided CRC and PS 2 were associated with worse<br />
outcome, while RAS status and other clinical factors had not shown prognostic value.<br />
Legal entity responsible for the study: Hospital de la Santa Creu i Sant Pau<br />
Funding: Hospital de la Santa Creu i Sant Pau<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
586P<br />
5-fluorouracil degradation rate (5-FU-DR) as a new toxicity<br />
predictive biomarker for adjuvant FOLFOX in colorectal cancer<br />
(CRC) patients<br />
C.E. Onesti 1 , A. Botticelli 1 ,F.Mazzuca 1 ,A.Milano 1 , A. Romiti 1 ,M.Roberto 1 ,<br />
R. Falcone 1 , M. Occhipinti 1 , F.R. Di Pietro 1 , L. Lionetto 2 , M. Simmaco 3 ,P.Marchetti 1<br />
1 Medical <strong>Oncology</strong>, Azienda Ospedaliera St. Andrea - Roma, Rome, Italy,<br />
2 Advanced Molecular Diagnostic Unit, Istituto Dermopatico dell’Immacolata,<br />
Rome, Italy, 3 Advanced Molecular Diagnostic Unit, Sapienza – Università di Roma,<br />
Rome, Italy<br />
Background: FOLFOX (5-FU, Oxaliplatin and Leucovorin) is the most effective<br />
treatment for CRC patients in adjuvant setting. However, the toxicity can lead to<br />
reduction, delay or discontinuation <strong>of</strong> treatment. DPD is the key enzyme involved in<br />
5-FU catabolism and 5-FU-DR is a phenotypic parameter, reflecting the entire<br />
metabolism <strong>of</strong> 5-FU. We investigated the association between 5-FU-DR and genetic<br />
polymorphisms <strong>of</strong> TSER, DPYD, MTHFR and with toxicity in CRC patients treated<br />
with adjuvant FOLFOX.<br />
Methods: We collected 126 blood samples before starting treatment. 5-FU-DR was<br />
determined by measuring the decrease <strong>of</strong> a fixed amount <strong>of</strong> 5-FU added to a solution <strong>of</strong><br />
Peripheral Blood Mononuclear Cells after 2 hours <strong>of</strong> incubation. Patients were classified<br />
as: poor metabolizers (PM: 5-FU-DR ≤ 0.85 ng/ml/10 6 cells/min); normal metabolizers<br />
(NM: 0.85 < 5-FU-DR > 2.2 ng/ml/10 6 cells/min); ultra-rapid metabolizers (UM:<br />
5-FU-DR ≥ 2.2 ng/ml/10 6 cells/min). DNA pyrosequensing was used to detect gene<br />
polymorphisms <strong>of</strong> MTHFR, DPYD and TSER. Toxicities were classified according to<br />
CTCAE v 4.0. Statistical analysis was performed with SPSS2 s<strong>of</strong>tware. Pearson’sChi<br />
Square test was used to correlate gene polymorphisms and 5-FU-DR with toxicities.<br />
Results: We analyzed 126 resected CRC patients (91 M, 35 F; median age 65 y, range<br />
36-81 y), receiving adjuvant FOLFOX. 7 patients were PM, 116 NM and 3 UM. Median<br />
5-FU-DR was 1.495 ng/ml/10 6 cells/min (range 0.42-2.29). G3-4 toxicities were<br />
observed in 22.2% <strong>of</strong> the cases: 59.3% hematological, 29.6% gastrointestinal, 7.4%<br />
neurological and 3.7% others. A higher G3-4 toxicity incidence was observed in PM<br />
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<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
and UM than in NM group (71.4% and 33.3% respectively vs 19%; p = 0.05). PM and<br />
UM required more frequently dose reduction due to toxicity (71.4% and 66.6% vs 31%;<br />
p = 0.04). One case <strong>of</strong> DPYD heterozygous mutated was detected and it was associated<br />
with 5-FU-DR PM (p = 0.04) and G4 hematological toxicity (p = 0.06). No statistically<br />
significant associations between toxicities and TSER (p = 0.2), MTHFR C677T<br />
(p = 0.5) and MTHFR A1298C (p = 0.8) were observed.<br />
Conclusions: 5-FU-DR seems to predict toxicity in resected CRC patients treated with<br />
5-FU. Larger and perspective studies are required to implement this results.<br />
Legal entity responsible for the study: N/A<br />
Funding: University <strong>of</strong> Rome "Sapienza"<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
587P<br />
Clinical characteristics <strong>of</strong> colorectal cancer patients with<br />
brain metastases: An "Association des Gastro-Éntérologues<br />
Oncologues" (AGEO) multicenter study<br />
P. Roussille 1 , M. Dior 2 , C. Locher 3 , M. Mabro 4 , P. Artru 5 , G. Tachon 6 , É. Frouin 7 ,<br />
A. Berger 8 , M. Wager 9 , J.-M. Goujon 7 , L. Karayan-Tapon 6 , D. Tougeron 10<br />
1 Radiotherapy, CHU Poitiers, Jean Bernard Hôpital, Poitiers, France,<br />
2 Gastroenterology, Hôpital Cochin, Paris, France, 3 Gastroenterology, CH de<br />
Meaux, Meaux, France, 4 Gastroenterology, Foch Hôpital, Paris, France,<br />
5 Gastroenterology, Hôpital Privé Jean Mermoz, Lyon, France, 6 Cancer Biology,<br />
CHU Poitiers, Jean Bernard Hôpital, Poitiers, France, 7 Pathology, CHU Poitiers,<br />
Jean Bernard Hôpital, Poitiers, France, 8 Radiotherapy, CHU Poitiers, Poitiers,<br />
France, 9 Neurosurgery, CHU Poitiers, Jean Bernard Hôpital, Poitiers, France,<br />
10 Gastroenterology, CHU Poitiers, Jean Bernard Hôpital, Poitiers, France<br />
Background: Brain metastases (BM) from colorectal cancer (CRC) are rare (1-3%) but<br />
their incidence seems to be increasing due to improvement <strong>of</strong> CRC prognosis. The<br />
prognosis <strong>of</strong> patients with BM from CRC is poor. The objective <strong>of</strong> this study was to<br />
evaluate the clinico-biological criteria <strong>of</strong> CRC with BM.<br />
Methods: This multicenter retrospective study included all patients with BM from CRC<br />
between 1995 and 2015. Overall Survival was calculated using the Kaplan-Meier method.<br />
Results: A total <strong>of</strong> 135 patients were included. Mean age at diagnosis <strong>of</strong> CRC was 63.5<br />
years [range 34-87] and 57.8% were men. Primary tumors were located preferentially in<br />
the rectum (37.1%) or sigmoid (24.3%). The median interval from CRC diagnosis to BM<br />
diagnosis was 34.2 months [IC95%: 28.2-38.7] and the one from the diagnosis <strong>of</strong> CRC<br />
metastases to BM diagnosis 20.7 months [IC95%: 13.2-26.1]. BM were mostly revealed<br />
by neurological symptoms (93.3%), predominantly unifocal (50.4%) and supratentorial<br />
(74.1%). At BM diagnosis, 71.1% <strong>of</strong> patients had lung metastases, 48.9% liver metastases<br />
and 11.9% had no extra-cerebral metastasis. BM resection was performed in 37.1% <strong>of</strong> the<br />
cases and 76.3% <strong>of</strong> patients underwent a brain radiotherapy. The mean overall survival<br />
from the time <strong>of</strong> BM diagnosis was 8.7 months [IC95%: 6.7-10.7], respectively 14.8<br />
months [IC95%: 10.8-18.7] in the group <strong>of</strong> patients who underwent surgical resection<br />
versus 4.9 months [IC95%: 3.0-6.8] for the others (p < 0.0001). Overall survival was 12.3<br />
months [IC95%: 9.0-15.7] for patients with unifocal BM versus 4.9 months [IC95%:<br />
3.2-6.6] for patients with multifocal BM (p < 0.0001). Molecular analyses (RAS and<br />
BRAF) are ongoing and will be presented at the congress. Among the 34 CRC with<br />
available KRAS status, KRAS mutation was observed in 58.8% <strong>of</strong> the cases.<br />
Conclusions: The prognosis <strong>of</strong> patients with BM from CRC remains poor. Patients<br />
with BM from CRC have frequently lung metastases. The time between diagnosis <strong>of</strong><br />
CRC metastases and BM raises the question <strong>of</strong> BM screening at 1-2 years <strong>of</strong> metastatic<br />
disease. Early detection <strong>of</strong> BM from CRC can allow curative-intent aggressive<br />
treatment with an expected benefit on survival and quality <strong>of</strong> life.<br />
Legal entity responsible for the study: Pauline Roussille<br />
Funding: AGEO<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
588P<br />
Is the derived neutrophil to lymphocyte ratio (dNLR) an<br />
independent prognostic marker in patients with metastatic<br />
colorectal cancer (mCRC)? Analysis <strong>of</strong> the CO.17 and CO.20<br />
studies<br />
C.I. Diakos 1 ,D.Tu 2 , V. Gebski 3 , S. Yip 3 , K. Wilson 3 , C.S. Karapetis 4 ,C.<br />
J. O’Callaghan 5 , J. Shapiro 6 , N. Tebbutt 7 , D.J. Jonker 8 , L.L. Siu 9 , R. Wong 10 ,<br />
C. Doyle 11 , A.H. Strickland 12 , T.J. Price 13 , J. Simes 3 , S. Clarke 14<br />
1 Kolling Institute <strong>of</strong> Medical Research, Royal North Shore Hospital, St Leonards,<br />
Australia, 2 Department <strong>of</strong> Mathematics and Statistics, Canadian Cancer Trials<br />
Group, Queens University, Kingston, ON, Canada, 3 NHMRC Clinical Trials Centre,<br />
NHMRC Clinical Trials Centre University <strong>of</strong> Sydney, Camperdown, Australia,<br />
4 Department <strong>of</strong> Medical <strong>Oncology</strong>, Flinders Centre for Innovation in Cancer,<br />
Flinders University and Flinders Medical Centre, Bedford Park, Australia,<br />
5 Department <strong>of</strong> Public Health Sciences, Canadian Cancer Trials Group, Queens<br />
University, Kingston, ON, Canada, 6 Department <strong>of</strong> Medicine, Monash University,<br />
Melbourne, Australia, 7 Medical <strong>Oncology</strong>, Austin Hospital, Heidelberg, Australia,<br />
8 Department <strong>of</strong> Medicine, Division <strong>of</strong> Medical <strong>Oncology</strong>, Ottawa Hospital<br />
Research Institute, University <strong>of</strong> Ottawa, Ottawa, ON, Canada, 9 Department <strong>of</strong><br />
Medical <strong>Oncology</strong> and Hematology, Princess Margaret Hospital, Toronto, ON,<br />
Canada, 10 Hematology and <strong>Oncology</strong>, St. Boniface General Hospital Cancercare<br />
Manitoba, Winnipeg, MB, Canada, 11 Laval University, Centre Hospitalier<br />
Universitaire de Quebec, Quebec City, QC, Canada, 12 Monash Cancer Centre,<br />
Monash University, Melbourne, Australia, 13 Haematology and <strong>Oncology</strong>, The<br />
Queen Elizabeth Hospital and University <strong>of</strong> Adelaide, Adelaide, Australia, 14 Medical<br />
<strong>Oncology</strong>, Royal North Shore Hospital, St Leonards, Australia<br />
Background: dNLR (neutrophil count /(total white cell - neutrophil count)) has shown<br />
prognostic utility for overall survival (OS) in a number <strong>of</strong> cancers. The CCTG/AGITG<br />
CO.17 and CO.20 studies examined the EGFR inhibitor, cetuximab (C), versus best<br />
supportive care, and in combination with the VEGF/FGFR inhibitor brivanib (B) or<br />
placebo, respectively, in previously treated patients with mCRC. Here, we examine<br />
dNLR in CO.17 and CO.20 for its utility to predict progression free survival (PFS),<br />
response rate (RR) and OS.<br />
Methods: Association between dNLR status and PFS, OS and RR was analysed using<br />
multivariate regression models adjusting for baseline (BL) disease and patient (pt)<br />
characteristics. Interaction between treatment and dNLR status was studied by<br />
including an additional interaction term in the models.<br />
Results: CO.17 recruited 572 pts; 570 pts had available BL dNLR data. CO.20 recruited<br />
750 pts; 718 had BL data available. In both, pts with high BL dNLR (≥2) were<br />
significantly more likely to have poorer ECOG status, received more lines <strong>of</strong> therapy,<br />
abnormal alkaline phosphatase levels, ≥ grade 1 anaemia, ascites, presented with lung<br />
metastases, have ≥2 sites <strong>of</strong> metastases. Multivariate analyses results are summarised in<br />
Table 1. Both studies showed pts with high dNLR had significantly shorter OS.<br />
Significant association <strong>of</strong> dNLR status with PFS was only found in CO.20 but no<br />
significant association with RR was found in either study. Significant association was<br />
found with OS in all four treatment groups, but for PFS, in C + B arm <strong>of</strong> CO.20 only. In<br />
both studies, no significant interaction was found between dNLR status and treatment<br />
for either OS or PFS.<br />
Table: 588P Multivariate analysis <strong>of</strong> dNLR in CO.17 and CO.20<br />
CO.17<br />
CO.20<br />
abstracts<br />
dNLR
abstracts<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
589P<br />
Is baseline neutrophil to lymphocyte ratio (NLR) an<br />
independent prognostic biomarker for progression free<br />
survival (PFS) and overall survival (OS) in metastatic colorectal<br />
cancer (mCRC)? Analysis <strong>of</strong> the AGITG MAX study<br />
590P<br />
Prognostic value <strong>of</strong> neutrophil/lymphocyte ratio (NLR),<br />
platelet/lymphocyte ratio (PLR) and mean platelet volume<br />
(MPV) in patients with colorectal carcinoma [Izmir <strong>Oncology</strong><br />
Group (IZOG) study]<br />
C.I. Diakos 1 , K. Wilson 2 , R. Asher 2 , V. Gebski 2 , S. Yip 2 , G. van Hazel 3 ,<br />
B. Robinson 4 , A. Broad 5 , T.J. Price 6 , J. Simes 7 , N. Tebbutt 8 , S. Clarke 9<br />
1 Kolling Institute <strong>of</strong> Medical Research, Royal North Shore Hospital, St Leonards,<br />
Australia, 2 NHMRC Clinical Trials Centre, NHMRC Clinical Trials Centre University<br />
<strong>of</strong> Sydney, Camperdown, Australia, 3 School <strong>of</strong> Medicine and Pharmacology,<br />
University <strong>of</strong> Western Australia, Perth, Australia, 4 <strong>Oncology</strong> Service, Christchurch<br />
Hospital, Christchurch, New Zealand, 5 Medical <strong>Oncology</strong>, Andrew Love Cancer<br />
Centre, Geelong, Australia, 6 Haematology and <strong>Oncology</strong>, The Queen Elizabeth<br />
Hospital and University <strong>of</strong> Adelaide, Adelaide, Australia, 7 <strong>Oncology</strong>, NHMRC<br />
Clinical Trials Centre, Sydney, Australia, 8 Medical <strong>Oncology</strong>, Austin Hospital,<br />
Heidelberg, Australia, 9 Medical <strong>Oncology</strong>, Royal North Shore Hospital, St<br />
Leonards, Australia<br />
Background: NLR (ratio <strong>of</strong> absolute neutrophil and lymphocyte counts) has shown<br />
prognostic utility for OS in a number <strong>of</strong> cancer types. The AGITG MAX study<br />
examined capecitabine (C) with C + bevacizumab (B) and C + B + mitomycin C (M) in<br />
first-line treatment <strong>of</strong> mCRC. CB demonstrated superiority over C for PFS and was<br />
comparable to CBM. We examine NLR in the MAX study to assess its utility for<br />
prediction <strong>of</strong> treatment effect, PFS and OS.<br />
Methods: PFS and OS estimates were obtained using the method <strong>of</strong> Kaplan-Meier and<br />
hazard ratios obtained using proportional hazards models. Analysis included adjusting<br />
for baseline (BL) disease and patient (pt) characteristics and investigating potential<br />
interaction effects between NLR status and significant BL predictors <strong>of</strong> outcome.<br />
Results: MAX study recruited 471 pts; relevant BL haematological data was available<br />
for 403 pts (86%). At BL, 24% <strong>of</strong> pts had high NLR (≥5). High NLR correlated with<br />
rectal primary (p = 0.007), higher ECOG status (p < 0.001), more prior therapy (i.e.<br />
prior adjuvant/neoadjuvant) (p = 0.01), more sites <strong>of</strong> metastases (p = 0.006). Results<br />
<strong>of</strong> univariate analysis summarised in Table 1. On univariate analysis, pts with high<br />
NLR had significantly increased risk <strong>of</strong> progression & death. On multivariate analysis,<br />
high NLR, treatment group, ECOG status & liver involvement were significantly<br />
associated with PFS; high NLR, treatment group, ECOG status, prior adjuvant/<br />
neoadjuvant treatment & primary tumour site were significantly associated with OS.<br />
No significant interaction was observed between treatment & NLR status for both PFS<br />
& OS.<br />
Table: 589P Univariate analysis <strong>of</strong> baseline NLR in MAX study<br />
Outcome Factor Median (mo)<br />
(95% CI)<br />
PFS NLR < 5<br />
NLR ≥ 5<br />
OS NLR < 5<br />
NLR ≥ 5<br />
7.5 (6.9-8.5)<br />
5.9 (4.7-7.3)<br />
19.8<br />
(17.3-21.4)<br />
12.1<br />
(8.4-14.8)<br />
HR (95% CI)<br />
p-value<br />
Univariate<br />
1.4 (1.1-1.8)<br />
0.006<br />
1.9 (1.4-2.4)<br />
183 had 78.7 months (p = 0.016); the group MPV ≤ 8.3<br />
had 59.7 months, the group MPV > 8.3 had 87.2 months; the group MPV > 8.3 had<br />
87.2 months and the group MPV < 8.3 had 59.7 months (p = 0.057).<br />
Table: 590P Clinical characteristics <strong>of</strong> the patients with colorectal<br />
cancer<br />
Characteristics <strong>of</strong> the patients n (%)<br />
Age (years), Mean (range) 62.2 ± 11.8 (33-86)<br />
Gender<br />
Male 211 (62.8)<br />
Female 125 (37.2)<br />
TNM stage<br />
Stage 1 27 (8.0)<br />
Stage 2 160 (47.6)<br />
Stage 3 149 (44.4)<br />
Degree <strong>of</strong> differentiation<br />
Well-differentiated 85 (25.3)<br />
Moderately-differentiated 207 (61.6)<br />
Poorly-differentiated 44 (13.1)<br />
Disease status at last follow-up<br />
Evidence <strong>of</strong> disease (ED) 89 (26.4)<br />
No evidence <strong>of</strong> disease (NED) 247 (73.6)<br />
Tumor localization<br />
rectal 66 (19.6)<br />
colon 270 (80.3)<br />
Conclusions: Our study demonstrated that NLR, PLR and MPV levels can actually be<br />
relied on as a prognostic factor in patients with CRC. MPV, NLR and PLR values<br />
displayed by recently diagnosed patients with CRC may be a reflection <strong>of</strong> an increased<br />
cytokine level and thereby change depending on it.<br />
Legal entity responsible for the study: N/A<br />
Funding: Izmir <strong>Oncology</strong> Group(IZOG) Study<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
591P<br />
Reduction <strong>of</strong> blood total lymphocyte count after neoadjuvant<br />
treatment is correlated with good tumor regression—results<br />
from a prospective randomized control trial<br />
Z. Wu, Y. Deng, J. Zhang, Y. Cai, H. Hu, L. Yang<br />
Medical <strong>Oncology</strong>, The Sixth Affiliated Hospital <strong>of</strong> Sun Yat-sen University,<br />
Guangzhou, China<br />
Background: Blood total lymphocyte count (TLC) before treatment had been reported<br />
to be play an important role in tumor immune response. The study aimed to evaluate<br />
whether the change <strong>of</strong> TLC was correlate with tumor regression grade (TRG) after<br />
neoadjuvant treatment in locally advanced rectal cancer patients.<br />
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<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Methods: TLC before and after neoadjuvant therapy were collected from available 307<br />
patients in FOWARC study. The ratio <strong>of</strong> TLC reduction after neoadjuvant therapy was<br />
calculated. TRG 0-1 was defined as good responder. The correlation between TRG and<br />
the ratio <strong>of</strong> lymphocyte reduction was evaluated.<br />
Results: Of the 307 patients, 153 patients were good responder (TRG 0-1), and 154 had<br />
poor response (TRG 2-3). The base-line TLC before neoadjuvant therapy have no<br />
significant difference (p = 0.296) between good and poor responders. After<br />
neoadjuvant therapy, 85% <strong>of</strong> patients experienced TLC reduction. TLC after<br />
neoadjuvant treatment was lower in good response group than that <strong>of</strong> poor response<br />
group, with a median TLC <strong>of</strong> 1.08 and 1.29, respectively (p = 0.011). In the group with<br />
neoadjuvant chemotherapy alone, TLC reduction was more obvious in good responder.<br />
The median ratio <strong>of</strong> TLC reduction after neoadjuvant were 39.41% and 33.33% in good<br />
and poor responder group, respectively (p = 0.037).<br />
Table: 591P<br />
Items Good response group Poor response group<br />
TRGO TRG1 TRG2 TRG3<br />
Ratio <strong>of</strong> TLC reduction <strong>of</strong> all 36.00% ± 3.06% 36.00% ± 2.99% 32.00% ± 2.99% 16.00% ± 5.955<br />
307 patients<br />
Ratio <strong>of</strong> TLC reduction in 27.0% ± 4.16% 9.78% ± 5.16% 11.04% ± 3.58 5.06% ± 6.46%<br />
chemotherapy group<br />
TLC before neoadjuvant 2.003 ± 0.056 2.041 ± 0.048<br />
TLC after neoadjuvant 1.263 ± 0.044 1.427 ± 0.056<br />
Conclusions: TLC reduction is more apparent in patients with good response after<br />
neoadjuvant treatment. The consumption <strong>of</strong> lymphocytes might indicate the immune<br />
response inside tumors after neoadjuvant treatment, which could be a predictor <strong>of</strong><br />
sensitivity to preoperative therapy.<br />
Legal entity responsible for the study: Yanhong Deng<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
592P<br />
Is neutropenia a prognostic or a predictive factor for second<br />
line metastatic colorectal cancer (mCRC) patients (Pts)?<br />
Exploratory analysis from RAISE, a randomized, double-blind,<br />
phase III study <strong>of</strong> ramucirumab (RAM) + FOLFIRI vs placebo<br />
(PBO) + FOLFIRI<br />
T.-E. Ciuleanu 1 , G. Bodoky 2 , R. Garcia-Carbonero 3 , P. García Alfonso 4 ,E.Van<br />
Cutsem 5 , K. Muro 6 , D. Mytelka 7 , O. Lipkovich 8 , D. Ferry 9 , A. Sashegyi 8 ,<br />
F. Nasroulah 10 , J. Tabernero 11<br />
1 Radiochemotherapy Department, Institutul Oncologic Chiricuta and UMF, Cluj<br />
Napoca, Romania, 2 Medical <strong>Oncology</strong>, St. Laszlo Hospital, Budapest, Hungary,<br />
3 Medical <strong>Oncology</strong> Department, Hospital Virgen del Rocio, Seville, Spain,<br />
4 Medical <strong>Oncology</strong>, Hospital General University Gegorio Marañon, Madrid, Spain,<br />
5 Digestive <strong>Oncology</strong>, University Hospitals Leuven and KU Leuven, Leuven,<br />
Belgium, 6 Department <strong>of</strong> Clinical <strong>Oncology</strong>, Aichi Cancer Center Hospital, Nagoya,<br />
Japan, 7 <strong>Oncology</strong>, Eli Lilly and Company, Indianapolis, IN, USA, 8 Statistics, Eli Lilly<br />
and Company, Indianapolis, IN, USA, 9 <strong>Oncology</strong>, Eli Lilly and Company,<br />
Bridgewater, NJ, USA, 10 <strong>Oncology</strong>, Eli Lilly Argentina, Buenos Aires, Argentina,<br />
11 Oncologia Médica, Vall d’Hebron University Hospital and Institute <strong>of</strong> <strong>Oncology</strong><br />
(VHIO), Barcelona, Spain<br />
Background: In the RAISE study, RAM + FOLFIRI improved the outcomes <strong>of</strong> pts with<br />
previously treated mCRC as compared to pts treated with PBO + FOLFIRI with an<br />
increase in adverse events. Notably, neutropenia occurred at a higher frequency in pts<br />
receiving RAM + FOLFIRI and <strong>of</strong>ten led to dose modifications or discontinuations. We<br />
conducted an exploratory analysis to determine whether the incidence <strong>of</strong> neutropenia<br />
affected outcomes in the RAISE pt population.<br />
Methods: In the RAISE study, pts were randomized 1:1 to receive 8 mg/kg IV<br />
RAM + FOLFIRI or PBO + FOLFIRI every 2 weeks. Pts from both treatment arms were<br />
included in the analysis if they developed any-grade neutropenia after the initiation <strong>of</strong><br />
study treatment. Overall survival (OS) was analyzed using the Kaplan-Meier method<br />
and a Cox proportional hazards model.<br />
Results: The frequency <strong>of</strong> any-grade neutropenia was 59% (311/529) in RAM pts<br />
(grade ≥3; 38%) vs 46% (241/528) in PBO pts (grade ≥3; 23%). Dose modifications <strong>of</strong><br />
one or more study drugs were required in most pts with neutropenia (RAM: 81% [253/<br />
311]; PBO: 80% [193/241]). Pts with any-grade neutropenia treated with RAM had a<br />
median OS (mOS) <strong>of</strong> 16.1 vs 12.6 months for those on PBO (HR = 0.79; 95% CI, 0.64,<br />
0.96). Pts who did not experience neutropenia had a mOS <strong>of</strong> 10.7 months in both arms<br />
(HR = 1.05; 0.86, 1.28). Among pts who had at least one neutropenic event, 83%<br />
developed the event within 2 months <strong>of</strong> starting treatment. Similar efficacy was seen<br />
among pts with grade ≥1, ≥2, or ≥3 neutropenia.<br />
Conclusions: Neutropenia may be a prognostic or predictive factor for pts with mCRC.<br />
Pts from the RAISE study with any-grade neutropenia in both treatment arms seemed<br />
to have longer survival compared to those who did not experience neutropenia;<br />
however, mOS for pts with neutropenia in the RAM arm was higher than that in the<br />
PBO arm. These results suggest that the treatment effect <strong>of</strong> RAM in neutropenic pts<br />
with mCRC is unlikely to be compromised despite lower chemotherapy dose intensity.<br />
Additional analyses are underway to elucidate the meaning and the biological<br />
mechanism <strong>of</strong> the effect <strong>of</strong> RAM in neutropenic pts.<br />
Clinical trial identification: ClinicalTrials.gov NCT01183780<br />
Legal entity responsible for the study: Eli Lilly and Company<br />
Funding: Eli Lilly and Company<br />
Disclosure: T.-E. Ciuleanu: Consultant/ Advisory board Eli Lilly, Roche, Merck,<br />
Amgen. G. Bodoky: I was attending an advisory board <strong>of</strong> Lilly. NO financial interest in<br />
products or processes involved in this research. This includes stock ownership,<br />
corporate-sponsored research, or other substantive relationships. R. Garcia-Carbonero:<br />
Scientific advise to Roche, Merck, San<strong>of</strong>i, Amgen, Bayer, Lilly. P. García Alfonso:<br />
Advisory role: Roche, Merck, Amgen, Bayer, San<strong>of</strong>i, Celgene, Lilly. Speaker: Roche,<br />
Merck, Amgen, Lilly. E. Van Cutsem: Research Grant from Lilly: Consultant:<br />
Lilly. D. Mytelka, O. Lipkovich, D. Ferry, A. Sashegyi, F. Nasroulah: Employee and<br />
shareholder <strong>of</strong> Eli Lilly and Company. J. Tabernero: Consultant/Advisory role: Amgen,<br />
Bayer, Boehringer Ingelheim, Celgene, Chugai, Lilly, MSD, Merck Serono, Novartis,<br />
Roche, San<strong>of</strong>i, Symphogen, Takeda, Taiho. All other authors have declared no conflicts<br />
<strong>of</strong> interest.<br />
593P<br />
Prognostic value <strong>of</strong> signet ring cell histology for survival in<br />
stage I and II colon cancer patients: a population-based,<br />
propensity score matched analysis<br />
U. Gueller 1 , T. Cerny 2 , B. Schmied 3 , R. Warschkow 3<br />
1 Department <strong>of</strong> <strong>Oncology</strong>/Hematology, Kantonsspital St. Gallen, St. Gallen,<br />
Switzerland, 2 Internal Medicine, Kantonsspital St. Gallen, St. Gallen, Switzerland,<br />
3 Surgery, Kantonsspital St. Gallen, St. Gallen, Switzerland<br />
Background: Previous retrospective research associated signet ring cell histology with<br />
poor oncologic outcomes in colon cancer patients. However, potential bias can not be<br />
ruled out in previous studies. This is the first propensity-score based investigation<br />
assessing the prognostic impact <strong>of</strong> signet ring cell histology on overall and<br />
cancer-specific survival in patients with stage I and II colon cancer.<br />
Methods: Stage I and II colon cancer patients undergoing surgery between 2004 and<br />
2013 were identified in the Surveillance, Epidemiology, and End Results (SEER)<br />
database. Overall survival (OS) and cancer-specific survival (CSS) were assessed using<br />
risk-adjusted Cox proportional hazards regression models and propensity score<br />
methods.<br />
Results: Overall, 75,134 stage I-II colon cancer patients were included, <strong>of</strong> which 380<br />
(0.5%) with signet ring cell histology. In unadjusted analyses, the 5-year OS and CSS in<br />
patients with signet ring cell histology was 64.7% (95% confidence interval (CI):<br />
59.3-70.6%) and 84.1% (95% CI: 79.9-88.6%) compared with 73.9% (95% CI:<br />
73.6-74.3%) and 88.6% (95% CI: 88.3-88.9%), respectively, in patients with non-signet<br />
ring adenocarcinoma (P = 0.003 and P = 0.026). The survival disadvantage disappeared<br />
in risk-adjusted Cox proportional hazard regression analysis (OS: hazard ratio<br />
(HR) = 0.96, 95% CI: 0.80-1.15, P = 0.647; CSS 0.88, 95% CI: 0.66-1.17, P = 0.368), and<br />
after propensity score matching (OS: HR= 0.92, 95% CI: 0.76-1.11, P = 0.357 and CSS:<br />
HR = 0.86, 95% CI: 0.65-1.16, P = 0.315).<br />
Conclusions: This is the first propensity-score adjusted population-based investigation<br />
on exclusively stage I and II colon cancer patients providing compelling evidence that<br />
signet ring cell histology does not negatively impact survival. Therefore, standard<br />
treatment strategies can be applied in these patients.<br />
Legal entity responsible for the study: N/A<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
594P<br />
abstracts<br />
Evolution <strong>of</strong> skeletal muscle mass (SMM) during palliative<br />
systemic treatment in metastatic colorectal cancer (mCRC)<br />
patients participating in the randomized phase 3 CAIRO3<br />
study<br />
S.A. Kurk 1 , P.H.M. Peeters 2 , B. Dorresteijn 3 , M. Jourdan 3 , H.J. Kuijf 4 , C. Punt 5 ,<br />
M. Koopman 1 , A.M. May 6<br />
1 Medical <strong>Oncology</strong>, University Medical Center Utrecht, Utrecht, Netherlands,<br />
2 Public Health, Imperial College London-South Kensington Campus, London, UK,<br />
3 <strong>Oncology</strong>, Nutricia Research, Utrecht, Netherlands, 4 Image Science Institute,<br />
University Medical Center Utrecht, Utrecht, Netherlands, 5 Medical <strong>Oncology</strong>,<br />
Academic Medical Center, University <strong>of</strong> Amsterdam, Amsterdam, Netherlands,<br />
6 Julius Center for Health Sciences and Primary Care, University Medical Center<br />
Utrecht, Utrecht, Netherlands<br />
Background: Observational studies suggest that low SMM is associated with<br />
chemotherapy-related toxicity and poor survival in mCRC patients. Little is known<br />
about patterns <strong>of</strong> SMM during palliative systemic therapy. Here we use data <strong>of</strong> the<br />
CAIRO3 study (Simkens et al. Lancet 2015) in which mCRC patients with stable<br />
disease or better after 6 cycles capecitabine + oxaliplatin + bevacizumab (CAPOX-B)<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw370 | vi201
abstracts<br />
were randomized between maintenance treatment with capecitabine + bevacizumab<br />
(CAP-B, M) and observation (O). In both groups CAPOX-B or other treatment was<br />
reintroduced upon disease progression until second disease progression, which was<br />
also the primary study endpoint. We used repeated scan data <strong>of</strong> 101 CAIRO3 patients<br />
to investigate SMM during treatment.<br />
Methods: 307 CT-scans <strong>of</strong> 101 randomly chosen CAIRO3 patients (63.1 ± 9.0 years, M<br />
n = 51; O n = 50) were analyzed for SMM at four time points (i.e. prior to start<br />
pre-randomization induction treatment, at randomization, at first and at second<br />
disease progression) using single slice evaluation at L3. A linear mixed effects model<br />
was used to assess SMM changes both within and between study arms.<br />
Results: Before CAIRO3 randomization during 6 cycles <strong>of</strong> CAPOX-B induction<br />
treatment, SMM decreased significantly in all patients (M: -0.8kg, (95% CI -0,14; -1,2)<br />
and O: -0,7kg (-0,4; -1,6)). After randomization, SMM recovered during maintenance<br />
treatment by 0,2kg (-0.3; 0,8) and observation -0.5kg (-1,1; 0,2) both compared to<br />
pre-induction SMM levels (median time 9.0 months and 4.3 months for M and O,<br />
respectively). After first progression and during reinduction treatment with CAPOX-B<br />
or other treatment, SMM again decreased significantly and similarly in both arms, M:<br />
-0,9kg (-0,1; -1.6), and O: -1,5kg (-0,8; -2,3) compared to pre-induction SMM levels<br />
(median time from first progression until second progression M: 4,7 months and O: 6,1<br />
months).<br />
Conclusions: Our data shows that muscle loss in mCRC patients during palliative<br />
systemic therapy is reversible and varies with treatment regimen. Although studies have<br />
shown prognostic capacity for SMM, the effect <strong>of</strong> subsequent changes in SMM are<br />
unknown and may be clues for new future therapeutic interventions.<br />
Clinical trial identification: ClinicalTrials.gov NCT00442637<br />
Legal entity responsible for the study: Sophie Kurk<br />
Funding: University Medical Center Utrecht<br />
Disclosure: B. Dorresteijn, M. Jourdan: Employee <strong>of</strong> Nutricia Research. C. Punt:<br />
Advisory role: Roche, Amgen, Bayer, Nordic Pharma, Merck-Serono. M. Koopman:<br />
Advisory role: Amgen, Roche, Bayer, Merck. Research funding: Roche, Merck, Bayer.<br />
All other authors have declared no conflicts <strong>of</strong> interest.<br />
595P<br />
Correlation between alternative endpoints and overall survival<br />
in metastatic colorectal cancer patients eligible to a<br />
maintenance strategy<br />
A. Turpin 1 , S. Paget-Bailly 2 , A. Ploquin 1 , A. Hollebecque 3 , S. Dominguez 4 ,<br />
F. Bonnetain 2 , F. El Hajbi 5 , M. Hebbar 1<br />
1 Oncologie Médicale, C.H.U. Claude Huriez, Lille, France, 2 Unité de Méthodologie<br />
et Qualité de vie en cancérologie (EA3181), CHU Besançon, Hôpital Jean Minjoz,<br />
Besançon, France, 3 Department <strong>of</strong> Medicine DITEP, Institut Gustave Roussy,<br />
Villejuif, France, 4 Oncologie médicale, Hopital Saint Vincent, Lille, France, 5 Dept de<br />
Cancerologie Digestive, Centre Oscar Lambret, Lille, France<br />
Background: In this study, our first aim was to assess the relation between different<br />
intermediate criteria and overall survival (OS) in patients treated for a metastatic<br />
colorectal cancer (mCRC) receiving a first-line chemotherapy associated with<br />
bevacizumab.<br />
Methods: We collected retrospective data from patients with mCRC treated with<br />
1 st -line chemotherapy (generally FOLFIRI-FOLFOX regimen) plus bevacizumab<br />
between January 2006 and December 2012. We assessed the following time to event<br />
endpoints: OS; progression free survival (PFS); duration <strong>of</strong> disease control (DDC), the<br />
sum <strong>of</strong> the periods in which the disease did not progress, and the time to failure <strong>of</strong><br />
strategy (TFS), the whole period before the introduction <strong>of</strong> second-line treatment.<br />
Linear correlation and linear regression models were used to study relations between<br />
OS and TFS, and OS and DDC, respectively. Prentice criteria for surrogacy were<br />
investigated.<br />
Results: We included 216 patients from 6 centers. 91 (42%) patients received a<br />
maintenance strategy. With a median follow-up <strong>of</strong> 57.6 (43.6-94.0) months, median OS<br />
was 24.5 (21.3-29.7) months, median PFS was 8.9 (8.4-9.7) months, median DDC was<br />
11.0 (9.8-12.4) months, and median TFS was 11.1 (10.0-13.0) months. Pearson<br />
coefficient (coeff) was 0.79 (CI 95% 0.73-0.83) and determination coeff was 0.62,<br />
suggesting <strong>of</strong> a satisfactory correlation between OS and DDC. Similarly, the correlation<br />
between OS and TFS was rather satisfactory with a Pearson coeff at 0.79 (CI 95%<br />
0.73-0.84) and a determination coeff at 0.63. Linear regression analysis showed a<br />
significant association between OS and DDC, and between OS and TFS, respectively.<br />
These relationships can be modeled by the formulas: cube root (SG) = 0.9547 + 0,8286<br />
cubic root (DDC) and cubic root (SG)= 0.9655 +0,8186 cubic root (TFS). Considering<br />
resection <strong>of</strong> metastases as the treatment, Prentice criteria were verified for both TFS<br />
and DDC.<br />
Conclusions: DDC and TFS were correlated to OS and Prentice criteria were validated<br />
for both endpoints. This makes them relevant as intermediate criteria, in the setting <strong>of</strong><br />
patients with mCRC treated with 1 st -line bevacizumab-based regimen.<br />
Legal entity responsible for the study: CHRU de Lille<br />
Funding: CHRU de Lille<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
596P<br />
Prognostic role <strong>of</strong> tumor location in stage 3 colorectal cancer<br />
patients received adjuvant chemotherapy<br />
N. Ozdemir 1 , S. Aslan 2 , K. Erdogan 3 , O. Yazici 4 , M.A. Sendur 1 , Y. Bozkaya 4 ,<br />
N. Zengin 1<br />
1 Department <strong>of</strong> Medical <strong>Oncology</strong>, YıldırımBeyazıt University, Faculty <strong>of</strong> Medicine,<br />
Ankara, Turkey, 2 Department <strong>of</strong> Radiation <strong>Oncology</strong>, Yıldırım Beyazıt University,<br />
Faculty <strong>of</strong> Medicine, Ankara, Turkey, 3 Internal medicine, Ankara Numune Education<br />
and Research Hospital, Ankara, Turkey, 4 Medical <strong>Oncology</strong>, Ankara Numune<br />
Education and Research Hospital, Ankara, Turkey<br />
Background: There are well defined clinic and pathologic risk factors in colorectal<br />
carsinomas (CRC). One <strong>of</strong> the most importantone is stage. Adjuvant systemic therapy<br />
is a part <strong>of</strong> standard treatment in stage 3. It is not known whether if location <strong>of</strong> tumor<br />
effects outcome. In current study we aimed to examine the effect <strong>of</strong> tumor location on<br />
prognosis in patients diagnosed as stage 3 CRC treated with adjuvant chemotherapy.<br />
Methods: Records <strong>of</strong> 245 stage 3 CRC patients operated between January 2010 and<br />
December 2014 we retrospectively evaluated. All cohorts received either adjuvan<br />
FOLFOX6 or infusional FU. They divided 3 subgroups; right colon (includes transver<br />
scolon), left colon and rectosigmoid according to the place <strong>of</strong> the tumor originated.<br />
Clinicopathologic differences and their effect on outcome were evaluated.<br />
Results: Median age was 63 (range; 25-80) with slightly male predominance (62%).<br />
Tumor was located on right colon (14.3%), left colon (12.2 %) and rectosigmoid 73.5%.<br />
All but 3 (neoadjuvant chemoradiotherapy) patients received adjuvant treatment.<br />
Adjuvant chemo consisted <strong>of</strong> FOLFOX6 in nearly 4/5 (77.7 %). There were no<br />
statistical significance between groups in terms <strong>of</strong> demographics, grade, tumor<br />
deposits, LVI, PNI and the adjuvan treatment type (p). N2 disease distribution had<br />
statistical significance between groups (Right Colon 19.0%, left colon 9.1% and<br />
rectosigmoid 32.4% p = 0.024). The 5-year OS was 72% in right colon carsinomas, 90%<br />
in left colon carsinomas and 63% in rectosigmoid carsinomas. Difference between OS<br />
was nearly statistically significant (p = 0.053). Other negative prognostic factors were<br />
ECOG, undifferentiated tumor and N2 disease (p < 0.05).<br />
Conclusions: In stage 3 operated colorectal cancer patients received adjuvant<br />
chemotherapy, poor differentiation, ECOG and N2 disease are associated with worse<br />
outcome. Left colon carsinomas have better survival rates compared with other<br />
locations. This can be associated with high N2 disease rate in patients having primary<br />
tumor in right colon and rectosigmoid region.<br />
Legal entity responsible for the study: Ankara Numune Hospital<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
597P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Neutrophil-to-lymphocyte ratio as a biomarker for prognosis in<br />
localized colorectal carcinoma<br />
N. Chic 1 , G. Bruixola 2 , O. Reig 1 , R. Diaz- Beveridge 2 , E. Buxo 1 , E. Pineda 1 ,<br />
A. Prat 1 , J. Aparicio 2 , J. Maurel 1<br />
1 Medical <strong>Oncology</strong>, Hospital Clinic y Provincial de Barcelona, Barcelona, Spain,<br />
2 Medical <strong>Oncology</strong>, Hospital Universitari i Politècnic La Fe, Valencia, Spain<br />
Background: Adjuvant therapy in Stage II colorectal cancer is controversial. Recently a<br />
molecular classification has identified four main molecular subtypes (canonical,<br />
mesenchymal, metabolic and immune) with potential clinical implication (Guinney,<br />
2015). Because neutrophil-to-lymphocyte ratio (NLR) has been described as a<br />
surrogate marker <strong>of</strong> the immune sub-type, we evaluate if NLR characterize a subgroup<br />
<strong>of</strong> patients (pts) with different prognosis.<br />
Methods: The aim <strong>of</strong> this study was to develop a cut<strong>of</strong>f for NLR to predict relapse-free<br />
survival <strong>of</strong> CRC pts in a training-set and validate it in an independent cohort <strong>of</strong> pts.<br />
Receiver operating characteristic (ROC) curve was used to determine the optimal cut<strong>of</strong>f<br />
for NLR. Relapse-free survival (RFS) was estimated by the Kaplan-Meier method.<br />
Results: The training set consist <strong>of</strong> 187 resected CRC pts <strong>of</strong> Hospital de la Fe de<br />
Valencia (HFV) and the validation set consist <strong>of</strong> 423 resected CRC pts <strong>of</strong> Hospital<br />
Clínic de Barcelona (HCB). At baseline, HFV pts were younger 65 years (25-85 years)<br />
vs 75 (50-94 years), with more advanced stage (stage III; 53% vs 41%) and treated more<br />
frequently with adjuvant therapy (58.3% vs 26.9%), than pts in the HCB cohort. The<br />
optimal cut<strong>of</strong>f in the training set was 2.2 (80.4% <strong>of</strong> sensitivity and a 99% <strong>of</strong> specificity).<br />
Accordingly to the cut<strong>of</strong>f, 77 pts (41.2%) have high NLR. Relapse-free survival was 17%<br />
in high NLR group vs 74% in the low NLR at 3 year follow up (FU) (p = 0.0001) with a<br />
Hazard ratio (HR) <strong>of</strong> 3.6 (95%CI 1.88-6.38) in the multivariate analysis. According to<br />
the previous cut<strong>of</strong>f, high NLR ratio was found in 309 (73%) out <strong>of</strong> 423 patients. RLF<br />
was 72.2% (95% IC 66.9-77.5) in high NLR and 88.3% (95 IC 81.8-94.8) in low NLR at<br />
3-year FU (p = 0.01) with a HR <strong>of</strong> 1.9 (95% CI 1.05-3.3) in the multivariate analysis.<br />
Conclusions: High NRL identify a group <strong>of</strong> resected patients more likely to relapse.<br />
NLR could be useful for stratification, especially with novel therapies (i.e.<br />
immunotherapy).<br />
Legal entity responsible for the study: Hospital Clinic de Barcelona<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
vi202 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
598TiP<br />
APOLLON study: a phase I/II study for the safety and efficacy<br />
<strong>of</strong> panitumumab in combination with TAS-102 for patients<br />
with RAS wild-type metastatic colorectal cancer refractory to<br />
standard chemotherapy<br />
K. Yamaguchi 1 , Y. Komatsu 2 , E. Oki 3 , T. Yoshino 4 , K. Yamazaki 5 , K. Shibuya 6 ,<br />
K. Oba 7 ,T.Kato 8<br />
1 Department <strong>of</strong> Gastroenterology, Cancer Institute Hospital <strong>of</strong> JFCR, Tokyo,<br />
Japan, 2 Cancer Center, Hokkaido University Hospital, Sapporo, Japan, 3 Surgery<br />
and Science, Graduate School <strong>of</strong> Medical Sciences, Kyushu University, Fukuoka,<br />
Japan, 4 Gastroenterology & Gastrointestinal <strong>Oncology</strong>, National Cancer Center<br />
Hospital East, Kashiwa, Japan, 5 Gastrointestinal <strong>Oncology</strong> and Endoscopy,<br />
Shizuoka Cancer Center, Shizuoka, Japan, 6 Medical Affairs, Takeda<br />
Pharmaceutical Company Ltd., Tokyo, Japan, 7 Department <strong>of</strong> Biostatistics,<br />
School <strong>of</strong> Public Health, Graduate School <strong>of</strong> Medicine, University <strong>of</strong> Tokyo, Tokyo,<br />
Japan, 8 Gastrointestinal Surgery, Kansai Rosai Hospital, Amagasaki, Japan<br />
Background: Anti-EGFR antibodies (Panitumumab (Pmab)/Cetuximab (Cmab)) have<br />
established efficacy and manageable safety pr<strong>of</strong>iles either in monotherapy or in<br />
combination with chemotherapy for the treatment <strong>of</strong> metastatic colorectal cancer<br />
(mCRC) patients (pts). In recent global phase III RECOURCE study, TAS-102<br />
significantly improved OS and PFS over placebo for mCRC pts refractory to standard<br />
therapies. In preclnical models, the combination <strong>of</strong> Pmab with TAS-102 demonstrated<br />
enhanced activities compared with either drug alone. This phase I/II study is designed<br />
to investigate the safety and efficacy <strong>of</strong> Pmab combination with TAS-102 for pts with<br />
RAS (KRAS/NRAS) wild-type mCRC refractory to standard chemotherapy.<br />
Trial design: Eligible pts are aged 20-74 y, ECOG performance status 0-1 with<br />
histologically/cytologically confirmed RAS wild-type mCRC, and refractory or<br />
intolerant to fluoropyrimidines, irinotecan, oxaliplatin, and anti-angiogenesis therapy<br />
and had neither prior anti-EGFR antibody nor regorafenib treatment. Phase I part is<br />
designed to determine recommended phase II dose (RP2D) in the dose de-escalation<br />
design <strong>of</strong> Pmab (6 mg/kg) every 2 weeks combination with TAS-102 (35 mg/m 2 BID<br />
on days 1–5 and 8–12, every 4 weeks). The primary objectives are to evaluate the<br />
incidence proportion <strong>of</strong> DLTs (phase I) and to evaluate the investigator assessed PFS<br />
rate at 6 months (phase II). In order to evaluate the effect <strong>of</strong> TAS-102 in addition to<br />
Pmab monotherapy, an exact binomial test with a nominal one-sided 5% significance<br />
level was predicted to have at least 80% power to detect the difference between the null<br />
hypothesis proportion <strong>of</strong> 29% PFS rate and the alternative proportion <strong>of</strong> 48% PFS rate<br />
with the sample size <strong>of</strong> 47 patients. To assure an adequate number <strong>of</strong> evaluable<br />
patients, target number <strong>of</strong> subjects are defined 52 (addition to Phase I patients<br />
administered with RP2D). As <strong>of</strong> May 2016, 6 pts have been enrolled. Results are<br />
expected in 2017.<br />
Clinical trial identification: ClinicalTrials.gov NCT02613221<br />
Legal entity responsible for the study: MHLW, Japan.<br />
Funding: Takeda pharmaceutical Co., ltd.<br />
Disclosure: K. Yamaguchi: Honoraria (speaker’s bureau): Takeda, Taiho, Merch,<br />
Chugai, Eli-Lily: Research funding for clinical trials from Takeda. Y. Komatsu:<br />
Honoraria (speaker’s bureau) and Research funding from Novartis, Pfizer, Bayer,<br />
Yakult, Daiichi-Sankyo, Kyowa-Kirin, Chugai, Merck-Serono, BMS, Taiho, Takeda,<br />
Eli-Lilly. E. Oki: has received Honoraria (lecture fee) from Takeda, Taiho. T. Yoshino:<br />
Research funding for clinical trials from GlaxoSmithKline, Boehringer<br />
Ingelheim. K. Yamazaki: Honoraria (lecture and/or manuscript fee) from Bayer,<br />
Yakult, Daiichi-Sankyo, Chugai, Merck-Serono, BMS, Taiho, Takeda. Research funding<br />
from BMS. K. Shibuya: Employee <strong>of</strong> Takeda. K. Oba: Honoraria (lecture and/or<br />
manuscript fee) from Takeda, BMS, Ono, Chugai. T. Kato: Honoraria (lecture fee) from<br />
Bayer, Yakult, Chugai, Merck-Serono, Takeda.<br />
599TiP<br />
abstracts<br />
A randomized phase III trial <strong>of</strong> capecitabine with or without<br />
irinotecan driven by UGT1A1 in neoadjuvant chemoradiation<br />
<strong>of</strong> locally advanced rectal cancer (CinClare)<br />
J. Zhu 1 , J. Chen 2 ,Y.Zhu 3 , J. Zhou 4 , Y. Zhu 5 , T. Zhang 6 , J. Jia 7 , C. Zhang 8 ,<br />
X. Wang 9 , Y. Gao 10 , G. Cai 11 , B. Luo 12 ,J.Wu 13 , A. Liu 14 ,B.Xu 15 , Z. Zhang 1<br />
1 Department <strong>of</strong> Radiation <strong>Oncology</strong>, Fudan University Shanghai Cancer Center,<br />
Shanghai, China, 2 Department <strong>of</strong> Radiation <strong>Oncology</strong>, Jiangsu Provincial People’s<br />
Hospital, 1st Affiliated Hospital <strong>of</strong> Nanjing Medical University, Nanjing, China,<br />
3 Department <strong>of</strong> Radiation <strong>Oncology</strong>, 2nd Affiliated Hospital Suzhou (Soochow)<br />
University, Suzhou, China, 4 Department <strong>of</strong> Radiation <strong>Oncology</strong>, 1st Affiliated<br />
Hospital <strong>of</strong> Suzhou (Soochow) University, Suzhou, China, 5 Department <strong>of</strong><br />
Radiation <strong>Oncology</strong>, Zhejiang Cancer Hospital, Hangzhou, China, 6 Department <strong>of</strong><br />
Radiation <strong>Oncology</strong>, 1st Affiliated Hospital <strong>of</strong> Chongqing Medical University,<br />
Chongqing, China, 7 Department <strong>of</strong> Radiation <strong>Oncology</strong>, Liaoning Cancer Hospital<br />
& Institute, Shenyang, China, 8 Department <strong>of</strong> Radiation <strong>Oncology</strong>, Ningbo No.2<br />
Hospital, Ningbo, China, 9 Department <strong>of</strong> Radiation <strong>Oncology</strong>, West China<br />
Hospital, Huaxi, Sichuan University, Chengdu, China, 10 Department <strong>of</strong> Radiation<br />
<strong>Oncology</strong>, Cancer Centre Sun Yat-Sen University, Guangzhou, China,<br />
11 Department <strong>of</strong> Radiation <strong>Oncology</strong>, Shanghai Ruijin Hospital, Shanghai Jiao<br />
Tong University, College <strong>of</strong> Medicine, Shanghai, China, 12 Department <strong>of</strong> Radiation<br />
<strong>Oncology</strong>, Hubei Provincial Cancer Hospital, Wuhan, China, 13 Department <strong>of</strong><br />
Radiation <strong>Oncology</strong>, Fujian Provincial Cancer Hospital, Fuzhou, China,<br />
14 Department <strong>of</strong> Radiation <strong>Oncology</strong>, 2nd Affiliated Hospital <strong>of</strong> Nanchang<br />
University, Nanchang, China, 15 Department <strong>of</strong> Radiation <strong>Oncology</strong>, Fujian Medical<br />
University Union Hospital, Fuzhou, China<br />
Background: Irinotecan is an effective drug for rectal cancer. Early small sample size<br />
trials have assessed the addition <strong>of</strong> irinotecan to standard CRT with fluoropyrimidines<br />
in neoadjuvant phase <strong>of</strong> locally advanced rectal cancer, in which pCR rates varied from<br />
13.7 to 37%. ARISTOTLE trial, a multicentre UK-based phase III trial, will complete<br />
recruitment in autumn 2016. However, all patients in case group were prescribed with<br />
weekly irinotecan dose <strong>of</strong> 60mg/m 2 for four times, regardless <strong>of</strong> the genetype <strong>of</strong><br />
UGT1A1, which has been regarded in favor <strong>of</strong> predicting toxicities. In our previous<br />
phase I trial, the weekly dose <strong>of</strong> irinotecan was escalated to 65mg/m 2 and 80mg/m 2<br />
guided by UGT1A1*28 6/6 and 6/7 genetypes in neoadjuvant chemoradiation.<br />
Therefore, this phase III trial was designed to confirm the potential improvement in<br />
outcomes seen with the addition <strong>of</strong> irinotecan to CRT.<br />
Trial design: Eligible patients are randomly allocated to either radiotherapy 50 Gy with<br />
concurrent capecitabine, followed by a cycle <strong>of</strong> capecitabine and oxaliplatin two weeks<br />
after the end <strong>of</strong> CRT (Control arm) or radiotherapy 50 Gy with concurrent<br />
capecitabine and irinotecan, followed by a cycle <strong>of</strong> capecitabine and irinotecan (Case<br />
arm). Capecitabine is prescribed with 825mg/m 2 twice daily from first day <strong>of</strong><br />
radiotherapy and given 5 days per week during radiotherapy in control group. In the<br />
other group, capecitabine dose is 625mg/m 2 twice daily and additional weekly<br />
irinotecan dose is 80mg/m 2 or 65mg/m 2 guided by UGT1A1*28 6/6 or 6/7 genetypes<br />
(total <strong>of</strong> five times). Stratification was performed by center, UGT1A1*28 genetype (6/6,<br />
6/7), T stage (cT3, cT4), and distance from anal verge (5cm). Surgery is<br />
schedule 8 weeks after the end <strong>of</strong> CRT, then, five cycles <strong>of</strong> XELOX are recommended<br />
during the course <strong>of</strong> adjuvant chemotherapy. The primary end point is ypCR. The<br />
hypothesis is to increase ypCR from 12% in the control group to 25% in the case group.<br />
To detect such a difference, with alpha = 0.05 (two-tailed) and belta = 0.15, 360<br />
randomly assigned patients are required. Secondary end points are toxicities, surgical<br />
complications, local control, progression-free survival and overall survival.<br />
Clinical trial identification: NCT02605265, released on December 24, 2015<br />
Legal entity responsible for the study: Fudan University Shanghai Cancer Center<br />
Funding: Fudan University Shanghai Cancer Center<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
600TiP<br />
A phase 1B study <strong>of</strong> pegylated liposomal mitomycin-C<br />
prodrug with or without capecitabine and bevacizumab in<br />
third line chemotherapy <strong>of</strong> colorectal cancer<br />
A.A. Gabizon 1 , T. Grenader 1 , E. Tahover 1 , H. Shmeeda 1 , T. Golan 2 , R. Berger 2 ,<br />
R. Geva 3 , I. Wolf 3 , R. Perets 4 , Y. Amitay 5 , P. Ohana 5<br />
1 <strong>Oncology</strong>, Shaare Zedek Medical Centre <strong>Oncology</strong> Institute, Jerusalem, Israel,<br />
2 <strong>Oncology</strong>, Chaim Sheba Medical Center, Ramat Gan, Israel, 3 <strong>Oncology</strong>, Tel Aviv<br />
Sourasky Medical Center-(Ichilov), Tel Aviv, Israel, 4 <strong>Oncology</strong>, Rambam Health<br />
Care Center, Haifa, Israel, 5 Lipomedix Pharmaceuticals, Lipomedix<br />
Pharmaceuticals Ltd., Jerusalem, Israel<br />
Background: Promitil® is a pegylated liposome formulation <strong>of</strong> a lipid-based prodrug <strong>of</strong><br />
mitomycin C (MLP). MLP is activated to mitomycin C (MMC) by thiolytic cleavage. A<br />
Phase 1, dose-escalating study, in 27 patients with advanced cancer showed that the<br />
maximal tolerated dose <strong>of</strong> Promitil® (in mitomycin C-equivalents) is ∼3-fold greater<br />
than the maximal recommended dose <strong>of</strong> MMC. The cumulative dose-limiting toxicity<br />
<strong>of</strong> Promitil® is thrombocytopenia. Pharmacokinetic (PK) analysis indicates that<br />
Promitil® has a slow blood clearance, with a half-life <strong>of</strong> ∼24 hours (in contrast to ∼15<br />
minutes for MMC). This Phase 1 study has been expanded to a Phase 1B study that<br />
includes 3 cohorts <strong>of</strong> patients with advanced colorectal cancer (CRC), after failure to 2<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw370 | vi203
abstracts<br />
or more lines <strong>of</strong> chemotherapy. The study includes 3 successive cohorts <strong>of</strong> Promitil®<br />
either as single agent (Cohort A), in combination with Capecitabine (Cap) (Cohort B),<br />
or in combination with Cap and Bevacizumab (Bev) (Cohort C). Cohorts A and B have<br />
been completed. Cohort C is ongoing. The primary objectives <strong>of</strong> this Phase 1B study<br />
are to clear a safe dose-schedule, and characterize the PK pr<strong>of</strong>ile <strong>of</strong> Promitil® with or<br />
without Cap and Bev in advanced CRC patients. Secondary objectives are evaluation <strong>of</strong><br />
safety pr<strong>of</strong>ile and anti-tumor responses to Promitil® with or without Cap and Bev.<br />
Trial design: Fifty to 60 patients are scheduled to receive three 28-day treatment cycles<br />
with PK analysis in 1 st cycle, and undergo re-evaluation at the 12 th week, unless early<br />
discontinuation is clinically indicated. Treatment continuation beyond 3 cycles is at the<br />
discretion <strong>of</strong> the investigators. 42 patients diagnosed with advanced CRC, 3 rd line<br />
chemotherapy (i.e., post-Oxaliplatin-5FU and post-Irinotecan-5FU, with or w/o Bev,<br />
and, if indicated, post-Cetuximab/Panitumumab) have been enrolled. A regimen <strong>of</strong> 2.0<br />
mg/kg Promitil®, i.v., on day 1, Cap at a flat dose <strong>of</strong> 1,000 mg bid, p.o., on days 1-14,<br />
given every 28 days, has been cleared and established as safe for 3 consecutive cycles. In<br />
Cohort C, Bev 5.0 mg/kg, i.v., on days 1 and 15 is added to the Promitil-Cap regimen.<br />
Safety, efficacy and comparative PK data <strong>of</strong> the 3 cohorts will be presented.<br />
Clinical trial identification: NCT01705002<br />
Legal entity responsible for the study: Lipomedix Pharmaceuticals Ltd.<br />
Funding: Lipomedix Pharmaceuticals Ltd.<br />
Disclosure: A.A. Gabizon: Shareholder and President <strong>of</strong> Lipomedix Pharmaceuticals,<br />
the company financing the clinical trial. All other authors have declared no conflicts <strong>of</strong><br />
interest.<br />
601TiP<br />
NORDIC9: A randomized phase II trial exploring treatment <strong>of</strong><br />
older patients with metastatic colorectal cancer (mCRC) by<br />
comparing full dose monotherapy (S-1 followed by<br />
irinotecan) with reduced combination regimen (S-1/<br />
oxaliplatin followed by S-1/irinotecan)<br />
S.B. Winther 1 , P. Østerlund 2 , Å. Berglund 3 , B. Glimelius 4 , C. Qvortrup 1 ,<br />
H. Sorbye 5 , P. Pfeiffer 1<br />
1 Department <strong>of</strong> <strong>Oncology</strong>, Odense University Hospital, Odense, Denmark,<br />
2 Department <strong>of</strong> <strong>Oncology</strong>, HUCH Helsinki University Central Hospital, Helsinki,<br />
Finland, 3 Department <strong>of</strong> <strong>Oncology</strong>, University Hospital Uppsala Akademiska<br />
Sjukhuset, Uppsala, Sweden, 4 Department <strong>of</strong> Immunology, Genetics and<br />
Pathology, University Hospital Uppsala Akademiska Sjukhuset, Uppsala, Sweden,<br />
5 Department <strong>of</strong> <strong>Oncology</strong>, Haukeland Universitetssykehus, Bergen, Norway<br />
Background: More than half <strong>of</strong> the patients diagnosed with mCRC are elderly (70+<br />
years). Older patients comprise a heterogeneous group, they are underrepresented in<br />
clinical trials, and knowledge about the best treatment strategy in patients who are not<br />
candidates for standard full-dose combination therapy is sparse and it is uncertain<br />
whether full dose or reduced dose chemotherapy is the optimal strategy. The oral<br />
prodrug S-1 (Teysuno®) is well tolerated as monotherapy and in combinations and<br />
could be an ideal drug for older patients (Winther et al, Acta Oncol 2015), but more<br />
data to predict toxicity and efficacy is needed. The NORDIC9 study will add knowledge<br />
on how to select and tailor the optimal treatment strategy for older mCRC patient who<br />
are not candidates for standard combination therapy.<br />
Trial design: NORDIC9 is a randomized phase II trial exploring treatment <strong>of</strong> older<br />
mCRC patients (≥ 70 years) who are not candidates to full-dose combination therapy,<br />
by comparing full dose monotherapy (S-1 30 mg/m 2 twice daily days 1-14 every 3<br />
weeks, followed by second line irinotecan 250-350 mg/m 2 iv day 1 every 3 weeks or<br />
180-240 mg/m 2 iv day 1 every 2 weeks) with reduced dose (80%) combination therapy<br />
regimen (S-1 20 mg/m 2 days 1-14 + oxaliplatin 100 mg/m 2 iv day 1 every 3 weeks,<br />
followed by second line S-1 20 mg/m 2 days 1-14 + irinotecan 180 mg/m 2 day 1 every 3<br />
week). Bevacizumab (7.5 mg/kg) may be added at the discretion <strong>of</strong> the treating<br />
clinician. Geriatric screening tools (G-8, VES-13, Timed-Up-and-Go, Grip strength),<br />
Charlson Comorbidity Index and Quality <strong>of</strong> Life (EORTC QLQ-C30) will be evaluated<br />
at baseline. Blood samples and tumor tissue will be collected to investigate predictive<br />
value. Enrollment was initiated in March 2015, and 52 patients are currently included.<br />
Primary endpoint is progression-free survival and secondary endpoints are<br />
time-to-failure <strong>of</strong> strategy, overall survival, response rate, toxicity, and correlations<br />
between biomarkers, pre-treatment characteristics and geriatric assessments.<br />
Clinical trial identification: EudraCT 2014-000394-39<br />
Legal entity responsible for the study: Clinical Research Unit, Department <strong>of</strong><br />
<strong>Oncology</strong>, Odense University Hospital<br />
Funding: Taiho<br />
Disclosure: P. Østerlund: Amgen, Bayer, Baxalta, Celgene, Eli Lilly, Merck, Nordic<br />
Drugs, Prime <strong>Oncology</strong>, Roche, San<strong>of</strong>i. P. Pfeiffer: Research grant: Taiho. All other<br />
authors have declared no conflicts <strong>of</strong> interest.<br />
602TiP<br />
Re-RAD-I external beam radiotherapy for pelvic recurrences<br />
in rectal cancer patients previously treated with radiotherapy<br />
M.G. Guren 1 , H.K. Christensen 2 , S.G. Larsen 3 , A.L. Appelt 4 , J. Lindegaard 5 , K.-L.<br />
G. Spindler 5<br />
1 Department <strong>of</strong> <strong>Oncology</strong>, Oslo University Hospital, Oslo, Norway, 2 Dept. <strong>of</strong><br />
Surgery, Aarhus University Hospital, Aarhus, Denmark, 3 Department <strong>of</strong> Surgery,<br />
Oslo University Hospital, Oslo, Norway, 4 Dept. <strong>of</strong> <strong>Oncology</strong>, Vejle Hospital, Vejle,<br />
Denmark, 5 Department <strong>of</strong> <strong>Oncology</strong>, Aarhus University Hospital, Aarhus,<br />
Denmark<br />
Background: Multimodal treatment <strong>of</strong> rectal cancer has improved outcome, but some<br />
patients still experience local recurrence, which is a major therapeutic challenge after<br />
previous radiotherapy (RT). Re-irradiation may improve the rate <strong>of</strong> radical surgery (R0), as<br />
reported in previous studies, where hyperfractionated chemo-RT resulted in 35% R0 rate.<br />
Surgery, RT techniques, and imaging have improved recent years, allowing for increased<br />
treatment precision with less morbidity. This study investigates re-irradiation <strong>of</strong> patients<br />
with local recurrence in a phase II clinical, imaging and translational study.<br />
Trial design: A prospective multicenter phase II, open label, non-randomised study.<br />
Therapy: External beam RT <strong>of</strong> 40.8 Gy / 1.2 F BID by intensity-modulated RT + CBCT<br />
guidance, concomitant capecitabine 825 mg/m2 BID all RT days, and surgery 8 weeks<br />
post-RT. The primary endpoint is R0 rate. Secondary objectives: Recurrence-free,<br />
disease-free and overall survival, acute and late toxicity, patient reported outcomes,<br />
translational research, imaging studies for future adaptive RT, mapping <strong>of</strong> recurrences<br />
according to previous RT, and simulation studies <strong>of</strong> other RT modalities (proton<br />
therapy). Main inclusion criteria: Locally recurrent rectal cancer, previous pelvic RT and<br />
surgery, potentially resectable tumor, age ≥18 years, adequate organ function, acceptable<br />
bowel and bladder function, acceptance for translational research. Main exclusion<br />
criteria; central small recurrences deemed resectable, non-resectable distant metastases,<br />
medical comorbidities precluding radical surgery, previous RT
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
604TiP<br />
PRODIGE 25 (FFCD 11-01) - Phase II randomized trial<br />
evaluating aflibercept associated with LV5FU2 regimen as<br />
first line treatment <strong>of</strong> non-resectable metastatic colorectal<br />
cancers (FOLFA)<br />
J.L. Legoux 1 , K. Le Malicot 2 , R. Faroux 3 , V. Boige 4 , N. Barriere 5 , J. Egreteau 6 ,<br />
Y. Rinaldi 7 , E. Maillard 8 , M. Baconnier 9 , C. Lecaille 10 , S. Herrmann-Gandara 1 ,<br />
A. Vimal 11 , Y. Touchefeu 12 , J. Raimbourg 13 , T. Aparicio 14<br />
1 Hepato-Gatroenterology and Digestive <strong>Oncology</strong>, C.H.R. Orleans - La Source,<br />
Orleans, France, 2 Biostatistics, Fédération Francophone de Cancérologie<br />
Digestive (FFCD), Dijon, France, 3 Service d’HGE, CHD Vendee - Hopital Les<br />
Oudairies, La Roche Sur Yon, France, 4 Digestive <strong>Oncology</strong>, Institut Gustave<br />
Roussy, Villejuif, France, 5 Hepato-Gatroenterology and Digestive <strong>Oncology</strong>,<br />
Hôpital Européen, Marseille, France, 6 Medical <strong>Oncology</strong>, CH Sud Bretagne,<br />
Lorient, France, 7 Service d’HGE, Hôpital Européen, Marseille, France,<br />
8 Hepato-Gastroenterology, CH d’Annecy, Annecy, France,<br />
9 Hepato-Gatroenterology and Digestive <strong>Oncology</strong>, CH d’Annecy, Annecy, France,<br />
10 Hepato-Gatroenterology and Digestive <strong>Oncology</strong>, Polyclinique Bordeaux Nord<br />
Aquitaine, Bordeaux, France, 11 Medical <strong>Oncology</strong>, CHU Estaing,<br />
Clermont-Ferrand, France, 12 Hepato-gastroenterology, CHU de Nantes, Nantes,<br />
France, 13 Medical <strong>Oncology</strong>, Institut de Cancérologie de l’Ouest, Nantes, France,<br />
14 Gastroenterology, Hôpital Avicenne, Bobigny, France<br />
Background: Aflibercept has already been used in combination with FOLFIRI in the<br />
VELOUR trial (1). The aflibercept-LV5FU2 combination can be useful and well<br />
tolerated in patients (pts) with never resectable/non symptomatic metastatic colorectal<br />
cancer, for whom 5-FU monotherapy can be suggested to delay the toxicities <strong>of</strong><br />
combined chemotherapies, then eligible for sequential treatment with first-line 5-FU<br />
monotherapy. Within this context, it is possible for aflibercept to provide a survival<br />
benefit. VELOUR trial did not indicate that toxicity would have a major effect on<br />
quality <strong>of</strong> life and increase the hope <strong>of</strong> prolonged progression-free survival in the arm<br />
with aflibercept. A previous pharmacogenetic analysis <strong>of</strong> the FFCD 2000-05 phase III<br />
trial (2) showed a prognostic and predictive effect <strong>of</strong> the thymidylate synthase<br />
(TS)-5’UTR polymorphism for response and PFS: the 5-FU monotherapy efficacy was<br />
increased in TS 5’3R/3R pts vs 2R2R-2R3R (2). Stratification in this criterion will<br />
confirm or not the prognostic or predictive value <strong>of</strong> these polymorphisms if linked to<br />
the 5-FU efficacy.<br />
Trial design: The major eligibility criteria are: age ≥ 65, performance status WHO ≤ 2,<br />
central genotyping <strong>of</strong> TS in blood DNA. Treatment is administered every14 days with<br />
simplified LV5FU2 regimen, preceded or not by perfusion <strong>of</strong> 4 mg/kg aflibercept. The<br />
treatment will be stopped in case <strong>of</strong> progression (evaluation each 8 weeks) or<br />
inacceptable toxicity. The main judgement criterion is proportion <strong>of</strong> pts alive and<br />
without radiologic progression within 6 months. A proportion <strong>of</strong> more than 40% pts<br />
will be interesting and a rate <strong>of</strong> 60% is expected (α = 5%, Binomial-exact method and a<br />
power <strong>of</strong> 90%). Secondary criteria are: tolerance <strong>of</strong> the LV5FU2-aflibercept<br />
combination, time to final deterioration in quality <strong>of</strong> life, overall survival, prognostic<br />
value <strong>of</strong> TS-5’UTR polymorphism on PFS. Stratification factors are: centre, age: < 75<br />
vs > 75, TS-5’UTR polymorphism, metastatic site (1 vs >1). Status: 18 <strong>of</strong> planned 118<br />
patients have been randomized. References: (1) Van Cutsem E et al: J Clin Oncol<br />
30:3499-506, 2012 (2), Boige V et al: J Clin Oncol 28:2556-64, 2010<br />
Clinical trial identification: EudraCT 2014-001837-10; 05 September 2014<br />
Legal entity responsible for the study: FFCD<br />
Funding: San<strong>of</strong>i<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
605TiP<br />
Randomized phase II study <strong>of</strong> maintenance treatment with<br />
5-FU/FA plus panitumumab vs 5-FU/FA alone after induction<br />
(mFOLFOX6 plus panitumumab) in patients with RAS WT<br />
metastatic colorectal cancer<br />
D.P. Modest 1 , S. Kasper 2 , S. Stintzing 3 , N. Prasnikar 4 , L. Müller 5 ,K.Caca 6 ,<br />
E. Gökkurt 7 , L. Fischer von Weikersthal 8 , H.-G. Kopp 9 , T. Trarbach 10<br />
1 Med. Klinik III Klinikum Großhadern, Ludwig Maximilians University -<br />
Grosshadern, Munich, Germany, 2 Medical <strong>Oncology</strong>, University Hospital Essen<br />
Westdeutsches Tumorzentrum, Essen, Germany, 3 Hematology and <strong>Oncology</strong>,<br />
Ludwig Maximilians University - Grosshadern, Munich, Germany, 4 <strong>Oncology</strong>, AK<br />
Asklepios Klinik Altona, Hamburg, Germany, 5 <strong>Oncology</strong>, Onkologie UnterEms,<br />
Leer, Germany, 6 Klinik f. Innere Medizin, Gastroenterologie, Hämato-Onkologie,<br />
Klinikum Ludwigsburg Hämatologie/Onkologie, Palliativmedizin, Ludwigsburg,<br />
Germany, 7 Hope Eppendorf, Facharztzentrum Eppendorf, Eppendorf, Germany,<br />
8 <strong>Oncology</strong>, Klinikum St. Marien Amberg, Amberg, Germany, 9 Klinik für innere<br />
Medizin II, Universitätsklinikum Tübingen, Tübingen, Germany, 10 Center for Tumor<br />
Biology and Integrative Medicine, Hospital Wilhelmshaven, Wilhelmshaven,<br />
Germany<br />
Background: Combination chemotherapy plus anti-EGFR (epidermal growth factor<br />
receptor) antibody is approved for first-line therapy in metastatic colorectal cancer in<br />
patients with RAS wild type tumors. The combination <strong>of</strong> FOLFOX with panitumumab<br />
has led to significantly better outcome when compared to chemotherapy alone. The<br />
cumulative oxaliplatin toxicity resulting in dose limiting neurotoxicity has led to the<br />
development <strong>of</strong> maintenance strategies. For FOLFOX plus bevacizumab treated<br />
patients a maintenance concept with 5-FU plus bevacizumab has been established by<br />
multiple clinical trials. For the use <strong>of</strong> FOLFOX plus panitumumab, no clear<br />
maintenance concept has been defined. The PanaMa study is evaluating the concept <strong>of</strong><br />
limiting the application <strong>of</strong> chemotherapeutic agents while continuing with a<br />
maintenance treatment including an anti-EGFR antibody. As the EGFR antibody<br />
panitumumab is approved for first-line therapy in metastatic colorectal cancer in RAS<br />
wild-type patients, this study aims to investigate whether addition <strong>of</strong> a target agent, i. e.,<br />
panitumumab, to a standard maintenance backbone (5-fluorouracil plus leucovorin)<br />
can add / maintain clinical benefit.<br />
Trial design: Primary Objectives: Efficacy <strong>of</strong> panitumumab plus 5-FU/FA as<br />
maintenance after 12 weeks with mFOLFOX6 plus panitumumab in the first-line<br />
treatment <strong>of</strong> RAS wild-type metastatic colorectal cancer patients compared to 5-FU/FA<br />
maintenance alone in terms <strong>of</strong> progression-free survival (superiority design in favour<br />
<strong>of</strong> the combination arm). Secondary Objectives: •Time from randomization until<br />
failure <strong>of</strong> treatment strategy (death/progression) •Progression-free survival <strong>of</strong><br />
re-induction •Objective response after induction and during maintenance and<br />
re-induction •Overall survival •Safety •Health and skin related Quality <strong>of</strong> life Sample<br />
size Approx. 380 patients will be enrolled. 252 patients should be accrued for<br />
randomisation to reach the required number <strong>of</strong> 218 events (PD or death after treatment<br />
with maintenance).<br />
Clinical trial identification: NCT01991873<br />
Legal entity responsible for the study: AIO Studien gGmbH<br />
Funding: AIO Studien gGmbH, funding from AMGEN<br />
Disclosure: D.P. Modest: Honoraria: Amgen, Merck, Roche, Bayer. Travel support:<br />
Amgen, Merck, San<strong>of</strong>i, Bayer, Research grant: Amgen, Merck, Roche. S. Kasper:<br />
Receipt <strong>of</strong> grants/research supports: Merck. Receipt <strong>of</strong> honoraria or consultation fees:<br />
Amgen, Merck. S. Stintzing: Receipt <strong>of</strong> honoraria or consultation fees: Amgen, Roche,<br />
Merck KgaA, San<strong>of</strong>i, Bayer. N. Prasnikar: Receipt <strong>of</strong> grants/research supports: Celgene.<br />
Receipt <strong>of</strong> honoraria or consultation fees: Amgen, Lilly. T. Trarbach: Honoraria/<br />
Speakers bureau: Amgen, Merck, Roche, San<strong>of</strong>i, Novartis, Lilly. Travel support: Amgen,<br />
Merck, Roche, San<strong>of</strong>i, Novartis, Lilly. Research support: Amgen, Merck, Roche, San<strong>of</strong>i.<br />
All other authors have declared no conflicts <strong>of</strong> interest.<br />
606TiP<br />
abstracts<br />
Selection with a molecUlar PanEl foR Panitumumab EfficAcy<br />
in K-ras and n-ras wild type metastatic colorectal cancer<br />
(SUPER- PEAK)<br />
M. Puzzoni 1 , G. Pusole 1 , R. Mascia 1 , L. Demurtas 1 , A. Dessì 1 , A. Cubeddu 1 ,<br />
E. Lai 1 , S. Tolu 1 , P. Ziranu 1 , L. Orgiano 1 , V. Pusceddu 1 , G. Astara 1 , C. Madeddu 1 ,<br />
E. Massa 1 , L. Casula 1 , G. Palmieri 2 , M. Scartozzi 1<br />
1 Medical <strong>Oncology</strong>, University <strong>of</strong> Cagliari, Cagliari, Italy, 2 Institute <strong>of</strong> Biomolecular<br />
Chemistry (ICB), Unit <strong>of</strong> Cancer Genetics, National Research Council (CNR),<br />
Sassari, Italy<br />
Background: Currently we are able to exclude from anti-epidermal growth factor<br />
receptor (EGFR) treatment patients with putative refractory colorectal tumours (i.e.<br />
those harboring a RAS mutant status). However on the other hand a nonnegligible<br />
proportion <strong>of</strong> patients don’t fully benefit from the use <strong>of</strong> chemotherapy in combination<br />
with anti-EGFR treatment (cetuximab or panitumumab), although in the absence <strong>of</strong> a<br />
mutation <strong>of</strong> the RAS genes. Published research data suggested that EGFR gene copy<br />
number, PIK3CA mutations, PTEN mutations or copy number variations and BRAF<br />
mutations may all represent predictive determinants for anti-EGFR therapy. However<br />
these factors were not incorporated into clinical practice particularly because<br />
prospective validation is lacking.<br />
Trial design: The SUPER-PEAK is an ongoing, multicentre, biologically enriched,<br />
double blinded, prospectively stratified observational study. Patients receiving<br />
oxaliplatin, 5-fluorouracil and leucovorin (FOLFOX) plus panitunumab as per<br />
indication, are divided into 2 prognostic groups on the basis <strong>of</strong> their molecular pr<strong>of</strong>ile:<br />
favourable and unfavourable (respectively high and low probability for improved RR).<br />
According to PIK3CA mutational status, BRAF mutational status and EGFR gene copy<br />
number (GCN), patients are prospectively allocated to either the favourable group<br />
(PIK3CA and BRAF wild type and EGFR GCN ≥ 2.6) or the unfavourable group<br />
(PIK3CA mutation or BRAF mutation or EGFR GCN < 2.6). The study objective is to<br />
define a molecular panel able to identify patients more likely to benefit from the use <strong>of</strong><br />
first-line panitumumab in combination with FOLFOX in terms <strong>of</strong> response rate (RR)<br />
as primary endpoint. Secondary endpoints include early tumour shrinkage (ETS),<br />
depth <strong>of</strong> response (DoR), median progression free-survival (PFS) and median overall<br />
survival (OS). To detect a difference in terms <strong>of</strong> RR among patients with an<br />
unfavourable pr<strong>of</strong>ile and patients with a favourable pr<strong>of</strong>ile assuming a probability alpha<br />
<strong>of</strong> 0.05 and beta <strong>of</strong> 0.10, required sample size is 90 patients.<br />
Clinical trial identification: EudraCT 2015-001408-72<br />
Legal entity responsible for the study: Pr<strong>of</strong> Mario Scartozzi<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw370 | vi205
abstracts<br />
607TiP<br />
TransSCOT – translational research based on the Short<br />
Course <strong>Oncology</strong> Therapy (SCOT) cohort<br />
B.E. Engelmann 1 , T. Iveson 2 , E. Høgdall 3 , N.H. Holländer 4<br />
1 Department <strong>of</strong> Clinical <strong>Oncology</strong>, Herlev and Gent<strong>of</strong>te Hospital, Herlev, Denmark,<br />
2 Medical <strong>Oncology</strong>, Southampton General Hospital Southampton University<br />
Hospitals NHS Trust, Southampton, UK, 3 Department <strong>of</strong> Pathology, Herlev and<br />
Gent<strong>of</strong>te Hospital, Herlev, Denmark, 4 <strong>Oncology</strong>, Zealand University Hospital,<br />
Naestved, Denmark<br />
Background: The Short Course <strong>Oncology</strong> Therapy (SCOT) study <strong>of</strong> adjuvant<br />
chemotherapy in colorectal cancer aims to ascertain whether 3 months <strong>of</strong> treatment is<br />
as efficacious as 6 months. The study is designed to assess clinical, quality <strong>of</strong> life and<br />
cost-effectiveness outcomes. However, the unique patient material in the SCOT study<br />
could help answer questions in the following translational research areas: · Molecular<br />
tumour characteristics with prognostic significance in colorectal cancer · Molecular<br />
characteristics with predictive significance regarding treatment efficacy and toxicities <strong>of</strong><br />
5-FU and oxaliplatin adjuvant treatment in colorectal cancer · Identification <strong>of</strong><br />
circulating prognostic markers that could be used in personalized follow-up after<br />
adjuvant treatment · Identification <strong>of</strong> genes that could be useful as targets for<br />
personalized adjuvant chemotherapy in high-risk patients<br />
Trial design: SCOT recruited patients from 2008 to 2013. 6144 patients were<br />
randomised at 243 sites in 6 countries; 311 patients in Denmark. For TransSCOT, all<br />
patients that have consented to participation in SCOT are asked for further blood<br />
samples and permission to access tumour specimen. TransSCOT is currently recruiting<br />
in the UK, Sweden and Denmark. Tumour blocks from 2833 TransSCOT participants<br />
are collected in Glasgow, UK, and blood samples from 2964 participants in Oxford,<br />
UK, whereas tumour specimens and blood samples from the Danish TransSCOT<br />
cohort are collected in the Danish Cancer Biobank (DCB) at Herlev Hospital. Tissue<br />
slides and tissue microarrays (TMAs) are prepared for immunohistochemical staining<br />
and in-situ hybridization. DNA extraction from blood samples and corresponding<br />
tumour tissue is performed for next generation sequencing (NGS). Furthermore,<br />
miRNA are extracted in expression arrays. Design <strong>of</strong> TMAs, panels <strong>of</strong> markers for NGS<br />
and miRNAs <strong>of</strong> interest are currently defined in the TransSCOT Biorepository<br />
Management Group.<br />
Clinical trial identification: NCT00749450<br />
Legal entity responsible for the study: Department <strong>of</strong> <strong>Oncology</strong>, Næstved Hospital,<br />
Næstved, Denmark<br />
Funding: Zealand Healthcare Regiońs Foundation for Health Science Research<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
608TiP<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
CanStem303C trial: A phase III study <strong>of</strong> BBI-608<br />
(napabucasin) in combination with 5-fluorouracil (5-FU),<br />
leucovorin, irinotecan (FOLFIRI) in adult patients with<br />
previously treated metastatic colorectal cancer (mCRC)<br />
A. Grothey 1 , N. Tebbutt 2 , E. Van Cutsem 3 , J. Taieb 4 , A. Falcone 5 , T. Yoshino 6 ,<br />
A. Cervantes 7 , L. Borodyansky 8 , C.J. Li 8<br />
1 Medical <strong>Oncology</strong>, Mayo Clinic, Rochester, NY, USA, 2 Medical <strong>Oncology</strong>, Austin<br />
Hospital, Heidelberg, Australia, 3 Digestive <strong>Oncology</strong>, University Hospitals Leuven -<br />
Campus Gasthuisberg, Leuven, Belgium, 4 <strong>Oncology</strong>, Sorbonne Paris Cite, Paris<br />
Descartes University, Georges Pompidou European Hospital, Paris, France,<br />
5 <strong>Oncology</strong>, Presidio Ospedaliero, University <strong>of</strong> Pisa, Livorno, Italy, 6 Exploratory<br />
<strong>Oncology</strong> Research and Clinical Trial Center, National Cancer Center, Chiba,<br />
Japan, 7 Medical <strong>Oncology</strong>, Hospital Clinico Universitario de Valencia, Valencia,<br />
Spain, 8 Boston Biomedical, Inc., Cambridge, MA, USA<br />
Background: BBI-608 (aka napabucasin) is an orally-administered first-in-class cancer<br />
stemness inhibitor. By targeting Stat3, BBI-608 blocks cancer stem cell (CSC)<br />
self-renewal and survival through suppressing stemness pathways as well as immune<br />
evasion. Potent anti-CSC and anti-metastatic activity was observed in preclinical<br />
models, with strong synergy between BBI-608 and 5-FU or irinotecan. Moreover,<br />
expression <strong>of</strong> cancer stemness genes stat3 and β-catenin, poor prognostic biomarkers<br />
in many cancer types, predict sensitivity to BBI-608. Encouraging anticancer activity in<br />
advanced CRC was observed in a phase Ib (O’Neil et al, ASCO 2016) study including<br />
46 pts. On the basis <strong>of</strong> these data, a phase III trial is being conducted in North<br />
America, Europe, Australia, and Asia.<br />
Trial design: This study (ClinicalTrials.gov NCT02753127) will assess the efficacy <strong>of</strong><br />
BBI-608 + FOLFIRI vs FOLFIRI in pts with mCRC (n = 1250). Addition <strong>of</strong><br />
bevacizumab (bev) to the FOLFIRI regimen, per investigator choice, will be<br />
permissible. Pts must have failed one prior line <strong>of</strong> therapy containing bev, oxaliplatin,<br />
and a fluoropyrimidine for metastatic disease. Pts are randomized in a 1:1 ratio to<br />
receive BBI-608 240 mg twice daily continuously plus standard FOLFIRI IV, bi-weekly,<br />
or standard FOLFIRI IV, bi-weekly alone. If Investigator elects, pts will receive bev<br />
prior to FOLFIRI infusion. Treatment will continue until disease progression, death,<br />
intolerable toxicity, or patient/investigator decision to stop. Primary endpoint is overall<br />
survival (OS) in the general study population (HR 0.80 for OS improvement from<br />
12.54 to 15.68 months); secondary endpoints include OS in the biomarker positive<br />
population, progression free survival (PFS) in general study population, PFS in<br />
biomarker positive population, overall response rate and disease control rate in the<br />
general study population and in biomarker positive population, safety and quality <strong>of</strong><br />
life. In addition, blood and tumor archival tissue will be assessed for pharmacokinetic<br />
and biomarker analyses. As <strong>of</strong> May 11, 2016, study recruitment process is active.<br />
Clinical trial identification: ClinicalTrials.gov NCT02753127<br />
Legal entity responsible for the study: Boston Biomedical, Inc.<br />
Funding: Boston Biomedical, Inc.<br />
Disclosure: L. Borodyansky: Employee at Boston Biomedical, Inc. C.J. Li: CMO at<br />
Boston Biomedical, Inc. Stock ownership and Member <strong>of</strong> Advisory Board and Board <strong>of</strong><br />
Directors. All other authors have declared no conflicts <strong>of</strong> interest.<br />
vi206 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong> 27 (Supplement 6): vi207–vi242, 2016<br />
doi:10.1093/annonc/mdw371<br />
gastrointestinal tumours,<br />
non-colorectal<br />
609O<br />
Is centralization needed for esophago-gastric cancer patients<br />
with low operative risk? a nationwide study<br />
C. Gronnier 1 , A. Pasquer 1 , F. Renaud 2 ,F.Hec 1 , A. Gandon 1 , M. Vanderbeken 1 ,<br />
V. Drubay 1 , G. Caranhac 3 , G. Piessen 1 , C. Mariette 1<br />
1 Departement <strong>of</strong> Digestive and Oncological Surgery, Lille University Hospital,<br />
France, Lille, France, 2 Department <strong>of</strong> Pathology, Lille University Hospital, France,<br />
Lille, France, 3 Hox-Com, Analytiques, Paris, France<br />
611O<br />
A phase III clinical trial <strong>of</strong> neoadjuvant chemoradiotherapy<br />
followed by surgery versus surgery alone for locally advanced<br />
squamous cell carcinoma <strong>of</strong> the esophagus<br />
610O<br />
An AGITG trial –A randomised phase II study <strong>of</strong> pre-operative<br />
cisplatin, fluorouracil and DOCetaxel +/-radioTherapy based<br />
on poOR early response to cisplatin and fluorouracil for<br />
resectable esophageal adenocarcinoma<br />
A. Barbour 1 , E. Walpole 2 , G.T. Mai 3 , H. Chan 4 , E. Barnes 4 , D. Watson 5 ,<br />
S. Ackland 6 , V. Wills 7 , J. Martin 8 , M. Burge 9 , C. Karapetis 10 , J. Shannon 11 ,<br />
L. Nott 12 , V. Gebski 4 , K. Wilson 4 , J. Thomas 13 , G. Lampe 14 , J. Zalcberg 15 ,<br />
J. Simes 4 , M. Smithers 16<br />
1 Department <strong>of</strong> Surgery, Princess Alexandra Hospital, Brisbane, Australia,<br />
2 Medical <strong>Oncology</strong>, Princess Alexandra Hospital, Brisbane, Australia, 3 Radiation<br />
<strong>Oncology</strong>, Princess Alexandra Hospital, Brisbane, Australia, 4 NHMRC Clinical<br />
Trials Centre, University <strong>of</strong> Sydney, Sydney, Australia, 5 Oesophago-Gastric<br />
Surgical Unit, Flinders Medical Center, Bedford Park, Australia, 6 Medical<br />
<strong>Oncology</strong>, Calvary Mater Hospital Newcastle, Newcastle, Australia, 7 Division <strong>of</strong><br />
Surgery, John Hunter Hospital, Newcastle, Australia, 8 Radiation <strong>Oncology</strong>, Calvary<br />
Mater Hospital Newcastle, Newcastle, Australia, 9 Medical <strong>Oncology</strong>, Royal<br />
Brisbane and Women’s Hospital, Herston, Australia, 10 Department <strong>of</strong> Medical<br />
<strong>Oncology</strong>, Flinders Medical Center, Bedford Park, Australia, 11 Medical <strong>Oncology</strong>,<br />
Nepean Cancer Care Centre, Kingswood, Australia, 12 Medical <strong>Oncology</strong>, Royal<br />
Hobart Hospital, Hobart, Australia, 13 Mater Medical Centre, Princess Alexandra<br />
Hospital, Brisbane, Australia, 14 Pathology Queensland, Princess Alexandra<br />
Hospital, Brisbane, Australia, 15 Epidemiology and Preventative Medicine, Monash<br />
University, The Alfred Hospital, Melbourne, Australia, 16 The University <strong>of</strong><br />
Queensland, Princess Alexandra Hospital, Brisbane, Australia<br />
H. Yang 1 ,J.Fu 1 , M. Liu 2 , Y. Chen 3 , Z. Chen 4 , C. Zhu 5 , H. Yang 6 ,W.Fang 7 ,<br />
J. Wang 8 ,Z.Yu 9 , Q. Pang 10 , W. Mao 11 , X. Zheng 12 , J. Xiang 13 , H. Yang 14 ,<br />
Y. Han 15<br />
1 Thoracic <strong>Oncology</strong>, Cancer Centre Sun Yat-Sen University, Guangzhou, China,<br />
2 Radiation <strong>Oncology</strong>, Cancer Centre Sun Yat-Sen University, Guangzhou, China,<br />
3 Thoracic <strong>Oncology</strong>, Cancer Hospital <strong>of</strong> Shantou University, Shantou, China,<br />
4 Radiotherapy, Cancer Hospital <strong>of</strong> Shantou University, Shantou, China, 5 Thoracic<br />
<strong>Oncology</strong>, Taizhou Hospital <strong>of</strong> Zhejiang Province, Taizhou, China, 6 Radiotherapy,<br />
Taizhou Hospital <strong>of</strong> Zhejiang Province, Taizhou, China, 7 Thoracic Surgery,<br />
Shanghai Chest Hospital, Shanghai, China, 8 Radiotherapy, Shanghai Chest<br />
Hospital, Shanghai, China, 9 Thoracic <strong>Oncology</strong>, Tianjin Medical University Cancer<br />
Institute and Hospital, Tianjin, China, 10 Radiotherapy, Tianjin Medical University<br />
Cancer Institute and Hospital, Tianjin, China, 11 Thoracic <strong>Oncology</strong>, Zhejiang<br />
Cancer Hospital, Hangzhou, China, 12 Radiotherapy, Zhejiang Cancer Hospital,<br />
Hangzhou, China, 13 Thoracic <strong>Oncology</strong>, Shanghai Cancer Center Fudan<br />
University, Shanghai, China, 14 Radiotherapy, Shanghai Cancer Center Fudan<br />
University, Shanghai, China, 15 Thoracic <strong>Oncology</strong>, Sichuan Cancer Hospital,<br />
Chengdu, China<br />
abstracts<br />
© European Society for Medical <strong>Oncology</strong> 2016. Published by Oxford University Press on behalf <strong>of</strong> the European Society for Medical <strong>Oncology</strong>.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com.
abstracts<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
613O<br />
Genomic pr<strong>of</strong>iling <strong>of</strong> small bowel adenocarcinoma: Insights<br />
from a comparative analysis with gastric and colorectal<br />
cancer and opportunities for targeted therapy<br />
A.B. Schrock 1 , C.E. Devoe 2 , R. McWilliams 3 , J. Sun 4 , J.T. Ruggiero 5 ,<br />
P. Stephens 6 , J.S. Ross 7 , R. Wilson 8 , V.A. Miller 1 , S.M. Ali 1 , M.J. Overman 9<br />
1 Clinical Development, Foundation Medicine, Inc., Cambridge, MA, USA,<br />
2 Northwell Health, The Monter Cancer Cencer, Lake Success, NY, USA, 3 Medical<br />
<strong>Oncology</strong>, Mayo Clinic, Rochester, NY, USA, 4 Biomarker Development,<br />
Foundation Medicine, Inc., Cambridge, MA, USA, 5 Medical <strong>Oncology</strong>, Weill<br />
Cornell Medical College, New York, NY, USA, 6 Clinical Genomics, Foundation<br />
Medicine, Inc., Cambridge, MA, USA, 7 Pathology, Foundation Medicine, Inc.,<br />
Cambridge, MA, USA, 8 Centre for Cancer Research and Cell Biology, Queen’s<br />
University Belfast, Belfast, UK, 9 Gastrointestinal Medical <strong>Oncology</strong>, MD Anderson<br />
Cancer Center, Houston, TX, USA<br />
612O<br />
Clinical next generation sequencing (NGS) <strong>of</strong> esophagogastric<br />
(EG) adenocarcinomas identifies distinct molecular<br />
signatures <strong>of</strong> response to HER2 inhibition, first-line<br />
5FU/platinum and PD1/CTLA4 blockade<br />
Y.Y. Janjigian 1 , F. Sanchez-Vega 2 , P. Jonsson 3 ,Y.Tuvy 1 , N. Bouvier 4 , J. Riches 1 ,<br />
R. Kundra 3 ,G.Ku 2 , J.F. Hechtman 5 , D. Kelsen 1 , L. Tang 5 , D. Ilson 1 , E. Vakiani 5 ,<br />
Z. Stadler 1 , M. Callahan 1 , D.B. Solit 1 , M.F. Berger 4 , B.S. Taylor 3 , N. Schultz 3<br />
1 Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA,<br />
2 Gastrointestinal <strong>Oncology</strong> Service, Memorial Sloan Kettering Cancer Center,<br />
New York, NY, USA, 3 Bioinformatics, Memorial Sloan-Kettering Cancer Center,<br />
New York, NY, USA, 4 Memorial Sloan-Kettering Cancer Center, New York, NY,<br />
USA, 5 Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA<br />
vi208 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
614O<br />
Final results <strong>of</strong> the FAST study, an international, multicenter,<br />
randomized, phase II trial <strong>of</strong> epirubicin, oxaliplatin, and<br />
capecitabine (EOX) with or without the anti-CLDN18.2<br />
antibody IMAB362 as first-line therapy in patients with<br />
advanced CLDN18.2+ gastric and gastroesophageal junction<br />
(GEJ) adenocarcinoma<br />
M. Schuler 1 , S.-E. Al-Batran 2 , Z. Zvirbule 3 , G. Manikhas 4 , F. Lordick 5 ,A.Rusyn 6 ,<br />
Y. Vinnyk 7 , I. Vynnychenko 8 , N. Fadeeva 9 , M. Nechaeva 10 , A. Dudov 11 ,<br />
E. Gotovkin 12 , A. Pecheniy 13 , I. Bazin 14 , I. Bondarenko 15 , B. Melichar 16 ,<br />
C. Huber 17 , Ö. Türeci 18 , U. Sahin 17<br />
1 Medical <strong>Oncology</strong>, University Hospital Essen Westdeutsches Tumorzentrum,<br />
Essen, Germany, 2 Medical <strong>Oncology</strong>, Institute <strong>of</strong> Clinical Cancer Research (IKF),<br />
UCT-University Cancer Center, Frankfurt, Germany, 3 Department <strong>of</strong> <strong>Oncology</strong>,<br />
<strong>Oncology</strong> Center <strong>of</strong> Latvia Riga East University Hospital, Riga, Latvia, 4 Department<br />
<strong>of</strong> Gynaecological <strong>Oncology</strong>, City Clinical <strong>Oncology</strong> Center, St-Petersburg,<br />
Russian Federation, 5 University Cancer Center Leipzig, University Clinic Leipzig,<br />
Leipzig, Germany, 6 Department <strong>of</strong> Chemotherapy, Zakarpattya Regional Clinical<br />
Oncological Center, Uzhhorod, Ukraine, 7 <strong>Oncology</strong>, CHI Kharkiv Regional Clinical<br />
Oncological Center, Kharkiv, Ukraine, 8 <strong>Oncology</strong>, Sumy Regional <strong>Oncology</strong><br />
Center, Sumy, Ukraine, 9 Chemotherapy Department, Chelyabinsk Regional<br />
Clinical <strong>Oncology</strong> Center, Chelyabinsk, Russian Federation, 10 Chemotherapy<br />
Department, Arkhangelsk Regional Clinical <strong>Oncology</strong> Dispensary, Arkhangelsk,<br />
Russian Federation, 11 Medical <strong>Oncology</strong> Department, University Hospital Queen<br />
Giovanna UMHAT Tsaritsa Yoanna- ISUL, S<strong>of</strong>ia, Bulgaria, 12 Chemotherapy<br />
Department, Ivanovo Regional <strong>Oncology</strong> Center, Ivanovo, Russian Federation,<br />
13 <strong>Oncology</strong> Department, Orel <strong>Oncology</strong> Center, Orel, Russian Federation,<br />
14 Clinical Pharmacology and Chemotherapy, N. N. Blokhin Russian Cancer<br />
Research Center, Moscow, Russian Federation, 15 Department <strong>of</strong> <strong>Oncology</strong>,<br />
Radiodiagnosis and Radiotherapy, Dnipropetrovsk Municipal Clinical Hospital #4,<br />
Dnepropetrovsk, Ukraine, 16 Clinic <strong>of</strong> <strong>Oncology</strong>, University Hospital Olomouc,<br />
Olomouc, Czech Republic, 17 TRON-Translational <strong>Oncology</strong> at the University<br />
Medical Center <strong>of</strong> the Johannes Gutenberg University Mainz, University Medical<br />
Center <strong>of</strong> the Johannes Gutenberg University, Mainz, Germany, 18 Ganymed<br />
Pharmaceuticals AG, Mainz, Germany<br />
615O<br />
abstracts<br />
Safety and preliminary efficacy <strong>of</strong> nivolumab (nivo) in patients<br />
(pts) with advanced hepatocellular carcinoma (aHCC): Interim<br />
analysis <strong>of</strong> the phase 1/2 CheckMate-040 study<br />
I. Melero 1 , B. Sangro 2 ,T.Yau 3 , C. Hsu 4 , M. Kudo 5 , T. Crocenzi 6 , T.-Y. Kim 7 ,<br />
S.-P. Choo 8 , J. Trojan 9 ,T.Meyer 10 , T.H. Welling, III 11 ,W.Yeo 12 , A. Chopra 13 ,<br />
J. Anderson 14 , C. Dela Cruz 15 , L. Lang 16 , J. Neely 17 , A. El-Khoueiry 18<br />
1 Laboratory <strong>of</strong> Immunology, Universidad de Navarra, Pamplona, Spain,<br />
2 Laboratory <strong>of</strong> Immunology, Universidad de Navarra and CIBERehd, Pamplona,<br />
Spain, 3 Medicine, Queen Mary Hospital University <strong>of</strong> Hong Kong, Hong Kong,<br />
China, 4 Graduate Institute <strong>of</strong> <strong>Oncology</strong>, National Taiwan University NTU, College <strong>of</strong><br />
Medicine, Taipei, Taiwan, 5 Hepatology and Gastroenterology, Kinki University,<br />
Osaka, Japan, 6 Medical <strong>Oncology</strong>, Providence Portland Medical Center, Portland,<br />
OR, USA, 7 Internal Medicine, Seoul National University, Seoul, Republic <strong>of</strong> Korea,<br />
8 Medical <strong>Oncology</strong>, National Cancer Center, Singapore, 9 Medizinische Klinik,<br />
Universitätsklinikum Frankfurt (Johannes-Wolfgang Goethe Institute), Frankfurt,<br />
Germany, 10 <strong>Oncology</strong>, Royal Free London NHS Foundation Trust, London, UK,<br />
11 General Surgery, University <strong>of</strong> Michigan, Ann Arbor, MI, USA, 12 Clinical<br />
<strong>Oncology</strong>, The University <strong>of</strong> Hong Kong, Hong Kong, China, 13 Hematology and<br />
<strong>Oncology</strong>, Johns Hopkins Singapore International Medical Center, Singapore,<br />
14 <strong>Oncology</strong>, Bristol-Myers Squibb, Princeton, NJ, USA, 15 Global Clinical<br />
Research, Bristol-Myers Squibb Company, Singapore, 16 Immuno-oncology,<br />
Bristol-Myers Squibb, Princeton, NJ, USA, 17 <strong>Oncology</strong> Biomarkers, Bristol-Myers<br />
Squibb, Princeton, NJ, USA, 18 Clinical Medicine, University <strong>of</strong> Southern California<br />
Norris Comprehensive Cancer Center, Los Angeles, CA, USA<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw371 | vi209
abstracts<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
617PD<br />
Ramucirumab (RAM) as second-line treatment in patients<br />
(pts) with advanced hepatocellular carcinoma (HCC):<br />
Prognosis, efficacy, and safety by liver disease etiology<br />
616PD<br />
Phase III study comparing intraperitoneal paclitaxel plus S-1/<br />
paclitaxel with S-1/cisplatin in gastric cancer patients with<br />
peritoneal metastasis: PHOENIX-GC trial<br />
Y. Fujiwara 1 , H. Ishigami 2 , R. Fukushima 3 , A. Nashimoto 4 , H. Yabusaki 5 ,<br />
H. Imamoto 6 , M. Imano 6 , Y. Kodera 7 , Y. Uenosono 8 , K. Amagai 9 , S. Kadowaki 10 ,<br />
H. Miwa 11 , H. Yamaguchi 12 , T. Yamaguchi 13 , J. Kitayama 14<br />
1 Department <strong>of</strong> Gastroenterological Surgery, Osaka Medical Center for Cancer<br />
and Cardiovascular Dideases, Osaka, Japan, 2 Department <strong>of</strong> Chemotherapy, The<br />
University <strong>of</strong> Tokyo, Tokyo, Japan, 3 Department <strong>of</strong> Surgery, Teikyo University,<br />
Tokyo, Japan, 4 Department <strong>of</strong> Surgery, Nanbugo General Hospital, Gosen, Japan,<br />
5 Department <strong>of</strong> Gastroenterological Surgery, Niigata Cancer Center Hospital,<br />
Niigata, Japan, 6 Department <strong>of</strong> Surgery, Kinki University, Osakasayama, Japan,<br />
7 Department <strong>of</strong> Gastroenterological Surgery, Nagoya University, Nagoya, Japan,<br />
8 Department <strong>of</strong> Digestive Surgery, Kagoshima University, Kagoshima, Japan,<br />
9 Division <strong>of</strong> Gastroenterology, Ibaraki Prefectural Central Hospital, Kasama, Japan,<br />
10 Department <strong>of</strong> Clinical <strong>Oncology</strong>, Aichi Cancer Center Hospital, Nagoya, Japan,<br />
11 Department <strong>of</strong> Gastroenterology, Hyogo College Of Medicine, Nishinomiya,<br />
Japan, 12 Department <strong>of</strong> Clinical <strong>Oncology</strong>, Jichi Medical University, Shimotsuke,<br />
Japan, 13 Division <strong>of</strong> Biostatistics, Tohoku University Graduate School <strong>of</strong> Medicine,<br />
Sendai, Japan, 14 Support Center for Clinical Investigation, Jichi Medical University,<br />
Shimotsuke, Japan<br />
Background: Intraperitoneal (IP) paclitaxel (PTX) provides sustained high local<br />
concentrations, and its efficacy has been shown in ovarian cancer. We developed a<br />
regimen combining IP PTX with S-1/PTX for the treatment <strong>of</strong> gastric cancer, and<br />
obtained promising results with a one-year overall survival (OS) rate <strong>of</strong> 78% in a phase<br />
II study. This phase III study evaluated the efficacy <strong>of</strong> IP PTX plus S-1/PTX compared<br />
to standard systemic chemotherapy.<br />
Methods: Eligibility criteria included pathologically confirmed gastric<br />
adenocarcinoma, peritoneal metastasis, and no or short-term (
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
p = 0.05) pts; in females, AR tended to increase with age (6%, 7% and 15%, p > 0.05).<br />
MRP1 expression decreased in YAs (60%) vs IA (86%, p = 0.04) and E pts (95%,<br />
p = 0.02). MGMT was higher in IA than YA (71% vs. 49%, p = 0.007) and SPARC<br />
higher in E than YA (13% vs.0, p = 0.005). PDGFR and PD-L1 were expressed in IA<br />
(14% and 10%) and E pts (29% and 17%) but not YAs. Of 47 genes analyzed, TP53 was<br />
the most frequent alteration in YAs (19%) while CTNNB1 was the most frequent in E<br />
(33%) and IA (30%) and only 9.5% in YA . PIK3CA, PTEN, and PTPN11 mutations<br />
were more prevalent in E (13.3%, 7.1% and 6.7%, respectively) vs IA pts (1.4%, 0.7%<br />
and 0%, all p < 0.05) and were absent in YA. An ATM mutation occurred in 1/21 YAs,<br />
but not in IA (0/144) or E (0/21). The overall frequency <strong>of</strong> P/PP mutations was lower in<br />
YAs (0.38 mutation/case) vs. IA (0.71, p = 0.012) and E (0.93, p = 0.038).<br />
Conclusions: HCCs from YAs were associated with female sex, decreased drug<br />
resistance protein and AR expression. YAs may be more sensitive to alkylating agents<br />
whereas E pts may be more sensitive to PIK3CA/Akt/mTOR or MAPK pathway<br />
inhibitors. Our results provide important knowledge to prospective studies among a<br />
network <strong>of</strong> cancer centers that will also incorporate etiological factors and molecular<br />
features into investigations for HCC therapies.<br />
Legal entity responsible for the study: Celina Ang<br />
Funding: N/A<br />
Disclosure: J. Xiu, Z. Gatalica, S. Reddy: Employee <strong>of</strong> Caris Life Sciences. All other<br />
authors have declared no conflicts <strong>of</strong> interest.<br />
619PD<br />
Prognostic factors in curative treatment <strong>of</strong> gallbladder<br />
cancer - Data <strong>of</strong> 950 cases <strong>of</strong> “The German- Registry”<br />
T.O. Goetze, S.-E. Al-Batran<br />
Institute <strong>of</strong> Clinical Cancer Research, Nordwest-Krankenhaus, Frankfurt am Main,<br />
Germany<br />
Background: In most cases an immediate radical re-resection (IRR) after simple<br />
cholecystectomy in incidental gallbladder carcinoma (IGBC) is needed. The S3<br />
guidelines valid till 2015 have recommended IRR in T2 and more advanced stages. The<br />
new S3- guidelines will recommend more aggressive surgery even in T1b, due to<br />
German- Registry (GR) data. According to the data <strong>of</strong> the GR the indication for IRR<br />
depends more on the experience <strong>of</strong> the hospitals in liver surgery than on complying<br />
with the guidelines, so most <strong>of</strong> IGBC- patients are staged incorrectly and not treated<br />
oncological sufficient. In practice, the following questions are <strong>of</strong> interest. Depends<br />
treatment <strong>of</strong> IGBC on the surgical or oncological expertise <strong>of</strong> the clinics? Which<br />
technique <strong>of</strong> liver resection (LR) is meaningful in which stage? What is important<br />
regarding lymph node ratio (LNR). What’s about multimodal aspects.<br />
Methods: For data analysis we used the GR. The GR includes more than 1000 cases <strong>of</strong><br />
IGBC and is the largest gbc registry in Europe.<br />
Results: To date more than 950 cases <strong>of</strong> IGBC in the GR have been analyzed. In 42 <strong>of</strong><br />
113 T1b cases there was an IRR, with a significant survival benefit for T1b after IRR.<br />
There was also a significant survival benefit for the 228 T2 and 80 T3 with IRR <strong>of</strong> the 461<br />
T2 and 215 T3 tumors. Comparison <strong>of</strong> LR showed good results for the wedge resection<br />
technique (WRT) in T1b and T2. For T3 more radical techniques showed better results.<br />
Less than 50% <strong>of</strong> T2–3 tumors in the registry have been re-resected. LR was performed<br />
significantly more <strong>of</strong>ten in High- volume (HV) clinics. In 212 patients the LNR could be<br />
calculated. Statistic showed that LNR is a significant prognostic factor. The results show<br />
that the referral <strong>of</strong> patients from a LV to a HV has no practical relevance.<br />
Conclusions: IGBC’suptoT1bneedsradicalsurgery.WRTisanattractiveprocedurefor<br />
T1b / T2 IGBC due to the lower invasiveness and implantation should also be possible in<br />
LV’s with few experience in liver surgery. Also the count <strong>of</strong> retrieved lymph nodes is <strong>of</strong><br />
essential interest. By following the correct decision processes more patients have the<br />
possibility for cure. For further increasing the cure rate in T2-3 GBC patients a multimodal<br />
therapy trial has been planned by the investigator supported by <strong>of</strong> more than 300 clinics.<br />
Legal entity responsible for the study: N/A<br />
Funding: The German- registry/ no commercial founding Part <strong>of</strong> UCT (University<br />
Cancer Center Frankfurt)<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
620PD<br />
Comparative molecular analyses <strong>of</strong> pancreatic cancer (PC):<br />
Younger vs. older patients (pts)<br />
M. Salem 1 , P. Philip 2 , R. Feldman 3 , J. Hwang 4 , M. Pishvaian 1 , J. Xiu 3 , W. Eldeiry 5 ,<br />
S. Reddy 6 , Z. Gatalica 7 , N. Trivedi 1 , A. Zareb 8 , B.S. Colton 1 , H. Wang 1 ,<br />
A. Shields 2 , J. Marshall 1<br />
1 Division <strong>of</strong> Hematology and <strong>Oncology</strong>, Lombardi Cancer Center Georgetown<br />
University, Washington, DC, USA, 2 <strong>Oncology</strong>, Karmanos Cancer Institute, Detroit,<br />
MI, USA, 3 Pathology, Caris Life Sciences, Phoenix, AZ, USA, 4 <strong>Oncology</strong>, Levine<br />
Cancer Institute, Charlotte, NC, USA, 5 <strong>Oncology</strong>, Fox Chase Cancer Center,<br />
Philadelphia, PA, USA, 6 Pathology, Caris Life Sciences, Phoenix, AZ, USA,<br />
7 <strong>Oncology</strong>, Caris Life Sciences, Phoenix, AZ, USA, 8 <strong>Oncology</strong>, King Fahad<br />
Specialist Hospital, Dammam, Saudi Arabia<br />
Background: There is limited data on molecular tumor characteristics and outcome in<br />
younger pts with PC. The effect <strong>of</strong> an individual’s age on their tumor molecular pr<strong>of</strong>ile<br />
is unknown.<br />
Methods: Molecular pr<strong>of</strong>iles—using protein expression (IHC), gene amplification<br />
(ISH) and sequencing—<strong>of</strong> PC tumors were reviewed and correlated with pt outcomes.<br />
A Chi-squared test determined differences between age groups; Kaplan-Meier<br />
methodology estimated survival.<br />
Results: In total, 2426 PC tumors were examined. The most frequently mutated genes<br />
were KRAS (85%), TP53 (63%), SMAD4 (13%), BRCA2 (12%), ATM/APC/NTRK1<br />
(5% each), BRCA1 (4%), and cMET/PIK3CA (3% each) Subgroup analysis <strong>of</strong> tumors<br />
from 568 younger (median age 50; range 21-55 yr) and 1113 older (71; 65-90) pts was<br />
performed. When compared with older pts, younger pts’ tumors had a greater<br />
frequency <strong>of</strong> mutations in MLH1 (4% vs. 0.3%, p = 0.003), PTEN (3% vs. 0.5%,<br />
p = 0.008), EGFR (2.2% vs. 0%, p = 0.003), CTNNB1 (2.3% vs. 0.5%; p = 0.04), c-KIT<br />
(2% vs. 0.3%; p = 0.02), and NTRK1 (20% vs. 0%; p = 0.002; assessed in only 10 and 45<br />
pts, respectively), whereas KRAS mutations were significantly higher in older pts (80%<br />
vs. 70%, p = 0.0003). The mutation rates (older vs. younger) <strong>of</strong> BRCA1 (both 5%),<br />
BRCA2 (14% vs. 12%), BRAF (both 1%), GNAS (2.4% vs. 1.6%), PIK3CA (both 3%),<br />
NOTCH1 (0.9% vs. 1.6%), cMET (2.8% vs. 3.9%), and RET (0.4% vs. 0.8% were similar<br />
in both age groups. Older pts’ tumors had higher rates <strong>of</strong> low RRM1 expression (85%<br />
vs. 79%, p = 0.03) and high PDGFR expression (22% vs. 7%, p = 0.03), whereas younger<br />
pts had higher TOP2A expression (59% vs. 50%, p = 0.02). There was no difference in<br />
either PD-L1 expression in tumor cells (8% vs. 7%) or the frequency <strong>of</strong> PD-1<br />
expression on tumor-infiltrating lymphocytes (41% vs. 37%). Outcomes were evaluable<br />
for 73 pts. There were no survival differences between the two age groups. Low ERCC1,<br />
MGMT, PRM1, and TLE3 expressions appeared to be associated with prolonged<br />
survival in older but not younger pts; however, larger studies are needed to define the<br />
significance <strong>of</strong> this finding.<br />
Conclusions: Young pts with PC may carry genetic alterations that are different from<br />
older pts. A wider gene panel is needed to aid in the discovery <strong>of</strong> targeted mutations<br />
and provide therapeutic opportunities.<br />
Legal entity responsible for the study: Georgetown University<br />
Funding: N/A<br />
Disclosure: R. Feldman, J. Xiu, S. Reddy, Z. Gatalica: Employment by Caris LS.All<br />
other authors have declared no conflicts <strong>of</strong> interest.<br />
621PD<br />
abstracts<br />
Randomized phase II study <strong>of</strong> S-1 and concurrent<br />
radiotherapy with versus without induction chemotherapy <strong>of</strong><br />
gemcitabine for locally advanced pancreatic cancer (LAPC):<br />
Final analysis <strong>of</strong> JCOG1106<br />
T. Ioka 1 , A. Fukutomi 2 , J. Mizusawa 3 , H. Katayama 4 , S. Nakamura 5 , Y. Ito 6 ,<br />
N. Hiraoka 7 , M. Ueno 8 , M. Ikeda 9 , K. Sugimori 10 , K. Shimizu 11 , T. Okusaka 12 ,<br />
M. Ozaka 13 , H. Yanagimoto 14 , S. Nakamori 15 , T. Azuma 16 , A. Hosokawa 17 ,<br />
N. Sata 18 , T. Mine 19 , J. Furuse 20<br />
1 Department <strong>of</strong> Cancer Survey and Gastrointestinal <strong>Oncology</strong>, Osaka Medical<br />
Center for Cancer and Cardiovascular Dideases, Osaka, Japan, 2 Gastrointestinal<br />
<strong>Oncology</strong>, Shizuoka Cancer Center, Shizuoka, Japan, 3 Japan Clinical <strong>Oncology</strong><br />
Group Data Center, National Cancer Center, Tokyo, Japan, 4 Japan Clinical<br />
<strong>Oncology</strong> Group Data Center, Center for Research Administration and Support<br />
National Cancer Center, Tokyo, Japan, 5 Division <strong>of</strong> Radiation <strong>Oncology</strong>, Kansai<br />
Medical University, Osaka, Japan, 6 Department <strong>of</strong> Radiation <strong>Oncology</strong>, National<br />
Cancer Center Hospital, Tokyo, Japan, 7 Division <strong>of</strong> Pathology and Clinical<br />
Laboratories, National Cancer Center Hospital, Tokyo, Japan, 8 Division <strong>of</strong><br />
Hepatobiliary and Pancreatic <strong>Oncology</strong>, Kanagawa Cancer Center, Yokohama,<br />
Japan, 9 Department <strong>of</strong> Hepatobiliary and Pancreatic <strong>Oncology</strong>, National Cancer<br />
Center Hospital East, Kashiwa, Japan, 10 Gastroenterological Center, Yokohama<br />
City University Medical Center, Yokohama, Japan, 11 Institute <strong>of</strong> Gastroenterology,<br />
Tokyo Women’s Medical University, Tokyo, Japan, 12 Department <strong>of</strong> Hepatobiliary<br />
and Pancreatic <strong>Oncology</strong>, National Cancer Center Hospital, Tokyo, Japan,<br />
13 Department <strong>of</strong> Gastroenterology, Cancer Institute Hospital <strong>of</strong> JFCR, Tokyo,<br />
Japan, 14 Department <strong>of</strong> Surgery, Kansai Medical University Hirakata Hospital,<br />
Hirakata, Japan, 15 Department <strong>of</strong> Hepatobiliary and Pancreatic Surgery, National<br />
Hospital Organization Osaka National Hospital, Osaka, Japan, 16 Division <strong>of</strong><br />
Gastroenterology, Department <strong>of</strong> Internal Medicine, Kobe University Graduate<br />
School <strong>of</strong> Medicine, Kobe, Japan, 17 Department <strong>of</strong> Gastroenterology and<br />
Hematology, Faculty <strong>of</strong> Medicine, University <strong>of</strong> Toyama, Toyama, Japan,<br />
18 Department <strong>of</strong> Surgery, Jichi Medical University School <strong>of</strong> Medicine,<br />
Shimotsuke, Japan, 19 Department <strong>of</strong> Gastroenterology, Tokai University School <strong>of</strong><br />
Medicine, Isehara, Japan, 20 Department <strong>of</strong> Medical <strong>Oncology</strong>, Kyorin University<br />
School <strong>of</strong> Medicine, Tokyo, Japan<br />
Background: JCOG1106 is a phase II trial to evaluate the efficacy and safety <strong>of</strong><br />
chemoradiotherapy (CRT) with and without induction chemotherapy (CT) to<br />
determine which is more promising CRT regimen for LAPC. Primary endpoint was<br />
overall survival (OS). 102 patients (pts) were randomized to CRT (Arm A) or<br />
induction CT followed by CRT (Arm B), and 100 pts (Arm A/B n = 51/49) were<br />
eligible. In the primary analysis performed 1 year after completion <strong>of</strong> enrollment,<br />
1-year OS for Arm A/B were reported to be 66.7/69.3% (hazard ratio [HR] 1.16),<br />
and Arm B was considered more promising based on pre-specified decision rule (J<br />
Clin Oncol 33, 2015, suppl; abst 4116). Although the probability <strong>of</strong> survival was<br />
greater in Arm B in the first 12 months, there was a possibility that it would be<br />
greater in Arm A in the following period. We performed final analysis 1 year after<br />
primary analysis.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw371 | vi211
abstracts<br />
Methods: Pts in Arm A received RT (50.4 Gy/28 fr) with concurrent S-1 (40 mg/m 2 /<br />
dose, b.i.d. on the day <strong>of</strong> irradiation). Pts in Arm B received induction gemcitabine<br />
(GEM) (1,000 mg/m 2 , iv, days 1, 8 and 15, every 4 weeks) for 12 weeks, and then, only<br />
pts with controlled disease received same CRT as Arm A. After CRT, GEM was<br />
continued until disease progression or unacceptable toxicity in both arms. Decision<br />
rule was set as follows: Arm B, which was expected to be less-toxic, will be considered<br />
more promising if point estimate <strong>of</strong> HR <strong>of</strong> OS for Arm B to Arm A is smaller than<br />
1.186.<br />
Results: In the final analysis, 2-year OS for Arm A/B were 36.9/18.9% and HR was 1.26<br />
[95%CI 0.82-1.93]. 2-year progression-free survival were 8.6/4.2% (HR 1.03), and<br />
2-year distant metastasis-free survival were 14.8/4.2% (HR 1.20). Incidences <strong>of</strong> grade 3/<br />
4 toxicities in Arm A/B were leukopenia 62/61%, neutropenia 54/57%, anemia 18/12%,<br />
thrombocytopenia 10/14%, anorexia 16/4%, fatigue 8/4%, nausea 8/2%, diarrhea 6/4%,<br />
gastroduodenal (GD) hemorrhage 10/6%, GD ulcer 6/4%, and biliary infection 20/27%.<br />
Three treatment-related deaths occurred in Arm A (pneumonitis, GD hemorrhage,<br />
biliary infection).<br />
Conclusions: Compared to CRT alone, CRT with Induction CT <strong>of</strong> gemcitabine<br />
resulted in a poorer long-time outcome, in spite <strong>of</strong> a favorable short-time outcome.<br />
Clinical trial identification: UMIN 000006811<br />
Legal entity responsible for the study: Akira Fukutomi<br />
Funding: Grants from MHLW, Japan. Grants from Japan AMED.<br />
Disclosure: T. Ioka: Honoraria: Eisai, Nippon Kayaku, Taiho Pharmaceutical.<br />
Consultant: Taiho Pharmaceutical. Funding: Eisai, Taiho Pharmaceutical. Grants:<br />
MHLW, Japan, Japan AMED. A. Fukutomi: Honoraria: Eli Lilly, Taiho Pharmaceutical.<br />
Research funding: Taiho Pharmaceutical. Grants: MHLW, Japan. Grants: Japan<br />
AMED. J. Mizusawa, H. Katayama, S. Nakamura, Y. Ito, N. Hiraoka, K. Sugimori,<br />
K. Shimizu, M. Ozaka, H. Yanagimoto, T. Azuma, N. Sata: Grants: MHLW, Japan,<br />
Japan AMED. M. Ueno: Honoraria: Eli Lilly, Novartis, Taiho Pharmaceutical. Research<br />
funding: Eisai, Taiho Pharmaceutical. Grants: MHLW, Japan, Japan AMED. M. Ikeda:<br />
Honoraria: Taiho Pharmaceutical. Grants: MHLW, Japan, Japan AMED.T. Okusaka:<br />
Research funding and Honoraria: Eli Lilly, Taiho Pharmaceutical. Grants: MHLW,<br />
Japan, Japan AMED. S. Nakamori: Research funding: Eizai. Grants: MHLW, Japan,<br />
Japan AMED. A. Hosokawa: Honoraria: Eisai, Taiho Pharmaceutical. Research<br />
funding: Taiho Pharmaceutical. Grants: MHLW, Japan, Japan AMED. T. Mine:<br />
Resarch funding: Eli Lily, Taiho Pamrmaceutical. Grants: MHLW, Japan, Japan<br />
AMED. J. Furuse: Personal financial interests: Eizai, Eli Lilly, Nippon Kayaku, Novartis,<br />
Pfizer, Sandoz, Taiho Pharmaceutical, Takeda Pharmaceutical. Institutional financial<br />
interests: Taiho Pharmaceutical. Grants; MHLW, Japan, Japan AMED.<br />
622PD<br />
Final results <strong>of</strong> NAPOLI-1: A phase 3 study <strong>of</strong> nal-IRI<br />
(MM-398) ± 5-fluorouracil and leucovorin (5-FU/LV) vs 5-FU/<br />
LV in metastatic pancreatic cancer (mPAC) previously treated<br />
with gemcitabine-based therapy<br />
L-T. Chen 1 , A. Wang-Gillam 2 , C-P. Li 3 , G. Bodoky 4 , A. Dean 5 , Y-S. Shan 6 ,G.<br />
S. Jameson 7 , T. Macarulla 8 , K-H. Lee 9 , D. Cunningham 10 , J-F. Blanc 11 ,<br />
R. Hubner 12 , C-F. Chiu 13 , G. Schwartsmann 14 , F. Braiteh 15 , B. Belanger 16 ,<br />
E. Bayever 16 , F. de Jong 17 , D.D. von H<strong>of</strong>f 7 , J.T. Siveke 18<br />
1 National Institute <strong>of</strong> Cancer Research, National Health Research Institutes,<br />
Tainan, Taiwan, 2 Medicine, Washington University School <strong>of</strong> Medicine, St. Louis,<br />
MO, USA, 3 Medicine, Taipei Veterans General Hospital and National Yang-Ming<br />
University School <strong>of</strong> Medicine, Taipei, Taiwan, 4 Medical <strong>Oncology</strong>, St. László<br />
Teaching Hospital, Budapest, Hungary, 5 Cancer Services, St John <strong>of</strong> God<br />
Hospital, Subiaco, Australia, 6 National Cheng Kung University, National Cheng<br />
Kung University Hospital, Tainan, Taiwan, 7 Medical <strong>Oncology</strong>, TGen, Phoenix, AZ,<br />
USA, 8 <strong>Oncology</strong> Service, Vall d’Hebron University Hospital and Vall d’Hebron<br />
Institute <strong>of</strong> <strong>Oncology</strong>, Barcelona, Spain, 9 Internal Medicine, Seoul National<br />
University Hospital, Seoul, Republic <strong>of</strong> Korea, 10 GI & Lymphoma Unit, Royal<br />
Marsden Hospital, Sutton, UK, 11 Hepato-Gastroenterology and Digestive<br />
<strong>Oncology</strong>, Hôpital Saint-André, Bordeaux, France, 12 Medical <strong>Oncology</strong>, The<br />
Christie NHS Foundation Trust, Manchester, UK, 13 Cancer Center, China Medical<br />
University Hospital, Taichung, Taiwan, 14 UFRGS, Hospital de Clínicas de Porto<br />
Alegre, Porto Alegre, Brazil, 15 Medicine, Comprehensive Cancer Centers <strong>of</strong><br />
Nevada, Las Vegas, NV, USA, 16 Medicine, Merrimack Pharmaceuticals, Inc.,<br />
Cambridge, MA, USA, 17 Medicine, Baxalta GmbH, Zurich, Switzerland,<br />
18 University Hospital Essen, West German Cancer Center, Essen, Germany<br />
Background: nal-IRI, a liposomal formulation <strong>of</strong> irinotecan, plus 5-FU/LV is approved<br />
in the US for patients (pts) with mPAC previously treated with gemcitabine-based<br />
therapy. Primary analysis (data cut<strong>of</strong>f, Feb 14, 2014) <strong>of</strong> the NAPOLI-1 trial<br />
(NCT01494506) showed that, after 313 events, nal-IRI + 5-FU/LV significantly<br />
improved median overall survival (OS) vs 5-FU/LV (6.1 vs 4.2 mo; HR 0.67; 95% CI<br />
0.49-0.92; P = 0.012; Wang-Gillam et al, Lancet. 2016). Here we report the final analysis<br />
<strong>of</strong> NAPOLI-1 (data cut<strong>of</strong>f, Nov 16, 2015).<br />
Methods: 417 pts were randomly assigned to nal-IRI 70 mg/m 2 (equivalent to 80 mg/<br />
m 2 irinotecan HCl trihydrate salt) + 5-FU/LV 2400/400 mg/m 2 q2w (n = 117), nal-IRI<br />
100 mg/m 2 (equivalent to 120 mg/m 2 irinotecan HCl trihydrate salt) q3w (n = 151), or<br />
5-FU/LV 2000/200 mg/m 2 weekly for weeks 1-4 q6w (n = 149). Log-rank P values are<br />
2-sided.<br />
Results: After 382 events, median OS was improved with nal-IRI + 5-FU/LV vs 5-FU/<br />
LV (6.2 vs 4.2 mo; HR 0.75; 95% CI 0.57-0.99; P = 0.038), but not for nal-IRI vs 5-FU/<br />
LV (4.9 vs 4.2 mo; HR 1.07; 95% CI 0.84-1.36; P = 0.567). Kaplan-Meier estimates <strong>of</strong><br />
OS for nal-IRI + 5-FU/LV and 5-FU/LV, respectively, were 53% and 38% at 6 mo, and<br />
26% and 16% at 12 mo. Median progression-free survival was longer for<br />
nal-IRI + 5-FU/LV vs 5-FU/LV (3.1 vs 1.5 mo; HR 0.57; 95% CI 0.43-0.76; P < 0.001),<br />
but not for nal-IRI vs 5-FU/LV (2.7 vs 1.6 mo; HR 0.81; 95% CI 0.63-1.04; P = 0.111).<br />
Response rates per RECIST v1.1 were higher for nal-IRI + 5-FU/LV vs 5-FU/LV (17%<br />
vs 1%; P < 0.001) and for nal-IRI vs 5-FU/LV (6% vs 1%; P = 0.020). Grade ≥3<br />
treatment-emergent adverse events in ≥10% <strong>of</strong> pts in either nal-IRI arm were<br />
neutropenia (28%, 15%, and 1% in the nal-IRI + 5-FU/LV, nal-IRI, and 5-FU/LV arms,<br />
respectively), fatigue (14%, 6%, and 4%), diarrhea (13%, 21%, and 5%), vomiting (12%,<br />
14%, and 4%), anemia (9%, 11%, and 7%), and hypokalemia (3%, 12%, and 2%).<br />
Conclusions: Final results from NAPOLI-1 continue to show OS benefit for<br />
nal-IRI + 5-FU/LV vs 5-FU/LV. No new safety concerns were identified.<br />
nal-IRI + 5-FU/LV provides a new treatment option for pts with mPAC previously<br />
treated with gemcitabine-based therapy.<br />
Clinical trial identification: NCT01494506<br />
Legal entity responsible for the study: Merrimack Pharmaceuticals, Inc.<br />
Funding: Merrimack Pharmaceuticals, Inc.<br />
Disclosure: L-T. Chen: Merrimack/ NAPOLI-1 study Steering Committee Member,<br />
uncompensated. Advisory Meeting, honorarium: Baxalta. Consultant, honorarium:<br />
PharmaEngine. A. Wang-Gillam: Advisory Board: Merrimack, Pfizer. A. Dean:<br />
Investigator meeting, travel grant: Merrimack. D. Cunningham: Research funding to<br />
institution: Amgen, AstraZeneca, Bayer, Celgene, Medimmune, Merck Serono,<br />
Merrimack, San<strong>of</strong>i. J-F. Blanc: Honoraria: Baxalta. F. Braiteh: Research funding:<br />
Merrimack. B. Belanger: Employee <strong>of</strong> Merrimack. E. Bayever: Former employee, stock<br />
options: Merrimack. F. de Jong: Employee and stock options: Baxalta. D.D. von H<strong>of</strong>f:<br />
Clinical trial: Merrimack. J.T. Siveke: Advisory Board, Honoraria: Baxalta. All other<br />
authors have declared no conflicts <strong>of</strong> interest.<br />
623P<br />
Multimodality treatment (MMT) and outcomes <strong>of</strong> gastric<br />
adenocarcinoma (GC) in National Cancer DataBase(NCDB)<br />
A. Barzi 1 , D. Yang 2 , H-J. Lenz 1 , S. Sadeghi 3<br />
1 Medical <strong>Oncology</strong>, University <strong>of</strong> Southern California Norris Comprehensive<br />
Cancer Center, Los Angeles, CA, USA, 2 Preventive Medicine, University <strong>of</strong><br />
Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA,<br />
3 Medicine, University <strong>of</strong> Southern California Norris Comprehensive Cancer Center,<br />
Los Angeles, CA, USA<br />
Background: In patients (pts) with non-metastatic GC, MMT added to surgery<br />
improves the cure rate. The MMT includes adjuvant chemoradiation (ACR),<br />
neoadjuvant chemoradiation (NACR), and perioperative chemotherapy (CT). We used<br />
the NCDB data to compare different MMT in pts with non-metastatic GC.<br />
Methods: A total <strong>of</strong> 79369 pts with non-metastatic GC diagnosed 2004- 2013 were<br />
identified. Pts with known tumor site who underwent surgery and received MMT were<br />
selected for this analysis. Treatment included NACR, CT, and ACR. Pts divided into<br />
two cohorts cardia GC (cGC) and non-cardia GC (nGC). Among 10796 pts with cGC<br />
and 10681 with nGC, demographics, tumor characteristics, and treatment data were<br />
abstracted. Overall survial (OS) was selected as the primary study outcome. Cox<br />
regression model was used to examine the effect <strong>of</strong> choice <strong>of</strong> MMT on OS adjusting for<br />
all known prognostic factors.<br />
Results: Summary <strong>of</strong> results included in the table. In 10796 pts with cGC MMT<br />
distribution was 24%, 55%, and 21% for ACR, NACR, and CT. These numbers for nGC<br />
were 10681, 55%, 7%, and 38%. OS in the treament groups: ACR 42.1 (95%CI:<br />
42.2-44.1), NACR 35.9 (95%CI: 34.2-37.9), CT 34.2 (32.7 -35.8). In cGC, ACR<br />
remained superior with median OS <strong>of</strong> 36.4 (34.5-39.0) vs. NACR 34.0 (32.5-35.6: HR<br />
1.13) and CT 33.3 (31.2-35.6: HR 1.11) p < .0001. These number for nGC were 48.3<br />
(45.6-52.0), 35.1 (31.0-40.9: HR 1.18), and 35.9 (33.5-38.3: HR 1.20) p < .0001. In the<br />
cGC, CT resulted in a significant (p < 0.001) reduction in the size <strong>of</strong> tumor with the<br />
median tumor size <strong>of</strong> 4 cm as compared to 4.5 cm in the ACR, there was no difference<br />
in the size <strong>of</strong> the tumor between CT and ACR group for ncGC.<br />
Table: 623P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
ACR NACR CT<br />
N (%) (cGC, nGC) 8517 (40) (2618,<br />
5899)<br />
6630 (31) (5892,<br />
738)<br />
6330 (29) (2286,<br />
4044)<br />
Mean Age 63 62 64<br />
Male (%) 66 82 66<br />
Race: White/Black/East-Asia/ 58/18/7/3/12/1/1 87/5/1/1/4/1/1 63/15/5/3/12/1/1<br />
Hispanic/others (%)<br />
Path Stage (0/I, II/III, IV,<br />
unknown) (%)<br />
0/13/32/48/7 3/23/34/37/2 1/17/30/43/8<br />
Conclusions: ACR increased the odds <strong>of</strong> survival by 20% in the nGC and by 10% in<br />
cGC pts. Although this is a retrospective analysis the large sample size and long follow<br />
up provides confidence in the observation. There is a statistically significat difference in<br />
vi212 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
the presentation and outcomes <strong>of</strong> cGC and nGC. Caution should be exercised in<br />
combining these pts in prospective trials.<br />
Legal entity responsible for the study: USC/ Norris Comprehensive Cancer Center<br />
Funding: University <strong>of</strong> Southern California, Norris Comprehensive Cancer Center<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
624P<br />
Programmed death-ligand 1 (PD-L1) and immune infiltrates<br />
are prognostic for better outcome and enriched in the ATM<br />
(ataxia telangiectasia mutated)-low segment <strong>of</strong> gastric cancer<br />
(GC)<br />
E. Kilgour 1 , H. Angell 2 , K-M. Kim 3 , S. Ahn 3 , S.T. Kim 4 , A. Sharpe 5 , J. Ogden 2 ,<br />
A. Davenport 6 , J.C. Barrett 7 , D. Hodgson 1 , J. Lee 4<br />
1 <strong>Oncology</strong> Translational Science, AstraZeneca, Macclesfield, UK, 2 <strong>Oncology</strong><br />
Translational Science, AstraZeneca, Cambridge, UK, 3 Pathology and Translational<br />
Genomics, Samsung Medical Center Sungkyunkwan University School <strong>of</strong><br />
Medicine, Seoul, Republic <strong>of</strong> Korea, 4 Division <strong>of</strong> Hematology-<strong>Oncology</strong>, Samsung<br />
Medical Center Sungkyunkwan University School <strong>of</strong> Medicine, Seoul, Republic <strong>of</strong><br />
Korea, 5 Discovery Sciences, AstraZeneca, Cambridge, UK, 6 South Manchester,<br />
University Hospital, Manchester, UK, 7 <strong>Oncology</strong> Translational Science,<br />
AstraZeneca, Boston, MA, USA<br />
Background: In GC an urgent need exists for effective targeted therapies and predictive<br />
markers. In a PhII study, low ATM expression in tumour was associated with greater<br />
overall survival (OS) benefit in GC patients treated with olaparib/paclitaxel (1).<br />
Antibodies targeting the programmed death-1 checkpoint have reported clinical<br />
efficacy in GC, with tumour PD-L1 expression and microsatellite instability (MSI)<br />
emerging as predictive markers. We have assessed the prognostic significance <strong>of</strong> PD-L1<br />
and immune infiltrates in GC and their association with the ATM-low segment.<br />
Methods: PD-L1, CD3+ T-lymphocytes, CD8+ cytotoxic T-cells, human epidermal<br />
growth factor receptor 2 (HER2) and ATM expression were assessed by<br />
immunohistochemistry (IHC) in a cohort <strong>of</strong> 384 Korean gastric cancers.<br />
Results: PD-L1 positivity (>0%) on tumour cells (TC) and immune infiltrates (IC) was<br />
16% and 90% respectively and a correlation was observed with MSI (p < 0.01) and<br />
immune infiltrates (CD3 P < 0.05; CD8 P < 0.01). PD-L1 TC and CD8 were not<br />
associated with Lauren subtype. Multivariate analysis showed PD-L1 TC positivity,<br />
CD3 and CD8 were significantly associated with better OS (p < 0.01) and disease free<br />
survival (p < 0.01). Prevalence <strong>of</strong> HER2-high (IHC 3+) was 7% and ATM-low (
abstracts<br />
627P<br />
Histopathological response to neoadjuvant chemotherapy is<br />
predictive for prognosis in locally advanced gastroesophageal<br />
cancer<br />
S. Spoerl 1 , S-E. Al-Batran 2 , M. Feith 3 , F. Lordick 4 , P. Thuss-Patience 5 , C. Pauligk 2 ,<br />
B. Haller 6 , A. Novotny 3 , S. Lorenzen 1<br />
1 3rd Department <strong>of</strong> Internal Medicine, Klinikum rechts der Isar, Technische<br />
Universität München, Munich, Germany, 2 UCT University Cancer Center,<br />
Nordwest-Krankenhaus, Frankfurt am Main, Germany, 3 Department <strong>of</strong> Surgery,<br />
Klinikum rechts der Isar, Technische Universität München, Munich, Germany,<br />
4 University Cancer Center Leipzig, University Clinic Leipzig, Leipzig, Germany,<br />
5 Department <strong>of</strong> Hematology, <strong>Oncology</strong> and Tumorimmunology, Charité, Campus<br />
Virchow Klinikum, Berlin, Germany, 6 Institute for Medical Statistics and<br />
Epidemiology, Technische Universität München, Munich, Germany<br />
Background: Neoadjuvant chemotherapy (neoCTx) improves the prognosis <strong>of</strong> patients<br />
(pts) with localized esophagogastric adenocarcinoma (EGC). This retrospective<br />
analysis evaluates the predictive value <strong>of</strong> histopathology on neoCTX.<br />
Methods: 461 pts with locally advanced EGC (T2/T3 and/or N+) who received<br />
neoCTx followed by surgery between 2000 and 2013 were analyzed from four<br />
institutions: 314 (68.1%) with intestinal, 94 (20.4%) with diffuse and 53 (11.5%) with<br />
mixed histological type according to Laurens classification.<br />
Taxane-platinum-fluoropyrimidine (5FU) based triplet or platinum-FU based doublet<br />
neoCTX was administered preoperatively to 185 (40.1%) and 276 (59.9%) pts,<br />
respectively. Pathological response evaluation according to Becker was performed<br />
locally.<br />
Results: Median patients’ age was 63 years, 79.8% were male. Tumors were localized in<br />
the stomach in 32.5% and EG junction in 67.5%. 96.5% had clinical stage T3/T4 and<br />
93.7% were N+. With a median follow up <strong>of</strong> 39.6 months (mos), median overall<br />
survival (OS) was 66.4 mos. For pts with intestinal type, median OS was 77.9 mos<br />
compared to 34.6 mos for diffuse (p < 0.001) and 64.4 mos for mixed type (p = 0.657).<br />
Median disease-free survival (DFS) was 48.7 mos for intestinal compared to 17.3 for<br />
diffuse (p = 0.002) and 29.2 mos for mixed type (p = 0.327). Pathological complete<br />
response (pCR) was 9.1% and combined complete und subtotal response (pCR + pSR)<br />
was 26.7% for all pts. 25/261 (9.6%) <strong>of</strong> pts with intestinal type had a pCR compared to<br />
4/65 pts (6.2%) with diffuse and 4/37 (10.8%) with mixed type. pCR + pSR rate was<br />
significantly higher in intestinal (30.3%) compared to diffuse (15.4%; p = 0.024), but<br />
not compared to mixed type (21.6%; p = 0.373). Pts with pCR had a mean OS <strong>of</strong> 124.1<br />
compared to 89.4 mos for pts with other regression grades (p = 0.004). For pts with<br />
intestinal type, 3-yr OS was 87.5% with pCR and 68.4% with other regression grades<br />
(p = 0.091). All pts with diffuse and mixed type and pCR were alive after 3 yrs<br />
compared to 41.9% and 68.9% with other regression grades (p = 0.043).<br />
Conclusions: Pathologic complete response is associated with long-term survival in<br />
EGC independent <strong>of</strong> histopathological subtype. Efforts to increase the rate <strong>of</strong> pCR by<br />
more effective neoCTX are warranted.<br />
Legal entity responsible for the study: Technical University Munich<br />
Funding: Technical University Munich<br />
Disclosure: F. Lordick: Receipt <strong>of</strong> grant/research supports: GSK, Fresenius Biotech,<br />
Boehringer. Receipt <strong>of</strong> honoraria or consultation fees: Amgen, Eli Lilly, Garrymed,<br />
MSD. Merck-Serono, Roche, Taiko. Travel support: Bayer, MSD, Amgen, Roche. All<br />
other authors have declared no conflicts <strong>of</strong> interest.<br />
628P<br />
The role <strong>of</strong> antiangiogenic therapy in advanced<br />
gastro-esophageal cancer: a systematic review and<br />
meta-analysis<br />
M.C. Riesco-Martinez 1 , A. Díaz-Serrano 1 , C. Gomez-Martin 1 , J. Adeva Alfonso 1 ,<br />
E. Sabater Cabrera 2 , R. Garcia-Carbonero 1<br />
1 Medical <strong>Oncology</strong>, Hospital Universitario 12 de Octubre, Madrid, Spain,<br />
2 Pharmacoeconomics & Outcomes Research, PORIB, Madrid, Spain<br />
Background: Antiangiogenic therapy (AT) has demonstrated a significant<br />
improvement in overall survival (OS) in advanced gastro-esophageal cancer (AGC) in<br />
the second line (2L) setting. However results in the first line (1L) are unalike and its<br />
role is still unclear. The small size <strong>of</strong> the majority <strong>of</strong> the studies may be<br />
underestimating the effect <strong>of</strong> this treatment. We aimed to perform a systematic review<br />
and meta-analysis <strong>of</strong> randomized clinical trials (RCT) in this setting to synthesize the<br />
available data and help decision-making.<br />
Methods: A systematic search was performed through MEDLINE, EMBASE, Cochrane<br />
Central Register <strong>of</strong> Controlled Trials and ASCO meeting abstracts up to April 2016 to<br />
identify RCTs for AGC comparing standard treatment + AT vs standard treatment<br />
alone in 1L and 2L. Studies were reviewed by two authors and discrepancies were<br />
resolved by consensus or by a third author. Data including progression-free survival<br />
(PFS), OS and response rate (RR) were extracted. The primary endpoint was OS. A<br />
meta-analysis (MA) with fixed and random effects models comparing the different<br />
regimens with direct comparisons was conducted.<br />
Results: Ten RCT including 2769 patients were identified. Six evaluated AT in 1L, and<br />
four in 2L. Overall, the pooled analysis demonstrated that AT improved OS (HR = 0.84,<br />
95% CI 0.77-0.92) and PFS (HR = 0.74, 95% CI 0.61-0.89). When 1L and 2L RCT were<br />
analyzed separately, a statistically significantly improvement in OS (HR = 0.79, 95%CI<br />
0.70-0.89,p = 0.0001) and PFS (HR= 0.56, 95% CI 0.45-0.70,p < 0.0001) was seen in 2L<br />
favouring the AT containing arm compared to non-AT. However, non-statistically<br />
significant differences in OS (HR = 0.9, 95%CI 0.70-1.03) or PFS (HR= 0.96, 95%CI<br />
0.8-1.15) were demonstrated in 1L. No significant heterogeneity was found among<br />
RCTs.<br />
Conclusions: The results <strong>of</strong> direct MA suggest that AT vs. non-AT improves OS and<br />
PFS for patients in the 2L setting for AGC, however no benefit was demonstrated in<br />
the 1L.<br />
Legal entity responsible for the study: Hospital Universitario 12 de Octubre<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
629P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Molecular characterization <strong>of</strong> HER2-positive (HER2+)<br />
metastatic gastric and gastro-esophageal junction cancer<br />
patients (mGC): Identification <strong>of</strong> resistance mechanisms to<br />
trastuzumab-based therapy (TTZ)<br />
M. Alsina 1 , C. Hierro 1 , J. Sastre 2 , R. Guardeño 3 , C. Lopez 4 , E. Pineda 5 ,<br />
E. Aranda 6 , J.L. Manzano 7 , M. Galán 8 , F. Longo 9 , L. Visa 10 , S. Landolfi 11 ,<br />
J. Jimenez 12 , J. Sperinde 13 , A. Pandiella 14 , J. Tabernero 1 , J. Hernandez-Losa 11 ,<br />
J. Arribas 12 , M. Scaltriti 15 , P. Nuciforo 12<br />
1 Medical <strong>Oncology</strong>, Vall Hebron University Hospital and VHIO-Vall d’Hebron<br />
Institute <strong>of</strong> <strong>Oncology</strong>, Barcelona, Spain, 2 <strong>Oncology</strong> Department, Clínico San<br />
Carlos Hospital, Madrid, Spain, 3 Medical <strong>Oncology</strong>, Catalan Institute <strong>of</strong> <strong>Oncology</strong><br />
(ICO)-Hospital Universitari Josep Trueta, Girona, Spain, 4 Medical <strong>Oncology</strong>,<br />
Hospital Universitario Marques de Valdecilla, Santander, Spain, 5 Medical<br />
<strong>Oncology</strong>, Hospital Clinic y Provincial de Barcelona, Barcelona, Spain, 6 Medical<br />
<strong>Oncology</strong>, Reina S<strong>of</strong>ía Hospital, University <strong>of</strong> Córdoba, Maimonides Institute <strong>of</strong><br />
Biomedical Research (IMIBIC), Spanish Cancer Network (RTICC), Instituto de<br />
Salud Carlos III, Cordoba, Spain, 7 Medical <strong>Oncology</strong>, Catalan Institute <strong>of</strong> <strong>Oncology</strong><br />
(ICO Badalona), Hospital Germans Trias i Pujol, Badalona, Spain, 8 Medical<br />
<strong>Oncology</strong>, Institut Català d’Oncologia Hospital Duran i Reynals, Barcelona, Spain,<br />
9 Medical <strong>Oncology</strong>, Hospital Universitario Ramon y Cajal, Madrid, Spain,<br />
10 Department Medical <strong>Oncology</strong>, University Hospital del Mar, Barcelona, Spain,<br />
11 Pathology, Vall d’Hebron University Hospital Institut d’Oncologia, Barcelona,<br />
Spain, 12 Molecular <strong>Oncology</strong> Group, Vall d’Hebron Institute <strong>of</strong> <strong>Oncology</strong>,<br />
Barcelona, Spain, 13 Laboratory Corporation <strong>of</strong> America Holdings, Monogram<br />
Biosciences, San Francisco, CA, USA, 14 Pathology, Centro de Investigación del<br />
Cáncer-IBMCC University <strong>of</strong> Salamanca-CSIC, Salamanca, Spain, 15 Pathology,<br />
Memorial Sloan-Kettering Cancer Center, New York, NY, USA<br />
Background: mGC represents the 3rd leading cause <strong>of</strong> cancer death worldwide.<br />
Chemotherapy is efficient but limited, overall survival (OS) <strong>of</strong> mGC patients (pts)<br />
remains poor. Almost 40% <strong>of</strong> them harbor ERK and PIK3CA-pathway gene<br />
amplifications (amp). HER2+ mGC patients benefit from TTZ, however response is<br />
seen in < 50% and not durable in time. We aim to study potential molecular<br />
determinants <strong>of</strong> TTZ resistance.<br />
Methods: We analyzed baseline biopsies <strong>of</strong> 105 HER2+ mGC pts from 10 Spanish<br />
hospitals. All pts received TTZ. Median follow up was 13 months (m), 22m for alive<br />
pts. We evaluated Cyclin E/D1 and PIK3CA amp (Fluorescence In Situ Hybridation),<br />
expression <strong>of</strong> cyclin E/D1, PTEN, HER3 and p95HER2 (Immunohistochemistry-IHC),<br />
HER2 and p95HER2 quantification (VeraTag® fluorescence assays), and PIK3CA<br />
mutations (mut) (Sanger sequencing).<br />
Results: The median age <strong>of</strong> pts was 65 years (63-67), 75% men. Location <strong>of</strong> primary<br />
tumor was gastric (57%) and gastro-esophageal (43%). The most common histologies<br />
were intestinal (74%) and diffuse (13%). Predominant metastatic locations were liver<br />
(33%), lymph nodes (30%), peritoneum (14%) and lung (10%). Median OS was 12.8m<br />
(10.6-15.4). Median progression-free survival was 7.3m (6.7-7.9). Amp (gene/CEP ≥2)<br />
were found in cyclin E (21%) and cyclin D1 (15%). A positive correlation between<br />
amp/overexpression was detected for cyclin E (p < 0.001), but not for cyclin D1<br />
(p = 0.37). PTEN expression was low (Hscore = 1-49) in 12.4%, and undetectable<br />
(Hscore = 0) in 5.7%. HER3 was overexpressed in 36.7% (IHC 3+ in ≥ 10% <strong>of</strong> cells).<br />
There was a positive correlation between levels <strong>of</strong> p95HER2 and HER2. PI3KCA amp/<br />
mut were found in 4% and 2%, respectively. Survival analyses according to molecular<br />
findings will be presented.<br />
Conclusions: To our knowledge, this is the largest molecular characterization <strong>of</strong><br />
HER2-positive mGC pts. Whereas levels <strong>of</strong> HER2 have been associated with intrinsic<br />
sensitivity to TTZ, cyclin E amp/overexpression has been described as a TTZ resistance<br />
mechanism in breast cancer. Final survival analysis will shed light <strong>of</strong> the real role <strong>of</strong><br />
these molecular alterations in HER2+ mGC.<br />
Legal entity responsible for the study: VHIO Vall d’Hebron University Institute <strong>of</strong><br />
<strong>Oncology</strong><br />
Funding: VHIO Vall d’Hebron University Institute <strong>of</strong> <strong>Oncology</strong><br />
Disclosure: J. Tabernero: Consultant/Advisory role: Amgen, Bayer, Boehringer<br />
Ingelheim, Celgene, Chugai, Lilly, MSD, Merck Serono, Novartis, Roche, San<strong>of</strong>i,<br />
Symphogen, Takeda, Taiho. All other authors have declared no conflicts <strong>of</strong> interest.<br />
vi214 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
630P<br />
Clinical significance <strong>of</strong> serum factors relating to ERBB signal<br />
pathways in a phase II trial <strong>of</strong> S-1 plus cisplatin combined with<br />
trastuzumab for HER2-positive advanced gastric or<br />
esophagogastric junction cancer: WJOG7212G (T-SPACE) TR<br />
study<br />
Y. Sukawa 1 , K. Nosho 2 , Y. Miura 3 , T. Takano 3 , M. Ito 2 , K. Yonesaka 4 , M. Mori 5 ,<br />
S. Tokunaga 6 , J. Kawada 7 , H. Okuda 8 , T. Sakamoto 9 , Y. Hirashima 10 , K. Uchino 11 ,<br />
Y. Miyata 12 , K. Yoshimura 13 , K. Yamazaki 14 , S. Hironaka 15 , N. Boku 16 , I. Hyodo 17 ,<br />
K. Muro 18<br />
1 Division <strong>of</strong> Gastroenterology and Hepatology, Keio University School <strong>of</strong> Medicine,<br />
Tokyo, Japan, 2 Department <strong>of</strong> Gastroenterology, Rheumatology and Clinical<br />
immunology, Sapporo Medical University, Sapporo, Japan, 3 Department <strong>of</strong><br />
Medical <strong>Oncology</strong>, Toranomon Hospital, Tokyo, Japan, 4 Department <strong>of</strong> Medical<br />
<strong>Oncology</strong>, Kindai University, Faculty <strong>of</strong> Medicine, Osaka, Japan, 5 Department <strong>of</strong><br />
Clinical <strong>Oncology</strong>, Jichi Medical University, Tochigi, Japan, 6 Medical <strong>Oncology</strong>,<br />
Osaka City General Hospital, Osaka, Japan, 7 Department <strong>of</strong> Surgery, Osaka<br />
General Medical Center, Osaka, Japan, 8 Department <strong>of</strong> Medical <strong>Oncology</strong>,<br />
Keiyukai Sapporo Hospital, Sapporo, Japan, 9 Department <strong>of</strong> Gastroenterological<br />
<strong>Oncology</strong>, Hyogo Cancer Center, Akashi, Japan, 10 Department <strong>of</strong> Medical<br />
<strong>Oncology</strong> and Hematology, Oita University Faculty <strong>of</strong> Medicine, Oita, Japan,<br />
11 Department <strong>of</strong> Medical <strong>Oncology</strong>, National Hospital Organization Kyusyu<br />
Medical Center, Fukuoka, Japan, 12 Department <strong>of</strong> Medical <strong>Oncology</strong>, Saku<br />
Central Hospital Advanced Care Center, Nagano, Japan, 13 Innovative Clinical<br />
Research Center, Kanazawa University Hospital, Kanazawa, Japan, 14 Division <strong>of</strong><br />
Gastrointestinal <strong>Oncology</strong>, Shizuoka Cancer Center, Shizuoka, Japan, 15 Clinical<br />
Trial Promotion Department, Chiba Cancer Center, Chiba, Japan,<br />
16 Gastrointestinal Medical <strong>Oncology</strong> Division, National Cancer Center Hospital,<br />
Tokyo, Japan, 17 Division <strong>of</strong> Gastroenterology, University <strong>of</strong> Tsukuba, Tsukuba,<br />
Japan, 18 Department <strong>of</strong> Clinical <strong>Oncology</strong>, Aichi Cancer Center Hospital, Nagoya,<br />
Japan<br />
Background: No biomarker other than HER2 expression for anti-HER2 therapy has<br />
been established in gastric cancer. We explored serum ERBB-related biomarkers for<br />
efficacy in a phase II trial (WJOG7212G) <strong>of</strong> triweekly trastuzumab (Tmab) (first dose<br />
8 mg/kg then 6mg/kg) in combination with 5-weekly S-1 (40-60mg, twice daily, for 21<br />
days) plus cisplatin (60mg/m 2 , on day 8) for HER2-positive (IHC3 + , or IHC2+ and<br />
FISH+) advanced gastric or esophagogastric junction cancer.<br />
Methods: Serum samples were collected in 31 <strong>of</strong> 44 patients enrolled in the phase II<br />
study. Serum HER2, EGF, TGF-alpha, neuregulin 1 (NRG1), HGF, IGF1 and TIMP1<br />
were measured by ELISA at following 4 points; pre-treatment, immediately before 2nd<br />
and 4th Tmab administration, and after PD. Pre-treatment serum levels were<br />
compared between responders (CR + PR) and non-responders (SD + PD). Progression<br />
free survival (PFS) and overall survival (OS) were compared between the high and low<br />
groups divided at median <strong>of</strong> pre-treatment value <strong>of</strong> each serum marker.<br />
Results: Patient characteristics were: median age 65.0 years, males 23 (74%), PS 0-1 29<br />
(93%), primary site <strong>of</strong> stomach 27 (87%), histology <strong>of</strong> diffuse type 14 (45%), IHC 3+ 22<br />
(71%) patients. The response rate was 68% (95% CI 50 - 81). The median PFS was 183<br />
days (95% CI 133 - 420). The median OS was 515 days (95% CI 373 - not reached).<br />
Pre-treatment HER2 and NRG1 levels were higher in responders than in<br />
non-responders (Mean; HER2 96 ± 68 ng/ml vs. 12 ± 2 ng/ml, p = 0.026, NRG1<br />
2467 ± 886 pg/ml vs. 186 ± 186 pg/ml, p = 0.012). HER2, NRG1 and EGF levels<br />
decreased after treatment (p < 0.05). Patients with high pre-treatment NRG1 levels<br />
showed significantly longer PFS (median; 322 vs. 160 days, p = 0.022) and marginally<br />
longer OS (median; not reached vs. 373 days, p = 0.09) than those with the low levels.<br />
Pre-treatment HER2 level was not associated with either PFS (median; 247 vs. 177<br />
days, p = 0.50) or OS (median; 544 vs. 503 days, p = 0.53).<br />
Conclusions: Serum NRG1 may be a candidate <strong>of</strong> a predictive marker for the efficacy<br />
<strong>of</strong> Tmab in combination with S-1 plus cisplatin in patients with HER2 positive gastric<br />
or esophagogastric junction cancer.<br />
Clinical trial identification: Protocol number: UMIN000008389; Release date: 9, July,<br />
2012<br />
Legal entity responsible for the study: West Japan <strong>Oncology</strong> Group<br />
Funding: Taiho Pharmaceutical Co.,Ltd.<br />
Disclosure: Y. Miura: Honoraria: Kyowa Hakko Kirin, Novartis. T. Takano: Honoraria:<br />
Chugai, Taiho. K. Yamazaki: Honoraria: Chugai, Taiho. S. Hironaka: Honoraria:<br />
Taiho. N. Boku: Honoraria: Taiho, Chugai, Bristol-Myers. I. Hyodo: Honoraria:<br />
Daiichi-Sankyo, Chugai, Taiho, Yakult Pharmaceutical Companies. All other authors<br />
have declared no conflicts <strong>of</strong> interest.<br />
631P<br />
The role <strong>of</strong> cardiovascular risk factors on postoperative course<br />
after esophageal cancer surgery<br />
D. Collet 1 , C. Gronnier 1 , G. Luc 1 , R. Chevalier 1 , E. Guinard 2 , K. Dantrem 1 ,<br />
B. Meunier 2<br />
1 Department <strong>of</strong> Oeso-Gastric and Endocrine Surgery, Centre Magellan Hôpital<br />
Haut-Lévêque, Bordeaux, France, 2 Department <strong>of</strong> Digestive Surgery, CHU de<br />
Pontchaillou, Rennes, France<br />
Background: After an esophagectomy vascularization <strong>of</strong> the gastric conduit is provided<br />
only by the right gastric artery. It is admitted that the risk <strong>of</strong> anastomotic leakage (AL) is<br />
increased by a low blood supply. Patients with esophageal cancer have frequently an<br />
impaired cardiac function and/or a atherosclerotic vascular disease (AVD). No data has<br />
previously emerged from studies regarding the role <strong>of</strong> cardiovascular risk factors (CRF)<br />
in patients who developed anastomotic leakage (AL) after esophagectomy in curative<br />
intent. The main objective was to determine if CRF can predict AL after Ivor-Lewis<br />
procedure in patients with intrathoracic esophageal cancer (EC).<br />
Methods: We performed a retrospective study including all 352 consecutive patients<br />
operated on for EC in a curative intent between 2004 and 2014 in 2 referral centers.<br />
Patients treated by Ivor-Lewis procedure were analyzed. Nine CRF were identified<br />
according international consensus. Dindo Clavien classification was used to define<br />
postoperative complication. Predictive factors <strong>of</strong> AL were analyzed by multivariable<br />
regression analysis.<br />
Results: Among 292 patients with EC treated with Ivor-Lewis procedure, 271 (92.8%)<br />
patients had one or more CRF. The median age was 64 years [range, 33 – 85], with a<br />
male to female sex ratio <strong>of</strong> 4.4:1. Squamous cell carcinoma (SCC) was present in 141<br />
(73.8%) patients. Among the 111 (38%) patients with postoperative complications, 39<br />
(13.4%) patients developed anastomotic leakage, 15 (5.1%) developed necrosis <strong>of</strong> the<br />
gastric conduit. Others main complications were pneumonia (n = 37 patients, 12.7%),<br />
chylothorax (n = 13 patients, 4.5%) and hemorrhage (n = 7 patients, 2.4%). In<br />
multivariate analysis, transfusion (odd ratio: 3.030, 95% CI [1.545 – 5.952], p = 0.001)<br />
and CRF > 3 (odd ratio: 2.958, 95% CI [1.132 – 7.751], p = 0.027) were predictive<br />
factors <strong>of</strong> AL.<br />
Conclusions: Patients with >3 CRF have a higher risk <strong>of</strong> AL after Ivor-Lewis<br />
procedure. Further studies should focus on how to improve postoperative outcomes in<br />
this population.<br />
Legal entity responsible for the study: CHU Bordeaux<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
632P<br />
abstracts<br />
KRAS mutation and protein levels in gastric cancer patients<br />
and response to MEK inhibitors<br />
J. Wei, Y. Huang, N. Wu, L. Yu, B. Liu<br />
Medical <strong>Oncology</strong>, The Comprehensive Cancer Centre <strong>of</strong> Drum Tower Hospital,<br />
Medical School <strong>of</strong> Nanjing University & Clinical Cancer Institute <strong>of</strong> Nanjing<br />
University, Nanjing, China<br />
Background: Recent studies have suggested that KRAS plays an important role in<br />
gastric cancer. The aim <strong>of</strong> this study was to assess the prognostic effect <strong>of</strong> KRAS<br />
mutation and expression levels in gastric cancer patients and to explore its potential<br />
role in targeted therapy.<br />
Methods: We examined KRAS protein levels in 132 stage I-IV gastric cancer using<br />
immunochemistry. KRAS mutation was detected by next generation exome<br />
sequencing. KRAS mutation was examined in five human gastric cell lines (AGS,<br />
SNU601, SNU668, KATO-III and NUGC-4) by Sanger sequencing. Cytosensitivity <strong>of</strong><br />
MEK inhibitors (AZD6244) in the five cell lines was examined by MTT.<br />
Results: The median age <strong>of</strong> the total number <strong>of</strong> 132 gastric cancer patients was 58 years<br />
(range: 30-82). There were 75 gastric cancer samples with the pathology <strong>of</strong> signet-ring<br />
cell carcinoma (SRCC), while another 57 samples with adenocarcinoma. 80% <strong>of</strong> gastric<br />
SRCC samples have high expression <strong>of</strong> KRAS protein compared with 34.69% <strong>of</strong> gastric<br />
adenocarcinomas (P < 0.001). Among 75 gastric SRCC cancer patients, KRAS<br />
mutations in codon 12 and 151 were detected in 8 (10.67%) patients, including 7<br />
mutations <strong>of</strong> G12V and one mutation <strong>of</strong> G151A. Kato-III and NUGC-4 cell expressed<br />
higher KRAS levels compared to the other three, while KRAS mutation was detected in<br />
AGS, SNU601 and SNU668. Two GC cell lines with KRAS mutation were<br />
hypersensitive to the MEK inhibitor compared with KRAS wild type cell lines. The<br />
median overall survival (OS) was 12.5 months (95% CI = 9.57 to 15.43 months) for<br />
patients with KRAS mutation, and 15.8 months (95% CI = 11.76 to 19.84 months) for<br />
patients without KRAS mutation (P = .031). However, no difference in OS was<br />
observed between low and high KRAS protein levels.<br />
Conclusions: KRAS is highly expressed in SRCC. Patients with KRAS mutations have<br />
shorter OS. Gastric SRCC cell lines with KRAS mutation are sensitive to MEK<br />
inhibitor (AZD6244). The results provide insights into the important role <strong>of</strong> mutant<br />
KRAS in the prognosis and response to MEK inhibitor <strong>of</strong> gastric SRCC patients.<br />
Legal entity responsible for the study: Jia Wei<br />
Funding: Nation Science Foundation<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw371 | vi215
abstracts<br />
633P<br />
Efficacy and safety <strong>of</strong> dose-dense taxotere cisplatin<br />
fluorouracil regimen (mTCF-dd) in a large cohort <strong>of</strong> patients<br />
(pts) with metastatic or locally advanced non-squamous<br />
gastroesophageal cancer (GEC)<br />
L. Toppo 1 , G. Tomasello 1 , M. Ghidini 1 , C. Caminiti 2 , G. Maglietta 2 , S. Lazzarelli 1 ,<br />
W. Liguigli 1 , M. Rovatti 3 , V. Ranieri 3 , G. Tanzi 4 , F. Buffoli 5 , M. Martinotti 3 ,<br />
R. Passalacqua 1<br />
1 Division <strong>of</strong> <strong>Oncology</strong>, ASST CREMONA, Cremona, Italy, 2 Unità Ricerca ed<br />
Innovazione, Azienda Ospedaliera di Parma, Parma, Italy, 3 Surgery Unit, ASST<br />
CREMONA, Cremona, Italy, 4 <strong>Oncology</strong>, ASST CREMONA, Cremona, Italy,<br />
5 Endoscopic Unit, ASST CREMONA, Cremona, Italy<br />
Background: TCF is one <strong>of</strong> the most effective first-line options in metastatic GEC. We<br />
previously reported the significant activity <strong>of</strong> mTCF-dd (Tomasello G et al: Gastric<br />
Cancer 2014 Oct;17(4):711-7). Aim <strong>of</strong> this study is to describe clinical outcomes, safety<br />
and studying potential clinical prognostic factors <strong>of</strong> this intensified regimen in a very<br />
large consecutive cohort <strong>of</strong> pts coming from a single center<br />
Methods: 201 consecutive pts with measurable or evaluable GEC treated in the<br />
sameinstitution were longitudinally followed. 136 were enrolled in 3 different Clinical<br />
Trials and 65 treated according to clinical practice. We considered pts with PS ECOG<br />
0-2 and adequate organ function who received from 2004 to 2015 mTCF-dd: Docetaxel<br />
(50-85 mg/m2 d 1), Cisplatin (50-75 mg/m2 d 1),l-Folinic Acid (100 mg/m2 d 1-2),<br />
5-FU (400 mg/m2 bolus d 1-2, and 600 mg/m2 as a 44 h c.i. d 1), plus Pegfilgrastim 6<br />
mg d 3, q2w. Analysis was done according to ITT principle.<br />
Results: Median age was 63 (range 25-81), M:F 140:51. Metastatic sites were: liver 38%,<br />
peritoneum 33.5%, bone 14%, lung 12%. A median <strong>of</strong> 4 cycles (range 1-8) per patient<br />
were administered: 15% required a dose reduction, 48% were treated without any delay.<br />
At a median follow up <strong>of</strong> 60 months, 192 pts were evaluable. We observed 6% CR, 52%<br />
PR, 14% SD, 13% PD and 13% NE, for an ORR <strong>of</strong> 59% (95% CI 52-66); DCR was 76%.<br />
Median OS was 11.1 months (95% CI 9.5-13.5). Most frequent grade 3/4 toxicities:<br />
neutropenia (26%), asthenia (31%), thrombocytopenia (17%), hypokalemia (16%),<br />
diarrhea (13%), febrile neutropenia (11%). 18 pts (9%) became resectable after<br />
mTCF-dd and underwent surgery. Finally, we identified 18 pts (9%) [12 metastatic, 6<br />
locally advanced] with OS > 3 years and 7 (4%) still maintaining a response at the time<br />
<strong>of</strong> the current analysis.Moreover, we identifued a specific cohort <strong>of</strong> 21 pts with bone<br />
metastases at diagnosis bearing a very poor prognosis (OS: 7.8 m 95% CI 3.8-10 ). A<br />
multivariate Cox model will be presented at the meeting.<br />
Conclusions: mTCF-dd in GEC is an effective and feasible option. A careful<br />
monitoring <strong>of</strong> adverse events is recommended. A biomolecular analysis <strong>of</strong> long-term<br />
survivors is underway.<br />
Legal entity responsible for the study: Azienda Socio Sanitaria di Cremona<br />
Funding: MEDEA ONLUS<br />
Disclosure: R. Passalacqua: Member <strong>of</strong> Scientific Boards: Amgen, Lilly, Pfizer,<br />
Novartis. All other authors have declared no conflicts <strong>of</strong> interest.<br />
634P<br />
Association <strong>of</strong> disease measurability, quality <strong>of</strong> life (QoL) and<br />
tumor status in patients (pts) with previously treated<br />
advanced gastric or gastroesophageal junction (GEJ) cancer<br />
I. Chau 1 , S-E. Al-Batran 2 , A. Barzi 3 , A.M. Liepa 4 , Z. Cui 4 , Y. Hsu 5 , S. Chin 4<br />
1 Department <strong>of</strong> Medicine, Royal Marsden Hospital, London & Surrey, UK,<br />
2 Department <strong>of</strong> Medicine, Institute <strong>of</strong> Clinical Cancer Research (IKF),<br />
UCT-University Cancer Center, Frankfurt, Germany, 3 Department Clinical<br />
Medicine, University <strong>of</strong> Southern California Norris Comprehensive Cancer Center,<br />
Los Angeles, CA, USA, 4 Medical <strong>Oncology</strong>, Eli Lilly and Company, Indianapolis, IN,<br />
USA, 5 Medical <strong>Oncology</strong>, Eli Lilly and Company, Bridgewater, NJ, USA<br />
Background: Association <strong>of</strong> radiological tumor status (TS; progressed vs<br />
non-progressed) and QoL has not been systematically explored in randomized clinical<br />
trials (RCTs) <strong>of</strong> gastroesophageal cancers. Furthermore, TS is affected by disease<br />
measurability (DM) as defined by RECIST. We explored these factors using data from<br />
two phase 3 RCTs <strong>of</strong> previously treated gastric or GEJ cancer: RAINBOW<br />
(ramucirumab + paclitaxel vs placebo + paclitaxel) and REGARD (ramucirumab vs<br />
placebo).<br />
Methods: Pts completed the EORTC QLQ-C30 at baseline and every 6 weeks (wks)<br />
while on therapy. DM was assessed at baseline. Multivariate logistic regression<br />
evaluated associations among DM, TS and QoL with covariates <strong>of</strong> gender, age,<br />
ethnicity, geographical regions and performance status (PS). Models explored QoL and<br />
TS as dependent variables and were varied by using data from specific timepoints or<br />
maximum change.<br />
Results: Of 1020 randomized pts, 97% provided baseline QoL, 53% at Wk 6, and 46%<br />
at Wk 12. DM was reported for 1019 (measurable 83%, non-measurable [NMD] 17%).<br />
More pts with measurable disease vs NMD were male (73% vs 57%), white (69% vs<br />
55%) and from Europe, North America and Australia (66% vs 49%); no differences<br />
were seen for age, PS or ethnicity. Baseline QoL scores were not statistically different<br />
between pts with measurable versus NMD even when adjusted by covariates. At Wk 6,<br />
NMD predicted worsening in diarrhea (p = .02) and non-progression predicted better<br />
role functioning (fxn) (p = .01) and pain (p = .02) especially in NMD pts. At Wk 12,<br />
NMD predicted worsening in emotional fxn (p = .03) and dyspnea (p = .01). DM<br />
interacted with both emotional and role fxn to predict non-progression (all p < .05).<br />
Best change in pain and in appetite loss was predicted by non-progression with<br />
significant interactions (all p < .05); predictive values were demonstrated only in NMD<br />
pts. Improved role fxn predicted non-progression at Wk 6 (p = .03) especially in NMD<br />
pts.<br />
Conclusions: This is the largest RCT dataset exploring DM, TS and QoL in pts with<br />
previously treated gastric or GEJ cancer. Although baseline QoL did not differ based on<br />
DM, changes in QoL were associated with disease (non-) progression and these<br />
changes differed by DM.<br />
Clinical trial identification: NCT01170663<br />
Legal entity responsible for the study: Eli Lilly and Company<br />
Funding: Eli Lilly and Company<br />
Disclosure: I. Chau: Advisory Board: San<strong>of</strong>i <strong>Oncology</strong>, Eli-Lilly, Bristol Meyers Squibb,<br />
MSD, Merck Serono, Gilead Science. Research funding: Janssen-Cilag, San<strong>of</strong>i<br />
<strong>Oncology</strong>, Roche, Merck-Serono, Novartis. Honoraria: Taiho, Pfizer, Amgen, Eli Lilly,<br />
Bayer. S-E. Al-Batran: Advisory role: Merck, Roche, Celgene, Lilly, Nordic Pharma.<br />
Speaker: Roche, Celgene, Lilly, Nordic Pharma. Research grants: Merck, Roche,<br />
Celgene, Vifor, Medac, Hospira, Lilly. A.M. Liepa, Z. Cui, Y. Hsu, S. Chin: Employee<br />
and stock owner. All other authors have declared no conflicts <strong>of</strong> interest.<br />
635P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Genetic analysis <strong>of</strong> gastric cancer with distinctive family<br />
history<br />
M. Terashima 1 , K. Hatakeyama 2 , M. Kusuhara 3 , R. Makuuchi 1 , M. Tokunaga 1 ,<br />
Y. Tanizawa 1 , E. Bando 1 , T. Kawamura 1 , M. Hikage 1 , S. Kaji 1 , K. Ohshima 2 ,<br />
S. Ohnami 4 , K. Urakami 4 , K. Yamaguchi 5<br />
1 Division <strong>of</strong> Gastric Surgery, Shizuoka Cancer Center, Shizuoka, Japan, 2 Medical<br />
Genetics, Shizuoka Cancer Center, Shizuoka, Japan, 3 Region Resources,<br />
Shizuoka Cancer Center, Shizuoka, Japan, 4 Cancer Diagnostic Research,<br />
Shizuoka Cancer Center, Shizuoka, Japan, 5 Research Institution, Shizuoka Cancer<br />
Center, Shizuoka, Japan<br />
Background: Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant<br />
susceptibility for diffuse gastric cancer. Germ line mutation <strong>of</strong> CDH1 is observed in<br />
30-50% <strong>of</strong> the HDGC, however, disease susceptibility genes have not yet identified in<br />
remaining 50-70%. Project HOPE is a comprehensive genetic analysis project including<br />
whole exome sequencing and gene expression analysis using fresh frozen samples<br />
obtained from various patients undergoing surgery in Shizuoka Cancer center. In order<br />
to evaluate the genetic alterations in diffuse gastric cancer with family history, genetic<br />
analysis results were compared between patients with and without family history.<br />
Methods: Out <strong>of</strong> 188 patients registered in HOPE project, 51 patients with diffuse<br />
gastric cancer were included. In these patients, results from exome sequencing and<br />
gene expression analysis were compared between patients with family history (FDGC)<br />
and those without family history (NFDGC). Family history was defined as the presence<br />
<strong>of</strong> two or more documented cases <strong>of</strong> diffuse gastric cancer in first- or second-degree<br />
relatives OR solitary diffuse gastric cancer diagnosed prior to age 40years. Whole<br />
exome sequencing was performed using Ion Proton to identify tumor specific gene<br />
mutations and to estimate the copy number with lymphocytes as normal control. Gene<br />
expression analysis was performed using DNA Microarray with adjacent normal tissue<br />
as a control.<br />
Results: Three patients were classified to FDGC and 48 were to NFDGC. FDGC were<br />
tended to be younger, predominantly female and more advanced stage than NFDGC.<br />
Germline mutation <strong>of</strong> CDH1 was not observed. Diffuse gastric cancer were separated<br />
into two groups, 27 patients with FDGC and 24 patients without FDGC, by gene<br />
expression pr<strong>of</strong>iling. In patients including FDGC, gene expression <strong>of</strong> PPP1R14C,<br />
ABCG5, NR1I2, APOC2, MLK7-AS1 and PRB2 were observed. In somatic mutation<br />
analyses, the incidence <strong>of</strong> RHOA and CDH1 mutations was higher in patients with<br />
FDGC (19% vs 4%, 22% vs 13%). CDH1 mutation was observed in 2 <strong>of</strong> 3 FDGC.<br />
Conclusions: Gene cluster that was highly expressed in FDGC was identified. Diffuse<br />
gastric cancer was classified into two groups by cluster analysis with these genes.<br />
Somatic mutation <strong>of</strong> CDH1 was frequently observed in patients group with FDGC.<br />
Legal entity responsible for the study: Shizuoka Cancer Center<br />
Funding: Shizuoka Cancer Center<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
vi216 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
636P<br />
Safety and efficacy pr<strong>of</strong>ile <strong>of</strong> ramucirumab alone or combined<br />
with paclitaxel in metastatic gastric cancer (MGC): A real-life<br />
overview <strong>of</strong> compassionate-use named patients (pts) (RAMoss<br />
study)<br />
M. Di Bartolomeo 1 , M. Niger 1 , M.M. Laterza 2 , C. Vivaldi 3 , E. Giommoni 4 ,<br />
A. Zaniboni 5 , S. Bozzarelli 6 , G. Tomasello 7 ,T.Sava 8 , M. Spada 9 , A. Bittoni 10 ,<br />
S. Galdy 11 , A. Spallanzani 12 , F. Bassan 13 , S. Scagnoli 14 , F. Morano 1 , R. Berenato 1 ,<br />
M. Caporale 1 , P. Filippo 1 ,F.DeVita 2<br />
1 Medical <strong>Oncology</strong> Department, Fondazione IRCCS - Istituto Nazionale dei<br />
Tumori, Milan, Italy, 2 Medical <strong>Oncology</strong>, AOU Seconda Università degli Studi di<br />
Napoli (AOU-SUN), Naples, Italy, 3 Oncologia Medica Universitaria, Azienda<br />
Ospedaliera Universitaria S.Chiara, Pisa, Italy, 4 <strong>Oncology</strong>, Azienda Ospedaliera<br />
Careggi U.O. Medical <strong>Oncology</strong>, Florence, Italy, 5 <strong>Oncology</strong>, Fondazione<br />
Poliambulanza, Brescia, Italy, 6 Humanitas Cancer Center, Humanitas Clinical and<br />
Research Center, Istituto Clinico Humanitas, Rozzano, Italy, 7 Division <strong>of</strong> <strong>Oncology</strong>,<br />
Istituti Ospitalieri di Cremona, Cremona, Italy, 8 Medical <strong>Oncology</strong>, U.L.S.S.15 Alta<br />
Padovana, Camposampiero, Italy, 9 Medical <strong>Oncology</strong>, Fondazione Istituto San<br />
Raffaele - G. Giglio di Cefalù, Cefalù, Italy, 10 Medical <strong>Oncology</strong>, AOU Ospedali<br />
Riuniti Ancona Università Politecnica delle Marche, Ancona, Italy, 11 Gastrointestinal<br />
and NET Unit, Istituto Europeo di Oncologia, Milan, Italy, 12 Medical <strong>Oncology</strong>,<br />
Azienda Ospedaliero - Universitaria Policlinico di Modena, Modena, Italy, 13 Medical<br />
<strong>Oncology</strong>, Ospedale Alto Vicentino, Santorso, Italy, 14 Medicina Sperimentale,<br />
Policlinico Umberto I, Rome, Italy<br />
Background: Ramucirumab, an anti-VEGFR2 monoclonal antibody, improved the<br />
outcome <strong>of</strong> MGC pts both as a single agent and in combination with paclitaxel,<br />
achieving recent approval in second-line therapy. However, few ”real life” data are<br />
available. The objective <strong>of</strong> the RAMoss study is to evaluate the safety and efficacy <strong>of</strong><br />
ramucirumab in the Italian compassionate-use program, prior to marketing<br />
authorization.<br />
Methods: The primary endpoint was safety and secondary were overall response rate<br />
(ORR), progression free-survival (PFS) and overall survival (OS). Pts received<br />
ramucirumab 8 mg/kg/iv every 2 weeks or in combination with paclitaxel 80 mg/m2/iv<br />
on days 1, 8, and 15 <strong>of</strong> a 28-days cycle until progression, death or unacceptable toxicity.<br />
Complete blood test were performed before each drug administration and disease was<br />
assessed every 2 cycles.<br />
Results: 109 pts were enrolled with the following characteristics: median age: 61 yrs;<br />
gastric site: 69,7%, cardias: 23,8%, distal oesophagus: 6,4%; PS ECOG: 0(56,8%) 1<br />
(34,8%) ≥2(8.2%); monotherapy : 12,9%, combination therapy: 87,1%; peritoneal<br />
metastasis: 41,2%. Median treatment duration was 3 mos(1-12 mos). The most<br />
frequent grade ≥ 3 AEs were: neutropenia (5.5%), asthenia (2.7%), hypertension<br />
(1.8%). Febrile neutropenia occurred in 0.9% <strong>of</strong> the pts. No bleeding <strong>of</strong> grade ≥ 2was<br />
reported. There were no treatment-related deaths. ORR was 17,4%, 7.1%<br />
(monotherapy) and 18,9% (combination), respectively. Stable disease was observed in<br />
30.2%; disease control rate (DCR) was 47,6%. With a median follow-up <strong>of</strong> 8.0 mos<br />
(95% CI: 6.5-9.5), median PFS was 3.0 mos (95% CI: 2.32-3.67), median OS was 7.0<br />
mos (95% CI: 5.76-8.23). On a multivariate analysis, age 61 (HR 3.18, 95% CI:<br />
1.8-5.6, p= 0.0001) and PS ECOG
abstracts<br />
639P<br />
The final results <strong>of</strong> a multicenter phase II study <strong>of</strong> TAS-102<br />
monotherapy in patients with pre-treated advanced gastric<br />
cancer (EPOC1201)<br />
H. Bando 1 ,T.Doi 1 ,K.Muro 2 , H. Yasui 3 , T. Nishina 4 , K. Yamaguchi 5 , S. Takahashi 6 ,<br />
H. Hasegawa 7 ,S.Nomura 7 ,H.Kuno 8 , K. Shitara 1 ,A.Sato 7 , A. Ohtsu 1<br />
1 Department <strong>of</strong> Gastroenterology and Gastrointestinal <strong>Oncology</strong>, National Cancer<br />
Center Hospital East, Kashiwa, Japan, 2 Department <strong>of</strong> Clinical <strong>Oncology</strong>, Aichi<br />
Cancer Center Hospital, Nagoya, Japan, 3 Division <strong>of</strong> Gastrointestinal <strong>Oncology</strong>,<br />
Shizuoka Cancer Center, Shizuoka, Japan, 4 Department <strong>of</strong> Gastrointestinal<br />
Medical <strong>Oncology</strong>, Shikoku Cancer Center, Matsuyama, Japan, 5 Department <strong>of</strong><br />
Gastroenterological Chemotherapy, Cancer Institute Hospital <strong>of</strong> JFCR, Tokyo,<br />
Japan, 6 Department <strong>of</strong> Medical <strong>Oncology</strong>, Cancer Institute Hospital <strong>of</strong> JFCR,<br />
Tokyo, Japan, 7 Office <strong>of</strong> Clinical Research Support, National Cancer Center<br />
Hospital East, Kashiwa, Japan, 8 Department <strong>of</strong> Diagnostic Radiology, National<br />
Cancer Center Hospital East, Kashiwa, Japan<br />
Background: American phase I studies have reported that the recommended dose <strong>of</strong><br />
TAS-102 (trifluridine/tipiracil) was 25 mg/m 2 b.i.d., although this schedule did not provide<br />
clinically relevant improvements in a phase II study <strong>of</strong> advanced gastric cancer (AGC).<br />
However, a pivotal phase III study revealed that TAS-102 at 35 mg/m 2 b.i.d. provided a<br />
clinically relevant improvement in overall survival among patients with metastatic<br />
colorectal cancer. Thus, we re-evaluated the efficacy, safety, and pharmacokinetic (PK)<br />
parameters <strong>of</strong> TAS-102 at 35 mg/m 2 b.i.d. in patients with AGC. In an expanded cohort,<br />
we also evaluated the safety and PK parameters <strong>of</strong> a 40 mg/m 2 b.i.d. schedule.<br />
Methods: All patients had undergone one or two previous chemotherapy regimens that<br />
contained fluoropyrimidine, platinum agents, and taxanes or irinotecan. In this study,<br />
we assessed the investigator-determined and the independent central review’s disease<br />
control rate (DCR), response rate, progression-free survival (PFS), overall survival<br />
(OS), safety pr<strong>of</strong>iles, and PK pr<strong>of</strong>iles.<br />
Results: Twenty-nine patients were assessable after completing the 35 mg/m 2 b.i.d.<br />
schedule. The investigator-determined DCR was 65.5% (95% confidence interval [CI],<br />
45.7–82.1%) and the independent central review’s DCR was 51.9% (n = 27, 95% CI,<br />
31.9–71.3%). The median PFS and OS were 2.9 months (95% CI, 1.1–5.3 months) and<br />
8.7 months (95% CI, 5.7–14.9 months), respectively. The grade 3/4 adverse events<br />
included neutropenia (69.0%), leukopenia (41.4%), anemia (20.7%), and anorexia<br />
(10.3%). No AGC-specific toxicities were detected. In the expanded cohort, the<br />
averages <strong>of</strong> PK parameters dose-dependently increased for 6 patients treated with the<br />
40 mg/m 2 b.i.d. dosage. Although slightly higher grade 3–4 neutropenia (83.3%) and<br />
leukopenia (66.7%) were observed, the investigator-determined DCR was 50.0% (SD: 3;<br />
PD: 3) and no partial response cases were observed.<br />
Conclusions: The 35 mg/m 2 b.i.d. dose <strong>of</strong> TAS-102 provided positive efficacy and an<br />
acceptable toxicity pr<strong>of</strong>ile in patients with AGC. A randomized, double-blind,<br />
placebo-controlled, phase III study is ongoing to validate these findings.<br />
Clinical trial identification: UMIN000007421<br />
Legal entity responsible for the study: Exploratory <strong>Oncology</strong> Research & Clinical<br />
Trial Center, National Cancer Center<br />
Funding: The Renovation Project <strong>of</strong> Early and Exploratory Clinical Trial Center,<br />
National Cancer Center Research and Development Fund (24-A-1)<br />
Disclosure: K. Muro, T. Nishina, A. Ohtsu: Honoraria: Taiho Pharmaceutical<br />
Company. S. Takahashi: Research funding: Taiho Pharmaceutical<br />
Company. S. Nomura: Japan Breast Cancer Research Group (JBCRG). Grants: Japan<br />
Agency for Medical Research and Development (AMED). A. Sato:<br />
Corporate-sponsored Research: Taiho, Boehringer-Ingelheim, Novartis, Bayer. All<br />
other authors have declared no conflicts <strong>of</strong> interest.<br />
640P<br />
Early results <strong>of</strong> a randomized two-by-two factorial phase II<br />
trial comparing neoadjuvant chemotherapy with 2 and 4<br />
courses <strong>of</strong> cisplatin/S-1 (CS) and docetaxel/cisplatin/S-1<br />
(DCS) as neoadjuvant chemotherapy for locally advanced<br />
gastric cancer<br />
K. Nishikawa 1 , T. Yoshikawa 2 , K. Fujitani 3 , K. Tanabe 4 , S. Ito 5 , T. Matsui 6 , A. Miki 7 ,<br />
H. Nemoto 8 , K. Sakamaki 9 , H. Cho 2 , T. Fukunaga 10 , Y. Kimura 11 , N. Hirabayashi 12<br />
1 Department <strong>of</strong> Surgery, National Hospital Organization Osaka National Hospital,<br />
Osaka, Japan, 2 Department <strong>of</strong> Gastrointestinal Surgery, Kanagawa Cancer<br />
Center, Yokohama, Japan, 3 Department <strong>of</strong> Surgery, Osaka General Medical<br />
Center, Osaka, Japan, 4 Department <strong>of</strong> Gastroenterological and Transplant<br />
Surgery, Hiroshima University, Hiroshima, Japan, 5 Department <strong>of</strong> Gastrointestinal<br />
Surgery, Aichi Cancer Center Hospital, Nagoya, Japan, 6 Department <strong>of</strong> Surgery,<br />
Aichi Cancer Center - Aichi Hospital, Okazaki, Japan, 7 Department <strong>of</strong> Surgery,<br />
Kobe City Medical Center General Hospital, Kobe, Japan, 8 Department <strong>of</strong><br />
Surgery, Showa University Fujigaoka Hospital, Yokohama, Japan, 9 Department <strong>of</strong><br />
Biostatistics and Epidemiology, Yokohama City University Medical Center,<br />
Yokohama, Japan, 10 Department <strong>of</strong> Surgery, St. Marianna University School <strong>of</strong><br />
Medicine, Kawasaki, Japan, 11 Department <strong>of</strong> Surgery, Sakai City Medical Center,<br />
Sakai, Japan, 12 Department <strong>of</strong> Surgery, Hiroshima City Asa Hospital, Hiroshima,<br />
Japan<br />
Background: Neoadjuvant chemotherapy is promising to improve the survival <strong>of</strong><br />
resectable gastric cancer. Cisplatin/S-1 (CS) and docetaxel/cisplatin/S-1 (DCS) are both<br />
active for metastatic gastric cancer.<br />
Methods: Patients with M0 and either T4 or T3 in case <strong>of</strong> junctional cancer or<br />
schirrhous type received 2 or 4 courses <strong>of</strong> cisplatin (60 mg/m2 at day 8) / S-1 (80 mg/<br />
m2 for 21 days with 1 week rest) or docetaxel (40 mg/m2 at day 1) / cisplatin (60 mg/<br />
m2 at day 1) / S-1 (80 mg/m2 for 14 days with 2 weeks rest) as neoadjuvant<br />
chemotherapy. Then, patients underwent D2 gastrectomy and adjuvant S-1<br />
chemotherapy for 1 year. The primary endpoint was 3-year overall survival. The<br />
planned sample size was 120 to achieve 10% improvement <strong>of</strong> 3-year OS by four courses<br />
or by CS with >85% probability <strong>of</strong> the correct selection.<br />
Results: Between Oct 2011 and Sep 2014, 132 patients were assigned to CS (n = 66; 33<br />
in 2-courses and 33 in 4-courses) and DCS (n = 66; 33 in 2-courses and 33 in<br />
4-courses). Major grade 3/4 hematological toxicities (CS/DCS) were leukocytopenia<br />
(14.1%/26.2%), neutropenia (29.7%/47.7%), anemia (14.1%/12.3%), and platelet<br />
decreased (3.1%/1.5%). Febrile neutropenia was observed in 6.3% <strong>of</strong> CS and 4.6% <strong>of</strong><br />
DCS. Major non-hematological toxicities (CS/DCS) were appetite loss (64.1%/76.9%),<br />
fatigue (42.2%/47.7%), nausea (31.3%/49.2%), diarrhea (28.1%/40.0%), mucositis<br />
(14.1%/32.3%), and vomiting (12.5%/18.5%). Pathological response, defined by<br />
disappearance more than one third <strong>of</strong> the primary tumor, was 42.4% in CS and 51.5%<br />
in DCS, while that was 50.0% in 2-courses and 43.9% in 4-courses. Pathological<br />
complete response was 10.6% in CS and 6.1% in DCS, while that was 9.1% in 2-courses<br />
and 7.6% in 4-courses. R0 resection rate was 72.7% in CS and 81.8% in DCS, while that<br />
was 80.3% in 2-courses and 74.2% in 4-courses. No treatment related death was<br />
observed.<br />
Conclusions: 2- and 4-courses <strong>of</strong> CS and DCS had acceptable toxicities and led high<br />
pathological response as neoadjuvant chemotherapy for gastric cancer. Primary<br />
endpoint will be opened in 2018.<br />
Clinical trial identification: UMIN000006378<br />
Legal entity responsible for the study: N/A<br />
Funding: non-pr<strong>of</strong>it organization KSATTS<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
641P<br />
FcγR IIA and IIIA polymorphisms predict clinical outcome <strong>of</strong><br />
trastuzumab treated metastatic gastric cancer<br />
R. Xu, D. Wang<br />
Department <strong>of</strong> Medical <strong>Oncology</strong>, Cancer Centre Sun Yat-Sen University,<br />
Guangzhou, China<br />
Background: Trastuzumab has substantial anti-tumor activity in metastatic gastric<br />
cancer, and one mechanism is antibody-dependent cell-mediated cytotoxicity<br />
(ADCC), which has been reported to be influenced by FcγR II A and III A<br />
polymorphisms. This retrospective study is the first to assess their impact on<br />
trastuzumab efficacy in patients with metastatic gastric cancer.<br />
Methods: We retrospectively included 42 Her-2 positive patients receiving fluorouracil<br />
and platinum based chemotherapy and trastuzumab, and 68 Her-2 negative patients<br />
receiving fluorouracil and platinum based chemotherapy only as first line treatment.<br />
FcγR II A and III A polymorphisms were assessed and their associations with efficacy<br />
in both settings were analyzed.<br />
Results: In patients treated with trastuzumab, FcγR II A H/H genotype was associated<br />
with significantly superior progression-free survival (PFS) (hazard ratio (HR) and 95%<br />
confidence interval (CI): 0.36 (0.16-0.82), adjusted HR and 95% CI: 0.18 (0.07-0.48),<br />
P = 0.001). Combining FcγR II A and III A polymorphisms, FcγR II A H/H or FcγRIII<br />
AV/V genotype was associated with significantly improved disease control rate (DCR)<br />
(P = 0.04) and PFS (HR and 95% CI: 0.29 (0.13-0.67), adjusted HR and 95% CI: 0.17<br />
(0.07-0.45), P < 0.001). As expected, no association <strong>of</strong> FcγR II A and III A<br />
polymorphisms with efficacy was identified in patients receiving chemotherapy only.<br />
Conclusions: FcγR II A and III A polymorphisms might predict DCR and PFS in<br />
metastatic gastric cancer receiving trastuzumab treatment.<br />
Legal entity responsible for the study: Accept<br />
Funding: Major Special Project from Guangzhou Health and Medical Collaborative<br />
Innovation (No. 201508020247).<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
642P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Plasma mRNA as liquid biopsy in individualized chemotherapy<br />
<strong>of</strong> gastric cancer<br />
J. Shen, J. Wei, X. Qian, B. Liu<br />
Medical <strong>Oncology</strong>, The Comprehensive Cancer Centre <strong>of</strong> Drum Tower Hospital,<br />
Medical School <strong>of</strong> Nanjing University & Clinical Cancer Institute <strong>of</strong> Nanjing<br />
University, Nanjing, China<br />
Background: Biomarker from blood could be a useful and non-invasive tool to provide<br />
real-time information in the procedure <strong>of</strong> treatment.<br />
Methods: To further understand the role <strong>of</strong> plasma mRNA in chemo-efficiency<br />
prediction, several mRNA levels were assessed in plasma and paired FFPE tumor<br />
tissues, and were correlated with chemosensitivity.<br />
Results: In the 133 patients with locally advanced gastric cancer (Stage III), significant<br />
correlations were observed between plasma and tumor mRNA levels <strong>of</strong> BRCA1<br />
(rho = 0.532, P < 0.001), ERCC1(rho = 0.570, P < 0.001), TS(rho = 0.506, P = 0.002),<br />
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<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Topo1 (rho = 0.310, P = 0.031), and APTX (rho = 0.561, P < 0.001). Correlations were<br />
also observed between the mRNA expression <strong>of</strong> plasma/tumor BRCA1 levels and<br />
docetaxel sensitivity (P < 0.001), plasma/tumor TS and pemetrexed sensitivity<br />
(P < 0.001), plasma/tumor BRCA1 and platinum sensitivity (plasma, P = 0.016; tumor,<br />
P < 0.001), and plasma/tumor Topo1 and irinotecan sensitivity (plasma, P = 0.015;<br />
tumor, P = 0.011). Among another 64 patients with advanced cancer (Stage IV), 55<br />
patients were in the test group receiving chemotherapy according to plasma gene<br />
detection, and 9 patients were in the control. The median overall survival <strong>of</strong> test group<br />
was 15.5 months (95% CI = 10.1 to 20.9 months), the progress free survival was 9.1<br />
months (95% CI = 8.0 to 10.2 months), which were significant longer than the control<br />
(P = 0.047 for OS, P = 0.038 for PFS). The risk <strong>of</strong> mortality was higher in the control<br />
than patients treated according to the plasma gene detection (HR in the control = 2.34,<br />
95% CI = 0.93 to 5.88, P = 0.071).<br />
Conclusions: Plasma mRNA expression levels mirror those in the tumor and can be<br />
used as promising predictive biomarkers to predict chemo-efficiency.<br />
Legal entity responsible for the study: The Comprehensive Cancer Centre <strong>of</strong> Drum<br />
Tower Hospital<br />
Funding: This work was funded by grants from the National Natural Science<br />
Foundation <strong>of</strong> China (Grant No. 81401969, 812101060 and 81300339.<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
643P<br />
A randomized phase II study <strong>of</strong> leucovorin, 5-fluorouracil with<br />
or without oxaliplatin (LV5FU2 vs. FOLFOX) for<br />
curatively-resected, node-positive esophageal squamous cell<br />
carcinoma<br />
S.H. Lim 1 , Y-L. Choi 2 , S-H. Jung 3 , M-J.A. Ahn 4 , K. Park 4 , J.I. Zo 5 , Y.M. Shim 5 ,<br />
J-M. Sun 4<br />
1 Division <strong>of</strong> Hematology-<strong>Oncology</strong>, Department <strong>of</strong> Internal Medicine, Hallym<br />
University Dongtan Sacred Heart Hospital, Hwaseong-si, Republic <strong>of</strong> Korea,<br />
2 Department <strong>of</strong> Pathology, Samsung Medical Center Sungkyunkwan University<br />
School <strong>of</strong> Medicine, Seoul, Republic <strong>of</strong> Korea, 3 Department <strong>of</strong> Biostatistics and<br />
Bioinformatics, Duke University, Durham, NC, USA, 4 Division <strong>of</strong><br />
Hematology-<strong>Oncology</strong>, Department <strong>of</strong> Medicine, Samsung Medical Center<br />
Sungkyunkwan University School <strong>of</strong> Medicine, Seoul, Republic <strong>of</strong> Korea,<br />
5 Department <strong>of</strong> Thoracic and Cardiovascular Surgery, Samsung Medical Center<br />
Sungkyunkwan University School <strong>of</strong> Medicine, Seoul, Republic <strong>of</strong> Korea<br />
Background: Optimal perioperative treatment for resectable esophageal squamous cell<br />
carcinoma remains investigational. In this study, we evaluated the efficacy and safety <strong>of</strong><br />
leucovorin and 5-fluorouracil (LV5FU2) and LV5FU2 plus oxaliplatin (FOLFOX)<br />
combination chemotherapy given as adjuvant therapy for curatively-resected,<br />
node-positive esophageal squamous cell carcinoma.<br />
Methods: Patients with pathological node-positive esophageal cancer after curative R0<br />
resection were enrolled in a Fleming’s single-stage phase II design. Patients were<br />
randomly assigned to receive LV5FU2 (leucovorin 200 mg/m 2 and 5-FU 400 mg/m 2<br />
intravenously on day 1, followed by a 46-h infusion <strong>of</strong> 5-FU 2,400 mg/m 2 ) or FOLFOX<br />
(oxaliplatin 85mg/m 2 as 2-hr infusion on day 1 plus LV5FU2). Patients received either<br />
LV5FU2 or FOLFOX biweekly up to 8cycles except disease progression or unacceptable<br />
toxicity. The primary endpoint was disease-free survival (DFS) and secondary<br />
endpoints included overall survival (OS), safety and quality <strong>of</strong> life assessments.<br />
Results: Between Jan 2011 and Mar 2015, 66 patients were randomized (35 in LV5FU2<br />
arm and 31 in FOLFOX arm). The median age <strong>of</strong> all patients was 60 years (range,<br />
43-77) and both groups had similar pathologic characteristics in tumor, nodal status<br />
and location. About 70% <strong>of</strong> patients had stage II or III disease. Treatment completion<br />
rates were similarly high in both groups (P = 0.227). DFS rate at 12 month was 63% in<br />
LV5FU2 group versus 61% in FOLFOX group with hazard ratio (HR) <strong>of</strong> 1.3 (95% CI<br />
0.68-2.52). After a median follow up <strong>of</strong> 27 months, the median DFS was 24.6 months<br />
(95% CI 4.5-44.7) in LV5FU2 arm and 15.6 months (95% CI 6.3-24.9) for FOLFOX<br />
arm (P = 0.423), respectively and median OS was not reached in both arms (P = 0.817).<br />
Grade 3 or higher neutropenia was more frequent in patients in the FOLFOX arm<br />
compared to with the LV5FU2 arm (19.3% vs 2.9%), but none had febrile neutropenia.<br />
Conclusions: No evidence was found that the addition <strong>of</strong> oxaliplatin (FOLFOX)<br />
improves efficacy compared to LV5FU2 chemotherapy as adjuvant setting in<br />
esophageal cancer patients with lymph node-positive.<br />
Clinical trial identification: ClinicalTrials.gov NCT01467921<br />
Legal entity responsible for the study: Institutional review boards <strong>of</strong> Samsung<br />
Medical Center<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
644P<br />
Associations between deepness <strong>of</strong> response and clinical<br />
outcomes with advanced HER2-positive gastric cancer with<br />
1st-line chemotherapy and trastuzumab<br />
H. Osumi, E. Shinozaki, K. Chin, M. Ogura, T. Matsushima, T. Wakatsuki,<br />
I. Nakayama, T. Ichimura, D. Takahari, K. Yamaguchi<br />
Department <strong>of</strong> Gastroenterology, Cancer Institute Hospital <strong>of</strong> JFCR, Tokyo, Japan<br />
Background: Early tumor shrinkage (ETS) and deepness <strong>of</strong> response (DpR) is an<br />
efficacy outcome measure in metastatic colorectal cancer patients receiving<br />
chemotherapy plus epidermal growth factor receptor (EGFR) inhibitor. Trastuzumab is<br />
a monoclonal antibody against EGFR2 (HER2). It is controversial whether ETS and<br />
DpR is an efficacy outcome measure in HER2-positive advanced gastric cancer<br />
(HPAGC) or not. We aimed to evaluate the relationship between clinical outcome and<br />
ETS, DpR in HPAGC patients treated with 1 st -line chemotherapy and trastuzumab<br />
(CT).<br />
Methods: A total <strong>of</strong> 100 patients with histopathologically confirmed HPAGC treated<br />
with 1st-line CT between March 2011 and November 2015 were enrolled<br />
retrospectively. OS was defined as the time from the first day <strong>of</strong> treatment to death<br />
from any cause. PFS was defined as the time from the first day <strong>of</strong> treatment to either<br />
the first objective evidence <strong>of</strong> disease progression or to death from any cause. ETS was<br />
defined relative change in the sum <strong>of</strong> the longest diameters at week 8 (±4) compared to<br />
baseline. (Cut-<strong>of</strong>f :20%). DpR was defined relative change in the sum <strong>of</strong> the longest<br />
diameters at the nadir compared to baseline. (Cut-<strong>of</strong>f :median).<br />
Results: The median duration follow up at the time <strong>of</strong> the analysis was 19.8 months<br />
(14.9-25.1). An overall RR and the disease control rate were 64% and 87%, respectively<br />
(CR2, PR 62, SD 23, PD13). The median PFS was 7.9 months (5.8-11) and the median<br />
OS was 20.8 months (14.3-24.8). Median DpR <strong>of</strong> 44% (interquartile range: 16%, 55%)<br />
The median period until DpR was 9.5 weeks. ETS ≧ 20% was associated with<br />
significantly longer OS and PFS when compared with ETS < 20%. (ETS ≧ 20%<br />
vs < 20%: OS 24.4 vs 9.6 months, HR 0.21 p < 0.05 PFS 11.9 vs 2.9 months, HR 0.13<br />
p < 0.05) DpR ≧ 44% was also associated with significantly longer OS and PFS when<br />
compared with DpR < 44%. (DpR ≧ 44% vs < 44%: OS 29.7 vs 11.5 months, HR 0.24<br />
p < 0.05 PFS 14 vs 5.2 months, HR 0.22 p < 0.05) There was a weak positive correlation<br />
between DpR and clinical outcomes (OS: r = 0.35, P = 0.0003; PFS: r = 0.40,<br />
P = 0.00003).<br />
Conclusions: These results indicate the potential <strong>of</strong> both ETS and DpR as a new<br />
measure <strong>of</strong> efficacy in HPAGC patients treated with 1st-line CT.<br />
Legal entity responsible for the study: N/A<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
645P<br />
abstracts<br />
Capecitabine/cisplatin versus 5-fluorouracil/cisplatin in<br />
Chinese patients with advanced and metastatic gastric<br />
cancer: Re-analysis <strong>of</strong> efficacy and safety data from the<br />
ML17032 study<br />
J. Chen 1 , J. Xiong 2 , J. Wang 3 , L. Zheng 4 ,Y.Gao 5 , Z. Guan 6<br />
1 Department <strong>of</strong> <strong>Oncology</strong>, Jiangsu Cancer Institute and Hospital, Nanjing, China,<br />
2 Department <strong>of</strong> <strong>Oncology</strong>, 1st Affiliated Hospital <strong>of</strong> Nanchang Universi, Nanchang,<br />
China, 3 Department <strong>of</strong> <strong>Oncology</strong>, Shanghai Changzheng Hospital, Shanghai,<br />
China, 4 Department <strong>of</strong> <strong>Oncology</strong>, Xinhua Hospital, Shanghai Jiaotong University<br />
School <strong>of</strong> Medicine, Shanghai, China, 5 Medical Affairs, Shanghai Roche<br />
Pharmaceuticals Ltd, Shanghai, China, 6 Department <strong>of</strong> <strong>Oncology</strong>, Cancer Centre<br />
Sun Yat-Sen University, Guangzhou, China<br />
Background: This study presents a re-analyses <strong>of</strong> the efficacy and safety data from the<br />
ML17032 trial to confirm the non-inferiority and test the potential superiority <strong>of</strong> a<br />
capecitabine (Xeloda®)/ cisplatin (XP) combination over a 5-fluorouracil (5-FU)/<br />
cisplatin (FP) regimen as first-line treatment for advanced gastric cancer (AGC) in<br />
Chinese patients.<br />
Methods: In this open label phase III trial, patients with advanced gastric cancer (Stage<br />
IIIA-IV) with or without metastases were randomized 1:1 to receive Cisplatin (80mg/<br />
m2/day IV day 1) with either Capecitabine (1000mg/m2/day PO BID, days1-14) (XP)<br />
or 5-FU (800mg/m2/day continuous IV days 1-5) (FP) every 3 weeks. The primary<br />
objective was to confirm the non -inferiority <strong>of</strong> XP over FP for progression free survival<br />
(PFS).<br />
Results: A total <strong>of</strong> 126 Chinese patients (XP-62, FP-64; 75.4% male, median age 55.5<br />
years) were enrolled as the intent to treat population. The per-protocol population<br />
consisting <strong>of</strong> 105 patients (XP-51, FP-54; 64.7% male) served as the primary analysis<br />
group for establishing non-inferiority. Median PFS in the XP and FP groups was 7.2<br />
and 4.5 months respectively. The primary efficacy endpoint <strong>of</strong> PFS was met with an<br />
adjusted hazard Ratio (HR) <strong>of</strong> 0.52 (95% Confidence interval [CI]: [0.32-0.83],<br />
p = 0.006). Unadjusted HR for PFS in ITT population was 0.63 (95% CI: [0.42-0.94],<br />
p = 0.022). Among secondary efficacy endpoints OS (adjusted HR 0.61 [0.37-1.01],<br />
p = 0.053) and TTF (HR 0.54, [0.35, 0.84], p = 0.006) demonstrated a trend towards<br />
superiority <strong>of</strong> XP over FP. Drug exposure was similar among 2 groups in the safety<br />
population (XP-58, FP-62, 68.3% male). The most frequent drug related Grade 3/4 AEs<br />
were neutropenia (XP-20.7%; FP-17.7%) and gastrointestinal disorders (XP-19.0%;<br />
Volume 27 | Supplement 6 | October 2016<br />
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abstracts<br />
FP-19.4%). The overall incidence <strong>of</strong> grade 3/4 AEs (XP-43.1%; FP-46.8%), SAEs<br />
(XP-1.7%; FP-3.2%), and AEs related to treatment discontinuation (XP-10.3%;<br />
FP-16.1%) were comparable among the 2 groups.<br />
Conclusions: XP may demonstrate superiority for PFS and TTF compared to FP in the<br />
first-line treatment <strong>of</strong> Chinese patients with AGC and had a similar safety pr<strong>of</strong>ile to FP.<br />
Clinical trial identification: ClinicalTrials.gov NCT02563054.<br />
Legal entity responsible for the study: N/A<br />
Funding: This study was sponsored by Shanghai Roche Pharmaceuticals Ltd, China<br />
(ML 17032)<br />
Disclosure: Y. Gao: Employee <strong>of</strong> Shanghai Roche Pharmaceuticals Ltd. All other<br />
authors have declared no conflicts <strong>of</strong> interest.<br />
646P<br />
Clinical significance <strong>of</strong> microRNA expression in patients with<br />
Epstein-Barr virus associated gastric cancer<br />
J.G. Kim 1 , B.W. Kang 1 , Y.S. Chae 1 , S.J. Lee 1 , J.H. Baek 2<br />
1 <strong>Oncology</strong>/Hematology, Kyungpook National University Medical Center, Daegu,<br />
Republic <strong>of</strong> Korea, 2 Hematology/<strong>Oncology</strong>, Ulsan University Hospital, Ulsan,<br />
Republic <strong>of</strong> Korea<br />
Background: Previous reports have shown that the expression <strong>of</strong> miRNA was involved<br />
in the development or prognosis <strong>of</strong> Epstein-Barr virus associated gastric cancer<br />
(EBVaGC). Therefore, the expression or target genes <strong>of</strong> the EBV miRNA can be useful<br />
as biomarker for EBVaGC. This study investigated the clinical significance <strong>of</strong> EBV<br />
miRNA expressions in patients with EBVaGC.<br />
Methods: After reviewing 1318 consecutive cases <strong>of</strong> surgically resected or endoscopic<br />
submucosal dissected gastric cancers, 120 patients were identified as EBV-positive<br />
using EBV-encoded RNA in-situ hybridization. Among the 120 patients, the miRNA<br />
expression was examined in 39 tumor and 39 paired normal mucosal tissues from<br />
available formalin-fixed paraffin embedded tissues. The ebv-miRNAs expression levels<br />
for ebv-miR-BART1-5p, ebv-miR-BART4-5p, and ebv-miR-BART20-5p were<br />
determined by quantitative real-time PCR and the data were normalized relative to U6<br />
expression. The average value <strong>of</strong> ebv-miRNAs expression levels was used as the cut<strong>of</strong>f<br />
point.<br />
Results: The median age <strong>of</strong> the patients was 64 years (40-76) and 31 (79.5%) were<br />
male. The pathologic stages after surgical resection were as follows: stage I (n = 13),<br />
stage II (n = 12), and stage III (n = 14). The expression <strong>of</strong> these miRNAs was<br />
significantly higher in tumor tissue than paired normal tissue (P < 0.001 for each). Of<br />
these 39 patients, 14 patients (35.9%), 11 patients (28.2%), and 13 patients (33.3%)<br />
were determined as BART1-5p-high expression group, BART4-5p-high expression<br />
group, and BART20-5p-high expression group, respectively. In a univariate analysis,<br />
BART20-5p were significantly associated with longer recurrence-free survival (RFS)(<br />
P = 0.028), yet not overall survival. In a multivariate analysis, BART20-5p expression<br />
level has a tendency <strong>of</strong> favorable outcome indicator for RFS (P = 0.093, HR = 0.219,<br />
95% CI = 0.037-1.290).<br />
Conclusions: The ebv-miR-BART1-5p, ebv-miR-BART4-5p, and<br />
ebv-miR-BART20-5p were highly expressed in EBVaGC tissues, and the expression<br />
level <strong>of</strong> ebv-miR-BART20-5p may predict RFS for patients with EBVaGC. Further<br />
studies are warranted to elucidate the roles <strong>of</strong> EBV miRNAs in carcinogenesis <strong>of</strong><br />
EBVaGC, which would be a potential therapeutic target.<br />
Legal entity responsible for the study: N/A<br />
Funding: Ministry <strong>of</strong> Health & Welfare, Korea<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
647P<br />
New approach to gastric cancer classification based on TP53<br />
mutation<br />
R. Makuuchi 1 , K. Hatakeyama 2 , M. Terashima 1 , M. Kusuhara 2 , M. Tokunaga 1 ,<br />
Y. Tanizawa 1 , E. Bando 1 , T. Kawamura 1 , M. Hikage 1 , S. Kaji 1 , K. Ohshima 2 ,<br />
K. Urakami 2 , K. Yamaguchi 2<br />
1 Gastric Surgery, Shizuoka Cancer Center, Shizuoka, Japan, 2 Research Institute,<br />
Shizuoka Cancer Center, Shizuoka, Japan<br />
Background: Recently, novel classifications based on molecular pr<strong>of</strong>iling have been<br />
advocated for various solid tumors. In gastric cancer, the Cancer Genome Atlas and<br />
the Asian Cancer Research Group (ACRG) have proposed a new classifications using<br />
genomic alterations. We previously reported that the ACRG classification was also<br />
applicable to Japanese patients. However, there was no difference <strong>of</strong> survival depending<br />
on TP53 activation signature, though progress between tumors <strong>of</strong> microsatellite<br />
instability (MSI) and epithelial-mesenchymal transition (EMT) was obviously<br />
different. The aim <strong>of</strong> this study is to propose a new classification which clearly<br />
categorize gastric cancer using TP53 tumor specific single nucleotide mutation.<br />
Methods: We have launched a comprehensive molecular pr<strong>of</strong>iling in project HOPE<br />
(High-tech Omics-based Patient Evaluation) that analyzes genomes and<br />
transcriptomes <strong>of</strong> tumors obtained from the cancer patients admitted to Shizuoka<br />
Cancer Center from January 2014. Surgically-resected fresh tumor samples were<br />
analyzed by whole-exome sequencing (Ion Proton) and gene expression pr<strong>of</strong>iling<br />
(DNA microarray). A total <strong>of</strong> 188 patients with gastric cancer were included in this<br />
study. The patients were first subgrouped into MSI and EMT based on the ACRG<br />
classification. The remaining patients were then subgrouped by TP53 mutation status<br />
which depress its function (TP53+ and TP53-). Clinicopathological features and<br />
survival outcomes were compared among the groups.<br />
Results: The number <strong>of</strong> patients classified into the MSI, EMT, TP53 + , and TP53-<br />
group was 21, 22, 15 and 130, respectively. The median follow-up period was 349 days.<br />
The patients were significantly younger in EMT. The undifferentiated type was<br />
significantly dominant in MSI. There was no statistically significant difference in tumor<br />
depth, lymph node metastasis, or tumor stage among the groups. Two-year<br />
cause-specific survival (CSS) rates were 95.5% in MSI, 49.9% in EMT, 65.5% in<br />
TP53 + , and 78.5% in TP53- (p = 0.048). Although the follow-up period was<br />
insufficient, CSS was worse in TP53+ than in TP53-.<br />
Conclusions: Using a modified version <strong>of</strong> the ARGC classification focusing on TP53<br />
mutation, we found that selected TP53 mutations is a potential factor to define the<br />
genotype <strong>of</strong> gastric cancer as well as MSI and EMT.<br />
Legal entity responsible for the study: Shizuoka Cancer Center<br />
Funding: Shizuoka Cancer Center<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
648P<br />
Prognostic significance <strong>of</strong> neutrophil to lymphocyte ratio<br />
(NLR) in patients (pts) with resectable gastric/<br />
gastroesophageal junction (GOJ) adenocarcinoma undergoing<br />
perioperative chemotherapy<br />
Z. Salih, A.M. Conway, G. Papaxoinis, A. Patrao, K. Fletcher, R. Noble,<br />
V. Owen-Holt, W. Mansoor<br />
Medical <strong>Oncology</strong>, The Christie NHS Foundation Trust, Manchester, UK<br />
Background: No validated preoperative prognostic markers exist for pts with resectable<br />
gastric/GOJ adenocarcinoma (AC). There is evidence that NLR and<br />
platelet-to-lymphocyte ratio (PLR) predict outcomes in different types <strong>of</strong> malignancies.<br />
We aimed to explore the prognostic significance <strong>of</strong> NLR in pts with resectable gastric/<br />
GOJ AC undergoing perioperative chemotherapy.<br />
Methods: In this retrospective cohort study, baseline neutrophil, lymphocyte and<br />
platelet blood count levels were recorded for all pts with resectable gastric/GOJ AC<br />
commenced on neoadjuvant ECX-based chemotherapy (Jul’09-Dec’14). The<br />
prognostic significance <strong>of</strong> baseline characteristics and blood count levels on overall<br />
survival (OS) and tumour resectability was tested by Cox-regression analysis. All<br />
comparisons were two-sided with level <strong>of</strong> significance p < 0.05.<br />
Results: Of 368 pts included, 95 pts (26%) had gastric and 273 (74%) had GOJ<br />
primaries. ECOG Performance status (PS) was 0 in 133 (36%) and 1-2 in 235 pts<br />
(64%); 294 pts (80%) had curative surgery. After a median follow-up <strong>of</strong> 42 months<br />
(mo) (range 0.5-77) 209 (57%) pts were deceased. Increasing NLR associated with<br />
shorter OS (HR = 1.13, 95%CI = 1.06-1.19, p < 0.001) and correlated negatively with<br />
tumour resectability (OR = 0.84, 95%CI = 0.72-0.98, p = 0.024). Analysis <strong>of</strong> baseline<br />
data showed NLR, PS and clinical T stage independently predicts OS. Pts with NLR<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
hypothesized that genomic LOH would be associated with survival in pts treated with<br />
EOC ± P in the REAL3 study.<br />
Methods: Methods: REAL3 was a randomised, open-label phase 3 trial in pts with<br />
treatment naïve, metastatic or locally advanced oesophagogastric cancer (OGC)<br />
assessing addition <strong>of</strong> P to EOC; no survival benefit was associated with EOC-P therapy.<br />
Pre-treatment tumour biopsies were selected for high tumour content (>30%). The<br />
percentage <strong>of</strong> interrogable genome with LOH (%LOH) was quantified by assessment <strong>of</strong><br />
single-nucleotide polymorphisms spanning the whole genome using a next-generation<br />
sequencing based assay (Frampton et al., Nat. Biotechnol. 2013). Optimisation <strong>of</strong><br />
survival benefit as measured by Hazard Ratio (HR), its significance, sensitivity and<br />
specificity was used to derive an LOH cut-<strong>of</strong>f separating pts into LOH high and low<br />
cohorts which were associated with survival.<br />
Results: Results: Eighty six (<strong>of</strong> a total 553 pts treated) tumours were sequenced (n = 42<br />
EOC, n = 44 EOC-P). LOH was inferred for 54 (63%). Median %LOH for the entire<br />
cohort was 12.1%; this was highest for oesophagogastric junction (OGJ) tumours<br />
(15.4%), median %LOH for stomach and oesophageal tumours were 11.4% and 11.6%<br />
respectively. Pts with LOH ≥21% (n = 9/54, 17%) appeared to have a progression free<br />
(HR 0.48 (95% CI 0.21-1.09), p = 0.08) and overall survival (HR 0.43 (95% CI<br />
0.19-0.97), p = 0.04) benefit. The proportion <strong>of</strong> pts with oesophageal, OGJ and stomach<br />
cancers with LOH ≥21% were 16%, 23% and 8% respectively.<br />
Conclusions: Conclusions: Genomic LOH was inferred for the majority <strong>of</strong> sequenced<br />
samples. OGJ tumours had the highest median LOH. An LOH high cut<strong>of</strong>f <strong>of</strong> ≥21%<br />
(17% <strong>of</strong> the population) was associated with an overall survival benefit for pts treated<br />
with platinum chemotherapy. LOH high platinum sensitive pts may benefit from<br />
PARP inhibitor therapy; we will investigate this hypothesis using rucaparib in the<br />
PLATFORM trial.<br />
Legal entity responsible for the study: The Royal Marsden Hospital NHS Foundation<br />
Trust<br />
Funding: Clovis <strong>Oncology</strong><br />
Disclosure: I. Chau: Advisory board: San<strong>of</strong>i <strong>Oncology</strong>, Eli-Lilly, Bristol Meyers Squibb,<br />
MSD, Merck Serono, Gilead Science. Research Funding: Janssen-Cilag, San<strong>of</strong>i<br />
<strong>Oncology</strong>, Roche, Merck-Serono, Novartis Honoraria: Taiho, Pfizer, Amgen, Eli-Lilly,<br />
Bayer. D. Cunningham: Research funding: Amgen, AstraZeneca, Bayer, Celgene,<br />
Medimmune, Merck Serono, San<strong>of</strong>i, Clovis. All other authors have declared no<br />
conflicts <strong>of</strong> interest.<br />
650P<br />
Efficacy and tolerability <strong>of</strong> first-line chemotherapy in elderly<br />
patients (age ≥70 years) with metastatic gastric cancer:<br />
a multicenter study <strong>of</strong> the Anatolian Society <strong>of</strong> Medical<br />
<strong>Oncology</strong> (ASMO)<br />
M.N. Aldemir 1 , M. Turkeli 1 , B. Hacioglu 2 , A. Sakin 3 , E. Yaman 4 , E. Coban 5 ,<br />
D. Koca 6 , M. Karaca 7 , M. Simsek 1 , A. Bahceci 8 , E. Sen 9 ,T.Eren 10 ,B.<br />
Ö. Aliustaoglu 11 , T. Sakalar 12 , N.O. Kalkan 13 , G. Aktas 14 , M. Bilici 1 , S. Turhal 15 ,<br />
M. Benekli 7 , S.B. Tekin 1<br />
1 Medical <strong>Oncology</strong>, Ataturk University Medical Faculty, Erzurum, Turkey, 2 Medical<br />
<strong>Oncology</strong>, Trakya University Rektörlüğü, Edirne, Turkey, 3 Medical <strong>Oncology</strong>, S.B.<br />
Okmeydani Education And Research Hospital, Istanbul, Turkey, 4 Medical<br />
<strong>Oncology</strong>, Mersin University School <strong>of</strong> Medicine, Mersin, Turkey, 5 Medical<br />
<strong>Oncology</strong>, Bezmialem Vakif University Hospital, Istanbul, Turkey, 6 Medical<br />
<strong>Oncology</strong>, Medical Park Hospital, Kocaeli, Turkey, 7 Medical <strong>Oncology</strong>, GUTF (Gazi<br />
Üniversitesi Tip Fakültesi)-Gazi University Faculty <strong>of</strong> Medicine, Ankara, Turkey,<br />
8 Medical <strong>Oncology</strong>, Cumhuriyet University Hospital, Sivas, Turkey, 9 Medical<br />
<strong>Oncology</strong>, Selcuk University Meram Medical Faculty, Konya, Turkey, 10 Medical<br />
<strong>Oncology</strong>, Diskapi YıldırımBeyazıt Teaching and Research Hospital, Ankara,<br />
Turkey, 11 Medical <strong>Oncology</strong>, Haydarpasa Numune Education and Research<br />
Hospital, Istanbul, Turkey, 12 Medical <strong>Oncology</strong>, Erciyes University Medical Faculty<br />
M.Kemal Dedeman, <strong>Oncology</strong> Hospital, Kayseri, Turkey, 13 Medical <strong>Oncology</strong>,<br />
Yuzuncu Yil University Medical Faculty, Van, Turkey, 14 Medical <strong>Oncology</strong>,<br />
Gaziantep University Onkoloji Hastanesi, Gaziantep, Turkey, 15 Medical <strong>Oncology</strong>,<br />
Anadolu Medical Center, Kocaeli, Turkey<br />
Background: Gastric cancer that is generally diagnosed in advanced stages is the<br />
second leading cause <strong>of</strong> cancer-related death worldwide. Although chemotherapy has<br />
benefit on quality <strong>of</strong> life and overall survival (OS) in metastatic gastric cancer (MGC),<br />
OS usually remains less than a year. Here, the efficacy and tolerability <strong>of</strong> first-line<br />
chemotherapy in MGC patients aged 70 years and older was investigated<br />
Methods: As a multicenter study <strong>of</strong> ASMO, 305 patients followed in 17 centers<br />
between 2005 and 2015 were included. Patients who were 70 years and older at the time<br />
<strong>of</strong> MGC diagnosis and who had received at least two cycles <strong>of</strong> chemotherapy in the<br />
first-line setting were evaluated retrospectively.<br />
Results: The clinical and demographical features <strong>of</strong> the patients were presented in<br />
Table 1. Median age was 73 (min-max 70-90). Median follow-up time was determined<br />
as 8 months (min-max 1-78), median PFS as 6 months (95%CI: 5.2-6.7) and median<br />
OS as 10 months (95%CI: 8.4-11.6). Partial response was achieved in 26.2% and stable<br />
disease in 16.7% <strong>of</strong> the patients. The most common chemotherapy related grade 3-4<br />
hematologic toxicity was neutropenia (22%). Poor ECOG performance status, history<br />
<strong>of</strong> surgical treatment and less number <strong>of</strong> metastatic organs had statistically significant<br />
benefit on PFS and OS (p < 0.05). The number <strong>of</strong> drugs in the regimens was positively<br />
correlated with both response rates <strong>of</strong> treatment and with grade 3-4 neutropenia rates<br />
(p = 0.004, p < 0.001; respectively).<br />
Table: 650P<br />
n %<br />
Gender Male 216 70.8<br />
ECOG 0 45 14.8<br />
1 159 52.1<br />
2 96 31.5<br />
3 5 1.6<br />
Age (years) 70-74 187 61.3<br />
74-79 78 25.6<br />
≥80 40 13.1<br />
Chemotherapy regimen 1 drug 58 19<br />
2 drugs 105 34.4<br />
3 drugs 142 46.6<br />
Conclusions: We observed that first-line chemotherapy was effective and tolerable in<br />
elderly patients. The chemotherapy regimen (multiple or single) and the dose<br />
reduction at the beginning did not affect treatment response. It is reasonable to choose<br />
the minimum toxic and maximum tolerable chemotherapy regimen. It will be more<br />
relevant to use physiological age evaluations like ECOG performance status than<br />
biological age in treatment decision.<br />
Legal entity responsible for the study: Anatolian Society <strong>of</strong> Medical <strong>Oncology</strong><br />
(ASMO)<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
651P<br />
Nab-paclitaxel as second line treatment in advanced gastric<br />
cancer: A HORG multicenter phase II study<br />
P. Katsaounis, N. Kentepozidis, A. Kotsakis, A. Polyzos, L. Vamvakas,<br />
M. Bakogiorgos, I. Boukovinas, E. Hartabilas, E. Prinarakis, T. Skaltsi,<br />
V. Georgoulias, J. Souglakos<br />
Medical <strong>Oncology</strong>, Hellenic <strong>Oncology</strong> Research Group (HORG), Athens, Greece<br />
Background: There are few therapeutic options for the treatment <strong>of</strong> metastatic gastric<br />
and gastroesophageal junction adenocarcinomas which fail front-line chemotherapy. A<br />
phase II multicenter study <strong>of</strong> second line nab-paclitaxel was conducted aiming to<br />
evaluate its efficacy and tolerance in patients with advanced gastric and<br />
gastroesophageal junction (GEJ) adenocarcinoma.<br />
Methods: Thirty-nine patients (median age 62 years) with locally advanced inoperable<br />
and metastatic gastric and GEJ adenocarcinoma were enrolled. All patients had a PS <strong>of</strong><br />
0-1, 17 pts (43.6%) had prior surgery, 4 had received prior adjuvant chemotherapy, and<br />
33 (84.6%) had receiver DCF in the first line setting. The median time from the prior<br />
treatment was 2.6 months (range, 1.0-13.8). Nab-paclitaxel was given weekly (125mg/<br />
m 2 , d1,d8, and d15 every 28 days).<br />
Results: Partial response (PR) was achieved in nine pts (23.1%), disease stabilization<br />
(SD) in 11 (28.2%) and disease progression in 18 (46.2%) for an ORR <strong>of</strong> 23.1% (95%<br />
CI; 9.85-36.3) and a DCR <strong>of</strong> 51.3%. Responses were observed irrespectively <strong>of</strong> the prior<br />
administration docetxel-based chemotherapy. The median progression free survival<br />
was 3.0 months (95% CI 2.1-3.8) and the median overall survival 6.8 months (95% CI<br />
0.7-8.8). Six (15.3%) pts developed grade 3/4 neutropenia, 7 pts (18%) grade 2/3<br />
asthenia and 8 (20.5%) grade 2/3 neurotoxicity. Other AE were mild (grade
abstracts<br />
652P<br />
Prognostic implications <strong>of</strong> baseline neutrophil-lymphocyte<br />
ratio (NLR) and platelet-lymphocyte ratio (PLR) in metastatic<br />
gastric cancer (GC) patients<br />
A. Petrillo, M.M. Laterza, J. Ventriglia, B. Savastano, G. Tirino, L. Pompella,<br />
E. Martinelli, F. Morgillo, M. Orditura, F. Ciardiello, F. De Vita<br />
Medical <strong>Oncology</strong>, AOU Seconda Università degli Studi di Napoli (AOU-SUN),<br />
Naples, Italy<br />
Background: The outcome <strong>of</strong> metastatic gastric cancer is poor. Recent studies have<br />
shown that systemic inflammatory response markers such as NLR and PLR affect<br />
survival <strong>of</strong> GC pts. This study was carried out to create a prognostic model using<br />
inflammatory-based scores to predict survival in patients with metastatic GC before<br />
chemotherapy.<br />
Methods: We studied the prognostic value <strong>of</strong> systemic inflammatory factors such as<br />
circulating white blood cell count and its components in 110 pts with metastatic GC<br />
receiving first-line chemotherapy. NLR and PLR were determined before starting<br />
chemotherapy. Median value was used to determine the cut-<strong>of</strong>f levels for these<br />
biomarkers. Univariate and multivariate analyses were performed to examine the<br />
impact <strong>of</strong> inflammatory markers on overall survival (OS). Statistical analysis was<br />
performed by SPSS 21.0 s<strong>of</strong>tware.<br />
Results: The median values <strong>of</strong> NLR and PLR were 2.22 (95% CI: 0.36-18.46) and<br />
157.01 (95% CI: 32.79-720), respectively. Pts were divided into two groups according to<br />
the cut-<strong>of</strong>f values (NLR: 75 years old, a higher proportion <strong>of</strong> whom are<br />
not treated.<br />
Table: 653P<br />
YA MA EE<br />
Sex (N = 118,417) Male/Female 52.8%/47.2% 66.6%/33.4% 58.1%/41.9%<br />
Race (N = 115,372) White/Black/<br />
Asian<br />
72.0%/ 18.5%/<br />
9.5%<br />
76.6%/ 16.6%/<br />
6.8%<br />
80.9%/ 12.9%/<br />
6.1%<br />
Ethnicity (N = 111,467) Hispanic/ 29.6%/70.3% 11.3%/88.7% 7.2%/92.8%<br />
non-Hispanic<br />
Stage (N = 118,417) I/II/III/IV 16.0%/10.5%/<br />
18.4%/55.2%<br />
22.9%/15.2%/<br />
21.1%/40.9%<br />
30.5%/16.0%/<br />
18.4%/35.1%<br />
Grade (N = 94,326) 1/2/3 6.2%/13.9%/<br />
79.9%<br />
7.6%/26.9%/<br />
65.5%<br />
7.5%/32.4%/<br />
60.1%<br />
Subtype (N = 11,110) Intestinal/ 30.3%/69.7% 66.7%/33.3% 80.1%/19.9%<br />
diffuse<br />
Treatment (N = 82,765) Surgery<br />
Surgery + chemo<br />
Surgery + chemoRT None<br />
25.7% 23.6%<br />
28.8% 21.8%<br />
34.6% 17.3%<br />
27.6% 20.4%<br />
47.9% 7.2% 8.7%<br />
36.2%<br />
Conclusions: Differences exist between age extremes in GA patients compared to those<br />
traditionally represented in landmark trials including demographics, stage <strong>of</strong><br />
presentation, histologic subtype, and treatment utilization. Further investigation is<br />
warranted to determine the effects <strong>of</strong> these differences on outcome.<br />
Legal entity responsible for the study: This study is a retrospective review. No legal<br />
entities were involved in the conduct <strong>of</strong> this study.<br />
Funding: Mount Sinai School <strong>of</strong> Medicine<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
654P<br />
A randomized phase II study <strong>of</strong> pancrelipase in patients with<br />
gastrectomy to assess the prevention <strong>of</strong> weight loss<br />
S. Tamura 1 , H. Taniguchi 2 , A. Takeno 1 , K. Murakami 1 , Y. Katsura 1 , Y. Ohmura 1 ,<br />
A. Naito 1 , Y. Kagawa 1 , Y. Takeda 1 , T. Kato 1<br />
1 Surgery, Kansai Rosai Hospital, Amagasaki, Japan, 2 Surgery, Minoh City<br />
Hospital, Minoh, Japan<br />
Background: Gastrectomy for gastric cancer is associated with weight loss, which<br />
could lead to deterioration <strong>of</strong> quality <strong>of</strong> life and even prognosis <strong>of</strong> patients.<br />
Pancrelipase (PL) is pharmaceutical preparation <strong>of</strong> extracted pancreatic enzyme<br />
(pancreatin) with high density from pancreas <strong>of</strong> the pig. We conducted a randomized<br />
phase II single-center study was performed, in which the effects <strong>of</strong> pancrelipase for the<br />
suppression <strong>of</strong> weight loss and the improvement <strong>of</strong> nutrition after gastrectomy wrre<br />
assessed.<br />
Methods: Patients were randomly divided to receive the PL or not. The PL group<br />
received 1800mg/day for 6 months and more after surgery, starting from the day the<br />
patients took normal diets. The primary endpoint was the percentage <strong>of</strong> body weight<br />
loss (%BWL) from the presurgical weight to that 6 months after surgery. Body<br />
composition, BT-PABA(PFD) test and various blood test results were evalutated at 3, 6<br />
and 12 months after surgery.<br />
Results: 172 patients (distal gastrectomy in 128 patients, total gastrectomy in 44<br />
patients) were enrolled from July 2012 through March 2015. 88 patients were PL group<br />
and 84 patients were non-PL group. The % BWL after total gastrectomy in 6 months<br />
were significantly higher than that after distal gastrectomy (15.2% vs 7.9%). The %<br />
BWL <strong>of</strong> PL group was lower than that <strong>of</strong> non-PL group, but which was not statistically<br />
significant (8.3% vs 10.6%: p = 0.06). The % <strong>of</strong> reduction <strong>of</strong> the lean body mass was<br />
lower in PL group than that in non-PL group (p = 0.09), whereas the % <strong>of</strong> fat mass were<br />
not difference in two groups.<br />
Conclusions: Administration <strong>of</strong> PL might be lessened postoperative BWL by means <strong>of</strong><br />
keeping lean body mass.<br />
Legal entity responsible for the study: N/A<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
655P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Conditional survival probability in patients with resected<br />
oesophageal adenocarcinoma receiving neoadjuvant<br />
chemotherapy<br />
D.M. Graham 1 , F.J. Bannon 2 , F. Noble 3 ,R.O’Neill 4 , J.K. Blayney 5 ,T.<br />
J. Underwood 3 , R.D. Kennedy 1 , R.C. Fitzgerald 6 , R.C. Turkington 1<br />
1 Centre for Cancer Research and Cell Biology, Queen’s University Belfast, Belfast,<br />
UK, 2 Centre for Public Health, Queen’s University Belfast, Belfast, UK,<br />
3 Department <strong>of</strong> Surgery, University Hospital Southampton NHS Foundation Trust,<br />
Southampton, UK, 4 Clinical Surgery, Edinburgh Cancer Research UK-University <strong>of</strong><br />
Edinburgh, Edinburgh, UK, 5 Department <strong>of</strong> Bioinformatics, Centre for Cancer<br />
Research and Cell Biology, Queen’s University Belfast, Belfast, UK, 6 Hutchison/<br />
MRC Cancer Unit, University <strong>of</strong> Cambridge, Cambridge, UK<br />
Background: Traditional recurrence and survival figures are based upon factors<br />
determined at baseline and become less relevant for patients over time. Conditional<br />
vi222 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
survival (CS) estimates future prognosis based upon survival to a specific time point<br />
since treatment. We analysed CS and conditional recurrence-free survival (CRFS) data<br />
for patients in the United Kingdom undergoing surgery and neoadjuvant<br />
chemotherapy for gastro-oesophageal junction (GOJ) or oesophageal adenocarcinoma<br />
(OAC).<br />
Methods: 378 patients with GOJ/OAC treated with neoadjuvant chemotherapy and<br />
surgical resection from 2003-2012 were identified. Clinicopathological and survival<br />
data was collected as part <strong>of</strong> the Oesophageal Cancer Clinical and Molecular<br />
Stratification (OCCAMS) consortium. A multivariable parametric survival model was<br />
used to analyse factors associated with overall survival and recurrence from time <strong>of</strong><br />
surgery.<br />
Results: The cohort includes 305 males (80.7%) with median age 65 (range 28-83)<br />
years. 5-year RFS conditional on recurrence-free years to date increased over time (see<br />
table). For those with stage T3/4, moderately-poorly differentiated tumours with<br />
lymphovascular invasion, 5-year disease-specific survival (DSS) improved from 7.7%<br />
for those with node-positive, R1 disease to 45.4% conditional on 3 years post-treatment<br />
survival; compared with 55.6% actuarial 5-year DSS increasing to 86.7% conditional on<br />
3 years post-treatment survival for patients with N0 R0 disease. Age, sex, year <strong>of</strong><br />
surgery, and Siewert classification had no association with recurrence or mortality rate.<br />
Table: 655P Recurrence-free survival (RFS) by prognostic factors<br />
Poor Prognostic factor<br />
T-stage:<br />
3or4<br />
Nodes<br />
positive<br />
Margins<br />
involved<br />
5-year<br />
RFS<br />
(%)<br />
5-year RFS<br />
conditional<br />
on 1 year (%)<br />
5-year RFS<br />
conditional<br />
on 2 years<br />
(%)<br />
1 1 1 7.2 13.2 28.7 49.5<br />
1 1 0 35.4 45.1 61.2 75.8<br />
1 0 1 25.6 35.1 52.4 69.5<br />
1 0 0 58.5 66.2 77.6 86.7<br />
0 1 1 20.0 29.1 46.7 65.0<br />
0 1 0 53.1 61.5 74.1 84.4<br />
0 0 1 43.5 52.7 67.4 80.0<br />
0 0 0 72.0 77.7 85.6 91.6<br />
5-year RFS<br />
conditional<br />
on 3 years<br />
(%)<br />
Conclusions: CRFS and CS provide a more dynamic estimation <strong>of</strong> future recurrence<br />
risk and survival among patients who have accrued survival time, especially in patients<br />
with high-risk features, including positive resection margins. Margin and node<br />
positivity govern early relapse events but as the time from surgery increases these<br />
factors become less relevant.<br />
Legal entity responsible for the study: Queen’s University Belfast<br />
Funding: Queen’s University Belfast<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
656P<br />
Results <strong>of</strong> a prospective, multicenter, non-interventional trial<br />
to analyze disease- and treatment-related effects on the<br />
functionality <strong>of</strong> patients with gastrointestinal tumors ≥ 75<br />
years<br />
J. H<strong>of</strong>mann 1 , N. Härtel 1 , J. H<strong>of</strong>mann 1 , M. Neugebauer 1 , A. Berger 2 , S. Zschäbitz 2 ,<br />
H. Schulze-Bergkamen 3 , J. Betge 1 , S. Belle 1 , R. Jesen<strong>of</strong>sky 1 , N. Schulte 1 ,<br />
U. Wedding 4 , M. Ebert 1 , J. Chi-Kern 1<br />
1 II. Medizinische Klinik, Universitätsklinikum Mannheim, Mannheim, Germany,<br />
2 Medical <strong>Oncology</strong>, National Center for Tumor Diseases, Heidelberg, Germany,<br />
3 Department for Internal Medicine, Marien-Hospital Wesel, Wesel, Germany,<br />
4 Department for Internal Medicine, Klinik fuer Innere Medizin II Klinikum der<br />
Friedrich- Schiller-Universitaet, Jena, Germany<br />
Background: Cancer is a disease <strong>of</strong> the elderly (average age <strong>of</strong> onset >69yrs). However,<br />
there is few data available on treatment- and disease-related interactions with the<br />
functional reserve <strong>of</strong> these patients (pts).<br />
Methods: Prospective, multicenter non-interventional trial at two university hospitals<br />
in Germany. Included were pts ≥ 75yrs (n = 30) with gastrointestinal tumors receiving<br />
chemotherapy “ctx” in the period Q1/2015 - Q1/2016. To objectify the functionality <strong>of</strong><br />
these pts sequential geriatric assessments (G8-Questionaire, ECOG, IADL, ADL) were<br />
performed. The analysis is based on data from 2 patient cohorts (C1: ctx 8 wks, n = 15).<br />
Results: An initial dose reduction tended to stabilize the ADL/IADL <strong>of</strong> pts with newly<br />
initiated ctx (C1) when compared to those pts who received a 100%-dosage initially<br />
(p = 0,0986). Less ≥2° toxicities (tox) were detected after initial dose reduction<br />
(p = ns). However, at the time <strong>of</strong> the analysis the tox did not correlate with a<br />
deterioration in the IADL or ADL. Pts who started ctx with a pathological<br />
G8-Screening ( 8 wks (C2), a continued<br />
100%-dosage did not result in a deterioration in the ADL/IADL (additionally no<br />
correlation between tox and the IADL/ADL has been detected). C2 pts with an intial<br />
G8 < 14 showed no further improvement, however pts with a G8-score ≥14 tended to<br />
reach a better functional performance over time (IADL/ADL: p = 0,0986). Furthermore<br />
for C2 pts disease control (PR + SD) was also significantly associated with a functional<br />
improvement (G8/ECOG: p = 0,0003; ADL: p = 0,0261).<br />
Conclusions: These data suggest, that dose-escalating strategies maintain the<br />
functional reserve <strong>of</strong> pts ≥75yrs with gastrointestinal tumors. However disease control<br />
was the strongest predictor for stabilized functionality.<br />
Clinical trial identification: AIO YMO project<br />
Legal entity responsible for the study: N/A<br />
Funding: Funded by the government<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
657P<br />
Esophageal adenocarcinoma: Impact <strong>of</strong> a large hiatal hernia<br />
on outcomes after surgery<br />
C. Gronnier 1 , A. Gandon 1 , F. Renaud 2 , P. Borde 3 , M. Vanderbeken 1 , F. Hec 1 ,<br />
G. Piessen 1 , A. Adenis 4 , X. Mirabel 4 , C. Mariette 1<br />
1 Department <strong>of</strong> Digestive and Oncological Surgery, Lille University Hospital,<br />
France, Lille, France, 2 Department <strong>of</strong> Pathology, Lille University Hospital, France,<br />
Lille, France, 3 Department <strong>of</strong> Radiology, Lille University Hospital, France, Lille,<br />
France, 4 Service Cancérologie Digestive, Centre Oscar Lambret, Lille, France<br />
Background: Hiatal hernia (HH) is a risk factor for esophageal and junctional<br />
adenocarcinoma (EGJA). Its impact on the outcomes after EGJA surgery is unknown.<br />
Objectives were to evaluate complete tumor resection rate (primary objective), 30-day<br />
postoperative outcomes and survival (secondary objectives) in patients with a<br />
HH ≥ 5cm (HH group) compared to those who did not have a HH or presented with a<br />
HH < 5cm (control group).<br />
Methods: Among 367 patients who underwent surgery for EGJA, a HH was searched<br />
for on CT scan and barium swallow, with comparison between the HH (n = 42) and<br />
control (n = 325) groups.<br />
Results: In the HH group, EGJAs exhibited higher rates <strong>of</strong> pN3 stages (28.5% vs.<br />
10.1%, P = 0.002), <strong>of</strong> incomplete resection (50.0% vs. 4.0%, P < 0.001) and lower<br />
median survival (20.9 vs. 41.0 months, P = 0.001). After adjustment, a HH ≥5cm was a<br />
predictor <strong>of</strong> incomplete resection (OR 21.0, 95%CI 9.4–46.8, P < 0.001) and a poor<br />
prognostic factor (HR 1.6, 95%CI 1.1–2.5, P = 0.025). In the HH group, 30-day<br />
mortality was significantly higher in patients who received neoadjuvant radiotherapy<br />
(20.0% vs. 0%, P = 0.040), which was related to greater cardiac and pulmonary toxicity.<br />
Conclusions: For the first time, we showed that a HH ≥5cm is associated with a poor<br />
prognosis in patients who had surgery for EGJA, linked to greater incomplete resection<br />
and lymph node involvement. Neoadjuvant radiotherapy was associated with a<br />
significant toxicity in patients with a HH ≥5cm.<br />
Legal entity responsible for the study: None<br />
Funding: University Hospital <strong>of</strong> Lille<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
658P<br />
"Many ways to skin gastric cancer" - Robotic versus<br />
laparoscopic versus open gastrectomy<br />
E. Kakiashvili 1 , O. Ben Yshai 1 , R. Almog 2 , A. Beny 3 , Y. Kluger 1<br />
1 General Surgery, Rambam Health Care Center, Haifa, Israel, 2 Epidemiology,<br />
Rambam Health Care Center, Haifa, Israel, 3 Medical <strong>Oncology</strong>, Rambam Health<br />
Care Center, Haifa, Israel<br />
Background: Robotic surgery has gained acceptance in oncological surgery. Its<br />
relevance in gastric cancer surgery is being examined. The study presents preliminary<br />
comparison <strong>of</strong> operative and postoperative outcome between robotic, laparoscopic and<br />
open gastrectomies for gastric adenocarcinoma.<br />
Methods: Retrospective cohort <strong>of</strong> 85 consecutive patients that underwent total or<br />
partial gastrectomy for gastric adenocarcinoma at Rambam Hospital during<br />
2012-2015. For each patient data was collected on basic demographic<br />
characteristics, BMI, operating room time(ORT), number <strong>of</strong> dissected lymph<br />
nodes(LN), length <strong>of</strong> hospitalization(LOH), intra and postoperative complications.<br />
Non parametric statistical tests MW and Kruskal-Wallis were used for group<br />
comparisons.<br />
Results: Study population included 55 patients after total gastrectomies, 10 <strong>of</strong> them<br />
robotic and 30 partial gastrectomies, 12 <strong>of</strong> them robotic. Age, gender and BMI were<br />
similar between patients who underwent robotic, laparoscopic and open procedures.<br />
Median length <strong>of</strong> hospitalization(LOH) for robotic total gastrectomy was 4.5 days and<br />
it was significantly shorter than both laparoscopic total gastrectomy(LTG) 7.0 days<br />
(p = 0.003) and open total gastrectomy(OTG) 9.0 days (p < 0.001). Similar significant<br />
differences in LOH between the 3 groups were observed among patients who<br />
underwent partial gastrectomy, but the comparison between robotic and laparoscopic<br />
procedures was limited due to small numbers <strong>of</strong> LPG. Median ORT was significantly<br />
longer among robotic gastrectomies compared to open, the difference was 64 min in<br />
total gastrectomy group and 145 min in partial gastrectomy group (p < 0.001 for both<br />
differences), but the difference in ORT between laparoscopic and robotic procedures<br />
were smaller and non-significant. The number <strong>of</strong> dissected LN was similar between the<br />
3 procedures in total gasrectomies. In partial gastrectomies, the number <strong>of</strong> dissected<br />
Volume 27 | Supplement 6 | October 2016<br />
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abstracts<br />
LN was even higher among both laparoscopic and robotic gastrectomies compared to<br />
open (p < 0.001).<br />
Conclusions: Robotic total and partial gastrectomies for gastric adenocarcinoma are<br />
associated with oncologically adequate lymphadenectomy and faster patient recovery,<br />
but longer operating time.<br />
Legal entity responsible for the study: Rambam Hospital<br />
Funding: Rambam Hospital<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
659P<br />
PIK3CA mutations up-regulate Akt expression and confer<br />
aggressive tumor biology in gastric cancer<br />
K-W. Lee 1 , J-W. Kim 1 , J.W. Kim 1 , H.S. Lee 2<br />
1 Department <strong>of</strong> Internal Medicine, Seoul National University Bundang Hospital,<br />
Seongnam, Republic <strong>of</strong> Korea, 2 Department <strong>of</strong> Pathology, Seoul National<br />
University Bundang Hospital, Seongnam, Republic <strong>of</strong> Korea<br />
Background: PIK3CA mutations are frequently observed in gastric cancer (GC).<br />
However, their pathologic and clinical implications have not been well understood yet.<br />
Methods: Clinical and pathological data <strong>of</strong> patients with stage I-IV GC who underwent<br />
gastrectomy between May 2003 and December 2005 were retrospectively analyzed<br />
according to their PIK3CA mutation status using real-time polymerase chain reaction.<br />
Results: A total <strong>of</strong> 302 patients (male, 202) were included and the median age <strong>of</strong><br />
patients was 61 years (range, 29-89). PIK3CA mutations were detected in 40 patients<br />
(13%). Compared with PIK3CA wild-type tumors, cytoplasmic expression <strong>of</strong> Akt was<br />
significantly increased in PIK3CA mutant tumors [immunohistochemstry 3 + : 17%<br />
(mutant) vs. 2% (wild type); p = 0.001]. PIK3CA mutant tumors were more likely to be<br />
located in the upper third <strong>of</strong> stomach (37% vs. 18%; p = 0.021) and presented with<br />
more advanced T stage (pT4: 53% vs. 33%; p = 0.018). PIK3CA mutant tumors were<br />
significantly associated with poorly differentiated histology (73% vs. 46%; p = 0.018),<br />
and increased lymphatic (93% vs. 75%; p = 0.015), vascular (35% vs. 16%; p = 0.005),<br />
and perineural invasion (73% vs. 54%; p = 0.026). In addition, these tumors exhibited<br />
significantly more lymphocyte and neutrophil infiltration in stroma (p < 0.001), and<br />
were significantly related to Epstein-Barr virus positivity (43% vs. 6%; p < 0.001) and<br />
microsatellite instability (20% vs. 7%; p = 0.015). Nevertheless, overall survival was<br />
similar between PIK3CA mutant and wild-type patients (p = 0.944).<br />
Conclusions: PIK3CA mutations up-regulate Akt expression and seem to confer<br />
aggressive tumor biology in GC. These data suggest that PIK3CA-mutated GC may be<br />
a distinct disease entity. However, the existence <strong>of</strong> PIK3CA mutation was not<br />
associated with poor prognosis in GC patients receiving gastrectomy.<br />
Legal entity responsible for the study: None<br />
Funding: This study was partially supported by research grants from the Seoul<br />
National University Bundang Hospital Research Fund (02-2015-009).<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
660P<br />
A retrospective study <strong>of</strong> chemoradiotherapy (CRT) versus<br />
chemotherapy (CT) as adjuvant treatment for localized gastric<br />
cancer (LGC)<br />
D.D.M. Girardi 1 , G.C. Pereira 1 , M. Negrão 1 , M.A. Lima 1 , M.M. Felizola 1 ,R.<br />
N. Fogace 1 , F.C. Capareli 1 , J. Sabbaga 2 , P.M. H<strong>of</strong>f 2<br />
1 <strong>Oncology</strong>, Instituto do Câncer do Estado de São Paulo, São Paulo, Brazil,<br />
2 Oncologia Clínica, ICESP - Instituto do Câncer do Estado de São Paulo, Sao<br />
Paulo, Brazil<br />
Background: Treatment <strong>of</strong> LGC consists <strong>of</strong> surgical resection followed by adjuvant<br />
treatment. Indeed either CRT or CT regimen have shown benefit in survival outcomes<br />
versus observation. However, there are few data comparing these approaches. This<br />
study aims to compare the toxicity and efficacy <strong>of</strong> CRT versus CT.<br />
Methods: This retrospective study included consecutive patients (pts) with LGC<br />
treated at Instituto do Cancer do Estado de Sao Paulo (ICESP) from 2012-2015. CRT<br />
(group 1) was based on the INT-0116 regimen and CT (group 2) consisted <strong>of</strong> a<br />
platinum and fluoropyrimidine doublet. Treatment choice was based on physician’s<br />
preference. Toxicity was evaluated for every cycle. Overall survival (OS) analysis was<br />
performed by Kaplan Meier.<br />
Results: A total <strong>of</strong> 309 pts were evaluated, 227 in group 1 and 82 in group 2<br />
(chemotherapy regimen: XELOX 78; XP 4). Groups were very similar regarding pts<br />
characteristics. Median age at diagnosis was 58.7y and 56.5y with male predominance<br />
(59.9% and 58.5%). Most pts presented with ECOG 0/1 (92% and 92,3%), in clinical<br />
stage III (53,3% and 69,5%). Type <strong>of</strong> surgical procedure was also well balanced with D2<br />
node dissection been performed in 73,1% and 79,3% and R0 resection in 91,2% and<br />
87,8% <strong>of</strong> pts. More prevalent grade 3 and 4 toxicities in groups 1 and 2 respectively<br />
were: nausea and vomiting (9.2% vs 4.9%), asthenia (9.3% vs 2.4%), mucositis (4.4% vs<br />
1.2%), neutropenia (37.8% vs 20.9%), febrile neutropenia (3.9% vs 0%); anemia (4.3%<br />
vs 6.1%), thrombocytopenia (2.6% vs 4.9%), neuropathy (0 vs 2.4%) and hand-foot<br />
syndrome (0.4% vs 2.4%). Two grade 5 toxicities (febrile neutropenia and anemia) had<br />
occurred in group 1. Dose reductions were more common in group 2 (11% vs 52.4%).<br />
Treatment discontinuation rates were similar (35.7% vs 35.4%), with toxicity being the<br />
most common cause (48.2% vs 41.4%). After median follow up <strong>of</strong> 21 months (group 1)<br />
and 16.5 months (group 2), there was no difference in OS (2-year OS: 69.1% vs 65.2%).<br />
Conclusions: CT appears to be equally effective and less toxic than CRT as adjuvant<br />
treatment for LGC and may be a reasonable option for centers with limited access to<br />
radiotherapy.<br />
Legal entity responsible for the study: Instituto do Câncer do Estado de São Paulo<br />
Funding: Instituto do Câncer do Estado de São Paulo<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
661P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
A phase II study for triplet combination <strong>of</strong> oxaliplatin,<br />
irinotecan, and S-1 in patients with metastatic or recurrent<br />
gastric cancer<br />
B. Han 1 , S.R. Park 2 , H.S. Kim 1 , M-H. Ryu 2 , J-S. Kim 3 , S-Y. Rho 4 , B.W. Kang 5 ,K.<br />
H. Lee 6 , S.Y. Rha 7 , W.K. Kang 8 , Y-K. Kang 2 , D.Y. Zang 1<br />
1 Internal Medicine, Hallym University Medical Center Hallym University College <strong>of</strong><br />
Medicine, Anyang, Republic <strong>of</strong> Korea, 2 Department <strong>of</strong> <strong>Oncology</strong>, Asan Medical<br />
Center, University <strong>of</strong> Ulsan College <strong>of</strong> Medicine, Seoul, Republic <strong>of</strong> Korea, 3 Internal<br />
Medicine, Boramae Medical Center, Seoul, Republic <strong>of</strong> Korea, 4 Internal Medicine,<br />
Seoul St. Mary’s Hospital, <strong>of</strong> the Catholic University, Seoul, Republic <strong>of</strong> Korea,<br />
5 <strong>Oncology</strong>/Hematology, Kyungpook National University Medical Center, Daegu,<br />
Republic <strong>of</strong> Korea, 6 Internal Medicine, Yeungnam University Medical Center,<br />
Daegu, Republic <strong>of</strong> Korea, 7 Medical <strong>Oncology</strong>, Internal Medicine, Yonsei<br />
Severance Hospital Cancer Center, Seoul, Republic <strong>of</strong> Korea, 8 Division <strong>of</strong><br />
Hematology-<strong>Oncology</strong>, Department <strong>of</strong> Medicine, Samsung Medical Center,<br />
Sungkyunkwan University School <strong>of</strong> Medicine, Seoul, Republic <strong>of</strong> Korea<br />
Background: Doublet chemotherapy <strong>of</strong> platinum and 5-fluorouracil is considered as a<br />
standard front-line treatment for patients with unresectable gastric cancer. Although<br />
addition <strong>of</strong> taxane or irinotecan to this regimen has yielded promising efficacy, it has<br />
been used in limited patients due to severe toxicities. To overcome this limitation, we<br />
evaluated the efficacy and safety <strong>of</strong> the combination <strong>of</strong> irinotecan, oxaliplatin, and S-1<br />
for the treatment <strong>of</strong> unresectable gastric cancer.<br />
Methods: Chemotherapy-naïve patients with pathologically proven unresectable<br />
recurrent or metastatic gastric adenocarcinoma were assessed for eligibility. Irinotecan<br />
at 135 mg/m 2 and oxaliplatin at 65 mg/m 2 were administered intravenously on day 1,<br />
and S-1 was administered orally at 80 mg/m 2 on days 1–7 <strong>of</strong> every 14-day cycle, which<br />
have been derived from our phase I study.<br />
Results: Forty-three patients (median age 57 years) were enrolled. A total <strong>of</strong> 259 cycles<br />
<strong>of</strong> chemotherapy were administered (median <strong>of</strong> eight; range 1–23 cycles). Toxicities<br />
were evaluated in 41 patients, and the responses were evaluated in 32 patients. Major<br />
toxicities included grade 3/4 neutropenia (41.5%), febrile neutropenia (14.6%),<br />
abdominal pain (12.2%), and diarrhea (7.3%). The overall response rate was 59.4%<br />
[95% confidence interval (CI) 42.3-74.5%]. The median progression-free survival and<br />
overall survival were 8.4 months (95 % CI 5.5-11.3 months) and 13.1 months (95 % CI<br />
11.8–14.5 months), respectively.<br />
Conclusions: These data suggest that the oxaliplatin, irinotecan, and S-1 combination<br />
regimen is effective and relatively well tolerable, and it seems to have potential to be a<br />
reasonable therapeutic strategy in patients with unresectable gastric cancer.<br />
Legal entity responsible for the study: Hallym Sacred Heart Hospital Institutional<br />
Review Board<br />
Funding: Korean Cancer Study Group<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
662P Efficacy <strong>of</strong> staging laparoscopy for type 4 and large type 3<br />
gastric cancer<br />
M. Tokunaga, R. Makuuchi, Y. Tanizawa, E. Bando, T. Kawamura, M. Terashima<br />
Gastric Surgery, Shizuoka Cancer Center, Shizuoka, Japan<br />
Background: In patients with advanced gastric cancer, staging laparoscopy (SL) is<br />
regarded as a useful procedure for detecting minute peritoneal metastasis, which is<br />
difficult to identify by conventional imaging modalities. However, indications for the<br />
procedure differ across reports and remain unclear. Infiltrative type gastric cancers<br />
could be suitable candidates for SL because <strong>of</strong> the high risk <strong>of</strong> peritoneal metastasis.<br />
The present study aimed to clarify the effectiveness and limitations <strong>of</strong> SL for patients<br />
with type 4 and large type 3 gastric cancers.<br />
Methods: We included 140 consecutive patients with cM0, type 4 or large type 3 (8cm<br />
or larger in diameter) gastric cancer who underwent SL at the Shizuoka Cancer Center<br />
from August 2008 to December 2015. Patients who received chemotherapy before the<br />
SL were excluded. We determined the detection rate <strong>of</strong> peritoneal metastasis by SL, and<br />
calculated the false negative rate <strong>of</strong> SL by recruiting patients who were diagnosed as P0<br />
at SL and underwent laparotomy within 28 days after the SL.<br />
Results: P0CY0, P0CY1, P1CY0, and P1CY1 were diagnosed in 64 (45.7%), 29<br />
(20.7%), 16 (11.4%), and 31 (22.1%) patients, respectively. Accordingly, clinically<br />
non-evident peritoneal metastasis was found in 33.6% <strong>of</strong> patients, and 54.3% <strong>of</strong><br />
vi224 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
patients were diagnosed as stage IV. In addition, 51 patients diagnosed as P0 at SL<br />
underwent laparotomy within 28 days after the SL. Among them, peritoneal metastasis<br />
was found in seven patients. Thus, the false negative rate was 13.7% (7/51).<br />
Conclusions: SL is useful for detecting previously unsuspected peritoneal metastasis<br />
and for avoiding unnecessary laparotomy, although the high false negative rate cannot<br />
be ignored. Peritoneal metastasis was found by SL in approximately one third <strong>of</strong><br />
patients with cM0, type 4 and large type 3 gastric cancers, and therefore, they are<br />
considered suitable candidates for SL.<br />
Legal entity responsible for the study: Masanori Tokunaga<br />
Funding: Shizuoka Cancer Center<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
663P<br />
Predictive biomarkers to ramucirumab in Asian metastatic<br />
gastric cancer patients: Circulating angiogenic factors <strong>of</strong><br />
VEGFR2 and neurophilin are predictive to ramucirumab<br />
efficacy in Asian recurrent/metastatic gastric cancer patients<br />
S. Lim 1 , S.J. Heo 2 , T.S. Kim 2 , H.J. Kwon 1 , J.H. Kim 2 , M.K. Jeong 2 , H.S. Kim 2 ,S.<br />
H. Beom 2 , H.C. Chung 2 , S.Y. Rha 2<br />
1 Haemato-<strong>Oncology</strong>, Yonsei University Wonju Christian Hospital, Wonju, Republic<br />
<strong>of</strong> Korea, 2 Internal Medicine, Yonsei Cancer Center, Seoul, Republic <strong>of</strong> Korea<br />
Background: We conducted an exploratory study to identify potential biomarkers to<br />
predict therapeutic effect <strong>of</strong> ramucirumab in combination with paclitaxel as a second<br />
line treatment for recurrent/metastatic Korean gastric cancer (GC) patients.<br />
Methods: We retrospectively reviewed clinical efficacay and toxicity in 70 GC patients<br />
who received ramucirumab with weekly paclitaxel in an open-label expanded access<br />
program after failure to first line chemotherapy. To find potential biomarker <strong>of</strong><br />
ramucirumab, we investigated the association between efficacy <strong>of</strong> ramucirumab and<br />
tissue molecular characteristics (EBV, MMR, HER2, EGFR, C-MET etc.). Also, we<br />
measured circulating biomarkers (VEGF, sVEGFR2, HGF, neuropillin-1, IL-8, and<br />
PIGF,) by ELISA method before and after treatment in a subset <strong>of</strong> patients (n = 44 vs.<br />
n = 14, respectively).<br />
Results: With the median follow up <strong>of</strong> 5.3 months (range 0.5 ∼ 10.5 months), the<br />
median progression free survival (PFS) was 4.1 months (95% CI, 3.3 ∼ 4.9 months),<br />
and median overall survival (OS) was not reached. Of the 55 evaluable patients, the<br />
overall response rate (ORR) was 14.5% (8 partial responses), and disease control rate<br />
was 74.5%. Although there was no difference in PFS, OS or ORR according to receptor<br />
status, higher DCR was found in patients with EGFR high expression tumors (2 + ∼3+)<br />
compared with low expression tumors (0 ∼ 1+) (87.5% vs. 50%, p = 0.02). Regarding<br />
circulating biomarkers related to angiogenesis, longer PFS was seen in patients with<br />
higher level <strong>of</strong> pretreatment serum VEGFR2 (4.1 vs. 2.4 months; p = 0.01) and lower<br />
level <strong>of</strong> pretreatment serum neuropillin-1 (5.8 vs. 2.4 months; p < 0.01). The circulatory<br />
biomarkers were not related to toxicity. Currently, test <strong>of</strong> tissue based biomarkers are<br />
also under way.<br />
Conclusions: Current study suggested that circulating biomarkers related to<br />
angiogenesis quantified by ELISA method may predict prolonged response to<br />
ramucirumab in the treatment <strong>of</strong> gastric cancer patient.<br />
Legal entity responsible for the study: N/A<br />
Funding: N/A<br />
Disclosure: S.Y. Rha: Consulting or advisory role in 2years: Merck & Co.Inc. Speakers’<br />
Bureau in 2 years: Novartis, Eli Lilly, Merck. All other authors have declared no<br />
conflicts <strong>of</strong> interest.<br />
664P<br />
Adjuvant concurrent chemoradiotherapy(CRT) plus docetaxelcisplatin-<br />
fluorouracil (DCF) versus CRT plus fluorouracil<br />
folinic acid (FUFA) in gastric cancer<br />
A. Alkan 1 ,D.Mızrak 1 , E. Karcı 1 ,A.Yaşar 1 , E.B. Köksoy 1 , M. Ürün 1 , T. Kütük 2 ,<br />
Y. Ürün 1 ,F.ÇaySȩnler 1 , S. Akyürek 2 , G. Utkan 1 , A. Demirkazık 1 ,Ş.Ç. Gökçe 2 ,<br />
H. Akbulut 1<br />
1 Medical <strong>Oncology</strong>, Ankara University Medical School-Cebeci Hastaneleri Tıbbi<br />
Onkoloji, Ankara, Turkey, 2 Radiation <strong>Oncology</strong>, Ankara University Medical<br />
School-Cebeci Hastaneleri Tıbbi Onkoloji, Ankara, Turkey<br />
Background: Adjuvant chemoradiotherapy is the optimal management strategy in<br />
resectable gastric cancer. There is a debate about the efficacy <strong>of</strong> more aggressive CRT<br />
plus chemotherapy regimens in adjuvant setting. This study aimed to compare the<br />
efficacy <strong>of</strong> adjuvant CRT plus DCF versus CRT plus FUFA in stage III gastric cancer.<br />
Methods: Patients with a diagnosis <strong>of</strong> stage III gastric cancer, treated with adjuvant<br />
therapy after curative resection were analyzed. Patients’ and disease characteristics,<br />
impacts <strong>of</strong> the regimen on median progression free survival (mPFS) and median<br />
overall survival (mOS) were analyzed retrospectively. DCF arm had been treated with 2<br />
cycles DCF (docetaxel 75mg/m2, cisplatin 75mg/m2 on day 1, fluorouracil 750mg/m2<br />
for 4 days every 3 weeks) followed by concurrent CRT with 2 cycles <strong>of</strong> FUFA<br />
(fluorouracil 425mg/m2, folinic acid 20mg/m2, 3 days) and 2 cycles <strong>of</strong> DCF. FUFA<br />
arm was treated with Macdonald regimen (1 cycle <strong>of</strong> FUFA for 5 days, followed by<br />
CRT with 2 cycles <strong>of</strong> FUFA and further 2 cycles <strong>of</strong> FUFA.<br />
Results: 140 gastric cancer patients, 94 in FUFA and 46 in DCF arms, were evaluated.<br />
Patient and disease characteristics were similar between groups. There were more renal<br />
toxicity (40% v 7%, p < 0.001), emergency department admissions (66.7% v 24.6%,<br />
p < 0.001), hospitalization due to toxicity (40.9% v 25.7%, p = 0.068) in the CRT plus<br />
DCF regimen. Treatment related mortality was similar between groups (p = 0.41).<br />
Recurrences while under adjuvant therapy were 15.2% and 17.9% in DCF and FUFA<br />
regimens, respectively (p = 0.45). Median DFS was similar between groups (19.0 v 18.0<br />
months, p = 0.79). 24 months OS were 53.2% for DCF and 51.9% for FUFA arms.<br />
There was no statistically significant difference in mOS (not reached v 24 months,<br />
p = 0.772).<br />
Conclusions: There is no DFS or OS advantage <strong>of</strong> CRT plus DCF over CRT plus<br />
FUFA. More aggressive adjuvant therapy with CRT plus DCF is also more toxic than<br />
Macdonald regimen.<br />
Legal entity responsible for the study: None<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
665P<br />
Personalized medicine for advanced pancreas cancer: access<br />
to treatment according to molecular pr<strong>of</strong>ile<br />
C. Romeo 1 , P. Cassier 1 , A. De la Fouchardière 1 , D. Pissaloux 2 , V. Attignon 3 ,<br />
Q. Wang 4 , M. Sarabi 1 , F. Desseigne 5 , P. Guibert 5 , D. Perol 6 , O. Tredan 7 ,<br />
J-Y. Blay 8 , C. de la Fouchardiere 5<br />
1 Medical <strong>Oncology</strong>, Léon Bérard Cancer Center, Lyon, France, 2 Biology, Léon<br />
Bérard Cancer Center, Lyon, France, 3 Clinical Research, Léon Bérard Cancer<br />
Center, Lyon, France, 4 Départment de recherche translationnelle, Centre Léon<br />
Bérard, Lyon, France, 5 Digestive <strong>Oncology</strong>, Centre Léon Bérard, Lyon, France,<br />
6 Clinical Research, Centre Léon Bérard, Lyon, France, 7 Medecine, Centre Léon<br />
Bérard, Lyon, France, 8 Medical <strong>Oncology</strong>, Centre Léon Bérard, Lyon, France<br />
Background: With a dramatic increase in incidence and a very poor prognosis, the<br />
pancreatic cancer‘s treatment remains a real challenge. We investigated here the<br />
feasibility and efficacy <strong>of</strong> personalized treatment according to molecular analysis in<br />
heavily pre-treated advanced pancreatic adenocarcinoma patients included in the<br />
Pr<strong>of</strong>iLER protocol (NCT 02029001).<br />
Methods: Between February 2013 and July 2015, 74 patients with metastatic pancreatic<br />
cancer were included in the Pr<strong>of</strong>iLER trial. Tumor samples were analyzed for<br />
mutations/insertions/deletions and copy number variations using target<br />
high-throughput sequencing (NGS) and comparative genomic hybridization array<br />
(CGH). Blood samples were also collected. The patients, for whom an actionable<br />
alteration was identified, were treated according to their molecular pr<strong>of</strong>ile.<br />
Results: Tumor biopsy and archived tumor samples were collected from 74 patients<br />
and successfully analyzed in 45/74 (60.8%). Actionable molecular aberrations were<br />
identified in 22 patients (48.9%): 17 KRAS hotspot mutations, 2 CDKN2A<br />
homozygous deletions, 2 FGFR amplification (FGFR1/FGFR4), 1 ALK mutation, 1<br />
HER2 amplification, 1 PI3KCA mutation and 1 MYC amplification. There was a<br />
median <strong>of</strong> 4.5 molecular aberrations per patient (range: 1–7). 14/22 tumor samples<br />
were issued from the primary site, 6 from distant metastases biopsy and 2 from fine<br />
needle aspiration. Low cellularity and insufficient DNA were the main reasons for<br />
molecular analysis failure. The median time between the patient’s inclusion and the<br />
molecular tumor board patient presentation was 87.5 days [43-399]. To date, only 3<br />
patients have been treated according to the molecular results, but unfortunately died.<br />
Most <strong>of</strong> participants were unable to be treated due to their worsening condition or<br />
further progression <strong>of</strong> their disease.<br />
Conclusions: Identifying molecular targets in patients with metastatic pancreatic<br />
adenocarcinoma is feasible but forces clinicians and biologists to face very specific<br />
challenges due to the aggressive and rapidly fatal outcome <strong>of</strong> this disease. Molecular<br />
screening and accrual <strong>of</strong> patients in early-phase clinical trials have to be improved and<br />
anticipated.<br />
Clinical trial identification: Pr<strong>of</strong>iLER protocol: NCT 02029001; date: 28/11/2012<br />
Legal entity responsible for the study: Pr Jean-Yves Blay<br />
Funding: Le LYRIC (Lyon recherche intégrée en Cancerologie)<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
666P<br />
abstracts<br />
A modified regimen <strong>of</strong> nab-paclitaxel and gemcitabine in<br />
advanced pancreatic cancer<br />
M.A.M. Osman 1 , R. McDermott 2 , D. Fennelly 1<br />
1 Department <strong>of</strong> <strong>Oncology</strong>, St Vincents University Hospital, Dublin, Ireland,<br />
2 Department <strong>of</strong> Medical <strong>Oncology</strong>, AMNCH Adelaide and Meath Hospital, Dublin,<br />
Ireland<br />
Background: Nab-Paclitaxel in combination withGemcitabine has significantly<br />
improved outcomes in advanced pancreatic cancer. However, the published regimen <strong>of</strong><br />
day1,8 and15 every28 days cycle is associated with significant toxicities and is not<br />
deliverable in a timely fashion in many patients. The objective <strong>of</strong> this study was to<br />
evaluate the activity, deliverability, and toxicity associated with the modified regimen <strong>of</strong><br />
Nab-Paclitaxel andGemcitabine.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw371 | vi225
abstracts<br />
Methods: Nab-Paclitaxel and Gemcitabine regimen was adapted and implemented<br />
atthe Irish national pancreatic surgery centre.This constitutes a retrospective study.<br />
Patients had locally advanced or metastatic Pancreatic cancer, no prior chemotherapy<br />
for Pancreatic cancer and Performance Status1-2. Treatment regimen was<br />
Nab-Paclitaxel 125mg/m2 and Gemcitabine1000mgs/m2 on days1 and8 <strong>of</strong> each21day<br />
cycle.Treatment was continued until disease progression or unacceptable toxicity.<br />
Results: Between January2013 and December2015, 64patients were treated with the<br />
regimen.The median number <strong>of</strong> cycles was 6. A total <strong>of</strong>360 cycles was administered. 62<br />
patients (97%) underwent response evaluation. No patient (0%) achieved CR.<br />
12patients (19%) had a PR and 28 patients (46%) achieved SD. The median PFS was<br />
6.0months and the median OS was 8.5 months.The 6-monthPFS was 41%, while the 6-<br />
monthsOS was 64%. Survival was better in patients with performance status 0-1 vs 2,<br />
locally advanced disease vs metastatic, lung only metastases, patients with only one site<br />
<strong>of</strong> metastases and those with CA 19.9 less than 2 times upper limit <strong>of</strong> normal.<br />
Treatment protocol was generally tolerated well.Grade3 or higher side effects were<br />
observed in 27.5% <strong>of</strong> cycles. There were no treatment related deaths. Treatment<br />
protocol was delivered on time in87% <strong>of</strong> cycles without any delay. Dose reductions<br />
occurred in11% <strong>of</strong> cycles. Treatment was discontinued in6% <strong>of</strong> patients.<br />
Conclusions: The 21day regimen <strong>of</strong> days1 and8 Nab-Paclitaxel and Gemcitabine<br />
demonstrated comparable efficacy to the 28 day 1,8,15 regimen and was associated with<br />
an improved toxicity pr<strong>of</strong>ile and deliverability. It represents an active alternate<br />
treatment schedule for patients with advanced pancreatic cancer.<br />
Legal entity responsible for the study: Mohammed Abdel Osman (1st. Author)<br />
Funding: HSE<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
667P<br />
Definitive concurrent chemoradiotherapy using S-1 in the<br />
treatment <strong>of</strong> elderly patients with esophageal cancer<br />
Y. Jia<br />
Department <strong>of</strong> Radiation <strong>Oncology</strong>, Zhejiang Provincial People’s Hospital,<br />
Hangzhou, China<br />
Background: Definitive concurrent chemoradiotherapy (CCRT) with 5-florouracil<br />
(5-FU) and cisplatin (CDDP) are <strong>of</strong>ten associated with signifiant incidence <strong>of</strong> toxicities<br />
in elderly patients with esophageal cancer. This reteospective study was aimed at<br />
investigating the efficiency and safety <strong>of</strong> using S-1 as mono and maintenance therapy<br />
combined with concurrent radiotherapy (RT) for elderly patients with esophageal cancer.<br />
Methods: From January 2009 to December 2010, 68 (aged over 70 years) elderly<br />
patients were included. RT was delivered with a daily fraction <strong>of</strong> 1.8-2.0Gy to a total<br />
radiation dose <strong>of</strong> 54.0-60.0Gy using the three-dimensional conformal technique<br />
(3D-CRT). Preplanned concurrent S-1 (80mg/m 2 /day) was given on Days 1-14, every 3<br />
weeks. After concurrent chemoradiotherapy (CCRT), maintenance S-1 was repeated<br />
up to four cycles.<br />
Results: The median age was 76 years (range: 70-88 years), and the clinical stages were<br />
stage I (two patients), stage II (24 patients), stage III (28 patients), and stage IV (14<br />
patients). 51 (75.0%) patients finished treatment on schedule and the median cycles <strong>of</strong><br />
S-1 was five, <strong>of</strong> which 35 (51.5%) patients achieved complete response. The median<br />
follow-up time was 42.7 months, and the median overall survival (OS) and<br />
progression-free survival (PFS) time were 25.7 and 21.5 months, respectively. The 1-<br />
and 3-year OS and PFS rates were 70.6%, 41.8% and 68.1%, 32.9%, respectively. Grade<br />
≥3 neutropenia and leukopenia were found in 14 and 13 patients, respectively. The<br />
most common non-hematologic toxicity was esophagitis including six and one patients<br />
with grade 3 and 4.<br />
Conclusions: For elderly patients with esophageal cancer, S-1 as mono and<br />
maintenance chemotherapy in combination with RT could improve survival outcomes<br />
with tolerable toxicities. More clinical trials (like NCT02716688) are highly warranted<br />
to further clarify this issue.<br />
Legal entity responsible for the study: N/A<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
668P<br />
Risk factors for esophageal fistula in esophageal squamous<br />
cell carcinoma invading adjacent organs (T4b) treated with<br />
definitive chemoradiotherapy<br />
T. Kawakami 1 , T. Tsushima 1 , K. Hayashi 1 , H. Shirasu 1 , M. Kawahira 1 ,S.Kawai 1 ,<br />
Y. Kito 1 , Y. Yoshida 1 , S. Hamauchi 1 , A. Todaka 1 , N. Machida 1 , K. Yamazaki 1 ,<br />
T. Yokota 1 , A. Fukutomi 1 , Y. Onozawa 2 , H. Yasui 1<br />
1 Gastrointestinal <strong>Oncology</strong>, Shizuoka Cancer Center, Shizuoka, Japan, 2 Medical<br />
<strong>Oncology</strong>, Shizuoka Cancer Center, Shizuoka, Japan<br />
Background: Standard treatment for unresectable esophageal squamous cell carcinoma<br />
(ESCC) without distant metastasis is definitive chemoradiotherapy (dCRT). The<br />
frequency <strong>of</strong> esophageal fistula (EF) is 10–12% in patients (pts) receiving dCRT for T4b<br />
ESCC and the prognosis for pts harboring EF is poor. However, its risk factors are still<br />
unclear. Therefore, we investigated risk factors for EF in T4b ESCC treated with dCRT.<br />
Methods: We retrospectively analyzed the data <strong>of</strong> consecutive T4b ESCC pts who<br />
received dCRT with cisplatin plus fluorouracil (CF) at Shizuoka Cancer Center between<br />
Sep. 2004 and Apr. 2015. All data were collected from electronic medical records. EF<br />
was diagnosed by radiological or endoscopic examination, and/or clinical course.<br />
Inclusion criteria were as follows: (1) ECOG performance status (PS) 0–1; (2)<br />
histologically proven SCC; (3) clinically T4b (TNM 7th); (4) no EF before dCRT; and<br />
(5) CCr ≥50 mL/min. dCRT consisted <strong>of</strong> intravenous infusion <strong>of</strong> 70 mg/m 2 cisplatin<br />
on days 1 and 29, continuous infusion <strong>of</strong> 700 mg/m 2 fluorouracil on days 1–4 and 29–<br />
32, and concomitant radiation <strong>of</strong> 50–60 Gy (2 Gy/Fr).<br />
Results: In total, 143 pts who met the inclusion criteria were analyzed, excluding 6 with<br />
EF due to iatrogenic intervention. With a median follow-up time <strong>of</strong> 31 months in<br />
censored cases, EF was observed in 34 pts (24%). The median time to EF was 2.5<br />
months. Characteristics <strong>of</strong> pts who experienced EF versus those who did not were as<br />
follows: median age (range), 64 (41–75) vs. 65 (40–80) years; PS 0/1, 22/12 vs. 71/38<br />
pts; circumferential lesion (CL), 24 vs. 52 pts; aorta invasion, 16 vs. 46 pts; trachea or<br />
bronchus invasion, 23 vs. 77 pts; Hb
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
impact <strong>of</strong> primary tumour resection on survival and CTH tolerance in patients with<br />
mOGA undergoing palliative CTH.<br />
Methods: Patients with mOGA who started palliative CTH between January 2010 and<br />
May 2015 were identified from the electronic database <strong>of</strong> the Department <strong>of</strong> <strong>Oncology</strong><br />
at the University Hospital in Krakow. We performed a charts review to obtain baseline<br />
demographics, performance status, laboratory parameters, dates <strong>of</strong> progression, death<br />
and last follow-up. Patients were divided into two groups: A-primary tumour resected,<br />
B-primary tumour present. Overall survival (OS) and progression-free survival (PFS)<br />
were estimated using the Kaplan–Meier method.<br />
Results: One hundred sixty-five patients were identified: group A n = 89, group B<br />
n = 76. No significant differences in baseline characteristics were observed. Median OS<br />
was 10.5 months (95% CI 8.5-13.5) in group A vs 8.4 months (6.0-10.5) in group B<br />
(log-rank p = 0.013). Median PFS was 6.4 months (4.8-7.5) and 5.1 months (4.1-6),<br />
respectively (log-rank p = 0.019). There were no statistically significant differences in<br />
grade 3 or 4 chemotherapy-related adverse events between groups: anaemia (gr. A 5.8%<br />
vs gr. B 9.7%), leukopenia (11.6% vs 15.3%), neutropenia (47.7% vs 43.1%), febrile<br />
neutropenia (4.7% vs 5.6%), thrombocytopenia (1.2% vs 0.0%), nausea (1.2% vs 1.4%),<br />
vomiting (2.3% vs 1.4%), diarrhoea (5.8% vs 1.4%), anorexia (3.5% vs 4.2%), fatigue<br />
(3.5% vs 4.2%), mucositis (1.2% vs 1.4%), hand-foot syndrome (1.2% vs 0.0%),<br />
peripheral neuropathy (1.2% vs 0.0%). No statistically significant differences were<br />
observed for CTH cycle delays (gr. A 71.6% vs gr. B 68.5%; p = 0.799) and CTH dose<br />
reductions (gr. A 28.4% vs gr. B 20.3%; p = 0.311).<br />
Conclusions: In this retrospective analysis, primary tumour resection in patients with<br />
mOGA improved OS and did not influence the tolerance <strong>of</strong> palliative CTH. Updated<br />
data with a longer follow-up will be presented.<br />
Legal entity responsible for the study: Jagiellonian University Medical College,<br />
Krakow, Poland<br />
Funding: Jagiellonian University Medical College, Krakow, Poland<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
671P<br />
Chemoradiotherapy versus surgery for clinical stage I<br />
esophageal squamous cell carcinoma: A long-term<br />
comparison<br />
S. Mitani 1 , S. Kadowaki 1 , I. Oze 2 , T. Masuishi 1 , Y. Narita 1 , H. Taniguchi 1 ,T.Ura 1 ,<br />
M. Ando 1 , M. Tajika 3 , C. Makita 4 , T. Kodaira 4 , N. Uemura 5 ,T.Abe 5 , K. Muro 1<br />
1 Department <strong>of</strong> Clinical <strong>Oncology</strong>, Aichi Cancer Center Hospital, Nagoya, Japan,<br />
2 Department <strong>of</strong> Epidemiology, Aichi Cancer Center Hospital, Nagoya, Japan,<br />
3 Department <strong>of</strong> Endoscopy, Aichi Cancer Center Hospital, Nagoya, Japan,<br />
4 Department <strong>of</strong> Radiation <strong>Oncology</strong>, Aichi Cancer Center Hospital, Nagoya,<br />
Japan, 5 Department <strong>of</strong> Gastroenterological Surgery, Aichi Cancer Center Hospital,<br />
Nagoya, Japan<br />
Background: Definitive chemoradiotherapy (CRT) is an alternative to surgery for stage<br />
I esophageal squamous cell carcinoma (ESCC). The aim <strong>of</strong> this study was to evaluate<br />
the long-term outcome <strong>of</strong> CRT and surgery for stage I ESCC.<br />
Methods: Patients (pts) with clinical stage I (cT1N0M0) ESCC treated with CRT or<br />
surgery at Aichi Cancer Center Hospital between January 2003 and September 2012<br />
were retrospectively analyzed. Pts were excluded if they had a history <strong>of</strong> invasive cancer<br />
within 1 year before the treatment.<br />
Results: Among 102 pts included, 63 were treated with CRT (cohort C) and 39 with<br />
surgery (cohort S). Although there was a higher proportion <strong>of</strong> pts with Charlson<br />
comorbidity index ≥ 1 (39.7% vs. 23.1%), pack-year history <strong>of</strong> smoking ≥ 30 (65.1% vs.<br />
48.7%) and a past history <strong>of</strong> cancer (28.6% vs. 10.3%) in cohort C than in cohort S, no<br />
statistically significant difference was observed between the two cohorts with respect to<br />
pts’ characteristics. Fifty-nine pts (93.7%) achieved a complete response in cohort C,<br />
and R0 resection was performed in all pts in cohort S. Only one treatment-related<br />
death was observed in cohort C. Recurrences occurred more frequently in cohort C<br />
(40.0% vs. 15.3%), most <strong>of</strong> which were curatively treated by salvage therapy. With a<br />
median follow-up <strong>of</strong> 6.0 years, the 5-year overall survival rates were 83.9% in cohort C<br />
and 89.5% in cohort S (HR = 1.72; 95% CI: 0.65–4.53; P = 0.27). The 5-year<br />
disease-specific survival rates were similar in both cohorts (91.8% vs. 88.4%; HR = 1.11;<br />
95% CI: 0.34–3.63; P = 0.87). In cohort C, death due to other causes was frequently<br />
observed (12.7% vs. 2.6%); in particular, five pts (7.9%) died <strong>of</strong> a second primary<br />
cancer in other organs (second primary). The rate <strong>of</strong> second primary was 28.6% in<br />
cohort C and 12.8% in cohort S.<br />
Conclusions: Our findings suggest that CRT yields a disease-specific survival<br />
comparable to surgery for clinical stage I ESCC due to successful salvage therapy after<br />
recurrences. A high incidence <strong>of</strong> second primary indicates the need for surveillance<br />
during long-term follow-up.<br />
Legal entity responsible for the study: None<br />
Funding: Aichi Cancer Center Hospital<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
672P<br />
Cardiotoxicity <strong>of</strong> trastuzumab in the patients with HER2<br />
positive advanced gastric cancer<br />
M. Jung 1 , J.S. Park 1 , C-K. Lee 1 , J.H. Kim 1 , H.S. Park 1 , S.J. Heo 1 , S.H. Beom 1 ,H.<br />
S. Kim 1 , S.Y. Rha 1 , H.C. Chung 1 , J-C. Youn 2<br />
1 Internal Medicine, Yonsei Cancer Center, Seoul, Republic <strong>of</strong> Korea, 2 Internal<br />
Medicine, Yonsei University College <strong>of</strong> Medicine Department <strong>of</strong> Internal Medicine,<br />
Seoul, Republic <strong>of</strong> Korea<br />
Background: Trastuzumab induced cardiotoxicy (TIC) is a main adverse event that<br />
limits the using <strong>of</strong> trastuzumab in HER2 positive breast cancer patients. However, the<br />
incidence and risk factors <strong>of</strong> TIC are still not known in HER2 positive gastric cancer.<br />
Therefore, we evaluated the incidence and predictive factors <strong>of</strong> TIC in gastric cancer<br />
patients treated with trastuzumab in clinical practice.<br />
Methods: We retrospectively reviewed the cardiac dysfunction in HER2 positive gastric<br />
cancer between December 2005 and April 2015 through prospectively collected data<br />
base at Yonsei Cancer Center, Republic <strong>of</strong> Korea. TIC was defined as an absolute<br />
decline <strong>of</strong> at least 10 percentage points from the baseline to a value less than 55%<br />
identified by MUGA scan or echocardiogram.<br />
Results: Among 87 patients, 54 patients (62%) received trastuzumab combination<br />
chemotherapy, and 33 patients (38%) did chemotherapy alone as first line<br />
chemotherapy. Symptomatic heart failure was not observed in both groups, and<br />
asymptomatic significant LVEF drop was developed 3 (5.6%) in trastuzumab<br />
combination group and 1 (3.3%) in chemotherapy only group (hazard ratio [HR],<br />
1.810; 95% confidence interval [CI], 0.188-17.43; P = 0.607). Among baseline<br />
characteristics, age older than 70 years (HR, 15.0; 95% CI, 1.18-191.6; P = 0.037) was<br />
the only significant associated factor with TIC.<br />
Conclusions: TIC in gastric cancer patients seems to be not higher than breast cancer<br />
patients. However, asymptomatic LVEF drop should be continued surveillance in<br />
HER2 positive gastric cancer patients treated with trastuzumab, especially in elderly<br />
patients.<br />
Legal entity responsible for the study: Minkyu Jung<br />
Funding: Yonsi University<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
673P<br />
abstracts<br />
The prognostic role and association <strong>of</strong> 18F-FDG PET CT and<br />
HER2 expression in gastric cancer<br />
J.S. Park 1 , N. Lee 2 , J.H. Kim 3 , H.S. Park 3 , S.J. Heo 3 , S.H. Beom 3 , H.S. Kim 3 ,S.<br />
Y. Rha 3 , H.C. Chung 3 , M. Yun 2 , A. Cho 2 , M. Jung 3<br />
1 Cancer Prevention Center, Yonsei Cancer Center, Seoul, Republic <strong>of</strong> Korea,<br />
2 Department <strong>of</strong> Nuclear Medicine, Yonsei Cancer Center, Seoul, Republic <strong>of</strong><br />
Korea, 3 Division <strong>of</strong> Medical <strong>Oncology</strong>, Yonsei Cancer Center, Seoul, Republic <strong>of</strong><br />
Korea<br />
Background: Human epidermal receptor 2 (HER2) status predicts therapy response<br />
with antibody targeted to HER2 in gastric cancer. The objective <strong>of</strong> this study was to<br />
examine the clinical value and relationship <strong>of</strong> pretreatment fluorine-18<br />
fluorodeoxyglucose positron emission tomography computed tomography ( 18 F-FDG<br />
PET/CT) and HER2 status in gastric cancer.<br />
Methods: Retrospective review <strong>of</strong> 141 gastric cancer patients at our institution between<br />
January 2005 and December 2014 who had baseline 18 F-FDG-PET/CT before<br />
chemotherapy. SUV max <strong>of</strong> the primary lesion was recorded, and whole body metastatic<br />
burden was calculated using PET metabolic parameters (SUV max , SUV mean , MTV,<br />
TLG) on all metabolically active metastatic lesions (SUV threshold ≥2.5 or 40%<br />
isocontour for ≤2.5).<br />
Results: Gastric cancers <strong>of</strong> HER2 positivity had higher FDG uptake compared to<br />
HER2 negative <strong>of</strong> diffuse type pathology (SUV max <strong>of</strong> the primary lesion, 9.9 vs. 5.9,<br />
p < 0.001). HER2 positive gastric cancer also had larger metabolically active metastatic<br />
burden compared to HER2 negative gastric cancers (SUV max 12 vs. 7.4, p < 0.001;<br />
SUV mean 4.9 vs. 3.3, p < 0.001; MTV 146.5 vs. 93.6, p = 0.031, and TLG 764.8 vs. 331,<br />
p = 0.002). The high TLG group (>1200) showed significantly shorter PFS and OS<br />
compared to the low TLG group (PFS, 5.3 vs. 6.9 months, p = 0.026; OS, 8.2 vs.14.6,<br />
months, P < 0.001). In multivariate analysis, TLG and MTV were independent<br />
prognostic factors for PFS (TLG, HR = 2.01, 95% CI, 1.27-3.20, p = 0.003; MTV,<br />
HR = 2.13, 95% CI, 1.49-3.61, p < 0.001) and OS (TLG, HR = 2.41, 95% CI, 1.57-3.71,<br />
p < 0.001; MTV, HR = 2.16, 95% CI, 1.42-3.28, p < 0.001).<br />
Conclusions: HER2 positive gastric cancer had higher FDG uptake in the primary<br />
lesion compared to HER2 negative cancers, and had higher metabolically active<br />
metastatic burden. In addition, whole body TLG and MTV may be more useful than<br />
SUV mean and SUV max for predicting survival in gastric cancer.<br />
Legal entity responsible for the study: None<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw371 | vi227
abstracts<br />
674P<br />
Dynamics <strong>of</strong> the HER2 receptor in esophageal<br />
adenocarcinoma: New opportunities for targeted therapy<br />
A. Creemers 1 , E.A. Ebbing 1 , G.K.J. Hooijer 2 , A.R.A. Jibodh-Mulder 1 ,S.<br />
S. Gisbertz 3 , M.G.H. van Oijen 4 , M.I. van Berge Henegouwen 3 , M.F. Bijlsma 5 ,S.<br />
L. Meijer 2 , H.W.M. van Laarhoven 1<br />
1 LEXOR/Medical <strong>Oncology</strong>, Academic Medical Center (AMC), Amsterdam,<br />
Netherlands, 2 Pathology, Academic Medical Center (AMC), Amsterdam,<br />
Netherlands, 3 Surgery, Academic Medical Center (AMC), Amsterdam,<br />
Netherlands, 4 Biostatistics/Medical <strong>Oncology</strong>, Academic Medical Center (AMC),<br />
Amsterdam, Netherlands, 5 LEXOR, Academic Medical Center (AMC), Amsterdam,<br />
Netherlands<br />
Background: Trastuzumab, a monoclonal antibody directed against HER2, has<br />
become standard <strong>of</strong> care for metastatic HER2 overexpressing esophagogastric<br />
adenocarcinoma and is currently investigated as (neo)adjuvant treatment in esophageal<br />
adenocarcinoma (EAC). In clinical practice HER2 overexpression is usually determined<br />
on archived tumor material, from primary tumor biopsies or resection specimens.<br />
However, HER2 overexpression may change in the course <strong>of</strong> treatment or disease<br />
progression. The aim <strong>of</strong> this study was to assess the dynamics and clinical implications<br />
<strong>of</strong> HER2 expression in both curative and palliative setting.<br />
Methods: Matched biopsies and resection specimens <strong>of</strong> 108 EAC patients treated with<br />
neoadjuvant chemoradiation, and 68 EAC resection specimens and matched biopsies<br />
<strong>of</strong> metachronous distant metastases were collected. All samples and specimens were<br />
simultaneously stained for HER2 on an automated immunostainer using the<br />
anti-HER-2/c-erB-2/neu (clone SP3) antibody. Discordance, either up- or<br />
downregulated HER2 expression between biopsy and resection specimen or resection<br />
specimen and metastases, was determined using the standardized HER2 expression<br />
scoring system by H<strong>of</strong>mann et al. (H<strong>of</strong>mann, Stoss et al. 2008).<br />
Results: HER2 overexpression (immunohistochemistry scores 2+ and 3+) was detected<br />
in 14.8% <strong>of</strong> the pre-treatment biopsies and 14.2% <strong>of</strong> the neoadjuvantly treated<br />
resection specimens. A significant discordance between biopsy and resection specimen<br />
(p < 0.05), was observed. Discordance was detected in 3.1% <strong>of</strong> the metastatic cases,<br />
HER2 overexpression was identified in 9.2% and 7.8% <strong>of</strong> the resection specimen and<br />
metachronous distant metastases, respectively.<br />
Conclusions: HER2 overexpression is observed in 14% <strong>of</strong> the primary EAC biopsies,<br />
with significant dynamics in HER2 expression between pre-treatment biopsy and<br />
neoadjuvantly treated resection specimen. Remarkably, only 3% discordance was<br />
observed between resection specimen and metachronous distant metastases. Therefore,<br />
the assessment <strong>of</strong> HER2 expression in the metastatic setting should preferably be<br />
performed on the most recent acquired material, but HER2 determination on resection<br />
material may also be valid.<br />
Legal entity responsible for the study: AMC<br />
Funding: AMC<br />
Disclosure: H.W.M. van Laarhoven: Consultant: Nordic, Lilly. Research funding:<br />
Bayer, Cell Gene, MSD, Roche, Nordic, Lilly, Janssen- Cilag, GSK. All other authors<br />
have declared no conflicts <strong>of</strong> interest.<br />
675P<br />
CPI-613 enhances FOLFIRINOX response rate in stage IV<br />
pancreatic cancer<br />
A.T. Alistar 1 , R. Desnoyers 1 , R.J. D’Agostino 2 , B. Pasche 1<br />
1 Hematology <strong>Oncology</strong>, Wake Forest University Comprehensive Cancer Center,<br />
Winston Salem, NC, USA, 2 Biostatistical Sciences, Wake Forest University<br />
Comprehensive Cancer Center, Winston Salem, NC, USA<br />
Background: Pancreatic cancer has a current five-year survival rates <strong>of</strong> less than 10%.<br />
Current standard treatment is combination chemotherapy with FOLFIRINOX or<br />
Gemcitabine + Abraxane. The glycolic and mitochondrial metabolism is aberrant in<br />
pancreatic cancer and translates into chemo-resistance. Inhibition <strong>of</strong> glutamine<br />
metabolism can potentially synergize with therapies that increase intracellular reactive<br />
oxygen species such as chemotherapy. The lipoate derivative CPI-613 is a first-in-class<br />
agent that targets mitochondrial metabolism. Whether this novel anti-cancer agent<br />
could enhance the efficacy <strong>of</strong> FOLFIRINOX is unknown.<br />
Methods: This phase 1 study employed a two-stage dose-escalation schema to<br />
determine the maximum-tolerated dose (MTD) and safety <strong>of</strong> CPI-613 when used in<br />
combination with modified FOLFIRINOX in patients with metastatic pancreatic<br />
adenocarcinoma. Efficacy was assessed through response rates and estimates <strong>of</strong><br />
progression-free (PFS) and overall survival (OS).<br />
Results: The maximum-tolerated dose (MTD) was 1000 mg/m 2 . The treatment was<br />
well tolerated, establishing that a reduced dose FOLFIRINOX combination with<br />
CPI-613 is feasible. Among the 18 patients enrolled at the MTD, there were 3 (16.6%)<br />
patients with a complete response (CR), 9 with a partial response (PR), 2 with stable<br />
disease and 4 with progressive disease. The PR + CR rate was 67% with a 95%<br />
Clopper-Pearson (exact) confidence interval <strong>of</strong> 41% to 87%. As follow-up is ongoing,<br />
estimates <strong>of</strong> PFS and OS are still immature, with current median PFS estimated as at<br />
least 186 days and median OS estimated as at least 268 days to date.<br />
Conclusions: CPI-613 is a first in class non redox active lipoate derivative being tested<br />
in phase I clinical trial in combination with FOLFIRINOX. The response rate was 67%,<br />
which is more than twice higher than FOLFIRINOX (32%). The CR rate is also higher<br />
than FOLFIRINOX. This novel combination therapy may emerge as the most effective<br />
treatment for patients with stage IV adenocarcinoma <strong>of</strong> the pancreas as response rate is<br />
commonly associated with PFS and OS. Whole Exome sequencing <strong>of</strong> tumors from<br />
exceptional responders and non-responders is underway. A randomized phase 2-3<br />
study <strong>of</strong> FOLFIRINOX vs. m FOLFIRINOX+ CPI613 is scheduled to be initiated in late<br />
2016.<br />
Clinical trial identification: NCT01835041<br />
Legal entity responsible for the study: Wake Forest University<br />
Funding: Cornerstone pharmaceutical<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
676P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Intensified chemotherapy for metastatic pancreatic cancer:<br />
interim analysis <strong>of</strong> a large retrospective pan-European<br />
database and real life evaluation<br />
S. Krug 1 ,G.Beyer 2 , M.A. Javed 3 ,N.Le 4 , A. Vinci 5 , R.D. Morgan 6 , R. Hubner 6 ,J.<br />
W. Valle 7 , H. Wong 8 , S. Chowdhury 9 , Y. Ting Ma 9 , D. Palmer 10 , P. Maisonneuve 11 ,<br />
A. Neesse 12 , M. Sund 13 , M. Schober 1<br />
1 Department <strong>of</strong> Internal Medicine I, Martin Luther University <strong>of</strong> Halle, Halle,<br />
Germany, 2 Department <strong>of</strong> Medicine A, University Medicine Greifswald, Greifswald,<br />
Germany, 3 NIHR Liverpool Pancreas Biomedical Research Unit, Institute <strong>of</strong><br />
Translational Medicine, Royal Liverpool University Hospital, Liverpool, UK,<br />
4 Gastroenterology Division, Semmelweis University, 2nd Dept. <strong>of</strong> Internal<br />
Medicine, Budapest, Hungary, 5 Department <strong>of</strong> Surgery, University <strong>of</strong> Pavia,<br />
Matteo University Hospital Foundation, Pavia, Italy, 6 Department <strong>of</strong> Medical<br />
<strong>Oncology</strong>, The Christie NHS Foundation Trust, Manchester, UK, 7 Department <strong>of</strong><br />
Medical <strong>Oncology</strong>, ENETS Centre <strong>of</strong> Excellence; Manchester Academic Health<br />
Sciences Centre, Institute <strong>of</strong> Cancer Sciences, University <strong>of</strong> Manchester, The<br />
Christie NHS Foundation Trust, Manchester, UK, 8 Department <strong>of</strong> Quality and<br />
Information Intelligence, Clatterbridge Cancer Center, Wirral, UK, 9 Department <strong>of</strong><br />
Hepatobiliary <strong>Oncology</strong>, Queen Elizabeth-University Hospital Birmingham NHS<br />
Foundation Trust, Birmingham, UK, 10 Molecular and Clinical Cancer Medicine,<br />
University <strong>of</strong> Liverpool, Liverpool, UK, 11 Division <strong>of</strong> Epidemiology and Biostatistics,<br />
European Institute <strong>of</strong> <strong>Oncology</strong>, Milan, Italy, 12 Department <strong>of</strong> Gastroenterology and<br />
Gastrointestinal <strong>Oncology</strong>, University Medical Center Göttingen, Göttingen,<br />
Germany, 13 Department <strong>of</strong> Surgical and Perioperative Sciences, Umea University,<br />
Umea, Sweden<br />
Background: For a long time gemcitabine (gem) has been the standard <strong>of</strong> care for<br />
patients with pancreatic ductal adenocarcinoma (PDAC). Recently, FOLFIRINOX and<br />
nab-paclitaxel/gemcitabine (nab-P/gem) were introduced showing significantly<br />
improved survival in clinical trials. This study aims to investigate the efficacy and<br />
tolerability <strong>of</strong> FOLFIRINOX and nab-P/gem versus gem monotherapy in real-life<br />
settings across different European institutions and to analyze the decision-making<br />
process among physicians administering these drugs.<br />
Methods: 634 patients from 8 centers with PDAC receiving palliative chemotherapy<br />
between 2012 and 2015 were included in a retrospective multinational study design. In<br />
an independent survey, a web-based questionnaire containing 15 questions regarding<br />
the use <strong>of</strong> different chemotherapy options in metastatic PDAC was distributed among<br />
5420 doctors in 19 European countries.<br />
Results: Of the 634 included patients, 351 (55%) were male and 97 (15%) had been<br />
surgically resected before systemic recurrence. Gem treatment<br />
(monotherapy + /-capecitabine/cisplatin) was the regimen most commonly used in<br />
European centers (74%) as compared to FOLFIRINOX (9%) and nab-P/gem (3%). The<br />
median overall survival in different groups were: FOLFIRINOX 12.0m (95%<br />
CI8.5-15.5), nab-P/gem 7.0m (95%CI4.7-9.3) and gem monotherapy 5.0m (95%<br />
CI4.4-5.6). Only FOLFIRINOX was associated with improved survival as compared to<br />
gem monotherapy (p < 0.001). The additional international survey led to 153 valid<br />
responses. As first-line therapy, 47% used nab-P/gem, 42% used FOLFIRINOX and<br />
11% used gem. Dose reductions were more common for FOLFIRINOX likely due to<br />
higher toxicity. FOLFIRINOX was rated over nab-P/gem in achieving longer survival<br />
with acceptable quality <strong>of</strong> life (52%vs44%).<br />
Conclusions: Our retrospective cohort showed that gem therapy was still<br />
predominantly used. However, the pan-European questionnaire revealed a more<br />
frequent use <strong>of</strong> intensified regimens indicating an increasing acceptance among<br />
European physicians in 2015. Intensified regimens are widely available throughout<br />
Europe, but used variably in clinical routine dependent on hospital setting and<br />
country.<br />
Legal entity responsible for the study: N/A<br />
Funding: Pancreas2000, an educational and research program for tomorrows<br />
pancreatologists in Europe.<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
vi228 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
677P<br />
Phase 1b study <strong>of</strong> WNT inhibitor vantictumab (VAN, human<br />
monoclonal antibody) with nab-paclitaxel (Nab-P) and<br />
gemcitabine (G) in patients (pts) with previously untreated<br />
stage IV pancreatic cancer (PC)<br />
W. Messersmith 1 , S. Cohen 2 , S. Shahda 3 , H-J. Lenz 4 , C. Weekes 5 , E. Dotan 2 ,<br />
C. Denlinger 2 ,B.O’Neil 3 , A. Kapoun 6 , C. Zhang 6 , R. Henner 6 , F. Cattaruzza 6 ,<br />
L. Xu 6 , J. Dupont 6 , R. Brachmann 6 , S. Uttamsingh 6 , A. Farooki 7 , J. Berlin 8<br />
1 Medicine/Medical <strong>Oncology</strong>, University <strong>of</strong> Colorado Cancer Center<br />
Anschutz Cancer Pavilion, Aurora, CO, USA, 2 Medicine/Medical <strong>Oncology</strong>,<br />
Fox Chase Cancer Center, Philadelphia, PA, USA, 3 <strong>Oncology</strong>, Indiana<br />
University Simon Cancer Center, Indianapolis, IN, USA, 4 Department <strong>of</strong><br />
Medical <strong>Oncology</strong>, University <strong>of</strong> Southern California Norris Comprehensive<br />
Cancer Center, Los Angeles, CA, USA, 5 Department <strong>of</strong> Medicine, University <strong>of</strong><br />
Colorado Cancer Center Anschutz Cancer Pavilion, Aurora, CO, USA, 6 Clinical<br />
Research, OncoMed Pharmaceuticals, Redwood, CA, USA, 7 Medicine/Medical<br />
<strong>Oncology</strong>, Memorial Sloan-Kettering Cancer Center, New York, NY, USA,<br />
8 Department <strong>of</strong> Medical <strong>Oncology</strong>, Vanderbilt Ingram Cancer Center, Nashville,<br />
TN, USA<br />
Background: VAN is a first-in-class antibody that blocks WNT signaling by interacting<br />
with 5 Frizzled receptors (1, 2, 5, 7, 8). VAN, with Nab-P and G, was very effective in<br />
causing tumor regression in pt-derived PC xenografts. A biomarker signature was<br />
developed in these models. In Phase (P) 1a, VAN was tolerated well except for fragility<br />
fractures. Thus, serum markers <strong>of</strong> bone turnover and bone density were monitored<br />
with triggers for zoledronic acid (ZA). Target modulation was seen in tumor tissues at<br />
VAN ≥0.5 mg/kg every 2 weeks (q2w).<br />
Methods: Dose escalation began with intravenous VAN q2w with a standard 3 + 3<br />
design and was then pursued for q4w with 6-pt cohorts (with baseline ZA, if indicated,<br />
increased monitoring and more sensitive ZA triggers). Nab-P at 125 mg/m 2 and G at<br />
1000 mg/m 2 were given on Days 1, 8 and 15 <strong>of</strong> 28-day cycles. Objectives were<br />
determination <strong>of</strong> safety, maximum tolerated dose, recommended P2 dose,<br />
pharmacokinetics (PK), immunogenicity, pharmacodynamics, predictive biomarkers<br />
and efficacy.<br />
Results: 19 pts have been treated to date, the 1 st 8 pts in 2 q2w cohorts (3.5 & 7 mg/kg).<br />
After 2 Grade (G) 2 fragility fractures, 11 pts were treated with a revised safety plan in 2<br />
q4w cohorts (3 & 5 mg/kg) without further fragility fractures. With a PK half-life <strong>of</strong> 4<br />
days (unchanged by chemotherapy), q4w dosing allowed drug washout that correlated<br />
with less fracture risk. ZA at baseline or on-study was triggered for 9 <strong>of</strong> 11 (82%) pts.<br />
VAN-related adverse events (AEs) ≥10% were nausea, fatigue, dysgeusia, rash and<br />
constipation. Only related G ≥ 3 AEs were fatigue (1) and nausea (1), both G3. No dose<br />
limiting toxicities were observed. Of 15 evaluable pts, 8 (53%) had a partial response<br />
and 4 (27%) stable disease. Median progression free survival (PFS) was 7.2 months,<br />
95% CI [1.8, 9.2] (9/19 with PFS events).<br />
Conclusions: VAN can be safely administered at relevant doses in combination with<br />
Nab-P and G in pts with stage IV PC. A revised safety plan appears to have addressed<br />
bone toxicity encountered early in the study. Updated results, including predictive<br />
biomarker analyses in pt tumors, with PFS and overall survival, will be presented.<br />
Clinical trial identification: NCT02005315<br />
Legal entity responsible for the study: OncoMed<br />
Funding: OncoMed<br />
Disclosure: W. Messersmith, C. Weekes: This clinical trial was sponsored by<br />
OncoMed, which had a contract with the University <strong>of</strong> Colorado. I am named in the<br />
contract, so I am disclosing it as "research support" even though funding went to the<br />
University <strong>of</strong> Colorado. S. Cohen: Fox-Chase Cancer Ctr received funding for this<br />
study. Dr. Cohen has done an Ad Board for Bayer. S. Shahda, B. O’Neil: The University<br />
<strong>of</strong> Indiana received funding for this trial from OncoMed. H-J. Lenz: Advisory board<br />
and lectures for Bayer, which has partnered with OncoMed for this agent. E. Dotan:<br />
Fox-Chase Cancer Ctr received funding from OncoMed to perform this trial.<br />
C. Denlinger: Fox-Chase Cancer Ctr received funding for this study. Dr. Denlinger has<br />
done an Ad Board for Bayer. A. Kapoun, C. Zhang, F. Cattaruzza, L. Xu, J. Dupont,<br />
R. Brachmann, S. Uttamsingh: employee <strong>of</strong> OncoMed and owns OncoMed<br />
stock. R. Henner: employee <strong>of</strong> OncoMed, owns stock. A. Farooki: research support and<br />
consultant, OncoMed. J. Berlin: This clinical trial was sponsored by OncoMed, which<br />
had a contract with the Vanderbilt. I am named in the contract. The same applies to<br />
Bayer (research funding for clinical trials).<br />
678P<br />
abstracts<br />
Observational study <strong>of</strong> FOLFIRINOX (FFX) for unresectable/<br />
recurrent pancreatic cancer (PC) in Japanese patients (pts)<br />
(JASPAC 06): final results<br />
N. Mizuno 1 , A. Todaka 2 , K. Mori 3 , N. Boku 4 , M. Ozaka 5 , H. Ueno 6 , S. Kobayashi 7 ,<br />
K. Uesugi 8 , N. Kobayashi 9 , H. Hayashi 10 , K. Sudo 11 , N. Okano 12 , Y. Horita 13 ,<br />
K. Kamei 14 , S. Yukisawa 15 , S. Nakamori 16 ,Y.Yachi 17 , T. Henmi 18 , M. Kobayashi 19 ,<br />
A. Fukutomi 2<br />
1 Department <strong>of</strong> Gastroenterology, Aichi Cancer Center Hospital, Nagoya, Japan,<br />
2 Division <strong>of</strong> Gastrointestinal <strong>Oncology</strong>, Shizuoka Cancer Center, Shizuoka, Japan,<br />
3 Clinical Research Promotion Unit, Clinical Research Center, Shizuoka Cancer<br />
Center, Shizuoka, Japan, 4 Division <strong>of</strong> Gastrointestinal Medical <strong>Oncology</strong> Division,<br />
National Cancer Center Hospital, Tokyo, Japan, 5 Department <strong>of</strong> Gastroenterology,<br />
Cancer Institute Hospital <strong>of</strong> JFCR, Tokyo, Japan, 6 Hepatobiliary and Pancreatic<br />
<strong>Oncology</strong> Division, National Cancer Center Hospital, Tokyo, Japan, 7 Division <strong>of</strong><br />
Hepatobiliary and Pancreatic Medical <strong>Oncology</strong>, Kanagawa Cancer Center,<br />
Yokohama, Japan, 8 Departments <strong>of</strong> Gastroenterology, Shikoku Cancer Center,<br />
Matsuyama, Japan, 9 Department <strong>of</strong> <strong>Oncology</strong>, Yokohama City University Hospital,<br />
Yokohama, Japan, 10 Department <strong>of</strong> Gastroenterology and Hepatology, Hokkaido<br />
University Hospital, Sapporo, Japan, 11 Division <strong>of</strong> Gastroenterology, Chiba Cancer<br />
Center, Chiba, Japan, 12 Department <strong>of</strong> Medical <strong>Oncology</strong>, Kyorin University<br />
School <strong>of</strong> Medicine, Mitaka, Japan, 13 Department <strong>of</strong> Medical <strong>Oncology</strong>, Toyama<br />
Prefectural Central Hospital, Toyama, Japan, 14 Department <strong>of</strong> Surgery, Kindai<br />
University Faculty <strong>of</strong> Medicine, Osaka-sayama, Japan, 15 Department <strong>of</strong> Medical<br />
<strong>Oncology</strong>, Tochigi Cancer Center, Utsunomiya, Japan, 16 Department <strong>of</strong><br />
Hepato-Biliary-Pancreatic Surgery, National Hospital Organization Osaka National<br />
Hospital, Osaka, Japan, 17 Pharmacovigilance Department, Daiichi Sankyo Co.,<br />
Ltd., Tokyo, Japan, 18 Post-Marketing Surveilance Pharmacovigilance Department,<br />
Yakult Honsha Co.,Ltd., Tokyo, Japan, 19 Clinical Trial Promotion Section, Public<br />
Interest Incorporated Foundation-Shizuoka Industrial Foundation- Pharma Valley<br />
Center, Shizuoka, Japan<br />
Background: For Japanese pts, there are limited data <strong>of</strong> a small phase II trial <strong>of</strong> FFX<br />
(Okusaka, Cancer Sci 2014). In this multi-center retrospective study, we previously<br />
reported the preliminary results focusing on adverse events (AEs) <strong>of</strong> FFX (Ozaka, 2016<br />
Gastrointestinal Cancers Symposium). In this presentation, we report updated results<br />
including efficacy.<br />
Methods: The subjects were unresectable/recurrent PC pts who received FFX in<br />
practice during one year from 20 December 2013 and were followed until December<br />
2015.<br />
Results: Totally, 400 pts were registered from 27 institutions in Japan. One pt was<br />
excluded from the analysis because <strong>of</strong> no administration <strong>of</strong> CPT-11. Pts characteristics<br />
were: median age 63 years; ECOG-PS 0/1/2 70/29/1%; disease status recurrent (rec)/<br />
locally advanced (LA)/metastatic (met) 20/20/60%; prior chemotherapy yes/no 37/<br />
63%; biliary stent before FFX 23%; UGT1A1 polymorphism *28 and *6 wild /single<br />
heterozygous/homozygous or double heterozygous 55/38/4%. 273 pts (68%) met the<br />
inclusion criteria <strong>of</strong> the Japanese phase II trial (ECOG-PS 6 M, adequate organ<br />
function). Median number <strong>of</strong> treatment cycles was 6. The relative dose intensities <strong>of</strong><br />
L-OHP, CPT-11, bolus 5-FU and infusional 5-FU were 73%, 66%, 7%, 80%. The main<br />
grade 3/4 AEs were neutropenia (64%), leucopenia (31%), anorexia (14%), febrile<br />
neutropenia (13%). There were 5 treatment-related deaths. Multivariate analysis<br />
showed that female (Odds ratio (OR) 1.67; 95% CI, 1.07–2.61), ECOG-PS (OR 1.65;<br />
1.06-2.57) and serum albumin level (OR 1.64; 1.08–2.49) were significant predictive<br />
factors <strong>of</strong> grade 3/4 AEs. Median overall (OS) and progression-free survivals (PFS)<br />
were 327 (95% CI, 294–360) and 140 (95% CI, 122–158) days. The overall response and<br />
disease control rates were 20% and 62%. Limited to the first-line chemotherapy,<br />
median OS and PFS by disease status (rec/LA/met) were 150/563/336 and 100/230/147<br />
days.<br />
Conclusions: Practical use <strong>of</strong> FFX for Japanese pts with unresectable/recurrent PC<br />
showed acceptable toxicities and compatible efficacy to the previous clinical trials.<br />
Clinical trial identification: UMIN000014658 26 July 2014<br />
Legal entity responsible for the study: N/A<br />
Funding: Yakult Honsha Co.,Ltd., and Daiichi Sankyo Co.,Ltd.<br />
Disclosure: N. Mizuno: Research funding: Taiho Pharmaceutical Co. Ltd., Merck<br />
Serono, AstraZeneca, Zeria Pharmaceutical, NanoCarrier, Eisai, MSD. Honoraria:<br />
Taiho Pharmaceutical Co. Ltd., Elli Lilly Japan K.K., Yakult Honsha Novartis, Pfizer,<br />
Kyowa-Hakko Kirin. N. Boku: Honorarium fron Yakult. H. Ueno: Honoraria: Taiho<br />
Pharmaceutical, Yakult Honsha, Chugai Pharmaceutical. Research Funding: Taiho<br />
Pharmaceutical, OncoTherapy Science, Eli Lilly Japan, Merck Serono Japan, Zeria<br />
Pharmaceutical, NanoCarrier. S. Kobayashi: Yakult Honsha: Honoraria: S. Nakamori:<br />
Eizai. Y. Yachi: Employee <strong>of</strong> Daiichi Sankyo CO., LTD. T. Henmi: Employee <strong>of</strong> Yakult<br />
Honsha Co.,Ltd. A. Fukutomi: Honoraria: Yakult Honsha Co.,Ltd, Daiichi Sankyo CO.,<br />
LTD. All other authors have declared no conflicts <strong>of</strong> interest.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw371 | vi229
abstracts<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
679P<br />
Gabrinox: A phase I-II <strong>of</strong> nab-paclitaxel plus gemcitabine<br />
followed by folfirinox in metastatic pancreatic<br />
adenocarcinoma<br />
680P<br />
Chemotherapy for patients with non-resectable pancreatic<br />
cancer with additional chemo-radiotherapy for patients with<br />
potentially resectable tumours: Final results<br />
E. Assenat 1 , C. de la Fouchardiere 2 , C. Mollevi 3 , E. Samalin 1 , F. Portales 1 ,<br />
F. Desseigne 2 , C. Carenco 1 , M. Dupuy 4 , E. Lopez-Martinez 5 , C. Fiess 6 ,<br />
T. Mazard 1 , M. Ychou 1<br />
1 Digestive <strong>Oncology</strong>, ICM Regional Cancer Institute <strong>of</strong> Montpellier, Montpellier,<br />
France, 2 Digestive <strong>Oncology</strong>, Centre Léon Bérard, Lyon, France, 3 Biometrics Unit,<br />
ICM Regional Cancer Institute <strong>of</strong> Montpellier, Montpellier, France, 4 Medical<br />
<strong>Oncology</strong>, Hopital Saint-Eloi (Montpellier), Montpellier, France, 5 Medical <strong>Oncology</strong>,<br />
ICM Regional Cancer Institute <strong>of</strong> Montpellier, Montpellier, France, 6 Clinical<br />
Research, ICM Regional Cancer Institute <strong>of</strong> Montpellier, Montpellier, France<br />
Background: Folfirinox (FFX) and Nab-paclitaxel/Gemcitabine (AG) showed<br />
significant improvement in efficacy compared to Gemcitabine alone in metastatic<br />
pancreatic cancer (mPC). Alternating AG and FFX may overcome resistance to<br />
primary therapy and delay tumor progression. We designed a multicenter phase I-II<br />
trial with a new sequential regimen <strong>of</strong> AG followed by FFX in first-line treatment <strong>of</strong><br />
mPC. The phase I primary objective was to determine the recommended AG and FFX<br />
doses. Primary endpoint was to determine the dose-limiting toxicities (DLTs). The<br />
phase II will assess the efficacy <strong>of</strong> the recommended doses.<br />
Methods: AG and FFX were administered sequentially, each AG cycle followed by a<br />
FFX cycle. Dose-escalation was:<br />
One cycle<br />
D1 = D57<br />
AG (mg/m 2 ) D1, D8, D15<br />
Table: 679P<br />
FFX (mg/m 2 ) D29, D43<br />
Dose level Nab-paclitaxel Gemcitabine Oxaliplatin Irinotecan LV 5-FU<br />
1 100 800 70 150<br />
2a 100 800 85 180 Leucovorin:<br />
200<br />
2b 125 1000 70 150 5-FU bolus:<br />
400<br />
3 125 1000 85 180 5-FU infusion:<br />
2400<br />
Chemotherapeutic agents were administered according to standard practice, except for<br />
Gemcitabine (10mg/m 2 /min).<br />
Results: From September 2013 to October 2015, 33 mPC patients were included: 7, 6<br />
and 7 patients in levels 1, 2a and 2b, respectively, and 13 in level 3. 31 patients were<br />
evaluable for tolerance (2 not evaluable at levels 1 and 2b). Patients’ characteristics at<br />
baseline were: male 54.8%, median age 61 years (42-75), ECOG PS 0 (35.5%) or 1<br />
(64.5%). Five DLTs were reported: 1, 2 and 2 in levels 2a, 2b and 3, respectively. All<br />
DLTs were grade 4 transient, asymptomatic neutropenia with spontaneous resolution.<br />
They occurred at treatment initiation, probably due to the absence <strong>of</strong> prophylactic<br />
GCSF treatment during AG administration. There was no limiting neurotoxicity.<br />
Promising efficacy results (response and survival) will be presented at the meeting.<br />
Conclusions: This new regimen alternating AG and FFX shows acceptable toxicity and<br />
promising efficacy results. The recommended dose (level 3) is being confirmed in a 12<br />
patient-expansion cohort before starting the phase II accrual.<br />
Clinical trial identification: NCT01964287<br />
Legal entity responsible for the study: Institut régional du Cancer de Montpellier<br />
(ICM), France<br />
Funding: This project was supported by Celgene.<br />
Disclosure: E. Assenat: Honoraria: Ipsen, Novartis, San<strong>of</strong>i Consulting. Advisory Role:<br />
Ipsen. Research Funding: Bayer (Institution), Celgene (Institution). Travel,<br />
Accomodations, Expenses: Novartis, Celgene.C. de la Fouchardiere: Consulting or<br />
Advisory Role: Bayer, Celgene Research. Funding: Roche/Genentech (Institution).<br />
Travel, Accomodations, Expenses: Ipsen, Bayer, Roche. E. Samalin: Honoraria: Lilly,<br />
San<strong>of</strong>i, Amgen, Roche. Consulting or Advisory Role: Amgen, San<strong>of</strong>i, Roche. Research<br />
funding: Bayer (institution). Travel, Accommodations, Expenses: Novartis, Lilly, Ipsen,<br />
Roche. F. Portales: Honoraria: San<strong>of</strong>i Consulting or Advisory Role: San<strong>of</strong>i. Research<br />
funding: Celgene (Institution). Travel, Accommodations, Expenses: Ipsen. T. Mazard:<br />
Honoraria: Amgen, San<strong>of</strong>i. Research funding: Roche, Parma AG (Institution). Travel,<br />
Accomodations, Expenses: Amgen. M. Ychou: Honoraria: Bayer, Merck-Serono,<br />
Roche/Genentech, Celgene. Consulting or Advisory Role: Bayer, Celgene, Roche. All<br />
other authors have declared no conflicts <strong>of</strong> interest.<br />
P. Pfeiffer 1 , M. Ladekarl 2 , M.B. Mortensen 3 , A-L. Fromm 4 , J.K. Bjerregaard 1<br />
1 Department <strong>of</strong> <strong>Oncology</strong>, Odense University Hospital, Odense, Denmark,<br />
2 Department <strong>of</strong> <strong>Oncology</strong>, Aarhus University Hospital, Aarhus, Denmark,<br />
3 Department <strong>of</strong> Surgery, Odense University Hospital, Odense, Denmark,<br />
4 Department <strong>of</strong> <strong>Oncology</strong>, University Hospital Herlev, Herlev, Denmark<br />
Background: Locally advanced pancreatic cancer (LAPC) is <strong>of</strong>ten a mix <strong>of</strong> borderline<br />
and never-resectable tumors. Multimodality treatment might downstage these tumors<br />
to allow a potential radical resection, especially the borderline group. In this ongoing<br />
phase II study we examined the feasibility <strong>of</strong> FOLFIRINOX with or without CRT<br />
followed by surgery for both borderline and never-resectable tumors (NCT-01397019).<br />
Methods: Patients in performance status 0-1, with initially non-resectable stage II/III<br />
pancreatic cancer were <strong>of</strong>fered FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180<br />
mg/m 2 , leucovorin 400 mg/m 2 , 5FU 400 mg/m 2 + 2400 mg/m 2 ) every 14 days. Every 4 th<br />
series the patients were evaluated and <strong>of</strong>fered CRT (50.4 Gy/27F & capecitabine) if<br />
deemed potentially resectable. Resections were performed if deemed possible by the<br />
MDT.<br />
Results: Between August 2012 and present, 59 patients have been recruited with a<br />
median observation time <strong>of</strong> 17.4 months. Median age was 65(range 38-75) years, with<br />
40%/60% stage II/III distribution. Median CA19-9 was 268(range 1-13,432).<br />
Three-hundred-sixty-two courses <strong>of</strong> FOLFIRINOX have been given, with a median <strong>of</strong><br />
6.0 per patient, with a median <strong>of</strong> 2 without dose modifications. Presently twenty-two<br />
patients have been treated with CRT. Six-teen patients have been resected, <strong>of</strong> which 8<br />
received prior CRT. Median survival for all patients was 21.1 months (14-NR) with a<br />
1-year survival <strong>of</strong> 74% (58-85). For patients not resected the median survival was 14.1<br />
months (10-16) for resected the median survival has not yet been reached. The<br />
FOLFIRINOX was associated with adverse events similar to what is expected in<br />
metastatic patients.<br />
Conclusions: FOLFIRINOX with or without CRT in patients with LAPC shows<br />
promising efficacy in patients with both borderline and never-resectable tumors.<br />
Unmodified FOLFIRINOX had acceptable toxicity, however dose reductions are <strong>of</strong>ten<br />
needed. CRT following initial FOLFIRINOX was feasible and without unexpected<br />
toxicity.<br />
Clinical trial identification: NCT-01397019<br />
Legal entity responsible for the study: N/A<br />
Funding: Danish Pancreatic Cancer Group<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
681P<br />
Randomized phase 2 trial <strong>of</strong> nab-paclitaxel plus<br />
gemcitabine, ± capecitabine, cisplatin (PAXG regimen) in<br />
unresectable or borderline resectable pancreatic<br />
adenocarcinoma<br />
M. Reni 1 , S. Zanon 1 , G. Balzano 2 , P. Passoni 3 , A. Costantino 1 , C. Pircher 1 ,<br />
M. Chiaravalli 1 , R. Nicoletti 4 , P.G. Arcidiacono 5 , G. Pepe 6 , S. Crippa 2 , C. Doglioni 7 ,<br />
C. Fugazza 1 , D. Ceraulo 1 , M. Falconi 2 , L. Gianni 1<br />
1 Medical <strong>Oncology</strong>, IRCCS San Raffaele, Milan, Italy, 2 Surgery, IRCCS San<br />
Raffaele, Milan, Italy, 3 Radiotherapy, IRCCS San Raffaele, Milan, Italy, 4 Radiology,<br />
IRCCS San Raffaele, Milan, Italy, 5 Gastroenterology, IRCCS San Raffaele, Milan,<br />
Italy, 6 Nuclear Medicine, IRCCS San Raffaele, Milan, Italy, 7 Pathology, IRCCS San<br />
Raffaele, Milan, Italy<br />
Background: A phase 1b trial defined the recommended phase 2 dose <strong>of</strong> nab-paclitaxel<br />
(150 mg/m 2 ) in combination with cisplatin, capecitabine, and gemcitabine (800, 30,<br />
and 1250 mg/m 2 every 2 weeks, respectively; PAXG regimen). A randomized phase 2<br />
trial <strong>of</strong> PAXG or nab-paclitaxel-gemcitabine (AG) was performed (NCT01730222).<br />
Methods: Chemo-naive patients with 18-75 years, pathologic diagnosis <strong>of</strong> unresectable<br />
or borderline resectable pancreatic adenocarcinoma (NCCN definition), Karn<strong>of</strong>sky<br />
Performance Status ≥ 70 were eligible for the study. The primary endpoint was<br />
resectability rate. According to A’ Hern design (p0 = 5%; p1 = 20%; α = 0.05;<br />
power = 80%), the total number <strong>of</strong> patients to enrol in each arm was 27. With ≥ 4<strong>of</strong>27<br />
eligible patients resected, each regimen will be considered active.<br />
Results: Between Apr 2014 and Feb 2016, 54 patients (table 1) were randomized at a<br />
single Institution to receive PAXG (arm A; N = 26) or AG (arm B; N = 28). Resection<br />
after 4-6 cycles <strong>of</strong> chemotherapy was performed only in initially borderline resectable<br />
patients (5 arm A; 5 R0; 4 N0; 5 arm B; 5 R0; 1 N0). One arm A and 2 arm B patients<br />
were deemed resectable and are waiting for surgery. Treatment is ongoing in 4 patients.<br />
Main grade 3/4 toxicity was (A/B): neutropenia 76/57%; thrombocytopenia 5/9%;<br />
fatigue 10/26%; neuropathy 0/22%; diarrhea 5/13%; nausea 5/13%; serious adverse<br />
events 22/29%. A partial response was observed in (A/B) 50/32% and stable disease in<br />
50/61% patients. CA19-9 decreased by > 49% in 95/86%; >89% in 36/19% patients with<br />
elevated basal value. Progression was observed in 7 arm A and 17 arm B patients:<br />
PFS-6 (A/B) was 100%/61%.<br />
vi230 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
Table: 681P<br />
Baseline Characteristic PAXG AG<br />
Number 26 28<br />
Male/female 13/13 lug-21<br />
KPS 90-100 19 (73%) 24 (86%)<br />
70-80 7 (27%) 4 (14%)<br />
Age median 60 66<br />
range 35-75 50-75<br />
Unresectable 16 (62%) 13 (46%)<br />
Borderline 10 (38%) 15 (54%)<br />
Head 18 (69%) 20 (71%)<br />
Biliary stent 14 15<br />
CA19.9 >ULN 22 (85%) 21 (75%)<br />
median 290 278<br />
Conclusions: Both AG and PAXG regimens reached the primary endpoint.<br />
Preliminary results suggest that the addition <strong>of</strong> cisplatin and capecitabine to AG<br />
backbone is feasible and seems to improve disease control. The PAXG regimen warrant<br />
further exploration in this setting <strong>of</strong> patients.<br />
Clinical trial identification: ClinicalTrials.gov NCT01730222<br />
Legal entity responsible for the study: IRCCS San Raffaele, Milan, Italy<br />
Funding: Celgene<br />
Disclosure: M. Reni: Advisory role: Celgene, Boehringer Ingelheim, Genentech, Lilly,<br />
Merck Serono, Baxalta, Pfizer, Novocure, Halozyme. All other authors have declared<br />
no conflicts <strong>of</strong> interest.<br />
682P<br />
Nab-paclitaxel in substitution <strong>of</strong> oxaliplatin and irinotecan in<br />
folfirinox schedule as first-line therapy in patients with<br />
metastatic pancreatic cancer: results <strong>of</strong> phase I dose finding<br />
<strong>of</strong> NabucCO study by GOIRC<br />
E. Giommoni 1 , E. Maiello 2 , G. Tortora 3 , V. Vaccaro 4 , E. Rondini 5 , L. Toppo 6 ,<br />
G. Giordano 7 , T.P. Latiano 2 , L. Calvetti 3 , L. Antonuzzo 1 , C. Lamperini 1 , L. Boni 8 ,<br />
F. Di Costanzo 1<br />
1 <strong>Oncology</strong>, Azienda Ospedaliera Careggi U.O. Medical <strong>Oncology</strong>, Florence, Italy,<br />
2 Onco-Hematology, Ospedale Casa Sollievo della S<strong>of</strong>ferenza, San Giovanni<br />
Rotondo, Italy, 3 <strong>Oncology</strong>, Azienda Ospedaliera Universitaria Integrata<br />
Verona-"Borgo Roma", Verona, Italy, 4 <strong>Oncology</strong>, Istituto Regina Elena, Rome, Italy,<br />
5 <strong>Oncology</strong>, Azienda Ospedaliera Arcispedale Santa Maria Nuova - IRCCS, Reggio<br />
Emilia, Italy, 6 <strong>Oncology</strong>, Istituti Ospitalieri di Cremona, Cremona, Italy, 7 <strong>Oncology</strong>,<br />
Ospedale "Sacro Cuore di Gesù" Fatebenefratelli, Benevento, Italy, 8 Istituto<br />
Toscano Tumori, AOU Careggi, Florence, Italy<br />
Background: FOLFIRINOX and nab-paclitaxel (nab-p) plus gemcitabine are effective<br />
regimens in first line treatment for metastatic pancreatic cancer (mPC). NabucCO<br />
study is designed to define dose limiting toxicities (DLTs) and maximum tolerated<br />
dose (MTD) <strong>of</strong> nab-p added to FOLFIRI or FOLFOX in first line for mPC.We report<br />
final results <strong>of</strong> dose-finding for both schedules.<br />
Methods: Patients with mPC, untreated for metastatic disease and PS ECOG 0-1<br />
received leucovorin 400 mg/m 2 ,5FUbolus400mg/m 2 , 5FU 48h ci 2400 mg/m 2 ,<br />
and irinotecan 180 mg/m 2 (Arm A) or oxaliplatin 85 mg/m 2 (Arm B) plus nab-p<br />
iv per cohort escalation assignment every 2 weeks for up to 12 cycles.The design<br />
was the standard 3 + 3 phase I dose escalation, with a nab-p dose increased by<br />
10 mg/m 2 for each cohort starting with 90 mg/m 2 .The MTD was established by<br />
DLTs according with Common Toxicity Criteria for Adverse Events (CTCAE)<br />
v. 4.03 during the first cycle <strong>of</strong> therapy. Recommended dose for phase II<br />
evaluation was defined as the highest dose level at which less than 2 <strong>of</strong> 6 pts<br />
experienced a DLT during cycle I, with a confirmatory cohort expansion <strong>of</strong> at<br />
least additional 3 pts.<br />
Results: From February 2014 to October 2015, a total <strong>of</strong> 63 pts were enrolled, 27<br />
pts received nab-FOLFIRI while 36 pts were treated with nab-FOLFOX. For Arm<br />
A median age was 62 years (range 38-75) and in Arm B was 60 years (range<br />
43-74). DLTs during first cycle at corresponding dose level are listed in the table<br />
below.<br />
Table: 682P<br />
DLTs with FOLFIRI DLTs with FOLFOX<br />
LEVEL Nab-p<br />
mg/m 2<br />
1 90 None None<br />
2 100 None None<br />
3 110 Liver toxicity G3 (1/6) None<br />
4 120 None (MTD) None<br />
5 130 Neutropenia G4 and leucopenia<br />
G3 (1/6) Thrombocytopenia<br />
G3 (1/6)<br />
6 140 Neutropenia G4 and<br />
thrombocytopenia G3 (1/3)<br />
Fever G3 and asthenia G3<br />
with hospitalization (1/3)<br />
Nausea G3 diarrhea<br />
G3 and anorexia<br />
G3 (1/3)<br />
None<br />
7 150 NA None<br />
8 160 NA Nausea G3 (1/6)<br />
(MTD)<br />
9 170 NA Febrile neutropenia<br />
and leucopenia G3<br />
(1/3) Sepsis (1/3)<br />
Conclusions: According to the study plan, the MTD <strong>of</strong> nab-p with FOLFIRI is 120<br />
mg/m 2 , and with FOLFOX is 160 mg/m 2 . The phase II study to assess efficacy <strong>of</strong> these<br />
regimen in term <strong>of</strong> overall response rate (ORR) is currently ongoing.<br />
Clinical trial identification: EudraCT 2013-002275-18<br />
Legal entity responsible for the study: GOIRC Gruppo Oncologico Italiano di Ricerca<br />
Clinica<br />
Funding: Celgene<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
683P<br />
Impact <strong>of</strong> age, bilirubin, and disease burden in unresectable<br />
pancreatic cancer patients receiving first-line chemotherapy:<br />
A population-based analysis<br />
Y. Wang 1 , P. Camateros 2 , W. Cheung 1<br />
1 Medical <strong>Oncology</strong>, British Columbia Cancer Agency, Vancouver, BC, Canada,<br />
2 Medicine, University <strong>of</strong> British Columbia, Vancouver, BC, Canada<br />
Background: FOLFIRINOX (FFN), nab-paclitaxel plus gemcitabine (NG), and<br />
gemcitabine (gem) are 3 systemic therapies that provide clinically meaningful benefit to<br />
patients with unresectable pancreatic cancer (UPC). Clinical trials have previously excluded<br />
patients with advanced age, elevated bilirubin, or locally advanced disease. Our aim was to<br />
examine whether age, bilirubin, and disease extent affected treatment outcomes.<br />
Methods: Patients diagnosed with UPC who initiated palliative chemotherapy from<br />
August 2014 to August 2015 at any 1 <strong>of</strong> 5 cancer centers in British Columbia were<br />
identified from the provincial pharmacy. Clinical, pathological, treatment, and<br />
outcome characteristics were compared.<br />
Results: 150 patients were included: 53% men, 78% ECOG 0/1, and 71% with<br />
metastatic disease. Patients who received FFN and NG were younger (p < 0.001), in<br />
better performance status (p < 0.001), and exhibited fewer metastases at presentation<br />
(p = 0.032) (Table). Bilirubin did not alter treatment selection (p = 0.502). Patients<br />
treated with FFN or NG also experienced significantly longer median overall survival<br />
(OS) when compared to those treated with gem after adjusting for confounders (11.2 vs<br />
11.6 vs 4.1 months, respectively; FFN: HR 0.391, 95%CI 0.192-0.796, p = 0.009, and<br />
NG: HR 0.239, 95%CI 0.132-0.430, p < 0.001). Likewise, progression-free survival<br />
(PFS) was longer among patients on FFN or NG in comparison to gem. Neither<br />
advanced age nor elevated bilirubin at presentation affected OS (p >0.05). Having<br />
metastatic instead <strong>of</strong> locally advanced disease significantly impacted OS (p 18 19% 19% 28% 0.502<br />
Metastatic disease 59% 78% 80% 0.032<br />
Conclusions: Receipt <strong>of</strong> FFN and NG portended a better prognosis than gem alone. In<br />
the absence <strong>of</strong> a randomized comparison <strong>of</strong> all 3 regimens, our population-based study<br />
revealed that the introduction <strong>of</strong> modified FFN and NG confers real world effectiveness<br />
for UPC patients regardless <strong>of</strong> age and bilirubin at presentation.<br />
Legal entity responsible for the study: Ying Wang<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw371 | vi231
abstracts<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
684P<br />
Nab-paclitaxel/gemcitabine first line therapy in patients with<br />
metastatic pancreatic carcinoma and high-bilirubin values -<br />
Data from the German QoliXane pancreatic cancer registry<br />
685P<br />
An elevated fibrinogen/CRP ratio predicts a remarkable<br />
survival advantage in patients with metastatic pancreatic<br />
cancer<br />
G. zur Hausen 1 , O. Waidmann 2 , M.A. Woerns 3 , H.G. Hoeffkes 4 , S. Doerfel 5 ,M.<br />
O. Zahn 6 , A. Aldaoud 7 , M. Stauch 8 , C. Springfeld 9 , N. Haertel 10 , A. Reichart 1 ,T.<br />
O. Goetze 1 , S. Schwarz 1 , C. Pauligk 1 , J. Roemmler-Zehrer 11 , R.D. H<strong>of</strong>heinz 12 ,<br />
S-E. Al-Batran 1<br />
1 Institute <strong>of</strong> Clinical Cancer Research, Nordwest-Krankenhaus, Frankfurt am Main,<br />
Germany, 2 Medical Hospital 1, Universitätsklinikum Frankfurt (Johannes-Wolfgang<br />
Goethe Institute), Frankfurt am Main, Germany, 3 1. Medical Hospital,<br />
Universitätsmedizin Mainz, Mainz, Germany, 4 MVZ Osthessen, Klinikum Fulda<br />
gAG, Fulda, Germany, 5 Fachärzte für Innere Medizin, Onkozentrum Dresden,<br />
Dresden, Germany, 6 Onkologische Kooperation Harz, MVZ, Goslar, Germany,<br />
7 Haematologie/Onkologie, Gemeinschaftspraxis, Leipzig, Germany, 8 Practice,<br />
Kronach, Germany, 9 University Hospital Heidelberg, National Center for Tumor<br />
Diseases, Heidelberg, Germany, 10 II. Medical Hospital, Universitätsklinikum<br />
Mannheim, Mannheim, Germany, 11 Celgene GmbH, Munich, Germany,<br />
12 Interdisziplinäres Tumorzentrum Mannheim, Universitätsklinikum Mannheim,<br />
Mannheim, Germany<br />
Background: Hyperbilirubinaemia is a common disease effect in patients (pts) with<br />
metastatic pancreatic cancer (mPC). As clinical trials <strong>of</strong>ten exclude them, data on<br />
management <strong>of</strong> these pts are rare. In the framework <strong>of</strong> a German observational<br />
multicenter study (QoliXane), quality <strong>of</strong> life and therapy data are currently being<br />
collected in pts with mPC receiving a combination <strong>of</strong> nab-paclitaxel and gemcitabine.<br />
This is an interim analysis on hyperbilirubinaemia management.<br />
Methods: Pts were included to this analysis if they entered the trial with a bilirubin<br />
level ≥ 1.2 mg/dl and completed at least 2 cycles. Bilirubin levels were documented for<br />
up to 4 cycles and methods <strong>of</strong> hyperbilirubinaemia management have been assessed. A<br />
both descriptive and explorative analysis was performed using IBM SPSS V 23.<br />
Results: 25 <strong>of</strong> 294 pts (8.5%) were included. Mean bilirubin level was 2.96 mg/dl (range<br />
1.2-12.3) at baseline and dropped considerably by the 2nd cycle to 0.84 (range 0.29-3.9;<br />
p = 0.0001). Bilirubin levels decreased in 24 (96%) and increased in 1 (4%) pts upon<br />
treatment start. 18 (72%) pts started treatment with standard dosage, 7 (28%) with a<br />
reduced regime. 10 (40%) pts underwent additional intervention: either stenting (7 pts,<br />
28%) or bile duct anastomosis (3 pts, 12%). Mean bilirubin values dropped from 4.59<br />
to 1.09 in pts with and from 1.87 to 0.68 in pts without additional intervention. Grade<br />
3/4 toxicity was seen in 60% <strong>of</strong> pts and most common 3/4 events were anemia, nausea,<br />
and fever. Mean Bilirubin Levels 1 .<br />
Table: 684P<br />
Baseline Cycle 2 Cycle 3 Cycle 4<br />
All pts (n = 25) 2.96 0.84 0.83 0.53<br />
no add. intervention (n = 15) 1.87 0.68 0.92 0.61<br />
any add. intervention (n = 10) 4.59 1.09 0.68 0.46<br />
add. stenting (n = 7) 4.52 1.19 0.84 0.35<br />
add. bile duct anastomosis (n = 3) 4.80 0.87 0.47 0.53<br />
p (all pts) 2 0.0001 0.002 0.008<br />
T. Winder 1 , F. Posch 2 , E. Asamer 2 , M. Stotz 2 , A. Siebenhüner 1 , K. Schlick 3 ,<br />
T. Magnes 4 , P. Samaras 1 , J. Szkandera 2 , P-A. Clavien 5 , D. Neureiter 6 , R. Greil 7 ,B.<br />
C. Pestalozzi 1 , H. Stoeger 8 , A. Gerger 8 , A. Egle 3 , M. Pichler 8<br />
1 Medizinische Onkologie, Universitätsspital Zürich, Zurich, Switzerland,<br />
2 Department <strong>of</strong> Internal Medicine, Medical University Graz, Graz, Austria, 3 Division<br />
<strong>of</strong> <strong>Oncology</strong>, Paracelsus University Hospital Salzburg, Salzburg, Austria, 4 IIIrd<br />
Medical Department with Hematology and Medical <strong>Oncology</strong>, Oncologic Center,<br />
Paracelsus University Hospital Salzburg, Salzburg, Austria, 5 Klinik für Viszeral- und<br />
Transplantationschirurgie, University Hospital Zürich, Zurich, Switzerland,<br />
6 Pathology, Paracelsus University Hospital Salzburg, Salzburg, Austria, 7 Head <strong>of</strong><br />
the IIIrd Medical Department, Paracelsus University Hospital Salzburg, Salzburg,<br />
Austria, 8 Clinical Division <strong>of</strong> Medical <strong>Oncology</strong>, Department <strong>of</strong> Internal Medicine,<br />
Medical University Graz, Graz, Austria<br />
Background: Both fibrinogen and C-reactive protein (CRP) are biomarkers <strong>of</strong> systemic<br />
inflammation, but differ regarding their half-life, underlying pathophysiological<br />
triggers, genetic background and cellular as well as molecular effects. The aim <strong>of</strong> this<br />
study was to investigate the fibrinogen/CRP ratio (FCR) as a prognostic blood-based<br />
biomarker for survival outcome in patients with pancreatic cancer.<br />
Methods: 609 consecutive patients with pancreatic adenocarcinoma (Stage I-III:<br />
n = 253 (41.5%), Stage IV: n = 356 (58.5%) from a tri-center cohort study (Austria and<br />
Switzerland) had routine measurements <strong>of</strong> fibrinogen and CRP levels at the time <strong>of</strong><br />
diagnosis, and were followed until the occurrence <strong>of</strong> death-from-any-cause. The FCR<br />
was defined as the ratio <strong>of</strong> fibrinogen (in mg/dL) to CRP (in mg/L).<br />
Results: During a median follow-up period <strong>of</strong> 3.8 years (range: 3 days-8.4 years), 511<br />
(83.9%) patients died (1-, 3-, and 5-year overall survival (OS) probabilities (95%CI):<br />
45.2% (41.1-49.2), 14.0% (11.2-17.2), and 7.4% (5.0-10.4), respectively. Patients with an<br />
elevated FCR, defined as an FCR > 75 th percentile <strong>of</strong> the FCR distribution (cut-<strong>of</strong>f:<br />
145.3 units), had a significantly higher 1-year OS than patients ≤ this cut-<strong>of</strong>f (60.2% vs.<br />
40.2%, p < 0.001). In univariable time-to-death regression, the risk <strong>of</strong> death at any time<br />
<strong>of</strong> follow-up was 30% lower in patients with an elevated FCR (Hazard ratio<br />
(HR) = 0.70, 95%CI: 0.57-0.86, p = 0.001). This result prevailed in multivariable<br />
analysis adjusting for age, tumor stage, grade, and levels <strong>of</strong> CA19-9 (HR for an elevated<br />
FCR = 0.69, 95%CI: 0.55-0.86, p = 0.001). A significant interaction was found between<br />
the FCR and tumor stage (p = 0.008), with the magnitude <strong>of</strong> association being strong<br />
in patients with stage IV disease (HR = 0.53, p < 0.0001), and absent in patients with<br />
stage I-III disease (HR = 0.91, p = 0.58).<br />
Conclusions: In this large tri-center cohort <strong>of</strong> patients with pancreatic<br />
adenocarcinoma, we observed a strong association between a high FCR and a lower<br />
risk <strong>of</strong> death in patients with metastatic disease but not in patients with localized<br />
disease. An elevated FCR at baseline defines a novel clinical subset <strong>of</strong> patients with<br />
metastatic pancreatic cancer who have a remarkable survival advantage.<br />
Legal entity responsible for the study: N/A<br />
Funding: University Graz, Salzburg, Zurich<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1 n’s indicate # <strong>of</strong> pts at baseline 2 Wilcoxon test to baseline (related samples),<br />
level <strong>of</strong> significance p = .05<br />
686P<br />
Advanced pancreatic adenocarcinoma outcomes with<br />
transition from devolved to centralised care in a UK regional<br />
cancer centre<br />
Conclusions: Data show that bilirubin levels drop considerably after start <strong>of</strong> nab-pac/<br />
gem therapy. The treatment seems to be feasible, although considerable frequencies <strong>of</strong><br />
Grade 3/4 toxicities were observed.<br />
Clinical trial identification: Clinicaltrials.gov: NCT02691052 AIO; trial number:<br />
AIO-LQ-0214/ass<br />
Legal entity responsible for the study: Institute <strong>of</strong> Clinical Cancer Research,<br />
Krankenhaus Nordwest gGmbH, Pr<strong>of</strong>. Salah-Eddin Al-Batran, Steinbacher Hohl 2-26,<br />
60488 Frankfurt<br />
Funding: Celgene GmbH<br />
Disclosure: G. zur Hausen: Travel grants: Celgene, Lilly. O. Waidmann: Consulting/<br />
Advisory: Bayer, Roche, Novartis <strong>Oncology</strong>. Research Funding: Novartis <strong>Oncology</strong>,<br />
Medac. Travel Grants: Bayer, Celgene, Ipsen, Novartis <strong>Oncology</strong>, Abbvie, Gilead. M.A.<br />
Woerns: Sponsored Lectures: Celgene. Advisory Board: Celgene. C. Springfeld:<br />
Consulting/Advisory Role: Celgene. Travel Grants: Celgene. N. Haertel: Research<br />
Grant: Celgene. A. Reichart: Travel Grants: Ipsen. T.O. Goetze: Baxalta, Celgene,<br />
BMS. S. Schwarz: Travel Grants: Hospira. J. Roemmler-Zehrer: Employment: Celgene.<br />
Stock ownership: Celgene. Travel Grants: Celgene. S-E. Al-Batran: Advisory Role:<br />
Merck, Celgene, Roche, Lilly, Nordic Pharma. Speaker: Roche, Lilly, Celgene, Nordic<br />
Pharma. Research Grants: Merck, Roche, Celgene, Vifor, Medac, Hospira, Lilly.All<br />
other authors have declared no conflicts <strong>of</strong> interest.<br />
O. Faluyi 1 , J. Connor 1 , B. Chatterjee 1 , C. Ikin 2 , H. Wong 2 , D. Palmer 1<br />
1 Medical <strong>Oncology</strong>, Clatterbridge Cancer Centre, Liverpool, UK, 2 Clinical<br />
Excellence Team, Clatterbridge Cancer Centre, Liverpool, UK<br />
Background: Clinical trials have demonstrated modest survival and quality <strong>of</strong> life<br />
benefits for palliative chemotherapy in advanced pancreatic cancer but this is rarely<br />
translated into real-world outcomes. We hypothesised that centralisation <strong>of</strong> advanced<br />
pancreatic adenocarcinoma management could increase chemotherapy use and<br />
potentially improve survival rates. Within Merseyside and Cheshire (UK), we<br />
transitioned from devolved to centralised pancreatic cancer management during<br />
2011-2012. We now determine the effect <strong>of</strong> such change with respect to chemotherapy<br />
use and patient outcomes.<br />
Methods: Data were collected for all cases <strong>of</strong> advanced pancreatic adenocarcinoma<br />
reviewed through Clatterbridge Cancer Centre according to two groups; 1 st Oct 2009-<br />
31 st Dec 2010 (Early Group, E) or 1 st Jan 2013- 31 st Mar 2014 (Late Group, L). Data<br />
collected included patient demographics, treatment received and date <strong>of</strong> death.<br />
Analysis <strong>of</strong> data included overall survival (OS) and 30-day chemotherapy mortality<br />
rates.<br />
Results: Chemotherapy was received by 43% (n= 52/121) in Group E and 67% (n= 77/<br />
115) in Group L. Reduced time to start <strong>of</strong> treatment was seen in Group L compared<br />
with Group E (18 vs 28 days, p = 0.001). More patients received second-line<br />
chemotherapy in Group L versus Group E (23.4% vs 1.9%, p =< 0.001). Fewer patients<br />
aged >70 were treated in Group E compared to Group L (24.5% vs 57.4%, p =
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
months, HR 0.785, p= 0.045). Sub-analysis showed that it was those with a poorer<br />
performance status, elderly or with metastatic disease who benefited the most from a<br />
transition to central care.<br />
Conclusions: A centralised clinic model for advanced pancreatic cancer management<br />
resulted in higher use <strong>of</strong> chemotherapy with shorter time to treatment compared to<br />
devolved care. The increased use <strong>of</strong> chemotherapy resulted in a modest increase in OS<br />
but did not increase 30-day mortality on chemotherapy.<br />
Legal entity responsible for the study: Dr O Faluyi<br />
Funding: Clatterbridge Cancer Centre<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
687P<br />
Clinical utility <strong>of</strong> circulating tumor DNA (ctDNA) in resectable<br />
pancreatic ductal adenocarcinoma (PDAC)<br />
H-L. Wong 1 , K. Bushell 2 , J. Karasinska 3 , S. Arthur 2 , P. Pararajalingam 2 , R. Morin 2 ,<br />
D.F. Schaeffer 4 , D.J. Renouf 1<br />
1 Division <strong>of</strong> Medical <strong>Oncology</strong>, BC Cancer Agency, Vancouver, BC, Canada,<br />
2 Department <strong>of</strong> Molecular Biology and Biochemistry, Simon Fraser University,<br />
Vancouver, BC, Canada, 3 Pancreas Centre BC, Vancouver, BC, Canada, 4 Division<br />
<strong>of</strong> Anatomical Pathology, Vancouver General Hospital, Vancouver, BC, Canada<br />
Background: There is considerable interest in investigating ctDNA as a non-invasive<br />
biomarker, with potential utility in screening, detecting minimal residual disease after<br />
curative resection and monitoring treatment response or resistance. Here we perform<br />
sequential ctDNA quantification in patients (pts) with resectable PDAC using a novel<br />
and highly sensitive multiplex technology to explore the clinical utility <strong>of</strong> ctDNA as a<br />
diagnostic and prognostic biomarker.<br />
Methods: Banked plasma and tumor samples from 32 pts with resected PDAC were<br />
retrieved. Plasma samples were collected 0-28 days before, and 28-70 days after surgery.<br />
DNA was extracted using standard protocols and analyzed using the OnTarget system,<br />
which enriches for DNA molecules containing hot spot mutations prior to sequencing.<br />
A 96-plex panel that includes the most prevalent mutations in KRAS, PIK3CA and<br />
TP53 was used.<br />
Results: 29 pts (91%) had at least 1 mutation detected by OnTarget in the tumor<br />
sample, most frequently in KRAS codon 12 (n = 26). 25 <strong>of</strong> 29 pts with a panel-detected<br />
tumor mutation had a pre-operative blood sample available, where a concordant<br />
mutation was detected in 8 pts (sensitivity 32%). There was no correlation between<br />
pre-operative ctDNA and tumor pathologic features. At median follow-up <strong>of</strong> 16.5<br />
months, there was no difference in recurrence-free survival (RFS) between pts with and<br />
without detectable pre-operative ctDNA (p = 0.595). Of the 22 available post-operative<br />
blood samples, a concordant mutation was detected for 5 pts. RFS was significantly<br />
shorter in pts with concordant ctDNA detected after surgery (median 2.1 vs 11.6<br />
months, p < 0.001). A discordant mutation was detected in 3 pre-operative and 3<br />
post-operative samples, most frequently in GNAS and PIK3CA; these pts had similar<br />
median RFS as those with no detectable plasma mutation.<br />
Conclusions: Pre-operative ctDNA has low sensitivity, suggesting limited utility in<br />
PDAC screening, and does not appear to be prognostic. RFS was significantly shorter<br />
in pts with detectable tumor-specific ctDNA post-operatively; this analysis is limited by<br />
small numbers and short follow-up. The significance <strong>of</strong> discordant plasma and tumor<br />
mutations is unknown.<br />
Legal entity responsible for the study: Pancreas Centre BC<br />
Funding: Pancreas Centre BC<br />
Disclosure: D.J. Renouf: Honorarium from Celgene Canada. All other authors have<br />
declared no conflicts <strong>of</strong> interest.<br />
688P<br />
Prognostic impact <strong>of</strong> KRAS mutation in metastatic (met)<br />
pancreatic cancer patients (pts)<br />
H. Verdaguer 1 , T. Sauri 1 , F. Ruiz 2 , A. Vivancos 3 , P. Nuciforo 4 , J. Capdevila 1 ,<br />
E. Elez 1 , M. Alsina 1 , G. Argiles Martinez 1 , C. Hierro 1 , J. Grasselli 1 , I. Matos 1 ,<br />
J. Tabernero 1 , R. Dienstmann 2 , T. Macarulla 1<br />
1 Medical <strong>Oncology</strong>, Vall d’Hebron University Hospital Institut d’Oncologia,<br />
Barcelona, Spain, 2 <strong>Oncology</strong> Data Science, Vall d’Hebron University Hospital<br />
Institut d’Oncologia, Barcelona, Spain, 3 Cancer Genomics Group, Vall d’Hebron<br />
Institute <strong>of</strong> <strong>Oncology</strong>, Barcelona, Spain, 4 Molecular <strong>Oncology</strong> Group, Vall<br />
d’Hebron Institute <strong>of</strong> <strong>Oncology</strong>, Barcelona, Spain<br />
Background: Pancreatic adenocarcinoma is the 4th leading cause <strong>of</strong> cancer-related<br />
death, with 80% <strong>of</strong> pts presenting with met disease at diagnosis and 5-year survival<br />
rates less than 10%. Activating KRAS mutations are found in more than 90% <strong>of</strong> cases<br />
and its prognostic impact is unknown. The aim <strong>of</strong> this study is to describe the<br />
frequency <strong>of</strong> KRAS mutations and correlate it with clinical outcomes in pts with met<br />
pancreatic cáncer.<br />
Methods: From January 2011 to December 2015, 92 metastatic pancreatic cancer pts<br />
were included in the molecular prescreening program <strong>of</strong> our centre. Archived tumour<br />
samples were analysed using mass spectrometry (Mass ARRAY, Sequenom, 20 cases)<br />
until June 2014 or next-generation sequencing (Amplicon, MiSeq, 72 cases) thereafter.<br />
All demographic, treatment and survival data were extracted retrospectively from<br />
electronic medical records.<br />
Results: Median age at diagnosis was 64 years (range 35-82). 56 pts (61%) were male,<br />
37 pts (40%) were diagnosed with met disease, 58 pts (63%) had liver metastases.<br />
Prevalence <strong>of</strong> KRAS mutations was 89%, only 10 pts (11%) had KRAS wild type. The<br />
most common KRAS mutation was G12D (39 pts, 47%), followed by G12V (25 pts,<br />
30%), G12R (2 pts, 13%) and Q61H (2 patients, 2%). A146V, G12A and G12C<br />
mutations were found in single cases. In the overall population, median survival after<br />
metastases diagnosis (SAM) was 16.1 months (CI95% 13.8-20.1). In KRAS mutated<br />
pts, median SAM, was 14.5 months, while in KRAS wild type pts median SAM was not<br />
reached (HR = 5.0 [CI95% 1.2-20.7], p = 0.01). The clonality <strong>of</strong> KRAS mutations (allele<br />
fractions adjusted for tumour purity) had no significant impact on TRD (p = 0.73).<br />
Progression-free survival (PFS) in 1 st line chemotherapy was not different according to<br />
KRAS mutation status (5.3 months in KRAS mutated, 4.2 months in KRAS wild type,<br />
HR = 1.1 [CI95% 0.5-2.9], p = 0.77).<br />
Conclusions: With highly sensitive next-generation sequencing, KRAS mutations are<br />
found in close to 90% <strong>of</strong> met pancreatic cancer pts. The absence <strong>of</strong> KRAS mutations is<br />
associated with improved outcomes in the met setting (prognostic marker), which is<br />
not explained by higher treatment benefit during 1 st line chemotherapy (not a<br />
predictive marker).<br />
Legal entity responsible for the study: Vall d’Hebron Institut d’Oncologia<br />
Funding: Vall d’Hebron Institut d’Oncologia<br />
Disclosure: J. Tabernero: Consultant/Advisory role: Amgen, Bayer, Boehringer<br />
Ingelheim, Celgene, Chugai, Lilly, MSD, Merck Serono, Novartis, Roche, San<strong>of</strong>i,<br />
Symphogen, Takeda and Taiho. All other authors have declared no conflicts <strong>of</strong> interest.<br />
689P<br />
abstracts<br />
The role <strong>of</strong> risk factors on survival for patients with pancreatic<br />
cancer<br />
K. Bagni 1 , C. Dehlendorff 2 , B.V. Jensen 1 , A.Z. Johansen 1 , P. Pfeiffer 3 ,C.<br />
P. Hansen 4 , S.E. Nielsen 5 , M.K. Yilmaz 6 , N.H. Holländer 7 , J. Johansen 1<br />
1 Department <strong>of</strong> <strong>Oncology</strong>, Herlev and Gent<strong>of</strong>te Hospital, Herlev, Denmark,<br />
2 Research Center, Danish Cancer Society Institute <strong>of</strong> Cancer Biology,<br />
Copenhagen, Denmark, 3 Department <strong>of</strong> <strong>Oncology</strong>, Odense University Hospital,<br />
Odense, Denmark, 4 Department <strong>of</strong> Gastroenterology, Surgery, Rigshospitalet,<br />
Copenhagen University Hospital, Copenhagen, Denmark, 5 Department <strong>of</strong><br />
<strong>Oncology</strong> and Palliative Care, Hillerod Hospital, Hillerod, Denmark, 6 Department <strong>of</strong><br />
<strong>Oncology</strong>, Aalborg University Hospital, Aalborg, Denmark, 7 Department <strong>of</strong><br />
<strong>Oncology</strong>, Naestved Hospital, Naestved, Denmark<br />
Background: Previous epidemiological studies have shown that diabetes mellitus<br />
(DM), alcohol, smoking and pancreatic cancer (PC) in close relatives are risk factors<br />
for developing PC. We investigated if these known risk factors are associated with short<br />
overall survival (OS) in patients with PC.<br />
Methods: 629 patients with pancreatic ductal adenocarcinoma (PDAC) (M/F 346/283,<br />
stage I (n = 22), stage II (n = 183), stage III (90) and stage IV (n = 334)) and 53 patients<br />
with ampullary adenocarcinoma (AAC) (M/F 32/20, stage I (n = 11), stage II (n = 26),<br />
stage III (13) and stage IV (n = 3)) were included from 6 hospitals in the Danish<br />
BIOPAC project from July 2008 to April 2016. Baseline clinical characteristics, IDDM,<br />
NIDDM, patient’s history <strong>of</strong> cancer or family history <strong>of</strong> cancer were retrospectively<br />
registered and analyzed. Hazard ratios (HR) were estimated for OS by means <strong>of</strong> Cox<br />
proportional hazards model.<br />
Results: 117 (19%) <strong>of</strong> the PDAC and 5 (11%) <strong>of</strong> the AAC patients had known IDDM<br />
or NIDDM at time <strong>of</strong> diagnosis. 471 (69%) had family history <strong>of</strong> cancer; most common<br />
types were breast cancer (7%), colorectal cancer (6.7%), lung cancer (6.7%), PC (6%)<br />
and uterus (3.4%). 36.7% were former smokers and 30% were current smokers. 25%<br />
had previous or present high alcohol intake. Known IDDM and NIDDM at time <strong>of</strong><br />
diagnosis were associated with short OS (HR = 1.52, 95% CI 1.11-2.07, p = 0.01 and<br />
HR = 1.36, 95% CI 1.00-1.83, p = 0.05, respectively). Present or previous high alcohol<br />
intake, tobacco use, family history <strong>of</strong> cancer or own earlier cancer or gastrointestinal<br />
inflammation were not associated with poor prognosis.<br />
Conclusions: In this Danish multicenter study we demonstrated that known IDDM<br />
and NIDDM at time <strong>of</strong> diagnosis were the only risk factors associated with poor<br />
prognosis.<br />
Legal entity responsible for the study: The National Committee on Health Research<br />
Ethics The Danish Data Protection Agency<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw371 | vi233
abstracts<br />
690P<br />
Efficacy <strong>of</strong> neoadjuvant FOLFIRINOX for borderline resectable<br />
pancreatic adenocarcinoma<br />
J. Kang 1 , K-P. Kim 1 , C. Yoo 1 , J-L. Lee 1 , B-Y. Ryoo 1 , H-M. Chang 1 , S.S. Lee 2 ,D.<br />
H. Park 2 , T.J. Song 2 , D.W. Seo 2 , S.K. Lee 2 , M-H. Kim 2 , D.W. Hwang 3 , K.B. Song 3 ,<br />
J.H. Lee 3 , S.C. Kim 3<br />
1 Department <strong>of</strong> <strong>Oncology</strong>, Asan Medical Center, University <strong>of</strong> Ulsan College <strong>of</strong><br />
Medicine, Seoul, Republic <strong>of</strong> Korea, 2 Department <strong>of</strong> Gastroenterology, Asan<br />
Medical Center, University <strong>of</strong> Ulsan College <strong>of</strong> Medicine, Seoul, Republic <strong>of</strong> Korea,<br />
3 Department <strong>of</strong> Surgery, Asan Medical Center, University <strong>of</strong> Ulsan College <strong>of</strong><br />
Medicine, Seoul, Republic <strong>of</strong> Korea<br />
Background: Neoadjuvant treatment strategy has been investigated for patients (pts)<br />
with borderline resectable pancreatic cancer (BRPC). Although FOLFIRINOX has<br />
been more widely used based on its success in patients with metastatic disease, there is<br />
lack <strong>of</strong> data based on the prospective randomized trial in this setting. Therefore, we<br />
performed retrospective analysis comparing the efficacy <strong>of</strong> FOLFIRINOX and<br />
gemcitabine-based regimen.<br />
Methods: Between February 2013 and December 2014, a total <strong>of</strong> 18 patients with<br />
histologically confirmed BRPC according to the NCCN resectability criteria were<br />
treated with FOLFIRINOX. For the comparative analysis, data <strong>of</strong> all patients with<br />
BRPC (n = 18) in our previous phase 2 study <strong>of</strong> neoadjuvant gemcitabine plus<br />
capecitabine (GEM-CAP) were extracted and included in the current analysis (Lee<br />
et al., Surgery 2012;152:851-62).<br />
Results: In pts treated with FOLFIRINOX, median age was 54 year old (range, 29-73),<br />
and 9 patients (50%) were male. There were no significant differences in baseline<br />
characteristics between FOLFIRINOX and GEM-CAP groups, except the number <strong>of</strong><br />
chemotherapy cycles (median 6 vs 3, respectively, p = 0.02). Surgical resection was<br />
performed in 12 pts (67%) with FOLFIRINOX and 11 pts (61%) with GEM-CAP<br />
(p = 1.00). R0 resection rates were 50% (n = 9) in each group. Progression-free survival<br />
(PFS) was significantly higher in the FOLFIRINOX group compared to GEM-CAP<br />
group (median 16.8 months [95% CI, 9.4-24.2] vs 6.5 months [1.6-11.3]; p = 0.044) and<br />
there was a trend toward improved overall survival (OS) in the FOLFIRINOX group<br />
(median 21.2 months [95% CI, 15.0-27.3] vs 13.6 months [11.8-15.4]; p = 0.17). In the<br />
FOLFIRINOX and GEM-CAP groups, 1-year PFS rates were 62% (95% CI, 35%-88%)<br />
and 22% (95% CI, 3%-41%), respectively, and 2-year OS rates were 45% (95% CI,<br />
20%-70%) and 28% (95% CI, 7%-49%), respectively. The trends for the improved OS in<br />
the FOLFIRINOX group were observed regardless <strong>of</strong> surgical resection.<br />
Conclusions: FOLFIRINOX might be associated with improved efficacy outcomes<br />
compared with GEM-CAP regimen in patients with BRPC. Further validations are<br />
necessary in the randomized trials.<br />
Legal entity responsible for the study: Asan Medical Center<br />
Funding: Asan Medical Center<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
691P<br />
Neutrophil to lymphocyte ratio is a predictor <strong>of</strong> outcome in<br />
metastatic pancreatic cancer patients (MPC) treated with<br />
nab-paclitaxel and gemcitabine<br />
J. Ventriglia 1 , A. Petrillo 1 , M. Huerta 2 , M.M. Laterza 1 , B. Savastano 1 ,<br />
V. Gambardella 2 , G. Tirino 1 , L. Pompella 1 , A. Diana 1 , A. Febbraro 3 , T. Troiani 1 ,<br />
M. Orditura 1 , A. Cervantes 2 , F. Ciardiello 1 , F. De Vita 1<br />
1 Medical <strong>Oncology</strong>, AOU Seconda Università degli Studi di Napoli (AOU-SUN),<br />
Naples, Italy, 2 Medical <strong>Oncology</strong>, Hospital Clinico Universitario de Valencia,<br />
Valencia, Spain, 3 Medical <strong>Oncology</strong>, Ospedale "Sacro Cuore di Gesù"<br />
Fatebenefratelli, Benevento, Italy<br />
Background: High neutrophil to lymphocyte ratio (NLR) can be a predictor <strong>of</strong> poor<br />
outcomes in various malignancies, including pancreatic cancer (PC). Based on these<br />
data, we investigated NLR as prognostic markers in MPC pts who received first-line<br />
chemotherapy with nab-paclitaxel/gemcitabine; furthermore a prognostic model using<br />
inflammatory-based scores to predict survival was planned.<br />
Methods: We assessed 70 pts with histologically confirmed MPC who received<br />
chemotherapy with nab-paclitaxel/gemcitabine at two different European oncologic<br />
centres between January 2012 and November 2015. The cut-<strong>of</strong>f for the NLR was<br />
5. Variables assessed for prognostic correlations included age ≥ 66, sex, Karn<strong>of</strong>sky PS<br />
score, primary tumor site, baseline CA19.9 level ≥ 59xULN, 12-week decrease <strong>of</strong><br />
CA19.9 level ≥ 50% from baseline, basal bilirubin level, baseline neutrophil to<br />
lymphocyte ratio, biliary stent implantation and liver metastasis. Survival analyses were<br />
generated according to the Kaplan-Meier method. Univariate and multivariate analyses<br />
were performed by Cox proportional hazard model.<br />
Results: With a median follow up <strong>of</strong> 32 months, median PFS and OS were 7.0 months<br />
(95% C.I. 6.221 – 7.779) and 12 months (95% C.I. 9.926-14.074), respectively with a<br />
12-month OS rate <strong>of</strong> 34.3%. According to NLR values, the patients were divided into<br />
two groups. Median PFS and OS were 5 months and 7 months (p= 0.02) and 7 months<br />
and 13 months (p= 0.003) in high (NLR ≥ 5) and low (NLR 1 measurable lesion (RECIST<br />
1.1), ECOG PS 2<br />
chemotherapy lines (range 1-3). 2–month PFR was 25% (5/20 pts, all stable disease,<br />
SD). At a median follow up <strong>of</strong> 5.3 mos, median PFS and OS were 1.6 mos (range<br />
0.7-5.9) and 3.0 mos (range 1.1-6.1) respectively. Reasons for treatment<br />
discontinuation were radiological disease progression (55%), adverse events (AEs) or<br />
clinical deterioration (45%). Dose reductions or delays for AEs were required in 35%<br />
and 65% <strong>of</strong> pts respectively. Main G3-4 AEs were hand-foot skin reaction (20%) and<br />
hepatic toxicity (10%), and G1-2 AEs were anorexia (60%), fatigue, anemia, diarrhea<br />
and fever (40%), hypophosphatemia and hypertension (30%).<br />
Conclusions: Although the primary endpoint was not achieved in this cohort <strong>of</strong> pts<br />
with mPC, SD was observed in 25% <strong>of</strong> pts.<br />
Clinical trial identification: NCT01892527<br />
Legal entity responsible for the study: Humanitas Clinical and Research Centre<br />
Funding: Bayer<br />
Disclosure: L. Rimassa: Member <strong>of</strong> Advisory Board: Eli Lilly, Merck, Bayer, Amgen,<br />
Arqule. A. Santoro: Member <strong>of</strong> Advisory Board: Bayer. All other authors have declared<br />
no conflicts <strong>of</strong> interest.<br />
693P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Time course <strong>of</strong> selected treatment emergent adverse events<br />
(TEAEs) in NAPOLI-1: A phase 3 study <strong>of</strong> nal-IRI<br />
(MM-398) ± 5-fluorouracil and leucovorin (5-FU/LV) vs 5-FU/LV<br />
in metastatic pancreatic cancer (mPAC) previously treated<br />
with gemcitabine-based therapy<br />
R.A. Hubner 1 , L-T. Chen 2 , J.T. Siveke 3 , C-P. Li 4 , G. Bodoky 5 , A. Dean 6 ,<br />
Y-S. Shan 7 , G.S. Jameson 8 , T. Macarulla 9 , K-H. Lee 10 , D. Cunningham 11 ,<br />
J-F. Blanc 12 , C-F. Chiu 13 , G. Schwartsmann 14 , F. Braiteh 15 , K. Mamlouk 16 ,<br />
B. Belanger 16 , F. de Jong 17 , D.D. von H<strong>of</strong>f 8 , A. Wang-Gillam 18<br />
1 Department <strong>of</strong> Medical <strong>Oncology</strong>, Christie NHS Foundation Trust, Manchester,<br />
UK, 2 National Institute <strong>of</strong> Cancer Research, National Health Research Institutes,<br />
Tainan, Taiwan, 3 University Hospital Essen, West German Cancer Center, Essen,<br />
Germany, 4 Medicine, Taipei Veterans General Hospital and National Yang-Ming<br />
University School <strong>of</strong> Medicine, Taipei, Taiwan, 5 Medical <strong>Oncology</strong>, St. László<br />
Teaching Hospital, Budapest, Hungary, 6 Cancer Services, St John <strong>of</strong> God<br />
Hospital, Subiaco, Australia, 7 National Cheng Kung University, National Cheng<br />
Kung University Hospital, Tainan, Taiwan, 8 Medical <strong>Oncology</strong>, TGen, Phoenix, AZ,<br />
USA, 9 <strong>Oncology</strong> Service, Vall d’Hebron University Hospital and Vall d’Hebron<br />
Institute <strong>of</strong> <strong>Oncology</strong>, Barcelona, Spain, 10 Internal Medicine, Seoul National<br />
University Hospital, Seoul, Republic <strong>of</strong> Korea, 11 GI & Lymphoma Unit, Royal<br />
Marsden Hospital, Sutton, UK, 12 Hepato-Gastroenterology and Digestive<br />
<strong>Oncology</strong>, Hôpital Saint-André, Bordeaux, France, 13 Cancer Center, China<br />
Medical University Hospital, Taichung, Taiwan, 14 UFRGS, Hospital de Clínicas de<br />
Porto Alegre, Porto Alegre, Brazil, 15 Medicine, Comprehensive Cancer Centers <strong>of</strong><br />
Nevada, Las Vegas, NV, USA, 16 Medicine, Merrimack Pharmaceuticals, Inc.,<br />
Cambridge, MA, USA, 17 Medicine, Baxalta GmbH, Zurich, Switzerland,<br />
18 Medicine, Washington University School <strong>of</strong> Medicine, St. Louis, MO, USA<br />
Background: Liposomal irinotecan (nal-IRI) plus 5-FU/LV is approved in the US for<br />
patients (pts) with mPAC previously treated with gemcitabine-based therapy. Primary<br />
analysis from NAPOLI-1 (NCT01494506) showed a significant median survival<br />
advantage for nal-IRI + 5-FU/LV vs 5-FU/LV (6.1 vs 4.2 mo; HR 0.67; 95% CI 0.49-0.92;<br />
vi234 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
P = 0.012; Wang-Gillam et al, Lancet. 2016). The most common TEAEs included<br />
diarrhea, vomiting, nausea, decreased appetite, fatigue, neutropenia, and anemia. Here<br />
we report incidence and prevalence <strong>of</strong> selected TEAEs over time in NAPOLI-1.<br />
Methods: Pts were randomly assigned to nal-IRI + 5-FU/LV, nal-IRI, or 5-FU/LV. In<br />
this post hoc analysis (data cut<strong>of</strong>f, Feb 14, 2014), incidence (ie, first occurrence) and<br />
prevalence (ie, first occurrence, ongoing event, or recurrence) <strong>of</strong> selected TEAEs were<br />
analyzed by treatment period (first 6 wk [period 1], second 6 wk [period 2], and<br />
beyond second 6 wk [period 3]). Denominators for percentages were the number <strong>of</strong> pts<br />
in the risk set during each period (for incidence: pts still on treatment without a<br />
previous event; for prevalence: all safety-evaluable pts).<br />
Results: 398 pts were treated with nal-IRI + 5-FU/LV (n = 117), nal-IRI (n = 147), or<br />
5-FU/LV (n = 134). In the nal-IRI + 5-FU/LV arm, most first occurrences <strong>of</strong><br />
neutropenia, diarrhea, nausea, and vomiting were during the first 6 wk <strong>of</strong> treatment,<br />
with incidence and severity generally decreasing thereafter (Table). Similarly,<br />
prevalence and severity were highest in the first 6 wk and tended to decrease over time.<br />
Similar trends were observed in the nal-IRI and 5-FU/LV arms.<br />
Table: 693P<br />
Incidence, % nal-IRI + 5-FU/LV nal-IRI 5-FU/LV<br />
Period Period Period<br />
1 2 3 1 2 3 1 2 3<br />
Neutropenia grade n = 117 n = 73 n = 34 n = 147 n = 95 n = 43 n = 134 n = 111 n = 43<br />
1 1 3 3 1 2 0 1 0 0<br />
2 8 3 3 8 3 0 1 2 2<br />
3 14 4 9 5 1 0 2 0 0<br />
4 7 0 0 6 2 0 0 0 0<br />
5 0 0 0 0 0 0 0 0 0<br />
Diarrhea grade n = 117 n = 51 n = 24 n = 147 n = 46 n = 11 n = 134 n = 89 n = 32<br />
1 21 4 0 25 11 18 15 5 6<br />
2 17 12 4 20 7 9 2 1 0<br />
3 12 0 4 16 4 0 2 1 3<br />
4 0 0 0 1 0 0 0 0 0<br />
5 0 0 0 1 0 0 0 0 0<br />
Nausea grade n = 117 n = 56 n = 28 n = 147 n = 53 n = 25 n = 134 n = 87 n = 26<br />
1 21 5 7 23 4 8 19 4 12<br />
2 16 0 7 27 4 8 5 4 4<br />
3 7 2 0 5 2 0 2 2 0<br />
4 0 0 0 0 0 0 0 0 0<br />
5 0 0 0 0 0 0 0 0 0<br />
Vomiting grade n = 117 n = 61 n = 35 n = 147 n = 61 n = 28 n = 134 n = 89 n = 29<br />
1 19 5 11 27 2 7 16 2 4<br />
2 14 0 9 10 3 4 5 1 4<br />
3 10 0 3 12 2 0 1 1 4<br />
4 0 0 0 0 0 0 0 0 0<br />
5 0 0 0 0 0 0 0 0 0<br />
Conclusions: Neutropenia, diarrhea, nausea, and vomiting typically first occur early<br />
during the course <strong>of</strong> treatment with nal-IRI + 5-FU/LV and tend to decrease in<br />
incidence and severity thereafter.<br />
Clinical trial identification: NCT01494506<br />
Legal entity responsible for the study: Merrimack Pharmaceuticals, Inc.<br />
Funding: Merrimack Pharmaceuticals, Inc.<br />
Disclosure: L-T. Chen: 1. Merrimack/ NAPOLI-1 study Steering Committee Member,<br />
uncompensated 2. Baxalta/ Advisory Meeting, honorarium 3. PharmaEngine/<br />
Consultant, honorarium. J.T. Siveke: 1. Baxalta/ Ad Board, honoraria. A. Dean:<br />
Merrimack/ Investigator meeting, travel grant. D. Cunningham: Amgen, AstraZeneca,<br />
Bayer, Celgene, Medimmune, Merck Serono, Merrimack, San<strong>of</strong>i: research funding to<br />
my institution. J-F. Blanc: Baxalta, honoraria. F. Braiteh: Merrimack, institutional<br />
research funding.K. Mamlouk: Merrimack, employee and stock. B. Belanger:<br />
Merrimack, employee. F. de Jong: Baxalta, employee and stock. D.D. von H<strong>of</strong>f:<br />
Merrimack/ Clinical trial. A. Wang-Gillam: 1. Merrimack/ Ad Board 2. Newlink/ Ad<br />
Board 3. Pfizer/ Ad Board. All other authors have declared no conflicts <strong>of</strong> interest.<br />
694P<br />
Prognostic value <strong>of</strong> the immune-related transcriptome in<br />
biliary tract cancers<br />
M. Ghidini 1 , L. Cascione 2 , A. Lampis 3 , R. Pandolfo 4 , P. Carotenuto 4 , F. Trevisani 3 ,<br />
J.C. Hahne 3 , D. Zito 3 , V. Guzzardo 5 , A. Zerbi 6 , G. Torzilli 6 , M. Roncalli 7 ,<br />
L. Rimassa 1 , A. Santoro 1 , M. Fassan 5 , N. Valeri 3 , C. Braconi 4<br />
1 Medical <strong>Oncology</strong>, Istituto Clinico Humanitas, Rozzano, Italy, 2 Bioinformatics<br />
Core Unit, IOSI Istituto Oncologico Svizzera Italiana Ospedale Regionale Bellinzona<br />
e Valli, Bellinzona, Switzerland, 3 Laboratory <strong>of</strong> Gastrointestinal Cancer Biology and<br />
Genomics, Division <strong>of</strong> Molecular Pathology, The Institute <strong>of</strong> Cancer Research ICR,<br />
Sutton, UK, 4 Cancer Therapeutics, The Institute <strong>of</strong> Cancer Research ICR, London,<br />
UK, 5 Internal Medicine, Azienda Ospedaliera di Padova Università, Padua, Italy,<br />
6 Surgical <strong>Oncology</strong>, Istituto Clinico Humanitas, Rozzano, Italy, 7 Pathology, Istituto<br />
Clinico Humanitas, Rozzano, Italy<br />
immune pr<strong>of</strong>ile (IP) is activated in BTC and represents a feature <strong>of</strong> biological<br />
behaviour.<br />
Methods: RNA was extracted by tumour tissues (TT) and matched adjacent tissues<br />
(AT). IP <strong>of</strong> 700+ immune-related transcripts was performed in TT and AT <strong>of</strong> 24 BTCs<br />
by nCounter assay. CD80 expression was assessed by immunohistochemistry (IHC).<br />
Cox regression analysis and Kaplan Meier methods were used to correlate with Relapse<br />
Free Survival (RFS) and derive a prognostic gene signature.<br />
Results: 132 transcripts were aberrantly expressed in TT vs AT. Ingenuity Pathway<br />
Analysis showed that leucocyte migration was the top function annotation.<br />
De-regulation <strong>of</strong> PDZ Binding Kinase (PBK) in TT appeared to differentiate cases with<br />
worse prognosis (nCounter p:0.08; Taqman p:0.07). We derived a list <strong>of</strong> genes whose<br />
expression was associated with RFS. We observed that risk <strong>of</strong> recurrence was associated<br />
with a greater number <strong>of</strong> genes deregulated in AT than in TT. We shortlisted genes that<br />
maintained statistical significance at multivariate analysis (gene expression, tumour<br />
site, adjuvant chemotherapy (AC) and R0/1 resection). We observed correlation<br />
between high expression <strong>of</strong> cytotoxic T-lymphocyte antigen-4 (CTLA-4) in the AT and<br />
RFS (p:0.0004). Cases with low CTLA4 had reduced expression <strong>of</strong> CD80, while cases<br />
with high CTLA4 had increased CD80 expression. IHC expression <strong>of</strong> CD80 varied in<br />
TT and AT. No association was seen between AT CD80 expression and RFS. However,<br />
CD80 expression seemed to differentiate prognosis in patients who did not receive AC<br />
(p:0.01), suggesting that activation <strong>of</strong> this pathway may promote relapse and may be<br />
affected from adjuvant treatment. Number <strong>of</strong> CD8+ and CD4+ cells did not correlate<br />
with RFS. We also derived a immuno-gene signature that could significantly<br />
differentiate relapsed cases and was an independent prognostic factor (HR 29.43,<br />
p:0.001).<br />
Conclusions: We showed that IP is deregulated in the AT <strong>of</strong> resected BTC and<br />
correlates with relapse suggesting that deregulation <strong>of</strong> immune infiltrate in the normal<br />
tissue creates a favourable soil for cancer cell growth.<br />
Legal entity responsible for the study: N/A<br />
Funding: Institute <strong>of</strong> Cancer Research.<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
695P<br />
Oral rivaroxaban versus subcutaneous low molecular weight<br />
heparin treatment for venous thromboembolism in patients<br />
with upper gastrointestinal, hepatobiliary and pancreatic<br />
cancer<br />
S. Seo, M-H. Ryu, Y-K. Kang, K-P. Kim, H-M. Chang, B-Y. Ryoo, S.B. Kim,<br />
J-L. Lee, S.R. Park<br />
Department <strong>of</strong> <strong>Oncology</strong>, Asan Medical Center, University <strong>of</strong> Ulsan College <strong>of</strong><br />
Medicine, Seoul, Republic <strong>of</strong> Korea<br />
Background: Although low molecular weight heparin (LMWH) is preferred treatment<br />
<strong>of</strong> cancer-related venous thromboembolism (VTE), rivaroxaban is increasingly used<br />
owing to its convenience. We aimed to compare the LMWH and rivaroxaban<br />
maintenance therapy for VTE in patients with upper gastrointestinal (GI),<br />
hepatobiliary and pancreatic (HBP) cancer.<br />
Methods: From JAN 2004 to DEC 2014, a totla <strong>of</strong> 777 and 217 patients with upper GI<br />
or HBP cancer were prescribed LMWH and rivaroxaban, respectively. With exclusion<br />
<strong>of</strong> patients who had resectable disease, received treatment less than 14 days unless<br />
discontinued due to bleeding and took anticoagulation not for therapeutic purpose,<br />
111 and 78 patients were analyzed, respectively.<br />
Results: Most baseline characteristics were similar between the two groups<br />
(rivaroxaban vs. LMWH), except age ≥65 (57.1% vs. 29.7%, p = 0.001) and ECOG ≥2<br />
(6.4% vs. 19.8%, p = 0.009). The recurrent or aggravated VTEs during anticoagulation<br />
were observed at 4 (5.1%) in the rivaroxaban group and 1 (0.9%) in the LMWH group<br />
(HR 4.41, 95% CI 0.48-40.13, p = 0.188). Regarding the safety, the rivaroxaban group<br />
had significantly higher incidences <strong>of</strong> total events <strong>of</strong> bleeding (37.2% vs. 18.0%; HR<br />
2.06, 95% CI 1.17-3.65, p = 0.013) and clinical relevant bleeding (29.5% vs. 13.5%; HR<br />
2.16, 95% CI 1.13-4.14, p = 0.021). Major bleeding events also tended to occur more<br />
frequently in the rivaroxaban group (16.7% vs. 7.2%; HR 2.29, 95% CI 0.95-5.53,<br />
p = 0.066). In multivariate analysis, treatment with rivaroxaban was significantly<br />
associated with total bleeding (HR 2.34, 95% CI 1.30-4.23, p = 0.005) and clinical<br />
relevant bleeding (HR 2.16, 95% CI 1.13-4.14, p = 0.021) after adjusting for possible<br />
confounding factors, such as age ≥65, sex, presence <strong>of</strong> a GI mucosa lesion, poor<br />
performance status, lower BMI (
abstracts<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
696P<br />
Extended RAS and BRAF mutation analysis <strong>of</strong> circulating<br />
tumor DNA in patients with biliary tract cancer<br />
Funding: Ohio State University Wexner Medical Center<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
L.H. Jensen 1 , R.F. Andersen 2 , A. Jakobsen 1<br />
1 <strong>Oncology</strong>, Vejle Hospital Sygehus Lillebaelt, Vejle Sygehus, Vejle, Denmark,<br />
2 Clinical Biochemistry, Vejle Hospital Sygehus Lillebaelt, Vejle Sygehus, Vejle,<br />
Denmark<br />
698P<br />
Phase I study <strong>of</strong> DKN-01 (D), an anti-DKK1 monoclonal<br />
antibody, in combination with gemcitabine (G) and cisplatin (C)<br />
in patients (pts) with advanced biliary cancer (ABC)<br />
Background: Clinical trials have failed to show benefit from adding anti-EGFR<br />
antibodies to chemotherapy in the systemic treatment <strong>of</strong> biliary tract cancer with<br />
respect to progression free and overall survival, but a trend towards higher response<br />
rate. In colorectal cancer, effect <strong>of</strong> anti-EGFR therapy is restricted to patients with RAS<br />
and BRAF wild-type tumors. Mutation analysis <strong>of</strong> circulating DNA may be a clinically<br />
applicable method for serial analyses. The purpose <strong>of</strong> this early cancer biomarker study<br />
was to evaluate the feasibility <strong>of</strong> extended RAS and BRAF mutation analysis <strong>of</strong> cell free<br />
DNA in blood derived from patients with metastatic biliary tract cancer.<br />
Methods: Patients with KRAS exon 2 codons 12/13 wild type metastatic biliary tract<br />
cancer and available blood samples were included. DNA was isolated from 4 ml<br />
plasma, pre-amplified and analyzed using Droplet Digital PCR. Adequate positive and<br />
negative controls were included. The extended RAS and BRAF analysis covered a total<br />
<strong>of</strong> 27 mutations in KRAS exons 3/4, NRAS exon 2/3 and BRAF V600E.<br />
Results: A total <strong>of</strong> 52 patients were included. In 12 patients (23.1%), a mutation was<br />
found; BRAF n = 4, KRAS n = 4 and NRAS n = 4. Except for one patient with a NRAS<br />
mutation in plasma and wild-type in tumor, tumor biopsies harbored an identical<br />
mutation.<br />
Conclusions: Extended RAS and BRAF mutation analysis in cell free DNA from blood<br />
derived from patients with metastatic biliary tract cancer was feasible. The fraction <strong>of</strong><br />
mutations was 23.1% and equally distributed in KRAS, NRAS and BRAF. The high<br />
frequency <strong>of</strong> mutations beyond KRAS exon 2 may explain the lacking effect <strong>of</strong> EGFR<br />
inhibition in previous studies and justify extended mutation analysis.<br />
Legal entity responsible for the study: Lars Henrik Jensen<br />
Funding: Lillebaelt Hospital<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
697P<br />
Updated, expanded analysis with next generation sequencing<br />
(NGS) <strong>of</strong> biliary tract cancer confirms association between<br />
tumor somatic variants and chemotherapy resistance<br />
D.H. Ahn 1 , D. Catenacci 2 , C.W. Ahn 3 , A. Jain 4 , R.K. Kelley 5 , A.G. Bocobo 5 ,<br />
R. Rendak 2 , S. Mikhail 1 ,C.Wu 1 , R.T. Shr<strong>of</strong>f 4 , M. Borad 6 , J.L. Chen 1 , M. Javle 4 ,<br />
T. Bekaii-Saab 6<br />
1 Medical <strong>Oncology</strong>, The Ohio State University James Cancer Hospital, Columbus,<br />
OH, USA, 2 Medical <strong>Oncology</strong>, The University <strong>of</strong> Chicago Medical Centre, Chicago,<br />
IL, USA, 3 Clinical Sciences, University <strong>of</strong> Texas Southwestern Medical Center at<br />
Dallas, Dallas, TX, USA, 4 Medical <strong>Oncology</strong>, MD Anderson Cancer Center,<br />
Houston, TX, USA, 5 Medical <strong>Oncology</strong>, UCSF Helen Diller Family Comprehensive<br />
Cancer Center, San Francisco, CA, USA, 6 Hematology/<strong>Oncology</strong>, Mayo Clinic,<br />
Phoenix, AZ, USA<br />
Background: BTC are uncommon and associated with a dismal prognosis.<br />
Gemcitabine and platinum combination (GP) form the standard approach for treating<br />
advanced BTC with a modest improvement in survival. To identify potential<br />
biomarkers for response to GP in BTC, we used NGS to evaluate the genomic BTC<br />
landscape and specifically, identify whether mutations affecting cell cycle function and<br />
DNA repair associated with GP resistance and prognosis.<br />
Methods: Pretreatment formalin-fixed, paraffin-embedded (FFPE) samples from 232<br />
patients (pts) with BTC treated with GP were analyzed with a commercial targeted<br />
NGS platform. Genes with incidence >10% were included in our analysis. Cox<br />
regression models were used to determine the association between mutations,<br />
progression free survival (PFS) and overall survival (OS). Survival from start <strong>of</strong> GP was<br />
estimated using the Kaplan Meier method and compared by the log-rank test.<br />
Results: In the 232 pts analyzed, the most common mutations included CDKN2A<br />
(28%), TP53 (31%), KRAS (23%), and ARID1A (13%). Considering genes with an<br />
incidence >10%, no individual gene was independently predictive <strong>of</strong> GP response. In<br />
pts with unresectable, advanced BTC who received GP as first-line therapy, the joint<br />
status <strong>of</strong> CDKN2A, TP53 and ARID1A were associated with PFS (P = 0.0008) and OS<br />
(P = 0.0002). 7% <strong>of</strong> pts had mutations in CDKN2A and TP53 with wild type ARID1A<br />
were identified as a poor prognostic cohort with a median PFS <strong>of</strong> 2.63 months (mos)<br />
and a median OS 5.22 mos. Pts with mutant ARID1A, regardless <strong>of</strong> the single<br />
mutational status <strong>of</strong> TP53 or CDKN2A had statistically similar PFS and OS. In a pt<br />
who exhibited mutations in all three genes, the median PFS was 20.37 mos and median<br />
OS not reached.<br />
Conclusions: In the largest exploratory analysis <strong>of</strong> this nature to date in BTC, we found<br />
that the presence <strong>of</strong> three prevalent mutations (TP53, CKDN2A and ARID1A)<br />
represent distinct pt cohorts. These mutations are prognostic and may represent a<br />
predictive biomarker to GP therapy response. Prospective studies are needed to validate<br />
these findings, including the incorporation <strong>of</strong> novel agents that exploit the cell cycle<br />
abberations or genomic alterations observed with these mutations with GP in BTC.<br />
Legal entity responsible for the study: Ohio State University Wexner Medical Center<br />
J. Eads 1 , S. Stein 2 , A. El-Khoueiry 3 , G. Manji 4 , T. Abrams 5 , A.A. Khorana 6 ,<br />
R. Miksad 7 , D. Mahalingam 8 , C. Sirard 9 , A.X. Zhu 10 , L. Goyal 10<br />
1 Seidman Cancer Center, University Hospitals Case Medical Center, Cleveland,<br />
OH, USA, 2 Cancer Center, Yale University School <strong>of</strong> Medicine Medical <strong>Oncology</strong>,<br />
New Haven, CT, USA, 3 Norris Comprehensive Cancer Center, University <strong>of</strong><br />
Southern Callifornia, Los Angeles, CA, USA, 4 Division <strong>of</strong> Hematology and<br />
<strong>Oncology</strong>, Columbia University, New York, NY, USA, 5 Gastrointestinal Cancer,<br />
Dana Farber Cancer Institute, Boston, MA, USA, 6 Hematology and <strong>Oncology</strong>,<br />
Cleveland Clinic, Cleveland, OH, USA, 7 Hematology/<strong>Oncology</strong>, Beth Israel<br />
Deaconess Medical Center, Boston, MA, USA, 8 Cancer Therapy & Research<br />
Center, University <strong>of</strong> Texas Health Science Center San Antonio, San Antonio, TX,<br />
USA, 9 Clinical Research, Leap Therapeutics, Inc., Cambridge, MA, USA,<br />
10 Hematology/<strong>Oncology</strong>, Massachusetts General Hospital, Boston, MA, USA<br />
Background: DKK1 is an inhibitor <strong>of</strong> the canonical Wnt/β-catenin pathway and a<br />
modulator <strong>of</strong> non-canonical signaling. High tissue DKK1 expression in intrahepatic<br />
cholangiocarcinoma (CCA) is associated with advanced stage and shorter survival.<br />
DKK1 may enhance the invasive properties <strong>of</strong> CCA, promoting lymph node metastasis<br />
by induction <strong>of</strong> MMP9 and VEGF-C. D has previously demonstrated activity in lung<br />
and esophageal cancers. This study evaluated the maximum tolerated dose (MTD),<br />
safety and efficacy <strong>of</strong> D in combination with GC in pts with ABC.<br />
Methods: Patients with histologically confirmed, advanced ABC were eligible. In Part<br />
A (3 + 3 design), pts received D at either 150 or 300 mg with G 1000 mg/m2 and C 25<br />
mg/m2 on days 1 and 8 <strong>of</strong> each 21 day cycle. Part B (300 mg D expansion) has<br />
completed enrollment. Response was assessed every 2 cycles using RECISTv1.1.<br />
Results: 24 pts were enrolled; 22 pts evaluable for safety; 4 dosed at 150 mg and 18<br />
dosed at 300 mg; 86% screened ABC (21 pts) had DKK1+ tumor tissue. Median age:<br />
65; Female: 68%; White: 86%. Gallbladder cancer 36%, intrahepatic CCA 59%. 3 pts<br />
had prior adjuvant G. Median number <strong>of</strong> cycles: 2 (range 1, 10+); 15 pts still on<br />
therapy. No dose limiting toxicities, related serious AEs or treatment emergent adverse<br />
events (TEAEs) which lead to discontinuation or dose reduction <strong>of</strong> D. 13 pts (59%)<br />
had grade 3/4 TEAEs; events in ≥ 2 pts include: neutropenia (n = 10), leukopenia,<br />
thrombocytopenia (n = 3 each), anemia and AST elevation (n = 2 each). 8 pts (36%)<br />
had D-related grade 3/4 TEAEs; events in ≥ 2 pts include: neutropenia (n = 5),<br />
thrombocytopenia and AST elevation (n = 2 each). The MTD <strong>of</strong> D + GC was 300 mg.<br />
At the MTD, 9 <strong>of</strong> 18 patients are evaluable for response; 3 pts had a partial response<br />
(PR), 5 pts had stable disease (SD), and 1 pt had progressive disease (PD). Among 4 pts<br />
dosed at 150 mg D, 3 pts had SD, 1 pt had PD. Responses and SD have been durable.<br />
Conclusions: Study enrollment is complete. D + GC is well tolerated; safety pr<strong>of</strong>ile <strong>of</strong><br />
this regimen appears similar to GC alone. Preliminary data with D (300 mg) + GC<br />
demonstrate a response rate <strong>of</strong> 33% in pts with advanced ABC. Further investigation is<br />
ongoing.<br />
Clinical trial identification: NCT02375880.<br />
Legal entity responsible for the study: Jennifer Eads<br />
Funding: Leap Therapeutics, Inc.<br />
Disclosure: J. Eads: Research: BMS. Consulting: ClearView Healthcare<br />
Partners. A. El-Khoueiry: Honoraria: BMS, Bayer, Astra Zeneca, Genentech, GSK.<br />
Consulting/Advisory Role: BMS, Astra Zeneca, Genentech/Roche. Speakers Bureau:<br />
Merimak. Research Funding: Astex. G. Manji: Merck. Research Funding: Conquer<br />
Cancer Foundation. Research Funding Ardelyx – Consultant Celgene – ConsultantA.<br />
A. Khorana: Janssen, San<strong>of</strong>i, Pfizer, Roche and Halozyme. R. Miksad: corporate<br />
sponsored research (to the institution): Bayer, Exelixis, Novartis,<br />
Macrogenics. D. Mahalingam: Consulting or Advisory Role - Azaya Therapeutics;<br />
Baxalta; Bayer; Dendreon; Genspera; Oncolytics Speakers’ Bureau - Bayer; Dendreon.C.<br />
Sirard: Employment - Leap Therapeutics, Inc. Stock and Other Ownership Interests -<br />
Leap Therapeutics, Inc. Patents, Royalties, Other Intellectual Property - Leap<br />
Therapeutics, Inc.All other authors have declared no conflicts <strong>of</strong> interest.<br />
699P<br />
High incidence <strong>of</strong> metastases detected on 18F-FDG PET-CT in<br />
patients with gall bladder cancer incidentally discovered after<br />
laparoscopic cholecystectomy<br />
A. Bhattacharya, R. Kumar, S.K. Vadi, A.K.R. Gorla, A. Sood, B.R. Mittal<br />
Department <strong>of</strong> Nuclear Medicine, Post Graduate Institute <strong>of</strong> Medical Education<br />
and Research (PGIMER), Chandigarh, India<br />
Background: Gall bladder cancer (GBC) is a relatively rare disease with clinical and<br />
imaging features similar to benign gall bladder diseases (BGBD) like gall stone disease<br />
or cholecystitis. A few <strong>of</strong> the BGBD patients who undergo laparoscopic<br />
cholecystectomy (LC) are later found to have GBC. In these patients, it is important to<br />
evaluate the extent <strong>of</strong> disease for further management. This study was conducted to<br />
vi236 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
evaluate the incidence <strong>of</strong> metastases in patients referred for 18 F-fluorodeoxyglucose<br />
positron emission tomography-computed tomography (FDG PET-CT) following<br />
incidental discovery <strong>of</strong> GBC after LC for BGBD.<br />
Methods: We retrospectively evaluated the data <strong>of</strong> patients referred to our department<br />
between January 2011 and December 2015 for FDG PET-CT with GBC diagnosed on<br />
histopathology (HP) after LC for BGBD. Abnormal FDG uptake on PET images<br />
corresponding to morphological abnormalities on contrast enhanced CT images was<br />
considered positive for disease. HP examination and clinical or imaging follow-up were<br />
used as the reference standard for confirmation <strong>of</strong> diagnosis.<br />
Results: FDG PET-CT imaging was performed 1-8 (median 3.5) months after LC in 44<br />
patients (8M, 36F) aged 30-75 (median 50.2) years. PET-CT was positive in 32/44<br />
(72.7%) and negative in 12/44 patients (27.3%). Loco-regional disease was detected in<br />
30/44 patients (68.2%) involving the gall bladder fossa, liver or regional lymph nodes.<br />
Metastatic seeding to the omentum, mesentery or laparoscopic port sites was found in<br />
15 (34.1%) and distant metastasis in 5 patients (11.3%). Based on the reference<br />
standard, 28 patients had true positive scans. Findings in 4 scan-positive patients could<br />
not be confirmed; these were presumed false positive and remain on follow-up. All 12<br />
scan-negative patients were true negative. PET-CT showed sensitivity, specificity, PPV,<br />
NPV and accuracy <strong>of</strong> 100%, 75.0%, 87.5%, 100%, and 90.9% respectively in detecting<br />
residual / recurrent disease.<br />
Conclusions: There is high propensity for seeding metastasis when GBC is discovered<br />
after LC for BGBD. FDG PET-CT has high diagnostic performance in detecting<br />
residual / recurrent disease as well as metastases in these patients.<br />
Legal entity responsible for the study: Department <strong>of</strong> nuclear medicine, PGIMER,<br />
Chandigargh, India<br />
Funding: Postgraduate Institute <strong>of</strong> Medical Education and Research, Chandigarh, India<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
700P<br />
NAB-PACLITAXEL as third-line therapy after failure <strong>of</strong><br />
gemcitabine and 5-FU based combinations in advanced gall<br />
bladder cancer patients<br />
S. Singh Manana, V. Goel, V. Talwar, S. Raina<br />
Medical <strong>Oncology</strong>, Rajiv Gandhi Cancer Institute & Research Center, New Delhi,<br />
India<br />
Background: There is no standard third-line chemotherapy after progression on<br />
two-lines <strong>of</strong> therapy including gemcitabine/platinum and FOLFOX-4 based<br />
chemotherapy regimens in metastatic gall bladder cancer patients. So this study was<br />
undertaken to assess the efficacy and safety <strong>of</strong> single agent nab-paclitaxel in this setting.<br />
Methods: The was a single arm prospective study, patients with performance status ≤2,<br />
who progressed on two-lines <strong>of</strong> therapy, were enrolled from May 2012 to December<br />
2015. Single agent nab-paclitaxel (dose 125mg/m 2 ) was administered on Day 1, 8 and<br />
15 in a cycle <strong>of</strong> 28 days and i.e. until progression or unacceptable toxicity. Response<br />
evaluation was done after 2 cycles <strong>of</strong> chemotherapy.<br />
Results: A total <strong>of</strong> 24 patients were enrolled in this study. The median age <strong>of</strong> patients<br />
was 60 years (31–71 years), <strong>of</strong> which 10 (41.66%) were males and 14 (58.33%) were<br />
females. The median number <strong>of</strong> cycles could be given were 3.07 (0.5 – 9.6). 13 patients<br />
(54.16%) could be given more than 3 cycles <strong>of</strong> chemotherapy and only 3 patients<br />
(12.5%) in this study received more than 6 cycles <strong>of</strong> chemotherapy. Disease control rate<br />
was seen in 16 (66.66%) patients, with complete response in none, partial response in 9<br />
(37.5%), stable disease in 7 (29.16%) and progressive disease in 8 (33.33%) patients.<br />
The median progression free survival was 2.86 months (95% CI: 2.31-3.41); The main<br />
Grade 3/4 side effects seen were hematological in 33.33% (n = 8). 7 patients (29.16%)<br />
had Grade 1/2 peripheral neuropathy.<br />
Conclusions: Nab-paclitaxel is an effective and well-tolerated agent as a third-line<br />
option in metastatic gall bladder cancer patients. Further studies are required,<br />
especially in the Indian subcontinent.<br />
Legal entity responsible for the study: Rajiv Gandhi Cancer Institute<br />
Funding: Rajiv Gandhi Cancer Institute<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
701P<br />
TrkB/BDNF signaling promotes EMT mediated invasiveness<br />
and is a potential therapeutic target for gallbladder cancer<br />
M. Kawamoto 1 , H. Onishi 1 , K. Ozono 2 , A. Yamasaki 1 , A. Imaizumi 1 , M. Nakamura 2<br />
1 Cancer Therapy and Research, Kyushu University Hospital, Fukuoka, Japan,<br />
2 Surgery and <strong>Oncology</strong>, Kyushu University Hospital, Fukuoka, Japan<br />
Background: Tropomyosin-related kinase B (TrkB)/ brain derived neurotrophic factor<br />
(BDNF) signaling has been shown to be activated and be involved with inducing<br />
malignant phenotype in several cancers. However, the contribution <strong>of</strong> its signaling to<br />
one <strong>of</strong> refractory malignancies, gallbladder cancer (GBC), still remains unclear. This<br />
study assessed the biological function <strong>of</strong> TrkB/BDNF signaling in GBC and<br />
investigated whether it could be a new therapeutic target in GBC.<br />
Methods: 1) Clinical experiment: 69 patients with GBC who underwent curative<br />
surgical resection were enrolled in this study. Correlation between TrkB expression and<br />
clinicopathological findings was analyzed immunohistochemically. 2) In vitro<br />
experiment: TrkB/BDNF signaling was inhibited using k252a, siRNA and shRNA, and<br />
was activated by recombinant BDNF (rBDNF). Then, whether TrkB/BDNF signaling<br />
contributes to the invasiveness was estimated by Matrigel invasion assay using TrkB<br />
expressing GBC cell lines (TGBC, GBd15, NOZ, TYGBK − 1, TYGBK − 2). Epithelial<br />
Mesenchymal Transition (EMT) related protein levels were analyzed by western<br />
blotting. 3) In vivo experiment: In Xenograft mice model, tumorigenesis and<br />
invasiveness <strong>of</strong> TrkB shRNA transfected cells (NOZ, TYGBK-1) was analyzed.<br />
Results: 1) Clinical results; TrkB expression was detected in 63 (91.3%) GBC<br />
specimens. TrkB expression detected in invasive front significantly correlated with T<br />
factor (p = 0.0391) and clinical staging (p = 0.0391). Overall survival in patients with<br />
high TrkB expression was significantly lower than those with low TrkB expression<br />
(p = 0.0363). 2) In vitro results; Addition <strong>of</strong> rBDNF significantly increased invasiveness<br />
and K252a treatment significantly decreased invasiveness <strong>of</strong> GBC cells. TrkB and<br />
BDNF siRNA transfection significantly inhibited the invasiveness <strong>of</strong> GBC cells. SiRNA<br />
transfection increased the expression <strong>of</strong> E-cadherin and decreased the expressions <strong>of</strong><br />
vimentin, slug, snail, and twist. 3) In vivo results; Tumors from mice injected with<br />
TrkB shRNA transfected cells significantly reduced the tumorigenicity and<br />
invasiveness.<br />
Conclusions: TrkB/BDNF signaling enhances invasiveness <strong>of</strong> GBC, and it could be a<br />
potential therapeutic target.<br />
Legal entity responsible for the study: Department <strong>of</strong> Cancer Therapy and Research,<br />
Graduate School <strong>of</strong> Medical Sciences, Kyushu University<br />
Funding: Department <strong>of</strong> Cancer Therapy and Research, Graduate School <strong>of</strong> Medical<br />
Sciences, Kyushu University<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
702P<br />
Analysis <strong>of</strong> efficacy and prognostic factors for second-line<br />
chemotherapy in gemcitabine-refractory advanced biliary<br />
tract cancer<br />
N. Okano, K. Kawai, T. Kobayashi, D. Naruge, F. Nagashima, J. Furuse<br />
Medical <strong>Oncology</strong>, Kyorin university Hospital, Mitaka, Japan<br />
Background: No standard second-line chemotherapy regimen has been established for<br />
gemcitabine (GEM)-refractory advanced biliary tract cancer (aBTC).<br />
Methods: We examined the transition rate to second-line chemotherapy and its safety<br />
and efficacy in patients with aBTC who had received first-line treatment with<br />
GEM-based chemotherapy between January 2009 and December 2015 in our hospital.<br />
We also investigated prognostic factors associated with overall survival (OS) by<br />
multivariable Cox regression analysis.<br />
Results: Forty-six (45.1%) patients received second-line chemotherapy. One patient was<br />
excluded from this study, because second-line treatment was initiated in another<br />
hospital. The median age was 68 years, and there were 25 males and 20 females. Tumor<br />
sites were: gallbladder (n = 18), extrahepatic (n = 15), intrahepatic (n = 10) bile duct and<br />
ampulla <strong>of</strong> Vater (n = 2). Performance status was 0 and 1 in 25 and 20 patients,<br />
respectively. Cancer was metastatic in 27, recurrent in 15, and locally advanced in<br />
3. Median CA 19-9 value was 487 U/mL. Modified Glasgow prognostic score (mGPS)<br />
were: 0 (n = 24), 1 (n = 10), and 2 (n = 10). First-line chemotherapy were included:<br />
GEM + cisplatin (CDDP) (n = 19), GEM + S-1 (n = 14), GEM (n = 7), GEM + OTS102<br />
(n = 4), and GEM + radiation (n = 1). Second-line chemotherapy included: S-1 (n = 20),<br />
GEM + oxaliplatin (n = 6), GEM + CDDP (n = 5), GEM (n = 5), tyrosine kinase<br />
inhibitors (n = 5), GEM + S-1 (n = 2), and fixed-dose GEM + S-1 (n = 2). The main grade<br />
3/4 adverse events were biliary tract infection (n = 6), neutropenia (n = 5), and anemia<br />
(n = 5). There was one treatment-related death due to biliary tract infection. Median OS<br />
was 8.3 months, and median progression-free survival was 3.0 months. Response rate<br />
was 0% and disease control rate was 58.1%. Multivariate analysis showed that CA 19-9<br />
≥500 U/mL (hazard ratio: [HR] 3.45, p = 0.003), mGPS ≥1 (HR 3.05, p = 0.005), and<br />
liver metastasis (HR 2.62, p = 0.048) were significant prognostic factors for OS.<br />
Conclusions: Second-line chemotherapy for GEM-refractory aBTC was inadequate.<br />
Randomized controlled trials with an appropriate stratification criteria, including CA<br />
19-9 value, mGPS and liver metastasis, are required.<br />
Legal entity responsible for the study: Kyorin University<br />
Funding: Kyorin University<br />
Disclosure: J. Furuse: Personal financial interests from Taiho Pharmaceutical Co., Ltd,<br />
and Eli Lilly Japan. Institutional financial interests from Taiho Pharmaceutical Co.,<br />
Ltd.All other authors have declared no conflicts <strong>of</strong> interest.<br />
703P<br />
abstracts<br />
HER2/HER3 pathway in biliary tract cancers: A systematic<br />
review and meta-analysis. A novel therapeutic druggable<br />
target?<br />
S. Galdy 1 , A. Lamarca 2 , M. McNamara 2 , R. Hubner 2 , C.A. Cella 1 , N. Fazio 1 ,J.<br />
W. Valle 2<br />
1 Gastrointestinal and NET Unit, Istituto Europeo di Oncologia, Milan, Italy, 2 Medical<br />
<strong>Oncology</strong>, The Christie NHS Foundation Trust, Manchester, UK<br />
Background: HER2 overexpression and/or amplification has been reported as<br />
predictive factor to HER2 targeted therapy in breast and gastric cancer, whereas HER3<br />
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is emerging as a potential resistance factor. The aim <strong>of</strong> this study was to perform a<br />
systematic review and meta-analysis <strong>of</strong> the HER2 and HER3 up-regulation in biliary<br />
tract cancers (BTCs).<br />
Methods: An electronic search <strong>of</strong> MEDLINE, ASCO, ESMO and AACR was<br />
performed to identify studies reporting HER2 and/or HER3 membrane protein<br />
expression by immunohistochemistry (IHC) and/or gene amplification by in situ<br />
hybridisation (ISH) in BTCs.<br />
Results: Out <strong>of</strong> 440 studies screened, 40 met the inclusion criteria. Globally, HER2<br />
expression rate was 26.5% (95% CI, 18.9% - 34.1%). Studies were classified as<br />
“high-quality” (HQ; 27 studies) [IHC overexpression defined as presence <strong>of</strong> moderate/<br />
strong staining] and “low-quality” (11 studies) [“any” expression was considered<br />
positive]. When HQ studies were analysed, extra-hepatic BTCs (EH-BTCs) showed a<br />
higher HER2 overexpression rate compared to intrahepatic cholangiocarcinoma<br />
(IHCC) [19.9% (95% CI, 12.8 – 27.1%) vs. 4.8% (95% CI, 0 – 14.5%); p-value 0.0049].<br />
HER2 amplification rate was higher in those patients selected by HER2 overexpression<br />
[57.6% (95% CI, 16.2 - 99%)] compared to “unselected” patients [17.9% (95% CI, 0.1 –<br />
35.4%); p-value 0.0072]. HER3 overexpression (4/4 HQ studies) and amplification rates<br />
were 27.9% (95% CI, 9.7 - 46.1%) and 26.5% (one study), respectively.<br />
Conclusions: Up to 20% <strong>of</strong> EH-BTCs might be HER2 overexpressed, ∼60% <strong>of</strong> HER2<br />
overexpressed BTCs can be considered amplified while HER3 is overexpressed or<br />
amplified in ∼25% <strong>of</strong> BTCs. These findings may be considered in future trial<br />
development.<br />
p = 0.005). Early TGR as categorical covariate in a Cox model analysis <strong>of</strong> OS was a<br />
strong prognostic factor for time to death <strong>of</strong> similar strength in both treatment arms.<br />
The table shows hazard ratios (HR) and p-values in UV and MV analyses <strong>of</strong> OS with<br />
TGR for PLC and SOR separately and for TGR together with treatment. Interaction<br />
terms with treatment were always non-significant; thus, TGR is prognostic in both<br />
treatment arms, but does not predict whether patients respond differentially to SOR<br />
and PLC.<br />
Conclusions:<br />
SHARP Trial<br />
Table: 704P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
AP Trial<br />
PLC SOR PLC SOR<br />
TGR categorical, HR (p-value)<br />
HR by treatment 0.717 (0.001) 0.685 (0.017)<br />
HR by TGR 0.518 (
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Table: 705P First line treatment and Adherence to AASLD Guidelines<br />
Treatment<br />
BCLC A<br />
n = 139<br />
BCLC B<br />
n=56<br />
BCLC C<br />
n=83<br />
BCLC D<br />
n=34<br />
Surgical resection 32 7 14 2<br />
Transplant referral 24 3 0 6<br />
RFA 28 3 0 0<br />
Cyberknife 7 3 5 1<br />
Y90 11 11 10 1<br />
TACE 28 15 12 1<br />
Sorafenib 3 5 21 3<br />
Clinical trial 0 1 0 0<br />
Supportive care 6 8 21 20<br />
Adherence to AASLD<br />
guidelines (%)<br />
73.3% 26.8% 25.3% 58.8%<br />
Conclusions: In clinical practice, the adherence to published guidelines is limited and<br />
subject to the heterogeneity <strong>of</strong> the patients and their comorbidities. MTB had a positive<br />
impact on BCLC D OS. The findings in our study suggest the need to refine the current<br />
staging and guidelines for HCC, especially for BCLC B, C, and D. MTBs need to have a<br />
bigger role in facilitating clinical trial participation.<br />
Legal entity responsible for the study: N/A<br />
Funding: Case Medical Center<br />
Disclosure: P. Gholam: Consultant: Bayer. All other authors have declared no conflicts<br />
<strong>of</strong> interest.<br />
706P<br />
Prognostic value <strong>of</strong> the neutrophil-to-lymphocyte ratio in<br />
advanced hepatocellular carcinoma: An exploratory analysis<br />
from the ARQ197-215 study<br />
N. Personeni 1 , L. Giordano 1 , G. Abbadessa 2 , C. Porta 3 , I. Borbath 4 , B. Daniele 5 ,<br />
S. Salvagni 6 , J-L. van Laethem 7 , H. Van Vlierberghe 8 , J. Trojan 9 , A. Weiss 10 ,<br />
A. Gasbarrini 11 , D. Shuster 12 , E.N. De Toni 13 , M. Lencioni 14 , S. Miles 15 ,M.<br />
E. Lamar 2 , B. Schwartz 16 , A. Santoro 1 , L. Rimassa 1<br />
1 Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano,<br />
Italy, 2 Clinical Development & Translational Medicine, ArQule, Burlington, VT, USA,<br />
3 Oncologia Medica, IRCCS San Matteo University Hospital Foundation, Pavia,<br />
Italy, 4 Gastro-Enterology, Cliniques Universitaires St. Luc, Brussels, Belgium,<br />
5 <strong>Oncology</strong>, Azienda Ospedaliera G. Rummo, Benevento, Italy, 6 Medical <strong>Oncology</strong>,<br />
Azienda ospedaliero-universitaria Policlinico Sant’Orsola Malpighi, Bologna, Italy,<br />
7 Gastroenterology, Erasme University Hospital-(Universite Libre de Bruxelles),<br />
Brussels, Belgium, 8 Gastroenterology, Gent University Hospital, Gent, Belgium,<br />
9 Medizinische Klinik, Universitätsklinikum Frankfurt(Johannes-Wolfgang Goethe<br />
Institute), Frankfurt am Main, Germany, 10 Gastroenterology, Vancouver General<br />
Hospital & HSC, British Columbia University, Vancouver, BC, Canada, 11 Patologia<br />
Speciale Medica e Semeiotica Medica, Policlinico Universitario Agostino Gemelli,<br />
Rome, Italy, 12 Clinical Development, Daiichi-Sankyo, Edison, NJ, USA,<br />
13 Department <strong>of</strong> Internal Medicine II, Ludwig Maximilians University -<br />
Grosshadern, Munich, Germany, 14 Medical <strong>Oncology</strong>, Azienda Ospedaliera<br />
Universitaria S.Chiara, Pisa, Italy, 15 <strong>Oncology</strong>, Cedar Sinai, Los Angeles, CA, USA,<br />
16 Clinical Development, ArQule, Burlington, VT, USA<br />
Background: The ARQ197-215 study randomized patients (pts) to tivantinib or<br />
placebo and pre-specified efficacy analyses indicated the predictive value <strong>of</strong> MET<br />
expression as a marker <strong>of</strong> benefit from tivantinib for second-line treatment <strong>of</strong><br />
hepatocellular carcinoma (HCC). The aim <strong>of</strong> the current analysis was to evaluate in the<br />
ARQ197-215 cohort the neutrophil-to-lymphocyte ratio (NLR), which is thought to be<br />
a prognostic factor associated with clinical outcomes in several solid tumours.<br />
Methods: A post hoc exploratory analysis was carried out on 98 ARQ197-215 pts with<br />
available absolute neutrophil count and absolute lymphocyte count, and preserved liver<br />
function. The cut-<strong>of</strong>f used to define a high versus low NLR was the predefined value <strong>of</strong><br />
3.0, which corresponds to the median value. The effect <strong>of</strong> NLR was estimated with<br />
respect to overall survival (OS) and time to progression (TTP).<br />
Results: No association was detected between the NLR and other known prognostic<br />
factors, including portal vein thrombosis (p = 0.671), MET expression (p = 0.552),<br />
alpha-fetoprotein levels (p = 0.837), and distant metastases (p = 0.521). In univariate<br />
analysis, compared with low NLR, a high NLR was associated with a hazard ratio (HR)<br />
for OS <strong>of</strong> 1.58 [95% confidence interval: 1.01; 2.47; p = 0.046]. Also, in multivariate<br />
analysis, the NLR and portal vein thrombosis remained independent prognostic factors<br />
for OS within the entire cohort. Median OS was 7.8 months versus 5.1 months for<br />
patients with NLR 20% decline <strong>of</strong> AFP levels from baseline within the first 4 weeks <strong>of</strong> treatment.<br />
Vascular response (VR), evaluated using dynamic contrast enhanced-magnetic<br />
resonance imaging, was defined as a >40% decline in Ktrans after 2 weeks <strong>of</strong> treatment.<br />
Results: Fifty-five patients (M/F: 45/10, median age 59.8 years) were enrolled.<br />
Underlying liver diseases included hepatitis B (93%), hepatitis C (18%), and alcoholism<br />
(11%). All patients had documented progression after sorafenib treatment. The<br />
response rate (RR) was 13% (0 complete and 7 partial responses; 22 durable [≥ 8<br />
weeks] stable disease), and the disease control rate (DCR) was 53%. The 6-month PFS<br />
rate was 9.1%. The median PFS and overall survival (OS) was 1.8 and 8.9 months,<br />
respectively. Early AFP response (17 <strong>of</strong> 40 patients, 43%) was borderline significantly<br />
associated with higher RR (29% vs. 4%, p = 0.067) and significantly associated with<br />
higher DCR (76% vs. 22%, p = 0.001) and longer PFS (median, 5.4 vs. 0.9 months,<br />
p = 0.020). However, patients with and without AFP response exhibited similar OS<br />
(median, 10.7 vs. 8.0 months, p = 0.307). VR (14 <strong>of</strong> 44 patients, 32%) was not<br />
associated with RR (p = 0.364), DCR (p = 0.752), PFS (p = 0.706), or OS (p = 0.135).<br />
The safety pr<strong>of</strong>ile was comparable with other lenalidomide trials.<br />
Conclusions: Lenalidomide exhibited moderate activity as second-line therapy for<br />
advanced HCC. Its immunomodulatory effects should be further explored.<br />
Clinical trial identification: NCT01545804.<br />
Legal entity responsible for the study: National Taiwan University Hospital<br />
Funding: Celgene<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
708TiP<br />
abstracts<br />
Multicentric prospective study <strong>of</strong> validation <strong>of</strong> angiogenesis<br />
polymorphisms in HCC patients treated with sorafenib.<br />
INNOVATE study<br />
A. Casadei Gardini 1 , L. Faloppi 2 , B. Daniele 3 , S. Cascinu 4 , S. Lonardi 5 , G. Masi 6 ,<br />
F. Negri 7 , D. Santini 8 , N. Silvestris 9 , V. Zagonel 5 , M. Scartozzi 2<br />
1 Medical <strong>Oncology</strong>, Istituto Tumori della Romagna I.R.S.T., Meldola, Italy, 2 Clinica<br />
di Oncologia Medica, University <strong>of</strong> Cagliari, Cagliari, Italy, 3 <strong>Oncology</strong>, Azienda<br />
Ospedaliera G. Rummo, Benevento, Italy, 4 Medical <strong>Oncology</strong>, Azienda<br />
Ospedaliero - Universitaria Policlinico di Modena, Modena, Italy, 5 Department <strong>of</strong><br />
<strong>Oncology</strong>, Istituto Oncologico Veneto IRCCS, Padua, Italy, 6 Medical <strong>Oncology</strong>,<br />
Azienda Ospedaliera Universitaria S.Chiara, Pisa, Italy, 7 Medical <strong>Oncology</strong>,<br />
Azienda Ospedaliera di Parma, Parma, Italy, 8 Medical <strong>Oncology</strong>, Libero Istituto<br />
Universitario Campus Bio-Medico (LIUCBM), Rome, Italy, 9 Medical <strong>Oncology</strong>,<br />
Istituto Tumori Giovanni Paolo II, Bari, Italy<br />
Background: Preclinical data suggested that significant HCC growth is dependent<br />
on angiogenesis.In the ALICE-2 we study patients (PT) receiving sorafenib(S) for<br />
HIF-1α,VEGF-A and VEGF-C SNPs.At multivariate analysis rs12434438 <strong>of</strong><br />
HIF-1α,rs2010963 <strong>of</strong> VEGF-A and rs4604006 <strong>of</strong> VEGF-C have been confirmed as<br />
independent factors for PFS and OS. At the combined analysis <strong>of</strong> significant<br />
SNPs the presence <strong>of</strong> 2 favourable alleles <strong>of</strong> VEGF compared to only 1 or to none<br />
favourable alleles, identifies three populations with different PFS(respectively:10.8<br />
vs. 5.6 vs. 3.7 months,p < 0,0001)and OS(respectively:19.0vs13.5vs7.5months;<br />
p < 0,0001).Furthermore the presence <strong>of</strong> GG genotype <strong>of</strong> rs12434438 (HIF-1α)<br />
select a population with a particularly poor outcome independently from the<br />
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abstracts<br />
clinical effect <strong>of</strong> the two VEGF SNPs(PFS: 2.6 months,p < 0,0001;OS:6.6 months,<br />
p < 0,0001).In ePHAS we study PT homozygous for a specific haplotype(Ht1:T-4b<br />
at eNOS-786/eNOS VNTR)showed a lower median PFS(2.1vs6.2 months,<br />
p < 0.0001)and OS(5.0vs14.9 months, p < 0.0001)compared to other genotypes.<br />
Data confirmed in multivariate. On the basis <strong>of</strong> these data we want to validate in<br />
a prospective study the potential role <strong>of</strong> VEGF,VEGFR,HIF-1,Ang2 and eNOS<br />
SNPs in PT with HCC treated with S.<br />
Trial design: This is a prospective non pharmacological study. The study population<br />
consisted <strong>of</strong> PT with advanced-stage HCC and PT not eligible for locoregional<br />
treatments or liver transplantation.The primary aim <strong>of</strong> the study is to validated the<br />
prognostic or predictive role <strong>of</strong> eNOS,Ang2,HIF-1, VEGF and VEGFR SNPs in relation<br />
to clinical outcome <strong>of</strong> PT treated with S. The secondary aim <strong>of</strong> the study is to verify the<br />
prognostic value <strong>of</strong> the basal level <strong>of</strong> ldh, blood pressure, plasma level <strong>of</strong> Ang2 and<br />
plasma level <strong>of</strong> VEGF in relation to clinical outcome (progression-free survival and<br />
overall survival) <strong>of</strong> patients treated with S. The study was planned to have a 90% power<br />
at the 5% significance level (two-sided) to detect a 42% relative reduction in the<br />
progression rate (absolute increase in PFS <strong>of</strong> 2.5 months). Assuming a 24-month<br />
accrual period and a 12-month follow-up, 160 patients were required.<br />
Legal entity responsible for the study: Andrea Casadei Gardini<br />
Funding: IRST-IRCCS<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
709TiP<br />
Randomized controlled phase II trial <strong>of</strong> S-1 maintenance<br />
therapy in Caucasian population with metastatic<br />
esophagogastric cancer– the multinational MATEO study<br />
G.M. Haag 1 , G. Stocker 2 , J. Quidde 3 , D. Jaeger 1 , F. Lordick 2<br />
1 NCT - Med. <strong>Oncology</strong>, University Hospital Heidelberg, Heidelberg, Germany,<br />
2 University Cancer Center Leipzig, University Clinic Leipzig, Leipzig, Germany,<br />
3 University Cancer Center Hamburg, UKE Universitätsklinikum<br />
Hamburg-Eppendorf KMTZ, Hamburg, Germany<br />
Background: Chemotherapy including a fluoropyrimidine and a platinum<br />
compound is still the mainstay for the majority <strong>of</strong> patients with esophagogastric<br />
adenocarcinoma. The optimal duration <strong>of</strong> firstline chemotherapy is unknown. In<br />
most clinical trials therapy is given until tumor progression or dose-limiting toxicity.<br />
Maintenance concepts have been established in other tumor types but not in<br />
esophagogastric cancer. S-1 is an oral fluoropyrimidine with proven efficacy in<br />
metastatic esophagogastric cancer. Given as a monotherapy S-1 showed a beneficial<br />
toxicity pattern.<br />
Trial design: MATEO is a randomized, multinational, phase II trial in patients<br />
with previously untreated, Her-2 negative metastatic esophagogastric<br />
adenocarcinoma. After having completed, without tumor progression, a 12-week<br />
induction chemotherapy (including a platinum compound, a fluoropyrimidine<br />
with or without a taxane or an anthracycline), 297 patients will be randomized in<br />
a 2:1 allocation to receive S-1 monotherapy or to continue the same<br />
polychemotherapy until progression or limiting toxicities. Patients will be<br />
stratified according to the response to the induction therapy at the time <strong>of</strong><br />
randomization (CR/PR vs. SD) and the polychemotherapy used during the<br />
induction phase (doublet vs. triplet regimen). The primary endpoint is overall<br />
survival, secondary endpoints include progression-free survival, safety and quality<br />
<strong>of</strong> life. Sample size estimation is based on the statistical goal to allow for a first<br />
formal within-study comparison <strong>of</strong> efficacy and to exclude any increase <strong>of</strong> risk <strong>of</strong><br />
death due to de-escalation with S-1 by more than 33% compared to continuation<br />
<strong>of</strong> polychemotherapy. A non-inferiority testing approach on a 10% significance<br />
level will be used. Tissue- and blood based translational analysis will focus on the<br />
identification <strong>of</strong> a subgroup with a sustained benefit from S-1 based maintenance<br />
therapy. This trial is lead by the Gastric Cancer Group and Young Medical<br />
Oncologists group <strong>of</strong> the AIO (Arbeitsgemeinschaft Internistische Onkologie) with<br />
the participation <strong>of</strong> sites in 6 European countries.<br />
Clinical trial identification: EudraCT-Number: 2013-002742-37; ClinicalTrials.gov<br />
NCT02128243<br />
Legal entity responsible for the study: AIO-Studien-gGmbH Kuno-Fischer-Straße 8<br />
14057 Berlin Germany<br />
Funding: TAIHO Pharmaceuticals<br />
Disclosure: G.M. Haag: GMH has received support for participation in scientific<br />
congresses from Ipsen and Celgene. He receives research support from Taiho and<br />
Nordic. He has also served on advisory boards for San<strong>of</strong>i, Eli Lilly, Roche and Taiho.D.<br />
Jaeger: Consulting or Advisory Role: Bristol-Myers Squibb Travel, Accommodations,<br />
Expenses: Amgen; Bristol-Myers Squibb; Roche Pharma AG.F. Lordick: Lectured/<br />
chaired symposia: Amgen, Celgene, Lilly, Elsevier, Roche, Taiho. Travel costs: Amgen,<br />
Bayer, Lilly, Merck-Serono, Roche, Taiho. Research support: Fresenius, GSK, Nordic,<br />
Roche, Taiho, Merck- Serono. Adv. role: BMS, Lilly, Nordic, Roche, Taiho.All other<br />
authors have declared no conflicts <strong>of</strong> interest.<br />
710TiP<br />
A randomized, double-blind, placebo-controlled phase III<br />
study <strong>of</strong> ramucirumab versus placebo as second-line<br />
treatment in patients with hepatocellular carcinoma and<br />
elevated baseline alpha-fetoprotein following first-line<br />
sorafenib (REACH-2)<br />
A.X. Zhu 1 , P.R. Galle 2 , M. Kudo 3 , R. Finn 4 , L. Yang 5 ,P.Abada 6 , J.M. Llovet 7<br />
1 Medicine, Dana-Farber Cancer Institute, Boston, MA, USA, 2 Internal Medicine/<br />
Gastroenterology, Johannes Gutenberg-University Mainz, Mainz, Germany,<br />
3 Hepatology, Gastroenterology, Kinki University, Osaka, Japan, 4 Medicine, UCLA,<br />
Santa Monica, CA, USA, 5 Biostatistics, Eli Lilly and Company, Bridgewater, NJ,<br />
USA, 6 <strong>Oncology</strong>, Eli Lilly and Company, Indianapolis, IN, USA, 7 Department <strong>of</strong><br />
Medicine, Icahn School <strong>of</strong> Medicine at Mount Sinai, New York, NY, USA<br />
Background: Ramucirumab (RAM) is a humanized IgG1 monoclonal antibody that<br />
inhibits VEGF-A, C and D activation <strong>of</strong> the vascular endothelial growth factor receptor<br />
2 (VEGFR2). The Phase 3 REACH study assessed RAM versus placebo (PBO) in the<br />
treatment <strong>of</strong> patients with advanced hepatocellular carcinoma (HCC) after prior<br />
sorafenib. Significant improvement in overall survival (OS) in the overall population<br />
(N = 565) was not achieved (Hazard Ratio [HR] = 0.866; 95% CI 0.717–1.046;<br />
p = 0.1391); median OS was 9.2m for RAM and 7.6m for PBO. However, a meaningful<br />
improvement in OS was observed in a pre-specified subgroup <strong>of</strong> patients with baseline<br />
alpha-fetoprotein (AFP) ≥400ng/mL (N = 250)(HR = 0.674; p = 0.0059); median OS<br />
was 7.8m for RAM and 4.2m for PBO. The safety pr<strong>of</strong>ile <strong>of</strong> RAM in HCC patients was<br />
considered manageable.<br />
Trial design: REACH-2 is a randomized, double-blind, placebo-controlled phase III<br />
study <strong>of</strong> RAM and best supportive care (BSC) vs placebo and BSC in patients with<br />
HCC and elevated baseline AFP following prior therapy with sorafenib. Eligible<br />
patients will be randomized 2:1 to receive RAM (8mg/kg, IV) or PBO on Day 1 <strong>of</strong> each<br />
14-day cycle until disease progression or other discontinuation criteria. Eligible<br />
patients must have a diagnosis <strong>of</strong> HCC (tissue or tumor with classical imaging<br />
characteristics); prior sorafenib; Child-Pugh score 5 or 6; Barcelona Clinic Liver Cancer<br />
Stage C or Stage B disease not amenable/refractory to locoregional therapy; AFP ≥400<br />
ng/mL; ECOG performance status <strong>of</strong> 0 or 1. Patients with history <strong>of</strong> encephalopathy,<br />
ongoing clinically meaningful ascites, liver transplant, or hepatic locoregional therapy<br />
after sorafenib are not eligible. The primary objective is to assess OS for patients treated<br />
with RAM vs PBO. Target enrollment is 399 patients with final analysis at 318 events<br />
(20% censoring). Secondary objectives include progression free survival, objective<br />
response rate, safety, and patient focused outcomes. Additional objectives include<br />
assessment <strong>of</strong> biomarkers relevant to angiogenesis and HCC.<br />
Clinical trial identification: NCT02435433<br />
Legal entity responsible for the study: Eli Lilly and Company<br />
Funding: Eli Lilly and Company<br />
Disclosure: A.X. Zhu: Research funding from Eli Lilly and Company.P.R. Galle:<br />
Honoraria, Advisory Role, and Travel from Bayer, BMS, Lilly, Transgene, Arqule;<br />
Speaker for Bayer.M. Kudo: Honoraria from Bayer, Eisai, Ajinomoto, Kaken Pharma;<br />
Advisory Role for Taiho, Bayer, BMS, Kowa, Chugai. Research funding from Taiho,<br />
Bayer, BMS, Kowa, Chugai, Lilly, Novartis, Pfizer.R. Finn: Consultant: Pfizer, Merck,<br />
Bayer, Novartis, Bristol Meyers Squibb.L. Yang: Eli Lilly and Company employee and<br />
stock owner.P. Abada: Eli Lilly and Company employee and stock owner.J.M. Llovet:<br />
Honoraria, Consulting/Advisory roles for Eli Lilly, BMS, Merck, Blueprint, Eisai,<br />
Biocompatibles, Guerbert, Roche, Bayer, Genentech, Boehringer-Ingelheim, GSK,<br />
Celsion, Novartis. Research funding from Eli Lilly, Bayer, Novartis,<br />
Boehringer-Ingelheim.<br />
711TiP<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
A phase II study <strong>of</strong> S-1 with concurrent radiotherapy for<br />
elderly esophageal cancer patients<br />
T. Song, S. Lv<br />
Department <strong>of</strong> Radiation <strong>Oncology</strong>, Zhejiang Provincial People’s Hospital,<br />
Hangzhou, China<br />
Background: Concurrent chemoradiotherapy (CCRT) with 5-florouracil (5-Fu) and<br />
cisplatin (CDDP) are <strong>of</strong>ten associated with significant incidence <strong>of</strong> toxicities in elderly<br />
esophageal cancer patients. The compound drug S-1, composed <strong>of</strong> a combination <strong>of</strong><br />
tegafur-gimeracil-oteracil has been widely used in a variety <strong>of</strong> solid tumors, including<br />
esophageal cancer. Preclinical studies indicate that S-1 shows far superior anti-tumor<br />
activities than 5-Fu and enhances the sensitivity <strong>of</strong> cancer cells to the effects <strong>of</strong><br />
radiotherapy (RT).<br />
Trial design: This trial was designed as a prospective, single center, non-randomize,<br />
phase II study. The primary end point was the response rate which was assessed<br />
according to RECIST system 3-4 weeks after the completion <strong>of</strong> CCRT. The secondary<br />
end points were survival outcomes including OS and PFS and treatment-related<br />
toxicity. The study was designed to measure an objective response rate (CR plus PR) <strong>of</strong><br />
85% compared with a minimal, clinically meaningful response rate <strong>of</strong> 70%. Upon<br />
employing an α= 0.05 and a β = 0.20, the target number <strong>of</strong> patients required to achieve<br />
this level <strong>of</strong> significance was 20 cases. Considering some deviant cases, the preplanned<br />
number <strong>of</strong> enrolled patients was set to 22 patients. OS was determined as the time<br />
between the first day <strong>of</strong> CCRT and the last follow-up or the date <strong>of</strong> death. PFS was<br />
calculated from the date <strong>of</strong> treatment initiation to the date <strong>of</strong> documented failure or the<br />
vi240 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
date <strong>of</strong> the last follow-up for those remaining. Toxicities were evaluated according to<br />
the common toxicity criteria for adverse events version 3.0 (CTCAE v3.0). Preplanned<br />
concurrent S-1 (70mg/m 2 /day) was given on Days 1-14, every 3 weeks. Radiotherapy<br />
was delivered with a daily fraction <strong>of</strong> 1.8-2.0Gy to a total radiation dose <strong>of</strong> 54.0-60.0Gy.<br />
After CCRT, maintenance S-1 was repeated up to four cycles. Patients were regarded<br />
eligible according to the following criteria: i) ages ≥ 70 years; ii) cytologically or<br />
histologically confirmed esophageal carcinoma; iii) Eastern Cooperative <strong>Oncology</strong><br />
Group (ECOG) PS <strong>of</strong> 0 or 1; iv) no evidence <strong>of</strong> severe organ dysfunction; v) expectancy<br />
life >= 3 months; vi) at least one measurable lesion on CT, MRI or esophageal barium<br />
exam; and vii) no cancer treatments prior to enrollment.<br />
Clinical trial identification: NCT02716688.<br />
Legal entity responsible for the study: N/A<br />
Funding: Zhejiang Provincial People’s Hospital.<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
712TiP<br />
Cisplatin and gemcitabine plus ramucirumab or merestinib<br />
or placebo in first-line treatment for advanced or metastatic<br />
biliary tract cancer: A double-blind, randomized phase 2 trial<br />
J.W. Valle 1 , N. Bousmans 2 , W. Zhang 3 , R.A. Walgren 3 , A. Vogel 4<br />
1 Medical <strong>Oncology</strong>, University <strong>of</strong> Manchester/The Christie NHS Foundation Trust,<br />
Manchester, UK, 2 <strong>Oncology</strong>, Eli Lilly and Company Benelux, Belgium, UK,<br />
3 <strong>Oncology</strong>, Eli Lilly and Company, Indianapolis, IN, USA, 4 Gastroenterology,<br />
Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany<br />
Background: Angiogenesis and aberrant MET signaling are implicated in the<br />
pathogenesis and progression <strong>of</strong> invasive biliary tract cancers (BTC), including<br />
adenocarcinomas <strong>of</strong> the gallbladder, intra- and extra-hepatic bile ducts, and ampulla <strong>of</strong><br />
Vater. Study JSBF (NCT02711553) is a phase 2, multicenter, randomized,<br />
double-blinded, multi-arm study designed to evaluate the efficacy and safety <strong>of</strong><br />
standard <strong>of</strong> care (SOC) cisplatin and gemcitabine in combination with either<br />
merestinib (oral type II MET kinase inhibitor) or ramucirumab (human IgG1 VEGFR2<br />
monoclonal antibody) or respective placebo for the first-line treatment <strong>of</strong> advanced or<br />
metastatic BTC.<br />
Trial design: Patients (n = 300) with advanced or metastatic BTC meeting eligibility<br />
requirements will be randomized to IV ramucirumab 8 mg/kg, IV placebo, oral<br />
merestinib 80 mg, or oral placebo, in a 2:1:2:1 fashion, and stratified by primary tumor<br />
site, geographic region, and presence <strong>of</strong> metastases. In addition to the randomly<br />
assigned treatment, all patients will receive SOC 1st-line treatment with up to 8 cycles<br />
<strong>of</strong> IV cisplatin 25mg/m 2 + gemcitabine 1000mg/m 2 on days 1 and 8 <strong>of</strong> 21-day cycles.<br />
IV ramucirumab and placebo will be given on days 1 and 8 <strong>of</strong> each cycle; oral<br />
treatments will be taken daily. Investigational treatment or placebo may continue past 8<br />
cycles until disease progression or a criterion for discontinuation is met. The primary<br />
study endpoint is progression-free survival (PFS), analyzed by intention-to-treat.<br />
Secondary endpoints are overall survival, objective response, disease control rate, safety,<br />
pharmacokinetics, immunogenicity (ramucirumab), and patient reported outcomes.<br />
An exploratory endpoint is to correlate biomarkers with safety and clinical outcome;<br />
blood, plasma, serum, and tumor tissue collection is mandatory. The study began in<br />
May 2016. Primary analysis will occur after a minimum <strong>of</strong> 210 PFS events in the study<br />
have been observed to detect potential superiority <strong>of</strong> each investigational treatment<br />
over pooled control.<br />
Clinical trial identification: NCT02711553<br />
Legal entity responsible for the study: Eli Lilly and Company<br />
Funding: Eli Lilly and Company<br />
Disclosure: J.W. Valle: Eli Lilly- Honorarium.A. Vogel: Dr. Vogel reports personal<br />
from Eli Lilly and Company, outside the submitted work.All other authors have<br />
declared no conflicts <strong>of</strong> interest.<br />
713TiP<br />
Pembrolizumab vs best supportive care for second-line<br />
advanced hepatocellular carcinoma: Randomized, phase 3<br />
KEYNOTE-240 study<br />
R. Finn 1 , S.L. Chan 2 , A.X. Zhu 3 , J. Knox 4 , A-L. Cheng 5 , A. Siegel 6 , O. Bautista 7 ,P.<br />
A. Watson 8 , M. Kudo 9<br />
1 <strong>Oncology</strong>, Geffen School <strong>of</strong> Medicine at the University <strong>of</strong> California, Los Angeles,<br />
Los Angeles, CA, USA, 2 Clinical <strong>Oncology</strong>, Chinese University <strong>of</strong> Hong Kong<br />
Prince <strong>of</strong> Wales Hospital, Hong Kong, China, 3 Medicine, Massachusetts General<br />
Hospital, Boston, MA, USA, 4 Princess Margaret Cancer Centre, University <strong>of</strong><br />
Toronto, Toronto, ON, Canada, 5 Department <strong>of</strong> <strong>Oncology</strong>, National Taiwan<br />
University Hospital, Taipei, Taiwan, 6 <strong>Oncology</strong> Clinical Research, Merck & Co, Inc.,<br />
Kenilworth, NJ, USA, 7 <strong>Oncology</strong>, Merck & Co, Inc., Kenilworth, NJ, USA, 8 Clinical<br />
Research, Merck & Co, Inc., Kenilworth, NJ, USA, 9 Gastroenterology and<br />
Hepatology, Kindai University, Osaka, Japan<br />
Background: Liver cancer is the second leading cause <strong>of</strong> cancer deaths worldwide. The<br />
tyrosine kinase inhibitor sorafenib is the standard <strong>of</strong> care for first-line hepatocellular<br />
carcinoma (HCC), and there is currently no clear standard <strong>of</strong> care for second-line<br />
HCC. Because most HCC is driven by inflammation, there is a strong rationale to<br />
evaluate immunotherapy in patients with this type <strong>of</strong> cancer. The randomized,<br />
double-blind, placebo-controlled phase 3 KEYNOTE-240 study (ClinicalTrials.gov,<br />
NCT02702401) was designed to compare the efficacy and safety <strong>of</strong> pembrolizumab, an<br />
anti–PD-1 antibody, + best supportive care (BSC) versus placebo + BSC in patients<br />
with previously treated advanced HCC.<br />
Trial design: Eligibility criteria include age ≥18 years, histologically or cytologically<br />
confirmed diagnosis <strong>of</strong> HCC, documented progression after stopping treatment with<br />
sorafenib or intolerance to sorafenib, and disease not amenable to a curative treatment<br />
approach (eg, transplantation, surgery, or ablation). Patients must also have measurable<br />
disease confirmed by central imaging vendor per RECIST v1.1, Child-Pugh liver score<br />
A, ECOG performance status 0-1, and predicted life expectancy >3 months. ∼408<br />
patients will be randomized 2:1 to receive pembrolizumab 200 mg IV Q3W + BSC or<br />
placebo Q3W + BSC for up to 35 cycles (∼2 years) or until disease progression,<br />
unacceptable toxicity, or investigator decision. Randomization will be stratified by<br />
geographic region, macrovascular invasion, and α-fetoprotein. BSC will be provided by<br />
the investigator per local treatment practices. Response will be assessed every 6 weeks<br />
per RECIST v1.1 by central imaging vendor review. Adverse events (AEs) will be<br />
assessed throughout treatment and for 30 days thereafter (90 days for serious AEs) and<br />
graded per NCI CTCAE v4.0. Primary objectives are comparison <strong>of</strong> progression-free<br />
survival per RECIST v1.1 by central imaging vendor review and overall survival<br />
between treatment arms. Secondary objectives are comparison <strong>of</strong> objective response<br />
rate, duration <strong>of</strong> response, disease control rate, and time to progression per RECIST<br />
v1.1 by central imaging vendor review; and evaluation <strong>of</strong> safety and tolerability.<br />
Clinical trial identification: NCT02702401<br />
Legal entity responsible for the study: Merck & Co., Inc.<br />
Funding: Merck & Co., Inc.<br />
Disclosure: R. Finn: Consultant: Pfizer, Merck, Bayer, Novartis, Bristol Meyers Squibb.<br />
S.L. Chan: Advisory board member: Novartis, Merck Corporate-sponsored research:<br />
Novartis, Celgene, Eli Lilly, SIRTeX, AB Science, Merck, Medimmune.A. Siegel:<br />
Employment, stock ownership at Merck & Co, Inc..O. Bautista: Employee, shareholder<br />
at Merck & Co, Inc. Corporate research funding.P.A. Watson: Employee, stock owner:<br />
Merck & Co, Inc.M. Kudo: Bayer Co., Lecture fee.All other authors have declared no<br />
conflicts <strong>of</strong> interest.<br />
714TiP<br />
abstracts<br />
A multicenter phase 4 geriatric assessment directed trial to<br />
evaluate gemcitabine +/- nab-paclitaxel in elderly pancreatic<br />
cancer patients (GrantPax)<br />
N. Härtel 1 , J. Chi-Kern 1 , J. Betge 1 , S. Belle 1 , N. Schulte 1 , M. Maenz 2 ,<br />
U. Wedding 3 , M. Ebert 1<br />
1 II. Med. Klinik, Universitätsklinikum Mannheim, Mannheim, Germany, 2 Clinical<br />
Research, AIO-Studien-gGmbH, Berlin, Germany, 3 Department <strong>of</strong> Medicine II,<br />
Universitätsklinikum Jena, Jena, Germany<br />
Background: Recent studies demonstrated that nab-paclitaxel/gemcitabine “nab/gem”<br />
is an effective 1st line regimen for metastatic pancreatic ductal adenocarcinomas<br />
“mPDAC”. There is clinical evidence indicating “nab/gem” not to be feasible in<br />
mPDAC pts ≥75 yrs. However the analyzed patients lacked a geriatric assessment to<br />
properly evaluate their functional reserve. The aim <strong>of</strong> this study is to determine<br />
whether comprehensive geriatric assessments “CGAs” can predict the benefit from<br />
combined nab/gem therapy for elderly mPDAC pts in 1st line. A stratified treatment<br />
approach shall result in patient groups with a stable or improving CGA performance<br />
during the 1rst cycle <strong>of</strong> treatment.<br />
Trial design: Grantpax is a multicenter, open label phase 4 interventional trial with<br />
stratified parallel treatment groups (n = 45 / treatment arm). The hypothesis is that<br />
individualized assessment directed treatment algorithms identify elderly pts (≥70 yrs),<br />
who benefit from combined nab/gem therapy. The project uses a CGA to stratify pts as<br />
GOGO, SLOWGO or FRAIL. Depending on test results pts receive chemotherapy<br />
(GOGO: nab/gem; SLOWGO: gemcitabine) or best supportive care (FRAIL). After 1st<br />
cycle <strong>of</strong> chemotherapy (4 wks) a subsequent CGA and a safety assessment will be<br />
performed to assign pts to their definite treatment arm. The primary objective is that<br />
CGA-stratified pts do not decline in their CGA performance in response to<br />
chemotherapy measured as a loss <strong>of</strong> 5 points or less in Barthel’s activities <strong>of</strong> daily living<br />
(ADL1 vs. ADL2 during CGA core assessment). The expected proportion <strong>of</strong> pts with<br />
ADL decline in each treatment group is 6%. Under this assumption it shall be shown<br />
with 80% power at 1-sided significance level α <strong>of</strong> 0.05 that the proportion <strong>of</strong> pts with<br />
functional decline is less than 20% (n = 43 / group; ADL decline: n = 2 / group).<br />
Secondary endpoints are CGA scores during the course <strong>of</strong> therapy (CGA1-4), response<br />
rates, safety, survival rates, duration <strong>of</strong> treatment, cumulative dose, quality <strong>of</strong> life and<br />
discrepancy between CGA strata estimation by the investigator and true CGA<br />
assessment. Grantpax is the first trial that realizes a CGA-driven treatment approach to<br />
individualize cancer therapy for elderly pts.<br />
Clinical trial identification: AIO-GER-0115; EudraCT-No.: 2015-002890-40<br />
Legal entity responsible for the study: This Abstract have not been presented until<br />
now.<br />
Funding: Celgene Corporation<br />
Disclosure: N. Härtel: This investigator initiated trial is funded by the Celgene<br />
Coporation. Dr. Nicolai Haertel participated at advisory boards organized by the<br />
Celgene Corporation (presentation incl.). There are no further conflicts <strong>of</strong> interest to<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw371 | vi241
abstracts<br />
declare.M. Ebert: This investigator initiated trial is funded by the Celgene Coporation.<br />
Dr. Nicolai Haertel participated at advisory boards organized by the Celgene<br />
Corporation. There are no further conflicts <strong>of</strong> interest to declare.All other authors have<br />
declared no conflicts <strong>of</strong> interest.<br />
715TiP<br />
Global phase 3, randomized, double-blind,<br />
placebo-controlled study evaluating PEGylated recombinant<br />
human hyaluronidase PH20 (PEGPH20) plus nab-paclitaxel<br />
and gemcitabine in patients with previously untreated,<br />
hyaluronan (HA)-high, stage IV pancreatic ductal<br />
adenocarcinoma<br />
E. Van Cutsem 1 , A.E. Hendifar 2 , M. Reni 3 , W.P. Harris 4 , M. Ducreux 5 , A. Bullock 6 ,<br />
P. Corrie 7 , V. Heinemann 8 , T. Seery 9 , D. Chondros 10 , L. Zheng 11<br />
1 Digestive <strong>Oncology</strong>, University Hospital Gasthuisberg, Leuven, Belgium,<br />
2 Gastrointestinal <strong>Oncology</strong>, Samuel Oschin Cancer Center, Cedars-Sinai Medical<br />
Center, Los Angeles, CA, USA, 3 Medical <strong>Oncology</strong>, Ospedale San Raffaele, Milan,<br />
Italy, 4 Medical <strong>Oncology</strong>, University <strong>of</strong> Washington School <strong>of</strong> Medicine, Seattle,<br />
WA, USA, 5 Medical <strong>Oncology</strong>, Gustave Roussy, Paris, France,<br />
6 Hematology-<strong>Oncology</strong>, Beth Israel Deaconess Medical Center, Boston, MA,<br />
USA, 7 Medical <strong>Oncology</strong>, Cambridge Cancer Centre, Addenbrooke’s Hospital,<br />
Cambridge, UK, 8 Medical <strong>Oncology</strong>, Comprehensive Cancer Center,<br />
Krebszentrum München, Munich, Germany, 9 Hematology <strong>Oncology</strong>, UC Irvine<br />
Medical Center, Irvine, CA, USA, 10 Medical <strong>Oncology</strong>, Halozyme Therapeutics,<br />
Inc, San Diego, CA, USA, 11 Medical <strong>Oncology</strong>, The Johns Hopkins University<br />
Hospital, Baltimore, MD, USA<br />
Background: Poor outcome in pancreatic ductal adenocarcinoma (PDA) is associated<br />
partly with stromal hyaluronan (HA) accumulation, which may compromise<br />
chemotherapy access to tumors. In animal models, PEGPH20 degrades HA in tumors.<br />
Interim data from a phase 2 study showed that PEGPH20 plus chemotherapy improved<br />
efficacy over chemotherapy alone in tumors retrospectively identified to accumulate<br />
HA (“HA-High”). The objectives <strong>of</strong> this phase 3 study are to compare efficacy and<br />
safety <strong>of</strong> standard-dose nab-paclitaxel (NAB) and gemcitabine (GEM) combined with<br />
either PEGPH20 or placebo in patients with HA-High, previously untreated, Stage IV<br />
PDA. Primary endpoints are progression-free survival (PFS) and overall survival (OS).<br />
Secondary endpoints are objective response rate, duration <strong>of</strong> response, and safety.<br />
Trial design: 420 patients ≥18 years with untreated HA-High metastatic PDA, ECOG<br />
PS 0-1 will be randomized (stratified by geographic region: North America/Europe/<br />
Other) 2:1 to NAB 125 mg/m 2 + GEM 1000 mg/m 2 + PEGPH20 3.0 µg/kg or to<br />
placebo. Patients with HA-High tumors will be prospectively identified by a<br />
companion diagnostic test and scoring algorithm (Ventana Medical Systems, Inc.),<br />
which defines HA-High staining in the extracellular matrix as ≥50% <strong>of</strong> the tumor<br />
surface. Treatment will be provided in 4-week cycles (Wk 1-3, Wk 4 rest) until disease<br />
progression, unacceptable toxicity, death, or consent withdrawal. PEGPH20 or placebo<br />
will be given twice weekly (Cycle 1) then weekly (Cycles 2+), NAB + GEM once weekly<br />
for all cycles. Dexamethasone will be given before and after PEGPH20 to reduce<br />
treatment-related musculoskeletal symptoms and enoxaparin will be given to minimize<br />
thromboembolic events. Tumor response will be assessed by an independent central<br />
reader by RECIST v1.1. Adverse events will be graded per NCI CTCAE v4.03. An<br />
independent Data Monitoring Committee will evaluate safety and interim data for PFS<br />
and OS analyzed by an independent statistical analysis center.<br />
Clinical trial identification: EudraCT 2015-004068-13; NCT02715804<br />
Legal entity responsible for the study: Halozyme Therapeutics<br />
Funding: Halozyme Therapeutics<br />
Disclosure: E. Van Cutsem: Research funding: Halozyme.A.E. Hendifar: Advisory<br />
boards: Ipsen, Genentech; Research Support: Halozyme.M. Reni: Grants: Celgene,<br />
Baxalta, Merck-Serono, Helsinn. Personal Fees: Celgene, Baxalta, Merck-Serono,<br />
Boheringer, Lilly, Pfizer, Astra-Zeneca, Novocure, Genentech. Non-financial support:<br />
Celgene.M. Ducreux: Grants/research supports: Roche, Chugai, Pfizer. Honoraria/<br />
consultation fees: Roche, Celgene, Merck Serono, Amgen, Novartis, San<strong>of</strong>i, Pfizer, Lilly,<br />
Servier, Halozyme; Spouse. Head <strong>of</strong> BU, Sandoz.A. Bullock: Advisory board honoraria:<br />
Halozyme.P. Corrie: Advisory Board honoraria: Roche, Novartis, Bristol Myers Squibb,<br />
Merck, Baxalta; Ad hoc honoraria for lectures/meeting presentations: Novartis,<br />
Celgene; Research funding: Celgene.V. Heinemann: Advisory board: Merck, Roche,<br />
San<strong>of</strong>i, Amgen, Baxalta, SIRTEX, Halozyme, Lilly. Corporate-sponsored research:<br />
Merck, Roche, Amgen; Honorary fees for talks: Merck, Roche, San<strong>of</strong>i, Amgen, Baxalta,<br />
SIRTEX.T. Seery: Advisory board: Bayer.D. Chondros: Employee: Halozyme<br />
Therapeutics.L. Zheng: Stock: Z&L Medical International; Consulting/Advisory:<br />
Halozyme, Percans (personalized medicine), Lifemax (target therapy). Research<br />
funding: iTeos (research grant), Halozyme (not the clinical trial). Patents: Gvax<br />
(co-inventor, licensed to Aduro). All other authors have declared no conflicts <strong>of</strong><br />
interest.<br />
716TiP<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Pembrolizumab in patients with previously treated advanced<br />
hepatocellular carcinoma: Phase 2 KEYNOTE-224 study<br />
A. Zhu 1 , J. Knox 2 , M. Kudo 3 , S. Chan 4 , R. Finn 5 , A. Siegel 6 ,J.Ma 6 , P.A. Watson 6 ,<br />
A-L. Cheng 7<br />
1 Medical <strong>Oncology</strong>, Massachusetts General Hospital, Boston, MA, USA,<br />
2 Princess Margaret Cancer Centre, University <strong>of</strong> Toronto, Toronto, ON, Canada,<br />
3 Medicine, Kinki University School <strong>of</strong> Medicine, Osaka, Japan, 4 Medical <strong>Oncology</strong>,<br />
Prince <strong>of</strong> Wales Hospital, Shatin, Hong Kong, China, 5 Medicine, University <strong>of</strong><br />
California, Los Angeles, Los Angeles, CA, USA, 6 Medical <strong>Oncology</strong>, Merck & Co,<br />
Inc., Kenilworth, NJ, USA, 7 Graduate Institute <strong>of</strong> <strong>Oncology</strong>, National Taiwan<br />
University Hospital, Taipei, Taiwan<br />
Background: Liver cancer is the second leading cause <strong>of</strong> cancer deaths worldwide. The<br />
tyrosine kinase inhibitor sorafenib is the standard <strong>of</strong> care for first-line hepatocellular<br />
carcinoma (HCC), and there is currently no clear standard <strong>of</strong> care for second-line<br />
HCC. Because most HCC is driven by inflammation, there is a strong rationale to<br />
evaluate immunotherapy in patients with this type <strong>of</strong> cancer. The single-arm, multisite,<br />
phase 2 KEYNOTE-224 study (ClinicalTrials.gov, NCT02702414) was designed to<br />
evaluate the efficacy and safety <strong>of</strong> the anti–PD-1 antibody pembrolizumab in patients<br />
with previously treated advanced HCC.<br />
Trial design: Approximately 100 patients will be enrolled. Inclusion criteria include<br />
age ≥18 years, histologically or cytologically confirmed diagnosis <strong>of</strong> HCC, documented<br />
objective radiographic progression after stopping treatment with sorafenib or<br />
intolerance to sorafenib, and disease not amenable to a curative treatment approach<br />
(eg, transplantation, surgery, or ablation). Patients must also have measurable disease<br />
confirmed by central imaging vendor per RECIST v1.1, Child-Pugh liver score A,<br />
ECOG performance status 0-1, and predicted life expectancy >3 months. Patients will<br />
be allocated to receive pembrolizumab 200 mg IV Q3W for up to 35 cycles (∼2 years)<br />
or until disease progression, unacceptable toxicity, or investigator decision. Response<br />
will be assessed every 9 weeks per RECIST v1.1 by central imaging vendor review.<br />
Adverse events (AEs) will be assessed throughout treatment and for 30 days thereafter<br />
(90 days for serious AEs) and graded per NCI CTCAE v4.0. The primary end point is<br />
objective response rate per RECIST v1.1 by central imaging vendor review. Secondary<br />
end points are duration <strong>of</strong> response, disease control rate, time to progression, and<br />
progression-free survival per RECIST v1.1 by central imaging vendor review; overall<br />
survival; and safety and tolerability.<br />
Clinical trial identification: NCT02702414<br />
Legal entity responsible for the study: Merck & Co., Inc.<br />
Funding: Merck & Co., Inc.<br />
Disclosure: M. Kudo: Lecture fee from Bayer Co.S. Chan: Advisory Board Member:<br />
Novartis; Merck Corporate-Sponsored research: Novartis, Celgene, Eli Lilly, SIRTeX,<br />
AB Science, Merck, Medimmune.R. Finn: Consultant: Pfizer, Merck, Bayer, Novartis,<br />
Bristol Meyers Squibb.A. Siegel: Employee, stockholder Merck & Co., Inc.J. Ma:<br />
Employee, stockholder: Merck & Co., Inc.P.A. Watson: Employee and Stockholder,<br />
Merck & Co., Inc.All other authors have declared no conflicts <strong>of</strong> interest.<br />
vi242 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong> 27 (Supplement 6): vi243–vi265, 2016<br />
doi:10.1093/annonc/mdw372<br />
genitourinary tumours, prostate<br />
717O<br />
Metastasis free survival (MFS) is a surrogate for overall<br />
survival (OS) in localized prostate cancer (CaP)<br />
W. Xie 1 , C. Sweeney 2 , M. Regan 1 , M. Nakabayashi 2 , M. Buyse 3 , N. Clarke 4 ,<br />
L. Collette 5 , J. Dignam 6 , K. Fizazi 7 , M. Habibian 8 , S. Halabi 9 , P. Kant<strong>of</strong>f 10 ,<br />
W. Parulekar 11 , H.M. Sandler 12 , O. Sartor 13 , H. Soule 14 , M. Sydes 15 , B. Tombal 16 ,<br />
S. Williams 17<br />
1 Department <strong>of</strong> Biostatistics and Computational Biology, Dana-Farber Cancer<br />
Institute, Boston, MA, USA, 2 Lank Center for Genitourinary <strong>Oncology</strong>, Dana Farber<br />
Cancer Institute, Boston, MA, USA, 3 IDDI International Drug Development<br />
Institute, Louvain-la-Neuve, Belgium, 4 Urological <strong>Oncology</strong>, The Christie NHS<br />
Foundation Trust, Manchester, UK, 5 Headquarters, EORTC, Brussels, Belgium,<br />
6 Department <strong>of</strong> Public Health Science, University <strong>of</strong> Illlinois at Chicago, Chicago,<br />
IL, USA, 7 Department <strong>of</strong> Cancer Medicine, Institut Gustave Roussy, Villejuif,<br />
France, 8 R & D, UNICANCER, Paris, France, 9 Biostatistics and Bioinformatics,<br />
Duke University, Durham, NC, USA, 10 Department <strong>of</strong> Medicine, Memorial Sloan<br />
Kettering Cancer Center, New York, NY, USA, 11 NCIC Clinical Trials Group,<br />
Cancer Research Institute, Queen’s University, Kinston, ON, Canada, 12 Radiation<br />
<strong>Oncology</strong>, Cedars-Sinai Medical Center, Los Angeles, CA, USA, 13 Department Of<br />
Medicine & Urology, Tulane University, New Orleans, LA, USA, 14 PCF, Prostate<br />
Cancer Foundation, Santa Monica, CA, USA, 15 MRC Clinical Trials Unit, Institute <strong>of</strong><br />
Clinical Trials and Methodology-UCL, London, UK, 16 Institut de Recherche<br />
Clinique, Université Catholique de Louvain, Brussels, Belgium, 17 Urological Cancer<br />
Research, Peter MacCallum Cancer Centre, East Melbourne, Australia<br />
718O<br />
PTEN loss as a predictive biomarker for the Akt inhibitor<br />
ipatasertib combined with abiraterone acetate in patients with<br />
metastatic castration-resistant prostate cancer (mCRPC)<br />
J.S. de Bono 1 , U. De Giorgi 2 , C. Massard 3 , S. Bracarda 4 , D. Nava Rodrigues 1 ,<br />
I. Kocak 5 , A. Font 6 , J. Arranz Arija 7 , K. Shih 8 , G.D. Radavoi 9 ,W.Yu 10 , W. Chan 10 ,<br />
S. Gendreau 10 , L. Zhang 10 , R. Riisnaes 1 , M.J. Wongchenko 10 , D. Maslyar 10 ,<br />
V. Jinga 9<br />
1 The Royal Marsden, Institute <strong>of</strong> Cancer Research, London, UK, 2 Medical<br />
<strong>Oncology</strong>, Istituto Tumori della Romagna I.R.S.T., Meldola, Italy, 3 Medicine, Institut<br />
Gustave Roussy, Villejuif, France, 4 <strong>Oncology</strong>, Ospedale San Donato and U.O.C. <strong>of</strong><br />
Medical <strong>Oncology</strong>, Arezzo, Italy, 5 <strong>Oncology</strong>, Masaryk Memorial Cancer Institute,<br />
Brno, Curacao, 6 Institut Català d’Oncologia, Hospital Universitari Germans Trias i<br />
Pujol, Badalona, Spain, 7 Servicio de Oncologia Medica, Hospital General<br />
Universitario Gregorio Marañon, Madrid, Spain, 8 <strong>Oncology</strong>, Tennessee <strong>Oncology</strong>,<br />
Nashville, TN, USA, 9 <strong>Oncology</strong>, “Carol Davila” University <strong>of</strong> Medicine and<br />
Pharmacy, Bucharest, Romania, 10 <strong>Oncology</strong>, Genentech, Inc., South<br />
San Francisco, CA, USA<br />
abstracts<br />
© European Society for Medical <strong>Oncology</strong> 2016. Published by Oxford University Press on behalf <strong>of</strong> the European Society for Medical <strong>Oncology</strong>.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com.
abstracts<br />
719O<br />
First evidence <strong>of</strong> significant clinical activity <strong>of</strong> PD-1 inhibitors<br />
in metastatic, castration resistant prostate cancer (mCRPC)<br />
J.N. Graff 1 , J.J. Alumkal 1 , C.G. Drake 2 , G.V. Thomas 1 , W.L. Redmond 3 ,<br />
M. Farhad 1 , R. Slottke 1 , T.M. Beer 1<br />
1 Knight Cancer Institute, Oregon Health Science University, Portland, OR, USA,<br />
2 Sidney Kimmel Comprehensive Cancer Center and the Brady Urological Institute,<br />
Johns Hopkins University, Baltimore, MD, USA, 3 Robert W. Franz Cancer<br />
Research Center, Earle A. Chiles Research Institute, Providence Medical Center,<br />
Portland, OR, USA<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
deprivation therapy (ADT) over ADT alone. Patients with low volume disease have a<br />
more favorable natural history with ADT alone and the benefit <strong>of</strong> early D for this<br />
distinct subset requires longer follow-up<br />
Methods: 790 men were accrued from 7/28/06 to 11/21/2012 and randomized to ADT<br />
alone or ADT + D at 75mg/m2 every 3 weeks for 6 cycles within 4 mos <strong>of</strong> ADT.<br />
Patients were prospectively stratified into high volume (HV) vs. low volume (LV)<br />
disease (HV: visceral metastases and/or 4 or more bone metastases with at least one<br />
outside <strong>of</strong> the vertebral column and pelvis).<br />
Results: As <strong>of</strong> April 23, 2016, the median follow-up was 53.7 months and there were<br />
299 deaths <strong>of</strong> 513 HV pts and 100 deaths <strong>of</strong> the 277 LV pts. The overall median OS was<br />
57.6 mos for ADT + D [95% CI: (52.0, 63.9)] and 47.2 (41.8, 52.8) for ADT alone HR:<br />
0.73 (0.59, 0.89), p = 0.0018 (stratified log rank). Deaths and distribution <strong>of</strong> OS by arm<br />
and volume <strong>of</strong> disease are in Table 1. The evaluation <strong>of</strong> outcome by disease volume<br />
interaction with treatments revealed a p-value <strong>of</strong> 0.029 indicating the impact <strong>of</strong> early<br />
docetaxel differed between the HV and LV pts. The burden <strong>of</strong> cancer and therapy was<br />
assessed by FACT-P score and notable findings were (i) HV pts had lower baseline<br />
QOL than LV pts, (ii) there was a decline in QOL from baseline to 3 months in<br />
ADT + D LV ps and (iii) the lowest FACT-P score at 12 months was in ADT alone HV<br />
pts (see Table).<br />
Table: 720PD<br />
Survival ADT + D ADT p-value HR (95%CI*)<br />
LV Deaths / N (%) 51/134 (38.1%) 49/143 (34.3%)<br />
LV Median OS mos* 63.5 (58.3, 78.5) NR (59.8, - ) 0.86 1.04 (0.70, 1.55)<br />
HV Deaths/ N (%) 137/263 (52.1%) 162/250<br />
(64.8%)<br />
HV Median OS mos* 51.2 (45.2, 58.1) 34.4 (30.1, 42.1)
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
721PD<br />
FIRSTANA: Health-related quality <strong>of</strong> life (HRQL) and post-hoc<br />
analyses for the phase III study assessing cabazitaxel (C) vs<br />
docetaxel (D) in chemotherapy-naïve patients (pts) with<br />
metastatic castration-resistant prostate cancer (mCRPC)<br />
S. Oudard 1 , O. Sartor 2 , L. Sengeløv 3 , G. Daugaard 4 , F. Saad 5 , S. Hansen 6 ,<br />
M. Hjelm-Eriksson 7 , J. Jassem 8 , A. Thiery-Vuillemin 9 ,O.Caffo 10 , D. Castellano 11 ,<br />
P.N. Mainwaring 12 , J. Bernard 13 , L. Shen 14 , M. Chadjaa 15 , K. Fizazi 16<br />
1 Medical <strong>Oncology</strong> Service, Hopital European George Pompidou, Paris, France,<br />
2 Medicine and Urology, Tulane Cancer Center, New Orleans, LA, USA,<br />
3 Department <strong>of</strong> <strong>Oncology</strong>, University Hospital Herlev, Herlev, Denmark,<br />
4 Department <strong>of</strong> <strong>Oncology</strong>, Rigshospitalet, Copenhagen University Hospital,<br />
Copenhagen, Denmark, 5 Urologic <strong>Oncology</strong>, University <strong>of</strong> Montreal Health Center,<br />
Montreal, QC, Canada, 6 <strong>Oncology</strong>, Odense University Hospital, Odense,<br />
Denmark, 7 <strong>Oncology</strong>, Karolinska University Hospital-Radiumhemmet, Stockholm,<br />
Sweden, 8 <strong>Oncology</strong> and Radiotherapy, Medical University <strong>of</strong> Gdansk, Gdansk,<br />
Poland, 9 Medical <strong>Oncology</strong>, CHU Minjoz Besançon, Besançon, France, 10 Medical<br />
<strong>Oncology</strong>, Ospedale Sta Chiara, Trento, Italy, 11 Medical <strong>Oncology</strong>, University<br />
Hospital 12 De Octubre, Madrid, Spain, 12 Medical <strong>Oncology</strong>, ICON Cancer Care,<br />
Brisbane, Australia, 13 Research and Development, San<strong>of</strong>i Genzyme, Cambridge,<br />
MA, USA, 14 Research and Development, San<strong>of</strong>i Genzyme, Bridgewater, NJ, USA,<br />
15 Research and Development, San<strong>of</strong>i Genzyme, Vitry-sur-Seine, France,<br />
16 Department <strong>of</strong> Cancer Medicine, Institut Gustave Roussy, University <strong>of</strong> Paris<br />
Sud, Villejuif, France<br />
Background: FIRSTANA (NCT01308567), a post-marketing requirement, assessed the<br />
superiority <strong>of</strong> C 20 and 25 mg/m 2 (C20, C25) versus D, in terms <strong>of</strong> overall survival<br />
(OS), in chemotherapy-naïve mCRPC pts.<br />
Methods: Pts were randomized 1:1:1 to receive C20, C25 or D (plus prednisone).<br />
Primary endpoint was OS. Secondary endpoints: safety, progression-free survival<br />
(PFS), prostate-specific antigen (PSA) and tumor response (TR), HRQL (Functional<br />
Assessment <strong>of</strong> Cancer Therapy-Prostate [FACT-P] questionnaire) and pain response<br />
(PR; Present Pain Intensity score on McGill-Melzack scale). Post-hoc analyses assessed<br />
association <strong>of</strong> grade 3-4 neutropenia and neutrophil-lymphocyte ratio (NLR) with OS.<br />
Results: 1168 pts were randomized (C20 389; C25 388; D 391) with similar pt<br />
characteristics across arms. OS, PFS and PSA response were not significantly different;<br />
TR was superior for C25 vs D (Table). Rates <strong>of</strong> Grade 3–4 treatment-emergent adverse<br />
events were: C20 41.2%; C25 60.1%; D 46.0%. Change from baseline to Cycle 16 in<br />
FACT-P total score differed between the C20 and D arms. Grade 3-4 neutropenia and<br />
NLR < 3 were associated with increased OS in all arms.<br />
Table: 721PD<br />
C20 N = 389 C25 N = 388 D N = 391<br />
Median OS, mos HR vs D, 95% CI 24.5 1.009, 25.2 0.975, 0.819–1.16 24.3 -<br />
0.85–1.197<br />
Median PFS, mos 4.4 5.1 5.3<br />
TR,% 32.4 - 41.6 vs D p = 0.0370 30.9 -<br />
≥ 50% PSA decline,% 60.7 68.7 68.4<br />
PR,% 42.4 39.4 40.7<br />
Median OS, mos, 95% CI<br />
Grade 3─4 neutropenia No 22.3, 19.0─24.9 22.1, 16.7─23.7 22.3, 14.9─27.6<br />
Yes 27.9, 24.6─32.8 30.7, 25.7─34.0 27.3, 23.6─30.7<br />
p value 0.0193 0.0044 0.021<br />
NLR < 3 29.2, 25.7─33.7 31.6, 26.5─34.3 30.1, 25.1─35.7<br />
≥ 3 20.6, 15.7─22.4 23.4, 19.5─26.6 23.0, 19.0─25.5<br />
p value < 0.0001 0.0033 0.0011<br />
FACT-P total score<br />
Mean change from baseline to<br />
Cycle 16, 95% CI p value vs D<br />
N = 58 1.62,<br />
-2.11─5.35 0.019<br />
N = 58 0.5,<br />
-3.3─4.3 0.063<br />
N = 42 -3.83,<br />
-7.89─0.23 -<br />
Conclusions: In chemotherapy-naïve mCRPC pts, OS was not superior for C20 or C25<br />
vs D. TR was significantly higher for C25 vs D. C20 may have greater HRQL benefit<br />
than D. Grade 3–4 neutropenia and low NLR correlated with increased OS and may<br />
have prognostic value. Funding: San<strong>of</strong>i Genzyme.<br />
Clinical trial identification: NCT01308567<br />
Legal entity responsible for the study: San<strong>of</strong>i Genzyme<br />
Funding: San<strong>of</strong>i Genzyme<br />
Disclosure: S. Oudard: Personal fees from San<strong>of</strong>i, during the conduct <strong>of</strong> the study and<br />
personal fees from San<strong>of</strong>i, Janssen, Astellas, Roche, and BMS, outside the submitted<br />
work.O. Sartor: Personal fees and grants from San<strong>of</strong>i, outside the submitted work.L.<br />
Sengeløv: Grants from MSD, grants from Ipsen Pharma, grants from Roche, grants<br />
from Ely Lilly, grants from AstraZeneca, personal fees from Novo Nordisk, outside the<br />
submitted work.F. Saad: Personal fees from Abbvie, Astellas, Janssen, Amgen, San<strong>of</strong>i,<br />
Novartis, Bavarian Nordic, Millennium, Bayer, and grants from Astellas, Bayer,<br />
Amgen, Janssen, Bristol-Myers Squibb, Oncogenex, San<strong>of</strong>i, outside the submitted<br />
work.A. Thiery-Vuillemin: Personal fees from San<strong>of</strong>i, during the conduct <strong>of</strong> the study,<br />
and personal fees from AstraZeneca, Janssen, and Astellas outside the submitted work.<br />
O. Caffo: Personal fees from San<strong>of</strong>i Aventis, Astellas, Bayer, and Janssen, outside the<br />
submitted work.P.N. Mainwaring: Personal fees from Roche, Astellas, Janssen,<br />
Novartis, Merck, Pfizer, other from Xing technologies, Astellas, Janssen, Merck, Pfizer,<br />
outside the submitted work.J. Bernard: Employee <strong>of</strong> San<strong>of</strong>i Genzyme.L. Shen:<br />
Employee <strong>of</strong> San<strong>of</strong>i GenzymeM. Chadjaa: Employee <strong>of</strong> San<strong>of</strong>i.K. Fizazi: Personal fees<br />
from Janssen, Astellas, San<strong>of</strong>i, Orion Pharma, Dendreon, Curevac, Novartis, Takeda,<br />
Ipsen, other from Amgen, and personal fees from Janssen, San<strong>of</strong>i, Astellas, Takeda,<br />
outside the submitted work.All other authors have declared no conflicts <strong>of</strong> interest.<br />
722PD<br />
PROSELICA: Health-related quality <strong>of</strong> life (HRQL) and<br />
post-hoc analyses for the phase 3 study assessing<br />
cabazitaxel 20 (C20) vs 25 (C25) mg/m2 post-docetaxel (D) in<br />
patients (pts) with metastatic castration-resistant prostate<br />
cancer (mCRPC)<br />
J.S. de Bono 1 , A-C. Hardy-Bessard 2 , C.S. Kim 3 , L. Géczi 4 , D. Ford 5 , L. Mourey 6 ,<br />
J. Carles 7 , P. Parente 8 , A. Font 9 , G. Kacsó 10 , M. Chadjaa 11 , W. Zhang 12 ,<br />
J. Bernard 13 , M. Eisenberger 14<br />
1 Division <strong>of</strong> Clinical Studies, Drug Development Unit, Royal Marsden NHS<br />
Foundation Trust/The Institute <strong>of</strong> Cancer Research, Sutton, UK, 2 Centre<br />
Armoricain d’Oncologie, CARIO, Plérin, France, 3 Urology, Prostate Center,<br />
Urologic Cancer Center, Asan Medical Center, Seoul, Republic <strong>of</strong> Korea, 4 Medical<br />
<strong>Oncology</strong> and Clinical Pharmacology, National Institute <strong>of</strong> <strong>Oncology</strong>, Budapest,<br />
Hungary, 5 City Hospital, Cancer Center Queen Elizabeth Hospital, Birmingham,<br />
UK, 6 Institut Claudius Regaud, IUCT-O, Toulouse, France, 7 Vall d’Hebron<br />
University Hospital, Vall d’Hebron Institute <strong>of</strong> <strong>Oncology</strong>, Barcelona, Spain,<br />
8 Eastern Health Clinical School, Monash University, Box Hill Hospital, Melbourne,<br />
Australia, 9 Institut Català d’Oncologia, Hospital Universitari Germans Trias i Pujol,<br />
Badalona, Spain, 10 Medical <strong>Oncology</strong>, Amethyst Radiotherapy Center-Cluj, Cluj<br />
Napoca, Romania, 11 Research and Development, San<strong>of</strong>i, Vitry-sur-Seine, France,<br />
12 Research and Development, San<strong>of</strong>i Genzyme, Bridgewater, NJ, USA,<br />
13 Research and Development, San<strong>of</strong>i Genzyme, Cambridge, MA, USA, 14 The<br />
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Hospital,<br />
Baltimore, MD, USA<br />
Background: PROSELICA (NCT01308580) was a post-marketing requirement to<br />
demonstrate non-inferiority <strong>of</strong> C20 vs C25 in terms <strong>of</strong> overall survival (OS) in mCRPC<br />
pts who progressed on D.<br />
Methods: Post-D mCRPC pts were randomized 1:1 to receive C25 or C20 (+<br />
prednisone). To show non-inferiority <strong>of</strong> C20 (preservation <strong>of</strong> ≥ 50% <strong>of</strong> the incremental<br />
C25 efficacy over mitoxantrone in the TROPIC trial) with 95% confidence interval<br />
(CI), hazard ratio (HR) could not exceed 1.214 under a 1-sided 98.89% CI after interim<br />
analyses. Secondary endpoints: progression-free survival (PFS), prostate-specific<br />
antigen (PSA) and tumor response (TR), safety, HRQL (Functional Assessment <strong>of</strong><br />
Cancer Therapy-Prostate [FACT-P] questionnaire) and pain response (PR; Present<br />
Pain Intensity score on McGill-Melzack scale). Post-hoc analyses assessed association<br />
<strong>of</strong> Grade 3–4 neutropenia on treatment and baseline (BL) neutrophil-lymphocyte ratio<br />
(NLR) with OS.<br />
Results: 1200 pts were randomized (598 C20; 602 C25). BL pt characteristics were similar<br />
for C20 and C25. See Table for efficacy results. Rates <strong>of</strong> Grade 3–4 treatment-emergent<br />
adverse events were 39.7% C20, 54.5% C25. Change in FACT-P total score from BL was<br />
not significantly different for C20 and C25. Grade 3–4 neutropenia on treatment and BL<br />
NLR < 3 was associated with increased OS in both arms (Table).<br />
Table: 722PD<br />
C20 N = 598 C25 N = 602<br />
Median OS, mos 13.4 14.5<br />
98.89% upper CI <strong>of</strong> HR = 1.184<br />
Median PFS, mos 2.9 3.5<br />
HR, 95% CI = 1.099, 0.97–1.24<br />
≥ 50% PSA decline,<br />
%<br />
29.5 42.9<br />
P < 0.001<br />
TR, % 18.5 23.4<br />
P = 0.192<br />
PR, % 34.7 37.3<br />
P = 0.479<br />
FACT-P total score<br />
Least square means N = 137 0.02, -2.57–2.61 N = 141 1.33, -1.26–3.93<br />
change from BL to<br />
P = 0.369<br />
Cycle 10, 95% CI<br />
Median OS, mos, 95% CI<br />
Grade 3–4 neutropenia<br />
No Yes 14.8, 12.7–16.3 P = 0.073 14.6, 11.8–16.5 P = 0.051<br />
16.1, 13.7–18.3<br />
16.3, 15.1–18.2<br />
BL NLR<br />
abstracts<br />
and CNCSIS.M. Chadjaa: Is an employee <strong>of</strong> San<strong>of</strong>i Genzyme.W. Zhang: Is an employee<br />
<strong>of</strong> San<strong>of</strong>i Genzyme and owns stock in San<strong>of</strong>i Genzyme.J. Bernard: Is an employee <strong>of</strong><br />
San<strong>of</strong>i Genzyme.M. Eisenberger: Provided a consulting/advisory role for and received<br />
reimbursement for expenses from Astellas, Bayer and San<strong>of</strong>i Genzyme, has received<br />
honoraria from San<strong>of</strong>i Genzyme and research funding from San<strong>of</strong>i Genzyme, Tokai<br />
Pharmaceuticals and Genentech.All other authors have declared no conflicts <strong>of</strong><br />
interest.<br />
723PD<br />
Modelling relapse in patients with high-risk localised<br />
prostate cancer treated randomly in the GETUG 12 phase III<br />
trial reveals two populations <strong>of</strong> relapsing patients<br />
C. Vicier 1 , L. Faivre 2 , F. Lesaunier 3 , R. Delva 4 , G. Gravis 5 , F. Rolland 6 , F. Priou 7 ,<br />
J-M. Ferrero 8 , N. Houede 9 , L. Mourey 10 , C. Theodore 11 , I. Krakowski 12 ,<br />
J-F. Berdah 13 , M. Baciuchka 14 , B. Laguerre 15 , A. Flechon 16 , S. Oudard 17 ,<br />
M. Habibian 18 , S. Culine 19 , K. Fizazi 1<br />
1 Cancer Medicine, Institut de Cancérologie Gustave Roussy, Villejuif, France,<br />
2 Biostatitics and Epidemiology, Institut Gustave Roussy, Villejuif, France, 3 Medical<br />
<strong>Oncology</strong>, Centre Francois Baclesse, Caen, France, 4 Medical <strong>Oncology</strong>, Centre<br />
Paul Papin, Angers, France, 5 Medical <strong>Oncology</strong>, Institute Paoli Calmettes,<br />
Marseille, France, 6 Medical <strong>Oncology</strong>, CHU de Nantes, Nantes, France, 7 Medical<br />
<strong>Oncology</strong>, CHD Vendee - Hopital Les Oudairies, La Roche Sur Yon, France,<br />
8 Medical <strong>Oncology</strong>, Centre Antoine Lacassagne, Nice, France, 9 Medical<br />
<strong>Oncology</strong>, CHU Nimes, Caremeau, Nimes, France, 10 Medical <strong>Oncology</strong>, Centre<br />
Claudius-Regaud, Toulouse, France, 11 Medical <strong>Oncology</strong>, Hopital Foch Service<br />
d’Oncologie, Suresnes, France, 12 Medical <strong>Oncology</strong>, Centre Alexis Vautrin, Nancy,<br />
France, 13 Medical <strong>Oncology</strong>, Clinique Sainte-Marguerite, Hyeres, France,<br />
14 Medical <strong>Oncology</strong>, CHU La Timone Adultes, Marseille, France, 15 Medical<br />
<strong>Oncology</strong>, Centre Eugene - Marquis, Rennes, France, 16 Medical <strong>Oncology</strong>, Centre<br />
Léon Bérard, Lyon, France, 17 Medical <strong>Oncology</strong>, Hopital European George<br />
Pompidou, Paris, France, 18 Research and development, UNICANCER, Paris,<br />
France, 19 Medical <strong>Oncology</strong>, Hôpital St. Louis, Paris, France<br />
Background: The patterns <strong>of</strong> relapse in patients with high-risk prostate cancer treated<br />
with modern therapy are poorly described. In the present study, we aimed to analyse<br />
the patterns <strong>of</strong> relapse in the randomized phase III trial Groupe d’Etude des Tumeurs<br />
Uro-Genitales 12 (GETUG 12) in patients with high-risk localised prostate cancer.<br />
Methods: Patients were enrolled and randomly assigned to receive either androgen<br />
deprivation therapy (ADT) with goserelin every 3 months for 3 years combined<br />
upfront with 4 cycles <strong>of</strong> docetaxel and estramustine (ADT + DE) or ADT alone, plus<br />
local therapy. We analysed the pattern <strong>of</strong> second event-free-survival (PFS2) in patients<br />
with biochemical progression (bPFS). Adjusting factors were stratification factors (T<br />
stage, Gleason score, baseline PSA, and pN status) and treatment.<br />
Results: 413 patients were randomized from 2002 to 2006, 206 treated with ADT alone<br />
and 207 with ADT + DE. Median follow-up was 8.8 years (IQR: 8.1-9.7). A total <strong>of</strong> 130<br />
patients exhibited biochemical relapse, with a median bPFS <strong>of</strong> 5 years (range: 0.23-10.4)<br />
for relapsing patients. 77/130 patients subsequently developed a second event: metastatic<br />
progression (53), clinical progression (13) and death (7). The analysis <strong>of</strong> relapsing patients<br />
revealed the following data: 1) the median time from biochemical failure to a clinical event<br />
was2years[95%CI:1.07– 2.91]; 2) biochemical relapses were rare (n = 27; 21%) within<br />
the first 3 years ( 20 µg/L.<br />
Conclusions: Our data demonstrate, that the first systematic TRUS-gb does indeed<br />
diagnose patients at risk <strong>of</strong> PCa death. Our study supports the results from ERSPC,<br />
underlining that men with low PSA and an initial normal TRUS-gb rarely harbor lethal<br />
PCa. This information has implications for the future strategy <strong>of</strong> how to advise men<br />
with benign biopsies.<br />
Legal entity responsible for the study: N/A<br />
Funding: The Danish Cancer Society, The Capital Region <strong>of</strong> Denmarks Fund for<br />
Health Research, Krista and Viggo Petersens Foundation<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
725PD<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Pembrolizumab for patients with advanced prostate<br />
adenocarcinoma: Preliminary results from the KEYNOTE-028<br />
study<br />
A. Hansen 1 , C. Massard 2 , P.A. Ott 3 , N. Haas 4 , J. Lopez 5 , S. Ejadi 6 , J. Wallmark 7 ,<br />
B. Keam 8 , J-P. Delord 9 , R. Aggarwal 10 , M. Gould 11 ,P.Qiu 12 , S. Saraf 13 ,<br />
S. Keefe 14 , S.A. Piha-Paul 15<br />
1 <strong>Oncology</strong>, Princess Margaret Cancer Centre, Toronto, ON, Canada, 2 Medicine,<br />
Istitute Gustave Roussy, Villejuif, France, 3 Immunooncology, Harvard Medical<br />
School, Boston, MA, USA, 4 Medical <strong>Oncology</strong>, Hospital <strong>of</strong> the University <strong>of</strong><br />
Pennsylvania, Philadelphia, PA, USA, 5 Medical <strong>Oncology</strong>, Institute <strong>of</strong> Cancer<br />
Research ICR, London, UK, 6 Clinical Trials, Virginia G. Piper Cancer Center,<br />
Scottsdale, USA, 7 <strong>Oncology</strong>, Associates in <strong>Oncology</strong> & Hematology, Rockville,<br />
MD, USA, 8 Internal Medicine, Seoul National University Hospital, Seoul, Korea,<br />
Republic <strong>of</strong>, 9 <strong>Oncology</strong>, Institut Claudius Régaud, Toulouse, France, 10 Medicine,<br />
UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA,<br />
USA, 11 Clinical Research, Merck & Co, Inc., Kenilworth, NJ, USA, 12 Genomic<br />
Biomarkers, Merck & Co, Inc., Kenilworth, NJ, USA, 13 Biostats, Merck & Co., Inc.,<br />
Kenilworth, NJ, USA, 14 <strong>Oncology</strong>, Merck & Co., Inc., Kenilworth, NJ, USA,<br />
15 Department <strong>of</strong> Investigational Cancer Therapeutics, UT MD Anderson Cancer<br />
Center, Houston, TX, USA<br />
Background: Therapies currently available for castrate-refractory prostate cancer<br />
(CRPC) provide only modest clinical benefit. Expression <strong>of</strong> the programmed death 1<br />
(PD-1) receptor and its ligand, PD-L1, has been reported in CRPC. Pembrolizumab, an<br />
anti–PD-1 antibody, blocks the interaction between PD-1 and PD-L1. KEYNOTE-028<br />
(NCT02054806) is a nonrandomized, phase 1b trial to evaluate the safety and efficacy<br />
<strong>of</strong> pembrolizumab in 20 advanced solid tumor cohorts. Herein are the results from the<br />
prostate adenocarcinoma cohort <strong>of</strong> this study.<br />
Methods: Key eligibility criteria included advanced adenocarcinoma <strong>of</strong> the prostate,<br />
failure <strong>of</strong> standard therapy, measurable disease per RECIST v1.1, ECOG PS 0-1, and<br />
PD-L1 expression in ≥1% <strong>of</strong> tumor or stroma cells by immunohistochemistry.<br />
Pembrolizumab 10 mg/kg was administered every 2 weeks (wk) for up to 24 months<br />
(mo) or until disease progression (PD), intolerable toxicity, death, or withdrawal <strong>of</strong><br />
consent. Stable patients (pts) with PD could remain on treatment until PD was<br />
confirmed by a follow-up scan. Response was assessed every 8 wk for the first 6 mo and<br />
every 12 wk thereafter. The primary end point was ORR per RECIST v1.1 by<br />
investigator review. As an exploratory objective, a NanoString platform was used to<br />
assess baseline tumor tissue for the gene expression pr<strong>of</strong>ile (GEP) <strong>of</strong> an 18-gene panel<br />
hypothesized to be associated with a Th1-derived IFN-γ immune response.<br />
Results: Of the 23 pts enrolled in this cohort, median age was 65 years, 74% had an<br />
ECOG PS <strong>of</strong> 1 (1 pt had an ECOG PS <strong>of</strong> 2), and 74% received ≥2 prior therapies for<br />
metastatic disease. As <strong>of</strong> February 17, 2016, median follow-up duration was 33 wk<br />
(range, 6-79 wk). Fourteen pts (61%) had treatment-related adverse events (TRAEs),<br />
most commonly nausea (n = 3, 13%). Three pts (13%) had grade 3-4 TRAEs; 1 pt had<br />
grade 3 fatigue, 1 pt had grade 3 peripheral neuropathy, and 1 pt had grade 3 asthenia<br />
and grade 4 lipase increase. No pts died or discontinued pembrolizumab because <strong>of</strong> a<br />
TRAE. Three pts had a confirmed PR, for an ORR <strong>of</strong> 13% (95% CI, 3%-34%); median<br />
duration <strong>of</strong> response was 59 wk (range, 28-62 wk). Stable disease rate was 39% (n = 9;<br />
vi246 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
95% CI, 20%-61%). Median OS was 8 mo, and the 6-mo PFS rate was 39%. Two pts<br />
remained on treatment at data cut<strong>of</strong>f. Exploratory assessment <strong>of</strong> the relationship<br />
between GEP score and clinical outcome revealed the putative T cell inflamed signature<br />
to be associated with better clinical outcome, consistent with pembrolizumab findings<br />
published previously.<br />
Conclusions: Pembrolizumab produced durable responses among heavily pretreated<br />
pts with advanced PD-L1–positive prostate cancer. Treatment was associated with a<br />
favorable side-effect pr<strong>of</strong>ile.<br />
Clinical trial identification: NCT02054806<br />
Legal entity responsible for the study: Merck & Co. Inc.<br />
Funding: Merck & Co., Inc.<br />
Disclosure: C. Massard: Advisory Board Member: Astra Zeneca, Bayer, Celgene,<br />
Genentech, Ipsen, Jansen, Lilly, Novartis, Pfizer, Roche, San<strong>of</strong>i, Orion, MedImmune,<br />
New <strong>Oncology</strong>, DebioPharm.M. Gould, P. Qiu, S. Saraf, S. Keefe: Employee, stock<br />
ownership Merck & Co., Inc.S.A. Piha-Paul: Corporate-sponsored research:<br />
GlaxoSmithKline, Novartis, Puma Biotechnology, Inc., Merck, Sharp and Dohme,<br />
BioMarin Pharmaceutical, Inc., Principia Biopharma, Inc., Abbvie, XuanZhu<br />
Biopharma, Helix BioPharma Corp., Incyte, Inc., Curis.All other authors have declared<br />
no conflicts <strong>of</strong> interest.<br />
726PD<br />
Early responses to enzalutamide in AR-V7 positive first line<br />
metastatic castration-resistant prostate cancer (mCRPC). A<br />
prospective SOGUG clinical trial: The PREMIERE study<br />
E. Grande 1 , M.P. Fernández Pérez 2 , A. Font 3 , S. Vazquez 4 , B. Mellado 5 ,<br />
O. Fernandez Calvo 6 , M.J. Méndez Vidal 7 , M.A. Climent 8 , A. González del Alba 9 ,<br />
E. Gallardo 10 , A. Rodríguez Sánchez 11 , C. Santander 12 , M.I. Sáez 13 , I. Duran 14 ,<br />
J. Puente 15 , T. Alonso Gordoa 1 , J. Tudela 16 , A. Martínez 17 , D. Castellano 18 ,<br />
E. González Billalabeitia 2<br />
1 Medical <strong>Oncology</strong>, Hospital Universitario Ramon y Cajal, Madrid, Spain, 2 Servicio<br />
de Hematología y Oncología Médica, Hospital G.U. Morales Meseguer.<br />
Universidad Católica de Murcia., Murcia, Spain, 3 Medical <strong>Oncology</strong>, Catalan<br />
Institute <strong>of</strong> <strong>Oncology</strong> (ICO Badalona), Hospital Germans Trias i Pujol, Badalona,<br />
Spain, 4 Medical <strong>Oncology</strong>, Hospital Lucus Augusti, Lugo, Spain, 5 Medical<br />
<strong>Oncology</strong>, Hospital Clinic y Provincial de Barcelona, Barcelona, Spain, 6 Medical<br />
<strong>Oncology</strong>, Complejo Hospitalario De Orense, Ourense, Spain, 7 Medical <strong>Oncology</strong>,<br />
Hospital Universitario Reina S<strong>of</strong>ía, Cordoba, Spain, 8 Medical <strong>Oncology</strong>, Fundación<br />
Instituto Valenciano de Oncología, Valencia, Spain, 9 Medical <strong>Oncology</strong>, Hospital<br />
Universitario Son Espases, Palma de Mallorca, Spain, 10 Medical <strong>Oncology</strong>,<br />
Hospital de Sabadell Corporacis Parc Tauli, Sabadell, Spain, 11 Medical <strong>Oncology</strong>,<br />
University Hospital <strong>of</strong> León, Leon, Spain, 12 Medical <strong>Oncology</strong>, Hospital Miguel<br />
Servet, Zaragoza, Spain, 13 Medical <strong>Oncology</strong>, Hospital Universitario Virgen de la<br />
Victoria, Malaga, Spain, 14 Medical <strong>Oncology</strong>, Hospital Universitario Virgen del<br />
Rocio, Seville, Spain, 15 Medical <strong>Oncology</strong>, Hospital Clinico Universitario San<br />
Carlos, Madrid, Spain, 16 Servicio de Anatomía Patológica, Hospital Universitario<br />
Morales Meseguer, Murcia, Spain, 17 Biobanco Región de Murcia, Nodo 3,<br />
Hospital Universitario Morales Meseguer, Murcia, Spain, 18 Medical <strong>Oncology</strong>,<br />
University Hospital 12 De Octubre, Madrid, Spain<br />
Background: AR-V7 has been proposed as a biomarker for early resistance to<br />
enzalutamide in heavily pretreated mCRPC. We prospectively assessed the effect <strong>of</strong><br />
AR-V7 expression in basal CTCs on response to first-line enzalutamide in<br />
chemo-naive mCRPC patients (pts).<br />
Methods: Phase II open-label study in chemo-naïve mCRPC pts ECOG 0-1. PCWG2<br />
criteria are used for response evaluation. Pts received enzalutamide 160 mg/d until clinical<br />
and/or radiographic disease progression. Primary objective is to assess the predictive value<br />
<strong>of</strong> TMPRSS2-ERG and secondary endpoints included assessment <strong>of</strong> biomarkers <strong>of</strong><br />
resistance in CTCs, including AR-V7. Here we report the first results on AR-V7. Selection<br />
and detection <strong>of</strong> CTCs were performed using AdnaTest PCa Select and Detect kits<br />
following manufacturer’s instructions. Specific primers were used to detect AR-V7 by<br />
qPCR. The accuracy <strong>of</strong> the PCR product was confirmed by Sanger sequencing.<br />
Results: 98 pts were included between February 5th and November 23th 2015. Pts<br />
characteristics are: median age 77.8y; ECOG 0/1 in 55/45%, median basal PSA 20 ng/dl<br />
and metastastic sites were: bone (81%), LN (50%), lung (15%) and liver (3%). With a<br />
median follow-up <strong>of</strong> 8.2 months, confirmed PSA response >50%/ > 90% was 80.6%/<br />
39.8%. Radiologic response was: PR 12.5%, SD 77.1% and PD 10.4%. Basal CTCs were<br />
observed in 35.7% (N = 35). AR-V7 expression in CTCs was observed in 24.2% (N = 8).<br />
In the AR-V7 pts, PSA response >50% was present in 50% (4/8 pts), and >90 in 37.5%<br />
(3/8pts). Radiologic response was: PR 12.5% (1/8), SD 50% (4/8), PD 25 (2/8). One pt<br />
(1/8) was lost <strong>of</strong> follow-up. No association was observed between AR-V7 and primary<br />
resistance (p = 0,67).<br />
Conclusions: Detection <strong>of</strong> AR-V7 in basal CTCs is not an absolute predictor for early<br />
resistance to enzalutamide in first-line chemo-naive mCPRC. Further follow-up is<br />
needed to assess the quality <strong>of</strong> the responses and its impact on other efficacy endpoints<br />
(PFS and OS). Additional biomarkers are needed to guide treatment selection in this<br />
scenario.<br />
Clinical trial identification: EudraCT: 2014-003192-28 / NCT02288936<br />
Legal entity responsible for the study: SOGUG (Spanish <strong>Oncology</strong> Genitourinary<br />
Group)<br />
Funding: Astellas<br />
Disclosure: E. Grande: Research grant: Astellas. Speaker: Astellas Advisory: Janssen.A.<br />
González del Alba: Advisory Boards: Bayer, San<strong>of</strong>i, Pfizer, Novartis, BMS.I. Duran:<br />
Compensated Advisory Board: Roche-Genentech, Jansen, Amgen, Astellas, Pierre<br />
Fabre and Novartis. Research Funding: Jansen, San<strong>of</strong>i.All other authors have declared<br />
no conflicts <strong>of</strong> interest.<br />
727PD<br />
Abiraterone acetate (AA) followed by randomization to<br />
dasatinib (D) or sunitinib malate (S) in metastatic castrate<br />
resistant prostate cancer (mCRPC)<br />
E. Efstathiou, A. Tsikkinis, S. Wen, E. Li Ning Tapia, A. Hoang, A. Aparicio,<br />
S-M. Tu, G. Rangel, P. Troncoso, P. Corn, J. Araujo, C. Logothetis<br />
Genitourinary Medical <strong>Oncology</strong>, MD Anderson Cancer Center, Houston, TX, USA<br />
Background: Src and Vegf, targeted by D and S respectively, have been implicated in<br />
CRPC progression. Moreover the unmet need for predictive markers has become<br />
pressing. We conducted a study to determine if the addition <strong>of</strong> either agents could<br />
prolong time to progression (TTP) on AA and to test a prespecified molecular<br />
signature.<br />
Methods: This is a phase II study <strong>of</strong> AA in bone mCRPC patients randomized upon<br />
progression to combination with D or S, comparing the two treatment strategy.<br />
Endpoints include PFS, safety, survival, assessment <strong>of</strong> aprespecified signaling signature<br />
in pts with benefit vs primary resistance to AA (progression ≤ 4 months). Pts had<br />
pretreatment bone biopsy. Tumor Markers included, Androgen Receptor-N terminal<br />
(AR-N), AR-C terminal (AR-C), CYP17, Ki67, GR, ERG, Ki67 (%), pSrc, vegf, DNA<br />
repair genes by IHC and steroids by LCMS.<br />
Results: Study (03/2011-02/2015) accrued 179 bone mCRPC pts and median follow up<br />
27ms (9-57). Medians: Age, 68 ys (range 45-87), PS ECOG 1 (range 0-1) baseline PSA<br />
20.6 (range 0.5-1655). 27 (16%) pts have visceral mets, 40 (22%) prior chemo.<br />
Diagnostic Gleason Score was ≥8 in 71%. Upon progression 128/179 pts were<br />
randomized: 64 to D (AD) and 64 to S (AS). Of these 61 crossed over and 30 are still on<br />
treatment. Fifty Five pts had primary resistance to AA. Thirteen pts discontinued due<br />
to adverse events (2 AA, 6AD and 5 AS) Median (CI 95%) TTP and Overall Survival<br />
(OS) for the cohort are 12.85 (11.08, 14.98 ) and 26.26 ( 23.21, 31.93 ) ms respectively.<br />
There is no difference for drug sequence. On multivariate analysis, primary resistance<br />
to AA (p
abstracts<br />
were followed up to 29.5 months (range 1.3 to 29.5). Samples were rescored by readers,<br />
blinded to outcome to determine the frequency <strong>of</strong> and outcome with cytoplasmic<br />
AR-V7.<br />
Results: Inclusion <strong>of</strong> non-nuclear localized AR-V7 protein as positive scoring criteria<br />
increased the incidence <strong>of</strong> detection in all lines <strong>of</strong> therapy, an equivalent increase in<br />
false positives (PSA responders), and loss <strong>of</strong> the significance <strong>of</strong> the treatment-specific<br />
survival interaction in multivariate model.<br />
AR-V7<br />
Localization<br />
Nuclear<br />
(alone)<br />
Cytoplasmic<br />
(alone)<br />
Any (Nuc &<br />
Cyto)<br />
Detection Rate by<br />
Line <strong>of</strong> Therapy (1 st ,<br />
2 nd ,3 rd +)<br />
Table: 728PD<br />
HR <strong>of</strong> OS on<br />
ARSi<br />
Therapy Interaction<br />
(Taxanes vs. ARSi)<br />
3%, 18%, 31% 11.5, p < 0.0001 0.242, p = 0.0350<br />
13%, 8%, 12% 1.11, p = 0.844 1.21, p = 0.838<br />
16%, 26%, 43% 4.93, p < 0.0001 1.04, p = 0.943<br />
Conclusions: Including cytoplasmic AR-V7 in the “positive” test definition reduces the<br />
prognostic power <strong>of</strong> the assay and negates the treatment predictive value <strong>of</strong> AR-V7.<br />
Not all AR-V7 signal is equivalent. It remains to be seen if non-nuclear localized<br />
AR-V7 protein samples would test positive via mRNA methods.<br />
Legal entity responsible for the study: Memorial Sloan Kettering Cancer Center<br />
Funding: Epic Sciences<br />
Disclosure: H. Scher: Consulting: Astellas, AstraZeneca, BIND Therapeutics, Blue<br />
Earth, Bristol-Myers Squibb, Chugai, Endocyte, Ferring, Genentech, Janssen, Med IQ,<br />
Medivation, <strong>Oncology</strong>STAT, Palmetto GBA, Pfizer, San<strong>of</strong>i, Takeda, Ventana,<br />
WIRB-Copernicus Group. R. Graf, D. Lu, J. Louw, R. Dittamore: Epic Sciences<br />
Employee. All other authors have declared no conflicts <strong>of</strong> interest.<br />
729PD<br />
AR-V7 detection in plasma-derived exosomal RNA strongly<br />
predicts resistance to hormonal therapy in metastatic<br />
prostate cancer<br />
M. Del Re 1 , E. Biasco 2 , S. Crucitta 1 , L. Derosa 2 , E. R<strong>of</strong>i 1 , A. Farnesi 2 , A. Sbrana 2 ,<br />
G. Restante 1 , L. Galli 2 , A. Falcone 2 , G. Jenster 3 , R.H.N. van Schaik 4 , R. Danesi 1<br />
1 Clinical and Experimental Medicine, University <strong>of</strong> Pisa, Pisa, Italy, 2 Translational<br />
Research and New Technologies in Medicine, University <strong>of</strong> Pisa, Pisa, Italy,<br />
3 Department <strong>of</strong> Urology, Erasmus University Medical Center, Rotterdam,<br />
Netherlands, 4 Department <strong>of</strong> Clinical Chemistry, Erasmus University Medical<br />
Center, Rotterdam, Netherlands<br />
Background: The androgen receptor splice variant 7 (AR-V7) is associated with<br />
resistance to hormonal therapy in castration resistant prostate cancer (CRPC). Due to<br />
the limitations <strong>of</strong> methods available for AR-V7 analysis, the identification <strong>of</strong> a reliable<br />
detection method may facilitate the use <strong>of</strong> this biomarker in clinical practice. In order<br />
to provide a reliable laboratory approach to AR-V7 assessment, the present study was<br />
conducted to: 1) confirm the role <strong>of</strong> AR-V7 in prediction <strong>of</strong> resistance to hormonal<br />
therapy; 2) develop a new methodological approach to reliably and easily assess AR-V7<br />
by a digital droplet PCR in exosomal-derived RNA from plasma samples and 3)<br />
provide new data to address the correlation between exosomal-derived AR-V7 RNA<br />
and resistance, being the translation CTC to exosomes not obvious.<br />
Methods: Two ml <strong>of</strong> plasma samples were collected from 36 CRPC patients before the<br />
beginning <strong>of</strong> second-line hormonal treatment. Exosomes were isolated and RNA<br />
extracted for analysis <strong>of</strong> AR-V7 by digital droplet PCR.<br />
Results: 39% <strong>of</strong> patients were found carriers <strong>of</strong> the AR-V7 transcript. Twenty-six<br />
patients received abiraterone and 10 enzalutamide. The median clinical or radiographic<br />
progression free survival was significantly longer in AR-V7 negative compared to<br />
positive patients (20 vs 3 months; P < 0.001). Overall survival was significantly shorter<br />
in men with detectable AR-V7 at baseline compared to those with undetectable AR-V7<br />
(median 8 months vs. not reached) (P < 0.001). In the AR-V7-positive patients, the<br />
PSA response rates was 7% (1 out <strong>of</strong> 14 men), while in the AR-V7 negative patients the<br />
PSA response rate was 64% (14 <strong>of</strong> 22 men). The AR-V7 positive subjects were more<br />
likely to be younger, Gleason Score at least 8, visceral metastases, higher PSA levels, and<br />
prior docetaxel treatment than AR-V7 negative patients.<br />
Conclusions: The present study demonstrates that plasma-derived exosomal RNA is a<br />
reliable source <strong>of</strong> AR-V7 and its detection predicts resistance to anti-hormonal<br />
therapy. The method is sensitive, fast and represents a convenient alternative to other<br />
potentially more expensive and less sensitive approaches, i.e., circulating tumor cells.<br />
Legal entity responsible for the study: Pr<strong>of</strong>. Romano Danesi<br />
Funding: Academic fundings<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
730PD<br />
Prediction <strong>of</strong> PARP inhibitor response and resistance<br />
utilizing a CTC phenotypic classifer in patients (pts) with<br />
metastatic castration-resistant prostate cancer (mCRPC):<br />
Results from the NCI 9012 trial<br />
F.Y. Feng 1 , S. Daignault-Newton 2 , A. Jendrisak 3 , Y. Wang 3 , S. Greene 3 ,<br />
A. Rodriguez 3 , J. Lee 3 , L. Dugan 3 , J. Siddiqui 4 , J. Louw 3 , C. Johnson 3 ,<br />
P. Twardowski 5 , C. Albany 6 , M. Stein 7 , W.M. Stadler 8 , L. Kunju 4 ,A.<br />
M. Chinnaiyan 4 , M. Landers 3 , R. Dittamore 9 , M. Hussain 10<br />
1 Radiation <strong>Oncology</strong>, UCSF Helen Diller Family Comprehensive Cancer Center,<br />
San Francisco, CA, USA, 2 Biostatistics, University <strong>of</strong> Michigan, Ann Arbor, MI,<br />
USA, 3 Translational Research, Epic Sciences, Inc, San Diego, CA, USA, 4 Michigan<br />
Center For Translational Pathology, University <strong>of</strong> Michigan, Ann Arbor, MI, USA,<br />
5 Medical <strong>Oncology</strong> and Experimental Therapeutics, City <strong>of</strong> Hope, Duarte, CA,<br />
USA, 6 Medical <strong>Oncology</strong>, Indiana University Simon Cancer Center, Indianapolis,<br />
IN, USA, 7 Division <strong>of</strong> Medical <strong>Oncology</strong>, The Cancer Institute <strong>of</strong> New Jersey, New<br />
Brunswick, NJ, USA, 8 Medical <strong>Oncology</strong>, The University <strong>of</strong> Chicago Medical<br />
Centre, Chicago, IL, USA, 9 Translational Research, Epic Sciences Inc., San Diego,<br />
CA, USA, 10 Medical <strong>Oncology</strong>, University <strong>of</strong> Michigan, Ann Arbor, MI, USA<br />
Background: PARP inhibitors (PARPi) have efficacy in mCRPC harboring<br />
homologous recombination DNA repair deficiencies (HRD), but there is no<br />
non-invasive assay to predict PARPi response. Previous work characterizing single<br />
CTCs from mCRPC pts has identified subclonal populations <strong>of</strong> CTCs with unique<br />
phenotypes and somatic genomic instability consistent with HRD and resulting in<br />
worse outcomes following abiraterone (A) treatment. NCI 9012 evaluated A alone with<br />
or without the PARPi veliparib (V) in mCRPC pts. We now determine if the addition<br />
<strong>of</strong> V to A improves pts response and its association with phenotypic HRD CTC<br />
signature.<br />
Methods: 84 baseline & 58 on-therapy blood samples from unique pts randomized to<br />
V + A vs A arms on NCI 9012 (baseline n = 44 vs 40, follow-up n = 34 vs 24,<br />
respectively) were analyzed with the Epic Sciences CTC platform. CTC analysis<br />
included digital pathology <strong>of</strong> 20 discrete phenotypic cell features inclusive <strong>of</strong> AR, CK,<br />
size and shape. 3323 single CTCs were characterized and analyzed for HRD+ signature<br />
utilizing the previously developed classifier. A subset <strong>of</strong> CTCs (n= 309) from 40<br />
samples (30 patients) were individually sequenced and analyzed for genomic instability<br />
and resistant mechanism.<br />
Results: The HRD+ CTC phenotype was confirmed to have high cell level concordance<br />
(79%) vs. genomic scar (NGS). In baseline samples, HRD+ CTC phenotype occurred<br />
in 39% (V + A) and 30% (A), and had a higher ORR (>50% PSA drop) in the V + A vs<br />
the A cohort (88% vs 42%, p = 0.01). No significant difference observed in V + A vs the<br />
A cohort (62% vs 78%, p = 0.24) for HRD- patients. For patients with both baseline<br />
and short term follow up (
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
polymerization. In PSMA-positive LNCaP and MDA PCa 2b xenografts, complete<br />
responses and cures have been observed following EC1169 treatment. EC1169 does not<br />
show activity in PSMA-negative models, demonstrating its specificity. EC0652 is a<br />
companion radiodiagnostic conjugate <strong>of</strong> a 99m Tc chelator and a PSMA-targeting<br />
moiety designed to characterize PSMA-expressing disease in real time. Rapid tumor<br />
uptake <strong>of</strong> 99m Tc-EC0652 and rapid normal tissue clearance result in enhanced tumor:<br />
background ratios with SPECT imaging.<br />
Methods: Key inclusion criteria are age ≥18 years, ECOG PS 0–1, and adequate organ<br />
function. Patients (pts) must have failed androgen-deprivation therapy, progressed on<br />
abiraterone or enzalutamide, and have been previously treated with a taxane unless<br />
contraindicated. Patients are to undergo a 99m Tc-EC0652 SPECT scan prior to therapy.<br />
PSMA positivity is not a requirement for study entry. EC1169 is administered as an<br />
intravenous bolus on Days (D) 1, 8 (QW) every 21 D. Dose escalation is based upon<br />
the “3+3” method. Study objectives include determination <strong>of</strong> EC1169 MTD and<br />
recommended phase II dose, safety, pharmacokinetics, antitumor activity and its<br />
correlation with PSMA expression as identified on 99m Tc-EC0652 SPECT imaging.<br />
Results: 23 pts have been treated on the QW schedule. Median age is 70 (range: 57-82).<br />
The median number <strong>of</strong> administered EC1169 cycles is 2 (range: 1-11). 12 (52%)<br />
treatment related AEs have been reported. Most common Grade 3/4 AEs were anaemia<br />
(2; 8.7%) and lymphopenia (2; 8.7%). No DLT, related SAEs or toxicity requiring dose<br />
reductions occurred. PSA response (≥50% max decline) has been observed in 2 pts.<br />
Data will be updated at the meeting.<br />
Conclusions: To date, EC1169 has been well tolerated. There are promising signs <strong>of</strong><br />
early efficacy in this heavily pre-treated population.<br />
Clinical trial identification: ClinicalTrials.gov NCT02202447<br />
Legal entity responsible for the study: Endocyte, Inc.<br />
Funding: Endocyte, Inc.<br />
Disclosure: M.J. Morris: MSKCC receives funding from Endocyte for the conduct <strong>of</strong><br />
this study. I’ve received funding for advisory boards from Progenics, Tokai, &<br />
Millennium Pharmaceuticals. I’m an uncompensated advisor for Bayer, which my<br />
institution also receives funding. O. Sartor, D. Petrylak: Endocyte: consultancy fees.A.<br />
Armour: Alison Armour is an employee <strong>of</strong> Endocyte. H.M. Babiker: Endocyte:<br />
consultancy fees. Celgene: Consultant/Advisory Board. SirTex: Honorarium. All other<br />
authors have declared no conflicts <strong>of</strong> interest.<br />
732P<br />
A phase II study <strong>of</strong> TKI258 in patients with castration-resistant<br />
prostate cancer (KCSG-GU11-05)<br />
Y.J. Choi 1 , H.S. Kim 2 , S.H. Park 3 , B.S. Kim 4 , K.H. Kim 5 , H.J. Lee 6 , H.S. Song 7 ,D.<br />
Y. Shin 8 , H.Y. Lee 9 , H-G. Kim 10 , K.H. Lee 11 , J-L. Lee 12 , K.H. Park 1<br />
1 <strong>Oncology</strong>, Korea University Anam Hospital, Seoul, Republic <strong>of</strong> Korea, 2 <strong>Oncology</strong>,<br />
Myongji Hospital, Goyang, Republic <strong>of</strong> Korea, 3 Medicine, Samsung Medical<br />
Center Sungkyunkwan University School <strong>of</strong> Medicine, Seoul, Republic <strong>of</strong> Korea,<br />
4 Medical <strong>Oncology</strong>, VHS Medical Center, Seoul, Republic <strong>of</strong> Korea, 5 Internal<br />
Medicine, Seoul SoonChunHyang University Hospital, Seoul, Republic <strong>of</strong> Korea,<br />
6 Internal Medicine, Chungnam National University Hospital, Daejeon, Republic <strong>of</strong><br />
Korea, 7 Internal Medicine, Keimyung University Dongsan Medical Centre, Daegu,<br />
Republic <strong>of</strong> Korea, 8 Medical <strong>Oncology</strong>, Korea Cancer Center Hospital, Seoul,<br />
Republic <strong>of</strong> Korea, 9 Medical <strong>Oncology</strong>, Dongnam Institute <strong>of</strong> Radological and<br />
Medical Sciences-DIRAMS, Busan, Republic <strong>of</strong> Korea, 10 Medicine, Gyeongsang<br />
National University Hospital and Gyeongsang National University School <strong>of</strong><br />
Medicine, Jinju, Republic <strong>of</strong> Korea, 11 Internal Medicine, Yeungnam University<br />
Medical Center, Daegu, Republic <strong>of</strong> Korea, 12 <strong>Oncology</strong>, Asan Medical Center,<br />
University <strong>of</strong> Ulsan College <strong>of</strong> Medicine, Seoul, Republic <strong>of</strong> Korea<br />
Background: FGF signals are important in carcinogenesis and progression <strong>of</strong> prostate<br />
cancer. TKI258 (dovitinib) is an oral, pan-class VEGFR, PDGFR, and FGFR inhibitor.<br />
Preclinical data demonstrated a significant activity <strong>of</strong> TKI258 in mouse xenograft<br />
models. We evaluated the efficacy and toxicity <strong>of</strong> TKI258 in men with metastatic<br />
CRPC.<br />
Methods: This study was a single-arm, phase II, open-label, multicenter trial <strong>of</strong><br />
TKI258 (500mg orally according to a 5-days-on and 2-days-<strong>of</strong>f schedule). The primary<br />
endpoint was progression-free survival (PFS). Secondary endpoints were overall<br />
survival (OS), toxicity and PSA response rate. Biomarker analyses for serum FGFR,<br />
FGF-23 and VEGFR using multiplex ELISA were performed. This study is registered<br />
with ClinicalTrials.gov, number NCT01741116.<br />
Results: Forty-four men were accrued from 11 hospitals: 80% post-docetaxel; median<br />
PSA was 100 ng/dl, median age was 69, 82% had bone metastases, 23% had liver<br />
metastases. Median cycles <strong>of</strong> TKI258 was 2 (range 0-33). Median PFS was 3.67 months<br />
(95% CI: 1.36-5.98) and median OS was 13.7 months (95% CI: 0-27.41).<br />
Chemotherapy-naïve patients had longer PFS (17.9 months, 95% CI, 9.23-28.57)<br />
compared with docetaxel-treated patients (2.07 months, 95% CI, 1.73-2.41, p = 0.001)<br />
and the patients with high serum VEGFR2 level over median level (7800 pg/ml)<br />
showed longer PFS compared with others. (6.03 [95% CI, 4.26-7.80] vs 1.97 [95% CI,<br />
1.79-2.15] months, p = 0.023). The PSA decline was observed in 32.3% and 12.9% <strong>of</strong><br />
patients achieved a > 50% decline. Four objective responses were observed with ORR <strong>of</strong><br />
12.5% (95% CI: 5.0-28.1%). Grade 3 related AEs were seen in 40.9% <strong>of</strong> patients with<br />
7.0% stopping TKI258 due to toxicity. The most common related AEs included grade<br />
1-2 nausea, diarrhea, fatigue, anorexia and all grade thrombocytopenia (29.5%).<br />
Conclusions: TKI258 showed modest antitumor activity with manageable toxicities in<br />
men with mCRPC. Especially, patients who were chemo-naïve or with high levels <strong>of</strong><br />
serum VEGFR2 had the benefit from TKI258.<br />
Clinical trial identification: ClinicalTrials.gov NCT01741116<br />
Legal entity responsible for the study: KCSG (Korean Cancer Study Group)<br />
Funding: KCSG (Korean Cancer Study Group)<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
733P<br />
abstracts<br />
E2809. Androgen receptor (AR) modulation by bicalutamide<br />
(Bic) and MK-2206 (MK) in prostate cancer (PC) patients (pts)<br />
with rising PSA at high risk <strong>of</strong> progression after local<br />
treatment (tx)<br />
A. Ferrari 1 , Y-H. Chen 2 , G. Hudes 3 , M. Carducci 4 , E.S. Antonarakis 5 , N.M. Hahn 6 ,<br />
H. Ma 7 , Y-N. Wong 3 ,T.Mayer 1 , R.A. Somer 8 , B. Carthon 9 , R. Dipaola 1<br />
1 Medical <strong>Oncology</strong>, The Cancer Institute <strong>of</strong> New Jersey, New Brunswick, NJ,<br />
USA, 2 Biostastictics, Dana-Farber Cancer Institute, Boston, MA, USA, 3 Medical<br />
<strong>Oncology</strong>, Fox Chase Cancer Center, Philadelphia, PA, USA, 4 <strong>Oncology</strong>, Johns<br />
Hopkins University, Baltimore, MD, USA, 5 Medical <strong>Oncology</strong>, Johns Hopkins<br />
University, Baltimore, MD, USA, 6 Cancer Pavilion, Johns Hopkins Medical<br />
Institution, Indianapolis, IN, USA, 7 Cancer Center, New York University, New York,<br />
NY, USA, 8 Medical <strong>Oncology</strong>, Cooper University Hospital, Camden, NJ, USA,<br />
9 Hematology <strong>Oncology</strong>, Emory University Winship Cancer Institute, Atlanta, GA,<br />
USA<br />
Background: Men with a PSA doubling time (PSADT) 2 ng/mL, PSADT < 12 mo were randomized 1:1 to<br />
4-week cycles (cy): A) cy 1-3, observation, cy 4-11/max18, Bic 50 mg daily; B) cy 1-3<br />
MK 200 mg once/wk orally, cy 4-11/max18 MK + Bic. Endpoints: Primary: proportion<br />
<strong>of</strong> pts with PSA
abstracts<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
734P<br />
Neo/adjuvant ADT to EBRT: Randomized phase 2 trial <strong>of</strong> the<br />
oral GnRH antagonist, TAK-385 (relugolix, RGX) and degarelix<br />
(DGX) in patients (pts) with prostate cancer (PC)<br />
D. Dearnaley 1 , D.R. Saltzstein 2 , J.E. Sylvester 3 , L. Karsh 4 , B.A. Mehlhaff 5 ,<br />
C. Pieczonka 6 , J.L. Bailen 7 , D.B. Maclean 8 , S. Sankoh 9 , H.M. Faessel 10 ,H.<br />
M. Lin 11 , N.D. Shore 12<br />
1 Academic Radiotherapy, The Institute <strong>of</strong> Cancer Research/Royal Marsden NHS<br />
Foundation Trust, Sutton, UK, 2 Clinical Research, Urology San Antonio, San<br />
Antonio, TX, USA, 3 Radiation <strong>Oncology</strong>, 21st Century <strong>Oncology</strong>, Bradenton, FL,<br />
USA, 4 Clinical Research, The Urology Center <strong>of</strong> Colorado, Denver, CO, USA,<br />
5 Urologic <strong>Oncology</strong>, Oregon Urology, Springfield, OR, USA, 6 Advanced<br />
Therapeutics, Associated Medical Pr<strong>of</strong>essionals <strong>of</strong> NY, Syracuse, NY, USA,<br />
7 Clinical Research, First Urology, Jeffersonville, IN, USA, 8 <strong>Oncology</strong> Clinical<br />
Research, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary <strong>of</strong> Takeda<br />
Pharmaceutical Company Limited, Cambridge, MA, USA, 9 Global Statistics,<br />
Millennium Pharmaceuticals, Inc., a wholly owned subsidiary <strong>of</strong> Takeda<br />
Pharmaceutical Company Limited, Cambridge, MA, USA, 10 Quantitative Clinical<br />
Pharmacology, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary <strong>of</strong><br />
Takeda Pharmaceutical Company Limited, Cambridge, MA, USA, 11 Global<br />
Outcomes Research, Millennium Pharmaceuticals, Inc., a wholly owned subsidiary<br />
<strong>of</strong> Takeda Pharmaceutical Company Limited, Cambridge, MA, USA, 12 Urology,<br />
Carolina Urologic Research Center, Myrtle Beach, SC, USA<br />
Background: RGX is an investigational, non-peptide gonadotropin-releasing hormone<br />
(GnRH) antagonist <strong>of</strong> the human GnRH receptor (IC50 0.12 nM). This open label,<br />
parallel group study evaluated the testosterone (T)-lowering efficacy, safety and PK <strong>of</strong><br />
RGX vs the injectable peptide GnRH antagonist DGX in pts with PC.<br />
Methods: Men aged ≥18 y with intermediate risk localized PC appropriate for EBRT<br />
and 6 mos ADT, with baseline T >150.0 ng/dL, and prostate specific antigen (PSA)<br />
>2.0 ng/mL received oral RGX 320.0 mg on d 1 then 120.0 mg once daily (QD) or<br />
DGX 240.0 mg on d 1 then 80.0 mg SC Q4W for 24 wks. The primary endpoint was %<br />
<strong>of</strong> pts with castrate T levels 20 ng/mL or Gleason score 8–10. Pts in the<br />
Americas (n = 60), Europe (n = 97) and China (n = 224) were randomized to receive<br />
degarelix (n = 193), or LHRH agonist (n = 188). PSA-PFS was defined as death from any<br />
cause or PSA recurrence (two consecutive increases ≥50% [≥2 weeks apart] and ≥5ng/<br />
mL increase from nadir). Unadjusted Kaplan-Meier analyses (log-rank p-value) and<br />
Cox-proportional hazard models (Wald Chi-square p-value) were used (stratified by<br />
baseline PSA categories, and adjusted for treatment, PCa stage, age and region) to assess<br />
treatment differences in PSA-PFS.<br />
Results: PSA-PFS was significantly improved in the degarelix group among metastatic<br />
or high risk pts (p = 0.011). Region did not influence difference between antagonist<br />
and agonist in PSA-PFS (treatment-by-region interaction p = 0.884), however, Chinese<br />
(HR = 0.48 [95% CI: 0.31–0.74]) and American (HR = 0.26 [95%CI: 0.10–0.68]) pts<br />
had lower risk for PSA-PFS compared to European pts. There was a lower hazard for<br />
PSA-PFS with degarelix across all regions when stratifying for PSA (and adjusting for<br />
confounders); HR = 0.67 (95%CI: 0.44–1.01), p = 0.053.<br />
Conclusions: Improved PSA-PFS was shown in pts treated with degarelix vs LHRH<br />
agonists in metastatic or high risk PCa pts irrespective <strong>of</strong> region. These results suggest<br />
delay <strong>of</strong> disease progression with initial use <strong>of</strong> a GnRH antagonist as compared with<br />
LHRH agonists across global regions.<br />
Legal entity responsible for the study: Ferring Pharmaceuticals<br />
Funding: Ferring Pharmaceuticals<br />
Disclosure: N. Shore: Consultant/advisor for AbbVie, Ferring Pharmaceuticals, Takeda<br />
Pharmaceutical, TolmarZ. Bosnyak, A. Malmberg, P-A. Abrahamsson: Employee <strong>of</strong><br />
Ferring Pharmaceuticals.M. Gittelman, L-P. Xie: The author declares no conflict <strong>of</strong> interest.<br />
736P<br />
Pantoprazole affecting docetaxel resistance pathways via<br />
autophagy (PANDORA): A phase II trial in men with metastatic<br />
castrate resistant prostate cancer (mCRPC)<br />
A. Hansen 1 , I. Tannock 1 , A.J. Templeton 1 , A. Prawira 1 , J. Knox 1 , F. Vera-Badillo 1 ,<br />
E. Chen 1 , M.B. Zavitz 1 , L. Wang 2 , A. Evans 3 ,Q.Tan 4 , B. Wouters 4 , S. Sridhar 1 ,<br />
A. Joshua 1<br />
1 Medical <strong>Oncology</strong>, Princess Margaret Cancer Centre, Toronto, ON, Canada,<br />
2 Biomedical Statistics, University <strong>of</strong> Toronto, Toronto, ON, Canada, 3 Pathology,<br />
University Health Network, Toronto, ON, Canada, 4 Campbell Family Institute for<br />
Cancer Research, University Health Network, Toronto, ON, Canada<br />
Background: Enhancing the effectiveness <strong>of</strong> docetaxel for men with mCRPC is an<br />
unmet clinical need. Preclinical studies in our laboratory demonstrated that high dose<br />
Table: 734P<br />
Median (range) Baseline After 24 Wks 4 Wks Post-Rx<br />
Discontinuation<br />
8 Wks Post-Rx<br />
Discontinuation<br />
12 Wks Post-Rx<br />
Discontinuation<br />
RGX LH, IU/L 4.7 (0.8–32.2) 0.1 (0.1–3.9) 3.1 (0.2–15.7) 8.3 (0.1–32.4) 10.7 (0.1–38.7)<br />
DGX LH, IU/L 4.8 (1.3–42.0) 0.1 (0.1–3.7) 0.2 (0.1–2.8) 0.5 (0.1–7.7) 1.4 (0.1–15.7)<br />
RGX T, ng/dL 355.9 (149.0–1290.0) 8.1 (3.2–125.0) 94.0 (2.9–818.8) 238.4 (10.1–929.8) 257.0 (9.5–858.8)<br />
DGX T, ng/dL 404.0 (138.0–937.8) 8.9 (2.9–272.8) 9.7 (2.9–225.0) 16.1 (3.2–263.0) 30.0 (3.7–378.8)<br />
RGX PSA, ug/L 7.3 (2.6–31.5) 0.1 (0.1–1.6) 0.1 (0.1–1.5) 0.19 (0.1–3.2) 0.19 (0.1–2.3)<br />
DGX PSA, ug/L 7.3 (2.5–88.9) 0.1 (0.1–1.8) 0.1 (0.1–2.1) 0.1 (0.1–2.2) 0.07 (0.1–2.0)<br />
vi250 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
pantoprazole can prevent or delay resistance to docetaxel via the inhibition <strong>of</strong><br />
autophagy in several solid tumor xenografts.<br />
Methods: Men with chemotherapy-naïve mCRPC with a PSA >10ng/ml and adequate<br />
organ function were eligible for enrolment. The study regimen included intravenous<br />
pantoprazole (240mg) and docetaxel (75mg/m 2 ) every 21 days, with continuous<br />
prednisone 5mg twice daily. The primary endpoint was a confirmed >50% decline <strong>of</strong><br />
PSA. Progression free (PFS) and overall survival (OS) were assessed by the<br />
Kaplan-Meier method. This trial used a Simon’s 2-stage design.<br />
Results: Between November 2012 and March 2015, 21 men with a median age <strong>of</strong> 70<br />
years (range 58-81 years) were treated (median 6 cycles, range 2 to 11). Participants<br />
(pts) had received prior systemic therapies (median 4, range 1 to 8) and 14 had<br />
received abiraterone and/or enzalutamide. The PSA response rate was 52% (11/21)<br />
which did not meet the prespecified criterion (≥13/21 responders) to proceed to stage<br />
2 <strong>of</strong> the study. At interim analysis with a median follow-up <strong>of</strong> 12 months, 13 (62%) pts<br />
were deceased (10 CRPC, 2 unknown, 1 radiation complication). Of the pts with<br />
RECIST measurable disease, the radiographic partial response rate was 31% (4/13). The<br />
estimated median PFS was 5.3 months (95%CI: 2.6-12.9) and median OS was 15.7<br />
months (95% CI: 9.3-19.6). There were no toxic deaths and most adverse events were<br />
attributed to docetaxel (hematological: 14% febrile neutropenia, 14% G4 neutropenia,<br />
19% G3/4 anemia; non-hematological: 24% G3 fatigue and 5% G3 anorexia).<br />
Conclusions: The combination <strong>of</strong> docetaxel and pantoprazole was tolerable, but the<br />
resultant clinical activity was not sufficient to meet the ambitious predefined target to<br />
warrant further testing. Planned correlative studies to evaluate tumor samples for<br />
autophagy are in progress, and are expected to provide insights into autophagy in the<br />
context <strong>of</strong> docetaxel resistance.<br />
Clinical trial identification: NCT01748500<br />
Legal entity responsible for the study: Princess Margaret Cancer Centre<br />
Funding: Supported by a grant from the Canadian Institutes <strong>of</strong> Health Research.<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
737P<br />
Increased choline uptake in androgen receptor (AR) copy<br />
number gain castration-resistant prostate cancers (CRPC)<br />
V. Conteduca 1 , V. Casadio 2 , P. Caroli 3 , E. Scarpi 1 , C. Lolli 1 , C. Menna 1 ,<br />
E. Bianchi 4 , G. Schepisi 1 , S. Testoni 5 , G. Gurioli 2 , S. Salvi 2 , D. Amadori 1 ,<br />
G. Paganelli 3 , F. Matteucci 3 , G. Attard 6 , U. De Giorgi 1<br />
1 Medical <strong>Oncology</strong>, Istituto Tumori della Romagna I.R.S.T., Meldola, Italy,<br />
2 Biosciences Laboratory, Istituto Tumori della Romagna I.R.S.T., Meldola, Italy,<br />
3 Diagnostic Nuclear Medicine Unit, Istituto Tumori della Romagna I.R.S.T.,<br />
Meldola, Italy, 4 Medical <strong>Oncology</strong>, Ospedale Infermi, Rimini, Italy, 5 Biostatistics<br />
and Clinical Trials, Istituto Tumori della Romagna I.R.S.T., Meldola, Italy, 6 Section<br />
<strong>of</strong> Medicine, The Institute <strong>of</strong> Cancer Research/Royal Marsden NHS Foundation<br />
Trust, Sutton, UK<br />
Background: Preliminary data suggests an association between choline uptake and<br />
androgen receptor (AR) expression with upregulation <strong>of</strong> choline kinase alpha protein<br />
in prostate cancer. We aimed to make a direct comparison between circulating AR copy<br />
number variations (CNV) and 18F-fluorocholine (FCH) uptake on PET/CT in patients<br />
with metastatic CRPC.<br />
Methods: We determined AR CNV by digital droplet PCR and Taqman on<br />
pre-treatment plasma from 80 patients with metastatic CRPC progressing after<br />
docetaxel treated with abiraterone (n = 47) or enzalutamide (n = 33) as we described<br />
previously (Romanel et al, Sci Transl Med 2015; Salvi et al, Br J Cancer 2015; Salvi et al,<br />
Oncotarget 2016). For all patients, an FCH PET/CT scans was performed at baseline<br />
and total lesion activity (TLA) and metabolic tumor volume (MTV) calculated. The<br />
primary end point was the correlation between circulating AR CNV and TLA and<br />
MTV. The secondary end points were progression-free survival (PFS) and overall<br />
survival (OS) stratified by circulating AR CNV and TLA/MTV.<br />
Results: We observed AR copy number gain in 24 (30%) <strong>of</strong> 80 patients, 14 (30%) <strong>of</strong> 47<br />
patients treated with abiraterone and 10 (29%) <strong>of</strong> 33 treated with enzalutamide. The<br />
number <strong>of</strong> metastatic lesions and previous therapeutic lines were higher in the<br />
enzalutamide group (P = 0.03 and P = 0.02, respectively). We observed a significant<br />
correlation between AR gain and TLA and MTV values (P = 0.001 and P = 0.004,<br />
respectively; Rs >0.6). Multivariate analysis revealed that AR CNV and TLA value were<br />
associated with both shorter PFS (P < 0.0009 and P = 0.026, respectively) and OS<br />
(P < 0.031 and P = 0.039, respectively).<br />
Conclusions: Choline uptake is higher in AR gained cancers. This introduces the<br />
possibility <strong>of</strong> identifying this molecularly distinct group using non-invasive imaging<br />
and supports the hypothesis <strong>of</strong> increased choline uptake in cancers overexpressing AR.<br />
Legal entity responsible for the study: Ugo De Giorgi<br />
Funding: IRST IRCCS<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
738P<br />
Meta-analysis <strong>of</strong> randomized clinical trials in metastatic<br />
castration resistant prostate cancer: Comparison <strong>of</strong><br />
hypertension, neurological and psychiatric adverse events on<br />
enzalutamide and abiraterone acetate plus prednisone<br />
treatment<br />
P. Ruiz Gracia 1 , L. Dearden 2 , L. Antoni 3 , R. Parra Gabilondo 2 ,A.<br />
Garcia Garcia-Porrero 1 , M. Iznaola 2<br />
1 MAF Departement <strong>Oncology</strong>, Janssen Cilag, Madrid, Spain, 2 Health Economics<br />
and Market Access, Janssen Pharmaceuticals, Madrid, Spain, 3 Medical, Jansen<br />
Cilag, Paris, France<br />
Background: Enzalutamide (ENZ) and abiraterone acetate (AA) are oral hormonal<br />
agents for the treatment <strong>of</strong> metastatic castration resistant prostate cancer (mCPRC)<br />
patients. Although these two drugs target the androgen signaling pathway, they have<br />
different mechanisms <strong>of</strong> action, with ENZ targeting the androgen receptor 1 whilst<br />
abiraterone targeting the activity <strong>of</strong> CYP17 2 .Consequently, they also differ in the nature<br />
<strong>of</strong> their adverse events pr<strong>of</strong>ile<br />
Methods: Following a meta-analysis presented at ASCO GU 2016 3 on fatigue and<br />
cardiovascular adverse events (AEs) a further analysis, using the same methodology,<br />
was performed on hypertension, neurological and psychiatric AEs based on a literature<br />
search <strong>of</strong> randomized controlled trials (RCTs) that included AA + prednisone (P) or<br />
ENZ. The risk <strong>of</strong> these AEs was assessed by the overall relative risk <strong>of</strong> all the RCTs that<br />
comply with the inclusion criteria. Summary <strong>of</strong> incidence, relative-risks (RR), and 95%<br />
confidence intervals (CI) were calculated using random-effects or fixed-effects models<br />
based on the heterogeneity <strong>of</strong> included studies.<br />
Results: RR for hypertension (all grades) was 2.26 (1.06-4.81) for ENZ and 1.61<br />
(1.30-2.00) for AA + P, for hypertension grade ≥ 3 was 2.52 (1.61-3.95) and 1.72<br />
(0.97-3.06) respectively. The RR for neurological disorders was 1.44 (1.31-1.58) for<br />
ENZ and 1.13 (0.99-1.29) for AA + P. RR for psychiatric disorders was 1.43 (1.21-1.69)<br />
for ENZ and 1.04 (0.9-1.20) for AA + P. No evidence <strong>of</strong> publication bias was observed.<br />
Conclusions: The aim <strong>of</strong> this study is to contrast the hypertension, psychiatric and<br />
central nervous system disorders safety pr<strong>of</strong>ile <strong>of</strong> AA + P and ENZ. This analysis<br />
suggests that mCRPC patients treated with ENZ had a higher risk <strong>of</strong> developing<br />
hypertension, neurological and psychiatric disorders than the patients treated with<br />
AA + P. One may speculate that the affinity <strong>of</strong> ENZ for GABA receptor may play a role<br />
in the toxicities related to the central nervous system 4 .<br />
Legal entity responsible for the study: Janssen. Spain<br />
Funding: jannsen, Spain<br />
Disclosure: P. Ruiz Gracia: Current employee at Janssen pharmaceuticals -<strong>Oncology</strong><br />
dpt. L. Dearden: Current employee at Jansseńs EMEA Health economics and market<br />
research (head manager).L. Antoni: Current employe at Janssen pharmaceuticals-<br />
MAF EMEA manager.R. Parra Gabilondo: Current Janssen employee.A. Garcia<br />
Garcia-Porrero: Currently Janssen employee.M. Iznaola: Jansseńs Health economics<br />
and market access research department employee.<br />
739P<br />
abstracts<br />
Fatigue in men with metastatic castration-resistant prostate<br />
cancer treated with enzalutamide: data from randomised<br />
clinical trials<br />
S. Chowdhury 1 , N. Shore 2 , F. Saad 3 , C.S. Higano 4 , K. Fizazi 5 , P. Iversen 6 ,<br />
K. Miller 7 , A. Heidenreich 8 , T. Ueda 9 , C.S. Kim 10 , D. Phung 11 , A. Krivoshik 12 ,<br />
F. Wang 13 ,K.Wu 14 , B. Tombal 15<br />
1 Medical <strong>Oncology</strong>, Guy’s, King’s and St Thomas’ Hospitals, London, UK,<br />
2 Urology, Carolina Urologic Research Center, Myrtle Beach, SC, USA, 3 Urology,<br />
CRCUM-Universite de Montreal, Montreal, QC, Canada, 4 Medicine, University <strong>of</strong><br />
Washington, and Fred Hutchinson Cancer Research Center, Seattle, WA, USA,<br />
5 Cancer Medicine, Institut Gustave Roussy, University <strong>of</strong> Paris Sud, Paris, France,<br />
6 Urology, University <strong>of</strong> Copenhagen, Rigshospitalet, Copenhagen, Denmark,<br />
7 Urology, Charité Campus Benjamin Franklin, Berlin, Germany, 8 Urology, Cologne<br />
University, Cologne, Germany, 9 Prostate Center and Division <strong>of</strong> Urology, Chiba<br />
Cancer Center, Chiba, Japan, 10 Urology, Prostate Center, Urologic Cancer<br />
Center, Asan Medical Center, Seoul, Republic <strong>of</strong> Korea, 11 Data Science, Astellas<br />
Pharma, Inc., Leiden, Netherlands, 12 Medical <strong>Oncology</strong>, Astellas Pharma Global<br />
Development, Astellas Pharma, Inc., Northbrook, IL, USA, 13 Clinical Development,<br />
Medivation, Inc., San Francisco, CA, USA, 14 Biometrics, Medivation, Inc., San<br />
Francisco, CA, USA, 15 Urology, Cliniques Universitaires Saint-Luc, Brussels,<br />
Belgium<br />
Background: Fatigue is common in men with advanced prostate cancer and may be<br />
related to disease progression, ongoing systemic therapy, comorbidities, concomitant<br />
medications or a combination <strong>of</strong> these factors. Fatigue adverse events (AEs) across four<br />
double-blind, randomised, placebo- or bicalutamide-controlled trials <strong>of</strong> enzalutamide<br />
(ENZA) for men with metastatic castration-resistant prostate cancer are summarised to<br />
assess incidence, timing and effect <strong>of</strong> age on fatigue.<br />
Methods: Safety data from ENZA trials (AFFIRM NCT00974311, PREVAIL<br />
NCT01212991, TERRAIN NCT01288911 and STRIVE NCT01664923) with men with<br />
metastatic castration-resistant prostate cancer were evaluated for fatigue AEs. As per<br />
CTCAE, v 4.0, fatigue is defined as a state <strong>of</strong> generalised weakness, with a pronounced<br />
inability to summon sufficient energy to accomplish daily activities. Analyses included<br />
unadjusted and per-100 patient-years fatigue AE incidences assessed by grade, time<br />
and age (
abstracts<br />
Results: With 2051 men in the ENZA arms and 1630 in the control arms, total treatment<br />
exposure patient-years were longer for ENZA (range, 219–1294) vs control (range, 143–<br />
560). The unadjusted percentages <strong>of</strong> men reporting fatigue for all grades were slightly<br />
higher in the ENZA arms (range, 28% − 38%) vs the control arms (range, 20% − 29%).<br />
Grade 3 fatigue AEs were reported by
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Conclusions: Our data show a high prevalence and intensity <strong>of</strong> fatigue and impact in<br />
QoL in chemo-naïve CRPC patients. The study highlights the relevance <strong>of</strong> fatigue<br />
awareness and its management in CRPC patients. Table.<br />
Table: 741P<br />
FACT-G total score<br />
FACT-P total score<br />
FATIGUE Mean SD N Mean SD N<br />
Abscence 88.0 13.3 60 127.7 16.9 60<br />
Mildly 79.3 12.9 84 110.1 16.3 84<br />
Moderate 71.5 14.7 64 110.8 19.3 64<br />
Severe 63.2 19.2 25 87.7 25.1 25<br />
p-valor* 20 −≤50 33 86.7 (74.5–100.0) 0.89 (0.4–1.8) 0.849 92.4 (83.3–100.0) 5.06 (1.3–16.1) 0.062<br />
>50 1 100.0 (100.0–100.0) NE 100.0 (100.0–100.0) NE<br />
Median<br />
≤20 288 90.2 (86.8–93.7) 1 98.9 (97.8–100.0) 1<br />
>20 −≤50 54 89.1 (80.6–98.9) 0.84 (0.4–1.6) 0.598 95.4 (89.8–100.0) 3.92 (1.2–12.3) 0.083<br />
>50 3 83.3 (56.7–100.0) 2.74 (0.2–12.7) 100.0 (100.0–100.0) NE<br />
Maximum<br />
≤20 257 90.6 (87.0–94.2) 1 99.2 (98.1–100.0) 1<br />
>20 −≤50 78 87.8 (80.3–95.5) 1.13 (0.6–1.9) 0.196 96.8 (92.9–100.0) 2.79 (0.8–9.3) 0.165<br />
>50 10 83.3 (59.5–100.0) 3.59 (0.9–10.0) 95.0 (85.7–100.0) 4.57 (0.2–26.8)<br />
CI, confidence interval; HR, hazard ratio; CRPC, castrate-resistant prostate<br />
cancer; NE, not estimable; PSA, prostate-specific antigen.<br />
a Likelihood ratio<br />
test.<br />
Conclusions: In pts receiving CAD, CSS and time to PSA (CRPC) progression did not<br />
differ according to T levels in the 1st year <strong>of</strong> therapy. This finding may have been due,<br />
at least in part, to the effectiveness <strong>of</strong> leuprorelin (Eligard®) in lowering T, as maximum<br />
T levels ≤20 ng/dL were achieved in 75% <strong>of</strong> pts over the 1st year <strong>of</strong> CAD.<br />
Legal entity responsible for the study: Astellas Pharma, Inc. and Medivation, Inc.<br />
Funding: Astellas Pharma, Inc. and Medivation, Inc.<br />
Disclosure: B. Tombal: Advisory board member: Astellas, Bayer, Medivation, Ferring,<br />
Amgen, San<strong>of</strong>i. Aventis. Corporate-sponsored research: Astellas, Bayer, Medivation,<br />
Ferring, Amgen, San<strong>of</strong>i Aventis.T.L. Tammela: Advisory board member: Astellas,<br />
Orion Pharma, Bayer. Corporate-sponsored research: Astellas, Orion Pharma,<br />
Medivation, Jansen-Cilag, Bayer, Ferring, Camurus Ab, Lidds Ab.All other authors<br />
have declared no conflicts <strong>of</strong> interest.<br />
743P<br />
Outcomes <strong>of</strong> metastatic castration-resistant prostate cancer<br />
(mCRPC) patients (pts) treated with different new agents (NAs)<br />
sequence in post-docetaxel (DOC) setting. An updated<br />
analysis from a multicenter Italian study<br />
O. Caffo 1 , E. Biasco 2 , G. Facchini 3 , L. Fratino 4 , D. Gasparro 5 , C. Mosillo 6 ,<br />
U. Basso 7 , D. Santini 8 , M. Tucci 9 , C. Ortega 10 , F. Verderame 11 , S. Scagliarini 12 ,G.<br />
Lo Re 13 , G. Procopio 14 , G. Fornarini 15 , E. Campadelli 16 , R. Sabbatini 17 ,<br />
F. Maines 18 , U. De Giorgi 19<br />
1 <strong>Oncology</strong>, Ospedale Santa Chiara, Trento, Italy, 2 Polo Oncologico, Azienda<br />
Ospedaliera Universitaria S.Chiara, Pisa, Italy, 3 Genitourinary <strong>Oncology</strong>, Istituto<br />
Nazionale Tumori – I.R.C.C.S - Fondazione Pascale, Naples, Italy, 4 Medical<br />
<strong>Oncology</strong>, Centro di Riferimento Oncologico, Aviano, Italy, 5 Medical <strong>Oncology</strong>,<br />
Azienda Ospedaliera di Parma, Parma, Italy, 6 Medical <strong>Oncology</strong>, Sapienza –<br />
Università di Roma, Rome, Italy, 7 Medical <strong>Oncology</strong> Unit 1, Istituto Oncologico<br />
Veneto IRCCS, Padua, Italy, 8 Medical <strong>Oncology</strong>, Libero Istituto Universitario<br />
Campus Bio-Medico (LIUCBM), Rome, Italy, 9 Medical <strong>Oncology</strong>, Azienda<br />
Ospedaliero-Universitaria ASOU San Luigi Gonzaga, Orbassano, Italy, 10 Medical<br />
<strong>Oncology</strong>, Istituto di Candiolo-IRCCS-Fondazione Piemontese per la Ricerca sul<br />
Cancro-Onlus, Candiolo, Italy, 11 Medical <strong>Oncology</strong>, Ospedale Cervello, Palermo,<br />
Italy, 12 Medical <strong>Oncology</strong>, Azienda Ospedaliera di Rilievo Nazionale "Antonio<br />
Cardarelli"-AORN A. Cardarelli, Naples, Italy, 13 Medical <strong>Oncology</strong>, Azienda<br />
Ospedaliera Sta Maria degli Angeli, Pordenone, Italy, 14 Oncologia Medica,<br />
Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy, 15 Medical<br />
<strong>Oncology</strong>, IRCCS AOU San Martino - IST-Istituto Nazionale per la Ricerca sul<br />
Cancro, Genoa, Italy, 16 Medical <strong>Oncology</strong>, Ospedale Civile, Lugo Di Romagna,<br />
Italy, 17 Medical <strong>Oncology</strong>, Azienda Ospedaliero - Universitaria Policlinico di<br />
Modena, Modena, Italy, 18 Medical <strong>Oncology</strong>, Ospedale Sta Chiara, Trento, Italy,<br />
19 Medical <strong>Oncology</strong>, Istituto Tumori della Romagna I.R.S.T., Meldola, Italy<br />
Background: Abiraterone acetate (AA), cabazitaxel (CABA), and enzalutamide (ENZ)<br />
may prolong survival in mCRPC pts progressing after DOC, although it is not clear<br />
how to use NAs, to best exploit their efficacy and avoiding their possible cross<br />
resistances. In 2015, we reported the outcomes <strong>of</strong> a series <strong>of</strong> 260 mCRPC pts, receiving<br />
at least 2 NAs, after DOC progression in routine clinical practice (Eur Urol.<br />
2015;68:147-53). In the present study we updated the analysis with longer follow-up<br />
and by assessing a larger series <strong>of</strong> pts.<br />
Methods: Based on a multi-institutional collaboration, we collected data <strong>of</strong> pts who<br />
received at least 2 NAs after DOC: we assessed biochemical (bRR) and objective response<br />
rates (oRR) and progression free survival (PFS) <strong>of</strong> each NA by treatment line; moreover,<br />
we evaluated the overall survival (OS) from the second line start by sequence strategy. For<br />
the OS analysis we differentiated three different types <strong>of</strong> NAs sequences after DOC: one<br />
new hormone agent (AA or ENZ) followed by CABA (NHA > CABA); CABA followed<br />
by AA or ENZ (CABA > NHA); one NHA followed by the other NHA (NHA > NHA).<br />
Results: A consecutive series <strong>of</strong> 344 mCRPC pts, median age 71 yrs (43-91), with bone<br />
(86%), nodal (55%) or visceral (16%) mets, was identified. All received NDs as 2 nd and 3 rd<br />
line after DOC. The outcomes by both treatment lines and NAs are detailed in the table.<br />
Second<br />
line<br />
Table: 743P<br />
Third<br />
line<br />
abstracts<br />
# pts bRR oRR PFS # pts bRR oRR PFS<br />
AA 190 38.9% 20.0% 7.4 mos 105 27.6% 13.3% 4.6 mos<br />
CABA 113 41.6% 16.8% 6.3 mos 143 27.3% 15.3% 4.4 mos<br />
ENZ 41 41.5% 17.1% 6.2 mos 96 19.8% 8.3% 3.3 mos<br />
We observed a statistically significant difference in terms <strong>of</strong> OS when compared the three<br />
sequence strategies: the median OS <strong>of</strong> pts treated with NHA®CABA, CABA ®NHA, and<br />
NHA ®NHA was respectively 11.9 mos, 13.4 mos, and 8.3 mos, respectively (p = 0.01).<br />
Conclusions: At our knowledge this retrospective study reports the highest number <strong>of</strong><br />
pts treated post-DOC with at least 2 NAs. Our data confirmed that the activity <strong>of</strong> NAs<br />
decreased in the 3 rd line compared to the 2 nd line and suggested a cumulative OS<br />
advantage when CABA is used in the sequence.<br />
Legal entity responsible for the study: Medical <strong>Oncology</strong> Dept - Santa Chiara<br />
Hospital Trento (Italy)<br />
Funding: N/A<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw372 | vi253
abstracts<br />
Disclosure: O. Caffo: Honoraria from Astellas, Bayer, Janssen, San<strong>of</strong>i Aventis.G.<br />
Procopio: Advisor Astellas,Bayer,BMS,Janssen,Novartis Honoraria Amgen,Pfizer. All<br />
other authors have declared no conflicts <strong>of</strong> interest.<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Astellas, Ipsen, Janssen, Ferring, Bayer.J. Alexandre: Consulting fees (or other payment):<br />
Roche, Pharmamar, Novartis.S. Oudard: Consulting fees (or other payment): San<strong>of</strong>i,<br />
Bayer, Astellas, Janssen.All other authors have declared no conflicts <strong>of</strong> interest.<br />
744P<br />
Efficacy <strong>of</strong> cabazitaxel, abiraterone, enzalutamide and<br />
docetaxel sequence in men with metastatic castration-resistant<br />
prostate cancer (mCRPC) in real life practice: The multinational,<br />
retrospective, observational CATS study<br />
A. Angelergues 1 , A.J. Birtle 2 , A.C. Hardy-Bessard 3 ,O.Caffo 4 , S. Le Moulec 5 ,<br />
M. Krainer 6 , A. Guillot 7 , A. Hasbini 8 , G. Daugaard 9 , S. Chowdhury 10 , D. Spaeth 11 ,<br />
P. Beuzeboc 12 , J-C. Eymard 13 , A. Flechon 14 , J. Alexandre 15 , F. Priou 16 ,<br />
N. Delanoy 1 , N. El Awadly 1 , E. Braychenko 17 , S. Oudard 1<br />
1 Department <strong>of</strong> Medical <strong>Oncology</strong>, Hopital European George Pompidou, Paris,<br />
France, 2 Rosemere Cancer Centre, Royal Preston Hospital-Lancashire Teaching<br />
Hospitals NHS Foundation Trust, Preston, UK, 3 Department <strong>of</strong> Medical <strong>Oncology</strong>,<br />
Centre Armoricain d’Oncologie, CARIO, Plerin, France, 4 <strong>Oncology</strong> Department,<br />
Ospedale Santa Chiara, Trento, Italy, 5 Medical <strong>Oncology</strong>, HIA Val de Grace/Institut<br />
Bergonie, Bordeaux, France, 6 Department <strong>of</strong> Medical <strong>Oncology</strong>, Medical<br />
University <strong>of</strong> Vienna, Vienna, Austria, 7 Loire, Institut de Cancérologie de la Loire,<br />
Saint Priest En Jarez, France, 8 Medical <strong>Oncology</strong>, Clinique Pasteur, Brest, France,<br />
9 Department <strong>of</strong> <strong>Oncology</strong>, Rigshospitalet, Copenhagen University Hospital,<br />
Copenhagen, Denmark, 10 <strong>Oncology</strong>, Guy’s and St. Thomas’ Hospital NHS Trust,<br />
London, UK, 11 <strong>Oncology</strong>, Centre d’Oncologie de Gentilly, Nancy, France,<br />
12 Department <strong>of</strong> <strong>Oncology</strong>, Institut Curie, Paris, France, 13 Medical <strong>Oncology</strong>,<br />
Institut Jean Godinot, Reims, France, 14 Medical <strong>Oncology</strong>, Centre Léon Bérard,<br />
Lyon, France, 15 Medical <strong>Oncology</strong>, Hôpital Cochin, Paris, France, 16 Department <strong>of</strong><br />
Oncohématology, CHD Vendee - Hopital Les Oudairies, La Roche Sur Yon,<br />
France, 17 ARTIC (Department <strong>of</strong> Medical <strong>Oncology</strong>), Hopital European George<br />
Pompidou, Paris, France<br />
Background: Optimal sequencing <strong>of</strong> new androgen-receptor targeted agents (ART)<br />
abiraterone and enzalutamide with docetaxel (D) and cabazitaxel (C) is unknown. In<br />
this large retrospective cohort <strong>of</strong> mCRPC patients, we evaluated the impact <strong>of</strong> 3<br />
different sequences: D -> C-> ART (group 1), or D -> ART -> C (group 2), or ART -><br />
D -> C (group 3)<br />
Methods: Records <strong>of</strong> 560 consecutive mCRPC patients were retrospectively collected in<br />
31 centres in 7 European countries from Jan 2011 to Jan 2016. Disease history and<br />
clinical characteristics at initiation <strong>of</strong> each therapy were collected. PSA response ≥ 50%,<br />
radiological or clinical progression-free survival (PFS) and overall survival (OS) with<br />
each treatment sequence were evaluated.<br />
Results: At sequence initiation, patient characteristics were similar between the 3<br />
sequences: median age was 67 years, 95% were ECOG 0-1, 59% had high disease<br />
volume, 42.6% had pain and 8% had visceral metastases. Median number <strong>of</strong> D cycles<br />
was 6 in the 3 groups. Median numbers <strong>of</strong> C cycles were 7, 6 and 5 in groups 1, 2 and 3<br />
respectively. Median duration <strong>of</strong> follow-up was 33.7, 31.1, and 23.7 months in groups 1,<br />
2 and 3. Main results are provided in the table.<br />
Sequence<br />
Table: 744P<br />
PSA response ≥50% / Radiological or<br />
clinical PFS*<br />
OS from<br />
Treatment 1*<br />
Treatment 1 Treatment 2 Treatment 3<br />
D- > C- > ART 61% / 11.5 61% / 11.0 37% / 12.4 37.3 [32.4; 45.2]<br />
(n = 129)<br />
D- > ART- > C 63% / 11.9 39% / 9.0 38% / 11.3 36.0 [33.4; 39.7]<br />
(n = 390)<br />
ART- > D- > C 60% / 7.4 42% / 6.9 31% / 8.9 30.1 [24.3; 52.7]<br />
(n = 41)<br />
p value 0.92 /
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
First documented<br />
treatment received on study<br />
(treatments with n ≥ 50)<br />
Chemotherapy-naïve<br />
treatment<br />
Abiraterone<br />
acetate +<br />
prednisone (n = 324)<br />
Chemotherapy-naïve<br />
treatment<br />
Enzalutamide (n = 53)<br />
Table: 746P<br />
First chemotherapy<br />
treatment<br />
Docetaxel<br />
(n = 326)<br />
Post-chemotherapy<br />
treatment<br />
Abiraterone<br />
acetate +<br />
prednisone<br />
(n = 164)<br />
Post-chemotherapy<br />
treatment<br />
Enzalutamide<br />
(n = 111)<br />
Post-chemotherapy<br />
treatment<br />
Docetaxel<br />
(n = 58)`<br />
Post-chemotherapy<br />
treatment<br />
Cabazitaxel<br />
(n = 119)<br />
Number <strong>of</strong> previous mCRPC<br />
treatments, n (%)<br />
0 313 (96.6) 42 (79.2) 295 (90.5) 0 0 0 0<br />
1 11 (3.4) 11 (20.8) 29 (8.9) 121 (73.8) 61 (55.0) 35 (60.3) 43 (36.1)<br />
2 0 0 2 (0.6) 37 (22.6) 29 (26.1) 14 (24.1) 59 (49.6)<br />
≥3 0 0 0 6 (3.6) 21 (18.9) 9 (15.5) 17 (14.3)<br />
Median time to next therapy,<br />
days (95% CI)*<br />
601 (467, NE) 503 (251, NE) 278 (259, 307) 428 (359, 514) 366 (296, NE) 322 (239, 404) 264 (240, 321)<br />
*Kaplan–Meier estimates; patients with no next therapy were censored. Time to next therapy: time from start <strong>of</strong> 1st therapy to start <strong>of</strong> next therapy. NE, not estimable.<br />
Results: Median follow-up at database close was 14.2 months (range: 0.2-28.6). Mean<br />
age at enrolment was 72.6 years; 55% <strong>of</strong> patients had a Gleason score ≥ 8 at diagnosis.<br />
58.5% <strong>of</strong> patients had comorbidities at enrolment, most commonly cardiovascular<br />
disorders (51.7%; 41.3% hypertension) and diabetes (15.2%). 876 patients (63.8%) were<br />
chemotherapy-naïve at enrolment. During the 12-month observation period, 1191<br />
patients (86.7%) initiated new mCRPC treatment. Descriptive, non-comparative data<br />
on previous treatment lines and time to next therapy by first documented treatment<br />
received on study are in the table.<br />
Conclusions: The results provide unique insights into treatment and outcomes in a<br />
large, real-world mCRPC patient population. These older patients have a high<br />
prevalence <strong>of</strong> comorbidities that are common in clinical practice but <strong>of</strong>ten not taken<br />
into account in the results <strong>of</strong> interventional clinical trials. Follow-up <strong>of</strong> these patients<br />
will allow assessment <strong>of</strong> treatment patterns and outcomes, and thereby contribute to<br />
optimising outcomes in subsets <strong>of</strong> mCRPC patients in clinical practice.<br />
Clinical trial identification: ClinicalTrials.gov NCT02236637<br />
Legal entity responsible for the study: Janssen Pharmaceutic<br />
Funding: Janssen Pharmaceutic<br />
Disclosure: S. Chowdhury: Consultant - Janssen Pharmaceuticals; Speakers’ Bureau -<br />
Janssen Pharmaceuticals, San<strong>of</strong>i, Astellas Pharma Pr<strong>of</strong>ession: Consultant medical<br />
oncologist. A.J. Birtle: Educational grants and advisory boards fees Janssen San<strong>of</strong>i Aventis<br />
Astellas, Roche. A. Bjartell: Consultant: EXINI Diagnostics, Speakers’ Bureau: Astellas<br />
Pharma, Bayer Schering Pharma, Patents, Royalties, Other Intellectual Property: Glactone<br />
Pharma. L.A.;. Costa: Speakers’ Bureau: Janssen. E. Kalinka-Warzocha: Honoraria,<br />
Consultant. Research Funding: Bristol-Myers Squibb, MSD, Roche, Novartis, Janssen,<br />
Angelini Pharmaceuticals. Travel, Accommodations, Expenses: MSD, Bristol-Myers<br />
Squibb, Roche.G. Kramer: Honoraria – Janssen, Bayer, Astellas Pharma, San<strong>of</strong>i;<br />
Consultant – Janssen, Bayer, Astellas Pharma, GlaxoSmithKline, San<strong>of</strong>i, Ipsen, Takeda.<br />
Research Funding - Janssen, Bayer, Astellas PharmaJ.P. Maroto Rey: Consultant - Janssen<br />
Pharmaceuticals, Amgen, Bayer Schering Pharma, Novartis, Roche. Speakers’ Bureau -<br />
Janssen Pharmaceuticals, Amgen, Bayer, Novartis, Roche.N. Lumen: Honoraria – Lilly,<br />
Janssen, AstraZeneca; Consultant – Bayer; Research Funding – Janssen, Bayer, Astellas<br />
Pharma, Ipsen; Travel, Accommodations, Expenses – Bayer, Janssen, Ipsen, Astellas<br />
Pharma.D. Spaeth: Honoraria – Roche, San<strong>of</strong>i, Amgen, Pfizer; Consultant – Roche,<br />
San<strong>of</strong>i, Amgen, Pfizer. Research Funding – Roche, Pierre Fabre; Other Relationship –<br />
Roche, Novartis, Pierre Fabre, San<strong>of</strong>i.L. Antoni: Employment - Janssen Pharmaceutica.E.<br />
Klumper: Consultant - Janssen Pharmaceuticals.R. Wapenaar: Stock and Other<br />
Ownership Interests - Johnson & Johnson.E. Lee: Stock and Other Ownership Interests –<br />
Janssen.All other authors have declared no conflicts <strong>of</strong> interest.<br />
747P<br />
Global treatment patterns for late-stage prostate cancer:<br />
Updated results from ASPIRE-PCa<br />
N.W. Clarke 1 , M. De Santis 2 , A.J. Costello 3 , Y-H. Chang 4 , T. Pickles 5 ,A.<br />
C. Pompeo 6 , S. Bazarbashi 7 , G.P. Haas 8 , M.R. Cooperberg 9<br />
1 Urology, The Christie Hospital, Manchester, UK, 2 Cancer Research Centre,<br />
University <strong>of</strong> Warwick, Coventry, UK, 3 <strong>Oncology</strong>, The Royal Melbourne Hospital,<br />
Melbourne, Australia, 4 Division <strong>of</strong> General Urology, Taipei Veterans General<br />
Hospital, Taipei, Taiwan, 5 Developmental Radiotherapy and Radiotherapeutics,<br />
University <strong>of</strong> British Columbia, Vancouver, BC, Canada, 6 Urology, FM-ABC, Sao<br />
Paulo, Brazil, 7 <strong>Oncology</strong>, King Faisal Specialist Hospital and Research Centre,<br />
Riyadh, Saudi Arabia, 8 Astellas Pharma Global Development, Astellas Pharma Inc.,<br />
Northbrook, IL, USA, 9 Urologic Surgery and <strong>Oncology</strong>, University <strong>of</strong> California,<br />
San Francisco, CA, USA<br />
Background: ASPIRE-PCa is an observational study that aims to describe the pattern<br />
<strong>of</strong> care for men with late-stage prostate cancer (PC). 1200 patients (pts) from the<br />
Americas, Europe, Asia, and the Middle East/North Africa are targeted for enrolment.<br />
We present updated data from December 2015.<br />
Methods: Men with prostate adenocarcinoma enrol at the diagnosis <strong>of</strong>: biochemical<br />
failure after curative-intent therapy with a prostate-specific antigen (PSA) doubling<br />
Volume 27 | Supplement 6 | October 2016<br />
time <strong>of</strong> ≤1 year; castration-resistant PC (CRPC); or metastatic PC (mPC) at initial<br />
presentation. Initial treatment decision and planned follow-up data were collected.<br />
Results: 507 pts have enrolled from 72 sites in 21 countries: Americas, n = 53; Europe,<br />
n = 172; Asia, n = 271; and the Middle East/North Africa, n = 11. Biochemical failure,<br />
n = 90 (18%); CRPC, n = 181 (36%); mPC, n = 235 (46%); and missing, n = 1 (100%, as >1 option/pt).<br />
Enzalutamide was less frequently chosen (n = 7; 3%). The most favoured follow-up was<br />
PSA testing every 3 months. Updated regional differences will be presented.<br />
Table: 747P<br />
New treatment, a n (%) 277 (109%)<br />
Androgen-deprivation therapy 244 (88%)<br />
Chemotherapy, immunotherapy, targeted therapy 46 (17%)<br />
Salvage radiotherapy 11 (4%)<br />
Androgen-deprivation therapy, n (%)<br />
223 (∼100%)<br />
GnRH agonist and anti-androgen 90 (40%)<br />
GnRH agonist alone 67 (30%)<br />
Anti-androgen alone 26 (12%)<br />
2nd-generation androgen-directed therapy 25 (11%)<br />
Treatment missing 7 (3%)<br />
GnRH antagonist alone 4 (2%)<br />
GnRH antagonist and anti-androgen 2 (
abstracts<br />
Clinical trial identification: NCT02066961 - First received: February 18, 2014; Last<br />
updated: February 4, 2016<br />
Legal entity responsible for the study: Astellas Pharma, Inc.<br />
Funding: Astellas Pharma, Inc.<br />
Disclosure: N.W. Clarke: Advisory boards for Astellas, AstraZeneca, Bayer, Ferring,<br />
Janssen, Ipsen, San<strong>of</strong>i Aventis and Pfizer.M. De Santis, S. Bazarbashi: The author discloses<br />
that they are a member <strong>of</strong> the ASPIRE steering comitee and have received a research grant<br />
from Astellas Pharma Inc.T. Pickles: The author discloses that they have a substantive<br />
relationship with San<strong>of</strong>i Aventis and Oncurra.G.P. Haas: The author discloses that they<br />
are the senior medical director at Astellas Pharma Inc.M.R. Cooperberg: Employee <strong>of</strong><br />
Astellas Pharma, Inc.All other authors have declared no conflicts <strong>of</strong> interest.<br />
748P<br />
Switch from abiraterone + prednisone to<br />
abiraterone + dexamethasone after PSA progression under<br />
abiraterone + prednisone in asymptomatic metastatic<br />
castration-resistant prostate cancer (mCRPC) patients<br />
C. Fenioux 1 , C. Louvet 1 , D. Prapotnich 2 , S. Ropert 3 , E. Barret 2 ,<br />
R. Sanchez-Salas 2 , A. Mombet 2 , N. Cathala 2 , B. Poullennec 1 , M-L. Joulia 1 ,<br />
M. Ung 1 , X. Cathelineau 2 , M. Bennamoun 1<br />
1 Medical <strong>Oncology</strong>, Institute Mutualiste Montsouris, Paris, France, 2 Urology,<br />
Institute Mutualiste Montsouris, Paris, France, 3 Medical <strong>Oncology</strong>, Hopital Privé,<br />
Antony, France<br />
Background: Abiraterone acetate (AA) is active in mCRPC. AA is usually administrated<br />
with prednisone (P) to prevent mineralocorticoid excess until radiological or symptomatic<br />
progression regardless <strong>of</strong> PSA. A switch from P to dexamethasone (D) was reported to<br />
induce tumor responses in patients progressing on AA + P. This prospective study was<br />
designed to evaluate outcome <strong>of</strong> patients (pts) with asymptomatic PSA progression on<br />
AA + P after the switch, and to determine predictive factors <strong>of</strong> switch efficiency.<br />
Methods: Among 120 pts treated with AA between Jan 2013 and Apr 2016 in our<br />
institution, 48 consecutive asymptomatic mCRPC pts, progressing only biologically on<br />
AA + P 10mg daily, were switched to AA + D 0.5mg daily at the time <strong>of</strong> PSA increase.<br />
AA + D was administered until radiological and/or symptomatic progression.<br />
Results: Median age at switch was 82 ± 7yrs (57–92). Median time <strong>of</strong><br />
hormonosensitivity was 82 months (mo). 7 pts previously received docetaxel. Median<br />
time to PSA progression on AA + P was 8.6 mo. Median (med) follow-up time from<br />
switch was 14 mo. Actuarial median PFS’s on AA + D and on AA+ corticosteroids (P<br />
then D) were 14.5 and 23.1 mo, respectively. 45.8% <strong>of</strong> pts had a PSA decrease after the<br />
switch. Univariate prognostic factors <strong>of</strong> switch efficiency were long hormonosensitivity<br />
duration (> 5 yrs; med PFS 16.6 vs 3.9 mo, p = 0.0012, HR : 4.46 (1.8 – 11.03)), low<br />
PSA level at switch (< 50 ng/ml; med PFS 15.2 mo vs 3.8 mo, p= 0.0041, HR 3.23 (1.45<br />
– 7.20)), and short time to PSA progression on AA + P (
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Table: 750P Concomitant treatment with Ra-223 (administered after the<br />
first injection <strong>of</strong> Ra-223, or before the study and continued after the first<br />
Ra-223 injection)<br />
Denosumab BPs No denosumab /no BPs<br />
N = 127 N = 125 N = 435<br />
Baseline characteristics<br />
ECOG PS, n (%)<br />
0 58 (46%) 55 (44%) 144 (33%)<br />
1 55 (43%) 54 (43%) 234 (54%)<br />
≥2 14 (11%) 16 (13%) 57 (13%)<br />
Pain, n (%) 123 122 413<br />
Mild 75 (61%) 72 (59%) 218 (53%)<br />
Moderate-severe 19 (15%) 24 (20%) 113 (27%)<br />
None 29 (24%) 26 (21%) 82 (20%)<br />
ALP (U/L), n 127 125 433<br />
Median 121.0 137.0 168.0<br />
PSA (µg/L), n 127 124 433<br />
Median 91.2 118.5 174.6<br />
Efficacy outcome<br />
Overall survival<br />
Median, months NR 12.7 13.4<br />
95% CI NA 10.9–NA 11.7–NA<br />
Hazard ratio (95% CI) 0.630 (0.431–0.922) 0.846 (0.584–1.226) -<br />
Time to first SSE<br />
Median, months 17.0 NR 15.8<br />
95% CI 17.0–17.5 NA 10.9–19.1<br />
Hazard ratio (95% CI) 0.761 (0.493–1.173) 0.498 (0.294–0.845) -<br />
NR/A = not reached/available.<br />
Conclusions: In this EAP, pts treated with Ra-223 and a concomitant BTA appeared to<br />
have longer time to first SSE than those treated without a concomitant BTA. However,<br />
improvement in OS with a BTA was observed with denosumab but not with BPs.<br />
Prospective randomized controlled studies are required to confirm the benefit <strong>of</strong> this<br />
specific treatment combination in metastatic CRPC.<br />
Clinical trial identification: ClinicalTrials.gov NCT01618370<br />
Legal entity responsible for the study: Pharmaceutical Division <strong>of</strong> Bayer<br />
Funding: Pharmaceutical Division <strong>of</strong> Bayer<br />
Disclosure: F. Saad: Grants, personal fees and non-financial support from Bayer, Amgen,<br />
Janssen, and Astellas, during the conduct <strong>of</strong> the study.A. Heidenreich: Grants and<br />
personal fees from Bayer during the conduct <strong>of</strong> the study; grants and personal fees from<br />
Astellas and San<strong>of</strong>i Aventis, personal fees from Amgen, Dendreon, Ferring, Hexal, IPSEN,<br />
Janssen-Cilag, Pfizer, and Takeda; outside the submitted work.D. Heinrich: Grant from<br />
Bayer, during the conduct <strong>of</strong> the study; personal fees from Bayer, Amgen, Astellas, San<strong>of</strong>i,<br />
and Johnson & Johnson, outside the submitted work.J.M. O’Sullivan: Advisory boards for:<br />
Bayer, Astellas, San<strong>of</strong>i.J. Carles: Scientific advisory board membership/consultancy:<br />
Johnson & Johnson, Astellas, Bayer, Amgen, Pfizer, BMS; Speakers Bureau: Bayer,<br />
Johnson & Johnson.M. Wirth: Personal fees from Apogepha, Astellas, Bayer,<br />
Janssen-Cilag, Merck, Roche, and San<strong>of</strong>i-Aventis outside the submitted work.K. Miller:<br />
Advisory board membership: Bayer.J. Gratt: Personal fees from Bayer Healthcare during<br />
the conduct <strong>of</strong> the study.M. Seger-van Tol: Employment: Bayer.S. Nilsson: Participated in<br />
Bayer Healthcare advisory boards and as speaker in scientific meetings.S. Gillessen:<br />
Advisory Boards (compensated): Astellas, Bayer, Curevac, Dendreon, Janssen Cilag,<br />
Janssen Diagnostics, Millennium, Novartis, Orion Pharma, Pfizer, San<strong>of</strong>i Aventis.<br />
Speakers Bureau (without honorarium): Bayer. Pending patent application: WO<br />
2009138392 A1.All other authors have declared no conflicts <strong>of</strong> interest.<br />
751P<br />
Changes in alkaline phosphatase (ALP) dynamics and overall<br />
survival (OS) in metastatic castration-resistant prostate<br />
cancer (mCRPC) patients treated with radium-223 in an<br />
international early access program (EAP)<br />
D. Heinrich 1 , S. Gillessen 2 , A. Heidenreich 3 , D. Keizman 4 , J.M. O’Sullivan 5 ,<br />
J. Carles 6 , M. Wirth 7 , K. Miller 8 , G. Procopio 9 , J. Gratt 10 , M. Seger-Van Tol 11 ,<br />
S. Nilsson 12 , F. Saad 13<br />
1 Department <strong>of</strong> <strong>Oncology</strong>, Akershus University Hospital, Lorenskog, Norway,<br />
2 Department <strong>of</strong> <strong>Oncology</strong>/Haematology, Kantonsspital St. Gallen, St. Gallen,<br />
Switzerland, 3 Department <strong>of</strong> Urology, University Hospital Cologne, Cologne,<br />
Germany, 4 Genitourinary <strong>Oncology</strong> Service, Meir Medical Center, Kfar Saba,<br />
Israel, 5 The Centre for Cancer Research and Cell Biology, Queen’s University<br />
Belfast and the Northern Ireland Cancer Centre, Belfast, UK, 6 Department <strong>of</strong><br />
<strong>Oncology</strong>, Vall d’Hebron University Hospital Institut d’Oncologia, Barcelona,<br />
Spain, 7 Department <strong>of</strong> Urology, University Hospital Carl-Gustav Carus, Dresden,<br />
Germany, 8 Department <strong>of</strong> Urology, Charité University Medicine Berlin, Berlin,<br />
Germany, 9 Medical <strong>Oncology</strong>, Fondazione IRCCS - Istituto Nazionale dei Tumori,<br />
Milan, Italy, 10 Biostatistics, Modular Informatics LLC, New York, NY, USA,<br />
11 Pharmaceutical Division, Bayer, Whippany, NJ, USA, 12 Department <strong>of</strong><br />
<strong>Oncology</strong>-Pathology, Karolinska University Hospital, Stockholm, Sweden,<br />
13 Department <strong>of</strong> Surgery, University <strong>of</strong> Montreal Hospital Center, Montreal, QC,<br />
Canada<br />
Background: Identifying a reliable marker <strong>of</strong> efficacy for radium-223 dichloride<br />
(Ra-223) would aid in the clinical management <strong>of</strong> mCRPC patients (pts). In<br />
exploratory analyses <strong>of</strong> mCRPC pts with symptomatic bone metastases treated with<br />
Ra-223 in the ALSYMPCA trial, OS was significantly longer in pts with a confirmed<br />
decline in ALP levels from baseline at week 12, compared with pts without a confirmed<br />
ALP decline. Here, we present data on ALP dynamics and OS and time to first<br />
symptomatic skeletal event (SSE) in pts treated with Ra-223 in an international EAP.<br />
Methods: This was a prospective single-arm phase IIIb study <strong>of</strong> CRPC pts with<br />
symptomatic or asymptomatic bone metastases (no visceral disease) recruited from 14<br />
countries. Pts received Ra-223 50 kBq/kg (55 kBq/kg after NIST update) iv, every 4<br />
weeks for up to 6 cycles. Co-primary endpoints were safety and OS. Exploratory<br />
analyses investigated whether a confirmed decline (any magnitude) in ALP levels was<br />
associated with OS and time to first SSE.<br />
Results: 696 pts received at least one Ra-223 cycle. Of those, 398 (57%) pts had a<br />
confirmed decline in ALP and 298 (43%) had no confirmed ALP decline. Key baseline<br />
characteristics are shown (Table). More pts with a confirmed ALP decline (374, 94%)<br />
received 5–6 Ra-223 injections than those with no ALP decline (99, 33%). Hazard<br />
ratios (HR) for confirmed ALP decline at week 12 vs no decline suggest a strong<br />
association <strong>of</strong> ALP decline with both longer OS (HR 0.299, 95% CI 0.227–0.395) and<br />
longer time to first SSE (HR 0.474, 95% CI 0.340–0.662) (Table).<br />
Table: 751P<br />
Confirmed ALP<br />
decline<br />
No confirmed ALP<br />
decline<br />
N = 398 N = 298<br />
Baseline<br />
characteristics<br />
ECOG PS, n (%)<br />
0 170 (43%) 91 (31%)<br />
1 189 (47%) 159 (53%)<br />
≥2 39 (10%) 48 (16%)<br />
Pain a , n (%) 380 287<br />
Mild 217 (57%) 153 (53%)<br />
Moderate-severe 79 (21%) 79 (28%)<br />
None 84 (22%) 55 (19%)<br />
ALP (U/L), n 398 296<br />
Median 149.0 148.5<br />
PSA (µg/L), n 398 295<br />
Median 117.2 202.0<br />
Hemoglobin, g/dL<br />
Median 12.4 11.8<br />
Efficacy outcome<br />
Overall survival<br />
Events, n (%) 86 (22%) 124 (42%)<br />
Median, months NR 10.0<br />
95% CI NA 8.6–11.5<br />
Hazard ratio b 0.299<br />
95% CI 0.227–0.395<br />
Time to first SSE<br />
Events, n (%) 76 (19%) 67 (22%)<br />
Median, months 17.5 NR<br />
95% CI 17.0–18.1 NA<br />
Hazard ratio b 0.474<br />
95% CI 0.340–0.662<br />
abstracts<br />
NR/A, not reached/available. a Measured from the brief pain inventory short<br />
form. b Calculated from Cox proportional hazards model.<br />
Conclusions: In this EAP, which is relevant for pts currently treated in clinical practice,<br />
decline in ALP was associated with longer OS and time to first SSE.<br />
Clinical trial identification: ClinicalTrials.gov NCT01618370<br />
Legal entity responsible for the study: Pharmaceutical Division <strong>of</strong> Bayer<br />
Funding: Pharmaceutical Division <strong>of</strong> Bayer<br />
Disclosure: D. Heinrich: Grant from Bayer, during the conduct <strong>of</strong> the study; personal<br />
fees from Bayer, Amgen, Astellas, San<strong>of</strong>i, and Johnson & Johnson, outside the<br />
submitted work.S. Gillessen: Advisory Boards (compensated): Astellas, Bayer, Curevac,<br />
Dendreon, Janssen Cilag, Janssen Diagnostics, Millennium, Novartis, Orion Pharma,<br />
Pfizer, San<strong>of</strong>i Aventis. Speakers Bureau (without honorarium): Bayer. Pending patent<br />
application: WO 2009138392 A1.A. Heidenreich: Grants and personal fees from Bayer<br />
during the conduct <strong>of</strong> the study; grants and personal fees from Astellas and San<strong>of</strong>i<br />
Aventis, personal fees from Amgen, Dendreon, Ferring, Hexal, IPSEN, Janssen-Cilag,<br />
Pfizer, and Takeda; outside the submitted work.J.M. O’Sullivan: Advisory boards for:<br />
Bayer, Astellas, San<strong>of</strong>i.J. Carles: Scientific advisory board membership/consultancy:<br />
Johnson & Johnson, Astellas, Bayer, Amgen, Pfizer, BMS; Speakers Bureau: Bayer,<br />
Johnson & Johnson.M. Wirth: Personal fees from Apogepha, Astellas, Bayer,<br />
Janssen-Cilag, Merck, Roche, and San<strong>of</strong>i-Aventis outside the submitted work.K. Miller:<br />
Advisory board membership: Bayer.J. Gratt: Personal fees from Bayer Healthcare<br />
during the conduct <strong>of</strong> the study.M. Serger-van Tol: Employment: Bayer.S. Nilsson:<br />
Participated in Bayer Healthcare advisory boards and as speaker in scientific meetings.<br />
F. Saad: Grants, personal fees and non-financial support from Bayer, Amgen, Janssen,<br />
and Astellas, during the conduct <strong>of</strong> the study.All other authors have declared no<br />
conflicts <strong>of</strong> interest.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw372 | vi257
abstracts<br />
752P<br />
Radium-223 re-treatment from an international, prospective,<br />
open-label study in patients with castration-resistant prostate<br />
cancer and bone metastases<br />
O. Sartor 1 , D. Heinrich 2 , N. Mariados 3 , M.J. Méndez Vidal 4 , D. Keizman 5 ,C.<br />
Thellenberg Karlsson 6 , A. Peer 7 , G. Procopio 8 , S.J. Frank 9 , K.J. Pulkkanen 10 ,<br />
E. Rosenbaum 11 , S. Severi 12 , J.M. Trigo Perez 13 , V. Wagner 14 , J. Garcia-Vargas 15 ,<br />
R. Li 16 , L.T. Nordquist 17<br />
1 Medicine and Urology, Tulane Cancer Center, New Orleans, LA, USA, 2 <strong>Oncology</strong>,<br />
Akershus University Hospital, Lorenskog, Norway, 3 Radiation <strong>Oncology</strong>, Associated<br />
Medical Pr<strong>of</strong>essionals <strong>of</strong> New York, PLLC, Syracuse, NY, USA, 4 Medical<br />
<strong>Oncology</strong>, Hospital Universitario Reina S<strong>of</strong>ía, Cordoba, Spain, 5 Genitourinary<br />
<strong>Oncology</strong>, Meir Medical Center, Kfar Saba, Israel, 6 Radiation Sciences, Cancer<br />
Center Norrlands University, Umea, Sweden, 7 <strong>Oncology</strong>, Rambam Medical<br />
Center, Haifa, Israel, 8 Medical <strong>Oncology</strong>, Foundation IRCCS National Cancer<br />
Institute, Milan, Italy, 9 <strong>Oncology</strong>, Hadassah Hebrew University Medical Center,<br />
Jerusalem, Israel, 10 <strong>Oncology</strong>, Kuopio University Hospital, Kuopio, Finland,<br />
11 Clinical <strong>Oncology</strong>, Rabin Medical Center–David<strong>of</strong>f Center, Petach Tikva, Israel,<br />
12 Nuclear Medicine Therapeutic Unit, Romagnolo Scientific Institute for the Study<br />
and Care <strong>of</strong> Cancer—IRST IRCCS, Meldola, Italy, 13 Medical <strong>Oncology</strong>, Hospital<br />
Universitario Virgen de la Victoria, Malaga, Spain, 14 Global Clinical Development<br />
<strong>Oncology</strong>, Bayer Pharma AG, Basel, Switzerland, 15 Global Clinical <strong>Oncology</strong>,<br />
Pharmaceuticals Division <strong>of</strong> Bayer, Whippany, NJ, USA, 16 Global Research and<br />
Development Statistics, Pharmaceuticals Division <strong>of</strong> Bayer, Whippany, NJ, USA,<br />
17 Medical <strong>Oncology</strong>, GU Research Network, LLC, Omaha, NE, USA<br />
Background: Radium-223 (Ra-223) 50 kBq/kg IV (55 kBq/kg after NIST update) every<br />
4 wk × 6 injections (inj) is indicated in symptomatic bone-metastatic<br />
castration-resistant prostate cancer (mCRPC) patients (pts) with no visceral metastases<br />
(mets). In an international prospective trial in mCRPC pts (NCT01934790), Ra-223<br />
re-treatment (re-tx) after initial 6 inj was well tolerated, with very low radiologic bone<br />
progression rates (Sartor. ASCO GU 2016). Reported are safety and total alkaline<br />
phosphatase (ALP) and prostate-specific antigen (PSA) dynamics.<br />
Methods: All pts had CRPC with bone mets and completed 6 Ra-223 inj with no bone<br />
progression during that initial tx. Pts had radiologic or clinical progression after initial<br />
Ra-223 tx, and adequate hematologic (heme) values. Pts who started subsequent<br />
anticancer tx must have progressed on the last anticancer tx. Concomitant agents<br />
(except cytotoxic) were allowed at investigator discretion. Addition <strong>of</strong> abiraterone and<br />
enzalutamide was not allowed during Ra-223 re-tx. Primary end point was safety;<br />
exploratory efficacy end points included times to ALP and PSA progression, and ALP<br />
and PSA response rates (≥30% decline from baseline).<br />
Re-tx<br />
Study,<br />
N=44<br />
Re-tx<br />
Study,<br />
N=44<br />
Table: 752P<br />
Re-tx<br />
Study,<br />
N=44<br />
ALSYMPCA<br />
Ra-223 Arm,<br />
N = 600<br />
ALSYMPCA<br />
Ra-223 Arm,<br />
N=600<br />
ALSYMPCA<br />
Ra-223 Arm,<br />
N = 600<br />
Treatment-emergent All Gr Gr 3 Gr 4 All Gr Gr 3 Gr 4<br />
adverse events*<br />
≥1 TEAE, % † 93 41 7 93 35 9<br />
Heme, %<br />
Anemia 14 5 0 31 11 2<br />
Thrombocytopenia 2 2 0 12 3 3<br />
Neutropenia 0 0 0 5 2 1<br />
Leukopenia 2 0 0 4 1 20% pts<br />
§ ALSYMPCA intent-to-treat population ⍰ n/N = pts with response/pts with<br />
valid lab assessment For ALSYMPCA, ALP response: ≥ 30% decline from<br />
baseline confirmed by a second measurement ≥4 wk later; PSA<br />
response: ≥ 30% decline from baseline # ALSYMPCA: End <strong>of</strong> tx (4 wks after<br />
last inj) **N = safety population; pts with no valid postbaseline lab assessment<br />
counted as nonresponders; database cut<strong>of</strong>f date was June 11, 2015 NA = not<br />
applicable<br />
Results: Of 44 Ra-223 re-tx pts, 29 (66%) received all 6 inj. Median time from last inj <strong>of</strong><br />
initial Ra-223 tx was 6 mo. There were no marked alterations in tx-emergent adverse<br />
event (TEAE) incidence vs ALSYMPCA (Table) and no grade 4 or 5 heme TEAEs; 3<br />
(7%) re-tx pts had grade 3 or 4 tx-related TEAEs. Maximum follow-up times for ALP<br />
and PSA progression were 12.8 and 11.4 mo, respectively. Median time to ALP<br />
progression was not reached. Median time to PSA progression was 2 mo. ALP and PSA<br />
response rates at wk 12, 24, and any time before database cut<strong>of</strong>f are reported (Table).<br />
ALP, PSA, and heme lab values will be reported.<br />
Conclusions: Ra-223 re-tx was well tolerated, with minimal heme toxicity and ALP<br />
and PSA pr<strong>of</strong>iles similar to those <strong>of</strong> ALSYMPCA.<br />
Clinical trial identification: NCT01934790<br />
Legal entity responsible for the study: Pharmaceuticals Division <strong>of</strong> Bayer<br />
Funding: Pharmaceuticals Division <strong>of</strong> Bayer<br />
Disclosure: O. Sartor: Consultant or advisory role for Astellas, Bavarian Nordic, Bayer,<br />
Bellicum, Biscayne, Johnson & Johnson, Medivation, Oncogenex, San<strong>of</strong>i, Algeta,<br />
Aragon, and Pfizer; research funding from Bayer, Johnson & Johnson, Progenics,<br />
San<strong>of</strong>i, Algeta, and Takeda.D. Heinrich: Honoraria from and consultant or advisor for<br />
Bayer, Johnson & Johnson, and Astellas; research funding from Bayer, Johnson &<br />
Johnson, BMS, and Aragon Pharmaceuticals.N. Mariados: Stock or ownership interest<br />
in and travel, accommodations, expenses from Augmenix; honoraria from and speakers<br />
bureau for Bayer.M.J. Méndez Vidal: Consulting or advisory role for Janssen-Cilag,<br />
Pfizer, Astellas, GlaxoSmithKline, San<strong>of</strong>i, and Bayer; travel, accommodations, expenses<br />
from Janssen-Cilag, Pfizer, Astellas, and GlaxoSmithKline.D. Keizman: Consulting or<br />
advisory role for, honoraria from, and travel, accommodations, and expenses from<br />
Bayer, Pfizer, San<strong>of</strong>i, and Janssen <strong>Oncology</strong>.C. Thellenberg Karlsson: Consulting or<br />
advisory role for Bayer and San<strong>of</strong>i.G. Procopio: Consulting or advisory role for Janssen,<br />
Novartis, and Bayer; honoraria from Astellas and Janssen.S. Severi: Speakers bureau for<br />
Bayer.V. Wagner: Was employed by Merck; is now employed by Bayer; stock or other<br />
ownership in Bayer, Merck, and Amgen.J. Garcia-Vargas: Employed by Bayer; travel,<br />
accommodations, expenses from Bayer.R. Li: Employed by Bayer.All other authors<br />
have declared no conflicts <strong>of</strong> interest.<br />
753P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Phase II study <strong>of</strong> weekly cabazitaxel for ‘unfit’ metastatic<br />
castration resistant prostate cancer patients (mCRPC)<br />
progressing after docetaxel (D) treatment. Circulating tumour<br />
cell (CTC) analysis (SOGUG-CABASEM Trial)<br />
U. Anido 1 , M.J. Juan Fita 2 , L. Munielo-Romay 3 , B. Pérez-Valderrama 4 ,<br />
B. Mellado 5 , M. Ochoa de Olza 6 , O. Fernandez Calvo 7 , D. Castellano 8 , E.M.<br />
Fernandez Parra 9 , M. Domenec 10 , S. Hernando 11 , J. Arranz Arija 12 , C. Caballero 13 ,<br />
I. Duran 14 , M. Campayo 5 , M.A. Climent 15<br />
1 Medical <strong>Oncology</strong>, Complejo Hospitalario Universitario de Santiago de<br />
Compostela SERGAS, Santiago De Compostela, Spain, 2 Medical <strong>Oncology</strong>,<br />
Fundación Instituto Valenciano de Oncología, Valencia, Spain, 3 Traslational<br />
Medical <strong>Oncology</strong> Group, Liquid biopsy analysis Unit, Complejo Hospitalario<br />
Universitario de Santiago de Compostela SERGAS, Santiago De Compostela,<br />
Spain, 4 Medical <strong>Oncology</strong>, Hospital Universitario Virgen del Rocio, Seville, Spain,<br />
5 Medical <strong>Oncology</strong>, Hospital Clinic y Provincial de Barcelona, Barcelona, Spain,<br />
6 Medical <strong>Oncology</strong>, Vall d’Hebron University Hospital Institut d’Oncologia,<br />
Barcelona, Spain, 7 Medical <strong>Oncology</strong>, Complejo Hospitalario De Orense,<br />
Ourense, Spain, 8 Medical <strong>Oncology</strong>, University Hospital 12 De Octubre, Madrid,<br />
Spain, 9 Medical <strong>Oncology</strong>, Hospital Virgen Valme, Seville, Spain, 10 Medical<br />
<strong>Oncology</strong>, Althaia, Xarxa Assistencial i Universitària de Manresa, Manresa, Spain,<br />
11 Medical <strong>Oncology</strong>, HUFA Hospital Universitario Fundacion Alcorcon, Alcorcon,<br />
Spain, 12 Servicio de Oncologia Medica, Hospital General Universitario Gregorio<br />
Marañon, Madrid, Spain, 13 Medical <strong>Oncology</strong>, Hospital General Universitario<br />
Valencia, Valencia, Spain, 14 <strong>Oncology</strong>, Hospital Universitario Virgen del Rocio,<br />
Seville, Spain, 15 Servicio de Oncología Médica, Instituto Valenciano de Oncología,<br />
Valencia, Spain<br />
Background: Cabazitaxel (C), a novel taxane developed to overcome D resistance,<br />
showed an overall survival improvement after D in mCRPC in a three-weekly schedule.<br />
Its main toxicity is hematological,. We aimed to evaluate the relation <strong>of</strong> CTC counts<br />
and its early response with efficacy <strong>of</strong> weekly C/prednisone (P) schedule in "unfit"<br />
mCRPC previously treated with D.<br />
Methods: Unfit pts (ECOG 2, dose reduction due to febrile neutropenia during<br />
treatment with D or radiation therapy affecting more than 25% <strong>of</strong> bone marrow<br />
reserve) with mCRPC progressing after D with adequate bone marrow, liver and kidney<br />
functions were included. C 10 mg/m2 was administered on days 1, 8, 15 and 22 <strong>of</strong><br />
5-week cycles with daily prednisone 5 mg b.i.d. Radiological and PSA response was<br />
evaluated according to the PCCTWG II criteria. CellSearch system was used for<br />
counting the CTC. Early CTC response defined as a drop <strong>of</strong> ≥30% at 4 weeks from<br />
baseline. Toxicity was evaluated according NCI-CTC AE.<br />
Results: 70 pts have been enrolled. Median age was 73 y (range 54-85), 71% pts had<br />
ECOG 2, 84% had bone, 16% liver and 11% lung metastases. Twenty-four pts (34.3%)<br />
achieve ≥50% PSA response and 7 (10.0%) ≥80%. Radiological response (PR) was<br />
observed in 4 pt (5.7%) and SD in 32 pts (45.7%). Median PSA PFS was 4.8 months<br />
and 12 weeks PSA PFS was 68.6%. Median OS was 12.6 months. Most frequent<br />
toxicities <strong>of</strong> all grades and grade 3-4 as % <strong>of</strong> pts were: anemia (80-17%), asthenia<br />
(54-19%), thrombocytopenia (20-10%), diarrhea (36-1%), nauseas (27-1%),<br />
neutropenia (14-1%), peripheral neuropathy (19-0%), and anorexia (30-3%). Neither<br />
vi258 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
grade IV diarrhea nor febrile neutropenia were observed. Nineteen <strong>of</strong> 32 pts (59%) had<br />
early CTC response. Results show a favorable association between early CTC response<br />
and PSA response (77% vs 53%) (p = 0,267), clinical benefit (RP + EE) (68% vs 31%)<br />
(p = 0,070), overall survival (15.8 m vs 7.2 m) (p = 0,175) and PSA PFS (7.8 m vs 3.1<br />
m) (p = 0,004).<br />
Conclusions: Our results suggest that weekly C plus P in unfit pts is an effective<br />
regimen with lower toxicity than the 3-weekly standard treatment. Early CTC response<br />
seems to be related with efficacy and could be <strong>of</strong> value as early efficacy endpoint.<br />
Clinical trial identification: NCT01518283 / EudraCT: 2011-004627-12<br />
Legal entity responsible for the study: SOGUG (Spanish <strong>Oncology</strong> Genitourinary<br />
Group)<br />
Funding: San<strong>of</strong>i<br />
Disclosure: I. Duran: Consulting or advisory role: Amgen, Astellas, Roche-Genetech,<br />
Novartis, Janssen, Pierre-Fabre. Research funding: San<strong>of</strong>i, Janssen.All other authors<br />
have declared no conflicts <strong>of</strong> interest.<br />
754P<br />
Bone biomarkers and overall survival (OS) in men with castrate<br />
resistant prostate cancer (CRPC) and skeletal metastases:<br />
Updated results from SWOG 0421, a phase III trial <strong>of</strong> docetaxel<br />
+/- atrasentan<br />
P.N. Lara 1 , M. Plets 2 , C. Tangen 2 , E. Gertz 3 , N.J. Vogelzang 4 , D.I. Quinn 5 ,<br />
I. Thompson 6 , M. van Loan 3<br />
1 Internal Medicine/Hematology-<strong>Oncology</strong>, University <strong>of</strong> California Davis Cancer<br />
Center, Sacramento, CA, USA, 2 Statistics, Fred Hutchinson Cancer Research<br />
Center, Seattle, WA, USA, 3 USDA, Univesity <strong>of</strong> California Davis, Davis, CA, USA,<br />
4 Medical <strong>Oncology</strong>, US <strong>Oncology</strong> Research c/o Comprehensive Cancer Crts <strong>of</strong><br />
NV, Las Vegas, NV, USA, 5 Medicine, University <strong>of</strong> Southern California Norris<br />
Comprehensive Cancer Center, Los Angeles, CA, USA, 6 Urology, University <strong>of</strong><br />
Texas Health Science Center San Antonio, San Antonio, TX, USA<br />
Background: Skeletal metastasis is seen in most CRPC patients and is a common<br />
source <strong>of</strong> morbidity. We previously reported that bone biomarkers in CRPC patients<br />
are independently prognostic for OS, and that in men with highly elevated markers<br />
there is benefit from bone-targeted therapy (Lara, et al. JNCI 2014). Here we report our<br />
prospectively planned classification & regression tree (CART) analysis <strong>of</strong> clinical<br />
covariates and bone biomarkers as part <strong>of</strong> the phase III S0421 trial <strong>of</strong> docetaxel +/-<br />
atrasentan.<br />
Methods: Markers for bone resorption [N-telopeptide (NTx) & pyridinoline (PYD)] &<br />
formation [C-terminal collagen propeptide (CICP) & bone alkaline phosphatase<br />
(BAP)] were measured in pre-treatment sera from men on S0421. Bone biomarkers &<br />
baseline clinical covariates were included in a Cox model for OS; significant variables<br />
were allowed to compete in a CART analysis to identify prognostic groups using<br />
CTREE in the R package "party". Hazard ratios (HR) were calculated by comparing OS<br />
in each <strong>of</strong> the terminal nodes to a reference group in a Cox PH model. Kaplan Meier<br />
curves for each prognostic group defined by the tree were constructed.<br />
Results: 750 men with evaluable bone marker & clinical data were included. Each bone<br />
marker significantly contributed to the final Cox model, with higher levels associated<br />
with worse OS. Cox stepwise selection identified BAP, CICP, PYD, hemoglobin (Hgb),<br />
pain score, age, black race, PSA, and visceral disease as associated with OS. CART<br />
analysis selected CICP, BAP, Hgb, & pain score for the final model, & identified 5<br />
prognostic groups:<br />
Prognostic<br />
Group<br />
Table: 754P<br />
Description N Median OS<br />
(months)<br />
Hazard<br />
Ratio<br />
(95% CI)<br />
p-value<br />
1 Hgb < =11.3 177 12.4 REF REF<br />
2 Hgb > 11.3 CICP < =6.8 191 31.6 0.28 (0.22, 11.3 CICP > 6.8 Worst 144 15.3 0.79 (0.63, 0.04<br />
pain > =4<br />
0.99)<br />
4 Hgb > 11.3 CICP > 6.8 Worst 140 27.1 0.34 (0.27, 11.3 CICP > 6.8 Worst<br />
pain < 4 BAP > 90.9<br />
98 17.1 0.68 (0.53,<br />
0.88)<br />
0.003<br />
Conclusions: Elevated serum levels <strong>of</strong> bone biomarkers are strongly associated with<br />
worse OS in CRPC. CART analysis incorporating bone biomarkers identified five<br />
distinct prognostic CRPC groups with differential OS outcomes. These results further<br />
define & establish the role <strong>of</strong> bone biomarkers in the design and conduct <strong>of</strong> CRPC<br />
clinical trials.<br />
Clinical trial identification: ClinicalTrials.gov NCT00134056; NCI 5R01-CA120469,<br />
CA180888 and CA180819<br />
Legal entity responsible for the study: Southwest <strong>Oncology</strong> Group (SWOG) and the<br />
University <strong>of</strong> California Davis<br />
Funding: National Cancer Institute (USA)<br />
Disclosure: P.N. Lara: In the past 3 years I have served as a consultant (advisory board<br />
or DSMC member) for Clovis, Exelixis, Pfizer, Teva, Halozyme, Novartis, San<strong>of</strong>i,<br />
LPath, Lilly, Astra Zeneca, Bayer, and Genentech/Roche.D.I. Quinn: San<strong>of</strong>i, Astellas,<br />
and Bayer for honoraria (ad boards) and Dendreon and San<strong>of</strong>i for trial support.All<br />
other authors have declared no conflicts <strong>of</strong> interest.<br />
755P<br />
Neutropenia grade ≥ 3 during treatment with docetaxel (DOC)<br />
is associated with an improved overall survival (OS): A<br />
retrospective analysis <strong>of</strong> the TAX327 phase III trial<br />
A. Meisel 1 , D. Vogt 2 , R. de Wit 3 , J.S. de Bono 4 , O. Sartor 5 , M. Eisenberger 6 ,<br />
F. Stenner-Liewen 7<br />
1 Department <strong>of</strong> Internal Medicine - Hematology & <strong>Oncology</strong>, Stadtspital Waid,<br />
Zurich, Switzerland, 2 Clinical Trial Unit, University Hospital <strong>of</strong> Basel, Basel,<br />
Switzerland, 3 Medical <strong>Oncology</strong>, Erasmus University Medical Center, Rotterdam,<br />
Netherlands, 4 Division <strong>of</strong> Clinical Studies, Drug Development Unit, Royal Marsden<br />
NHS Foundation Trust/The Institute <strong>of</strong> Cancer Research, Sutton, UK, 5 Medicine<br />
and Urology, Tulane Cancer Center, New Orleans, LA, USA, 6 The Sidney Kimmel<br />
Comprehensive Cancer Center, Johns Hopkins Hospital, Baltimore, MD, USA,<br />
7 Department <strong>of</strong> <strong>Oncology</strong>, University Hospital <strong>of</strong> Basel, Basel, Switzerland<br />
Background: We previously showed that mCRPC patients developing grade ≥3<br />
neutropenia (NP) with cabazitaxel had a prolonged progression-free survival (PFS) and<br />
OS (Meisel EJC 2016; 56:93-100). A risk model combining the<br />
neutrophil-to-lymphocyte ratio (NLR) and grade ≥ 3 NP was built to distinguish<br />
patients with a poor, intermediate and good prognosis.<br />
Methods: The prospective phase III trial TAX327 randomly assigned (1:1:1)<br />
chemonaïve mCRPC patients to DOC (30 mg/m 2 for 5/6 weeks), DOC (75 mg/m 2<br />
every 3 weeks) or mitoxantrone 12 mg/m 2 +prednisone 5 mg twice daily. Hematology<br />
was collected before each cycle. Prophylactic G-CSF was allowed in case <strong>of</strong> febrile<br />
neutropenia. This post-hoc analysis evaluates the influence <strong>of</strong> grade ≥ 3 NP and NLR<br />
on OS.<br />
Results: OS in the DOC arms was significantly associated with the frequency <strong>of</strong> grade 3<br />
3 NP (HR 0.89 [95% CI: 0.81 – 0.98], p = 0.02). There was an even stronger association<br />
(HR 0.82 [95% CI: 0.71 – 0.94], p = 0.005), when patients with at least one episode <strong>of</strong><br />
grade 3 3 NP were analysed. Therefore we compared the OS <strong>of</strong> patients with multiple<br />
episodes <strong>of</strong> grade ≥3 NP to those with ≤ 1 episode <strong>of</strong> grade ≥3 NP and found a<br />
significantly prolonged OS for patients with multiple grade ≥3 NP episodes (HR 0.61<br />
[95% CI: 0.39 – 0.97], p = 0.038). The median OS was 17.1 months for patients with a<br />
single episode <strong>of</strong> grade ≥3 NP, 18.2 months for those without grade ≥3 NP and 22.8<br />
months for those with multiple episodes <strong>of</strong> grade ≥3 NP. The same association could<br />
be shown, when only the subgroup <strong>of</strong> patients treated with 3-weekly DOC, todays<br />
standard first line chemotherapy, was considered (HR 0.61 [95% CI: 0.38 – 0.96],<br />
p = 0.033). The biparametric risk model was applicable for mCRPC patients treated<br />
with 1 st -line chemotherapy with DOC. The HR between risk category 0 (low NLR
abstracts<br />
hypothesized the DDRD positive molecular subtype in prostate cancer would confer a<br />
worse outcome following docetaxel treatment.<br />
Methods: We used siRNA-mediated knockdown <strong>of</strong> DNA repair genes in DU145 cells<br />
to test for activation <strong>of</strong> the DDRD immune signal and sensitivity to docetaxel versus<br />
DNA damaging agents. We obtained FFPE diagnostic core biopsies from 52 men with<br />
Castrate Resistant Prostate Cancer (CRPC) treated with Docetaxel. Response to<br />
docetaxel was measured as a >50% decline in Prostate Specific Antigen (PSA).<br />
Samples were microarray pr<strong>of</strong>iled, signature scored and defined as DDRD positive or<br />
negative.<br />
Results: siRNA mediated knockdown <strong>of</strong> BRCA1, BRCA2 and ATM resulted in<br />
increased resistance to docetaxel and increased sensitivity to cisplatin. Ten patients<br />
(19.23%) were DDRD positive and 42 (80.76%) were DDRD negative; 80% <strong>of</strong> DDRD<br />
positive and 47% <strong>of</strong> DDRD negative patients failed to benefit from docetaxel. DDRD<br />
positive tumour samples demonstrated an association with poorer overall survival<br />
post-docetaxel (HR 0.464; 95% CI 0.13 to 0.89; p = 0.0317; Median survival DDRD<br />
positive 12.43months vs. DDRD negative 21.83 months).<br />
Conclusions: The DDRD positive molecular subtype <strong>of</strong> prostate cancer, characterised<br />
by an immune response to DNA damage, has a reduced benefit from docetaxel. We<br />
intend to validate this observation in the STAMPEDE trial, investigating advanced<br />
prostate cancer patients who received docetaxel as primary therapy. These studies may<br />
lead to clinical trials where DDRD positive patients receive specific DNA damaging<br />
agents like carboplatin or an immune targeted therapy such as a PD-L1 inhibitor.<br />
Legal entity responsible for the study: Queens University Belfast<br />
Funding: Cancer Research UK<br />
Disclosure: S. Walker: This Author is an employee for ALMAC diagnostics.N.<br />
McCabe: Is an employee <strong>of</strong> Almac Daignostics and her research is funded by Almac in<br />
part.L. Hill: Is an employee <strong>of</strong> ALMAC diagnostics and her work is funded by ALMAC.<br />
R. Kennedy: Employee <strong>of</strong> Almac diagnostics.All other authors have declared no<br />
conflicts <strong>of</strong> interest.<br />
757P<br />
Myeloid-derived suppressor cells (MDSCs) in metastatic<br />
castration-resistant prostate cancer (CRPC) patients (PTS)<br />
N. Mehra 1 , G. Seed 1 , M. Lambros 1 , A. Sharp 1 , M. Sousa Fontes 1 , M. Crespo 1 ,<br />
S. Sumanasuriya 1 , W. Yuan 1 , G. Boysen 1 , R. Riisnaes 1 , A. Calcinotto 2 ,<br />
S. Carreira 1 , J. Goodall 1 , Z. Zafeiriou 1 , D. Bianchini 1 , A. Morilla 3 , R. Morilla 3 ,<br />
A. Alimonti 2 , J.S. de Bono 1<br />
1 Cancer Studies, The Institute <strong>of</strong> Cancer Research (ICR), London, UK, 2 Institute <strong>of</strong><br />
<strong>Oncology</strong> Research (IOR), <strong>Oncology</strong> Institute <strong>of</strong> Southern Switzerland (IOSI),<br />
Bellinzona, Switzerland, 3 Centre for Molecular Pathology, Institute <strong>of</strong> Cancer<br />
Research ICR, London, UK<br />
Background: The relevance <strong>of</strong> targeting MDSCs in CRPC is increasingly recognized;<br />
preclinical studies implicate MDSCs with senescence evasion, treatment resistance, loss<br />
<strong>of</strong> tumour suppressors (TSL) function or oncogene activation (OA). We investigated<br />
MDSC subsets in CRPC PTS with regard to their molecular underpinnings and<br />
associated with PSA response.<br />
Methods: We prospectively evaluated MDSCs in 46 progressing CRPC PTS prior to<br />
new lines <strong>of</strong> therapy (n = 65), and in 14 male healthy volunteers (HV). Following blood<br />
draw MDSCs were analysed within 24 hours according to a gating strategy designed to<br />
standardize MDSC phenotyping. Here we report 5 MDSC subsets (phenotypes<br />
described in table), <strong>of</strong> which 2 are monocytic (M)/granulocytic (Gr) lineage-negative<br />
(MDSC3 and MDSC9), 2 with Gr (MDSC8 and MDSC8A) and 1 with a M phenotype<br />
(MDSC4). Subsets are expressed as % <strong>of</strong> their parental population. Data were acquired<br />
with a BD Canto II with FACS-Diva and analysed using Kaluza 1.3. We tested for the<br />
association between MDSCs subsets and copy number aberrations <strong>of</strong> 8q gain, loss (het/<br />
homdel) <strong>of</strong> PTEN and RB1 in cell-free circulating DNA by targeted amplicon-based<br />
sequencing (IonTorrent) using CNVkit V0.3.5. Differences in levels <strong>of</strong> the 5 MDSC<br />
subsets were assessed using non-parametric testing (Mann-Whitney) and associations<br />
<strong>of</strong> dichotomized MDSC subsets (at median) with PSA response were tested by<br />
Chi-square.<br />
Results: Overall, 65 baseline samples were analysed from 46 PTS with 4 <strong>of</strong> 5 MDSC<br />
subsets significantly increased in CRPC samples compared to HV (Table).<br />
Table: 757P<br />
Subset Phenotype CRPC<br />
(%)<br />
CRPC<br />
(N)<br />
HV<br />
(%)<br />
HV<br />
(N)<br />
0.86 65 2.17 13 0.034<br />
MDSC3 CD14 neg CD15 neg<br />
HLA-DR low CD33 pos<br />
MDSC9 CD14 neg CD15 neg CD33 pos 5.76 65 5.16 13 0.373<br />
MDSC8 CD15 pos CD33 pos 1.99 65 0.40 14 5<br />
(36,7%), with both groups characteristics balanced. Median OS was 16,6 months in the<br />
NLR > 5 group and 27,1 months in the NLR < 5 group (HR 0,507, p = 0,024). NLR<br />
remained predictive <strong>of</strong> a worse OS in a multivariate analysis that included<br />
pre-therapeutic prognostic factors. 21 patients (63,6%) with a NLR > 5 at baseline<br />
converted to < 5 at 12 weeks <strong>of</strong> treatment with AA, and this was associated with a trend<br />
for a better OS (10,5 vs 8,5 months, p = 0,197). Median PFS was 10,4 months in the<br />
NLR > 5 group and 9,7 months in the NLR < 5 group (p = 0,867).<br />
Conclusions: The NLR was prognostic in this analysis, with a NLR > 5 at baseline<br />
associated to a worse OS. There was no relation between NLR and response duration,<br />
with similar PFS in both groups. There was a trend for better OS in patients with a<br />
NLR > 5 at baseline that converted to < 5 at 12 weeks <strong>of</strong> treatment with AA. Further<br />
studies are warranted to validate NLR as a prognostic tool with the use <strong>of</strong> AA.<br />
Legal entity responsible for the study: Centro Hospitalar Lisboa Norte, Hospital de<br />
Santa Maria<br />
Funding: Serviço de Oncologia Médica, Centro Hospitalar Lisboa Norte, Hospital de<br />
Santa Maria<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
759P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Prognostic factors in men with metastatic castration-resistant<br />
prostate cancer (mCRPC) treated with enzalutamide (ENZA) or<br />
bicalutamide (BIC) in TERRAIN<br />
A. Heidenreich 1 , N. Shore 2 , A. Villers 3 , L. Klotz 4 , D.R. Siemens 5 , S. van Os 6 ,<br />
B. Baron 7 ,F.Wang 8 , S. Chowdhury 9<br />
1 Urology, Cologne University, Cologne, Germany, 2 Urology, Carolina Urologic<br />
Research Center, Myrtle Beach, SC, USA, 3 Urology, Lille University, Lille, France,<br />
4 Urology, Sunnybrook Health Sciences Centre, Toronto, ON, Canada, 5 Urology,<br />
Centre for Applied Urological Research, Queen’s University, Kingston, ON,<br />
Canada, 6 Global Development <strong>Oncology</strong>, Astellas Pharma, Inc., Leiden,<br />
Netherlands, 7 Data Science, Astellas Pharma, Inc., Leiden, Netherlands, 8 Clinical<br />
Development, Medivation, Inc., San Francisco, CA, USA, 9 Medical <strong>Oncology</strong>,<br />
Guy’s, King’s and St. Thomas’ Hospitals, London, UK<br />
Background: In TERRAIN, men with mCRPC who had progressed during luteinising<br />
hormone receptor hormone agonist/antagonist (LHRHa) treatment or after bilateral<br />
orchiectomy were randomised to ENZA or BIC. This post hoc analysis explores<br />
pre-treatment factors associated with progression-free survival (PFS) and time to<br />
prostate serum antigen (PSA) progression (TTP) and a risk group classification model<br />
based on the statistically and clinically predictive value <strong>of</strong> these factors.<br />
Methods: Data from randomised men in TERRAIN were analysed. Cox regression<br />
analysis was used to identify pre-treatment factors associated with PFS and TTP as<br />
single or multiple variables in the model and to determine a risk group classification.<br />
PSA, testosterone, lactate dehydrogenase (LDH), alkaline phosphatase (ALP), albumin<br />
(ALB), haemoglobin, neutrophil-lymphocyte ratio (NLR), LHRHa/orchiectomy start<br />
date relative to diagnosis <strong>of</strong> metastasis, ECOG performance status, Gleason score,<br />
vi260 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
disease location and prior anti-androgen use were used as continuous or categorical<br />
variables. Models were stratified by study treatment.<br />
Results: Data from 375 men were analysed. PSA, LDH, ALP, ALB and disease location<br />
were prognostic factors for PFS and/or TTP in single and multiple variable models.<br />
NLR, haemoglobin and LHRHa start were prognostic factors in single variable models.<br />
For PFS and TTP, an efficient risk group classification with three prognostic risk<br />
groups was derived based on ALP, PSA and ALB (table). Median PFS for the best risk<br />
group (0–1) was 16.6 months vs 3.3 months for the worst risk group (4) [hazard ratio,<br />
5.7; 95% confidence interval 4.0, 8.2].<br />
Baseline parameter<br />
Table: 759P<br />
ALP PSA ALB<br />
ALP
abstracts<br />
including treatment efficacy (measured by a PSA decline, physician assessment <strong>of</strong><br />
clinical benefit, and time to events), and toxicity (NCI-CTC grading).<br />
Results: 245 pts received at least one anticancer treatment at CRPC progression. The<br />
treatments most frequently used and their efficacy are detailed in the Table. Toxicity<br />
was mild, with only rare grade 3-4 events (17%). Median overall survival measured<br />
after the onset <strong>of</strong> CRPC was respectively 2.29 years (IC95% [1.84-2.59]) and 1.97 years<br />
(IC95% [1.64-2.73]) in the ADT and ADT + D arms.<br />
First<br />
treatment<br />
for CRPC<br />
Second<br />
treatment<br />
for CRPC<br />
Table: 761P Efficacy <strong>of</strong> treatments used for CRPC<br />
Treatment used for<br />
CRPC (N = 245<br />
pts)<br />
Docetaxel based<br />
chemotherapy<br />
(N = 104)<br />
Bicalutamide<br />
(N = 61)<br />
Abiraterone or<br />
Enzalutamide<br />
(N = 13)<br />
Docetaxel based<br />
chemotherapy<br />
(N = 49)<br />
Abiraterone or<br />
Enzalutamide<br />
(N = 34)<br />
Mitoxantrone<br />
(N = 17)<br />
Platin based<br />
chemotherapy<br />
(N = 15)<br />
PSA response<br />
(ADT vs<br />
ADT + D)<br />
23/68 (34%)<br />
vs 3/18<br />
(17%)<br />
12/28 (43%)<br />
vs 4/24<br />
(17%)<br />
Symptomatic<br />
response (ADT vs<br />
ADT + D)<br />
16/55 (29%) vs 5/<br />
17 (29%)<br />
0/12 (0%) vs 3/21<br />
(14%)<br />
1/2 vs 6/9 1/2 vs 1/4<br />
12/17 (71%)<br />
vs 0/9 (0%)<br />
5/7 (71%) vs<br />
4/7 (57%)<br />
5/17 (29%) vs 5/<br />
12 (42%)<br />
0/8 vs 0/4 1/6 vs 2/7<br />
0/6 vs 1/2 4/10 vs 0/1<br />
Median PFS<br />
Months (95%<br />
CI) (ADT vs<br />
ADT + D)<br />
7.0 (4.3-9.2) vs<br />
4.1 (1.3-5.0)<br />
5.1 (3.2-11.7 ) vs<br />
3.2 (2.1-6.9 )<br />
6.0 (4.2-8.5) vs<br />
2.5 (0.9-6.2)<br />
4/8 vs 2/11 6.0 (1.0-9.1 ) vs<br />
5.6 (1.0- )<br />
Conclusions: In this retrospective analysis, anticancer activity was suggested with<br />
androgen receptor axis-targeted agents even in patients with metastatic prostate cancer<br />
treated upfront with ADT + docetaxel. We observed that docetaxel rechallenge had<br />
rather limited activity in this setting.<br />
Clinical trial identification: NCT00104715; release date: 2013 Februray (Lancet<br />
Oncol)<br />
Legal entity responsible for the study: Unicancer<br />
Funding: French Health Ministry and Institut National du Cancer (PHRC),<br />
San<strong>of</strong>i-Aventis, AstraZeneca, and Amgen<br />
Disclosure: F. Joly: Roche, Pfizer, Novartis, San<strong>of</strong>i, Jansen, Astellas.M. Soulié: Amgen,<br />
Astellas, Astra Zeneca, Ferring, Glaxo Smith K, Ipsen, Jansen, Keocyt, Novartis, Pierre<br />
Fabre, San<strong>of</strong>i, Takeda, Zambon.B. Laguerre: Pfizer, Novartis, Jansen.K. Fizazi:<br />
Participation to advisory boards and honorarium : San<strong>of</strong>i, Janssen, Astellas.All other<br />
authors have declared no conflicts <strong>of</strong> interest.<br />
762P<br />
Effect <strong>of</strong> baseline metabolic aberrations in men with locally<br />
advanced/metastatic prostate cancer treated with ADT on<br />
time to disease progression, prostate cancer specific and all<br />
cause death<br />
D. Crawley 1 , M. van Hemelrijck 1 , S. Chowdhury 2 , N. James 3 , C. Gilson 4 ,<br />
M. Spears 4 , M.R. Sydes 4 , S. Rudman 2<br />
1 Research <strong>Oncology</strong>, King’s College London Guy’s Hospital, London, UK,<br />
2 <strong>Oncology</strong>, Guy’s and St. Thomas’ Hospital NHS Trust, London, UK, 3 Clinical Trial<br />
Unit, University <strong>of</strong> Warwick, Coventry, UK, 4 Clinical Trials Unit, Medical Research<br />
Council (MRC) MRC Clinical Trials Unit, London, UK<br />
Background: Metabolic conditions (diabetes, obesity, or dyslipidaemia) may be linked<br />
with prostate cancer (PCa) aggressiveness and death. The presence <strong>of</strong> these metabolic<br />
aberrations may enable us to identify those men who are at risk <strong>of</strong> early treatment<br />
failure. Here, we examine the effect <strong>of</strong> baseline metabolic aberrations on time to disease<br />
progression, PCa specific and all cause death in a cohort <strong>of</strong> men with locally advanced/<br />
metastatic PCa treated with long term androgen deprivation therapy (ADT).<br />
Methods: This study was conducted using a retrospective review <strong>of</strong> case report forms<br />
(CRF) <strong>of</strong> 2,617 men with locally advanced/metastatic hormone naïve PCa commencing<br />
long term ADT who enrolled in the control arm <strong>of</strong> the STAMPEDE trial<br />
(ISRCTN78818544) between 2005 and 2015. Data on the following metabolic<br />
aberrations at baseline was included: hypertension (systolic blood pressure ≥140mmHg<br />
and/or diastolic blood pressure ≥90mmHg or confirmed history <strong>of</strong> hypertension),<br />
obesity (BMI >30kg/m 2 ),dyslipidaemia (HDL
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
castration-resistant prostate cancer (CRPCa). The impact <strong>of</strong> these treatments on<br />
cognitive functions has never been evaluated whereas cognitive impairment may have<br />
an impact on the autonomy and the adherence <strong>of</strong> the treatment. The aim <strong>of</strong> this study<br />
is to prospectively assess the incidence <strong>of</strong> cognitive impairment in elderly men after<br />
treatment by NGH for a metastatic CRPCa.<br />
Trial design: The Cog-Pro study is a multicentre longitudinal study including<br />
patients > 70 years treated with NGH (n = 134), control patients treated with first<br />
generation <strong>of</strong> androgen deprivation therapy (n = 55) and healthy subjects (n = 33).<br />
Cognitive tests, questionnaires and biological tests are performed at baseline, 3, 6 and<br />
12 months after the start <strong>of</strong> treatment. The primary endpoint is the proportion <strong>of</strong><br />
elderly patients receiving the NGH who will experience a decline in cognitive<br />
performances within 3 months after inclusion. Secondary endpoints include<br />
autonomy, quality <strong>of</strong> life, anxiety, depression, cognitive reserve, adherence to<br />
hormone-therapy, comparison <strong>of</strong> the 2 new agents (abiraterone acetate and<br />
enzalutamide), impact <strong>of</strong> co-morbidities and biological assessments. Our results will<br />
provide up-to date information for patients and caregivers on impact <strong>of</strong> NGH on<br />
cognitive functions in order to develop some strategies to help them. This study should<br />
help to improve cancer care <strong>of</strong> metastatic CRPCa elderly patients.<br />
Legal entity responsible for the study: Pr Florence Joly<br />
Funding: Institut National du Cancer (InCA, France)<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
765TiP<br />
Metformin and longevity (METAL): A window <strong>of</strong> opportunity<br />
study investigating the biological effects <strong>of</strong> metformin in<br />
localised prostate cancer<br />
D. Crawley 1 , A. Chandra 2 , M. Loda 3 , C. Gillett 4 , P. Cathcart 5 , B. Challacombe 5 ,<br />
G. Cook 6 , D. Cahill 7 , F. Cahill 1 , A. Santa Olalla 1 , G. George 1 , S. Rudman 8 , M. van<br />
Hemelrijck 1<br />
1 Research <strong>Oncology</strong>, King’s College London Guy’s Hospital, London, UK,<br />
2 Histopathology, Guy’s and St. Thomas’ Hospital NHS Trust, London, UK,<br />
3 Molecular Pathology, Dana-Farber Cancer Institute, Boston, MA, USA, 4 Division<br />
<strong>of</strong> Cancer Studies, King’s College London Guy’s Hospital, London, UK, 5 Urology,<br />
Guy’s and St. Thomas’ Hospital NHS Trust, London, UK, 6 Nuclear Medicine,<br />
Guy’s and St. Thomas’ Hospital NHS Trust, London, UK, 7 Urology, Royal<br />
Marsden Hospital NHS Foundation Trust, London, UK, 8 Medical <strong>Oncology</strong>, Guy’s<br />
and St. Thomas’ Hospital NHS Trust, London, UK<br />
Background: Metformin (1,1-dimethylbiguanide hydrochloride) is a biguanide oral<br />
hypoglycaemic agent commonly used for the treatment <strong>of</strong> type 2 diabetes mellitus. In<br />
addition to it’s anti-diabetic effect, metformin has also been associated with a reduced<br />
risk <strong>of</strong> cancer incidence <strong>of</strong> a number <strong>of</strong> solid tumour including prostate cancer (PCa).<br />
However, the underlying biological mechanisms for these observations have not been<br />
fully characterised in PCa. One hypothesis is that the indirect insulin lowering effect<br />
may have an anti-neoplastic effect as elevated insulin and insulin like growth factor -1<br />
(IGF-1) levels play a role in PCa development and progression. In addition, metformin<br />
is a potent activator <strong>of</strong> activated protein kinase (AMPK) which in turn inhibits the<br />
mammalian target <strong>of</strong> rapamycin (mTOR) and other signal transduction mechanisms .<br />
These direct effects can lead to reduced cell proliferation. Given its wide availability and<br />
tolerable side effect pr<strong>of</strong>ile, metformin represents an attractive potential therapeutic<br />
option for men with PCa. Hence, the need for a clinical trial investigating its biological<br />
mechanisms in PCa.<br />
Trial design: METAL is a multi-centre, randomized, placebo-controlled, double-blind,<br />
window <strong>of</strong> opportunity study investigating the biological mechanism <strong>of</strong> metformin in<br />
prostate cancer. 180 patients with newly-diagnosed, localised PCa scheduled for radical<br />
prostatectomy will be randomised 1:1 to receive metformin (1g bd) or placebo for four<br />
weeks (+/- 1 week) prior to prostatectomy. Tissue will be collected from both diagnostic<br />
biopsy and prostatectomy specimens. The primary endpoint is the difference in expression<br />
levels <strong>of</strong> markers <strong>of</strong> the FASN/AMPK pathway pre and post treatment between the<br />
placebo and metformin arms. Secondary endpoints include the difference in expression<br />
levels <strong>of</strong> indicators <strong>of</strong> proliferation (ki67 and TUNEL) pre and post treatment between the<br />
placebo and metformin arms. METAL is currently open to recruitment at Guy’s and St<br />
Thomas’ Hospital and the Royal Marsden Hospital, London.<br />
Clinical trial identification: EudraCT 2014-005193-11<br />
Legal entity responsible for the study: Co sponsored by King’s College London and<br />
Guy’s and St Thomas NHS Trust<br />
Funding: JP Moulton Charitable Foundation<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
766TiP<br />
CARD: A randomized phase 4 trial comparing cabazitaxel<br />
and an androgen receptor (AR)-targeted agent in men with<br />
metastatic castration-resistant prostate cancer (mCRPC)<br />
progressing after docetaxel and an alternative AR-targeted<br />
agent<br />
R. de Wit 1 , K. Fizazi 2 , E. Efstathiou 3 , R. Dittamore 4 , S. Hitier 5 , K. Pantel 6 ,<br />
C. Sternberg 7 , B. Tombal 8 , C. Wülfing 9 , J. de Bono 10<br />
1 Medical <strong>Oncology</strong>, Erasmus University Medical Center, Rotterdam, Netherlands,<br />
2 Cancer Medicine, Institut Gustave Roussy, Villejuif, France, 3 GU Medical<br />
<strong>Oncology</strong>, MD Anderson Cancer Center, Houston, TX, USA, 4 Translational<br />
Research, Epic Sciences Inc., San Diego, CA, USA, 5 75, San<strong>of</strong>i, Paris, France,<br />
6 Tumour Biology, UKE Universitätsklinikum Hamburg-Eppendorf KMTZ,<br />
Hamburg, Germany, 7 <strong>Oncology</strong>, San Camillo–Forlanini Hospital, Rome, Italy,<br />
8 Urology, Cliniques Universitaires St. Luc, Brussels, Belgium, 9 Urology, Asklepios<br />
Klinik Altona, Hamburg, Germany, 10 <strong>Oncology</strong>, Royal Marsden Hospital NHS<br />
Foundation Trust, London, UK<br />
Background: mCRPC is highly heterogeneous with coexistence <strong>of</strong> AR-dependent and<br />
AR-independent tumor clones. New AR-targeted agents (abiraterone acetate,<br />
enzalutamide) and taxanes (docetaxel (DOC), cabazitaxel - specifically developed to<br />
overcome DOC resistance) are the backbone <strong>of</strong> mCRPC therapy. The rising concern <strong>of</strong><br />
cross-resistance between mCRPC therapies and the evidence that some patients may<br />
not respond to all available drugs have increased the complexity <strong>of</strong> managing mCRPC.<br />
There is thus a need to design trials helping to define the optimal sequence <strong>of</strong> therapies<br />
to optimize patient outcomes.<br />
Trial design: CARD is a randomized phase 4 trial involving 79 sites in 12 European<br />
countries. A total <strong>of</strong> 324 patients with mCRPC previously treated with DOC and who<br />
failed a prior AR-targeted agent (abiraterone acetate or enzalutamide, either before or<br />
after DOC) within 12 months <strong>of</strong> AR-targeted treatment initiation will be randomized<br />
(1:1) to receive cabazitaxel (25mg/m 2 every 3 weeks plus daily prednisone and<br />
prophylactic G-CSF) or the alternative AR-targeted agent until radiographic progression,<br />
unacceptable toxicity or patient’s request. Randomization will be stratified by ECOG<br />
performance status (0-1 vs. 2), time to progression with prior AR-targeted agent (
abstracts<br />
receptor blocker, improves progression-free and overall survival (OS) in the metastatic<br />
castration-resistant setting. The efficacy and safety <strong>of</strong> ENZA plus ADT in the metastatic<br />
hormone-sensitive PC (mHSPC) setting will be assessed.<br />
Trial design: ARCHES is a multinational, Phase 3, randomised, double-blind,<br />
placebo-controlled efficacy and safety trial <strong>of</strong> ENZA (160 mg once daily) plus ADT vs<br />
placebo plus ADT in men with mHSPC. All men will be required to maintain ADT<br />
during study treatment, by either using a luteinising hormone-releasing hormone<br />
agonist/antagonist (LHRHa) or having undergone a bilateral orchiectomy. About 1100<br />
men with histologically or cytologically confirmed PC and mPC, documented by a<br />
positive bone scan or metastatic lesions on a CT or MRI scan, will be enrolled from<br />
about 250 global centres and randomised centrally 1:1. Randomisation will be stratified<br />
by disease volume (low vs high) and prior DOC therapy for prostate cancer (no prior<br />
DOC, 1–5 cycles, 6 cycles). For men receiving DOC, ENZA treatment will begin<br />
following DOC chemotherapy. Bicalutamide treatment will be permitted only when<br />
given concurrently with LHRHa for the prevention <strong>of</strong> flare-ups. The primary end point<br />
is radiographic progression-free survival (defined as the time from randomisation to<br />
the first objective evidence <strong>of</strong> radiographic disease progression [assessed by central<br />
review] or death, whichever occurs first). Secondary end points include OS, time to<br />
castration resistance and safety. All men will be followed for OS. As <strong>of</strong> 15 April 2016,<br />
four men have been randomised.<br />
Clinical trial identification: EudraCT 2015-003869-28<br />
Legal entity responsible for the study: Astellas Pharma, Inc. and Medivation, Inc.<br />
Funding: Astellas Pharma, Inc. and Medivation, Inc.<br />
Disclosure: A. Stenzl: Advisory board member: Ipsen Pharma, Janssen, Alere.<br />
Corporate-sponsored research: Johnson & Johnson, Amgen Inc, Bayer AG, CureVac,<br />
Immatics Biotechnologies GmbH, Novartis AG, Karl Storz AG.A. Krivoshik: Employee<br />
<strong>of</strong> Astellas. Owns Abbott and Abbvie stock.B. Baron: Employee <strong>of</strong> Astellas.M.<br />
Hirmand: Employee <strong>of</strong> Medivation. Owns Medivation stock.A. Armstrong: Advisory<br />
board member: Medivation, Janssen, Eisai, Bayer. Corporate-sponsored research:<br />
San<strong>of</strong>i Aventis, Medivation/Astellas, Janssen, Bayer, Dendreon, Gilead, Active Biotech,<br />
Bristol Myers Squibb, Novartis, Pfizer. Speaker for Dendreon and San<strong>of</strong>i.<br />
769TiP<br />
ATLAS: A phase 3 trial evaluating the efficacy <strong>of</strong> apalutamide<br />
(ARN-509) in patients with high-risk localized or locally<br />
advanced prostate cancer receiving primary radiation<br />
therapy<br />
A. Bossi 1 , D. Dearnaley 2 , M. McKenzie 3 , E. Baskin-Bey 4 , R. Tyler 4 , B. Tombal 5 ,S.<br />
J. Freedland 6 , M. Roach, III 7 , A. Widmark 8 , A.P. Dicker 9 , T. Wiegel 10 , N. Shore 11 ,<br />
M. Smith 12 ,M.Yu 4 , T. Kheoh 13 , S. Thomas 14 , H.M. Sandler 15<br />
1 Radiation <strong>Oncology</strong>, Institut Gustave Roussy, Villejuif, France, 2 Academic<br />
Radiotherapy, The Institute <strong>of</strong> Cancer Research and The Royal Marsden Hospital,<br />
London, UK, 3 Medical <strong>Oncology</strong>, British Columbia Cancer Agency, Vancouver,<br />
BC, Canada, 4 WC Clinical <strong>Oncology</strong>, Janssen Research & Development, Los<br />
Angeles, CA, USA, 5 Urology, Cliniques Universitaires St. Luc, Brussels, Belgium,<br />
6 Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA, 7 Radiation<br />
<strong>Oncology</strong>, Helen Diller Family Comprehensive Cancer Center, University <strong>of</strong><br />
California San Francisco, San Francisco, CA, USA, 8 Radiation Sciences, Umea<br />
University, Umea, Sweden, 9 Radiation <strong>Oncology</strong>, Thomas Jefferson University,<br />
Philadelphia, PA, USA, 10 Radiation <strong>Oncology</strong>, Ulm Medical University, Ulm,<br />
Germany, 11 Urology, Carolina Urologic Research Center, Myrtle Beach, SC, USA,<br />
12 Hematology-<strong>Oncology</strong>, Massachusetts General Hospital Cancer Center and<br />
Harvard Medical School, Boston, MA, USA, 13 Clinical Biostatistics, Janssen<br />
Research & Development, San Diego, CA, USA, 14 <strong>Oncology</strong> Translational<br />
Research, Janssen Pharmaceuticals, Spring House, PA, USA, 15 Radiation<br />
<strong>Oncology</strong>, Cedars-Sinai Medical Center, Los Angeles, CA, USA<br />
Background: Current management <strong>of</strong> high-risk localized or locally advanced prostate<br />
cancer includes 2 to 3 years <strong>of</strong> androgen deprivation therapy (ADT;<br />
gonadotropin-releasing hormone agonist [GnRHa]) along with primary radiation<br />
therapy (RT). Despite aggressive treatment, there is still a higher risk <strong>of</strong> metastasis and<br />
prostate cancer–related death in these patients. We hypothesize that the addition <strong>of</strong> the<br />
selective androgen receptor antagonist apalutamide to GnRHa will improve<br />
metastasis-free survival in high-risk patients receiving primary RT.<br />
Trial design: This is a randomized, double-blind, placebo-controlled, phase 3 trial<br />
evaluating the efficacy <strong>of</strong> apalutamide in patients with high-risk localized or locally<br />
advanced prostate cancer (Gleason score <strong>of</strong> ≥ 8 and ≥ cT2c or a Gleason score <strong>of</strong> ≥ 7<br />
and prostate-specific antigen ≥ 20 ng/mL and ≥ cT2c) receiving primary RT.<br />
Stratification: Gleason score (7 or ≥ 8), N0 or N1, brachytherapy boost (yes or no), and<br />
region (North American, European Union, or other). All patients will receive active<br />
treatment with GnRHa throughout the 30 (28-day) treatment cycles. Randomization:<br />
1:1 to apalutamide or control. Neoadjuvant/concurrent (cycles 1-4) to RT (74-80 Gy):<br />
apalutamide 240 mg/d vs bicalutamide 50 mg/d; adjuvant to RT (cycles 5-30):<br />
apalutamide 240 mg/d vs placebo. Primary end point: metastasis-free survival.<br />
Secondary end points: time to local-regional recurrence, time to castration-resistant<br />
disease, time to distant metastasis, and overall survival. Imaging and bone scan will be<br />
conducted at baseline and then every 6 months following biochemical failure until<br />
documented distant metastasis by blinded independent central review or death.<br />
Approximately 1500 patients will be accrued to provide appropriate statistical power to<br />
detect the hypothesized risk reduction (25%) in metastasis or death. An independent<br />
data monitoring committee is commissioned to review trial data. Approximately 300<br />
study sites are planned in 20 countries across North America, Latin America, Europe,<br />
and Asia. Sites in 11 countries are currently recruiting.<br />
Clinical trial identification: NCT02531516.<br />
Legal entity responsible for the study: Janssen Research & Development<br />
Funding: Janssen Research & Development<br />
Disclosure: D. Dearnaley: Consulting or Advisory Role - Cadence Research and<br />
Consulting, FirstWord, Janssen Pharmaceuticals, Janssen Pharmaceuticals, Sandoz,<br />
and Takeda; Travel, Accommodations, Expenses - Takeda; Expert Testimony - Vitality<br />
Life; Honoraria - Takeda.M. McKenzie: Honoraria - Amgen and Bayer; Consulting or<br />
Advisory Role - Johnson & Johnson.E. Baskin-Bey: Employee <strong>of</strong> Janssen Research &<br />
Development.R. Tyler, T. Kheoh, S. Thomas: Employee <strong>of</strong> Janssen Research &<br />
Development and holds stock in Johnson & Johnson.B. Tombal: Speaker and<br />
Investigator Fees - Janssen.S.J. Freedland: Consulting or Advisory Role - Astellas<br />
Pharma, Dendreon, Janssen Biotech, MDxHealth, Medivation, and San<strong>of</strong>i; Speakers’<br />
Bureau - Dendreon; Travel, Accommodations, Expenses - Myriad Genetics and San<strong>of</strong>i.<br />
A. Widmark: Employment - San<strong>of</strong>i; Honoraria - Astellas Pharma, Bayer, Janssen, and<br />
San<strong>of</strong>i; Consulting or Advisory Role - EXINI Diagnostics.A.P. Dicker: Consulting or<br />
Advisory role - Glenview, Janssen, Merck, and Redhill.T. Wiegel: Honoraria - Ferring,<br />
Hexal, Ipsen, and Siemens; Consulting or Advisory Role - Ferring and Ipsen.N. Shore:<br />
Consulting or Advisory Role - Astellas, Bayer, Ferring, Janssen, Millennium, Pfizer,<br />
and San<strong>of</strong>i; Research Funding - Carolina Urologic Research Center; Travel,<br />
Accomodations, Expenses - Astellas, Bayer, Ferring, Janssen, Millennium, Pfizer, and<br />
San<strong>of</strong>i.M. Smith: Consulting or Advisory Role - Astellas Pharma, Bayer, and Janssen<br />
<strong>Oncology</strong>.M. Yu: Employee <strong>of</strong> Janssen Research & Development and holds stock in<br />
Johnson & Johnson.H.M. Sandler: Consulting or Advisory Role - Medivation/Astellas,<br />
Blue Earth, Eviti, Ferring, Janssen Pharmaceuticals, and San<strong>of</strong>i; Honoraria - Varian<br />
Medical Systems.All other authors have declared no conflicts <strong>of</strong> interest.<br />
770TiP<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
EMBARK: A phase 3, randomized, efficacy and safety study<br />
<strong>of</strong> enzalutamide plus leuprolide, enzalutamide monotherapy<br />
and placebo plus leuprolide in men with high-risk<br />
nonmetastatic prostate cancer progressing after definitive<br />
therapy<br />
K. Miller 1 , P. Mulders 2 , S.J. Freedland 3 , H. Scher 4 , N. Shore 5 , E. Park 6 ,<br />
A. Krivoshik 7 , D. Phung 8 , K. Modelska 6 , P. Scardino 9<br />
1 Urology, Charité – Universitätsmedizin Berlin, Berlin, Germany, 2 Urology,<br />
Radboud University Medical Centre Nijmegen, Nijmegen, Netherlands, 3 Surgery,<br />
Cedars-Sinai Medical Center, Los Angeles, CA, USA, 4 Medicine, Memorial<br />
Sloan-Kettering Cancer Center, New York, NY, USA, 5 Urology, Carolina Urologic<br />
Research Center, Myrtle Beach, SC, USA, 6 Clinical Development, Medivation, Inc.,<br />
San Francisco, CA, USA, 7 Medical <strong>Oncology</strong>, Astellas Pharma Global<br />
Development, Inc., Northbrook, IL, USA, 8 Biostatistics, Astellas Pharma, Leiden,<br />
Netherlands, 9 Urology, Memorial Sloan-Kettering Cancer Center, New York, NY,<br />
USA<br />
Background: After radical prostatectomy or radiotherapy, about 1 <strong>of</strong> 4 men with<br />
adenocarcinoma <strong>of</strong> the prostate will develop a biochemical recurrence manifested by<br />
increasing levels <strong>of</strong> prostate-specific antigen (PSA). Of these, approximately 1 <strong>of</strong> 3 will<br />
eventually develop clinically detectable metastatic disease. To date, there is no approved<br />
therapy for patients who have PSA relapse after surgery and/or radiotherapy and are at<br />
high risk for metastatic disease. Androgen deprivation is the de facto standard and<br />
most commonly prescribed treatment in this setting. The EMBARK trial is designed to<br />
address this unmet need in high-risk, nonmetastatic, hormone-sensitive prostate<br />
cancer patients who recur after primary therapy.<br />
Trial design: The EMBARK trial will randomize approximately 1860 subjects globally,<br />
across 200 international sites, into 3 treatment arms: leuprolide + enzalutamide,<br />
leuprolide + placebo and enzalutamide monotherapy. Enrolment is ongoing since Jan<br />
2015. Subjects must fulfil the following entry criteria indicative <strong>of</strong> having biochemical<br />
relapse and high-risk disease: PSA doubling time ≤ 9 months; screening PSA threshold<br />
<strong>of</strong> ≥ 2.0 ng/mL for subjects who had prior radical prostatectomy or ≥ 5.0 ng/mL<br />
and ≥ nadir + 2 ng/mL for subjects who had radiotherapy as the primary therapy;<br />
androgen deprivation therapy ≤ 36 months in duration and ≥ 9 months before<br />
randomization and administered only in the neoadjuvant/adjuvant setting; no evidence<br />
<strong>of</strong> s<strong>of</strong>t-tissue or bone metastases at the time <strong>of</strong> enrollment; and testosterone level > 150<br />
ng/dL. In each arm, subjects will be evaluated every 12 wks through the treatment<br />
course. Imaging studies with computed tomography/magnetic resonance imaging and<br />
bone scans will be performed every 25 wks until the primary efficacy endpoint <strong>of</strong><br />
metastasis-free survival is met. Subjects are allowed 1 treatment suspension (<strong>of</strong> the<br />
study drugs) at wk 37 if the PSA levels are < 0.2 ng/mL. Treatment will be reinitiated if<br />
PSA values rise ≥ 2.0 ng/mL for patients with prior prostatectomy or ≥ 5.0 ng/mL for<br />
those with only prior radiotherapy.<br />
Clinical trial identification: NCT02319837<br />
Legal entity responsible for the study: Medivation, Inc. and Astellas Pharma, Inc.<br />
Funding: Medivation, Inc. and Astellas Pharma, Inc.<br />
Disclosure: K. Miller: reports consulting fees: Medivation, Astellas; outside submitted<br />
work consulting fees: Astellas, Amgen, Janssen-Cilag, Medivation, Novartis, Roche,<br />
and speaker bureau fees: Novartis, Janssen-Cilag, Pierre-Fabre.P. Mulders: receives<br />
vi264 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
consulting fees and participates in review activities from Janssen J&J; outside submitted<br />
work consultancy and lectures/speaker bureaus: AstraZeneca, Astellas,<br />
GlaxoSmithKline; grants to institution: Bayer.S.J. Freedland: is a consultant to<br />
Medivation and Astellas.H. Scher: reports grants: Medivation, personal fees: Endo/<br />
Orion, Ferring, Chugai, non-financial support from Exelisis, Janssen, Novartis, BMS,<br />
Celgene, Takeda Millennium, outside submitted work: Astellas, Novartis, AZ,<br />
Genentech, Endocyte, Pfizer, San<strong>of</strong>i-Aventis.N. Shore: reports personal fees from<br />
Astellas, personal fees from Medivation, during the conduct <strong>of</strong> the study.E. Park:<br />
employee at Medivation Inc.A. Krivoshik: an employee <strong>of</strong> Astellas and hold stock in<br />
Abbott and Abbvie.K. Modelska: reports personal fees and other from Medivation,<br />
during the conduct <strong>of</strong> the studyAll other authors have declared no conflicts <strong>of</strong> interest.<br />
abstracts<br />
Consulting or Advisory role - Astellas Pharma and Pierre Fabre; Speakers Bureau -<br />
Astellas Pharma, GlaxoSmithKline, and Prizer; Research funding - Astellas Pharma,<br />
Allergan, and Pierre Fabre.T. Lebret: Consulting or Advisory Role - Bayer, Janssen, and<br />
MSD; Speakers’ Bureau - Janssen, Roche, and Ipsen; Research funding - Astellas;<br />
Travel, Accomodations, Expenses - Novartis and Astellas.C. Sternberg: Honoraria -<br />
Astellas, Bayer, Janssen, BMS, Novartis, and San<strong>of</strong>i.R.B. Sims, M. Yu, V. Naini,<br />
M. Darif: Employee <strong>of</strong> Janssen Research & Development and owns stock in Johnson &<br />
Johnson.A.S. Merseburger: Honoraria - Janssen, Astellas, and Ipsen; Consulting or<br />
Advisory Role - Janssen, Astellas, and Ipsen; Speakers’ Bureau - Janssen, Astellas, and<br />
Ipsen; Travel, Accomodations, Expenses - Janssen, Astellas, and Ipsen.All other<br />
authors have declared no conflicts <strong>of</strong> interest.<br />
771TiP<br />
TITAN: A randomized, double-blind, placebo-controlled,<br />
phase 3 trial <strong>of</strong> apalutamide (ARN-509) plus androgen<br />
deprivation therapy (ADT) in metastatic hormone-sensitive<br />
prostate cancer (mHSPC)<br />
K.N. Chi 1 , S. Chowdhury 2 , P. Radziszewski 3 , T. Lebret 4 , M. Ozguroglu 5 ,<br />
C. Sternberg 6 , R.B. Sims 7 ,M.Yu 7 , V. Naini 7 , M. Darif 8 , A.S. Merseburger 9<br />
1 Experimental Therapeutics, British Columbia Cancer Agency, Vancouver, BC,<br />
Canada, 2 <strong>Oncology</strong>, Guy’s and St Thomas’ NHS Foundation Trust, London, UK,<br />
3 Urology, Medical University <strong>of</strong> Warsaw, Warsaw, Poland, 4 Urology, Hospital Foch,<br />
Suresnes, France, 5 Medical <strong>Oncology</strong>, Istanbul University, Istanbul, Turkey,<br />
6 <strong>Oncology</strong>, San Camillo and Forlanini Hospitals, Rome, Italy, 7 WC Clinical<br />
<strong>Oncology</strong>, Janssen Research & Development, Los Angeles, CA, USA, 8 Clinical<br />
Biostats, Janssen Research & Development, San Diego, CA, USA, 9 Urology,<br />
University Hospital Schleswig-Holstein, Lübeck, Germany<br />
Background: There is an increased focus on improving outcomes <strong>of</strong> prostate cancer<br />
(PC) patients (pts) by introducing treatments before castration resistance occurs.<br />
Results from CHAARTED (Sweeney NEJM. 2015) and STAMPEDE (James Lancet.<br />
2015) demonstrate a survival advantage with ADT (gonadotropin-releasing hormone<br />
analog or surgical castration) in combination with docetaxel (DOC) for pts with<br />
metastatic PC, and practice guidelines recommend ADT + DOC for pts with metastatic<br />
disease. Inhibition <strong>of</strong> the androgen receptor (AR) in addition to ADT may provide<br />
more complete blockade <strong>of</strong> androgen signaling vs ADT alone. We hypothesize that<br />
apalutamide (APA), a selective AR antagonist, plus ADT will improve radiographic<br />
progression-free survival (rPFS) and overall survival (OS) compared with ADT alone,<br />
and have an acceptable safety pr<strong>of</strong>ile in pts with mHSPC.<br />
Trial design: This is a randomized, multicenter, double-blind, placebo-controlled,<br />
phase 3 trial evaluating the efficacy and safety <strong>of</strong> APA + ADT in pts with Eastern<br />
Cooperative <strong>Oncology</strong> Group performance status ≤ 1 and mHSPC (metastatic disease<br />
documented by ≥ 1 bone lesions with or without visceral metastasis). Pts will be<br />
stratified by Gleason score (≤ 7 vs > 7), region (North America, European Union vs<br />
other), and prior DOC use (yes/no). Up to 6 cycles <strong>of</strong> DOC for mHSPC is allowed,<br />
with last dose within 2 mos <strong>of</strong> randomization. Up to 6 mos ADT for mHSPC is allowed<br />
prior to randomization. Approximately 1000 pts will be randomized (1:1) to APA (240<br />
mg/d) + ADT or placebo + ADT in 28-day cycles. Co-primary end points: rPFS and<br />
OS. Secondary end points: time to pain progression, time to skeletal-related event, time<br />
to chronic opioid use, and time to initiation <strong>of</strong> cytotoxic chemotherapy. Samples for<br />
pharmacokinetics and biomarkers will be collected to correlate with clinical<br />
parameters. An independent data monitoring committee will review safety and efficacy<br />
data.<br />
Clinical trial identification: NCT02489318<br />
Legal entity responsible for the study: Janssen Global Services, LLC<br />
Funding: Janssen Global Services, LLC<br />
Disclosure: K.N. Chi: Membership on an advisory board - Janssen; Research funding -<br />
JanssenS. Chowdhury: Honoraria - San<strong>of</strong>i; Research funding – San<strong>of</strong>i.P. Radziszewski:<br />
772TiP<br />
Anti-prostate-specific membrane antigen (PSMA)<br />
monoclonal antibody (mAb) J591 immunotherapy for<br />
prostate cancer<br />
S.T. Tagawa 1 , D. Scherr 2 ,J.Batra 2 , Y. Jhanwar 3 , B. Robinson 4 , D. Nanus 1 ,<br />
H. Beltran 1 , A. Molina 1 , P. Christos 5 , N. Bander 2<br />
1 Division <strong>of</strong> Hematology & Medical <strong>Oncology</strong>, Weill Cornell Medical College,<br />
New York, NY, USA, 2 Urology, Weill Cornell Medical College, New York, NY, USA,<br />
3 Radiology, Weill Cornell Medical College, New York, NY, USA, 4 Pathology, Weill<br />
Cornell Medical College, New York, NY, USA, 5 Division <strong>of</strong> Biostatistics and<br />
Epidemiology, Weill Cornell Medical College, New York, NY, USA<br />
Background: PSMA is a highly restricted cell-surface protein whose expression is<br />
increased with grade, stage, and attenuated AR signaling. J591 is a mAb against the<br />
external domain <strong>of</strong> PSMA and has demonstrated safety in numerous human-studies<br />
with anti-tumor activity when radiolabeled and conjugated with drug, with PSA and<br />
CTC declines. It was originally engineered to elicit antibody-dependent cellular<br />
cytotoxicity (ADCC) and we have made 2 important options leading to the current<br />
prospective clinical trials. First, studies <strong>of</strong> 177 Lu-J591 have demonstrated >90% CTC<br />
control. While initially thought to represent delivery <strong>of</strong> 177 Lu into CTCs and tumors,<br />
we retrospectively observed 4 <strong>of</strong> 7 patients with CTC count decline with a small<br />
amount (20 mg) <strong>of</strong> J591 without an effector molecule when used for imaging. Second,<br />
we analyzed long-term follow up from a 2001 study in men with biochemically<br />
recurrent or metastatic CRPC where men received unlabeled J591 plus low dose IL-2.<br />
Using validated nomograms, pen with biochemical relapse survived a median on 87<br />
months longer than predicted without metastatic disease and in the pre-docetaxel era,<br />
men with mCRPC lived a median <strong>of</strong> 28.5 months longer than predicted. Based upon<br />
the preliminary data pointing towards CTC clearance and long-term survival, we have<br />
launched 2 prospective clinical trials.<br />
Trial design: In study 1 [NCT02552394], men with progressive mCRPC by PCWG2<br />
criteria and unfavorable CTC counts (>5 by CellSearch) on a stable hormonal regimen<br />
will receive a single dose <strong>of</strong> J591 in dose de-escalation cohorts followed by an<br />
expansion cohort at the lowest dose level with >4 <strong>of</strong> 6 men responding (i.e. achieve<br />
CTC 4 <strong>of</strong> the initial 10 men achieve the primary endpoint <strong>of</strong><br />
peri-tumoral inflammation, an additional 20 will be treated. Additional endpoints<br />
include ADCC and lymphocyte subset analysis. Both studies include 89 Zr-J591 PET/<br />
CT (pre- and post-therapy for the mCRPC CTC study and pre-op for the<br />
prostatectomy study). Each study has received IRB and FDA clearance and have begun<br />
enrollment.<br />
Clinical trial identification: Clinicaltrials.gov NCT02552394 and NCT02693860<br />
Legal entity responsible for the study: N/A<br />
Funding: Weill Cornell Medicine<br />
Disclosure: N. Bander: Patent holder for J591.All other authors have declared no<br />
conflicts <strong>of</strong> interest.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw372 | vi265
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong> 27 (Supplement 6): vi266–vi295, 2016<br />
doi:10.1093/annonc/mdw373<br />
abstracts<br />
genitourinary tumours, non-prostate<br />
773PD<br />
Axitinib in combination with pembrolizumab in patients (pts)<br />
with advanced renal cell carcinoma (aRCC): Preliminary<br />
safety and efficacy results<br />
M.B. Atkins 1 , E.R. Plimack 2 , I. Puzanov 3 , M.N. Fishman 4 , D. McDermott 5 ,<br />
D.C. Cho 6 , U. Vaishampayan 7 , S. George 8 , T. Olencki 9 , J. Tarazi 10 , B. Rosbrook 10 ,<br />
K. Fernandez 11 , S. Keefe 12 , T. Choueiri 13<br />
1 Medical <strong>Oncology</strong>, Lombardi Comprehensive Cancer Center, Georgetown<br />
University, Washington, DC, USA, 2 Hematology/<strong>Oncology</strong>, Fox Chase Cancer<br />
Center, Philadelphia, PA, USA, 3 Hematology <strong>Oncology</strong>, Vanderbilt Ingram Cancer<br />
Center, Nashville, TN, USA, 4 Medical <strong>Oncology</strong>, H. Lee M<strong>of</strong>fitt Cancer Center<br />
University <strong>of</strong> South Florida, Tampa, FL, USA, 5 Division <strong>of</strong> Hematology/<strong>Oncology</strong>,<br />
Beth Israel Deaconess Med. Center, Boston, MA, USA, 6 Medical <strong>Oncology</strong>, NYU<br />
Langone Medical Center, New York, NY, USA, 7 Medical <strong>Oncology</strong>, Karmanos<br />
Cancer Institute, Detroit, MI, USA, 8 Medicine, Roswell Park Cancer Institute,<br />
Buffalo, NY, USA, 9 Medical <strong>Oncology</strong>, Ohio State Univ Medical Center, Columbus,<br />
OH, USA, 10 <strong>Oncology</strong>, Pfizer Inc, San Diego, CA, USA, 11 Onclology, Pfizer,<br />
Cambridge, MA, USA, 12 <strong>Oncology</strong>, Merck & Co., Inc., Kenilworth, NJ, USA,<br />
13 Medical <strong>Oncology</strong>, Dana-Farber cancer Institute, Boston, MA, USA<br />
Background: Axitinib, an inhibitor <strong>of</strong> vascular endothelial growth factor receptors, is<br />
approved for 2nd-line treatment <strong>of</strong> aRCC. Pembrolizumab is a humanized monoclonal<br />
antibody that blocks binding <strong>of</strong> the immune-checkpoint receptor programmed death-1<br />
(PD-1) to its ligands (PD-L1/2). Here we report preliminary safety and efficacy results<br />
from an ongoing phase Ib study <strong>of</strong> axitinib plus pembrolizumab in treatment-naïve pts<br />
with aRCC.<br />
Methods: Pts included have clear-cell aRCC with primary tumor resected, ≥1<br />
measureable lesion, ECOG performance status 0-1, controlled hypertension, and no<br />
prior systemic therapy for aRCC. Axitinib is administered orally 5 mg twice daily;<br />
pembrolizumab is administered 2 mg/kg intravenously on Day 1 <strong>of</strong> each 3-week cycle.<br />
Tumors are assessed, using RECIST v1.1, at baseline, week 12, and every 6 weeks<br />
thereafter. Study endpoints include adverse events (AEs), other safety measures and<br />
tumor response. IHC-based assay was used to stain tumor cells for PD-L1 expression.<br />
Results: As <strong>of</strong> March 1, 2016, 52 pts (79% male; 87% white; mean age 61 years) were<br />
enrolled. Eleven (21.2%) pts discontinued both treatments: disease progression (n = 4);<br />
treatment-emergent AEs (n = 6; diarrhea, headache/joint pain, fatigue/joint pain,<br />
colitis/hepatitis, aggravated rheumatoid arthritis/psoriasis, and drug-induced liver<br />
injury); and other (n = 1). Thirty-five (67.3%) pts had objective response: 2 had<br />
complete response and 33 had partial responses; 11 pts had stable disease. For the 11<br />
pts enrolled in the dose finding phase, 7 remained progression free at 11 months and<br />
the median PFS is not yet mature. Ten pts tested positive for PD-L1. Most common (>2<br />
pts) grade 3 AEs included hypertension (n = 10), diarrhea, headache, hyponatraemia,<br />
alanine aminotransferase (ALT) increased, and aspartate aminotransferase (AST)<br />
increased (n = 3 each). Grade 4 AEs included dyspnea and hyperuricaemia (n = 1<br />
each). Immune-related ≥grade 3 AEs included ALT and AST (n = 2 each), and diarrhea<br />
and colitis (n = 1 each).<br />
Conclusions: This preliminary analysis indicates axitinib plus pembrolizumab is well<br />
tolerated and exhibits antitumor activity in treatment-naïve pts with aRCC.<br />
Clinical trial identification: NCT02133742<br />
Legal entity responsible for the study: Pfizer Inc<br />
Funding: Pfizer Inc<br />
Disclosure: M.B. Atkins: declares receiving fees for consulting BMS, Pfizer, Novartis,<br />
Genentech-Roche, Merck, Amgen, Nektar, Eisai, AstraZeneca, GlaxoSmithKline,<br />
Peleton, and Acceleron. E.R. Plimack: consulting fees from Merck, GlaxoSmithKline,<br />
Pfizer, Bristol-Myers SquibbNovartis, Acceleron and Genentech/Roche, and grant<br />
support to her institution from Bristol-Myers Squibb, AstraZeneca, Peloton, Merck,<br />
GlaxoSmithKline, Acceleron, and Pfizer. M.N. Fishman: research funding from<br />
Amgen, Altor Biosciences, AstraZeneca, Aveo, Bayer, Bristol-Myers Squibb, Eisai,<br />
Exelixis, Genentech, GlaxoSmithKline, Merck, and Pfizer; speakers bureaus from<br />
Bayer, Exelixis, GlaxoSmithKline, Novartis, Pfizer, and Prometheus. D. McDermott:<br />
declares receiving fees for consulting BMS, Pfizer, Novartis, Genentech-Roche, Merck,<br />
and Exelixis. D.C. Cho: declares receiving fees for consulting from Pfizer, Genentech,<br />
Prometheus, Bristol-Meyers Squibb, and Exelixis. U. Vaishampayan: Consulting,<br />
honoraria and research support from Pfizer Inc and research support from Merck Inc.<br />
S. George: fees for consulting and advisory boards from Pfizer, Exelixis, Bristol-Myers<br />
Squibb, Novartis, Bayer, San<strong>of</strong>i-Aventis, Astellas, Xcenda, and Onclive, and grant<br />
support from Bristol-Myers Squibb, Novartis, Bayer, Pfizer, Acceleron, Merck, and<br />
Agensys. J. Tarazi: an employee <strong>of</strong> and own stock in Pfizer. B. Rosbrook: an employee<br />
<strong>of</strong> and own stock in Pfizer. K. Fernandez: an employee <strong>of</strong> and own stock in Pfizer. S.<br />
Keefe: an employee <strong>of</strong> Merck & Co., Inc. T. Choueiri: fees for consulting, advisory<br />
boards: GSK, Novartis, Pfizer, Merck, AstraZeneca, Bayer, Prometheus; grant support<br />
through his institution: Bristol-Myers Squibb, GSK, Novartis, Exelixis, Pfizer, Merck,<br />
Roche, AstraZeneca, TRACON, Peloton. All other authors have declared no conflicts <strong>of</strong><br />
interest.<br />
774PD<br />
A phase I study <strong>of</strong> cabozantinib plus nivolumab (CaboNivo) in<br />
patients (pts) refractory metastatic urothelial carcinoma<br />
(mUC) and other genitourinary (GU) tumors<br />
A.B. Apolo 1 , A. Mortazavi 2 , M. Stein 3 , S.K. Pal 4 , N. Davarpanah 1 , H.L. Parnes 5 ,Y.<br />
M. Ning 5 , D.C. Francis 1 , L.M. Cordes 1 , M. Berniger 1 , S.M. Steinberg 5 , P. Monk 2 ,<br />
T. Lancaster 2 , T. Mayer 6 , R. Costello 1 , D.P. Bottaro 1 , W.L. Dahut 1<br />
1 Genitourinary Malignancies Branch, Center for Cancer Research-National Cancer<br />
Institute, Bethesda, MD, USA, 2 Internal Medicine, Ohio State Univ Medical Center,<br />
Columbus, OH, USA, 3 Division <strong>of</strong> Medical <strong>Oncology</strong>, The Cancer Institute <strong>of</strong> New<br />
Jersey, New Brunswick, NJ, USA, 4 Medical <strong>Oncology</strong>, City <strong>of</strong> Hope, Duarte, CA,<br />
USA, 5 Medical <strong>Oncology</strong>, National Cancer Institute, Bethesda, MD, USA, 6 Medical<br />
<strong>Oncology</strong>, The Cancer Institute <strong>of</strong> New Jersey, New Brunswick, NJ, USA<br />
Background: Cabo is a multiple receptor tyrosine kinase inhibitor primarily targeting<br />
MET and VEGFR2. Correlative studies support the theory that cabozantinib has<br />
immunomodulatory properties. Nivo is a monoclonal IgG4 antibody to PD-1. We<br />
report the safety and clinical activity <strong>of</strong> the combination <strong>of</strong> CaboNivo in pts with mUC<br />
and other GU tumors (NCT02496208).<br />
Methods: This phase I trial used a rolling 6 design. 6 pts were treated at 4 dose levels<br />
(DL) for part 1 (CaboNivo) <strong>of</strong> the study. Pts received Cabo PO daily and Nivo IV<br />
q2wks: DL1 Cabo 40mg/Nivo 1mg/kg, DL2 Cabo 40mg/Nivo 3mg/kg, DL3 Cabo<br />
60mg/Nivo1mg/kg, DL4 Cabo 60mg/Nivo 3mg/kg. Tumors were assessed for overall<br />
response rate (ORR) q8wks (RECIST 1.1). Adverse events (AEs) were graded (G) by<br />
NCI-CTCAE v4.0.<br />
Results: From 7/22/15-5/11/16, 24pts (mUC N = 6; bladder urachal N = 4; bladder<br />
squamous cell carcinoma (SCC) N = 3; germ cell tumor (GCT) N = 5; castrate-resistant<br />
prostate cancer (CRPC) N = 4; renal cell carcinoma (RCC) N = 1, and trophoblastic<br />
tumor N = 1) were treated. Median age was 55 (range 35-75), 21 (88%) were male. 9 pts<br />
required dose reductions (N = 2 DL1; N = 1 DL2; N = 2 DL3; N = 4 DL4), for PPE G2<br />
N = 3 (DL1/2/4)); fatigue G1/2 N = 2 (DL3), diarrhea G2 N = 1 (DL3), lipase/amylase<br />
elevation G3 (DL1), weight loss G1 N = 1 (DL4), and anorexia/dehydration G2 N = 2<br />
(DL4). Common treatment-related G1/2 AEs were transaminitis N = 20, diarrhea<br />
N = 11, hoarseness N = 7, dysgeusia N = 5, thrombocytopenia N = 5, hyponatremia<br />
N = 5. Grade 3 AEs included neutropenia N = 3 (DL1), fatigue N = 2 DL2, mucositis<br />
N = 1 (DL4), vomiting N = 1 (DL3). There were no G4/5 toxicities, no immune-related<br />
AEs and no DLTs. 18 pts were evaluable for response. ORR was 33% 6/18 (1 CR<br />
(bladder SCC); 5 PRs (mUC, RCC, urachal, urethral SCC, CRPC). All responses were<br />
ongoing at cut<strong>of</strong>f. SD 38% 7/18.<br />
Conclusions: CaboNivo was well tolerated with no DLTs. Cabo 60mg resulted in more<br />
dose reductions due to clinically significant AEs. The recommended dose is<br />
Cabo40mg/Nivo3mg/kg. Part II <strong>of</strong> the phase I (triplet with ipilimumab (CaboNivoIpi)<br />
is ongoing. Expansion studies in pts with mUC and RCC are planned.<br />
Clinical trial identification: NCT02496208<br />
Legal entity responsible for the study: N/A<br />
Funding: NCI<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
© European Society for Medical <strong>Oncology</strong> 2016. Published by Oxford University Press on behalf <strong>of</strong> the European Society for Medical <strong>Oncology</strong>.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com.
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
775PD<br />
Phase 1b dose-finding study <strong>of</strong> avelumab<br />
(anti-PD-L1) + axitinib in treatment-naïve patients with<br />
advanced renal cell carcinoma<br />
J. Larkin 1 , B.I. Rini 2 , P. Nathan 3 , F. Thistlethwaite 4 , M. Gordon 5 , M. Martgnoni 6 ,<br />
D. Magazzu 6 , C. Chiruzzi 6 , A. Di Pietro 6 , T.K. Choueiri 7<br />
1 Department <strong>of</strong> Medical <strong>Oncology</strong>, Royal Marsden Hospital, London, UK,<br />
2 Department <strong>of</strong> Hematology and <strong>Oncology</strong>, Cleveland Clinic Taussig Cancer<br />
Institute, Cleveland, OH, USA, 3 Department <strong>of</strong> Medical <strong>Oncology</strong>, Mount Vernon<br />
Cancer Centre, Northwood, UK, 4 Department <strong>of</strong> Medical <strong>Oncology</strong>, University <strong>of</strong><br />
Manchester, The Christie NHS Foundation Trust, Manchester, UK, 5 Division <strong>of</strong><br />
Arizona Center for Cancer Care, Pinnacle <strong>Oncology</strong> Hematology, Scottsdale, AZ,<br />
USA, 6 Immuno-<strong>Oncology</strong>, Pfizer Inc., Milan, Italy, 7 Lank Center for Genitourinary<br />
<strong>Oncology</strong>, Dana-Farber Cancer Institute/Brigham and Women’s Hospital, Boston,<br />
MA, USA<br />
Background: Axitinib, a tyrosine kinase inhibitor (TKI) selective for VEGFRs, is<br />
approved in 2 nd -line advanced renal cell carcinoma (aRCC). Combining a TKI with a<br />
checkpoint inhibitor has the potential to improve patient (pt) outcomes. Avelumab*<br />
(MSB0010718C) is a fully human IgG1 antibody that inhibits PD-L1. This ongoing<br />
phase 1b study (NCT02493751) evaluates safety and tolerability <strong>of</strong> avelumab + axitinib<br />
in treatment-naïve pts with aRCC to determine the maximum tolerated dose (MTD)<br />
and recommended phase 2 dose (RP2D).<br />
Methods: Eligible pts have histologically confirmed aRCC with a clear-cell component,<br />
primary tumour resection, ≥1 measurable lesion, available tumour specimen, ECOG<br />
PS ≤1, and no prior systemic therapy for aRCC. MTD was estimated using the<br />
modified toxicity probability interval method, which determines the dose for future<br />
cohorts using all pts treated in prior and current cohorts. Adverse events (AEs) were<br />
graded by NCI CTCAE v4. Objective response rate (ORR; RECIST v1.1) was evaluated.<br />
Results: The starting dose was avelumab 10 mg/kg (1h IV infusion) Q2W + axitinib 5<br />
mg PO BID. By 5 Apr 2016, 6 pts (median 59.5 yrs [range 45-73]) were treated with<br />
avelumab for a median <strong>of</strong> 17.0 wks (range 11.9-21.7) and axitinib for 16.3 wks (range<br />
12.7-22.7). One DLT <strong>of</strong> grade 3 proteinuria occurred. The most common<br />
treatment-related adverse events (TRAEs) <strong>of</strong> any grade were dysphonia and<br />
hypertension (n = 4 pts each) and fatigue and headache (n = 3 each). Grade 3-4 TRAEs<br />
occurred in 4 pts: hypertension (n = 2), palmar-plantar erythrodysaesthesia syndrome<br />
(n = 1), lipase increased (n = 1), and proteinuria (n = 1). No pt discontinued due to a<br />
TRAE. Confirmed PR was observed in 5 pts (ORR 83.3%, 95% CI: 35.9, 99.6) and<br />
stable disease in 1 pt with tumour shrinkage not meeting PR.<br />
Conclusions: The combination <strong>of</strong> avelumab 10 mg/kg Q2W + axitinib 5 mg BID met<br />
MTD criteria and RP2D. Clinical benefit was observed in all 6 pts studied, with PR in 5<br />
pts. Enrolment is ongoing in the expansion cohort. These results provide a rationale to<br />
investigate efficacy and safety <strong>of</strong> avelumab + axitinib vs current monotherapies for<br />
aRCC, including a pivotal, randomised phase 3 trial vs sunitinib that began in Mar<br />
2016. *Proposed INN<br />
Clinical trial identification: NCT02493751<br />
Legal entity responsible for the study: N/A<br />
Funding: Pfizer Inc.<br />
Disclosure: B.I. Rini: Advisory Role: Pfizer, Roche, BMS, Acceleron, Novartis, GSK<br />
Travel: Pfizer Research Funding: Pfizer, BMS, Acceleron, Immatics, Peleton. P. Nathan:<br />
Advisory Role and Honoraria: BMS, AZ, Novartis, Roche, MSD. Speakers’ Bureau:<br />
Novartis and BMS. Travel Accommodations: MSD and BMS Institution. Research<br />
Funding: Novartis and AZ F. Thistlethwaite: Consulting/Advisory Role: Nordic<br />
Bioscience, BMS, Medarex Travel, accommodations, expenses: BMS, Ipsen. M. Gordon:<br />
Research Funding: Merck Serono. M. Martgnoni, D. Magazzu, C. Chiruzzi, A. Di<br />
Pietro: Employee and stockholder: Pfizer Inc. T.K. Choueiri: Institution Research<br />
Funding: Pfizer, Novartis, Merck, Exelixis, Tracon, GSK, BMS, AstraZeneca, Peloton,<br />
Roche Consulting/Advisory Role: Pfizer, Bayer, Novartis, GSK, Merck, BMS, Roche,<br />
Eisai, Prometheus Labs Inc, Foundation Medicine Inc., Cerulean. All other authors<br />
have declared no conflicts <strong>of</strong> interest.<br />
776PD<br />
A phase 1b trial <strong>of</strong> lenvatinib (LEN) plus pembrolizumab<br />
(PEM) in patients with selected solid tumors<br />
M. Taylor 1 , C.E. Dutcus 2 , E. Schmidt 3 , T. Bagulho 2 ,D.Li 2 , R. Shumaker 2 ,<br />
D. Rasco 4<br />
1 Knight Cancer Institute, Oregon Health Science University, Portland, OR, USA,<br />
2 Eisai, Inc., Woodcliff Lake, NJ, USA, 3 Merck Co., Inc., Kenilworth, NJ, USA,<br />
4 START, San Antonio, TX, USA<br />
Background: Greater antitumor activity was seen with LEN/PEM vs either agent alone<br />
in colorectal and lung cancer models. We report initial results <strong>of</strong> an ongoing,<br />
open-label, multicenter, phase 1b trial <strong>of</strong> LEN/PEM in patients (pts) with selected solid<br />
tumors (non-small cell lung cancer [NSCLC], renal cell carcinoma [RCC], endometrial<br />
cancer, urothelial cancer, head and neck squamous cell carcinoma, and melanoma).<br />
Methods: The study enrolled pts aged ≥18 y with histologically and/or cytologically<br />
confirmed metastatic selected solid tumors that progressed after approved therapies or<br />
for which no standard effective therapies were available. Pts received 200 mg PEM IV<br />
once every 3 wks, and 1 <strong>of</strong> 2 LEN dose levels (DL) PO (DL1: 24 mg/d; DL2: 20 mg/d).<br />
Primary endpoint was maximum tolerated dose (MTD); key secondary endpoints were<br />
safety, tolerability, and objective response rate (ORR) per irRECIST. Tumor<br />
assessments were performed every 6 wks until wk 24, then every 9 wks.<br />
Results: As <strong>of</strong> 10 Apr 2016, enrollment was completed with 13 pts (NSCLC: n = 2;<br />
RCC: n = 8, endometrial cancer: n = 2; melanoma: n = 1) (DL1: n = 3; DL2: n = 10). At<br />
DL1, there were 2 dose-limiting toxicities (DLTs): 1 grade 3 arthralgia and 1 grade 3<br />
fatigue; no DLTs have been reported in DL2. DL2 was determined to be the MTD. All<br />
pts had at least 1 treatment-emergent adverse event (TEAE). TEAEs requiring dose<br />
modifications included increased liver function tests, fatigue, hypertension, arthralgia,<br />
decreased appetite, dehydration, diarrhea, hyponatremia, noncardiac chest pain,<br />
palmar-plantar erythrodysesthesia, proteinuria, maculopapular rash, and<br />
rhabdomyolysis. No pts have discontinued treatment due to TEAEs. At data cut<strong>of</strong>f, all<br />
pts had postbaseline tumor assessments (Table).<br />
Conclusions: LEN had an MTD <strong>of</strong> 20mg/d in the LEN/PEM regimen, which showed<br />
promising activity with all partial responses (PR). Toxicities were manageable with<br />
dose modification <strong>of</strong> LEN, and no new safety signals were identified.<br />
n (%)<br />
Table: 776PD<br />
LEN 24 mg/d<br />
(n = 3)<br />
LEN 20 mg/d<br />
(n = 10)<br />
Total<br />
(n = 13)<br />
ORR 3 (100) 4 (40) 7 (54)<br />
Best Overall Response<br />
Complete response 0 0 0<br />
PR 3 (100) 4 (40 ) 7 (54) a<br />
Stable disease 0 6 (60) 6 (46) b<br />
Progressive disease 0 0 0<br />
a 4 RCC, 1 NSCLC, 1 endometrial, 1 melanoma b 4 RCC, 1 NSCLC, I<br />
endometrial All pts received at least 2 post-treatment tumor assessments<br />
Clinical trial identification: NCT02501096<br />
Legal entity responsible for the study: Eisai Inc., and Merck & Co., Inc<br />
Funding: Eisai Inc and Merck & Co., Inc<br />
Disclosure: M. Taylor: Honoraria: Eisai Advisory Board: Eisai, ONYX. C.E. Dutcus,<br />
T. Bagulho: Employee <strong>of</strong> Eisai Inc.,. C.E. Dutcus, D. Li, R. Shumaker: Employee <strong>of</strong> Eisai<br />
Inc.,. E. Schmidt: Employee <strong>of</strong> Merck Research Labs (with stock). D. Rasco: Research<br />
Funding: Aeglea, Asana, Bayer, Celgene, FivePrime, Pharmacyclics, Eisai, Takeda,<br />
Rexahn, Santa Maria Travel Expenses- Takeda.<br />
777PD<br />
Avelumab (MSB0010718C; anti-PD-L1) in patients with<br />
metastatic urothelial carcinoma progressed after<br />
platinum-based therapy or platinum ineligible<br />
M.R. Patel 1 , J. Ellerton 2 , M. Agrawal 3 , M. Gordon 4 , L. Dirix 5 , K-W. Lee 6 , J. Infante 7 ,<br />
M. Schlichting 8 , K. Chin 9 , A.B. Apolo 10<br />
1 Sarah Cannon Research Institute, Florida Cancer Specialists, Sarasota, FL, USA,<br />
2 Department <strong>of</strong> Medical <strong>Oncology</strong>, Nevada Cancer Research Foundation, Las<br />
Vegas, NV, USA, 3 Department <strong>of</strong> Medical <strong>Oncology</strong>, Associates in <strong>Oncology</strong>,<br />
Rockville, MD, USA, 4 Division <strong>of</strong> Arizona Center for Cancer Care, Pinnacle<br />
<strong>Oncology</strong> Hematology, Scottsdale, AZ, USA, 5 Department <strong>of</strong> Medical <strong>Oncology</strong>,<br />
<strong>Oncology</strong> Center, Sint-Augustinus Hospital, Antwerp, Belgium, 6 Department <strong>of</strong><br />
Internal Medicine, Seoul National University College <strong>of</strong> Medicine, Seoul National<br />
University Bundang Hospital, Seongnam, Republic <strong>of</strong> Korea, 7 Department <strong>of</strong><br />
Medical <strong>Oncology</strong>, Sarah Cannon Research Institute/Tennessee <strong>Oncology</strong>, PLLC,<br />
Nashville, TN, USA, 8 Department <strong>of</strong> Biostatistics, Merck KGaA, Darmstadt,<br />
Germany, 9 Immuno-<strong>Oncology</strong>, EMD Serono, Inc., Billerica, MA, USA, 10 National<br />
Institutes <strong>of</strong> Health, Genitourinary Malignancies Branch, Center for Cancer<br />
Research-National Cancer Institute, Bethesda, MD, USA<br />
Background: Avelumab* is a fully human IgG1 antibody that inhibits PD-L1. In a<br />
large phase 1b study (NCT01772004), avelumab showed preliminary safety and efficacy<br />
in a cohort <strong>of</strong> 44 patients (pts) with metastatic urothelial carcinoma (mUC) progressed<br />
after platinum-based chemotherapy or platinum ineligible. An additional cohort was<br />
enrolled to further characterise efficacy and safety <strong>of</strong> avelumab in mUC.<br />
Methods: Eligible pts received avelumab 10 mg/kg (1h IV infusion) Q2W until<br />
confirmed progression, unacceptable toxicity, or withdrawal. Tumours were assessed<br />
every 6 wks (RECIST 1.1) and reviewed by an independent committee. Confirmed<br />
objective response rate (ORR) and progression-free survival (PFS) were evaluated.<br />
Adverse events (AEs) were graded by NCI-CTCAE v4.0.<br />
Results: As <strong>of</strong> Jan 18, 2016, 129 pts were treated with avelumab, including 113 (87.6%)<br />
with disease progression after platinum-based therapy and 9 (7.0%) who were platinum<br />
ineligible. Primary tumour sites were bladder (74 pts, 57.4%), urethra (23 pts, 17.8%),<br />
renal pelvis (22 pts, 17.1%), or ureter (8 pts, 6.2%). Median time from metastatic<br />
diagnosis was 10.7 mos. Pts had received a median <strong>of</strong> 2 prior lines (range, 0-6) for<br />
advanced disease. Median duration <strong>of</strong> treatment was 10.4 wks (range, 2-36). 78 pts<br />
(60.5%) had a treatment-related (TR) AE; most common (≥10%) were infusion-related<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw373 | vi267
abstracts<br />
reaction (29 pts [22.5%]) and fatigue (19 pts [14.7%]). 9 pts (7.0%) had grade 3-4<br />
TRAEs, <strong>of</strong> which only fatigue (2 pts [1.6%]) occurred in >1 pt. There was 1<br />
treatment-related death (pneumonitis). Among 109 pts with ≥4 mos follow-up,<br />
confirmed ORR was 16.5% (95% CI: 10.1, 24.8) with 3 complete responses and 15<br />
partial responses; 17/18 ongoing (94.4%). 21 pts (19.3%) had stable disease. Median<br />
PFS was 6.1 wks (95% CI: 6.0, 8.3) and PFS rate at 12 wks was 35.6% (95% CI: 26.5,<br />
44.7).<br />
Conclusions: Avelumab showed promising efficacy with durable responses and a<br />
manageable safety pr<strong>of</strong>ile in pts with mUC who were platinum ineligible or progressed<br />
after platinum chemotherapy, confirming previous findings. Enrolment <strong>of</strong> 200 pts is<br />
planned. PD-L1 expression analysis is ongoing, as is a randomised phase 3 trial in<br />
mUC. *Proposed INN.<br />
Clinical trial identification: NCT01772004<br />
Legal entity responsible for the study: N/A<br />
Funding: EMD Serono, Inc. and Merck KGaA<br />
Disclosure: J. Ellerton: Research Funding: Merck. M. Gordon: Research Funding:<br />
Merck Serono. K-W. Lee: Research Funding: Merck Serono, AstraZeneca, Taiho,<br />
Roche, and Ono Pharmaceuticals. J. Infante: Consulting or Advisory Role and Research<br />
Funding: EMD Serono. M. Schlichting: Employment: Merck KGaA, Darmstadt,<br />
Germany. K. Chin: Employment and Research Funding: EMD Serono Stock or Other<br />
Ownership: Bristol-Myers Squibb. All other authors have declared no conflicts <strong>of</strong><br />
interest.<br />
778PD<br />
Quality <strong>of</strong> life (QoL) and neurotoxicity in germ-cell cancer<br />
survivors (GCCS)<br />
J. Lauritsen 1 , M. Bandak 1 , M.S. Mortensen 1 , M.G.G. Kier 1 , M. Agerbaek 2 ,N.<br />
V. Holm 3 , R. Gupta 4 , C. Johansen 5 , G. Daugaard 1<br />
1 Department <strong>of</strong> <strong>Oncology</strong>, Rigshospitalet, Copenhagen University Hospital,<br />
Copenhagen, Denmark, 2 Department <strong>of</strong> <strong>Oncology</strong>, Aarhus University Hospital,<br />
Aarhus, Denmark, 3 Department <strong>of</strong> <strong>Oncology</strong>, Odense University Hospital,<br />
Odense, Denmark, 4 Center for Biological Sequence Analysis, Technical University<br />
<strong>of</strong> Denmark, Lyngby, Denmark, 5 Unit <strong>of</strong> Survivorship, Danish Cancer Society<br />
Research Center, Copenhagen, Denmark<br />
Background: The majority <strong>of</strong> patients with testicular cancer become long-term<br />
survivors. However, treatment is associated with late effects which may hamper QoL.<br />
The aims <strong>of</strong> the present study were to assess the impact <strong>of</strong> treatment on long-term QoL<br />
and evaluate the influence <strong>of</strong> neurotoxicity on QoL.<br />
Methods: All GCCS identified in the Danish DaTeCa database were asked to fill in a<br />
questionnaire concerning late-effects Nov 2014 – Jan 2016. QoL was assessed with<br />
EORTC-QLQ C30 including 30 items divided into 15 subscales. Neurotoxicity was<br />
assessed with the FACT/GOG NTX12-scale including 12 items, divided into 4<br />
subscales (neuropathy, ototoxicity, motor impairment, and dysfunction). Patients were<br />
divided into treatment groups; surveillance only (reference), n = 1092, radiotherapy<br />
(RT), n = 299, BEP chemotherapy (CT), n = 790, and more than one line <strong>of</strong> treatment<br />
(MTOL), n = 82. Outcomes were compared with ordinal logistic regression using<br />
treatment and attained age as covariates.<br />
Results: In total, 2308 patients answered the questionnaire. Median attained age was<br />
53.5 years (range: 24.9 - 94.5), and median time from treatment was 18.8 years (range:<br />
7.0 - 32.2). Overall, Global health status was good, mean: 75.4, SD: 20.0. Treatments<br />
were significantly negatively associated with QoL in many subscales; CT: dyspnea,<br />
financial difficulties, impaired cognitive function, impaired social function, MTOL:<br />
impaired global health status, fatigue, dyspnea, financial difficulties, impaired physical<br />
function, impaired cognitive function, and impaired social function. Neurotoxicity was<br />
closely correlated to treatment. RT was associated with three <strong>of</strong> four subscales; CT and<br />
MTOL were associated with all subscales. When adjusting QoL outcomes for<br />
neurotoxicity, all negative associations between QoL and treatment disappeared except<br />
dyspnea and impaired social function in the MTOL-group. Neurotoxicity was<br />
associated with all EORTC-subscales (p < .001).<br />
Conclusions: Treatment with BEP and MTOL were associated with several QoL<br />
subscales in GCCS. However, when adjusting for neurotoxicity the associations<br />
generally disappeared. Neurotoxicity correlated strongly with QoL.<br />
Legal entity responsible for the study: Rigshospitalet<br />
Funding: Danish Cancer Society Preben and Anna Simonsen Foundation<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
779PD<br />
Large retroperitoneal lymphadenopathy (RPLN) and<br />
increased risk <strong>of</strong> venous thromboembolism (VTE) in patients<br />
(pts) with metastatic germ cell tumours (mGCT): a global<br />
germ cell cancer group (G3) study<br />
B. Tran 1 , J.M. Ruiz-Morales 2 , E. González Billalabeitia 3 ,E.Amir 4 , C. Seidel 5 ,<br />
C. Bokemeyer 5 , C. Fankhauser 6 , T. Hermanns 6 , A. Rumyantsev 7 , A. Tryakin 7 ,<br />
M. Brito 8 , A. Flechon 9 , D. Castellano 10 , X. Garcia del Muro 11 , A. Hamid 12 ,<br />
G. Palmieri 13 , R. Kitson 14 , A. Reid 14 , D. Heng 2 , P. Bedard 4<br />
1 Medical <strong>Oncology</strong>, The Royal Melbourne Hospital, Parkville, Australia, 2 Medical<br />
<strong>Oncology</strong>, Tom Baker Cancer Centre, Calgary, AB, Canada, 3 Servicio de<br />
Hematología y Oncología Médica, Hospital Universitario Morales Meseguer,<br />
Murcia, Spain, 4 Medical <strong>Oncology</strong>, Princess Margaret Hospital, Toronto, ON,<br />
Canada, 5 Hemato/<strong>Oncology</strong>, UKE Universitätsklinikum Hamburg-Eppendorf<br />
KMTZ, Hamburg, Germany, 6 Urology, University Hospital Zürich, Zurich,<br />
Switzerland, 7 Medical <strong>Oncology</strong>, N. N. Blokhin Russian Cancer Research Center,<br />
Moscow, Russian Federation, 8 Medical <strong>Oncology</strong>, Instituto Portuguès de<br />
Oncologia de Lisboa Francisco Gentil, E.P.E. (IPOLFG EPE), Lisbon, Portugal,<br />
9 Medical <strong>Oncology</strong>, Centre Léon Bérard, Lyon, France, 10 Medical <strong>Oncology</strong>,<br />
University Hospital 12 De Octubre, Madrid, Spain, 11 Medical <strong>Oncology</strong>, Institut<br />
Català d’Oncologia Hospital Duran i Reynals, Barcelona, Spain, 12 Medical<br />
<strong>Oncology</strong>, Austin Hospital, Heidelberg, Australia, 13 Medical <strong>Oncology</strong>, Università<br />
Degli Studi di Napoli Federico II, Naples, Italy, 14 Medical <strong>Oncology</strong>, Royal Marsden<br />
Hospital NHS Foundation Trust, London, UK<br />
Background: Prior data indicate that large RPLN significantly increases the risk <strong>of</strong><br />
VTE in pts with mGCT receiving first line platinum based chemotherapy (chemo). The<br />
aim <strong>of</strong> this multinational G3 study was to validate large RPLN as a risk factor for VTE<br />
and evaluate other predictive factors.<br />
Methods: Data were collected retrospectively from sequential pts with mGCT receiving<br />
first line chemo from 2000-2014 at 22 centres. Pre-defined variables <strong>of</strong> interest<br />
included IGCCCG risk classification, axial long axis diameter <strong>of</strong> largest RPLN,<br />
Khorana score (validated predictor for chemo associated VTE), LDH, prior VTE and<br />
presence <strong>of</strong> venous access device (VAD). VTE occurring at baseline, during chemo and<br />
within 90 days <strong>of</strong> completion were analysed. Pts receiving thromboprophylaxis (TP)<br />
were excluded. Predictive accuracy was assessed using logistic regression and<br />
discriminatory accuracy explored using area under the receiver operating curve (AUC).<br />
Results: Data from 1135 pts were collected. Median age was 31 (range 10-74).<br />
Testicular primary (92%), non-seminoma histology (72%) and BEP chemo (82%) were<br />
most common. IGCCCG risk distribution was 64% good, 20% intermediate and 16%<br />
poor. VTE occurred in 150 pts (13%). RPLN >3.5cm demonstrated highest<br />
discriminatory accuracy (AUC 0.68, p < 0.001). RPLN >3.5cm was associated with<br />
significantly higher risk <strong>of</strong> VTE (22% versus 8%, OR 3.4, p < 0.001). Univariable<br />
analyses identified other risk factors: retroperitoneal primary (OR 5.4, p = 0.02), poor<br />
prognosis (OR 3.8, p < 0.001), LDH 5-10xULN (OR 3.9, p < 0.001), prior VTE (OR<br />
34.5, p = 0.001), VAD (OR 3.8, p < 0.001) and Khorana score ≥3 (OR 3.9, p < 0.001).<br />
Multivariable analyses confirmed RPLN >3.5cm as an independent risk factor for VTE<br />
(OR 2.6, p < 0.001). Other factors maintaining significance include retroperitoneal<br />
primary (OR 3.3, p = 0.04), Khorana score ≥3 (OR 2.0, p = 0.049), prior VTE (OR 19.1,<br />
p = 0.015) and VAD (OR 2.9, p < 0.001).<br />
Conclusions: This study confirms large RPLN (>3.5cm) as an independent risk factor<br />
for VTE in mGCT pts receiving first line chemo. Prospective trials examining TP in<br />
this high risk population are warranted.<br />
Legal entity responsible for the study: N/A<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
780PD<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Interim analysis <strong>of</strong> a phase I dose escalation trial <strong>of</strong> the<br />
antibody drug conjugate (ADC) AGS15E (ASG-15ME) in<br />
patients (Pts) with metastatic urothelial cancer (mUC)<br />
D. Petrylak 1 , E. Heath 2 , G. Sonpavde 3 , S. George 4 , A.K. Morgans 5 , B.J. Eigl 6 ,<br />
J. Picus 7 , S. Cheng 8 , S.J. Hotte 9 , E. Gartner 10 , M. Vincent 11 , R. Chu 11 ,<br />
B. Anand 11 , K. Morrison 11 , L. Jackson 11 , A. Melhem-Bertrandt 12 , E.Y. Yu 13<br />
1 Medical <strong>Oncology</strong>, Smilow Cancer Hospital at Yale-New Haven, New Haven, CT,<br />
USA, 2 Medical <strong>Oncology</strong>, Karmanos Cancer Institute, Detroit, MI, USA, 3 Medical<br />
<strong>Oncology</strong>, University <strong>of</strong> Alabama at Birmingham Hospital, Birmingham, AL, USA,<br />
4 Department <strong>of</strong> Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA,<br />
5 Hematology/<strong>Oncology</strong>, Vanderbilt Ingram Cancer Center, Nashville, TN, USA,<br />
6 <strong>Oncology</strong>, British Columbia Cancer Agency, Vancouver, BC, Canada, 7 <strong>Oncology</strong>,<br />
Washington University School <strong>of</strong> Medicine, St Louis, MO, USA, 8 Medical<br />
<strong>Oncology</strong>, Sunnybrook Odette Cancer Center, Sunnybrook HSC, Toronto, ON,<br />
Canada, 9 <strong>Oncology</strong>, Juravinski Cancer Centre, Hamilton, ON, Canada,<br />
10 Development, Seattle Genetics, Inc., Seattle, WA, USA, 11 Development,<br />
Agensys Inc., Santa Monica, CA, USA, 12 Clinical Research, Astellas Pharma,<br />
Northbrook, IL, USA, 13 Medical <strong>Oncology</strong>, Univ. Washington/VAPSHCS, Seattle,<br />
WA, USA<br />
Background: SLITRK6 is a protein highly expressed on bladder cancer cells.<br />
ASG-15ME is an ADC that delivers a small molecule microtubule-disrupting agent,<br />
monomethyl auristatin E (MMAE), to tumors expressing SLITRK6.<br />
vi268 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
Methods: mUC pts previously treated with ≥ 1 prior chemo were enrolled using a<br />
modified continual reassessment method design. Slitrk6 expression was determined by<br />
immunohistochemistry (IHC). Disease assessments were performed every 8 weeks (wks)<br />
using RECIST v 1.1. ASG-15ME was administered IV wkly for 3 out <strong>of</strong> every 4 wks until<br />
no further benefit. Six dose levels were studied: 0.1, 0.25, 0.5, 0.75, 1, and 1.25 mg/kg.<br />
Results: As <strong>of</strong> 5/2/16, 51 pts were enrolled. 93% were SLITRK6 positive. Median age<br />
was 64 yrs; 100% were ECOG PS ≤ 1; 26 pts (52%) had ≥ 2 prior therapies (tx). Of 42<br />
evaluable pts at doses considered active (doses ≥0.5 mg/kg), 1 has a complete response<br />
(CR) currently at 39 wks and 13 had a partial response (PR) (ORR =33%), including 4/<br />
11 pts (36%) with liver metastases and 5/12 pts (42%) who failed checkpoint inhibitor<br />
(CPI) tx. Median duration on ASG-15ME is currently 13 wks. Median progression free<br />
survival and duration <strong>of</strong> response are 16 and 15 wks, respectively. 42 pts (91%) had<br />
adverse events (AEs). The most common tx-related AE was fatigue (44%). 23 pts (50%)<br />
had Grade (G) 3/4 AEs, 9 (20%) <strong>of</strong> which were considered related. Ten pts had<br />
reversible ocular AEs (1 G3). 4 pts had protocol defined dose limiting toxicities. There<br />
were 2 deaths, none related to tx. Serum concentrations <strong>of</strong> ASG-15ME decreased<br />
multi-exponentially and half-life is 3.1 days. Exposure was dose-proportional.<br />
Enrollment continues at the 1 and 1.25 mg/kg dose levels to define a dose for future<br />
studies. Updated results will be presented.<br />
Table: 780PD Antitumor Activity<br />
Dose (mg/kg) 0.5 0.75 1 1.25<br />
Evaluable pts* (n = 42) 8 14 15 5<br />
ORR (CR + PR) n (%) 1 (13) 4 (29) 7 (47) 2 (40)<br />
* ≥ 1 dose <strong>of</strong> drug and ≥ 1 post-baseline DA<br />
Conclusions: ASG-15ME, a novel ADC, is well tolerated with encouraging antitumor<br />
activity in heavily pretreated mUC pts. These results warrant further studies in mUC.<br />
Clinical trial identification: Protocol AGS15E-13-1<br />
Legal entity responsible for the study: Agensys Inc.<br />
Funding: Agensys Inc.<br />
Disclosure: D. Petrylak: Bayer, Bellicum Pharmaceuticals, Dendreon, San<strong>of</strong>i, Johnson<br />
& Johnson, Exelixis, Ferring, Millenium, Medivation, Pfizer, Progenics, Genentech,<br />
Astellas, Oncogenix, Merck, GTX, and Novartis. E. Heath: I do business with or have<br />
received research funding from the following conpanies: Agensys, Bayer, Dendreon,<br />
San<strong>of</strong>i, Tokai Pharmaceuticals, Seattle Genetics, Genentech/Roche, Millennium,<br />
Celdex, Inovio Pharmaceutical and Celgene. G. Sonpavde: Bayer, Genentech Inc,<br />
San<strong>of</strong>i, Merck, Novartis, Pfizer, Argos Therapeutics, Agensys Inc. Onyx, Bayer and<br />
Boehringer Ingelheim. S. George: I have done business with or have research funding<br />
from the following companies: Amgen, Briston Meyers Squibb, Novartis, Pfizer, Bayer,<br />
Acceleron, Agensys, Astellas, Xcenda and Onclive. A.K. Morgans: I have done business<br />
with or have received research funding from the following companies: Genentech,<br />
Bayer and Dendreon. J. Picus, B. Anand, K. Morrison, L. Jackson: Agensys Inc. S.<br />
Cheng: Roche Boehringer Ingelheim. S.J. Hotte: Astellas Scientific and Medical Affairs,<br />
Janssen <strong>Oncology</strong>, Janssen Pharmaceuticals, Oncogenex, Astra Zeneca, Novartis,<br />
Bayer, Boehringer Ingelheim, Roche Genentech, and San<strong>of</strong>i E. Gartner: Seattle<br />
Genetics Inc. M. Vincent: Amgen Pfizer. R. Chu: Amgen Inc. Vertex Gilead. A.<br />
Melhem-Bertrandt: Astellas Pharma. E.Y. Yu: Dendreon, Janssen Pharmaceuticals,<br />
Medivation, San<strong>of</strong>i, Bayer, Tolmar, Seattle Genetics Inc, Merck,Genentech/Roche,<br />
Tokai Pharmaceutical, Agensys, Ferring, Exelixis, Lilly, Astellas, GTX, Oncogenex and<br />
Lilly/ImClone. All other authors have declared no conflicts <strong>of</strong> interest.<br />
781PD<br />
Safety and activity <strong>of</strong> the pan–fibroblast growth factor<br />
receptor (FGFR) inhibitor erdafitinib in phase 1 study patients<br />
with advanced urothelial carcinoma<br />
J-C. Soria 1 , A. Italiano 2 , A. Cervantes 3 , J. Tabernero 4 , J. Infante 5 , P.N. Lara 6 ,<br />
A. Spira 7 , E. Calvo 8 , V. Moreno 9 , J-Y. Blay 10 , R. Lauer 11 , N. Chan 12 , B. Zhong 13 ,A.<br />
Ademi Santiago-Walker 14 , J. Bussolari 15 , F.R. Luo 16 , H. Xie 16 , P. Hammerman 17<br />
1 Department <strong>of</strong> Medicine DITEP, Gustave Roussy Cancer Campus and University<br />
Paris-Sud, Villejuif, France, 2 Medical <strong>Oncology</strong>, Institute Bergonié, Bordeaux,<br />
France, 3 Medical <strong>Oncology</strong>, Vall d’Hebron University Hospital and Institute <strong>of</strong><br />
<strong>Oncology</strong> (VHIO), Barcelona, Spain, 4 Medical <strong>Oncology</strong>, Hospital General Vall<br />
d’Hebrón, Barcelona, Spain, 5 Drug Development Unit, Sarah Cannon Research<br />
Institute, Nashville, TN, USA, 6 Internal Medicine/Hematology-<strong>Oncology</strong>, University<br />
<strong>of</strong> California Davis Cancer Center, Sacramento, CA, USA, 7 Medical <strong>Oncology</strong>, US<br />
<strong>Oncology</strong> Research, The Woodlands, TX, USA, 8 START Madrid, Early Clinical<br />
Drug Development Unit, START Madrid-CIOCC, Centro Integral Oncologico Clara<br />
Campal, Madrid, Spain, 9 Medical <strong>Oncology</strong>, START Madrid-FJD, Hospital<br />
Universitario Fundación Jiménez Díaz Hospital, Madrid, Spain, 10 University Claude<br />
Bernard Lyon I, Centre Léon Bérard, Lyon, France, 11 Internal Medicine, University<br />
<strong>of</strong> New Mexico, Albuquerque, NM, USA, 12 Department <strong>of</strong> Medicine, Rutgers<br />
University, New Brunswick, NJ, USA, 13 Biostatistics, Janssen Research and<br />
Development, Raritan, NJ, USA, 14 <strong>Oncology</strong> Translational Research, Janssen<br />
Research and Development, Raritan, NJ, USA, 15 Compound Development,<br />
Janssen Research and Development, Raritan, NJ, USA, 16 Experimental Medicine,<br />
Janssen Research and Development, Raritan, NJ, USA, 17 Medical <strong>Oncology</strong>,<br />
Dana-Farber Cancer Institute, Boston, MA, USA<br />
Background: Erdafitinib (JNJ-42756493) is a potent, oral pan-FGFR tyrosine kinase<br />
inhibitor that demonstrated encouraging preliminary clinical activity and manageable<br />
adverse events (AEs) in its first-in-human phase 1 study in advanced solid tumors<br />
(NCT01703481). Here we report results from patients with urothelial carcinoma (UC)<br />
from this study.<br />
Methods: This 4-part study enrolled patients age ≥ 18 years with advanced solid<br />
tumors. Dose escalation (Part 1) followed a 3 + 3 design, with patients receiving<br />
ascending doses <strong>of</strong> erdafitinib either once daily (QD) or intermittently (7 days on/7<br />
days <strong>of</strong>f). Subsequent parts <strong>of</strong> the study (Part 2, pharmacodynamics cohort; Parts 3 and<br />
4, dose-expansion cohorts for recommended phase 2 doses <strong>of</strong> 9 mg QD and 10 mg<br />
intermittently, respectively) required documented FGFR-biomarker positive disease<br />
(including activating mutations and translocations; or other FGFR-activating<br />
aberrations, Parts 2 and 3).<br />
Results: Twenty-eight patients with UC were treated at 2 mg QD (n = 1), 9 mg QD<br />
(n = 12), 10 mg intermittent (n = 13), 12 mg QD (n = 1), or 12 mg intermittent (n = 1).<br />
Across these dose levels, median treatment duration was 3.3 mo. The most common<br />
drug-related AEs were hyperphosphatemia (57%), dry mouth (50%), diarrhea (46%),<br />
and dry skin (46%); all <strong>of</strong> these were grade 1 or 2 severity, except for 1 case <strong>of</strong> grade 3<br />
hyperphosphatemia (4%) and 2 cases <strong>of</strong> grade 3 diarrhea (7%). The most common<br />
grade ≥3 AEs were anemia (18%), hand-foot syndrome (14%), and stomatitis (11%).<br />
Among FGFR-positive, response evaluable patients (as <strong>of</strong> 22 Apr 2016), the objective<br />
response rate (Complete Response + Partial Response [PR]) was 43.5% (10/23; 95% CI<br />
23.2%, 65.5%); 17.4% (4/23) had stable disease. 6/11(54.5%) patients treated at 9 mg<br />
QD and 4/11(36.4%) patients treated 10 mg intermittent achieved PR. With a median<br />
follow-up <strong>of</strong> 3.8 mo, median duration <strong>of</strong> response was 7.2 mo (95% CI 3.3, 15.3) and<br />
progression-free survival was 5.1 mo (95% CI 2.8, 5.9).<br />
Conclusions: Erdafitinib produces encouraging clinical activity and tolerability in<br />
patients with FGFR-positive UC, warranting further study.<br />
Clinical trial identification: NCT01703481; Release date: March 22, 2012<br />
Legal entity responsible for the study: Janssen Research & Development, LLC<br />
Funding: Janssen Research & Development, LLC<br />
Disclosure: J-C. Soria: Honoraria: Johnson and Johnson. A. Cervantes: Research<br />
funding: Janssen. J. Tabernero: Consultant/Advisory: Amgen, Boehringer Ingelheim,<br />
Celgene, Chugai, Imclone, Lilly, Merck, Merck Serono, Millennium, Novartis, Roche,<br />
San<strong>of</strong>i, Symphogen and Taiho. P.N. Lara: Research funding: Johnson & Johnson. A.<br />
Spira: Consultant/Advisory: Novartis, Clovis, Roche, Astellas, Ariad Honoraria: Roche,<br />
Ariad, Clovis Research funding: Janssen . B. Zhong, A. Ademi Santiago-Walker,<br />
J. Bussolari, F.R. Luo, H. Xie: Employee <strong>of</strong> Janssen Research & Development and<br />
Johnson & Johnson stock holder. P. Hammerman: Consultant/Advisory: Janssen<br />
Honoraria: Janssen. All other authors have declared no conflicts <strong>of</strong> interest.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw373 | vi269
abstracts<br />
782PD<br />
IMvigor210: updated analyses <strong>of</strong> first-line (1L) atezolizumab<br />
(atezo) in cisplatin (cis)-ineligible locally advanced/<br />
metastatic urothelial carcinoma (mUC)<br />
J. Bellmunt 1 , A. Balar 2 , M.D. Galsky 3 , Y. Loriot 4 , C. Theodore 5 , E. Grande Pulido 6 ,<br />
D. Castellano 7 , M. Retz 8 , G. Niegisch 9 , S. Bracarda 10 , A. Necchi 11 ,<br />
U. Vaishampayan 12 , S. Sridhar 13 , B.J. Eigl 14 , S. Hussain 15 , M. van der Heijden 16 ,<br />
B. Danner 17 , S. Mariathasan 17 , F. Legrand 17 , J.E. Rosenberg 18<br />
1 Bladder Cancer Center, Dana-Farber Cancer Institute, Boston, MA, USA,<br />
2 Perlmutter Cancer Center, NYU Langone Medical Center, New York, NY, USA,<br />
3 <strong>Oncology</strong>, Tisch Cancer Institute, Icahn School <strong>of</strong> Medicine at Mount Sinai,<br />
New York, NY, USA, 4 <strong>Oncology</strong>, Institut Gustave Roussy, Villejuif, France, 5 Medical<br />
<strong>Oncology</strong>, Hopital Foch Service d’Oncologie, Suresnes, France, 6 Medical<br />
<strong>Oncology</strong>, Hospital Universitario Ramon y Cajal, Madrid, Spain, 7 Medical<br />
<strong>Oncology</strong>, University Hospital 12 De Octubre, Madrid, Spain, 8 Technische<br />
Universität München, Urologische Klinik und Poliklinik, Munich, Germany, 9 Heinrich<br />
Heine University Düsseldorf, Univesitätsklinikum Düsseldorf, Düsseldorf, Germany,<br />
10 Department <strong>of</strong> <strong>Oncology</strong>, USL Toscana Sud-Est Ospedale San Donato, Arezzo,<br />
Italy, 11 Medical <strong>Oncology</strong>/Urology Unit, Fondazione IRCCS - Istituto Nazionale dei<br />
Tumori, Milan, Italy, 12 Medical <strong>Oncology</strong>, Karmanos Cancer Institute, Detroit, MI,<br />
USA, 13 <strong>Oncology</strong>, Princess Margaret Hospital, Toronto, ON, Canada, 14 <strong>Oncology</strong>,<br />
British Columbia Cancer Agency, Vancouver, BC, Canada, 15 Molecular and<br />
Clinical Cancer Medicine, University <strong>of</strong> Liverpool-Royal Liverpool University<br />
Hospital, Liverpool, UK, 16 <strong>Oncology</strong>, The Netherlands Cancer Institute,<br />
Amsterdam, Netherlands, 17 <strong>Oncology</strong>, Genentech, Inc., South San Francisco,<br />
CA, USA, 18 <strong>Oncology</strong>, Memorial Sloan-Kettering Cancer Center, New York, NY,<br />
USA<br />
Background: Up to half <strong>of</strong> mUC pts are ineligible for cis due to ECOG PS or<br />
comorbidities. These pts have been underserved in clinical trials and have a high unmet<br />
need. Carboplatin-based regimens are associated with notable toxicity, transient<br />
responses and mOS <strong>of</strong> 6-9 mo. Atezo is effective and tolerable in platinum-treated<br />
mUC and was tested in cis-ineligible pts as 1L treatment (tx).<br />
Methods: Cis ineligibility criteria included any <strong>of</strong>: renal impairment (CrCl 30-60 ml/<br />
min), hearing loss or peripheral neuropathy ≥ G2 or ECOG PS2 (Table). Pts with no<br />
prior tx for mUC (> 12 mo since any perioperative tx) received 1200 mg atezo IV q3w<br />
until RECIST v1.1 PD. Primary endpoint was ORR (central review). PD-L1 on<br />
immune cells (IC) was centrally scored as IC2/3, 1 or 0 (SP142 IHC assay).<br />
Results: Of 119 evaluable pts, most (70%) had renal impairment. Confirmed ORR was<br />
24%; CR rate was 7%. Responses were durable (21/28 ongoing at the 14 Mar 2016 data<br />
cut <strong>of</strong>f), with mDOR not reached at 14.4 mo median follow up (mDOR range 3.7-16.6<br />
+). Responses occurred across all IC subgroups, in pts with poor prognostic factors and<br />
were enriched in upper tract primary disease (Table). mOS was 14.8 mo in all-comer<br />
pts (95% CI 10.1, NE; 47% event:pt ratio). With a median <strong>of</strong> 15 wk on tx, atezo was well<br />
tolerated (6% AE tx withdrawal) with no decline in renal function and a low<br />
immune-mediated AE rate. Common (≥ 10%) tx-related AEs were fatigue, pruritus<br />
and diarrhea. 1 tx-related G5 AE, sepsis, was seen. Updated OS and efficacy by<br />
molecular subtype, mutation load and microsatellite status will be presented.<br />
Table: 782PD IMvigor210 a Cohort 1: ORR by Baseline Subgroups (All<br />
Pts) b n ORR 95% CI CR Rate<br />
Overall<br />
All 119 24% 16, 32 7%<br />
Subgroup<br />
Primary tumor site<br />
Bladder 77 17% 9, 27 4%<br />
Renal pelvis 20 35% 15, 59 15%<br />
Ureter 13 54% 25, 81 15%<br />
Metastatic site<br />
Visceral 78 15% 8, 25 1%<br />
Lymph node only 31 32% 17, 51 16%<br />
Prior systemic therapy 22 36% 17, 59 9%<br />
Bajorin risk factors c<br />
0 35 34% 19, 52 17%<br />
1 66 21% 12, 33 3%<br />
2 18 11% 1, 35 0%<br />
Cisplatin ineligibility criteria d<br />
Renal impairment (GFR > 30 but < 60 mL/min) 83 27% 17, 37 7%<br />
Hearing loss (25 dB hearing loss at 2 contiguous frequencies) 17 12% 1, 36 0%<br />
≥ G2 peripheral neuropathy 7 14% 0, 58 0%<br />
ECOG PS2 24 25% 10, 47 4%<br />
PD-L1 IC status<br />
IC2/3 32 28% 14, 47 6%<br />
IC1/2/3 80 25% 16, 36 6%<br />
IC1 32 23% 12, 37 6%<br />
IC0 39 21% 9, 36 8%<br />
a<br />
b<br />
Study NCT02108652. Demographics were consistent across PD-L1<br />
subgroups with a few exceptions: IC2/3 pts were younger (67 y vs 73 y for all),<br />
more likely PS2 (28% vs 20% for all) and less likely to have visceral mets (56%<br />
vs 66% for all pts).<br />
c Defined as baseline: ECOG PS > 1 and/or visceral<br />
metastases. d Galsky, et al. J Clin Oncol. 2011.<br />
Conclusions: 1L atezo provided clinical benefit in cis-ineligible mUC, with a<br />
well-tolerated AE pr<strong>of</strong>ile. Responses were persistent and continue to evolve with<br />
additional PRs/CRs observed with more follow up. These encouraging DOR and OS<br />
(vs historic and real world data) support atezo as a favorable alternative to chemo in the<br />
broader 1L mUC pt population.<br />
Clinical trial identification: ClinicalTrials.gov NCT02108652<br />
Legal entity responsible for the study: Joaquim Bellmunt<br />
Funding: F. H<strong>of</strong>fmann-La Roche Ltd.<br />
Disclosure: J. Bellmunt: Advisory board with Genentech,inc. A. Balar: Consulting/<br />
advisory role: Roche, Cerulean, Pfizer, Dendreon. Research funding: Roche, Merck M.<br />
D. Galsky: Advisory Board: Genentech, Merck, Astellas, Novartis, Consulting:<br />
BioMotiv. Research funding: Novartis, NMS, Celgene. Y. Loriot: personal fees from<br />
Roche, grants and personal fees from San<strong>of</strong>i, personal fees from Astellas, personal fees<br />
from Jannsen, personal fees from Ipsen, personal fees from BMS, from null, outside the<br />
submitted work. C. Theodore: Travel and accomodations from Novartis and San<strong>of</strong>i. S.<br />
Bracarda: Advisory Board Member for: Bayer, Pfizer, Astellas, BMS, Novartis, Exelixis,<br />
Roche. Honoraria: Pfizer, Novartis, Astellas, Bayer, BMS. A. Necchi: personal fees from<br />
Roche, grants and personal fees from Merck Sharp & Dohme, from null, during the<br />
conduct <strong>of</strong> the study. S. Sridhar: Honoraria:Astellas Pharma, Janssen <strong>Oncology</strong>.<br />
Consulting/advisory: AstellaPharma, Janssen Pharmaceuticals, San<strong>of</strong>i, Bayer, Roche/<br />
Genentech, Bristol-Meyers Squibb Research funding: San<strong>of</strong>i M. van der Heijden:<br />
Roche/Genentech, Astellas, Astra Zeneca. B. Danner, S. Mariathasan, F. Legrand:<br />
Employee <strong>of</strong> Genentech, Inc. J.E. Rosenberg: non-financial support and other from<br />
Roche-Genetech; personal fees from Agensys, Eli Lilly, Merck, San<strong>of</strong>i, Oncogenex. All<br />
other authors have declared no conflicts <strong>of</strong> interest.<br />
783P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Atezolizumab (atezo) in platinum (plat)-treated locally<br />
advanced/metastatic urothelial carcinoma (mUC): Updated<br />
OS, safety and biomarkers from the Ph II IMvigor210 study<br />
Y. Loriot 1 , J.E. Rosenberg 2 , T.B. Powles 3 , A. Necchi 4 , S. Hussain 5 , R. Morales 6 ,<br />
M. Retz 7 , G. Niegisch 8 , I. Duran 9 , C. Theodore 10 , J.L. Perez-Gracia 11 , E. Grande<br />
Pulido 12 , A. Thåström 13 , B. Danner 13 , S. Mariathasan 13 , O. Abidoye 13 , M. van der<br />
Heijden 14<br />
1 <strong>Oncology</strong>, Institut Gustave Roussy, Villejuif, France, 2 Medical <strong>Oncology</strong>, Memorial<br />
Sloan-Kettering Cancer Center, New York, NY, USA, 3 Department <strong>of</strong> Medical<br />
<strong>Oncology</strong>, Barts Cancer Institute-Queen Mary University <strong>of</strong> London, London, UK,<br />
4 Medical <strong>Oncology</strong>/Urology Unit, Fondazione IRCCS - Istituto Nazionale dei<br />
Tumori, Milan, Italy, 5 Molecular and Clinical Cancer Medicine, University <strong>of</strong><br />
Liverpool-Royal Liverpool University Hospital, Liverpool, UK, 6 Medical <strong>Oncology</strong>,<br />
Vall d’Hebron University Hospital Institut d’Oncologia, Barcelona, Spain,<br />
7 Technische Universität München, Urologische Klinik und Poliklinik, Munich,<br />
Germany, 8 Heinrich Heine University Düsseldorf, Univesitätsklinikum Düsseldorf,<br />
Düsseldorf, Germany, 9 <strong>Oncology</strong>, Hospital Universitario Virgen del Rocio, Seville,<br />
Spain, 10 Medical <strong>Oncology</strong>, Hopital Foch Service d’Oncologie, Suresnes, France,<br />
11 Medical <strong>Oncology</strong>, Universidad de Navarra, Pamplona, Spain, 12 Medical<br />
<strong>Oncology</strong>, Hospital Universitario Ramon y Cajal, Madrid, Spain, 13 <strong>Oncology</strong>,<br />
Genentech, Inc., South San Francisco, CA, USA, 14 <strong>Oncology</strong>, The Netherlands<br />
Cancer Institute, Amsterdam, Netherlands<br />
Background: Plat-refractory mUC pts have no therapies that significantly extend OS,<br />
which is < 7 mo in the 2L setting (Bellmunt J Clin Oncol 2009). Atezo (anti-PDL1) has<br />
demonstrated tolerability and efficacy in plat-treated mUC. Here we present updated<br />
data on pts with ≈ 1.5-y median follow-up (mFU).<br />
Methods: Pts who had progressed during/following plat received 1200 mg atezo IV<br />
q3w and could continue treatment past RECIST v1.1 PD until loss <strong>of</strong> clinical benefit.<br />
Co-primary endpoints were confirmed RECIST v1.1 ORR (central review) and<br />
immune-modified RECIST ORR (per investigator). PD-L1 status on immune cells (IC)<br />
was scored centrally (SP142 IHC assay): IC2/3, 1, 0.<br />
Results: 310 pts (median 66 y) were evaluable: 78% had visceral mets; 43% had ≥ 2<br />
prior mUC regimens. RECIST v1.1 ORR was 28% in IC2/3 pts (95% CI: 19, 38), 19%<br />
(14, 25) in IC1/2/3 and 16% (12, 20) in all pts. Both CRs (15% in IC2/3; 9% in IC1/2/3;<br />
7% in all pts) and PRs occurred in pts with poor prognostic factors and were durable<br />
(71% ongoing at the 14 Mar 2016 data cut <strong>of</strong>f). mDOR was not reached with a 17.5-mo<br />
mFU (range, 0.2 + -21.1). Among 134 pts continuing treatment post PD, 19% had<br />
subsequent ≥ 30% decrease in target lesions. 1-y OS was 50% in IC2/3 pts (95% CI: 40,<br />
60), 40% (33, 47) in IC1/2/3 and 37% (31, 42) overall, with 30% <strong>of</strong> all pts alive. Overall<br />
and subgroup mOS are in the Table. Atezo remained well tolerated with low rates <strong>of</strong><br />
immune-mediated AEs and discontinuations. 70% <strong>of</strong> pts had a related AE (mostly<br />
fatigue [31%]; nausea [14%]), 16% were G3-4 (no G5 events). > 1-y safety, biomarker<br />
correlates <strong>of</strong> OS (immune gene expression, mutation load) and TCGA classification<br />
will be presented.<br />
vi270 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Table: 783P Median OS in IMvigor210 a Cohort 2 Subgroups<br />
IC2/3 IC1/2/3 All<br />
Subgroup n mo 95% CI n mo 95% CI n mo 95% CI<br />
All 100 11.9 9.0, 17.9 207 9.0 7.1, 10.9 310 7.9 6.7, 9.3<br />
Prior regimens for mUC<br />
0 24 8.5 3.9, NE 42 9.5 5.7, 12.8 58 9.5 5.9, 15.5<br />
1 34 NE 10.9, NE 79 10.9 8.0, 13.3 120 9.0 7.2, 11.3<br />
2 20 17.0 2.8, NE 43 6.2 3.1, 17.8 66 5.9 3.3, 8.7<br />
3 12 8.7 5.0, 16.5 26 6.6 4.5, 10.2 42 6.4 3.8, 10.2<br />
≥4 10 13.8 2.7, NE 17 8.0 2.5, 17.9 24 7.4 4.6, 11.1<br />
Bellmunt risk factors: b<br />
0 31 NE 17.1, NE 61 NE 17.8, NE 83 NE 17.1, NE<br />
1 35 11.9 5.1, NE 72 8.3 5.1, 13.3 117 6.8 5.4, 10.3<br />
2 28 9.0 2.5, 11.4 59 5.1 2.9, 8.0 89 5.0 3.1, 6.5<br />
3 6 5.3 2.8, 7.2 15 3.4 2.8, 5.7 21 3.4 2.1, 5.0<br />
Primary tumor site<br />
Upper tract 18 10.9 7.4, NE 42 8.3 5.1, 11.4 69 7.6 5.0, 10.5<br />
Bladder 79 12.8 7.2, NE 160 9.0 6.7, 11.4 233 7.9 6.4, 9.6<br />
Metastatic site<br />
Lymph node only 24 17.7 9.3, NE 39 17.8 9.3, NE 43 17.8 9.3, NE<br />
Visceral 66 9.9 6.2, 16.5 152 7.3 5.8, 9.5 243 7.0 5.9, 8.1<br />
a<br />
b<br />
Study ID NCT02108652. Defined as baseline ECOG PS ≥ 1, liver<br />
metastasis, and/or hemoglobin < 10 g/dL. NE = not estimable.<br />
Conclusions: Heavily pre-treated mUC pts on atezo monotherapy had durable<br />
responses, with encouraging OS. Combined with favorable safety, atezo may transform<br />
treatment <strong>of</strong> plat-treated mUC. A randomized Ph III study vs chemo in this population<br />
is ongoing (NCT02302807).<br />
Clinical trial identification: ClinicalTrials.gov NCT02108652<br />
Legal entity responsible for the study: F. H<strong>of</strong>fmann-La Roche Ltd<br />
Funding: F. H<strong>of</strong>fmann-La Roche Ltd<br />
Disclosure: Y. Loriot: grants and personal fees from San<strong>of</strong>i, personal fees from Roche,<br />
Astellas, Jannsen, Ipsen. Personal fees from BMS, from null, outside the submitted<br />
work. J.E. Rosenberg: Non-financial support and other from Roche-Genetech, personal<br />
fees from Agensys, Eli Lilly, Merck, San<strong>of</strong>i, Oncogenex. T.B. Powles: Honoraria: Roche,<br />
BMS, Merck. Research Funding: Roche, AstraZeneca. A. Necchi: personal fees from<br />
Roche, grants and personal fees from Merck Sharp & Dohme. I. Duran: Cnsulting/<br />
advisory: Jansen, Roche, Amgen, Novartis, Pierre fabre. Travel, Accomdations: Astellas.<br />
C. Theodore: Travel and accommodation expenses from Novartis, San<strong>of</strong>i. J.L.<br />
Perez-Gracia: Grant from Roche. A. Thåström, B. Danner, S. Mariathasan, O. Abidoye:<br />
Employee and shareholder <strong>of</strong> Genentech, Inc. M. van der Heijden: Roche/Genentech -<br />
Reimbursement for patient care and data management <strong>of</strong> study subjects. advisory<br />
board: Roche/GenentechAstellas, Astra Zeneca. Astellas - Research grant. All other<br />
authors have declared no conflicts <strong>of</strong> interest.<br />
784P<br />
Nivolumab monotherapy in metastatic urothelial cancer<br />
(mUC): Updated efficacy by subgroups and safety results from<br />
the CheckMate 032 study<br />
J.E. Rosenberg 1 , P. Bono 2 , J. Kim 3 , P. Spiliopoulou 4 , E. Calvo 5 , R. Pillai 6 ,P.<br />
A. Ott 7 ,F.deBraud 8 , M. Morse 9 ,D.Le 10 , D. Jaeger 11 , E. Chan 12 , C. Harbison 13 ,<br />
C.S. Lin 14 , M. Tschaika 15 , A. Azrilevich 15 , P. Sharma 16<br />
1 Clinical <strong>Oncology</strong>, Memorial Sloan-Kettering Cancer Center, New York, NY, USA,<br />
2 Comprehensive Cancer Center, Helsinki University Hospital and University <strong>of</strong><br />
Helsinki, Helsinki, Finland, 3 Prostate and Urologic Cancers Program, Yale School<br />
<strong>of</strong> Medicine, New Haven, CT, USA, 4 Medical <strong>Oncology</strong>, Beatson West <strong>of</strong> Scotland<br />
Cancer Centre Gartnavel General Hospital, Glasgow, UK, 5 START Madrid, Early<br />
Clinical Drug Development Unit, START Madrid-CIOCC, Centro Integral<br />
Oncologico Clara Campal, Madrid, Spain, 6 Hematology and <strong>Oncology</strong>, Emory<br />
University Winship Cancer Institute, Atlanta, GA, USA, 7 Immuno<strong>Oncology</strong>, Dana<br />
Farber Cancer Institute, Boston, MA, USA, 8 <strong>Oncology</strong>, University <strong>of</strong> Milan,<br />
Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy, 9 Cancer, Duke<br />
Cancer Institute, Durham, NC, USA, 10 <strong>Oncology</strong>, Johns Hopkins Medicine, The<br />
Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA, 11 Medical<br />
<strong>Oncology</strong>, University Medical Center Heidelberg, Heidelberg, Germany,<br />
12 Medicine and Hematology/<strong>Oncology</strong>, Vanderbilt Ingram Cancer Center,<br />
Nashville, TN, USA, 13 Research, Bristol-Myers Squibb, Princeton, NJ, USA,<br />
14 Statistics, Bristol-Myers Squibb, Princeton, NJ, USA, 15 Global Clinical Research,<br />
Bristol-Myers Squibb, Princeton, NJ, USA, 16 Genitourinary Medical <strong>Oncology</strong>, The<br />
University <strong>of</strong> Texas M.D. Anderson Cancer Center, Houston, TX, USA<br />
Background: Nivolumab has shown promising efficacy and acceptable safety in an<br />
open-label, multicenter phase I/II study in patients (pts) with mUC after ≥1 prior<br />
platinum-based therapy (NCT01928394). Here we report updated efficacy and safety<br />
results for the overall population based on additional follow-up and outcomes by<br />
differing levels <strong>of</strong> PD-L1 expression.<br />
Methods: Pts with mUC, unselected by PD-L1 expression status, received nivolumab 3<br />
mg/kg IV every 2 wk until progression or discontinuation. Pts who met protocol<br />
criteria could continue treatment beyond progression and cross over to<br />
nivolumab + ipilimumab. Tumor PD-L1 membrane expression was assessed with Dako<br />
PD-L1 immunohistochemical staining. Primary endpoint: objective response rate<br />
(ORR; RECIST 1.1); other endpoints: safety, progression-free survival (PFS), overall<br />
survival (OS), and duration <strong>of</strong> response.<br />
Results: Of 78 treated pts (median age 65.5 years; range, 31–85), 52 received ≥2 prior<br />
therapies. At a minimum follow-up <strong>of</strong> 9 months, 23.1% <strong>of</strong> pts are on monotherapy and<br />
23.1% switched to combination. Treatment discontinuation was mainly due to disease<br />
progression. PD-L1 was evaluable in 67 pts (86%). Table shows overall efficacy. In pts<br />
with PD-L1 expression ≥1% (n = 25) vs
abstracts<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
<strong>of</strong> clinical interest.3 pts with substantial clinical benefit (1CR,1SD, 1PR) had mutations<br />
in TSC1/TSC2 and the 4th with a PR did not have alterations in the mTOR pathway<br />
but a FGFR3-TACC3 fusion, predicting response to P. No PD had mTOR or FGFR<br />
pathways alterations in. Upon progression 2 pts were re-biopsied looking for resistance<br />
mechanisms. MDR was 7m and median PFS/OS 3.6 (95%CI 1.8-5.6) and 8m (95%CI:<br />
4.9-10.3), respectively.<br />
Table: 785P AEs <strong>of</strong> Clinical Interest<br />
Toxicity Grade 1-2 Grade 3-4<br />
Diarrhea 7 1<br />
Fatigue 5 2<br />
Hyperglycemia 5<br />
Hypertriglyceridemia 4<br />
Hypomagnesemia 4<br />
Hypophosphatemia 6 4<br />
Mucositis Oral 3 1<br />
Thrombocytopenia 5 2<br />
Pneumonitis 3<br />
Rash Acneiform 3<br />
Transaminase 2 1<br />
Conclusions: While overall E/P has moderate response rate in mUC, selected pts<br />
derive significant benefit. E/P is worth pursuing in a selected subset <strong>of</strong> mUC pts who<br />
have alterations in the mTOR or FGFR pathways.<br />
Clinical trial identification: NCT 01184326<br />
Legal entity responsible for the study: Joaquim Bellmunt<br />
Funding: Novartis, Dana-Farber<br />
Disclosure: J. Bellmunt: Lectures and advisory board compensated from Novartis. T.<br />
Choueiri, J.E. Rosenberg: Research Funding Novartis. All other authors have declared<br />
no conflicts <strong>of</strong> interest.<br />
786P<br />
Fibroblast growth factor receptor 3 (FGFR3) mutant muscle<br />
invasive bladder cancers (MIBC) are associated with low<br />
immune infiltrates<br />
E. Kilgour 1 , H. Angell 2 , N.R. Smith 1 , M. Ahdesmaki 2 , J.C. Barrett 3 ,E.<br />
A. Harrington 2 , C. Hurst 4 , M.A. Knowles 4<br />
1 <strong>Oncology</strong> Translational Science, AstraZeneca, Macclesfield, UK, 2 <strong>Oncology</strong><br />
Translational Science, AstraZeneca, Cambridge, UK, 3 <strong>Oncology</strong> Translational<br />
Science, AstraZeneca, Boston, MA, USA, 4 Institute <strong>of</strong> Cancer and Pathology,<br />
University <strong>of</strong> Leeds, Leeds, UK<br />
Background: Activating FGFR3 mutations occur in about 15% MIBC and 70%<br />
non-MIBC (NMIBC), raising the potential for FGFR inhibitors as a therapy option.<br />
Clinical trials <strong>of</strong> anti-programmed cell death protein 1 (PD1) and anti-PD1 ligand<br />
(PD-L1) agents have shown benefit in advanced bladder cancer patients and provided<br />
evidence for PD-L1 as a predictive marker. We have assessed the association <strong>of</strong> FGFR3<br />
mutations with FGFR3 expression, PD-L1 and T-cell infiltrates in MIBC samples.<br />
Methods: FGFR3, PD-L1 and CD8 (cytotoxic T-cell marker) expression were assessed<br />
by immunohistochemistry (IHC) and FGFR3 mutations by SNaPshot analysis in a<br />
cohort <strong>of</strong> 60 MIBC. FGFR3/FGFR1 expression were also assessed in a cohort <strong>of</strong> 40<br />
MIBC, 30 NMIBC and 18 normal urothelium (NU) tissues.<br />
Results: FGFR3 expression (H-score >20) was observed in 20% (8/40) <strong>of</strong> MIBC<br />
compared to 60% (23/39) <strong>of</strong> NMIBC while 94% (17/18) NU were negative. In contrast,<br />
FGFR1 expression was low and did not differ between MIBC, NMIBC and NU. FGFR3<br />
mutations were detected in 16% MIBC (10/60) and an association was observed with<br />
FGFR3 expression (p < 0.05). In MIBC the prevalence <strong>of</strong> tumour cell (TC) PD-L1<br />
positivity (defined as >25% cells positive) was 12% (7/59) and immune cell (IC)<br />
positivity was 32% (19/59) and FGFR3 mutant samples all displayed low TC PD-L1<br />
(≤5% cells expressing PD-L1) and low CD8 ( 5% cells PDL1 positive) and CD8 from 5-1453 cells/mm 2 (23% with > 250 cells/<br />
mm 2 positive). Consistent with these observations, analysis <strong>of</strong> the Cancer Genome<br />
Atlas MIBC data-set showed FGFR3 mutant/fusion bladder cancers cluster into a low<br />
immune subtype.<br />
Conclusions: FGFR3 mutation is associated with increased FGFR3 expression and low<br />
PD-L1 and cytotoxic T-cell infiltrates, suggesting these tumours may respond<br />
differently to anti-PD1/PD-L1 therapy and supporting investigation <strong>of</strong> FGFR3<br />
inhibitors as a therapeutic option. Clinical studies with FGFR inhibitors in bladder<br />
cancer are ongoing, including assessment <strong>of</strong> AZD4547 in monotherapy and<br />
combination with the anti-PD-L1 agent durvalumab (NCT02546661).<br />
Legal entity responsible for the study: AstraZeneca<br />
Funding: AstraZeneca<br />
Disclosure: E. Kilgour, H. Angell, N.R. Smith, M. Ahdesmaki, J.C. Barrett, E.A.<br />
Harrington: Employee <strong>of</strong> AstraZeneca and holds stock in AstraZeneca. All other<br />
authors have declared no conflicts <strong>of</strong> interest.<br />
787P<br />
A phase II study <strong>of</strong> cabozantinib in patients (pts) with<br />
relapsed/refractory metastatic urothelial carcinoma (mUC)<br />
R. Nadal 1 , H.L. Parnes 1 , D.C. Francis 1 , L.M. Cordes 1 , M. Berninger 1 , R. Costello 1 ,<br />
L. Folio 1 , M. Linderberg 1 , L. Machado 1 , S.M. Steinberg 1 , J.J. Wright 1 , Y.M. Ning 1 ,<br />
D.P. Bottaro 1 , W.L. Dahut 2 , A.B. Apolo 3<br />
1 Medical <strong>Oncology</strong>, National Cancer Institute, Bethesda, MD, USA, 2 Genitourinary<br />
Malignancies Branch, National Cancer Institute, Bethesda, MD, USA, 3 National<br />
Institutes <strong>of</strong> Health, Genitourinary Malignancies Branch, Center for Cancer<br />
Research-National Cancer Institute, Bethesda, MD, USA<br />
Background: Hepatocyte growth factor (HGF) and its receptor (MET) are activated in<br />
UC. In translational studies, cabozantinib, a receptor tyrosine kinase inhibitor<br />
primarily targeting MET and VEGFR2, reversed HGF-driven UC cell growth and<br />
invasion.<br />
Methods: In this phase II study, pts received cabozantinib 60 mg/day in 28-day cycles<br />
in 3 cohorts: 1) mUC, 2) bone-only mUC, and 3) metastatic rare bladder histology.<br />
Primary objective was overall response rate (ORR) by RECIST v1.1. In cohort 1, we also<br />
report on the tumor responses by site <strong>of</strong> metastases (mets). Secondary objectives were<br />
to assess the progression-free survival (PFS) and overall survival (OS) in all cohorts.<br />
Results: Of 67 pts enrolled, 70% <strong>of</strong> male, median age: 63 (22–82), KPS 80% in 73% pts.<br />
Primary sites: 69% bladder, 25% upper tract, 6% both. No. prior therapies: 1/2/3/ ≥ 4<br />
(range 1–6) in 34/39/16/9% <strong>of</strong> pts, respectively. Of 41 evaluable pts in cohort 1, there<br />
was 1 complete response (CR), 7 partial responses (PR) (ORR = 19.5%; 95% CI: 8.8–<br />
34.9%), 18 stable disease (SD), and 15 progressive disease (PD). Median<br />
progression-free survival (mPFS): 3.7 mos(95% CI: 2.3–6.5); 6-month PFS: 38.0%(95%<br />
CI: 23.3–52.6%). Median overall survival (mOS): 8.2 mos (95% CI: 5.2–10.3); 6-month<br />
OS: 65.1%(95% CI: 48.3–77.6%); 12-month OS: 25.7% (95% CI: 13.0–40.3%). ORR in<br />
cohort 1 was evaluated by site <strong>of</strong> mets in 63 target-lesions: 25.3%lung,/9.5%liver/6.3%<br />
adrenal/1.6%kidney/1.6% pancreatic/39.8% LN/15.9% ST. Lung mets had 25% PR/75%<br />
SD/0%PD. Treatment resulted in lung lesion cavitation, which could not be interpreted<br />
as CR (at best PR). Liver mets had 83.3%SD/16.7%PD. There was no ORR in liver/<br />
adrenal/kidney/pancreatic mets. LN mets had 8%CR/8%PR/72%SD/12%PD. ST mets<br />
had 90%SD/10%PD. Of 5 pts in cohort 2, 60% had improvement by NaF FDG/PET.<br />
mOS: 9.3 mos (95% CI: 3.6–12.5). Of 10 evaluable pts in cohort 3, there were 0%CR/<br />
PR/50%SD/50%PD. mPFS: 2.9 mos (95% CI: 1.8–3.7); mOS: 4.6 mos (95% CI: 2.6–<br />
8.0).<br />
Conclusions: Cabozantinib has clinical activity in relapsed/refractory pts with mUC.<br />
Lung and LN mets had higher ORR. Lung lesion cavitation was frequently noted in<br />
responders. Further studies are underway to correlate responses with MET expression,<br />
immune subsets, CTCs, and cytokine/mutational pr<strong>of</strong>iles.<br />
Clinical trial identification: NCT01688999<br />
Legal entity responsible for the study: NCI/NHI<br />
Funding: CTEP NIH<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
788P<br />
Interim analysis <strong>of</strong> a phase I dose escalation trial <strong>of</strong> ASG-22CE<br />
(ASG-22ME; enfortumab vedotin), an antibody drug conjugate<br />
(ADC), in patients (Pts) with metastatic urothelial cancer (mUC)<br />
J.E. Rosenberg 1 , E. Heath 2 , R. Perez 3 , J. Merchan 4 , J. Lang 5 , D. Ruether 6 ,<br />
D. Petrylak 7 , R. Sangha 8 , D.C. Smith 9 , S. Sridhar 10 , E. Gartner 11 , M. Vincent 12 ,<br />
R. Chu 13 , B. Anand 13 , F. Donate 14 , A. Melhem-Bertrandt 15 , J. Zhang 16<br />
1 Genitourinary <strong>Oncology</strong>, Memorial Sloan-Kettering Cancer Center, New York, NY,<br />
USA, 2 Medical <strong>Oncology</strong>, Karmanos Cancer Institute, Detroit, MI, USA, 3 Medical<br />
<strong>Oncology</strong>, University <strong>of</strong> Kansas Cancer Center, Fairway, KS, USA, 4 Medical<br />
<strong>Oncology</strong>, University <strong>of</strong> Miami Sylvester Comprehensive Cancer Center, Miami, FL,<br />
USA, 5 Genitourinary <strong>Oncology</strong>, UW Carbone Cancer Center, Madison, WI, USA,<br />
6 Medical <strong>Oncology</strong>, Tom Baker Cancer Centre, Calgary, AB, Canada, 7 Medical<br />
<strong>Oncology</strong>, Smilow Cancer Hospital at Yale-New Haven, New Haven, CT, USA,<br />
8 <strong>Oncology</strong>, University <strong>of</strong> Alberta Cross Cancer Institute, Edmonton, AB, Canada,<br />
9 Internal Medicine and Urology, University <strong>of</strong> Michigan, Ann Arbor, MI, USA,<br />
10 <strong>Oncology</strong>, Princess Margaret Hospital, Toronto, ON, Canada, 11 Development,<br />
Seattle Genetics, Inc., Seattle, WA, USA, 12 Clinical Research and Development,<br />
Agensys, Inc., Santa Monica, CA, USA, 13 Development, Agensys Inc., Santa<br />
Monica, CA, USA, 14 Translational Research, Agensys Inc., Santa Monica, CA,<br />
USA, 15 Clinical Research, Astellas Pharma, Northbrook, IL, USA, 16 Medical<br />
<strong>Oncology</strong>, H. Lee M<strong>of</strong>fitt Cancer Center University <strong>of</strong> South Florida, Tampa, FL,<br />
USA<br />
Background: Nectin-4 is a protein expressed on several tumors, including mUC.<br />
Enfortumab vedotin is an ADC that delivers a small molecule microtubule-disrupting<br />
agent, monomethyl auristatin E (MMAE), to tumors expressing Nectin-4.<br />
Methods: Pts with solid tumors, including mUC, treated with ≥ 1 prior chemo were<br />
enrolled using a modified continual reassessment method design. Pts were prescreened<br />
for Nectin-4 expression (IHC assay) and enrolled if H-score ≥150. Disease assessments<br />
were performed every 8 weeks (wks) using RECIST v 1.1. Enfortumab vedotin was<br />
administered IV wkly for 3 out <strong>of</strong> every 4 wks. 4 dose levels were studied: 0.5, 0.75, 1, or<br />
1.25 mg/kg.<br />
vi272 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Results: As <strong>of</strong> 4/29/16, 49 solid tumor pts were enrolled; 42 with mUC reported here.<br />
Of analyzed tumor tissues, 98% were Nectin-4 positive (93% had H-score ≥ 150).<br />
Median age 67 y; 100% ECOG PS ≤ 1; 25 mUC pts (60%) had ≥ 2 prior therapies (tx).<br />
Of 33 response evaluable pts, 10 had a partial response (PR) (ORR =30%), including 4/<br />
10 pts (40%) with liver metastasis and 3/12 (25%) who failed checkpoint inhibitor tx.<br />
Antitumor activity is seen at all dose levels. Median duration on treatment is 12 wks.<br />
Both median progression free survival and duration <strong>of</strong> response are 16 wks. 38 pts<br />
(91%) had adverse events (AEs). The most common tx related AE was fatigue (38%).<br />
23 pts (55%) had Grade (G) 3/4 AEs, 10 pts (24%) considered related. 9 pts (21%) had<br />
ocular AEs (G1/2). 2 pts had protocol defined dose limiting toxicities. There were 2<br />
deaths, unrelated to tx. Serum concentration <strong>of</strong> enfortumab vedotin decreased<br />
multi-exponentially with half-life ∼1.6 days. Exposure was dose proportional.<br />
Expansion cohorts are open at 1.25 mg/kg: updated results will be presented.<br />
Table: 788P mUC Pts Only<br />
Dose (mg/kg) 0.5 0.75 1 1.25<br />
Evaluable pts* (n = 33) 2 12 12 7<br />
ORR (CR + PR) n (%) 1 (50) 4 (33) 1 (8) 4 (57)<br />
* ≥ 1 dose <strong>of</strong> drug and ≥ 1 post-baseline DA.<br />
Conclusions: This novel Nectin-4 targeted ADC, enfortumab vedotin, is well tolerated<br />
in mUC pts with encouraging antitumor activity. These results warrant further studies<br />
in mUC.<br />
Clinical trial identification: ASG-22CE-13-2<br />
Legal entity responsible for the study: Agensys Inc.<br />
Funding: Agensys Inc. and Seattle Genetics Inc.<br />
Disclosure: J.E. Rosenberg: Boehringer Ingelheim, Bristol Meyers Squibb, Dendreon,<br />
Janssen <strong>Oncology</strong>, Johnson & Johnson, Oncogenex, Onyx, Lilly, Merck, Genentech/<br />
Roche, Illumina, Agensys and Mirati Therapeutics E. Heath: Agensys Inc., Bayer,<br />
Dendreon, San<strong>of</strong>i, Tokai Pharma, Seattle Genetics, Genentech/Roche, Millennium,<br />
Celdex, Inovio Pharma and Celgene. R. Perez, B. Anand, F. Donate: Agensys Inc. J.<br />
Merchan: Lilly, Tracon Pharmaceutical, Acceleron, Agensys, Rexahn Pharmaceutical. J.<br />
Lang: Salus Discovery, Agensys, Medivation, Innocrin Pharmaceutical, and Salus LLC.<br />
D. Petrylak: Bayer, Bellicum Pharma, Dendreon, San<strong>of</strong>i, Johnson & Johnson, Exelixis,<br />
Ferring, Millenium, Medivation, Pfizer, Porgenics, Genentech Inc., Astellas,<br />
Oncogenix, Merck, GTX and Novartis. R. Sangha: Boehringer Ingelheim, Astra Zeneca,<br />
Merck, Bristol Meyers Squibb, Pfizer, and Roche Glycart. D.C. Smith: Agensys Inc.,<br />
Aragon Pharma, Atterocor, Bayer, Boston Biomedical, Celgene, Eisai, Exelixis,<br />
ImClone Systems, Incyte, Lilly, Millennium, Novartis, Oncogenex, Oncomed, PSMA,<br />
Puma Biotech, Seattle Genetics, Regeneron, Teva, Tekmira and BMS/Medarex. S.<br />
Sridhar: Astellas Pharma, Janssen, San<strong>of</strong>i, Bayer, Roche/Genentech and BMS. E.<br />
Gartner: Seattle Genetics Inc. M. Vincent: Pfizer and Amgen. R. Chu: Agensys Inc.,<br />
Vertex, and Gilead. A. Melhem-Bertrandt: Astellas Pharmaceutical. J. Zhang: Bayer and<br />
Astellas Pharma. All other authors have declared no conflicts <strong>of</strong> interest.<br />
789P<br />
Pharmacokinetics (PK) <strong>of</strong> the pan-FGFR inhibitor erdafitinib in<br />
urothelial carcinoma<br />
J. Tabernero 1 , J.R. Infante 2 , A. Mita 3 , C. Keung 4 ,D.Skee 4 , H. Xie 5 , T. Parekh 6 ,<br />
P. De Porre 7 , F.R. Luo 8 , J-C. Soria 9<br />
1 Medical <strong>Oncology</strong>, Vall d’Hebron University Hospital and Institute <strong>of</strong> <strong>Oncology</strong><br />
(VHIO), Barcelona, Spain, 2 Drug Development Program, Sarah Cannon Research<br />
Institute/Tennessee <strong>Oncology</strong>, PLLC, Nashville, TN, USA, 3 Experimental<br />
Therapeutics Program, Samuel Oschin Comprehensive Cancer Institute<br />
Cedars-Sinai Medical Center, Los Angeles, CA, USA, 4 Clinical Pharmacology,<br />
Janssen Research and Development, Raritan, NJ, USA, 5 Experimental Medicine,<br />
Janssen Research and Development, Spring House, PA, USA, 6 CDTL <strong>Oncology</strong>,<br />
Janssen Research and Development, Raritan, NJ, USA, 7 Clinical <strong>Oncology</strong>,<br />
Janssen Research and Development, Beerse, Belgium, 8 Experimental Medicine,<br />
Janssen Research and Development, Raritan, NJ, USA, 9 Medicine DITEP,<br />
Gustave Roussy Cancer Campus and University Paris-Sud, Villejuif, France<br />
Background: Erdafitinib (JNJ-42756493) potently inhibits cell proliferation in FGFR<br />
pathway-activated cancer cell lines. The targeted therapeutic range for unbound plasma<br />
erdafitinib is >0.5 to 2.4 ng/mL based on efficacious concentrations in preclinical<br />
tumor models. This analysis examined the PK <strong>of</strong> erdafitinib in the targeted population<br />
<strong>of</strong> patients with urothelial carcinoma and FGFR aberrations.<br />
Methods: The first-in-human, open-label, multicenter, phase 1 study included patients<br />
with advanced or refractory solid tumors or lymphoma and FGFR aberrations. Patients<br />
received erdafitinib 0.5–12 mg once daily (QD) continuously (C) or erdafitinib 10 or<br />
12 mg 7d on/7d <strong>of</strong>f intermittently (I) in 28d cycles. A phosphate binder (sevelamer)<br />
could be used to manage elevated phosphate. This analysis focused on PK for 9 mg C,<br />
10 mg I, and 12 mg I. Blood samples for PK were obtained at steady state on Cycle 1<br />
Day 8 (9 mg C) or Cycle 1 Day 7 (10 or 12 mg I) and analyzed for total erdafitinib, <strong>of</strong><br />
which ∼0.3% is unbound.<br />
Results: Among 28 patients with urothelial carcinoma, 5 received erdafitinib 9 mg C,<br />
10 mg I, or 12 mg I and provided extensive PK samples at steady state. Maximum<br />
concentration (C max ) for total erdafitinib was 1,130 to 2,690 ng/mL and area under the<br />
24-hour concentration-time curve (AUC 24h ) was 19,900 to 52,600 ng•h/mL. Phosphate<br />
concentration, a pharmacodynamics biomarker, increased when erdafitinib<br />
concentrations increased and returned toward baseline when erdafitinib was stopped.<br />
Among patients with any tumor type and PK data at steady state, total drug<br />
concentrations were similar with or without concurrent sevelamer use (Table).<br />
Anti-tumor efficacy and safety are reported separately.<br />
Table: 789P Total Erdafitinib Concentrations* at Steady State by<br />
Sevelamer Use - Any Tumor Type, Mean (Coefficient <strong>of</strong> Variance %)<br />
Dose N C max , ng/<br />
mL<br />
9 mg continuous (without<br />
AUC 24, ng•h/<br />
mL<br />
6 1,140 (44.8) 21,900 (44.8)<br />
sevelamer)<br />
10 mg intermittent 15<br />
With sevelamer 11 1,850 (34.7) 34,300 (50.6)<br />
Without sevelamer 4 1,520 (25.1) 31,500 (30.4)<br />
12 mg intermittent 14<br />
With sevelamer 9 1,950 (60.6) 34,000 (50.2)<br />
Without sevelamer 5 2,160 (60.2) 31,900 (115.7)<br />
* Approximately 0.3% <strong>of</strong> total erdafitinib is unbound in plasma.<br />
Conclusions: Exposure for the pan-FGFR inhibitor erdafitinib at 9 mg C, 10mg I, and<br />
12 mg I achieved or exceeded the targeted therapeutic range in patients with urothelial<br />
carcinoma and FGFR aberrations. Concurrent use <strong>of</strong> a phosphate binder did not affect<br />
erdafitinib PK.<br />
Clinical trial identification: NCT01703481<br />
Legal entity responsible for the study: Janssen Research & Development, LLC<br />
Funding: Janssen Research & Development, LLC<br />
Disclosure: J. Tabernero: Consultant/Advisory role: Amgen, Bayer, Boehringer<br />
Ingelheim, Celgene, Chugai, Lilly, MSD, Merck Serono, Novartis, Roche, San<strong>of</strong>i,<br />
Symphogen, Takeda and Taiho. A. Mita: Speakers’ Bureau: Genentech. C. Keung,<br />
D. Skee, H. Xie, T. Parekh, P. De Porre, F.R. Luo: Employee <strong>of</strong> Janssen Research &<br />
Development and Johnson & Johnson stock holder. J-C. Soria: Honoraria: Johnson and<br />
Johnson. All other authors have declared no conflicts <strong>of</strong> interest.<br />
790P<br />
abstracts<br />
Proteomics pr<strong>of</strong>iling predicts poor prognosis in patients with<br />
muscle invasive urothelial carcinoma<br />
G. De Velasco 1 , A. Gámez-Pozo 2 , M. Urbanowicz 1 , G. Ruiz-Ares 1 ,J.<br />
M. Sepulveda 1 , R. Manneh 1 , B. Homet 1 , L. Trilla-Fuertes 2 , I. Otero 1 , P. Celiz 1 ,<br />
F. Villacampa 1 , L. Paz-Ares 1 , J. Fresno Vara 2 , D. Castellano 1<br />
1 Medical <strong>Oncology</strong>, Hospital Universitario Doce de Octubre, Madrid, Spain,<br />
2 Molecular <strong>Oncology</strong> and Pathology Lab, Instituto de Investigación Hospital<br />
Universitario La Paz, Madrid, Spain<br />
Background: Despite platinum-based chemotherapy nearly 40% <strong>of</strong> patients (pts) with<br />
localized muscle-invasive urothelial carcinoma (MIUC) will develop recurrent disease<br />
following surgical resection. The aim <strong>of</strong> this analysis was to identify whether<br />
differentially expressed protein biomarkers in tumor tissue may predict disease<br />
recurrence.<br />
Methods: Tissue samples were obtained from 57 pts who underwent curative surgical<br />
resection at “Universitary Hospital 12 Octubre” between 2006 and 2012. Medical<br />
records were reviewed for histology, stage, adjuvant chemotherapy, disease-free<br />
survival, and overall survival. We have analyzed the proteome applying a<br />
high-throughput proteomics approach to routinely archived formalin-fixed,<br />
paraffin-embedded tumor (FFPE) tissue. Protein extracts from FFPE samples were<br />
prepared in 2% SDS buffer and digested with trypsin. SDS was removed from digested<br />
lysates, and resulting peptides were analyzed in a Q-Exactive mass spectrometer.<br />
Protein abundance was calculated on the basis <strong>of</strong> the normalized spectral protein<br />
intensity (LFQ intensity) using MaxQuant. A prognostic protein signature was built.<br />
Data analysis was done using MeV, BRBArray Tools, R and Cytoscape s<strong>of</strong>tware suites<br />
and Uniprot (http://www.uniprot.org/) and DAVID (http://david.abcc.ncifcrf.gov)<br />
webtools.<br />
Results: 57 pts with a median age <strong>of</strong> 65.9 years were included in the analysis. After a<br />
median follow up <strong>of</strong> 38 months, 26 (45%) pts relapsed. We were able to identify and<br />
quantify 1,456 proteins. Supervised analyses identified 6 proteins associated with<br />
higher risk <strong>of</strong> relapse (5 year DFS 70% vs. 20% [p < 0.001], HR 3.53, [95% CI 1.8 –<br />
6.7]). By stage status at time <strong>of</strong> surgery the protein pr<strong>of</strong>ile remained significant: stage<br />
III (5 year DFS 67% vs. 20%, [p = 0.05]) and stage IV (5 year DFS 70% vs.20%,<br />
[p = 0.01])<br />
Conclusions: The discovery <strong>of</strong> proteins as biomarkers in bladder cancer is feasible. In<br />
this preliminary analysis we identified 6 proteins that can predict the outcome <strong>of</strong><br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw373 | vi273
abstracts<br />
patients with MIUC as prognostic factor. Additional validation analysis will be<br />
performed. Supported by a grant from the FMM (2012-0085).<br />
Legal entity responsible for the study: N/A<br />
Funding: FMM (Fundacion Mutua Madrilena)<br />
Disclosure: G. De Velasco: Advisory Board: Pfizer. No conflicts with the abstract<br />
presented. All other authors have declared no conflicts <strong>of</strong> interest.<br />
791P<br />
Transcriptomic analysis <strong>of</strong> collecting duct carcinoma <strong>of</strong> the<br />
kidney<br />
A. Tessari 1 , I. Testa 2 , E. Verzoni 2 , G. Nigita 1 , M. Colecchia 3 , D. Palmieri 1 ,<br />
P. Grassi 2 , M. Pawlikowski 1 , C. Maggi 2 , A. Martinetti 2 , F. de Braud 2 , C.M. Croce 1 ,<br />
G. Procopio 2<br />
1 Molecular Virology Immunology and Medical Genetics, Ohio State Univ Medical<br />
Center, Columbus, OH, USA, 2 Medical <strong>Oncology</strong>, Fondazione IRCCS - Istituto<br />
Nazionale dei Tumori, Milan, Italy, 3 Pathology, Fondazione IRCCS Istituto<br />
Nazionale dei Tumori, Milan, Italy<br />
Background: Collecting duct carcinoma (CDC) <strong>of</strong> the kidney is a rare tumor. It<br />
originates from the renal medulla, and it represents less than 2% <strong>of</strong> all renal tumors.<br />
The clinical course <strong>of</strong> this disease is characterized by aggressive behavior. The locally<br />
advanced and/or metastatic presentation, along with the resistance to treatments,<br />
confers CDC a poor prognosis. Due to its rarity, little is known about CDC biology,<br />
and to date no targeted therapy is available. Here, we aimed to identify deregulated<br />
pathways that discriminate between CDC, clear cell carcinoma (CCC) and healthy<br />
renal tissue.<br />
Methods: We collected 9 cases <strong>of</strong> CDC treated at Istituto Nazionale dei Tumori<br />
(Milan), together with 7 cases <strong>of</strong> CCC and 7 healthy normal adjacent renal tissues<br />
(NAT). Gene expression pr<strong>of</strong>iling was performed by GeneChip® Human<br />
Transcriptome Array 2.0 (HTA 2.0 -Affymetrix). 827 coding and 252 non-coding genes<br />
were differentially expressed between the three subtypes (p < 0.05).<br />
Results: Among those genes, we confirmed the differential expression levels <strong>of</strong><br />
fibronectin 1 (FN1), periostin (POSTN) and stratifin (SFN), by Real Time PCR. The<br />
subsequent functional enrichment analyses identified histones modifications,<br />
cytoplasmic ribosomal proteins, senescence, autophagy and focal adhesion pathways as<br />
the most deregulated in CDC vs both CCC and normal tissues.<br />
Conclusions: Our analysis, in agreement with clinical observations, suggests that CDC<br />
genetic basis should be considered distinct from other renal tumors. A better<br />
understanding <strong>of</strong> the specific molecular alterations causally involved in this disease<br />
may lead to new prognostic factors and therapeutic approaches for this currently<br />
incurable malignancy.<br />
Legal entity responsible for the study: N/A<br />
Funding: Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy Ohio State<br />
University Medical Center, Columbus, Ohio, USA Pelotonia, The Ohio State<br />
University, Columbus, Ohio, USA<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
792P<br />
Clinical significance <strong>of</strong> early circulating tumor cells (CTC)<br />
changes, analyzed by AdnaTest, in patients (pts) receiving<br />
first-line methotrexate, vinblastine, doxorubicin, and cisplatin<br />
(MVAC) chemotherapy (CT) for metastatic urothelial cancer<br />
(UC)<br />
E. Fina 1 , A. Necchi 2 , P. Giannatempo 2 , M. Colecchia 3 , D. Raggi 2 , M.G. Daidone 1 ,<br />
V. Cappelletti 1<br />
1 Experimental <strong>Oncology</strong> and Molecular Medicine, Fondazione IRCCS Istituto<br />
Nazionale dei Tumori, Milan, Italy, 2 Medical <strong>Oncology</strong>, Fondazione IRCCS Istituto<br />
Nazionale dei Tumori, Milan, Italy, 3 Pathology, Fondazione IRCCS Istituto<br />
Nazionale dei Tumori, Milan, Italy<br />
Background: The therapeutic paradigm <strong>of</strong> metastatic UC is rapidly shifting due to the<br />
advent <strong>of</strong> new promising targeted therapies or immunotherapies. Liquid biopsies and<br />
the early identification <strong>of</strong> reliable predictive and prognostic factors in the treatment<br />
course may be a key to optimize the available standard therapies.<br />
Methods: 5 mL <strong>of</strong> whole blood from pts receiving first-line MVAC were collected at<br />
baseline (t0) and after 2 cycles (t2). Samples were processed by immunomagnetic beads<br />
(AdnaTest ProstateCancerSelect kit) and the expression <strong>of</strong> EPCAM, MUC1 and ERBB2<br />
was studied using multiplex-PCR. CTC positivity and cut<strong>of</strong>fs, obtained by ROC curve<br />
analysis in healthy donors, were: ≥1 positive marker among EPCAM (≥0.40 ng/µl),<br />
MUC1 (≥0.10 ng/µl) and ERBB2 (≥0.20 ng/µl). CTC variation (t0/t2) was split in<br />
favorable (+/-, -/-, -/+) and unfavorable group (+/+) due to small numbers. Univariable<br />
analyses were undertaken for progression-free (PFS) and overall survival (OS).<br />
Multivariable analyses with bivariable associations with clinical factors were also done<br />
to improve understanding <strong>of</strong> effects.<br />
Results: Among the 31 analyzed pts, 17 (54.8%) were CTC+ at t0 and no association<br />
was found with any baseline pt and tumor characteristic, as well as with CTC status<br />
and objective response to MVAC. Unfavorable CTC trend was observed in 10/26<br />
(38.5%) cases. CTC dynamic changes better predicted for 3-year (3y) PFS and OS<br />
probability compared to CTC status assessed at single time points. Unfavorable trend<br />
was univariably detrimental on both 3y PFS probability (10% vs 49.2%, p = 0.006) and<br />
3y OS probability (20% vs 63.5%, p = 0.017). Significance was maintained after<br />
adjusting for liver metastases (p = 0.031 and p = 0.025 for PFS and OS) and MSKCC<br />
risk score (p = 0.014 and 0.025).<br />
Conclusions: We proposed a novel technique to early assess CTC status in metastatic<br />
UC receiving MVAC CT. Early CTC changes may be useful to improve our prognostic<br />
ability. Pending validation, these results may lead to improved trial designs and to<br />
refine the sequence <strong>of</strong> conventional CT options in the clinical setting.<br />
Legal entity responsible for the study: Fondazione IRCCS Istituto Nazionale dei<br />
Tumori<br />
Funding: Fondazione IRCCS Istituto Nazionale dei Tumori<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
793P<br />
Radio guided sentinel lymph node detection and mapping in<br />
invasive urinary bladder cancer - a prospective clinical study<br />
F. Aljabery 1 , I. Shabo 2 , H. Olsson 3 , O. Gimm 4 , S. Jahnson 1<br />
1 Department <strong>of</strong> Urology, Institution <strong>of</strong> Clinical and Experimental Medicine,<br />
Linköping, Sweden, 2 Unit <strong>of</strong> endocrine and sarcoma surgery, Institutionen för<br />
molekylär medicin och kirurgi (MMK), K1, Stockholm, Sweden, 3 Department <strong>of</strong><br />
Pathology, Institution <strong>of</strong> Clinical and Experimental Medicine, Linköping, Sweden,<br />
4 Department <strong>of</strong> Surgery, Institution <strong>of</strong> Clinical and Experimental Medicine,<br />
Linköping, Sweden<br />
Background: Muscle invasive urinary bladder cancer (UBC) is associated with<br />
pathologic lymph node (LN). Lymphadenectomy is a routine surgical method to treat<br />
UBC, but it cause great surgical trauma and morbidity. Sentinel node biopsy technique<br />
(SNB) is a successful surgical procedure used in evaluating LN metastasis in treatment<br />
<strong>of</strong> several tumor types. In this study, we investigated systematically the reliability <strong>of</strong><br />
SNB for detection <strong>of</strong> pathological LN during cystectomy, the significance <strong>of</strong> tumor<br />
localization in the bladder to predict the site <strong>of</strong> LN metastasis, as well as the prognostic<br />
significance <strong>of</strong> LN metastasis density (LNMD) on survival.<br />
Methods: The study included 103 patients with UBC, stages T1-T4, who were treated<br />
with cystectomy and pelvic lymph node dissection during 2005-2011 at the<br />
Department <strong>of</strong> Urology, Linköping University Hospital. Intravesical injections <strong>of</strong> the<br />
radioactive tracer Nanocoll 70 MBq and blue dye were injected in the bladder wall<br />
around the primary tumor prior to surgery. SNB was detected ex vivo during the<br />
operation with a hand-hold Geiger probe (Neoprobe Gamma Detection System). All<br />
LNs were formalin-fixed, sectioned three times and stained with haematoxylin-eosin.<br />
All slides were evaluated by an experienced uro-pathologist.<br />
Results: The mean age <strong>of</strong> the patients was 69 years and 80 (77%) patients were male.<br />
Pathological staging was T1 N = 12 (12%), T2 N = 20 (19 %), T3 N = 48 (47%) and T4<br />
N = 23 (22%). There were 3253 nodes examined, mean 31 LN/patient, range 7-68. LN<br />
metastases occurred in 41 (40 %) patients. Sentinel nodes were detected in 83 (80%)<br />
patients. The sensitivity and specificity <strong>of</strong> detecting metastatic disease by SNB varied<br />
between pelvic LN stations with an average value <strong>of</strong> 67% and 90% respectively. LNMD<br />
≥8% were significantly related to shorter survival (p < 0.01). Lymphovascular invasion<br />
(LVI) in non-organ confined tumors was significantly associated poor prognosis<br />
(p < 0.01).<br />
Conclusions: SNB is not a reliable technique for per-operative localization <strong>of</strong> LN<br />
metastases during cystectomy for UBC. LNMD and LVI have a significant prognostic<br />
value in UBC and may be a useful variables in the clinical context and in UBC research.<br />
Tumor localization in the bladder predicts location <strong>of</strong> positive LN in pelvis.<br />
Legal entity responsible for the study: Department <strong>of</strong> urology, University Hospital in<br />
Linköping, Sweden.<br />
Funding: FoU and ALF research grants from the County Council <strong>of</strong> Östergötland,<br />
Linköping, Sweden.<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
794P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Impact <strong>of</strong> race on survival following radical cystectomy for<br />
muscle-invasive bladder cancer (MIBC): Analysis <strong>of</strong> the US<br />
National Cancer Database (NCDB)<br />
N. Dizman 1 , S.K. Pal 2 , R.A. Nelson 3 , J. Hsu 2 , P. Bergerot 4 , J. Nix 5 , G. Sonpavde 6<br />
1 Internal Medicine, Medeniyet University Göztepe Training and Research Hospital,<br />
Istanbul, Turkey, 2 Medical <strong>Oncology</strong>, City <strong>of</strong> Hope, Duarte, CA, USA,<br />
3 Biostatistics, City <strong>of</strong> Hope, Duarte, CA, USA, 4 Medical <strong>Oncology</strong>, Universidade<br />
Federal de São Paulo, São Paulo, Brazil, 5 Urology, University <strong>of</strong> Alabama at<br />
Birmingham Hospital, Birmingham, AL, USA, 6 Medical <strong>Oncology</strong>, University <strong>of</strong><br />
Alabama at Birmingham Hospital, Birmingham, AL, USA<br />
Background: The impact <strong>of</strong> race as an independent factor on overall survival (OS)<br />
following radical cystectomy (RC) for muscle invasive bladder cancer (MIBC) is<br />
unclear. Small retrospective studies suggest an unfavorable impact <strong>of</strong> black race on<br />
outcomes. We conducted a retrospective analysis <strong>of</strong> the large NCDB database to<br />
vi274 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
evaluate the impact <strong>of</strong> race, specifically African American race, in patients undergoing<br />
RC for MIBC.<br />
Methods: The NCDB was employed including patients (pts) with new diagnoses <strong>of</strong><br />
urothelial carcinoma <strong>of</strong> bladder who underwent RC in the US from 2004-2013. Those<br />
with prior malignancy and prior radiotherapy were excluded. Race status was collected<br />
as white (W), black (B), white Hispanic (H) and Asian or Pacific islander (API).<br />
Multivariate analyses were conducted to determine whether race conferred an<br />
independent impact on OS in 3 separate cohorts: those who underwent RC alone, those<br />
who underwent neoadjuvant chemotherapy (NC) and those who underwent adjuvant<br />
chemotherapy (AC) after controlling for baseline stage (clinical stage for NC group,<br />
and pathologic stage for RC and AC groups), age, year <strong>of</strong> diagnosis, Charlson<br />
Comorbidity Index (CCI), number <strong>of</strong> lymph nodes examined at RC and gender.<br />
Results: A total <strong>of</strong> 31,619 pts were available for analysis: 18,939 in the RC group<br />
(W = 17,117, B = 1075, H = 481, API = 266), 4059 in the AC group (W = 3672, B = 236,<br />
H = 107, API = 44) and 8621 in the NC group (W = 7848, B = 445, H = 204,<br />
API = 124). On multivariate analysis, black race was statistically significantly and<br />
independently associated with poor OS compared to white race in the RC alone<br />
(HR = 1.17, p = 0.0004), AC (HR = 1.32, p = 0.0007) and NC (HR = 1.21, p = 0.0034)<br />
groups. Limitations <strong>of</strong> a retrospective analysis apply.<br />
Conclusions: Black race was validated to be an independently significant poor<br />
prognostic factor for OS in this large cohort <strong>of</strong> pts with bladder cancer undergoing RC<br />
with or without perioperative chemotherapy. The incorporation <strong>of</strong> race in<br />
post-operative nomograms and prognostic models is warranted to improve risk<br />
stratification.<br />
Legal entity responsible for the study: City <strong>of</strong> Hope<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
795P<br />
Concurrent chemoradiotherapy with paclitaxel and cisplatin in<br />
muscle-invasive bladder cancer<br />
R. Abdel Wahab 1 , H.H. Essa 1 , A. Eltaher 2 , M. Aboziada 3 , S. Shehata 1<br />
1 Clinical <strong>Oncology</strong>, Assiut University Hospitals, Assiut, Egypt, 2 Urology, Assiut<br />
University Hospitals, Assiut, Egypt, 3 Radiotherapy, South Egypt Cancer Institute<br />
SECI Assiut University, Assiut, Egypt<br />
Background: There is a debate regarding the optimal chemotherapeutic regimens that<br />
can be used concurrently with radiotherapy (Rth) in muscle invasive bladder cancer<br />
(MIBC). Taxanes started to be widely used with evidence <strong>of</strong> response rates<br />
improvement when compared to cisplatin. Our aims were to evaluate the tumor<br />
response, treatment toxicity, and disease outcome in MIBC patients who treated with<br />
concurrent chemo-radiotherapy (CCRTh) either with paclitaxel and cisplatin or<br />
cisplatin alone.<br />
Methods: Between July 2007 and December 2010, sixty T2-4a N0 M0 bladder cancer<br />
patients were enrolled, <strong>of</strong> whom 55 were eligible for analysis. We randomized our<br />
patients into two group; group I received CCRTh with weekly cisplatin (n = 30) and<br />
group II received CCRTH with weekly paclitaxel and cisplatin (n = 25). Kaplan-Meier<br />
curve used to estimate overall survival (OS) and recurrence free survival (RFS) with log<br />
rank test used to assess the significant difference between patients’ subgroups.<br />
Results: A durable complete cure (CR) was achieved in 75% and 87% in group I and II<br />
respectively. The 2-year OS and recurrence free survival (RFS) were 60 % and 30% for<br />
group I, while, 80 % and 40% for group II, respectively. Multivariate analysis showed<br />
that tumor stage was the only survival predictor (P < .0001). In both groups, the<br />
majority <strong>of</strong> acute and late toxicities were grade 2 with no treatment-related mortality.<br />
Conclusions: Achieving high initial durable CR rates, with acceptable toxicity in both<br />
group; showed that addition <strong>of</strong> paclitaxel to cisplatin did not significantly add benefit<br />
to the treatment outcome.<br />
Legal entity responsible for the study: Pr<strong>of</strong>. Samir Shehata<br />
Funding: Assiut University Hospital<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
796P<br />
abstracts<br />
Randomized placebo controlled phase II trial (MAJA): Efficacy<br />
results <strong>of</strong> maintenance vinflunine after cisplatin<br />
chemotherapy (CT) in patients with advanced urothelial<br />
carcinoma (UC). SOGUG 2011-02<br />
B. Pérez-Valderrama 1 , A. Font 2 , J.A. Virizuela Echaburu 3 , S. Hernando 4 ,M.<br />
A. Climent 5 , J. Arranz Arija 6 , J.C. Villa Guzman 7 , M. Llorente 8 , N. Lainez Milagro 9 ,<br />
B. Mellado 10 , A. González del Alba 11 , E. Gallardo 12 , D. Castellano 13 , U. Anido 14 ,<br />
M. Domenech 15 , X. Garcia del Muro 16 , J. Puente 17 , R. Morales 18 , J. Bellmunt 19 ,<br />
J. Garcia-Donas 20<br />
1 Medical <strong>Oncology</strong>, Hospital Universitario Virgen del Rocio, Seville, Spain,<br />
2 Medical <strong>Oncology</strong>, Catalan Institute <strong>of</strong> <strong>Oncology</strong> (ICO Badalona), Hospital<br />
Germans Trias i Pujol, Badalona, Spain, 3 Medical <strong>Oncology</strong>, Hospital Universitario<br />
Virgen Macarena, Seville, Spain, 4 Medical <strong>Oncology</strong>, HUFA Hospital Universitario<br />
Fundacion Alcorcon, Alcorcon, Spain, 5 Medical <strong>Oncology</strong>, Fundación Instituto<br />
Valenciano de Oncología, Valencia, Spain, 6 Medical <strong>Oncology</strong>, Hospital General<br />
Universitario Gregorio Marañon, Madrid, Spain, 7 Medical <strong>Oncology</strong>, Hospital<br />
General Ciudad Real, Ciudad Real, Spain, 8 Medical <strong>Oncology</strong> Unit, Hospital<br />
General Universitario de Elda, Alicante, Spain, 9 <strong>Oncology</strong>, Complejo Hospitalario<br />
de Navarra, Pamplona, Spain, 10 Medical <strong>Oncology</strong>, Hospital Clinic y Provincial de<br />
Barcelona, Barcelona, Spain, 11 Medical <strong>Oncology</strong>, Hospital Universitario Son<br />
Espases, Palma de Mallorca, Spain, 12 Medical <strong>Oncology</strong>, Hospital de Sabadell<br />
Corporacis Parc Tauli, Sabadell, Spain, 13 Medical <strong>Oncology</strong>, University Hospital 12<br />
De Octubre, Madrid, Spain, 14 Medical <strong>Oncology</strong>, Complejo Hospitalario<br />
Universitario de Santiago de Compostela SERGAS, Santiago De Compostela,<br />
Spain, 15 Medical <strong>Oncology</strong>, Althaia - Xarxa Assitencial de Manresa, Manresa,<br />
Spain, 16 Medical <strong>Oncology</strong>, Institut Català d’Oncologia Hospital Duran i Reynals,<br />
Barcelona, Spain, 17 Medical <strong>Oncology</strong>, Hospital Clinico Universitario San Carlos,<br />
Madrid, Spain, 18 Medical <strong>Oncology</strong>, Vall d’Hebron University Hospital Institut<br />
d’Oncologia, Barcelona, Spain, 19 Medical <strong>Oncology</strong>, University Hospital del Mar,<br />
Barcelona, Spain, 20 Medical <strong>Oncology</strong>, Centro Integral Oncólogico Clara Campal,<br />
Madrid, Spain<br />
Background: Vinflunine (VFL) is a microtubule inhibitor approved by EMA as<br />
treatment after platinum progressionin metastatic UC. We evaluated whether<br />
maintenance VFL delays progression after response to CT.<br />
Methods: Patients (pts) with measurable disease, locally recurrent/metastatic UC and<br />
adequate organ functionwith radiological response or stabilization after 4-6cycles (cy)<br />
<strong>of</strong> a cisplatin/gemcitabine chemotherapy (carboplatinallowed after cy 4) were<br />
randomized (R) 1:1 to receive VFL 320 or 280mg/m2 (in case <strong>of</strong> PS1, age ≥75years,<br />
priorpelvic radiotherapy (RT) or CrCl < 60ml/min) every 21days vs best supportive<br />
care (BSC), until disease progression.Primary endpoint was progression free survival<br />
(PFS). With a median PFS considered unacceptable for theexperimental arm <strong>of</strong><br />
4months (m) (p0) and acceptable 6.5m (p1). 78 eligible were required for an α-error <strong>of</strong><br />
0.05(one-tailed test) and a 0.1 β-error.<br />
Results: 88pts from 21 institutions <strong>of</strong> SOGUG were R between 04/2012-01/2015. Forty<br />
five in the VFL arm and 43 inthe BSC arm. 1pt was not treated. 1 <strong>of</strong> 87 treated pts was<br />
not eligible due to an excess <strong>of</strong> time between the last dose<strong>of</strong> cisplatin and the start <strong>of</strong><br />
VFL. At the beginning <strong>of</strong> treatment: median age 64years [42-83]; PS1 50%; Hb
abstracts<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
797P<br />
Nomogram-based prediction <strong>of</strong> overall survival (OS) <strong>of</strong> patients<br />
(pts) with metastatic urothelial carcinoma (UC) receiving<br />
first-line platinum-based chemotherapy: retrospective<br />
international study <strong>of</strong> invasive/advanced cancer <strong>of</strong> the<br />
urothelium (RISC)<br />
A. Necchi 1 , G. Sonpavde 2 , S. Lo Vullo 3 , A. Bamias 4 , S.J. Crabb 5 , L. Harshman 6 ,<br />
J. Bellmunt 7 , U. De Giorgi 8 , C. Sternberg 9 , S. Ladoire 10 , Y-N. Wong 11 , E.Y. Yu 12 ,<br />
S. Chowdhury 13 , G. Niegisch 14 , S. Srinivas 15 , U. Vaishampayan 16 , S.K. Pal 17 ,<br />
J. Rosenberg 18 , L. Mariani 3 , M.D. Galsky 19<br />
1 Medical <strong>Oncology</strong>, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy,<br />
2 Medical <strong>Oncology</strong>, University <strong>of</strong> Alabama at Birmingham Hospital, Birmingham,<br />
AL, USA, 3 Clinical Epidemiology and Trials Organization Unit, Fondazione IRCCS<br />
Istituto Nazionale dei Tumori, Milan, Italy, 4 Clinical Therapeutics, University <strong>of</strong><br />
Athens, Athens, Greece, 5 Medical <strong>Oncology</strong>, University <strong>of</strong> Southampton,<br />
Southampton, UK, 6 Medical <strong>Oncology</strong>, Dana-Farber Cancer Institute, Boston,<br />
MA, USA, 7 Bladder Cancer Center, Dana-Farber Cancer Institute, Boston, MA,<br />
USA, 8 Medical <strong>Oncology</strong>, Istituto Tumori della Romagna I.R.S.T., Meldola, Italy,<br />
9 <strong>Oncology</strong>, San Camillo–Forlanini Hospital, Rome, Italy, 10 Medical <strong>Oncology</strong>,<br />
Centre Georges-François Leclerc (Dijon), Dijon, France, 11 Medical <strong>Oncology</strong>, Fox<br />
Chase Cancer Center, Philadelphia, PA, USA, 12 Medical <strong>Oncology</strong>, Univ.<br />
Washington/VAPSHCS, Seattle, WA, USA, 13 <strong>Oncology</strong>, Guy’s and St. Thomas’<br />
Hospital NHS Trust, London, UK, 14 Medical <strong>Oncology</strong>, Univesitätsklinikum<br />
Düsseldorf, Düsseldorf, Germany, 15 Medical <strong>Oncology</strong>, Stanford University<br />
Medical Center, Stanford, CA, USA, 16 Medical <strong>Oncology</strong>, Karmanos Cancer<br />
Institute, Detroit, MI, USA, 17 Medical <strong>Oncology</strong> and Experimental Therapuetics, City<br />
<strong>of</strong> Hope, Duarte, CA, USA, 18 Medical <strong>Oncology</strong>, Memorial Sloan Kettering Cancer<br />
Center, New York, NY, USA, 19 Tisch Cancer Institute, Mount Sinai School <strong>of</strong><br />
Medicine, New York, NY, USA<br />
Background: The available prognostic models <strong>of</strong> OS for pts with metastatic UC were<br />
derived from clinical trial populations <strong>of</strong> cisplatin-treated pts only. We aimed to<br />
develop a new model based on ‘real world’ pts.<br />
Methods: Individual pt-level data from 29 centers was collected. Pts had to be treated<br />
for metastatic UC at the participating sites between 01/2006 and 01/2011. Selection<br />
criteria included metastatic UC, and first-line cisplatin- or carboplatin-based<br />
chemotherapy. The overall sample was randomly split into a development and a<br />
validation cohort. Generalized Boosted Regression Modeling was used first to exclude<br />
variables not associated with OS. Backward variable selection was then undertaken.<br />
Platinum-type was incorporated in the analysis as a stratification factor. Two<br />
nomograms were built to estimate OS probability, the first based on baseline factors<br />
and the second incorporating objective response (OR). The performance <strong>of</strong> the present<br />
nomogram and that <strong>of</strong> the other available models was assessed for accuracy (Brier<br />
score), calibration (Hosmer-Lemeshow test), and discrimination (Harrell c-index).<br />
Results: 1,020 pts were analyzed (development: 687; validation: 333). In the<br />
platinum-stratified Cox model, significant variables for OS were: performance status<br />
(p < .001), white blood cell count (p = 0.013), body mass index (p = 0.003), ethnicity<br />
(p = 0.012), lung, liver, or bone metastases (p < .001), and prior peri-operative<br />
chemotherapy (p = 0.012). The c-index was 0.66. The distribution <strong>of</strong> the nomogram<br />
scores was associated with OR (p < .001) and incorporating OR in the model further<br />
improved the c-index (0.67, with 4-month landmark analysis). The two nomograms<br />
both performed better than the available models in terms <strong>of</strong> accuracy and<br />
discrimination in the validation cohort.<br />
Conclusions: We developed and validated two nomograms that accounted for novel<br />
prognostic factors and can be used before and after completion <strong>of</strong> chemotherapy,<br />
respectively. These two nomograms may be suitable tools to enhance patient<br />
stratification and inform pts in the clinic.<br />
Legal entity responsible for the study: Fondazione IRCCS Istituto Nazionale dei<br />
Tumori<br />
Funding: Fondazione IRCCS Istituto Nazionale dei Tumori<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
798P<br />
Patterns <strong>of</strong> chemotherapy utilization in metastatic urothelial<br />
cancer (mUC): analysis from the retrospective international<br />
study <strong>of</strong> invasive/advanced cancer <strong>of</strong> the urothelium (RISC)<br />
database<br />
A. Bamias 1 , K. Tzannis 1 , M. Liontos 2 , L. Harshman 3 , S.J. Crabb 4 , Y-N. Wong 5 ,S.<br />
K. Pal 6 , T.B. Powles 7 , J. Bellmunt 8 , U. De Giorgi 9 , S. Ladoire 10 , N. Agarwal 11 ,E.<br />
Y. Yu 12 , G. Niegisch 13 , C.N. Sternberg 14 , A. Alva 15 , S. Srinivas 16 , J. Rosenberg 17 ,<br />
R. Investigators 18<br />
1 Clinical Therapeutics, National and Kapodistrian University <strong>of</strong> Athens, Athens,<br />
Greece, 2 <strong>Oncology</strong> Unit, Department <strong>of</strong> Clinical Therapeutics, Alexandra Hospital,<br />
Athens, Greece, 3 Medical <strong>Oncology</strong>, Dana-Farber Cancer Institute, Boston, USA,<br />
4 Medical <strong>Oncology</strong>, University <strong>of</strong> Southampton, Southampton, UK, 5 Medical<br />
<strong>Oncology</strong>, Fox Chase Cancer Center, Philadelphia, USA, 6 Medical <strong>Oncology</strong> and<br />
Experimental Therapuetics, City <strong>of</strong> Hope, Duarte, USA, 7 Department <strong>of</strong> Medical<br />
<strong>Oncology</strong>, St. Bartholomew’s Hospital, London, UK, 8 <strong>Oncology</strong>, Dana-Farber<br />
Cancer Institute, Boston, Ma, USA, 9 Medical <strong>Oncology</strong>, Istituto Tumori della<br />
Romagna I.R.S.T., Meldola, Italy, 10 Medical <strong>Oncology</strong>, Centre Georges-François<br />
Leclerc (Dijon), Dijon, France, 11 Medical <strong>Oncology</strong>, Huntsman Cancer Institute,<br />
Salt Lake City, UT, USA, 12 Medical <strong>Oncology</strong>, Univ. Washington/VAPSHCS,<br />
Seattle, USA, 13 Medical <strong>Oncology</strong>, Univesitätsklinikum Düsseldorf, Düsseldorf,<br />
Germany, 14 Medical <strong>Oncology</strong>, Azienda Ospedaliera S. Camillo Forlanini, Roma,<br />
Italy, 15 Medical <strong>Oncology</strong>, University <strong>of</strong> Michigan, East Lansing, MI, USA,<br />
16 Medical <strong>Oncology</strong>, Stanford University, Palo Alto, USA, 17 Medical <strong>Oncology</strong>,<br />
Memorial Sloan Kettering Cancer Center, New York, USA, 18 <strong>Oncology</strong>, Mount<br />
SInai Medical College, New York, USA<br />
Background: Cisplatin-based chemotherapy is the treatment <strong>of</strong> choice in mUC. A<br />
significant proportion <strong>of</strong> patients do not receive chemotherapy, while about 50% <strong>of</strong><br />
treated patients do not receive cisplatin. We used the multinational RISC database to<br />
map patterns <strong>of</strong> chemotherapy utilization and adherence to recently published UFC<br />
criteria (Galsky, 2011) in unselected mUC patients<br />
Methods: Selection criteria: diagnosis <strong>of</strong> mUC, transitional-cell, mixed, squamous and<br />
adeno histologies.<br />
Results: Of 1974 mUC patients 475 (25%) did not receive 1 st -line chemotherapy. No<br />
chemotherapy administration was associated with: non-pure TCC histology, higher<br />
Charslon Comorbidity Index (CCI), non-caucasian race, non-european country, low<br />
volume center (contribution <strong>of</strong>
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
799P<br />
Adherence to cisplatin-based regimens prescription in "fit"<br />
patients fulfilling platinum eligibility criteria. Impact on<br />
outcomes: a retrospective international study <strong>of</strong> invasive/<br />
advanced cancer <strong>of</strong> the urothelium (RISC) analysis<br />
A. Bamias 1 , K. Tzannis 1 , M. Liontos 2 , S.J. Crabb 3 , L. Harshman 4 , U. De Giorgi 5 ,<br />
J. Bellmunt 6 , Y-N. Wong 7 , S.K. Pal 8 , S. Ladoire 9 , C.N. Sternberg 10 , T.B. Powles 11 ,<br />
E.Y. Yu 12 , G. Niegisch 13 , A. Necchi 14 , U. Vaishampayan 15 , N. Agarwal 16 ,<br />
J. Rosenberg 17 , R. Investigators 18<br />
1 Clinical Therapeutics, University <strong>of</strong> Athens, Athens, Greece, 2 <strong>Oncology</strong> Unit,<br />
Department <strong>of</strong> Clinical Therapeutics, Alexandra Hospital, Athens, Greece,<br />
3 Medical <strong>Oncology</strong>, University <strong>of</strong> Southampton, Southampton, UK, 4 Medical<br />
<strong>Oncology</strong>, Dana-Farber Cancer Institute, Boston, MA, USA, 5 Medical <strong>Oncology</strong>,<br />
Istituto Tumori della Romagna I.R.S.T., Meldola, Italy, 6 <strong>Oncology</strong>, Dana-Farber<br />
Cancer Institute, Boston, MA, USA, 7 Medical <strong>Oncology</strong>, Fox Chase Cancer<br />
Center, Philadelphia, PA, USA, 8 Medical <strong>Oncology</strong> and Experimental<br />
Therapeutics, City <strong>of</strong> Hope, Duarte, CA, USA, 9 Medical <strong>Oncology</strong>, Centre<br />
Georges-François Leclerc (Dijon), Dijon, France, 10 Medical <strong>Oncology</strong>, Azienda<br />
Ospedaliera S. Camillo Forlanini, Rome, Italy, 11 Department <strong>of</strong> Medical <strong>Oncology</strong>,<br />
St. Bartholomew’s Hospital, London, UK, 12 Medical <strong>Oncology</strong>, Univ. Washington/<br />
VAPSHCS, Seattle, WA, USA, 13 Medical <strong>Oncology</strong>, Univesitätsklinikum Düsseldorf,<br />
Düsseldorf, Germany, 14 Medical <strong>Oncology</strong>, Fondazione IRCCS Istituto Nazionale<br />
dei Tumori, Milan, Italy, 15 Medical <strong>Oncology</strong>, Karmanos Cancer Institute, Detroit,<br />
MI, USA, 16 Medical <strong>Oncology</strong>, Huntsman Cancer Institute, Salt Lake City, UT,<br />
USA, 17 Medical <strong>Oncology</strong>, Memorial Sloan Kettering Cancer Center, New York, NY,<br />
USA, 18 <strong>Oncology</strong>, Mount SInai Medical College, New York, NY, USA<br />
Background: Cisplatin-based chemotherapy is the treatment <strong>of</strong> choice in metastatic<br />
urothelial cancer (mUC). Nevertheless, about 50% <strong>of</strong> patients do not receive this<br />
treatment. Recently, specific criteria for unfitness-for-cisplatin (UFC) have been<br />
published. We used a multinational database to study the impact <strong>of</strong> adherence to UFC<br />
criteria in the outcome <strong>of</strong> unselected mUC patients<br />
Methods: Selection criteria: diagnosis <strong>of</strong> mUC, transitional, mixed, squamous and<br />
adeno histologies, survival data available. Major end point: Overall survival (OS). UFC<br />
was defined according to Galsky et al (2011).<br />
Results: From 1828 mUC patients 441 (24%) did not receive any chemotherapy. These<br />
patients had a significantly shorter median OS (Table). 1361 patients (median fup: 31<br />
months) were included in the analysis <strong>of</strong> the following treatment types: cisplatin-based<br />
(689;50%), carboplatin-based (404;30%), no cis- or carbo-platin [other (268;20%)].<br />
Cisplatin therapy was associated with longer OS (Table). 971 patients had full data<br />
regarding UFC. The following deviations from the UFC criteria were noted: 21% and<br />
32% <strong>of</strong> the carboplatin and the other groups were fit-for-cisplatin, while 38% <strong>of</strong> the<br />
cisplatin-treated patients fulfilled at least one UFC criterion. UFC patients had inferior<br />
outcome. This effect was significant only in cisplatin-treated patients (Table), while the<br />
benefit from cisplatin was also more pronounced within the fit-for-cisplatin patients.<br />
This cisplatin therapy-UFC interaction was significant (p = 0.0343)<br />
Conclusions: A sizable proportion <strong>of</strong> fit-for-cisplatin patients do not receive<br />
cisplatin-based chemotherapy. Use <strong>of</strong> cisplatin for those patients may have potential to<br />
improve outcomes. On the contrary, unfit-for-cisplatin patients have a worse outcome<br />
and more efficient therapies should be sought.<br />
Legal entity responsible for the study: N/A<br />
Funding: Icahn School <strong>of</strong> Medicine at Mount Sinai, USA<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
800P<br />
VICTOR: Vinflunine in advanced metastatic transitional cell<br />
carcinoma <strong>of</strong> the urothelium (TCCU): a retrospective analysis<br />
<strong>of</strong> the use <strong>of</strong> vinflunine in multi-centre real life setting as<br />
second line chemotherapy through free <strong>of</strong> charge programme<br />
(FOCP) for patients in the UK and Ireland<br />
S. Hussain 1 , J. Ansari 2 , R. Huddart 3 ,D.Power 4 , J. Lyons 5 , J. Wylie 5 ,<br />
M. Vilarino-Varela 6 , N. Elander 1 , R. McMenemin 7 , L. Pickering 8 , G. Faust 9 ,<br />
S. Chauhan 1 , R. Jakson 1<br />
1 Molecular and Clinical Cancer Medicine, University <strong>of</strong> Liverpool-Royal Liverpool<br />
University Hospital, Liverpool, UK, 2 Clinical <strong>Oncology</strong>, Beatson West <strong>of</strong> Scotland<br />
Cancer Centre Gartnavel General Hospital, Glasgow, UK, 3 Clinical <strong>Oncology</strong>,<br />
Royal Marsden Hospital Institute <strong>of</strong> Cancer Research, Sutton, UK, 4 Medical<br />
<strong>Oncology</strong>, Cork University Hospital, Cork, Ireland, 5 Clinical <strong>Oncology</strong>, The Christie<br />
NHS Foundation Trust, Manchester, UK, 6 Radiotherapy/<strong>Oncology</strong>, Royal Free<br />
Hospital School <strong>of</strong> Medicine, London, UK, 7 Clinical <strong>Oncology</strong>, The Freeman<br />
Hospital (NHS Foundation Trust) Northern Centre for Cancer Care, Newcastle<br />
Upon Tyne, UK, 8 <strong>Oncology</strong>, St George’s Hospital NHS Trust, London, UK,<br />
9 Clinical <strong>Oncology</strong>, Northampton General Hospital NHS Trust, Northampton, UK<br />
Background: There is no standard <strong>of</strong> care currently in UK for second line<br />
chemotherapy for patients with advanced TCC. Vinflunine is approved for TCCU for<br />
patients who have failed a platinum-based regimen and is now the standard<br />
chemotherapy in 2nd line in Europe based on large phase III randomised trial data<br />
showing 2.6 months survival advantage. ESMO guidelines recommended it as the only<br />
option for patients in the 2nd line setting. Vinflunine is not currently available in NHS<br />
practice in UK as it is not on the approved list <strong>of</strong> drugs on cancer drug fund.<br />
Methods: Data are collected retrospectively on patients who received Vinflunine as a<br />
2nd line treatment through FOCP. The dose <strong>of</strong> Vinflunine was 320/280/240 mg/m2<br />
every 3 weeks as per the SPc. The aim was to document the toxicity, radiological RR<br />
and OS in a real life setting within the FOCP.<br />
Results: Data were collected on 49 patients from 9 sites across the UK and Ireland<br />
(median age: 64 (IQR: 57-70) years, 33 males ). All patients had advanced metastatic<br />
TCCU. Thirteen patients had bone or liver metastases, 4 patients had PS 2 and 11<br />
patients had HB
abstracts<br />
demonstrated modest activity. The treatment and outcomes <strong>of</strong> real-world patients with<br />
mUC treated with second-line (2L) systemic therapies remains underexplored.<br />
Methods: Pts diagnosed with stage IV transitional cell carcinoma <strong>of</strong> the bladder from<br />
1/2004 to 12/2011 were identified in the US SEER-Medicare database. Other criteria<br />
included ≥ 66 y <strong>of</strong> age at diagnosis (1 y after Medicare eligibility), with no prior cancer<br />
diagnosis and enrolled in Medicare Parts A and B. 2L chemotherapy regimens were<br />
defined as any change in 1L chemotherapy or start <strong>of</strong> new treatment upon completion<br />
<strong>of</strong> 1L. Kaplan-Meier methods were used to assess survival by 2L treatment approach<br />
(follow up through 12/2013).<br />
Results: 240 mUC pts treated with 2L chemotherapy were included. Median age at<br />
diagnosis was 75 y (IQR 71-79 y), and 81% <strong>of</strong> pts were aged ≥ 70 y; 74% were male and<br />
93% were white. Most pts (199/240, 83%) received cisplatin- or carboplatin-based prior<br />
1L therapies. The most common comorbidities included diabetes (16%) and chronic<br />
obstructive pulmonary disease (10%). Among pts receiving 2L chemotherapy, 40% (97/<br />
240) received single agents. The majority <strong>of</strong> pts who received single-agents had taxanes<br />
(paclitaxel 37/97, 38%; docetaxel 20/97, 21%), followed by gemcitabine (19/97, 20%)<br />
and other single agents (21/97, 21%). The median overall survival (OS) in pts receiving<br />
any single-agent 2L chemotherapy was 6.4 mo (95% CI, 4.4,-8.5 mo), with a 24-mo OS<br />
rate <strong>of</strong> 13%. The median OS in pts receiving single-agent taxanes was 5.2 mo (95% CI,<br />
3.5-8.6 mo), with a 24-mo OS rate <strong>of</strong> 8%.<br />
Conclusions: In this real-world mUC population, pts received a wide variety <strong>of</strong><br />
therapies in the 2L setting. Regardless <strong>of</strong> the treatment approach, outcomes were<br />
generally poor with a low likelihood <strong>of</strong> durable disease control. These results may serve<br />
as a benchmark for the effectiveness <strong>of</strong> novel therapies currently being developed for<br />
the treatment <strong>of</strong> mUC.<br />
Legal entity responsible for the study: F. H<strong>of</strong>fmann-La Roche Ltd.<br />
Funding: F. H<strong>of</strong>fmann-La Roche Ltd.<br />
Disclosure: M.D. Galsky: Advisory Board: Genentech, Merck, Astellas, Novartis,<br />
Consulting: BioMotiv. Research funding: Novartis, NMS, Celgene. S-W. Lin, S. Ogale,<br />
C. Derleth: Employee <strong>of</strong> Genentech, Inc. M. Zivkovic: Employee <strong>of</strong> Genesis Research. J.<br />
Simpson: Employee <strong>of</strong> Genentech, Inc. All other authors have declared no conflicts <strong>of</strong><br />
interest.<br />
802P<br />
281 small cell bladder cancer analysis from spanish<br />
institutions<br />
M.J. Juan Fita 1 , M. Ramirez-Backhaus 2 , X. Bonet Puntí 3 , J. Gomez 4 , E. Ramos 5 ,<br />
L. Pesquera 6 , A. Rodriguez-Vida 7 , I. Lacasa Viscasillas 8 , J.C. Villa Guzman 9 ,<br />
R. Sanchez-Salas 10 , J.L. Sanchez Sanchez 11 , M.J. Miranda 12 , S. Valverde 13 ,<br />
L. Izquierdo 14 , A. Serrano 15 , P. Pellejero 16 , I. Garcia 17 , I. Ortiz 18 , J. Rubio Briones 2 ,<br />
M.A. Climent 1<br />
1 Medical <strong>Oncology</strong>, Fundación Instituto Valenciano de Oncología, Valencia, Spain,<br />
2 Urology, Fundación Instituto Valenciano de Oncología, Valencia, Spain, 3 Urology,<br />
Hospital de Bellvitge, Barcelona, Spain, 4 Urology, Hospital Universitario La Paz,<br />
Madrid, Spain, 5 Urology, Hospital Universitario Marques de Valdecilla, Santander,<br />
Spain, 6 Medical <strong>Oncology</strong>, Hospital Clinico Universitario de Valladolid, Valladolid,<br />
Spain, 7 Medical <strong>Oncology</strong>, University Hospital del Mar, Barcelona, Spain,<br />
8 Urology, Hospital de Basurto, Bilbao, Spain, 9 Medical <strong>Oncology</strong>, Hospital<br />
General Ciudad Real, Ciudad Real, Spain, 10 Urology, Institute Mutualiste<br />
Montsouris, Paris, France, 11 Medical <strong>Oncology</strong>, Hospital de Villajoyosa, Alicante,<br />
Spain, 12 Medical <strong>Oncology</strong>, Hospital Universitario St Joan de Reus, Reus, Spain,<br />
13 Urology, Hospital Nuestra Señora de Sonsoles, Ávila, Spain, 14 Urology, Hospital<br />
Clinic y Provincial de Barcelona, Barcelona, Spain, 15 Urology, Hospital Clinico<br />
Universitario San Carlos, Madrid, Spain, 16 Urology, Hospital Universitario Central<br />
de Asturias (HUCA), Oviedo, Spain, 17 Medical <strong>Oncology</strong>, Hospital Virgen de la<br />
Salud, Toledo, Spain, 18 Matemáticas, Universidad de Almería, Almeria, Spain<br />
Background: Representing the 0,7% <strong>of</strong> all bladder cancers, the small cell carcinomas<br />
(SCBC) are characterized by their aggressiveness, rapid progression and early<br />
metastasis. Therapeutic outcomes have not improved over the last 20 years and, due to<br />
lack <strong>of</strong> prospective studies, standard treatments for localized or metastatic disease are<br />
not yet well established.<br />
Methods: Pooled analysis <strong>of</strong> 281 patients with pure or mixed SCBC from 28 spanish<br />
centers, treated between 1992 and 2015, has been performed. Endpoints <strong>of</strong> this study<br />
were: disease clinical and pathological characteristics, treatments performed and<br />
differences in OS. Differences among treatment options for localized SCBC are<br />
reported: radical cistectomy (RC), neoadjuvant (NeoQT) and adjuvant chemotherapy<br />
(AdjQT) (carboplatin-etoposide (CA-VP16) or cisplatin-etoposide (C-VP16).<br />
Results: With a median follow up <strong>of</strong> 108 months, 281 SCBC patients are included.<br />
Median age at diagnosis was 71,9 years, 86,1% were male and 77,4% smokers.<br />
Histology was predominantly SCBC in 100% <strong>of</strong> the cases, 60(50,4%) were pure<br />
microcytic histology, 33(27,7%) had transitional component and 36(30,2%) had<br />
sarcomatoid, micropapillary or other lineage. RC was performed in 119 patients<br />
(49,2%). Nine (7%) tumors were pT0, 11(8,6%) were non muscle invasive, 83(64,8%)<br />
invaded muscular and 25(19,5%) were pT4. Twenty four (11, 8%) patients received<br />
NeoQT (41,8% C-VP16 and 44,3% CA-VP16); AdjQT was given in 47(23,2%) cases,<br />
(31,3% C-VP16 and 45,8% CA-VP16). Median OS among treatments were: 98,3<br />
months for RC, 73,2 months for NeoQT (C-VP16 43,9m; CA-VP16: 30,8m) and 100,4<br />
months for AdjQT (C-VP16: 137,4 m; CA-VP16: 45,4m), the differences found not to<br />
be statistically significant (p = 0,75).<br />
Conclusions: We present the largest published series on SCBC. Outcome data from<br />
281 SCBC cases has not shown statistically significant differences in OS among patients<br />
who have undergone RC alone compared to those receiving NeoQT or AdjQT<br />
(p = 0,75). Furthermore, no significant differences among the different QT schemes<br />
were observed.<br />
Legal entity responsible for the study: N/A<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
803P<br />
Phase 1 study <strong>of</strong> selective internal radiation therapy (SIRT)<br />
with yttrium-90 (Y-90) resin microspheres in patients (pts)<br />
with renal cell carcinoma (RCC): RESIRT<br />
P. de Souza 1 , P. Aslan 2 , W. Clark 3 , M. Patel 4 , J.A. Vass 5 , D. Cade 6 , S.J. de Silva 7<br />
1 Department <strong>of</strong> Medical <strong>Oncology</strong>, Western Sydney University School <strong>of</strong> Medicine,<br />
Sydney, Australia, 2 Department <strong>of</strong> Urology, Watarah Private Hospital, Sydney,<br />
Australia, 3 Department <strong>of</strong> Radiology, St George Private Hospital, Sydney,<br />
Australia, 4 Department <strong>of</strong> Urology, Westmead Hospital, Sydney, Australia,<br />
5 Department <strong>of</strong> Urology, Royal North Shore Hospital, Sydney, Australia, 6 Medical<br />
Affairs, Sirtex Medical Limited, Sydney, Australia, 7 Department <strong>of</strong> Radiology, The<br />
Sutherland Hospital, Sydney, Australia<br />
Background: Some patients with RCC are unsuitable for nephrectomy. SIRT is used<br />
for unresectable liver cancers, and has properties that make it potentially useful for<br />
primary RCC. RESIRT is the first-in-human study to evaluate safety and feasibility <strong>of</strong><br />
SIRT for primary RCC.<br />
Methods: Pts not amenable for or who declined conventional therapy were eligible;<br />
metastases were permitted. A single transfemoral microcatheter administration <strong>of</strong> Y-90<br />
resin microspheres (SIR-Spheres; Sirtex, Australia) was delivered superselectively via the<br />
renal artery to the tumour at intended radiation doses <strong>of</strong> 75, 100, 150, 200, 300 Gy and a<br />
final cohort with a procedural endpoint <strong>of</strong> imminent stasis, in a dose-escalation design.<br />
Post-SIRT follow-up was 12 months. The primary endpoint was safety and toxicity at 30<br />
days post-SIRT. Secondary endpoints included tumour response (RECIST v1.1).<br />
Results: The study enrolled 21 pts with RCC, mean age 74.9 years and WHO<br />
performance status <strong>of</strong> 0 (81%) or 1 (19%). Six (29%) pts had metastatic RCC, 7 (33%)<br />
had previously undergone total nephrectomy <strong>of</strong> the contralateral kidney, 1 (5%) received<br />
prior chemotherapy, 1 (5%) progressed after cryotherapy to the target organ and 3 (14%)<br />
received other prior therapy. Median follow-up was 11.9 months (95% CI 11.8–12.0).<br />
The intended doses were delivered without any dose-limiting toxicity. 15/21 (71%) pts<br />
experienced 44 AEs within 30 days post-SIRT. Eight (38%) pts had AEs grade ≥3, all<br />
unrelated to SIRT; 8 pts (38%) had 12 AEs that were related to SIRT (all grade 1–2, no<br />
SAEs), <strong>of</strong> which 1 occurred pre SIRT. Treatment-related AEs were fatigue/tiredness, pain,<br />
hypertension, lack <strong>of</strong> appetite, ‘heaviness’, bruised groin and hypomagnesemia. 15 SAEs<br />
were reported in 8 (38%) pts; 2 within 30 days post-SIRT (shortness <strong>of</strong> breath, prolonged<br />
hospitalisation). Best overall tumour responses were partial response 1/19 (5.3%), stable<br />
disease 17/19 (89.5%) and progressive disease 1/19 (5.3%).<br />
Conclusions: This pilot study demonstrates good tolerability <strong>of</strong> SIRT at all dose levels<br />
including imminent stasis in treating primary tumours in RCC pts otherwise<br />
unsuitable for conventional therapy.<br />
Clinical trial identification: Australian New Zealand Trials Registry: Trial ID<br />
ACTRN12610000690055<br />
Legal entity responsible for the study: Sirtex Technology Pty Ltd.<br />
Funding: Sirtex Medical Limited<br />
Disclosure: P. de Souza: Australian Advisory Boards until 2014, nil afterwards: GSK,<br />
Pfizer, Janssen, Astellas. D. Cade: Full time employee <strong>of</strong> Sirtex Medical Limited<br />
Receives salary from Sirtex Medical Limited S.J. de Silva: Proctor for Sirtex (unpaid).<br />
All other authors have declared no conflicts <strong>of</strong> interest.<br />
804P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
A phase 1b dose-escalation study <strong>of</strong> TRC105 (endoglin<br />
antibody) in combination with axitinib in patients with<br />
metastatic renal cell carcinoma (mRCC)<br />
T. Choueiri 1 , M.D. Michaelson 2 , E. Posadas 3 , G. Sonpavde 4 , D. McDermott 5 ,<br />
B. Seon 6 , M. Jivani 7 , R. Shazer 7 , B. Adams 7 , C. Theuer 7<br />
1 Kidney Cancer Center, Dana-Farber Cancer Institute, Boston, MA, USA, 2 Medical<br />
<strong>Oncology</strong>, Massachusetts General Hospital, Boston, MA, USA, 3 Urologic<br />
<strong>Oncology</strong> Program, Cedars-Sinai Medical Center, Los Angeles, CA, USA,<br />
4 Medical <strong>Oncology</strong>, University <strong>of</strong> Alabama at Birmingham Hospital, Birmingham,<br />
LA, USA, 5 Division <strong>of</strong> Hematology/<strong>Oncology</strong>, Beth Israel Deaconess Med. Center,<br />
Boston, MA, USA, 6 Immunology, Roswell Park Cancer Institute, Buffalo, NY, USA,<br />
7 Clinical Operations, TRACON Pharmaceuticals, Inc., San Diego, CA, USA<br />
Background: Resistance to VEGF-targeted therapy is a major challenge in<br />
contemporary treatment <strong>of</strong> mRCC, and endoglin (CD105) activation may be an<br />
important mechanism leading to resistance. Endoglin is an essential angiogenic<br />
receptor expressed on proliferating tumor vessels and mRCC cancer stem cells, and is<br />
upregulated following VEGF inhibition. TRC105 is an endoglin monoclonal antibody<br />
that potentiates the anti-tumor activity <strong>of</strong> bevacizumab and VEGF receptor tyrosine<br />
kinase inhibitors in preclinical models.<br />
vi278 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Methods: Heavily pretreated mRCC pts with ECOG PS 0-1 and acceptable organ<br />
function were treated with TRC105 weekly (8mg/kg and then 10mg/kg) in<br />
combination with axitinib (initially at 5 mg BID and then escalated per patient<br />
tolerance to a maximum <strong>of</strong> 10 mg BID).<br />
Results: Eighteen mRCC pts (median age = 61.5; M:F 16:2; median number <strong>of</strong> prior<br />
therapies = 3, including > 1 VEGFR TKI, clear cell = 13, prior axitinib = 1) were treated.<br />
TRC105 dose escalation proceeded from 8 mg/kg (n = 3) to 10 mg/kg (n = 15) without<br />
dose limiting toxicity. Adverse events characteristic <strong>of</strong> each drug were not increased in<br />
frequency or severity when the two drugs were administered concurrently, and most<br />
commonly included epistaxis, headache, fatigue, diarrhea, and gingival bleeding.<br />
TRC105 and axitinib demonstrated preliminary evidence <strong>of</strong> activity, including partial<br />
responses in 29% <strong>of</strong> patients by RECIST 1.1, and longer PFS than expected with<br />
axitinib as a single agent. The overall disease control rate (CR/PR/SD > 2 months) was<br />
88% (15 <strong>of</strong> 17). Median PFS overall was 8.4 months, and was 9.6 months among<br />
patients with clear cell RCC. Tumor response will be correlated with baseline protein<br />
biomarkers. TRC105 pharmacokinetic parameters will be reported.<br />
Conclusions: TRC105 at 8 and 10 mg/kg was well tolerated in combination with<br />
axitinib, with encouraging evidence <strong>of</strong> activity in patients with mRCC. A multicenter<br />
randomized Phase 2 trial <strong>of</strong> axitinib +/- TRC105 is actively enrolling at this time<br />
(NCT01806064).<br />
Clinical trial identification: Protocol # 105RC101 (NCT01806064)<br />
Legal entity responsible for the study: Sponsor: TRACON Pharmaceuticals, Inc. Lead<br />
PI: Toni Choueiri<br />
Funding: Sponsor: TRACON Pharmaceuticals, Inc.<br />
Disclosure: T. Choueiri: Consulting or Advisory Role: Pfizer, GSK, Bayer, Novartis<br />
Research Funding (institution): Pfizer. M.D. Michaelson: Consulting or Advisory Role:<br />
Mellenium, Astellas, Novartis, Medivation Research Funding (Institution): Pfizer,<br />
Eisas, Argos, Mellenium, Novartis, Tracon. E. Posadas: Consulting or Advisory Role:<br />
Medivation, Bavarian Nordic Immunotherapeutics Research Funding (Institution):<br />
Janssen, Bavarian Nordic Immunotherapeutics, Tracon. D. McDermott: Consulting or<br />
Advisory Role: Genentech, Merck, BMS, Pfizer Research Funding: Promethus Labs. B.<br />
Seon: Patents - Roswell Park Cancer Institute. M. Jivani: Employee <strong>of</strong> TRACON<br />
Pharmaceuticals, Inc. Stock ownership <strong>of</strong> TRACON Pharmaceuticals, Inc. R. Shazer:<br />
Employee <strong>of</strong> TRACON Pharmaceuticals, Inc. Stock ownership <strong>of</strong> BMS B. Adams,<br />
C. Theuer: Employee <strong>of</strong> TRACON Pharmaceuticals, Inc. Stock ownership <strong>of</strong> TRACON<br />
Pharmaceuticals, Inc. All other authors have declared no conflicts <strong>of</strong> interest.<br />
806P<br />
New insights in oncogenic alterations in clear-cell renal cell<br />
carcinoma with sarcomatoid dedifferentiation<br />
R. Flippot 1 , G.G. Malouf 1 , E. Comperat 2 ,X.Su 3 , R. Mouawad 1 , M. Roupret 4 ,<br />
J-P. Spano 1 , D. Khayat 1<br />
1 Medical <strong>Oncology</strong>, Groupe Hospitalier Pitié Salpetriere, Paris, France, 2 Pathology,<br />
Groupe Hospitalier Pitié Salpetriere, Paris, France, 3 Bioinformatics and<br />
Computational Biology, MD Anderson Cancer Center, Houston, TX, USA,<br />
4 Urology, Groupe Hospitalier Pitié Salpetriere, Paris, France<br />
Background: Sarcomatoid dedifferentiation in renal cell carcinoma (sRCC) has been<br />
associated with aggressive disease and poor outcome. However, the molecular<br />
landscape <strong>of</strong> sRCC remains largely unknown, notably regarding chromatin remodeling<br />
genes alterations and the alterations <strong>of</strong> wild-type VHL tumors.<br />
Methods: Sixteen primary sRCCs and matched normal tissues underwent<br />
whole-exome sequencing, with a median coverage <strong>of</strong> 110x and 50x for cancer and<br />
normal samples, respectively. These data were compared to 417 non-sarcomatoid<br />
RCCs from the Cancer Genome Atlas RCC data set. Associations with clinical and<br />
pathological tumor features were performed.<br />
Results: Most frequent somatic mutations included VHL (11/16, 69%), and chromatin<br />
remodeling genes PBRM1 (7/16, 44%) and SETD2 (3/16, 19%). BAP1 mutations were<br />
only present in 2 cases (12%). These alterations <strong>of</strong> chromatin remodeling genes were<br />
not enriched compared to the TCGA cohort <strong>of</strong> clear-cell RCC. Of note, chromatin<br />
remodeling genes alterations were not mutually exclusive, with concurrent mutations<br />
<strong>of</strong> PBRM1 and BAP1, and PBRM1 and KDM5C reported in one and two patients,<br />
respectively. No recurrent alterations <strong>of</strong> known oncogenic pathways such as MAPK,<br />
PIK3Ca/mTOR, p53 or tumor metabolism were reported. Out <strong>of</strong> 5 patients (31%)<br />
without VHL alterations, 2 (40%) had a metastatic evolution compared to only 18% in<br />
patients with VHL mutations. All had at least one alteration <strong>of</strong> chromatin remodeling<br />
genes including BAP1, PBRM1 and SMARCA4. Interestingly, mutational load was not<br />
correlated with clinical and pathological tumor features such as Fuhrman grade and<br />
TNM stage, nor with alterations <strong>of</strong> known described oncogenes.<br />
Conclusions: The genetic landscape <strong>of</strong> sRCC <strong>of</strong> clear-cell type might not be different<br />
from other clear-cell RCC. Patients with wild-type VHL tumors represent nearly one<br />
third <strong>of</strong> those cancers, had more aggressive tumors and constant chromatin remodeling<br />
gene alterations. These data underline the urgent need for the characterization <strong>of</strong><br />
epigenetic modifications that might further explain the distinctive features <strong>of</strong> sRCC.<br />
Legal entity responsible for the study: Assistance Publique - Hôpitaux de Paris<br />
Fondation AVEC<br />
Funding: Fondation AVEC<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
807P<br />
Novel angiogenesis markers as long-term prognostic factors<br />
in renal cell cancer<br />
J.P. Virman 1 , A. Lampinen 2 , P. Bono 3 , T. Luukkaala 4 , K. Sunela 5 , P. Kujala 6 ,<br />
P. Saharinen 7 , P-L. Kellokumpu-Lehtinen 5<br />
1 Department <strong>of</strong> Anesthesia and School <strong>of</strong> Medicine, Tampere University Hospital<br />
and University <strong>of</strong> Tampere, Tampere, Finland, 2 Translational Cancer Biology<br />
Program, University <strong>of</strong> Helsinki and Wihuri Research Institute, Helsinki, Helsinki,<br />
Finland, 3 Comprehensive Cancer Center, Helsinki University Hospital and<br />
University <strong>of</strong> Helsinki, Helsinki, Finland, 4 Science Center, Pirkanmaa Hospital<br />
District and School <strong>of</strong> Health Sciences, University <strong>of</strong> Tampere, Tampere, Finland,<br />
5 Department <strong>of</strong> <strong>Oncology</strong>, Tampere University Hospital (Tays), Tampere, Finland,<br />
6 Department <strong>of</strong> Pathology, Fimlab Laboratories, Tampere, Finland,<br />
7 Comprehensive Cancer Center, HUCH Helsinki University Central Hospital,<br />
Helsinki, Finland<br />
Background: Angiopoetin-2 (Ang-2), vascular endothelial growth factor receptors<br />
(VEGFRs) and CD31, a member <strong>of</strong> immunoglobulin superfamily, regulate normal<br />
vascular development and remodeling, as well as pathological neovascularization in<br />
cancer. The aim <strong>of</strong> this study was to investigate Ang-2 expression alone as single<br />
prognostic factor and in combination with other angiogenesis markers (VEGFR3 and<br />
CD31) and cell proliferation and survival markers (MIB-1 and BCL-2).<br />
Methods: This study included 224 RCC patients whose nephrectomies were performed<br />
between 1985-1995 at Tampere University Hospital or Tampere Hospital. All tumor<br />
samples were re-evaluated and reclassified using Fuhrman grading system and<br />
Heidelberg classification. Two parallel multi tissue blocks were obtained fur further<br />
immunological analysis. Ang-2 expression was measured from digital images and<br />
positive area was expressed as the percentage <strong>of</strong> total tumor area. Ang-2 expression<br />
were categorized both by median into low (≤ 5.5) or high (>5.5) and by upper quartile<br />
into low (
abstracts<br />
Results: Eleven <strong>of</strong> 34 evaluable patients (32%) had % tumor reduction >30% with a<br />
median <strong>of</strong> 13.5%. Major adverse events (Grade 3) were hypertension in 17 (43%),<br />
proteinuria in 7 (18%), respectively. Among several PK parameters, total clearance<br />
(CL-tot; dosage/AUC) was the most significantly associated with patient outcomes, i.e.,<br />
reverse correlation with % reduction (R2 = 0.2542, p = 0.0017), and with proteinuria<br />
(p = 0.0058). There was a significant correlation between estimated CL-tot by<br />
prediction model and actual CL-tot (r2 = 0.6356, p < 0.0001). Estimated CL-tot was<br />
also significantly associated with % reduction (p = 0.0053, sensitivity, specificity:<br />
76.5%) and proteinuria (p = 0.0357). Surprisingly, hypertension was associate with<br />
neither % tumor reduction, nor CL-tot.<br />
Conclusions: Estimated CL-tot may be more beneficial than hypertension to<br />
determine the optimal initial dose <strong>of</strong> axitinib in individual RCC patient.<br />
Clinical trial identification: UMIN000011147 (2013/07/10)<br />
Legal entity responsible for the study: Institutional Review Board Yamaguchi<br />
University Hospital<br />
Funding: Yamaguchi University Hospital Yamaguchi Prefecture<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
809P<br />
Inverse association between baseline renal function and<br />
overall survival in patients with metastatic renal cell<br />
carcinoma who were treated with molecular-targeted agents<br />
M. Hiroyuki, H. Miyake, M. Fujisawa<br />
Urology, Kobe University Graduate School <strong>of</strong> Medicine, Kobe, Japan<br />
Background: Renal toxicity is regarded as one <strong>of</strong> the most frequently observed adverse<br />
events in metastatic renal cell carcinoma (mRCC) patients, irrespective <strong>of</strong> the type <strong>of</strong><br />
targeted agent introduced. The objective <strong>of</strong> this study was to investigate the prognostic<br />
significance <strong>of</strong> the baseline renal function in mRCC patients treated with<br />
molecular-targeted agents.<br />
Methods: This study included a total <strong>of</strong> 408 consecutive mRCC patients receiving<br />
molecular-targeted therapy, consisting <strong>of</strong> 124 (group A) and 284 (group B) who had<br />
baseline estimated glomerular filtration rates ≥ 60 mL/min/1.73 m 2 and < 60 mL/min/<br />
1.73 m 2 , respectively.<br />
Results: Compared with group A, group B was significantly less likely to have poor<br />
prognostic factors, such as a high proportion <strong>of</strong> patients without nephrectomy,<br />
unfavorable risk classified by the Memorial Sloan Kettering Cancer Center or Heng’s<br />
system, high C-reactive protein level, and high incidence <strong>of</strong> lymph node, bone or liver<br />
metastasis. The median overall survivals (OSs) after the initiation <strong>of</strong> targeted therapy in<br />
groups A and B were 21.4 and 35.8 months, respectively, and there was a significant<br />
difference in the OS between these two groups; however, multivariate analysis showed<br />
the lack <strong>of</strong> independent impact <strong>of</strong> the baseline renal function on the OS. Furthermore,<br />
when patients without nephrectomy were excluded, no significant difference was noted<br />
in the OS between the two groups.<br />
Conclusions: There appeared to be an inverse association between the baseline renal<br />
function and OS in mRCC patients receiving molecular-targeted therapy, suggesting<br />
no adverse impact <strong>of</strong> an unfavorable baseline renal function on the efficacy <strong>of</strong> targeted<br />
agents against mRCC. Accordingly, molecular-targeted therapy should not be avoided<br />
in mRCC patients with an impaired baseline renal function.<br />
Legal entity responsible for the study: N/A<br />
Funding: Kobe University<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
810P<br />
Influence <strong>of</strong> diabetes and congestive heart failure (CHF) on<br />
selection <strong>of</strong> first-line (1L) treatment for metastatic renal cell<br />
carcinoma (mRCC)<br />
J. Gong 1 , D. George 2 , S. Mhatre 3 , S-W. Lin 3 , A. Surinach 4 , H. Wallen 5 , R. Vohra 5 ,<br />
J. Simpson 5 , S. Ogale 5 , S.K. Pal 1<br />
1 Medical <strong>Oncology</strong> and Experimental Therapeutics, City <strong>of</strong> Hope, Duarte, CA,<br />
USA, 2 Medical <strong>Oncology</strong>, Duke University, Durham, NC, USA, 3 Real World Data<br />
Science, Genentech Inc., San Francisco, CA, USA, 4 Genesis Research, Genesis<br />
Research, Hoboken, CA, USA, 5 <strong>Oncology</strong>, Genentech, Inc., South San Francisco,<br />
CA, USA<br />
Background: VEGF- and mTOR-directed therapies are the mainstay <strong>of</strong> mRCC<br />
treatment. Guidelines recommend risk stratification for treatment selection. Here, we<br />
examined how demographics and comorbidities may impact treatment selection.<br />
Methods: Patients (pts) initiating 1L mRCC therapy from 2011 to 2013 were identified<br />
in MarketScan, a US claims database with ≈40 million pts with employer-sponsored<br />
insurance. Pts with non-RCC histologies and previous primary cancers were excluded.<br />
Pts were stratified by 1L drug category (VEGF- or mTOR-directed) and dosage form<br />
(intravenous [IV] or oral [PO]). Clinical and demographic characteristics (eg, age, sex,<br />
employment, region, insurance type), baseline comorbidities, and Charlson<br />
Comorbidity Index (CCI) were assessed. Multivariate logistic regression models<br />
examined associations between these characteristics and receipt <strong>of</strong> (1) VEGF- vs<br />
mTOR-directed and (2) IV vs PO therapy.<br />
Results: 1262 mRCC pts initiated 1L therapy between 2011 and 2013 and met selection<br />
criteria. Median age was 62 y; 70% were male; 84% had a CCI <strong>of</strong> 0-1, with diabetes<br />
(26%) and chronic kidney disease (19%) being the most frequent. VEGF-directed<br />
therapy was more common than mTOR-directed therapy (87% vs 13%). PO therapy<br />
was more common than IV therapy (83% vs 17%). Diabetes was more common in pts<br />
taking VEGF-directed therapy, while the opposite was seen for CHF; these factors<br />
remained independently associated with 1L therapy in multivariate analyses (Table).<br />
Pts receiving IV therapy were older than those receiving PO therapy (mean, 65 vs 62 y),<br />
and age remained significant in the multivariate-adjusted model (P = .04).<br />
Table: 810P Association between baseline diabetes and CHF and<br />
receipt <strong>of</strong> mTOR-directed therapy in 1L mRCC<br />
Adjusted odds <strong>of</strong><br />
receiving mTOR a<br />
Characteristic mTOR N = 165 VEGF N = 1094 OR (95% CI) P value<br />
Diabetes<br />
No 81% 72% Ref<br />
Yes 19% 28% 0.57 (0.37-0.87) .01<br />
CHF<br />
No 87% 94% Ref<br />
Yes 13% 6% 2.39 (1.4-41) .001<br />
a Adjusted for age, sex, employment status, geographic region, insurance type,<br />
CCI score, and other baseline comorbidities that were statistically significant<br />
(P < .05) in univariate analyses.<br />
Conclusions: Baseline diabetes and CHF as well as age are independent predictors <strong>of</strong><br />
1L mRCC treatment selection. Differences in treatment safety pr<strong>of</strong>iles and pt health<br />
may drive this difference. These results will inform ongoing studies that compare<br />
treatment selection in 1L mRCC.<br />
Legal entity responsible for the study: F. H<strong>of</strong>fmann La-Roche<br />
Funding: F. H<strong>of</strong>fmann La-Roche<br />
Disclosure: S. Mhatre, S-W. Lin, H. Wallen, J. Simpson, S. Ogale: Employee <strong>of</strong><br />
Genentech, Inc. A. Surinach: Employee <strong>of</strong> Genesis Research. R. Vohra: Former<br />
employee <strong>of</strong> Genentech, Inc. All other authors have declared no conflicts <strong>of</strong> interest.<br />
811P<br />
Prognostic ability <strong>of</strong> early tumor shrinkage on overall survival<br />
(OS) in metastatic renal cell carcinoma (mRCC) – a validation<br />
study<br />
G.R. Pond 1 , M. Dietrich 2 , V. Grünwald 3<br />
1 <strong>Oncology</strong>, Escarpment Cancer Research Institute, McMaster Medical Centre,<br />
Hamilton, ON, Canada, 2 Natural Sciences, Leibniz University Hannover, Hannover,<br />
Germany, 3 Clinic for Hematology, Hemostasis, <strong>Oncology</strong> and<br />
Stemcelltransplantation, Hannover Medical School, Hannover, Germany<br />
Background: Early tumor shrinkage (eTS) <strong>of</strong> 10% has been identified as a putative<br />
prognostic marker in mRCC, which could serve as an early read-out in clinical trials.<br />
We aimed to validate the prognostic role <strong>of</strong> eTS in first line TKI treatment using data<br />
from the COMPARZ study (NCT00720941).<br />
Methods: A retrospective analysis on data <strong>of</strong> 1100 1 st line patients treated with<br />
sunitinib or pazopanib was performed. Tumor response was measured according to<br />
RECIST 1.1. eTS was a priori defined as tumor shrinkage by ≥10%. The Kaplan-Meier<br />
method was used to estimate time-to-event outcomes. A landmark analysis was<br />
performed on day (d) 42 and d 90 after randomization. Cox proportional hazards<br />
regression was performed to evaluate the effect <strong>of</strong> prognostic factors on overall survival<br />
after d 42 and d 90.<br />
Results:<br />
Table: 811P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
At d 42 and 90, 582 and 1007 patients were evaluable for landmark analysis, <strong>of</strong> whom<br />
56.5% and 65.2% achieved eTS, respectively. In patients with eTS median OS was 34.1<br />
(CI95% 28.4; not reached(NR)) and 33.6 (CI95% 30.1; NR) mo. at d 42 and d 90,<br />
respectively, compared to 19.6 (CI95% 14.0; 28.9) and 15.1 (CI95% 12.4; 18.7) mo for<br />
patients without eTS. There was no interaction between type <strong>of</strong> treatment and eTS (d<br />
42 p = 0.79, d 90 p = 0.37). In multivariable analyses, adjusted for age, sex, performance<br />
status, nephrectomy, anemia, neutrophils, platelets, LDH, organs involved, liver<br />
metastases, time from diagnosis, calcium, treatment, and baseline tumor burden, eTS<br />
≥10% remained an independent prognostic marker <strong>of</strong> OS for both d 42: HR 0.53 (0.41;<br />
0.69), p < 0.001 and d 90: HR 0.49 (CI95% 0.40; 0.60), p
abstracts<br />
Legal entity responsible for the study: Exelixis, Inc<br />
Funding: Exelixis, Inc<br />
Disclosure: T.B. Powles: Honoraria- Roche, Genentech, Novartis Consulting/<br />
Advisory- Roche, Genentech, Bristol Meyers Squibb Research Funding- AZ/<br />
Medimmune, Roche, Genentech, GlaxoSmithKline B. Escudier: Honoraria- Exelixis,<br />
Novartis, Pfizer, BMS, Roche. S. Chowdhury: Membership on an advisory board or<br />
board <strong>of</strong> directors: San<strong>of</strong>i, Astellas, Novartis, Janssen, Bayer, Essa, Pfizer, Clovis,<br />
Corporate-sponsored research or other substantive relationships:San<strong>of</strong>i, Astellas. D.<br />
Pook: Travel, Accommodations, Expenses - Astellas, Pfizer, Novartis. U. Harmenberg:<br />
Leadership- Medivir, Oncopeptides, Glionova Stock Ownership-Medivir, Ahihion. N.<br />
Basappa: Honoraria -Astellas, Janssen, Pfizer, Novartis, BMS Consulting Role-<br />
Research Funding - Lilly, Agensys, Amgen, Bayer, BI. D. Geynisman: Consulting and<br />
Advisory Role- Pfizer, Novartis, Prometheus Research Funding - Pfizer J. Merchan:<br />
Research Funding - Exelixis, Agensys, Rexaham, Eli Lilly. C. Ryan: Research Funding-<br />
Janssen, MabVax, Morphotek, OSI, Threshold, Argos, BMS, CytRx, Eisai, Exelixis,<br />
GSK, Consulting and Advisory Role- Karyopharm, EMD-Serono, Eisai, Pfizer, Onyx,<br />
Janssen O. Goodman: Honoraria - Medivation Consultancy/Advisory Role-<br />
Medivation, Exelixis Speakers Bureau – Medivation. P. Singh: Consulting and Advisory<br />
Role- Prometheus, Genentech Speakers’ Bureau - Genentech J. Lougheed, M. Patel:<br />
Employment and Stock – Exelixis. J.J. Knox: Research Funding - Pfizer, Astra Zeneca<br />
Consulting and Advisory Role – Cellgene. R.J. Motzer: Consulting Advisory Role-<br />
Exelixis, Novartis, Eisai, Inc Research Funding- Exelixis, BMS, Novartis, Pfizer,<br />
Genentech, Roche. T.K. Choueiri: Consulting/Advisory Role: Pfizer, GSK, Novartis,<br />
Merck, Bayer, Eisai, Roche, Prometheus Labs Inc, BMS, Foundation Medicine Inc.<br />
Research Funding: Pfizer, GSK, Novartis, BMS, Merck, Exelixis, Roche, AstraZeneca,<br />
Tracon, Peloton. All other authors have declared no conflicts <strong>of</strong> interest.<br />
815P<br />
Evaluation <strong>of</strong> the novel “trial within a trial” design <strong>of</strong> METEOR,<br />
a randomized phase 3 trial <strong>of</strong> cabozantinib versus everolimus<br />
in patients (pts) with advanced renal cell carcinoma (RCC)<br />
C. Hessel 1 , M. Mangeshkar 1 , R.J. Motzer 2 , B. Escudier 3 , T.B. Powles 4 ,<br />
G. Schwab 5 , T.K. Choueiri 6<br />
1 Biostatistics, Exelixis, Inc., South San Francisco, CA, USA, 2 Medical <strong>Oncology</strong>,<br />
Memorial Sloan Kettering Cancer Center, New York, NY, USA, 3 Medical <strong>Oncology</strong>,<br />
Institut Gustave Roussy, Villejuif, France, 4 Medical <strong>Oncology</strong>, Barts Cancer<br />
Institute-Queen Mary University <strong>of</strong> London, London, UK, 5 Product Development<br />
and Medical Affairs, Exelixis, Inc., South San Francisco, CA, USA, 6 Genitourinary<br />
<strong>Oncology</strong>, Dana-Farber Cancer Institute/Brigham and Women’s Hospital, Boston,<br />
MA, USA<br />
Background: Comparative studies <strong>of</strong> time-to-event endpoints should be designed to<br />
yield a wide range <strong>of</strong> event times to accurately characterize the hazard function (HF)<br />
relationship and ensure valid hazard ratio (HR) estimates. The total sample size (N) is<br />
ideally small relative to the required number <strong>of</strong> events. The primary endpoint <strong>of</strong><br />
progression-free survival (PFS) in METEOR (NCT01865747) required 259 events; the<br />
secondary overall survival (OS) endpoint required 408. As a result, the planned total N<br />
(650) was much larger than required to evaluate PFS. Shorter PFS times would be<br />
overrepresented if an event-driven analysis was conducted among all 650 pts,<br />
potentially undermining the ability to assess the proportional hazards assumption. To<br />
address this, METEOR employed a novel “trial within a trial” design: PFS was analyzed<br />
in the first 375 randomized pts (PFS Pop); OS was analyzed in all 658 randomized pts<br />
(ITT Pop). Both populations follow the intention-to-treat principle.<br />
Methods: To assess the impact <strong>of</strong> the design, PFS was reanalyzed at the date <strong>of</strong> the<br />
247th event in the ITT Pop (minimum follow-up [min f/up] 2 days) and compared to<br />
both the primary endpoint results for 247 events in the PFS Pop (min f/up 11 mo) and<br />
supportive results for 394 events in the ITT Pop (min f/up 6 mo).<br />
Results: The HFs were reasonably proportional between arms in all analyses. The HR<br />
and median estimate for the cabozantinib arm in the primary analysis <strong>of</strong> 247 events in<br />
the PFS Pop (0.58, 7.4 mo) are close to the estimates in the larger analysis <strong>of</strong> 394 events<br />
in the ITT Pop (0.52, 7.4 mo) using the same cut<strong>of</strong>f date. Despite the similar<br />
relationship among HFs, an analysis using an earlier cut<strong>of</strong>f based upon 247 events in<br />
the ITT Pop is biased, overestimating the treatment benefit as represented by the HR<br />
and underestimating the median PFS in the cabozantinib arm (0.49, 6 mo).<br />
Conclusions: The “trial within a trial” design provided critical data required to<br />
characterize the HF relationship in METEOR and demonstrate robust results. This<br />
design should be considered when the HF relationship is unknown and the total N is<br />
large relative to the number <strong>of</strong> events needed for a time-to-event endpoint.<br />
Clinical trial identification: NCT01865747<br />
Legal entity responsible for the study: Exelixis, Inc.<br />
Funding: Exelixis, Inc.<br />
Disclosure: C. Hessel: Employee: Exelixis Stock or other Ownership: Exelixis. M.<br />
Mangeshkar: Employee and Stock Ownership: Exelixis, Inc. R.J. Motzer: Consulting or<br />
Advisory Role: Pfizer, Novartis, Eisai Inc. Research Funding: Exelixis, BMS, Novartis,<br />
Pfizer, Genentech/Roche. B. Escudier: Honoraria: Exelixis, Novartis, Pfizer, BMS,<br />
Roche. T.B. Powles: Honoraria: Genentech/Roche, Novartis Consulting/Advisory Role:<br />
Genentech/Roche, BMS Research Funding: AZ/MedImmune, Genentech/Roche,<br />
GlaxoSmithKline. G. Schwab: Employee, Stock Ownership, Officer <strong>of</strong> the Company:<br />
Exelixis, Inc. T.K. Choueiri: Consulting/Advisory Role: Pfizer, GSK, Novartis, Merck,<br />
Bayer, Eisai, Roche, Prometheus. Labs Inc, BMS, Foundation Medicine Inc. Research<br />
Funding: Pfizer, GSK, Novartis, BMS, Merck, Exelixis, Roche, AstraZeneca, Tracon,<br />
Peloton.<br />
816P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Quality <strong>of</strong> life (QoL) in the phase 3 METEOR trial <strong>of</strong><br />
cabozantinib vs everolimus for advanced renal cell carcinoma<br />
(RCC)<br />
D. Cella 1 , B. Escudier 2 , N. Tannir 3 , T. Powles 4 , F. Donskov 5 , K. Peltola 6 ,<br />
M. Schmidinger 7 , D. Heng 8 , P. Mainwaring 9 , H. Hammers 10 , J-L. Lee 11 , B.I. Rini 12 ,<br />
B. Roth 13 , J. Baer 14 , M. Mangeshkar 15 , C. Scheffold 16 , T. Hutson 17 ,S.Pal 18 ,R.<br />
J. Motzer 19 , T.K. Choueiri 20<br />
1 Department <strong>of</strong> Medical Social Sciences, Northwestern University, Chicago, IL,<br />
USA, 2 Department <strong>of</strong> Medical <strong>Oncology</strong>, Institut Gustave Roussy, Villejuif, France,<br />
3 Department <strong>of</strong> Genitourinary <strong>Oncology</strong>, MD Anderson Cancer Center, Houston,<br />
TX, USA, 4 Experimental Cancer Medicine, Barts Cancer Institute-Queen Mary<br />
University <strong>of</strong> London, London, UK, 5 Department <strong>of</strong> <strong>Oncology</strong>, Aarhus University,<br />
Aarhus, Denmark, 6 Comprehensive Cancer Center, HUCH Helsinki University<br />
Central Hospital, Helsinki, Finland, 7 Department <strong>of</strong> Medicine I, Medical University<br />
<strong>of</strong> Vienna, Vienna, Austria, 8 Medical <strong>Oncology</strong>, Tom Baker Cancer Centre, Calgary,<br />
AB, Canada, 9 Medical <strong>Oncology</strong>, ICON Cancer Care, South Brisbane, Australia,<br />
10 Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University,<br />
Baltimore, MD, USA, 11 Department <strong>of</strong> <strong>Oncology</strong> and Internal Medicine, Asan<br />
Medical Center/Asan GU Medical Center, Seoul, Republic <strong>of</strong> Korea, 12 Department<br />
<strong>of</strong> Hematology and <strong>Oncology</strong>, Cleveland Clinic Taussig Cancer Institute,<br />
Cleveland, OH, USA, 13 Division <strong>of</strong> <strong>Oncology</strong>, Section <strong>of</strong> Medical <strong>Oncology</strong>,<br />
Washington University School <strong>of</strong> Medicine, St Louis, MO, USA, 14 Translational<br />
Medicine, Exelixis, Inc., South San Francisco, CA, USA, 15 Biostatistics, Exelexis,<br />
Inc., South San Francisco, CA, USA, 16 Clinical Research, Exelixis, Inc., South<br />
San Francisco, CA, USA, 17 Charles A Sammons Cancer Center, Baylor University<br />
Medical Center, Dallas, TX, USA, 18 Department <strong>of</strong> Medical <strong>Oncology</strong> and<br />
Therapeutic Research, City <strong>of</strong> Hope, Duarte, CA, USA, 19 Medical <strong>Oncology</strong>,<br />
Memorial Sloan Kettering Cancer Center, New York, NY, USA, 20 Department <strong>of</strong><br />
Genitourinary <strong>Oncology</strong>, Dana-Farber Cancer Institute/Brigham and Women’s<br />
Hospital, Boston, MA, USA<br />
Background: In a randomized Phase 3 trial in advanced RCC after prior VEGFR TKI<br />
therapy (Choueiri N Engl J Med 2015, ASCO 2016 abstract 4506) cabozantinib was<br />
superior to everolimus in the primary endpoint <strong>of</strong> PFS (median 7.4 vs 3.8 mo; HR 0.58;<br />
p < 0.0001) and significantly improved secondary endpoints <strong>of</strong> OS (median 21.4 vs<br />
16.5 mo; HR 0.66; p = 0.0003) and ORR (17% vs 3%; p < 0.0001). QoL outcomes were<br />
exploratory endpoints.<br />
Methods: 658 patients were randomized 1:1 to receive cabozantinib 60 mg qd<br />
(n = 330), or everolimus 10 mg qd (n = 328). QoL questionnaires (Functional<br />
Assessment <strong>of</strong> Cancer Therapy-Kidney Symptom Index [FKSI-19] and EuroQol<br />
EQ-5D-5L) were administered on Day 1 (pre-dose), every 4 weeks through W25D1,<br />
then every 8 weeks through final tumor assessment. The FKSI-19 has 19 items each<br />
scored on a 5-point scale (0-4); a 9-item disease-related symptom index (FKSI-DRS) is<br />
a subset. Higher scores indicate better QoL. A priori statistical methods included a<br />
repeated-measures mixed-effects model change from baseline (BL) analysis. An<br />
important change was defined as an effect size (ES) ≥ 0.3.<br />
Results: Completion rates were ≥ 75% <strong>of</strong> patients (# completed/expected at each<br />
timepoint) through Week 48 for both instruments. The FKSI-19 total score was<br />
similarly sustained in each arm over time: estimated mean change from BL −3.48<br />
cabozantinib vs −2.21 everolimus (ES difference −0.13). Scores at end <strong>of</strong> treatment<br />
(mainly due to progression) were ∼7 points lower than BL in each arm. On the<br />
Treatment Side Effects subscale, diarrhea and nausea were worse for cabozantinib (ES<br />
-0.77 and -0.34, respectively), shortness <strong>of</strong> breath was worse for everolimus (ES +0.30).<br />
Diarrhea and nausea are frequent AEs for VEGFR TKIs. No treatment differences were<br />
observed for the other three FKSI subscales (DRS-Physical, DRS-Emotional, Function/<br />
Well Being) or for the EQ-5D-5L questionnaire. In a post hoc analysis, median time to<br />
deterioration (earlier <strong>of</strong> death, progression, or ≥ 4-point decrease in FKSI-DRS) was<br />
longer in the cabozantinib arm (5.5 vs 3.7 mo; p < 0.0001).<br />
Conclusions: Cabozantinib improved PFS, OS, and ORR, and resulted in QoL similar<br />
to everolimus in patients with advanced RCC. The benefits <strong>of</strong> cabozantinib are further<br />
supported by a delay <strong>of</strong> time to deterioration.<br />
Clinical trial identification: NCT01865747<br />
Legal entity responsible for the study: Exelixis, Inc.<br />
Funding: Exelixis, Inc.<br />
Disclosure: D. Cella: Stock or Other Ownership: Facit.org Patents, Royalties, Other<br />
Intellectual Prop.: Facit.org B. Escudier: Honoraria: Exelixis, Novartis, Pfizer, BMS,<br />
Roche. N. Tannir: Honoraria: Novartis, BMS, GSK, Pfizer, Exelixis, Nektar Consulting<br />
Fees: Novartis, BMS, GSK, Pfizer, Exelixis, Nektar Research Funding: Novartis, BMS,<br />
Exelixis, Epizyme Travel, Accomodations, Expenses: Novartis, BMS, GSK, Pfizer,<br />
Exelixis, Nektar. T. Powles: Honoraria: Roche/Genentech, Novartis Consulting or<br />
Advisory Role: Roche/Genentech, BMS Research Funding: AZ/MedImmune, Roche/<br />
Genentech, GSK. F. Donskov: Research Funding: Novartis, GSK, Pfizer (received by<br />
institution). K. Peltola: Employee: Part-time, Orion Pharma Stock/other Ownership:<br />
Faron Pharma Honoraria: Novartis, Lilly Consulting/Advisory: Lilly, BMS, San<strong>of</strong>i,<br />
Baxter, Pfizer, MSD, Astellas. Travel Accomodations: Pierre Fabre, BMS, Novartis,<br />
vi282 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Lilly. M. Schmidinger: Honoraria: Pfizer, Roche, BMS, Novartis Consulting/Advisory:<br />
Pfizer, Roche, BMS, Novartis, Exelixis Research Funding: Pfizer, Roche. D. Heng:<br />
Consulting/Advisory: Pfizer, Novartis, BMS, Exelixis. P. Mainwaring: Honoraria,<br />
Consulting/Advisory, Speakers’ Bureau: Astellas, Janssen, Roche, Novartis Patents,<br />
Royalties, Other Intellectual Prop: Xing Technologies P/L Travel Accomodations:<br />
Astellas, Janssen, Roche. H. Hammers: Research Funding: sfj, BMS, Newlink, Pfizer,<br />
GSK, Tracon Consulting/Advisory: BMS, Exelixis, Pfizer, Cerulean. J-L. Lee:<br />
Honoraria: Pfizer, Astellas, Novartis Consulting/Advisory: AZ Research Funding:<br />
Pfizer, Bayer, Novartis, Exelixis, MSD, Roche, AZ. B.I. Rini: Research Funding: Pfizer,<br />
BMS, Peleton, Acceleron, Furmatics Consulting/Advisory: Pfizer, Roche, BMS,<br />
Acceleron, Novartis, GSK Travel Accomodations, Expenses: Pfizer. B. Roth: Research<br />
Funding: Argos, Medivation, Exelixis, Jansen. J. Baer: Employment: Exlexis Stock or<br />
other ownership: Exelixis, GSK. M. Mangeshkar: Employee and Stock Ownership:<br />
Exelixis, Inc. C. Scheffold: Employee: Exelixis Stock or other ownership: Exelixis. T.<br />
Hutson: Research Funding: Pfizer, Bayer, BMS, Novartis Honoraria: Pfizer, Novartis,<br />
Bayer, BMS Consulting/Advisory: Pfizer, Novartis, Bayer, Exelixis, Eisai, BMS<br />
Speakers’ Bureau: Pfizer, Novartis, Bayer, BMS. S. Pal: honoraria: Novartis, Medivation,<br />
Astellas Pharma consulting fees: Pfizer, Novartis, Aveo, Genentech, Exelixis, BMS,<br />
Astellas, GSK. R.J. Motzer: Consulting/Advisory: Pfizer, Novartis, Eisai Research<br />
Funding: Exelixis, BMS, Novartis, Pfizer, Genentech/Roche. T.K. Choueiri: Consulting/<br />
Advisory Role: Pfizer, GSK, Novartis, Merck, Bayer, Eisai, Roche, Prometheus Labs Inc,<br />
BMS, Foundation Medicine Inc. Research Funding: Pfizer, GSK, Novartis, BMS,<br />
Merck, Exelixis, Roche, AstraZeneca, Tracon, Peloton.<br />
817P<br />
Prognostic ability <strong>of</strong> HR-QoL parameters in metastatic renal<br />
cell carcinoma (mRCC)<br />
V. Grünwald 1 , M. Dietrich 2 , G.R. Pond 3<br />
1 Clinic for Hematology, Hemostasis, <strong>Oncology</strong> and Stemcelltransplantation,<br />
Hannover Medical School, Hannover, Germany, 2 Natural Sciences, Leibniz<br />
University Hannover, Hannover, Germany, 3 <strong>Oncology</strong>, Escarpment Cancer<br />
Research Institute, McMaster Medical Centre, Hamilton, ON, Canada<br />
Background: MSKCC and IMDC risk classification scores consist <strong>of</strong> clinical and<br />
laboratory parameters, which are able to classify patients prognosis. Baseline health<br />
related quality <strong>of</strong> life (HR-QoL) has been previously shown to have prognostic<br />
relevance in cancers. We therefore tested whether the addition <strong>of</strong> HR-QoL parameters<br />
to these tools can improve prognostic accuracy.<br />
Methods: 1100 1 st line patients treated with sunitinib or pazopanib within the<br />
COMPARZ study (NCT00720941) were analyzed retrospectively. Baseline<br />
FACIT-Fatigue (F), FKSI-19 and the DRS-P subscale were used as continuous variable<br />
in prognostic factor analysis. Cox proportional hazards regression was performed to<br />
evaluate the potential prognostic ability <strong>of</strong> HR-QoL parameters on OS. Scores were<br />
adjusted for MSKCC and IMDC risk group scores separately.<br />
Results:<br />
Table: 817P Univariable analysis on prognosis, adjusted for risk<br />
groups.<br />
IMDC risk<br />
FACIT-F<br />
IMDC risk<br />
FKSI-19<br />
IMDC risk DRS-P<br />
Favorable<br />
Intermediate<br />
Unfavorable<br />
Unknown<br />
Continuous<br />
Favorable<br />
Intermediate<br />
Unfavorable<br />
Unknown<br />
Continuous<br />
Favorable<br />
Intermediate<br />
Unfavorable<br />
Unknown<br />
Continuous<br />
HR (CI95%)<br />
0.77 (0.37, 1.60) 1.42<br />
(0.70, 2.87) 3.10 (1.50,<br />
6.38) REFERENCE<br />
0.97 (0.97, 0.98)<br />
0.82 (0.39, 1.71) 1.47<br />
(0.73, 2.97) 3.32 (1.61,<br />
6.84)<br />
REFERENCE 0.97 (0.96,<br />
0.98)<br />
0.80 (0.38, 1.66) 1.44<br />
(0.71, 2.92) 3.16 (1.53,<br />
6.50) REFERENCE<br />
0.96 (0.95, 0.97)<br />
P<br />
abstracts<br />
Disclosure: N. Tannir: Honoraria: Novartis, BMS, GSK, Pfizer, Exelixis, Nektar<br />
Consulting/Advisory: Novartis, BMS, GSK, Pfizer, Exelixis, Nektar Travel,<br />
Accomodations, expenses: Novartis, BMS, GSK, Pfizer, Exelixis, Nektar Research<br />
Funding: Novartis, BMS, Exelixis, Epizyme. T. Powles: Honoraria: Roche/Genentech,<br />
Novartis Consulting or Advisory Role: Roche/Genentech, BMS Research Funding: AZ/<br />
MedImmune, Roche/Genentech, GSK. R.J. Motzer: Consulting or Advisory Role:<br />
Pfizer, Novartis, Eisai Inc. Research Funding: Exelixis, BMS, Novartis, Pfizer,<br />
Genentech/Roche. F. Rolland: Honoraria: Novartis Consulting/Advisory Role:<br />
Novartis. G. Gravis: Consulting/Advisory Role: Novartis, Pfizer. M. Staehler:<br />
Consulting/Advisory Role: Bayer, Pfizer, GSK, Novartis, BMS, Roche Speakers’ Bureau:<br />
Bayer, Pfizer, GSK, Novartis, BMS, Roche Research Funding: Bayer, Pfizer, GSK,<br />
Novartis, BMS, Roche, Exelixis. U. De Giorgi: Advisory/Consulting Role: Pfizer,<br />
Novartis, Bayer. C. Caserta: Speakers’ Bureau: Pfizer Travel, Accommodations and<br />
Expenses: Astellas, Merck Serona, Roche Pharma AG, San<strong>of</strong>i. I. Duran: Advisory/<br />
Consulting Role: San<strong>of</strong>i-Aventis, Bayer, BMS, Astellas, Roche/Genentech, Jansen,<br />
Pierre Fabre Research Funding: Jansen, San<strong>of</strong>i-Aventis Travel, Accomodations,<br />
Expenses: Astellas J.G. Larkin: Research Funding: Pfizer, Novartis, BMS, MSD. W.<br />
Berg: Employee and Stock Ownership: Exelixis, Inc. D. Clary: Employee: Exelixis, Inc.<br />
Stock Ownership: Exelixis, Inc. B. Escudier: Honoraria: Exelixis, Novartis, Pfizer, BMS,<br />
Roche. T.K. Choueiri: Consulting/Advisory Role: Pfizer, GSK, Novartis, Merck, Bayer,<br />
Eisai, Roche, Prometheus Labs Inc, BMS, Foundation Medicine Inc. Research Funding:<br />
Pfizer, GSK, Novartis, BMS, Merck, Exelixis, Roche, AstraZeneca, Tracon, Peloton. All<br />
other authors have declared no conflicts <strong>of</strong> interest.<br />
819P<br />
Real world outcomes <strong>of</strong> patients with metastatic renal cell<br />
carcinoma (mRCC) using first-line sunitinib or pazopanib:<br />
the Canadian experience<br />
A-K. Lalani 1 ,H.Li 2 , D. Heng 3 , L. Wood 4 , A. Kalirai 5 , G. Bjarnason 6 , H-W. Sim 7 ,C.<br />
K. Kollmannsberger 8 , A. Kapoor 9 , S.J. Hotte 10 , M. Vanhuyse 11 , P. Czaykowski 12 ,<br />
M.N. Reaume 13 , D. Soulieres 14 , P. Venner 1 , S. North 1 , N. Basappa 1<br />
1 Medical <strong>Oncology</strong>, University <strong>of</strong> Alberta Cross Cancer Institute, Edmonton, AB,<br />
Canada, 2 <strong>Oncology</strong> & Community Health Sciences, University <strong>of</strong> Calgary, Calgary,<br />
AB, Canada, 3 Medical <strong>Oncology</strong>, Tom Baker Cancer Centre, Calgary, AB,<br />
Canada, 4 Medical <strong>Oncology</strong>, QEII Health Sciences Centre, Halifax, NS, Canada,<br />
5 Faculty <strong>of</strong> Sciences, University <strong>of</strong> Alberta, Edmonton, AB, Canada, 6 Medical<br />
<strong>Oncology</strong>, Sunnybrook Odette Cancer Center, Sunnybrook HSC, Toronto, ON,<br />
Canada, 7 Medical <strong>Oncology</strong>, Princess Margaret Hospital, Toronto, ON, Canada,<br />
8 Medical <strong>Oncology</strong>, BCCAVancouver Cancer Centre, Vancouver, BC, Canada,<br />
9 Surgery, McMaster Institute <strong>of</strong> Urology, Hamilton, ON, Canada, 10 Medical<br />
<strong>Oncology</strong>, Juravinski Cancer Centre, Hamilton, ON, Canada, 11 Medical <strong>Oncology</strong>,<br />
McGill University Health Center The Montreal General Hospital, Montreal, QC,<br />
Canada, 12 Medical <strong>Oncology</strong>, CancerCare Manitoba MacCharles, Winnipeg, MB,<br />
Canada, 13 Medical <strong>Oncology</strong>, The Ottawa Hospital Regional Cancer Centre,<br />
Ottawa, ON, Canada, 14 Medical <strong>Oncology</strong>, Université de Montreal, Montreal, QC,<br />
Canada<br />
Background: Standard first-line treatment for mRCC includes VEGF-targeted therapy.<br />
Clinical trial data has shown similar efficacy between sunitinib and pazopabib;<br />
however, a real world experience in Canadian patients is unknown. We aim to<br />
determine outcomes and compare toxicities <strong>of</strong> patients with mRCC treated with<br />
first-line sunitinib or pazopanib.<br />
Methods: Data were retrieved from the prospective Canadian Kidney Cancer<br />
Information System (CKCis) database from January 2011 to November 2015. Patients<br />
with clear cell mRCC treated with first-line sunitinib or pazopanib were included.<br />
Time-to-Treatment Failure (TTF) and overall survival (OS) were calculated using<br />
Kaplan-Meier methods. Cox regression analysis allowed for adjustment <strong>of</strong><br />
International Metastatic RCC Database Consortium (IMDC) criteria and age was<br />
treated as a continuous variable. Fisher’s exact tests were used to compare<br />
dose-modifying toxicities between the two therapies.<br />
Results: Our cohort included 670 patients: 93 treated with pazopanib and 577 with<br />
sunitinib. Median TTF was greater in patients treated with sunitinib versus pazopanib<br />
(6.0 vs 3.7 mos, p = 0.046) and maintained significance when adjusted for IMDC<br />
criteria (hazard ratio [HR] 0.61, 0.41-0.90 95% CI, p = 0.013). Median OS was better in<br />
patients treated with sunitinb (31.9 vs 20.6 mos, p = 0.028) and maintained significance<br />
when adjusted for IMDC criteria (HR 0.60, 0.38-0.95 95% CI, p = 0.028). Common<br />
toxicities requiring dose modification, including fatigue and diarrhea, were similar<br />
between both groups. However, patients treated with sunitinib had a significantly<br />
higher incidence <strong>of</strong> mucositis, hand-foot syndrome, and GERD; patients treated with<br />
pazopanib had a significantly higher incidence <strong>of</strong> liver toxicity and a trend towards<br />
weight loss.<br />
Conclusions: In Canadian patients with clear cell mRCC, survival and treatment<br />
duration appears to favour sunitinib over pazopanib. Plausible explanations include<br />
potential differences in patient selection for pazopanib, the contemporary experience<br />
with individualized dosing on sunitinib, and small sample size. These data on real<br />
world toxicities are informative and may aid physicians and patients in guiding<br />
treatment decisions.<br />
Legal entity responsible for the study: Canadian Kidney Cancer Information System<br />
(CKCis), Kidney Cancer Canada<br />
Funding: Canadian Kidney Cancer Information System (CKCis), Kidney Cancer<br />
Canada<br />
Disclosure: D. Heng: Consulting or Advisory Role - Astellas Pharma; Bristol-Myers<br />
Squibb; Janssen; Novartis; Pfizer L. Wood: Research Funding - Bristol-Myers Squibb<br />
(Inst); GlaxoSmithKline (Inst); Pfizer (Inst); Roche Canada (Inst) Travel,<br />
Accommodations, Expenses - Novartis Other Relationship - Janssen <strong>Oncology</strong>; Pfizer.<br />
H-W. Sim: Travel, Expenses – Roche. A. Kapoor: Honoraria - Amgen;<br />
GlaxoSmithKline; Novartis; Pfizer Speakers’ Bureau - Amgen; GlaxoSmithKline;<br />
Novartis; Pfizer Research Funding – Novartis. S.J. Hotte: Consulting or Advisory Role -<br />
Astellas Pharma; Janssen Pharmaceuticals. M. Vanhuyse: Consulting or Advisory Role<br />
- Astellas Pharma; Bayer Schering Pharma; Pfizer; San<strong>of</strong>i Research Funding - san<strong>of</strong>i<br />
(Inst). M.N. Reaume: Consulting or Advisory Role - GlaxoSmithKline; Janssen;<br />
Novartis; Pfizer; San<strong>of</strong>i Canada S. North: Honoraria - Astellas Pharma; Janssen-Ortho;<br />
Novartis; Pfizer. N. Basappa: Honoraria - Astellas Pharma; Janssen; Novartis; Pfizer;<br />
San<strong>of</strong>i Consulting or Advisory Role - Amgen; Astellas Pharma; Bayer; Janssen;<br />
Novartis; Pfizer; Trelstar Research Funding - Pfizer (Inst) All other authors have<br />
declared no conflicts <strong>of</strong> interest.<br />
820P<br />
Sunitinib (2 weeks on/1 week <strong>of</strong>f schedule) in metastatic renal<br />
cell cancer patients. Progression free and overall survival<br />
F. Gyergyay 1 , B. Budai 2 , K. Nagyivanyi 1 , K. Biró 1 , L. Géczi 1<br />
1 Department <strong>of</strong> Medical <strong>Oncology</strong> Pharmacology C, National Institute <strong>of</strong><br />
<strong>Oncology</strong>, Budapest, Hungary, 2 Department <strong>of</strong> Molecular Immunology and<br />
Toxicology, National Institute <strong>of</strong> <strong>Oncology</strong>, Budapest, Hungary<br />
Background: The recommended schedule <strong>of</strong> sunitinib (SU) for metastatic renal cell<br />
cancer (mRCC) pts is 50 mg/day p.o. for 4 weeks and 2 weeks rest. The half-life <strong>of</strong> SU<br />
and its active metabolite is very slow: 40-60 and 80-110 hours, respectively. Given on<br />
several consecutive days the accumulation is 3-4-fold and 7-10-fold, respectively. The<br />
steady state concentration is achieved on days 7-10 and 10-14. 50 mg daily is enough to<br />
achieve the target concentration <strong>of</strong> ≥ 50 ng/mL. During the 14 days rest the<br />
concentration will decrease to the starting level. The correlation between the SU AUC<br />
and the time to progression is well known.<br />
Methods: Based on the above in case <strong>of</strong> short term adverse events (AEs) we have<br />
applied the 2 weeks on/1 week <strong>of</strong>f schedule instead <strong>of</strong> dose reduction.<br />
Results: Altogether 130 mRCC pts (median age: 61 yrs, M/F: 91/39) were enrolled in<br />
the study. 121 (93%) pts were nephrectomized, 95% (123pts) had RCC histology. 67<br />
(30%); 49 (38%) and 42 (32%) pts belongs to the good, intermediate and poor MSKCC<br />
prognostic groups, respectively. SU was the first-line treatment in 75 cases (58%), 34<br />
(26%) had IFN and 21 (16%) patients had IL-2 treatment before. Patients received<br />
altogether 1617 cycles <strong>of</strong> SU (median 8, range: 1-68); 344 (range1-56) cycles were given<br />
according to 4/2, and 1273 (1-18) according to 2/1 schedule, respectively. Upon<br />
progression on SU the following therapies were given: sorafenib (n = 10), axitinib (7),<br />
pazopanib (1), cabozantinib (1), everolimus (16). The median progression-free survival<br />
(mPFS) was: 13.5 (95%CI 12-16.5) mos and the median overall survival (mOS) was 30<br />
(24-36) mos. If the 2/1 schedule was given in more than 2/3 <strong>of</strong> the total cycles (n = 83)<br />
the mPFS was 18 (13.5-28.5) mos and mOS was 38 (30-44) mos compared to those<br />
who had 2/1 schedule in less than 2/3 <strong>of</strong> the total cycles (n = 47) with mPFS 6 (4.5-9;<br />
P = .0002) mos and mOS 11 (7-21); P = .0001) mos. Short-term AEs were as follows:<br />
fatigue 41%; anorexia 25%; mucositis 35%, diarrhea 37%; hand-foot syndrome 35%;<br />
hypertension: 30%. Although the AEs were quite frequent they lasted shorter and dose<br />
reduction had to be performed only in 12% (n = 16) during the 2/1 schedule.<br />
Conclusions: Changing the SU 4/2 to 2/1 schedule instead <strong>of</strong> reducing the dose, was<br />
safe and resulted in a longer median progression-free and overall survival.<br />
Legal entity responsible for the study: N/A<br />
Funding: None<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
821P<br />
Tolerability associated with sunitinib (SU) 2-week on and<br />
1-week <strong>of</strong>f schedule (2/1 schedule) compared with its<br />
standard schedule in metastatic RCC (mRCC): Meta-analysis<br />
H.J. Kang, S. Lee<br />
Medical Affairs Korea, Pfizer <strong>Oncology</strong>, Seoul, Republic <strong>of</strong> Korea<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Background: SU is the 1st line standard treatment for mRCC and it requires 4-week on<br />
treatment and 2-week <strong>of</strong>f as a standard schedule for mRCC. The treatment is associated<br />
with several adverse events (AEs), such as fatigue, hand-foot syndrome (HFS),<br />
neutropenia, thrombocytopenia etc. Schedule modifications <strong>of</strong> SU including 2/1<br />
schedule are studied and the results provided the total number <strong>of</strong> treatment-related<br />
adverse events decreased in 2/1 schedule without compromising efficacy. However, the<br />
effect <strong>of</strong> 2/1 schedule on individual AEs was not clearly understood.<br />
Methods: This analysis included 1 randomized controlled trial (RCT): Lee et al. 2015<br />
(RESTORE trial, NCT00570882) and 4 non-randomized controlled studies<br />
(non-RCT): Neri et al. 2013, Kondo et al. 2014, Bradarda et al. 2015 and Pan et al.<br />
2015. The primary objective was to estimate risk <strong>of</strong> individual adverse events in SU 2/1<br />
schedule versus standard one and secondary objectives were to evaluate efficacy<br />
vi284 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
outcomes. 7 AEs were evaluated with a standard data <strong>of</strong> RCT compared with the<br />
weighted meta-analysis data (non-RCT meta). Meta-analysis technique, including<br />
fixed effects modelling with Review Manager v5.3 was used to pool study-level data<br />
using the inverse-variance <strong>of</strong> each study as the weight. Data cut-<strong>of</strong>f for this analysis:<br />
Apr 2015<br />
Results: The selected studies included a total <strong>of</strong> 484 patients with mRCC, which<br />
comprised 74 and 410 from RCT and non-RCTs, respectively. The risk ratio <strong>of</strong> fatigue<br />
and neutropenia for 2/1 schedule vs. standard significantly decreased in both RCT and<br />
non-RCT meta (risk ratio (RR) <strong>of</strong> fatigue: 0.69 [95% confidence intervals (CI) 0.51,<br />
0.95] vs. 0.75 [0.63, 0.89]; RR <strong>of</strong> neutropenia 0.60 [0.37, 0.99] vs. 0.58 [0.41, 0.83]).<br />
Other AEs also tended to decrease in both sets except diarrhea and anorexia. Efficacy<br />
outcomes were comparable between 2/1 and standard schedule.<br />
Conclusions: This meta-analysis suggests that 2/1 schedule <strong>of</strong> SU compared to its<br />
standard one decreases risk <strong>of</strong> fatigue and neutropenia and also favoured to control<br />
other AEs without compromising efficacy even with limited sources <strong>of</strong> data. A<br />
patient-level meta-analysis to confirm these findings is warranted.<br />
Legal entity responsible for the study: Pfizer Pharmaceutical Korea Ltd.<br />
Funding: Pfizer Pharmaceutical Korea Ltd.<br />
Disclosure: H.J. Kang, S. Lee: Employee <strong>of</strong> Pfizer Pharmaceutical Korea Ltd.<br />
822P<br />
Outcome <strong>of</strong> patients with multiple glandular metastases from<br />
renal cell carcinoma treated with targeted agents<br />
P. Grassi 1 , L. Doucet 2 , P. Giglione 3 , V. Grünwald 4 , B. Melichar 5 , L. Galli 6 ,U.De<br />
Giorgi 7 , A. Guida 8 , C. Ortega 9 , M. Santoni 10 , A. Bamias 11 , E. Verzoni 1 , L. Derosa 6 ,<br />
H. Studentova 5 , L. Porcu 12 , F. de Braud 1 , C. Porta 13 , B. Escudier 2 , G. Procopio 1<br />
1 Medical <strong>Oncology</strong>, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy,<br />
2 Medical <strong>Oncology</strong>, Institut Gustave Roussy, Villejuif, France, 3 Medical <strong>Oncology</strong>,<br />
Ospedale San Matteo, Pavia, Italy, 4 Clinic for Hematology, Hemostasis, <strong>Oncology</strong>,<br />
and Stem Cell Transplantation, Medical School Hannover, Hannover, Germany,<br />
5 <strong>Oncology</strong>, University Hospital Olomouc, Olomouc, Czech Republic, 6 Translational<br />
Research and New Technologies in Medicine, University <strong>of</strong> Pisa, Pisa, Italy,<br />
7 Medical <strong>Oncology</strong>, Istituto Tumori della Romagna I.R.S.T., Meldola, Italy,<br />
8 Oncologia, Ematologia e Malattie dell’Apparato Respiratorio, Azienda Ospedaliero<br />
- Universitaria Policlinico di Modena, Modena, Italy, 9 Medical <strong>Oncology</strong>, Istituto di<br />
Candiolo-IRCCS-Fondazione Piemontese per la Ricerca sul Cancro-Onlus,<br />
Candiolo, Italy, 10 Medical <strong>Oncology</strong>, AOU Ospedali Riuniti Ancona Università<br />
Politecnica delle Marche, Ancona, Italy, 11 Clinical Therapeutics, Alexandra<br />
Hospital, Athens, Greece, 12 <strong>Oncology</strong>, Istituto Mario Negri, Milan, Italy, 13 Medical<br />
<strong>Oncology</strong>, Ospedale San Matteo, Pavia, Italy<br />
Background: Pancreatic metastases (PM) from renal cell carcinoma (RCC) are rare<br />
and have been associated with long-term survival. The purpose <strong>of</strong> this study was to<br />
evaluate the outcome <strong>of</strong> RCC patients (pts) with multiple glandular metastases (GM),<br />
defined as RCC metastasis to pancreas and at least one other gland including thyroid,<br />
parotid, adrenals, breast, ovaries or testes, treated with targeted therapies (TTs)<br />
Methods: GM pts treated between 1993 and 2014 were retrospectively identified from a<br />
database <strong>of</strong> RCC pts with PM <strong>of</strong> 11 European centers. Survival <strong>of</strong> GM pts was<br />
compared with that reported in either PM pts and in a population <strong>of</strong> 330 mRCC pts<br />
with extraglandular metastases treated with TTs at Istituto Nazionale Tumori between<br />
2006 and 2012 (control group). Overall survival (OS) was defined as the time from<br />
diagnosis <strong>of</strong> metastatic disease to death. Survival functions were estimated using the<br />
Kaplan–Meier method for left-truncated data and statistically compared using the<br />
log-rank test<br />
Results: Among 276 PM pts, 64 pts with at least one additional GM were evaluated.<br />
Median age was 61 yrs, sex ratio M/F was 42/22, 59 pts (92%) received prior<br />
nephrectomy. Fifty-six pts (88%) had at least 2 additional GM, 7 pts (11%) had at least<br />
3 GM and 1 pt had 4 GM. GM were the only metastasic site for 4 pts (6%) while<br />
extraglandular metastases were present in the remaining pts. First-line TTs included<br />
sunitinib, sorafenib, pazopanib, interferon + bevacizumab and temsirolimus, 28 pts<br />
(44%) reveived cytokines and 35 (56%) pts received subsequent lines <strong>of</strong> TTs. After a<br />
median follow-up <strong>of</strong> 58.8 months (IQR 26.4-106.8 mo) median OS was 56.4 months<br />
(95%CI 25.2-85.5 mo) for GM and 80.4 months (95%CI 64.8-99.6 mo) for PM pts.<br />
After a median follow-up <strong>of</strong> 51.6 months (IQR 27.6-63.6 mo) median OS in the control<br />
group was 22.8 months (95%CI 19.2-34.8 mo). OS in the control group was statistically<br />
inferior to either RCC pts with GM (p
abstracts<br />
another anti-VEGF/anti-mTOR combination in this population. Nevertheless, toxicity<br />
was considerable leading to the discontinuation <strong>of</strong> therapy in 1/3 <strong>of</strong> patients.<br />
Clinical trial identification: NCT01264341; EudraCT 2010-020664-38<br />
Legal entity responsible for the study: Hellenic Cooperative <strong>Oncology</strong> Group<br />
Funding: Pfizer<br />
Disclosure: K. Koutsoukos: Honoraria from Novartis. F. Zagouri: Honoraria from<br />
Novartis, Roche. E. Kostouros: Honoraria Janssen. M. Liontos: Janssen Honoraria. M.<br />
Dimopoulos: Honoraria from Celgene, Janssen, Takeda and Amgen. A. Bamias: Pfizer,<br />
Roche, Novartis, Bayer (Honoraria). All other authors have declared no conflicts <strong>of</strong><br />
interest.<br />
825P<br />
Long-term duration <strong>of</strong> axitinib treatment in advanced renal<br />
cell carcinoma<br />
B.I. Rini 1 , V. Grünwald 2 , E. Jonasch 3 , M.N. Fishman 4 , Y. Tomita 5 ,M.<br />
D. Michaelson 6 , J. Tarazi 7 , L. Cisar 8 , A.H. Blair 7 , B. Rosbrook 7 , T. Hutson 9<br />
1 Department <strong>of</strong> Hematology and <strong>Oncology</strong>, Cleveland Clinic Taussig Cancer<br />
Institute, Cleveland, OH, USA, 2 Clinic for Hematology, Hemostasis, <strong>Oncology</strong>, and<br />
Stem Cell Transplantation, Medical School Hannover, Hannover, Germany,<br />
3 Genitourinary <strong>Oncology</strong>, MD Anderson Cancer Center, Houston, TX, USA,<br />
4 Medical <strong>Oncology</strong>, H. Lee M<strong>of</strong>fitt Cancer Center University <strong>of</strong> South Florida,<br />
Tampa, FL, USA, 5 Development <strong>of</strong> Urology, Niigata University Graduate School <strong>of</strong><br />
Medical and Dental Sciences., Niigata, Japan, 6 Medical <strong>Oncology</strong>, Massachusetts<br />
General Hospital, Boston, MA, USA, 7 <strong>Oncology</strong>, Pfizer Inc, San Diego, CA, USA,<br />
8 <strong>Oncology</strong>, Pfizer Inc, New York, NY, USA, 9 GU Medical <strong>Oncology</strong>, Texas<br />
<strong>Oncology</strong> - Baylor Sammons Cancer Center, Dallas, TX, USA<br />
Background: Axitinib is a potent, selective, second-generation inhibitor <strong>of</strong> vascular<br />
endothelial growth factor receptors approved globally in advanced renal cell carcinoma<br />
(aRCC). A subset <strong>of</strong> patients (pts) treated with axitinib achieve long-term disease<br />
control. This analysis characterized the duration <strong>of</strong> treatment (DT) and clinical<br />
outcome <strong>of</strong> pts with aRCC who achieved a DT >18 months on axitinib therapy.<br />
Methods: A retrospective analysis <strong>of</strong> data from 402 treatment-naïve pts with aRCC<br />
treated with axitinib in phase II (NCT00835978) or III (NCT00920816) clinical trials<br />
was conducted. Data on DT, objective response rate (ORR) per RECIST v1 criteria, and<br />
early tumor shrinkage (defined as ≥10% shrinkage at first scan) were compared<br />
between pts who had DT >18 months (longer DT) vs pts who had DT ≤ 18 months<br />
(shorter DT). Analysis was conducted to identify baseline characteristics associated<br />
with longer DT.<br />
Results: Of the 402 pts, 152 (37.8%) had longer DT and 250 (62.2%) had shorter DT.<br />
Overall, 119 (29.6%) had DT > 2 years, 71 (17.7%) had DT > 3 years, and 28 (7.0 %)<br />
had DT > 4 years. The median (range) DT was 34.7 (18.4–60.1) months for longer DT<br />
vs 6.5 (0.1–17.7) months for shorter DT. ORR was 75% for longer DT vs 24.4% for<br />
shorter DT (difference, 50.6%; 95% CI 41.9–59.3%; p 13 g/dL or female: > 11.5), no bone or<br />
liver metastases, and baseline tumor burden below overall median sum <strong>of</strong> longest<br />
diameter (96 mm) were associated with longer DT.<br />
Conclusions: Among aRCC patients treated with first-line axitinib, a substantial<br />
proportion <strong>of</strong> patients remain on therapy for a prolonged period <strong>of</strong> time. Longer<br />
axitinib treatment duration (>18 months) is associated with increased ORR and<br />
increased frequency <strong>of</strong> early tumor shrinkage.<br />
Clinical trial identification: NCT00835978 and NCT00920816<br />
Legal entity responsible for the study: Pfizer, Inc.<br />
Funding: Pfizer, Inc.<br />
Disclosure: B.I. Rini, E. Jonasch: has received research funding and consulting fees<br />
from Pfizer. V. Grünwald: has received consulting fees and honoraria from Pfizer,<br />
Roche, GSK and Novartis, research funding from Wyeth <strong>Oncology</strong>, and a lecture<br />
honorarium from Bayer. M.N. Fishman: reports research funding and honoraria from<br />
Aveo, Altor Biosciences, Bayer, Genentech, GSK, and Pfizer; research funding from<br />
BMS, Eisai and Exelixis; honoraria from Alkermes and Prometheus. Y. Tomita: served<br />
as a consultant for Novartis and Ono, and received speaker honoraria and grants from<br />
Pfizer, Bayer and Novartis, grants from AstraZeneca and Astellas, and speaker<br />
honoraria from GlaxoSmithKline. M.D. Michaelson: received research funding and<br />
consulting fees from Pfizer, Novartis, and Exelixis. J. Tarazi, L. Cisar, A.H. Blair,<br />
B. Rosbrook: is a full-time employee <strong>of</strong> and declares stocks from Pfizer. T. Hutson: has<br />
received consulting fees and research funding from Pfizer, Exelexis, Eisai, Novartis, and<br />
BMS.<br />
826P<br />
Post-randomization analysis <strong>of</strong> OS for patients who did not<br />
switch to second line targeted therapy in the TIVO-1 study<br />
J. Belsey, E. Kemadjou<br />
Biostatistics, JB Medical Ltd, Sudbury, UK<br />
Background: The TIVO-1 study compared tivozanib (tivo) and sorafenib (sora) in<br />
patients with renal cell carcinoma. It demonstrated statistically significant PFS benefit<br />
for tivo over sora, but a trend towards poorer OS with tivo. The authors attributed this<br />
to a crossover effect, since most sora patients crossed over to tivo on progression. We<br />
initially carried out a crossover analysis on the intention to treat dataset to assess<br />
whether this was the case. However, limitations <strong>of</strong> the techniques used meant that any<br />
sequential benefit <strong>of</strong> second line targeted therapy could not be taken into account.<br />
Further analysis was performed to explore OS benefit in post-randomized subgroups <strong>of</strong><br />
patients who did not crossover to targeted therapy.<br />
Methods: Firstly, Cox proportional regression from observed data for patients who did<br />
not crossover was used to derive OS benefit. Propensity score matching was then used<br />
to minimize potential bias induced by post-randomization subgroup analyses.<br />
Matching was used to create a data set closer to one resulting from a perfectly blocked<br />
(and possibly randomized) study. The exact match was used to match each patient in<br />
the tivo group to possible patients in the sora group with exactly the same values on all<br />
covariates. This data set was used to derive a Cox proportional regression <strong>of</strong> tivo vs.<br />
sora. As a sensitivity analysis, propensity score using optimal matching was performed.<br />
Results: Survival curves from the observed data <strong>of</strong> patients who did not crossover (211<br />
tivo patients, 94 sora patients) set yielded a numerically better OS with tivo vs sora<br />
(HR = 0.9405, p = 0.74). The exact matching data set yielded an even more improved<br />
OS benefit with tivo vs sora, although still not statistically significant (HR = 0.84, p=<br />
0.62). The HR for OS using the optimal matching approach was 0.99, p = 0.98.<br />
Conclusions: After matching treatment groups, the HR <strong>of</strong> tivo vs. sora improved,<br />
suggesting that tivo yields a better OS benefit when data is adjusted for potential<br />
confounding variables. Although there is a discrepancy in the HR estimate between the<br />
two propensity score methods used in our analysis (exact and optimal), we suspect that<br />
the result from the exact matching is plausible given the similarity <strong>of</strong> the baseline<br />
covariates between the two groups.<br />
Legal entity responsible for the study: Dr Jonathan Belsey<br />
Funding: AVEO Pharmaceuticals and Eusa Pharma<br />
Disclosure: J. Belsey, E. Kemadjou: JB Medical Limited was funded by Eusa Pharma to<br />
carry out the data analysis and to produce a report <strong>of</strong> their findings.<br />
827P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Clinical outcomes and dosing patterns <strong>of</strong> 2nd targeted therapy<br />
in metastatic renal carcinoma: a retrospective chart review in<br />
the EU<br />
D. Heng 1 , J. Park 2 , J.E. Signorovitch 3 , H. Yang 3 , J. Song 4 , J. Weiss 5 , L. Dezzani 2 ,<br />
T.B. Powles 6<br />
1 Medical <strong>Oncology</strong>, Tom Baker Cancer Centre, Calgary, AB, Canada, 2 Novartis<br />
<strong>Oncology</strong>, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA, 3 Health<br />
Economics and Outcomes Research, Analysis Group, Boston, MA, USA, 4 Health<br />
Economics and Outcomes Research, Analysis Group, Los Angeles, CA, USA,<br />
5 Life Sciences, Navigant, London, UK, 6 Medical <strong>Oncology</strong>, Royal Free Hospital<br />
School <strong>of</strong> Medicine, London, UK<br />
Background: This study evaluates the real-world outcomes and dosing patterns <strong>of</strong><br />
metastatic renal cell carcinoma (mRCC) patients treated with everolimus (EVE),<br />
axitinib (AXI), and sorafenib (SOR), and as 2 nd targeted therapy in Europe. We<br />
expanded the study to include patients from an additional country and updated the<br />
results presented at ASCO GU 2016 (#558).<br />
Methods: Oncologists and urologists in the UK, Germany, France, and the<br />
Netherlands reviewed charts <strong>of</strong> adult mRCC patients who experienced disease<br />
progression on 1 st targeted therapy with sunitinib or pazopanib and initiated 2 nd<br />
targeted therapy with EVE, AXI, or SOR between 10/2012 and 6/2013. Overall survival<br />
(OS) and progression-free survival (PFS) and from the initiation <strong>of</strong> 2 nd targeted<br />
therapies were evaluated using Kaplan-Meier analyses, and compared across cohorts<br />
using multivariable Cox proportional hazards models. Proportions <strong>of</strong> patients with<br />
dose adjustments and dose intensities relative to the recommended doses were also<br />
compared.<br />
Results: A total <strong>of</strong> 309 charts were reviewed, with 115, 96, and 98 mRCC patients<br />
receiving EVE, AXI, and SOR as 2 nd targeted therapy, respectively. Mean age was 60.2<br />
years and 66.7% were male. The majority <strong>of</strong> patients received sunitinib as 1 st targeted<br />
therapy (79.3%) and the rest received pazopanib (20.7%). No statistically significant<br />
differences were observed in OS or PFS after adjusting for patient characteristics [AXI<br />
vs. EVE: hazard ratio (HR) (95% CI): 1.22 (0.77-1.94) and 1.26 (0.81-1.95); SOR vs.<br />
EVE: HR (95% CI): 1.25 (0.75-2.10) and 1.47 (0.95-2.28)]. A significantly greater<br />
proportion <strong>of</strong> AXI-treated patients had a dose increase (AXI: 13.2% vs. EVE: 0.9%,<br />
p < 0.01; vs. SOR: 0.0%, p < 0.01). Relative dose intensity was also significantly higher<br />
in AXI-treated patients (AXI: 1.02 vs. EVE: 0.91, p < 0.01; vs. SOR: 0.88, p < 0.01).<br />
Conclusions: In this retrospective study, no statistically significant differences in OS or<br />
PFS were observed among patients treated with EVE, AXI, and SOR. Rates <strong>of</strong> dose<br />
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<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
escalation and relative dose intensities were significantly higher among AXI-treated<br />
patients compared to EVE- or SOR-treated patients.<br />
Legal entity responsible for the study: Novartis Pharmaceuticals Corporation<br />
Funding: Novartis Pharmaceuticals Corporation<br />
Disclosure: J. Park, L. Dezzani: is an employee <strong>of</strong> Novartis Pharmaceuticals. J.E.<br />
Signorovitch, H. Yang, J. Song: is an employee <strong>of</strong> Analysis Group, which received<br />
research funding from Novartis Pharmaceuticals for this project. J. Weiss: is an<br />
employee <strong>of</strong> Navigant, which received research funding from Novartis Pharmaceuticals<br />
for this project. All other authors have declared no conflicts <strong>of</strong> interest.<br />
828P<br />
Rechallenge with axtinib in metastatic renal cell carcinoma<br />
(mRCC) - Experience from Gustave Roussy<br />
M. Matias, A. Guida, L. Albiges, Y. Loriot, C. Massard, K. Fizazi, B. Escudier<br />
Department <strong>of</strong> Medical <strong>Oncology</strong>, Institut Gustave Roussy, Villejuif, France<br />
Background: Axitinib (Ax) is used in routine practice in mRCC patients (pts) since<br />
2012 in France. Efficacy in real word setting is well known, but no experience with<br />
rechallenge has been reported so far. That is the purpose <strong>of</strong> our study.<br />
Methods: mRCC pts treated at Gustave Roussy with Ax in 2nd or further line between<br />
11/12 and 11/15 were analysed, in order to determine rechallenge (Rech). Rech was<br />
defined as reintroduction <strong>of</strong> Ax after interruption ≥ 2 months (mo), independently<br />
whether they receive or not another systemic therapy (ST) in this period. Collected data<br />
included patient’s characteristics, outcome and toxicities. If pts performed ≥ 1 Rech,<br />
only 1 st Rech was considered.<br />
Results: Among 108 mRCC pts treated with Ax from 11/12 and 11/15, Rech was<br />
performed in 12 pts (2 pts had a second Rech): in 8 cases, without any ST in between,<br />
and in 4 after another ST. Median age at Rech was 63 years (46-74) with 75% men.<br />
IMDC risk group was good, intermediate and poor in 20, 47 and 33% respectively.<br />
Reason for interruption was toxicity (5 pts), intercurrent problem (4 pts), progressive<br />
disease (PD) (2 pts) and drug holiday (1 pt). Median duration <strong>of</strong> interruption was 2.6<br />
mo (2-8.3). Median Ax duration before Rech was 5.7 mo (2.4-13.5) with 33% partial<br />
response (PR) and 10.2 mo PFS. At the time <strong>of</strong> Rech, 9 pts had PD, while 3 had<br />
recovered from toxicity without PD. Median duration <strong>of</strong> Rech was 13.1 mo (1.6-13.6),<br />
with 27% PR and 6.9 mo PFS. Median OS is not yet achieved with a median follow-up<br />
<strong>of</strong> 17.2 mo (6.2-25.7). Grade (G) 2 and G3 adverse effects occurred in 75 and 50% <strong>of</strong><br />
pts, mostly due to hypertension (25, 50 and 8% for G2, G3 and G4 HT). No other G4<br />
toxicities occurred. In general, toxicities were easy manageable with standard measures.<br />
Conclusions: Rechallenge with Ax is feasible and demonstrates efficacy with acceptable<br />
safety pr<strong>of</strong>ile. Such Rech can be a therapeutic option for the management <strong>of</strong> mRCC pts.<br />
Legal entity responsible for the study: Institut Gustave Roussy<br />
Funding: Institut Gustave Roussy<br />
Disclosure: L. Albiges: Consulting/ advisory Board: Novartis, Pfizer, Amgen, Bayer,<br />
BMS, Ceruleon (compensated - myself ). Research funding: Novartis, Pfizer (myself ).<br />
B. Escudier: Honorarium from Pfizer, Novartis, Exelixis, BMS, Roche. All other<br />
authors have declared no conflicts <strong>of</strong> interest.<br />
829P<br />
Denosumab in patients with bone metastases from renal-cell<br />
carcinoma treated with anti-angiogenic therapy:<br />
a retrospective study from the GETUG (Groupe Etude des<br />
Tumeurs Uro Genitales)<br />
A. Guillot 1 , C. Joly 2 , P. Barthelemy 3 , E. Meriaux 4 , S. Negrier 5 , D. Pouessel 6 ,<br />
C. Chevreau 7 , H. Mahammedi 8 , N. Houede 9 , G. Roubaud 10 , G. Gravis 11 ,<br />
S. Tartas 12 , L. Albiges 13 , C. Vassal 1 , M. Oriol 1 , F. Tinquaut 14 , S. Espenel 15 ,<br />
S. Culine 6 , K. Fizazi 13<br />
1 Medical <strong>Oncology</strong>, Institut de Cancérologie de la Loire, Saint Priest En Jarez,<br />
France, 2 Val de Marne, CHU Henri Mondor, Créteil, France, 3 Medical <strong>Oncology</strong>, C.<br />
H.U. Strasbourg-Nouvel Hopital Civil, Strasbourg, France, 4 Medical <strong>Oncology</strong>,<br />
Centre Francois Baclesse, Caen, France, 5 <strong>Oncology</strong>, Centre Léon Bérard, Lyon,<br />
France, 6 Medical <strong>Oncology</strong>, Hôpital St. Louis, Paris, France, 7 <strong>Oncology</strong>, Centre<br />
Claudius-Regaud, Toulouse, France, 8 Medical <strong>Oncology</strong>, Centre Jean Perrin,<br />
Clermont-Ferrand, France, 9 Medical <strong>Oncology</strong>, CHU Nimes, Caremeau, Nimes,<br />
France, 10 Medical <strong>Oncology</strong>, Institute Bergonié, Bordeaux, France, 11 Medical<br />
<strong>Oncology</strong>, Institute Paoli Calmettes, Marseille, France, 12 Medical <strong>Oncology</strong>,<br />
Hospice Civil de Lyon Centre Hospitalier Lyon Sud, Lyon, France, 13 Medicine,<br />
Institut Gustave Roussy, Villejuif, France, 14 Biostatistics, Institut de Cancérologie de<br />
la Loire, Saint Priest En Jarez, France, 15 <strong>Oncology</strong> Radiotherapy, Institut de<br />
Cancérologie de la Loire, Saint Priest En Jarez, France<br />
Background: Metastatic renal-cell carcinoma (mRCC) treatment relies on<br />
anti-angiogenic therapies. Bone metastases occur in nearly 30% <strong>of</strong> mRCC and can<br />
induce symptomatic skeletal-events (SSE) such as pain requiring radiotherapy,<br />
pathologic fractures, and spinal cord compression. SSE can be prevented using<br />
bone-targeted agents, e.g. bisphosphonates or denosumab. Data about denosumab and<br />
anti-angiogenic combination are scarce.<br />
Methods: This multicenter retrospective study led by GETUG included mRCC<br />
patients (pts) who received anti-angiogenic therapies associated with denosumab from<br />
January 2013 to December 2015. The primary endpoint was toxicity related to<br />
denosumab, especially osteonecrosis <strong>of</strong> the jaw (ONJ) and hypocalcaemia.<br />
Results: 37 pts were identified and 36 analyzed. The mean age was 60.9 year-old (range<br />
42-81). Twenty-four pts (68%) had an odontological consultation before denosumab<br />
introduction and 20 pts (58.3%) had a dental panoramic radiography. Five pts (13.9%)<br />
developed an ONJ, among them 3 had a dental extraction while on denosumab<br />
treatment. Only one out <strong>of</strong> the 5 pts has completely recovered from his ONJ. No grade<br />
3-4 hypocalcaemia was reported. SSE occurred in 22 pts (61.1%) including bone pain<br />
requiring radiation, clinical fractures, and spinal compression in 22, 3, and 2 pts,<br />
respectively.<br />
Conclusions: In this real life population, the incidence <strong>of</strong> SSE was very high in mRCC<br />
pts with bone metastases. The combination <strong>of</strong> denosumab with anti-angiogenic drugs<br />
was associated with a high incidence <strong>of</strong> ONJ that may have been favored by dental<br />
extraction while on treatment. The present study underlines the need to improve<br />
strategies to prevent the onset <strong>of</strong> SSE in this population <strong>of</strong> pts.<br />
Legal entity responsible for the study: N/A<br />
Funding: GETUG<br />
Disclosure: A. Guillot: board PFIZER. S. Negrier: honoraria from Pfizer, Novartis et<br />
BMS. D. Pouessel: Board: roche, astellas, Lilly, Novartis, San<strong>of</strong>i Advisory: MSD,<br />
AstraZeneca. Speaker : Astellas, Janssen, Boehringer-ingelheim, San<strong>of</strong>i. C. Chevreau:<br />
board advisory: Pharmamar Inc, Novartis Inc. L. Albiges: consultaant or advisory role:<br />
novartis, pfizer, amgen, BMS, Bayer, San<strong>of</strong>i, Cerulean. K. Fizazi: consultant/advisor for<br />
Amgen Inc.,Novartis,Clovis, Pfizer, CSL, Behring, and Bayer- GlaxoSmithKline, and<br />
Genentech- speakers’ bureau for Genomic Health research funding from Amgen Inc.,<br />
Novartis, Bayer, and Puma. All other authors have declared no conflicts <strong>of</strong> interest.<br />
830P<br />
abstracts<br />
Everolimus-induced pneumonitis as predictor <strong>of</strong> outcome in<br />
patients with metastatic renal cell carcinoma<br />
P. Penttila 1 , J. Rautiola 1 , K. Peltola 1 , M. Laukka 2 , P. Bono 1<br />
1 Comprehensive Cancer Center, HUCH Helsinki University Central Hospital,<br />
Helsinki, Finland, 2 Comprehensive Cancer Center, Department <strong>of</strong> Radiology,<br />
HUCH Helsinki University Central Hospital, Helsinki, Finland<br />
Background: Previous research has shown that certain treatment related adverse events<br />
correlate with clinical efficacy <strong>of</strong> targeted therapies in the treatment <strong>of</strong> patients with<br />
metastatic renal cell carcinoma (mRCC). A well-known class effect <strong>of</strong> mammalian<br />
target <strong>of</strong> rapamycin inhibitors is non-infectious pneumonitis. We evaluated the<br />
possible association <strong>of</strong> pneumonitis with outcomes in mRCC patients treated with<br />
everolimus.<br />
Methods: 303 consecutive patients with mRCC were treated in a single university<br />
hospital cancer center. We identified 85 patients (28.1%), who received sequential<br />
everolimus after first-line targeted therapy. Treatment-induced adverse events<br />
including pneumonitis were assessed and analyzed for the possible association with<br />
outcome using the Kaplan-Meyer method and Cox regression adjusted for known risk<br />
factors.<br />
Results: 33 patients (38.8%) developed clinical symptoms and radiological findings <strong>of</strong><br />
pneumonitis during everolimus treatment. In univariate analysis patients with<br />
pneumonitis had both a longer overall survival (OS) (19.67 vs. 8.50 months; P < 0.001)<br />
and progression-free survival (PFS) (4.17 vs. 3.27 months; P < 0.05) as compared to<br />
patients with no pneumonitis. Additionally, the over all best response was partial<br />
response or stable disease in 50.0% <strong>of</strong> patients with pneumonitis as compared to 26.0%<br />
<strong>of</strong> the patients with no pneumonitis (P < 0.05). In multivariate analysis adjusted for<br />
age, gender and Memorial Sloan-Kettering Cancer Center (MSKCC) risk score for<br />
previously treated patients, pneumonitis was significantly associated with a longer OS<br />
(adjusted HR, 0.45; 95%CI 0.26-0.77; P < 0.01). A similar pattern was seen for PFS<br />
although the result was not statistically significant (adjusted HR, 0.63; 95%CI<br />
0.38-1.03; P = 0.06). Pneumonitis remained significantly associated with longer OS<br />
(adjusted HR, 0.47; 95%CI 0.27-0.81; P < 0.01) in a multivariable model with<br />
pneumonitis as a time-dependent covariate.<br />
Conclusions: Our results suggest that pneumonitis may be associated with everolimus<br />
treatment efficacy. Further validation studies are warranted to confirm our findings.<br />
Legal entity responsible for the study: Comprehensive Cancer Center, Helsinki<br />
University Hospital<br />
Funding: Helsinki University Hospital and grant from Novartis<br />
Disclosure: P. Penttila: P. Penttila has received honoraria from Novartis. K. Peltola:<br />
K. Peltola has received honoraria from Novartis, BMS, Pfizer, Amgen, Astellas, San<strong>of</strong>i,<br />
Merck, Eli Lilly. P. Bono: P. Bono has received honoraria from Pfizer, Novartis, Orion<br />
Pharma, BMS and MSD. PB has received research funding from Novartis. All other<br />
authors have declared no conflicts <strong>of</strong> interest.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw373 | vi287
abstracts<br />
831P<br />
Outcome <strong>of</strong> patients with metastatic chromophobe renal cell<br />
carcinoma treated with sunitinib<br />
V. Neiman 1 , D. Keizman 2 , D. Sarid 3 , J-L. Lee 4 , A. Sella 5 , M. Gottfried 2 ,<br />
H. Hammers 6 , M. Eisenberger 6 , M. Carducci 6 , V. Sinibaldi 6 , E. Rosenbaum 1 ,<br />
A. Peer 7 , A. Neumann 7 , W. Mermershtain 8 , K.R. Rouvinov 8 , R. Berger 9 , I. Yildiz 10<br />
1 Clinical <strong>Oncology</strong>, Rabin Medical Center David<strong>of</strong>f Cancer Centre, Beilinson<br />
Campus, Petach Tikva, Israel, 2 <strong>Oncology</strong>, Meir Medical Center, Kfar Saba, Israel,<br />
3 <strong>Oncology</strong>, Tel Aviv Sourasky Medical Center-(Ichilov), Tel Aviv, Israel, 4 <strong>Oncology</strong>,<br />
Asan Medical Center, University <strong>of</strong> Ulsan College <strong>of</strong> Medicine, Seoul, Republic <strong>of</strong><br />
Korea, 5 <strong>Oncology</strong>, Asaf Har<strong>of</strong>eh Medical Center, Zerifin, Israel, 6 <strong>Oncology</strong>,<br />
Johns Hopkins Hospital, Baltimore, MD, USA, 7 <strong>Oncology</strong>, Rambam Health Care<br />
Center, Haifa, Israel, 8 <strong>Oncology</strong>, Soroka University Medical Center, Beer Sheva,<br />
Israel, 9 <strong>Oncology</strong>, Chaim Sheba Medical Center, Ramat Gan, Israel,<br />
10 <strong>Oncology</strong>, Ataturk Training and Research Hospital,Izmir Katip Celebi University,<br />
Izmir, Turkey<br />
Background: Sunitinib is a standard treatment for metastatic clear cell renal cell<br />
carcinoma (mccRCC). Data on its activity in the rare variant <strong>of</strong> metastatic<br />
chromophobe RCC (mchRCC), is limited. We aimed to analyze the activity <strong>of</strong><br />
sunitinib in a relatively large and homogenous international cohort <strong>of</strong> mchRCC<br />
patients, in terms <strong>of</strong> outcome and comparison to mccRCC.<br />
Methods: Records from mchRCC patients treated with first line sunitinb in 10 centers<br />
across 4 countries were retrospectively reviewed. Univariate and multivariate analyses<br />
<strong>of</strong> association between clinicopathologic factors and outcome were performed.<br />
Subsequently, mchRCC pts were individually matched to mccRCC pts. We compared<br />
the clinical benefit rate (CBR), progression free survival (PFS), and overall survival<br />
(OS) between the groups.<br />
Results: Between 2004-2014, 36 patients (median age 64, 47% male) with mchRCC<br />
were treated with first line sunitinib. 78% achieved a clinical benefit (partial<br />
response + stable disease). Median progression free survival (PFS) and overall survival<br />
(OS) were 10 and 26 months, respectively. Factors associated with PFS were the HENG<br />
risk (HR 3.3, p = 0.03) and pre-treatment neutrophil to lymphocyte ratio (NLR) >3<br />
(HR 0.63, p = 0.02). Factors associated with OS were the HENG risk (HR 4.1, p = 0.04),<br />
liver metastases (HR 3.8, p = 0.03), and pre-treatment NLR < 3 (HR 0.55, p = 0.03).<br />
Treatment outcome was not significantly different between mchRCC patients and<br />
individually matched mccRCC patients. In mccRCC patients (p value versus<br />
mchRCC), 72% achieved a clinical benefit (p = 0.4), and median PFS and OS were 9<br />
(p = 0.6) and 25 (p = 0.7) months, respectively.<br />
Conclusions: In metastatic chromophobe renal cell carcinoma, sunitinib therapy may<br />
be associated with similar outcome and toxicities as in metastatic clear cell renal cell<br />
carcinoma. The HENG risk and pre-treatment NLR may be associated with PFS and<br />
OS.<br />
Legal entity responsible for the study: N/A<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
832P<br />
First-line PAzopanib in NOn-clear cell Renal cArcinoMA:<br />
the Italian retrospective multicenter PANORAMA study<br />
M. Bersanelli 1 , F. Maines 2 , G. Facchini 3 , F. Gelsomino 4 , F. Zustovich 5 , M. Santoni 6 ,<br />
E. Verri 7 , U. De Giorgi 8 , C. Masini 9 , F. Morelli 10 , M.G. Vitale 11 ,T.Sava 12 , G. Prati 13 ,<br />
C. Librici 14 , A.P. Fraccon 15 , G. Fornarini 16 , M. Maruzzo 17 , F. Leonardi 1 ,O.Caffo 2 ,<br />
S. Buti 1<br />
1 Medical <strong>Oncology</strong>, University Hospital <strong>of</strong> Parma, Parma, Italy, 2 Medical <strong>Oncology</strong>,<br />
Ospedale Santa Chiara, Trento, Italy, 3 Medical <strong>Oncology</strong>, Istituto Nazionale Tumori<br />
– I.R.C.C.S - Fondazione Pascale, Naples, Italy, 4 Medical <strong>Oncology</strong>, Policlinico<br />
S. Orsola-Malpighi, Bologna, Italy, 5 Medical <strong>Oncology</strong>, Ospedale di Belluno,<br />
Belluno, Italy, 6 Medical <strong>Oncology</strong>, AOU Ospedali Riuniti Ancona Università<br />
Politecnica delle Marche, Ancona, Italy, 7 Medical <strong>Oncology</strong>, Istituto Europeo di<br />
Oncologia, Milan, Italy, 8 Medical <strong>Oncology</strong>, Istituto Tumori della Romagna I.R.S.T.,<br />
Meldola, Italy, 9 Medical <strong>Oncology</strong>, Azienda Ospedaliera Arcispedale Santa Maria<br />
Nuova - IRCCS, Reggio Emilia, Italy, 10 Medical <strong>Oncology</strong>, Ospedale Casa Sollievo<br />
della S<strong>of</strong>ferenza, San Giovanni Rotondo, Italy, 11 Medical <strong>Oncology</strong>, Azienda<br />
Ospedaliera di Rilievo Nazionale "Antonio Cardarelli"-AORN A. Cardarelli, Naples,<br />
Italy, 12 Medical <strong>Oncology</strong>, Azienda Ospedaliera Universitaria Integrata<br />
Verona-"Borgo Trento", Verona, Italy, 13 Medical <strong>Oncology</strong>, Hospital <strong>of</strong> Guastalla,<br />
Guastalla, Italy, 14 Medical <strong>Oncology</strong>, Ospedali Riuniti Villa S<strong>of</strong>ia – Cervello Hospital,<br />
Palermo, Italy, 15 <strong>Oncology</strong>, Casa di Cura Dott. Pederzoli, Peschiera Del Garda,<br />
Italy, 16 Medical <strong>Oncology</strong>, IRCCS AOU San Martino - IST-Istituto Nazionale per la<br />
Ricerca sul Cancro, Genoa, Italy, 17 Medical <strong>Oncology</strong> 1, Istituto Oncologico<br />
Veneto IRCCS, Padua, Italy<br />
Background: Pazopanib is a standard first line treatment for metastatic clear cell renal<br />
cell carcinoma (RCC). Very few data on its activity in non-clear cell RCC (nccRCC) are<br />
currently available in the literature. We retrospectively analyzed efficacy and toxicity <strong>of</strong><br />
Pazopanib in an Italian multicenter cohort <strong>of</strong> nccRCC patients.<br />
Methods: Records from nccRCC patients treated with first line Pazopanib were<br />
reviewed and collected. Response rate (RR), progression free survival (PFS), and overall<br />
survival (OS) were evaluated in this cohort. Univariate analysis were conducted to<br />
correlate clinicopathological factors with outcome. Descriptive analysis <strong>of</strong> patients and<br />
diseases characteristics were also performed.<br />
Results: Between 2010 and 2015, 37 patients with nccRCC were treated with Pazopanib<br />
as first line therapy at 17 Italian centers. 24% had chromophobe histology, 51%<br />
papillary, 22% unclassified and 3% had Xp11 translocation. Motzer and Heng risk were<br />
good in 22% and 24%, intermediate in 68% and 49% and poor in 10% and 22% <strong>of</strong><br />
patients respectively. 76% had nephrectomy. 57% had ECOG performance status<br />
(PS) = 0, 27% PS = 1 and 16% PS = 2-3. 22% had a basal neutrophil to lymphocyte ratio<br />
(NLR) ≥ 3. Dose reductions/interruptions <strong>of</strong> Pazopanib for toxicity were required in<br />
46% <strong>of</strong> cases; G3-4 toxicity occurred in 32% <strong>of</strong> patients, G1-2 in 89%. 81% achieved<br />
clinical benefit (partial response or stable disease), while 16% had disease progression<br />
as best response. Median PFS (38% censored) and OS (46% censored) were 15.9 [95%<br />
CI 5.9–25.8] and 17.3 [95%CI 11.5-23.0] months, respectively. At the univariate<br />
analysis, factors associated with PFS were nephrectomy (p = 0.02), Motzer score<br />
(p < 0.0001), NLR (p = 0.009) and PS (p = 0.001). Factors associated with OS at the<br />
univariate analysis were Motzer score (p < 0.0001), Heng score (p = 0.003), PS<br />
(p < 0.0001), nephrectomy (p = 0.002), histology (p = 0.035), dose reductions/<br />
interruptions (p = 0.039), best response to treatment (p < 0.0001) and NLR<br />
(p = 0.008).<br />
Conclusions: In nccRCC patients, treatment with Pazopanib demonstrated to be<br />
effective and feasible, despite dose reductions <strong>of</strong>ten required for toxicity in this<br />
population.<br />
Legal entity responsible for the study: Santa Chiara Hospital, Trento.<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
833P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Retrospective analysis <strong>of</strong> metastatic non-clear cell renal<br />
carcinoma (NCCRC): the Spanish Grupo Centro Experience<br />
L. Rodriguez Lajusticia 1 , A. Martín 2 , A. Pinto Marin 3 , C. Aguado 4 ,T.<br />
Alonso Gordoa 5 , A. Herrero 6 , C. Maximiano 7 , M. Garrido Arevalo 8 , I. Gallegos 9 ,<br />
L. Villalobos 10 , J. Cassinello 11 , I. Garcia 12 , J. Espinosa Arranz 13 ,<br />
J. Garcia-Donas 14 , J.J. Tafalla 15 , G. Torres 6 , J. Puente 4 , E. Grande Pulido 5<br />
1 Medical <strong>Oncology</strong>, Hospital Universitario de Fuenlabrada, Fuenlabrada, Spain,<br />
2 Medical <strong>Oncology</strong>, Hospital Infanta Leonor, Vallecas, Spain, 3 Medical <strong>Oncology</strong>,<br />
Hospital Universitario La Paz, Madrid, Spain, 4 Medical <strong>Oncology</strong>, Hospital Clinico<br />
Universitario San Carlos, Madrid, Spain, 5 Medical <strong>Oncology</strong>, Hospital Universitario<br />
Ramon y Cajal, Madrid, Spain, 6 Medical <strong>Oncology</strong>, Hospital General Universitario<br />
Gregorio Marañon, Madrid, Spain, 7 Medical <strong>Oncology</strong>, Hospital Universitario<br />
Puerta de Hierro, Madrid, Spain, 8 Medical <strong>Oncology</strong>, Hospital Universitario Severo<br />
Ochoa, Leganés, Spain, 9 Medical <strong>Oncology</strong>, Hospital General Segovia, Segovia,<br />
Spain, 10 Medical <strong>Oncology</strong>, Hospital Universitario Príncipe de Asturias, Alcalá De<br />
Henares, Spain, 11 Medical <strong>Oncology</strong>, Hospital Universitario de Guadalajara,<br />
Guadalajara, Spain, 12 Medical <strong>Oncology</strong>, Hospital Virgen de la Salud, Toledo,<br />
Spain, 13 Medical <strong>Oncology</strong>, Hospital General Ciudad Real, Ciudad Real, Spain,<br />
14 Medical <strong>Oncology</strong>, CIOCC-Fundacion Hospital de Madrid, Madrid, Spain,<br />
15 Medical <strong>Oncology</strong>, Hospital La Luz, Madrid, Spain<br />
Background: Non-clear cell renal carcinoma (NCCRC) represents a group <strong>of</strong> multiple<br />
histologic subtypes, with different clinical outcomes and uncertain optimal treatment.<br />
Due to the unfrequency <strong>of</strong> these histologies, they are usually grouped as one and<br />
treated the same way as clear cell renal carcinoma.<br />
Methods: We performed a retrospective, multicenter study including patients (pts)<br />
with metastatic NCCRC diagnosed between 1995 and 2015. Data were collected from<br />
medical records at 14 hospitals. We evaluated the baseline clinical features, histologic<br />
subtypes, therapeutic management and survival status.<br />
Results: We collected a total <strong>of</strong> 173 patients, with a median age at diagnosis <strong>of</strong> 65 years<br />
[24-90], 67.1% men, and 85.5% had undergone nephrectomy. Histologic subtypes were<br />
55.5% papillary carcinoma, 13.9% chromophobe, 0,6% oncocytoma, 23.1%<br />
sarcomatoid and 6.9% unclassified tumours. Assignment according to MSKCC risk<br />
groups were: 21.4% favourable, 53.8% intermediate, 20.2% poor, 4.6% unknown. 62.4%<br />
pts recieved tirosyne kinase inhibitors (TKI) as first line (82.4% sunitinib, 9.3%<br />
pazopanib and 8.3% sorafenib), 11% mammalian target <strong>of</strong> rapamycin inhibitors<br />
(mTORI: 89.5% temsirolimus), 6.9% chemotherapy, 5.8% inmunotherapy and 4% local<br />
treatment. Only 8.1% pts did not recived any kind <strong>of</strong> treatment. Response rate (RR) in<br />
evaluable pts (142) were: complete 5.6% pts, partial 17.6%, stable disease 40.8% and<br />
progression in 35.9%. 59.5% pts had discontinued treatment due to progression and<br />
13.3% due to toxicity. 90 pts recieved a second line <strong>of</strong> treatment, most <strong>of</strong> them TKI<br />
(50%). 30% pts were treated with everolimus. At the time <strong>of</strong> data cut-<strong>of</strong>f (April 1,<br />
2016), 125 pts had died, with a median overall survival (OS) <strong>of</strong> 11 months (m) [1-73].<br />
OS according to histology: papillary 18 m, chromophobe 16 m, sarcomatoid 5m and<br />
unclassified 5m. Favourable prognosis NCCRC pts lived longer than intermediate or<br />
poor prognosis ones (32 m vs 11 m vs 5.5m).<br />
Conclusions: Clinical outcome reported in this study shows lower RR and OS than<br />
published by other authors, probably due to the high percentage <strong>of</strong> sarcomatoid and<br />
poor prognosis tumours in this population. In view <strong>of</strong> these results, further research is<br />
needed in this area<br />
Legal entity responsible for the study: Spanish Grupo Centro<br />
vi288 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Funding: Spanish Grupo Centro<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
834P<br />
Results from 4 different risk-adapted surveillance strategies<br />
in a single Hospital for patients for stage I seminomatous germ<br />
cell tumours<br />
P. Maroto 1 , C. Martin 1 , G. Sancho 2 , J. Palou 3<br />
1 Medical <strong>Oncology</strong>, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain,<br />
2 Radiation <strong>Oncology</strong>, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain,<br />
3 Urology, Fundació Puigvert, Barcelona, Spain<br />
Background: Purpose: To describe treatment results in 4 cohorts <strong>of</strong> patients with stage<br />
I seminomatous germ cell cancer (SGCC) treated within 4 different risk-adapted<br />
surveillance strategies according to national guidelines.<br />
Methods: From January 1, 1994, to December 31, 2015, 186 patients with stage I<br />
SGCC, were included in 4 different cohorts and treated within different risk-adapted<br />
surveillance strategies. Group 1: 994 to 1999, patients with T > T1 received two cycles<br />
<strong>of</strong> carboplatin (CBDCAx2), Group 2:1999 to 2003, patients received CBDCAx2 if<br />
either tumour size >4 cm or rete testis invasion, Group 3: 004 to 2009, patients<br />
received CBDCAx2 if both tumour size >4cm and rete testis invasion were present, and<br />
Group 4: patients received CBDCAx1 cycle if either rete testis invasion or size >4 cm<br />
were present, two patients that received radiotherapy were included in Group<br />
4. Follow-up consisted <strong>of</strong> serum tumour markers and physical exam every 3 months<br />
plus abdominal CT scans every 6 m the first two years, and at longer intervals<br />
thereafter.<br />
Results: Disease-specific survival: 100%. Three patients died, one because car accident,<br />
two patients due to metastatic colorectal and pancreatic cancer. Table summarize<br />
results by cohort: N CBDCA (relapse) Follow-up PFS (5yr) Platinum/ patient Group 1<br />
38 8 (0) 30 (3) 92% 25, 0.67 Group 2 49 23 (1) 26 (3) 92% 58, 1.18 Group 3 52 18 (0) 34<br />
(4) 91% 48, 0.92 Group 4 47 24 (3) 23 (3) 75% 42, 0.89 Relapse: All patients had good<br />
prognosis disease. Only one patient who progressed after 2 cycles <strong>of</strong> Carboplatin need<br />
TIP chemotherapy and finally High Dose Chemotherapy and he is currently free <strong>of</strong><br />
disease 8 years later. A trend for a later relapse was observed in patients relapsing after<br />
being treated with carboplatin.<br />
Conclusions: A risk adapted surveillance programme provided an overall specific<br />
survival <strong>of</strong> 100%. Relapse rate in patients receiving Carboplatin x 1 cycle seems to be<br />
higher than for patients included in protocols receiving Carboplatin x 2. Then number<br />
<strong>of</strong> total (CBDCA + CDDP) was higher for the Groups with CBDCAx2. These results<br />
suggest that vascular invasion was a better predictor for selecting patients for adjuvant<br />
chemotherapy, although the number <strong>of</strong> patient per cohort is low to provide final<br />
conclusions.<br />
Legal entity responsible for the study: <strong>Oncology</strong> Service, Germ Cell Cancer Unit,<br />
Hospital Sant Pau<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
835P<br />
Carboplatin dose based on actual renal function vs. dose<br />
capping: no excess <strong>of</strong> hematotoxicity in treatment <strong>of</strong><br />
seminoma stage I<br />
M. Fehr 1 , H. Reichegger 1 , A. Fischer Maranta 2 , S. Gillessen 1 , R. Cathomas 2<br />
1 Medical <strong>Oncology</strong>/Haematology, Kantonsspital St. Gallen, St. Gallen,<br />
Switzerland, 2 Medical <strong>Oncology</strong>, Kantonsspital Graubünden, Chur, Switzerland<br />
Background: Single-dose Carboplatin (C) AUC7 is an adjuvant treatment option in<br />
Seminoma stage I. Many <strong>of</strong> these patients have very good renal function and hence<br />
high absolute doses <strong>of</strong> C are frequently administered. Some experts and clinical<br />
guidelines recommend capping <strong>of</strong> C dose at Creatinine-Clearance (Crea-Cl) <strong>of</strong> 125 ml/<br />
min because <strong>of</strong> concerns <strong>of</strong> excessive toxicity. The rationale for these concerns has not<br />
been explored in patients with Seminoma stage I so far.<br />
Methods: Analysis <strong>of</strong> a cohort <strong>of</strong> patients with stage I Seminoma treated with C AUC 7<br />
in 2 Swiss centres 2005 – 2015. Main inclusion criteria: Normal blood count at<br />
treatment, minimum <strong>of</strong> 2 measurements during first 8 weeks <strong>of</strong> follow-up. Comparison<br />
<strong>of</strong> incidence and grade (CTCAE v4.0) <strong>of</strong> hematological adverse events (AEs) in patients<br />
with Crea-Cl < vs. > 125 ml/min without dose capping.<br />
Results: 74 patients with 229 documented measurements were identified. Median age<br />
41 years (Range 22 – 71), Crea-Cl (Cockr<strong>of</strong>t-Gault) 126 ml/min (70 - 206), C dose<br />
1013 mg (700 - 1477). 12 patients with Crea-Cl >125 ml/min and capped C dose<br />
(resulting in AUC vs. < 125 ml/min<br />
were noted. In each group one clinical relevant AE with subsequent interventions<br />
occurred: Febrile neutropenia in 1 patient with with Crea-Cl 125 ml/min received one platelet transfusion (2.8% vs. 3.7%, P= .85).<br />
For further details see table.<br />
Table: 835P<br />
Crea-Cl 125 ml/min<br />
& no dose capping<br />
(N = 27)<br />
Decreased Haemoglobin 71% (25) 56% (15) .28<br />
Decreased Platelet Count 57% (20) 78% (21) .11<br />
Decreased Platelet Count >G2 11% (4) 29% (6) .31<br />
Decreased White Cell Count 37% (13) 48% (13) .44<br />
Decreased Neutrophil Count 46% (16) 44% (12) .92<br />
Decreased Neutrophil Count >G2 20% (7) 19% (5) .88<br />
AEs with clinical interventions 2.8% (1<br />
hospitalisation<br />
with febrile<br />
neutropenia<br />
G3)<br />
3.7% (1 platelet<br />
transfusion in<br />
thrombocytopenia<br />
G4)<br />
Conclusions: Concerns <strong>of</strong> excessive toxicity in patients with Seminoma stage I and<br />
Crea-Cl >125 ml/min treated with adjuvant C AUC7 are not supported by our data.<br />
Most AEs were grade 1 (>80%). There was also no statistically significant excess <strong>of</strong><br />
AEs > grade 2. Therefore capping <strong>of</strong> C dose is not justified in this Situation.<br />
Clinical trial identification: BASEC Nr. 2016-00472<br />
Legal entity responsible for the study: Kantonsspital St. Gallen, Switzerland, Dr<br />
Martin Fehr<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
836P<br />
abstracts<br />
Outcome <strong>of</strong> patients with metastatic germ cell cancer treated<br />
between 2000 and 2013 at two centers in Munich<br />
A. Gerl 1 , J. Debole 1 , M. Hentrich 2<br />
1 Hematology and <strong>Oncology</strong>, Private Practice <strong>of</strong> <strong>Oncology</strong>, Munich, Germany,<br />
2 Hematology and <strong>Oncology</strong>, Rotkreuzklinikum München, Munich, Germany<br />
Background: Treatment <strong>of</strong> metastatic germ cell cancer (GCC) is based on the<br />
International Germ Cell Cancer Collaborative Group (IGCCCG) prognostic<br />
classification published in 1997. 5-year survival rates were reported to be 91%, 79%,<br />
and 48% for patients with good, intermediate and poor prognosis, respectively. The<br />
question arises whether treatment results improved over time due to cumulative<br />
experience and whether there is still a need for dose intensification in intermediate and<br />
poor risk patients.<br />
Methods: The records <strong>of</strong> all patients (pts) with metastatic GCC treated at two<br />
institutions in Munich between 2000 and 2013 were reviewed with regard to time <strong>of</strong><br />
initial diagnosis, histopathology, stage, tumor marker levels, metastatic spread, type<br />
and duration <strong>of</strong> chemotherapy (CT), and outcome. Progression-free survival (PFS) and<br />
overall survival (OS) were estimated with the Kaplan-Meyer method. The Log-rank test<br />
was used to compare survival distributions <strong>of</strong> different groups.<br />
Results: Of 255 patients identified, 30 pts were excluded due to incomplete data. 189 <strong>of</strong><br />
225 pts (84%) included into the study were treated as outpatients and 36 (16%) as<br />
inpatients. The median age was 35 years, seminoma and nonseminoma were diagnosed<br />
in 72 (32%) and 153 (68%) pts, and 204 pts (91%) had a primary gonadal GCC. 175<br />
(78%), 30 (13%) and 20 pts (9%) had good, intermediate and poor prognosis according<br />
to the IGCCCG classification system. The vast majority <strong>of</strong> pts received 3 to 4 cycles <strong>of</strong><br />
platinum-based CT while primary high-dose CT was applied to 3 pts in the poor<br />
prognosis group. The 2-year-PFS <strong>of</strong> pts with good, intermediate and poor prognosis<br />
was 91%, 83% and 37%, and the 5-year-OS was 98%, 96%, and 66%, respectively. There<br />
was no significant difference in the 5-year-OS between pts in the good and<br />
intermediate prognosis group.<br />
Conclusions: Compared to data from the 1997 IGCCCG classification system, the<br />
outcome <strong>of</strong> pts with metastastic GCC has considerably improved. Notably, no<br />
significant differences in the 5-year-OS were observed between pts with good and<br />
intermediate prognosis. While the outcome <strong>of</strong> pts with intermediate-prognosis is<br />
excellent, treatment results in the poor-prognosis group are still unsatisfactory.<br />
Legal entity responsible for the study: N/A<br />
Funding: Ludwig-Maximilians-University Munich<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
P<br />
.85<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw373 | vi289
abstracts<br />
837P<br />
Long-term changes in testosterone levels in testicular cancer<br />
survivors<br />
M. Bandak 1 , N. Jørgensen 2 , A. Juul 2 , J. Lauritsen 1 , M.S. Mortensen 1 , M.G.<br />
G. Kier 1 , G. Daugaard 1<br />
1 Department <strong>of</strong> <strong>Oncology</strong>, Rigshospitalet, Copenhagen University Hospital,<br />
Copenhagen, Denmark, 2 Department <strong>of</strong> Growth and Reproduction,<br />
Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark<br />
Background: Few studies have used serial measurements <strong>of</strong> total testosterone (TT) to<br />
evaluate long-term changes after testicular cancer treatment. We aimed to evaluate<br />
changes in TT after completion <strong>of</strong> a five or ten year follow-up programme.<br />
Methods: From a long-term follow-up study <strong>of</strong> testicular cancer survivors<br />
(NCT02240966), 78 patients were included. Inclusion criteria were: Available<br />
post-treatment measurements <strong>of</strong> TT and luteinizing hormone (LH) within the<br />
follow-up programme (visit 1) and measurement <strong>of</strong> TT and LH after completion <strong>of</strong><br />
follow-up (visit 2). Androgen substitution and age > 65 years at visit 2 were exclusion<br />
criteria. Patients were divided according to treatment: unilateral<br />
orchiectomy + radiotherapy (14-20 Gy) due to contralateral germ cell neoplasia in situ<br />
(GCNIS) (n = 18), standard dose bleomycin, etoposide and cisplatin (BEP) (n = 19),<br />
retroperitoneal radiotherapy (n = 16) (RT), unilateral orchiectomy alone (Stage I)<br />
(n = 25). LH, TT and sexual hormone-binding globuline (SHBG) at visit 1 and visit 2<br />
were compared within each treatment group with paired t-test.<br />
Results: Time from treatment, age and reproductive hormones at visit 1 and visit 2 are<br />
presented in the table (median, interquartile range). TT declined in all treatment<br />
groups. In the GCNIS-group, 9/18 patients had TT levels < 10 nmol/l at visit 2. LH<br />
increased in the GCNIS-group while there were no significant changes in the other<br />
groups. There were no changes in SHBG between visit 1 and visit 2.<br />
Years from<br />
treatment Visit 1<br />
Visit 2<br />
Age (years) Visit 1<br />
Visit 2<br />
Total testosterone<br />
(nmol/l) Visit 1<br />
Visit 2 P-value<br />
LH (IU/l) Visit 1<br />
Visit 2 P-value<br />
SHBG (nmol/l)<br />
Visit 1 Visit 2<br />
P-value<br />
Table: 837P<br />
Stage I (n = 25) RT (n = 16) BEP (n = 19) GCNIS (n = 18)<br />
0.8 (0.2-3.0) 8.9<br />
(7.2-13.9)<br />
34.1 (28.7-41.0)<br />
43.2<br />
(38.1-49.6)<br />
15.2 (12.2-17.6)<br />
12.4<br />
(10.1-15.0)<br />
0.002<br />
6.6 (4.1-8.5) 7.0<br />
(4.2-9.4) 0.5<br />
37 (29-47) 30<br />
(26-39) 0.2<br />
0.6 (0.2-1.3)<br />
13.7<br />
(9.4-17.2)<br />
38.8 (31.6-40.7)<br />
49.3<br />
(44.5-54.3)<br />
14.7 (11.0-18.8)<br />
10.8<br />
(9.2-14.1)<br />
0.03<br />
9.9 (6.4-12.6)<br />
7.0<br />
(5.0-10.2)<br />
0.2<br />
35 (26-42) 35<br />
(23-42) 0.7<br />
3.3 (1.5-4.0)<br />
16.7<br />
(10.7-19.6)<br />
34.5 (28.6-39.4)<br />
47.2<br />
(41.7-50.8)<br />
13.0 (11.7-15.1)<br />
10.9<br />
(9.6-14.8)<br />
0.02<br />
6.26 (3.6-9.2)<br />
6.07<br />
(4.0-9.0) 0.5<br />
32 (24-38) 32<br />
(25-49) 0.2<br />
6.6 (2.4-8.9)<br />
16.3<br />
(13.1-22.4)<br />
34.0 (27.3-35.8)<br />
44.5<br />
(38.8-51.9)<br />
12.4 (9.3-14.2)<br />
9.5<br />
(7.2-11.6)<br />
0.009<br />
9.5 (8.3-13.3)<br />
12.9<br />
(9.1-14.0)<br />
0.05<br />
28 (24-44) 29<br />
(24-46) 0.7<br />
Conclusions: Total testosterone declines after the completion <strong>of</strong> follow-up,<br />
irrespectively <strong>of</strong> treatment. TT is lowest in patients treated with radiotherapy due to<br />
contralateral GCNIS. Evaluation <strong>of</strong> testosterone levels should be continued beyond ten<br />
years in patients with GCNIS.<br />
Clinical trial identification: NCT02240966<br />
Legal entity responsible for the study: The Local Ethical Committee <strong>of</strong> the Capital<br />
Region <strong>of</strong> Denmark<br />
Funding: Copenhagen University Hospital Rigshospitalet<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
838P<br />
Prognostic factors and survival in germ cell cancer (GCC)<br />
patients treated with bleomycin, etoposide, and cisplatin<br />
(BEP): A population-based study<br />
M.G.G. Kier 1 , J. Lauritsen 1 , M.S. Mortensen 1 , M. Bandak 1 , K.K. Andersen 2 ,M.<br />
K. Hansen 2 , M. Agerbaek 3 , N.V. Holm 4 , S.O. Dalton 5 , C. Johansen 5 ,<br />
G. Daugaard 1<br />
1 Department <strong>of</strong> <strong>Oncology</strong>, Rigshospitalet, Copenhagen University Hospital,<br />
Copenhagen, Denmark, 2 Unit <strong>of</strong> Statistics, Danish Cancer Society Research<br />
Center, Copenhagen, Denmark, 3 Department <strong>of</strong> <strong>Oncology</strong>, Aarhus University<br />
Hospital, Aarhus, Denmark, 4 Department <strong>of</strong> <strong>Oncology</strong>, Odense University<br />
Hospital, Odense, Denmark, 5 Unit <strong>of</strong> Survivorship, Danish Cancer Society<br />
Research Center, Copenhagen, Denmark<br />
Background: The prognostic classification applied in disseminated GCC was<br />
established in 1997, based on patients treated with cisplatin containing regimens. Only<br />
a minority <strong>of</strong> the patients were treated with BEP. We aimed to estimate overall survival<br />
(OS) and propose new prognostic factors for GCC patients treated with first line BEP.<br />
Methods: From the nationwide Danish Testicular Cancer database, a total <strong>of</strong> 1889 BEP<br />
treated patients were included, divided in 440 seminoma GCC (SGCC) patients and<br />
1449 with non-seminoma GCC (NSGCC). The median follow-up was 14 years. We<br />
evaluated the following factors for 3-year progression-free survival: age,<br />
non-pulmonary visceral metastases, pulmonary metastases, smoking status, primary<br />
site, and level <strong>of</strong> tumor markers.<br />
Results: For SGCC, the 5-year OS was 92% and 68% for patients in the good and<br />
intermediate prognostic group; for NSGCC, the 5-year OS was 96%, 85%, and 65% for<br />
patients in the good, intermediate, and poor prognostic group, respectively. For SGCC<br />
patients, we found the following adverse prognostic factors not included in the current<br />
classification: older age (hazard ratio (HR), 1.44; 95% confidence interval (CI) 1.17–<br />
1.78 per 10 years), pulmonary metastases (HR, 2.80; 95% CI 1.35–5.82), and lactate<br />
dehydrogenase > 1.5 times the upper limit <strong>of</strong> normal (HR, 2.06; 95% CI 1.19–3.57). For<br />
NSGCC patients, we identified older age (HR, 1.45; 95% CI 1.29–1.64 per 10 years) and<br />
pulmonary metastases (HR, 2.15; 95% CI 1.61–2.87) as possible additional adverse<br />
prognostic factors.<br />
Conclusions: Survival for all prognostic groups has increased since publication <strong>of</strong> the<br />
IGCCCG classification. Based on a nationwide cohort <strong>of</strong> patients treated with BEP, we<br />
have identified new possible prognostic factors not included in the current prognostic<br />
classification for patients with disseminated GCC. The findings should be validated in<br />
larger cohorts.<br />
Legal entity responsible for the study: Rigshospitalet, Copenhagen University<br />
Hospital<br />
Funding: Danish Cancer Society Anna and Preben Simonsens Foundation<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
839P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Outcomes <strong>of</strong> peri-operative chemotherapy (PO-CT) for locally<br />
advanced penile squamous cell carcinoma (LA-PSCC): results<br />
from a multicenter analysis<br />
A. Necchi 1 , G.R. Pond 2 , D. Raggi 3 , S. Ottenh<strong>of</strong> 4 , S. Horenblas 4 , V. Khoo 5 ,<br />
O. Hakenberg 6 , A. Heidenreich 7 , B.J. Eigl 8 , L. Nappi 9 , K. Matsumoto 10 ,<br />
U. Vaishampayan 11 , M. Woods 12 , P. Giannatempo 13 , D. Geynisman 14 , M. Preto 15 ,<br />
E. Xylinas 16 , M.I. Milowsky 17 , G. Di Lorenzo 18 , G. Sonpavde 19<br />
1 Medical <strong>Oncology</strong>, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy,<br />
2 <strong>Oncology</strong>, McMaster University, Hamilton, ON, Canada, 3 Medicine, Fondazione<br />
IRCCS - Istituto Nazionale dei Tumori, Milan, Italy, 4 Urology, The Netherlands<br />
Cancer Institute Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands,<br />
5 Medicine, Royal Marsden Hospital NHS Foundation Trust, London, UK, 6 Urology,<br />
Universitätsklinikum Rostock, Rostock, Germany, 7 Urology, Uniklinik Köln,<br />
Universitätsfrauenklinik Köln, Cologne, Germany, 8 <strong>Oncology</strong>, British Columbia<br />
Cancer Agency, Vancouver, BC, Canada, 9 Urological Sciences, Vancouver<br />
Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada, 10 Urology,<br />
Kitasato University East Hospital, Sagamihara, Japan, 11 Medical <strong>Oncology</strong>,<br />
Karmanos Cancer Institute, Detroit, MI, USA, 12 Urology, Lineberger<br />
Comprehensive Cancer Center University <strong>of</strong> North Carolina, Chapel Hill, NC, USA,<br />
13 Genitourinary, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy,<br />
14 Medical <strong>Oncology</strong>, Fox Chase Cancer Center, Philadelphia, PA, USA, 15 Urology,<br />
Università degli Studi di Torino, Turin, Italy, 16 Urology, Hôpital Cochin, Paris,<br />
France, 17 Medical <strong>Oncology</strong>, Lineberger Comprehensive Cancer Center University<br />
<strong>of</strong> North Carolina, Chapel Hill, NC, USA, 18 Medical <strong>Oncology</strong>, Istituto Nazionale<br />
Tumori – I.R.C.C.S - Fondazione Pascale, Naples, Italy, 19 Medical <strong>Oncology</strong>,<br />
University <strong>of</strong> Alabama at Birmingham Hospital, Birmingham, AL, USA<br />
Background: Patients (pts) with LA-PSCC have a poor prognosis, primarily related to<br />
extent <strong>of</strong> nodal disease, and surgery alone is suboptimal in most cases. Information on<br />
patient outcomes with PO-CT still relies on small numbers.<br />
Methods: A retrospective, multicenter, individual patient-level analysis was performed.<br />
A total <strong>of</strong> 12 centers contributed data for pts who received neoadjuvant (NA) or<br />
adjuvant (A) CT in addition to surgery from 1991 to 2016. Cox regression models<br />
investigated potential prognostic factors (PF) for relapse-free (RFS) and overall survival<br />
(OS). Multivariable (MVA) models were constructed to evaluate treatment effects.<br />
Treatment center was used as a stratification factor.<br />
Results: 201 pts were analyzed. At clinical staging, 20 (10%) had cT3-4N0 disease, 68<br />
(33.8%) cN3, 42 (20.9%) pelvic nodes and 76 (37.8%) a bilateral involvement. 70<br />
(34.8%) had recurrence after prior lymphadenectomy (LAD). 94 pts received NA-CT,<br />
78 A-CT, and 21 NA and A-CT (8 unknown). Taxanes were more frequently used in<br />
NA (75%) than in A setting, with taxane-CDDP-5FU being the most frequent NA CT<br />
regimen (n = 65). 43 pts (21.4%) received concomitant radiotherapy (RT). The 2-year<br />
OS (95%CI) for all pts was 43.7% (35.8-51.3), however among pelvic cN+ and bilateral<br />
cN+ subgroups it was 37.4% (20.5-54.4) and 38.1% (25.9-50.1). On MVA for OS<br />
(n = 166), bilateral disease (HR: 1.93, 95%CI: 1.04-3.56, p = 0.037) was a negative PF,<br />
while pelvic cN+ trended toward significance (HR: 2.26, 95%CI: 0.96-5.36, p = 0.063).<br />
50 pts (53.2%) had an objective response to NA-CT, and 13 (13.8%) achieved a<br />
pathologic CR. Timing <strong>of</strong> CT (NA vs A vs NA > A) was significantly associated with<br />
RFS (NA: HR: 4.55, 95%CI: 1.35-15.36, p = 0.012) in univariable analysis, but not with<br />
OS (p = 0.45). No significant difference was observed in any outcome related to CT<br />
type or CT ± RT.<br />
Conclusions: The survival benefit from PO-CT, either pre- or post-LAD, remained<br />
uncertain for PSCC pts at highest risk (pelvic cN+ or bilateral lymph-node disease).<br />
These results may be useful to inform pts and provide a benchmark for prospective<br />
studies. Further research should identify more active drugs in PSCC and evaluate the<br />
role <strong>of</strong> RT.<br />
vi290 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Legal entity responsible for the study: Fondazione IRCCS Istituto Nazionale dei<br />
Tumori, Milan, Italy<br />
Funding: Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
840P<br />
Dacomitinib as first-line treatment <strong>of</strong> locally-advanced (LA) or<br />
metastatic penile squamous cell carcinoma (PSCC): Interim<br />
analysis <strong>of</strong> an open-label, single-group, phase 2 trial<br />
A. Necchi 1 , D. Giardiello 2 , D. Raggi 1 , P. Giannatempo 1 , N. Nicolai 3 , M. Catanzaro 3 ,<br />
T. Torelli 3 , D. Biasoni 3 , L. Piva 3 , S. Stagni 3 , G. Calareso 4 , E. Togliardi 5 , L. Mariani 2 ,<br />
R. Salvioni 3<br />
1 Medical <strong>Oncology</strong>, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy,<br />
2 Clinical Epidemiology and Trials Organization Unit, Fondazione IRCCS Istituto<br />
Nazionale dei Tumori, Milan, Italy, 3 Surgical <strong>Oncology</strong>, Fondazione IRCCS Istituto<br />
Nazionale dei Tumori, Milan, Italy, 4 Radiology, Fondazione IRCCS Istituto<br />
Nazionale dei Tumori, Milan, Italy, 5 Pharmacy Unit, Fondazione IRCCS Istituto<br />
Nazionale dei Tumori, Milan, Italy<br />
Background: The survival results <strong>of</strong> neoadjuvant or 1st-line chemotherapy (CT) for<br />
LA or metastatic PSCC are poor. HER pathway alterations may be a driver and a<br />
suitable therapeutic target in PSCC. An open-label, single-arm, phase 2 trial <strong>of</strong> 1st-line/<br />
neoadjuvant Dacomitinib, an irreversible pan-HER tyrosine kinase inhibitor, is<br />
currently recruiting patients (pts, NCT01728233) The results <strong>of</strong> a planned interim<br />
analysis are presented.<br />
Methods: 37 pts with chemonaive cN2-3 or M1 disease will receive Dacomitinib 45 mg<br />
daily until surgery or disease progression (PD)/unacceptable toxicity. Computed<br />
tomography and PET scan are repeated q2 months. Simon’s Optimal 2-stage design is<br />
applied. The primary endpoint (PE) is the objective response-rate (ORR = CR/PR<br />
according to RECIST v1.1: H0 ≤ 5%, H1 ≥ 20%, α and β = 10% resulting in ≥4<br />
responses required). Univariable Cox analyses were done. Next generation sequencing<br />
(NGS) with on tumor tissue from all pts is planned (Ion Torrent, Life Technologies).<br />
Results: From 06/13 to 02/16, 20 pts were enrolled (18 evaluable for response). Median<br />
age was 59 yrs (IQR: 54-78). 5 (25%) pts had a metastatic and 15 a LA-PSCC. At<br />
clinical staging, 9 (45%) had clinical pelvic nodes and 11 (55%) bilateral nodal disease.<br />
There were 5 confirmed PR (ORR = 27.8%, 95% confidence interval [CI]: 9.7-53.5), 9<br />
stable diseases and 4 PD. 11 pts (61.1%) had a PET PR. 10 pts underwent<br />
post-dacomitinib lymphadenectomy: >90% necrosis was seen in one patient. Median<br />
follow-up was 13.1 months, 6-month PFS was 37.9% (95%CI: 20.2-71.1), 6-months OS<br />
was 85.7% (95%CI: 69.2-100). No significant factor was found for PFS/OS. Skin<br />
toxicity was observed in 9 pts (2 Grade 1, 7 Grade 2-3 [CTCAE v4.03 3]), Grade 2<br />
diarrhea in 2. Tissue from one PR pt harbored missense mutations in FBXW7 (R505S),<br />
PTEN (A3T), and TP53 (R273H, loss <strong>of</strong> function mutation) genes.<br />
Conclusions: Dacomitinib is endowed with promising single-agent activity in PSCC.<br />
Pending the final results, the PE was already met. Translational results may provide<br />
insights into the targeting <strong>of</strong> HER pathway in PSCC. Preliminary data on molecular<br />
alterations linked to clinical benefit are being observed.<br />
Legal entity responsible for the study: Fondazione IRCCS Istituto Nazionale dei<br />
Tumori<br />
Funding: Fondazione IRCCS Istituto Nazionale dei Tumori<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
841P<br />
Micro-RNA and mRNA integrative analysis revealed MMP1 as a<br />
predictor <strong>of</strong> lymph node metastasis in penile carcinomas<br />
H. Kuasne 1 , M.C. Barros-Filho 1 , A. Busso-Lopes 1 , F. Marchi 1 , M. Pinheiro 1 ,<br />
C. Scapulatempo-Neto 2 , J.J. Muñoz 1 , A. Lopes 3 , G.C. Guimarães 3 , E.F. Faria 4 ,J.<br />
C.D.S. Trindade-Filho 5 , S.A. Drigo 5 , S.R. Rogatto 6<br />
1 CIPE, AC Camargo Cancer Center, São Paulo, Brazil, 2 Department <strong>of</strong> Pathology,<br />
Hospital De Cancer De Barretos Fundacao Pio XII, Barretos, Brazil, 3 Deparment <strong>of</strong><br />
Urology, AC Camargo Cancer Center, São Paulo, Brazil, 4 Department <strong>of</strong> Urology,<br />
Hospital De Cancer De Barretos Fundacao Pio XII, Barretos, Brazil, 5 Department<br />
<strong>of</strong> Urology, UNESP, Botucatu, Brazil, 6 Clinical Genetic, Vejle Hospital Sygehus<br />
Lillebaelt, Vejle Sygehus, Vejle, Denmark<br />
Background: Penile carcinoma (PeCa), a relevant public health problem in poor and<br />
developing countries, has only recently been explored by genetic and epigenetic studies<br />
aiming to identify markers useful to the clinical practice. Herein, we aimed to integrate<br />
miRNA and mRNA pr<strong>of</strong>iles data to identify molecular drivers <strong>of</strong> PeCa development<br />
and progression.<br />
Methods: miRNA expression pr<strong>of</strong>ile (TaqMan Human MicroRNA Array v2.0; Applied<br />
Biosystems) and mRNA expression data (4x44K, Agilent Technologies) were assayed in<br />
23 PeCa tissues and 12 non-neoplastic penile tissues (NPT). Integrative analysis was<br />
based on predicted and experimentally validated miRNA/mRNA interaction.<br />
RT-qPCR confirmed the data in an independent set <strong>of</strong> cases (PeCa = 36; NPT = 27).<br />
Results: Eighty-one miRNA and 2,697 mRNAs differentially expressed were identified<br />
comparing tumor and non-neoplastic tissues. Integrated data analysis revealed that 255<br />
abstracts<br />
mRNAs were specifically regulated by 68 miRNAs. Eight miRNAs and 10 mRNAs<br />
were evaluated by RT-qPCR in an array-dependent and -independent set <strong>of</strong> cases<br />
(PeCa = 36; NPT = 27), confirming the results. Molecular diagnostic classifiers<br />
including MMP1, MMP12 and PPARG transcripts were able to distinguish tumors<br />
from NPT with 92% <strong>of</strong> sensitivity and 83% <strong>of</strong> specificity. Similarly, three miRNAs<br />
(hsa-miR-31-5p, hsa-miR-224-5p, and hsa-miR-223-3p) revealed to have the potential<br />
to discriminate tumors from NPT (82% <strong>of</strong> sensitivity and 74% <strong>of</strong> specificity).<br />
Interestingly, higher MMP1 expression levels were capable to predict lymph node<br />
metastasis more efficiently than clinical-pathological data. Growth factors related<br />
pathways, human embryonic stem cell pluripotency and matrix metalloproteases were<br />
the main deregulated pathways in PeCa.<br />
Conclusions: The integrated data analysis revealed molecular markers and pathways<br />
involved in the PeCa development. Furthermore, MMP1 overexpression was identified<br />
as a new potential biomarker to predict lymph node metastasis.<br />
Legal entity responsible for the study: Silvia Regina Rogatto<br />
Funding: FAPESP<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
842TiP A multicentre, international, randomised, open-label phase 3<br />
trial <strong>of</strong> avelumab + best supportive care (BSC) vs BSC alone<br />
as maintenance therapy after first-line platinum-based<br />
chemotherapy in patients with advanced urothelial cancer<br />
(JAVELIN bladder 100)<br />
T. Powles 1 , P. Grivas 2 , J.B. Aragon-Ching 3 , Y. Faroun 4 , E.R. Kessler 5 , Y. Tomita 6 ,<br />
D. Chakrabarti 7 , R.J. Laliberte 7 , M. Shnaidman 7 , D. Petrylak 8<br />
1 Medical <strong>Oncology</strong>, Royal Free Hospital, London, UK, 2 Medical <strong>Oncology</strong>,<br />
Cleveland Clinic, Cleveland, OH, USA, 3 Medical <strong>Oncology</strong>, Inova Schar Cancer<br />
Institute, Fairfax, VA, USA, 4 Medical <strong>Oncology</strong>, St. Luke’s Hospital & Health<br />
Network, Bethlehem, PA, USA, 5 Medical <strong>Oncology</strong>, University <strong>of</strong> Colorado<br />
Anschutz Medical Campus, Aurora, CO, USA, 6 Urology, Niigata University<br />
Graduate School <strong>of</strong> Medical and Dental Sciences., Niigata, Japan, 7 Research,<br />
Pfizer Inc., New York, NY, USA, 8 Medical <strong>Oncology</strong>, Yale Cancer Center, New<br />
Haven, CT, USA<br />
Background: Although first-line cisplatin-based chemotherapy prolongs survival in<br />
advanced urothelial cancer (UC), most patients (pts) progress within 8 months and no<br />
standard second-line therapies are currently available. Recent studies with anti-PD-L1<br />
agents in pretreated UC have shown antitumour activity and promising survival<br />
compared with historical controls. Avelumab* (MSB0010718C) is a fully human<br />
anti-PD-L1 IgG1 antibody that has shown an acceptable safety pr<strong>of</strong>ile and clinical<br />
activity across a range <strong>of</strong> tumour types in a large phase 1b study. In an expansion<br />
cohort <strong>of</strong> pts with pretreated UC, treatment with avelumab resulted in a 16% objective<br />
response and 59% disease control rate. A phase 3 study (NCT02603432) has been<br />
initiated to determine if maintenance therapy with avelumab can prolong the benefit <strong>of</strong><br />
first-line chemotherapy in pts with advanced UC.<br />
Trial design: JAVELIN Bladder 100 is a phase 3, international, open-label trial <strong>of</strong><br />
avelumab + best supportive care (BSC) compared with BSC alone administered as<br />
maintenance treatment for pts with locally advanced/metastatic UC whose disease did<br />
not progress after first-line treatment with 4–6 cycles <strong>of</strong> gemcitabine + cisplatin or<br />
gemcitabine + carboplatin. Other eligibility criteria include measurable disease prior to<br />
chemotherapy and adequate hematologic/organ function. Avelumab 10 mg/kg is<br />
administered every 2 wks as a 1 hr infusion. An estimated 668 pts will be randomized<br />
1:1 and stratified based on best response to first-line chemotherapy and metastatic site.<br />
This trial has 2 co-primary populations: pts with PD-L1–positive tumours and all pts.<br />
The primary endpoint is overall survival and secondary endpoints include<br />
progression-free survival (PFS), objective response, safety, and symptoms/quality <strong>of</strong><br />
life. Tumour response and PFS (RECIST v1.1) are assessed by blinded central review.<br />
Trial enrolment began in May 2016. *Proposed INN.<br />
Clinical trial identification: NCT02603432<br />
Legal entity responsible for the study: N/A<br />
Funding: Pfizer Inc.<br />
Disclosure: T. Powles: Research Funding: AZ and Roche Honoraria: Novartis, BMS,<br />
Merck. P. Grivas: Consulting/Advisory/Honoraria: Genentech, Deudreon, Bayer<br />
Speaker Bureau: Genentech. Research Funding: Pfizer, Merck, Oncogenex, Mirati,<br />
Roche, Bayer. J.B. Aragon-Ching: Honoraria/Consulting/Advisory: AZ, Algeta/Bayer,<br />
Dendreon Speakers Bureau: BMS. Y. Faroun: Honoraria: Celgene Speakers’ Bureau:<br />
BMS, Celgene Travel/Accommodations/Expenses: Celgene. Y. Tomita: Consulting/<br />
Advisory Role: Novartis Research funding: Pfizer, Astellas, AZ. D. Chakrabarti:<br />
Employee and stockholder: Pfizer Inc. R.J. Laliberte: Employee: Pfizer Inc, Galena<br />
Biopharma, Inc. M. Shnaidman: Employee: Merck KGaA. All other authors have<br />
declared no conflicts <strong>of</strong> interest.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw373 | vi291
abstracts<br />
843TiP<br />
Surf: Open label, randomized multi-centre phase II study to<br />
assess the efficacy and tolerability <strong>of</strong> sunitinib by dose<br />
administration regimen (dose modification or dose<br />
interruptions) in patients with advanced or metastatic renal<br />
cell carcinoma (mRCC)<br />
G. Mouillet 1 , T. Maurina 2 , M-J. Paillard 2 , P. Montcuquet 2 , T. Nguyen Tan Hon 2 ,<br />
H. Almotlak 2 , U. Stein 2 , D. Berthod 2 , E. Robert 3 , A. Meurisse 1 , F. Bonnetain 1 ,<br />
A. Thiery-Vuillemin 2<br />
1 Methodology and Quality <strong>of</strong> Life in <strong>Oncology</strong> Unit, CHU Besançon, Hôpital Jean<br />
Minjoz, Besançon, France, 2 Medical <strong>Oncology</strong>, CHU Besançon, Hôpital Jean<br />
Minjoz, Besançon, France, 3 Innovation and Clinical Trial Unit, CHU Besançon,<br />
Hôpital Jean Minjoz, Besançon, France<br />
Background: Sunitinib is a tyrosine kinase inhibitor approved in first line mRCC<br />
setting at the dose <strong>of</strong> 50 mg daily for 4 weeks followed by a pause <strong>of</strong> 2 weeks (schedule<br />
4/6 50mg). Due to toxicity this schedule 4/6 50mg can induce up to 50% <strong>of</strong> sunitinib<br />
dose modification (reduction and/or interruption). Current recommendation in such<br />
case is to reduce the dose to 37.5 mg per day (schedule 4/6 37.5mg). Retrospective and<br />
prospective data highlight an alternative schedule: 2 weeks <strong>of</strong> treatment followed by<br />
one week <strong>of</strong> pause (schedule 2/3 50mg). SURF trial is set up to compare schedule 2/3<br />
50mg to schedule 4/6 37.5mg when toxicity occurs.<br />
Trial design: SURF [NCT02689167] is a prospective, randomized, open-label phase<br />
IIb study. Patients are included at sunitinib initiation while receiving schedule 4/6<br />
50mg according to the Marketing Authorization Indication. When a dose adjustment<br />
<strong>of</strong> sunitinib is required, patients are randomized between arm A with schedule 4/6<br />
37.5mg and arm B with schedule 2/3 50mg. Main eligibility criteria are: patients with<br />
locally advanced inoperable or mRCC who are starting first line treatment with<br />
Sunitinib; with histologically or cytologically confirmed renal cancer clear cell variant<br />
or with a clear cell component and with Karn<strong>of</strong>sky performance status ≥ 70%. Primary<br />
objective is to assess the median duration <strong>of</strong> sunitinib treatment (DOT) in each group.<br />
Key secondary objectives are progression-free survival, overall survival, time to<br />
randomization, objective response rate, safety, sunitinib dose intensity, quality <strong>of</strong> life<br />
and the description <strong>of</strong> main drivers triggering randomization. We hypothesized that<br />
schedule 2/3 50mg would result in an improvement in median DOT from 6 months to<br />
8.5 months. It was estimated that 112 patients would be need in each arm during 24<br />
months. In order to take account the possibility <strong>of</strong> treatment discontinuation before<br />
randomization 248 patients are necessary. Study start was in February 2016; at April<br />
2016, 5 patients were enrolled. Update on trial enrolment kinetics will be shown during<br />
ESMO congress.<br />
Clinical trial identification: NCT02689167; Trial protocol number 2015-002575-16<br />
Legal entity responsible for the study: University Hospital <strong>of</strong> Besancon, France<br />
Funding: Pfizer<br />
Disclosure: G. Mouillet: Membership on an advisory board: Pfizer, Novartis<br />
Corporate-sponsored research: Pfizer, Novartis. F. Bonnetain: Amgen Celgene Roche<br />
(plus grant) Novartis (plus grant) Integragen Janssen Ipsen Merck Serono Nestlé Santé<br />
Bayer Bms Chugai Eisai. A. Thiery-Vuillemin: Consulting: Pfizer, Novartis Funding:<br />
Pfizer. All other authors have declared no conflicts <strong>of</strong> interest.<br />
844TiP<br />
Phase 3 study <strong>of</strong> avelumab in combination with axitinib<br />
versus sunitinib as first-line treatment for patients with<br />
advanced renal cell carcinoma (aRCC)<br />
R.J. Motzer 1 , T. Choueiri 2 , J. Larkin 3 , L. Albiges 4 , J.B. Haanen 5 , M. Schmidinger 6 ,<br />
M.B. Atkins 7 , M. Mariani 8 , M. Shnaidman 9 , A. Di Pietro 8 , B.I. Rini 10<br />
1 Department <strong>of</strong> Medical <strong>Oncology</strong>, Memorial Sloan Kettering Cancer Center,<br />
New York, NY, USA, 2 The Lank Center for Genitourinary <strong>Oncology</strong>, Dana-Farber<br />
Cancer Institute and Brigham and Women’s Hospital, Boston, MA, USA,<br />
3 Department <strong>of</strong> Medical <strong>Oncology</strong>, Royal Marsden Hospital, London, UK,<br />
4 Department <strong>of</strong> Cancer Medicine, Gustave Roussy Cancer Campus, University <strong>of</strong><br />
Paris Sud, Villejuif, France, 5 Department <strong>of</strong> Medical <strong>Oncology</strong>, The Netherlands<br />
Cancer Institute, Amsterdam, Netherlands, 6 Department <strong>of</strong> Medicine I, Medical<br />
University <strong>of</strong> Vienna, Vienna, Austria, 7 Department <strong>of</strong> Medical <strong>Oncology</strong>, Lombardi<br />
Comprehensive Cancer Center, Georgetown University, Washington, DC, USA,<br />
8 Immuno-<strong>Oncology</strong>, Pfizer Inc., Milan, Italy, 9 Immuno-<strong>Oncology</strong>, Pfizer Inc.,<br />
New York, NY, USA, 10 Department <strong>of</strong> Hematology and <strong>Oncology</strong>, Cleveland Clinic<br />
Taussig Cancer Institute, Cleveland, OH, USA<br />
Background: Combining a checkpoint inhibitor with an anti-VEGF therapy is a<br />
promising treatment strategy for advanced renal cell carcinoma (aRCC). Avelumab*<br />
(MSB0010718C) is a fully human IgG1 anti-PD-L1 antibody with clinical activity in<br />
aRCC and other tumour types (eg, Apolo et al. ECC-ESMO 2015; Gulley et al.<br />
ECC-ESMO 2015). Axitinib is an anti-VEGF receptor tyrosine kinase inhibitor<br />
approved for second-line treatment <strong>of</strong> aRCC (Rini et al. Lancet 2011), which has also<br />
shown clinical activity as a first-line (1L) therapy (Hutson et al. Lancet Oncol 2013).<br />
An ongoing phase 1b study <strong>of</strong> avelumab + axitinib, administered at standard doses,<br />
showed tolerable safety and encouraging antitumour activity in treatment-naïve pts<br />
with aRCC. JAVELIN Renal 101, a randomized, multicenter, phase 3 study<br />
(NCT02684006) compares avelumab + axitinib vs sunitinib in treatment-naïve pts with<br />
aRCC.<br />
Trial design: The primary objective is to demonstrate superiority <strong>of</strong> 1L<br />
avelumab + axitinib vs sunitinib monotherapy in prolonging progression-free survival<br />
(PFS). Eligibility criteria include: aRCC with a clear cell component, ECOG PS ≤1, no<br />
prior systemic therapy for advanced disease, and measurable disease per RECIST v1.1.<br />
Approximately 583 pts will be randomized (1:1) and stratified based on ECOG PS (0 vs<br />
1) and region (US vs Canada/Europe vs rest <strong>of</strong> the world). Pts receive either avelumab<br />
10 mg/kg IV Q2W + axitinib 5 mg orally BID continuously (cycle length 6 weeks) or<br />
sunitinib 50 mg orally once daily for 4 weeks followed by 2 weeks <strong>of</strong>f. Treatment is<br />
discontinued for unacceptable toxicity or if any criteria for withdrawal are met. Pts may<br />
continue treatment beyond progression (RECIST v1.1) if investigator-assessed clinical<br />
benefit is achieved and treatment is well tolerated. PFS will be assessed by blinded<br />
independent central review. Secondary endpoints include overall survival, PFS by<br />
investigator assessment, objective response, duration <strong>of</strong> response, time to response,<br />
safety, tumour biomarker assessments, and patient-reported outcomes. Enrolment in<br />
this pivotal phase 3 trial began in March 2016. *Proposed INN.<br />
Clinical trial identification: NCT02684006<br />
Legal entity responsible for the study: N/A<br />
Funding: Pfizer Inc.<br />
Disclosure: R.J. Motzer: Consulting or Advisory Role: Pfizer, Novartis, Eisai Inc.<br />
Research Funding: Exelixis, BMS, Novartis, Pfizer, Genentech/Roche. T. Choueiri:<br />
Consulting or advisory role: Pfizer, Bayer, Novartis, GSK, Merck, BMS, Roche, Eisai,<br />
Prometheus Labs Inc, Foundation Medicine Inc., Cerulean. Research funding: Pfizer,<br />
Novartis, Merck, Exelixis, Tracon, GSK, BMS, AstraZeneca, Peloton, Roche. L. Albiges:<br />
Consulting or Advisory Role: Novartis, Pfizer, Amgen, BMS, Bayer, San<strong>of</strong>i, and<br />
Cerulean. Research Funding: Novartis and Pfizer. J.B. Haanen: Consulting/Advisory<br />
Role: BMS, MSD, Roche, Pfizer, Novartis, Neon Institution Research Funding: BMS,<br />
MDS, GSK. M. Schmidinger: Honoraria for lectures or consultancy from Pfizer,<br />
Novartis, Roche, BMS, Exelixis, Astellas Travel grants from Roche and Pfizer M.B.<br />
Atkins: Consulting or Advisory Role: Merck, Pfizer, AstraZeneca, BMS, Eisai,<br />
Genentech, Novartis, X4, Acceleron, Peloton, and Nektar. M. Mariani, M. Shnaidman:<br />
Employee and Stockholder: Pfizer Inc. A. Di Pietro: Employment: Pfizer. B.I. Rini:<br />
Consulting or Advisory Role: Roche, BMS, Pfizer, Acceleron, Novartis, GSK. Research<br />
Funding: Pfizer, BMS, Acceleron, Immatics, Peloton. Travel, Accommodations,<br />
Expenses: Pfizer. All other authors have declared no conflicts <strong>of</strong> interest.<br />
845TiP<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Ongoing phase 2 study <strong>of</strong> erdafitinib (JNJ-42756493), a<br />
pan-fibroblast growth factor receptor (FGFR) tyrosine kinase<br />
inhibitor, in patients (pts) with metastatic or unresectable<br />
urothelial carcinoma (M/UR UC) and FGFR gene alterations<br />
A.O. Siefker-Radtke 1 , B. Mellado 2 , K. Decaestecker 3 , J.M. Burke 4 ,A.O’Hagan 5 ,<br />
A. Avadhani 5 , B. Zhong 6 , A. Santiago-Walker 7 , P. De Porre 8 , S. Brookman-May 9 ,<br />
J. Garcia-Donas 10<br />
1 Genitourinary Medical <strong>Oncology</strong>, University <strong>of</strong> Texas, M.D. Anderson Cancer<br />
Center, Houston, TX, USA, 2 Medical <strong>Oncology</strong>, Hospital Clinic de Barcelona,<br />
Barcelona, Spain, 3 Urology, Ghent University Hospital, Ghent, Belgium, 4 Medical<br />
<strong>Oncology</strong>, US <strong>Oncology</strong> Research and Rocky Mountain Cancer Centers, Aurora,<br />
CO, USA, 5 Clinical <strong>Oncology</strong>, Janssen Research & Development, Raritan, NJ,<br />
USA, 6 Biostatistics, Janssen Research & Development, Raritan, NJ, USA,<br />
7 Translational Research and Biomarkers, Janssen Research & Development,<br />
Raritan, NJ, USA, 8 Clinical <strong>Oncology</strong>, Janssen Research & Development, Beerse,<br />
Belgium, 9 Clinical <strong>Oncology</strong>, Janssen Research & Development and<br />
Ludwig-Maximilians-Universität München, Neuss, Germany, 10 Gyn, GU and Skin<br />
Cancer Unit, Centro Integral Oncólogico Clara Campal, Madrid, Spain<br />
Background: European Society for Medical <strong>Oncology</strong> guidelines recommend<br />
cisplatin-based combination chemotherapy for M/UR UC; however, ∼50% <strong>of</strong> pts<br />
cannot tolerate cisplatin. Following progression, the only European Medicines<br />
Agency-approved treatment is vinflunine, which <strong>of</strong>fers modest survival improvement.<br />
FGFRs are involved in UC development, and ∼10%-20% <strong>of</strong> pts with metastatic UC<br />
have FGFR alterations. In a phase 1 trial <strong>of</strong> pan-FGFR (FGFR1-4) inhibitor erdafitinib<br />
in pts with advanced solid tumors, promising antitumor activity and manageable safety<br />
pr<strong>of</strong>ile were observed, including 3 partial responses among 8 pts with UC (Tabernero J,<br />
et al. J Clin Oncol. 2015;33:3401-3408). Efficacy and safety <strong>of</strong> 2 erdafitinib dose<br />
regimens are being evaluated in an open-label, phase 2 study in M/UR UC pts with<br />
specific FGFR translocations or mutations.<br />
Trial design: Pts must have measurable (Response Evaluation Criteria In Solid Tumors<br />
v1.1) M/UR UC and either progression following chemotherapy or relapse within 12<br />
months <strong>of</strong> last dose <strong>of</strong> neoadjuvant/adjuvant chemotherapy. They may have received<br />
any number <strong>of</strong> prior lines <strong>of</strong> treatment, including immunotherapy. Those who are<br />
chemotherapy naïve must be cisplatin ineligible per protocol. Eastern Cooperative<br />
<strong>Oncology</strong> Group performance status ≤ 2 and adequate bone marrow, liver, and kidney<br />
function (creatinine clearance ≥ 40 mL/min) are required. Pts are excluded if they have<br />
baseline phosphate persistently above the upper limit <strong>of</strong> normal or uncontrolled<br />
cardiovascular disease. Pts are randomized to an intermittent (10 mg/d, 7 d on/7 d <strong>of</strong>f)<br />
or continuous (6 mg/d) regimen, both orally administered in a 28-d cycle, until a dose<br />
regimen is selected, with a plan to treat ∼110 pts at the selected dose. The primary end<br />
point is objective response rate. Progression-free survival, duration <strong>of</strong> response, overall<br />
survival, safety, biomarker, and pharmacokinetic assessments are secondary end<br />
points. Enrollment is ongoing at 107 sites in 13 countries (NCT02365597).<br />
vi292 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Clinical trial identification: NCT02365597<br />
Legal entity responsible for the study: Janssen Research & Development, LLC<br />
Funding: Janssen Research & Development, LLC<br />
Disclosure: A.O. Siefker-Radtke: Participated in scientific advisory committees for<br />
Janssen, Eisai, and Genentech, received honoraria from Genentech, and her institution<br />
received clinical trial funding from Janssen, Millennium, Genentech, and AstraZeneca.<br />
K. Decaestecker: Received research funding from Janssen R&D, Beerse, Belgium. J.M.<br />
Burke: Participated in advisory boards or been a consultant for Gilead, Incyte, Takeda,<br />
Janssen, and Pfizer, and has received travel grant funds with TG Therapeutics. A.<br />
O’Hagan, A. Avadhani, B. Zhong, A. Santiago-Walker, P. De Porre, S. Brookman-May:<br />
Employee <strong>of</strong> Janssen R & D and holds stock in Johnson & Johnson. All other authors<br />
have declared no conflicts <strong>of</strong> interest.<br />
846TiP<br />
APACHE: An open label, randomized, phase 2 study <strong>of</strong> the<br />
anti-programmed death-ligand 1 (PD-L1) durvalumab (D,<br />
MEDI4736), alone or in combination with tremelimumab (T),<br />
in patients (pts) with advanced germ cell tumors (GCT)<br />
A. Necchi 1 , L. Mariani 2 , A. Anichini 3 , P. Giannatempo 1 , D. Raggi 1 , E. Togliardi 4 ,<br />
G. Calareso 5 , N. Di Genova 1 , F. Crippa 6 , R. Salvioni 7<br />
1 Medical <strong>Oncology</strong>, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy,<br />
2 Clinical Epidemiology and Trials Organization Unit, Fondazione IRCCS Istituto<br />
Nazionale dei Tumori, Milan, Italy, 3 Experimental <strong>Oncology</strong> and Molecular<br />
Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, 4 Pharmacy<br />
Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, 5 Radiology,<br />
Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, 6 Nuclear Medicine<br />
and PET Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy,<br />
7 Surgical <strong>Oncology</strong>, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy<br />
Background: The prognosis <strong>of</strong> pts who have failed multiple chemotherapy (CT)<br />
regimens is quite dismal. PD-L1 is frequently expressed by immunohistochemistry<br />
(IHC) in GCT. D is a monoclonal antibody (mAb) that inhibits the binding <strong>of</strong> PD-L1.<br />
T, an anti-CTLA4 mAb, is an immunomodulatory therapy. Combination<br />
immunotherapy has shown improved activity compared to monotherapy. We aimed to<br />
investigate the activity <strong>of</strong> D, alone or in combination with T, in chemorefractory GCT.<br />
Trial design: This is an open-label, randomized, 3-stage, phase 2 study. Pts who have<br />
failed ≥2 prior CT regimens (including high-dose CT) will be randomized to receive<br />
one <strong>of</strong> the following: D, 1.5 g via IV infusion q4w, for up to a total <strong>of</strong> 12 months (13<br />
doses/cycles) alone or with T, 75 mg IV q4w, starting on week 0, for up to 4 months (4<br />
doses/cycles). Serum tumor markers, computed tomography and FDG-PET scans will<br />
be repeated q8 weeks. The primary endpoint is the objective response-rate<br />
(ORR = complete response or partial response with normal markers). H0: ORR rate<br />
≤10%, H1: ORR ≥25%, type I and II error rates at 10%. In stage 1, 11 pts will be<br />
allocated in each arm. According to Gehan’s rule, the trial will be terminated whenever<br />
no response will be observed. 29 additional pts will be added to each arm fulfilling stage<br />
1 criteria. ORR in ≥7 pts will be required. In stage 3, pts from stage 1-2 <strong>of</strong> both arms<br />
will be retrospectively evaluated for PDL-1 IHC. The Ventana PD-L1 IHC assay will be<br />
used. In case <strong>of</strong> negative findings at the end <strong>of</strong> stage 2, if the target benefit is likely to<br />
occur only in PD-L1+ pts, further study prosecution in accordance with an enrichment<br />
strategy will be undertaken. In particular, predictive power (PP) will be calculated<br />
assuming expansion <strong>of</strong> PD-L1+ cohorts up to a maximum <strong>of</strong> 60 pts. Each arm will be<br />
categorized as not-promising (PP < 30%) or promising (PP ≥30%). The promising one<br />
will enter the stage 3. Should both arms be judged promising, the one yielding ≥20%<br />
PP advantage will be selected; monotherapy will be preferred otherwise. Details on the<br />
algorithm to be used for PD-L1 IHC in this study will be finalized (EudraCT number<br />
2016-001688-35).<br />
Clinical trial identification: EudraCT 2016-001688-35<br />
Legal entity responsible for the study: Fondazione IRCCS Istituto Nazionale dei<br />
Tumori<br />
Funding: AstraZeneca<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
847TiP<br />
PURE01: An open label, single-arm, phase 2 study <strong>of</strong> the<br />
anti-programmed death (PD)-1 monoclonal antibody (moAb)<br />
pembrolizumab for neoadjuvant therapy <strong>of</strong> muscle-invasive<br />
urothelial bladder carcinoma (miUBC)<br />
A. Necchi 1 , L. Mariani 2 , A. Anichini 3 , P. Giannatempo 1 , D. Raggi 1 , E. Togliardi 4 ,<br />
G. Calareso 5 , N. Di Genova 1 , F. Crippa 6 , R. Salvioni 7<br />
1 Medical <strong>Oncology</strong>, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy,<br />
2 Clinical Epidemiology and Trials Organization Unit, Fondazione IRCCS Istituto<br />
Nazionale dei Tumori, Milan, Italy, 3 Experimental <strong>Oncology</strong> and Molecular<br />
Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, 4 Pharmacy<br />
Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, 5 Radiology,<br />
Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, 6 Nuclear Medicine<br />
and PET Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy,<br />
7 Surgical <strong>Oncology</strong>, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy<br />
Background: After cystectomy (Cy), >40% <strong>of</strong> patients (pts) with miUBC will develop a<br />
recurrence. Neoadjuvant chemotherapy (CT) yields Level 1 evidence in the guidelines,<br />
yet it is underutilized worldwide and a small survival improvement is deemed over Cy<br />
alone. Pembrolizumab (MK-3475) is a humanized IgG4, high-affinity, anti-PD-1 mAb<br />
that has demonstrated significant activity in metastatic UBC. PDL-1<br />
immunohistochemical (IHC) expression can predict drug activity. Our hypothesis was<br />
that Pembrolizumab, given neoadjuvantly, could downstage miUBC and reduce<br />
recurrence.<br />
Trial design: Pts with T2-T4a N0 UBC with residual disease after transurethral<br />
resection <strong>of</strong> the bladder (TURB, surgical opinion, cystoscopy or radiological presence)<br />
will receive 3 cycles <strong>of</strong> MK-3475 at 200mg 3 weekly prior to surgery (radical Cy). Cy<br />
will be planned to be done within 3 weeks <strong>of</strong> the last dose (accounting for a total <strong>of</strong> 9<br />
weeks). Computed tomography (CT) scan and fluorodeoxyglucose positron emission<br />
tomography (FDG-PET)/CT scan will be done during screening and before Cy. After<br />
Cy, pts with the evidence <strong>of</strong> pT3-4 and/or pN+ disease will be managed according to<br />
local guidelines. Further anti PD-1 therapy will not be given post-operatively. PD-L1<br />
status will be assessed on TURB specimen using the anti-PD-L1 Ab clone 22C3 and a<br />
prototype IHC assay and centralized to Qualtek, Goleta, CA. PD-L1 positivity will be<br />
defined as any staining in the stroma or in ≥1% <strong>of</strong> tumor cells. Pathologic complete<br />
response (pCR) is the primary endpoint. All pts enrolled who receive at least 1 cycle <strong>of</strong><br />
study drug will be includes in the ITT analysis. The H 1 is pCR ≥20% and H 0<br />
pCR ≤ 10%. A 2-stage design will be used to estimate the number <strong>of</strong> pts required. Out<br />
<strong>of</strong> 90 pts overall, with the first stage <strong>of</strong> 49 pts, ≥6 pCR will be required in the first stage,<br />
and ≥13 pCR in the whole study population (80% power and a 2-sided test <strong>of</strong><br />
significance at the 10% level). Correlative research on tissue/blood samples will include<br />
immune-cell pr<strong>of</strong>iling in tumor and blood during Pembrolizumab, cytokine<br />
assessment, and molecular pr<strong>of</strong>iling <strong>of</strong> tumor samples (ClinicalTrials.gov<br />
NCT02736266).<br />
Clinical trial identification: ClinicalTrials.gov NCT02736266<br />
Legal entity responsible for the study: Fondazione IRCCS Istituto Nazionale dei<br />
Tumori<br />
Funding: Merck Sharp & Dohme<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
848TiP<br />
abstracts<br />
Pembrolizumab with ChemoRadiotherapy for Muscle<br />
Invasive Bladder Cancer: the ANZUP PCR-MIB trial<br />
A.J. Weickhardt 1 , F. Foroudi 1 , S. Sengupta 1 , P. Grimison 2 , N. Patanjali 2 , S. Leslie 2 ,<br />
S. Ng 3 , C. Tang 3 , R. Goodwin 3 ,E.Hovey 4 , T. Jarvis 4 , C. Chen 4 , A. Herschtal 5 ,<br />
L. Galletta 5 , S. Sandhu 6 , K-H. Tai 6 , N. Lawrentschuk 6 , I. Davis 7<br />
1 Olivia Newton-John Cancer and Wellness Centre, Austin Hospital, Melbourne,<br />
Australia, 2 Genitourinary <strong>Oncology</strong>, Chris O’Brien Lifehouse, Sydney, Australia,<br />
3 Cancer Centre, Sir Charles Gairdner Hospital, Perth, Australia, 4 Nelune Cancer<br />
Centre, Prince <strong>of</strong> Wales Hospital, Sydney, Australia, 5 Centre for Biostatistics and<br />
Clinical Trials, Peter MacCallum Cancer Center, Melbourne, Australia,<br />
6 Genitourinary <strong>Oncology</strong>, Peter MacCallum Cancer Center, Melbourne, Australia,<br />
7 ANZUP, Australian and New Zealand Urogenital and Prostate Cancer Trials<br />
Group, Melbourne, Australia<br />
Background: Pembrolizumab leads to responses in 20-30% <strong>of</strong> metastatic bladder<br />
cancer patients. Irradiation <strong>of</strong> bladder cancer cells in-vitro and in-vivo leads to<br />
upregulation <strong>of</strong> PD-L1, and in immunocompetent mouse models blockade <strong>of</strong> PD-L1<br />
leads to longer tumour growth delay following irradiation. A trial <strong>of</strong><br />
chemoradiotherapy with pembrolizumab in muscle invasive localised bladder cancer<br />
will assess safety and synergy <strong>of</strong> the combination.<br />
Trial design: This pilot study will enrol patients with maximally resected<br />
non-metastatic muscle invasive bladder cancer, who either wish for bladder<br />
preservation or are ineligible for cystectomy. This study will assess the safety and<br />
feasibility <strong>of</strong> combining pembrolizumab with chemoradiotherapy in ECOG 0-1<br />
patients without contraindications to pembrolizumab. The study will enrol 30 patients.<br />
All patients will be treated with 64Gy <strong>of</strong> radiation therapy in 32 fractions over 6 weeks<br />
and 2 days. Patients will receive cisplatin 35mg/m 2 IV concurrently weekly with<br />
radiation therapy for 6 doses total. Pembrolizumab will commence concurrently with<br />
radiation and be given 200mg IV q21 days, continuing until the 12 week cystoscopy<br />
Volume 27 | Supplement 6 | October 2016<br />
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abstracts<br />
and assessment. Surveillance cystoscopy will be performed 12 and 24 weeks after the<br />
commencement <strong>of</strong> chemoradiotherapy, and assess the rate <strong>of</strong> complete response to<br />
therapy. Patients will enter follow up with clinical assessment, cystoscopy and CT<br />
staging performed at intervals until close <strong>of</strong> study. The primary endpoint assessed will<br />
be safety, as defined by a satisfactorily low rate <strong>of</strong> unacceptable toxicity (G3-4 adverse<br />
events or failure <strong>of</strong> completion <strong>of</strong> planned chemotherapy and radiotherapy according<br />
to defined parameters). The secondary endpoint will be efficacy, as assessed by the<br />
proportion <strong>of</strong> patients achieving a best response <strong>of</strong> complete responsebased on the first<br />
two 12 and 24 week post chemoradiotherapy cystoscopic assessments. Exploratory<br />
analysis will include assessment <strong>of</strong> tumour histopathological, molecular, genetic and<br />
immunological parameters. It is expected that it will take two years to accrue the<br />
required 30 patients across 5 Australian centres<br />
Clinical trial identification: NCT02662062<br />
Legal entity responsible for the study: N/A<br />
Funding: Australian and New Zealand Urogenital and Prostate Cancer Trials Group<br />
With Funding from Merck Sharp & Dohme (Australia)<br />
Disclosure: A.J. Weickhardt: Research support: Novartis Advisory board: Roche;<br />
Bayer; Novartis. All other authors have declared no conflicts <strong>of</strong> interest.<br />
849TiP<br />
Pembrolizumab in patients with Bacillus Calmette Guérin<br />
(BCG)-unresponsive, high-risk non–muscle-invasive bladder<br />
cancer (NMIBC): Phase 2 KEYNOTE-057 study<br />
R. de Wit 1 , A.M. Kamat 2 , J. Bellmunt 3 , T.K. Choueiri 4 , K. Nam 5 , M. De Santis 6 ,<br />
R. Dreicer 7 , N.M. Hahn 8 , R. Perini 5 , A.O. Siefker-Radtke 9 , G. Sonpavde 10 ,J.<br />
A. Witjes 11 , S. Keefe 5 , D. Bajorin 12<br />
1 <strong>Oncology</strong>, Erasmus MC Cancer Institute, Rotterdam, Netherlands, 2 Urology, The<br />
University <strong>of</strong> Texas MD Anderson Cancer Center, Houston, TX, USA, 3 Bladder<br />
Cancer Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston,<br />
MA, USA, 4 <strong>Oncology</strong>, Dana-Farber Cancer Institute/Brigham and Women’s<br />
Hospital, Boston, MA, USA, 5 Medical <strong>Oncology</strong>, Merck & Co., Inc., Kenilworth,<br />
NJ, USA, 6 <strong>Oncology</strong>, University <strong>of</strong> Warwick, Coventry, UK, 7 Department <strong>of</strong><br />
Medicine, Division Hematology/<strong>Oncology</strong>, University <strong>of</strong> Virginia School <strong>of</strong><br />
Medicine, Charlottesville, VA, USA, 8 <strong>Oncology</strong>, Sidney Kimmel Comprehensive<br />
Cancer Center at Johns Hopkins University, Baltimore, MD, USA, 9 Genitourinary<br />
Medical <strong>Oncology</strong>, University <strong>of</strong> Texas, M.D. Anderson Cancer Center, Houston,<br />
TX, USA, 10 Hematology, Medical <strong>Oncology</strong>, University <strong>of</strong> Alabama at Birmingham<br />
Comprehensive Cancer Center, Birmingham, AL, USA, 11 Urology, University<br />
Radboud, Nijmegen, Netherlands, 12 Genitourinary <strong>Oncology</strong> Service in the<br />
Division <strong>of</strong> Solid Tumor <strong>Oncology</strong>, Memorial Sloan Kettering Cancer Center,<br />
New York, NY, USA<br />
Background: Despite standard-<strong>of</strong>-care therapy with transurethral resection <strong>of</strong> bladder<br />
tumor (TURBT) and intravesical BCG instillation, a large percentage <strong>of</strong> patients with<br />
NMIBC have disease recurrence/progression. PD-L1 is widely expressed in urothelial<br />
tumors, providing a therapeutic rationale for targeting the PD-1/PD-L1 pathway in<br />
NMIBC. KEYNOTE-057 (NCT02625961) is an open-label, phase 2 study designed to<br />
evaluate the efficacy <strong>of</strong> the anti–PD-1 antibody pembrolizumab (pembro) in patients<br />
with high-risk, BCG-unresponsive NMIBC.<br />
Trial design: Eligible patients must be age ≥18 years; have histologically confirmed<br />
diagnosis <strong>of</strong> high-risk, BCG-unresponsive NMIBC (high-grade Ta, T1, and/or<br />
carcinoma in situ [CIS] despite adequate BCG treatment); be ineligible for or have<br />
declined radical cystectomy; and have ECOG PS 0-2. Patients must have undergone ≥2<br />
cystoscopic procedures with the most recent ≤8 weeks <strong>of</strong> study start, including<br />
complete TURBT (tissue sample must be available). Patients will receive pembro 200<br />
mg Q3W for 24 months or until disease recurrence, progression, or unacceptable<br />
toxicity. Patients will be placed into cohorts by presence (cohort A) or absence (cohort<br />
B) <strong>of</strong> CIS based on tissue pathology at screening. Response will be assessed using<br />
cystoscopy and urine cytology every 12 weeks for the first 2 years, every 24 weeks for<br />
the next 2 years, and every 52 weeks thereafter. CT imaging will be used to assess for<br />
metastatic or nodal disease. At 18 months, patients with no evidence <strong>of</strong> disease may<br />
discontinue treatment. Low-grade Ta recurrence will not be considered treatment<br />
failure; these patients may undergo repeat TURBT and remain on treatment. AEs will<br />
be monitored throughout the study and for 30 days after end <strong>of</strong> treatment (90 days for<br />
serious AEs and events <strong>of</strong> clinical interest) and graded per CTCAE v4.0. Primary end<br />
points are complete response (cohort A) and disease-free survival (cohort B);<br />
secondary end points include progression-free survival, overall survival, duration <strong>of</strong><br />
response, and the relationship between PD-L1 expression and response to treatment.<br />
Enrollment will continue until ∼260 patients have enrolled.<br />
Clinical trial identification: NCT02625961<br />
Legal entity responsible for the study: Merck & Co., Inc.<br />
Funding: Merck & Co., Inc.<br />
Disclosure: T.K. Choueiri: Research funding: Pfizer, Novartis, Merck, Exelixis, Tracon,<br />
GSK, BMS, AstraZeneca, Peloton, Roche Consulting/Advisory Role: Pfizer, Bayer,<br />
Novartis, Merck, BMS, Roche, Eisai, Prometheus Labs Inc, Foundation Medicine Inc.,<br />
Cerulean, Peloton, AstraZeneca. K. Nam, R. Perini, S. Keefe: Employee <strong>of</strong> Merck & Co.,<br />
Inc. R. Dreicer: Advisory board member: Genentech, Medivation, Exelexis, Ferring<br />
Corporate-sponsored research: Genentech, Lilly, Asana. D. Bajorin: Advisory board<br />
member: Novartis, Pfizer, Genentech, Urogen, BMS Corporate-sponsored research:<br />
Novartis, BMS, Amgen. All other authors have declared no conflicts <strong>of</strong> interest.<br />
850TiP<br />
JaNEO – A phase Ib/II study assessing the neo-adjuvant<br />
combination therapy <strong>of</strong> vinflunine (VFL) with cisplatin (CDDP)<br />
followed by radical cystectomy (RC) in patients with<br />
muscle-invasive bladder cancer (MIBC)<br />
A. Hegele 1 , C-H. Ohlmann 2 , H. Rexer 3 , G. Gakis 4<br />
1 Urology, University Hospital Marburg, Marburg, Germany, 2 Clinical trials, Ligartis<br />
GmbH, Homburg, Germany, 3 Clinical trials, MeckEvidence, Schwarz, Germany,<br />
4 Urology, Universitätsklinikum Tübingen, Tübingen, Germany<br />
Background: Neo-adjuvant chemotherapy (CTx) prior to RC leads to a significant<br />
improvement in 5-year survival in MIBC. Guidelines recommend CDDP-based CTx.<br />
However, the optimal regimen is still controversial and no standard has been defined<br />
so far. VFL, as a single agent, has proven clinical activity in urothelial carcinoma. VFL<br />
and CDDP mediate complementary mechanisms <strong>of</strong> action and their combination may<br />
provide a relevant benefit in the neoadjuvant setting.<br />
Trial design: Systemically untreated patients with MIBC, clinically staged as T2-T4a<br />
(cN0, cM0) and with an ECOG performance status <strong>of</strong> 0-1 will be enrolled in this<br />
national, multi-center, prospective, open, single-arm Phase Ib/II trial. Study treatment<br />
consists <strong>of</strong> 4 cycles (q3w) <strong>of</strong> VFL (280mg/m 2 ) and CDDP (70mg/m 2 ), followed by RC<br />
within 4 weeks after CTx. In the phase Ib part <strong>of</strong> the study, a 3 + 6 patient safety cohort<br />
will be treated first to prove safety <strong>of</strong> the combination. Occurrence <strong>of</strong> ≥2 unacceptable<br />
toxicities (UT) or any grade 5 event will lead to discontinuation within the first cohort<br />
(3 patients), as well ≥4 UTs or any grade 5 event within the complete safety period<br />
(consisting <strong>of</strong> the 3 + 6 patients). Following this safety period, up to a total <strong>of</strong> 36<br />
evaluable patients will be recruited into the phase II part <strong>of</strong> the trial in the frame <strong>of</strong> a<br />
Simon-two-stage design. Pathological tumor response based on central pathology<br />
review is the primary endpoint. The null hypothesis, which is the defined as a true<br />
response rate <strong>of</strong> 25%, will be tested against a one-sided alternative. In the first stage, 17<br />
patients will be accrued. If there are ≥5 responses in these 17 patients, the study will be<br />
continued to full recruitment to a total <strong>of</strong> 36 patients. The null hypothesis will be<br />
rejected if ≥14 responses are observed in 36 patients, with a type I error rate <strong>of</strong> 0.05<br />
(one-sided) and a power <strong>of</strong> 0.8 when the true response rate is 45%. Further endpoints<br />
are the rate <strong>of</strong> radiological response and progression (RECIST 1.1), cancer-specific<br />
survival, quality <strong>of</strong> life and safety. A translational research program aiming at the<br />
identification <strong>of</strong> predictive biomarkers will accompany this clinical trial.<br />
Clinical trial identification: EudraCT 2016-000081-33<br />
Legal entity responsible for the study: Ligartis GmbH<br />
Funding: Pierre Fabre GmbH<br />
Disclosure: A. Hegele, G. Gakis: Pierre Fabre: Advisory Role, Honoraria, Research<br />
Funding C-H. Ohlmann: Pierre Fabre: Advisory Role, Honoraria. All other authors<br />
have declared no conflicts <strong>of</strong> interest.<br />
851TiP<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
TRAXAR study: a randomized phase 2 trial <strong>of</strong> axitinib and<br />
TRC105 versus axitinib alone in patients with advanced or<br />
metastatic renal cell carcinoma (mRCC)<br />
T. Choueiri 1 , N. Agarwal 2 ,T.Ho 3 , S.K. Pal 4 , B. Seon 5 , M. Jivani 6 , B. Adams 6 ,<br />
R. Shazer 6 , C. Theuer 6<br />
1 Kidney Cancer Center, Dana-Farber Cancer Institute, Boston, MA, USA, 2 Medical<br />
<strong>Oncology</strong>, Huntsman Cancer Institute, Salt Lake City, UT, USA, 3 Division <strong>of</strong><br />
Hematology/<strong>Oncology</strong>, Mayo Clinic Cancer Center, Scottsdale, CA, USA,<br />
4 Medical <strong>Oncology</strong> and Experimental Therapeutics, City <strong>of</strong> Hope, Duarte, CA,<br />
USA, 5 Immunology, Roswell Park Cancer Institute, Buffalo, NY, USA, 6 Clinical<br />
Operations, TRACON Pharmaceuticals, Inc., San Diego, CA, USA<br />
Background: Resistance to VEGF-targeted therapy is a major challenge in the<br />
contemporary treatment <strong>of</strong> mRCC, and endoglin activation may be an important<br />
mechanism leading to resistance. Endoglin is an essential angiogenic receptor<br />
expressed on proliferating tumor vessels and RCC stem cells, and is upregulated<br />
following VEGF inhibition. TRC105 is an endoglin monoclonal antibody that<br />
potentiates the anti-tumor activity <strong>of</strong> bevacizumab and VEGF receptor tyrosine kinase<br />
inhibitors in preclinical models. 18 patients were enrolled in phase 1b trial and,<br />
TRC105 dose escalation proceeded from 8 mg/kg (n = 3) to 10 mg/kg (n = 15) without<br />
dose limiting toxicity. TRC105 at its RP2D <strong>of</strong> 10 mg/kg was well tolerated with axitinib<br />
(A) 5 mg BID in RCC patients. Dose escalation <strong>of</strong> A to 10 mg BID was possible with<br />
the RP2D <strong>of</strong> TRC105. In phase 1b, the combination <strong>of</strong> TRC105 and A demonstrated<br />
preliminary evidence <strong>of</strong> activity, including partial responses in 29% <strong>of</strong> patients by<br />
RECIST 1.1, and longer PFS than expected with A as a single agent. The overall disease<br />
control rate (CR/PR/SD > 2 months) was 88% (15 <strong>of</strong> 17). Median PFS overall was 8.4<br />
months, and was 9.6 months among patients with clear cell RCC. Adverse events<br />
characteristic <strong>of</strong> each drug were not increased in frequency or severity when the two<br />
drugs were administered concurrently, and most commonly included epistaxis,<br />
diarrhea, fatigue, headache, and gingival bleeding.<br />
vi294 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Trial design: Phase 2 is a multicenter study that is actively enrolling at this time across<br />
approximately 30 sites in the US. In phase 2, 150 patients are randomized 1:1 to A +/-<br />
TRC105. Key inclusion criteria: 1 prior VEGF inhibitor, clear cell RCC, ECOG ≤ 1; one<br />
prior mTOR and one prior immune therapy are allowed. Primary endpoint is PFS and<br />
secondary endpoints are ORR, disease control rate, and to characterize the<br />
pharmacokinetic pr<strong>of</strong>ile <strong>of</strong> TRC105 and A. (NCT01806064).<br />
Clinical trial identification: Protocol # 105RC101 (NCT01806064)<br />
Legal entity responsible for the study: TRACON Pharmacuticals, Inc. Lead PI: Toni<br />
Choueiri<br />
Funding: TRACON Pharmacuticals, Inc.<br />
Disclosure: T. Choueiri: Consulting or Advisory Role: Pfizer, Novartis, GSK, Merck,<br />
BMS, Roche, Eisai, Prometheus Labs, Inc., Foundation Medicine Inc. Cerulean<br />
Research Funding (Institution): Pfizer, Novartis, Merck, Exelixis, TRACON, GSK,<br />
BMS, AstraZeneca, Peloton, Roche. N. Agarwal: Consultancy to Pfizer, Exelixis, Argos,<br />
Cerulean, and Medivation. S.K. Pal: consulting for Pfizer. B. Seon: patents - roswell<br />
park cancer institute. M. Jivani, B. Adams, C. Theuer: Employee <strong>of</strong> TRACON<br />
Pharmaceuticals, Inc. Stock ownership in TRACON Pharmaceuticals, Inc. R. Shazer:<br />
Employee <strong>of</strong> TRACON Pharmaceuticals, Inc. Stock ownership in BMS All other<br />
authors have declared no conflicts <strong>of</strong> interest.<br />
852TiP<br />
The PAZOREAL non-interventional study to assess efficacy<br />
and safety <strong>of</strong> pazopanib and everolimus in the changing<br />
metastatic renal cell carcinoma (mRCC) treatment landscape<br />
P. Goebell 1 , C. Doehn 2 , C. Grüllich 3 , V. Grünwald 4 , T. Steiner 5 , R. Ehness 6 ,<br />
M. Welslau 7<br />
1 Department <strong>of</strong> Urology, University Erlangen, Erlangen, Germany, 2 Department <strong>of</strong><br />
Urology, Urologikum Lübeck, Lübeck, Germany, 3 Department <strong>of</strong> Medical<br />
<strong>Oncology</strong>, University <strong>of</strong> Heidelberg, Heidelberg, Germany, 4 Clinic for Hematology,<br />
Hemostasis, <strong>Oncology</strong>, and Stem Cell Transplantation, Medical School <strong>of</strong><br />
Hannover, Hannover, Germany, 5 Department <strong>of</strong> Urology, HELIOS Klinikum Erfurt,<br />
Erfurt, Germany, 6 Department <strong>of</strong> <strong>Oncology</strong>, Novartis Pharma GmbH, Nuernberg,<br />
Germany, 7 Onkologische Schwerpunktpraxis am Klinikum, Onkologie<br />
Aschaffenburg, Aschaffenburg, Germany<br />
Background: Renal cell carcinoma (RCC) is diagnosed in about 15,500 patients per<br />
year in Germany, with up to 60% <strong>of</strong> patients requiring systemic treatment in the<br />
metastatic setting. Vascular endothelial growth factor receptor (VEGFR) and<br />
mammalian target <strong>of</strong> rapamycin (mTOR) inhibitors are broadly used in mRCC<br />
therapy and sequential first-line pazopanib (VEGFR inhibitor) and second-line<br />
everolimus (mTOR inhibitor) is a standard treatment option. Nivolumab was recently<br />
approved in Europe for use after previous therapy. The non-interventional PAZOREAL<br />
study is designed to observe the real-world use <strong>of</strong> first-line through third-line therapy<br />
in the evolving treatment environment.<br />
Trial design: This is a prospective, non-interventional study that will evaluate the<br />
efficacy, tolerability, safety, and quality <strong>of</strong> life (QoL) in patients with mRCC treated<br />
with first-line pazopanib, second-line nivolumab or everolimus, or third-line<br />
everolimus after nivolumab. Adults with histologically confirmed mRCC <strong>of</strong> any<br />
subtype, who have a life expectancy <strong>of</strong> at least 6 months, and whose systemic treatment<br />
will either start with first-line pazopanib or continue with third-line everolimus after<br />
second-line nivolumab, are eligible. Treatment will follow the respective German drug<br />
labels. Patients’ history, treatment, disease assessment, concomitant medication,<br />
adverse events, follow-up treatments, and survival will be documented. Variables will<br />
include the time on drug for documented therapies, overall survival, dosing<br />
parameters, safety, and QoL (assessed by EQ-5D-5L questionnaire). Recruitment <strong>of</strong><br />
patients started in December 2015 and is planned to end in December 2018, with a<br />
goal <strong>of</strong> 450 documented patients at about 150 sites in Germany. Four interim analyses<br />
are planned, and the first analysis will be performed in April 2017. Immediately after<br />
approval <strong>of</strong> nivolumab in Germany, the study was opened for documentation <strong>of</strong><br />
therapy sequences including in-label nivolumab treatment in the second-line setting.<br />
Legal entity responsible for the study: Novartis Pharma GmBH<br />
Funding: Novartis Pharma GmBH<br />
Disclosure: P. Goebell: Advisory boards: Bayer, Bristol-Myers-Squibb, Novartis, Pfizer,<br />
Janssen, San<strong>of</strong>i-Aventis Honoraria, Travel: Astellas, Bayer, Bristol-Myers-Squibb,<br />
Novartis, Pfizer, Janssen, San<strong>of</strong>i-Aventis C. Doehn: Consulting/Advisory board: Roche<br />
Honoraria: Amgen, Bayer, BMS, Novartis, Pfizer Stock: AstraZeneca. C. Grüllich:<br />
Consulting/Advisory Board: Novartis, Nierenzell CA Honoraria: Novartis, Nierenzell<br />
CA Research: Novartis. T. Steiner: Consulting/Advisory Board: Novartis, BMS<br />
Research: BMS Studienteilnahe. R. Ehness: Employment: Novartis Germany Stock:<br />
GSK, Novartis. M. Welslau: Consulting/Advisory Board: Novartis, GSK, Pfizer, BMS<br />
Honoraria: Novartis, GSK, Pfizer, BMS. All other authors have declared no conflicts <strong>of</strong><br />
interest.<br />
853TiP<br />
abstracts<br />
Phase I/II dose-finding, safety and efficacy study <strong>of</strong><br />
radium-223 dichloride in renal cell carcinoma patients with<br />
bone metastases<br />
R. Elaidi 1 , Y.A. Vano 1 , N. Aide 2 , L. Fournier 3 , D. Deandreis 4 , F. Tenenbaum 5 ,<br />
R. Lebtahi 6 , H. De Clermont-Galleran 7 , L. Albiges 8 , B. Escudier 9 ,F.Joly 10 ,<br />
J. Alexandre 11 , M. Bernardini 12 , S. Baron 13 , J. Arfi-Rouche 14 , C. Noel 15 ,<br />
E. Braychenko 1 ,J.O’Quigley 16 , J. Medioni 1 , S. Oudard 1<br />
1 Medical <strong>Oncology</strong>, Hopital European George Pompidou, Paris, France, 2 Nuclear<br />
Medicine, Centre Francois Baclesse, Caen, France, 3 Radiology, European<br />
Georges Pompidou Hospital, Paris, France, 4 Nuclear Medicine, Institut G. Roussy,<br />
Villejuif, France, 5 Nuclear Medicine, Hôpital Cochin, Paris, France, 6 Nuclear<br />
Medicine, Assistance Publique - Hopitaux De Paris, Paris, France, 7 Nuclear<br />
Medicine, CHU de Bordeaux Pellegrin, Bordeaux, France, 8 Cancer Medicine,<br />
Institut Gustave Roussy, Villejuif, France, 9 Medical <strong>Oncology</strong>, Institut de<br />
Cancérologie Gustave Roussy, Villejuif, France, 10 Medical <strong>Oncology</strong>, Centre<br />
Francois Baclesse, Caen, France, 11 Medical <strong>Oncology</strong>, Hôpital Cochin, Paris,<br />
France, 12 Nuclear Medicine, Hopital European George Pompidou, Paris, France,<br />
13 Biology, Hopital European George Pompidou, Paris, France, 14 Radiology, Institut<br />
de Cancérologie Gustave Roussy, Villejuif, France, 15 Radiology, Centre Francois<br />
Baclesse, Caen, France, 16 Matematic and Statistic, Paris University, Paris, France<br />
Background: Presence <strong>of</strong> bone metastases (BM) is a factor <strong>of</strong> poor prognosis in<br />
metastatic renal cell carcinoma (mRCC). Radium-223 is a bone targeted active short<br />
half-life a-emitter approved in prostate cancer. Its activity in mRCC osteolytic lesions is<br />
unknown.<br />
Trial design: The pro<strong>of</strong> <strong>of</strong> concept study EIFFEL is a French multicentric phase I/II<br />
designed to assess the value <strong>of</strong> Radium-223 for treatment <strong>of</strong> mRCC bone lesions. Main<br />
objective is to identify the most-successful dose among 4 activity levels: 27.5, 55, 82.5,<br />
110KBq/kg. Primary endpoints are the 6 weeks dose-limiting toxicity (DLT) for<br />
escalation cohort and conditional efficacy upon whole-body MRI (WB-MRI) and<br />
NaF-PET scan for expansion cohort. In order to optimize the precision <strong>of</strong> the results, 4<br />
innovative methods were implemented in a context <strong>of</strong> early phases: 1) a continual<br />
reassessment model is used for the 2 phases and expected to provide an optimal dose (<br />
most efficient activity given the acceptable toxicity) 2) Radium-223 to DLT causal<br />
relationship assessment uses an intrinsic imputability score to avoid confounding<br />
adverse events for DLT qualification, 3) a modified RECIST for bone lesions upon<br />
WB-MRI and NaF-PET (considering the entire bone metastatic burden) is used to<br />
monitor efficacy in the expansion cohort and 4) efficacy data gathered during the<br />
escalation phase will provide prior hypothesis to define the optimal efficacy threshold<br />
for the expansion cohort. Analysis <strong>of</strong> correlations between Radium-223 biodistribution<br />
scintigraphy, longitudinal WB-MRI, NaF-PET, and circulating bone remodeling<br />
markers will further address important questions in clinical, imagery, metabolism and<br />
nuclear medicine domains. The EIFFEL study should provide a large amount <strong>of</strong> useful<br />
data for evaluation and treatment <strong>of</strong> bone metastasis in mRCC. Results <strong>of</strong> phase I are<br />
expected Q1 2018 and Q4 2019 for final phase II results.<br />
Clinical trial identification: EURACT # 2014-003774-16 - CODE: EIFFEL<br />
Legal entity responsible for the study: ARTIC - Association pour la Recherche de<br />
Thérapeutiques Innovantes en Cancérologie Siège social : Service de Cancérologie<br />
Médicale Hôpital Européen Georges Pompidou 20-30, rue Leblanc, 75908 Paris Cedex<br />
15<br />
Funding: Bayer Healthcare<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw373 | vi295
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong> 27 (Supplement 6): vi296–vi312, 2016<br />
doi:10.1093/annonc/mdw374<br />
gynaecological cancers<br />
854O<br />
Results <strong>of</strong> a phase 2 trial <strong>of</strong> selinexor, an oral selective<br />
inhibitor <strong>of</strong> nuclear export (SINE) in 114 patients with<br />
gynaecological cancers<br />
I. Vergote 1 , B. Lund 2 , H. Havsteen 3 , Z. Ujmajuridze 4 , E. Van Nieuwenhuysen 1 ,<br />
C. Haslund 2 , T. Juhler-Nøttrup 4 , P. Neven 1 , M. Mau-Sørensen 4 , P. Berteloot 1 ,<br />
A. Kranich 5 , T. Rashal 6 , J. Meade 6 , Y. Landesman 6 , J-R. Saint-Martin 6 , G. Wright 6 ,<br />
M. Crochiere 6 , S. Shacham 6 , M. Kauffman 6 , M. Raza Mirza 6<br />
1 Obstetrics & Gynecology, Katholieke Universiteit, Leuven, Belgium, 2 <strong>Oncology</strong>,<br />
Aalborg University Hospital, Aalborg, Denmark, 3 <strong>Oncology</strong>, University Hospital<br />
Herlev, Herlev, Denmark, 4 <strong>Oncology</strong>, Rigshospitalet, Copenhagen University<br />
Hospital, Copenhagen, Denmark, 5 GSO, Hamburg, Germany, 6 Karyopharm,<br />
Karyopharm Therapeutics, Newton, MA, USA<br />
abstracts<br />
855O A phase II study <strong>of</strong> the cell cycle checkpoint kinases 1 and 2<br />
inhibitor (LY2606368; Prexasertib monomesylate<br />
monohydrate) in sporadic high-grade serous ovarian cancer<br />
(HGSOC) and germline BRCA mutation-associated ovarian<br />
cancer (gBRCAm+ OvCa)<br />
J-M. Lee 1 , F.H. Karzai 2 , A. Zimmer 1 , C.M. Annunziata 1 , S. Lipkowitz 1 , B. Parker 1 ,<br />
N. Houston 1 , I. Ekwede 1 , E.C. Kohn 1<br />
1 Women’s Malignancies Branch, National Cancer Institute, Rockville, MD, USA,<br />
2 Division <strong>of</strong> Intramural Research, National Institute on Minority Health and Health<br />
Disparities, Rockville, MD, USA<br />
856O<br />
Clinical activity <strong>of</strong> the poly(ADP-ribose) polymerase (PARP)<br />
inhibitor rucaparib in patients (pts) with high-grade ovarian<br />
carcinoma (HGOC) and a BRCA mutation (BRCAmut): Analysis<br />
<strong>of</strong> pooled data from Study 10 (parts 1, 2a, and 3) and ARIEL2<br />
(parts 1 and 2)<br />
R.S. Kristeleit 1 , R. Shapira-Frommer 2 , A. Oaknin 3 , J. Balmaña 3 , I.L. Ray-Coquard 4 ,<br />
S. Domchek 5 , A.V. Tinker 6 , C.M. Castro 7 , S. Welch 8 , A.M. Poveda 9 ,<br />
K. Bell-Mcguinn 10 , G. Konecny 11 , H. Giordano 12 , L. Maloney 12 , S. Goble 13 ,<br />
L. Rolfe 14 ,A.Oza 15<br />
1 <strong>Oncology</strong>, University College London, Cancer Institute, London, UK, 2 Medical<br />
<strong>Oncology</strong>, Sheba Medical Center, Ramat Gan, Israel, 3 Medical <strong>Oncology</strong>, Vall<br />
d’Hebron University Hospital, Vall d’Hebron Institute <strong>of</strong> <strong>Oncology</strong>, Barcelona,<br />
Spain, 4 <strong>Oncology</strong>, GINECO, Centre Léon Bérard and University Claude Bernard,<br />
Lyon, France, 5 Medical <strong>Oncology</strong>, University <strong>of</strong> Pennsylvania, Philadelphia, PA,<br />
USA, 6 Medicine, British Columbia Cancer Agency, Vancouver, BC, Canada,<br />
7 Medicine, Gynecological <strong>Oncology</strong>, Massachusetts General Hospital, Harvard<br />
Medical School, Boston, MA, USA, 8 Division <strong>of</strong> Medical <strong>Oncology</strong>, London<br />
Regional Cancer Program, London, ON, Canada, 9 Gynecology, Clinical Area <strong>of</strong><br />
Gynecologic <strong>Oncology</strong>, Valencian Institute <strong>of</strong> <strong>Oncology</strong>, Valencia, Spain,<br />
10 Gynecologic Medical <strong>Oncology</strong>, Memorial Sloan-Kettering Cancer Center,<br />
New York, NY, USA, 11 Medicine, Hematology & <strong>Oncology</strong>, University <strong>of</strong> California<br />
Los Angeles (UCLA), Los Angeles, CA, USA, 12 Clinical Science, Clovis <strong>Oncology</strong>,<br />
Inc., Boulder, CO, USA, 13 Biostatistics, Clovis <strong>Oncology</strong>, Inc., Boulder, CO, USA,<br />
14 Clinical and Preclinical Development, Clovis <strong>Oncology</strong>, Inc., Boulder, CO, USA,<br />
15 Medical <strong>Oncology</strong>, Princess Margaret Cancer Centre, University Health<br />
Network, Toronto, ON, Canada<br />
© European Society for Medical <strong>Oncology</strong> 2016. Published by Oxford University Press on behalf <strong>of</strong> the European Society for Medical <strong>Oncology</strong>.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com.
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
858PD<br />
A DGOG open-label multicenter phase II study <strong>of</strong> pazopanib<br />
in metastatic and locally advanced hormone-resistant<br />
endometrial cancer<br />
L.E. Boom 1 , P.B. Ottevanger 2 , A. Reyners 3 , J.R. Kroep 4 , P. Witteveen 5 ,<br />
R. Lalisang 6 , A.M. Westermann 1<br />
1 Medical <strong>Oncology</strong> F4-224, Academic Medical Center (AMC), Amsterdam,<br />
Netherlands, 2 Medical <strong>Oncology</strong>, Radboud University Medical Centre Nijmegen,<br />
Nijmegen, Netherlands, 3 Medical <strong>Oncology</strong>, University Hospital Groningen<br />
(UMCG), Groningen, Netherlands, 4 Medical <strong>Oncology</strong>, Leiden University Medical<br />
Center (LUMC), Leiden, Netherlands, 5 Medical <strong>Oncology</strong>, University Medical<br />
Center Utrecht, Utrecht, Netherlands, 6 Medical <strong>Oncology</strong>, Maastricht University<br />
Medical Center (MUMC), Maastricht, Netherlands<br />
857PD<br />
The predictive value <strong>of</strong> the CA-125 modeled kinetic<br />
parameter KELIM is validated in 3 independent datasets<br />
(AGO-OVAR 7 & 9; ICON 7 AGO/GINECO/GCIG trials)<br />
B.M. You 1 , O. Colomban 1 ,M.Tod 1 , I.L. Ray-Coquard 2 , A. Lortholary 3 ,A.<br />
C. Hardy-Bessard 3 , A. Du Bois 4 , J. Huober 5 , W. Meier 6 , C. Kurzeder 4 , J. Pfisterer 7<br />
1 EMR UCBL-HCL 3738, Université Claude Bernard Lyon 1, Pierre Bénite, France,<br />
2 Département d’Oncologie médicale adulte, Centre Léon Bérard, Lyon, France,<br />
3 Oncologie, Centre Catherine de Sienne, Nantes, France, 4 Gynecology, Kliniken<br />
Essen Mitte Evang. Huyssens-Stiftung, Essen, Germany, 5 Gynecology, Ulm<br />
Medical University, Ulm, Germany, 6 Gynecology, Evangelisches Krankenhaus<br />
Düsseldorf, Düsseldorf, Germany, 7 Gynecology, Womens Cancer Center, Kiel,<br />
Germany<br />
Background: Mathematical modeling can be used to analyze longitudinal CA125<br />
kinetics, and predict treatment efficacy. The modeled CA-125 elimination parameter<br />
KELIM was a predictive factor <strong>of</strong> efficacy in CALYPSO trial (You et al. Gynecol Oncol<br />
2013). The present study aims at validating the independent predictive value <strong>of</strong> KELIM<br />
in phase III trial datasets with different 1 st line treatments.<br />
Methods: Data from AGO-OVAR 7 (carboplatin-paclitaxel (CP) +/- topotecan;<br />
n = 1308); AGO-OVAR 9 (CP +/- gemcitabine; n = 1742) and ICON-7 trials (CP +/-<br />
bevacizumab; French dataset only, n= 196) were analyzed. The biggest AGO 9 dataset<br />
was used as a training set, while AGO 7 & ICON7 were used as validation sets. CA125<br />
concentration-time pr<strong>of</strong>iles was fit with following parameters: tumor growth rate<br />
(BETA); CA 125 tumor production (KPROD); CA 125 elimination rate (KELIM) &<br />
treatment indirect effect (Emax relationships) “d[CA125]/dt = (KPROD* exp<br />
(BETA*t)) * (1 - (A/(A + A50))) – KELIM * [CA125]” where t is time. The predictive<br />
value <strong>of</strong> KELIM dichotomized by the median was tested regarding progression free<br />
survival (PFS) against other reported prognostic factors (stage; pathology; surgery/<br />
completeness if any; grade; arms; Rustin) using Cox-models.<br />
Results: Individual CA125 pr<strong>of</strong>iles were well described by the model in training and<br />
validation datasets, as validated by visual predictive checks. KELIM ( 0.0598)<br />
exhibited strong independent predictive value regarding PFS in training dataset<br />
(univariate: 24.0 vs 11.3 months, P < 0.001; multivariate: HR = 0.67, CI95% 0.58-0.76),<br />
and in validation AGO-OVAR 7 set (univariate: 28.9 vs 11.1 m, P < 0.001; multivariate:<br />
HR = 0.58, CI95% 0.40-0.83) & ICON-7 dataset (univariate: 37.5 vs 14.7 m, P < 0.001;<br />
multivariate: HR = 0.65, CI95% 0.44-0.96). KELIM predictive value was consistently<br />
significant using multivariate tests against reported prognostic factors, and higher than<br />
Rustin cut<strong>of</strong>f.<br />
Conclusions: The independent predictive value <strong>of</strong> KELIM was reproducible in large 3<br />
datasets <strong>of</strong> ovarian cancer patients treated with different regimens. This may be a novel<br />
predictive factor, helpful for early selection <strong>of</strong> the best candidates during drug<br />
development.<br />
Legal entity responsible for the study: Benoit You<br />
Funding: ARACGY-GINECO<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
Background: There is a pressing need for second-line systemic treatment for<br />
metastatic, recurrent and/or locally advanced endometrial cancer (AEC) after<br />
hormonal therapy or chemotherapy. We studied the effect <strong>of</strong> the selective<br />
multi-targeted receptor tyrosine kinase inhibitor pazopanib on progression free<br />
survival (PFS) at three months for patients with AEC.<br />
Methods: In this prospective phase II open label study, patients were recruited from six<br />
oncology departments in the Netherlands. Eligible patients had histologically or<br />
cytologically confirmed AEC, documented progressive disease and a WHO performance<br />
status <strong>of</strong> ≤ 2. All participants received treatment with pazopanib 800 mg once daily until<br />
progression, unacceptable toxicity or patient refusal. Dose reductions for toxicity were<br />
allowed. Patients were evaluable for the primary endpoint <strong>of</strong> PFS at three months if they<br />
had received pazopanib for at least four weeks. All participants were analysed for toxicity<br />
and overall survival (OS). The study was powered to demonstrate 50% PFS at 3 months<br />
(vs
abstracts<br />
to increase response rate to chemotherapy both in first-line (ICON7) and in relapse<br />
(OCEANS and AURELIA). Due to concerns about bevacizumab impact on IDS wound<br />
healing, the safety and efficacy <strong>of</strong> nintedanib, an orally available anti-VEGF/PDGFR/<br />
FGFR tyrosine kinase inhibitor with a short half-life was explored in the neo-adjuvant<br />
setting.<br />
Methods: All patients underwent laparoscopy and their disease was considered as<br />
unresectable (impossibility to achieve CC0 at primary surgery). Eligible patients were<br />
randomized (2:1) to receive 3 cycles <strong>of</strong> NACT before IDS and 3 cycles <strong>of</strong> chemotherapy<br />
after IDS with carboplatin + paclitaxel and nintedanib or placebo (at cycle 1&2, 5&6<br />
and at maintenance therapy as single agent during 2 years). The aim <strong>of</strong> IDS was to<br />
achieve CC0. Surgical complications were scored according to Clavien Dindo<br />
classification.<br />
Results: A total <strong>of</strong> 188 patients were included and 121 (64%) patients underwent IDS<br />
(49 in placebo arm and 72 in experimental arm). Pts characteristics are well balanced<br />
between both arms. No significant difference was observed between the placebo and the<br />
nintedanib arm in terms <strong>of</strong> operating procedure duration (360 vs 330 minutes) and<br />
per-operative (18 vs 13%) complications. Bleeding (2 vs 9% <strong>of</strong> the pts), blood losses<br />
(500 vs 675 ml), and transfusion rate (12 vs 26% <strong>of</strong> the pts) were slightly less frequent<br />
in the placebo arm. Around half <strong>of</strong> the patients experienced at least one postoperative<br />
complication: 53% versus 47% in the placebo and nintedanib arm respectively. They<br />
were mostly <strong>of</strong> grade I-II (86% grade I-II, 14% grade III-IVa) with no significant<br />
difference between the two arms in type and grade <strong>of</strong> postoperative complications.<br />
Conclusions: Compare to placebo, the addition <strong>of</strong> the anti-VEGF nintedanib to<br />
neo-adjuvant chemotherapy did not significantly increase the rate <strong>of</strong> per-operative and<br />
post-operative complications <strong>of</strong> the interval debulking surgery.<br />
Clinical trial identification: NCT01583322<br />
Legal entity responsible for the study: ARCAGY-GINECO<br />
Funding: Boehringer Ingelheim<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
860PD<br />
Complete resection rate at interval debulking surgery after<br />
bevacizumab containing neoadjuvant therapy: primary<br />
objective <strong>of</strong> the ANTHALYA trial<br />
R. Rouzier 1 , S. Gouy 2 , F. Selle 3 , E. Lambaudie 4 , F. Guyon 5 , V. Fourchotte 6 ,<br />
C. Pomel 7 , P-E. Colombo 8 , E. Kalbacher 9 , S. Martin-Francoise 10 , R. Fauvet 11 ,<br />
P. Follana 12 , A. Lesoin 13 , F. Lecuru 14 , Y. Ghazi 15 , J. Dupin 15 , E. Chereau 4 ,<br />
S. Zohar 16 , P. Cottu 17 , F. Joly 18<br />
1 Surgery, Curie, St-Cloud, France, 2 Service de Chirurgie Générale, Gustave<br />
Roussy, Villejuif, France, 3 Medical <strong>Oncology</strong>, APHP, CancerEst, Tenon University<br />
Hospital, Paris, France, 4 Chirurgie Oncologique, Institute Paoli Calmettes,<br />
Marseille, France, 5 Surgery, Institute Bergonié, Bordeaux, France, 6 Surgical<br />
<strong>Oncology</strong>, Institut Curie, Paris, France, 7 Surgery, Centre Jean Perrin,<br />
Clermont-Ferrand, France, 8 Surgery, ICM Regional Cancer Institute <strong>of</strong> Montpellier,<br />
Montpellier, France, 9 Surgery, CHU Besançon, Hôpital Jean Minjoz, Besançon,<br />
France, 10 Surgery, Centre Francois Baclesse, Caen, France, 11 Gynecology, CHU<br />
Amiens-Picardie, Amiens, France, 12 Medical <strong>Oncology</strong>, Centre Antoine<br />
Lacassagne, Nice, France, 13 Département de Gynécologie, Centre Oscar<br />
Lambret, Lille, France, 14 Gynecology, Hopital European George Pompidou, Paris,<br />
France, 15 Medical Affairs, Roche, Boulogne-Billancourt, France, 16 U1138, team<br />
22, Inserm, Paris, France, 17 Medical <strong>Oncology</strong>, Institut Curie, Paris, France,<br />
18 Medical <strong>Oncology</strong>, Centre Francois Baclesse, Caen, France<br />
Background: Previously reported safety data from ANTHALYA indicated that adding<br />
3 cycles <strong>of</strong> bevacizumab (B) to neoadjuvant carboplatin and paclitaxel (CP) was<br />
feasible in FIGO stage IIIc/IV ovarian, tubal or peritoneal adenocarcinoma, initially<br />
deemed unresectable. BCP had a good safety pr<strong>of</strong>ile and a pre-specified stopping rule<br />
for toxicity based on Bev-related adverse events (AEs) <strong>of</strong> special interest was not<br />
reached. Here, we evaluated if BCP could help to achieve optimal debulking, as<br />
measured by the complete resection rate (CRR) at interval debulking surgery (IDS).<br />
Methods: In this multicenter, open-label, randomized non comparative Phase II study,<br />
patients were randomized 2:1 to 4 cycles <strong>of</strong> neoadjuvant CP ±3 cycles <strong>of</strong> B (15 mg/kg).<br />
IDS was scheduled 28 ±7 days after the last neoadjuvant treatment course. The primary<br />
objective was to assess the superiority <strong>of</strong> the CRR at IDS (defined as a Completeness <strong>of</strong><br />
Cytoreduction score [CC] <strong>of</strong> 0) in the BCP group compared to a reference rate <strong>of</strong> 45%<br />
(Vergote et al. N Engl J Med 2010;363:943-53) using the Fleming A’Hern method<br />
(p0 = 45%; p1 = 65%; α = 5%; β = 10%).<br />
Results: 205 patients were screened at 15 French sites and 95 were randomized and<br />
included in the modified intention to treat population. Median age was 63 years, 92%<br />
had ECOG-PS 0/1, with 70% FIGO stage IIIc and 30% stage IV tumors. In the BCP<br />
group (58 patients) the CRR at IDS was 58.6% (34 patients) with a lower confidence<br />
limit <strong>of</strong> 47.0%, significantly higher than the prespecified minimum threshold <strong>of</strong> 45%.<br />
IDS was performed in 69% (40 patients) <strong>of</strong> whom 85% had a complete resection. The<br />
CRR was 63.5% in patients with ≥2 cycles <strong>of</strong> Bev (52 patients). In the CP group (37<br />
patients), IDS was done in 22 (60%) patients with a CRR <strong>of</strong> 51.4%.<br />
Conclusions: The study primary objective was met as the CRR was significantly higher<br />
than the previously reported reference rate. Adding Bev to neoadjuvant CP achieved an<br />
encouraging CRR at IDS in patients with initially unresectable FIGO stage IIIc/IV<br />
ovarian, tubal or peritoneal adenocarcinoma.<br />
Clinical trial identification: NCT01739218<br />
Legal entity responsible for the study: Roche<br />
Funding: Roche<br />
Disclosure: R. Rouzier: Advisory board. S. Gouy, F. Selle, C. Pomel, E. Chereau,<br />
P. Cottu, F. Joly: Board Y. Ghazi, J. Dupin: Employee. All other authors have declared<br />
no conflicts <strong>of</strong> interest.<br />
861P<br />
ICON8 Stage 1A and 1B analysis: safety and feasibility <strong>of</strong><br />
weekly carboplatin and paclitaxel regimens in first-line<br />
ovarian cancer<br />
E.C. James 1 , J. Hook 1 , S. Stenning 1 , A. Cook 1 , C. Coyle 1 , J. Petrie 1 , R. Kaplan 1 ,<br />
I. McNeish 2 , T. Perren 3 , R. Naik 4 , S. Banerjee 5 , J.A. Ledermann 6 , A. Clamp 7<br />
1 MRC Clinical Trials Unit at UCL, Institute <strong>of</strong> Clinical Trials and Methodology-UCL,<br />
London, UK, 2 Institute <strong>of</strong> Cancer Sciences, University <strong>of</strong> Glasgow, Glasgow, UK,<br />
3 Leeds Institute <strong>of</strong> Cancer Medicine and Pathology, Univeristy <strong>of</strong> Leeds and<br />
St. James University Hospital, Leeds, UK, 4 Northern Gynaecological <strong>Oncology</strong><br />
Centre, Queen Elizabeth Hospital, Gateshead, UK, 5 Gynaecological Unit, The<br />
Royal Marsden NHS Foundation Trust, London, UK, 6 CR-UK & UCL Cancer Trials<br />
Centre, UCL Cancer Institute, University College London, London, UK, 7 Medical<br />
<strong>Oncology</strong>, The Christie NHS Foundation Trust and Institue <strong>of</strong> Cancer Sciences,<br />
University <strong>of</strong> Manchester, Manchester, UK<br />
Background: ICON8 is a randomised GCIG phase III 3-arm trial comparing 6 cycles<br />
<strong>of</strong> standard 3-weekly (q3w) carboplatin/paclitaxel with weekly (q1w) dose-dense<br />
treatment. Patients had immediate primary surgery (IPS) or neo-adjuvant<br />
chemotherapy and delayed primary surgery (DPS) after 3 cycles. Two interim analyses<br />
were planned: 1A, first 50 patients (pts) in each arm; 1B, first 50 DPS pts in each arm,<br />
ICON8 being the first trial <strong>of</strong> dose-dense treatment with DPS.<br />
Methods: 1566 women were randomised between Jun 2011 and Nov 2014 to: Arm 1 -<br />
q3w carboplatin AUC5/6 + paclitaxel 175mg/m 2 ; Arm 2 - q3w carboplatin AUC5/<br />
6 + q1w paclitaxel 80mg/m 2 ; Arm 3 - q1w carboplatin AUC2 + paclitaxel 80 mg/m 2 .<br />
The interim safety analyses included 237 patients. Feasibility was measured by<br />
completion <strong>of</strong> protocol treatment, safety by the rate <strong>of</strong> any G3+ toxicity experienced<br />
per patient.<br />
Results: Stage 1A analysis included 85 IPS and 65 DPS pts, median age 59 years and<br />
64% stage IIIC/IV disease. Stage 1B included 87 further DPS pts (total DPS = 152),<br />
median age 62 years, 92% stage IIIC/IV. Protocol treatment completion was lower than<br />
expected but >80% 1A and >75% 1B pts received 6 cycles <strong>of</strong> platinum chemotherapy.<br />
Increased paclitaxel dose intensity was achieved (see table). Most common reason for<br />
not completing protocol treatment was toxicity. G3+ toxicity was more frequent in<br />
arms 2 and 3, mainly due to uncomplicated neutropenia.<br />
Arm 1<br />
n=50<br />
Feasibility<br />
Protocol treatment completion, N(%) 39 (78%)<br />
P-value (compared to arm 1)<br />
-<br />
6 cycles platinum chemotherapy, N(%) 44 (88%)<br />
P-value (compared to arm 1)<br />
-<br />
Carboplatin dose intensity (AUC/week)<br />
median<br />
Paclitaxel dose intensity (mg/m 2 /weed)<br />
median<br />
Toxicity<br />
Table: 861P<br />
Stage 1A Stage 1A Stage 1A Stage 1B Stage 1B Stage 1B<br />
Arm 2<br />
n=50<br />
Arm 3<br />
n=50<br />
Arm 1<br />
n=50<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Arm 2<br />
n=52<br />
Arm 3<br />
n=50<br />
29 (58%)<br />
0.03<br />
29 (58%)<br />
0.03<br />
29 (58%)<br />
-<br />
34 (65%)<br />
0.47<br />
25 (50%)<br />
0.42<br />
46 (92%) 40 (80%) 40 (80%) 46 (88%) 39 (78%)<br />
0.51 0.23 - 0.27 0.81<br />
1.79 1.86 1.83 1.82 1.78 1.77<br />
53.5 64.1 67.8 51.3 65.5 67.9<br />
G3/4+ Toxicity, N(%) 17 (35%) 29 (58%) 24 (48%) 24 (50%) 33 (63%) 23 (46%)<br />
G3/4+ Uncomplicated neutropenia, N 4 (8%) 16 (32%) 11 (22%) 5 (10%) 19 (37%) 13 (26%)<br />
(%)<br />
G3/4+ Febrile neutropenia, N(%) 2 (4%) 1 (2%) 1 (2%) 1 (2%) 3 (6%) 0<br />
G3/4+ Thrombocytopenia, N(%) 2 (4%) 2 (4%) 1 (2%) 2 (4%) 3 (6%) 1 (2%)<br />
G2+ Sensory neuropathy, N(%) 12 (25%) 15 (30%) 9 (18%) 16 (33%) 6 (12%) 5 (10%)<br />
Conclusions: Completion <strong>of</strong> 6 cycles <strong>of</strong> platinum chemotherapy was high; however,<br />
protocol-defined q1w regimens were frequently modified. Protocol treatment<br />
completion differed significantly between arms in stage 1A, but not 1B, perhaps<br />
reflecting q3w paclitaxel toxicity in DPS patients. Rates <strong>of</strong> clinically relevant toxicity<br />
were acceptable, and despite aggressive dosing thresholds febrile neutropenia was rare.<br />
No dose modifications were implemented following stage 1A/1B analyses, but early use<br />
<strong>of</strong> G-CSF was recommended. PFS results are expected in Q2 2017, OS in 2018.<br />
Clinical trial identification: ISCCTN ISRCTN10356387; EudraCT 2010-022209-16<br />
Legal entity responsible for the study: Medical Research Council<br />
Funding: Cancer Research UK<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
vi298 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
862P<br />
Hormonal therapy for epithelial ovarian cancer: a systematic<br />
review and meta-analysis <strong>of</strong> phase II studies<br />
L. Paleari 1 , N. Provinciali 1 , M. Puntoni 2 , C. Defferrari 1 , M. Di Luca 3 , F. Gorlero 3 ,<br />
A. Decensi 1<br />
1 Medical <strong>Oncology</strong>, Ospedali Galliera, Genoa, Italy, 2 Clinical Trial and Biostatistical<br />
Unit, Scientific Direction, Ospedali Galliera, Genoa, Italy, 3 Division <strong>of</strong> Gynecology<br />
and Obstetrics, Ospedali Galliera, Genoa, Italy<br />
Background: Endocrine therapy is a common clinical practice in epithelial ovarian<br />
cancer (EOC) and hormonal receptors have been associated with response and survival<br />
in recent studies. However, the degree <strong>of</strong> activity <strong>of</strong> endocrine therapy overall and by<br />
specific agents remains unclear.<br />
Methods: Objective response rates (ORR) from phase II trials <strong>of</strong> different hormonal<br />
manipulations in EOC patients were meta-analyzed. Pooled estimates (PES) from<br />
random effect models were calculated according to type <strong>of</strong> intervention, ER/PgR status,<br />
tamoxifen dose, year <strong>of</strong> study and platinum resistance. Two randomized trials were<br />
excluded from analysis given their low number.<br />
Results: The analyses encompassed a total <strong>of</strong> 35 phase II trials including 1.690 patients.<br />
Overall, we obtained a PES = 0.37 [95%CI, 0.28-0.46] with any endocrine treatment. By<br />
specific agent class, PES was = 0.31 [95%CI, 0.23-0.39] for aromatase inhibitors, 0.40<br />
[95%CI, 0.21-0.58] for tamoxifen, 0.41 [95%CI, 0.23-0.59] for estro-progestins, 0.39<br />
[95%CI, 0.25-0.52] for tamoxifen plus progestins, 0.30 [95%CI, 0.20-0.40] for<br />
progestins, 0.14 [95%CI, 0-0.58] for the anti-androgen flutamide, 0.50 [95%CI,<br />
0.31-0.69] for tamoxifen plus goserelin, 0.52 [95%CI, 0.32-0.72] for the ER<br />
downregulator fulvestrant, even though the last three categories included only one<br />
study each. The PES was better in studies including patients with ER + ve or PgR + ve<br />
disease [PES= 0.43, 95%CI, 0.34-0.52] compared with hormone receptor -ve [PES=<br />
0.17, 95%CI, 0.09-0.24] or mixed [PES= 0.31 95%CI, 0.17-0.46] disease. High<br />
tamoxifen doses (>20 mg/day) exhibited a worse PES= 0.36 [95%CI, 0.16-0.57] than<br />
the standard dose <strong>of</strong> 20 mg/day (PES = 0.50 [95%CI, 0.13-0.87]. A slightly better<br />
response was noted in platinum resistant [PES= 0.35, 95%CI, 0.19-0.50] vs platinum<br />
sensitive patients [PES= 0.43, 95%CI, 0.3-0.57]. There was no evidence for a response<br />
trend by year <strong>of</strong> study.<br />
Conclusions: The activity <strong>of</strong> endocrine therapy in advanced EOC looks promising but<br />
has not adequately been evaluated in definitive clinical trials. Given the recent evidence<br />
for a prognostic value <strong>of</strong> hormone receptors in EOC, our findings support the<br />
implementation <strong>of</strong> randomized trials in hormone receptor positive EOC.<br />
Legal entity responsible for the study: E.O. Galliera<br />
Funding: Italian Association for Cancer Research (AIRC)<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
863P<br />
Non pegylated liposomal doxorubicin (npld,<br />
myocettm) + carboplatin (cb) in patients (pts) with ovarian<br />
cancer in late relapse (oclr): a phase 2 gineco study<br />
B. You 1 , F. Joly 2 , I.L. Ray-Coquard 3 , C. El Kouri 4 , A. Mercier-Blas 5 ,<br />
D. Berton-Rigaud 6 , E. Kalbacher 7 , O. Cojocarasu 8 , M. Fabbro 9 , J. Cretin 10 ,<br />
A. Zannetti 11 , S. Abadie-Lacourtoisie 12 , D. Mollon 13 , A-C. Hardy-Bessard 14 ,<br />
M. Provansal 15 ,G.Freyer 1<br />
1 Oncologie Médicale, Centre Hospitalier Lyon Sud, Pierre Bénite, France,<br />
2 Oncologie, Centre Francois Baclesse, Caen, France, 3 Service 2B Nord, Centre<br />
Léon Bérard, Lyon, France, 4 Oncologie Médicale, Centre Catherine de Sienne,<br />
Nantes, France, 5 Oncologie Médicale, Centre Hospitalier Privé de Saint-Grégoire,<br />
Saint-Grégoire, France, 6 <strong>Oncology</strong>, ICO Centre René Gauducheau,<br />
Saint-Herblain, France, 7 Radiothérapie - Oncologie, CHU Besançon, Hôpital Jean<br />
Minjoz, Besançon, France, 8 Médecine Interne et Oncologie Médicale, Pavillon<br />
Reilly, Centre Hospitalier Du Mans, Le Mans, France, 9 Médecine B2, ICM Val<br />
d’Aurelle, Montpellier, France, 10 Oncologie - Radiothérapie, Polycliniques Kenval -<br />
Site Valdegour, Nimes, France, 11 Oncologie Médicale, CH Cholet, Cholet, France,<br />
12 Oncologie Médicale, ICO Paul Papin, Angers, France, 13 Service Radiothérapie et<br />
Oncologie Médicale, Centre Hospitalier Intercommunal de Cornouaille, Quimper,<br />
France, 14 Oncologie Médicale, Centre CARIO - HPCA, Plerin-sur-Mer, France,<br />
15 Oncologie Médicale, Institute Paoli Calmettes, Marseille, France<br />
Background: Cb + pegylated liposomal doxorubicin (PLD) is standard in OCLR.<br />
Because <strong>of</strong> recurrent PLD shortage, we explored the efficacy and tolerance <strong>of</strong> Cb-NPLD<br />
Methods: From 11/2012 to 07/2014, 86 pts with OCLR received Cb AUC 5 mg.min/ml<br />
and NPLD 50 mg/m 2 , day 1 q4weeks with prophylactic G-CSF support. Primary<br />
objective was disease control rate (DCR) at 12 mos. Disease progression was defined<br />
according to GCIG criteria including RECIST, CA125 or clinical deterioration.<br />
Results: A total <strong>of</strong> 69 pts (80%) completed 6 cycles and 7 (9%) continued up to 9<br />
cycles, with G-CSF support (96%). Pts characteristics were: median age 67 years (range<br />
60-75); serous histology (90%); prior platinum (100%), taxane (94%) and bevacizumab<br />
(33%); platinum-free interval 6-12 (PFI) (44%) or > 12 mos (56%); 67 (78%) pts had 1<br />
previous line <strong>of</strong> chemotherapy (CT) and 19 (22%) had 2. DCR at 12 mos was 40%.<br />
Median PFS was 11.4 mos (95% CI: 10.2-13.1). OS is not mature (33% events).<br />
Complete response rate was 21% and objective response rate was 58% (95% CI: 47-68),<br />
49% (95% CI: 32-65) and 64% (95% CI: 50-78) in the global population, in pts with<br />
6-12 or > 12 mos PFI, respectively. Grade (G) 3/4 neutropenia, thrombocytopenia and<br />
anemia were observed in 23, 13 and 11% respectively with febrile neutropenia in 6%.<br />
Non hematological toxicities were the followings: G3 fatigue (13%), nausea (8%),<br />
vomiting (6%), hand-foot syndrome (1%), pulmonary embolism (1%); G2 alopecia<br />
(39%). Junctional tachycardia (JT) in a pt with JT history was the only cardiac event<br />
observed. One pt who did not receive prophylactic G-CSF support died from febrile<br />
neutropenia.<br />
Conclusions: Cb + NPLD is an alternative carboplatin-based regimen for OC in late<br />
relapse. Activity and toxicity pr<strong>of</strong>ile are in the range <strong>of</strong> other regimens, but<br />
prophylactic G-CSF support is required.<br />
Clinical trial identification: NCT01705158<br />
Legal entity responsible for the study: ARCAGY-GINECO<br />
Funding: Teva<br />
Disclosure: F. Joly: For consulting or advisory role : Roche, San<strong>of</strong>i, Pfizer For Research<br />
funding : Astellas, Pfizer For travel, accomodations, expenses : Roche, Janssen,<br />
Novartis. I.L. Ray-Coquard: For consulting or advisory role: Pharmamar, Roche,<br />
AstraZeneca, MSD For travel, accomodations, expenses: Pharmamar, Roche. A-C.<br />
Hardy-Bessard: For Travel, accomodation, expenses: Astrazeneca, Novartis, Roche G.<br />
Freyer: For consulting or advisory role: Teva. All other authors have declared no<br />
conflicts <strong>of</strong> interest.<br />
864P<br />
abstracts<br />
A phase 1b study <strong>of</strong> the nanoparticle-drug conjugate (NDC)<br />
CRLX101 in combination with weekly paclitaxel in patients<br />
(pts) with platinum-resistant ovarian cancer (OC)<br />
C.N. Krasner 1 , R.J. Schilder 2 , W.E. Brady 3 , L.R. Duska 4 ,D.O’Malley 5 ,P.<br />
A. Disilvestro 6 ,J.Li 7 , W. Downing 7 , A. Senderowicz 7<br />
1 Hematology/<strong>Oncology</strong>, Massachusetts General Hospital, Boston, MA, USA,<br />
2 Medical <strong>Oncology</strong>, Thomas Jefferson University, Philadelphia, PA, USA,<br />
3 Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY, USA,<br />
4 Gynecologic <strong>Oncology</strong>, University <strong>of</strong> Virginia, Charlottesville, VA, USA, 5 Obstetrics<br />
and Gynecology, The Ohio State University James Cancer Hospital, Columbus,<br />
OH, USA, 6 Gynecologic <strong>Oncology</strong>, Women & Infants Hospital Warren Alpert<br />
Medical School <strong>of</strong> Brown Univ, Providence, RI, USA, 7 Medical Affairs, Cerulean<br />
Pharma, Inc., Waltham, MA, USA<br />
Background: Cerulean Pharma, Inc. is developing CRLX101, an investigational NDC<br />
with a camptothecin payload. CRLX101 has been investigated in more than 350 pts as<br />
monotherapy or in combination with bevacizumab in pts with renal cell carcinoma<br />
(Keefe, ASCO 2015, abstract #4543) and platinum-refractory OC (Krasner, ASCO<br />
2014, abstract #5581). Preclinical and early clinical data suggest synergy between<br />
taxanes and topoisomerase 1 inhibitors. We started a Phase 1b trial for this<br />
combination in pts with platinum-resistant OC.<br />
Methods: Cohorts <strong>of</strong> 3 pts were accrued in this trial. Two dose levels <strong>of</strong> CRLX101<br />
(every other week) in combination with weekly [wkly] paclitaxel 80 mg/m 2 (3 wks on/1<br />
wk <strong>of</strong>f) were planned: dose level 1, CRLX101 12 mg/m 2 ; dose level 2, CRLX101 15 mg/<br />
m 2 . The primary objective was to determine the maximum tolerated dose <strong>of</strong> CRLX101<br />
in combination with wkly paclitaxel. Secondary objectives included pharmacokinetics,<br />
safety, tolerability, and clinical activity.<br />
Results: As <strong>of</strong> March 11, 2016, 9 pts have been enrolled and treated at dose levels 1<br />
(n = 3) and 2 (n = 6); all pts were evaluable for safety and response. Median age was 61<br />
years (range, 49–73); median number <strong>of</strong> previous regimens was 3 (range, 1–4). GOG<br />
score performance status was 0 (6 pts) or 1 (3 pts). No dose-limiting toxicities have<br />
been reported at either dose level, thus the RP2D is CRLX101 15 mg/m 2 (every other<br />
week) and paclitaxel 80 mg/m 2 (3 weeks on/1 week <strong>of</strong>f). Treatment-related adverse<br />
events (AEs) included fatigue (6/9, 67%), neutrophil count decreased (4/9, 44%),<br />
nausea (4/9, 44%), vomiting, alopecia, headache, infusion-related reaction, and urinary<br />
tract infection (2/9, 22% for all). The only grade ≥3 treatment-related AE was<br />
neutropenia, which occurred in 2 pts (1 grade 3; 1 grade 4). Partial response and stable<br />
disease rates were 56% (5/9) and 11% (1/9), respectively. Moreover, CA125 responses<br />
(≥50% decline from baseline) were demonstrated in 33% (3/9) <strong>of</strong> pts. Two pts (at 15<br />
mg/m 2 ) are still receiving therapy.<br />
Conclusions: CRLX101 given every other wk in combination with wkly paclitaxel has<br />
demonstrated early signs <strong>of</strong> antitumor activity and has been generally well tolerated to<br />
date in pts with platinum-resistant OC.<br />
Clinical trial identification: NCT02389985<br />
Legal entity responsible for the study: Cerulean Pharma, Inc.<br />
Funding: Cerulean Pharma, Inc.<br />
Disclosure: R.J. Schilder: reports personal fees from Millennium, Clovis, MedImmune<br />
and Merck Serrano. D. O’Malley: reports personal fees from Clovis, Janssen,<br />
AstraZeneca, Genentech/Roche, Eisai and Clovis. J. Li, W. Downing, A. Senderowicz: is<br />
an employee <strong>of</strong> Cerulean Pharma, Inc. All other authors have declared no conflicts <strong>of</strong><br />
interest.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw374 | vi299
abstracts<br />
865P<br />
Hypersensitivity reactions to antineoplastic agents in<br />
BRCA-mutated ovarian cancer (OC) patients: a single centre<br />
experience<br />
E. Maccaroni 1 , R. Bracci 1 , R. Giampieri 2 , F. Bianchi 1 , L. Belvederesi 1 , C. Brugiati 1 ,<br />
S. Pagliaretta 1 , A. Della Mora 3 , F. Tronconi 3 , M. Pistelli 4 , A. Pagliacci 4 , N. Battelli 4 ,<br />
Z. Ballatore 3 , M. De Lisa 3 , R. Berardi 1<br />
1 1. Clinica di Oncologia Medica e Centro Regionale di Genetica Oncologica, AOU<br />
Ospedali Riuniti Ancona Università Politecnica delle Marche, Ancona, Italy,<br />
2 <strong>Oncology</strong>, Università Politecnica delle Marche, Dipartimento Scienze Cliniche e<br />
Molecolari - Azienda Ospedaliera Ospedali Riuniti di Ancona, Ancona, Italy,<br />
3 Clinica di Oncologia Medica-AOU Ospedali Riuniti, Università Politecnica delle<br />
Marche, Ancona, Italy, 4 Clinica di Oncologia Medica-AOU Ospedali Riuniti, AOU<br />
Ospedali Riuniti Ancona Università Politecnica delle Marche, Ancona, Italy<br />
Background: Platinum-based chemotherapy represents the standard <strong>of</strong> care after<br />
surgery for OC, improving survival in patients (pts) with newly diagnosed advanced<br />
OC and in pts with recurrent platinum-sensitive disease. About 10-15% <strong>of</strong> OC pts has<br />
a germline mutation in BRCA 1/2 genes. Patients with BRCA mutation have a better<br />
prognosis and response to platinum-based therapy. Hypersensitivity reactions (HSRs)<br />
to chemotherapeutic agents are common and can limit their use: HSRs to carboplatin<br />
have been reported in about 15-20% <strong>of</strong> women. The aim <strong>of</strong> our study was to evaluate<br />
the incidence <strong>of</strong> HRSs to platinum compounds and other antineoplastic agents<br />
(taxanes, lyposomal anthracyclines) in BRCA-mutated OC pts.<br />
Methods: Patients eligible for analysis were OC pts treated in Our Center from 2010 to<br />
2015. We retrospectively collected data regarding histopathological type, treatment,<br />
HSRs and genetic testing results. We assessed the correlation between incidence <strong>of</strong><br />
HSRs and BRCA mutation status. The analysis was performed by Fisher exact test or by<br />
Chi-square test for categorical variables.<br />
Results: Out <strong>of</strong> 60 OC eligible pts, BRCA was evaluated in 32 pts. Among them, 16 had<br />
a pathogenic BRCA mutation (9 pts with a BRCA2 mutation, 6 pts with a BRCA1<br />
mutation and 1 pts with both BRCA1 and BRCA2 mutations), in 16 patients genetic<br />
testing resulted negative. In pts with BRCA-mutated OC, a significant increase in HSRs<br />
to drugs was observed [11/16 (68%) vs 4/16 (25%), p = 0.03]. Looking at the group <strong>of</strong><br />
patients who developed HSRs to platinum-based compounds (10 total cases <strong>of</strong> HSRs in<br />
both groups, 9 in BRCA-mutated pts and 1 case in BRCA wild-type (wt) pts), a<br />
significantly higher incidence <strong>of</strong> HSRs was observed in the group <strong>of</strong> BRCA-mutated pts<br />
[9/14 (64%) vs 1/13 (8%), p = 0.004].<br />
Conclusions: Our analysis suggests that BRCA mutated OC pts might have an<br />
increased incidence <strong>of</strong> HSRs compared to BRCA wt pts. This might be due to a<br />
repeated exposure to platinum-based compounds or to an increased immune reactivity<br />
in this group <strong>of</strong> pts. If confirmed, these data may complicate the use <strong>of</strong><br />
PARP-inhibitors in BRCA-mutated pts, registered only for relapsed OC pts in<br />
maintenance after rechallenge <strong>of</strong> platinum-based chemotherapy.<br />
Legal entity responsible for the study: The study was coordinated by Clinica di<br />
Oncologia Medica.<br />
Funding: This study was performed in AOU Clinica di Oncologia Medica without any<br />
external funding<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
866P<br />
The socioeconomic burden <strong>of</strong> ovarian cancer in Spain<br />
L. Delgado-Ortega 1 , A.G. Domínguez 2 , C. Moya-Alarcón 1 , Á. Hidalgo 3 ,<br />
L. Cordero 1 , M. Jiménez 2 , A. Gascó 4 , R. Villoro 2 , J. Borras 5 , E. González-Haba 6 ,<br />
S. Menjón 7 , J. Oliva 8 , P. Pérez 9 , D. Vicente 10<br />
1 HEOR, AstraZeneca España, Madrid, Spain, 2 HEOR, Weber Economía y Salud,<br />
Madrid, Spain, 3 Foundations <strong>of</strong> Economic Analysis, University <strong>of</strong> Castilla-La<br />
Mancha, Toledo, Spain, 4 Medical Department, AstraZeneca España, Madrid,<br />
Spain, 5 <strong>Oncology</strong>, CatSalut, Barcelona, Spain, 6 Oncological Pharmacy, Hospital<br />
General Universitario Gregorio Marañón, Madrid, Spain, 7 Gynecologic <strong>Oncology</strong>,<br />
Hospital Universitario Virgen de las Nieves, Granada, Spain, 8 Economy, University<br />
<strong>of</strong> Castilla-La Mancha, Toledo, Spain, 9 Genetics, Instituto de Salud Carlos III<br />
(ISCIII), Madrid, Spain, 10 <strong>Oncology</strong>, Hospital Universitario Virgen Macarena,<br />
Seville, Spain<br />
Background: Ovarian cancer (OC) has relatively low prevalence and incidence rates in<br />
Spain (11.1 and 10.2 per 100,000 women per year, respectively), but is the second most<br />
frequent gynecological cancer and the sixth leading cause <strong>of</strong> cancer death in Spain.<br />
Survival is related to the diseasés stage at time <strong>of</strong> diagnosis. Epithelial OC represents<br />
90% <strong>of</strong> total OC cases. Its economic burden in Spain was previously unknown.<br />
Methods: We developed a Markov model from a social perspective simulating the<br />
natural history <strong>of</strong> epithelial OC and its four stages, with a 10-year time horizon, 3 week<br />
cycles, 3% discount rate, and 2015 €. Healthcare resource utilization and costs were<br />
estimated by disease stage. Direct healthcare costs (DHC) included early screening,<br />
genetic counselling, medical visits, diagnostic tests, surgery, chemotherapy,<br />
hospitalizations, emergency services, and palliative care. Direct non-healthcare costs<br />
(DNHC) included formal and informal care. Indirect costs (IC) included labour<br />
productivity losses due to temporary and permanent leaves, and premature death.<br />
Epidemiological data and resource use in all stages were taken from the literature and<br />
validated for Spain by the Ovarcost group (a Spanish multidisciplinary advisory board)<br />
using a Delphi process.<br />
Results: The total cost <strong>of</strong> epithelial OC over 10 years was €2,469 mill: €278 mill (11%)<br />
in stage I, €142 mill (6%) in stage II, €1,478 mill (60%) in stage III and €572 mill (23%)<br />
in stage IV. Mean total cost per patient per year was €30,098: €9,723€, €16,080, €42,308<br />
€ and €44,798 in stages I to IV. Of total costs, 69% were due to DHC, 28% to DNHC<br />
and 3.0% to IC. DHC were €162 mill in stage I, €82 mill in stage II, €979 mill in stage<br />
III and €487 mill in stage IV. Mean DHC per patient per year was €21,499. DNHC<br />
were €60 mill in stage I, €52 mill in stage II, and €490 mill and €85 mill in stages III<br />
and IV, respectively. Mean DNHC per patient per year was €7,718.<br />
Conclusions: Epithelial OC imposes a significant burden on the national health system<br />
and society as a whole in Spain. Investment in better early diagnosis techniques might<br />
increase survival and patientś quality <strong>of</strong> life, which would likely reduce costs <strong>of</strong> late<br />
stages, leading in turn to a substantial reduction <strong>of</strong> the economic burden associated<br />
with OC.<br />
Legal entity responsible for the study: AstraZeneca<br />
Funding: AstraZeneca<br />
Disclosure: L. Delgado-Ortega, C. Moya-Alarcón, L. Cordero, A. Gascó: Working in<br />
Astrazeneca. Astrazeneca but it has not interfered in the results. A.G. Domínguez, Á.<br />
Hidalgo, M. Jiménez, R. Villoro: Astrazeneca has funded the project but has not<br />
intervened in the same. J. Borras: Honoraria as an expert consultant to the project. E.<br />
González-Haba, S. Menjón, J. Oliva, P. Pérez, D. Vicente: Honoraria as an expert<br />
consultant to the project.<br />
867P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Impact <strong>of</strong> age on the safety and efficacy <strong>of</strong> bevacizumab<br />
(BEV)-containing therapy in patients (pts) with primary ovarian<br />
cancer (OC): Analyses <strong>of</strong> the OTILIA German<br />
non-interventional study on behalf <strong>of</strong> the North-Eastern<br />
German Society <strong>of</strong> Gynaecological <strong>Oncology</strong> Ovarian Cancer<br />
Working Group<br />
A. Mustea 1 , P. Wimberger 2 , G. Oskay-Oezcelik 3 , P. Jungberg 4 , W. Meinerz 5 ,<br />
D. Reichert 6 , J. Janssen 7 , M. Keller 8 , R. Richter 9 , J. Harde 10 , S. Klawitter 11 ,<br />
A. Wegenaer 12 , M. Mueller 13 , J. Sehouli 9<br />
1 Gynecology, University Medicine Greifswald, Greifswald, Germany, 2 Gynecology<br />
and Obstetrics, Carl-Gustav-Carus University Dresden, TU Dresden, Dresden,<br />
Germany, 3 Gynecologic <strong>Oncology</strong>, Praxisklinik Krebsheilkunde fuer Frauen, Berlin,<br />
Germany, 4 Gynecologic <strong>Oncology</strong>, Private Practice, Chemnitz, Germany,<br />
5 Gynecology and Obstetrics, St. Vincenz-Krankenhaus, Paderborn, Germany,<br />
6 <strong>Oncology</strong> and Hematology, Medizinische Studiengesellschaft Nord-West GmbH,<br />
Westerstede, Germany, 7 <strong>Oncology</strong>, Private Practice, Westerstede, Germany,<br />
8 Charité Medical University <strong>of</strong> Berlin, North-Eastern-German Society <strong>of</strong><br />
Gynaecological <strong>Oncology</strong> (NOGGO e.V.), Berlin, Germany, 9 Gynecology, Charité /<br />
University Hospital Berlin, Berlin, Germany, 10 Statistics, Data Management and<br />
Medical Informatics, IOMEDICO AG, Freiburg, Germany, 11 Biostatistics and<br />
Epidemiology, Roche Pharma AG, Grenzach-Wyhlen, Germany, 12 Medical Affairs,<br />
Roche Pharma AG, Grenzach-Wyhlen, Germany, 13 Hematology/<strong>Oncology</strong>,<br />
Outpatient Therapy Centre Offenburg, Offenburg, Germany<br />
Background: The efficacy and tolerability <strong>of</strong> front-line BEV combined with<br />
carboplatin–paclitaxel (CP) for OC has been demonstrated in randomised phase III<br />
trials. To assess the safety and effectiveness <strong>of</strong> front-line BEV-containing therapy in the<br />
real-world setting in Germany, we initiated the single-arm non-interventional OTILIA<br />
study. The latter part <strong>of</strong> OTILIA focused on elderly pts. We report the second interim<br />
analysis.<br />
Methods: Pts with FIGO stage IIIB–IV OC received front-line BEV + CP according to<br />
the EU label. Adverse events were recorded at each cycle and graded using CTCAE<br />
v4.0. Investigators assessed response according to local practice. Exploratory analyses<br />
compared safety and efficacy according to age.<br />
Results: Between Feb 2012 and Jan 2016, 713 pts from 200 centres received<br />
BEV-containing treatment per the EU label. More pts aged
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Parameter<br />
Table: 867P<br />
Age A (rs699947) and c.-1154G > A (rs1570360), and the<br />
variant allele <strong>of</strong> VEGF c.-460C > T (rs833061) polymorphisms were associated with<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw374 | vi301
abstracts<br />
higher VEGF production than the remaining alleles. We aimed to analyze herein the<br />
roles <strong>of</strong> these SNPs in outcome <strong>of</strong> EOC patients.<br />
Methods: Our analysis included 85 EOC patients seen at diagnosis seen from 1996 to<br />
2007 (median age: 53 years; tumor <strong>of</strong> type I: 56, type II: 29; tumor at stage I: 37, stages<br />
II to IV: 48). Patients were treated with tumour resection and cisplatin-based<br />
chemotherapy. DNA from peripheral blood was analyzed by real-time polymerase<br />
chain reaction for genotyping <strong>of</strong> the polymorphisms. Progression free survival (PFS)<br />
and overall survival (OS) were estimated using the Kaplan-Meier method and curves<br />
were compared by the log-rank test. The Cox hazards model was used to identify<br />
prognostic variables influencing survival in univariate analysis, and significant results<br />
were validated using a bootstrap resembling study to investigate the stability <strong>of</strong> risk<br />
estimates (1,000 replications).<br />
Results: The median follow-up was 96 months. At 24 months <strong>of</strong> follow-up, PFS was<br />
shorter in patients with 50 years or more (71.6% versus 89.2%, P= 0.01), tumour <strong>of</strong><br />
type II (62.1% versus 86.8%, P= 0.02) and at stage II to IV (63.6% versus 97.5%, P=<br />
0.0001), and VEGF c.2578 CC genotype (72.4% versus 90.5%, P= 0.04) compared to<br />
others. OS was shorter in patients with tumour <strong>of</strong> type II (75.9% versus 93.3%, P=<br />
0.009) and at stage II to IV (79.5% versus 97.5%, P= 0.0001) at this time. Patients with<br />
the VEGF c.2578 CC genotype had 2.15 more chances <strong>of</strong> presenting disease<br />
progression than others. Differences between groups remained the same in univariate<br />
Cox analysis, and were validated by the bootstrap study.<br />
Conclusions: Our data suggest that inherited abnormality in AG pathway, related to<br />
VEGF c.-2578C > A SNP, acts as a prognostic factor in EOC.<br />
Legal entity responsible for the study: UNICAMP<br />
Funding: UNICAMP<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
871P<br />
Safety, clinical activity and biomarkers <strong>of</strong> atezolizumab (atezo)<br />
in advanced ovarian cancer (OC)<br />
J.R. Infante 1 , F. Braiteh 2 , L.A. Emens 3 , A.S. Balmanoukian 4 , A. Oaknin 5 ,Y.Wang 6 ,<br />
B. Liu 6 , L. Molinero 7 , M. Fasso 8 ,C.O’Hear 8 , M. Gordon 9<br />
1 Drug Development Program, Sarah Cannon Research Institute/Tennessee<br />
<strong>Oncology</strong>, PLLC, Nashville, TN, USA, 2 Medicine, Comprehensive Cancer Centers<br />
<strong>of</strong> Nevada, Las Vegas, NV, USA, 3 School <strong>of</strong> Medicine, Johns Hopkins University,<br />
Baltimore, MD, USA, 4 Medical <strong>Oncology</strong>, The Angeles Clinic and Research<br />
Institute, Los Angeles, CA, USA, 5 Vall d’Hebron University Hospital Institut<br />
d’Oncologia, Barcelona, Spain, 6 Biostatistics, Genentech, Inc., South<br />
San Francisco, CA, USA, 7 <strong>Oncology</strong> Biomarker Department, Genentech, Inc.,<br />
South San Francisco, CA, USA, 8 Product Development <strong>Oncology</strong>, Genentech Inc,<br />
A Member <strong>of</strong> the Roche Group, South San Francisco, CA, USA, 9 Division <strong>of</strong><br />
Arizona Center for Cancer Care, Pinnacle <strong>Oncology</strong> Hematology, Scottsdale, AZ,<br />
USA<br />
Background: OC usually presents at an advanced stage and has high rates <strong>of</strong><br />
recurrence and mortality. Most pts die <strong>of</strong> drug-resistant OC within 5 y, highlighting the<br />
need for new therapies. As OC with high T cell infiltrates at diagnosis has longer OS,<br />
we examined atezolizumab (atezo; anti-PDL1) in pts with recurrent OC.<br />
Methods: Pts received atezo IV q3w (0.3-15 mg/kg) in a Ph Ia dose-escalation/<br />
expansion study (NCT01375842) and were treated until loss <strong>of</strong> clinical benefit.<br />
Confirmed ORR and PFS were assessed by RECIST v1.1. PD-L1 status on immune cells<br />
(IC) was centrally evaluated (VENTANA SP142 IHC assay) and scored as IC0, 1, 2,<br />
3. After dose-escalation, only IC2 or 3 pts were enrolled. Molecular subtyping was<br />
performed using nanostring.<br />
Results: As <strong>of</strong> Dec 15, 2015, 12 pts with ECOG PS 0/1 (50%/50%) and median age <strong>of</strong><br />
61 y (range 39-72) were evaluable for safety. 11/12 received ≥ 2 lines <strong>of</strong> therapy. Atezo<br />
doses (mg/kg) were: 0.3 (n = 2), 10 (n = 1) and 15 (n = 9). With a median treatment<br />
duration <strong>of</strong> 2.8 mo, 11/12 pts had a treatment-related AE. These were mainly Gr 1-2;<br />
fatigue and pain were most common (5 pts each). 2 pts (17%) had a Gr 3 related AE<br />
(autoimmune hepatitis; maculopapular rash). There were no Gr 4 or 5 related AEs or<br />
AEs leading to withdrawal. Of 9 response-evaluable pts (10-15 mg/kg atezo and ≥ 12<br />
wk followup; 1 pt without RECIST measurable disease at baseline was evaluable for<br />
PFS/OS but not response), 2 pts (22%) had a PR. 1 responder had an 8.1 mo DOR and<br />
the other remains on study at 16.6+ mo with a 100% reduction in target lesion volume<br />
(1 nontarget lesion remained). 5 pts had PD and 2 were nonevaluable. Median PFS was<br />
2.9 mo (95% CI 1.3-5.5). Median OS was 11.3 mo (95% CI 5.5-27.7) and 17.4 mo (95%<br />
CI 5.9-27.7) in 9 IC2/3 pts. Of the 10 evaluable for PFS/OS, 1 pt was IC0/1, 9 were IC2/<br />
3 and all belonged to an RNA-defined immunoreactive subgroup <strong>of</strong> OC that is<br />
associated with T cell activation and high PD-L1 expression. Atezo responders were<br />
IC2/3 and had low baseline CA125 levels vs pts who progressed.<br />
Conclusions: In this single-agent OC cohort, atezo demonstrated tolerable safety and<br />
encouraging clinical activity. Scientifically rational combinations with chemotherapy,<br />
targeted therapy or other cancer immunotherapies may augment the clinical benefit <strong>of</strong><br />
atezo in OC pts.<br />
Clinical trial identification: NCT01375842<br />
Legal entity responsible for the study: F. H<strong>of</strong>fmann-La Roche, Ltd.<br />
Funding: F. H<strong>of</strong>fmann-La Roche Ltd.<br />
Disclosure: J.R. Infante: I have no personal conflicts <strong>of</strong> interest, my institution gets<br />
funding for research and consulting from Genentech. L.A. Emens: Grant from Roche/<br />
Genentech. A.S. Balmanoukian: speakers bureaus for Merck and BMS. Y. Wang, B. Liu,<br />
L. Molinero, M. Fasso, C. O’Hear: Employee <strong>of</strong> Genentech. All other authors have<br />
declared no conflicts <strong>of</strong> interest.<br />
872P<br />
Lymph node dissection in early epithelial ovarian cancer (EOC)<br />
– Results from a population based study<br />
J.T. Man 1 , C.C.H. Khoo 1 , B. Gao 1 , S. Fereday 2 , J. Hung 3 , A.O.C.S. Group 2 ,<br />
P. Harnett 1 , D.D. Bowtell 2 , A. Brand 3 , A. Defazio 4<br />
1 Medical <strong>Oncology</strong>, Crown Princess Mary Cancer Care Center, Westmead<br />
Hospital, Sydney, Australia, 2 Medical <strong>Oncology</strong>, Peter MacCallum Cancer Center,<br />
Melbourne, Australia, 3 Gynecological <strong>Oncology</strong> Department, Westmead Hospital,<br />
Sydney, Australia, 4 Medical <strong>Oncology</strong>, The Westmead Institute for Medical<br />
Research, Sydney, Australia<br />
Background: For patients with early epithelial ovarian cancer (EOC), current<br />
guidelines recommend adequate surgical assessment including bilateral<br />
salpingo-oophorectomy, total hysterectomy, omentectomy, multiple peritoneal<br />
biopsies, peritoneal washings and lymph node assessment. However the extent <strong>of</strong><br />
lymph node assessment is not well defined and practices are variable. The clinical<br />
benefit <strong>of</strong> lymphadenectomy in women with early disease apart from providing more<br />
accurate staging is unclear. The aims <strong>of</strong> this project are to determine the rate <strong>of</strong><br />
lymphadenectomy and assess its association with disease recurrence in early EOC in a<br />
large population based study.<br />
Methods: Patients with FIGO stage I and II EOC were identified through the<br />
Australian Ovarian Cancer Study (AOCS) database. Details on the extent <strong>of</strong> surgical<br />
staging including lymph node assessment were collected from pathology and operation<br />
reports. Cox proportional hazards model was used to assess the factors associated with<br />
disease progression.<br />
Results: Among 317 women with early EOC in the AOCS database, pathological report<br />
review was conducted in 241 (76.0%) cases. After a median follow-up <strong>of</strong> 73 months, 77<br />
(32.0%) patients had disease recurrence. Lymph node assessment was conducted in 154<br />
(63.9%) patients, with pelvic nodal dissection in 148 (61.4%), para-aortic node<br />
dissection in 76 (31.5%) and both in 70 (29%). The median number <strong>of</strong> lymph nodes<br />
removed was 8 (range 1-35). A lower disease recurrence rate was seen in patients who<br />
underwent lymph node dissection (41.3% vs. 26.2%, p = 0.018). The extent <strong>of</strong><br />
lymphadenectomy (0 nodes, less than 5 nodes, and 5 or more nodes) decreased the<br />
recurrence rate from 41.4% to 33.3% to 24.1%, respectively (p = 0.041).<br />
Conclusions: Early EOC patients who underwent lymphadenectomy in our study had<br />
a lower disease recurrence rate. This may be due to the identification <strong>of</strong> higher stage<br />
disease at the time <strong>of</strong> lymphadenectomy, and subsequent exclusion from analysis.<br />
Further analysis, including a review <strong>of</strong> cases with lymph node metastasis in otherwise<br />
early EOC is required to address this question.<br />
Legal entity responsible for the study: Western Sydney Local Health District<br />
Funding: Crown Princess Mary Cancer Care Center, Westmead Hospital<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
873P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Effect <strong>of</strong> age on completion <strong>of</strong> intraperitoneal chemotherapy<br />
in ovarian cancer<br />
M. Tamburelli 1 , M.V. Bluthgen 2 , C. Lindsay 2 , F.L. Bianchi 3 , J.O. Castillo 1 ,R.<br />
E. Castaño 3 , C.A. Bas 1 , G. Gomez-Abuin 1<br />
1 Medical <strong>Oncology</strong>, Hospital Aleman, Buenos Aires, Argentina, 2 Cancer Medicine,<br />
Institut Gustave Roussy, Villejuif, France, 3 Gynecologic <strong>Oncology</strong>, Hospital<br />
Aleman, Buenos Aires, Argentina<br />
Background: Intraperitoneal chemotherapy (IP) shows benefits in terms <strong>of</strong><br />
progression-free survival (PFS) and overall survival (OS) compared with intravenous<br />
chemotherapy (IV) for optimally debulked ovarian cancer. However, it is associated<br />
with higher toxicity and early discontinuation. Our objective was to evaluate the<br />
influence <strong>of</strong> age on IP chemotherapy completion rate.<br />
Methods: We conducted a retrospective analysis <strong>of</strong> patients with ovarian epithelial<br />
cancer who received adjuvant IV/IP or IP chemotherapy at a single institution from<br />
May 2006 to December 2015. Association <strong>of</strong> age subgroups with baseline clinical<br />
characteristics was assessed using Fisher’s exact tests. Survival rates for progression-free<br />
survival (PFS) analysis were based on Kaplan-Meier estimation and compared using<br />
log-rank testing.<br />
Results: A total <strong>of</strong> 71 patients (pts) with IP catheter port placement were identified. Of<br />
them, 48 pts received at least 1 cycle <strong>of</strong> IP chemotherapy. Median age was 57 years<br />
[range 32-74], 41 pts had serous histology (85%), 12 pts (25%) had stage I-II and 36 pts<br />
(75%) stage III-IV disease. Among them, 38 pts (79%) had ≤65 years and 10 pts (21%)<br />
were >65 years. Median follow-up was 53.3 months [range 35.2–71.3]. Complete<br />
resection (89% vs 60%, p = 0.047) and completion rate <strong>of</strong> IP chemotherapy (84% vs<br />
30%, p = 0.002), were found to be significantly different between patients ≤65<br />
compared to >65 years, respectively. Five-year progression-free survival (PFS) was<br />
54.1% versus 34.3%, respectively (HR: 0.79 [95% CI 0.23-2.78], p = 0.719). Neither<br />
vi302 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
statistical significantly differences in comorbidities (84% vs 70%) nor grade 3-4 toxicity<br />
pr<strong>of</strong>ile (47% vs 70% p = 0.292) were observed between both groups <strong>of</strong> patients<br />
respectively. Reasons for treatment discontinuation include: renal failure in 4 pts,<br />
abdominal pain in 3 pts, withdrawal for 2 pts, syncope, neurologic toxicity, and<br />
intestinal occlusion in 1 pt each; and 1 pt due to catheter related complication.<br />
Conclusions: In this cohort, the IP chemotherapy completion rate in elderly patients<br />
was lower than in younger counterparts. However, grade 3-4 toxicity rates and survival<br />
outcomes differences were not observed.<br />
Legal entity responsible for the study: Hospital Aleman<br />
Funding: Medical <strong>Oncology</strong> Section, Hospital Aleman<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
874P<br />
Outcomes <strong>of</strong> clinical testing for tumor BRAC1 and BRCA2<br />
gene analysis for 354 patients: first experience with tumor<br />
companion diagnostic for PARP inhibitors<br />
K.L. Copeland 1 , S.B. Wehnelt 2 , L.E. Wange 2 , B. Anwald 2 , A. Weicht 2 , A. Pfeufer 2<br />
1 Medical Affairs, Myriad Genetics GmbH, Zurich, Switzerland, 2 Laboratory, Myriad<br />
GmbH, Munich, Germany<br />
Background: Ovarian cancer patients with deficiencies in the DNA repair pathway<br />
have shown to have a higher probability to respond to PARP inhibitors. Pathogenic<br />
mutations in the genes BRCA1 and BRCA2 lead to defects in the DNA repair pathway.<br />
It has been shown that the prevalence <strong>of</strong> mutations in the BRCA genes is higher in the<br />
tumor cells than in germline. Thus, a tumor-based test could identify a higher number<br />
<strong>of</strong> potential responders than a germline test.<br />
Methods: This study assessed 354 consecutive individuals undergoing BRCA1 and<br />
BRCA2 full sequencing and large rearrangement analysis <strong>of</strong> DNA derived from FFPE<br />
tumor tissue in a DAkkS accredited laboratory in Munich, Germany from Jan 2015<br />
through April 2016. The tumor-based BRCA test consists <strong>of</strong> sequencing and large<br />
rearrangement analyses <strong>of</strong> the BRCA1 and BRCA2 genes using next generation<br />
sequencing (NGS). The large rearrangements are detected by NGS dosage analysis to<br />
determine copy number abnormalities indicative <strong>of</strong> deletion or duplication mutations.<br />
Results: Out <strong>of</strong> the 354 analyzed samples, 93 (26,5%) tested positive for a laboratory<br />
classified pathogenic mutation; 57 were found in BRCA1 and 37 in BRCA2. One<br />
specimen contained a pathogenic mutation in both BRCA1 and BRCA2. Due to<br />
different quality and age <strong>of</strong> the tumor samples, large rearrangement analysis could not<br />
be completed in 24 cases (6,8%). VUS rate in the analyzed tumors was 4.2%. Of the<br />
pathogenic mutations detected, 93,6% were sequencing variants and 6,4% were large<br />
rearrangements. Overall cancellation rate due to insufficient tumor, insufficient DNA,<br />
incorrect tumor type or other cancellation reasons is less than 9% in the observed<br />
timespan <strong>of</strong> 16 months.<br />
Conclusions: The current study demonstrates that a robust diagnostic platform can<br />
detect BRCA-related mutations in ovarian tumors. While the quality <strong>of</strong> specimens<br />
received into a commercial laboratory is quite variable, a positive rate <strong>of</strong> over 26% and<br />
an overall success rate (result generated) <strong>of</strong> over 91% indicates that tumor BRCA<br />
testing should be considered for ovarian cancer patients. In addition, a small but<br />
significant number <strong>of</strong> large rearrangements indicates that tumor BRCA testing should<br />
include dosage analysis for large rearrangements.<br />
Legal entity responsible for the study: Myriad GmbH<br />
Funding: Myriad GmbH<br />
Disclosure: K.L. Copeland: Employee <strong>of</strong> Myriad Genetics GmbH including stock<br />
ownership. S.B. Wehnelt, L.E. Wange, B. Anwald, A. Weicht, A. Pfeufer: Myriad<br />
Employee.<br />
875P<br />
Impact <strong>of</strong> genomic heterogeneity and mutation patterns on the<br />
outcome <strong>of</strong> patients with epithelial ovarian cancer (EOC)<br />
V. Kotoula 1 , S. Lakis 1 , E. Giannoulatou 2 , G. Kouvatseas 3 , G. Lazaridis 1 , I. Tikas 1 ,<br />
I. Efstratiou 1 , S. Chrisafi 1 , E. Charalambous 1 , A. Papanikolaou 1 , F. Fostira 1 ,<br />
B. Tarlatzis 1 , G. Fountzilas 1<br />
1 Data Office, Hellenic Cooperative <strong>Oncology</strong> Group (HeCOG), Athens, Greece,<br />
2 Bioinformatics, Victor Chang Cardiac Research Institute, Darlinghurst, Australia,<br />
3 Biostatistics, Health Data Specialists Ltd, Athens, Greece<br />
Background: EOC <strong>of</strong>ten display genomic heterogeneity and mutations associated with<br />
homologous recombination repair deficiency (HRD), which may have prognostic/<br />
predictive relevance. In the present study, we examined the mutational evolution in<br />
EOC and its association with patient outcome.<br />
Methods: We examined coding mutations in 306 paraffin tissue samples from 69<br />
patients with stage III-IV EOC treated with standard chemotherapy. The samples (2-9<br />
per patient) were derived from normal salpinx epithelium (N), primary tumors (P) and<br />
metastatic sites (M). Coding regions in 39 EOC-related genes were sequenced at high<br />
depth (mean 2739; median 2362) and a genomic heterogeneity index (HGi) was<br />
calculated. Progression-free survival (PFS) was the clinical endpoint.<br />
Results: In 64/69 patients, at least 2 paired N, P and M samples shared 640 mutations<br />
(16% <strong>of</strong> all mutations) in 15 genes. Shared mutations (s-mut) exhibited higher allelic<br />
frequency as compared to private ones (all p < 0.001). S-mut were found up to 60% in<br />
HRD genes (21% BRCA1; 37% BRCA2) and up to 25% in TP53. BRCA1 and BRCA2<br />
s-mut prevailed in paired N/N, N/P and N/M; TP53 s-mut prevailed in paired P/M and<br />
M/M. Higher HGi was associated with absence <strong>of</strong> any s-mut (p = 0.017) and BRCA1<br />
s-mut (p = 0.043) in paired N/P and with presence <strong>of</strong> TP53 s-mut in P/M (p = 0.018).<br />
In patients with serous EOC, median PFS was 25.3 vs. 13.9 months for those with high<br />
HGi (n = 31), compared to those with low HGi (n = 13; log-rank p = 0.024); no<br />
association was observed for non-serous tumors (interaction p = 0.08). Among patients<br />
with low HGi, those with HRD s-mut in paired N/P (n = 5) did not progress in 120<br />
months, while patients without HRD s-mut had median PFS <strong>of</strong> 18 months (n = 11;<br />
p < 0.001). Among patients with HRD s-mut in paired N/P, those with high HGi<br />
(n = 20) had worse PFS than those with low HGi (n = 5; p = 0.001), while in patients<br />
without HRD s-mut no difference in PFS was detected.<br />
Conclusions: A temporal mutation order in the evolution <strong>of</strong> EOC is suggested; HRD<br />
mutations seem important in the transition from normal to primary tumor and TP53<br />
mutations in metastatic spread. Genomic heterogeneity seems to interact with tumor<br />
histology and shared normal/tumor HRD mutations for patient prognosis. Validation<br />
in larger patient series is needed.<br />
Legal entity responsible for the study: Hellenic Cooperative <strong>Oncology</strong> Group<br />
Funding: Astra-Zeneca S.A.<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
876P<br />
abstracts<br />
A phase 1 study <strong>of</strong> single agent veliparib in Japanese subjects<br />
with advanced solid tumors<br />
K. Matsumoto 1 , K. Tamura 2 , H. Yoshida 3 , T. Nishikawa 3 , Y. Imai 3 , A.M. Miyasaka 3 ,<br />
T. Onoe 1 , S. Yamaguchi 1 , C. Shimizu 2 , K. Yonemori 2 , T. Shimoi 2 , M. Yunokawa 2 ,<br />
H. Xiong 4 , H. Hashiba 5 , T. Kiriyama 5 , T. Leahy 4 , S. Shepherd 4 , K. Fujiwara 3<br />
1 Medical <strong>Oncology</strong>, Hyogo Cancer Center, Hyogo, Japan, 2 Breast and Medical<br />
<strong>Oncology</strong>, National Cancer Center Hospital, Tokyo, Japan, 3 Gynecologic<br />
<strong>Oncology</strong>, Saitama Medical University International Medical Center, Saitama,<br />
Japan, 4 <strong>Oncology</strong>, AbbVie, Inc., North Chicago, IL, USA, 5 Clinical Science Group,<br />
AbbVie, GK, Tokyo, Japan<br />
Background: Veliparib (V) is a potent, orally bio-available PARP inhibitor that<br />
inhibits DNA damage repair. Up to 50% high-grade serous ovarian cancer (HGSOC) is<br />
considered to have deficiencies in homologous recombination and thus be particularly<br />
sensitive to PARP inhibition. V has single-agent activity in HGSOC, as well as in<br />
BRCA-mutated breast, pancreatic or prostate cancers. The objectives <strong>of</strong> this study were<br />
to determine the recommended phase 3 dose (RPTD) <strong>of</strong> V monotherapy, to assess<br />
pharmacokinetics (PK) and to evaluate preliminary efficacy in Japanese subjects with<br />
HGSOC or other BRCA mutated cancers.<br />
Methods: Tolerability was assessed in 2 dose cohorts (200 mg and 400 mg BID) on<br />
Days 1 - 28 <strong>of</strong> a 28 day cycle), and an expansion cohort (400 mg BID). Subjects<br />
continued to receive V until PD or predefined discontinuation criteria were met.<br />
Adverse events (AEs) were reported according to CTCAE Ver. 4.03. PK parameters<br />
were analyzed. Tumor response was measured by RECIST 1.1 and tumor markers<br />
including CA-125.<br />
Results: A total <strong>of</strong> 16 subjects treated were all female, with a median age <strong>of</strong> 59 yrs<br />
(range 43 - 83). All but 1 subject with BRCA-mutated breast cancer were with HGSOC.<br />
All had prior surgeries and chemotherapies (range 1 - 7). The most common treatment<br />
emergent AEs were nausea and vomiting (15/16, 94% each), decreased appetite (10/16,<br />
63%), and abdominal pain, diarrhea and malaise (5/16, 31% each). Grade 3 AEs<br />
occurring in 2 or more subjects were anemia, nausea and vomiting (2/16, 13% each).<br />
One subject developed DLTs (nausea, vomiting, decreased appetite and fatigue, all<br />
Grade 3) at 400 mg BID. The RPTD was determined to be 400 mg BID. Nausea and<br />
vomiting were observed at higher incidence than Western and were the major cause <strong>of</strong><br />
dose modification or discontinuation. PK parameters were dose proportional and<br />
comparable to Western. The objective response rate was 14% (2/14 subjects, [95%CI:<br />
1.8% – 42.8%]) with no CR, 2 PR (14%), 8 SD (57%), and 3 PD (21%). Additional<br />
CA-125 responder was reported with the longest study duration <strong>of</strong> 340 days.<br />
Conclusions: V 400 mg BID (RPTD for Western) was considered to be tolerable for<br />
Japanese; however, anti-emetic therapy may be needed. Manageable safety pr<strong>of</strong>ile and<br />
no ethnic difference <strong>of</strong> PK warrant participation <strong>of</strong> Japan in multinational Phase 3<br />
study.<br />
Clinical trial identification: NCT02210663<br />
Legal entity responsible for the study: AbbVie, Inc.<br />
Funding: AbbVie, Inc.<br />
Disclosure: K. Matsumoto: Institution has received grants from Ono Pharmaceutical,<br />
MSD, and AbbVie. K. Tamura: Institution has received grants from Ono<br />
Pharmaceutical, MSD, AstraZeneca, Daiichi-Sankyo, Eisai, Pfizer and AbbVie. C.<br />
Shimizu: Institution has received grants from Chugai Pharmaceutical, Eli Lilly, and<br />
Pfizer. M. Yunokawa: Has received payment for lectures/speakers from AstraZeneca.<br />
H. Xiong, T. Kiriyama, T. Leahy, S. Shepherd: Employed by AbbVie and may own<br />
stock. H. Hashiba: Employed by AbbVie. K. Fujiwara: Lectures/speakers: Kyowa Hakko<br />
Kirin, Taiho Phar., Yakult Honsha, Nippon Kayaku and Asahi Kasei Medical. Advisory<br />
boards (AB): GSK, Chugai Phar. Institution grants (IG): Zeria Phar., San<strong>of</strong>i, Kaken<br />
Phar., and AbbVie. AB/IG: AstraZeneca, Pfizer, and Eisai. All other authors have<br />
declared no conflicts <strong>of</strong> interest.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw374 | vi303
abstracts<br />
877P<br />
Treatment patterns and BRCA testing practices in<br />
platinum-sensitive recurrent serous ovarian cancer: a Spanish<br />
medical record review<br />
I. Bover 1 , N. Colombo 2 ,J.Korach 3 , K.L. Davis 4 , J.A. Kaye 5 , J.R. Robert Lewis 6 ,<br />
A. Callejo 7 , A. Gascó 8<br />
1 Servicio de Oncología Médica, Hospital Son Llatzer, Palma de Mallorca, Spain,<br />
2 Divisione di Ginecologia Oncologica Medica, Istituto Europeo di Oncologia, Milan,<br />
Italy, 3 Department <strong>of</strong> Gynecological <strong>Oncology</strong>, Sheba Medical Center, Tel<br />
Hashomer, Israel, 4 Health Economics, RTI Health Solutions, Waltham, MA, USA,<br />
5 Epidemiology, RTI Health Solutions, Waltham, MA, USA, 6 Global Medical Affairs,<br />
AstraZeneca, Cambridge, UK, 7 Clinical Operations, APICES, Pinto, Spain, 8 Local<br />
Medical Affairs, AstraZeneca Spain, Madrid, Spain<br />
Background: Platinum-based chemotherapy is considered standard treatment for<br />
platinum-sensitive recurrent ovarian cancer (PSR OC). Real-world data on BRCA<br />
mutation (BRCAm) testing, treatment patterns and characteristics <strong>of</strong> patients (pts)<br />
diagnosed with PSR OC will help to identify unmet medical needs in this population.<br />
Methods: We retrospectively reviewed a random sample <strong>of</strong> medical records <strong>of</strong> women<br />
having serous PSR OC after 1st-line platinum completion, during 2009-2013, to assess<br />
PSR OC treatment patterns and BRCAm testing. Study index date was defined as PSR<br />
OC diagnosis date.<br />
Results: Data from 298 pts were collected in Spain. At diagnosis, median age: 58 years;<br />
ECOG 0, 1: 38%, 52%; advanced disease stage (≥IIb):93%;highgrade:80%.Primary<br />
tumour sites: ovary (88%); fallopian tube (8%); primary peritoneum (4%). 70% <strong>of</strong> pts had<br />
received primary cytoreductive surgery, 88% received carboplatin + paclitaxel as 1st-line<br />
(with or without bevacizumab) (median number <strong>of</strong> cycles 6) and 4% received<br />
intraperitoneal treatment. 7% <strong>of</strong> pts received maintenance therapy after 1st-line, mainly<br />
bevacizumab (95%). The majority <strong>of</strong> pts (78%) received 2nd-line therapy: platinum based<br />
91%; mainly carboplatin + paclitaxel (31%), gemcitabine (15%) or pegylated liposomal<br />
doxorubicin (9%); 20% concomitant bevacizumab. Median times from initial ovarian cancer<br />
diagnosis to index date and from index date to end <strong>of</strong> follow-up were 20 months. BRCA<br />
testing was performed in 83 (28%) <strong>of</strong> pts and 76 (92%) had a conclusive result available. Of<br />
those, 34% were BRCAm. 16% <strong>of</strong> total pts (69% <strong>of</strong> BRCAm pts) had family history <strong>of</strong><br />
BRCA-related cancer (breast 81%; ovarian 41%). BRCA tests were performed on blood<br />
(76%) and tumour tissue (24%) samples. BRCA testing method unknown: 65%. When<br />
known, direct DNA sequencing was the most used BRCA testing method (16 pts, 55%).<br />
Conclusions: Platinum-based chemotherapy for PSR OC was the standard <strong>of</strong> care in this<br />
review. Bevacizumab was associated with chemotherapy in only 20% <strong>of</strong> pts. Family<br />
history <strong>of</strong> BRCA related cancer was absent in 31% <strong>of</strong> BRCAm pts. BRCA testing was not<br />
routinely performed. Physicians were mostly unfamiliar with the BRCA testing method<br />
used; when known, direct DNA sequencing was the most commonly used method.<br />
Clinical trial identification: ClinicalTrials.gov NCT02262273 (October 6, 2014)<br />
Legal entity responsible for the study: AstraZeneca<br />
Funding: AstraZeneca<br />
Disclosure: N. Colombo: I disclosure my participation in advisory board by Astra<br />
Zeneca and corporate-sponsored trials (SOLO1, SOLO2 and ORZORA). K.L. Davis, J.<br />
A. Kaye: I am an employee <strong>of</strong> RTI Health Solutions, which received contract research<br />
funding from AstraZeneca for the implementation and conduct <strong>of</strong> this study and the<br />
analyses contained therein. J.R. Robert Lewis, A. Gascó: I’m an AstraZeneca’s<br />
employee. A. Callejo: I’m an APICES’s employee, working as Project Manager for<br />
AstraZeneca. All other authors have declared no conflicts <strong>of</strong> interest.<br />
878P<br />
Quantification <strong>of</strong> genetic variants as marker <strong>of</strong> Brca-like<br />
phenotype in ovarian cancer<br />
J. Garcia-Donas 1 , N. Lainez Milagro 2 , E.M. Guerra Alia 3 , M. Garrido 4 , R. Guarch 5 ,<br />
A. Acosta 1 , A. Herrador 6 , M. Prieto Pozuelo 1 , J.F. Rodriguez-Moreno 1<br />
1 Hospital Madrid Norte San Chinarro Centro Integral Oncologico Clara Campal,<br />
Madrid, Spain, 2 <strong>Oncology</strong>, Complejo Hospitalario de Navarra, Pamplona, Spain,<br />
3 <strong>Oncology</strong>, Hospital Universitario Ramon y Cajal, Madrid, Spain, 4 Medical<br />
<strong>Oncology</strong>, Hospital Universitario Severo Ochoa, Madrid, Spain, 5 Pathology,<br />
Complejo Hospitalario de Navarra, Pamplona, Spain, 6 Research Unit, Hospital<br />
Madrid Norte San Chinarro Centro Integral Oncologico Clara Campal, Madrid,<br />
Spain<br />
Background: PARP inhibitors have repeatedly been demonstrated to be active in<br />
BRCA mutant ovarian cancers. However, tumors with a BRCA-like phenotype could<br />
also benefit from such treatments. Thus, defining molecularly this subtype <strong>of</strong> ovarian<br />
neoplasias has become a priority. We aimed to study the potential role <strong>of</strong> the<br />
quantification <strong>of</strong> genetic variants in a limited set <strong>of</strong> genes in this regard.<br />
Methods: We designed a retrospective multicenter study in four collaborating<br />
institutions in Spain. Adult patients diagnosed with epithelial ovarian cancer, stage IC<br />
or superior, from 2008 to date were eligible. Clinical data (regarding demographics and<br />
treatment outcome) were extracted from medical records by an external data monitor.<br />
Whole exome sequencing was performed in extreme cases (best and worst responders)<br />
while a panel <strong>of</strong> five genes highly involved in homologous recombination (BRCA 1 and<br />
2, ATM, CHEK2, RAD51C) was studied through Next Generation Sequencing in<br />
middle cases, not previously tested for BRCA mutations. We present the quantitative<br />
results <strong>of</strong> these last patients.<br />
Results: In total 220 patients have been included so far. Discovery cohort accomplish<br />
for the first 90 cases. Median age was 61 (range 37-87) and tumor stage was I in 10<br />
cases (9%), II in 5 (6%), III in 59 (66%), IV in 13 (14%) and not available in 3 (5%).<br />
Tumor histologies were papillary serous 73 (81%), mucinous 1 (1%), endometroid 5<br />
(6%), clear cell 7 (13%), adenocarcinoma 2 (2%), and non-epithelial in 2 (2%). Up to<br />
37 cases have been already analyzed. Median number <strong>of</strong> genetic variants was 26 (range<br />
12-41). Kaplan Meier test showed a platinum-free interval <strong>of</strong> 14.3 months (95%<br />
Confidence Interval [CI] 10.2-18.5) vs 48.3 (95% CI 0-101.2) for patients with a<br />
number <strong>of</strong> variants below or above the median, respectively.<br />
Conclusions: Though exploratory, our results point towards an association between<br />
the number <strong>of</strong> genetic variants in selected genes and a better outcome in advanced<br />
ovarian cancer. Mature data <strong>of</strong> the whole cohort will be presented at the meeting.<br />
Legal entity responsible for the study: Clara Campal Comprehensive Cancer Center<br />
Funding: Astra Zeneca Inc<br />
Disclosure: J. Garcia-Donas: Research funding from Astra Zeneca Inc. All other<br />
authors have declared no conflicts <strong>of</strong> interest.<br />
879P<br />
Loss <strong>of</strong> ARID1A expression is associated with poor prognosis<br />
in patients with stage I/II clear cell carcinoma <strong>of</strong> the ovary<br />
S. Sato 1 , H. Itamochi 1 , N. Oumi 2 , T. Oishi 2 , T. Shoji 1 , H. Fujiwara 3 , M. Suzuki 3 ,<br />
J. Kigawa 4 , T. Harada 2 , T. Sugiyama 1<br />
1 Obstetrics and Gynecology, Iwate Medical University School <strong>of</strong> Medicine,<br />
Morioka, Japan, 2 Obstetrics and Gynecology, Tottori University School <strong>of</strong><br />
Medicine, Yonago, Japan, 3 Obstetrics and Gynecology, Jichi Medical University<br />
School <strong>of</strong> Medicine, Shimotsuke, Japan, 4 Obstetrics and Gynecology, Matsue City<br />
Hospital, Matsue, Japan<br />
Background: Clear cell carcinoma <strong>of</strong> the ovary (CCC) has a poor prognosis because <strong>of</strong><br />
its resistance to conventional platinum- or taxane-based chemotherapy. Consequently,<br />
there is a need to discover biomarkers for predicting the outcome <strong>of</strong> patients with CCC<br />
and develop novel treatment strategies for this disease. Recent studies have shown that<br />
somatic mutations in the AT-rich interactive domain 1A (SWI-like) gene (ARID1A)<br />
are the most common genetic changes in CCC. This gene is located in chromosome<br />
1p36 and encodes a member <strong>of</strong> the switch/sucrose-nonfermentable (SWI/SNF) family<br />
protein BAF250a (ARID1A). Here, we investigated whether ARID1A could be a<br />
prognostic biomarker for this disease.<br />
Methods: Paraffin-embedded specimens were collected from 220 Japanese patients<br />
with epithelial ovarian cancer, including 112 CCC and 108 high-grade serous<br />
adenocarcinoma <strong>of</strong> the ovary (HG-SAC). We analyzed the protein expression <strong>of</strong><br />
ARID1A in these samples by immunohistochemical staining, and evaluated the<br />
association <strong>of</strong> these molecular parameters with clinical outcome.<br />
Results: The loss <strong>of</strong> ARID1A expression was found in 39.3 % (44/112) <strong>of</strong> CCC, and strong<br />
expression <strong>of</strong> the protein was not observed. ARID1A protein was present mainly in the cell<br />
nuclei <strong>of</strong> the tumors; however, in tumors with HG-SAC, only 8 (7.4 %) tumors showed loss<br />
<strong>of</strong> ARID1A expression. The rate <strong>of</strong> absent expression <strong>of</strong> ARID1A in CCC tumors was<br />
significantly higher than in HG-SAC tumors (P < 0.0001). We found no significant<br />
association between ARID1A expression and patient age, FIGO stage, and status <strong>of</strong> residual<br />
tumorinCCC.The5-yearsurvivalrateforFIGOstageIorIICCCpatientswithnegative<br />
tumor expression <strong>of</strong> ARID1A was lower than those with positive tumor expression <strong>of</strong><br />
ARID1A (74 % vs 91 %), but this difference was not observed in FIGO stage III or IV<br />
patients. Multivariable analysis revealed that FIGO stage and residual tumor were<br />
independent prognostic factors, but ARID1A expression was not. However, ARID1A<br />
expression was an independent prognostic factor in FIGO stage I or II CCC patients.<br />
Conclusions: The ARID1A protein may be a promising prognostic marker for FIGO<br />
stage I and II CCC.<br />
Legal entity responsible for the study: N/A<br />
Funding: This work was supported by a Grant-in-Aid for Scientific Research from the<br />
Ministry <strong>of</strong> Education, Culture, Sports, Science and Technology <strong>of</strong> Japan (17244120 to<br />
H. Itamochi).<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
880P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Molecular characterization and comparison <strong>of</strong> epithelial<br />
ovarian carcinoma (EOC) and primary peritoneal carcinoma<br />
(PCC)<br />
A.M. Knipprath 1 , D. Arguello 2 , K. Russell 3 , A. Voss 3 , V. Heinzelmann-Schwarz 1<br />
1 Gynecology, Universitätsspital Basel, Basel, Switzerland, 2 Medical Affairs, Caris<br />
Life Sciences, Phoenix, AZ, USA, 3 Medical Affairs, Caris Life Sciences, Basel,<br />
Switzerland<br />
Background: EOC and PPC are two cancers currently treated in a similar manner.<br />
Molecular tumor pr<strong>of</strong>iling, with its emphasis on individualized therapy, is altering prior<br />
treatment paradigms by focusing on molecular aberrations rather than organ primary to<br />
guide therapy. Studies at our institution on EOC and PPC suggest these are two distinct<br />
cancer types, with PPC being more aggressive. The aim <strong>of</strong> this study is to identify further<br />
differences in the molecular pr<strong>of</strong>iles <strong>of</strong> EOC and primary peritoneal carcinoma in order<br />
to identify treatment/resistant mechanisms and clinical trial opportunities.<br />
vi304 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Methods: In total, 5,685 EOC and 521 primary peritoneal carcinoma specimens were<br />
evaluated (Caris Life Sciences) by immunohistochemistry (IHC), in situ hybridization<br />
(ISH), fusion gene analysis, and next-generation sequencing (NGS). Initial diagnosis<br />
was made by the submitting institution and confirmation <strong>of</strong> diagnosis was made by a<br />
pathologist at the centralized laboratory.<br />
Results: Significant differences were found between IHC and NGS. Protein expression in<br />
androgen receptor (28.8% v. 36.5%, p = 0.0011), EGFR (48.9% v. 59.0%, p = 0.0081), ER<br />
(46.0% v. 55.6%, p = 0.0001), PD-L1 (9.5% v. 5.7%, p = p = 0.0300), PR (22.5% v. 14.6%,<br />
p = 0.0001), TLE3 (18.4% v. 13.2% p = 0.0120), TOP2A (75.9% v. 66.8%, p = 0.0001), and<br />
TS (54.3% v. 44.1%, p = 0.0001) varied significantly between EOC and PPC, respectively.<br />
Significant differences in mutation rates were found in CTNNB1 (3.3% v. 0.7%,<br />
p = 0.0033), KRAS (9.4% v. 3.7%, p = 0.0001), PIK3CA (9.3% v. 4.8%, p = 0.0027), PTEN<br />
(3.9% v. 1.6%, p = 0.0222), and TP53 (63.3% v. 74.5%, p = 0.0001). No significant<br />
differences were found in amplification rates, as measured by ISH and CNV by NGS.<br />
Conclusions: Multiplatform pr<strong>of</strong>iling reveals various potential targets in ovarian and<br />
primary peritoneal carcinomas for investigational and drug therapy. Comparison <strong>of</strong><br />
their genetic pr<strong>of</strong>iles reveals two distinct cancers. Dysregulation <strong>of</strong> the PIK3CA/AKT/<br />
mTOR pathway appears to be more common in EOC while loss <strong>of</strong> TP53 is a more<br />
common event in PPC based on this cohort. More studies are urgently needed to assess<br />
differences between EOC and PPC.<br />
Legal entity responsible for the study: N/A<br />
Funding: Caris Life Sciences<br />
Disclosure: D. Arguello, K. Russell, A. Voss: Employee (Caris Life Sciences) Stock<br />
(Caris Life Sciences) All other authors have declared no conflicts <strong>of</strong> interest.<br />
881P<br />
Response to chemotherapy in relapsed low-grade serous<br />
ovarian carcinoma: Royal Marsden series <strong>of</strong> 46 patients<br />
J.M. McLachlan, N. Tunariu, J.P. Lima, A. George, M. Gore, S. Kaye, S. Banerjee<br />
Gynaecology Unit, Royal Marsden Hospital NHS Foundation Trust, London, UK<br />
Background: Low-grade serous carcinoma (LGSC) <strong>of</strong> the ovary/peritoneum is<br />
characterised by relative resistance to chemotherapy, however there are no reported<br />
prospective studies <strong>of</strong> chemotherapy specifically in this rare subtype. The purpose <strong>of</strong><br />
this study was to evaluate the response to chemotherapy in patients with relapsed<br />
LGSC treated at a single cancer centre.<br />
Methods: A search <strong>of</strong> a database <strong>of</strong> patients with histologically confirmed LGSC<br />
treated at the Royal Marsden Hospital between 1990-2015 was performed. Patients<br />
treated with chemotherapy in the relapsed setting with radiologically evaluable disease<br />
were included in the study. Histological confirmation <strong>of</strong> LGSC was performed by a<br />
gynae-oncology pathologist. Response was determined by Response Evaluation Criteria<br />
in Solid Tumours (RECIST) 1.1 and confirmed by a radiologist. The primary endpoint<br />
was objective response rate (ORR). Secondary endpoints included overall survival (OS)<br />
and progression-free survival (PFS).<br />
Results: Forty-six patients with relapsed LGSC with evaluable disease, treated with 77<br />
separate chemotherapy regimens were included in the study. The median age at diagnosis<br />
was 49 years (range 22-80 years). There were 8 partial responses with an ORR <strong>of</strong> 10.4%.<br />
The median duration <strong>of</strong> response was 11.2 months. Stable disease was achieved in 58 <strong>of</strong><br />
77 (75.3%) treatment regimens. The stable disease rate at 6 months was 43%. The ORR<br />
for the platinum-sensitive cohort was 11.3% and 8.3% for the platinum-resistant cohort.<br />
The median OS was 62 months and median PFS was 8.2 months.<br />
Conclusions: Relapsed LGSC is relatively resistant to chemotherapy in comparison to<br />
the most common subtype, high-grade serous carcinoma. In our series, the response<br />
rate to chemotherapy (10.4%) for recurrent LGSC is higher than previously published<br />
retrospective series (3.7%). Chemotherapy should be considered an option for<br />
recurrent LGSC. There is an urgent need for better therapies and identification <strong>of</strong><br />
LGSC patients who are more likely to respond to chemotherapy. Patients should be<br />
enrolled into clinical trials <strong>of</strong> novel targeted agents.<br />
Legal entity responsible for the study: N/A<br />
Funding: Royal Marsden NHS Foundation Trust<br />
Disclosure: S. Banerjee: Chief investigator for the MILO Study in the United Kingdom.<br />
All other authors have declared no conflicts <strong>of</strong> interest.<br />
882P<br />
Treatment efficacy and prognostic factors in patients (pts)<br />
with malignant ovarian germ cell tumors (MOGCT):<br />
Single-center experience<br />
D. Chekini 1 , A. Tryakin 1 , M. Fedyanin 1 , A. Bulanov 1 , M. Ahmedova 2 , I. Pokataev 1 ,<br />
T. Zakharova 3 , S. Tjulandin 1<br />
1 Clinical Pharmacology and Chemotherapy, N. N. Blokhin Russian Cancer<br />
Research Center, Moscow, Russian Federation, 2 Ultrasound Diagnostics,<br />
N. N. Blokhin Russian Cancer Research Center, Moscow, Russian Federation,<br />
3 Pathology, N. N. Blokhin Russian Cancer Research Center, Moscow, Russian<br />
Federation<br />
Background: to evaluate the long-term survival and clinicopathologic factors in pts<br />
after treatment for MOGCT.<br />
Methods: A total <strong>of</strong> 163 pts treated for MOGCT in our center between 1987-2015 were<br />
included into this retrospective study. Clinical data including symptoms,<br />
demographics, stage, surgery, chemotherapy, survival were collected from medical<br />
records and assessed in univariate analysis.<br />
Results: The median age was 21 years (range, 12-49 years). 109 (66.9%) <strong>of</strong> 163<br />
underwent fertility-preserving surgery followed by chemotherapy. Histologically<br />
(n = 159) 27.7% <strong>of</strong> cases were pure dysgerminoma, in 4 pts histologic data were not<br />
available. 129 (79%) pts received BEP regimen as a first line treatment, and 34 (20.9%)<br />
treated with other regimens. 13 (8%) pts had gonadal dysgenesis. With median<br />
follow-up <strong>of</strong> 88 month (range 1-337 month) 10-year OS was 84% and 48 (29.4%) pts<br />
had disease recurrence. The 5-year disease free survival in pts with dysgerminoma and<br />
non-dysgerminoma was 87% and 66% respectively (HR 0.45, p = .04). BEP regimen<br />
was significantly superior to non-BEP regimen in 10-year OS (94% vs 55%, HR 7.1, p<br />
abstracts<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
events. PIK3CAmut had a significant correlation with endometriosis (p:0.026) and<br />
with early stages FIGO I-II (p: 0.04).<br />
Conclusions: In our series, around 25% <strong>of</strong> CCC had a PI3KCA mut. This mutation<br />
was correlated with initial stage disease (I-II) and endometriosis antecedent. Even if<br />
MSI-H was infrequent, both molecular events were mutually exclusive. This study was<br />
realized with the support <strong>of</strong> the Jan B. Vermorken Grant from GEICO.<br />
Legal entity responsible for the study: Fundación Instituto Valenciano de Oncología<br />
Funding: Grupo Español de Investigación en Cancer de Ovario<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
884P<br />
Ovarian granulosa cell tumours: hormone receptor positivity<br />
and response to aromatase inhibitors<br />
K. Herring 1 , R. Ganesan 2 , A. Rao 1 , L. Edwards 2 , J. Pascoe 1 , S. Williams 1<br />
1 Medical <strong>Oncology</strong>, University Hospitals NHS Trust, Birmingham, UK,<br />
2 Histopathology, Birmingham Womens Hospitals NHS Trust, Birmingham, UK<br />
Background: Ovarian granulosa cell tumours (GCT) are rare gynaecological<br />
malignancies with recurrence possible decades after initial treatment. Although mostly<br />
treated surgically, <strong>of</strong>ten chemotherapy and aromatase inhibitors (AIs) are used with<br />
little supporting data. Despite evidence in breast and epithelial ovarian cancer that<br />
hormone receptor expression predicts response to AIs, there is no such evidence in<br />
GCTs. Oestrogen/progesterone receptor (ER/PR) status poorly reported in case series.<br />
Study aim: evaluate clinical efficacy <strong>of</strong> hormonal manipulation in GCT, correlation <strong>of</strong><br />
efficacy with immunohistochemical (IHC) marker presence.<br />
Methods: Clinical details, demographics, survival data collected- 15 patients with recurrent<br />
GCT treated 2004-2014 in large UK centre. ER/PR IHC performed on tumour samples<br />
available. Primary outcome: progression free survival on hormonal manipulation (PFS).<br />
Secondary outcomes: ER/PR positivity, correlation with response to treatment.<br />
Results: Median age at diagnosis 54 years (range 29-78years). Median interval from<br />
diagnosis to detection <strong>of</strong> recurrence/advanced disease 5 years (range 0.3-21years). Ten<br />
patients (67%) received hormonal manipulation, <strong>of</strong>ten previously heavily pretreated.<br />
Chemotherapy trialed in 4 patients, multiple lines given prior to commencing<br />
hormonal manipulation. AI/GnRH prescribed on 14 occasions, sometimes multiple<br />
lines in the same patient. Median PFS 14 months (95%CI 11.04-16.95), 5 patients<br />
continue to respond at time <strong>of</strong> analysis. Tumour analysed in 9 instances <strong>of</strong> hormonal<br />
manipulation. ER+ related to longer PFS in those treated with AIs, median 20.5<br />
months (range 9-32); 14 months (range 3-24) in ER- cases.<br />
Table: 884P ER/PR status and progression free survival in episodes <strong>of</strong><br />
management with hormonal manipulation<br />
Hormonal<br />
agent<br />
Line <strong>of</strong> treatment<br />
post recurrence<br />
ER/PR<br />
(Q score)<br />
GnRH 2nd 5/8 3^<br />
2nd 0/8 4<br />
Letrozole 1st 0/5 15<br />
3rd 0/8 3<br />
4th 6/7 32^*<br />
4th 4/8 9<br />
4th 5/8 32*<br />
4th 0/8 24<br />
5th 2/6 13<br />
^= same patient<br />
*= censored data, continues to respond<br />
Time to radiological progression from<br />
commencement <strong>of</strong> hormonal agent<br />
(months)<br />
Conclusions: PFS comparable to previous reviews with particularly good response<br />
from letrozole. ER+ potentially correlates with prolonged response with AIs,but also<br />
seen in ER-. Prospective studies would further clarify usefulness <strong>of</strong> AIs as standard <strong>of</strong><br />
care and utility <strong>of</strong> ER IHC to predict response.<br />
Legal entity responsible for the study: NHS<br />
Funding: Charitable funding donated to Dr Sarah Williams<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
885P<br />
Fibroblast growth factor receptor 2 (FGFR2) amplification and<br />
polysomy in serous ovarian cancer<br />
A. Tyulyandina 1 , I. Demidova 2 , M. Gikalo 2 , I. Tsimafeyeu 3 , S. Tjulandin 1<br />
1 Clinical Pharmacology and Chemotherapy, N. N. Blokhin Russian Cancer<br />
Research Center, Moscow, Russian Federation, 2 Molecular Genetics, Moscow<br />
City <strong>Oncology</strong> Hospital No. 62, Moscow, Russian Federation, 3 RUSSCO, Russian<br />
Society <strong>of</strong> Clinical <strong>Oncology</strong>, Moscow, Russian Federation<br />
Background: In recent studies the overexpression <strong>of</strong> FGFR2 was detected in 95% <strong>of</strong><br />
clear cell ovarian carcinomas. FGFR2 aberrations were detected in 9% <strong>of</strong> ovarian<br />
cancers. Up to date there is no data about FGFR2 amplification and its predictive role<br />
in ovarian cancer patients.<br />
Methods: 78 paraffin-embedded samples from 33 patients with stage III-IV serous<br />
adenocarcinoma <strong>of</strong> ovary were analyzed by fluorescence in situ hybridization (FISH) to<br />
identify FGFR2 amplification and level <strong>of</strong> polysomy. All patients received primary and<br />
secondary cytoreduction for recurrence and standard chemotherapy. Scoring for<br />
amplification and polysomy level was adopted from previous studies for gastric cancer<br />
[Su et al. BJC 2014]. Material from each patient included 3 samples: from primary<br />
ovarian tumor, from primary metastatic lesions, and from relapse lesions. The analysis<br />
was performed in all three samples regardless <strong>of</strong> the presence <strong>of</strong> FGFR2 amplification<br />
or heterogeneity in primary tumor.<br />
Results: Amplification <strong>of</strong> FGFR2 was detected in 5 patients (15.1%). High-level<br />
polysomy (HLP) was observed in 16 patients (48.5%). Intratumoral heterogeneity was<br />
detected in 13 <strong>of</strong> 21 (61.9%) patients with FGFR2 abnormalities in all three samples.<br />
Interestingly, FGFR2 amplification/HLP were observed in 55.5% (10 <strong>of</strong> 18 samples) <strong>of</strong><br />
metastatic lesions after primary surgery and in 67.8% (19 <strong>of</strong> 28) <strong>of</strong> relapsed tumors, but<br />
only in 26.1% (6 <strong>of</strong> 23) <strong>of</strong> primary tumors. Median progression-free survival (PFS)<br />
after first line platinum-based chemotherapy was 6.3 months in patients with<br />
amplification and 17.2 months in patients without amplification (p = 0.05). Median<br />
interval between the end <strong>of</strong> first line therapy and progression after second line therapy<br />
(PFS2) was 18.7 and 59.5 months in patients with and without amplification,<br />
respectively (p = 0.005). HLP did not correlate with PFS (P = 0.11) and PFS2<br />
(p = 0.45). Overall survival data is still premature.<br />
Conclusions: For the first time we described amplification and HLP <strong>of</strong> FGFR2 in<br />
63.6% <strong>of</strong> patients with serous ovarian cancer. Most <strong>of</strong> these patients had intratumoral<br />
heterogeneity. FGFR2 amplification could significantly impact on long-term outcomes.<br />
Legal entity responsible for the study: RUSSCO<br />
Funding: RUSSCO<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
886P<br />
Circulating tumor cell number predicts time to progression<br />
(TTP) in patients with heavily pretreated gynecological<br />
cancers treated with selinexor (SEL)<br />
M. Crochiere 1 , I.B. Vergote 2 , B. Lund 3 , H. Havsteen 4 , Z. Ujmajuridze 5 ,E.<br />
Van Nieuwenhuysen 6 , C. Haslund 3 , T. Juhler-Nøttrup 5 , M. Mau-Sørensen 5 ,<br />
P. Berteloot 6 , A. Kranich 7 , J. Meade 1 , G. Wright 1 , E. Shacham 1 , T. Rashal 1 ,<br />
J-R. Saint-Martin 1 , S. Shacham 1 , M. Kauffman 1 , M. Raza Mirza 1 , Y. Landesman 1<br />
1 Karyopharm, Karyopharm Therapeutics, Newton, MA, USA, 2 Obstetrics &<br />
Gynaecology, University Hospitals Leuven - Campus Gasthuisberg, Leuven,<br />
Belgium, 3 <strong>Oncology</strong>, Aalborg University Hospital, Aalborg, Denmark, 4 <strong>Oncology</strong>,<br />
University Hospital Herlev, Herlev, Denmark, 5 <strong>Oncology</strong>, Rigshospitalet,<br />
Copenhagen University Hospital, Copenhagen, Denmark, 6 Obstetrics &<br />
Gynecology, Katholieke Universiteit, Leuven, Belgium, 7 GSO, Hamburg, Germany<br />
Background: SEL, an oral, first-in-class selective inhibitor <strong>of</strong> XPO1-mediated nuclear<br />
export (SINE), induces nuclear retention and activation <strong>of</strong> tumour suppressor proteins<br />
including p53, BRCA1/2, CDKN2A and pRB. SEL has anti-cancer activity in<br />
preclinical models <strong>of</strong> cervical cancer (CC) & ovarian cancer (OC) and in a phase I<br />
clinical study. In an effort to identify markers predictive <strong>of</strong> disease control with SEL,<br />
circulating tumour cells (CTCs) were enumerated during the phase 2 trial from patients<br />
(pts) with heavily pretreated OC, CC & endometrial cancer (EC). NCT02025985.<br />
Methods: Patients with ≥ 2 lines <strong>of</strong> prior therapy, ECOG PS 0-1, were treated with<br />
single agent SEL. At predose C1D1, 7.5 mL <strong>of</strong> blood was collected in CellSave tubes<br />
and CTCs were identified using the Janssen Diagnostics CellSearch System. Intact cells<br />
that measured at least 4 microns in size and stained positive for DAPI, EpCAM, and<br />
cytokeratin while negative for CD45 were counted as CTCs.<br />
Results: CTC were enumerated at predose C1D1 in 47 (33 OC, 8 EC, 6 CC) <strong>of</strong> 114<br />
patients. To date, 31 pts had 2 CTCs with a median days on study <strong>of</strong> 56 days (p = 0.01).<br />
Ten patients with
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
887P<br />
Screening for Lynch syndrome among endometrial cancer<br />
patients less than 60 years<br />
E. Aguirre 1 , M. Mele 2 , N. Tuset 3 , A. Velasco 4 , J. Tarragona 5 , M. Sampayo 6 ,<br />
S. Serrano 2 ,F.Riu 7 , M. Rodriguez-Balada 7 , X. Matias-Guiu 5 , E. Garcia 8 ,<br />
E. Ortega 3 , J. BalmaÑa 9<br />
1 <strong>Oncology</strong>, Hospital Quiron, Zaragoza, Spain, 2 <strong>Oncology</strong>, University Hospital<br />
St. Joan de Reus, Reus, Spain, 3 <strong>Oncology</strong>, Hospital Universitario Arnau Vilanova<br />
de Lleida, Lerida, Spain, 4 Molecular Biology, Hospital Universitario Arnau Vilanova<br />
de Lleida, Lerida, Spain, 5 Pathologhy, Hospital Universitario Arnau Vilanova de<br />
Lleida, Lerida, Spain, 6 Statistic, Medica Scientia Innovation Research, Barcelona,<br />
Spain, 7 Pathologhy, University Hospital St. Joan de Reus, Reus, Spain,<br />
8 Radiotherapy, Hospital Universitario Arnau Vilanova de Lleida, Lerida, Spain,<br />
9 <strong>Oncology</strong>, Vall d’Hebron University Hospital Institut d’Oncologia, Barcelona, Spain<br />
Background: Lynch Syndrome (LS) is an autosomal dominant disorder caused by<br />
germline mutations in any <strong>of</strong> the mismatch repair genes (MMR): MLH1, MSH2,<br />
MSH6 or PMS2. Although colorectal cancer is the most common tumour associated to<br />
the syndrome, the risk <strong>of</strong> endometrial cancer may be higher in some mutation carriers<br />
and be diagnosed at an earlier age. Therefore, identifying LS among endometrial cancer<br />
patients is crucial to identify LS and also help preventing colorectal cancer as a<br />
potential secondary malignancy.<br />
Methods: Patients with endometrial cancer diagnosed less than 60 years <strong>of</strong> age were<br />
prospectively enrolled and their personal and family history was collected. All cases<br />
were evaluated for microsatellite instability (MSI), MMR protein expression by<br />
immunohistochemistry (IHC) and hypermethylation <strong>of</strong> the MLH1 promoter (if lack <strong>of</strong><br />
expression <strong>of</strong> MLH1 was found). Patients with MSI and/or abnormal<br />
immunohistochemical staining were tested for germline mutations by DNA<br />
sequencing and large rearrangements analysis, once hypermethylation <strong>of</strong> the MLH1<br />
promoter was ruled out.<br />
Results: 76 endometrial cancer patients were included, median age was 53 years (range<br />
33-60 years). 27 patients (35%) had molecular findings suggestive <strong>of</strong> Lynch syndrome and<br />
were referred for germline genetic testing. 14 patients (18%) with LS due to a germline<br />
mutation in the MMR genes were detected: two patients with a MLH1 mutation, six<br />
patients with a MSH2 mutation and six patients with a MSH6 mutation. Despite mutation<br />
carriers met classical clinical criteria more frequently than no carriers (p = 0.001), 29% <strong>of</strong><br />
mutation carriers did not fulfil them. IHC combined with MLH1 promoter<br />
hypermethylation analysis was the most efficient method to select patients for genetic testing<br />
with sensitivity <strong>of</strong> 100%, specificity <strong>of</strong> 81% and positive predictive value <strong>of</strong> 54%.<br />
Conclusions: Almost one out five patients with endometrial cancer less than 60 years<br />
is carrier <strong>of</strong> a germline mutation in LS. This justifies referring these patients for genetic<br />
counselling and testing. The best screening method to select patients is the<br />
combination <strong>of</strong> IHC with MLH1 promoter hypermethylation for those cases with lack<br />
<strong>of</strong> expression <strong>of</strong> MLH1.<br />
Legal entity responsible for the study: N/A<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
888P<br />
Sequenced aromatase inhibitor use associated with lower risk<br />
<strong>of</strong> endometrial cancer in tamoxifen-treated breast cancer<br />
patients: a population-based study<br />
S-C. Chu 1 , C-J. Hsieh 2 , T-F. Wang 1 , M-K. Hong 3 , T-Y. Chu 3<br />
1 Hematology/<strong>Oncology</strong>, Hualian Buddhist Tzu Chi General Hospital, Hualian,<br />
Taiwan, 2 Public Health, Tzu-Chi University, Hualian, Taiwan, 3 Obstetrics and<br />
Gynecology, Hualian Buddhist Tzu Chi General Hospital, Hualian, Taiwan<br />
Background: Western studies reveal older ( >50 years) breast cancer survivors with<br />
tamoxifen treatment had higher risk <strong>of</strong> endometrial cancer. The purpose <strong>of</strong> the study is<br />
to disclose whether sequenced aromatase inhibitor (AI) use could reduce the incidence<br />
<strong>of</strong> endometrial cancer in tamoxifen-treated breast cancer patients.<br />
Methods: A population-based cohort <strong>of</strong> 40740 newly diagnosed breast cancer patients<br />
with and without antiestrogen therapy were identified from the Taiwan National<br />
Health Insurance Database from 1999 to 2012. Endometrial cancer risk was compared<br />
with Cox regression analysis with competing risk analysis by the Fine and Gray<br />
method, and adjusted for antiestrogen use, age, diabetes, hypertension and<br />
chemotherapy.<br />
Results: During the 14-year study period, 135 patients were diagnosed with subsequent<br />
endometrial cancers and the incidence per 10 5 person-years patients were 24.8, 91.9<br />
and 46.7 in nonuser (n = 14588), tamoxifen (n = 19302) and AI-included group<br />
(n = 6850), respectively. When compared with nonuser, tamoxifen had a higher risk <strong>of</strong><br />
endometrial cancer (14-year incidence 1.4% vs 0.3%; HR 3.92; 95% CI, 2.38 to 6.46;<br />
p < 0.0001), but AI-included users had an non-significantly higher risk (14-year<br />
incidence 0.6% vs 0.3%; HR 1.67; 95% CI, 0.86 to 3.04; p = 0.1384). Our older ( >50<br />
years) tamoxifen-treated patients had higher risk <strong>of</strong> endometrial cancer. But our<br />
younger (40-50 years) tamoxifen-treated patients also had higher risk <strong>of</strong> endometrial<br />
cancer (HR 3.74; 95% CI, 1.65 to 8.48; p = 0.0015). The 4004 tamoxifen-treated<br />
patients taking sequenced AI were matched with 8008 tamoxifen-only patients after<br />
adjusting for age, cumulative dose <strong>of</strong> tamoxifen and year <strong>of</strong> breast cancer diagnosis.<br />
The risk <strong>of</strong> endometrial cancer was lower in patients with sequenced AI (14-year<br />
incidence 0.6% vs 1.4%; HR 0.4; 95% CI, 0.22 to 0.73; p = 0.0028).<br />
Conclusions: In Taiwan, not only older( >50 years) but younger (40-50 years) patients<br />
with tamoxifen treatment had higher risk <strong>of</strong> subsequent endometrial cancer. The risk<br />
<strong>of</strong> endometrial cancer still increased after patients had discontinued tamoxifen for<br />
several years. Sequenced AI use may reverse endometrial cancer risk in<br />
tamoxifen-treated breast cancer patients.<br />
Legal entity responsible for the study: This study was approved by the Research<br />
Ethics Committee <strong>of</strong> Buddhist Tzu Chi General Hospital, Hualien, Taiwan<br />
(IRB101-98).<br />
Funding: The National Science Council <strong>of</strong> the Republic <strong>of</strong> China, and Buddhist Tzu<br />
Chi General Hospital Taiwan were appreciated for supporting this research under<br />
Contract No. NSC 101-2314-B-303-020 and TCRD102-52.<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
889P<br />
Immunohistochemistry (IHC) evaluation <strong>of</strong> a novel 4-protein<br />
prognostic and predictive biomarker panel in endometrial<br />
cancer (EC)<br />
B. Kularatne 1 ,R.Arora 2 , G. Elshstein 3 , N. Guppy 3 , A. Kirkwood 4 ,T.Meyer 1 ,<br />
R.S. Kristeleit 5<br />
1 Medical <strong>Oncology</strong>, University College London Cancer Institute, London, UK,<br />
2 Histopathology, University College London Hospital, London, UK, 3 UCL<br />
Advanced Diagnostics, University College London Hospital UCLH NHS<br />
Foundation Trust, London, UK, 4 Cancer Research UK & UCL Cancer Trials Centre,<br />
UCL - University College London, London, UK, 5 <strong>Oncology</strong>, University College<br />
London, Cancer Institute, London, UK<br />
Background: EC is common and incidence has increased by 65% in 40 years. There are<br />
no validated biomarkers or approved targeted therapies in clinical use. This study<br />
evaluates a novel biomarker panel in EC by correlating clinico-pathological features<br />
and tumour tissue expression levels <strong>of</strong> p53, PTEN, phospho-P70S6K (pS6),<br />
phospho-Stathmin (pSTMN). pS6 and pSTMN activity is influenced by PI3K/Akt<br />
pathway activation which frequently occurs in EC.<br />
Methods: The 144 EC patients who had primary surgery from January 2006 to<br />
December 2010 at University College London Hospital were retrospectively identified<br />
and included in this analysis. Patient characteristics are shown in Table 1. Antibodies<br />
for p53, PTEN, pS6 and pSTMN were optimised for use in this study. IHC was<br />
performed on surgical resection specimens. Standard scoring methods incorporating<br />
percentage <strong>of</strong> cells stained and staining intensity were applied.<br />
889P Table: Cox proportional hazard regression model comparing clinico-pathological features and biomarker expression with DSS. NA-Not applicable.<br />
HR-Hazard ratio. CI- Confidence interval.<br />
Variable Categories Univariate Analysis Multivariate Analysis<br />
n Deaths HR (95% CI) p value HR(95% CI) p value<br />
Age >65 ≥65 59 85 7 17 1.91 (0.79-4.62) 0.15 3.43 (0.33-35.14) 0.3<br />
Histological sub-type Endometrioid Non-endometrioid 128 16 16 8 4.90 (2.09-11.48)
abstracts<br />
Results: Univariate analysis for disease specific survival (DSS) showed, as expected,<br />
non-endometrioid histology, grade 3 tumour, presence <strong>of</strong> lymphovascular invasion<br />
(LVI) or myometrial invasion (MI) and advanced International Federation <strong>of</strong><br />
Gynaecology and Obstetrics (FIGO) stage conferred poor DSS. The overexpression <strong>of</strong><br />
p53 and pSTMN was also associated with poor DSS. In multivariate analysis grade 3<br />
histology, MI, p53 and pSTMN overexpression were the only factors that remained<br />
significantly associated with poor DSS.<br />
Conclusions: We demonstrate for the first time that p53 and pSTMN overexpression<br />
are independent predictors <strong>of</strong> DSS in EC and may be useful prognostic biomarkers.<br />
Overexpression <strong>of</strong> pSTMN may predict sensitivity to PI3K pathway inhibitors in EC.<br />
Prospective evaluation is warranted in clinical studies.<br />
Legal entity responsible for the study: UCL Cancer Institute<br />
Funding: UCL Cancer Institute<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
890P<br />
Cervical cancer: Awareness and misconceptions <strong>of</strong> risk<br />
factors among lay persons and physicians<br />
X. Pivot 1 , J-F. Morère 2 , S. Couraud 3 , C. Touboul 4 , J-Y. Blay 5 , A.B. Cortot 6 ,<br />
C. Lhomel 7 , F. Eisinger 8 , L. Greillier 9 , J. Viguier 10<br />
1 Service Oncologie Medicale, CHU Besançon, Hôpital Jean Minjoz, Besançon,<br />
France, 2 Medical <strong>Oncology</strong>, Hopital Paul Brousse, Villejuif, France, 3 Respiratory<br />
Diseases and Thoracic <strong>Oncology</strong>, Centre Hospitalier Lyon Sud, Pierre Bénite,<br />
France, 4 Statistics, KantarHealth, Paris, France, 5 Medical <strong>Oncology</strong>, Centre Léon<br />
Bérard, Lyon, France, 6 Pneumology and Thoracic <strong>Oncology</strong>, DRC / CHRU <strong>of</strong> Lille,<br />
Lille, France, 7 <strong>Oncology</strong>/Hematology Institutionnal, Roche, Boulogne-Billancourt,<br />
France, 8 Cancer Control, Institute Paoli Calmettes, Marseille, France,<br />
9 Multidisciplinary <strong>Oncology</strong> and Therapeutic Innovations, Hopital Nord, Marseille,<br />
France, 10 Medical <strong>Oncology</strong>, CHRU Bretonneau, Tours, France<br />
Background: Cervical cancer (CC) is the fourth most common cancer in women<br />
worldwide. Human papillomavirus (HPV) subtypes 16 and 18 account for 70% <strong>of</strong><br />
cases <strong>of</strong> CC. 80% <strong>of</strong> sexually active French women are infected by HPV at least once in<br />
their lifetime. Vaccination and screening are the main weapons against CC. This<br />
branch <strong>of</strong> the EDIFICE survey focuses on awareness <strong>of</strong> CC risk factors among the lay<br />
population and physicians.<br />
Methods: The 4th nationwide observational survey was conducted by phone interviews<br />
using the quota method. A representative sample <strong>of</strong> 737 women (age, 40-75 yrs) was<br />
interviewed between June 12 and July 10, 2014. A mirror survey on a representative<br />
sample <strong>of</strong> 105 female physicians was conducted between July 9 and August 8, 2014.<br />
Interviewees were asked to cite the five main risk factors for CC.<br />
Results: For 30.3% <strong>of</strong> lay population participants, heredity/family history was the main<br />
CC risk factor while 39.0% <strong>of</strong> physicians (non-significant difference, NS) ranked it<br />
second after other factors related to sexually-transmitted infections (STI) and risky<br />
sexual behavior. STI were cited by 85.7% <strong>of</strong> the physicians; notably, 76.2% also<br />
mentioned HPV whereas these risk factors were cited by only 21.7% and 8.0% <strong>of</strong> the<br />
lay population (P < 0.01). Sexual practices were cited by 81.9% <strong>of</strong> physicians and 18.5%<br />
<strong>of</strong> the lay population (P < 0.01), including multiple partners (70.5% vs. 9.7%, P < 0.01)<br />
and unprotected sexual activity (35.2% vs. 9.8%, P < 0.01). Tobacco was cited by 23.8%<br />
<strong>of</strong> physicians and 6.6% <strong>of</strong> the lay population (P < 0.01). Other known risk factors were<br />
cited at very low rates (differences between physicians and lay persons, NS):<br />
contraceptive pill (3.8% vs 6.2%) and multiple pregnancies (1.9% vs. 0.5%).<br />
Conclusions: Although not a recognized risk factor for CC, heredity/family history was<br />
ranked first by lay persons and second by physicians. Physicians were largely aware <strong>of</strong><br />
HPV as a major risk factor for CC. They also widely cited notorious risky sexual<br />
behavior associated with the risk <strong>of</strong> contracting HPV, and tobacco, a known c<strong>of</strong>actor.<br />
Lay persons however, were inadequately aware <strong>of</strong> these risk factors. Other recognized<br />
c<strong>of</strong>actors such as the pill or multiple pregnancies were cited far less frequently both by<br />
physicians and lay persons.<br />
Legal entity responsible for the study: Edifice surveys were funded by Roche S.A.<br />
Funding: Edifice surveys were funded by Roche S.A.<br />
Disclosure: X. Pivot, J-F. Morère, S. Couraud, J-Y. Blay, A.B. Cortot, F. Eisinger,<br />
L. Greillier: Honorarium fees from Roche. C. Lhomel: Employee <strong>of</strong> Roche. All other<br />
authors have declared no conflicts <strong>of</strong> interest.<br />
891P<br />
Sexual satisfaction, anxiety, depression and quality <strong>of</strong> life<br />
amoung Turkish gynecological cancer patients<br />
Y. Yildiz 1 , M. Akyol 2 , A. Alacacioglu 2 , Y. Kucukzeybek 2 ,N.Asık 2 , H. Taskaynatan 2 ,<br />
U. Varol 2 , I. Yildiz 3 , U. Oflazoglu 4 , T. Salman 2 , S.U. Ozaltas 2 , M.O. Tarhan 5<br />
1 Katip Celebi University, Ataturk Training and Research Hospital, Izmir Katip Celebi<br />
University, Izmir, Turkey, 2 Medical <strong>Oncology</strong>, Ataturk Training and Research<br />
Hospital, Izmir Katip Celebi University, Izmir, Turkey, 3 <strong>Oncology</strong>, Ataturk Training<br />
and Research Hospital, Izmir Katip Celebi University, Izmir, Turkey, 4 Medical<br />
<strong>Oncology</strong>, Ataturk Egitim ve Arastirma Hastanesi Tibbi Onkoloji Klinik, Izmir, Turkey,<br />
5 Medical <strong>Oncology</strong>, Dokuz Eylul University School <strong>of</strong> Medicine, Institute <strong>of</strong><br />
<strong>Oncology</strong>, Izmir, Turkey<br />
Background: Treatments <strong>of</strong> gynecologic cancer can impact a patient’s self-esteem and<br />
body image and can create significant physical barriers, such as pain, to satisfactory<br />
sexual experiences, as treatments affect the organs associated with sexuality and in the<br />
period <strong>of</strong> life in which sexuality is <strong>of</strong> great importance. Gynecological cancer patients<br />
(GCPs) suffer from several physical and psychological problems. We aimed to<br />
investigate anxiety, depression, quality <strong>of</strong> life and sexual satisfaction levels <strong>of</strong><br />
gynecological cancer patients (GCPs).<br />
Methods: In this study, 62 patients with gynecologic cancer were included. The forms<br />
consist <strong>of</strong> Golombok- Rust Inventory <strong>of</strong> Ssexual Satisfaction (GRISS), State-Trait<br />
Anxiety (STAI) and European Organization for Research on Treatment <strong>of</strong> Cancer<br />
Questionnaires Quality <strong>of</strong> Life-C30 were used.<br />
Results: The EORTC-QLQ-C30 scores <strong>of</strong> the patients were compared with their anxiety,<br />
depression and hopelessness. There was a statistical significance in the physical<br />
functioning (p = 0.020), role functioning(p = 0.006) and emotional functioning (p=<br />
0.0001) when the anxiety scores were high. There was a similar significance in the<br />
physical (p = 0.014), cognitive (p = 0.001) and social functions (p= 0.001) when the<br />
depression scores were high. When hopelessness scores were high, only physical<br />
functioning (p = 0.013) was notable. When we evaluated GRISS subscores and anxiety<br />
levels, we found significant increase in satisfaction (p = 0.03) and vaginismus (p = 0.002)<br />
in the GCPs. When we evaluated GRISS subscores and depression levels, GRISS<br />
subscores <strong>of</strong> the GCPs who had high depression scores were also high. However,<br />
statistical significance was found in satisfaction (p = 0.027), and erectile dysfunction<br />
(p = 0.043) subscores in the GCPs. There was a significance in the frequency (p= 0.017),<br />
satisfaction (p= 0.019) and avoidance (p = 0.032) in the high hopelessness score.<br />
Conclusions: This study shows that there is a significant association with anxiety,<br />
depression symptoms and quality <strong>of</strong> life scores and sexual dysfunction. Patients’ quality<br />
<strong>of</strong> life may be increased by taking precautions to reduce their psychosocial and<br />
psychosexual concerns.<br />
Legal entity responsible for the study: Ahmet Alacacıoglu<br />
Funding: ızog (Izmir <strong>Oncology</strong> Group )<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
892P<br />
Virological studies in the secondary prevention <strong>of</strong> cervical<br />
cancer<br />
E.V. Bakhidze 1 , O.Y. Lavrynovych 1 , A.V. Belyaeva 2 , I.V. Berlev 1<br />
1 Gynecological <strong>Oncology</strong>, N.N.Petrov Research Inst. <strong>of</strong> <strong>Oncology</strong>, St. Petersburg,<br />
Russian Federation, 2 Surgical Department <strong>of</strong> Abdominal <strong>Oncology</strong>, N.N.Petrov<br />
Research Inst. <strong>of</strong> <strong>Oncology</strong>, St. Petersburg, Russian Federation<br />
Background: Metastases in regional lymph nodes in CC significantly reduces patients’<br />
survival. Study demonstrates possibility <strong>of</strong> molecular diagnosis <strong>of</strong> metastases in<br />
regional lymph nodes.<br />
Methods: 112 patients with squamous CC IB - IIB stages by FIGO underwent surgical<br />
or combined treatment since 1995 to 2008 were enrolled. Distribution <strong>of</strong> patients by<br />
TNM stage: I (T1N0M0) - 32, II (T2N0M0) - 33, III (T1,2N1M0) - 33 patients. All<br />
patients were tracked during 36 to 120 months after treatment. High cancerogenic risk<br />
HPV DNA in cells <strong>of</strong> primary tumor derived from endocervical brushstrokes was<br />
detected using PCR method with DNA-sorb-A. HPV DNA in cells <strong>of</strong> iliac lymph<br />
nodes removed during surgery and stored in paraffin blocks was detected with PCR.<br />
Results: HPV DNA test in primary tumor revealed a prevalence <strong>of</strong> HPV 16 genotype (in<br />
81 patients - 82.7%), the other: 33 type - 31.7%, 18 -24.5%, 31-10.2%, 56-10.2%, 58-10.2%,<br />
45-9.2%, 39 -5.1%, 52 -5.1%, 51-4.1%, 53-2.0% and 42 type -1.0%. HPV DNA in regional<br />
lymph nodes was found in 29 <strong>of</strong> 98 patients (29.6%) using PCR. In 27 <strong>of</strong> these 29 patients<br />
there were confirmed lymph nodes metastases (93.1% <strong>of</strong> all patients with lymph node<br />
metastases (p ≤ 0.05)). HPV DNA 16 type in lymph nodes was detected in 15 patients<br />
(51.7%), 18 type - in 4 (13.8%), 31 - in 5 (17.2%),33 – in 5 (17.2%). In all cases HPV type<br />
in lymph nodes matched the type in primary tumor. Identification <strong>of</strong> HPV DNA in iliac<br />
lymph nodes was significantly more consistent with detection <strong>of</strong> HPV in primary cervical<br />
tumors with one HPV type (58.62%) than infection with multiple HPV types (p ≤ 0.05).<br />
Method <strong>of</strong> DNA HPV detection in regional lymph nodes showed its high specificity:<br />
96.9% (95% CI: 89 ÷ 100%) and relatively high sensitivity: 81.8% (95% CI: 65 ÷ 93%) in<br />
diagnostics <strong>of</strong> metastases. Diagnostic efficiency <strong>of</strong> test was 91.8% (false-negative response<br />
-18.2%, false positive - 3.1%). Bilateral (66.7%) metastatic lymph nodes were found more<br />
<strong>of</strong>ten if HPV type 16 was detected in iliac lymph nodes (p ≤ 0.05). Detection <strong>of</strong> HPV<br />
DNA type 18 was <strong>of</strong>ten associated with unilateral metastases (p = 0.014).<br />
Conclusions: Method <strong>of</strong> HPV DNA detection in iliac lymph nodes <strong>of</strong> patients with CC<br />
has high specificity and enough high sensitivity in diagnostics <strong>of</strong> lymph node<br />
metastases including investigation <strong>of</strong> sentinel lymph nodes.<br />
Legal entity responsible for the study: N.N.Petrov Research Institute <strong>of</strong> <strong>Oncology</strong><br />
Funding: N.N.Petrov Research Institute <strong>of</strong> <strong>Oncology</strong><br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
893P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Chemotherapy-related toxicity in patients receiving concurrent<br />
chemoradiation for locally advanced cervical cancer<br />
M. Etsebeth 1 , S. Bassa 2 , R. Lakier 1<br />
1 Radiation <strong>Oncology</strong>, Steve Biko Academic Hospital, Pretoria, South Africa,<br />
2 Clinical & Radiation <strong>Oncology</strong>, Curo <strong>Oncology</strong>, Pretoria, South Africa<br />
Background: In South Africa the majority <strong>of</strong> cases <strong>of</strong> cervical cancer are locally<br />
advanced. Radiotherapy with weekly Cisplatin, 40mg/m 2 , is the treatment <strong>of</strong> choice.<br />
vi308 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
This dosage is <strong>of</strong>ten tolerated poorly in the developing world. This study determined<br />
the frequency <strong>of</strong> severe chemotherapy-related toxicity, at a dosage <strong>of</strong> 30mg/m 2 in<br />
patients receiving radical chemoradiotherapy.<br />
Methods: A retrospective review was performed <strong>of</strong> patients receiving concurrent<br />
chemoradiation for cervical cancer, using weekly Cisplatin, 30mg/m 2 . The frequency <strong>of</strong><br />
severe chemotherapy-related toxicity (grade 3 and 4) was determined in the following<br />
categories: haematologic, renal and upper gastro-intestinal tract toxicity. In order to<br />
determine the tolerability <strong>of</strong> weekly Cisplatin, the number <strong>of</strong> completed cycles was<br />
compared to the intended number, and the average number <strong>of</strong> cycles completed by<br />
each patient was calculated. Age, FIGO stage and HIV status were confounding<br />
variables included in the analysis.<br />
Results: The incidence <strong>of</strong> severe toxicity was low, with renal toxicity (17%) the most<br />
common. FIGO stage and HIV status did not influence toxicity significantly. Patients<br />
older than 50 years showed a trend for higher toxicity, p-value = 0.094. Approximately<br />
three quarter <strong>of</strong> planned chemotherapy cycles were administered. Sixty-eight per cent<br />
<strong>of</strong> patients received four or five doses <strong>of</strong> Cisplatin. The remainder received three cycles<br />
or less which was deemed inadequate. Reasons for omitted doses were not only toxicity<br />
but also included logistical and administrative issues. Outcome data will be presented.<br />
Conclusions: Weekly Cisplatin, 30mg/m 2 , with chemoradiation for cervical cancer is<br />
well tolerated. HIV infection did not influence toxicity, but patients over 50 years may<br />
have increased risk for adverse events. Stricter adherence to guidelines is<br />
recommended.<br />
Legal entity responsible for the study: University <strong>of</strong> Pretoria, South Afrca Steve Biko<br />
Academic Hospital, Pretoria, South Africa<br />
Funding: Personal funds<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
894P<br />
Comprehensive genomic pr<strong>of</strong>iling <strong>of</strong> uterine carcinosarcomas<br />
identifies potential targeted therapy opportunities<br />
J.A. Elvin 1 , L.M. Gay 1 , C. Gunderson 2 , M. Greenwade 2 , S. Ramkissoon 1 , S. Ali 3 ,<br />
J-A. Vergilio 1 , J. Suh 1 , J.S. Ross 4 , K.N. Moore 5<br />
1 Pathology, Foundation Medicine, Inc., Cambridge, MA, USA, 2 Obstetrics and<br />
Gynecology, Stephenson Oklahoma Cancer Center, Oklahoma City, OK, USA,<br />
3 Clinical Development, Foundation Medicine, Inc., Cambridge, MA, USA,<br />
4 Pathology, Albany Medical Center, Albany, NY, USA, 5 Gynecologic <strong>Oncology</strong>,<br />
Stephenson Cancer Center/University <strong>of</strong> Oklahoma, Oklahoma City, OK, USA<br />
Background: Uterine carcinosarcomas (UCS) are highly aggressive malignancies that<br />
are felt to derive from pluripotent malignant cells in Müllerian tract. Studies <strong>of</strong> primary<br />
chemotherapy for stage III, IV or recurrent disease report median OS ranging from<br />
9-15 mos. No effective therapies are available after progression from front line therapy.<br />
Comprehensive genomic pr<strong>of</strong>iling (CGP) increases the ability to screen for somatic<br />
mutations that may direct therapies. This study characterized CGP results for advanced<br />
or recurrent UCS disease and compared results to similar analyses for endometrial<br />
adenocarcinomas (EA).<br />
Methods: DNA was extracted from FFPE clinical specimens for 100 UCS and 257 EA<br />
(including endometrioid and non-endometrioid subtypes). Hybridization captured<br />
libraries <strong>of</strong> 315 genes, plus select introns frequently rearranged in cancer, were<br />
sequenced to high (median 780x), uniform coverage. All classes <strong>of</strong> genomic alterations<br />
(base subs, small indels, rearrangements, and copy number alterations) were evaluated<br />
and reported. Clinically relevant genetic alternations (CRGA) were defined as GA<br />
associated with on-label targeted therapies and targeted therapies in mechanism-driven<br />
clinical trials.<br />
Results: 55% <strong>of</strong> UCS had at least one clinically relevant alteration (not counting TP53).<br />
Mutation frequencies for commonly altered genes are displayed below.<br />
Table: 894P<br />
Gene UCS EA<br />
TP53 80% 55%<br />
PIK3CA 27% 44%<br />
CCNE1 21% 10%<br />
PTEN 18% 40%<br />
RB1 17% 8%<br />
MYC 16% 8%<br />
FBXW7 14% 14%<br />
LYN 14% 3%<br />
KRAS 13% 17%<br />
ARID1A 12% 32%<br />
CTNNB1 6% 21%<br />
AKT1 6% 3%<br />
NF1 6% 9%<br />
FGFR1 4% 2%<br />
BRCA1/2 4% 8%<br />
ERBB2 4% 11%<br />
EGFR 4% 1%<br />
Conclusions: Advanced/recurrent UCS are highly malignant neoplasms with poor<br />
durable responses to conventional chemotherapy. CGP in this series and others reveals<br />
CRGAs also seen in EA, and indicate potential therapeutic sensitivities. More frequent<br />
mutation <strong>of</strong> CCNE1, LYN, and MYC suggest a mechanism for the more aggressive<br />
phenotype <strong>of</strong> UCS. Targeting TP53 GA with WEE-1 inhibitors, KRAS GA with MEK<br />
inhibitors, and treating with PARPi when appropriate may benefit patients.<br />
Consideration for basket trials based on CGP for patients with UCS may confirm active<br />
agents for this disease.<br />
Legal entity responsible for the study: Foundation Medicine, Inc.<br />
Funding: Foundation Medicine, Inc.<br />
Disclosure: J.A. Elvin, L.M. Gay, S. Ramkissoon, S. Ali, J-A. Vergilio, J. Suh, J.S. Ross:<br />
Employee <strong>of</strong> and shareholder in Foundation Medicine, Inc. All other authors have<br />
declared no conflicts <strong>of</strong> interest.<br />
895P<br />
Use <strong>of</strong> bevacizumab (Bev) in real life for first-line (fl) treatment<br />
<strong>of</strong> ovarian cancer (OC). Part1: the ENCOURAGE cohort <strong>of</strong> 1158<br />
patients (pts) by GINECO<br />
D. Berton-Rigaud 1 , F. Selle 2 , A. Floquet 3 , D. Mollon 4 , W. Lescaut 5 ,<br />
M-C. Kaminsky 6 , I.L. Ray-Coquard 7 , R. Largillier 8 , A-M. Savoye 9 , H. Barletta 10 ,<br />
P. Pautier 11 , H. Orfeuvre 12 , M. Baron 13 , A. Marti 14 , J-L. Mouysset 15 , J-B. Paoli 16 ,<br />
P-E. Cailleux 17 , C. Cornea 18 , E. Pujade-Lauraine 19<br />
1 Oncologie, ICO Centre René Gauducheau, Saint-Herblain, France, 2 Oncologie<br />
Médicale, Hôpital Tenon, Paris, France, 3 Oncologie Médicale, Institute Bergonié,<br />
Bordeaux, France, 4 Service Radiothérapie et Oncologie Médicale, CH de<br />
Cornouaille - Hopital Laennec, Quimper, France, 5 Service de Médecine Interne<br />
Hématologie Oncologie, Centre Hospitalier Princesse Grâce CHPG-Monaco,<br />
Monaco, Monaco, 6 Oncologie Médicale, ICL Institut de Cancérologie de Lorraine,<br />
Vandoeuvre Les Nancy, France, 7 Service 2B Nord, Centre Léon Bérard, Lyon,<br />
France, 8 Oncologie Médicale, Centre Azuréen de Cancérologie, Mougins, France,<br />
9 Service Rubis - Oncologie Médicale, Institut Jean Godinot, Reims, France,<br />
10 Cancérologie Médicale, Hôpital Privé Drôme Ardèche - Clinique Pasteur,<br />
Guilherand-granges, France, 11 Oncologie Médicale, Centre Léonard de Vinci,<br />
Dechy, France, 12 Service Onco-Hématologie, Centre Hospitalier de<br />
Bourg-en-Bresse (Fleyriat) CH De Fleyriat, Bourg En Bresse, France, 13 Oncologie<br />
Médicale, Clinique Mathilde, Rouen, France, 14 Service Oncologie, CH Auxerre,<br />
Auxerre, France, 15 Oncologie, Clinique Provençale, Aix-en-Provence, France,<br />
16 Oncologie, Hôpital Saint-Joseph, Marseille, France, 17 Oncologie, Pôle Santé<br />
Léonard de Vinci, Chambray-lès-Tours, France, 18 Oncologie, Centre Hospitalier<br />
Jean Bernard, Valenciennes, France, 19 Cancer de la Femme et Recherche<br />
Clinique, AP-HP, Hôpitaux Universitaires Paris Centre site Hôtel-Dieu, Paris,<br />
France<br />
Background: Bev has obtained European (EU) approval for EOC pts treated in fl on<br />
12/2011. This study addresses the question <strong>of</strong> how Bev is used in routine practice for<br />
the fl treatment <strong>of</strong> OC pts.<br />
Methods: 102 centers were selected to be representative <strong>of</strong> the distribution <strong>of</strong> OC pts in<br />
France. All consecutive OC pts treated in fl in each center were screened in order to<br />
include at least 500 pts who gave their consent to participate to the ENCOURAGE<br />
cohort evaluating the long term Bev use in routine practice. We report here how Bev<br />
was prescribed in this series <strong>of</strong> pts.<br />
Results: From 04/2013 to 02/2015, 1158 evaluable pts representing 15% <strong>of</strong> French<br />
incidence cases were screened in academic hospital (15%), cancer center (29%), general<br />
hospital (25%), private center (31%). Bev was administered in 557 (48%) pts and<br />
mostly according to the label: with carboplatin (99%) and paclitaxel (98%), for stage<br />
IIIB-IV (97%), and at a dose <strong>of</strong> 15mg/kg (80.2%). Bev was NOT prescribed in 601/1158<br />
pts and reasons were specified for 487pts. These were comorbidity including age over<br />
70 (29%), neo-adjuvant strategy (22%), early stage (20%), inclusion in a trial (13%), no<br />
macroscopic residue after initial surgery (11%), early disease progression or death<br />
(3%), patient refusal (2%). Interestingly, in this series <strong>of</strong> 1158 consecutive pts, only<br />
about 1/3 <strong>of</strong> pts with comorbidity/age over 70, or no residue after initial surgery or<br />
treated with a neo-adjuvant strategy were excluded from Bev treatment, reflecting the<br />
heterogeneity <strong>of</strong> practice among centers.<br />
Conclusions: Bev was administered in 1 st line EOC treatment according to the EU<br />
label for the great majority <strong>of</strong> pts . However, the large variability <strong>of</strong> Bev prescription<br />
when patients had comorbidity, age over 70 or were treated with a neo-adjuvant<br />
strategy reflects the need <strong>of</strong> OC trials focusing on these populations <strong>of</strong> patients.<br />
Clinical trial identification: NCT01832415<br />
Legal entity responsible for the study: ARCAGY-GINECO<br />
Funding: Roche<br />
Disclosure: J-L. Mouysset: Roche, Astellas, San<strong>of</strong>i, Janssen, Hospira, Novartis, Sandoz,<br />
Pierre Fabre. All other authors have declared no conflicts <strong>of</strong> interest.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw374 | vi309
abstracts<br />
896P<br />
Overxpression <strong>of</strong> HER2/neu in uterine carcinosarcoma<br />
T. Nishikawa, K. Yonemori, H. Okuma, A. Kawachi, A. Kitano, T. Shimoi,<br />
A. Shimomura, E. Noguchi, M. Yunokawa, H. Yoshida, C. Shimizu, Y. Fujiwara,<br />
K. Tamura<br />
Breast and Medical <strong>Oncology</strong>, National Cancer Center Hospital, Tokyo, Japan<br />
Background: Uterine carcinosarcoma (UCS) is a rare tumor in gynecologic<br />
malignancy comprising less than 5% <strong>of</strong> uterine cancers, and is known to be clinically<br />
highly aggressive. UCS is <strong>of</strong>ten excluded from the eligibility <strong>of</strong> clinical trials, because <strong>of</strong><br />
its rarity and poor prognosis. For recurrent or metastatic UCS, combination therapy <strong>of</strong><br />
ifosfamide and paclitaxel is recommended as first line chemotherapy, and combination<br />
therapy <strong>of</strong> carboplatin and paclitaxel is also useful. However, the efficacy <strong>of</strong> existing<br />
chemotherapy for UCS is relatively limited and the research <strong>of</strong> molecular targeted<br />
therapy for UCS is behind in development because <strong>of</strong> its property. The main aim <strong>of</strong><br />
this study is to evaluate HER2/neu expression status in UCS.<br />
Methods: After approval by the internal review board, we retrospectively evaluate HER2/<br />
neu expression status in UCS, using the archives with formalin-fixed paraffin-embedded<br />
tissue blocks <strong>of</strong> UCS from patients. All patients were treated in National Cancer Center<br />
Hospital, Tokyo, Japan from 1998 to 2016, and the expression <strong>of</strong> HER2/neu in UCS was<br />
examined by immunohistochemistry (IHC), using polyclonal rabbit anti-HER2/neu<br />
antibody (A0485, DAKO, Carpinteria, CA). The expression <strong>of</strong> HER2/neu was scored as<br />
negative (0, 1+), equivocal (2+), positive (3+) in accordance with ASCO/CAP clinical<br />
practice guideline <strong>of</strong> breast cancer. Furthermore, carcinoma component (CC) and sarcoma<br />
component (SC) <strong>of</strong> the tumor were evaluated separately for its expression intensity.<br />
Results: Eighty-four cases were evaluated as UCS and 47 cases (56%) were negative/0,<br />
1 + , 18 cases (21%) were equivocal/2 + , and 19 cases (23%) were positive/3+ in IHC.<br />
About the difference <strong>of</strong> HER2/neu expression between in CC and in SC, 37 cases (44%)<br />
stained 2 + /3+ over 10% in CC, whereas 0 cases (0%) stained 3+ and 8 cases (9.5%)<br />
stained 1 + /2+ over 10% in SC. HER2/neu in CC was significantly more expressed<br />
than in SC (p < 0.01).<br />
Conclusions: HER2/neu expression was identified in half <strong>of</strong> patients with UCS, and we<br />
must verify the significance <strong>of</strong> HER2 2+ in UCS by in situ hybridization (ISH). The<br />
current results suggest that molecular therapy targeted HER2 has a potential to be a<br />
new treatment for UCS.<br />
Legal entity responsible for the study: Natinal Cancer Center Hospital, Tokyo, Japan<br />
Funding: Natinal Cancer Center Hospital, Tokyo, Japan<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
897P<br />
Comprehensive genomic pr<strong>of</strong>iling <strong>of</strong> uterine leiomyosarcomas<br />
identifies opportunities for personalized therapies<br />
K.N. Moore 1 , C. Gunderson 2 , S. Ramkissoon 3 , S. Ali 4 , C. McMahon 5 , L.M. Gay 3 ,<br />
J.S. Ross 6 , J.A. Elvin 3<br />
1 Gynecologic <strong>Oncology</strong>, Stephenson Cancer Center/University <strong>of</strong> Oklahoma,<br />
Oklahoma City, OK, USA, 2 Obstetrics and Gynecology, University <strong>of</strong> Oklahoma<br />
Health Sciences Center, Oklahoma City, OK, USA, 3 Pathology, Foundation<br />
Medicine, Inc., Cambridge, MA, USA, 4 Clinical Development, Foundation<br />
Medicine, Inc., Cambridge, MA, USA, 5 Computational Biology, Foundation<br />
Medicine, Inc., Cambridge, MA, USA, 6 Pathology, Albany Medical Center, Albany,<br />
NY, USA<br />
Background: Uterine leiomyosarcoma (uLMS) respond poorly to conventional<br />
chemotherapeutic agents, and personalized therapies have not yet been systematically<br />
explored. We hypothesize that comprehensive genomic pr<strong>of</strong>iling (CGP) <strong>of</strong> uLMS will<br />
identify therapeutic targets and provide insight into the biology <strong>of</strong> this highly<br />
aggressive tumor.<br />
Methods: CGP <strong>of</strong> 232 FFPE uLMS and 138 male LMS clinical specimens by<br />
hybridization-capture <strong>of</strong> up to 405 cancer-related genes provided genomic alterations<br />
(GA; SV, indels, CNA, rearrangements) and tumor mutational burden (TMB). TMB was<br />
calculated by counting mutations across a 1.25Mb region encompassing these genes.<br />
Results: Analysis <strong>of</strong> clinically advanced/recurrent uLMS from women with a median<br />
age 54 years (range 23-76 years) revealed that 96.5% harbor at least one GA (mean 3.5;<br />
range 0-17), most frequently in one or both <strong>of</strong> the TP53 (66%) and RB1 (50%) genes.<br />
Mutation frequencies in uLMS were compared to those in a cohort <strong>of</strong> 138 LMS cases<br />
from male patients. GA significantly more frequent in uLMS were PTEN (17.6% vs.<br />
8%; p = .009) and MED12 (12% vs. 2.9%; p = 0.0019) while TP53 was enriched in male<br />
LMS (77.5% vs. 66%; p= 0.019). GA predicted to activate the PI3K/AKT/mTOR<br />
pathway were identified in 33% <strong>of</strong> uLMS versus 25% <strong>of</strong> male LMS samples, including<br />
loss <strong>of</strong> function in negative regulators (PTEN, NF1, TSC1, STK11, TSC2, PIK3R1) and<br />
gain <strong>of</strong> function in positive regulators (RICTOR, IGF1R, AKT2, AKT1, PIK3CA). 34%<br />
<strong>of</strong> uLMS and 26% <strong>of</strong> male LMS harbored inactivation <strong>of</strong> the chromatin remodeling<br />
regulator ATRX. Potentially targetable fusions were identified in 4% <strong>of</strong> patients<br />
(NTRK1, ALK, BRAF, ROS1, MET), with several responses to TKIs. The median TMB<br />
for uLMS was 2.9 mut/Mb (range 0-55) and 2.6% <strong>of</strong> cases had > 10 mut/Mb, suggesting<br />
a limited role for single agent immune checkpoint inhibitors.<br />
Conclusions: Two therapies commonly used to treat s<strong>of</strong>t tissue sarcomas (STS),<br />
pazopanib and trabectedin, demonstrate limited efficacy for uLMS (RR 6-10%; median<br />
PFI 4.5 mo), highlighting the need for other treatment options. In contrast, case reports<br />
<strong>of</strong> responses to CGP-matched targeted therapy support systematic genomic<br />
characterization <strong>of</strong> uLMS to drive molecularly informed clinical trials for this rare and<br />
deadly malignancy.<br />
Legal entity responsible for the study: Foundation Medicine, Inc.<br />
Funding: Foundation Medicine, Inc.<br />
Disclosure: S. Ramkissoon, S. Ali, C. McMahon, L.M. Gay, J.S. Ross, J.A. Elvin:<br />
Employee <strong>of</strong> and shareholder in Foundation Medicine, Inc. All other authors have<br />
declared no conflicts <strong>of</strong> interest.<br />
898P<br />
Uterine carcinosarcoma: a retrospective clinical cohort<br />
analysis<br />
C. Perna 1 , G. Eminowicz 2 , U. Asghar 3 , G. Imseeh 4 , A. Kirkwood 5 , A. Mitra 6 ,<br />
R. Arora 7 , R.S. Kristeleit 8 , M. McCormack 6<br />
1 Clinical <strong>Oncology</strong>, Royal Surrey County Hospital St Luke’s Cancer Centre,<br />
Guildford, UK, 2 Radiotherapy, University College London Hospital UCLH NHS<br />
Foundation Trust, London, UK, 3 Medical <strong>Oncology</strong> Department, The Institute <strong>of</strong><br />
Cancer Research (ICR), London, UK, 4 Clinical Research Facility, University College<br />
London Cancer Institute, London, UK, 5 Cancer Research UK & UCL Cancer Trials<br />
Centre, UCL - University College London, London, UK, 6 Clinical <strong>Oncology</strong>,<br />
University College London Hospital UCLH NHS Foundation Trust, London, UK,<br />
7 Histopathology, University College London Hospital UCLH NHS Foundation<br />
Trust, London, UK, 8 <strong>Oncology</strong>, University College London, Cancer Institute,<br />
London, UK<br />
Background: Carcinosarcomas are rare, heterogeneous tumours with a poor prognosis<br />
where carcinomatous and sarcomatous elements co-exist. There is no well-defined<br />
treatment pathway. Through analysis <strong>of</strong> University College London Hospital (UCLH)<br />
patients, we correlated survival with treatment and patient’s characteristics to assess<br />
potential prognostic factors.<br />
Methods: Women with uterine carcinosarcoma treated at UCLH from 2003 to 2014<br />
were retrospectively identified and analyzed. Clinico-pathological data included poor<br />
prognostic factors and treatment. Kaplan-Meier Survival curves were generated using<br />
Stata version 14.1; survival differences were estimated using the long-rank test, p
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
primers targeting the L1 region <strong>of</strong> HPV DNA. The Ion AmpliSeq Cancer Hotspot<br />
Panel v2 is being used to examine the presence <strong>of</strong> 50 known mutations.<br />
Results: Forty-seven pts with VSCC were included. 22/47 (47%) were HPV+ and 25/47<br />
(53%) were HPV-. Median age at diagnosis was 60 years (IQR 49-76) and 69 years (IQR<br />
58-77), for HPV+ and HPV-, respectively. Disease stage by HPV status (+ vs -) was: I (15 vs<br />
16), II (2 vs 0), III (2 vs 9) and IV (3 vs 0). Molecular data is available on 31 pts (17 HPV + ,<br />
14 HPV-). Among HPV+ pts, 15/17 had ≥ 1 mutation. Mutational frequencies among<br />
HPV+ pts were: TP53 7/17, PIK3CA 6/17, KDR 5/17, KIT: 3/17, FGFR3 3/17, and one<br />
mutationeach<strong>of</strong>PTEN,CTNNB1,APC,KRAS,ERBB4,ATM,SMARCB1,FLT3,CDK2A.<br />
Among the HPV- pts, 12/14 had ≥ 1 mutation. Mutational frequencies among HPV- pts<br />
were: TP53 8/14, HRAS 3/14, CDKN2A 2/14, PI3KCA 2/14, KDR 1/14 and GNA11 1/14.<br />
Conclusions: VSCC is characterized by a high mutation rate and a high prevalence <strong>of</strong><br />
HPV infection. HPV-dependent and HPV-independent disease have unique mutational<br />
pr<strong>of</strong>iles. The high prevalence <strong>of</strong> “actionable” mutations supports the need for trials <strong>of</strong><br />
targeted therapies. Molecular data on the full study cohort (n = 47) will be presented.<br />
Legal entity responsible for the study: N/A<br />
Funding: University <strong>of</strong> Ottawa Pathology and Laboratory Medicine (PALM)<br />
Enrichment Fund<br />
Disclosure: G. Goss: Previously received honoraria and consulting fees from<br />
AstraZeneca, Roche, Boehringer-Ingelheim Pharmaceuticals Inc, Bristol-Myers Squibb<br />
and Pfizer and research monies from AstraZeneca. All other authors have declared no<br />
conflicts <strong>of</strong> interest.<br />
900TiP<br />
KEYNOTE-100: Phase 2 trial <strong>of</strong> pembrolizumab in patients<br />
with advanced recurrent ovarian cancer<br />
U.A. Matulonis 1 , M. Chen 2 , M. Puhlmann 2 , Y. Shentu 2 , J. Ledermann 3<br />
1 Medical <strong>Oncology</strong>, Dana-Farber Cancer Institute, Boston, MA, USA, 2 Medical<br />
<strong>Oncology</strong>, Merck & Co., Inc., Kenilworth, NJ, USA, 3 <strong>Oncology</strong>, University College<br />
London Hospitals, London, UK<br />
Background: Ovarian cancer is the most lethal gynecologic cancer, with approximately<br />
80% <strong>of</strong> patients experiencing disease recurrence following standard front-line therapy.<br />
Currently, no curative therapy is available for recurrent ovarian cancer (ROC), which is<br />
an area with high unmet medical need. Pembrolizumab is a programmed death 1<br />
(PD-1) inhibitor designed to directly block the interaction between PD-1 and its<br />
ligands, PD-L1 and PD-L2. This blockade enhances functional activity <strong>of</strong> the target<br />
lymphocytes to facilitate tumor regression and, ultimately, immune rejection. Prior<br />
study <strong>of</strong> pembrolizumab in advanced epithelial ovarian cancer showed promising<br />
clinical activity. Here, we further evaluate the efficacy and safety <strong>of</strong> pembrolizumab in<br />
patients (pts) with advanced ROC in the open-label, single-arm, 2-cohort<br />
KEYNOTE-100 study (NCT02674061).<br />
Trial design: Pts who are ≥18 years old with epithelial ovarian cancer, fallopian tube<br />
cancer, or primary peritoneal cancer and confirmed disease recurrence following<br />
front-line platinum-based therapy can be enrolled. Cohort A will include<br />
approximately 250 pts who received ≤2 prior therapies for ROC and had a<br />
platinum-free interval (PFI) or treatment-free interval (TFI) <strong>of</strong> ≥3 to 12 mo based on<br />
the last regimen received. Cohort B will include approximately 75 pts who received 3-5<br />
prior therapies for ROC and had a PFI or TFI <strong>of</strong> ≥3 mo based on the last regimen<br />
received. Pts must also have measurable disease and ECOG performance status <strong>of</strong> 0-1<br />
at baseline and must provide a tumor sample for PD-L1 analysis. Pts will be treated<br />
with pembrolizumab 200 mg every 3 wk for 35 cycles or until disease progression,<br />
death, unacceptable toxicity, or withdrawal <strong>of</strong> consent. Pts will have regular imaging<br />
and safety assessments during the study. The primary study objectives are to evaluate<br />
objective response rate per RECIST v1.1 (primary end point) in cohort A and cohort B<br />
all-comer populations and in tumor PD-L1 high-expression populations. Duration <strong>of</strong><br />
response, progression-free survival, overall survival, and safety will also be evaluated.<br />
Clinical trial identification: NCT02674061<br />
Legal entity responsible for the study: Merck & Co., Inc.<br />
Funding: Merck & Co., Inc<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
901TiP<br />
Phase Ib/II study to evaluate the efficacy and tolerability <strong>of</strong><br />
PM01183 (lurbinectedin) in combination with olaparib in<br />
patients with advanced solid tumors<br />
A.M. Poveda 1 , A. Oaknin 2 , I. Romero 1 , A. Guerrero 3 , L. Fariñas Madrid 4 , A. Soto 5 ,<br />
C. Peris 6 , J.A. Lopez Guerrero 7<br />
1 Oncogyn Department, Fundación Instituto Valenciano de Oncología, Valencia,<br />
Spain, 2 Vall d’Hebron University Hospital Institut d’Oncologia, Barcelona, Spain,<br />
3 Medical <strong>Oncology</strong>, Fundación Instituto Valenciano de Oncología, Valencia, Spain,<br />
4 Medical <strong>Oncology</strong>, Vall d’Hebron University Hospital Institut d’Oncologia,<br />
Barcelona, Spain, 5 Clinical Research, PhamaMar, Madrid, Spain, 6 Data Center,<br />
Fundación Instituto Valenciano de Oncología, Valencia, Spain, 7 Laboratory <strong>of</strong><br />
Molecular Biology, Fundación Instituto Valenciano de Oncología, Valencia, Spain<br />
patients in terms <strong>of</strong> Response Rates (RR), has been reported (Poveda A et al. ASCO<br />
2014.abstr #5505). PM01183 is currently being studied in different solid tumors.<br />
Olaparib (AZD2281, KU-0059436) is a potent Polyadenosine 5’diphosphoribose [poly<br />
(ADP ribose] polymerisation (PARP) inhibitor (PARP-1,-2 and-3) with proven<br />
antitumoral activity in homologous recombination deficient (HRD) tumors. Olaparib<br />
is being developed as an oral therapy, both as a monotherapy (including maintenance)<br />
and for combination with chemotherapy and other anti-cancer agents. The<br />
combination <strong>of</strong> PM01183 and Olaparib has shown synergistic activity in cell-lines<br />
independent <strong>of</strong> HRD status.<br />
Trial design: This first-in-human phase I-II study evaluates the safety and tolerability<br />
<strong>of</strong> PM1183 in combination with short course <strong>of</strong> Olaparib through a 3 + 3 dose<br />
escalation design Selection <strong>of</strong> patients: Phase-I patients with advanced or metastatic<br />
solid tumors without established standard therapeutic alternatives. Phase-II expansion<br />
cohort: platinum-resistant ovarian cancer patients (epithelial non-mucinous), triple<br />
negative breast and endometrial cancer patients. For patients included in the phase-II<br />
part <strong>of</strong> the study, evidence <strong>of</strong> measurable disease per Response Evaluation Criteria in<br />
Solid Tumors (RECIST) version 1.1 will be required. Primary endpoints are Phase-I:<br />
safety (MTD, DLT and RP2D); Phase-II: overall response rate. Secondary enpoints:<br />
Progression Free survival, Overall survival, PK and pharmacodynamic pr<strong>of</strong>iles, safety<br />
pr<strong>of</strong>ile. Additional translational research to analyze predictive factors to further select<br />
potential candidates will be explored. The trial is in progress; 13 <strong>of</strong> up to 48 planned pts<br />
in the phase-I part have been recruited at the end <strong>of</strong> April 2016 (enrollment started<br />
Nov 2015).<br />
Clinical trial identification: NCT02684318<br />
Legal entity responsible for the study: N/A<br />
Funding: Pharmamar, AstraZeneca<br />
Disclosure: A.M. Poveda: Roche, AstraZeneca, Pharmamar, Clovis Advisor. A.<br />
Oaknin: Roche, AstraZeneca, Clovis Advisor. A. Soto: Pharmamar employee and<br />
market share owner. All other authors have declared no conflicts <strong>of</strong> interest.<br />
902TiP<br />
abstracts<br />
ENDOLA : A GINECO-GINEGEPS French NCI sponsored<br />
phase I/II trial to assess the safety and efficacy <strong>of</strong><br />
metronomic cyclophosphamide, metformin and OLAparib in<br />
recurrent advanced/metastatic ENDometrial cancer patients<br />
B. You 1 , A. Dugue 2 , A. Leary 3 , M. Rodrigues 4 , P. Follana 5 , D. Maucort-Boulch 6 ,<br />
S. Verane 7 ,M.Tod 8 ,G.Freyer 1<br />
1 Medical <strong>Oncology</strong>, Hospices Civils de Lyon, Lyon, France, 2 Biostatistics, Centre<br />
Francois Baclesse, Caen, France, 3 Medical <strong>Oncology</strong>, Institut Gustave Roussy,<br />
Villejuif, France, 4 Medical <strong>Oncology</strong>, Institut Curie, Paris, France, 5 Medical<br />
<strong>Oncology</strong>, Centre Antoine Lacassagne, Nice, France, 6 Statistics, Hospices Civils<br />
de Lyon, Lyon, France, 7 Pharmacy, Hospices Civils de Lyon, Lyon, France,<br />
8 Pharmacology, Hospices Civils de Lyon, Lyon, France<br />
Background: Beyond first line treatment with platinum-based chemotherapy, there is<br />
lack <strong>of</strong> effective and well tolerated regimens for patients with metastatic endometrial<br />
carcinomas (EC). The combination <strong>of</strong> metronomic<br />
cyclophosphamide + metformin + olaparib may be effective because ECs are<br />
characterized by frequent alterations in the PI3K, IGF1R andf DNA repair pathways. In<br />
addition, PI3K signaling promotes effective DNA repair via homologous<br />
recombination (HR) and PI3K inhibition induces HR deficiency. Metronomic<br />
cyclophosphamide may be synergistic with olaparib via both its alkylating and<br />
anti-angiogenic effects, with a favorable toxicity pr<strong>of</strong>ile. Finally, metformin may<br />
increase the anti-proliferative effects <strong>of</strong> olaparib because it suppresses IGF1R and<br />
PI3K-AKT-mTor pathways, with no additive toxicity.<br />
Trial design: Trial design: ENDOLA is a prospective multicenter phase I/II open-label<br />
dose-escalation study to assess the safety, the phase 2 trial recommended dose (RP2D),<br />
potential PD interactions, as well as the efficacy <strong>of</strong> olaparib combined with metronomic<br />
cyclophosphamide and metformin in patients with recurrent advanced ECs. Phase 1:<br />
Dose escalation: a continual reassessment method (CRM) will be used to guide<br />
inclusion <strong>of</strong> a maximum 23 patients in drug dose levels pre-specified based on<br />
observations <strong>of</strong> dose-limiting toxicity <strong>of</strong> olaparib. Phase 2 (expansion cohort): once<br />
RP2D is determined, additional 6 to 13 patients will be enrolled, in order to obtain<br />
preliminary data about efficacy in a 2-stage Simon’s design. During cycle 1 only, the 3<br />
drugs will be gradually given in gradual run-in periods. It will enable assessment <strong>of</strong> PD<br />
interactions induced by the 3 drugs in blood and PBMCs (PI3KCA-AKT-mTor, IGF-1<br />
and PARP-1). Olaparib tablet dose will be dose-escalated on 4 dose levels, guided by a<br />
continual reassessment method (CRM). One cycle will be 28 days (4 weeks) in<br />
duration, except for cycle 1 which will be 6 weeks. The primary endpoint is safety based<br />
on NCICTAE v4 criteria in order to determine the RP2D.<br />
Clinical trial identification: NCT02755844<br />
Legal entity responsible for the study: Benoit You<br />
Funding: Institut National du Cancer. Astra Zeneca. ARCAGY-GINECO<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
Background: PM01183 is a new anticancer drug that exerts antitumor activity through<br />
inhibition <strong>of</strong> trans-activated transcription and modulation <strong>of</strong> tumor<br />
microenvironment. Recently a significant activity in platinum-resistant ovarian cancer<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw374 | vi311
abstracts<br />
903TiP<br />
Preoperative olaparib in early-stage endometrial cancer (EC):<br />
A phase 0, window <strong>of</strong> opportunity trial to evaluate the PARP<br />
inhibition effect, targeting cell cycle-related proteins (POLEN<br />
study)<br />
I. Romero 1 , M.J. Rubio 2 , R. Serrano 2 , M. Medina 3 , L. Minig 4 , A. Casado 5 ,<br />
P. Coronado 6 , S. Martínez 7 , C. Orbegoso 8 , P. Fusté 9 , E.M. Guerra Alia 10 ,M.<br />
C. Sánchez-Martínez 11 , D. Rubio 10 , M. Santacana 12 , M. Ruiz 12 ,<br />
A. Llombart-Cussac 13 , X. Matias-Guiu 12 , A.M. Poveda 4<br />
1 <strong>Oncology</strong>, Fundación Instituto Valenciano de Oncología and MedSIR-ARO,<br />
Valencia, Spain, 2 Medical <strong>Oncology</strong>, University Hospital Reina S<strong>of</strong>ia, Cordoba,<br />
Spain, 3 Pathology, University Hospital Reina S<strong>of</strong>ia, Cordoba, Spain, 4 <strong>Oncology</strong>,<br />
Fundación Instituto Valenciano de Oncología, Valencia, Spain, 5 Medical <strong>Oncology</strong>,<br />
Hospital Clinico Universitario San Carlos, Madrid, Spain, 6 Gynecology, Hospital<br />
Clinico Universitario San Carlos, Madrid, Spain, 7 Gynecology, Hospital Clinic y<br />
Provincial de Barcelona, Barcelona, Spain, 8 Medical <strong>Oncology</strong>, Hospital Clinic y<br />
Provincial de Barcelona, Barcelona, Spain, 9 Pathology, Hospital Clinic y Provincial<br />
de Barcelona, Barcelona, Spain, 10 Medical <strong>Oncology</strong>, Hospital Universitario<br />
Ramon y Cajal, Madrid, Spain, 11 Gynecology, Hospital Universitario Ramon y<br />
Cajal, Madrid, Spain, 12 Institut de Recerca Biomédica-IRB, Institut de Recerca<br />
Biomédica-IRB, Lerida, Spain, 13 MedSIR-ARO, MedSIR-ARO, Barcelona, Spain<br />
Background: Olaparib (AZD2281, KU-0059436) is a poly ADP ribose polymerase<br />
(PARP) inhibitor. Previous studies have shown relevant clinical activity as single agent<br />
in ovarian, breast and prostate cancers with BRCA1/2 mutations. However, little is<br />
known about the activity <strong>of</strong> PARP inhibitors in EC. The aim <strong>of</strong> this study is to identify<br />
pharmacodynamic and pharmacogenetic biomarkers associated with a short term<br />
exposure to olaparib in type I primary EC patients (pts).<br />
Trial design: Phase 0, multicenter, single arm, window <strong>of</strong> opportunity trial in women<br />
with type I primary EC candidate to surgery. They receive a 28 days course <strong>of</strong> olaparib<br />
tablets, 300 mg twice daily before surgery. The study was approved by the IRB from 5<br />
participating sites in Spain. Major eligibility criteria are (1) pts aged ≥18 years with<br />
histologically confirmed type I primary EC; (2) who have not received prior anticancer<br />
therapies for current disease and (3) adequate organ function and performance status.<br />
The trial uses an exact single stage design. The primary endpoints are the significant<br />
inhibition <strong>of</strong> cyclin D1, Ki67 and active caspase 3 activity in post-treatment against<br />
pre-treatment. We define significant inhibition in a patient if he shows ≥50%<br />
histoscore reduction, with a 95% confidence that it is not due to chance compared to<br />
the variation among the baseline values in all the sample. These pts are considered<br />
responders. The inhibition rate below which the treatment is considered inactive is 5%.<br />
The inhibition rate above which the treatment warrants further exploration is 35%;<br />
with type I and II errors <strong>of</strong> 5%, the sample size is 36 pts, with ≥6 responders as<br />
threshold. The secondary objectives include the measurement <strong>of</strong> the correlation<br />
between PARP inhibition and mitosis, angiogenesis and apoptosis tumor-tissue<br />
biomarkers, and to estimate the potential predictive role <strong>of</strong> microsatellite instability and<br />
PTEN loss in clinical tumor changes and PARP inhibition. Four women have been<br />
recruited for the trial since study start on March 2016. The expected end <strong>of</strong> accrual will<br />
be on November 2016.<br />
Clinical trial identification: NCT02506816; EudraCT 2015-001156-30<br />
Legal entity responsible for the study: Medica Scientia Innovation, MedSIR-ARO<br />
Funding: Astra Zeneca<br />
Disclosure: I. Romero: advisory board: Astra Zeneca, Roche Speaker’s bureau: Astra<br />
Zeneca, Roche, Pharmamar Accomodation travel expenses: Astra Zeneca, Roche,<br />
Pharmamar. A. Llombart-Cussac: has received honoraria lectures and advisory boards<br />
from Roche, GlaxoSmithKline, Novartis, Celgene, Eisai and AstraZeneca and research<br />
funding from GlaxoSmithKline, San<strong>of</strong>i and Puma Biotechnology. All other authors<br />
have declared no conflicts <strong>of</strong> interest.<br />
904TiP<br />
METRO-BIBF Phase II, randomised, placebo controlled,<br />
multicentre, feasibility study <strong>of</strong> low dose (metronomic)<br />
cyclophosphamide (MCy) with and without nintedanib in<br />
advanced ovarian cancer (AOC)<br />
M. Hall 1 , R. Lillywhite 2 , S. Nicum 3 , R. Lord 4 , R. Glasspool 5 , M. Feeney 2 ,<br />
A. Hackshaw 2<br />
1 Medical <strong>Oncology</strong>, Mount Vernon Cancer Centre, Northwood, UK, 2 Gynaecology<br />
Trials, Cancer Research UK & University College London Cancer Trials Centre,<br />
London, UK, 3 Medical <strong>Oncology</strong>, The Oxford Cancer Centre, Churchill Hospital,<br />
Oxford Radcliffe Hospitals NHS Trust, Oxford, UK, 4 Medical <strong>Oncology</strong>, University<br />
<strong>of</strong> Liverpool-Royal Liverpool University Hospital, Liverpool, UK, 5 Medical<br />
<strong>Oncology</strong>, Beatson West <strong>of</strong> Scotland Cancer Centre Gartnavel General Hospital,<br />
Glasgow, UK<br />
Background: AOC patients have generally been heavily pretreated with intravenous<br />
(IV) chemotherapy (CT) and their prospects are limited – median overall survival (OS)<br />
- 9 mo. MCy is an oral option which is well tolerated, does not require IV access or<br />
numerous hospital visits and has clinical benefit lasting >4 months for 19-25%<br />
(Kummar 2015, Hall 2010). MCy has anti-angiogenic properties; it has been shown to<br />
inhibit endothelial cells in tumour and host vasculature. Augmenting this mechanism<br />
has been explored in AOC by the addition <strong>of</strong> bevacizumab to MCy where ORR <strong>of</strong><br />
∼30% have been reported for high grade serous AOC (PFS-6.2mo and median OS 16.9<br />
mo) (Chura 2007, Garcia 2008). Nintedanib (N) is an oral tyrosine kinase inhibitor<br />
(TKI) which inhibits VEGFR, PDGFR and FGFR. Combining MCy with N <strong>of</strong>fers an<br />
oral option to control symptoms in patients with AOC maintaining QoL with minimal<br />
toxicity. This trial <strong>of</strong> MCy +/- N will explore the activity <strong>of</strong> MCy alone and the<br />
potential benefits <strong>of</strong> adding N.<br />
Trial design: A placebo controlled, randomised phase II design, with direct<br />
comparison <strong>of</strong> OS, aiming to detect an increase <strong>of</strong> 2 mo, i.e. median OS in the<br />
combination arm <strong>of</strong> 7 mo (HR 0.71). Patients with AOC who have received 2 or more<br />
lines <strong>of</strong> chemotherapy for AOC, are platinum resistant / intolerant and/or not suitable<br />
for any further IV CT, with ECOG PS 0-2 and life expectancy <strong>of</strong> >6 weeks will be<br />
recruited. All receive MCy 100mg/day continuously with N/placebo at 200mg bd until<br />
progression. The starting dose was later reduced to nintedanib / placebo 150mg bd due<br />
to a perceived excess <strong>of</strong> TKI related toxicity (abdominal cramps and diarrhoea).<br />
Patients will be stratified for prior treatment with bevacizumab but previous<br />
antiangiogenic TKI is NOT permissible. Primary outcome is OS. Secondary outcomes<br />
include safety, ORR only for patients with evaluable disease at trial entry, PFS and QoL.<br />
89 <strong>of</strong> 124 patients have been recruited to date.<br />
Clinical trial identification: NCT01610869 References: Kummar S et al. Clin Cancer<br />
Res. 2015 Apr 1;21(7):1574-82. Hall M et al. (2010). IJGC abstract no. 467 Chura JC<br />
et al (2007). Gyn Onc. 107(2):326-30 Garcia AA et al (2008). J Clin. Onc. 26:76-82<br />
Legal entity responsible for the study: University College London<br />
Funding: Boerhinger Ingelheim<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
905TiP<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Interim statistical analysis on a phase III randomised trial<br />
investigating the addition <strong>of</strong> modulated<br />
electro-hyperthermia to chemoradiation for cervical cancer<br />
in HIV positive and negative women in South Africa<br />
C.A. Minnaar 1 , J.A. Kotzen 1 , A. Baeyens 2<br />
1 Radiation Sciences, University <strong>of</strong> Witwatersrand Medical School, Johannesburg,<br />
South Africa, 2 Radiation Biophysics, IThemba LABS, Cape Town, South Africa<br />
Background: Cervical cancer is the second most common cancer in South Africa<br />
where funding and resources for treatment are limited and HIV infection rates are<br />
high. A Cochrane review (2010) on pooled data from six randomised trials showed a<br />
potential benefit to the addition <strong>of</strong> hyperthermia (HT) to radiotherapy (RT) protocols<br />
for cervical cancer. The Dutch Deep Hyperthermia trial (2010) reported a cost saving<br />
per quality adjusted life year when HT was added to RT protocols. The potential<br />
cost-saving resulting from the addition <strong>of</strong> HT to cervical cancer treatment protocols<br />
may lower the burden on healthcare facilities in South Africa and improve treatment<br />
options in HIV positive patients.<br />
Trial design: The aim is to determine the clinical effects <strong>of</strong> the addition <strong>of</strong> modulated<br />
electro-hyperthermia (mEHT) on the standard treatment protocols for locally<br />
advanced cervical cancer patients in state healthcare in South Africa. The objectives<br />
are to assess the effects <strong>of</strong> the addition <strong>of</strong> mEHT on local disease control, quality <strong>of</strong><br />
life, acute and late toxicity and survival. Method: This is an ongoing phase III<br />
randomised clinical trial conducted at the Charlotte Maxeke Johannesburg Academic<br />
Hospital. The study aims to enrol 236 female participants with FIGO stage IIB (initial<br />
distal parametrium involvement) to IIIB cervical cancer (no bilateral<br />
hydronephrosis). Participants are being randomised into a “Hyperthermia” group<br />
(mEHT plus chemoradiation) and a “Control” group (chemoradiation alone), based<br />
on HIV status, age and stage <strong>of</strong> disease. All participants are receiving 25 fractions <strong>of</strong><br />
2Gy external beam radiation, 3 doses <strong>of</strong> high dose rate brachytherapy (8Gy) and up<br />
to 3 doses <strong>of</strong> cisplatin (80mg/m 2 ). The Hyperthermia group is receiving two 55<br />
minute local mEHT treatments per week during radiation therapy. Local disease<br />
control is being assessed by Positron Emission Tomography (PET) scans. Adverse<br />
events, quality <strong>of</strong> life and overall survival are being recorded and the data is being<br />
analysed. Ethics was obtained by the Human Research and Ethics Council (clearance<br />
number: M120477)<br />
Clinical trial identification: South African Department <strong>of</strong> Health Trial Registration<br />
number: DOH-27-0113-4012; Issued 26 June 2012<br />
Legal entity responsible for the study: University <strong>of</strong> the Witwatersrand<br />
Funding: National Research Foundation: Technology and Human Resources for<br />
Industry Programme (THRIP; iThemba Labs; C-Therm Africa (pty) Ltd<br />
Disclosure: C.A. Minnaar: Shareholder in C-Therm Africa (Pty) Ltd, and has been<br />
placed by the company at the university as a PhD candidate, on a National Research<br />
Foundation Grant. All other authors have declared no conflicts <strong>of</strong> interest.<br />
vi312 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong> 27 (Supplement 6): vi313–vi327, 2016<br />
doi:10.1093/annonc/mdw375<br />
haematological malignancies<br />
906O<br />
Phase 3 randomised study <strong>of</strong> daratumumab, bortezomib and<br />
dexamethasone (DVd) vs bortezomib and dexamethasone (Vd)<br />
in patients (pts) with relapsed or refractory multiple myeloma<br />
(RRMM): CASTOR<br />
K. Weisel 1 ,A.Palumbo 2 , A. Chanan-Khan 3 ,A.K.Nooka 4 ,I.Spicka 5 ,T.Masszi 6 ,<br />
M. Beksac 7 ,V.Hungria 8 ,M.Munder 9 ,M-V.Mateos 10 ,T.M.Mark 11 ,A.Spencer 12 ,<br />
M. Qi 13 , J. Schecter 14 ,H.Amin 14 ,X.Qin 15 ,W.Deraedt 16 ,T.Ahmadi 13 ,P.Sonneveld 17<br />
1 Department <strong>of</strong> Hematology, <strong>Oncology</strong>, Immunology, Rheumatology and<br />
Pulmonology, Universitaetsklinikum Tuebingen der Eberhard-Karls-Universitaet,<br />
Abteilung fuer Innere Medizin II, Tuebingen, Germany, 2 Department <strong>of</strong><br />
Hematology, University <strong>of</strong> Turin, Turin, Italy, 3 Division <strong>of</strong> Hematology & Medical<br />
<strong>Oncology</strong>, Mayo Clinic Florida, Jacksonville, FL, USA, 4 Department <strong>of</strong> Hematology<br />
and Medical <strong>Oncology</strong>, Winship Cancer Institute, Emory University, Atlanta, GA,<br />
USA, 5 Clinical Department <strong>of</strong> Haematology, 1st Medical Department, Charles<br />
University in Prague, Prague, Czech Republic, 6 Department <strong>of</strong> Haematology and<br />
Stem Cell Transplantation, St László Hospital, Semmelweis University, Budapest,<br />
Hungary, 7 Department <strong>of</strong> Hematology, Ankara University, Ankara, Turkey,<br />
8 Irmandade Da Santa Casa De Misericordia De São Paulo, São Paulo, Brazil,<br />
9 Third Department <strong>of</strong> Medicine, University Medical Center <strong>of</strong> the Johannes<br />
Gutenberg-University, Mainz, Germany, 10 University Hospital <strong>of</strong> Salamanca/<br />
IBSAL, Salamanca, Spain, 11 Weill Cornell Medical College, New York, NY, USA,<br />
12 Malignant Haematology and Stem Cell Transplantation Service, Alfred<br />
Health-Monash University, Melbourne, Australia, 13 Janssen Research &<br />
Development, LLC, Spring House, PA, USA, 14 Janssen Research & Development,<br />
LLC, Raritan, NJ, USA, 15 Janssen Research & Development, LLC, Horsham, PA,<br />
USA, 16 Janssen Research & Development, Beerse, Belgium, 17 Department <strong>of</strong><br />
Hematology, Erasmus MC, Rotterdam, Netherlands<br />
907O<br />
Safety and efficacy <strong>of</strong> clarithromycin monotherapy in patients<br />
(pts) with extranodal marginal zone lymphoma (EMZL)<br />
C. Cecchetti 1 , B. Kiesewetter 2 , M. Sassone 1 , T. Calimeri 1 , L. Scarfò 1 , M. Raderer 2 ,<br />
A. Ferreri 1<br />
1 Department <strong>of</strong> OncoHematology, IRCCS San Raffaele, Milan, Italy, 2 Univ. Klinik<br />
für Innere Medizin I / Onkologie, Vienna General Hospital (AKH) - Medizinische<br />
Universität Wien, Vienna, Austria<br />
abstracts<br />
© European Society for Medical <strong>Oncology</strong> 2016. Published by Oxford University Press on behalf <strong>of</strong> the European Society for Medical <strong>Oncology</strong>.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com.
abstracts<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
908O<br />
High-dose methotrexate (HD-MTX) as CNS prophylaxis<br />
significantly improves outcome in patients with high-risk<br />
diffuse large B-cell lymphoma (DLBCL)<br />
T. Calimeri 1 , C. Cecchetti 1 , A. Vignati 1 , M. Sassone 1 , M. Foppoli 1 , L. Scarfò 1 ,<br />
M. Ponzoni 2 , A. Ferreri 1<br />
1 Department <strong>of</strong> OncoHematology, IRCCS San Raffaele, Milan, Italy, 2 Pathology<br />
Unit, IRCCS San Raffaele, Milan, Italy<br />
910P<br />
Outcome <strong>of</strong> primary gastrointestinal compared to nodal<br />
diffuse large B cell lymphoma in a series <strong>of</strong> consecutive<br />
patients treated at a single institution<br />
J. Romejko-Jarosinska, M. Osowiecki, E. Paszkiewicz-Kozik, A. Druzd-Sitek,<br />
K. Martyna, M. Szymański, L. Targonski, J. Walewski<br />
Lymphoroliferative Diseases Department, MSC Memorial Cancer Centre and<br />
Institute Maria Sklodowska-Curie, Warsaw, Poland<br />
909O<br />
R-da-EPOCH vs R-CHOP in patients with primary mediastinal<br />
large B-cell lymphoma: Results <strong>of</strong> randomised (prospective)<br />
multicenter study<br />
I. Kryachok 1 , I. Stepanishyna 1 , I. Tytorenko 1 , A.V. Martynchyk 1 , K. Filonenko 2 ,<br />
O. Novosad 1 , T. Kadnikova 1 , I. Pastushenko 1 , Y. Kushchevyy 1 , T. Skrypets 1 ,<br />
O. Aleksyk 2 , K. Ulianchenko 1<br />
1 Oncohematology, National Cancer Institute <strong>of</strong> the MPH Ukraine, Kiev, Ukraine,<br />
2 Oncohematology with adjuvant chemotherapy, National Cancer Institute <strong>of</strong> the<br />
MPH Ukraine, Kiev, Ukraine<br />
Background: Gastrointestinal tract is the most frequent site <strong>of</strong> involvement in the<br />
primary extranodal lymphoma representing around40% <strong>of</strong> new diffuse large B-cell<br />
lymphoma (DLBCL) cases.The new enhanced(NCCN-IPI for patients uniformly<br />
treated with immunochemotherapy includes gastrointestinal tract as one <strong>of</strong><br />
unfavourable extranodalsites<strong>of</strong> involvement in DLBCL. We evaluated outcomes <strong>of</strong><br />
patients with nodal compared to primary gastrointestinal DLBCL after<br />
R-CHOPtreatment.<br />
Methods: Of 528 consecutive patients with DLBCL treated at our institution between<br />
2004-2011 we identified 237 patients with de novo DLBCL, median age (range) 63<br />
(17-90),male/female 116/121, including 148patients with nodal and 89 with primary<br />
gastrointestinallymphoma (PGL). None <strong>of</strong> PGL patients had a radical surgery for the<br />
primary disease.<br />
Results: There wereno statistically significant differencies in median age, CS, rate <strong>of</strong><br />
IPI ≥ 3 between nodal and PGL patients (pts). Characteristics frequency in patients with<br />
nodal disease and PGL were the following, respectively: performance status (PS) > 1:34%<br />
and 43%(p = 0.03), elevated LDH: 59% and 41% (p = 0.05), GCB-DLBCL subtype: 23%<br />
and 18%(p > 0.05). A minimum <strong>of</strong> 6 cycles <strong>of</strong> R-CHOP therapy was completed in 123<br />
pts(83%) with nodal disease and 71 pts (72%) with PGL lymphoma, 5-year overall<br />
survival was 68% (95% CI; 60, 76) and 60% (95%CI; 49, 71), respectively (p = 0.22),<br />
and5-year progression free survivalwas 62% (95%CI; 54, 70) and60% (95%CI; 48, 72),<br />
respectively(p = 0.47). Relapse occurred in 32 (22%) pts with nodal disease and in 15 pts<br />
(18%) with PGL (p = 0.27) including relapse in central nervous system in 3 <strong>of</strong> 32 (9%)<br />
relapsed ptswith nodal disease and in 4 <strong>of</strong> 15(26%) relapsed ptswith GI lymphoma<br />
(p = 0.12). In a long term follow up, second primary malignancy was recordedin 10 (7%)<br />
<strong>of</strong> pts with nodal disease and in 3 (4%) <strong>of</strong> pts with PGI lymphoma (p = 0.53).<br />
Conclusions: Our data is not in support <strong>of</strong> unfavorable role <strong>of</strong> GI site <strong>of</strong> primary<br />
involvement compared to nodal DLBCL. Central nervous system relapse was more<br />
frequent in PGL than in nodal lymphoma but the difference was not statistically<br />
significant.<br />
Legal entity responsible for the study: Lymphoproliferative<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
911P<br />
Outcome <strong>of</strong> primary bone lymphoma: Single center experience<br />
M.S. Rauf, S. Akhtar, A. Badran, M.A. Ilyas, Q. Shaikh, M.N. Zahir, Y. Khafaga,<br />
I. Maghfoor<br />
Medical <strong>Oncology</strong>, King Faisal Specialist Hospital and Research Center, Riyadh,<br />
Saudi Arabia<br />
Background: Primary bone lymphoma (PBL) represents less than 1% <strong>of</strong> all malignant<br />
lymphomas. In this retrospective study, we assessed the disease pr<strong>of</strong>ile, outcome, and<br />
prognostic factors in PBL patients.<br />
Methods: All patients treated at our center between 1987 and 2013 were reviewed, 113<br />
cases were identified<br />
Results: Male: female 1:1.5, median age 35 years (14-77 yrs), diffuse large B cell<br />
lymphoma 86%. Stage I-II in 51/108 and stage III-IV in 57/108 patients. Bulky disease<br />
in 56%, B symptoms present in 40% patients. Median follow up (survivors) is 60<br />
vi314 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
months (39,75 interquartile range). 108 patients received curative intent treatment,<br />
chemotherapy (CT) alone in 26%, radiation and CT (CTXRT) in 74%. Median<br />
radiation dose was 38 Gy (range 30-60 Gy), 96/108 received 6-8 cycles <strong>of</strong><br />
chemotherapy. At the end <strong>of</strong> planned treatment, 82.5% were in complete remission<br />
(CR), 13.8% showed partial response and only 4 patients had primary progressive<br />
disease. Systemic relapse or progression was observed in 22%, with no local recurrence.<br />
5-year overall survival (OS), and progression free survival (PFS) were 82.5% and 76.2%<br />
respectively. Disease status at last follow-up was 77 % patients were alive and in CR, 2%<br />
alive with disease, 16% died <strong>of</strong> disease and 5% died <strong>of</strong> another cause or lost to<br />
follow-up. 28 patients progressed or relapsed, 6 received high dose CT and autologous<br />
bone marrow transplant (all are alive and in CR) and 19 died <strong>of</strong> disease. In univariate<br />
analyses (log rank test), favorable prognostic factors for PFS were low or low<br />
intermediate International Prognostic Index (IPI) score (P = 0.06), CTXRT (P = 0.033),<br />
and no B symptoms (P = 0.001). For OS, low or low intermediate IPI score (P = 0.007),<br />
stage I-II disease (P = 0.05), CTXRT (P = 0.005), and no B symptoms (P = 0.01) were<br />
favorable. Multivariate analysis showed low or low intermediate IPI score, CTXRT and<br />
no B symptoms independently influencing PFS. Absence <strong>of</strong> B symptoms was the only<br />
predicting factor for OS.<br />
Conclusions: This is largest data from the Middle East. PBL has good prognosis. Local<br />
control is excellent, and systemic failure occurs infrequently. Good IPI score ( 60 years <strong>of</strong> age (p = 0.05); ECOG > 1 (p = 0.002); Stage<br />
III-IV (p = 0.004); more nodal and extranodal involvement (p = 0.003); > LDH<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw375 | vi315
abstracts<br />
(p = 0.007); and higher FLIPI (p = 0.02). Nevertheless, patients with a high-risk<br />
disease, according to the FLIPI benefited the most from the addition <strong>of</strong> R whereas<br />
statistical significance was not reached for patients with a low/intermediate FLIPI score.<br />
Conclusions: In our experience, R is associated with better overall survival, especially<br />
in patients with high risk FLIPI.<br />
Legal entity responsible for the study: Hospital Universitario Puerta de Hierro<br />
Funding: Spanish Lymphoma <strong>Oncology</strong> Group (GOTEL)<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
915P<br />
Cause-specific mortality after follicular non-Hodgkin lymphoma:<br />
a report from the Spanish Lymphoma Study Group (GOTEL)<br />
M. Provencio 1 , A. Royuela 2 , J. Gomez Codina 3 , M. Torrente 1 , P. Sabin 4 ,<br />
M. Llanos 5 , J. Guma I Padro 6 , C. Quero 7 , A. Blasco 8 , M.A. Cruz 9<br />
1 Medical <strong>Oncology</strong>, Hospital Universitario Puerta de Hierro Majadahond,<br />
Majadahonda, Spain, 2 Biostatistics, Hospital Universitario Puerta de Hierro<br />
Majadahond, Majadahonda, Spain, 3 Medical <strong>Oncology</strong>, Hospital Universitari i<br />
Politècnic La Fe, Valencia, Spain, 4 Medical <strong>Oncology</strong>, Hospital General<br />
Universitario Gregorio Marañon, Madrid, Spain, 5 Medical <strong>Oncology</strong>, Hospital<br />
Universitario de Canarias, Santa Cruz De Tenerife, Spain, 6 Medical <strong>Oncology</strong>,<br />
University Hospital St. Joan de Reus, Reus, Spain, 7 Medical <strong>Oncology</strong>, Hospital<br />
Universitario Virgen de la Victoria, Malaga, Spain, 8 Medical <strong>Oncology</strong>, Hospital<br />
General Universitario Valencia, Valencia, Spain, 9 Medical <strong>Oncology</strong>, Hospital<br />
Virgen de la Salud, Toledo, Spain<br />
Background: Few investigations have quantified the observed survival in patients with<br />
follicular lymphoma (FL) compared with those expected in the general population. For<br />
one thing, this disease presents a median survival <strong>of</strong> approximately 10 years and is<br />
considered incurable, many treatments have been incorporated to this disease and<br />
hence our interest in studying its influence in overall survival compared with the<br />
general population.<br />
Methods: We reviewed 1074 patients treated and diagnosed with FL who were included<br />
in the Follicular Lymphoma Registry, a prospective registry that includes all new<br />
lymphoma cases, regardless <strong>of</strong> their histological subtype. Standardized mortality ratios<br />
(SMRs) were obtained for 1074 patients with Follicular non-Hodgkin Lymphoma,<br />
from 1980 to 2013.<br />
Results: The overall survival rates were 234 months (95% CI: 212-255). The overall<br />
standardized mortality ratio (SMR) <strong>of</strong> cancer patients was, including all death causes,<br />
2.54 (95% CI: 2.22-2.90), being higher for women, with an SMR <strong>of</strong> 3.04 (95% CI:<br />
2.51-3.69) and in young adults 5.55 (95% CI: 2.89-10.66) in patients under 40, whereas<br />
in patients over 60 it was 2.14 (95% CI: 1.82-2.52). After 10 years from diagnosis, the FL<br />
mortality rate becomes lower than in the general population (SMR 0.46, 95% CI:<br />
0.28-0.77). Excluding FL as a cause <strong>of</strong> death, the overall SMR was 1.14 (95% CI: 0.93 to<br />
1.38). None <strong>of</strong> the age segments studied showed a statistically significant mortality excess<br />
compared with the general population <strong>of</strong> the same age and gender. In the multivariable<br />
Cox analysis, rituximab is associated with a lower mortality rate compared with patients<br />
who did not receive it (HR 0.57. 95% CI 0.41 to 0.78, p = 0.001).<br />
Conclusions: This is the first European population-based study, to our knowledge, to<br />
quantify short-term and long-term follicular lymphoma mortality after diagnosis,<br />
along with analyzing its mortality compared with the general population <strong>of</strong> the same<br />
sex and age. Our registry provides information concerning cause-specific long-term<br />
mortality among 5613 person-year survivors with follow-up for death extending from<br />
1980 through 2013. Unlike other types <strong>of</strong> lymphoma, such as Hodgkin’s lymphoma,<br />
non-tumor causes have little influence on the long-term mortality.<br />
Legal entity responsible for the study: N/A<br />
Funding: Spanish Lymphoma Study Group (GOTEL)<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
916P<br />
Survival in young adults diagnosed with follicular lymphoma in<br />
a national registry from the Spanish Lymphoma <strong>Oncology</strong><br />
Group<br />
V. Calvo de Juan 1 , M. Provencio 1 , J. Gomez Codina 2 , D. Rodriguez Abreu 3 ,<br />
A. Rueda 4 , R. García Arroyo 5 , L. de la Cruz Merino 6 , M. Llanos 7 , J. Guma I Padro 8 ,<br />
J.J. Sánchez Hernández 9<br />
1 Medical <strong>Oncology</strong>, Hospital Universitario Puerta de Hierro Majadahond,<br />
Majadahonda, Spain, 2 Medical <strong>Oncology</strong>, Hospital Universitari i Politècnic La Fe,<br />
Valencia, Spain, 3 Medcal <strong>Oncology</strong> service, Hospital Universitario Insular de Gran<br />
Canaria, Las Palmas, Spain, 4 Medical <strong>Oncology</strong>, Hospital Costa del Sol, Malaga,<br />
Spain, 5 Medical <strong>Oncology</strong>, Complejo Hospitalario de Pontevedra, Pontevedra,<br />
Spain, 6 Medical <strong>Oncology</strong>, Hospital Universitario Virgen Macarena, Seville, Spain,<br />
7 Medical <strong>Oncology</strong>, Hospital Universitario de Canarias, Santa Cruz, Spain,<br />
8 <strong>Oncology</strong> Service, University Hospital St. Joan de Reus, Reus, Spain, 9 Medicine,<br />
Facultad de Medicina UANL, Monterrey, Mexico<br />
diagnosed each year. The cut-<strong>of</strong>f age in the prognostic evaluation <strong>of</strong> patients is 60 years<br />
<strong>of</strong> age. A recently published study compared the clinicopathological characteristics <strong>of</strong><br />
155 patients diagnosed with follicular lymphoma before 40 years <strong>of</strong> age with older<br />
patients in a series <strong>of</strong> 1002 cases in 4 European centres over a 25-year period between<br />
1985 and 2010.<br />
Methods: The Spanish Lymphoma <strong>Oncology</strong> Group analyzed the survival and<br />
clinicopathological characteristics <strong>of</strong> patients registered in our national database <strong>of</strong><br />
1178 FL patients recruited between 1986 and 2012, and who were diagnosed prior to 40<br />
years <strong>of</strong> age. A survival analysis was made using SPSS v19.<br />
Results: The median age at diagnosis was 58 years, similar to the 56 years <strong>of</strong> age<br />
reported previously. The median survival in our series was 234 months, almost 20 years<br />
(95% CI 212-255), while the series reported in the recent article referred to was only<br />
12.5 years. Similarly, we observed longer survival in those who were younger than 40<br />
years at diagnosis, who have not yet reached the median survival, and a median <strong>of</strong> 16.3<br />
years in patients older than 40 years, with these differences being statistically significant<br />
(P < 0.00001). In our series, in patients younger than 40 years <strong>of</strong> age, we also observed a<br />
greater incidence <strong>of</strong> elevated beta2-microglobulin, less high-risk FLIPI and a lower rate<br />
<strong>of</strong> increased LDH, with the latter at the limit <strong>of</strong> statistical significance (P = 0.062).<br />
However, the differences found with respect to bone marrow involvement, involvement<br />
<strong>of</strong> more than 4 lymph nodes or the presence <strong>of</strong> bulky mass (>7cm) at diagnosis were<br />
not statistically significant. Nevertheless we did find differences in performance status<br />
(PS) with a higher percentage <strong>of</strong> ECOG ≤ 1 in FL patients younger than 40 years <strong>of</strong> age<br />
(P = 0.000).<br />
Conclusions: We believe that 40 should be the cut-<strong>of</strong>f age in the prognostic evaluation<br />
<strong>of</strong> patients with follicular lymphoma rather than the classic 60 years <strong>of</strong> age.<br />
Legal entity responsible for the study: Spanish Lymphoma <strong>Oncology</strong> Group<br />
Funding: Spanish Lymphoma <strong>Oncology</strong> Group<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
917P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
The role <strong>of</strong> radiation therapy in DLBCL treatment in a single<br />
institution study<br />
I. Kryachok 1 , O. Aleksyk 2 , K. Filonenko 1 , Z. Fedorenko 4 , I. Tytorenko 1 ,A.<br />
V. Martynchyk 2 , I. Stepanishyna 3 , L. Koutsenko 4<br />
1 Oncohematology, National Cancer Institute <strong>of</strong> the MPH Ukraine, Kiev, Ukraine,<br />
2 <strong>Oncology</strong>/Haematology, National Cancer Institute <strong>of</strong> the MPH Ukraine, Kiev,<br />
Ukraine, 3 Department <strong>of</strong> Chemotherapy <strong>of</strong> Hemablastoses, National Cancer<br />
Institute, Kyiv, Ukraine, 4 Department <strong>of</strong> Cancer Epidemiology and National Cancer<br />
Registry, National Cancer Institute, Kyiv, Ukraine<br />
Background: The role <strong>of</strong> radiation therapy in patients with diffuse large B-cell<br />
lymphoma (DLBCL) is not clearly defined, especially in patients with advanced stages<br />
<strong>of</strong> the disease.<br />
Methods: We have analyzed the data <strong>of</strong> 364 patients with DLBCL, stage I-IV, 176<br />
males and 186 females, age 18-84 years old, treated in our department from 2010 to<br />
2016. We have analyzed overall survival (OS) in patients treated with or without<br />
radiation therapy depending on the stage (early vs. advanced) and presence <strong>of</strong><br />
rituximab in the chemotherapy (R-CHOP vs. CHOEP).<br />
Results: Early stages had 199 patients, advanced stages – 165 patients. Chemotherapy<br />
with rituximab received 66 patients, without rituximab – 21 patients.<br />
Chemoradiotherapy with rituximab received 206 patients, without rituximab – 71<br />
patients. 5-year OS in the group <strong>of</strong> chemotherapy with rituximab was 74%,<br />
chemotherapy without rituximab – 61%, chemoradiotherapy with rituximab – 81%,<br />
chemoradiotherapy without rituximab – 82%. The significant difference in OS rates<br />
was revealed only between the groups <strong>of</strong> chemoradiotherapy with vs. without<br />
rituximab (p = 0.026) and chemotherapy with rituximab vs. chemoradiotherapy with<br />
rituximab (p = 0.01). In the early stages group 5-year OS was 77% in patients treated<br />
with chemotherapy vs. 84% in patients treated with chemoradiotherapy, p = 0.24. In<br />
the late stages group 5-year OS was 64% in patients treated with chemotherapy vs. 78%<br />
in patients treated with chemoradiotherapy, p = 0.26.<br />
Conclusions: Significantly higher 5-year OS was sen in the group <strong>of</strong> patients with<br />
DLBCL treated with chemotherapy with rituximab compared with those who were<br />
treated without rituximab. Significantly higher 5-year OS was seen in the group <strong>of</strong><br />
patients treated with chemoradiotherapy with rituximab compared with those treated<br />
with chemotherapy with rituximab. There were no significant differences between<br />
other groups <strong>of</strong> patients. Radiotherapy did not influence OS rate depending on the<br />
stage <strong>of</strong> the disease.<br />
Legal entity responsible for the study: N/A<br />
Funding: Ministry <strong>of</strong> Health <strong>of</strong> Ukraine<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
Background: Follicular lymphoma is the second most common tumor <strong>of</strong> lymphoid<br />
lineage. In Spain, between 3,000 and 5,000 new cases <strong>of</strong> follicular lymphoma are<br />
vi316 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
918P<br />
A pooled data analysis <strong>of</strong> 12 clinical trials <strong>of</strong> Fondazione<br />
Italiana Linfomi (FIL): Khorana score and histotype predict the<br />
incidence <strong>of</strong> early venous thromboembolism (VTE) in<br />
non-Hodgkin lymphoma (NHL)<br />
R.M. Santi 1 , M. Ceccarelli 2 , C. Monagheddu 2 , A. Evangelista 2 , E. Bernocco 1 ,<br />
F. Monaco 1 , M. Federico 3 , U. Vitolo 4 , S. Cortellazzo 5 , M.G. Cabras 6 , M. Spina 7 ,<br />
L. Baldini 8 , C. Boccomini 2 , A. Chiappella 2 , A. Bari 3 , S. Luminari 3 , C. Visco 9 ,<br />
L. Contino 1 , G. Ciccone 2 , M. Ladetto 1<br />
1 Hematology, Presidio Ospedaliero Civile SS. Antonio e Biagio, Alessandria, Italy,<br />
2 Centro Onco-ematologico Subalpino, Azienda Ospedaliera Universitaria<br />
S. Giovanni Battista - Molinette Centro Onco-Ematologico Subalpino, Turin, Italy,<br />
3 Medical <strong>Oncology</strong>, Azienda Ospedaliero - Universitaria Policlinico di Modena,<br />
Modena, Italy, 4 Hematology-<strong>Oncology</strong>, Hematology Section, AOU S. Giovanni<br />
Battista - Molinette, Turin, Italy, 5 Hematology, Ospedale Centrale di Bolzano<br />
ASDAA/SABES, Bolzano, Italy, 6 Hematology, Ospedale Oncologico "A. Businco",<br />
Cagliari, Italy, 7 Hematology, Centro di Riferimento Oncologico, Aviano, Italy,<br />
8 Hematology, IRCCS Ospedale Maggiore Policlinico, Milan, Italy, 9 Hematology,<br />
Ospedale San Bortolo, Vicenza, Italy<br />
Background: VTE in NHL occurs in most cases within 3 months from diagnosis and<br />
can have substantial impact on treatment delivery and outcome. However, few data are<br />
available on potential predictors. We conducted a pooled data analysis <strong>of</strong> 12 clinical<br />
trials from FIL. Our analysis included basic demographic features, lymphoma-related<br />
characteristics as well the Khorana score (based on histology, BMI, platelets WBC and<br />
HB counts) which is extensively used in solid tumors to predict VTE risk.<br />
Methods: From Jan. 2010 to Dec. 2014, all pts with B-cell NHL enrolled in prospective<br />
clinical trials from FIL for frontline treatment were included. The analyses were<br />
conducted based on CRFs as well as pharmacovigilance reports. Cumulative incidence<br />
<strong>of</strong> VTE from the study enrollment was estimated using the method described by<br />
Gooley et al. accounting for death from any causes as a competing risk. The Fine &<br />
Gray survival model was used to identify predictors <strong>of</strong> VTE among NHL pts. Factors<br />
predicting the grade <strong>of</strong> VTE were investigated using an ordinal logistic regression<br />
model.<br />
Results: Overall, 1717 patients belonging to 12 studies were evaluated. M/F ratio was<br />
1.41, median age was 57. Histologies were: DLCL-B 34%, FL 41%, MCL 18%, other 6%.<br />
Median BMI was 25. Median Hb, WBC and platelets counts were : 13 g/dl, 7,1 x 10 9 /l,<br />
224 x 10 9 /l, respectively. Overall 59 any grade VTE episodes occurred in 51 pts (2.9%).<br />
None was fatal. Median time from study enrolment to VTE was 63 days . Considering<br />
death as a competitive event the 6 months cumulative incidence <strong>of</strong> VTE was 2.2% in<br />
low risk Khorana score, 4.5% in intermediate and 6.6% in high risk (p = 0.012) . The<br />
Fine and Gray multivariate analyses, adjusted for age and stage, showed that Khorana<br />
score and DLCL-B histotype were independently associated to an increased risk <strong>of</strong><br />
VTE. Moreover an ordinal logistical regression model indicated that the increase <strong>of</strong> one<br />
point in the Khorana score resulted in an increased risk <strong>of</strong> VTE.<br />
Conclusions: Our results suggest that DLCL-B histotype and Khorana score are<br />
predictors <strong>of</strong> VTE in NHL. The latter might become a simple and effective tool to<br />
assess the risk <strong>of</strong> VTE in NHL.<br />
Clinical trial identification: Study ID: FIL_TVP<br />
Legal entity responsible for the study: Fondazione Italiana Linfomi<br />
Funding: Fondazione Italiana Linfomi<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
919P<br />
17P deletion and TP53 gene mutation (17P/TP53) testing<br />
behaviour and treatment patterns for chronic lymphocytic<br />
leukemia (CLL) patients in France, Germany, Italy, Spain and<br />
UK (EU5)<br />
F.A. Bermudez Canta 1 , L. Mitr<strong>of</strong>an 2 , Y.B. Karanis 1 , H. Mistry 1 , C. Anger 1<br />
1 Global <strong>Oncology</strong>, IMS Health, London, UK, 2 Global <strong>Oncology</strong>, IMS Health, La<br />
Defence, France<br />
Background: CLL patients with 17P/TP53 frequently progress earlier to symptomatic<br />
disease and have shorter response durations with traditional chemoimmunotherapy. In<br />
2013, two new targeted therapies, ibrutinib and idelalisib, were introduced into the<br />
CLL market. Both are indicated for patients tested positive for either 17P/TP53, or<br />
patients who have received at least one previous treatment. The objective <strong>of</strong> this study<br />
is to demonstrate the progression in 17P/TP53 testing in EU5 since 2012, and to<br />
evaluate how treatment choices have evolved in carriers <strong>of</strong> these chromosomal<br />
abnormalities.<br />
Methods: IMS <strong>Oncology</strong> Advantage CLL, an anonymised patient database collected<br />
retrospectively through quarterly physician panel survey has been used, looking at 4<br />
years <strong>of</strong> data from 2012 to 2015 for EU5 countries.<br />
Results: Out <strong>of</strong> 2800, 2693, 2657 and 2983 patients diagnosed in 2012, 2013, 2014 and<br />
2015 respectively, 17P/TP53 testing was performed in 48% (2012) to 78% (2015) <strong>of</strong><br />
patients in all lines <strong>of</strong> therapy. Within the tested population, the level <strong>of</strong> positivity for<br />
17P/TP53 has remained stable with an average <strong>of</strong> 15%; among which, usage <strong>of</strong><br />
ibrutinib and idelalisib grew from 0% in 2012 to 66% in 2015, bendamustine/rituximab<br />
combination therapy decreased from 18% to 10% and alemtuzumab monotherapy<br />
from 27% to 2%. Negativity for 17P/TP53 among 2 nd + Line patients remained stable<br />
with an average <strong>of</strong> 83%; among which usage <strong>of</strong> ibrutinib or idelalisib containing<br />
regimens increased from 0% in 2012 to 30% in 2015, bendamustine/rituximab<br />
remained stable at around 37% and FCR (fludarabine/cyclophosphamide/rituximab)<br />
decreased from 18% to 7%.<br />
Conclusions: Over 2/3 <strong>of</strong> all CLL patients in EU5 are now tested for 17P/ TP53, which<br />
coincides with the increase in ibrutinib and idelalisib usage in 17P/TP53 positive<br />
patients and 17P/TP53 negative patients in 2 nd + line. Although bendamustine/<br />
rituximab still holds the lead among 17P/TP53 negative 2 nd + line patients, it is likely<br />
that ibrutinib and idelalisib based regimens will continue to take patient share in the<br />
coming year. The launch <strong>of</strong> venetoclax, indicated for the same population, could have<br />
an impact on the positive trend we have observed for these two molecules.<br />
Legal entity responsible for the study: IMS Health<br />
Funding: IMS Health<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
920P<br />
VEGF, VEGFR2 and GSTM1 polymorphisms in outcome <strong>of</strong><br />
multiple myeloma patients in the thalidomide era<br />
L. Lopes-Aguiar 1 , M.T. Delamain 2 , A.B.C. Brito 1 , G.J. Lourenço 1 , E.F.D. Costa 1 ,<br />
G.B. Oliveira 2 , J. Vassallo 3 , C.A. De Souza 2 , C.S.P. Lima 1<br />
1 Department <strong>of</strong> Internal Medicine, Faculty <strong>of</strong> Medical Sciences, University <strong>of</strong><br />
Campinas, Campinas, Brazil, 2 Haematology and Haemotherapy Centre, University<br />
<strong>of</strong> Campinas, Campinas, Brazil, 3 Laboratory <strong>of</strong> Molecular and Investigative<br />
Pathology, Faculty <strong>of</strong> Medical Sciences, University <strong>of</strong> Campinas, Campinas, Brazil<br />
Background: Angiogenesis (AG) abnormalities are crucial in pathogenesis <strong>of</strong> multiple<br />
myeloma (MM), and give support to treat patients with antiangiogenic agents.<br />
However, patients with similar clinicopathological aspects may present distinct<br />
outcome under AG inhibitors treatment. Single nucleotide polymorphisms (SNPs) in<br />
genes involved in blood vessels formation may constitute a plausible explanation for<br />
this finding. This study aimed to investigate the roles <strong>of</strong> VEGF c.-2595C > A<br />
(rs699947), c.-1154G > A (rs1570360), c.-634G > C (rs2010963), c.*237C > T<br />
(rs3025039), VEGFR2 c.-906T > C (rs2071559) and c.889G > A (rs2305948) SNPs, and<br />
GSTM1 and GSTT1 genes in outcome <strong>of</strong> MM patients treated with thalidomide-based<br />
regimen.<br />
Methods: The study comprised 102 MM patients diagnosed between June 2005 and<br />
June 2013. The tumor was diagnosed and staged by standard criteria. Therapeutic<br />
regimens consisted in thalidomide combined with steroids and chemotherapy, followed<br />
or not by autologous steam cell transplantation. Response was evaluated at the end <strong>of</strong><br />
therapy using the International Myeloma Working Group guidelines. Genotypes were<br />
analyzed in genomic DNA by polymerase chain reaction based methods. The<br />
chi-square test and logistic regression model were used to identify variables influencing<br />
response to therapy. Survival was estimated by Kaplan-Meier method, log-rank test<br />
and Cox hazards models.<br />
Results: Patients with the wild-type allele <strong>of</strong> VEGF c.-2595C > A alone or plus the<br />
wild-type allele <strong>of</strong> VEGFR2 c.-906T > C SNPs, and the CGGC haplotype <strong>of</strong> all<br />
respective VEGF SNPs had 3.55, 9.91, and 3.86 more chances <strong>of</strong> achieving better<br />
response to therapy than others. At 60 months <strong>of</strong> follow-up, patients with VEGFR2<br />
c.889GG, VEGF c.-634GG plus VEGFR2 c.889GG, and VEGFR2 c.889GG plus<br />
GSTM1 present genotypes had 2.62, 2.64, and 2.80 more chances <strong>of</strong> presenting disease<br />
relapse or progression, and 2.21, 4.88, and 4.23 more chances <strong>of</strong> evolving to death in<br />
multivariate analysis, respectively.<br />
Conclusions: Our data present, for the first time, a preliminary evidence that VEGF<br />
c.-2595C > A, c.-1154G > A, c.-634G > C, c.*237C > T, VEGFR2 c.-906T > C and<br />
c.889G > A SNPs, and GSTM1 gene alter outcome <strong>of</strong> MM patients under thalidomide<br />
therapy.<br />
Legal entity responsible for the study: University <strong>of</strong> Campinas<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
921P<br />
PD-L1 status in refractory lymphomas<br />
abstracts<br />
S. Vranic 1 , J. Jin 2 , J. Kimbrough 3 , N. Ghosh 4 , N. Bilalovic 1 , D. Arguello 3 ,<br />
Y. Veloso 3 , T. Hendershot 2 , A. Dizdarevic 5 , S. Reddy 3 , Z. Gatalica 3<br />
1 Pathology, Clinical Centre <strong>of</strong> Sarajevo University, Sarajevo, Bosnia and<br />
Herzegovina, 2 Pathology, Agilent Technologies Inc., Santa Clara, CA, USA,<br />
3 Pathology, Caris Life Sciences, Phoenix, AZ, USA, 4 Department <strong>of</strong> Hematologic<br />
<strong>Oncology</strong> and Blood Disorders, Levine Cancer Institute, Charlotte, NC, USA,<br />
5 Hematology, Clinical Centre <strong>of</strong> Sarajevo University, Sarajevo, Bosnia and<br />
Herzegovina<br />
Background: Targeted immune therapy based on PD-1/PD-L1 suppression has<br />
revolutionized the treatment <strong>of</strong> various solid tumors. A remarkable improvement has<br />
also observed in the treatment <strong>of</strong> patients with refractory/relapsing classical Hodgkin<br />
lymphoma (cHL). We investigated PD-L1 status in a variety <strong>of</strong> treatment resistant<br />
lymphomas.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw375 | vi317
abstracts<br />
Methods: FFPE samples from 79 patients with refractory/resistant lymphomas <strong>of</strong> B-<br />
and T-cell lineages were explored for the expression <strong>of</strong> PD-L1 (clones: SP142 and<br />
SP263, Ventana) using immunohistochemistry. Twelve PD-L1+ cases by IHC were<br />
further tested for PD-L1/JAK2/PD-L2 co-amplification using FISH/CISH assays or<br />
analyzed for gene copy number variations (CNV) using massively parallel sequencing<br />
(Illumina, NGS).<br />
Results: PD-L1 positivity (≥5% positive cancer cells) was present in 32/78 (41%) and<br />
33/72 cases (46%) using SP142 and SP263 antibodies, respectively. Concordance<br />
between the two clones was high with only three (4%) discrepant cases (Spearman’s<br />
correlation coefficient 0.965). The strongest (3 + / ≥ 50% cells) and consistent (10/11<br />
cases) expression was observed in Reed-Sternberg cells <strong>of</strong> cHL and primary mediastinal<br />
B-cell (3/3) lymphoma. Diffuse large B-cell lymphomas (DLBCL) were frequently<br />
positive (13/26) irrespective <strong>of</strong> subtype. Follicular (1/8), peripheral T-cell (2/9) and<br />
mantle cell (1/8) lymphomas were rarely positive, while small lymphocytic lymphoma/<br />
CLL and marginal zone lymphomas were consistently negative. Co-amplification/<br />
CNVs <strong>of</strong> PD-L1/JAK2/PD-L2 were observed in 3 cases <strong>of</strong> DLBCL and cHL,<br />
respectively.<br />
Conclusions: Over-expression <strong>of</strong> PD-L1 with an excellent concordance between SP142<br />
and SP263 antibodies was observed in cHL, DLBCL, primary mediastinal B-cell,<br />
follicular and peripheral T-cell lymphomas. Clinical relevance and therapeutic<br />
implications <strong>of</strong> co-amplification <strong>of</strong> PD-L1/JAK2/PD-L2 (50% <strong>of</strong> tested IHC+ cases)<br />
should be further investigated, as other mechanisms are also underlying the<br />
overexpression <strong>of</strong> PD-L1 in lymphomas.<br />
Legal entity responsible for the study: N/A<br />
Funding: Caris Life Sciences<br />
Disclosure: J. Kimbrough: Employee <strong>of</strong> Caris Life Sciences, Phoenix, Arizona, USA D.<br />
Arguello, Y. Veloso, S. Reddy, Z. Gatalica: Employee <strong>of</strong> Caris Life Sciences, Phoenix,<br />
AZ, USA All other authors have declared no conflicts <strong>of</strong> interest.<br />
922P<br />
The role <strong>of</strong> indoleamine 2,3-dioxygenase expression in diffuse<br />
large B-cell lymphoma prognosis<br />
I. Kryachok 1 , T. Skrypets 1 , O. Novosad 1 , N. Khranovska 2 , O. Skachkova 2 ,<br />
K. Ulianchenko 1 , A.V. Martynchyk 1 , I. Tytorenko 1 , K. Filonenko 1 , I. Stepanishyna 1 ,<br />
N. Svergun 2 , O. Gorbach 2 , O. Nevdakh 1<br />
1 Oncohematology, National Cancer Institute <strong>of</strong> the MPH Ukraine, Kiev, Ukraine,<br />
2 Experimental <strong>Oncology</strong>, National Cancer Institute <strong>of</strong> the MPH Ukraine, Kiev,<br />
Ukraine<br />
Background: Indoleamine 2,3-dioxygenase (IDO) is an intracellular enzyme that<br />
mediates the metabolism <strong>of</strong> the essential amino acid L-tryptophan into<br />
immunosuppressive metabolites, such as kynurenine and 3-hydroxyanthranilic acid.<br />
IDO is a key factor maintaining immune tolerance, and is overexpressed in several<br />
human cancers: prostate, breast, brain, and hematologic malignancies. Mechanisms<br />
leading to expression <strong>of</strong> IDO in human tumors are still unknown. Our study aims to<br />
investigate the role <strong>of</strong> IDO expression in clinical behavior <strong>of</strong> diffuse large B-cell<br />
lymphoma (DLBCL).<br />
Methods: The case group included 23 patients (6 males, 17 females) with DLBCL<br />
(median age: 48.5 years, range: 23-74). The patients were treated with R-CHOP/CHOP,<br />
CHOEP, R-DA-EPOCH. Remission was achieved in 52.1% <strong>of</strong> the cases and in 47.8%<br />
disease progression after treatment was continued. The relative mRNA expression<br />
levels <strong>of</strong> IDO were measured in pre-treatment tumour tissue specimens from DLBCL<br />
patients using qPCR analysis.<br />
Results: The mRNA expression <strong>of</strong> IDO was found in 11 cases (48%) and further this<br />
group was considered as IDO-positive. The presence <strong>of</strong> IDO expression was<br />
significantly associated with advanced stage <strong>of</strong> disease (p < 0.05), ABC subtype and<br />
progression <strong>of</strong> DLBCL (17.4% vs. 4.3%, p < 0.05). The complete remission rate was<br />
significantly increased in IDO-negative group compared to IDO-positive DLBCL<br />
(34.7% vs. 21.7%, p < 0.05). ROC analysis revealed that IDO-positive expression in<br />
tumor is an important marker associated with reduced progression-free survival (PFS)<br />
in DLBCL patients (Se = 72.7%; Sp = 75%; AUC = 0.73). The 4-year PFS rate for<br />
IDO-positive DLBCL patients was 50% compared to 73% for IDO-negative DLBCL<br />
patients (p = 0.002).<br />
Conclusions: Results suggest that IDO expression correlates with the disease<br />
progression and impaired clinical outcome in DLBCL patients. The presence <strong>of</strong> IDO<br />
expression in tumour tissue should be considered as an additional unfavorable<br />
prognostic risk factor to patients with DLBCL, especially for ABC subtype. It may<br />
represent a promising therapeutic target for DLBCL patients with resistance to<br />
chemotherapy. Ongoing studies from our group are currently evaluating the impact <strong>of</strong><br />
immune escape checkpoints on patients’ survival.<br />
Legal entity responsible for the study: N/A<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
923P<br />
The predictive value <strong>of</strong> immunohistochemical expression <strong>of</strong><br />
Bcl-2, Bcl-6, MUM1, CD10 and CD30 in patients with diffuse<br />
large cell lymphoma<br />
I. Kryachok 1 , A.V. Martynchyk 1 , K. Filonenko 1 , A.N. Grabovoy 2 , S.A. Antoniuk 2 ,<br />
I. Tytorenko 1 , O. Novosad 1 , T. Kadnikova 1 , O. Aleksik 1 , I. Stepanishyna 1<br />
1 Oncohematology with Adjuvant Chemotherapy, National Cancer Institute <strong>of</strong> the<br />
MPH Ukraine, Kiev, Ukraine, 2 Pathological Anatomy and Histology, National<br />
Cancer Institute <strong>of</strong> the MPH Ukraine, Kiev, Ukraine<br />
Background: Diffuse large B-cell lymphoma (DLBCL) is a potentially curable disease,<br />
but the first line <strong>of</strong> therapy is not effective for 40% <strong>of</strong> patients, and new markers for<br />
prognosis are needed. Immunohistochemistry (IHC) markers commonly used for<br />
lymphomas diagnosing may have predictive significance. There are some publications<br />
regarding predictive and prognostic roles <strong>of</strong> IHC expression <strong>of</strong> Bcl-2, Bcl-6, MUM1,<br />
CD10 and CD30, but their results are controversial.<br />
Methods: The retrospective analysis <strong>of</strong> IHC expression <strong>of</strong> Bcl-2, Bcl-6, MUM1, CD10<br />
and CD30 in 267 DLBCL patients was done. Patients were treated at the National<br />
Cancer Institute since 2011 and received first-line CHOP-like chemotherapy.<br />
Results: There was positive expression <strong>of</strong> Bcl-2 in 84% <strong>of</strong> patients, positive expression<br />
<strong>of</strong> Bcl-6 – in 63%, positive expression <strong>of</strong> MUM1 – in 62%, positive expression <strong>of</strong> CD10<br />
– in 39% and positive CD30 expression was determined in 26% <strong>of</strong> patients with<br />
DLBCL. There were 43 patients (16%) with primary-refractory disease and 224 patients<br />
(84%) with at least a partial response to first-line therapy. We analyzed the expression<br />
<strong>of</strong> IHC markers in patients who responded to first-line treatment ("R") compared to<br />
the expression in primary refractory patients ("PR"). There were no significant<br />
differences in the positive expression <strong>of</strong> such markers as Bcl-2, MUM1 and CD30<br />
between groups "R" and the "PR" (84.7% vs 82.1%, 60.2% vs 66.7%; 23.3% vs 25.0%,<br />
p > 0.05, respectively). There was a trend toward more frequent positive expression <strong>of</strong><br />
CD10 in the "R" group: 44.3% vs 28.6%, p > 0.05. The positive expression <strong>of</strong> Bcl-6 was<br />
significantly more common in the “R” group in comparison with a "PR" group (69.9%<br />
vs 38.1%, p < 0.05). There was no difference in gender, age, the number <strong>of</strong> high risk<br />
patients, patients with advanced disease and patients who received<br />
immunochemotherapy between compared groups.<br />
Conclusions: Positive expression <strong>of</strong> Bcl-6 is significantly more common in patients<br />
who responded to first line treatment. It may indicate the predictive value <strong>of</strong> this<br />
biomarker for identifying the group <strong>of</strong> patients who respond to the first line therapy.<br />
Legal entity responsible for the study: N/A<br />
Funding: National Cancer Institute<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
924P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Identification <strong>of</strong> exosomes in non-Hodgkin B-cell lymphomas.<br />
Prognostic usefulness in patients treated with<br />
rituximab-chemotherapy: a prospective, multicenter<br />
correlation study by the Spanish Lymphoma <strong>Oncology</strong> Group<br />
(GOTEL)<br />
M. Provencio 1 , M. Rodriguez-Balada 2 , B. Cantos 3 , C. Quero 4 , R. García Arroyo 5 ,<br />
A. Rueda 6 , C. Maximiano 3 , D. Rodriguez Abreu 7 , A. Sanchez 1 , V. Garcia 3<br />
1 Medical <strong>Oncology</strong>, Hospital Universitario Puerta de Hierro Majadahond,<br />
Majadahonda, Spain, 2 Pathology, University Hospital St. Joan de Reus, Reus,<br />
Spain, 3 Medical <strong>Oncology</strong>, Hospital Universitario Puerta de Hierro, Madrid, Spain,<br />
4 Medical <strong>Oncology</strong>, Hospital Universitario Virgen de la Victoria, Malaga, Spain,<br />
5 Medical <strong>Oncology</strong>, Complejo Hospitalario de Pontevedra, Pontevedra, Spain,<br />
6 Medical <strong>Oncology</strong>, Hospital Costa del Sol, Malaga, Spain, 7 Medcal <strong>Oncology</strong><br />
Service, Hospital Universitario Insular de Gran Canaria, Las Palmas, Spain<br />
Background: To determine the presence <strong>of</strong> mRNAs (C-MYC, BCL-XL, BCL-6, NF-κβ,<br />
PTEN and AKT) in exosomes <strong>of</strong> plasma from patients with B-Cell Lymphoma, and its<br />
relationship with their response to rituximab-based chemotherapy and survival.<br />
Methods: Exosomes were isolated <strong>of</strong> 98 patients with B-cell Lymphoma and 68 healthy<br />
controls. mRNAs were analyzed by quantitative PCR. 31 post-treatment samples were<br />
also studied.<br />
Results: Exosome levels were not associated with response to treatment and outcome<br />
<strong>of</strong> patients. In general series and follicular lymphomas (FL), presence <strong>of</strong> AKT mRNA<br />
was associated with non-response to rituximab-based treatment. Patients with first<br />
relapse or disease progression showed a lower percentage <strong>of</strong> presence <strong>of</strong> PTEN and<br />
BCL-XL mRNA. Presence <strong>of</strong> BCL-6 mRNA was associated with high rate <strong>of</strong> death <strong>of</strong><br />
patients. Absence <strong>of</strong> PTEN mRNA, in general series, and presence <strong>of</strong> C-MYC mRNA,<br />
in FL, was associated with short Progression-Free Survival. BCL-6 and C-MYC mRNA<br />
were independent prognostic variables for OS. C-MYCmRNA interacted with response<br />
to treatment, giving prognostic value for OS in non responsive patients. In<br />
post-treatment samples, presence <strong>of</strong> BCL-XL mRNA was associated with high rate <strong>of</strong><br />
death; and appearance <strong>of</strong> BCL-6 mRNA and loss <strong>of</strong> PTENmRNA were associated with<br />
non-response to treatment.<br />
Conclusions: It is possible to identify exosomes in plasma <strong>of</strong> lymphoma patients. This<br />
may assist in prognosis, both at the start <strong>of</strong> treatment and during follow-up, and in<br />
identification <strong>of</strong> those patients at greater risk <strong>of</strong> progression. In both situations, the<br />
presence <strong>of</strong> BCL-6 identifies the patients with worse prognosis.<br />
vi318 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Legal entity responsible for the study: N/A<br />
Funding: Spanish Lymphoma <strong>Oncology</strong> Group (GOTEL).<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
925P<br />
Role <strong>of</strong> FDG-PET in detecting bone marrow involvement in<br />
mature T-/NK-cell neoplasms<br />
Y.S. Choi 1 , K. Kim 2 , I-C. Song 1 , Y.J. Yang 3 , H.J. Lee 1 , D-Y. Jo 1 , S.Y. Park 3 ,<br />
S. Kim 1 , H-J. Yun 1<br />
1 Department <strong>of</strong> Internal Medicine, Chungnam National University College <strong>of</strong><br />
Medicine, Daejeon, Republic <strong>of</strong> Korea, 2 Department <strong>of</strong> Nuclear Medicine,<br />
Chungnam National University College <strong>of</strong> Medicine, Daejeon, Republic <strong>of</strong> Korea,<br />
3 Department <strong>of</strong> Internal Medicine, The Catholic University <strong>of</strong> Korea Daejeon<br />
St. Mary’s Hospital, Daejeon, Republic <strong>of</strong> Korea<br />
Background: The determination <strong>of</strong> bone marrow (BM) involvement <strong>of</strong> non-Hodgkin’s<br />
lymphoma is based on blind BM biopsy, assessing only a small portion <strong>of</strong> the entire<br />
BM. Positron emission tomography using 18 F-fluoro-2-deoxy-D-glucose (FDG-PET)<br />
has become an essential diagnostic procedure to enable more accurate staging in many<br />
types <strong>of</strong> lymphomas. Herein, we aimed to evaluate the role <strong>of</strong> FDG-PET in detecting<br />
BM involvement <strong>of</strong> T-/NK-cell lymphomas.<br />
Methods: Patients who were diagnosed mature T-/NK-cell neoplasm according to the<br />
WHO classification and uniformly treated in a single center between Jan 2008 and Dec<br />
2014 were examined. BM biopsy from bilateral iliac crests was performed for all<br />
subjects. FDG uptake in BM was interpreted in two ways: (1) visual assessment<br />
according to international harmonization project (IHP), (2) 5-point scale (Deauville<br />
criteria) based on SUVmax <strong>of</strong> iliac bone and L4 vertebral body relative to liver.<br />
Results: Thirty-one patients were eligible for analysis, including 12 PTCL-NOS, 13<br />
extranodal NK/T-cell lymphoma/nasal type, 5 angioimmunoblastic T cell lymphoma<br />
and 1 ALK + anaplastic large cell lymphoma. Based on BM biopsy, 8 subjects (25.8%)<br />
showed BM involvement. According to IHP recommendations, only 2 patients (6.5%)<br />
revealed BM involvement in FDG-PET and they were also positive in BM biopsy. In<br />
contrast, 11 patients (35.5%) showed Deauville 4/5 <strong>of</strong> 5-point scale, including all 8<br />
subjects positive for BM biopsy. FDG-PET interpretation based on Deauville criteria,<br />
associated with higher concordance rate (90.3%) with BM biopsy, however, was less<br />
powerful in predicting difference in overall survival between presence and absence <strong>of</strong><br />
BM involvement.<br />
Conclusions: While FDG-PET might provide with higher sensitivity in detection <strong>of</strong><br />
BM involvement, the impact on prognostication <strong>of</strong> patients with T-/NK-cell<br />
lymphoma was limited. Taken together, FDG-PET cannot obviate the need for BM<br />
biopsy in mature T-/NK-cell neoplasms.<br />
Legal entity responsible for the study: N/A<br />
Funding: Chungnam National University, Daejeon, Republic <strong>of</strong> Korea<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
926P<br />
Reader variability <strong>of</strong> PET/CT-based response criteria in<br />
DLBCL and association to outcome<br />
E.J. Han, W.H. Choi, J.H. O<br />
Radiology, The Catholic University <strong>of</strong> Korea, Seoul, Republic <strong>of</strong> Korea<br />
Background: F-18-fluoro-2-deoxyglucose (FDG) positron emission tomography/<br />
computed tomography (PET/CT) is essentially recommended for monitoring response<br />
to treatment in patients with diffuse large B cell lymphoma (DLBCL) and qualitative<br />
interpretation is commonly applied in clinical practice. We aimed to evaluate<br />
interobserver agreements <strong>of</strong> qualitative PET/CT-based response criteria and evaluate<br />
predictive value <strong>of</strong> PET/CT results by each reader for outcome.<br />
Methods: FDG PET/CT images were obtained for patients with DLBCL at baseline, at<br />
interim after 3 cycles <strong>of</strong> first-line chemotherapy and after completion <strong>of</strong> chemotherapy.<br />
Two nuclear medicine physicians (with 3 and 8 years <strong>of</strong> experience with FDG PET/CT)<br />
blinded to clinical data retrospectively assessed response to chemotherapy using visual<br />
qualitative analyses from the International Working Group (IWG) criteria and Lugano<br />
classification, respectively. The associations between PET/CT results and<br />
progression-free survival (PFS) and overall survival (OS) were assessed using Cox<br />
regression analysis.<br />
Results: Included were 112 PET/CT images from 59 patients with DLBCL (36 male, 23<br />
female; mean age 53 ± 14 years). In interpretation using binary scoring system from<br />
IWG criteria, interobserver agreement was substantial (Cohen’s ĸ = 0.76) with absolute<br />
agreement consistency <strong>of</strong> 89%. In interpretation using Deauville five-point scale from<br />
Lugano classification, interobserver agreement was moderate (Cohen’s weighted<br />
ĸ = 0.54) and absolute consistency was 62%. The most common cause <strong>of</strong> disagreements<br />
was discordant interpretation <strong>of</strong> presence <strong>of</strong> residual tumor uptake. With mean<br />
follow-up period <strong>of</strong> 88 months, estimated 5-year PFS and OS were 81% and 92%,<br />
respectively. Neither interim nor post-treatment PET/CT results by both readers were<br />
significantly associated with PFS. Interim PET/CT result using Deauville scale was the<br />
only significant factor for OS.<br />
Conclusions: Moderate to substantial interobserver agreement was observed for<br />
response assessment according to visual analysis and interim PET/CT result could<br />
predict OS in patients with DLBCL. Further studies are necessary to validate<br />
completely PET/CT-based response criteria and further standardize and consistent<br />
PET/CT interpretation.<br />
Legal entity responsible for the study: N/A<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
927P<br />
Proposal <strong>of</strong> improved prognostic index for patients with<br />
extranodal natural killer/T cell lymphoma treated with<br />
non-anthracycline based treatment<br />
Y. Kang 1 , S. Seo 2 , J.Y. Hong 2 , D.H. Yoon 2 , S. Kim 2 , J.S. Park 2 , J. Huh 3 ,<br />
S-W. Lee 4 , J-S. Ryu 5 , C. Suh 2<br />
1 Internal Medicine, Asan Medical Center, University <strong>of</strong> Ulsan College <strong>of</strong> Medicine,<br />
Seoul, Republic <strong>of</strong> Korea, 2 <strong>Oncology</strong>, Asan Medical Center, University <strong>of</strong> Ulsan<br />
College <strong>of</strong> Medicine, Seoul, Republic <strong>of</strong> Korea, 3 Pathology, Asan Medical Center,<br />
University <strong>of</strong> Ulsan College <strong>of</strong> Medicine, Seoul, Republic <strong>of</strong> Korea, 4 Radiation<br />
<strong>Oncology</strong>, Asan Medical Center, University <strong>of</strong> Ulsan College <strong>of</strong> Medicine, Seoul,<br />
Republic <strong>of</strong> Korea, 5 Nuclear Medicine, Asan Medical Center, University <strong>of</strong> Ulsan<br />
College <strong>of</strong> Medicine, Seoul, Republic <strong>of</strong> Korea<br />
Background: Although serum beta-2 microglobulin (B2M) has been suggested as a<br />
potential prognostic predictor for patients with extranodal natural killer/T cell<br />
lymphoma (ENKTL), there are no prognostic models using B2M. We aimed to<br />
investigate the prognostic role <strong>of</strong> B2M by incorporating B2M into the most recently<br />
prognostic models, Prognostic Index <strong>of</strong> Natural Killer Lymphoma (PINK) and PINK-E<br />
(Epstein- Barr virus).<br />
Methods: Between January 2005 to December 2014, 141 patients with ENKTL were<br />
identified in the database <strong>of</strong> the Asan Medical Center, Lymphoma Registry. Among<br />
them, 108 patients were treated with non-anthracycline based treatment.<br />
Results: Median B2M value was 2.45 mg/L (range, 1.0-22.0) and baseline B2M was<br />
elevated in patients (45.4%). With median follow-up duration <strong>of</strong> 32.1 months (range,<br />
0.3-131.0), and median overall survival (OS) was not reached. In univariate analysis,<br />
elevated B2M level was significantly associated with poorer OS (HR = 3.66; 95% CI:<br />
1.96-6.82; p < 0.0001). We performed multivariate analysis with risk groups by PINK<br />
and elevated B2M was demonstrated as a significant prognostic factor for OS<br />
(HR = 2.12; 95% CI: 1.07-4.19; p = 0.032). Considering the multicollinearity between<br />
elevated B2M and EBV infection, multivariate analysis <strong>of</strong> B2M with risk groups by<br />
PINK-E was not conducted. We tried to develop a new prognostic model with 4<br />
elements <strong>of</strong> PINK and B2M (PINK-B). Three risk groups were composed as followings:<br />
low risk (0-1 points), intermediate risk (2-3 points), and high risk (4 or more points).<br />
The current model, PINK-B showed better discriminative power compared with PINK<br />
and similar with PINK-E for predicting 3-year OS <strong>of</strong> low-, intermediate-, and high-risk<br />
group; 79%, 74%, and 27% for PINK, 80%, 46%, and 23% for PINK-B, 83%, 47% and<br />
26% for PINK-E, respectively.<br />
Conclusions: For ENKTL patients treated with non-anthracycline based therapy, we<br />
suggest a new prognostic index, consisting <strong>of</strong> age, stage, distant node involvement,<br />
non-nasal type disease and serum B2M, which could be good for discriminating poor<br />
risk groups and convenient to apply real practice.<br />
Legal entity responsible for the study: N/A<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
928P<br />
abstracts<br />
Chemotherapy-induced interstitial pneumonia in patients with<br />
lymphoma<br />
W.P. Liu, X.P. Wang, W. Zheng, M.F. Tu, Y. Xie, N.J. Lin, L. Ping, Z.T. Ying,<br />
C. Zhang, L.J. Deng, Y.Q. Song, J. Zhu<br />
Lymphoma, Peking University Cancer Hospital-Beijing Cancer Hospital, Beijing,<br />
China<br />
Background: The incidence, characteristics and risk factors <strong>of</strong> interstitial pneumonia<br />
(IP) in patients with lymphoma receiving first-line chemotherapy remained unclear.<br />
Methods: Between 2009 and 2014, 2212 consecutive patients with newly diagnosed<br />
lymphoma were enrolled as subjects. IP was defined as diffuse pulmonary interstitial<br />
infiltrates found on computed tomography scans. IP was observed in 106 patients. Of<br />
these, 23 were excluded from the study: 6 due to infection, 7 due to clinical trials with<br />
new drugs, 8 due to onset during salvage chemotherapy for recurrent/relapsed<br />
lymphoma, 2 due to incomplete medical records. Finally, 83 patients with IP were<br />
included in this study. The clinical features, laboratory results, and histological types<br />
were analyzed. Patients were paired according to age, sex and pathological type. Risk<br />
factors <strong>of</strong> IP were investigated with matched pair analysis.<br />
Results: The incidence <strong>of</strong> IP was 3.9% (7/287) in Hodgkin lymphoma and 2.4% (76/<br />
1925) in non-Hodgkin lymphoma (P = 0.210). The median number <strong>of</strong> chemotherapy<br />
courses before IP was 3 cycles. The median time from the cessation <strong>of</strong> chemotherapy to<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw375 | vi319
abstracts<br />
IP was 17 days. All patients were administrated with glucocorticoids, but 11 (13.3%)<br />
developed respiratory failure, and 3 (3.6%) died from a progression <strong>of</strong> pneumonia.<br />
Sixty-six (79.5%) patients experienced chemotherapy delays, and 14 (16.9%) had<br />
premature termination <strong>of</strong> their chemotherapy. Sixty-nine patients were re-treated with<br />
chemotherapy after remission <strong>of</strong> IP, <strong>of</strong> which 22 (31.9%) experienced IP recurrence.<br />
The incidence <strong>of</strong> IP recurrence was significantly higher in patients re-treated with<br />
previous regimen than those with alternative regimen (65.4% vs. 11.6%, P < 0.001). In a<br />
multivariate Cox regression model, B symptom (HR = 4.221, P = 0.001) and history <strong>of</strong><br />
drug allergy (HR = 4.019, P = 0.011) were identified as risk factors <strong>of</strong> IP.<br />
Conclusions: IP is a rare but life-threatening complication in lymphoma patients.<br />
Therapy with glucocorticoids may be a favorable strategy for IP. However, IP may recur<br />
in patients re-treated with chemotherapy, especially when previous regimen is<br />
re-administrated.<br />
Legal entity responsible for the study: Peking University Cancer Hospital<br />
Funding: National Natural Science Foundation <strong>of</strong> China (Grant No. 81241073)<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
929P<br />
Pharmacokinetics (PK) and safety <strong>of</strong> carfilzomib (CFZ) in<br />
patients (Pts) with advanced malignancies and varying<br />
degrees <strong>of</strong> hepatic impairment (HI): an open-label, single-arm,<br />
phase 1 study<br />
J. Brown 1 , R. Plummer 2 , T.M. Bauer 3 , S. Anthony 4 , J. Sarantopoulos 5 ,F.DeVos 6 ,<br />
M. White 7 , M. Schupp 8 ,Y.Ou 9 , U. Vaishampayan 10<br />
1 Molecular Cell Biology, Beatson West <strong>of</strong> Scotland Cancer Centre, Glasgow, UK,<br />
2 Cancer Research, Sir Bobby Robson Cancer Trials Research Centre, Northern<br />
Centre for Cancer Care, Newcastle-upon-Tyne, Newcastle Upon Tyne, UK, 3 Drug<br />
Development, Sarah Cannon Research Institute/Tennessee <strong>Oncology</strong>, Nashville,<br />
TN, USA, 4 Hematology <strong>Oncology</strong>, Evergreen Hematology & <strong>Oncology</strong>, Spokane,<br />
WA, USA, 5 Genitourinary <strong>Oncology</strong> Clinic, Cancer Therapy & Research Center at<br />
University <strong>of</strong> Texas Health Science Center at San Antonio, San Antonio, TX, USA,<br />
6 Medical <strong>Oncology</strong>, University Medical Centre Utrecht, Roermond, Netherlands,<br />
7 Biostatistics, Amgen, Thousand Oaks, CA, USA, 8 International Development,<br />
Amgen, Zug, Switzerland, 9 Clinical Pharmacology, Amgen, South San Francisco,<br />
CA, USA, 10 <strong>Oncology</strong>, Karmanos Cancer Institute, Detroit, MI, USA<br />
Background: To support CFZ dose recommendations for Pts with baseline HI, this<br />
study evaluated PK and safety <strong>of</strong> CFZ in Pts with relapsed or progressive advanced<br />
malignancies.<br />
Methods: Adult Pts with normal (Norm) hepatic function (fcn) or, mild, moderate<br />
(Mod), severe HI received CFZ infusion on 2 consecutive days (D) each week (wk) for<br />
3 wks (D 1, 2, 8, 9, 15, and 16) in 28-D cycles (C); 20 mg/m 2 on D1-D2 <strong>of</strong> C1; escalated<br />
to 27 mg/m 2 on D8 <strong>of</strong> C1; if tolerated, 56 mg/m 2 started on D1 <strong>of</strong> C2. PK parameters<br />
were evaluated using a non-compartmental approach. The CFZ PK in HI Pts was<br />
compared with Norm Pts using summary statistics and analysis <strong>of</strong> variance (ANOVA)<br />
<strong>of</strong> ln-transformed PK parameters.<br />
Results: 11 Norm, 17 Mild, 14 Mod, 4 Severe Pts enrolled; 61% male, mean age 62<br />
years. Following CFZ 27 and 56 mg/m 2 , an overlapping exposure was observed between<br />
groups. There was an inconsistent trend for increased area under the curve (AUC) and<br />
maximum serum concentration (C max ) in mild/Mod HI Pts (table). Median duration<br />
<strong>of</strong> exposure was 6 (Norm), 4.3 (Mild), 2.3 (Mod), and 0.8 (severe) wks. No severe HI<br />
Pts were PK-evaluable. Thirty-five (76%) Pts had grade ≥ 3 adverse events (AEs)<br />
including 15 Pts with treatment-related grade ≥ 3 AEs. Grade ≥ 3 increased blood<br />
bilirubin (22%; Mod HI Pts only), anemia (15%), fatigue (15%), and increased alanine<br />
aminotransferase (9%; Mod HI Pts only) occurred in >3 Pts.<br />
Conclusions: No marked differences in exposures (AUC and C max ) were observed<br />
between Norm Pts and mild/Mod HI Pts following the CFZ dose. No consistent trend<br />
in CFZ exposure related to HI severity was seen. HI did not appear to substantially<br />
increase severity <strong>of</strong> AEs; however, the number <strong>of</strong> Pts was small. Based on PK and<br />
limited safety results, no CFZ dose adjustment appears to be warranted in Pts with<br />
relapsed or progressive advanced malignancies and mild or Mod HI.<br />
Clinical trial identification: ClinicalTrials.gov NCT01949545; First received:<br />
September 6, 2013<br />
Legal entity responsible for the study: Amgen<br />
Funding: Amgen<br />
Disclosure: S. Anthony: Consultant for Zymeworks Pharmaceuticals. Evidence Review<br />
Board for Paradigm Diagnostics. Speaker’s Bureau for Spectrum Pharmaceuticals. M.<br />
White: Amgen employee. M. Schupp, Y. Ou: Amgen employee; have stock ownership.<br />
All other authors have declared no conflicts <strong>of</strong> interest.<br />
930P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Evaluation <strong>of</strong> safety, tolerability and efficacy <strong>of</strong> temsirolimus in<br />
patients (pts) with relapsed or refractory mantle cell<br />
lymphoma (rel/refr MCL) in routine clinical practice<br />
M. Dreyling 1 , G. Krekeler 2 , A. Neuh<strong>of</strong> 2 , M. Woike 2 , G. Hess 3 , D. Kalanovic 2<br />
1 Medizinische Klinik III, Ludwig Maximilians University - Grosshadern, Munich,<br />
Germany, 2 Medical <strong>Oncology</strong>, Pfizer Pharma GmbH, Berlin, Germany, 3 III.<br />
Medizinische Klinik, Universitätsmedizin Mainz, Mainz, Germany<br />
Background: Temsirolimus (TEM), an mTOR inhibitor, is approved in the EU for the<br />
treatment <strong>of</strong> pts with rel/refr MCL. A pivotal study demonstrated significantly longer<br />
progression free survival (PFS) with TEM (175 mg weekly for 3 weeks followed by 75<br />
mg weekly) in rel/refr MCL pts compared to investigator’s choice therapy (4.8 vs 1.9<br />
months (mo); P = 0.0009). To evaluate safety and efficacy <strong>of</strong> TEM in an unselected<br />
clinical routine patient population, a prospective non-interventional study with TEM<br />
in rel/refr MCL pts is useful.<br />
Methods: A German multicenter registry for rel/refr MCL pts treated with TEM was<br />
started in Oct 2009 (NCT00700258). Objectives are the evaluation <strong>of</strong> the safety pr<strong>of</strong>ile,<br />
tolerability, and anti-tumor activity <strong>of</strong> TEM as well as patient’s pr<strong>of</strong>ile, and the<br />
sequence <strong>of</strong> systemic therapies.<br />
Results: From Oct 2009 to Feb 2016, 28 study sites recruited 53 pts. Baseline<br />
characteristics are available for 53 pts: 69.8% male; median age 74.4 years (range<br />
54.5-96.4); bone marrow involvement in 39.6% <strong>of</strong> the pts; ECOG PS (n = 52) 0 or 1 in<br />
82.7%, ECOG PS 2 in 17.3%; MIPI score (n = 51): 21.6%, 33.3%, and 45.1% are<br />
classified as low, intermediate and high risk at the time <strong>of</strong> enrollment. Median time<br />
between diagnosis and start <strong>of</strong> treatment with TEM is 2.7 years (range 0.4-14.9).The<br />
median number <strong>of</strong> prior therapies is 2 (range 1-10) with 43.4% <strong>of</strong> the pts treated<br />
in ≥ 4 th line. Severe adverse events (drug related) are general, metabolic, psychiatric,<br />
skin, renal, gastrointestinal, respiratory (in 1 pt each) and blood system disorders (in 2<br />
pts) and infections (in 4 pts). Efficacy analyses are available for 38 pts and show an<br />
objective response in 31.6%, a clinical benefit (CR, PR, MR and SD) in 60.5% and PD<br />
in 39.5%. Median PFS for all pts is 3.7 mo. For the subgroup <strong>of</strong> pts treated with TEM in<br />
2 nd and 3 rd line PFS is 3.3 mo, for ≥ 4 th line pts 4.9 mo.<br />
Conclusions: The registry was started to evaluate the safety and efficacy <strong>of</strong> TEM in pts<br />
with rel/refr MCL in routine clinical practice. 45.1% high-risk pts were included in the<br />
analysis. In this comparatively poor-prognosis patient population, TEM showed a<br />
predictable, manageable tolerability pr<strong>of</strong>ile. Efficacy parameters were consistent with<br />
published phase III data.<br />
Clinical trial identification: NCT00700258<br />
Legal entity responsible for the study: Pfizer Pharma GmbH, Berlin (Dep. Medical<br />
<strong>Oncology</strong>)<br />
Funding: Pfizer Pharma GmbH, Berlin, Dep. Medical <strong>Oncology</strong><br />
Disclosure: M. Dreyling, G. Hess: Consultant or Advisory Role for Pfizer Honoraria,<br />
Pfizer. G. Krekeler, A. Neuh<strong>of</strong>, M. Woike, D. Kalanovic: employee <strong>of</strong> Pfizer Pharma<br />
GmbH, Germany.<br />
Table: 929P<br />
27 mg/m 2 56 mg/m 2<br />
PK Parameter<br />
Norm<br />
(n = 10)<br />
Mild HI<br />
(n = 14)<br />
Mod HI<br />
(n = 9)<br />
Norm<br />
(n = 8)<br />
Mild HI<br />
(n = 8)<br />
Mod HI<br />
(n = 5)<br />
AUC0-last (ng·h/mL)<br />
Geometric mean 378 546 477 765 1107 927<br />
Geometric CV, % 40.8 39.2 33.1 100.5 73.7 45.8<br />
Geometric means ratio,<br />
% (90% CI)<br />
- 144.4 (111.5,<br />
187.1)<br />
126.1 (94.6,<br />
168.1)<br />
- 144.7 (79.2,<br />
264.2)<br />
121.1 (60.9,<br />
240.7)<br />
AUC 0-∞(ng·h/mL)<br />
Geometric mean 348 529 500 609 1108 929<br />
Geometric CV, % 35.4 a 40.3 b 38.4 c 99.6 d 73.7 46.2<br />
Geometric means ratio,<br />
% (90% CI)<br />
- 151.8 (113.6,<br />
203.0)<br />
143.5 (103.3,<br />
199.5)<br />
- 181.9 (96.4,<br />
343.2)<br />
152.6 (74.9,<br />
311.0)<br />
a n=8; b n = 12; c n=7; d n = 6 CV, coefficient <strong>of</strong> variation<br />
vi320 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
931P<br />
Final results <strong>of</strong> a phase II trial <strong>of</strong> R-IDEA as salvage therapy in<br />
patients with relapsed/refractory diffuse large B-cell<br />
lymphoma<br />
E. Kondo 1 , K. Yamamoto 2 , T. Masunari 3 , J. Takizawa 4 , K. Miura 5 , Y. Masaki 6 ,<br />
T. Matsumura 7 , Y. Hiramatsu 8 , J. Murakam 9 , H. Tsujimura 10 , N. Tomita 11 ,<br />
Y. Maeda 12 , M. Kanno 13<br />
1 Department <strong>of</strong> General Medicine, Okayama University Hospital, Okayama, Japan,<br />
2 Department <strong>of</strong> Hematology, Okayama City General Medical Center, Okayama,<br />
Japan, 3 Department <strong>of</strong> Hematology, Chugoku Central Hospital, Fukuyama, Japan,<br />
4 Department <strong>of</strong> Hematology, Endocrinology and Metabolism, Niigata University<br />
Medical and Dental Hospital, Niigata, Japan, 5 Division <strong>of</strong> Hematology and<br />
Rheumatology, Nihon University School <strong>of</strong> Medicine, Itabashi, Japan, 6 Division <strong>of</strong><br />
Hematology and Immunology, Kanazawa Medical University, Uchinada, Kahoku,<br />
Japan, 7 Department <strong>of</strong> Internal Medicine, Himeji St. Mary’s Hospital, Himeji,<br />
Japan, 8 Department <strong>of</strong> Hematology, Japanese Red Cross Society Himeji Hospital,<br />
Himeji, Japan, 9 Department <strong>of</strong> Gastroenterology and Hematology, Toyama<br />
University Hospital, Toyama, Japan, 10 Division <strong>of</strong> Hematology-<strong>Oncology</strong>, Chiba<br />
Cancer Center Hospital, Chiba, Japan, 11 Division <strong>of</strong> Hematology and <strong>Oncology</strong>,<br />
St. Marianna University School <strong>of</strong> Medicine, Kawasaki, Japan, 12 Department <strong>of</strong><br />
Hematology and <strong>Oncology</strong>, Okayama University Hospital, Okayama, Japan,<br />
13 <strong>Oncology</strong> Center, Nara Medical University Hospital, Kashihara, Japan<br />
Background: High dose chemotherapy (HDT) with autologous stem cell support<br />
(ASCT) has been proven effective in relapsed/refractory DLBCL, who are sensitive to<br />
salvage chemotherapy. The salvage regimen IDEA was previously reported as effective<br />
(ORR; 67.6%) and feasible to mobilize PBSCs (77.8%). (Nishimori et al. Antican Res<br />
2009) The interim analysis <strong>of</strong> this phase II trial addressing safety and efficacy was<br />
presented in ESMO 2014. Herein, we report final results <strong>of</strong> the survival analysis.<br />
Methods: This study includes pts aged 18-65 years with primary refractory or first<br />
relapse CD20+ DLBCL after R-CHOP. The R-IDEA regimen consisits <strong>of</strong> R 375mg/m2<br />
on day 1, IFO 1.3g/m2, ETP 150mg/m2 on days 2-4, Dex 33mg IV on days 2-5 and<br />
Ara-C 750mg/m2 twice daily on days 3-4. R-IDEA was administered every 21 days for<br />
a total <strong>of</strong> 3 cycles. PBSCs were harvested after cycle 3. HDT regimen was based on<br />
institutional preference. Primary endpoint was mobilization adjusted response rate<br />
(MARR; [CR] + [PR] - mobilization failure). Secondary endpoints included 2-year<br />
overall survival (OS), 2-year progression-free survival (PFS), transplanted rate,<br />
mobilization efficiency and toxicity.<br />
Results: 20 pts were enrolled (median age 59.5, range 42-65; M:F ratio 11:9). 17 pts<br />
were enrolled after first relapse and three were refractory to first line chemotherapy.<br />
Five pts relapsed within 1 year after diagnosis. The most frequent grade 3/4 adverse<br />
events were neutropenia, thrombocytopenia, anemia and febrile neutropenia. After<br />
completion <strong>of</strong> R-IDEA chemotherapy, seven pts achieved CR, five PR, one had SD,<br />
seven had PD. The median CD34+ cell count was 2.6 million/kg (0.17-43.7) and<br />
median number <strong>of</strong> apheresis days was two. In 12 sensitive relapsed pts, two failed to<br />
mobilization, for a MARR <strong>of</strong> 50% (10/20). No patient <strong>of</strong> primary refractory or relapsed<br />
within 1 year after diagnosis achieved MARR. In total, 12 pts (10 pts with MARR, 1pt<br />
in SD and 1 pt in CR with CD34+ 1.5million/kg) received HDT/ASCT. The OS and<br />
PFS at two years was 38.5% and 29.2%, respectively.<br />
Conclusions: As previously reported in PARMA study and CORAL study, primary<br />
refractory and early relapsed DLBCL pts had an extremely poor prognosis. New<br />
treatment strategy seems to be warranted for the high risk pts.<br />
Clinical trial identification: UMIN000004892 (release date: 20 Jan, 2011)<br />
Legal entity responsible for the study: The society <strong>of</strong> lymphoma treatment in Japan<br />
Funding: The society <strong>of</strong> lymphoma treatment in Japan (SoLT-J) and the west japan<br />
hematology/oncology group (WestJHOG)<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
932P<br />
Chemotherapy alone or combined chemotherapy and involved<br />
field radiotherapy in favorable risk early-stage classical<br />
Hodgkin lymphoma-a 10 years experience<br />
S. Ali, A. Basit, A.S. Kazmi, F. Badar, A. Sidhu, A. Hameed<br />
Department <strong>of</strong> Medical <strong>Oncology</strong>, Shaukat Khanum Memorial Cancer Hospital<br />
and Reserch Centre (SKM), Lahore, Pakistan<br />
Background: Early-stage Hodgkin lymphoma is divided into favorable and<br />
unfavorable disease. Trials for patients with limited-stage HL have demonstrated that<br />
treatment with chemotherapy plus involved-field radiation therapy (IFRT) and<br />
chemotherapy alone with Doxorubicin (Adriamycin), Bleomycin, Vinblastine, and<br />
Dacarbazine (ABVD) may both be acceptable options. The aim <strong>of</strong> this study was to<br />
determine the outcomes <strong>of</strong> favorable risk early-stage Hodgkin lymphoma treated either<br />
with chemotherapy alone or chemotherapy plus IFRT.<br />
Methods: Retrospective study done on newly diagnosed patients <strong>of</strong> early-stage classical<br />
HL with favorable risk prognostic features. Patients were divided in 2 groups i.e<br />
chemotherapy alone or combined modality treatment (CMT) comprising <strong>of</strong><br />
chemotherapy followed by radiotherapy. Baseline characteristics in both groups were<br />
compared using cross tab and chi square test. PFS and OS for both groups was<br />
calculated using survival curves.<br />
Results: Out <strong>of</strong> 101 patients, 71.3% were male. Sixty three (62.4%) patients received<br />
CMT and 38 (37.6%) patients had chemotherapy alone. Radiotherapy dose was 20 to<br />
36 gray. Patients treated with CMT had OS compared to chemotherapy alone: 100%<br />
versus 91% at 5 years and 96% versus 81% at 10 years respectively (p = 0.03). PFS with<br />
CMT against chemotherapy alone at 5 years (98% versus 81%) and 10 years (82%<br />
versus 71%) (p = 0.01).<br />
Conclusions: Patients treated with CMT had better progression free survival and<br />
overall survival compared to chemotherapy alone.<br />
Legal entity responsible for the study: Shaukat Khanum Memorial Cancer Hospital<br />
and research Centre, Lahore, Pakistan was responsible for the governance, coordination<br />
and running <strong>of</strong> the study.<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
933P<br />
CagA and NFAT co-operatively participate in the<br />
lymphomagenesis <strong>of</strong> gastric MALT lymphoma<br />
S-H. Kuo 1 , H-J. Tsai 2 , K-H. Yeh 1 , C-W. Lin 3 , Y-S. Zeng 1 , M-S. Wu 4 , P-N. Hsu 4 ,<br />
L-T. Chen 2 , A-L. Cheng 1<br />
1 Department <strong>of</strong> <strong>Oncology</strong>, National Taiwan University Hospital and National<br />
Taiwan University Cancer Center, Taipei, Taiwan, 2 National Institute <strong>of</strong> Cancer<br />
Research, National Health Research Institutes, Tainan, Taiwan, 3 Department <strong>of</strong><br />
Pathology, National Taiwan University Hospital and National Taiwan University<br />
Cancer Center, Taipei, Taiwan, 4 Department <strong>of</strong> Internal Medicine, National Taiwan<br />
University Hospital and National Taiwan University Cancer Center, Taipei, Taiwan<br />
Background: Previous studies revealed that in gastric epithelial cell, CagA can inhibit<br />
progression <strong>of</strong> the cell cycle through activation <strong>of</strong> nuclear factor <strong>of</strong> activated T-cell<br />
(NFAT) and NFAT-dependent genes, such as p21. We recently reported that CagA and<br />
its signaling molecules, p-SHP-2, p-ERK, and Bcl-xL were associated with H. pylori<br />
(HP) dependence <strong>of</strong> gastric mucosa-associated lymphoid tissue lymphoma<br />
(MALToma). In this study, we further assessed if CagA and NFAT co-operatively<br />
participate in the lymphomagenesis <strong>of</strong> gastric MALToma.<br />
Methods: HP strains were cultured from patients with HP-dependent gastric<br />
MALToma. We co-cultured gastric epithelial cell, MA-1 cell (t(14;18)(q32;q21)/<br />
IGH-MALT1-positive B-cell lymphoma), and Pfeiffer cell (diffuse large B-cell<br />
lymphoma) with HP strains and further evaluated the expression pattern <strong>of</strong> CagA,<br />
CagA-signaling molecules and NFATc1 using western blotting and confocal<br />
immunoinfluence. The cell cycle, p21, and p27 were analyzed. The association between<br />
CagA and NFATc1 expression in malignant B cells and tumor response to HP<br />
eradication therapy (HPE) was further evaluated in 67 patients with stage IE/IIE1<br />
gastric MALToma.<br />
Results: NFATc1 was activated by CagA in HP-co-cultured gastric epithelial cells and<br />
MA-1 cells, but NFATc1 was not activated in HP-co-cultured Pfeiffer cell. In<br />
HP-co-cultured MA-1 cells, we revealed that CagA up-regulated the expression <strong>of</strong><br />
p-SHP-2, p-ERK, and Bcl-xL, and CagA-inducing nuclear NFATc1 translocation was<br />
abolished by inhibiting calcineurin using cyclosporine A. The HP-co-cultured MA-1<br />
cell exhibited G1 cell-cycle retardation through the activation <strong>of</strong> NFATc1, p21, and<br />
p27. The nuclear NFATc1 expression rate was significantly higher in HP-dependent<br />
than in HP-independent tumors (70.0% [28/40] vs. 29.6% [8/27]; P = 0.001). Similarly,<br />
CagA expression was closely correlated with the HP-dependence <strong>of</strong> these tumors<br />
(P < 0.001). Moreover, nuclear NFATc1 expression was closely associated with the<br />
CagA expression (P < 0.001).<br />
Conclusions: Our results indicate that CagA can derive direct NFAT signaling<br />
cooperate in HP-induced lymphomagenesis <strong>of</strong> gastric MALToma, and the<br />
co-expression <strong>of</strong> CagA and NFATc1 is clinically and biologically significant.<br />
Legal entity responsible for the study: N/A<br />
Funding: Ministry <strong>of</strong> Science and Technology, Taiwan<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
934P<br />
abstracts<br />
Dynamics <strong>of</strong> changes in endocrine status in adolescents with<br />
lymphoma<br />
E. Pak 1 , O. Kit 2 , E. Frantsiyants 3 , V. Dmitrieva 4 , O. Kozyuk 1 , I. Lysenko 1 ,<br />
L. Vladimirova 5<br />
1 Department <strong>of</strong> Hematology, Rostov Research Institute <strong>of</strong> <strong>Oncology</strong>,<br />
Rostov-on-Don, Russian Federation, 2 Surgical Department, Rostov Research<br />
Institute <strong>of</strong> <strong>Oncology</strong>, Rostov-on-Don, Russian Federation, 3 Laboratory <strong>of</strong> Study <strong>of</strong><br />
Malignant Tumor Pathogenesis, Rostov Research Institute <strong>of</strong> <strong>Oncology</strong>,<br />
Rostov-on-Don, Russian Federation, 4 Department <strong>of</strong> Pediatric Surgery, Rostov<br />
Research Institute <strong>of</strong> <strong>Oncology</strong>, Rostov-on-Don, Russian Federation, 5 Department<br />
<strong>of</strong> Chemotherapy, Rostov Research Institute <strong>of</strong> <strong>Oncology</strong>, Rostov-on-Don,<br />
Russian Federation<br />
Background: The purpose <strong>of</strong> the study was to analyze the endocrine status <strong>of</strong> patients<br />
with Hodgkin lymphoma (HL) before treatment and the effect <strong>of</strong> chemotherapy on sex,<br />
pituitary and glucocorticoid hormones.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw375 | vi321
abstracts<br />
Methods: Gonadal function, its regulation by tropic pituitary hormones and levels <strong>of</strong><br />
prolactin and cortisol were studied by radioimmunoassay in 32 HL patients aged 12-21<br />
years receiving chemotherapy.<br />
Results: Before therapy females showed estradiol decreased by 10 times compared with<br />
the norm in follicular and luteal phases <strong>of</strong> the cycle, with testosterone increase by 3.7<br />
times in phase I and by 10 times in phase II <strong>of</strong> the cycle. Follicle-stimulating hormone<br />
(FSH) was 10 times lower than the norm. Luteinizing hormone in the luteal phase was<br />
similar to the norm in all disease stages, and in the follicular phase it was decreased by<br />
15 times in patients with stage III-IV disease, compared with the norm. Male patients,<br />
especially those with stage III-IV disease, showed low testosterone levels in the blood<br />
before treatment. Significant overproduction <strong>of</strong> estradiol was observed, especially in<br />
stages III-IV. FSH levels in stage III-IV patients were 11 times lower than the norm;<br />
cortisol content did not change in stages I-II, and in stages III-IV it was 2.5 times<br />
higher than the norm. Prolactin and progesterone levels were similar to the norm.<br />
Conclusions: HL development in adolescents is accompanied by significant changes in<br />
levels <strong>of</strong> sex and pituitary hormones and cortisol depending on the disease stage.<br />
Chemotherapy provides high antitumor effect and normalizes the levels <strong>of</strong> circulating<br />
hormones that have changed before the treatment.<br />
Legal entity responsible for the study: Rostov Research Institute <strong>of</strong> <strong>Oncology</strong><br />
Funding: Ministry <strong>of</strong> Health <strong>of</strong> the Russian Federation<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
935P<br />
Development <strong>of</strong> PF-05280586, a potential biosimilar to<br />
rituximab<br />
I. Jacobs 1 , L.A. Melia 2 , C. Kirchh<strong>of</strong>f 3 , C. Kobryn 4 , P. Nava-Parada 1 , J. Rosenberg 5 ,<br />
A.M. Ryan 6 , D. Yin 7<br />
1 Global Medical Affairs, Pfizer Inc., New York, NY, USA, 2 Biotechnology Clinical<br />
Development, Pfizer Inc, San Diego, CA, USA, 3 Global Technology Services<br />
Biotechnology and Aseptic Sciences, Pfizer Inc, Chesterfield, MO, USA,<br />
4 Biosimilars Regulatory Strategy, Pfizer Inc, Groton, CT, USA, 5 Pfizer Global<br />
Research and Development, Pfizer Inc, Groton, CT, USA, 6 Drug Safety Research<br />
and Development, Pfizer Inc, Groton, CT, USA, 7 Clinical Pharmacology, Pfizer Inc.,<br />
San Diego, CA, USA<br />
Background: PF-05280586 is being developed as a potential biosimilar to rituximab.<br />
Similarity <strong>of</strong> PF-05280586 to rituximab sourced from the EU and US (rituximab-EU<br />
and -US) was assessed using structural, functional, nonclinical pharmacokinetic (PK),<br />
tolerability, and toxicity studies, and clinical studies.<br />
Methods: Structural similarity was determined by peptide mapping and other<br />
analytical methods. Functional similarity was measured using complement-dependent<br />
cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and apoptosis.<br />
Pharmacodynamic (PD) effects <strong>of</strong> PF-05280586 and rituximab-EU on B-cell repletion<br />
were compared in sexually mature cynomolgus monkeys in single-dose PK and<br />
repeat-dose toxicity studies. In a clinical study, 220 patients with active rheumatoid<br />
arthritis on a background <strong>of</strong> methotrexate and inadequate response to one or more<br />
tumour necrosis factor–antagonist therapies were randomized to intravenous<br />
PF-05280586, rituximab-EU or rituximab-US 1000 mg on study days 1 and 15 to<br />
assess PK similarity; PD, safety, tolerability, and immunogenicity were also evaluated.<br />
Results: State-<strong>of</strong>-the-art characterization methods show PF-05280586 has similar<br />
structure and function to rituximab-EU and rituximab-US. Nonclinical results<br />
indicated PK, PD, and in vivo findings <strong>of</strong> PF-05280586 are similar to rituximab-EU. In<br />
patients, PF-05280586, rituximab-EU, and rituximab-US exhibited similar clinical PK<br />
pr<strong>of</strong>iles; the 90% confidence intervals <strong>of</strong> test-to-reference ratios were within the<br />
bioequivalence margin <strong>of</strong> 80.00–125.00%. All treatments resulted in rapid and<br />
pr<strong>of</strong>ound reduction <strong>of</strong> CD19+ B-cells and sustained pr<strong>of</strong>ound B-cell suppression<br />
through week 25. No clinically meaningful differences in adverse events or<br />
immunogenicity were identified.<br />
Conclusions: Evaluation <strong>of</strong> PF-05280586 thus far supports its development as a<br />
potential biosimilar to rituximab. A randomized clinical trial comparing efficacy,<br />
safety, PK, and immunogenicity <strong>of</strong> PF-05280586 monotherapy to rituximab-EU<br />
monotherapy in treatment-naïve patients with CD20 + , low tumour burden follicular<br />
lymphoma is ongoing.<br />
Clinical trial identification: NCT01526057 and NCT02213263.<br />
Legal entity responsible for the study: Pfizer Inc.<br />
Funding: Pfizer Inc.<br />
Disclosure: I. Jacobs, L.A. Melia, C. Kirchh<strong>of</strong>f, C. Kobryn, P. Nava-Parada,<br />
J. Rosenberg, A.M. Ryan, D. Yin: Full time employee <strong>of</strong> Pfizer Inc and stock ownership<br />
and/or options from Pfizer Inc.<br />
936P<br />
Do MDR1 & CYP3A5 genetic polymorphisms influence the risk<br />
<strong>of</strong> cytogenetic relapse in patients with chronic myeloid<br />
leukemia on imatinib therapy?<br />
H. Natarajan 1 , L. Kumar 2 , S. Bakhshi 2 , A. Sharma 2 , M. Kabra 3 , T. Velpandian 1 ,<br />
A. Gogia 2 , S. Shastri 4 , Y.K. Gupta 1<br />
1 Clinical Pharmacology, All India Institute <strong>of</strong> Medical Sciences, New Delhi, India,<br />
2 Medical <strong>Oncology</strong>, All India Institute <strong>of</strong> Medical Sciences, New Delhi, India,<br />
3 Pediatrics, All India Institute <strong>of</strong> Medical Sciences, New Delhi, India, 4 Genetics, All<br />
India Institute <strong>of</strong> Medical Sciences, New Delhi, India<br />
Background: Genetic polymorphisms in the genes coding for imatinib transporters &<br />
metabolizing enzymes might be responsible for marked inter-individual<br />
pharmacokinetic variability seen with imatinib. Whether these polymorphisms<br />
influence the risk <strong>of</strong> cytogenetic relapse in patients with CML on imatinib therapy is<br />
unknown.<br />
Methods: Patients with chronic phase CML on imatinib therapy & have completed 5<br />
years <strong>of</strong> follow-up were enrolled. The following single nucleotide polymorphisms were<br />
genotyped- C1236T, C3435T, G2677T & G2677A in MDR1 gene and A6986G in<br />
CYP3A5 gene. Genotyping was done using PCR-RFLP method & validated by direct<br />
gene sequencing. Plasma trough levels <strong>of</strong> imatinib were measured using LC-MS/MS.<br />
Cytogenetic relapse was defined as the presence <strong>of</strong> Philadelphia chromosome positive<br />
metaphases in conventional bone marrow cytogenetic study in patients who had<br />
already achieved complete cytogenetic response.<br />
Results: A total <strong>of</strong> 104 chronic phase CML patients (52 cases with cytogenetic relapse<br />
& 52 controls without cytogenetic relapse) were included. Mean age at diagnosis was 36<br />
years. Among the SNPs genotyped, statistically significant difference in the frequency<br />
<strong>of</strong> various genotypes was seen for MDR1-C1236T & C3435T polymorphisms, between<br />
the patients with & without relapse (table 1). Patients with CC genotype for<br />
MDR1-C1236T polymorphism were at a significantly higher risk <strong>of</strong> relapse<br />
[OR = 4.382, 95%CI (1.145, 16.774), p = 0.022], while those with TT genotype for<br />
MDR1-C3435T polymorphism had a significantly lower risk <strong>of</strong> relapse [OR = 0.309,<br />
95%CI (0.134, 0.708), p = 0.005]. Patients with cytogenetic relapse had lower trough<br />
levels <strong>of</strong> imatinib compared to those without relapse (table).<br />
Table: 936P Frequency <strong>of</strong> genotypes and trough levels <strong>of</strong> imatinib in<br />
patients with and without cytogenetic relapse<br />
SNP<br />
Genotype Patients with<br />
cytogenetic relapse<br />
(n = 52)<br />
Patients without<br />
cytogenetic relapse<br />
(n = 52)<br />
P<br />
value<br />
CYP3A5- A6986G AA 8 (57%) 6 (43%) 0.492<br />
AG 23 (55%) 19 (45%)<br />
GG 21 (44%) 27 (56%)<br />
MDR1-C1236T CC 11 (79%) 3 (21%) 0.024<br />
CT 34 (50%) 34 (50%)<br />
TT 7 (32%) 15 (68%)<br />
MDR1- C3435T CC 11 (73%) 4 (27%) 0.010<br />
CT 28 (57%) 21 (43%)<br />
TT 13 (32%) 27 (68%)<br />
MDR1-G2677T/A GG 7 (70%) 3 (30%) 0.453<br />
GT 23 (52%) 21 (48%)<br />
TT 16 (40%) 24 (60%)<br />
TA 4 (57%) 3 (43%)<br />
GA 2 (67%) 1 (33%)<br />
Trough levels <strong>of</strong> Imatinib<br />
(ng/mL)<br />
1551.4 ± 1324.1 2154.2 ± 1358.3 0.041<br />
Conclusions: C1236T & C3435T genetic polymorphisms in MDR1 gene significantly<br />
influence the risk <strong>of</strong> cytogenetic relapse in patients with CML. Genotyping <strong>of</strong> MDR1<br />
gene may be considered in patients with CML to individualize the therapy & optimize<br />
the outcomes.<br />
Legal entity responsible for the study: All India Institute <strong>of</strong> Medical Sciences, New<br />
Delhi<br />
Funding: All India Institute <strong>of</strong> Medical Sciences, New Delhi (Institute funding)<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
937P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Relationship between adherence, drug level and clinical<br />
response achieved in patients with chronic myeloid leukemia<br />
on imatinib<br />
M.M. Omran 1 , R. Abdelfatah 2 , H. Mousa 3 , N. Alieldin 4 , S. Shouman 1<br />
1 Cancer Biology Department, National Cancer Institute, Cairo, Egypt, 2 Medical<br />
<strong>Oncology</strong> Department, National Cancer Institute, Cairo, Egypt, 3 Clinical Pathology<br />
Department, National Cancer Institute, Cairo, Egypt, 4 Medical Statistics<br />
Department, National Cancer Institute, Cairo, Egypt<br />
Background: Imatinib mesylate (IM) has been shown to be highly efficacious in the<br />
treatment <strong>of</strong> chronic myeloid leukemia (CML). Continuous and adequate dosing is<br />
essential for optimal outcomes so patient adherence is critical. There is a considerable<br />
vi322 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
variability in the level <strong>of</strong> molecular responses achieved with IM therapy. These<br />
differences could result from variable drug levels which may be due to adherence factor<br />
or other factors. This study was designed to determine the relation between drug<br />
adherence, imatinib plasma level and clinical response.<br />
Methods: This study was designed as a prospective, observational, non-interventional<br />
study. A total <strong>of</strong> 101 patients with chronic-phase CML treated with IM were enrolled.<br />
The study protocol was approved by the Institutional Review Board <strong>of</strong> the National<br />
Cancer Institute <strong>of</strong> Cairo University, Egypt. Adherence was monitored by using Morisky<br />
medication adherence scores (MMAS). Drug level was measured as peak and trough<br />
concentration after reaching steady state using high performance liquid chromatography<br />
mass spectroscopy (HPLC/MS) and peak/ trough ratio (P/T ratio) was calculated.<br />
Results: The mean IM trough plasma level in patients who achieved unfavorable response<br />
(n = 37) was 1183.92 ng/ml, and in patients who achieved favorable response (n = 64)<br />
1560.16 ng/ml (p = 0.006). The P/T ratio in patients who achieved unfavorable response<br />
was 3.03 and in patients who achieved favorable response 2.06 (p = 0.001). There was no<br />
significant correlation between adherence score and clinical response. Multivariate analysis<br />
identified P/T ratio as the only independent predictors <strong>of</strong> clinical response.<br />
Conclusions: In patients with CML treated with IM the significant independent factor<br />
affecting response was P/T ratio. As the peak/trough ratio increase by one, the risk <strong>of</strong><br />
poor response increased by more than double compared with a good response with<br />
95% CI:1.28 – 3.92 (P = 0.005).<br />
Legal entity responsible for the study: National Cancer Institute<br />
Funding: National Cancer Institute, Cairo University<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
938P<br />
Is there any association between vitamin D receptor<br />
polymorphisms and acute myeloid leukemia?<br />
A. Esfahani 1 , Z. Ghoreishi 2<br />
1 Hematology and <strong>Oncology</strong> Research Center, Tabriz University <strong>of</strong> Medical<br />
Sciences, Tabriz, Iran, 2 Nutrition Research Center, Tabriz University <strong>of</strong> Medical<br />
Sciences, Tabriz, Iran<br />
Background: Vitamin D receptor (VDR) can influence cancer development through<br />
binding with vitamin D. various studies examined the possible association <strong>of</strong> VDR<br />
polymorphism with the risk <strong>of</strong> solid tumors. In this study, the association <strong>of</strong> VDR<br />
polymorphism with acute myeloid leukemia (AML) and its possible effect on treatment<br />
outcomes was investigated for the first time.<br />
Methods: VDR polymorphisms (FokI, BsmI, TaqI and ApaI) were compared between<br />
eligible patients with AML and control <strong>of</strong> healthy people using the PCR-RFLP<br />
procedure. Then, the effect <strong>of</strong> VDR polymorphisms on complete remission was<br />
examined.<br />
Results: 133 patients with AML (76 male, 57 female; mean age: 42.27± 15.84) and 300<br />
control (173 male, 127 female; mean age: 41.55± 6.70) were enrolled. The frequency <strong>of</strong><br />
VDR gene polymorphisms in both study groups were summarized in the Table 1.<br />
Thirty percent <strong>of</strong> the patients who achieved CR had TT genotype, while remaining 70%<br />
had TC genotype. The distribution <strong>of</strong> TaqI polymorphism in the patients without CR<br />
was as follows: 55% TT, 31% TC, and 14% CC; Therefore TaqI polymorphism was<br />
associated with CR. Table 1- The differences <strong>of</strong> VDR gene polymorphisms between<br />
patients with AML and control.<br />
VDR gene<br />
polymorphisms<br />
Table: 938P<br />
Patients with AML<br />
(n = 133)<br />
Control<br />
(n = 300)<br />
P<br />
value<br />
FokI<br />
FF 62.3 49.7<br />
Ff 29.2 33<br />
ff 8.5 17.3 .017<br />
BsmI<br />
BB 15.6 37<br />
Bb 41 53.7<br />
bb 43.4 9.3 < .001<br />
TaqI<br />
TT 43 31.3<br />
TC 44.7 56.3<br />
CC 12.3 12.3 .072<br />
ApaI<br />
AA 67.8 43<br />
Aa 27.3 36<br />
aa 5 21 < .001<br />
P value was calculated based on Fisher’s exact test.<br />
Conclusions: Like solid tumors, there is a significant association between VDR<br />
polymorphism and AML and TaqI polymorphism was associated with complete<br />
remission in patients with AML.<br />
Legal entity responsible for the study: Tabriz University <strong>of</strong> Medical Sciences, Tabriz,<br />
Iran<br />
Funding: Tabriz University <strong>of</strong> Medical Sciences, Tabriz, Iran<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
939P<br />
Identification <strong>of</strong> aberrant DNA methylation in pediatric acute<br />
myeloid leukaemia by multiplex methylation sensitive PCR<br />
V. Rudenko 1 , S. Kazakova 2 , A. Tanas 1 , A. Popa 3 , V. Nemirovchenko 3 ,<br />
E. Kuznetsova 2 , D. Zaletaev 2 , V. Strelnikov 1<br />
1 Epigenetic Laboratory, Research Centre for Medical Genetics, Moscow, Russian<br />
Federation, 2 Laboratory <strong>of</strong> Human Genetics, IM Sechenov First Moscow State<br />
Medical University, Moscow, Russian Federation, 3 Hematology/<strong>Oncology</strong><br />
Department, Institute <strong>of</strong> Pediatric <strong>Oncology</strong> and Hematology, N. N. Blokhin<br />
Russian Cancer Research Center, Moscow, Russian Federation<br />
Background: The aim <strong>of</strong> this study is to develop a system <strong>of</strong> DNA methylation markers<br />
<strong>of</strong> acute myeloid leukaemia (AML) in children. Aberrant methylation diagnostic<br />
potential can be used for determining minimal residual disease (MRD), as well as to<br />
identify AML subtypes having different sensitivity to therapeutic regimens in particular<br />
with the use <strong>of</strong> epigenetic modifiers.<br />
Methods: Our study involves 53 bone marrow samples from pediatric AML patients<br />
before treatment and after the first course <strong>of</strong> chemotherapy. Primary identification <strong>of</strong><br />
aberrant DNA methylation is carried out by an unbiased DNA differential methylation<br />
screening method developed within this study. We propose a system <strong>of</strong> 13 DNA<br />
methylation markers (belonging to the promoter regions <strong>of</strong> ABCG4, AIFM3, CLDN7,<br />
CXCL14, DLK2, EGFLAM, GSG1L, KHSRP, MAFA, RXRA, SOX8, TMEM200B,<br />
TMEM176A /TMEM176B genes) for the assessment <strong>of</strong> aberrant DNA methylation.<br />
The DNA methylation frequency is estimated using the system <strong>of</strong> 4 multiplex<br />
methylation sensitive PCR reactions with the internal controls. Methylation is<br />
determined at the BstHHI restriction enzyme site; it was used because having many<br />
restriction sites within the loci studied, to determine the homogeneity <strong>of</strong> the CpG<br />
methylation across the region.<br />
Results: Methylation frequencies for 6 genes are as follows (before treatment/after the<br />
first course <strong>of</strong> chemotherapy): TMEM176A/TMEM176B (0,642/0,472), SOX8(0,434/<br />
0), CLDN7(0,283/0,66), DLK2(0,113/0), EGFLAM (0,113/0,226), GSG1L(0,094/0,038).<br />
The promoter regions <strong>of</strong> ABCG4, AIFM3, CXCL14, KHSRP, MAFA, RXRA,<br />
TMEM200B demonstrated high heterogeneity <strong>of</strong> methylation <strong>of</strong> CpG pairs and were<br />
not included in the analysis. Significant association was shown for TMEM176A<br />
/TMEM176B methylation status with the acute myeloid leukemia without maturation<br />
(p = 0,0481, 19/34). Differential methylation <strong>of</strong> these 6 genes in the samples before and<br />
after treatment may be indicative <strong>of</strong> clonal evolution <strong>of</strong> malignant transformation.<br />
Conclusions: Our study provides technical opportunities for determine the minimal<br />
residual disease in AML. And also for pr<strong>of</strong>iling the epigenetic abnormalities for a given<br />
individual, promising the development <strong>of</strong> individualized approaches in the therapy <strong>of</strong><br />
AML.<br />
Legal entity responsible for the study: Research Centre <strong>of</strong> Medical Genetics<br />
Funding: Research Centre <strong>of</strong> Medical Genetics<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
940TiP<br />
Pembrolizumab in combination with lenalidomide and<br />
low-dose dexamethasone in newly diagnosed and<br />
treatment-naive multiple myeloma (MM): randomized, phase<br />
3 KEYNOTE-185 study<br />
A. Palumbo 1 , M-V. Mateos 2 , J. San Miguel 3 , J. Shah 4 , S. Thompson 5 ,<br />
P. Marinello 5 , S. Jagannath 6<br />
1 Medical <strong>Oncology</strong>, University <strong>of</strong> Turin, Turin, Italy, 2 Medical <strong>Oncology</strong>, University<br />
Hospital <strong>of</strong> Salamanca/IBSAL, Salamanca, Spain, 3 Hematology, University <strong>of</strong><br />
Navarra, Pamplona, Spain, 4 Division <strong>of</strong> Cancer Medicine, The University <strong>of</strong> Texas<br />
MD Anderson Cancer Center, Houston, TX, USA, 5 Medical <strong>Oncology</strong>, Merck &<br />
Co., Inc., Kenilworth, NJ, USA, 6 Medical <strong>Oncology</strong>, Mount Sinai Medical Center,<br />
New York, NY, USA<br />
Background: PD-L1 is expressed on MM plasma cells and has been associated with<br />
higher MM cell proliferation. Thus, PD-L1 blockade with pembrolizumab may act<br />
synergistically with immunomodulatory drugs to enhance MM tumor suppression. In<br />
the phase 1 KEYNOTE-023 study, pembrolizumab + lenalidomide and low-dose<br />
dexamethasone showed an acceptable safety pr<strong>of</strong>ile and promising preliminary efficacy<br />
in patients with relapsed/refractory MM, supporting further evaluation <strong>of</strong> this<br />
treatment combination. The randomized, open-label, phase 3 KEYNOTE-185 study<br />
(ClinicalTrials.gov, NCT02579863) was designed to compare the efficacy and safety <strong>of</strong><br />
lenalidomide and low-dose dexamethasone (standard <strong>of</strong> care) with or without<br />
pembrolizumab in patients with newly diagnosed and treatment-naive MM.<br />
Trial design: Key eligibility criteria include age ≥18 years, newly diagnosed,<br />
treatment-naive, active MM with measurable disease, and ineligibility for autologous<br />
stem cell transplantation. Patients will be randomized 1:1 to receive lenalidomide 25<br />
mg daily on days 1-21 and low-dose dexamethasone 40 mg on days 1, 8, 15, and 22 <strong>of</strong><br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw375 | vi323
abstracts<br />
repeated 28-day cycles, with or without pembrolizumab 200 mg every 3 weeks. Patients<br />
will be stratified based on age (
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
943TiP<br />
ZUMA-1: A phase 2 multi-center study evaluating anti-CD19<br />
chimeric antigen receptor (CAR) T cells in patients with<br />
refractory aggressive non-Hodgkin lymphoma (NHL)<br />
S.S. Neelapu 1 , F.L. Locke 2 , N.L. Bartlett 3 , T. Siddiqi 4 , I. Braunschweig 5 ,L.<br />
J. Lekakis 6 , A. Goy 7 , J. Castro 8 , O. Oluwole 9 , D. Miklos 10 , J. Timmerman 11 ,<br />
C. Jacobson 12 , P.M. Reagan 13 , I. Flinn 14 , U. Farooq 15 , P. Stiff 16 , L. Navale 17 ,<br />
M. Elias 17 , J. Wiezorek 17 ,W.Y.Go 17<br />
1 Department <strong>of</strong> Lymphoma/Myeloma, The University <strong>of</strong> Texas MD Anderson<br />
Cancer Center, Houston, TX, USA, 2 Department <strong>of</strong> Blood and Marrow<br />
Transplantation, M<strong>of</strong>fitt Cancer Center, Tampa, FL, USA, 3 Siteman Cancer Center,<br />
Washington University School <strong>of</strong> Medicine, St. Louis, MO, USA, 4 Department <strong>of</strong><br />
Hematology & Hematopoietic Cell Transplantation, City <strong>of</strong> Hope National Medical<br />
Center, Duarte, CA, USA, 5 Department <strong>of</strong> <strong>Oncology</strong>, Montefiore Medical Center/<br />
Albert Einstein College <strong>of</strong> Medicine, Bronx, NY, USA, 6 Sylvester Cancer Center,<br />
University <strong>of</strong> Miami, Miami, FL, USA, 7 Clinical Divisions, John Theurer Cancer<br />
Center at Hackensack University Medical Center, Hackensack, NJ, USA, 8 Moores<br />
Cancer Center, University <strong>of</strong> California San Diego, La Jolla, CA, USA, 9 Hematology<br />
and Stem Cell Transplantation Section, Division <strong>of</strong> Hematology/<strong>Oncology</strong>,<br />
Department <strong>of</strong> Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University<br />
Medical Center, Nashville, TN, USA, 10 Division <strong>of</strong> Blood and Marrow<br />
Transplantation, Stanford University School <strong>of</strong> Medicine, Stanford, CA, USA,<br />
11 Division <strong>of</strong> Hematology & <strong>Oncology</strong>, Department <strong>of</strong> Medicine, and Department<br />
<strong>of</strong> Pathology & Laboratory Medicine, University <strong>of</strong> California, Los Angeles, CA,<br />
USA, 12 Department <strong>of</strong> Medical <strong>Oncology</strong>, Dana-Farber Cancer Institute, Boston,<br />
MA, USA, 13 Department <strong>of</strong> Medicine, University <strong>of</strong> Rochester Medical Center,<br />
Rochester, NY, USA, 14 Department <strong>of</strong> Hematology & <strong>Oncology</strong>, Sarah Cannon<br />
Research Institute, Nashville, TN, USA, 15 Division <strong>of</strong> Hematology, <strong>Oncology</strong> and<br />
Blood and Marrow Transplantation, University <strong>of</strong> Iowa Hospitals and Clinics, Iowa<br />
City, IA, USA, 16 Cardinal Bernardin Cancer Center, Loyola University Medical<br />
Center, Maywood, IL, USA, 17 Kite Pharma, Santa Monica, CA, USA<br />
Background: Diffuse large B-cell Lymphoma (DLBCL) is 30%-58% <strong>of</strong> all NHL and has<br />
an incidence <strong>of</strong> 3.8/100,000 in Europe (Tilly et al, Ann Oncol 2015). KTE-C19 is an<br />
autologous anti-CD19 CAR T cell therapy with CD28/CD3ζ signaling domains<br />
centrally manufactured using a streamlined 6-8–day process (Better et al, ASCO 2014).<br />
The multicenter phase 1 portion <strong>of</strong> ZUMA-1 found that KTE-C19 was safe for further<br />
study in refractory, aggressive NHL. Toxicities include generally reversible cytokine<br />
release syndrome and neurotoxicity. The phase 1 overall response rate (ORR) was 71%;<br />
complete remission (CR) rate was 57% (Locke et al, ASH 2015). Here, we describe the<br />
enrolling phase 2 portion <strong>of</strong> ZUMA-1.<br />
Trial design: Approximately 112 patients with refractory, aggressive NHL will be<br />
enrolled into cohort 1 (approximately 72 patients with DLBCL) or cohort 2<br />
(approximately 40 patients with primary mediastinal large B cell lymphoma or<br />
transformed follicular lymphoma). Patients will receive a fixed dose <strong>of</strong> 30 mg/m 2 /day<br />
fludarabine and 500 mg/m 2 /day cyclophosphamide conditioning chemo (chemo) x 3<br />
days followed by a single infusion <strong>of</strong> KTE-C19 at a target dose <strong>of</strong> 2 × 10 6 anti-CD19<br />
CAR T cells/kg. Eligible patients will have chemo-refractory disease (progressive<br />
disease [PD] or stable disease to most recent chemo or PD/recurrence ≤12 months <strong>of</strong><br />
prior autologous stem cell transplant), ≥18 years old, ECOG PS 0-1, adequate marrow,<br />
renal, hepatic, and cardiac function, and prior anti-CD20 monoclonal antibody and an<br />
anthracycline-containing chemo regimen. Patients with prior CAR T cell or other<br />
genetically modified T cell therapy, clinically significant infection, or current or history<br />
<strong>of</strong> central nervous system lymphoma are ineligible. The primary objective is to evaluate<br />
KTE-C19 efficacy by ORR (CR + partial remission). Key secondary objectives include<br />
duration <strong>of</strong> response, progression-free survival, overall survival, safety,<br />
pharmacokinetics, pharmacodynamics, and predictive biomarker analyses. The study is<br />
planned at approximately 25 sites in the US and EU. Accrual began November 2, 2015.<br />
Clinical trial identification: NCT02348216<br />
Legal entity responsible for the study: Kite Pharma<br />
Funding: Kite Pharma<br />
Disclosure: S.S. Neelapu, U. Farooq: Research funding from Kite Pharma. F.L. Locke:<br />
Scientific advisory for Kite Pharma. N.L. Bartlett: Scientific advisory for Gilead. T.<br />
Siddiqi: Speaker’s bureau for Pharmacyclics, Janssen, and Seattle Genetics. A. Goy:<br />
Honoraria, consultancy, speaker’s bureau for Pharmacyclics and Johnson and Johnson;<br />
Honoraria and consultancy for Celgene, Takea, and Acerta; Consultancy for Infinity.<br />
D. Miklos: Research funding from Kite Pharma, Pharmacyclics, Janssen, Roche,<br />
Genentech, Novartis, Adaptive Biotechnology; scientific advisory for Pharmacyclics,<br />
Novartis, Seattle Genetics, and BMS; speaker’s honoraria for San<strong>of</strong>i. I. Flinn: Research<br />
funding from Pharmacyclics and Janssen. L. Navale, J. Wiezorek, W.Y. Go:<br />
Employment with Kite Pharma. M. Elias: Employment from Kite Pharma. All other<br />
authors have declared no conflicts <strong>of</strong> interest.<br />
944TiP<br />
Pembrolizumab in patients with relapsed/refractory primary<br />
mediastinal large B-cell lymphoma (rrPMBCL) or relapsed or<br />
refractory Richter syndrome (rrRS): Phase 2 KEYNOTE-170<br />
study<br />
J-M. Michot 1 , P. Armand 2 , W. Ding 3 , V. Ribrag 1 , B. Christian 4 , A. Balakumaran 5 ,<br />
P. Marinello 5 , S. Chlosta 5 , Y. Zhang 5 , M. Shipp 2 , P.L. Zinzani 6<br />
1 <strong>Oncology</strong>, Institut Gustave Roussy, Villejuif, France, 2 <strong>Oncology</strong>, Dana-Farber<br />
Cancer Institute, Boston, MA, USA, 3 <strong>Oncology</strong>, Mayo Clinic, Rochester, MN, USA,<br />
4 Internal Medicine, The Ohio State University, Columbus, OH, USA, 5 Medical<br />
<strong>Oncology</strong>, Merck & Co., Inc., Kenilworth, NJ, USA, 6 <strong>Oncology</strong>, Università di<br />
Bologna, Bologna, Italy<br />
Background: The PD-L1/PD-1 pathway may be an important mechanism <strong>of</strong> tumor<br />
immune escape in hematologic malignancies. In the multicohort, phase 1b<br />
KEYNOTE-013 study <strong>of</strong> pembrolizumab (pembro) in patients with hematologic<br />
malignancies, pembro was associated with a tolerable safety pr<strong>of</strong>ile and a promising<br />
objective response rate (ORR, 40% [4/10]) in patients with rrPMBCL. In the phase 2<br />
MC1485 study in patients with chronic lymphocytic leukemia (CLL) including RS,<br />
pembro showed promising preliminary efficacy (ORR, 43% [3/7]) in patients with rrRS.<br />
The open-label, multicenter, phase 2 KEYNOTE-170 study (NCT02576990) was<br />
designed to further evaluate the safety and efficacy <strong>of</strong> pembro in patients with<br />
rrPMBCL and rrRS.<br />
Trial design: Eligible patients must be aged ≥18 years and have either (1) diagnosis <strong>of</strong><br />
rrPMBCL according to WHO 2008 criteria, failed to achieve a complete response (CR)<br />
or relapsed after autologous stem-cell transplantation (auto-SCT), or are ineligible for<br />
auto-SCT and have failed to respond or relapsed after ≥2 lines <strong>of</strong> prior treatment; or<br />
(2) pathologic diagnosis per local institutional review <strong>of</strong> rrRS that transformed from<br />
underlying CLL, have received at ≥1 prior therapy for rrRS, and have relapsed or<br />
refractory disease. Patients are to receive pembro 200 mg intravenously every 3 weeks<br />
for up to 35 cycles or until disease progression or unacceptable toxicity. In patients<br />
with rrRS, additional standard therapies to treat the underlying CLL may be added at<br />
the physician’s discretion. Eligible patients who attain a CR as determined by the<br />
independent central imaging vendor may stop trial treatment and would be eligible for<br />
retreatment if they experience disease progression. Response is to be assessed every 12<br />
weeks by independent central imaging vendor review based on International Working<br />
Group (IWG) response criteria. The primary end point is ORR by independent central<br />
imaging vendor according to IWG response criteria or IWG response criteria with<br />
special considerations for RS; secondary end points include PFS, OS, and safety and<br />
tolerability. Enrollment will continue until ∼106 patients have been enrolled.<br />
Clinical trial identification: NCT02576990<br />
Legal entity responsible for the study: Merck & Co., Inc.<br />
Funding: Merck & Co., Inc.<br />
Disclosure: J-M. Michot: Advisory board member Bristol Myers Squibb. W. Ding:<br />
Corporate-sponsored research: Merck, research funding. A. Balakumaran, P. Marinello,<br />
S. Chlosta, Y. Zhang: Employee <strong>of</strong> Merck & Co, Inc. All other authors have declared no<br />
conflicts <strong>of</strong> interest.<br />
945TiP<br />
abstracts<br />
ZUMA-2: A phase 2 multi-center study evaluating the<br />
efficacy <strong>of</strong> KTE-C19 (Anti-CD19 CAR T cells) in patients with<br />
relapsed/refractory Mantle cell lymphoma (R/R MCL)<br />
M. Wang 1 , F.L. Locke 2 , T. Siddiqi 3 , J. Castro 4 , B. Shah 2 , H. Lee 1 , L.E. Budde 3 ,<br />
M. Choi 4 , C. Anasetti 2 , R. Champlin 1 , S. Forman 3 , T. Kipps 4 , A. Bot 5 , J.M. Rossi 5 ,<br />
L. Navale 5 , Y. Jiang 5 , J. Aycock 5 , M. Elias 5 , J. Wiezorek 5 , W.Y. Go 5<br />
1 Department <strong>of</strong> Lymphoma/Myeloma, The University <strong>of</strong> Texas MD Anderson<br />
Cancer Center, Houston, TX, USA, 2 Department <strong>of</strong> Blood and Marrow<br />
Transplantation, M<strong>of</strong>fitt Cancer Center, Tampa, FL, USA, 3 Department <strong>of</strong><br />
Hematology & Hematopoietic Cell Transplantation, City <strong>of</strong> Hope National Medical<br />
Center, Duarte, CA, USA, 4 Moores Cancer Center, University <strong>of</strong> California San<br />
Diego, La Jolla, CA, USA, 5 Kite Pharma, Santa Monica, CA, USA<br />
Background: R/R MCL is an aggressive, generally incurable, B cell malignancy,<br />
representing approximately 6% <strong>of</strong> non-Hodgkin lymphomas with an incidence rate <strong>of</strong><br />
0.45/100,000 in Europe (Sant et al, Blood 2010). An ongoing study at the National<br />
Cancer Institute (NCI) using anti-CD19 CAR T cells with CD28/CD3ζ signaling<br />
domains showed durable remissions in patients with R/R B cell malignancies, including<br />
MCL (Kochenderfer et al, J Clin Oncol 2015; NCT00924326). KTE-C19 is an<br />
autologous, anti-CD19 CAR T cell therapy that utilizes the construct investigated in the<br />
NCI study and manufactured in a streamlined 6- to 8-day process. Here, we describe a<br />
phase 2 study evaluating KTE-C19 in patients with R/R MCL.<br />
Trial design: We plan to enroll approximately 70 patients with R/R MCL for treatment<br />
with a fixed dose <strong>of</strong> 30 mg/m 2 /day fludarabine and 500 mg/m 2 /day cyclophosphamide<br />
conditioning chemotherapy followed by a single infusion <strong>of</strong> KTE-C19 at a target dose<br />
<strong>of</strong> 2 × 10 6 anti-CD19 CAR T cells/kg. Patients should have R/R disease with up to 5<br />
prior therapies, which must have included an anthracycline- or<br />
bendamustine-containing chemotherapy, anti-CD20 monoclonal antibody therapy,<br />
and ibrutinib. Additional inclusion criteria include age ≥18 years old, ECOG PS 0-1,<br />
and adequate marrow, renal, hepatic, and cardiac function. Patients with prior CAR T<br />
cell or other genetically modified T cell therapy, clinically significant infection, or<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw375 | vi325
abstracts<br />
current or history <strong>of</strong> central nervous system lymphoma or comorbidities are not<br />
allowed. The primary objective is to evaluate the safety and efficacy <strong>of</strong> KTE-C19, as<br />
measured by overall response rate (complete remission + partial remission). Key<br />
secondary objectives include describing duration <strong>of</strong> response, progression-free survival,<br />
overall survival, pharmacokinetics, pharmacodynamics, and predictive biomarker<br />
analyses. The study is planned at approximately 25 sites in the US and EU. Accrual<br />
began on November 9, 2015. Clinical trial information: NCT02601313.<br />
Clinical trial identification: NCT02601313<br />
Legal entity responsible for the study: Kite Pharma<br />
Funding: Kite Pharma<br />
Disclosure: M. Wang: Research funding from Kite Pharma. F.L. Locke: Scientific<br />
advisory board for Kite Pharma. T. Siddiqi: Speaker’s bureau for Pharmacyclics,<br />
Jannsen, and Seattle Genetics. B. Shah: Advisory board, speaker’s bureau, honorarium<br />
from Celgene; honorarium from Bayer, Baxalta, Plexus Communications; speaker’s<br />
bureau for Spectrum, Pharmacyclics; research funding from Rosetta Genomics;<br />
scientific advisory board for Acetilon, Pfizer. S. Forman: Patents with Mustang<br />
Therapeutics. T. Kipps: Consultancy, advisory, and research funding from AbbVie,<br />
Genentech, and Pharmacyclics. A. Bot, J.M. Rossi, L. Navale, Y. Jiang, J. Aycock,<br />
M. Elias, J. Wiezorek, W.Y. Go: Employment with Kite Pharma. All other authors have<br />
declared no conflicts <strong>of</strong> interest.<br />
946TiP<br />
A randomized comparative study <strong>of</strong> PF-05280586 (a potential<br />
biosimilar) vs rituximab for patients with CD20 + , low tumor<br />
burden, follicular lymphoma<br />
I. Jacobs 1 , M. Suster 2 , B. Jin 3 , D. Yin 4 , L.A. Melia 2<br />
1 Global Medical Affairs, Pfizer Inc., New York, NY, USA, 2 Biotechnology Clinical<br />
Development, Pfizer Inc, San Diego, CA, USA, 3 <strong>Oncology</strong>–Rinat R&D–Therapeutic<br />
Vaccines Development Statistics, Pfizer Inc., Cambridge, MA, USA, 4 Clinical<br />
Pharmacology, Pfizer Inc., San Diego, CA, USA<br />
Background: Use <strong>of</strong> single-agent rituximab may provide a useful alternative to<br />
watchful waiting by delaying the time to initiation <strong>of</strong> chemotherapy in patients with<br />
low tumor burden follicular lymphoma (LTB-FL). However, access to biologics like<br />
rituximab can be restricted. Biosimilars to rituximab represent a potential opportunity<br />
to increase patient access and lower treatment cost. PF-05280586, a proposed<br />
biosimilar to rituximab, has the same primary amino acid sequence, similar<br />
physicochemical and in vitro functional properties, and demonstrated similarity to<br />
rituximab in nonclinical evaluations and a pharmacokinetics (PK) similarity trial in<br />
patients with active rheumatoid arthritis. This confirmatory trial will evaluate efficacy,<br />
safety, and immunogenicity <strong>of</strong> PF-05280586 and rituximab sourced from the EU<br />
(rituximab-EU) in patients with treatment-naïve CD20 + , LTB-FL in a monotherapy<br />
setting, which allows assessment <strong>of</strong> biosimilarity without potentially confounding<br />
factors such as chemotherapy.<br />
Trial design: Patients (N = 394) will be stratified by risk level and randomized (1:1;<br />
double-blind) to 4 weekly doses <strong>of</strong> IV PF-05280586 or rituximab-EU (375 mg/m 2 <strong>of</strong><br />
body surface area). The primary endpoint is overall response rate at Wk 26. Secondary<br />
endpoints include safety, time to treatment failure, progression-free survival, complete<br />
remission rate at Wk 26, response duration, overall survival, PK, CD19+ B-cell<br />
depletion, and immunogenicity. Eligible patients are ≥18 yrs with histologically<br />
confirmed, Grade 1-3a, low tumor burden, CD20+ follicular lymphoma with no<br />
elements <strong>of</strong> diffuse large B-cell lymphoma; Ann Arbor Stage II, III or IV; and ECOG<br />
status <strong>of</strong> 0-1. Key exclusion criteria are: patients who are not candidates for rituximab<br />
monotherapy; evidence <strong>of</strong> histologic transformation to high-grade or diffuse large<br />
B-cell lymphoma; central nervous system, meningeal involvement or cord compression<br />
by the lymphoma; ≥5000/mm 3 circulating lymphoma cells; prior systemic therapy for<br />
lymphoma; prior treatment with rituximab; impaired bone marrow function;<br />
symptomatic ischemic heart disease or congestive heart failure; or active uncontrolled<br />
infection.<br />
Clinical trial identification: NCT02213263<br />
Legal entity responsible for the study: Pfizer Inc.<br />
Funding: Pfizer Inc.<br />
Disclosure: I. Jacobs, B. Jin, D. Yin, L.A. Melia: Full time employee <strong>of</strong> and stock<br />
holdings and/or stock options from Pfizer Inc. M. Suster: is a consultant for Pfizer Inc.<br />
947TiP<br />
Pembrolizumab versus brentuximab vedotin in relapsed or<br />
refractory classical Hodgkin lymphoma (cHL): randomized<br />
phase 3 KEYNOTE-204 study<br />
M.A. Fanale 1 , J. Kline 2 , R. Chen 3 , V. Ribrag 4 , G. Salles 5 , I. Matsumura 6 ,Y.Zhu 7 ,A.<br />
D. Ricart 7 , A. Balakumaran 7 , P.L. Zinzani 8<br />
1 Department <strong>of</strong> Medicine, The University <strong>of</strong> Texas MD Anderson Cancer Center,<br />
Houston, TX, USA, 2 Hematology/<strong>Oncology</strong>, University <strong>of</strong> Chicago, Chicago, IL,<br />
USA, 3 Hematology/<strong>Oncology</strong>, City <strong>of</strong> Hope National Medical Center, Duarte, CA,<br />
USA, 4 <strong>Oncology</strong>, Institut Gustave Roussy, Villejuif, France, 5 Hematology, Centre<br />
Hospitalier Lyon Sud, Pierre Bénite, France, 6 Internal Medicine, Kinki University,<br />
Osaka, Japan, 7 Medical <strong>Oncology</strong>, Merck & Co, Inc., Kenilworth, NJ, USA,<br />
8 Medicine, University <strong>of</strong> Bologna, Bologna, Italy<br />
Background: Patients with cHL who relapse after autologous stem-cell transplantation<br />
(auto-SCT) or are ineligible to proceed to transplantation have poor prognosis. The<br />
PD-1 ligands, PD-L1 and PD-L2, are frequently overexpressed in relapsed or refractory<br />
(R/R) cHL, and this is typically associated with chromosome 9p24.1 amplification. In<br />
the phase 1b KEYNOTE-013 study, PD-1 blockade with pembrolizumab (pembro)<br />
demonstrated an objective response rate (ORR) <strong>of</strong> 65% in heavily pretreated patients<br />
with cHL. KEYNOTE-204 (NCT02684292) is a randomized, international, open-label<br />
phase 3 study designed to compare the efficacy and safety <strong>of</strong> pembro vs brentuximab<br />
vedotin (BV) in patients with R/R cHL.<br />
Trial design: This study will enroll patients age ≥18 years with R/R cHL who (1) have<br />
failed to achieve a response or progressed after auto-SCT and have not received prior<br />
BV; or (2) are not auto-SCT candidates because <strong>of</strong> chemo-resistant disease (unable to<br />
achieve complete or partial remission to salvage chemotherapy), advanced age, or<br />
comorbidities, and have received ≥2 prior multi-agent chemotherapy regimens that did<br />
not include BV. ∼300 patients will be randomized 1:1 to receive either pembro 200 mg<br />
Q3W or BV 1.8 mg/kg Q3W for up to 35 cycles or until documented disease<br />
progression, unacceptable toxicity, or investigator decision. Response will be assessed<br />
every 12 weeks by PET/CT scans per Revised Response Criteria for Malignant<br />
Lymphoma from the International Working Group (IWG) by central imaging vendor<br />
review. Primary end points are PFS and OS; secondary end points are ORR and<br />
complete remission rate. The primary assessment <strong>of</strong> efficacy end points will be based<br />
on blinded independent central review according to the IWG criteria; secondary/<br />
exploratory analyses <strong>of</strong> efficacy end points will be conducted using investigator<br />
assessment. Exploratory end points include PK pr<strong>of</strong>ile, duration <strong>of</strong> response, and<br />
comparison <strong>of</strong> ORR in patients with PD-L1–positive versus PD-L1–negative lymphoid<br />
tumors. Enrollment to KEYNOTE-204 is ongoing.<br />
Clinical trial identification: NCT02684292<br />
Legal entity responsible for the study: Merck & Co., Inc.<br />
Funding: Merck & Co., Inc.<br />
Disclosure: Y. Zhu, A.D. Ricart, A. Balakumaran: Employee and stock ownership at<br />
Merck & Co, Inc. All other authors have declared no conflicts <strong>of</strong> interest.<br />
948TiP<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Phase 3 study <strong>of</strong> quizartinib (AC220) monotherapy vs salvage<br />
chemotherapy (SC) in patients (pts) with FLT3-ITD+ acute<br />
myeloid leukemia (AML) refractory to or relapsed (R/R) after<br />
1st-line treatment with or without hematopoietic stem cell<br />
transplant (HSCT) consolidation: the QuANTUM-R study<br />
J. Cortes 1 , G. Gammon 2 , S. Khaled 3 , G. Martinelli 4 , A. Kramer 5 , B. Steffen 6 ,<br />
D. Hogge 7 , B.A. Jonas 8 , H. Dombret 9 , A. Perl 10<br />
1 Department <strong>of</strong> Leukemia, Division <strong>of</strong> Cancer Medicine, MD Anderson Cancer<br />
Center, Houston, TX, USA, 2 Clinical Development, Daiichi Sankyo, Inc., San Diego,<br />
CA, USA, 3 Hematology & Hematopoietic Cell Transplantation, City <strong>of</strong> Hope,<br />
Duarte, CA, USA, 4 Specialised, Experimental, and Diagnostic Medicine, Università<br />
di Bologna, Bologna, Italy, 5 Molecular Hematology/<strong>Oncology</strong>, University <strong>of</strong><br />
Heidelberg, Heidelberg, Germany, 6 Department <strong>of</strong> Medicine II, Hematology/<br />
<strong>Oncology</strong>, Universitätsklinikum Frankfurt (Johannes-Wolfgang Goethe Institute),<br />
Frankfurt am Main, Germany, 7 Terry Fox Laboratory, Vancouver General Hospital &<br />
HSC, British Columbia University, Vancouver, BC, Canada, 8 Hematology and<br />
<strong>Oncology</strong>, University <strong>of</strong> California Davis Cancer Center, Sacramento, CA, USA,<br />
9 Hematology, University Paris Diderot, Paris, France, 10 Medicine, University <strong>of</strong><br />
Pennsylvania-Perelman Center for Advanced Medicine, Philadelphia, PA, USA<br />
Background: Approximately 25% <strong>of</strong> pts with AML have FLT3-internal tandem<br />
duplications (ITD) mutations, which are key oncogenic drivers <strong>of</strong> the disease.<br />
FLT3-ITD–positive AML is associated with poorer prognosis, decreased response to<br />
salvage therapy, increased risk <strong>of</strong> relapse, and shorter survival than FLT3-ITD–negative<br />
disease. Currently, there are no approved therapies targeting FLT3-ITD mutations, and<br />
improved therapeutic options are needed in this setting. Quizartinib is an oral, highly<br />
potent, and selective inhibitor that targets FLT3-ITD mutations. Previous studies <strong>of</strong><br />
quizartinib monotherapy have reported composite complete response rates up<br />
to ≈ 46% in pts with R/R FLT3-ITD AML (Cortes JE, J Clin Oncol. 2013;31:3681-3687;<br />
Levis M, ASCO 2014 [abstract 7093]). Here, we describe QuANTUM-R, a multicenter,<br />
open-label, randomized phase 3 study (NCT02039726) to determine the efficacy <strong>of</strong><br />
quizartinib in pts with FLT3-ITD–positive AML who are R/R within 6 months after<br />
first-line therapy.<br />
vi326 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Trial design: Eligible pts include adults aged ≥ 18 years with FLT3-ITD–positive AML<br />
in first relapse or refractory to prior therapy, with or without HSCT. Pts with prior<br />
exposure to quizartinib or other targeted FLT3-ITD inhibitors are excluded from this<br />
study. Approximately 326 pts will be randomized 2:1 to receive quizartinib or SC<br />
selected for each pt by the investigator prior to randomization. Options for SC<br />
regimens include mitoxantrone, etoposide, and intermediate-dose cytarabine (MEC);<br />
or fludarabine, cytarabine, and granulocyte colony stimulating factor with idarubicin<br />
(FLAG-IDA); or low-dose cytarabine (LoDAC). Quizartinib will be administered until<br />
lack <strong>of</strong> benefit or HSCT. The primary objective <strong>of</strong> this study is to determine whether<br />
quizartinib prolongs overall survival compared with SC in pts with R/R FLT3-ITD–<br />
positive AML. The secondary objective is to determine event-free survival with<br />
quizartinib vs SC. This study is currently recruiting pts.<br />
Clinical trial identification: NCT02039726<br />
Legal entity responsible for the study: Daiichi Sankyo, Inc.<br />
Funding: Daiichi Sankyo, Inc.<br />
abstracts<br />
Disclosure: J. Cortes: Consulting/Advisory Role with ARIAD, Ambit Pharmaceuticals,<br />
Astellas and Novartis. Research funding received from ARIAD, Ambit, Astells, Arog,<br />
Flexus and Novartis. G. Gammon: Employee <strong>of</strong> Daiichi Sankyo. S. Khaled:<br />
Honorarium, consulting/advisory role, speakers’ bureau, travel, accommodations,<br />
expenses with Alexion; Research funding received from Ambit, MEI, San<strong>of</strong>i, Omeros.<br />
G. Martinelli: Consulting or Advisory Role with ARIAD, Amgen, Pfizer, and Roche;<br />
Speakers’ Bureau with Novartis and BMS. A. Kramer: Honoraria received from Teva,<br />
Consulting/Advisory Role with Neo<strong>Oncology</strong>, Research funding received from Bayer,<br />
Merck Serono, Travel, Accomodations, Expenses recieved from Teva. B. Steffen: Travel,<br />
accommodations, expenses received from Novartis, GSK, Astellas. D. Hogge:<br />
Consulting or advisory role with San<strong>of</strong>i; Travel, accommodations, expenses from<br />
Roche. B.A. Jonas: Consulting – Rigel Honorarium/Speaking – Celgene Research<br />
Funding – Pharmacyclics. H. Dombret: Honoraria received from Abmit and Daiichi<br />
Sankyo, Consulting/Advisory Role with Ambit and Daiichi Sankyo. A. Perl: Consulting<br />
fees recieved from, Daiichi Sankyo, Astellas Pharmaceuticals, Seattle Genetics, Asana<br />
Biosciences, and Actinium Pharmaceuticals.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw375 | vi327
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong> 27 (Supplement 6): vi328–vi350, 2016<br />
doi:10.1093/annonc/mdw376<br />
head and neck cancer<br />
949O<br />
Updated safety and efficacy <strong>of</strong> durvalumab (MEDI4736), an<br />
anti-PD-L 1 antibody, in patients from a squamous cell<br />
carcinoma <strong>of</strong> the head and neck (SCCHN) expansion cohort<br />
abstracts<br />
N.H. Segal 1 , S-H.I. Ou 2 , A.S. Balmanoukian 3 , E. Massarelli 4 , J.R. Brahmer 5 ,<br />
J. Weiss 6 , P. Sch<strong>of</strong>fski 7 , S.J. Antonia 8 , C. Massard 9 , D.P. Zandberg 10 , C. Maher 1 ,<br />
S. Khleif 11 , X. Jin 12 , M. Rebelatto 13 , K. Steele 13 , J. Antal 14 , A. Gupta 14 ,<br />
A. Spreafico 15<br />
1 Department <strong>of</strong> Medicine, Memorial Sloan Kettering Cancer Center, New York, NY,<br />
USA, 2 Department <strong>of</strong> Medicine, Division <strong>of</strong> Hematology/<strong>Oncology</strong>, UC Irvine<br />
School <strong>of</strong> Medicine, Irvine, CA, USA, 3 Medical <strong>Oncology</strong>, The Angeles Clinic and<br />
Research Institute, Los Angeles, CA, USA, 4 Department <strong>of</strong> Thoracic and Head/<br />
Neck Medical <strong>Oncology</strong>, The University <strong>of</strong> Texas MD Anderson Cancer Center,<br />
Houston, TX, USA, 5 Department <strong>of</strong> <strong>Oncology</strong>, The Sidney Kimmel Comprehensive<br />
Cancer Center at Johns Hopkins, Baltimore, MD, USA, 6 Division <strong>of</strong> Hematology<br />
and <strong>Oncology</strong>, Lineberger Comprehensive Cancer Center, University <strong>of</strong> North<br />
Carolina, Chapel Hill, NC, USA, 7 Department <strong>of</strong> General Medicine <strong>Oncology</strong>,<br />
University Hospitals Leuven, Leuven, Belgium, 8 Department <strong>of</strong> Thoracic <strong>Oncology</strong>,<br />
M<strong>of</strong>fitt Cancer Center, Tampa, FL, USA, 9 Drug Development Department, Institut<br />
Gustave Roussy, Villejuif, France, 10 Medical <strong>Oncology</strong>, University <strong>of</strong> Maryland<br />
Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD, USA,<br />
11 Immune Therapy Program and Experimental Therapeutics, Georgia Regents<br />
University Cancer Center, Augusta, GA, USA, 12 Biostatistics, Medlmmune,<br />
Gaithersburg, MD, USA, 13 Pathology, Medlmmune, Gaithersburg, MD, USA,<br />
14 Clinical Development, Medlmmune, Gaithersburg, MD, USA, 15 Division <strong>of</strong><br />
Medicine Department <strong>of</strong> Medical <strong>Oncology</strong> and Hematology Drug Development<br />
Program, Princess Margaret Cancer Centre, Toronto, ON, Canada<br />
950O<br />
Meta-analysis <strong>of</strong> chemotherapy in head and neck cancer<br />
(MACH-NC): An update on 100 randomized trials and 19,248<br />
patients, on behalf <strong>of</strong> MACH-NC group<br />
P. Blanchard 1 , C. Landais 2 , C. Petit 2 , Q. Zhang 3 , V. Grégoire 4 , J. Tobias 5 ,<br />
B. Burtness 6 , M.G. Ghi 7 , F. Janot 8 , J. Overgaard 9 , G. Wolf 10 , F. Lewin 11 , R. Hitt 12 ,<br />
R. Corvo 13 ,V.Budach 14 , A. Trotti 15 , C. Fortpied 16 , A. Hackshaw 17 , J. Bourhis 18 ,<br />
J-P. Pignon 19<br />
1 Radiation Therapy, Gustave Roussy Cancer Campus, Villejuif, France,<br />
2 Biostatistics, Institut Gustave Roussy, Villejuif, France, 3 Statistics and Data<br />
Management Center, NRG <strong>Oncology</strong>, Philadelphia, PA, USA, 4 Radiation<br />
<strong>Oncology</strong>, Cliniques Universitaires St. Luc, Brussels, Belgium, 5 Radiation<br />
<strong>Oncology</strong>, University College London Hospital UCLH NHS Foundation Trust,<br />
London, UK, 6 Medical <strong>Oncology</strong>, Yale University School <strong>of</strong> Medicine Medical<br />
<strong>Oncology</strong>, New Haven, CT, USA, 7 Medical <strong>Oncology</strong>, Ospedale dell’Angelo e<br />
Ospedale SS Giovanni e Paolo, Venezia, Italy, 8 Head and Neck Surgery, Institut<br />
Gustave Roussy, Villejuif, France, 9 Radiation <strong>Oncology</strong>, Aarhus University Hospital,<br />
Aarhus, Denmark, 10 Head and Neck Surgery, University <strong>of</strong> Michigan, Ann Arbor,<br />
MI, USA, 11 Radiation <strong>Oncology</strong>, County Hospital Ryhov, Jönköping, Sweden,<br />
12 Medical <strong>Oncology</strong>, Hospital Universitario Severo Ochoa, Madrid, Spain,<br />
13 Radiation <strong>Oncology</strong>, IRCCS AOU San Martino - IST-Istituto Nazionale per la<br />
Ricerca sul Cancro, Genoa, Italy, 14 Radiation <strong>Oncology</strong>, Charité, Campus Virchow<br />
Klinikum, Berlin, Germany, 15 Radiation <strong>Oncology</strong>, H. Lee M<strong>of</strong>fitt Cancer Center<br />
University <strong>of</strong> South Florida, Tampa, FL, USA, 16 Biostatistics, EORTC<br />
Headquarters, Brussels, Belgium, 17 Clinical Trials, Cancer Research UK &<br />
University College London Cancer Trials Centre, London, UK, 18 <strong>Oncology</strong>, Centre<br />
Hospitalier Universitaire Vaudois - CHUV, Lausanne, Switzerland, 19 Service de<br />
Biostatistique et d’Epidemiologie, CESP, Inserm U1018, Univ. Paris Sud, Univ.<br />
Paris-Saclay, Ligue contre le Cancer, Gustave Roussy Cancer Campus, Villejuif,<br />
France<br />
© European Society for Medical <strong>Oncology</strong> 2016. Published by Oxford University Press on behalf <strong>of</strong> the European Society for Medical <strong>Oncology</strong>.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com.
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
954O<br />
Comprehensive genomic pr<strong>of</strong>iles <strong>of</strong> metastatic and relapsed<br />
salivary gland carcinomas are associated with tumor type and<br />
reveal new routes to targeted therapies<br />
951O<br />
Surrogate endpoints for overall survival in loco-regionally<br />
advanced nasopharyngeal carcinoma: Results from the<br />
individual patient data meta-analysis MAC-NPC2<br />
F. Rotolo 1 , J-P. Pignon 1 , S. Marguet 2 ,J.Ma 3 , A.T.C. Chan 4 , P-Y. Huang 3 , G. Zhu 5 ,<br />
D.T. Chua 6 , Y. Chen 3 , H-Q. Mai 3 , D.W. Kwong 7 , Y.L. Soong 8 , J. Moon 9 ,Y.Tung 10 ,<br />
K-H. Chi 11 , G. Fountzilas 12 , L. Zhang 3 , A. Lee 13 , P. Blanchard 14 , S. Michiels 1<br />
1 Service de Biostatistique et d’Epidemiologie, CESP, Inserm U1018, Univ. Paris<br />
Sud, Univ. Paris-Saclay, Ligue contre le Cancer, Gustave Roussy Cancer Campus,<br />
Villejuif, France, 2 Service de Biostatistique et d’Epidemiologie, Gustave Roussy<br />
Cancer Campus, Villejuif, France, 3 State Key Laboratory <strong>of</strong> <strong>Oncology</strong> in South<br />
China, Sun Yat-sen University Cancer Center, Guangzhou, China, 4 Sir YK Pao<br />
Centre for Cancer, The Chinese University <strong>of</strong> Hong Kong, Hong Kong, China,<br />
5 Shanghai Ninth People’s Hospital, Shanghai Jiaotong Univerisity School <strong>of</strong><br />
Medicine, Shanghai, China, 6 Department <strong>of</strong> Radiotherapy, Hong Kong Sanatorium<br />
& Hospital, Hong Kong, China, 7 Department <strong>of</strong> Clinical <strong>Oncology</strong>, Queen Mary<br />
Hospital, Hong Kong, China, 8 Division <strong>of</strong> Radiation <strong>Oncology</strong>, National Cancer<br />
Center, Singapore, 9 SWOG Statistical Center, Fred Hutchinson Cancer Research<br />
Center, Seattle, WA, USA, 10 Department <strong>of</strong> Clinical <strong>Oncology</strong>, Tuen Mun Hospital,<br />
Hong Kong, China, 11 Department <strong>of</strong> Radiation Therapy and <strong>Oncology</strong>, Shin Kong<br />
Wu Ho-Su Memorial Hospital, Taipei, Taiwan, 12 Medical <strong>Oncology</strong> Clinic,<br />
Papageorgiou Hospital Aristotle University <strong>of</strong> Thessaloniki, Thessaloniki, Greece,<br />
13 Department <strong>of</strong> Clinical <strong>Oncology</strong>, Pamela Youde Nethersole Eastern Hospital,<br />
Hong Kong, China, 14 Department <strong>of</strong> Radiation Therapy, Gustave Roussy Cancer<br />
Campus, Villejuif, France<br />
L.M. Gay 1 , J.S. Ross 2 , K. Wang 3 , J-A. Vergilio 1 , J. Suh 1 , S. Ramkissoon 1 ,<br />
D. Bowles 4 , H. Serracino 4 , J. Russell 5 , S. Ali 6 , V. Miller 6 , P. Stephens 7 , J.A. Elvin 1<br />
1 Pathology, Foundation Medicine, Inc., Cambridge, MA, USA, 2 Pathology, Albany<br />
Medical Center, Albany, NY, USA, 3 Genetics, Zhejiang Cancer Hospital,<br />
Hangzhou, China, 4 Division <strong>of</strong> Medical <strong>Oncology</strong>, University <strong>of</strong> Colorado Denver,<br />
Denver, CO, USA, 5 Medical <strong>Oncology</strong>, M<strong>of</strong>fitt Cancer Center, Tampa, FL, USA,<br />
6 Clinical Development, Foundation Medicine, Inc., Cambridge, MA, USA, 7 Clinical<br />
Genomics, Foundation Medicine, Inc., Cambridge, MA, USA<br />
952PD<br />
PET-CT surveillance for advanced head and neck cancer:<br />
a cost-effective alternative to planned neck dissection?<br />
A.F. Smith 1 , P.S. Hall 2 , C. Hulme 1 , C. McConkey 3 , J.A. Dunn 3 , J. Rahman 3 ,<br />
H. Mehanna 4<br />
1 Academic Unit <strong>of</strong> Health Economics, University <strong>of</strong> Leeds-Institute <strong>of</strong> Health<br />
Sciences, Leeds, UK, 2 Cancer Research Centre, Edinburgh Cancer Centre<br />
Western General Hospital, Edinburgh, UK, 3 Clinical Trials Unit, University <strong>of</strong><br />
Warwick, Coventry, UK, 4 Institute <strong>of</strong> Head and Neck Studies and Education, The<br />
University <strong>of</strong> Birmingham Institute for Cancer Studies, Birmingham, UK<br />
Background: Despite controversy, planned neck dissection (ND) remains standard<br />
treatment for patients with locally advanced head and neck squamous cell carcinoma<br />
after radical chemo-radiotherapy. FDG-PET-CT scanning has demonstrated high<br />
negative predictive values for persistent disease, and could thereby enable low risk<br />
patients to be spared from unnecessary surgery. Evidence <strong>of</strong> the cost-effectiveness <strong>of</strong><br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw376 | vi329
abstracts<br />
PET-CT surveillance strategies is limited however, and no evaluations have yet been<br />
conducted from a UK perspective.<br />
Methods: An economic evaluation was conducted to assess the lifetime<br />
cost-effectiveness <strong>of</strong> PET-CT surveillance versus planned ND from a UK secondary<br />
care perspective. Cost and health outcomes associated with the initial 6-month<br />
treatment period (CRT +/- ND) were derived from individual data on 564 patients<br />
from a recent UK multicentre randomised controlled trial (PET-Neck). Subsequent<br />
outcomes were derived using a constructed Markov model to track patients through<br />
four health states: disease-free, local recurrence, distant recurrence and dead. Model<br />
inputs were derived from trial data and literature sources.<br />
Results: PET-CT surveillance results in a lifetime cost saving <strong>of</strong> -£1,485 (95% CI:<br />
-2,815 to 159) and health gain <strong>of</strong> +0.13 (95% CI: -0.49 to +0.79) quality-adjusted<br />
life-years (QALYs) per patient. The intervention therefore dominates standard care,<br />
being more effective and less costly, with an incremental net benefit (INB) <strong>of</strong> +0.21<br />
QALYs (95% CI: -0.41 to +0.85). At a willingness-to-pay per QALY threshold <strong>of</strong><br />
£20,000, PET-CT is associated with a 75% probability <strong>of</strong> being cost-effective, dropping<br />
to 68% at a £100,000/QALY threshold. The intervention remained cost-effective when<br />
considering a broader NHS and personal social services perspective; however,<br />
uncertainty around the mean cost-effectiveness values was wide.<br />
Conclusions: PET-CT surveillance appears to be cost-effective, leading to expected<br />
lifetime cost savings and a marginal health increment. There is significant uncertainty<br />
in the longer term which may warrant additional survivor-ship research.<br />
Clinical trial identification: ISRCTN 13735240<br />
Legal entity responsible for the study: Warwick Medical School.<br />
Funding: National Institute for Health Research (NIHR) Health Technology<br />
Assessment (HTA) Programme (project number 06/302/129).<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
953PD<br />
Final overall survival analysis <strong>of</strong> patients with locally<br />
advanced or metastatic radioactive iodine-refractory<br />
differentiated thyroid cancer (RAI-rDTC) treated with<br />
sorafenib in the phase 3 DECISION trial: An exploratory<br />
crossover adjustment analyses<br />
M. Brose 1 , B. Jarzab 2 , R. Elisei 3 , L. Giannetta 4 , L. Bastholt 5 ,C.de<br />
la Fouchardiere 6 , F. Pacini 7 , R. Paschke 8 , C. Nutting 9 , Y.K. Shong 10 ,<br />
S. Sherman 11 , J. Smit 12 , J. Chung 13 , G. Meinhardt 14 , M. Schlumberger 15 ,<br />
C. Kappeler 16<br />
1 Department <strong>of</strong> Otorhinolaryngology, Abramson Cancer Center, University <strong>of</strong><br />
Pennsylvania, Perelman School <strong>of</strong> Medicine, Philadelphia, PA, USA, 2 Department<br />
<strong>of</strong> Nuclear Medicine and Endocrine <strong>Oncology</strong>, Maria Sklodowska Curie MSC<br />
Memorial Cancer Institute in Gliwice, Gliwice, Poland, 3 Endocrine Unit,<br />
Department <strong>of</strong> Clinical and Experimental Medicine, University <strong>of</strong> Pisa, Pisa, Italy,<br />
4 Division <strong>of</strong> Medical <strong>Oncology</strong>, Dirigente Medico, S. C. Oncologia Falck, Milan,<br />
Italy, 5 <strong>Oncology</strong>, Odense University Hospital, Odense, Denmark, 6 Medical<br />
<strong>Oncology</strong> Department, Consortium Cancer Throidien, Hispices Civils-Center<br />
Anticancereux, Lyon, France, 7 Unit <strong>of</strong> Endocrinology, University <strong>of</strong> Siena, Siena,<br />
Italy, 8 Department <strong>of</strong> Endocrinology and Nephrology, University <strong>of</strong> Leipzig, Leipzig,<br />
Germany, 9 Clinical <strong>Oncology</strong>, Royal Marsden Hospital and The Institute <strong>of</strong> Cancer<br />
Research, London, UK, 10 Division <strong>of</strong> Endocrinology, Asian Medical Center, Seoul,<br />
Republic <strong>of</strong> Korea, 11 Endocrine Neoplasia and Hormonal Disorders, Division <strong>of</strong><br />
Internal Medicine, The University <strong>of</strong> Texas MD Anderson Cancer Center, Houston,<br />
TX, USA, 12 Internal Medicine, Radboud University Medical Centre Nijmegen,<br />
Nijmegen, Netherlands, 13 Study Medical Experts- <strong>Oncology</strong>, Bayer Healthcare<br />
Pharmaceuticals, Whippany, NJ, USA, 14 Global Clinical Development <strong>Oncology</strong>,<br />
Bayer Healthcare Pharmaceuticals, Whippany, NJ, USA, 15 Nuclear Medicine and<br />
Endocrinology, Institut Gustave Roussy, Villejuif, France, 16 Clinical Statistics<br />
Europe, Bayer Pharma AG, Berlin, Germany<br />
Background: The phase 3 DECISION trial (NCT00895674) met its primary endpoint<br />
<strong>of</strong> progression-free survival for patients with RAI-rDTC and showed a significant PFS<br />
prolongation in favor <strong>of</strong> sorafenib (SOR) vs placebo (PBO) (HR 0.587; p < 0.0001).<br />
Overall survival (OS) was immature at the time <strong>of</strong> primary analysis in Aug 2012. We<br />
report OS results from 9- and 36-months follow up with exploratory crossover<br />
adjustment analyses.<br />
Methods: Patients were randomized to SOR or PBO. PBO patients were allowed to<br />
receive SOR open-label (OL) upon progression. OS data were analyzed using 2<br />
adjustment methods for crossover: iterative parameter estimation (IPE) and rank<br />
preserving structural failure time (RPSFT). For all analyses CIs were calculated with the<br />
Cox model and with bootstrapping to include additional variance originating from the<br />
crossover adjustment.<br />
Results: A total <strong>of</strong> 417 patients were randomized (207 SOR; 210 PBO). After<br />
progression, 158 <strong>of</strong> 210 patients (75%) crossed over to SOR. Hazard ratios (HRs) and<br />
95% confidence intervals (CI) at the 3 data cut<strong>of</strong>fs are shown in the table. Although not<br />
significant, a consistent separation <strong>of</strong> the KM curves in favor <strong>of</strong> SOR was seen. OS<br />
crossover adjustment results showed larger treatment effects than ITT (ITT: 0.80-0.88;<br />
IPE : 0.70-0.80; RPSFT: 0.61-0.77).<br />
Conclusions: Due to the increasing effect <strong>of</strong> SOR in PBO patients over time, the<br />
separation between the 2 KM curves became smaller. Although significance was not<br />
reached in ITT, a trend in OS prolongation favoring SOR was observed consistently<br />
over successive time points. OS crossover adjustment results suggest that the true OS<br />
treatment effect may be larger than seen in the ITT analysis. The IPE method appears<br />
to produce more stable adjusted HRs across the 3 time points than RPSFT. These<br />
results should be considered as exploratory.<br />
Table: 953PD<br />
Database HR (Cox model 95% CI) (bootstrapping 95% CI )<br />
cut<strong>of</strong>f<br />
ITT* IPE RPSFT<br />
2012 Aug 0.80 (0.54–1.19)<br />
(0.53, 1.18)<br />
0.70 (0.47–1.04)<br />
(0.40, 1.38)<br />
0.61 (0.40–0.94)<br />
(0.18, 2.16)<br />
2013 May 0.88 (0.63–1.24)<br />
(0.63, 1.25)<br />
0.79 (0.57–1.11)<br />
(0.46, 1.61)<br />
0.69 (0.49–0.99)<br />
(0.33, 1.65)<br />
2015 Jul 0.92 (0.71–1.21)<br />
(0.71, 1.21)<br />
0.80 (0.61–1.05)<br />
(0.48, 1.71)<br />
0.77 (0.58–1.02)<br />
(0.42, 1.79)<br />
*Unadjusted for treatment switch<br />
Clinical trial identification: NCT 00895674<br />
Legal entity responsible for the study: N/A<br />
Funding: Bayer Healthcare Pharmaceuticals<br />
Disclosure: M. Brose: Received consultancy fees/honorarium and research support<br />
from Bayer HealthCare Pharmaceuticals; consultancy fees and research support from<br />
Exelixis; consultancy fees from Onyx Pharmaceuticals; and research support from<br />
Eisai, Novartis, & Roche/Genentech. B. Jarzab: Received honorarium and research<br />
support from Bayer Healthcare Pharmaceuticals; consultancy fees/honorarium from<br />
AstraZeneca and Sobi; and honorarium from Eisai, Ipsen, Novartis, OxiGene, Pfizer,<br />
Roche, and San<strong>of</strong>i. R. Elisei: Consultancy fees/honorarium and research support from<br />
Bayer Healthcare Pharmaceuticals; and consultancy fees/honorarium from<br />
AstraZeneca and Genzyme. L. Bastholt: Consultancy fees and research support from<br />
Bayer Healthcare Pharmaceuticals; and consultancy fees from AstraZeneca. C. de la<br />
Fouchardiere: Consultancy fees/honorarium and research support from Bayer<br />
Healthcare Pharmaceuticals; consultancy feels from AstraZeneca, San<strong>of</strong>i-Aventis, and<br />
Sobi; and a grant from Roche. F. Pacini: Honorarium and research support from Bayer<br />
Healthcare Pharmaceuticals. R. Paschke: Research support from Bayer Healthcare<br />
Pharmaceuticals. S. Sherman: Research support from Bayer Healthcare<br />
Pharmaceuticals, Genzyme, and Pfizer; consultancy fees/honorarium and research<br />
support from Amgen; consultancy fees/honorarium from AstraZeneca, Eisai, Exelixis,<br />
Lilly, NovoNordisk, Veracyte, Onyx, and Roche. J. Smit: Member <strong>of</strong> the DECISION<br />
steering committee and has received honorarium and research support from Bayer<br />
Healthcare Pharmaceuticals. J. Chung, G. Meinhardt: Employee <strong>of</strong> Bayer Healthcare<br />
Pharmaceuticals. M. Schlumberger: Received consultancy fees and research support<br />
from Bayer Healthcare. Pharmaceuticals and Eisai; consultancy fees/honorarium and<br />
research support from AstraZeneca and Genzyme-San<strong>of</strong>i; consultancy fees from<br />
Exelixis; and consultancy fees/honorarium from Sobi. C. Kappeler: Employee <strong>of</strong> Bayer<br />
Pharma AG. All other authors have declared no conflicts <strong>of</strong> interest.<br />
955PD<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
A comparative study <strong>of</strong> PD-L1 diagnostic assays in squamous<br />
cell carcinoma <strong>of</strong> the head and neck (SCCHN)<br />
M.J. Ratcliffe 1 , A. Sharpe 2 , M. Rebelatto 3 , M. Scott 1 , C. Barker 2 , P. Scorer 2 ,<br />
J. Walker 2<br />
1 Personalised Healthcare and Biomarkers, AstraZeneca, Alderley Park,<br />
Macclesfield, UK, 2 Personalised Healthcare and Biomarkers, AstraZeneca,<br />
Cambridge, UK, 3 Translational Medicine, MedImmune, Gaithersburg, MD, USA<br />
Background: PD-1/PD-L1 directed antibodies are emerging as effective therapeutics in<br />
multiple oncology settings. In the SCCHN Checkmate 141 study, improved efficacy<br />
with nivolumab, a PD-1 targeted therapy, was observed in pts with tumour PD-L1<br />
expression ≥1% vs pts with PD-L1 expression below this cut <strong>of</strong>f. Multiple diagnostic<br />
PD-L1 tests are available using different antibody clones, different staining protocols<br />
and different cut <strong>of</strong>fs. A better understanding <strong>of</strong> the technical performance <strong>of</strong> these<br />
assays will allow appropriate interpretation <strong>of</strong> clinical outcomes with different drugs.<br />
Methods: 108 tumour biopsy samples from stage I–IV SCCHN pts, obtained from a<br />
commercial source and including HPV positive and HPV negative, were assessed using<br />
3 PD-L1 diagnostic assays: the Ventana SP263 assay currently being used in<br />
durvalumab (anti-PD-L1) clinical trials, the Dako 28-8 and Dako 22C3 assays,<br />
commonly used in nivolumab (Opdivo®) and pembrolizumab (Keytruda®) trials,<br />
respectively. Assays were performed in an accredited laboratory, following the device<br />
protocol. Concordance between tumour membrane staining was assessed across a<br />
range <strong>of</strong> clinically relevant cut <strong>of</strong>fs, including ≥1%, ≥10% and ≥25%. Lower 95% CI<br />
were calculated using the Clopper-Pearson method.<br />
Results: Data indicated strong association, with a Spearman correlation coefficient <strong>of</strong><br />
≥0.9 for each pairwise comparison. Overall percent agreement (OPA) <strong>of</strong> >90% was<br />
seen between the three assays across multiple clinically relevant cut points. Assessment<br />
vi330 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
<strong>of</strong> a further 392 samples is ongoing to complement the current data set with a larger<br />
dynamic range <strong>of</strong> PD-L1 expression.<br />
Table: 955PD<br />
Ventana SP263 vs Dako<br />
28-8<br />
Dako 22C3 vs Dako 28-8<br />
Assay cut <strong>of</strong>f OPA (%) Lower 95% CI OPA (%) Lower 95% CI<br />
≥1% 91.7 85.9 96.3 91.7<br />
≥10% 92.6 87.0 95.4 90.5<br />
≥25% 94.4 89.3 97.2 93.0<br />
Conclusions: This study indicates that the SCCHN patient population defined by<br />
Ventana SP263, Dako 28-8 and Dako 22C3 assays is similar where an identical cut<br />
point is used. The findings align with those <strong>of</strong> a similar study in NSCLC, and build<br />
optimism that it may be possible to compare studies using different PD-L1 tests and<br />
deliver harmonization <strong>of</strong> PD-L1 diagnostic testing.<br />
Legal entity responsible for the study: AstraZeneca PLC<br />
Funding: AstraZeneca<br />
Disclosure: M.J. Ratcliffe, A. Sharpe, M. Scott, C. Barker, P. Scorer, J. Walker:<br />
AstraZeneca employee and holds stocks/shares. M. Rebelatto: Employee <strong>of</strong><br />
MedImmune LLC and hold stocks or shares in AstraZeneca.<br />
956PD<br />
Development <strong>of</strong> a predictive radiomics signature for<br />
response to immune checkpoint inhibitors (ICIs) in patients<br />
with recurrent or metastatic squamous cell carcinoma <strong>of</strong> the<br />
head and neck (RM-SCCHN)<br />
A. Prawira 1 , P. Dufort 2 , J. Halankar 2 , D.M. Paravasthu 2 , A. Hansen 1 , A. Spreafico 1 ,<br />
A.R. Abdul Razak 1 , E. Chen 1 , R.W. Jang 1 , U. Metser 2 , L.L. Siu 1<br />
1 Department <strong>of</strong> Medical <strong>Oncology</strong> and Hematology, Princess Margaret Hospital,<br />
Toronto, ON, Canada, 2 Joint Department <strong>of</strong> Medical Imaging, University Health<br />
Network, Toronto, ON, Canada<br />
Background: Early phase clinical trials <strong>of</strong> ICIs in RM-SCCHN have shown promising<br />
results, but there is no validated predictive marker <strong>of</strong> response to date. We hypothesize<br />
that baseline host immune recognition creates a distinct microenvironment that is<br />
captured in computed tomography (CT)-images. Radiomics uses advanced image<br />
processing techniques to extract a large set <strong>of</strong> quantitative texture and geometric<br />
features from tumor regions <strong>of</strong> interest (ROI), and subject these to a machine learning<br />
protocol to train a classifier, which we exploit to develop as a predictive signature <strong>of</strong><br />
response to ICIs.<br />
Methods: We performed a retrospective analysis <strong>of</strong> clinical data and CT-images from<br />
prospectively enrolled cohorts <strong>of</strong> RM-SCCHN patients treated with ICIs in our<br />
institution. Tumor ROIs were manually contoured from baseline and first<br />
on-treatment CT-images. Extracted and computed radiomics features were employed<br />
to train a radial basis function support vector machine classifier to discriminate<br />
responders from non-responders. Ten-fold cross-validation protocol was employed to<br />
determine classifier accuracy.<br />
Results: Forty-two target lesions were contoured from 15 patients: median age = 58,<br />
males = 80%, p16-positive = 9, p16-negative = 5, p16-unknown = 1. Primary site:<br />
oropharynx = 11, oral cavity = 2, hypopharynx= 2. Treatment: anti-PD-L1<br />
monotherapy = 8, combination <strong>of</strong> anti-PD-L1 and anti-CTLA-4 = 7. Excluded lesions:<br />
clinical data prematurity = 11. Per-lesion radiological outcomes: 20 responders, 11<br />
non-responders. The radiomics classifier trained on the first on-treatment CT data<br />
achieved an accuracy <strong>of</strong> 79% (65.1% sensitivity, 88% specificity, p = 0.029) with an area<br />
under the ROC curve <strong>of</strong> 0.75. The classifier trained on the pre-treatment baseline CT<br />
data achieved an accuracy <strong>of</strong> 70.8% (37.9% sensitivity, 91.5% specificity, p = 0.16) with<br />
an area under the ROC curve <strong>of</strong> 0.60.<br />
Conclusions: This pilot study showed early promising results. Patient accrual is<br />
ongoing, and further improvement in the accuracy <strong>of</strong> the developed algorithm is<br />
expected with increasing patient numbers.<br />
Legal entity responsible for the study: Amy Prawira<br />
Funding: Princess Margaret Cancer Centre, Drug Development Program, Toronto,<br />
Canada.<br />
Disclosure: L.L. Siu: Research funding from Merck to conduct clinical trials. All other<br />
authors have declared no conflicts <strong>of</strong> interest.<br />
957PD<br />
Pembrolizumab after progression on platinum and cetuximab<br />
in head and neck squamous cell carcinoma (HNSCC): results<br />
from KEYNOTE-055<br />
R. Haddad 1 , T. Seiwert 2 , D.G. Pfister 3 , F. Worden 4 , S.V. Liu 5 , J. Gilbert 6 ,N.<br />
F. Saba 7 , J. Weiss 8 , L.J. Wirth 9 , A. Sukari 10 , H. Kang 11 , M.K. Gibson 12 ,<br />
E. Massarelli 13 , S. Powell 14 , A. Meister 15 , X. Shu 15 , J. Cheng 15 , J. Bauml 16<br />
1 <strong>Oncology</strong>, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA,<br />
USA, 2 <strong>Oncology</strong>, University <strong>of</strong> Chicago, Chicago, IL, USA, 3 <strong>Oncology</strong>, Memorial<br />
Sloan Kettering Cancer Center, New York, NY, USA, 4 <strong>Oncology</strong>, University <strong>of</strong><br />
Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA, 5 <strong>Oncology</strong>,<br />
Georgetown University Hospital, Washington, DC, USA, 6 <strong>Oncology</strong>, Vanderbilt<br />
University School <strong>of</strong> Medicine, Nashville, TN, USA, 7 <strong>Oncology</strong>, Winship Cancer<br />
Institute/Emory University, Atlanta, GA, USA, 8 Thoracic <strong>Oncology</strong>, Lineberger<br />
Comprehensive Cancer Center at the University <strong>of</strong> North Carolina, North Carolina,<br />
NC, USA, 9 <strong>Oncology</strong>, Massachusetts General Hospital, Boston, MA, USA,<br />
10 <strong>Oncology</strong>, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA,<br />
11 <strong>Oncology</strong>, Johns Hopkins University School <strong>of</strong> Medicine, Baltimore, MD, USA,<br />
12 <strong>Oncology</strong>, University Hospitals Case Medical Center, Cleveland, OH, USA,<br />
13 <strong>Oncology</strong>, The University <strong>of</strong> Texas MD Anderson Cancer Center, Houston, TX,<br />
USA, 14 <strong>Oncology</strong>, Sanford Health, Sioux Falls, SD, USA, 15 Medical <strong>Oncology</strong>,<br />
Merck & Co., Inc., Kenilworth, NJ, USA, 16 <strong>Oncology</strong>, University <strong>of</strong> Pennsylvania,<br />
Philadelphia, PA, USA<br />
Background: There are few treatment options in recurrent/metastatic (R/M) HNSCC<br />
after progression on platinum and cetuximab, and their efficacy is disappointing.<br />
During KEYNOTE-012, pembrolizumab, an anti–PD-1 antibody that blocks the<br />
interaction between PD-1 and its ligands, showed promising antitumor activity in R/M<br />
HNSCC. The efficacy and safety <strong>of</strong> pembrolizumab in patients with R/M HNSCC after<br />
progression on platinum and cetuximab are being investigated in the phase 2,<br />
nonrandomized KEYNOTE-055 (NCT02255097) study.<br />
Methods: Pts receive pembrolizumab 200 mg every 3 weeks. Key eligibility criteria<br />
include R/M HNSCC resistant to platinum and cetuximab therapies, measurable<br />
disease, and ECOG PS 0-1. Primary outcomes include overall response rate (ORR,<br />
RECIST v1.1 by central imaging vendor) performed every 6-9 wk and safety. Adverse<br />
events (AEs) were graded using CTCAE, v4.0.<br />
Results: Of the 171 pts who received ≥1 dose <strong>of</strong> pembrolizumab, median age was 61 y,<br />
81% were male, 75% had ≥2 prior lines <strong>of</strong> therapy for metastatic disease. As <strong>of</strong> Jan 29,<br />
2016, median follow-up time was 4 mo (range, 0-14). Treatment-related AEs (TRAEs)<br />
occurred in 102 (60%) pts, with 20 (12%) pts experiencing a grade 3-5 TRAE. 4 (2%)<br />
pts discontinued and 1 (1%) pt died because <strong>of</strong> a TRAE. AEs <strong>of</strong> special immunologic<br />
interest occurred in 35 (20%) pts; hypothyroidism (n = 23; grade 1 or 2) and<br />
pneumonitis (n = 3, grade 1 or 2; n = 1, grade 3; n = 1, grade 5) were the most common.<br />
When confirmed responses were evaluated, the ORR was 15% (PR, n = 25; 95% CI,<br />
10%-21%) with a median duration <strong>of</strong> response <strong>of</strong> 7 mo (range, 0-8+); the stable disease<br />
rate was 22% (n = 37; 95% CI, 16%-29%). When unconfirmed and confirmed<br />
responses were evaluated, the ORR was 22% (CR, n = 2; PR, n = 35; 95% CI, 16%-29%)<br />
and the stable disease rate was 15% (n = 25; 95% CI, 10%-21%).<br />
Conclusions: The clinically significant antitumor activity and safety pr<strong>of</strong>ile <strong>of</strong><br />
pembrolizumab in heavily pretreated R/M HNSCC shown here confirm findings from<br />
KEYNOTE-012 and support ongoing phase 3 trials in head and neck cancer. Further<br />
analyses <strong>of</strong> biomarker data including immunohistochemistry (PD-L1/PD-L2) and<br />
interferon gamma gene signatures will be presented.<br />
Clinical trial identification: NCT02255097<br />
Legal entity responsible for the study: Merck and Co., Inc.<br />
Funding: Merck and Co., Inc.<br />
Disclosure: T. Seiwert: Honoraria: Merck/MSD, Amgen, BMS, Astra Zeneca, Celgene,<br />
Serono. D.G. Pfister: Research funding: Merck, Exelixis, Medimmune, Astra Zeneca,<br />
Novartis Consulting or Advisory role: Boerhringer Ingelheim - Data Safety Monitoring<br />
Committee. S.V. Liu: Consulting Or Advisory Role: Genentech, Boehringer Ingleheim,<br />
Caris Life Sciences. J. Gilbert: Research Funding: AstraZeneca (Local PI), Merck, BMS,<br />
Steering Committee (unfunded). A. Sukari: Research funding: AstraZenca (PI), Merck<br />
(PI), MedImmune (PI), Karyopharm (PI), Boehringer Ingelheim (PI), VentiRx (PI),<br />
Mallinckrodt, Inc (PI), Acceleron Pharma (PI), Lilly (PI) Speakers Bureau: Novartis<br />
<strong>Oncology</strong>. E. Massarelli: Research funding: Merck, Bristol Myers Squibb, AstraZeneca,<br />
Medimmune Honoraria: Nektar Therapeutics Consulting or Advisory role: Nektar<br />
Therapeutics. S. Powell: Research Funding: Boerhringer Ingelheim - Data Safety<br />
Monitoring Committee. A. Meister, X. Shu, J. Cheng: Employee <strong>of</strong> Merck and Co, Inc.<br />
J. Bauml: Research funding: BMS, Merck, Astra Zeneca, Celgene,Venti-Rx Consulting<br />
or Advisory role: BMS, Merck, Celgene, Eisai. All other authors have declared no<br />
conflicts <strong>of</strong> interest.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw376 | vi331
abstracts<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
958P<br />
Tumor growth rate analysis <strong>of</strong> progression-free survival (PFS)<br />
and overall survival (OS) for thyroid cancer patients receiving<br />
placebo or sorafenib in the phase 3 DECISION trial<br />
C. Kappeler 1 , G. Meinhardt 2 , R. Elisei 3 , M. Brose 4 , M. Schlumberger 5<br />
1 Clinical Statistics EU, Bayer Pharma Aktiengesellschaft, Berlin, Germany, 2 Global<br />
Clinical Development <strong>Oncology</strong>, Bayer HealthCare Pharmaceuticals, Whippany,<br />
NJ, USA, 3 Endocrine Unit, Department <strong>of</strong> Clinical and Experimental Medicine,<br />
University <strong>of</strong> Pisa, Pisa, Italy, 4 Department <strong>of</strong> Otorhinolaryngology, Abramson<br />
Cancer Center, University <strong>of</strong> Pennsylvania, Perelman School <strong>of</strong> Medicine,<br />
Philadelphia, PA, USA, 5 Nuclear Medicine and Endocrinology, Institut Gustave<br />
Roussy, Villejuif, France<br />
Background: In the randomized, controlled phase 3 DECISION trial (NCT00895674),<br />
sorafenib (SOR) significantly improved progression-free survival (PFS) vs placebo<br />
(PLC) in patients with radioactive iodine refractory differentiated thyroid cancer (HR,<br />
0.587; p < 0.0001). Here we report the analysis exploring prognostic characteristics <strong>of</strong><br />
tumor growth rate (TGR) for PFS and OS.<br />
Methods: The primary endpoint <strong>of</strong> DECISION was PFS and OS was a secondary<br />
endpoint. Target lesions were assessed by central radiologic review every 8 weeks based<br />
on RECIST 1.0 criteria. Changes in target lesions over time were approximated by a<br />
parabola-like 3-parametric model. TGR was defined as % change per month <strong>of</strong> sum <strong>of</strong><br />
target lesion diameters (SLD). To explore the association between TGR and PFS and<br />
OS, values <strong>of</strong> early TGR were split into quartiles separately by treatment arm. PFS<br />
(cut<strong>of</strong>f in 2012) and OS (cut<strong>of</strong>f 2015) were compared in each subgroup population by<br />
median times derived from KM curves and from modeling with a Weibull distribution.<br />
Correlation <strong>of</strong> TGR with maximum reduction in SLDs was examined.<br />
Results: TGR subgroup statistics and median times <strong>of</strong> PFS and OS are shown in<br />
table 1. For these endpoints there is no simple proportional relation between TGR and<br />
median PFS or OS times. Better prognosis for PFS and OS is associated with Q2 or Q3<br />
TGR quartiles. Early TGR values close to zero indicate a better prognosis. TGR and<br />
SLD show a high correlation.<br />
Conclusions: In this exploratory analysis, stabilization <strong>of</strong> tumor lesions at treatment<br />
start seems to be associated with better PFS and OS outcomes than a pronounced early<br />
reduction <strong>of</strong> tumor lesion sizes. TGR may be an additional efficacy parameter to<br />
consider when monitoring SOR treatment.<br />
Table: 958P Weibull model <strong>of</strong> KM curves; durations in months<br />
PLC<br />
Quartile<br />
1<br />
Quartile<br />
2<br />
Quartile<br />
3<br />
Quartile<br />
4<br />
SOR<br />
Quartile<br />
1<br />
Quartile<br />
2<br />
Quartile<br />
3<br />
Quartile<br />
4<br />
Med early TGR - 0.082 0.003 0.026 0.079 - 0.106 - 0.047 - 0.021 0.019<br />
Med PFS 7.9 13.9 6.7 2.8 7.9 12.3 17.6 10.1<br />
Med OS 46.3 47.6 48.2 27.8 34.3 45.4 60.5 35.8<br />
Clinical trial identification: NCT00895674<br />
Legal entity responsible for the study: N/A<br />
Funding: Bayer Healthcare Pharmaceuticals<br />
Disclosure: C. Kappeler: Employee <strong>of</strong> Bayer Pharma AG. G. Meinhardt: Employee <strong>of</strong><br />
Bayer Healthcare Pharmaceuticals. R. Elisei: Consultancy fees/honorarium and<br />
research support from Bayer Healthcare Pharmaceuticals; and consultancy fees/<br />
honorarium from AstraZeneca and Genzyme. M. Brose: Consultancy fees/honorarium/<br />
research support from Bayer HealthCare Pharmaceuticals; consultancy fees/research<br />
support from Exelixis; consultancy fees from Onyx Pharmaceuticals; and research<br />
support from Eisai, Novartis, and Roche/Genentech. M. Schlumberger: Consultancy<br />
fees/research support from Bayer Healthcare Pharmaceuticals and Eisai; consultancy<br />
fees/honorarium and research support from AstraZeneca and Genzyme-San<strong>of</strong>i;<br />
consultancy fees from Exelixis; and consultancy fees/honorarium from Sobi.<br />
959P<br />
PIK-ORL: A phase II, multicenter trial aiming to evaluate<br />
BKM120 in monotherapy in patients (pts) with metastatic/<br />
recurrent head and neck squamous cell carcinoma (HNSCC)<br />
after failure <strong>of</strong> platin and cetuximab or anti-EGFR-based<br />
therapy<br />
J. Fayette 1 , L. Digue 2 , C. Ferlay 3 , I. Treilleux 4 , G. Garin 3 , Q. Wang 5 , C. Hebert 6 ,<br />
C. Even 7 , D. Cupissol 8 , S. Couchon-Thaunat 9 , L. Jaouen 3 , A. Guyennon 9 ,C.Le<br />
Tourneau 10 , G. Lefebvre 11 , A. Mailliez 11 , M. Matias 7 , M. Degardin 11 , S. Tartas 12 ,<br />
G. Clapisson 13 , D. Perol 3<br />
1 Medical <strong>Oncology</strong>, Centre Léon Bérard, Lyon, France, 2 Department <strong>of</strong> Medical<br />
<strong>Oncology</strong>, CHU Bordeaux Hopital St. André, Bordeaux, France, 3 Clinical<br />
Research, Centre Léon Bérard, Lyon, France, 4 Biopathology Department, Centre<br />
Léon Bérard, Lyon, France, 5 Translational Research Department, Centre Léon<br />
Bérard, Lyon, France, 6 Medical <strong>Oncology</strong>, Centre Antoine Lacassagne, Nice,<br />
France, 7 Medical <strong>Oncology</strong>, Institut Gustave Roussy, Villejuif, France, 8 Medicine,<br />
Clinique Val d’Aurelle, Montpellier, France, 9 Department <strong>of</strong> Radiology, Centre Léon<br />
Bérard, Lyon, France, 10 Department <strong>of</strong> Medical <strong>Oncology</strong>, Institut Curie, Paris,<br />
France, 11 Medical <strong>Oncology</strong>, Centre Oscar Lambret, Lille, France, 12 Medical<br />
<strong>Oncology</strong>, Hospice Civil de Lyon centre Hospitalier Lyon Sud, Lyon, France,<br />
13 Biological Ressouces Center, Centre Léon Bérard, Lyon, France<br />
Background: The PI3K/AKT pathway activation is an early event in HNSCC and an<br />
independent marker <strong>of</strong> poor outcome that seems to be involved in resistance to<br />
cetuximab. BKM120 is an oral, pan-Class I PI3K inhibitor that inhibits tumor growth<br />
in HNSCC xenografts.<br />
Methods: This Phase II evaluates the clinical benefit <strong>of</strong> BKM120 (100mg/d, po) in 2<br />
parallel cohorts <strong>of</strong> HNSCC pts with or without mutation in PI3KCA. Eligible pts<br />
progressed after platin and cetuximab or anti-EGFR therapy, and had documented<br />
PIK3CA status (exons 9 and 20). The primary endpoint was 2-month Disease Control<br />
Rate (DCR 2m ) as per RECIST 1.1. Secondary endpoints were ORR, PFS, OS, and safety.<br />
Blood and tumor samples were obtained for pharmacodynamics (PD). Imaging data<br />
were centrally reviewed. Considering that BKM120 would be uninteresting if<br />
DCR 2m ≤ 10% and promising if ≥ 30% and using Simon’s optimal two-stage design (α:<br />
5% unilateral, power: 90%), 7 successes/35 evaluable pts were required for each cohort.<br />
Only results <strong>of</strong> the cohort without PI3KCA mutation are presented. .<br />
Results: 36 HNSCC pts without PI3KCA mutation (median age: 58.6 yrs) received at<br />
least one dose <strong>of</strong> BKM120. They were heavily pretreated (33% with at least 3 previous<br />
lines). Median treatment duration was 8 wks [min-max: 4 d-55.9 wks]. At the end <strong>of</strong><br />
2 nd Simon’s Stage, the DCR 2m was 38.9% (14/36pts). No OR was observed. The most<br />
common related AE (>25%) included hyperglycemia, asthenia, anxiety, depression,<br />
lymphopenia, anemia, leucocyte increase, hematocrit decrease, nausea and diarrhea. 20<br />
pts (55.6%) presented at least one related AE ≥ Grade 3 (>5%: hyperglycemia,<br />
lymphopenia, asthenia, Na or K decrease) and 10 pts (27.8%) prematurely<br />
discontinued BKM120 due to an AE. 11pts (30.6%) experienced a related SAE<br />
including 3 SUSARs (1 fatal hyperglycemic coma, 1 death <strong>of</strong> uncertain relationship, 1<br />
severe dehydration). PFS, OS and PD data will be presented at the meeting. Cohort<br />
with PI3KCA mutation is ongoing (n = 17).<br />
Conclusions: BKM120 deserves further investigation in relapsing HNSCC pts without<br />
PI3KCA mutation, nevertheless with close monitoring <strong>of</strong> metabolic tolerance.<br />
Clinical trial identification: NCT01737450<br />
Legal entity responsible for the study: Centre Leon Bérard<br />
Funding: Institut National du Cancer and Fondation ARC<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
960P<br />
Causes <strong>of</strong> death statistics underestimate the burden <strong>of</strong> head<br />
and neck (H&N) cancers: a nationwide study from France in<br />
2008-2012 (EPICORL study)<br />
C. Even 1 , Y. Pointreau 2 , L. Ge<strong>of</strong>frois 3 , M. Schwarzinger 4 , M. Bec 5 , C. Godard 5 ,<br />
F. Huguet 6 , S. Témam 7 , S.P. Thiébaut 4<br />
1 Medical <strong>Oncology</strong>, Institut Gustave Roussy, Villejuif, France, 2 <strong>Oncology</strong>, Centre<br />
Jean Bernard, Le Mans, France, 3 Medical <strong>Oncology</strong>, Institut de Cancérologie de<br />
Lorraine - Alexis Vautrin, Vandoeuvre Les Nancy, France, 4 Epidemiology, THEN<br />
(Translational Health Economics Network), Paris, France, 5 Market Access, MSD,<br />
Courbevoie, France, 6 Radiation <strong>Oncology</strong>, Tenon Hospital, Paris, France, 7 Surgical<br />
<strong>Oncology</strong>, Institut Gustave Roussy, Villejuif, France<br />
Background: Patients with H&N cancer carry the highest risk <strong>of</strong> secondary primary<br />
cancers. Determining the underlying cause <strong>of</strong> death is conflicting in presence <strong>of</strong><br />
multiple primary cancer sites, and the actual burden <strong>of</strong> H&N cancers may be<br />
underestimated by causes <strong>of</strong> death statistics.<br />
Methods: Using the French National Hospital Discharge (PMSI) database, we<br />
identified all adult patients residing in Metropolitan France and diagnosed with H&N<br />
cancer (ICD-10: C00-C06; C09-C14; C30.0; C31; C32) in 2008-2012. Overall death was<br />
ascertained from in-hospital mortality with use <strong>of</strong> imputation methods to estimate<br />
death outside hospital in 2008-2012. Among deceased patients, we considered<br />
advanced H&N cancer (stage III/IV at diagnosis or relapse in the follow-up) as a cause<br />
<strong>of</strong> death. A competing cause <strong>of</strong> death from other primary cancer sites was categorized<br />
vi332 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
according to its timing relative to the index date <strong>of</strong> H&N cancer: former (180 days) cancers. Study results<br />
were compared to National causes <strong>of</strong> death statistics (CEPIDC) with use <strong>of</strong> the same<br />
ICD-10 definitions.<br />
Results: Of 131,965 French patients identified with H&N cancer in 2008-2012, 58,562<br />
(44.4%) died in the same period including 46,463 (79.3%) deaths recorded at hospital.<br />
Of 58,562 deceased patients, 50,910 (86.9%) were recorded with advanced H&N cancer<br />
and involved 82.4% male patients at a median (IQR) age <strong>of</strong> 64 (57-74) at death.<br />
Overall, 20,926 (41.1%) patients had another primary cancer site than H&N cancer<br />
recorded before death: 4,751 (9.3%) former, 11,030 (21.7%) synchronous, and 5,145<br />
(10.1%) metachronous cancers were recorded with increasing likelihood to be<br />
considered as the underlying cause <strong>of</strong> death. The death toll <strong>of</strong> H&N cancers<br />
represented 0.96% <strong>of</strong> all-cause mortality (2.65% <strong>of</strong> all premature deaths before 65 years<br />
old) in France and increased annually by 6.1% on average. In National causes <strong>of</strong> death<br />
statistics, only 25,647 deaths were attributed to H&N cancers in 2008-2012 without<br />
time trends.<br />
Conclusions: The study results suggest that National causes <strong>of</strong> death statistics<br />
underestimate the burden <strong>of</strong> H&N cancer. It may be explain by the frequency <strong>of</strong><br />
secondary primary cancers.<br />
Legal entity responsible for the study: THEN (Translational Health Economics<br />
Network)<br />
Funding: MSD France<br />
Disclosure: C. Even, Y. Pointreau, L. Ge<strong>of</strong>frois, M. Schwarzinger, F. Huguet, S. Témam,<br />
S.P. Thiébaut: Corporate-sponsored research. M. Bec, C. Godard: MSD employee.<br />
961P<br />
Axitinib in recurrent or metastatic nasopharyngeal carcinoma<br />
(NPC): final result <strong>of</strong> a phase 2 clinical trial with<br />
pharmacokinetic (PK) correlation<br />
E.P. Hui 1 , B.B. Ma 1 ,F.Mo 2 , M.K. Kam 1 , S.L. Chan 1 , H.H. Loong 1 ,R.Ho 2 ,S.<br />
F. Leung 1 , A.D. King 3 , K. Wang 3 , A. Ahuja 3 , C.M. Chan 4 , C.W. Hui 5 , C.H. Wong 5 ,<br />
A.T.C. Chan 1<br />
1 Department <strong>of</strong> Clinical <strong>Oncology</strong>, The Chinese University <strong>of</strong> Hong Kong, Shatin,<br />
Hong Kong, China, 2 Comprehensive Cancer Trials Unit, The Chinese University <strong>of</strong><br />
Hong Kong, Shatin, Hong Kong, China, 3 Department <strong>of</strong> Imaging and Interventional<br />
Radiology, The Chinese University <strong>of</strong> Hong Kong, Shatin, Hong Kong, China,<br />
4 Tumor Marker Laboratory, The Chinese University <strong>of</strong> Hong Kong, Shatin, Hong<br />
Kong, China, 5 Cancer Drug Testing Unit, Partner State Key Laboratory <strong>of</strong><br />
<strong>Oncology</strong> in South China, Sir YK Pao Center for Cancer, Hong Kong Cancer<br />
Institute and Li Ka Shing Institute <strong>of</strong> Health Sciences, The Chinese University <strong>of</strong><br />
Hong Kong, Shatin, Hong Kong, China<br />
Background: Axitinib is approved in advanced renal cell cancer patients (pts) who<br />
failed one prior systemic therapy. It has also demonstrated potent activity in preclinical<br />
models <strong>of</strong> NPC [Cancer Res 2012; 72 (8 Suppl): A1373].<br />
Methods: We conducted a phase 2 clinical trial <strong>of</strong> axitinib monotherapy in recurrent<br />
or metastatic NPC pts who progressed after ≥1 line <strong>of</strong> platinum-based chemotherapy<br />
(CT). Pts with local recurrence or vascular invasion were excluded. Axitinib was started<br />
at 5 mg twice daily in continuous 4-weeks cycles until progression or unacceptable<br />
toxicity. Primary endpoint was clinical benefit rate (CBR), defined as % <strong>of</strong> pts<br />
achieving complete response (CR), partial response (PR) or stable disease (SD) by<br />
RECIST for >12 weeks. Secondary endpoints included time to progression (TTP),<br />
overall survival (OS), safety and PK pr<strong>of</strong>ile. Simon’s Minimax 2-stage phase 2 design<br />
(P0 = 0.50, P1 = 0.70, type I error 0.05, power 80%) was used to calculate sample size<br />
(n = 37; evaluable for response).<br />
Results: We recruited 40 pts. Median age 52 (22-74). M:F = 35:5. Pts received a median<br />
<strong>of</strong> 3 lines <strong>of</strong> prior CT (range 1-6). As <strong>of</strong> 31 Mar 2016, the median follow up was 36.1<br />
months. Pts received axitinib for a median <strong>of</strong> 4.5 cycles (range 1-21), with 16 pts (40%)<br />
received ≥ 6 cycles, 7 (18%) pts ≥ 10 cycles and 2 pts ≥ 18 cycles. 9 (23%) pts had dose<br />
escalation and 12 (30%) had dose reduction. Of 37 pts evaluable for response, 3-month<br />
CBR = 78.4% (95% CI: 65.6-91.2%; 1 confirmed PR, 6 unconfirmed PR, 22 SD).<br />
6-month CBR = 43.2% (30.4-56.1%). Median TTP = 5.0 months (95% CI: 3.9-5.7).<br />
Median OS = 10.4 months (6.5-18.6). 1-year survival rate = 45.4%. Treatment-related<br />
adverse events by CTCAE, all grades (Gr) in ≥ 25% <strong>of</strong> pts included: hand-foot 50% (Gr<br />
3: 3%), hypothyroidism 48% (Gr 3: 3%), fatigue 40% (Gr 3: 3%), hypertension 38% (Gr<br />
3: 8%), diarrhea 30% (Gr 3: 5%), pain 28% (Gr 3: 5%), mucositis 28% (Gr 3: 0%). All<br />
hemorrhages were Gr 1 (15%) or Gr 2 (3%). Diastolic blood pressure ≥ 90 mmHg was<br />
significantly associated with better OS (HR 0.3, p = 0.0016). Axitinib PK parameters<br />
and correlations with dose, efficacy and toxicity will be presented.<br />
Conclusions: Single agent axitinib achieved meaningful disease control with<br />
manageable toxicity in heavily pretreated NPC.<br />
Clinical trial identification: CCTU-NPC022; ClinicalTrials.gov NCT01249547<br />
Legal entity responsible for the study: Comprehensive Cancer Trials Unit,<br />
Department <strong>of</strong> Clinical <strong>Oncology</strong>, Prince <strong>of</strong> Wales Hospital, The Chinese University <strong>of</strong><br />
Hong Kong<br />
Funding: Department <strong>of</strong> Clinical <strong>Oncology</strong>, The Chinese University <strong>of</strong> Hong Kong<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
962P<br />
Responses in specific metastases following treatment with<br />
lenvatinib (LN): Results from the phase 3 SELECT trial<br />
B. Robinson 1 , M. Schlumberger 2 , L.J. Wirth 3 , C.E. Dutcus 4 , T.A. Binder 4 ,M.Guo 4 ,<br />
M. Taylor 5 , S.B. Kim 6 , M.K. Krzyzanowska 7 , J. Capdevilla 8 , S.I. Sherman 9 ,<br />
M. Tahara 10<br />
1 Kolling Institute <strong>of</strong> Medical Research, University <strong>of</strong> Sydney, St Leonards, Australia,<br />
2 Department <strong>of</strong> Nuclear Medicine and Endocrine <strong>Oncology</strong>, Gustave Roussy and<br />
University Paris-Sud, Villejuif, France, 3 Department <strong>of</strong> Medicine, Massachusetts<br />
General Hospital, Boston, MA, USA, 4 Eisai, Inc., Woodcliff Lake, NJ, USA, 5 Knight<br />
Cancer Institute, Oregon Health Science University, Portland, OR, USA,<br />
6 Department <strong>of</strong> <strong>Oncology</strong>, Asan Medical Center, University <strong>of</strong> Ulsan College <strong>of</strong><br />
Medicine, Seoul, Republic <strong>of</strong> Korea, 7 Division <strong>of</strong> Medical <strong>Oncology</strong> & Hematology,<br />
Princess Margaret Cancer Centre, Toronto, ON, Canada, 8 Medical <strong>Oncology</strong><br />
Department Vall d’Hebron University Hospital, Vall d’Hebron Institute <strong>of</strong> <strong>Oncology</strong><br />
(VHIO), Barcelona, Spain, 9 Department <strong>of</strong> Endocrine Neoplasia and Hormonal<br />
Disorders, Division <strong>of</strong> Internal Medicine, The University <strong>of</strong> Texas MD Anderson<br />
Cancer Center, Houston, TX, USA, 10 Department <strong>of</strong> Head and Neck Medical<br />
<strong>Oncology</strong>, National Cancer Center Hospital East, Kashiwa, Japan<br />
Background: LN is an oral, multikinase inhibitor that significantly prolonged median<br />
progression-free survival vs placebo (PB) in a phase 3 study <strong>of</strong> patients (pts) with<br />
radioiodine-refractory differentiated thyroid cancer (RR-DTC; 18.3 vs 3.6 months;<br />
hazard ratio [HR] 0.21; 99% confidence interval [CI] 0.14–0.31; P < 0.001). As<br />
metastatic RR-DTC is associated with poor overall survival, we report a subanalysis <strong>of</strong><br />
this study to examine response to LN and PB in specific metastasis sites.<br />
Methods: Pts with RR-DTC in this double-blind, multicenter study were randomized<br />
2:1 to LN or PB (24mg/d; 28-d cycle). Tumor assessments in specific metastasis sites<br />
were evaluated by independent radiologic review using the Response Evaluation<br />
Criteria in Solid Tumors v1.1 at baseline and 8-week intervals. Sites evaluated were<br />
lung, liver, lymph nodes, and bone.<br />
Results: Following LN treatment, pts showed tumor shrinkage in all targeted sites<br />
compared with baseline (Table 1). The mean maximum change in sum <strong>of</strong> target lesions<br />
(in mm; see table) from baseline was significantly greater in pts treated with LN vs PB<br />
in the lungs (–15.1 vs 1.4), liver (–17.7 vs 2.5), lymph nodes (–17.4 vs –0.8), and bone<br />
(–6.7 vs 3.4). In pts treated with LN vs PB, a greater percent change from baseline (%)<br />
was observed in the lung (–45.9 vs 2.7), liver (–35.6 vs 5.1), lymph nodes (–47.5 vs 2.9),<br />
and bone (–10.7 vs 6.5). In the LN arm, median duration <strong>of</strong> objective response was not<br />
estimable (NE; 95% CI 16.6─NE; n = 139), 7.3 (1.9─NE; n = 7), 16.8 (95% CI 12.9─NE;<br />
n = 84), and 12.9 (95% CI 3.6─NE; n = 10) months for pts with lung, liver, lymph<br />
node, and bone metastases, respectively.<br />
Conclusions: In targeted metastasis sites, greater tumor shrinkage was observed<br />
following LN treatment vs PB. These data provide additional evidence <strong>of</strong> the clinical<br />
benefit <strong>of</strong> LN in the treatment <strong>of</strong> RR-DTC, particularly in pts with specific metastases,<br />
although responses are also seen in bone metastases.<br />
Table: 962P<br />
Lung Liver Lymph<br />
node<br />
Bone<br />
PB LN PB LN PB LN PB LN<br />
Baseline<br />
n 107 199 12 15 57 126 17 41<br />
Mean, mm 36.5 35.0 54.9 47.6 39.8 37.5 63.1 65.9<br />
Maximum change<br />
n 103 189 12 14 55 119 16 34<br />
Mean, mm 1.4 -15.1 † 2.5 -17.7* -0.8 -17.4 † 3.4 -6.7*<br />
Mean, % 2.7 -45.9 † 5.1 -35.6 † -2.9 -47.5 † 6.5 -10.7*<br />
* P
abstracts<br />
Sharpe & Dohme; and received personal fees from Merck Serono, Bristol Myer Squibb,<br />
Otsuka, and Bayer. All other authors have declared no conflicts <strong>of</strong> interest.<br />
963P<br />
Survival <strong>of</strong> patients with head and neck (H&N) cancers:<br />
a nationwide study from France in 2008-2012 (EPICORL study)<br />
F. Huguet 1 , S. Témam 2 , Y. Pointreau 3 , S.P. Thiébaut 4 , M. Bec 5 , L. Lévy-Bachelot 5 ,<br />
C. Even 6 , L. Ge<strong>of</strong>frois 7 , M. Schwarzinger 4<br />
1 Radiation <strong>Oncology</strong>, Tenon Hospital, Paris, France, 2 Surgical <strong>Oncology</strong>, Institut<br />
Gustave Roussy, Villejuif, France, 3 <strong>Oncology</strong>, Centre Jean Bernard, Le Mans,<br />
France, 4 Epidemiology, THEN (Translational Health Economics Network), Paris,<br />
France, 5 Market Access, MSD, Courbevoie, France, 6 Medical <strong>Oncology</strong>, Institut<br />
Gustave Roussy, Villejuif, France, 7 Medical <strong>Oncology</strong>, Institut de Cancérologie de<br />
Lorraine - Alexis Vautrin, Vandoeuvre Les Nancy, France<br />
Background: Tobacco smoking and heavy alcohol use are the main risk factors <strong>of</strong><br />
H&N cancer. The same risk factors entail severe comorbidities that may worsen<br />
prognosis in patients diagnosed with H&N cancer.<br />
Methods: We completed a retrospective cohort study using the French National<br />
Hospital Discharge (PMSI) database. We identified all adult patients residing in<br />
Metropolitan France and diagnosed with H&N cancer (ICD-10: C00-C06; C09-C14;<br />
C30.0; C31; C32) in 2008-2012. Cancer location and stage (early I/II; advanced III/IVb;<br />
distant metastatic IVc) were determined at diagnosis. Time to relapse, secondary<br />
primary H&N cancer, other primary cancers, Charlson comorbidities were recorded<br />
until last hospital stay in 2013. Hazard ratios (HR) for in-hospital death were estimated<br />
in a multivariate Cox model with use <strong>of</strong> time-dependent variables.<br />
Results: 131,965 French adults were identified with H&N cancer in 2008-2012: 79.4%<br />
were male with median (IQR) age <strong>of</strong> 61 (54-71) at diagnosis. Overall survival at 5 years was<br />
34.0% (95% CI, 33.5%-34.4%) over a follow-up <strong>of</strong> 196,000 person-years. As compared to<br />
23.2% patients with laryngeal cancer, survival was significantly lower for 29.3% patients<br />
with oral cavity cancer (HR = 1.25), 19.5% patients with oropharynx cancer (HR = 1.22),<br />
or 12.8% patients with hypopharynx cancer (HR = 1.26). As compared to 30.7% patients<br />
with early cancer at diagnosis, survival was significantly lower for 12.1% patients with<br />
distant metastasis (HR = 3.02) and 57.2% patients with advanced cancer (HR = 1.76). The<br />
relapse rate was 22.8% in patients with early cancer and 37.9% in patients with advanced<br />
cancer, with significantly lower survival (HR = 6.77). Secondary primary H&N cancers<br />
were detected in 6.1% patients at diagnosis (HR = 1.15) and 2.3% patients in the follow-up<br />
(HR = 1.79). About 31% patients had another primary cancer cared in the study period<br />
(including 10.1% lung: HR = 1. 71). About 52% patients had other severe comorbidities<br />
incurring significantly lower survival.<br />
Conclusions: This is the first national study on the survival <strong>of</strong> patients with H&N<br />
cancer in France. Relapse had the strongest impact on prognosis. In addition, about<br />
two-third patients had another primary cancer or severe comorbidities worsening<br />
prognosis.<br />
Legal entity responsible for the study: THEN (Translational Health Economics<br />
Network)<br />
Funding: MSD France<br />
Disclosure: F. Huguet, S. Témam, Y. Pointreau, S.P. Thiébaut, C. Even, L. Ge<strong>of</strong>frois,<br />
M. Schwarzinger: Corporate-sponsored research. M. Bec, L. Lévy-Bachelot: MSD<br />
employee.<br />
964P<br />
Molecular pr<strong>of</strong>iling <strong>of</strong> locally advanced/metastatic olfactory<br />
neuroblastomas<br />
Z. Gatalica 1 , A. Ghazalpour 1 , J. Swensen 1 , R. Bender 1 , S. Vranic 2 , R. Feldman 1 ,<br />
S. Reddy 1<br />
1 Pathology, Caris Life Sciences, Phoenix, AZ, USA, 2 Pathology, Clinical Centre <strong>of</strong><br />
Sarajevo University, Sarajevo, Bosnia and Herzegovina<br />
Background: Olfactory neuroblastoma (esthesioneuroblastoma) [ONB] is a rare<br />
malignant neoplasm arising from the olfactory epithelium in the nasal vault. It usually<br />
takes an aggressive clinical course for which there are no specific treatment guidelines.<br />
Pursuing the goals <strong>of</strong> personalized medicine, we investigated a cohort <strong>of</strong> recurrent and/<br />
or metastatic ONBs using multiplatform molecular pr<strong>of</strong>iling approach.<br />
Methods: Formalin-fixed paraffin-embedded tissue samples <strong>of</strong> twenty (10 male, 10<br />
female patients, age range: 29-84 years) ONBs were pr<strong>of</strong>iled at Caris Life Sciences<br />
(Phoenix, Arizona) using DNA sequencing (Sanger sequencing, massively parallel<br />
sequencing [Illumina NGS] and gene fusions [Archer FusionPlex]), whole genome<br />
RNA microarray (HumanHT-12 v4 beadChip, Illumina), gene copy number assays<br />
(chromogenic and fluorescent in situ hybridization) and immunohistochemistry.<br />
Results: Mutations were detected in 8/14 (57%) ONBs including TP53 (3 cases),<br />
CTNNB1 (2 cases), APC, cKIT, cMET and PDGFRA, and SMAD4 gene (single cases,<br />
respectively). When compared with control tissues, 21 genes were over expressed and<br />
19 genes under expressed by microarray assay (>10x). Some <strong>of</strong> the upregulated genes<br />
included stem cell marker CD24, SCG2 (Secretogranin II) and Insulin-Like Growth<br />
Factor Binding Protein 2 (IGFBP-2). None <strong>of</strong> the cases harbored copy number<br />
variations <strong>of</strong> EGFR, HER2 and cMET genes, and no gene fusions were identified. No<br />
case expressed PD-L1 (0/6) or IDO-1 (0/3). Multiple protein biomarkers <strong>of</strong> response or<br />
resistance to classic chemotherapy drugs were identified: low ERCC1 [cisplatin<br />
sensitivity] in 82% (9/11), high TOPO1 [irinotecan sensitivity] in 63% [12/19], high<br />
TUBB3 [vincristine resistance] in 92% (12/13) and high MRP1 (multidrug resistance)<br />
in 100% (6/6).<br />
Conclusions: Our study indicates that a subset <strong>of</strong> ONBs exhibits molecular alterations,<br />
notably in the Wnt and cKIT/PDGFRA pathways, that are potentially treatable using<br />
novel targeted therapies. Optimization <strong>of</strong> cytotoxic chemotherapy approaches based on<br />
protein expression may be worthy <strong>of</strong> further investigation.<br />
Legal entity responsible for the study: Caris Life Sciences, Phoenix, Arizona, USA<br />
Funding: Caris Life Sciences, Phoenix, Arizona, USA<br />
Disclosure: Z. Gatalica, A. Ghazalpour, J. Swensen, R. Bender, R. Feldman, S. Reddy:<br />
Employee <strong>of</strong> Caris Life Sciences. All other authors have declared no conflicts <strong>of</strong> interest.<br />
965P<br />
Prognostic relevance <strong>of</strong> molecular characterization <strong>of</strong><br />
circulating tumor cells (CTC) in head and neck squamous cell<br />
carcinoma (HNSCC)<br />
G. Koutsodontis 1 , A. Strati 2 , G. Papaxoinis 3 , N. Charalambakis 1 , I. Kotsantis 1 ,<br />
P. Oikonomopoulou 1 , L. Hoxhallari 1 , E. Lianidou 2 , A. Psyrri 1<br />
1 <strong>Oncology</strong> Unit, Attikon University Hospital, Athens, Greece, 2 Chemistry, National<br />
and Kapodistrian University <strong>of</strong> Athens, Athens, Greece, 3 Medical <strong>Oncology</strong>, The<br />
Christie NHS Foundation Trust, Manchester, UK<br />
Background: CTCs are considered indicators <strong>of</strong> residual disease and thus are<br />
associated with an increased risk <strong>of</strong> metastasis. Moreover, hypoxic microenviroment, a<br />
major feature <strong>of</strong> HNSCC, plays a pivotal role in the emergence <strong>of</strong> CTCs and cancer<br />
stem cells. Although rare and exposed to immune mediated destruction, these cells<br />
manage to evade the immune system <strong>of</strong> the host. Therefore, a better understanding <strong>of</strong><br />
the immunogenicity <strong>of</strong> these cells and their cross talk with immune cells may shed light<br />
to potential immunotherapy opportunities in HNSCC.<br />
Methods: We quantified by RT-qPCR TWIST1, Stem Cell (SC) markers (CD24, CD44,<br />
ALDH1) and PD-L1 in immunomagnetically positively selected CTCs from 90 locally<br />
advanced (LA) HNSCC, 33 recurrent/metastatic (R/M) HNSCC and 20 healthy<br />
individuals. Patients (pts) with LA disease were treated with cisplatin<br />
chemoradiotherapy +/- TPF induction chemotherapy (IC). We assessed the expression<br />
<strong>of</strong> TWIST1, SC markers and PD-L1 at baseline, after completion <strong>of</strong> IC, at end <strong>of</strong><br />
chemoradiotherapy and at relapse in pts with LA disease and at baseline in pts with R/<br />
M HNSCC. To assess univariate differences <strong>of</strong> study parameters according to gene<br />
expression chi-square test was used for the categorical clinicopathological variables,<br />
while patients’ survival curves according to gene expression were generated by<br />
Kaplan-Meier analysis and tested for significance using the Mantel-Cox log-rank test.<br />
Results: Pts with PD-L1 positive CTCs at the end <strong>of</strong> treatment had shorter Progression<br />
Free Survival (PFS) (p < 0.001) and Overall Survival (OS) (p < 0.001). Multivariate Cox<br />
regression analysis confirmed that PD-L1 overexpression in pts at the end <strong>of</strong> treatment<br />
was an independent prognostic factor for PFS (p = 0.012) and OS (p = 0.009).<br />
Expression <strong>of</strong> CD44 on CTCs at the end <strong>of</strong> treatment was associated with expression <strong>of</strong><br />
PD-L1 (p = 0.014).<br />
Conclusions: Liquid biopsies could identify pts at high risk for relapse after adjuvant<br />
chemoradiation that may derive benefit from adjuvant therapy in LA disease. PD-L1<br />
expression in CTCs at the end <strong>of</strong> treatment is a potential biomarker for pt selection for<br />
treatment with adjuvant PD1 checkpoint inhibitors.<br />
Legal entity responsible for the study: Attikon General University Hospital, National<br />
and Kapodistrian University <strong>of</strong> Athens<br />
Funding: National and Kapodistrian University <strong>of</strong> Athens<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
966P<br />
Mutation pr<strong>of</strong>iles <strong>of</strong> nasopharyngeal carcinomas in<br />
South-Eastern European patients<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
G. Fountzilas 1 , A. Psyrri 1 , E. Giannoulatou 2 , G. Kouvatseas 3 , D. Rontogianni 1 ,<br />
E. Ciuleanu 4 , T-E. Ciuleanu 5 , L. Resiga 4 , T. Zaramboukas 1 , M. Bobos 1 ,<br />
S. Chrisafi 1 , E. Tsolaki 1 , K. Papadopoulou 1 , K. Markou 1 , N. Charalambakis 1 ,<br />
A. Koutras 1 , A. Kalogera-Fountzila 1 , M. Skondra 1 , D. Pectasides 1 , V. Kotoula 1<br />
1 Data Office, Hellenic Cooperative <strong>Oncology</strong> Group (HeCOG), Athens, Greece,<br />
2 Bioinformatics, Victor Chang Cardiac Research Institute, Darlinghurst, Australia,<br />
3 Biostatistics, Health Data Specialists Ltd, Athens, Greece, 4 Radiation, Ion<br />
Chiricuta <strong>Oncology</strong> Institute-IOCN, Cluj Napoca, Romania, 5 Medical <strong>Oncology</strong>, Ion<br />
Chiricuta <strong>Oncology</strong> Institute-IOCN, Cluj Napoca, Romania<br />
Background: Nasopharyngeal cancer (NPC) is characterized by a remarkable<br />
geographical variation and biologic diversity. Importantly, studies investigating<br />
mutation pr<strong>of</strong>iles <strong>of</strong> NPC in European populations are scarce.<br />
Methods: We investigated the mutational pr<strong>of</strong>ile <strong>of</strong> 127 NPC (89% EBV positive) in 93<br />
Greek (GR) and 34 Romanian (RO) patients with locally advanced disease, treated with<br />
concomitant chemo-radiotherapy (CCRT) or induction chemotherapy (IC) followed<br />
by CCRT. In 19 tumors, dissected matched tumor/lymphocyte (T/L) pairs were<br />
compared. Mutation (amino acid changing, minor allele frequency
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
changing) data were obtained with next generation sequencing (mean depth 3261.5)<br />
with a panel targeting areas in 100 NPC, DNA repair, and immune response related<br />
genes. Disease-free survival at 3 years (3yrDFS) was the clinical endpoint.<br />
Results: We identified 1562 mutations in 101/129 tumors (94%). Mutations were<br />
mostly found in homologous recombination repair (HRR; 34%), chromatin<br />
remodelling (15%) and immune response related (IRR; 10%) genes. In the matched T/<br />
L samples, common mutations were identified in 10 cases only, the rest harbouring<br />
private mutations. Shared T/L mutations occurred at higher frequencies within the<br />
same tumor than T- and L-private mutations (p < 0.001). HRR and tyrosine kinase<br />
signalling genes, as well as POLE and TP53 carried mostly L-private (p = 0.003). In<br />
comparison to GR, RO patients were younger (p = 0.027), had almost exclusively<br />
WHO type II and III tumors (p = 0.025) and presented more <strong>of</strong>ten with stage IV<br />
disease (p = 0.026), while their tumors had significantly higher mutation load<br />
(p < 0.001) and higher numbers <strong>of</strong> mutations in particular genes, e.g., BRCA1<br />
(p < 0.001). Multivariate analysis revealed BRCA1 mutations (odds ratio [OR] 6.3; 95%<br />
CI 1.3-31.4; p = 0.024) and absence <strong>of</strong> EBV infection (OR: 6.2; 95% CI 1.1-35.9;<br />
p = 0.040) as unfavourable prognostic parameters.<br />
Conclusions: Different genes and sets <strong>of</strong> genes are affected in stromal and tumor<br />
components <strong>of</strong> NPC, which is important for targeted treatment considerations. Ethnic<br />
differences in mutation pr<strong>of</strong>iles exist but do not seem to interfere with patient outcome,<br />
which seems adversely affected by the absence <strong>of</strong> EBV and by the presence <strong>of</strong> BRCA1<br />
mutations.<br />
Legal entity responsible for the study: Hellenic Cooperative <strong>Oncology</strong> Group<br />
Funding: Hellenic Cooperative <strong>Oncology</strong> Group<br />
Disclosure: G. Fountzilas: Advisory Board: Astra Zeneca S.A. All other authors have<br />
declared no conflicts <strong>of</strong> interest.<br />
967P<br />
Observational study <strong>of</strong> the cetuximab relative dose intensity<br />
(RDI) in the first-line treatment <strong>of</strong> recurrent and/or metastatic<br />
squamous cell carcinoma <strong>of</strong> the head and neck (R/M SCCHN):<br />
Data on the maintenance and every two weeks use (DIRECT<br />
study)<br />
J. Guigay 1 , E. Chamorey 2 , P. Céruse 3 , F. Mornex 4 , M. Degardin 5 , M. Alfonsi 6 ,<br />
L. Digue 7 , A. Berrier 8 , X. Artignan 9 , L. Cals 10 , S. Faivre 11 , E. Vuillemin 12 ,<br />
F. Rolland 13 , A. Timochenko 14 , E. Babin 15 , A. Seronde-Delmas 16 , A. Prevost 17 ,<br />
O. Romano 18 ,F.Peyrade 1 , C. Le Tourneau 19<br />
1 Medical <strong>Oncology</strong>, Centre Antoine Lacassagne, Nice, France, 2 Epidemiology and<br />
Biostatistics Unit, Centre Antoine Lacassagne, Nice, France, 3 Rhône, Lyon<br />
University Hospital, Lyon, France, 4 Radiotherapy, Lyon University Hospital, Lyon,<br />
France, 5 Medical <strong>Oncology</strong>, Centre Oscar Lambret, Lille, France,<br />
6 <strong>Oncology</strong>-Radiotherapy, Institut Ste Catherine, Avignon, France,<br />
7 <strong>Oncology</strong>-Radiotherapy, CHU Bordeaux Hopital St. André, Bordeaux, France,<br />
8 ORL, Centre Hospitalier de Lens, Lens, France, 9 Medical <strong>Oncology</strong> and<br />
Radiotherapy, Centre Hospitalier Privé St Grégoire, St. Grégoire, France,<br />
10 Medical <strong>Oncology</strong>, Centre Hospitalier Belfort-Montbeliard - site du Mittan,<br />
Montbéliard, France, 11 Cancerologie, Hôpital Beaujon, Clichy, France, 12 Medical<br />
<strong>Oncology</strong>, Centre Hospitalier Bretagne Atlantique, Vannes, France, 13 Medical<br />
<strong>Oncology</strong>, ICO Institut de Cancerologie de l’Ouest René Gauducheau,<br />
St. Herblain, France, 14 ORL, Institute de Cancerologie de la Loire, St. Priest En<br />
Jarez, France, 15 ORL, CHU de Caen, Caen, France, 16 Medical Affairs, Merck,<br />
Lyon, France, 17 Medical <strong>Oncology</strong>, Institut Jean Godinot, Reims, France,<br />
18 Medical <strong>Oncology</strong>, Hôpital Privé de la Louvière, Lille, France, 19 Medical<br />
<strong>Oncology</strong>, Institut Curie, Paris, France<br />
Background: In EXTREME pivotal Phase III trial, Cetuximab (CTX) associated with<br />
chemotherapy (CT) based on platinum (cisplatin or carboplatin) + 5-fluorouracil<br />
(5-FU), followed by cetuximab single agent (maintenance) has demonstrated improved<br />
survival outcomes compared to CT alone in R/M SCCHN in first-line therapy.<br />
DIRECT is the first observational, prospective study evaluating CTX RDI in this<br />
setting. Here, we focus on CTX maintenance phase and every two weeks usage<br />
(administration frequency at physician discretion).<br />
Methods: 157 adult patients with R/M SCCHN treated in first-line with CTX<br />
according to the scheme <strong>of</strong> the pivotal study in usual medical practice were included in<br />
this national multicenter study (56 centers in France) over two years (Nov 2012-June<br />
2014) and were followed-up during a maximum period <strong>of</strong> 12 months.<br />
Results: 45.8 % (n = 72) <strong>of</strong> the patients have received CTX maintenance. The median<br />
duration <strong>of</strong> maintenance was 15.8 ± 10.5 weeks (n = 72). 12-month-PFS rate was 23.1%<br />
(CI95% [14.0%; 33.5%]). 12-month-OS rate was 70.1% ([57.5%; 79.6%]). For patients<br />
with disease free interval less than 6 months (n = 55), 12-month-OS rate was 41.2%<br />
([27.1%; 54.8]). During maintenance, 54.2% (n = 39) <strong>of</strong> patients have received CTX every<br />
two weeks (e2w) administration and 45.8 (n = 33) once a week. 12-month-PFS rate and<br />
12-month-OS rate were not worse in patients with e2w versus weekly administration<br />
(weekly, n = 33 vs e2w, n = 39): 18.2% ([7.4% 32.8%]) vs 27.5% ([14.3%; 42.3%]), p = 0.2;<br />
62.6% ([43.6% 76.8%]) vs 77% ([59.1%; 87.8%]), p = 0.2 respectively for PFS and OS<br />
rates. Cutaneous toxicities (grade ≥ 3) were observed in 12/157 patients (7.6%).<br />
Conclusions: This real life data indicates that CTX maintenance treatment every other<br />
week is feasible in R/M SCCHN patients and seems not to result in a reduced efficacy<br />
compared with weekly administration. In addition, cutaneous toxicity rate (grade ≥ 3)<br />
was similar in the Extreme study.<br />
Legal entity responsible for the study: Merck France<br />
Funding: Merck France<br />
Disclosure: J. Guigay: Member <strong>of</strong> Merck Advisory Board Corporate-sponsored<br />
researches from Merck Member and coordination <strong>of</strong> Scientific Committee for this<br />
study. E. Chamorey: Member <strong>of</strong> Scientific Committee for this study. P. Céruse,<br />
F. Mornex: Member <strong>of</strong> Scientific Committee for this study Member <strong>of</strong> Merck Advisory<br />
Board. L. Digue, A. Berrier: Member <strong>of</strong> Scientific Committee for this study. S. Faivre:<br />
Speaker in Merck event. A. Seronde-Delmas: Merck employee. F. Peyrade: Member <strong>of</strong><br />
Scientific Committee for this study Member <strong>of</strong> Merck Advisory Board. C. Le Tourneau:<br />
Speaker for Merck event Member <strong>of</strong> Scientific Committee for this study. All other<br />
authors have declared no conflicts <strong>of</strong> interest.<br />
968P<br />
Cytokeratin 4 is a novel predictive marker in early stage (T1/2)<br />
oral tongue squamous cell carcinoma (TSCC)<br />
T. Enokida 1 , S. Fujii 2 , M. Takahashi 3 , T. Wakasugi 1 , T. Yamazaki 1 , S. Okano 1 ,<br />
R. Hayashi 4 , M. Tahara 1<br />
1 Department <strong>of</strong> Head and Neck Medical <strong>Oncology</strong>, National Cancer Center<br />
Hospital East, Kashiwa, Japan, 2 Division <strong>of</strong> Pathology, Exploratory <strong>Oncology</strong><br />
Research & Clinical Trial Center, National Cancer Center, Kashiwa, Japan,<br />
3 Department <strong>of</strong> Digestive Endoscopy, National Cancer Center Hospital East,<br />
Kashiwa, Japan, 4 Head and Neck Surgery Division, National Cancer Center<br />
Hospital East, Kashiwa, Japan<br />
Background: We have already shown that cytokeratin 4 (CK4) protein expression is a<br />
favorable prognostic factor for the patients with locally advanced TSCC. The aim <strong>of</strong><br />
this study is to identify predictive markers <strong>of</strong> TSCC recurrence and cancer specific<br />
death among clinicopathological factors including CK4 protein expression.<br />
Methods: Two cohorts including discovery (79 cases) and validation (94 cases) cohorts<br />
consisting <strong>of</strong> the patients with primary TSCC were evaluated. Eligibility criteria were as<br />
follows: 1) preoperative imaging diagnosis <strong>of</strong> cT1/2N0; 2) primary partial glossectomy<br />
without lymph node dissection; and 3) TSCCs with pT1/2. The relationship between<br />
clinicopathological factors and relapse-free survival (RFS) and cancer specific survival<br />
(CSS) was statistically analyzed.<br />
Results: Median age, pT, median tumor thickness and rate <strong>of</strong> positive<br />
immunohisthochemical staining for CK4 in tumor cells in discovery cohort were 63<br />
years (26-89), pT1/2 = 47%/53%, 6 mm (0.75-16), and 59%, respectively. 3-year RFS and<br />
3-year CSS rates were 70.3% and 94.5%, respectively. Multivariate analysis indicated that<br />
pT [pT2 vs. pT1, hazard ratio (HR) <strong>of</strong> 2.63], tumor thickness [≥5mm vs.
abstracts<br />
Results: Among the first cohort, 125 <strong>of</strong> 931 cases (13.4%) have post-RT detectable EBV<br />
DNA signals but in very low copy number. We observed a significantly higher relapse<br />
rate (64.8% vs. 21.3%, P < 0.001) and poor survivals (5-yr OS, 49.5% vs. 85.3%,<br />
P < 0.001) in patients with detectable than those with undetectable EBV DNA after a<br />
median follow-up <strong>of</strong> 99 months. In the prospective cohort, we classified 441 patients<br />
into three subgroups according to blood tests. The subsequent recurrence rates <strong>of</strong><br />
patients with DNA-negative (n = 362), DNA-trace (n = 15), and DNA-positive (n = 64)<br />
were 1.4%, 40%, and 100%, respectively (P < 0.001). Our analysis <strong>of</strong> the 426 patients<br />
with test results showing negative and positive revealed that the sensitivity, specificity,<br />
positive predictive value, negative predictive value, and accuracy were 92.8%, 100%,<br />
100%, 98.6%, and 98.8%, respectively. The latent intervals from DNA-trace to<br />
DNA-positive and DNA-positive to verified recurrence ranged from 28-771 days<br />
(mean 171) and 0-693 days (mean 119).<br />
Conclusions: NPC patients with post-RT persistently detectable EBV DNA may be<br />
regarded as potential existence <strong>of</strong> “minimal residual disease” and warrant future<br />
adjuvant therapy trials. Patients with blood tests showing EBV DNA-positive during<br />
follow-up should be regarded as “biomarker failure” and candidates for future trials <strong>of</strong><br />
early intervention.<br />
Clinical trial identification: CG11133 and CE12111 <strong>of</strong> the Taichung Veterans General<br />
Hospital, Taiwan.<br />
Legal entity responsible for the study: Department <strong>of</strong> Radiation <strong>Oncology</strong>, Taichung<br />
Veterans General Hospital, Taiwan<br />
Funding: The Grant from the Ministry <strong>of</strong> Science and Technology (MOST<br />
103-2314-B-075A-005 -MY3), Taichung Veterans General Hospital<br />
(TCVGH-1027102C, 1037103C, 1047106C), and Bodok’s Trading Co., Ltd., Taiwan.<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
970P<br />
Triweekly versus weekly cisplatin concurrent with<br />
radiotherapy in locally advanced nasopharyngeal carcinoma<br />
M. Lan 1 ,S.Wu 1 , F. Han 1 , M. Deng 1 , C. Chen 1 , Y. Huang 1 , Z. Duan 2 , J. Liao 1 ,<br />
L. Tian 3 , L. Zheng 3 ,T.Lu 1<br />
1 Radiation <strong>Oncology</strong>, Cancer Centre Sun Yat-Sen University, Guangzhou, China,<br />
2 Radiation Diagnosis and Interventional Center, General Hospital <strong>of</strong> Chengdu<br />
Military Region, Chengdu, China, 3 Imaging Diagnosis and Interventional Center,<br />
Cancer Centre Sun Yat-Sen University, Guangzhou, China<br />
Background: Comparative studies on triweekly and weekly cisplatin in locally<br />
advanced nasopharyngeal carcinoma (NPC) were all based on small sample size, and<br />
no definitive conclusion has been reached. The aim <strong>of</strong> this study was to compare the<br />
outcomes <strong>of</strong> concurrent chemoradiotherapy (CCRT) using two different schedules <strong>of</strong><br />
cisplatin in patients with locally advanced NPC.<br />
Methods: From January 2007 to December 2011, 1582 patients with stage II-IVb NPC,<br />
treated with CCRT alone were reviewed. Eight hundred and two patients received<br />
triweekly cisplatin (80-100 mg/m 2 every three weeks, two to three cycles) and 780<br />
patients received weekly cisplatin (30-40 mg/m 2 every week, over five cycles). Clinical<br />
characteristics and treatment factors were well balanced in two groups. Overall survival<br />
(OS), disease–free survival (DFS), locoregional recurrence–free survival (LRRFS),<br />
distant metastasis-free survival (DMFS) and acute toxicity pr<strong>of</strong>iles were calculated.<br />
Results: Median follow-up time was 64 months (range, 4–194 months). For the entire<br />
cohort, the distant metastasis risk was decreased by 30% in the triweekly group than<br />
weekly group (hazard ratio [HR] = 0.70; 95% confidence interval [CI]: 0.49-0.99).<br />
Subgroup analysis revealed that triweekly cisplatin could further improve patients’<br />
5-year DMFS (92.6% vs. 85.8%, P < 0.001, respectively) and DFS (82.6% vs. 77.6%,<br />
P = 0.016, respectively) compared with the weekly group, for patients treated with<br />
intensity-modulated radiotherapy (IMRT). Furthermore, the 5-year DMFS rates were<br />
significantly improved by using triweekly cisplatin in patients with N3 diseases<br />
(HR = 0.37; 95% CI: 0.14-0.94) and stage IV diseases (HR = 0.52; 95% CI: 0.29-0.93).<br />
Grade 3-4 acute toxicities were similar in two groups.<br />
Conclusions: Triweekly cisplatin treatment is more effective than weekly cisplatin<br />
regimen in reducing distant metastases in patients with locally advanced NPC,<br />
especially for those with N3 or stage IV diseases and who were treated with IMRT.<br />
Legal entity responsible for the study: N/A<br />
Funding: This research was supported by Grants from the Natural Science Foundation<br />
<strong>of</strong> China (81402244).<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
971P<br />
High incidence <strong>of</strong> cetuximab-related infusion reactions in<br />
head and neck cancer pts (real life data)<br />
V. Palomar, M. Annereau, N. Lezghed, C. Even, L. Mayache-Badis, M. Iacob,<br />
C. Leibu, M. Matias, P. Bravo, C. Ferte<br />
Institut Gustave Roussy, Villejuif, France<br />
EXTREME trial (NEJM 2008), higher rates were reported in small series <strong>of</strong> SCCHN<br />
(6-10%). There is an urgent need to better appraise the natural history and the<br />
predictive factors for IRs in HNSCC pts exposed to Cetuximab.<br />
Methods: The medical records from all consecutive SCCHN patients (n = 451) treated<br />
by cetuximab at Gustave Roussy (Cancer Campus Grand Paris) from January 2013 to<br />
December 2015 were reviewed. IR severity was defined as per the NCI-CTCAE v4.0.<br />
The impact <strong>of</strong> potential risk factors was analyzed (history <strong>of</strong> allergy, biological and<br />
clinicopathological variables).<br />
Results: All patients analyzed received pre-medication including corticosteroids and<br />
antihistamines. Out <strong>of</strong> 441 patients, 34 patients (7.5%) presented grade 3-4 IR, nearly<br />
all <strong>of</strong> them requiring intensive care unit referral. Most <strong>of</strong> the IRs occurred during the<br />
first cycle (range: 1-3). The occurrence <strong>of</strong> grade 3-4 IR was associated with prior allergy<br />
history (P < 0.05) but not with previous radiotherapy or chemotherapy. Further<br />
analyses (eosinophils, concomitant drugs, etc) will be presented during the ESMO 2016<br />
meeting.<br />
Conclusions: In real life, grade 3-4 IR consecutive to cetuximab appears far more<br />
common (7.5%) than reported in prospective trials. This is the largest series <strong>of</strong> patients<br />
ever focusing on the risk <strong>of</strong> IR induced by cetuximab in SCCHN pts. History <strong>of</strong> prior<br />
allergy is a strong predictor <strong>of</strong> IR and could be used to better allocate treatment and<br />
supervise pts. Further prospective data are however required to confirm this.<br />
Legal entity responsible for the study: Gustave Roussy, Université Paris-Saclay,<br />
Villejuif, France<br />
Funding: Gustave Roussy, Université Paris-Saclay, Villejuif, France<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
972P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Dovitinib in advanced adenoid cystic carcinoma <strong>of</strong> the salivary<br />
glands: Ontario Clinical <strong>Oncology</strong> Group DOVE trial<br />
S.J. Hotte 1 , D. Hao 2 , G.R. Pond 3 , S.A. Laurie 4 , E. Winquist 5 , M. Filion 6 ,M.<br />
N. Levine 3<br />
1 Medical <strong>Oncology</strong>, Escarpment Cancer Research Institute (ECRI) and McMaster<br />
University, Hamilton, ON, Canada, 2 <strong>Oncology</strong>, Tom Baker Cancer Centre, Calgary,<br />
AB, Canada, 3 <strong>Oncology</strong>, Ontario Clinical <strong>Oncology</strong> Group (OCOG), McMaster<br />
University and Escarpment Cancer Research Institute (ECRI), Hamilton, ON,<br />
Canada, 4 <strong>Oncology</strong>, The Ottawa Hospital Regional Cancer Centre, Ottawa, ON,<br />
Canada, 5 <strong>Oncology</strong>, London Regional Cancer Center, London Health Science<br />
Center, University <strong>of</strong> Western Ontario, London, ON, Canada, 6 <strong>Oncology</strong>, Ontario<br />
Clinical <strong>Oncology</strong> Group (OCOG) and McMaster University, Hamilton, ON, Canada<br />
Background: Metastatic adenoid cystic carcinoma (ACC) is a rare, incurable<br />
malignancy <strong>of</strong> the salivary glands with no reliable treatment. Over 90% <strong>of</strong> ACC carry a<br />
t(6;9) translocation that leads to MYB overexpression and upregulation <strong>of</strong> the<br />
fibroblast growth factor 2 (FGF2) ligand. Dovitinib (DOV) is a receptor TKI with<br />
multiple targets including FGFR and VEGFR. In preclinical studies, DOV showed a<br />
suppressive effect in ACC xenografts. We hypothesized that DOV would have<br />
beneficial clinical effects.<br />
Methods: Patients (pts) with incurable ACC were recruited if they had progressed<br />
within 12 months prior to study entry (> 10% change, new lesion(s), or worsening<br />
clinical status). The primary outcome was clinical benefit rate (CBR), a composite<br />
endpoint <strong>of</strong> CR, PR, or SD <strong>of</strong> > six months. Sample size <strong>of</strong> 20 evaluable pts was based<br />
on a CBR <strong>of</strong> 75%, estimated from natural history and previous studies. Archival tissue<br />
was obtained for MYB-NFIB gene translocation by FISH analysis and FGFR and<br />
phospho-FGFR expression. Pts received DOV 500mg orally 5 days on/2 days <strong>of</strong>f on a<br />
28-day cycle with response assessed every 12 weeks.<br />
Results: 21 pts (11 female) with a mean age <strong>of</strong> 55.9 years (range 38.1, 81.5) were<br />
enrolled. Best response was SD in 15 pts. CBR was 7/21 (33.3%). Five <strong>of</strong> 18 pts with<br />
measurable disease (27.8%) had some regression. PFS at 12 months was 37.6%, and<br />
1-year OS was 61.6%. Most patients tolerated DOV reasonably well but six pts<br />
discontinued because <strong>of</strong> toxicity and five required dose reductions. The most frequent<br />
attributable AEs were diarrhea (91%), nausea (67%), fatigue (71%), rash (38%),<br />
anorexia, and vomiting (33% each). Six <strong>of</strong> 15 pts (40%) had wild type MYB by FISH.<br />
Wild type (WT) status was not prognostic for OS (p = 0.38) or PFS (p = 0.18). MYB<br />
IHC was not prognostic for either OS (p = 0.086) or PFS (p = 0.74), but pFGFR IHC<br />
score was significantly prognostic for OS (HR = 1.35, 95% CI = 1.01-1.80, p = 0.040),<br />
but not PFS (p = 0.11).<br />
Conclusions: DOV toxicity was generally manageable with predominantly<br />
gastrointestinal adverse events. However, objective responses were not observed and<br />
the primary endpoint <strong>of</strong> clinical benefit was not met. Although tumor pFGFR IHC<br />
score appeared prognostic, no pharmacodynamic predictors <strong>of</strong> clinical activity from<br />
DOV were identified.<br />
Clinical trial identification: NCT01678105<br />
Legal entity responsible for the study: N/A<br />
Funding: Novartis<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
Background: Cetuximab is crucial in the management <strong>of</strong> squamous cell carcinoma <strong>of</strong><br />
the head and neck (SCCHN) patients. Grade 3-4 infusion reactions (IRs) occur in 2%<br />
<strong>of</strong> colorectal cancer (ASPECCT study, ∼1000 pts). Despite the 2.7% IR rate in the<br />
vi336 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
973P<br />
The role <strong>of</strong> pre-treatment plasma Epstein-Barr virus (EBV)<br />
DNA as a predictive biomarker <strong>of</strong> induction chemotherapy for<br />
stage IVA or IVB nasopharyngeal carcinoma (NPC) patients – A<br />
Subgroup Analysis on Taiwan Cooperative <strong>Oncology</strong> Group<br />
(TCOG) 1303 study<br />
H-F. Kao 1 , C-F. Hsiao 2 , S-C. Lai 2 , C-W. Wang 1 , J-Y. Ko 3 , P-J. Lo 3 , T-J. Lee 1 ,<br />
T-W. Liu 4 , R-L. Hong 1<br />
1 Department <strong>of</strong> <strong>Oncology</strong>, National Taiwan University Hospital, Taipei, Taiwan,<br />
2 Institute <strong>of</strong> Population Health Sciences, National Health Research Institutes,<br />
Miao-Li, Taiwan, 3 Department <strong>of</strong> Otorhinolaryngology, National Taiwan University<br />
Hospital, Taipei, Taiwan, 4 National Health Research Institutes, Taiwan Cooperative<br />
<strong>Oncology</strong> Group, Taipei, Taiwan<br />
Background: Pre-treatment plasma EBV DNA is considered as a prognostic biomarker<br />
for NPC patients. Whether the pre-treatment EBV DNA could be a biomarker guiding<br />
the treatment for advanced NPC patients warrants investigation.<br />
Methods: TCOG 1303 was a phase III trial comparing induction chemotherapy (IC)<br />
followed by concurrent chemoradiation (CCRT) versus CCRT alone in stage IVA or<br />
IVB NPC patients. In both arms, radiotherapy would be delivered with weekly cisplatin<br />
(30mg/m2). For patients in IC arm, chemotherapy with mitomycin C, epirubicin,<br />
cisplatin, 5-fluorouracil, and leucovorin were administered for 3 cycles before the<br />
CCRT. The primary endpoint was disease free survival. Pre-treatment plasma EBV<br />
DNA was analyzed.<br />
Results: From September 2003 to August 2009, 479 patients were enrolled. The<br />
pre-treatment plasma EBV DNA were collected from 264 patients. The median<br />
follow-up were 66 months. The median <strong>of</strong> plasma EBV DNA was 7862.5 copies/mL.<br />
135 pts were grouped in EBV DNA < 8000 copies/mL (EBV-low) and 129 pts in EBV<br />
DNA >= 8000 copies/mL (EBV-high). High plasma EBV DNA is statistically<br />
significant with larger tumor size (p < 0.0001), advanced N stage (p = 0.001) and<br />
overall stage (p = 0.0002). Between the EBV-low and EBV-high groups, there was no<br />
statistically significant difference in DFS (HR = 1.26 (95% CI: 0.85-1.87), p = 0.25) and<br />
overall survival (OS) (HR = 1.39 (0.84-2.28), p = 0.20) with Cox proportional hazard<br />
model. Between the IC-CCRT arm and CCRT arm in the EBV-low group or EBV-high<br />
group, no significant difference in characteristics was observed between two arms. By<br />
univariate Cox-regression analysis, there was no statistically significant difference on<br />
DFS and OS between IC-CCRT and CCRT in both groups (EBV-high: IC-CCRT vs<br />
CCRT, DFS: HR = 0.788 (0.46-1.37), p = 0.40, and OS: HR = 0.85 (0.43-1.69), p = 0.65;<br />
EBV-low: IC-CCRT vs CCRT: DFS: HR = 0.73 (0.41-1.28), p = 0.27, and OS: HR = 0.64<br />
(0.32-1.27), p = 0.20).<br />
Conclusions: Pre-treatment plasma EBV DNA cannot be a biomarker <strong>of</strong> induction<br />
MEPFL for stage IVA or IVB NPC patients. The biology role <strong>of</strong> pre-treatment EBV<br />
DNA should be explored.<br />
Clinical trial identification: NCT00201396<br />
Legal entity responsible for the study: Hsiang-Fong Kao<br />
Funding: National Taiwan University Hospital, Taiwan National Health Research<br />
Institutes, Taiwan<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
974P<br />
Prospective study <strong>of</strong> cetuximab with cisplatin plus docetaxel<br />
followed by concurrent radiotherapy plus cetuximab and<br />
cisplatin in patients with chemotherapy-naive metastatic<br />
nasopharyngeal carcinoma<br />
T. Lin, M. Zhang, H. Huang, X. Li, Y. Huang, C. Chen, Z. Wang, X. Fang<br />
Department <strong>of</strong> Medical <strong>Oncology</strong>, Cancer Centre Sun Yat-Sen University,<br />
Guangzhou, China<br />
Background: Metastatic nasopharyngeal carcinoma (mNPC) is generally considered as<br />
incurable using conventional therapy. We incorporated cetuximab into the induction<br />
therapy and subsequent chemoradiotherapy to treat mNPC in a prospective study.<br />
Methods: Between Jul 2006 to Dec 2014, eligible patients (≥18 years old) with<br />
chemotherapy-naive mNPC, including initial metastases (IM) and first relapse<br />
metastases (RM), entered into the trial according to their willingness. Patients in the<br />
study group were treated with docetaxel 75 mg/m2, cisplatin 75 mg/m2, and cetuximab<br />
250 mg/m2 days 1, 8, and 15 (after an initial loading dose <strong>of</strong> 400 mg/m2), repeated<br />
every 3 weeks up to a maximum <strong>of</strong> 6 cycles, followed by IMRT (68-70 Gy) with<br />
concurrent cetuximab 250 mg/m2 weekly for six cycles and cisplatin 75 mg/m2 per<br />
three weeks for two cycles, and maintenance capecitabine plus celecoxib for 3 years.<br />
Patients in the control group received conventional chemoradiotherapy.<br />
Results: Totally 43 patients in the study group (17 IM and 26 RM patients), and 66<br />
patients in the control group were enrolled. The ORR and CRR after induction<br />
chemotherapy were 79.1% and 34.9% for the study group and 47% and 3% for the<br />
control group respectively. With a median follow-up <strong>of</strong> 60 months, 5yOS and PFS were<br />
28.9% and 16.7% in the study group and 10.9% and 0% in the control group,<br />
respectively. In the study group the ORR and CRR were higher in the IM than in the<br />
RM subgroup (94.1% vs. 69.2%, 52.9% vs. 23.1%, both p < 0.05), and IM patients had a<br />
longer 5yOS (45.7% vs 19.2%, p = 0.006). In the study group 13 survivors remained<br />
disease-free >36 months, 10 <strong>of</strong> them were still alive with disease-free survival time<br />
ranging from 46 to 92+ months. Five patients (11.6%) had grade 3 cetuximab-related<br />
acneiform rash. Occurrence <strong>of</strong> other most common toxicities were similar between the<br />
two groups.<br />
Conclusions: The cetuximab-containing induction and consolidation chemoradiation<br />
in patients with chemotherapy-naive mNPC resulted in excellent long-term<br />
disease-free survival and safety, indicating that mNPC is potential curable, especially in<br />
patients with initial metastases.<br />
Legal entity responsible for the study: Department <strong>of</strong> Medical <strong>Oncology</strong>, Sun Yat-sen<br />
University Cancer Center, Guangzhou, China<br />
Funding: Department <strong>of</strong> Medical <strong>Oncology</strong>, Sun Yat-sen University Cancer Center,<br />
Guangzhou, China; Sun Yat-sen University Cancer Center<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
975P<br />
Individual ADCC capability predict treatment outcome under<br />
cetuximab-based therapy in head and neck cancer?<br />
L. Lattanzio 1 , D. Vivenza 1 , F. Tonissi 1 , C. Varamo 1 , M. Ferrero 1 , G. Strola 2 ,<br />
G. Milano 3 , C. Lo Nigro 1 , M.C. Merlano 1<br />
1 Clinical <strong>Oncology</strong>, S. Croce Teaching Hospital, Cuneo, Italy, 2 Laboratory,<br />
S. Croce Teaching Hospital, Cuneo, Italy, 3 Oncopharmacology, Centre Antoine<br />
Lacassagne, Nice, France<br />
Background: Cetuximab is a IgG1 monoclonal antibody against epidermal growth<br />
factor receptor (EGFR) used for the treatment <strong>of</strong> local advanced-head and neck<br />
squamous cell carcinoma (LA-HNSCC). A working mechanism <strong>of</strong> cetuximab include<br />
the ability to develop antibody-dependent cell-mediated cytotoxicity (ADCC),<br />
triggered by the interaction <strong>of</strong> the Fc portion <strong>of</strong> the antibody with the Fc receptor on<br />
the immune cell, mainly on Natural Killer (NK) cells. Invariant NKT (iNKT) cells play<br />
an important role in the activation <strong>of</strong> immune cell subset, including NK cells, and their<br />
deficiency is related to poor clinical outcome in LA-HNSCC. The aim <strong>of</strong> this work was<br />
to investigate the predictive role <strong>of</strong> ADCC and iNKT in LA-HNSCC patients treated<br />
with cetuximab-based therapy.<br />
Methods: Twenty-eight LA-HNSCC patients treated with curative intent with<br />
cetuximab-based radio-chemotherapy were analysed. Peripheral blood samples were<br />
collected at start <strong>of</strong> therapy. ADCC was evaluated as ex vivo NK-dependent activity<br />
measuring LDH release as previously standardized in our laboratory. EGFR tumoral<br />
expression was analyzed by immunohistochemistry.<br />
Results: ADCC activity above the median value (high) correlated with a better OS as<br />
compared to ADCC below the median (low) in LA-HNSCC (p = 0.033). We observed a<br />
correlation also between high ADCC and response rate (p = 0.038). By univariate<br />
analysis on OS there were ADCC activity tumor size and HPV status as significant<br />
pronostic indicators. According to multivariate log-rank analysis only ADCC remained<br />
a significant predictor for OS (p = 0.03). If we stratified the EGFR 3+ patients into high<br />
and low ADCC performers, we observed an impressive increased OS in those with high<br />
ADCC (p = 0.024). iNKT cells number didn’t significantly correlate with OS:<br />
nonetheless, we observed a trend to a longer survival after 10 months in patients with<br />
high iNKT cells (above the median values).<br />
Conclusions: ADCC has a strong predictive value <strong>of</strong> cetuximab response in HNSCC.<br />
High tumoral EGFR expression and high ADCC confer a particularly long overall<br />
survival and suggest to combine this two biomarkers in order to predict clinical<br />
outcome in cetuximab-treated HNSCC patients.<br />
Legal entity responsible for the study: M.C. Merlano<br />
Funding: ARCO foundation<br />
Disclosure: M.C. Merlano: Consultant for Merck Serono. All other authors have<br />
declared no conflicts <strong>of</strong> interest.<br />
976P<br />
abstracts<br />
Prognostic value <strong>of</strong> HPV infection by E1 detection and p16<br />
expression in 78 oropharyngeal squamous cell carcinomas<br />
C. Lo Nigro 1 , D. Vivenza 1 , L. Lattanzio 1 , M. Fortunato 2 , N. Denaro 1 , C. Varamo 1 ,<br />
M. Ferrero 3 , E. Russi 4 , M.C. Merlano 1<br />
1 Clinical <strong>Oncology</strong>, S. Croce Teaching Hospital, Cuneo, Italy, 2 Pathology, S. Croce<br />
Teaching Hospital, Cuneo, Italy, 3 Clinical <strong>Oncology</strong>, Pathology, S. Croce Teaching<br />
Hospital, Cuneo, Italy, 4 Radiotherapy, S. Croce Teaching Hospital, Cuneo, Italy<br />
Background: HPV infection is a strong prognostic marker in oropharyngeal squamous<br />
cell carcinomas (OSCCs). HPV-positive pts are associated with better survival than<br />
HPV-negative ones. Currently, the expression <strong>of</strong> p16 is the standard test to identify<br />
HPV positive OSCCs in clinical practice. The combined use <strong>of</strong> p16 and HPV DNA<br />
detection is the recommended standard for clinical research, at least in USA. In the<br />
present study we compare the prognostic value <strong>of</strong> a genomic viral fragment, E1, with<br />
p16 expression in a series <strong>of</strong> OSCC pts in terms <strong>of</strong> overall survival (OS) and<br />
progression free survival (PFS).<br />
Methods: HPV was searched in 78 OSCC pts (63M/15F; median age 61; range 35-77)<br />
treated with chemoradiotherapy between 1997 and 2014. We used a specific E1 primer<br />
pair for HPV type 16 in a DNA-PCR assay on formalin-fixed paraffin-embedded (FFPE)<br />
tissues collected at diagnosis. Those primers were designed inside the coding region most<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw376 | vi337
abstracts<br />
frequently disrupted during viral integration in host chromosome, in order to get a<br />
fragment <strong>of</strong> 168 bp. Positivity for p16 was defined as ≥ 70% positive cells by IHC.<br />
Results: Twenty-six pts (33.4%) were HPV positive for E1 fragment, while 27 (34.6%)<br />
showed a pos ≥70% for p16. In terms <strong>of</strong> prognostic value, positive OSCC pts showed<br />
improved OS (p = 0.01 for E1 and p = 0.04 for p16) and PFS (p = 0.03 for E1 and<br />
p = 0.02 for p16), compared to negative ones. The concordance between p16 and E1<br />
positivity was high (k = 0.74) and HPV power detection was similar to p16. Moreover,<br />
among positive p16 pts (n = 27), the E1 positive ones (n = 22) resulted to have a<br />
significant more favourable OS than the negative (n = 5) (p = 0.03). On the contrary,<br />
among positive E1 pts (n = 26), the p16 positive ones (n = 22) did not shown any<br />
difference in OS from the p16 negative ones (n = 4) (p = 0.25).<br />
Conclusions: We observed a good concordance between p16 by IHC and E1 by<br />
DNA-PCR for HPV detection on FFPE tissues, in the present series <strong>of</strong> OSCCs. E1<br />
might become a strong prognostic marker for OS and PFS in OSCCs and clinically as<br />
relevant as IHC for p16. Moreover the concurrent positivity for both markers<br />
(E1 + p16+) allowed the selection <strong>of</strong> pts with the best OS. When E1 and p16 resulted<br />
discordant, our data support the more accurate value <strong>of</strong> E1 in predicting OS.<br />
Legal entity responsible for the study: Merlano<br />
Funding: ARCO Foundation<br />
Disclosure: M.C. Merlano: Consultant for Merck Serono. All other authors have<br />
declared no conflicts <strong>of</strong> interest.<br />
977P<br />
Comorbidity and nutritional factors influence on<br />
bioradiotherapy (BRT) outcome in head and neck squamous<br />
cell carcinoma (HNSCC) patients<br />
M. Oliva 1 , M. Taberna 1 , A.J. Rullan Iriarte 1 , M. Bergamino 1 , A. Rovira 2 , R. Montal 1 ,<br />
L. Hurtos 3 , L. Arribas 3 , E. Vilajosana 4 , A. Lozano 5 , V. Navarro 6 , S. Vazquez 1 ,<br />
M. Maños 2 , R. Mesía 1<br />
1 Medical <strong>Oncology</strong> - Head and Neck, Institut Catala de Oncologia, Barcelona,<br />
Spain, 2 ENT Specialist, Hospital Universitari de Bellvitge, Barcelona, Spain,<br />
3 Nutrition - Head and Neck, Institut Catala de Oncologia, Barcelona, Spain,<br />
4 Nursing - Head and Neck, Institut Catala de Oncologia, Barcelona, Spain,<br />
5 Radiation <strong>Oncology</strong> - Head and Neck, Institut Catala de Oncologia, Barcelona,<br />
Spain, 6 Biostatistics for Medical <strong>Oncology</strong>, Institut Catala de Oncologia,<br />
Barcelona, Spain<br />
Background: BRT is a validated conservative treatment for patients (pts) with locally<br />
advanced HNSCC. Our aim is to analyze the outcome <strong>of</strong> a large consecutive cohort <strong>of</strong><br />
pts treated with radiotherapy plus cetuximab and to determine disease control and<br />
survival related factors.<br />
Methods: 253 pts diagnosed with HNSCC were treated radically with BRT +/-<br />
induction chemotherapy (iCT) in our Institution (2006-2014). We performed a<br />
multivariate analysis (COX) adjusted by classic risk factors, stage, iCT, comorbidity,<br />
weight loss (WL), pre-treatment albumin (PTA), albumin drop (AD) and magnesium<br />
(Mg). Pts were divided in 3 groups: A1(stage III), A2 (stage IVa-b), B(presence <strong>of</strong><br />
comorbidity regardless stage). We analyzed complete response rate (CRR), 2-year<br />
locorregional control rate (2yLCR), median progression free survival (mPFS) and<br />
median overall survival (mOS) using Kaplan-Meier stratified by iCT.<br />
Results: Median follow-up: 60 months (m) (11-115). Overall results: CRR: 76,4 %,<br />
2yLCR: 72%, mPFS 31 m (24.7-38.5), mOS 45 m (29-61.7), iCT LogRank .00. Group<br />
results on table1: comorbidity impact on OS in group B was mantained when stratified<br />
by stage. Multivariate analysis: comorbidity and stage IV were the main risk factors for<br />
PFS (HR 2,43, p .00; HR 2,76, p .00 respectively) and OS (HR 3,05, p .00; HR 2,28, p .00<br />
respectively). iCT influenced positively on OS (HR 0.58, p .02). WL and PTA didn’t<br />
impact on PFS/OS. AD >10% during treatment was a risk factor for OS (35m vs 85m,<br />
HR 2 p .02) and influenced on 2yLCR (regression tree - 3 clusters: AD 2,21% and PTA 15% impacted on OS (18.8m vs 85.5m,<br />
HR 3.65 p .002).<br />
Table: 977P Groups stratified results<br />
A1 26<br />
(10.3%)<br />
A2 97<br />
(38.3%)<br />
B 130 (51.4%) Stage III:12,3%<br />
Stage IVa,b: 39,1%<br />
CRR (%) 84 72,9 77,7<br />
2-year LCR 95 82 57,1<br />
(%)<br />
mPFS (m) Not Reached NR 17,8 (IC 11,9-22,5 p: .000)<br />
(NR)<br />
mOS (m) NR NR 32 (IC 25.4-40.3, p .004)<br />
Conclusions: Comorbidity and stage IV are the main prognostic factors in this group<br />
<strong>of</strong> pts. As it clearly impacts on survival, comorbidity should be considered when<br />
choosing the best treatment. AD at the end <strong>of</strong> treatment could be a useful prognostic<br />
biomarker. Detecting Mg drop and starting supplementation might be essential in pts<br />
treated with BRT.<br />
Legal entity responsible for the study: Institut Català d’Oncologia - Hospita Duran i<br />
Reynals.<br />
Funding: Institut Català d’Oncologia - Hospita Duran i Reynals<br />
Disclosure: M. Taberna: the author has taken part in advisory broads as a speaker for<br />
Merck Serono Group. R. Mesía: has taken part in advisory boards and educational<br />
meetings as faculty and speaker for Merck Serono, Bayer and AstraZeneca, he has also<br />
received occasional travel fund to conferences/symposia/ meetings by Merck Serono.<br />
All other authors have declared no conflicts <strong>of</strong> interest.<br />
978P<br />
Prevalence, pattern, and impact <strong>of</strong> PD-L1 expression and<br />
HPV-status in head and neck squamous cell carcinoma<br />
T. Chureemas 1 , N. Larbcharoensub 2 , J. Juengsamarn 1 , T. Layangkool 3 ,<br />
C. Jiarpinitnun 4 , P. Chansriwong 1 , N. Trachu 5 , P. Pattaranutaporn 4 ,<br />
N. Ngamphaiboon 1<br />
1 Medical <strong>Oncology</strong>, Ramathibodi Hospital, Bangkok, Thailand, 2 Pathology,<br />
Ramathibodi Hospital, Bangkok, Thailand, 3 Internal Medicine, Ramathibodi<br />
Hospital, Bangkok, Thailand, 4 Radiation <strong>Oncology</strong>, Ramathibodi Hospital,<br />
Bangkok, Thailand, 5 Molecular Biology, Ramathibodi Hospital, Bangkok, Thailand<br />
Background: Early phase clinical studies showed activities <strong>of</strong> anti PD-L1/PD-1<br />
antibody in head and neck squamous cell carcinomas (HNSCC). PD-L1 expression was<br />
extensively evaluated as a biomarker though no standardized method <strong>of</strong> detection has<br />
been defined. HPV status is a well-established prognostic maker <strong>of</strong> HNSCC.<br />
Prevalence, pattern, and impact <strong>of</strong> PD-L1 expression in HPV-associated HNSCC<br />
remain unclear and may vary in different ethnicity.<br />
Methods: HNSCC patients treated at the Ramathibodi Cancer Center between 1/2007<br />
and 12/2013 were identified through the cancer registry database. Patient<br />
characteristics, treatments, and survivals were abstracted. Archrival formalin-fixed<br />
paraffin-embedded (FFPE) tissues were retrieved for PD-L1 and p16 analyses. PD-L1<br />
expression was evaluated by using an anti-human PD-L1 rabbit monoclonal antibody<br />
(clone SP142; Ventana) on an automated staining platform (Ventana). PD-L1 was<br />
evaluated on tumor cells (TC) and tumor-infiltrating immune cells (IC), and scored<br />
ranging between 0-100%. For overall survival (OS) analysis, specimens were scored as<br />
≥5% on TCs or ICs to define PD-L1 positive. HPV status was determined by p16<br />
immunohistochemistry.<br />
Results: 204 HNSCC patients with available FFPE tissues were analyzed. PD-L1 on<br />
TCs was expression (≥1%) and highly expressed (≥50%) in 72.2% and 18.4% <strong>of</strong><br />
patients, respectively. With a definition <strong>of</strong> PD-L1 ≥5% on TCs or ICs, 79.7% <strong>of</strong> patients<br />
was considered as PD-L1+. No statistically difference in patient characteristics between<br />
PD-L1 positive and negative, except age ≥65 was associated with a higher incidence <strong>of</strong><br />
PD-L1 positive (53.4% vs 21.1%; p = 0.001). Overall, 74 patients (36.3%) was p16+. No<br />
association <strong>of</strong> PD-L1 and p16 was observed (p = 0.116). OS was significantly longer in<br />
PD-L1+ patients (34.5 vs 21.5 months; p = 0.044). In subgroup analysis <strong>of</strong> PD-L1/p16<br />
status, OS was superior in patients with +/ + , +/-, -/-, and -/ + , respectively (67.4 vs<br />
23.6 vs 21.5 vs 15.8 months; p = 0.006).<br />
Conclusions: A high prevalence <strong>of</strong> PD-L1 expression was observed in HNSCC. PD-L1<br />
expression was a strong prognostic maker for OS, especially in p16+ HNSCC patients.<br />
These results support further development <strong>of</strong> anti PD-L1/PD-1 antibody in HNSCC.<br />
Legal entity responsible for the study: Ramathibodi hospital<br />
Funding: Ramathibodi Cancer Center<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
979P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Does post-induction chemotherapy PET/CT response predict<br />
outcome in young adult nasopharyngeal carcinoma?<br />
Prospective study from CCHE<br />
S.A. Ahmed 1 , M. Amr Abdelwahab 2 , E. A.el-Kholy 2 , A. Kamel 3 , S. A.fadel 3 ,<br />
H. Taha 4 , I. Zaky 5 , A. Elnashar 6<br />
1 Radiotherapy, Children’s Cancer Hospital Egypt, Cairo, Egypt, 2 Nuclear<br />
Medicine, Children’s Cancer Hospital Egypt, Cairo, Egypt, 3 Pediatric <strong>Oncology</strong>,<br />
National Cancer Institute Egypt, CCHE, Cairo, Egypt, 4 Surgical Pathology,<br />
Children’s Cancer Hospital Egypt, Cairo, Egypt, 5 Radiodiagnosis, Children’s<br />
Cancer Hospital Egypt, Cairo, Egypt, 6 Biostatistics, Children’s Cancer Hospital<br />
Egypt, Cairo, Egypt<br />
Background: This is a prospective study aiming to evaluate the predictive value <strong>of</strong><br />
18 F-fluorodeoxyglucose positron emission tomography ( 18 F-FDG PET/CT), reflected<br />
in terms <strong>of</strong> disease-free survival (DFS) and overall survival (OS), in pediatric patients<br />
who had received post induction chemotherapy for locally advanced nasopharyngeal<br />
carcinoma (LANPC). Pediatric patients were treated definitively with 3 courses <strong>of</strong><br />
induction platinum-based chemotherapy followed by concurrent chemoradiation<br />
(CRT) with simultaneous integrated boost intensity-modulated radiotherapy<br />
(SIB-IMRT) .<br />
Methods: This is a prospective study included LANPC (stage II-III) pediatric patients<br />
treated definitively and consecutively between January 2008 and December 2014 with<br />
induction chemotherapy; cisplatin, and 5-fluorouracil (PF) followed by SIB-IMRT to a<br />
total dose 61.2Gy with utilizing weekly cisplatin. The volume <strong>of</strong> radiotherapy was<br />
vi338 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
based on tumor response to Induction chemotherapy. All patients had baseline<br />
pretreatment and post induction chemotherapy 18F-FDG PET/CT. Metabolic response<br />
<strong>of</strong> the primary tumor and LN was assessed using maximum standardized uptake value<br />
(SUV max ) that was correlated with treatment outcomes; OS and EFS.<br />
Results: The study included 38 eligible pediatric LANPC patients. The 3-year OS and<br />
DFS rates were 84.6 % and 79.5%, respectively. The median OS and EFS intervals were<br />
not reached. On a univariate analysis, the 3-years OS and EFS were significantly higher<br />
in patients with post induction metabolic regression <strong>of</strong> SUV max >65% for the primary<br />
and 57% for the nodal metastases (P = 0.02). Furthermore, OS and EFS were lower in<br />
patients with initial high nodal metabolic activity (P = 0.004) and (P = 0.005) with SUV<br />
max cut<strong>of</strong>f values (14.5) and (6.9) respectively. Also Initial SUV-LN > SUV-Primary<br />
showed significant lower OS (P = 0.004) and EFS (P = 0.005).<br />
Conclusions: In this study, the degree <strong>of</strong> metabolic regression in post-induction<br />
chemotherapy 18F-FDG PET/CT was a potential independent prognostic indicator for<br />
clinical outcomes in LANC pediatric patients (treated definitively with PF induction<br />
chemotherapy followed by CRT). Further controlled clinical trials are worthwhile.<br />
Legal entity responsible for the study: CCHE<br />
Funding: CCHE<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
980P<br />
Advanced acinic cell carcinoma harbors kinase<br />
rearrangements including BRAF kinase domain duplications<br />
S.M. Ali 1 , K. Fedorchak 1 , A.B. Schrock 2 , J. Johnson 3 ,K.Gowen 1 , J.A. Elvin 4 ,<br />
J-A. Vergilio 4 , S.J. Klempner 5 , R. Mehra 6 ,A.Ho 7 , D. Pavlick 1 , J. Suh 4 , R. Bordoni 8 ,<br />
D.H. Jung 9 , P. Stephens 1 , C.H. Chung 10 , J.S. Ross 11 , V. Miller 2<br />
1 Research and Development, Foundation Medicine, Inc, Cambridge, MA, USA,<br />
2 Clinical Development, Foundation Medicine, Inc., Cambridge, MA, USA, 3 Medical<br />
<strong>Oncology</strong>, Kimmel Cancer Center-Thomas Jefferson University, Philadelphia, PA,<br />
USA, 4 Pathology, Foundation Medicine, Inc., Cambridge, MA, USA, 5 Medical<br />
<strong>Oncology</strong>, The Angeles Clinic and Research Institute, Los Angeles, CA, USA,<br />
6 <strong>Oncology</strong>, Fox Chase Cancer Center, Philadelphia, PA, USA, 7 Medical <strong>Oncology</strong>,<br />
Memorial Sloan Kettering Cancer Center, New York, NY, USA, 8 Medical <strong>Oncology</strong>,<br />
Georgia Cancer Specialists, Marietta, GA, USA, 9 Otolarynology, Mass Eye and Ear<br />
Infirmary, Boston, MA, USA, 10 Medical <strong>Oncology</strong>, H. Lee M<strong>of</strong>fitt Cancer Center<br />
University <strong>of</strong> South Florida, Tampa, FL, USA, 11 Pathology, Albany Medical Center,<br />
Albany, NY, USA<br />
Background: A subset <strong>of</strong> patients with acinic cell carcinoma (AcCC), a typically<br />
indolent tumor arising from the exocrine cells <strong>of</strong> salivary glands, will experience<br />
substantial morbidity and mortality from recurrent and metastatic disease. No<br />
consensus guidelines exist for management <strong>of</strong> advanced AcCC.<br />
Methods: 72 advanced AcCC cases were assayed with hybrid-capture based<br />
comprehensive genomic pr<strong>of</strong>iling (CGP) in the course <strong>of</strong> clinical care to identify<br />
genomic alterations (GA) suggesting benefit from targeted therapy.<br />
Results: 61 (85%) <strong>of</strong> AcCC had at least one GA (mean 2.1 GA per case), and clinically<br />
relevant genomic alterations (CRGA) were identified in 27 (38%) AcCC cases. The<br />
genes most commonly altered were CDKN2A (60%), PTEN (8%), and TP53 (7%).<br />
Other genes altered at 4% or less included FBXW7, ATM1, NF1 and BRAF. GAs<br />
affecting the PI3K/AKT/mTOR pathway (PTEN, PIK3CA, FBXW7) were present in<br />
15% <strong>of</strong> cases, and no other signaling pathways were repeatedly perturbed. Of three<br />
BRAF altered cases (4%), one harbored a V600E mutation and two harbored BRAF<br />
kinase domain duplications (KDD), with one <strong>of</strong> the latter patients having a >6 month<br />
dramatic response to the promiscuous RAF inhibitor regorafenib. Three cases (4%), all<br />
<strong>of</strong> parotid origin, harbored ETV6-NTRK3 fusions. One patient responded to<br />
entrectinib (Drillon et al 2016), and another has been enrolled in a trial for<br />
investigational inhibitor.<br />
Conclusions: Advanced AcCC is the first tumor type to be identified as harboring<br />
recurrent BRAF KDD, which is associated with clinical benefit from regorafenib.<br />
Moreover, detection <strong>of</strong> ETV6-NTRK3 in these cases is widely interpreted as a<br />
diagnostic <strong>of</strong> mammary analogue secretory carcinoma (MASC) with such patients<br />
predicted to benefit from NTRK inhibitors. Further investigations including<br />
RNA-sequencing are underway to define additional targetable oncogenic drivers in<br />
advanced AcCC cases not harboring the above alterations.<br />
Legal entity responsible for the study: Siraj Ali<br />
Funding: N/A<br />
Disclosure: S.M. Ali, K. Fedorchak, A.B. Schrock, K. Gowen, J.A. Elvin, J-A. Vergilio,<br />
D. Pavlick, J. Suh, P. Stephens, J.S. Ross, V. Miller: Employee <strong>of</strong> and equity interest in<br />
foundation medicine inc. S.J. Klempner: Speakers bureau for foundation medicine inc.<br />
All other authors have declared no conflicts <strong>of</strong> interest.<br />
981P<br />
Pharmacogenomic predictors <strong>of</strong> cisplatin oto- and<br />
nephrotoxicity in head and neck cancer patients treated with<br />
chemoradiation<br />
E. Winquist 1 , W.A. Teft 2 , A. Nichols 3 , C. Parker 3 , M. Trinnear 1 , P. Francis 1 ,<br />
N. Bukhari 1 , J. Lukovic 1 , Y-H. Choi 2 , S. Kuruvilla 1 , S. Richter 1 , A. Hammond 1 ,<br />
D. Macneil 3 , N. Read 1 , K. Fung 3 , V. Venkatesan 1 , S. Welch 1 , D. Palma 1 ,J.Yoo 3 ,R.<br />
B. Kim 2<br />
1 Department <strong>of</strong> <strong>Oncology</strong>, University <strong>of</strong> Western Ontario, London, ON, Canada,<br />
2 Department <strong>of</strong> Medicine, University <strong>of</strong> Western Ontario, London, ON, Canada,<br />
3 Department <strong>of</strong> Otolaryngology-Head&Neck Surgery, University <strong>of</strong> Western<br />
Ontario, London, ON, Canada<br />
Background: Cisplatin-based chemoradiotherapy (CRT) remains a standard treatment<br />
for patients (pts) with locally advanced head and neck squamous cell carcinomas<br />
(HNSCCs). However, use <strong>of</strong> cisplatin may cause oto- and nephrotoxicity which may<br />
compromise both treatment delivery and longterm quality <strong>of</strong> life. We hypothesized that<br />
polymorphisms (SNPs) in cisplatin methyltransferases (TPMT, COMT),<br />
acylphosphatases (ACYP2) and transporters (CTR1, OCT2, MATE1, ABCC2, ABCC3)<br />
could predict oto- and nephrotoxicity and investigated this in a prospective cohort<br />
study.<br />
Methods: Consenting HNSCC pts with adequate baseline hearing and renal function<br />
treated with CRT were prospectively enrolled. Audiometric testing was done at<br />
baseline, and 3, 6, 12 & 18 months. Serum creatinine was assessed baseline & weekly<br />
during CRT. Ototoxicity was defined as ≥grade 2 audiometric change from baseline<br />
(CTCAE v4.02) present 12 months post-treatment. Nephrotoxicity was defined as<br />
≥grade 2 acute kidney injury after initiation <strong>of</strong> cisplatin. Relationships between clinical<br />
variables, genotype and outcomes were assessed using Cox regression with interval<br />
censoring and reported as a hazard ratio (HR).<br />
Results: 207 consecutive HNSCC pts have been enrolled. To date ≥grade 2 ototoxicity<br />
has developed in 64% and ≥grade 2 nephrotoxicity observed in 22% <strong>of</strong> 170 evaluable<br />
pts. In multivariate analyses TPMT and COMT SNP carriers were at increased risk <strong>of</strong><br />
developing ototoxicity (HR 4.47 [95%CI 1.66-12.03, p < 0.05] and HR 3.09 [95%CI<br />
1.65-5.82, p < 0.001, respectively). MATE1 SNP carriers were at reduced risk (HR 0.36<br />
[95%CI 0.14-0.96 p < 0.05]). SNP allele prevalence was: TPMT rs12201199 7.8%,<br />
COMT rs9332377 32.3%, MATE1 rs2289669 14.4%. Analyses including all remaining<br />
pts, ACYP2 as a predictor and nephrotoxicity as outcome are underway and will be<br />
presented.<br />
Conclusions: Oto- and nephrotoxicity occur frequently in HNSCC pts treated with<br />
CRT. SNPs in both cisplatin metabolizing enzymes and transporters appear to predict<br />
vulnerability to these. We plan to assess the clinical utility <strong>of</strong> these SNPs for toxicity<br />
avoidance in a prospective clinical trial.<br />
Legal entity responsible for the study: University <strong>of</strong> Western Ontario<br />
Funding: Ontario Institute <strong>of</strong> Cancer Research, Cancer Care Ontario, London<br />
Regional Cancer Program, LRCP Medical <strong>Oncology</strong> Research Fund<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
982P<br />
abstracts<br />
Metronomic oral cyclosphosphamide as 3rd line systemic<br />
treatment or beyond in patients with inoperable locoregionally<br />
advanced recurrent or metastatic nasopharyngeal carcinoma<br />
V.H. Lee, D.W. Kwong, Y-C. Lai, Y. Li, K-O. Lam, P.Y.P. Ho, W-L. Chan,<br />
L-S. Wong, D.K. Leung, S-Y. Chan, F-T. Chan, K-S. Lau, R.P. Tse, T-W. Leung,<br />
A. Lee<br />
Department <strong>of</strong> Clinical <strong>Oncology</strong>, The University <strong>of</strong> Hong Kong, Hong Kong, China<br />
Background: There is no standard 3 rd line or further systemic treatment for patients<br />
inoperable locoregionally advanced recurrent/metastatic nasopharyngeal carcinoma<br />
(NPC). Oral cyclophosphamide provides a convenient and cheap option for these<br />
heavily pretreated patients who have very limited choices <strong>of</strong> treatment options. We<br />
conducted a prospective single-arm open-label study <strong>of</strong> metronomic oral<br />
cyclophosphamide in this setting.<br />
Methods: Patients with locoregionally advanced recurrent inoperable (rT3/T4,<br />
rN2-N3b) or metastatic (rM1) NPC who had good ECOG performance status (PS)<br />
(0-2) and had progressed after at least 2 lines <strong>of</strong> palliative systemic chemotherapy were<br />
eligible. They received open-label oral cyclophosphamide between 50mg to 150mg<br />
daily dose. Best objective response rate (ORR), disease control rate (DCR), biochemical<br />
response assessed by plasma EBV DNA, progression-free survival (PFS), overall<br />
survival (OS) and safety pr<strong>of</strong>iles were evaluated.<br />
Results: Of 56 patients who received cyclophosphamide, 16 and 37 (66.1%) had ECOG<br />
performance status (PS) 1 and 2 respectively. 33, 13, 6, 3 and 1 patients received<br />
cyclophosphamide as 3 rd ,4 th ,5 th ,6 th and 7 th line <strong>of</strong> therapy respectively. After a<br />
median follow-up <strong>of</strong> 8.95 months (range 0.76-58.51), the ORR was 8.9% and the DCR<br />
was 57.1% after cyclophosphamide. Biochemical response with 2 consecutive decline in<br />
plasma EBV DNA was seen in 10 (17.9%) patients. The median PFS and OS were 4.47<br />
and 9.20 months. Those with PS 1 had a longer median PFS (5.49 months) compared<br />
to those with PS 2 (3.75 months, p = 0.011). Univariable (p = 0.021) and multivariable<br />
analysis (p = 0.010) revealed that ECOG PS 1 was the only significant prognostic factor<br />
<strong>of</strong> PFS. 16 (28.6%) patients developed 3 G3 adverse events, including malaise (5.4%),<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw376 | vi339
abstracts<br />
haematological (8.9%), gastrointestinal (3.6%) and feverish (3.6%) and hemorrhagic<br />
(1.8%) events. The median cost <strong>of</strong> the whole drug treatment was 51.65 USD (1<br />
USD = 7.8 HKD).<br />
Conclusions: Oral cyclophosphamide is an acceptable 3 rd line or subsequent line<br />
systemic therapy for locoregionally advanced recurrent or metastatic NPC with<br />
acceptable toxicity and limited financial burden to patients.<br />
Legal entity responsible for the study: Institutional Review Board <strong>of</strong> the University <strong>of</strong><br />
Hong Kong/Hospital Authority Hong Kong West Cluster<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
983P<br />
An advanced tumor shape radiomic signature predicts<br />
recurrence <strong>of</strong> locally advanced (LA) HNSCC patients (pts)<br />
E.J.C. Limkin, A. Schernberg, S. Reuze, L. Behar, D. Ou, Y.G. Tao, E. Deutsch,<br />
C. Robert, C. Ferte<br />
Radiation <strong>Oncology</strong>, Institut Gustave Roussy, Villejuif, France<br />
Background: Radiomics delivers multifaceted tumor characterization with complex<br />
quantitative features extraction from medical imaging related with prognostic clinical<br />
outcomes in cancer decision support. Distinct from texture and histogram analysis,<br />
advanced 2D and 3D shape parameters could reflect tumor local invasion and outcome<br />
as well as histological invasion patterns in LA HNSCC pts.<br />
Methods: Tumor contours were defined from semi-automatic delineation <strong>of</strong> baseline<br />
contrast-enhanced CT scan. We trained a radiomic signature made <strong>of</strong> 27 complex<br />
parameters reflecting tumor convolution and shape complexity from 120 LA HNSCC<br />
pts retrospectively evaluated at Gustave Roussy Institute. We validated this particular<br />
shape signature on 86 LA HNSCC pts from TCGA database with assessable<br />
pre-treatment CT. Theses 3D silhouette parameters (n = 27) comprised fraction <strong>of</strong><br />
convex on concave edges, distance to arithmetic mean average position, and<br />
Minkowski dimension. We connected it to PFS, OS, and outcome events. Concordance<br />
Index (CI) and Kaplan Meier estimations assessed our signature’s competence.<br />
Unsupervised bi-clustering methods linked radiomics features and clinical endpoints.<br />
Results: We successively trained a powerful shape signature based on 9 complex<br />
parameters in these populations, significant through OS, PFS and local control<br />
predictions. Combining our shape radiomic signature with clinical factors (age, tumor<br />
location …) significantly improved results over clinical evaluation alone. Particularly,<br />
an unsupervised analysis <strong>of</strong> radiomics shape factors alone linked with tumor location<br />
(p < 0.05) independently <strong>of</strong> tumor volume, translating histological invasive traits<br />
through radiomics analysis.<br />
Conclusions: We created a shape-based radiomic signature presenting a potential<br />
prediction <strong>of</strong> invasive histological characters, correlated recurrence and prognosis in<br />
LA HNSCC pts, independently from TNM stage, tumor location, surgery,<br />
chemoradiation or further treatment, which could change the initial treatment plan for<br />
LA HNSCC pts and improve patient stratification.<br />
Legal entity responsible for the study: N/A<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
984P<br />
Utility <strong>of</strong> algorithm-based chemoradioselection for advanced<br />
laryngeal and hypopharyngeal carcinoma<br />
M. Masuda 1 , T. Wakasaki 1 ,S.Toh 1 , N. Kunitake 2 , F. Rikimaru 1 , Y. Higaki 1<br />
1 Head and Neck Surgery, National Kyushu Cancer Center, Fukuoka, Japan,<br />
2 Radiology, National Kyushu Cancer Center, Fukuoka, Japan<br />
Background: At our institute, a “chemoradioselection” strategy has been used to select<br />
patients with head and neck cancer for organ preservation. In brief, tumor responses<br />
are evaluated at 40 Gy <strong>of</strong> concurrent chemoradiotherapy (CRT). Responders (i.e.,<br />
chemoradioselected, CRS) receive further CRT up to 70 Gy, while non-responders<br />
(N-CRS) are recommended to undergo radical surgery (N-CRS-ope). To those who<br />
refuse surgery (N-CRS-refu), continuous CRT is administered. In this study, the results<br />
<strong>of</strong> advanced laryngeal and hypopharyngeal carcinomas were examined.<br />
Methods: From 2000 to 2012, 123 patients with stage III (44), IV (79) laryngeal (64)<br />
and hypopharyngeal carcinoma (59) excluding T4 cases were enrolled to this<br />
algorithm-based treatment. Split (15mg/m 2 x 5 days, 2000-20008) or bolus (80mg/m 2 ,<br />
2009-present) CDDP was administered at the onset <strong>of</strong> initial 40 Gy and additional<br />
30Gy <strong>of</strong> CRT, respectively.<br />
Results: Based on the algorithm, 64 patients were CRS. The remaining 59 N-CRS<br />
patients proceeded to either N-CRS-ope (34) or N-CRS-refu (25) arm. The 5-yr OS<br />
and DSS were 67% and 77%, respectively. The 5-yr OS <strong>of</strong> N-CRS-refu (47%) was<br />
significantly (p = 0.0193) lower than that <strong>of</strong> CRS (73%) or N-CRS-ope (70%).<br />
Intriguingly, multivariate analyses including 4 candidate prognostic factors: T (T1, 2 vs<br />
T3), N (N1 vs N2, 3), primary site (larynx vs hypopharynx), and planned treatment or<br />
not (CRS + N-CRS-ope vs N-CRS-refu) demonstrated that unplanned treatment alone<br />
was significantly correlated with poor OS (HR: 2.584, 95% CI: 1.313–4.354, p = 0.007).<br />
This result indicates that chemoradioselection, probably reflecting the biological<br />
aggressiveness <strong>of</strong> each tumor, can segregate patients for organ preservation from those<br />
who are better treated with surgery. The overall 5-yr laryngo-esophageal<br />
dysfunction-free survival (LEDFS) was 41%. The CRS group demonstrated<br />
significantly (P < 0.0001) better 5-yr LEDFS (69%) compared to the N-CRS-refu (20%),<br />
albeit identical treatment regimen.<br />
Conclusions: Algorithm-based chemoradioselection might provide a novel platform<br />
for the treatment <strong>of</strong> advanced head and neck cancer, taking full advantages <strong>of</strong> CRT and<br />
radical surgery, and thereby achieving optimization <strong>of</strong> the treatment intensity.<br />
Legal entity responsible for the study: N/A<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
985P<br />
Prognostic implication <strong>of</strong> ERCC-1 protein expression in<br />
resected head and neck cancer<br />
Y.H. Ko 1 , H.J. An 2 , C.K. Jung 3 , J.H. Kang 4 , M.S. Kim 5 , K.J. Cho 6 , H.S. Won 1 ,D.<br />
S. Sun 1<br />
1 Medical <strong>Oncology</strong>, Uijeongbu St. Mary’s hospital Catholic University,<br />
Uijeongbu-si, Republic <strong>of</strong> Korea, 2 Medical <strong>Oncology</strong>, Suwon St. Vincent’s hospital<br />
Catholic University, Suwon, Republic <strong>of</strong> Korea, 3 Hospital Pathology, Seoul<br />
St. Mary’s hospital Catholic University, Seoel, Republic <strong>of</strong> Korea, 4 Medical<br />
<strong>Oncology</strong>, Seoul St. Mary’s hospital Catholic University, Seoul, Republic <strong>of</strong> Korea,<br />
5 Surgical <strong>Oncology</strong>, Seoul St. Mary’s hospital Catholic University, Seoul, Republic<br />
<strong>of</strong> Korea, 6 Surgical <strong>Oncology</strong>, Uijeongbu St. Mary’s hospital Catholic University,<br />
Uijeongbu-si, Republic <strong>of</strong> Korea<br />
Background: The excision repair cross-complement group 1 (ERCC1) expression is<br />
related to prognosis and sensitivity to platinum-based chemotherapy in various<br />
cancers, especially lung. Platinum is the most frequently chemotherapeutic used in<br />
treatment <strong>of</strong> squamous cell carcinoma <strong>of</strong> the head and neck cancer (SCCHN), and<br />
ERCC1 has been studied as a predictive biomarker <strong>of</strong> cisplatin-containing chemo or<br />
chemo-radiotherapy. In this study, we assessed the prognostic role <strong>of</strong> ERCC1 protein<br />
expression in surgically resected SCCHN.<br />
Methods: Between 1994 and 2012, 204 patients who were diagnosed with oropharynx<br />
or oral cavity cancer and underwent curative surgical resection were included. ERCC1<br />
protein expression was evaluated by immunohistochemistry. Clinical and pathologic<br />
records were retrospectively reviewed.<br />
Results: ERCC1 protein was positive in 136 (66.7%) patients. High ERCC1 expression<br />
was associated with oral cavity cancer (P < 0.001), well differentiated tumor (P = 0.036),<br />
and HPV negativity (P < 0.001). High ERCC1 expression showed trend toward poor<br />
prognosis but not statistically significant (P = 0.117 for PFS, P = 0.332 for OS). The<br />
prognostic role <strong>of</strong> ERCC1 was not different according to the HPV status or following<br />
chemo or radiotherapy. However, patients with high ERCC1 showed poor prognosis in<br />
advanced TNM stage (III/IV), but no difference in early stage (I/II).<br />
Conclusions: ERCC1 protein expression can help to predict prognosis in surgically<br />
resected oropharynx or oral cavity SCCHN, especially in advanced stage.<br />
Legal entity responsible for the study: N/A<br />
Funding: The Catholic University <strong>of</strong> Korea<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
986P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Pazopanib in patients with progressive recurrent or metastatic<br />
(R/M) salivary gland carcinoma (SGC): Further evaluation <strong>of</strong><br />
efficacy including tumor growth rates (GR) analysis. H&N<br />
Unicancer Group PACSA trial with the REFCOR<br />
J. Guigay 1 , F. Bidault 2 , J. Fayette 3 ,C.Even 4 , D. Cupissol 5 , F. Rolland 6 ,<br />
F. Peyrade 1 , B. Laguerre 7 , C. Le Tourneau 8 , S. Zanetta 9 , L. Bozec Le Moal 10 ,<br />
C. Borel 11 , L. Digue 12 , J. Delaye 13 , S. Diffetocq 2 , V. Costes 14 , A. Auperin 15 ,<br />
L. Faivre 15<br />
1 Medical <strong>Oncology</strong>, Centre Antoine Lacassagne, Nice, France, 2 Medical Imaging,<br />
Institut Gustave Roussy, Villejuif, France, 3 <strong>Oncology</strong>, Centre Léon Bérard, Lyon,<br />
France, 4 Head and Neck Cancer, Institut Gustave Roussy, Villejuif, France,<br />
5 Medicine, ICM Regional Cancer Institute <strong>of</strong> Montpellier, Montpellier, France,<br />
6 Medical <strong>Oncology</strong>, ICO Institut de Cancerologie de l’Ouest René Gauducheau,<br />
St. Herblain, France, 7 Medical <strong>Oncology</strong>, Centre Eugene – Marquis, Rennes,<br />
France, 8 Medical <strong>Oncology</strong>, Institut Curie, Paris, France, 9 <strong>Oncology</strong> Department,<br />
Centre Georges-François Leclerc (Dijon), Dijon, France, 10 Medical <strong>Oncology</strong>,<br />
Hôpital René Huguenin, Institut Curie, Paris, France, 11 Medical <strong>Oncology</strong>, Centre<br />
Paul Strauss Centre de Lutte contre le Cancer, Strasbourg, France, 12 Medical<br />
<strong>Oncology</strong>, CHU Bordeaux Hopital St. André, Bordeaux, France, 13 H&N Group,<br />
UNICANCER, Paris, France, 14 Pathology, CHU Hôpital Gui de Chauliac,<br />
Montpellier, France, 15 Biostatitics and Epidemiology, Institut Gustave Roussy,<br />
Villejuif, France<br />
Background: SGC <strong>of</strong> head and neck (SGCHN) are rare tumors including adenoid<br />
cystic carcinoma (ACC) and non-ACC, with no standard treatment for R/M patients<br />
(pts). Pazopanib (Pb) is an oral inhibitor <strong>of</strong> VEGFR, PDGFR and KIT. We conducted a<br />
vi340 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
phase II trial to assess Pb efficacy in SGCHN, and present here results <strong>of</strong> the ancillary<br />
GR study.<br />
Methods: Pts with confirmed progressive R/M SGCHN received Pb 800 mg daily until<br />
progression (PD). Primary endpoint was 6-mo PFS rate, with inacceptable and<br />
promising rates <strong>of</strong> 20% and 40%. Tumor volumes were assessed with a medical<br />
imaging workstation (Advantage Workstation, GE Healthcare) Assuming exponential<br />
growth, GR was defined as log 10 (V t /V 0 )/dt, where V 0 and V t are tumour volumes at<br />
time 0 and t and dt the time in months between time 0 and t. Two time periods:<br />
pretrial period, from 3-6 mo before inclusion to inclusion (GR pre ) and trial period,<br />
from inclusion to 3 mo later (GR post ). GR variation was defined as the difference GR post<br />
minus GR pre ., a negative difference means a GR break (GR post
abstracts<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
(z = 1.98, p = 0.04). Analysis for hearing deterioration in the subgroup <strong>of</strong> baseline<br />
hearing < 50 dB is shown in table 1. For the group <strong>of</strong> baseline threshold > 50 dB mean<br />
deterioration was less, approximately 10 dB. In 15 pts we could compare data from 12<br />
versus 4 months after end <strong>of</strong> treatment. These showed no clinically relevant at 8 kHz.<br />
Table: 989P<br />
Frequency Cis100 + RT Cis40 + ART<br />
8 kHz 41 dB 20 dB<br />
4 kHz 30 dB 12 dB<br />
2 kHz 7 dB 3 dB<br />
Conclusions: After TPF CRT with cis40 + ART is less ototoxic than CRT with<br />
cis100 + RT.<br />
Clinical trial identification: NCT00774319<br />
Legal entity responsible for the study: Carla van Herpen<br />
Funding: Sanovi Aventis Netherlands Dutch Cancer Society<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
990P<br />
Comparison <strong>of</strong> the toxicity and response <strong>of</strong> a novel outpatient<br />
weekly CDFLEM (cisplatin, docetaxel, fluorourcil, leucovorin,<br />
epirubicin, methotrexate) induction chemotherapy versus<br />
triweekly TPF or PF in locally advanced SCCHN<br />
J-C. Lin, Y-C. Liu, P-J. Lin<br />
Department <strong>of</strong> Radiation <strong>Oncology</strong>, Taichung Veterans General Hospital,<br />
Taichung, Taiwan<br />
Background: Triweekly TPF and PF induction chemotherapy (IndCT) are the most<br />
popular and effective regimen for locally advanced squamous cell carcinoma <strong>of</strong> the<br />
head and neck (SCCHN). However, significant ethnic differences in susceptibility to<br />
the effects and toxicities exist. We designed a novel weekly CDFLEM IndCT and<br />
compared treatment outcome with TPF/PF from literature in locally advanced<br />
SCCHN.<br />
Methods: A four-drug regimen (C-D-FL-EM) consisting <strong>of</strong> (1) cisplatin 60 mg/m 2 ,day<br />
1, (2) docetaxel 50 mg/m 2 , day 8, (3) 5-fluorouracil 2500 mg/m 2 + leucovorin 250 mg/<br />
m 2 , day 15, (4) epirubicin 30 mg/m 2 + methotrexate 30 mg/m 2 , day 22, were<br />
alternatively delivered once per week, 4 weeks per cycle. From September 2011 to<br />
December 2013, 78 patients with stage III/IV SCCHN received 3-4 cycles IndCT <strong>of</strong><br />
CDFLEM, followed by local therapy (including surgery, radiotherapy, concurrent<br />
chemoradiotherapy, or bio-radiotherapy).<br />
Results: Baseline characteristics <strong>of</strong> 78 patients are as follows: primary <strong>of</strong> oral cavity/<br />
oropharynx/hypophayrnx/larynx = 23/26/24/5; stage III/IV = 10/68; median age = 51<br />
(range 33-77); male/female = 73/5; performance status ECOG 0-1/2 = 75/3.<br />
Synchronous second or triple primary tumors were also noted in 10 patients. We<br />
obtained an overall response rate <strong>of</strong> 97.3% (CR 39.2% + PR 58.1%) for 74 evaluable<br />
patients. The Overall response rate in the TAX-323 trial was 53.6% (CR 6.6% + PR<br />
47.0%) for the PF and 67.8% (CR 8.5% + PR 59.3%) for the TPF regimens, respectively.<br />
The corresponding figures in the TAX-324 trial was 64% (CR 15% + PR 49%) and 72%<br />
(CR 17% + PR 55%), respectively. Gr 3/4 mucositis occurred in 7.7% for our weekly<br />
CDFLEM, 11.2% and 4.6% for PF and TPF in the TAX-323, 27% and 22% for PF and<br />
TPF in the TAX-324. Gr 3/4 leucopenia was 38.4% for our CDFLEM, 22.9% and 41.6%<br />
for PF and TPF in the TAX-323, 56% and 83% for PF and TPF inf the TAX-324.<br />
Conclusions: IndCT with our weekly CDFLEM regimen has a higher response rate and<br />
a lower Gr 3/4 mucositis/neutropenia than triweekly PF/TPF in patients with locally<br />
advanced SCCHN.<br />
Clinical trial identification: JF11153A <strong>of</strong> the Taichung Veterans General Hospital<br />
Legal entity responsible for the study: Department <strong>of</strong> Radiation <strong>Oncology</strong>, Taichung<br />
Veterans General Hospital, Taiwan<br />
Funding: San<strong>of</strong>i, Taiwan branch<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
991P<br />
Retrospective study <strong>of</strong> weekly paclitaxel-cetuximab (WPC) in<br />
unselected patients (p) with recurrent/metastatic head and<br />
neck squamous cell carcinoma (RM-SCCHN)<br />
I. Pajares Bernad 1 , J. Mártinez Trufero 1 , L. Calera Urquizu 1 , A. Cebolleo de<br />
Miguel 1 , R. Pazo Cid 1 , M. Lanzuela Valero 2 , M.J. Agsustín 3 , E. Millastre 1 ,C.<br />
Santander Lobera 1 , M. Alvarez Alejandro 1 , N. Gimeno 4 , M. Malo Yague 5 ,<br />
Y. Llorente 6 , A. Antón Torres 1<br />
1 Department <strong>of</strong> Medical <strong>Oncology</strong>, Hospital Miguel Servet, Zaragoza, Spain,<br />
2 Department <strong>of</strong> Radiotherapy, Hospital Miguel Servet, Zaragoza, Spain,<br />
3 Department <strong>of</strong> Pharmacy, Hospital Miguel Servet, Zaragoza, Spain, 4 Department<br />
<strong>of</strong> Medical <strong>Oncology</strong>, Hospital Royo Villanova, Zaragoza, Spain, 5 Hematology<br />
Department, Hospital Ernest Lluch, Calatayud, Spain, 6 Supportive care, Arrabal<br />
centre, Zaragoza, Spain<br />
Background: WPC is an active treatment in RM-SCCHN, specially for unfit p not<br />
candidates to platinum. There are limited data so far about pronostic factors (PFs) in<br />
real-life practice.<br />
Methods: Outcome data (Response and survival) along with PFs analysis <strong>of</strong><br />
RM-SCCHN p treated in our centre with weekly paclitaxel (80 mg/m2) and Cetuximab<br />
(400/250 mg/m2) were retrospectively reviewed.<br />
Results: 148p were treated with WPC between January 2008 and July 2014. Female 15p<br />
(10,3%).Median age 62 years (38-87). Location: larynx 44p (29,7%), oral cavity 44p<br />
(29,7%), oropharynx 26p (17,6%), hipopharynx 11p (7,4%) and other 25p (15,6).<br />
Previous platinum-based therapy: 103p (69,6%) as initial treatment for localized stage,<br />
31p (20,9%) for recurrent/metastatic disease. Stage: 101p (68,2%) unresectable/<br />
advanced disease, 9p(6,1%) metastatic disease and 38p (25,7%) both . Median number<br />
cycles: 9(1-27). 64p (43,2%) received cetuximab maintenance. Response rate (RR): 70p<br />
(47.3%) objetive response (OR)(complete + partial), 30p (20.3%) stable disease (SD),<br />
48p (32.4%) progressive disease (PD). Median overall survival (OS) was 10 months(m)<br />
(95%CI;8.31-11.69) and progression free survival (PFS) was 7 m (95%CI;5.88-8.12).<br />
Analyzed PFs: Age, Sex, ECOG, Comorbidity index (CI)(ACE27 and Charslton CI),<br />
location, RR, stage, and albumin (Al), hemoglobin(Hb) and magnesium (Mg) serum<br />
levels were analyzed at baseline and monthly during therapy until PD or death. PD,<br />
basalAl level 1, Charslton CI >3, ECOG >1,<br />
previous disease free interval ≤ 20 m, Al basal level< 3gr/dl, Hb and Mg decrease. In<br />
MA, both PD and a 10% or less decrease in serum Mg levels were the only independent<br />
PFs for poor OS.<br />
Conclusions: OS and PFS <strong>of</strong> a non-selected population <strong>of</strong> RM-SCCHN p treated with<br />
WPC was similar to that reported in a previous phase II trial, and comparable to<br />
platinum based treatment.Decrease <strong>of</strong> Mg levels during WPC therapy might be a<br />
prognostic biomarker that could be tested in prospective trials.<br />
Legal entity responsible for the study: Isabel Pajares Bernad<br />
Funding: Department <strong>of</strong> Medical <strong>Oncology</strong>. Miguel Servet University Hospital<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
992P<br />
Clinical-dosimetric analysis <strong>of</strong> factors predisposing to chronic<br />
dysphagia measured using CTCAE criteria among locally<br />
advanced oropharyngeal cancer patients treated definitely by<br />
intensity modulated radiotherapy with concurrent<br />
chemotherapy<br />
K. Periasamy, R. Pasricha, N. Patni, T.P. Soni<br />
Radiation <strong>Oncology</strong>, Bhagwan Mahaveer Cancer Hospital and Research Centre<br />
(BMCHRC), Jaipur, India<br />
Background: Concurrent chemoradiotherapy in oropharyngeal cancers results in<br />
anatomical changes to the pharyngeal constrictors (PCM), larynx and parotid gland<br />
leading to chronic dysphagia. This study was done in to find out the incidence <strong>of</strong><br />
chronic dysphagia after CRT and analyse its correlation with patient clinical factors<br />
and specific dose volume parameters <strong>of</strong> PCM, larynx, oral cavity and parotid glands in<br />
locally advanced oropharyngeal cancer patients undergoing concurrent<br />
chemoradiotherapy.<br />
Methods: 52 patients with KPS ≥70 <strong>of</strong> stage III-IVA oropharyngeal cancers were<br />
enrolled and treated with concurrent chemoradiotherapy between 2012-2014 with<br />
IMRT dose <strong>of</strong> 66Gy in 30 fractions and 5 cycles <strong>of</strong> weekly cisplatin 40mg/m 2 . Patient<br />
clinical factors and Doses to the PCM, larynx, oral cavity and parotid glands such as<br />
Mean dose, V 50 and V 60 were measured from dose volume histograms. Clinical<br />
dysphagia was measured at baseline and after 6 months <strong>of</strong> completing CRT using<br />
CTCAE v4.03. These factors were analysed for their correlation with the severity <strong>of</strong> post<br />
CRT chronic dysphagia.<br />
Results: It was found that the clinical factors such as pretreatment dysphagia, nodal<br />
stage, TNM stage, tumor volume and mucositis grade at CRT completion had a<br />
significant correlation with post CRT chronic dysphagia. On applying spearman’s<br />
correlation coefficient for dosimetric factors it was found that the Mean dose, V 50 and<br />
V 60 <strong>of</strong> PCM, larynx and the mean dose <strong>of</strong> parotid gland and oral cavity had a positive<br />
significant correlation with the severity <strong>of</strong> post CRT chronic dysphagia. On ANOVA<br />
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<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
statistical analysis it was found that the Mean dose, V 50 and V 60 <strong>of</strong> pharyngeal<br />
constrictor, larynx were significant in predicting the post CRT chronic dysphagia.<br />
Predictive equations to Odds <strong>of</strong> post CRT chronic dysphagia were generated.<br />
Conclusions: Post CRT chronic dysphagia is significant and based on this study results<br />
the following dosimetric parameters are recommended in predicting and reducing post<br />
CRT chronic dysphagia.Dose for PCM: Mean dose
abstracts<br />
tyrosine kinase activity. The purpose <strong>of</strong> the research was to study the EGF/sEGFR ratio<br />
in tumor tissue and blood <strong>of</strong> patients with HNC depending on tumor response to the<br />
therapy with anti-EGFR MA- Сetuximab (C).<br />
Methods: Levels <strong>of</strong> EGF and sEGFR and their ratio were studied by ELISA in tumor<br />
tissue and blood <strong>of</strong> 30 patients with HNC squamous cell carcinoma. C- 400 mg/m 2 was<br />
administered on day 1 and 250 mg/m 2 weekly, combined with cisplatin 100mg/m 2 on<br />
day 1, fluorouracil 100mg/m 2 - 96-hour continuous iv infusion q3w. The blood <strong>of</strong> 20<br />
healthy donors was used as the control.<br />
Results: EGF/sEGFR ratio in the blood <strong>of</strong> pts before the treatment was various and<br />
influenced on the tumor response: in 17 pts with complete and partial response (CR +<br />
PR) it was 30% lower than in 13 patients with stabilization (S) and progression (P).<br />
Compared to the donors, the ratio was 12.6 and 16 times higher in pts with CR + PR<br />
and S + P correspondingly. After the therapy EGF/sEGFR was 2.5 times lower in pts<br />
with CR + PR than in pts with S + P but exceeded the normal level by 4.6 times. The<br />
ratio was still 11.5 times higher in pts with S + P than in the donors. The data aquired<br />
from the tumor tissue were similar: EGF/sEGFR level in pts with CR + PR was 2.8<br />
times lower than in those with S + P.<br />
Conclusions: EGF/sEGFR ratio is supposed to be a specific biological index for the<br />
EGFR cascade in the tumor tissue and in the blood and reflects the tumor response for<br />
anti-EGFR MA- С et in pts with HNC.<br />
Legal entity responsible for the study: Rostov Research Institute <strong>of</strong> <strong>Oncology</strong><br />
Funding: Ministry <strong>of</strong> Health <strong>of</strong> the Russian Federation<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
996P<br />
Genetic polymorphisms in DNA mismatch repair-related genes<br />
predict outcome in patients with head and neck squamous cell<br />
carcinoma treated with cisplatin and radiotherapy<br />
G.J. Lourenço 1 , G.A.S. Nogueira 1 , L. Lopes-Aguiar 1 , E.F.D. Costa 1 , T.R.P. Lima 1 ,<br />
M.B. Visacri 2 , E.C. Pincinato 1 , L. Calonga 3 , F.V. Mariano 4 , A.M.A.M. Altemani 4 ,J.<br />
M.C. Altemani 5 , C.M. Coutinho-Camillo 6 , M.A.V.F.R. Alves 7 , P. Moriel 2 ,C.<br />
T. Chone 3 , C.D. Ramos 5 , C.S.P. Lima 7<br />
1 Laboratory <strong>of</strong> Cancer Genetics, Faculty <strong>of</strong> Medical Sciences, University <strong>of</strong><br />
Campinas, Campinas, Brazil, 2 Department <strong>of</strong> Clinical Pathology, Faculty <strong>of</strong> Medical<br />
Sciences, University <strong>of</strong> Campinas, Campinas, Brazil, 3 Department <strong>of</strong><br />
Ophthalmology and Otorhinolaryngology, Faculty <strong>of</strong> Medical Sciences, University<br />
<strong>of</strong> Campinas, Campinas, Brazil, 4 Department <strong>of</strong> Pathology, Faculty <strong>of</strong> Medical<br />
Sciences, University <strong>of</strong> Campinas, Campinas, Brazil, 5 Department <strong>of</strong> Radiology,<br />
Faculty <strong>of</strong> Medical Sciences, University <strong>of</strong> Campinas, Campinas, Brazil,<br />
6 Department <strong>of</strong> Pathology, A.C. Camargo Cancer Center, São Paulo, Brazil,<br />
7 Department <strong>of</strong> Internal Medicine, Faculty <strong>of</strong> Medical Sciences, University <strong>of</strong><br />
Campinas, Campinas, Brazil<br />
Background: Cisplatin (CDDP) associated with radiotherapy (RT) has been used in<br />
treatment <strong>of</strong> patients with head and neck squamous cell carcinoma (HNSCC) with<br />
distinct results among those with similar clinicopathological aspects. The aim <strong>of</strong> this<br />
study was to access whether MLH1 c. − 93G > A, MSH2 c.211 + 9C > G, MSH3<br />
c.3133G > A, EXO1 c.1765G > A and EXO1 c.2270C > T single nucleotide<br />
polymorphisms (SNPs) <strong>of</strong> the mismatch repair (MMR) pathway, alter the outcome <strong>of</strong><br />
90 consecutive HNSCC patients treated with CDDP and RT.<br />
Methods: Genotypes were analyzed by polymerase chain reaction (PCR) based<br />
methods in DNA <strong>of</strong> peripheral blood. Treatment response and toxicities were assessed<br />
using conventional criteria.<br />
Results: Patients with the MSH3 c.3133GG genotype and GG or GA genotype were<br />
under a 4.27-fold and 10.29-fold increased risks <strong>of</strong> presenting moderated or severe<br />
nephrotoxicity and ototoxicity after chemoradiation than others, respectively. The<br />
EXO1 c.1765GA or AA genotype conferred to patients 9.55 more chances <strong>of</strong> achieving<br />
partial (PR) or stable disease (SD) than others. Patients with the EXO1 c.2270CC<br />
genotype were under a 4.69-fold and a 4.03-fold increased risks <strong>of</strong> presenting moderate<br />
or severe nephrotoxicity and none or mild ototoxicity after chemoradiation than<br />
others. The GT and AC haplotypes <strong>of</strong> EXO1 c.1765G > A and c.2270C > T SNPs were<br />
associated with a 9.11 and 4.00-fold increased risks <strong>of</strong> none or mild nefrotoxicity and<br />
moderate or severe ototoxicity, and a 9.55-fold increased risk <strong>of</strong> achieving PR or SD<br />
than others, respectively.<br />
Conclusions: Our data present, for the first time, preliminary evidence that inherited<br />
abnormalities in MMR pathway, related to MSH3 c.3133G > A, EXO1 c.1765G > A and<br />
EXO1 c.2270C > T SNPs, may change rate <strong>of</strong> complete response and side effects in<br />
patients with HNSCC treated with CDDP and RT.<br />
Legal entity responsible for the study: University <strong>of</strong> Campinas<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
997P<br />
Influence <strong>of</strong> FASL and FAS polymorphisms, enrolled in<br />
extrinsic apoptosis pathway, in the inherited increased risk <strong>of</strong><br />
head and neck squamous cell carcinoma<br />
C.S.P. Lima, V.T. Liutti, T.R.P. Lima, E.F.D. Costa, L. Lopes-Aguiar, G.A.<br />
S. Nogueira, F. Leal, V.C.A. Santos, C.B.M. Oliveira, J.A. Rinck-Junior, G.<br />
J. Lourenço<br />
Department <strong>of</strong> Internal Medicine, Faculty <strong>of</strong> Medical Sciences, University <strong>of</strong><br />
Campinas, Campinas, Brazil<br />
Background: Apoptosis plays an important role in origin <strong>of</strong> head and neck squamous<br />
cell carcinoma (HNSCC). Inherited genetic alterations, such as single nucleotide<br />
polymorphisms (SNPs), may influence the individual apoptotic capacity, having<br />
development <strong>of</strong> tumors as consequence. To the best <strong>of</strong> our knowledge, the roles <strong>of</strong><br />
FASL c.-844C > T and FAS c.-671A > G SNPs in HNSCC risk, clinic pathological<br />
aspects and outcome are unclear, and therefore these were the aims <strong>of</strong> the present<br />
study.<br />
Methods: DNA <strong>of</strong> 463 patients and 470 controls were analyzed by PCR-RFLP. Patients<br />
were treated according to the Institutional protocol, including surgery, radio and<br />
chemotherapy. The statistical analyses were realized using chi-square, logistic<br />
regression model, multifactor dimensionality reduction (MDR), Kaplan-Meier, and<br />
univariate and multivariate Cox analyses.<br />
Results: FASL TT genotype was more frequent in overall HNSCC patients (27.9% vs<br />
16.2%, P= 0.001) and in those with SCC <strong>of</strong> oral cavity (30.0% vs 16.2%, P= 0.006),<br />
pharynx (29.9% vs 16.2%, P= 0.007), and larynx (25.4% vs 16.2%, P= 0.03) than in<br />
controls. Carriers <strong>of</strong> the genotypes were under a 3.24, 5.86, 2.93 and 2.54-fold increased<br />
risks <strong>of</strong> overall HNSCC and SCC <strong>of</strong> the mentioned subsites than others, respectively.<br />
An excess <strong>of</strong> FASL CT or TT plus FAS AA or AG combined genotype was seen in<br />
overall HNSCC patients compared to controls (91.1% vs 84.1%, P= 0.04); carriers <strong>of</strong><br />
the genotype were under a 2.31-fold increased risk overall HNSCC than others. Among<br />
smokers, FASL TT and FAS AA genotypes were associated with 165.89 and 81.05-fold<br />
increased risks <strong>of</strong> HNSCC (P< 0.001), respectively. FASL c.-844C > T, FAS c.-671A > G<br />
SNPs and tobacco was the best interaction MDR model for risk <strong>of</strong> overall HNSCC and<br />
SCC <strong>of</strong> oral cavity, pharynx and larynx (P< 0.001). The median follow-up time <strong>of</strong><br />
HNSCC patients was 46.0 months (1.6-166.0); no association <strong>of</strong> SNPs and patientś<br />
survival was seen in study.<br />
Conclusions: Our data present preliminary evidence that inherited abnormalities in<br />
FASL c.-844C > T and FAS c.-671A > G SNPs are determinants <strong>of</strong> overall HNSCC and<br />
SCC <strong>of</strong> oral cavity, pharynx and larynx, particularly among smokers, possibly due to<br />
their action in tumor carcinogenesis.<br />
Legal entity responsible for the study: University <strong>of</strong> Campinas<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
998P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
An optimal cumulative dose <strong>of</strong> cisplatin in chemoradiotherapy<br />
as a definitive treatment for non-metastatic nasopharyngeal<br />
carcinoma: a retrospective multicenter study<br />
P. Danchaivijitr 1 , N. Ngamphaiboon 2 , C. Jiarpinitnun 3 , E. Sirachainan 4 ,<br />
P. Pattaranutaporn 3 , J. Setakornnukul 5<br />
1 Medical <strong>Oncology</strong> Division, Department <strong>of</strong> Medicine, Siriraj Hospital, Mahidol<br />
University, Bangkok, Thailand, 2 Division <strong>of</strong> Medical <strong>Oncology</strong>, Department <strong>of</strong><br />
Medicine, Ramathibodi Hospital, Bangkok, Thailand, 3 Radiation <strong>Oncology</strong>,<br />
Ramathibodi Hospital, Bangkok, Thailand, 4 Medicine, Ramathibodi Hospital,<br />
Bangkok, Thailand, 5 Radiation <strong>Oncology</strong>, Siriraj Hospital, Mahidol University,<br />
Bangkok, Thailand<br />
Background: To date, there is no recommended optimal cumulative dose (OCD) <strong>of</strong><br />
cisplatin in definitive chemoradiotherapy (CRT) for non-metastatic nasopharyngeal<br />
carcinoma (NPC). We conducted a retrospective study to determine a MCCD in NPC<br />
treated with CRT.<br />
Methods: Histologically confirmed non-metastatic NPC patients treated at the<br />
Ramathibodi and Siriraj Hospitals between 2007 and 2015 were identified. Baseline<br />
patient characteristics, treatment modality and survivals were abstracted. The OCD <strong>of</strong><br />
cisplatin >200 mg/m2 was used as a stratification dose level. Primary end point was<br />
3-year survival (OS). The Kaplan-Meier with log-rank test were used for analysis. A<br />
p-value 200 mg/m2, while 58 patients did not. Median<br />
age was 52 (range 17-75). Median radiation dose was 6996 cGY (range 1440-7840).<br />
Median cisplatin dose was 240 mg/m2 (range 75-361). There was no statistical<br />
difference in demographics between these 2 groups, except radiation interruption was<br />
more common in patients who received ODC <strong>of</strong> cisplatin >200 mg/m2 (27% vs 3%,<br />
p < 0.001). Median follow up time was 30.5 months. 3-year OS was similar between<br />
both groups (48.9 vs 48.3 months, p = 0.256). 3-year disease free survival (DFS) was<br />
not different (45.4% vs 37.9%, p = 0.322).<br />
Conclusions: Our study demonstrated no significant difference in 3 year OS and DFS<br />
between OCD <strong>of</strong> cisplatin greater or lesser than 200 mg/m2. A prospective study<br />
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<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
comparing standard vs lower dose <strong>of</strong> cisplatin is warranted to minimize cisplatin<br />
related toxicity during chemoradiotherapy for NPC.<br />
Legal entity responsible for the study: N/A<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
999P<br />
Presence <strong>of</strong> percutaneous endoscopic gastrostomy tube<br />
(PEG) is an independent negative prognostic factor in<br />
recurrent/metastatic head and neck squamous cell cancer (r/<br />
mHNSCC) patients<br />
M. Siano 1 , N.S. Jarisch 2 , M. Jörger 1<br />
1 <strong>Oncology</strong>/Hematology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland,<br />
2 Nutrition Counseling, Cantonal Hospital St. Gallen, St. Gallen, Switzerland<br />
Background: HNSCC pts <strong>of</strong>ten need a PEG during their disease. While PEG is studied<br />
in depth for locally advanced disease, this is not the case for r/mHNSCC, where<br />
therapeutic PEG it supposed to compensate for impaired swallowing, aspiration and to<br />
improve the patient’s nutrition status with a potential positive effect on outcome.<br />
Methods: We retrospectively analyzed patients with r/mHNSCC referred for palliative<br />
systemic treatment between 2005 and 2015. Patients, disease and treatment<br />
characteristics were assessed, including the presence <strong>of</strong> PEG at the start <strong>of</strong> 1st-line<br />
systemic therapy. Known prognostic factors according to Argiris et al were assessed and<br />
considered for analysis. Correlation between survival and PEG status was calculated<br />
using Kaplan-Meier method and multivariate Cox regression models.<br />
Results: We included 110pts in our analysis. 100pts received first-line therapy.<br />
Forty-two patients (42%) had a PEG at the time <strong>of</strong> palliative 1st-line systemic<br />
treatment. Mean age was 61years (range 38-85). 84% <strong>of</strong> pts were male and 16% female.<br />
80% had an ECOG PS <strong>of</strong> 0 or 1. Oropharynx, oral cavity, larynx and hypopharynx were<br />
the primary cancer sites in 29, 26, 20 and 16% respectively, with 9% other sites. Median<br />
survival from start <strong>of</strong> 1 st line systemic treatment was 8.0months (95% CI,<br />
6.5-12.0months). ECOG PS was the strongest prognostic factor in our cohort<br />
(HR = 2.55, p < 0.001). Overall survival was 4.5months (95% CI, 6.1-11.7months) for<br />
pts with PEG and 11.5months (95% CI, 10.9-16.9months) without PEG (adjusted<br />
HR = 1.98, P = 0.11). Survival from first occurrence <strong>of</strong> distant metastases was<br />
significantly lower in PEG carriers as compared to patients without a PEG (7.5 v 15.5<br />
months, adjusted HR = 2.60, P < 0.001).<br />
Conclusions: The presence <strong>of</strong> PEG feeding tubes in patients with r/mHNSCC is an<br />
independent negative prognostic factor. Currently applied prognostic factors could be<br />
insufficient for an adequate adjusted multivariate analysis in r/mHNSCC. Presence or<br />
placement <strong>of</strong> PEG does not seem to prolong survival in this advanced patient<br />
population. These data is hypothesis generating. The impact can be important and<br />
outweigh other survival benefits due to systemic therapy.<br />
Legal entity responsible for the study: Cantonal Hospital St. Gallen<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1000P<br />
Outcomes <strong>of</strong> critically ill head and neck cancer (HNC)<br />
patients (pts) admitted in medical intensive care units (mICU)<br />
after oncological treatments<br />
A.C.D. Freitas 1 , M.T. Alexandre 1 , I. Sargento 1 , M. Ferreira 1 , M. Ramos 2 ,<br />
A. Marques 1 , A. Moreira 1<br />
1 Medical <strong>Oncology</strong>, Instituto Portuguès de Oncologia de Lisboa Francisco Gentil,<br />
E.P.E. (IPOLFG EPE), Lisbon, Portugal, 2 Biostatistics, Instituto Portuguès de<br />
Oncologia de Lisboa Francisco Gentil, E.P.E. (IPOLFG EPE), Lisbon, Portugal<br />
Background: Multimodality treatment improved survival <strong>of</strong> locally advanced HNC<br />
pts. Nevertheless some pts still face poor outcomes due to acute treatment-related<br />
toxicities and some will require intensive care during the course <strong>of</strong> treatment. Literature<br />
is limited on this subject.<br />
Methods: We did a retrospective analysis <strong>of</strong> all consecutive HNC pts critically ill<br />
admitted to <strong>Oncology</strong> Department and transferred to a mICU between Jan 2009-Dec<br />
2014. Main aims: to evaluate clinical and demographic features, treatments, outcomes,<br />
and to explore mortality associated factors.<br />
Results: We found 25 HNC pts, 20 (80%) males and 5 (20%) females with a median<br />
age <strong>of</strong> 63 years (range 47-76). Pre-ICU performance status was 0/1 in 24 pts. Twenty<br />
one pts (84%) had a Charlson Comorbidity Index (CCI) ≥4. Locoregional advanced<br />
disease (stage III/IV) was observed in 24 pts (96%), 21 on tube feeding. The most<br />
common primary sites were oral cavity and oropharynx. Prior to ICU, 21(84%) pts<br />
were in active treatment: 8 (32%) with neoadjuvant chemotherapy (CT) with TPF<br />
(docetaxel, cisplatin, fluorouracil), 11 (44%) with chemoradiation with cisplatin, 1 (4%)<br />
with adjuvant CT with PF and 1 (4%) with immunoradiation. Prior to ICU admission<br />
16 pts had grade 3/4 toxicity (renal, hematological, mucosal, hyponatremia,<br />
hipoalbuminemia). The main causes for ICU admission were respiratory insufficiency<br />
in 14 pts (56%), septic shock in 5 (20%) and both in 5 (20%). Median time to ICU<br />
admission was 4 days and the median length <strong>of</strong> stay was 6 days (range 0-36). At ICU<br />
mechanical ventilation was used in 12 pts (48%) and vasoactive support in 11 (44%).<br />
Thirteen pts (52%) died during ICU stay and 5 (20%) just after ICU discharge. Seven<br />
pts (28%) were discharged, 4 <strong>of</strong> them continued treatment with reduced intensity. Only<br />
3 pts are long survivals. The overall survival for this group was 7,3 months.<br />
Conclusions: The TPF regimen contributed to a significant number <strong>of</strong> pts admitted in<br />
ICU. A high mortality <strong>of</strong> HNC pts was observed after an ICU admission, explained by<br />
the high comorbidity index and G3/4 treatment related-toxicities. HNC pts <strong>of</strong>ten need<br />
a careful evaluation to better select those who can tolerate/benefit from aggressive<br />
treatment.<br />
Legal entity responsible for the study: Instituto Português de Oncologia de Lisboa<br />
Francisco Gentil<br />
Funding: Instituto Português de Oncologia de Lisboa Francisco Gentil<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1001P<br />
Expression <strong>of</strong> calreticulin is a novel independent prognostic<br />
factor for oral squamous cell carcinoma<br />
T. Takenawa, K. Harada, T. Ferdous, Y. Ueyama<br />
Oral and Maxill<strong>of</strong>acial Surgery, Yamaguchi University Graduate School <strong>of</strong><br />
Medicine, Ube, Japan<br />
Background: We focused on Calreticulin (CALR) on the basis <strong>of</strong> proteomic differential<br />
display analysis data using the regressive murine fibrosarcoma cell clone QR-32 and the<br />
progressive malignant tumor cell clone QRsP-11, derived from QR-32. CALR is an<br />
endoplasmic reticulum luminal Ca2 + -binding chaperone protein. CALR is thought to<br />
affect the tumor behavior <strong>of</strong> various malignancies. The purpose <strong>of</strong> this study was to<br />
determine whether CALR expression could be a useful prognostic factor in patients<br />
with oral squamous cell carcinoma (OSCC).<br />
Methods: CALR expression was investigated by immunohistochemistry in tissue<br />
samples from 111 patients with OSCC. The association between CALR expression and<br />
clinicopathological characteristics, and patient survival were analyzed.<br />
Results: Immunohistchemical staining <strong>of</strong> CALR was observed in the cytoplasm <strong>of</strong> the<br />
cancer cells. Among 111 OSCC patients, high expression <strong>of</strong> CALR was observed in 44<br />
patients (39.6%), whereas 67 patients (60.4%) showed low expression <strong>of</strong> CALR.<br />
Significant association was found between CALR expression and T classification<br />
(p = 0.0027), N classification (p = 0.0219), stage (p = 0.0013), and patient outcome<br />
(p = 0.0014). The 3-year survival rates <strong>of</strong> patients with CALR high- and low-expression<br />
tumors were 50.1% and 86.6% respectively, which was significantly different<br />
(p < 0.0001) as estimated by log-rank test. Multivariate analysis revealed that the<br />
reduced term survival was correlated to high levels <strong>of</strong> CALR expression (p < 0.0001).<br />
Conclusions: These results suggest that elevated expression <strong>of</strong> CALR might play an<br />
important role in the progression <strong>of</strong> OSCC and could be considered as a useful<br />
prognostic factor in patients with OSCC.<br />
Legal entity responsible for the study: Yamaguchi University Graduate School <strong>of</strong><br />
Medicine<br />
Funding: Grant-in-Aid from the Japanese Ministry <strong>of</strong> Education, Science and Culture<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1002P<br />
abstracts<br />
Phase I study <strong>of</strong> ribociclib plus cetuximab in patients with<br />
recurrent or metastatic squamous cell carcinoma <strong>of</strong> the head<br />
and neck<br />
E. Seront 1 , S. Schmitz 2 , S. Rottey 3 , S. Henry 4 , C. Lonchay 5 , G. van Caloen 6 ,<br />
A. Gilain 6 , J-P. Machiels 6<br />
1 Medical <strong>Oncology</strong>, Centre Hospitalier Jolimont-Lobbes, Haine Saint Paul,<br />
Belgium, 2 Head and Neck Surgery, Roi Albert II - Cliniques universitaires<br />
Saint-Luc, Brussels, Belgium, 3 Medical <strong>Oncology</strong>, Gent University Hospital, Gent,<br />
Belgium, 4 Medical <strong>Oncology</strong>, Clinique Ste Elisabeth, Namur, Belgium, 5 Medical<br />
<strong>Oncology</strong>, Grand Hopital de Charleroi Site Notre Dame, Charleroi, Belgium,<br />
6 <strong>Oncology</strong>, Roi Albert II - Cliniques Universitaires Saint-Luc, Brussels, Belgium<br />
Background: The majority <strong>of</strong> Human Papilloma Virus (HPV)-negative squamous cell<br />
carcinoma <strong>of</strong> the head and neck (SCCHN) has inactivation <strong>of</strong> p16, an inhibitor <strong>of</strong> the<br />
Cyclin-Dependent Kinases (CDK) 4 and 6, and 20-30% present CCND1 amplification.<br />
These alterations promote cell cycle progression and tumor proliferation. EGFR<br />
upregulation could also induce elevation <strong>of</strong> cyclin D1 and CDK4. Cetuximab, an<br />
anti-EGFR mAb, improves survival in combination with platinum-based<br />
chemotherapy in recurrent SCCHN. This study is investigating the combination <strong>of</strong><br />
ribociclib, an orally highly selective inhibitor <strong>of</strong> CDKs 4/6, and cetuximab in recurrent<br />
SCCHN.<br />
Methods: p16-negative recurrent and/or metastatic SCCHN patients (pts) who<br />
progress after platinum-based chemotherapy were included in this phase 1 study. All<br />
the pts received cetuximab at the recommended dose (400 mg/m2 followed by 250 mg/<br />
m2/week, IV), combined with ribociclib (3 weeks on/1 week <strong>of</strong>f), in a classical 3 + 3<br />
dose-escalation design. The first dose level <strong>of</strong> ribociclib was 400 mg/day and the second<br />
dose level 600 mg/day. The primary endpoint was to determine the maximum tolerated<br />
dose (MTD) <strong>of</strong> Ribociclib in combination with cetuximab.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw376 | vi345
abstracts<br />
Results: Between April 2015 and January 2016, 10 pts (median age: 62.5 years; site<br />
location: larynx (2), hypopharynx (2), oropharynx (2), oral cavity (4)) were enrolled,<br />
including 6 pts previously treated with cetuximab. No dose limiting toxicities (DLTs)<br />
were observed at the first dose level. At the second dose level, 1 pt presented rapid<br />
disease progression and was therefore replaced as he could not be evaluated for toxicity.<br />
One pt out <strong>of</strong> 6 experienced DLT (Grade 4 thrombopenia lasting more than 7 days).<br />
The most common grade 3/4 treatment-related adverse events were neutropenia<br />
(n = 2), anemia (n = 2), thrombopenia (n = 1), hypocalcemia (n = 2), hypokaliemia<br />
(n = 2), hypomagnesemia (n = 1) and hypoglycemia (n = 1). No objective responses<br />
were observed but 4 pts achieved a stable disease according to RECIST v1.1, including 2<br />
pts previously treated with cetuximab.<br />
Conclusions: The MTD <strong>of</strong> ribociclib in combination with standard dose <strong>of</strong> cetuximab<br />
is 600mg daily (3 weeks on/1 week <strong>of</strong>f). An expansion cohort is currently ongoing.<br />
Clinical trial identification: EudraCT 2014-005371-83<br />
Legal entity responsible for the study: Cliniques universitaires Saint Luc, Brussel,<br />
Belgium<br />
Funding: Novartis company<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1003P<br />
A comparison <strong>of</strong> cetuximab-containing regimens for<br />
recurrent/metastatic squamous cell head and neck<br />
carcinoma: the clinical significance <strong>of</strong> weekly paclitaxel and<br />
cetuximab<br />
K. Nakano 1 , S. Marshall 1 , S. Taira 1 ,Y.Sato 2 , J. Tomomatsu 1 , T. Sasaki 3 ,<br />
W. Shimbashi 3 , H. Fukushima 3 , H. Yonekawa 3 , H. Mitani 3 , K. Kawabata 3 ,<br />
S. Takahashi 1<br />
1 Medical <strong>Oncology</strong>, Cancer Institute Hospital <strong>of</strong> JFCR, Tokyo, Japan, 2 Pathology,<br />
Cancer Institute Hospital <strong>of</strong> JFCR, Tokyo, Japan, 3 Head and Neck Surgery,<br />
Cancer Institute Hospital <strong>of</strong> JFCR, Tokyo, Japan<br />
Background: The combination chemotherapy <strong>of</strong> weekly paclitaxel and cetuximab has<br />
been a treatment option for recurrent/metastatic squamous cell carcinoma <strong>of</strong> head and<br />
neck (R/M SCCHN); however, the effectiveness <strong>of</strong> the regimen has been not yet been<br />
compared with the current standard regimen, EXTREME (combination <strong>of</strong> 5-FU,<br />
cisplatin and cetuximab).<br />
Methods: We retrospectively reviewed the clinical records <strong>of</strong> R/M SCCHN patients<br />
who received cetuximab-containing chemotherapy as 1st line; <strong>of</strong> them, patients<br />
receiving weekly paclitaxel and cetuximab regimen (cohort A) and the EXTREME<br />
regimen (cohort B) were extracted. The responses, prognoses and adverse events <strong>of</strong><br />
these two regimens were evaluated.<br />
Results: A total <strong>of</strong> 86 patients were included (cohort A: 49, cohort B: 36). Patients with<br />
histories <strong>of</strong> platinum-based chemotherapy were more allocated in cohort A. Though<br />
the response rates were similar in each cohort (44.9 % in cohort A and 51.4 % in cohort<br />
B; p = 0.83), the progression-free survival (PFS) was significantly more favorable in<br />
cohort A, as shown by the log-rank test (6.0 months vs 5.0 months; p = 0.027). The<br />
overall survival (OS) was also longer in cohort A, but there was no statistically<br />
significance (16.8 months vs 11.8 months; p = 0.072). In the Cox-regression hazard<br />
analyses, male sex (hazard ratio [HR] = 2.1, p = 0.010), older age (≥ 70 yo) (HR = 5.0,<br />
p = 0.018), PS 0 (HR = 2.2, p = 0.027), the absence <strong>of</strong> histories <strong>of</strong> platinum<br />
chemotherapy (HR = 3.2, p = 0.003) and the presence <strong>of</strong> tracheostoma (HR = 2.3,<br />
p = 0.039) were favorable factors <strong>of</strong> cohort A.<br />
Conclusions: In our retrospective analyses, R/M SCCHN patients receiving weekly<br />
paclitaxel and cetuximab showed longer PFS than those receiving the EXTREME<br />
regimen. In selected patients, the combination <strong>of</strong> weekly paclitaxel and cetuximab<br />
could be the better treatment option.<br />
Legal entity responsible for the study: Cancer Institute Hospital<br />
Funding: Cancer Institute Hospital<br />
Disclosure: K. Nakano: Personal fees for lectures and advisory board services <strong>of</strong> Eisai<br />
Pharmaceutical, GlaxoSmithKline, MSD Serono, Novartis and Taiho Pharmaceutical<br />
outside the submitted work. All other authors have declared no conflicts <strong>of</strong> interest.<br />
1004P<br />
Effect <strong>of</strong> Hedgehog signaling pathway on the proliferation <strong>of</strong><br />
high-grade gliomas<br />
S.A. Cherepanov<br />
Department <strong>of</strong> Medical Nanobiotechnologies, N.I. Pirogov Russian National<br />
Research Medical University, Moscow, Russian Federation<br />
Background: High-grade gliomas are the most aggressive brain tumors. A clear<br />
understanding <strong>of</strong> the oncogenesis mechanisms and searching for specific targets<br />
among the proteins <strong>of</strong> signaling pathways involved in oncogenesis are needed to<br />
develop more effective therapy. According to current data, the Hedgehog pathway is<br />
involved in oncogenesis <strong>of</strong> glioma. In the case where the signal pathway is activated,<br />
GLI transcription factors alter the level <strong>of</strong> expression <strong>of</strong> the target genes, thus affecting<br />
the processes <strong>of</strong> proliferation, angiogenesis, chemoresistance, invasive and migratory<br />
activity. The aim <strong>of</strong> this study was to evaluate the effect <strong>of</strong> the activator (SHH) and<br />
inhibitor (cyclopamine) <strong>of</strong> Hedgehog signaling pathway on the proliferation <strong>of</strong> human<br />
glioma cell lines U87-MG, U251-MG and cells <strong>of</strong> human astrocytes.<br />
Methods: Cell proliferation was investigated using xCELLigence system, which allows<br />
measurement <strong>of</strong> the electrical resistance <strong>of</strong> the gold microelectrodes located on the<br />
bottom <strong>of</strong> 16-well E-plates.<br />
Results: It was shown that the SHH ligand increases proliferation <strong>of</strong> U251-MG cell line<br />
and human astrocytes. SHH ligand has no effect on proliferation <strong>of</strong> U87-MG cell line.<br />
Cyclopamine has an inhibitory effect on the proliferation <strong>of</strong> human glioma cell lines<br />
U87-MG and U251-MG, and has no effect on human astrocytes. Mann-Whitney test<br />
and Student’s t-test with significance level α = 0.05 was used for statistical analysis.<br />
Cyclopamine has an inhibitory effect on U251-MG culture, so we can assume that the<br />
pathway is active. Proliferation <strong>of</strong> U87-MG cell line was decreased by adding<br />
cyclopamine and adding SHH has no effect. The pathway also is active, but the<br />
addition <strong>of</strong> an activator does not provide additional stimulus. It can be assumed that<br />
the signaling pathway is most active. In human astrocytes cyclopamine has no effect on<br />
the proliferative activity <strong>of</strong> cells, and it is increased with the SHH addition. In this case<br />
the pathway is inactive, but SHH has an activating effect.<br />
Conclusions: Our experiments with cyclopamine and SHH provide additional<br />
information for determining the activity <strong>of</strong> a signaling pathway that will help to<br />
develop a quantitative assessment <strong>of</strong> functioning Hedgehog signaling pathway in the<br />
known cell lines and in primary cell cultures.<br />
Clinical trial identification: Extract from the protocol <strong>of</strong> the meeting <strong>of</strong> the Ethics<br />
Committee RNRMU named after Pirogov N.I. N131 dated January 27 2014<br />
Legal entity responsible for the study: RNRMU named after Pirogov N.I.<br />
Funding: Grant <strong>of</strong> the Russian Science Foundation Number 14-14-00882<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1005P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Molecular analysis in serial biopsies in sinonasal mucosal<br />
melanoma<br />
G. Anguera Palacios 1 , M.Á. Molina-Vila 2 , J.R. Gras-Cabrerizo 3 , X. León 3 ,<br />
C. Mayo 2 , J. Codony Servat 2 , A. Pérez-Rosado 2 , S. Rodríguez 2 ,<br />
M. González-Cao 4 , N. Karachaliou 4 , A. Barnadas 1 , R. Rosell 4 , M. Majem 1<br />
1 Medical <strong>Oncology</strong>, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain,<br />
2 Laboratory <strong>of</strong> Cellular and Molecular Biology, Pangaea Biotech SL, IOR<br />
Quirón-Dexeus University Institute, Barcelona, Spain, 3 Otolaryngology/Head and<br />
Neck Surgery, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain, 4 Medical<br />
<strong>Oncology</strong> Service, Instituto Oncológico Dr Rosell (IOR), Hospital Universitario<br />
Quirón-Dexeus, Barcelona, Spain<br />
Background: Melanomas from the mucosal surface are a rare entity, <strong>of</strong> which<br />
approximately 25% arise from the nasosinusal region. Given the low incidence <strong>of</strong> this<br />
entity, it is not well known the incidence <strong>of</strong> genetic alterations in sinonasal mucosal<br />
melanomas (SMM). The purpose <strong>of</strong> this study is to analyse mutational status <strong>of</strong><br />
patients (pts) with SMM in primary tumors and in locoregional and/or distant relapse.<br />
Methods: From 1988 to 2015, 25 pts were diagnosed <strong>of</strong> SMM in our institution. We<br />
collected formalin-fixed paraffin blocks from 19 primary tumors and, in 12 <strong>of</strong> them,<br />
from local recurrence and/or distant metastasis. Median number <strong>of</strong> samples per patient<br />
was 3 (range 1-9). We analysed the spectrum <strong>of</strong> mutations in KIT gene (exon 9, 11 13<br />
and 17) by standard PCR followed by Sanger sequencing, NRAS gene (exon 2, 3 and 4)<br />
by pyrosequencing and BRAF gene (exon 15) by Taqman PCR.<br />
Results: The median age at diagnosis was 75 (range 42-86), 13 were males and 12<br />
females. According to the TNM-SMM system, the pts were classified as T3 in 12 cases<br />
(48%), as T4a in 5 cases (20%), and 8 pts (32%) as T4b. 23/25 pts underwent surgery<br />
followed by radiotherapy, if needed, as first treatment and 2 pts received palliative<br />
chemotherapy with a DTIC-based schedule. 9/25 pts (36%) presented locoregional<br />
recurrence (36%) and 8 <strong>of</strong> 25 pts (32%) develop distant metastasis. We performed<br />
molecular analysis in 19 cases and we identified gene mutations in 5 cases, all from the<br />
nasal cavity. We found 2 cases (10.5%) with mutations in NRAS gene (both in exon 2:<br />
G12V) and 3 cases (15.8%) with mutations in KIT (all in the exon 11: R586K, G565R,<br />
M552I). No BRAF mutations were detected. Interestingly, we found discrepancies in<br />
the NRAS mutational status <strong>of</strong> tumor samples obtained from 2 pts. In the first case, at<br />
diagnosis, we identified the NRAS mutation in 1 <strong>of</strong> 2 samples, and in 2 <strong>of</strong> 3 samples at<br />
the time <strong>of</strong> local recurrence. In the second case, the NRAS mutation was present at<br />
diagnosis but only in 2 <strong>of</strong> 4 samples <strong>of</strong> distant recurrence.<br />
Conclusions: In our series <strong>of</strong> SMM, we have found a KIT mutation rate <strong>of</strong> 15,8% and a<br />
10.5% in NRAS mutation. No BRAF mutations were detected. We have observed<br />
differences in mutation status between different tumor samples in 2 pts with NRAS<br />
mutations that might be explained by tumor heterogeneity.<br />
Legal entity responsible for the study: Hospital de la Santa Creu i Sant Pau and<br />
Laboratory on <strong>Oncology</strong>/Pangaea Biotech<br />
Funding: Hospital de la Santa Creu i Sant Pau and Laboratory on <strong>Oncology</strong>/Pangaea<br />
Biotech<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
vi346 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
1006P<br />
Expression pr<strong>of</strong>ile <strong>of</strong> papillary thyroid carcinomas according<br />
to cervical lymph node metastasis status<br />
M. Barros Filho 1 , F. Marchi 1 , C.A. Pinto 1 , S.R. Rogatto 2 , L.P. Kowalski 1<br />
1 CIPE - International Center for Research, A. C. Camargo Cancer Center, Sao<br />
Paulo, Brazil, 2 Department <strong>of</strong> Clinical Genetics, Vejle Hospital Sygehus Lillebaelt,<br />
Vejle Sygehus, Vejle, Denmark<br />
Background: A high incidence <strong>of</strong> lymph node metastasis has been described in<br />
papillary thyroid carcinoma (PTC), which is related to an increased risk <strong>of</strong> tumor<br />
recurrence. Biomarkers have potential to be used as predictive tool to identify patients<br />
with high risk to recur in comparison with imaging tests, which present low sensitivity<br />
to detect lymph node metastasis. The aim <strong>of</strong> this study is to identify molecular markers<br />
able to predict lymph node metastasis in PTC patients.<br />
Methods: Messenger RNA sequencing data obtained from TCGA (Illumina HiSeq<br />
level 3) <strong>of</strong> PTC were used in a preliminary screening. From 507 patients, 200 were<br />
filtered to avoid confounding factors. Cases presenting lymph nodes (LN) positive<br />
(N1 = 107) had pathological confirmation <strong>of</strong> LN metastasis at diagnosis with unicentric<br />
primary tumor. Cases LN negative (N0 = 93) had pathological confirmation <strong>of</strong> LN<br />
disease-free; they were no submitted to ablation by radioiodine therapy neither<br />
presented loco-regional recurrence after 1-year <strong>of</strong> follow-up. Differentially expressed<br />
genes were submitted to in silico pathway analysis using the Reactome tool. Selected<br />
transcripts were further assessed by RT-qPCR using Taqman assays (Applied<br />
Biosystems) to confirm the findings in an independent set <strong>of</strong> 72 PTC samples.<br />
Results: Based on TCGA database, 334 transcripts were detected by comparing N1<br />
versus N0 tumors (random variance t test FDR 2). Pathway<br />
analysis revealed an enrichment <strong>of</strong> genes related to collagen degradation and<br />
formation, degradation <strong>of</strong> the extracellular matrix and activation <strong>of</strong> matrix<br />
metalloproteinases (FDR < 1%). From the 28 genes selected for validation by<br />
RT-qPCR, AREG, S100A2, S100A10, SCEL and PDLIM4 were confirmed as higher<br />
expressed and DIO2 as lower expressed in N1 cases.<br />
Conclusions: This study revealed a potential involvement <strong>of</strong> extracellular matrix<br />
remodeling pathways in the LN metastasis in PTC. In addition, AREG, S100A2,<br />
S100A10, SCEL, PDLIM4 and DIO2 genes are promising markers to discriminate PTC<br />
tumors with higher risk <strong>of</strong> presenting cervical LN metastasis at diagnosis.<br />
Legal entity responsible for the study: AC Camargo Cancer Center<br />
Funding: FAPESP, CNPQ<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1007P<br />
Phase II-trial <strong>of</strong> concomitant hyperfractionated-accelerated<br />
radiotherapy (HART) with cisplatin (Cis) plus cetuximab (Cet)<br />
for locoregionally advanced inoperable squamous cell head<br />
and neck cancer: 5-year end results<br />
T. Kuhnt 1 , A. Schreiber 2 , A. Pirnasch 3 , M.G. Hautmann 4 , P. Hass 5 , F.P. Sieker 6 ,R.<br />
Engenhart- Cabilic 7 , M. Richter 8 , K. Dellas 9 , J. Dunst 9<br />
1 Department <strong>of</strong> Imaging and Radiation Medicine, University <strong>of</strong> Leipzig, Leipzig,<br />
Germany, 2 Private Praxis for Radiooncology, Krankenhaus<br />
Dresden-Friedrichstadt, Dresden, Germany, 3 Department <strong>of</strong> Radiation <strong>Oncology</strong>,<br />
Universitätsklinikum Rostock, Rostock, Germany, 4 Department <strong>of</strong> Radiotherapy,<br />
University <strong>of</strong> Regensburg, Regensburg, Germany, 5 Department <strong>of</strong> Radiotherapy,<br />
Otto-von Guericke-Universität, Magdeburg, Germany, 6 Department <strong>of</strong><br />
Radiotherapy, Martin Luther Universität Halle-Wittenberg, Halle/Saale, Germany,<br />
7 Department <strong>of</strong> Radiotherapy, Philipps University Marburg, Marburg, Germany,<br />
8 Coordination Center for Clinical Trials, Martin Luther Universität Halle-Wittenberg,<br />
Halle/Saale, Germany, 9 North European Radiooncological Center, University<br />
Hospital UKSH, Kiel, Germany<br />
Background: Cet is a potent inhibitor <strong>of</strong> the epidermal growth factor receptor and has<br />
shown activity in squamous cell carcinoma <strong>of</strong> the head and neck (SCCHN) enhancing<br />
both radiotherapy and chemotherapy. We conducted a single arm phase II-trial to<br />
investigate the feasibility, efficacy and safety <strong>of</strong> combination therapy with Cis, Cet and<br />
HART.<br />
Methods: Patients (pts) with stage III or IV, M0 SCCHN were enrolled and treated<br />
with an initial dosage <strong>of</strong> Cet (400mg/m 2 ), followed by weekly dosage <strong>of</strong> 250mg/m 2<br />
during HART, which started with a prescribed dosage <strong>of</strong> 2.0 Gy per day for three weeks<br />
followed by 1.4 Gy twice daily to a total dosage <strong>of</strong> 70.6 Gy to the gross tumor volume.<br />
Cis 40 mg/m 2 was administered weekly (d1,8,15,22,29,36).<br />
Results: From November 2007 through November 2010, 74 pts were enrolled, 65 pts<br />
(83% men) with a median age <strong>of</strong> 56 years (range 37 to 69 years) were evaluable. The<br />
median Karn<strong>of</strong>sky status, 90%; range, 50% to 100%; oropharynx primary tumor, 49%<br />
<strong>of</strong> patients; T4a,b, 65%; N2/3, 95%; stage IVA/B disease, 92%. Of theses were 85%<br />
smokers or ex-smokers. In the OPC patients neither p16 and HPV16 status was<br />
investigated. Of these 60 pts (92%) > 90% RT dosage, 49 pts (75%) > 90% Cet dosage<br />
and 56 pts (82%) > 4 cycles Cis 40 mg/m 2 were applied. Complete remission rate (CR)<br />
was observed in 23/65 (35%). The most common grade >3 toxicity were mucositis<br />
(58%) and dysphagia (52%), grade >2 Cet related toxicity included dermatitis<br />
acneiform (15%) within the radiotherapy portals. With a median follow-up <strong>of</strong> 27<br />
months; range 0 to 69 months; the 2- and 5-year overall survival rates are 64% and<br />
41%, the 2-and 5- year progression-free survival rate are 45% and 32%, and the 2-year<br />
and 5-locoregional control rates are 47% and 33%.<br />
Conclusions: Combination therapy <strong>of</strong> SCCHN consisting <strong>of</strong> HART-Cis-Cet is an<br />
highly active regimen in this smoke - and alcohol-induced cancers. Further<br />
investigation is warranted to evaluate the efficacy <strong>of</strong> the trimodal approach in this very<br />
high risk patient Population.<br />
Clinical trial identification: EudraCT 2005-000355-15<br />
Legal entity responsible for the study: N/A<br />
Funding: Merck Serono GmbH Darmstadt<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1008P<br />
Effect <strong>of</strong> protracted radiotherapy treatment on outcome <strong>of</strong><br />
head and neck SCC patients (NEMROCK experience)<br />
L. Ahmed, H. Darwish, S. El-Haddad, T. El-Nahas<br />
Clinical <strong>Oncology</strong>, Kasr Al-Aini Ctr <strong>of</strong> Clin <strong>Oncology</strong> and Nuclear Medicine<br />
(NEMROCK), Cairo Univ, Cairo, Egypt<br />
Background: Patients with head and neck cancer receiving radiation therapy alone or<br />
with concurrent chemotherapy <strong>of</strong>ten develop mucositis that may lead to unplanned<br />
treatment interruptions, these decreases in treatment intensity may reduce rates <strong>of</strong><br />
loco-regional tumor control and survival.<br />
Methods: A total number <strong>of</strong> one hundred twenty head and neck cancer patients<br />
included in this retrospective study presented to NEMROCK between January 2005<br />
and December 2010 after they underwent surgery and received their post operative<br />
adjuvant radiotherapy with or without concomitant chemotherapy. The impact <strong>of</strong> both<br />
overall treatment time <strong>of</strong> radiation and treatment gaps on loco regional tumor control<br />
and overall survival were studied.<br />
Results: Radiation treatment gaps lasting 5 days or less did not influence LC (86%) at<br />
3-years, which may suggest that the average dose intensity (>9 Gy/week), appeared<br />
high enough to compensate for few days <strong>of</strong> treatment break meanwhile patients<br />
received low DI ( 10 days gap<br />
(87.8% vs. 61%, p = 0.001). An increased OTT (> 60 days) and low DI (9 Gy/week) are<br />
seem to be related to a decreased OAS among our patients in multivariate analysis.<br />
Conclusions: In this retrospective study, patients with head-and-neck cancer, who<br />
have unplanned interruptions in radiotherapy have an increased risk <strong>of</strong> death and<br />
tumor recurrence. This analysis have several limitations. It is impossible to fully remove<br />
the effect <strong>of</strong> unmeasured factors that are associated both with presence <strong>of</strong> treatment<br />
interruptions and risk <strong>of</strong> death like mucositis, xerostomia, dysphagia, and aspiration,<br />
each <strong>of</strong> which may also be associated with decreased survival time. Thus, the observed<br />
increased risk <strong>of</strong> death associated with interruptions in radiotherapy may not be<br />
entirely attributable to the interruptions themselves.<br />
Legal entity responsible for the study: Kasr El-Aini Centre <strong>of</strong> Clinical <strong>Oncology</strong> &<br />
Nuclear Medicine (NEMROCK)<br />
Funding: Kasr El-Aini Centre <strong>of</strong> Clinical <strong>Oncology</strong> & Nuclear Medicine (NEMROCK)<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1009P<br />
abstracts<br />
A novel treatment <strong>of</strong> radiation induced xerostomia by<br />
autologous platelet-rich-plasma and peripheral stem cells<br />
A. Taghizadeh Kermani 1 , P. Izadpanahi 1 , K. Khazaeni 1 , M. Pezeshki Rad M 2 ,<br />
R. Asadi 1 , M. Asadi 1 , D. Hamidi Alamdari 3<br />
1 <strong>Oncology</strong> Department, Cancer Research Center, Mashhad, Iran, 2 Radiology<br />
Department, Cancer Research Center, Mashhad, Iran, 3 Stem Cell Laboratory,<br />
Biochemistry and Nutrition Research Center, Mashhad, Iran<br />
Background: There are 30000 to 40000 head and neck cancers cases in United States<br />
each year. Radiotherapy is one <strong>of</strong> the best treatment options in these patients.<br />
Unfortunately, Xerostomia is one <strong>of</strong> most common side effects. This study aimed to<br />
evaluate effect <strong>of</strong> autologous platelet rich plasma (PRP) and PRP along with peripheral<br />
blood cells (PC) application in treatment <strong>of</strong> radiation induced xerostomia for the first<br />
time in the world.<br />
Methods: 21 patients with head and neck cancers who suffered from post radiation<br />
xerostomia were selected regard to inclusion criteria. Patients were divided into PRP or<br />
PRP + PC group randomly. They were followed up for 6 months. Data was analyzed by<br />
SPSS version 20 and parametric and nonparametric tests<br />
Results: 21 patients with the age between 20 and 61 years were entered the pilot study.<br />
47.6% were female and other was male. Mean left parotid uptake to back ground (first<br />
month after injection) in PRP and RPR + PC group was 0.31 ± 1.6 and 1.3± 0.62 and<br />
this difference was significant (P = 0.33). This index in right submandibul (sixth month<br />
after injection) was -0.31 ± 0.43 and 1.3 ± 1.2 (P = 0/033). All quality <strong>of</strong> life parameters<br />
show improvement in first and sixth month after treatment (P < 0.001).<br />
Conclusions: All quality <strong>of</strong> life parameters show improvement after treatment and<br />
these findings were qualified by objective results <strong>of</strong> Scintigraphy scan. Absorption<br />
parameters in Scintigraphy show significant improvement in all salivary glands.<br />
Secretion parameters show significant improvement in both parotid glands not sub<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw376 | vi347
abstracts<br />
mandibular glands. These may be due to small sample size or short follow up period.<br />
Result <strong>of</strong> scan showed that PRP + PC are more effective than RPR<br />
Legal entity responsible for the study: N/A<br />
Funding: Mashhad University <strong>of</strong> Medical Sciences<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1010P<br />
The role <strong>of</strong> interim FDG-PET after induction chemotherapy as<br />
a prediction <strong>of</strong> the efficacy <strong>of</strong> concurrent chemoradiotherapy<br />
in locally advanced squamous carcinoma <strong>of</strong> the head and<br />
neck<br />
K-R. Kim 1 , H-J. Shim 1 , J-E. Hwang 1 , S-H. Cho 1 , I-J. Chung 1 , S.Y. Kwon 2 ,<br />
W-K. Bae 1<br />
1 Hemato-<strong>Oncology</strong>, Chonnam National University Hwasun Hospital,<br />
Hwasun-Gun, Republic <strong>of</strong> Korea, 2 Nuclear Medicine, Chonnam National University<br />
Hwasun Hospital, Hwasun-Gun, Republic <strong>of</strong> Korea<br />
Background: Having advantage for organ preservation and systemic control, induction<br />
chemotherapy (ICT) using docetaxel, cisplatin and 5-FU (DCF) followed concurrent<br />
chemoradiotherapy (CCRT) has been used for nonsurgical management <strong>of</strong> locally<br />
advanced head and neck squamous cell carcinoma (HNSCC). Early prediction <strong>of</strong> efficacy<br />
<strong>of</strong> CCRT could be helpful to select patients with more effective in surgery than CCRT. We<br />
evaluated the role <strong>of</strong> interim 18-fluoro-2-deoxy-glucose positron emission tomography<br />
(FDG-PET) after ICT as a prediction <strong>of</strong> the efficacy <strong>of</strong> CCRT and clinical outcomes.<br />
Methods: Tumor responses were retrospectively reviewed based on Response<br />
Evaluation Criteria in Solid Tumors after ICT and CCRT in locally advanced HNSCC.<br />
FDG-PET/CT scans were performed in all patients before and after three cycles <strong>of</strong><br />
DCF. We examined the association <strong>of</strong> metabolic response by the percentage decrease <strong>of</strong><br />
maximum standardized uptake value (SUVmax) after ICT with complete response<br />
(CR) to CCRT and clinical outcomes including progression-free survival (PFS) and<br />
overall survival (OS).<br />
Results: Forty-four patients with locally advanced HNSCC were evaluated with a<br />
median follow-up <strong>of</strong> 31.7 months. The SUVmax after ICT from baseline was more<br />
decreased in CR to CCRT group than non-CR group (78.8% vs. 62.5%, p = 0.004). A<br />
78% decrease <strong>of</strong> SUVmax after ICT from baseline predicted CR after CCRT (59.3% vs.<br />
17.6%, p = 0.012), PFS (median, not reached vs. 15.0 months, p = 0.002) and OS<br />
(median, not reached vs. 43.3 months, p = 0.005) <strong>of</strong> the patients.<br />
Conclusions: The SUVmax on interim FDG-PET after ICT could be useful to select<br />
patients benefitting from CCRT in locally advanced HNSCC and to predict survival<br />
outcomes.<br />
Legal entity responsible for the study: N/A<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1011P<br />
High expression <strong>of</strong> FOXM1 is a potential prognostic marker<br />
for oral squamous cell carcinoma patients treated with<br />
docetaxel-containing regimens<br />
T. Ferdous, K. Harada, Y. Ueyama<br />
Oral and Maxill<strong>of</strong>acial Surgery, Yamaguchi University Graduate School <strong>of</strong><br />
Medicine, Ube, Japan<br />
Background: Forkhead box protein M1 (FOXM1) is an oncoprotein that regulates cell<br />
growth and differentiation, angiogenesis, apoptosis and aging; and it is reported to play<br />
an important role in progression and drug sensitivity <strong>of</strong> various cancers. The purpose<br />
<strong>of</strong> this study was to determine whether FOXM1 expression could be a useful prognostic<br />
factor for oral squamous cell carcinoma (OSCC).<br />
Methods: FOXM1 expression was investigated by immunohistochemistry in tissue<br />
samples <strong>of</strong> 56 OSCC patients treated with docetaxel (DOC)-containing regimens. In<br />
this study, we investigated the relationship between FOXM1 expression and<br />
clinicopathological features <strong>of</strong> OSCC, as well as the prognosis <strong>of</strong> above patients.<br />
Moreover, we examined the expression <strong>of</strong> FOXM1 in DOC-resistant human tongue<br />
carcinoma cell lines (HSC2/DOC, HSC3/DOC and HSC4/DOC) in vitro. We<br />
established these DOC-resistant cell lines by exposing HSC2, HSC3 and HSC4 parental<br />
cells to increasing concentrations <strong>of</strong> DOC over approximately two years.<br />
Results: FOXM1 was detected both in nucleus and cytoplasm <strong>of</strong> OSCC tumor cells.<br />
FOXM1 expression in tumor tissues was significantly correlated with N classification<br />
(P = 0.0395), stage (P = 0.004), therapeutic efficacy (P = 0.0113) and outcome <strong>of</strong> patient<br />
(P = 0.0134); although there was no correlation between FOXM1 expression and<br />
patient’s gender, age or T classification. Moreover, high expression <strong>of</strong> FOXM1 in tumor<br />
cells was associated with shorter overall survival (OS, P = 0.0257). Multivariate analysis<br />
also revealed that high expression <strong>of</strong> FOXM1 was a predictor <strong>of</strong> reduced survival<br />
(P = 0.0327). Additionally, DOC-resistant OSCC cell lines showed significantly higher<br />
expression <strong>of</strong> FOXM1 compared to the parental cell lines in vitro.<br />
Conclusions: These findings suggest that high expression <strong>of</strong> FOXM1 in OSCC tumors<br />
is correlated with DOC resistance, as well as poor therapeutic effects and worse clinical<br />
outcomes in OSCC patients treated with DOC -containing regimen. Therefore,<br />
FOXM1 might have prognostic significance in oral squamous cell carcinoma patients.<br />
Legal entity responsible for the study: Yamaguchi Unversity Graduate School <strong>of</strong><br />
medicine<br />
Funding: Grant-in-Aid from the Japanese Ministry <strong>of</strong> Education, Science and Culture<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1012P<br />
A multi-institutional dose-finding and efficacy confirmation<br />
trial <strong>of</strong> superselective intra-arterial infusion <strong>of</strong> cisplatin and<br />
concomitant radiotherapy for patients with locally advanced<br />
maxillary sinus cancer (JCOG1212, RADPLAT-MSC): Results<br />
<strong>of</strong> dose-finding phase<br />
T. Sakashita 1 , A. Homma 1 , R. Onimaru 2 , K. Matsuura 3 , H. Shinomiya 4 ,<br />
R. Hayashi 5 , K. Shiga 6 , H. Tachibana 7 , K. Nakamura 8 , J. Mizusawa 9 , M. Fujii 10<br />
1 Otolaryngology-Head and Neck Surgery, Hokkaido University Hospital, Sapporo,<br />
Japan, 2 Radiology, Hokkaido University Hospital, Sapporo, Japan, 3 Head and<br />
Neck Surgery, Miyagi Cancer Center, Natori, Japan, 4 Otolaryngology-Head and<br />
Neck Surgery, Kobe University Graduate School <strong>of</strong> Medicine, Kobe, Japan, 5 Head<br />
and Neck Surgery Division, National Cancer Center Hospital East, Kashiwa,<br />
Japan, 6 Otolaryngology - Head and Neck Surgery, Iwate Medical University<br />
School <strong>of</strong> Medicine, Morioka, Japan, 7 Radiation <strong>Oncology</strong>, Aichi Cancer Center<br />
Hospital, Nagoya, Japan, 8 Japan Clinical <strong>Oncology</strong> Group Operations Office,<br />
National Cancer Center Hospital, Tokyo, Japan, 9 JCOG Data Center/Operations<br />
Office, Center for Research Administration and Support, National Cancer Center<br />
Hospital, Tokyo, Japan, 10 Otorhinolaryngology, National Tokyo Medical Center,<br />
Tokyo, Japan<br />
Background: Superselective intra-arterial infusion <strong>of</strong> high-dose cisplatin with<br />
concomitant radiotherapy (RADPLAT) has been performed for the patients with<br />
locally advanced maxillary sinus squamous cell carcinomas (LA-MSSCCs) in several<br />
institutions and has been reported to result in a favorable survival. This<br />
multi-institutional prospective trial was aimed to confirm the adequate dose and<br />
efficacy <strong>of</strong> RADPLAT for the patients with LA-MSSCCs. The dose-finding phase was<br />
performed to evaluate the incidence <strong>of</strong> dose-limiting toxicity (DLT) and to determine<br />
the recommended cycle <strong>of</strong> intra-arterial infusion <strong>of</strong> cisplatin.<br />
Methods: Eighteen patients were registered from 7 institutions for this study. In this<br />
dose-finding study, 100 mg/m 2 <strong>of</strong> cisplatin was administered intra-arterially weekly for<br />
7 weeks with concomitant radiotherapy (total 70 Gy). Cisplatin was skipped in the case<br />
<strong>of</strong> adverse events that met the skipping rule defined by the protocol. The recommended<br />
number <strong>of</strong> cycles was determined according to the distribution <strong>of</strong> the number <strong>of</strong> cycles<br />
<strong>of</strong> administered cisplatin and the incidence <strong>of</strong> DLT.<br />
Results: The median age <strong>of</strong> all participants was 64 years old (range, 40-75 years old).<br />
Sixteen patients were diagnosed as T4aN0M0, and two patients as T4bN0M0. All<br />
patients achieved full dose <strong>of</strong> radiotherapy. The number <strong>of</strong> cycles <strong>of</strong> administered<br />
cisplatin was 7 in 13 patients and 6 in 5. DLT was observed in 5 patients; Gr 3 liver<br />
dysfunction (1), Gr 4 thrombocytopenia (1), Ccr < 40 (1), Gr 3 retinopathy (1), and Gr<br />
3 retinal detachment (1). There was not either treatment-related death or neural<br />
complication.<br />
Conclusions: RADPLAT appears to be safe and well-tolerated at 7 cycles <strong>of</strong> cisplatin at<br />
a dose <strong>of</strong> 100 mg/m 2 each cycle, which were determined to be the recommended<br />
number <strong>of</strong> cycles for LA-MSSCC.<br />
Clinical trial identification: UMIN000013706.<br />
Legal entity responsible for the study: N/A<br />
Funding: Research Funding Source Name: the Practical Research for Innovative<br />
Cancer Control(15ck0106137h0002)<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1013P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Cercival lymph node metastasis <strong>of</strong> squamous cell carcinoma<br />
<strong>of</strong> an unknown primary (SCCUP): a single institutional review<br />
J.P. Silva 1 , M.T. Alexandre 1 , D. Ferreira 1 , M. Ramos 2 , P. Pereira 3 , N. Ferreira 4 ,<br />
I. Sargento 1 , E. Netto 4 , M. Magalhaes 5 , M. Ferreira 1 , A. Moreira 1<br />
1 Medical <strong>Oncology</strong>, Instituto Portuguès de Oncologia de Lisboa Francisco Gentil,<br />
E.P.E. (IPOLFG EPE), Lisbon, Portugal, 2 Biostatistics, Instituto Portuguès de<br />
Oncologia de Lisboa Francisco Gentil, E.P.E. (IPOLFG EPE), Lisbon, Portugal,<br />
3 Radiology, Instituto Portuguès de Oncologia de Lisboa Francisco Gentil, E.P.E.<br />
(IPOLFG EPE), Lisbon, Portugal, 4 Radiotherapy, Instituto Portuguès de Oncologia<br />
de Lisboa Francisco Gentil, E.P.E. (IPOLFG EPE), Lisbon, Portugal,<br />
5 Otorhinolaryngology, Instituto Portuguès de Oncologia de Lisboa Francisco<br />
Gentil, E.P.E. (IPOLFG EPE), Lisbon, Portugal<br />
Background: Squamous cell carcinoma <strong>of</strong> unknown primary (SCCUP) represents 1%<br />
to 4% <strong>of</strong> all head and neck malignancies. Five-year survival rates <strong>of</strong> 30% to 50% are<br />
reported with radical neck surgery, high-dose radiotherapy (RT) and combination<br />
modalities.<br />
Methods: A retrospective analysis from chart review <strong>of</strong> all consecutive non metastatic<br />
SCCUP patients (pts) diagnosed and treated at our Institution between January 2009<br />
and December 2014 was performed. Primary aim: to characterize the clinical,<br />
demographic and treatment data. Secondary aim: to evaluate overall survival (OS) and<br />
vi348 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
event-free survival (EFS) at 3 and 5-years using the Kaplan-Meier method and the<br />
related prognostic factors by Cox’s multivariate proportional risk.<br />
Results: From a total <strong>of</strong> 80 pts, 66 (82%) were males and 14 (18%) were females with a<br />
median age <strong>of</strong> 62 years (range 41-84). Alcohol and tobacco abuse was found in 69 and<br />
76% <strong>of</strong> pts, respectively. Diagnostic evaluation consisting <strong>of</strong> PET-CT, cervical and<br />
thorax CT-scan, ENT examination and laryngoscopy, endoscopy and bronchoscopy<br />
were completed in 33 (41%) <strong>of</strong> pts. Distribution <strong>of</strong> pts by N status was N1 –5 pts, N2a<br />
– 7 pts, N2b – 31 pts, N2c - 3pts and N3 -34 pts. Level neck node IV/V involvement<br />
was seen in 56% pts. Extracapsular spread was found in 54 (67%) pts and G3 in 32<br />
(40%) pts. Upfront neck dissection (ND) with biopsy <strong>of</strong> base <strong>of</strong> tongue and<br />
hypopharynx and bilateral amigdalectomy were performed in 51 pts (64%), and in 42<br />
<strong>of</strong> those pts was followed by adjuvant treatment (RT in 17, chemoradiation (CRT) in<br />
25). Two pts received definitive CRT, 10 isolated RT and 9 induction chemotherapy<br />
followed by CRT. Eight pts were treated with best supportive care. Seven cervical and<br />
16 systemic (lung in 11 pts) recurrences were documented. In the multivariate analysis,<br />
ND significantly affected survival (non-surgery group hazard ratio 5.7 IC95%<br />
2.93-11.2), p < 0.0001. The 3- and 5-years OS rate and EFS rate was 55%/53% and 37%/<br />
35%, respectively.<br />
Conclusions: Despite the N-stage being higher than expected, our survival data were<br />
similar to the published literature. The only prognostic factor for survival in our pts<br />
was upfront neck dissection. Other prognostic factors were not statistically significant<br />
probably due to the small sample.<br />
Legal entity responsible for the study: Instituto Português de Oncologia de Lisboa<br />
Francisco Gentil EPE<br />
Funding: Instituto Português de Oncologia de Lisboa Francisco Gentil EPE<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1014P<br />
Impact <strong>of</strong> second primary tumors <strong>of</strong> head and neck region<br />
after a previous tumor in that area<br />
C. Salvador Coloma 1 , J.T. Amerigo 2 , Ó.M. Niño 1 , J. Caballero Daroqui 1 ,<br />
D. Akhoundova 1 , C. Escoin 1 , M. Melián Sosa 1 , E. Navarro 1 , J. Montalar 1 ,<br />
M. Pastor 1<br />
1 Medical <strong>Oncology</strong>, Hospital Universitari i Politècnic La Fe, Valencia, Spain,<br />
2 Maxill<strong>of</strong>acial, Hospital Universitari i Politècnic La Fe, Valencia, Spain<br />
Background: The incidence <strong>of</strong> head and neck cancer is increasing. A significant<br />
problem is the high incidence <strong>of</strong> second primary tumours (SPTs) <strong>of</strong> head and neck<br />
area, which has the greatest impact on survival rates. However, there is nothing to<br />
distinguish between patients with high and low risk <strong>of</strong> developing a SPT. We evaluated<br />
the incidence and pattern <strong>of</strong> STP <strong>of</strong> head and neck area, the impact <strong>of</strong> SPT on survival,<br />
treatments and prognostic factors.<br />
Methods: We conducted a retrospective study in a series <strong>of</strong> 394 patients at the Hospital<br />
La Fe in whom a diagnosis <strong>of</strong> head and neck cancer was made between January 2005<br />
and February 2015.<br />
Results: Of 394 patients, a total <strong>of</strong> 35 patients (8.9%) developed a STP. Of them 10<br />
were synchronous neoplasia (SN), 25 metachronous neoplasia (MN)) and 1 patient<br />
developed a third MN. The median follow-up was 149 months (25-297). The<br />
characteristics <strong>of</strong> the first primary tumour (FPT) are in the table. Recurrent disease <strong>of</strong><br />
FPT developed in 3 patients (1 locally and 2 loco-regional). The median time for<br />
recurrence was 10.6 months (4.8-31). The characteristics <strong>of</strong> the SPT are listed in the<br />
table. The treatment intention was radical in 27 patients with complete response in 17<br />
patients (48.6%) and palliative in 9 (25.7%). Of all patients with SPT, 10 <strong>of</strong> them (28%)<br />
presented a recurrence <strong>of</strong> it. The median time from initial diagnosis <strong>of</strong> the SPT was 62<br />
months (0-168), including SN. The median overall survival was 149 months (84-214).<br />
The log-rank test, when comparing the groups <strong>of</strong> SN or MN <strong>of</strong> SPT, showed a<br />
significant difference for OS (p < 0.0001). The multivariate Cox regression analyses <strong>of</strong><br />
the associations among various clinic-pathological variables with OS revealed that SN<br />
or MN <strong>of</strong> SPT was the only independent predictor <strong>of</strong> lower OS (p = 0.04, HR: 4.84).<br />
Table: 1014P Patients and tumor characteristics<br />
Characteristics %<br />
Man/Female 80/20<br />
Age (median) 57<br />
First primary tumor characteristics<br />
Stage I II III IV Unknown 20 28.6 8.6 37.2 5.7<br />
Surgery Radiotherapy (RT) Chemotherapy (CT) y RT<br />
Surgery + QT + RT Surgery + RT Unknown<br />
34.3 2.9 20 5.7 31.4<br />
5.7<br />
Second primary tumor<br />
Oral cavity Oropharynx Larynx Esophagus Others 28.7 25.7 20.1 14.3<br />
11.5<br />
Local /loco-regional afection Metastatic Unknown 37.1/45.7 11.5 5.7<br />
Surgery Radiotherapy (RT) Chemotherapy (CT) y RT CT + RT<br />
Surgery + QT + RT Surgery + RT No treatment<br />
11.4 2.9 25.7 20<br />
28.6 8.6 2.9<br />
Conclusions: SPT represents the leading long-term cause <strong>of</strong> mortality in these patients.<br />
SN or MN <strong>of</strong> SPT was the only independent predictor <strong>of</strong> lower OS in our study. If we<br />
identified features that prelude a higher risk for the appearance <strong>of</strong> SPT, follow-up could<br />
be optimized for patients with higher risk.<br />
Legal entity responsible for the study: Hospital Universitario La Fe<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1015P<br />
Percutaneous gastrostomy or tracheostomy do not<br />
compromise overall survival in patients treated with<br />
chemotherapy for relapsed head and neck cancer<br />
K. Geršak 1 , C. Grasic Kuhar 2 , B. Zakotnik 2<br />
1 Onkološki inštitut - H1, Institute <strong>of</strong> <strong>Oncology</strong> Ljubljana, Ljubljana, Slovenia,<br />
2 Department <strong>of</strong> Medical <strong>Oncology</strong>, Institute <strong>of</strong> <strong>Oncology</strong> Ljubljana, Ljubljana,<br />
Slovenia<br />
Background: Survival in patients with relapsed/metastatic squamous cell head and<br />
neck cancer (SCHNC) is poor. Dysphagia, fatigue, dyspnoea and pain are common<br />
symptoms. Percutaneous endoscopic gastrostomy tube (PEG), tracheostomy and<br />
analgesics are frequently needed for supportive care. In addition to best supportive<br />
care, palliative systemic chemotherapy can be delivered in select patients with a good<br />
performance status.<br />
Methods: We retrospectively analysed the outcome <strong>of</strong> patients with relapsed or<br />
primary metastatic SCHNC treated with palliative chemotherapy at the Institute <strong>of</strong><br />
<strong>Oncology</strong> Ljubljana, Slovenia in years 2014 and 2015. We evaluated the impact <strong>of</strong><br />
performance status (PS), pain control and the presence <strong>of</strong> PEG and/or tracheostomy on<br />
overall survival (OS).<br />
Results: 43 patients (median age at diagnosis 59 years, range 40-78) were referred to a<br />
medical oncologist for palliative chemotherapy treatment. Primary cancer locations were<br />
oral cavity (18%), oropharynx (35%), larynx (16%), hypopharynx (26%) and paranasal<br />
sinuses (5%). The PS score was either 0 (19%), 1 (64%) or 2 (17%). 42% <strong>of</strong> patients had<br />
recurrence loco-regionally, 30% loco-regionally with distant metastases and 28% had<br />
distant metastases only. 16% <strong>of</strong> patients had PEG, 7% tracheostomy and 27% both PEG<br />
and tracheostomy. Palliative chemotherapy administered was either 5FU/cisplatin/<br />
cetuximab, methotrexate or paclitaxel. Median OS in all patients was 14.4 months (95%<br />
CI 11.8-16.9). Patients with PS 0-1 had longer median OS than patients with PS 2 (15.3<br />
vs. 3.8 months; p = 0.068). The presence <strong>of</strong> PEG and/or tracheostomy did not<br />
compromise chemotherapy treatment or adversely affect OS. Additionally, we found that<br />
patients with suboptimally managed pain tended to have shorter survival than patients<br />
with optimal analgesic support (3.8 vs. 9.5 months; p = 0.06).<br />
Conclusions: Presence <strong>of</strong> PEG and/or tracheostomy do not compromise OS in patients<br />
with relapsed/metastatic SCHNC. Patients with optimal pain control and PS 0-1 live<br />
longer.<br />
Clinical trial identification: 03-Z/KSOPKR-7<br />
Legal entity responsible for the study: Klara Geršak<br />
Funding: Onkološki Inštitut Ljubljana<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1016TiP<br />
abstracts<br />
A randomized, open-label, phase 3 study <strong>of</strong> nivolumab in<br />
combination with ipilimumab vs extreme regimen<br />
(cetuximab + cisplatin/carboplatin + fluorouracil) as<br />
first-line therapy in patients with recurrent or metastatic<br />
squamous cell carcinoma <strong>of</strong> the head and neck-CheckMate<br />
651<br />
A. Argiris 1 , M. Gillison 2 , R.L. Ferris 3 , K. Harrington 4 , T.K. Sanchez 5 , C. Baudelet 6 ,<br />
W.J. Geese 7 , J. Shaw 8 , R. Haddad 9<br />
1 Medical <strong>Oncology</strong>, Hygeia Hospital, Athens, Greece, 2 Internal Medicine, College<br />
<strong>of</strong> Medicine, The Ohio State University, Columbus, OH, USA, 3 Division <strong>of</strong> Head<br />
and Neck Surgery Departments <strong>of</strong> Otolaryngology, University <strong>of</strong> Pittsburgh, Eye<br />
and Ear Institute, Pittsburgh, PA, USA, 4 Division <strong>of</strong> Radiotherapy and Imaging, The<br />
Institute <strong>of</strong> Cancer Research, London, UK, 5 Global Clinical Research, <strong>Oncology</strong>,<br />
Bristol-Myers Squibb, Princeton, NJ, USA, 6 Biostatistics, Bristol-Myers Squibb,<br />
Princeton, NJ, USA, 7 <strong>Oncology</strong>, Bristol-Myers Squibb, Lawrence Township, NJ,<br />
USA, 8 Clinical Outcomes Assessment and I-O LCM Worldwide Health Economics<br />
and Outcomes Research, Bristol-Myers Squibb, Princeton, NJ, USA, 9 Head and<br />
Neck <strong>Oncology</strong> Program , Dana-Farber/Harvard Cancer Center, Boston, MA, USA<br />
Background: Patients (pts) with recurrent/metastatic (R/M) SCCHN have a poor<br />
prognosis. Addition <strong>of</strong> cetuximab to platinum and 5-FU (Extreme regimen) improved<br />
overall survival (OS) vs platinum-fluorouracil alone as first-line (1L) treatment <strong>of</strong> pts<br />
with R/M SCCHN and is a widely accepted standard <strong>of</strong> care in this setting. However,<br />
treatment results remain disappointing with
abstracts<br />
is a randomized, open-label, phase 3 study comparing the combination <strong>of</strong> nivo and ipi<br />
with the Extreme regimen as 1L therapy in pts with R/M SCCHN.<br />
Trial design: Pts aged ≥18 yr with histologically confirmed R/M SCCHN not<br />
amenable to curative therapy who have received no prior systemic therapy for their<br />
disease (except chemotherapy given as part <strong>of</strong> a multimodal treatment regimen that<br />
was completed 6 mo or more before enrollment) will be eligible. Approximately 490 pts<br />
will be randomized to receive nivo in combination with ipi or the Extreme regimen<br />
until progression or unacceptable toxicity. Primary endpoints are OS and<br />
progression-free survival. Secondary endpoints are objective response rate, time to<br />
symptomatic deterioration based on the 10-item Functional Assessment <strong>of</strong> Cancer<br />
Therapy-Head & Neck Symptom Index, and PD-L1 expression as a predictive<br />
biomarker for efficacy.<br />
Clinical trial identification: NCT02741570<br />
Legal entity responsible for the study: Sponsored by Bristol-Myers Squibb.<br />
Funding: Sponsored by Bristol-Myers Squibb.<br />
Disclosure: A. Argiris: Consultant for BMS. M. Gillison: Consultant and clinical trials<br />
contract to OSU with Bristol-Myers Squibb. Consultant for Merck Inc and Lilly. R.L.<br />
Ferris: Grant received from VentiRx, Bristol-Myers Squibb, and AZ/Medimmune.<br />
Member <strong>of</strong> ad-hoc advisory board for Merck, Celgene, Bristol-Myers Squibb, AZ/<br />
Medimmune. K. Harrington: Advisory Board member for BMS, Astra-Zeneca, Merck<br />
and Pfizer. T.K. Sanchez, C. Baudelet, W.J. Geese: Employee <strong>of</strong> Bristol-Myers Squibb.<br />
J. Shaw: Employee and shareholder <strong>of</strong> Bristol-Myers Squibb. R. Haddad: Grants and<br />
personal fees received from BMS during the conduct <strong>of</strong> the study. Grants received from<br />
Astra Zeneca, Celgene, and Venti-Rx. Received personal fees from Merck, Pfizer,<br />
Celgene, Eisai.<br />
1017TiP<br />
Double-blind, two-arm, phase 2 study <strong>of</strong> nivolumab (nivo) in<br />
combination with ipilimumab (ipi) versus nivo and<br />
ipi-placebo (PBO) as first-line (1L) therapy in patients (pts)<br />
with recurrent or metastatic squamous cell carcinoma <strong>of</strong><br />
the head and neck (R/M SCCHN)—CheckMate 714<br />
R. Haddad 1 , M. Gillison 2 , R.L. Ferris 3 , K. Harrington 4 , M. Monga 5 , C. Baudelet 6 ,<br />
W.J. Geese 7 , A. Argiris 8<br />
1 Head and Neck <strong>Oncology</strong> Program, Dana-Farber/Harvard Cancer Center,<br />
Boston, MA, USA, 2 Internal Medicine, College <strong>of</strong> Medicine, The Ohio State<br />
University, Columbus, OH, USA, 3 Division <strong>of</strong> Head and Neck Surgery Departments<br />
<strong>of</strong> Otolaryngology, University <strong>of</strong> Pittsburgh Cancer Institute, Pittsburgh, PA, USA,<br />
4 Division <strong>of</strong> Radiotherapy and Imaging, The Institute <strong>of</strong> Cancer Research and Royal<br />
Marsden Hospital, London, UK, 5 Global Clinical Research, Bristol-Myers Squibb,<br />
Princeton, NJ, USA, 6 Biostatistics, Bristol-Myers Squibb, Princeton, NJ, USA,<br />
7 <strong>Oncology</strong>, Bristol-Myers Squibb, Princeton, NJ, USA, 8 Medical <strong>Oncology</strong>, Hygeia<br />
Hospital, Athens, Greece<br />
Background: R/M SCCHN causes substantial morbidity and mortality, with a median<br />
overall survival (OS) <strong>of</strong> less than 12 months (mo). Thus, improvement in the standard<br />
<strong>of</strong> care is needed. Nivo, a fully human IgG4 monoclonal antibody to the PD-1 receptor,<br />
has shown increased OS in pts with solid tumors, including SCCHN. The combination<br />
<strong>of</strong> nivo with ipi (a humanized IgG1 CTLA-4 checkpoint inhibitor) is approved in<br />
advanced melanoma and has demonstrated clinical activity and manageable safety in<br />
various solid tumors. This randomized, double-blind, two-arm, phase 2 study will<br />
examine the safety and efficacy <strong>of</strong> nivo combined with ipi vs nivo alone when given as<br />
1L therapy in pts with R/M SCCHN. Also underway, a companion randomized,<br />
open-label, phase 3 study (CheckMate 651; NCT02741570) will compare nivo<br />
combined with ipi vs the Extreme regimen (cetuximab + cisplatin/<br />
carboplatin + fluorouracil) as 1L therapy in pts with R/M SCCHN.<br />
Trial design: Eligible pts include those aged ≥18 years with histologically confirmed<br />
untreated R/M SCCHN not amenable to curative therapy. Pts will be screened as<br />
platinum eligible (no prior systemic therapy except as adjuvant or neoadjuvant, or<br />
chemotherapy as part <strong>of</strong> multimodal treatment for locally advanced disease [LAD]<br />
completed >6 mo prior) or platinum refractory (relapse within 6 mo after platinum<br />
therapy in adjuvant or LAD setting). Approximately 315 pts will be stratified by PD-L1<br />
status, HPV p16 status (oropharyngeal cancer pts only), and platinum-refractory<br />
subgroup status, then randomized (2:1) to receive nivo every 2 wks (Q2W) + ipi every 6<br />
wks (Q6W) or nivo Q2W + intravenous PBO Q6W. Treatment will continue until<br />
progression or unacceptable toxicity. The primary endpoint is objective response rate<br />
(ORR; RECIST v1.1 criteria) in platinum-refractory pts. Secondary endpoints include<br />
ORR in the platinum-eligible subgroup, progression-free survival and OS in<br />
platinum-refractory and -eligible subgroups, and ORR by PD-L1 expression and HPV<br />
p16 status. Exploratory endpoints include safety and pt-reported outcomes.<br />
Legal entity responsible for the study: Sponsored by Bristol-Myers Squibb.<br />
Funding: Sponsored by Bristol-Myers Squibb.<br />
Disclosure: R. Haddad: Clinical trial support to institution, advisory board, consulting<br />
from BMS. Grants from Astra Zeneca, Celgene, Venti-Rx. Personal fees from Merck,<br />
Pfizer, Celgene, Eisai. M. Gillison: Consulting and Clinical Trials Contract to OSU from<br />
BMS. R.L. Ferris: Grants from VentiRx. Paid Member <strong>of</strong> Advisory Board(AdHoc) for<br />
Merck, Celgene, AZ/Medimmune, and BMS. K. Harrington: Advisory Board member<br />
for BMS, Astra-Zeneca, Merck and Pfizer. M. Monga, C. Baudelet: Employee <strong>of</strong> BMS.<br />
A. Argiris: Consultant for BMS. All other authors have declared no conflicts <strong>of</strong> interest.<br />
1018TiP<br />
A phase I dose escalation trial <strong>of</strong> stereotactic body<br />
radiotherapy and concurrent cisplatin for re-irradiation <strong>of</strong><br />
unresectable, recurrent carcinomas <strong>of</strong> the head and neck<br />
J. Caudell 1 , A. Trotti 1 , J. Kish 2 , J. Russell 2<br />
1 Radiation <strong>Oncology</strong>, M<strong>of</strong>fitt Cancer Center, Tampa, FL, USA, 2 Medical <strong>Oncology</strong>,<br />
M<strong>of</strong>fitt Cancer Center, Tampa, FL, USA<br />
Background: Locally/Regionally recurrent squamous cancers <strong>of</strong> the head and neck<br />
following radiotherapy are <strong>of</strong>ten not amenable to surgical salvage. Conventionally<br />
fractionated re-irradiation has been investigated, but survivals are poor. Stereotactic<br />
radiotherapy (SBRT) has been proposed as an alternative to conventionally<br />
fractionated re-irradiation, but reports to date have not shown significantly improved<br />
outcomes. Cisplatin has been shown to sensitize squamous carcinomas to radiotherapy<br />
even at doses > 2 Gy. We therefore designed a phase I dose escalation study <strong>of</strong> SBRT for<br />
re-irradiation with concurrent cisplatin (MCC 17799, ClinicalTrials.gov:<br />
NCT02158234).<br />
Trial design: This is a phase I, open label, dose escalation safety and tolerability study<br />
<strong>of</strong> SBRT in combination with cisplatin in patients with locally or regionally recurrent<br />
squamous cell carcinoma <strong>of</strong> the head and neck with prior radiotherapy > 45 Gy.<br />
Cohort 1 will receive 30 Gy SBRT given every other day for 5 fractions with cisplatin at<br />
15 mg/m 2 prior to each fraction. Dose escalation <strong>of</strong> SBRT to 35 or 40 Gy may occur<br />
based on evaluation <strong>of</strong> dose limiting toxicities up to 90 days following therapy.<br />
Approximately 21 patients will be enrolled at our institution. The primary endpoint is<br />
to define the maximum tolerated dose <strong>of</strong> SBRT with concurrent cisplatin. Secondary<br />
endpoints include loco-regional control, overall survival, and adverse events.<br />
Clinical trial identification: MCC 17799; ClinicalTrials.gov NCT02158234<br />
Legal entity responsible for the study: N/A<br />
Funding: Department <strong>of</strong> Radiation <strong>Oncology</strong>, M<strong>of</strong>fitt Cancer Center<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1019TiP<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Phase 1b trial <strong>of</strong> LY2606368 in combination with<br />
chemoradiation in patients with locally advanced head and<br />
neck squamous cell cancer<br />
E. Yang 1 , W. William 2 , J. Fayette 3 , W. Zhang 4 , A. Fink 5 , A.B. Lin 6 , E. Deutsch 7<br />
1 Radiation <strong>Oncology</strong>, University <strong>of</strong> Alabama at Birmingham, Birmingham, AL, USA,<br />
2 Thoracic/Head and Neck Medical <strong>Oncology</strong>, MD Anderson Cancer Center,<br />
Houston, TX, USA, 3 Radiotherapy, Centre Léon Bérard, Lyon, France, 4 Statistics,<br />
Eli Lilly and Company, Indianapolis, IN, USA, 5 Clinical Trial Management, Eli Lilly<br />
and Company, Indianapolis, IN, USA, 6 Clinical Research, Eli Lilly and Company,<br />
Indianapolis, IN, USA, 7 Radiotherapy, Institut Gustave Roussy, Villejuif, France<br />
Background: Checkpoint Kinase 1 (CHK1) is a multifunctional protein kinase and<br />
regulator <strong>of</strong> DNA damage response. LY2606368, an ATP-competitive inhibitor <strong>of</strong><br />
CHK1, has been tested in Phase I studies as a monotherapy and in combination with<br />
cytotoxic and targeted agents. Objective responses have been observed following<br />
LY2606368 monotherapy in patients with squamous cell tumors, including head and<br />
neck cancer (HNSCC). Transient Grade 4 neutropenia (typically
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong> 27 (Supplement 6): vi351–vi358, 2016<br />
doi:10.1093/annonc/mdw377<br />
health economics<br />
1021PD<br />
What does society value about oncology drugs? A discrete<br />
choice experiment in the Belgian population<br />
K. Pauwels 1 , I. Huys 1 , M. Casteels 1 , M. Vandebroek 2 , S. Simoens 1<br />
1 Clinical Pharmacology and Pharmacotherapy, University <strong>of</strong> Leuven, Leuven,<br />
Belgium, 2 Operations Research and Business Statistics, University <strong>of</strong> Leuven,<br />
Leuven, Belgium<br />
Background: Current debate on price setting and reimbursement <strong>of</strong> oncology drugs<br />
highlights the need to establish the value <strong>of</strong> oncology drugs. The aim <strong>of</strong> this study is to<br />
quantify societal preferences for oncology drugs with a discrete choice experiment in<br />
the Belgian population.<br />
Methods: Six attributes with three levels each are selected based on literature review and<br />
focus group discussions with lay persons. The experimental design was generated using<br />
SAS 9.4 built-in capabilities. The final survey was sent to a random sample <strong>of</strong> 3,500<br />
individuals in the Dutch speaking and French speaking community in Belgium. The<br />
preference <strong>of</strong> an average person was first estimated by a conditional logit model in SAS<br />
9.4. Attributes were selected based on 0.05 significance level. Then, individual<br />
parameters are estimated with a mixed logit model using the R-package bayesm 3.0-2.<br />
Willingness to pay (WTP) was calculated taking into account interactions if appropriate.<br />
Results: Based on 961 respondents, societal value <strong>of</strong> oncology drugs is positively<br />
affected by a higher number <strong>of</strong> patients eligible for treatment, a high initial life<br />
expectancy and quality <strong>of</strong> life <strong>of</strong> patients, a high gain in quality <strong>of</strong> life and life<br />
expectancy due to the treatment and a low cost related to the treatment. The value <strong>of</strong><br />
one point gain in quality <strong>of</strong> life, based on a 10-point scale, is however higher for<br />
patients with a low initial quality <strong>of</strong> life than for patients from which quality <strong>of</strong> life is<br />
less affected by the disease. The WTP <strong>of</strong> one year gain in life expectancy 3.55€,<br />
irrespective <strong>of</strong> the initial life expectancy. One year increase in life expectancy has the<br />
same value as one point increase in quality <strong>of</strong> life for a patient with an initial quality <strong>of</strong><br />
life <strong>of</strong> 4/10. When the initial quality <strong>of</strong> life <strong>of</strong> the patient is higher than 4/10, one point<br />
gain in quality <strong>of</strong> life is worth less than one year gain in life expectancy. When the<br />
initial quality <strong>of</strong> life <strong>of</strong> the patient is lower than 4/10, one point gain in quality <strong>of</strong> life is<br />
worth more than one year gain in life expectancy.<br />
Conclusions: The value <strong>of</strong> oncology drugs is context specific. Identification <strong>of</strong> valuable<br />
oncology drugs cannot be achieved by applying a “one size fits all principle”, which is<br />
now too <strong>of</strong>ten the case based on conventional instruments for market access <strong>of</strong> drugs.<br />
Legal entity responsible for the study: KU Leuven<br />
Funding: Flanders Innovation & Entrepreneurship + Reserach Foundation Flanders<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1022P<br />
Assessing the impact <strong>of</strong> clinical trial designs on progress<br />
against cancer using the PACE Continuous Innovation<br />
Indicators<br />
S. Paddock 1 , S. Thomas 1 , A. Kanli 2 , J. Zummo 3 , D. Grainger 3 ,R.Li 1<br />
1 PACE Team, Rose Li and Associates, Inc., Bethesda, MD, USA, 2 Corporate<br />
Affairs <strong>Oncology</strong>, Europe, Eli Lilly and Company, Brussels, Belgium, 3 Global<br />
<strong>Oncology</strong> Corporate Affairs, Eli Lilly and Company, Indianapolis, IN, USA<br />
Background: Clinical trial designs undergo constant evolution driven by changing<br />
scientific needs and corresponding regulatory demands. Early clinical research was<br />
dominated by case series and anecdotal reports. Randomized controlled trials emerged<br />
by the 1940s, and increasingly rigorous standards led to the modern 3-phase system.<br />
Recent studies have shifted from larger trials with post-hoc identification <strong>of</strong> subgroups<br />
to smaller trials conducted in selected populations. As trial designs continue to evolve,<br />
the field must monitor the success <strong>of</strong> new approaches to confirm that they lead to faster<br />
rates <strong>of</strong> progress with reproducible results.<br />
Methods: The PACE Continuous Innovation Indicators (CII) is a comprehensive<br />
historical database <strong>of</strong> evidence supporting cancer treatments for 12 solid tumors. The<br />
CII systematically tracks results from published studies measuring overall survival. An<br />
interactive user interface allows users to examine how progress against cancer occurs<br />
over time, including the contribution <strong>of</strong> different types <strong>of</strong> evidence.<br />
Results: Data from the CII illustrate the accumulation <strong>of</strong> evidence for improved overall<br />
survival over decades <strong>of</strong> clinical research. Historically, Phase 3 trials contribute only 28%<br />
<strong>of</strong> the evidence, while Phase 2 trials contribute an additional 7%. The remaining<br />
evidence arises from observational and retrospective studies, meta-analyses, and<br />
systematic reviews. Moreover, approximately 27% <strong>of</strong> the evidence is from studies<br />
combining data from different cohorts to increase statistical power. These larger and<br />
heterogeneous designs <strong>of</strong>ten provide the first evidence <strong>of</strong> efficacy at the group or class<br />
level and are followed by additional studies to better understand the underlying effect.<br />
CII data can be used to track the impact <strong>of</strong> the current transition toward smaller,<br />
targeted studies. Our results highlight the need for timely and data-driven tracking <strong>of</strong><br />
progress across the spectrum <strong>of</strong> cancer research and fast learning from real-world<br />
evidence to validate outcomes.<br />
Conclusions: We make the CII freely available to all stakeholders and encourage users<br />
to perform their own custom analyses. https://pacenetworkusa.com/<br />
continuousinnovation<br />
Legal entity responsible for the study: Eli Lilly and Company; Rose Li and Associates,<br />
Inc.<br />
Funding: Eli Lilly and Company<br />
Disclosure: S. Paddock, S. Thomas, R. Li: Consultant/advisor for Eli Lilly and Company.<br />
Industry employee <strong>of</strong> Rose Li and Associates, Inc. A. Kanli, J. Zummo: Shareholder <strong>of</strong>:<br />
Eli Lilly and Company. Industry employee <strong>of</strong> Eli Lilly and Company. D. Grainger:<br />
Shareholder <strong>of</strong>: Eli Lilly and Company. Grant/research support: Steering Committees for<br />
Projects Funded by Eli Lilly and Company. Industry employee <strong>of</strong> Eli Lilly and Company.<br />
1023P<br />
Are the newer chemotherapy drugs worth their high cost? - A<br />
survey <strong>of</strong> UK public’s perception <strong>of</strong> reasonable price for<br />
chemotherapy drugs according to their health benefit<br />
S. Sundar, H.D. Johnson, S. Taylor, S. Thomason<br />
Department <strong>of</strong> <strong>Oncology</strong>, Nottingham University Hospitals NHS Trust-City<br />
Hospital Campus, Nottingham, UK<br />
Background: The cost <strong>of</strong> oncology drugs has skyrocketed recently. Many newly<br />
approved drugs have modest survival benefits <strong>of</strong> only a few extra months. In USA,<br />
newer oncology drugs place a direct heavy economic burden on patients who make<br />
huge co-payments out <strong>of</strong> pocket (Saltz JCO 2015;33:1093–4). In UK the burden falls<br />
on the taxpayer. A face to face survey was done to assess UK public’s perception <strong>of</strong><br />
reasonable price for a course <strong>of</strong> chemotherapy drug relative to their potential benefits.<br />
Methods: A ‘tick box’ survey form with 15 price bands (low to high) including a free<br />
text box was used. (Price Bands: 500K). Place <strong>of</strong> recruitment: (1) Market Town <strong>of</strong> Chesterfield: 20 recruited,56<br />
declined (2) City <strong>of</strong> Nottingham 61 recruited, 23 declined. Recruitment period: March<br />
2015. Survey done by Clinical research nurse or medical student on oncology elective.<br />
The regional ethics committee advised that a formal ethical approval is not needed for<br />
public surveys in public places.<br />
Results: Female 53%; Mean age 36 yrs (range 16 to 87 yrs). Subjects suggested a<br />
significantly lower value as a reasonable price for a course <strong>of</strong> cancer drugs even when<br />
drugs have significant curative potential. (table). Only a small minority felt that drug<br />
costs <strong>of</strong> more than 100,000 British pounds are reasonable . Because UK has a taxpayer<br />
funded health service, UK public probably have very poor knowledge about the actual<br />
cost <strong>of</strong> chemotherapy drugs.<br />
Conclusions: The survey results indicate that the UK public might be willing to<br />
politically support value-based-commissioning if it is done in a fair and explicit manner.<br />
What price do you think it is reasonable for a<br />
pharmaceutical company to charge for the<br />
chemotherapy drug…………<br />
Table: 1023P<br />
Less<br />
than<br />
10,000<br />
British<br />
pounds<br />
10,000 to<br />
100,000<br />
British<br />
pounds<br />
More<br />
than<br />
100,000<br />
British<br />
pounds<br />
If drug cures 1 in 2 cancer patients (50% cure rate) 58% 27% 15%<br />
If drug cures 1 in 5 cancer patients (20% cure rate) 67% 22% 11%<br />
If drug does not cure but makes cancer patients live 67% 23% 10%<br />
longer by an extra 12 months<br />
If drug does not cure but makes cancer patients live 69% 26% 5%<br />
longer by an extra 6 months<br />
If drug does not cure but makes cancer patients live 83% 17% 0%<br />
longer by an extra 3 months<br />
If drug does not cure but makes cancer patients live 89% 10% 0%<br />
longer by an extra 1 month<br />
If drug does not cure and does not make a cancer<br />
patients live longer but relieves cancer related pain<br />
and other symptoms<br />
79% 20% 1%<br />
chi-square test for all qs p =
abstracts<br />
Legal entity responsible for the study: N/A<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1024P<br />
Methodological differences and the appropriate application<br />
<strong>of</strong> oncology value frameworks to assess clinical value<br />
G. Monnickendam 1 , K. Mortaki 2 , J. McKendrick 1<br />
1 HEOR, PRMA Consulting Ltd, Fleet, UK, 2 HEOR, PRMA Consulting Ltd,<br />
Maroussi, Greece<br />
Background: A number <strong>of</strong> value frameworks have been developed recently as tools to<br />
evaluate new oncology products. The frameworks differ in stated objectives and<br />
methodology, and each uses a different set <strong>of</strong> criteria for evaluating products. We<br />
compare and contrast the frameworks, to identify the important differences and<br />
similarities between them, and conclude with the implications for clinical<br />
decision-making.<br />
Methods: The methodologies <strong>of</strong> six value frameworks (ASCO, NCCN, ESMO,<br />
MSKCC, DrugAbacus, and ICER) were reviewed. Using the published scoring systems<br />
where available, we evaluated 33 recently approved oncology drugs by scoring them<br />
against individual framework criteria, using published data from pivotal trials. We<br />
compared results and identified the origins <strong>of</strong> the differences in scoring outcomes<br />
within the underlying methodologies, focusing on the clinical domains.<br />
Results: The range <strong>of</strong> approaches to assessing clinical value, both in terms <strong>of</strong> assigning<br />
scores and the relative importance given to those scores, can produce considerable<br />
variability in the value assigned to a treatment in different value frameworks. Scoring<br />
frameworks are <strong>of</strong>ten complex and some important aspects remain subjective. Specific<br />
attributes, such as whether a treatment is considered to have curative potential or the<br />
pivotal trial is a single-arm Phase 2 study, have a significant bearing on value<br />
framework scores but the reasons for assigning this level <strong>of</strong> impact are not clear.<br />
Conclusions: Understanding the methodology employed by a value framework to<br />
assess clinical value is critical to interpreting the scores <strong>of</strong> a product within it. The<br />
assessed clinical value <strong>of</strong> a treatment can depend on assumptions made during the<br />
assessment <strong>of</strong> efficacy and safety and the context in which the assessment takes place.<br />
To avoid inconsistencies in clinical decision-making and unintended consequences on<br />
incentives for innovation, the results <strong>of</strong> value frameworks should be used cautiously.<br />
Further evolution <strong>of</strong> value frameworks will be necessary to produce more transparent<br />
and robust tools for decision-makers.<br />
Legal entity responsible for the study: PRMA Consulting Ltd<br />
Funding: PRMA Consulting Ltd<br />
Disclosure: G. Monnickendam, K. Mortak, J. McKendrick: Employee <strong>of</strong> PRMA<br />
Consulting Ltd.<br />
1025P<br />
The cost-effectiveness <strong>of</strong> combination therapy: Challenges<br />
<strong>of</strong> the present, solutions for the future? A myeloma analysis<br />
J.P. Harrison 1 , N. Rabin 2 , H. Pang 3 , C. Davis 4 , H. Kim 5<br />
1 Health Economics, Bristol-Myers Squibb, London, UK, 2 Haematology, University<br />
College London Hospitals NHS Trust, London, UK, 3 Medical, Bristol-Myers<br />
Squibb, London, UK, 4 Health Economics, Bristol-Myers Squibb, Princeton, NJ,<br />
USA, 5 Health Economics, Bristol-Myers Squibb, Melbourne, Australia<br />
Background: The number <strong>of</strong> treatments for cancer has increased over recent years.<br />
Monotherapy for some malignancies delivers only marginal benefit, whilst<br />
combination therapy (CT) improves results by using synergistic mechanisms <strong>of</strong> action.<br />
CT increases treatment cost however, and in an era <strong>of</strong> health care constrained by<br />
cost-containment, national reimbursement <strong>of</strong> CT conditional on cost-effectiveness is<br />
challenging. This research assesses drivers <strong>of</strong> CT cost-effectiveness, using myeloma as<br />
an example, to inform approaches to evidence based approaches to reimbursement.<br />
Methods: A 3-state cost-effectiveness model (pre-progression; post-progression; dead)<br />
for front-line treatment <strong>of</strong> myeloma was developed. Continuous lenalidomide +<br />
dexamethasone (Ld) data were extracted from published results and, using parametric<br />
modelling, extrapolated to 20 years, with costs based on UK prices. Add-on drug X was<br />
assumed to deliver survival benefit (PFS HR = 0.7; OS HR = 0.7), be dosed Q4W until<br />
disease progression, and cost £2,000/dose. Post-progression costs were £4,000/month.<br />
Scenario analyses considering differing evidence and treatment approaches included:<br />
improved PFS and OS; reduced dosing schedules; limited treatment duration; use as a<br />
doublet (i.e. Xd); reduced Drug X cost.<br />
Results: Combination therapy XLd compared with Xd resulted in a base-case<br />
incremental cost-effectiveness ratio (ICER) <strong>of</strong> £111K/quality-adjusted life year (QALY).<br />
Scenario analysis representing 28.5% improvement in both PFS (ICER = £131K/QALY)<br />
and OS (ICER = £96K/QALY) did not substantially improve CE. In contrast, scenarios<br />
which induced substantial cost savings improved CE (X dosed Q8W, ICER = £69K/<br />
QALY; X cost = £1000/dose, ICER = £64k/QALY; halved Ld dosing, ICER = £8K/<br />
QALY; 24-month treatment cap, ICER = -£89K/QALY; doublet, ICER = -£96k/QALY).<br />
Conclusions: Clinical trials assess clinical outcomes, however these results suggest<br />
clinical outcomes alone may be insufficient to establish CT cost-effectiveness in<br />
myeloma. Pursuit <strong>of</strong> economic benefit beyond clinical outcomes, including<br />
resource-sparing approaches to treatment, may mitigate this risk and facilitate national<br />
reimbursement, and should therefore be considered in clinical trial design.<br />
Legal entity responsible for the study: Bristol-Myers Squibb<br />
Funding: Bristol-Myers Squibb<br />
Disclosure: J.P. Harrison: Employee <strong>of</strong> Bristol-Myers Squibb. N. Rabin: Advisory<br />
boards for Bristol-Myers Squibb. H. Pang, C. Davis, H. Kim: Employed by<br />
Bristol-Myers Squibb.<br />
1026P<br />
A shared-risk model linking patient-level clinical outcomes<br />
and drug company reimbursement in cancer care<br />
O. Oren 1 , D.H. Henry 2<br />
1 Internal Medicine, University <strong>of</strong> Pennsylvania-CRB, Philadelphia, PA, USA,<br />
2 Hematology/<strong>Oncology</strong>, University <strong>of</strong> Pennsylvania-CRB, Philadelphia, PA, USA<br />
Background: Pharmaceutical companies are investing heavily in the development <strong>of</strong><br />
compounds with similar mechanism <strong>of</strong> action to that <strong>of</strong> drugs already on the market.<br />
New and potentially expensive medications are then approved with minimal if any<br />
advantage over existing drugs. We suggest a value-driven model that will tie the<br />
economical gains <strong>of</strong> drug companies with real-world patient outcomes, <strong>of</strong>fering<br />
companies a strong incentive to develop novel and superior regimens.<br />
Methods: We focused on advanced colorectal cancer that progressed after 1st-line<br />
chemotherapy. PFS Kaplan-Meier curves <strong>of</strong> five common drugs were analyzed (1-5).<br />
“Integrated” PFS (iPFS) was defined as the mean <strong>of</strong> median PFSs <strong>of</strong> those drugs. For<br />
the subset <strong>of</strong> patients (in those studies) whose disease progressed earlier than a defined<br />
iPFS cut<strong>of</strong>f, the manufacturer were to lose a certain fraction <strong>of</strong> revenues. For the subset<br />
<strong>of</strong> patients with sustained response longer than a defined iPFS cut<strong>of</strong>f, the company<br />
were to gain extra pr<strong>of</strong>its. Total extra revenues and losses for all companies were to<br />
equal zero. Drug prices and incidence rates were derived from DrugAbacus and<br />
American Cancer Society websites. A mathematical calculation was done to show<br />
model feasibility.<br />
Results: iPFS thresholds chosen were 1 and 0.7. For every patient with no progression<br />
at 1 iPFS, the company were to gain a randomly-selected value <strong>of</strong> 30% <strong>of</strong> launch price.<br />
To maintain net zero financial loss/gain for all manufacturers together, it was<br />
calculated that companies should lose 41.4% <strong>of</strong> launch price for every patient who<br />
progressed before 0.7 iPFS. With model application, Amgen, Regeneron and Elli Lilli<br />
achieved revenues <strong>of</strong> 105.6% to 109.7% compared with non-model settings. These<br />
pr<strong>of</strong>its amounted to extra annual gains <strong>of</strong> approximately 25 million dollars (Amgen)<br />
and 53 million dollars (Regeneron). Bristol-Myers and Genentech lost 18.7% and 3.1%<br />
<strong>of</strong> anticipated revenues, respectively. Their absolute annual deductions approximated 8<br />
million dollars (Genentech) and 105 million dollars (Bristol-Myers).<br />
Conclusions: A shared-risk model <strong>of</strong> cancer drug reimbursement would create a<br />
potent incentive for companies to develop medications that significantly improve the<br />
overall value <strong>of</strong> existing compounds.<br />
Legal entity responsible for the study: Ohad Oren<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1027P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Novel therapy options for advanced & metastatic melanoma<br />
patients in EU5 countries result in a changing treatment<br />
pattern especially in BRAF mutant patients<br />
M. Bernhardt, N. Schmidt, K. Acker<br />
IMS Global <strong>Oncology</strong>, IMS Health GmbH & Co. OHG, Frankfurt, Germany<br />
Background: Real world data on treatment (TX) patterns in advanced and metastatic<br />
melanoma is <strong>of</strong> great value to demonstrate the use <strong>of</strong> novel therapy options. We<br />
provide an overview about the application <strong>of</strong> diagnostic marker testing and its<br />
implication on melanoma TX patterns in regard to novel targeting drugs that recently<br />
entered the market.<br />
Methods: This study is based on IMS <strong>Oncology</strong> Analyzer, a quarterly physician<br />
panel survey including anonymous retrospective patient (PT) data about disease and<br />
TX history, across all cancer types. Melanoma PTs treated within the year 2013 and<br />
2015 in EU5 countries (France, Germany, Italy, Spain and UK) were analyzed.<br />
Results: In 2013, 45.7% <strong>of</strong> adv. & met. melanoma PTs received chemotherapy (CT) in<br />
their 1st line, ∼45% received a targeted therapy either against members <strong>of</strong> the MAPK<br />
or the CTLA-4 pathway while 9% were treated with others drugs. In 2015, the<br />
percentage <strong>of</strong> CT PTs decreased to ∼10% while ∼85% <strong>of</strong> PTs received a targeted<br />
therapy including anti-PD1/PD-L1 TXs. Distribution <strong>of</strong> the PTs according their BRAF<br />
status shows that 2% <strong>of</strong> BRAF mutant (MUT) but ∼20% <strong>of</strong> wild type (WT) PTs are<br />
treated with CTs in their first line in 2015.<br />
vi352 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Table: 1027P<br />
1st line TX<br />
2013 2015<br />
regimens**<br />
Base (sample PTs) All PTs (304) BRAF* WT BRAF* MUT All PTs (481) BRAF* WT BRAF* MUT<br />
(44.9%) (55.1%.)<br />
(39.6%) (60.4%)<br />
MEK&BRAF 40.8% 1.7% 83.6% 48.4% 1.1% 84.5%<br />
CTLA-4 4.3% 4.2% 4.1% 32.2% 66.9% 12.2%<br />
PD1/PD-L1 - - - 4.2% 8.4% 1.5%<br />
CT 45.7% 89.9% 9.6% 9.6% 19.1% 1.8%<br />
Others 9.2% 4.2% 2.7% 5.6% 4.5% -<br />
** PTs included in a clinical trial or don’t receiving a systemic therapy were<br />
not considered *PTs with an unknown BRAF status or PTs awaiting test<br />
results were excluded Table 1: Stage III/IV melanoma 1st line TX landscape<br />
Conclusions: This study indicates a switch towards targeted therapies accounting for<br />
more than 80% <strong>of</strong> 1st line melanoma therapies in 2015. Hereby, the information on the<br />
BRAF status is crucial and determines the TX decision in regard <strong>of</strong> the drug type.<br />
However, nearly 20% <strong>of</strong> BRAF WT PTs receive CTs in their 1st line irrespective <strong>of</strong><br />
novel available therapy options. Further research is necessary to understand the<br />
missing uptake <strong>of</strong> novel TX options and the related clinical practice.<br />
Legal entity responsible for the study: IMS Health GmbH & Co. Ohg<br />
Funding: IMS Health GmbH & Co. Ohg<br />
Disclosure: M. Bernhardt, N. Schmidt, K. Acker: Employee <strong>of</strong> IMS Health<br />
1028P<br />
The relative clinical value <strong>of</strong> immun-oncology treatment, the<br />
NNT values <strong>of</strong> PD1-inhibitor nivolumab and pembrolizumab in<br />
metastatic melanoma patients<br />
E. Porneczy 1 , I. Boncz 2<br />
1 Chemotherapy-D, National Institute <strong>of</strong> <strong>Oncology</strong>, Budapest, Hungary, 2 Health<br />
Insurance, University <strong>of</strong> Pecs, Pecs, Hungary<br />
Background: The immun-oncology innovations <strong>of</strong> cancer treatment, the PD-1<br />
inhibitor pembro and nivo were registered by EMA for the treatment <strong>of</strong> metastatic<br />
melanoma. The monoclonal, humanized, IgG4k antibody pembro and the human<br />
IgG4 nivo block the PD-L1 and/or PD-L2 interactions and enhance the antitumor<br />
immune response <strong>of</strong> T cells. The current outcome measures do not assess the long<br />
term benefit <strong>of</strong> I-O therapies. In the Keynote-002 ipi refracter group, the pembro 2mg/<br />
kg arm CR was 2%, PR 19%, and SD 18%. In the 10 mg/kg pembro arm CR was 3%,<br />
PR 23%, SD 18%. In the chemotherapy group, ICC, there was no CR, while PR<br />
occurred in 4%, SD in 18%.<br />
Methods: To evaluate the efficacy <strong>of</strong> pembro and nivo, to measure their relative clinical<br />
value by calculating NNT, the number <strong>of</strong> patients who need to be treated to prevent<br />
one death. We analyzed the survival data and calculated the NNT values <strong>of</strong> the PhII<br />
Keynote-002 study pembro vs ICC in ipi-refracter group, the PhIII Keynote-006 study<br />
pembro vs ipi group, the PhIII CheckMate-066 study nivo vs DTIC group data.<br />
Results: In the Keynote-002, the 2mg/kg pembro arm NNT:3,8, the NNT value <strong>of</strong> the<br />
10mg/kg group: 4,5.In the Keynote-006 pembro vs ipi study, the 1Y OS rate was 71,4%<br />
in the 10mgQ2W group, 68,4% in the 10mgQ3W group, and 58,2% in the ipi group.<br />
The NNT <strong>of</strong> the 10mgQ2W patient group: 4,67, the NNT <strong>of</strong> the 10mg/Q3W was 6,66.<br />
In the CheckMate-066 study the nivo group 1YOS% 70,7, the estimated 2Y OS% was<br />
57,7% and the DTIC group 1YOS% was 46,3% and 2Y 26,7%. The NNT value <strong>of</strong> nivo<br />
group was 4,16-9,17.<br />
Conclusions: Based on PhII-III studies, the NNT values <strong>of</strong> novel immunotherapies<br />
demonstrate the exceptional relative clinical value <strong>of</strong> PD-1 inhibitors. The prevention<br />
<strong>of</strong> one death, their clinical value is based on their NNT values, pembro: 3,8-6,66, nivo<br />
4,16-9,17. These results show the future potential <strong>of</strong> I-O clinical benefit. Over the<br />
follow up time the risk reduction is not constant it is recommended to calculate the<br />
NNT values at least twice, not only at one specific time point, if necessary data are<br />
available from the trials.<br />
Legal entity responsible for the study: N/A<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1029P<br />
Real-world comparative effectiveness analysis <strong>of</strong> second-line<br />
(2L) nab-paclitaxel (nab-P) vs paclitaxel (Pac) in patients (Pts)<br />
with metastatic breast cancer (MBC)<br />
C. Pelletier 1 , M. Parisi 1 , S. Glück 2 ,Q.Ni 1 , F. Braiteh 3<br />
1 U.S. Health Economics and Outcomes Research, Celgene Corporation, Summit,<br />
NJ, USA, 2 Pancreatic Cancer and Immuno-<strong>Oncology</strong>, Celgene Corporation,<br />
Summit, NJ, USA, 3 Clinical Associate Pr<strong>of</strong>essor <strong>of</strong> Medicine, Comprehensive<br />
Cancer Centers <strong>of</strong> Nevada, Las Vegas, NV, USA<br />
Background: nab-P monotherapy is approved for 2L treatment (Tx) <strong>of</strong> MBC. This<br />
real-world analysis evaluated comparative effectiveness <strong>of</strong> 2L nab-P vs Pac in pts with MBC.<br />
Methods: A retrospective cohort study was performed using fully de-identified data<br />
from a US electronic medical record platform <strong>of</strong> 1300 community (non-university<br />
based) oncologists. This analysis included pts with MBC who initiated 2L nab-P or Pac<br />
monotherapy from 12/1/10 to 4/6/15 (≥ 2 doses <strong>of</strong> nab-P or Pac required to be<br />
included in the analysis). The primary objectives were time to Tx discontinuation<br />
(TTD) and time to next Tx (TTNT). Adverse events (AEs) and supportive care were<br />
also examined. Subanalyses in pts with hormone receptor–positive (HR+)/human<br />
epidermal growth factor receptor 2–negative (HER2−) or triple-negative (TN) MBC<br />
were conducted.<br />
Results: This analysis included 411 pts (109 treated with nab-P Tx and 302 with Pac<br />
Tx). Pts treated with nab-P were older (mean 61 vs 57 y) and more frequently had HR+<br />
(78% vs 65%) or HER2− (83% vs 70%) disease. Most pts received weekly Tx (Table).<br />
Prior use <strong>of</strong> a taxane or concurrent use <strong>of</strong> a targeted agent was similar between groups.<br />
nab-P was associated with significantly longer TTD vs Pac. TTNT was similar between<br />
groups. Pts treated with nab-P had less fatigue, pain, and neuropathy but more nausea<br />
and vomiting vs Pac. Antiemetics (IV) and Tx for hydration and allergic reaction were<br />
used less with nab-P, and Tx for bone loss and granulocyte colony-stimulating factor<br />
(G-CSF) were used less with Pac. In subgroup analyses, TTD was significantly longer<br />
with nab-P vs Pac in pts with HR + /HER2− or TN MBC, and TTNT was numerically<br />
longer with nab-P vs Pac in pts with HR + /HER2− MBC.<br />
Table: 1029P<br />
nab-P<br />
n = 109<br />
Pac n = 302<br />
Unadjusted<br />
P-value<br />
Adjusted<br />
P-value<br />
Overall population<br />
Tx schedule, weekly, n (%) 90 (83) 286 (95) - -<br />
TTD, median, mos 4.5 2.8 < 0.001 < 0.001<br />
TTNT, median, mos 5.9 4.2 0.014 0.214<br />
Any grade AE in > 5% pts, %<br />
Overall 45.0 58.3 0.017 0.032<br />
Anemia 26.6 36.8 0.055 0.050<br />
Neutropenia 15.6 10.6 0.167 0.245<br />
Neuropathy 4.6 13.6 0.011 0.039<br />
Pain 1.8 12.3 0.002 -<br />
Thrombocytopenia 7.3 3.0 0.087 -<br />
Nausea + Vomiting 9.2 3.0 0.008 -<br />
Diarrhea 2.8 7.0 0.109 -<br />
Dehydration 6.4 3.0 0.145 0.467<br />
Infection 0.9 6.3 0.025 0.059<br />
Fatigue 0.5 5.6 0.001 0.023<br />
Hypersensitivity 0.0 5.6 0.009 -<br />
Supportive Care doses/pt/100 days<br />
Antimetics 5.91 8.49
abstracts<br />
Tx discontinuation (TTD, day 1 to last date + 7 days for 7-day cycle and day 1 to last<br />
date + 21 days for 21-day cycle) and time to next Tx (TTNT; day 1 <strong>of</strong> line 2 to day 1 <strong>of</strong><br />
line 3) were the primary objectives. Adverse events (AEs) and supportive care were also<br />
examined. Subset analyses examined outcomes in pts with hormone receptor–positive<br />
(HR+)/human epidermal growth factor receptor 2–negative (HER2−)or<br />
triple-negative (TN) MBC.<br />
Results: This analysis included 176 pts (107 treated with nab-P and 69 with Erib).<br />
Baseline characteristics were similar between groups except that more pts treated with<br />
2L nab-P had HR+ disease (P = 0.02) and were on combination Tx with a targeted<br />
agent (P = 0.03). More pts in the Erib group had used a taxane prior to MBC diagnosis<br />
(P = 0.01 for ≤ 1 year). Few pts with TN MBC were treated with 2L nab-P or Erib<br />
(Table). Overall, nab-P was associated with numerically longer TTD and TTNT vs<br />
Erib. AE rates were similar except that thrombocytopenia occurred more <strong>of</strong>ten with<br />
Erib. Antiemetics (IV) and G-CSF were used less <strong>of</strong>ten with nab-P. Steroids were used<br />
less <strong>of</strong>ten with Erib. Similar trends were reported in pts with HR + /HER2− or TN<br />
MBC.<br />
Table: 1030P<br />
nab-P n = 107<br />
Eribulin<br />
n=69<br />
Unadjusted<br />
P Value<br />
Adjusted<br />
P Value<br />
Overall population<br />
Age, mean, years 60 61 0.688 -<br />
Schedule, weekly, % 75 - - -<br />
TTD, median, mos 4.0 3.1 0.074 0.507<br />
TTNT, median, mos 6.0 4.7 0.538 0.759<br />
Any grade AE in > 5% pts, %<br />
Anemia 28.0 42.0 0.055 0.130<br />
Neutropenia 18.7 23.2 0.470 0.376<br />
Thrombocytopenia 7.5 18.8 0.023 0.107<br />
Nausea + vomiting 11.2 5.8 0.222 0.299<br />
Dehydration 8.4 2.9 0.205 -<br />
Fatigue 2.8 7.2 0.266 -<br />
Pain 2.8 7.2 0.266 -<br />
Supportive Care doses/pt/100 days<br />
Antimetic (IV Only) 5.77 6.92
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
<strong>of</strong> continuous enrollment pre-index and no evidence <strong>of</strong> cystectomy were included. A<br />
subset <strong>of</strong> 5,531 (58.6%) had survival data available.<br />
Results: The population was majority male (74%); with a mean age <strong>of</strong> 70. Among<br />
chemotherapy treated (T) patients (N = 3,750), the median number <strong>of</strong> days to tx<br />
initiation was 28; and among untreated (NT) patients (no therapy observed), the<br />
median follow-up was 218 days. NT compared to T patients, were older (72 vs. 67) and<br />
had higher National Cancer Institute (NCI) comorbidity score (1 vs. 0.8). Among T<br />
patients, gemcitabine (GEM; 48%), carboplatin (CAR; 42%), cisplatin (CIS; 25%), and<br />
paclitaxel (PAC; 21%) were the 4 most common txs included in a first-line (1L)<br />
regimen. Patients treated with CIS were younger (62 vs. 69 and 68) and healthier (NCI<br />
comorbidity score 0.7 vs. 1.1, and 1.0) vs. patients treated with CAR and other<br />
treatments (OT), respectively. Second-line (2L) tx was observed in 1,204 (13%)<br />
patients. A greater proportion <strong>of</strong> 1L CIS patients started 2L therapy (31%) vs. CAR<br />
(29%) and OT (18%). GEM (30%), CAR (30%) and PAC (30%) were the most<br />
common txs included in a 2L regimen. In the overall survival analysis, CAR patients<br />
have poorer survival than CIS or OT patients (median months from 1L initiation: 14.4<br />
vs. 19.5 and 16.8, respectively; log rank p = 0.001).<br />
Conclusions: The majority (60%) <strong>of</strong> mUC patients did not receive chemotherapy in<br />
this study. NT patients had characteristics similar to CAR patients, while those<br />
receiving CIS were younger, healthier, and had better outcomes. These findings provide<br />
further insight into treatment strategies in real world settings and highlight the unmet<br />
need in this patient population.<br />
Legal entity responsible for the study: N/A<br />
Funding: Genentech Inc.<br />
Disclosure: E. Malangone-Monaco, K. Wilson, H. Varker: Employee <strong>of</strong> Truven Health<br />
Analytics, Inc., which was paid by Genentech to conduct this study. S. Satram-Hoang:<br />
Consultant to Genentech, which provided funding for this research. S-W. Lin,<br />
D. Tayama, S. Ogale: Employed by Genentech and own Genentech/Roche stock.<br />
1034P<br />
Economic evaluation <strong>of</strong> pazopanib as first-line treatment <strong>of</strong><br />
metastatic renal cell carcinoma in Greece<br />
A. Solakidi 1 , G. Kourlaba 1 , L. Kontovinis 2 , E. Bournakis 3 , A. Boutis 4 ,<br />
K. Koutsoukos 5 , J. Syrios 6 , A. Tzovaras 7 , M. Chatzikou 8 , C. Michailidi 9 ,<br />
N. Maniadakis 10<br />
1 Health Economics, EVROSTON LP, Athens, Greece, 2 Medical <strong>Oncology</strong>,<br />
Oncomedicare, Thessaloniki, Greece, 3 Medical <strong>Oncology</strong>, Areteion Hospital,<br />
University <strong>of</strong> Athens, Athens, Greece, 4 1st Department <strong>of</strong> Clinical <strong>Oncology</strong>/<br />
Chemotherapy, Theagenion Cancer Hospital, Thessaloniki, Greece, 5 <strong>Oncology</strong><br />
Unit/ Department <strong>of</strong> Clinical Therapeutics, Alexandra Hospital, Athens, Greece,<br />
6 Medical <strong>Oncology</strong>, Hygeia Hospital, Athens, Greece, 7 Medical <strong>Oncology</strong>,<br />
Hippokration General Hospital, Athens, Greece, 8 Health Economics, Novartis<br />
Hellas, Athens, Greece, 9 Medical, Novartis Hellas, Athens, Greece, 10 Health<br />
Services Organization and Management, National School <strong>of</strong> Public Health, Athens,<br />
Greece<br />
Background: The NCCN Kidney Cancer Panel lists pazopanib and sunitinib as<br />
category 1 options for first-line treatment for stage IV renal cell carcinoma (RCC)<br />
patient. The aim <strong>of</strong> this study was to evaluate the cost-effectiveness <strong>of</strong> pazopanib vs<br />
sunitinib as first-line treatment <strong>of</strong> metastatic RCC (mRCC) from a Greek third-party<br />
payer’s perspective.<br />
Methods: A 3-state partitioned survival model was used. Estimates <strong>of</strong> progression free<br />
survival (PFS) and overall survival (OS) were from the COMPARZ trial. Utility values<br />
were based on adverse events in COMPARZ and EQ-5D data from the VEG105192 trial.<br />
Cost inputs included drug acquisition and other treatment related costs including<br />
physician visits and lab and radiology tests. Resource use data were collected by DELPHI<br />
method from an expert panel <strong>of</strong> clinicians from private and public hospitals in Greece. A<br />
5-year time horizon was used consistent with the maximum duration <strong>of</strong> follow-up in the<br />
final analysis <strong>of</strong> OS in COMPARZ. The incremental cost-effectiveness ratio (ICER) was<br />
calculated. A threshold <strong>of</strong> €35,000 per QALY gained was used, per WHO Guidelines.<br />
Deterministic and probabilistic sensitivity analyses (DSA and PSA) were conducted.<br />
Results: In the base case, pazopanib was less costly and more effective (“dominant”)<br />
compared with sunitinib, with €3,676 lower lifetime costs per patient and 0.058 greater<br />
discounted QALYs (€25,464 vs €29,140 and 1.617 vs 1.558). DSA and PSA suggest these<br />
results are robust. In DSA, pazopanib was dominant for different assumptions regarding<br />
PFS and utilities (Table). In 66% <strong>of</strong> PSA simulations, pazopanib was projected to yield<br />
more QALYs and lower costs vs sunitinb. The probability that pazopanib is cost-effective<br />
vs sunitinib was estimated to be 90% given the ICER threshold.<br />
Scenario<br />
Table: 1034P<br />
Incremental<br />
Costs<br />
Incremental<br />
QALYs<br />
ICER<br />
Base case (IRC PFS) -€3,676 0.058 Dominant<br />
Investigator-assessed PFS -€2,804 0.059 Dominant<br />
Conclusions: Pazopanib is likely to be dominant compared with sunitinib as first-line<br />
treatment <strong>of</strong> mRCC in the Greek healthcare setting.<br />
Legal entity responsible for the study: Dr. Georgia Kourlaba<br />
Funding: Novartis Hellas<br />
Disclosure: A. Solakidi, G. Kourlaba: EVROSTON LP received funding from Novartis<br />
Hellas for this study M. Chatzikou: Novartis employee. However, the study sponsor<br />
had no influence on the study design, data collection or writing <strong>of</strong> the abstract. C.<br />
Michailidi: Novartis employee. However, the study sponsor had no influence on the<br />
study design, data collection or writing <strong>of</strong> the abstract. All other authors have declared<br />
no conflicts <strong>of</strong> interest.<br />
1035P<br />
Understanding real world treatment patterns, healthcare<br />
resource utilization (HRU) and costs among metastatic renal<br />
cell carcinoma (mRCC) patients<br />
R. Copher 1 , S. Dacosta Byfield 2 , P. Buzinec 2 , S. Korrer 2 , M. Baig 3<br />
1 Health Economics and Outcomes Research, Eisai, Inc, Woodcliff Lake, NJ, USA,<br />
2 Health Economics and Outcomes, Optum, Eden Prairie, MN, USA, 3 Global<br />
<strong>Oncology</strong> Business Unit, Eisai, Inc, Woodcliff Lake, NJ, USA<br />
Background: Therapy targeting the vascular endothelial growth factor and mammalian<br />
target <strong>of</strong> rapamycin pathways are now the standard <strong>of</strong> care for patients (pts) with<br />
mRCC. However few studies have examined real-world treatment patterns and the<br />
impact on HRU and costs associated with these novel agents.<br />
Methods: A retrospective study using a large, national US claims database from 7/2009-6/<br />
2015 was conducted. Commercially insured (COM) and Medicare Advantage (MA) newly<br />
diagnosed adult RCC pts (≥2 claims with ICD-9 189.0x) with ≥2claimsformetastases<br />
(mets) were identified; the first met claim date was the index date. Pts were required to be<br />
continuously enrolled (CE) in the health plan for 6m pre- and ≥1m post-index date and<br />
initiate systemic cancer therapy. Pts with other cancers or systemic cancer therapy in the<br />
baseline were excluded. Treatment patterns by line <strong>of</strong> therapy (LOT) were examined. A<br />
LOT started at the first date <strong>of</strong> cancer therapy and the regimen included all drugs received<br />
within 30 days. LOTs ended at the earliest <strong>of</strong>, start <strong>of</strong> a new drug, ≥60-day gap in initial<br />
regimen, death or CE end. All-cause per patient per month (PPPM) HRU and costs (in US<br />
$) during LOT1, LOT2 and LOT3 by regimen were examined.<br />
Results: There were 929 mRCC pts identified; 67% <strong>of</strong> pts were male, 47% were ≥65 yrs<br />
(mean age 63) and 37% were MA pts vs. 63% COM. Among all pts, 44% (n = 409) and<br />
20% (n = 187) had a LOT2 and LOT3 during the study period. Mean total follow-up<br />
time was 17m, and mean duration <strong>of</strong> LOT1, LOT2 and LOT3 was 4.9m, 4.6m and 4.2<br />
m respectively. The most common regimens were sunitinib (42%), pazopanib (22%)<br />
and temsirolimus (16%) for LOT1, everolimus (24%), pazopanib (20%) and sunitinib<br />
(17%) for LOT2, and axitinib (24%), pazopanib (21%) and everolimus (17%) for LOT3.<br />
HRU, including inpatient stays (0.29, 0.24 and 0.26 PPPM for LOT1, LOT2 and LOT3),<br />
varied by regimen. Total PPPM costs were US$21,884, US$20,116 and US$21,173 for<br />
LOT1, LOT2 and LOT3 respectively but varied by regimen.<br />
Conclusions: With the emergence <strong>of</strong> new therapy options for mRCC, there is<br />
heterogeneity in treatment patterns with high associated HRU and costs. Future studies<br />
should examine optimal treatment sequencing.<br />
Legal entity responsible for the study: Eisai, Inc and Optum<br />
Funding: Eisai, Inc<br />
Disclosure: R. Copher: Employment at Eisai, Inc Stock ownership (Eisai). S. Dacosta<br />
Byfield, P. Buzinec: Employment with Optum. Optum received payment from Eisai,<br />
Inc to conduct the study being presented but employment is not dependent on<br />
Optum’s study with Eisai. Stock ownership (Optum/UnitedHealth). S. Korrer:<br />
Employment with Optum. Optum received payment from Eisai, Inc to conduct the<br />
study being presented but employment is not dependent on Optum’s study with Eisai.<br />
Stock ownership (Optum/UnitedHealth). M. Baig: Employment with Eisai, Inc.<br />
1036P<br />
A real-world study <strong>of</strong> patterns <strong>of</strong> Bacillus Calmette-Guerin<br />
(BCG) use and associated adverse events (AEs) in<br />
non-muscle invasive bladder cancer (NMIBC) patients in the<br />
United States<br />
K. Wilson 1 , E. Malangone-Monaco 1 , S. Satram-Hoang 2 , D. Diakun 1 , S-W. Lin 3 ,<br />
D. Tayama 4 , S. Ogale 5<br />
1 Health Outcomes Research, Truven Health Analytics, Bethesda, MD, USA,<br />
2 Department <strong>of</strong> Epidemiology, Q.D. Research, Inc., Granite Bay, MD, USA, 3 Real<br />
World Data Science, Genentech Inc., San Francisco, CA, USA, 4 Medical Affairs,<br />
Genentech Inc., San Francisco, CA, USA, 5 Health Economics Outcomes<br />
Research, Genentech Inc., San Francisco, CA, USA<br />
Background: Patterns <strong>of</strong> BCG use and associated AEs are not well understood. This<br />
study describes the demographic and clinical characteristics <strong>of</strong> NMIBC patients, and<br />
reports BCG-related AEs during BCG exposures.<br />
Methods: This was a retrospective, observational cohort study <strong>of</strong> 59,935 patients from a U.<br />
S. insurance claims database between 1/1/2005-6/30/2015. Adult patients with ≥ 1<br />
diagnosis code for bladder cancer (BC); ≥ 1 procedure code for transurethral resection<br />
(TUR; first TUR = index date); ≥ 12 months <strong>of</strong> continuous enrollment pre-index; no<br />
evidence <strong>of</strong> BCG, chemotherapy, metastasis, or cystectomy pre-index; and no evidence <strong>of</strong><br />
TUR in the 6 months pre-index were included. A total <strong>of</strong> 15,922 (27%) patients had BCG<br />
Volume 27 | Supplement 6 | October 2016<br />
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use post-index and <strong>of</strong> these, 13,579 (23%) received BCG prior to chemotherapy, metastasis<br />
or cystectomy and were used to further examine BCG treatment patterns and AEs.<br />
Results: The population was majority male (75%), with an average age <strong>of</strong> 70 yrs. BCG<br />
treated patients were similar to non-BCG treated patients in terms <strong>of</strong> age, region,<br />
insurance type, and index year. A greater proportion <strong>of</strong> BCG treated patients were male<br />
(80% vs. 74%; p < .0001) and had lower National Cancer Institute (NCI) comorbidity<br />
score (47.7% vs. 49.1% with score ≥1; p < .0001) compared to non-BCG treated<br />
patients. Approximately 37% <strong>of</strong> all patients had more than 1 TUR procedure in<br />
follow-up. Within the BCG-treated cohort, approximately 31% initiated BCG within 30<br />
days <strong>of</strong> their last TUR, and 19% received BCG more than 45 days after their last TUR.<br />
On average, patients received 8.6 administrations <strong>of</strong> BCG. Hematuria (11.8%), urinary<br />
tract infection (13.9%), arthralgia/myalgia (6.2%), and cystitis (4.9%) were the most<br />
prevalent AEs in BCG-treated patients.<br />
Conclusions: Despite evidence that BCG treatment following TUR procedure can<br />
prevent disease recurrence or progression, the majority (73%) <strong>of</strong> NMIBC patients did<br />
not receive BCG treatment following their TUR. BCG treated patients were similar to<br />
non-BCG treated patients in terms <strong>of</strong> demographics, but BCG treated patients were<br />
generally healthier compared to non-BCG treated patients.<br />
Legal entity responsible for the study: N/A<br />
Funding: Genentech Inc.<br />
Disclosure: K. Wilson, E. Malangone-Monaco, D. Diakun: Employee <strong>of</strong> Truven Health<br />
Analytics, Inc., which was paid by Genentech to conduct this study. S. Satram-Hoang:<br />
Paid consultant to Genentech, which provided funding for this research. S-W. Lin,<br />
D. Tayama, S. Ogale: Employed by Genentech and own Genentech/Roche stock.<br />
1037P<br />
Economic burden <strong>of</strong> cancer associated thrombosis in<br />
Germany<br />
R. Lipp 1 , M. Feuerbach 1 , F. Freigang 1 , N. Schmidt 2 , E. Reimer 3<br />
1 RWE Research, German<strong>Oncology</strong> GmbH, Hamburg, Germany, 2 RWES, IMS<br />
Health, Frankfurt am Main, Germany, 3 Patient Access Thrombosis, Leo Pharma A/<br />
S, Copenhagen, Denmark<br />
Background: The risk <strong>of</strong> developing a Venous Thromboembolism (VTE) is especially<br />
high in cancer patients. Despite thrombosis being a relatively common co-morbidity in<br />
several types <strong>of</strong> cancers, there are only a few studies on the ecomonic burden <strong>of</strong><br />
cancer-associated thrombosis (CAT) worldwide. The aim <strong>of</strong> this study was to analyse<br />
the patients with most common types <strong>of</strong> cancer who experience a CAT, and to calculate<br />
the associated total health utilization costs in Germany.<br />
Methods: Patient’s data (e.g. anticancer medication, hospitalisations, oncological<br />
services etc.) were sampled under real-world conditions in 26 German oncological<br />
practices by reviewing and evaluating every medical record from each patient. In the<br />
analysis n = 2.361 patients with colorectal (CRC – 21%), breast (BC – 42%), lung (LC –<br />
21%) and prostate cancer (PC – 16%) who received at least one systemic antitumor<br />
treatment in 2014-2015 were included. The total health utilization and costs were<br />
calculated for different patient groups (all patients vs. patients with CAT vs. patients<br />
without CAT) and for cancer types. Therefore, all treatments and procedures in the<br />
database were transferred into German reimbursement systems for health care services.<br />
Results: 2,361 cancer patients were included in the analysis with a mean follow-up<br />
duration <strong>of</strong> 41 months. n = 407 patients (17%) developed a CAT and were treated with<br />
antithrombotic medication. In total n = 407 hospitalizations (9.8% due to VTE) with a<br />
mean length <strong>of</strong> 10 days (8 days with a cause <strong>of</strong> VTE) were found. The annual health<br />
utilization costs per patient were in mean 16,199 €. The distribution <strong>of</strong> costs were: 20%<br />
for hospitalizations, 11% for medical CAT therapies and 69% for non-CAT related<br />
services or medications. 17% <strong>of</strong> patients with CRC, BC, LC and PC developed a CAT<br />
during an anticancer treatment. 59% <strong>of</strong> these patients were hospitalized with a total<br />
length <strong>of</strong> 17 days over a mean <strong>of</strong> 1.7 inpatient stays during the 41 months.<br />
Conclusions: The economic burden <strong>of</strong> CAT is substantial, as the majority <strong>of</strong> CAT<br />
patients were hospitalized for a longer period <strong>of</strong> time. However, costs for CAT<br />
therapies (including medication and inpatient CAT therapy) were only 11% <strong>of</strong> the total<br />
costs in patients during the period in which patients were receiving anticancer therapy.<br />
Legal entity responsible for the study: German<strong>Oncology</strong> GmbH<br />
Funding: LEO Pharma<br />
Disclosure: R. Lipp, M. Feuerbach, F. Freigang, N. Schmidt: Research support by LEO<br />
Pharma. E. Reimer: Employed by LEO Pharma.<br />
1038P<br />
The impact <strong>of</strong> cancer-associated thrombosis and treatment<br />
related bleedings on patients’ quality <strong>of</strong> life<br />
S. Noble 1 , A.J. Lloyd 2 , S. Dewilde 3 , E. Reimer 4 , A. Lee 5<br />
1 Institute <strong>of</strong> Cancer & Genetics, Cardiff University School <strong>of</strong> Medicine, Cardiff, UK,<br />
2 Outcomes Research, Bladon Associates Ltd, Oxford, UK, 3 SHE, Services in<br />
Health Economics, Brussels, Belgium, 4 Patient Access Thrombosis, Leo Pharma<br />
A/S, Copenhagen, Denmark, 5 Department <strong>of</strong> Medicine, Gordon and Leslie<br />
Diamond Health Care Centre, Vancouver, BC, Canada<br />
Background: Venous thromboembolism (VTE), is common in cancer patients and its<br />
treatment is associated with a high risk <strong>of</strong> recurrent VTE (rVTE) and bleeding. The<br />
initial VTE is known to reduce health-related quality <strong>of</strong> life (HRQL) but little is known<br />
about the impact <strong>of</strong> later events and complications. The CATCH trial investigated the<br />
benefits <strong>of</strong> extended anticoagulation for the prevention <strong>of</strong> rVTE events in 900 patients<br />
with active cancer and acute VTE from 32 countries. We present analyses <strong>of</strong> the trial<br />
data here to describe the impact <strong>of</strong> rVTE and bleeding events on HRQL.<br />
Methods: EQ-5D-3L data were collected at baseline and every month for seven<br />
months. EQ-5D scores range from 1.0 (full health) through 0 (dead) and down to<br />
-0.594. Analyses were designed to control for effects <strong>of</strong> covariates such as age, gender,<br />
metastatic status, primary site <strong>of</strong> cancer, ECOG status, and history <strong>of</strong> VTE, while<br />
estimating the specific impact <strong>of</strong> a rVTE or bleeding event. Mixed models for repeated<br />
measures were designed to accommodate correlations in the dataset through different<br />
specifications <strong>of</strong> the variance-covariance matrices. The impact <strong>of</strong> an event was reflected<br />
when it occurred within ±2 weeks from a planned data collection point.<br />
Results: HRQL data were available from 883 patients. A total <strong>of</strong> 76 rVTE and 141<br />
bleeding events occurred during follow-up, which was reflected in 183 HRQL<br />
assessments.<br />
Table: 1038P Estimated HRQL scores<br />
Number <strong>of</strong> events EQ-5D mean 95% CI<br />
No event 4525 0.64 0.62-0.67<br />
Non-fatal DVT 36 0.61 0.52-0.68<br />
Non-fatal PE 3 0.62 0.48-0.73<br />
Fatal PE 16 0.46 0.27-0.60<br />
Recurrent VTE 55 0.57 0.49-0.64<br />
Major bleed 15 0.59 0.46-0.69<br />
Non-major bleed 113 0.62 0.57-0.67<br />
Conclusions: The trial data shows that experiencing rVTE or bleeding significantly<br />
worsens HRQL. The data allow us to quantify the burden for patients and the value <strong>of</strong><br />
secondary VTE prevention. Detecting VTE related HRQL signals against the<br />
background <strong>of</strong> many other influences on HRQL measurement, proved to be<br />
challenging when analysing the data. Not all events were captured in the planned<br />
HRQL assessments, which was a study limitation. Further work (possibly using<br />
qualitative methods) could help us to understand how and why patients’ HRQL is<br />
affected.<br />
Clinical trial identification: NCT01130025<br />
Legal entity responsible for the study: Leo Pharma A/S<br />
Funding: Leo Pharma A/S<br />
Disclosure: A.J. Lloyd: was paid a fixed fee for his work on the statistical analysis and<br />
report writing from this project S. Dewilde: was paid a fixed fee for her work analysing<br />
the data and supporting dissemination. E. Reimer: Employee <strong>of</strong> Leo Pharma A/S. A.<br />
Lee: Consultancy to Leo Pharma. Honoraria from Pfizer, Bayer and research funding<br />
from Bristol-Myers Squibb. All other authors have declared no conflicts <strong>of</strong> interest.<br />
1039P<br />
Health care resource use and costs <strong>of</strong> cancer-associated<br />
thrombosis in Sweden<br />
H. Norrlid 1 , M.V. Holm 2 , J. Norlin 1 , P. Svensson 3 , G. Ragnarson Tennvall 1<br />
1 The Swedish Institute for Health Economics, IHE, Lund, Sweden, 2 LEO Pharma,<br />
AB, Malmo, Sweden, 3 Department <strong>of</strong> Coagulation Disorders, Lund University,<br />
Malmo, Sweden<br />
Background: Cancer-associated thrombosis (CAT) is a severe disease that requires<br />
special medical attention as about 10% <strong>of</strong> cancer patients die from thrombotic events.<br />
Knowledge about resource utilization and costs <strong>of</strong> CAT is currently limited. The<br />
objective <strong>of</strong> this study was to identify CAT patients and examine mortality and<br />
utilization <strong>of</strong> health care and drug treatment for patients with CAT in Sweden, and<br />
estimate the associated costs.<br />
Methods: This observational, retrospective study <strong>of</strong> patients with CAT was based on<br />
national registry data from the Swedish National Board <strong>of</strong> Health and Welfare<br />
(NBHW). Persons diagnosed with cancer and thrombosis in 2012 were identified via<br />
ICD10 codes for cancer and venous thromboembolism (VTE) in the national patient<br />
register. Inpatient and specialized outpatient care resource utilization, along with data<br />
on pharmaceutical treatment and mortality in the study population, were elicited from<br />
the NBHW registries. Data was analysed for a 2-year period after each patient’s index<br />
date, i.e. after VTE diagnosis. Health care unit costs were collected from regional price<br />
lists and drug costs were extracted from the prescribed drugs registry.<br />
Results: A total <strong>of</strong> 1504 cases were identified in 2012 (mean age 69 years; 45% male)<br />
out <strong>of</strong> which 16% had lung cancer, 13% colorectal cancer, 9% breast cancer and 5%<br />
prostate cancer while the majority (57%) had other cancer types. The most common<br />
VTE diagnoses were pulmonary embolism (56%) and deep vein thrombosis (37%), and<br />
19% had more than one thrombosis related diagnosis. On average, patients were<br />
hospitalized fora total <strong>of</strong> 14 days and had 0.69 outpatient visits during the follow-up<br />
period. After 2 years, the mortality rate was 68%. Cancer was reported as the main<br />
cause <strong>of</strong> death in most cases (91%). Pulmonary embolism was reported as a<br />
contributing factor in 17% <strong>of</strong> the deaths. The total cost <strong>of</strong> CAT during the 2 years was<br />
€14 million (€9400 per patient), out <strong>of</strong> which 88% were related to inpatient care.<br />
Among the four major cancer diagnoses, the cost <strong>of</strong> CAT per patient was highest for<br />
colorectal cancer (€9800) and lowest for breast cancer (€4700).<br />
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abstracts<br />
Conclusions: CAT is associated with significant resource utilization and costs, out <strong>of</strong><br />
which the largest portion is attributed to inpatient care.<br />
Legal entity responsible for the study: The Swedish Institute for Health Economics<br />
Funding: Leo Pharma AB<br />
Disclosure: M.V. Holm: Employeed at LEO Pharma AB, Sweden. All other authors<br />
have declared no conflicts <strong>of</strong> interest.<br />
1040P<br />
Dalteparin vs. vitamin K antagonist (VKA) for the prevention<br />
<strong>of</strong> recurrent venous thromboembolism (VTE) in cancer<br />
patients with renal insufficiency: A patient level<br />
pharmacoeconomic analysis in three European countries<br />
L. Shane 1 , G. Dranitsaris 2 , S. Woodruff 3 , J-P. Galanaud 4 , G. Stemer 5 ,<br />
P. Debourdeau 6 , B. Valtier 7 , L. Burgers 8<br />
1 Global Health and Value, Pfizer Inc., New York, NY, USA, 2 Outcomes Research,<br />
Augmentium Pharma Consulting Inc, Toronto, ON, Canada, 3 Medical, Pfizer Inc.,<br />
New York, NY, USA, 4 Department <strong>of</strong> Internal Medicine, Montpellier University<br />
Hospital, Montpellier, France, 5 Pharmacy, Vienna General Hospital (AKH) -<br />
Medizinische Universität Wien, Vienna, Austria, 6 <strong>Oncology</strong>, Hopital Desgenettes,<br />
Lyon, France, 7 Medical, Pfizer France, Paris, France, 8 Public Affairs and Policy,<br />
Pfizer BV, Capelle aan den Ijssel, Netherlands<br />
Background: In a randomized trial (i.e. CLOT) which evaluated extended duration<br />
prophylaxis <strong>of</strong> recurrent VTE in cancer patients (Lee et al, 2003), dalteparin reduced<br />
the relative risk <strong>of</strong> recurrent VTE by 52% compared to oral VKA therapy (P = 0.002). A<br />
recent subgroup analysis in patients with moderate to severe renal impairment at<br />
randomization also revealed lower absolute VTE rates with dalteparin (3% vs. 17%;<br />
p = 0.011). A patient level pharmacoeconomic analysis was conducted to evaluate these<br />
indications from the French, Austrian and Dutch health care system perspectives.<br />
Methods: Resource utilization data contained within the database was extracted and<br />
converted into direct cost estimates for each country. Univariate analysis was used to<br />
compare the total cost <strong>of</strong> therapy between patients randomized to dalteparin or VKA<br />
therapy for each country. To estimate the cost per quality adjusted life year (QALY)<br />
gained with dalteparin, health state utilities were measured in 24 members <strong>of</strong> the<br />
general public using the Time Trade-Off technique.<br />
Results: When all <strong>of</strong> the cost components were combined for the entire population<br />
(n = 676), the dalteparin group had significantly higher mean overall costs than the<br />
VKA group in each <strong>of</strong> the respective countries (Table). However, the preference<br />
assessment revealed that 21 <strong>of</strong> 24 respondents (88%) selected dalteparin over VKA with<br />
an associated gain <strong>of</strong> 0.14 (95%CI: 0.10 – 0.18) QALYs, resulting in favourable cost<br />
effectiveness ratios.<br />
Table: 1040P<br />
Country* Dalteparin VKA Cost / QALY<br />
France €2,267 (80) €1,352 (94) €6,600<br />
Austria €2,687 (81) €2,012 (102) €4,900<br />
Netherlands €2,376 (81) €1,724 (102) €4,697<br />
*p < 0.001; SE = standard error The analysis in patients with renal impairment<br />
suggested an even better economic pr<strong>of</strong>ile, with the cost per QALY gained<br />
being less than €4,000 in all three countries.<br />
Conclusions: Extended duration prophylaxis with dalteparin is a clinically and cost<br />
effective alternative to VKA for the prevention <strong>of</strong> recurrent VTEs in patients with<br />
cancer, especially in those with renal impairment.<br />
Legal entity responsible for the study: Pfizer Inc<br />
Funding: Pfizer Inc<br />
Disclosure: L. Shane: Employed by the sponsor; Pfizer Inc. G. Dranitsaris: Consultant<br />
to Pfizer Inc. S. Woodruff, B. Valtier, L. Burgers: Employed by Pfizer Inc. All other<br />
authors have declared no conflicts <strong>of</strong> interest.<br />
1041P<br />
Health state utility measured by EQ-5D-5L for EGFRm T790M<br />
NSCLC patients treated with osimertinib<br />
C. Bodnar, J. Ryan, M. Green<br />
Global Payer Evidence & Pricing, AstraZeneca Global Product & Portfolio Strategy,<br />
Cambridge, UK<br />
Background: EQ-5D-5L is a standardized patient reported outcome instrument to<br />
capture a patient’s health state. EQ-5D-5L consists <strong>of</strong> a descriptive health system<br />
covering five dimensions (mobility, self-care, usual activities, pain/discomfort and<br />
anxiety/depression) with five levels each (no problems, slight problems, moderate<br />
problems, severe problems, and extreme problems) and a visual analogue scale (VAS)<br />
assessing overall health. It also provides a health state utility value frequently used in<br />
economic evaluations. To our knowledge this is the first EQ-5D data published for<br />
T790M EGFRm NSCLC. EQ-5D-5L was included as an exploratory endpoint in<br />
AURA2, a Phase II single arm study <strong>of</strong> osimertinib for the treatment <strong>of</strong> advanced<br />
EGFR T790M NSCLC (NTC02094261).<br />
Methods: AURA2 recruited 210 patients to osimertinib 80mg QD tablet. EQ-5D-5L<br />
was included to explore the impact <strong>of</strong> osimertinib on health state utility. It was<br />
collected electronically at first dose and every 6w including during follow-up<br />
post-progression. Using the EQ-5D-5L crosswalk value set for the UK, mean utility<br />
values for progression-free (PF) and progressive disease (PD) health-state were<br />
calculated.<br />
Results: A total <strong>of</strong> 175 patients completed the questionnaire at baseline. The main<br />
improvements in health state observed were reduced depression/anxiety and pain/<br />
discomfort. Mean utility at baseline was 0.745. At 6w post treatment initiation, the<br />
utility had increased to 0.819, and the improvement maintained above baseline values<br />
until 60w <strong>of</strong> treatment (0.798). The same trend was observed in the VAS (at baseline<br />
65, rising to 72 at 6w, falling to below baseline only after progression). The mean<br />
health-state utilities for PF and PD were 0.812 and 0.751, respectively. Pre-progression,<br />
patients with complete or partial response (defined by objective response) showed a<br />
higher utility (0.883) than those with stable disease (0.754).<br />
Conclusions: Patients treated with osimertinib experienced a numerical improvement<br />
in health dimensions and associated health state utility values, which increased from<br />
baseline to 6w and were maintained above baseline values for nearly 14 months.<br />
EQ-5D will be explored further in an ongoing Phase III study (AURA3).<br />
Clinical trial identification: NTC02094261<br />
Legal entity responsible for the study: AstraZeneca<br />
Funding: AstraZeneca<br />
Disclosure: C. Bodnar: Employee <strong>of</strong> AstraZeneca. J. Ryan, M. Green: Employee <strong>of</strong> and<br />
shareholder in AstraZeneca<br />
1043P<br />
Modeling maintenance therapy in ovarian cancer<br />
C. Jones 1 , B. Harrow 2 , E. Badamgarav 3 , S. Agarwal 4 , J. Ledermann 5 , C. Quinn 1<br />
1 HEOR and Market Access, PRMA Consulting, Fleet, UK, 2 Health Economics and<br />
Outcomes Research, TESARO, Inc., Waltham, MA, USA, 3 International Market<br />
Access, TSRO Bio GmbH, Zug, Switzerland, 4 Department <strong>of</strong> Medical Affairs,<br />
Tesaro, Inc, Waltham, MA, USA, 5 <strong>Oncology</strong>, University College London Cancer<br />
Institute, London, UK<br />
Background: Maintenance therapy (MT) is a relatively new concept in the<br />
management <strong>of</strong> solid tumors, and it is difficult to determine how MT early in the<br />
treatment pathway may impact long-term outcomes. The objective <strong>of</strong> this study was to<br />
develop a model <strong>of</strong> the natural history <strong>of</strong> ovarian cancer (OC) and determine the<br />
impact <strong>of</strong> MT on overall survival and quality-adjusted life years (QALYs).<br />
Methods: A microsimulation model was developed to allow patients to progress<br />
through therapy from first line to fifth, with MT following each <strong>of</strong> first-, second-, and<br />
third-line treatment. Progression was tracked using progression-free disease (PFS),<br />
treatment-free intervals (TFI), and survival in progressive disease. Overall survival is<br />
thus the accumulation <strong>of</strong> all survival in the model. Data to support the model were<br />
extracted from various sources describing studies in predominantly serous OC: PFS<br />
from a study <strong>of</strong> survival in 1,620 patients after initial platinum + taxane-based therapy;<br />
rates <strong>of</strong> discontinuing active therapy at each line, and rates and duration <strong>of</strong><br />
chemotherapy, from a published survey <strong>of</strong> clinicians; and health state utility values<br />
from NICE Technology Appraisals for OC. Outcomes in the BRCA-defined subgroups<br />
were estimated using hazard ratios from a meta-analysis and clinical trial.<br />
Results: Simulations were run with n = 2,000 with stable results. In the absence <strong>of</strong> MT,<br />
life years (LYs) per patient were 1.11 and QALYs per patient were 0.69. Gains <strong>of</strong> 0.04<br />
LYs and 0.05 QALYs were observed when MT was included after treatment for first,<br />
second, and third relapses; the TFI increased from 0.78 to 0.81 LYs and the<br />
chemotherapy-free interval increased by 0.09 LYs.<br />
Conclusions: The model results are consistent with previous publications for OC; the<br />
impact <strong>of</strong> MT is demonstrated through delayed progression to subsequent therapy,<br />
longer treatment-free intervals, and sustained QALYs from delayed disease progression<br />
and fewer adverse events. Although the model was developed for subgroups <strong>of</strong> ovarian<br />
cancer (based on platinum sensitivity or BRCA status), data for these populations are<br />
limited. Further research, and more clinical trial or real-world data, are recommended<br />
to explore the impact <strong>of</strong> MT in subgroups.<br />
Legal entity responsible for the study: PRMA Consulting Ltd<br />
Funding: Tesaro Inc.<br />
Disclosure: C. Jones: Employee <strong>of</strong> PRMA Consulting. Tesaro Inc provided funding to<br />
PRMA Consulting to conduct the study. B. Harrow: Employee <strong>of</strong> Tesaro Inc. E.<br />
Badamgarav, S. Agarwal: Employee <strong>of</strong> Tesaro. J. Ledermann: Advisory Boards (no<br />
personal remuneration) for: Astra Zeneca, Clovis, Tesaro. Chief investigator for Astra<br />
Zeneca Study 19. C. Quinn: Employee <strong>of</strong> PRMA Consulting. Tesaro Inc provided<br />
funding to PRMA Consulting to conduct the study.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw377 | vi357
abstracts<br />
1044P<br />
Incremental cost-effectiveness analysis <strong>of</strong> hepatic<br />
metastasectomy in patients with advanced colon cancer and<br />
liver metastasis<br />
S. Chainitikun<br />
Medical <strong>Oncology</strong>, King Chulalongkorn Memorial Hospital, Bangkok, Thailand<br />
Background: Colorectal cancer with liver metastasis is a potentially curable<br />
malignancy. Multidisciplinary treatment including hepatic tumor resection provides<br />
20-40% 5 year survival rate. However, the utility <strong>of</strong> hepatic resection for liver<br />
metastases in colorectal cancer is still debatable. Liver metastasectomy requires<br />
specialized centers having expertise, resources, and awareness which consume<br />
significant amount <strong>of</strong> hospital budgets. We aimed to evaluate the cost-effectiveness <strong>of</strong><br />
hepatic metastasectomy in patients with advanced colon cancer with liver metastasis.<br />
Methods: Medical records <strong>of</strong> advanced colon cancer patients with liver metastasis only<br />
who treated at the King Chulalongkorn Memorial Hospital during January 2007 to 31<br />
December 2010 were reviewed. The study endpoint is to compare the cost per life-year<br />
gained in term <strong>of</strong> incremental cost-effectiveness ratio (ICER) between with or without<br />
hepatic metastasectomy by the decision model. Data regarding site <strong>of</strong> primary tumor,<br />
characteristics <strong>of</strong> liver metastases, treatment strategies, chemotherapy regimens,<br />
biologic agents, complications, health coverage and survival data were collected and<br />
analyzed.<br />
Results: There were 34 patients in liver surgery group and 28 patients in without<br />
surgery group. There was significantly longer median survival time in the surgery<br />
group vs no surgery, 42.22 vs 18.04 months, respectively (HR = 23.3, P < 0.001).<br />
Individual mean cost per patient was higher in the surgery group at 1,975,349 baht<br />
(60,446 USD)/case compared to no surgery group at 1,451,028 baht (44,402 USD)/<br />
case. The ICER <strong>of</strong> liver surgery over no surgery was 247,150 baht (7,563 USD) per<br />
life-year gained which is lower than the threshold derived from the national gross<br />
domestic product per capita.<br />
Conclusions: Under the routine clinical service, hepatic metastasectomy is a<br />
cost-effective option for patients with colon cancer with liver only metastasis in the<br />
tertiary care hospital setting.<br />
Legal entity responsible for the study: Medical <strong>Oncology</strong> Department, Faculty <strong>of</strong><br />
Medicine, Chulalongkorn University<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1045P<br />
An Italian cost-effectiveness analysis <strong>of</strong> paclitaxel albumin<br />
(nab®-paclitaxel) + gemcitabine vs gemcibatine alone for<br />
metastatic pancreatic cancer patients: The APICE study<br />
C. Lazzaro 1 , C. Barone 2 , F. Caprioni 3 , S. Cascinu 4 , A. Falcone 5 , E. Maiello 6 ,<br />
M. Milella 7 , C. Pinto 8 , M. Reni 9 , G. Tortora 10<br />
1 Pharmacoeconomics, Studio di Economia Sanitaria, Milan, Italy, 2 Medicina<br />
Interna - U.O.C. di Oncologia Medica, Policlinico Universitario A. Gemelli, Rome,<br />
Italy, 3 Oncologia medica 1, IRCCS AOU San Martino - IST-Istituto Nazionale per la<br />
Ricerca sul Cancro, Genoa, Italy, 4 Medical <strong>Oncology</strong>, Azienda Ospedaliero -<br />
Universitaria Policlinico di Modena, Modena, Italy, 5 Department <strong>of</strong><br />
<strong>Oncology</strong>-Presidio Ospedaliero, Azienda Ospedaliera Universitaria S.Chiara, Pisa,<br />
Italy, 6 Onco-Hematology Department, IRCCS Casa Sollievo della S<strong>of</strong>ferenza, San<br />
Giovanni Rotondo, Italy, 7 S. C. Oncologia Medica A, Istituto Regina Elena, Rome,<br />
Italy, 8 S. C. Oncologia, Azienda Ospedaliera Arcispedale Santa Maria Nuova -<br />
IRCCS, Reggio Emilia, Italy, 9 Medical <strong>Oncology</strong>, IRCCS San Raffaele, Milan, Italy,<br />
10 Medical <strong>Oncology</strong>, Azienda Ospedaliera Universitaria Integrata Verona-"Borgo<br />
Roma", Verona, Italy<br />
Background: In a Phase III clinical trial, nab-paclitaxel + gemcitabine (G) significantly<br />
improved overall survival, time to progression and response rate compared to G<br />
monotherapy in MPC. The aim <strong>of</strong> APICE study was to evaluate the cost-effectiveness<br />
<strong>of</strong> nab-paclitaxel + G vs G in the treatment <strong>of</strong> MPC patients in Italy.<br />
Methods: A Markov model with four health states (progression-free, progressed, end<br />
<strong>of</strong> life and death) was developed to estimate costs, outcomes and quality-adjusted<br />
life-years (QALYs) over 4 years from the Italian National Health Service (INHS)<br />
perspective. Patients were assumed to receive G 1000mg/m 2 weekly or nab-paclitaxel<br />
125mg/m 2 + G 1000mg/m 2 weekly. Data on efficacy was derived from MPACT trial,<br />
while data on health care resource consumption was collected from a survey performed<br />
on nine Italian centres. Resources were valued at Euro (€) 2015. Published utility<br />
weights were applied to health states to estimate the impact <strong>of</strong> response, disease<br />
progression and adverse events on QALYs. Two sensitivity analyses tested the<br />
robustness <strong>of</strong> the base case incremental cost-effectiveness ratio (ICER).<br />
Results: Compared to G in monotherapy, nab-paclitaxel + G gains an extra 0.154<br />
QALYs (0.196 life-year saved) and incurs additional costs <strong>of</strong> €7088 per patient treated.<br />
This translates to an ICER <strong>of</strong> €46,022 (95%CI: €33,292; €78,960). One-way sensitivity<br />
analysis underscores ICER for nab-paclitaxel + G to be robust. Probabilistic sensitivity<br />
analysis highlighted that nab-paclitaxel has a 0.98 probability to be cost-effective for a<br />
threshold-value <strong>of</strong> €80,000 and is the optimal alternative from a threshold-value <strong>of</strong><br />
€46,746 onwards.<br />
Conclusions: Based on those findings, nab-paclitaxel + G can be considered<br />
cost-effective when compared to the informal acceptability threshold-value for ICER<br />
adopted for reimbursing other oncology drugs in Italy (€87,330; 95%CI: €37,024;<br />
€137,636).<br />
Legal entity responsible for the study: Celgene Italia srl, Milan, Italy<br />
Funding: Celgene Italia srl, Milan, Italy<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1046P<br />
Incidence, epidemiology and outcome in adults and children<br />
with ALL: A review <strong>of</strong> population-based cancer registries<br />
(PBCRs), an experience from Eastern India<br />
S. Banerjee<br />
Clinical Research, University <strong>of</strong> Calcutta, Kolkata, India<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Background: Acute lymphoblastic leukemia (ALL) is the most common cancer<br />
diagnosed in children. With the introduction <strong>of</strong> a classification system for<br />
hematopoietic and lymphoid neoplasms, assessment <strong>of</strong> ALL epidemiology is now<br />
possible. Our aim is to provide an updated overview <strong>of</strong> the incidence <strong>of</strong> cancer on the<br />
basis <strong>of</strong> the report from the National Cancer Registry Program (NCRP) for the years<br />
2006- 2015 that covered population aged 0 to 64 years.<br />
Methods: The NCRP report (2013) provides data from PBCRs covering 70.45% <strong>of</strong> the<br />
state’s population aged (0-75) years. Age-specific incidence data for ALL and data for<br />
incidence-mortality rates were collected. Based on Age-adjusted cancer incidence rates<br />
for children aged 0-14years were collected.<br />
Results: With significant age-related variations (0.53 at 40–65years, ∼1.0 at 54–73<br />
years), overall survival (68%; 33%) or event-free survival (46%, 29%) with respective<br />
age groups, overall survival (OS) improved from 29.8% in the years 2000–2005 to<br />
41.1% in 2010–2015 (P < 0.0001). Compared with the reference group (age 14–39<br />
years: OS >48%), OS was 5 cases per 0.1<br />
million per year), with rates increasing more than 10 cases per 0.1 million by age 8<br />
years. ALL among children aged 2 to 3 years is greater than that for infants and<br />
children aged 10 years and older. Cancer incidence AARpm is 28.6189.6 between age<br />
(0.58.8) years.<br />
Conclusions: Childhood cancer contribute to 5.6% to 13.8% <strong>of</strong> all cancers (CCI as 5 to<br />
15 per 0.1 million) in India for the years 2010-2015. Among children with ALL, more<br />
than 95% attain remission, 80% <strong>of</strong> patients aged 1 to 18 years with newly diagnosed<br />
ALL treated on current regimens are expected to be long-term event-free survivors.<br />
Childhood cancer in developing countries are increasing and sharper differences are<br />
seen than those <strong>of</strong> western countries due to exposures during prenatal development in<br />
low and middle income countries.<br />
Legal entity responsible for the study: Sangita Banerjee<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
vi358 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong> 27 (Supplement 6): vi359–vi378, 2016<br />
doi:10.1093/annonc/mdw378<br />
immunotherapy <strong>of</strong> cancer<br />
1047O<br />
Baseline tumor T cell receptor (TcR) sequencing analysis and<br />
neo antigen load is associated with benefit in melanoma<br />
patients receiving sequential nivolumab and ipilimumab<br />
J. Weber 1 , C. Horak 2 , F.S. Hodi 3 , H. Chang 2 , D. Woods 4 , C. Sanders 5 , H. Robins 6 ,<br />
E. Yusko 5<br />
1 Laura and Isaac Perlmutter Cancer Center, NYU Langone Medical Center,<br />
New York, NY, USA, 2 Biomarkers, BMS, Princeton, NJ, USA, 3 <strong>Oncology</strong>,<br />
Dana-Farber Cancer Institute, Boston, MA, USA, 4 Cancer Center, Laura and Isaac<br />
Perlmutter Cancer Center, New York, NY, USA, 5 Computational Biology, Adaptive<br />
Biotechnologies, Seattle, WA, USA, 6 Public Health Sciences, Fred Hutchinson<br />
Cancer Research Center, Seattle, WA, USA<br />
1048O<br />
Ongoing complete remissions in phase 1 <strong>of</strong> ZUMA-1: a phase<br />
1-2 multi-center study evaluating the safety and efficacy <strong>of</strong><br />
KTE-C19 (anti-CD19 CAR T cells) in patients with refractory<br />
aggressive B cell non-Hodgkin lymphoma (NHL)<br />
F.L. Locke 1 , S.S. Neelapu 2 , N.L. Bartlett 3 , T. Siddiqi 4 , J.C. Chavez 5 , C.M. Hosing 6 ,<br />
A. Cashen 3 , L.E. Budde 4 , M. Sherman 7 , J.M. Rossi 7 , L. Navale 7 , Y. Jiang 7 ,<br />
J. Aycock 7 , M. Elias 7 , J. Wiezorek 7 ,W.Y.Go 7<br />
1 Blood and Marrow Transplantation, M<strong>of</strong>fitt Cancer Center, Tampa, FL, USA,<br />
2 Department <strong>of</strong> Lymphoma and Myeloma, The University <strong>of</strong> Texas MD Anderson<br />
Cancer Center, Houston, TX, USA, 3 Siteman Cancer Center, Washington<br />
University School <strong>of</strong> Medicine, St. Louis, MO, USA, 4 Department <strong>of</strong> Hematology<br />
and Hematopoietic Cell Transplantation, City <strong>of</strong> Hope National Medical Center,<br />
Duarte, CA, USA, 5 Department <strong>of</strong> Malignant Hematology, M<strong>of</strong>fitt Cancer Center,<br />
Tampa, FL, USA, 6 Department <strong>of</strong> Stem Cell Transplantation and Cellular Therapy,<br />
The University <strong>of</strong> Texas MD Anderson Cancer Center, Houston, TX, USA, 7 Kite<br />
Pharma, Santa Monica, CA, USA<br />
abstracts<br />
1055O<br />
Changes in serum IL8 levels reflect and predict response to<br />
anti-PD-1 treatment in melanoma and non-small cell lung<br />
cancer patients<br />
M.F. Sanmamed 1 , J.L. Perez-Gracia 2 ,J.P.Fusco 2 ,C.Oñate 3 ,G.Perez 3 , C. Alfaro 3 ,<br />
S. Martín-Algarra 2 , A. González 4 ,M.E.Rodriguez-Ruiz 3 ,M.P.Andueza 2 ,J.Wang 1 ,<br />
A. Bacchiocchi 5 ,R.Halaban 5 ,H.Kluger 6 ,M.Sznol 6 ,I.Melero 3<br />
1 Immunobiology, Yale School <strong>of</strong> Medicine, New Haven, CT, USA, 2 Medical<br />
<strong>Oncology</strong>, Clinica Universitaria de Navarra, Pamplona, Spain, 3 Laboratory <strong>of</strong><br />
Immunology, Universidad de Navarra, Pamplona, Spain, 4 Biochemistry, Clinica<br />
Universitaria de Navarra, Pamplona, Spain, 5 Dermatology, Yale School <strong>of</strong><br />
Medicine, New Haven, CT, USA, 6 Medical <strong>Oncology</strong>, Yale School <strong>of</strong> Medicine,<br />
New Haven, CT, USA<br />
© European Society for Medical <strong>Oncology</strong> 2016. Published by Oxford University Press on behalf <strong>of</strong> the European Society for Medical <strong>Oncology</strong>.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com.
abstracts<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
AZD9150 was 3 mg/kg QW. In the A5 + D arm, 20 pts were enrolled (DL1 = 9; DL2 = 11)<br />
with most common drug related AEs <strong>of</strong> neutropenia (35%), fatigue or anorexia (20%). One<br />
DLT <strong>of</strong> Gr 3 neutropenia occurred at 40 mg bid; 2 similar DLTs were noted at DL2. The<br />
MTD/RP2D for AZD5069 was 40 mg po bid. Two pts in the A9 + D arm achieved a<br />
confirmed PR (MSH2/6 mutant mCRPC, GE jxn tumor) per modified iRECIST. Three<br />
more pts on A9 + D (laryngeal, colorectal, leiomyosarcoma) and two on A5 + D (breast,<br />
urothelium) demonstrated stable disease; the last pt’s course was clearly consistent with<br />
pseudoprogression. Target engagement was shown in peripheral blood <strong>of</strong> A9 + D (STAT3<br />
knockdown) and A5 + D (CXCR2-elicited cytokines) pts.<br />
Conclusions: Combinations <strong>of</strong> durvalumab with AZD9150 or AZD5069 have a<br />
manageable toxicity pr<strong>of</strong>ile and encouraging evidence <strong>of</strong> activity. Enrollment into<br />
phase 2 SCCHN expansion cohorts continues. Pharmacokinetic and<br />
pharmacodynamic data will be presented.<br />
Clinical trial identification: NCT02499328<br />
Legal entity responsible for the study: AstraZeneca Pharmaceuticals LP<br />
Funding: AstraZeneca Pharmaceuticals LP<br />
Disclosure: D. Hong, G. Falchook, W. Harb, J.S. Wang: Research funding for clinical<br />
trials from AstraZeneca. C.E. Cook: AstraZeneca employee and stock holder. P. Lyne,<br />
P. McCoon, M. Mehta, P. Mitchell, M. Scott, G.M. Mugundu: Employee <strong>of</strong><br />
AstraZeneca Pharmaceuticals LP.<br />
1050PD<br />
Combination <strong>of</strong> MEDI0680, an anti-PD-1 antibody, with<br />
durvalumab, an anti-PD-L1 antibody: A phase 1, open-label<br />
study in advanced malignancies<br />
O. Hamid 1 , L.Q. Chow 2 , R.E. Sanborn 3 , S. Marshall 4 , C. Black 5 , M. Gribbin 6 ,<br />
J. McDevitt 4 , J.J. Karakunnel 4 , J.E. Gray 7<br />
1 Melanoma Therapeutics, The Angeles Clinic and Research Institute, Los Angeles,<br />
CA, USA, 2 Department <strong>of</strong> Medicine, Division <strong>of</strong> Medical <strong>Oncology</strong>, University <strong>of</strong><br />
Washington, Seattle, WA, USA, 3 Department <strong>of</strong> Medical <strong>Oncology</strong>, Earle A. Chiles<br />
Research Institute, Providence Cancer Center, Portland, OR, USA, 4 Clinical<br />
Development, MedImmune, Gaithersburg, MD, USA, 5 Translational Medicine,<br />
MedImmune, Gaithersburg, MD, USA, 6 Biostatistics, MedImmune, Gaithersburg,<br />
MD, USA, 7 Department <strong>of</strong> Thoracic <strong>Oncology</strong>, M<strong>of</strong>fitt Cancer Center and<br />
Research Institute, Tampa, FL, USA<br />
1049PD<br />
A phase 1b study (SCORES) assessing safety, tolerability,<br />
pharmacokinetics, and preliminary anti-tumor activity <strong>of</strong><br />
durvalumab combined with AZD9150 or AZD5069 in<br />
patients with advanced solid malignancies and SCCHN<br />
D. Hong 1 , G. Falchook 2 , C.E. Cook 3 , W. Harb 4 , P. Lyne 5 , P. McCoon 6 , M. Mehta 3 ,<br />
P. Mitchell 7 , G.M. Mugundu 8 , M. Scott 3 , J.S. Wang 9<br />
1 Investigational Cancer Therapeutics, MD Anderson Cancer Center, Houston, TX,<br />
USA, 2 Drug Development, Sarah Cannon Research Institute at HealthONE,<br />
Denver, CO, USA, 3 Early Clinical Development, AstraZeneca Pharmaceuticals,<br />
Waltham, MA, USA, 4 Horizon <strong>Oncology</strong> Center, Unity Campus, Lafayette, IN,<br />
USA, 5 <strong>Oncology</strong> iMed, AstraZeneca Pharmaceuticals, Waltham, MA, USA,<br />
6 Translational Science, AstraZeneca Pharmaceuticals, Waltham, MA, USA, 7 Early<br />
Clinical Biometrics, AstraZeneca Pharmaceuticals, Waltham, MA, USA,<br />
8 Quantitative Clinical Pharmacology, Early Clinical Development, AstraZeneca<br />
Pharmaceuticals, Waltham, MA, USA, 9 Drug Development Unit, Florida Cancer<br />
Specialists/Sarah Cannon Research Institute, Sarasota, FL, USA<br />
Background: Activating the immune system for therapeutic benefit in cancer has long<br />
been a goal in immunooncology. Combining a PD-L1 antagonist, durvalumab (D),<br />
with novel agents targeting immunosuppression in the tumor bed such as AZD9150<br />
(A9, an antisense oligonucleotide against STAT3) or AZD5069 (A5, a CXCR2<br />
antagonist) may strongly enhance anti-tumor responses.<br />
Methods: Patients (pts) with advanced solid malignancies (N = 31) were enrolled using<br />
a CRM–based approach to identify dose combinations <strong>of</strong> A9 + D and A5 + D with an<br />
incidence <strong>of</strong> dose-limiting toxicities (DLT) less than 33%. Up to 6 evaluable pts per<br />
cohort were initially assessed. For all, D was fixed at 20 mg/kg Q4W with A9 at dose<br />
levels (DL) <strong>of</strong> (1) 2mg/kg QW or (2) 3mg/kg QW i.v; A5 was started at DL1 40 mg po<br />
bid, then DL2 80 mg bid. The primary objective was to determine the MTD and<br />
recommended phase II dose (RP2D), and secondarily safety, PK, pharmacodynamics,<br />
biological and clinical activity for each combination.<br />
Results: IntheA9+Darm,11pts(DL1=4,DL2=7)weretreated.Themostcommon<br />
drug related adverse events (AEs) were thrombocytopenia (64%), neutropenia (45%) and<br />
ALT/AST increase (36%) with no DLTs or drug-related Gr 4 events. The MTD/RP2D for<br />
Background: The PD-1/PD-L1 pathway is a key regulator <strong>of</strong> T-cell activation and a<br />
promising target for cancer treatment. MEDI0680 (M) is a humanized IgG4κ mAb<br />
specific for human PD-1 that blocks interaction with PD-L1 and programmed cell<br />
death ligand-2 (PD-L2). Durvalumab (D; MEDI4736) is a selective, high-affinity,<br />
engineered human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD80. Blocking<br />
both the PD-1 receptor and its ligand by combining M + D <strong>of</strong>fers the potential for<br />
complete PD-1/PD-L1 axis inhibition.<br />
Methods: This ongoing Phase 1 open-label, dose-escalation and expansion study is<br />
evaluating M + D in patients (pts) ≥18 years with relapsed/refractory advanced solid<br />
malignancies and ECOG performance status 0-1 (NCT02118337). The primary<br />
objectives are safety and maximum tolerated dose (MTD). Secondary objectives<br />
include antitumor activity.<br />
Results: As <strong>of</strong> 2 November 2015, 30 pts across various histologies were treated in 6<br />
dose cohorts (Table) with 50% remaining on study. 1 dose-limiting toxicity occurred<br />
(Cohort 5; Grade 3 elevated AST/ALT). The MTD has not been reached. The most<br />
common drug-related AEs were pruritus (17%); diarrhea and fatigue (both 13%); and<br />
flushing, peripheral edema, and pyrexia (each 10%). Immune-related AEs were similar<br />
to those seen with other checkpoint blockade agents. No drug-related AEs led to death.<br />
2 pts (7%) discontinued due to drug-related AEs. Of 26 evaluable pts, 1 had a complete<br />
response (CR; Cohort 5; bladder cancer), 3 had a partial response (PR) and 9 had<br />
stable disease (SD). Increased Ki67+ (proliferating) CD4+ and CD8+ T cells and<br />
elevated circulating IFNγ, CXCL9, CXCL10, and CXCL11 levels were observed with<br />
M + D, indicating pharmacodynamic activity <strong>of</strong> PD-1/PD-L1 pathway blockade.<br />
Updated clinical data will be presented.<br />
Table: 1050PD<br />
Cohort 1 2 3 4 5 6 Total<br />
Dose every 2 weeks (Q2W) 0.1 + 3 0.1 + 10 0.5 + 10 2.5 + 10 10 + 10 20 + 10<br />
(mg/kg), M + D<br />
N 4 5 3 3 9 6 30<br />
Patients with drug-related<br />
AEs, n (%)<br />
All grades 2 (50) 3 (60) 3 (100) 2 (67) 8 (89) 3 (50) 21 (70)<br />
Grade ≥3 1 (25) 0 1 (33) 0 3 (33) 0 5 (17)<br />
All grades leading to<br />
1 (25) 1 (20) 1 (33) 1 (33) 2 (22) 0 6 (20)<br />
discontinuation<br />
Responses*<br />
Objective response rate 1/4 (25) 0 0 0 3/8 (38) 0 4/26 (15)<br />
(CR + PR), n/N (%)<br />
Disease control<br />
(CR + PR + SD ≥8<br />
weeks), n/N (%)<br />
2/4 (50) 1/5 (20) 1/3 (33) 0 5/8 (63) 0 9/26 (35)<br />
*Response evaluable population<br />
vi360 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Conclusions: M 10 mg/kg + D 10 mg/kg Q2W appears to be well-tolerated and active<br />
in this population.<br />
Clinical trial identification: NCT02118337<br />
Legal entity responsible for the study: MedImmune<br />
Funding: MedImmune<br />
Disclosure: O. Hamid: Consulting/Advisory: Merck, Merck Serono, Pfizer, Amgen,<br />
Novartis, Roche, BMS, Genentech Speakers Bureau: BMS, Genentech, Novartis<br />
Research funding: None. L.Q. Chow: Honoraria: Astellas Consulting/Advisory:<br />
Novartis, Amgen, Emergent Research funding: Novartis, BMS, Eli Lilly/Imclone<br />
Advisory board; travel & accommodations/Research funding: Merck. R.E. Sanborn:<br />
Consulting/Advisory: Amgen Research funding: BMS, Medimmune. S. Marshall:<br />
Employment: MedImmune, Amplimmune Stock options: MedImmune. C. Black:<br />
Employment: MedImmune Stock/ownership: AZ. M. Gribbin: Employment:<br />
Medimmune Stock ownership: MedImmune. J. McDevitt: Employment: MedImmune<br />
Stock/ownership: MedImmune (AZ). J.J. Karakunnel: Employee <strong>of</strong> MedImmune and<br />
own stock or options in AstraZeneca. JJK is also an employee <strong>of</strong> MedStar Montgomery<br />
Medical Center and Fauquier Hospital. J.E. Gray: Consulting/Advisory: AZ Travel,<br />
accommodation, expenses: AZ.<br />
1051PD<br />
The MITCI (phase 1b) study: a novel immunotherapy<br />
combination <strong>of</strong> coxsackievirus A21 and ipilimumab in<br />
patients with advanced melanoma<br />
B. Curti 1 , J. Richards 2 , M. Faries 3 , R.H.I. Andtbacka 4 , M. Grose 5 , R. Karpathy 5 ,<br />
D. Shafren 5<br />
1 <strong>Oncology</strong> and Hematology, Providence Portland Medical Center, Portland, OR,<br />
USA, 2 <strong>Oncology</strong>, <strong>Oncology</strong> Specialists, Chicago, IL, USA, 3 Surgical <strong>Oncology</strong>,<br />
John Wayne Cancer Center, Los Angeles, CA, USA, 4 Surgical <strong>Oncology</strong>,<br />
Huntsman Cancer Institute, Utah, UT, USA, 5 Viralytics, Viralytics Limited, Sydney,<br />
Australia<br />
Background: CAVATAK TM is a novel bio-selected oncolytic and immunotherapeutic<br />
strain <strong>of</strong> Coxsackievirus A21 (CVA21). In a phase 2 study, intratumoral (i.t.) CVA21<br />
injection <strong>of</strong> advanced melanoma lesions with CVA21 resulted in increases in tumor<br />
immune-cell infiltration, up-regulation <strong>of</strong> γ-INF response and immune-checkpoint<br />
molecule genes, including CD122 which may be a potential prognostic factor for<br />
anti-tumor activity by anti-CTLA-4 blockade strategies. Presented are the preliminary<br />
data <strong>of</strong> the open-label, Phase Ib MITCI (Melanoma Intra-Tumoral Cavatak and<br />
Ipilimumab) study <strong>of</strong> novel immunotherapy combination CVA21 and ipilimumab in<br />
patients (pts) with advanced melanoma.<br />
Methods: The Phase Ib MITCI study is investigating the efficacy and safety <strong>of</strong> i.t.<br />
CVA21 and i.v. ipilimumab in 26 pts with treated or untreated unresectable Stage<br />
IIIC-IVM1c melanoma. Pts received up to 3 x 10 8 TCID 50 CVA21 i.t. on study days 1,<br />
3, 5, 8 and 22, and then q3w for a further 6 series <strong>of</strong> injections. Ipilimumab (3 mg/kg)<br />
q3w was given as 4 i.v. infusions starting at Day 22. The first response assessment<br />
(irWHO) occurred at study Day 106. The primary endpoint was to assess safety <strong>of</strong><br />
CVA21 in combination with ipilimumab treatment (tx).<br />
Results: At present, <strong>of</strong> the 16 pts enrolled, no DLT’s have been reported. Combination<br />
tx has been generally well-tolerated with only one Gr 3 or higher tx-related AE being<br />
ipilimumab-related fatigue. The study has met its primary statistical futility endpoint <strong>of</strong><br />
achieving ≥ 4 confirmed objective responses (CR or PR) in the first 12 pts enrolled.<br />
Currently, <strong>of</strong> the first 7 pts eligible for investigator response assessment, ORR for the<br />
ITT population is 57.1% (4/7), with the ORR for ipilimumab-naïve pts being 67% (4/<br />
6). The DCR (CR + PR + SD) on the ITT population is currently 86% (6/7). All<br />
responses were observed by 3.5 mths with complete tumor responses being observed in<br />
individual injected and non-injected lesions.<br />
Conclusions: Intratumoral CVA21 + ipilimumab tx <strong>of</strong> pts with advanced melanoma<br />
has been generally well tolerated. The combination immunotherapy tx has displayed<br />
anti-tumor activity in both local, visceral and non-visceral lesions in a number <strong>of</strong><br />
patients that have failed previous lines <strong>of</strong> immunotherapy.<br />
Clinical trial identification: NCT02307149<br />
Legal entity responsible for the study: Viralytics Limited<br />
Funding: Viralytics Limited<br />
Disclosure: B. Curti: Honoraria: Prometheus Clinical trial support; Prometheus<br />
Bristol-Myers Squibb MedImmune. J. Richards: Stock Ownership - Bristol-Myers<br />
Squibb (I). M. Faries: Served as an advisor or consultant for: Amgen Inc.; Astellas<br />
Pharma, Inc.; Genentech, Inc. R.H.I. Andtbacka: Consulting or Advisory Role - Amgen<br />
Speakers’ Bureau - Novartis Research Funding - Amgen (Inst); Viralytics (Inst). M.<br />
Grose, R. Karpathy: Viralytics stock and employment at Viralytics. D. Shafren: stock<br />
ownership and CSO.<br />
1052PD<br />
abstracts<br />
Phase 1 study <strong>of</strong> MEDI0562, a humanized OX40 agonist<br />
monoclonal antibody (mAb), in adult patients (pts) with<br />
advanced solid tumors<br />
B.S. Glisson 1 , R. Leidner 2 , R.L. Ferris 3 , J. Powderly 4 , N. Rizvi 5 , J.D. Norton 6 ,<br />
J. Burton 7 , M.C. Lanasa 6 , S.P. Patel 8<br />
1 Thoracic/Head and Neck Medical <strong>Oncology</strong>, MD Anderson Cancer Center,<br />
Houston, TX, USA, 2 Medical <strong>Oncology</strong>, Hematology, Providence Cancer Center<br />
<strong>Oncology</strong> and Hematology Care Clinic Eastside Portland, Portland, OR, USA,<br />
3 Division <strong>of</strong> Head and Neck Surgery Departments <strong>of</strong> Otolaryngology, University <strong>of</strong><br />
Pittsburgh, Eye and Ear Institute, Pittsburgh, PA, USA, 4 Carolina Bio<strong>Oncology</strong><br />
Institute LLC, Carolina Bio<strong>Oncology</strong> Institute LLC, Huntersville, NC, USA,<br />
5 Hematology and <strong>Oncology</strong>, Columbia Medical Center College <strong>of</strong> physicians &<br />
surgeons, New York, NY, USA, 6 <strong>Oncology</strong>, MedImmune LLC, Gaithersburg, MD,<br />
USA, 7 <strong>Oncology</strong>, MedImmune Ltd, Cambridge, UK, 8 Experimental Therapeutics,<br />
Thoracic <strong>Oncology</strong>, UC San Diego Moores Cancer Center, La Jolla, CA, USA<br />
Background: In preclinical studies, OX40 agonists have been shown to stimulate<br />
immune effector and memory T cell function while attenuating immunosuppressive<br />
function <strong>of</strong> regulatory T cells, leading to anti-tumor activity.<br />
Methods: This is a Phase 1 study evaluating MEDI0562, a humanized OX40 agonist<br />
mAb, in adult pts with advanced solid tumors. The study has 2 phases: dose escalation<br />
and dose expansion. Dose escalation follows 3 + 3 design with pts enrolled in<br />
sequential cohorts <strong>of</strong> up to 6 dose levels <strong>of</strong> MEDI0562 (0.03, 0.1, 0.3, 1.0, 3.0, or 10 mg/<br />
kg, via intravenous infusion). Tumor assessments are performed every 8 weeks.<br />
Selected pts have mandatory pre- and on-treatment tumor biopsies to explore the<br />
relationship between drug exposure and pharmacodynamics. We report the<br />
preliminary results <strong>of</strong> safety, tumor response, pharmacokinetics, and<br />
pharmacodynamics in the dose escalation phase.<br />
Results: As <strong>of</strong> April 01 2016, 27 pts were treated (n = 7, 9, 7, 4 received 0.03, 0.1, 0.3,<br />
and 1 mg/kg MEDI0562, respectively). Adverse events (AEs) and treatment-related<br />
AEs were seen in 24 (88.9%) and 16 (59.3%) pts, respectively; the only related AE<br />
occurring in ≥ 10% <strong>of</strong> pts was fatigue (8/27, 29.6%). Most pts experienced AEs <strong>of</strong><br />
Grade 1 and 2 in severity. Serious AEs (SAEs) were seen in 12 (44.4%) pts; no<br />
treatment-related or immune-related SAEs were observed. No related treatment<br />
discontinuations, deaths or dose limiting toxicities have occurred. Of 19 evaluable pts,<br />
1 pt (0.03 mg/kg) with squamous cell carcinoma <strong>of</strong> the larynx had partial response at<br />
first tumor assessment and maintained for 3.7+ months (ongoing); 4 pts had stable<br />
disease. Serum exposure <strong>of</strong> MEDI0562 increased approximately dose proportionally. A<br />
2-3-fold mean increase in peripheral Ki67+ CD4+ memory T cells was observed.<br />
Paired tumor biopsies showed induction <strong>of</strong> PD-L1 expression and increased CD8+ T<br />
cell infiltration in 2 <strong>of</strong> 3 evaluated pts, including 1 pt at 0.03 mg/kg. Updated clinical<br />
data will be presented at the meeting.<br />
Conclusions: Preliminary data showed that MEDI0562 is generally well tolerated in<br />
adult pts with advanced solid tumors and exhibits clinical and pharmacological<br />
activity. A maximum tolerated dose has not been determined.<br />
Clinical trial identification: NCT02318394<br />
Legal entity responsible for the study: MedImmune LLC<br />
Funding: MedImmune LLC<br />
Disclosure: B.S. Glisson: Research funding for Clinical Trials from Pfizer, Bristol<br />
Myers Squibb, Oncomed, Stemcentrx, and Medimmune provided for MD Anderson. I<br />
am a PI on these grants. R. Leidner: Research is being supported by: Medimmune/<br />
Astra Zeneca and Bristol-Myers Squibb R.L. Ferris: Paid member <strong>of</strong> Advisory Board<br />
(Ad-Hoc)- Merck, Celgene, Bristol Myers Squibb, AZ/Medimmune Research/Grant<br />
Funding- VentiRx, Bristol Myers Squibb AZ/Medimmune. J. Powderly: Lion<br />
BioTechnologies, Juno Therapeutics, BlueBird Bio, Kite Pharma, ZioPharm <strong>Oncology</strong>,<br />
BMS, Genentech, EMD, Serono, AstraZeneca, InCyte, Macrogenics, Sequenom,<br />
Corvus, Carolina Bio<strong>Oncology</strong> Institute, PLLC, BioCytics Inc., Human Applications<br />
Lab, Merck. N. Rizvi: Consulting for AstraZeneca, Merck, Roche, Novartis, Lilly. C<strong>of</strong>ounder<br />
and shareholder, Gritstone <strong>Oncology</strong>. J.D. Norton: I am an employee <strong>of</strong><br />
MedImmune LLC, a subsidiary <strong>of</strong> AstraZeneca, and hold restricted AstraZeneca stock<br />
shares. J. Burton: Employee <strong>of</strong> MedImmune Ltd. M.C. Lanasa: Employee <strong>of</strong><br />
MedImmune LLC / AstraZeneca. S.P. Patel: Dr. Patel receives research funding from:<br />
MedImmune, Genentech, Pfizer, Amgen, Xcovery, Lilly, Bristol-Myers Squibb. He<br />
receives consulting fees from: Lilly, Pfizer. He receives speaking fees from: Boehringer<br />
Ingelheim, Merck.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw378 | vi361
abstracts<br />
1053PD<br />
A first-in-human (FIH) study <strong>of</strong> PF-04518600 (PF-8600)<br />
OX40 agonist in adult patients (pts) with select advanced<br />
malignancies<br />
A. Diab 1 , A. El-Khoueiry 2 , F.A. Eskens 3 ,W.Ros 4 , J.A. Thompson 5 , C. Konto 6 ,<br />
C. Bermingham 6 ,T.Joh 7 , K. Liao 7 , B. Ganguly 6 , O. Hamid 8<br />
1 Cancer Center, MD Anderson Cancer Center, Houston, TX, USA, 2 Clinical<br />
Medicine, University <strong>of</strong> Southern California Norris Comprehensive Cancer Center,<br />
Los Angeles, CA, USA, 3 Medical <strong>Oncology</strong>, Erasmus MC Daniel den Hoed Cancer<br />
Center, Rotterdam, Netherlands, 4 Molecular Pathology, The Netherlands Cancer<br />
Institute, Amsterdam, Netherlands, 5 Medical <strong>Oncology</strong>, University <strong>of</strong> Washington<br />
Seattle Cancer Care Alliance, Seattle, WA, USA, 6 Global R&D, Rinat-Pfizer, South<br />
San Francisco, CA, USA, 7 Global R&D, Pfizer Inc., La Jolla, CA, USA,<br />
8 Translational Research and Immunotherapy, The Angeles Clinic and Research<br />
Institute, Los Angeles, CA, USA<br />
Background: Co-stimulation <strong>of</strong> activated T cells with agonistic monoclonal antibodies<br />
(mAb) against the tumor necrosis factor receptor superfamily member OX40 <strong>of</strong>fers a<br />
novel immunotherapeutic approach to cancer. OX40 engagement may co-stimulate<br />
effector T cells and deplete regulatory T cells, resulting in enhanced tumor immunity.<br />
PF-8600 is a fully human agonist IgG2 mAb that targets OX40.<br />
Methods: A Phase 1, open label, multicenter study is ongoing to evaluate safety,<br />
pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity <strong>of</strong> PF-8600<br />
in pts with advanced melanoma, head and neck squamous cell, renal cell, or<br />
hepatocellular carcinoma. PF-8600 was administered intravenously at increasing doses<br />
(0.01 – 3 mg/kg) every 2 weeks until disease progression or unacceptable toxicity.<br />
Additional biomarker cohorts (opened at each dose level except 0.01 mg/kg) enrolled<br />
pts who consented to baseline and on-treatment tumor biopsies for immune pr<strong>of</strong>iling<br />
by immunohistochemistry and RNAseq.<br />
Results: As <strong>of</strong> 09 MAR 2016, 31 pts have enrolled in the dose-escalation phase <strong>of</strong><br />
PF-8600 study: 0.01 mg/kg (2 pts), 0.1 mg/kg (10 pts), 0.3 mg/kg (8 pts), 1.5 mg/kg (7<br />
pts) and 3 mg/kg (4 pts). 25.8% <strong>of</strong> patients received ≥ 4 prior therapies for advanced<br />
disease. No dose limiting toxicities, no drug-related or immune related grade (G) 3-5<br />
adverse events (AEs) were observed. Drug-related AEs (DRAEs) were all G1/2 events<br />
and occurred in 21 pts (67.7%). The most common DRAEs were fatigue (29.0%) and<br />
decreased appetite (9.7%). Out <strong>of</strong> 25 pts evaluable for response, 1 pt experienced partial<br />
response (PR, -50%, confirmed), and 15 pts experienced stable disease (SD). 11 pts<br />
remain on treatment, and 5 patients continued treatment for >13 weeks. Assessment <strong>of</strong><br />
peripheral blood lymphocyte indicated full OX40 receptor occupancy at ≥0.3 mg/kg,<br />
and maximal memory T cell proliferation at 0.1 and 0.3 mg/kg.<br />
Conclusions: These preliminary results demonstrate that PF-8600 is safe up to 3 mg/<br />
kg. Updated safety, antitumor activity, and biomarker data will be presented.<br />
Clinical trial identification: NCT02315066.<br />
Legal entity responsible for the study: Pfizer, Inc.<br />
Funding: Pfizer, Inc.<br />
Disclosure: A. Diab: Advisory board for Nektar Therapeutics. A. El-Khoueiry: Grants:<br />
NCI/NIH, CTEP, SWOG Consultant: Genentech, Bayer, Astra-Zeneca, Medimmune,<br />
Celgene, BMS, Transgene Speakers Bureau: Merrimack Contracted. Research: Pfizer,<br />
CeloNova, Novartis, AstraZeneca, BMS, Genentech, Pfizer, Astex, Daiichi Sankyo,<br />
Nektar, Exelixis, Chiltern. F.A. Eskens: Adboard for Baxalta, Merck, AMGEN. C.<br />
Konto: Pfizer’s employee and shareholder. C. Bermingham: I have Pfizer stock as part<br />
<strong>of</strong> my 401K. T. Joh: I am Pfizer employee, and stock owner. K. Liao: Currently, I am<br />
employed by Pfizer Inc. and own Pfizer stock. B. Ganguly: I am a Pfizer employee and<br />
that I own Pfizer stock. O. Hamid: Consulting: Amgen, Novartis, Roche, BMS. Speaker:<br />
Amgen, BMS, Genentech, Merck, Novartis. Contracted Research: Astra Zeneca, BMS,<br />
Celldex, Genentech, Immunocore, Incyte, Merck, Merck-Serano, MedImmune,<br />
Novartis, Pfizer, Rinat, Roche. All other authors have declared no conflicts <strong>of</strong> interest.<br />
1054PD<br />
Phase I/II CANON study: oncolytic immunotherapy for the<br />
treatment <strong>of</strong> non-muscle invasive bladder (NMIBC) cancer<br />
using intravesical coxsackievirus A21<br />
H.S. Pandha 1 , N. Annels 1 , M. Arif 1 , H. Mostafid 1 , S. Sandhu 2 , K. Harrington 3 ,<br />
A. Melcher 4 , D. Mansfield 3 ,G.Au 5 , M. Grose 5 , R. Karpathy 5 , D. Shafren 5<br />
1 Clinical and Experimental Medicine, University <strong>of</strong> Surrey, Guildford, UK, 2 Urology,<br />
Kingston Hospital, Kingston, UK, 3 Targeted Therapy, Institute <strong>of</strong> Cancer Research<br />
ICR, London, UK, 4 <strong>Oncology</strong> and Clinical Research, Leeds Institute <strong>of</strong> Cancer and<br />
Pathology, Leeds, UK, 5 Viralytics, Viralytics Limited, Sydney, Australia<br />
Background: CAVATAK® is a novel, bio-selected Intercellular Adhesion Molecule 1<br />
(ICAM-1) targeted immunotherapeutic Coxsackievirus A21 (CVA21). Surface ICAM-1<br />
is up-regulated on NMIBC. CVA21 displays potent oncolytic activity against in vitro<br />
cultures <strong>of</strong> NMIBC cancer cells and ex-vivo human bladder tumor. Combining CVA21<br />
with mitocycin C (MMC) synergistically enhances viral replication by increasing<br />
expression levels <strong>of</strong> ICAM-1.<br />
Methods: The CANON study investigated the tolerance <strong>of</strong> escalating intravesical (IV)<br />
doses <strong>of</strong> CVA21 in 16 first-line NMIBC cancer pts. Stage 1 Cohort 1 (n = 3) and Cohort<br />
2 (n = 3), pts received a single CVA21 administration at 1 x 10 8 and 3 x 10 8 TCID50,<br />
respectively. In Cohort 3 (n = 3), pts received 2 doses <strong>of</strong> CVA21 at 3 x 10 8 TCID50.<br />
Stage 2: Cohort 1 (n = 3), pts received a single CVA21 dose <strong>of</strong> 3 x 10 8 TCID50 and<br />
Cohort 2 (n = 3) with 2 doses <strong>of</strong> CVA21 at 3 x 10 8 TCID50, both in combination with<br />
MMC (10mg). Cystoscopy photography was performed before and after treatment (tx).<br />
IV tx was followed by TURBT surgery after 8-11 days, with tissues analysed for CVA21<br />
replication, apoptosis, evidence <strong>of</strong> viral-induced changes immune cell infiltrates<br />
(multi-spectral imaging) and immune checkpoint molecules.<br />
Results: Data indicate tolerance <strong>of</strong> IV CVA21 tx. Serial cystoscopy identified<br />
viral-induced surface haemorrhage and immune inflammation <strong>of</strong> the tumor<br />
micro-environment. Virus replication within tumor was highlighted by detection <strong>of</strong><br />
secondary viral load peaks in the urine. TURBT tissue analysis displayed marked<br />
tumor specific viral replication and evidence <strong>of</strong> viral-induced apoptotic cell death.<br />
NanoString analysis identified widespread increases in interferon (IFN), viral RNA and<br />
immune-checkpoint genes in CVA21-treated tissues compared to untreated historical<br />
controls.<br />
Conclusions: Clinical activity <strong>of</strong> CVA21 was demonstrated by evidence <strong>of</strong> complete<br />
tumor response, viral replication and notable signs <strong>of</strong> tumor inflammation. The<br />
observed up-regulation <strong>of</strong> IFN/immune checkpoint genes provides evidence for the<br />
generation <strong>of</strong> both strong local and systemic anti-tumor immune responses.<br />
Clinical trial identification: VLA-012<br />
Legal entity responsible for the study: Viralytics Ltd<br />
Funding: Viralytics Ltd<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1056PD<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Preventive dendritic cell vaccination in healthy Lynch<br />
syndrome mutation carriers<br />
H. Westdorp 1 , M.A.J. Gorris 2 , S. Boudewijns 1 , T. Bisseling 3 , A.L. de Goede 4 ,M.<br />
M. van Rossum 5 , M.J.L. Ligtenberg 6 , G. Schreibelt 2 , I.D. Nagtegaal 7 ,C.<br />
G. Figdor 2 , W. Gerritsen 8 , N. Hoogerbrugge 6 , I.J.M. de Vries 1<br />
1 Tumor Immunology and Medical <strong>Oncology</strong>, Radboud University Medical Centre<br />
Nijmegen, Nijmegen, Netherlands, 2 Tumor Immunology, Radboud University<br />
Medical Centre Nijmegen, Nijmegen, Netherlands, 3 Gastroenterology, Radboud<br />
University Medical Centre Nijmegen, Nijmegen, Netherlands, 4 Pharmacy,<br />
Radboud University Medical Centre Nijmegen, Nijmegen, Netherlands,<br />
5 Dermatology, Radboud University Medical Centre Nijmegen, Nijmegen,<br />
Netherlands, 6 Human Genetics, Radboud University Medical Centre Nijmegen,<br />
Nijmegen, Netherlands, 7 Pathology, Radboud University Medical Centre<br />
Nijmegen, Nijmegen, Netherlands, 8 Medical <strong>Oncology</strong>, Radboud University<br />
Medical Centre Nijmegen, Nijmegen, Netherlands<br />
Background: Lynch syndrome (LS) is an autosomal dominantly inherited syndrome<br />
caused by monoallelic germline aberrations affecting one <strong>of</strong> the DNA mismatch repair<br />
(MMR) genes. Defects in the DNA MMR pathway underlie the development <strong>of</strong><br />
microsatellite instability in LS-associated cancer. The cumulative risk <strong>of</strong> colorectal<br />
cancer varies between 10-80% and is strongly associated with the causative germline<br />
defect. MMR deficiency in tumor DNA causes shifts in the translational reading frame<br />
resulting in the production <strong>of</strong> altered peptides, called neopeptides. These are<br />
considered ‘foreign’ by the immune system. This was the rationale for a preventive<br />
neoantigen-based vaccination study with dendritic cells (DCs). DCs are the<br />
antigen-presenting cells <strong>of</strong> our immune system as a result <strong>of</strong> their naive T cell priming<br />
and T cell activation capabilities.<br />
Methods: We recruited HLA-A*02.01 positive patients known to be a germline<br />
MMR-gene mutation carrier without signs <strong>of</strong> LS-associated disease or more than<br />
5-years beyond detection <strong>of</strong> a non-metastasized LS-associated cancer. The primary<br />
endpoint was to investigate the safety and feasibility <strong>of</strong> DC vaccinations. Secondary<br />
objectives were to evaluate whether monocyte-derived peptide-loaded DC can induce<br />
an immune response to the selected neoantigens (caspase-5 and TGF-βRII) and the<br />
tumor-associated antigen carcinoembryonic antigen (CEA).<br />
Results: All patients (n = 20) were recruited within a year. DC vaccinations were on<br />
average well tolerated. No participants were hospitalized during study treatment. In all<br />
vaccinated mutation carriers flu-like symptoms occurred. In 17 <strong>of</strong> 20 patients an<br />
injection site reaction developed upon intradermal DC administration. One patient<br />
experienced grade 4 fever (>40 °C > 24 hours), as a result study treatment was<br />
discontinued. In all tested patients a cellular immune response against the control<br />
antigen was seen. Functional neoantigen- or CEA-specific T cells were shown in the<br />
challenged skin upon DC vaccination in 15 <strong>of</strong> 20 patients.<br />
Conclusions: Preventive DC vaccination is feasible and safe in LS mutation carriers<br />
and functional neoantigen- and CEA-specific immune responses were shown. This<br />
study opens perspectives for future immunotherapy trials with the intention <strong>of</strong> cancer<br />
prevention.<br />
Clinical trial identification: ClinicalTrials.gov NCT01885702<br />
Legal entity responsible for the study: N/A<br />
Funding: This work was supported by Grant 951.00.106 <strong>of</strong> the Netherlands<br />
Organization for Scientific Research (NWO), two Radboudumc Ph.D. grants and a<br />
Koningin Wilhelmina Onderzoeksprijs (KWO)-Grant KUN2009-4402 from the Dutch<br />
Cancer Society (KWF). CG Figdor is recipient <strong>of</strong> European Research Council (ERC)<br />
Advanced grant PATHFINDER (269019) and a NWO Spinoza grant. IJM de Vries is<br />
recipient <strong>of</strong> NWO Vici Grant 918.14.655.<br />
vi362 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Disclosure: W. Gerritsen: Consult for Aglaia Biomedical Ventures, Supervisory board<br />
for PsytoBe, Speakers fee from J&J and BMS, and Advisory boards for Amgen, BMS,<br />
Janssen-Cilag, San<strong>of</strong>i, Astellas, Bayer, and Merck. All other authors have declared no<br />
conflicts <strong>of</strong> interest.<br />
1057P<br />
Noninvasive PET imaging <strong>of</strong> the PD-1/PD-L1 checkpoint in<br />
naïve and irradiated tumor-bearing mice<br />
G. Niedermann, M. Hettich<br />
Department <strong>of</strong> Radiation <strong>Oncology</strong>, University Clinics Freiburg, Freiburg, Germany<br />
Background: There is increasing evidence that antibodies blocking the PD-1/PD-L1<br />
checkpoint (either anti-PD-1 or anti-PD-L1) increase in-field anti-tumor responses to<br />
ionizing radiation and enhance abscopal effects on non-irradiated metastases. Here, we<br />
developed PET tracers based on therapeutic antibodies to visualize whole-body<br />
expression <strong>of</strong> PD-1 and PD-L1 in mice and the biodistribution <strong>of</strong> the surrogate<br />
checkpoint-blocking antibodies.<br />
Methods: Two novel PET tracers were developed based on anti-PD-1 and anti-PD-L1<br />
checkpoint-blocking antibodies. Non-invasive PET imaging was performed on naïve<br />
and tumor-bearing mice. Mice bearing s.c. B16 melanomas were treated with<br />
hyp<strong>of</strong>ractionated radiation therapy (hRT) in combination with CTLA-4 checkpoint<br />
blockade before PET imaging. PD-1 or PD-L1 knockout mice and PD-L1-deficient B16<br />
cells generated using the CRISPR/Cas technology served as specificity controls.<br />
Results: The newly developed PET tracers allowed the highly specific and<br />
high-resolution imaging <strong>of</strong> PD-1 and PD-L1 expression. In addition, they permitted<br />
the noninvasive imaging <strong>of</strong> the biodistribution <strong>of</strong> the two therapeutic antibodies in<br />
both naïve and tumor-bearing mice treated with hRT and CTLA-4 checkpoint<br />
blockade. Imaging <strong>of</strong> the respective knockout mice, blocking experiments with an<br />
excess amount <strong>of</strong> unlabeled antibodies, and the analysis <strong>of</strong> animals bearing both<br />
wild-type B16 melanomas and PD-L1-CRISPR knockout melanomas demonstrated the<br />
high specificity <strong>of</strong> the two newly developed PET tracers. The in vivo imaging data were<br />
confirmed by ex vivo biodistribution analyses. The targets <strong>of</strong> the PET tracer antibodies<br />
were verified by ex vivo flow cytometric analyses. Visualization <strong>of</strong> immune-related<br />
adverse events was also possible.<br />
Conclusions: In conclusion, we have developed two innovative PET tracers that allow<br />
imaging the expression <strong>of</strong> the receptor/ligand pair <strong>of</strong> the important PD-1/PD-L1<br />
checkpoint and the biodistribution <strong>of</strong> surrogate checkpoint-blocking antibodies in fully<br />
immunocompetent mice. This technology also enables whole-body pictures <strong>of</strong><br />
combination radio/immunotherapies.<br />
Legal entity responsible for the study: Animal care committee Freiburg<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1058P<br />
MVX-ONCO-1 phase 1 final results <strong>of</strong> the first personalized<br />
cell-based immunotherapy using cell encapsulation<br />
technology<br />
N. Mach 1 , R. Vernet 1 , M-C. Belkouch 1 ,P.Luy 1 , V. Ancrenaz 1 , P. Teta 1 , N. Blazek 1 ,<br />
N. Grandjean 1 , J. Wasem 1 , J. Grogg 2 ,T.Perez 2 , D. Migliorini 1<br />
1 <strong>Oncology</strong>, Hôpitaux Universitaires de Genève - HUG, Geneva, Switzerland,<br />
2 Clinical Operation, MaxiVAX SA, Geneva, Switzerland<br />
Background: Cell Encapsulation Technology (CET) allows the standardized release <strong>of</strong><br />
GM-CSF by genetically modified allogeneic cells loaded within a capsule. We present<br />
the final results <strong>of</strong> the Phase I clinical trial assessing this patient specific, cell-based<br />
therapy, combining the implantation <strong>of</strong> irradiated autologous tumor cells and capsules<br />
containing allogeneic cells genetically engineered to produce huGM-CSF.<br />
Methods: For this single center, first in human Phase 1 trial, 15 pts with progressing,<br />
solid tumors refractory to all standard treatments were enrolled. Immunizations was<br />
performed in healthy skin, distant from tumor deposits. Patients were treated with 6 sc<br />
immunizations (week 1-2-3-4-6-8) combining 4x10 6 irradiated autologous tumor cells<br />
and 2 capsules containing 8x10 5 MVX-1 cells, producing >20ng/24h <strong>of</strong> huGM-CSF.<br />
Capsules were removed after 8 days and analyzed for huGM-CSF production. Primary<br />
endpoints are safety and feasibility. Secondary endpoints include clinical outcome and<br />
immunomonitroing.<br />
Results: 15 patients are available for safety and feasibility. Tt is very well tolerated with<br />
only one G3 AE related to IMP. Main toxicity is G1-2 minor discomfort during<br />
caspules sc implantation. No treatment related SAE were reported. Clinical grade<br />
therapeutic products were successfully manufactured for all patients. 95% % <strong>of</strong><br />
explanted macrocapsules showed good ex-vivo huGM-CSF production. >50% <strong>of</strong><br />
patients (8/15) experienced either PR or SD including disappearance <strong>of</strong> lung<br />
metastasis, prolong survival. Correlation between positive DTH and OS was observed.<br />
Immunomonitoring by Elispot shows increased INFg production by PBMC after<br />
immunization.<br />
Conclusions: MVX-ONCO-1 is the first personalized cell-based immunotherapy<br />
combining autologous tumor cells and sustained local production <strong>of</strong> GM-CSF at the<br />
vaccination site using cell encapsulation technology. This technology has a very good<br />
safety pr<strong>of</strong>ile safe with no systemic SAE related to therapy. In this heavily pretreated<br />
population, clinical activity (partial response and stable disease ) was observed in >50<br />
<strong>of</strong> patients.<br />
Clinical trial identification: NCT02193503<br />
Legal entity responsible for the study: Geneva University Hospital, Unité de<br />
recherche clinique de la Fondation Dr Henri Dubois-Ferrière Dinu Lipatti<br />
Funding: MaxiVAX<br />
Disclosure: N. Mach: I am the co-founder <strong>of</strong> MaxiVAX SA, I am the inventor <strong>of</strong><br />
MVX-ONCO-1 I am a minority shareholder <strong>of</strong> MaxiVAX SA. All other authors have<br />
declared no conflicts <strong>of</strong> interest.<br />
1059P<br />
abstracts<br />
Phase I study <strong>of</strong> nivolumab (nivo) + nab-paclitaxel (nab-P) in<br />
solid tumors: results from the pancreatic cancer (PC) and<br />
non-small cell lung cancer (NSCLC) cohorts<br />
B. George 1 , K. Kelly 2 ,A.Ko 3 , H. Soliman 4 , N. Trunova 5 , Z. Wainberg 6 ,<br />
D. Waterhouse 7 ,P.O’Dwyer 8 , H. Hochster 9<br />
1 Division <strong>of</strong> Hematology and <strong>Oncology</strong>, Froedtert and the Medical College <strong>of</strong><br />
Wisconsin, Milwaukee, WI, USA, 2 Internal Medicine, UC Davis Comprehensive<br />
Cancer Center, Sacramento, CA, USA, 3 Biostats, Celgene Corporation, Summit,<br />
NJ, USA, 4 Hematology, Women’s <strong>Oncology</strong> and Experimental Therapeutics and<br />
University <strong>of</strong> South Florida, M<strong>of</strong>fitt Cancer Center, Tampa, FL, USA, 5 Medical<br />
Affairs, Celgene Corporation, Summit, NJ, USA, 6 Internal Medicine, David Geffen<br />
School <strong>of</strong> Medicine at the University <strong>of</strong> California, Los Angeles, Los Angeles, CA,<br />
USA, 7 Medical <strong>Oncology</strong>, <strong>Oncology</strong> Hematology Care, Cincinnati, OH, USA,<br />
8 Medicine, University <strong>of</strong> Pennsylvania, Abramson Cancer Center, Philadelphia, PA,<br />
USA, 9 Medical <strong>Oncology</strong>, Yale Cancer Center, New Haven, CT, USA<br />
Background: Combining a taxane with an immune checkpoint inhibitor has<br />
demonstrated improved response across multiple tumors. Here we present interim<br />
results from the PC and NSCLC cohorts <strong>of</strong> a phase I safety trial <strong>of</strong> nivo + nab-P in<br />
advanced NSCLC (+ carboplatin [C]), advanced PC (± gemcitabine [G]), and<br />
metastatic breast cancer.<br />
Methods: The primary objective <strong>of</strong> part 1 is to evaluate dose-limiting toxicities (DLTs).<br />
Patients (pts) treated with ≥ 2 cycles <strong>of</strong> nivo with chemotherapy (CT) and remained on<br />
study for 14 calendar days or who discontinued due to DLT prior to completing 2<br />
cycles <strong>of</strong> nivo were considered DLT evaluable. If deemed safe, treatment arms will be<br />
expanded in Part 2 to further assess safety, tolerability, and antitumor activity. In Arm<br />
A Part 1, pts with advanced PC and 1 prior chemotherapy (CT) regimen received<br />
nab-P 125 mg/m 2 on D 1, 8, and 15 (qw 3/4) + nivo 3 mg/kg on D 1 and 15 <strong>of</strong> a 28-day<br />
cycle. If Arm A is safe, a cohort <strong>of</strong> CT-naive pts will be enrolled in Arm B and treated<br />
with nab-P + G 1000 mg/m 2 qw 3/4 + nivo. In Arm C, treatment-naive pts with stage<br />
IIIB/IV NSCLC received 4 cycles <strong>of</strong> nab-P 100 mg/m 2 on D 1, 8, and 15 + C AUC 6 on<br />
D 1 + nivo 5 mg/kg on D 15 <strong>of</strong> a 21-day cycle. If Arm C is safe, pts in Arm D will<br />
receive the Arm C regimen, except nivo will start at cycle 3. In both NSCLC arms, nivo<br />
monotherapy begins at cycle 5.<br />
Results: As <strong>of</strong> Apr 21, 2016, 11 and 20 pts have been treated in Arms A and C. In Arm<br />
A, at the time <strong>of</strong> DLT evaluation (Dec 21, 2015), no DLTs were observed, and no grade<br />
3/4 adverse events (AEs) occurred in > 1 pt. Of the 8 response evaluable pts, 2 achieved<br />
a partial response (PR). In Arm C, no DLTs were observed at the time <strong>of</strong> DLT<br />
evaluation (Nov 9, 2015). Of the 14 nivo-treated, response evaluable pts in Arm C, 7<br />
had a PR, and 7 had stable disease. Grade 2 pneumonitis was reported in 1 pt but<br />
resolved, and the pt continued on the study. The most common any-grade AEs in<br />
either arm were fatigue, nausea, and alopecia.<br />
Conclusions: Addition <strong>of</strong> nivo to nab-P or nab-P/C was tolerable with no DLTs or<br />
unexpected AEs in Arms A or C. Efficacy data in Arm C, although preliminary and<br />
unconfirmed, is encouraging. Arm B is currently enrolling pts with advanced PC for<br />
first-line treatment with nivo + nab-P + G.<br />
Clinical trial identification: NCT02309177<br />
Legal entity responsible for the study: Ben George, MD<br />
Funding: Celgene Corporation<br />
Disclosure: B. George: Consultant to Celgene Corporation. A. Ko, N. Trunova:<br />
Employee <strong>of</strong> Celgene Corporation. H. Soliman: Advisory role, Celgene. D. Waterhouse:<br />
Consultant or advisory role, BMS and Eli Lilly, speakers bureau, BMS, Celgene, Eli<br />
Lilly, Genentech/Roche. P. O’Dwyer: consultant: Five Prime Therapeutics; Genentech<br />
research funding: BBI Healthcare; Bristol-Myers Squibb; Celgene; Genentech;<br />
GlaxoSmithKline; Mirati Therapeutics; Novartis; Pfizer; stock: TetraLogic; expert<br />
testimony: Lilly. H. Hochster: consultant: Bayer HealthCare Pharmaceuticals,<br />
Boehringer Ingelheim, Genentech, Amgen, Sirtex Medical, Bristol-Myers Squibb;<br />
speakers bureau: Genomic Health. All other authors have declared no conflicts <strong>of</strong><br />
interest.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw378 | vi363
abstracts<br />
1060P<br />
Prevalence <strong>of</strong> PD-L1 expression in patients with non-small<br />
cell lung cancer screened for enrollment in KEYNOTE-001,<br />
-010, and -024<br />
C. Aggarwal 1 , D. Rodriguez Abreu 2 , E. Felip 3 , E. Carcereny 4 , M. Gottfried 5 ,<br />
T. Wehler 6 , M-J. Ahn 7 , M. Dolled-Filhart 8 , J. Zhang 8 , Y. Shentu 8 , R. Rangwala 8 ,<br />
B. Piperdi 8 , P. Baas 9<br />
1 Medicine, University <strong>of</strong> Pennsylvania-Perelman Center for Advanced Medicine,<br />
Philadelphia, PA, USA, 2 Medcal <strong>Oncology</strong> service, Hospital Universitario Insular de<br />
Gran Canaria, Las Palmas, Spain, 3 Medical <strong>Oncology</strong>, Vall d’Hebron University<br />
Hospital Institut d’Oncologia, Barcelona, Spain, 4 <strong>Oncology</strong>, Catalan Institute <strong>of</strong><br />
<strong>Oncology</strong> (ICO Badalona), Hospital Germans Trias i Pujol, Badalona, Spain,<br />
5 <strong>Oncology</strong>, Meir Medical Center, Kfar Saba, Israel, 6 <strong>Oncology</strong>, Universitätsmedizin<br />
Mainz, Mainz, Germany, 7 Medical <strong>Oncology</strong>, Samsung Medical Center<br />
Sungkyunkwan University School <strong>of</strong> Medicine, Seoul, Republic <strong>of</strong> Korea, 8 Medical<br />
<strong>Oncology</strong>, Merck & Co., Inc., Kenilworth, NJ, USA, 9 Thoracic <strong>Oncology</strong>, The<br />
Netherlands Cancer Institute, Amsterdam, Netherlands<br />
Background: The anti–PD-1 humanized monoclonal antibody pembrolizumab has<br />
recently been approved in the United States to treat metastatic non–small cell lung<br />
cancer (NSCLC) in patients (pts) who are PD-L1 positive and have progressed on<br />
platinum therapy and an EGFR/ALK inhibitor if EGFR/ALK positive. Here, we report<br />
on the prevalence <strong>of</strong> PD-L1 expression in pts screened for enrollment in 3 global<br />
clinical trials that investigated the efficacy and safety <strong>of</strong> pembrolizumab in pts with<br />
advanced NSCLC: KEYNOTE-001 (NCT01295827), KEYNOTE-010 (NCT01905657),<br />
and KEYNOTE-024 (NCT02142738).<br />
Methods: All 3 studies required provision <strong>of</strong> a tumor sample (archival or newly<br />
obtained) for PD-L1 testing as an entry criterion. PD-L1 expression was determined<br />
using the companion diagnostic PD-L1 IHC 22C3 pharmDx assay. PD-L1 expression<br />
was determined based on percentage <strong>of</strong> tumor cells with positive membranous staining<br />
and was reported as the tumor proportion score (TPS).<br />
Results: A total <strong>of</strong> 5879 pts were screened for eligibility in KEYNOTE-001 (n = 1242),<br />
KEYNOTE-010 (n = 2699), and KEYNOTE-024 (n = 1938). Of these, 4784 (81%) were<br />
evaluable for PD-L1; 1596 (33%) had TPS
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
Methods: Pts with mRCC were randomized to intravenous (IV) nivo 3 mg/kg + ipi 1<br />
mg/kg (nivo3 + ipi1), nivo 1 mg/kg + ipi 3 mg/kg (nivo1 + ipi3), or nivo 3 mg/kg + ipi<br />
3 mg/kg (nivo3 + ipi3) every 3 weeks for 4 doses, followed by nivo3 IV every 2 weeks<br />
until progression or toxicity. Key endpoints included safety, objective response rate<br />
(ORR), duration <strong>of</strong> response (DOR), OS, and progression-free survival (PFS).<br />
Results: Both the nivo3 + ipi1 and nivo1 + ipi3 arms enrolled 47 pts, with median<br />
follow-up <strong>of</strong> 22 (range, 1–34) months (nivo3 + ipi3 arm [n = 6] discontinued due to<br />
toxicity). Baseline pt characteristics were generally balanced between the arms. Prior<br />
systemic therapy was administered in 47% and 55% in nivo3 + ipi1 and nivo1 + ipi3<br />
arms, respectively. Grade 3–4 treatment-related adverse events (TRAEs) were reported<br />
in 38% (nivo3 + ipi1) and 62% (nivo1 + ipi3) <strong>of</strong> patients; <strong>of</strong> these, the most common<br />
were ↑ lipase (15% vs 28%), ↑ ALT (4% vs 21%), diarrhea (4% vs 15%), ↑ AST (4% vs<br />
13%), and colitis (0% vs 15%). The most common grade 3–4 select TRAEs were<br />
gastrointestinal (4% vs 23%) and hepatic (6% vs 21%). Efficacy is summarized in the<br />
table.<br />
Conclusions: Almost 2 years <strong>of</strong> follow-up <strong>of</strong> patients with mRCC treated with<br />
nivo + ipi shows manageable safety as observed previously, high ORR and durable<br />
responses with promising OS. Ipi showed dose-related toxicity, which further supports<br />
development <strong>of</strong> nivo3 + ipi1 in the first-line setting.<br />
Table: 1062P<br />
Nivo3 + ipi1<br />
Nivo1 + ipi3<br />
n=47 n=47<br />
ORR, n (%) 19 (40) 19 (40)<br />
Median DOR, mos (range) 20.4 (2.1–32.2+) 19.7 (2.8 + –31.7+)<br />
Stable disease, n (%) 19 (40) 17 (36)<br />
Progressive disease, n (%) 8 (17) 8 (17)<br />
Median OS, mos (range) Not reached (3.5–34.5+) 32.6 (1.1–34.3+)<br />
Median PFS, mos (range) 6.6 (1.1 + –33.7+) 9.1 (1.0–33.1+)<br />
+= censored<br />
Clinical trial identification: NCT01472081<br />
Legal entity responsible for the study: Bristol-Myers Squibb<br />
Funding: Bristol-Myers Squibb<br />
Disclosure: H. Hammers: Consulting/Advisory: BMS, Exelixis, Pfizer, Cerulean<br />
Research Funding: SFJ, BMS, Exelixis, Newlink, Pfizer, GSK, Tracon. E.R. Plimack:<br />
Consulting/Advisory: Merck, Dendreon, Novartis, BMS, Pfizer, GSK, Acceleron<br />
Pharma, Genentech/Roche Research Funding: Merck, BMS, GSK, Acceleron Pharma,<br />
Dendreon, Lilly, AZ Patents: U.S. Patent No.: 14/588.503 Filed 1/2/2015. B.I. Rini:<br />
Consulting/Advisory: Pfizer, Novartis, Acceleron Research Funding: Pfizer, BMS,<br />
Peleton Travel: Pfizer. D. McDermott: Consulting/Advisory: BMS, Merck, Genentech,<br />
Novartis, Pfizer, Eisai, Exelixis Research Funding: Prometheus Labs. M.H. Voss:<br />
Honoraria: Novartis Consulting/Advisory: Novartis, GSK, Exelixis, Natera, Calithera<br />
Research Funding: BMS Travel/Accomodations: Takeda, Novartis. P. Sharma:<br />
compensation/leadership role and stock with Kite, Jounce, Evelo, and Neon.<br />
Consultant role with GSK. Amgen, BMS, and AZ. Own patient licensed to Jounce and<br />
patients licensed to BMS, Jounce Merck. Research as principal investigator for BMS,<br />
GSK, and AZ. S.K. Pal: Honoraria from Novartis, Medivation and Astellas Pharma<br />
Receives consulting fees from Pfizer, Novartis, Aveo, Genentech, Exelixis, BMS,<br />
Astellas and GSK. C.K. Kollmannsberger: Honoraria: Pfizer, Novartis, BMS,<br />
Participated in national or international advisory boards for Pfizer, Novartis, BMS,<br />
San<strong>of</strong>i, Astellas, Lilly. D. Heng: My conflicts are consultant/advisory role to BMS Pfizer<br />
Novartis. J. Spratlin: Honoraria: Lilly and Celgene Consulting/Advisory: Lilly and<br />
Celgene Research Funding: Celgene and San<strong>of</strong>i and Roche. B. McHenry: Employment:<br />
BMS Stock: BMS Research: BMS. P. Gagnier: Employment: BMS Stock: BMS Research:<br />
BMS Travel: BMS. A. Amin: Consulting/Advisory: BMS, Merck Speakers’ Bureau:<br />
BMS, Merck, Pfizer Research Funding: BMS, Merck, Prometheus, Argos. All other<br />
authors have declared no conflicts <strong>of</strong> interest.<br />
1063P<br />
Anti-PD1 therapy effects on T cell repertoire and functions in<br />
patients with NSCLC cancer: a preliminary study to identify<br />
biomarkers <strong>of</strong> efficacy<br />
G. Barra 1 , G. Pasquale 1 , C.M. Della Corte 2 , F. Papaccio 2 , M. Orditura 2 , F. DeVita 2 ,<br />
F. Ciardiello 2 , R. De Palma 1 , F. Morgillo 2<br />
1 Clinical Immunology, AOU Seconda Università degli Studi di Napoli (AOU-SUN),<br />
Naples, Italy, 2 Medical <strong>Oncology</strong>, AOU Seconda Università degli Studi di Napoli<br />
(AOU-SUN), Naples, Italy<br />
Methods: We used PBMC to study T cell repertoire by a PCR based technique<br />
discriminating clonotype length and nucleotide sequences, and cytokine production.<br />
RNA and cDNA were prepared from PBMC <strong>of</strong> patients, and the different families <strong>of</strong> T<br />
cell receptors were amplified and sequenced with specific primers. The message for<br />
γ-IFN, IL-2, IL-4, IL-12, IL-13 and IL-17 was studied by Quantitative PCR. Presence <strong>of</strong><br />
cytokine message was confirmed measuring the protein in the serum. Each patient was<br />
studied at the end <strong>of</strong> chemotherapy and after each anti-PD1 shot.<br />
Results: We found that chemotherapy shaped a specific T cell repertoire in these<br />
patients, expanding several T cell clonotypes. Importantly, the T cell clonotypes<br />
expanded upon chemotherapy were <strong>of</strong>ten maintained by anti-PD1 administration<br />
undergoing a long-lasting expansion. Production <strong>of</strong> cytokines was fluctuating during<br />
therapy with anti-PD1 and we observed a subversion <strong>of</strong> cytokine pr<strong>of</strong>ile. To note, a<br />
prolonged effect in term <strong>of</strong> clinical outcome was paired with a consolidated production<br />
<strong>of</strong> IL-12 and γ-IFN.<br />
Conclusions: These data show that chemotherapy reshapes a specific T cell repertoire<br />
possibly involved in antitumor response, and the functional pr<strong>of</strong>ile <strong>of</strong> these cells<br />
marked a prolonged efficient anti-tumor T cell response. Although these are<br />
preliminary data, these results pave the ground to better understand how to study and<br />
monitor the patients undergoing therapy with anti immune checkpoints. This is <strong>of</strong><br />
critical importance due to the need to identify biomarkers and monitoring tools to<br />
optimize the use <strong>of</strong> these drugs, also in light <strong>of</strong> the high costs <strong>of</strong> these therapies.<br />
Legal entity responsible for the study: Dept. <strong>of</strong> Clinical & Experimental Medicine,<br />
Second University <strong>of</strong> Naples<br />
Funding: Dept. <strong>of</strong> Clinical & Experimental Medicine, Second University <strong>of</strong> Naples<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1064P<br />
Gamma-delta T cell CARs; a combinatorial approach to<br />
immunotherapy<br />
M.D. Leek, A. Patakas, A. Hannigan, D. Paruzina<br />
Clinical Research, TC BioPharm, Edinburgh, UK<br />
Background: The ability <strong>of</strong> Vγ9+ γδ T cells to target cancer cells via recognition <strong>of</strong><br />
phosphoantigens has resulted in treatments such as ImmuniCell®, which is currently<br />
being evaluated in an adaptive phase II/III study. In addition, we have developed γδ T<br />
cells expressing chimeric antigen receptors (CARs) to maximise the therapeutic<br />
potential <strong>of</strong> both γδ T cell and CAR-T therapy. We rationally designed a CAR<br />
construct that takes advantage <strong>of</strong> the defined antigen specificity <strong>of</strong> Vγ9+ γδ T cells<br />
resulting in a potential cellular therapy with enhanced effector functions whilst<br />
minimising ‘on-target, <strong>of</strong>f-tumour’ side effects.<br />
Methods: A CD19 targeting CAR was designed comprising costimulatory domains<br />
from CD28 and CD137 (‘signal-2’). This design was tested against a classical CAR,<br />
comprising the aforementioned costimulatory domains plus a ‘signal-1’ providing<br />
CD3ζ activation domain. Vγ9+ γδ T cells from healthy individuals were expanded in<br />
culture, and CAR expression achieved by lentiviral transduction. Ability <strong>of</strong> transduced<br />
γδ Τ cells to target CD19 + cancer cell lines, RAMOS and DAUDI, was assessed using a<br />
flow cytometry based cytotoxicity assay.<br />
Results: γδ T cells were successfully transduced with both CAR constructs, these were<br />
discriminated by qPCR using two primer sets. γδ Τ cells transduced with either<br />
construct exhibited increased cytotoxicity against the CD19+ DAUDI and RAMOS<br />
target cells. Strikingly, a 3-fold increase in cytotoxicity was measured against RAMOS<br />
cells, which usually display low sensitivity to unmodified γδ Τ cell-mediated killing.<br />
Conclusions: We have demonstrated a novel γδ specific CAR design that does not<br />
require incorporation <strong>of</strong> a CD3ζ signalling domain to elicit effector function. ‘Signal 1’<br />
is provided by the γδ T cell receptor (TCR) resulting in a TCR-tuneable CAR construct.<br />
As healthy cells do not accumulate phosphoantigens, this CAR design should only<br />
elicit effector function against cancer cells, reducing ‘on-target, <strong>of</strong>f tumour’ side effects<br />
– a major safety concern. Moreover, CAR expressing γδ Τ cells may result in a potent<br />
targeted treatment, as both phosphoantigens and the CAR target contribute to<br />
identification and killing <strong>of</strong> cancerous cells in vivo.<br />
Legal entity responsible for the study: TC BioPharm Limited<br />
Funding: TC BioPharm Limited<br />
Disclosure: M.D. Leek: Founder and employee <strong>of</strong> the presenting institution - TC<br />
BioPharm. A. Patakas, A. Hannigan, D. Paruzina: Employee <strong>of</strong> the institution<br />
submitting this abstract.<br />
Background: Immune responses have a pivotal role in protecting against tumors, since<br />
conventional chemotherapy may effectively treat cancer but its efficacy is compromised<br />
by tumor relapse. Chemotherapy “per se” can have immunostimulatory effects, and the<br />
ability to sustain an antitumor T cell response activate host immunity and prevent<br />
tumor re-growth. Anti-PD1 antibodies may be used in clinics to boost immune<br />
responses through the blocking <strong>of</strong> an inhibitor receptor on T cells. Here, we evaluate<br />
the T cell repertoire and cytokines in five NSCLC patients who underwent anti-PD1<br />
therapy after chemotherapy.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw378 | vi365
abstracts<br />
1065P<br />
T cell responses in the microenvironment <strong>of</strong> primary renal<br />
cell carcinoma<br />
R. Andersen 1 , M.C.W. Westergaard 2 , J.W. Kjeldsen 2 , Ö. Met 1 ,<br />
B. Kromann-Andersen 3 , T. Hasselager 4 , M. Donia 1 , I.M. Svane 1<br />
1 Department <strong>of</strong> Hematology and Department <strong>of</strong> <strong>Oncology</strong>, Center for Cancer<br />
Immune Therapy, Herlev University Hospital, Herlev, Denmark, 2 Department <strong>of</strong><br />
Hematology, Center for Cancer Immune Therapy, Herlev University Hospital,<br />
Herlev, Denmark, 3 Department <strong>of</strong> Urology, Herlev University Hospital, Herlev,<br />
Denmark, 4 Department <strong>of</strong> Pathology, Herlev University Hospital, Herlev, Denmark<br />
Background: Adoptive cell therapy (ACT) with tumor infiltrating lymphocytes (TILs)<br />
is based on the infusion <strong>of</strong> T cells isolated and expanded from tumor lesions <strong>of</strong> the<br />
individual patients. This treatment can induce unprecedented rates <strong>of</strong> durable complete<br />
responses in metastatic melanoma. The aim <strong>of</strong> this study was to characterize TILs from<br />
primary renal cell carcinoma (RCC), in order to initiate a clinical trial testing TIL<br />
therapy for patients with RCC. Preliminary data on TIL expansion were previously<br />
presented at ESMO Symposium on Immuno-<strong>Oncology</strong> 2015 (1). Here, final results <strong>of</strong><br />
expansion, functional characterization and comparison with T cell responses in<br />
melanoma are presented.<br />
Methods: Primary tumor lesions from 25 patients with RCC scheduled for radical or<br />
partial nephrectomy were collected. TIL were isolated and expanded from tumor<br />
fragments with standard methods derived from clinical trials <strong>of</strong> melanoma. Autologous<br />
tumor cell lines were established from the same lesions and used as killing-targets for<br />
TILs.<br />
Results: TIL cultures from primary RCC were successfully generated and expanded to<br />
clinical numbers from 23 <strong>of</strong> 25 (92%) samples. Expanded TILs showed phenotypic<br />
characteristics similar to melanoma, with >95% T cells and a considerably variable<br />
CD4/CD8 ratio. CD8 + T cell responses against autologous tumor cell lines were<br />
detected in 11 <strong>of</strong> 15 RCC patients (73%) where an autologous RCC cell line was<br />
available. Tumoricidal capacity was confirmed with cytotoxicity assays. However, both<br />
frequency and magnitude <strong>of</strong> CD8 + T cell responses were significantly higher in<br />
melanoma. Multidimensional characterization <strong>of</strong> three types <strong>of</strong> functional T cell<br />
responses revealed a unique pattern <strong>of</strong> anti-tumor reactivity <strong>of</strong> RCC-TIL compared to<br />
melanoma.<br />
Conclusions: TILs from RCC specimens can be isolated and expanded to clinical<br />
numbers. Tumor-recognition in vitro can be demonstrated for the majority <strong>of</strong> samples.<br />
However, immune responses <strong>of</strong> expanded CD8 + TILs from RCC are on average weaker<br />
than in melanoma and display a unique functional pattern, typical <strong>of</strong> heavily exhausted<br />
immune cells. 1) Andersen R. et al. Preclinical development <strong>of</strong> adoptive cell therapy<br />
with tumor-infiltrating lymphocytes for patients with renal cell carcinoma. <strong>Annals</strong> <strong>of</strong><br />
<strong>Oncology</strong> (2015) 26 (suppl_8): 5-14.<br />
Legal entity responsible for the study: Herlev Hospital<br />
Funding: Herlev Hospital<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1066P<br />
Rapid and objective CT-scan prognostic scoring identifies<br />
patients with long-term clinical benefit on phase I trials<br />
L. Dercle 1 , S. Ammari 1 , S. Champiat 1 , C. Massard 2 , C. Ferte 3 , M. Texier 3 ,<br />
E. Lanoy 2 , L. Taihi 3 , R-D. Seban 3 , S. Aspeslagh 4 , S. Antoun 4 , L. Mahjoubi 4 ,<br />
N. Kamsu-Kom 4 , C. Robert 4 , A. Marabelle 4 , M. Schlumberger 5 , J-C. Soria 4 ,<br />
S. Postel-Vinay 4<br />
1 Nuclear Medicine, Institut de Cancérologie Gustave Roussy, Villejuif, France,<br />
2 Drug Development Department, Institut Gustave Roussy, Villejuif, France,<br />
3 Département de Médecine Oncologique, Institut Gustave Roussy, Villejuif, France,<br />
4 Drug Development Department (DITEP), Institut Gustave Roussy, Villejuif, France,<br />
5 Nuclear Endocrinology, Institut Gustave Roussy, Villejuif, France<br />
Background: Drugs targeting programmed death receptor-1 and its ligand PD-L1<br />
(aPD(L)1) have shown activity in multiple malignancies. Considering their novel<br />
mechanism <strong>of</strong> action, whether traditional prognostic scores also apply to patients<br />
receiving aPD(L)1 is unknown. We investigated whether a baseline 3-points (pts)<br />
CT-scan (PS3-CT) score and a 7-pts prognostic score (PS7) allowed identifying<br />
long-term survivors on aPD(L)1 as compared to molecularly targeted agents (MTA).<br />
Methods: We reviewed all consecutive patients enrolled in phase I (PhI) trials<br />
evaluating aPD(L)1 between 12/2011 and 07/2015, and in PhI trials evaluating MTA<br />
between 03/2008 and 07/2012. PS3-CT was calculated using high tumor burden<br />
(TB > 9 cm), low-skeletal muscle index (SMI< 53 cm2.m-2) and non-pulmonary<br />
visceral metastases (NPVM) (1 pt each). PS7 was calculated by adding performance<br />
status >1, low albumin, high LDH and >2 metastases (1 pt. each). Effect on overall<br />
survival (OS) <strong>of</strong> each parameter was tested using Kaplan Meier and Multivariate Cox<br />
analyses.<br />
Results: 461 patients (251 receiving aPD(L)1 and 210 receiving MTA) were included.<br />
Patients characteristics were comparable in both groups, excepted for melanoma<br />
patients (40% and 5% <strong>of</strong> the patients in the aPD(L)1 and MTA groups, respectively).<br />
PS3-CT was a significant independent predictor <strong>of</strong> OS in the aPD(L)1 (HR = 1.39 [95%<br />
CI = 1.07-1.81]; p = 0.01) and MTA (HR = 1.35 [95%CI = 1.08-1.68]; p = 0.01) groups,<br />
when compared to the Royal Marsden Hospital, Barbot and AJCC scores. High-TB and<br />
low-SMI were independent predictors <strong>of</strong> OS (HR = 2.00 [95%CI = 1.38-2.88], p < 10-5;<br />
and HR = 1.75 [95% CI = 1.15-2.66]; p < 10-2, respectively) in the aPD(L)1 group; in<br />
the MTA group, high-TB only was an independent predictor <strong>of</strong> OS (HR = 1.61 [95%<br />
CI = 1.15-2.25]; p < 10-2). PS7 was a significant predictor <strong>of</strong> OS in the aPD(L)1 group<br />
(HR = 1.40 [95%CI = 1.25-1.56]; p < 10-5)) and in the MTA group (HR = 1.39 [95%<br />
CI = 1.25-1.54]; p < 10-5)).<br />
Conclusions: Objective and rapid risk scoring based on three CT-scan parameters<br />
allows identifying patients with prolonged OS on anti-PD(L)1 and MTA PhI trials,<br />
independently from conventional clinico-biological prognostic scores.<br />
Legal entity responsible for the study: N/A<br />
Funding: None<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1067P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Phase 1b/2, open-label, multicenter, dose escalation and<br />
expansion trial <strong>of</strong> intratumoral SD 101 in combination with<br />
pembrolizumab in patients with metastatic melanoma<br />
A. Ribas 1 , R. Gonzalez 2 , J. Drabick 3 , S. Kummar 4 , S. Agarwala 5 , J. Nemunaitis 6 ,<br />
R. C<strong>of</strong>fman 7 , C.J. Berman 8 , E. Schmidt 9 , E. Chartash 10 , C. Guiducci 7 ,<br />
A. Candia 11 , R. Janssen 12<br />
1 Medicine, David Geffen School <strong>of</strong> Medicine at UCLA, Los Angeles, Ca, CA, USA,<br />
2 Medicine/Medical <strong>Oncology</strong>, University <strong>of</strong> Colorado Cancer Center Anschutz<br />
Cancer Pavilion, Aurora, CO, USA, 3 Medical <strong>Oncology</strong>, Penn State Hershey<br />
Medical Center, Hershey, PA, USA, 4 Phase I Clinical Research, Division <strong>of</strong><br />
<strong>Oncology</strong>, Stanford University, Palo Alto, CA, USA, 5 Medical <strong>Oncology</strong>, St Lukes,<br />
Easton, PA, USA, 6 <strong>Oncology</strong>, Mary Crowley Cancer Research Center, Dallas, TX,<br />
USA, 7 Discovery, Dynavax Technologies, Berkeley, CA, USA, 8 Clinical Research,<br />
Dynavax Technologies, Berkeley, CA, USA, 9 Clinical, Merck Co, Kenilworth, NJ,<br />
USA, 10 Clinical Development, Merck, Kenilworth, NJ, USA, 11 Preclinical<br />
Development, Dynavax Technologies, Berkeley, CA, USA, 12 Clinical Research,<br />
Dynavax, Berkeley, CA, USA<br />
Background: SD-101 is a synthetic Class C CpG-ODN that stimulates plasmacytoid<br />
dendritic cells to release interferon-alpha and mature into efficient antigen presenting<br />
cells. SD-101 in combination with low dose radiation has demonstrated abscopal<br />
activity in indolent B-cell lymphoma (Levy et al AACR 2016). Pre-clinically, in a CT26<br />
mouse model, SD-101 in combination with an anti-PD-1 induced T cell infiltration<br />
and durable complete responses in all treated animals (Campos et al, AACR 2016).<br />
Pembrolizumab is a PD-1 inhibitor that has been approved for the treatment <strong>of</strong><br />
metastatic melanoma.<br />
Methods: The MEL-01 trial (NCT02521870) is assessing the safety and preliminary<br />
efficacy <strong>of</strong> SD-101 + pembrolizumab in unresectable stage IIIC-IV melanoma. Phase 1b<br />
is a modified 3 + 3 design <strong>of</strong> 3 dose levels <strong>of</strong> SD-101 (2, 4, and 8 mg) followed by a<br />
phase 2 dose expansion (n = 85). SD-101 is injected into a tumor lesion weekly X 4<br />
followed by q 3 weekly X 3. Pembrolizumab dose is 200 mg IV q 3 weeks. Biopsies <strong>of</strong><br />
the injected tumor are taken pretreatment and on treatment. Tumor responses are<br />
assessed using RECIST v1.1.<br />
Results: In the phase 1b study, 5 patients were enrolled in the 2 mg group and 5 in the<br />
4 mg group. Treatment was well tolerated; there were no DLTs. Adverse events<br />
associated with SD-101 were flu-like symptoms the evening following an injection that<br />
were treated with over-the-counter medications. No increased toxicity <strong>of</strong> the<br />
combination <strong>of</strong> drugs has been observed. At 12 weeks, in the 2 mg group, there were 2<br />
PRs, 1 SD, 1 PD (at day 22) and 1 not yet available. One <strong>of</strong> the patients with a PR had a<br />
tumor biopsy that was negative for melanoma. Five patients were enrolled in late April<br />
2016 in the 4 mg cohort; response data will be available by October. Additionally,<br />
mechanistic insight into therapeutic activity obtained through examination <strong>of</strong> tumor<br />
biopsies by IHC, PD-L1 expression, and NanoString RNA expression pr<strong>of</strong>iling will be<br />
presented.<br />
Conclusions: Preliminary results suggest that the combination <strong>of</strong><br />
SD-101 + pembrolizumab shows activity in metastatic melanoma.<br />
Clinical trial identification: Clinical trials.gov NCT02521870; Date <strong>of</strong> initial posting:<br />
30 July 2015<br />
Legal entity responsible for the study: Dynavax Technologies, Berkeley, California<br />
Funding: Dynavax Technologies, Berkeley, California and Merck and Company, Inc,<br />
Kenilworth, New Jersey<br />
Disclosure: A. Ribas: Consultant to Merck with honoraria paid to UCLA. R. Gonzalez:<br />
Receiving grants and consulting for MERCK, BMS, Novartis, Amgen, Roche/<br />
Genentech. J. Drabick: Consultant at Merck and Novartis. J. Nemunaitis: Founder <strong>of</strong><br />
two companies, Gradalis and Strike which are not related to this research R. C<strong>of</strong>fman:<br />
Full time employee <strong>of</strong> Dynavax. C.J. Berman: Paid consultant for Dynavax<br />
Technologies. E. Schmidt: Full time employee <strong>of</strong> Merck. E. Chartash: Employee <strong>of</strong><br />
Merck. C. Guiducci, A. Candia, R. Janssen: Employee <strong>of</strong> Dynavax. All other authors<br />
have declared no conflicts <strong>of</strong> interest.<br />
vi366 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
1068P<br />
Adenosine A2A receptor antagonist, CPI-444, blocks<br />
adenosine-mediated T cell suppression and exhibits<br />
anti-tumor activity alone and in combination with anti-PD-1<br />
and anti-PD-L1<br />
S. Willingham 1 ,P.Ho 1 , R. Leone 2 , C. Choy 1 , J. Powell 2 , I. McCaffery 1 , R. Miller 3<br />
1 Translational Sciences, Corvus Pharmaceuticals, Burlingame, CA, USA,<br />
2 Department <strong>of</strong> <strong>Oncology</strong>, Johns Hopkins University, Baltimore, MD, USA,<br />
3 Clinical Development, Corvus Pharmaceuticals, Burlingame, CA, USA<br />
Background: Elevated extracellular adenosine in the tumor microenvironment<br />
generates an immunosuppressive niche that promotes tumor growth and metastasis.<br />
Adenosine signaling via A2A receptor (A2AR) on immune cells suppresses anti-tumor<br />
immunity and may also limit efficacy <strong>of</strong> immunotherapies such as anti-PD-L1 and<br />
anti-PD-1 antibodies.<br />
Methods: CPI-444 is a potent, oral, selective A2AR antagonist that has been well<br />
tolerated in Ph 1 and 2 studies in non-oncology indications. The efficacy <strong>of</strong><br />
CPI-444 ± Anti-PD-L1 or Anti-PD-1 was evaluated in MC38 and CT26 syngeneic<br />
mouse tumor models.<br />
Results: In MC38, daily treatment <strong>of</strong> mice with CPI-444 (1, 10, 100 mg/kg) led to<br />
dose-dependent inhibition <strong>of</strong> tumor growth, leading to tumor elimination in 9/30<br />
mice. Combining CPI-444 with anti-PD-L1 treatment in MC38 synergistically<br />
inhibited tumor growth and eliminated tumors in 90% <strong>of</strong> treated mice. In an additional<br />
model, CT26, CPI-444 alone or anti-PD-1 alone led to non-significant reductions in<br />
tumor growth; however, the combination <strong>of</strong> CPI-444 and anti-PD-1 led to a synergistic<br />
inhibition <strong>of</strong> tumor growth and prolonged survival compared to either agent alone.<br />
When cured mice were later re-challenged with MC38 cells, tumor growth was fully<br />
inhibited, indicating that CPI-444 induced systemic anti-tumor immune memory.<br />
CD8 + T cell depletion abrogated the efficacy <strong>of</strong> CPI-444 ± anti-PD-L1 treatment,<br />
demonstrating a role for CD8 + T cells in mediating primary and secondary immune<br />
responses. Anti-tumor efficacy <strong>of</strong> CPI-444 ± anti-PD-L1 was associated with increased<br />
CD8 + cell infiltration and activation in MC38 tumor tissues. Additionally, levels <strong>of</strong><br />
immune checkpoints were modulated by treatment with CPI-444, including GITR,<br />
OX40, and LAG3 on tumor infiltrating lymphocytes and circulating T cells, suggesting<br />
a broad role for adenosine mediated immunosuppression.<br />
Conclusions: Based on these results and others, we have initiated a Phase 1b clinical<br />
trial to examine safety, tolerability, biomarkers, and preliminary efficacy <strong>of</strong> CPI-444 as<br />
a single agent and in combination the investigational anti-PD-L1 antibody,<br />
Atezolizumab, in patients with solid tumors.<br />
Clinical trial identification: NCT02655822<br />
Legal entity responsible for the study: Corvus Pharmaceuticals<br />
Funding: Corvus Pharmaceuticals<br />
Disclosure: S. Willingham, P. Ho, C. Choy, I. McCaffery, R. Miller: Employee and<br />
stock holder <strong>of</strong> Corvus Pharmaceuticals. R. Leone, J. Powell: Grant support and stock<br />
from Corvus Pharmaceuticals.<br />
1069P<br />
Interim safety analysis <strong>of</strong> a phase II trial combining<br />
trastuzumab and NeuVax, a HER2-targeted peptide vaccine,<br />
to prevent breast cancer recurrence in HER2 low expression<br />
D.O. Jackson 1 , K.M. Peace 1 , D.F. Hale 1 , T.J. Vreeland 2 , G. Choy 3 , B. Nejadnik 3 ,J.<br />
M. Greene 1 , E.J. Schneble 1 , J.S. Berry 1 , A.F. Trappey, III 1 , M.O. Hardin 4 ,G.<br />
T. Clifton 1 , G.S. Herbert 1 , E. Mittendorf 5 , J.P. Holmes 6 , G.E. Peoples 7<br />
1 General Surgery, San Antonio Military Medical Center, San Antonio, TX, USA,<br />
2 General Surgery, Womack Army Medical Center, Fayetteville, NC, USA, 3 Galena<br />
Biopharma, Galena Biopharma, San Francisco, CA, USA, 4 General Surgery,<br />
Madigan Army Medical Center, Tacoma, WA, USA, 5 Surgery, MD Anderson<br />
Cancer Center, Houston, TX, USA, 6 Medical <strong>Oncology</strong>, Redwood Regional<br />
Medical Group, Santa Rosa, CA, USA, 7 Clincal Research, Cancer Vaccine<br />
Development Program, San Antonio, TX, USA<br />
Background: The HER2-targeted monoclonal antibody, trastuzumab (Tz), is standard<br />
<strong>of</strong> care (SOC) for breast cancer (BCa) patients (pts) with HER2 over-expressing (IHC<br />
3 + , OE) tumors and reduces recurrence by 50%. Tz may also have some efficacy in<br />
HER2 1-2+ by IHC (low expression, LE), but is not currently approved for these pts. LE<br />
patients are at increased risk for recurrence. We have previously shown that NeuVax<br />
(E75 peptide + GM-CSF), a HER2-targeted cancer vaccine, is safe, immunogenic, and<br />
has clinical efficacy, particularly in LE pts. We are conducting a phase II trial<br />
combining Tz and NeuVax to prevent BCa recurrence in HER2 LE pts. Given the<br />
known cardiac toxicity (tox) <strong>of</strong> Tz, there is concern that combination therapy may<br />
worsen this tox. Here, we present the initial safety data.<br />
Methods: Disease-free, HLA-A2, A3, A24, or A26 + , HER2 LE BCa pts at high risk for<br />
recurrence were enrolled after SOC treatment and randomized to vaccine group (VG)<br />
receiving Tz and NeuVax or control group (CG) receiving Tz and GM-CSF only.<br />
Cardiac ejection fraction (EF) was assessed at baseline and serially throughout<br />
treatment. Tz dosing was 8mg/kg loading, then 6mg/kg every 3 weeks. Pts received 6<br />
total inoculations <strong>of</strong> NeuVax or GM-CSF, one every 3 weeks starting with the third Tz<br />
infusion. Demographic and safety data were collected and analyzed with appropriate<br />
statistical tests.<br />
Results: In March 2016, the 150th pt was randomized triggering this pre-specified<br />
safety analysis (VG n = 81, CG n = 69). There were no significant differences in<br />
treatment factors. There were no related tox > grade 3 nor difference between treatment<br />
arms. There was no difference in EF over time (baseline (T0) to 6mo (T6)) between VG<br />
v CG (T0: 61.4 + 0.6%, T6: 60.5 + 0.9% v T0: 61.6 + 0.7%, T6: 60.7 + 1.0%, p = 0.9).<br />
There was 1 CG pt who experienced a grade 3 cardiac adverse event, but their EF<br />
returned to baseline after discontinuation <strong>of</strong> Tz.<br />
Conclusions: This novel combination <strong>of</strong> Tz and NeuVax in HER2 LE pts is well<br />
tolerated and the cardiac effects <strong>of</strong> Tz are not impacted by the addition <strong>of</strong> NeuVax. We<br />
will continue to enroll in this ongoing trial, and will report immunologic and clinical<br />
outcomes in a planned interim analysis after 12 months follow-up.<br />
Clinical trial identification: NCT 02297698<br />
Legal entity responsible for the study: N/A<br />
Funding: Galena Biopharma<br />
Disclosure: G. Choy: Senior Vice President <strong>of</strong> Clinical Sciences and Operations for<br />
Galena Biopharma. B. Nejadnik: Executive Vice President and Chief Medical Officer<br />
for Galena Biopharma. G.E. Peoples: Inventor rights to Neuvax (E75 + GM-CSF).<br />
Consultant for Galena Biopharma. All other authors have declared no conflicts <strong>of</strong><br />
interest.<br />
1070P<br />
Impact <strong>of</strong> non-proportionality <strong>of</strong> hazards on time-to-event<br />
endpoints with nivolumab: Re-analysis <strong>of</strong> melanoma and<br />
NSLCC pivotal trials<br />
K. Vásquez Vivas 1 , S. Oudard 2 ,J.O’Quigley 1 , R.T. El Aidi 3<br />
1 Mathematics, Université Paris 7, Paris, France, 2 Medical <strong>Oncology</strong>, Hopital<br />
European George Pompidou, Paris, France, 3 <strong>Oncology</strong>, ARTIC, Paris, France<br />
Background: Immunotherapy could become the standard treatment in many types <strong>of</strong><br />
cancer in the near future. Treatment effects on time-to-event endpoints are described<br />
by proportional-hazards models (PH). PH assumption leads to powerful tests when<br />
correct but in the context <strong>of</strong> IT, it can be poor, leading to significant power losses.<br />
More, non-PH models work poorly in PH situations and require some knowledge <strong>of</strong><br />
the form <strong>of</strong> non-PH which is not available. We propose a method that works well in<br />
both situations applicable to IT.<br />
Methods: Data from nivolumab pivotal clinical trials (melanoma: NCT01721772,<br />
NSCLC: NCT01642004) were analyzed to investigate the impact <strong>of</strong> non-PH on OS.<br />
These studies relied on a hypothesis <strong>of</strong> PH situation but did not investigate the impact<br />
<strong>of</strong> its possible violation on final results. We used a general multivariate non-PH model<br />
in which very broad families <strong>of</strong> situations can be described. This allowed construction<br />
<strong>of</strong> a test based on integrated Brownian motion (O’Quigley 2003).<br />
Results: Melanoma trial exhibited PH whereas NSCLC did not. Our test was applied in<br />
both trials and exhibited an almost identical power to that <strong>of</strong> the log-rank test under<br />
PH situations but had typically much greater power under non-PH situations. For the<br />
NSCLC data, the test showed the data to be well modeled by a PH model (p < 0.001)<br />
was obtained with both tests. For the melanoma data, p-value for our test was more<br />
powerful that the log-rank test (p < 0.001) due to non-PH behavior <strong>of</strong> data.<br />
Nevertheless, nivolumab effect in melanoma was strong enough to compensate for<br />
non-PH effect.<br />
Conclusions: Immunotherapy survival curves exhibit peculiarities which may violate<br />
the underlying PH assumption. We analyzed nivolumab pivotal trials for OS and<br />
demonstrated usefulness <strong>of</strong> our test. This test may be suitable for any condition<br />
encountered in immunotherapy trials and is not dependent on any PH assumption.<br />
Legal entity responsible for the study: ARTIC<br />
Funding: ARTIC<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1071P<br />
abstracts<br />
A phase I dose escalation trial to assess the safety and<br />
preliminary efficacy <strong>of</strong> mFOLFOX6 combined with<br />
pembrolizumab (MK3475) in advanced gastrointestinal<br />
malignancies<br />
D. Stenehjem, S. Gupta, M. Wade, G. Gilcrease, I. Garrido-Laguna, J.R. Weis,<br />
J. Whisenant, S. Sharma<br />
Center for Investigational Therapeutics, Huntsman Cancer Institute, Salt Lake City,<br />
UT, USA<br />
Background: Combining chemotherapy with immune checkpoint inhibitors may have<br />
additive or synergistic clinical activity. The objective <strong>of</strong> this phase I study was to assess<br />
safety and dose limiting toxicities (DLTs) <strong>of</strong> combining mFOLFOX6 and<br />
pembrolizumab in advanced gastrointestinal (GI) malignancies.<br />
Methods: This phase I trial used a 3 + 3 dose escalation design and included patients<br />
with advanced GI malignancies for which FOLFOX is indicated. Study treatment<br />
consisted <strong>of</strong> a phased regimen with patients receiving two cycles <strong>of</strong> mFOLFOX6 every 2<br />
weeks followed by subsequent treatments with mFOLFOX6 plus pembrolizumab<br />
(75mg or 200mg) IV every 2 weeks. A DLT was considered if there was at least a<br />
possible causal relationship to pembrolizumab or the combination and occurred in<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw378 | vi367
abstracts<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
weeks 4-6 <strong>of</strong> treatment (Cycles 3 and 4). Safety measures, disease response and<br />
biomarkers were assessed.<br />
Results: Ten patients (6 male) with a median age <strong>of</strong> 60 years (26-72 years) with<br />
advanced colon (7), biliary (1), small intestine (1) and gastric (1) malignancies were<br />
enrolled to complete this phase I study cohort. Nine had received prior FOLFOX<br />
treatment. Three patients enrolled on the 75 mg dose <strong>of</strong> pembrolizumab and no DLTs<br />
were observed. The next seven patients were dose escalated to 200 mg <strong>of</strong><br />
pembrolizumab. Of the seven patients treated in the 200 mg cohort, one patient was<br />
not evaluable for DLTs due to dose reductions to FOLFOX in the first two cycles. There<br />
were no DLTs observed at this dose level. The most common grade 3 or 4 adverse<br />
events were neutropenia (40%) and hyponatremia (30%). In the 75mg cohort, one<br />
patient was evaluable for disease response and had progressive disease. As <strong>of</strong> April 19,<br />
2016, the following best overall responses have been observed: 2 (28.6%) partial<br />
response, 4 (57.1%) stable disease, and 1 (14.3%) progressive disease. Biomarker<br />
assessments will be presented.<br />
Conclusions: The combination <strong>of</strong> mFOLFOX6 with pembrolizumab (200 mg IV every<br />
2 weeks) has an acceptable safety pr<strong>of</strong>ile. Further assessment <strong>of</strong> safety and efficacy is<br />
being evaluated in phase II dose-expansion cohorts.<br />
Clinical trial identification: ClinicalTrials.gov NCT02268825; First received: October<br />
15, 2014<br />
Legal entity responsible for the study: University <strong>of</strong> Utah and the Huntsman Cancer<br />
Institute<br />
Funding: Merck & Co., Inc<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1072P<br />
A Phase 1 first-in-human study <strong>of</strong> MEDI0680, an anti-PD-1<br />
monoclonal antibody (mAb) in adult patients (pts) with<br />
advanced tumors<br />
A. Naing 1 , S. Goel 2 , B. Curti 3 , A. Weise 4 , J.P. Eder 5 , S. Marshall 6 , C. Morehouse 7 ,<br />
X. Li 8 , J.J. Karakunnel 6 , J. Infante 9<br />
1 Department <strong>of</strong> Investigational Cancer Therapeutics, MD Anderson Cancer<br />
Center, Houston, TX, USA, 2 Department <strong>of</strong> Medical <strong>Oncology</strong>, Montefiore Medical<br />
Park at Eastchester, New York, NY, USA, 3 Department <strong>of</strong> Medical <strong>Oncology</strong>,<br />
Providence Cancer Center and Earle A. Chiles Research Institute, Portland, OR,<br />
USA, 4 Department <strong>of</strong> <strong>Oncology</strong>, Karmanos Cancer Center, Detroit, MI, USA, 5 Yale<br />
School <strong>of</strong> Medicine, Yale Cancer Center, New Haven, CT, USA, 6 Clinical<br />
Development, MedImmune, Gaithersburg, MD, USA, 7 Translational Medicine,<br />
MedImmune, Gaithersburg, MD, USA, 8 Biostatistics, MedImmune, Gaithersburg,<br />
MD, USA, 9 Phase I Drug Development Unit, Sarah Cannon Research Institute/<br />
Tennessee <strong>Oncology</strong>, PLLC, Nashville, TN, USA<br />
Background: Programmed cell death-1 (PD-1) inhibits T-cell activation. Blocking the<br />
PD-1/programmed cell death ligand 1/2 (PD-L1/2) axis has an acceptable safety<br />
pr<strong>of</strong>ile, induces antitumor responses, and provides clinical benefit across tumors.<br />
MEDI0680 is a humanized IgG4κ mAb specific for human PD-1 that blocks<br />
interaction with PD-L1/2.<br />
Methods: This is an ongoing Phase 1, multicenter, open-label, first-in-human,<br />
dose-escalation and expansion study <strong>of</strong> single-agent MEDI0680 in<br />
immunotherapy-naïve pts with advanced solid tumors. Primary objectives are safety/<br />
tolerability and maximum tolerated dose (MTD). Secondary objectives include<br />
pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activity (modified<br />
RECIST v1.1).<br />
Results: As <strong>of</strong> 2 Nov 2015, 58 pts have enrolled across 9 cohorts (0.1–20 mg/kg given<br />
Q3W, Q2W, QWx2 then Q2W, or QWx4 then Q2W). MTD was not reached.<br />
Treatment-related AEs occurred in 46 pts; most common (>10%) were fatigue (21%),<br />
nausea (14%) and arthralgia (14%). Related Grade 3/4 AEs occurred in 10 pts; most<br />
common (>1 pt) were anemia, arthralgia and increased AST (3% each). 2 pts<br />
discontinued due to related AEs: pyrexia in 1 pt; and increased AST, myasthenia gravis<br />
and myositis in 1 pt. There were no Grade 5 related AEs. MEDI0680 had a linear PK<br />
pr<strong>of</strong>ile with dose-proportional increases in peak serum concentration. Median PD-1<br />
receptor occupancy on CD3+ T cells was ≥70% after 1 cycle <strong>of</strong> 10 or 20 mg/kg Q2W.<br />
Increased percentages <strong>of</strong> Ki67 + , ICOS+ and HLA-DR+ T cells; increased levels <strong>of</strong><br />
plasma IFNγ; and enhanced intra-tumor gene expression for these factors were seen<br />
after treatment, demonstrating biological activity <strong>of</strong> MEDI0680. Of 51 evaluable pts, 9<br />
(18%) had an objective response (8 had renal cancer or melanoma), including 1 (2%)<br />
complete response (renal cancer). 14 (28%) pts had stable disease as their best<br />
response. The recommended dose is 20 mg/kg Q2W, based on PK, PD, safety and<br />
efficacy.<br />
Conclusions: MEDI0680 has an acceptable safety pr<strong>of</strong>ile, with preliminary signs <strong>of</strong><br />
efficacy. A Phase 1 combination study with durvalumab to test the concept <strong>of</strong> complete<br />
PD-1/PD-L1 axis blockade is ongoing in advanced solid tumors.<br />
Clinical trial identification: NCT02013804 (release date: December 12, 2013)<br />
Legal entity responsible for the study: MedImmune<br />
Funding: MedImmune<br />
Disclosure: A. Naing: Research funding: NCI; EMD Serono; Medimmune; Healios<br />
Onc. Nutrition, ATTEROCOR; Amplimmune; ARMO BioSciences; Karyopharm<br />
Therapeutics; Incyte; Novartis. B. Curti: Honoraria: Prometheus Speaker Bureau:<br />
Prometheus Research funding: Prometheus, Viralytics, Galectin Therapeutics Travel,<br />
accommodation, expenses: BMS, Medimmune, AgonOx, Prometheus. J.P. Eder:<br />
Honoraria: Merck. S. Marshall: Employment and stock options: Medimmune,<br />
Amplimmune. C. Morehouse: Employment: Medimmune Stock/ownership:<br />
Medimmune (AstraZeneca). X. Li: Employment: MedImmune. J.J. Karakunnel:<br />
Employee <strong>of</strong> MedImmune and own stock or options in AstraZeneca. Also an employee<br />
<strong>of</strong> MedStar Montgomery Medical Center and Fauquier Hospital. J. Infante:<br />
Consulting/advisory: MedImmune Research funding: MedImmune. All other authors<br />
have declared no conflicts <strong>of</strong> interest.<br />
1073P<br />
Is anti-PD-1/PD-L1 immunotherapy sensitizing for<br />
conventional cancer therapies?<br />
M. Matias 1 , S. Aspeslagh 2 , V. Palomar 3 , E. Lanoy 4 , L. Dercle 5 ,C.Even 3 , C. Ferte 3 ,<br />
A. Hollebecque 2 , A. Marabelle 2 , C. Massard 2 , J-C. Soria 2 , S. Postel-Vinay 2<br />
1 Department <strong>of</strong> Medical <strong>Oncology</strong>, Institut Gustave Roussy, Villejuif, France, 2 Drug<br />
Development Department (DITEP), Institut Gustave Roussy, Villejuif, France,<br />
3 Department <strong>of</strong> Head and Neck Cancer, Institut Gustave Roussy, Villejuif, France,<br />
4 Department <strong>of</strong> Biostatistics, Institut Gustave Roussy, Villejuif, France, 5 Nuclear<br />
Medicine, Institut de Cancérologie Gustave Roussy, Villejuif, France<br />
Background: Anti-PD1/PD-L1 immunotherapies (IT) can target tumor cells and/or<br />
tumour-infiltrating immune cells. Thereby they modify the tumour microenvironment,<br />
which can also modulate the sensitivity to conventional cancer therapies (CT).<br />
Whether exposure to IT impacts sensitivity to CT has not been evaluated yet. Here, we<br />
explored if patients (pts) presented differential responses to CT pre- and post- IT.<br />
Methods: Gustave Roussy pts treated with IT between 02/2012 and 12/2015, and<br />
having received at least one line <strong>of</strong> CT pre- and post-IT, were eligible. Pre- and post-IT<br />
Progression Free Survival (PFS) and best response to CT were described overall and<br />
according to ST therapeutic class. In the subgroup <strong>of</strong> pts with identical pre- and<br />
post-IT therapy (paired data subset), PFS and ORR were compared using Wilcoxon<br />
Signed-Rank and McNemar tests, respectively.<br />
Results: Among 102 included pts, 63 and 37% received anti-PD1 and anti-PD-L1,<br />
respectively. Main primary tumour types were: lung (28%), genitourinary (23%),<br />
hematologic (16%), breast and gynecologic (16%). Median nb <strong>of</strong> previous CT lines was<br />
3 (1-11). Median PFS pre- and post-IT were 4.4 vs 3.6 months (m), respectively. When<br />
analysing all pts data by therapeutic class <strong>of</strong> CT, PFS post-IT tended to be better for<br />
anthracyclines (4.7 vs 3.1m), topoisomerase inhibitors (i.) (3 vs 2m) and<br />
antimicrotubule agents (a.) (3.7 vs 2.9m), but worse for alkylating a. (4.2 vs 5.6m) and<br />
signal transduction i. (STi.) (2.9 vs 4m). Results for the subgroup <strong>of</strong> paired data subset<br />
(n = 58) are presented in Table 1. ORRs post-IT tended to be higher for antimetabolites<br />
and antimicrotubule a. and lower for alkylating a., without reaching significance.<br />
Table: 1073P PFS pre- and post-IT <strong>of</strong> paired data subset (subgroup <strong>of</strong><br />
pts who received the same pre- and post-IT therapy, n = 58)<br />
Type <strong>of</strong> CT n mPFS pre<br />
(months)<br />
mPFS post<br />
(months)<br />
PFS Pre<br />
better<br />
(pts n)<br />
PFS Post<br />
better<br />
(pts n)<br />
p-value<br />
Platines 9 3.8 6.7 4 5 0.441<br />
Other alkylating a. 2 10.3 3 2 0 0.18<br />
Antimetabolites 5 5.8 7.4 3 2 0.5<br />
Anthracyclines 1 NE NE 0 1 0.317<br />
Topoisomerase i. 2 1.4 3 1 1 0.655<br />
Antimicrotubule 11 2.5 3.7 4 7 0.594<br />
Anti-angiogenic 11 8 9.2 6 5 0.594<br />
STi. 6 2.6 1.6 4 1 0.14<br />
Hormonal 1 NE NE 1 0 0.317<br />
Others 10 9 9.9 8 2 0.059<br />
Total 58<br />
Conclusions: PFS and ORR post-IT tend to be better for selected classes <strong>of</strong> CT.<br />
Legal entity responsible for the study: Institut Gustave Roussy<br />
Funding: Institut Gustave Roussy<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1074P<br />
Antibody mediated blockade <strong>of</strong> phosphatidylserine improves<br />
immune checkpoint blockade by repolarizing immune<br />
suppressive mechanisms <strong>of</strong> the tumor microenvironment<br />
J. Hutchins<br />
Pre-Clinical Research, Peregrine Pharmaceuticals, Tustin, CA, USA<br />
Background: The expression <strong>of</strong> phosphatidylserine (PS) on cell surfaces drives<br />
immunosuppressive mechanisms associated with tolerogenic cell death. In the tumor<br />
microenvironment, PS is exposed on tumor cells and tumor vascular endothelial cells<br />
and is further exposed with conventional anti-neoplastic therapies. PS signals through<br />
multiple immune cell signaling receptors where it drives the expansion <strong>of</strong><br />
vi368 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
myeloid-derived suppressor cells (MDSCs), regulatory T cells, M2 macrophages, and<br />
stimulates the production <strong>of</strong> immunosuppressive cytokines. PS targeting antibodies<br />
have significant anti-tumor effects in multiple preclinical tumor models to re-activate<br />
the immune response in the tumor microenvironment.<br />
Methods: The combination <strong>of</strong> PS-targeting antibody ch1N11 with anti-PD-1 or<br />
anti-PD-L1 antibodies was compared to single agent therapy in E0771 and EMT-6<br />
mouse syngeneic breast tumor models. Mice were treated IP up to twice per week with<br />
ch1N11, anti-PD-1, or anti-PD-L1 as single agents or combinations <strong>of</strong> antibodies.<br />
Tumor and spleen tissue were analyzed by FACS, ELISPOT, immunohistochemistry<br />
and RNA expression pr<strong>of</strong>iling.<br />
Results: In both tumor models examined, the anti-tumor effect <strong>of</strong> ch1N11 with<br />
combination therapy was significantly superior to single agent therapy. Combination<br />
therapy <strong>of</strong> ch1N11 with anti-PD-1 or anti-PD-L1 significantly inhibited tumor growth<br />
by over 90% with greater complete tumor regression compared to single agent therapy<br />
in E0771 tumors. Furthermore, combination treatment induced greater rejection <strong>of</strong><br />
tumors upon tumor re-challenge. Analysis <strong>of</strong> the tumor microenvironment indicated<br />
that the combination <strong>of</strong> antibody-mediated blockade <strong>of</strong> PS and PD-1 significantly<br />
enhanced tumor infiltration by CD8 + T cells, up regulation <strong>of</strong> immune activation genes<br />
and a decrease in tumor promoting genes.<br />
Conclusions: These results support the combination <strong>of</strong> PS-targeting antibodies with<br />
anti-PD-1 or anti-PD-L1 antibodies for immunotherapy <strong>of</strong> cancer, including breast<br />
cancer.<br />
Legal entity responsible for the study: Peregrine Pharmaceuticals<br />
Funding: Peregrine Pharmaceuticals<br />
Disclosure: J. Hutchins: I am an employee <strong>of</strong> Peregrine Pharmaceuticals, the sponsor<br />
<strong>of</strong> this work.<br />
1075P<br />
Open label non-randomized multi-cohort pilot study <strong>of</strong><br />
genetically engineered NY-ESO-1 specific NY-ESO-1c259<br />
SPEAR T-cellsTM in HLA-A*02+ patients with synovial<br />
sarcoma (NCT01343043)<br />
C. Mackall 1 ,S.D’Angelo 2 , S. Grupp 3 , J. Glod 4 , M. Druta 5 , W. Chow 6 , K. Chagin 7 ,<br />
M. Mehler 8 , G. Kari 8 , T. Trivedi 8 , T. Holdich 9 , L. Pandite 8 , R. Amado 8<br />
1 Stanford Cancer Institute, Stanford University Medical Center, Stanford, CA,<br />
USA, 2 Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA,<br />
3 Pediatrics, Children’s Hospital <strong>of</strong> Philadelphia, Philadelphia, PA, USA, 4 Center for<br />
Cancer Research, National Cancer Institute, Washington, DC, USA, 5 <strong>Oncology</strong>,<br />
M<strong>of</strong>fitt Cancer Center, Tampa, FL, USA, 6 Medical <strong>Oncology</strong>, City <strong>of</strong> Hope, Duarte,<br />
CA, USA, 7 Global Clinical Development, Adaptimmune, Philadelphia, PA, USA,<br />
8 Global Clinical Development, Adaptimmune LLC, Philadelphia, PA, USA, 9 Global<br />
Clinical Development, Adaptimmune LTD, Oxford, UK<br />
Background: NY-ESO-1, a member <strong>of</strong> the cancer-testis family <strong>of</strong> tumor antigens, is<br />
expressed in ∼ 70% <strong>of</strong> Synovial Sarcoma (SS) cases. NY-ESO-1 c259 SPEAR T-cells TM<br />
recognizing the NY-ESO-1 derived SLLMWITQC peptide complexed with HLA-A*02<br />
have been developed for study in SS.<br />
Methods: The primary endpoint <strong>of</strong> overall response rate [ORR (CR + PR)] will be<br />
evaluated in high NY-ESO expressers [2 + , 3+ NY-ESO in ≥50% <strong>of</strong> tumor cells by IHC<br />
(Cohorts 1, 3, and 4)] and low expressers [1+ in >1%, 2 + , 3+ in
abstracts<br />
Methods: We reviewed all ICI cancer clinical trials (103; 201 arms) that reported irAE<br />
and were published on PubMed or presented at an ASCO meeting (only if not<br />
published on PubMed) during 2005-2015. 127 arms from 81 trials were eligible for this<br />
meta-analysis (11400 pts). We collected and compared arm-specific data including ICI<br />
target, number <strong>of</strong> pts with irAE any grade, grade 3+ and grade 5, specific irAE, and<br />
ORR. R package “meta” was used for the meta-analysis to calculate and compare % <strong>of</strong><br />
pts with irAE and ORR.<br />
Results: 23 studies with 2392 pts from 34 arms treated with ICI reported the incidence<br />
(%) <strong>of</strong> patients with any grade irAE per immune checkpoint target inhibition. The<br />
majority <strong>of</strong> arms (91%) and pts (88%) studied were on phase 1/2 clinical trials. Pts were<br />
treated for solid malignancy on 33 arms (97%), mainly melanoma (44.1%). No arms<br />
included ICI combinations. Incidence (%) <strong>of</strong> pts with irAE any grade was higher with ICI<br />
targeting CTLA-4 (54%) than PD-1 (26%) and PD-L1 ICI (13.7%) (P
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
tolerance and the immunosuppressive tumor microenvironment. Human data from<br />
cancer patients treated with oncolytic adenovirus indicated that lymphocytes traffic to<br />
tissues following virotherapy. Therefore, we hypothesized to enable successful T-cell<br />
therapy by arming viruses with immunostimulatory cytokines which can counteract<br />
tumor immunosuppression locally.<br />
Methods: Previously, we have identified interleukin 2 (IL-2) and Tumor Necrosis<br />
Factor alpha (TNFa) as the most promising factors to stimulate the graft used in<br />
adoptive T-cell therapy. Also, we have established that our arming approach results in<br />
long lasting, high level cytokine expression locally but low levels systemically in vivo<br />
and in patients, which is important for safety versus efficacy. One attractive aspect <strong>of</strong><br />
this approach is the ease <strong>of</strong> combinations with standard therapies including checkpoint<br />
inhibiting antibodies (ongoing experiments).<br />
Results: We developed oncolytic adenoviruses expressing TNFa and/or IL2. Virus<br />
injections were given in combination with intraperitoneal adoptive transfer <strong>of</strong> OT-1<br />
TCR transgenic T-cells to treat C57BL/6 mice bearing B16-OVA melanoma tumors.<br />
The best results were obtained when virally coded IL2 and TNFa were both used with<br />
T-cell transfer. Furthermore, in a hamster model permissive to human virus and<br />
human transgenes, oncolytic virus encoding human cytokines successfully improved<br />
the efficacy <strong>of</strong> tumor infiltrating lymphocyte therapy and protected animals from<br />
tumor rechallenge.<br />
Conclusions: TILT Biotherapeutics is in the process <strong>of</strong> confirming the results in<br />
clinical trials.<br />
Legal entity responsible for the study: University <strong>of</strong> Helsinki<br />
Funding: TILT Biotherapeutics Ltd<br />
Disclosure: A. Hemminki: Shareholder in Targovax AS. Employee and shareholder in<br />
TILT Biotherapeutics Ltd. M. Siurala, S. Parviainen: Employee <strong>of</strong> TILT Biotherapeutics<br />
Ltd. All other authors have declared no conflicts <strong>of</strong> interest.<br />
1081P<br />
The efficacy <strong>of</strong> everolimus relies on a modulation <strong>of</strong><br />
adaptative anti tumor T cell immunity<br />
O. Adotévi 1 , L. Mansi 1 , L. Beziaud 1 , P. Ravel 2 , E. Lauret Marie-Joseph 1 ,<br />
C. Laheurte 1 , L. Rangan 1 , T. Maurina 1 , G. Mouillet 1 , T. Nguyen Tan Hon 1 ,<br />
E. Curtit 1 , X. Pivot 1 , Y. Godet 1 , C. Borg 1 , A. Thiery-Vuillemin 1<br />
1 Medical <strong>Oncology</strong>, CHU Besançon, Hôpital Jean Minjoz, Besançon, France,<br />
2 Biostatistic, ICM Regional Cancer Institute <strong>of</strong> Montpellier, Montpellier, France<br />
evaluate cost and dosing using pharmacokinetic (PK) simulation and data from 42<br />
patients entered into the MHRA Early Access to Medicines Scheme for<br />
pembrolizumab and 24 patients enrolled in checkmate-172 trial for nivolumab.<br />
Methods: Consecutive patients receiving pembrolizumab (n = 42) or nivolumab<br />
(n = 24) and with a median weight <strong>of</strong> 79.5kg (range 44-130kg) and 73.3kg (range<br />
52-103kg) respectively were analysed. The costs were based on 12 weeks <strong>of</strong> treatment<br />
which was the time take to first assessment for both drugs. This was 4 cycles <strong>of</strong><br />
pembrolizumab every 21 days (Q3W) and 6 cycles <strong>of</strong> nivolumab every 14 days (Q2W).<br />
1000 random individuals were evaluated in a simulated study for pharmacokinetic and<br />
pharmacodynamic assessment. Published population PK models were used to simulate<br />
exposure and probability <strong>of</strong> trough levels achieving target level (10mg/L) required for<br />
maximum target engagement or receptor occupancy for pembrolizumab and<br />
nivolumab respectively.<br />
Results: The costs <strong>of</strong> different strategies are illustrated in Table 1. The table also include<br />
simulated area under the curve (over the last two cycles) and mean probability <strong>of</strong><br />
trough levels (after the first cycle <strong>of</strong> treatment) achieving 10mg/L or receptor<br />
occupancy for the different dosing strategies.<br />
Pembrolizumab<br />
Q3W<br />
Cost <strong>of</strong> 4<br />
cycles*<br />
(n = 42)<br />
Table: 1082P<br />
Relative Drug Cost<br />
Saving (-) /Expense<br />
(+)<br />
Simulated AUC<br />
Mean mg.day/L<br />
(SD)<br />
Mean prob <strong>of</strong><br />
Target Engagement<br />
2mg/kg £ 836,340 0% 1365 (385) 0.52<br />
Dose Band (10% £ 707,470 -16% 1360 (369) 0.53<br />
variance)<br />
150mg Fixed dose £662,760 -19% 1387 (406) 0.56<br />
200mg Fixed dose £883,680 +8% 1849 (542) 0.92<br />
PK derived £694,320 -17% 1437 (383) 0.64<br />
Nivolumab Q2W Cost <strong>of</strong> 6<br />
cycles*<br />
(n = 24)<br />
Mean prob <strong>of</strong><br />
Receptor<br />
Occupancy<br />
3mg/kg £ 404,135 0% 2098 (879) 0.91<br />
Dose Band (10% £ 372,541 -8% 2036 (845) 0.90<br />
variance)<br />
240mg Fixed dose £ 379,123 -6% 2280 (989) 0.94<br />
PK derived £ 363,326 -10% 2068 (820) 0.91<br />
*UK cost excluding VAT; company’s submission<br />
abstracts<br />
Background: The rapalogs everolimus that inhibit mTOR signaling are used as<br />
anti-proliferative drugs in metastatic renal cell carcinoma (mRCC). The influence <strong>of</strong><br />
immune modulation mediated by everolimus on its antitumor efficacy is poorly<br />
investigated.<br />
Methods: We performed a prospective immunomonitoring study in 23 mRCC patients<br />
treated with everolimus.<br />
Results: Study showed that everolimus promoted high expansion <strong>of</strong><br />
FoxP 3 + Helios + Ki67 + regulatory CD4 T cells (T regs ). Everolimus exposure strongly<br />
enhanced the suppressive functions <strong>of</strong> patients’ T regs . Paradoxically, a concurrent<br />
activation <strong>of</strong> tumor-specific Th1 immunity also occurred during everolimus treatment.<br />
Interestingly, an early change <strong>of</strong> the T regs /antitumor Th1 balance can differentially<br />
shapes the treatment efficacy. Thus, patients presenting a shift towards T regs decrease<br />
and high expansion <strong>of</strong> antitumor Th1 response had a better survival (PFS: 13.2 months<br />
vs 4.1 months P = 0.02). At the time <strong>of</strong> disease progression upon everolimus treatment,<br />
the majority <strong>of</strong> mRCC patients totally lost the anti-tumor Th1 response in favor to a<br />
marked increase <strong>of</strong> circulating T regs .<br />
Conclusions: Altogether, our results describe for the first time a dual impact <strong>of</strong> host<br />
adaptive antitumor T cell immunity on the clinical effectiveness <strong>of</strong> everolimus. So there<br />
is a strong rational to combine everolimus with T regs or immune checkpoint blockade<br />
to shift host immune responses toward protective antitumor immunity.<br />
Legal entity responsible for the study: University Hospital <strong>of</strong> Besançon France<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1082P<br />
A rational approach to dose optimisation <strong>of</strong> pembrolizumab<br />
and nivolumab using cost analysis and pharmacokinetic<br />
modelling and simulation<br />
K. Ogungbenro 1 , A. Patel 2 , R. Duncombe 3 , J. Clark 3 , P. Lorigan 4<br />
1 1Centre for Applied Pharmacokinetic Research, The University <strong>of</strong> Manchester,<br />
Manchester, UK, 2 Experimental Cancer Medicine Team, The Christie NHS<br />
Foundation Trust, Manchester, UK, 3 Pharmacy, The Christie NHS Foundation<br />
Trust, Manchester, UK, 4 Medical <strong>Oncology</strong>, University <strong>of</strong> Manchester - Christie<br />
NHS Foundation Trust, Manchester, UK<br />
Background: Pembrolizumab and nivolumab are PDL1 inhibitors approved for the<br />
treatment <strong>of</strong> advanced malignancies. Both are approved based on body size (mg/kg)<br />
dosing, which can be associated with significant wastage due to available vial sizes and<br />
acquisition cost <strong>of</strong> the drugs. Dose banding is using a defined set <strong>of</strong> ranges (±10%)<br />
<strong>of</strong>fers an alternative approach to body weight dosing. The aim <strong>of</strong> this work is to<br />
Conclusions: Banded fixed dose strategies result in comparable levels <strong>of</strong> exposure and<br />
target engagement or receptor occupancy and can <strong>of</strong>fer significant cost reduction. Vial<br />
size availability can contribute to the level <strong>of</strong> savings to be gained.<br />
Legal entity responsible for the study: Kayode Ogungbenro<br />
Funding: N/A<br />
Disclosure: R. Duncombe: Paid consultant to Bayer; Janssen; Amgen; Pfizer; MSD;<br />
Roche; San<strong>of</strong>i Support for travel from Novartis. No funding received for this study. P.<br />
Lorigan: Paid consultant to BMS, Merck, Amgen, Novartis, Roche, GSK and Chugai.<br />
Support for travel from BMS and Merck. No funding received for this study. All other<br />
authors have declared no conflicts <strong>of</strong> interest.<br />
1083P<br />
CXCL12 inhibition with NOX-A12 (olaptesed pegol) increases<br />
T and NK cell infiltration and synergizes with immune<br />
checkpoint blockade in tumour-stroma spheroids<br />
D. Zboralski 1 , A. Kruschinski 2 , D. Eulberg 2 , A. Vater 1<br />
1 Preclinical Development, Noxxon Pharma AG, Berlin, Germany, 2 Clinical<br />
Development, Noxxon Pharma AG, Berlin, Germany<br />
Background: Effective cancer immunotherapy requires physical contact between<br />
cytotoxic immune cells and malignant cells which is restricted by the tumour<br />
microenvironment (TME). The chemokine CXCL12 has recently been described as an<br />
important T cell exclusion factor in the TME-driven immune suppression. In this<br />
study we aimed to investigate whether CXCL12 inhibition by the clinical stage<br />
L-aptamer (Spiegelmer®) NOX-A12 is able to enhance immune cell infiltration into 3D<br />
tumour-stroma spheroids.<br />
Methods: We established 3D multicellular spheroids that mimic a solid tumour with a<br />
CXCL12-expressing TME. For this purpose, CXCL12-secreting murine stromal MS-5<br />
cells were co-cultured with human cancer cell lines in ultra-low attachment plates.<br />
Peripheral blood mononuclear cells from healthy donors were added to the spheroids<br />
in the presence <strong>of</strong> various concentrations <strong>of</strong> NOX-A12. The next day, spheroids were<br />
dissociated for analysis <strong>of</strong> infiltrated immune cells by flow cytometry. In parallel,<br />
cellular distribution within the spheroids was assessed by immunohistochemistry. A<br />
reporter-based T cell activation assay was adapted to the 3D format in order to<br />
examine the combination <strong>of</strong> NOX-A12 with immune checkpoint blockade.<br />
Results: We found that CXCL12 inhibition with NOX-A12 enhanced infiltration <strong>of</strong><br />
CD8 + T cells, CD4 + T cells and NK cells, and to a lesser extent <strong>of</strong> Treg and B cells into<br />
the homogeneous, CXCL12-expressing tumour-stroma spheroids. Monocyte<br />
infiltration was not increased by NOX-A12. By facilitating physical contact <strong>of</strong> T cells<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw378 | vi371
abstracts<br />
with matching tumour cells, NOX-A12 also enhanced activation <strong>of</strong> T cells and<br />
synergized with PD-1 checkpoint inhibition.<br />
Conclusions: Mechanistically, NOX-A12 appears to generate CXCL12 gradients<br />
within the densely packed in vitro tumour structure and may thereby break the<br />
immune privilege <strong>of</strong> the TME in vivo. Furthermore, a lower monocyte-to-lymphocyte<br />
ratio, as found in NOX-A12 treated spheroids, has been recognized as an indicator for<br />
better prognosis in various cancer types. These data provide a rationale for the<br />
combination <strong>of</strong> NOX-A12 with checkpoint inhibitors as well as other T and NK<br />
cell-based therapies in cancer patients, such as CAR-T and CAR-NK.<br />
Legal entity responsible for the study: Noxxon Pharma AG<br />
Funding: Noxxon Pharma AG<br />
Disclosure: D. Zboralski, A. Kruschinski, D. Eulberg, A. Vater: Employee Noxxon<br />
Pharma AG<br />
1084P<br />
Safety <strong>of</strong> immune check-point inhibitors in patients with<br />
autoimmune conditions and advanced cancer<br />
G. Gard 1 , T. Van Hagen 2 , M. Ariyapperuma 3 , K. Feeney 4 , R. Roberts-Thomson 5 ,<br />
M. Millward 6 , M. Khattak 7<br />
1 Medical <strong>Oncology</strong>, Fiona Stanley Hospital, Perth, Australia, 2 Medical <strong>Oncology</strong>,<br />
St John <strong>of</strong> God Hospital, Perth, Australia, 3 Medical <strong>Oncology</strong>, Sir Charles Gairdner<br />
Hospital, Perth, Australia, 4 Medical <strong>Oncology</strong>, Notre Dame University, Perth,<br />
Australia, 5 Medical <strong>Oncology</strong>, The Queen Elizabeth Hospital, Adelaide, Australia,<br />
6 Medical <strong>Oncology</strong>, Sir Charles Gairdner Hospital, University Western Australia,<br />
Perth, Australia, 7 Medical <strong>Oncology</strong>, Fiona Stanley Hospital, University Western<br />
Australia, Perth, Australia<br />
Background: Immune check-point inhibitors (ICI) have revolutionised the treatment<br />
<strong>of</strong> advanced cancer. However, ICI treatment is associated with immune related adverse<br />
events (irAEs) leading to patient morbidity and mortality. Safety and efficacy <strong>of</strong> ICI is<br />
not well known in patients with auto-immune (AI) conditions as historically this group<br />
has been excluded from clinical trials. The aim <strong>of</strong> our study was to evaluate the safety<br />
and efficacy <strong>of</strong> primarily anti-PD1 therapy in patients with known AI conditions.<br />
Methods: This was a retrospective analysis <strong>of</strong> patients with advanced cancer treated<br />
with ICI at 5 Australian hospitals.<br />
Results: 17 patients were identified: melanoma (11), NSCLC (5) and 1 with mRCC. AI<br />
conditions: Crohn’s disease (1), Ulcerative colitis (3), rheumatoid arthritis (5 including<br />
1 with common variable immune-deficiency), psoriasis (4) and 4 patients with other<br />
AI disease. Treatment received: Nivolumab (7 including 1 with prior Ipilimumab),<br />
Pembrolizumab (8) and Ipilimumab (2). 11 patients previously received systemic<br />
therapy for their AI condition, 2 had topical therapy and 4 had no previous therapy.<br />
Two patients had symptoms <strong>of</strong> active AI disease at time <strong>of</strong> starting ICI. Disease flared<br />
in 6/17 (35%): 3 with G2 arthritis (2 treated with moderate dose steroids, one with<br />
anti-inflammatories), G3 colitis treated with high dose steroids, G3 dyspnoea treated<br />
with high dose steroids and G2 psoriatic rash treated with low dose steroids. Nil<br />
required steroid sparing agents. irAEs unrelated to AI disease flare: 3 patients with<br />
pneumonitis, two G2, one G3 all requiring high dose steroids and one patient with G3<br />
colitis requiring high dose steroids. Response rates: complete (1), partial (7), stable (2)<br />
progressive disease (5), non-evaluable (2).<br />
Conclusions: Disease flared in 35% <strong>of</strong> patients with AI conditions undergoing<br />
treatment with ICI. Most patients were successfully managed with steroids and<br />
treatment was permanently discontinued in only one patient. Although use <strong>of</strong> ICI in<br />
patients with AI conditions seems generally manageable, our data should be<br />
interpreted with caution as many patients with AI conditions had no symptoms <strong>of</strong><br />
active disease at the start <strong>of</strong> therapy. Response to ICI is similar to historical controls.<br />
Legal entity responsible for the study: G Gard and M Khattak.<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1085P<br />
Dendritic cell vaccination in combination with docetaxel for<br />
patients with prostate cancer – a randomized phase II study<br />
P. Kongsted 1 , E. Ellebæk 2 , T.H. Borch 1 , T.Z. Iversen 2 , R. Andersen 1 , Ö. Met 1 ,<br />
M. Hansen 1 , L. Sengeløv 2 , I.M. Svane 1<br />
1 Department <strong>of</strong> Hematology and <strong>Oncology</strong>, Center for Cancer Immune Therapy,<br />
Herlev University Hospital, Herlev, Denmark, 2 Department <strong>of</strong> <strong>Oncology</strong>, Herlev<br />
University Hospital, Herlev, Denmark<br />
Background: In this study we investigate whether the addition <strong>of</strong> an autologous<br />
dendritic cell (DC) based cancer vaccine provokes an immune response in patients<br />
with metastatic castration-resistant prostate cancer (mCRPC) treated with docetaxel<br />
based chemotherapy.<br />
Methods: 43 patients were randomized 1:1 to receive up to 10 cycles <strong>of</strong> docetaxel alone,<br />
75 mg/m 2 /q3 weeks or in combination with an autologous DC based vaccine. CD14 +<br />
monocytes were initially isolated from patients randomized to combinational therapy<br />
following a leukapheresis procedure. Harvested cells were incubated with GM-CSF and<br />
IL-4 and the resulting immature DCs were further matured using IL-1β, TNFα, IL-6<br />
and PGE2. mRNA encoding prostate specific antigen, prostatic acid phosphatase,<br />
survivin and hTERT was transfected into mature DCs using electroporation. Vaccines<br />
were administered intradermally at day 8 and 15 through treatment cycles 1 - 4 and at<br />
day 8 only through treatment cycles 5 – 10. Delayed type hypersensitive (DTH) tests<br />
were applied. Immune cell composition and antigen specific responses in blood<br />
samples were analyzed using flow cytometry and ELISPOT. Prostate cancer clinical<br />
trials working group 2 guidelines were followed. Toxicity was graded according to<br />
CTCAE version 4.0. Progression free survival (PFS) and disease specific survival (DSS)<br />
was calculated using the Kaplan-Meier method.<br />
Results: Baseline mCRPC prognostic factors were equally distributed in the two<br />
treatment groups. Median number <strong>of</strong> treatment cycles was 7. Rates <strong>of</strong> 50%<br />
PSA-responses were 63% vs 38% (p = 0.11) in the docetaxel alone (n = 19) and<br />
combinational therapy group (n = 21), respectively. Median PFS and DSS was 5.5 vs 5.7<br />
months (p = 0.62, log-rank) and 24.7 vs 25.1 months (p = 0.70, log-rank). Vaccine<br />
induced toxicity was limited to mild local skin reactions and pain. Analysis <strong>of</strong><br />
chemotherapy induced toxicity, DTH and immune monitoring is currently ongoing<br />
and will be presented.<br />
Conclusions: The addition <strong>of</strong> an autologous DC based cancer vaccine was safe in this<br />
study. Survival endpoints were similar in both groups <strong>of</strong> patients investigated.<br />
Clinical trial identification: ClinicalTrials.gov NCT01446731<br />
Legal entity responsible for the study: N/A<br />
Funding: Center for Cancer Immune Therapy and Department <strong>of</strong> oncology, Herlev<br />
University Hospital<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1086P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Safety <strong>of</strong> the natural killer (NK) cell-targeted anti-KIR<br />
antibody, lirilumab (liri), in combination with nivolumab (nivo)<br />
or ipilimumab (ipi) in two phase 1 studies in advanced<br />
refractory solid tumors<br />
N.H. Segal 1 , J.R. Infante 2 , R.E. Sanborn 3 , G.T. Gibney 4 , D.P. Lawrence 5 , N. Rizvi 6 ,<br />
R. Leidner 3 , T.F. Gajewski 7 , E. Bertino 8 , W.H. Sharfman 9 , S. Cooley 10 ,S.<br />
L. Topalian 11 , W.J. Urba 12 , J.D. Wolchok 1 ,X.Gu 13 , C. Passey 14 , D. McDonald 15 ,<br />
P. Aanur 15 , S. Srivastava 14 , F.S. Hodi 16<br />
1 Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA,<br />
2 Medicine, Tennessee <strong>Oncology</strong>, PLLC, Nashville, TN, USA, 3 Medical <strong>Oncology</strong>,<br />
Chiles Research Institute, Providence Cancer Center, Portland, OR, USA,<br />
4 Melanoma Disease Group, Lombardi Cancer Center Georgetown University,<br />
Washington, DC, USA, 5 Hematology/<strong>Oncology</strong>, Massachusetts General Hospital,<br />
Boston, MA, USA, 6 Hematology and <strong>Oncology</strong>, Memorial Sloan-Kettering Cancer<br />
Center, New York, NY, USA, 7 Pathology and Medicine, Section <strong>of</strong> Hematology/<br />
<strong>Oncology</strong>, University <strong>of</strong> Chicago, Chicago, IL, USA, 8 Internal Medicine, Division <strong>of</strong><br />
Medical <strong>Oncology</strong>, Ohio State Univ Medical Center, Columbus, OH, USA,<br />
9 <strong>Oncology</strong> and Dermatology, Johns Hopkins Sidney Kimmel Comprehensive<br />
Cancer Center, Baltimore, MD, USA, 10 Division <strong>of</strong> Hematology, <strong>Oncology</strong> and<br />
Transplantation, University <strong>of</strong> Minnesota Masonic Cancer Center, Minneapolis,<br />
MN, USA, 11 Surgery, The Sidney Kimmel Comprehensive Cancer Center at Johns<br />
Hopkins, Baltimore, MD, USA, 12 Providence Melanoma Program, Earle A. Chiles<br />
Research Institute-Providence Cancer Center, Portland, OR, USA, 13 Biostatistics,<br />
Bristol-Myers Squibb, Princeton, NJ, USA, 14 <strong>Oncology</strong>, Bristol-Myers Squibb,<br />
Princeton, NJ, USA, 15 Immuno-<strong>Oncology</strong>, Bristol-Myers Squibb, Princeton, NJ,<br />
USA, 16 <strong>Oncology</strong>, Dana-Farber Cancer Institute, Boston, MA, USA<br />
Background: NK cells play a critical role in immune surveillance and control <strong>of</strong> tumor<br />
growth. Killer-cell immunoglobulin-like receptors (KIR) are important in regulating<br />
NK cell activation and blocking KIR function may be a key strategy potentiating<br />
anti-tumor immune response, particularly in combination with other<br />
immuno-oncology therapies. Here we report the safety <strong>of</strong> liri, a fully human mAb that<br />
blocks KIR on NK cells, in combination with anti-PD-1, nivo (CA223-001;<br />
NCT01714739) or anti-CTLA4, ipi (CA223-002, NCT01750580).<br />
Methods: A phase 1 study evaluated escalating doses <strong>of</strong> liri 0.1–3 mg/kg every 4<br />
wk + nivo 3 mg/kg every 2 wk up to 2 yr. A companion phase 1 study examined liri<br />
0.1–3mg/kg every 4 wk + ipi 3 mg/kg every 3 wk for 4 doses then every 12 wk for 4<br />
doses. Treatment continued until disease progression or toxicity. Both studies enrolled<br />
pts with advanced solid tumors. Primary endpoints were safety and maximum<br />
tolerated combined dose.<br />
Results: Adverse events (AEs) occurred in 135/136 pts and 22/22 pts across all doses in<br />
the liri + nivo and liri + ipi studies, respectively. Treatment-related (TR) AEs are<br />
summarized in Table 1. Of pts receiving liri + nivo, 10 (7.4%) pts developed serious<br />
TRAEs (n = 1 Grade 4 thrombocytopenia, n = 1 each Grade 3 pancreatitis or radiation<br />
skin injury). Two pts had DLTs (iridocyclitis and rash) with liri + ipi. No dose-related<br />
trends occurred in any AE up to the maximum tested dose <strong>of</strong> liri 3 mg/kg + nivo or ipi.<br />
No TR deaths occurred in either study.<br />
Conclusions: Liri + nivo or ipi was tolerable in pts with advanced solid tumors. The<br />
larger number <strong>of</strong> pts treated with liri + nivo demonstrated safety consistent with nivo<br />
monotherapy, with the exception <strong>of</strong> increased infusion-related reactions, which were<br />
manageable. These data support ongoing evaluation <strong>of</strong> liri + nivo.<br />
Legal entity responsible for the study: Sponsored by Bristol-Myers Squibb<br />
Funding: Sponsored by Bristol-Myers Squibb<br />
vi372 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
Table: 1086P TRAEs reported in >5% <strong>of</strong> pts or <strong>of</strong> Grade 3–4 from CA223-001 and CA223-002<br />
CA223-001 Liri + Nivo (N = 136) CA223-002 Liri +Ipi (N = 22)<br />
All Grades n (%) Grades 3–4 n (%) All Grades n (%) Grades 3–4 n (%)<br />
Any TRAE 97 (71.3) 18 (13.2) Any TRAE 15 (68.2) 2 (9.1)<br />
TRAE in >5% pts and all Grade 3–4<br />
Pruritus 25 (18.4) 0 Fatigue 6 (27.3) 0<br />
Fatigue 25 (18.4) 0 Diarrhea 5 (22.7) 0<br />
Infusion-related reaction 25 (18.4) 0 Nausea 4 (18.2) 0<br />
Rash, other 18 (13.2) 0 Decreased appetite 4 (18.2) 0<br />
Diarrhea 12 (8.8) 1 (0.7) Vomiting 4 (18.2) 0<br />
Rash maculopapular 11 (8.1) 2 (1.5) Chills 4 (18.2) 0<br />
Amylase increased 10 (7.4) 3 (2.2) Rash, other 3 (13.6) 0<br />
Nausea 8 (5.9) 0 Rash pruritic 3 (13.6) 0<br />
Dry mouth 7 (5.1) 0 Pyrexia 3 (13.6) 0<br />
Pyrexia 7 (5.1) 0 Hyperhidrosis 2 (9.1) 0<br />
Arthralgia 7 (5.1) 0 Rash maculopapular 2 (9.1) 0<br />
Lipase increased 6 (4.4) 4 (2.9) Headache 2 (9.1) 0<br />
Leukopenia 4 (2.9) 1 (0.7) Pruritus 2 (9.1) 1 (4.5)<br />
Hypophosphatemia 3 (2.2) 2 (1.5) Hypertension 2 (9.1) 0<br />
Hypopituitarism 1 (4.5) 1 (4.5)<br />
Rash erythematous 1 (4.5) 1 (4.5)<br />
Disclosure: R.E. Sanborn: Grants from Bristol-Meyers Squibb, during the conduct<br />
<strong>of</strong> the study; grants and other from Medimmune, other from Seattle Genetics, other<br />
from Peregrine Pharmaceuticals, other from Merck, outside the submitted work.<br />
G.T. Gibney: Personal fees from MERCK, personal fees from Novartis, outside the<br />
submitted work. N. Rizvi: Consulting for astrazeneca, merck, roche, novartis, lilly<br />
Co-founder and shareholder, gritstone oncology. W.H. Sharfman: Grants from<br />
BMS, during the conduct <strong>of</strong> the study; personal fees from Merck, personal fees from<br />
Castle Bioscience, outside the submitted work. S.L. Topalian: Grants from<br />
Bristol-Myers Squibb; personal fees from Five Prime Therapeutics,<br />
GlaxoSmithKline, ImaginAb, & Jounce Therapeutics, Melanoma Research Alliance;<br />
Patents with Bristol-Myers Squibb, MedImmune/AstraZeneca, and Potenza<br />
Therapeutics. W.J. Urba: Celldex and Medimmune.J.D.Wolchok:Dr.Wolchok<br />
reports grants from Bristol Myers Squibb, grants from Merck, grants from<br />
Medimmune, grants from Genentech, during the conduct <strong>of</strong> the study; other from<br />
BMS, other from Merck, other from Genentech, other from Medimmune. X. Gu,<br />
C. Passey, D. McDonald, P. Aanur, S. Srivastava: Employee <strong>of</strong> BMS. F.S. Hodi:<br />
Research support form Bristol-Myers Squibb to institution. All other authors have<br />
declared no conflicts <strong>of</strong> interest.<br />
1087P<br />
A mechanism <strong>of</strong> action study <strong>of</strong> intra-tumoral or intravenous<br />
dosing <strong>of</strong> enadenotucirev, an oncolytic adenovirus in<br />
patients with colon, lung, bladder and renal carcinoma<br />
undergoing resection <strong>of</strong> primary tumor<br />
R. Garcia-Carbonero 1 , V. Boni 2 , I. Duran 3 , M. Gil 4 , M. Espinosa 3 , R. Salazar 4 ,<br />
A. Cubillo 2 , M. Jurado 5 , B. Champion 6 , S. Alvis 6 , K. Fisher 6 , J. Beadle 6 ,G.Pover 6 ,<br />
H. McElwaine-Johnn 6 , C. Ellis 6 , C. Blanc 6 , E. Calvo 2<br />
1 Servicio de Oncología Médica, Hospital Universitario Virgen del Rocio, Seville,<br />
Spain, 2 <strong>Oncology</strong>, START-Madrid, Madrid, Spain, 3 <strong>Oncology</strong>, Hospital<br />
Universitario Virgen del Rocio, Seville, Spain, 4 Medical <strong>Oncology</strong>, Catalan Institute<br />
<strong>of</strong> <strong>Oncology</strong>, ĹHospitalet, Spain, 5 Clinical Research, Pivotal, Madrid, Spain,<br />
6 Research & Development, PsiOxus Therapeutics Limited, Abingdon, UK<br />
Background: Demonstrating intravenous (IV) delivery in patients is key for the<br />
development <strong>of</strong> enadenotucirev (EnAd), a tumor selective chimeric Ad11/Ad3 group B<br />
adenovirus. Initial results from colon cancer (CC) patients receiving intra-tumoral (IT)<br />
or IV administration have been reported [ESMO 2015 Abstract 1086P]. Here we report<br />
the full study results, including an expansion to include lung (NSCLC), bladder and<br />
renal (RCC) cancer patients. The primary study objective was to describe the pattern <strong>of</strong><br />
EnAd delivery within tumors.<br />
Methods: Patients with histologically confirmed cancer scheduled for surgical removal<br />
<strong>of</strong> primary tumor received either 1x10 12 viral particles (VP) IV over 5 min on D 1, 3<br />
and 5; or 10 11 VP/mL IT with a variable volume injected based on the tumor surface<br />
area on D 1. Immunohistochemistry (IHC) staining <strong>of</strong> formalin fixed (FFPE) sections<br />
for EnAd hexon protein (only produced late during replication), was used to visualise<br />
virus activity. A quantitative polymerase chain reaction (qPCR) specific to EnAd was<br />
used to detect virus genome. Further IHC studies were conducted with a panel <strong>of</strong><br />
immune markers and gene expression was analysed using RNA extracted from FFPE<br />
sections (Nanostring).<br />
Results: The study recruited 10 CC (5 IT / 5 IV), 2 bladder, 2 NSCLC and 3 RCC (all<br />
IV) patients. Surgery was between D 8 and 51. IV and IT EnAd was well tolerated with<br />
common adverse events consistent with ‘flu like illness as previously described. Both<br />
IHC staining and qPCR confirm that IV dosing can deliver EnAd selectively to all 4<br />
tumor types and is as reliable as IT in CC. Evidence <strong>of</strong> enhanced immune responses in<br />
tumors included high levels <strong>of</strong> CD8+ cells within tumor nests and peritumoral stroma.<br />
CD4+ cells were largely restricted to stroma. Nanostring highlighted potential<br />
treatment-responsive genes for further evaluation.<br />
Conclusions: Delivery <strong>of</strong> EnAd to tumor cells following IV dosing has been confirmed<br />
by IHC and qPCR studies <strong>of</strong> surgically resected tumor samples from patients with CC,<br />
NSCLC, RCC and bladder cancer. Delivery appears to be associated with inflammatory<br />
changes within the first weeks after administration.<br />
Clinical trial identification: EudraCT 2012-001067-79<br />
Legal entity responsible for the study: PsiOxus Therapeutics Limited<br />
Funding: PsiOxus Therapeutics Limited<br />
Disclosure: B. Champion, S. Alvis, K. Fisher, H. McElwaine-Johnn, C. Ellis: Stock<br />
options in PsiOxus. J. Beadle: Chief Executive Officer, serves as a board member and<br />
holds stock options in PsiOxus. All other authors have declared no conflicts <strong>of</strong> interest.<br />
1088P<br />
Comprehensive assessment <strong>of</strong> the feasibility <strong>of</strong> adoptive cell<br />
therapy in colorectal carcinoma<br />
B. Navarro Rodrigo 1 , S. Viganò 1 , P.O. Gannon 1 , P. Baumgartner 1 ,<br />
C. Maisonneuve 1 , C. Sempoux 2 , M-O. Sauvain 3 , D. Hahnloser 3 , M. Hubner 3 ,<br />
N. Demartines 3 , L. Kandalaft 1 , M. Montemurro 1 , A. Harari 1 , G. Coukos 1<br />
1 Department <strong>of</strong> <strong>Oncology</strong>, Ludwig Institute for Cancer Research, CHUV/UNIL,<br />
Lausanne, Switzerland, 2 Institute <strong>of</strong> Pathology, CHUV/UNIL, Lausanne,<br />
Switzerland, 3 Department <strong>of</strong> Surgery, CHUV/UNIL, Lausanne, Switzerland<br />
Background: Adoptive cell therapy (ACT) can induce objective clinical responses in<br />
solid tumors. However, its potential in colorectal cancer (CRC) remains poorly<br />
exploited. To this end, several questions need to be addressed: Can tumor-infiltrating<br />
lymphocytes (TIL) be isolated from CRC, including cryopreserved samples? Can the<br />
contamination by the gut microbiota be circumvented? Are CRC TIL similar to those<br />
expanded in melanoma trials?<br />
Methods: Cryopreserved samples (n = 10) were obtained from primary colon<br />
adenocarcinoma tumors (n = 5) or liver metastasis (n = 5). Dissected fragments (n= 10<br />
- 32) were plated and stimulated with IL-2 (6’000 IU/ml) for 21-28 days (pre-REP). A<br />
rapid expansion protocol (REP) consisting <strong>of</strong> a polyclonal stimulation with PHA was<br />
performed in cases where the pre-REP yield was low (< 50 x10 6 TIL). Microbiological<br />
testing (BD BACTEC TM ) was performed at Day 0 (D0) and was repeated at D14 <strong>of</strong> the<br />
pre-REP after culturing in antibiotic-containing media. Polychromatic flow cytometry<br />
analyses were performed at harvest.<br />
Results: Sufficient TIL were successfully obtained from all patients tested. The yield <strong>of</strong><br />
TIL at harvest was broad, not linked to fragments numbers and ranged from 10 6 to 10 9<br />
cells (198 ± 90.9 x106; mean ± SEM). Only 4/10 patients required a secondary REP to<br />
reach >50 x10 6 TIL. Among the primary tumors, the highest potential for TIL isolation<br />
was observed for the right-side colon tumors, as opposed to the left side (478 ± 329<br />
x10 6 vs 5.3 ± 3.8 x10 6 cells), while no significant difference was observed between<br />
primary and metastatic samples. Bacterial contamination was detected at D0 in all<br />
primary tumors (and none in metastatic samples; p = 0.02, χ2), but microbiological<br />
tests turned negative at D14. Flow cytometry analyses showed that T cells represented<br />
78 ± 6% <strong>of</strong> the pre-REP TIL with CD4/CD8 ratios ranging from 0.5 to 180 (median<br />
1.62). CD8+ T cells were 74 ± 9.4% effector memory (CCR7 − CD45RA − ) and<br />
Volume 27 | Supplement 6 | October 2016<br />
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abstracts<br />
5.9 ± 2.3% central memory (CCR7 + CD45RA − ), and had an activated phenotype<br />
(HLADR + CD25 + PD-1 + ), which is similar to the documented results <strong>of</strong> melanoma TIL.<br />
Conclusions: Consistent with previous findings in melanoma, we demonstrated the<br />
feasibility <strong>of</strong> TIL expansion in CRC and provide the rationale to move forward with<br />
personalized immunotherapy in CRC.<br />
Legal entity responsible for the study: Centre de Therapies expérimentales. CHUV/<br />
UNIL<br />
Funding: Centre de Therapies expérimentales. CHUV/UNIL - This Research Project<br />
was supported by ESMO with the aid <strong>of</strong> a grant from Amgen. Any views, opinions,<br />
findings, conclusions, or recommendations expressed in this material are those solely<br />
<strong>of</strong> the authors and do not necessarily reflect those <strong>of</strong> ESMO or Amgen.<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1089P<br />
Personalized PD-1/PD-L1 inhibitor therapy for advanced non<br />
small cell lung cancer beyond first line; a meta-analysis <strong>of</strong><br />
potential predictive factors<br />
O.M. Abdel-Rahman<br />
<strong>Oncology</strong>, Ain Shams University Faculty <strong>of</strong> Medicine, Cairo, Egypt<br />
Background: Non small cell lung cancer (NSCLC) comprises the majority <strong>of</strong> primary<br />
lung cancers and it is usually fatal in its advanced stages. the objective <strong>of</strong> this analysis is<br />
to assess the potential clinical and biological predictive markers <strong>of</strong> survival in<br />
pretreated advanced NSCLC patients treated with the three PD-1/PD-L1 inhibitors<br />
(nivolumab, pembrolizumab, atezolizumab).<br />
Methods: MEDLINE and EMBASE databases have been searched. Randomized<br />
clinical trials comparing the three PD-1 /PD-L1 inhibitors versus other treatments for<br />
the management <strong>of</strong> Pretreated advanced NSCLC were evaluated.<br />
Results: Four randomized trials with 2163 were included. Two studies evaluated<br />
nivolumab versus docetaxel, one study evaluated pembrolizumab versus docetaxel and<br />
one study evaluated atezolizumab versus docetaxel. Comparing EGFR mutant to wild<br />
type disease, patients with EGFR wild type disease derive greater benefit from PD-1/<br />
PD-L1 inhibitors. The pooled HR for death for patients with mutant disease was 1.05<br />
[95% CI: 0.69, 1.60; P= 0.81]; while pooled HR for death for patients with wild type<br />
disease was 0.66 [95% CI: 0.57, 0.77; P < 0.00001]. Taking 1% as the cut<strong>of</strong>f value<br />
between PD-L1 +ve and -ve disease and comparing +ve to -ve disease, patients with<br />
PD-L1 +ve disease derive greater benefit from PD-1/PD-L1 inhibitors. The pooled HR<br />
for death for patients with +ve disease was 0.61 [95% CI: 0.50, 0.76; P < 0.00001]; while<br />
pooled HR for death for patients with -ve disease was 0.83 [95% CI: 0.66, 1.04;<br />
P = 0.10]. However because <strong>of</strong> the high risk <strong>of</strong> bias and the low to moderate quality <strong>of</strong><br />
data, these conclusions may change with publication <strong>of</strong> other ongoing trials. Smoking<br />
and KRAS status were reported by one study only and it suggests a possible predictive<br />
value for both <strong>of</strong> them. However this needs prospective confirmation. CNS metastasis<br />
and ALK status as predictive factors were not reported by any <strong>of</strong> the included trials.<br />
Conclusions: Further controlled studies are required to properly confirm the predictive<br />
value <strong>of</strong> PD-L1 and EGFR statuses in this setting as well as evaluate more clearly the<br />
predictive role <strong>of</strong> smoking, KRAS status, ALK status and CNS metastasis.<br />
Legal entity responsible for the study: N/A<br />
Funding: Ain Shams University<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1090P<br />
Identification <strong>of</strong> patients at risk for severe toxicity under PD1<br />
inhibitors: role <strong>of</strong> sarcopenic overweight<br />
P. Boudou Rouquette 1 , A. Jouinot 1 , O. Huillard 1 , J. Arrondeau 1 , C. Tlemsani 1 ,<br />
V. Heidelberg 1 , J. Chapron 2 , N. Kramkimel 3 , D. Damotte 4 , F. Batteux 5 ,<br />
L. Dehghani 6 , B. Terrier 7 , L. Groussin 8 , N. Dupin 3 , B. Blanchet 9 , M. Alifano 10 ,<br />
K. Leroy 11 , M-P. Revel 12 , J. Alexandre 1 , F. Goldwasser 1<br />
1 Medical <strong>Oncology</strong>, CERTIM, Hôpital Cochin, Paris, France, 2 Pneumo-<strong>Oncology</strong>,<br />
Hôpital Cochin, Paris, France, 3 Onco-Dermatology, Hôpital Cochin, Paris, France,<br />
4 Pathology, Hôpital Cochin, Paris, France, 5 Immunology, Hôpital Cochin, Paris,<br />
France, 6 Diabetology, Hôpital Cochin, Paris, France, 7 Internal Medicine, Hôpital<br />
Cochin, Paris, France, 8 Endocrinology, Hôpital Cochin, Paris, France, 9 Functional<br />
Unit <strong>of</strong> Pharmacokinetics and Pharmacochemistry, Hôpital Cochin, Paris, France,<br />
10 Thoracic Surgery, Hôpital Cochin, Paris, France, 11 Biology, Hôpital Cochin,<br />
Paris, France, 12 Radiology, Hôpital Cochin, Paris, France<br />
Background: PD-1 checkpoint inhibitors are associated with a specific spectrum <strong>of</strong><br />
immune-related adverse events (irAEs). Body composition has been proven to<br />
influence the pharmacokinetics <strong>of</strong> many anti-neoplastic drugs. We evaluated the effect<br />
<strong>of</strong> decreased muscle mass (sarcopenia) on PD-1 inhibitors toxicity.<br />
Methods: Pre-therapeutic biological and clinical assessments were prospectively<br />
performed for patients (pts) treated with anti-PD1. Muscle mass was estimated using<br />
Creatinine/Cystatine C (Cr/CysC) clearance ratio (Kim SW, 2016). Univariate and<br />
multivariate analysis tested the association between anti-PD1 induced severe toxicity<br />
and age, sex, Performans Status (PS), (Cr/CysC) clearance ratio, body mass index<br />
(BMI), lymphocytes, C-Reactive Protein (CRP) and albuminemia. The severity <strong>of</strong> AEs<br />
was graded according to the NCI CTC for AE V4.<br />
Results: From July 2015 to April 2016, 74 pts, median age 65 years (41-84), 58.1%<br />
men, received at least one infusion <strong>of</strong> nivolumab (85%) or pembrolizumab (15%), for<br />
lung cancer (n = 44), melanoma (n = 13), renal carcinoma (n = 9) and others (n = 8). A<br />
total <strong>of</strong> 418 cycles (median per pt: 4, range 1-20) were analyzed. Median Cr/CysC<br />
clearance ratio was 1.17. Twenty pts (27%) had both Cr/CysC clearance ratio >1.17,<br />
reflecting low lean body mass and a BMI > 25 kg.m −2 . Fifteen pts (20.2%) developed<br />
grade 3-5 AEs, some rare, such as insipid diabetes with hypophysitis (n = 1) after 1 st<br />
cycle (C1), pulmonary arterial hypertension (n = 3, C1, C1, C5), polymyositis (n = 2,<br />
C2, C2) and thrombocytopenia (n = 1, C6). In univariate analysis, gr 3-5 AE was<br />
associated with Cr/CysC clearance ratio >1.17 (p = 0.006), high CRP (p = 0.036) and<br />
the combination <strong>of</strong> Cr/Cyst clearance ratio >1.17 with BMI > 25 kg/m 2 (p= 0.024). In<br />
multivariate analysis, Cr/CysC clearance ratio >1.17 (p = 0.03) and the combination <strong>of</strong><br />
Cr/CysC clearance ratio >1.17 with BMI >25 kg/m 2 (p = 0.014) remained significant.<br />
Conclusions: The Creatinine/Cystatine C clearance ratio associated with BMI helps to<br />
identify sarcopenic overweight pts who are at high risk <strong>of</strong> severe PD-1 inhibitors<br />
induced toxicity. To date, it is unknown if the development <strong>of</strong> irAEs is an inherent<br />
component <strong>of</strong> checkpoint blockade with anti–PD-1 or if modifying the dosage can<br />
decrease the rates <strong>of</strong> these events.<br />
Legal entity responsible for the study: Pascaline Boudou-Rouquette<br />
Funding: AP-HP<br />
Disclosure: D. Damotte: research contract (MSD) All other authors have declared no<br />
conflicts <strong>of</strong> interest.<br />
1091P<br />
Prolactin as a potential negative predictive factor in<br />
metastatic non-small cell lung cancers (NSCLC) patients in<br />
treatment with Nivolumab (NIVO)<br />
S. Caponnetto 1 , M. Mancini 1 , C. Manai 1 , V. Magri 1 , G.M. Iannantuono 1 ,<br />
D. Pellegrino 1 , C. Mosillo 1 , G. Piesco 1 , G. Pomati 1 , S. Scagnoli 1 , F. Urbano 1 ,<br />
S. Verkhovskaya 1 , G. Barchiesi 1 , S. Zancla 1 , E. Cortesi 2<br />
1 Experimental Medicine, Policlinico Umberto I, Rome, Italy, 2 Department <strong>of</strong><br />
Radiological, Oncological and Pathological Sciences, Policlinico Umberto I, Rome,<br />
Italy<br />
Background: Prolactin (PRL) is a peptide hormone secreted by the anterior pituitary<br />
gland. Several studies have demonstrated the role <strong>of</strong> PRL as a cytokine in human T<br />
cell-mediated immunity. T-cells secrete PRL and express on their surface the receptor<br />
for prolactin (PRL-R). The interaction <strong>of</strong> PRL with PRL-R leads to an intracellular<br />
cascade mediated by Jak2/Stat5 which regulates T cells activation. Although it is still<br />
unclear if PRL is a positive or negative immune-modulator, its effects on T cells<br />
regulation could inhibit the antitumor activity elicited by NIVO through immune<br />
checkpoint blockade. As a result, we decide to evaluate whether occurrence <strong>of</strong><br />
hyperprolactinemia in NSCLC patients in treatment with NIVO is associated with poor<br />
clinical outcomes.<br />
Methods: We conducted a retrospective study on 26 NSCLC patients treated with<br />
NIVO, for whom PRL, TSH and ACTH levels prior and during NIVO treatment were<br />
available. Firstly, blood samples were collected in every patient to evaluate basal<br />
hormones levels before starting the therapy with NIVO. The same procedure was<br />
repeated before each following administration <strong>of</strong> NIVO as well. After completing the<br />
whole treatment, all patients underwent conventional CT to investigate the effect <strong>of</strong><br />
therapy according to RECIST criteria.<br />
Results: 26 NSCLC patients with normal PRL, TSH and ACTH levels before treatment,<br />
received NIVO until the CT evaluation. 18 patients (69%) developed<br />
hyperprolactinemia during the therapy whereas 8 patients (31%) had stable levels <strong>of</strong><br />
PRL during the entire treatment (p = 0,001). No symptoms caused by<br />
hyperprolactinemia were reported in patients. 100% <strong>of</strong> the 18 patients with<br />
hyperprolactinemia had a progressive disease (PD) according CT results, whereas only<br />
1 patient (12,1%) out <strong>of</strong> 8 with stable PRL levels had a PD (p = 0,03).<br />
Conclusions: If validated prospectively, the occurrence <strong>of</strong> hyperprolactinemia in<br />
NSCLC patients in treatment with NIVO could potentially represent a negative<br />
predictive factor for poor clinical outcomes anticipating the PD showed by imaging<br />
tests in patients.<br />
Legal entity responsible for the study: Enrico Cortesi<br />
Funding: Policlinico Umberto I - Rome Sapienza-University <strong>of</strong> Rome<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1092P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Patterns <strong>of</strong> steroid use in diarrhoea and/or colitis (D/C) from<br />
immune checkpoint inhibitors (ICPI)<br />
L. Spain 1 , S. Diem 2 , K. Khabra 3 , S. Turajlic 1 , M. Gore 1 , N. Yousaf 1 , J. Larkin 1<br />
1 Medical <strong>Oncology</strong>, Royal Marsden Hospital NHS Foundation Trust, London, UK,<br />
2 Medical <strong>Oncology</strong>, Kantonsspital St. Gallen, St. Gallen, Switzerland, 3 Research<br />
Statistics, Royal Marsden Hospital NHS Foundation Trust, London, UK<br />
Background: D/C is reported in up to 30% <strong>of</strong> patients treated with ICPI. Treatment<br />
algorithms advocate corticosteroids (CS) for moderate to severe symptoms. Patterns <strong>of</strong><br />
endoscopic change and duration <strong>of</strong> CS are not described. Rates <strong>of</strong> CS toxicity in this<br />
group <strong>of</strong> patients are unclear.<br />
vi374 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Methods: Medical records <strong>of</strong> melanoma patients treated with ICPI at the Royal<br />
Marsden Hospital from 2010-2015 were reviewed. The grade, duration <strong>of</strong> CS and<br />
infliximab (INF) use was recorded for each D/C episode. Patients who had flexible<br />
sigmoidoscopy (FS) were labeled as having macroscopic + /-microscopic (macro),<br />
microscopic (micro) changes alone or no changes (normal). CS toxicities were noted.<br />
Results: 414 ICPI treatment episodes were undertaken in 353 patients. The rate <strong>of</strong><br />
all-grade D/C was 23% (96/414): 27% (77/282) with ipilimumab, 8% (8/101) with<br />
anti-PD-1 agents and 38% (8/21) with combination ipilimumab + nivolumab. Median<br />
age 61 years, 54% were male.<br />
Table: 1092P Steroid use by Flexible Sigmoidoscopy Findings<br />
N<br />
Received<br />
CS (%)<br />
No<br />
CS<br />
Median CS<br />
duration days<br />
(range)<br />
UNK re CS<br />
duration<br />
On CS at<br />
3mths<br />
(%)<br />
UNK re INF<br />
CS at (%)<br />
3mths (%)<br />
Median days<br />
CS to INF<br />
(range)<br />
Macro 27 24 (89) 3 69 (5-278) 4 10 (42) 4 (15) 8 (33) 15 (6-60)<br />
Micro 8 7 (88) 1 51 (12-162) 0 2 (29) 0 0 na<br />
Normal 9 8 (89) 1 40 (7-156) 0 1 (13) 0 2 (25) 11 (2-20)<br />
FS<br />
Unknown 6 5 (8) 1 67 (36-91) 1 1 (20) 0 1 (20) 9<br />
57% (55/96) required CS. 52% (50/96) underwent FS: 88% (44/50) received CS.<br />
Median duration <strong>of</strong> CS was higher in macro patients compared to a normal FS (69 vs<br />
40 days; p = 0.07) and in micro patients compared to a normal FS (51 vs 40 days;<br />
p = 0.32; Table 1). 11% (11/96) <strong>of</strong> D/C was treated with INF and median CS duration in<br />
this population was 91 days, versus 52 days for those who received CS alone. Median<br />
time from first steroid to INF was 15 days (range 2-60). 25% (14/55) were on steroids at<br />
3 months. At least 15% (8/55) developed new or worse diabetes, 13% (7/55) had mood<br />
change and 16% (9/55) developed an antibiotic-requiring infection.<br />
Conclusions: We describe different phenotypes <strong>of</strong> D/C associated with ICPI therapy.<br />
Appearances at FS may predict for duration <strong>of</strong> CS use. All patients should be<br />
monitored for stigmata <strong>of</strong> CS use and considered for PJP prophylaxis. CS sparing<br />
strategies should be prospectively evaluated.<br />
Legal entity responsible for the study: James Larkin<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1093P<br />
Switch maintenance therapy with racotumomab or<br />
nimotuzumab vs docetaxel for NSCLC patients<br />
M. Hernandez 1 , E. Neninger 2 , R.A. Ortiz 3 , K. Camacho 4 , R.M. Amador 5 , L. Bello 6 ,<br />
Y. Flores 7 , S. Acosta 8 , G. Pichs 9 , M. Cala 10 , M. Corella 11 , Y. Jimenez 12 , Y. Diaz 13 ,<br />
C.E. Viada 1 , M. Robina 14 , A. Valdes 1 , I.C. Mendoza 14 , P.P. Guerra 14 , A. Macias 1 ,<br />
T. Crombet 1<br />
1 Clinical Research, Center <strong>of</strong> Molecular Immunology, Havana, Cuba, 2 Clinical<br />
<strong>Oncology</strong>, Hermanos Ameijeiras Hospital, Havana, Cuba, 3 Clinical <strong>Oncology</strong>,<br />
Celestino Hernandez Hospital, Santa Clara, Cuba, 4 Clinical <strong>Oncology</strong>, Jose R<br />
Lopez Tabranes Hospital, Matanzas, Cuba, 5 Clinical <strong>Oncology</strong>, III Congreso<br />
Hospital, Pinar del Rio, Cuba, 6 Clinical <strong>Oncology</strong>, Antonio Luaces Hospital, Ciego<br />
De Avila, Cuba, 7 Clinical <strong>Oncology</strong>, National Institute <strong>of</strong> <strong>Oncology</strong>, Havana, Cuba,<br />
8 Clinical <strong>Oncology</strong>, Saturnino Lora Hospital, Santiago De Cuba, Cuba, 9 Clinical<br />
<strong>Oncology</strong>, Celia Sanchez Hospital, Manzanillo, Cuba, 10 Clinical <strong>Oncology</strong>, Juan<br />
Bruno Zayas Hospital, Santiago de Cuba, Cuba, 11 Clinical <strong>Oncology</strong>, Vladimir Ilich<br />
Lenin Hospital, Holguin, Cuba, 12 Clinical <strong>Oncology</strong>, Camilo Cienfuegos Hospital,<br />
Sancti Spiritus, Cuba, 13 Clinical <strong>Oncology</strong>, Comandante Pinares Hospital,<br />
Artemisa, Cuba, 14 Clinical Research, National Coordinating Center for Clinical<br />
Trials, Havana, Cuba<br />
Background: Maintenance therapy is a common strategy in NSCLC treatment that<br />
improves PFS and OS. Racotumomab-alum is an anti-idiotypic vaccine that induces<br />
immunological response against N-glycolilated gangliosides in NSCLC patients.<br />
Nimotuzumab is a humanized anti-EGFR monoclonal antibody that has shown<br />
activity in NSCLC patients. The aim <strong>of</strong> this study is to evaluate safety and efficacy <strong>of</strong><br />
racotumomab-alum or nimotuzumab versus docetaxel as second line or switch<br />
maintenance therapy for advanced NSCLC.<br />
Methods: This phase III, multicenter, open label, randomized trial is designed to enroll<br />
743 stage IIIB-IV NSCLC patients, after first line therapy, with PS 0-2, with written<br />
informed consent. The primary endpoint is OS. Patients are been randomized (2:2:1)<br />
to 3 arms: racotumomab-alum, nimotuzumab or docetaxel, and stratified according to<br />
response to first line. Racotumomab-alum treatment consists in 5 bi-weekly<br />
intradermal doses and re-immunizations every 4 weeks. Nimotuzumab arm receives 6<br />
weekly infusions followed by bi-weekly doses. Docetaxel is used at 75 mg/m 2 for 6<br />
cycles, if there are no evidences <strong>of</strong> progressive disease after 3 cycles. As switch<br />
maintenance therapy, both experimental drugs will be classified as non-inferior (NI) to<br />
docetaxel, if 1- year OS rate is 36% (HR C/T = 0.66) [ d 0 (0,41), d 0= - ln HR (C/T) ] using a<br />
15% NI margin. Here we report the final analysis in non-progressor patients (n = 237).<br />
Results: 93 patients in each experimental arm and 51 in docetaxel arm with at least 1<br />
year follow up were analyzed (ITT). The median OS and 1-year survival rate were 11.4<br />
months (CI: 7.07-12.46) and 48.3 % with nimotuzumab, 9.67 months (CI: 6.52-12.82)<br />
and 45.5 % with racotumomab-alum and 9.76 months (CI: 7.07-12.46) and 33.5 %<br />
with docetaxel, respectively. Most frequent treatment-related adverse events were<br />
induration, local erythema and pain in injection site with racotumomab-alum; myalgia,<br />
nausea and fever with Nimotuzumab, and anemia, nausea and malaise after docetaxel.<br />
Conclusions: Racotumomab-alum [CI 90% NI (-∞;0.14)] and Nimotuzumab [CI 90%<br />
NI (- ∞; -0.002) are non-inferior to docetaxel as switch maintenance therapy. Both<br />
experimental treatments were safely administered at primary level <strong>of</strong> health assistance.<br />
Clinical trial identification: RPCEC00000179<br />
Legal entity responsible for the study: Cuban Ministry <strong>of</strong> Health Center <strong>of</strong> Molecular<br />
Immunology<br />
Funding: Cuban Ministry <strong>of</strong> Health Center <strong>of</strong> Molecular Immunology<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1094P<br />
Preclinical development <strong>of</strong> tumor-infiltrating lymphocyte<br />
(TIL) based adoptive cell transfer (ACT) immunotherapy for<br />
patients with sarcoma<br />
M. Nielsen 1 , A. Krarup-Hansen 2 , D. Hovgaard 3 , M.M. Petersen 3 , A.C. Loya 4 ,<br />
N. Junker 1 , I.M. Svane 1<br />
1 Center for Cancer Immune Therapy, Department <strong>of</strong> <strong>Oncology</strong>, Herlev Hospital,<br />
Copenhagen, Denmark, 2 Department <strong>of</strong> <strong>Oncology</strong>, Herlev Hospital, Copenhagen,<br />
Denmark, 3 Department <strong>of</strong> Orthopaedic Surgery, Rigshospitalet, Copenhagen<br />
University Hospital, Copenhagen, Denmark, 4 Department <strong>of</strong> Pathology,<br />
Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark<br />
Background: ACT based on infusion <strong>of</strong> autologous TILs has the ability to induce<br />
complete and durable response in some patients with advanced malignant melanoma.<br />
We believe that this approach could also be effective in sarcoma. In this preclinical<br />
study we are investigating feasibility <strong>of</strong> expanding TILs from sarcoma, as well as<br />
performing functional in vitro analyses on these TILs.<br />
Methods: A portion (> 1 cm 3 ) <strong>of</strong> the excised sarcoma tumor tissue is cut into<br />
fragments and placed in a growth medium containing IL-2 for initial TIL expansion.<br />
Afterwards TIL cultures are undergoing a Rapid Expansion Protocol (REP) expansion<br />
by adding OKT-3 and feeder cells. Phenotype and functional analyses is performed<br />
using flowcytometri and Elispot.<br />
Results: To this date we were able to expand TILs from 14 <strong>of</strong> 15 tumor samples. TILs<br />
were harvested and frozen when an estimated number <strong>of</strong> 100x10 6 to 200x10 6 cells were<br />
reached. Mean expansion time were 32 days (16 - 61). 87,9 % (36,4 – 99,1) <strong>of</strong> these cells<br />
were CD3 + , and <strong>of</strong> these 64,7 % (16,3 – 99,1) were CD4 + , and 24,1 % (0,1 – 50,6)<br />
were CD8+. REP expansion rates ranged from 630 fold to 2.300 fold, and followed<br />
expansion pattern similar to TILs from malignant melanoma. TILs from four tumor<br />
samples with three different sarcoma subtypes (undifferentiated pleomorphic sarcoma,<br />
myx<strong>of</strong>ibrosarcoma and osteosarcoma) demonstrated reactivity against autologous<br />
tumor cells using Elispot. Further assessment is ongoing.<br />
Conclusions: We were able to expand TILs from 93% <strong>of</strong> the included tumor samples to<br />
numbers needed for possible future clinical implementation. TILs were a mix <strong>of</strong> CD4+<br />
and CD8+ with CD4+ being predominant. As <strong>of</strong> yet we have demonstrated TIL<br />
reactivity against autologous tumor cells from four patients with three different<br />
sarcoma subtypes. Thus, we conclude that it is feasible to translate TIL ACT into<br />
clinical testing in sarcoma patients.<br />
Legal entity responsible for the study: Danish Data Protection Agency<br />
(HEH-2015-057-03792) Scientific Ethics Committee (H-15007073)<br />
Funding: Center for Cancer Immune Therapy Department <strong>of</strong> <strong>Oncology</strong> Herlev<br />
Hospital<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1095P<br />
abstracts<br />
T cell therapy for patients with advanced ovarian cancer:<br />
a pilot study in progress<br />
M. Pedersen 1 , M.C.W. Westergaard 1 , T.H. Borch 1 , M. Nielsen 1 , P. Kongsted 1 ,<br />
T. Juhler-Nottrup 2 , M. Donia 1 , I-M. Svane 1<br />
1 Department <strong>of</strong> Hematology and Department <strong>of</strong> <strong>Oncology</strong>, Center for Cancer<br />
Immune Therapy, Herlev University Hospital, Herlev, Denmark, 2 Department <strong>of</strong><br />
<strong>Oncology</strong>, University Hospital Herlev, Herlev, Denmark<br />
Background: Adoptive cell therapy (ACT) with tumor infiltrating lymphocytes (TILs)<br />
is based on infusion <strong>of</strong> activated and expanded cells isolated from autologous tumor<br />
tissue and has primarily been used with success for treatment <strong>of</strong> malignant melanoma<br />
with clinical effect in approximately 50% <strong>of</strong> patients including 20% obtaining a<br />
complete response. Recent studies suggest that TIL based ACT can potentially be used<br />
with success in other cancers, including ovarian cancer (OC). The age-standardized<br />
incidence <strong>of</strong> OC in Europe is 13 per 100.000 and it is the 5 th leading cause <strong>of</strong> cancer<br />
death among women. If inoperable, the treatment is a combination <strong>of</strong> chemotherapy.<br />
Recurrent disease has a poor prognosis. The primary aim <strong>of</strong> this study is to assess<br />
feasibility and tolerability <strong>of</strong> T cell therapy for OC. Secondarily, to describe objective<br />
response using RECIST 1.1 and clarify if the treatment can induce a measurable<br />
immune response against tumor cells.<br />
Methods: Patients with progressive/recurrent OC and histologically verified serous<br />
adenocarcinoma are potential candidates. Surgery is performed with removal <strong>of</strong> tumor<br />
tissue for T cell expansion. Stem cells are then harvested for potential use if patients are<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw378 | vi375
abstracts<br />
having difficulties recovering from lymphodepleting chemotherapy before T cell<br />
therapy. The treatment consists <strong>of</strong> high-dose chemotherapy (60 mg/kg<br />
cyclophosphamide for 2 days and 25 mg/m 2 fludarabine for 5 days) followed by T cell<br />
administration and subsequent high-dose decrescendo interleukin-2 for up to 5 days.<br />
Patients are evaluated for up to 5 years or until progression.<br />
Results: Five patients are presently included and 3 have received T cell therapy. One<br />
had a partial metabolic response, stable disease (SD) with nearly 20% tumor regression<br />
and > 50% reduction <strong>of</strong> CA-125 at 6 weeks, but progressive disease (PD) at 12 weeks.<br />
The second had SD at 6 weeks with a small decrease in CA-125, but PD at 12 weeks.<br />
The third had SD at 6 weeks with a 25% drop in CA-125 and awaits 2 nd evaluation.<br />
Only expected and manageable toxicities have been observed and all patients recovered<br />
without the need <strong>of</strong> stem cell support. Immune analyses are pending.<br />
Conclusions: So far, T cell therapy for patients with advanced OC seems to be<br />
manageable and tolerable.<br />
Clinical trial identification: Clinicaltrials.gov ID: NCT02482090<br />
Legal entity responsible for the study: Center for Cancer Immune Therapy<br />
Funding: Center for Cancer Immune Therapy University <strong>of</strong> Copenhagen Kræftens<br />
Bekæmpelse OvaCure<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1096P<br />
Expression pattern <strong>of</strong> immune checkpoint-associated<br />
molecules in radical nephrectomy specimens as a prognostic<br />
predictor in patients with metastatic renal cell carcinoma<br />
treated with tyrosine kinase inhibitors<br />
T. Hara 1 , H. Miyake 2 , M. Fujisawa 1<br />
1 Urology, Kobe University Graduate School <strong>of</strong> Medicine, Kobe, Japan, 2 Urology,<br />
Hamamatsu University School <strong>of</strong> Medicine, Hamamatsu, Japan<br />
Background: It has not been established whether activation <strong>of</strong> immune checkpoint<br />
pathways is correlated with the clinical course <strong>of</strong> systemic therapies for metastatic renal<br />
cell carcinoma (mRCC), particularly tyrosine kinase inhibitors (TKIs). The objective <strong>of</strong><br />
this study was to analyze the expression pattern <strong>of</strong> immune checkpoint-associated<br />
molecules in tumor tissues to determine the prognostic significance <strong>of</strong> these molecules<br />
in mRCC patients treated with TKIs.<br />
Methods: Radical nephrectomy specimens were obtained from 62 patients treated with<br />
TKIs as first-line systemic therapy for mRCC. The proportions <strong>of</strong> programmed death-1<br />
(PD-1)-positive tumor infiltrating lymphocytes (TILs) as well as those <strong>of</strong> tumor cells<br />
positive for PD-ligand 1 (PD-L1) and PD-L2 were analyzed by immunohistochemical<br />
staining.<br />
Results: Twelve patients (19.3%) were revealed to be positive for PD-1-positive TILs,<br />
while positive expression <strong>of</strong> PD-L1 and PD-L2 were detected in 12 (19.3%) and 10<br />
(16.1%) patients, respectively. Patients with positive PDL-L1 expression had<br />
significantly unfavorable progression-free survival (PFS) compared with those without<br />
positive PD-L1 expression, despite the remaining two molecules having no significant<br />
impact on PFS. Additionally, overall survival (OS) in patients positive for PD-1, PD-L1<br />
or PD-L2 expression was significantly poorer than that in those without expression <strong>of</strong><br />
each immune checkpoint-associated molecule. Multivariate analyses <strong>of</strong> several<br />
parameters identified the following independent prognostic predictors after the<br />
introduction <strong>of</strong> TKIs: PD-L1 expression status for PFS, and lymph node metastasis,<br />
Memorial Sloan-Kettering Cancer Center classification and expression statuses <strong>of</strong><br />
PD-1-positive TILs and PD-L1 for OS.<br />
Conclusions: Positive expression <strong>of</strong> immune checkpoint-associated molecules in<br />
tumor tissues, particularly that <strong>of</strong> PD-L1, could be useful prognostic indicator in<br />
mRCC patients receiving TKIs as first-line systemic therapy.<br />
Legal entity responsible for the study: N/A<br />
Funding: Kobe University<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1097P<br />
Optimized neoantigen selection based on tumor exome data<br />
C. Kyzirakos 1 , C. Mohr 2 , S. Armeanu-Ebinger 1 , M. Feldhahn 1 , D. Hadaschik 1 ,<br />
M. Walzer 3 , D. Döcker 1 , M. Menzel 1 , S. Nahnsen 4 , O. Kohlbacher 5 , S. Biskup 1<br />
1 Tumor diagnostics, CeGaT GmbH, Tübingen, Germany, 2 Center for<br />
Bioinformatics and Dept. <strong>of</strong> Computer Science, Quantitative Biology Center<br />
(QBiC), University <strong>of</strong> Tübingen, Tübingen, Germany, 3 Center for Bioinformatics<br />
and Dept. <strong>of</strong> Computer Science, University <strong>of</strong> Tübingen, Tübingen, Germany,<br />
4 Quantitative Biology Center (QBiC), University <strong>of</strong> Tübingen, Tübingen, Germany,<br />
5 Center for Bioinformatics and Dept. <strong>of</strong> Computer Science, Quantitative Biology<br />
Center (QBiC), University <strong>of</strong> Tübingen; Max Planck Institute for Developmental<br />
Biology, Tübingen, Germany<br />
Background: Virtually every tumor harbors somatic mutations. These mutations can<br />
lead to mutation-derived neoantigenic peptides presented on the MHC molecules <strong>of</strong><br />
the patient’s tumor. T cells are able to recognize those alterations and may in turn kill<br />
the transformed cells. The importance <strong>of</strong> such neoantigens in an effective T<br />
cell-derived tumor defense has recently been demonstrated in various<br />
immunotherapeutic contexts like immune checkpoint inhibition, TIL therapy and<br />
vaccination. The quality and quantity <strong>of</strong> those neoantigens was shown to be <strong>of</strong> high<br />
prognostic and therapeutic value. To provide a practicable method for the<br />
identification <strong>of</strong> these highly individual tumor-specific neoantigens, we have<br />
established an optimized workflow combining exome and transcriptome sequencing,<br />
database derived expression data, HLA genotyping and peptide epitope prediction. The<br />
workflow is applicable to FFPE as well as fresh frozen tumor samples.<br />
Methods: FFPE samples are revised and macrodissected by pathologists to maximize<br />
the tumor content <strong>of</strong> the sample. Exome sequencing <strong>of</strong> a tumor and normal tissue<br />
sample is performed and tumor-specific somatic single nucleotide variants and the<br />
patient’s HLA type are determined. Transcriptome analysis can be performed in<br />
parallel using fresh frozen or RNA-stabilized tumor samples. A complex bioinformatics<br />
pipeline integrates these results and predicts affected neo-epitopes for the patient’s<br />
HLA type. Resulting peptide sequences are ranked using expression data, peptide<br />
motifs, potential relevance <strong>of</strong> the respective variant for tumor development and<br />
biochemical features.<br />
Results: Datasets from FFPE and fresh frozen tumor samples were generated. For both<br />
sample types, a set <strong>of</strong> highly promising peptides could be compiled. The whole<br />
workflow can be accomplished within three weeks.<br />
Conclusions: The established workflow provides an efficient and time saving method<br />
for the identification <strong>of</strong> tumor-specific mutations and putative patient-individual<br />
neoantigens for multiple purposes including the development <strong>of</strong> cancer-specific<br />
vaccines, adoptive T-cell transfer, prediction <strong>of</strong> clinical utility <strong>of</strong> immune checkpoint<br />
inhibitors and immune monitoring.<br />
Legal entity responsible for the study: CeGaT<br />
Funding: CeGaT<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1098P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Assessment <strong>of</strong> nivolumab (Nivo) benefit-risk pr<strong>of</strong>ile from a<br />
240-mg flat dose versus a 3-mg/kg dosing regimen in<br />
patients (Pts) with solid tumors<br />
X. Zhao 1 , S. Suryawanshi 1 , M. Hruska 1 ,Y.Feng 1 , X. Wang 1 , J. Shen 1 ,<br />
B. McHenry 2 , I.M. Waxman 1 , A. Achanta 1 , A. Bello 1 ,A.Roy 1 , S. Agrawal 1<br />
1 Clinical Pharmacology and Pharmacometrics, Bristol-Myers Squibb, Princeton,<br />
NJ, USA, 2 Biostatistics, Bristol-Myers Squibb, Princeton, NJ, USA<br />
Background: Nivo 3 mg/kg every 2 weeks (Q2W) has shown overall survival (OS)<br />
benefit over the standard <strong>of</strong> care in multiple advanced cancers and is currently<br />
approved for treatment <strong>of</strong> renal cell carcinoma (RCC), melanoma (MEL), and<br />
squamous and non-squamous non-small cell lung cancer (SQ/NSQ NSCLC) in the US,<br />
EU, and other countries. Nivo, a programmed death-1-blocking antibody, displays flat<br />
exposure-response (E-R) relationships. Relative to body weight (BW)-based dosing, a<br />
flat dose is expected to reduce prescription dosing errors, shorten pharmacy<br />
preparation time, and improve ease <strong>of</strong> administration. This integrated analysis<br />
evaluated the exposure, efficacy, and safety <strong>of</strong> a 240-mg flat dose relative to 3-mg/kg<br />
dosing in the approved indications.<br />
Methods: A flat dose <strong>of</strong> 240 mg was selected based on equivalence to the approved<br />
3-mg/kg dose at the median BW <strong>of</strong> ∼80 kg in pts with solid tumors. Demographic data<br />
from pts with RCC (n = 603), MEL (n = 826), or SQ/NSQ NSCLC (n = 648) across 9<br />
CheckMate studies were included in the pooled dataset. Exposures produced by doses<br />
<strong>of</strong> 3 mg/kg or 240 mg Q2W were simulated based on established quantitative<br />
pharmacokinetic models and further used to predict efficacy and safety from E-R<br />
models in each tumor type. A safety review <strong>of</strong> clinical data in pts with solid tumors<br />
who received nivo 3 or 10 mg/kg was conducted to evaluate the association between<br />
BW or exposure measures and incidence <strong>of</strong> adverse events (AEs).<br />
Results: The geometric mean <strong>of</strong> summary measures <strong>of</strong> nivo exposure predicted from<br />
the 240-mg flat dose Q2W was ≤5% different than corresponding exposures produced<br />
by 3-mg/kg Q2W dosing. The predicted OS benefit and risk <strong>of</strong> AEs leading to<br />
discontinuation or death were similar across tumor types for both dosing regimens.<br />
Subgroup safety analyses did not demonstrate a clinically meaningful relationship<br />
between nivo exposure or BW and frequency or severity <strong>of</strong> AEs.<br />
Conclusions: Based on model-predicted nivo pharmacokinetics, efficacy, and safety,<br />
clinical safety review, and an understanding <strong>of</strong> nivo E-R relationships, no clinically<br />
meaningful difference in the benefit-risk pr<strong>of</strong>ile <strong>of</strong> nivo is expected with 240-mg Q2W<br />
vs 3-mg/kg Q2W dosing in RCC, MEL, or NSCLC.<br />
Legal entity responsible for the study: Sponsored by Bristol-Myers Squibb<br />
Funding: Sponsored by Bristol-Myers Squibb<br />
Disclosure: S. Suryawanshi, M. Hruska, B. McHenry, I.M. Waxman, A. Roy: Employee<br />
<strong>of</strong> and stock ownership in Bristol-Myers Squibb. X. Wang, J. Shen, A. Achanta,<br />
A. Bello: Employee <strong>of</strong> Bristol-Myers Squibb. S. Agrawal: Employee <strong>of</strong> and stock<br />
ownership in Bristol-Myers Squibb. Stock Ownership in Eli Lilly and Celldex. All other<br />
authors have declared no conflicts <strong>of</strong> interest.<br />
vi376 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
1100TiP<br />
An open-label, multicenter, phase 1 study <strong>of</strong> ramucirumab<br />
(R) plus durvalumab (D) in patients (pts) with locally<br />
advanced and unresectable or metastatic gastric or<br />
gastroesophageal junction (G/GEJ) adenocarcinoma,<br />
non-small cell lung cancer (NSCLC), or hepatocellular<br />
carcinoma (HCC)<br />
Y-J. Bang 1 , L.W. G<strong>of</strong>f 2 , H. Wasserstrom 3 , J. Yang 3 ,G.Mi 4 , M. Karasarides 5 ,<br />
M. Reck 6<br />
1 Department <strong>of</strong> Internal Medicine, Seoul National University College <strong>of</strong> Medicine,<br />
Seoul, Republic <strong>of</strong> Korea, 2 Hematology/<strong>Oncology</strong>, Vanderbilt Ingram Cancer<br />
Center, Nashville, TN, USA, 3 Medical <strong>Oncology</strong>, Eli Lilly and Company,<br />
Bridgewater, NJ, USA, 4 Medical <strong>Oncology</strong>/Biostatistics, Eli Lilly and Company,<br />
Bridgewater, NJ, USA, 5 Immuno<strong>Oncology</strong>, AstraZeneca, Waltham, MA, USA,<br />
6 Department <strong>of</strong> Thoracic <strong>Oncology</strong>, Lungen Clinic Großhansdorf GmbH,<br />
Grosshansdorf, Germany<br />
Background: Hallmarks <strong>of</strong> tumor growth include angiogenesis and<br />
immunosuppression, and combining R (anti-vascular endothelial growth factor<br />
receptor 2 antibody) with D(anti-programmed death ligand-1 antibody) to target both<br />
processes demonstrates synergy in preclinical models. This global phase 1 trial<br />
(NCT02572687) will assess safety, toxicities, pharmacokinetics, immunogenicity, and<br />
preliminary efficacy <strong>of</strong> the combination in pts with locally advanced and unresectable<br />
or metastatic G/GEJ adenocarcinoma, NSCLC, or HCC.<br />
Trial design: Key inclusion criteria include pts who have progressed on therapies, can<br />
provide a tumor biopsy sample, and have an ECOG PS <strong>of</strong> 0-1. Two combination dose/<br />
schedules will be evaluated in the Phase 1A/dose limiting toxicity (DLT) observation<br />
phase, following 6 + 3 dose de-escalation with a starting dose <strong>of</strong> R (10 mg/kg<br />
intravenous [IV]) and D (1125mg IV) Q3W for NSCLC and R (8 mg/kg IV) and D<br />
(750 mg IV) Q2W for G/GEJ and HCC (1 treatment cycle [21 days for the NSCLC<br />
cohort and 28 days for the Gastric-GEJ and HCC cohorts]). Phase 1A will include<br />
18-54 pts. After the Phase 1A/DLT evaluation, each cohort will be expanded to<br />
approximately 20 pts who will receive study treatment until confirmed disease<br />
progression or unacceptable toxicity (Phase 1B). A final analysis will be performed 12<br />
months after the last patient’s first dose <strong>of</strong> study treatment. The primary objective is the<br />
assessment <strong>of</strong> the safety and tolerability <strong>of</strong> the combination <strong>of</strong> R + D, and the<br />
secondary objectives are pharmacokinetics (Phase 1A/1B) and preliminary efficacy and<br />
immunogenicity (Phase 1B). Interim analyses will occur after all pts within a cohort<br />
have completed (or discontinued from) approximately 24 weeks <strong>of</strong> treatment.<br />
Clinical trial identification: NCT02572687<br />
Legal entity responsible for the study: Eli Lilly and Company<br />
Funding: Eli Lilly and Company<br />
Disclosure: Y-J. Bang: Research fundings (through the institution) from Lilly, and<br />
consulting roles <strong>of</strong> Lilly.L.W. G<strong>of</strong>f: Advisory role for Celgene; research funding from<br />
Astellas Pharma, Pfizer, Onyx, Sun Pharma, Lilly, and Bristol-Myers<br />
Squibb. H. Wasserstrom, J. Yang, G. Mi: Employee <strong>of</strong> Eli Lilly and Company and holds<br />
equity in the company. M. Reck: Advisory role for Roche, Lilly, Bristol-Myers Squibb,<br />
AstraZeneca, Pfizer, Boehringer-Ingelheim, and Celgene. All other authors have<br />
declared no conflicts <strong>of</strong> interest.<br />
1101TiP<br />
Phase II multi-centre, non randomized, open label study <strong>of</strong><br />
nivolumab in combination with ipilimumab as first line in<br />
adults patients with metastatic uveal melanoma. GEM<br />
14-02<br />
A.J. Rullan Iriarte 1 , S. Martín-Algarra 2 , L. de la Cruz Merino 3 , D. Rodriguez Abreu 4 ,<br />
E. Espinosa 5 , A. Berrocal 6 , R. López Castro 7 , T. Curiel 8 , P. Luna 9 , A. Lorenzo 10 ,J.<br />
M. Piulats 1<br />
1 Medical <strong>Oncology</strong>, Institut Catala de Oncologia, Barcelona, Spain, 2 Medical<br />
<strong>Oncology</strong>, Clinica Universitaria de Navarra, Pamplona, Spain, 3 Medical <strong>Oncology</strong>,<br />
Hospital Universitario Virgen Macarena, Seville, Spain, 4 Medcal <strong>Oncology</strong> service,<br />
Hospital Universitario Insular de Gran Canaria, Las Palmas, Spain, 5 Servicio de<br />
Oncología Médica, Hospital Universitario La Paz, Madrid, Spain, 6 Medical<br />
<strong>Oncology</strong>, Hospital General Universitario Valencia, Valencia, Spain, 7 Medical<br />
<strong>Oncology</strong>, University Hosptial de Valladolid, Valladolid, Spain, 8 Medical <strong>Oncology</strong>,<br />
Complejo Hospitalario Universitario de Santiago de Compostela SERGAS,<br />
Santiago De Compostela, Spain, 9 Medical <strong>Oncology</strong>, Hospital Universitario Son<br />
Espases, Palma de Mallorca, Spain, 10 Medical <strong>Oncology</strong>, Hospital Universitario<br />
Virgen de la Victoria, Malaga, Spain<br />
Background: Uveal melanoma (UM) is the most common primary intraocular<br />
malignancy in adults (6 cases per million). Up to 35% <strong>of</strong> patients develop metastatic<br />
disease affecting primarily the liver (95%). After systemic dissemination the prognosis<br />
is poor, estimated median Overall Survival (mOS) <strong>of</strong> 6 months (m) without treatment.<br />
Efficacy <strong>of</strong> conventional chemotherapy is limited, with overall response rate round 5%<br />
and mOS 8-10 m. Trials evaluating new targeted therapies (e.g. Mek inhibitors) have<br />
failed to achieve positive results. As a result mOS <strong>of</strong> metastatic UM patients has not<br />
improved in the last 25 years. UM cells express PD-L1, and have others characteristics<br />
that suggest they could respond to immune-checkpoint blocking antibodies. Indeed<br />
our group recently reported a study <strong>of</strong> Ipilimumab 10mg/kg with promising results,<br />
mOS 10 months, 48% alive at 1y. The afore mentioned lead us to design this trial with<br />
the hypothesis that combination <strong>of</strong> Nivolumab and Ipilimumab will improve OS on<br />
these patients.<br />
Trial design: This is a phase II, multi-center, non randomized, open label study <strong>of</strong><br />
nivolumab combined with ipilimumab in subjects with previously untreated metastatic<br />
uveal melanoma. Patients must have histologically confirmed uveal melanoma, with<br />
progressive metastatic disease at baseline, >18y old and adequate organ function. Prior<br />
systemic treatment and autoimmune or infectious diseases are the main exclusion<br />
criteria. Dosing schedule is described in Table 1. Patients will be treated until<br />
progression, unacceptable toxicity or patient withdrawal. Selected cases will be treated<br />
beyond progression specified per protocol. Objectives: Primary Endpoint is 1 year OS.<br />
Safety, PFS according to RECIST 1.1 criteria and correlation between biomarkers and<br />
clinical results will be evaluated. Statistics: Predicted sample size is 48pts. H 0 1yOS=<br />
27% (pooled external data). H 1 1yOS= 50%.<br />
Table: 1101TiP Cycle 1 and 2. (1 cycle = 6 weeks)<br />
D1W1 D1W2 D1W3 D1W4 D1W5 D1W6<br />
Nivolumab 1mg/<br />
kg + Ipilimumab<br />
3 mg/kg<br />
Cycle 3 and beyond, starting week 13.<br />
Nivolumab 1mg/<br />
kg + Ipilimumab<br />
3 mg/kg<br />
D1W1 D1W2 D1W3 D1W4 D1W5 D1W6<br />
Nivolumab 1mg/kg<br />
Nivolumab<br />
Nivolumab<br />
1mg/kg<br />
1mg/kg<br />
Clinical trial identification: EudraCT: 2015-004429-15. Sponsor Protocol Number:<br />
GEM-1402 NCT: NCT02626962<br />
Legal entity responsible for the study: Grupo Español Multidisciplinar de Melanoma<br />
Funding: Bristol-Myers-Squibb<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1102TiP<br />
abstracts<br />
A phase 1b/2 dose escalation and cohort expansion study <strong>of</strong><br />
the safety, tolerability and efficacy <strong>of</strong> a transforming growth<br />
factor-beta (TGF-β) receptor I kinase inhibitor (galunisertib)<br />
in combination with anti–PD-1 (nivolumab) in advanced<br />
refractory solid tumours<br />
S.C. Guba 1 , S. Mukhopadhyay 2 , D. Desaiah 1 , V.A.M. Andre 3<br />
1 <strong>Oncology</strong>, Eli Lilly and Company, Indianapolis, IN, USA, 2 <strong>Oncology</strong>, Bristol-Myers<br />
Squibb, Princeton, NJ, USA, 3 European Early Phase Stats, Erl Wood ELCL,<br />
Windlesham, UK<br />
Background: TGF-β signaling plays an important role in tumorigenesis and<br />
contributes to the hallmarks <strong>of</strong> cancer, including tumor proliferation, invasion and<br />
metastasis, inflammation, angiogenesis, and escape <strong>of</strong> immune surveillance.<br />
Galunisertib (LY2157299 monohydrate) is an oral small molecule inhibitor <strong>of</strong> the<br />
TGF-β receptor I kinase that specifically down-regulates the phosphorylation <strong>of</strong><br />
SMAD2, abrogating activation <strong>of</strong> the canonical pathway. Programmed Cell Death-1<br />
(PD-1) is expressed on activated T cells and can act to dampen the immune response.<br />
Tumor cells overexpress PD-1 ligand (PD-L1) and inhibit the local immune response.<br />
Nivolumab blocks the binding <strong>of</strong> PD-L1 to its PD-1 receptor, allowing the activated T<br />
cells to identify and attack cancer cells. Thus, blockade <strong>of</strong> both TGF-β and PD-1 could<br />
be expected to reverse the immune escape and to potentially provide immune<br />
restoration to improve immune response and induce tumor regression.<br />
Trial design: This study (NCT02423343) is a phase 1b/2 open-label study that will be<br />
conducted in 2 parts. The phase 1b is an open-label, dose-escalation assessment <strong>of</strong> the<br />
safety and tolerability <strong>of</strong> galunisertib administered in escalating doses over 4 cohorts<br />
ending with 150 mg BID in combination with nivolumab 3 mg/kg IV every 2 weeks in<br />
patients with advanced refractory solid tumors. The phase 2 will be disease restricted<br />
and includes 3 expansion cohorts <strong>of</strong> patients with non-small cell lung cancer (n = 25),<br />
hepatocellular carcinoma (n = 25), or glioblastoma (n = 25). Patients in the 3 cohorts<br />
will be assigned to treatment concurrently, and enrollment will be complete when all<br />
cohorts have reached the prespecified enrollment target. Enrollment <strong>of</strong> patients in<br />
phase 1b began on 09 October 2015; as <strong>of</strong> 27April2016, seven patients entered the<br />
study; one withdrew for a non-DLT reason, and one patient remains on treatment<br />
every 2 weeks.<br />
Clinical trial identification: NCT02423343<br />
Legal entity responsible for the study: Eli Lilly and Company<br />
Funding: Eli Lilly and Company<br />
Disclosure: S.C. Guba, D. Desaiah, V.A.M. Andre: Author is an employee <strong>of</strong> Eli Lilly<br />
and Company and holds company stock. All other authors have declared no conflicts<br />
<strong>of</strong> interest.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw378 | vi377
abstracts<br />
1103TiP<br />
MEDIOLA: A phase I/II, open-label trial <strong>of</strong> olaparib in<br />
combination with durvalumab (MEDI4736) in patients (pts)<br />
with advanced solid tumours<br />
S. Domchek 1 , Y-J. Bang 2 , G. Coukos 3 , K. Kobayashi 4 , N. Baker 5 , E. McMurtry 6 ,<br />
W. Song 4 , B. Kaufman 7<br />
1 Basser Research Center, Abramson Cancer Center, Philadelphia, PA, USA,<br />
2 Biomedical Research Institute, Seoul National University College <strong>of</strong> Medicine,<br />
Seoul, Republic <strong>of</strong> Korea, 3 Ludwig Institute for Cancer Research, University<br />
Hospital <strong>of</strong> Lausanne, Lausanne, Switzerland, 4 <strong>Oncology</strong>, AstraZeneca,<br />
Gaithersburg, MD, USA, 5 Statistical Science, AstraZeneca, Cambridge, UK,<br />
6 <strong>Oncology</strong>, AstraZeneca, Macclesfield, UK, 7 Breast Cancer Unit, Sheba Medical<br />
Center, Tel Hashomer, Israel<br />
Background: Olaparib (Lynparza) is a potent, oral PARP inhibitor that induces<br />
synthetic lethality in tumours deficient in homologous recombination repair.<br />
Durvalumab is a selective, high-affinity, engineered, human IgG1 mAb that blocks<br />
PD-L1 binding to PD-1 and CD80, preventing PD-L1-mediated inhibition <strong>of</strong> T-cell<br />
activation, and promoting antitumour immune responses. In a Phase I study<br />
(NCT02484404), olaparib plus durvalumab was tolerable, and a recommended<br />
combination dose was determined (Lee et al, ASCO 2016). MEDIOLA<br />
(NCT02734004) is using this combination dose to assess olaparib and durvalumab,<br />
which may have complementary mechanisms <strong>of</strong> action, in pts selected using criteria<br />
that predict sensitivity to olaparib.<br />
Trial design: MEDIOLA has four pt cohorts: pts with platinum-sensitive recurrent<br />
ovarian cancer (OC) who have received ≥2 lines <strong>of</strong> platinum-based therapy and have a<br />
known/suspected deleterious germline BRCA1/2 mutation (gBRCAm); pts with<br />
unresectable, advanced, gBRCAm, HER2-negative breast cancer (BC) who have<br />
received anthracycline/taxane therapy; pts with small-cell lung cancer (SCLC) that has<br />
relapsed >12 weeks (wks) after platinum-based therapy; and pts with advanced<br />
ATM-negative gastric cancer (GC) that has progressed after first-line chemotherapy.<br />
Pts will receive olaparib monotherapy (300 mg bid, tablets) for 4 wks, then olaparib<br />
(300 mg bid) plus durvalumab (1500 mg IV q4w) until disease progression. Disease<br />
will be assessed by CT/MRI at baseline, after olaparib monotherapy and every 8 wks<br />
during the combination phase. Primary objectives are disease control rate (DCR) at 12<br />
wks (includes pts with complete/partial response or stable disease) by modified<br />
RECIST 1.1 (using a post-progression scan), safety and tolerability. Secondary<br />
endpoints include pharmacokinetics, DCR at 28 wks, objective response rate,<br />
progression-free survival and overall survival. Cohorts will be considered as individual<br />
Bayesian predictive probability designs. Initially, 10 pts/cohort will be enrolled across<br />
∼17 centres worldwide, with expansion to n = 30 (OC), n = 38 (BC), n = 34 (SCLC)<br />
and n = 37 (GC) after interim assessment. Enrolment began in Q1 2016.<br />
Clinical trial identification: NCT02734004<br />
Legal entity responsible for the study: AstraZeneca<br />
Funding: AstraZeneca<br />
Disclosure: S. Domchek: The University <strong>of</strong> Pennsylvania has received research funding<br />
from AbbVie, and Clovis. Dr. Domchek has received an honorarium from EMD<br />
Serrano. Y-J. Bang: Research funds from AstraZeneca (through institution), and<br />
consulted for AstraZeneca. G. Coukos: Commercial research grants: Celgene,<br />
Boehringer-Ingelheim. Honoraria from Speakers Bureau: Roche, Genentech.<br />
Consultant or Advisory Roles: Genentech, Roche, Novartis,<br />
San<strong>of</strong>i-Aventis. K. Kobayashi, N. Baker, E. McMurtry, W. Song: AstraZeneca employee<br />
and AstraZeneca stock ownership. B. Kaufman: Participation in an advisory board for<br />
AstraZeneca.<br />
1104TiP<br />
Intravenous coxsackievirus A21 in combination with<br />
pembrolizumab in advanced cancer patients: phase Ib<br />
KEYNOTE 200 study<br />
H.S. Pandha 1 , K. Harrington 2 , C. Ralph 3 , A. Melcher 4 , E. Schmidt 5 ,D.<br />
R. Kaufman 6 , M. Grose 7 , R. Karpathy 7 , D. Shafren 7<br />
1 <strong>Oncology</strong>, University <strong>of</strong> Surrey, Surrey, UK, 2 Division <strong>of</strong> Radiotherapy and<br />
Imaging, The Institute <strong>of</strong> Cancer Research and Royal Marsden Hospital, London,<br />
UK, 3 St. James’s Institute <strong>of</strong> <strong>Oncology</strong>, University <strong>of</strong> Leeds, Leeds, UK, 4 <strong>Oncology</strong><br />
and Clinical Research, Leeds Institute <strong>of</strong> Cancer and Pathology, Leeds, UK,<br />
5 Clinical, Merck Co, Kenilworth, NJ, USA, 6 <strong>Oncology</strong> Clinical Research, Merck &<br />
Co., Inc., Kenilworth, NJ, USA, 7 Viralytics, Viralytics Limited, Sydney, Australia<br />
Background: CAVATAK TM is a novel, bio-selected ICAM-1-targeted<br />
immunotherapeutic Coxsackievirus A21 (CVA21). Infection <strong>of</strong> the tumour<br />
micro-environment by CVA21 can increase levels <strong>of</strong> immune-checkpoint molecules,<br />
immune-cell infiltration and enhancement <strong>of</strong> systemic antitumour immune response.<br />
Pembrolizumab is a human programmed death receptor-1 (PD-1) blocking antibody<br />
that has induced responses in a number <strong>of</strong> tumour types via reversal <strong>of</strong><br />
tumour-induced T-cell suppression. Preclinical studies in immune-competent mouse<br />
models <strong>of</strong> NSCLC and melanoma suggest combinations <strong>of</strong> IV CVA21 + anti-PD-1<br />
mAbs mediate greater antitumour activity compared to single agent use. As such, we<br />
propose that the combination <strong>of</strong> CVA21 + pembrolizumab may translate to similar<br />
benefits in the clinic. The KEYNOTE 200 Phase Ib study (NCT02043665) assesses<br />
tolerance and efficacy <strong>of</strong> IV-delivered CVA21 ± pembrolizumab in advanced cancer<br />
pts.<br />
Trial design: Primary objectives are to assess dose-limiting toxicities (DLT) <strong>of</strong><br />
CVA21 ± pembrolizumab. Secondary objectives include ORR by irRECIST criteria,<br />
PFS, and OS. Treatment: Part A: Pts are infused with CVA21 in Cohort 1 (n = 3), at a<br />
dose <strong>of</strong> 1 x 10 8 TCID 50 , in Cohort 2 (n = 3) at a dose <strong>of</strong> 3 x 10 8 TCID 50 and in Cohort 3<br />
(n = 12-18) at a dose <strong>of</strong> 1 x 10 9 TCID 50 on study days 1,3,5,22 and Q3W for 6<br />
additional infusions. Part A enrollment is almost complete. Part B: Pts are infused with<br />
CVA21 + pembrolizumab. In Cohort 1 (n = 3), CVA21 is administered at a dose <strong>of</strong> 1 x<br />
10 8 TCID 50 , in Cohort 2 (n = 3) at a dose <strong>of</strong> 3 x 10 8 TCID 50 and in Cohort 3 (n = ∼80)<br />
at a dose <strong>of</strong> 1 x 10 9 TCID 50 on study days 1,3,5,8,29,and Q3W for 6 additional<br />
infusions. All subjects receive pembrolizumab at 200 mg IV Q3W from Day 8 for up to<br />
2 years. Treatment with IV CVA21 ± pembrolizumab will continue until confirmed CR<br />
or PD (whichever comes first) per irRECIST or DLT. Key eligibility: Pts with advanced<br />
disease, lesion(s) accessible for core biopsy, ECOG PS 0-1, no active cerebral<br />
metastases, no autoimmunity/immunosuppression.<br />
Clinical trial identification: NCT02043665<br />
Legal entity responsible for the study: Viralytics Limited<br />
Funding: Viralytics Limited<br />
Disclosure: H.S. Pandha: Research Funding - Viralytics Limited Travel,<br />
Accommodations, Expenses – Viralytics. K. Harrington: Honoraria - Amgen; Celgene;<br />
Merck Sharp & Dohme; Oncos Therapeutics Consulting - Amgen; Merck Sharp &<br />
Dohme; Viralytics (Inst). Research Funding - AstraZeneca; Genelux Oncolytics<br />
Biotech, Viralytics Travel - Boehringer Ingelheim, Viralytics. C. Ralph: Travel,<br />
Accommodations, Expenses – Viralytics. A. Melcher: Research Funding - Oncolytics<br />
Biotech, Viralytics Limited Travel, Accommodations, Expenses –<br />
Viralytics. E. Schmidt, D.R. Kaufman: Employment: Merck & Co. M. Grose,<br />
R. Karpathy, D. Shafren: Viralytics stock and employment.<br />
1105TiP<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Phase 1/1b multicenter trial <strong>of</strong> the adenosine A2a receptor<br />
antagonist (A2aR) CPI-444 as single agent and in<br />
combination with atezolizumab (ATZ) in patients(Pts) with<br />
advanced cancers<br />
A. Patnaik 1 , J. Powderly 2 , J. Luke 3 , R. Miller 4 , G. Laport 4<br />
1 Medical <strong>Oncology</strong>, South Texas Accelerated Research Therapeutics (START),<br />
San Antonio, TX, USA, 2 Medical <strong>Oncology</strong>, Carolina Bio<strong>Oncology</strong> Institute,<br />
Huntersville, NC, USA, 3 Section <strong>of</strong> Hematology/<strong>Oncology</strong>, The University <strong>of</strong><br />
Chicago Medical Centre, Chicago, IL, USA, 4 Clinical Development, Corvus<br />
Pharmaceuticals, Burlingame, CA, USA<br />
Background: Adenosine is an extracellular signaling molecule that increases in<br />
response to acute tissue injury/inflammation to restore tissue homeostasis. Elevated<br />
levels <strong>of</strong> adenosine are produced in the tumor microenvironment and signaling<br />
through A2aR on immune cells leads to immunosuppression, promoting tumor<br />
growth. CPI-444 is an oral A2aR antagonist that has been evaluated in phase 1 and 2<br />
clinical trials outside the oncology setting. CPI-444 binds to A2aR with a K i <strong>of</strong> 3.5 nM<br />
and > 50 fold selectivity over other adenosine receptor subtypes. Preclinical studies<br />
with various mouse tumor models demonstrate efficacy <strong>of</strong> CPI-444 as a single agent<br />
(SA) and in combination with anti-PD1/PDL1 antibodies.<br />
Trial design: We have initiated a phase 1/1b multicenter, open label trial to evaluate<br />
CPI-444 as a SA and in combination with ATZ(anti-PDL1), in pts with advanced<br />
cancers. The objectives are 1)evaluate the safety and tolerability <strong>of</strong> multiple doses <strong>of</strong><br />
CPI-444 2) identify a recommended dose and schedule for further study and 3)<br />
evaluate efficacy. Eligibility criteria: 1)histology: non-small cell lung cancer, melanoma,<br />
renal cell cancer, triple-negative breast cancer, bladder cancer, head and neck cancer<br />
and MSI colorectal cancer and 2) 1 but not more than 5 prior therapies. This phase 1/<br />
1b adaptive design is composed <strong>of</strong> 2 steps with multiple expansion cohorts within Step<br />
2 based on a 3-stage expansion design. Step 1 is a dose selection step with 4 cohorts (3<br />
SA cohorts with CPI-444 at various dosing schedules and 1 cohort combined with<br />
ATZ). After Step 1, the optimal dose SA cohort <strong>of</strong> CPI-444 determined by safety and<br />
other biomarkers and the optimal dose from the combination cohort will proceed to<br />
Step 2. Step 2 has 10 multiple expansion cohorts: 5 cohorts (stratified by disease)will<br />
receive CPI-444 as a SA and 5 cohorts will receive the combination. The total sample<br />
size is up to 534 pts. This trial is accruing in N America and will expand to Australia<br />
and Europe.<br />
Clinical trial identification: NCT02655822 Release date: January 08, 2016<br />
Legal entity responsible for the study: Corvus Pharmaceuticals<br />
Funding: Corvus Pharmaceuticals<br />
Disclosure: A. Patnaik: Research support to institution: Corvus<br />
Pharmaceuticals. J. Powderly: Clinical Research Funding: Bristol Myers Squibb,<br />
Genentech, Corvus, AstraZeneca, Incyte, Macrogenics, EMD Serono, Sequonom Stock<br />
Equity: Bluebird Bio, Kite PHarma ZioPHarm <strong>Oncology</strong>, Juno Therapeutics, Lion<br />
BioTechnologies. J. Luke: Ad board: Amgen, Array Research support to institution:<br />
Novartis, MedImmune, Bristol-Myers Squibb, Pharmacyclics, Merck, BBI<br />
Therapeutics, Five Prime Therapeutics, Genentech, Corvus Pharmaceuticals, Delcath,<br />
Abbvie, Celldex, EMD Serono, Incyte. R. Miller: Employee and stockholder <strong>of</strong> Corvus<br />
Pharmaceuticals. G. Laport: Employee and stockholder <strong>of</strong> company.<br />
vi378 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong> 27 (Supplement 6): vi379–vi400, 2016<br />
doi:10.1093/annonc/mdw379<br />
melanoma and other skin tumours<br />
1106O<br />
Overall survival (OS) and safety results from a phase 3 trial <strong>of</strong><br />
ipilimumab (IPI) at 3 mg/kg vs 10 mg/kg in patients with<br />
metastatic melanoma (MEL)<br />
P.A. Ascierto 1 , M. Del Vecchio 2 , C. Robert 3 , A. Mackiewicz 4 , V. Chiarion-Sileni 5 ,A.<br />
M. Arance Fernandez 6 , H. Schmidt 7 , C. Lebbe 8 , L. Bastholt 9 , O. Hamid 10 ,<br />
P. Rutkowski 11 , C. McNeil 12 , C. Garbe 13 , C. Loquai 14 , B. Dreno 15 , L. Thomas 16 ,J.<br />
J. Grob 17 , D. Hennicken 18 , A. Qureshi 19 , M. Maio 20<br />
Melanoma, Cancer Immunotherapy and Innovative Therapy Unit, Istituto<br />
Nazionale Tumori Fondazione Pascale, Naples, Italy, 2 Medical <strong>Oncology</strong>, National<br />
Cancer Institute, Milan, Italy, 3 Dermatology, Institut Gustave Roussy, Villejuif,<br />
France, 4 Department <strong>of</strong> Diagnostics and Cancer Immunology, Poznan Medical<br />
University, Poznan, Poland, 5 Melanoma and Skin Cancer Unit, Istituto Oncologico<br />
Veneto IRCCS, Padua, Italy, 6 Medical <strong>Oncology</strong>, Hospital Clinic, Barcelona, Spain,<br />
Dept. <strong>of</strong> <strong>Oncology</strong>, Aarhus University Hospital, Aarhus, Denmark, 8 Dermatology,<br />
Hôpital St. Louis, Paris, France, 9 <strong>Oncology</strong>, Odense University Hospital, Odense,<br />
Denmark, 10 Research, The Angeles Clinic and Research Institute, Los Angeles,<br />
CA, USA, 11 S<strong>of</strong>t Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie<br />
Memorial Cancer Center, Warsaw, Poland, 12 <strong>Oncology</strong>, Chris O’Brien Lifehouse<br />
and Royal Prince Alfred Hospital, Camperdown, Australia, 13 Dermatology,<br />
University Hospital Tübingen, Tübingen, Germany, 14 Dermatology, University<br />
Medical Center, Mainz, Germany, 15 Oncodermatology, INSERM Research Unit<br />
892, University Hospital, Nantes, France, 16 Dermatology, Centre Hospitalier Lyon<br />
Sud, Pierre Bénite, France, 17 Service de Dermatologie et Cancérologie Cutanée,<br />
Hopital de la Timone, Marseille, France, 18 Global Biometric Sciences,<br />
Bristol-Myers Squibb, Princeton, NJ, USA, 19 Global Clinical Research,<br />
Bristol-Myers Squibb, Princeton, NJ, USA, 20 Medical <strong>Oncology</strong> and<br />
Immunotherapy, University Hospital <strong>of</strong> Siena, Siena, Italy 1107O Final overall survival for KEYNOTE-002: pembrolizumab<br />
(pembro) versus investigator-choice chemotherapy (chemo)<br />
for ipilimumab (ipi)-refractory melanoma<br />
O. Hamid 1 , I. Puzanov 2 , R. Dummer 3 , J. Schachter 4 , A. Daud 5 , D. Schadendorf 6 ,<br />
C. Blank 7 , L.D. Cranmer 8 , C. Robert 9 , A.C. Pavlick 10 , R. Gonzalez 11 , F.S. Hodi 12 ,<br />
P.A. Ascierto 13 , A. Salama 14 , K.A. Margolin 15 , T.C. Gangadhar 16 ,Z.Wei 17 ,S.<br />
W. Ebbinghaus 17 , N. Ibrahim 17 , A. Ribas 18<br />
1 Melanoma & Skin Cancers Center, The Angeles Clinic and Research Institute, Los<br />
Angeles, CA, USA, 2 Hematology <strong>Oncology</strong>, Vanderbilt Ingram Cancer Center,<br />
Nashville, TN, USA, 3 Dermatology, University <strong>of</strong> Zürich, Zurich, Switzerland,<br />
4 <strong>Oncology</strong>, Ella Institute <strong>of</strong> Melanoma, Sheba Cancer Research Center, Tel<br />
Hashomer, Israel, 5 Medicine, University <strong>of</strong> California San Francisco UCSF,<br />
San Francisco, CA, USA, 6 Dermatology, University Hospital Essen, Essen,<br />
Germany, 7 Medical <strong>Oncology</strong>, The Netherlands Cancer Institute Antoni van<br />
Leeuwenhoek Hospital, Amsterdam, Netherlands, 8 Medicine, University <strong>of</strong><br />
Washington and Seattle Cancer Care Alliance, Seattle, WA, USA, 9 Dermatology,<br />
Gustave Roussy and Paris-Sud University, Villejuif, France, 10 Medicine, New York<br />
University Cancer Institute, New York, NY, USA, 11 Medicine, University <strong>of</strong> Colorado<br />
Denver, Aurora, CO, USA, 12 Medical <strong>Oncology</strong>, Dana-Farber Cancer Institute,<br />
Boston, MA, USA, 13 Unit <strong>of</strong> Melanoma, Cancer Immunotherapy and Innovative<br />
Therapy, Istituto Nazionale Tumori – I.R.C.C.S - Fondazione Pascale, Naples, Italy,<br />
14 Medicine, Duke University, Durham, NC, USA, 15 Medical <strong>Oncology</strong>, City <strong>of</strong> Hope<br />
National Medical Center, Duarte, CA, USA, 16 Hematology/<strong>Oncology</strong> Division,<br />
Abramson Cancer Center <strong>of</strong> the University <strong>of</strong> Pennsylvania, Philadelphia, PA, USA,<br />
17 Clinical research, Merck & Co., Inc., Kenilworth, NJ, USA, 18 Medicine, University<br />
<strong>of</strong> California, Los Angeles, Los Angeles, CA, USA<br />
abstracts<br />
© European Society for Medical <strong>Oncology</strong> 2016. Published by Oxford University Press on behalf <strong>of</strong> the European Society for Medical <strong>Oncology</strong>.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com.
abstracts<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
1111O<br />
Genomic features <strong>of</strong> complete responders (CR) versus fast<br />
progressors (PD) in patients with BRAFV600-mutated<br />
metastatic melanoma treated with<br />
cobimetinib + vemurafenib or vemurafenib alone<br />
Y. Yan 1 , C. Robert 2 , J. Larkin 3 , P.A. Ascierto 4 , B. Dreno 5 , M. Maio 6 , C. Garbe 7 ,P.<br />
B. Chapman 8 , J.A. Sosman 9 , M.J. Wongchenko 1 , J.J. Hsu 10 , I. Chang 10 ,<br />
I. Caro 11 , I. Rooney 11 , G. McArthur 12 , A. Ribas 13<br />
1 <strong>Oncology</strong> Biomarker Development, Genentech, Inc., South San Francisco, CA,<br />
USA, 2 Dermatology, Institut Gustave Roussy, Villejuif, France, 3 Medicine, Royal<br />
Marsden Hospital NHS Foundation Trust, London, UK, 4 Melanoma, Cancer<br />
Immunotherapy and Innovative Therapy Unit, Istituto Nazionale Tumori Fondazione<br />
Pascale, Naples, Italy, 5 Dermato Cancerology, Nantes University, Nantes, France,<br />
6 Medical <strong>Oncology</strong> and Immunotherapy, University Hospital <strong>of</strong> Siena, Siena, Italy,<br />
7 Department <strong>of</strong> Dermatology, Universitätsklinikum Tübingen, Tübingen, Germany,<br />
8 <strong>Oncology</strong>, Memorial Sloan-Kettering Cancer Center, New York, NY, USA,<br />
9 Medicine (Hematology-<strong>Oncology</strong>), Vanderbilt University, Nashville, TN, USA,<br />
10 Biostatistics, Genentech, Inc., South San Francisco, CA, USA, 11 Product<br />
Development <strong>Oncology</strong>, Genentech, Inc., South San Francisco, CA, USA,<br />
12 <strong>Oncology</strong>, Peter McCallum Cancer Centre, Melbourne, Australia, 13 Medicine,<br />
Hematology & <strong>Oncology</strong>, Jonsson Comprehensive Cancer Center at the University<br />
<strong>of</strong> California, Los Angeles, Los Angeles, CA, USA<br />
1108PD<br />
Interim safety and efficacy <strong>of</strong> a randomized (1:1), open-label<br />
phase 2 study <strong>of</strong> talimogene laherparepvec (T) and<br />
ipilimumab (I) vs I alone in unresected, stage IIIB-IV<br />
melanoma<br />
J. Chesney 1 , F. Collichio 2 , R.H.I. Andtbacka 3 , I. Puzanov 4 , J. Glaspy 5 , M. Milhem 6 ,<br />
O. Hamid 7 , L. Cranmer 8 , Y. Saenger 9 , M. Ross 10 , L. Chen 11 , J.J. Kim 12 ,H.<br />
L. Kaufman 13<br />
1 Medical <strong>Oncology</strong> and Hematology, University <strong>of</strong> Louisville, Louisville, KY, USA,<br />
2 School <strong>of</strong> Medicine, University <strong>of</strong> North Carolina - Chapel Hill, Chapel Hill, NC,<br />
USA, 3 Surgical <strong>Oncology</strong>, Huntsman Cancer Institute, Salt Lake City, UT, USA,<br />
4 Hematology <strong>Oncology</strong>, Vanderbilt Ingram Cancer Center, Nashville, TN, USA,<br />
5 Hematology & <strong>Oncology</strong>, David Geffen School <strong>of</strong> Medicine at UCLA, Los Angeles,<br />
CA, USA, 6 Medical <strong>Oncology</strong>, University <strong>of</strong> Iowa, Iowa City, IA, USA, 7 Melanoma<br />
Therapeutics, The Angeles Clinic and Research Institute, Los Angeles, CA, USA,<br />
8 Clinical Medicine, University <strong>of</strong> Arizona Cancer Center, Tucson, AZ, USA,<br />
9 Department <strong>of</strong> Medicine, New York Presbyterian Hospital, Columbia University<br />
Medical Center, New York, NY, USA, 10 Surgical <strong>Oncology</strong>, MD Anderson Cancer<br />
Center, Houston, TX, USA, 11 Global Biostatistical Science, Amgen Inc., Thousand<br />
Oaks, CA, USA, 12 Global Development, Amgen Inc., Thousand Oaks, CA, USA,<br />
13 Surgical <strong>Oncology</strong>, Rutgers Cancer Institute <strong>of</strong> New Jersey, New Brunswick, NJ,<br />
USA<br />
Background: T is a herpes simplex virus 1-based oncolytic immunotherapy designed<br />
to selectively replicate in tumors, produce GM-CSF, and stimulate antitumor immune<br />
responses. I (anti-CTLA-4 Ab) blocks inhibition <strong>of</strong> antitumor T-cells and improves<br />
overall survival (OS) in advanced melanoma. This phase 1b/2 study <strong>of</strong> T + I evaluates<br />
safety and efficacy in unresected stage IIIB-IV melanoma.<br />
Methods: The 1° endpoint for phase 2 is ORR by immune-related response criteria. Key<br />
2° endpoints are safety, progression-free survival, time to response, duration <strong>of</strong> response,<br />
and OS. Key eligibility criteria are unresectable stage IIIB-IV melanoma, ≤1 prior<br />
treatment (tx) if BRAF WT or 2 prior tx if BRAF MT, measurable/injectable tumor(s),<br />
and no symptomatic autoimmunity or clinically significant immunosuppression. T was<br />
given ≤4x10 6 plaque forming units (PFU) on d1, w1; ≤4x10 8 PFU d1, w4, then q2w in<br />
vi380 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
arm 1 until no injectable tumors, disease progression, or intolerance. I started with the<br />
3 rd dose <strong>of</strong> T in arm 1 or alone in arm 2 at 3 mg/kg IV q3w x 4. An ORR interim analysis<br />
(IA) was performed when 82 patients (pts) had ≥48 w <strong>of</strong> follow up.<br />
Results: 173 pts were randomized: 88 T + I; 85 I. Characteristics for all pts were similar:<br />
54% stage IIIB-IVM1a, 45% IVM1b/c. Median follow up time for 82 pts was 61.2 w<br />
(range: 0.14-113.9). Confirmed ORR was 35.7% (T + I) and 17.5% (I); unconfirmed<br />
ORR was 50% (T + I) and 27.5% (I; table). Of 165 pts in the safety set (85 T + I, 80 I),<br />
most common adverse events (AEs) for T + I, I (%) were fatigue (52, 39), chills (51, 3),<br />
diarrhea (39, 34), pyrexia (39, 8), rash (39, 31), and pruritus (38, 35). 20% T + I and<br />
18% I pts had grade 3/4 tx-related AEs. A grade 5 autoimmune hepatitis occurred in<br />
the T + I arm (attributed to I per investigator).<br />
Table: 1108PD<br />
Confirmed* n (%) Unconfirmed^ n (%)<br />
T+In=42 In=40 T+In=42 In=40<br />
ORR - n (%) 15 (35.7) (21.6, 52.0) 7 (17.5) (7.3, 32.8) 21 (50.0) (34.2, 65.8) 11 (27.5) (14.6, 43.9)<br />
(95% CI)<br />
CR 4 (9.5) 4 (10.0) 6 (14.3) 7 (17.5)<br />
PR 11 (26.2) 3 (7.5) 15 (35.7) 4 (10.0)<br />
SD 13 (31.0) 11 (27.5) 7 (16.7) 7 (17.5)<br />
PD 6 (14.3) 5 (12.5) 11 (26.2) 17 (42.5)<br />
UE 5 (11.9) 13 (32.5) 0 (0.0) 1 (2.5)<br />
DCR - n (%)<br />
(95% CI)<br />
28 (66.7) (50.5, 80.4) 18 (45.0) (29.3, 61.5) 28 (66.7) (50.5, 80.4) 18 (45.0) (29.3, 61.5)<br />
*Confirmation <strong>of</strong> initial CR/PR/PD by subsequent assessment by ≥4 w apart.<br />
A CR/PR without confirmation is classified as SD and an unconfirmed PD is<br />
classified as UE.<br />
^Unconfirmed is response or PD without confirmation requirement.<br />
CR: complete response; PR: partial response; SD: stable disease; PD: progressive<br />
disease; UE: unable to evaluate; DCR: disease control rate (SD or better).<br />
Conclusions: ORR was higher for T + I vs I alone at this IA. AEs were comparable<br />
between arms except for increased fatigue, chills, and pyrexia in the T + I arm.<br />
Clinical trial identification: NCT01740297<br />
Legal entity responsible for the study: Amgen Inc.<br />
Funding: Amgen Inc.<br />
Disclosure: J. Chesney: Advisory Board: Amgen Inc. Institution receives funds for<br />
clinical trial costs from Amgen Inc. F. Collichio: Consultant for Amgen Inc. Institution<br />
receives funding for clinical trials from Amgen Inc. R.H.I. Andtbacka: Received<br />
honoraria from Amgen Inc., Merck, and Provectus. I. Puzanov: Consultant for Amgen<br />
Inc. M. Milhem: Advisory boards for EMD Serono, Genentech, Amgen Inc., and<br />
Novartis. O. Hamid: Consultant to Amgen Inc., Novartis, Roche, BMS, Merck. Speaker<br />
for BMS, Genentech, Novartis, Amgen, Inc. Research support from AstraZeneca, BMS,<br />
Celldex, Genentech, Immunocore, Incyte, Merck, Merck-Serono, MedImmune,<br />
Novartis, Pfizer, Rinat, Roche. Y. Saenger: Receive funding through a preclinical award<br />
from Amgen Inc. Recipient <strong>of</strong> an academic/industry paartnership award funded by<br />
Amgen Inc. and the Melanoma Research Alliance. Served on melanoma research<br />
advisory boards for Amgen Inc. more than 12 months ago. M. Ross: Research grants/<br />
support from GSK, Amgen Inc., Merck, and Provectus. Honoraria or consulting fees<br />
from Amgen Inc., GSK, and Merck. Speaker’s bureaus for GSK and Merck.<br />
Compensated for travel expenses from GSK, Amgen Inc., Merck, Provectus, and<br />
Caladrius. L. Chen: Employee and stockholder <strong>of</strong> Amgen Inc. J.J. Kim: Employee <strong>of</strong><br />
Amgen Inc. H.L. Kaufman: Advisory boards for Amgen Inc., EMD Serono, Merck,<br />
Prometheus, and San<strong>of</strong>i. Speaker’s bureau for Merck but returns all honoraria to his<br />
institution. Research funding from Amgen Inc., BMS, EMD Serono, Merck,<br />
Prometheus, and Viralytics. All other authors have declared no conflicts <strong>of</strong> interest.<br />
1109PD<br />
Preliminary safety and clinical activity <strong>of</strong> atezolizumab<br />
combined with cobimetinib and vemurafenib in BRAF<br />
V600-mutant metastatic melanoma<br />
P. Hwu 1 , O. Hamid 2 , R. Gonzalez 3 , J.R. Infante 4 , M.R. Patel 5 , F.S. Hodi 6 ,K.<br />
D. Lewis 3 , J. Wallin 7 , G. Mwawasi 7 , E. Cha 7 , N. Richie 7 , M. Ballinger 7 , R. Sullivan 6<br />
1 Melanoma Medical <strong>Oncology</strong>, MD Anderson Cancer Center, Houston, TX, USA,<br />
2 Melanoma Therapeutics, The Angeles Clinic and Research Institute, Los Angeles,<br />
CA, USA, 3 <strong>Oncology</strong>, University <strong>of</strong> Colorado Comprehensive Cancer Center,<br />
Aurora, CO, USA, 4 Drug Development Program, Sarah Cannon Research Institute/<br />
Tennessee <strong>Oncology</strong>, PLLC, Nashville, TN, USA, 5 Sarah Cannon Research<br />
Institute, Florida Cancer Specialists, Sarasota, FL, USA, 6 <strong>Oncology</strong>, Dana-Farber<br />
Cancer Institute, Boston, MA, USA, 7 <strong>Oncology</strong>, Genentech, Inc., South<br />
San Francisco, CA, USA<br />
Background: Targeted therapy with MEK inhibitor cobimetinib (C) + BRAF inhibitor<br />
vemurafenib (V) in BRAF V600 -mutant melanoma can result in anti-cancer immune<br />
activation and rapid clinical response. Inhibition <strong>of</strong> PD-L1 with atezolizumab (A;<br />
anti-PDL1) can also lead to anti-cancer immune activity and durable responses.<br />
Combining C + V with A, which may enhance and perpetuate antitumor immune<br />
activity, can potentially improve both clinical response and durability.<br />
Methods: In a Phase 1b study, patients (pts) with untreated BRAF V600 -mutant<br />
unresectable or metastatic melanoma received A + C + V after a 28 d run-in period with<br />
C + V. A was dosed IV q2w at 800 mg, C was PO QD at 60 mg for first 21 d <strong>of</strong> each 28 d<br />
cycle and V was PO BID at 960 mg during 1-21 d <strong>of</strong> run-in and 720 mg subsequently.<br />
Results: 14 pts who received ≥ 1 dose <strong>of</strong> A were safety and efficacy evaluable. Median<br />
safety follow-up was 5.6 mo (range 1.5-12.8). All-grade (G) AEs that occurred in > 20%<br />
pts and reported as related to A and/or C and/or V were nausea, fatigue, flu-like<br />
symptoms, photosensitivity, maculopapular rash, elevated ALT/AST and bilirubin,<br />
mucosal inflammation and arthralgia. 6 pts had C- and/or V-related G3-4 AEs during<br />
run-in period, and 5 pts had A- and/or C- and/or V-related G3-4 AEs during the triple<br />
combination period; all were manageable and reversible. There were no unexpected<br />
AEs or G5 AEs. No A-related SAEs occurred. 1 pt discontinued all study treatment due<br />
to elevated ALT/AST. 13/14 pts (93%) showed responses (RECIST v1.1), including 1<br />
CR and 12 PRs. 1 pt with PR had a 100% reduction in target lesions. Responses were<br />
unconfirmed, and median DOR and PFS were not estimable due to limited follow-up<br />
at the time <strong>of</strong> data cut (Feb 15, 2016). 11/13 pts continue in response. Updated data<br />
with functional biomarkers <strong>of</strong> T-cell activation will be presented.<br />
Conclusions: A + C + V combination therapy results in a manageable safety pr<strong>of</strong>ile<br />
and promising anti-tumor activity in pts with BRAF V600 -mutant metastatic melanoma.<br />
These preliminary data show that anti-PDL1 therapy can be successfully combined<br />
with MEK and BRAF inhibitors and warrant further exploration. NCT01656642<br />
Clinical trial identification: NCT01656642<br />
Legal entity responsible for the study: F. H<strong>of</strong>fmann-La Roche Ltd<br />
Funding: F. H<strong>of</strong>fmann-La Roche Ltd<br />
Disclosure: O. Hamid: Consultant, speaker and receives funding from: AstraZeneca<br />
Bristol-Myers Squibb. Celldex Genentech/Roche Immunocore Incyte Merck Merck<br />
Serono MedImmune Novartis Pfizer Rinat. R. Gonzalez: Grants recieved from Roche/<br />
Genentech, BMS, Merck, Amgen. Consultant fees from Roche/Genentech and Novartis.<br />
J.R. Infante: I have no personal financial conflicts <strong>of</strong> interest but my institution receives<br />
research funding and consulting from Genentech. F.S. Hodi: Non-paid advisor to<br />
Genentech, BMS, Merck; member <strong>of</strong> the Amgen advisory board; compenstated advisor<br />
to Novartis; received clinical trials support from Genentech, BMS, Merck and<br />
Novartis. J. Wallin, G. Mwawasi, E. Cha, N. Richie, M. Ballinger: Employee <strong>of</strong><br />
Genentech, Inc. R. Sullivan: Grants from Merck, personal fees from Novartis, outside the<br />
submitted work. All other authors have declared no conflicts <strong>of</strong> interest.<br />
1110PD<br />
abstracts<br />
Epacadostat plus pembrolizumab in patients with advanced<br />
melanoma and select solid tumors: Updated phase 1 results<br />
from ECHO-202/KEYNOTE-037<br />
T.C. Gangadhar 1 , O. Hamid 2 , D.C. Smith 3 , T.M. Bauer 4 , J.S. Wasser 5 ,A.<br />
J. Olszanski 6 , J.J. Luke 7 , A.S. Balmanoukian 2 , D.R. Kaufman 8 , Y. Zhao 9 ,<br />
J. Maleski 9 , M.J. Jones 9 , L. Leopold 9 , T.F. Gajewski 10<br />
1 Hematology/<strong>Oncology</strong> Division, Abramson Cancer Center <strong>of</strong> the University <strong>of</strong><br />
Pennsylvania, Philadelphia, PA, USA, 2 Research Department, The Angeles Clinic<br />
and Research Institute, Los Angeles, CA, USA, 3 Department <strong>of</strong> Internal Medicine<br />
and Department <strong>of</strong> Urology, University <strong>of</strong> Michigan, Ann Arbor, MI, USA, 4 Drug<br />
Development Unit, Sarah Cannon Research Institute/Tennessee <strong>Oncology</strong>,<br />
Nashville, TN, USA, 5 Division <strong>of</strong> Hematology and Medical <strong>Oncology</strong>, University <strong>of</strong><br />
Connecticut Health Center, Farmington, CT, USA, 6 Department <strong>of</strong> Medical<br />
Hematology/<strong>Oncology</strong>, Fox Chase Cancer Center, Philadelphia, PA, USA,<br />
7 Department <strong>of</strong> Medicine, Section <strong>of</strong> Hematology/<strong>Oncology</strong>, University <strong>of</strong><br />
Chicago, Chicago, IL, USA, 8 <strong>Oncology</strong> Clinical Research, Merck & Co., Inc.,<br />
Kenilworth, NJ, USA, 9 Drug Development, Incyte Corporation, Wilmington, DE,<br />
USA, 10 Department <strong>of</strong> Pathology and Department <strong>of</strong> Medicine, Section <strong>of</strong><br />
Hematology/<strong>Oncology</strong>, University <strong>of</strong> Chicago, Chicago, IL, USA<br />
Background: Epacadostat (epac) is an oral, potent, selective inhibitor <strong>of</strong> indoleamine<br />
2,3-dioxygenase 1 (IDO1), a tryptophan-catabolizing enzyme that induces immune<br />
tolerance by T-cell suppression. Preliminary phase 1 results from this ongoing study <strong>of</strong><br />
epac with pembrolizumab (pembro) showed promising clinical activity and an<br />
acceptable safety pr<strong>of</strong>ile (Gangadhar et al, SITC 2015; Hamid et al, SMR 2015).<br />
Updated data from all 62 phase 1 pts as <strong>of</strong> 28March2016 are reported.<br />
Methods: Pts with advanced melanoma and select solid tumors were enrolled; pts<br />
previously treated with checkpoint inhibitors were excluded. Enrollment is complete<br />
for dose escalation (epac 25, 50, 100 mg BID + pembro 2 mg/kg IV Q3W or epac 300<br />
mg BID + pembro 200 mg IV Q3W) and dose expansion (epac 50, 100, and 300 mg<br />
BID + pembro 200 mg IV Q3W). Safety, tolerability, and response (RECIST 1.1) were<br />
evaluated.<br />
Results: The MTD has not been established. The most common (≥15%) all-grade<br />
treatment-related AEs (TRAEs) were fatigue, rash, arthralgia, pruritus, diarrhea, and<br />
nausea. Grade ≥3 TRAEs were observed in 18% (most common: rash [8%] and<br />
increased lipase [3%]). No treatment-related deaths occurred. Among 19 pts who were<br />
treatment-naive for advanced melanoma (M1c 53%), 4 CRs, 7 PRs, and 3 SDs were<br />
observed. Responses were observed in all epac dose cohorts ≥50 mg BID and all sites <strong>of</strong><br />
target lesions including liver, lung, and lymph nodes. All responses are confirmed and<br />
ongoing (median follow-up [min, max]: 42 wks [31.7, 75.9]). Median PFS has not been<br />
reached. Responses were also observed in pts previously treated for advanced<br />
melanoma (n = 3; 1 CR, 1 SD) and pts with NSCLC (n = 12; 5 PRs, 2 SDs), RCC<br />
(n = 11; 3 PRs, 5 SDs), endometrial adenocarcinoma (n = 7; 1 CR, 1 PR), TCC (n = 5; 3<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw379 | vi381
abstracts<br />
PRs), TNBC (n = 3; 2 SDs), SCCHN (n = 2; 1 PR, 1 SD). Based on overall safety and<br />
efficacy, epac 100 mg BID was selected as the RP2D. Biomarker evaluation is ongoing.<br />
Conclusions: Epac with pembro continues to be well tolerated and showed promising<br />
clinical activity. Based on these results, enrollment in tumor-specific cohorts is ongoing<br />
in phase 2 <strong>of</strong> this study and a phase 3 study in pts who are treatment-naive for<br />
advanced melanoma has been initiated (NCT02752074).<br />
Clinical trial identification: NCT02178722<br />
Legal entity responsible for the study: Incyte Corporation and Merck & Co., Inc.<br />
Funding: Incyte Corporation and Merck & Co., Inc.<br />
Disclosure: T.C. Gangadhar, D.C. Smith, T.M. Bauer, J.S. Wasser:<br />
Corporate-sponsored Research - Incyte Corporation (Institution), Merck & Co., Inc.<br />
(Institution). O. Hamid: Consulting - Amgen, BMS, Genentech, Merck & Co., Inc.,<br />
Merck Serono, Novartis, Pfizer, Roche; Speaker - BMS, Genentech, Novartis;<br />
Corporate-sponsored Research (Institution) - Incyte Corporation, Merck & Co., Inc. A.<br />
J. Olszanski: Advisory Board - Merck & Co., Inc, BMS; Corporate-sponsored Research<br />
- Incyte Corporation (Institution), Merck & Co., Inc. (Institution), BMS, Novartis,<br />
Teva, Takeda, Pfizer; Data Safety Monitoring Board: Takeda. J.J. Luke: Advisory Board<br />
- Amgen, Array; Corporate-sponsored Research (Institution) - Novartis, MedImmune,<br />
BMS, Pharmacyclics, BBI Therapeutics, Five Prime Therapeutics, Genentech, Corvus,<br />
Delcath, Abbvie, Celldex, EMD Serono, Incyte Corporation, Merck & Co., Inc. A.S.<br />
Balmanoukian: Corporate-sponsored Research - MedImmune, Merck Serono,<br />
Genentech, Pfizer, Pharmacyclics, Incyte Corporation (Institution), Merck & Co., Inc.<br />
(Institution); Speaker’s Bureau - BMS and Merck & Co., Inc. D.R. Kaufman:<br />
Employment and stock ownership at Merck & Co., Inc. Y. Zhao, J. Maleski, M.J. Jones,<br />
L. Leopold: Employment and stock ownership at Incyte Corporation. T.F. Gajewski:<br />
Advisory Board - Merck & Co., Inc; Corporate-sponsored Research - Incyte<br />
Corporation (Institution), Merck & Co., Inc. (Institution).<br />
1112PD<br />
PD-L1 expression as a biomarker for nivolumab (NIVO) plus<br />
ipilimumab (IPI) and NIVO alone in advanced melanoma<br />
(MEL): A pooled analysis<br />
G.V. Long 1 , J. Larkin 2 , P.A. Ascierto 3 , F.S. Hodi 4 , P. Rutkowski 5 , V. Sileni 6 ,<br />
J. Hassel 7 , C. Lebbe 8 , A.C. Pavlick 9 , J. Wagstaff 10 , D. Schadendorf 11 ,<br />
R. Dummer 12 , D. Hogg 13 , J.B.A.G. Haanen 14 , P. Corrie 15 , C. Hoeller 16 , C. Horak 17 ,<br />
J. Wolchok 18 , C. Robert 19<br />
1 Medical <strong>Oncology</strong>, Melanoma Institute Australia, Sydney, Australia, 2 Department<br />
<strong>of</strong> Medical <strong>Oncology</strong>, Royal Marsden Hospital, London, UK, 3 Melanoma, Cancer<br />
Immunotherapy and Innovative Therapy Unit, Istituto Nazionale Tumori Fondazione<br />
Pascale, Naples, Italy, 4 <strong>Oncology</strong>, Dana-Farber Cancer Institute, Boston, MA,<br />
USA, 5 <strong>Oncology</strong>, MSC Memorial Cancer Centre and Institute Maria<br />
Sklodowska-Curie, Warsaw, Poland, 6 <strong>Oncology</strong>, Istituto Oncologico Veneto,<br />
Padua, Italy, 7 <strong>Oncology</strong>, University Hospital Heidelberg, Heidelberg, Germany,<br />
8 Dermatology, Hôpital St. Louis, Paris, France, 9 Department <strong>of</strong> Medicine,<br />
New York University School <strong>of</strong> Medicine, New York, NY, USA, 10 South West Wales<br />
Cancer Institute, South West Wales Cancer Institute Singleton Hospital, Sketty,<br />
Swansea, UK, 11 Cancer, University Hospital <strong>of</strong> Essen, Essen, Germany,<br />
12 Department <strong>of</strong> Dermatology, University Hospital Zurich, Zurich, Switzerland,<br />
13 Department <strong>of</strong> Medical <strong>Oncology</strong> and Hematology, Princess Margaret Hospital,<br />
Toronto, ON, Canada, 14 Department <strong>of</strong> Medical <strong>Oncology</strong>, The Netherlands<br />
Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands,<br />
15 <strong>Oncology</strong> Centre, Addenbrooke’s Hospital University <strong>of</strong> Cambridge Hospitals,<br />
Cambridge, UK, 16 Dpt. <strong>of</strong> Dermatology and Dermatooncology, Medizinische<br />
Universitaet Wien (Medical University <strong>of</strong> Vienna), Vienna, Austria, 17 Clinical<br />
Biomarkers, BMS, Princeton, NJ, USA, 18 Ludwig Center, Memorial Sloan<br />
Kettering Cancer Center, New York, NY, USA, 19 <strong>Oncology</strong>, Gustave Roussy and<br />
Paris-Sud University, Villejuif, France<br />
Background: NIVO + IPI and NIVO showed superior clinical activity vs IPI in a phase<br />
3 trial <strong>of</strong> MEL patients (pts), irrespective <strong>of</strong> PD-L1 tumor expression. Among pts with<br />
high PD-L1 expression (≥5%), median progression-free survival (mPFS) was similar<br />
between NIVO + IPI and NIVO, but overall response rate (ORR) was higher with<br />
NIVO + IPI. We describe PD-L1 as a biomarker for NIVO + IPI and NIVO efficacy<br />
across phase 2 (CheckMate 069) and phase 3 (CheckMate 066 and 067) trials.<br />
Methods: Treatment-naïve pts (N = 832) with MEL received NIVO 1 mg/kg + IPI 3<br />
mg/kg Q3W × 4 or NIVO 3 mg/kg Q2W, followed by NIVO 3 mg/kg Q2W until<br />
progression or unacceptable toxicity. Tumor tissue from primary or metastatic sites,<br />
obtained at screening, was assessed for PD-L1 expression using a validated Dako<br />
immunohistochemistry assay. Minimum pt follow-up was 18 months (mos). Survival<br />
data remain immature.<br />
Results: The proportion <strong>of</strong> pts with PD-L1 expression ≥5% was 26% (92/358) for<br />
NIVO + IPI and 29% (139/474) for NIVO. Pt characteristics were similar between<br />
PD-L1 subgroups, although fewer pts had LDH > ULN in the PD-L1 ≥5% subgroup.<br />
Among pts with PD-L1 expression ≥5%, mPFS <strong>of</strong> NIVO + IPI was not reached (NR)<br />
and was 22.0 mos for NIVO alone (hazard ratio [HR]: 0.99, 95% CI: 0.66─1.46). For<br />
pts with low to no PD-L1 (
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
>75 than those ≤75 (14/35, [40%] and 95/256, [37%], p > 0.05), and the rates <strong>of</strong><br />
discontinuation for toxicity were similar (0.05% and 0.05%, p > 0.05). Median PFS and<br />
OS was similar in older (8.7 months and 33.5 months) and younger (4.6months and<br />
48.1m onths) patients (P = 0.48). Updated analysis including efficacy associations with<br />
primary melanoma features and blood parameters at baseline and early during<br />
treatment across the whole cohort will be presented.<br />
Conclusions: Anti-PD-1 antibodies are safe and effective in elderly patients, with<br />
response and toxicity pr<strong>of</strong>iles similar to that observed in younger patients.<br />
Clinical trial identification: Not applicable<br />
Legal entity responsible for the study: Royal Prince Alfred HREC<br />
Funding: Academic group<br />
Disclosure: A. Guminski: Advisory board member: Pfizer, BMS. M.S. Carlino:<br />
Advisory board member for MSD, BMS, Amgen, Novartis. Honoraria: MSD, BMS,<br />
Novartis. M. Davies: Advisory board: Novartis, GlaxoSmithKline, Genetech,<br />
San<strong>of</strong>i-Aventis, Vaccinex Reseasrh funding: Glaxosmithkline, Genentech, Astazaneca,<br />
Oncothyreon, San<strong>of</strong>i-Aventis. D.B. Johnson: Advisory board: BMS, Genoptix. G.V.<br />
Long: Consultant advisor to BMS, Merck, MSD, Amgen, Novartis. Honoraria for<br />
Merck, BMS and Novartis. A.M. Menzies: Advisory board MSD, Chugai. Honoraria –<br />
BMS, Novartis. All other authors have declared no conflicts <strong>of</strong> interest.<br />
1114PD<br />
Efficacy <strong>of</strong> anti-PD-1 therapy in patients with melanoma<br />
brain metastases<br />
J.J. Park 1 , S. Parakh 2 , S. Mendis 3 , R. Rai 4 ,S.Lo 4 , A. Haydon 3 , M.C. Andrews 2 ,<br />
J. Cebon 2 , A. Guminski 4 , R. Kefford 1 , G.V. Long 4 , A.M. Menzies 4 , O. Klein 2 ,M.<br />
S. Carlino 1<br />
1 Medical <strong>Oncology</strong>, Crown Princess Mary Cancer Centre, Westmead Hospital,<br />
Sydney, Australia, 2 Department <strong>of</strong> Medical <strong>Oncology</strong>, Olivia Newton-John Cancer<br />
and Wellness Centre, Austin Hospital, Melbourne, Australia, 3 Medical <strong>Oncology</strong>,<br />
Alfred Hospital, Melbourne, Australia, 4 Melanoma, Melanoma Institute <strong>of</strong> Australia<br />
and The University <strong>of</strong> Sydney, Sydney, Australia<br />
Background: Patients (pts) with metastatic melanoma and untreated, symptomatic or<br />
progressing brain metastasis (BM) have a poor prognosis and have been excluded from<br />
the published trials <strong>of</strong> the anti-programmed death 1 (PD-1) antibodies pembrolizumab<br />
and nivolumab; as a result there is limited data on the efficacy and safety <strong>of</strong> these agents<br />
in this cohort <strong>of</strong> patients.<br />
Methods: We retrospectively assessed the efficacy <strong>of</strong> PD-1 agents in pts with metastatic<br />
melanoma with BM treated across four centres. Patient demographics, tumour<br />
characteristics, and treatment history including corticosteroid use were collected.<br />
Intracranial (IC) and extracranial (EC) response rates (RR) and progression-free<br />
survival (PFS) were analysed. Response was determined by modified RECIST where up<br />
to 5 IC target lesions were used for IC assessment.<br />
Results: 81 pts were identified with interim analysis <strong>of</strong> 39 reported here with median F/<br />
U <strong>of</strong> 8.5 months (95% CI 5.1 to 11.4). 77% pts were male. At PD-1 inhibitor<br />
commencement, 56% had an elevated LDH; 64%, 26% and 10% had an ECOG <strong>of</strong> 0-1, 2<br />
and >2 respectively. Median no. <strong>of</strong> IC lesions was 4 (range 1-20). 26 (67%) had local<br />
therapy (RT or surgery) to BM prior to PD-1 therapy. 23 (59%) were BRAF mutant, 9<br />
(23%) started anti-PD-1 as 1 st line therapy. Dexamethasone was used in 13 (33%) pts<br />
with dose range <strong>of</strong> 0.5 – 8mg. The IC RR was 10/39 (26%), including pts with<br />
symptomatic BM and pts receiving steroids (see Table). 2/10 IC RR had no prior<br />
RT (SRS or WBRT), 3/10 had concurrent RT and 5/10 had prior RT. The EC RR was<br />
6/35 (17%).<br />
Best IC<br />
response<br />
All pts<br />
(N = 39)<br />
Symptomatic<br />
BM (N = 18)<br />
Table: 1114PD<br />
Corticosteroids for<br />
BM (N = 13)<br />
CR/PR 10 2 2 8<br />
SD 8 5 4 8<br />
PD 12 5 5 8<br />
Clinical PD<br />
(without<br />
imaging)<br />
9 6 2 4<br />
Radiotherapy prior<br />
to or during PD-1<br />
(N = 28)<br />
Median IC PFS was 2.1 months (95% CI 1.3 – 2.9) and median EC PFS was 2.1<br />
months (95% CI 1.9 – 3.4). Updated analysis with the full cohort and with longer<br />
follow-up will be presented.<br />
Conclusions: IC responses to anti-PD-1 agents were seen in pts with symptomatic BM<br />
and those requiring corticosteroids. Prospective trials evaluating anti-PD-1 therapy in<br />
pts with BM are underway, although pts with the poor prognostic features included in<br />
this series are unlikely to be represented in prospective trials.<br />
Legal entity responsible for the study: Melanoma Institute Australia, Medical<br />
<strong>Oncology</strong> Department, Westmead Hospital<br />
Funding: Melanoma Institute Australia, Medical <strong>Oncology</strong> Department, Westmead<br />
Hospital<br />
Disclosure: R. Kefford: Advisory boards: Merck, BMS. Honoraria: Merck, BMS<br />
Conference Reporting: BMS. G.V. Long: Consultant Advisor to Amgen, BMS, Merck,<br />
Novartis and Roche. Honoraria Merck, Novartis and BMS. A.M. Menzies: Advisory<br />
board - MSD, Chugai; Honoraria - BMS, Novartis. M.S. Carlino: Advisory board<br />
member for MSD, BMS, Amgen, Novartis. Honoraria: MSD, BMS, Novartis. All other<br />
authors have declared no conflicts <strong>of</strong> interest.<br />
1115P<br />
Estimating the percentage <strong>of</strong> patients with advanced<br />
melanoma achieving long-term survival with pembrolizumab<br />
(Pembro) treatment in KEYNOTE-006<br />
C. Blank 1 ,J.Ma 2 , J.J. Grob 3 , J. Larkin 4 , B. Neyns 5 , C. McNeil 6 , M. Lotem 7 ,<br />
E. Richtig 8 , G. Masucci 9 , T. Petrella 10 , A. Ribas 11 , J. Wang 2 , N. Ibrahim 2 ,K.<br />
M. Anderson 2 , A. Arance 12<br />
1 Dept Medical <strong>Oncology</strong>, The Netherlands Cancer Institute, Amsterdam,<br />
Netherlands, 2 <strong>Oncology</strong>, Merck & Co., Inc., Kenilworth, NJ, USA, 3 <strong>Oncology</strong>,<br />
Hôpital de la Timone, Marseille, France, 4 <strong>Oncology</strong>, The Royal Marsden, London,<br />
UK, 5 Medical <strong>Oncology</strong>, Universitair Ziekenhuis Brussel, Brussels, Belgium,<br />
6 <strong>Oncology</strong>, Chris O’Brien Lifehouse, Camperdown, Australia, 7 <strong>Oncology</strong>,<br />
Hadassah University Hospital, Jerusalem, Israel, 8 Dermatology and Venereology,<br />
Medical University <strong>of</strong> Graz, Graz, Austria, 9 <strong>Oncology</strong>-Pathology, Karolinska<br />
Univeritetssjukhuset, Solna, Sweden, 10 <strong>Oncology</strong>, Sunnybrook Hospital, Toronto,<br />
ON, Canada, 11 Medicine, Hematology & <strong>Oncology</strong>, University <strong>of</strong> California, Los<br />
Angeles, Los Angeles, CA, USA, 12 <strong>Oncology</strong>, Hospital Clínic Barcelona,<br />
Barcelona, Spain<br />
Background: The superior efficacy <strong>of</strong> pembro in prolonging overall survival (OS) over<br />
ipilimumab (ipi) has been demonstrated in the randomized phase 3 KEYNOTE-006<br />
study (ClinicalTrials.gov, NCT01866319). Accumulating evidence suggests that<br />
immunotherapies such as pembro can even help some patients with advanced<br />
melanoma achieve long-term survival. The percentage <strong>of</strong> these long-term survivors<br />
over a defined population can be estimated by statistical methods, and herein is referred<br />
to as the “long-term survival” (LTS) rate <strong>of</strong> treatment. With the emergence <strong>of</strong><br />
immunotherapies, LTS rate is increasingly important for quantifying the effectiveness<br />
and overall benefit <strong>of</strong> different treatment options.<br />
Methods: Since conventional parametric survival models do not account for the<br />
concept <strong>of</strong> LTS rate, an alternative, but well-established, class <strong>of</strong> statistical models called<br />
“cure-rate” survival models were used to estimate the percentage <strong>of</strong> long-term<br />
survivors. The intention-to-treat population <strong>of</strong> KEYNOTE-006 included 834 patients<br />
with advanced melanoma; 556 were randomized to pembro, and the remainder to ipi<br />
(control). LTS rates were estimated using the March 3, 2015, data cut and were<br />
subsequently updated using the December 3, 2015, data cut as validation.<br />
Results: With the initial data set, the pembro and ipi LTS rates were estimated as 54.9%<br />
(95% confidence interval [CI], 39.2%-63.7%) and 39.5% (23.5%-50.7%), respectively.<br />
With the subsequent data set, the pembro and ipi LTS rates were estimated as 49.2%<br />
(42.6%-55.3%) and 34.8% (26.5%-42.2%), respectively. The widths <strong>of</strong> CIs <strong>of</strong> the second<br />
data set narrowed substantially with longer follow-up.<br />
Conclusions: The estimated long-term benefits <strong>of</strong> pembro and ipi were reasonably<br />
consistent between the 2 data sets from KEYNOTE-006, suggesting that early estimates<br />
can be useful, with later estimates improving accuracy. The analysis suggests that about<br />
50% <strong>of</strong> patients with advanced melanoma could achieve long-term survival with<br />
pembro treatment.<br />
Clinical trial identification: NCT01866319<br />
Legal entity responsible for the study: Merck & Co., Inc.<br />
Funding: Merck & Co., Inc.<br />
Disclosure: J. Ma, J. Wang, K.M. Anderson: Employee <strong>of</strong> Merck & Co, Inc. N. Ibrahim:<br />
Employee and Stockholder <strong>of</strong> GSK and Merck & Co, Inc. All other authors have<br />
declared no conflicts <strong>of</strong> interest.<br />
1116P<br />
abstracts<br />
Complete responders to anti-PD1 antibodies. What happens<br />
when we stop?<br />
V.G. Atkinson 1 , R. Ladwa 2<br />
1 Division <strong>of</strong> Cancer Services, University <strong>of</strong> Queensland, Brisbane, Australia,<br />
2 Division <strong>of</strong> Cancer Services, Princess Alexandra Hospital, Brisbane, Australia<br />
Background: PD-1 antibodies are now recognized as a standard therapy for advanced<br />
melanoma. The optimal duration is unknown, with initial trials ceasing therapy on<br />
progression or intolerance. Subsequent trials have had a pre-defined stopping point <strong>of</strong><br />
2 years <strong>of</strong> therapy. Within trials with Pembrolizumab there has also been the potential<br />
to cease therapy after 6 months if the patient is a complete responder (CR). The data<br />
from these trials and the number <strong>of</strong> patients (pts) who stopped for CR has not been<br />
reported. In practice pts <strong>of</strong>ten request to cease therapy after CR, this is the first report<br />
<strong>of</strong> a cohort <strong>of</strong> pts who has chosen to do this.<br />
Methods: A retrospective review was conducted <strong>of</strong> CR to PD-1 based therapy across 2<br />
institutions from a single prescriber. Pts were from Pembrolizumab Named Patient<br />
Program (PEM NPP), Nivolumab monotherapy (NIVO) and reimbursed<br />
Pembrolizumab (r PEM). To be eligible, pts had to have experienced a CR to PD-1<br />
based therapy and ceased therapy because <strong>of</strong> this. Data were included from pts<br />
including assessments <strong>of</strong> select (immune-related) adverse events, time to onset <strong>of</strong> CR,<br />
number <strong>of</strong> doses <strong>of</strong> PD-1 antibody, time <strong>of</strong>f therapy and relapses.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw379 | vi383
abstracts<br />
Results: Twenty-four pts were noted to have had a CR and ceased therapy. The median<br />
age was 64 (27-83) years. Twenty pts (83%) were BRAF wild type and 4 (17%) pts<br />
BRAF mutant. The median number <strong>of</strong> cycles were 15 on PEM NPP, 18 on NIVO and<br />
11 on r PEM. The median time to CR was 10 months in the PEM NPP/ r PEM groups<br />
and 17 months in the NIVO group. The median time <strong>of</strong>f therapy in PEM NPP was 7<br />
months, NIVO was 8 months and r PEM was 2 months. To date only one patient from<br />
PEM NPP has relapsed and been successfully re-induced.<br />
Conclusions: This is the first report <strong>of</strong> a cohort <strong>of</strong> patients who have intentionally<br />
ceased PD-1 based therapy because <strong>of</strong> CR. While the follow up is short as yet only one<br />
patient has relapsed <strong>of</strong>f therapy and has been successfully re-induced. Data such as this<br />
is both clinically relevant as we need to be able to discuss cessation for CR with our<br />
patients and relevant from a pharmaco-economic perspective given the cost <strong>of</strong> PD-1<br />
antibodies to society.<br />
Legal entity responsible for the study: This has been at the review by the Ethics<br />
Committee <strong>of</strong> Princess Alexandra Hospital<br />
Funding: N/A<br />
Disclosure: V.G. Atkinson: BMS, MSD, Novartis Advisory Board BMS, MSD,<br />
Novartis Speaker fees and travel support. All other authors have declared no conflicts<br />
<strong>of</strong> interest.<br />
1117P<br />
A dose escalation phase 1 study <strong>of</strong> radiotherapy (RT) in<br />
combination with anti-cytotoxic-T-lymphocyte-associated<br />
antigen 4 (CTLA-4) monoclonal antibody ipilimumab (Ipi) in<br />
patients (pts) with metastatic melanoma<br />
C. Boutros 1 , C. Mateus 1 , E. Routier 1 , S. Chouaib 2 , C. Libenciuc 1 , M. Reigneau 1 ,<br />
I. Girault 3 , C. Caramella 4 , S. Hibat 4 , S. Vagner 5 , Y.G. Tao 6 , N. Chaput 7 , J. Adam 8 ,<br />
J-C. Soria 9 , A. Eggermont 1 , E. Deutsch 6 , C. Robert 1<br />
1 Department <strong>of</strong> Cancer Medicine, Gustave Roussy, University Paris-Saclay,<br />
Villejuif, France, 2 INSERM U1186, Gustave Roussy, University Paris-Saclay,<br />
Villejuif, France, 3 INSERM U981, Gustave Roussy, University Paris-Saclay, Villejuif,<br />
France, 4 Department <strong>of</strong> Radiology, Gustave Roussy, University Paris-Saclay,<br />
Villejuif, France, 5 UMR3348, Institut Curie, Paris, France, 6 Department <strong>of</strong><br />
Radiotherapy, Gustave Roussy, University Paris-Saclay, Villejuif, France,<br />
7 Laboratory <strong>of</strong> Immunomonitoring in <strong>Oncology</strong>, UMS 3655 CNRS/US 23 INSERM,<br />
Gustave Roussy, University Paris-Saclay, Villejuif, France, 8 Department <strong>of</strong><br />
Pathology, Gustave Roussy, University Paris-Saclay, Villejuif, France, 9 Drug<br />
Development Department (DITEP), Gustave Roussy, University Paris-Saclay,<br />
Villejuif, France<br />
Background: A synergy between RT and anti-CTLA-4 monoclonal antibody has been<br />
demonstrated preclinically and preliminary clinical data suggest that it could be due to<br />
an abscopal effect <strong>of</strong> RT. The Mel-Ipi-Rx phase 1 study aimed to determine the<br />
maximum tolerated dose (MTD) and safety pr<strong>of</strong>ile <strong>of</strong> RT combined with Ipi in pts with<br />
metastatic melanoma.<br />
Methods: A 3 + 3 dose escalation design was used with 9, 15, 18 and 24 Gy <strong>of</strong> RT (in 3<br />
fractions) at week 4 combined with 10 mg/kg Ipi (every 3 weeks for 4 doses). Pts with<br />
evidence <strong>of</strong> clinical benefit at week 12 were eligible for maintenance Ipi at 10 mg/kg<br />
every 12 weeks starting at week 24 until severe toxicity or disease progression based on<br />
immune-related response criteria (irRC). The adverse events (AEs) were graded<br />
according to the National Cancer Institute Common Terminology Criteria for AEs,<br />
version 4.0. Tumors and blood were collected before and during treatment for<br />
translational research analyses.<br />
Results: 19 pts received Ipi between August 2011 and July 2015. 9 pts received the 4<br />
doses <strong>of</strong> Ipi and 2 pts received maintenance Ipi (1 and 2 cycles respectively). All pts<br />
received the combined RT at week 4 in 3 fractions. All pts presented at least one AE <strong>of</strong><br />
any grade. The most common AEs were asthenia, diarrhea, fever, nausea and vomiting.<br />
Grade 3 AEs occurred in 8 pts. They included colitis (n = 3), hepatitis (n = 2), anemia<br />
(n = 2), asthenia (n = 1), thyroid disorders (n = 1) and nausea/vomiting (n = 1). 9 pts<br />
discontinued the study owing to treatment-related adverse events including colitis<br />
(n = 6), hepatitis (n = 2) and DRESS syndrome (Drug Rash with Eosinophilia and<br />
systemic syndrome) (n = 1). DLT occurred in 2/6 pts in the cohort receiving 15 Gy. No<br />
drug-related death occurred. According to irRC, 4 partial responses (ORR: 21%) and 4<br />
stable diseases were observed at week 24. The MTD was 9 Gy. One pt out <strong>of</strong> 12 treated<br />
in the 9 Gy cohort presented a DLT (grade 3 colitis).<br />
Conclusions: When combined with Ipi at 10 mg/kg, in the present design, the MTD <strong>of</strong><br />
RT was 9 Gy. This combination appears to be associated with antitumor activity.<br />
Translational research results will be available and presented.<br />
Clinical trial identification: EUDRACT 2010-020317-93 (release date not applicable)<br />
Legal entity responsible for the study: N/A<br />
Funding: Gustave Roussy, Villejuif, France<br />
Disclosure: C.Mateus:Consultant<strong>of</strong>BMSandMerck.E.Routier:Consultant<strong>of</strong><br />
andBMSandRoche.J-C.Soria:Consultant <strong>of</strong> Astra-Zeneca, Merus, MSD, Pfizer,<br />
Roche, Servier and Symphogen. A. Eggermont: Member <strong>of</strong> the Scientific Advisory<br />
Board <strong>of</strong> BMS, Incyte, Medimmune and Merck. C. Robert: Consultant <strong>of</strong> Amgen,<br />
BMS, GSK, Merck, Novartis and Roche. All other authors have declared no conflicts<br />
<strong>of</strong> interest.<br />
1118P<br />
GRAY-B: An open label multicenter phase-2 GEM study on<br />
ipilimumab and radiation in patients with melanoma and<br />
brain metastases<br />
J.A. Lopez Martin 1 , L. de la Cruz Merino 2 , A.M. Arance Fernandez 3 , A. Illescas 4 ,I.<br />
Valduviecu Ruiz 5 , A. Berrocal 6 , J. Lopez-Torrecilla 7 , I. Marquez Rodas 8 , M.V.<br />
Soriano Teruel 9 , A. Alvarez Gonzalez 10 , M.L. Chust Vicente 11 ,D.<br />
Rodriguez Abreu 12 , R. Cabrera 13 , M.C. Penas Sanchez 14 , T. Curiel 15 ,E.<br />
Munoz Couselo 16 , J.J. Aristu 17 , A. Gomez-Caamano 18 , J. Medina Martinez 19 ,<br />
S. Martin-Algarra 20<br />
1 Medical <strong>Oncology</strong>, 12 de Octubre University Hospital & Research Institute,<br />
Madrid, Spain, 2 Medical <strong>Oncology</strong>, Hospital Universitario Virgen Macarena, Seville,<br />
Spain, 3 Medical <strong>Oncology</strong>, Hospital Clinic y Provincial de Barcelona, Barcelona,<br />
Spain, 4 Radiation <strong>Oncology</strong>, Hospital Universitario Virgen Macarena, Seville,<br />
Spain, 5 Radiation <strong>Oncology</strong>, Hospital Clinic y Provincial de Barcelona, Barcelona,<br />
Spain, 6 Medical <strong>Oncology</strong>, Hospital General Universitario Valencia, Valencia,<br />
Spain, 7 Radiation <strong>Oncology</strong>, Hospital General Universitario Valencia, Valencia,<br />
Spain, 8 Medical <strong>Oncology</strong>, Hospital General Universitario Gregorio Marañon,<br />
Madrid, Spain, 9 Medical <strong>Oncology</strong>, Fundación Instituto Valenciano de Oncología,<br />
Valencia, Spain, 10 Radiation <strong>Oncology</strong>, Hospital General Universitario Gregorio<br />
Marañon, Madrid, Spain, 11 Radiation <strong>Oncology</strong>, Fundación Instituto Valenciano de<br />
Oncología, Valencia, Spain, 12 Medical <strong>Oncology</strong>, Hospital Universitario Insular de<br />
Gran Canaria, Las Palmas, Spain, 13 Radiation <strong>Oncology</strong>, Hospital Universitario<br />
Insular de Gran Canaria, Las Palmas, Spain, 14 Radiation <strong>Oncology</strong>, 12 de Octubre<br />
University Hospital & Research Institute, Madrid, Spain, 15 Medical <strong>Oncology</strong>,<br />
Complejo Hospitalario Universitario de Santiago de Compostela SERGAS,<br />
Santiago De Compostela, Spain, 16 Medical <strong>Oncology</strong>, Vall d’Hebron University<br />
Hospital Institut d’Oncologia, Barcelona, Spain, 17 Radiation <strong>Oncology</strong>, Clinica<br />
Universitaria de Navarra, Pamplona, Spain, 18 Radiation <strong>Oncology</strong>, Complejo<br />
Hospitalario Universitario de Santiago de Compostela SERGAS, Santiago De<br />
Compostela, Spain, 19 Medical <strong>Oncology</strong>, Hospital Virgen de la Salud, Toledo,<br />
Spain, 20 Medical <strong>Oncology</strong>, Clinica Universitaria de Navarra, Pamplona, Spain<br />
Background: Estimated median overall survival (OS) in patients (pts) with brain<br />
metastases (BM) ranges between 1.8-10.5 months (mo). Ipilimumab (IPI) has shown<br />
activity against mel-BM. Radiation (RT) might be synergistic to anti-CTLA-4 blockade<br />
through an ‘abscopal’ effect.<br />
Methods: Open label single stage multicenter phase 2 study, assuming a historical 20%<br />
1-year survival rate (1y SR) with RT. Target sample size: 56 evaluable pts. Target 1y SR:<br />
35% (α= 0.05, β= 0.2). Objectives: Primary: 1y SR; Secondary: progression free survival<br />
(PFS); OS; objective response rate (mWHO); safety and feasibility. Treatment: IPI 3<br />
mg/Kg iv q 3 weeks (4 cycles); whole brain RT (WBRT) 30 Gy in 10 fractions (or<br />
equivalent), started between C1 and C2. Main eligibility: First episode <strong>of</strong> BM in mel<br />
pts; Karn<strong>of</strong>sky PS > 70%; Barthel Index > 10; RTOG-RPA class 2; measurable disease;<br />
LDH < 2 x ULN; not eligible for radical therapy; not experiencing rapid clinical<br />
deterioration; not requiring dexamethasone > 16 mg/d (or equivalent).<br />
Results: This is a preliminary analysis after recruiting 43/56 pts (Apr 2014 - Mar 2016).<br />
Demographical characteristics are shown in the table.<br />
Table: 1118P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Age (median (range)) 65 (37-83)<br />
Gender (male; female) 25; 18<br />
Karn<strong>of</strong>sky PS(100-90; 70-80) 33; 8<br />
Barthel Index (>15; 10-15) 35; 2<br />
BRAF mutation 33% (11/33)<br />
Previous lines (0; 1; >1) 22; 14; 7<br />
Previous BRAF/MEK inh 9.3% (4/43)<br />
Brain mets (single; multiple; NA) 8; 29; 6<br />
Liver mets 10/43<br />
Corticosteroids at baseline/C1 32.4%<br />
Treatment exposure: IPI: 19 pts completed 4 cycles; RT: 3 pts had early termination.<br />
Efficacy: Estimated 1y SR: 31.4% (95%CI 14.0;48.8%), median OS 5.2 mo (95%CI<br />
3.1;6.3); median PFS: 3.21 mo (95%CI 1.7;4.7). Safety: Serious AEs were reported for 23<br />
pts (53.5%), 4 were treatment-related, G3 hepatic toxicity (IPI), G3 cephalalgia and<br />
vomiting (RT), G2 scalp erythema (RT) and G3 left hemiparesis. Treatment-related G3<br />
toxicities were seen in 6 pts (14%): asthenia, skin rash, cephalalgia, emesis,<br />
hypothyroidism, liver toxicity, hemiparesia. A total <strong>of</strong> 22 pts died; none <strong>of</strong> the deaths<br />
were study-related.<br />
Conclusions: Concomitant IPI + WBRT is feasible. There were no unexpected safety<br />
issues. Despite the frequent need for costicosteroids at baseline, interim 1y SR is 31.4%.<br />
The trial is ongoing. Updated results will be presented.<br />
Clinical trial identification: EudraCT 2013-001132-22<br />
Legal entity responsible for the study: GEM (Grupo Español de Melanoma /<br />
Melanoma Spanish Group)<br />
Funding: BMS<br />
Disclosure: J.A. Lopez Martin: BMS: research grant, Advisory Board MSD: research<br />
grant, advisory board Roche: research grant Novartis: research grant. I. Marquez Rodas:<br />
vi384 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Advisory role: BMS honoraria and travel accomodation: BMS. S. Martin-Algarra: BMS:<br />
Advisory Board, paid lectures. All other authors have declared no conflicts <strong>of</strong> interest.<br />
1119P<br />
The efficacy <strong>of</strong> nivolumab for unresectable metastatic<br />
mucosal melanoma<br />
A. Takahashi, A. Tsutsumida, K. Namikawa, Y. Nakamura, I. Muto, N. Yamazaki<br />
Dermatologic oncology, National Cancer Center Hospital, Tokyo, Japan<br />
Background: As there is no established systemic therapy for unresectable metastatic<br />
mucosal melanoma, treatment has been selected on the basis <strong>of</strong> the available treatment<br />
for primary cutaneous melanomas. In Japan, although dacarbazine (DTIC) or<br />
DTIC-based combination therapy has been performed, it has been difficult to achieve<br />
certain therapeutic outcomes. After nivolumab, an anti-PD-1 antibody, was approved,<br />
it was anticipated to be effective against primary mucosal melanomas; however, this<br />
remains unclear. This study was conducted to investigate the efficacy <strong>of</strong> nivolumab<br />
against unresectable metastatic mucosal melanoma.<br />
Methods: We retrospectively analysed 27 unresectable metastatic mucosal melanoma<br />
cases for which nivolumab had been administered at National Cancer Center Hospital<br />
between July 2014 and January 2016. All cases were administered nivolumab (2 mg/kg,<br />
every 3 weeks) at least three times and therapeutic effects were evaluated according to<br />
RECIST 1.1 on the basis <strong>of</strong> diagnostic imaging.<br />
Results: The subjects included 12 men and 15 women, and the median age was 68<br />
years (48–85 years). The primary onset sites included the nasal cavity (12 cases),<br />
esophagus (4 cases), conjunctiva (4 cases), the palate (3 cases), the urethra/bladder (2<br />
cases), and rectum (2 cases). The number <strong>of</strong> metastasized organs including lymph<br />
node metastasis prior to nivolumab administration ranged from 1 to a maximum <strong>of</strong><br />
7. The best overall responses were complete response (2 cases: 7.4%), partial response<br />
(7 cases: 25.9%), stable disease (4 cases: 14.8%), and progressive disease (14 cases;<br />
51.9%), resulting in the overall response rate <strong>of</strong> 33.3%. The response rates for the<br />
melanoma <strong>of</strong> primary onset sites were 25% (3/12 cases) for the nasal cavity, 50% (2/4<br />
cases) for the esophagus, 50% (2/4 cases) for the conjunctiva, 50% (1/2 cases) for the<br />
urethra/bladder, 33.3% (1/3 cases) for the palate, and 0% (0/2 cases) for the rectum.<br />
The therapeutic effects were still maintained for 8 <strong>of</strong> the 9 successful cases as <strong>of</strong> April<br />
2016.<br />
Conclusions: Nivolumab was effective for unresectable metastatic mucosal melanoma<br />
as well as for primary cutaneous melanoma. Furthermore, the therapeutic effects were<br />
maintained in successful cases.<br />
Legal entity responsible for the study: National Cancer Center Hospital<br />
Funding: National Cancer Center Hospital<br />
Disclosure: N. Yamazaki: Advisory Board role for Chugai Pharma, Bristol-Myers<br />
Squibb (BMS) Japan and Ono Pharmaceutical. The institution has received clinical<br />
trial support from Chugai, BMS Japan, Ono, GSK, Takeda, AstraZeneca Japan,<br />
Boehringer Ingelheim, and Maruho. All other authors have declared no conflicts <strong>of</strong><br />
interest.<br />
1120P<br />
Single center experience on patients with advanced<br />
melanoma treated with short-term anti-CTLA4 directly<br />
followed by anti-PD-1<br />
E.A. Rozeman 1 , A. Meerveld-Eggink 1 , F. Lalezari 2 , J.V. van Thienen 1 , J.B.A.<br />
G. Haanen 1 , C. Blank 1<br />
1 Department <strong>of</strong> Medical <strong>Oncology</strong>, The Netherlands Cancer Institute - Antoni van<br />
Leeuwenhoek Hospital, Amsterdam, Netherlands, 2 Department <strong>of</strong> Radiology, The<br />
Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam,<br />
Netherlands<br />
Background: Combination <strong>of</strong> T-cell checkpoint blockade by anti-CTLA4 (ipilimumab,<br />
IPI) and anti-PD-1 (nivolumab, NIVO) is one <strong>of</strong> the most promising therapies in<br />
patients with late stage melanoma. It induces a superior objective response rate (ORR)<br />
(58%) as compared to single agent NIVO (44%) or IPI (19%) therapy (Checkmate 067<br />
study). This superior efficacy is, however, associated with a high percentage <strong>of</strong> ≥ grade<br />
3 adverse events (AEs)(55% versus 16% and 27%). The combination therapy is<br />
currently not available in the Netherlands, which prompted physicians to treat patients<br />
with short-term IPI directly followed by NIVO or pembrolizumab (PEM).<br />
Methods: In this retrospective analysis, patients were included who were treated with<br />
short-term IPI q3wk (two courses day 0 and 21), directly followed by anti-PD-1<br />
(starting at day 22 and onwards depending on the schedule (every 2 weeks for NIVO<br />
and 3 weeks for PEM)). Treatment related AEs data were collected from electronic<br />
patient dossiers and scored according to CTCAE 4.0 criteria. Response was evaluated<br />
using RECIST 1.1 for CT-scans and EORTC criteria for PET-scans.<br />
Results: Between May and December 2015, 40 patients with advanced melanoma were<br />
treated with IPI directly followed by anti-PD-1 (29/40 PEM, 11/40 NIVO). Baseline<br />
characteristics were: median age 54; male 55%; primary tumor site: skin 73%, mucosal<br />
10%, unknown 17%; BRAFV600 mutation 58%; AJCC stage IV M1c 80%; brain<br />
metastases 20%; LDH >ULN 25%; prior systemic treatment 28%. Median follow-up<br />
(FU) so far is 31 weeks (range: 5-42 weeks) and an update will be presented. Treatment<br />
related grade ≥3 AEs occurred in 33% <strong>of</strong> patients; most prevalent were colitis (18%),<br />
increased ALT/AST (8%) and maculopapular rash (5%). In 6 patients (15%) treatment<br />
was permanently discontinued due to toxicity. ORR was 48% (95%CI: 32-64) and<br />
disease control rate was 75% (95%CI: 54-85). Ongoing responses were observed in 84%<br />
<strong>of</strong> responding patients.<br />
Conclusions: Short-term IPI directly followed by NIVO/PEM seems to induce similar<br />
disease control as compared to concurrent IPI + NIVO, while grade 3/4 toxicity is<br />
lower. A randomized controlled clinical trial is in preparation to evaluate this<br />
alternative regimen.<br />
Legal entity responsible for the study: Netherlands Cancer Institute -Antoni van<br />
Leeuwenhoek hospital<br />
Funding: Netherlands Cancer Institute -Antoni van Leeuwenhoek hospital<br />
Disclosure: J.V. van Thienen: Advisory role: MSD and Bristol-Meyers-Squibb. J.B.A.G.<br />
Haanen: Research grants: MSD, Bristol-Myers-Squibb and GlaxoSmithKline. Advisory<br />
role: MSD <strong>Oncology</strong>, Pfizer, Bristol-Myers-Squibb, Novartis, Neon Therapeutics and<br />
Roche/Genentech. C. Blank: Research grant: Novartis. Advisory role: Novartis, Roche/<br />
Genentech, MSD, GlaxoSmithKline, Bristol-Myers-Squibb, Lilly and Pfizer. All other<br />
authors have declared no conflicts <strong>of</strong> interest.<br />
1121P<br />
abstracts<br />
Real-world survival results <strong>of</strong> metastatic melanoma patients<br />
treated with ipilimumab in the Netherlands<br />
A. Jochems 1 , M. Schouwenburg 1 , M. Aarts 2 , F. van den Berkmortel 3 , A. van den<br />
Eertwegh 4 , G. Groenewegen 5 , J-W. de Groot 6 , J.B.A.G. Haanen 7 , G. Hospers 8 ,<br />
E. Kapiteijn 1 , R. Koornstra 9 , W. Kruit 10 , B. Leeneman 11 , M. Louwman 12 ,<br />
D. Piersma 13 , R. van Rijn 14 , A.J. Ten Tije 15 , G. Vreugdenhil 16 , M. Wouters 17 , J. van<br />
der Hoeven 1<br />
1 Medical <strong>Oncology</strong>, Leiden University Medical Center (LUMC), Leiden,<br />
Netherlands, 2 Medical <strong>Oncology</strong>, Maastricht University Medical Center (MUMC),<br />
Maastricht, Netherlands, 3 Medical <strong>Oncology</strong>, Zuyderland MC, Heerlen,<br />
Netherlands, 4 Medical <strong>Oncology</strong>, Vrije University Medical Centre (VUMC),<br />
Amsterdam, Netherlands, 5 Medical <strong>Oncology</strong>, University Medical Center Utrecht,<br />
Utrecht, Netherlands, 6 Medical <strong>Oncology</strong>, Isala Klinieken, Zwolle, Netherlands,<br />
7 Department <strong>of</strong> Medical <strong>Oncology</strong>, The Netherlands Cancer Institute - Antoni van<br />
Leeuwenhoek Hospital, Amsterdam, Netherlands, 8 Medical <strong>Oncology</strong>, University<br />
Hospital Groningen (UMCG), Groningen, Netherlands, 9 Medical <strong>Oncology</strong>,<br />
Radboud University Medical Centre Nijmegen, Nijmegen, Netherlands, 10 Medical<br />
<strong>Oncology</strong>, Erasmus MC Daniel den Hoed Cancer Center, Rotterdam, Netherlands,<br />
11 X, Institute for Medical Technology Assessment, Rotterdam, Netherlands,<br />
12 Epidemiology, Netherlands Comprehensive Cancer Organisation (IKNL),<br />
Utrecht, Netherlands, 13 Medical <strong>Oncology</strong>, Medisch Spectrum Twente (MST),<br />
Enschede, Netherlands, 14 Medical <strong>Oncology</strong>, Medical Center Leeuwarden,<br />
Leeuwarden, Netherlands, 15 Medical <strong>Oncology</strong>, Amphia ziekenhuis, Breda,<br />
Netherlands, 16 Medical <strong>Oncology</strong>, Maxima Medical Center, Eindhoven,<br />
Netherlands, 17 Department <strong>of</strong> Surgical <strong>Oncology</strong>, The Netherlands Cancer<br />
Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands<br />
Background: Since 2012 ipilimumab is available for metastatic melanoma patients in<br />
the Netherlands. We investigated the survival <strong>of</strong> this treatment in real-world clinical<br />
practice.<br />
Methods: Data were retrieved from the Dutch Melanoma Treatment Registry (DMTR),<br />
follow up data cut-<strong>of</strong>f April 14 th 2016. This registry records detailed data on tumor and<br />
patient characteristics, systemic treatment, grade 3 and 4 adverse events (according to<br />
the CTCAE v. 4), outcome and resource use <strong>of</strong> all patients with unresectable stage IIIc<br />
and stage IV melanoma. Kaplan-Meier estimates are used to assess the median overall<br />
survival (OS) and survival rates.<br />
Results: From July 2012 until April 2016, 891 patients received at least one cycle <strong>of</strong><br />
ipilimumab. 458 patients (51%) had received a previous therapeutic regimen. A shift<br />
towards applying ipilimumab in treatment naïve patients with metastatic melanoma<br />
was seen from February 2014 as at that time approval by the National Health Care<br />
Institute was obtained for this patient group. Median follow-up was 21 months (95%<br />
CI 18.6-23.3) for previously treated patients and 11.3 months (95% CI 10.4-12.3) for<br />
treatment naïve patients. The median overall survival for previously treated patients<br />
was 8.0 months (95% CI 6.8-9.3) with a one year survival rate <strong>of</strong> 37% (95% CI 32-42)<br />
and a two year survival rate <strong>of</strong> 24% (95% CI 19-28). In this group, patients presenting<br />
with normal LDH (71%) had a median OS <strong>of</strong> 9.9 months (95% CI 8.4-11.5). For<br />
treatment naïve patients the median overall survival was 14.5 months (95% CI<br />
11.8-17.3) and the one-year survival rate was 54% (95% CI 48-60). Two-year survival<br />
rate could not be calculated because the follow-up duration was too short.<br />
Conclusions: The discrepancy between real-world one year survival rates <strong>of</strong> previously<br />
treated patients receiving ipilimumab and pivotal trial results could be due to more<br />
stringent patient selection in clinical trials. Inexperience with disease management<br />
outside <strong>of</strong> a controlled clinical trial may have contributed as well. Importantly, two year<br />
survival rates for previously treated patients and one year survival rate <strong>of</strong> treatment<br />
naïve patients are consistent with patient outcome found in clinical trials with<br />
ipilimumab.<br />
Legal entity responsible for the study: Dutch Society for Medical <strong>Oncology</strong> (NVMO)<br />
Funding: 1. The Netherlands Organisation for Health Research and Development<br />
(ZonMw); 2. Roche; 3. Bristol- Myers Squibb (BMS); 4. MSD; 5. Novartis <strong>Oncology</strong>.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw379 | vi385
abstracts<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Disclosure: A. van den Eertwegh: Advisory/consulting role: BMS, Roche, MSD,<br />
Novartis, GSK Research funding: Roche. G. Groenewegen: Speakers bureau Astellas.<br />
J-W. de Groot: Consulting/ advisory role: Servier, Amgen, BMS, Bayer, Celgene, Merck,<br />
Roche. J.B.A.G. Haanen: Consulting/Advisory role: BMS, MSD, Roche, Novartis,<br />
Pfizer, Neon Research funding: BMS, GSK, MSD. R. Koornstra: Consulting/Advisory<br />
role: BMS, MSD, Roche, Novartis Honoraria: MSD. W. Kruit: Consulting/Advisory<br />
role: BMS, Novartis, GSK. D. Piersma: Consulting/Advisory role: Amgen, Novartis<br />
Research Funding: Novartis, Astra Zeneca, BMS. R. van Rijn: Consulting/Advisory<br />
Role: BMS, Amgen, Takeda Research funding: Celgene, GSK. G. Vreugdenhil:<br />
Consulting/Advisory role: BMS. M. Wouters: Research funding: Novartis. All other<br />
authors have declared no conflicts <strong>of</strong> interest.<br />
1122P<br />
Impact <strong>of</strong> ipilimumab on metastatic melanoma: Evaluation<br />
using patient registry in Canada<br />
D.S. Ernst 1 , T. Petrella 2 , A. Joshua 3 , T. Cheng 4 , M. Smylie 5 , T. Baetz 6 , A. Hamou 7 ,<br />
F. Gwadry-Sridhar 8<br />
1 <strong>Oncology</strong>, University <strong>of</strong> Western Ontario, London, ON, Canada, 2 <strong>Oncology</strong>,<br />
Sunnybrook Odette Cancer Center, Sunnybrook HSC, Toronto, ON, Canada,<br />
3 <strong>Oncology</strong>, Princess Margaret Hospital, Toronto, ON, Canada, 4 <strong>Oncology</strong>, Tom<br />
Baker Cancer Centre, Calgary, AB, Canada, 5 <strong>Oncology</strong>, University <strong>of</strong> Alberta<br />
Cross Cancer Institute, Edmonton, AB, Canada, 6 <strong>Oncology</strong>, Cancer Centre <strong>of</strong><br />
Southeastern Ontario, Kingston, ON, Canada, 7 Bioinformatics, University <strong>of</strong><br />
Western Ontario, London, ON, Canada, 8 Bioinformatics, Unversity <strong>of</strong> Western<br />
Ontario, London, ON, Canada<br />
Background: The evaluation <strong>of</strong> new treatments on patients outside <strong>of</strong> clinical trials is<br />
crucial. The Canadian Melanoma Research Network (CMRN), is a multi-center<br />
pan-Canadian registry <strong>of</strong> melanoma patients. We utilize the CMRN to determine the<br />
clinical impact <strong>of</strong> Ipilimumab (Ipi) as 1 st and 2 d line therapy.<br />
Methods: 584 eligible patients, 353 males:231 females (mean age: 52 yrs), who treated<br />
for metastatic disease from 2000 to 2015 were included with their respective follow-up<br />
to Dec 2015. Patients in each year were selected based on the start date <strong>of</strong> their first<br />
metastatic treatment. The incorporation <strong>of</strong> Ipi into clinical practice was evaluated by<br />
the year <strong>of</strong> introduction. Patients may overlap in years if a patient received 2 regimens<br />
in 2 separate years, then this patient would exist in both categories.<br />
Results: We divided oor cohort into 2 groups, 388 patients who received Ipi and 196<br />
who did not. Baseline characteristics, such as age, gender, performance status, presence<br />
<strong>of</strong> brain metastases for each cohort were similar. From 2011 to 2015, the percentage <strong>of</strong><br />
patients who received Ipi increased from 68% to 81%. In patients who received Ipi, Cox<br />
exhibits a survival rate significantly better (p-value = 0.0010) than patients that were<br />
not treated with Ipi. The 3-year survival rate for Ipi treated patients was 32% compared<br />
to non-Ipi patients 25%. The survival over time data is available for Ipi patients: 1, 2<br />
and 3 year survival 2011 (52%, 35%, 33%), 2012 (61%, 50%, 49%), 2013 (69, 62%),<br />
2014 (75%), illustrating improved survival rates over time. Patients receiving Ipi 1 st line<br />
had a 1-year survival rate <strong>of</strong> 43%, 2-year <strong>of</strong> 32% and 3 year <strong>of</strong> 23%. For Ipi given as 2 nd<br />
line treatment, 1-year survival rate was 72%, 2-year <strong>of</strong> 47% and 3-year <strong>of</strong> 33%. For<br />
patients who received Ipi as 3 d or more, 1-year survival rate was 70%, 2-year <strong>of</strong> 49%,<br />
and 3-year <strong>of</strong> 35%. Because Ipi 1 st line was introduced after 2 nd line, mean follow-up is<br />
necessarily shorter.<br />
Conclusions: This observational study illustrates the positive impact that Ipi has had<br />
on survival rates. Although the follow-up is still limited, the benefit seems to be<br />
incremental as higher proportion <strong>of</strong> patients received Ipi over time. The efficacy<br />
appears to be independent <strong>of</strong> whether it is given as 1 st ,2 nd or 3 d + line.<br />
Legal entity responsible for the study: Canadian Melanoma Research Network<br />
Funding: BMS, Roche, Merck<br />
Disclosure: D.S. Ernst: Advisory Board: BMS, Novartis, Merck, H<strong>of</strong>fman<br />
Laroche. T. Petrella: Advisory Board: Merck, BMS, Roche, Novartis, GSK Research<br />
Funding: Roche. All other authors have declared no conflicts <strong>of</strong> interest.<br />
1123P<br />
Safety pr<strong>of</strong>ile <strong>of</strong> nivolumab (NIVO) and ipilimumab (IPI)<br />
combination therapy in patients (pts) with advanced<br />
melanoma (MEL)<br />
M. Sznol 1 , P.F. Ferrucci 2 , D. Hogg 3 , M. Atkins 4 , P. Wolter 5 , M. Guidoboni 6 ,<br />
C. Lebbe 7 , J. Kirkwood 8 , J. Schachter 9 , G. Daniels 10 , J. Hassel 11 , J. Cebon 12 ,<br />
W. Gerritsen 13 , V. Atkinson 14 , L. Thomas 15 , J. McCaffrey 16 ,D.Power 17 , J. Jiang 18 ,<br />
F.S. Hodi 19 , J. Wolchok 20<br />
1 Medical <strong>Oncology</strong>, Yale University School <strong>of</strong> Medicine Medical <strong>Oncology</strong>, New<br />
Haven, CT, USA, 2 Melanoma and Sarcoma, Istituto Europeo di Oncologia, Milan,<br />
Italy, 3 Department <strong>of</strong> Medical <strong>Oncology</strong> and Hematology, Princess Margaret<br />
Hospital, Toronto, ON, Canada, 4 Hematology/<strong>Oncology</strong>, Lombardi Cancer Center<br />
Georgetown University, Washington, DC, USA, 5 Department <strong>of</strong> General Medical<br />
<strong>Oncology</strong>, University Hospitals Leuven - Campus Gasthuisberg, Leuven, Belgium,<br />
6 Immunotherapy Unit, Istituto Tumori della Romagna I.R.S.T., Meldola, Italy,<br />
7 Dermatology, Hôpital St. Louis, Paris, France, 8 Medical <strong>Oncology</strong> and<br />
Hematology, Hillman Cancer Center, Pittsburgh, PA, USA, 9 Ella Lemelbaum<br />
Institute <strong>of</strong> Melanoma, Sheba Medical Center, Ramat Gan, Israel, 10 Medicine,<br />
Moores UCSD Cancer Center, La Jolla, CA, USA, 11 <strong>Oncology</strong>, University Hospital<br />
Heidelberg, Heidelberg, Germany, 12 Cancer Immunobiology, Olivia Newton-John<br />
Cancer Research Institute, Heidelberg, Australia, 13 Department <strong>of</strong> Medical<br />
<strong>Oncology</strong>, Radboud University Medical Centre Nijmegen, Nijmegen, Netherlands,<br />
14 <strong>Oncology</strong>, Gallipoli Medical Research Foundation and Princess Alexandra<br />
Hospital, Greenslopes, Australia, 15 Dermatology, Centre Hospitalier Lyon Sud,<br />
Pierre Bénite, France, 16 Medical <strong>Oncology</strong>, Irish Clinical <strong>Oncology</strong> Research<br />
Group, Dublin, Ireland, 17 Medical <strong>Oncology</strong>, Irish Clinical <strong>Oncology</strong> Research<br />
Group, Cork, Ireland, 18 <strong>Oncology</strong>, BMS, Princeton, NJ, USA, 19 <strong>Oncology</strong>,<br />
Dana-Farber Cancer Institute, Boston, MA, USA, 20 Ludwig Center, Memorial<br />
Sloan Kettering Cancer Center, New York, NY, USA<br />
Background: Cumulative data indicate greater tumor response from the addition <strong>of</strong> IPI<br />
(anti-CTLA-4 antibody) to NIVO (anti-PD-1 antibody) in MEL pts, but with a higher<br />
frequency <strong>of</strong> adverse events (AEs) than observed with either agent alone. The objective<br />
<strong>of</strong> this pooled analysis is to describe the safety pr<strong>of</strong>ile <strong>of</strong> NIVO + IPI across MEL<br />
studies in which established guidelines for AE management were utilized.<br />
Methods: A retrospective safety review was conducted for three phase 1-3 trials in<br />
which all MEL pts who received at least 1 dose <strong>of</strong> the standard regimen, NIVO 1 mg/<br />
kg + IPI 3 mg/kg Q3W x 4, then NIVO 3 mg/kg Q2W until disease progression or<br />
unacceptable toxicity. Analyses included AEs, select (immune-related) AEs, time to<br />
onset and resolution, use <strong>of</strong> immune-modulating agents (IMs) for management <strong>of</strong><br />
toxicity, and effect <strong>of</strong> IMs on outcome.<br />
Results: Among 448 pts, median age was 61 (range:18-87) and 25% had ECOG PS > 0.<br />
Median duration <strong>of</strong> follow-up was 13.2 months. Treatment-related grade 3–4 AEs<br />
occurred in 55% <strong>of</strong> pts, and led to discontinuation in 28%. The most frequent<br />
treatment-related select AEs <strong>of</strong> any grade were skin (64%) and gastrointestinal (47%);<br />
the most frequent grade 3–4 select AEs were hepatic (17%) and gastrointestinal (16%;<br />
Table). 30% developed a grade 2-4 select AE in >1 organ category. Median time to<br />
onset <strong>of</strong> grade 3–4 treatment-related select AEs ranged from 3.1 wks (skin) to 16.3 wks<br />
(renal). Excluding endocrine AEs, median time to resolution <strong>of</strong> grade 3–4 select AEs<br />
with IMs ranged from 1.1 wks (renal) to 7.3 wks (pulmonary). Resolution rates for<br />
non-endocrine grade 3–4 select AEs ranged between 79─100% using IMs. 4 (
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Funding: Bristol-Myers Squibb<br />
Disclosure: M. Sznol: Consultant: BMS, Genentech-Roche, AZ-Medimmune,<br />
Anaeropharma, Merus, Symphogen, Nektar, Amgen, Kyowa-Kirin, Astellas-Agensys,<br />
Lion Biotech, Neostem, Seattle Genetics, Pfizer, TRM <strong>Oncology</strong>, Physicians Education<br />
Resource, Imedex, Research to Practice. P.F. Ferrucci: Honoraria from Delcath Systems,<br />
consultant for GSK, Roche, and BMS, provided expert testimony for GSK, Roche, and<br />
BMS, received travel support from GSK, Roche, and BMS. D. Hogg: Served as a<br />
consultant for BMS, Roche, Novartis, and GSK. M. Atkins: Served as a consultant for<br />
BMS, Merck, Novartis, Genentech Roche, Pfizer, Nektar, Caladrius, SAB for Merck,<br />
DSMB for Novartis and GSK. P. Wolter: Served as a consultant for GSK and BMS,<br />
received research funding from GSK, Pfizer, and Novartis. M. Guidoboni: Advisor for<br />
BMS, Novartis, Amgen, travel support from BMS, Novartis, research support from<br />
MSD. C. Lebbe: Advisory boards for BMS, MSD, Roche, GSK, and<br />
Novartis. J. Kirkwood: Consultant for BMS, Merck, GSK, Amgen, Green Peptide,<br />
Roche, Genentech. G. Daniels: Dr. Daniels institution received research funding from<br />
BMS and Site Pl. J. Hassel: Received honoraria from BMS, GSK, Roche, MSD, and<br />
Amgen, served as a consultant for Amgen and GSK, participated in speakers bureau for<br />
BMS, GSK, Roche, MSD, and Amgen, received reimbursements on travel,<br />
accommodations, expenses from Amgen and BMS. W. Gerritsen: Advisory boards and<br />
speaker’s bureau for BMS. V. Atkinson: Received honoraria from Glasko Smith Kline,<br />
BMS, Merck, and Sharp & Dohme, served as a consultant for Merck, Sharp & Dohme,<br />
and BMS, received reimbursements on travel, accommodations, expenses from BMS<br />
and Roche. J. Jiang: Employee <strong>of</strong> BMS. F.S. Hodi: Institution served as a consultant for<br />
BMS (non-paid), institution received research funding from BMS, and institution has a<br />
patent pending on immune target. J. Wolchok: Honoraria: EMD Serono, Janssen<br />
Oncol; consultant: BMS, Merck, MedImmune, Ziapharm, Polynoma, Polaris, Jounce,<br />
GSK; institutional research funding: BMS, MedImmune, GSK, Merck; co-investor on<br />
patent for DNA vaccines <strong>of</strong> cancer in animals; travel support: BMS. All other authors<br />
have declared no conflicts <strong>of</strong> interest.<br />
1124P<br />
Detailed safety pr<strong>of</strong>ile <strong>of</strong> the anti-PD-1 monoclonal antibody<br />
pembrolizumab in 78 consecutive patients (pts) with<br />
advanced melanoma<br />
C. Boutros 1 , E. Routier 1 , C. Hua 1 , M. Texier 2 , C. Mateus 1 , C. Libenciuc 1 ,<br />
M. Reigneau 1 , N. Benannoune 1 ,S.Roy 1 , E. Lanoy 2 ,J.LePavec 3 , F.L. Ladurie 3 ,<br />
F. Carbonnel 4 , O. Lambotte 5 , H. Izzedine 6 , A. Berdelou 7 , S. Champiat 8 ,<br />
J-C. Soria 8 , A. Eggermont 1 , C. Robert 1<br />
1 Department <strong>of</strong> Cancer Medicine, Gustave Roussy, University Paris-Saclay,<br />
Villejuif, France, 2 Department <strong>of</strong> Biostatistics and Epidemiology, Gustave Roussy,<br />
University Paris-Saclay, Villejuif, France, 3 Thoracic and Vascular Surgery Service,<br />
Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France, 4 Department<br />
<strong>of</strong> Gastroenterology, University Hospital <strong>of</strong> Bicêtre, Le Kremlin Bicetre, France,<br />
5 Internal Medicine Service, University Hospital <strong>of</strong> Bicêtre, Le Kremlin Bicetre,<br />
France, 6 Department <strong>of</strong> Nephrology, Pitié-Salpêtrière Hospital, Paris, France,<br />
7 Department <strong>of</strong> Nuclear Medicine and Endocrine <strong>Oncology</strong>, Gustave Roussy,<br />
University Paris-Saclay, Villejuif, France, 8 Drug Development Department (DITEP),<br />
Gustave Roussy, University Paris-Saclay, Villejuif, France<br />
Background: The programmed death receptor 1 (PD-1) inhibitor pembrolizumab has<br />
shown clinical benefit with acceptable tolerability in pts with advanced melanoma. We<br />
provide detailed information on the safety pr<strong>of</strong>ile <strong>of</strong> pembrolizumab in one institution.<br />
Methods: In the KEYNOTE-001 phase 1 trial, pts with advanced melanoma received<br />
either pembrolizumab 10 mg/kg every 2 weeks or 10 mg/kg every 3 weeks or 2 mg/kg<br />
every 3 weeks until disease progression or severe toxicity. The severity <strong>of</strong> the adverse<br />
events (AEs) was graded according to the National Cancer Institute Common<br />
Terminology Criteria for AEs, version 4.0. AEs were depicted using percentages. The<br />
cumulative incidence <strong>of</strong> AEs from treatment initiation was estimated with the<br />
Kaplan-Meier method.<br />
Results: 78 pts received pembrolizumab: 2 mg/kg Q3W (n = 20), 10 mg/kg Q2W<br />
(n = 23) or 10 mg/kg Q3W (n = 35) in our institution. The median duration <strong>of</strong><br />
follow-up was 20 months. Treatment was well tolerated, with a similar cumulative<br />
incidence <strong>of</strong> AEs with the 3 pembrolizumab dosing regimens and no drug-related<br />
death. AEs <strong>of</strong> any grade were observed in 73 pts (94%). The most common AEs were<br />
fatigue, arthralgia, vitiligo, pruritus and diarrhea. The time to onset <strong>of</strong> AEs did not<br />
differ between the 3 dosing regimens (p > 0.4). The median times to onset <strong>of</strong> skin<br />
disorders and musculoskeletal disorders were 8.3 months and 17.3 months<br />
respectively, whereas the median time to onset <strong>of</strong> gastrointestinal disorders was not<br />
reached. Grade 3 or 4 AEs occurred in 11 pts (14%). Permanent discontinuation was<br />
reported in 7 pts (9%) due to treatment-related AEs, including colitis, thromboembolic<br />
events, pneumonitis, interstitial nephritis and hemolytic anemia. Unexpected AEs were<br />
reported, including infections in 31 pts (40%), teeth/gingival abnormalities in 8 pts<br />
(10%) and pleural effusion in 3 (4%). Vitiligo was reported in 21 pts (27%) and seemed<br />
associated with clinical response.<br />
Conclusions: This safety analysis provides a detailed characterization <strong>of</strong> the AE pr<strong>of</strong>ile<br />
<strong>of</strong> pembrolizumab, and reports new unanticipated AEs potentially related to the drug.<br />
Legal entity responsible for the study: N/A<br />
Funding: N/A<br />
Disclosure: E. Routier: Consultant <strong>of</strong> and BMS and Roche. C. Mateus: Consultant <strong>of</strong><br />
BMS and Merck. F. Carbonnel: Consultant <strong>of</strong> Abbvie, Enterome, Ferring, Genentech,<br />
Hospira, Jansen, Mayoly, MSD, Otsuka, Splindler, and Takeda and Vifor. O. Lambotte:<br />
Consultant <strong>of</strong> Genzyme and MSD. J-C. Soria: Consultant <strong>of</strong> Astra-Zeneca, Merus,<br />
MSD, Pfizer, Roche, Servier and Symphogen. A. Eggermont: Member <strong>of</strong> the scientific<br />
advisory board <strong>of</strong> BMS, Incyte, Medimmune and Merck. C. Robert: Consultant <strong>of</strong><br />
Amgen, BMS, GSK, Merck, Novartis and Roche. All other authors have declared no<br />
conflicts <strong>of</strong> interest.<br />
1125P<br />
abstracts<br />
Safety <strong>of</strong> reduced infusion times for nivolumab plus<br />
ipilimumab (N + I) and nivolumab alone (N) in advanced<br />
melanoma<br />
S. Martin-Algarra 1 , J.B. Haanen 2 , C. Horak 3 , S. Bhatia 4 , A. Ribas 5 , W-J. Hwu 6 ,C.<br />
L. Slingluff, 7 , W.H. Sharfman 8 , M. Callahan 9 , F.S. Hodi 10 , J.D. Wolchok 9 , J. Luke 11 ,<br />
T.C. Young 3 , A. Qureshi 12 , W.J. Urba 13<br />
1 Medical <strong>Oncology</strong>, University <strong>of</strong> Navarra, Pamplona, Spain, 2 Department <strong>of</strong><br />
Medical <strong>Oncology</strong>, The Netherlands Cancer Institute, Amsterdam, Netherlands,<br />
3 Clinical Biomarkers, BMS, Princeton, NJ, USA, 4 Medical <strong>Oncology</strong>, University <strong>of</strong><br />
Washington, Seattle, WA, USA, 5 Medicine, University <strong>of</strong> California, Los Angeles,<br />
Los Angeles, CA, USA, 6 Medical <strong>Oncology</strong>, University <strong>of</strong> Texas MD Anderson<br />
Cancer Center, Houston, TX, USA, 7 Surgery, University <strong>of</strong> Virginia School <strong>of</strong><br />
Medicine, Charlottesville, VA, USA, 8 <strong>Oncology</strong> and Dermatology, Johns Hopkins<br />
Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA, 9 Medicine,<br />
Memorial Sloan Kettering Cancer Center, New York, NY, USA, 10 <strong>Oncology</strong>,<br />
Dana-Farber Cancer Institute, Boston, MA, USA, 11 Section <strong>of</strong> Hematology/<br />
<strong>Oncology</strong>, The University <strong>of</strong> Chicago Medical Centre, Chicago, IL, USA, 12 Global<br />
Clinical Research, BMS, Princeton, NJ, USA, 13 Providence Melanoma Program,<br />
Earle A. Chiles Research Institute-Providence Cancer Center, Portland, OR, USA<br />
Background: The phase 3 melanoma (MEL) study CheckMate 067 showed improved<br />
progression-free survival and objective response rates with N + I or N versus<br />
ipilimumab monotherapy, with treatment-related grade 3/4 adverse events (AEs)<br />
reported in 55%, 16%, and 27% <strong>of</strong> patients (pts), respectively. The objective <strong>of</strong> this<br />
analysis was to assess the safety pr<strong>of</strong>ile associated with reduced infusion times for N + I<br />
(from 180 to 90 min) and N (from 60 to 30 min) using data from a phase 1 biomarker<br />
study (CA209-038).<br />
Methods: The primary objective <strong>of</strong> the study was to assess the pharmacodynamic<br />
activity <strong>of</strong> N + I and N on the tumor microenvironment. Exploratory objectives<br />
included assessment <strong>of</strong> safety, tolerability, and pharmacokinetics <strong>of</strong> reduced infusion<br />
times for N + I and N. Pts with previously treated or untreated MEL were divided into<br />
4 non-randomized groups with different follow-up times: N + I (1 mg/kg + 3 mg/kg<br />
Q3W for 4 doses then N 3 mg/kg Q2W for either 180 min [N + I 180 group, n = 27] or<br />
90 min [N + I 90 group, n = 36]) or N (3 mg/kg Q2W for either 60 min [N 60 group,<br />
n = 85] or 30 min [N 30 group, n = 20]). Pts were treated for up to 2 years or until<br />
confirmed disease progression or intolerable toxicity.<br />
Results: Across the 4 study groups (n = 168), the majority <strong>of</strong> pts did not experience an<br />
infusion (97%) or hypersensitivity (96%) reaction. 5 (3%) pts had any grade infusion<br />
reaction and 3 (2%) experienced any grade hypersensitivity; no grade 3/4 infusion or<br />
hypersensitivity reactions were reported. In the N + I 180 and N + I 90 groups, 4% and<br />
8% <strong>of</strong> pts, respectively, had 1 or more infusion interruptions; in the N 60 and N 30<br />
groups, the rate was 14% and 5%, respectively. The rate <strong>of</strong> treatment-related grade 3/4<br />
AEs for N + I 180, N + I 90, N 60, and N 30 groups was 52%, 31%, 5%, and 0%,<br />
respectively.<br />
Conclusions: Reducing the infusion times for N + I (from 180 to 90 min) and N (from<br />
60 to 30 min) resulted in similar low levels <strong>of</strong> infusion reactions, suggesting that this<br />
approach may speed up treatment administration for pts and treatment centers.<br />
Additional data on safety, pharmacokinetics and response rates will be presented.<br />
Clinical trial identification: NCT01621490<br />
Legal entity responsible for the study: Bristol-Myers Squibb<br />
Funding: Bristol-Myers Squibb<br />
Disclosure: S. Martin-Algarra: Advisor and speaker in boards and educational<br />
events organized by BMS J.B. Haanen: Served as a consultant for MSD, Roche, and<br />
Pfizer, and received research funding from BMS & GSK. C. Horak: Employed by and<br />
owns stock in BMS. S. Bhatia: Institution has received research funding from<br />
BMS. A. Ribas: Owns stock in Kite Pharma and consultant for Pfizer, Roche,<br />
Amgen. C.L. Slingluff, Jr: Honoraria from Castle Biosciences and holds a patent with<br />
UVA Licensing and Ventures Group, research funding from GSK, Merck, BMS,<br />
Polynoma, and 3M, and his institution has served in an advisory role for Polynoma<br />
and Immatics Biotechnologies. W.H. Sharfman: Served as a consultant for Merck<br />
and received research funding from BMS. M. Callahan: Received research funding<br />
from MSKCC and has a family member employed at BMS. F.S. Hodi: Served as a<br />
consultant for BMS, received research funding from BMS, and has a patent pending<br />
for an immune target. J.D. Wolchok: Honoraria: EMD Serono and Janssen<br />
<strong>Oncology</strong>; consultant: BMS Merck, MedImmune, Ziopharm, Polynoma, Polaris,<br />
Jounce, GSK; research funding: BMS, MedImmune, GSK and Merck; co-investor in<br />
a patent for DNA vaccines <strong>of</strong> cancer in animals; travel funding: BMS. J. Luke:<br />
Institution received research funding from BMS. T.C. Young, A. Qureshi: Employed<br />
by BMS. W.J. Urba: Consultant for Celldex, Green peptide, MedImmune, BMS. All<br />
other authors have declared no conflicts <strong>of</strong> interest.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw379 | vi387
abstracts<br />
1126P<br />
Slow natural history predicts higher response rate to<br />
nivolumab and pembrolizumab in advanced melanoma<br />
patients<br />
N. Kramkimel 1 , V. Heidelberger 2 , O. Huillard 2 , P. Boudou Rouquette 2 , J. Chanal 1 ,<br />
N. Franck 1 , J. Arrondeau 2 , J. Alexandre 2 , B. Blanchet 3 , J. Mullaert 4 , S. Aractingi 1 ,<br />
N. Dupin 1 , F. Goldwasser 2<br />
1 Department <strong>of</strong> Dermatology, Hôpital Cochin, Paris, France, 2 Medical <strong>Oncology</strong>,<br />
Hôpital Cochin, Paris, France, 3 Functional Unit <strong>of</strong> Pharmacokinetics and<br />
Pharmacochemistry, Hôpital Cochin, Paris, France, 4 Biostatistics, Hopital Bichat<br />
Claude Bernard, Paris, France<br />
Background: Anti PD-1 antibodies nivolumab and pembrolizumab are checkpoint<br />
inhibitors widely used in metastatic melanoma with a 40% response rate. Little is<br />
known on predictive factors <strong>of</strong> response. Given the mechanism <strong>of</strong> action, we<br />
investigated whether features <strong>of</strong> natural history <strong>of</strong> melanoma correlated with response.<br />
Methods: All melanoma patients treated with anti PD-1 between August 2014 and<br />
January 2016 in our center were retrospectively reviewed. Objective response to<br />
treatment was defined as complete response or partial response according to 1.1<br />
RECIST criteria. Patients who received only 1 infusion were excluded. No clear<br />
definition <strong>of</strong> lymphatic or hematogenous dissemination in melanoma could be found<br />
in the literature. We defined lymphatic dissemination as exclusive lymphatic metastases<br />
or occurrence <strong>of</strong> a lymph node metastasis prior to a visceral metastasis. The rest was<br />
considered hematogenous dissemination. We excluded patients with only in-transit<br />
metastases (stage N2c). Time-in-node was defined as the delay between first lymphatic<br />
metastasis and first visceral metastasis. Time-to-treatment was defined as the delay<br />
between melanoma diagnosis and anti PD-1 therapy initiation.<br />
Results: 65 patients were included (31 females; median age 65 years [21 to 90]).<br />
Treatment was initiated in patients having disease progression. 73% received<br />
pembrolizumab and 27% nivolumab. 28% <strong>of</strong> tumors harbored BRAF V600 mutations.<br />
Anti PD-1 was the first line therapy for 36% <strong>of</strong> the patients. Dissemination was<br />
lymphatic in 23 patients (37%) and hematogenous in 39 (63%). Objective response rate<br />
in the total population was 40%. Mean time-in-node was 26 months [2 to 132 months].<br />
Mean time-to-treatment was 71 months [2 to 409 months]. There was no statistical<br />
correlation between response and either lymphatic vs hematogenous dissemination or<br />
time-in-node. Time-to-treatment was statistically associated with response (mean<br />
time-to-treatment 99 months in responders and 53 in non-responders, p = 0, 01). The<br />
same analysis with time from diagnosis to first line therapy was also positive (85<br />
months in responders and 45 in non-responders, p = 0, 02).<br />
Conclusions: Melanomas with slow natural history exhibit a higher sensitivity to<br />
nivolumab and pembrolizumab.<br />
Legal entity responsible for the study: Hôpital Cochin APHP<br />
Funding: Hôpital Cochin APHP<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1127P<br />
Correlation between baseline characteristics and clinical<br />
outcome <strong>of</strong> patients with advanced melanoma treated with<br />
pembrolizumab (PEMBRO)<br />
Y. Jansen 1 , E.A. Rozeman 2 , L. Højberg 3 , M. Geukes Foppen 4 , M. Schreuer 5 ,J.<br />
V. van Thienen 6 , L. Bastholt 7 , H. Schmidt 8 , J.B.A.G. Haanen 9 , I.M. Svane 10 , A.M.<br />
Arance Fernandez 11 , C. Blank 12 , B. Neyns 13<br />
1 <strong>Oncology</strong>, UZ Brussel, Brussels, Belgium, 2 Immunology and Medical <strong>Oncology</strong>,<br />
Het Nederlands Kanker Instituut Antoni van Leeuwenhoek (NKI-AVL), Amsterdam,<br />
Netherlands, 3 <strong>Oncology</strong>, Rigshospitalet, Copenhagen University Hospital,<br />
Copenhagen, Denmark, 4 Medical <strong>Oncology</strong>, Het Nederlands Kanker Instituut<br />
Antoni van Leeuwenhoek (NKI-AVL), Amsterdam, Netherlands, 5 Medical<br />
<strong>Oncology</strong>, UZ Brussel, Brussels, Belgium, 6 Department <strong>of</strong> Medical <strong>Oncology</strong>, The<br />
Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam,<br />
Netherlands, 7 Onkologisk afdeling R, Odense University Hospital, Odense,<br />
Denmark, 8 Dept. <strong>of</strong> <strong>Oncology</strong>, Aarhus University Hospital, Aarhus, Denmark,<br />
9 Department <strong>of</strong> Medical <strong>Oncology</strong>, The Netherlands Cancer Institute, Amsterdam,<br />
Netherlands, 10 Department <strong>of</strong> hematology and oncology, Center for Cancer<br />
Immune Therapy, Herlev University Hospital, Herlev, Denmark, 11 <strong>Oncology</strong>,<br />
Hospital de Barcelona, Barcelona, Spain, 12 Dept Medical <strong>Oncology</strong>, The<br />
Netherlands Cancer Institute, Amsterdam, Netherlands, 13 Medical <strong>Oncology</strong>, Vrije<br />
Universiteit Brussel-Campus Jette, Brussels, Belgium<br />
Background: The PD-1 blocking mAb pembrolizumab (PEMBRO) is approved for the<br />
treatment <strong>of</strong> patients (pts) with advanced melanoma. Correlation between baseline<br />
characteristics and outcome <strong>of</strong> pts treated outside <strong>of</strong> a prospective clinical trial has not<br />
been established.<br />
Methods: Using Kaplan-Meier statistics, log-rank testing and multivariate<br />
Cox-regression analysis, correlations were investigated between baseline variables and<br />
PFS and OS in pts with advanced melanoma who received PEMBRO outside a clinical<br />
trial. An independent confirmatory cohort (CC) <strong>of</strong> pts from the Netherlands and Spain<br />
served to confirm correlations found in an exploratory Belgian cohort (EC). Additional<br />
data from 180 Scandinavian pts are being collected.<br />
Results: All pts in the EC (N = 123) and CC (N = 165) received at least one<br />
administration <strong>of</strong> PEMBRO (2 mg/kg q3wks). Baseline characteristics <strong>of</strong> the total<br />
cohort (TC) (N = 288) were: median age 60y (range 27-93); 49% Male; 61%<br />
performance score (PS) 0; primary site: 80% skin, 15% UKN, 4% mucosal; 49% BRAF<br />
V600mut; 76% AJCC stage IV-M1c; 29% brain metastases; 82% pretreated; 48% CRP<br />
>ULN; 33% LDH >ULN; 16% absolute lymphocyte count (ALC) 1.5ULN, CRP > 5xULN or<br />
ALC < 500/mm 3 had a significantly worse PFS/OS. However, only the correlation with<br />
PS, LDH and ALC could be confirmed in CC pts. In the TC a significant correlation<br />
could be found between PFS/OS and PS2, ALC 5xULN<br />
and LDH > 1.5ULN with a typical “lower PFS plateau" beyond 30 wks. All pts with a<br />
baseline ALC 500/mm 3 (N = 281), multivariate analysis identified baseline PS2, LDH > 1.5xULN<br />
and CRP > 5xULN as independent unfavorable prognostic factors for PFS/OS.<br />
Conclusions: While confirming encouraging survival outcome <strong>of</strong> advanced melanoma<br />
patients treated with PEMBRO outside a clinical trial setting, significant correlations<br />
were found between baseline PS, ALC, LDH, CRP and survival.<br />
Clinical trial identification: NCT02673970<br />
Legal entity responsible for the study: UZ Brussel<br />
Funding: UZ Brussel, NKI AVL<br />
Disclosure: J.V. van Thienen: advisory role Bristol-Myers-Squibb and MSD. J.B.A.G.<br />
Haanen: advisory role: MSD, Pfizer, Bristol-Myers-Squibb, Novartis, Neon<br />
Therapeutics and Roche/Genentech. Research grant: MSD, BMS, GSK. C. Blank:<br />
advisory role: MSD, Pfizer, Bristol-Myers-Squibb, Novartis, GSK, Roche/Genentech,<br />
Lilly. Research grant: Novartis. B. Neyns: Personal compensation: Roche, Bristol-Myers<br />
Squibb, Merck Sharp & Dohme, Novartis, AstraZeneca, CryoStorage for public<br />
speaking, consultancy and participation in advisory board meetings. All other authors<br />
have declared no conflicts <strong>of</strong> interest.<br />
1128P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
CARAMEL study: Clinical prognostic biomarkers for<br />
ipilimumab-related outcome in metastatic melanoma<br />
patients<br />
L. Orgiano 1 , F. Bruder 2 , C. Madeddu 1 , R. Marconcini 3 , E. Gambale 4 , E. Galizia 5 ,<br />
S. Stucci 6 , F. Spagnolo 7 , L. Di Guardo 8 , C. Loi 2 , F. Pani 9 , D. Massa 2 , E. Massa 1 ,<br />
G. Astara 1 , M. Del Vecchio 8 , F. Silvestris 6 , M. de tursi 4 , A. Falcone 3 , P. Queirolo 7 ,<br />
M. Scartozzi 1<br />
1 Medical <strong>Oncology</strong>, Azienda Ospedaliero Universitaria di Cagliari, Monserrato,<br />
Italy, 2 Medical <strong>Oncology</strong>, Ospedale Oncologico "A. Businco", Cagliari, Italy, 3 Dept.<br />
<strong>of</strong> <strong>Oncology</strong>-Presidio Ospedaliero, Azienda Ospedaliera Universitaria S.Chiara,<br />
Pisa, Italy, 4 Department <strong>of</strong> Medical <strong>Oncology</strong>, AOU Chieti, Chieti, Italy, 5 Medical<br />
<strong>Oncology</strong>, Ospedale E. Pr<strong>of</strong>ili U.O. Oncologia Medica, Fabriano, Italy,<br />
6 Department <strong>of</strong> Medical <strong>Oncology</strong>, Azienda Ospedaliero-Universitaria Consorziale<br />
Policlinico di Bari, Bari, Italy, 7 Medical <strong>Oncology</strong>, IRCCS AOU San Martino -<br />
IST-Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy, 8 Medical <strong>Oncology</strong>,<br />
Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy, 9 Department <strong>of</strong><br />
Medical Sciences, Endocrinology Unit, University <strong>of</strong> Cagliari, Cagliari, Italy<br />
Background: Ipilimumab is an inhibitor <strong>of</strong> CTLA4 receptor <strong>of</strong> T lymphocytes<br />
approved by the FDA both as first and second line treatment for patients with<br />
metastatic melanoma. Despite the efficacy observed in about 20% <strong>of</strong> patients, it still<br />
remains a therapy with a considerable outlay, both from an economic and safety point<br />
<strong>of</strong> view: the aim <strong>of</strong> our study was to explore prognostic biomarkers among<br />
hematological parameters normally used in clinical practice.<br />
Methods: This is a retrospective multicenter study which enrolled 120 patients with<br />
hystologically confirmed metastatic melanoma treated with Ipilimumab between<br />
January 2013 and January 2016 (mean age 62.2 ± 14.58). Full blood count with<br />
absolute WBC (aWBC), neutrophil count, eosinophil count, neutrophil/lymphocyte<br />
ratio (NLR), platelets/lymphocyte ratio (PLR) and LDH serum levels were assessed at<br />
baseline and every 3 weeks during treatment. We evaluated the mutational BRAF status<br />
and the number <strong>of</strong> metastatic sites involved before treatment (more or less than 3<br />
sites). The cut-<strong>of</strong>f values for our parameters were determined with time-dependent<br />
receiver operating characteristic (ROC) analysis. To identify prognostic and predictive<br />
biomarkers the above parameters have been correlated with Progression-Free Survival<br />
(PFS) and Overall Survival (OS).<br />
Results: After a median follow up <strong>of</strong> 21 months, median PFS was 4 months and median<br />
OS was 17 months. Patients with low serum LDH levels at baseline had significantly<br />
longer PFS (p = 0.018) and OS (p < 0.05). Higher NLR (p = 0.043) and PLR values<br />
(p < 0.05) were related to worse PFS. Interestingly, we found that women had shorter OS<br />
(p = 0.002) and PFS (p = 0.003) compared with men. The presence <strong>of</strong> >3 sites <strong>of</strong><br />
metastases seems to be correlated to a worse OS (p < 0.04) and PFS (p < 0.03).<br />
Conclusions: Although these findings need to be confirmed and validated and the<br />
multivariate analysis is still in progress, we suggest that the parameters explored in our<br />
study, which are normally assessed in clinical practice, may be useful to assist<br />
disease-management strategies for advanced melanoma patients.<br />
Legal entity responsible for the study: Pr<strong>of</strong>. Mario Scartozzi, AOU Cagliari<br />
Funding: Pr<strong>of</strong>. Mario Scartozzi, AOU Cagliari<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
vi388 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
1129P<br />
Pretreatment prognostic factors and early markers for<br />
outcome in advanced melanoma treated with nivolumab<br />
Y. Nakamura 1 , S. Kitano 2 , A. Takahashi 1 , A. Tsutsumida 1 , K. Namikawa 1 , I. Muto 1 ,<br />
M. Ueno 1 , Y. Muto 1 , N. Yamazaki 1<br />
1 Dermatologic <strong>Oncology</strong>, National Cancer Center Hospital, Tokyo, Japan,<br />
2 Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan<br />
Background: Anti-programmed cell death protein 1(PD-1) monoclonal antibody,<br />
nivolumab, is one <strong>of</strong> the most effective drugs for advanced melanoma. Serum lactate<br />
dehydrogenase (LDH) and cutaneous adverse events have been described as early<br />
predictors for outcomes <strong>of</strong> advanced melanoma treated with nivolumab in some<br />
literature. We tried to seek further clinical predictors in daily clinical practice.<br />
Methods: We retrospectively analyzed clinical findings <strong>of</strong> 54 unresectable stage III or<br />
IV melanoma patients treated with nivolumab at the National Cancer Center Hospital,<br />
Tokyo, Japan, between September 2014 and December 2015. The patients who took<br />
steroid orally were excluded from this study. Those patients were administered<br />
nivolumab at a dose <strong>of</strong> 2mg/kg every 3 weeks.<br />
Results: Median overall survival (OS) was 12.7 months. Response rate was 25.9%.<br />
Delayed response was shown in only one patient. Patients with baseline ECOG<br />
performance status (PS) =0, baseline normal LDH and baseline normal C-related<br />
protein (CRP) had significantly longer OS compared with patients with PS ≥ 1 (hazard<br />
ratio[HR] 0.25, 95%CI 0.09-0.68, P < 0.01), elevated LDH(HR 0.25, 95%CI 0.10-0.60,<br />
P = 0.010) and elevated CRP (HR 0.36, 95%CI 0.15-0.87, P = 0.018). As for early<br />
markers through the therapy, patients with absolute lymphocyte count (ALC) ≥ 1000/<br />
ml and neutrophil-to-lymphocyte ratio (NLR) < 4 after 1 st nivolumab dose had longer<br />
OS significantly compared with those with ALC < 1000/l (Week3: HR 0.30, 95%CI<br />
0.12-0.78, P = 0.016, Week6: HR 0.38, 0.15-0.95, P = 0.030) and NLR ≥ 4 (Week3: HR<br />
0.38, 95%CI 0.17-0.87, P = 0.018, Week6: HR 0.37, 95%CI 0.15-0.92, P = 0.026).<br />
Conclusions: Delayed response may rarely occur in daily clinical practice. ALC ≥ 1000/<br />
ml and NLR < 4 during treatment appear to be early markers associated with better OS.<br />
Pretreatment PS = 0 and low CRP can be also good prognostic factors as well as low LDH.<br />
Legal entity responsible for the study: National Cancer Center Hospital<br />
Funding: National Cancer Center Hospital<br />
Disclosure: N. Yamazaki: Advisory board role for Chugai Pharma, Bristol-Myers<br />
Squibb (BMS) Japan and Ono Pharmaceutical. The institution has received clinical<br />
trial support from Chugai, BMS Japan, Ono, GSK, Takeda, AstraZeneca Japan,<br />
Boehringer Ingelheim, and Maruho. All other authors have declared no conflicts <strong>of</strong><br />
interest.<br />
1130P<br />
Sarcopenia associated with a body mass index (BMI) > 25 kg/<br />
m 2 predicts severe acute toxicity <strong>of</strong> nivolumab and<br />
pembrolizumab in melanoma patients<br />
V. Heidelberger 1 , N. Kramkimel 2 , O. Huillard 1 , P. Boudou Rouquette 1 , J. Chanal 2 ,<br />
J. Arrondeau 1 , N. Franck 2 , J. Alexandre 1 , B. Blanchet 3 , N. Dupin 2 , S. Aractingi 2 ,<br />
F. Goldwasser 1<br />
1 Medical <strong>Oncology</strong>, Hôpital Cochin, Paris, France, 2 Dermatology, Hôpital Cochin,<br />
Paris, France, 3 Functional Unit <strong>of</strong> Pharmacokinetics and Pharmacochemistry,<br />
Hôpital Cochin, Paris, France<br />
Background: Anti PD-1 antibodies nivolumab and pembrolizumab are checkpoint<br />
inhibitors widely used in metastatic melanoma. Although less frequent than with<br />
anti-CTLA4 therapy, severe immune-related adverse events can occur. Since the dose is<br />
calculated in mg/kg, we hypothesized that patients with abnormal body composition<br />
resulting in reduced distribution volume may be overexposed. We studied whether<br />
body composition could predict early severe toxicity in patients with advanced<br />
melanoma receiving either nivolumab or pembrolizumab.<br />
Methods: All melanoma patients treated with anti PD-1 between August 2014 and<br />
February 2016 in our center were retrospectively reviewed. Early severe toxicity was<br />
defined as any toxicity occurring in the first 3 months <strong>of</strong> treatment leading to definitive<br />
or temporary treatment discontinuation. Muscle mass was measured on CT scan<br />
performed closest to treatment initiation. Patients having a skeletal muscle index<br />
inferior to the median <strong>of</strong> the studied population were defined as sarcopenic.<br />
Results: 71 patients were included (33 females; median age 65 years, range 22 to 91<br />
years). 68% received pembrolizumab and 32% nivolumab. 30% <strong>of</strong> tumors harbored<br />
BRAF V600 mutations, 23% NRAS mutations and 39% were wild type. Anti PD-1<br />
antibody was the first line therapy for 36% <strong>of</strong> the patients. 42 (59%) patients had a<br />
BMI > 25 kg/m 2 and 10 (14%) had both sarcopenia and a BMI > 25 kg/m 2 . A total <strong>of</strong><br />
11 (15%) patients experienced severe acute toxicity: pneumonitis (n = 1), nephritis<br />
(n = 1), polymyositis (n = 1), hepatitis (n = 2), uveitis (n = 1), cytopenia (n = 3) or<br />
polyarthritis (n = 2). No toxic death occurred. These events occurred early, 72%<br />
following either the first or second infusion. Treatment discontinuation was definitive<br />
(n = 9) or temporary (n = 2). Sarcopenic patients with a BMI > 25 kg/m 2 experienced<br />
more early severe toxicities: 40% <strong>of</strong> early severe toxicity (n = 4) among<br />
sarcopenic-overweight patients compared to 11% (n = 7) among the other patients<br />
(p = 0, 04).<br />
Conclusions: Patients with sarcopenia and a BMI > 25 kg/m 2 experienced significantly<br />
more early severe toxicities, suggesting an abnormally high exposure. Precautions<br />
should be taken when prescribing anti PD-1 antibodies in this subset <strong>of</strong> patients.<br />
Legal entity responsible for the study: Hôpital Cochin APHP<br />
Funding: Hôpital Cochin APHP<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1131P<br />
Radiographic myosteatosis is prognostic and predictive <strong>of</strong><br />
ipilimumab outcomes in melanoma<br />
M.P. Chu, Y. Li, S. Ghosh, J. Walker, M. Smylie, M. Sawyer<br />
<strong>Oncology</strong>, University <strong>of</strong> Alberta Cross Cancer Institute, Edmonton, AB, Canada<br />
Background: Fatty infiltration <strong>of</strong> muscle appears as low radiographic density (also<br />
called skeletal muscle density, SMD) on computed tomography (CT) imaging. Its<br />
presence is prognostic <strong>of</strong> outcomes across cancers. SMD in malignant melanoma<br />
(MM) has not been investigated in the immunotherapy era. This retrospective study<br />
examined the prognostic ability <strong>of</strong> SMD in ipilimumab-treated MM patients.<br />
Methods: In this single center, retrospective study, advanced/metastatic MM patients<br />
(pts) treated with ipilimumab from 2009-2014 were reviewed. Pre-treatment CT<br />
images were used to determine body composition at the third lumbar vertebrae (L3)<br />
given its very accurate approximation <strong>of</strong> total body muscle and fat. SMD at L3 was<br />
measured and expressed in Hounsfield Units (HU). Cutpoint analysis determined<br />
whether a particular level <strong>of</strong> SMD demonstrated differences in progression free (PFS)<br />
and overall survival (OS). Secondary endpoints included objective response rates<br />
(ORR) and toxicities.<br />
Results: Of 121 identified, 97 pts were evaluable. Baseline demographics included: 56<br />
years median age, 58 male (60%), and 23 with BRAF mutations (23.7%). Cutpoint<br />
analysis found a prognostically significant difference between pts with SMD < 42 and<br />
20 HU for pts with BMI < 25 and ≥ 25 kg/m 2 , respectively. Pts with low SMD had<br />
significantly poorer median PFS (2.4 vs. 2.7 months, hazard ratio [HR] 1.76, p = 0.008)<br />
and OS (5.4 vs. 17.5 months, HR 2.47, p = 0.001) compared to pts with SMD above the<br />
cutpoint. This PFS (HR) and OS (HR) difference remained in multivariate Cox<br />
proportional hazards modeling taking into consideration age, gender, BRAF status, and<br />
line <strong>of</strong> treatment. There was no statistical difference in toxicity number or severity<br />
between SMD groups, but ORR trended in favor <strong>of</strong> higher SMD (17.9 vs. 3.3%,<br />
p = 0.051). SMD may relate to inflammation given a higher prevalence <strong>of</strong> high<br />
neutrophil-to-lymphocyte ratio in low SMD pts (39 vs. 21%, p = 0.049).<br />
Conclusions: Low SMD is prognostic <strong>of</strong> melanoma outcomes in the immunotherapy<br />
era. SMD may relate to an underlying inflammatory state and therefore predict who<br />
may or may not respond to such therapy. It may also therefore point toward to<br />
immunotherapy resistance mechanisms.<br />
Legal entity responsible for the study: University <strong>of</strong> Alberta<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1132P<br />
abstracts<br />
More than 50% <strong>of</strong> patients with metastatic melanoma are not<br />
represented in pivotal phase 3 immunotherapy registration<br />
trials<br />
M. Donia 1 , M.L. Kimper-Karl 2 , L. Bastholt 2 , I.M. Svane 1<br />
1 Center for Cancer Immune Therapy and Department <strong>of</strong> <strong>Oncology</strong>, University<br />
Hospital Herlev, Herlev, Denmark, 2 Dept. <strong>of</strong> <strong>Oncology</strong>, Odense University Hospital,<br />
Odense, Denmark<br />
Background: Recent randomized trials with strict patient (pt) selection criteria led to<br />
the approval <strong>of</strong> several immune checkpoint inhibitors for unresectable or metastatic<br />
melanoma (MM). It is currently unknown how large is the proportion <strong>of</strong> real life pts<br />
with MM not represented in these trials<br />
Methods: Data from all MM patients referred in 2014 to assessment for systemic<br />
treatment were retrieved from the Danish MM Database. Data were available from two<br />
<strong>of</strong> three reference centers, where all resident pts diagnosed with MM are referred. A<br />
total <strong>of</strong> 194 cases (uveal melanoma was excluded) were retrieved, and 183 pts with<br />
sufficient records were included in the analysis. Seven pre-defined enrolment eligibility<br />
criteria, all employed in five recent randomized phase 3 immunotherapy trials, were<br />
analyzed<br />
Results: At 1 st visit, the majority <strong>of</strong> pts (82%, n = 150) had confirmed cutaneous<br />
melanoma, 15% melanoma <strong>of</strong> unknown primary origin and 3% had mucosal melanoma.<br />
32% <strong>of</strong> the pts had PS ≥ 2; 22% active/untreated known brain metastases; 22% significant<br />
comorbidities; 10% other malignancies in the past 5 years; 6% autoimmune diseases and<br />
19% were on treatment with immunosuppressive drugs. 4 additional pts were not eligible<br />
because <strong>of</strong> the absence <strong>of</strong> target lesions. In total, 59% <strong>of</strong> the total population did not fulfil<br />
at least one enrolment criteria (non-eligible group). Median survival <strong>of</strong> the non-eligible<br />
group was 5.2 months vs 17.3 months for the eligible (p < 0.0001, HR 2.39), reflected by<br />
significantly poorer baseline prognostic features. In contrast, baseline characteristics <strong>of</strong><br />
the eligible group were very similar to the average <strong>of</strong> patients (n = 3375) enrolled in five<br />
recent phase 3 trials. Median survival <strong>of</strong> the eligible group was comparable to the control<br />
group (ipilimumab) <strong>of</strong> patients enrolled in Keynote-006 trial, reflecting similar pts<br />
characteristics and treatment options<br />
Conclusions: At least half the patients evaluated for systemic treatment <strong>of</strong> MM are not<br />
represented in phase 3 registration immunotherapy trials. These data reveal a huge<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw379 | vi389
abstracts<br />
knowledge gap regarding the usefulness <strong>of</strong> new immunotherapies in the broader<br />
patient population, and urge additional testing <strong>of</strong> known regimens in selected poor<br />
prognosis cohorts<br />
Legal entity responsible for the study: Herlev Hospital<br />
Funding: Herlev Hospital<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1133P<br />
Systemic treatment influences on immune accessibility <strong>of</strong><br />
melanoma: A retrospective histopathological investigation<br />
L. Krähenbühl 1 , S.M. Goldinger 2 , K. Kerl 1 , W. Kempf 1 , I. Chevolet 3 , L. Brochez 3 ,<br />
P. Cheng 1 , J. Mangana 2 , M.P. Levesque 1 , R. Dummer 4<br />
1 Dermatology, University Hospital Zürich-Dermatology, Zurich, Switzerland,<br />
2 Department <strong>of</strong> Dermatology, University Hospital Zurich, Zurich, Switzerland,<br />
3 Dermatology, Gent University Hospital, Gent, Belgium, 4 Department <strong>of</strong><br />
Dermatology, Universitätsspital Zürich, Zurich, Switzerland<br />
Background: Major progress has been achieved in immunohistochemical stainings<br />
over the last few decades. The latter allowed for studies microscopically analyzing tissue<br />
in metastasized melanoma. Aims have been on generally improving understanding in<br />
this tumor as well as investigating it’s susceptibility for specific treatments. Stainings<br />
for PD-1 and PD-L1 are <strong>of</strong> particular interest as immunotherapies targeting this<br />
interaction have recently been approved by the FDA and other relevant authorities.<br />
PD-L1 expression as a prognostic factor for survival has been established. However no<br />
clear predictive role for subsequent treatments with anti-PD-1 or anti-PD-L1<br />
antibodies was found. We have previously presented preliminary data on the influence<br />
<strong>of</strong> systemic treatments on immune accessibility. This is the final evaluation along with<br />
the clinical correlation.<br />
Methods: Pre- and post systemic treatment tumor tissue was stained for multiple<br />
markers including CD3, CD8, PD-1, PD-L1 and IDO and analyzed with the focus on<br />
changes in lymphocyte distribution under treatment.<br />
Results: In this study, a total <strong>of</strong> 40 paired metastases pre- and post systemic treatments<br />
including both immunotherapies (n = 16) and targeted therapies (n = 25), including<br />
multiple treatments per patient, were stained and analyzed. We observe an increase in<br />
tumor infiltrating lymphocytes in 15 out <strong>of</strong> the 40 pairs with a positive trend towards<br />
improved survival, whilst in 25 pairs, we observe generally stable lymphocyte<br />
infiltration or very small decreases after treatment. Increased infiltration is more <strong>of</strong>ten<br />
associated with targeted therapy than immunotherapy. Shorter survival in tumors<br />
displaying IDO-positive high endothelial venules is confirmed in this study.<br />
Conclusions: Increased tumor lymphocyte infiltration is associated with increased<br />
tumor control and can be interpreted as loss <strong>of</strong> a previous immune privilege <strong>of</strong> the<br />
tumor. The morphological correlate is the redistribution from a previous grenz zone<br />
like distribution towards tumor infiltration by lymphocytes and is particularly observed<br />
with targeted therapy. Independent from the treatment, IDO-positive endothelial cells<br />
are associated with shorter survival.<br />
Legal entity responsible for the study: Ethikkommision des Kantons Zürich<br />
Funding: Zurich University Hospital<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
Methods: The pooled population included randomized pts treated with D 150 mg<br />
twice daily + T 2 mg once daily in BRF113220 (Part C; cut<strong>of</strong>f Jan 2015), COMBI-d<br />
(cut<strong>of</strong>f Jan 2015), and COMBI-v (cut<strong>of</strong>f Mar 2015). Baseline factors (Table) were<br />
analyzed by regression tree analyses to identify predictors <strong>of</strong> D + T treatment (Tx),<br />
PFS, or OS lasting ≥ 24 mo.<br />
Results: Of 617 pts treated with D + T in BRF113220 (n = 54), COMBI-d (n = 211),<br />
and COMBI-v (n = 352), 165 (27%) received it for ≥ 24 mo. Long-term PFS (n = 472)<br />
and OS (n = 456) analyses excluded pts censored prior to 24 mo. A total <strong>of</strong> 85 pts<br />
(18%) had PFS ≥ 24 mo and 186 (41%) had OS ≥ 24 mo (Table). Regression tree<br />
analyses identified baseline lactate dehydrogenase (LDH) as the most predictive factor<br />
for durable benefit. Pts with normal vs elevated LDH had improved PFS (median: 12.1<br />
vs 5.5 mo; 2-y rate: 26% vs 5%) and OS (median: 31.6 vs 10.8 mo; 2-y rate: 56% vs<br />
15%). At data cut<strong>of</strong>f, 172 pts (28%) remained on D + T, including 140 (81%) with<br />
Tx ≥ 24 mo and 69 (40%) with PFS ≥ 24 mo.<br />
Table: 1134P<br />
PFS ≥ 24<br />
Characteristic PFS < 24<br />
(n = 387) a (n = 85)<br />
mo mo<br />
Baseline Factors Included in Regression Tree Analyses<br />
OS < 24 mo OS ≥ 24<br />
(n = 270) b mo<br />
(n = 186)<br />
Age, median, y 55 56 53 57<br />
BRAF mutation, n (%) V600E<br />
V600K or V600E and V600K<br />
334 (86)<br />
53 (14)<br />
75 (88)<br />
10 (12)<br />
233 (86)<br />
37 (14)<br />
161 (87)<br />
25 (13)<br />
Disease stage, n (%) III (any),<br />
IVM1a, or IVM1b IVM1c<br />
108 (28)<br />
279 (72)<br />
42 (49)<br />
43 (51)<br />
60 (22)<br />
210 (78)<br />
88 (47)<br />
98 (53)<br />
ECOG PS, n (%) 0 ≥ 1 258 (67)<br />
127 (33)<br />
66 (78)<br />
19 (22)<br />
155 (58)<br />
113 (42)<br />
146 (78)<br />
40 (22)<br />
Sex, n (%) Female Male 151 (39)<br />
236 (61)<br />
39 (46)<br />
46 (54)<br />
95 (35)<br />
175 (65)<br />
93 (50)<br />
93 (50)<br />
LDH, n (%)<br />
Normal ≥ 1 × ULN ≥ 2 × ULN<br />
215 (56)<br />
108 (28)<br />
62 (16)<br />
76 (89)<br />
9 (11)<br />
0<br />
124 (46)<br />
90 (34)<br />
54 (20)<br />
161 (87)<br />
24 (13)<br />
1(
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
1135P<br />
COMBI-rechallenge: a phase II clinical trial on dabrafenib<br />
plus trametinib in BRAFV600-mutant melanoma patients who<br />
previously experienced progression on BRAF<br />
(+MEK)-inhibition<br />
M. Schreuer 1 , V. Kruse 2 , Y. Jansen 1 , B. Neyns 1<br />
1 <strong>Oncology</strong>, UZ Brussel, Brussels, Belgium, 2 <strong>Oncology</strong>, Gent University Hospital,<br />
Gent, Belgium<br />
Background: Patients (pts) with BRAFV600-mutant advanced melanoma benefit from<br />
treatment with the combination <strong>of</strong> a BRAF- and a MEK-inhibitor. Acquired resistance<br />
could potentially be reversible when selective pressure by BRAF-inhibition is withheld<br />
for a sufficient period <strong>of</strong> time.<br />
Methods: This single-arm, 2-stage, phase II trial addresses the potential renewed<br />
anti-tumor activity <strong>of</strong> dabrafenib (150mg BD) and trametinib (2mg QD) in pts with<br />
unresectable BRAFV600-mutant melanoma who are documented with disease<br />
progression (PD) at least 12 weeks following the last day <strong>of</strong> dosing <strong>of</strong> a BRAF-inhibitor<br />
containing treatment regimen, and have experienced PD on immunotherapy. Tumor<br />
response rate served as the primary end point. Sample size (25 pts) was calculated<br />
according to a two-stage Simon Minimax design. Rechallenge with dabrafenib and<br />
trametinib will be considered sufficiently active for further clinical investigation if a<br />
confirmed tumor response is documented in at least 4 pts.<br />
Results: Between April 2014 and February 2016, 25 pts were recruited. Baseline<br />
characteristics: 15M/10F; median age 54.7y (range 29-72); AJCC stage<br />
IV-M1a/-M1b/-M1c: 1/1/23 pts. Median follow-up time is 6 months (range 1-23), and<br />
tumor response has been evaluated in all pts. A confirmed PR was documented in 8 pts<br />
(32%), SD was observed in 10 pts (40%). Median PFS was 4.8 months (95% CI: 2.8 -<br />
6.8), median OS was not reached. Most frequent treatment related adverse events (AE)<br />
were pyrexia in 10 pts (40%), fatigue and myalgia in 7 pts (28%), AST, CK and AP<br />
elevation in 6 pts (24%), ALT elevation in 5 pts (20%), panniculitis in 3 pts (12%).<br />
Grade 3/4 AE occurred in 3 pts (1x panniculitis, 1x GGT elevation, 1x pyrexia). There<br />
were no grade 5 AE.<br />
Conclusions: This phase II trial found that BRAFV600-mutant melanoma pts who<br />
experienced prior progression on BRAF(+MEK)-inhibitors, were <strong>of</strong>f BRAF(+MEK)<br />
inhibitor therapy for at least 12 weeks, and progressed on immunotherapy, benefitted<br />
sufficiently from rechallenge with dabrafenib and trametinib to warrant further<br />
investigation.<br />
Clinical trial identification: EudraCT 2013-004966-33<br />
Legal entity responsible for the study: Sponsor Legal Registered Address: UZ Brussel,<br />
Laarbeeklaan 101 1090 Brussels Belgium UZ Gent, De Pintelaan 185 9000 Gent<br />
Belgium<br />
Funding: Novartis<br />
Disclosure: B. Neyns: Financial compensation from Roche, Bristol-Myers Squibb,<br />
Merck Sharp & Dohme, Novartis, AstraZeneca, CryoStorage for public speaking,<br />
consultancy and participation in advisory board meetings. All other authors have<br />
declared no conflicts <strong>of</strong> interest.<br />
1136P<br />
Pimasertib (PIM) versus dacarbazine (DTIC) in patients (pts)<br />
with cutaneous NRAS melanoma: a controlled, open-label<br />
phase II trial with crossover<br />
C. Lebbe 1 , C. Dutriaux 2 , T. Lesimple 3 , W. Kruit 4 , J. Kerger 5 , L. Thomas 6 ,<br />
B. Guillot 7 ,F.deBraud 8 , C. Garbe 9 , J.J. Grob 10 , C. Loquai 11 , V. Ferraresi 12 ,<br />
C. Robert 13 ,P.Vasey 14 , R. Conry 15 , R. Isaacs 16 , E. Espinosa 17 , A. Schueler 18 ,<br />
A. Markivskyy 19 , B. Dreno 20<br />
1 APHP Service de dermatologie, INSERM U976 Hôpital Saint Louis, Paris, France,<br />
2 Dermatology, Hopital Saint-Andre – CHU, Bordeaux, France, 3 Medical <strong>Oncology</strong><br />
Department, Comprehensive Cancer Center Eugène Marquis CS 44229, Rennes,<br />
France, 4 Internal <strong>Oncology</strong>, Erasmus Cancer Institute, Rotterdam, Netherlands,<br />
5 Oncologie Médicale, Institute Jules Bordet, Brussels, Belgium, 6 Department <strong>of</strong><br />
Dermatology, Centre Hospitalier Lyon Sud, Pierre Bénite, France, 7 Départment <strong>of</strong><br />
Dermatology, Hôpital Saint Eloi, Montpellier, France, 8 Università degli Studi di<br />
Milano - Dipartimento di Medicina Oncologica, Istituto Nazionale dei Tumori, Milan,<br />
Italy, 9 Deptartment <strong>of</strong> Dermatology, University Hospital Tuebingen, Tübingen,<br />
Germany, 10 Service de Dermatologie et Cancérologie Cutanée, Hopital de la<br />
Timone, Marseille, France, 11 Department <strong>of</strong> Dermatology, University Medical<br />
Center, Mainz, Mainz, Germany, 12 Istituti Fisioterapici Ospedalieri, U.O. Oncologia<br />
Medica 1, Regina Elena National Cancer Institute, Rome, Italy, 13 Service de<br />
dermatologie, Institut Gustave Roussy, Villejuif, France, 14 Icon Cancer Care, The<br />
Wesley Hospital, Auchenflower, Australia, 15 Comprehensive Cancer Center,<br />
University <strong>of</strong> Alabama at Birmingham, Birmingham, AL, USA, 16 Regional Cancer<br />
Treatment Service, Palmerston North Hospital, Palmerston North, New Zealand,<br />
17 Servicio de Oncología Médica, Hospital Universitario La Paz, Madrid, Spain,<br />
18 Global Biostatistics <strong>Oncology</strong>, Merck KGaA, Darmstadt, Germany, 19 GCDU<br />
<strong>Oncology</strong>, Merck KGaA, Darmstadt, Germany, 20 Department <strong>of</strong> Dermato<br />
Cancerology, CHU Nantes, Nantes, France<br />
abstracts<br />
inhibitor PIM in a phase 1 trial in pts with melanoma, a population with an unmet<br />
medical need, triggered this phase 2 trial.<br />
Methods: In a multicenter, open-label phase 2 trial (EudraCT 2012-002669-37), pts<br />
with previously untreated unresectable stage IIIc/IV cutaneous NRAS melanoma were<br />
randomized (2:1) to receive PIM (60mg PO BID) or DTIC (1000mg/m 2 IV q3w) in<br />
21-day cycles. DTIC-treated pts could switch to PIM at progression. Key endpoints<br />
were progression-free survival (PFS, primary endpoint; investigator-read), objective<br />
response rate (ORR), disease control rate (DCR), overall survival (OS), and safety.<br />
Results: 194 pts were randomized (intent-to-treat [ITT] set); 41/64 pts in DTIC arm<br />
switched to PIM after progression. Baseline characteristics were similar in the arms.<br />
Median PFS was significantly longer with PIM than with DTIC (13.0 vs 6.9 weeks;<br />
hazard ratio (HR) = 0.59, 95% confidence interval [CI] 0.42-0.83; p = 0.0022). The table<br />
shows efficacy outcomes.<br />
Table: 1136P Efficacy outcomes in the PIM and DTIC treatment arms<br />
(ITT)<br />
Efficacy endpoint PIM (n = 130) DTIC (n = 64)<br />
Median PFS ab , weeks (HR [95% CI]) 13.0 6.9<br />
0.59 [0.42-0.83], p = 0.0022<br />
Median PFS c , weeks (HR [95% CI]) 12.7 6.4<br />
0.65 [0.45-0.94], p = 0.0195<br />
Median OS, months (HR [95% CI]) 8.9 10.6<br />
0.89 (0.61-1.30)<br />
ORR a , % (OR [95% CI]) 26.9 14.1<br />
2.24 [1.00-4.98], p = 0.0453<br />
ORR c ,% (OR [95% CI]) 23.1 14.1<br />
1.83 [0.81-4.13], p = 0.1430<br />
DCR a , % (OR [95% CI]) 33.1 15.6<br />
2.65 [1.23-5.69], p = 0.0106<br />
DCR c , % (OR [95% CI]) 37.7 26.6<br />
1.68 [0.87-3.26], p = 0.1235<br />
a Investigator read; b Primary endpoint; c Blinded independent read.<br />
OR, odds ratio<br />
The most common (% pts) adverse events (AEs)/drug-related AEs in the PIM arm<br />
were diarrhea (82.3/70.8), elevated creatine kinase (CPK) (68.5/68.5), peripheral edema<br />
(46.2/38.5) and serous retinal detachment (44.6/44.6); % pts with grade ≥3/<br />
drug-related grade ≥3 <strong>of</strong> these AEs were 6.2/3.8, 33.8/33.1, 2.3/2.3 and 3.1/3.1,<br />
respectively. Ocular AEs in PIM pts were reversible (>92%), mild to moderate (>95%)<br />
and did not impact on visual acuity (in >91%). Most (>90%) cases <strong>of</strong> CPK increase<br />
were asymptomatic, transient and reversible laboratory findings.<br />
Conclusions: The primary objective <strong>of</strong> significant PFS improvement in the PIM arm<br />
was achieved. Consistent trend in favor <strong>of</strong> the PIM arm for PFS, ORR and DCR was<br />
seen, but no difference in OS. The safety pr<strong>of</strong>ile <strong>of</strong> PIM was consistent with previous<br />
studies with no new safety signals.<br />
Clinical trial identification: EudraCT 2012-002669-37<br />
Legal entity responsible for the study: Merck KGaA<br />
Funding: Merck KGaA<br />
Disclosure: C. Lebbe: Member <strong>of</strong> advisory board for: Roche Novartis Bristol-Myers<br />
Squibb MSD. T. Lesimple: Research grants: Roche Advisory board member: Roche<br />
Novartis MSD. W. Kruit: Advisory Board Member: Novartis MSD Bristol-Myers<br />
Squibb. F. de Braud: Advisory board member for: Boehringer Ingelheim, Philogen,<br />
Novartis, Novartis <strong>Oncology</strong>, IRIS, GlaxoSmithKline, MSD, Bristol-Myers Squibb,<br />
Merck Serono, Eli Lilly, Servier, Tiziana Life Sciences. C. Garbe: Advisory board<br />
member for: Amgen Bristol-Myers Squibb MSD Novartis Leo Pharma Research<br />
funding from: Bristol-Myers Squibb Novartis Roche. C. Loquai: Advisory board<br />
member for: Roche Bristol-Myers Squibb Novartis Amgen MSD Speakers honoraria<br />
from Roche, Bristol-Myers Squibb, Novartis, MSD Travel reimbursement from Roche,<br />
Bristol-Myers Squibb, Novartis, MSD, Amgen. V. Ferraresi: Research funding:<br />
Bristol-Myers Squibb Roche GlaxoSmithKlein Merck. C. Robert: Advisory board<br />
member for: Amgen Bristol-Myers Squibb Novartis Merck Roche. R. Isaacs: On board<br />
<strong>of</strong> directors for: Australia New Zealand Breast Cancer Clinical Trials<br />
Group. E. Espinosa: Advisory Board Member: Bristol-Myers Squibb Merck Novartis<br />
Roche Research funding from: Bristol-Myers Squibb Merck Novartis<br />
Roche. A. Schueler, A. Markivskyy: Employed by Merck KGaA. B. Dreno: Member <strong>of</strong><br />
advisory board for: Roche GlaxoSmithKlein Novartis Bristol-Myers Squibb. All other<br />
authors have declared no conflicts <strong>of</strong> interest.<br />
Background: The MEK/ERK pathway is activated in many tumors and important for<br />
melanoma transformation and progression. Clinical activity observed with the MEK1/2<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw379 | vi391
abstracts<br />
1137P<br />
Health-related quality-<strong>of</strong>-life (HRQOL) impact <strong>of</strong> dabrafenib<br />
(D) and trametinib (T) vs BRAF inhibitor (BRAFi) monotherapy<br />
by lactate dehydrogenase (LDH) in patients (pts) with BRAF<br />
V600–mutant melanoma<br />
J.J. Grob 1 , C. Robert 2 , G.V. Long 3 , D. Stroyakovskiy 4 , E. Levchenko 5 ,<br />
V. Chiarion-Sileni 6 , K. Flaherty 7 , P. Nathan 8 , A. Ribas 9 , M. Davies 10 , J. Zhang 11 ,<br />
L. Chen 11 , B. Mookerjee 11 , S. Redhu 11 , D. Schadendorf 12<br />
1 Service de Dermatologie et Cancérologie Cutanée, Aix Marseille University,<br />
Marseille, France, 2 Dermatology, Gustave Roussy Comprehensive Cancer Center,<br />
Villejuif, France, 3 Medical <strong>Oncology</strong>, Melanoma Institute <strong>of</strong> Australia and The<br />
University <strong>of</strong> Sydney, Sydney, Australia, 4 Chemotherapy Department, Moscow<br />
City <strong>Oncology</strong> Hospital No. 62, Moscow, Russian Federation, 5 <strong>Oncology</strong>,<br />
N. N. Petrov Research Institute <strong>of</strong> <strong>Oncology</strong>, St-Petersburg, Russian Federation,<br />
6 Melanoma and Skin Cancer Unit, Veneto <strong>Oncology</strong> Institute, Padua, Italy,<br />
7 Melanoma, Dana-Farber Cancer Institute/Harvard Medical School and<br />
Massachusetts General Hospital, Boston, MA, USA, 8 Department <strong>of</strong> Medical<br />
<strong>Oncology</strong>, Mount Vernon Cancer Centre, Northwood, UK, 9 Medicine, Hematology<br />
& <strong>Oncology</strong>, UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA,<br />
USA, 10 Melanoma Medical <strong>Oncology</strong>, The University <strong>of</strong> Texas MD Anderson<br />
Cancer Center, Houston, TX, USA, 11 Global <strong>Oncology</strong>, Novartis Pharmaceuticals<br />
Corporation, East Hanover, NJ, USA, 12 Department <strong>of</strong> Dermatology, University<br />
Hospital <strong>of</strong> Essen, Essen, Germany<br />
Background: D + T improved outcomes and HRQOL in pts with BRAF V600–mutant<br />
melanoma vs BRAFi alone in COMBI-d (NCT01584648) and COMBI-v<br />
(NCT01597908). Although pooled analysis <strong>of</strong> melanoma clinical/prognostic<br />
characteristics across D + T registration trials identified baseline (BL) LDH as the most<br />
influential covariate on outcomes, D + T improved response, PFS, and OS vs BRAFi<br />
alone in both normal and elevated-LDH groups. This retrospective analysis <strong>of</strong><br />
COMBI-d and COMBI-v patient-reported outcomes (PROs) assessed whether<br />
HRQOL was consistently improved across LDH groups.<br />
Methods: COMBI-d and COMBI-v are phase 3, randomized, double-blind studies <strong>of</strong><br />
first-line D + T vs D + placebo (Pbo) or vemurafenib (V), respectively, in pts with<br />
unresectable stage IIIC or IV BRAF V600–mutant melanoma. HRQOL was evaluated<br />
in COMBI-d and COMBI-v by EORTC QLQ-C30 (global QOL, functional, and<br />
symptom domains) at BL, during treatment (Tx), and at disease progression (PD).<br />
PROs were analyzed by LDH (≤ and > ULN). ANCOVA adjusted for BL score using<br />
mixed-model repeated measures was carried out.<br />
Results: Across COMBI-d (D + T, n = 211 [77 with LDH > ULN]; D + Pbo, n = 212 [71<br />
with LDH > ULN]) and COMBI-v (D + T, n = 352 [118 with LDH > ULN]; V, n = 352<br />
[114 with LDH > ULN]), EORTC QLQ-C30 completion rates were > 85% through wk<br />
40 and ≥ 70% at PD. Clinically meaningful differences in mean scores between arms<br />
favoring D + T vs BRAFi alone were seen for most HRQOL domains for both LDH<br />
subgroups across time points, including at PD (Table). Results for D + T vs BRAFi<br />
alone by LDH in COMBI-d and COMBI-v for all EORTC QLQ-C3cl be presented.<br />
EORTC<br />
QLQ-C30<br />
Domain<br />
Table: 1137P<br />
Change From Baseline at PD<br />
COMBI-d<br />
COMBI-v<br />
LDH ≤ ULN LDH > ULN LDH ≤ ULN LDH > ULN<br />
Global health + +C +C* +C*<br />
Functioning<br />
Cognitive – + + +C*<br />
Emotional – +C +* +C<br />
Physical + + +* +C*<br />
Role + +C +C* +C*<br />
Social – +C +C* +C*<br />
Symptoms<br />
Appetite loss – +C* +C* +C*<br />
Constipation – + – –<br />
Diarrhea – + +C* +C*<br />
Dyspnea – + + +<br />
Fatigue + +C + +C*<br />
Insomnia + + +C* +C*<br />
Nausea & – Neither + +C*<br />
vomiting<br />
favored<br />
Pain +C* +C* +C* +C*<br />
Financial<br />
difficulties<br />
– – + +<br />
+ favors D + T; – favors BRAFi alone; C clinically meaningful difference (≥ 5<br />
points); * statistically significant (P < .05).<br />
Conclusions: D + T consistently improved HRQOL vs BRAFi alone for most EORTC<br />
QLQ-C30 domains, regardless <strong>of</strong> LDH, further supporting continued use <strong>of</strong> D + T in<br />
BRAF-mutant melanoma across LDH subgroups. HRQOL benefit with D + T may be<br />
greater in pts with LDH > ULN.<br />
Clinical trial identification: NCT01597908; first received by clinicaltrials.gov on May<br />
10, 2012 and NCT01584648; first received by clinicaltrials.gov on April 23, 2012.<br />
Legal entity responsible for the study: Supported by GlaxoSmithKline. Dabrafenib<br />
and trametinib are assets <strong>of</strong> Novartis AG as <strong>of</strong> 2 March 2015.<br />
Funding: Supported by GlaxoSmithKline. Dabrafenib and trametinib are assets <strong>of</strong><br />
Novartis AG as <strong>of</strong> 2 March 2015.<br />
Disclosure: J.J. Grob: Consultancy: Novartis, GSK, Roche, Merck, BMS,<br />
Amgen. C. Robert: Consultancy: Novartis, Amgen, BMS, Merck, Roche Honoraria:<br />
Novartis, Amgen, BMS, Merck, Roche. G.V. Long: Consultancy: Roche, BMS, Merck,<br />
Amgen, Novartis Honoraria: BMS, Merck, Novartis. V. Chiarion-Sileni: Consultancy:<br />
Novartis, BMS Speakers Bureau: GSK, Novartis Membership on Board <strong>of</strong> Directors or<br />
Advisory Committee: GSK, Novartis, Roche, BMS, MSD. K. Flaherty: Consultancy:<br />
Novartis, Roche, Array, Lilly, Takeda Research Funding: Novartis. P. Nathan:<br />
Consultancy: Novartis Speakers Bureau: Novartis Membership on Board <strong>of</strong> Directors<br />
or Advisory Committee: Novartis. A. Ribas: Consultancy: Novartis, Merck, Pfizer,<br />
Roche Equity Ownership: Kite Pharma Honoraria: Novartis. M. Davies: Research<br />
Funding: Genentech/Roche, GSK, AstraZeneca, San<strong>of</strong>i-Aventis, Merck Membership on<br />
Board <strong>of</strong> Directors or Advisory Committee: Novartis, Genentech/Roche, GSK,<br />
San<strong>of</strong>i-Aventis, Vaccinex. J. Zhang, L. Chen: Employment: Novartis Equity Ownership:<br />
Novartis. B. Mookerjee: Employment: Novartis Equity Ownership: Novartis, GSK,<br />
Incyte, AstraZeneca. S. Redhu: Employment: Novartis. D. Schadendorf: Consultancy/<br />
Honoraria/Speakers Bureau/Board <strong>of</strong> Directors: Amgen, Novartis, Roche, BMS, MSD<br />
Merck, Pfizer Research Funding: BMS, MSD Merck Board <strong>of</strong> Directors: Array. All<br />
other authors have declared no conflicts <strong>of</strong> interest.<br />
1138P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Cobimetinib plus vemurafenib to treat unresectable or<br />
metastatic melanoma: Data from the French temporary<br />
authorization for use<br />
N. Meyer 1 , D-M. Anne-Bénédicte 2 , B. Dreno 3 , C. Lebbe 4 , O. Zehou 5 , A. Gorana 6 ,<br />
M. Mouri 6 , A. Bardet 6 , M. Moreau 6 , C. Mateus 7<br />
1 Dermatology, Institut Universitaire du Cancer -Toulouse- Oncopole, Toulouse,<br />
France, 2 Dermatology, CHU Hôpitaux de Rouen-Charles Nicolle, Rouen, France,<br />
3 Service Dermatologie, Chu Nantes Hotel Dieu, Nantes, France, 4 Dermatology,<br />
Hôpital St. Louis, Paris, France, 5 Dermatology, CHU Henri Mondor, Créteil,<br />
France, 6 Clinical Operations, Roche S.A.S, Boulogne-Billancourt, France,<br />
7 Dermatology, Institut Gustave Roussy, Villejuif, France<br />
Background: Given the positive findings from the coBRIM phase III study having<br />
assessed cobimetinib (C) plus vemurafenib (V) in patients (pts) with BRAF V600<br />
mutation-positive unresectable locally advanced or metastatic melanoma, a Temporary<br />
Authorization for Use (TAU) program (pre-approval access to new treatment options<br />
where unmet medical need exists) has been settled in France for cobimetinib from 27<br />
Apr 2015 to 04 Jan 2016.<br />
Methods: Analysis was performed in pts with approved treatment-access delivered<br />
within TAU. Specific forms had to be completed at C initiation (in combination with<br />
V) and monthly after first treatment intake. All adverse events (AEs) had to be reported<br />
during pts’ follow-up.<br />
Results: A total <strong>of</strong> 376 pts had approved early access to the combined therapy (C plus<br />
V). Following baseline data were available for 328 pts (87%). Mean age was 57 ± 15<br />
years and 59% were male. A total <strong>of</strong> 290 pts (89%) had stage IV melanoma (M1a: 11%,<br />
M1b: 13%, M1c: 64%) and 79 pts (24%) presented with brain metastasis. During<br />
follow-up, 280 AEs were reported in 134 <strong>of</strong> 376 pts (36%), including 208 (74%)<br />
C-related AEs reported in 108 pts (29%) and/or 160 (57%) V-related AEs reported in<br />
82 pts (22%). Among the 101 (36%) serious AEs (SAEs) reported in 63 pts (17%), 67<br />
SAEs (24%) reported in 42 pts (11%) were assessed as related to C. Twenty-two AEs<br />
(8%) reported in 12 pts (3%) led to permanent C discontinuation. Fifty-three<br />
predefined specific AEs (19%) were reported in 49 pts (13%): 23 increased creatine<br />
phosphokinase (including 2 SAEs), 12 photosensitivity reactions (7 SAEs), 7 retinal<br />
detachments (3 SAEs), 7 renal failures (3 SAEs), and 4 left ventricular ejection fraction<br />
decreases (1 SAE). No squamous cell carcinoma nor C-related death were reported<br />
during follow-up.<br />
Conclusions: These real-life data from this French TAU program are consistent with<br />
safety data collected during clinical development program and showed no new safety<br />
signal for C when combined with V to treat pts with unresectable or metastatic<br />
melanoma.<br />
Legal entity responsible for the study: Roche S.A.S<br />
Funding: Roche S.A.S<br />
Disclosure: N. Meyer: Financial interest for pr<strong>of</strong>essor Nicolas Meyer, in Melanoma,<br />
with differents pharmaceuticals companies: -Roche -Novartis -BMS -MSD -Amgen<br />
-GSK. D-M. Anne-Bénédicte: Financial interest for doctor Duval Modeste with<br />
differents pharmaceuticals laboratories: -Roche -Novartis -BMS -Abbvie -Janssen Cilag<br />
-Pfizer. B. Dreno: Finantial interest for pr<strong>of</strong>essor Dreno Brigitte with differents<br />
pharmaceuticals companies: -Roche -Novartis -BMS -Amgen. C. Lebbe: Financial<br />
interest in Melanoma for Doctor Celeste Lebbe: -Roche -Novartis -BMS -MSD<br />
-Amgen. O. Zehou: Financial interest for doctor Ouidad Zehou in melanoma, with<br />
other pharmaceuticals laboratories: Roche Novartis BMS. A. Gorana: Financial interest<br />
vi392 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
for Adrian Gorana: He is doctor in drug monitoring for Roche S.A.S. M. Mouri:<br />
Financial interest for Mehdi Mouri: He works for Roche S.A.S, he is doctor and<br />
medical responsible in dermatology and hematology. A. Bardet: Financial interest in<br />
Melanoma for Aurélie Bardet: She is Bio-statistician for Roche S.A.S. M. Moreau:<br />
Project manager for Roche S.A.S. C. Mateus: Financial interest for doctor Christina<br />
Mateus in melanoma with other Pharmaceuticals companies: -Roche<br />
1139P<br />
Survival in BRAF-mutant metastatic melanoma in the<br />
real-world setting: results from the Dutch Melanoma<br />
Treatment Registry<br />
M. Schouwenburg 1 , A. Jochems 1 , M. Aarts 2 , F. van den Berkmortel 3 , A. van<br />
den Eertwegh 4 , M. Franken 5 , G. Groenewegen 6 , J-W. de Groot 7 , J.B.A.<br />
G. Haanen 8 , G. Hospers 9 , E. Kapiteijn 10 , R. Koornstra 11 , W. Kruit 12 ,<br />
M. Louwman 13 , D. Piersma 14 , R. van Rijn 15 , A.J. Ten Tije 16 , G. Vreugdenhil 17 ,<br />
M. Wouters 18 , J. van der Hoeven 1<br />
1 Medical <strong>Oncology</strong>, Leiden University Medical Center (LUMC), Leiden,<br />
Netherlands, 2 Medical <strong>Oncology</strong>, Maastricht University Medical Center (MUMC),<br />
Maastricht, Netherlands, 3 Medical <strong>Oncology</strong>, Atrium Medisch Centrum Parkstad,<br />
Heerlen, Netherlands, 4 Medical <strong>Oncology</strong>, Vrije University Medical Centre (VUMC),<br />
Amsterdam, Netherlands, 5 Medical Technology Assessment, Institute for Medical<br />
Technology Assessment, Erasmus University, Rotterdam, Netherlands, 6 Medical<br />
<strong>Oncology</strong>, University Medical Center Utrecht, Utrecht, Netherlands, 7 Medical<br />
<strong>Oncology</strong>, Isala Klinieken, Zwolle, Netherlands, 8 Department <strong>of</strong> Medical <strong>Oncology</strong>,<br />
The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital,<br />
Amsterdam, Netherlands, 9 Medical <strong>Oncology</strong>, University Hospital Groningen<br />
(UMCG), Groningen, Netherlands, 10 Clinical <strong>Oncology</strong>, Leiden University Medical<br />
Center (LUMC), Leiden, Netherlands, 11 Medical <strong>Oncology</strong>, Radboud University<br />
Medical Centre Nijmegen, Nijmegen, Netherlands, 12 Internal <strong>Oncology</strong>, Erasmus<br />
MC Daniel den Hoed Cancer Center, Rotterdam, Netherlands, 13 Epidemiology,<br />
Netherlands Comprehensive Cancer Organisation (IKNL), Utrecht, Netherlands,<br />
14 Medical <strong>Oncology</strong>, Medisch Spectrum Twente (MST), Enschede, Netherlands,<br />
15 Medical <strong>Oncology</strong>, Medical Center Leeuwarden, Leeuwarden, Netherlands,<br />
16 Medical <strong>Oncology</strong>, Amphia ziekenhuis, Breda, Netherlands, 17 Medical<br />
<strong>Oncology</strong>, Maxima Medical Center, Eindhoven, Netherlands, 18 Department <strong>of</strong><br />
Surgical <strong>Oncology</strong>, The Netherlands Cancer Institute - Antoni van Leeuwenhoek<br />
Hospital, Amsterdam, Netherlands<br />
Background: Vemurafenib improved survival in patients with BRAF-mutant<br />
metastatic melanoma in phase III trials. We examined the survival <strong>of</strong> vemurafenib in<br />
real-world clinical practice in the Netherlands and factors associated with survival.<br />
Methods: Data <strong>of</strong> all metastatic melanoma patients in The Netherlands who at least<br />
received one dose <strong>of</strong> vemurafenib between July 1 st 2012 and March 29 th 2016 were<br />
retrieved from the Dutch Melanoma Treatment Registry (follow-up data cut-<strong>of</strong>f March<br />
29 th 2016). We assessed overall median survival (OS) using Kaplan-Meier estimates. A<br />
multivariable cox regression analysis was used to identify factors associated with survival.<br />
Results: A total <strong>of</strong> 662 patients (treatment naïve or previously treated) with BRAF-mutant<br />
metastatic melanoma received at least one dose <strong>of</strong> vemurafenib. Median follow-up was<br />
27.8 months (95% CI 25.5-30.1). Median OS was 7.3 months (95%CI 6.6-8.0). Subgroup<br />
analysis showed a median OS <strong>of</strong> 4.0 months (95% CI 3.5-4.5) for patients with a WHO<br />
performance score ≥2 (n = 124), 6.3 months (95%CI 5.6-6.9), for patients with M1c stage<br />
(n = 546), 4.9 months (95%CI 4.4-5.4) for patients with elevated serum LDH levels<br />
(n = 280) and 5.4 months (95% CI 4.3-6.4) for patients with symptomatic brain metastases<br />
(n = 122). A subset <strong>of</strong> patients with a combination <strong>of</strong> more favorable features (WHO score<br />
0-1 and normal LDH levels without brain metastases; n = 118) had a median OS <strong>of</strong> 9.8<br />
months (95%CI 7.9 – 11.6). Multivariable cox regression showed that a lower disease stage<br />
and normal LDH levels were the strongest predictors for a higher survival.<br />
Conclusions: Real-world median overall survival in The Netherlands <strong>of</strong> patients<br />
treated with vemurafenib appears to be somewhat lower than reported in earlier trials.<br />
However, in our cohort more patients with poor prognostic factors were registered and<br />
patients were included with brain metastases and WHO ≥ 2, both exclusion criteria<br />
from earlier trials. We have demonstrated that subgroups with more favorable baseline<br />
factors have a higher survival. This knowledge can be used to further characterize<br />
baseline characteristics as prognostic markers for selecting BRAF-mutant metastatic<br />
patients who may benefit most from vemurafenib.<br />
Legal entity responsible for the study: Dutch Society <strong>of</strong> Medical Oncologists<br />
(NVMO)<br />
Funding: The DMTR is funded by a grant form the Netherlands Organization for<br />
Health Research and Development (ZonMw) (no.836002002). The DMTR is<br />
financially established with sponsoring <strong>of</strong> Roche Nederland B.V, Bristol- Myers Squibb<br />
(BMS), GlaxoSmithKline (GSK)/ Novartis and Merck Sharp & Dohme (MSD).<br />
Disclosure: A. van den Eertwegh: reports serving on advisory boards <strong>of</strong> Bristol-Myers<br />
Squibb, Merck Sharp & Dohme, Novartis, Applied Molecular Genetics Inc. and<br />
Roche. G. Groenewegen: reports participation in a speakers’ bureau <strong>of</strong> Astellas. J-W. de<br />
Groot: reports serving on advisory boards <strong>of</strong> BMS, Roche, Celgene, Merck, Bayer and<br />
Amgen. J.B.A.G. Haanen: is on advisory boards <strong>of</strong> Bristol-Myers Squibb, Merck Sharp &<br />
Dohme, Novartis, Roche, Pfizer, and NEON therapeutics and has received research<br />
funding from Bristol-Myers Squibb, Merck Sharp & Dohme, and Glaxo Smith<br />
Kline. R. Koornstra: reports serving on advisory boards <strong>of</strong> BMS, Roche, MSD and<br />
Novartis. W. Kruit: reports serving on advisory boards <strong>of</strong> BMS, Novartis and<br />
GSK. D. Piersma: reports serving on advisory boards <strong>of</strong> Novartis and Amgen and received<br />
research funding from Novartis, BMS and AstraZeneca. R. van Rijn: reports serving on<br />
advisory boards <strong>of</strong> BMS, Amgen and Takeda and received research funding from GSK and<br />
Celgene. G. Vreugdenhil: reports serving on advisory boards <strong>of</strong> BMS. M. Wouters:<br />
received research funding from Novartis. All other authors have declared no conflicts <strong>of</strong><br />
interest.<br />
1140P<br />
abstracts<br />
Analysis <strong>of</strong> patient-reported outcomes by disease<br />
progression status in patients (pts) with BRAF V600–mutant<br />
metastatic melanoma in the COMBI-d and COMBI-v trials<br />
C. Robert 1 , D. Schadendorf 2 , G.V. Long 3 , D. Stroyakovskiy 4 , E. Levchenko 5 ,<br />
V. Chiarion-Sileni 6 , K. Flaherty 7 , P. Nathan 8 , A. Ribas 9 , M. Davies 10 , J. Zhang 11 ,<br />
L. Chen 11 , B. Mookerjee 11 , S. Redhu 11 , J.J. Grob 12<br />
1 Dermatology, Institut Gustave Roussy, Villejuif, France, 2 Department <strong>of</strong><br />
Dermatology, University Hospital Essen, Essen, Germany, 3 Melanoma, Melanoma<br />
Institute <strong>of</strong> Australia and The University <strong>of</strong> Sydney, Sydney, Australia,<br />
4 Chemotherapy Department, Moscow City <strong>Oncology</strong> Hospital No. 62, Moscow,<br />
Russian Federation, 5 <strong>Oncology</strong>, N. N. Petrov Research Institute <strong>of</strong> <strong>Oncology</strong>,<br />
St-Petersburg, Russian Federation, 6 Melanoma and Skin Cancer Unit, Veneto<br />
<strong>Oncology</strong> Institute, Padua, Italy, 7 Melanoma, Dana-Farber Cancer Institute/<br />
Harvard Medical School and Massachusetts General Hospital, Boston, MA, USA,<br />
8 Department <strong>of</strong> Medical <strong>Oncology</strong>, Mount Vernon Cancer Centre, Northwood,<br />
UK, 9 Medicine, Hematology & <strong>Oncology</strong>, UCLA Jonsson Comprehensive Cancer<br />
Center, Los Angeles, CA, USA, 10 Melanoma Medical <strong>Oncology</strong>, The University <strong>of</strong><br />
Texas MD Anderson Cancer Center, Houston, TX, USA, 11 Global <strong>Oncology</strong>,<br />
Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA, 12 Service de<br />
Dermatologie et Cancérologie Cutanée, Aix Marseille University, Marseille, France<br />
Background: Dabrafenib (D) + trametinib (T) improved efficacy and better<br />
maintained health-related quality <strong>of</strong> life (HRQOL) vs BRAF inhibitor monotherapy<br />
in 2 phase 3 trials <strong>of</strong> pts with BRAF V600–mutant metastatic melanoma, COMBI-d<br />
(D + T vs D + placebo) and COMBI-v (D + T vs vemurafenib). Here, we examine<br />
the association <strong>of</strong> tumor response with HRQOL and symptom scores in COMBI-d<br />
and COMBI-v.<br />
Methods: COMBI-d and COMBI-v are randomized, double-blind phase 3 trials in pts<br />
with unresectable BRAF V600–mutant metastatic melanoma. The EORTC QLQ-C30<br />
was used to assess HRQOL and symptom scores at baseline and during treatment.<br />
Treatment arms in each study were pooled and analyzed by best response (complete<br />
response [CR]/partial response [PR] vs stable disease [SD]/progressive disease [PD]).<br />
Maximum improvement (MI) was defined as maximum increase from baseline in<br />
functional domains and maximum decrease in symptom scores. P values were<br />
calculated by 2-sample t test.<br />
Results: In COMBI-d (N = 423; CR/PR, n = 256; SD/PD, n = 148) and COMBI-v<br />
(N = 704; CR/PR, n = 417; SD/PD, n = 250), completion rates allowed mean MI scores<br />
to be calculated for ≥ 90% <strong>of</strong> pts. In COMBI-d, pts with CR/PR had greater mean MI<br />
in HRQOL vs pts with SD/PD in the global health dimension (13.8 vs 7.5; P = .004)<br />
and all functional domains (role [10.2 vs 7.9; P = .425]; social [10.3 vs 6.2; P = .112];<br />
emotional [15.4 vs 10.3; P = .018]; physical [6.0 vs 5.3; P = .664]; cognitive [4.9 vs 1.9;<br />
P = .070]). Pts with CR/PR also had greater MI in most symptom scores vs pts with SD/<br />
PD, including > 5-point improvements in pain (P = .034) and insomnia (P = .065).<br />
Similarly, in COMBI-v, pts with CR/PR had a greater mean MI vs pts with SD/PD in<br />
the global health dimension (12.9 vs 7.1; P = .001) and all functional domains (role [9.7<br />
vs 8.3; P = .548]; social [10.1 vs 6.8; P = .134]; emotional [16.1 vs 10.3; P < .001];<br />
physical [6.8 vs 4.0; P = .066]; cognitive [5.1 vs 3.1; P = .148]). Larger MIs were reported<br />
in most symptom scores for pts with CR/PR vs SD/PD.<br />
Conclusions: Pts with a response had a greater MI from baseline in HRQOL and<br />
symptom scores vs pts without a response, demonstrating the association between<br />
tumor shrinkage and HRQOL in COMBI-d and COMBI-v.<br />
Clinical trial identification: NCT01597908; first received by clinicaltrials.gov on May<br />
10, 2012 and NCT01584648; first received by clinicaltrials.gov on April 23, 2012<br />
Legal entity responsible for the study: Supported by GlaxoSmithKline. Dabrafenib<br />
and trametinib are assets <strong>of</strong> Novartis AG as <strong>of</strong> 2 March 2015.<br />
Funding: Supported by GlaxoSmithKline. Dabrafenib and trametinib are assets <strong>of</strong><br />
Novartis AG as <strong>of</strong> 2 March 2015.<br />
Disclosure: C. Robert: Consultancy: Novartis, Amgen, BMS, Merck, Roche Honoraria:<br />
Novartis, Amgen, BMS, Merck, Roche. D. Schadendorf: Consultancy, Honoraria,<br />
Speakers Bureau: Amgen, Novartis, Roche, BMS, MSD Merck, Pfizer Research Funding:<br />
BMS, MSD Merck Membership-Advisory Committee: Amgen, Novartis, Roche, BMS,<br />
MSD Merck, Pfizer, Array. G.V. Long: Consultancy: Roche, BMS, Merck, Amgen,<br />
Novartis Honoraria: BMS, Merck, Novartis. V. Chiarion-Sileni: Consultancy: Novartis,<br />
BMS Speakers Bureau: GSK, Novartis Membership on Board <strong>of</strong> Directors or Advisory<br />
Committee: GSK, Novartis, Roche, BMS, MSD. K. Flaherty: Consultancy: Novartis,<br />
Roche, Array, Lilly, Takeda Research Funding: Novartis. P. Nathan: Consultancy:<br />
Novartis Speakers Bureau: Novartis Membership on Board <strong>of</strong> Directors or Advisory<br />
Committee: Novartis. A. Ribas: Consultancy: Novartis, Merck, Pfizer, Roche Equity<br />
Ownership: Kite Pharma Honoraria: Novartis. M. Davies: Research Funding: Genentech/<br />
Roche, GSK, AstraZeneca, San<strong>of</strong>i-Aventis, Merck Membership on Board <strong>of</strong> Directors or<br />
Advisory Committee: Novartis, Genentech/Roche, GSK, San<strong>of</strong>i-Aventis,<br />
Vaccinex. J. Zhang: Employment: Novartis Equity Ownership: Stockholder. L. Chen:<br />
Employment: Novartis Equity Ownership: Novartis. B. Mookerjee: Employment:<br />
Novartis Equity Ownership: Novartis, GSK, Incyte, AstraZeneca. S. Redhu: Employment:<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw379 | vi393
abstracts<br />
Novartis. J.J. Grob: Consultancy: Novartis, GSK, Roche, Merck, BMS, Amgen. All other<br />
authors have declared no conflicts <strong>of</strong> interest.<br />
1141P<br />
Neurological benefit <strong>of</strong> BRAF-inhibition and MEK-inhibition<br />
in patients with brain metastases from BRAF-mutated<br />
melanoma<br />
M. Geukes Foppen 1 , W. Boogerd 2 , C. Blank 1 , J.B.A.G. Haanen 1 , J.V. van<br />
Thienen 1 , D. Brandsma 1<br />
1 Medical <strong>Oncology</strong>, The Netherlands Cancer Institute, Amsterdam, Netherlands,<br />
2 Neuro-<strong>Oncology</strong>, The Netherlands Cancer Institute, Amsterdam, Netherlands<br />
Background: Patients (pts) with brain metastases (BM) from melanoma have a<br />
median survival <strong>of</strong> 2 to 6 months after whole brain radiotherapy. Targeted therapy<br />
(TT) improves OS in pts with BRAF-mutated metastatic melanoma. In this<br />
retrospective analysis we investigated response, neurological benefit and survival in pts<br />
with BM from BRAF-mutated melanoma treated with TT.<br />
Methods: We analysed 147 pts diagnosed with BM from BRAF-mutated melanoma<br />
between 2010 and 2016 treated at the Netherlands Cancer Institute. Pts either received<br />
vemurafenib, dabrafenib, or the combination <strong>of</strong> vemurafenib/cobimetinib or<br />
dabrafenib/trametinib. Neurological symptoms were scored before treatment and every<br />
4 weeks until cessation <strong>of</strong> therapy. Response was assessed with MRI brain and CT<br />
thorax/abdomen after 8 weeks. Kaplan-Meier analyses were used to estimate PFS<br />
and OS.<br />
Results: Median OS <strong>of</strong> all pts was 6.6 months (mo) (95%CI 5.7–7.4). Median<br />
intracranial PFS <strong>of</strong> all pts was 4.2 mo (95%CI 3.3–5.2). Sixty-three pts (43%) had<br />
symptomatic BM (sBM) before start <strong>of</strong> TT and had a median intracranial PFS <strong>of</strong><br />
3.7 mo (95%CI 2.7–4.7). The intracranial radiological response rate (RRR: stable<br />
disease/partial or complete response) was 63% versus extracranial 68%.<br />
Twenty-nine pts with sBM showed a clinical neurological response (46%), 13 were<br />
stable (21%), 16 progressive (25%) and 5 were not evaluable (8%). Pts with<br />
improving or stable neurological symptoms had a significantly better OS compared<br />
to pts with worsening symptoms; 8.8 vs 4.4 mo (p 0), baseline<br />
disease stage (IIIC/M1a/M1b vs M1c), and ppRx (IT/TT vs other) were significant<br />
prognostic factors for ppOS, producing 7 pt subgroups. Among all pts, 169 received IT<br />
(ipilimumab in 96%), 32 received TT, and 608 received other ppRx. After adjusting for<br />
other covariates (including initial treatment), ppRx with IT/TT was associated with<br />
longer ppOS. Pooled data for all pts, VEM and DTIC cohorts are in the Table. ppOS<br />
data for the COBI + VEM cohort were immature, but followed a similar pattern.<br />
Conclusions: A combination <strong>of</strong> LDH, disease stage at baseline, ppRx, and ECOG PS at<br />
PD identified 7 pt subgroups prognostic for ppOS. After adjusting for other covariates,<br />
ppRx was associated with ppOS, with similar results in DTIC and VEM cohorts.<br />
Legal entity responsible for the study: F. H<strong>of</strong>fman-La Roche, Ltd.<br />
Funding: F. H<strong>of</strong>fman-La Roche, Ltd.<br />
Disclosure: P.A. Ascierto: Consultant Or Advisory Role: BMS, Roche/Genentech,<br />
MSD, Ventana, Novartis, Amgen, and Array); Research funding (institution): BMS,<br />
Roche/Genentech, and Ventana. A. Ribas: Stock or Other Ownership: Compugen,<br />
CytomX, Five Prime, and Kite Pharma; Consulting or Advisory Role: Pfizer, Merck,<br />
Amgen, and Roche. J. Larkin: Institutional research support from MSD, BMS, Pfizer,<br />
and Novartis and nonremunerated consultancy for GSK, Novartis, MSD, BMS, Pfizer,<br />
and Roche/Genentech. G.A. McArthur: Consulting or Advisory Role: Provectus;<br />
Research Funding: Pfizer, Celgene, and Ventana; Travel, Accommodations, Expenses:<br />
Roche and Novartis. K.D. Lewis: Honoraria and Advisory Board: Roche/<br />
Genentech. A. Hauschild: Consulting or Advisory Role, Honoraria, and Travel Grants:<br />
Amgen, BMS, Celgene, Eisai, GSK, MedImmune, MelaSciences, Merck Serono, MSD/<br />
Merck, Novartis, Oncosec, and Roche Pharma. K.T. Flaherty: Consultant, honoraria:<br />
Roche/Genentech. E. McKenna, Y. Mun: Employment and stock or other ownership:<br />
Genentech/Roche. Q. Zhu: Employment: Genentech/Roche. B. Dréno: Consulting or<br />
Table: 1142P ppOS: Pooled Analysis <strong>of</strong> All pts and VEM and DTIC Cohorts<br />
Prognostic Subgroup All pts VEM Cohort DTIC Cohort<br />
N<br />
(events)<br />
ppOS, median,<br />
mo (95% CI)<br />
3-year ppOS, %<br />
(95% CI)<br />
N<br />
(events)<br />
ppOS, median,<br />
mo (95% CI)<br />
3-year ppOS, %<br />
(95% CI)<br />
N<br />
(events)<br />
ppOS, median,<br />
mo (95% CI)<br />
3-year ppOS, %<br />
(95% CI)<br />
Normal LDH + stage IIIC/M1a/M1b 196 (127) 11.8 (9.7-15.1) 22.2 (16.0-30.8) 108 (66) 11.2 (9.4-15.6) 22.3 (13.9-36.0) 58 (45) 13.0 (9.1-21.5) 24.6 (15.6-38.8)<br />
Normal LDH + stage M1c + ppRx IT/TT 64 (46) 11.8 (9.9-16.1) 22.4 (13.4-37.7) 35 (25) 12.5 (10.4-19.9) 21.3 (10.3-44.1) 18 (18) 12.3 (9.7-NE) 25.9 (11.5-58.3)<br />
Normal LDH + stage M1c + ppRx 84 (67) 7.5 (5.8-12.2) 4.9 (1.4-17.4) 50 (42) 7.5 (5.2-13.2) 3.9 (0.6-24.0) 14 (13) 7.2 (5.8-17.7) 7.1 (1.1-47.2)<br />
other + ECOG PS at PD 0<br />
Normal LDH + stage M1c + ppRx 71 (66) 3.6 (3.0-5.5) 1.8 (0.3-12.4) 41 (37) 4.6 (3.2-7.0) 3.9 (0.6-24.3) 19 (19) 3.4 (2.2-15.7) NE (NE-NE)<br />
other + ECOG PS at PD >0<br />
Elevated LDH (≤2× ULN) + ppRx IT/TT 64 (50) 7.9 (6.7-12.5) 7.8 (2.4-24.9) 37 (29) 8.9 (6.7-16.0) NE (NE-NE) 14 (12) 6.6 (4.9-NE) 14.3 (4.0-51.5)<br />
Elevated LDH (≤2× ULN) + ppRx other 188 (161) 4.5 (3.7-5.2) NE (NE-NE) 99 (82) 3.7 (2.9-5.0) NE (NE-NE) 47 (46) 4.7 (3.8-6.6) NE (NE-NE)<br />
Elevated LDH (>2× ULN) 142 (131) 2.3 (1.9-2.9) 4.5 (2.0-10.1) 89 (84) 2.4 (1.9-3.3) 3.9 (1.3-11.4) 25 (23) 2.4 (1.3-7.5) NE (NE-NE)<br />
Abbreviations: CI, confidence interval; NE, not estimable.<br />
vi394 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
advisory role: BMS, GSK, Roche, Novartis; speakers’ bureau: BMS, GSK, Roche;<br />
research funding: BMS, GSK; travel, accommodations, expenses: BMS, Roche.<br />
1143P<br />
Lower risk <strong>of</strong> cutaneous squamous cell carcinomas induced<br />
by vemurafenib in non melanoma patients<br />
E. Maubec 1 , A. Levy 2 , C. Cropet 3 , J. Mazieres 4 , X. Troussard 5 , S. Leboulleux 6 ,<br />
D. Malka 7 , M. Dinulescu 8 , F. Granel-Brocard 9 , D. Le Goupil 10 , F. Truchetet 11 ,<br />
S. Dalle 12 , M.T. Leccia 13 , N. Hoog-Labouret 14 , C. Mahier Ait Oukhatar 15 ,<br />
B. Busser 16 , J. Charles 13 , J-Y. Blay 17<br />
1 Service <strong>of</strong> dermatology, Hôpital Avicenne, Bobigny, France, 2 Service <strong>of</strong><br />
Pathology, Centre de pathologie cutanée de la Roquette, Paris, France, 3 Direction<br />
de la Recherche Clinique et de l’Innovation, Centre Léon Bérard, Lyon, France,<br />
4 Thoracic <strong>Oncology</strong>, CHU Toulouse, Hôpital de Larrey, Toulouse, France, 5 Service<br />
<strong>of</strong> hematology, CHU de Caen, Caen, France, 6 Nuclear Medicine and Endocrine<br />
<strong>Oncology</strong>, Institut de Cancérologie Gustave Roussy, Villejuif, France, 7 Digestive<br />
oncology, Institut de Cancérologie Gustave Roussy, Villejuif, France, 8 Dermatology,<br />
CHU de Pontchaillou, Rennes, France, 9 Dermatology, Institut de Cancérologie de<br />
Lorraine - Alexis Vautrin, Vandoeuvre Les Nancy, France, 10 Dermatology, C.H.U.<br />
Brest - Hôpital Morvan, Brest, France, 11 Dermatology, Hopital de Mercy, Metz,<br />
France, 12 Dermatology, Centre Léon Bérard, Lyon, France, 13 Dermatology, CHU<br />
de Grenoble, Grenoble, France, 14 Research and Innovation, Institut National du<br />
Cancer, Boulogne-Billancourt, France, 15 Research and Development,<br />
UNICANCER, Paris, France, 16 Medical Biology, CHU de Grenoble, Grenoble,<br />
France, 17 Medical <strong>Oncology</strong>, Centre Léon Bérard, Lyon, France<br />
Background: Cutaneous squamous cell carcinomas (cSCCs) occur in about 20% <strong>of</strong><br />
melanoma (M) patients (pts) treated with vemurafenib (V), mostly within the first 3<br />
months. We aimed to determine the frequency <strong>of</strong> cSCCs in non-M pts treated by V in<br />
the AcSé-V French national phase II trial and to study their clinical, pathological and<br />
molecular characteristics.<br />
Methods: Pts included in the AcSé-V trial had a dermatological monitoring under the<br />
supervision <strong>of</strong> the French “Groupe de Cancérologie Cutanée”. Only pts with a<br />
follow-up <strong>of</strong> ≥4 months and without a history <strong>of</strong> M are included. Pathological reports<br />
<strong>of</strong> resected cSCCs and precursors were analysed by a pathologist. Central pathological<br />
review and molecular characterization <strong>of</strong> cSCCs will be performed. Frequency <strong>of</strong> cSCCs<br />
was compared to BRIM 3 published data.<br />
Results: Among 56 pts included in the AcSé trial, six pts (11%; 4F,2M) treated for a<br />
BRAF V600E-mutated lung, thyroid or brain tumour developed 10 cutaneous<br />
neoplasms. Median size was 5.5 mm (range, 5-10 mm). Location was upper (n = 4) or<br />
lower (n = 3) extremities, head and neck (n = 2), and trunk (n = 1). There were 8<br />
cSCCs, 1 papilloma with a keratoacanthoma-like architecture and 1 preepitheliomatous<br />
keratosis. Five pts (9%) <strong>of</strong> median age 76 years old (range, 23-83 years) had cSCCs<br />
(multiple cSCCs in 2 pts). Pathological review <strong>of</strong> cSCCs (7/8 available) showed<br />
crateriform (n = 4) or papilliform (n = 2), poorly (n = 1) or well-differentiated (n = 6)<br />
cSCCs. The median time to first diagnosis <strong>of</strong> cSCC or precursor lesion was 71 days<br />
(range, 29-161 days); 5/6 pts had a phototype 3; none had a medical history <strong>of</strong> skin<br />
cancer but 3 presented actinic keratosis before V initiation.<br />
Conclusions: V-induced cSCCs seem to have similar pathological characteristics in M<br />
and non-M pts. The lower frequency <strong>of</strong> cSCCs in non-M pts compared with M pts in<br />
BRIM 3 (p = 0.039) might be due to differences in risk factor frequencies. Potential risk<br />
factors <strong>of</strong> V-induced cSCCs are older age and preexisting actinic keratosis. Analysis <strong>of</strong><br />
final data might help for dermatological monitoring.<br />
Clinical trial identification: NCT02304809<br />
Legal entity responsible for the study: UNICANCER, GCC<br />
Funding: UNICANCER<br />
Disclosure: X. Troussard: Advisory Board : Gilead. Roche. Janssen. S. Leboulleux:<br />
Consulting : Genzyme, San<strong>of</strong>i, Astra Zeneca. Travel : Genzyme, San<strong>of</strong>i,<br />
Bayer. D. Malka: Honoraria : Roche, Amgen, Bayer, Teva, Celgene, Lilly, Merck, Merck<br />
Serono, San<strong>of</strong>i-Aventis. Consulting : Roche, Merck. Travel : Roche,<br />
San<strong>of</strong>i-Aventis. S. Dalle: Received research grant from Roche-Genentech. J-Y. Blay:<br />
Advisory Board: Roche, Novartis, Bayer, MSD, Lilly, Pharmamar, Deciphera.<br />
Corporate-sponsored Research: Roche, Novartis, Bayer, MSD, Lilly, Pharmamar. All<br />
other authors have declared no conflicts <strong>of</strong> interest.<br />
1144P<br />
Next generation sequencing for tissue and plasma pr<strong>of</strong>iling <strong>of</strong><br />
melanoma patients and plasma monitoring <strong>of</strong> treatment<br />
outcome: the MOBILY study<br />
H. Linardou 1 , S. Murray 2 , A. Laskarakis 1 , K. Giati 1 , C. Gouedard 2 , A. Tarampikou 1 ,<br />
K. Tsigaridas 1 , D. Bafaloukos 1<br />
1 A’ <strong>Oncology</strong> Clinic, Metropolitan Hospital, Athens, Greece, 2 Molecular <strong>Oncology</strong>,<br />
BioPath Innovations, Athens, Greece<br />
Background: Molecular pr<strong>of</strong>iling can identify potentially targetable mutations and<br />
facilitate treatment decisions. Recently BRAF mutant cell free DNA (cfDNA) was<br />
shown as an outcome predictor for melanoma patients on BRAF inhibitors (BRAFi).<br />
In this study we explore the potential <strong>of</strong> next generation sequencing (NGS) to<br />
molecularly characterise tissue and plasma and monitor outcome <strong>of</strong> melanoma<br />
patients.<br />
Methods: Tumour DNA was isolated from paraffin blocks and cfDNA from plasma<br />
prospectively collected from melanoma patients. Deep sequencing using multigene<br />
panels (22 genes-tumour, 5 key genes-cfDNA) was performed by NGS on Ion<br />
Torrent. Plasma samples were collected at baseline, first month, best response and<br />
progression. Tissue:plasma concordance was assessed at baseline. Tumour burden<br />
and outcome were correlated with mutational load (cfDNA) assessed by % allelic<br />
frequency.<br />
Results: Tissue and plasma samples were analysed for concordance from 43 metastatic<br />
melanoma (MM) patients (20 men 23 women, med age 62 yrs, 36 cutaneous 4 mucosal<br />
2 ocular). Mutations were detected in 9 genes (BRAF 27, NRAS 3, KIT 2, GNAQ 1,<br />
KRAS 1, MAP2K1 1, MC1R 3, CDKN2A 2, p53 1, AKT3 1). Five patients had >1<br />
mutation detected. A young patient with highly resistant MM had 4 simultaneous<br />
mutations (2 in resistance genes MAP2K1 and KRAS). Mutational concordance tissue:<br />
plasma was 72% (BRAF, NRAS). Seven patients with BRAF mutant MM in long<br />
remission with BRAFi had undetectable cfDNA mutational loads. Serial plasma<br />
samples were analysed from 3 BRAF mutant patients currently on BRAFi and 1 BRAF<br />
mutant patient on immune checkpoint inhibitor (IO). BRAF allelic load dramatically<br />
reduced to undetectable levels at 1 st month <strong>of</strong> BRAFi, almost one month before<br />
radiological response. Interestingly, significant reduction <strong>of</strong> mutation levels was<br />
detected in the patient on IO correlating with rapid clinical response. Further patient<br />
analysis will be presented.<br />
Conclusions: NGS tissue pr<strong>of</strong>iling is clinically relevant for melanoma providing<br />
prognostic information and cfDNA monitoring by NGS is feasible. In our population,<br />
serial plasma mutation assessment was in agreement with the clinical course and<br />
should be further explored as a monitoring tool <strong>of</strong> outcome.<br />
Legal entity responsible for the study: Metropolitan Hospital Scientific & Ethics<br />
Institutional Board<br />
Funding: Hellenic Society for the Study <strong>of</strong> Melanoma (ELEMMEL)<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1145P<br />
abstracts<br />
Analysis <strong>of</strong> BRAF V600E mutation status – concordance <strong>of</strong><br />
results from circulating tumor DNA and tissue-based testing<br />
and impact on prediction <strong>of</strong> the clinical course in patients<br />
undergoing BRAFi therapy<br />
V.H. Haselmann 1 , C. Gebhardt 2 , I. Brechtel 1 , A. Duda 1 , A. Sucker 3 , J. Utikal 2 ,<br />
D. Schadendorf 3 , M. Neumaier 1<br />
1 Institute for Clinical Chemistry, Universitätsklinikum Mannheim, Mannheim,<br />
Germany, 2 Department <strong>of</strong> Dermatology, Venereology and Allergology,<br />
Universitätsklinikum Mannheim, Mannheim, Germany, 3 Department <strong>of</strong><br />
Dermatology, University Hospital <strong>of</strong> Essen, Essen, Germany<br />
Background: The current standard for determining eligibility <strong>of</strong> patients with<br />
metastatic melanoma for BRAF-targeted therapy is the tissue-based testing <strong>of</strong> BRAF<br />
mutations. As patients are rarely re-biopsied, the detection in blood in real-time might<br />
be advantageous reflecting the current mutational status <strong>of</strong> the patient’s disease.<br />
Furthermore, metastatic melanoma lacks clinically efficient biomarkers. Here, genetic<br />
testing in plasma may represent a useful noninvasive biomarker for monitoring BRAF<br />
therapy.<br />
Methods: Blood samples from melanoma patients in two independent studies were<br />
subjected to plasma testing using the OncoBEAM TM BRAF V600E assay and<br />
tissue-based analysis using Sanger sequencing. In the first study, the tissue-based BRAF<br />
mutation status was compared with matched plasma samples from 74 patients<br />
diagnosed with progressive metastatic melanoma being either treatment-naïve or<br />
undergoing BRAFi therapy. In the second study, the mutational status in tissue and<br />
plasma samples from 131 patients <strong>of</strong> melanoma stage III or IV was compared in<br />
follow-up.<br />
Results: Overall, results from BRAF plasma testing revealed a high degree <strong>of</strong><br />
concordance with tissue testing in both studies with 89.2% (study 1) and 94% (study<br />
2), respectively. In the second study 2 <strong>of</strong> 3 patients with negative OncoBEAM results in<br />
plasma, but with positive test in tumor tissue, did not respond to BRAFi therapy<br />
potentially due to a false positive result. 5 <strong>of</strong> 10 patients originally classified<br />
BRAF-negative in tumor, tested BRAF mutation-positive in plasma. In these cases,<br />
secondary malignancies were found to be responsible. Importantly, dynamic changes<br />
<strong>of</strong> BRAF mutant ctDNA over time correlated with the clinical course and response to<br />
treatment. Positivity <strong>of</strong> BRAF plasma testing was significantly earlier detectable than<br />
relapse using radio-imaging.<br />
Conclusions: Blood-based testing favorably compares with standard-<strong>of</strong>-care<br />
tissue-based BRAF mutation testing. Importantly, blood-based BRAF testing may be<br />
used to predict response to treatment and resistance prior to radio-imaging under<br />
BRAFi therapy thereby allowing for an improved treatment management.<br />
Legal entity responsible for the study: Institute for Clinical Chemistry,<br />
Universitätsklinikum Mannheim, Germany<br />
Funding: Reagents for the study were financed by Sysmex Inostics GmbH Falkenried<br />
88 D-20251 Hamburg, Germany<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw379 | vi395
abstracts<br />
1146P<br />
Tumor response from phase II study <strong>of</strong> combination<br />
treatment with intratumoral HF10, a replicationcompetent<br />
HSV-1 oncolytic virus, and ipilimumab in<br />
patients with stage IIIB, IIIC, or IV unresectable or<br />
metastatic melanoma<br />
R. Andtbacka 1 , M. Ross 2 , S.S. Agarwala 3 , M. Taylor 4 , J. Vetto 4 , R.I. Neves 5 ,<br />
A. Daud 6 , H. Khong 1 , R.S. Ungerleider 7 , S. Welden 7 , M. Tanaka 8 , K. Grossmann 1<br />
1 Surgical <strong>Oncology</strong>, Huntsman Cancer Institute, Salt Lake City, UT, USA, 2 Surgical<br />
<strong>Oncology</strong>, MD Anderson Cancer Center, Houston, TX, USA, 3 Cancer Center,<br />
St. Luke’s Hospital & Health Network, Bethlehem, PA, USA, 4 Knight Cancer<br />
Institute, Oregon Health Science University, Portland, OR, USA, 5 Surgical<br />
<strong>Oncology</strong>, Penn State Hershey Medical Center, Hershey, PA, USA, 6 Department<br />
<strong>of</strong> Medicine (Hematology/<strong>Oncology</strong>), UCSF Helen Diller Family Comprehensive<br />
Cancer Center, San Francisco, CA, USA, 7 Clinical Operations, Theradex <strong>Oncology</strong><br />
Experts, Princeton, NJ, USA, 8 Project Management Dept, Takara Bio, Inc., Shiga,<br />
Japan<br />
Background: HF10 is a replication-competent oncolytic virus derived from HSV-1.<br />
We report on the safety and preliminary antitumor activity <strong>of</strong> HF10 i.t. + ipilimumab<br />
(ipi) i.v. combination in an ongoing Ph2 trial in melanoma pts.<br />
Methods: Entry criteria: age ≥18y, ECOG ≤ 2, Stage IIIB, IIIC or IV unresectable<br />
melanoma, ipi naïve and measurable non-visceral lesion(s) suitable for injection. HF10<br />
was injected into single or multiple tumors (1x10 7 TCID 50 /mL/dose, up to 5mL based<br />
on tumor size and number); 4 inj qwk; then up to 15 inj q3wk. 4 ipi IV inf (3 mg/<br />
kg; + HF10) were administered q3wk. Tumor responses (mWHO & irRC) at 12, 18,<br />
24wks, and at 36, 48wks for pts continuing on HF10 monotherapy. Primary endpoint<br />
is Best Overall Response Rate (BORR) at 24wks. DLTs defined as ≥G3<br />
nonhematologic/hematologic toxicity, ≥G2 neurologic toxicity or allergic event<br />
occurring within 1 st 3wks <strong>of</strong> therapy.<br />
Results: Of 46 pts treated: 58% men; median age 68.4 yrs (range 29-92yrs); disease<br />
stage 20% IIIB, 43% IIIC and 37% IV. Of all patients, 49% with ≥1 prior cancer<br />
therapy. Of the 17 patients with stage IV, 25% had M1a, 31% M1b, 44% M1c. Majority<br />
<strong>of</strong> HF10-related AEs were ≤G2, similar to HF10 monotherapy and consistent with<br />
other oncolytic viruses. No DLTs reported. 4 G4 AEs reported, none were<br />
treatment-related. 30.4% <strong>of</strong> pts had G3 AEs. HF10-related G3 AEs (n = 3) were: left<br />
groin pain, a thromboembolic event and lymphedema; hypoglycemia; and diarrhea. Of<br />
43 efficacy evaluable pts, preliminary BORR at 24 wks by irRC is 39.5% (11.6% CR,<br />
27.9% PR), disease stability rate is 65.1% (25.6% SD). 8 responders (53%) were Stage<br />
IV. 5 responders (33%) were ≥2 nd line. Overall study BORR, including those after 24<br />
weeks, by irRC is 48.9% (14.0% CR, 34.9% PR), disease stability rate is 65.2% (16.3%<br />
SD). DCO = 10May16<br />
Conclusions: The results indicate ipi + HF10 does not exacerbate ipi toxicity and the<br />
combination is safe and well tolerated. Preliminary efficacy evaluation suggests<br />
HF10 + ipi has both local and systemic antitumor activity and substantially improves<br />
the response rate <strong>of</strong> ipi alone. HF10 + ipi is a potential novel therapeutic approach for<br />
metastatic melanoma.<br />
Clinical trial identification: NCT02272855<br />
Legal entity responsible for the study: Takara Bio Inc<br />
Funding: Takara Bio, Inc<br />
Disclosure: R. Andtbacka: Has been recipient <strong>of</strong> honoraria or consultation fees<br />
from Amgen, Merck, Provectus. M. Ross: Grants/Research Supports: GSK, Amgen,<br />
Merck, Provectus Honoraria or Consultation Fees: Amgen, GSK, Merck Travel<br />
Expenses: GSK, Amgen, Merck, Provectus, Caladrius. M. Taylor: Has received<br />
honoraria for consultation from Onyx and Eisai. A. Daud: Receipt <strong>of</strong> grants/<br />
research supports: Merck, Oncosec, BMS, GSK Receipt <strong>of</strong> honoraria and<br />
consultation fees: Merck, Oncosec. H. Khong: Received grant and research<br />
support: Celgene, BMS, AstraZeneca. M. Tanaka: Works at Takara Bio Inc, the<br />
sponsor for the study. K. Grossmann: Receipt <strong>of</strong> honoraria or consultation fees:<br />
Genentech and Castle Biosciences. All other authors have declared no conflicts <strong>of</strong><br />
interest.<br />
1147P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
A phase 2 study <strong>of</strong> glembatumumab vedotin (GV), an<br />
antibody-drug conjugate (ADC) targeting gpNMB, in<br />
advanced melanoma<br />
P.A. Ott 1 , A.C. Pavlick 2 , D.B. Johnson 3 , L.L. Hart 4 , J.R. Infante 5 , J.J. Luke 6 ,<br />
J. Lutzky 7 , N. Rothschild 8 , L. Spitler 9 , C.L. Cowey 10 , A. Alizadeh 11 , A. Salama 12 ,<br />
Y. He 13 , R.G. Bagley 14 , J. Zhang 14 , O. Hamid 15<br />
1 Melanoma Center & Center for Immuno-<strong>Oncology</strong>, Dana-Farber Cancer Institute,<br />
Boston, MA, USA, 2 Department <strong>of</strong> Medicine, New York University School <strong>of</strong><br />
Medicine, New York, NY, USA, 3 Department <strong>of</strong> Medicine, Vanderbilt-Ingram<br />
Cancer Center, Nashville, TN, USA, 4 Hematology/<strong>Oncology</strong>, Florida Cancer<br />
Specialists, Ft. Myers, FL, USA, 5 Department <strong>of</strong> Medicine, Tennessee <strong>Oncology</strong>,<br />
PLLC, Nashville, TN, USA, 6 Hematology/<strong>Oncology</strong>, University <strong>of</strong> Chicago,<br />
Chicago, IL, USA, 7 Department <strong>of</strong> Medicine, Division <strong>of</strong> Hematology/<strong>Oncology</strong>,<br />
Mount Sinai Comprehensive Cancer Center, Miami Beach, FL, USA, 8 Department<br />
<strong>of</strong> Medicine, Florida Cancer Specialists, West Palm Beach, FL, USA, 9 Northern<br />
California Melanoma Center, St. Mary’s Medical Center, San Francisco, CA, USA,<br />
10 Baylor Skin Malignancy & Treatment Center, Baylor University Medical Center,<br />
Dallas, TX, USA, 11 Central Research, Georgia Cancer Specialists, Decatur, GA,<br />
USA, 12 Department <strong>of</strong> Medicine, Duke University, Durham, NC, USA,<br />
13 Biostatistics, Celldex Therapeutics, Inc., Hampton, NJ, USA, 14 Clinical Science,<br />
Celldex Therapeutics, Inc., Hampton, NJ, USA, 15 Department <strong>of</strong> Translational<br />
Research/Immuno<strong>Oncology</strong>, The Angeles Clinic and Research Institute, Los<br />
Angeles, CA, USA<br />
Background: gpNMB is an internalizable transmembrane glycoprotein expressed in<br />
multiple tumor types including melanoma. The ADC GV (CDX-011) delivers the<br />
potent cytotoxin MMAE to gpNMB+ cells. GV has shown promising activity in<br />
advanced melanoma and breast cancer (Ott JCO 2014; Yardley JCO 2015).<br />
Methods: In this Phase 2 single-arm study (CDX011-05), efficacy and safety <strong>of</strong> GV<br />
(1.9 mg/kg q3w) is assessed in advanced melanoma patients (pts) with disease<br />
progression after ≤1 chemotherapy, ≥1 checkpoint inhibitor, and if BRAF mutation<br />
≥1 BRAF or MEK + BRAF inhibitor. gpNMB expression is determined retrospectively<br />
by central IHC on archival tumor and/or pre-treatment tumor biopsy. Primary<br />
endpoint is objective response rate (ORR) (RECIST 1.1) with ≥6 responders out <strong>of</strong> 52<br />
evaluable pts as threshold for determining statistical positive outcome. Additional<br />
endpoints include progression free survival and overall survival (PFS, OS) (95% CI),<br />
duration <strong>of</strong> response (DOR), safety, pharmacodynamics, pharmacokinetics, and<br />
correlation <strong>of</strong> outcome with gpNMB expression.<br />
Results: Enrollment (n = 62) completed in April 2016: median age = 67 years; 55%<br />
male; 21% BRAF mutation; 53% >2 lines prior therapy. Preliminary tumor response<br />
data (n = 57 evaluable; 5 pts pending 1 st response assessment): 1 complete response<br />
(CR) and 7 partial response (PR [current confirmed ORR = 14%]); 1 single time-point<br />
PR; 26 stable disease (SD) (duration 6-51+ weeks, 11 ongoing). Thus far, 50/51<br />
evaluable pts had gpNMB+ tumors, and 38/51 had 100% <strong>of</strong> epithelial cells gpNMB+.<br />
Toxicities include rash, alopecia, fatigue, neuropathy, nausea, neutropenia, decreased<br />
appetite and diarrhea; rash may correlate with efficacy.<br />
Conclusions: GV has shown promising activity including induction <strong>of</strong> partial and<br />
complete responses in patients with heavily pre-treated melanoma. The safety pr<strong>of</strong>ile is<br />
manageable and consistent with cytotoxic treatment. DOR, PFS, OS, and correlation <strong>of</strong><br />
biomarkers with outcome will be analyzed on the mature dataset. An additional cohort<br />
will be treated with GV in combination with varlilumab, an activating anti-CD27<br />
monoclonal antibody, in order to evaluate safety and efficacy <strong>of</strong> the combination.<br />
Clinical trial identification: NCT #02302339<br />
Legal entity responsible for the study: Celldex Therapeutics, Inc.<br />
Funding: Celldex Therapeutics, Inc.<br />
Disclosure: P.A. Ott: Grants and personal fees from Bristol-Myers Squibb, personal<br />
fees from Amgen and Alexion, and grants from Merck and AztraZeneca/MedImmune<br />
outside <strong>of</strong> the submitted work. D.B. Johnson: Advisory board for Genoptix and BMS.<br />
L.L. Hart: My only COI is research funding to my institution nothing to me personally.<br />
J.J. Luke: Ad board - amgen, array Research support to institution: –Novartis,<br />
MedImmune, Bristol-Myers Squibb, Pharmacyclics, Merck, BBI Therapeutics, Five<br />
Prime Therapeutics, Genentech, Corvus Pharmaceuticals, Delcath,Abbvie, Celldex,<br />
EMD Serono, Incyte. A. Salama: research funding (paid to institution) BMS, merck,<br />
genentech, immunocore, reata advisory board: BMS. Y. He, R.G. Bagley, J. Zhang: Full<br />
time employee <strong>of</strong> and stock ownership in Celldex Therapeutics, Inc. All other authors<br />
have declared no conflicts <strong>of</strong> interest.<br />
vi396 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
1148P<br />
A phase I, open-label study <strong>of</strong> pasireotide in patients with<br />
BRAF- and NRAS-wild type, unresectable and or metastatic<br />
melanoma<br />
R. Dummer 1 , O.A. Michielin 2 , M. Nägeli 1 , S.M. Goldinger 1 , F. Campigotto 3 ,<br />
U. Kriemler-Krahn 4 , H. Schmid 4 , A. Pedroncelli 4 , S. Micaletto 1 , D. Schadendorf 5<br />
1 Department <strong>of</strong> Dermatology, University Hospital Zurich, Zurich, Switzerland,<br />
2 Department <strong>of</strong> <strong>Oncology</strong>, Ludwig Cancer Center(Division d’Onco-Immunologie<br />
Clinique) <strong>of</strong> the University <strong>of</strong> Lausanne - CHUV, Lausanne, Switzerland, 3 Global<br />
Medical Affairs, Novartis Pharmaceuticals Corporation, East Hannover, NJ, USA,<br />
4 Clinical Development, Novartis Pharma AG, Basel, Switzerland, 5 Department <strong>of</strong><br />
Dermatology, University Hospital Essen, Essen, Germany<br />
Background: Somatostatin receptors (SSTR) and insulin-like growth factor receptors<br />
(IGFR) have been shown to be strongly expressed in melanoma cells. This phase I study<br />
evaluated the preliminary safety, pharmacokinetics (PK), and efficacy <strong>of</strong> pasireotide, a<br />
somatostatin analogue with broad SSTR affinity, in patients (pts) with BRAF-and<br />
NRAS-wild type, confirmed unresectable and/or metastatic melanoma.<br />
Methods: Patients (planned N = 18) with unresectable (stage III) and/or metastatic<br />
(stage IV) melanoma and confirmed unresectable and/or metastatic Merkel cell<br />
carcinoma (MCC) were eligible. The study was divided into 3 phases: screening,<br />
intra-patient dose-escalation (8 weeks), and follow-up (6 months). The primary<br />
endpoint was safety during the 8-wk escalation phase. Secondary endpoints included<br />
safety at study completion, disease control rate (DCR, by CT or MRI per RECIST 1.0),<br />
PK, effect <strong>of</strong> pasireotide on biomarkers.<br />
Results: The study was terminated early due to slow recruitment after 2 years (y) from<br />
study initiation. Of the 10 melanoma pts enrolled, 50% completed the dose-escalation<br />
phase and entered follow-up. Median age: 71.5 y (range, 60-77); ≥ 65 y: 7 (70%) pts; 8<br />
(80%) males. Median duration <strong>of</strong> exposure: 6.71 wks (range, 1.6-8.1) for escalation<br />
phase; 7.57 wks (range, 1.6-32.1) for overall phase. Most frequent adverse events (AEs)<br />
during escalation phase in ≥ 2 (20%) pts were: diarrhea (50%), nausea (50%), fatigue<br />
(20%), hyperglycemia (20%), hypophosphatemia (20%), chills (20%), and tumor pain<br />
(20%). Grade 3-4 drug-related AEs were reported in 1 pt. One pt had partial response<br />
(PR) and one had stable disease (SD). DCR was 20% and objective response rate was<br />
10%. PK exposures increased with increasing dose. Low levels <strong>of</strong> tumor biomarkers<br />
were consistently observed in pts with response (PR or SD).<br />
Conclusions: In pts with BRAF-andNRAS-wild type melanoma, pasireotide is well<br />
tolerated and its safety pr<strong>of</strong>ile is consistent with prior reports in other indications with<br />
the exception <strong>of</strong> lower frequency <strong>of</strong> hyperglycemia. Preliminary anti-tumor efficacy <strong>of</strong><br />
pasireotide is encouraging. Pasireotide may be a candidate for combination therapy in<br />
advanced melanoma.<br />
Clinical trial identification: NCT01652547<br />
Legal entity responsible for the study: Novartis Pharmaceutical Corporation<br />
Funding: Novartis Pharmaceutical Corporation<br />
Disclosure: R. Dummer: Research funding from Novartis, Merck Sharp & Dhome<br />
(MSD), Bristol-Myers Squibb (BMS), Roche, GlaxoSmithKline (GSK), and has a<br />
consultant or advisory board relationship with Novartis, MSD, BMS, Roche, GSK, and<br />
Amgen outside the submitted work. O.A. Michielin: Has a consultant or advisory<br />
board relationship with Bristol-Myers Squibb, Novartis, Roche, Merck Sharp &<br />
Dhome. S.M. Goldinger: Has a consultant or advisory board relationship with<br />
Bristol-Myers Squibb, Merck Sharpe & Dhome, Roche, and Novartis. F. Campigotto:<br />
Has employment and stock ownership with Novartis and has receives research funding<br />
from Novartis. U. Kriemler-Krahn: Has employment and stock ownership with<br />
Novartis. H. Schmid: Has employment and stock ownership with Novartis, received<br />
research funding from Novartis. A. Pedroncelli: Has employment with<br />
Novartis. D. Schadendorf: Institution receives research funding from Bristol-Myers<br />
Squibb (BMS) and Merck Sharp & Dhome, and he has a consultant or advisory board<br />
relationship with Amgen, Bristol-Myers Squibb (BMS), Merck, Merck Sharp & Dhome,<br />
Pfizer, Novartis and Roche. All other authors have declared no conflicts <strong>of</strong> interest.<br />
1149P<br />
Chemotherapy in patients with metaststic melanoma after<br />
progression on BRAF/MEK inhibitors<br />
I.V. Samoylenko, G. Kharkevich, L.V. Demidov<br />
Tumor biotherapy, N. N. Blokhin Russian Cancer Research Center, Moscow,<br />
Russian Federation<br />
Background: Metastatic melanoma remains a disease with poor prognosis even in<br />
patients with BRAF mutation, treated by BRAF/MEK inhibitors. In many countries<br />
immune checkpoints inhibitors which could be used for 2nd line treatment are not<br />
registered, or not reimbursed. At the same time, experimantal evidence supports<br />
enhancing the effectiveness <strong>of</strong> chemotherapy after blocking the MAP-kinase pathway.<br />
We evaluated the immediate effectiveness <strong>of</strong> chemotherapy in patients after<br />
progression or intolerance on BRAF/MEK inhibitors<br />
Methods: We conducted a retrospective analysis <strong>of</strong> all patients (pts) who received<br />
paclitaxel 175 mg / m2 day1 + carboplatin AUC = 5 day 1 (PC) from January 1 2012 to<br />
Mar 30 2016 (n = 55). Group 1 (n = 26) was treated with BRAF / MEK inhibitors<br />
(vemurafenib, dabrafenib, trametinib, encorafenib or binimetinib) before PC, group 2<br />
(n = 29) received no inhibitors <strong>of</strong> BRAF / MEK prior to PC<br />
Results: Both groups did not differ in demographic characteristics (mean age<br />
52.5 ± 12,4 years in group 1 and 53.7 ± 11,6 years respectively, p = 0.5, males 46.1% and<br />
58.6% respectively, p = 0.78), the primary tumor origin (Unknown 15% and 17.2%<br />
respectively, skin 85% and 81.8% respectively p> 0.5), or the tumor stage at the start <strong>of</strong><br />
chemo (III unresectable 7.6% and 0%, IV M1a 11.5% and 13.6%, IV M1b 15.4% and<br />
18.2%, IV M1c 65.3% and 68.2%, respectively, p > 0.5). BRAF mutations rate was<br />
higher in Group 1 (96,2% vs 24,1%, p < 0.05). NRAS mutations rate did not differ<br />
between groups (3.8% and 13,8% respectively, p > 0.05). Best overall response rate was<br />
calculated (Table 1). The median time to progression in Group 1 was 16 weeks (95% CI<br />
6.12 to 23.87 months) and 7.0 weeks (95% CI 5.17 to 8,28) in Group 2; p = 0.019,<br />
HR = 2,14 (95% CI 1.08 to 4.21). The median overall survival can not be calculated<br />
correctly due to short follow-up (median 28 weeks).<br />
Table: 1149P Best overall response rate<br />
Group 1, n (%) Group 2, n (%) p value<br />
CR 1 (4) 0 (0) >0.05<br />
PR 10 (38) 1 (3.4) >0.05<br />
OR 11 (42) 1 (3.4) >0.05<br />
SD 5 (19) 3 (10.3)
abstracts<br />
1152P<br />
Evaluation <strong>of</strong> the pharmacokinetic (PK) pr<strong>of</strong>ile <strong>of</strong> vismodegib<br />
(VISMO) in patients (pts) with multiple basal cell carcinomas<br />
(BCCs) across two intermittent treatment regimens in the<br />
MIKIE study<br />
D. Schadendorf 1 , A. Hauschild 2 , S. Fosko 3 , D. Zloty 4 , B. Labeille 5 , J.J. Grob 6 ,<br />
S. Puig 7 , M. Makrutzki 8 , I. Templeton 9 , G. Rogers 10 , B. Dreno 11 , R. Kunstfeld 12<br />
1 Department <strong>of</strong> Dermatology, Universitätsklinikum Essen, Essen, Germany,<br />
2 Department <strong>of</strong> Dermatology, University <strong>of</strong> Kiel (UKSH), Kiel, Germany,<br />
3 Department <strong>of</strong> Dermatology, Saint Louis University Medical School, St. Louis,<br />
MO, USA and Mayo Clinic, Jacksonville, FL, USA, 4 Department <strong>of</strong> Dermatology,<br />
University <strong>of</strong> British Columbia, Vancouver, BC, Canada, 5 Department <strong>of</strong><br />
Dermatology, University Hospital <strong>of</strong> Saint-Etienne, Saint-Etienne, France,<br />
6 Department <strong>of</strong> Dermatology and Cutaneous <strong>Oncology</strong>, Aix-Marseille University,<br />
Hopital Timone APHM, Marseille, France, 7 Melanoma Unit, Dermatology<br />
Department, Hospital Clinic de Barcelona, Barcelona, Spain, 8 <strong>Oncology</strong>,<br />
F. H<strong>of</strong>fmann-La Roche, Ltd., Basel, Switzerland, 9 Clinical Pharmacology,<br />
Genentech, Inc., South San Francisco, CA, USA, 10 Surgery, Tufts University<br />
School <strong>of</strong> Medicine, Boston, MA, USA, 11 Dermato Cancerology, Nantes<br />
University, Nantes, France, 12 Dermatology, Medical University <strong>of</strong> Vienna, Vienna,<br />
Austria<br />
Background: VISMO is a first-in-class Hedgehog pathway inhibitor approved for the<br />
treatment <strong>of</strong> adult pts with advanced BCC. Pts with multiple BCCs, including those<br />
with BCC nevus syndrome, require long-term treatment with VISMO; however,<br />
continuous treatment may not be optimal over extended periods due to risk <strong>of</strong> chronic<br />
low-grade toxicity. MIKIE (NCT01815840) was designed to assess the efficacy and<br />
safety <strong>of</strong> two long-term intermittent VISMO dosing regimens in pts with multiple<br />
BCCs.<br />
Methods: Pts with ≥1 histopathologically confirmed BCC and ≥6 clinically evident<br />
BCCs were randomized in a 1:1 ratio to receive VISMO 150 mg once daily on one <strong>of</strong><br />
two intermittent schedules for 72 weeks: VISMO for 12 weeks alternating with placebo<br />
for 8 weeks (Regimen A), or VISMO for 24 weeks followed by placebo for 8 weeks<br />
alternating with VISMO for 8 weeks (Regimen B). The primary end point was %<br />
reduction in number <strong>of</strong> clinically evident BCC lesions from baseline to Week 73. At<br />
selected sites, samples for PK analysis were obtained at pre-dose and 2 hours post dose<br />
at Week 13, and at pre-dose at all subsequent visits. PK outcomes measured included<br />
an average plasma concentration <strong>of</strong> total and unbound VISMO. The PK analysis<br />
population included all randomized pts who received ≥1 dose <strong>of</strong> study treatment and<br />
had at least one PK assessment.<br />
Results: A total <strong>of</strong> 229 pts were randomized to Regimen A (n = 116) or Regimen B<br />
(n = 113). At clinical cut-<strong>of</strong>f for the primary analysis (August 27, 2015), the mean<br />
reduction from baseline in the total number <strong>of</strong> clinically evident BCC lesions at Week<br />
73 was 62.7% for Regimen A and 54.0% for Regimen B. The PK analysis population<br />
comprised 68 pts (58.6%) in Regimen A and 57 pts (50.4%) in Regimen B. PK<br />
outcomes for each study arm will be presented and discussed.<br />
Conclusions: The reduction in total number <strong>of</strong> clinically evident BCCs at Week 73<br />
demonstrates that intermittent VISMO dosing schedules are effective in pts with<br />
multiple BCCs. The PK analysis <strong>of</strong> the MIKIE study will characterize the PK pr<strong>of</strong>iles<br />
for each dosing regimen and will be helpful in informing PK modeling to further<br />
optimize the dosing schedule.<br />
Clinical trial identification: NCT01815840<br />
Legal entity responsible for the study: Roche-Genentech<br />
Funding: Roche-Genentech<br />
Disclosure: D. Schadendorf: Consultant or Advisory Role: GSK, Roche, Novartis, BMS,<br />
Amgen Honoraria: GSK, Roche, Novartis, BMS, Amgen. A. Hauschild: Consulting/<br />
Advisory, Honoraria, Trial Grants: Amgen, BMS, Celgene, Eisai, GSK, MedImmune,<br />
MelaSciences, Merck Serono, MSD/Merck, Novartis, Oncosec, Roche Pharma.<br />
S. Fosko: Saint Louis University received monies on behalf <strong>of</strong> his work with Genentech<br />
with regard to consultant, advisory panel and speakers bureau activities. Funding for<br />
this clinical trial was provided by Genentech to Saint Louis University. D. Zloty:<br />
Consulting/Advisory, Honoraria, Speakers Bureau, Travel, Accommodations,<br />
Expenses: Roche. J.J. Grob: Consulting/Advisory:GSK, BMS, Roche, Amgen, Merck,<br />
Novartis Honoraria:GSK, Roche, BMS Speakers’ Bureau: GSK Research Funding:<br />
Roche, BMS, author institution Travel, Accommodations, Expenses: Roche. S. Puig:<br />
Cons: Roche, BMS, AMGEN, Leo, Novartis; Honor: Roche, BMS, Merck, MSD, ISDIN,<br />
MEDA, La Roche Posay, Leo; Spkr Bur: Roche, BMS, MSD, ISDIN, La Roche Posay,<br />
Leo, Almirall, Novartis; Resrch: Roche, BMS, Merck, MEDA, La Roche Posay, Leo,<br />
Almirall, AMGEN, GSK. M. Makrutzki: Employee H<strong>of</strong>fman-La Roche. I. Templeton:<br />
Employment, Stock or Other Ownership: Genentech. G. Rogers: Consulting/Advisory,<br />
Honoraria, Research: Genentech. B. Dreno: Consulting/Advisory: BMS, GSK, Roche,<br />
Novartis Speaker Bureau: BMS, GSK, Roche Research: BMS, GSK Travel,<br />
Accommodations, Expenses: BMS, Roche. R. Kunstfeld: Consulting/Advisory: Roche,<br />
Novartis, Menarini, Meda‐Pharma, Spirig, Leo Pharma Honoraria: Roche, Novartis,<br />
Menarini, Meda‐Pharma. All other authors have declared no conflicts <strong>of</strong> interest.<br />
1153P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Subgroup analysis <strong>of</strong> patients (pts) with Gorlin syndrome<br />
treated with vismodegib (VISMO) in the STEVIE study<br />
N. Basset-Seguin 1 , J. Hansson 2 , R. Kunstfeld 3 , J.J. Grob 4 , B. Dreno 5 , L. Mortier 6 ,<br />
P.A. Ascierto 7 , N. Dimier 8 , A. Fittipaldo 9 , I. Xynos 10 , A. Hauschild 11<br />
1 Dermatology, Hôpital St. Louis, Paris, France, 2 Department <strong>of</strong><br />
<strong>Oncology</strong>-Pathology, Karolinska University Hospital, Stockholm, Sweden,<br />
3 Dermatology, Medical University <strong>of</strong> Vienna, Vienna, Austria, 4 Department <strong>of</strong><br />
Dermatology and Cutaneous <strong>Oncology</strong>, Aix-Marseille University, Hopital Timone<br />
APHM, Marseille, France, 5 Dermato Cancerology, Nantes University, Nantes,<br />
France, 6 Dermatology, University <strong>of</strong> Lille 2, Lille Regional University Hospital, Lille,<br />
France, 7 Melanoma, Cancer Immunotherapy, and Innovative Therapy Unit, Istituto<br />
Nazionale Tumori Fondazione G. Pascale, Naples, Italy, 8 Department <strong>of</strong><br />
Biostatistics, Roche Products, Ltd., Welwyn Garden City, UK, 9 Pharma<br />
Development, Roche Products, Ltd., Welwyn Garden City, UK, 10 Product<br />
Development, Roche Products, Ltd., Welwyn Garden City, UK, 11 Department <strong>of</strong><br />
Dermatology, University Hospital Schleswig-Holstein, Kiel, Germany<br />
Background: VISMO, a first-in-class Hedgehog pathway inhibitor, is approved (US<br />
and EU) in adults with locally advanced BCC (laBCC) or metastatic BCC (mBCC).<br />
STEVIE (ClinicalTrials.gov NCT1367665), is evaluating safety and efficacy <strong>of</strong> VISMO<br />
in pts with advanced BCC, including pts with Gorlin syndrome, a hereditary condition<br />
characterised by multiple BCCs. Data from the subset <strong>of</strong> Gorlin pts in the primary<br />
analysis are presented.<br />
Methods: Pts with Gorlin syndrome could enrol in the study if they met<br />
protocol-defined criteria for laBCC or mBCC. Pts received oral VISMO 150 mg/<br />
day until progressive disease, unacceptable toxicity, or withdrawal. The<br />
primary outcome was safety. Secondary outcomes included efficacy and quality<br />
<strong>of</strong> life.<br />
Results: The analysis includes 219 Gorlin pts (laBCC, n = 214; mBCC, n = 5) with a<br />
median age <strong>of</strong> 52 (range 18–88) years. Median treatment duration was 374 days and<br />
median dose intensity was 95.8%. At cut-<strong>of</strong>f (March 16, 2015), all Gorlin pts<br />
experienced ≥1 treatment-emergent adverse event (TEAE). Most common TEAEs<br />
were muscle spasm (78.1%), alopecia (78.1%), dysgeusia (58.0%), diarrhoea (30.6%),<br />
nausea (23.3%), fatigue (23.3%) and asthenia (20.5%). Most TEAEs (56%) were grade<br />
1–2 and serious TEAEs were reported in 17.8% <strong>of</strong> pts. Treatment discontinuation due<br />
to TEAEs occurred in 29.2% <strong>of</strong> pts and included muscle spasms (8.2%), alopecia<br />
(6.8%) and dysgeusia (5.0%); most were grade 1–2 (20.6%). Five pts (2.3%) died due to<br />
grade 5 AEs (n = 4) and other reasons (n = 1). All grade 5 AEs presented with<br />
confounding factors and assessed as unrelated to VISMO per investigator. Best overall<br />
response (Response Evaluation Criteria in Solid Tumors version 1.1; investigator<br />
assessed) was 81.7% (95% confidence interval [CI] 75.8–86.6). Median time to<br />
response was 2.9 months (95% CI 2.8–3.7). Median progression-free survival was 32.5<br />
months (95% CI 29.4–not estimable [NE]). Median duration <strong>of</strong> response was 28.8<br />
months (95% CI 24.8–NE).<br />
Conclusions: TEAES reported in Gorlin pts are similar to those observed in previous<br />
studies <strong>of</strong> VISMO. The results confirmed clinical efficacy <strong>of</strong> VISMO in Gorlin pts, and<br />
support the use <strong>of</strong> VISMO in this pt population.<br />
Clinical trial identification: NCT01367665<br />
Legal entity responsible for the study: Roche-Genentech<br />
Funding: Roche-Genentech<br />
Disclosure: N. Basset-Seguin: Employment: Genentech Consultant/Advisory:<br />
Novartis, Roche, Leo Pharma, Galderma, Pierre Fabre Patents, Royalties, Other:<br />
Genentech Travel, Accommodation, Expenses: Roche, Galderma, Leo<br />
Pharma. J. Hansson: Consultant/Advisory: BMS, GSK, MSD/Merck, Novartis,Roche<br />
Pharma Trial Grants/Research Funding: Amgen, BMS, GSK, MSD/Merck, Novartis,<br />
Roche. R. Kunstfeld: Honoraria: Roche, Novartis, Menarini, Meda‐Pharma<br />
Consulting/Advisory Role: Roche, Novartis, Menarini, Meda‐Pharma, Spirig, Leo<br />
Pharma. J.J. Grob: Honoraria: GSK, Roche, BMS Consulting/Advisory: GSK, BMS,<br />
Roche, Amgen, Merck, Novartis Speaker Bureau: GSK Research: Roche, BMS Travel,<br />
Accommodations, Expenses: Roche. B. Dreno: Consulting/Advisory: BMS, GSK,<br />
Roche, Novartis Speaker Bureau: BMS, GSK, Roche Research: BMS, GSK Travel,<br />
Accommodations, Expenses: BMS, Roche. L. Mortier: Research funding (institution<br />
received): Roche, BMS, GSK, CSO, and Novartis. P.A. Ascierto: Consultant/<br />
Advisory: BMS, Roche/Genentech, MSD, Ventana, Novartis, Amgen, Array<br />
Research: BMS, Roche/Genentech, Ventana. N. Dimier: Employment: Roche Stock/<br />
Other Ownership: Roche, GSK. A. Fittipaldo: Employee, Stockholder: H<strong>of</strong>fman-La<br />
Roche. I. Xynos: Advisory Board, Honoraria, Investigator: Roche/<br />
Genentech. A. Hauschild: Consulting/Advisory, Honoraria, Trial Grants: Amgen,<br />
BMS, Celgene, Eisai, GSK, MedImmune, MelaSciences, Merck Serono, MSD/Merck,<br />
Novartis, Oncosec, Roche Pharma.<br />
vi398 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
1154P<br />
Evaluation <strong>of</strong> real world treatment outcomes in patients with<br />
metastatic merkel cell carcinoma (MCC) following second<br />
line chemotherapy<br />
J. Becker 1 , E. Lorenz 2 , G. Haas 2 , C. Helwig 3 , D. Oksen 3 , L. Mahnke 4 , M. Bharmal 3<br />
1 Pr<strong>of</strong>essor <strong>of</strong> Translational <strong>Oncology</strong>, University <strong>of</strong> Duisburg-Essen, Essen,<br />
Germany, 2 GmbH & Co. OHG, IMS Health, Frankfurt am Main, Germany,<br />
3 Immuno-<strong>Oncology</strong>, Merck KGaA, Darmstadt, Germany, 4 Immuno-<strong>Oncology</strong>,<br />
EMD Serono, Inc., Rockland, MA, USA<br />
Background: MCC is a rare, cutaneous, neuroendocrine tumor. MCC is an aggressive<br />
disease associated with frequent locoregional recurrences and visceral metastases, and a<br />
high mortality rate. This retrospective observational study aimed to assess treatment<br />
outcomes among second line (2L) or later chemotherapy in a real-world setting to<br />
better understand treatment pathways and prognosis in distant metastatic MCC<br />
patients (pts).<br />
Methods: Data consisted <strong>of</strong> anonymized pt level information, extracted from a MCC<br />
specific registry in Europe. This registry contains data collected from 56 clinical sites in<br />
3 countries (Germany: 53, Austria: 2, and Switzerland: 1). Endpoints described for the<br />
study population included objective response rate (ORR), progression-free survival<br />
(PFS), duration <strong>of</strong> response (DOR), durable response rate (DRR) and overall survival<br />
(OS). Best overall response was assessed using data from real-world practice provided<br />
by physicians to the registry, and thus based on routine radiology data and clinical<br />
judgment instead <strong>of</strong> Response Evaluation Criteria in Solid Tumors (RECIST) criteria.<br />
Results: Of the total 971 pts with MCC in the registry, 326 pts were diagnosed with<br />
locally advanced or metastatic disease. Thirty four pts were identified with distant<br />
metastatic MCC and received 2nd or later line chemotherapy were included. Of these<br />
34, 29 were eligible for the subgroup analyses <strong>of</strong> immunocompetent pts. Of the 5<br />
immunocompromised pts, four had a B-cell chronic lymphocytic leukemia (B-CLL)<br />
and one received immunosuppressive treatment. Among all pts, 64.7% were male and<br />
the mean age <strong>of</strong> this cohort was 64.4 years. ORR to 2L or later chemotherapy was 8.8%<br />
(3/34). The median PFS from chemotherapy initiation was 3.0 months, median OS was<br />
5.3 months and median DOR was 1.9 months. The 6-month DRR was 0% and PFS rate<br />
was 2.9%. Results in the immunocompetent pt subgroup were consistent with those in<br />
the entire population.<br />
Conclusions: Both response rate and duration <strong>of</strong> response are very poor for 2L or later<br />
chemotherapy in distant metastatic MCC pts. Chemotherapy in the second line<br />
appears to be most useful for palliation in symptomatic pts. New treatment approaches<br />
with durable benefit are needed for these MCC pts.<br />
Legal entity responsible for the study: EMD Serono and Merck KGaA<br />
Funding: EMD Serono and Merck KGaAN/A –Authors wrote the abstract<br />
Disclosure: J. Becker: Consultant/advisory for Merck Serono, BMS, Roche, CureVac,<br />
Rigontec, Lytex, Amgen. Speaker’s Bureau for Merck Serono, Amgen. Research<br />
funding from BMS, Merck Serono. Travel expenses from Amgen and Merck<br />
Serono. E. Lorenz: Travel, accommodations, and/or expenses provided by Merck<br />
KGaA. G. Haas: Employee: IMS Health Stockholder: San<strong>of</strong>i. C. Helwig, D. Oksen,<br />
M. Bharmal: Employee <strong>of</strong> Merck KGaA. L. Mahnke: Employee <strong>of</strong> EMD Serono.<br />
1155P<br />
VISMONEO - a phase II study assessing vismodegib in the<br />
neoadjuvant treatment <strong>of</strong> locally advanced basal cell<br />
carcinoma - Patients characteristics<br />
N. Basset-Seguin 1 , A. Dupuy 2 , P. Saiag 3 , S. Dalac-Rat 4 , B. Guillot 5 , E. Routier 6 ,M.<br />
T. Leccia 7 , A. Duhamel 8 , X. Mirabel 9 , I. Benbouta 10 , L. Mirakovska 10 ,<br />
D. Meddour 10 , M. Dib 10 , A. Mahmoudi 11 , P. Guerreschi 12 , L. Mortier 13<br />
1 Dermatology, Hôpital St. Louis, Paris, France, 2 Dermatology, CHU de<br />
Pontchaillou, Rennes, France, 3 General and <strong>Oncology</strong> Dermatology, Hopital<br />
Ambroise Pare, Boulogne-Billancourt, France, 4 Dermatology, CHU Dijon, Dijon,<br />
France, 5 Dermatology, Hopital Saint-Eloi (Montpellier), Montpellier, France,<br />
6 Dermatology, Institut Gustave Roussy, Paris, France, 7 Dermato-vénérologie,<br />
photobiologie et allergologie, CH Mutualiste de Grenoble, Grenoble, France, 8 Dpt<br />
<strong>of</strong> digestive and oncological surgery, Lille University Hospital, France, Lille, France,<br />
9 Service Cancérologie Digestive, Centre Oscar Lambret, Lille, France, 10 CRA, Lille<br />
University Hospital, France, Lille, France, 11 Unité Hématologie/Oncodermatologie,<br />
Roche France, Boulogne-Billancourt, France, 12 Plastic and reconstructive surgery,<br />
Lille University Hospital, France, Lille, France, 13 Dermatology, Lille University<br />
Hospital, France, Lille, France<br />
Background: The neoadjuvant administration <strong>of</strong> vismodegib in unresectable locally<br />
advanced basal cell carcinoma (laBCC) may reduce tumor size, facilitate resection and<br />
potentially preserve the functional and the aesthetic aspect <strong>of</strong> the affected area.<br />
VISMONEO is conducted to assess the efficacy and safety <strong>of</strong> vismodegib in the<br />
neoadjuvant treatment <strong>of</strong> laBCC.<br />
Methods: VISMONEO is an open-label, non-comparative, multicenter, phase II study.<br />
Patients (pts) with at least one histologically confirmed lesion <strong>of</strong> laBCC and lesion with<br />
a diameter ≥ 3cm in zones at intermediate risk <strong>of</strong> tumor recurrence and a BCC with a<br />
diameter <strong>of</strong> ≥ 2 cm in the zones at higher risk <strong>of</strong> tumor recurrence are included. Oral<br />
vismodegib 150 mg once-daily is administered for a maximum <strong>of</strong> 10 months. A total <strong>of</strong><br />
55 expected pts will be followed for 3 years. The primary endpoint is the percentage <strong>of</strong><br />
BCC pts with tumor down-staging following surgical resection after at least 4 months<br />
<strong>of</strong> vismodegib. Secondary endpoints include clinical benefits assessed by an<br />
independent panel <strong>of</strong> experts; medico-economic impact <strong>of</strong> this neoadjuvant strategy,<br />
safety (NCI-CTCAE, v4.0) and quality <strong>of</strong> life (Skindex-16 questionnaire).<br />
Results: Between November 2014 and June 2015, 55 pts have been included in 17<br />
centers in France. Half <strong>of</strong> pts are men (51%), their mean age is 72 years (±SD 12) and<br />
73% (n = 40) are > 65 years old; 58% (n = 32) have an ECOG performance status <strong>of</strong> 0,<br />
35% (n = 19) ECOG1 and 7% (n = 4) ECOG ≥ 2. Disease is measurable in all pts and 3<br />
(5.5%) pts have a Gorlin syndrome. BCC sites are mainly eye (35%; n = 19); ear (14%;<br />
n = 8); temporal (14%; n = 8); nose (13%; n = 7), forehead (11%; n = 6), cheek (5%;<br />
n = 3), scalp (4%; n = 2); and others (lips, parietal: 4%; n = 2). No previous radiotherapy<br />
for most pts 98% (n = 54). In December 2015, 8 pts were still under treatment and 47<br />
completed the protocol (including pts still followed-up and pts resected with a less<br />
heavy surgery than planned and a complete response).<br />
Conclusions: The characteristics <strong>of</strong> patients with laBCC treated with neoadjuvant<br />
vismodegib and surgical resection are consistent with the few resectable laBCC patients<br />
included in clinical trials. This phase II study is ongoing.<br />
Clinical trial identification: EudraCT 2013-004338-13<br />
Legal entity responsible for the study: N/A<br />
Funding: Roche<br />
Disclosure: N. Basset-Seguin: Roche, Galderma, Novartis, Leo, Pierre Fabre,<br />
Genentech. P. Saiag, S. Dalac-Rat: Roche, BMS, GSK, MSD, Novartis. D. Meddour:<br />
abbvie Algeria. M. Dib: Lille University Hospital. A. Mahmoudi: Roche. All other<br />
authors have declared no conflicts <strong>of</strong> interest.<br />
1156TiP<br />
abstracts<br />
CONVERCE: evaluation <strong>of</strong> cobimetinib and vemurafenib<br />
combination treatment in patients with brain metastases<br />
from BRAFV600 mutated melanoma<br />
T. Lesimple 1 , B. Campillo-Gimenez 2 , M.T. Leccia 3 , A. Mahmoudi 4 , C. Lebbe 5<br />
1 <strong>Oncology</strong> Department, Centre Eugene - Marquis, Rennes, France, 2 Santé<br />
publique et médecine sociale, Centre Eugene - Marquis, Rennes, France,<br />
3 Dermato-vénérologie, photobiologie et allergologie, CH Mutualiste de Grenoble,<br />
Grenoble, France, 4 Unité Hématologie/Oncodermatologie, Roche France,<br />
Boulogne-Billancourt, France, 5 Dermatology, Hôpital St. Louis, Paris, France<br />
Background: Brain Metastases (BM) occur in 10 to 20% <strong>of</strong> patients (pts) at initial<br />
diagnosis <strong>of</strong> metastatic melanoma (MM) and develop in up to 73% <strong>of</strong> pts with MM.<br />
BRAF V600 mutations are found in around 50% <strong>of</strong> cutaneous melanomas. Vemurafenib,<br />
a BRAF inhibitor, is a standard 1st-line treatment <strong>of</strong> BRAF V600 MM in Europe, and<br />
recent data suggest a benefit for patients with BM. Resistance to a monotherapy with a<br />
BRAF inhibitor is frequent. Results <strong>of</strong> a phase III trial comparing<br />
vemurafenib + cobimetinib (MEK inhibitor) to vemurafenib in pts with BRAF mutated<br />
MM showed improved PFS and OS. Patients with symptomatic BM were excluded<br />
from this study. The objective <strong>of</strong> CONVERCE, a phase II interventional study, is to<br />
determine whether the combination <strong>of</strong> vemurafenib + cobimetinib is effective in the<br />
treatment <strong>of</strong> BRAF V600 mutated melanoma with BM.<br />
Trial design: Pts with histologically confirmed metastatic cutaneous melanoma,<br />
mucosal melanoma, or melanoma <strong>of</strong> unknown primary origin, and BM for which<br />
surgical resection is not a reasonable option, will be enrolled into 3 cohorts (n = 137):<br />
neurologically asymptomatic pts with previously locally untreated (Cohort A) or<br />
treated (Cohort B) BM, and neurologically symptomatic patients with previously<br />
locally treated or not BM (Cohort C). Pts will be treated with vemurafenib 960 mg PO,<br />
twice daily from D1 to D28, continuously, and cobimetinib 60 mg PO, once daily, from<br />
D1 to D21 (1 cycle = 28 days) until progression (intracranial or extracranial),<br />
unacceptable toxicity, withdrawal <strong>of</strong> consent, death or decision <strong>of</strong> the investigator. The<br />
primary endpoint is the complete or partial intracranial response rate in cohort A<br />
based on the evaluation <strong>of</strong> patient’s best tumor response assessed by the centralized<br />
review committee according to modified RECIST 1.1 criteria). Secondary endpoints<br />
include objective intracranial response rates in cohorts B and C; intracranial duration<br />
<strong>of</strong> response, progression-free survival, overall response rate and overall survival in all<br />
cohorts; safety; pharmacokinetic study including cerebrospinal fluid, kinetic study <strong>of</strong><br />
BRAF mutation rate in circulating tumor DNA; pharmacogenetics study. Preliminary<br />
results are expected in 2018.<br />
Clinical trial identification: NCT02537600<br />
Legal entity responsible for the study: N/A<br />
Funding: Roche<br />
Disclosure: T. Lesimple: Roche, BMS, Novartis, MSD. A. Mahmoudi: Roche. C. Lebbe:<br />
Roche, BMS, Novartis, MSD, Amgen. All other authors have declared no conflicts <strong>of</strong><br />
interest.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw379 | vi399
abstracts<br />
1157TiP<br />
Phase Ib study <strong>of</strong> intratumoral oncolytic coxsackievirus A21<br />
(CVA21) and pembrolizumab in subjects with advanced<br />
melanoma<br />
H.L. Kaufman 1 , K. Spencer 2 , J. Mehnert 2 , A. Silk 2 , J. Wang 2 , A. Zloza 1 , M. Kane 2 ,<br />
D. Moore 2 , M. Grose 3 , D. Shafren 3<br />
1 Surgical <strong>Oncology</strong>, Rutgers Cancer Institute <strong>of</strong> Mew jersey, New Brunswick, NJ,<br />
USA, 2 Medical <strong>Oncology</strong>, Rutgers Cancer Institute <strong>of</strong> Mew jersey, New Brunswick,<br />
NJ, USA, 3 Clinical Research, Viralytics, New Lambton Heights, Australia<br />
Background: Pembrolizumab is a programmed death receptor-1 (PD-1) blocking<br />
antibody that has demonstrated overall and durable response rates in advanced<br />
melanoma patients, although less than half <strong>of</strong> treated patients respond.<br />
Therapeutic responses have been associated with tumor expression <strong>of</strong> PD-L1.<br />
Oncolytic viruses are live viral particles that can be injected into tumors resulting<br />
in lysis <strong>of</strong> tumor cells, release <strong>of</strong> tumor-associated antigens and increased<br />
expression <strong>of</strong> PD-L1. Coxsackievirus A21 (CVA21) is a native oncolytic virus that<br />
in phase I and II studies has been safe and well-tolerated with an overall response<br />
rate <strong>of</strong> 28.1% and a 1-year survival rate <strong>of</strong> 73.7% (Andtbacka et al). We<br />
hypothesize that combination CVA21 and pembrolizumab will be safe and<br />
well-tolerated, and result in improved clinical efficacy through increased expression<br />
<strong>of</strong> PD-L1 following virus therapy.<br />
Trial design: In this phase I trial (NCT02565992), we will enroll 30 patients with<br />
advanced melanoma with at least one tumor deposit accessible for injection. The<br />
primary endpoint is the safety <strong>of</strong> CVA21 with pembrolizumab with secondary<br />
endpoints <strong>of</strong> overall response rate, progression-free and overall survival. Correlates<br />
include measures <strong>of</strong> T-cell subsets and antibody responses to melanoma antigens<br />
in tumor tissue and peripheral blood. Pre- and post-treatment tumor PD-L1<br />
expression will be assessed and correlated with clinical benefit. Patients will receive<br />
up to 4.0 mL <strong>of</strong> intratumoral CVA21 on days 1, 3, 5, and 8 every 3 weeks for a<br />
maximum <strong>of</strong> 19 total injections, and pembrolizumab 2mg/kg IV every 3 weeks<br />
starting on day 8 for up to 2 years. Patients will be evaluated for toxicities until<br />
the dose-limiting toxicity (DLT) <strong>of</strong> CVA21 is reached, and for response by<br />
modified WHO criteria. Peripheral blood mononuclear cells will be collected at<br />
baseline, prior to pembrolizumab administration, and at study termination, and<br />
optional tumor biopsies will be obtained at baseline and at periodic intervals<br />
thereafter. The trial is currently screening eligible subjects.<br />
Clinical trial identification: NCT02565992<br />
Legal entity responsible for the study: Viralytics, Limited<br />
Funding: Viralytics, Limited<br />
Disclosure: H.L. Kaufman: Advisory boards for Amgen, EMD Serono, Merck,<br />
Prometheus and San<strong>of</strong>i. Speaker’s bureau for Merck but returns all honoraria to<br />
Rutgers University. M. Grose, D. Shafren: Employee <strong>of</strong> Viralytics. All other authors<br />
have declared no conflicts <strong>of</strong> interest.<br />
1158TiP<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Intralesional rose bengal for stage III and IV melanoma<br />
S.S. Agarwala 1 , R.H.I. Andtbacka 2 , A. Hauschild 3 , K.N. Rice 4 , M. Ross 5 ,C.<br />
R. Scoggins 6 , M. Smithers 7 , E. Whitman 8 , E.A. Wachter 9<br />
1 Cancer Center, St. Luke’s Hospital & Health Network, Bethlehem, PA, USA,<br />
2 Surgical <strong>Oncology</strong>, Huntsman Cancer Institute, Salt Lake City, UT, USA,<br />
3 Department <strong>of</strong> Dermatology, University <strong>of</strong> Kiel (UKSH), Kiel, Germany,<br />
4 Hematology/<strong>Oncology</strong>, Sharp Memorial Hospital, San Diego, CA, USA, 5 Surgical<br />
<strong>Oncology</strong>, MD Anderson Cancer Center, Houston, TX, USA, 6 Surgical <strong>Oncology</strong>,<br />
University <strong>of</strong> Louisville, Louisville, KY, USA, 7 The University <strong>of</strong> Queensland,<br />
Princess Alexandra Hospital, Brisbane, Australia, 8 <strong>Oncology</strong>, Atlantic Melanoma<br />
Center, Morristown, NJ, USA, 9 Clinical Development, Provectus<br />
Biopharmaceuticals, Knoxville, TN, USA<br />
Background: Intralesional rose bengal (PV-10) is an investigational small molecule<br />
ablative immunotherapy that can elicit primary ablation <strong>of</strong> injected tumors and<br />
anti-tumor immune response via secondary T-cell activation. Phase 2 testing in Stage<br />
III-IV melanoma yielded a 51% objective response rate (ORR) with 50% complete<br />
response (CR) when all disease was injected. PV-10 is currently undergoing phase 3<br />
testing as a single agent in patients with locally advanced cutaneous melanoma and phase<br />
1b testing in combination with immune checkpoint inhibition for more advanced disease.<br />
Trial design: Study PV-10-MM-31 (NCT02288897) is an international multicenter,<br />
open-label, randomized controlled trial <strong>of</strong> PV-10 versus investigator’s choice <strong>of</strong><br />
chemotherapy (dacarbazine or temozolomide) or oncolytic viral therapy (talimogene<br />
laherparepvec). A total <strong>of</strong> 225 subjects with locally advanced cutaneous melanoma (Stage<br />
IIIB, IIIC or IV-M1a melanoma) randomized 2:1 will be assessed for progression free<br />
survival (PFS) by RECIST 1.1 (using blinded Independent Review Committee<br />
assessment <strong>of</strong> study photography and radiology data). Comprehensive disease<br />
assessments, including review <strong>of</strong> photography and radiology data, are performed at 12<br />
week intervals; clinical assessments <strong>of</strong> progression status are performed at 28-day<br />
intervals. Study PV-10-MM-1201 (NCT02557321) is an international multicenter,<br />
open-label, sequential phase study <strong>of</strong> PV-10 in combination with pembrolizumab. Stage<br />
IV metastatic melanoma patients with at least one injectable cutaneous or subcutaneous<br />
lesion who are candidates for pembrolizumab are eligible. In the current phase 1b<br />
portion <strong>of</strong> the study, up to 24 subjects will receive the combination <strong>of</strong> PV-10 and<br />
pembrolizumab (PV-10 + standard <strong>of</strong> care). In phase 2 an estimated 120 participants will<br />
be randomized 1:1 to receive either PV-10 and pembrolizumab or pembrolizumab alone.<br />
The primary endpoint for phase 1b is safety and tolerability with PFS a key secondary<br />
endpoint; PFS is the primary endpoint for phase 2.<br />
Clinical trial identification: NCT02288897; NCT02557321<br />
Legal entity responsible for the study: Provectus Biopharmaceuticals, Inc.<br />
Funding: Provectus Biopharmaceuticals, Inc.<br />
Disclosure: E.A. Wachter: Employee and shareholder <strong>of</strong> Provectus, sponsor <strong>of</strong> the<br />
subject clinical trials. All other authors have declared no conflicts <strong>of</strong> interest.<br />
vi400 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong> 27 (Supplement 6): vi401–vi406, 2016<br />
doi:10.1093/annonc/mdw380<br />
new diagnostics<br />
1159PD<br />
Analytic validation <strong>of</strong> a clinical circulating tumor DNA assay<br />
for patients with solid tumors<br />
P.J. Stephens 1 , T. Clark 1 , M. Kennedy 1 ,J.He 1 , G. Young 1 , M. Zhao 1 , M. Coyne 1 ,<br />
V. Breese 1 , L. Young 1 , S. Zhong 1 , M. Bailey 1 , B. Fendler 1 , V.A. Miller 2 ,<br />
E. Schleifman 3 , E. Peters 4 , G. Otto 1 , D. Lipson 1 , J.S. Ross 5<br />
1 Clinical Genomics, Foundation Medicine, Inc., Cambridge, MA, USA, 2 Clinical<br />
Development, Foundation Medicine, Inc., Cambridge, MA, USA, 3 <strong>Oncology</strong><br />
Biomarker Development, Genentech, Inc., South San Francisco, CA, USA,<br />
4 Companion Diagnostics Development, Genentech, Inc., South San Francisco,<br />
CA, USA, 5 Pathology, Albany Medical Center, Albany, NY, USA<br />
Background: Several circulating tumor DNA (ctDNA) pr<strong>of</strong>iling assays are<br />
commercially available, and physicians must be empowered to identify assays with the<br />
high level <strong>of</strong> accuracy required to meet the diagnostic needs <strong>of</strong> their patients. This<br />
study describes the analytic validation <strong>of</strong> a ctDNA assay optimized for clinical care.<br />
Methods: Accuracy and reproducibility were validated using 117 reference samples<br />
with known alterations and 268 clinical ctDNA samples. A CLIA-validated NGS assay,<br />
droplet digital PCR, and break-point PCR were used to validate the alterations<br />
identified. A highly optimized, integrated workflow was developed that includes sample<br />
collection, storage and transport, ctDNA purification, library generation, and<br />
enrichment (solution hybridization capture), followed by high-depth sequencing<br />
(HiSeq2500). Computational methods were developed to enable sensitive and specific<br />
detection <strong>of</strong> all alteration classes, including base substitutions, small insertions and<br />
deletions (indels), copy number changes, and rearrangements/fusions.<br />
Results: This ctDNA assay demonstrated unprecedented accuracy: >99% sensitivity<br />
and >99% positive predictive value (PPV) for base substitutions and indels, >99%<br />
sensitivity and 98% PPV for rearrangements/fusions with a limit-<strong>of</strong>-detection below<br />
0.5%, plus robust detection <strong>of</strong> high-level, focal amplifications. The assay also accurately<br />
reports allele frequency. In 48 clinical ctDNA samples, 95 alterations <strong>of</strong> all classes were<br />
100% confirmed by orthogonal testing. We also report results comparing alterations<br />
from patient-matched ctDNA and FFPE biopsies.<br />
Conclusions: Developing a commercial ctDNA assay requires rigorous analytic<br />
validation and the availability <strong>of</strong> clinically relevant test metrics to ensure reliable<br />
interpretation and reporting to optimize targeted treatment options. This rigorous<br />
analytic validation study demonstrates high-accuracy detection in blood for all<br />
alteration classes, even when mutations are present at low allele frequency, thereby<br />
realizing the potential <strong>of</strong> ctDNA-based molecular pr<strong>of</strong>iling for the management <strong>of</strong><br />
cancer. A large, ongoing prospective clinical trial will provide additional data on the<br />
appropriate clinical settings for use <strong>of</strong> this assay in patient care.<br />
Legal entity responsible for the study: Foundation Medicine, Inc.<br />
Funding: Foundation Medicine, Inc.<br />
Disclosure: P.J. Stephens, V.A. Miller: Employee <strong>of</strong>, stockholder in, and holds a<br />
leadership position for Foundation Medicine, Inc. T. Clark, M. Kennedy, J. He,<br />
G. Young, M. Zhao, M. Coyne, V. Breese, L. Young, S. Zhong, M. Bailey, B. Fendler,<br />
G. Otto, D. Lipson, J.S. Ross: Employee <strong>of</strong> and stockholder in Foundation Medicine,<br />
Inc. All other authors have declared no conflicts <strong>of</strong> interest.<br />
1160P<br />
Genetic testing by a novel high-purity concentration system<br />
for circulating tumor cells independent <strong>of</strong> epithelial markers<br />
H. Ito 1 , H. Takagi 1 , M. Kozuka 1 , S.H. Kim 2 , M. Hirai 1 , T. Fujii 2<br />
1 Reserch & Development Division, Arkray, Inc., Kyoto, Japan, 2 Institute <strong>of</strong> Industrial<br />
Science, The University <strong>of</strong> Tokyo, Tokyo, Japan<br />
Background: Genetic analysis <strong>of</strong> circulating tumor cells (CTCs) is useful as liquid<br />
biopsy. However, there are 3 challenging issues in processing <strong>of</strong> CTC samples for<br />
clinical use <strong>of</strong> the analysis: [1] numerous residual blood cells in processed samples, [2]<br />
loss <strong>of</strong> CTCs that do not express epithelial markers, and [3] very laborious process.<br />
Here, we developed a novel system capable <strong>of</strong> overcoming all <strong>of</strong> these problems, which<br />
is perfect for the analysis <strong>of</strong> CTCs.<br />
Methods: Our CTC analysis system is composed <strong>of</strong> 5 steps: [1] filtering whole blood<br />
followed by immunostaining and magnetic labeling <strong>of</strong> cells trapped on the filter, [2]<br />
depletion <strong>of</strong> white blood cells (WBCs) in the cells recovered from the filter by magnetic<br />
separation, [3] trapping the resultant cells at an observation chamber in a micr<strong>of</strong>luidic<br />
enrichment device using dielectrophoresis, [4] recovering the cells as a concentrated<br />
sample after fluorescence microscope observation, and [5] detecting genetic mutation<br />
<strong>of</strong> the cells without nucleic acid purification using the whole sample by quenching<br />
probe method. Using whole blood spiked with cultured cancer cell lines (NCI-H2228,<br />
NCI-H1650, NCI-H1975, SW620 or MCF-7), we demonstrated our system and<br />
detected their genetic mutations (EML4-ALK, EGFR, KRAS or PIK3CA).<br />
Results: Our system successfully detected EML4-ALK, EGFR, KRAS or PIK3CA<br />
mutations <strong>of</strong> the cell lines spiked in 8 mL <strong>of</strong> whole blood. The detection sensitivity <strong>of</strong><br />
our method was 1 cell/mL, and the average number <strong>of</strong> residual nucleated cells was 87<br />
(Table 1). Our system could report the results <strong>of</strong> genetic mutation detection and each<br />
enumeration <strong>of</strong> cancer cells and residual nucleated cells within 9 hours <strong>of</strong> starting the<br />
processing <strong>of</strong> whole blood.<br />
Table: 1160P Sensitivity and reproducibility results for spiking test<br />
test cell line expected<br />
count [cells<br />
in 8 mL]<br />
detected<br />
count<br />
[cells]<br />
residual<br />
nucleated cell<br />
[cells]<br />
detected<br />
EGFR<br />
mutation<br />
1 NCI-H1650 8 (SD ± 1) 2 98 ex19del<br />
2 8 (SD ± 1) 3 121 ex19del<br />
3 8 (SD ± 3) 2 25 ex19del<br />
4 8 (SD ± 3) 2 48 ex19del<br />
5 12 (SD ± 3) 2 30 ex19del<br />
6 NCI-H1975 11 (SD ± 4) 5 80 L858R<br />
7 7 (SD ± 3) 4 129 L858R<br />
8 12 (SD ± 3) 9 79 L858R<br />
9 7 (SD ± 3) 1 165 L858R<br />
10 10 (SD ± 3) 3 91 L858R<br />
Conclusions: Our system would be useful for the analysis <strong>of</strong> gene mutations in<br />
wide-ranging CTC subsets independent <strong>of</strong> expression <strong>of</strong> a certain antigen, and may be<br />
particularly effective for CTCs that have changed their phenotype.<br />
Legal entity responsible for the study: Arkray, Inc.<br />
Funding: Arkray, Inc.<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1161P<br />
Utility <strong>of</strong> a targeted NGS oncology assay for circulating tumor<br />
DNA in a multi-histology clinical setting<br />
T. Eerkes 1 , A. Ademi Santiago-Walker 2 , M. Loreen 3 , L. Lim 1 , J. Hernandez 4 ,<br />
C. Raymond 1 , S. Henderson 1 , D. Dipasquo 1 , T. Shaffer 1 , C. Motely 2 , C. Moy 2 ,<br />
S. Wallace 3 , K. Eaton 3 , J. Karkera 2 ,M.Li 1<br />
1 Clinical Operations, Resolution Bioscience, Bellevue, WA, USA, 2 <strong>Oncology</strong><br />
Translational Research, Janssen Research and Development, Raritan, NJ, USA,<br />
3 <strong>Oncology</strong>, University <strong>of</strong> Washington Seattle Cancer Care Alliance, Seattle, WA,<br />
USA, 4 Clinical Operations, Resolution Bioscience, Bellevue, WA, USA<br />
Background: Genomic pr<strong>of</strong>iling <strong>of</strong> tumor tissue at diagnosis is the standard <strong>of</strong> care for<br />
various cancers. Pr<strong>of</strong>iling <strong>of</strong> circulating-tumor DNA (ctDNA) found in peripheral<br />
blood <strong>of</strong> cancer patients is an attractive alternative to invasive tissue biopsy. We<br />
describe the use <strong>of</strong> a comprehensive NGS sequencing assay <strong>of</strong> ctDNA in the clinical<br />
setting.<br />
Methods: The Resolution Bioscience ctCDx assay comprehensively targets actionable<br />
somatic SNVs, indels, fusions and copy number variants in 16 genes implicated in lung<br />
and other cancers, using a proprietary, high-efficiency hybrid capture system and NGS<br />
sequencing <strong>of</strong> ctDNA from plasma. 385 patients (335 from 42756493EDI1001 clinical<br />
trial screening, and 50 from a University <strong>of</strong> Washington study CC9372) were analyzed<br />
in the Resolution Bioscience CLIA laboratory. Patients had previously been diagnosed<br />
with one <strong>of</strong> ten histologies, including lung, breast, and ovarian cancer. The patient<br />
cohort was a clinically relevant sampling, <strong>of</strong> treatment-naïve patients, those on therapy,<br />
and those with refractory disease after >= 1 therapy course.<br />
Results: Average turn-around-time (TAT) was 8.6 calendar days. The ctCDx assay<br />
detected >435 somatic mutations <strong>of</strong> all 4 types; SNVs, indels, fusions, and copy<br />
number variation. Somatic lesions were detected in 61% <strong>of</strong> patients. At least 25% <strong>of</strong><br />
patients demonstrated canonical driver mutations, including KRAS SNVs, EGFR<br />
indels, ERBB2 amps., and EML4-ALK fusions. Resistance mutations such as EGFR<br />
T790M were detected in refractory patients. Detection rates <strong>of</strong> driver mutations in each<br />
indication closely mirrored the published detection rates in tumor tissue. At least 8% <strong>of</strong><br />
patients from one clinic had complications that precluded a tissue biopsy, thus<br />
benefiting from access to a blood-based assay.<br />
Conclusions: Our comprehensive blood-based genomic ctCDx platform has the<br />
demonstrated capacity to improve access in a clinically relevant TAT for oncology<br />
abstracts<br />
© European Society for Medical <strong>Oncology</strong> 2016. Published by Oxford University Press on behalf <strong>of</strong> the European Society for Medical <strong>Oncology</strong>.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com.
abstracts<br />
patients in many indications. Variant detection frequencies in blood from a<br />
representative clinical cohort generally aligned with expected alteration frequencies<br />
identified in tissue from published literature.<br />
Clinical trial identification: 42756493EDI1001<br />
Legal entity responsible for the study: Janssen Pharmaceutica, University <strong>of</strong><br />
Washington<br />
Funding: Janssen Pharmaceutica, Resolution Bioscience<br />
Disclosure: T. Eerkes, J. Hernandez, S. Henderson, D. Dipasquo, T. Shaffer:<br />
Disclosures: I am an employee and minor shareholder in Resolution Bioscience<br />
Inc. A. Ademi Santiago-Walker, C. Moy: Employed by Janssen Research &<br />
Development, and holds stock in Johnson & Johnson. L. Lim, C. Raymond, M. Li:<br />
Disclosures: I am an employee and shareholder in Resolution Bioscience<br />
Inc. C. Motely, J. Karkera: Employed by Janssen Research & Development, and holds<br />
stock in Johnson & Johnson. All other authors have declared no conflicts <strong>of</strong> interest.<br />
1162P<br />
Analytical performance <strong>of</strong> a new liquid biopsy mutation panel<br />
for detection <strong>of</strong> clinically actionable variants<br />
C. Svedman, G. Alexander, A. Bergamaschi, J. Han, P.B. Harrington, C-J. Ku,<br />
Y. Ma, W. Gibb, A. Dei Rossi, L. Shen, A.D. Goddard, D.A. Eberhard, K.<br />
M. Clark-Langone<br />
Research and Development, Genomic Health Inc, Redwood City, CA, USA<br />
Background: Assessing genomic alterations in circulating tumor DNA (ctDNA) from<br />
liquid biopsies may better reflect tumor heterogeneity, facilitate monitoring <strong>of</strong> tumor<br />
evolution and overcome the challenges <strong>of</strong> obtaining tissue biopsies. Analytic<br />
performance <strong>of</strong> such assays should be established on a per sample basis, using clinically<br />
relevant variants at levels representative <strong>of</strong> ctDNA. Here we report the analytic<br />
performance <strong>of</strong> a 17-gene panel (Oncotype SEQ, Liquid Select) and illustrate its<br />
ability to detect ctDNA in cancer patients.<br />
Methods: Analytical specificity and sensitivity were characterized through<br />
determination <strong>of</strong> Limit <strong>of</strong> Blank (LoB) and Limit <strong>of</strong> Detection (LoD) respectively. 73<br />
cell-free DNA (cfDNA) samples from 60 healthy donors were used to determine the<br />
LoB and set detection thresholds. A model system using cell line DNA harboring<br />
clinically actionable variants was then used to determine the allele fraction (AF)/copy<br />
number (CN) required for a 95% rate <strong>of</strong> detection (LoD), using 30-50ng DNA input.<br />
Repeatability and reproducibility was assessed using pools <strong>of</strong> cfDNA from cancer<br />
patients. Finally, liquid biopsies from 15 stage II-IV cancer patients (on or after<br />
therapy) were assayed for genomic alterations.<br />
Results: Detection thresholds were set above the LoB corresponding to >99% per<br />
sample specificity. LoD was calculated using 105 samples for each variant tested. Mean<br />
LoDs were as follows; single nucleotide variants (SNVs), 0.56% AF; insertions/<br />
deletions (indels), 0.19% AF; fusions, 0.37% AF, and CN gain, 2.7 copies. Accuracy was<br />
verified using additional variant positive and variant negative standards. In the<br />
repeatability and reproducibility study using cfDNA pools, on average >95% <strong>of</strong><br />
expected variants were detected in each run. 10 SNVs and 2 indels were found in the 15<br />
patient plasma samples, ranging from
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
enrichment strategy for NGS that, by its scalable and quantitative nature, is well suited<br />
for detection <strong>of</strong> each <strong>of</strong> the modes deregulation <strong>of</strong> MET.<br />
Methods: We developed AMP-based VariantPlex and FusionPlex library<br />
preparation assays for NGS to detect mutations from DNA and RNA, respectively. We<br />
designed AMP probes covering the MET gene to detect copy numbers and SNVs from<br />
DNA, and fusions, exon skipping and expression levels from RNA.<br />
Results: VariantPlex and FusionPlex kits enabled detection <strong>of</strong> MET amplifications,<br />
confirmed by FISH, and the resulting overexpression in FFPE samples. Exon 14<br />
skipping was also detected and confirmed by RT-PCR in FFPE and in cells, with<br />
concomitant splice site mutations. Lastly, a GTF2I:MET gene fusion and a Y1253D<br />
activating point mutation were detected.<br />
Conclusions: These results show that AMP enables comprehensive and sensitive<br />
NGS-based detection <strong>of</strong> multiple mutation types from low-input clinical sample types.<br />
Legal entity responsible for the study: ArcherDX, Inc.<br />
Funding: ArcherDX, Inc.<br />
Disclosure: B. Kudlow, J.D. Haimes, M. Bessette, N. Manoj, L. Griffin, J. Stahl:<br />
Full-time employee at ArcherDX, Inc.D. Murphy: Full-time employee for Ignyta,<br />
Inc. R. Shoemaker: Full-time employee at Ignyta, Inc.<br />
1166P<br />
Internal tandem duplications in FLT3 detected by anchored<br />
multiplex PCR and next-generation sequencing<br />
B. van Deusen, M. Bessette, L. Johnson, A. Berlin, M. Banos, L. Griffin,<br />
E. Reckase, J. Stahl, A. Licon, J.W. Myers, B. Kudlow<br />
Research and Development, ArcherDX, Inc., Boulder, CO, USA<br />
Background: Internal tandem duplications (ITDs) in FLT3 are detected in more than<br />
20% <strong>of</strong> pediatric and adult acute myeloid leukemia (AML) and are associated with an<br />
aggressive phenotype. As FLT3-ITD expressed kinases are sensitive to tyrosine kinase<br />
inhibitors, they are <strong>of</strong> considerable interest for the development <strong>of</strong> novel AML<br />
treatments. Capillary gel electrophoresis can detect ITDs but cannot be easily coupled<br />
with assays to detect other mutation types common in AML. Next-generation<br />
sequencing (NGS)-based methods enable comprehensive detection <strong>of</strong> multiple<br />
mutation types. However, detection <strong>of</strong> ITDs by NGS is challenging, in part because <strong>of</strong><br />
their highly variable nature and the difficulties <strong>of</strong> mapping repeated sequences to a<br />
wild-type reference. Anchored Multiplex PCR (AMP) is a target enrichment strategy<br />
for NGS that uses molecular barcoded adaptors and gene-specific primers, permitting<br />
open-ended capture <strong>of</strong> DNA fragments from a single end. We tested whether<br />
AMP-based NGS is suitable for FLT3-ITD detection.<br />
Methods: We developed the Archer VariantPlex Core AML library preparation assay<br />
for NGS to detect FLT3-ITDs from genomic DNA extracted from clinical samples. We<br />
designed AMP probes to cover the commonly mutated juxtamembrane domain and<br />
tyrosine kinase domain 1. We further developed a novel de novo sequence assembly<br />
algorithm based on over 2000 in silico datasets representing a large range <strong>of</strong> known ITDs.<br />
Results: In silico datasets enabled optimization <strong>of</strong> the VariantPlex Core AML analysis<br />
algorithm, resulting in the detection over 98% <strong>of</strong> in silico ITDs with no false positives.<br />
The VariantPlex Core AML library preparation assay in conjunction with the<br />
optimized analysis algorithm enabled sensitive NGS-based detection <strong>of</strong> ITDs in 16<br />
AML-positive blood samples. These results were consistent with results obtained from<br />
standard capillary gel electrophoresis.<br />
Conclusions: Our data show that AMP enables accurate NGS-based detection <strong>of</strong><br />
FLT3-ITDs from clinical DNA samples. As this approach can detect multiple mutation<br />
types from a single sample, our VariantPlex Core AML kit enables simultaneous<br />
detection <strong>of</strong> multiple mutations relevant in AML.<br />
Legal entity responsible for the study: ArcherDX, Inc.<br />
Funding: ArcherDX, Inc.<br />
Disclosure: B. van Deusen, M. Bessette, L. Johnson, A. Berlin, M. Banos, L. Griffin,<br />
E. Reckase, J. Stahl, A. Licon, B. Kudlow: Full-time employee at ArcherDX, Inc.<br />
1167P<br />
Functional characterization <strong>of</strong> variants <strong>of</strong> unknown<br />
significance (VUS) in patients and their responsiveness to<br />
targeted therapy drugs (TTD)<br />
G. Tarcic 1 , C.M. Walko 2 , H.L. McLeod 2 , J.K. Hicks 2 , Z. Barbash 1 , O. Edelheit 1 ,<br />
B. Miron 3 , M. Vidne 1 , E. Padron 2<br />
1 R&D, NovellusDx, Jerusalem, Israel, 2 Malignant Hematology, H. Lee M<strong>of</strong>fitt<br />
Cancer Center University <strong>of</strong> South Florida, Tampa, FL, USA, 3 Medical Affairs,<br />
NovellusDx, Jerusalem, Israel<br />
Background: Molecular diagnostics revolutionized cancer care, allowing precision<br />
medicine to identify actionable mutations in patients’ tumors. However, VUS are<br />
frequently found in potentially actionable genes and lack information for inclusion in<br />
treatment strategy. Uncovering the clinical relevance <strong>of</strong> these variants and their response<br />
to TTDs, is a crucial step in the development <strong>of</strong> precision medicine. To address this, we<br />
utilized NovellusDx’s Functional Annotation for Cancer Treatment (FACT) platform,<br />
which monitors the activity <strong>of</strong> signaling pathways by means <strong>of</strong> a transfected cell-based<br />
personalized assay. As a functional platform, FACT reveals activated pathways regardless<br />
<strong>of</strong> the type <strong>of</strong> mutation, and measures their activity in the presence <strong>of</strong> TTDs<br />
Methods: We analyzed advanced stage patients, some after multiple lines <strong>of</strong> treatment,<br />
in which a VUS was identified in potentially actionable genes. The patients’ variants<br />
were synthesized from the clinically derived NGS data and analyzed with the FACT<br />
platform. We compared the activity level induced by the patient’s variants compared to<br />
corresponding known hotspots, as well as their response to relevant TTDs<br />
Results: Two Non-small cell lung cancer and one salivary gland patients are presented.<br />
VUS mutations were present in the key oncogenes KRAS, BRAF and EGFR. One<br />
patient’s VUS (BRAF N581Y) was functionally inactive by the FACT system compared<br />
to the known hot spot mutations, therefore the use <strong>of</strong> the relevant TTD was predicted<br />
to be ineffective. On the other hand, two additional patients’ VUS (KRAS G13P, EGFR<br />
S720Y) were found to be active. When measuring the potential benefit <strong>of</strong> TTDs<br />
(Erlotinib, Gefitinib or Trametinib), these active VUS were responsive to <strong>of</strong>f-label<br />
TTDs at levels comparable to the known hotspot mutations providing sound evidence<br />
for <strong>of</strong>f-label drug use<br />
Conclusions: The diversity <strong>of</strong> VUS identified in cancer patients requires a functional<br />
assay to segregate clinically relevant variants which may predict response to TTD from<br />
those that are clinically inconsequential. The FACT platform can successfully provide<br />
sound rationale for considering novel oncogenic mutations as therapeutic, providing<br />
new treatment opportunities for these patients<br />
Legal entity responsible for the study: NovellusDx<br />
Funding: NovellusDx<br />
Disclosure: G. Tarcic: A full time employee <strong>of</strong> NovellusDx. Z. Barbash, O. Edelheit,<br />
B. Miron, M. Vidne: A full time employee <strong>of</strong> NovellusDx. All other authors have<br />
declared no conflicts <strong>of</strong> interest.<br />
1168P<br />
Functional characterization <strong>of</strong> mutations and their<br />
interaction using the novel functional annotation for cancer<br />
treatment (FACT) platform<br />
B. Miron 1 , N. Peled 2 , Z. Barbash 1 , O. Edelheit 1 , M. Vidne 1 , R. Sharivkin 1 ,<br />
G. Tarcic 1<br />
1 R&D, NovellusDx, Jerusalem, Israel, 2 Thoracic Cancer Unit, David<strong>of</strong>f Cancer<br />
Center, Petach Tiqwa, Israel<br />
Background: Mounting evidence indicates that histologically identical cancers are<br />
fueled by different sets <strong>of</strong> driving mutations in each patient. Most tumors possess<br />
several genetic alterations capable <strong>of</strong> stimulating growth and enabling resistance to<br />
treatment. Targeted therapy drugs (TTD) have demonstrated efficacy by inducing<br />
significant tumor regression. A percentage <strong>of</strong> patients do not respond to TTDs or<br />
develop drug resistance due to the interaction or "cross-talk" between multiple<br />
alterations providing a bypass mechanism for tumor survival. FACT is capable <strong>of</strong><br />
functionally quantifying cross-talk driven by multiple mutations, including variants <strong>of</strong><br />
unknown significance, to improve tailored therapy.<br />
Methods: FACT is a cell-based assay which utilizes fluorescent reporters to quantify<br />
activity <strong>of</strong> multiple oncogenic signaling pathways. We focused on canonical resistance<br />
mechanisms driven by cross-talk which enact resistance to TTDs. Co-transfection is<br />
used to test cross-talk between multiple mutations. Relevant TTDs were tested in FACT<br />
to predict patient response to single-drug and combination therapies.<br />
Results: FACT quantified activation in a wide range <strong>of</strong> known oncogenes altered by<br />
patients’ mutations in relevant signaling pathways. Using FACT, we were able to<br />
demonstrate cross-talk between co-existing mutations in known oncogenes<br />
(EGFR + KRAS, ERBB2 + BRAF, etc). These combinations were shown to affect<br />
resistance to certain TTDs which could be bypassed with TTD combination therapy.<br />
Conclusions: These results demonstrate the value <strong>of</strong> an assay capable <strong>of</strong> providing<br />
actionable information regarding resistance, fueled by cross-talk, as well as use <strong>of</strong><br />
combination therapy, in order to select the optimal course <strong>of</strong> treatment. These interactions,<br />
unidentified by NGS, are critical to predicting treatment response and provide another<br />
layer <strong>of</strong> critical information to physicians in the age <strong>of</strong> precision medicine.<br />
Legal entity responsible for the study: N/A<br />
Funding: NovellusDx<br />
Disclosure: B. Miron, N. Peled, Z. Barbash, O. Edelheit, M. Vidne, R. Sharivkin,<br />
G. Tarcic: NovellusDx.<br />
1169P<br />
abstracts<br />
Validation <strong>of</strong> novel diagnostic kits using the semi-dry dot-blot<br />
method for detecting metastatic lymph nodes in breast<br />
cancer; distinguishing macrometastases and<br />
micrometastases<br />
R. Otsubo 1 , H. Hirakawa 2 , M. Oikawa 3 , A. Tanaka 1 , M. Matsumoto 1 , H. Yano 1 ,<br />
N. Kinoshita 4 ,K.Abe 4 , J. Fukuoka 4 , T. Nagayasu 1<br />
1 Department <strong>of</strong> surgical oncology, Nagaski University Hospital, Nagasaki, Japan,<br />
2 Gynecology, Chiba Aiyuukai Memorial Hospital, Chiba, Japan, 3 Breast surgery,<br />
Oikawa Hospital, Fukuoka, Japan, 4 Department <strong>of</strong> pathology, Nagaski University<br />
Hospital, Nagasaki, Japan<br />
Background: The semi-dry dot-blot (SDB) method is a diagnostic procedure for<br />
detecting lymph node (LN) metastases. Metastases are confirmed by the presence <strong>of</strong><br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw380 | vi403
abstracts<br />
cytokeratin (CK) in lavage fluid <strong>of</strong> sectioned LNs that contain anti-pancytokeratin<br />
antibody, based on the theory that epithelial components such as CK are not found in<br />
normal LNs. We evaluated two novel SDB kits that use the newly developed anti-CK19<br />
antibody for diagnosing LN metastases in breast cancer.<br />
Methods: We obtained 139 LNs dissected from 79 breast cancer patients from July<br />
2013 to April 2015 at Nagasaki University Hospital, including 32 dissected axillary LNs<br />
and 107 sentinel LNs, sliced at 2-mm intervals and washed with phosphate-buffered<br />
saline. The suspended cells in the lavage fluid <strong>of</strong> sliced LNs were centrifuged and lysed<br />
to extract protein. This extracted protein was used with a low-power and a high-power<br />
kit to diagnose LN metastasis. The washed LNs were blindly diagnosed by pathologists<br />
using hematoxylin and eosin (H&E) stain. Diagnoses based on the kit were compared<br />
with their H&E counterparts.<br />
Results: Of the 139 LNs, 55 were assessed as positive and 84 as negative by permanent<br />
pathological examination with H&E. Sensitivity, specificity, and accuracy <strong>of</strong> the<br />
low-power kit for detecting LN metastases was 80.7%, 100%, and 92.2%, respectively.<br />
In 10 false-negative cases, there were eight micrometastases, producing a sensitivity <strong>of</strong><br />
95.3% for detecting macrometastases. Sensitivity, specificity, and accuracy <strong>of</strong> the<br />
high-power kit for detecting LN metastases was 90.9%, 91.7%, and 92.1%, respectively.<br />
Combining the low- and high-power kit results, sensitivity, specificity and accuracy for<br />
distinguishing macrometastases from micrometastases was 95.3%, 95.8%, and 95.7%,<br />
respectively. Diagnosis was achieved in approximately 20 min using the kits, at a cost <strong>of</strong><br />
less than 25 USD.<br />
Conclusions: The kits in our study were accurate, quick, and cost-effective in<br />
diagnosing LN metastases without the loss <strong>of</strong> LN tissue. The kits’ ability to distinguish<br />
macrometastases from micrometastases was excellent, which is important, clinically.<br />
Legal entity responsible for the study: Ryota Otsubo<br />
Funding: Nagasaki University Hospital, Department <strong>of</strong> Surgical <strong>Oncology</strong><br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1170P<br />
A novel Tc-99m and fluorescence labeled peptide:<br />
Multimodal imaging agent for targeting angiogenesis in a<br />
murine tumor model<br />
D-W. Kim 1 , S-G. Kim 2 , M.H. Kim 3 , W.H. Kim 4 , C.G. Kim 3<br />
1 Department <strong>of</strong> Nuclear Medicine and Research Unit <strong>of</strong> Molecular Imaging Agent<br />
(RUMIA), Wonkwang University Hospital, Iksan, Republic <strong>of</strong> Korea, 2 Research Unit<br />
<strong>of</strong> Molecular Imaging Agent (RUMIA), Wonkwang University Hospital, Iksan,<br />
Republic <strong>of</strong> Korea, 3 Department <strong>of</strong> Nuclear Medicine, Wonkwang University<br />
Hospital, Iksan, Republic <strong>of</strong> Korea, 4 Department <strong>of</strong> Nuclear Medicine, Chonbuk<br />
National University Medical School and Hospital, Jeon Ju, Republic <strong>of</strong> Korea<br />
Background: The serine-aspartic acid-valine (SDV) peptide binds specifically to<br />
integrin αvβ3. In the present study, we successfully developed both Tc-99m and<br />
TAMRA labeled TAMRA-GHEG-ECG-SDV peptide to target the integrin αvβ3<strong>of</strong><br />
tumor cells; furthermore, we evaluated the diagnostic performance <strong>of</strong> Tc-99m<br />
TAMRA-GHEG-ECG-SDV as a dual-modality imaging agent for tumor <strong>of</strong> the murine<br />
model.<br />
Methods: TAMRA-GHEG-ECG-SDV synthesized using Fmoc solid-phase peptide<br />
synthesis. Radiolabeling <strong>of</strong> TAMRA-GHEG-ECG-SDV with Tc-99m was done using<br />
ligand exchange methods. Labeling stability and cytotoxicity studies were performed.<br />
Gamma camera imaging, biodistribution and ex vivo imaging studies were performed<br />
in murine models with HT-1080 and HT-29 tumors. Tumor tissue slide was prepared<br />
and analyzed using confocal microscopy.<br />
Results: After radiolabeling procedures with Tc-99m, the Tc-99m<br />
TAMRA-GHEG-ECG-SDV complexes were prepared in high yield (>99%). Tc-99m<br />
TAMRA-GHEG-ECG-SDV was found to be nontoxic to HUVEC and HT-1080 cells at<br />
all concentration. On gamma camera imaging study, a substantial uptake <strong>of</strong> Tc-99m<br />
TAMRA-GHEG-ECG-SDV into HT-1080 tumor (integrin αvβ3-positive) and low<br />
uptake <strong>of</strong> Tc-99m TAMRA-GHEG-ECG-SDV in HT-29 tumor (integrin<br />
αvβ3-negative) were demonstrated. The HT-1080 tumor-to-normal muscle uptake<br />
ratio <strong>of</strong> Tc-99m TAMRA-GHEG-ECG-SDV reached 6.8 ± 2.3 at 3 h (2.8 ± 0.7, 5.3 ± 1.5<br />
and 6.8 ± 2.3 at 1, 2 and 3 h, respectively). The HT-29 tumor-to-normal muscle uptake<br />
ratios <strong>of</strong> Tc-99m TAMRA-GHEG-ECG-SDV (1.6 ± 0.4, 1.7 ± 0.4 and 2.0 ± 0.5 at 1, 2<br />
and 3 h, respectively) were significantly lower than those <strong>of</strong> HT-1080 tumor (p < 0.05).<br />
Competition study revealed that HT-1080 tumor uptake was effectively blocked by the<br />
co-injection <strong>of</strong> excess concentration SDV. Specific uptake <strong>of</strong> Tc-99m<br />
TAMRA-GHEG-ECG-SDV was confirmed by biodistribution, ex vivo imaging and<br />
confocal microscopy studies.<br />
Conclusions: Our in vivo and in vitro studies revealed substantial uptake <strong>of</strong> Tc-99m<br />
TAMRA-GHEG-ECG-SDV on the integrin αvβ3-positive tumor. Tc-99m<br />
TAMRA-GHEG-ECG-SDV could be a good candidate for dual-modality imaging<br />
agent targeting tumor angiogenesis.<br />
Legal entity responsible for the study: Wonkwang University School <strong>of</strong> Medicine<br />
Funding: This work was supported by Basic Science Research Program through the<br />
National Research Foundation <strong>of</strong> Korea (NRF) funded by the Ministry <strong>of</strong> Education<br />
(2013R1A1A2059262).<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1171P<br />
The SP142 PD-L1 IHC assay for atezolizumab (atezo) reflects<br />
pre-existing immune status in NSCLC and correlates with<br />
PD-L1 mRNA<br />
J. Williams 1 , M. Kowanetz 2 , H. Koeppen 3 , Z. Boyd 4 , E.E. Kadel, III 3 , D. Smith 3 ,<br />
M. McCleland 3 , W. Zou 5 , P.S. Hegde 6<br />
1 Diagnostic lead, Genentech, Inc, South San Francisco, CA, USA, 2 <strong>Oncology</strong><br />
Biomarker Development, Genentech, Inc, South San Francisco, Armenia,<br />
3 <strong>Oncology</strong> Biomarker Development, Genentech, Inc., South San Francisco, CA,<br />
USA, 4 Diagnostic development, Genentech, Inc, South San Francisco, CA, USA,<br />
5 <strong>Oncology</strong> Biomarker, Genentech, Inc., South San Francisco, CA, USA,<br />
6 <strong>Oncology</strong> Biomarker Department, Genentech, Inc., South San Francisco, CA,<br />
USA<br />
Background: PD-L1 expression as measured by the SP142 PD-L1 IHC assay is<br />
associated with improved efficacy with atezo in patients with NSCLC, including overall<br />
survival. In capturing PD-L1 on both tumor cells (TC) and tumor-infiltrating immune<br />
cells (IC), this assay is able to determine preexisting immune status, underscoring the<br />
predictive value <strong>of</strong> PD-L1 IHC. In this study, we further investigated intratumoral<br />
immune infiltration status by measuring T effector (Teff) gene signature and correlated<br />
PD-L1 mRNA expression with SP142 PD-L1 IHC.<br />
Methods: Using the SP142 IHC assay, procured samples from NSCLC tumors were<br />
scored according to the percent <strong>of</strong> TC expressing PD-L1 (TC0 < 1%; TC1 ≥ 1%<br />
and < 5%; TC2 ≥ 5% and < 50%; TC3 ≥ 50%). IC were scored as percentage <strong>of</strong> tumor<br />
area (IC0 < 1%; IC1 ≥ 1% and < 5%; IC2 ≥ 5% and < 10%; IC3 ≥ 10%). Four mutually<br />
exclusive groups increasing in PD-L1 expression (TC0 and IC0, TC1 or IC1, TC2 or<br />
IC2, TC3 or IC3) were designated. mRNA levels for PD-L1 and Teff signature were<br />
measured in the same NSCLC specimens using the Fluidigm platform and correlated<br />
with each <strong>of</strong> the PD-L1 IHC sub-groups.<br />
Results: In 86 NSCLC specimens, mRNA levels for PD-L1 increased incrementally<br />
with higher PD-L1 IHC status, from 0 median expression for TC0 and IC0 tumors to<br />
3.14 median expression for TC3 or IC3 tumors. A similar trend was seen for the Teff<br />
signature, with values increasing from 0 to 1.65 median expression with increasing IHC<br />
cut<strong>of</strong>fs (Table).<br />
Conclusions: Results from the SP142 PD-L1 IHC assay associates with PD-L1 and Teff<br />
mRNA transcripts, reflecting pre-existing immunity associated with adaptive PD-L1<br />
expression on IC as well as intrinsic PD-L1 expression on TC in NSCLC, thus<br />
providing an independent orthogonal correlation <strong>of</strong> IHC to gene expression. The value<br />
<strong>of</strong> mRNA gene expression as a predictive marker <strong>of</strong> efficacy for atezo in NSCLC is<br />
being studied in ongoing randomized trials <strong>of</strong> atezo.<br />
Table: 1171P PD-L1 IHC vs PD-L1 mRNA and T effector gene signature<br />
PD-L1 IHC PD-L1 mRNA T Effector a<br />
n Median b 95% CI n Median b 95% CI<br />
expression<br />
expression<br />
TC0 and IC0 46 0 −0.22, 0.36 46 0 −0.39, 0.16<br />
TC1 or IC1 22 0.89 0.53, 1.66 22 0.73 0.25, 0.95<br />
TC2 or IC2 11 2.66 2.49, 2.85 11 1.53 0.55, 1.57<br />
TC3 or IC3 7 3.14 1.4, 4.29 7 1.65 0.46, 1.95<br />
a b<br />
Includes CD8A, GZMA, GZMB, EOMES, CXCL9, CXCL10, TBX21.<br />
Median expressions are log scale expression (−ΔCT) relative to the median <strong>of</strong><br />
TC0 and IC0 group. Larger values indicate higher expression.<br />
Legal entity responsible for the study: F. H<strong>of</strong>fmann-La Roche, Ltd.<br />
Funding: F. H<strong>of</strong>fmann-La Roche, Ltd.<br />
Disclosure: J. Williams, M. Kowanetz, H. Koeppen, Z. Boyd, E.E. Kadel III, D. Smith,<br />
M. McCleland, W. Zou, P.S. Hegde: Employee <strong>of</strong> Genentech.<br />
1172P<br />
NSCLC multiplex IHC diagnosis <strong>of</strong> small biopsies<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
K. Holmstrøm 1 , T. Møller 1 , H. Stender 2 , M. Kristensson 3 , B.S. Nielsen 1 ,<br />
E. Santoni-Rugiu 4<br />
1 Biomedical Technologies, Bioneer, Hørsholm, Denmark, 2 Clinical Consultancy,<br />
Stender Diagnostics, Gent<strong>of</strong>te, Denmark, 3 Technical Sales, Visiopharm,<br />
Hørsholm, Denmark, 4 Dept. <strong>of</strong> Pathology, Rigshospitalet, Copenhagen University<br />
Hospital, Copenhagen, Denmark<br />
Background: Non-small cell lung cancer (NSCLC) is the most common type <strong>of</strong> lung<br />
cancer and in 75% <strong>of</strong> cases is inoperable and diagnosed on small biopsies. The<br />
histological subtyping <strong>of</strong> NSCLC, especially the differentiation between<br />
adenocarcinomas (AC) and squamous cell carcinomas (SCC) is important for therapy.<br />
Histopathological evaluation <strong>of</strong> small samples to discriminate between AC and SCC<br />
subtypes is <strong>of</strong>ten challenging because <strong>of</strong> poor morphology and insufficient size <strong>of</strong> the<br />
biopsies. Thus, confirmatory immunostainings to support the diagnosis are necessary,<br />
while the limited material requires prioritizing the diagnostic and predictive<br />
vi404 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
biomarkers to be tested. Multiple immunostainings in NSCLC help discriminating AC<br />
from SCC including cytokeratin 5 and 7 (CK5 and CK7) and the transcriptional factors<br />
TTF1 and P40, and in addition ALK-staining is required for selecting patients to<br />
targeted therapy. To avoid prioritizing the biomarkers and save tissue for molecular<br />
testing we have developed a multiplexing immunochemical diagnostic analysis that<br />
allows the detection <strong>of</strong> the 5 biomarkers on a single tissue section using established,<br />
clinically used primary antibodies.<br />
Methods: Surgical samples and needle biopsies from NSCLC patients <strong>of</strong> AC and SCC<br />
subtypes were obtained from Rigshospitalet. Unmodified primary antibodies for the<br />
detection <strong>of</strong> CK5, CK7, TTF1, P40 and ALK were used.<br />
Results: Multiplex immunohistochemical staining <strong>of</strong> tissue sections with primary<br />
antibodies <strong>of</strong> the same origin and isotype required designing a sequential assay format<br />
that allows each biomarker assay to be performed individually followed by imaging the<br />
result and subsequently ‘deleting’ the signal before moving on with the next biomarker<br />
assay. We show that this can be done on one single tissue section, by providing<br />
evidence <strong>of</strong> the efficiency <strong>of</strong> eluting antibodies in between assays, and the ability to<br />
combine and superimpose individual images <strong>of</strong> biomarker assays at the end <strong>of</strong> the<br />
sequential analysis.<br />
Conclusions: We have developed a immun<strong>of</strong>luorescent diagnostic assay that can detect<br />
up to five different biomarkers relevant for NSCLC-diagnostics applicable to both<br />
surgical and bioptic samples. The assay format is independent <strong>of</strong> the origin and isotype<br />
<strong>of</strong> primary antibodies.<br />
Legal entity responsible for the study: Bioneer<br />
Funding: Bioneer<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1173P Fully automated and sensitive detection <strong>of</strong> EGFR exon 18, 19,<br />
20 and 21 mutational status in less than 2.5 hours from a<br />
single FFPE slice<br />
M. Reijans 1 , G. Vandercruyssen 1 , I. Keuleers 1 , C. Vandesteene 1 ,<br />
I. Vandenbroucke 2 , G. Maertens 1 , E. Sablon 1<br />
1 Biocartis, Mechelen, Belgium, 2 Multiplicom, Niel, Belgium<br />
Background: Current testing for mutations, insertions and deletions in EGFR exons<br />
18, 19, 20, and 21 is still laborious and <strong>of</strong>ten requires >5 working days and multiple<br />
slices <strong>of</strong> formalin-fixed paraffin-embedded (FFPE) tissue. Lack <strong>of</strong> time or tissue for<br />
molecular testing are among the main reasons why patients are <strong>of</strong>ten deprived <strong>of</strong> the<br />
proper targeted therapies.<br />
Methods: Idylla is a fully integrated and automated molecular diagnostics platform<br />
that combines speed and ease <strong>of</strong> use with high sensitivity and high multiplexing<br />
capabilities. Moreover, it overcomes the current problem <strong>of</strong> lack <strong>of</strong> tissue, and the<br />
time-consuming step <strong>of</strong> processing FFPE tissue samples. After insertion <strong>of</strong> a single<br />
FFPE slice into the cartridge, the complete process <strong>of</strong> sample liquefaction, nucleic acid<br />
preparation, real-time PCR, data analysis, and reporting is fully automated and takes<br />
less than 2.5 hours. The Idylla EGFR prototype assay allows the sensitive detection <strong>of</strong><br />
53 mutations including insertions and deletions in exons 18, 19, 20 and 21.<br />
Results: Sensitivity was assessed for 20 mutations using cell line derived materials<br />
embedded in paraffin containing defined ratios <strong>of</strong> mutants and dilutions there<strong>of</strong> in a<br />
WT background. Allelic frequencies ranging from 1 to 50% were tested in triplicate and<br />
showed analytical sensitivities <strong>of</strong> ≤1% up to ≤5% for all targets. The Idylla EGFR<br />
prototype assay was also tested with single FFPE slices from 141 clinical NSCLC<br />
samples with known mutations as analyzed by NGS and digital droplet PCR. It<br />
demonstrated excellent clinical specificity and sensitivity with a negative percentage<br />
agreement <strong>of</strong> 100% and an overall percentage agreement <strong>of</strong> 96.3%.<br />
Conclusions: The new and fully automated Idylla EGFR prototype assay demonstrates<br />
excellent specificity, high sensitivity, ease <strong>of</strong> use combined with a fast turnaround time<br />
for complete EGFR testing on FFPE samples from NSCLC patients.<br />
Legal entity responsible for the study: N/A<br />
Funding: Biocartis<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1174P<br />
Detection <strong>of</strong> NRAS, KRAS and BRAF mutations in FFPE<br />
derived DNA with a novel targeted resequencing-based<br />
diagnostics assay<br />
C. Marques, K. Bettens, D. Goossens, L. Heyrman, C. Heusdens, S. Kupers,<br />
S. Berwouts, D. Van Barel, A. Rotthier, J. Del-Favero<br />
R&D, Multiplicom, Antwerp, Belgium<br />
Background: Identification <strong>of</strong> cancer-associated mutations has become standard care<br />
for cancer treatment. Somatic mutations in NRAS, KRAS and BRAF genes are<br />
important to decide the treatment options for patients with cancer. Mutations in<br />
NRAS, KRAS or BRAF help to determine the treatment options for patients when<br />
EGFR inhibitor or BRAF inhibitor treatment is considered. The novel SOMATIC 1<br />
MASTR TM Plus Dx® assay has been developed to allow analysis <strong>of</strong> the hotspot<br />
mutations or <strong>of</strong> the full coding region <strong>of</strong> KRAS, NRAS and BRAF genes in<br />
combination with Next Generation Sequencing (NGS).<br />
Methods: To assess the performance characteristics <strong>of</strong> the SOMATIC 1 MASTR TM<br />
Plus Dx® assay, a multicenter study was performed. The performance <strong>of</strong> SOMATIC 1<br />
MASTR Plus Dx to detect single nucleotide variants (SNV) and small insertions and/<br />
or deletions (indels) in the NRAS, KRAS and BRAF genes at a variant allele frequency<br />
(VAF) as 5% in the entire coding region and for specific hotspot mutations was<br />
evaluated. The sample population comprised 252 formalin-fixed, paraffin-embedded<br />
(FFPE) clinical samples derived from a variety <strong>of</strong> different cancer types and 4<br />
pr<strong>of</strong>iciency samples (Tru-Q Reference Standards, Horizon Discovery). Amplicon<br />
libraries were analysed using Illumina MiSeq platform. Data analysis was performed<br />
with the SeqNext module (JSI Medical Systems) and the Sophia DDM platform<br />
(ILL1MR1S5_somatic1_v2).<br />
Results: SOMATIC 1 MASTR TM Plus Dx® showed amplification uniformity <strong>of</strong> 97.8%<br />
(% <strong>of</strong> amplicons covered at 0.2x <strong>of</strong> the mean coverage) and a target specificity <strong>of</strong> 99.1%.<br />
The overall limit <strong>of</strong> detection (LOD) <strong>of</strong> the assay was determined as 2% VAF, and<br />
showed to be as low as 1% for hotspot mutations. Diagnostically, the assay showed<br />
99.96% (95 % CI ≥ 99.90 %) accuracy, 99.96% (95 % CI ≥ 99.90 %) specificity and<br />
100% (95 % CI ≥ 98.54 %) sensitivity. Furthermore, Somatic 1 MASTR TM Plus Dx®<br />
assay showed to be 99.99% (95 % CI ≥ 99.97 %) repeatable and 99.96% (95 %<br />
CI ≥ 99.91%) reproducible.<br />
Conclusions: We have established a targeted and cost-effective NGS assay for the<br />
detection <strong>of</strong> KRAS, NRAS, and BRAF somatic mutations in clinical FFPE samples that<br />
can be routinely incorporated into clinical practice.<br />
Legal entity responsible for the study: Multiplicom<br />
Funding: Multiplicom<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1175P<br />
abstracts<br />
Ultra-rapid, sensitive, and fully automated extended RAS<br />
testing for metastatic colorectal cancer – evaluation <strong>of</strong> an<br />
NRAS/BRAF/EGFR492 module<br />
E. Vercauteren 1 , E. Bellon 1 , K. Vermeiren 1 , F. De Freitas 1 , E. De Haes 1 ,S.Van<br />
Gestel 1 , S. Murray 2 , M. Grauslund 3 , L. Melchior 3 ,N.D’Haene 4 , M. Le Mercier 4 ,<br />
B. Bellosillo 5 , C. Montagut 6 , M. Van Brussel 1 , E. Sablon 1 , G. Maertens 1<br />
1 Biocartis, Mechelen, Belgium, 2 Molecular <strong>Oncology</strong>, BioPath Innovations,<br />
Athens, Greece, 3 Pathology, Rigshospitalet, Copenhagen University Hospital,<br />
Copenhagen, Denmark, 4 Anatomic Pathology Laboratory, Erasme University<br />
Hospital-(Universite Libre de Bruxelles), Brussels, Belgium, 5 Pathology<br />
Department, University Hospital del Mar, Barcelona, Spain, 6 Medical <strong>Oncology</strong>,<br />
University Hospital del Mar, Barcelona, Spain<br />
Background: Extended RAS testing in codons 12, 13, 59, 61, 117, and 146 in exons 2,<br />
3, and 4 <strong>of</strong> the KRAS and NRAS genes is now mandatory before anti-EGFR therapy in<br />
metastatic colorectal cancer (mCRC) patients. BRAF and EGFR ectodomain mutation<br />
status have been shown to play a crucial role in predicting non-responsiveness in<br />
mCRC patients receiving anti-EGFR therapy. Current methods for testing <strong>of</strong> extended<br />
RAS, BRAF and the new EGFR ectodomain mutations are laborious and <strong>of</strong>ten require<br />
5-20 working days.<br />
Methods: The Idylla platform (Biocartis, Mechelen, Belgium) is a CE marked, fully<br />
automated sample-to-result, real-time PCR molecular diagnostics system. The Idylla<br />
NRAS-BRAF-EGFRS492R Mutation Assay (for Research Use Only) is an assay for<br />
formalin-fixed paraffin-embedded (FFPE) tissue samples from mCRC patients for the<br />
analysis <strong>of</strong> 18 NRAS (codons 12, 13, 59, 61, 117, and 146 in exons 2, 3, and 4), 2 BRAF<br />
(codon 600), and 2 EGFR (codon 492) mutations. The Idylla<br />
NRAS-BRAF-EGFRS492R Mutation Assay was compared with routine sequencing<br />
technologies at five centers (BioPath Innovations, Copenhagen University Hospital,<br />
Hôpital Erasme, Hospital del Mar, Biocartis). In addition, LOD was established using<br />
cell lines embedded in paraffin containing defined ratios <strong>of</strong> mutants and dilutions<br />
there<strong>of</strong> in an FFPE WT background.<br />
Results: Positive predictive agreement was 97.2% (n = 106), 100% (n = 40) and 100%<br />
(n = 1) and negative predictive agreement was 99.4% (n = 348), 99.5% (n = 412) and<br />
100% (n = 444) for NRAS, BRAF and EGFR, respectively. One BRAF V600E sample<br />
detected by Idylla only was confirmed with digital droplet PCR. No cross-reactivity was<br />
observed in KRAS positive samples indicating the high specificity <strong>of</strong> the assay towards<br />
NRAS mutations. Fourteen mutations showed an LOD <strong>of</strong> ≤1%, 10 mutations <strong>of</strong> ≤5%<br />
and one mutation showed an LOD <strong>of</strong> 6%.<br />
Conclusions: Given its high sensitivity and specificity, the Idylla<br />
NRAS-BRAF-EGFRS492R Mutation Assay is ideally suited for rapid detection <strong>of</strong><br />
NRAS, BRAF and EGFR mutations. Together with the Idylla KRAS Mutation Test<br />
(CE-IVD), sample-to-result extended RAS testing on 39 mutations can now be<br />
performed in only 2 hours.<br />
Legal entity responsible for the study: Biocartis<br />
Funding: Biocartis<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw380 | vi405
abstracts<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
1176P<br />
Hybrid-capture based sequencing assays to detect novel<br />
alterations in BRAF from tissue and liquid biopsies<br />
1177TiP<br />
Early non-invasive detection <strong>of</strong> gastric cancer with plasma<br />
pepsinogens in Croatian patients<br />
J. Müller 1 , S. Lakis 1 , E. Mariotti 1 , P. Schneider 1 , C. Glöckner 1 , F. Leenders 1 ,<br />
A. Hube 1 , G. Gullo 2 ,J.Crown 2 , F. Griesinger 3 , J. Heuckmann 1 , L. Heukamp 1 ,<br />
R. Menon 1<br />
1 Diagnostics, NEO New <strong>Oncology</strong>, Cologne, Germany, 2 Medical <strong>Oncology</strong>, St<br />
Vincents University Hospital, Dublin, Ireland, 3 Department <strong>of</strong> <strong>Oncology</strong> and<br />
Hematology, Pius Hospital Oldenburg, University <strong>of</strong> Oldenburg, Oldenburg,<br />
Germany<br />
Background: In recent years advances in translational cancer research have led to the<br />
characterization <strong>of</strong> oncogenic drivers and to the development <strong>of</strong> their respective<br />
targeted inhibitors. Melanomas harbouring the activating BRAF V600E mutation, for<br />
example, exhibit high sensitivity towards site-directed inhibitors, translating into a<br />
beneficial clinical response. In contrast to standard PCR or FISH- based diagnostics,<br />
limited to detect specific, well-established mutations or translocations, NEO is a<br />
comprehensive molecular diagnostics platform, capable <strong>of</strong> detecting genomic<br />
alterations including point mutations, small insertions and deletions (InDels), copy<br />
number alterations and translocations from both, liquid biopsy (NEOliquid) and<br />
tumor tissue (NEOplus) samples.<br />
Methods: NEO New <strong>Oncology</strong> is able to detect clinically relevant genomic alterations<br />
from clinical specimen with high sensitivity and specificity using a hybrid-capture<br />
based NGS technology. NEOliquid is specifically designed for detection genomic<br />
alterations from cell-free DNA <strong>of</strong> liquid biopsies and covers a panel <strong>of</strong> more than 30<br />
cancer-related genes. NEOplus is applied to FFPE tumor tissue and can detect somatic<br />
alterations in more than 90 clinically relevant cancer genes.<br />
Results: Using the NEO platform we were able to detect previously unidentified<br />
alterations in BRAF from tissue specimen and liquid biopsies, which would have<br />
remained undetected by current routine diagnostics. A likely activating in-frame<br />
kinase-domain deletion was detected in a liquid biopsy from a kidney cancer, a tumor<br />
entity not commonly linked to alterations in BRAF. Additionally, we detected novel<br />
genomic rearrangements involving the BRAF gene locus in a lung cancer and strikingly<br />
in a pre-diagnosed BRAF(V600E)-negative melanoma sample. Patients harbouring<br />
these atypical BRAF alterations might potentially benefit from treatment with<br />
pan-BRAF or MEK inhibitors.<br />
Conclusions: In addition to the reliable and comprehensive detection <strong>of</strong> known<br />
hot-spot alterations routinely tested in cancer diagnostics, the NEO platform is efficient<br />
in detecting novel and potentially targetable alterations even in already established,<br />
well-defined oncogenes.<br />
Legal entity responsible for the study: NEO New <strong>Oncology</strong><br />
Funding: NEO New <strong>Oncology</strong><br />
Disclosure: J. Crown: member <strong>of</strong> the aboard <strong>of</strong> NEO New <strong>Oncology</strong>. All other authors<br />
have declared no conflicts <strong>of</strong> interest.<br />
D. Trivanovic 1 , L. Honovic 1 , J. Vlasic 1 , I. Hrstic 2<br />
1 <strong>Oncology</strong>, General Hospital Pula, Pula, Croatia, 2 Gastroenterology, General<br />
Hospital Pula, Pula, Croatia<br />
Background: Gastric cancer (GC) is the eight most common cancer and fifth leading<br />
cause <strong>of</strong> cancer deaths in Croatia. GC <strong>of</strong> the intestinal type is usually preceded by a<br />
chronic atrophic gastritis (CAG) which is a precancerous change in the stomach. Loss<br />
<strong>of</strong> chief cells leads to lower pepsinogens I (PGI) levels and PGI/PGII ratio in the<br />
peripheral blood. The potential usefulness <strong>of</strong> serum PG tests has been evaluated in<br />
many countries but this evidence has not resulted in generalized use in GC screening<br />
and prevention. Infection with Helicobacter pylori and its associated (CAG) is a strong<br />
risk factor for the development <strong>of</strong> both atrophic gastritis and gastric cancer. Screening<br />
programs have led to an improvement <strong>of</strong> overall 5-year survival rate for gastric cancer<br />
in Japan and PG method was suggested to reduce mortality from gastric cancer. The<br />
primary objective <strong>of</strong> the study is to assess if the addition <strong>of</strong> serum reagents for GC<br />
detection will improve detection <strong>of</strong> suspicious GC. The secondary objectives <strong>of</strong> the<br />
study are to evaluate serum GC reagents in Croatian population, evaluate sensitivity<br />
and specificity <strong>of</strong> reagents, and to determine if these reagents can be part <strong>of</strong> routine<br />
diagnostic procedures for gastric cancer diagnosis.<br />
Trial design: This single-center trial, will randomize 120 patients suspected to have<br />
GC. Inclusion criteria for the study are: signed informed consent, life expectancy > 12<br />
weeks, and exclusion criteria will be: previous oncological treatments for any<br />
malignancy, current usage <strong>of</strong> IPP or NSAIDs medication, poor ECOG performance<br />
status ≥3, known history <strong>of</strong> H. pylori eradication treatment or gastric surgery. Patients<br />
will be divided in 1:1:1 ratio between groups. Experimental group <strong>of</strong> patients will be<br />
patients already in diagnostic procedure for possible GC, Confirmative group will be<br />
patients who already have patohistologicaly confirmed gastric adenocarcinoma and<br />
Control group will be patients with endoscopically and clinically excluded GC disease.<br />
We will use cut <strong>of</strong>f points to evaluate gastric cancer risk: PGI ≤ 70 and PGI/II<br />
ratio ≤ 3.0. Associations will be analyzed using conditional logistic regression models<br />
to estimate adjusted OR and 95% CI for the association between GC and plasma<br />
concentrations <strong>of</strong> PG, or th PG1:2 ratio.<br />
Clinical trial identification: EudraCT number 2016-000519-34 has been issued for<br />
your Sponsor’s Protocol Code Number 1068.<br />
Legal entity responsible for the study: General Hospital Pula<br />
Funding: General Hospital Pula<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
vi406 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong> 27 (Supplement 6): vi407–vi410, 2016<br />
doi:10.1093/annonc/mdw381<br />
NSCLC, early stage<br />
1178O<br />
Multi-centre randomized controlled study comparing<br />
adjuvant vs neo-adjuvant chemotherapy with docetaxel plus<br />
carboplatin in resectable stage IB to IIIA NSCLC: final results<br />
<strong>of</strong> CSLC0501<br />
Y-L. Wu 1 , X-N. Yang 1 , W. Zhong 1 , X. Ben 1 , G-B. Qiao 2 , Q. Wang 3 , C. Wang 4 ,<br />
H-H. Luo 5 , Z. Wang 6 , H-H. Yan 1<br />
1 Guangdong Lung Cancer Institute, Guangdong General Hospital & Guangdong<br />
Academy <strong>of</strong> Medical Sciences, Guangzhou, China, 2 Thoracic Surgery, General<br />
Hospital <strong>of</strong> Guangzhou Military Command, Guangzhou, China, 3 Thoracic Surgery,<br />
Zhongshan Hospital, Fudan University, Shanghai, China, 4 Thoracic Surgery,<br />
Tianjin Medical University General Hospital, Tianjin, China, 5 Thoracic Surgery, 1st<br />
Affiliated Hospital <strong>of</strong> Sun Yat-sen University, Guangzhou, China, 6 Thoracic Surgery,<br />
Shenzhen People’s Hospital, Jinan University, Shenzhen, China<br />
through Cox regression in terms <strong>of</strong> survival for all causes, all cancers, lung cancer and<br />
pleural mesothelioma. Multivariate models were adjusted for smoking habits, age at<br />
start <strong>of</strong> follow-up, level <strong>of</strong> exposure to asbestos and Charlson-Quan comorbidity index.<br />
External comparison was possible by estimating the standardized mortality rate ratio<br />
(SMR) using Friuli Venezia Giulia regional standard rates (SMR_FVG) and Italian<br />
standard rates (SMR_ITA).<br />
Results: Among the total population, 926 men were allocated the to LDCT cohort<br />
(ATOM002-P) and 1507 to standard follow-up (ATOM002-NP). Lung cancer crude<br />
mortality was 99.4 per 100,000 person-year in ATOM002-P (Obs = 8) compared to<br />
430.4 per 100,000 person-year in ATOM002-NP (Obs = 50). Multivariate analysis<br />
highlighted a significant mortality reduction in the ATOM002-P cohort (HR = 0.41<br />
IC95% 0.17-0.96). Even though it was observed a reduction <strong>of</strong> the all-causes mortality<br />
(HR = 0.61 IC95% 0.44-0.84), all cancers mortality and pleural mesothelioma mortality<br />
were not significantly affected (HR = 0.97 IC95% 0.62-1.50; HR = 0.86 IC95%<br />
0.31-2.41, respectively). Notably, a reduction in mortality <strong>of</strong> the ATOM002-P cohort<br />
was also observed in respect to the general population (SMR_FVG = 0.55 IC95%<br />
0.24-1.09, SMR_ITA = 0.51 IC95% 0.22-1.01).<br />
Conclusions: In our study we found a reduction in the risk <strong>of</strong> death from lung cancer,<br />
compared with national figures but no reduction in risk <strong>of</strong> death from pleural<br />
mesothelioma. These data could reasonably be considered within public surveillance<br />
programs for selected, high risk, population.<br />
Legal entity responsible for the study: University Hospital <strong>of</strong> Udine<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1180P<br />
Elevated fraction <strong>of</strong> CTLA-4(+) and PD-1(+) T cells in<br />
peripheral blood with stimulation <strong>of</strong> Th1, Th2 and Th17 type<br />
immune response after stereotactic radiotherapy for early<br />
lung cancer – a prospective study<br />
J. Rutkowski 1 ,T.Sĺebioda2 , R. Zaucha 1<br />
1 Department <strong>of</strong> Clinical <strong>Oncology</strong> and Radiotherapy, Medical University <strong>of</strong><br />
Gdansk, Gdansk, Poland, 2 Department <strong>of</strong> Histology, Medical University <strong>of</strong><br />
Gdansk, Gdansk, Poland<br />
1179PD<br />
Low dose CT scan screening versus empiric surveillance in<br />
asbestos exposed subjects: Update <strong>of</strong> ATOM 002 study<br />
G. Fasola 1 , A. Follador 1 , F. Barbiero 2 , V. Rosolen 2 , O. Belvedere 3 , F. Grossi 4 ,<br />
C. Rossetto 1 , S. Rizzato 1 , M. Giavarra 1 , L. Gerratana 1 , F. Barbone 2<br />
1 Department <strong>of</strong> <strong>Oncology</strong>, University Hospital <strong>of</strong> Udine, Udine, Italy, 2 Department<br />
<strong>of</strong> <strong>Oncology</strong>, University <strong>of</strong> Udine, Udine, Italy, 3 Department <strong>of</strong> <strong>Oncology</strong>, York<br />
Teaching Hospital, York, UK, 4 Lung Cancer Unit, IRCCS AOU San Martino -<br />
IST-Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy<br />
Background: Low dose CT scan screening (LDCT) has been proven effective in<br />
detecting early stage lung cancer in asbestos exposed workers, but there is no evidence<br />
based indication concerning the follow up <strong>of</strong> these subjects. Aim <strong>of</strong> this study is to<br />
evaluate whether LDCT screening, compared with empiric health surveillance<br />
program, could be effective in reducing mortality for lung cancer and/or malignant<br />
pleural mesothelioma in asbestos-exposed former workers.<br />
Methods: The ATOM002 prospective non randomized study enrolled a cohort <strong>of</strong> 2433<br />
occupationally asbestos-exposed men. The prognostic role <strong>of</strong> LDCT was investigated<br />
Background: Stereotactic ablative radiotherapy (SABR) has been succesfully used in<br />
patients with medically inoperable non-small cell lung cancer (NSCLC). High physical<br />
doses <strong>of</strong> radiotherapy translate into extremely high biological doses more effective in<br />
tumor control. Other mechanisms including immune are also postulated.The aim <strong>of</strong><br />
our study was to prospectively assess the effect <strong>of</strong> high dose ionizing radiation <strong>of</strong> the<br />
lung tumor on changes in the expression <strong>of</strong> peripheral T cell activation markers (AM)<br />
– CTLA-4, PD-1 and transcription factors (TF) associated with Th1, Th2, Th17 and<br />
regulatory T cell subpopulations (T-bet, GATA-3, ROR-yt, Fox-P3) and secretion <strong>of</strong><br />
characteristic cytokines.<br />
Methods: In patients with previously untreated NSCLC in stage T1-2aN0M0 receiving<br />
SABR peripheral blood mononuclear cells (PBMC) and blood serum was drawn three<br />
times - before 1 fraction (D1), two weeks (D2) and 3 months (D3) after radiotherapy.<br />
Expression level <strong>of</strong> selected AM, TF and cytokines was measured by flow cytometry.<br />
Results: From September 2013 to March 2016 we enrolled 94 patients aged 53 to 87<br />
years (median 74 years). All patients underwent SABR in accordance with local<br />
standards. The D1, D2 and D3 control points were achieved by 92, 92 and 79 patients,<br />
respectively. A significant increase in the fraction <strong>of</strong> CD4+ and CD8+ T-cells with<br />
expression <strong>of</strong> PD-1 and CTLA-4 AM was found in all patients at D2 and D3 control<br />
points. Additionally increased level <strong>of</strong> Th1, Th2 and Th17 type <strong>of</strong> CD4+ T cells (T-bet,<br />
GATA-3, ROR-yt positive, respectively), and a reduction <strong>of</strong> T-reg - Fox-P3 (+) fraction<br />
with simultaneous elevation <strong>of</strong> Th1 (Il12, INF-y), Th2 (Il-4, Il-13) and Th17 (Il17)<br />
cytokines was also detected at D2 and D3 control points.<br />
Conclusions: In patients with early NSCLC, enhanced expression <strong>of</strong> AM after SABR<br />
suggests the activation <strong>of</strong> CD4+ and CD8+ T-cells. These changes correlate with<br />
stimulation <strong>of</strong> Th1, Th2 and Th17 type systemic immune response and reduction <strong>of</strong><br />
the number <strong>of</strong> T-reg cells. The project was financed by the Polish National Science<br />
Centre, Grant no UMO-2012/07/B/NZ5/00587.<br />
Legal entity responsible for the study: Medical University <strong>of</strong> Gdansk<br />
Funding: Polish National Science Centre, Grant no UMO-2012/07/B/NZ5/00587.<br />
Disclosure: R. Zaucha: Travel grants from Amgen, Roche, MSD, BMS. Educational<br />
grants from Roche, MSD, Nutricia. All above were not connected to presented reserch.<br />
All other authors have declared no conflicts <strong>of</strong> interest.<br />
abstracts<br />
© European Society for Medical <strong>Oncology</strong> 2016. Published by Oxford University Press on behalf <strong>of</strong> the European Society for Medical <strong>Oncology</strong>.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com.
abstracts<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
1181P Clinicopathological analysis <strong>of</strong> programmed death-ligand 1<br />
(PD-L1) expression on tumor cells (TC) and tumor-infiltrating<br />
immune cells (IC) in surgically resected non-small cell lung<br />
cancer (NSCLC) patients (pts)<br />
1182P<br />
RICTOR/PI3K/mTOR as a clinically relevant driver <strong>of</strong> poor<br />
prognosis in squamous cell lung carcinoma (SqCLC):<br />
Preliminary results <strong>of</strong> prognostic outliers according to a<br />
validated clinicopathological model<br />
K. Saruwatari 1 , G. Ishii 2 , S. Nomura 3 , K. Kirita 1 , S. Umemura 1 , S. Matsumoto 1 ,<br />
K. Yoh 1 , S. Niho 1 , H. Ohmatsu 1 , M. Tsuboi 4 , M. Kowanetz 5 , M. Sakai 6 ,<br />
J. Itabashi 6 , Y. Kamihara 6 , R. Shiokawa 7 , A. Morioka 8 , M. Ueda 9 , K. Goto 1<br />
1 Department <strong>of</strong> Thoracic <strong>Oncology</strong>, National Cancer Center Hospital East,<br />
Kashiwa, Japan, 2 Division <strong>of</strong> Pathology, Exploratory <strong>Oncology</strong> Research & Clinical<br />
Trial Center, Kashiwa, Japan, 3 Biostatistics Division, Center for Research<br />
Administration and Support, National Cancer Center Hospital East, Kashiwa,<br />
Japan, 4 Department <strong>of</strong> Thoracic Surgery, National Cancer Center Hospital East,<br />
Kashiwa, Japan, 5 <strong>Oncology</strong> Biomarker Development, Genentech, Inc, South<br />
San Francisco, Armenia, 6 <strong>Oncology</strong> Lifecycle Management Dept., Chugai<br />
Pharmaceutical Co., Ltd., Tokyo, Japan, 7 Translational Clinical Research Science<br />
& Strategy Dept., Chugai Pharmaceutical Co., Ltd., Tokyo, Japan, 8 Medical<br />
Science Dept., Chugai Pharmaceutical Co., Ltd., Tokyo, Japan, 9 Clinical Science<br />
& Strategy Dept., Chugai Pharmaceutical Co., Ltd., Tokyo, Japan<br />
Background: Advanced NSCLC with PD-L1 expression on TC and IC has shown<br />
higher sensitivity to the PD-L1 inhibitor atezolizumab. This study is to examine the<br />
association between PD-L1 expression on TC and IC and clinicopathological<br />
characteristics, EGFR/ALK driver oncogenes status and prognosis in surgically resected<br />
NSCLC.<br />
Methods: We analyzed 514 NSCLC pts who underwent surgical resection from<br />
November 2005 to March 2011 at the National Cancer Center Hospital East. The<br />
PD-L1 expression on TC (4 levels <strong>of</strong> expression: TC0-3) and IC (IC0-3) was evaluated<br />
using the Ventana PD-L1 (SP142) antibody IHC assay as recently described (Lancet.<br />
2016; 387: 1837-46). TC1-3 and IC1-3 were defined as positive, respectively.<br />
Results: Median age at tumor resection was 68 (range 30-93) years; male/female 63/<br />
37%; smoker/non-smoker 69/31%; squamous cell carcinoma (Sq)/non-Sq 13/87%;<br />
EGFR mutations (mut) +/- 26/74%; ALK fusion +/- 3/97%; p-stage I/II/III/IV 60/19/<br />
19/2%. PD-L1 expression was as follows; TC0/1/2/3: 81/7/9/4%, IC0/1/2/3: 38/34/22/<br />
6%. PD-L1 expression on TC was observed in 19% <strong>of</strong> tumors, and on IC in 62% <strong>of</strong><br />
specimens. PD-L1 expression on TC or IC (i.e. TC1-3 or IC1-3) was observed in 63%.<br />
Smoking and p-stage II-IV were associated with PD-L1 expression on both TC and IC<br />
(P < 0.05), while EGFR mut (-) and Sq were characterized by higher expression on TC<br />
and IC, respectively (P < 0.05). Overall survival (OS) in NSCLC pts with PD-L1<br />
expression on TC and IC was significantly shorter by univariate analysis than those<br />
without PD-L1 expression, respectively (5-year survival rate TC; 60.0% vs. 73.1%,<br />
P < 0.05, IC; 66.7% vs. 76.9%, P < 0.05). However multivariate analysis for survival<br />
including age, histology, p-stage, and PD-L1 expression revealed that age ≥ 70years,<br />
male and advanced p-stage were negative independent prognostic factors while PD-L1<br />
expression on TC and IC was not.<br />
Conclusions: Smoking and advanced p-stage were associated with PD-L1 expression<br />
on both TC and IC while Sq was associated with PD-L1 expression on IC and EGFR<br />
mut (-) on TC. PD-L1 expression on TC and IC was not independent prognostic<br />
factor.<br />
Legal entity responsible for the study: National Cancer Center Hospital East<br />
Funding: Chugai Pharmaceutical Co., Ltd.<br />
Disclosure: S. Nomura: Mr. Nomura received personal fees from Japan Breast Cancer<br />
Research Group (JBCRG), and grants from Japan Agency for Medical Research and<br />
Development (AMED), outside the submitted work. S. Matsumoto: I reports grants<br />
from Chugai, MSD.,Astra Zeneka, Taiho,Ono, Eisai, Pfizer, Kyowa Hakko Kirin, Eli<br />
Lilly, Takeda, Novartis, DAIICHI SANKYO, Astellas, and Amgen Astellas. BioPharma,<br />
and personal fees from Novartis Pharma K.K., outside the submitted work. K. Yoh:<br />
Honoraria: Chugai.S. Niho: I received grants from Pfizer, Eli Lilly, and AstraZeneca,<br />
and honoraria from AstraZeneca, Eli Lilly, Taiho, Boehringer Ingelheim, and<br />
Chugai. M. Tsuboi: Honoraria: AstraZeneca,Eli Lilly Japan,Boehringer-Ingelheim<br />
Japan,Daiichi-Sankyo,Chugai, Taiho,Johnson & Johnson Japan,Covidien Japan,Teijin,<br />
CSL Behring Japan. Research grants outside the submitted work:<br />
AstraZeneca. M. Kowanetz: Employee <strong>of</strong> Genentech + Genentech stock + Genentech<br />
patents, or other IP. Patent biomarkers and methods <strong>of</strong> treating PD-1 AND PD-L1<br />
related conditions pending. M. Sakai, J. Itabashi, R. Shiokawa, A. Morioka, M. Ueda:<br />
Employee <strong>of</strong> Chugai Pharmaceutical Co., LtdY. Kamihara: Employee <strong>of</strong> Chugai<br />
Pharmaceutical Co., Ltd. K. Goto: This study: Chugai Outside the submitted work:<br />
MSD, AstraZeneka, Taiho, Nippon Boehringer Ingelheim, Ono, Quintiles, GSK,<br />
OxOnc, Pfizer, Kyowa Hakko Kirin, Eli Lilly Japan, Yakult, Sumitomo Dainippon,<br />
Takeda, Novartis, Daiichi Sankyo, Astellas, Eisai, Amgen Astellas, BMS. All other<br />
authors have declared no conflicts <strong>of</strong> interest.<br />
S. Pilotto 1 , M. Simbolo 2 , I. Sperduti 3 , S. Novello 4 , C. Vicentini 2 , U. Peretti 1 ,<br />
S. Pedron 2 , M. Milella 5 , A. Mafficini 2 , P. Visca 6 , M. Volante 4 , F. Facciolo 7 , A. Santo 8 ,<br />
M. Infante 9 , L. Carbognin 1 , M. Brunelli 2 , M. Chilosi 2 , A. Scarpa 2 , G. Tortora 1 ,<br />
E. Bria 1<br />
1 Medical <strong>Oncology</strong>, AOU Integrata Verona "Borgo Roma", Verona, Italy,<br />
2 Pathology and Diagnostics, Azienda Ospedaliera Universitaria Integrata<br />
Verona-"Borgo Roma", Verona, Italy, 3 Biostatistic Unit, Istituto Regina Elena,<br />
Rome, Italy, 4 Department <strong>of</strong> <strong>Oncology</strong>, University <strong>of</strong> Turin, Orbassano, Italy,<br />
5 S. C. Oncologia Medica A, Istituto Regina Elena, Rome, Italy, 6 Anatomia<br />
Patologica, Istituto Regina Elena, Rome, Italy, 7 Thoracic Surgery, Istituto Regina<br />
Elena, Rome, Italy, 8 Medical <strong>Oncology</strong>, Azienda Ospedaliera Universitaria Integrata<br />
Verona-"Borgo Roma", Verona, Italy, 9 Chirurgia Toracica, AOU Integrata Verona,<br />
Verona, Italy<br />
Background: We previously validated a clinical risk classification model for resected<br />
SqCLC by combining clinicopathological predictors to discriminate patients’ (pts)<br />
prognosis (Pilotto JTO 2015). Here we investigate the molecular portrait <strong>of</strong> prognostic<br />
outliers to identify differentially expressed, potentially druggable molecular targets<br />
(AIRCMFAG project no. 14282).<br />
Methods: On the basis <strong>of</strong> the published 3-class model, 176 and 46 pts with good and<br />
poor prognosis, respectively, were identified. Next Generation Sequencing (NGS)<br />
analysis (Ion Proton system, Ion Ampliseq custom panel) evaluating Somatic<br />
Mutations (SM) and Copy Number Alternations (CNA) <strong>of</strong> 44 genes was performed;<br />
RNA expression, immunohistochemistry (IHC), immun<strong>of</strong>luorescence (FISH) were<br />
performed on Tissue Micro-Arrays (TMA). Descriptive statistics was adopted;<br />
continuous variables were dichotomized according to AUC or medians.<br />
Results: The distribution <strong>of</strong> relevant SM and CNA analysis <strong>of</strong> 60 pts according to<br />
prognosis (good: 27; poor: 33) is reported in the table.<br />
Table: 1182P<br />
Analysis (NGS) Gene Good: 27 pts [%] Poor: 33 pts [%] p-value<br />
SM PI3KCA 0 3 [9.1] 0.24<br />
NOTCH1 2 [7.4] 0 0.19<br />
CUL3 2 [7.4] 0 0.19<br />
DDR2 3 [11.1] 0 0.085<br />
CDH10 4 [14.8] 1 [3.0] 0.16<br />
CDH1 3 [11.1] 1 [3.0] 0.3<br />
CNA Gains RICTOR 1 [3.7] 9 [27.3] 0.017<br />
SOX2 20 [74.1] 17 [51.5] 0.11<br />
CNA Losses CDKN2A 6 [22.2] 1 [3.0] 0.038<br />
PTEN 11 [40.7] 17 [51.5] 0.57<br />
RB1 8 [29.6] 17 [51.5] 0.12<br />
SMAD4 9 [33.3] 19 [57.6] 0.074<br />
No significant differences in terms <strong>of</strong> phospho-mTOR and PD-L1 IHC expression were<br />
found in the 2 different prognostic subgroups. Patients with concurrent high PD1,<br />
SNAI, and Vimentin RNA expression were significantly more likely to be at poor<br />
prognosis (p = 0.003).<br />
Conclusions: Although performed on a limited number <strong>of</strong> pts, the approach to<br />
comprehensively analyze DNA, RNA and proteins, using different methodologies,<br />
strengthens the clinically relevance <strong>of</strong> RICTOR/PI3K/mTOR signaling cascade<br />
activation in determining the poor prognosis <strong>of</strong> SqCLC. The possibility to inhibit this<br />
pathway with selective agents is currently under investigation in in vitro preclinical<br />
models.<br />
Legal entity responsible for the study: University <strong>of</strong> Verona, Verona, Italy<br />
Funding: Associazione Italiana per la Ricerca sul Cancro (AIRC): MFAG Project<br />
14282.<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1183P<br />
Assessment <strong>of</strong> efficacy <strong>of</strong> adjuvant chemotherapy for<br />
non-small cell lung cancer with metastatic ability involving<br />
ACTN4<br />
K. Honda 1 , N. Miura 1 , H. Shiraishi 2 , K. Onidani 1 , H. Shoji 1 , T. Yamada 1 ,<br />
Y. Fujiwara 2 ,Y.Ohe 2<br />
1 Division <strong>of</strong> Chemotherapy and Clinical Research, National Cancer Center<br />
Reseach Institute, Tokyo, Japan, 2 Department <strong>of</strong> Thoracic <strong>Oncology</strong>, National<br />
Cancer Center Hospital, Tokyo, Japan<br />
Background: Selection <strong>of</strong> patients with high metastatic ability <strong>of</strong> non-small cell lung<br />
cancer (NSCLC) has the potential to predict the clinical benefit <strong>of</strong> adjuvant<br />
chemotherapy (ADC). ACTN4 is an oncogene associated with cancer metastasis. To<br />
vi408 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
demonstrate the clinical utility <strong>of</strong> a predictive biomarker for the efficacy <strong>of</strong> ADC for<br />
NSCLC, we analyzed clinical and preclinical data.<br />
Methods: In Step 1, we reanalyzed the impact <strong>of</strong> ACTN4 on the efficacy <strong>of</strong> ADC from<br />
clinical information and mRNA pr<strong>of</strong>iles from the public database <strong>of</strong> a randomized<br />
phase III trial <strong>of</strong> adjuvant vinorelbine plus cisplatin after complete resection <strong>of</strong> stage IB<br />
or II NSCLC (JBR.10), which was a clinical trial probing the clinical benefits <strong>of</strong> ADC in<br />
stage IB/II patients with NSCLC. In Step 2, we measured ACTN4 protein levels in<br />
patients with completely resected stage II or IIIA lung adenocarcinoma at the National<br />
Cancer Center Hospital (NCCH) from 2008 to 2011 using immunohistochemistry<br />
(IHC). We then retrospectively compared survival between ADC treated with platinum<br />
doublet and observation (OBS) groups. In Step 3, we investigated the biological<br />
functions <strong>of</strong> ACTN4 with the A549 lung adenocarcinoma cell line, which has gene<br />
amplification <strong>of</strong> ACTN4.<br />
Results: In Step 1, the 133 patients enrolled in JBR.10 were divided into two groups by<br />
expression <strong>of</strong> the ACTN4 transcript: an ACTN4-positive (ACTN4(+)) group (n = 25)<br />
and an ACTN4-negative (ACTN4(-)) group (n = 108). In the ACTN4(+) group, overall<br />
survival (OS) was significantly longer in ADC subjects (n = 15) compared with OBS<br />
(n = 10) (hazard ratio [HR] = 0.27; p = 0.042). However, no differences in OS were<br />
noted between ADC (n = 56) and OBS (n = 52) subjects in the ACTN4(-) group. In<br />
Step 2, 148 eligible patients were classified into two groups based on IHC findings. In<br />
the ACTN4-IHC(+) group (n = 75), mean survival was longer in the ADC patients<br />
(n = 22) than in OBS patients (n = 53) (HR = 0.307; p = 0.028). In contrast, the<br />
ACTN4-IHC(-) group (n = 73) showed no tangible survival benefit with ADC. In Step<br />
3, the metastatic potential <strong>of</strong> A549 was significantly reduced by ACTN4 shRNA.<br />
Conclusions: Clinical data and biological assays suggested ACTN4 as a potential<br />
predictive biomarker for the efficacy <strong>of</strong> ADC in patients with NSCLC.<br />
Legal entity responsible for the study: N/A<br />
Funding: AMED<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1184P<br />
Are the criteria indicating patients to be “medically<br />
inoperable” that are used in clinical trials on stereotactic<br />
body radiotherapy appropriate for patients with early stage<br />
non-small cell lung cancer?<br />
K. Takamochi, A. Hattori, T. Maeyashiki, T. Matsunaga, T. Banno, S. Oh, K. Suzuki<br />
General Thoracic Surgery, Juntendo University School <strong>of</strong> Medicine, Tokyo, Japan<br />
Background: The standard treatment for patients with early stage non-small cell lung<br />
cancer (NSCLC) is surgical resection. Stereotactic body radiotherapy (SBRT) has<br />
recently been investigated as an alternative treatment in place <strong>of</strong> surgery in clinical<br />
trials, especially for medically inoperable (MI) patients. However, no clear rationale for<br />
the criteria used to determine whether or not a patient is MI has yet been<br />
demonstrated.<br />
Methods: Between January 2004 and October 2012, 740 patients underwent surgical<br />
resection for clinical stage IA NSCLC. In the present study, MI was defined as patients<br />
with FEV1.0 ≤ 0.8L, %DLCO < 40%, PaO2 ≤ 70mmHg, PaCO2 > 50mmHg, or three or<br />
more severe comorbidities, based on the criteria <strong>of</strong> MI that are frequently used in<br />
clinical trials in SBRT for NSCLC patients. The clinicopathological characteristics and<br />
surgical outcomes were compared between the MI patients (n = 91) and operable<br />
patients (n =649).<br />
Results: The proportion <strong>of</strong> males, elderly, smokers and those with a<br />
non-adenocarcinoma histology were higher in MI patients than in operable patients.<br />
No statistical difference was observed in the proportion <strong>of</strong> pathological stage IA<br />
between the groups (P = 0.09). Limited operation (wedge lung resection or<br />
segmentectomy) was performed for 37 (41%) MI and 227 (35%) operable patients<br />
(P = 0.3). The rates <strong>of</strong> overall morbidity (39% vs 23%, P = 0.002) and 90-day mortality<br />
(3% vs 0.5%, P = 0.03) were higher in the MI patients than those in the operable<br />
patients. Although overall survival was significantly worse in the MI patients<br />
(P = 0.004), there were no significant differences in cancer-specific survival between the<br />
groups (P = 0.5).<br />
Conclusions: Surgical resection can be performed safely in the MI patients with an<br />
equivalent cancer-specific survival to that observed in the operable patients. The overall<br />
survival was superior to that noted in previously reported clinical trials <strong>of</strong> SBRT in MI<br />
patients with early stage NSCLC. Therefore, the current criteria <strong>of</strong> MI used in clinical<br />
trials <strong>of</strong> SBRT in NSCLC patients are not appropriate for evaluating the true degree <strong>of</strong><br />
operability.<br />
Legal entity responsible for the study: The institutional review board <strong>of</strong> Juntendo<br />
University School <strong>of</strong> Medicine<br />
Funding: A Grant-in-Aid for Cancer Research from the Ministry <strong>of</strong> Health, Labor and<br />
Welfare <strong>of</strong> Japan<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1185P<br />
Prognostic role <strong>of</strong> texture analysis in lung cancer treated with<br />
stereotactic ablative radiotherapy (SABR)<br />
V. Nardone 1 , P. Tini 1 , L.N. Mazzoni 2 , A. La Penna 3 , M. Biondi 2 , L. Sebaste 1 ,<br />
T. Carfagno 1 , E. Vanzi 2 , G. De Otto 2 , G. Battaglia 1 , P. Pastina 1 , S.F. Carbone 3 ,F.<br />
Banci Buonamici 2 , L. Pirtoli 1<br />
1 Unit <strong>of</strong> Radiation <strong>Oncology</strong>, University Hospital <strong>of</strong> Siena, Siena, Italy, 2 Unit <strong>of</strong><br />
Medical Physics, University Hospital <strong>of</strong> Siena, Siena, Italy, 3 Unit <strong>of</strong> Diagnostic<br />
Radiology, University Hospital <strong>of</strong> Siena, Siena, Italy<br />
Background: Stereotactic ablative radiotherapy (SABR) is widely used in lung cancer<br />
primary treatment. The aim <strong>of</strong> present study is to evaluate the texture analysis as a<br />
predictive factor <strong>of</strong> treatment response.<br />
Methods: This single center retrospective study included fifty-six consecutive patients<br />
(January 2011 – December 2014) with early stage lung cancer (T1-2a, N0) treated with<br />
SABR. The diagnostic CT DICOM images pre- and post- SABR were collected and<br />
analysed with an homemade ImageJ macro and typical texture analysis parameters<br />
were evaluated: mean (m), standard deviation (sd), skewness(sk), kurtosis (k), entropy<br />
(e) and uniformity (u). We analyzed progression free survival with modality <strong>of</strong> lung<br />
progression (PFS in-field and PFS out-field) after treatment and overall survival (OS),<br />
calculated with Kaplan-Meier method.<br />
Results: During the observation period 15 patients (26,8%) showed evidence <strong>of</strong><br />
recurrence, divided in recurrence “in-field” in 9 patients (16,1%), and “out <strong>of</strong> field”<br />
recurrence in 11 patients (19,6%). Five patients developed both “in field” and “out <strong>of</strong><br />
field” recurrence; 14 patients (25%) died. Pre SABR parameters Entropy (e) and<br />
uniformity (u) were significantly associated with PFS “in field” (p:0,030), whereas<br />
kurtosis (k) was significantly associated with PFS “out <strong>of</strong> field” (p:0,031) and Mean (m)<br />
was significantly associated with OS (p < 0,001). Post SABR parameters entropy (e) was<br />
associated with PFS “in field” (p:0,009), whereas mean (m) was associated with PFS<br />
“out <strong>of</strong> field” (p < 0,001). A rise in mean (p < 0,001), entropy (p:0,028) and a decrease<br />
in uniformity (p:0,028) resulted to be significantly associated with PFS “out <strong>of</strong> field”.<br />
Conclusions: Our results appear to be very promising since the knowledge <strong>of</strong> the<br />
predictive factors <strong>of</strong> SABR could drive the selection <strong>of</strong> the best treatment in these<br />
patients (i.e. dose increasing in the patients at higher risk? Concurrent chemoradiation?<br />
Intensified follow up?). Further studies on large patient series are needed to best<br />
estimate the present preliminary data.<br />
Legal entity responsible for the study: Unit <strong>of</strong> Radiation <strong>Oncology</strong>, University<br />
Hospital <strong>of</strong> Siena<br />
Funding: Unit <strong>of</strong> Radiation <strong>Oncology</strong>, University Hospital <strong>of</strong> Siena<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1186P<br />
abstracts<br />
Good news for French NSCLC patients: Distance between<br />
chest and surgical departments did not impair outcome<br />
D. Debieuvre 1 , B. Asselain 2 , M.L. Braud 3 , C. Fouret 4 , S. Larive 5 , L. Falchero 6 ,<br />
Y. Duval 7 , B. Lemaire 8 , M. Farny 9 , P. Brun 10 , C. Dujon 11 , C. Nocent 12 ,<br />
P. Dumont 13 , P. Le Lann 14 , G-J. Kassem 15 , M. Grivaux 16<br />
1 Pneumologie, Hopital Emile Muller, Mulhouse, France, 2 Epidemiology, Freelance,<br />
Paris, France, 3 Pneumologie, Centre Hospitalier de Bourg-en-Bresse (Fleyriat) CH<br />
De Fleyriat, Bourg En Bresse, France, 4 Pneumologie, Centre hospitalier<br />
intercommunal, Villeneuve Saint-Georges, France, 5 Pneumologie, Centre<br />
Hospitalier, Macon, France, 6 Pneumologie, Hôpital Nord Ouest, Villefranche Sur<br />
Saone, France, 7 Pneumologie, Centre Hospitalier de Cannes, Cannes, France,<br />
8 Pneumologie, C.H.R. Orleans - La Source, Orleans, France, 9 Pneumologie,<br />
Centre Hospitalier, Cahors, France, 10 Pneumologie, CH de Valence, Valence,<br />
France, 11 Pneumologie, Centre hospitalier de Versailles André Mignot, Le<br />
Chesnay, France, 12 Pneumologie, Centre Hospitalier de la Côte Basque, Bayonne,<br />
France, 13 Pneumologie, CH DE Chauny, Chauny, France, 14 Pneumologie, Groupe<br />
Hospitalier Public du Sud de l’Oise, Creil, France, 15 Pneumologie, Centre<br />
Hospitalier, Sedan, France, 16 Pneumologie, Centre hospitalier général Meaux,<br />
Meaux, France<br />
Background: Surgery remains a major treatment option in lung cancer in particular at<br />
early stages.Recent Australian and UK studies have shown that patients with NSCLC<br />
were less likely to have surgery and more likely to die if they were first seen at a<br />
non-specialized surgical centre, or with increasing distance to the nearest specialist<br />
hospital. In France, not all general hospitals have a thoracic surgery department. We<br />
assessed the impact on patient outcome <strong>of</strong> the distance between the chest and thoracic<br />
surgery Departments.<br />
Methods: KBP-2010-CPHG is a prospective multicentre epidemiological study<br />
promoted by the French College <strong>of</strong> General Hospital Respiratory Physicians (CPHG),<br />
including 7,051 patients followed for primary lung cancer diagnosed in 2010 in the<br />
chest department <strong>of</strong> 104 general hospitals. The distance from the usual thoracic surgery<br />
department in 2010 was collected for each chest department in 2015. Univariate and<br />
multivariate analyses were performed to identify independent factors for surgery and<br />
mortality. Distance was included in the model as a 4-class variable: 0 (same hospital),<br />
1-34, 35-79, and ≥80 km.<br />
Results: 23% <strong>of</strong> hospitals had a thoracic surgery department; otherwise, mean distance<br />
between the hospital and the surgical centre was 65 km. 6,083 patients had a NSCLC;<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw381 | vi409
abstracts<br />
1157 (19%) were operated on. Independent factors for surgery were: young age, early<br />
disease, good performance status, and cancer histological type. Distance was not an<br />
independent factor for surgery: OR [95% CI] was 0.971 [0.74-1.274] (p = 0.833), 0.883<br />
[0.662-1.178] (p = 0.399), and 1.015 [0.783-1.317] (p = 0.91) for 1-34, 35-79, and ≥80<br />
km vs. 0 km. 1,939 patients had stage I to IIIA NSCLC; 1070 (55%) were operated on.<br />
Independent risk factors for mortality were old age, male gender, advanced disease,<br />
and poor performance status. Distance was not an independent risk factor for<br />
mortality: OR [95% CI] was 1.016 [0.83-1.244] (p = 0.878), 1.089 [0.882-1.344]<br />
(p = 0.427), and 1.011 [0.829-1.233] (p = 0.915) for 1-34, 35-79, and ≥80 km vs. 0 km.<br />
Conclusions: In France, in 2010, the absence <strong>of</strong> an on-site thoracic surgery department<br />
did not impair outcome in NSCLC patients managed in the chest department <strong>of</strong><br />
general hospitals.<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Legal entity responsible for the study: Collège des Pneumologues des Hopitaux<br />
Généraux (CPHG)<br />
Funding: KBP-2010-CPHG is a study promoted by the CPHG with the help <strong>of</strong> the<br />
endowment fund Recherche en Santé Respiratoire <strong>of</strong> the CNMR and Pneumologie<br />
development, and funded by the following laboratories: AstraZeneca, BMS, Boehringer<br />
Ingelheim, Chugai, GlaxoSmithKline, Lilly France, Pierre Fabre Oncologie,Pfizer,<br />
Roche, and San<strong>of</strong>i-Aventis.<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
vi410 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong> 27 (Supplement 6): vi411–vi415, 2016<br />
doi:10.1093/annonc/mdw382<br />
NSCLC, locally advanced<br />
1188P<br />
Poly-therapy with EGFR, STAT3 and Src-YAP1 signaling<br />
pathway inhibition; A breakthrough for EGFR mutant NSCLC<br />
1187P<br />
Multigene expression pr<strong>of</strong>ile for predicting efficacy <strong>of</strong><br />
cisplatin and vinorelbine in non-small cell lung cancer<br />
I.K. Buhl 1 , I.J. Christensen 2 , E. Santoni-Rugiu 3 ,J.Ravn 4 , A. Hansen 5 , T. Jensen 6 ,<br />
J. Askaa 5 , P.B. Jensen 5 , S. Knudsen 7 , J.B. Soerensen 8<br />
1 Section Molecular Disease Biology, Dep. Veterinary Disease Biology, Faculty <strong>of</strong><br />
Health, University <strong>of</strong> Copenhagen, Copenhagen, Denmark, 2 Gastroenterology,<br />
Hvidovre Hospital, Hvidovre, Denmark, 3 Dept. <strong>of</strong> Pathology, Rigshospitalet,<br />
Copenhagen University Hospital, Copenhagen, Denmark, 4 Cardiothoracic<br />
Surgery, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark,<br />
5 Denmark, Medical Prognosis Institute, Hoersholm, Denmark, 6 Biology, Medical<br />
Prognosis Institute, Scottsdale, AZ, USA, 7 Biology, Medical Prognosis,<br />
Scottsdale, AZ, USA, 8 Dept. <strong>Oncology</strong>, Finsen Centre/National University Hospital,<br />
Copenhagen, Denmark<br />
Background: There is a need for biomarkers to predict efficacy <strong>of</strong> adjuvant<br />
chemotherapy in resected non-small cell lung cancer (NSCLC). Presented is a<br />
combined cisplatin and vinorelbine marker from a previously validated model system<br />
[1] tested in two cohorts.<br />
Methods: The pr<strong>of</strong>iles consist <strong>of</strong> correlated in vitro cytotoxicity <strong>of</strong> cisplatin and<br />
vinorelbine and mRNA expressions. Then each pr<strong>of</strong>ile is correlated to mRNA<br />
expression <strong>of</strong> 3500 tumors. The cohorts are 1) a publically available dataset with 133<br />
completely resected stage Ib-II NSCLC patients, 71 <strong>of</strong> whom received adjuvant<br />
cisplatin and vinorelbine (ACT) and 62 patients who had no adjuvant treatment (OBS)<br />
[2] and 2) 95 stage Ib-IIIb completely resected NSCLC patients who all received<br />
adjuvant cisplatin and vinorelbine [3]. Endpoint is cancer specific survival.<br />
Results: The combined cisplatin and vinorelbine pr<strong>of</strong>iles scored as a continuous<br />
covariate showed 1) a Hazard Ratio (HR) <strong>of</strong> 0.265 ((95% CI:0.079-0.889), p = 0.032) in<br />
the ACT cohort (sensitive versus resistant), and no significant discrimination in the<br />
OBS cohort (HR = 1.328 (95% CI:0.46-3.835), p = 0.60). A multivariate model adjusted<br />
for stage demonstrated significance for ACT (HR = 0.284 (95% CI:0.086-0.944),<br />
p = 0.040) but not for OBS (HR = 1.702 (95% CI: 0.575-5.036), p = 0.34). The<br />
combined pr<strong>of</strong>iles resulted in 2) a significant prediction for up to 3 years from surgery<br />
(HR = 0.143 (95% CI:0.038-0.542), p = 0.004, scored as a continuous covariate). A<br />
multivariate model adjusting for stage showed that the predictor remained significant<br />
(HR = 0.123 (95% CI:0.030-0.512), p = 0.004). A pooled analysis <strong>of</strong> the two treated<br />
cohorts resulted in a significant prediction (HR = 0.187, (95% CI:0.069-0.508),<br />
p = 0.001) up to 3 years from surgery using a random effects model.<br />
Conclusions: The combined pr<strong>of</strong>iles demonstrate that NSCLC patients who benefit<br />
from cisplatin and vinorelbine can be identified. The pr<strong>of</strong>iles did not discriminate<br />
patients in the untreated arm. This holds promise for a predictive effect <strong>of</strong> the pr<strong>of</strong>iles<br />
and it is currently being validated in a prospective study [4]. [1] PLoS ONE 2016, 11<br />
(2): e0148070. [2] Zhu et al JCO 2010;28:4417-4424. [3] ASCO 2016 abstract e20007.<br />
[4] AACR 2016 Abstract CT154.<br />
Clinical trial identification: Danish Trial Protocol Number H-B-2007-099<br />
Legal entity responsible for the study: Medical Prognosis Institute, Hoersholm,<br />
Denmark Dept. <strong>of</strong> <strong>Oncology</strong>, Rigshospitalet, Copenhagen, Denmark<br />
Funding: Medical Prognosis Institute, biotech company Markedsmodningsfonden<br />
Kræftens Bekæmpelse<br />
Disclosure: I.K. Buhl: Employment: Medical Prognosis Institute. I.J. Christensen:<br />
Consulting or Advisory Role: Medical Prognosis Institute. E. Santoni-Rugiu:<br />
Honoraria: Novartis; Pfizer; Roche Pharma AG Consulting or Advisory Role: Pfizer<br />
Travel, Accommodations, Expenses: Pfizer; Roche Pharma AG.J. Ravn: Stock and<br />
Other Ownership Interests: Novo Nordisk. A. Hansen, T. Jensen, P.B. Jensen,<br />
S. Knudsen: Employment: Medical Prognosis Institute Leadership: Medical Prognosis<br />
Institute Stock and Other Ownership Interests: Medical Prognosis Institute. J. Askaa:<br />
Employment: Medical Prognosis Institute Stock and Other Ownership Interests:<br />
Medical Prognosis Institute. J.B. Soerensen: Honoraria: Lilly; Pfizer; Roche Pharma AG<br />
Consulting or Advisory Role: Roche Pharma AG Travel, Accommodations, Expenses:<br />
Roche Pharma AG.<br />
N. Karachaliou 1 , I. Chaib 2 , X. Cai 3 ,X.Li 4 , A.F. Cardona 5 , G. López-Vivanco 6 ,<br />
A. Vergnenegre 7 , J.M. Sanchez Torres 8 , M. Provencio 9 , F. de Marinis 10 ,<br />
E. Carecereny 11 , N. Reguart 12 , R. García Campelo 13 , S. Viteri 1 , M.A. Molina Vila 14 ,<br />
C. Zhou 4 , P. Cao 3 ,P.Ma 15 , T. Bivona 16 , R. Rosell 17<br />
1 Medical <strong>Oncology</strong> Service, Instituto Oncológico Dr Rosell (IOR), Hospital<br />
Universitario Quirón-Dexeus, Barcelona, Spain, 2 Laboratory <strong>of</strong> Cellular and<br />
Molecular Biology, Institut d’Investigació en Ciències Germans Trias i Pujol,<br />
Badalona, Spain, 3 Laboratory <strong>of</strong> Cellular and Molecular Biology, Academy <strong>of</strong><br />
Traditional Chinese Medicine, Nanjing, China, 4 Lung Cancer <strong>Oncology</strong> &<br />
Immunology, Tongji Hospital <strong>of</strong> Tongji University, Shanghai, China, 5 Medical<br />
<strong>Oncology</strong>, Clinica del Country, Bogota, Colombia, 6 Medical <strong>Oncology</strong>, Hospital de<br />
Cruces, Barakaldo, Spain, 7 Service de l’UOTC, CHU Limoges - Hopital Dupuytren,<br />
Limoges, France, 8 Medical <strong>Oncology</strong> Service, Hospital Universitario de La<br />
Princesa, Madrid, Spain, 9 Medical <strong>Oncology</strong>, Hospital Universitario Puerta de<br />
Hierro Majadahond, Majadahonda, Spain, 10 1 Unità Operativa di Pneumologia<br />
Oncologica, Istituto Europeo di Oncologia, Milan, Italy, 11 Medical <strong>Oncology</strong>,<br />
Catalan Institute <strong>of</strong> <strong>Oncology</strong> (ICO Badalona), Hospital Germans Trias i Pujol,<br />
Badalona, Spain, 12 Medical <strong>Oncology</strong>, Hospital Clinic y Provincial de Barcelona,<br />
Barcelona, Spain, 13 Medical <strong>Oncology</strong>, Hospital Universitario a Coruna - a<br />
Corunac, A Coruna, Spain, 14 Laboratory <strong>of</strong> Cellular and Molecular Biology,<br />
Pangaea Biotech SL, IOR Quirón-Dexeus University Institute, Barcelona, Spain,<br />
15 Solid Tumor <strong>Oncology</strong>, West Virginia University Mary Babb Randolph Cancer<br />
Center, Morgantown, WV, USA, 16 Hematology and <strong>Oncology</strong>, UCSF Helen Diller<br />
Family Comprehensive Cancer Center, San Francisco, CA, USA, 17 Translational<br />
Research Unit, Laboratory <strong>of</strong> Molecular Biology, Catalan Institute <strong>of</strong> <strong>Oncology</strong> (ICO<br />
Badalona), Hospital Germans Trias i Pujol, Badalona, Spain<br />
Background: Since the discovery <strong>of</strong> epidermal growth factor receptor (EGFR)<br />
mutations in 2004 as a driver alteration in non-small-cell lung cancer (NSCLC),<br />
mono-therapy with EGFR tyrosine kinase inhibitors (TKIs) is the conventional<br />
therapy. Growing evidence demonstrates that single EGFR TKI hyper-activates signal<br />
transducer and activator <strong>of</strong> transcription 3 (STAT3) almost immediately after starting<br />
treatment.<br />
Methods: We conducted clinical and preclinical studies <strong>of</strong> key components <strong>of</strong> signaling<br />
pathways limiting EGFR TKI efficacy in EGFR mutant NSCLC.<br />
Results: Gefitinib suppressed EGFR, ERK1/2 and AKT phosphorylation but increased<br />
STAT3 phosphorylation on the critical tyrosine residue 705 (pSTAT3-Tyr705) in a<br />
time and dose-dependent manner in PC9 cells. Gefitinib with TPCA-1 (STAT3<br />
inhibitor) abolished pSTAT3-Tyr705. In addition to STAT3 activation, co-activation <strong>of</strong><br />
Src-YES-associated protein 1 (YAP1) was also unexpectedly observed in our study.<br />
Gefitinib with TPCA-1 blocked STAT3, but not the YAP1 phosphorylation on tyrosine<br />
residue 357 by Src family kinases (SFKs). The triple combination <strong>of</strong> gefitinib, TPCA-1<br />
and AZD0530 (SFK inhibitor) ablated both STAT3 and YAP1 phosphorylation and<br />
had greater effect than gefitinib alone or double combinations in vitro and in vivo.High<br />
levels <strong>of</strong> STAT3 or YAP1 mRNA expression were associated with worse outcome to<br />
EGFR TKI in two independent cohorts <strong>of</strong> EGFR-mutant NSCLC patients. In the initial<br />
cohort <strong>of</strong> 64 patients, progression-free survival (PFS) was shorter among the patients<br />
with high STAT3 than among those with low STAT3 (hazard ratio [HR] for disease<br />
progression, 3.02; 95% confidence interval [CI], 1.54-5.93; P = 0.0013). PFS was shorter<br />
among the patients with high YAP1 than among those with low YAP1 (HR for disease<br />
progression, 2.57; 95%CI, 1.30-5.09; P = 0.0067). The results were similar in the<br />
validation cohort <strong>of</strong> 55 patients.<br />
Conclusions: Co-targeting STAT3 and Src-YAP1-NOTCH signaling pathways could<br />
be a feasible solution that would have a major impact in prolonging cancer free survival<br />
in EGFR mutant NSCLC patients.<br />
Legal entity responsible for the study: N/A<br />
Funding: This work was supported by grants from the La Caixa Foundation and Red<br />
Tematica de Investigacion Cooperativa en Cancer (RTICC; grant RD12/0036/ 0072),<br />
the National Natural Science Foundation <strong>of</strong> China (No. 81573680), and the Jiangsu<br />
Province Funds for Distinguished Young Scientists (No. BK20140049).<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
abstracts<br />
© European Society for Medical <strong>Oncology</strong> 2016. Published by Oxford University Press on behalf <strong>of</strong> the European Society for Medical <strong>Oncology</strong>.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com.
abstracts<br />
1189P<br />
Functional pr<strong>of</strong>iling <strong>of</strong> oncogenic mutations in lung cancer<br />
patients (NCT02274025) - interim results<br />
B. Miron 1 , N. Peled 2 , G. Tarcic 1 , Z. Barbash 1 , O. Edelheit 1 , M. Vidne 1 ,<br />
M.R. Kramer 3<br />
1 R&D, NovellusDx, Jerusalem, Israel, 2 Thoracic Cancer Unit, David<strong>of</strong>f Cancer<br />
Center, Petach Tiqwa, Israel, 3 Pulmonary Institute, Rabin Medical Center,<br />
Beilinson Campus, Petach Tikva, Israel<br />
Background: Epidermal growth factor receptor (EGFR) inhibitors have shown efficacy<br />
in treating EGFR mutation-positive (EGFR+) non-small cell lung cancer (NSCLC).<br />
However, selecting EGFR inhibitors is challenging due to differential responses<br />
between pts and resistance mutations. We pr<strong>of</strong>iled EGFR mutations and their response<br />
to EGFR inhibitors using the Functional Annotation for Cancer Treatment (FACT)<br />
platform, which characterizes mutations by monitoring the activity <strong>of</strong> signaling<br />
pathways, via a transfected cell-based assay. As a functional platform, FACT reveals<br />
activation regardless <strong>of</strong> prior knowledge <strong>of</strong> a specific mutation.<br />
Methods: The study included pts with suspected lung cancer undergoing biopsy/<br />
resection. EGFR mutational status was verified by NGS. Using the FACT platform, we<br />
analyzed the oncogenic signaling activity <strong>of</strong> EGFR mutations in these pts and response<br />
to physician chosen EGFR inhibitors compared to observed clinical responses assessed<br />
by cross-sectional imaging.<br />
Results: Of 23 pts enrolled thus far, 4 pts were EGFR+ and 3 were treated with EGFR<br />
inhibitors (erlotinib, gefitinib, afatinib, AZD9291). The first pt had a complex EGFR<br />
mutation (T638M/E709A/L858R) and initially responded to erlotinib and after<br />
metastatic PD was treated with afatinib. The second pt had two alterations (exon 19<br />
deletion/T790M) failed gefitinib and switched to AZD9291 with good response. The<br />
third patient had a common (L858R) mutation treated with erlotinib with good<br />
response. In all three pts, FACT assessed oncogenic signaling <strong>of</strong> the mutations and<br />
predicted responsiveness to EGFR inhibitors in accordance with observed clinical<br />
outcomes.<br />
Conclusions: This study highlights the utility <strong>of</strong> functionally pr<strong>of</strong>iling mutations,<br />
specifically in cases where multiple treatment options are available. We demonstrate<br />
that measured signaling activity <strong>of</strong> the EGFR mutations tested and sensitivity to<br />
different targeted therapies was correlated with clinical outcomes in these pts.<br />
Clinical trial identification: NCT02274025<br />
Legal entity responsible for the study: N/A<br />
Funding: NovellusDx<br />
Disclosure: B. Miron, G. Tarcic, Z. Barbash, O. Edelheit, M. Vidne:<br />
NovellusDx. N. Peled: NovellusDx.All other authors have declared no conflicts <strong>of</strong><br />
interest.<br />
1190P<br />
Randomized phase II trial <strong>of</strong> S-1 plus cisplatin or docetaxel<br />
plus cisplatin with concurrent thoracic radiotherapy for<br />
inoperable stage III non-small cell lung cancer (TORG1018):<br />
An interim report<br />
K. Yamada 1 , T. Shimokawa 2 , H. Okamoto 2 , H. Tanaka 2 , K. Kubota 2 , K. Kishi 2 ,<br />
H. Saitho 2 , Y. Takiguchi 2 , Y. Hosomi 2 ,T.Kato 2 , D. Harada 2 , N. Masuda 2 , T. Kasai 2 ,<br />
Y. Nakamura 2 , K. Minato 2 , T. Kaburagi 2 , K. Naoki 2 , K. Hikino 2 , T. Yamanaka 2 ,<br />
K. Watanabe 2<br />
1 Division <strong>of</strong> Respirology, Neurology, and Rheumatology, Department <strong>of</strong> Internal<br />
Medicine, Kurume University, Kurume, Japan, 2 TORG1018 study group, Thoracic<br />
<strong>Oncology</strong> Research Group, Yokohama, Japan<br />
Background: Concurrent chemoradiotherapy (CCRT) is the current standard<br />
treatment for inoperable stage III non-small cell lung cancer (NSCLC), and a clearly<br />
superior regimen has not yet been identified. This study was conducted to evaluate<br />
cisplatin with S-1 (SP) or docetaxel (DP) with concurrent thoracic radiotherapy in<br />
patients with inoperable stage III NSCLC.<br />
Methods: In this open-label, non-comparative phase II trial, patients with inoperable<br />
stage IIIA/B NSCLC were randomized (1:1) to SP (S-1 40 mg/m 2 twice a day on days<br />
1-14 and 29-42, and cisplatin 60 mg/m 2 on days 1 and 29) or DP (docetaxel 50 mg/m 2<br />
and cisplatin 60 mg/m 2 on days 1 and 29). In both arms, concurrent radiotherapy was<br />
started on day 1 (total 60 Gy in 30 fractions). After CCRT, patients in each group<br />
received two additional cycles <strong>of</strong> consolidation chemotherapy with the same regimen<br />
as that for the CCRT part. The primary endpoint was the 2-year overall survival (OS)<br />
rate,, and secondary endpoints were OS, progression-free survival (PFS), toxicity<br />
pr<strong>of</strong>ile, dose intensity and objective response rate (ORR).<br />
Results: Between May 2011 and August 2014, 110 patients from 19 institutions were<br />
enrolled. Finally, 106 patients (56 in each arm) were evaluable for efficacy and safety.<br />
The patient characteristics were: male/female, 83/23; median age, 65 (range 42-74) yr;<br />
ECOG performance status 0/1, 59/47; IIIA/IIIB, 59/47. After a median follow-up <strong>of</strong><br />
23.1 months, ORR and median PFS were 71.7% (95%CI: 57.7-83.2) and 11.5 months<br />
(95%: 9.00-14.1) in the SP arm, and 67.9% (95%CI: 53.7-80.1) and 17.2 months (95%:<br />
9.62-24.0) in the DP arm, respectively. Grade 3-4 leukopenia (34.0%/62.3%) and<br />
neutropenia (28.3%/56.6%) were significantly higher in the DP arm than in the SP arm.<br />
Incidences <strong>of</strong> non-hematological toxicity including febrile neutropenia, anorexia,<br />
nausea, diarrhea, radiation pneumonitis and esophagitis tended to be high in the DP<br />
arm. No treatment-related death occurred.<br />
Conclusions: At this preliminary stage, it appears that although the DP arm may have<br />
more toxic effects than the SP arm, it has a favorable PFS. The OS data will be available<br />
soon.<br />
Clinical trial identification: UMIN000005993<br />
Legal entity responsible for the study: Thoracic <strong>Oncology</strong> Research Group<br />
Funding: Thoracic <strong>Oncology</strong> Research Group<br />
Disclosure: T. Shimokawa, H. Okamoto: I have received research funding from Takeda,<br />
MSD, Ono, Astrazeneca, Merck, Chugai, Taiho, Bristol, Eli Lilly and<br />
Parexel. K. Kubota: Honoraria: Taiho, Chugai, Eli-Lilly.Y. Takiguchi: Grants and<br />
lecture fees from Chugai, Bristol-Myers Squibb, Kyowa Hakko Kirin, Merck Serono,<br />
Boehringer Ingelheim Japan, Ono, Taiho, grants from Eli Lilly Japan, Mochida, lecture<br />
fees from AstraZeneca Japan, outside the submitted work. Y. Hosomi: Speaker Fees as<br />
honoraria from Chugai, Eli Lilly Japan, AstraZeneca, Taiho and Ono, outside the<br />
submitted work. T. Kato: Taiho pharmaceuticals: Lecture fee and research<br />
grant. T. Yamanaka: Honoraria: Taiho, Chugai, Takeda. All other authors have<br />
declared no conflicts <strong>of</strong> interest.<br />
1191P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
A phase I / II trial <strong>of</strong> pemetrexed plus radiation therapy in<br />
elderly patients with locally advanced NSCLC<br />
S. Atagi 1 , A. Tamiya 2 , S. Fukuda 3 , Y. Naoki 2 , M. Morimoto 4 , T. Ibe 5 , K. Okishio 1 ,<br />
H. Goto 6 , A. Yoshii 7 , T. Kita 8 , Y. Tomizawa 7 , N. Nogami 9 , Y. Fujita 10<br />
1 Clinical Research Center, Kinki-chuo Chest Medical Center, Sakai, Japan,<br />
2 Internal Medicine, Kinki-chuo Chest Medical Center, Sakai, Japan, 3 Radiology<br />
department, Kinki-chuo Chest Medical Center, Sakai, Japan, 4 Radiotherapy and<br />
Nuclear Medicine, Nara Medical University Hospital, Kashihara, Japan,<br />
5 Respiratory medicine, Disaster Medical Center, Tatekawa, Japan, 6 Respiratory<br />
medicine, Yokohama Medical Center, Yokohama, Japan, 7 Respiratory medicine,<br />
Shibukawa Medical Center, Shibukawa, Japan, 8 Respiratory medicine, Kanazawa<br />
Medical University Hospital, Kanazawa, Japan, 9 Respiratory medicine, Shikoku<br />
Cancer Center, Matsuyama, Japan, 10 Respiratory medicine, Asahikawa Medical<br />
Center, Asahikawa, Japan<br />
Background: Although the clinical efficacy <strong>of</strong> radiation therapy (RT) has been<br />
demonstrated in elderly patients with locally advanced non-small-cell lung cancer<br />
(NSCLC), the combination <strong>of</strong> pemetrexed (PEM) and RT has not been examined in<br />
clinical trials yet. Therefore, we conducted a phase I / II study to evaluate the<br />
appropriate PEM dose, efficacy and safety <strong>of</strong> PEM plus RT in elderly patients with<br />
locally advanced NSCLC.<br />
Methods: Eligibility criteria included performance status (PS) 0-2, aged 71 years or<br />
older, pathologically confirmed NSCLC, locally advanced stage (IIIA / IIIB), adequate<br />
organ function, and written informed consent. Patients received PEM (500mg/m 2 on<br />
day1 <strong>of</strong> a 28-day cycle, 4 course) and RT (total 60 Gy / 30 fractions over 6 weeks). The<br />
primary endpoint was objective response rate (ORR). Secondary endpoints included<br />
progression-free survival (PFS), overall survival (OS), and adverse events (AEs).<br />
Results: A total <strong>of</strong> 41 patients (4 patients in phase I, 37 patients in phase II) were<br />
enrolled. Median age was 79 years old (range 71-87) and 31 patients were male.<br />
Eighteen patients were squamous cell carcinoma, 27 <strong>of</strong> 41 patients were stage IIIA, and<br />
38 patients were PS 0-1. ORR was 80.5%. Median OS was 24.6 months and median PFS<br />
was 6.8 months. There were 2 treatment related deaths, caused by RT pneumonitis in<br />
one patient and severe infection in one patient. Common hematological AEs were<br />
leucopenia and neutropenia, whereas, common non-hematological AEs were anorexia<br />
and constipation. Interstitial lung disease caused by PEM developed in 3 patients. RT<br />
related AEs were mainly observed, including radiation esophagitis (grade 1: 22 patients,<br />
2: 6 patients, 3: 1 patient) and RT pneumonitis (grade 1: 11 patients, 2: 14 patients, 3: 7<br />
patients, 5: 1 patient).<br />
Conclusions: This combination treatment shows promising activity, but RT related<br />
toxicities were relatively severe. Therefore, the use <strong>of</strong> this treatment require close<br />
caution for elderly patients.<br />
Clinical trial identification: UMIN000005036<br />
Legal entity responsible for the study: Shinji Atagi<br />
Funding: National hospital organization network funding<br />
Disclosure: S. Atagi: Honoraria: Eli Lilly Japan, Chugai, Taiho, Boehringer Ingelheim,<br />
Pfizer Japan, Ono, and AstraZeneca. Research Funding: Chugai, Pfizer, Ono, Merck<br />
Serono, Boehringer Ingelheim, AstraZeneca, Taiho, Yakult, Eli Lilly. N. Nogami:<br />
Honoraria: Chugai, Taihou, Eli Lilly, Pfizer, AstraZeneca, Ono, BMS, Nippon<br />
Boehringer. All other authors have declared no conflicts <strong>of</strong> interest.<br />
vi412 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
1192P<br />
Recurrence pattern and its prognostic impact following<br />
definitive chemo-radiotherapy in stage III non-small cell lung<br />
cancer<br />
M. Saigi Morgui 1 , A.J. Rullan Iriarte 1 , M. Bergamino 1 , A. Navarro 2 , M.M. Arnaiz 2 ,<br />
R. Palmero 1 , M. Plana Serrahima 1 , C. Mesía 1 , S. Padrones 3 , S. Aso 3 ,<br />
J. Ruffinelli Rodriguez 1 , V. Navarro 4 , I. Brao 5 , E. Nadal 1 , F. Cardenal Alemany 1<br />
1 Medical <strong>Oncology</strong>, Thoracic <strong>Oncology</strong> Unit, Institut Català d’Oncologia Hospital<br />
Duran i Reynals, Barcelona, Spain, 2 Radiotherapy <strong>Oncology</strong>, Thoracic <strong>Oncology</strong><br />
Unit, Institut Català d’Oncologia Hospital Duran i Reynals, Barcelona, Spain,<br />
3 Pneumologist, Thoracic <strong>Oncology</strong> Unit, Hospital Universitari de Bellvitge,<br />
Barcelona, Spain, 4 Biostatistics for Medical <strong>Oncology</strong>, Institut Catala de<br />
Oncologia, Barcelona, Spain, 5 Nurse specialist, Thoracic <strong>Oncology</strong> Unit, Institut<br />
Català d’Oncologia Hospital Duran i Reynals, Barcelona, Spain<br />
Background: The influence <strong>of</strong> the recurrence pattern on outcome <strong>of</strong> patients (pts)<br />
with stage III NSCLC following definitive chemo-radiotherapy (CRT) has been scarcely<br />
addressed in the literature. The aim <strong>of</strong> this study was to assess the relevance <strong>of</strong><br />
oligoprogression (OP) in this clinical setting.<br />
Methods: Pts diagnosed with stage III NSCLC who underwent concurrent CRT from<br />
2010 to 2014 at the Catalan Institute <strong>of</strong> <strong>Oncology</strong> were retrospectively studied.The<br />
recurrence pattern at the first progression was recorded. OPwas defined as a single<br />
metastatic site with no more than 3 lesions. Overall Survival (OS),Progression-Free<br />
Survival (PFS) and Postprogression OS (PPOS) were plotted using the Kaplan<br />
Meiermethod and multivariate Cox proportional hazards models were developed.<br />
Results: From 171 pts: median age 62 (37-81),male 87%; ECOG ≤ 1 92%; smoking<br />
status: current 49%, former 46%, never 5%; histology: adenocarcinoma (ADC) 34%,<br />
squamous (SCC) 43%, NSCLC (NOS + large cell) 23%; Stage:IIIA 51%, IIIB 49%;<br />
cN0-1 21%, cN2 60%, cN3 19%.Platinum doublet CT: Cisplatin 62%, Carboplatin 38%.<br />
Rate between 60 and 70 Gy:94%. At a median follow-up <strong>of</strong> 48months (m), 108 patients<br />
relapsed (63%), the mPFS was 13m (95% CI 10-16) and the mOS was 28m (95% CI<br />
22-34). Recurrence pattern: Distant (D) 36%; Loco-regional (LR) 33%;both(LR + D)<br />
30%.Twenty-five pts (23%) developed OP (48% ADC, 52% SCC) and the organs<br />
involved were17 visceral, 3 lymph nodes, 4 brain and 1 bone. Treatments performed in<br />
OP pts: 4 surgery, 4 stereotactic radiosurgery, 1 salvage CRT, 3 RT (WBRTx2 + 1 RTE<br />
20 Gy), 9 CT, 4 none. From all pts who progressed (n = 108)mOS was 26m for those<br />
who received 2nd line treatment (n = 77,72%), vs 13m for those without treatment<br />
(p < 0.037). OS was longer in pts with OP(32m) as compared to nonOP(18m,<br />
p < 0.007). In the multivariate Cox regressionanalysis <strong>of</strong> PPOS, OP stood out as a<br />
favourable prognostic factor (HR = 0.36, 95% CI 0.17-0.74) independently <strong>of</strong> age, stage,<br />
histology, ECOG PS, smoking history and platinum doublet.<br />
Conclusions: In this cohort, the frequency <strong>of</strong> OP was remarkable and associated with<br />
improved OS. Pts with OP that might benefit from salvage therapies should be better<br />
characterized and proactively detected during follow-up after definitive CRT.<br />
Legal entity responsible for the study: Institut Català d’Oncologia<br />
Funding: Institut Català d’Oncologia<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1193P<br />
Comparison <strong>of</strong> combined chemoradiotherapy regimens;<br />
Paclitaxel plus carboplatin and cisplatin plus etoposide for<br />
locally advanced non-small-cell lung cancer: A randomized<br />
phase III trial<br />
A. Ata 1 , A. Küçük 2 , E. Nayir 3 ,Ş. Eskici 2<br />
1 Medical <strong>Oncology</strong>, Medical Park Hospital, Mersin, Turkey, 2 Radiation <strong>Oncology</strong>,<br />
Mersin State Hospital, Mersin, Turkey, 3 Medical <strong>Oncology</strong>, Necip Fazıl State<br />
Hospital, Kahramanmaras¸, Turkey<br />
Background: The optimal chemotherapy regimen to use with radiotherapy in stage III<br />
non–small-cell lung cancer (NSCLC) is unknown. This phase III comparative<br />
randomized trial was conducted to determine the optimal chemotherapy regimen with<br />
standard daily concurrent thoracic radiation therapy (CTRT), in patients with locally<br />
advanced unresected stage III NSCLC.<br />
Methods: We recruited 108 patients aged 18–72 years with stage III, histologically<br />
confirmed NSCLC, an Eastern Cooperative <strong>Oncology</strong> Group (ECOG) performance<br />
status <strong>of</strong> 0–2, an estimated life expectancy <strong>of</strong> greater than 3 months, and adequate<br />
organ function from January 2011 to December 2014. Patients were randomised (1:1)<br />
to paclitaxel plus carboplatin and cisplatin plus etoposide arms.<br />
Results: Patients with unresected stages IIIA and IIIB NSCLC received carboplatin<br />
(AUC = 2) and paclitaxel (45 mg/m 2 ) given weekly with CTRT (63 Gy) followed by<br />
two cycles <strong>of</strong> consolidation therapy (carboplatin AUC = 6, paclitaxel 200 mg/m 2 ) (arm<br />
CP) and cisplatin (50 mg/m 2 on days 1, 8, 29, and 36) plus etoposide (50 mg/m 2 daily<br />
on days 1 to 5, and 29 to 33) with CTRT followed by consolidation cisplatin plus<br />
etoposide (arm EP) were included. Ninety nine eligible patients were evaluated. With<br />
median follow-up time <strong>of</strong> 39.4 months, median overall survival was 17.1 and 16.6<br />
months for arms CP and EP, respectively (P = 0.279). But patients in arm EP,<br />
compared with patients in arm CP, had more grade 4 neutropenia (18.1% vs 11.1%,<br />
p < 0.001), grade 3-4 mucositis/esophagitis (22.2% vs 12.1%, p < 0.001) and acute<br />
kidney disease (27.2% vs 14.1%, p < 0.001).<br />
Conclusions: In patients with stage III NSCLC treated with cisplatin plus etoposide<br />
and carboplatin plus paclitaxel had similar overall survival, but cisplatin plus etoposide<br />
arm was associated with increased toxicity.<br />
Legal entity responsible for the study: N/A<br />
Funding: Turkish <strong>Oncology</strong> Group<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1194P<br />
Reaching the pinnacle <strong>of</strong> stage III NSCLC treatment<br />
A. D’Silva 1 , H. Lau 2 , S. Otsuka 1 , R. Tudor 1 , D.G. Bebb 2<br />
1 <strong>Oncology</strong>, Faculty <strong>of</strong> Medicine, University <strong>of</strong> Calgary, Calgary, AB, Canada,<br />
2 Medical <strong>Oncology</strong>, Tom Baker Cancer Centre, Calgary, AB, Canada<br />
Background: Standard treatment for stage III non-small cell lung cancer (NSCLC) is<br />
concurrent radical chemo-radiation (CRCR). However, many stage III patients are not<br />
candidates for CRCR and there is no level I based consensus on the optimal chemotherapy,<br />
duration <strong>of</strong> systemic treatment or dose <strong>of</strong> radiation. We examined the uptake and outcome<br />
<strong>of</strong> CRCR at the Tom Baker Cancer Centre (TBCC) over a 12 year period.<br />
Methods: The Glans-Look Lung Cancer database was used to identify all stage III<br />
NSCLC patients seen at the TBCC January 1 st 1999 to June 30 th 2012. Basic<br />
demographics, treatment, progression date, and overall survival were reviewed. Median<br />
survival (MS) was compared between different treatment modalities using<br />
Kaplan-Meier survival analysis. Radical radiation (RR) was defined as ≥60G.<br />
Results: 1232 stage III NSCLC patients were identified, median age 69, 55% male, 90%<br />
current or former smokers, and MS <strong>of</strong> 14.7 months (m) (95% CI, 13.7, 15.8). 74%<br />
received radiation therapy (MS 16.6 m) <strong>of</strong> whom 73% received palliative radiation with<br />
MS <strong>of</strong> 15.3 m (95% CI, 14.2, 16.4). The 27% who received RR had a MS <strong>of</strong> 24.1 m (95%<br />
CI, 21.0, 27.3; p < 0.001). Median age <strong>of</strong> those who received RR vs palliative radiation<br />
was 63.8 vs 66.8 years (p < 0.001). No statistically significant differences were found<br />
based on histology or smoking history. Of those who received RR, 91% did so in<br />
combination with platin-based chemotherapy MS <strong>of</strong> 28.9 m (95% CI, 26.6, 31.1) vs<br />
16.6 m with RR alone (95% CI, 13.6, 19.6; p = 0.484). 73.5% <strong>of</strong> patients treated with<br />
concurrent platin-based chemotherapy received Vinorelbine as the second drug, (MS<br />
24.5 m; 95% CI, 20.6. 28.4), 14.4% Etoposide (MS 18.9 m; 95% CI, 4.9, 33.0), and<br />
12.1% Paclitaxel (MS 32.4 m; 95% CI, 17.7, 47.2). No statistically significant survival<br />
differences were observed based on the number <strong>of</strong> cycles received (≤2or≥3; p = 0.174).<br />
RR uptake has not increased since 1999 (R 2 = 0.002).<br />
Conclusions: Although the highest MS in stage III NSCLC patients is associated with<br />
CRCR, almost 80% did not receive guideline recommended treatment for their disease.<br />
In this retrospective study, platin/Paclitaxel <strong>of</strong>fered highest MS, however the uptake <strong>of</strong><br />
CRCR has plateaued. New, more palatable treatment for Stage III NSCLC is required.<br />
Legal entity responsible for the study: University <strong>of</strong> Calgary<br />
Funding: Private donations<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1195P<br />
abstracts<br />
Final overall survival (OS) results <strong>of</strong> the feasibility study <strong>of</strong><br />
adjuvant chemotherapy with docetaxel (DOC) plus cisplatin<br />
(CDDP) followed by maintenance chemotherapy <strong>of</strong> S-1 in<br />
completely resected non-small cell lung cancer (NSCLC):<br />
Thoracic <strong>Oncology</strong> Research Group (TORG) 0809<br />
S. Niho 1 , N. Ikeda 2 , H. Michimae 3 , K. Suzuki 4 , H. Sakai 5 , T. Kaburagi 6 ,<br />
K. Yoshiya 7 , K. Minato 8 ,T.Kato 9 , H. Okamoto 10 , T. Seto 11 , Y. Hosomi 12 ,<br />
K. Shimizu 13 , H. Saito 14 , M. Tsuchida 15 , H. Kunitoh 16 , M. Tsuboi 17 , M. Takeuchi 3 ,<br />
K. Watanabe 18<br />
1 Department <strong>of</strong> Thoracic <strong>Oncology</strong>, National Cancer Center Hospital East,<br />
Kashiwa, Japan, 2 Department <strong>of</strong> Surgery, Tokyo Medical University Hospital,<br />
Tokyo, Japan, 3 Department <strong>of</strong> Biostatistics and Pharmaceutical Medicine, School<br />
<strong>of</strong> Pharmaceutical Sciences, Kitasato University School <strong>of</strong> Medicine, Tokyo,<br />
Japan, 4 Thoracic Surgery, Juntendo University Hospital, Tokyo, Japan, 5 Thoracic<br />
<strong>Oncology</strong>, Saitama Cancer Center, Saitama, Japan, 6 Department <strong>of</strong> Respiratory<br />
Medicine, Ibaraki Prefectural Central Hospital, Kasama, Japan, 7 Division <strong>of</strong> Chest<br />
Surgery, Niigata Cancer Center Hospital, Niigata, Japan, 8 Department <strong>of</strong><br />
Respiratory Medicine, Gunma Prefectural Cancer Center, Ota, Japan,<br />
9 Department <strong>of</strong> Respiratory Medicine, Kanagawa Cardiovascular and Respiratory<br />
Center, Yokohama, Japan, 10 Department <strong>of</strong> Respiratory Medicine, Yokohama<br />
Municipal Citizen’s Hospital, Yokohama, Japan, 11 Department <strong>of</strong> Thoracic<br />
<strong>Oncology</strong>, National Kyushu Cancer Center, Fukuoka, Japan, 12 Department <strong>of</strong><br />
Thoracic <strong>Oncology</strong> and Respiratory Medicine, Tokyo Metropolitan Cancer and<br />
Infectious Diseases Center Komagome Hospital, Tokyo, Japan, 13 Department <strong>of</strong><br />
Thoracic and Visceral Organ Surgery, Gunma University Faculty <strong>of</strong> Medicine,<br />
Maebashi, Japan, 14 Department <strong>of</strong> Thoracic <strong>Oncology</strong>, Kanagawa Cancer Center,<br />
Yokohama, Japan, 15 Division <strong>of</strong> Thoracic and Cardiovascular Surgery, Niigata<br />
University Medical and Dental Hospital, Niigata, Japan, 16 Division <strong>of</strong><br />
Chemotherapy, Department <strong>of</strong> Internal Medicine, Japanese Red Cross Medical<br />
Center, Tokyo, Japan, 17 Thoracic Surgery & <strong>Oncology</strong>, National Cancer Center<br />
Hospital East, Kashiwa, Japan, 18 TORG0809 study group, Thoracic <strong>Oncology</strong><br />
Research Group, Yokohama, Japan<br />
Background: Efficacy <strong>of</strong> maintenance chemotherapy with oral S-1 (tegafur, 5-chloro-2,<br />
4-dihydroxypyridine, and potassium oxonate) following post-operative DOC + CDDP<br />
in patients with completely resected stage II and IIIA (according to the UICC 5th<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw382 | vi413
abstracts<br />
edition) NSCLC was evaluated; feasibility, safety and compliance data were previously<br />
reported (Niho S, et al. BJC 2013; 109, 545-51).<br />
Methods: Patients received 3 cycles <strong>of</strong> DOC (60mg/m2, d1) plus CDDP (80mg/m2,<br />
d1), q3-4w, and subsequently received S-1 at 40mg/m2 twice daily for 14 consecutive<br />
days, q3w, for more than 6 months (maximum, 1 year).<br />
Results: Between June 2009 and November 2010, 131 patients were enrolled in this<br />
study from 20 institutions in Japan. A total <strong>of</strong> 129 patients were eligible and assessable.<br />
The median age was 63 years (range, 23-74 years); 17 patients had p-stage IIA, 32 had<br />
IIB, and 80 had IIIA; 100 patients had adenocarcinoma, and 29 had<br />
non-adenocarcinoma. Of the 129 patients, 109 patients (84.5%) completed 3 cycles <strong>of</strong><br />
DOC + CDDP, and 66 patients (51.2%) completed 8 or more cycles <strong>of</strong> S-1 treatment.<br />
At the cut<strong>of</strong>f date <strong>of</strong> April 13, 2016, median follow-up time was 5.9 years. Forty-three<br />
patients had died, and 74 patients had recurred or died. Median OS time has not been<br />
reached. The five-year OS rate was 70% (95%CI, 61 to 77). The-five-year OS rates<br />
among patients with stage II and IIIA were 73% and 68%, respectively. Median<br />
recurrence-free survival (RFS) time was 3.6 years (95%CI, 2.4-). The five-year RFS rate<br />
was 44% (95%CI, 35 to 53). The five-year RFS rates among patients with stage II and<br />
IIIA were 57% and 36%, respectively.<br />
Conclusions: Survival data in this study is promising. Analysis about post-study<br />
treatment after recurrence will be also presented.<br />
Clinical trial identification: UMIN000001779<br />
Legal entity responsible for the study: N/A<br />
Funding: Taiho Pharmaceutical Co., Ltd. Funding<br />
Disclosure: S. Niho: Honoraria from Taiho. Research funding from Pfizer, Lilly, and<br />
AstraZeneca. N. Ikeda: Honoraria from Taiho and Aventis. Research funding from<br />
Taiho and Aventis. K. Suzuki, M. Tsuboi: Honoraria from Taiho. H. Sakai: Honoraria<br />
form Taiho, Aventis, Chugai, and Lilly. T. Kato, H. Kunitoh: Honoraria from Taiho and<br />
Aventis. H. Okamoto: Honoraria from Chugai, Aventis, Lilly, Kyowa, Taiho, and<br />
Janssen.T. Seto: Honoraria from Taiho and Aventis. Research funding from Taiho. All<br />
other authors have declared no conflicts <strong>of</strong> interest.<br />
1196P<br />
Secondary efficacy results from a phase 3 study comparing<br />
efficacy and safety <strong>of</strong> biosimilar candidate ABP 215 with<br />
bevacizumab in patients with non-squamous non-small cell<br />
lung cancer (NSCLC)<br />
N. Thatcher 1 , M. Thomas 2 , G. Ostoros 3 ,J.Pan 4 , J. Goldschmidt 5 , V. Hanes 4<br />
1 Medical <strong>Oncology</strong>, The Christie NHS Foundation Trust, Manchester, UK,<br />
2 Internistische Onkologie der Thoraxtumoren, Thoraxklinik Heidelberg, Heidelberg,<br />
Germany, 3 3Koranyi National institute for TB and Pulmonology, National Koranyi<br />
Institute <strong>of</strong> Pulmonology, Budapest, Hungary, 4 Biosimilars, Amgen, Inc.,<br />
Thousand Oaks, CA, USA, 5 <strong>Oncology</strong> and Hematology Associates <strong>of</strong> Southwest<br />
Virginia, US <strong>Oncology</strong> Research, McKesson Specialty Health, Blue Ridge Cancer<br />
Care, Christianburg, VA, USA<br />
Background: ABP 215 is a biosimilar candidate to bevacizumab, a VEGF inhibitor.<br />
Analytical, functional and pharmacokinetic similarity assessments between ABP 215<br />
and bevacizumab have been completed. Here we present results <strong>of</strong> secondary efficacy<br />
variables, focusing on the risk difference (RD) <strong>of</strong> the overall response rate (ORR) and<br />
progression-free survival (PFS). Primary efficacy and safety results from this phase 3<br />
study have been previously reported.<br />
Methods: In this randomized, double-blind, active-controlled study in adults with<br />
NSCLC receiving first-line chemotherapy with carboplatin and paclitaxel, patients were<br />
randomized (1:1) to receive 15 mg/kg <strong>of</strong> the investigational product (IP) (ABP 215 or<br />
bevacizumab) administered as an IV infusion every 3 weeks for 6 cycles. Patients<br />
remained on treatment until 21 days after the last dose <strong>of</strong> IP or study-specified<br />
chemotherapy. Clinical equivalence was demonstrated by comparing the 2-sided 90%<br />
confidence interval (CI) <strong>of</strong> the risk ratio <strong>of</strong> ORR (primary endpoint) between patients<br />
randomized to each study arm with the margin <strong>of</strong> (0.67, 1.5).<br />
Results: A total <strong>of</strong> 328 and 314 patients were randomized to ABP 215 (Arm 1) and<br />
bevacizumab (Arm 2) groups; the groups were balanced in demographic and baseline<br />
characteristics. There were 128 (39.0%) responders in Arm 1 and 131 (41.7%) in Arm<br />
2. The RD for ORR was −2.90% (90% CI: −9.26%–3.45%; 95% CI: −10.48%–4.67%).<br />
The PFS analysis included 256 events; 131 patients (39.9%) in Arm 1 and 125 patients<br />
(39.8%) in Arm 2 in the intent-to-treat population had progressed or died before the<br />
study ended. The estimated hazard ratio from a stratified Cox proportional hazards<br />
regression model (Arm 1 relative to Arm 2) was 1.03 (90% CI: 0.83–1.29; 95% CI: 0.80–<br />
1.34) ). Safety results were comparable between groups (previously reported). Patients<br />
developing binding antibodies were 1.4% in Arm 1 vs 2.5% in Arm 2; no subject tested<br />
positive for neutralizing antibodies.<br />
Conclusions: Along with the primary efficacy results <strong>of</strong> this study, these data are<br />
further evidence <strong>of</strong> clinical equivalence between ABP 215 and bevacizumab in this<br />
patient population.<br />
Clinical trial identification: NCT01966003<br />
Legal entity responsible for the study: N/A<br />
Funding: Amgen, Inc.<br />
Disclosure: N. Thatcher: Received honoraria from Lilly, Amgen, Boehringer Ingelheim<br />
(BI), Otsuka and Roche. Received consulting/advisory payments from Lilly, Amgen, BI,<br />
Otsuka Served on Speaker Bureau for Lilly, BI, Otsuka, Roche Provided paid testimony<br />
on behalf <strong>of</strong> Lilly. M. Thomas: Received honoraria, consulting/advisory payment from<br />
BMS, MSD, AZ, Lilly, Novartis, Roche, Celgene, Pfizer Received research funding from<br />
BMS, MSD, AstraZeneca Received travel, accomodations, expenses from Pfizer, BMS,<br />
Lilly. G. Ostoros: Investigator, Amgen. J. Pan, V. Hanes: Amgen employee and<br />
stockholder. J. Goldschmidt: Received honoraria from Roche/Genentech, BMS,<br />
Celgene Received consulting/advisory payments from BMS Served on speakers’ bureau<br />
for Roche, BMS, Celgene Received travel, accomodations, expenses from Roche, BMS.<br />
1197P<br />
Pathologic response and survival after cisplatin, pemetrexed,<br />
and bevacizumab followed by surgery for clinical stage II/IIIA<br />
non-squamous non-small cell lung cancer<br />
Y. Tsutani 1 , Y. Miyata 1 , K. Suzuki 2 , K. Takamochi 2 , F. Tanaka 3 , H. Nakayama 4 ,<br />
Y. Yamashita 5 , M. Oda 6 , M. Tsuboi 7 , M. Okada 1<br />
1 Surgical <strong>Oncology</strong>, Hiroshima University, Hiroshima, Japan, 2 General Thoracic<br />
Surgery, Juntendo University School <strong>of</strong> Medicine, Tokyo, Japan, 3 Thoracic<br />
Surgery, University <strong>of</strong> Occupational and Environmental Health, Kitakyushu, Japan,<br />
4 Thoracic Surgery, Kanagawa Cancer Center, Yokohama, Japan, 5 Thoracic<br />
Surgery, Kure Medical Center/Chugoku Cancer Center, Kure, Japan, 6 Thoracic<br />
Surgery, Kanazawa University, Kanazawa, Japan, 7 Thoracic Surgery & <strong>Oncology</strong>,<br />
National Cancer Center Hospital East, Kashiwa, Japan<br />
Background: Pathologic response after neoadjuvant therapy may be a surrogate<br />
marker <strong>of</strong> survival for lung cancer patients. The purpose <strong>of</strong> this study is to investigate<br />
the prognostic role <strong>of</strong> pathologic response after neoadjuvant chemotherapy with<br />
bevacizumab (BEV) in patients with clinical stage II/IIIA non-squamous non-small cell<br />
lung cancer (NSCLC).<br />
Methods: In a phase II feasibility study <strong>of</strong> neoadjuvant chemotherapy with cisplatin<br />
(CDDP), pemetrexed (PEM), and BEV followed by surgery for resectable clinical stage<br />
II/IIIA non-squamous NSCLC (NAVAL study), the relationships between pathologic<br />
response and recurrence-free survival (RFS) or overall survival (OS) were analyzed.<br />
Less than 33% residual viable primary tumor after neoadjuvant chemotherapy was<br />
defined as pathologic response. None <strong>of</strong> study patient received postoperative adjuvant<br />
chemotherapy.<br />
Results: Twenty-five <strong>of</strong> 30 (83%) study patients underwent surgery after 3 cycles <strong>of</strong><br />
neoadjuvant CDDP (75 mg/m2) + PEM (500 mg/m2) + BEV (15 mg/kg). Twenty-two<br />
(88%) and 3 (12%) patients underwent lobectomy and bilobectomy with systematic<br />
lymphadenectomy, respectively. Six (24%) patients were classified as pathologic<br />
responders, whereas 19 (76%) as non-responders. Three (12%) patients achieved<br />
pathologic complete response. Pathologic responders significantly correlated to RFS<br />
with 3-year RFS for pathologic responders <strong>of</strong> 100% versus 15.8% for non-responders<br />
(P = 0.002). Similar trend was observed in OS with 3-year OS for pathologic responders<br />
<strong>of</strong> 100% versus 63.2% for non-responders (P = 0.102).<br />
Conclusions: Pathologic response can be a surrogate marker for survival in patients<br />
who underwent surgery after neoadjuvant CDDP + PEM + BEV. Additional treatment<br />
such as postoperative adjuvant chemotherapy may be needed for pathologic<br />
non-responders.<br />
Clinical trial identification: UMIN000004278<br />
Legal entity responsible for the study: Morihito Okada<br />
Funding: Hiroshima University<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1198P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
First site <strong>of</strong> relapse can predict different clinical courses in<br />
recurrent stage IIIA non-small cell lung cancer after definitive<br />
chemoradiotherapy<br />
K. Goto 1 , H. Horinouchi 1 , Y. Goto 1 , S. Kanda 1 , Y. Fujiwara 1 , H. Nokihara 2 ,<br />
N. Yamamoto 1 ,Y.Ohe 1<br />
1 Department <strong>of</strong> Thoracic <strong>Oncology</strong>, National Cancer Center Hospital, Tokyo,<br />
Japan, 2 National Cancer, Center Hospital, Tokyo, Japan<br />
Background: The standard treatment for stage IIIA non-small cell lung cancer<br />
(NSCLC) is definitive chemoradiotherapy (dCRT). However, approximately 80% <strong>of</strong><br />
patients experience relapse, resulting in a poor prognosis. The aim <strong>of</strong> this study was to<br />
evaluate the relapse patterns <strong>of</strong> patients with stage IIIA NSCLC after dCRT and their<br />
clinical courses.<br />
Methods: A retrospective review <strong>of</strong> patients treated for stage IIIA NSCLC at the<br />
National Cancer Center between 2002 and 2011 was performed. Data on patients<br />
characteristics, the first relapse site after dCRT (inside or outside <strong>of</strong> the radiotherapy<br />
field, presence or absence <strong>of</strong> brain metastasis), salvage treatment, and the disease<br />
progression site after salvage treatment were collected. The post-progression overall<br />
survival (PPOS) was evaluated using the Kaplan-Meier method.<br />
Results: Among the 152 patients who were treated with dCRT, 115 (76%) relapsed and<br />
were included in this analysis. Of these, infield recurrence (IR) and brain metastasis<br />
(BM) as a first relapse were observed in 30 (26%) and 14 (12%) patients, respectively.<br />
The other 71 patients (62%) experienced mixed recurrences (MR) including infield and<br />
distant metastases. Salvage treatments including radiotherapy, chemotherapy, and<br />
vi414 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
surgery were performed in 83 (72%) patients. In patients with IR, 2 patients (7%)<br />
underwent surgery, and the others were treated using chemotherapy. The median<br />
PPOS (mPPOS) and the 3-year PPOS (3yPPOS) rate in patients with IR were 16.8<br />
months and 0%, respectively. All the patients with BM underwent local radiotherapy.<br />
The mPPOS and the 3yPPOS rate in patients with BM were 25.3 months and 39.3%,<br />
respectively. After salvage treatment, 17 (56%) <strong>of</strong> the 30 patients with IR experienced<br />
infield disease progression, and 10 (71%) <strong>of</strong> the 14 patients with BM developed CNS<br />
progression. In patients with MR, the mPPOS and 3yPPOS rate were 10.9 months and<br />
17.2%, respectively.<br />
Conclusions: Patients with IR tended to have a poorer prognosis than those with other<br />
patterns <strong>of</strong> relapse because <strong>of</strong> persistent local disease progression, while patients with<br />
BM experienced a better survival outcome. The development <strong>of</strong> an effective salvage<br />
therapy taking the recurrence pattern into account is mandatory.<br />
Clinical trial identification: The study protocol was approved by the institutional<br />
review boards <strong>of</strong> theNational Cancer Center Hospital (number: 2015-355)<br />
Legal entity responsible for the study: National Cancer Center<br />
Funding: N/A<br />
Disclosure: H. Horinouchi: Corporate-sponsored research: Taiho, Merck Serono,<br />
MSD, Astellas, Novartis. H. Nokihara: Honoraria: Boehringer Ingelheim, Taiho,<br />
AstraZeneca, Ono, San<strong>of</strong>i, Lilly Research Funding: Merck, Pfizer, Taiho, Eisai, Chugai,<br />
Lilly, Novartis, Daiichi Sankyo, GlaxoSmithKline, Yakult, Quintiles, Astellas,<br />
AstraZeneca, Boehringer Ingelheim, Ono. N. Yamamoto: Research funds (as<br />
institutions): Quintiles, Astellas, Chugai, Esai, Taiho, BMS, Pfizer, Novartis,<br />
Daiichi-Sankyo, Boehringer Ingelheim, Kyowa-Hakko Kirin. Honoraria: AstraZeneca,<br />
Pfizer, Lilly, Chugai. Y. Ohe: Reserch: AstraZeneca, Chugai, Lilly, Ono, BMS, Kyorin,<br />
Dainippon-Sumitomo, Pfizer, Taiho, Novaltis, Merc honoraria: AstraZeneca, Chugai,<br />
Lilly, Daiichi-Snkyo, Nippopnkayaku, Boehringer Ingelheim, Beyer, MSD, Taiho,<br />
Clovis, San<strong>of</strong>i. All other authors have declared no conflicts <strong>of</strong> interest.<br />
1199P<br />
Cardiotoxic effects <strong>of</strong> gemcitabin/cisplatin vs paclitaxel/<br />
carboplatin first-line chemotherapy in patients with<br />
advanced non-small cell lung cancer<br />
D.S. Bursac, T. Sarcev, D. Sazdanic Velikic, A. Tepavac<br />
Clinic for thoracic oncology, Department for chemotherapy, Institute for pulmonary<br />
diseases <strong>of</strong> Vojvodina, Novi Sad, Serbia<br />
Background: Introduction: The aim <strong>of</strong> this study was to establish the frequency <strong>of</strong><br />
cardiotoxicity in the patients treated with the first-line chemotherapy (gemcitabine/<br />
cisplatin and paclitaxel/carboplatin), with or without the history <strong>of</strong> cardiovascular<br />
co-morbidities.<br />
Methods: This prospective study included 240 patients with cytologically or<br />
histopathologically confirmed NSCLC at the clinical stages III and IV, divided into<br />
subgroups according to the type <strong>of</strong> chemotherapy and the presence <strong>of</strong> cardiovascular<br />
co-morbidities. Physical examination, electrocardiogram and NT-proBNP and<br />
troponin T levels were performed before and after the application <strong>of</strong> each cycle <strong>of</strong><br />
chemotherapy. Echocardiography was performed before and after chemotherapy, as<br />
well as in the follow-up examinations every three months, a total <strong>of</strong> one year. Cardiac<br />
toxicity was determined based on the presence <strong>of</strong> cardiovascular symptoms, changes in<br />
the electrocardiogram, elevated levels <strong>of</strong> NT-proBNP and troponin T and a decrease in<br />
left ventricular ejection fraction.<br />
Results: In the study group 184 patients (76.7%) were male. The most frequent was<br />
adenocarcinoma, in 120 patients (50%). Most common cardiovascular toxic effects<br />
were increase in the level <strong>of</strong> NT-proBNP (44.85%), cardiac arrhythmias (26.18%),<br />
venous thromboembolism (19.9%) and decreased left ventricular ejection fraction<br />
(6.96%). Patients treated with the first-line chemotherapy gemcitabine/cisplatin<br />
developed cardiotoxicity more frequently if they had a former history <strong>of</strong> cardiovascular<br />
diseases, but without statistical significance. Patients treated with the first-line<br />
chemotherapy paclitaxel/carboplatin developed cardiotoxicity more frequently if they<br />
had a former history <strong>of</strong> cardiovascular diseases, and the statistical significance was<br />
registered at the first follow-up examination in stage III NSCLC patients (p = 0.037).<br />
Conclusions: Chemotherapy induced cardiotoxocity frequently occurs in patients with<br />
cardiovascular co-morbidities. Balance between the effectiveness <strong>of</strong> chemotherapy and<br />
the risk <strong>of</strong> cardiotoxicity requires close cooperation oncologists and cardiologists, with<br />
the aim <strong>of</strong> creating individual therapy for each patient<br />
Legal entity responsible for the study: N/A<br />
Funding: The Faculty <strong>of</strong> Medicine Novi Sad<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1200P<br />
The impact <strong>of</strong> staging by positron emission tomography (PET)<br />
on overall survival (OS) and progression-free survival (PFS) in<br />
the phase III PROCLAIM study<br />
N. Iscoe 1 , R. Govindan 2 , A.M. Hossain 3 , B. San Antonio 4 , N. Chouaki 5 ,<br />
M. Koczywas 6 , E. Vokes 7 , S. Senan 8<br />
1 Global Medical Affairs, Eli Lilly and Company, Toronto, ON, Canada, 2 Division <strong>of</strong><br />
<strong>Oncology</strong>, Washington University School <strong>of</strong> Medicine, St. Louis, MO, USA,<br />
3 Statistics, Eli Lilly and Company, Indianapolis, IN, USA, 4 Medical, Eli Lilly and<br />
Company, Madrid, Spain, 5 <strong>Oncology</strong>, Eli Lilly and Company, Neuilly Sur Seine,<br />
France, 6 Medical <strong>Oncology</strong> & Therapeutic Research, City <strong>of</strong> Hope, Duarte, CA,<br />
USA, 7 Hematology/<strong>Oncology</strong>, The University <strong>of</strong> Chicago Medical Centre, Chicago,<br />
IL, USA, 8 Radiotherapy <strong>Oncology</strong>, Vrije University Medical Centre (VUMC),<br />
Amsterdam, Netherlands<br />
Background: Real-world evidence <strong>of</strong> the significant impact <strong>of</strong> PET staging on survival<br />
outcomes because <strong>of</strong> stage migration (upstaging) has been previously documented.<br />
However, the effect <strong>of</strong> stage migration as a result <strong>of</strong> PET has rarely been measured in<br />
randomized trials in the locally advanced (stage IIIA/B) setting. Here, we report the<br />
results from post-hoc subgroup analyses based on PET scan use in non-small cell lung<br />
cancer (NSCLC) patients in the PROCLAIM study.<br />
Methods: The intent-to-treat (ITT) population <strong>of</strong> 598 patients with stage IIIA/B<br />
nonsquamous NSCLC were randomized to either pemetrexed (Pem) plus cisplatin<br />
(Cis) and concurrent radiotherapy (RT) for 3 cycles, followed by 4 cycles <strong>of</strong> Pem<br />
consolidation, or etoposide plus Cis and concurrent RT for 2 cycles, followed by a<br />
consolidation platinum-based doublet regimen for up to 2 cycles. PET scan (yes vs no)<br />
was one <strong>of</strong> the stratification factors since its use was not required per protocol.<br />
Subgroup analyses (yes vs no PET) <strong>of</strong> OS and PFS were conducted on the ITT<br />
population regardless <strong>of</strong> treatment since the study did not demonstrate superior<br />
efficacy for either arm. Kaplan-Meier methods and Cox regression models were used to<br />
estimate hazard ratios.<br />
Results: Of the 598 patients, the majority (n = 491; 82.1%) had PET scan staging<br />
performed. The OS and PFS by PET scan use are presented in the table. In addition,<br />
results <strong>of</strong> subgroup analyses for each treatment arm were consistent with those <strong>of</strong> the<br />
ITT population.<br />
Table: 1200P PFS and OS by PET Use<br />
Intent-to-Treat Patients PET Scan<br />
Yes (N = 491) No (N = 107)<br />
Median OS, months 27.2 20.8<br />
95% CI 22.6, 31.0 16.5, 26.3<br />
HR (95% CI) 0.81 (0.62, 1.06)<br />
Log-rank P-value 0.130<br />
Median PFS, months 11.3 9.2<br />
95% CI 9.8, 12.5 8.8, 11.3<br />
HR (95% CI) 0.73 (0.56, 0.93)<br />
Log-rank P-value 0.012<br />
CI, confidence interval; HR, hazard ratio; N, number <strong>of</strong> patients<br />
Conclusions: Both a significantly improved PFS and a numerically longer OS in the<br />
subgroup <strong>of</strong> patients with PET scans, compared to patients with conventional staging,<br />
are consistent with improved survival due to stage migration. The magnitude <strong>of</strong><br />
differences in OS and PFS based on PET is a reminder <strong>of</strong> the potential for factors other<br />
than the therapeutic intervention to affect outcomes.<br />
Clinical trial identification: NCT00686959<br />
Legal entity responsible for the study: Eli Lilly and Company<br />
Funding: Eli Lilly and Company<br />
Disclosure: N. Iscoe: Employee <strong>of</strong> Eli Lilly Canada Inc. R. Govindan: Boehringer<br />
Ingelheim, GSK, Celgene, Roche, Bayer, Genentech, Clovis, Helsinn Healthcare,<br />
Baxalta, Astellas, ARAID Pharmaceuticals. A.M. Hossain: Employed by Eli Lilly and<br />
Company. B. San Antonio, N. Chouaki: Employee <strong>of</strong> Eli Lilly and Company.E. Vokes:<br />
Amgen, AstraZeneca, Boehringer Ingelheim, Celgene, Lilly, Genentech, Merck, Synta,<br />
VentiRx.S. Senan: Lilly, Varian Medical Systems. All other authors have declared no<br />
conflicts <strong>of</strong> interest.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw382 | vi415
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong> 27 (Supplement 6): vi416–vi454, 2016<br />
doi:10.1093/annonc/mdw383<br />
NSCLC, metastatic<br />
1201O<br />
Gefitinib/chemotherapy vs chemotherapy in EGFR<br />
mutation-positive NSCLC after progression on 1st line<br />
gefitinib (IMPRESS study): Final overall survival (OS) analysis<br />
abstracts<br />
J-C. Soria 1 , S-W. Kim 2 , Y-L. Wu 3 , K. Nakagawa 4 , J-J. Yang 3 , M-J. Ahn 5 ,<br />
J. Wang 6 , J.C-H. Yang 7 ,Y.Lu 8 , S. Atagi 9 , S. Ponce Aix 10 , Y. Rukazenkov 11 ,<br />
R. Taylor 11 , T.S.K. Mok 12<br />
1 Department <strong>of</strong> Medicine, Institut de Cancérologie Gustave Roussy, Villejuif,<br />
France, 2 Department <strong>of</strong> <strong>Oncology</strong>, Asan Medical Center, University <strong>of</strong> Ulsan<br />
College <strong>of</strong> Medicine, Seoul, Republic <strong>of</strong> Korea, 3 Guandong Lung Cancer Institute,<br />
Guangdong General Hospital, Guangzhou, China, 4 Department <strong>of</strong> Medical<br />
<strong>Oncology</strong>, Kindai University, Osaka, Japan, 5 Department <strong>of</strong> Medicine, Samsung<br />
Medical Center Sungkyunkwan University School <strong>of</strong> Medicine, Seoul, Republic <strong>of</strong><br />
Korea, 6 Department <strong>of</strong> Thoracic Medical <strong>Oncology</strong>, Beijing Cancer Hospital and<br />
Institute, Beijing, China, 7 Department <strong>of</strong> <strong>Oncology</strong>, National Taiwan University<br />
Hospital, Taipei, Taiwan, 8 Department <strong>of</strong> Thoracic Cancer, West China Medical<br />
School, Sichuan University, Sichuan, China, 9 Department <strong>of</strong> Thoracic <strong>Oncology</strong>,<br />
Kinki-chuo Chest Medical Center, Osaka, Japan, 10 Medical <strong>Oncology</strong> Service,<br />
University Hospital 12 De Octubre, Madrid, Spain, 11 Global Medicines<br />
Development, AstraZeneca, Macclesfield, UK, 12 Department <strong>of</strong> Clinical <strong>Oncology</strong>,<br />
Chinese University <strong>of</strong> Hong Kong Prince <strong>of</strong> Wales Hospital, Hong Kong, China<br />
1202O<br />
Clinical and biological characteristics <strong>of</strong> non-small cell lung<br />
cancer (NSCLC) harbouring EGFR mutation: Results <strong>of</strong> the<br />
nationwide programme <strong>of</strong> the French Cooperative Thoracic<br />
Intergroup (IFCT)<br />
C. Leduc 1 , H. Blons 2 , B. Besse 3 , J-P. Merlio 4 , D. Debieuvre 5 , A. Lemoine 6 ,<br />
I. Monnet 7 , D. Pouessel 8 , P.P. Bringuier 9 , M. Poudenx 10 , I. Rouquette 11 ,<br />
F. Vaylet 12 , F. Morin 13 , A. Langlais 13 , E. Quoix 1 , G. Zalcman 14 , D. Moro-Sibilot 15 ,<br />
J. Cadranel 16 , M. Beau-Faller 1 , F. Barlesi 17<br />
1 Pneumologie, C.H.U. Strasbourg-Nouvel Hopital Civil, Strasbourg, France,<br />
2 Department <strong>of</strong> Biology, Hopital European George Pompidou, Paris, France,<br />
3 Departement <strong>of</strong> Medicine, Institut Gustave Roussy, Villejuif, France, 4 Biologie des<br />
tumeurs, CHU Hôpital Haut-Lévêque, Bordeaux, France, 5 Pneumologie, Hopital<br />
Emile Muller, Mulhouse, France, 6 Oncogenetics and Biochemistry, Hopital Paul<br />
Brousse, Villejuif, France, 7 Pneumologie, CHI de Créteil, Créteil, France, 8 Medical<br />
<strong>Oncology</strong>, Hôpital St. Louis, Paris, France, 9 Laboratoire Central d’Anatomie et de<br />
Cytologie Pathologiques, Groupement Hospitalier Edouard Herriot, Lyon, France,<br />
10 Medical <strong>Oncology</strong> departement, Centre Antoine Lacassagne, Nice, France,<br />
11 Pathology, Institut Universitaire du Cancer -Toulouse- Oncopole, Toulouse,<br />
France, 12 Pneumologie, Hôpital Militaire Percy, Clamart, France, 13 Clinical<br />
Research Unit, IFCT (Intergroupe Francophone de Cancérologie Thoracique).,<br />
Paris, France, 14 Pneumologie, Hopital Bichat Claude Bernard, Paris, France,<br />
15 Thoracic <strong>Oncology</strong>, CHU Grenoble - Hopital Michallon, La Tronche, France,<br />
16 Pneumology, APHP, CancerEst, Tenon University Hospital, Paris, France,<br />
17 Multidisciplinary <strong>Oncology</strong> and Therapeutic Innovations Department,<br />
Aix-Marseille University - Faculté de Médecine Nord, Marseille, France<br />
© European Society for Medical <strong>Oncology</strong> 2016. Published by Oxford University Press on behalf <strong>of</strong> the European Society for Medical <strong>Oncology</strong>.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com.
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
1208O<br />
Phase 2 study <strong>of</strong> ceritinib in ALKi-naïve patients (pts) with<br />
ALK-rearranged (ALK+) non-small cell lung cancer (NSCLC):<br />
Whole body responses in the overall pt group and in pts with<br />
baseline brain metastases (BM)<br />
E. Felip 1 , S. Orlov 2 , K. Park 3 , C-J. Yu 4 , C-M. Tsai 5 , M. Nishio 6 , M.C. Dols 7 ,<br />
M. McKeage 8 , W-C. Su 9 , T.S.K. Mok 10 , G. Scagliotti 11 , D.R. Spigel 12 ,V.<br />
Q. Passos 13 , V. Chen 13 , F. Munarini 14 , A. Shaw 15<br />
1 Medical <strong>Oncology</strong>, Vall d’Hebron University Hospital Institut d’Oncologia,<br />
Barcelona, Spain, 2 Thoracic <strong>Oncology</strong>, Saint Petersburg State Pavlov Medical<br />
University, St-Petersburg, Russian Federation, 3 Hematology/<strong>Oncology</strong>, Innovative<br />
Cancer Medicine Institute, Seoul, Republic <strong>of</strong> Korea, 4 Internal Medicine, National<br />
Taiwan University College <strong>of</strong> Medicine, Taipei, Taiwan, 5 Thoracic <strong>Oncology</strong>, Taipei<br />
Veterans General Hospital, Taipei, Taiwan, 6 Thoracic Medical <strong>Oncology</strong>, Cancer<br />
Institute Hospital <strong>of</strong> JFCR, Tokyo, Japan, 7 Medical <strong>Oncology</strong>, Hospital<br />
Universitario Málaga General Carlos Haya, Malaga, Spain, 8 Clinical Pharmacology,<br />
University <strong>of</strong> Auckland, Auckland, New Zealand, 9 Internal Medicine, National<br />
Cheng Kung University Hospital, Tainan, Taiwan, 10 Clinical <strong>Oncology</strong>, Chinese<br />
University <strong>of</strong> Hong Kong, Hong Kong, China, 11 <strong>Oncology</strong>, University <strong>of</strong> Turin,<br />
Orbassano, Italy, 12 Medical <strong>Oncology</strong>, Sarah Cannon Research Institute, Nashville,<br />
TN, USA, 13 <strong>Oncology</strong>, Novartis Pharmaceuticals Corporation, East Hanover, NJ,<br />
USA, 14 <strong>Oncology</strong> Clinical Development, Novartis Pharma AG, Basel, Switzerland,<br />
15 Cancer Center, Massachusetts General Hospital, Boston, MA,USA<br />
1203PD<br />
LURET study: Phase 2 study <strong>of</strong> vandetanib in patients with<br />
advanced RET-rearranged non-small cell lung cancer<br />
(NSCLC)<br />
A. Horiike 1 ,K.Yoh 2 , T. Seto 3 , M. Satouchi 4 , M. Nishio 1 , N. Yamamoto 5 ,<br />
H. Murakami 6 , N. Nogami 7 , S. Nomura 8 ,A.Sato 9 , A. Ohtsu 10 , K. Goto 2<br />
1 Department <strong>of</strong> Thoracic Medical <strong>Oncology</strong>, The Cancer Institute Hospital <strong>of</strong><br />
Japanese Foundation for Cancer Research, Tokyo, Japan, 2 Department <strong>of</strong><br />
Thoracic <strong>Oncology</strong>, National Cancer Center Hospital East, Kashiwa, Japan,<br />
3 Department <strong>of</strong> Thoracic <strong>Oncology</strong>, National Kyushu Cancer Center, Fukuoka,<br />
Japan, 4 Thoracic <strong>Oncology</strong>, Hyogo Cancer Center, Akashi, Japan, 5 Department <strong>of</strong><br />
Thoracic <strong>Oncology</strong>, National Cancer Center Hospital, Tokyo, Japan, 6 Division <strong>of</strong><br />
Thoracic <strong>Oncology</strong>, Shizuoka Cancer Center, Shizuoka, Japan, 7 Respiratory<br />
Medicine, Shikoku Cancer Center, Matsuyama, Japan, 8 Biostatistics Division,<br />
Center for Research Administration and Support, National Cancer Center Hospital<br />
East, Kashiwa, Japan, 9 Office <strong>of</strong> Clinical Research Support, National Cancer<br />
Center Hospital East, Kashiwa, Japan, 10 Department <strong>of</strong> Gastroenterology and<br />
Gastrointestinal <strong>Oncology</strong>, National Cancer Center Hospital East, Kashiwa, Japan<br />
Background: RET rearrangements were identified as a new rare oncogenic alteration in<br />
NSCLC. Vandetanib is a multi-targeted tyrosine kinase inhibitor having RET kinase<br />
inhibitory activity.<br />
Methods: This was a multicenter, single-arm phase 2 study to evaluate the efficacy and<br />
safety <strong>of</strong> vandetanib in patients with advanced RET-rearranged NSCLC who failed at<br />
least one prior chemotherapy. Vandetanib was administered orally at 300 mg once daily<br />
in 28-day cycles. RET positive-patients were screened by a nationwide genomic screening<br />
project with approximately 200 institutions in Japan participating (LC-SCRUM-Japan).<br />
The primary endpoint was the independently assessed objective response rate (ORR).<br />
Exploratory subgroup analyses for ORR and progression-free survival (PFS) were<br />
performed with the factors including sex, smoking status, and type <strong>of</strong> RET fusions.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw383 | vi417
abstracts<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Results: With screening <strong>of</strong> 1536 advanced NSCLC patients in the LC-SCRUM-Japan, 34<br />
RET positive-patients (2%) were identified. A total <strong>of</strong> 19 patients (10 KIF5B-RET, 6<br />
CCDC6-RET, and 3 unknown) were enrolled in this study and 17 patients were eligible<br />
for primary efficacy analysis. Half <strong>of</strong> the patients had been heavily treated with 3 or more<br />
prior chemotherapy (range, 1 to 12). Among 17 eligible patients, ORR was 53% (90% CI,<br />
31 to 74) <strong>of</strong> which 9 partial responses and no complete response met the primary<br />
endpoint. Of 19 patients in ITT population, disease control rate was 90% and median<br />
PFS was 4.7 months (95% CI, 2.8 to 8.5). In the subgroup analyses according to type <strong>of</strong><br />
RET fusions, ORR and median PFS were 83% (5/6) and 8.3 months in CCDC6-RET,<br />
20% (2/10) and 2.9 months in KIF5B-RET and 67% (2/3) and 4.7 months in unknown.<br />
There were no significant differences for ORR and PFS among sex and smoking status.<br />
The most common adverse events were hypertension (84%), diarrhea (79%), rash (63%),<br />
dry skin (42%), and QT corrected interval prolonged (42%).<br />
Conclusions: Vandetanib demonstrated effective antitumor activity and manageable<br />
safety pr<strong>of</strong>ile in patients with advanced RET-rearranged NSCLC. The exploratory<br />
subgroup analyses demonstrated that tumors with CCDC6-RET fusion showed greater<br />
response to vandetanib than those with KIF5B-RET fusion.<br />
Clinical trial identification: UMIN000010095<br />
Legal entity responsible for the study: N/A<br />
Funding: Grants from an Japan Agency for Medical Research and Development<br />
(AMED) Practical Research for Innovation Cancer Control.<br />
Disclosure: K. Yoh, M. Satouchi, M. Nishio: Honoraria: AstraZeneca. Research<br />
funding: AstraZeneca. T. Seto: Honoraria: AstraZeneca, San<strong>of</strong>i. Research funding:<br />
AstraZeneca. N. Yamamoto, H. Murakami, N. Nogami: Honoraria: AstraZeneca. S.<br />
Nomura: Mr. Nomura received personal fees from Japan Breast Cancer Research<br />
Group (JBCRG), and grants from Japan Agency for Medical Research and<br />
Development (AMED), outside the submitted work. JBCRG: €500 - €20’000 AMED:<br />
€500 - €20’000. K. Goto: Research funding: AstraZeneca. All other authors have<br />
declared no conflicts <strong>of</strong> interest.<br />
1204PD<br />
Phase 2 study <strong>of</strong> lenvatinib (LN) in patients (Pts) with RET<br />
fusion-positive adenocarcinoma <strong>of</strong> the lung<br />
V. Velcheti 1 , T. Hida 2 , K.L. Reckamp 3 , J.C. Yang 4 , H. Nokihara 5 , P. Sachdev 6 ,<br />
K. Feit 6 , T. Kubota 7 , T. Nakada 7 , C.E. Dutcus 6 ,M.Ren 6 , T. Tamura 8<br />
1 Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA, 2 Aichi Cancer<br />
Center Hospital, <strong>Oncology</strong>, Nagoya, Japan, 3 City <strong>of</strong> Hope, Hospital, Duarte, CA,<br />
USA, 4 National Taiwan University Hospital, And National Taiwan University Cancer<br />
Center, Taipei City, Taiwan, 5 National Cancer, Center Hospital, Tokyo, Japan,<br />
6 Eisai Co., Inc., Woodcliff Lake, NJ, USA, 7 Eisai Co., Ltd., Tokyo, Japan, 8 Thoracic<br />
Center, St. Luke’s International Hospital, Tokyo, Japan<br />
Background: Adenocarcinoma, a type <strong>of</strong> non-small cell lung carcinoma (NSCLC), is<br />
one <strong>of</strong> the most common forms <strong>of</strong> lung cancer. RET fusions activate RET kinase and<br />
occur in 1% to 2% <strong>of</strong> these pts. LN, a multikinase inhibitor whose targets include RET,<br />
may be a treatment option for pts with NSCLC.<br />
Methods: This open label, phase 2 study enrolled pts with RET-positive lung<br />
adenocarcinoma. Pts received LN 24 mg/d in 28-d cycles until disease progression or<br />
unacceptable toxicity. Notably, pts may have received prior RET-targeted therapy. The<br />
primary endpoint was objective response rate (ORR). Secondary endpoints included<br />
progression-free survival (PFS), overall survival (OS), disease control rate (DCR;<br />
complete response [CR] + partial response [PR] + stable disease [SD, ≥ 7 weeks]),<br />
clinical benefit rate (CBR; CR + PR + durable SD [≥23 weeks]), and safety.<br />
Results: 25 Pts with RET-positive NSCLC enrolled (KIF5B-RET: 13, other RET fusion:<br />
12). 15 (60%) had ≥2 prior lines <strong>of</strong> therapy, 7 (28%) had prior RET therapy, and only 2<br />
(8%) had no prior therapy. 16 (64%) were never smokers, 1 (4%) current smoker, 7<br />
(28%) former smokers and 1 (4%) unknown. Tumor shrinkage occurred in the majority<br />
<strong>of</strong> pts; ORR was 16% (confirmed PRs). DCR was 76%. The table shows efficacy data by<br />
previous RET therapy. Median duration <strong>of</strong> treatment was 16 weeks (range: 2–117).<br />
Grade ≥3 treatment emergent adverse events (TEAEs) occurred in 23 (92%) pts. Of 3<br />
fatal AEs, 1 was possibly related to LN (pneumonia). TEAEs requiring drug withdrawal,<br />
dose reduction, and dose interruption occurred in 5 (20%), 16 (64%), and 19 (76%) pts,<br />
respectively. The most common TEAEs included hypertension (68%), nausea (60%),<br />
decreased appetite (52%), diarrhea (52%), proteinuria (48%), and vomiting (44%).<br />
Table: 1204PD<br />
Prior RET therapy All Pts n = 25<br />
Yes n = 7 No n = 18<br />
ORR,* n (%) 1 (14) 3 (17) 4 (16)<br />
Median PFS (95% CI), months - - 7.3 (3.6–10.2)<br />
Median OS (95% CI), months - - NE (5.8–NE)<br />
DCR, n (%) 6 (86) 13 (72) 19 (76)<br />
CBR, n (%) 4 (57) 8 (44) 12 (48)<br />
CI, confidence interval; DCR, disease control rate defined as CR + PR + SD<br />
lasting ≥ 7 weeks; NE, not evaluable. * All confirmed PRs<br />
Conclusions: LN showed promising clinical activity in pts with RET-positive NSCLC.<br />
For most pts, toxicities were manageable with dose modification. These results provide<br />
support for LN as a potential treatment for RET-positive NSCLC.<br />
Clinical trial identification: NCT01877083<br />
Legal entity responsible for the study: Eisai Inc.<br />
Funding: Eisai Inc.<br />
Disclosure: V. Velcheti: Corporate-sponsored research: Merck Inc., Eisai, Genoptix<br />
Inc., Genentech, Altor Biosciences, Heat Biologics, Alkermes, Amgen, Nantomics,<br />
NanoVision Diagnostics. T. Hida: Corporate sponsored research- Eisai. K.L. Reckamp:<br />
Corporate-sponsored research: Eisai Inc., (clinical trial, to institution); editorial<br />
assistance. J.C. Yang: Advisory board for: Boehringer Ingelheim, Eli Lilly, Bayer,<br />
Roche/Genentech/Chugai, AstraZeneca, Astellas, MSD, Merck Serono, Pfizer,<br />
Novartis, Clovis <strong>Oncology</strong>, Celgene, innopharma, Merrimack. H. Nokihara: Clinical<br />
trial-Eisai Inc. P. Sachdev, K. Feit, M. Ren: Employee <strong>of</strong> Eisai Inc. T. Kubota,<br />
T. Nakada: Employee <strong>of</strong> Eisai Co., Ltd., Tokyo Japan. C.E. Dutcus: Employee <strong>of</strong> Eisai<br />
Inc. T. Tamura: Received Honoraria from Eisai.<br />
1205PD<br />
Ceritinib in ROS1-rearranged non-small-cell lung cancer:<br />
a Korean nationwide phase II study<br />
S.M. Lim 1 , B.C. Cho 2 , H.R. Kim 2 , J-S. Lee 3 , K.H. Lee 4 , Y-G. Lee 5 , Y.J. Min 6 ,E.<br />
K. Cho 7 , S-S. Lee 8 , B-S. Kim 9 , M.Y. Choi 10 , H.S. Shim 11 , J.H. Chung 12 ,Y.<br />
L. Choi 13 , M.J. Lee 14 , M-J. Ahn 15<br />
1 Medical <strong>Oncology</strong>, CHA Bundang Medical Center, Gyeonggi-do, Republic <strong>of</strong><br />
Korea, 2 Internal Medicine, Yonsei Severance Hospital Cancer Center, Seoul,<br />
Republic <strong>of</strong> Korea, 3 Medical <strong>Oncology</strong>, Seoul National University Bundang<br />
Hospital, Seongnam-si, Republic <strong>of</strong> Korea, 4 Medical <strong>Oncology</strong>, Chungbuk<br />
National University Hospital, Cheong-ju, Republic <strong>of</strong> Korea, 5 Medical <strong>Oncology</strong>,<br />
Kangbuk Samsung Hospital Sungkyunkwan University, Seoul, Republic <strong>of</strong> Korea,<br />
6 Medical <strong>Oncology</strong>, Asan Medical Center, University <strong>of</strong> Ulsan College <strong>of</strong> Medicine,<br />
Seoul, Republic <strong>of</strong> Korea, 7 Medical <strong>Oncology</strong>, Gachon University Gil Hospital,<br />
Incheon, Republic <strong>of</strong> Korea, 8 Medical <strong>Oncology</strong>, Inje University Haeundae Paik<br />
Hospital, Busan, Republic <strong>of</strong> Korea, 9 Medical <strong>Oncology</strong>, Veterance Hospital,<br />
Seoul, Seoul, Republic <strong>of</strong> Korea, 10 Medical <strong>Oncology</strong>, Inje University Busan Paik<br />
Hospital, Busan, Republic <strong>of</strong> Korea, 11 Pathology, Yonsei Cancer Center Yonsei<br />
University, Seoul, Republic <strong>of</strong> Korea, 12 Pathology, Seoul National University<br />
Bundang Hospital, Seongnam-si, Republic <strong>of</strong> Korea, 13 Pathology, Samsung<br />
Medical Center Sungkyunkwan University School <strong>of</strong> Medicine, Seoul, Republic <strong>of</strong><br />
Korea, 14 Medical <strong>Oncology</strong>, Yonsei Cancer Center, Seoul, Republic <strong>of</strong> Korea,<br />
15 Medical <strong>Oncology</strong>, Samsung Medical Center Sungkyunkwan University School<br />
<strong>of</strong> Medicine, Seoul, Republic <strong>of</strong> Korea<br />
Background: ROS1 rearrangement is a distinct molecular subset <strong>of</strong> non-small-cell lung<br />
cancer (NSCLC). We investigated the efficacy and safety <strong>of</strong> ceritinib in patients with<br />
ROS1-rearranged NSCLC.<br />
Methods: We enrolled 32 patients with advanced NSCLC who tested positive for ROS1<br />
rearrangement by fluorescent in situ hybridization (FISH). ROS1<br />
immunohistochemistry (IHC) and next-generation sequencing (NGS) were performed<br />
in available tumor samples. The primary endpoint was objective response rate (ORR)<br />
by central independent radiologic review. The secondary endpoints included disease<br />
control rate (DCR), duration <strong>of</strong> response, progression-free survival (PFS), overall<br />
survival (OS), toxicity and concordance between FISH, IHC and NGS.<br />
Results: Between June 7, 2013, and February 1, 2016, a total <strong>of</strong> 404 patients underwent<br />
ROS1 prescreening, and 32 ROS1+ (by FISH) patients were enrolled. The median age<br />
<strong>of</strong> all patients was 62 years, and the majority <strong>of</strong> patients (84%) were never smokers, and<br />
all had adenocarcinoma histology. The median number <strong>of</strong> previous treatments was 3<br />
(range, 2-7) and 17 (53%) patients had received three or more lines <strong>of</strong> chemotherapy.<br />
At the time <strong>of</strong> the data cut-<strong>of</strong>f (April 18, 2016), the median follow-up was 7.5 months,<br />
and 15 (47%) patients had discontinued treatment. The ORR was 63% (95% CI,<br />
45.7-79.3), with 1 complete response and 19 partial responses. The median duration <strong>of</strong><br />
response was 10.0 months (range, 0.4 + -18.4+). Among 11 tumors that were tested by<br />
NGS, we identified 7 ROS1 fusion partners including ROS1-CD74, ROS1-SLC34A2,<br />
and ROS1-EZR. The median progression-free survival was 19.3 months (95% CI,<br />
7.2-not reached), and the median overall survival was not reached at the time <strong>of</strong> the<br />
data cut-<strong>of</strong>f. Of 5 patients with retrospectively confirmed brain metastases, intracranial<br />
disease control was reported in 4 patients (80%). Gastrointestinal adverse events,<br />
mostly grade 1-2, were the most frequent adverse events (80%); these events were<br />
manageable.<br />
Conclusions: Ceritinib demonstrated potent clinical activity in patients with advanced,<br />
ROS1-rearranged NSCLC, who received at least one prior line <strong>of</strong> platinum-based<br />
chemotherapy. ROS1 rearrangement defines a second molecular subgroup <strong>of</strong> NSCLC<br />
for which ceritinib is highly active.<br />
Clinical trial identification: NCT01964157<br />
Legal entity responsible for the study: N/A<br />
Funding: Novartis Pharmaceutical<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
vi418 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
1206PD<br />
Crizotinib in advanced ROS1-rearranged non-small cell lung<br />
cancer (NSCLC): updated results from PROFILE 1001<br />
A. Shaw 1 , G.J. Riley 2 , Y-J. Bang 3 , D-W. Kim 4 , D.R. Camidge 5 , M. Varella-Garcia 5 ,<br />
A.J. Lafrate 1 , G. Shapiro 6 , M. Winter 7 , T. Usari 8 , S.C. Wang 7 , K. Wilner 7 ,<br />
J.W. Clark 1 , S-H.I. Ou 9<br />
1 Massachusetts General Hospital Cancer Center, Massachusetts General<br />
Hospital, Boston, MA, USA, 2 Memorial Sloan-Kettering Cancer Center, Memorial<br />
Sloan-Kettering Cancer Center, New York, NY, USA, 3 Department <strong>of</strong> Internal<br />
Medicine, Seoul National University Hospital (SNUH)-Yongon Campus, Seoul,<br />
Republic <strong>of</strong> Korea, 4 Department <strong>of</strong> Internal Medicine, Seoul National University<br />
Hospital, Seoul, Republic <strong>of</strong> Korea, 5 Cancer Center, University <strong>of</strong> Colorado,<br />
Aurora, CO, USA, 6 Early Drug Development Centre, Dana-Farber Cancer Institute,<br />
Boston, MA, USA, 7 <strong>Oncology</strong>, Pfizer, La Jolla, CA, USA, 8 <strong>Oncology</strong>, Pfizer, Milan,<br />
Italy, 9 University <strong>of</strong> California at Irvine, University <strong>of</strong> California at Irvine, Irvine, CA, USA<br />
Background: In the phase I study PROFILE 1001, crizotinib showed marked<br />
antitumor activity in advanced ROS1-rearranged NSCLC (Shaw, N Engl J Med 2014).<br />
We present updated data for 53 patients (pts) with ROS1-rearranged NSCLC from this<br />
ongoing study (NCT00585195).<br />
Methods: ROS1 status was determined by break-apart FISH test or RT-PCR test. All<br />
pts received crizotinib at a starting dose <strong>of</strong> 250 mg orally twice daily.<br />
Results: Fifty-three pts enrolled and were treated with crizotinib for a median<br />
treatment duration <strong>of</strong> 23.2 months. All were included in the efficacy and safety<br />
analyses. At data cut<strong>of</strong>f (November 30, 2014), treatment was ongoing in 25 pts (47%).<br />
The median age <strong>of</strong> pts was 55 years, 57% were female, and 57% and 40% were white<br />
and Asian, respectively; all were never or former smokers. The objective response rate<br />
(ORR) was 70% (95% CI: 56, 82), which included five complete responses and 32<br />
partial responses; 11 pts had stable disease. By independent radiology review (n = 50),<br />
ORR was 66% (95% CI: 51, 79). Responses were durable (median duration <strong>of</strong> response<br />
not reached [NR]; 95% CI: 15.2, NR). ORR was consistent across baseline and disease<br />
characteristics, and appeared independent <strong>of</strong> the percentage <strong>of</strong> ROS1-rearranged cells.<br />
Median progression-free survival was 19.3 months (95% CI: 14.8, NR). At a median<br />
follow-up <strong>of</strong> 25.4 months, median overall survival was NR; the probabilities <strong>of</strong> survival<br />
at 6 and 12 months were 91% (95% CI: 79, 96) and 79% (95% CI: 65, 88), respectively.<br />
The safety pr<strong>of</strong>ile was similar to that <strong>of</strong> crizotinib in pts with ALK-positive NSCLC.<br />
The most common treatment-related adverse events (TRAEs) were vision disorder<br />
(85%), nausea (49%), edema (45%), diarrhea (42%), and vomiting (38%), mainly grade<br />
1 or 2 in severity. The most common grade 3 TRAEs were hypophosphatemia (13%),<br />
neutropenia (9%), and elevated transaminases (4%), and there were no grade 4 TRAEs.<br />
Of 16 deaths on study, none were attributed to crizotinib.<br />
Conclusions: These updated data confirm the clinically meaningful benefit and safety<br />
<strong>of</strong> crizotinib in pts with advanced ROS1-rearranged NSCLC.<br />
Clinical trial identification: Clinicaltrials.gov: NCT00585195<br />
Legal entity responsible for the study: N/A<br />
Funding: Pfizer<br />
Disclosure: Y-J. Bang: Research funding from Pfizer to their institution. D.R. Camidge:<br />
Honararia from Pfizer. M. Winter, T. Usari, S.C. Wang, K. Wilner: Pfizer employee. All<br />
other authors have declared no conflicts <strong>of</strong> interest.<br />
1207PD<br />
Brigatinib (BRG) in patients (Pts) with anaplastic lymphoma<br />
kinase (ALK)–positive non–small cell lung cancer (NSCLC) in<br />
a phase 1/2 trial<br />
L. Bazhenova 1 , S. Gettinger 2 , C. Langer 3 , R. Salgia 4 , K. Gold 1 , R. Rosell 5 ,<br />
A. Shaw 6 , G. Weiss 7 , J. Haney 8 , V. Rivera 9 , F. Haluska 8 , D. Kerstein 9 ,D.<br />
R. Camidge 10<br />
1 Moores Cancer Center, University <strong>of</strong> California San Diego, La Jolla, CA, USA,<br />
2 Yale Cancer Center, Yale School <strong>of</strong> Medicine, New Haven, USA, 3 <strong>Oncology</strong>,<br />
Abramson Cancer Center, University <strong>of</strong> Pennsylvania, Philadelphia, PA, USA,<br />
4 Department <strong>of</strong> Medical <strong>Oncology</strong> and Therapeutics Research, City <strong>of</strong> Hope,<br />
Duarte, CA, USA, 5 Medical <strong>Oncology</strong> Service, Catalan Institute <strong>of</strong> <strong>Oncology</strong> (ICO<br />
Badalona), Hospital Germans Trias i Pujol, Badalona, Spain, 6 Massachusetts<br />
General Hospital Cancer Center, Massachusetts General Hospital, Boston, MA,<br />
USA, 7 Western Regional Medical Center, Cancer Treatment Centers <strong>of</strong><br />
America-Western Regional Medical Center, Goodyear, AZ, USA, 8 Clinical<br />
Research & Development, ARIAD Pharmaceuticals, INC., Cambridge, MA, USA,<br />
9 Preclinical and Translational Research, ARIAD Pharmaceuticals Inc., Cambridge,<br />
MA, USA, 10 Cancer Center, University <strong>of</strong> Colorado, Aurora, CO, USA<br />
Background: BRG, an investigational oral ALK inhibitor with preclinical activity<br />
against ALK mutants resistant to crizotinib (CRZ) and other ALK inhibitors, was<br />
studied in pts with advanced malignancies, including ALK+ NSCLC.<br />
Methods: 137 pts (ALK+ NSCLC, n = 79) received oral BRG (30–300 mg/d) in an<br />
ongoing phase 1/2, single-arm, open-label, multicenter trial (NCT01449461). We<br />
report activity by RECIST v1.1 (in ALK+ NSCLC pts) and safety (in all pts).<br />
Results: As <strong>of</strong> 16 Nov 2015, 36/79 (46%) ALK+ NSCLC pts (median age 54 years, 49%<br />
female, 90% with prior CRZ) continued to receive BRG. Median time on treatment was<br />
17.0 months (1 day to 44.4 months). 51/71 (72%) pts with prior CRZ and 8/8 (100%)<br />
CRZ-naive pts achieved an objective response (see table). In pts with prior CRZ,<br />
median duration <strong>of</strong> response in confirmed responders and progression-free survival in all<br />
pts were 14.5 months and 12.9 months, respectively; in CRZ-naive pts, medians were not<br />
reached. Treatment-emergent adverse events (AEs) in ≥30% <strong>of</strong> all pts (mostly grade 1/2):<br />
nausea 51%; fatigue 42%; diarrhea 41%; headache 34%; cough 33%. Serious<br />
treatment-emergent AEs (excluding disease progression; any cause) in ≥2% <strong>of</strong> all pts:<br />
dyspnea 7%; pneumonia 7%; hypoxia 5%; pulmonary embolism 3%; malignant pericardial<br />
effusion 2%; pneumonitis 2%. Of 137 pts, 14 (10%) discontinued due to an AE.<br />
Conclusions: BRG had substantial antitumor activity in ALK+ NSCLC pts and an<br />
acceptable safety pr<strong>of</strong>ile in this study. A pivotal, randomized, phase 2 trial <strong>of</strong> BRG in<br />
CRZ-resistant ALK+ NSCLC (ALTA) evaluating 90 mg qd vs 180 mg qd with a 7-day<br />
lead-in at 90 mg is ongoing.<br />
Legal entity responsible for the study: ARIAD Pharmaceuticals, Inc.<br />
Funding: ARIAD Pharmaceuticals, Inc.<br />
Disclosure: L. Bazhenova: Stock and other ownership interests (Epic Sciences),<br />
honoraria (Novartis), consulting or advisory role (AbbVie, AstraZeneca, BMS,<br />
Boehringer Ingelheim, Clovis <strong>Oncology</strong>, Genoptix, Heat Biologics, Pfizer, Roche/<br />
Genentech, Seattle Genetics, and Trovagene), speakers bureau (AstraZeneca, Novartis,<br />
Pfizer, Roche/Genentech), research funding (AbbVie, ARIAD, Astellas, Astex,<br />
AstraZeneca, Boehringer Ingelheim, Chugai, Clovis <strong>Oncology</strong>, Eisai, Eli Lilly, Heat<br />
Biologics, Johnson & Johnson, MedImmune, Merck, Mirati, NanoCarrier, Novartis,<br />
Pfizer, Roche/Genentech). S. Gettinger: Consulting or advisory role (ARIAD, BMS,<br />
Janssen), research funding (ARIAD, AstraZeneca/MedImmune, BMS, Boehringer<br />
Ingelheim, Incyte, Pfizer, Roche/Genentech). K. Gold: Honoraria (BMS, Roche),<br />
consulting or advisory role (Pfizer), research funding (ARIAD, AstraZeneca, BMS,<br />
Puma, Roche/Genentech). C. Langer: Honoraria (BMS, Lilly/ImClone, Roche/<br />
Genentech), consulting or advisory role (Abbott, ARIAD, AstraZeneca, Bayer/Onyx,<br />
BMS, Cancer Support Community, Celgene, Clarient, Clovis <strong>Oncology</strong>, Lilly/ImClone,<br />
Merck, Millennium, Roche/Genentech), research funding (Advantagene, ARIAD,<br />
Celgene, Clovis <strong>Oncology</strong>, GSK, Inovio, Merck, Roche/Genentech). A. Shaw: Honoraria<br />
(Novartis, Pfizer, Roche), consulting or advisory role (ARIAD, Blueprint Medicines,<br />
Daiichi Sankyo, EMD Serono, Ignyta, Novartis, Pfizer, Roche/Genentech, Taiho),<br />
research funding (ARIAD, Ignyta, Novartis, Pfizer). G. Weiss: Employment (Cancer<br />
Treatment Centers <strong>of</strong> America), consulting or advisory role (Blend Therapeutics,<br />
Paradigm, Pharmatech), speakers bureau (Amgen, Celgene, Medscape, Merck, Novartis,<br />
Pfizer, Quintiles), travel, accommodations, expenses (Cambridge Healthtech Institute,<br />
Nantworks, Pharmatech). J. Haney, V. Rivera, F. Haluska, D. Kerstein: Employment,<br />
Table: 1207PD Response in ALK+ NSCLC Pts, With Prior CRZ Exposure (All and at Doses Explored in Phase 2) and CRZ-Naive<br />
Prior CRZ Prior CRZ Prior CRZ Prior CRZ CRZ-Naive<br />
All n = 71 90 mg qd n = 13 90 → 180 mg qd a n = 25 180 mg/d b n = 23 All n = 8<br />
ORR [95% CI] 51 (72) [60–82] 10 (77) [46–95] 20 (80) [59–93] 15 (65) [43–84] 8 (100) [63–100]<br />
CR c 4 (6) 0 2 (8) 2 (9) 3 (38)<br />
PR 47 (66) 10 (77) 18 (72) 13 (57) 5 (63)<br />
Confirmed ORR [95% CI] 44 (62) [50–73] 7 (54) [25–81] 19 (76) [55–91] 14 (61) [39–80] 8 (100) [63–100]<br />
DCR (CR + PR + SD d ) 62 (87) 13 (100) 22 (88) 18 (78) 8 (100)<br />
Data are n (%) CR = complete response, DCR = disease control rate, ORR = objective response rate, PR = partial response, SD = stable disease a 180 mg qd with 7-day lead-in<br />
at 90 mg b Includes 21 pts at 180 mg qd and 2 pts at 90 mg bid c All confirmed d Includes non-CR/non–progressive disease in pts with nonmeasurable disease at baseline<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw383 | vi419
abstracts<br />
stock and other ownership interests (ARIAD). D.R. Camidge: Honoraria, research<br />
funding (ARIAD). All other authors have declared no conflicts <strong>of</strong> interest.<br />
1209PD<br />
Time to response in patients with ALK+ NSCLC receiving<br />
alectinib in the phase II NP28673 and NP28761 studies<br />
L. Gandhi 1 , S. Gadgeel 2 , A. Shaw 3 , F. Barlesi 4 , L. Crinò 5 , J.C-H. Yang 6 , A-M.<br />
C. Dingemans 7 , D-W. Kim 8 , F. de Marinis 9 , M. Schulz 10 , S. Liu 10 , S. Fish 10 ,<br />
A. Kotb 11 , S-H.I. Ou 12<br />
1 Medical <strong>Oncology</strong>, Dana Farber Cancer Institute, Boston, MA, USA, 2 Wayne<br />
State University, Karmanos Cancer Institute, Detroit, MI, USA, 3 Massachusetts<br />
General Hospital Cancer Center, Massachusetts General Hospital, Boston, MA,<br />
USA, 4 Multidisciplinary <strong>Oncology</strong> & Therapeutic Innovations, Aix Marseille<br />
University, Marseille, France, 5 Medical <strong>Oncology</strong>, Santa Maria della Misericordia<br />
Hospital, Perugia, Italy, 6 Graduate Institute <strong>of</strong> <strong>Oncology</strong> & Cancer Research<br />
Centre, National Taiwan University Hospital, Taipei, Taiwan, 7 Pulmonology,<br />
MUMC, Maastricht, Netherlands, 8 Medical <strong>Oncology</strong>, Seoul National University<br />
Hospital, Seoul, Republic <strong>of</strong> Korea, 9 Thoracic Institute <strong>of</strong> <strong>Oncology</strong>, European<br />
Institute <strong>of</strong> <strong>Oncology</strong>, Milan, Italy, 10 US Medical Affairs, Genentech, Inc.,<br />
San Francisco, CA, USA, 11 Medical Affairs, F. H<strong>of</strong>fmann-La Roche Ltd, Basel,<br />
Switzerland, 12 Medical <strong>Oncology</strong>, University <strong>of</strong> California at Irvine, Orange, CA, USA<br />
Background: Alectinib was approved by the FDA based on the efficacy and safety shown<br />
in two phase II studies (NP28673 [NCT01801111] and NP28761 [NCT01871805]) <strong>of</strong><br />
patients (pts) with previously treated ALK+ non-small-cell lung cancer (NSCLC). Both<br />
studies showed that alectinib achieved high response rates (51% and 52%, respectively)<br />
and that responses were durable (median 14.1 mos and 13.5 mos, respectively) (Barlesi<br />
et al, ECC 2015; Shaw et al, WCLC 2015). This exploratory pooled analysis looked at the<br />
time to systemic response (TTR) and time to CNS response (TTCR) in both studies, to<br />
determine how rapidly patients can benefit from alectinib.<br />
Methods: Pts (n = 225) ≥18 years with confirmed ALK+ NSCLC, which had progressed<br />
after prior crizotinib, received 600 mg oral alectinib twice daily. Restaging scans,<br />
including brain scans, were obtained every 8 wks (NP28673) or every 6 wks (NP28761)<br />
thereafter. Response was assessed by an independent review committee (IRC), according<br />
to RECIST v1.1. TTR and TTCR were defined as time from date <strong>of</strong> first dose to date <strong>of</strong><br />
first occurrence <strong>of</strong> response in the response-evaluable population with confirmed<br />
response or in the safety population with confirmed CNS response, respectively.<br />
Results: Median follow-up was 14.5 mos (NP28673) and 9.9 mos (NP28761) (data<br />
cut-<strong>of</strong>f 27 Apr 2015). Median TTRs and TTCRs by IRC for both studies are shown in<br />
the Table, including sub-analyses by baseline measurable (M) or non-measurable<br />
(NM) disease and no prior radiation (RT). Results were consistent between IRC and<br />
investigator assessment. In all populations, most pts who achieved a response did so by<br />
the first evaluation.<br />
Conclusions: These data from the phase II alectinib studies suggest that alectinib can<br />
achieve a rapid response in patients, both systemically and in the CNS, with pts having<br />
RECIST response by first assessment in most cases. The ongoing phase III ALEX study<br />
will assess the efficacy <strong>of</strong> first-line alectinib vs crizotinib.<br />
Table: 1209PD<br />
NP28673 (N = 138) NP28761 (N = 87)<br />
Total no. <strong>of</strong><br />
responders (no.<br />
responders by<br />
wk 8, wk 16)<br />
Median, wks<br />
(95% CI)<br />
Total no. <strong>of</strong><br />
responders (no.<br />
responders by<br />
wk 6, wk 12)<br />
Median, wks<br />
(95% CI)<br />
TTR in all responders 62 (44, 55) 8.0 (8.0–8.3) 35 (28, 31) 6.0 (5.9–6.1)<br />
TTCR in M disease 20 (15, 17) 8.0 (7.9–10.3) 12 (9, 11) 6.0 (5.7–NE)<br />
TTCR in M/NM disease 37 (26, 31) 8.1 (7.9–9.9) 21 (16, 20) 6.0 (5.7–11.0)<br />
TTCR in M disease with 6 (5, 5) 7.9 (7.9–NE) 5 (4, 5) 5.7 (5.7–NE)<br />
no prior RT<br />
TTCR in M/NM disease<br />
with no prior RT<br />
12 (10, 10) 8.0 (7.9–NE) 12 (9, 12) 5.9 (5.7–NE)<br />
NE = not estimable<br />
Clinical trial identification: NP28673 [NCT01801111] and NP28761<br />
[NCT01871805].<br />
Legal entity responsible for the study: F. H<strong>of</strong>fmann-La Roche Ltd<br />
Funding: F. H<strong>of</strong>fmann-La Roche Ltd<br />
Disclosure: L. Gandhi: Honoraria for Merck, Consulting role for Merck, Genentech/<br />
Roche, AstraZeneca, Abbvie, Pfizer, Travel accommodation for Merck, BMS (grant<br />
recipient meeting)and Research funding from Bristol-Myers Squibb. S. Gadgeel: Advisory<br />
Board for Genentech/Roche, Pfizer, Ariad, Novartis. A. Shaw: Blueprint medicines<br />
Advisory board, Consulting for Genentech, Roche, Novartis, Pfizer, Ariad, Ignyta,<br />
Daiichi-sankyo, Taiho, EMD Serono. F. Barlesi: Roche Advisory board or board <strong>of</strong><br />
directors and Corporate-sponsored research. J.C-H. Yang: Advisory board for Boehringer<br />
Ingelheim, Eli Lilly, Bayer, Roche/Genentech/Chugai, Astrazeneca, Astellas, MSD, Merck<br />
Serono, Pfizer, Novartis, Clovis <strong>Oncology</strong>, Celgene, innopharma, Merrimack. A-M.C.<br />
Dingemans: Advisory board or board <strong>of</strong> directors for Roche. D-W. Kim: Consulting or<br />
Advisory role for Novartis. M. Schulz: Roche Stock Ownership. S. Liu, S. Fish: Employee<br />
and Stock ownership in Genentech, Inc. A. Kotb: Employee <strong>of</strong> Roche. S-H.I. Ou: Roche<br />
Advisory Board, Roche Corporate sponsored research and Roche speakers bureau. All<br />
other authors have declared no conflicts <strong>of</strong> interest.<br />
1210PD<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Phase I/II trial <strong>of</strong> X-396 in patients (pts) with ALK+<br />
non-small cell lung cancer (NSCLC): Correlation with<br />
plasma and tissue genotyping and response to therapy (tx)<br />
L. Horn 1 , H. Wakelee 2 , G. Blumenschein 3 , K. Reckamp 4 , S. Waqar 5 , C.A. Carter 6 ,<br />
B.J. Gitlitz 7 , J.R. Infante 8 , R.E. Sanborn 9 , J. Neal 2 , J.P. Gockerman 10 , G. Dukart 11 ,<br />
K. Harrow 11 , C. Liang 11 , J.J. Gibbons 11 , J. Hernandez 12 , T. Newman-Eerkes 12 ,<br />
L. Lim 12 , C. Lovly 1<br />
1 Thoracic <strong>Oncology</strong>, Vanderbilt Ingram Cancer Center, Nashville, TN, USA,<br />
2 Medicine-<strong>Oncology</strong>, Stanford University Medical Center, Stanford, CA, USA,<br />
3 Thoracic Head & Neck <strong>Oncology</strong>, MD Anderson Cancer Center, Houston, TX,<br />
USA, 4 Department <strong>of</strong> Medical <strong>Oncology</strong>, City <strong>of</strong> Hope, Duarte, CA, USA, 5 Division<br />
<strong>of</strong> <strong>Oncology</strong>, Washington University School <strong>of</strong> Medicine, St Louis, MO, USA,<br />
6 Thoracic <strong>Oncology</strong>, National Naval Medical Center (NNMC), Bethesda, MD, USA,<br />
7 Department <strong>of</strong> Medicine, University <strong>of</strong> Southern California Norris Comprehensive<br />
Cancer Center, Los Angeles, CA, USA, 8 Medical <strong>Oncology</strong>, Sarah Cannon<br />
Research Institute, Nashville, TN, USA, 9 Thoracic <strong>Oncology</strong> Program, Providence<br />
Portland Medical Center, Portland, OR, USA, 10 <strong>Oncology</strong>, Novella Clinical,<br />
Morristown, NC, USA, 11 <strong>Oncology</strong>, Xcovery Holding Company, Palm Beach<br />
Gardens, FL, USA, 12 Clinical Operations, Resolution Bioscience, Bellevue, WA, USA<br />
Background: X-396 is a novel, potent ALK small molecule TKI with additional activity<br />
against MET, ABL, Axl, EPHA2, LTK, ROS1 and SLK. We report on data from pts that<br />
includes detection/monitoring <strong>of</strong> ALK fusions by plasma next-generation sequencing<br />
(NGS).<br />
Methods: Pts with advanced solid tumors and ECOG PS 0-1 were tx’d with X-396 225<br />
mg qd on a continuous 28-day schedule. In expansion phase, required to have<br />
measurable ALK+ NSCLC. Asymptomatic brain metastases allowed. Tissue confirmed<br />
centrally via FISH or IHC. Targeted NGS <strong>of</strong> cfDNA was performed retrospectively at<br />
baseline and on study and compared with tissue results.<br />
Results: As <strong>of</strong> April 15, 71 pts (35 men, 36 women) enrolled. Median age 54 (20-79)<br />
yrs, 66% had ECOG PS 1. 37 ALK+ NSCLC pts tx’d at doses ≥ 200 mg evaluable for<br />
response; partial response (PR) achieved in 21 pts (76%), stable disease (SD) in 8<br />
(22%). In crizotinib-naïve pts (n = 8), responses in 7 (88%). In 20 pts with prior<br />
crizotinib but no other ALK TKI, 12 (60%) had PR, 7 (35%) SD. Tissue via FISH (F)<br />
and Plasma genotyping (P) available on 42 pts: RR for 25 F + P+ pts 52%, 6 F-P- pts<br />
0%, 11 F + P- pts 55%. Concordance between F and P was 74%. Tissue via NGS (N)<br />
and P genotyping available on 13 pts with 27 mutations and fusions identified; RR for<br />
18 T + P+ pts 78%, 4 T-P+ pts 100%, 5 T + P- pts 75%. 2 samples were T-P-.<br />
Concordance between N and P was 74%. Responses were seen in pts with L1196M,<br />
G1296M, G1202R, and T1151M resistant mutations. Serial sequencing demonstrated<br />
decrease in ALK in responding pts and increase at time <strong>of</strong> progression. CNS responses<br />
observed in crizotinib naïve and resistant pts. Median duration <strong>of</strong> tx in the 37 evaluable<br />
ALK+ pts is 23.6 wks, longest being 139+ wks. Most common drug-related AEs (>20%<br />
<strong>of</strong> pts) included rash (48%), nausea (28%), fatigue (25%), vomiting (23%). Most AEs<br />
were Grade (G) 1-2. Most common G3 tx-related AE was rash (8 pts). No G3 related<br />
GI AEs or liver enzyme elevations reported.<br />
Conclusions: X-396 is well-tolerated and induces responses in crizotinib-naïve &<br />
resistant ALK+ NSCLC pts, and pts with CNS lesions. Plasma sequencing may be used<br />
to select pts for tx and monitor for response and development <strong>of</strong> acquired resistance.<br />
Enrollment ongoing.<br />
Clinical trial identification: NCT01625234<br />
Legal entity responsible for the study: Xcovery Holding Company<br />
Funding: Xcovery Holding Company<br />
Disclosure: L. Horn: Consulting uncompensated: Bayer, Xcovery, BMS, BI Consulting<br />
compensated: Merck, Lilly, Genentech. Research funding: AZ. H. Wakelee: consultant<br />
and honorarium: Peregrine, Novartis, ACEA, Pfizer grants/research support: Novartis,<br />
Pfizer, BMS, Xcovery, Celegene, Roche, Medimmune, Lilly. G. Blumenschein:<br />
Consultant: Clovis, BMS, Bayer, Celgene, Abbvie Grants: Merck, Bayer, BMS, Celgene,<br />
Novartis, Xcovery, AZ. K. Reckamp: Ariad consultant and research funds to institution.<br />
Xcovery research funds to institution. C.A. Carter: Honoraria, Speakers Burea,<br />
Research funding: BMS. B.J. Gitlitz: speakers bureau for Lilly and Genentech. R.E.<br />
Sanborn: Institutional support: Bristol-Meyers Squibb, Medimmune; Research support:<br />
Merck Advisory boards: Peregrine Pharmaceuticals, Seattle Genetics; travel: BMS, Five<br />
Prime Therapeutics. J. Neal: Consulting: Clovis, CARET, Nektar, BI Research:<br />
Genentech, Merck, Arqule, Novartis, Exelixis, BI, Nektar. J.P. Gockerman: Employee<br />
Novello. G. Dukart: Consultant Xcovery. K. Harrow, C. Liang, J.J. Gibbons: Employee<br />
and stockholder <strong>of</strong> Xcovery. J. Hernandez: Employee and stockholder <strong>of</strong> Resolution<br />
Bio. T. Newman-Eerkes, L. Lim: Employee and stock holder <strong>of</strong> Resolution<br />
Bio. C. Lovly: consultant for Pfizer, Novartis, Genoptix, Sequenom, Clovis, Ariad, and<br />
Guidepoint invited speaker for Abbott and Qiagen. All other authors have declared no<br />
conflicts <strong>of</strong> interest.<br />
vi420 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
1211PD<br />
Cost-effectiveness <strong>of</strong> KRAS, EGFR and ALK testing for<br />
therapeutic decision making <strong>of</strong> advanced stage non-small<br />
cell lung cancer (NSCLC): the French IFCT-PREDICT.amm<br />
study<br />
A. Drezet 1 , S. Loubière 1 , M. Wislez 2 , M. Beau-Faller 3 , I. Nanni-Métellus 4 ,<br />
S. Garcia 5 , M-P. Chenard 6 , J-P. Ghnassia 7 ,R.Lacave 8 , M. Antoine 9 ,<br />
M. Duruisseaux 10 , S. Friard 11 , E. Fabre 12 , C. Daniel 13 , P. Missy 14 , F. Morin 14 ,<br />
F. Barlesi 15 , P. Auquier 16 , J. Cadranel 2<br />
1 Unité d’aide méthodologique à la recherche clinique et évaluation<br />
médico-économique, Assistance Publique Hôpitaux de Marseille, Marseille,<br />
France, 2 Pneumology, APHP, CancerEst, Tenon University Hospital, Paris, France,<br />
3 Pneumologie, C.H.U. Strasbourg-Nouvel Hopital Civil, Strasbourg, France,<br />
4 Laboratoire de Transfert d’Oncologie Biologique, Aix-Marseille University - Faculté<br />
de Médecine Nord, Marseille, France, 5 Hôpital Nord, Service d’Anatomie<br />
Pathologique, Assistance Publique Hôpitaux de Marseille, Marseille, France,<br />
6 Département de Pathologie, C.H.U. Hautepierre, Strasbourg, France,<br />
7 Département de biologie et pathologie, Centre Paul Strauss Centre de Lutte<br />
contre le Cancer, Strasbourg, France, 8 Biology, APHP, CancerEst, Tenon<br />
University Hospital, Paris, France, 9 Pathology, APHP, CancerEst, Tenon University<br />
Hospital, Paris, France, 10 Pneumologie, CHU Grenoble - Hopital Michallon,<br />
Grenoble, France, 11 Pneumologie, Hopital Foch, Suresnes, France, 12 Medical<br />
<strong>Oncology</strong>, Hopital Europeen Georges Pompidou, Paris, France, 13 Pneumologie,<br />
Institut Curie, Paris, France, 14 Clinical Research Unit, IFCT (Intergroupe<br />
Francophone de Cancérologie Thoracique)., Paris, France, 15 Multidisciplinary<br />
<strong>Oncology</strong> and Therapeutic Innovations Department, Aix-Marseille University -<br />
Faculté de Médecine Nord, Marseille, France, 16 Laboratoire de Santé Publique,<br />
Assistance Publique Hôpitaux de Marseille, Marseille, France<br />
Background: Knowledge <strong>of</strong> molecular status improves the clinical benefit <strong>of</strong> targeted<br />
therapies. ALK rearrangement and EGFR/KRAS mutation are the main biomarkers<br />
tested to deliver or not targeted therapies in advanced NSCLC, but their economic<br />
impact has not been studied in large prospective cohorts. One objective <strong>of</strong> the<br />
IFCT-PREDICT.amm study was to evaluate the incremental cost-effectiveness ratio<br />
(ICER) <strong>of</strong> a strategy including the knowledge <strong>of</strong> at least one biomarker status at first- or<br />
second-line and the most appropriate treatment (intervention strategy) compared with<br />
the standard <strong>of</strong> care without biomarker testing (reference strategy).<br />
Methods: A cost-effectiveness analysis was performed based on prospective individual<br />
data from 802 previously never treated French patients with advanced stage <strong>of</strong> NSCLC<br />
included between 01/2013 and 02/2014 in the IFCT-PREDICT.amm study. Overall<br />
survival (OS) during both first- and second-line and direct medical costs related to<br />
treatment, inpatient care and biomarker testing from the French payer perspective were<br />
valued. A propensity score matching was performed to compare patients with same<br />
baseline characteristics (n = 308). Probabilistic sensitivity analyses were performed to<br />
test the robustness <strong>of</strong> the results.<br />
Results: A total <strong>of</strong> 647 patients received the intervention strategy. The incremental OS<br />
in the intervention strategy group was 6 months (p < 0.001). Mean costs were €17,633<br />
and €13,516 for the intervention and reference strategies. The ICER was €8,308 per life<br />
years saved (LYS) compared with standard care. In matched analyses, the ICER<br />
decreased to €4,821 per LYS. Probabilistic sensitivity analyses showed that the<br />
intervention was not only cost-effective but also strongly dominant in more than 40%<br />
<strong>of</strong> simulations (more effective and less costly).<br />
Conclusions: Molecular testing before first- or second-line treatment initiation result<br />
in better survival with limited additional costs, validating it is a cost effective alternative<br />
in NSCLC management. These results can help decision maker to define conditions for<br />
appropriate diffusion <strong>of</strong> these technological innovations in general practices.<br />
Legal entity responsible for the study: N/A<br />
Funding: INCa, Roche, Boeringher Ingelheim, Lilly<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1212PD<br />
Lung sarcomatoid carcinoma (LSC) harbors targetable<br />
genomic alterations and high mutational burden as<br />
observed by comprehensive genomic pr<strong>of</strong>iling (CGP)<br />
B. Halmos 1 , G.M. Frampton 2 , J. Suh 3 , E. Braun 4 , R. Mehra 5 , S. Buck 6 , J.A. Bufill 4 ,<br />
N. Peled 7 , N.A. Karim 8 , P. Fishkin 9 , J. Knost 9 , S-H.I. Ou 10 , J.S. Ross 3 ,P.<br />
J. Stephens 11 , V.A. Miller 12 , S.M. Ali 12 , A.B. Schrock 12<br />
1 <strong>Oncology</strong>, Montefiore Medical Center, New York, NY, USA, 2 Bioinformatics,<br />
Foundation Medicine, Inc., Cambridge, MA, USA, 3 Pathology, Foundation<br />
Medicine, Inc., Cambridge, MA, USA, 4 Michiana, Hematology-<strong>Oncology</strong>,<br />
Mishawaka, IN, USA, 5 <strong>Oncology</strong>, Fox Chase Cancer Center, Philadelphia, PA,<br />
USA, 6 Medical <strong>Oncology</strong>, Tulsa Cancer Institute, Tulsa, OK, USA, 7 Thoracic<br />
Cancer Unit, David<strong>of</strong>f Cancer Center, Petach Tiqwa, Israel, 8 Division <strong>of</strong><br />
Hematology/<strong>Oncology</strong>, The University <strong>of</strong> Cincinnati, Cincinnati, OH, USA, 9 Medical<br />
<strong>Oncology</strong>, Illinois Cancer Care, Peoria, IL, USA, 10 Department <strong>of</strong> Medicine,<br />
Division <strong>of</strong> Hematology <strong>Oncology</strong>, UC Irvine School <strong>of</strong> Medicine, Irvine, CA, USA,<br />
11 Clinical Genomics, Foundation Medicine, Inc., Cambridge, MA, USA, 12 Clinical<br />
Development, Foundation Medicine, Inc., Cambridge, MA, USA<br />
Background: LSC is a rare, clinically aggressive, heterogeneous and poorly<br />
differentiated subtype <strong>of</strong> non-small cell lung cancer (NSCLC), which is typically<br />
difficult to diagnose and resistant to conventional therapies. We queried whether CGP<br />
could guide LSC patients to novel targeted therapies.<br />
Methods: Hybrid-capture based CGP was performed on 6,923 consecutive FFPE<br />
NSCLCs during the course <strong>of</strong> clinical care and 91 (1.3%) LSCs were identified.<br />
Results: In this series the median age was 67 years (range 32-86), 59% were male, and<br />
82% <strong>of</strong> tumors were stage 4. Overall, 57% <strong>of</strong> cases involved a genomic alteration (GA)<br />
in KRAS (34%) or one <strong>of</strong> 7 genes now recommended for testing in the NSCLC NCCN<br />
guidelines including: MET (8.8%), BRAF (7.7%), EGFR (6.6%), ERBB2 (2.2%) or RET<br />
(1.1%). No alterations were detected in ALK or ROS1. BRAF alterations included<br />
amplification and mutation at V600 or G469. EGFR alterations included amplification,<br />
exon 19 deletion, exon 20 insertion, and activating L858R mutation. Notably, MET<br />
exon 14 skipping alterations were enriched in this series (7/91, 7.7%) compared to<br />
non-LSC NSCLCs (2.8%). In 39 cases that were wild-type for the 7 NCCN genes and<br />
KRAS, potentially actionable GAs were most commonly detected in PTEN (10.3%),<br />
PIK3CA (7.7%), FGFR1 (7.7%), and PDGFRA (7.7%). Median tumor mutation burden<br />
(TMB) was 8 mutations/megabase (range: 0-165, mean: 14), and 21% (19/91) <strong>of</strong> cases<br />
had high TMB ≥ 20. Clinical outcomes were available for a subset <strong>of</strong> patients and we<br />
report clinical benefit in 4 LSC patients treated with targeted therapy whose tumors<br />
harbored alterations in MET, BRAF, and EGFR, as well as an ongoing response to<br />
anti-PD-1 therapy in one patient with TMB = 31.<br />
Conclusions: Targetable GAs, including MET exon 14 alterations, were found in a<br />
majority <strong>of</strong> LSC patients, some <strong>of</strong> which occur at greater frequency than that observed<br />
in non-LSC NSCLCs. An important portion <strong>of</strong> LSC cases had high TMB, which has<br />
been associated with increased likelihood <strong>of</strong> response to immunotherapy. Thus, CGP<br />
can lead to selection <strong>of</strong> appropriate targeted therapies in this population <strong>of</strong> patients,<br />
which has historically been poorly characterized and difficult to treat.<br />
Legal entity responsible for the study: Foundation Medicine<br />
Funding: Foundation Medicine<br />
Disclosure: G.M. Frampton, J. Suh, J.S. Ross, P.J. Stephens, V.A. Miller, S.M. Ali, A.B.<br />
Schrock: is an employee and has stock ownership in Foundation Medicine. S-H.I. Ou:<br />
has received honoraria as an advisory board and speaker bureau member for<br />
Boehringer Ingelheim. All other authors have declared no conflicts <strong>of</strong> interest.<br />
1213PD<br />
abstracts<br />
A comprehensive analysis <strong>of</strong> potentially targetable genetic<br />
aberrations and clinical findings in 821 patients with<br />
squamous-cell NSCLC – a comparison <strong>of</strong> NGM and TCGA<br />
LUSC data<br />
S. Koleczko 1 , C. Schäpers 1 , M. Scheffler 1 , M. Ihle 2 , A. Kostenko 3 , S. Michels 1 ,<br />
R. Fischer 1 , L. Nogova 1 , V. Brandes 1 , D. Abdulla 1 , F. Ueckeroth 2 , M. Thurat 1 ,<br />
R. Frank 1 , A. Eisert 1 , E. Bitter 1 , C. Wömpner 1 , L. Gogl 1 , S. Merkelbach-Bruse 2 ,<br />
R. Büttner 2 , J. Wolf 1<br />
1 Lung Cancer Group Cologne, Center for Integrated <strong>Oncology</strong>, University Hospital<br />
Cologne, Cologne, Germany, 2 Institute <strong>of</strong> Pathology, University Hospital Cologne,<br />
Cologne, Germany, 3 Dep. I for Internal Medicine, Center for Integrated <strong>Oncology</strong>,<br />
University Hospital Cologne, Cologne, Germany<br />
Background: In contrast to the improvements which have been made in the treatment<br />
<strong>of</strong> adenocarcinoma NSCLC, squamous-cell NSCLC (SqCLC) remains a therapeutic<br />
challenge. While there are recent advantages with immunotherapy approaches,<br />
targeted therapy still lacks <strong>of</strong> evidence regarding the frequency <strong>of</strong> driver aberrations in<br />
advanced SqCLC. We set out this study in order to characterize a large-scale set <strong>of</strong><br />
patients with SqCLC genetically and clinically and compared the findings to the<br />
early-stage The Cancer Genome Atlas (TCGA) LUSC cohort.<br />
Methods: Tumor biopsies <strong>of</strong> 821 patients were analyzed within the Network Genomic<br />
Medicine (NGM) lung cancer using next-generation parallel sequencing (NGS). The<br />
panel used consisted <strong>of</strong> 102 amplicons and 14 genes: KRAS, PIK3CA, BRAF, EGFR,<br />
ERBB2, NRAS, DDR2, TP53, ALK, CTNNB1, MET, AKT1, PTEN and MAP2K1. In<br />
subsets <strong>of</strong> patients, fluorescence in-situ hybridization (FISH) was performed for<br />
amplification detection <strong>of</strong> FGFR1 and MET. We queried the TCGA dataset with<br />
respect to the panel used and compared the findings. For the NGM patients, therapy<br />
and outcome were also collected.<br />
Results: Beside expected frequencies <strong>of</strong> TP53, DDR2, PTEN and PIK3CA mutations,<br />
we detected EGFR mutations in 3.2% and BRAF mutations in 1.8%. Unlike the TCGA<br />
dataset, where the frequencies were 2.8% and 3.9%, respectively, the detected mutations<br />
in the NGM cohort consisted <strong>of</strong> activating mutations (i. e., EGFR del19 and L858R,<br />
and BRAF V600E). FISH data revealed a presence <strong>of</strong> MET amplification in 14.2% and<br />
<strong>of</strong> FGFR1 amplification in 20.0%. The association and correlation <strong>of</strong> these aberrations<br />
with clinical findings and prognosis as well as with PD-L1 expression status and<br />
mutational load is still being analyzed. HER2 amplification, which occurred in 2.2% <strong>of</strong><br />
the TCGA cohort, will be analyzed in a subset <strong>of</strong> patients.<br />
Conclusions: Our data suggest that the presence <strong>of</strong> a potential targetable aberration<br />
might occur in up to 40% <strong>of</strong> SqCLC all-comers. Further analyses are warranted in<br />
order to characterize SqCLC patients according to their biomarker pr<strong>of</strong>iles for<br />
potential treatment recommendations.<br />
Legal entity responsible for the study: Lung Cancer Group Cologne, University<br />
Hospital Cologne<br />
Funding: Lung Cancer Group Cologne, University Hospital Cologne<br />
Disclosure: J. Wolf: Astrazeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis,<br />
MSD, Novartis, Pfizer, Roche. All other authors have declared no conflicts <strong>of</strong> interest.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw383 | vi421
abstracts<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
1214PD<br />
Detectability <strong>of</strong> druggable gene fusions by amplicon-based<br />
next generation sequencing in nationwide lung cancer<br />
genomic screening project (LC-SCRUM-Japan)<br />
1215PD<br />
Long-term outcomes with nivolumab (Nivo) vs docetaxel<br />
(Doc) in patients (Pts) with advanced (Adv) NSCLC:<br />
CheckMate 017 and CheckMate 057 2-y update<br />
S. Matsumoto 1 ,K.Yoh 1 , M. Kodani 2 , K. Ohashi 3 , S. Saeki 4 , N. Furuya 5 ,<br />
Y. Nishioka 6 ,Y.Ohe 7 , T. Seto 8 , R. Hayashi 9 , Y. Kataoka 10 ,T.Fukui 11 ,<br />
T. Sakamoto 2 , S. Ikemura 12 , T. Kohno 13 , K. Tsuta 14 , K. Tsuchihara 15 , K. Goto 1<br />
1 Department <strong>of</strong> Thoracic <strong>Oncology</strong>, National Cancer Center Hospital East,<br />
Kashiwa, Japan, 2 Division <strong>of</strong> Medical <strong>Oncology</strong> and Molecular Respirology, Tottori<br />
University Hospital, Yonago, Japan, 3 Department <strong>of</strong> Respiratory Medicine,<br />
Okayama University Hospital, Okayama, Japan, 4 Department <strong>of</strong> Respiratory<br />
Medicine, Kumamoto University Hospital, Kumamoto, Japan, 5 Division <strong>of</strong><br />
Respiratory Medicine, St. Marianna University School <strong>of</strong> Medicine, Kawasaki,<br />
Japan, 6 Department <strong>of</strong> Respiratory Medicine and Rheumatology, Tokushima<br />
University Hospital, Tokushima, Japan, 7 Department <strong>of</strong> Thoracic <strong>Oncology</strong>,<br />
National Cancer Center Hospital, Tokyo, Japan, 8 Department <strong>of</strong> Thoracic<br />
<strong>Oncology</strong>, National Kyushu Cancer Center, Fukuoka, Japan, 9 1st department <strong>of</strong><br />
medicine, Toyama University Hospital, Toyama, Japan, 10 Department <strong>of</strong><br />
Respiratory Medicine, Hyogo Prefectural Amagasaki General Medical Center,<br />
Amagasaki, Japan, 11 Department <strong>of</strong> Respiratory Medicine, Kitasato University<br />
School <strong>of</strong> Medicine, Tokyo, Japan, 12 Department Respiratory Medicine, Tokyo<br />
Dental College Ichikawa General Hospital, Ichikawa, Japan, 13 Division <strong>of</strong> Genome<br />
Biology, National Cancer Center Research Institute, Tokyo, Japan, 14 Department<br />
<strong>of</strong> Pathology and Laboratory Medicine, Kansai Medical University, Hirakata, Japan,<br />
15 Division <strong>of</strong> Translational Research, National Cancer Center, Kashiwa, Japan<br />
Background: Kinase gene fusions, such as ALK, ROS1 and RET fusions, are critical<br />
druggable targets for lung cancer, and the development <strong>of</strong> multiplexed testing for these<br />
fusions as well as gene mutations and amplifications is required in clinical settings. We<br />
evaluated the detectability <strong>of</strong> gene fusions by a next generation sequencing (NGS)<br />
system, which has been applied in our nationwide genomic screening project<br />
(LC-SCRUM-Japan) with academic-industrial collaboration since March 2015.<br />
Methods: DNA and RNA extracted from lung cancer samples were subjected to a NGS<br />
system, Oncomine Comprehensive Assay, which is an amplicon-based sequencing and<br />
enables the simultaneous analysis <strong>of</strong> >4000 different genomic variants including 183<br />
types <strong>of</strong> gene fusions. ROS1 and RET fusions were also analyzed using RT-PCR and<br />
detected fusions were confirmed by FISH.<br />
Results: As <strong>of</strong> April 2016, 1,118 patients from 209 institutions across Japan had been<br />
enrolled in this project. Among 989 available samples, including 900 non-small cell<br />
carcinomas and 89 small cell carcinomas, gene fusions were detected in 83 samples<br />
(8%). The detected fusion genes were 34 ROS1 (3%), 25 RET (3%), 19 ALK (2%), 2<br />
FGFR2 (0.2%) and 1 FGFR3 (0.1%). The concordance rates between NGS and RT-PCR<br />
for the detection <strong>of</strong> ROS1 and RET fusions were both 0.99, and the detection<br />
sensitivities/specificities <strong>of</strong> these two fusions in NGS assay were 0.94/1.00 and 0.95/<br />
1.00, respectively.<br />
Conclusions: Our nation-wide large scale screening revealed that this amplicon-based<br />
NGS assay allows for the detection <strong>of</strong> various druggable gene fusions, especially <strong>of</strong><br />
ROS1 and RET fusions with high sensitivities and specificities, indicating that this NGS<br />
assay is clinically applicable to a molecular diagnostics for targeted therapies in lung<br />
cancer.<br />
Legal entity responsible for the study: National Cancer Center<br />
Funding: Japan Agency for Medical Research and Development (AMED)<br />
Disclosure: S. Matsumoto, K. Yoh, K. Goto: Grants from Chugai Pharm., MSD, Astra<br />
Zeneka, Taiho Pharm., Ono Pharm., Eisai, Pfizer, Kyowa Hakko Kirin, Eli Lilly, Takeda<br />
Pharm., Novartis Pharma, Daiichi Sankyo, Astellas Pharma and Amgen Astellas<br />
BioPharma, during the conduct <strong>of</strong> the study. Y. Ohe: Grants and personal fees from<br />
AstraZeneca, Chugai, Lilly, Ono, Taiho, Novartis, Pfizer, Bristol Myers, Dainippon<br />
Sumitomo, Merck, Daiichi Sankyo, Nippon Kayaku, Boehringer Ingelheim, Bayer,<br />
MSD, Clovis <strong>Oncology</strong> and San<strong>of</strong>i, outside the submitted work. T. Seto: Grants and<br />
personal fees from AstraZeneca, Chugai, Lilly, Ono, Sumitomo, Taiho, Novartis,<br />
Merck, Daiichi Sankyo, Boehringer, MSD, San<strong>of</strong>i, Pfizer, Eisai, Fuji, Hisamitsu, Kyowa<br />
Hakko, Roche, Takeda, Astellas, Bayer and Yakult, outside the submitted work. T.<br />
Kohno: Grants from Daiichi Sankyo, outside the submitted work. K. Tsuchihara:<br />
Personal fees from Takeda, personal fees from Chugai Pharma, personal fees from<br />
AstraZeneca, personal fees from Eisai, personal fees from Merck Serono, outside the<br />
submitted work. All other authors have declared no conflicts <strong>of</strong> interest.<br />
F. Barlesi 1 , M. Steins 2 , L. Horn 3 , N. Ready 4 , E. Felip 5 , H. Borghaei 6 , D.R. Spigel 7 ,<br />
O. Arrieta 8 , S.J. Antonia 9 , J. Fayette 10 , N. Rizvi 11 , L. Crinò 12 , M. Reck 13 ,W.<br />
E. Eberhardt 14 , M. Hellmann 11 , W.J. Geese 15 ,A.Li 16 , D. Healey 17 , J.R. Brahmer 18 ,<br />
L. Paz-Ares 19<br />
1 Multidisciplinary <strong>Oncology</strong> and Therapeutic Innovations, Aix Marseille University;<br />
Assistance Publique Hôpitaux de Marseille, Marseille, France, 2 <strong>Oncology</strong>,<br />
Thoraxklinik-Heidelberg gGmbH, Heidelberg, Germany, 3 <strong>Oncology</strong>, Vanderbilt<br />
Ingram Cancer Center, Nashville, TN, USA, 4 <strong>Oncology</strong>, Duke University Medical<br />
Center, Durham, NC, USA, 5 Oncologia Médica, Vall d’Hebron University Hospital<br />
Institut d’Oncologia, Barcelona, Spain, 6 Department <strong>of</strong> Hematology/<strong>Oncology</strong>,<br />
Fox Chase Cancer Center, Philadelphia, PA, USA, 7 <strong>Oncology</strong>, Sarah Cannon<br />
Research Institute/Tennessee <strong>Oncology</strong>, PLLC, Nashville, TN, USA, 8 <strong>Oncology</strong>,<br />
Instituto Nacional de Cancerologia, Mexico City, Mexico, 9 Department <strong>of</strong><br />
<strong>Oncology</strong>, H. Lee M<strong>of</strong>fitt Cancer Center & Research Institute, Tampa, FL, USA,<br />
10 <strong>Oncology</strong>, Centre Léon Bérard, Lyon, France, 11 <strong>Oncology</strong>, Memorial Sloan<br />
Kettering Cancer Center, New York, NY, USA, 12 Oncologia Medica, Ospedale<br />
S. Maria della Misericordia, Perugia, Italy, 13 Thoracic <strong>Oncology</strong>, LungenClinic<br />
Grosshansdorf, Airway Research Center North (ARCN), German Center for Lung<br />
Research (DZL), Grosshansdorf, Germany, 14 Department <strong>of</strong> Medical <strong>Oncology</strong>,<br />
West German Cancer Centre, Essen, Germany, 15 <strong>Oncology</strong>, Bristol-Myers<br />
Squibb, Princeton, NJ, USA, 16 Biostatistics, Bristol-Myers Squibb, Princeton, NJ,<br />
USA, 17 I-O Global Clinical Research, Bristol-Myers Squibb, Princeton, NJ, USA,<br />
18 Department <strong>of</strong> <strong>Oncology</strong>, The Sidney Kimmel Comprehensive Cancer Center at<br />
Johns Hopkins, Baltimore, MD, USA, 19 <strong>Oncology</strong>, University Hospital 12 De<br />
Octubre, Madrid, Spain<br />
Background: The phase III trials CheckMate 017 (NCT01642004) and CheckMate 057<br />
(NCT01673867) demonstrated improved OS with the anti-programmed death (PD)-1<br />
antibody nivo vs doc as treatment (tx) for adv previously treated squamous (SQ) and<br />
non-SQ (NSQ) NSCLC, respectively. Approval <strong>of</strong> nivo in these indications was based<br />
on results <strong>of</strong> these studies. Updated results based on a minimum follow-up (f/u) <strong>of</strong> 2 y<br />
are reported.<br />
Methods: Pts received nivo 3 mg/kg Q2W or doc 75 mg/m 2 Q3W (1:1 randomization)<br />
until progression or discontinuation. The primary objective <strong>of</strong> each study was OS;<br />
additional objectives included investigator-assessed ORR, PFS, efficacy by PD ligand 1<br />
(PD-L1) expression, and safety.<br />
Results: With ≥2 y <strong>of</strong> f/u, 8% and 9% <strong>of</strong> pts remained on tx in the nivo groups <strong>of</strong><br />
CheckMate 017 and 057, respectively, vs 0 pts in either doc group. 2-y OS and PFS<br />
rates and ORRs were higher with nivo vs doc in both studies (table). Median duration<br />
<strong>of</strong> response was ≥3 times longer with nivo (25.2 and 17.2 mo) vs doc (8.4 and 5.6 mo),<br />
with responses in the nivo groups lasting up to 30.4 and 33.7+ mo (table). Responses<br />
were ongoing in 37% and 34% <strong>of</strong> nivo responders vs 0 doc responders. In CheckMate<br />
057, complete responses (n = 4; 1%) were observed across PD-L1 expression levels<br />
(PD-L1 ≥1%: n = 2; PD-L1 2 y. The safety pr<strong>of</strong>ile <strong>of</strong> nivo remained favorable vs<br />
doc, with no new safety concerns identified. Updated data on time to onset and<br />
resolution <strong>of</strong> TR select AEs will be presented.<br />
Clinical trial identification: CheckMate 017 = NCT01642004 CheckMate<br />
057 = NCT01673867<br />
Legal entity responsible for the study: Bristol-Myers Squibb<br />
Funding: Bristol-Myers Squibb<br />
Disclosure: F. Barlesi: Honoraria, research funding, and consulting/advisory role with<br />
Bristol-Myers Squibb. M. Steins: Honoraria and consulting/advisory role with<br />
Bristol-Myers Squibb. L. Horn: Compensated consulting/advisory role for Genentech/<br />
Merck as well as uncompensated role with BMS,BI, Xcovery and Bayer. Research<br />
funding provided by AZ and the author or family member had a relationship/role/<br />
activity/interest with Biodesix. N. Ready: Honoraria from BMS, Celgene, Heat Biologics<br />
and travel/accommodations/expenses from AZ. E. Felip: Honoraria and consulting/<br />
advisory role with Boeheringer Ingelheim, MSD, Eli Lilly, Roche, Pfizer, Novartis,<br />
BMS, Celgene. Speakers Bureau for BMS, Novartis, Roche. H. Borghaei: Honoraria for<br />
BMS and Celgene, a consulting/advisory role with BMS, Lilly, Clovis, Genentech and<br />
Pfizer. Travel/accommodations/expenses from BMS, Lilly, Genentech and Clovis. D.R.<br />
Spigel: Travel/accommodations/expenses from Novartis, Genentech and Pfizer.<br />
Speakers’bureau for Novartis (uncompensated) that funded all or part <strong>of</strong> this<br />
research. O. Arrieta: Speakers’ Bureau for Pfizer, MSD, AstraZeneca, Novartis, Lilly<br />
and Boehringer Ingelheim. Research Funding for AstraZeneca, Novartis, Bristol, Pfizer,<br />
MSD. S.J. Antonia: Honoraria, consulting/advisory role and travel/accommodations/<br />
expenses from BMS, Merck, AZ and BI. Stock or other ownership from Cellular<br />
Biomedicine Group. N. Rizvi: Honoraria from MSD, Amgen, research funding from<br />
AZ, consulting/advisory role with MSD, Roche, AZ, BMS, Novartis, Leadership at<br />
Gristone <strong>Oncology</strong>, and Stock or other ownership <strong>of</strong> Gritstone <strong>Oncology</strong>. L. Crinò:<br />
Speakers’ Bureau for BMS, Novartis and AZ. M. Reck: Speakers’ Bureau and<br />
vi422 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
Table: 1215PD<br />
CheckMate 017 (SQ NSCLC)<br />
CheckMate 057 (NSQ NSCLC)<br />
Efficacy measure Nivo (n = 135) Doc (n = 137) Nivo (n = 292) Doc (n = 290)<br />
OS<br />
Median, mo 9.2 6.0 12.2 9.5<br />
HR (95% CI) 0.62 (0.47, 0.80) 0.75 (0.63, 0.91)<br />
2-y OS, % 23 8 29 16<br />
PFS<br />
Median, mo 3.5 2.8 2.3 4.3<br />
HR (95% CI) 0.63 (0.48, 0.83) 0.89 (0.75, 1.07)<br />
2-y PFS, % 16 NC 12 1<br />
ORR, % 20 9 19 12<br />
Median DOR, mo (range) 25.2 (2.9–30.4) 8.4 (1.4 + −18.0+) 17.2 (1.8–33.7+) 5.6 (1.2 + –16.8)<br />
Ongoing response, a % 37 0 34 0<br />
No. ongoing/total responders 10/27 0/12 19/56 0/36<br />
Safety measure Nivo (n = 131) Doc (n = 129) Nivo (n = 287) Doc (n = 268)<br />
Grade 3–4 TRAEs, % 8 56 11 54<br />
TR select AE b category in ≥5% <strong>of</strong> pts, %<br />
Endocrine 5 0 10
abstracts<br />
Legal entity responsible for the study: MedImmune<br />
Funding: MedImmune<br />
Disclosure: S.J. Antonia: Consulting/Advisory: BMS, AZ, Merck. J.R. Brahmer:<br />
Consulting/Advisory: AZ/Medimmune Research funding: AZ/Medimmune. S. Khleif:<br />
Leader/stock: Advaxis Honor: MEDI, AZ, NewLink, Advaxis, Lucena, PDS Consult/<br />
AB: Gilead, Janssen, Nektan, Merus, GHI, BI Res fund: MEDI, AZ, NewLink, Advaxis,<br />
PDS, Serono, IOBiotech, Caretech, Medivation Travel: MEDI, AZ, NewLink, Advaxis,<br />
Lucena. A.S. Balmanoukian: Speaker Bureau: BMS, Merck Research funding:<br />
Medimmune, Genentech, BMS, Merck Serono. S-H.I. Ou: Consulting/advisory:<br />
ARIAD, Pfizer, Roche, AZ Speaker Bureau: Roche, AZ, BI Research funding: ARIAD,<br />
AZ, BI< Pfizer, Igyta, Daiichi Sankyo, Clovis. M. Gutierrez: Employment: Hackensack<br />
University Medical Center Other relationship: Speaker Bureau Merck/BMS. M-J. Ahn:<br />
Honoraria: MSD, BMS, AZ, BI, Novartis Consulting/Advisory: BI, BMS, AZ, MSD,<br />
Novartis Research funding: AZ. R. Jamal: Honoraria: BMS, Merck Consulting advisory:<br />
BMS, Merck Research funding: BMS, Merck. D. Jaeger: Consulting/Advisory: Roche,<br />
BMS, Bayer, Definiens. G. Jerusalem: Honoraria: Novartis, Roche, Celgene Consulting<br />
or advisory: Novartis, Roche, Celgene, Amgen, Pfizer Research funding: Novartis, Roche,<br />
MSD Travel, accommodations, expenses: Novartis, Roche, GSK. X. Jin: Employment:<br />
Unitech Heal Care, Medimmune Stock/other ownership: AZ, United Health<br />
group. A. Gupta: Employment: Medimmune Stock/ownership: BMS, AZ Patents,<br />
royalties, IP: BMS. J. Antal: Employment: Medimmune Stock/ownership: AZ, GSK. N.H.<br />
Segal: Consultancy: Medimmune/AZ, BMS, Roche, Pfizer Research funding:<br />
Medimmune/AZ, BMS. All other authors have declared no conflicts <strong>of</strong> interest.<br />
1217PD<br />
Overall health status (HS) in patients (pts) with advanced<br />
(adv) non-squamous (NSQ) NSCLC treated with nivolumab<br />
(nivo) or docetaxel (doc) in CheckMate 057<br />
M. Reck 1 , J.R. Brahmer 2 , B. Bennett 3 , F. Taylor 4 , J.R. Penrod 5 , M. Derosa 4 ,<br />
H. Dastani 5 , R. Gralla 6<br />
1 Thoracic <strong>Oncology</strong>, Lung Clinic Grosshansdorf, Airway Research Center North<br />
(ARCN), member <strong>of</strong> the German Center for Lung Research (DZL), Grosshansdorf,<br />
Germany, 2 Department <strong>of</strong> <strong>Oncology</strong>, The Sidney Kimmel Comprehensive Cancer<br />
Center at Johns Hopkins, Baltimore, MD, USA, 3 Patient-Centered Outcomes,<br />
Adelphi Values Ltd, Bollington, UK, 4 Patient-Centered Outcomes, Adelphi Values,<br />
Boston, MA, USA, 5 Global Health Economics and Outcomes Research,<br />
Bristol-Myers Squibb, Princeton, NJ, USA, 6 Department <strong>of</strong> Medicine (<strong>Oncology</strong>),<br />
Albert Einstein College <strong>of</strong> Medicine, New York, NY, USA<br />
Background: The CheckMate 057 randomized, open-label, phase III study evaluated<br />
the efficacy and safety <strong>of</strong> nivo vs doc in previously-treated pts with adv NSQ NSCLC.<br />
Overall survival was significantly improved with nivo vs doc, as were symptoms as<br />
assessed by the Lung Cancer Symptom Scale. Here we report the impact <strong>of</strong> nivo vs doc<br />
on overall pt-reported HS.<br />
Methods: The EuroQoL-5 Dimensions visual analog scale (EQ-5D VAS) and EQ-5D<br />
utility index (UI) (scaled 0 to 100 and −0.594 to +1, respectively) were assessed every<br />
other cycle (Q4W) for nivo and every cycle (Q3W) for doc for the first 6 mo on<br />
treatment (tx), then every 6 wks and at 2 post-tx follow-up visits. Changes from<br />
baseline (BL) at individual assessments (asmts), a mixed-effects model (MMRM) <strong>of</strong><br />
change from BL over all on-tx asmts, and time to first deterioration (TTD) in HS were<br />
evaluated. The minimally important difference (MID) is ≥7 points for the EQ-5D VAS<br />
and ≥0.08 points for the UI.<br />
Results: At on-tx asmts with >10 pts (through wk 78), EQ-5D VAS briefly worsened<br />
from BL in nivo pts at wk 4 (MID) at wks 24 and 36. There were no statistically significant changes<br />
from BL at any on-tx asmt in EQ-5D VAS scores for doc pts or in EQ-5D UI scores for<br />
nivo (apart from a worsening [
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Disclosure: M. Nishio: Honori: Pfizer,BMS, ONO, Chugai, Eli Lilly, TAIHO,<br />
AstraZeneca Daiichi Sankyo, Novartis Cooperate. Sponsored research for: Novartis,<br />
ONO, Chugai, Bristol-Myers Squibb, Taiho, Eli Lilly, Pfizer, Astellas, AstraZeneca. T.S.<br />
K. Mok: Stock ownership: Sanomics Advisory board:AZ, Roche/Genentech, Pfizer,<br />
Eli-Lilly, BI, Merck Serono, MSD, Janssen, Clovis, BioMarin, GSK, Novartis, SFJ,<br />
ACEA, Inc., Vertex, BMS. Sponsored research: AZ, BI, Pfizer, Novartis, SFJ, Roche,<br />
MSD, Clovis, BMS. L. Zhang: Advisory board for Boehringer Ingelheim, Astrazeneca,<br />
BMS Cooperate. Sponsored research for Pfizer, Astrazeneca, BMS. R. Soo: Advisory<br />
board for Astra-Zeneca, Boehringer Ingelheim, Merck, Novartis, Pfizer, Roche, Taiho<br />
Honorarium for Astra-Zeneca, Boehringer Ingelheim, Lilly, Merck, Novartis, Pfizer,<br />
Roche, Taiho. J. Yang: Advisory board for Boehringer, Eli-Lilly, Bayer, Roche/<br />
Genentech/Chugai, Astrazeneca, Astellas, MSD, Merck Serono, Pfizer, Novartis, Clovis<br />
<strong>Oncology</strong>, Celgene, innopharma, Merrimack. S. Morita, S. Sugawara, T. Tamura:<br />
Honorarium for Taiho. H. Nokihara: Cooperate – sponsored research for Merck<br />
Serono, Pfizer, Taiho, Eisai, Chugai, Eli Lilly, Novartis, Daiichi Sankyo, GSK, Yakult,<br />
Quintiles, Astellas, AZ, BI, Ono Honorarium for Boehringer, Taiho, AZ, Ono, San<strong>of</strong>i,<br />
Eli Lilly. T. Takahashi: Cooperate – sponsored research for AstraZeneca, Eli Lilly,<br />
Chugai, ONO, Pfizer,Takeda.Taiho, MSD Honorarium for AstraZeneca, Eli Lilly,<br />
Chugai, ONO, Boehringer. K. Goto: Cooperate – sponsored research for Taiho, MSD,<br />
Astra Zeneka, Chugai, Nippon, BI, Ono, Quintiles, GSK, OxOnc, Pfizer, Kyowa Hakko<br />
Kirin, Eli Lilly, Yakult, Sumitomo Dainippon, Takeda, Novartis, DAIICHI SANKYO,<br />
Astellas, Eisai, Amgen, BMS. Y. Ichinose: Cooperate – sponsored research for Takeda,<br />
Nippon Kayaku Honorarium for Chugai, Kyowa Hakko Kirin, Taiho, Taisho Toyama.<br />
All other authors have declared no conflicts <strong>of</strong> interest.<br />
1219P<br />
Assessment <strong>of</strong> health-related quality <strong>of</strong> life (HRQoL) in<br />
KEYNOTE-010: A phase 2/3 study <strong>of</strong> pembrolizumab vs<br />
docetaxel in patients with previously treated advanced<br />
NSCLC<br />
F. Barlesi 1 , E. Garon 2 , D-W. Kim 3 , E. Felip 4 , J-Y. Han 5 , J-H. Kim 6 , M-J.A. Ahn 7 ,M.<br />
J. Fidler 8 , M.A. Gubens 9 , G. Castro, 10 , V. Surmont 11 ,Q.Li 12 , A.C. Deitz 12 ,<br />
G. Lubiniecki 12 , R.S. Herbst 13<br />
1 <strong>Oncology</strong>, Aix Marseille University; Assistance Publique Hôpitaux de Marseille,<br />
Marseille, France, 2 Medicine, Hematology and <strong>Oncology</strong>, David Geffen School <strong>of</strong><br />
Medicine at UCLA, Santa Monica, CA, USA, 3 Internal Medicine, Seoul National<br />
University Hospital, Seoul, Republic <strong>of</strong> Korea, 4 Medical <strong>Oncology</strong>, Vall d’Hebron<br />
University Hospital Institut d’Oncologia, Barcelona, Spain, 5 Translational and<br />
Clinical Research, National Cancer Center, Goyang, Republic <strong>of</strong> Korea,<br />
6 Department <strong>of</strong> <strong>Oncology</strong>, CHA Bundang Medical Center, CHA University,<br />
Gyeonggi-do, Republic <strong>of</strong> Korea, 7 Medical <strong>Oncology</strong>, Samsung Medical Center,<br />
Seoul, Republic <strong>of</strong> Korea, 8 Internal Medicine, Rush University Medical Center,<br />
Chicago, IL, USA, 9 Department <strong>of</strong> Medicine, University <strong>of</strong> California San Francisco,<br />
San Francisco, CA, USA, 10 Internal Medicine, Instituto do Câncer do Estado de<br />
São Paulo, São Paulo, Brazil, 11 Medical <strong>Oncology</strong>, Universitar Ziekenhuis Ghent,<br />
Gent, Belgium, 12 Medical <strong>Oncology</strong>, Merck & Co, Inc, Kenilworth, NJ, USA,<br />
13 Medical <strong>Oncology</strong>, Yale School <strong>of</strong> Medicine, New Haven, CT, USA<br />
Background: In the randomized phase 2/3 KEYNOTE-010 study (NCT01905657),<br />
pembrolizumab significantly prolonged OS compared with docetaxel in previously<br />
treated, PD-L1–positive (tumor proportion score [TPS] ≥1% and ≥50%), advanced<br />
NSCLC. Here, we report HRQoL findings from KEYNOTE-010.<br />
Methods: Patients (pts) with PD-L1–positive NSCLC who progressed after<br />
platinum-based chemotherapy were randomized 1:1:1 to pembrolizumab 2 or 10 mg/<br />
kg Q3W or docetaxel 75 mg/kg. HRQoL was assessed using eEORTC QLQ-C30,<br />
QLQ-LC13, and eEuroQoL-5D. Analyses included mean change from baseline to wk<br />
12 in global QoL score, functioning and symptom domains; and time to deterioration<br />
in a QLQ-LC13 composite end point <strong>of</strong> cough, dyspnea, and chest pain.<br />
Results: Compliance was >90% at baseline and >80% at wk 12. Pts in the<br />
pembrolizumab arms (n = 131, 2 mg/kg; n = 145,10 mg/kg) reported either a numerical<br />
improvement in or less decrement <strong>of</strong> QLQ-C30 global QoL score from baseline to wk<br />
12 versus docetaxel (n = 125); the difference in least-squares means at wk 12 was<br />
statistically significant (8.3 [95% CI, 2.42-14.26]; P = 0.006) for pembrolizumab 2 mg/<br />
kg compared with docetaxel in the PD-L1 TPS ≥50% stratum. Changes from baseline<br />
in EORTC functioning and symptom domains were numerically superior for<br />
pembrolizumab versus docetaxel; fatigue, insomnia, dyspnea, hemoptysis, alopecia,<br />
peripheral neuropathy, and sore mouth reached statistical significance. Pembrolizumab<br />
also had a smaller proportion <strong>of</strong> “deteriorated” status and a larger proportion <strong>of</strong><br />
“stable” and “improved” status for QLQ-C30 global QoL and functional and symptom<br />
scales versus docetaxel. Pembrolizumab increased time to true deterioration in the<br />
QLQ-LC13 composite end point; statistical significance was achieved for the<br />
pembrolizumab 2 mg/kg, TPS ≥50% stratum (HR, 0.68 [95% CI, 0.48-0.96]; P = 0.030<br />
vs docetaxel). 12-wk EQ-5D visual analog scale analyses were consistent with the<br />
results <strong>of</strong> QLQ-C30 analyses.<br />
Conclusions: Pembrolizumab improved HRQoL and prolonged time to deterioration<br />
<strong>of</strong> lung cancer symptom scores compared with docetaxel.<br />
Clinical trial identification: NCT01905657<br />
Legal entity responsible for the study: Merck & Co., Inc.<br />
Funding: Merck & Co., Inc.<br />
Disclosure: Q. Li, G. Lubiniecki: Employee <strong>of</strong> Merck & Co, Inc. A.C. Deitz: Employee<br />
and Stockholder: Merck & Co., Inc. Corporate-sponsored research: Merck & Co., Inc.<br />
All other authors have declared no conflicts <strong>of</strong> interest.<br />
1220P<br />
Healthcare resource utilization (HCRU) in patients with<br />
advanced NSCLC in CheckMate 017 and 057 based on<br />
treatment-related (TR) adverse events (AEs)<br />
M. Venkatachalam 1 , D. Stenehjem 2 , G. Pietri 3 , J.R. Penrod 4 , B. Korytowsky 4<br />
1 Heron, PAREXEL International, Waltham, MA, USA, 2 Pharmacotherapy,<br />
University <strong>of</strong> Utah, College <strong>of</strong> Pharmacy, Salt Lake City, UT, USA, 3 Data Pyxis Ltd,<br />
Heron, PAREXEL International, Waltham, MA, USA, 4 Health Economics and<br />
Outcomes Research, Bristol-Myers Squibb, Princeton, NJ, USA<br />
Background: Nivolumab (nivo), a programmed death 1 (PD-1) immune checkpoint<br />
inhibitor, is approved in the US and EU for treatment <strong>of</strong> metastatic NSCLC on or after<br />
progression <strong>of</strong> platinum-based chemotherapy. Nivo has demonstrated improved<br />
survival and a favorable safety pr<strong>of</strong>ile versus docetaxel (doc) in two phase 3 trials,<br />
CheckMate 017 and 057, in squamous (SQ) and non-squamous (NSQ) NSCLC,<br />
respectively. Due to improved safety, nivo may bring additional benefits in terms <strong>of</strong><br />
AE-related HCRU relative to doc.<br />
Methods: Both trials assessed nivo 3 mg/kg Q2W versus doc 75 mg/m 2 Q3W until<br />
progression or unacceptable toxicity. HCRU components (concomitant medications<br />
[categorized using Anatomical Therapeutic Chemical Classification], laboratory tests,<br />
and procedures) were evaluated in patients experiencing TR AEs, specifically grade<br />
(Gr) 2, 3–4.<br />
Results: In CheckMate 017, 45 nivo patients and 87 doc patients experienced 356 Gr<br />
1–4 TR AEs. In CheckMate 057, 124 nivo patients and 194 doc patients experienced<br />
906 Gr 1–4 TR AEs (Table). In both trials, doc patients experienced more TR AEs than<br />
nivo patients, especially Gr 3/4 AEs (77 vs 6 in 017; 165 vs 29 in 057). Doc patients<br />
were generally treated with anti-infectives, immunostimulants, and/or corticosteroids,<br />
while nivo patients mostly received corticosteroids for TR AEs. Patients only<br />
underwent laboratory testing for serious TR AEs, most commonly hematology tests in<br />
patients receiving doc. Nivo patients underwent more procedures (lung-related) for Gr<br />
2 TR AEs than doc patients. With Gr 3/4 TR AEs, chest x-rays were common in doc<br />
patients in both 017 and 057 and lung-related evaluations in nivo patients in 057.<br />
Table: 1220P<br />
abstracts<br />
CheckMate 017 a Nivo (n = 45) Doc (n = 87)<br />
Gr 2 Gr 3–4 All Gr Gr 2 Gr 3–4 All Gr<br />
TR AEs, n 46 6 98 95 77 258<br />
Patients with concomitant medications, n 17 3 30 18 48 85<br />
Laboratory tests, b n 9 9 20 4 75 79<br />
Procedures, n 18 3 33 12 28 47<br />
CheckMate 057 c Nivo (n = 124) Doc (n = 194)<br />
Gr 2 Gr 3–4 All Gr Gr 2 Gr 3–4 All Gr<br />
TR AEs, n 128 29 304 205 165 602<br />
Patients with concomitant medications, n 29 19 76 34 106 181<br />
Laboratory tests, b n 54 49 103 72 263 336<br />
Procedures, n 38 40 78 23 49 78<br />
a Treated patients: nivo N = 131; doc N = 129.<br />
b Laboratory tests were<br />
categorized based on values (eg, coagulation, electrolytes, hematology I and II,<br />
immunology, and liver and kidney function). c Treated patients: nivo N = 287;<br />
doc N = 268.<br />
Conclusions: HCRU associated with nivo in CheckMate 017 and 057 was lower<br />
compared to doc for patients experiencing Gr 3/4 TR AEs and generally lower for Gr 2<br />
events. These data are consistent with the lower rate <strong>of</strong> TR AEs and a better tolerability<br />
pr<strong>of</strong>ile <strong>of</strong> nivo vs doc.<br />
Clinical trial identification: CheckMate 017 = NCT01642004 CheckMate<br />
057 = NCT01673867<br />
Legal entity responsible for the study: Bristol-Myers Squibb<br />
Funding: Bristol-Myers Squibb<br />
Disclosure: M. Venkatachalam: Employment & consulting/advisory role: PAREXEL;<br />
travel, accommodations, expenses: BMS. D. Stenehjem: Consulting/advisory role &<br />
research funding: BMS. G. Pietri: Employment: Parexel. J.R. Penrod, B. Korytowsky:<br />
Employment and stock options: BMS.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw383 | vi425
abstracts<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
1221P<br />
KEYNOTE-025: Phase 1b study <strong>of</strong> pembrolizumab (pembro)<br />
in Japanese patients (pts) with previously treated PD-L1+<br />
non-small cell lung cancer (NSCLC)<br />
1222P<br />
Immune checkpoint inhibitors (IC) induce paradoxical<br />
progression in a subset <strong>of</strong> non-small cell lung cancer<br />
(NSCLC)<br />
T. Kato 1 , T. Takahashi 2 , H. Yoshioka 3 , K. Nakagawa 4 , M. Maemondo 5 ,<br />
K. Yamada 6 , M. Ichiki 7 , H. Tanaka 8 , T. Seto 9 , H. Sakai 10 , K. Kasahara 11 ,<br />
M. Satouchi 12 , K. Noguchi 13 , T. Shimamoto 13 , M. Nishio 14<br />
1 Department <strong>of</strong> Respiratory Medicine, Kanagawa Cardiovascular and Respiratory<br />
Center, Yokohama, Japan, 2 Division <strong>of</strong> Thoracic <strong>Oncology</strong>, Shizuoka Cancer<br />
Center, Suntogun, Japan, 3 Department <strong>of</strong> Respiratory Medicine, Kurashiki Central<br />
Hospital, Kurashiki, Japan, 4 Department <strong>of</strong> Medical <strong>Oncology</strong>, Kindai University<br />
Faculty <strong>of</strong> Medicine, Osaka-Sayama, Japan, 5 Respiratory Medicine, Miyagi Cancer<br />
Center, Natori, Japan, 6 Division <strong>of</strong> Respirology, Neurology, and Rheumatology,<br />
Department <strong>of</strong> Internal Medicine, Kurume University, Kurume, Japan, 7 Respiratory<br />
Medicine, Kyushu Medical Center, Fukuoka, Japan, 8 Internal Medicine<br />
(Pneumonology), Niigata Cancer Center Hospital, Niigata, Japan, 9 Department <strong>of</strong><br />
Thoracic <strong>Oncology</strong>, National Kyushu Cancer Center, Fukuoka, Japan, 10 Thoracic<br />
<strong>Oncology</strong>, Saitama Cancer Center, Saitama, Japan, 11 Respiratory Medicine,<br />
Kanazawa University Hospital, Kanazawa, Japan, 12 Thoracic <strong>Oncology</strong>, Hyogo<br />
Cancer Center, Akashi, Japan, 13 <strong>Oncology</strong> Science Unit, MSD K.K., Tokyo,<br />
Japan, 14 Department <strong>of</strong> Thoracic Medical <strong>Oncology</strong>, The Cancer Institute Hospital<br />
<strong>of</strong> Japanese Foundation for Cancer Research, Tokyo, Japan<br />
Background: Pembro is a potent, highly selective humanized monoclonal antibody<br />
against PD-1. We present preliminary safety and efficacy results for Japanese pts in<br />
KEYNOTE-025 (NCT02007070).<br />
Methods: Pts had measurable disease, ECOG performance status <strong>of</strong> 0 or 1, and<br />
adequate organ function. Prior therapy with ≥1 platinum-doublet chemotherapy<br />
regimen was required; an appropriate tyrosine kinase inhibitor was required for pts<br />
with sensitizing EGFR mutations (mut) or ALK translocations. All pts had PD-L1+<br />
tumors, defined as staining in ≥1% <strong>of</strong> tumor cells as determined by a clinical trial IHC<br />
assay using the 22C3 antibody. Pembro 10 mg/kg was given every 3 weeks for up to 2<br />
years, until disease progression or unacceptable toxicity. Primary endpoints were safety,<br />
tolerability, and overall response rate (ORR) per RECIST v1.1 by central review. Chest<br />
CT images were assessed for diagnosis <strong>of</strong> interstitial lung disease (ILD) by an<br />
independent radiologist.<br />
Results: 38 pts were treated with pembro. Median (range) age was 66.0 (41-78) years;<br />
68.4% were Male; 26.3% were EGFR mut. 60.5% received ≥2 prior therapies. Most<br />
common drug-related adverse events (AEs) include malaise (n = 8), diarrhea (n = 6),<br />
AST increased, decreased appetite, pruritus, rash, maculopapular rash (n = 5 each).<br />
21.1% experienced grade 3-5 drug-related AEs. ILD was observed in 4 pts (3 grade 2, 1<br />
grade 5). In the 37 pts with measurable disease at baseline, ORR was 18.9% (95% CI,<br />
8.0-35.2). At the time <strong>of</strong> analysis (median follow-up, 11.5 months), 85.7% responses<br />
were ongoing, and the median response duration was not reached (range, 9.1+ to 46.1+<br />
months). Median progression-free survival (PFS) was 3.8 months (95% CI, 2.0-6.2),<br />
and 6-mo PFS and 1-year overall survival (OS) rates were 38.8% and 51.0%,<br />
respectively. In the 11 pts who had PD-L1 expression in ≥ 50% <strong>of</strong> tumor cells, ORR<br />
was 27.3% (95% CI, 6.0-61.0). Median PFS was 4.1 months (95% CI, 1.6-NR), and<br />
6-month PFS and 1-year OS rates were 41.7% and 56.3%, respectively.<br />
Conclusions: Pembro was generally well tolerated in Japanese pts, but ILD should be<br />
carefully monitored. Pembro showed promising anti-tumor efficacy in Japanese pts<br />
with previous treated PD-L1+ NSCLC.<br />
Clinical trial identification: NCT02007070<br />
Legal entity responsible for the study: MSD K.K.<br />
Funding: MSD K.K.<br />
Disclosure: T. Kato: Research fund: MSD. T. Takahashi: Grants from MSD K.K., grants<br />
and personal fees from Eli Lilly Japan K.K., grants and personal fees from Chugai,<br />
grants and personal fees from ONO, personal fees from AstraZeneca K.K., outside the<br />
submitted work. H. Yoshioka: Honoraia from Chugai pharmaceuticals and Ono<br />
pharmaceuticals. K. Nakagawa: Ono Pharmaceutical Co., Ltd. / AstraZeneca K.K. /<br />
Chugai Pharmaceutical Co., Ltd. for honoraria. MSD K.K. /Ono Pharmaceutical Co.,<br />
Ltd. / Chugai Pharmaceutical Co., Ltd. for research funding. M. Maemondo: Lecture<br />
fee from AstraZeneca, Chugai, Pfizer, and Lilley. Conducting a clinical study supported<br />
by Chugai. T. Seto: Honoraria or research funds for Astellas, AstraZeneca, Chugai,<br />
Daiichi Sankyo, Eisai, Eli Lilly, Kyowa Hakko Kirin, Merck Serono, MSD, Nippon<br />
Boehringer Ingelheim, Nippon Kayaku, Novartis Pharma, Ono, Pfizer, San<strong>of</strong>i, Taiho,<br />
Verastem, Yakult. K. Kasahara: AstraZeneca, Parexel, Quitales, MSD, Pfizer,<br />
BMS. M. Satouchi: Research Funding, Honoraria; MSD. K. Noguchi, T. Shimamoto:<br />
Employee <strong>of</strong> MSD K.K. M. Nishio: Honoraria: Pfizer, BMS, ONO, Chugai, Lilly,<br />
TAIHO, AstraZeneca. Consulting or Advisory role: Novartis, ONO, Chugai, Lilly,<br />
TAIHO, Pfizer, Daiichi Sankyo. Research funding: Novartis, ONO, Chugai, BMS,<br />
TAIHO, Eli Lilly, Pfizer, Astellas, AstraZeneca. All other authors have declared no<br />
conflicts <strong>of</strong> interest.<br />
J. Lahmar 1 , L. Mezquita 1 , S. Koscielny 2 , F. Facchinetti 1 , M.V. Bluthgen 1 , J. Adam 3 ,<br />
A. Gazzah 1 , J. Remon 1 , D. Planchard 1 , J-C. Soria 1 , C. Caramella 4 , B. Besse 1<br />
1 Department <strong>of</strong> medical oncology, Gustave Roussy, Villejuif, France, 2 Department<br />
<strong>of</strong> biostatistics, Gustave Roussy, Villejuif, France, 3 Department <strong>of</strong> Pathology,<br />
Gustave Roussy, Villejuif, France, 4 Department <strong>of</strong> Radiology, Gustave Roussy,<br />
Villejuif, France<br />
Background: Immune Checkpoint inhibitors (IC) represent a major step forward in<br />
treating advanced NSCLC by improving survival and clinical outcomes. In patients (pts)<br />
with non-squamous NSCLC PDL1 negative NSCLC, IC increases the risk <strong>of</strong> early death<br />
compared to docetaxel. Risks later reversed for the two study groups to increasingly favor<br />
IC, as reflected in the eventual crossing <strong>of</strong> the Kaplan–Meier curves. Tumor Growth Rate<br />
(TGR) integrates tumoral dynamics and kinetics. Therefore, TGR gives additional<br />
information vs RECIST criteria. We hypothesized that TGR could identify a subset <strong>of</strong> pts<br />
in which IC could accelerate tumor progression, leading to early death.<br />
Methods: We performed a clinical and radiological retrospective case study <strong>of</strong> all<br />
NSCLC pts treated by IC in a single institution between Dec. 12 and Feb. 16. For each<br />
patient, CT scan during immunotherapy and previous treatment were centrally reviewed<br />
by a senior radiologist and assessed according to RECIST criteria. We calculated TGR at<br />
baseline <strong>of</strong> IC (baseline CTscan (n) vs n-1 CTscan) and TGR during IC (n + 2 CTscan vs<br />
n + 1 CTscan). We further estimated the difference (deltaTGR) between TGR during IC<br />
and TGR at baseline. deltaTGR0 means that the treatment speeds up tumor growth.<br />
Results: 89 pts were eligible. 58% were male, median age 60 (41-78); 15% never<br />
smokers. 62 pts had adenocarcinoma, 21 squamous and 6 other histologies. Mutational<br />
status was unknown for 14 pts; 36% wild type, 9 pts EGFRmut, 25 pts KRASmut. PDL1<br />
expression was positive in 25 pts, unknown in 57 pts. 52 pts (58%) received nivolumab,<br />
25 pembrolizumab and 12 atezolizumab. During IC, deltaTGR was 0<br />
in 20 pts. Among the 20 pts with deltaTGR > 0, 9 had a deltaTGR > 50%, meaning that<br />
tumor growth, expressed as percent increase in tumor volume per month, increased by<br />
at least 50% during IC. Clinical characteristics (age, sex, smoking status, pathology) <strong>of</strong><br />
the 9 pts were not different from other pts.<br />
Conclusions: Our results suggest that IC increased tumor progression in around 10%<br />
pts and thus could illustrate a deleterious effect in this subset <strong>of</strong> pts. Further work is<br />
needed to confirm this finding and characterize this population.<br />
Legal entity responsible for the study: Dr Benjamin BESSE<br />
Funding: Gustave Roussy<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1223P<br />
HLA-A2 and immune checkpoints inhibitors in advanced<br />
non-small cell lung cancer (NSCLC) patients<br />
L. Mezquita 1 , M. Charrier 2 , J. Lahmar 1 , J. Remon 1 , M.V. Bluthgen 1 , F. Facchinetti 1 ,<br />
D. Planchard 1 , A. Gazzah 3 , L. Dupraz 2 , J. Adam 4 , N. Chaput 2 , B. Besse 1<br />
1 Medical <strong>Oncology</strong> Department, Gustave Roussy, Villejuif, France, 2 Laboratory <strong>of</strong><br />
Immunomonitoring in <strong>Oncology</strong>, UMS 3655 CNRS/US 23 INSERM, Gustave<br />
Roussy, Villejuif, France, 3 Drug Development Department (DITEP), Gustave<br />
Roussy, Villejuif, France, 4 Pathology Department, Gustave Roussy, Villejuif, France<br />
Background: The class I human leucocyte antigen (HLA) molecules play a critical role<br />
in tumor recognition by T cells and the loss <strong>of</strong> expression seems to be an escape<br />
mechanism <strong>of</strong> antitumoral immunity. Novel immune-targeting cancer vaccines are<br />
currently developped in HLA-A2 positive patients for modulating the T cells immune<br />
response. We hypothesized that HLA-A2 status could influence the prognosis and<br />
response to immunotherapy.<br />
Methods: Advanced NSCLC patients treated with nivolumab, pembrolizumab or<br />
atezolizumab were prospectively included from Nov. 2013 to Apr. 2016 in our institute.<br />
HLA-A2 status was analysed by flow cytometry; PDL1 was analysed by<br />
immunohistochemistry. Clinical and biological data were collected at baseline and after<br />
cycle 1. Statistical analysis was performed with SPSS v.20.<br />
Results: Out <strong>of</strong> 125 patients treated, HLA-A2 status was available for 30 patients. 50%<br />
were male, median age was 61 years (29-77); 86% were smokers and 83% had<br />
performance status 0-1. 18 (60%) were adenocarcinoma, 7 (23.3%) squamous and 5<br />
(16.7%) others histologies. 2 NSCLC were EGFRmut, 2 ALK positive, 7 KRASmut, 19<br />
wildtype. PDL1 expression was positive in 8 patients (26.7%), negative in 2 (6.7%) and<br />
unknown in 20 (66.7%). The median <strong>of</strong> previous lines <strong>of</strong> treatment was 1 (1-8). The<br />
patient and tumor characteristics were well balanced according to HLA-A2. The<br />
median progression free survival to immunotherapy (iPFS) was 1.47 months<br />
[confidence interval (CI) 95% 1.18-1.7]. HLA-A2 positive status was correlated with<br />
longer iPFS [2.04 vs. 1.3 months, log-rank; p = 0.020]. The median overall survival<br />
(OS) was 38.05 months [CI 95% 8.94-67.16]. The median OS was 55.9 months [CI 95%<br />
9.4-102.15] vs. 22.5 months [CI 95% 0- 54.8] in HLA-A2 positive vs. negative patients<br />
(p = 0.340). In univariate analysis, there was no correlation between outcome and<br />
patient or tumor characteristics.<br />
Conclusions: Our preliminary results suggest that HLA-A2 status could influence the<br />
outcome in NSCLC patients treated with immune checkpoint inhibitors. An updated<br />
analysis on 59 patients will be presented.<br />
vi426 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Legal entity responsible for the study: Dr Benjamin Besse<br />
Funding: Gustave Roussy<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1224P<br />
Cost effectiveness and estimate <strong>of</strong> economical impact <strong>of</strong><br />
immune checkpoint inhibitors for NSCLC relative to PD-L1<br />
expression<br />
P.N. Aguiar Junior 1 , R. De Mello 2 , H. Tadokoro 1 , H.M. Babiker 3 , G. Lopes, Jr 4<br />
1 Clinical <strong>Oncology</strong>, Unifesp - Universidade Federal São Paulo, Sao Paulo, Brazil,<br />
2 Medical <strong>Oncology</strong>, Portuguese Institute <strong>of</strong> <strong>Oncology</strong>-oncoclinica, Porto, Portugal,<br />
3 Clinical <strong>Oncology</strong>, Honor Health, Scottsdale, AZ, USA, 4 Oncologia Clínica, Grupo<br />
Oncoclínicas do Brasil, Sao Paulo, Brazil<br />
Background: Recent clinical trials have shown that immune checkpoint inhibitors are<br />
active against several neoplasms, including lung cancer. Tumor PD-L1 receptor<br />
expression is being studied as a predictive biomarker. The objective <strong>of</strong> our study is to<br />
assess the cost-effectiveness and economical impact <strong>of</strong> nivolumab and pembrolizumab<br />
with or without the use <strong>of</strong> PD-L1 as a biomarker.<br />
Methods: We developed a decision-analytic model to determine the cost-effectiveness <strong>of</strong><br />
PD-L1 assessment and second-line treatment with NIVO or PEMBRO versus docetaxel.<br />
The model used outcomes data from randomized clinical trials and drug acquisition costs<br />
from the United States. We also included the costs <strong>of</strong> adverse events and post-progression<br />
therapies. Published utility values were used. Health effects were expressed as<br />
quality-adjusted life-years (QALY) and incremental cost-effectiveness ratios (ICER) were<br />
calculated. Thereafter, we used US and Brazilian epidemiologic data to estimate the<br />
economical impact <strong>of</strong> the treatment with or without the use <strong>of</strong> PD-L1 as a biomarker.<br />
Results: We included 3 RCTs (2 with NIVO and 1 with PEMBRO). Among all patients<br />
with squamous histology, the incremental QALY <strong>of</strong> NIVO was 0.23. The ICER was US$<br />
128 K. PD-L1 expression improved incremental QALY only for patients with PD-L1 > 5%<br />
and > 10% (by 15% and 18% respectively). Among all patients with non-squamous<br />
histology, the incremental QALY <strong>of</strong> NIVO was 0.12. The ICER was US$ 121 K. PD-L1<br />
expression improved incremental QALY for patients with PD-L1 > 1%, > 5% and > 10%<br />
(by 67%, 157% and 137%, respectively). All patients treated with PEMBRO had at least 1%<br />
<strong>of</strong> PD-L1 expression; the incremental QALY was 0.13. The ICER was US$ 116 K. PD-L1<br />
expression above 50% improved QALY by 18%. The estimated cost <strong>of</strong> treating all<br />
American patients with NIVO in the second-line was $ 1.57 billion yearly. The estimate <strong>of</strong><br />
expenses treating only patients with PD-L1 > 1% with PEMBRO was $ 0.97 billion yearly.<br />
In Brazilian, these values were $ 251 million and $ 155 million, respectively.<br />
Conclusions: The use <strong>of</strong> PD-L1 expression as a biomarker increases cost-effectiveness<br />
and decreases the economical treatment burden with immune checkpoint inhibitors.<br />
Legal entity responsible for the study: Universidade Federal de São Paulo<br />
Funding: The authors<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1225P<br />
Preliminary efficacy and safety data <strong>of</strong> nivolumab in never<br />
smoker patients with advanced squamous NSCLC:<br />
Experience from Italian sites participating in the Expanded<br />
Access Programme (EAP)<br />
M. Vitali 1 , L. Crinò 2 , A.F. Logroscino 3 , A. Ardizzoni 4 , S. Caponnetto 5 , L. Landi 6 ,<br />
P. Bordi 7 , C. Luana 8 , F. Barbieri 9 , A. Santo 10 , M. Santarpia 11 , G. Carteni 12 ,<br />
E. Mini 13 , E. Vasile 14 , F. Morgillo 15 , F. De Galitiis 16 , R. Conca 17 , M. Macerelli 18 ,<br />
N. Tedde 19 , F. Vitiello 20<br />
1 Medical <strong>Oncology</strong> 1, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan,<br />
Italy, 2 Oncologia Medica, Ospedale S. Maria della Misericordia, Perugia, Italy,<br />
3 Medical <strong>Oncology</strong>, Istituto Oncologico Bari, Bari, Italy, 4 Medical <strong>Oncology</strong>,<br />
Policlinico S. Orsola-Malpighi, Bologna, Italy, 5 Medicina Sperimentale, Policlinico<br />
Umberto I, Rome, Italy, 6 Medical <strong>Oncology</strong>, Ospedali Riuniti Livorno, Livorno, Italy,<br />
7 Medical <strong>Oncology</strong>, Azienda Ospedaliera di Parma, Parma, Italy, 8 Medical<br />
<strong>Oncology</strong>, Azienda Ospedaliera Universitaria Senese - Santa Maria delle Scotte,<br />
Siena, Italy, 9 Medical <strong>Oncology</strong>, Azienda Ospedaliero - Universitaria Policlinico di<br />
Modena, Modena, Italy, 10 Medical <strong>Oncology</strong>, Azienda Ospedaliera Universitaria<br />
Integrata Verona-"Borgo Roma", Verona, Italy, 11 Medical <strong>Oncology</strong>, AOU<br />
Policlinico G. Martino Università di Messina, Messina, Italy, 12 Medical <strong>Oncology</strong>,<br />
Azienda Ospedaliera di Rilievo Nazionale "Antonio Cardarelli"-AORN A. Cardarelli,<br />
Naples, Italy, 13 Medical <strong>Oncology</strong>, Azienda Ospedaliera Universitaria Careggi,<br />
Florence, Italy, 14 Medical <strong>Oncology</strong>, Azienda Ospedaliera Universitaria S.Chiara,<br />
Pisa, Italy, 15 Medical <strong>Oncology</strong>, AOU Seconda Università degli Studi di Napoli<br />
(AOU-SUN), Naples, Italy, 16 Medical <strong>Oncology</strong>, Istituto Dermopatico<br />
dell’Immacolata, Rome, Italy, 17 Medical <strong>Oncology</strong>, Ospedale della Misericordia,<br />
Grosseto, Italy, 18 Medical <strong>Oncology</strong>, Azienda Ospedaliera Universitaria-Udine Sta<br />
Maria della Misericordia, Udine, Italy, 19 Medical <strong>Oncology</strong>, ASL Olbia, Olbia, Italy,<br />
20 Medical <strong>Oncology</strong>, Azienda Ospedaliera Dei Colli-Monaldi, Naples, Italy<br />
Background: Nivolumab is the first checkpoint inhibitor approved for the treatment <strong>of</strong><br />
squamous non-small cell lung cancer (Sq-NSCLC) to show a survival benefit in a<br />
randomised phase III trial. In prior studies nivolumab has shown a better clinical<br />
benefit in current and former smokers compared to never smokers. Nevertheless, no<br />
data are available from a real world setting. The EAP provided an opportunity to<br />
evaluate the feasibility <strong>of</strong> treatment in this patient population outside <strong>of</strong> a controlled<br />
clinical trial in Italy.<br />
Methods: Nivolumab was available upon physician request for patients (pts) aged ≥18<br />
years who had relapsed after a minimum <strong>of</strong> one prior systemic treatment for stage IIIB/<br />
stage IV Sq-NSCLC. Nivolumab 3 mg/kg is administered intravenously every 2 weeks<br />
to a maximum <strong>of</strong> 24 months. Pts included in the analysis had received ≥ 1 dose <strong>of</strong><br />
nivolumab and were monitored for adverse events using Common Terminology<br />
Criteria for Adverse Events.<br />
Results: Of 372 patients with Sq-NSCLC participating in the EAP in Italy, 38 (10.2%)<br />
were never smokers, in line to what observed in the registrational study Checkmate 017<br />
(10%). With a median number <strong>of</strong> doses 8 (range, 1–22) and a median follow-up <strong>of</strong> 5.6<br />
months, the disease control rate was 50%, including 9 patients with a partial response<br />
and 10 with stable disease. Eight pts were treated beyond RECIST defined progression,<br />
with 4 <strong>of</strong> these pts achieving a disease control. As <strong>of</strong> April 2016, median<br />
progression-free survival and overall survival were 3.5 months and not reached,<br />
respectively. Among 38 pts, 17 pts (44.7%) discontinued treatment for any reason<br />
except toxicity; 5 out <strong>of</strong> 38 discontinued due to AE (13.1%).<br />
Conclusions: With the limitation <strong>of</strong> a small sample size and type <strong>of</strong> study (EAP), these<br />
data seem to suggest that nivolumab might have a similar efficacy in non-smoker patients<br />
to that observed in the overall population, warranting further investigation in this area.<br />
Legal entity responsible for the study: N/A<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1226P<br />
An interim assessment <strong>of</strong> key biomarkers (programmed cell<br />
death receptor ligand 1 (PD-L1) expression and epidermal<br />
growth factor receptor (EGFR) in third-line therapy non-small<br />
cell lung cancer (NSCLC) patients: A Danish cohort study<br />
D. Cronin-Fenton 1 , T. Dalvi 2 , E. Hedgeman 3 , M. Norgaard 1 , L. Pedersen 1 ,<br />
K. Mortensen 4 , A. Midta 5 , N. Shire 2 , R. Brody 2 , J. Fryzek 6 , D. Lawrence 7 ,<br />
J. Rigas 8 , D. Potter 2 , J. Walker 9 , A. Mellemgaard 10 , T.R. Rasmussen 11 ,<br />
S. Hamilton-Dutoit 4 , H.T. Sørensen 1<br />
1 Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark, 2 Medical<br />
Evidence & Observational Research, AstraZeneca, Gaithersburg, MD, USA,<br />
3 Epidemiology, EpidStat Institute, Ann Arbor, MI, USA, 4 Institute <strong>of</strong> Pathology,<br />
Aarhus University Hospital, Aarhus, Denmark, 5 Personalised Healthcare and<br />
Biomarkers, AstraZeneca, Macclesfield, UK, 6 Epidemiology, Epidstat Institute,<br />
Rockville, MD, USA, 7 Biostatistics and Information Sciences, AstraZeneca,<br />
Cambridge, UK, 8 Geisel School <strong>of</strong> Medicine, Dartmouth College, Hanover, NH,<br />
USA, 9 Personalised Healthcare and Biomarkers, AstraZeneca, Cambridge, UK,<br />
10 <strong>Oncology</strong>, University Hospital Herlev, Herlev, Denmark, 11 Respiratory Medicine,<br />
Aarhus University Hospital, Aarhus, Denmark<br />
Background: Among NSCLC patients who received third-line therapy, we examined<br />
the association <strong>of</strong> PD-L1 expression and EGFR mutations with survival.<br />
Methods: Third-line therapy NSCLC patients diagnosed during 2001-2012 were<br />
selected from the Danish Lung Cancer Group Registry. We retrieved patient data from<br />
population-based medical registries, and paraffin-embedded tumor tissue from<br />
pathology archives. We assessed PD-L1 expression using the Ventana IHC (SP263)<br />
validated assay (using 25% cut<strong>of</strong>f for high versus low), and genotyped EGFR to identify<br />
mutations at Exon 18 (G719X (G719A, G719C, and G719S), Exon 19 (deletions and<br />
complex mutations), Exon 20 (S768I, T790M, and insertions), and Exon 21 (L858R)<br />
via a PCR-based kit. Follow-up was from third-line therapy start to the first <strong>of</strong> death,<br />
emigration, or 31/12/2014. We used Cox regression to compute hazard ratios (HR) and<br />
associated 95% confidence intervals (95% CI) for PD-L1 and EGFR.<br />
Results: Among 344 third-line therapy patients, 185 (54%) were men, 165 (48%) were<br />
aged >60 years at diagnosis, and the majority were ever-smokers. 200 (58%) had<br />
adenocarcinoma histology, 85 (25%) had high PD-L1 expression in their tumors and<br />
27 (8%) had EGFR mutations. Compared to patients with wildtype EGFR tumors,<br />
those with EGFR mutations less <strong>of</strong>ten showed high PD-L1 expression (21%, 95%<br />
CI = (4%, 38%) versus 25%, 95%CI = (19%, 31%); Fisher’s exact p-value = 0.81).<br />
Median overall survival differed little by PD-L1 status, but was longer in patients with<br />
mutant compared with wildtype EGFR. Neither PD-L1 expression nor EGFR<br />
mutations were significantly associated with survival.<br />
N<br />
No. <strong>of</strong><br />
deaths<br />
Table: 1226P<br />
Median Survival (months) (95%<br />
CI)<br />
Adjusted HR* (95%<br />
CI)<br />
PD-L1 low 249 208 8.0 (6.6, 9.1) ref.<br />
PD-L1 85 72 8.3 (6.1, 11.6) 0.89 (0.68, 1.17)<br />
high<br />
EGFR<br />
Wildtype 260 213 7,7 (6.5, 8.8) ref.<br />
Mutant 27 22 11.0 (6.9, 22.1) 0.79 (0.51, 1.24)<br />
*Adjusted for age, sex, histology (adenocarcinoma versus other)<br />
abstracts<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw383 | vi427
abstracts<br />
Conclusions: Our findings suggest no association <strong>of</strong> PD-L1 expression or EGFR<br />
mutations with survival in third-line therapy NSCLC patients.<br />
Clinical trial identification: Not applicable<br />
Legal entity responsible for the study: N/A<br />
Funding: AstraZeneca<br />
Disclosure: T. Dalvi: TD is an employee and shareholder <strong>of</strong> MedImmune/<br />
AstraZeneca. E. Hedgeman: Funding to support this work from AstraZeneca Inc.,<br />
Gaithersburg, MD 20878. A. Midta, N. Shire, R. Brody, D. Lawrence, D. Potter,<br />
J. Walker: Employee and shareholder <strong>of</strong> AstraZeneca. J. Fryzek: JPF was employed by<br />
AstraZeneca, 2009-2011. JPF received funding to support this work from AstraZeneca<br />
Inc., Gaithersburg, MD 20878. J. Rigas: Consultant physician to<br />
AstraZeneca. A. Mellemgaard: Honoraria and/or travel expenses from Lilly, Boehringer<br />
Ingelheim, BMS, MSD. S. Hamilton-Dutoit: Research funding from AstraZeneca.<br />
Honoraria or consulting Amgen. H.T. Sørensen: Research funding from Epidstat. All<br />
other authors have declared no conflicts <strong>of</strong> interest.<br />
1227P<br />
Impact <strong>of</strong> severe adverse events during second-line therapy<br />
on healthcare costs in patients with advanced non-small cell<br />
lung cancer (aNSCLC)<br />
Y.M. Yim 1 , M. Gandhi 1 , A. Guerin 2 , R. Ionescu-Ittu 2 , I. Pivneva 2 , S. Shi 2 ,E.Wu 3<br />
1 Health Economics and Outcomes Research, US Medical Affairs, Genentech, Inc.,<br />
San Francisco, CA, USA, 2 Health Economics and Outcomes Research, Analysis<br />
Group, Inc., Montreal, QC, Canada, 3 Health Economics and Outcomes Research,<br />
Analysis Group, Inc., Boston, MA, USA<br />
Background: Elderly with aNSCLC represents a population at higher risk <strong>of</strong> severe<br />
adverse events (AEs) due to poorer performance status and more comorbidities than<br />
younger patients (pts). Severe AEs may also impose a financial burden on the<br />
healthcare system. In a cohort <strong>of</strong> elderly pts with aNSCLC who received second-line<br />
therapy (2L), we assessed the impact <strong>of</strong> severe AEs on healthcare costs.<br />
Methods: The SEER-Medicare database was used to identify pts with aNSCLC aged<br />
≥65 years diagnosed between 2007-11 who initiated 2L up to end <strong>of</strong> Medicare data<br />
availability <strong>of</strong> 12/31/2013. Pts were divided into 2 cohorts <strong>of</strong> with and without severe<br />
AEs during time on 2L therapy. 57 AEs were pre-specified based on literature review<br />
and oncologist consult. Severe AEs were defined as AEs requiring a hospitalization.<br />
The incremental impact <strong>of</strong> severe AEs on all-cause healthcare costs incurred during 2L<br />
was estimated using two-part regression models adjusted for age, sex, region, stage at<br />
diagnosis (dx), and overall disease burden at 2L start.<br />
Results: Of 3,967 pts who initiated 2L, 1,624 (41%) had ≥1 severe AE. Use <strong>of</strong><br />
chemotherapy only or targeted therapy-based regimens were comparable between<br />
cohorts. Both cohorts had similar demographic and cancer characteristics at dx, but<br />
some comorbidities were more prevalent in pts with severe AEs during the period<br />
between the aNSCLC dx and 2L initiation (anemia 69% vs 60%; weight loss 27% vs<br />
20%, renal failure 15% vs 11%, congestive heart failure 25% vs 17%, bleeding 35% vs<br />
31%, all p
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
1229P<br />
First-line icotinib versus cisplatine/pemetrexed plus<br />
pemetrexed maintenance therapy in lung adenocarcinoma<br />
patients with EGFR mutation (CONVINCE)<br />
Y-K. Shi 1 , L. Wang 1 , B. Han 2 ,W.Li 3 ,P.Yu 4 ,Y.Liu 5 , C. Ding 6 , X. Song 7 ,Z.Ma 8 ,<br />
X. Ren 9 , J. Feng 10 , H. Zhang 11 , G. Chen 12 ,N.Wu 13 , X. Han 1 ,C.Yao 14 , Y. Song 15 ,<br />
S. Zhang 16 , L. Ding 17 ,F.Tan 18<br />
1 Medical <strong>Oncology</strong>, Beijing Key Laboratory <strong>of</strong> Clinical Study on Anticancer<br />
Molecular Targeted Drugs, National Cancer Center/ Cancer Hospital, Chinese<br />
Academy <strong>of</strong> Medical Sciences & Peking Union Medical College, Beijing, China,<br />
2 <strong>Oncology</strong>, Shanghai Chest Hospital, Shanghai, China, 3 <strong>Oncology</strong>, First Hospital<br />
Affiliated to Jilin University, Changchun, China, 4 Lung Cancer Medical <strong>Oncology</strong>,<br />
Sichuan Cancer Hospital, Chengdu, China, 5 Medical <strong>Oncology</strong>, The First Hospital<br />
<strong>of</strong> China Medical University, Shenyang, China, 6 <strong>Oncology</strong>, Hebei Provincial Tumor<br />
Hospital, Shijiazhuang, China, 7 Respiratory, Shanxi Tumor Hospital, Taiyuan,<br />
China, 8 <strong>Oncology</strong>, Henan Cancer Hospital, Zhengzhou, China, 9 Meidical<br />
<strong>Oncology</strong>, Xijing Hospital, 4th Military Medical University, Xi’an, China, 10 <strong>Oncology</strong>,<br />
Jiangsu Cancer Institute and Hospital, Nanjing, China, 11 <strong>Oncology</strong>, Tangdu<br />
Hospital, Fourth Military Medical University, Xi’an, China, 12 Medical <strong>Oncology</strong>, The<br />
Affiliated Tumor Hospital <strong>of</strong> Harbin Medical University, Harbin, China, 13 Imaging<br />
Diagnosis, National Cancer Center/ Cancer Hospital, Chinese Academy <strong>of</strong> Medical<br />
Sciences & Peking Union Medical College, Beijing, China, 14 Clinical Research,<br />
Peking University Clinical Research Institute, Beijing, China, 15 <strong>Oncology</strong>, Nanjing<br />
Military General Hospital, Nanjing, China, 16 Medical <strong>Oncology</strong>, Beijing Chest<br />
Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor<br />
Research Institute, Beijing, China, 17 Headquarter, Betta Pharmaceuticals Co.,Ltd.,<br />
Hangzhou, China, 18 R & D center, Betta Pharmaceuticals Co.,Ltd., Hangzhou,<br />
China<br />
Background: We assessed icotinib as first-line therapy compared with pemetrexed/<br />
cisplatine plus pemetrexed maintenance in advanced lung adenocarcinoma patients<br />
with sensitizing EGFR mutation.<br />
Methods: This phase 3, open-label, randomized study (CONVINCE) was conducted at<br />
18 sites in China. Eligible patients (pathologically confirmed lung adenocarcinoma, 19/<br />
21 EGFR mutation, treatment naive) were 1:1 randomized to receive icotinib (125 mg,<br />
three times daily) or pemetrexed (500 mg/m 2 , day 1) plus cisplatine (75 mg/m 2 ,day1)<br />
every 21 days, non-progressive patients after 4-cycle chemotherapy continue to receive<br />
pemetrexed (500 mg/m 2 , day 1, every 21 days) as maintenance until disease<br />
progression or intolerable toxicity. Randomization was stratified by performance status,<br />
smoking status, disease stage, and mutation type. The primary endpoint was<br />
progression free survival (PFS).<br />
Results: 669 patients were screened (January, 2013 to August, 2014), in which 296 were<br />
enrolled and randomized (148 for each group), and 285 patients were treated (icotinib:<br />
148, chemotherapy: 137). Patients’ characteristics were well balanced between groups.<br />
Icotinib significantly improved PFS (9.9 months [95%CI 8.5-11.2] vs 7.3 months<br />
[6.0-8.0]; HR 0.65, 95%CI 0.48-0.88, p = 0.004) compared with the chemotherapy<br />
group. Subgroup analyses showed the PFS benefit for icotinib persisted among most<br />
clinically relevant subgroups (gender, performance status, smoking status, and disease<br />
stage), especially in patients harboring EGFR 19del mutation (11.2 months [95%CI<br />
9.2-13.5] vs 7.3 months [5.7-8.4]; p < 0.001). Significantly fewer adverse events (AEs)<br />
and treatment-related AEs were seen in the icotinib group (AEs: 78.4% vs 94.2%,<br />
p < 0.001; TRAEs 50.7% vs 89.1%, p < 0.001). The most common adverse events were<br />
cough (17.6%), rash/acne (15.5%), and elevated AST (10.1%) for icotinib and nausea<br />
(49.0%), leukopenia (45.3%), and neutropenia (35.0%) for chemotherapy.<br />
Conclusions: First-line icotinib <strong>of</strong>fers superior efficacy compared with cisplatine/<br />
pemetrexed plus pemetrexed maintenance therapy in advanced lung adenocarcinoma<br />
patients with sensitizing EGFR mutation.<br />
Clinical trial identification: ClinicalTrials.Gov NCT01719536.<br />
Legal entity responsible for the study: Betta Pharmaceuticals Co.,Ltd.<br />
Funding: Betta Pharmaceuticals Co.,Ltd.<br />
Disclosure: L. Ding: Salaried, F. Tan: Salaried employee and stock owner <strong>of</strong> Betta<br />
Pharmaceuticals Co.,Ltd. All other authors have declared no conflicts <strong>of</strong> interest.<br />
1230P<br />
abstracts<br />
Time-to-treatment failure (TTF) with first-line afatinib (A) vs<br />
gefitinib (G) in patients (pts) with EGFR mutation-positive<br />
(EGFRm+) advanced non-small-cell lung cancer (NSCLC):<br />
Randomized phase IIb LUX-lung 7 (LL7) trial<br />
M. Schuler 1 , E-H. Tan 2 ,K.O’Byrne 3 , L. Zhang 4 , M. Boyer 5 , T.S.K. Mok 6 , V. Hirsh 7 ,<br />
J.C-H. Yang 8 , K.H. Lee 9 ,S.Lu 10 ,Y.Shi 11 , S-W. Kim 12 , J. Laskin 13 , D-W. Kim 14 ,C.<br />
Dubos Arvis 15 , K. Kölbeck 16 , D. Massey 17 ,J.Fan 18 , L. Paz-Ares 19 , K. Park 20<br />
1 Department <strong>of</strong> Medical <strong>Oncology</strong>, University Hospital Essen, Essen, Germany,<br />
2 Department <strong>of</strong> Medical <strong>Oncology</strong>, National Cancer Center, Singapore,<br />
3 Department <strong>of</strong> <strong>Oncology</strong>, Princess Alexandra Hospital, Brisbane, Australia,<br />
4 Department <strong>of</strong> Medical <strong>Oncology</strong>, Sun Yat-sen University Cancer Center,<br />
Guangzhou, China, 5 Department <strong>of</strong> Medical <strong>Oncology</strong>, Chris O’Brien Lifehouse,<br />
Sydney, Australia, 6 Department <strong>of</strong> Clinical <strong>Oncology</strong>, The Chinese University <strong>of</strong><br />
Hong Kong, Hong Kong, China, 7 Department <strong>of</strong> <strong>Oncology</strong>, McGill University,<br />
Montreal, QC, Canada, 8 Department <strong>of</strong> <strong>Oncology</strong>, National Taiwan University<br />
Hospital and National Taiwan University Cancer Center, Taipei, Taiwan, 9 Division <strong>of</strong><br />
Medical <strong>Oncology</strong>, Chungbuk National University Hospital, Cheong-ju, Republic <strong>of</strong><br />
Korea, 10 Department <strong>of</strong> Lung Cancer, Shanghai Chest Hospital, Shanghai, China,<br />
11 Department <strong>of</strong> Medical <strong>Oncology</strong>, Cancer Hospital, Chinese Academy <strong>of</strong><br />
Medical Sciences & Peking Union Medical College, Beijing, China, 12 Department<br />
<strong>of</strong> Medical <strong>Oncology</strong>, Asan Medical Center, Seoul, Republic <strong>of</strong> Korea,<br />
13 Department <strong>of</strong> Medical <strong>Oncology</strong>, British Columbia Cancer Agency, Vancouver,<br />
BC, Canada, 14 Department <strong>of</strong> Internal Medicine, Seoul National University<br />
Hospital, Seoul, Republic <strong>of</strong> Korea, 15 Department <strong>of</strong> <strong>Oncology</strong>, Centre Francois<br />
Baclesse, Caen, France, 16 Pulmonary diseases, Karolinska University<br />
Hospital-Solna, Stockholm, Sweden, 17 Biostatistics, Boehringer Ingelheim Ltd UK,<br />
Bracknell, UK, 18 Clinical Program, Boehringer Ingelheim Pharmaceuticals, Inc.,<br />
Ridgefield, CT, USA, 19 Department <strong>of</strong> <strong>Oncology</strong>, Hospital Universitario Doce de<br />
Octubre and CNIO, Madrid, Spain, 20 Department <strong>of</strong> Medicine, Samsung Medical<br />
Center Sungkyunkwan University School <strong>of</strong> Medicine, Seoul, Republic <strong>of</strong> Korea<br />
Background: LL7 compared the efficacy/safety <strong>of</strong> the irreversible ErbB family blocker<br />
A with the reversible EGFR TKI G in pts with treatment (tx)-naïve EGFRm+ advanced<br />
NSCLC. Co-primary endpoints were PFS, TTF and OS. PFS was significantly improved<br />
with A vs G, with manageable tolerability (Park et al. Lancet Oncol 2016). TTF was<br />
included as an endpoint to reflect real-world clinical practice <strong>of</strong> continuing TKI tx<br />
beyond radiologic progression in the absence <strong>of</strong> clinical deterioration. Detailed analysis<br />
<strong>of</strong> TTF is reported here.<br />
Methods: Pts with stage IIIb/IV adenocarcinoma and an activating EGFRm (Del19/<br />
L858R) were randomized (stratified by EGFRm type and brain metastases [BM]) to A<br />
40mg/day or G 250mg/day until progressive disease (PD) or beyond if deemed<br />
beneficial. TTF was analyzed using a stratified log-rank test; data were summarized<br />
with Cox-regression models/Kaplan-Meier methods.<br />
Results: 319 pts were randomized (160 A, 159 G). At data cut-<strong>of</strong>f (21 Aug 15), 87.5% A<br />
and 93.7% G pts had discontinued tx, mostly due to radiological PD (69.4 vs 74.8%) or<br />
toxicity (11.3 vs 10.7%). 35.0% A and 29.6% G pts with clinical benefit continued tx<br />
beyond radiologic PD; these pts had similar baseline characteristics to the overall pt<br />
population. Pts remained on tx significantly longer with A vs G (median TTF 13.7 vs<br />
11.5 mos, HR 0.73 [95% CI 0.58–0.92], p = 0.007; pts on tx at 2 yrs: 25.0 vs 13.2%).<br />
Prespecified TTF subgroup analyses including age, gender, ECOG PS, EGFRm type,<br />
and race also favored A. Risk <strong>of</strong> tx failure was reduced to a similar degree with A vs G<br />
regardless <strong>of</strong> EGFRm type (Del19: HR 0.73 [0.54–0.99], p = 0.044; L858R: HR 0.75<br />
[0.53–1.06], p = 0.104) or race (non-Asian: HR 0.66 [0.46–0.95], p = 0.024; Asian: HR<br />
0.82 [0.60–1.11], p = 0.19). Median tx duration beyond PD was 2.7 and 2.0 mos,<br />
respectively.<br />
Conclusions: TTF was significantly improved with first-line A vs G in EGFRm+<br />
advanced NSCLC, complementing PFS findings. Improved TTF with A testifies to its<br />
general tolerability and manageability <strong>of</strong> AEs and suggests that it may confer additional<br />
clinical benefit in pts who continue tx beyond radiologic PD.<br />
Clinical trial identification: NCT01466660<br />
Legal entity responsible for the study: Boehringer Ingelheim<br />
Funding: Boehringer Ingelheim<br />
Disclosure: M. Schuler: Advisory board/board <strong>of</strong> directors: AZ, BI, BMS, Celgene,<br />
IQWig, Lilly, Novartis Corporate-sponsored research: BI, BMS, Novartis Other: Lecure<br />
Fees received from Alexion, BI, Celgene, GSK, Lilly, Novartis Patents (University<br />
Duisburg-Essen). L. Zhang: Advisory board/board <strong>of</strong> directors: AZ, Lilly. M. Boyer:<br />
Advisory board/board <strong>of</strong> directors: AZ Corporate-sponsored research: AZ, BI, Clovis,<br />
Roche. T.S.K. Mok: Stock (Sanomics Ltd); advisory board (AZ, Roche/Genentech,<br />
Pfizer, Eli Lilly, BI, Merck Serono, MSD, Janssen, Clovis <strong>Oncology</strong>, BioMarin, GSK,<br />
Novartis, SFJ Pharmaceutical, ACEA Biosciences, Inc., Vertex Pharmaceuticals, Aveo &<br />
Biodesix, BMS, geneDecode Co., Ltd, OncoGenex Technologies Inc.); board <strong>of</strong><br />
directors (IASLC, Chinese Lung Cancer Research Foundation Ltd, CSCO, HKCTS);<br />
corporate-sponsored research (AZ, BI, Pfizer, Novartis, SFJ, Roche, MSD, Clovis<br />
<strong>Oncology</strong>, BMS). V. Hirsh: Advisory board (honorarium): BI. J.C-H. Yang: Advisory<br />
board/board <strong>of</strong> directors: BI, Lilly, Bayer, Roche/Genentech/Chugai, AZ, Astellas,<br />
MSD, Merck Serono, Pfizer, Novartis, Clovis <strong>Oncology</strong>, Celgene, innopharma,<br />
Merrimack. D. Massey, J. Fan: Employed by Boehringer Ingelheim. K. Park: Advisory<br />
board: BI Corporate-sponsored research: AZ. All other authors have declared no<br />
conflicts <strong>of</strong> interest.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw383 | vi429
abstracts<br />
1231P<br />
Efficacy <strong>of</strong> first-generation EGFR-TKIs on patients with<br />
NSCLC harboring EGFR uncommon mutations: a pooled<br />
analysis<br />
Y. Zhang, S. Tang, J. Zhang, Q. He, J. He, W. Liang<br />
Department <strong>of</strong> Thoracic <strong>Oncology</strong>, The 1st Affiliated Hospital <strong>of</strong> Guangzhou<br />
Medical University, Guangzhou, China<br />
Background: NSCLC Patients with common sensitive EGFR mutations (deletion in<br />
exon 19 or L858R mutation in exon 21) benefit remarkably from first-generation<br />
EGFR-TKIs (gefitinib and erlotinib). In this meta-analysis, we aim to investigate their<br />
treatment efficacy in patients with uncommon EGFR mutations (S768I, L861Q,<br />
G719X, R705K, etc.) by comparing with that in patients with common mutations.<br />
Methods: We searched PubMed for eligible studies from the date <strong>of</strong> inception to 31th<br />
December, 2015. Overall objective response rate (ORR) and 6-month progression free<br />
survival (PFS) rates were estimated by fix-effect model and relative effects were<br />
presented using odds ratio (OR). Mutations within the same exons were grouped in the<br />
subgroup analyses.<br />
Results: Of 6404 patients from 13 included studies, 466 (7.3%) patients were diagnosed as<br />
EGFR uncommon mutations and chose gefitinib and erlotinib as any line <strong>of</strong> treatment. In<br />
single-arm synthesis, the overall ORR in uncommon and common mutations was 34.0%<br />
(95% CI 22.5 to 45.5) and 71% (66.7 to 75.3), respectively. Direct comparison indicated<br />
significantly less response in uncommon-mutation patients (OR = 0.30, 95% CI 0.23 to<br />
0.41, P < 0.001). Patients with uncommon mutations, compared with common ones, were<br />
associated with an inferior 6-month PFS rate (OR = 0.44, 95% CI 0.32 to 0.59; P < 0.001).<br />
In exploratory analyses, ORR was 30.7% (16.3 to 45.0), 33.3% (N.A.), 32.1% (13.2 to 51.0)<br />
and 38.5% (19.5 to 57.6) in patients with rare mutations in EGFR exon 18, 19, 20 and 21<br />
exons, respectively. In patients with complex mutations (two or more uncommon mutant<br />
sites), the ORR was 64.2 % (49.9 to 78.5).<br />
Conclusions: Compared with those in sensitive mutations, first-generation<br />
EGFR-TKIs presented less clinical benefits in uncommon mutations; but the responses<br />
are still considerable, historically compared with that <strong>of</strong> chemotherapy, especially in<br />
complex mutations. First-generation EGFR-TKIs remained an option for uncommon<br />
mutations but decision-making should be cautious. Exact efficacy in each specific<br />
mutation site merits future studies with larger sample size.<br />
Legal entity responsible for the study: N/A<br />
Funding: The first affiliated hospital <strong>of</strong> Guangzhou medical university<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1232P<br />
P53 non-disruptive mutation is a negative predictive factor in<br />
EGFR M+ NSCLC treated with TKI<br />
F. Griesinger 1 , M. Netchaeva 1 , A. Lüers 1 , R. Prenzel 2 , D. Scriba 3 , K.C. Willborn 4 ,<br />
U. Stropiep 5 , C. Hallas 6 , M. Falk 6 , M. Tiemann 6 , N. Neemann 7 , L.C. Heukamp 7 ,<br />
J. Roeper 1<br />
1 Department <strong>of</strong> <strong>Oncology</strong> and Hematology, Pius Hospital Oldenburg, University <strong>of</strong><br />
Oldenburg, Oldenburg, Germany, 2 Department <strong>of</strong> Pneumology, Pius Hospital,<br />
Oldenburg, Germany, 3 Department <strong>of</strong> Thoracic Surgery, Pius Hospital, Oldenburg,<br />
Germany, 4 Department <strong>of</strong> Radiotherapy, Pius Hospital, Oldenburg, Germany,<br />
5 Department <strong>of</strong> <strong>Oncology</strong> and Hematology, Pius Hospital, Oldenburg, Germany,<br />
6 Department <strong>of</strong> Molecular pathology, Institut für Hämatopathologie Hamburg,<br />
Hamburg, Germany, 7 Department <strong>of</strong> Molecular pathology, New <strong>Oncology</strong><br />
Cologne, Cologne, Germany<br />
Background: P53 mutations are common in lung cancer, and have also been described in<br />
EGFR mutated patients. The impact <strong>of</strong> p53 mutations in EGFR M+ patients is<br />
controversial, especially if classified as disruptive and non-disruptive according to their<br />
functional effect on the p53 protein as proposed by Poeta and colleagues. The aim <strong>of</strong> the<br />
study was therefore to systematically analyze EGFR and p53 M+ within a cohort <strong>of</strong> patients<br />
with lung cancer stage IV (UICC 7), to correlate alterations with clinical characteristics and<br />
to investigate a potential impact <strong>of</strong> p53 mutations on treatment outcome.<br />
Methods: 409 patients from a single center diagnosed with lung cancer stage IV were<br />
studied for the presence <strong>of</strong> EGFR as well as inactivating p53 mutations. Methods for<br />
the detection <strong>of</strong> EGFR M+ included Sanger Sequencing and hybridization based<br />
COBAS testing, hybrid cage next generation sequencing. P53 mutations were detected<br />
by Sanger Sequencing and either MiSeq or hybrid cage NGS. Clinical characteristics<br />
including smoking status were available for more than 95% <strong>of</strong> the patients.<br />
Results: 409 consecutive patients at the lung cancer center <strong>of</strong> the Pius-Hospital<br />
Oldenburg were studied. The overall EGFR M+ rate was 18% (73/409) in all patients,<br />
73% (53/73) showing common mutations <strong>of</strong> exon 19 or 21. In 21/73 (29%) patients’<br />
p53 analysis was not successful. P53 disruptive mutations were demonstrated in 25%<br />
(13/52) <strong>of</strong> successfully tested patients, and p53 non-disruptive mutation occurred in<br />
31% (16/52) whereas p53 WT configuration was found in 44% (23/52). Median OS was<br />
28 months in p53 disruptive mutation and 42 month in p53 WT compared to 23<br />
months in p53 non-disruptive mutation (p < 0.018). PFS on 1st line TKI therapy was<br />
14 months in p53 disruptive mutation, 18 months in p53 WT and 7 months in p53<br />
non-disruptive mutation (p < 0.001). Similar results were shown in the EGFR common<br />
but not in the uncommon mutation subgroup.<br />
Conclusions: Significant differences in PFS and OS in EGFR M+ patients were<br />
observed depending on p53 mutation status. P53 mutational status is only predictive<br />
when disruptive and non-disruptive p53 mutations are differentiated. P53 should be<br />
tested prospectively in EGFR M+ patients as management <strong>of</strong> patients on 1st line TKI<br />
may be different.<br />
Legal entity responsible for the study: Pr<strong>of</strong>. Dr. Frank Griesinger<br />
Funding: Pius Hospital Oldenburg; University Oldenburg<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1233P<br />
Re-biopsy confers survival benefit through directing salvage<br />
treatment for patients failing prior EGFR-TKIs<br />
L. Zhang 1 , J. Sheng 2 , Y. Huang 2 ,Y.Yang 2 , H. Zhao 2 ,W.Fang 2 , Y. Zhao 2 ,<br />
Y. Zhang 2<br />
1 Medical <strong>Oncology</strong>, Sun Yat-sen University Cancer Center, Guangzhou, China,<br />
2 State Key Laboratory <strong>of</strong> <strong>Oncology</strong> in South China, Sun Yat-sen University Cancer<br />
Center, Guangzhou, China<br />
Background: Re-biopsy helps to reveal the resistance mechanisms and direct further<br />
treatment after resistance to EGFR-TKIs. This study was designed to describe the<br />
real-world situation about re-biopsy and reveal the prognosis <strong>of</strong> patients with advanced<br />
non-small lung cancer (NSCLC) failing on first-generation EGFR-TKIs.<br />
Methods: Advanced NSCLC patients with initial sensitive EGFR mutations and<br />
EGFR-TKI resistance were consecutively reviewed from June, 2011 to July, 2015. The<br />
clinical progression model were classified, with genetic resistance mechanisms<br />
identified in those received tumor that were re-biopsied. We further compared the<br />
post-progression survival (PPS) between different salvage treatments directed by<br />
resistant mechanism or clinical progression model after EGFR-TKI failure.<br />
Results: 227 cases were included. Among 107 patients (47.1%) who repeated biopsy, no<br />
major biopsy-related complications occured. We identified 45 patients (42.1%) with<br />
T790M mutation, 15 (14%) patients with C-met amplification. 2 developed SCLC<br />
transforming and another 1 presented EMLA4-ALK fusion gene. Patients who received<br />
treatment based on a molecular resistant mechanism had longer PPS (n = 70, median PPS:<br />
24.2 [95%CI: 11.0-37.3] months), compared with those who received re-biopsy and salvage<br />
regimen based on progression model (n = 37, median PPS: 15.2 [95%CI: 11.2-19.3]<br />
months, p = 0.002) and patients who did not receive re-biopsy (n = 120, median PPS: 9.7<br />
[95%CI: 7.0-12.4] months, p < 0.001). Meanwhile, there were 109, 29 and 89 patients<br />
separately classified as dramatic, local and gradual progression type. The median PPS was<br />
inferior in the dramatic progression subgroup compared with the gradual progression<br />
subgroup (10.5 versus 18.4 months, HR = 1.99, p < 0.001). There was no survival difference<br />
between gradual and local progression (18.4 versus 18.4 months, HR = 1.24, p = 0.458).<br />
Multivariate analysis revealed that receiving re-biopsy independently correlates with<br />
superior PPS (HR = 0.49, p < 0.001) for patients failing with initial TKI.<br />
Conclusions: Re-biopsy after EGFR-TKI resistance contributes to identifying<br />
resistance mechanism, performing individual salvage treatment and ultimately<br />
prolonging post-progression survival.<br />
Legal entity responsible for the study: Sun Yat-sen University Cancer Center<br />
Funding: AstraZeneca<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1234P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Osimertinib in EGFR T790M positive advanced NSCLC<br />
(aNSCLC) – real–life data from the French temporary<br />
authorization for use (ATU) program<br />
D. Planchard 1 , M. Pérol 2 , X. Quantin 3 , A. Cortot 4 , J. Cadranel 5 , R. Schott 6 ,<br />
E. Dansin 7 , G. Fraboulet 8 , D. Moro-Sibilot 9 , J-C. Soria 10 , J. Mazieres 11 ,S.<br />
Le Moulec 12 , M. Coudurier 13 , E. Pichon 14 , M. Licour 15 , D. Maribas 16 , A. Gourion 17 ,<br />
N. Radu 18 , N. Varoqueaux 15 , C. Chouaid 19<br />
1 Department <strong>of</strong> medical oncology, Institut Gustave Roussy, Villejuif, France,<br />
2 Medical <strong>Oncology</strong>, Centre Léon Bérard, Lyon, France, 3 Thoracic <strong>Oncology</strong>, CHU<br />
Montpellier, Montpellier, France, 4 Thoracic <strong>Oncology</strong>, DRC / CHRU <strong>of</strong> Lille, Lille,<br />
France, 5 Pneumology, APHP, CancerEst, Tenon University Hospital, Paris, France,<br />
6 Medical <strong>Oncology</strong>, Centre Paul Strauss Centre de Lutte contre le Cancer,<br />
Strasbourg, France, 7 Medical <strong>Oncology</strong> Department, Centre Oscar Lambret, Lille,<br />
France, 8 <strong>Oncology</strong>, Hopital René Dubos, Pontoise, France, 9 Thoracic <strong>Oncology</strong>,<br />
CHU Grenoble - Hopital Michallon, La Tronche, France, 10 Department <strong>of</strong> Medicine<br />
DITEP, Institut Gustave Roussy, Villejuif, France, 11 CHU Toulouse, Hôpital de<br />
Larrey, Toulouse, France, 12 <strong>Oncology</strong>, Institut Bergonié, Bordeaux, France,<br />
13 Pneumology, Hopital Chambéry, Chambéry, France, 14 Pneumology, CHU de<br />
Tours, Hôpital Trousseau, Chambray-lès-Tours, France, 15 Medical Department,<br />
AstraZeneca, Corolles, France, 16 Patient Safety, AstraZeneca, Corolles, France,<br />
17 Medical Department, AstraZeneca, Paris, France, 18 <strong>Oncology</strong> Medical Affairs,<br />
AstraZeneca, Courbevoie, France, 19 Pneumology, CHI creteil, Créteil, France<br />
Background: Osimertinib, an oral, irreversible EGFR-TKI selective for sensitising<br />
(EGFRm) and T790M resistance mutations, has been shown to be effective and well<br />
tolerated in clinical studies for pts with EGFR T790M positive aNSCLC. Pts in France<br />
had early access to osimertinib through an ATU program before approval.<br />
Methods: Pts with EGFR T790M positive aNSCLC were eligible if they had received<br />
prior EGFR-TKI therapy and a platinum-based chemotherapy (CT) or had CT<br />
vi430 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
intolerance; additional lines <strong>of</strong> therapy were permitted. T790M testing was performed<br />
by INCA (French National Cancer Institute) certified platforms.<br />
Results: From 07/04/2015 to 24/03/2016, 134 centres enrolled 364 pts; 99% had stage<br />
IV adenocarcinoma and 38.5% had brain metastases. Median therapies prior to<br />
osimertinib was 2 (1–9). The most frequent prior therapies were 1 st line EGFR-TKI<br />
(66.2%; median duration 15.2 mo) and 2 nd line platinum-based CT (42.0%).<br />
Table: 1234P<br />
N = 364<br />
Age, years Median (range) 68 (28–92)<br />
Sex, % Male/female 32.9/67.1<br />
Smoking status, % Never/former/current 77.5/19.6/1.8<br />
Performance status, % 0-1/ ≥ 2 82.6/17.4<br />
EGFR mutation at diagnosis, %<br />
Ex19del/L858R 66.7/27.7<br />
De novo T790M/Other 10.5/4.8<br />
T790M testing material post EGFR-TKI relapse, %<br />
Primary/metastasis 32.7/34.4<br />
Pleural fluid 2.8<br />
ctDNA 25.0<br />
Combination 5.1<br />
Including primary and/or metastasis + plasma 2.7<br />
Pleural fluid + plasma 0.6<br />
Osimertinib therapy line, % 2/3/ ≥ 4 22.5/38.2/39.3<br />
As <strong>of</strong> March 2016, 350 pts were treated, 14 excluded (prescriber decision / pt death).<br />
61% were treated ≥3 mo, 30% ≥6 mo and 14% ≥9 mo. Overall response rate (ORR) in<br />
123 pts evaluable was 61.8% (95% CI 53, 70) (CR 5.7%, PR 56.1%). Disease control rate<br />
(CR + PR + SD) was 80.5% (99/123). 309/350 pts (88.3%) ongoing at data cut<strong>of</strong>f, 23 pts<br />
withdrawn for disease progression. Investigator reported safety data (n = 350) showed<br />
36 pts (10.3%) experienced ≥1 treatment-related AE, 13 pts (3.7%) had AEs leading to<br />
discontinuation. 12 pts (3.4%) died (1 death drug related, attributed by investigator). 9<br />
pts (2.6%) had AEs resulting in dose reductions; 3 pts (0.9%) had temporary<br />
interruptions.<br />
Conclusions: In pts with EGFR T790M positive aNSCLC, osimertinib had antitumour<br />
activity with a similar ORR to that in clinical studies, with good tolerability.<br />
Identification <strong>of</strong> eligible pts is feasible in daily practice at tumour progression by<br />
T790M testing on rebiopsy or using ctDNA.<br />
Clinical trial identification: NL 46006-46007 September 2015<br />
Legal entity responsible for the study: AstraZeneca<br />
Funding: AstraZeneca<br />
Disclosure: D. Planchard: Personal fees from AstraZenaca, Boehringer, Clovis,<br />
Novartis, San<strong>of</strong>i aventis, BMS, Roche, Lilly, Pfizer, and grants from Novartis. M. Pérol:<br />
Personal fees from Astra-Zeneca, Clovis <strong>Oncology</strong>, Roche, Boehringer-Ingelhaim,<br />
outside the submitted work. A. Cortot: Personal fees from Astrazeneca. J. Cadranel:<br />
Personal fees from BI, Roche, AstraZeneca. R. Schott: Personal fees from Roche SAS<br />
and Pierre Fabre; and non-financial support from Roche SAS, Pierre Fabre, Novartis,<br />
Astra Zeneca, Lilly, and Amgen. E. Dansin: Personal fees from AstraZeneca, Roche and<br />
Clovis. D. Moro-Sibilot: Personal fees from Astrazeneca, Pfizer, Novartis, Clover, El<br />
Lilly, Roche, and Ariad. J-C. Soria: Personal fees from AstraZeneca, Pfizer, Pierre fabre,<br />
Roche, San<strong>of</strong>i, and Servier. M. Coudurier: Personal fees and non-financial support<br />
from Aztra Zeneca, Roche, BI, Clovis, during the study; grants, personal fees and<br />
non-financial support from Msd, BMS, Roche, Lilly, BI, Amgen, outside the submitted<br />
work. A. Gourion: Personal fees from AstraZeneca, during the conduct <strong>of</strong> the<br />
study. N. Varoqueaux: Other from AstraZeneca, during the conduct <strong>of</strong> the<br />
study. C. Chouaid: Grants, personal fees and nonfinancial support from Aztra Zeneca,<br />
Roche, BI, Clovis, during the conduct <strong>of</strong> the study; grants, personal fees and<br />
nonfinancial support from MSD, BMS, Roche, Lilly, BI, Amgen, outside the study. All<br />
other authors have declared no conflicts <strong>of</strong> interest.<br />
1235P<br />
Tumor heterogeneity affects the activity <strong>of</strong> epidermal growth<br />
factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR<br />
mutant non-small cell lung cancer (NSCLC) patients (pts)<br />
N. Normanno 1 , A.M. Rachiglio 2 , M. Lambiase 2 , F. Fenizia 2 , A. Iannaccone 2 ,<br />
N. Chicchinelli 1 , A. Morabito 3 , A. Montanino 3 , G. Rocco 4 , D. Galetta 5 ,E.<br />
S. Montagna 5 , L. Crinò 6 , V. Ludovini 6 , B. Vincenzi 7 , E. Barletta 8 , C. Pinto 9 ,<br />
F. Ferraù 10 , G. Botti 11 , M.C. Piccirillo 12 , F. Perrone 12<br />
1 Cell Biology and Biotherapy Unit, Istituto Nazionale Tumori – I.R.C.C.S -<br />
Fondazione Pascale, Naples, Italy, 2 Laboratory <strong>of</strong> Pharmacogenomics, CROM,<br />
Istituto Nazionale Tumori “Fondazione G. Pascale”-IRCCS, Mercogliano (av), Italy,<br />
3 Medical <strong>Oncology</strong> Unit, Thoracic Department, Istituto Nazionale Tumori<br />
“Fondazione G.Pascale”- IRCCS, Naples, Italy, 4 Thoracic <strong>Oncology</strong>, Istituto<br />
Nazionale Tumori – I.R.C.C.S - Fondazione Pascale, Naples, Italy, 5 Medical<br />
<strong>Oncology</strong> Department, Istituto Tumori Giovanni Paolo II, Bari, Italy, 6 Medical<br />
<strong>Oncology</strong>, Santa Maria della Misericordia Hospital, Perugia, Italy, 7 Medical<br />
<strong>Oncology</strong>, Libero Istituto Universitario Campus Bio-Medico (LIUCBM), Rome, Italy,<br />
8 Medical <strong>Oncology</strong>, Azienda Ospedaliera G. Rummo, Benevento, Italy,<br />
9 S. C. Oncologia, Azienda Ospedaliera Arcispedale Santa Maria Nuova - IRCCS,<br />
Reggio Emilia, Italy, 10 Medical <strong>Oncology</strong>, Ospedale San Vincenzo, Taormina, Italy,<br />
11 Dipartimento di anatomia patologica, Istituto Nazionale Tumori – I.R.C.C.S -<br />
Fondazione Pascale, Naples, Italy, 12 Clinical Trial Unit, Istituto Nazionale Tumori – I.<br />
R.C.C.S - Fondazione Pascale, Naples, Italy<br />
Background: Recent findings suggest that a fraction <strong>of</strong> EGFR mutant NSCLC carries<br />
additional driver mutations which could potentially affect the activity <strong>of</strong> EGFR TKIs.<br />
We investigated the role <strong>of</strong> KRAS, NRAS, BRAF, PIK3CA, MET and ERBB2 mutations<br />
(other mutations) on the outcome <strong>of</strong> NSCLC pts treated with EGFR TKIs.<br />
Methods: EGFR mutant NSCLC pts who received first line therapy with EGFR TKIs<br />
were eligible. Genomic DNA from EGFR mutant NSCLC samples as assessed with<br />
routine diagnostic methods, was retrospectively analyzed with the Ion AmpliSeq Colon<br />
and Lung Cancer Panel using Ion Torrent semiconductor sequencing. The panel<br />
assesses over 500 somatic mutations in 22 genes at a sensitivity <strong>of</strong> 2%. Mutations were<br />
detected using the Ion Reporter S<strong>of</strong>tware v4.6.<br />
Results: 132 pts, treated between Jun 2008 and Dec 2014 in 7 centers, were enrolled:<br />
median age 71 (range 41-92); 70% women; 61% never smokers. Analysis <strong>of</strong> EGFR mutant<br />
samples with NGS revealed the presence <strong>of</strong> hotspot mutations in genes other than the<br />
EGFR, including KRAS, NRAS, BRAF, ERBB2, PIK3CA or MET, in 29/132 cases (22%).<br />
In most cases the allelic frequency <strong>of</strong> the other mutations was different as compared with<br />
EGFR mutations, suggesting intra-tumor heterogeneity. A T790M mutation was also<br />
found in 9/132 tumor samples (6.8%). The progression free survival (PFS) <strong>of</strong> pts without<br />
othermutationswas11.3monthsversus7monthsinptswithothermutations(Log-rank<br />
test univariate: p = 0.0298). In a multivariate Cox regression model including the presence<br />
<strong>of</strong> other mutations, age, performance status, smoking status and the presence <strong>of</strong> T790M<br />
mutations, the presence <strong>of</strong> other mutations was the only factor significantly associated with<br />
PFS (Hazard Ratio 1.63, 95% CI 1.04-2.58; p = 0.035). Response rate in pts with or without<br />
other mutations was 59% and 68%, respectively (p = 0.349).<br />
Conclusions: These data suggest that a subgroup <strong>of</strong> EGFR mutant tumors have<br />
intra-tumor heterogeneity and that this phenomenon might affect the activity <strong>of</strong> first<br />
line EGFR TKIs.<br />
Clinical trial identification: This observational study was approved by the Ethical<br />
Committee <strong>of</strong> the Pascale Institute: protocol n. 16/14 OSS<br />
Legal entity responsible for the study: Istituto Nazionale Tumori “Fondazione<br />
G. Pascale”-IRCCS, Naples, Italy<br />
Funding: Associazione Italiana per la Ricerca sul Cancro (AIRC)<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1236P<br />
Global named patient use (NPU) program <strong>of</strong> afatinib, an oral<br />
ErbB family blocker, in heavily pretreated advanced<br />
non-small cell lung carcinoma (NSCLC) patients who<br />
progressed following prior therapies, including erlotinib or<br />
gefitinib (E/G)<br />
F. Cappuzzo 1 , R. Soo 2 , M. Hochmair 3 , M. Schuler 4 , T.S.K. Mok 5 , G. Stehle 6 ,<br />
A. Cseh 7 , R.M. Lorence 8 , S. Linden 9 , N.D. Forman 8 , C-M. Tsai 10<br />
1 <strong>Oncology</strong>, Istituto Toscano Tumori, Ospedale Civile, Ravenna, Italy,<br />
2 Haematology-<strong>Oncology</strong>, National University Health System and Cancer Science<br />
Institute <strong>of</strong> Singapore, 3 Respiratory <strong>Oncology</strong> Unit, Otto Wagner Spital, Vienna,<br />
Austria, 4 Department <strong>of</strong> Medical <strong>Oncology</strong>, West German Cancer Center,<br />
University Hospital Essen, University Duisburg-Essen, Essen, and German Cancer<br />
Consortium (DKTK), Heidelberg, Germany, 5 Clinical <strong>Oncology</strong>, State Key<br />
Laboratory <strong>of</strong> South China, The Chinese University <strong>of</strong> Hong Kong, Hong Kong,<br />
China, 6 TA <strong>Oncology</strong>, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach,<br />
Germany, 7 Department <strong>of</strong> Medical Affairs, Boehringer Ingelheim RCV GmbH & Co.<br />
KG, Vienna, Austria, 8 <strong>Oncology</strong> Clinical Research, Boehringer Ingelheim<br />
Pharmaceuticals Inc., Ridgefield, CT, USA, 9 Epidemiology, Boehringer Ingelheim<br />
GmbH, Ingelheim, Germany, 10 Department <strong>of</strong> Chest Medicine, Taipei Veterans<br />
General Hospital and National Yang-Ming University, Taipei, Taiwan<br />
Background: An afatinib NPU program started in 2010 after the Phase 2b/3<br />
LUX-Lung 1 trial demonstrated significantly improved progression-free survival and<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw383 | vi431
abstracts<br />
objective response rate (ORR) with afatinib versus placebo in advanced NSCLC<br />
patients following failure <strong>of</strong> E/G and 1–2 lines <strong>of</strong> chemotherapy.<br />
Methods: Eligible advanced NSCLC patients had either progressed after clinical benefit<br />
on prior E/G and/or had an activating EGFR/HER2 mutation; had exhausted all other<br />
treatments; and were ineligible for afatinib trials. Time to treatment failure (TTF) was<br />
defined as the time from drug start to the date <strong>of</strong> treatment discontinuation.<br />
Results: Data as <strong>of</strong> January 2016 from 3966 NSCLC patients from 41 countries (6<br />
continents) are reported here. Patients were heavily pretreated, with approximately<br />
50% receiving afatinib as ≥4th-line treatment. Among the 65.4% (n = 2595/3966) <strong>of</strong><br />
patients with known tumour EGFR status, 92.8% were EGFR mutation-positive.<br />
Median TTF for afatinib was calculated for 2862/3966 patients (72.2%) based on<br />
available data. TTF was 4.4 months for all patients, similar to the TTF for patients<br />
reported as EGFR mutation-positive, or as harbouring either common or uncommon<br />
EGFR mutations (each 4.3 months). For patients with response assessments reported<br />
(n = 1141/2862; 39.9%), the ORR was 23% (267/1141) for all patients and 25% (181/<br />
723) for those with NSCLC harbouring any EGFR mutation. Notably, a 26% (26/100)<br />
ORR was reported in patients with NSCLC harbouring uncommon EGFR mutations,<br />
including 19% (11/58) in T790M mutation-positive patients and 35% (7/20) in those<br />
with insertions in exon 20. No new/unexpected safety findings were observed<br />
Conclusions: This afatinib NPU program in ∼4000 NSCLC patients who were<br />
refractory to several therapies, including prior E/G, revealed encouraging TTF<br />
durations and ORR. The afatinib safety pr<strong>of</strong>ile was as anticipated.<br />
Clinical trial identification: N/A<br />
Legal entity responsible for the study: Boehringer Ingelheim<br />
Funding: Boehringer Ingelheim<br />
Disclosure: F. Cappuzzo: Membership on advisory board or board <strong>of</strong> directors (Roche,<br />
AstraZeneca, BMS, Pfizer). R. Soo: Membership on advisory board or board <strong>of</strong><br />
directors (AstraZeneca, Boehringer Ingelheim, Lilly, Merck, Novartis, Pfizer,<br />
Roche). M. Schuler: Membership on advisory board/board <strong>of</strong> directors (AZ, BI, BMS,<br />
Celgene, IQWig, Lilly, Novartis); corporate-sponsored research (BI, BMS, Novartis);<br />
lecture fees (Alexion, BI, Celgene, GSK, Lilly, Novartis); patents (University<br />
Duisburg-Essen). T.S.K. Mok: Stock (Sanomics Ltd); advisory board (AZ, Roche/<br />
Genentech, Pfizer, Eli Lilly, BI, Merck Serono, MSD, Janssen, Clovis <strong>Oncology</strong>,<br />
BioMarin, GSK, Novartis, SFJ Pharmaceutical, ACEA Biosciences, Inc., Vertex<br />
Pharmaceuticals, Aveo & Biodesix, BMS, geneDecode Co., Ltd, OncoGenex<br />
Technologies Inc.); board <strong>of</strong> directors (IASLC, Chinese Lung Cancer Research<br />
Foundation Ltd, CSCO, HKCTS); corporate-sponsored research (AZ, BI, Pfizer,<br />
Novartis, SFJ, Roche, MSD, Clovis <strong>Oncology</strong>, BMS). G. Stehle: Employment and<br />
patent/royalty/other intellectual property (Boehringer Ingelheim). A. Cseh:<br />
Employment (Boehringer Ingelheim); stock (MEDA). R.M. Lorence: Employment and<br />
consulting/advisory role (Boehringer Ingelheim). S. Linden: Employment (Boehringer<br />
Ingelheim). N.D. Forman: Employment (Boehringer Ingelheim); stock/other<br />
ownership (INSYS Therapeutics). C-M. Tsai: Honoraria (Pfizer, Roche, Eli Lilly,<br />
Boehringer Ingelheim, AstraZeneca). All other authors have declared no conflicts <strong>of</strong><br />
interest.<br />
1237P<br />
Correlation between programmed death-ligand 1 (PD-L1)<br />
expression and T790M status in EGFR-mutant non-small cell<br />
lung cancer (NSCLC)<br />
A. Hata 1 , N. Katakami 1 , S. Nanjo 1 , C. Okuda 2 , R. Kaji 2 , K. Masago 2 , S. Fujita 2 ,<br />
Y. Imai 3<br />
1 Division <strong>of</strong> Integrated <strong>Oncology</strong>, Institute <strong>of</strong> Biomedical Research and Innovation,<br />
Kobe, Japan, 2 Integrated <strong>Oncology</strong>, Institute <strong>of</strong> Biomedical Research and<br />
Innovation, Kobe, Japan, 3 Department <strong>of</strong> Pathology, Kobe City Medical Center<br />
General Hospital, Kobe, Japan<br />
Background: Correlation between PD-L1 expression and T790M status is unclear.<br />
Therapeutic interventions could affect PD-L1 expression, and rebiopsied fresh samples<br />
may be desirable to analyze PD-L1 expression.<br />
Methods: We retrospectively analyzed PD-L1 expression and T790M status in<br />
rebiopsied samples <strong>of</strong> EGFR-mutant NSCLC after acquired resistance. PD-L1<br />
immunohistochemistry was performed using the SP142 anti-PD-L1 antibody for<br />
tumor cell membrane staining. H-score was adopted to evaluate both percentage and<br />
intensity, and scores ≥1 were defined as PD-L1 + , and scores ≥10 as strong PD-L1+.<br />
T790M status was examined using the PNA-LNA PCR clamp or cycleave method.<br />
Survival analyses were done according to PD-L1 and T790M status at first rebiopsy.<br />
Results: We investigated 63 available rebiopsied histologic samples in 45 patients.<br />
Median H-score in T790M+ (n = 25) samples was 0 (range, 0-6), whereas T790M-<br />
(n = 38) was 1 (range, 0-91) (Wilcoxon, p = 0.0451). PD-L1+ was confirmed in 12<br />
(48%) <strong>of</strong> 25 T790M+ samples, and in 28 (74%) <strong>of</strong> 38 T790M- (p = 0.0383). Strong<br />
PD-L1+ was identified in 0 (0%) T790M + , but in 3 (8%) T790M- (p = 0.1500). Ten<br />
patients received multiple rebiopsies. In 7 <strong>of</strong> these 10 patients, T790M status had<br />
changed from T790M+ to T790M-. Among 4 <strong>of</strong> these 7, PD-L1 expression also<br />
changed from PD-L1- to PD-L1 + , in accordance with T790M status from T790M+ to<br />
T790M-. Median overall survival (OS) <strong>of</strong> PD-L1+ (n = 30) vs. PD-L1- (n = 15) were<br />
55.0 months vs. not reached months, respectively (p = 0.1071). Median OS <strong>of</strong> T790M+<br />
(n = 16) vs. T790M- (n = 29) were 80.3 vs. 55.0 months, respectively (p = 0.1340).<br />
Conclusions: T790M+ status was correlated to lower PD-L1 expression. Conversely,<br />
T790M- status was associated with higher PD-L1 expression, suggesting a potential<br />
efficacy <strong>of</strong> anti-PD-1/PD-L1 immunotherapies for T790M- population. PD-L1<br />
expression might have a prognostic value, even in EGFR-mutant NSCLC.<br />
Legal entity responsible for the study: N/A<br />
Funding: Foundation for Biomedical Research and Innovation<br />
Disclosure: A. Hata: Akito Hata received lecture fee from Chugai, Astra Zeneca,<br />
Boehringer Ingelheim, and Eli Lilly. All other authors have declared no conflicts <strong>of</strong><br />
interest.<br />
1238P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Evaluation <strong>of</strong> VeriStrat, a serum proteomic test, in the<br />
randomized, open-label, Phase 3 LUX-Lung 8 trial <strong>of</strong> afatinib<br />
versus erlotinib for the second-line treatment <strong>of</strong> advanced<br />
squamous cell carcinoma <strong>of</strong> the lung<br />
G. Goss 1 , K.H. Lee 2 , E. Felip 3 , M. Cobo 4 , K. Syrigos 5 , E. Goker 6 , V. Georgioulias 7 ,<br />
S.Z. Guclu 8 , D. Isla 9 , Y.J. Min 10 , A. Morabito 11 , N. Dupuis 12 , V.K. Chand 13 ,<br />
F. Solca 14 , N. Krämer 15 , N. Gibson 16 , E. Ehrnrooth 17 , J.C. Soria 18<br />
1 Medical <strong>Oncology</strong>, The Ottawa Hospital Regional Cancer Centre, Ottawa, ON,<br />
Canada, 2 Division <strong>of</strong> Medical <strong>Oncology</strong>, Chungbuk National University Hospital,<br />
Cheong-ju, Republic <strong>of</strong> Korea, 3 Department <strong>of</strong> <strong>Oncology</strong>, Vall d’ Hebron University<br />
Hospital and Vall d’Hebron Institute <strong>of</strong> <strong>Oncology</strong>, Madrid, Spain, 4 Department <strong>of</strong><br />
Medical <strong>Oncology</strong>, Hospital Carlos Haya, Malaga, Spain, 5 <strong>Oncology</strong> Unit, Athens<br />
School <strong>of</strong> Medicine, Athens, Greece, 6 Department <strong>of</strong> Medical <strong>Oncology</strong>, Ege<br />
University Faculty <strong>of</strong> Medicine, Izmir, Turkey, 7 Department <strong>of</strong> Medical <strong>Oncology</strong>,<br />
University Hospital <strong>of</strong> Heraklion, Heraklion, Greece, 8 Department <strong>of</strong> Chest<br />
Diseases, Izmir Chest Diseases Research Hospital, Izmir, Turkey, 9 Medical<br />
<strong>Oncology</strong> Department, Hospital Lozano Blesa, Zaragoza, Spain, 10 Department <strong>of</strong><br />
Medicine, Ulsan University Hospital, Ulsan, Republic <strong>of</strong> Korea, 11 Medical <strong>Oncology</strong><br />
Unit, Thoracic Department, Istituto Nazionale Tumori “Fondazione G.Pascale”-<br />
IRCCS, Naples, Italy, 12 Clinical Development, Biodesix Inc., Boulder, CO, USA,<br />
13 Clinical Development, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield,<br />
CT, USA, 14 Pharmacology and Translational Research, Boehringer Ingelheim RCV<br />
GmbH & Co KG, Vienna, Austria, 15 Biostatistics, Staburo GmbH, Munich,<br />
Germany on behalf <strong>of</strong> Boehringer Ingelheim Pharma GmBH & Co. KG, Munich,<br />
Germany, 16 Translational Medicine and Clinical Pharmacology,<br />
Boehringer-Ingelheim Pharmaceuticals GmbH & Co. KG, Biberach An Der Riss,<br />
Germany, 17 TA <strong>Oncology</strong>, Boehringer Ingelheim, Danmark A/S, Copenhagen,<br />
Denmark, 18 Department <strong>of</strong> Medicine, Gustave Roussy Cancer Campus and<br />
University Paris-Sud, Paris, France<br />
Background: Treatment (tx) options for patients (pts) with squamous cell carcinoma<br />
(SCC) <strong>of</strong> the lung following chemotherapy are limited. In LUX-Lung 8 (LL8), in 795<br />
pts with SCC <strong>of</strong> the lung, the irreversible ErbB family blocker, afatinib (A), significantly<br />
improved OS, PFS and DCR vs erlotinib (E), a reversible EGFR TKI. VeriStrat is a<br />
serum protein test that utilizes MALDI-TOF mass spectrometry to assign a ‘GOOD’<br />
(VS-G) or ‘POOR’ (VS-P) classification and has shown prognostic and predictive<br />
utility for EGFR targeted agents in NSCLC. 1 Here, the predictive ability <strong>of</strong> VeriStrat<br />
was tested in LL8; OS was the primary efficacy variable.<br />
Methods: Pre-tx serum samples, blinded to clinical outcome, were classified as VS-G<br />
or VS-P based on predefined reference groups. Clinical outcomes were analyzed with<br />
respect to VeriStrat status in the overall population (all pts with both clinical and<br />
VeriStrat data) and in pre-defined subgroups.<br />
Results: 675 pts were classified (VS-G: 412; VS-P: 263). In the VS-G group, median OS<br />
was 11.5 mo for A and 8.9 mo for E (HR [95% CI] 0.79 [0.63–0.98]; p = 0.03); median<br />
PFS was 3.3 mo for A and 2.0 mo for E (HR [95% CI] 0.73 [0.59–0.92]; p = 0.005). In<br />
the VS-P group, median OS was 4.7 mo for A and 4.8 mo for E (HR [95% CI] 0.90<br />
[0.70–1.16]; p = n.s.); median PFS was 1.9 mo for both A and E (HR [95% CI] 0.96<br />
[0.73–1.27]; p = n.s.). In pts treated with A, both OS (HR [95% CI] 0.40 [0.31–0.51];<br />
p < 0.0001) and PFS (HR [95% CI] 0.56 [0.43–0.72]; p < 0.0001) were longer in the<br />
VS-G group vs the VS-P group. Multivariate analysis showed that VeriStrat was an<br />
independent predictor <strong>of</strong> OS and PFS in pts treated with A, regardless <strong>of</strong> ECOG PS,<br />
best response to first-line therapy, age and race. However, there was no interaction<br />
between VeriStrat classification and tx group for OS (P interation = 0.53) or PFS<br />
(P interaction = 0.12).<br />
Conclusions: VeriStrat has a strong independent stratification effect in pts with<br />
relapsed/refractory SCC <strong>of</strong> the lung treated with A. In these difficult to treat pts, A<br />
conferred significantly better OS and PFS than E in the VS-G group, with a median OS<br />
<strong>of</strong> 11.5 mo vs 8.9 mo. 1. Gregorc V, et al. Lancet Oncol 2014;15:713–21.<br />
Clinical trial identification: NCT01523587<br />
Legal entity responsible for the study: Boehringer Ingelheim<br />
Funding: Boehringer Ingelheim<br />
Disclosure: G. Goss: Advisory board/board <strong>of</strong> directors: Astrazeneca, Pfizer,<br />
Boehringer Ingelheim, Lilly, Bristol Myers Squibb. E. Felip: Advisory board: Eli Lilly,<br />
Pfizer, Roche, BI Other: AZ, BMS, Novartis (Honoraria; lectures). A. Morabito: Other:<br />
Roche, AstraZeneca, Boehringer, Pfizer, Bayer (Honoraria). N. Dupuis: Stock<br />
ownership: Biodesix. V.K. Chand: Other: Current employer, EMD Serono; Previous<br />
employer BI. F. Solca: Other: Employed by BI. N. Krämer: Consultant to Boehringer<br />
Ingelheim Pharma GmBH & Co. KG, Biberach, Germany and receives compensation<br />
vi432 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
for these services. N. Gibson, E. Ehrnrooth: Employed by BI. J.C. Soria: Other: BI,<br />
Roche (honoraria). All other authors have declared no conflicts <strong>of</strong> interest.<br />
abstracts<br />
for AZ and Ariad. The institution received sponsored research funds from Clovis. All<br />
other authors have declared no conflicts <strong>of</strong> interest.<br />
1239P<br />
Rociletinib-associated cataracts in EGFR-mutant NSCLC<br />
Z. Piotrowska 1 , E. Liu 2 , A. Varga 3 , M. Thakur 4 , V. Narayanan 5 , S.V. Liu 6 , J. Neal 7 ,<br />
M. Spiegel 8 , B. Solomon 9 ,H.Yu 10 , S-H.I. Ou 11 , V.A. Papadimitrakopoulou 12 ,<br />
S. Gadgeel 13 , D.R. Camidge 14 , J-C. Soria 15 , H. Wakelee 7 , J. Goldman 16 ,<br />
K. Kopani 2 , L. Rolfe 17 , L.V. Sequist 18<br />
1 Center for Thoracic Cancers, Massachusetts General Hospital, Boston, MA,<br />
USA, 2 Ophthalmology, Tufts Medical Center Tufts University, Boston, MA, USA,<br />
3 Department <strong>of</strong> Medicine DITEP, Institut Gustave Roussy, Villejuif, France,<br />
4 Medical <strong>Oncology</strong>, Karmanos Cancer Institute, Detroit, MI, USA, 5 Medical<br />
<strong>Oncology</strong>, University <strong>of</strong> Colorado Denver, Denver, CO, USA, 6 Medicine, Lombardi<br />
Cancer Center Georgetown University, Washington, DC, USA, 7 Medical<br />
<strong>Oncology</strong>, Stanford University Medical Center, Stanford, CA, USA, 8 Hematology/<br />
<strong>Oncology</strong>, UCLA - School <strong>of</strong> Medicine, Los Angeles, CA, USA, 9 Medical<br />
<strong>Oncology</strong>, Peter MacCallum Cancer Center, Melbourne, Australia, 10 Medical<br />
<strong>Oncology</strong>, Memorial Sloan-Kettering Cancer Center, New York, NY, USA,<br />
11 Department <strong>of</strong> Medicine, Division <strong>of</strong> Hematology <strong>Oncology</strong>, UC Irvine School <strong>of</strong><br />
Medicine, Irvine, CA, USA, 12 Medical <strong>Oncology</strong>, MD Anderson Cancer Center,<br />
Houston, TX, USA, 13 Wayne State University, Karmanos Cancer Institute, Detroit,<br />
MI, USA, 14 Cancer Center, University <strong>of</strong> Colorado, Aurora, CO, USA, 15 Dept. <strong>of</strong><br />
Medicine, Institut de Cancérologie Gustave Roussy, Villejuif, France, 16 <strong>Oncology</strong>,<br />
University <strong>of</strong> California, Los Angeles, CA, USA, 17 Sheraton House, Clovis<br />
<strong>Oncology</strong> UK Ltd, Cambridge, UK, 18 Center for Thoracic Cancers, Massachusetts<br />
General Hospital, Boston, MA, USA<br />
Background: Rociletinib (roci) is a T790M-selective EGFR TKI. Among pts on the<br />
phase I/II TIGER-X study, we observed late-onset, quickly progressive cataracts (cats).<br />
We retrospectively contacted pts to assess the incidence <strong>of</strong> cats among pts treated at our<br />
centers, including those beyond the 30-day post-roci protocol follow-up (FU) period.<br />
Methods: To identify pts at risk for roci-associated cats, we excluded pts with<br />
pre-existing cats or prior cat surgery, pts treated with sub-therapeutic roci doses (< 900<br />
mg BID free base (FB), and those who lived < 120 days from roci initiation. We<br />
attempted to contact all pts at risk in Mar 2016 to update FU. Associations between cat<br />
surg and age, gender, starting roci dose, time on roci, presence <strong>of</strong> hyperglycemia and<br />
maximum Hgb A1c were tested with Fisher’s Exact and Student’s T-tests.<br />
Results: Of 284 pts enrolled at the participating sites through Feb 2015, 205 were at risk<br />
for cats (135 F, 70 M). The median age was 59 years (range 29-86). The median<br />
duration <strong>of</strong> roci exposure was 7.8 mos (range 0.3-29.5). Pts received starting BID roci<br />
doses <strong>of</strong> 900 mg FB (10 pts) or 500 (55), 625 (73), 750 (62) and 1000 (5) mg HBr<br />
tablets. Median FU was 10.4 mos. 69 (34%) pts developed cats; 53 (26%) required<br />
surgical repair. Among those successfully contacted for longterm FU, the rate <strong>of</strong> cats<br />
was 69/104 (66%). The median time from initial roci exposure to first cat surg was 14.0<br />
mos (95% CI, 2.8-29.6). Roci-associated cats frequently progressed to hypermature,<br />
surgical cats in wks to mos. Surgery was <strong>of</strong>ten more complex than typical senile cats,<br />
with increased risk <strong>of</strong> high intralenticular pressure and need for specialized intraop<br />
techniques. Variables significantly associated with an increased risk <strong>of</strong> cat surg<br />
included hyperglycemia (p = 0.043), maximum Hgb A1c (p = 0.022), and duration <strong>of</strong><br />
roci exposure (OR 1.25; p =
abstracts<br />
1241P<br />
Afatinib efficacy and cerebrospinal fluid concentration in<br />
NSCLC patients with EGFR mutation developing<br />
leptomeningeal carcinomatosis<br />
A. Tamiya 1 , M. Tamiya 2 , T. Nishihara 2 , T. Shiroyama 2 , K. Nakao 1 , T. Tsuji 1 ,<br />
N. Takeuchi 1 , S-I. Isa 3 , N. Omachi 1 , N. Okamoto 4 , H. Suzuki 4 , K. Okishio 3 ,<br />
A. Iwazaki 5 , K. Imai 5 , T. Hirashima 2 , S. Atagi 3<br />
1 Internal Medicene, Kinki-chuo Chest Medical Center, Sakai, Japan, 2 Department<br />
<strong>of</strong> Thoracic Malignancy, Osaka Prefectural Medical Center for Respiratory and<br />
Allergic Diseases, Habikino, Japan, 3 Clinical Research Center, Kinki-chuo Chest<br />
Medical Center, Sakai, Japan, 4 Thoracic Malignancy, Osaka Prefectural Hospital<br />
Organization Osaka Prefectural Medical Center for Respiratory and Allergic<br />
Diseases, Habikino, Japan, 5 Pharmaceutical Sciences, Setsunan University,<br />
Hirakata, Japan<br />
Background: Afatinib (AFA) is an effective treatment in advanced non-small-cell lung<br />
cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR)<br />
mutation. However, there are few reports about the cerebrospinal fluid (CSF)<br />
penetration rate and the efficacy for trreatment <strong>of</strong> central nervous system (CNS)<br />
metastasis. Therefore, we conducted a study to evaluate the CSF penetration rate and<br />
efficacy <strong>of</strong> AFA in NSCLC patients harboring EGFR mutation with leptomeningeal<br />
carcinomatosis (LC).<br />
Methods: Eligibility criteria included performance status (PS) 0-3, aged 20 years or<br />
older, pathologically proven NSCLC, harboring EGFR mutation, with LC, adequate<br />
organ function, and written informed consent. Patients received AFA (40mg/body<br />
every day). We analyzed the blood and CSF level <strong>of</strong> AFA before administrating AFA on<br />
the eighth day. The primary endpoint was the CSF penetration rate. Secondary<br />
endpoints included objective response rate (ORR), progression-free survival (PFS),<br />
overall survival (OS), and safety pr<strong>of</strong>ile.<br />
Results: A total <strong>of</strong> 11 patients were enrolled. And we could analyze the blood level in<br />
10 patients and the CSF level in 8 patients. Median patient age was 66 years. All<br />
patients were adenocarcinoma. In EGFR mutation status, 5 patients had exon 19<br />
deletion, 3 had L858R and 3 had minor (exon18) mutation. There were 3 patients <strong>of</strong><br />
PS2 and 4 patients were PS3. Almost all patients received AFA after third-line or<br />
further line chemotherapy. The median blood level was the 88.2 (range: 30.4-373) ng/<br />
ml, the median CSF level was 1.4 (range: 0.39-2.85) ng/ml and the median CSF<br />
penetration rate was 1.65 (range: 0.1-9.25) %. The ORR was 27.3%. Median OS was 3.8<br />
(95%CI: 1.1-13.1) months and median PFS was 2.0 (95%CI: 0.6-5.8) months.<br />
Hematological toxicity was mild; however diarrhea and skin toxicities were relatively<br />
strong, especially in patients with poor PS.<br />
Conclusions: The median CSF penetration rate <strong>of</strong> AFA was higher than the rate in<br />
previous reports; however the rate was lower compared with that <strong>of</strong> erlotinib in the<br />
prior reports. The efficacy for LC was moderate. And we have to take care <strong>of</strong> diarrhea<br />
and skin toxicities, especially in the patients with poor PS.<br />
Clinical trial identification: UMIN000014065<br />
Legal entity responsible for the study: Shinji Atagi<br />
Funding: Kinki-Chuo Chest Medical Center<br />
Disclosure: T. Hirashima: Astra Zeneka, Chugai Pharmaceutical Co., Inc., MSD,<br />
Merck & Co., Inc., Eli Lilly Japan K.K., Ono Pharmaceutical Co., Ltd. S. Atagi:<br />
Honoraria: Eli Lilly Japan, Chugai Pharmaceutical, Taiho Pharmaceutical, Boehringer<br />
Ingelheim, Pfizer Japan, Ono Pharmaceutical, and AstraZeneca. Research funding:<br />
Chugai Pharmaceutical, Pfizer, Ono Pharmaceutical, Merck Serono, Boehringer<br />
Ingelheim. All other authors have declared no conflicts <strong>of</strong> interest.<br />
1242P<br />
Progression <strong>of</strong> leptomeningeal metastases in advanced<br />
EGFR-mutated non-small cell lung cancer<br />
Q. Zhao 1 , L. Deng 2 , Y. Zhang 2 , X. Zhou 2 ,Y.Li 2 ,M.Yu 2 , L. Zhou 2 , B. Zou 2 , Y. Liu 2 ,<br />
Y. Lu 2<br />
1 West China School <strong>of</strong> Medicine, West China Hospital, Huaxi, Sichuan University,<br />
Chengdu, China, 2 Department <strong>of</strong> Thoracic <strong>Oncology</strong>, Cancer Center and State<br />
Key Laboratory <strong>of</strong> Biotherapy, West China Hospital, Huaxi, Sichuan University,<br />
Chengdu, China<br />
Background: Leptomeningeal metastasis (LM) has become increasingly common in<br />
patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC) treated<br />
with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), but data<br />
are incomplete with respect to clinical features and treatment outcomes <strong>of</strong> LM in this<br />
population.<br />
Methods: We retrospectively evaluated 420 advanced NSCLC patients effectively<br />
treated with EGFR-TKI. We studied LM progression <strong>of</strong> those patients, defining this as<br />
newly developed leptomeningeal metastases after a response to EGFR-TKI with or<br />
without pre-existing brain parenchyma lesions.<br />
Results: Among 420 patients, LM occurred in 29 (6.9 %). Patients with EGFR L858R<br />
mutations were more likely to experience LM than those with exon 19 deletions<br />
(P = 0.006). The median time to LM progression was 16.5 months (95% CI, 11.9-20.8).<br />
The prognosis for LM patients was poor and the median survival was 5.2 months (95%<br />
CI, 3.2-7.2) after LM diagnosis. Patients who received BSC are significantly shorter<br />
than those with anti- tumor treatment (1.9m vs 6.0m, P < 0.001). Patients who received<br />
whole brain radiotherapy (WBRT) had significantly longer survival time compared<br />
with who did not (6.0m vs 3.9m, P = 0.038). And there are significant difference<br />
between patients with performance status ≤2 and >2 (14.2m vs 2.3m, P < 0.001).<br />
However, no statistical difference were found between patients switched to erlotinib<br />
and those who did not after LM (P = 0.941), similar trends were observed in the subset<br />
analysis in patients with stop or continue taking gefitinib (P = 0.330).<br />
Conclusions: For advanced EGFR-mutated NSCLC patients who were effectively<br />
treated with EGFR-TKI, L858R mutation might be associated with higher risk <strong>of</strong> LM<br />
progression compared with exon 19 deletion. Performance status was an important<br />
prognostic factor. WBRT was a rational choice <strong>of</strong> the appropriate therapy and can<br />
improve the outcomes after LM progression.<br />
Legal entity responsible for the study: Yongmei Liu<br />
Funding: National Natural Science Foundation <strong>of</strong> China (No. 81472196)<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1243P<br />
Predictive factors for T790M mutation in plasma in patients<br />
after progression to 1st line tyrosine-kinase inhibitor (TKI)<br />
with or without subsequent lines <strong>of</strong> TKI or chemotherapy for<br />
metastatic epidermal growth factor receptor (EGFR)-mutated<br />
non-small-cell lung cancer (NSCLC)<br />
K-S. Lau, T-H. So, T-S. Choy, D.K. Leung, K-O. Lam, P.Y.P. Ho, W-L. Chan,<br />
L-S. Wong, S-Y. Chan, F-T. Chan, R.P. Tse, C-W. Choi, T-C. Lam, D.W. Kwong,<br />
A. Lee, T-W. Leung, V.H. Lee<br />
Department <strong>of</strong> Clinical <strong>Oncology</strong>, The University <strong>of</strong> Hong Kong, Hong Kong, China<br />
Background: Liquid re-biopsy has become an acceptable alternative to tumor re-biopsy<br />
to identify acquired T790M mutation after tyrosine-kinase inhibitors with or without<br />
subsequent chemotherapy for metastatic EGFR-mutated NSCLC. We prospectively<br />
investigated if there were any predictors for development <strong>of</strong> acquired T790M mutation<br />
in plasma DNA.<br />
Methods: Patients with tumour-biopsy proven activating EGFR mutations who<br />
received 1 st line TKI with or without subsequent lines <strong>of</strong> TKI and/or chemotherapy<br />
after failure to 1 st line TKI were prospectively recruited. Blood (10ml ETDA) was taken<br />
for plasma DNA for the detection <strong>of</strong> T790M mutation at the time <strong>of</strong> progressive<br />
disease to TKI with or without subsequent TKI/chemotherapy. Univariable and<br />
multivariable logistic regression was performed for clinical and molecular predictors<br />
for presence <strong>of</strong> T790M mutation.<br />
Results: 68 patients received TKI alone with or without further TKI/chemotherapy<br />
before liquid re-biopsy at the time <strong>of</strong> progressive disease. 19 (51.4%) patients with<br />
initial exon 19 deletion versus 8 (25.8%) patients with initial exon 21 mutation<br />
developed T790M on liquid re-biopsy (p = 0.032). Univariable analysis showed that<br />
age ≥75 years (OR 4.15, 95% CI 1.06-16.21, p = 0.041), ≥2 sites <strong>of</strong> distant metastases<br />
before 1 st line TKI (OR 13.51, 95% CI 1.65-111.11 p = 0.015) and exon 19 deletion (vs.<br />
exon 21 mutations) (OR 3.04, 95% CI 1.08-8.51, p = 0.035) were significant predictive<br />
factors, while multivariable analysis showed that ≥2 sites <strong>of</strong> distant metastases (OR<br />
13.70, 95% CI 1.64-111.11, p = 0.001) and exon 19 deletion (OR 3.09, 95% CI<br />
1.03-9.29, p = 0.039) were independent predictive factors <strong>of</strong> development <strong>of</strong> T790M<br />
mutation. Use <strong>of</strong> chemotherapy and use <strong>of</strong> more than 1 line <strong>of</strong> TKI were not<br />
predictors.<br />
Conclusions: Targeted patient subgroups were identified for the development <strong>of</strong><br />
T790M mutation after 1 st line TKI and/or subsequent TKI/chemotherapy, which were<br />
important to guide subsequent management.<br />
Legal entity responsible for the study: Department <strong>of</strong> Clinical <strong>Oncology</strong>, The<br />
University <strong>of</strong> Hong Kong<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1244P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
French real-life efficacy <strong>of</strong> 1st line gefitinib in EGFR<br />
mutation-positive NSCLC in the prospective EPIDAURE<br />
study: Results by EGFR exon 19 Del and L858R mutation<br />
subtypes<br />
M. Perol 1 , J-F. Morère 2 , E. Fabre 3 , B. Lemaire 4 , I. Monnet 5 , E. Brambilla 6 ,<br />
V. Rondeau 7 , M. Licour 8 , J. Cadranel 9<br />
1 Medical <strong>Oncology</strong>, Centre Léon Bérard, Lyon, France, 2 Medical <strong>Oncology</strong>,<br />
Hopital Paul Brousse, Villejuif, France, 3 Medical <strong>Oncology</strong>, Hopital Europeen<br />
Georges, Paris, France, 4 Pneumologie, C.H.R. Orleans - La Source, Orleans,<br />
France, 5 Pulmonology, Respiratory Medicine, <strong>Oncology</strong>, CHI de Créteil, Créteil,<br />
France, 6 Department <strong>of</strong> Pathology, Hôpital Albert Michallon, Tronch, France,<br />
7 ISPED, INSERM U1219, Université de Bordeaux, Bordeaux, France,<br />
8 Department <strong>of</strong> Epidemiology and Biometry, AstraZeneca, Courbevoie, France,<br />
9 Pneumology, Hôpital Tenon, Paris, France<br />
Background: The EGFR tyrosine kinase inhibitor (TKI) gefitinib (IRESSA TM ) received<br />
approval in France on 4 Nov 2009. At the French authority’s request, the EPIDAURE<br />
study was initiated in Jan 2012 to explore real-life gefitinib use in terms <strong>of</strong> patients<br />
(pts) population, EGFR mutation testing and efficacy.<br />
vi434 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Methods: Eligible French pts had NSCLC <strong>of</strong> any stage, histology or treatment line, and<br />
started gefitinib treatment between Jan 2011-Mar 2013 prior to study entry (‘prevalent<br />
pts’) or at study entry (‘incident pts’). Efficacy, safety and quality <strong>of</strong> life with gefitinib<br />
were assessed over a 2-year follow-up period (previously reported: ELCC 2016 #327).<br />
Efficacy data (objective response rate [ORR], progression-free survival [PFS], overall<br />
survival [OS]) in pts with EGFR common mutation-positive NSCLC who received 1 st<br />
line gefitinib are presented by mutation subtype.<br />
Results: Of 361 pts recruited across 104 sites in France (116 incident pts), 283 were<br />
EGFR mutation-positive and received 1st line gefitinib (94 incident pts); EGFR<br />
mutation subtypes data were available for 260 (82 incident pts). Median duration <strong>of</strong><br />
follow-up: 20.8 months. In the total 1st line population: median age was 71 years, 61%<br />
were never-smokers, 73% had performance status 0-1 and 33% had brain metastases.<br />
ORR was 68.5% (95% CI 61.9, 72.9), median PFS was 11.5 months (95% CI 10.0, 13.4)<br />
and median OS from initiation <strong>of</strong> gefitinib was 25.7 months (95% CI 23.4, 27.9). Better<br />
outcomes were observed with exon 19 Del vs L858R mutations (Table), especially in<br />
incident pts.<br />
Conclusions: EPIDAURE provided a large cohort <strong>of</strong> French pts with EGFR<br />
mutation-positive NSCLC treated with 1 st line gefitinib. Higher ORR and prolonged<br />
OS/PFS in exon 19 Del vs L858R mutations indicate that this subtype represents<br />
distinct tumours which may be more sensitive to EGFR TKI therapy. Findings were<br />
similar to afatinib data in Caucasian pts. Funding AstraZeneca.<br />
Table: 1244P<br />
Incident pts (n = 82) Total pts (n = 260)<br />
Exon 19 del L858R Exon 19 del L858R<br />
EGFR mutation 49 (60) 29 (35) 136 (52) 106 (41)<br />
subtype, n (%)<br />
ORR, n (%) (95% CI) 39 (83) (72.3,<br />
93.7)<br />
16 (59) (40.8,<br />
77.8)<br />
102 (78)<br />
(70.8,<br />
66 (64) (54.8,<br />
73.4)<br />
85.0)<br />
PFS, median months<br />
(95% CI)<br />
12.2 (9.1,<br />
18.1)<br />
6.4 (5.3,<br />
10.5)<br />
12.8 (10.2,<br />
14.9)<br />
11.0 (7.7,<br />
13.4)<br />
OS, median months<br />
(95% CI)<br />
27.2 (24.0,<br />
NC)<br />
18.1 (10.9,<br />
26.4)<br />
31.4 (25.6,<br />
34.6)<br />
19.6 (16.9,<br />
24.2)<br />
CI, confidence interval; EGFR, epidermal growth factor receptor; NC,<br />
non-calculable; OS, overall survival; PFS, progression-free survival<br />
Legal entity responsible for the study: AstraZeneca<br />
Funding: AstraZeneca<br />
Disclosure: M. Perol, J-F. Morère, J. Cadranel: Honoraria received from Astra Zeneca<br />
(Advisory Board) M. Licour: Employee <strong>of</strong> AstraZeneca. All other authors have declared<br />
no conflicts <strong>of</strong> interest.<br />
1245P<br />
Phase I, safety, tolerability and preliminary efficacy study <strong>of</strong><br />
tremelimumab (Trem) in combination with gefitinib (Gef) in<br />
EGFR-mutant (EGFR-mut) NSCLC (GEFTREM)<br />
D. Planchard 1 , F. Barlesi 2 , C. Gomez-Roca 3 , J. Mazieres 4 , A. Varga 5 , L. Greillier 2 ,<br />
N. Chaput 6 , C. Parlavecchio 7 , K. Malekzadeh 8 , M. Ngocamus 5 , S. Zahi 3 ,<br />
B. Besse 1 , E. Lanoy 8 , J-C. Soria 5<br />
1 Department <strong>of</strong> medical oncology, Institut Gustave Roussy, Villejuif, France,<br />
2 Multidisciplinary <strong>Oncology</strong> & Therapeutic Innovations, Aix Marseille University,<br />
Marseille, France, 3 Dept. Medical <strong>Oncology</strong>, Institut Universitaire du Cancer<br />
-Toulouse- Oncopole, Toulouse, France, 4 Thoracic <strong>Oncology</strong>, CHU Toulouse,<br />
Hôpital de Larrey, Toulouse, France, 5 Department <strong>of</strong> Medicine DITEP, Institut<br />
Gustave Roussy, Villejuif, France, 6 Laboratoire d’Immunomonitoring en Oncologie<br />
UMS 3655 CNRS / US 23 INSERM, Institut Gustave Roussy, Villejuif, France,<br />
7 Clinical research department, Institut Gustave Roussy, Villejuif, France,<br />
8 Department <strong>of</strong> biostatistics, Institut Gustave Roussy, Villejuif, France<br />
Background: A Phase I open-label multicenter study was initiated to evaluate the<br />
association <strong>of</strong> T-cell lymphocyte-4 (CTLA-4) inhibitor Trem with Gef in progressing<br />
EGFR-mut NSCLC (NCT02040064).<br />
Methods: Key inclusion criteria included advanced NSCLC with an EGFR-mut,<br />
progression after a response on any prior EGFR TKI (first line or beyond), adequate PS<br />
(0-1). The primary objective was to determine the safety and tolerability <strong>of</strong> the<br />
combination <strong>of</strong> Gef (oral 250mg once-daily) with escalating doses <strong>of</strong> Trem (starting<br />
dose <strong>of</strong> 3mg/kg IV every 4 weeks for 6 cycles and beyond every 12 weeks) and to<br />
establish a recommended phase 2 dose (RP2D). A rolling 6 design and a dose limiting<br />
toxicity (DLT) period <strong>of</strong> 42 days were applied. Three escalating doses <strong>of</strong> Trem were<br />
pre-planned (3, 6 and 10mg/kg).<br />
Results: Between January, 2014 and March, 2015, 26 stage IV pts (20pts in the<br />
escalating dose cohorts and 6 in expansion cohort pts at RP2D) received at least one<br />
dose <strong>of</strong> Trem (median age <strong>of</strong> 66 years, female 65%, never smoker 61% and 61% had<br />
received ≥2 lines). Previous line was an EGFR-TKI in 77% <strong>of</strong> pts. DLTs occurred in 5<br />
pts, 1 at 3mg/Kg (grade 3 colitis), 2 at 6mg/Kg (one grade 3 colitis and one AST-ALT<br />
increase grade 3 in expansion cohort) and 2 at 10mg/Kg (one grade 3 diarrhea and one<br />
AST-ALT increase grade 3) <strong>of</strong> Trem. All toxicities were reversible with discontinuation<br />
<strong>of</strong> Trem. Most common (≥20%) adverse events (AEs/grade 3-4 AEs) were diarrhea<br />
(92%/27%), asthenia (77%/4%), dry skin (54%/4%), nausea (38%/4%), anorexia (27%/<br />
8%), dyspnea (42%/0%), colitis (19%/4%), and vomiting (27%/4%). No pneumonitis or<br />
increases in cutaneous toxicity related to treatments were observed. Twenty four pts<br />
were evaluable for response. The best overall response was stable disease in 67% <strong>of</strong> pts<br />
(18/24pts, 69% at 3mg/Kg, 50% at 6mg/Kg and 80% at 10mg/Kg). All pts discontinued<br />
treatment after median duration <strong>of</strong> 8 weeks (range: 2 to 77 weeks), most frequently due<br />
to disease progression (60% <strong>of</strong> pts).<br />
Conclusions: The recommended dose <strong>of</strong> Trem in phased combination with Gef in<br />
EGFR-mut pts with NSCLC was identified as 3mg/kg. Antitumor activity was stable<br />
disease in two thirds <strong>of</strong> pts. The safety pr<strong>of</strong>ile was consistent with the previously<br />
defined AE pr<strong>of</strong>ile.<br />
Clinical trial identification: NCT02040064<br />
Legal entity responsible for the study: Gustave Roussy<br />
Funding: Gustave Roussy was the sponsor and coordinator <strong>of</strong> this trial. This research<br />
was conducted with support from AstraZeneca.<br />
Disclosure: D. Planchard: Advisory Board : Astrazeneca, Boehringer, Pfizer, Roche,<br />
BMS, Merck, Novartis, San<strong>of</strong>i-aventis, Lilly, Clovis. F. Barlesi:<br />
Astrazeneca. C. Gomez-Roca: advisory board San<strong>of</strong>i and Novartis. J. Mazieres,<br />
L. Greillier: advisory board Atrazeneca. A. Varga, J-C. Soria: advisory board Atrazeneca<br />
and Clovis. B. Besse: Research grants from Astrazeneca. All other authors have declared<br />
no conflicts <strong>of</strong> interest.<br />
1246P<br />
abstracts<br />
Adjusted indirect comparison using propensity score<br />
matching <strong>of</strong> osimertinib to doublet chemotherapy in patients<br />
with EGFRm T790M NSCLC who have progressed after<br />
EGFR-TKI<br />
F. Andersohn 1 , H. Mann 2 , T. Mitsudomi 3 , T.S.K. Mok 4 , J. Chih-Hsin Yang 5 ,<br />
K. Papadakis 6 , C. Hoyle 6<br />
1 Frank Andersohn Consulting & Research Services, Berlin, Germany, Institute for<br />
Social Medicine, Epidemiology and Health Economics, Charite University<br />
Medicine, Berlin, Germany, 2 B&I, AstraZeneca, Cambridge, UK, 3 Department <strong>of</strong><br />
Surgery, Division <strong>of</strong> Thoracic Surgery, Kinki University Faculty <strong>of</strong> Medicine,<br />
Osaka-Sayama, Japan, 4 State Key Laboratory <strong>of</strong> South China, Hong Kong Cancer<br />
Institute, Department <strong>of</strong> Clinical <strong>Oncology</strong>, The Chinese University <strong>of</strong> Hong Kong,<br />
Prince <strong>of</strong> Wales Hospital, Sha Tin, Hong Kong PRC, 5 Department <strong>of</strong> <strong>Oncology</strong> and<br />
Department <strong>of</strong> Medical Research, National Taiwan University Hospital, Taipei City,<br />
Taiwan, 6 Global Payer Evidence and Pricing, AstraZeneca, Cambridge, UK<br />
Background: In the absence <strong>of</strong> randomized data comparing osimertinib to<br />
platinum-based doublet chemotherapy (PBDC) in patients (pts) with metastatic<br />
epidermal growth factor receptor (EGFRm) T790M non-small cell lung cancer<br />
(NSCLC) who have progressed after EGFR-TKI, an adjusted indirect comparison can<br />
<strong>of</strong>fer a robust estimate <strong>of</strong> treatment effect. The IMPRESS study placebo arm (PBDC)<br />
(data cut-<strong>of</strong>f [DCO] 2014 May) included a subgroup <strong>of</strong> pts with the T790M mutation<br />
and disease progression following response to EGFR-TKI. Pts had similar demographic<br />
and disease characteristics as those in AURA extension (NCT01802632) and AURA2<br />
(NCT02094261) trials <strong>of</strong> osimertinib (DCO May 2015), and therefore represent a valid<br />
comparator to demonstrate differences in outcomes.<br />
Methods: The efficacy <strong>of</strong> osimertinib relative to PBDC was assessed using an adjusted<br />
indirect comparison <strong>of</strong> two non-randomized data sets comprising pts with a confirmed<br />
T790M mutation (by tissue or plasma ctDNA respectively): AURA (N = 405) and<br />
IMPRESS placebo arm (N = 60). A propensity score (PS) approach was used to adjust<br />
for differences in baseline demographics and disease characteristics. Baseline<br />
characteristics <strong>of</strong> both groups were compared using statistical tests. The PS model<br />
included 22 variables with P < 0.2. Only pts within the PS distributions <strong>of</strong> both<br />
treatment groups were included in the final analyses. To adjust for remaining<br />
differences between the groups, PS was incorporated as a covariate in the treatment<br />
comparison <strong>of</strong> osimertinib relative to PBDC for each endpoint.<br />
Results: Following estimation <strong>of</strong> PS for each pt and balancing across the groups<br />
(osimertinib N = 287, PBDC N = 51) osimertinib demonstrated: A statistically<br />
significant improvement in median progression-free survival (PFS) <strong>of</strong> 9.7 months vs<br />
5.3 months (HR 0.28, 95% CI 0.19–0.42, P < 0.0001) An improvement in objective<br />
response rate (ORR) <strong>of</strong> 64.6% vs 34.8% (OR 4.76, 95% CI 2.21–10.26, P < 0.001).<br />
Conclusions: In this indirect comparison, a statistically significant improvement in<br />
PFS and ORR was demonstrated for osimertinib compared to PBDC. AURA3 will<br />
provide a randomized comparison <strong>of</strong> osimertinib and PBDC.<br />
Legal entity responsible for the study: AstraZeneca<br />
Funding: AstraZeneca<br />
Disclosure: F. Andersohn: Consultancy fees from AstraZeneca. H. Mann, C. Hoyle:<br />
AstraZeneca employee and stock in AstraZeneca. T. Mitsudomi: Membership on<br />
advisory boards for AstraZeneca, Chugai, Boehringer Ingelheim, Roche and Pfizer.<br />
Corporate-sponsored research for Boehringer Ingelheim, Chugai and Pfizer. No stock<br />
ownership or other substantive relationships. T.S.K. Mok: Advisory boards: AZ, Roche,<br />
Pfizer, EliLilly, BI, MerckSerono, MSD, Janssen, Clovis, Bio Marin, GSK, Novartis, SFJ,<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw383 | vi435
abstracts<br />
ACEA, Vertex, Aveo&Biodesix, BMS, geneDecode, OncoGenex. Grants: AZ, BI, Pfizer,<br />
Novartis, SFJ, Roche, MSD, Clovis, BMS. Stock: Sanomics. Other: Prime<strong>Oncology</strong>,<br />
Amgen, PeerVoice. J. Chih-Hsin Yang: Advisory boards: Boehringer Ingelheim, Eli<br />
Lilly, Bayer, Roche / Genentech / Chugai, AstraZeneca, Astellas, MSD, Merck Serono,<br />
Pfizer, Novartis, Clovis <strong>Oncology</strong>, Celgene, Innopharma&Merrimack. No stock<br />
ownership, research grants or other substantive relationships. K. Papadakis: Employee<br />
<strong>of</strong> AstraZeneca. No stock ownership or other substantive relationships.<br />
1247P<br />
Monitoring <strong>of</strong> EGFRm level in cfDNA in patients with<br />
advanced NSCLC on the gefitinib therapy<br />
D.D. Sakaeva 1 , M. Gordiev 2 , M. Blokhina 1<br />
1 Chemotherapy department, Republican Clinical <strong>Oncology</strong> Center - Ufa, Ufa,<br />
Russian Federation, 2 Molecular genetic laboratory, Kazan Clinical <strong>Oncology</strong><br />
Center, Kazan, Russian Federation<br />
Background: The aims in this study were to evaluate level <strong>of</strong> EGFR mutations in<br />
plasma in advanced NSCLC on the treatment with TKIs in the 1 st and 2 nd lines, to<br />
compare mutation status in FFPE tissue and plasma samples and to evaluate diagnostic<br />
characteristics <strong>of</strong> real-time wild-type blocking PCR (LNA-clamp) assay and digital<br />
PCR (dPCR).<br />
Methods: Analysis was carried out in 2 groups: in the 1 st group patients received<br />
gefitinib in the 1st line (n = 22), in the 2 nd group- in the 2nd line (n = 13). Detection <strong>of</strong><br />
EGFR mutation in cfDNA was conducted prior to the target therapy and during this<br />
treatment in both groups. Some patients (n = 14) were enrolled 2-23 months after the<br />
start <strong>of</strong> therapy and EGFRm status prior to the gefitinib administration was not<br />
estimated. Plasma samples for detection <strong>of</strong> del19, L858R and T790M mutations were<br />
collected monthly prior to the next therapy cycle. EGFR mutation status was assessed<br />
using 2 methods - allele-specific PCR with the modifications (TaqMan-LNA,<br />
Real-time) and QuantStudio 3D Digital PCR.<br />
Results: A month after the start <strong>of</strong> the gefitinib administration, the EGFR mutations<br />
status in plasma has become negative in all patients. Negative EGFR mutations status<br />
persisted until progression. In total, progression has occurred in 19 (54%) patients. In 7<br />
(36,8%) <strong>of</strong> them it correlated with T790M mutation appearance, in 4 (21,1%)- with<br />
both T790M and activating EGFR mutation appearance, in 2 (10,5%)- with only<br />
activating mutation reappearance and in 6 (31,6%) patients EGFR mutation status<br />
persisted negative. The mean value <strong>of</strong> EGFR+ cfDNA prior the 1 st line <strong>of</strong> therapy was<br />
statistically higher than in progression and prior to the 2 nd line: 1,88% (95% CI:<br />
1,14;2.62), 0,3% (95% CI: 0.04;0.56) p < 0,05 and 0,6%(95% CI:0,28;0,92) p < 0,05<br />
respectively. After comparing the EGFR mutations status in plasma and tumor samples<br />
concordance was 88.7%, sensitivity– 83.3%, specificity– 100%, PPV– 100%. Digital<br />
PCR has demonstrated the best analytical sensitivity for EGFR mutations detection in<br />
plasma, whereas concordance with real-time PCR was 100%.<br />
Conclusions: Change <strong>of</strong> EGFR mutation level in cfDNA can be used as a marker <strong>of</strong><br />
efficacy <strong>of</strong> EGFR-TKIs therapy and as a progression predictor.<br />
Legal entity responsible for the study: Republican Clinical <strong>Oncology</strong> Center - Ufa,<br />
Kazan Clinical <strong>Oncology</strong> Center<br />
Funding: Republican Clinical <strong>Oncology</strong> Center - Ufa, Kazan Clinical <strong>Oncology</strong> Center<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1248P<br />
Discordance <strong>of</strong> EGFR mutation status between primary lung<br />
adenocarcinomas and corresponding metastatic tumors and<br />
the sensitivity to EGFR tyrosine kinase inhibitors<br />
H.S. Han 1 , J. Yang 2 , M.K. Choi 2 , J. Kwon 2 , K.H. Lee 1 , O-J. Lee 3<br />
1 Department <strong>of</strong> Internal Medicine, College <strong>of</strong> Medicine, Chungbuk National<br />
University, Cheongju, Republic <strong>of</strong> Korea, 2 Department <strong>of</strong> Internal Medicine,<br />
Chungbuk National University Hospital, Cheong-ju, Republic <strong>of</strong> Korea,<br />
3 Department <strong>of</strong> Pathology, College <strong>of</strong> Medicine, Chungbuk National University,<br />
Cheong-ju, Republic <strong>of</strong> Korea<br />
Background: A considerable proportion <strong>of</strong> non-small cell lung cancer has showed a<br />
discrepancy in epidermal growth factor receptor (EGFR) mutations between matched<br />
primary and metastatic tumors. The aim <strong>of</strong> this study was to clarify the distribution <strong>of</strong><br />
EGFR mutations in primary lung adenocarcinomas and corresponding metastatic<br />
tumors with highly sensitive method <strong>of</strong> detecting EGFR mutations and to identify a<br />
better predictive marker <strong>of</strong> the response to EGFR tyrosine kinase inhibitors.<br />
Methods: We performed peptide nucleic acid-mediated real-time polymerase chain<br />
reaction clamping to identify EGFR mutations in paired primary lung<br />
adenocarcinomas and metastatic tumors in 24 patients who were treated with EGFR<br />
tyrosine kinase inhibitors, but had not received EGFR tyrosine kinase inhibitors before<br />
both primary and metastatic tissues were sampled.<br />
Results: EGFR mutations were detected in 20 primary lung adenocarcinomas (83.3%)<br />
and in 19 corresponding metastatic tumors (79.2%). EGFR mutations showed a<br />
discordance rate <strong>of</strong> 20.8% (5 <strong>of</strong> 24 patients) between primary lung adenocarcinomas<br />
and corresponding metastatic tumors. Three patients with EGFR-mutated primary<br />
tumors lost their mutations in the metastatic tumors and showed no response to EGFR<br />
tyrosine kinase inhibitors. Two patients had EGFR mutations in the metastatic tumors<br />
but not in the primary lung adenocarcinomas and experienced a partial response to<br />
EGFR tyrosine kinase inhibitors.<br />
Conclusions: EGFR mutations were discordant between matched primary and<br />
metastatic tumors before EGFR tyrosine kinase inhibitor therapy in a significant<br />
portion <strong>of</strong> lung adenocarcinomas. Our findings suggest that the EGFR mutation status<br />
<strong>of</strong> metastatic tumors in patients with metastatic lung adenocarcinoma is a predictive<br />
marker <strong>of</strong> the response to EGFR tyrosine kinase inhibitors. EGFR tyrosine kinase<br />
inhibitors are used to treat metastatic disease, therefore, a more aggressive pursuit <strong>of</strong><br />
tissue sampling from metastatic lesions may be indicated to accurately determine<br />
EGFR mutations for planning <strong>of</strong> the use <strong>of</strong> EGFR tyrosine kinase inhibitors to treat<br />
metastatic lung adenocarcinoma.<br />
Legal entity responsible for the study: College <strong>of</strong> Medicine, Chungbuk National<br />
University Chungbuk National University Hospital<br />
Funding: College <strong>of</strong> Medicine, Chungbuk National University Chungbuk National<br />
University Hospital<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1249P<br />
Detection <strong>of</strong> EGFR T790M resistance mutation: real-time<br />
allele-specific PCR versus Sanger sequencing<br />
S.Y. Hor, K.S. Chan, E.X. Chen, M. Goh, L.L.E. Oon<br />
Pathology, Singapore General Hospital, Singapore<br />
Background: Lung cancer is the most common cause <strong>of</strong> death from cancer worldwide,<br />
and 85-90% <strong>of</strong> lung cancers are non-small cell lung cancer (NSCLC). Presence <strong>of</strong><br />
driver mutations in epidermal growth cell receptor (EGFR) gene in a subset <strong>of</strong> NSCLC<br />
has led to the use <strong>of</strong> tyrosine kinase inhibitors (TKI) that inhibit the EGFR signalling<br />
pathway. Tumours which harbour certain EGFR mutations may exhibit initial response<br />
to EGFR-TKIs, but many will develop resistance mutations post-treatment, commonly<br />
at amino acid position 790 (T790M) <strong>of</strong> exon 20. Newer EGFR inhibitors with activity<br />
against T790M-mutated NSCLC have recently been made available. Accurate detection<br />
<strong>of</strong> T790M in patients whose disease progressed on initial TKI therapy is thus vital for<br />
subsequent management. Here, we evaluated the performance <strong>of</strong> Sanger sequencing in<br />
detecting T790M mutation against a real-time allele-specific PCR.<br />
Methods: Ninety-six FFPE samples sent to our laboratory for T790M mutation<br />
detection by cobas® EGFR Mutation test (Roche), between July 2014 and March 2016<br />
were included in this study. Archived extracts were used for Sanger sequencing <strong>of</strong><br />
EGFR exon 20 using an in-house developed protocol.<br />
Results: T790M was detected in 49.5% (47/95) and 47.9% (46/96) <strong>of</strong> the samples by<br />
the cobas® assay and Sanger sequencing respectively. Taking cobas® assay as the gold<br />
standard for 95 samples with valid real-time PCR results, Sanger sequencing yielded a<br />
sensitivity <strong>of</strong> 95.7% (45/47) and specificity <strong>of</strong> 100% (48/48). Of the 3 discordant results,<br />
cobas® assay detected T790M in 2 samples (both with tumour contents
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
Methods: 461 advanced EGFR-wt NSCLC patients enrolled from Area Vasta Romagna<br />
between January 2013 to December 2014 were included in the study. KRAS, BRAF,<br />
ERBB2, PIK3CA, NRAS, ALK, MAP2K1, RET and DDR2 mutations were analyzed by<br />
Myriapod®Lung Status kit (Diatech Pharmacogenetics) on Maldi-TOF Mass<br />
Spectrometry (MassARRAY® AGENA BIOSCIENCE). ERBB4 was evaluated by direct<br />
sequencing and EML4-ALK and ROS1 rearrangements were assessed by<br />
immunohistochemistry or fluorescence in situ hybridization.<br />
Results: 217 (47%) patients showed at least one alteration. In particular, 71%, 6.5%,<br />
2.7%, 1.8%, 1.4% and 1.4% patients had mutations in KRAS, BRAF, PIK3CA, NRAS,<br />
ERBB2 and MAP2K1 genes, respectively. Only one (0.5%) patient showed a mutation<br />
in ERBB4 gene. EML4-ALK and ROS1 rearrangements were observed in 10.6% and<br />
4.1% patients, respectively. The clinical characteristics <strong>of</strong> mutated patients are reported<br />
in Table 1. Overlapping mutations were observed in 5 (2.3%) KRAS-mutated patients:<br />
one (20%) was mutated in PIK3CA, 3 (60%) showed an EML4-ALK translocation and<br />
one (20%) had a ROS1 rearrangement. One (0.5%) patient showed both BRAF and<br />
PIK3CA alterations. Correlation analyses between the different mutations and patient<br />
outcome are ongoing. Table.<br />
Gene<br />
No. <strong>of</strong><br />
mutated<br />
patients<br />
Table: 1250P<br />
Age Gender Smoking Habits<br />
abstracts<br />
Conclusions: For advanced NSCLC patients effectively treated with EGFR-TKIs,<br />
concurrent with individualized bone metastases lesions RT shows a favorable safety<br />
pr<strong>of</strong>ile and promising outcome, therefore can serve as a therapeutic option for<br />
advanced NSCLC patients with only bone oligometastases progression.<br />
Legal entity responsible for the study: Henan Province Anti-cancer Hospital<br />
Funding: Henan Province Anti-cancer Hospital<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1254P<br />
Tyrosine kinase inhibitors alone as a first-line treatment for<br />
patients with non-small-cell lung cancer harboring mutant<br />
epidermal growth factor receptor<br />
T. Iuchi 1 , M. Shingyoji 2 , M. Itakura 2 , Y. Hasegawa 1 , Y. Yoshida 2 , S. Ikegami 1 ,<br />
T. Setoguchi 1 , H. Ashinuma 2<br />
1 Neurological Surgery, Chiba Cancer Center Hospital, Chiba, Japan, 2 Respirology,<br />
Chiba Cancer Center Hospital, Chiba, Japan<br />
Background: Brain metastases (BMs) are a frequent complication <strong>of</strong> non-small-cell<br />
lung cancer (NSCLC). Whole brain radiation therapy (WBRT) is a standard treatment<br />
for BMs, but favorable response <strong>of</strong> BMs with mutant epidermal growth factor receptor<br />
(EGFR) against tyrosine kinase inhibitors (TKIs) have also been reported. The aim <strong>of</strong><br />
this study is to clarify the effect <strong>of</strong> TKIs alone without radiation therapy for BMs from<br />
EGFR-mutant NSCLC.<br />
Methods: BMs from NSCLC with EGFR-mutation were enrolled. Gefitinib was<br />
administrated first, and erlotinib or afatinib was used at tumor progression. Erlotinib<br />
(or afatinib) was also selected for patients whose BMs had developed after gefitinib (or<br />
erlotinib). The primary endpoint was overall survival after BM (OS), and the secondary<br />
endpoints were maximum response to TKIs, time to progression <strong>of</strong> intracranial lesions,<br />
and time to salvage radiation therapy (RT).<br />
Results: In this study, 108 patients with BMs were enrolled. The types <strong>of</strong> mutations<br />
were as follows: exon 19 deletion in 62, exon 20 L858R in 39, and other types <strong>of</strong><br />
mutations in 7 cases. During the follow-up period, 70 deaths were observed but only 17<br />
<strong>of</strong> these deaths were owing to the progression <strong>of</strong> intracranial lesions. The medium OS<br />
was 20.9 months. The response rates <strong>of</strong> first-line and second-line TKIs were 76.9% and<br />
70.6%, respectively. The medium time to progression <strong>of</strong> intracranial lesions was 14.5<br />
months, and medium time to salvage RT was 19.0 months. Among the patients,<br />
gefitinib was administrated in 83 (first-line) and erlotinib in 59 (fist-line:22,<br />
second-line, 37) cases. The response rates <strong>of</strong> gefitnib and erlotinib were 76.8% and<br />
78.6%, and the time to progression <strong>of</strong> intracranial lesions after gefitinib and erlotinib<br />
were 13.9 and 20.3 months, respectively. We could not find any significantly different<br />
response <strong>of</strong> BMs to TKIs owing to the types <strong>of</strong> mutations.<br />
Conclusions: TKIs showed favorable control <strong>of</strong> BMs harboring EGFR-mutation<br />
without RT. At progression, other types <strong>of</strong> TKIs still showed excellent effect. TKIs first<br />
treatment could postpone RT, and feasible for BMs from EGFR-mutant NSCLC.<br />
Legal entity responsible for the study: Chiba Cancer Center<br />
Funding: JSPS KAKENHI grant<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1255P<br />
Next generation sequencing identifies actionable mutations<br />
in EGFR-wild type and KRAS mutant non-small cell lung<br />
cancer patients<br />
A. Voutsina 1 , A. Kalikaki 1 , A. Koutsopoulos 2 , M. Sfakianaki 1 , M. Trypaki 1 ,<br />
E. Tsakalaki 1 , S. Agelaki 3 , V. Georgoulias 4 , D. Mavroudis 3<br />
1 Laboratory <strong>of</strong> Translational <strong>Oncology</strong>, School <strong>of</strong> Medicine, University <strong>of</strong> Crete,<br />
Heraklion, Greece, 2 Pathology, School <strong>of</strong> Medicine, University <strong>of</strong> Crete, Heraklion,<br />
Greece, 3 Medical <strong>Oncology</strong>, Laboratory <strong>of</strong> Translational <strong>Oncology</strong>, University<br />
Hospital <strong>of</strong> Heraklion, Heraklion, Greece, 4 Medical <strong>Oncology</strong>, Hellenic <strong>Oncology</strong><br />
Research Group (HORG), Athens, Greece<br />
Background: Identification <strong>of</strong> actionable mutations in patients’ tumors is essential in<br />
guiding therapy. The aims <strong>of</strong> this study were: a) to validate mutation detection by<br />
next-generation sequencing (NGS) in a cohort <strong>of</strong> NSCLC patients and b) to identify<br />
molecular subgroups within EGFR wild-type and KRAS mutant NSCLCs<br />
Methods: We used the Ion Torrent AmpliSeq Colon and Lung cancer panel to analyze<br />
formalin-fixed paraffin-embedded tumors from 76 NSCLC patients previously tested<br />
for EGFR mutations by Sanger Sequencing. The sensitivity <strong>of</strong> the method was assessed<br />
by using commercial reference FFPE standards with defined allelic frequencies. DNA<br />
was isolated from microdissected tumor tissue and sequencing was performed in the<br />
Ion PGM platform.<br />
Results: Tumors were sequenced to a median coverage <strong>of</strong> 650X. The sensitivity <strong>of</strong><br />
mutation detection was estimated at 4% and for mutation reporting we have used a<br />
baseline prevalence <strong>of</strong> ≥5%. Precision <strong>of</strong> the method was demonstrated by analyzing<br />
four tumor specimens two times in different library preparations and runs. A complete<br />
concordance was observed between the previously defined Sanger genotypes and the<br />
corresponding variants detected using NGS. A single mutation was detected in 30 <strong>of</strong> 76<br />
(39.5%) specimens, two in an additional 30 (39.5%) whereas mutations in more than<br />
two genes were detected in 11 (14.5%). The most frequently mutated genes were TP53<br />
(41/76; 54%) and KRAS (23/76; 30%). Among KRAS mutated tumors, 3 (13%) carried<br />
STK11, 2 (8.7%) kinase inactivating BRAF mutations and one (4.4%) the BRAF V600E.<br />
Between the EGFR/KRAS wild type tumors, 5 (13%) had a mutation in the PI3K<br />
pathway, 3 (7.3%) carried mutations in MET, 2 (4.9%) had the BRAF V600E and 6<br />
(14.6%) carried STK11 loss <strong>of</strong> function mutations<br />
Conclusions: NGS can be used for molecular diagnostics in NSCLC and may detect<br />
additional mutated pathways that can be targeted using novel therapies<br />
Legal entity responsible for the study: Medical School, University <strong>of</strong> Crete<br />
Funding: University <strong>of</strong> Crete<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1256P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Hypomagnesaemia and its management following treatment<br />
with anti-epidermal growth factor receptor (EGFR)<br />
monoclonal antibodies (mAbs): Results from 3 randomized<br />
studies <strong>of</strong> necitumumab (NECI) plus chemotherapy in<br />
first-line treatment <strong>of</strong> patients with stage IV non-small cell<br />
lung cancer (NSCLC)<br />
E. Vokes 1 , M. Socinski 2 , D.R. Spigel 3 , L. Paz-Ares 4 , R. Kurek 5 , S. Nanda 6 ,<br />
G. Grau 5 , J. Shahidi 7 , N. Thatcher 8 , D. Gandara 9<br />
1 Dept. <strong>of</strong> Medicine, The University <strong>of</strong> Chicago Medical Centre, Chicago, IL, USA,<br />
2 Medical <strong>Oncology</strong>, University <strong>of</strong> Pittsburgh UPMC Cancer Pavilion, Pittsburgh,<br />
PA, USA, 3 <strong>Oncology</strong>, Sarah Cannon Research Institute, Nashville, TN, USA,<br />
4 Medical <strong>Oncology</strong>, Hospital Universitario Doce de Octubre, Madrid, Spain,<br />
5 Global Medical Leader, Lilly Deutschland GmbH, Bad Homburg, Germany,<br />
6 Statistics- <strong>Oncology</strong>, Eli Lilly and Company, Bridgewater, NJ, USA, 7 <strong>Oncology</strong>, Eli<br />
Lilly and Company, Bridgewater, NJ, USA, 8 Medical <strong>Oncology</strong>, The Christie NHS<br />
Foundation Trust, Manchester, UK, 9 Internal Medicine, University <strong>of</strong> California<br />
Davis Cancer Center, Sacramento, CA, USA<br />
Background: Hypomagnesaemia is a known side effect <strong>of</strong> certain chemotherapies and<br />
an established class effect <strong>of</strong> EGFR mAbs. We present analyses <strong>of</strong> hypomagnesaemia<br />
and its management from 3 clinical trials <strong>of</strong> NECI, a human IgG1 anti-EGFR mAb<br />
recently approved in the US and the EU for the treatment <strong>of</strong> advanced squamous<br />
NSCLC.<br />
Methods: Three randomized global trials <strong>of</strong> 1st-line treatment for stage IV NSCLC<br />
were included in this analysis. SQUIRE (N = 1079) and INSPIRE (N = 616) were phase<br />
3 trials <strong>of</strong> gemcitabine (Gem)-cisplatin (Cis) +/- NECI in squamous NSCLC and<br />
pemetrexed (Pem)-Cis +/- NECI in non-squamous NSCLC, respectively. JFCL<br />
(N = 161) was a phase 2 trial <strong>of</strong> paclitaxel (Pac)-carboplatin (Carbo) +/- NECI in<br />
squamous NSCLC. Per protocols, hypomagnesaemia was managed by investigators<br />
based on local guidelines. Hypomagnesaemia frequency was assessed based on<br />
reported adverse events (AEs) and lab data.<br />
Results: Hypomagnesaemia was reported as an AE more frequently in the NECI arms<br />
as compared to the control arms. SQUIRE: NECI + Gem-Cis 31.2% (9.3% grade ≥3)<br />
vs. Gem-Cis 15.7% (1.1%); INSPIRE: NECI + Pem-Cis 26.6% (7.6%) vs. Pem-Cis<br />
12.8% (2.2%); JFCL: NECI + Pac-Carbo 24.5% (5.7%) vs. Pac-Carbo 12.7% (0%).<br />
Hypomagnesaemia rates based on lab values were higher as compared to reported AEs<br />
across trials and in both arms. A small number <strong>of</strong> patients discontinued treatment due<br />
to hypomagnesaemia (0.6% SQUIRE, 0% INSPIRE and JFCL). In SQUIRE, no clear<br />
association was seen between hypomagnesaemia and hypokalemia or cardiac events.<br />
Magnesium levels gradually reduced over time and stabilized. Magnesium<br />
supplementation was given to 31% and 16.7% <strong>of</strong> patients with hypomagnesaemia<br />
based on lab data for NECI + Gem-Cis and Gem-Cis, respectively.<br />
Conclusions: Hypomagnesaemia is a common side effect <strong>of</strong> the combinations <strong>of</strong><br />
chemotherapy with NECI, especially Cis-containing regimens. Our data suggest that<br />
hypomagnesaemia may be underreported and perhaps undertreated. Close monitoring<br />
<strong>of</strong> magnesium levels and prompt repletion is recommended.<br />
Clinical trial identification: NCT00981058; NCT00982111; NCT01769391<br />
Legal entity responsible for the study: Eli Lilly and Company<br />
Funding: Eli Lilly and Company<br />
Disclosure: E. Vokes: Eli Lilly and Company – Consultant. M. Socinski: Eli Lilly and<br />
Company - Steering Committee Member. L. Paz-Ares: Scientific advice (Roche, Eli<br />
Lilly and Company, Astra Zeneca, Merck Sharp, Boehringer Ing., Bristol Meyers<br />
Squibb, Pfizer, Clovis <strong>Oncology</strong>, Novartis, Bayer, Amgen). R. Kurek, S. Nanda,<br />
G. Grau, J. Shahidi: Eli Lilly and Company – Employee. N. Thatcher: Advisory Speaker<br />
- Eli Lilly and Company, Genentech, and AstraZeneca. D. Gandara: Eli Lilly and<br />
Company - Consultant and/or Advisor. All other authors have declared no conflicts <strong>of</strong><br />
interest.<br />
vi438 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
1257P<br />
Tepotinib plus gefitinib in patients with c-Met-positive/<br />
EGFR-mutant NSCLC: Recommended phase II dose (RP2D),<br />
tolerability, and efficacy<br />
Y-L. Wu 1 , R. Soo 2 , D-W. Kim 3 , J. Yang 4 , U. Stammberger 5 , W. Chen 6 ,<br />
G. Locatelli 5 , K. Park 7<br />
1 Guangdong Lung Cancer Institute, Guangdong General Hospital, Guangzhou,<br />
China, 2 Cancer Institute, National University Cancer Institute, Singapore,<br />
3 Department <strong>of</strong> Internal Medicine, Seoul National University Hospital<br />
(SNUH)-Yongon Campus, Seoul, Republic <strong>of</strong> Korea, 4 Department <strong>of</strong> <strong>Oncology</strong>,<br />
National Taiwan University Hospital, Taipei, Taiwan, 5 Global Clinical Development,<br />
Global Research and Development, Merck KGaA, Darmstadt, Germany, 6 Merck,<br />
Merck KGaA, Beijing, China, 7 Div <strong>of</strong> Hem/Onc, Dept <strong>of</strong> Med, Samsung Medical<br />
Center Sungkyunkwan University School <strong>of</strong> Medicine, Seoul, Republic <strong>of</strong> Korea<br />
Background: Patients (pts) with NSCLC treated with EGFR inhibitors (EGFRi)<br />
ultimately develop resistance, <strong>of</strong>ten through c-Met activation. Dual EGFR and c-Met<br />
inhibition is therefore a rational option to treat c-Met + , EGFRi-resistant NSCLC.<br />
Tepotinib is a highly selective c-Met inhibitor with good tolerability and promising<br />
efficacy against solid tumors. This phase Ib trial, conducted in Asia, examined tepotinib<br />
plus gefitinib in pts with c-Met + /EGFR-mutant NSCLC.<br />
Methods: Pts aged ≥18 years were eligible if they had locally advanced/metastatic<br />
NSCLC, ECOG PS 0–1, EGFR mutation confirmed by Therascreen EGFR RGQ PCR<br />
(Qiagen), and c-Met positivity determined by IHC using CONFIRM anti-c-Met mAb<br />
(SP44; Ventana/Roche). A 3 + 3 design was used with expansion at the RP2D. Pts<br />
received tepotinib 300 or 500 mg/day plus gefitinib 250 mg/day (T300G250 or<br />
T500G250). The primary objective was to determine the RP2D <strong>of</strong> tepotinib plus<br />
gefitinib; secondary objectives included pharmacokinetics (PK), safety, and antitumor<br />
activity.<br />
Results: 18 pts were enrolled (median age 65 [41–78], male 8). Pts had received a<br />
median <strong>of</strong> 2 (1–8) prior regimens including an EGFRi. 6 received T300G250, 12<br />
T500G250. No dose-limiting toxicities were observed, and tepotinib 500 mg/day was<br />
confirmed as the RP2D. T500G250 was associated with treatment-related grade ≥3<br />
increased amylase (n = 2), increased lipase (2), neutropenia (1) and hyperglycemia (1).<br />
No evidence <strong>of</strong> cumulative toxicity was noted. The best overall response was partial<br />
response in 5/18 pts, 4 with IHC 3+ tumors treated with T500G250 and 1 with an IHC<br />
2+ tumor (T300G250). 4/18 pts had stable disease (SD) (3 IHC 2+ [1 T300G250, 2<br />
T500G250], 1 IHC 3+ [T500G250]). PK were as expected based on historical<br />
comparisons.<br />
Conclusions: Tepotinib was well tolerated in combination with gefitinib; the RP2D <strong>of</strong><br />
tepotinib in combination with gefitinib in NSCLC is 500 mg/kg/day. Data show<br />
evidence <strong>of</strong> antitumor activity, with responses mainly in pts with c-Met IHC 3+ tumors<br />
and SD in pts with IHC 2+ tumors. A phase II trial is randomizing ∼136 pts with<br />
T790M–/c-Met+ tumors who have failed first-line gefitinib to tepotinib + gefitinib or<br />
cisplatin/pemetrexed.<br />
Clinical trial identification: NCT01982955<br />
Legal entity responsible for the study: Global Clinical Development Center Merck<br />
Serono (Beijing) Pharmaceutical R&D Co., Ltd<br />
Funding: Merck KGaA<br />
Disclosure: Y-L. Wu: Honoraria in the past two years from Roche, AstraZeneca, Eli<br />
Lilly, San<strong>of</strong>i. Research for Roche, AstraZeneca, Eli Lilly, Pfizer, Merck Serono, Novartis,<br />
BMS, ACEA Biosciences. R. Soo: Paid honoraria and consulted for AstraZeneca,<br />
Boehringer Ingelheim, Lilly, Merck, Novartis, Pfizer, Roche. Conducted research for<br />
AstraZeneca, Pfizer, Roche, Taiho, Merck-Serono, Novartis, Servier Bayer. J. Yang:<br />
Honoraria from AstraZeneca, Roche, Eli Lilly, Boehringer Ingelheim, Pfizer. Paid<br />
consultant to AstraZeneca, Roche/Genentech, Eli Lilly, Boehringer, Clovis, Novartis,<br />
Bayer, MSD, Merck, Pfizer, Astellas, Daichi-Sankyo, Celgene. Funder research<br />
Boehringer. U. Stammberger: Employee <strong>of</strong> Merck KGaA. W. Chen, G. Locatelli:<br />
Employee <strong>of</strong> Merck. K. Park: Advisory role for Astra Zeneca, Boehringer Ingeiheim,<br />
Clovis, Eli Lilly, Hanmi, ONO, Roche, in the past 2 years. Research for AstraZeneca. All<br />
other authors have declared no conflicts <strong>of</strong> interest.<br />
1258P<br />
Intercalated combination <strong>of</strong> chemotherapy and epidermal<br />
growth factor receptor inhibitors for patients with advanced<br />
non-small-cell lung cancer: A systematic review and<br />
meta-analysis<br />
A. Rossi 1 , A. La Salvia 2 , D. Galetta 3 , E. Gobbini 2 , E. De Luca 2 , S. Novello 2 ,M.Di<br />
Maio 2<br />
1 Division <strong>of</strong> Medical <strong>Oncology</strong>, Azienda Ospedaliera S. Giuseppe Moscati,<br />
Avellino, Italy, 2 Department <strong>of</strong> <strong>Oncology</strong>, Azienda Ospedaliero-Universitaria ASOU<br />
San Luigi Gonzaga, Orbassano, Italy, 3 Medical <strong>Oncology</strong> Department, Istituto<br />
Tumori Giovanni Paolo II, Bari, Italy<br />
Background: Trials investigating the efficacy <strong>of</strong> EGFR-tyrosine kinase inhibitors<br />
(TKIs) in combination with chemotherapy in unselected patients with advanced<br />
non-small-cell lung cancer (NSCLC) showed negative results. Preclinical data suggest<br />
that the intercalated administration could be effective. The aim <strong>of</strong> our study was to<br />
perform a systematic review and meta-analysis <strong>of</strong> randomized trials (RCTs) testing the<br />
addition <strong>of</strong> intercalated EGFR-TKIs to chemotherapy in patients with advanced<br />
NSCLC.<br />
Methods: A systematic review <strong>of</strong> articles published or presented at major meetings was<br />
performed in December 2015. RCTs comparing CT + intercalated EGFR TKI vs. CT<br />
alone in pts with advanced NSCLC were included. The primary outcome measure was<br />
overall survival (OS); secondary outcomes were progression-free survival (PFS),<br />
objective response rate (ORR) and toxicity.<br />
Results: 9 RCTs were eligible (5 with erlotinib, 4 with gefitinib): 37% <strong>of</strong> patients had<br />
known EGFR mutational status, and 46% were EGFR mutation-positive. Intercalated<br />
combination was associated with a significant improvement in OS (Hazard Ratio [HR]<br />
0.83, 95%CI 0.72-0.97, p = 0.02), PFS (HR 0.60, 95%CI 0.53-0.68, p < 0.00001) and<br />
ORR (Odds Ratio [OR] 2.69, 95%CI 2.07-3.50, p < 0.00001). Addition <strong>of</strong> EGFR-TKI<br />
produced a significant increase in skin rash (OR 4.60, 95%CI 3.46–6.11, p < 0.0001)<br />
and diarrhea (OR 2.73, 95%CI 1.93-3.87, p < 0.0001). Considering only first-line trials,<br />
similar differences were shown in OS (HR 0.85, 95%CI 0.72-1.00, p = 0.05), PFS (HR<br />
0.63, 95%CI 0.55-0.73, p < 0.00001), ORR (OR 2.21, 95%CI 1.65-2.95, p < 0.00001). In<br />
EGFR mutated patients, addition <strong>of</strong> intercalated EGFR-TKI produced a significant<br />
benefit in PFS (HR 0.24, 95%CI 0.16-0.37, p < 0.00001) and ORR (OR 11.59, 95%CI<br />
5.54-24.25, p < 0.00001).<br />
Conclusions: The addition <strong>of</strong> intercalated EGFR-TKI to chemotherapy is associated<br />
with a significant benefit in OS, PFS and objective response rate in patients with<br />
advanced NSCLC, although a definitive interpretation is jeopardized by the variable<br />
proportion <strong>of</strong> patients with EGFR mutation-positive tumors included.<br />
Legal entity responsible for the study: University <strong>of</strong> Turin<br />
Funding: University <strong>of</strong> Turin<br />
Disclosure: A. Rossi: Honoraria as speaker bureau for Roche, BoehringerIngelheim,<br />
AstraZeneca, and advisory board member for AstraZeneca and Eli-Lilly. D. Galetta:<br />
Advisory board member for BoehringerIngelheim and Eli-Lilly. S. Novello: Honoraria<br />
as speaker bureau for Roche, BoehringerIngelheim, AstraZeneca, and Eli-Lilly. M. Di<br />
Maio: Honoraria as speaker bureau for BoehringerIngelheim, AstraZeneca, Eli-Lilly<br />
and advisory board member for AstraZeneca and Eli-Lilly. All other authors have<br />
declared no conflicts <strong>of</strong> interest.<br />
1259P<br />
abstracts<br />
Differential efficacy <strong>of</strong> cisplatin plus pemetrexed between<br />
L858R and Del-19 in advanced EGFR-mutant non-squamous<br />
non-small cell lung cancer<br />
T. Kaneda 1 , H. Yoshioka 1 , M. Tamiya 2 , A. Tamiya 3 ,A.Hata 4 , A. Okada 5 , T. Niwa 1 ,<br />
T. Shiroyama 2 , M. Kanazu 3 , T. Ishida 1 , N. Katakami 4<br />
1 Department <strong>of</strong> Respiratory Medicine, Kurashiki Central Hospital, Kurashiki, Japan,<br />
2 Department <strong>of</strong> Thoracic Malignancy, Osaka Prefectural Medical Center for<br />
Respiratory and Allergic Diseases, Habikino, Japan, 3 Department <strong>of</strong> Internal<br />
Medicine, Kinki-chuo Chest Medical Center, Sakai, Japan, 4 Division <strong>of</strong> Integrated<br />
<strong>Oncology</strong>, Institute <strong>of</strong> Biomedical Research and Innovation, Kobe, Japan,<br />
5 Department <strong>of</strong> Respiratory Medicine, Saiseikai Suita Hospital, Suita, Japan<br />
Background: Combined analysis from two randomized phase 3 trials showed afatinib<br />
improved overall survival (OS) compared with platinum doublets in patients with Exon<br />
19 deletion (Del-19) mutation. However, in patients with Leu858Arg (L858R) point<br />
mutation, afatinib efficacy did not differ significantly from chemotherapy. We<br />
hypothesized that this discrepancy was due to differential efficacy <strong>of</strong> cisplatin plus<br />
pemetrexed between Del-19 and L858R.<br />
Methods: This study is a multicenter retrospective study. We reviewed medical records<br />
<strong>of</strong> patients who had received cisplatin plus pemetrexed as first line chemotherapy.<br />
Efficacies were evaluated among epidermal growth factor receptor (EGFR) mutation<br />
status: Del-19; L858R; and wild type.<br />
Results: Among 304 patients, 78 (25.7%) harbored EGFR mutations: Del-19 (36/78<br />
patients, 46.2%); and L858R (42/78, 53.8%). Median PFS <strong>of</strong> L858R group (9.4 months,<br />
95% confidence interval [CI]: 7.0-12.6) was significantly longer than Del-19 group (5.5<br />
months, 95% CI: 3.6-8.6) (p = 0.049). Response rate (RR) and OS presented no<br />
significant difference among L858R, Del-19 or wild type. In multivariate analysis,<br />
EGFR mutation status (L858R versus Del-19) was the only significant factor for longer<br />
PFS (Hazard ratio [HR]: 0.78, 95% CI: 0.62-0.98) (p = 0.033).<br />
Conclusions: Our study indicated better efficacy <strong>of</strong> cisplatin plus pemetrexed in L858R<br />
than in Del-19 patients. This result could be a valuable suggestion to consider better<br />
therapeutic strategies for L858R patients.<br />
Legal entity responsible for the study: Kurashiki Central Hospital<br />
Funding: Kurashiki Central Hospital<br />
Disclosure: H. Yoshioka: Hiroshige Yoshioka received lecture fees from Chugai, Astra<br />
Zeneca, Boehringer Ingelheim, and Eli Lilly. A. Hata: Akito Hata received lecture fees<br />
from Chugai, Astra Zeneca, Boehringer Ingelheim, and Eli Lilly. N. Katakami:<br />
Nobuyuki Katakami received grants from Astra Zeneca, Chugai, Eli Lilly, and<br />
Boehringer Ingelheim, and payment for lectures from Chugai, Boehringer Ingelheim,<br />
Astra Zeneca, and Eli Lilly. All other authors have declared no conflicts <strong>of</strong> interest.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw383 | vi439
abstracts<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
1260P<br />
Safety <strong>of</strong> necitumumab and pembrolizumab combination<br />
therapy in patients with stage IV non-small cell lung cancer<br />
(NSCLC): a phase 1b expansion cohort study<br />
1261P<br />
A phase I dose escalation study <strong>of</strong> the tolerability <strong>of</strong> the oral<br />
VEGFR and EGFR inhibitor vandetanib in combination with<br />
the oral MEK1/2 inhibitor selumetinib in solid tumors<br />
B. Besse 1 , P. Garrido 2 , J. Bennouna 3 , L. Mezquita 1 , A. Gazzah 1 , J. Remon 1 ,<br />
D. Planchard 1 , M.E. Olmedo Garcia 2 , J. Raimbourg 3 , G.Y. Chao 4 , M. Gil 5<br />
1 Department <strong>of</strong> Medicine, Institut Gustave Roussy, Villejuif, France, 2 Medical<br />
<strong>Oncology</strong>, Hospital Universitario Ramon y Cajal, Madrid, Spain, 3 Medical<br />
<strong>Oncology</strong>, Institut de Cancérologie de l’Ouest, Nantes, France, 4 Biostatistics, Eli<br />
Lilly & Company, Bridgewater, NJ, USA, 5 <strong>Oncology</strong>, Eli Lilly Polska, Warsaw,<br />
Poland<br />
Background: Safety <strong>of</strong> anti-EGFR necitumumab (neci) was evaluated in combination<br />
with anti-PD1 pembrolizumab (pembro) in pre-treated Stage IV NSCLC patients<br />
(pts).<br />
Methods: Single-arm, multicenter Phase 1b study with expansion cohort to investigate<br />
the safety and effectiveness <strong>of</strong> neci combined with pembro in pts with Stage IV NSCLC.<br />
Part A: escalating doses <strong>of</strong> neci (600 mg and 800 mg IV) were administered on Day 1<br />
and 8 every 3 weeks (Q3W) in combination with pembro (200 mg IV) on Day 1 Q3W.<br />
Part B: expansion cohort with neci at dose identified in Part A administered with<br />
pembro. Major eligibility criteria included progression after 1 platinum-based<br />
chemotherapy and ECOG PS 0-1. Tumor tissue was collected for analysis <strong>of</strong><br />
biomarkers. Treatment continued until disease progression or unacceptable toxicity.<br />
We present data from an interim safety analysis conducted after the first 15 pts who<br />
received the recommended neci 800mg dose completed ≥2 cycles <strong>of</strong> treatment or<br />
discontinued early. All pts in Part A were included.<br />
Results: Part A completed without dose-limiting toxicity. As <strong>of</strong> 11 Feb 2016, 18 pts<br />
(neci 600 mg n = 3, 800 mg n = 15) were eligible for inclusion. Patients were female<br />
44.4%, had median age 66.5 years [range 48-76], and adenocarcinoma histology 77.8%.<br />
All pts experienced ≥1 treatment-emergent adverse event (AE) with ≥1 related to<br />
study treatment. Four serious AEs occurred in 3 (16.7%) pts (all respiratory and<br />
mediastinal); none were treatment-related. No discontinuations or deaths were<br />
attributable to AEs. AEs occurring with >15% frequency are listed (table). Four (22.2%)<br />
pts experienced 8 grade >2 AEs: acute respiratory failure, hypokalaemia,<br />
hypophosphataemia, infusion-related reaction, pulmonary embolism, raised<br />
gamma-glutamyl transferase (1 pt each), and dyspnoea (2 pts).<br />
Table: 1260P Treatment-emergent AEs <strong>of</strong> frequency >15%, n (%)<br />
MedDRA preferred term Interim safety population (N = 18)<br />
Dermatitis acneiform 16 (88.9)<br />
Dry skin 8 (44.4)<br />
Asthenia 7 (38.9)<br />
Appetite decreased 4 (22.2)<br />
Constipation 4 (22.2)<br />
Headache 4 (22.2)<br />
Hypoalbuminaemia 4 (22.2)<br />
Hypophosphataemia 4 (22.2)<br />
Pruritus 4 (22.2)<br />
Anaemia 3 (16.7)<br />
Diarrhoea 3 (16.7)<br />
Dyspnoea 3 (16.7)<br />
Fatigue 3 (16.7)<br />
Hypokalaemia 3 (16.7)<br />
Respiratory tract infection 3 (16.7)<br />
Stomatitis 3 (16.7)<br />
Conclusions: The combination neci and pembro appears tolerable. The safety pr<strong>of</strong>ile<br />
corresponds to individual pr<strong>of</strong>iles for both drugs, with no additive toxicities.<br />
Clinical trial identification: NCT02451930<br />
Legal entity responsible for the study: Eli Lilly and Company<br />
Funding: Eli Lilly and Company<br />
Disclosure: B. Besse: Research funding: Puma Biotechnology, GlaxoSmithKline,<br />
AstraZeneca, Roche/Genentech, Clovis <strong>Oncology</strong>, Pfizer, Boehringer Ingelheim, Lilly,<br />
SERVIER, Onxeo, Bristol-Myers Squibb (BMS); expenses: Roche, Pfizer, BMS/<br />
Medarex, Novartis, Pierre Fabre. P. Garrido: Consulting or advisory roles: Roche,<br />
Novartis, Pfizer, Bristol-Myers Squibb (BMS), Boehringer Ingelheim (BI); speaker’<br />
bureau: Lilly, BMS, Novartis; expenses: BI, BMS, AstraZeneca. J. Bennouna: Advisory<br />
board and symposium presentation: Roche, Astra-Zeneca, Lilly,<br />
Boehringer-Ingelheim. J. Remon: Consultancy role: OESPharma. D. Planchard:<br />
Advisory Board : AstraZeneca, BMS, Clovis, GSK, Lilly, MSD, Pfizer, Roche, San<strong>of</strong>i,<br />
Pierre Fabre, Merck, Boehringer Ingelheim, Novartis. J. Raimbourg: Advisory board:<br />
BMS, Novartis and Roche. G.Y. Chao: Employed by Eli Lilly & Company. M. Gil:<br />
Employed: Eli Lilly & Company; Stocks: Eli Lilly & Company. All other authors have<br />
declared no conflicts <strong>of</strong> interest.<br />
S. Pacey 1 , F. Blackhall 2 , J. Garcia-Corbacho 3 , A. Lipplaa 4 , A. Fusi 2 , S. Kumar 3 ,<br />
M. Hategan 3 , J. Derham 4 , G. Laviste 2 , S. Halford 5 , C. Foxton 5 , R. McLeod 5 ,<br />
S. Wan 5 , D. Talbot 4<br />
1 <strong>Oncology</strong>, Addenbrooke’s Hospital, University <strong>of</strong> Cambridge, Cambridge, UK,<br />
2 Medical <strong>Oncology</strong>, The Christie NHS Foundation Trust, Manchester, UK,<br />
3 <strong>Oncology</strong>, Addenbrooke’s Hospital, Cambridge University Hospitals NHS<br />
Foundation Trust, Cambridge, UK, 4 Medical <strong>Oncology</strong>, Oxford Cancer and<br />
Haematology Centre, Churchill Hospital, Oxford University Hospitals NHS<br />
Foundation Trust, Oxford, UK, 5 Centre for Drug Development, Cancer Research<br />
UK, London, UK<br />
Background: The clinical utility <strong>of</strong> agents targeting EGFR and VEGFR signalling in<br />
Non-Small Cell Lung Cancer (NSCLC) is limited by resistance due to emergent<br />
alternative growth stimulatory pathways, particularly that <strong>of</strong> MEK. Thus, there is strong<br />
rationale for developing a strategy to combine EGFR, VEGFR and MEK inhibitors.<br />
Methods: Patients (any solid tumour) received treatment (continuous dosing) as follows:<br />
vandetanib (VAN) lead-in, 2-4 days (300mg bd or od) followed by VAN steady state (SDD)<br />
(100, 200 or 300mg od), 10-12 days, followed by VAN and selumetinib (SEL), (VAN SDD<br />
plus SEL at 25, 50 or 75mg bd or 100, 125mg od). Seven dose levels were explored.<br />
Results: Forty-seven pts received study treatment. GI and skin toxicities were the most<br />
prevalent related AEs (GI: 159 AEs in 94% pts; Skin: 90 AEs in 94% pts). Other related<br />
AEs included eye disorders in 18 pts (38%) (G1-3) including retinal detachment and<br />
retinopathy. QTc prolongation (G1-2) occurred in 10 pts (21%) and 4 pts (9%)<br />
experienced other cardiac AEs (G1-3). Evidence <strong>of</strong> dose dependent skin and eye<br />
toxicity was observed. The following AEs (six different dose levels) were assigned DLT<br />
status; hypertension, eye toxicity (x3), bradycardia, raised ALP and QTc prolongation.<br />
PK data <strong>of</strong> vandetanib alone and in combination with selumetinib was similar to<br />
previously reported for either drug alone.<br />
Conclusions: VAN and SEL have overlapping toxicities with the AE pr<strong>of</strong>ile consistent<br />
with the known monotherapy pr<strong>of</strong>iles. Doses <strong>of</strong> each agent able to be administered safely<br />
in combination were larger than anticipated and additional cohorts were included. A<br />
higher incidence <strong>of</strong> reversible eye events was observed in combination than reported<br />
with single agent SEL. PK has shown no drug interaction. Based on tolerability, the MTD<br />
<strong>of</strong> both single agent drugs in combination taken forward to the expansion cohort is VAN<br />
200mg od with SEL 50mg bd. This combination is likely to enable adequate inhibition <strong>of</strong><br />
target proteins based on pre-clinical studies. An expansion cohort in NSCLC, with<br />
known EGFR, VEGFR and MEK activation status, is recruiting with anti-tumour efficacy<br />
and pharmacodynamic blood and tumour endpoints.<br />
Clinical trial identification: NCT01586624<br />
Legal entity responsible for the study: Cancer Research UK, Centre for Drug<br />
Development<br />
Funding: Cancer Research UK, Centre for Drug Development<br />
Disclosure: S. Pacey: Research funding from AZ for prostate cancer and ctDNA<br />
research. Two grants
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
associated with longer OS and PFS (Cox-Regr. p = 0.031 PFS, p = 0.038 OS). For<br />
EGFRmut+ vs. EGFR-Wildtype mPFS was 9.5m and 3.7m (log-rank p = 0.069), mOS<br />
was not reached and 7.8m (log-rank p = 0.611), respectively. 459 treatment-related<br />
adverse events (AE) were documented in 148 patients (54.4%), the most common rash<br />
(30.9%) and diarrhea (18.8%). 14 patients (5.1%) died due to a treatment-related AE.<br />
No new safety signals were detected.<br />
Conclusions: Safety and effectiveness results <strong>of</strong> the study are in line with data <strong>of</strong> the<br />
SATURN trial. Improved PFS may be due to enrichment in EGFRmut+ patients.<br />
EGFRmut+ status was associated with improved PFS and OS. Of note, to reflect the<br />
findings <strong>of</strong> the IUNO trial (NCT01328951), the EU label <strong>of</strong> 1L Erlotinib maintenance<br />
was restricted in 01/2016 to patients with activating EGFR-mutations.<br />
Clinical trial identification: ClinicalTrials.gov NCT01194050<br />
Legal entity responsible for the study: Roche Pharma AG<br />
Funding: Roche Pharma AG<br />
Disclosure: P. Staib: Membership on an advisory board or board <strong>of</strong> directors: Roche,<br />
Celgene, Novartis, Amgen Corporate-sponsored research: Celgene, Roche, Novartis,<br />
Amgen. W. Brugger: Membership on an advisory board or board <strong>of</strong> directors: Roche,<br />
BI, Lilly, AstraZeneca, Novartis, Pfizer Other substantive relationships: Employee Astra<br />
Zeneca Cambridge since January 2016. All other authors have declared no conflicts <strong>of</strong><br />
interest.<br />
1263P<br />
Updated efficacy and safety from the global phase II NP28673<br />
study <strong>of</strong> alectinib in patients (pts) with previously treated<br />
ALK+ non-small-cell lung cancer (NSCLC)<br />
F. Barlesi 1 , A-M.C. Dingemans 2 , J.C-H. Yang 3 , S-H.I. Ou 4 , J.S. Ahn 5 ,L.De<br />
Petris 6 , B. Hughes 7 , H. Lena 8 , W. Bordogna 9 , S. Golding 10 , P.N. Morcos 11 ,<br />
B. Balas 12 , A. Zeaiter 9 , D-W. Kim 13<br />
1 Multidisciplinary <strong>Oncology</strong> & Therapeutic Innovations, Aix Marseille University;<br />
Assistance Publique Hôpitaux de Marseille, Marseille, France, 2 Pulmonology,<br />
Maastricht University Medical Center (MUMC), Maastricht, Netherlands,<br />
3 Graduate Institute <strong>of</strong> <strong>Oncology</strong>, National Taiwan University, Taipei, Taiwan, 4 Chao<br />
Family Comprehensive Cancer Centre, University <strong>of</strong> California Irvine School <strong>of</strong><br />
Medicine, Orange, CA, USA, 5 Department <strong>of</strong> Hematology & <strong>Oncology</strong>, Samsung<br />
Medical Center, Seoul, Republic <strong>of</strong> Korea, 6 <strong>Oncology</strong>, Karolinska University<br />
Hospital, Stockholm, Sweden, 7 Cancer Care Services, The Prince Charles<br />
Hospital Queensland Australia, Brisbane, Australia, 8 Pneumologie, Centre<br />
Hospitalier Universitaire, Rennes, France, 9 Product Development, F. H<strong>of</strong>fmann-La<br />
Roche Ltd, Basel, Switzerland, 10 PD Biostatistics, F. H<strong>of</strong>fmann-La Roche Ltd,<br />
Basel, Switzerland, 11 Clinical Pharmacology, F. H<strong>of</strong>fmann-La Roche Ltd,<br />
New York, NY, USA, 12 Safety Risk Management, F. H<strong>of</strong>fmann-La Roche Ltd,<br />
Basel, Switzerland, 13 Department <strong>of</strong> Internal Medicine, Seoul National University<br />
Hospital, Seoul, Republic <strong>of</strong> Korea<br />
Background: Alectinib is an FDA-approved ALK inhibitor for pts with ALK+ NSCLC,<br />
who have progressed on, or are intolerant to, crizotinib. Alectinib has shown systemic<br />
and CNS activity in previously treated pts in two pivotal phase II trials (NCT01801111<br />
[NP28673] and NCT01871805 [NP28761]). We report updated safety and efficacy<br />
(data cut-<strong>of</strong>f 01 Feb 2016) from the global NP28673 study (previously at ECC 2015<br />
[Barlesi et al]).<br />
Methods: Pts ≥18 yrs, ECOG PS 0–2 with confirmed ALK+ NSCLC (by<br />
FDA-approved FISH) previously treated with crizotinib received alectinib 600mg BID<br />
until progression, death or withdrawal. Co-primary endpoints were objective response<br />
rate (ORR) by Independent Review Committee (IRC) in the response evaluable (RE)<br />
population using RECIST v1.1 and in pts who had prior chemo. Secondary endpoints<br />
included duration <strong>of</strong> response (DOR); CNS ORR and DOR; disease control rate<br />
(DCR); PFS; OS; and safety (CTC v4.0).<br />
Results: 138 pts were enrolled (ITT), median age 52 yrs; 110 had received prior chemo, 84<br />
had baseline (BL) CNS mets. At this data cut-<strong>of</strong>f, median follow-up was 21 months. The<br />
co-primary endpoint IRC ORR (n = 122) was 50.8% (95% CI 41.6–60.0); DCR: 78.7%<br />
(95% CI 70.4–85.6); median DOR: 15.2 months (95% CI 11.2–24.9); and median PFS: 8.9<br />
months (95% CI 5.6–12.8). In pts with prior chemo (n = 96), IRC ORR was 44.8% (95% CI<br />
34.6–55.3); DCR: 77.1% (95% CI 67.4–85.1) and median DOR: 14.7 months (95% CI<br />
10.2–21.9). See table for data in pts with CNS mets at BL. Median OS in ITT pts was 26.0<br />
months (95% CI 21.5–NE) after 44% events. Most common AEs (any grade): constipation<br />
(38%); fatigue (31%); peripheral oedema (30%). Rates <strong>of</strong> AEs leading to dose modification/<br />
interruption (28%) or withdrawal (9%) show good tolerability.<br />
Table: 1263P<br />
Measurable CNS<br />
mets (n = 34)<br />
Measurable and<br />
non-measurable CNS mets<br />
(n = 84)<br />
IRC CNS ORR, % (95% CI) 58.8 (40.7–75.4) 46.4 (35.5–57.7)<br />
CNS DCR, % (95% CI) 85.3 (68.9–95.1) 84.5 (78.0–91.5)<br />
Complete response, n (%) 7 (21) 26 (31)<br />
Partial response, n (%) 13 (38) 13 (16)<br />
Stable disease, n (%) 9 (27) 32 (38)<br />
Median CNS DOR, mos (95% CI) 11.1 (7.1–NE) 11.2 (9.1–NE)<br />
Conclusions: The updated NP28673 data show that alectinib is well tolerated and<br />
efficacy is robust, both systemically and in the CNS. The ongoing phase III ALEX trial<br />
is evaluating alectinib vs crizotinib in a first-line setting.<br />
Clinical trial identification: NCT01801111 [NP28673] and NCT01871805<br />
[NP28761].<br />
Legal entity responsible for the study: F. H<strong>of</strong>fmann-La Roche Ltd<br />
Funding: F. H<strong>of</strong>fmann-La Roche Ltd<br />
Disclosure: F. Barlesi: Advisory board and Corporate-sponsored research for<br />
F. H<strong>of</strong>fman-La Roche. A-M.C. Dingemans: Roche Advisory board or board <strong>of</strong><br />
directors. J.C-H. Yang: Membership on an Advisory Board for BI, Eli Lilly, Bayer,<br />
Roche/Genentech/Chugai, Astrazeneca, Astellas, MSD, Merck Serono, Pfizer, Novartis,<br />
Clovis <strong>Oncology</strong>, Celgene, innopharma, Merrimack. S-H.I. Ou: Roche Advisory Board,<br />
Corporate Sponsored Research and Speakers Bureau. B. Hughes: Roche Advisory<br />
Board. H. Lena: Roche Corporate-sponsored research. W. Bordogna: Employment with<br />
H<strong>of</strong>fmann-La Roche. S. Golding, B. Balas: Employee and Stock ownership for<br />
F. H<strong>of</strong>fmann-La Roche. A. Zeaiter: Employee, Leadership and Stock Ownership for<br />
F. H<strong>of</strong>fmann-La Roche. All other authors have declared no conflicts <strong>of</strong> interest.<br />
1264P<br />
Automated nCounter-based assay for identifying clinically<br />
relevant ALK, ROS1 and RET rearrangements in advanced<br />
non-small cell lung cancer (NSCLC)<br />
N. Reguart 1 , L. Paré 1 , A. Giménez-Capitán 2 , C. Teixidó 2 , P. Galván 1 , S. Viteri 3 ,<br />
S. Rodríguez 2 ,V.Peg 2 , E. Aldeguer 2 , E. Ovalle 2 , N. Viñolas 1 ,<br />
S. Merkelbach-Bruse 4 , F. Lopez-Rios 5 , R. Rosell 3 , M.Á. Molina-Vila 2 ,A.Prat 1<br />
1 Medical <strong>Oncology</strong>, Hospital Clinic Barcelona, IDIBAPS, Barcelona, Spain,<br />
2 Laboratory <strong>of</strong> <strong>Oncology</strong>, Pangaea Biotech, Quirón-Dexeus University Institute,<br />
Barcelona, Spain, 3 Medical <strong>Oncology</strong>, Quirón-Dexeus University Institute,<br />
Barcelona, Spain, 4 Institute <strong>of</strong> Pathology, Center for Integrated <strong>Oncology</strong>,<br />
University Hospital Cologne, Cologne, Germany, 5 Medical <strong>Oncology</strong> Service,<br />
Hospital Madrid Norte San Chinarro Centro Integral Oncologico Clara Campal,<br />
Madrid, Spain<br />
Background: Targetable rearrangements in anaplastic lymphoma kinase (ALK), ROS1,<br />
and RET genes can be detected in ∼5-7% <strong>of</strong> patients with advanced NSCLC.<br />
Fluorescent in situ hybridization (FISH) and immunohistochemistry (IHC) are<br />
currently used for screening but present disadvantages in terms <strong>of</strong> sensitivity,<br />
reproducibility, cost and throughput. The Elements nCounter multiplexed platform<br />
has the potential for quick, sensitive and simultaneous detection <strong>of</strong> several clinically<br />
relevant fusion transcripts, but it needs validation in the clinical setting.<br />
Methods: A set <strong>of</strong> probes for detection <strong>of</strong> ALK, ROS1 and RET fusion transcripts were<br />
designed and initially assessed in a panel <strong>of</strong> cell lines. Subsequently, a total <strong>of</strong> 108 FFPE<br />
samples from advanced NSCLC patients were analyzed with the nCounter-multiplexed<br />
platform. Results were compared with FISH, IHC and, in the case <strong>of</strong> ALK, RT-PCR.<br />
Response to crizotinib was retrospectively collected in a subset <strong>of</strong> patients.<br />
Results: All patients categorized as positive for ALK by nCounter were concordant<br />
with IHC (100% sensitivity [CI = 88.3-100], 97.2% specificity [CI = 85.8-99.5]) while<br />
10/31 were negative by FISH (95.5% sensitivity [CI = 78.2-99.2], 84.9% specificity<br />
[CI = 74.3-91.6]). Twenty patients received crizotinib based on ALK results and 18<br />
derived clinical benefit. Of those, all were positive by nCounter while 3 were negative or<br />
not evaluable by FISH. In the case <strong>of</strong> ROS, 19/21 positive patients by nCounter were<br />
also positive by FISH (96.1% specificity [CI = 86.8-98.9]) but 8 samples were found<br />
positive by FISH and negative by nCounter (70.4% sensitivity [CI = 51.5-84.2]). Six <strong>of</strong><br />
them were also negative by IHC, indicating lack <strong>of</strong> protein expression. Ten patients<br />
received crizotinib based on ROS results. Of the seven patients deriving clinical benefit,<br />
six were positive by nCounter. Two patients were nCounter positive for RET, one <strong>of</strong><br />
them was FISH positive.<br />
Conclusions: We have validated an ALK/ROS1/RET nCounter multiplexed assay that<br />
allows for effective screening <strong>of</strong> FFPE samples and identifies advanced NSCLC patients<br />
who will benefit from targeted therapies.<br />
Legal entity responsible for the study: N/A<br />
Funding: Fundació Clínic, Hospital Clínic, Barcelona, Spain<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1265P<br />
Non-invasive detection <strong>of</strong> response and crizotinib induced<br />
resistance in ROS1 fusion advanced stage Chinese lung<br />
adenocarcinoma patients using next-generation genotyping<br />
from cfDNA<br />
X. Niu, S. Chuai, S. Lu<br />
Department <strong>of</strong> Shanghai Lung Cancer Center, Shanghai Chest Hospital,<br />
Shanghai, China<br />
Background: Recently Crizotinib has exhibited marked therapeutic efficacy in the<br />
treatment <strong>of</strong> the advanced stage ROS1 fusion non-small cell lung cancer (NSCLC).<br />
However, the challenge <strong>of</strong> acquired resistance to Crizotinib in ROS1 fusion NSCLC has<br />
been an issue, and the invasive nature <strong>of</strong> obtaining a second tissue biopsy does not<br />
allow for straightforward monitoring <strong>of</strong> disease status. Cell free plasma DNA (cfDNA)<br />
is a promising biomarker for non-invasive assessment <strong>of</strong> cancer burden. This study<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw383 | vi441
abstracts<br />
aims to assess whether liquid biopsies accurately reflect the response to Crizotinib<br />
treatment through analysis <strong>of</strong> cfDNA for ROS1 fusion lung adenocarcinoma, and try to<br />
elucidate the mechanisms <strong>of</strong> ROS1 targeted drug resistance.<br />
Methods: 12 plasma samples were collected from a cohort <strong>of</strong> four patients with ROS1<br />
fusion positive advanced stage lung adenocarcinoma, confirmed by FISH in tissue. A<br />
prospective-retrospective analysis on cfDNA was further performed from archived<br />
plasma samples using a capture based 168-gene targeted sequencing panel derived<br />
from CAncer Personalized Pr<strong>of</strong>iling by deep Sequencing (CAPP-Seq) genetic analysis,<br />
with concurrent CT or MRI imaging at baseline, at 8-week intervals during responsive<br />
Crizotinib treatment, and at progressive disease.<br />
Results: All patients showed detectable levels <strong>of</strong> ROS1 fusion products in cfDNA at<br />
baseline, upon treatment with Crizotinib a partial response was positively correlated<br />
with undetectable levels <strong>of</strong> ROS1 fusion. One patient exhibited a detectable<br />
CD74-ROS1 fusion with 13.5% concentration at baseline, an undetected CD74-ROS1<br />
fusion when receiving partial response, and a re-bounce CD74-ROS1 fusion with 8.2%<br />
concentration in cfDNA when disease progressed. Further CAPP-Seq genetic analysis<br />
elucidated Crizotinib resistance-associated mutation G2032R in this progressive<br />
patient.<br />
Conclusions: The non-invasive cfDNA CAPP-Seq analysis could be applied clinically<br />
to detect biopsy-free ROS1 fusion for accurate screening and convenient monitoring<br />
disease status, and could distinguish mutations associated with Crizotinib induced<br />
resistance in patients with NSCLC, thus facilitating personalized cancer therapy.<br />
Legal entity responsible for the study: Shun Lu<br />
Funding: Shanghai Chest Hospital<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1266P<br />
Clinical analysis <strong>of</strong> continuing crizotinib treatment beyond<br />
disease progression in ALK-positive non-small-cell lung<br />
cancer patients<br />
L. Hongmei 1 , M. Huang 2 ,Y.Xu 2 , X. Zhou 2 ,J.Li 3 , J. Wang 2 ,F.Peng 2 , Y. Gong 2 ,<br />
Z. Ding 2 , J. Zhu 2 ,P.Yu 3 ,L.Li 2 , M. Hou 2 ,L.Ren 2 , Y. Wang 2 ,Y.Lu 2<br />
1 Department <strong>of</strong> Thoracic <strong>Oncology</strong>, Cancer Center, West China Hospital, Huaxi,<br />
Sichuan University, Chengdu, China, 2 Department <strong>of</strong> Thoracic <strong>Oncology</strong>, Cancer<br />
Center, State Key Laboratory <strong>of</strong> Biotherapy, West China Hospital, Huaxi, Sichuan<br />
University, Chengdu, China, 3 Lung Cancer Medical <strong>Oncology</strong>, Sichuan Cancer<br />
Hospital, Chengdu, China<br />
Background: Continuing the treatment <strong>of</strong> tyrosine kinase inhibitors (TKIs) after<br />
disease progression (PD) in EGFR-mutation NSCLC was reported promising in several<br />
studies, but rare research presented continued ALK-TKIs beyond PD in NSCLC. Thus,<br />
we retrospectively analyzed the continuation <strong>of</strong> crizotinib treatment beyond PD in<br />
ALK-positive patients.<br />
Methods: The progression free survival (PFS, time from first crizotinib dose to first<br />
RECIST-defined PD), PFS2 (time from continuing crizotinib treatment beyond PD to<br />
drug withdrawal or death), overall survival (OS, time from first crizotinib dose to<br />
death), objective response rate (ORR) and disease control rate (DCR) were analyzed in<br />
this study. Patterns <strong>of</strong> PD were identified by patients underwent rapid radiographic/<br />
clinical disease progression or died within 3 months after PD.<br />
Results: Of 108 patients screened, 53 patients got PD at the cut<strong>of</strong>f time. Median<br />
follow-up was 12.3 months. After PD, 23 patients discontinued crizotinib treatment<br />
and 30 patients continued. Baseline characteristics showed that continued ones had a<br />
better ECOG performance status than discontinued ones (P = 0.006). Patterns <strong>of</strong> PD<br />
was significantly different in two groups (P < 0.001). Median PFS and median OS were<br />
6.6 months (95%CI 5.2-8.1) and 14.6 months (95%CI 10.1-19.1), respectively. In 23<br />
discontinued ones, median PFS were 6.8 months (95%CI 5.4-8.2). In 30 continued<br />
ones, median PFS and PFS2 were 6.2 months (95%CI 2.6-9.7) and 6.1 months (95%CI<br />
4.5-7.7), respectively. The patients who continued crizotinib treatment had a<br />
significantly longer median OS than those discontinued (18.4 versus 9.9 months,<br />
P = 0.010). Multivariate Cox regression analysis indicated that the continuing<br />
crizotinib-treated patients have a better OS (HR = 0.405, 95%CI 0.183-0.897,<br />
P = 0.026). Subgroup analysis <strong>of</strong> OS in continuing crizotinib-treated patients beyond<br />
PD with brain or bone metastasis was 30.8 moths (95%CI 18.2-43.3) , and in patients<br />
with other sites <strong>of</strong> PD was 12.0 moths (95%CI 3.9-20.1, P = 0.010).<br />
Conclusions: ALK-positive NSCLC may get clinical benefits from the continuation <strong>of</strong><br />
crizotinib beyond PD, especially in those patients with brain or bone metastases.<br />
Legal entity responsible for the study: Department <strong>of</strong> Thoracic <strong>Oncology</strong>, Cancer<br />
Center, State Key Laboratory <strong>of</strong> Biotherapy, West China Hospital, Medical School,<br />
Sichuan University<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1267P<br />
HER2 V659 and G660 transmembrane mutations that stabilize<br />
homo- and hetero-dimerization are rare oncogenic drivers in<br />
lung adenocarcinoma that are clinically responsive to afatinib<br />
S-H.I. Ou 1 , A.B. Schrock 2 , E.V. Bocharov 3 , S.J. Klempner 4 , C.K. Haddad 5 ,<br />
G. Steinecker 6 , M. Johnson 7 , B. Gitlitz 8 , J. Chung 9 , P. Campregher 10 , J.S. Ross 11 ,<br />
P.J. Stephens 12 , V.A. Miller 2 , J. Suh 11 , S.M. Ali 2 , V. Velcheti 13<br />
1 Hematology/<strong>Oncology</strong>, Chao Family Comprehensive Cancer Center, Irvine, CA,<br />
USA, 2 Clinical Development, Foundation Medicine, Inc., Cambridge, MA, USA,<br />
3 Department <strong>of</strong> Structural Biology, Shemyakin-Ovchinnikov Institute <strong>of</strong> Bioorganic<br />
Chemistry, Moscow, Russian Federation, 4 Medical <strong>Oncology</strong>, The Angeles Clinic<br />
and Research Institute, Los Angeles, CA, USA, 5 Medical <strong>Oncology</strong>, Hospital São<br />
José, Sao Paulo, Brazil, 6 Medical <strong>Oncology</strong>, Affiliated Oncologists, Oak Lawn, IL,<br />
USA, 7 <strong>Oncology</strong>, Sarah Cannon Research Institute/Tennessee <strong>Oncology</strong>,<br />
Nashville, TN, USA, 8 <strong>Oncology</strong>, University <strong>of</strong> Southern California Norris<br />
Comprehensive Cancer Center, Los Angeles, CA, USA, 9 Biomedical Informatics,<br />
Foundation Medicine, Inc., Cambridge, MA, USA, 10 Biologia Molecular, Hospital<br />
Israelita Albert Einstein, Sao Paulo, Brazil, 11 Pathology, Foundation Medicine, Inc.,<br />
Cambridge, MA, USA, 12 Clinical Genomics, Foundation Medicine, Inc., MA,<br />
Cambridge, MA, USA, 13 Medical <strong>Oncology</strong>, Cleveland Clinic Foundation,<br />
Cleveland, OH, USA<br />
Background: HER2 (ERBB2) transmembrane domain (TMD) mutations (V659E and<br />
G660D) have previously been identified in lung adenocarcinomas, but their frequency<br />
and clinical significance is unknown.<br />
Methods: We prospectively analyzed 8,551 lung adenocarcinomas using<br />
hybrid-capture based comprehensive genomic pr<strong>of</strong>iling (CGP) at the request <strong>of</strong> the<br />
individual treating physicians for the purpose <strong>of</strong> making therapy decisions.<br />
Results: We identified 15 cases (0.18%) <strong>of</strong> lung adenocarcinoma with HER2 TMD<br />
mutations at amino acid residues 659 or 660. These included 11 cases with V659D/E<br />
mutations, 2 with HER2 G660D, one with HER2 V659E/G660R, and one with a HER2<br />
V659_660VE insertion. In comparison, HER2 kinase domain (KD) mutations, the<br />
majority <strong>of</strong> which were exon 20 insertions, were identified in 3.2% (273/8,551) <strong>of</strong> cases.<br />
79% <strong>of</strong> patients with HER2 TMD mutations were female and <strong>of</strong> the 9 patients with known<br />
smoking history, 5 were never-smokers and 3 were light former-smokers. HER2 TMD<br />
mutations were mutually exclusive from HER2 KD mutations and other oncogenic drivers<br />
in lung adenocarcinoma. Only two cases with HER2 TMD mutations (13%) had<br />
concurrent HER2 amplification. Nuclear magnetic resonance analysis <strong>of</strong> HER2 TMD<br />
association revealed that mutations at position V659 and G660 to highly polar residues<br />
glutamic acid (E), aspartic acid (D) or arginine (R) stabilize homo- and hetero-dimerization<br />
<strong>of</strong> HER2 in the active conformation. Treatment <strong>of</strong> three patients with afatinib, a pan-HER<br />
inhibitor, resulted in ongoing clinical responses in all three cases, two harboring HER2<br />
V659E and one with double HER2 V659E/G660R mutations (response > 14 months).<br />
HER2 TMD mutations (V659 and G660) are found in other non-NSCLC malignancies<br />
and analogous TMD mutations are also found in EGFR, HER3 and HER4.<br />
Conclusions: This study expands the knowledge <strong>of</strong> targetable HER2 mutations in lung<br />
adenocarcinoma to the TMD and potentially other solid malignancies. CGP capable <strong>of</strong><br />
detecting diverse HER2 alterations, including HER2 TMD mutations, should be<br />
broadly adopted to identify all patients who may benefit from HER2-targeted therapies.<br />
Legal entity responsible for the study: Foundation Medicine.<br />
Funding: Foundation Medicine. Russian Science Foundation, project #14-50-00131 (to<br />
E.V. Bocharov). S-H I. Ou was partly supported by the University <strong>of</strong> California Irvine<br />
NIH P30 grant CA062203-19.<br />
Disclosure: S-H.I. Ou: Honoraria as an advisory board and speaker bureau member<br />
for Boehringer Ingelheim. A.B. Schrock, J. Chung, P. Campregher, J.S. Ross, P.J.<br />
Stephens, V.A. Miller, J. Suh, S.M. Ali: Employee with stock ownership in Foundation<br />
Medicine. S.J. Klempner: Honoraria from Foundation Medicine. All other authors have<br />
declared no conflicts <strong>of</strong> interest.<br />
1268P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Non small cell lung cancer (NSCLC) patients harboring BRAF<br />
mutation: Clinical characteristics and management in real<br />
world setting. Cohort BRAF EXPLORE GFPC 02-14<br />
J.B. Auliac 1 , S. Bayle 2 , A. Vergnenegre 3 , G. Fraboulet 4 , H. Lecaer 5 , L. Falchero 6 ,<br />
P. Dô 7 , H. Doubre 8 , P.A. Hauss 9 , A. Vinas 10 , S. Larive 11 , A.M. Chiappa 12 ,<br />
B. Marin 13 , C. Chouaid 10<br />
1 Service de pneumologie et oncologie thoracique, CH François Quesnay, Mantes<br />
La Jolie, France, 2 Pneumologie, Centre Hospitalier Universitaire de Saint-Etienne,<br />
St. Etienne, France, 3 Service de l’UOTC, CHU Limoges - Hopital Dupuytren,<br />
Limoges, France, 4 Oncologie, Hopital René Dubos, Pontoise, France, 5 Oncologie,<br />
CH de la Dracénie-Draguignan, Draguignan, France, 6 Pneumologie, Hôpital Nord<br />
Ouest, Villefranche Sur Saone, France, 7 Oncologie, Centre Francois Baclesse,<br />
Caen, France, 8 Oncologie, Hopital Foch Service d’Oncologie, Suresnes, France,<br />
9 Pneumologie, Ch elbeuf, Elbeuf, France, 10 Pneumologie, CH Intercommunal de<br />
Créteil, Créteil, France, 11 Pneumologie, Centre Hospitalier, Macon, France,<br />
12 Pneumologie, CH de Cornouaille - Hopital Laennec, Quimper, France, 13 Centre<br />
d’Epidémiologie, de BIostatistique et de MEthodologie de la Recherche<br />
(CEBIMER), CHU Limoges - Hopital du Cluzeau, Limoges, France<br />
Background: BRAF (v-Raf murine sarcoma viral oncogene homolog B) mutation is a<br />
rare oncogenic driver in NSCLC (2%) and few data are published on the management <strong>of</strong><br />
vi442 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
these patients (pts) outside patients included in clinical trial. Objective: to investigate<br />
clinical characteristics and management <strong>of</strong> these patients in real world setting.<br />
Methods: Inclusion <strong>of</strong> pts with a diagnosis <strong>of</strong> NSCLC harboring BRAF mutations<br />
between January 2012 and December 2014, collection <strong>of</strong> demographic and clinical<br />
characteristics, risk factors, Progression Free Survival (PFS), Overall Survival (OS),<br />
mode <strong>of</strong> progression and therapeutic management; sub group analysis according to the<br />
BRAF mutation (V600E versus others).<br />
Results: 59 patients recruited in 24 centers: 34 (57,6%) men; age: 64,5 ± 14,5 years; PS<br />
0/1 at diagnosis: 82%; current/former smokers: 23 (40,3%)/18 (32,6%);<br />
adenocarcinoma: 93%; Stage at diagnosis 4/3/2-1: 77%/16%/7%: BRAF V600E: 81%;<br />
co-mutations EGFR n = 2, ALK n = 2. Outcomes <strong>of</strong> stage IV (n = 44): first line<br />
treatment: chemotherapy: 61,9%, chemotherapy + radiotherapy : 9,5%, radiotherapy<br />
alone: 2.4%, Best supportive care (BSC): 11.9 %, anti BRAF: 14.2 %; response rate and<br />
PFS to first line treatment: 51.7% and 8.7 months (CI 6.4; 15.2), second line treatment<br />
(n = 21) : chemotherapy: 66.7%, anti BRAF 23.8%, BSC 9.5%; response rate and PFS to<br />
second line treatment: 35.3% and 4,8 months (CI 2,7;10,3); 2 years-OS: 58.5% (CI 45.8;<br />
74.8). 17 pts received BRAF inhibitor. Outcome <strong>of</strong> stage IV BRAF harboring V600 E<br />
(n = 32) didn’t showed any significant difference.<br />
Conclusions: In this real world analysis, the majority <strong>of</strong> NSCLC patients with BRAF<br />
mutation were men, smokers and appears to have a better survival to NSCLC pts<br />
without oncogenic driver.<br />
Clinical trial identification: EXPLORE GFPC 02-14 comité d’Ethique du CHU de<br />
Saint-Etienne Commission recherche de Terre d’éthique: IRBN 102016/CHUSTE<br />
Legal entity responsible for the study: N/A<br />
Funding: Clinical trial information: Supported by an academic grant from Lilly, Astra<br />
Zeneca, boehringer ingelheim<br />
Disclosure: J.B. Auliac: In the last five years, honoraria for attending scientific<br />
meetings, speaking, organizing research or consulting, from Boehringer Ingelheim,<br />
H<strong>of</strong>fman-Roche, Lilly and Pfizer. A. Vergnenegre: In the last five years, Honoraria for<br />
attending scientific meetings, speaking, organizing research or consulting, from<br />
Boehringer Ingelheim, H<strong>of</strong>fman- Roche, Lilly. C. Chouaid: Honoraria for attending<br />
scientific meetings, speaking, organizing research or consulting, from Astra Zeneca,<br />
Boehringer Ingelheim, GlaxoSmithKline, H<strong>of</strong>fman-la Roche, San<strong>of</strong>i Aventis, Lilly,<br />
Novartis and Amgen. All other authors have declared no conflicts <strong>of</strong> interest.<br />
1269P<br />
SELECT-3: A phase I study <strong>of</strong> selumetinib in combination<br />
with platinum doublet chemotherapy for advanced NSCLC in<br />
the first-line setting<br />
E. Dean 1 , N. Steele 2 , H-T. Arkenau 3 , F. Blackhall 1 , N.M. Haris 4 , C. Lindsay 2 ,<br />
S. Rafii 3 , R. Califano 1 , R. Plummer 5 , M. Voskoboynik 3 , Y.J. Summers 1 ,<br />
D. Ghiorghiu 6 , A. Dymond 7 ,K.So 6 , A. Greystoke 5<br />
1 Medical <strong>Oncology</strong>, The Christie NHS Foundation Trust, Manchester, UK,<br />
2 Medical <strong>Oncology</strong>, Beatson West <strong>of</strong> Scotland Cancer Centre, Gartnavel General<br />
Hospital, Glasgow, UK, 3 Drug Development Unit, Sarah Cannon Research<br />
Institute, London, UK, 4 Northern Centre for Cancer Care, The Freeman Hospital,<br />
Newcastle Upon Tyne, UK, 5 Northern Institute for Cancer Research, Newcastle<br />
University, Newcastle Upon Tyne, UK, 6 Global Medicines Development,<br />
AstraZeneca, Cambridge, UK, 7 Quantitative Clinical Pharmacology, AstraZeneca,<br />
Macclesfield, UK<br />
Background: Selumetinib (AZD6244, ARRY-142886), an oral, potent and highly<br />
selective, allosteric MEK1/2 inhibitor with a short half-life, has shown clinical activity<br />
in a Phase II study <strong>of</strong> patients (pts) with KRAS-mutant advanced NSCLC in the<br />
second-line setting. This study investigated selumetinib plus platinum doublet<br />
chemotherapy as first-line treatment for pts with advanced/metastatic NSCLC,<br />
unselected for KRAS mutation status.<br />
Methods: This Phase I, open-label, multicentre study (NCT01809210) enrolled pts into<br />
dose-finding cohorts <strong>of</strong> selumetinib (50 [sel50], 75 [sel75] or 100 [sel100] mg BID PO)<br />
plus standard doses <strong>of</strong> gemcitabine (gem) or pemetrexed (pem) plus cisplatin (cis) or<br />
carboplatin (carb). Escalation cohorts comprised 3–6 evaluable pts, and optional<br />
expansion cohorts (n ≤ 12) further assessed safety. For each dose regimen, safety,<br />
tolerability, pharmacokinetics (PK), and preliminary efficacy were assessed to select<br />
recommended Phase II doses (RP2D).<br />
Results: In total, 55 pts were treated (26 female; median age 62 years; 38 adenocarcinoma,<br />
13 squamous) in seven cohorts: C1/C3 sel50/75 + gem + cis, n = 3/7; C2 sel50 + gem + carb,<br />
n = 9; C4/5/7 sel50/75/100 + pem + carb, n = 3/6/12; C6 sel75 + pem + cis, n = 15. Median<br />
totalselumetinibexposurewas84days(range4–266). Most frequent AEs were fatigue,<br />
nausea, diarrhoea and vomiting. Grade (G) ≥3 selumetinib-related AEs were seen in 30<br />
(55%) pts. Dose-limiting toxicities (DLTs; all n = 1) were reported in: C2, G4<br />
thrombocytopenia/epistaxis and G4 thrombocytopenia; C3, G4 anaemia; C6, G3 lethargy;<br />
C7, G4 febrile neutropenia. Nine pts died during the study; none were causally related to<br />
selumetinib. Selumetinib PK was similar across the combination regimens. Of the 55<br />
patients treated, confirmed partial responses were observed in 11 (20%) pts and<br />
unconfirmed in 9 (16%) pts, and 21 (38%) pts had stable disease (≥6weeks).<br />
Conclusions: In the first-line setting, RP2Ds were identified as selumetinib 75 mg BID<br />
plus standard doses <strong>of</strong> pem + carb or pem + cis, which were tolerated with AE pr<strong>of</strong>iles<br />
consistent with the individual agents. RP2Ds were not determined for gem containing<br />
regimens. Preliminary anti-tumour activity was observed across all cohorts. We thank<br />
Stuart Hossack <strong>of</strong> Covance who provided analysis and interpretation <strong>of</strong> the<br />
pharmacokinetic data.<br />
Clinical trial identification: NCT01809210 - Clinical trial identification release date:<br />
March 8, 2013<br />
Legal entity responsible for the study: AstraZeneca<br />
Funding: AstraZeneca<br />
Disclosure: E. Dean: The Christie NHS Foundation Trust received income from the<br />
commercial sponsor AstraZeneca for the conduct <strong>of</strong> this study. F. Blackhall,<br />
R. Califano: Personal fees from Astrazeneca, outside <strong>of</strong> the submitted<br />
work. R. Plummer: Clinical research costs from AstraZeneca and personal fees from<br />
AstraZeneca, outside <strong>of</strong> the submitted work. Y.J. Summers, A. Greystoke: Personal fees<br />
from AstraZeneca, outside the submitted work. D. Ghiorghiu, A. Dymond:<br />
AstraZeneca employee and shareholder. K. So: AstraZeneca employee. All other<br />
authors have declared no conflicts <strong>of</strong> interest.<br />
1270P<br />
abstracts<br />
Id1 and Id3 genes confer poor prognosis in KRAS-mutant<br />
(KM) lung adenocarcinoma (LA) patients. Gene silencing<br />
reduces metastatic rate to the liver and increases survival<br />
M. Román 1 , I. Lopez 2 , L. Zubiri 1 , R. Sanchez 1 , D. Salas 1 , I. Gardeazabal 1 ,<br />
I. Baraibar 1 , M. Santisteban 1 , S. Vicent 2 , I. Gil-Aldea 3 , M. Martinez Aguillo 4 ,<br />
B. Hernandez 5 , J.M. Lopez-Picazo 1 , A. Gurpide 1 , E. Guruceaga 6 ,J.<br />
L. Perez-Gracia 1 , M. Collantes 7 , M. Ecay 7 , I. Gil-Bazo 1<br />
1 Medical <strong>Oncology</strong>, Clinica Universitaria de Navarra, Pamplona, Spain, 2 Tumores<br />
Solidos y Biomarcadores, Centro de Investigacion Medica Aplicada (cima),<br />
Pamplona, Spain, 3 Biobanco, Navarrabiomed, Pamplona, Spain, 4 <strong>Oncology</strong>,<br />
Navarrabiomed, Pamplona, Spain, 5 <strong>Oncology</strong>, Complejo Hospitalario de Navarra,<br />
Pamplona, Spain, 6 Bioinformatica, Centro de Investigacion Medica Aplicada<br />
(CIMA), Pamplona, Spain, 7 MicroPET, Clinica Universitaria de Navarra, Pamplona,<br />
Spain<br />
Background: Inhibitor <strong>of</strong> differentiation 1 (Id1) and 3 (Id3) genes confer poor<br />
prognosis being involved in LA spreading to the liver. KM may constitute a poor<br />
prognosis and a pro-metastatic feature. Here we study Id genes’ role in KM LA and<br />
liver metastasis (LM).<br />
Methods: 424 LA patients were studied to assess the survival impact <strong>of</strong> Id1 and Id3<br />
mRNA levels depending on KRAS status. The KM human LA cell line<br />
H1792-TGL-604 was used to address the impact <strong>of</strong> Id1 and Id3 genes on tumor cell<br />
proliferation and migration. A murine model <strong>of</strong> LM from LA was generated using<br />
immunocompromised mice by tumor cells intrasplenic injection. shRNA silencing was<br />
used to determine the impact <strong>of</strong> Idgenes. Two groups <strong>of</strong> mice inoculated with<br />
shRNA-Id1 and shRNA-Id1-Id3 tumor cells, were compared to those inoculated with<br />
twildtype (WT) cell line. FDG-PET was used to monitor LM. The effect <strong>of</strong> tumor cells<br />
genotype in the overall survival (OS) <strong>of</strong> the animals was also studied.<br />
Results: Id1 and Id3 mRNA higher tumor levels predicted a shorter OS among patients<br />
with KM but not in KRAS-wildtype LA (p = 0.02 and p = 0.03, respectively). In vitro,<br />
the proliferation rate <strong>of</strong> cells silenced for Id1 and Id1/Id3 genes was 20.1% CI95%<br />
(0.17, 0.23) and 31% CI95% (0.245, 0.37), compared to 60.1% CI95% (0.54, 0.67), in<br />
the WT cell line (p < 0.001). Tumor cells’ migration also decreased from 22.1% CI95%<br />
(16.7, 27.4) in the WT cells to 1.88% CI95% (1, 2.76) and 0.29% CI95% (0.03, 0.55) in<br />
the Id1 and Id1/Id3-silenced cells, respectively (p < 0.001). SUVmax50 values also<br />
showed a reduction in the metastatic rate <strong>of</strong> mice inoculated with shId1-cells [0.71<br />
CI95% (0.66, 0.76)], and with shId1shId3-cells, [0.71 CI95% (0.62, 0.81)], compared to<br />
the mice inoculated with WT cells, 1.86 [SD 0.51, CI 95% (1, 2.49)]; p < 0.001.<br />
Moreover, these mice showed a significant delay in LM onset, leading to an increased<br />
survival: 61 and 46 days CI95% (59.21, 62.79) respectively, compared to 28 days in the<br />
WT group (p < 0.01).<br />
Conclusions: Higher Id1 and Id3 mRNA tumor levels predicted a shorter OS in a large<br />
series <strong>of</strong> KM LA patients. Id1 and Id1/Id3 silencing in human KM tumor cells <strong>of</strong> LA<br />
decreased and delayed LM development in an in vivo model<br />
Legal entity responsible for the study: Clinica Universidad de Navarra<br />
Funding: Ministerio de Economía y Competitividad. Instituto de Salud Carlos III.<br />
Gobierno de España.<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw383 | vi443
abstracts<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
1271P<br />
KRAS mutations(m) in lung adenocarcinoma (AC) patients(p)<br />
receiving standard chemotherapy (ch) and immune<br />
checkpoint inhibitors (i-CI): Impact <strong>of</strong> KRAS clonality and<br />
coexisting TP53m<br />
N. Pardo Aranda 1 , F. Ruiz 2 , A. Martinez Marti 1 , S. Cedres 1 , A. Navarro Mendivil 1 ,I.<br />
de la fuente 1 , A. Martinez de Castro 1 , A. Vivancos 3 , R. Dienstmann 2 , E. Felip 1<br />
1 Medical <strong>Oncology</strong>, Vall d’Hebron University Hospital Institut d’Oncologia,<br />
Barcelona, Spain, 2 <strong>Oncology</strong> Data Science, Vall d’Hebron University Hospital<br />
Institut d’Oncologia, Barcelona, Spain, 3 Cancer Genomics Group, Vall d’Hebron<br />
Institute <strong>of</strong> <strong>Oncology</strong>, Barcelona, Spain<br />
Background: RASm the most frequent oncogene alteration in ADC is not directly<br />
targetable with agents currently available for clinical use.We studied the efficacy <strong>of</strong> ch<br />
and i-CI in RASm ADC and explored a potential effect <strong>of</strong> clonality <strong>of</strong> KRASm and<br />
coexisting KRAS/TP53m in outcome<br />
Methods: Out <strong>of</strong> 250 AC p with targeted mut pr<strong>of</strong>iling (Sequenom/Amplicon Seq)63<br />
RASm(25%) were eligible for retrospective analysis <strong>of</strong> clinical endpoints. Primary<br />
endpoints: to determine progression-free survival (PFS) on first-line platinum-based ch<br />
plus maintenance 2PFS on subsequent i-CI as single agent; OS in metastatic setting<br />
(metOS) Secondary endpoints: to correlate survival endpoints with the clonality <strong>of</strong><br />
KRAS mut allele fractions (MAFs, adjusted for tumor purity in the sample) and<br />
coexisting TP53m<br />
Results: Median age was 58yrs (range 33-75) 35male(55%) 24(38%)metastatic at<br />
diagnosis and in remaining pts, median time from diagnosis to relapse was 10 months<br />
(7-16) 61p had KRASm tumors, most frequent variants being G12C(25) G12V(10)<br />
G12D(9) G12other(6) G13(6) Q61(5) while 2p had NRASm tumors (Q61) with<br />
coexisting TP53m in 17/31(55%) Median KRAS MAF was 0.44( 0.32-0.55) with no<br />
differences if primary tumor (0.42 n = 36) or metastatic site biopsy (0.41 n = 5).19% <strong>of</strong><br />
samples had MAFs < 0.25 considered subclonal. 40p received first-line platinum-based<br />
ch median PFS was 6.7m( 5.1-8.2) and did not significantly change if subclonal<br />
KRASmut alleles (p = 0.72) or coexisting TP53m (p = 0.51).Median PFS in 17p that<br />
received i-CI (10nivolumab 4atezolizumab 2pembrolizumab 1avelumab) was 3.2m<br />
(3.1-not reached) with 22% <strong>of</strong> p PF at 12 months.KRASmut clonality (p = 0.39) and<br />
coexistance <strong>of</strong> TP53m (p = 0.15) did not affect PFS on i-CI.Median metOS was 30.5m<br />
(13.2-not reached)without significant differences if subclonal KRAS mut alleles<br />
(p = 0.88) or coexisting TP53m (p = 0.55)<br />
Conclusions: RAS mutated AC p have favorable outcomes when exposed to standard<br />
ch and i-CI.The majority <strong>of</strong> samples present KRAS MAFs suggesting clonal (truncal)<br />
events.TP53m is the most common coexisting driver alteration.In our exploratory<br />
cohort,these factors did not impact treatment benefit <strong>of</strong> ch, i-CI or survival in the<br />
metastatic setting<br />
Legal entity responsible for the study: N/A<br />
Funding: VHIO<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1272P<br />
Analysis <strong>of</strong> outcomes and brain metastases (BM) <strong>of</strong> molecular<br />
selected non-small cell lung cancer (NSCLC) patients<br />
included in clinical trials<br />
S. Cedres, N. Pardo Aranda, A. Martinez de Castro, A. Navarro Mendivil, A.<br />
Martinez Marti, C. Ortiz, F. Racca, M. Vilaro, L. Carbonell, A. Piera, I. de la fuente,<br />
E. Felip<br />
Medical <strong>Oncology</strong>, Vall d’Hebron University Hospital Institut d’Oncologia,<br />
Barcelona, Spain<br />
Background: The molecular pr<strong>of</strong>iling <strong>of</strong> patients (p) with advanced NSCLC identifies<br />
several oncogenic drivers that can be targeted with selective inhibitors. We aimed to<br />
assess the characteristics and prognostic factors <strong>of</strong> p with molecular alterations at our<br />
center treated with targeted agents.<br />
Methods: EGFR, KRAS,HER2 mutated p and ALK, ROS1 and RET rearrangements<br />
positive p enrolled onto clinical trials between 2009 and 2015 at our center were<br />
included in this analysis. A cohort <strong>of</strong> wild type (WT) adenocarcinoma p was selected as<br />
comparator. Survival was estimated by the Kaplan-Meier method.<br />
Results: 200 p were collected (76 WT, 45 EGFR, 51 ALK, 21 KRAS, 3 ROS1, 2 HER2<br />
and 2 RET). Median age 57 years (26-82), 52% men, 60% performance status (PS) 1,<br />
59% smokers, 98% stage IV and 92% adenocarcinoma. First treatment was selective<br />
inhibitor in 73% <strong>of</strong> EGFR and 58% <strong>of</strong> ALK p. Median follow up was 23 months (m)<br />
(95% CI 1.6-104.6). The overall survival (OS), still immature with 58% <strong>of</strong> deaths, was<br />
33m for all p and 57m EGFR, 40m ALK, 31m KRAS and 19m WT. We found<br />
differences in OS for molecular selected population vs WT (55m vs 19 m p < 0.001),<br />
women (55m vs 23m, p = 0.002), PS 0/1 vs PS2 (21 vs 7m, p < 0.001) and non-smokers<br />
(51 vs 23 m smokers, p = 0.002). Brain metastases were detected in 86 p (36 ALK, 25<br />
WT, 14 EGFR, 8 KRAS, 2 ROS and 1 RET) and 87% received local therapy. BM were<br />
more frequent in women, non-smokers and ALK p (p < 0.001). BM developed at a<br />
median <strong>of</strong> 6m from diagnosis <strong>of</strong> NSCLC (6m molecular selected and 5m WT, p = 0.44)<br />
and median OS after development <strong>of</strong> BM was 14m (28m EGFR, 26m ALK and 8m WT,<br />
p < 0.001). No differences in OS were detected in p with or without BM (p > 0.05).<br />
Independently <strong>of</strong> target agent, we did not found significant differences in OS p with<br />
BM treated with local therapy vs systemic treatment (p > 0.005).P who initiated the<br />
EGFR and ALK inhibitors after diagnosis <strong>of</strong> BM had greater benefit than those p who<br />
began treatment before diagnosis <strong>of</strong> BM (86m vs 57m for EGFR and 55m vs 35m for<br />
ALK respectively, p > 0.05 in both).<br />
Conclusions: Molecular selected p treated with targeted agents have prolonged<br />
survival. Brain metastases is a frequent site <strong>of</strong> disease progression, but the prognosis <strong>of</strong><br />
these p is impressive independently <strong>of</strong> local therapies.<br />
Legal entity responsible for the study: N/A<br />
Funding: VHIO<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1273P<br />
Cost <strong>of</strong> care in first line advanced NSCLC patients:<br />
Chemotherapy vs targeted therapy<br />
J. Radtchenko 1 , B. Korytowsky 2 , K. Tuell 3 ,M.Bhor 1 , B. Feinberg 4<br />
1 HEOR, Cardinal Health, Dublin, OH, USA, 2 Outcomes Research, Bristol-Myers<br />
Squibb, Princeton, NJ, USA, 3 HSOR, Bristol-Myers Squibb, Princeton, NJ, USA,<br />
4 <strong>Oncology</strong>, Cardinal Health, Dublin, OH, USA<br />
Background: Targeted therapies have increasingly placed drug cost in the spotlight.<br />
This represents only one aspect <strong>of</strong> cancer treatment cost. To provide a comprehensive<br />
view, we analyzed first-year drug costs, procedures and acute care interventions for a<br />
NSCLC patients on chemo vs TT in the 1L setting.<br />
Methods: Using Inovalon’s MORE 2 Registry® US claims data, aNSCLC pts were<br />
identified by International Classification <strong>of</strong> Diseases-9 codes from July 2013 to June<br />
2014. Inclusion: aNSCLC pts >18 years who received 1L systemic therapy within 6<br />
months (mo) <strong>of</strong> diagnosis. Exclusion: pts with small-cell lung cancer or secondary<br />
malignancies, clinical trial pts, pts with
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
1274P<br />
A phase 2 study <strong>of</strong> LY3023414 and necitumumab after<br />
first-line chemotherapy for metastatic squamous non-small<br />
cell lung cancer (NSCLC)<br />
M. Johnson 1 , V. Wacheck 2 , M. Hussein 3 , M. McCleod 4 , D. Daniel 5 ,<br />
D. Waterhouse 6 , M. Gil 2 , D. Strickland 7 , J.C. Bendell 1<br />
1 <strong>Oncology</strong>, Sarah Cannon Research Institute/Tennessee <strong>Oncology</strong>, PLLC,<br />
Nashville, TN, USA, 2 <strong>Oncology</strong>, Eli Lilly and Company, Indianapolis, IN, USA,<br />
3 <strong>Oncology</strong>, Florida Cancer Institute, St Petersburg, FL, USA, 4 <strong>Oncology</strong>, Florida<br />
Cancer Specialists, Ft. Myers, FL, USA, 5 <strong>Oncology</strong>, Tennessee <strong>Oncology</strong>,<br />
Chattanooga, TN, USA, 6 Medical <strong>Oncology</strong>, <strong>Oncology</strong> Hematology Care,<br />
Cincinnati, OH, USA, 7 <strong>Oncology</strong>, Sarah Cannon Research Institute, Nashville, TN,<br />
USA<br />
Background: The PI3K/AKT pathway is a promising target in NSCLC, especially in<br />
squamous (sq) tumors which show high frequencies <strong>of</strong> PI3K mutations and PTEN<br />
deletions. Epidermal growth factor receptor (EGFR) is also expressed in sq NSCLC<br />
tumors, and when treated with EGFR inhibitors, PI3K/AKT is up-regulated. In a sq<br />
NSCLC xenograft model, combination therapy with the EGFR monoclonal antibody,<br />
Necitumumab (Neci), and the PI3K/mTOR dual inhibitor, LY3023414 (LY), causes<br />
synergistic tumor regression. We initiated a phase 2 study evaluating these agents in pts<br />
with sq NSCLC. Here we report the first-in-human lead-in portion <strong>of</strong> the study.<br />
Methods: Patients (pts) with metastatic sq NSCLC after platinum-containing therapy<br />
for advanced disease were eligible. Prior immunotherapy was allowed. Pts who<br />
developed venous thromboembolism within 3 months prior to screening or had<br />
uncontrolled diabetes were excluded. Pts received LY 200 mg PO BID on days (d) 1-21<br />
and Neci 800 mg IV d1 and d8 <strong>of</strong> a 21 d cycle until disease progression or intolerable<br />
toxicity. Tumor assessments were performed every 6 weeks. Pts who had<br />
received ≥ 75% <strong>of</strong> the 1st cycle <strong>of</strong> treatment (tx) were considered evaluable for safety.<br />
Results: Fifteen pts were treated in the safety lead-in. Median age was 66, 86 % (13 pts)<br />
were male, 73 % (11 pts) were current or former smokers, and all had ECOG<br />
performance status 0-1. Seven pts were evaluable for safety. There were no<br />
dose-limiting toxicities and no serious tx-related adverse events (TRAEs). Common<br />
TRAEs are summarized in Table 1. Single-agent toxicity was not synergistic. Median<br />
duration <strong>of</strong> tx was 5 weeks (range 1-19+ weeks). Six pts remain on tx.<br />
Table: 1274P<br />
TRAE in ≥10% <strong>of</strong> pts, n (%) Grade 1-2 Grade 3-4 Total<br />
Acneiform Rash 7 (47%) 1 (7%) 8 (53%)<br />
Fatigue 4 (27%) 1 (7%) 5 (33%)<br />
Nausea 4 (27%) 0 4 (27%)<br />
Dehydration 3 (20%) 0 3 (20%)<br />
Headache 3 (20%) 0 3 (20%)<br />
Elevated ALT 1 (7%) 1 (7%) 2 (13%)<br />
Anorexia 2 (13%) 0 2 (13%)<br />
Chills 2 (13%) 0 2 (13%)<br />
Hypomagnesemia 2 (13%) 0 2 (13%)<br />
Mucositis 1 (7%) 1 (7%) 2 (13%)<br />
Vomiting 2 (13%) 0 2 (13%)<br />
Weakness 2 (13%) 0 2 (13%)<br />
Weight Loss 2 (13%) 0 2 (13%)<br />
Conclusions: The combination <strong>of</strong> Neci and LY in sq NSCLC has preclinical rationale,<br />
appears to be safe and tolerable in patients, and is without over-lapping toxicities.<br />
Enrollment <strong>of</strong> the post lead-in cohort to determine efficacy in a total <strong>of</strong> 48 pts is<br />
on-going.<br />
Clinical trial identification: NCT02443337<br />
Legal entity responsible for the study: Clinical Trials.gov<br />
Funding: Eli Lilly and Company<br />
Disclosure: V. Wacheck: Eli Lilly- Employee and Stock Ownership. D. Waterhouse:<br />
Lilly-speaker’s fee. M. Gil: Lilly-employee and stock ownership. All other authors have<br />
declared no conflicts <strong>of</strong> interest.<br />
1275P<br />
ANSELMA: ANtiangiogneic SEcond line Lung cancer<br />
Meta-Analysis in non-small cell lung cancer (NSCLC)<br />
J. Remon Masip 1 , C-T. Thuong 2 , J-P. Pignon 3 , B. Lacas 3 , J-C. Soria 1 , B. Besse 1<br />
1 Medicine - Oncologie Thoracique, Institut Gustave Roussy, Villejuif, France,<br />
2 Bioestatisitics, Institut Gustave Roussy, Villejuif, France, 3 Service de Biostatistique<br />
et d’Epidemiologie, Gustave Roussy Cancer Campus, Villejuif, France<br />
Background: Only 20% <strong>of</strong> NSCLC patients have a response to immune checkpoint<br />
inhibitors as second-line treatment. Several randomized phase II and III trials have<br />
tested the efficacy <strong>of</strong> the combination <strong>of</strong> antiangiogenic drugs (AD) plus chemotherapy<br />
(CT) or erlotinib (E) with inconsistent benefit. We performed a meta-analysis to<br />
validate the efficacy <strong>of</strong> these agents as strategy second-line option in advanced NSCLC<br />
patients.<br />
Methods: Randomized trials <strong>of</strong> AD plus standard second-line treatment, CT<br />
(docetaxel [Do], pemetrexed) or E compared to same standard treatment ending<br />
accrual before 2015 were included based on search <strong>of</strong> publication databases, abstract<br />
proceedings and trial registers. Data were extracted from publications. Random-effect<br />
models, in case <strong>of</strong> significant heterogeneity (Het), fixed-effect model otherwise, were<br />
used to compute pooled hazard ratios (HRs) for overall survival (OS, primary<br />
end-point) and PFS and pooled odds ratios (ORs) for response rate (RR) and adverse<br />
events. Het was studied using Q-test I 2 .<br />
Results: seventeen trials with 8,703 patients were included with 3 types <strong>of</strong><br />
combinations: 5 trials monoclonal antibodies AD + CT (Do for 5), 7 on tyrosine kinase<br />
inhibitor (TKI) AD + CT (Do for 3) and 5 AD (TKI for 4) + E. Trial size ranged from<br />
100 to 1391 patients. ADs evaluated were: cabozantinib (1 trial), aflibercept (1),<br />
nintedanib (2), ramucirumab (2), sorafenib (2), bevacizumab (3), vandetanib (3),<br />
sunitinib (3). Control arm was docetaxel (8 trials), pemetrexed (4), E (5). Compared<br />
with standard second-line treatment alone, AD significantly prolonged OS (HR 0.94<br />
[95% confidence interval 0.89-0.99, random-effect model; P = 0.03; P-Het = 0.004), PFS<br />
(0.79; [0.73- 0.85], random effect model; P < 0.0001; P-Het = 0.003), and improved RR<br />
(OR: 1.86 [1.63-2.12], fixed-effect model; P < 0.0001, P-Het = 0.30). There was no<br />
difference in the benefit in OS, PFS and RR between the 3 types <strong>of</strong> combination tested.<br />
Conclusions: Antiangiogenic drugs significantly prolong OS and PFS when added to<br />
standard second-line treatment in advanced NSCLC patients. Toxicity results will be<br />
presented during the congress<br />
Legal entity responsible for the study: N/A<br />
Funding: Gustave Roussy<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1276P<br />
Efficacy and safety <strong>of</strong> nintedanib (NIN)/docetaxel (DOC) in<br />
patients with lung adenocarcinoma: Further analyses from<br />
the LUME-Lung 1 study<br />
D. Heigener 1 , M. Gottfried 2 , J. Bennouna 3 , I. Bondarenko 4 , J-Y. Douillard 3 ,<br />
M. Krzakowski 5 , A. Mellemgaard 6 , S. Novello 7 ,S.Orlov 8 , Y.J. Summers 9 , J. von<br />
Pawel 10 , J. Hocke 11 , R. Kaiser 12 , M. Reck 13<br />
1 Department <strong>of</strong> Thoracic <strong>Oncology</strong>, LungenClinic Grosshansdorf, Grosshansdorf,<br />
Germany, 2 Lung Cancer Unit, Meir Medical Center, Kfar Saba, Israel,<br />
3 Département d’Oncologie Médicale, ICO Institut de Cancerologie de l’Ouest<br />
René Gauducheau, St. Herblain, France, 4 Department <strong>of</strong> <strong>Oncology</strong>,<br />
Radiodiagnosis and Radioth, Dnipropetrovsk Municipal Clinical Hospital #4,<br />
Dnepropetrovsk, Ukraine, 5 Lung & Thoracic Tumours Dept, MSC Memorial<br />
Cancer Centre and Institute Maria Sklodowska-Curie, Warsaw, Poland,<br />
6 Department <strong>of</strong> <strong>Oncology</strong>, University Hospital Herlev, Herlev, Denmark,<br />
7 Department <strong>of</strong> <strong>Oncology</strong>, Azienda Ospedaliero-Universitaria ASOU San Luigi<br />
Gonzaga, Orbassano, Italy, 8 Department <strong>of</strong> Thoracic <strong>Oncology</strong>, GOU VPO St<br />
Petersburg State Medical University, Saint Petersburg, Russian Federation,<br />
9 Department <strong>of</strong> Lung Cancer, The Christie NHS Foundation Trust, Manchester,<br />
UK, 10 <strong>Oncology</strong>, Asklepios-Fachklinikum, Gauting, Germany, 11 Medical Data<br />
Services and Biostatistics, Boehringer Ingelheim Pharma GmbH & Co.KG,<br />
Biberach, Germany, 12 Corporate Division Medicine, TA <strong>Oncology</strong>, Boehringer<br />
Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany, 13 Thoracic <strong>Oncology</strong>,<br />
Lung Clinic Grosshansdorf, Airway Research Center North (ARCN), member <strong>of</strong> the<br />
German Center for Lung Research (DZL), Grosshansdorf, Germany<br />
Background: NIN is a triple angiokinase inhibitor approved in the EU in combination<br />
with DOC for the treatment <strong>of</strong> adenocarcinoma non-small cell lung cancer patients<br />
after first-line therapy (FLT). A continuous linear correlation between overall survival<br />
(OS) benefit with NIN and the predictive marker “time from start <strong>of</strong> FLT” (TSFLT) has<br />
been observed in adenocarcinoma patients.<br />
Methods: First, analyses were conducted <strong>of</strong> European adenocarcinoma patients, who<br />
comprise the majority <strong>of</strong> the population from the Phase III LUME-Lung 1 trial<br />
comparing NIN/DOC with placebo (PLA)/DOC (NCT00805194). Second, in order to<br />
further characterise time from FLT, analyses were conducted in adenocarcinoma<br />
populations defined by the dichotomisation at appropriate cut-points <strong>of</strong> TSFLT or<br />
progressive disease (PD) as best response to FLT. Analyses based on “time from end <strong>of</strong><br />
FLT” (TEFLT) as described in other clinical trials were also performed.<br />
Results: In the overall adenocarcinoma population (n = 658), both independently<br />
assessed progression-free survival (median 4.0 vs 2.8 months, hazard ratio [HR] 0.77<br />
[95% CI 0.6–0.96]; p = 0.0193) and OS were significantly longer with NIN/DOC vs<br />
PLA/DOC (median OS [mOS] 12.6 vs 10.3 months, HR 0.83 [95% CI 0.70–0.99];<br />
p = 0.0359). OS improved both in the overall European adenocarcinoma (n = 463; mOS<br />
13.4 vs 8.7 months, HR 0.79 [0.65–0.97]; p = 0.0254) and in European adenocarcinoma<br />
patients with TSFLT < 9 months (n = 271; mOS 11.0 vs 6.9 months, HR 0.69 [0.53–<br />
0.89]; p = 0.0049). In the overall adenocarcinoma population, OS also improved in<br />
patients with TSFLT < 9 months (n = 405; mOS 10.9 vs 7.9 months, HR 0.75 [0.60–<br />
0.92]; p = 0.0073); TSFLT < 6 months (n = 232; mOS 9.5 vs 7.5 months, HR 0.73 [0.55–<br />
0.98]; p = 0.0327); and PD to FLT (n = 117; mOS 9.8 vs 6.3 months,HR 0.62 [0.41–<br />
0.94]; p = 0.0246). Analyses based on TEFLT provided similar results to TSFLT.<br />
Adverse events (AEs) reported with NIN included manageable gastrointestinal AEs<br />
and liver enzyme elevations.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw383 | vi445
abstracts<br />
Conclusions: NIN plus DOC exhibits significant OS benefits in the adenocarcinoma<br />
population and a more pronounced OS benefit in patients with a shorter time since<br />
FLT and more aggressive tumours.<br />
Clinical trial identification: NCT00805194<br />
Legal entity responsible for the study: Boehringer Ingelheim GmbH & Co. KG<br />
Funding: Boehringer IngelheimGmbH & Co. KG<br />
Disclosure: D. Heigener: Honoraria and travel reimbursements from Boehringer<br />
Ingelheim. Honoraria from Eli Lilly, Roche, Pfizer and BMS and non-financial funding<br />
from Boehringer Ingelheim during the conduct <strong>of</strong> this study. M. Gottfried:<br />
Non-financial support from Boehringer lngelheim during the conduct <strong>of</strong> the<br />
study. J. Bennouna: Personal fees from Roche, Astra-Zeneca and Boehringer Ingelheim<br />
and non-financial support from Boehringer Ingelheim in the conduct <strong>of</strong> this<br />
study. I. Bondarenko: Non-financial support from Boehringer Ingelheim during the<br />
conduct <strong>of</strong> this study. J-Y. Douillard: Personal fees from Boehringer Ingelheim, Astra<br />
Zeneca and NEKTAR. Non-financial funding from Boehringer Ingelheim. His institute<br />
receives grants from Merck Serono. M. Krzakowski: Honoraria from Boehringer<br />
Ingelheim, Merck, BMS and Roche and non-financial support from Boehringer<br />
Ingelheim. A. Mellemgaard: Honoraria from Boehringer Ingelheim. Non financial<br />
support during the conduct <strong>of</strong> this study from Boehringer Ingelheim. S. Novello:<br />
Honoraria from Boehringer Ingelheim, Eli Lilly, Roche, Astra-Zeneca and MSD.<br />
Non-financial support from Boehringer Ingelheim during the conduct <strong>of</strong> this<br />
study. S. Orlov: Non-financial funding from Boehringer Ingelheim during the conduct<br />
<strong>of</strong> this study. Y.J. Summers: Honoraria and non-financial funding from Boehringer<br />
Ingelheim. J. von Pawel: Non-financial support from Boehringer Ingelheim. J. Hocke,<br />
R. Kaiser: Employee <strong>of</strong> Boehringer Ingelheim. M. Reck: Non-financial support from<br />
Boehringer lngelheim. Honoraria from Boehringer lngelheim, Roche, Eli Lilly, MSD,<br />
BMS, AstraZeneca, Pfizer, and Novartis.<br />
1277P<br />
Bevacizumab in routine clinical practice for first-line therapy<br />
with platinum-based chemotherapy <strong>of</strong> patients with<br />
advanced adenocarcinoma <strong>of</strong> the lung in Germany<br />
H.R. Wirtz 1 , S. Lang 2 , J. Mezger 3 , S. Hammerschmidt 4 , T. Gaska 5 ,<br />
C. Lerchenmueller 6 , M. Reck 7 , S. Haas 8 , D. Reichert 9 , G. Hoeffken 10<br />
1 Medizinische Klinik und Poliklinik I, Universitaetsklinikum Leipzig, Leipzig,<br />
Germany, 2 Medizinische Klinik 2, SRH Wald-Klinikum Gera GmbH, Gera,<br />
Germany, 3 Medizinische Klinik 2, Hämatatologie, Onkologie, Immunologie,<br />
Palliativmedizin, ViDiaKliniken Karlsruhe, Karlsruhe, Germany, 4 Klinik für Innere<br />
Medizin IV, Klinikum Chemnitz gGmbH, Chemnitz, Germany, 5 Klinik fuer<br />
Haematologie und Onkologie, Bruederkrankenhaus St. Josef Paderborn,<br />
Paderborn, Germany, 6 Haematologie und Onkologie, Ueberoertliche<br />
Gemeinschaftspraxis, Münster, Germany, 7 Department <strong>of</strong> Thoracic <strong>Oncology</strong>,<br />
member <strong>of</strong> the German Center for Lung Research (DZL), LungenClinic, Airway<br />
Research Center North (ARCN), Grosshansdorf, Germany, 8 Klinik für<br />
Haematologie, Onkologie und Nephrologie, Friedrich-Ebert-Krankenhaus GmbH,<br />
Neumünster, Germany, 9 <strong>Oncology</strong> and Hematology, Medizinische<br />
Studiengesellschaft Nord-West GmbH, Westerstede, Germany, 10 Pneumologie,<br />
Medizinischen Klinik I des Universitätsklinikum Carl Gustav Carus, Dresden,<br />
Germany<br />
Background: This single-arm, non-interventional study ML28306 aimed at evaluating<br />
the effectiveness and safety <strong>of</strong> 1L Bevacizumab (BEV) treatment, focusing on 4 defined<br />
age groups, with platinum-based chemotherapy in patients with unresectable<br />
advanced, metastatic or recurrent adenocarcinoma <strong>of</strong> the lung in routine practice.<br />
Methods: The study is fully recruited with 1107 patients in 174 centers. 990 patients<br />
who received ≥1 BEV-dose to date are included in the present analysis. Enrollment<br />
started 02/2013; last patient out is expected 06/2017. Baseline characteristics, treatment<br />
regimen, effectiveness and safety data are documented for each patient. Primary<br />
endpoint is progression-free survival (PFS).<br />
Results: In terms <strong>of</strong> age, 34% <strong>of</strong> patients were
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
1279P<br />
nab-paclitaxel (nab-P) + carboplatin (C) induction therapy in<br />
patients (Pts) with squamous (SCC) NSCLC: Interim quality <strong>of</strong><br />
life (QoL) outcomes from the phase 3 ABOUND.sqm study<br />
M. Thomas 1 , S. Ponce Aix 2 ,A.Ko 3 , R. Jotte 4 , T.J. Ong 5 , R. Page 6 , M. Socinski 7 ,<br />
N. Trunova 8 , V. Villaflor 9 , D.R. Spigel 10<br />
1 <strong>Oncology</strong>, Internistische Onkologie der Thoraxtumoren, Thoraxklinik im<br />
Universitätsklinikum Heidelberg, Translational Lung Research Center Heidelberg<br />
(TLRC-H), Member <strong>of</strong> the German Center for Lung Research (DZL), Heidelberg,<br />
Germany, 2 <strong>Oncology</strong>, Unidad de Investigación Clínica de Cáncer Pulmón<br />
H12O-CNIO, Madrid, Spain, 3 Biostats, Celgene Corporation, Summit, NJ, USA,<br />
4 <strong>Oncology</strong>, Rocky Mountain Cancer Centers U.S. <strong>Oncology</strong> Network, Denver, CO,<br />
USA, 5 Medical Affairs, Celgene Corporation, Summit, NJ, USA, 6 <strong>Oncology</strong>, The<br />
Center for Cancer and Blood Disorders, Fort Worth, TX, USA, 7 Medical <strong>Oncology</strong>,<br />
University <strong>of</strong> Pittsburgh UPMC Cancer Pavilion, Pittsburgh, PA, USA, 8 Medical<br />
Affairs, Celgene Corporation, Summit, NJ, USA, 9 <strong>Oncology</strong>, University <strong>of</strong> Chicago<br />
Medicine, Chicago, IL, USA, 10 <strong>Oncology</strong>, Sarah Cannon Research Institute,<br />
Nashville, TN, USA<br />
Background: Limited QoL data exist for pts with advanced NSCLC treated with<br />
platinum-doublets, though these assessments can help interpret the clinical benefit <strong>of</strong><br />
chemotherapy. Interim QoL outcomes in pts with SCC NSCLC treated with nab-P/C<br />
during the induction part <strong>of</strong> the ongoing ABOUND.sqm study are reported here.<br />
Methods: Pts with advanced SCC NSCLC received first-line nab-P 100 mg/m 2 d1,8,<br />
15 + C area under the curve 6 d 1 (21-d cycles) for 4 cycles (induction). After 4 cycles,<br />
pts without progression continued to maintenance (randomized 2:1) nab-P 100 mg/m 2 d<br />
1 and 8 <strong>of</strong> each 21-d cycle + best supportive care (BSC) or BSC alone until progression or<br />
unacceptable toxicity. Progression-free survival from randomization into the<br />
maintenance part <strong>of</strong> the study is the primary endpoint. QoL (an exploratory endpoint <strong>of</strong><br />
induction and maintenance parts) was assessed on d 1 <strong>of</strong> each cycle using the Lung<br />
Cancer Symptom Scale (LCSS) and Euro-QoL-5 Dimensions-5 Levels (EQ-5D-5L). This<br />
pre-planned analysis reports interim QoL data from induction to data cut<strong>of</strong>f.<br />
Results: 195 pts were included in this interim report; 90% completed baseline (BL)<br />
and ≥ 1 post-BL QoL assessments. The median age was 68 years, 65% were male, and<br />
99% had 0-1 Eastern Cooperative <strong>Oncology</strong> Group performance status. During<br />
induction, the mean change from BL in LCSS symptom burden index and total score<br />
improved by ≥ 10.4% and ≥ 9.2%, respectively. Clinically meaningful improvements (≥<br />
10 mm [visual analog scale]) from BL in the individual LCSS items <strong>of</strong> cough, shortness<br />
<strong>of</strong> breath, and blood in sputum were observed in 59%, 47%, and 16% <strong>of</strong> all pts. Each<br />
dimension <strong>of</strong> the EQ-5D-5L was improved from BL in the majority <strong>of</strong> pts (81%-92%),<br />
and more than 33% <strong>of</strong> all pts reported complete resolution <strong>of</strong> ≥ 1 specific dimension<br />
problem reported at BL.<br />
Conclusions: nab-P/C treatment maintained or improved QoL in pts with SCC<br />
NSCLC in the induction part <strong>of</strong> this trial. Clinically meaningful improvements were<br />
observed in several LCSS items, and many pts had complete resolution <strong>of</strong> problems<br />
reported at BL in some EQ-5D-5L dimensions. NCT02027428<br />
Clinical trial identification: NCT02027428<br />
Legal entity responsible for the study: N/A<br />
Funding: Celgen Pharmaceutical<br />
Disclosure: M. Thomas: Honoraria speaker/advisor from: Celgene, Astra Zeneca,<br />
Roche, BMS, MSD, Lilly, Novartis, MI. A. Ko, T.J. Ong, N. Trunova: Employee <strong>of</strong><br />
Celgene and owns stock. M. Socinski: Hhonorarium from Celgene and member <strong>of</strong> their<br />
speakers’ bureau. V. Villaflor: Research funding from Celgene and Novartis that is paid<br />
directly to the University <strong>of</strong> Chicago. D.R. Spigel: Consultant to Celgene, researching<br />
funding from Celgene and travel expenses. All other authors have declared no conflicts<br />
<strong>of</strong> interest.<br />
1280P<br />
nab-paclitaxel (nab-P) + carboplatin (C) induction therapy in<br />
patients (Pts) with squamous (SCC) NSCLC: Interim safety<br />
results from the phase 3 ABOUND.sqm study<br />
O.J. Vidal 1 , D. Daniel 2 , M. Johnson 3 , J. Knoble 4 , T. Chen 5 , M. McCleod 6 ,T.<br />
J. Ong 5 , N. Trunova 5 , E. Kim 7<br />
1 <strong>Oncology</strong>, Hospital Universitari i Politècnic La Fe, Valencia, Spain, 2 <strong>Oncology</strong>,<br />
Tennessee <strong>Oncology</strong>, Chattanooga, TN, USA, 3 <strong>Oncology</strong>, Sarah Cannon<br />
Research Institute, Nashville, TN, USA, 4 Hematology/<strong>Oncology</strong>, The Mark<br />
H. Zangmeister Center, Columbus, OH, USA, 5 Medical Affairs, Celgene<br />
Corporation, Summit, NJ, USA, 6 <strong>Oncology</strong>, Florida Cancer Specialists, Ft. Myers,<br />
FL, USA, 7 <strong>Oncology</strong>, Levine Cancer Institute, Carolinas Healthcare System,<br />
Charlotte, NC, USA<br />
Background: Safe and effective chemotherapy options in the maintenance setting are<br />
limited for pts with SCC NSCLC. The ongoing phase 3 ABOUND.sqm study is<br />
evaluating nab-P as maintenance therapy after nab-P/C induction in pts with SCC<br />
NSCLC. Interim safety outcomes from the induction part <strong>of</strong> the study are reported<br />
here.<br />
Methods: Chemotherapy-naive pts with advanced SCC NSCLC received nab-P 100<br />
mg/m 2 d 1, 8, 15 + C area under the curve 6 d 1 (21-d cycles) for 4 cycles intravenously<br />
(induction). Pts without progression after 4 cycles were randomized 2:1 to<br />
maintenance nab-P 100 mg/m 2 d 1 and 8 <strong>of</strong> each 21-d cycle + best supportive care<br />
(BSC) or BSC alone until progression or unacceptable toxicity. The primary endpoint<br />
<strong>of</strong> the study is progression-free survival from randomization into the maintenance part<br />
<strong>of</strong> the study. The secondary endpoints include safety (analyzed as treatment-emergent<br />
adverse events [TEAEs]) and efficacy.<br />
Results: 212 pts were treated in the induction period. The median age <strong>of</strong> these pts was<br />
68 years, 66% were male, 87% were white, and 99% had an Eastern Cooperative<br />
<strong>Oncology</strong> Group performance status <strong>of</strong> 0-1. Overall, 44% <strong>of</strong> pts (94/212) discontinued<br />
induction treatment; <strong>of</strong> these, 37% discontinued due to progression, 24% due to<br />
adverse events, 12% due to other reasons, 11% due to death, 10% due to pt decision,<br />
and 6% due to symptomatic deterioration. The median percentage <strong>of</strong> per protocol dose<br />
<strong>of</strong> nab-P was 75%. Dose adjustments included at least 1 nab-P dose reduction, dose<br />
missed, or dose delay, in 41%, 51%, and 58% <strong>of</strong> treated pts, respectively. The median<br />
dose intensity for nab-P was 74.87 mg/m 2 /week. Grade 3/4 TEAEs included<br />
neutropenia (41%), anemia (25%), and thrombocytopenia (16%), and 8 pts (4%)<br />
experienced grade 3/4 peripheral sensory neuropathy.<br />
Conclusions: These interim results <strong>of</strong> the ABOUND.sqm study indicate no new safety<br />
signals in pts with SCC NSCLC receiving nab-P/C induction therapy. Updated results<br />
will be presented at the meeting. NCT02027428<br />
Clinical trial identification: NCT02027428<br />
Legal entity responsible for the study: N/A<br />
Funding: Celgene Corporation<br />
Disclosure: O.J. Vidal: Dr Juan Vidal: Advisory role or speaker: Roche, Astra, MSD,<br />
Boehringer, Bristol-Myers, Lilly, Pfizer, Pierre-Fabre. M. Johnson: Ad Board/<br />
Consultant/Honorarium from Celgene. J. Knoble: Consultant to Cardinal Health; is a<br />
member <strong>of</strong> the following Speakers’ Bureau: Novartis, Celgene, Alexion. T. Chen, T.J.<br />
Ong, N. Trunova: Employee <strong>of</strong> Celgene, owns stock. All other authors have declared no<br />
conflicts <strong>of</strong> interest.<br />
1281P<br />
abstracts<br />
Quality <strong>of</strong> life (QoL) in elderly patients (pts) with advanced<br />
NSCLC treated with nab-paclitaxel (nab-P) + carboplatin (C):<br />
Interim results from the ABOUND.70+ study<br />
J. Weiss 1 , E. Kim 2 , K.I. Amiri 3 , E. Anderson 4 , S. Dakhil 5 , D. Haggstrom 2 , R. Jotte 6 ,<br />
K. Konduri 7 , M. Modiano 8 , T.J. Ong 3 , A. Sanford 9 , D. Smith 10 , M. Socoteanu 11 ,<br />
J. Goldman 12 , C. Langer 13<br />
1 <strong>Oncology</strong>, Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA,<br />
2 <strong>Oncology</strong>, Levine Cancer Institute, Charlotte, NC, USA, 3 Medical Affairs, Celgene<br />
Corporation, Summit, NJ, USA, 4 <strong>Oncology</strong>, Knight Cancer Institute, Oregon<br />
Health and Science University, Portland, OR, USA, 5 Hematology, Cancer Center <strong>of</strong><br />
Kansas, Wichita, KS, USA, 6 <strong>Oncology</strong>, Rocky Mountain Cancer Centers U.S.<br />
<strong>Oncology</strong> Network, Denver, CO, USA, 7 <strong>Oncology</strong>, Baylor Charles A. Sammons<br />
Cancer Center, Dallas, TX; Texas <strong>Oncology</strong> PA, Dallas, TX, USA, 8 <strong>Oncology</strong>,<br />
ACRC/Arizona Clinical Research Center and Arizona <strong>Oncology</strong>, Tucson, AZ, USA,<br />
9 Biostats, Celgene Corporation, Summit, NJ, USA, 10 <strong>Oncology</strong>, Compass<br />
<strong>Oncology</strong>, Vancouver, WA, USA, 11 <strong>Oncology</strong>, Texas <strong>Oncology</strong> Tyler/Longview,<br />
Longview, TX, USA, 12 <strong>Oncology</strong>, University <strong>of</strong> California, Los Angeles, CA, USA,<br />
13 <strong>Oncology</strong>, Abramson Cancer Center, University <strong>of</strong> Pennsylvania, Philadelphia,<br />
PA, USA<br />
Background: The lack <strong>of</strong> QoL assessment in elderly pts receiving chemotherapy for<br />
NSCLC is an important issue that potentially hinders treatment decisions. We report<br />
interim QoL outcomes in elderly pts with advanced NSCLC treated with nab-P/C in<br />
the ABOUND.70+ study.<br />
Methods: Pts ≥ 70 years <strong>of</strong> age with locally advanced/metastatic NSCLC were<br />
randomized 1:1 to first-line nab-P 100 mg/m 2 d 1, 8, 15 + C area under the curve 6 d 1<br />
every 21 days (arm A) or the same nab-P/C regimen followed by a 1-week break between<br />
cycles (arm B, every 28 days). The percentage <strong>of</strong> pts with either grade ≥ 2 peripheral<br />
neuropathy or grade ≥ 3 myelosuppression adverse events is the primary endpoint. QoL<br />
(an exploratory endpoint) was assessed using the Lung Cancer Symptom Scale (LCSS)<br />
and Euro-QoL-5 Dimensions-5 Levels (EQ-5D-5L) on d 1 <strong>of</strong> each cycle.<br />
Results: Of 119 pts included in this report, > 85% completed baseline (BL) and > 70%<br />
completed BL +≥ 1 post-BL QoL assessments. The median age was 76 years (range, 70<br />
- 93 years), 56% were male, and 99% had an Eastern Cooperative <strong>Oncology</strong> Group<br />
performance status <strong>of</strong> 0-1. In general, LCSS symptom burden index and average total<br />
scores improved during the first 4 cycles. In the LCSS item <strong>of</strong> cough, a mean change<br />
from BL to end <strong>of</strong> cycle 4 <strong>of</strong> 18.98 mm was observed on the visual analog scale (VAS;<br />
95% CI, 8.42 - 29.54). Clinically meaningful improvements (≥ 10 mm [VAS]) from BL<br />
in the composite LCSS items <strong>of</strong> cough, shortness <strong>of</strong> breath, and hemoptysis were<br />
observed in 50% <strong>of</strong> pts. More than 80% <strong>of</strong> pts maintained or improved each dimension<br />
<strong>of</strong> the EQ-5D-5L from BL. In pts with radiological stable disease or better (75/108<br />
evaluable had BL +≥ 1 post-BL assessment), ≥ 77% <strong>of</strong> pts reported stability/<br />
improvement in 1 or more individual EQ-5D-5L items from BL during the first 4<br />
cycles <strong>of</strong> therapy; 95% <strong>of</strong> pts reported stability/improvement in their anxiety/<br />
depression score at least once.<br />
Conclusions: These interim results from the ABOUND.70+ study suggest that nab-P/<br />
C treatment resulted in clinically meaningful QoL improvements in elderly pts with<br />
NSCLC. The study is ongoing, and efficacy and safety data will be reported at future<br />
meetings. NCT02151149<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw383 | vi447
abstracts<br />
Clinical trial identification: NCT02151149<br />
Legal entity responsible for the study: N/A<br />
Funding: Celgene Corporation<br />
Disclosure: E. Kim: Grant reseach and speakers bureau. K.I. Amiri, T.J. Ong,<br />
A. Sanford: Employee <strong>of</strong> Celgene and owns stock. K. Konduri: Consultant/ Advisory<br />
Board: Boehringer Ingelheim; DAVA- Pharmaceuticals, Celgene. J. Goldman: Research<br />
funding from Celgene. C. Langer: Consultant/research Celgene. All other authors have<br />
declared no conflicts <strong>of</strong> interest.<br />
1282P<br />
A cross-trial comparison <strong>of</strong> pemetrexed-platinum followed by<br />
pemetrexed continuation maintenance versus<br />
gemcitabine-cisplatin without maintenance in<br />
chemotherapy-naive patients with advanced nonsquamous<br />
non-small-cell lung cancer<br />
Y-L. Wu 1 , B. Zhang 2 , X. Wang 2 , M. Orlando 3 , H. Chi 2<br />
1 Guangdong Lung Cancer Institute, Guangdong General Hospital & Guangdong<br />
Academy <strong>of</strong> Medical Sciences, Guangzhou, China, 2 <strong>Oncology</strong>, Lilly China Drug<br />
Development and Medical Affairs Center, Shanghai, China, 3 <strong>Oncology</strong>, Eli Lilly<br />
Interamerica Inc, Buenos Aires, Argentina<br />
Background: This cross-trial pooled analysis aimed to demonstrate improved efficacy<br />
<strong>of</strong> pemetrexed (pem) - platinum (plat) followed by pem continuation maintenance<br />
over gemcitabine (gem)-cisplatin (cis) without maintenance in advanced<br />
nonsquamous non-small-cell lung cancer (NSQ NSCLC) patients.<br />
Methods: Analysis populations consisted <strong>of</strong> patients with similar baseline<br />
characteristics selected from 3 trials (JMDB, PARAMOUNT, and JMII) using a<br />
propensity score method. JMDB investigated first-line pem-cis (pem 500 mg/m 2 + cis<br />
75 mg/m 2 every 21 days [q21d] for 6 cycles) and gem-cis (gem 1250 mg/m 2 on days 1,<br />
8 + cis 75 mg/m 2 day 1 q21d for 6 cycles). PARAMOUNT compared pem maintenance<br />
vs placebo after patients with NSQ NSCLC completed 4 cycles <strong>of</strong> first-line pem-cis<br />
without progressive disease (PD). JMII examined pem-carboplatin (carb) (pem 500<br />
mg/m 2 + carb area under the curve 6 mg/mL*min q21d for 4 cycles) induction therapy<br />
followed by pem maintenance in NSQ NSCLC patients. Kaplan-Meier method and<br />
Cox regression were used to analyze overall survival (OS) and progression-free survival<br />
(PFS). Statistical inference was conducted on the overall population (OP); the analysis<br />
on the maintenance eligible population (MEP [completed 4 cycles without PD]) was<br />
descriptive.<br />
Results: OP was created with 530 patients in pem-plat and 534 patients in gem-cis<br />
arms. Of these, 287 in pem-plat and 285 in gem-cis were the MEP. In the OP,<br />
significant improvement were observed in pem-plat group than gem-cis, both in PFS<br />
(hazard ratio [HR] = 0.87, 95% confidence interval (CI): 0.77-0.99, p = .029; median<br />
PFS 5.16 m vs 5.49 m) and in OS (HR = 0.79, 95% CI: 0.69-0.91, p = .001; median OS<br />
12.29 m vs 10.91 m). For the MEP, both median PFS (7.39 m vs 6.64 m) and median<br />
OS (18.37 m vs 13.63 m) were prolonged in pem-plat compared with gem-cis.<br />
Conclusions: This cross-trial analysis supports pem-plat induction followed by pem<br />
continuation maintenance therapy as a preferred choice over gem-cis without<br />
maintenance as first-line chemotherapy for patients with advanced NSQ NSCLC.<br />
Clinical trial identification: 1. JMDB: NCT00087711 (Last verified: May<br />
2009). 2. PARAMOUNT: NCT00789373 (Last verified: March 2016). 3. JMII:<br />
NCT01020786 (Last verified: June 2013)<br />
Legal entity responsible for the study: Eli Lilly and company<br />
Funding: Eli Lilly and company<br />
Disclosure: Y-L. Wu: Ongoing unpaid consultant with Eli Lilly and MSD, and has<br />
received speaker fee from Eli Lilly, Roche, Boehringer Ingelheim, and<br />
AstraZeneca. B. Zhang, X. Wang: Currently employee <strong>of</strong> Eli Lilly and<br />
Company. M. Orlando, H. Chi: Employee and shareholders <strong>of</strong> Eli Lilly and Company.<br />
1283P<br />
The role <strong>of</strong> thymidylate synthase in non-small-cell lung<br />
cancer treated with pemetrexed continuation maintenance<br />
therapy<br />
M. Yang, W-F. Fan, X-L. Pu, L-J. Meng, J. Wang<br />
<strong>Oncology</strong>, Jiangsu Province Geriatric Hospital, Nanjing, China<br />
Background: Pemetrexed contiunuation maintenance therapy has been proved to be<br />
beneficial for patients with advanced non-squamous NSCLC. The ongoing need to<br />
identify those patients who will benefit more from pemetrexed continuation<br />
maintenance suggests a more detailed research on resistance to pemetrexed is required.<br />
Our previous research has explored high expression <strong>of</strong> thymidylate synthase (TS) in<br />
pulmonary adenocarcinoma and shown it is associated with acquired resistance to<br />
pemetrexed, which may predict drug sensitivity to pemetrexed. Therefore, this trial was<br />
designed to assess prospectively the association between TS and clinical outcome <strong>of</strong><br />
pemetrexed continuation maintenance.<br />
Methods: The patients underwent two treatment phases: an induction phase and<br />
maintenance phase. Maintenance phase eligibility criteria included ECOG PS 0 or 1<br />
and completion <strong>of</strong> four cycles <strong>of</strong> induction chemotherapy with radiographic evidence<br />
<strong>of</strong> partial response (PR) or complete response (CR) or stable disease (SD). Collection <strong>of</strong><br />
tissue sample was mandatory before and after induction therapy. Real-time quantitative<br />
PCR was used to detect TS expression. TS expression level was correlated with clinical<br />
characteristic data, radiographic response, progression-free survival (PFS) and overall<br />
survival (OS).<br />
Results: As for all 127 patients, low TS expression was associated with objective<br />
response [mean 6.85 ± 3.67, median 6.14 for responders (CR + PR) vs. mean<br />
8.56 ± 3.69, median 8.89 for non-responders (SD + PD), P = 0.016], but not disease<br />
control (mean 7.76 ± 3.83, median 8.32 for CR/PR/SD vs. mean 8.55 ± 3.58, median<br />
8.43 for PD, P = 0.275) after four cycles <strong>of</strong> induction treatment. As for the 87 patients<br />
who received maintenance therapy, a median score <strong>of</strong> 8.47, detected after induction<br />
treatment, was used to clarify patients as “high” or “low” TS expression. There was a<br />
significantly longer median PFS (4.7 months vs. 3.5 months, P = 0.034) and median OS<br />
(Time from random assignment: 16.4 months vs. 11.7 months, P = 0.026; Time from<br />
induction: 19.7 months vs. 14.8 months, P = 0.022) in the patients with low TS<br />
expression compared with those with high expression.<br />
Conclusions: In NSCLC patients receiving pemetrexed continuation maintenance<br />
therapy, low TS expression is associated with improved PFS and OS.<br />
Legal entity responsible for the study: Department <strong>of</strong> <strong>Oncology</strong>, Jiangsu Geriatric<br />
Hospital<br />
Funding: Jiangsu Geriatric Institute<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1284P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Final results <strong>of</strong> a phase II study <strong>of</strong> oral vinorelbine (NVBo)<br />
monotherapy in patients (pts) with advanced EGFR-positive<br />
non-small-cell lung cancer (NSCLC) after failure <strong>of</strong> EGFR-TKI<br />
in first line (NAVoTRIAL 2)<br />
E-H. Tan 1 , G. Banna 2 , R. Ramlau 3 , G. Ceresoli 4 , A. Camerini 5 , J. Milanowski 6 ,<br />
M. Caruso 7 , P. Landreau 8 , J-C. Vedovato 8 , D. Kowalski 9<br />
1 Medical <strong>Oncology</strong>, National Cancer Center, Singapore, 2 UO di Oncologia<br />
Medica, Azienda Ospedaliera per l’Emergenza Cannizzaro, Catania, Italy,<br />
3 <strong>Oncology</strong> Department, Poznan University <strong>of</strong> Medical Sciences, Poznan, Poland,<br />
4 UO di Oncologia Medica, Cliniche Humanitas Gavazzeni, Bergamo, Italy, 5 UOC<br />
Oncologia Medica, Ospedale Unico Versilia, Lido Di Camaiore, Italy, 6 Department<br />
<strong>of</strong> Pneumology, <strong>Oncology</strong> and Allergology, Medical University <strong>of</strong> Lublin, Lublin,<br />
Poland, 7 Unità Funzionale di Oncologia Medica, Humanitas Centro Catanese di<br />
Oncologia, Catania, Italy, 8 Medical Affairs <strong>Oncology</strong>, Institut de Recherche Pierre<br />
Fabre, Boulogne, France, 9 Department <strong>of</strong> Lung Cancer and Chest Tumours, The<br />
Maria Sklodowska-Curie Institute <strong>of</strong> <strong>Oncology</strong>, Warsaw, Poland<br />
Background: In advanced/metastatic EGFR-positive (EGFR+) NSCLC pts progressing<br />
after EGFR-TKIs failure in first line, single-agent chemotherapy (CT) may be <strong>of</strong>fered in<br />
pts who are unfit for a platinum combination. In this study, NVBo was evaluated as<br />
monotherapy in advanced NSCLC EGFR+ pts who failed to EGFR-TKIs in first line.<br />
Methods: Phase II, multicentre, open-label, international study. Main eligibility<br />
criteria: stage IIIB/IV NSCLC, EGFR + , prior EGFR-TKI treatment failure, Karn<strong>of</strong>sky<br />
PS ≥70, no prior CT or immunotherapy. Study treatment until progression or<br />
unacceptable toxicity: NVBo 60 mg/m 2 weekly for 3 weeks (first cycle), followed by 80<br />
mg/m 2 weekly for subsequent cycles in absence <strong>of</strong> grade 3/4 toxicity. The primary<br />
endpoint was the disease control rate (DCR = CR + PR + SD, RECIST 1.1).<br />
Results: 30 pts included (March 2013 - November 2014). Main pts characteristics:<br />
median age: 66.8 years (60% ≥65 years); median Karn<strong>of</strong>sky PS 90%. Adenocarcinoma<br />
96.7%. ≥3 organs involved (53.3%). All pts harboured EGFR mutation and received<br />
prior EGFR-TKI therapy: Gefitinib 73.3%, Erlotinib 16.7%, Afatinib 10%; 33.3% <strong>of</strong> pts<br />
had ≥2 comorbidities; Total number <strong>of</strong> cycles: 166 (443 doses administered); median<br />
number <strong>of</strong> cycles: 3.5 (range 1-20); median relative dose intensity: 77.6% (range<br />
46.8-105); dose escalation was performed in 76.7 % <strong>of</strong> pts; Disease control rate 63.3%<br />
(95% CI [43.8-80]) and 23.3% <strong>of</strong> patients with stable disease ≥6 months. Median time<br />
to treatment failure: 2.7 months (range 0.4-13.6). Median PFS <strong>of</strong> 3.3 months (95% CI<br />
[1.6-5.4]) and OS <strong>of</strong> 13.1 months (95% CI [6.1-15.8]). Grade 3/4 toxicities per pt:<br />
neutropenia 53.3%, anemia 6.7%, leukopenia 26.7%, fatigue 16.7%, nausea 3.3% and<br />
vomiting 6.7%. Three cases <strong>of</strong> febrile neutropenia reported. No grade 3/4 diarrhoea,<br />
constipation, peripheral neuropathies or alopecia.<br />
Conclusions: NVBo as single-agent CT is a well-tolerated option in advanced EGFR+<br />
NSCLC pts beyond failure <strong>of</strong> EGFR-TKI in first line. Its favourable tolerability pr<strong>of</strong>ile<br />
allows a prolonged disease control in non-progressing pts.<br />
Clinical trial identification: EUDRACT Number 2012-003361-18 Sponsor’s Protocol<br />
Code Number: PM0259CA229J1.<br />
Legal entity responsible for the study: Institut de Recherche Pierre Fabre<br />
Funding: Institut de Recherche Pierre Fabre<br />
Disclosure: A. Camerini: Advisory board (Roche, Pierre-Fabre, Astra<br />
Zeneca). P. Landreau: Sponsor’s (Pierre Fabre Laboratory) employee. J-C. Vedovato:<br />
Sponsor’s employee (Pierre Fabre). All other authors have declared no conflicts <strong>of</strong> interest.<br />
vi448 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
1285TiP<br />
IFCT-1003 LADIE trial: Randomized phase II trial evaluating<br />
treatment with EGFR-TKI versus EGFR-TKI associated with<br />
anti-estrogen in women with non-squamous advanced<br />
stage NSCLC<br />
J. Mazieres 1 , F. Barlesi 2 , O. Molinier 3 , I. Monnet 4 , C. Audigier-Valette 5 , B. Besse 6 ,<br />
A-C. T<strong>of</strong>fart 7 , P.A. Renault 8 , S. Hiret 9 , S. Fraboulet-Moreau 10 , B. Mennecier 11 ,<br />
P. Masson 12 , V. Westeel 13 , P-J. Souquet 14 , E. Pichon 15 , E. Amour 16 , F. Morin 16 ,<br />
D. Moro-Sibilot 17<br />
1 Thoracic <strong>Oncology</strong>, CHU Toulouse, Hôpital de Larrey, Toulouse, France,<br />
2 Assistance Publique Hôpitaux de Marseille, Aix-Marseille University - Faculté de<br />
Médecine Nord, Marseille, France, 3 Pneumology, Centre Hospitalier Du Mans, Le<br />
Mans, France, 4 Pneumologie, CHI de Créteil, Créteil, France, 5 Pneumologie,<br />
CHITS Ste Musse (Toulon), Toulon, France, 6 Departement <strong>of</strong> Medicine, Institut<br />
Gustave Roussy, Villejuif, France, 7 Pneumologie, CHU Grenoble - Hopital<br />
Michallon, Grenoble, France, 8 Pneumologie, Centre hospitalier, Pau, France,<br />
9 Pneumologie, ICO Institut de Cancerologie de l’Ouest René Gauducheau,<br />
St. Herblain, France, 10 Pneumologie, Hopital Foch, Suresnes, France,<br />
11 Pneumologie, C.H.U. Strasbourg-Nouvel Hopital Civil, Strasbourg, France,<br />
12 Pneumologie, CH Cholet, Cholet, France, 13 Pneumologie, CHU Besançon,<br />
Hôpital Jean Minjoz, Besançon, France, 14 Thoracic <strong>Oncology</strong>, Centre Hospitalier<br />
Lyon Sud, Pierre Bénite, France, 15 Service de pneumologie, CHRU de Tours,<br />
Tours, France, 16 Clinical Research Unit, French Cooperative Thoracic Intergroup<br />
(IFCT), Paris, France, 17 Thoracic <strong>Oncology</strong>, CHU Grenoble - Hopital Michallon, La<br />
Tronche, France<br />
Background: The incidence <strong>of</strong> lung cancer is increasing dramatically in women and<br />
displays some specific epidemiological, radiological, clinical and pathological<br />
characteristics. Two main mechanisms emerged from recent findings in the field <strong>of</strong><br />
lung carcinogenesis in women: the preferential involvement <strong>of</strong> the EGFR pathway and<br />
the potential impact <strong>of</strong> hormonal factors. The interaction <strong>of</strong> estrogen receptors with<br />
growth factor receptor signalling has also been shown. Preclinical data have shown that<br />
the combination <strong>of</strong> an EGFR-Tyrosine Kinase Inhibitor (TKI) with an anti-estrogen<br />
could overcome resistance to EGFR-TKI by postponing the reactivation <strong>of</strong> the<br />
PI3K-AKT pathway through the estrogen-mediated non-genomic pathway.<br />
Trial design: We launched an open-label phase II randomized trial dedicated to<br />
women with advanced stage adenocarcinoma. Patients are treated by gefitinib (250 mg/<br />
d) vs. gefitinib + fulvestrant 500 mg MI / month (with a supplementary dose at day 15)<br />
in the EGFR mutated group (EGFR +) in first or second line setting and by erlotinib<br />
(150 mg/d, according to marketing authorization at trial initiation) vs.<br />
erlotinib + fulvestrant in the EGFR wild-type group (EGFR WT) in second or third line<br />
setting. Treatments are given until progression or unacceptable toxicity. Follow-up is<br />
performed in both arms every month to minimize the potential bias due to monthly<br />
fulvestrant injection. Primary objective is progression-free survival (PFS) at 3 and 9<br />
months for EGFR WT and EGFR + patients, respectively. Secondary objectives are<br />
safety, overall survival and quality <strong>of</strong> life. Exploratory objective is biomarkers analysis.<br />
The main inclusion criteria are histologically-confirmed non-squamous NSCLC,<br />
available tumor tissue for EGFR mutation analysis, post-menopausal women, PS 0-2.<br />
The study has been approved by all ethical committees. An ancillary study is ongoing<br />
in the EGFR mutated cohort to detect and monitor the EGFR T790M mutation in the<br />
serum. First patients have been enrolled in May 2012. To date, 326 patients (162<br />
EGFR + , 164 EGFR WT) have been enrolled and 394 (204 EGFR +, 190 EGFR WT)<br />
are expected.<br />
Clinical trial identification: NCT01556191<br />
Legal entity responsible for the study: N/A<br />
Funding: AstraZeneca, Ligue Nationale Contre le Cancer<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1286TiP<br />
abstracts<br />
NEJ026: Phase III study comparing bevacizumab plus<br />
erlotinib to erlotinib in patients with untreated NSCLC<br />
harboring activating EGFR mutations<br />
M. Maemondo 1 , T. Fukuhara 1 , S. Sugawara 2 , Y. Takiguchi 3 , A. Inoue 4 , S. Oizumi 5 ,<br />
Y. Ishii 6 , H. Yoshizawa 7 , T. Isobe 8 , A. Gemma 9 , S. Morita 10 , K. Hagiwara 11 ,<br />
K. Kobayashi 12 , T. Nukiwa 13<br />
1 Respiratory medicine, Miyagi Cancer Center, Natori, Japan, 2 Pulmonary<br />
Medicine, Sendai Kousei Hospital, Sendai, Japan, 3 Dept. <strong>of</strong> Medical <strong>Oncology</strong>,<br />
Chiba University, School <strong>of</strong> Medicine, Chiba, Japan, 4 Palliative Medicine, Tohoku<br />
University Hospital, Sendai, Japan, 5 Respiratory Medicine, Hokkaido Cancer<br />
Center, Sapporo, Japan, 6 Pulmonary Medicine and Clinical Immunology, Dokkyo<br />
Medical University, Tochigi, Japan, 7 Respiratory Medicine, Niigata Medical Center<br />
Hospital, Niigata, Japan, 8 Medical <strong>Oncology</strong> and respiratory medicine, Shimane<br />
University Faculty <strong>of</strong> Medicine, Shimane, Japan, 9 Respiratory medicine, Nippon<br />
Medical School Main Hospital, Tokyo, Japan, 10 Department <strong>of</strong> Biomedical<br />
Statistics and Bioinformatics, Kyoto University-Graduate school <strong>of</strong> medicine,<br />
Kyoto, Japan, 11 Pulmonary Medicine, Jichi Medical University, Tochigi, Japan,<br />
12 Respiratory Medicine, Saitama Medical University International Medical Center,<br />
Hidaka, Japan, 13 Respiratory Medicine, Japan Anti-Tuberculosis Association,<br />
Tokyo, Japan<br />
Background: Development <strong>of</strong> treatment for EGFR-mutated non-small-cell lung cancer<br />
(NSCLC) had been focused on monotherapy <strong>of</strong> gefitinib, erlotinib, or afatinib.<br />
However, more than half patients treated with EGFR-TKI monotherapy experience<br />
recurrence or progression <strong>of</strong> disease within a year. Some different strategies have been<br />
expected to overcome this efficacy limitations <strong>of</strong> EGFR-TKIs. One <strong>of</strong> these strategies is<br />
combination <strong>of</strong> EGFR-TKIs and VEGF inhibitors. A phase II study named JO25567<br />
comparing between erlotinib alone and erlotinib with bevacizumab as first-line therapy<br />
in patients with advanced non-squamous NSCLC harboring EGFR mutations was<br />
conducted in Japan. This study showed that the combined treatment had extremely<br />
prolonged progression free survival as a primary endpoint than the monotherapy<br />
(Hazard ratio 0.54, p = 0.0015). Consequently, we conducted a phase III study<br />
comparing combination with erlotinib plus bevacizumab with erlotinib monotherapy.<br />
Trial design: Chemotherapy-naïve patients with advanced non-squamous,<br />
EGFR-mutant NSCLC are randomly assigned to receive either erlotinib (150 mg) (E<br />
arm) or a combination with erlotinib (150 mg) plus bevacizumab (15 mg/kg) (EB arm)<br />
intravenously every 3 weeks. The doublet <strong>of</strong> platinum plus pemetrexed in EB arm and<br />
the triplet <strong>of</strong> platinum, pemetrexed, and bevacizumab in E arm are recommended as<br />
second-line therapy. Status <strong>of</strong> EGFR mutations in plasma samples are analyzed<br />
routinely from pretreatment <strong>of</strong> the first-line therapy until PD <strong>of</strong> the second-line<br />
therapy. The primary endpoint is PFS. Secondary endpoints are OS, response, safety,<br />
and patient oriented outcome. Exploratory endpoints are duration from initiation <strong>of</strong><br />
first-line treatment to PD <strong>of</strong> second-line, detection rate <strong>of</strong> plasma EGFR mutations,<br />
association between status <strong>of</strong> plasma EGFR mutation and efficacy <strong>of</strong> 1st or 2nd-line<br />
treatment, and OS analysis combined with the JO25567 study. We hypothesized that<br />
hazard ratio <strong>of</strong> PFS is 0.63. We estimated that 147 events would be needed for the study<br />
to have a power <strong>of</strong> 80% and a two-sided significance level <strong>of</strong> 5% and planned to enroll<br />
total 214 patients. The enrollment was initiated in June 2015.<br />
Clinical trial identification: UMIN000017069<br />
Legal entity responsible for the study: N/A<br />
Funding: Chugai pharm.<br />
Disclosure: M. Maemondo: Lecture fees from Chugai, AstraZeneca,<br />
Boehringer. S. Sugawara, A. Inoue, A. Gemma: Lecture fee from Chugai. Y. Takiguchi:<br />
Lecture fee from Chugai Pharmaceutical Co., AstraZeneca KK, and Boehringer<br />
Ingerheim Co. S. Oizumi: Lecture fee from AstraZeneca and Eli Lilly. S. Morita:<br />
Honorarium from Chugai and AstraZeneca. K. Kobayashi: Lecture fee from Chugai<br />
and AstraZeneca. T. Nukiwa: Lecture fee from Boehringer Ingelheim. All other authors<br />
have declared no conflicts <strong>of</strong> interest.<br />
1287TiP<br />
Design <strong>of</strong> a phase II trial comparing tepotinib + gefitinib<br />
with cisplatin + pemetrexed in EGFR inhibitor-resistant,<br />
c-Met+ NSCLC<br />
Y-L. Wu 1 , K. Park 2 , D-W. Kim 3 , R. Soo 4 , U. Stammberger 5 , W. Chen 6 ,<br />
G. Locatelli 5 , J. Yang 7<br />
1 Guangdong Lung Cancer Institute, Guangdong General Hospital, Guangzhou,<br />
China, 2 Div <strong>of</strong> Hem/Onc, Dept <strong>of</strong> Med, Samsung Medical Center Sungkyunkwan<br />
University School <strong>of</strong> Medicine, Seoul, Republic <strong>of</strong> Korea, 3 Department <strong>of</strong> Internal<br />
Medicine, Seoul National University Hospital (SNUH)-Yongon Campus, Seoul,<br />
Republic <strong>of</strong> Korea, 4 Cancer Institute, National University Cancer Institute,<br />
Singapore, 5 Global Clinical Development, Global Research and Development,<br />
Merck KGaA, Darmstadt, Germany, 6 Merck, Merck KGaA, Beijing, China,<br />
7 Department <strong>of</strong> <strong>Oncology</strong>, National Taiwan University Hospital, Taipei, Taiwan<br />
Background: The phase Ib part <strong>of</strong> this trial established a recommended phase II dose<br />
for tepotinib <strong>of</strong> 500 mg/day for use in combination with gefitinib for the treatment <strong>of</strong><br />
patients (pts) with gefitinib-resistant, locally advanced/metastatic c-Met+ NSCLC. The<br />
combination was well tolerated with evidence <strong>of</strong> antitumor activity, particularly in<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw383 | vi449
abstracts<br />
patients with c-Met+ tumors. The current design <strong>of</strong> the ongoing phase II part <strong>of</strong> the<br />
trial (NCT01982955) is described.<br />
Trial design: As previously described, eligible pts are adults <strong>of</strong> ECOG PS 0 or 1 with<br />
locally advanced/metastatic NSCLC bearing an EGFR-activating mutation and high<br />
levels <strong>of</strong> c-Met (2 + /3+ expression determined by IHC or MET amplification<br />
determined by ISH). In the randomized part, 136 pts with confirmed EGFR T790M–<br />
tumors are randomized to tepotinib 500 mg/day + gefitinib 250 mg/day PO or<br />
pemetrexed 500 mg/m 2 IV + cisplatin 75 mg/m 2 IV administered on day 1 <strong>of</strong> a 21-day<br />
cycle. In the non-randomized part, pts with EGFR T790M+ tumors receive<br />
tepotinib + gefitinib. Protocol updates have extended recruitment from Asia to include<br />
Europe and the USA, as well as making pts with acquired resistance to any approved<br />
first-line EGFR TKI, including erlotinib or afatinib as well as gefitinib, eligible. Pts with<br />
acquired resistance to any <strong>of</strong> these EGFR TKIs are expected to be resistant to gefitinib<br />
monotherapy. The primary objective is to evaluate whether progression-free survival <strong>of</strong><br />
second-line tepotinib in combination with gefitinib is superior to<br />
pemetrexed + cisplatin in pts with T790M–, c-Met+ locally advanced or metastatic<br />
NSCLC with acquired resistance to first-line EGFR TKIs. Secondary objectives are to<br />
evaluate the safety and tolerability <strong>of</strong> tepotinib in combination with gefitinib, the<br />
efficacy <strong>of</strong> tepotinib in combination with gefitinib in T790M–, c-Met+ pts, the<br />
antitumor activity <strong>of</strong> tepotinib in combination with gefitinib in T790M + , c-Met+ pts,<br />
and quality <strong>of</strong> life. This trial will establish whether the use <strong>of</strong> tepotinib in the treatment<br />
<strong>of</strong> patients with EGFR TKI-resistant, c-Met+ NSCLC merits further investigation.<br />
Legal entity responsible for the study: NCT01982955<br />
Funding: Merck KGaA<br />
Disclosure: Y-L. Wu: Paid honoraria by Roche, AstraZeneca, Eli Lilly, San<strong>of</strong>i in the<br />
past 2 years. Paid for research by Roche, AstraZeneca, Eli Lilly, Pfizer, Merck Serono,<br />
Novartis, BMS, ACEA Biosciences. K. Park: Paid for consulting or advisory role by the<br />
following companies in the past 2 years: Astra Zeneca, Boehringer Ingeiheim, Clovis,<br />
Eli Lilly, Hanmi, ONO, Roche, Novartis. Conducted paid research for AstraZeneca in<br />
the past 2 years. D-W. Kim: Paid consulting/advisory role for Novartis in the past 2<br />
years. R. Soo: Paid for consulting/advisory role in the past 2 years by AstraZeneca,<br />
Boehringer Ingelheim, Lilly, Merck, Novartis, Pfizer, Roche. Conducted research<br />
funded by AstraZeneca, Pfizer, Roche, Taiho, Merck-Serono, Novartis, Servier<br />
Bayer. U. Stammberger, G. Locatelli: Employee <strong>of</strong> Merck KGaA. W. Chen: Employee <strong>of</strong><br />
Merck Serono. J. Yang: Paid consultant/advisor to Astrazeneca, Roche/Genetech, Eli<br />
Lilly, Boehringer Ingelheim, Clovis, Novartis, Bayer, MSD, Merck, Pfizer, Astellas,<br />
Daichi-Sankyo, Celgene. Institute paid for consultation to Takeda. Research funded by<br />
Boehringer.<br />
1288TiP<br />
Efficacy and safety <strong>of</strong> first-line gefitinib treatment in<br />
metastatic lung adenocarcinoma patients with sensitizing<br />
EGFR mutation determined by ddPCR in plasma cell-free<br />
DNA (BENEFIT trial)<br />
J. Wang 1 , Y. Cheng 2 , Y-L. Wu 3 ,T.An 4 , H. Gao 5 , K. Wang 6 , Q. Zhou 3 ,Y.Hu 7 ,<br />
Y. Song 8 , C. Ding 9 ,X.Ye 10 ,F.Peng 11 , L. Liang 12 ,Y.Hu 13 , C. Huang 14 , C. Zhou 15 ,<br />
Y-K. Shi 16 , L. Zhang 17 ,Y.Gu 10<br />
1 Internal medicine, Cancer Institute and Hospital, Chinese Academy <strong>of</strong> Medical<br />
Sciences (CAMS), Beijing, China, 2 Medical <strong>Oncology</strong>, Jilin Province Cancer<br />
Hospital, Changchun, China, 3 Guangdong Lung Cancer Institute, Guangdong<br />
General Hospital, Guangzhou, China, 4 Thoracic medicine oncology, Peking<br />
University Cancer Hospital-Beijing Cancer Hospital, Beijing, China, 5 Medical<br />
<strong>Oncology</strong>, 307th Hospital <strong>of</strong> PLA (AMMS China), Beijing, China, 6 Genetics,<br />
Zhejiang Cancer Hospital, Hangzhou, China, 7 Medical <strong>Oncology</strong>, Hubei Province<br />
Tumor Hospital, Wuhan, China, 8 <strong>Oncology</strong>, Nanjing Military General Hospital,<br />
Nanjing, China, 9 <strong>Oncology</strong>, Hebei Provincial Tumor Hospital, Shijiazhuang, China,<br />
10 Asia & Emerging Markets iMed, AstraZeneca, Shanghai, China, 11 Medical<br />
<strong>Oncology</strong>, West China Hospital, Huaxi, Sichuan University, Chengdu, China,<br />
12 Medical <strong>Oncology</strong>, 3rd Hospital Beijing University, Beijing, China, 13 Medical<br />
<strong>Oncology</strong>, Chinese People’s Liberation Army General Hospital, Beijing, China,<br />
14 Medical <strong>Oncology</strong>, Fujian Provincial Cancer Hospital, Fuzhou, China, 15 Lung<br />
Cancer <strong>Oncology</strong> & Immunology, Tongji Hospital <strong>of</strong> Tongji University, Shanghai,<br />
China, 16 Medical <strong>Oncology</strong>, Cancer Institute and Hospital, Chinese Academy <strong>of</strong><br />
Medical Sciences (CAMS), Beijing, China, 17 State Key Laboratory <strong>of</strong> <strong>Oncology</strong> in<br />
South China, Sun Yat-sen University Cancer Center, Guangzhou, China<br />
Background: This study is to evaluate efficacy and safety <strong>of</strong> first-line gefitinib treatment<br />
in metastatic lung adenocarcinoma patients with sensitizing EGFR mutation<br />
determined by digital PCR (ddPCR) in plasma cell-free DNA (cf-DNA)<br />
Trial design: Adenocarcinoma NSCLC patients (stage IV, PS 0-2, available tumor<br />
tissue) with EGFR mutation detected by ddPCR in plasma will accept gefitinib<br />
treatment until PD. Primary endpoint is ORR. Secondary endpoints are PFS, DCR,<br />
QOL, and the concordance, sensitivity, specificity <strong>of</strong> EGFR mutation between ddPCR<br />
in plasma DNA and ARMS in tissue. EGFR mutation status in cf-DNA will be<br />
dynamically monitored every 8 weeks. A sample size <strong>of</strong> 159 will provide a precision <strong>of</strong><br />
7% (95% CI: 65%, 79%) assuming 72% ORR, 177 patients should be enrolled with 10%<br />
drop-<strong>of</strong>f rate. By Dec 25th, 2015, 426 patients were screened using ddPCR in plasma,<br />
188 patients were enrolled, and last patient last visit will be at October 2016.<br />
(NCT02282267).<br />
Clinical trial identification: NCT02282267<br />
Legal entity responsible for the study: N/A<br />
Funding: AstraZeneca R&D<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1289TiP<br />
ALTA-1L (ALK in lung cancer trial <strong>of</strong> BrigAtinib in 1st Line):<br />
A randomized, phase 3 trial <strong>of</strong> brigatinib (BRG) versus<br />
crizotinib (CRZ) in tyrosine kinase inhibitor (TKI)–naive,<br />
advanced anaplastic lymphoma kinase (ALK)–positive non–<br />
small cell lung cancer (NSCLC)<br />
S. Popat 1 , M. Tiseo 2 , S. Gettinger 3 , S. Peters 4 , J. Haney 5 , D. Kerstein 6 ,D.<br />
R. Camidge 7<br />
1 Medicine, Royal Marsden Hospital, London, UK, 2 Oncologia Medica, Azienda<br />
Ospedaliero-Universitaria di Parma, Parma, Italy, 3 Yale Cancer Center, Yale School<br />
<strong>of</strong> Medicine, New Haven, CT, USA, 4 Department <strong>of</strong> <strong>Oncology</strong>, Centre Hospitalier<br />
Universitaire Vaudois - CHUV, Lausanne, Switzerland, 5 Clinical Research &<br />
Development, ARIAD Pharmaceuticals, INC., Cambridge, MA, USA, 6 Preclinical<br />
and Translational Research, ARIAD Pharmaceuticals Inc., Cambridge, MA, USA,<br />
7 Cancer Center, University <strong>of</strong> Colorado, Aurora, CO, USA<br />
Background: The investigational oral ALK inhibitor BRG has potent preclinical<br />
activity against rearranged ALK and mutants resistant to CRZ. In a phase 1/2 study,<br />
BRG showed promising clinical activity, both systemically and in the brain, in ALK+<br />
NSCLC patients (pts), including those with prior CRZ therapy and those who were<br />
CRZ-naive. Based on the results <strong>of</strong> an ongoing pivotal randomized phase 2 trial<br />
exploring 2 regimens <strong>of</strong> BRG (90 mg once daily and 180 mg once daily with a 7-d<br />
lead-in at 90 mg), which demonstrated substantial efficacy in pts with CRZ-resistant<br />
ALK+ NSCLC and an acceptable safety pr<strong>of</strong>ile, the ALTA-1L trial was designed to<br />
evaluate the efficacy and safety <strong>of</strong> BRG vs CRZ in pts with advanced ALK+ NSCLC<br />
naive to ALK-targeted therapy.<br />
Trial design: The ALTA-1L trial (NCT02737501) is a multicenter, randomized,<br />
open-label, phase 3 trial. Eligible pts (≥18 years) must have locally advanced or<br />
metastatic ALK+ NSCLC without prior TKI therapy. Pts may have received up to 1<br />
regimen <strong>of</strong> systemic anticancer therapy in the advanced setting. Approximately 270 pts<br />
will be randomized 1:1 to receive BRG (180 mg once daily with a 7-d lead-in at 90 mg)<br />
or CRZ (250 mg twice daily). Pts will be stratified by brain metastases at baseline<br />
(present vs absent) and history <strong>of</strong> prior chemotherapy (yes vs no). The primary<br />
endpoint <strong>of</strong> this study is progression-free survival (PFS) assessed by a blinded<br />
independent review committee (BIRC). The primary analysis will be performed after<br />
198 events are observed, with 2 interim analyses planned after approximately 50% and<br />
75% <strong>of</strong> the total expected events. Secondary endpoints include objective response rate<br />
(ORR), duration <strong>of</strong> response, overall survival, intracranial ORR and intracranial PFS,<br />
safety and tolerability, and pt-reported outcomes. Pts randomized to CRZ are<br />
permitted to cross over to BRG (180 mg once daily with a 7-d lead-in at 90 mg) after<br />
BIRC-assessed progression. The trial was initiated in April 2016 with 150 planned sites<br />
in North America, Europe, and the Asia-Pacific region.<br />
Legal entity responsible for the study: ARIAD Pharmaceuticals, Inc.<br />
Funding: ARIAD Pharmaceuticals, Inc.<br />
Disclosure: S. Popat: Consulting role (ARIAD, Pfizer). M. Tiseo: Consulting or<br />
advisory role (Boehringer Ingelheim, Eli Lilly, Otsuka, AstraZeneca, Bristol Myers<br />
Squibb, Novartis, Pierre Fabre), research funding (ARIAD). S. Gettinger: Consulting or<br />
advisory role (ARIAD, BMS, Janssen), research funding (ARIAD, AstraZeneca/<br />
MedImmune, BMS, Boehringer Ingelheim, Incyte, Pfizer, Roche/Genentech). S. Peters:<br />
Research funding (ARIAD). J. Haney, D. Kerstein: Employment, stock and other<br />
ownership interests (ARIAD). D.R. Camidge: Honoraria, research funding (ARIAD).<br />
1290TiP<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
ALUR: a phase 3 study <strong>of</strong> alectinib versus chemotherapy in<br />
previously treated ALK+ non-small cell lung cancer (NSCLC)<br />
J. Wolf 1 , I-J. Oh 2 , J. Mazieres 3 , J. de Castro 4 , C. Revil 5 , A. Kotb 6 , H. Johansdottir 7 ,<br />
A. Zeaiter 5 , S. Novello 8<br />
1 Internal Medicine, University Hospital <strong>of</strong> Cologne, Cologne, Germany,<br />
2 Department <strong>of</strong> Internal Medicine, Chonnam National University Hwasun Hospital,<br />
Jeonnam, Republic <strong>of</strong> Korea, 3 Thoracic <strong>Oncology</strong>, CHU Toulouse, Hôpital de<br />
Larrey, Toulouse, France, 4 Medical <strong>Oncology</strong>, Hospital Universitario La Paz,<br />
Madrid, Spain, 5 Medical <strong>Oncology</strong>, F. H<strong>of</strong>fmann-La Roche Ltd, Basel, Switzerland,<br />
6 Medical Affairs, F. H<strong>of</strong>fmann-La Roche Ltd, Basel, Switzerland, 7 PDO,<br />
F. H<strong>of</strong>fmann-La Roche Ltd, Basel, Switzerland, 8 <strong>Oncology</strong>, University <strong>of</strong> Turin,<br />
Orbassano, Italy<br />
Background: Crizotinib is the current standard <strong>of</strong> care for NSCLC patients (pts) with<br />
ALK+ disease. However, most pts who get crizotinib will progress within a year.<br />
Further, until recently, crizotinib was only approved in Europe as 2nd-line treatment<br />
after failure <strong>of</strong> 1st-line platinum-based doublet chemotherapy (PDC), so many pts who<br />
relapse after crizotinib have also been pre-treated with PDC. Most will go on to receive<br />
standard relapse chemotherapy (SRC), e.g. pemetrexed or docetaxel. The ALK<br />
inhibitor alectinib was recently approved by the FDA based on the efficacy/safety<br />
shown in two phase 2 single-arm studies <strong>of</strong> pts with pre-treated ALK+ NSCLC<br />
(NP28673: Ou et al, JCO 2015; NP28761: Shaw et al, Lancet Oncol 2016). However, it<br />
vi450 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
is not yet confirmed whether this approach would be more or less effective than SRC in<br />
the 3rd line for ALK+ NSCLC pts who relapse after both PDC and crizotinib.<br />
Trial design: ALUR (NCT02604342) is a phase 3 open-label randomised study in pts<br />
with advanced or metastatic ALK+ NSCLC and ECOG PS 0–2 who have had one prior<br />
line each <strong>of</strong> PDC and crizotinib. Pts (n = 120) are randomised 2:1 to receive alectinib<br />
600mg BID or SRC (pemetrexed 500mg/m 2 q3w or docetaxel, 75mg/m 2 q3w; at<br />
investigator’s discretion) until progression, death or withdrawal. Crossover from SRC<br />
to alectinib is permitted on RECIST progression. At the investigators’ discretion,<br />
alectinib can be continued beyond progression for patients with clinical benefit. FPI<br />
was in Oct 2015 and LPI is expected in Q3 2016. The primary endpoint is<br />
progression-free survival (PFS) by investigator in the ITT population. Secondary<br />
endpoints include objective response rate (ORR) in the central nervous system (CNS)<br />
for pts with measurable CNS metastases (mets) at baseline; PFS by independent review<br />
committee (IRC); ORR, disease control rate (DCR) and duration <strong>of</strong> response (DOR) by<br />
investigator and IRC; time to CNS progression, CNS DOR and DCR by investigator<br />
and IRC; overall survival; health-related quality <strong>of</strong> life; time to symptom deterioration;<br />
and safety. Pts will be stratified by ECOG PS (0/1 vs 2), presence <strong>of</strong> baseline CNS mets<br />
and history <strong>of</strong> CNS radiation, with caps to ensure ≥50% have baseline CNS mets and<br />
both types <strong>of</strong> SRC are equally represented.<br />
Clinical trial identification: NCT01801111 [NP28673] and NCT01871805<br />
[NP28761].<br />
Legal entity responsible for the study: F. H<strong>of</strong>fmann-La Roche Ltd<br />
Funding: F. H<strong>of</strong>fmann-La Roche Ltd<br />
Disclosure: J. Wolf: Advisory Boards for AstraZeneca, Boehringer Ingelheim, Novartis,<br />
Pfizer and Roche. C. Revil: Roche Employee and Stock Ownership. A. Kotb: Employee<br />
<strong>of</strong> Roche. A. Zeaiter: Roche Employee, Stock Ownership and Roche Leadership. All<br />
other authors have declared no conflicts <strong>of</strong> interest.<br />
1291TiP<br />
Phase 1b study <strong>of</strong> crizotinib in combination with<br />
pembrolizumab in patients (pts) with untreated<br />
ALK-positive (+) advanced non-small cell lung cancer<br />
(NSCLC)<br />
F.R. Vizcarrondo 1 , S.P. Patel 2 , N.A. Pennell 3 , S. Pakkala 4 , H. West 5 , R. Kratzke 6 ,<br />
J. Tarazi 7 , K. Wilner 8 , A. Polli 9 ,W.Tan 7 ,Y.Liu 7 , O. Valota 9 , B. Piperdi 10 ,K.<br />
L. Reckamp 11<br />
1 University <strong>of</strong> Alabama at Birmingham Hospital, University <strong>of</strong> Alabama at<br />
Birmingham Hospital, Birmingham, AL, USA, 2 Experimental Therapeutics,<br />
Thoracic <strong>Oncology</strong>, UC San Diego Moores Cancer Center, La Jolla, CA, USA,<br />
3 Cleveland Clinic, Cleveland, OH, USA, 4 Emory Healthcare, Emory Healthcare,<br />
Atlanta, GA, USA, 5 Medical <strong>Oncology</strong>, Suite 200, Swedish Cancer Institute at<br />
Swedish Medical Center, Seattle, WA, USA, 6 University <strong>of</strong> Minnesota Medical<br />
Center, University <strong>of</strong> Minnesota Medical Center, Minneapolis, MN, USA,<br />
7 <strong>Oncology</strong>, Pfizer, La Jolla, CA, USA, 8 <strong>Oncology</strong>, Pfizer, La Jolla, CA, USA,<br />
9 <strong>Oncology</strong>, Pfizer, Milan, Italy, 10 Merck & Co., Inc, Merck & Co., Inc, Kenilworth,<br />
NJ, USA, 11 City <strong>of</strong> Hope Hospital, City <strong>of</strong> Hope Hospital, Durate, CA, USA<br />
Background: Crizotinib is approved internationally for the treatment <strong>of</strong> ALK+<br />
advanced NSCLC. However, disease progression ultimately occurs in the vast majority<br />
<strong>of</strong> pts, <strong>of</strong>ten due to the development <strong>of</strong> secondary crizotinib-resistant ALK mutations<br />
or signal transduction bypass pathways. The immune checkpoint programmed cell<br />
death 1 (PD-1) pathway can be exploited by tumors to limit T cell activity, allowing<br />
tumors to evade immune detection. ALK+ NSCLC is associated with high PD ligand 1<br />
(PD-L1) expression, and data from a preclinical model has suggested that combining<br />
PD-1- and ALK-targeted therapies may be beneficial (Ota et al, Clin Cancer Res 2015;<br />
Voena et al, Cancer Immunol Res 2015). The anti–PD-1 antibody, pembrolizumab is<br />
approved in the US for the treatment <strong>of</strong> advanced PD-L1+ NSCLC after progression on<br />
a platinum-based chemotherapy and an approved tyrosine kinase inhibitor for those<br />
with an EGFR or ALK genomic aberration.<br />
Trial design: The primary objectives <strong>of</strong> this ongoing multicenter study<br />
(NCT02511184) are to determine the maximum tolerated dose (MTD) <strong>of</strong> crizotinib<br />
combined with pembrolizumab (dose-finding; part 1) and the recommended phase 2<br />
dose (dose expansion; part 2), with secondary objectives to evaluate the safety pr<strong>of</strong>ile<br />
and antitumor activity <strong>of</strong> the combination, the pharmacokinetics <strong>of</strong> both drugs, and<br />
PD-L1 expression as a predictor <strong>of</strong> antitumor activity. Part 1 uses a modified toxicity<br />
probability interval method to determine the MTD, with a starting crizotinib dose <strong>of</strong><br />
250 mg twice daily on a continuous schedule and intravenous pembrolizumab 200 mg<br />
on day 1 <strong>of</strong> each 21-day cycle. Seventy patients are expected to be enrolled, with 30<br />
dose-limiting toxicity-evaluable patients expected in part 1, including a target <strong>of</strong> 10<br />
treated at the MTD who will also contribute to the planned 50 required for part 2. Key<br />
eligibility criteria include ALK+ advanced NSCLC, no prior systemic therapy for<br />
metastatic disease, measurable disease (RECIST v1.1), available archival tumor tissue,<br />
and ECOG performance status 0/1 (part 1) or 0–2 (part 2). Pts with stable treated<br />
brain metastases are eligible. Enrollment in part 1 began in Oct 2015, with 5 pts<br />
currently enrolled.<br />
Clinical trial identification: Clinical Trials Registration number: NCT02511184<br />
Legal entity responsible for the study: N/A<br />
Funding: Funding for this research was provided by Pfizer Inc. and Merck & Co., Inc.<br />
Disclosure: F.R. Vizcarrondo: Research funds from Pfizer. N.A. Pennell: Consultant for<br />
AstraZeneca, Boehringer Ingelheim. H. West: Consultant/honoraria for Ariad, BMS,<br />
AstraZeneca, Genentech/Roche, Novartis, Pfizer, Merck. J. Tarazi, K. Wilner, W. Tan,<br />
Y. Liu: Pfizer employee. A. Polli, O. Valota: Pfizer employee, owns stocks. B. Piperdi:<br />
Employee <strong>of</strong> Merch & Co., Inc. K.L. Reckamp: Research support from Pfizer to<br />
institution. All other authors have declared no conflicts <strong>of</strong> interest.<br />
1292TiP<br />
A phase II trial investigating the highly selective c-Met<br />
inhibitor tepotinib in stage IIIB/IV lung adenocarcinoma<br />
with MET exon 14 alterations after failure <strong>of</strong> at least one<br />
prior therapy<br />
P.K. Paik 1 , U. Stammberger 2 , R. Bruns 3<br />
1 Thoracic <strong>Oncology</strong> Service, Memorial Sloan Kettering Cancer Center, New York,<br />
NY, USA, 2 Global Clinical Development, Global Research and Development,<br />
Merck KGaA, Darmstadt, Germany, 3 Biostatistics, Merck KGaA, Darmstadt,<br />
Germany<br />
Background: Recently, splice site alterations at MET exon 14 that result in exon<br />
skipping and activation <strong>of</strong> the c-Met pathway have been identified in ≈3% <strong>of</strong> lung<br />
adenocarcinomas. MET exon 14 alterations appear to be a true oncogenic driver <strong>of</strong><br />
lung adenocarcinoma and appear to be mutually exclusive with other known oncogenic<br />
drivers such as EGFR and ALK. Emerging clinical data suggest that tumors with MET<br />
exon 14 alterations are sensitive to c-Met inhibition. The highly selective c-Met<br />
inhibitor tepotinib has been shown to be well tolerated and active in several phase I/Ib<br />
trials, with activity appearing greatest in c-Met-positive tumors. The recommended<br />
dose has been established as 500 mg/day. This open-label phase II trial (EudraCT<br />
2015-005696-24) is investigating the efficacy <strong>of</strong> tepotinib in patients with lung<br />
adenocarcinoma harboring MET exon 14 alterations.<br />
Trial design: The primary objective is to assess the efficacy <strong>of</strong> tepotinib based on<br />
independently assessed objective response determined using RECIST v1.1. Key<br />
secondary objectives include further assessment <strong>of</strong> efficacy, as well as assessment <strong>of</strong><br />
safety, pharmacokinetics, and quality <strong>of</strong> life. Eligible patients are adults with<br />
histologically confirmed advanced adenocarcinoma <strong>of</strong> the lung who have failed at least<br />
one line <strong>of</strong> systemic therapy, including a platinum doublet-containing regimen.<br />
Tumors must test positive for MET exon 14 skipping alterations as confirmed by a<br />
central laboratory. Exclusion criteria include EGFR mutations that confer sensitivity to<br />
EGFR TKIs, ALK rearrangements, and prior therapy (other than local palliative<br />
radiotherapy) within 21 days <strong>of</strong> the first dose <strong>of</strong> trial treatment. Patients receive<br />
tepotinib 500 mg/day in 21-day cycles until disease progression, intolerable toxicity, or<br />
withdrawal from treatment for other reasons. Recruitment <strong>of</strong> 60 patients in Europe,<br />
USA, and Japan is planned. This trial will establish the activity, safety, and tolerability<br />
<strong>of</strong> tepotinib in patients with lung adenocarcinoma harboring MET exon 14 alterations.<br />
Clinical trial identification: EudraCT 2015-005696-24<br />
Legal entity responsible for the study: Merck KGaA<br />
Funding: Merck KGaA<br />
Disclosure: U. Stammberger, R. Bruns: Employed by Merck KGaA, the manufacturer<br />
<strong>of</strong> tepotinib. All other authors have declared no conflicts <strong>of</strong> interest.<br />
1293TiP<br />
abstracts<br />
Amethyst NSCLC trial: Phase 2, parallel-arm study <strong>of</strong><br />
receptor tyrosine kinase (RTK) inhibitor, MGCD265 in<br />
patients with advanced or metastatic non-small cell lung<br />
cancer (NSCLC) with activating genetic alterations in<br />
mesenchymal-epithelial transition factor (MET)<br />
L. Bazhenova 1 , R. Mehra 2 , T. Nagy 3 , L. Cavanna 4 , J-S. Lee 5 , J-Y. Han 6 , H.K. Kim 7 ,<br />
B. Halmos 8 , M. Shum 9 , M. Schreeder 10 , I. Rybkin 11 , F. Badin 12 , R. Mena 13 ,P.<br />
A. Jänne 14 , J. Christensen 15 , V. Tassell 16 , R. Chao 16 , D. Faltaos 17 , D-W. Kim 18<br />
1 Moores Cancer Center, University <strong>of</strong> California San Diego, La Jolla, CA, USA,<br />
2 <strong>Oncology</strong>, Fox Chase Cancer Center, Philadelphia, PA, USA, 3 <strong>Oncology</strong>, National<br />
Institute <strong>of</strong> <strong>Oncology</strong>, Budapest, Hungary, 4 <strong>Oncology</strong>, Azienda Unità Sanitaria<br />
Locale di Piacenza-Ospedale Guglielmo da Saliceto, Piacenza, Italy, 5 <strong>Oncology</strong>,<br />
Seoul National University Bundang Hospital, Seongnam-si, Republic <strong>of</strong> Korea,<br />
6 Center for Lung Cancer, National Cancer Center, Goyang, Republic <strong>of</strong> Korea,<br />
7 <strong>Oncology</strong>, St Vincent Hospital The Catholic University <strong>of</strong> Korea, Suwon, Republic<br />
<strong>of</strong> Korea, 8 <strong>Oncology</strong>, Montefiore Medical Center, New York, NY, USA, 9 <strong>Oncology</strong>,<br />
Innovative Clinical Research Institute, Whittier, CA, USA, 10 <strong>Oncology</strong>, Clearview<br />
Cancer Institute, Huntsville, AL, USA, 11 <strong>Oncology</strong>, Henry Ford Health System,<br />
Detroit, MI, USA, 12 <strong>Oncology</strong>, Lexington <strong>Oncology</strong> Associates, LLC, Lexington,<br />
KY, USA, 13 <strong>Oncology</strong>, Providence Saint Joseph Medical Center, Burbank, CA,<br />
USA, 14 <strong>Oncology</strong>, Dana-Farber Cancer Institute, Boston, MA, USA, 15 Research,<br />
Mirati Therapeutics, San Diego, CA, USA, 16 Clinical Science, Mirati Therapeutics,<br />
San Diego, CA, USA, 17 Pharmacology, Mirati Therapeutics, San Diego, CA, USA,<br />
18 Department <strong>of</strong> Internal Medicine, Seoul National University Hospital<br />
(SNUH)-Yongon Campus, Seoul, Republic <strong>of</strong> Korea<br />
Background: MGCD265 is a potent, orally available, small molecule RTK inhibitor <strong>of</strong><br />
mutant and wild-type forms MET and <strong>of</strong> Axl, both <strong>of</strong> which mediate signals for cell<br />
growth, survival, and migration. Alterations in MET, including mutations and/or gene<br />
amplification, occur in approximately 7% <strong>of</strong> NSCLC and function as oncogenic drivers<br />
that promote cancer development and progression. Recently, various mutations located<br />
at or near the exon 14 splice site <strong>of</strong> MET (METex14del) have been identified and result<br />
in absence <strong>of</strong> expression <strong>of</strong> exon 14. Importantly, this non-expressed region encodes<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw383 | vi451
abstracts<br />
the Y1003 CBL ubiquitin ligase regulatory binding site that is required for<br />
CBL-dependent MET degradation and signal attenuation. Absence <strong>of</strong> this receptor<br />
domain results in sustained MET signaling, which has been implicated as an oncogenic<br />
driver in a subset <strong>of</strong> NSCLC. Furthermore, in xenograft models <strong>of</strong> NSCLC where<br />
METex14del and MET amplification are putative oncogenic drivers, MGCD265<br />
induces robust tumor regression, and confirmed partial responses have been observed<br />
in patients with MET-altered NSCLC treated with MGCD265 in the Phase 1 setting.<br />
Trial design: Pts with NSCLC characterized by activating genetic MET alterations<br />
identified in tumor tissue or circulating tumor DNA (ctDNA) and who have received<br />
at least one prior platinum-containing regimen for advanced disease are eligible for this<br />
global Phase 2 trial and are assigned to one <strong>of</strong> four cohorts based on the type <strong>of</strong> MET<br />
dysregulation and detection method: 1) mutations in tissue, 2) amplification in tissue,<br />
3) mutations in ctDNA, and 4) amplification in ctDNA. The primary endpoint is<br />
Objective Response Rate (ORR) in accordance with RECIST 1.1. A Bayesian Predictive<br />
Probability Design is applied independently to each cohort <strong>of</strong> up to 45 patients,<br />
assuming p 0 = 0.20 and p 1 = 0.40. Secondary objectives include safety, tolerability,<br />
response duration, survival, correlation between tissue and ctDNA testing, and PK/PD.<br />
This study is currently open, and recruitment is ongoing.<br />
Clinical trial identification: EudraCT: 2015-002070-21; Clinical trial registry number:<br />
NCT02544633<br />
Legal entity responsible for the study: Mirati Therapeutics<br />
Funding: Mirati Therapeutics<br />
Disclosure: J. Christensen, R. Chao, D. Faltaos: Employee <strong>of</strong> Mirati Therapeutics;<br />
stocks ownership in Mirati Therapeutics. V. Tassell: Employee <strong>of</strong> Mirati Therapeutics<br />
and own stock. All other authors have declared no conflicts <strong>of</strong> interest.<br />
1294TiP<br />
Phase III clinical trials in chemotherapy-naive patients with<br />
advanced NSCLC assessing the combination <strong>of</strong><br />
atezolizumab and chemotherapy<br />
M. Reck 1 , V.A. Papadimitrakopoulou 2 , F. Cappuzzo 3 , R. Jotte 4 , T.S.K. Mok 5 ,<br />
A. Sandler 6 , D. Waterkamp 6 , S. Coleman 6 , T. Asakawa 6 , M. Socinski 7<br />
1 Head <strong>of</strong> Department <strong>of</strong> Thoracic <strong>Oncology</strong>, Lung Clinic Grosshansdorf,<br />
Grosshansdorf, Germany, 2 Medical <strong>Oncology</strong>, MD Anderson Cancer Center,<br />
Houston, TX, USA, 3 U.O. Oncologia Medica, Ospedale Civile - Istituto Toscano<br />
Tumori, Livorno, Italy, 4 <strong>Oncology</strong>, Rocky Mountain Cancer Centers U.S. <strong>Oncology</strong><br />
Network, Denver, CO, USA, 5 <strong>Oncology</strong>, Chinese University <strong>of</strong> Hong Kong, Hong<br />
Kong, China, 6 Product Development <strong>Oncology</strong>, Genentech, Inc., South<br />
San Francisco, CA, USA, 7 Medical <strong>Oncology</strong>, University <strong>of</strong> Pittsburgh UPMC<br />
Cancer Pavilion, Pittsburgh, PA, USA<br />
Background: Current treatments for advanced NSCLC include platinum (plat)-based<br />
doublet chemotherapy (chemo), pemetrexed (pem), bevacizumab, targeted drugs and<br />
programmed death-ligand 1 (PD-L1)/PD-1–targeted immunotherapy. Atezolizumab<br />
(atezo; anti-PDL1) inhibits binding <strong>of</strong> PD-L1 to PD-1 and B7.1 and restores<br />
anti-tumor T-cell activity. Clinical efficacy and survival rates with atezo monotherapy<br />
increase with increasing PD-L1 levels on tumor cells (TC) and tumor infiltrating<br />
immune cells (IC) in patients with advanced NSCLC. A phase Ib study revealed the<br />
potential for chemo to further enhance responses to atezo with tolerable safety in pts,<br />
across PD-L1 expression levels. The combination <strong>of</strong> atezo and chemo is now being<br />
examined in phase III studies.<br />
Trial design: Three phase III randomized, multicenter, open-label studies are assessing<br />
plat-based chemo + atezo or plat-based chemo + atezo + pem as 1L therapy in<br />
chemo-naive pts with advanced NSCLC (Table). Pts will be enrolled regardless <strong>of</strong><br />
PD-L1 status and must have previously untreated stage IV NSCLC. Inclusion criteria<br />
include measurable disease per RECIST v1.1 and ECOG PS 0-1; pts with untreated<br />
CNS metastases, autoimmune disease or prior immunotherapy will be excluded.<br />
Stratification factors will include sex and ECOG status. Archival tumor or biopsy<br />
sample will be obtained at screening. In IMpower130 and 131, pts will be randomized<br />
to receive atezo 1200 mg with standard plat-based chemotherapy for 4 or 6 21-day<br />
cycles, then maintenance with atezo. In IMpower132, pts will receive atezo 1200 mg<br />
q3w + plat-based chemo + pem, then maintenance with atezo + pem. Endpoints<br />
include OS, PFS, ORR, DOR, safety, PK and QOL. Tumor biopsies at RECIST v1.1<br />
progression will be assessed to distinguish pseudoprogression/tumor-immune<br />
infiltration from actual progression and to evaluate biomarkers associated with<br />
response and immune escape.<br />
Table: 1294TiP<br />
Trial name Histology Planned Experimental arm Comparator arm Identifier<br />
enrollment<br />
IMpower130 Non-squamous 650 Atezo + carboplatin+<br />
nab-paclitaxel<br />
Carboplatin+<br />
nab-paclitaxel<br />
NCT02367781<br />
IMpower131 Squamous 1025 Atezo + carboplatin +<br />
paclitaxel<br />
Atezo + carboplatin +<br />
nab-paclitaxel<br />
IMpower132 Non-squamous 568 Atezo + carboplatin/<br />
cisplatin+ pemetrexed<br />
Carboplatin+<br />
nab-paclitaxel<br />
Carboplatin/<br />
cisplatin+<br />
pemetrexed<br />
NCT02367794<br />
NCT02657434<br />
Clinical trial identification: IMpower130: NCT02367781 IMpower131:<br />
NCT02367794 IMpower132: NCT02657434<br />
Legal entity responsible for the study: F. H<strong>of</strong>fmann-La Roche Ltd.<br />
Funding: F. H<strong>of</strong>fmann-La Roche Ltd.<br />
Disclosure: M. Reck: Consulting/advisory role and Speaker Bureau for Roche, Lilly,<br />
BMS, MSD, Astra Zeneca, Pfizer, Boehringer Ingeleim, Celgene. V.A.<br />
Papadimitrakopoulou: Consulting or advisory role with Genentech, Gensignis Life<br />
Sciences, Janssen, Clovis <strong>Oncology</strong>, Biothera, Merck. Research funding with Clovis,<br />
Astra Zeneca, Merck, Janssen, Bayer. F. Cappuzzo: Honoraria: Roche, Clovis, Pfizer.<br />
Consulting or Advisory: Roche, Clovis, Pfizer, Lilly. R. Jotte: Honoraria & Speakers<br />
Bureau: Eli Lilly, BMS. T.S.K. Mok: Leadership/stock: Sanomics, Honoraria/Consulting<br />
includes: AZ, Roche, Lily, Merck, MSD, BMS, BI, Novartis, Clovis, Amgen, Janssen,<br />
AVEO, Biodesix, Prime, ACEA Biosciences, Vertex, SFJ, GSK, Biomarin, Pfizer, vertex,<br />
SFS, ACFA, Biosciences, Genedecode. A. Sandler: Genentech employee, Compensated<br />
Consultant role for Genentech/Roche, Genentech/Roche stock, Honoraria recipient<br />
from Genentech/Roche, Genentech research funding paid to institution, Provided<br />
compensated expert testimony for Genentech/Roche. D. Waterkamp: Roche/<br />
Genentech employee. S. Coleman: Employment: Genentech Stock: Roche, Gilead<br />
Sciences, Celgene, Teva. T. Asakawa: Genentech employee. M. Socinski: Research<br />
support – Genentech Speaker’s Bureau – Genentech.<br />
1295TiP<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
A phase 2, fast real-time assessment <strong>of</strong> combination<br />
therapies in immuno-oncology trial in patients with<br />
advanced non-small cell lung cancer (FRACTION-lung)<br />
P.M. Fracasso 1 , D.J. Freeman 2 , K. Simonsen 3 , Y. Shen 3 , M. Gupta 4 , A. Comprelli 5 ,<br />
J.F. Gainor 6 , M. Hellmann 7 , L.Q. Chow 8 , P.M. Forde 9 , R. Govindan 10 , T.P. Reilly 11 ,<br />
J. Cassidy 5<br />
1 Immuno-<strong>Oncology</strong>/<strong>Oncology</strong>, Exploratory Clinical and Translational Research,<br />
Bristol-Myers Squibb, Princeton, NJ, USA, 2 <strong>Oncology</strong> Biomarkers, Bristol-Myers<br />
Squibb, Princeton, NJ, USA, 3 Biostatistics, Bristol-Myers Squibb, Princeton, NJ,<br />
USA, 4 Clinical Pharmacology and Pharmacometrics, Bristol-Myers Squibb,<br />
Princeton, NJ, USA, 5 <strong>Oncology</strong>, Bristol-Myers Squibb, Princeton, NJ, USA,<br />
6 Department <strong>of</strong> Medicine, Massachusetts General Hospital, Boston, MA, USA,<br />
7 <strong>Oncology</strong>, Memorial Sloan Kettering Cancer Center, New York, NY, USA,<br />
8 Department <strong>of</strong> Medicine, Division <strong>of</strong> Medical <strong>Oncology</strong>, University <strong>of</strong> Washington,<br />
Seattle, WA, USA, 9 Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins<br />
University, Baltimore, MD, USA, 10 Division <strong>of</strong> <strong>Oncology</strong>, Washington University<br />
School <strong>of</strong> Medicine, St. Louis, MO, USA, 11 Immuno-<strong>Oncology</strong>, Bristol-Myers<br />
Squibb, Princeton, NJ, USA<br />
Background: The unprecedented success <strong>of</strong> the immuno-oncology (I-O) agents,<br />
nivolumab and ipilimumab, in several malignancies has resulted in the rapid<br />
development <strong>of</strong> other I-O agents against novel immune targets. Given the potential<br />
promise <strong>of</strong> increased survival, these agents have not followed the traditional phase 2<br />
trial evaluation. FRACTION-Lung is a randomized, open-label, phase 2 trial with an<br />
adaptive design that <strong>of</strong>fers patients (pts) with advanced non-small cell lung cancer<br />
(NSCLC) expeditious access to early I-O therapies in combination with nivolumab.<br />
Based on both preclinical and clinical trial data, combinations <strong>of</strong> I-O therapies that<br />
have potential to produce transformational activity in lung cancer will be selected and<br />
<strong>of</strong>fered to pts in a continuous throughput design.<br />
Trial design: Methods: A master protocol defines the overarching framework for this<br />
clinical study in which pts with metastatic and/or recurrent NSCLC previously treated<br />
with platinum chemotherapy and tyrosine kinase inhibitors (if EGFR mutated or ALK<br />
rearranged) are eligible. Based on prior I-O therapy experience and PD-L1 expression,<br />
pts will be enrolled into various treatment tracks. Sub-protocols specify the preclinical<br />
and preliminary clinical data for new treatment combinations that will be added on a<br />
rolling basis. Pts will receive treatment until completion, progression, or toxicity. On<br />
progression, pts may enroll into other combination regimens allowing evolution <strong>of</strong><br />
treatment if needed. An assessment <strong>of</strong> peripheral blood and tumor biomarkers will<br />
enable interrogation <strong>of</strong> the biological basis for pt response. Primary endpoints are<br />
objective response rate, duration <strong>of</strong> response, and progression-free survival at 24 weeks,<br />
with the potential for early stopping; the secondary endpoint is safety. The study is<br />
actively enrolling (NCT02750514). Conclusion: FRACTION-Lung represents an<br />
innovative clinical trial that utilizes a rolling, adaptive design with novel I-O therapies.<br />
It will accelerate the development and selection <strong>of</strong> the next generation <strong>of</strong><br />
transformational I-O combinations for pts with metastatic NSCLC.<br />
Clinical trial identification: NCT02750514<br />
Legal entity responsible for the study: Sponsored by Bristol Myers-Squibb<br />
Funding: Sponsored by Bristol Myers-Squibb<br />
Disclosure: P.M. Fracasso, D.J. Freeman, K. Simonsen, Y. Shen, A. Comprelli,<br />
J. Cassidy: Employee <strong>of</strong> Bristol-Myers Squibb. M. Gupta: Employed by the study<br />
sponsor (Bristol-Myers Squibb) and has stock ownership or options in Bristol-Myers<br />
Squibb. J.F. Gainor: Personal fees from Bristol-Myers Squibb, Novartis, Merck,<br />
Genentech/Roche, Clovis, Boehringher Ingelheim, and non-financial support from<br />
Jounce outside the submitted work. M. Hellmann: Consultant/Advisory Board<br />
member for BMS, Merck, Genentech, AZ, and Neon. Research support from BMS. L.<br />
Q. Chow: Fees from Astellas, grants, fees & non-financial support from Novartis,<br />
grants & fees from BMS, fees & non-financial support from Merck, grants from Eli<br />
Lilly/Imclone, OSI Pharma, Genentech, VentiRx, Pfizer, GSK, AZ/MedImmune<br />
vi452 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
outside the submitted work. P.M. Forde: Grants from BMS during the conduct <strong>of</strong> the<br />
study, and grants from BMS, Novartis, AstraZeneca, and Kyowa outside the submitted<br />
work. R. Govindan: Personal fees from Boehringer Ingelheim, GlaxoSmithKline,<br />
Celgene, Roche, Merck, Bayer, Genentech, Clovis <strong>Oncology</strong>, Helsinn Healthcare, and<br />
Pacritinib outside the submitted work. T.P. Reilly: Employee and stockholder <strong>of</strong><br />
Bristol-Myers Squibb.<br />
1296TiP<br />
A phase 2 study <strong>of</strong> seribantumab (MM-121) in combination<br />
with docetaxel or pemetrexed versus docetaxel or<br />
pemetrexed alone in patients with heregulin positive (HRG<br />
+), locally advanced or metastatic non-small cell lung<br />
cancer (NSCLC)<br />
L.V. Sequist 1 , I. Anderson 2 , T.M. Bauer 3 , N. Demars 4 , E. Felip 5 ,N.Frost 6 ,<br />
W. Harb 7 , L. Horn 8 , R.M. Huber 9 , A.J. Kudla 4 , J. Lee 10 , S. Mathews 4 , R. Mehra 11 ,<br />
J. Nieva 12 , M. Perol 13 , F. Shepherd 14 ,A.Spira 15 , A. Czibere 4<br />
1 Medical <strong>Oncology</strong>, Massachusetts General Hospital, Boston, MA, USA,<br />
2 Research, St Joseph Heritage Healthcare, Santa Rosa, CA, USA, 3 Drug<br />
Development Unit, Sarah Cannon Research Institute/Tennessee <strong>Oncology</strong>,<br />
Nashville, TN, USA, 4 Clinical Development, Merrimack Pharmaceuticals,<br />
Cambridge, MA, USA, 5 Oncologia Médica, Vall d’Hebron University Hospital<br />
Institut d’Oncologia, Barcelona, Spain, 6 Infektiologie und Pneumologie, Charité,<br />
Campus Virchow Klinikum, Berlin, Germany, 7 Horizon <strong>Oncology</strong> Center, Unity<br />
Campus, Lafayette, IN, USA, 8 <strong>Oncology</strong>, Vanderbilt Ingram Cancer Center,<br />
Nashville, TN, USA, 9 Thoracic <strong>Oncology</strong> Centre Munich, LMU Klinikum der<br />
Universität München, Munich, Germany, 10 Medicine, NYU Medical Center,<br />
New York, NY, USA, 11 <strong>Oncology</strong>, Fox Chase Cancer Center, Philadelphia, PA,<br />
USA, 12 Department <strong>of</strong> Medicine, University <strong>of</strong> Southern California Norris<br />
Comprehensive Cancer Center, Los Angeles, CA, USA, 13 Service d’Oncologie<br />
Médicale, Centre Léon Bérard, Lyon, France, 14 Medicine, Princess Margaret<br />
Hospital, Toronto, ON, Canada, 15 Fairfax Office, Virginia Cancer Specialists,<br />
Arlington, VA, USA<br />
Background: The role <strong>of</strong> the HER3 receptor and its ligand heregulin (HRG) in the<br />
progression <strong>of</strong> multiple cancers has been well established. Seribantumab is a fully<br />
human, monoclonal IgG2 antibody that binds to the HRG domain <strong>of</strong> HER3, blocking<br />
HER3 activity. Three prior randomized Phase 2 studies <strong>of</strong> seribantumab plus standard<br />
<strong>of</strong> care (SOC) versus SOC alone in NSCLC, breast cancer and ovarian cancer were<br />
analyzed retrospectively for correlation between the level <strong>of</strong> HRG mRNA in tumor<br />
tissue and progression free survival (PFS). High levels <strong>of</strong> HRG mRNA predicted<br />
shortened PFS in patients who received SOC treatment, while the addition <strong>of</strong><br />
seribantumab to SOC improved PFS in patients with HRG+ tumors. This is consistent<br />
with the hypothesis that blockade <strong>of</strong> HRG-induced HER3 signaling by seribantumab<br />
can restore sensitivity to SOC impacted by HRG, improving outcomes for HRG+<br />
patients.<br />
Trial design: In the current randomized, open-label, international, Phase 2 study,<br />
NSCLC patients with HRG+ tumors will be prospectively selected using a HRG RNA<br />
in situ hybridization assay on a recent biopsy tissue sample. Approximately 560<br />
patients will be screened to support enrollment <strong>of</strong> 280 HRG+ patients, who will be<br />
randomized in a 2:1 ratio to receive seribantumab plus investigator’s choice <strong>of</strong><br />
docetaxel or pemetrexed, or docetaxel or pemetrexed alone. Patients will be wild-type<br />
for EGFR and ALK and will have progressed following one to three systemic therapies<br />
for locally advanced and/or metastatic disease, one <strong>of</strong> which must be an anti-PD-1 or<br />
anti-PD-L1 therapy. The primary endpoint is overall survival (OS). Secondary<br />
endpoints include PFS, objective response rate and time to progression. Safety and<br />
health-related quality <strong>of</strong> life will also be assessed. The study has > 80% power to detect<br />
a 33% risk improvement in median OS (hazard ratio ≤ 0.67), using a one-sided,<br />
stratified log-rank test at a significance level <strong>of</strong> 0.025. An interim analysis is planned<br />
when 50% <strong>of</strong> final OS events have been reported. Enrollment was initiated in June<br />
2015. Approximately 80 sites worldwide will be open to enrollment by the end <strong>of</strong> 2016.<br />
Clinical trial identification: Clinical Trials Registry number: NCT02387216<br />
Legal entity responsible for the study: Merrimack Pharmaceuticals<br />
Funding: Merrimack Pharmaceuticals<br />
Disclosure: N. Demars, A.J. Kudla, S. Mathews, A. Czibere: Employee <strong>of</strong> Merrimack<br />
Pharmaceuticals. L. Horn: Consulting: Bayer, BI, BMS, Genentech, Lilly, Merck,<br />
Xcovery. J. Lee: Consultant to Boehringer Ingelheim. Participated in Genentech<br />
Speakers’ Bureau and expenses reimbursed by Genentech. R. Mehra: Advisory Boards -<br />
Novartis, BMS, Genentech, Bayer, Innate Pharma Research funding – Genentech. All<br />
other authors have declared no conflicts <strong>of</strong> interest.<br />
1297TiP<br />
Phase 1b expansion cohort study to evaluate the safety and<br />
efficacy <strong>of</strong> necitumumab and abemaciclib combination<br />
therapy in patients with stage IV non-small cell lung cancer<br />
(NSCLC)<br />
B. Besse 1 , F. Barlesi 2 , M. Ceccarelli 3 , G.Y. Chao 4 , B. Frimodt-Moller 5 , M. Gil 6 ,<br />
J. Vansteenkiste 7<br />
1 Department <strong>of</strong> Medicine, Institut Gustave Roussy, Villejuif, France,<br />
2 Multidisciplinary <strong>Oncology</strong> and Therapeutic Innovations Department, Aix Marseille<br />
University - Assistance Publique Hôpitaux de Marseille, Marseille, France,<br />
3 <strong>Oncology</strong>, Eli Lilly and Company, Sesto Fiorentino, Italy, 4 Biostatistics, Eli Lilly and<br />
Company, Bridgewater, NJ, USA, 5 Clinical Research Department, Eli Lilly and<br />
Company, Copenhagen, Denmark, 6 <strong>Oncology</strong>, Eli Lilly, Polska, Warsaw, Poland,<br />
7 Department <strong>of</strong> Respiratory Diseases, University Hospital KU Leuven, Leuven,<br />
Belgium<br />
Background: Trials <strong>of</strong> anti-EGFR necitumumab (neci) and the CDK4 and CDK6<br />
inhibitor abemaciclib have demonstrated anti-tumor activity <strong>of</strong> each agent in patients<br />
with NSCLC.<br />
Trial design: Single-arm, multicenter Phase 1b expansion cohort study to investigate<br />
the effectiveness, safety and tolerability <strong>of</strong> neci combined with abemaciclib in ∼70<br />
patients with Stage IV NSCLC (NCT02411591). Part A: escalating doses <strong>of</strong> abemaciclib<br />
(100 mg, 150 mg, and 200 mg oral) are administered on a continuous schedule every<br />
12 hours on days 1–21 in combination with neci (800 mg IV) on days 1 and 8, every 21<br />
days. Part B: abemaciclib dose identified in Part A is administered with neci in<br />
squamous (sq) and non-sq NSCLC patients. Major eligibility criteria include:<br />
progression after platinum-based chemotherapy and 1 other prior chemotherapy for<br />
advanced and/or metastatic disease; ECOG PS 0-1; no symptomatic brain metastases.<br />
Patients with prior treatment with CDK4- or CDK6-targeting agents or neci are<br />
excluded. Tumor tissue is collected for investigation <strong>of</strong> NSCLC biomarkers including<br />
KRAS mutation and EGFR expression. Treatment will continue until disease<br />
progression, unacceptable toxicity, or withdrawal <strong>of</strong> consent by the patient. The<br />
objectives <strong>of</strong> the study are to evaluate tolerability and the efficacy <strong>of</strong> combination<br />
therapy in terms <strong>of</strong> progression-free survival rate at 3 months. Secondary objectives<br />
include overall survival, overall response rate (ORR) and disease control rate (DCR).<br />
The ORR and DCR denominator includes each patient enrolled who receives either<br />
study drug, who has complete radiographic assessment at baseline, and ≥1 complete<br />
radiographic assessment post-baseline. The ORR numerator includes patients counted<br />
in the denominator with a best overall tumor response (partial/complete response); the<br />
DCR numerator also includes stable disease. The Kaplan-Meier method will estimate<br />
parameters for time-to-event variables. Part A has fully enrolled (n = 15) with one<br />
dose-limiting toxicity (DLT) at abemaciclib 150mg. DLT evaluation <strong>of</strong> the 200mg<br />
abemaciclib cohort will identify recommended dosing for Part B.<br />
Clinical trial identification: NCT02411591<br />
Legal entity responsible for the study: Eli Lilly and Company<br />
Funding: Eli Lilly and Company<br />
Disclosure: B. Besse: Research funding: Puma Biotechnology, GlaxoSmithKline,<br />
AstraZeneca, Roche/Genentech, Clovis <strong>Oncology</strong>, Pfizer, Boehringer Ingelheim, Lilly,<br />
Servier, Onxeo, Bristol-Myers Squibb (BMS); expenses: Roche, Pfizer, BMS/Medarex,<br />
Novartis, Pierre Fabre. F. Barlesi: Honoraria: Lilly <strong>Oncology</strong>, Consulting or advisory:<br />
Lilly <strong>Oncology</strong>. M. Ceccarelli: Employment: Eli Lilly and Company; Stock: Eli Lilly and<br />
Company. G.Y. Chao: Employment: Eli Lilly and Company. B. Frimodt-Moller, M. Gil:<br />
Employment: Eli Lilly and Company; Stocks: Eli Lilly and Company. J. Vansteenkiste:<br />
Consulting or advisory roles: Novartis, Boehringer Ingelheim, Lilly, MSD <strong>Oncology</strong>,<br />
AstraZeneca; Research funding: AstraZeneca.<br />
1298TiP<br />
abstracts<br />
A single-arm, open-label, phase 2 study <strong>of</strong> nab-paclitaxel<br />
and carboplatin chemotherapy plus necitumumab in the<br />
first-line treatment <strong>of</strong> patients with stage IV squamous<br />
non-small cell lung cancer (NSCLC)<br />
M. Socinski 1 , M. Gil 2 , J. Shahidi 3 , G.Y. Chao 4 , L. Villaruz 1<br />
1 Medical <strong>Oncology</strong>, University <strong>of</strong> Pittsburgh UPMC Cancer Pavilion, Pittsburgh,<br />
PA, USA, 2 <strong>Oncology</strong>, Eli Lilly Polska, Warsaw, Poland, 3 <strong>Oncology</strong>, Eli Lilly and<br />
Company, Indianapolis, IN, USA, 4 Biostatistics, Eli Lilly and Company,<br />
Indianapolis, IN, USA<br />
Background: Necitumumab (neci), a human IgG1-type monoclonal antibody directed<br />
against the EGFR has recently been found to significantly improve outcomes in<br />
patients with Stage IV squamous NSCLC when combined with gemcitabine/cisplatin.<br />
These data coupled with the efficacy and safety advantages <strong>of</strong> nab-paclitaxel (nab-pac)<br />
over solvent-based paclitaxel provide a strong rationale for the investigation <strong>of</strong> neci in<br />
combination with nab-pac as first-line therapy in Stage IV squamous NSCLC.<br />
Trial design: JFCP (NCT02392507) is a single-arm, open-label, Phase 2 study being<br />
conducted to evaluate the effectiveness and safety and tolerability <strong>of</strong> nab-pac and<br />
carboplatin plus neci as first-line therapy in patients with Stage IV squamous NSCLC<br />
(life expectancy ≥12 weeks; ECOG PS ≤1; tumor tissue availability for<br />
immunohistochemistry analysis). Study therapy consists <strong>of</strong> an induction (triplet)<br />
regimen <strong>of</strong> nab-pac (100 mg/m 2 IV on Days 1, 8, and 15) and carboplatin (AUC 6 mg.<br />
min/mL IV on Day 1) plus neci (800 mg absolute dose IV on Days 1 and 8)<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw383 | vi453
abstracts<br />
administered for a maximum <strong>of</strong> 4 cycles (or until radiographic documentation <strong>of</strong><br />
progressive disease, toxicity requiring cessation, protocol noncompliance, or<br />
withdrawal <strong>of</strong> consent). Patients with a response <strong>of</strong> stable disease or better, assessed<br />
radiographically, after 4 cycles <strong>of</strong> induction regimen are eligible to receive the<br />
maintenance (doublet) regimen <strong>of</strong> neci (800 mg on Days 1and 8) plus nab-pac (100<br />
mg/m 2 on Days 1 and 8) every 3 weeks until disease progression occurs or other<br />
discontinuation criteria are met. The primary endpoint <strong>of</strong> this study is the best<br />
objective response rate (ORR); key secondary endpoints include PFS, OS, and DCR.<br />
Efficacy analyses for ORR and DCR will be performed for qualified patients (received<br />
any amount <strong>of</strong> study drug and had a complete radiographic assessment at baseline).<br />
Patients surviving for ≥8 weeks after first dose and with no post-baseline radiographic<br />
assessment will be disqualified. Efficacy analyses for PFS and OS will be performed for<br />
all patients who have received any amount <strong>of</strong> study drug. Enrollment began October<br />
2015; planned enrollment is 50 patients.<br />
Clinical trial identification: ClinicalTrails.gov identifier: NCT02392507<br />
Legal entity responsible for the study: Eli Lilly and Company<br />
Funding: Eli Lilly and Company<br />
Disclosure: M. Socinski: Research Support: Lilly and Celgene Speaker’s Bureau:<br />
Celgene. M. Gil, J. Shahidi, G.Y. Chao: Employee <strong>of</strong> Eli Lilly and Company. All other<br />
authors have declared no conflicts <strong>of</strong> interest.<br />
1299TiP<br />
Carboplatin (Cb) plus nab-paclitaxel (PTX) versus docetaxel<br />
(D) for elderly squamous (Sq) non-small cell lung cancer<br />
(NSCLC) (CAPITAL study)<br />
Y. Kogure 1 , H. Saka 1 , Y. Takiguchi 2 , S. Atagi 3 , T. Kurata 4 , N. Ebi 5 , A. Inoue 6 ,<br />
K. Kubota 7 , M. Takenoyama 8 , T. Seto 8 , A. Kada 9 , T. Yamanaka 10 , M. Ando 11 ,<br />
N. Yamamoto 12 , A. Gemma 13 , Y. Ichinose 14<br />
1 Department <strong>of</strong> Respiratory Medicine, National Hospital Organization, Nagoya<br />
Medical Center, Nagoya, Japan, 2 Dept. <strong>of</strong> Medical <strong>Oncology</strong>, Chiba University,<br />
School <strong>of</strong> Medicine, Chiba, Japan, 3 Department <strong>of</strong> Thoracic <strong>Oncology</strong>, National<br />
Hospital Organization Kinki-chuo Chest Medical Center, Sakai, Japan,<br />
4 Department <strong>of</strong> Thoracic <strong>Oncology</strong>, Kansai Medical University Hirakata Hospital,<br />
Hirakata, Japan, 5 Department <strong>of</strong> Respiratory <strong>Oncology</strong>, Iizuka Hospital, Iizuka,<br />
Japan, 6 Department <strong>of</strong> Respiratory Medicine, Tohoku University Hospital, Sendai,<br />
Japan, 7 Respiratory Medicine, Nippon Medical School Hospital Cancer Center,<br />
Tokyo, Japan, 8 Department <strong>of</strong> Thoracic <strong>Oncology</strong>, National Kyushu Cancer<br />
Center, Fukuoka, Japan, 9 Deaprtment <strong>of</strong> Clinical Trials and Rsearch, National<br />
Hospital Organization, Nagoya Medical Center, Nagoya, Japan, 10 Department <strong>of</strong><br />
Biostatistics, Yokohama City University, Yokohama, Japan, 11 Division <strong>of</strong><br />
Biostatistics, Center for Advanced Medicine and Clinical Research, Nagoya<br />
University Hospital, Nagoya, Japan, 12 Third Department <strong>of</strong> Internal Medicine,<br />
Wakayama Medical University, Wakayama, Japan, 13 Respiratory Medicine, Nippon<br />
Medical School Main Hospital, Tokyo, Japan, 14 Clinical Research Institute,<br />
National Kyushu Cancer Center, Fukuoka, Japan<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
standard therapies for them. 2 The 130-nm albumin-bound formulation <strong>of</strong> PTX<br />
(nab-PTX,) has shown activity in NSCLC. Cb + nab-PTX demonstrated a significantly<br />
higher overall response rate (ORR) than Cb + PTX in patients with Sq histology (41%<br />
vs 24%, p 70 years showed a significantly increased overall<br />
survival (OS) with Cb + nab-PTX versus Cb + PTX. 3<br />
Trial design: This is a randomized, multicenter, phase 3 trial to compare the efficacy<br />
and safety <strong>of</strong> Cb + nab-PTX with D for elderly patients for advanced Sq NSCLC.<br />
Elderly patients (> 70 years) who have received no prior chemotherapy for advanced/<br />
metastatic Sq NSCLC are randomized 1:1 to D (60 mg/m 2 i.v.) on day1 and Cb (AUC<br />
6) on day 1 plus nab-PTX (100 mg/m 2 i.v.) on day1, 8, and 15 <strong>of</strong> each 21-day cycle.<br />
Randomization is balanced by minimization for ECOG performance status, stage, age,<br />
gender and institutes. Treatment continues until radiographic progression or<br />
unacceptable toxicity. The primary endpoint is improvement <strong>of</strong> OS with Cb + nab-PTX<br />
versus D. Secondary endopoints are to assess ORR, progression-free survival, safety<br />
and quality <strong>of</strong> life. Recruitment began in December 2015 and planned enrollment is<br />
250 patients. 1 Quiox E et al. Lancet 2011 2 Kudoh S et al. J Clin Oncol 2006 3 Socinski<br />
MA et al. J Clin Oncol 2012<br />
Clinical trial identification: UMIN000019843.<br />
Legal entity responsible for the study: N/A<br />
Funding: This study was conducted by National Hospital Organization Nagoya<br />
Medical Center, under the funding contract with Taiho Pharmaceutical Co. Ltd., Japan.<br />
Disclosure: H. Saka: Research funding for AstraZeneca, Daiichi Sankyo, Ono, Lilly,<br />
Bristol Myers, Beyer, NPO-WJOG, Taiho, MSD, Linical. Y. Takiguchi: Honoraria for<br />
Taiho, Ono, Eli Lilly, Astra Zeneca, Nippon Kayaku, Kyowa-Hakko Kirin. Research<br />
Funding for Taiho Pharmaceutical, Ono Pharmaceutical, Eli Lilly, Boehringer<br />
Ingelheim, Pfizer, Chugai, Kyowa-Hakko Kirin. S. Atagi: Honoraria for Chugai,<br />
Boehringer Ingelheim, AstraZeneca, Taiho, Eli Lilly. Research Funding for Chugai,<br />
Pfizer, Ono, Merck Serono, Boehringer Ingelheim, AstraZeneca, Taiho, Yakult, Eli<br />
Lilly. T. Kurata: Honoraria for AstraZeneca, Eli Lilly, Chugai, Pfizer, Boehringer<br />
Ingelheim. A. Inoue: Honoraria for Taiho Pharmaceutical. K. Kubota: Honoraria for<br />
Chugai, Taiho, Daiichi-Sankyo. M. Takenoyama: Honoraria for AstraZeneca, Chugai,<br />
Eli Lilly Japan, Kyowa Hakko Kirin, Ono, Taiho. Research funding for Bristol-Myers,<br />
Chugai, Eli Lilly Japan, Nippon Boehringer Ingelheim, Novartis, Ono. T. Seto:<br />
Honoraria or Research funds for Astellas, AstraZeneca, Chugai, Daiichi Sankyo, Eisai,<br />
Eli Lilly, Kyowa Hakko Kirin, Merck Serono, MSD, Nippon Boehringer Ingelheim,<br />
Nippon Kayaku, Novartis Pharma, Ono, Pfizer, San<strong>of</strong>i, Taiho, Verastem, Yakult<br />
T. Yamanaka: Honoraria for Takeda, Chugai, Taiho. N. Yamamoto: Honoraria for<br />
Chugai, AstraZeneca, MSD, Pfizer, Boehringer Ingelheim, Taiho, Eli Lilly, Ono.<br />
Consulting or advisory role for Chugai, AstraZeneca, Pfizer, Boehringer Ingelheim,<br />
Taiho, Eli Lilly, Ono. Research Funding for Chugai, Boehringer Ingelheim. A. Gemma:<br />
Speaker’s Bureau for Taiho. Y. Ichinose: Honoraria for Chugai Pharmaceutical Co.,<br />
Ltd., Kyowa Hakko Kirin Co., Ltd., Taiho Pharmaceutical Co., Ltd., Taisho Toyama<br />
Pharmaceutical Co., Ltd. Research funding for Takeda Bio Development Center Ltd.,<br />
Nippon Kayaku Co., Ltd. All other authors have declared no conflicts <strong>of</strong> interest.<br />
Background: Cb + weekly PTX showed survival benefits compared with vinorelbine or<br />
gemcitabine in elderly patients with NSCLC. 1 However, D alone is still one <strong>of</strong> the<br />
vi454 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong> 27 (Supplement 6): vi455–vi461, 2016<br />
doi:10.1093/annonc/mdw384<br />
palliative care<br />
1300O<br />
Use <strong>of</strong> chemotherapy near the end <strong>of</strong> life for solid cancers:<br />
What factors matter?<br />
P. Rochigneux 1 , J.L. Raoul 1 , L. Morin 2<br />
1 Medical <strong>Oncology</strong>, Institute Paoli Calmettes, Marseille, France, 2 Aging Research<br />
Center, Karolinska Institutet, Stockholm, Sweden<br />
estimated median time between PC consultation and death was 60 days (IQR 14-120<br />
days) for outpatients and 20 days (IQR 10-42 days) for inpatients. In regard to education,<br />
55 (40%) <strong>of</strong>fered PC fellowship programmes; 43 (31%) had mandatory PC rotations for<br />
oncology fellows; 71 (51%) <strong>of</strong>fered didactic PC curriculum for oncology fellows; 102<br />
(73%) <strong>of</strong>fered combined educational activities; and 104 (75%) provided continuing<br />
medical education for oncologists. All ESMO-DCs reported PC research activity in the<br />
past 3 years, with pain being the most common topic (N = 99, 71%). Most centres<br />
(>80%) perceived the ESMO-DC programme to increase their status.<br />
Conclusions: The ESMO-DCs had high level <strong>of</strong> PC infrastructure and provided PC<br />
access to a large proportion <strong>of</strong> patients with advanced cancer. Areas for improvement<br />
include timing <strong>of</strong> referral, clinical processes <strong>of</strong> integration and educational components.<br />
Legal entity responsible for the study: ESMO<br />
Funding: ESMO<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1302P<br />
Active palliation for massive malignant ascites using<br />
KM-CART (Japanese original ascites treatment system)<br />
K. Matsusaki 1 , A. Yoshizawa 1 , M. Yokoi 1 , K. Ohta 2<br />
1 Ascites Treatment Center, Kanamecho Hospital, Tokyo, Japan, 2 Surgery, Nippon<br />
Medical School Main Hospital, Tokyo, Japan<br />
1301PD<br />
Characteristics and level <strong>of</strong> integration <strong>of</strong> ESMO Designated<br />
Centres <strong>of</strong> integrated oncology and palliative care<br />
D. Hui 1 , N. Cherny 2 , N. Latino 3 , F. Strasser 4<br />
1 Palliative Care and Rehabilitation Medicine, MD Anderson Cancer Center,<br />
Houston, TX, USA, 2 Dept Medical <strong>Oncology</strong>, Shaare Zedek Medical Centre<br />
<strong>Oncology</strong> Institute, Jerusalem, Israel, 3 Designated Centres Working Group,<br />
European Society for Medical <strong>Oncology</strong> (ESMO), Lugano, Switzerland, 4 Dept <strong>of</strong><br />
Internal Medicine, Kantonsspital St. Gallen, St. Gallen, Switzerland<br />
Background: The ESMO Designated Centres (ESMO-DCs) <strong>of</strong> Integrated <strong>Oncology</strong><br />
and Palliative Care (PC) Incentive Programme has grown steadily and now includes<br />
180 centres in 40 countries. We conducted a survey to determine the characteristics<br />
and level <strong>of</strong> integration <strong>of</strong> PC services at ESMO-DCs.<br />
Methods: An electronic survey was sent to leaders <strong>of</strong> all ESMO-DCs between April and<br />
May2016.Thesurveyconsisted<strong>of</strong>78questions examining the DC characteristics,<br />
palliative care clinical programme (structure, processes, outcomes), education, research and<br />
attitudes and beliefs toward the ESMO-DC programme. The level <strong>of</strong> integration was<br />
assessed based on 13 criteria developed from a Delphi survey (Hui et al. Ann Oncol 2015).<br />
Results: The response rate was 77% (139/180). 105 (76%) ESMO-DCs were from<br />
Europe, 50 (36%) were tertiary care cancer centres and 30 (22%) were tertiary care<br />
general hospitals. The median number <strong>of</strong> beds was 550 (interquartile range [IQR]<br />
277-925). 131 (94%) had inpatient consultation teams, 106 (76%) had outpatient<br />
palliative care clinics, 88 (63%) had dedicated acute care beds, and 75 (54%) <strong>of</strong>fered<br />
community-based PC. 132 (95%) had an interdisciplinary team, and 90 (65%) had<br />
dually certified palliative oncologists. These programmes reported that a median <strong>of</strong> 70%<br />
(IQR 28-80%) <strong>of</strong> patients with advanced cancer had a PC consultation before death. The<br />
Background: Massive cancerous ascites causes severe abdominal distention, dyspnea<br />
and appetite loss, resulting in loss <strong>of</strong> patients’ activities <strong>of</strong> daily living (ADL) and<br />
discontinuation <strong>of</strong> their cancer treatment such as chemotherapy.<br />
Methods: To improve the symptoms, we have developed a novel cell-free and<br />
concentrated ascites reinfusion therapy (KM-CART) which is modified from a<br />
conventional CART approved by the Ministry <strong>of</strong> Health, Labor and Welfare in Japan.<br />
KM-CART is easier to use and can be applied for massive malignant ascites. It is<br />
performed by removing the entire volume <strong>of</strong> ascitic fluid (maximum, 27 L) and<br />
administering the recovered autologous proteins (maximum, 420g) into blood vessels<br />
by infusion.<br />
Results: A total <strong>of</strong> 2940 patients, including 458 ovarian cancer, 457 pancreatic cancer,<br />
441 gastric cancer, 335 colon cancer patients, and 1249 patients with other disorders,<br />
underwent KM-CART between February 2009 and March 2016. Ascitic fluid was<br />
removed to the greatest extent possible (0.8–27.0 L; mean, 6.5 L).The mean processing<br />
rate was 10.4 min/L, and between 100 and 2500 mL (mean, 560 mL) <strong>of</strong> filtered<br />
concentrate was created and administered by intravenous infusion. Side effects<br />
consisted <strong>of</strong> only mild fever, with no serious side effects observed. In all 87 patients for<br />
whom a questionnaire survey could be conducted on both the day before and the day<br />
after KM-CART, symptom scores improved for 10 items, including abdominal fullness,<br />
respiratory discomfort, decreased appetite and gait impairment. In addition, some<br />
patients resumed chemotherapy as a result <strong>of</strong> regaining the motivation to fight disease.<br />
These patients were able to transition to their homes over the long-term. Furthermore,<br />
many cancer cells were recovered from the membrane filter washing fluid and these<br />
cells were able to be used for dendritic cell (DC) vaccine therapy.<br />
Conclusions: KM-CART system was considered easy to use and safe, and the recovery<br />
<strong>of</strong> large volumes <strong>of</strong> autologous proteins was possible to improve general status,<br />
nutrition, and immune status, as well as subjective symptoms. In addition, the<br />
recovered cancer cells were able to be used for immune cell therapy etc.<br />
Legal entity responsible for the study: N/A<br />
Funding: Asahi Kasei Medical Co.Ltd<br />
Disclosure: K. Matsusaki: Patent fee from Asahi Kasei Medical CO.,LTD. All other<br />
authors have declared no conflicts <strong>of</strong> interest.<br />
1303P<br />
Safety and effectiveness <strong>of</strong> interventions for malignant<br />
ascites with advanced cancer: Systematic review<br />
D. Martins-Branco, C. Ribeiro, B. Gomes<br />
King’s College, Cicely Saunders Institute, Department <strong>of</strong> Palliative Care, Policy and<br />
Rehabilitation, London, UK<br />
Background: Malignant ascites (MA) - fluid within abdominal cavity due to<br />
intraperitoneal (IP) invasion by cancer cells - is a sign <strong>of</strong> advanced cancer and causes<br />
distressful symptoms such as abdominal pain and dyspnea. Aim: To determine the<br />
safety and effectiveness <strong>of</strong> interventions for MA in adults with advanced cancer.<br />
Methods: We searched 5 electronic databases (April 2015), conducted citation searching<br />
and checked reference lists <strong>of</strong> included articles and 3 systematic reviews. We included<br />
randomised controlled trials and controlled clinical trials (RCTs / CCTs). 1 author<br />
screened titles/abstracts. Further screening, data extraction and quality assessment were<br />
independently conducted by 2 authors and a 3 rd in cases <strong>of</strong> disagreement.<br />
abstracts<br />
© European Society for Medical <strong>Oncology</strong> 2016. Published by Oxford University Press on behalf <strong>of</strong> the European Society for Medical <strong>Oncology</strong>.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com.
abstracts<br />
Results: We identified 5 studies (4 RCTs, 1 CCT), with 648 participants. When reported,<br />
age ranged between 23-92 years, 77% were women and most common primary cancers<br />
were ovarian (OC) (50%) and gastrointestinal (23%). 4 interventions were<br />
pharmacological: IP Cisplatin plus Bevacizumab did not cause adverse effects (AE) and<br />
enhanced quality <strong>of</strong> life (QoL) in MA <strong>of</strong> OC, compared to IP Cisplatin alone (1 RCT,<br />
n = 58); IP Catumaxomab when added to paracentesis induced more AE (abdominal pain,<br />
pyrexia, vomiting/nausea), despite reduction in MA-related symptoms (1 RCT, n = 258);<br />
IP Catumaxomab-induced AE failed to be prevented by Intravenous Prednisolone (1 RCT,<br />
n = 219); Intramuscular Long-acting (LA)-Octreotide did not increase AE, but had limited<br />
QoL benefit compared to placebo (1 RCT, n = 33). 1 non-pharmacological intervention,<br />
abdominal massage, was safe and reduced abdominal bloating, depression and anxiety,<br />
compared to social interaction (1 CCT, n = 58).<br />
Conclusions: Cisplatin plus Bevacizumab appears safe and effective for the<br />
management <strong>of</strong> MA in OC, Catumaxomab added to parencentesis increased AE,<br />
LA-Octreotide appears safe but with limited effectiveness, and abdominal massage is<br />
promising. However, these findings need to be confirmed in more trials.<br />
Legal entity responsible for the study: Systematic review for MSc in Palliative Care at<br />
KCL<br />
Funding: Systematic review for MSc in Palliative Care at KCL<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1304P<br />
Intraperitoneal bevacizumab (Bev) for control <strong>of</strong> refractory<br />
malignant ascites. A single centre experience<br />
C.T. Satheesh, S. Patil, H.P. Shashidhara<br />
Medical <strong>Oncology</strong>, HCG Bangalore Institute <strong>of</strong> <strong>Oncology</strong> Speciality Centre,<br />
Bangalore, India<br />
Background: Malignant ascites is debilitating for patients with advanced cancer which<br />
negatively impacts the quality <strong>of</strong> life (Qol). The therapeutic options are limited and<br />
<strong>of</strong>ten the goal <strong>of</strong> treatment is to target palliation <strong>of</strong> symptoms. Increased Vascular<br />
Endothelial Growth Factor might be a major cause <strong>of</strong> the formation <strong>of</strong> malignant<br />
ascites. Intraperitoneal low dose 100mg Bev could be an economical option for<br />
symptom control <strong>of</strong> refractory malignant ascites and to make cost effectiveness as<br />
compared to 400mg in other clinical studies. Aims: To analyze clinical efficacy <strong>of</strong><br />
Intraperitoneal Bevazumab in Patients with advanced cancer and refractory malignant<br />
ascites treated at HCG, Bangalore, from july-2014 to Jan-2016.<br />
Methods: Patients with advanced cancer and refractory malignant ascites who had<br />
received paracentesis at least once within the past 2 weeks were subjected to<br />
intraperitoneal Bevacizumab 100mg in 100 ml NaCl 0.9%) after paracentesis. During<br />
the 2 months treatment period, a minimum interval <strong>of</strong> 14d was kept between the<br />
applications <strong>of</strong> Bevazumab. The paracentesis-free survival (ParFS), best response (BR)<br />
defined as the longest paracentesis-free period and QoL were analyzed.<br />
Results: 29 Patients (median age 57yr), male: Female ratio 0.93:1 received at least one<br />
dose application <strong>of</strong> the Bevazumab and qualified for the intention to treat analysis. The<br />
most common underlying malignancy with Ascites were Ovary 34.48%, Stomach 31%.<br />
The types <strong>of</strong> ascetic fluid were Hemorrhagic 55.17%, straw /clear 24.13% and Chylous<br />
20.68%. The median ParFS was 15 days (10-23d) and The BR was 20d (10-60). The<br />
median ParFS in patients with hemorrhagic fluid was 20d, straw/clear-14d, chylous 10d<br />
and median BR in patients with hemorrhagic fluid was 26d, starw/clear-19d, chylous<br />
14 d. The median ParFS in patients with carcinoma ovary was 17d, & ca stomach 11d,<br />
and median BR in patients with ca ovary was 23d, & ca stomach 15d.<br />
Conclusions: Low dose intraperitoneal Bevazumab is an ecomical option and gives<br />
better symptom control <strong>of</strong> malignant ascites especially in hemorrhagic type. Further<br />
randomized studies should be conducted and compared between 100mg and 400mg<br />
bevazumab before routine clinical practice.<br />
Legal entity responsible for the study: HCG, Ethical Committee<br />
Funding: HCG<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1305P<br />
Knowledge <strong>of</strong> pain management in patients with painful bone<br />
metastases; A multicentre randomized trial on pain education<br />
J.I. Geerling 1 , A. Reyners 2 , Y. van der Linden 3 ,V.Mul 4 , P. Westh<strong>of</strong>f 5 , A. de Graeff 6 ,<br />
C. Rodenhuis 7 , E. de Nijs 8 , T. Muilenburg 7<br />
1 Centre <strong>of</strong> Expertise Palliative Care, University Hospital Groningen (UMCG),<br />
Groningen, Netherlands, 2 Medical <strong>Oncology</strong>, University Hospital Groningen<br />
(UMCG), Groningen, Netherlands, 3 Radiation oncology, Leiden University Medical<br />
Center (LUMC), Leiden, Netherlands, 4 Radiation oncology, University Hospital<br />
Groningen (UMCG), Groningen, Netherlands, 5 Radiation oncology, Radboud<br />
University Medical Centre Nijmegen, Nijmegen, Netherlands, 6 Medical <strong>Oncology</strong>,<br />
University Medical Center Utrecht, Utrecht, Netherlands, 7 Radiation oncology,<br />
University Medical Center Utrecht, Utrecht, Netherlands, 8 Centre <strong>of</strong> Expertise<br />
Palliative Care, Leiden University Medical Center (LUMC), Leiden, Netherlands<br />
Background: Education <strong>of</strong> patients regarding pain management may improve patient<br />
empowerment and, consequently, reduce pain intensity. To investigate the effect <strong>of</strong><br />
education on pain intensity, a multicentre phase 3 study was conducted between<br />
1-3-2011 and 1-4-2016. A total <strong>of</strong> 354 patients who received radiotherapy for painful<br />
bone metastases were randomized between nurse-led tailored education regarding pain<br />
management or care as usual. A worst pain score <strong>of</strong> ≥5 on a 0-10 numeric rating scale<br />
(NRS) was one <strong>of</strong> the inclusion criteria. The primary endpoint was pain intensity. Here<br />
we report on pain knowledge in patients randomized in the education arm.<br />
Methods: Patient characteristics, pain intensity (NRS) and patients’ thoughts regarding<br />
pain management were assessed using a structured interview. This interview took place<br />
between randomization and start <strong>of</strong> radiotherapy. Patients were asked whether they<br />
completely agreed-completely disagreed on a 5 point Likert scale with the following<br />
statements 1) cancer pain can be relieved effectively 2) pain medication should be given<br />
only when pain is severe 3) most cancer patients will become addicted to pain medication<br />
4) it is better to give the lowest amount <strong>of</strong> pain medication, so that larger doses can be used<br />
later if pain increases 5) it is better to give pain medication around the clock than only<br />
when needed 6) non-pharmacological interventions can relieve pain 7) patients are <strong>of</strong>ten<br />
overmedicated 8) use <strong>of</strong> pain medication can be changed without consulting a physician.<br />
Lack <strong>of</strong> knowledge was identified if they completely or fairly disagreed on statement 1, 5, 6<br />
or, completely or fairly agreed on statement 2-4, 7 or 8.<br />
Results: 167 patients were interviewed, mean age 65 ±10 years. Mean worst pain at<br />
inclusion was 7.9 ±1.4. 52% <strong>of</strong> patients used strong opioids (WHO step 3). Most patients<br />
(91%) lacked knowledge <strong>of</strong> at least one statement (median 2, range 1-6). Lacks were found<br />
most frequently for statements 4 (69%), 2 (41%), 3 and 7 (both 28%). Patients’ knowledge<br />
was best about statements 8 (77% disagreed), 5 (74% agreed) and 1 (73% agreed).<br />
Conclusions: Most patients lack sufficient knowledge on different topics <strong>of</strong> pain<br />
management, advocating tailored pain education.<br />
Clinical trial identification: ZonMW 11510007 07-10-2010<br />
Legal entity responsible for the study: N/A<br />
Funding: KWF ZonMW<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1306P<br />
Efficacy <strong>of</strong> Quadramet® (QUA) as treatment <strong>of</strong> painful bone<br />
metastasis: A large single-center study<br />
H. Kolesnikov-Gauthier 1 , N. Lemoine 2 , A. Oudoux 3 , A. Olivier 1 , E. Tresch-Bruneel 4 ,<br />
N. Penel 5<br />
1 Nuclear Medicine, Centre Oscar Lambret, Lille, France, 2 <strong>Oncology</strong>, Hôpital Privé<br />
de la Louvière, Lille, France, 3 Pediatric <strong>Oncology</strong>, Centre Oscar Lambret, Lille,<br />
France, 4 Clinical Research and Methodological Platform, Centre Oscar Lambret,<br />
Lille, France, 5 Medical <strong>Oncology</strong>, Centre Oscar Lambret, Lille, France<br />
Background: The aim <strong>of</strong> this study was to assess the efficacy <strong>of</strong> QUA ( 153 Sm-EDTMP<br />
ethylene-diamin-tetramethylene-phosphonate]) in a real-life setting.<br />
Methods: We have conducted a retrospective study <strong>of</strong> all consecutive patients (pts)<br />
treated with QUA for painful bone metastases, according to marketing authorization<br />
(e.g. painful bony met., with hot spots on bone scintigraphy). QUA have been<br />
administered IV at the dose <strong>of</strong> 37 MBq/kg. At each visit (before treatment, and D15<br />
and D30 after treatment), 4 parameters were collected: (i) pain assessment using 10<br />
steps visual analogue scale (VAS) (0 to 10), (ii) presence or absence <strong>of</strong> sleep disturbance<br />
related to pain, (iii) dose <strong>of</strong> analgesic medication, and (iv) answer to the following<br />
closed question “Do You think You get a benefit <strong>of</strong> treatment ?”. Success <strong>of</strong> treatment<br />
was defined by a combined criterion including these 4 parameters.<br />
Results: From January 2001 to December 2012, 370 consecutive QUA treatments for<br />
painful bone met. were delivered in our department. Primary tumors were: breast<br />
carcinoma (153), prostatic carcinoma (155), lung carcinoma (27), or other cancers (35).<br />
Mean age <strong>of</strong> the pts was 65 +/- 12 yrs. Fifty-eight percent <strong>of</strong> the pts had previous external<br />
osseous radiotherapy. Ninety-seven percent <strong>of</strong> pts had concomitant analgesics and 61%<br />
were under diphosphonates. Pts described benefit in 46.0% [95%-CI: 40.7 – 51.5] <strong>of</strong> cases<br />
at Day 15 and 55.0% [95%-CI: 48.8 – 60.7] at D30. Treatment was more effective in cases<br />
<strong>of</strong> breast and prostate cancers compared to other primaries. Pts described benefit at D15 in<br />
50%, 48%, 29%, and 33% <strong>of</strong> cases for breast, prostate, lung and others cancers, respectively<br />
(p= 0.12). Pts described benefit at D30 in 62%, 58%, 6%, and 38% <strong>of</strong> cases for breast,<br />
prostate, lung and others cancers, respectively (p < 0.001).Subjective efficacy was<br />
accompanied by a decrease in analgesic intake in 35.0% <strong>of</strong> cases.<br />
Conclusions: QUA therapy is an effective supportive treatment in pts suffering from<br />
bony met, especially in breast and prostate cancer pts.<br />
Legal entity responsible for the study: Centre Oscar Lambret<br />
Funding: Centre Oscar Lambret<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1307P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Use <strong>of</strong> treatments <strong>of</strong> questionable benefit in hospitalized<br />
patients with metastatic gastric or esophageal cancer near<br />
the end <strong>of</strong> life. A country-wide, register-based study<br />
E. Kempf 1 , L. Morin 2<br />
1 Medical <strong>Oncology</strong>, AP-HP Henri Mondor, Créteil, France, 2 Aging Research<br />
Center, Karolinska Institutet, Stockholm, Sweden<br />
Background: The benefit <strong>of</strong> life-prolonging treatments in terminally ill cancer patients<br />
is debated. Little is know, however, about the aggressiveness <strong>of</strong> care in patients with<br />
metastatic esophagus or stomach cancer.<br />
vi456 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Methods: Register-based study in France, including all hospitalized adults (≥20 years)<br />
who died as the result <strong>of</strong> metastatic esophageal or gastric cancer between 2010 and<br />
2013. The receipt <strong>of</strong> chemotherapy and the use <strong>of</strong> artificial nutrition during the last 3<br />
months <strong>of</strong> life were defined as primary outcomes.<br />
Results: 4,031 patients with metastatic esophageal cancer and 10,423 patients with<br />
metastatic gastric cancer were included (n total= 14,454). Overall, 47.6% <strong>of</strong> patients<br />
received chemotherapy in their last 3 months <strong>of</strong> life, with a significant decrease over<br />
time (from 35.9% during the third month before death to 7.9% in the final week <strong>of</strong><br />
life). In contrast, the receipt <strong>of</strong> artificial nutrition rose from 9.4% to 16% over the same<br />
period <strong>of</strong> time. This increase in the use <strong>of</strong> artificial nutrition was observed for both<br />
esophagus and stomach cancer, across all age-groups, and regardless <strong>of</strong> the number <strong>of</strong><br />
chronic comorbidities (p > 0.001 for trend). During the last week before death, the<br />
likelihood <strong>of</strong> receiving artificial nutrition decreased with age (adjusted OR= 0.80, 95%<br />
CI= 0.77-0.84 for each 10-year increase in age), and was significantly higher for<br />
patients with esophageal cancer compared with gastric cancer (adjusted OR= 1.25, 95%<br />
CI= 1.13-1.37). In addition, 3.5% <strong>of</strong> patients received invasive ventilation during the<br />
last month before death (5% <strong>of</strong> patients with esophageal cancer and 3% <strong>of</strong> patients with<br />
gastric cancer, p < 0.001). 6% <strong>of</strong> patients eventually died in Intensive Care Units, and<br />
only 12.6% died in Palliative Care Units.<br />
Conclusions: Our study shows that hospitalized patients with metastatic esophageal or<br />
gastric cancer are likely to receive treatments <strong>of</strong> questionable benefit near the end <strong>of</strong><br />
life. Interventional studies focusing on patient reported outcomes are needed to assess<br />
the clinical benefit <strong>of</strong> artificial nutrition for patients with terminal cancer.<br />
Legal entity responsible for the study: N/A<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1308P<br />
Undertreatment <strong>of</strong> cancer pain - a retrospective analysis <strong>of</strong><br />
medical records <strong>of</strong> advanced cancer patients hospitalized in<br />
a palliative care department<br />
N.R. Yordanov 1 , I. Marinova 1 , A. Marinova 1 , S. Aleksandrova 2<br />
1 Affiliation "pr<strong>of</strong>.Iv. Mitev"- Vratsa, MU S<strong>of</strong>ia, Vratsa, Bulgaria, 2 Faculty <strong>of</strong> public<br />
health, UMHAT Georgi Stranski, Pleven, Bulgaria<br />
Background: Pain control especially in advanced cancer patients is an unsolved<br />
problem <strong>of</strong> Bulgarian oncology. We aimed to evaluate the undertreatment <strong>of</strong> cancer<br />
pain among advanced cancer patients from Northwest Bulgaria and to identify<br />
patients’ predictive factors for pain undermedication.<br />
Methods: As predictive factors the following were used: cancer diagnosis, gender, age,<br />
education, place <strong>of</strong> living, social activity and performance status. Pain undertreatment<br />
was evaluated by the Pain Management Index that links pain intensity with prescribed<br />
medication for its control. Pain was categorized by its intensity using NRS 10 score in 4<br />
groups 0 = no pain (0); 1 = mild (1-3); 2 = moderate (4-6); 3 = severe pain (7-10).<br />
Prescribed analgesic medication was categorized by the WHO’s “analgesic ladder” also<br />
in 4 groups 0 = no medication; 1 = NSAIDS; 2 = mild opioids; 3 = strong opioids. PMI<br />
score was calculated by subtracting the pain score from analgesic score. Negative PMI<br />
score was considered as indicator <strong>of</strong> inadequate pain management. Descriptive<br />
statistics and Pearson’s r correlation were used to determine the relationship <strong>of</strong> PMI<br />
with predictive factors.<br />
Results: Medical records from 3096 hospitalizations were analyzed. 48 (0.015%) were<br />
excluded for incomplete data. 835 (27.4%) patients reported pain NRS 10 4 experience 2213 (72.6%) patients. Mean pain intensity score<br />
was NRS 10 =6.19. 152 (5%) patients had no pain treatment at all, another 341 (11.2%)<br />
had only NSAIDs. 892 (29.3%) patients were prescribed mild opioids, and 828 (27.2% )<br />
used strong opioids. Negative PMI was calculated in 780 (25.6%) patients. Negative<br />
PMI was more <strong>of</strong>ten found in unemployed (31.1%) and in farm workers (31%).<br />
Analysis revealed that negative PMI increases with patients’ age (p < 0.01), higher<br />
Karn<strong>of</strong>sky index (p < 0.01) and lower educational level (p < 0.01). There was no<br />
significant difference in PMI in both sexes and by patient’s diagnosis.<br />
Conclusions: Undertreatment <strong>of</strong> cancer pain in Northwest Bulgaria is still an unsolved<br />
problem especially for elderly, less educated, farm workers and unemployed advanced<br />
cancer patients.<br />
Legal entity responsible for the study: Dr. Nikolay Radev Yordanov, PhD<br />
Funding: Comprehensive Cancer Center - Vratsa<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1309P<br />
Analysis <strong>of</strong> patient-related barriers to management <strong>of</strong> cancer<br />
pain in Shanghai<br />
Y. Zhao, Q. Xu<br />
Department <strong>of</strong> Medical <strong>Oncology</strong>, 10th People’s Hospital <strong>of</strong> Shanghai, Tongji<br />
University, Shanghai, China<br />
barriers to effective pain management, some <strong>of</strong> which come from medical pr<strong>of</strong>essionals<br />
and the medical system. There are some other reasons caused by the patients<br />
themselves, such as erroneous beliefs and misconceptions. So we conducted a series <strong>of</strong><br />
questionnaires among patients receiving analgesics to investigate the patient-related<br />
barriers to pain management.<br />
Methods: Patients hospitalized in Shanghai Tenth People’s Hospital <strong>of</strong> Tongji<br />
University and the cooperative hospitals, receiving analgesia therapy, were enrolled in<br />
the study. Patients received questionnaires for assessment <strong>of</strong> mood, satisfaction with<br />
pain management, concerns about the agents and barriers in communication with<br />
doctors. The variables extracted were sex, cancer site and stage, education, smoking<br />
and drinking history, religion and marital status. We try to examine the correlation <strong>of</strong><br />
the barriers and the variables above.<br />
Results: Of 125 patients evaluated, 41.6% <strong>of</strong> the patients had experienced moderate to<br />
severe depression, and 53.6% experienced moderate to severe anxiety. The mean BQ- II<br />
scores were 2.02 for physiologic effects, 1.78 for fatalism, 1.76 for communication, 2.23<br />
for harmful effects and 1.97 in total. Patient characteristics including sex, smoking and<br />
drinking history, education, religion and marital status were not associated with high<br />
BQ scores. High scores for barriers to pain management were related to depression and<br />
anxiety.<br />
Conclusions: Patients involved showed great fear <strong>of</strong> becoming addicted to pain<br />
medication, the belief that pain medications harm the immune system and becoming<br />
resistant to the medications. Scores on concerning physiologic effects <strong>of</strong> analgesics may<br />
be decreased by timely symptomatic treatment for the side effects. Patients had less<br />
barriers to communication and confidence <strong>of</strong> overcoming cancer pain. Depression and<br />
anxiety state may influence communication with doctors and faith in defeating<br />
cancer-related pain.<br />
Legal entity responsible for the study: Shanghai Tenth People’s Hospital<br />
Funding: Shanghai Health System<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1310P<br />
abstracts<br />
Influence <strong>of</strong> age on opioid prescription <strong>of</strong> patients with<br />
advanced lung cancer<br />
H-S. Lee 1 , C-P. Lin 2 , H-M. Chen 3 , Y-Y. Shao 3<br />
1 Division <strong>of</strong> pulmonary medicine, Department <strong>of</strong> internal medicine, E-DA Hospital,<br />
Kaohsiung, Taiwan, 2 Department <strong>of</strong> Anesthesiology, National Taiwan University<br />
Hospital, Taipei, Taiwan, 3 Department <strong>of</strong> <strong>Oncology</strong>, National Taiwan University<br />
Hospital, Taipei, Taiwan<br />
Background: Opioid is crucial for cancer pain management, but there are concerns<br />
about its use in elder patients. We analyzed national data to explore whether age is a<br />
determining factor in opioid prescription for patients with advanced lung cancer.<br />
Methods: We searched the Taiwan Cancer Registry Database for patients with newly<br />
diagnosed stage IIIB or IV non-small cell lung cancer (NSCLC) from 2006 to 2010.<br />
Patients’ prescription data within 3 months <strong>of</strong> diagnosis were retrieved from the<br />
National Health Insurance Research Database. We classified the patients into the elder<br />
group (≥ 70 years old upon diagnosis) and the younger group. In multivariate analyses,<br />
gender, histology, stage, chemotherapy, radiotherapy, hospital level, and co-morbidities<br />
were adjusted. Opioids were categorized into strong (morphine and fentanyl) and weak<br />
opioids (buprenorphine, codeine, and tramadol).<br />
Results: A total <strong>of</strong> 26,664 patients were included; 61% were male, and the median age<br />
was 70 years. There were 13,332 and 13,332 patients in the elder group and the younger<br />
group, respectively. Elder patients were more likely to be male and have stage IIIB<br />
disease, but less likely to be treated in medical centers, have adenocarcinoma histology,<br />
and receive chemotherapy or radiotherapy. In the multivariate analysis, elder patients<br />
were less likely to receive analgesics (adjusted odds ratio [AOR] 0.70, p < 0.001).<br />
Among analgesic users, elder patients were less likely to receive opioids (AOR 0.92,<br />
p = 0.013). Stage IV disease, histology other than squamous cell carcinoma, and<br />
receiving radiotherapy were also associated with more opioid use, but receiving<br />
chemotherapy was associated with less opioid use. Among opioid users, elder patients,<br />
compared with younger patients, were more likely to receive strong opioids (51% vs<br />
46%, p < 0.001). This difference mainly resulted from immediate-release morphine.<br />
Elder opioid users were less likely to receive weak opioids (80% vs 85%, p < 0.001),<br />
regardless which weak opioids.<br />
Conclusions: Among patients newly diagnosed to have advanced NSCLC, elder<br />
patients were less likely to receive opioids for pain management. Among opioid users,<br />
elder patients were more likely to receive strong opioids.<br />
Legal entity responsible for the study: National Taiwan University Hospital & E-Da<br />
hospital<br />
Funding: National Taiwan University Hospital & E-Da hospital<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
Background: Cancer pain is the most common symptom in malignancy patients.<br />
Approximately 60-90% <strong>of</strong> advanced cancer patients have experienced severe pain,<br />
which has seriously affected the life quality <strong>of</strong> these patients. There are still numerous<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw384 | vi457
abstracts<br />
1311P<br />
End <strong>of</strong> life (EOL) chemotherapy (CT) in gastro-intestinal (GI)<br />
cancer patients (pts): A retrospective AGEO study<br />
A. Lapeyre-Prost 1 , G. Perkins 1 , M. Vallee 2 , A. Pozet 3 , D. Tougeron 2 , M. Maillet 4 ,<br />
C. Locher 5 , J. Dreanic 6 , J.L. Legoux 7 , A. Lievre 8 , C. Lecaille 9 , J-M. Sabate 10 ,<br />
F. Mary 11 , F. Bonnetain 3 , H. Jaulmes-Bouillot 12 , B. Landi 1 , J. Taieb 1<br />
1 GI oncology, Hopital European George Pompidou, Paris, France,<br />
2 Gastroenterology, CHU Poitiers, Jean Bernard Hôpital, Poitiers, France,<br />
3 Methodology and quality <strong>of</strong> Life in <strong>Oncology</strong> unit, CHU Besançon, Hôpital Jean<br />
Minjoz, Besançon, France, 4 Gastroenterology, Hôpital St. Louis, Paris, France,<br />
5 Service Gastroentérologie, CH de Meaux, Meaux, France, 6 Gastroenterology,<br />
Hôpital Cochin, Paris, France, 7 Hepato-Gatroenterology and Digestive <strong>Oncology</strong>,<br />
C.H.R. Orleans - La Source, Orleans, France, 8 Medical <strong>Oncology</strong>, Institut Curie,<br />
St. Cloud, France, 9 Hepato-Gatroenterology and Digestive <strong>Oncology</strong>, Polyclinique<br />
Bordeaux Nord Aquitaine, Bordeaux, France, 10 Gastroenterology, Hôpital Louis<br />
Mourier, Colombes, France, 11 GI <strong>Oncology</strong>, Hôpital Avicenne, Bobigny, France,<br />
12 Palliative care Unit, Hopital European George Pompidou, Paris, France<br />
Background: The use <strong>of</strong> CT during the EOL is poorly studied, with no dedicated study<br />
to GI cancer pts. Here, we report results <strong>of</strong> a retrospective study in this specific<br />
population, in the aim to analyze the factors associated to CT use within 3- and<br />
1-month before death.<br />
Methods: All pts that died from a GI cancer in 10 French tertiary care hospitals during<br />
2014 were included in this retrospective cohort. Clinical (primary tumor, treatment<br />
history, performance status (PS)), demographical (age, sex, date and place <strong>of</strong> death)<br />
and biological (albumin level) data were collected and compared between pts receiving<br />
or not CT within 3- and 1-month before death. Overall survival (OS), defined as the<br />
time from diagnostic until death from any cause, was estimated using Kaplan Meier<br />
method. Univariate Cox regression’s models were performed to estimate hazard ratio<br />
<strong>of</strong> all baseline variables with its 95% <strong>of</strong> confidence interval (CI).<br />
Results: 437 pts were included in this study. All had a metastatic GI cancer (colorectal:<br />
36.2%, pancreas: 28.4%, gastric: 10.3%, oesophageal: 9.8%, cholangiocarcinoma: 8.2%,<br />
hepatocarcinoma: 3.9%, others: 3.2%). Among them, 293 pts (67.0%) received CT<br />
within 3-months before death, and 144 (33.0%) did not, and 121 pts (27.7%) received<br />
CT within 1-month before death vs 316 (72.3%) who did not. Pts receiving CT within<br />
3-months before death were significantly younger (median age: 65.5 vs 72.8 years,<br />
p < 0.0001), with a better PS (PS 0 or 1: 53.9 vs 28.5%, p < 0.0001) and higher albumin<br />
level (median: 32.8 vs 31.0 g/L, p = 0.048), higher number <strong>of</strong> previous line <strong>of</strong> CT<br />
(median <strong>of</strong> line number: 2 vs 1, p < 0.0001). No difference in OS was found between the<br />
2 groups at 3-months before death. Pts receiving CT within 1-month before death had<br />
the same characteristics than the 3-month group and were more likely to die in medical<br />
GI oncology unit than in palliative care unit or at home (81.8 vs 64.2%, p = 0.001).<br />
Conclusions: In GI-cancer units, CT is given within 3- and 1- month before death, in<br />
two and one third <strong>of</strong> patients, respectively. Analysis <strong>of</strong> survivals together with a score<br />
aimed to drive treatment discontinuation decision will be presented at the meeting.<br />
Legal entity responsible for the study: Geraldine Perkins<br />
Funding: AGEO<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1312P<br />
Provision <strong>of</strong> spiritual care to advanced cancer patients by<br />
doctors and nurses in the Middle East<br />
G. Bar-Sela 1 , M. Schultz 1 , K. Khader 2 , M. Rassouli 3 , M. Doumit 4 , I. Ghrayeb 5 ,<br />
R. Kebudi 6 , K. Elshamy 7 , M. Faisal Al-Jadiry 8 , R. Fahmi 9 , H. Charalambous 10 ,<br />
S. Razaq 11 , N. Gafer 12 , G. Can 13 , R. Obeidat 14 , R. Punjwani 15 , H. Ayyash 16 ,<br />
M. Khleif 17 , M. Najajreh 18 , M. Silbermann 19<br />
1 <strong>Oncology</strong>, Rambam Health Care Center, Haifa, Israel, 2 <strong>Oncology</strong>, Taif University,<br />
Taif, Saudi Arabia, 3 <strong>Oncology</strong>, Shahid Beheshti University <strong>of</strong> Medical Sciences,<br />
Tehran, Iran, 4 <strong>Oncology</strong>, American University <strong>of</strong> Beirut Medical Center, Beirut,<br />
Lebanon, 5 <strong>Oncology</strong>, Makassed Charitable Hospital, East Jerusalem, Palestinian<br />
Territory, Occupied, 6 <strong>Oncology</strong>, Istanbul University Institute <strong>of</strong> <strong>Oncology</strong>, Istanbul,<br />
Turkey, 7 <strong>Oncology</strong>, Mansoura University Hospital School <strong>of</strong> Medicine, Mansoura,<br />
Egypt, 8 Pediatric, Children Welfare Teaching Hospital, University <strong>of</strong> Baghdad,<br />
Baghdad, Iraq, 9 <strong>Oncology</strong>, El-Salam oncology center, Cairo, Egypt, 10 <strong>Oncology</strong>,<br />
Bank <strong>of</strong> Cyprus <strong>Oncology</strong> Center, Nicosia, Cyprus, 11 <strong>Oncology</strong>, Children Teaching<br />
Hospital, Medical City Complex, Baghdad, Iraq, 12 <strong>Oncology</strong>, Radiation and<br />
Isotope Center Khartoum RICK, Khartoum, Sudan, 13 <strong>Oncology</strong>, Istanbul<br />
University Florence Nightingale Hemsirelik Facultesi, Istanbul, Turkey, 14 <strong>Oncology</strong>,<br />
Zarqa University, Zarqa, Jordan, 15 <strong>Oncology</strong>, Children’s Cancer Hospital, Karachi,<br />
Pakistan, 16 <strong>Oncology</strong>, European Khan Yunis Hospital, Khan Yunis, Palestinian<br />
Territory, Occupied, 17 Palliative Care, Al-Sadeel Society for Palliative Care,<br />
Bethlehem, Palestinian Territory, Occupied, 18 <strong>Oncology</strong>, Betjala Hospital,<br />
Bethlehem, Palestinian Territory, Occupied, 19 Research center, Middle East<br />
Cancer Consortium, Haifa, Israel<br />
Background: In the US, ∼75% <strong>of</strong> advanced cancer patients want doctors and nurses to<br />
provide some spiritual care, and a similar percentage <strong>of</strong> staff believe they should do so.<br />
When patients feel spiritually supported by staff, we find a higher QoL, increased use <strong>of</strong><br />
hospice, and reduced use <strong>of</strong> aggressive treatments in EoL. Yet only ∼25% <strong>of</strong> patients<br />
actually receive spiritual care, a service gap that bears understanding and addressing.<br />
Relatively little is known about staff spiritual care provision in the Middle East, which<br />
the present study aims to address.<br />
Methods: We distributed the Religion and Spirituality in Cancer Care Study via the<br />
Middle East Cancer Consortium to physicians and nurses caring for advanced cancer<br />
patients. Survey items include how <strong>of</strong>ten respondents think members <strong>of</strong> their<br />
pr<strong>of</strong>ession should provide spiritual care, how <strong>of</strong>ten they themselves do so in practice,<br />
and their perceived barriers to spiritual care provision.<br />
Results: We had 770 respondents (40% physicians, 60% nurses) from 14 Middle<br />
Eastern countries. Eighty percent <strong>of</strong> respondents think staff should provide patients<br />
with spiritual care at least occasionally, but 44% provide spiritual care less <strong>of</strong>ten than<br />
they think they should. Of their last three incurable patients, respondents <strong>of</strong>fered some<br />
form <strong>of</strong> spiritual care to 47%. In a multivariate analysis (MVA), predictors <strong>of</strong> spiritual<br />
care provision include spirituality, nurses more than doctors, and working in palliative<br />
care. How "developed" a country is (following the rankings <strong>of</strong> the Human<br />
Development Index) actually negatively predicts spiritual care provision (p < 0.001).<br />
Staff most commonly cite lack <strong>of</strong> time (67%) and <strong>of</strong> private space (58%) as reasons they<br />
provide spiritual care less <strong>of</strong>ten than they think they should. Yet in MVA vs. actual<br />
spiritual care provision, these reasons did not correlate with non-care provision. Only<br />
the third most commonly cited reason, lack <strong>of</strong> adequate training (55%), remained<br />
significant in the MVA (p = 0.004).<br />
Conclusions: Staff spiritual care provision in the Middle East is higher than in the US,<br />
but we still see a large gap between its desirability and its actual provision. The greatest<br />
barrier to spiritual care provision in practice is lack <strong>of</strong> training, which only 22%<br />
received.<br />
Legal entity responsible for the study: Middle East Cancer Consortium<br />
Funding: Rambam Health Care Campus<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1313P<br />
Study on Tong-Luo-San in treating hand-foot skin reaction<br />
induced by multikinase inhibitors: A randomized,<br />
placebo-controlled clinical trial<br />
L. Jia, B. Deng<br />
<strong>Oncology</strong>, China-Japan Friendship Hospital, Beijing, China<br />
Background: Hand-foot skin reaction (HFSR) is the most common and most serious<br />
adverse event induced by multikinase inhibitors (MKIs). About 9%–62% patients<br />
receiving sorafenib or sunitinib treatments develop HFSR. Severe HFSR leads to dose<br />
reduction or suspension <strong>of</strong> MKI treatment.<br />
Methods: Twenty-seven HFSR patients induced by sorafenib or sunitinib were<br />
included. SAS statistical s<strong>of</strong>tware was used and patients were randomly divided into 2<br />
groupx: experimental group (14 cases) and control group (13 cases). Tong-Luo-San<br />
(TLS) was locally administered for 7 days (20 min, bid), compared with placebo as<br />
blank control. Observation parameters included pain numerical rating scale (NRS)<br />
scores, HFSR grading <strong>of</strong> National Cancer Institute common terminology criteria for<br />
adverse events (NCI-CTCAE), clinical grading <strong>of</strong> National Comprehensive Cancer<br />
Network (NCCN) grade in Impact <strong>of</strong> Pain Measurement Scores, total effective rate,<br />
analgesic efficacy rate and adverse events.<br />
Results: NRS scores, HFSR grade and NCCN grade in impact <strong>of</strong> pain measurement<br />
scores decreased obviously after 7 days’ treatment in the experimental group (P < 0.01).<br />
Compared with control group, NRS scores decreased significantly (6.23 ± 1.36 vs. 2.36<br />
±1.65, P < 0.01), HFSR grade decreased significantly (2.15 ± 1.28 vs. 1.14 ± 1.86,<br />
P < 0.05) and NCCN grade decreased significantly (39.31 ± 13.87 vs. 15.57 ± 9.04,<br />
P < 0.01). Total effective rate was 85.71% (12/14), analgesic efficacy rate was 92.86%<br />
(13/14), significantly better than for the control group. No obvious adverse effects were<br />
found in the TLS group.<br />
Conclusions: TLS significantly reduced HFSR grade, alleviated pain and improved<br />
patients’ quality <strong>of</strong> life. It was also safe and convenient to use.<br />
Legal entity responsible for the study: China-Japan Friendship Hospital<br />
Funding: Ministry <strong>of</strong> Science and Technology <strong>of</strong> People’s Republic <strong>of</strong> China<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1314P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
An end <strong>of</strong> life prognostic score for patients with metastatic<br />
prostate cancer receiving palliative radiotherapy<br />
J. Donaghy 1 , A. Lopes 2 , M. Ali 1 , R. Davda 1 , J. Mascoll 1 , J. Forgenie 1 , S. Howard 1 ,<br />
U. McGovern 1 , H. Payne 3 , A. Mitra 1 , M. Linch 3<br />
1 <strong>Oncology</strong>, University College London Hospital, London, UK, 2 <strong>Oncology</strong>, Cancer<br />
Research UK & University College London Cancer Trials Centre, London, UK,<br />
3 <strong>Oncology</strong>, UCL/UCLH NIHR Biomedical Research Centre, London, UK<br />
Background: Radiotherapy can provide symptomatic relief in the<br />
palliativemanagement <strong>of</strong> patients with metastatic prostate cancer (mPC) however this<br />
would not usually be <strong>of</strong>fered to those patients with a prognosis <strong>of</strong> less than three<br />
months. This study aims to determine the predictive value <strong>of</strong> a set <strong>of</strong> routinely collected<br />
parameters with respect to prognosis in these patients.<br />
Methods: A retrospective analysis <strong>of</strong> 101 patients with metastatic prostatecancer who<br />
received palliative radiotherapy between 2009 and 2012 wasperformed. The variables<br />
vi458 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
measured were haemoglobin (Hb;g/dl), age (years), prostate-specific antigen (PSA;ng/<br />
ml), PSA doubling time (months),neutrophil:lymphocyte ratio (NLR) and albumin (g/<br />
L). Each variable wasmeasured within the 3 months preceding radiotherapy. The<br />
dataset was split randomly into a training set (n = 59) and a validation set (n = 29).<br />
Overall survival univariate cox models were performed in the training set using each <strong>of</strong><br />
the variables above. Those variables with a p-value < 0.10 were then included in an<br />
overall survival multivariate cox model performed in the training set. The overall<br />
survival multivariate cox model was then applied to the validation set. For each patient<br />
in the validation set a prognostic score was obtained and patients were classified by the<br />
event <strong>of</strong> interest (death within 3 months <strong>of</strong> radiotherapy).<br />
Results: Hb, age, NLR ratio and albumin were associated with survival in thetraining<br />
set. The multivariate cox model identified that high Hb values (HR: 0.90 [95%CI: 0.72;<br />
1.11]) and albumin values (0.89 [95%CI: 0.83; 0.95]) were associated with decreased<br />
risk <strong>of</strong> death and increase in age (1.04 [95%CI: 1.00; 1.08]) and NLR (1.02 [95%CI:<br />
0.92; 1.12]) were associated with higher risk <strong>of</strong> death. A prognostic score nomogram<br />
was derived from this model with a prognostic performance, measured using area<br />
under ROC curve, <strong>of</strong> 86% (95%CI 73%; 100%).<br />
Conclusions: This prognostic score allows for accurate prediction <strong>of</strong> survival in<br />
patients with mPC and could be a valuable tool to assist routine clinical decisions<br />
surrounding radiotherapy, chemotherapy and enrollment in clinical trials with respect<br />
to the end-<strong>of</strong>-life setting.<br />
Legal entity responsible for the study: University College London Hospitals<br />
Funding: UCL/UCLH-NIHR Biomedical Research Centre. M.L is also supported by<br />
Cancer Research UK and Prostate Cancer Foundation.<br />
Disclosure: H. Payne: Educational grants from Astellas and Jansen. M. Linch:<br />
Educational and research grants from Bayer, San<strong>of</strong>i, BMS. All other authors have<br />
declared no conflicts <strong>of</strong> interest.<br />
1315P<br />
Antineoplastic therapy near the end <strong>of</strong> life: A retrospective<br />
analysis <strong>of</strong> the clinical practice in oncological adult patients<br />
E. Llabrés Valentí 1 , J. Brenes 1 , A. Hernández 2 , A. Ramchandani Vaswani 2 ,<br />
L. Beltrá 2 , E. Vicente 2 , M. Cejuela 2 , D. Rejas 2<br />
1 Medical <strong>Oncology</strong>, Hospital Universitario Insular de Gran Canaria, Las Palmas,<br />
Spain, 2 Dept. <strong>of</strong> Medical <strong>Oncology</strong>, Hospital Universitario Insular de Gran Canaria,<br />
Las Palmas, Spain<br />
Background: Around 70% <strong>of</strong> oncological patients with disseminated disease are<br />
receiving chemotherapy with palliative intent. However, giving palliative chemotherapy<br />
near the end <strong>of</strong> life, is a balance between clinical benefit and potential harm in terms <strong>of</strong><br />
side effects. Treatment interruption in the final stages <strong>of</strong> life is considered a factor<br />
determining good clinical practice. Earle et al. (J Clin Oncol 2004) define the concept<br />
<strong>of</strong> treatment non-aggressiveness as chemotherapy administration below 10% during<br />
the last 14 days <strong>of</strong> life.<br />
Methods: A retrospective observational study was conducted in a tertiary hospital.The<br />
study included all oncological patients with advanced cancer who died between<br />
January 2014 and august 2015. For descriptive analysis, the statistical program SPSS ®<br />
was used.<br />
Results: Between January 2013 and August 2015, 452 patients with oncological<br />
advanced disease and palliative follow-up care, died. 67% (n = 306) <strong>of</strong> these patients<br />
had received antineoplastic treatment. These are the patients that were analyzed. The<br />
median age <strong>of</strong> patients was 64.5 years (range 17-86), 66.7% (n = 208) was male and<br />
33.3% (n = 104) was female. The most frequent tumors suffered by patients were 30.4%<br />
(n = 95) lung cancer and 14.1% (n = 44) colorectal cancer. The median number <strong>of</strong><br />
treatment regimens received was 2 (range 1-9). There were 69 patients who received<br />
more than 3 different regimens (22.5%). 57.8% (n = 177) <strong>of</strong> the patients maintained the<br />
antineoplastic treatment during the last 3 months before death; 20.6% (n = 63) <strong>of</strong> the<br />
patients received chemotherapy in the last 30 days <strong>of</strong> life; and 10.1% (n = 31) received<br />
chemotherapy in the last 14 days <strong>of</strong> life. 78% (n = 237) <strong>of</strong> the patients died at hospital,<br />
and 22% (n = 67) died at home.<br />
Conclusions: The use <strong>of</strong> chemotherapy during the last period <strong>of</strong> life <strong>of</strong> cancer patients<br />
is a controversial issue.The outcomes <strong>of</strong> our study show that the proportion <strong>of</strong> patients<br />
in the oncology department who received chemotherapy at the last stage <strong>of</strong> life is<br />
similar to that observed by Earle et al. We need more scientific evidence that<br />
consolidate data allowing us to establish criteria for the selection <strong>of</strong> patients who may<br />
benefit from receiving antineoplastic treatment.<br />
Legal entity responsible for the study: N/A<br />
Funding: Hospital Insular Las Palmas<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1316P<br />
The time frame <strong>of</strong> palliative care referrals<br />
M. Ebert Moltara<br />
Acute Palliative care Departent, Institute <strong>of</strong> <strong>Oncology</strong> Ljubljana, Ljubljana, Slovenia<br />
Background: Today we have much strong evidence that supports the early integration<br />
<strong>of</strong> palliative care into standard cancer care <strong>of</strong> all the patients with incurable cancer. At<br />
our Institution we have stablished an Acute Palliative Care Department (APCD) in<br />
2007 and today we can provide a specialist palliative care as inpatient, outpatient and<br />
consultation service. Aim: to analyse the time frame <strong>of</strong> the referrals to palliative care<br />
services at our institution.<br />
Methods: We collected data on the entire patient population who were supported with<br />
specialist palliative care at our instuitions between 2007–2015. We have also compared<br />
triads - periods between 2007-2009, 2010-2012 and 2013-2015.<br />
Results: In the observed period 1842 palliative care patients (942 males, 913 females)<br />
have been served by at least one <strong>of</strong> the APCD services. At the time <strong>of</strong> the analyse 98%<br />
had already died. 99.9% <strong>of</strong> them had incurable cancer. 60% <strong>of</strong> them were treated at<br />
APCD inpatient unit, 23.5% at outpatient clinic and 15.9% were advised by specialist<br />
palliative care consultation team. The mean time <strong>of</strong> palliative care service referrals for<br />
the whole group and period was 54 days. When we compared the three triads between<br />
each other we observed a small trend to earlier referrals (2007-2009: 42days,<br />
2010-2012: 51 days and 2013-2015: 61 days).<br />
Conclusions: We observed earlier palliative care referrals in the last triad <strong>of</strong> the APCD<br />
existence at our institutions comparing first and second triad; still the referrals are late<br />
in the illness trajectory.<br />
Legal entity responsible for the study: <strong>Oncology</strong> Institute <strong>of</strong> Ljubljana<br />
Funding: <strong>Oncology</strong> Institute <strong>of</strong> Ljubljana<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1317P<br />
Supportive home care service: A home-based simultaneous<br />
care intervention<br />
M.S. Pino 1 , L. Brogi 2 , G. Spinelli 2 , L. Fioretto 1<br />
1 <strong>Oncology</strong> Department, Santa Maria Annunziata Hospital, Azienda USL Toscana<br />
Centro, Florence, Italy, 2 Home Care Service, Associazione Tumori Toscana,<br />
Florence, Italy<br />
Background: An increasing amount <strong>of</strong> scientific evidence has confirmed the utility for<br />
cancer patients, in terms <strong>of</strong> quality and quantity <strong>of</strong> life, performance <strong>of</strong> therapeutic<br />
results, and gradual transition <strong>of</strong> care, <strong>of</strong> a simultaneous care approach. In a period <strong>of</strong><br />
human and financial resource constraints innovative forms <strong>of</strong> cooperation between<br />
oncologists and palliative care providers are needed.<br />
Methods: The <strong>Oncology</strong> Department in the Florence Health District with the support<br />
<strong>of</strong> the Tuscany Tumors Association, a non-pr<strong>of</strong>it organization, has conducted, from<br />
March to December 2015, a pilot project to test the feasibility <strong>of</strong> a Supportive Home<br />
Care Service, a dedicated home-based service for the prevention and treatment <strong>of</strong><br />
severe cancer symptoms, and <strong>of</strong> the side effects and toxicities secondary to palliative<br />
cancer therapies. Home care was guaranteed by a highly qualified staff, and was<br />
available 24 hours a day, every day <strong>of</strong> the year.<br />
Results: A total <strong>of</strong> 28 patients, median age 75 years (range 46-85), affected by advanced<br />
solid tumors were enrolled. The majority <strong>of</strong> patients had metastatic disease (82%), and<br />
they all received palliative and supportive care in the home setting and active<br />
anticancer treatment as outpatient. A total <strong>of</strong> 153 (range 1-27) medical and 146 (range<br />
1-37) nursing visits were perfomed, respectively. The average number <strong>of</strong> medical and<br />
nursing visits per patient was 6.95 and 9.73, respectively. Infusional therapy was<br />
administered in 28% <strong>of</strong> the patients for a total <strong>of</strong> 105 days <strong>of</strong> treatment. The average<br />
duration <strong>of</strong> care as <strong>of</strong> January 2016 was 122.67 days (range 13-311). The average<br />
number <strong>of</strong> intervening hospital admissions due to severe toxicity was 0.14 (calculated<br />
as the ratio between the number <strong>of</strong> admissions and the number <strong>of</strong> patients). Thirteen<br />
patients (46% <strong>of</strong> the total) have died at the time <strong>of</strong> this analysis, with an average<br />
duration <strong>of</strong> care <strong>of</strong> 76.92 days. The place <strong>of</strong> death was home in 92% <strong>of</strong> the cases. A<br />
pharmacoeconomic analysis <strong>of</strong> this intervention is currently ongoing.<br />
Conclusions: In our experience early integration <strong>of</strong> simultaneous care and active<br />
cancer treatments is effective. A home-based intervention guarantees personalization<br />
and humanization <strong>of</strong> cancer treatments, and reduces hospitalization, potentially<br />
leading to a more wise use <strong>of</strong> human and financial resources.<br />
Legal entity responsible for the study: <strong>Oncology</strong> Department, Azienda USL Toscana<br />
Centro, Florence<br />
Funding: Associazione Tumori Toscana<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1318P<br />
abstracts<br />
Percutaneous biliary drainage in malign obstructive jaundice:<br />
Is it really necessary for all patients with malign obstructive<br />
jaundice?<br />
C. Hocazade 1 , I. Akmangit 2 , B. Sever Sayın 2 , M. Dogăn 3 , Y. Bozkaya 3 ,<br />
G.U. Erdem 1 , N. Zengin 1<br />
1 Medical <strong>Oncology</strong>, Ankara Numune Education and Research Hospital, Ankara,<br />
Turkey, 2 Interventional radiology, Ankara Numune Education and Research<br />
Hospital, Ankara, Turkey, 3 Medical <strong>Oncology</strong>, Ankara Numune Education and<br />
Research Hospital, Ankara, Turkey<br />
Background: Malign obstructive jaundice (MOJ) in cancer is due to liver metastasis<br />
and/or biliary duct compression. Percutaneous biliary drainage (PBD) is a palliative<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw384 | vi459
abstracts<br />
procedure. Prognostic & predictive factors are needed for selection <strong>of</strong> the cancer<br />
patients who will get more benefit from PBD in MOJ. We evaluated cancer patients<br />
(CP) who had PBD for MOJ for clinicopathological features (CPF) & survival<br />
outcomes besides potential predictive markers for PBD.<br />
Methods: 110 CP who had PBD for MOJ between 2010 & 2016 were evaluated<br />
retrospectively. The correlation between biochemical values, CPF (extrahepatic<br />
metastasis (EM), obstruction cause (OC), stent localization) & total bilirubin (TB) was<br />
evaluated by ROC analysis. The CP were analyzed according to TB after PBD [groups<br />
A: normal (1 mg/dl or 20% decrease), C: stable/<br />
increase.<br />
Results: Median age was 60 (28-82) years. 57 were male. In univariate analysis, EM &<br />
OC were significant factors with concordance to biochemical values. Albumin<br />
(p = 0.007, OR: 5.2, 1,5-17,1), LDH (p = 0.041, OR:2.5, 1.02-6,2) & OC (p = 0.019,<br />
OR:3.4, 1.2-9,9) remained significant in multivariate analysis. The CP were grouped<br />
according to these risk factors (RF): groups 1 (22,7%: no RF), 2 (64,5%: 1-2 RF), 3<br />
(12,7%: >3 RF). TB normalization & OS after PBD are shown in table 1. Stenting<br />
proximal to choledoc had better TB normalization (44,7% vs 17,6%, p = 0.006).<br />
Chemotherapy rates were as 60% for group A, 36,8% for group B & 21,9% for group C<br />
(p = 0.004). 6-months OS was 41,3% for patients receiving chemotherapy & 17,7% for<br />
others (p < 0,001).<br />
Conclusions:<br />
Table: 1318P<br />
Group A*<br />
(%)<br />
Group A* (%)<br />
OS<br />
Total bilirubin (mg/dl)<br />
>13 19,6 18,5<br />
2,5 12,1 6<br />
250 27,1 44,6<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Polypharmacy assessment has been introduced as part <strong>of</strong> care <strong>of</strong> several high risk<br />
patient groups, however experience in oncology patients is limited and no standardized<br />
method is available. We aimed to develop a polypharmacy assessment method that can<br />
be integrated in routine care <strong>of</strong> geriatric oncology patients to improve quality <strong>of</strong> life and<br />
compliance, and to decrease toxicity and costs.<br />
Methods: Patients >65 years and with ≥5 chronic medications that visited our<br />
outpatient oncology clinic were <strong>of</strong>fered a polypharmacy assessment by a clinical<br />
pharmacist. The polypharmacy assessment was based on the Systematic Tool to Reduce<br />
Inappropriate Prescribing (STRIP) method and consisted <strong>of</strong> a polypharmacy<br />
anamnesis with the patient, a subsequent polypharmacy analysis, and an optimized<br />
polypharmacy treatment plan that was provided to the oncologist. In parallel, a<br />
geriatric assessment was performed using ACE-27, ECOG and G8 scoring systems to<br />
score comorbidity, performance and frailty, respectively.<br />
Results: The OncoSTRIP polypharmacy assessment is now integrated as part <strong>of</strong><br />
routine care <strong>of</strong> geriatric oncology patients in our hospital. At the time <strong>of</strong> the first<br />
analysis, 24 patients (17 male and 7 female; mean age 74.3 years) had undergone a<br />
polypharmacy assessment. The mean number <strong>of</strong> chronic medications, oncology<br />
medications, supportive medications and total medications was 8.0 (range 4-14), 2.3<br />
(range 1-5), 2.4 (range 0-6) and 12.7 (range 6-21), respectively. Polypharmacy<br />
treatment optimization was proposed for 19 (79%) <strong>of</strong> patients, with a total <strong>of</strong> 26<br />
suggested pharmacotherapeutic modifications. Mean time spent per patient was 53<br />
minutes.<br />
Conclusions: Polypharmacy assessment <strong>of</strong> geriatric oncology patients identifies many<br />
possible optimizations in pharmacotherapy. The OncoSTRIP method can be integrated<br />
in routine care <strong>of</strong> geriatric oncology patients. Supported by a grant from the Dutch<br />
Cancer Society.<br />
Legal entity responsible for the study: N/A<br />
Funding: Dutch Cancer Society<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1322P<br />
Stereotactic radiosurgery (SRS) for spinal tumors: The<br />
Philippine experience<br />
J.R.M. Baclay 1 , A.D. Gaerlan 1 , I.M. Sih 2 , K.J. Cortez 1 , J.C. Rojales 1 ,<br />
M.J. Calaguas 1 , J.M. Magsanoc 1 , R.A.D. Torcuator 2<br />
1 Radiation <strong>Oncology</strong>, St. Luke’s Medical Center, Taguig City, Philippines,<br />
2 Neurosurgery, St. Luke’s Medical Center, Taguig City, Philippines<br />
Background: Although stereotactic radiosurgery (SRS) for spinal tumors has shown<br />
promising results, it has been used sparingly. This study aims to establish the temporal<br />
pr<strong>of</strong>ile, as well as the number <strong>of</strong> patients who had pain relief, to characterize any<br />
toxicity experienced, and to determine the clinical outcomes <strong>of</strong> patients who<br />
underwent spine SRS.<br />
Methods: From Aug 2012- Dec 2015, 20 patients who underwent spine SRS in this<br />
institution were retrospectively reviewed. Pain outcome was measured using the<br />
Numerical Rating Pain Scale. Neurologic examination was done by the attending<br />
neurosurgeon and the radiation oncologist. Acute effects were scored according to the<br />
Common Terminology Criteria for Adverse Events (CTCAE) v4. The mean age <strong>of</strong><br />
patients was 58 ± 16.06 years. Radiation was delivered via intensity modulated<br />
radiation therapy (IMRT) and prescribed to cover at least 80% <strong>of</strong> the planning<br />
treatment volume (PTV), with organs-at-risk doses kept to tolerance level. Patients<br />
were treated to a median dose <strong>of</strong> 16Gy (range 12-25Gy), given in 1-5 fractions.<br />
Results: Spine SRS was performed in a total <strong>of</strong> 30 spinal tumors from 24 patients (7<br />
primary spinal tumors, 23 metastatic). The most common origins <strong>of</strong> the metastatic<br />
lesions were prostate (4/23), renal cell (2/23), lung (2/23), and breast (2/23) cancers.<br />
The most common treated primary spinal tumor was schwannoma (4/7). A total <strong>of</strong> 4,<br />
20, 1, and 5 lesions were treated in the cervical, thoracic, lumbosacral, and lumbar<br />
spine, respectively. None <strong>of</strong> the patients received previous irradiation to the spine. Pain<br />
was present in 18 <strong>of</strong> the patients pre-SRS. Thirty-eight presented with complete pain<br />
relief one day after the treatment, and increased to 83%, one month after SRS. The<br />
treatment was well tolerated with none <strong>of</strong> the patients experiencing toxicities such as<br />
nausea, vomiting, and headache. Only one patient experienced pain flare two days after<br />
the treatment, which resolved with steroids. One patient developed vertebral<br />
compression fracture two months after treatment, and was managed subsequently. Of<br />
the 10 patients who had motor deficits pre-SRS, 3 had complete recovery <strong>of</strong> motor<br />
function, while 7 had partial improvement.<br />
Conclusions: SRS for spinal tumors is well-tolerated, safe, and effective treatment<br />
option.<br />
Legal entity responsible for the study: N/A<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1323P<br />
Palliative medicine in Iran<br />
R. Malayeri, A. Hazini, P. Pirjani, M.R. Sharbafchi, S. Hojjat<br />
Palliative Medicine Unit, Firoozgar Hospital, Tehran, Iran<br />
abstracts<br />
Background: It is well known that palliative care is a necessity in cancer patients, as<br />
early on as the time <strong>of</strong> diagnosis. Palliative care for cancer patients is rather new in Iran<br />
and has a history <strong>of</strong> less than 8 years.<br />
Methods: Here we give an overview on the status <strong>of</strong> palliative care in Iran. We also<br />
present the demographics <strong>of</strong> our patients in the largest palliative care unit over the last<br />
two years.<br />
Results: Iran has a population <strong>of</strong> around 80 million people and, according to the<br />
<strong>of</strong>ficial cancer registry, a yearly cancer incidence <strong>of</strong> around 100 thousand. We currently<br />
have around 8 active palliative care units for cancer patients and one palliative care<br />
ward in Iran, all run by charities. In these palliative care units, we have oncologists,<br />
palliative care specialists, pain specialists, psychologists, spiritual care specialists, social<br />
workers and dieticians. A total number <strong>of</strong> 3677 patients, <strong>of</strong> whom 3277 (89%) had a<br />
cancer diagnosis were referred to our palliative care unit in Firoozgar Hospital, which is<br />
run by the Ala Charity, in Tehran in the last two years. 1770 female (54%) and 1457<br />
male (46%) cancer patients were referred. A number <strong>of</strong> 388 (12%) patients had breast<br />
cancer, 339 (10%) had hematologic malignancies, 312 (10%) had esophageal or gastric<br />
cancer, 311 (10%) had colorectal cancer, 105 (3%) had a cancer <strong>of</strong> the CNS, 101 (3%)<br />
had lymphoma, 93 (3%) had renal cancer, 87 patients (3%) had ovarian cancer, 81<br />
(2%) had lung cancer, 54 patients (2%) had prostate cancer and 50 (2%) had pancreatic<br />
cancer. The other 40% <strong>of</strong> the cancer patients had either less frequent cancers or their<br />
exact cancer site was not recorded.<br />
Conclusions: Iran, like many other countries, needs many more palliative care units.<br />
As palliative medicine is not financially lucrative, charities play a major role in setting<br />
up, maintaining and expanding these units.<br />
Legal entity responsible for the study: Ala charity<br />
Funding: Ala Charity<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw384 | vi461
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong> 27 (Supplement 6): vi462–vi468, 2016<br />
doi:10.1093/annonc/mdw385<br />
abstracts<br />
prevention and screening<br />
1324PD<br />
A survey among breast cancer specialists on the low uptake<br />
<strong>of</strong> breast cancer preventive therapy with tamoxifen or<br />
raloxifene<br />
A. De Censi 1 , S.F. Noonan 2 , A. Pasa 1 , S. Caviglia 1 , B. Bonanni 3 , A. Costa 4<br />
1 Medical <strong>Oncology</strong>, Ospedali Galliera, Genoa, Italy, 2 Clinical Research, Umberto<br />
Veronesi Foundation, Milan, Italy, 3 Division <strong>of</strong> Cancer Prevention and Genetics,<br />
Istituto Europeo di Oncologia, Milan, Italy, 4 Senology Center, IRCCS MultiMedica<br />
Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy<br />
Background: Despite the strong evidence <strong>of</strong> efficacy and FDA indication, breast cancer<br />
chemoprevention with tamoxifen or raloxifene has found so far little uptake in clinical<br />
practice. This survey aims to evaluate the knowledge, attitudes and beliefs <strong>of</strong> expert<br />
physicians regarding the reasons <strong>of</strong> this low uptake.<br />
Methods: In late 2012 and early 2013 a self administered questionnaire was given<br />
during breast cancer meetings in Italy and Switzerland or submitted electronically to<br />
the breast cancer European School <strong>of</strong> <strong>Oncology</strong> alumni. The questionnaire included 4<br />
personal questions (gender, age, country <strong>of</strong> work and specialty) and a 5-point (from<br />
very important to unimportant) 10-item Likert Scale with the following, here<br />
summarized, statements on the reasons <strong>of</strong> low uptake: 1. no demonstrated mortality<br />
effect, 2. Fear <strong>of</strong> side effects, 3. lack <strong>of</strong> reliable surrogate markers, 4. unclear who is the<br />
appropriate physician, 5. risk models are difficult, 6. lack <strong>of</strong> medical knowledge,<br />
7. prevention <strong>of</strong> otherwise curable cancer, 8. drugs have poor commercial interest,<br />
9. <strong>of</strong>f-label in EU, 10. waiting results <strong>of</strong> Aromatase Inhibitors trials.<br />
Results: Of the 246 surveys collected, 219 were filled in. In the 168 surveys with<br />
demographic information there were 88 female and 81 male, 110 European and 58 non<br />
European, 113 oncologist and 55 non-oncologist physicians. In the overall response on<br />
219 physicians, the <strong>of</strong>f-label use <strong>of</strong> drugs (17%), the lack <strong>of</strong> mortality data (15%), the<br />
lack <strong>of</strong> knowledge among physicians (13%), poor commercial interest in these drugs<br />
(12%) and the fear <strong>of</strong> side effects (11%) were the top five “very important” reasons for<br />
the low uptake. In subgroup analysis the top statement was: i) the <strong>of</strong>f-label use for<br />
physicians ≥ 45 years (47%), ii) the lack <strong>of</strong> mortality data for those < 45 years (39%)<br />
and non-oncologists (29%), iii) the fear <strong>of</strong> side effects for oncologists (53%) and<br />
European physicians (56%).<br />
Conclusions: This survey, which is the first to assess the attitudes <strong>of</strong> experts physicians<br />
towards breast cancer chemoprevention, highlights the complexity <strong>of</strong> this field and,<br />
coupled with the known barriers among potentially eligible women, may help to<br />
identify strategies to increase chemoprevention uptake.<br />
Legal entity responsible for the study: E.O. Ospedali Galliera di Genova<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1325PD<br />
A ‘one stop cancer screening shop’, a way <strong>of</strong> improving<br />
screening participation rates?<br />
A. Bobridge 1 , K. Price 1 , A. Taylor 2<br />
1 School <strong>of</strong> Nursing and Midwifery, University <strong>of</strong> South Australia, Adelaide,<br />
Australia, 2 School <strong>of</strong> Medicine, University <strong>of</strong> Adelaide, Adelaide, Australia<br />
Background: It is well established that cancer screening programs can reduce<br />
morbidity and mortality, however, research demonstrates that screening programs are<br />
underutilised by the target populations. Therefore the aim <strong>of</strong> this study was to<br />
investigate enablers and barriers to cancer screening and how screening participation<br />
may be improved.<br />
Methods: Participants who were randomly selected from northern and western<br />
suburbs <strong>of</strong> Adelaide, Australia answered online or paper based questionnaires about<br />
health issues and service utilization. Data were collected from 10 th August-20 th<br />
December 2015, weighted for selection probability, age and sex and analysed using<br />
SPSS v20 .<br />
Results: 2,895 questionnaires were sent, with 1,562 returned (54.1%). Respondents<br />
included 754 males and 808 females with a mean age <strong>of</strong> 54.1yrs (+ 15.2). Current<br />
cancer screening participation included cervical 34.4% (CI 32.1-36.8), bowel 34.1% (CI<br />
31.7-36.4), breast 28.7% (CI 26.5-31.0) and prostate, 17.4% (CI 15.6-19.4). Commonly<br />
cited reasons for screening participation included; preventing sickness (CI 56.1%,<br />
53.2-59.0), maintaining health (CI 51%, 48-53.9), free program (CI 30.9%, 38.2-33.6)<br />
and family history <strong>of</strong> cancer (20.9% (CI 18.7-23.4). The most common screening<br />
barrier was irrelevance <strong>of</strong> screening to the person (CI 20.8%, 17.2-24.8), with a small<br />
proportion stating time (CI 6.9%, 4.9-9.7) and cost restraints (CI 5.2%, 3.5-7.7). Ninety<br />
three percent (CI 91.7-94.2) <strong>of</strong> respondents thought cancer screening was beneficial,<br />
with the majority (85.3%, CI 83.4-86.9) supporting the concept <strong>of</strong> different types <strong>of</strong><br />
screening being provided at the one site.<br />
Conclusions: Participation rates in individually <strong>of</strong>fered cancer screening programs<br />
(colorectal, breast, cervical) remain low. The enablers and barriers to screening<br />
participation cited in this study are in concert with those in the published literature,<br />
however, an overwhelming percentage <strong>of</strong> respondents would support a combined<br />
cancer screening service. Offering a combined, co-located service - a ’one stop cancer<br />
screening shop’ has the potential to address barriers to screening (such as time<br />
constraints), improve participation rates and maximize utilization <strong>of</strong> public health<br />
resources.<br />
Legal entity responsible for the study: SA Health, The University <strong>of</strong> Adelaide, the<br />
University <strong>of</strong> South Australia, The Queen Elizabeth Hospital, the Lyell McEwin<br />
Hospital and the Institute <strong>of</strong> Medical and Veterinary Science<br />
Funding: SA Health<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1326PD<br />
HIV1-positive men who have sex with men (HIV1-MSM)<br />
knowledge and attitudes towards anal cancer screening: A<br />
cross-sectional study<br />
A. Vanhaesebrouck 1 , S. Pernot 2 , J. Pavie 3 , M.L. Lucas 3 , L. Collias 3 , H. Péré 4 ,<br />
J. Taieb 5 , S. Grabar 1 , L. Weiss 3<br />
1 Biostatistics and epidemiology unit, Groupe hospitalier Hôtel Dieu (AP-HP), Paris,<br />
France, 2 Gastrointestinal oncology, Hopital European George Pompidou, Paris,<br />
France, 3 Immunology, Hopital European George Pompidou, Paris, France,<br />
4 Biology, Hopital European George Pompidou, Paris, France, 5 Gastroenterology<br />
and digestive oncology, Hopital European George Pompidou, Paris, France<br />
Background: Despite combined antiretroviral therapy, risk <strong>of</strong> anal cancer is eighty<br />
times higher in HIV1-MSM than in general population. Although no international<br />
consensus exist for routine screening <strong>of</strong> anal cancer for HIV1-MSM, guidelines in most<br />
western countries include at least digital examination and suggest that anal Pap test<br />
may be beneficial to diagnose high grade squamous intraepithelial lesion. This<br />
monocentric cross-sectional study aims to describe HIV1-MSM knowledge and<br />
attitudes towards anal cancer screening (ACS).<br />
Methods: All adult patients (pts) HIV1-MSM who went to the Hôpital Européen<br />
Georges Pompidou in Paris (France) for a consultation were invited to complete a<br />
self-administered questionnaire about their knowledge regarding ACS and their<br />
previous experience. We explored factors associated with previous screening uptake,<br />
among patients familiar with ACS, with multivariable logistic regression.<br />
Results: Among an active list comprising 1019 pts HIV1-MSM, 410 completed the<br />
questionnaire between June 2015 and January 2016. Median age was 50 years (iqr,<br />
42.5-57.5) and median time from HIV diagnosis was 14.2 years (iqr, 6.9-23.1). HIV<br />
viral load was < 20 copies/mL for 381 (92.9%) pts and median CD4-cell count was 685<br />
cells/μL (iqr, 531-905). Most <strong>of</strong> the pts were aware <strong>of</strong> the existence <strong>of</strong> ACS (n = 335,<br />
81.7%) and among those 191 (57%) had already took a screening test. Absence <strong>of</strong><br />
screening (n = 144, 43%) was most <strong>of</strong>ten explained by lack <strong>of</strong> time (28.5%) and lack <strong>of</strong><br />
information (25.7%). Among pts familiar with ACS, those older than 50 years<br />
(versus < 50 years, OR a =2.3, 95% CI 1.2-4.5, p = 0.017) and those informed by<br />
healthcare providers (versus other information sources, OR a =8.5, 95% CI 2.6-33.6,<br />
p = 0.001) were more likely to have already been screened.<br />
Conclusions: Although 82% <strong>of</strong> the HIV1-MSM were familiar with ACS, only 57% <strong>of</strong><br />
them have already taken a screening test. Information by physician seems the best<br />
intervention to promote the screening. Encouraging physicians to inform HIV1-MSM<br />
pts on anal cancer may improve ACS uptake. Moreover, more detailed information and<br />
better accessibility <strong>of</strong> screening centers should help improve screening rate.<br />
Legal entity responsible for the study: APHP<br />
Funding: APHP<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
© European Society for Medical <strong>Oncology</strong> 2016. Published by Oxford University Press on behalf <strong>of</strong> the European Society for Medical <strong>Oncology</strong>.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com.
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
1327P<br />
Opinion on cancer screening: Impact on prescription and<br />
participation rates<br />
J-F. Morère 1 , J. Viguier 2 , S. Couraud 3 , L. Guibaudet 4 , J-Y. Blay 5 , A.B. Cortot 6 ,<br />
C. Lhomel 7 , L. Greillier 8 , X. Pivot 9 , F. Eisinger 10<br />
1 Medical <strong>Oncology</strong>, Hopital Paul Brousse, Villejuif, France, 2 Medical <strong>Oncology</strong>,<br />
CHRU Bretonneau, Tours, France, 3 Respiratory Diseases and Thoracic <strong>Oncology</strong>,<br />
Centre Hospitalier Lyon Sud, Pierre Bénite, France, 4 Statistics, KantarHealth,<br />
Paris, France, 5 Medical <strong>Oncology</strong>, Centre Léon Bérard, Lyon, France,<br />
6 Pneumology and thoracic oncology, DRC / CHRU <strong>of</strong> Lille, Lille, France,<br />
7 <strong>Oncology</strong>/Hematology Institutionnal, Roche, Boulogne-Billancourt, France,<br />
8 Multidisciplinary <strong>Oncology</strong> and Therapeutic Innovations, Hopital Nord, Marseille,<br />
France, 9 Service Oncologie Medicale, CHU Besançon, Hôpital Jean Minjoz,<br />
Besançon, France, 10 Cancer Control, Institute Paoli Calmettes, Marseille, France<br />
Background: The aim <strong>of</strong> the EDIFICE surveys is to improve insight into screening<br />
programs in France. We hypothesized that individual opinions may affect physicians’<br />
and laypersons’ attitudes toward prescribing or participating in screening, respectively;<br />
we assessed physicians’ and laypersons’ opinions, focusing on colorectal (CRC), breast<br />
(BC), cervical (CC), prostate (PC) and lung (LC) cancer screening.<br />
Methods: The 4th nationwide observational survey was conducted by phone interviews<br />
using the quota method. A representative sample <strong>of</strong> 1463 individuals with no history <strong>of</strong><br />
cancer (age 40-75 y; 726 men [m], 737 women [w]) was interviewed from 12 June-10 July<br />
2014. A mirror survey on a representative sample <strong>of</strong> 301 physicians (201 general<br />
practitioners [GP, 131 m, 70 w] and 100 oncologists [65 m, 35 w]) was conducted from 9<br />
July-8 August. We analyzed replies stating screening to be more reassuring than worrying.<br />
Results: In general, screening was more reassuring than worrying, more so for<br />
physicians than for laypersons (CRC 65% vs 51%, CC 74% vs 62%, PC 59% vs 43%,<br />
P < 0.05; BC 71% vs 63%, LC 45% vs 43%; not significant [NS]). Among physicians,<br />
oncologists tended to consider screening as more reassuring than worrying (BC 83% vs<br />
66%, P = 0.05; CRC 70% vs 63%, P = 0.05; CC 83% vs 70%, NS) except for PC (49% vs<br />
64%, P = 0.05) and LC (44% vs 45%, NS). GP declared they would prescribe screening<br />
regardless <strong>of</strong> their own opinion, i.e., whether they believe it to be reassuring or<br />
worrying (CRC 81% vs 82%, respectively, BC 93% vs 88%, LC 21% vs 15%, NS), except<br />
PC (80% vs. 64%, P < 0.01). Participation rates tended to be higher among reassured<br />
than worried laypersons (CRC 71% vs 48%, PC 63% vs 36%; P < 0.05 and BC 98% vs<br />
96%, CC 99% vs 98%, LC 12% vs 10%, NS).<br />
Conclusions: Physicians tend to be more reassured by screening than laypersons, and<br />
oncologists more so than GP, with the exception <strong>of</strong> PC screening. The <strong>of</strong>ficial<br />
guidelines for CRC and BC screening are a good setting for GPs’ medical practice. The<br />
most widely used screening programs (CRC, BC, PC) enable GP to make objective<br />
prescriptions, regardless <strong>of</strong> individual opinions. In the absence <strong>of</strong> guidelines (PC),<br />
prescription rates are correlated with physicians’ confidence in screening. Reassurance<br />
in screening has a positive impact on laypersons’ participation rates.<br />
Legal entity responsible for the study: EDIFICE surveys are funded by Roche<br />
Funding: EDIFICE surveys are funded by Roche<br />
Disclosure: Jean F. Morère,Sébastien Couraud, Jean-Yves Blay, Alexis B. Cortot,<br />
Laurent Greillier, Xavier B. Pivot, François Eisinger: Honorarium fees from Roche.<br />
C. Lhomel: Employee <strong>of</strong> Roche.All other authors have declared no conflicts <strong>of</strong> interest.<br />
1328P<br />
Immunohistochemical biomarkers for risk stratification <strong>of</strong><br />
neoplastic progression in Barrett esophagus<br />
V.T. Janmaat 1 , S.H. van Olphen 1 , K. Biermann 2 , L. Looijenga 2 , M.J. Bruno 1 , M.C.<br />
W. Spaander 1<br />
1 Gastroenterology and Hepatology, Erasmus University Medical Center,<br />
Rotterdam, Netherlands, 2 Pathology, Erasmus University Medical Center,<br />
Rotterdam, Netherlands<br />
Background: Barrett’s esophagus (BE) is the precursor lesion <strong>of</strong> esophageal<br />
adenocarcinoma (EAC). None <strong>of</strong> the current clinical or endoscopic criteria are able to<br />
accurately predict which patients will progress from BE to EAC. Immunohistochemical<br />
(IHC) biomarkers can be applied to intact histological morphology and are relatively<br />
easy applicable in daily practice. This study aimed to provide a systematic review and<br />
meta-analyses <strong>of</strong> all published studies on IHC biomarkers as predictors <strong>of</strong> neoplastic<br />
progression in BE.<br />
Methods: MEDLINE, EMBASE, Web <strong>of</strong> Science, CENTRAL, Pubmed publisher, and<br />
Google scholar were searched. All studies on IHC biomarkers in BE progression were<br />
included. Two authors independently extracted data. Meta-analyses were performed<br />
for biomarkers studied more than once. Pooled estimates <strong>of</strong> effect were calculated. If<br />
enough studies were present, sensitivity analyses and sub-analyses were performed.<br />
Sub-analyses were performed to investigate whether IHC biomarkers had a predictive<br />
value independent <strong>of</strong> the presence <strong>of</strong> LGD.<br />
Results: IHC biomarkers studied more than once were p53, Cyclin A, Cyclin D, and<br />
aspergillus oryzae lectin (AOL). The IHC biomarker investigated most frequently was<br />
p53. P53 was included in 12 studies, which contained 2023 patients, amongst which<br />
372 cases. The meta-analyses showed aberrant p53 IHC staining was significantly<br />
associated with the risk <strong>of</strong> neoplastic progression in BE patients with an OR <strong>of</strong> 4.15<br />
(95% CI 1.96 to 8.81). A sub-analysis stratifying for the presence or absence <strong>of</strong> LGD<br />
showed that aberrant p53 IHC staining was associated with neoplastic progression with<br />
an OR <strong>of</strong> 4.13 (95% CI 2.36 to 7.21). This association was confirmed for both<br />
non-dysplastic BE, and BE with low grade dysplasia. Of the other IHC biomarkers,<br />
Cyclin A (OR 1.54, 95% CI 0.62 to 3.79), Cyclin D (OR 1.87, 95% CI 0.17 to 20.63),<br />
and AOL, only AOL appeared to be able to predict neoplastic progression in BE<br />
patients with an OR <strong>of</strong> 3.04 (95% CI 2.05 to 4.49).<br />
Conclusions: In conclusion, p53 is the most studied IHC biomarker for neoplastic<br />
progression in patients with BE. Aberrant p53 IHC is significantly associated with an<br />
increased risk <strong>of</strong> neoplastic progression in BE patients, which appears to be<br />
independent <strong>of</strong> dysplasia grade.<br />
Legal entity responsible for the study: N/A<br />
Funding: Department <strong>of</strong> Gastroenterology and Hepatology <strong>of</strong> the ErasmusMC<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1329P<br />
A logistic regression model based on tongue image<br />
information for prediction precancerous lesions and early<br />
stage esophageal cancer in China<br />
L. Jia 1 , J. Duan 1 , B. Deng 1 ,W.Bai 2 , M. Liu 1 ,D.Li 3 , B. Jia 4<br />
1 <strong>Oncology</strong>, China-Japan Friendship Hospital, Beijing, China, 2 Endoscopy, CiXian<br />
Cancer Hospital, Handan, China, 3 CiXian Cancer Hospital, Handan, China,<br />
4 Brandeis University, Waltham, MA, USA<br />
Background: China is an esophageal cancer high incidence country, with more than<br />
50% esophageal cancer case <strong>of</strong> the world. Screening and diagnosis <strong>of</strong> precancerous<br />
lesions and early stage cancer are main measures <strong>of</strong> decreasing incidence rate and<br />
mortality rate.<br />
Methods: High-risk population (40-69 years old) in Cixian a high risk area <strong>of</strong><br />
esophageal cancer was screened, and 3053 cases were included. They were devided into<br />
3 groups: normal group, esophageal neoplasia low-level group and esophageal<br />
neoplasia high-level group, according to pathology and electronic gastroscope<br />
diagnosis. Diagnostic testing lingual information collection system (DS01-B) was used<br />
and tongue image were collected, including tongue color, coating color, fur character,<br />
tongue shape, local ecchymosis, et al. Difference <strong>of</strong> tongue image information was<br />
analyzed, related clinical variants were analyzed by multi-factor logistic regression.<br />
Results: Incidence <strong>of</strong> local ecchymosis in tongue image was 1.58% (45/2840) in normal<br />
group, 2.98% (4/134) in esophageal neoplasia low-level group and 6.32% (5/79)in<br />
esophageal neoplasia high-level group. Significant difference was found in 3 groups<br />
(P < 0.05). Logistic regression analysis showed that age, male, red tongue, tongue local<br />
ecchymosis, yellow and white coated tongue were risk factors for precancerous lesions<br />
and early stage esophageal cancer. Logistic regression model was established and this<br />
model had diagnostic specificity (80.35%), sensitivity (63.41%) and total coincidence<br />
rate (79.51%) for early esophageal cancer screening.<br />
Conclusions: Red tongue, tongue local ecchymosis, yellow and white coated tongue<br />
were risk factors for precancerous lesions and early stage esophageal cancer.<br />
Multi-factor (including tongue image information) logistic regression model has<br />
clinical value <strong>of</strong> prediction precancerous lesions and early stage esophageal cancer.<br />
Legal entity responsible for the study: China-Japan friendshop hospital<br />
Funding: National “twelfth five”science and technology support plan<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1330P<br />
Duodenal neoplasm in screening<br />
esophagogastroduodenoscopy<br />
abstracts<br />
T. Nakamura 1 , Y. Kon 1 , S. Shibata 1 , K. Konuma 1 , T. Sanada 1 , H. Gonda 1 ,<br />
Y. Suto 1 , K. Kobayashi 1 , N. Takita 2 , M. Shimura 2 , H. Yoshida 1 , A. Suzuki 1 ,<br />
S. Onuki 1 , M. Fukuda 1 , C. Aoyagi 1 , Y. Hasegawa 1 , A. Nishiwaki 1<br />
1 Health Evaluation and Promotion, Ota Memorial Hospital, Ota, Japan,<br />
2 Endoscopy, Ota Memorial Hospital, Ota, Japan<br />
Background: It is difficult and <strong>of</strong>ten impossible to screen the whole duodenum with<br />
esophagogastroduodenoscopy (EGD) technically. It seems sufficient for most <strong>of</strong> the<br />
EGD screening programs to search around the first and the second portions <strong>of</strong> the<br />
duodenum including duodenal papilla for duodenal neoplasms because other<br />
duodenal portions are believed to have rarely neoplastic lesions.<br />
Methods: The data <strong>of</strong> the EGD screening program from June 2012 through April 2016<br />
at Ota Memorial Hospital (OMH) in Japan was reviewed. All duodenal neoplasms<br />
detected in the EGD screening program were analyzed to reveal their characteristics.<br />
Results: 17,449 individuals were enrolled in EGD screening program <strong>of</strong> OMH during<br />
the above period. Thirteen cases had neoplastic lesions in their duodenum (0.07%). Four<br />
<strong>of</strong> them were malignant lesions those included one duodenal carcinoma, one cancer <strong>of</strong><br />
duodenal papilla, and two malignant lymphomas. All other nine neoplasms were<br />
adenoma. The first, the second, and the third portions <strong>of</strong> duodenum had one (7.7%),<br />
seven (53.8%), and five lesions (38.5%) respectively. A duodenal cancer located at the<br />
third portion <strong>of</strong> the duodenum. Ten cases were categorized as the superficial<br />
non-ampullary duodenal epithelial tumor (SNADET). Five <strong>of</strong> them (50%) located at the<br />
third portion <strong>of</strong> duodenum. The second and the first portions had four (40%) and one<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw385 | vi463
abstracts<br />
(10%) respectively. Twelve <strong>of</strong> all thirteen duodenal neoplasms (92.3%) were detected<br />
during the second half <strong>of</strong> this study period. The detection rate <strong>of</strong> the duodenal neoplasm<br />
in the second half term was 0.13% whereas that was 0.01% in the first half term.<br />
Conclusions: 38.5% <strong>of</strong> duodenal neoplasms were found at the third portion where<br />
usual EGD screening rarely approaches. 50% <strong>of</strong> SNADETs those include one case <strong>of</strong><br />
carcinoma were recognized at the third portion. The detection rate <strong>of</strong> duodenal<br />
neoplasm in EGD screening program <strong>of</strong> OMH increases recently because <strong>of</strong> technical<br />
and technological improvement <strong>of</strong> endoscopy probably. It is important for EGD<br />
screening to include the duodenal third portion carefully if possible.<br />
Legal entity responsible for the study: Retrospective study <strong>of</strong> one private screening<br />
center<br />
Funding: Ota Memorial Hospital<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1331P<br />
The prevalence and characteristics <strong>of</strong> Barrett esophagus <strong>of</strong><br />
general population in high risk area for esophagus cancer in<br />
North China (CiXian County)<br />
L. Jia 1 ,F.Wu 1 ,Y.Lou 1 ,Y.Li 1 ,J.Da 2 , W. Bai 3 , G. Jin 4 ,D.Li 5<br />
1 <strong>Oncology</strong>, China-Japan Friendship Hospital, Beijing, China, 2 Pathology,<br />
China-Japan Friendship Hospital, Beijing, China, 3 Endoscopy, CiXian Cancer<br />
Hospital, Handan, China, 4 Pathology, CiXian Cancer Hospital, Handan, China,<br />
5 CiXian Cancer Hospital, Handan, China<br />
Background: The prevalence <strong>of</strong> Barrett Esophagus (BE) has progressively increased in<br />
recent years in western countries, and there is a trend <strong>of</strong> increasing incidence in China.<br />
The CiXian County is a high risk area for esophagus cancer. It has been about 30 years<br />
since the Project <strong>of</strong> Early Detection and Treatment for cancer was initiated there. The<br />
data <strong>of</strong> cancer registration had been included by Cancer Incidence in Five Continents<br />
(International Agency for Research on Cancer, IARC). However, no epidemiological<br />
data <strong>of</strong> BE has been reported.<br />
Methods: From 2013 to 2014, residents <strong>of</strong>ficially registered by CiXian’s authority aged<br />
between 40 and 69, were mobilized to participate in the screening project. The process<br />
followed the protocol <strong>of</strong> the Project <strong>of</strong> Early Detection and Management. All eligibile<br />
individuals took endoscopy. If any abnormal lesion was found, biopsies were taken for<br />
pathological examination. The diagnosis criteria were according to AGA criteria 2008.<br />
Demographic data and endoscopic characteristics were retrospectively analyzed.<br />
Results: Of 24,081 eligible residents, 5548 participated in the screening. The<br />
compliance rate was 23.04%. Of the 5548, 2319 were male, the other 3229 were female,<br />
giving a sex ratio <strong>of</strong> 0.72. The mean age was 53.57 ± 7.95. The mean BMI was<br />
25.30 ± 3.41. 4481 accepted endoscopy, <strong>of</strong> which in 2484 biopsies were taken for<br />
further pathological examination. The rate <strong>of</strong> biopsy was 50.89%. 226 met the<br />
endoscopic diagnosis criteria <strong>of</strong> BE (4.63%), <strong>of</strong> which 118 were island types (52.21%),<br />
75 were tongue types (33.19%), 33 were circumferential types (14.60%). In those<br />
endoscopic BE, only 4 were long segment BE (1.77%), the others were short segment<br />
(98.23%). 28 BE were pathologically confirmed. The detection rate <strong>of</strong> BE was 0.50%. Of<br />
those confirmed cases, 16 were male, the others female, the sex ratio was 1.33. The<br />
mean age was 56.36 ± 8.08, and the mean BMI was 24.87 ± 3.33. 15 had family history<br />
<strong>of</strong> cancer (53.57%). Only 5 had typical reflux symptoms (17.86%), 4 <strong>of</strong> which were<br />
diagnosed GERD according to GerdQ (14.28%).<br />
Conclusions: Barrett esophagus is an important precancerous lesion in the high-risk<br />
area <strong>of</strong> North China. It’s necessary fpr it to be brought into the Project <strong>of</strong> Early<br />
Detection and Management as a routine item.<br />
Legal entity responsible for the study: China-Japan Friendship Hospital<br />
Funding: Ministry <strong>of</strong> Science and Technology <strong>of</strong> People’s Republic <strong>of</strong> China<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1332P<br />
The hormonal status <strong>of</strong> girls from Kyiv and evacuees from<br />
Pripyat<br />
D. Burlaka 1 , N. Hutnyk 2<br />
1 Department <strong>of</strong> Biotechnical Problems <strong>of</strong> Diagnostics, Institute <strong>of</strong> Cryobiology and<br />
Cryomedicine National Academy <strong>of</strong> Sciences <strong>of</strong> Ukraine, Kyiv, Ukraine,<br />
2 Department <strong>of</strong> Mechanisms <strong>of</strong> Metastasis, R.E. Kavetsky Institute <strong>of</strong> Experimental<br />
Pathology, <strong>Oncology</strong> and Radiobiology National Academy <strong>of</strong> Sciences <strong>of</strong> Ukraine,<br />
Kyiv, Ukraine<br />
Background: A study was conducted <strong>of</strong> serum hormone levels among girls from<br />
Pripyat and Kyiv 5 years after the Chornobyl accident. Variations <strong>of</strong> hormonal status in<br />
pre- and pubertal girls evacuated from the town Pripyat and girls from the city <strong>of</strong> Kyiv<br />
were this revealed.<br />
Methods: We investigated the hormones in the blood serum <strong>of</strong> 749 girls from Pripyat<br />
(504) and Kyiv (245). Age girl was 10-15 years. The study was conducted in Kyiv with<br />
the support <strong>of</strong> Ukrainian-French medical center "Children <strong>of</strong> Chornobyl".<br />
Radioimmunoassay was used to determine the the blood serum hormones: testosterone<br />
(T), follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2),<br />
prolactin (PRL), cortisol (F), triiodothyronine (T3) thyroxine (T4), progesterone (P4),<br />
adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH).<br />
Results: In surveys <strong>of</strong> girls from Pripyat we established 7 statistically significant<br />
diferences in 7 hormone levels: T, FSH, LH, E2, PRL, F, T4. Serum <strong>of</strong> girls from Pripyat<br />
compared with serum <strong>of</strong> girls from Kyiv had levels <strong>of</strong> T, FSH, LH higher than in controls<br />
(p < 0,05). In Kyiv girls differences were detected in 3 <strong>of</strong> 11 hormone LH, T4,<br />
K. Common to the two groups was an increase in cortisol to 500nmol/L and above. This<br />
was increase was larger in the girls from Kyiv. We can assume that prolonged activation<br />
<strong>of</strong> the pituitary-adrenal system in the inspected girls is the result <strong>of</strong> cumulative effect <strong>of</strong><br />
complex environmental and psychological factors, including damaging factors from the<br />
Chornobyl accident. Prolonged exposure to damaging factors can lead to suppression <strong>of</strong><br />
basic adaptive system with the development <strong>of</strong> the primary functional adrenal<br />
insufficiency. Since this system in children has less spare capacity to adapt compared<br />
with that in adults it is easily exhausted and can lead to functional disorders in other<br />
endocrine axes - especially pituitary-gonads, and pituitary-thyroid gland.<br />
Conclusions: Revealed abnormalities in the hormonal status <strong>of</strong> the girls surveyed,<br />
obviously, is the result <strong>of</strong> functional disorders <strong>of</strong> the endocrine system. Such<br />
dysfunction does not give explicit symptoms and thus remain unnoticed by the doctor.<br />
The girls identified with hormonal disorders, obviously, are a group at high risk for the<br />
occurrence <strong>of</strong> tumors caused by hormones.<br />
Legal entity responsible for the study: Ukrainian-French medical center "Children <strong>of</strong><br />
Chornobyl", NAS <strong>of</strong> Ukraine<br />
Funding: Prominvestbank, bank"LIS"<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1333P<br />
What is the optimal annual interpretive volume for a<br />
radiologist reading screening mammograms?<br />
A. Uluturk, L. Pylkkanen, S. Deandrea, A. Bramesfeld, L. Neamtiu, Z.<br />
Saz Parkinson, M. Ambrosio, D. Lerda<br />
Institute for Health and Consumer Protection, European Commission, Joint<br />
Research Centre, Ispra, Italy<br />
Background: A positive association between the annual screening volume and the<br />
performance <strong>of</strong> screening radiologists has been suggested. The majority <strong>of</strong> studies show<br />
that there is little or no relation between radiologist’s interpretive volume and<br />
sensitivity, but the association <strong>of</strong> interpretive volume to false-positive rate, cancer<br />
detection rate, recall rate or interval cancer rate is still unclear. As a consequence, many<br />
countries have adopted very variable minimum reading volume requirements (e.g.,<br />
from 500 to 5,000 per year). The aim <strong>of</strong> the study is to evaluate whether an optimal<br />
annual interpretive volume for screening radiologists can be established.<br />
Methods: A systematic review to assess the evidence <strong>of</strong> the association between<br />
radiologist interpretive volume and breast cancer screening performance outcomes,<br />
following standard Cochrane Collaboration methods, was carried out. The following<br />
databases were searched until November 2015: The Cochrane Database <strong>of</strong> Systematic<br />
Review, DARE, MEDLINE, EMBASE, PDQ, and McMaster Health Systems Evidence.<br />
GRADE methodology was applied.<br />
Results: From an initial set <strong>of</strong> 872 unique citations, 14 studies (2,935 radiologists, 32<br />
screening services) were included. These studies retrospectively analysed information<br />
from prospective databases, except one study with a cross-sectional design. The<br />
evidence suggested an association between a higher annual screening volume and a<br />
lower false-positive rate, with an optimal performance around 1,500 to 4,000 readings<br />
per year (moderate quality evidence). Cancer detection rate appeared to be optimised<br />
at about 1,000 readings per year and in the context <strong>of</strong> high volume facilities (moderate<br />
quality evidence). Recall rate appeared to increase above 3,000 readings per year (low<br />
quality evidence). The effect on false-negative rate and interval cancer rate is unclear<br />
(very low quality evidence).<br />
Conclusions: Screening radiologists should perform at least 1,500 to 4,000 screening<br />
mammograms per year to keep the performance outcomes at an acceptable level.This<br />
recommendation is provisional (due to uncertainty about the association between<br />
caseloads and the net benefits <strong>of</strong> screening), and conditional (depending on the<br />
availability <strong>of</strong> radiologist meeting the requirements).<br />
Legal entity responsible for the study: European Commission, Joint Research Centre<br />
Funding: European Commission, Joint Research Centre<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1334P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
A novel way to visualise tumour related angiogenesis and<br />
detect breast tumours in women: A combined clinical and<br />
optical method for breast cancer screening <strong>of</strong> well-women in<br />
Ghana<br />
F.N. Ghartey 1 , D.J. Watmough 2 , A. Anyanful 3 , S. Debrah 4 , M. Morna 4 , S. Eliason 5 ,<br />
M. Adamu 1 , L. Derkyi-Kwarteng 6<br />
1 Chemical pathology, University <strong>of</strong> Cape Coast, Cape Coast, Ghana, 2 Medical<br />
devices, Highland innovation centre, Invernesss, UK, 3 Medical Biochemistry,<br />
University <strong>of</strong> Cape Coast, Cape Coast, Ghana, 4 Surgery, University <strong>of</strong> Cape Coast,<br />
Cape Coast, Ghana, 5 Community medicine, University <strong>of</strong> Cape Coast, Cape<br />
Coast, Ghana, 6 Pathology, University <strong>of</strong> Cape Coast, Cape Coast, Ghana<br />
Background: Late stage neoplastic breast lesions abound in Ghana, especially,<br />
late-stage early-age breast cancer and therefore low survival rates after treatment <strong>of</strong><br />
breast cancer is prevalent. The median age at diagnosis for breast cancer is 39 years<br />
hence screening mammography (“the gold standard”) is not suitable and also not<br />
vi464 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
readily available in Ghana. Preliminary data suggests transillumination <strong>of</strong>fers a new<br />
mode <strong>of</strong> early detection for neoplastic breast lesions and is not limited by age.<br />
Methods: In all, over 10,000 women who were manually screened for breast lesions<br />
during mobile breast screening clinics with the view to enhance early detection were<br />
<strong>of</strong>fered transillumination with the breastlight/breast-i (optical torch devices used to<br />
detect angiogenesis) as well. These optical devices, (the breastlight/breast-i) developed by<br />
David J. Watmough were used to visually observe angiogenesis around breast tumours<br />
and lesions. The breastlight/breast-i operates on the principles <strong>of</strong> light travelling through<br />
tissues and the specific wavelength <strong>of</strong> light absorption by Heamoglobin in blood<br />
Results: Here we report on a total <strong>of</strong> 9,962 “well women", initially using Breastlight but<br />
since 2014 using a new improved instrument Breast-i. The significance <strong>of</strong> a dark<br />
shadow arises because light is multiply scattered within the breast tissues and excess<br />
absorption <strong>of</strong> red light occurs at a wavelength <strong>of</strong> around 620nm when a cancer is<br />
present, caused by angiogenesis. A sensitivity <strong>of</strong> 94.4% was obtained for detecting<br />
breast cancer.<br />
Conclusions: The advantage <strong>of</strong> Breast-i is that there is no radiation exposure, no tissue<br />
compression and it is quick and easy to carry out the examination. This is probaly the<br />
largest study <strong>of</strong> its kind in the world.<br />
Legal entity responsible for the study: Mammocare Ghana, Highland Innovation<br />
centre and University <strong>of</strong> CapeCoast, Ghana.<br />
Funding: Highland Innovation Centre<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1335P<br />
Multigene panel testing for breast cancer patients at high<br />
risk for hereditary cancer<br />
H-C. Shin 1 , T-K. Yoo 2 , E. Lee 3 , H-B. Kee 3 , J. Han 3 ,Y.Kim 3 , H-G. Moon 3 ,<br />
D-Y. Noh 3 , W. Han 3<br />
1 Department <strong>of</strong> Surgery, Chung-Ang University Hospital, Seoul, Republic <strong>of</strong> Korea,<br />
2 Department <strong>of</strong> Surgery, Seoul St. Mary’s Hospital, <strong>of</strong> the Catholic University,<br />
Seoul, Republic <strong>of</strong> Korea, 3 Department <strong>of</strong> Surgery, Seoul National University<br />
Hospital, Seoul, Republic <strong>of</strong> Korea<br />
Background: Next-generation sequencing and identification <strong>of</strong> additional cancer<br />
susceptible genes has made it feasible for patients at risk test for various hereditary<br />
cancer syndromes. We have evaluated the performance <strong>of</strong> a customized multi-gene<br />
panel test for hereditary cancer risk assessment in high-risk patients.<br />
Methods: A total <strong>of</strong> 252 patients with multiple primary cancers or high-risk hereditary<br />
cancer were identified. Among them, 179 patients (71.0%) had multiple primary<br />
cancers, 27 patients (10.7%) were diagnosed bilateral breast cancer younger than 40<br />
years old. Thirty-five patients (13.9%) had 2 ≥ breast cancer family history and 11<br />
patients (4.4%) were very young (≤25 years old) breast cancer patients. Mutations<br />
annotated in dbSNP, clinVAR and Ensembl comparative genomic resources were<br />
analyzed and reviewed.<br />
Results: In the 65-gene panel test, pathogenic or likely-pathogenic mutations (PM)<br />
were identified in 78 (31.0%) patients. Frequency <strong>of</strong> all PM or likely-PM was 59%, 40%,<br />
26%, and 9% in bilateral breast cancer with ≤ 40 years, breast cancer patients with<br />
2 ≥ family history, multiple primary cancer, and breast cancer patients ≤ 25 years,<br />
respectively. The distribution <strong>of</strong> high-risk genes for hereditary cancer including CDH1,<br />
MLH1, MSH2, MSH6, MUTYH, PTEN, TP53, BRCA1, and BRCA2 were 55% in<br />
multiple primary cancer patients, 25% in bilateral breast cancer with ≤ 40 years, 18% in<br />
breast cancer patients with 2 ≥ family history, and 2% in very young (≤25 years old)<br />
breast cancer patients, respectively.<br />
Conclusions: Using a 65-multigene panel test we have identified PMs, especially<br />
associated with hereditary cancer. We can use these results for detecting high-risk<br />
group <strong>of</strong> hereditary cancer in breast cancer patients.<br />
Legal entity responsible for the study: N/A<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1336P<br />
Evaluation <strong>of</strong> breast cancer patients with genetic risk: Before<br />
and after a multidisciplinary hered<strong>of</strong>amiliar cancer unit<br />
implementation<br />
M. Lobo 1 , S. Lopez-Tarruella 1 , S. Luque 2 , S. Lizarraga 2 , P. Rincon 2 ,<br />
A. Hernandez 2 , E. Mendizabal 2 , O. Bueno 3 , M. Cebollero 4 , S. Perez Ramirez 1 ,<br />
Y. Jerez 1 , M.I. Palomero Plaza 1 , R. Gonzalez del Val 1 , G. Garcia 1 , I. Echavarria<br />
Diaz-Guardamino 1 , A. Calin 5 , J.A. Blanco 5 , C. Flores Sanchez 1 , M. Martin 1 ,<br />
I. Marquez-Rodas 1<br />
1 Medical <strong>Oncology</strong>, Hospital General Universitario Gregorio Marañon, Madrid,<br />
Spain, 2 Gynaecology, Hospital General Universitario Gregorio Marañon, Madrid,<br />
Spain, 3 Radiology, Hospital General Universitario Gregorio Marañon, Madrid,<br />
Spain, 4 Pathology, Hospital General Universitario Gregorio Marañon, Madrid,<br />
Spain, 5 Radiation <strong>Oncology</strong>, Hospital General Universitario Gregorio Marañon,<br />
Madrid, Spain<br />
Background: Identifying Breast Cancer (BC) patients with genetic risk reduces the<br />
mortality for BC and the prevention <strong>of</strong> second tumors. In 2010, we implemented a<br />
multidisciplinar Hered<strong>of</strong>amilial Cancer Unit (HFCU). We hypothesized that the<br />
creation <strong>of</strong> this HFCU improved the referral and proper preventive management <strong>of</strong><br />
patients with BC and genetic risk.<br />
Methods: We retrospectively compared family history record (FHR), referral <strong>of</strong><br />
patients with high risk to genetic counseling (GC), detection and management <strong>of</strong><br />
BRCA 1/2 mutated (+) patients, <strong>of</strong> BC patients diagnosed and treated in our institution<br />
before (July 2007-June 2010, first period) and after the HFCU creation (July 2010-June<br />
2013, second period). Main characteristics <strong>of</strong> BRCA 1/2+ patients were also analyzed.<br />
Results: 893 patients from the first period and 902 in the second met inclusion criteria.<br />
Mean age at diagnosis was similar in both groups (57.6 vs 57.8y, p NS). 142 patients<br />
(15.9%) vs 70 (7.8%) were not analyzable because a lack <strong>of</strong> complete information to<br />
establish the genetic risk (p < 0.05). Among evaluable patients, 194 (25.8%) vs 225<br />
(27%) had one or more risk criteria (p NS). FHR, referral rate and preventive surgeries<br />
(2 bilateral mastectomy (BM) and 1 bilateral salpingo-o<strong>of</strong>orectomy (BSO) in the first<br />
period vs 12 BSO and 9 BM in the second) in BRCA + patients increased in the second<br />
period (table). 56 risk patients diagnosed in the first period with risk criteria were<br />
referred to the HFCU, detecting 9 additional BRCA mutations. 84.6% <strong>of</strong> BRCA1+<br />
patients and 91.7% <strong>of</strong> BRCA2+ were diagnosed
abstracts<br />
Legal entity responsible for the study: ASL Lecce<br />
Funding: ASL Lecce<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1338P<br />
Breast cancer in young women survivors <strong>of</strong> pediatric cancer<br />
C. Salvador Coloma 1 , A. Cañete 2 , J. Balaguer 2 , L. Montero 3 , R.M. Viguer 4 ,<br />
A. Santaballa 1<br />
1 Medical <strong>Oncology</strong>, Hospital Universitari i Politècnic La Fe, Valencia, Spain,<br />
2 Pediatrics <strong>Oncology</strong>, Hospital Universitari i Politècnic La Fe, Valencia, Spain,<br />
3 <strong>Oncology</strong>, Hospital Universitari i Politècnic La Fe, Valencia, Spain, 4 Radiology,<br />
Hospital Universitari i Politècnic La Fe, Valencia, Spain<br />
Background: Patients cured <strong>of</strong> a pediatric cancer have shown increased risk <strong>of</strong> second<br />
tumors. Women long-term survivors have a significantly increased risk <strong>of</strong> developing<br />
breast cancer (BC) at a young age. Screening programs for early detection <strong>of</strong> BC are<br />
well-established in healthy women. On the contrary, there is a scarcity <strong>of</strong> guidelines for<br />
young women cured <strong>of</strong> a pediatric cancer. We try to develop a multidisciplinary<br />
screening program for our survivors at risk.<br />
Methods: Patients were identified from Pediatric <strong>Oncology</strong> Department at the<br />
University Hospital La Fe. The cohort consists <strong>of</strong> young women with a prior diagnosis<br />
<strong>of</strong> a pediatric tumor, if treatment had included chest RT and/or high dose <strong>of</strong> alkylating<br />
chemotherapy before bone marrow transplantation. Imaging studies were performed<br />
according to age. If any suspicious lesion was detected, the patient was transferred to<br />
the Breast Unit in <strong>Oncology</strong>.<br />
Results: 17 women (10 Hodgkin Lymphoma, 4 Non Hodgkin Lymphoma and 3 Ewinǵs<br />
Sarcoma) were contacted. 4 women refused to be included (2 due to psychological<br />
reasons, 1 pregnancy, 1 just-diagnosed with BC). Median age was 27 years and median<br />
time since end-<strong>of</strong>-treatment was 14.5 years. The initial treatment was chemotherapy<br />
(CT) alone in 6 patients (46.2%) and combined CT and radiotherapy (RT) in 7 (53.8%).<br />
7 cases were irradiated (5 Hodgkińs Lymphoma, 1 Non Hodgkińs Lymphoma, 1 Ewing).<br />
The median dose <strong>of</strong> mediastinal RT was 22.6 Gy (range 15-25.2 Gy). Breast exams were<br />
normal. The MRI were performed in 8 <strong>of</strong> 13 patients. It revealed a suspicious lesion in 1<br />
patient (BI-RADS 4) and benign lesions in 3 patients (BI-RADS 2). MRI studies <strong>of</strong> the<br />
remaining 4 patients were normal, without findings. Benign lesions were fibroids. The<br />
patient with the malignant lesion was an invasive ductal carcinoma with positive<br />
hormonal receptors and negative Her-2 neu (pT1b N1a(sn) M0, grade II, ki67 15%).<br />
Conclusions: We have developed a complete early-detection-BC program for our<br />
population, that did not exist previously. Although a small number <strong>of</strong> women were<br />
involved, two BC were detected. We have shown the potential benefit <strong>of</strong> screening BC<br />
program, but the challenge to increase the attracting high-risk patients to these<br />
programs.<br />
Legal entity responsible for the study: Hospital Universitario y Politécnico La Fe<br />
Funding: GVA grant.<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1339P<br />
Leveraging six sigma instruments to optimize cancer<br />
screening in an urban community hospital<br />
U. Goldberg, M. Kalavar, V. Patel, R. Mukherji, K. Kodr<strong>of</strong>f, N. Pasco<br />
Internal Medicine, Kingsbrook Jewish Medical Center, Brooklyn, NY, USA<br />
Background: In 2010, the U.S. Department <strong>of</strong> Health and Human Services<br />
implemented a quality improvement initiative known as “Healthy People 2020”<br />
designed to improve outcomes across a broad array <strong>of</strong> illnesses by 2020. Within the<br />
category <strong>of</strong> cancer, the initiative’s goals include improving screening rates. As poor<br />
socioeconomic status has long been associated with lower screening and higher<br />
mortality rates, and given the low socioeconomic status <strong>of</strong> much <strong>of</strong> our patient<br />
population, our institution has implemented Six Sigma techniques designed to decrease<br />
variability in cancer screening measures, reduce healthcare disparities, and improve<br />
screening outcomes.<br />
Methods: Beginning in the 4 th quarter <strong>of</strong> 2013, our hospital’s Ambulatory Care<br />
department implemented a bimonthly rapid cycle evaluation <strong>of</strong> physicians designed to<br />
analyze a variety <strong>of</strong> patient care metrics including breast and colorectal cancer<br />
screening rates within each physician’s respective patient panel. Data for each quarter<br />
was systematically distributed to each physician and a care navigation team was<br />
assembled to ensure screening compliance via patient outreach in the form <strong>of</strong> phone<br />
calls and certified mail.<br />
Results: Data from the 1 st quarter <strong>of</strong> 2014 until the 2 nd quarter <strong>of</strong> 2015 were collected<br />
from two sites affiliated with our institution’s outpatient service. During that<br />
timeframe, the rate <strong>of</strong> colorectal screening—which includes colonoscopy and serial<br />
fecal occult blood testing—increased at Site 1 from 79.1% to 84.4% and at Site 2 from<br />
70.8% and 75%. With respect to breast cancer screening, the rate at Site 1 remained<br />
virtually unchanged (90.4% and 90.1%) while the rate at Site 2 increased from 80.7% to<br />
86.0%.<br />
Conclusions: As our intervention has demonstrated, cancer screening may be<br />
optimized by the use <strong>of</strong> a low-cost, easily implementable, and easily replicable<br />
intervention leveraging Six Sigma instruments. In light <strong>of</strong> the challenges affecting our<br />
institution’s predominately African-American and Latino populations—particularly as<br />
they relate to access to care and timely cancer diagnoses—our intervention may go a<br />
long way toward reducing disparities and improving outcomes in these increasingly<br />
disadvantaged populations.<br />
Legal entity responsible for the study: Uri Goldberg<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1340P<br />
Screening colonoscopy in family members <strong>of</strong> patients with<br />
colorectal cancer: A population-based study in Iran<br />
H. Salimzadeh 1 , A. Delavari 1 , M. Amani 1 , F. Bishesari 2 , R. Malekzadeh 1<br />
1 Digestive Diseases Research Institute, Shariati Hospital, Tehran University <strong>of</strong><br />
Medical Sciences, Tehran, Iran, 2 Department <strong>of</strong> Internal Medicine, Division <strong>of</strong><br />
Gastroenterology, Rush University Medical Center, Chicago, IL, USA<br />
Background: Relative risk <strong>of</strong> developing cancer among First degree relatives (FDRs) <strong>of</strong><br />
patients with colorectal cancer (CRC) is two- to three folds greater than the general<br />
population. Screening colonoscopy in Wetern countries contributes to more than 50%<br />
reduction in mortality from CRC in FDRs <strong>of</strong> patients with CRC. We previously showed<br />
that family history <strong>of</strong> CRC was common among CRCs in Iran, particularly if the<br />
proband was young. The current study presents clinical findings from a screening<br />
colonoscopy program in the FDRs <strong>of</strong> patients with CRC in Tehran.<br />
Methods: This is an ongoing population-level screenings study which targets the FDRs<br />
<strong>of</strong> patients with CRC registered in cancer registry system <strong>of</strong> the Deputy <strong>of</strong> health in the<br />
Tehran University <strong>of</strong> Medical Sciences. We included the data <strong>of</strong> the FDRs who<br />
underwent a colonoscopy in screening center <strong>of</strong> the Digestive Disease Research<br />
Institute. Data collected via face-to-face interviews, and we used Stata/MP s<strong>of</strong>tware,<br />
version 12 for analyses.<br />
Results: Overall 472 FDRs with age mean <strong>of</strong> 47.5 years performed a screening<br />
colonoscopy, <strong>of</strong> which 52.5% were female. About 411 (87.1%) had good or excellent<br />
bowel prep, and ceacal reach was reported in 96.0% (n = 453) <strong>of</strong> the procedures. The<br />
detection rate <strong>of</strong> polyps was 31.1% (n = 147). Adenomatous polyps, and<br />
advanced-adenomas were present in 22.5% (106), and 12.1% (n = 57) <strong>of</strong> the<br />
participants, respectively. There were 9 patients in this study who were diagnosed with<br />
CRC (1.9%), <strong>of</strong> which 7 cases were completely asymptomatic.<br />
Conclusions: Our study confirms that FDRs <strong>of</strong> CRCs in Iran are high risk for CRC.<br />
The relatively high number <strong>of</strong> asymptomatic cancer cases among family members <strong>of</strong><br />
CRC patients calls for a nationwide screening program among FDRs <strong>of</strong> CRCs in Iran.<br />
Legal entity responsible for the study: Digestive Diseases Research Institute,Tehran<br />
University <strong>of</strong> Medical Sciences<br />
Funding: Tehran University <strong>of</strong> Medical Sciences<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1341P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Proposal <strong>of</strong> a stage-specific surveillance strategy for<br />
colorectal cancer<br />
R. Okamura 1 , S. Hasegawa 2 , K. Hida 1 , R. Takahashi 1 , K. Kawada 1 , K. Sugihara 3 ,<br />
Y. Sakai 1<br />
1 Department <strong>of</strong> Surgery, Kyoto University Hospital, Kyoto, Japan, 2 Department <strong>of</strong><br />
Surgery, Fukuoka University Hospital, Fukuoka, Japan, 3 Department <strong>of</strong> Surgery,<br />
Tokyo Medical and Dental University, Tokyo, Japan<br />
Background: Current guidelines from ESMO, ASCO, NCCN, and JSCCR recommend<br />
intensive postoperative surveillance for colorectal cancer following curative resection,<br />
using periodic CEA test, CT scanning, clinic visit, and colonoscopy. However, the<br />
optimal frequency <strong>of</strong> these standard modalities and the duration <strong>of</strong> surveillance remain<br />
debatable.<br />
Methods: We analyzed cohort data from 22 member institutions <strong>of</strong> the Japanese Study<br />
Group for Postoperative Follow-up <strong>of</strong> Colorectal Cancer. Patients who underwent<br />
curative surgery for stage I to IV colorectal cancer between 1997 and 2006 were<br />
included. We assessed the cumulative incidence <strong>of</strong> recurrence, and estimated the<br />
proportion <strong>of</strong> patients in whom recurrences were detected by the standard surveillance<br />
modalities every year after surgery (detection rate; DR).<br />
Results: A total <strong>of</strong> 18,841 consecutive patients were identified. Overall recurrence rates<br />
in stage I, II, III, and IV were 4.2%, 14%, 32%, and 75%, respectively. Surgical resection<br />
<strong>of</strong> recurrence in each stage was performed in 55%, 51%, 43%, and 42% <strong>of</strong> patients,<br />
respectively. More than 95% <strong>of</strong> recurrences in every stage were first suspected or<br />
detected by the standard surveillance modalities. Over 80% <strong>of</strong> recurrences occurred<br />
within the first 3 years in stage II and III, 2 years in stage IV, and 5 years in stage<br />
I. Among patients with a 5-year recurrence-free survival, 2.2 % in stage III and 7.0 % in<br />
stage IV still experienced recurrence after the 5-year postoperative period. The DR in<br />
stage I was consistently low during the surveillance period. The DR in year 1 to 3 <strong>of</strong><br />
stage II was about twice that <strong>of</strong> stage I. Furthermore, the DR <strong>of</strong> stage III was about<br />
twice that <strong>of</strong> stage II. In year 1 to 2 <strong>of</strong> stage IV, the DR was more than triple that <strong>of</strong><br />
stage III.<br />
vi466 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Conclusions: These results suggest that a stage-specific approach to postoperative<br />
surveillance may improve the efficiency <strong>of</strong> detecting recurrences. Further study is<br />
needed for a prognostic non-inferiority assessment <strong>of</strong> this strategy.<br />
Legal entity responsible for the study: Japanese Study Group for Postoperative<br />
Follow-up <strong>of</strong> Colorectal Cancer<br />
Funding: Japanese Study Group for Postoperative Follow-up <strong>of</strong> Colorectal Cancer<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
abstracts<br />
agreed that women should be aware about the procedure, 85% agreed that it could<br />
reduce maternal mortality rates from cervical cancer.<br />
Conclusions: Despite limitations in funding, it is suggested that more research work<br />
can be done to assess possible ethical beliefs towards contraceptives, HPV vaccine and<br />
sexual practices and how they affect cervical cancer incidence and mortality rates.<br />
Legal entity responsible for the study: Adetule Cecilia Yemisi<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1342P<br />
Aspirin utilization, compliance and prevention <strong>of</strong> colorectal<br />
cancer – A single centre perspective<br />
1344P<br />
Prevelance <strong>of</strong> cyp1b1 mutations among lung cancer patients<br />
G. Singh Ranger 1 , C. McKinley-Brown 2<br />
1 General Surgery, Upper River Valley Hospital, Waterville, NB, Canada, 2 General<br />
Surgery, Upper River Valley Hospital, Waterville, NB, Canada<br />
Background: Recent randomised controlled trials indicate daily low dose aspirin may<br />
reduce the risk <strong>of</strong> colorectal cancer by up to 20%. Aspirin is currently prescribed or<br />
self-administered regularly to prevent heart disease. Considering wider<br />
population-based chemoprevention against colorectal cancer, a greater understanding<br />
<strong>of</strong> community use, compliance, adverse effects, and patient awareness is required. We<br />
performed a prospective observational study on aspirin use in our local population to<br />
examine these issues.<br />
Methods: Prospective data collected using questionnaires over a six month period from<br />
every patient attending surgical clinic at our hospital.<br />
Results: Aspirin: 137 patients; male: 72, female: 65. Mean age 65.8 years (range:<br />
23-100). 76.6% were taking aspirin 81mg. 32.9% did not know what dose they were<br />
taking, 5.8% were taking a dose over 300mg. 62% <strong>of</strong> patients were taking aspirin on<br />
physician advice. 25.6% <strong>of</strong> patients stated they never missed a dose <strong>of</strong> aspirin, 39%<br />
admitted to missing doses, 3% never took it. 5.8% reported side effects. Only 9.5% were<br />
aware <strong>of</strong> the anticancer effects <strong>of</strong> aspirin. Non-aspirin: 383 patients; male: 135, female:<br />
248. Mean age 53.3 (18-90). 1% used aspirin in the past and ceased treatment. 4.7%<br />
knew <strong>of</strong> anticancer effects. Mean ages differed significantly (unpaired t-test, p < 0.001).<br />
Patients not on aspirin were more likely to be female, younger, with heart disease /<br />
diabetes or on more than 5 medications (Fisher’s exact test; p = 0.0005, p < 0.0001,<br />
p = 0.002). No significant differences between groups in anticoagulation use, additional<br />
NSAID use or smoking (p = 0.51, p = 0.20, p = 0.19). Knowledge <strong>of</strong> anticancer effect<br />
showed trend to significance (p = 0.06) favoring the aspirin group, with main sources<br />
<strong>of</strong> information being the media or internet.<br />
Conclusions: Patients on aspirin in our community are older, with less co-morbidities<br />
and concurrent medication use. Overall awareness <strong>of</strong> anticancer effect was suboptimal,<br />
physician involvement in this area is low. Over 40% <strong>of</strong> our patients are non-compliant<br />
with treatment. These results have implications for any potential use <strong>of</strong> aspirin for<br />
chemoprevention <strong>of</strong> colorectal cancer.<br />
Legal entity responsible for the study: Gurpreet Singh Ranger<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1343P<br />
Knowledge <strong>of</strong> cervical cancer preventive strategies among<br />
market women in Nigeria<br />
Y.C. Adetule<br />
Department <strong>of</strong> Surgical Nursing, University College Hospital, Ibadan, Nigeria<br />
Background: Cervical cancer is the fourth most common cancer worldwide for females<br />
and the seventh most common cancer overall. Nigeria, a developing country, ranked<br />
tenth globally and fifth in Africa, has a mortality rate <strong>of</strong> 22.9 deaths per 100,000 with<br />
14,000 new cases being diagnosed annually. In an effort to reduce this mortality rate,<br />
this research was undertaken to assess the level <strong>of</strong> awareness, attitude and practice <strong>of</strong><br />
common cancer preventive strategies such as screening and the treatment <strong>of</strong><br />
precancerous lesions using LEEP as a case study among women.<br />
Methods: A descriptive design using simple random sampling methods with<br />
self-administered questionnaires or interview methods (for illiterates) were used to<br />
collect data from the sample population. Market women were used (4 major markets in<br />
Ibadan) because they provided a sample population <strong>of</strong> women both in their<br />
reproductive and menopausal groups, with various level <strong>of</strong> literacy. Data was analyzed<br />
using the SPSS version 15.<br />
Results: Of the total 100 respondents, only 55% had heard about cervical cancer while<br />
just 35% had heard about cervical screening test. 26% cited schools while 16% <strong>of</strong> the<br />
35% cited mass media as their sources <strong>of</strong> awareness about the disease. 96% agreed that<br />
it was important to be screened for early diagnosis, 90% <strong>of</strong> all acknowledged the<br />
importance <strong>of</strong> this screening test in reducing deaths from cervical cancer. However,<br />
only 4% had ever been screened in their lifetime. Despite this, 74% <strong>of</strong> total respondents<br />
had a positive attitude to being screened while an additional 16% would have loved to<br />
be screened if the test was made free. On the role <strong>of</strong> treatment <strong>of</strong> precancerous lesions<br />
as a means <strong>of</strong> reducing mortality rate, 26% were aware about the Loop Electrosurgical<br />
Excision Procedure (LEEP) while only 40% <strong>of</strong> that agreed that it was curative. 84%<br />
P. Sawrycki 1 ,M.Ga˛sior 2 , K. Domagalski 3 , J. Jarkiewicz-Tretyn 2 , M. Jackowski 4<br />
1 Oddzial Chemioterapii Nowotworow, Wojewodzki Szpital Zespolony<br />
im. L. Rydygiera w Toruniu, Torun, Poland, 2 Pracownia Genetyki Nowotworów,<br />
NZOZ Poradnia Genetyki Nowotworów, Torun, Poland, 3 Centre For Modern<br />
Interdisciplinary Technologies, Nicolaus Copernicus Univerity, Torun, Poland,<br />
4 Katedra I Klinika Chirurgii Ogòlnej, Gastroentorologicznej I Onkologicznej,<br />
Wojewodzki Szpital Zespolony im. L. Rydygiera w Toruniu, Torun, Poland<br />
Background: Lung cancer is the leading cause <strong>of</strong> cancer death in the world. The most<br />
important risk factor is smoking. Only about 10% <strong>of</strong> patients never smoked, on the<br />
other hand, only about 15% <strong>of</strong> smokers get lung cancer. One <strong>of</strong> the possibile reason<br />
can be individual, genetic factors. This is supported by the evidence <strong>of</strong> more frequent<br />
occurrence <strong>of</strong> this disease in first-degree relatives <strong>of</strong> patients with lung cancer. In<br />
addition, there are many reports about lung cancer relationships with certain genetic<br />
disorders.<br />
Methods: Correlation <strong>of</strong> CYP1B1 gene polymorphisms (variants C142G, G355T and<br />
C4326G) with the risk <strong>of</strong> lung cancer was analyzed. The selection <strong>of</strong> these genes is<br />
associated with their impact on the transformation <strong>of</strong> carcinogens contained for<br />
instance in tobacco smoke (CYP1B1). The frequency <strong>of</strong> CYP1B1 polymorphisms<br />
between 112 patients with lung cancer and the control group, consisting <strong>of</strong> 100<br />
neonatal umbilical cord blood, is compared. Patients were also evaluated in terms <strong>of</strong><br />
gender, type <strong>of</strong> cancer, the amount <strong>of</strong> pack-years and age <strong>of</strong> onset. Association <strong>of</strong><br />
genetic variations with lung cancer were analyzed in terms <strong>of</strong> single nucleotide<br />
polymorphisms, haplotypes and combination <strong>of</strong> genotypes.<br />
Results: Statistically significant higher incidence <strong>of</strong> G allele variants <strong>of</strong> C142G<br />
polymorphism and allele C <strong>of</strong> C4326G polymorphism in patients with lung cancer was<br />
found. G355T polymorphism showed no statistically significant differences in terms <strong>of</strong><br />
allele frequencies between the compared groups. Haplotype GTC and haplotypes GT<br />
(C142G-G355T), GC (C142G-C4326G) and TC (G355T-C4326G) occur significantly<br />
more frequently in the lung cancer group. Genotype combinations containing allele G<br />
<strong>of</strong> polymorphic variants C142G occur significantly more <strong>of</strong>ten in patients with lung<br />
cancer.<br />
Conclusions: The results demonstrate a significant relationship <strong>of</strong> some<br />
polymorphisms with the risk <strong>of</strong> developing lung cancer. Inclusion <strong>of</strong> genetic data into<br />
screening could contribute to more accurately determine the population at risk <strong>of</strong> lung<br />
cancer and improve the results <strong>of</strong> lung cancer screening.<br />
Legal entity responsible for the study: 1. Wojewodzki Szpital Zespolony<br />
im. L. Rydygiera w Toruniu 2. NZOZ Pracownia Genetyki Nowotworów w Toruniu<br />
Funding: 1. Wojewodzki Szpital Zespolony im. L. Rydygiera w Toruniu 2. NZOZ<br />
Pracownia Genetyki Nowotworów w Toruniu<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1347P<br />
Naturally occurring immune response against biologically<br />
and clinically relevant targets<br />
J.P. Marquez 1 , S. Carrillo 2 , A. Suplee-Rivera 2 , E. Ramos 1 , P.A. Lucero-Diaz 2 ,<br />
A. Camacho-Hernandez 2 , J.A. Matute-Briseno 2 , R. Soto-Soto 2<br />
1 <strong>Oncology</strong>, Tumor Vaccine Group University <strong>of</strong> Washington, Seattle, WA, USA,<br />
2 Immuno-<strong>Oncology</strong>, Centro de Investigacion del Cancer en Sonora, Sonora,<br />
Mexico<br />
Background: Few studies evaluate the immunogenicity <strong>of</strong> biological relevant targets in<br />
tumors with high-world prevalence and early relapse such as ovarian, triple negative<br />
breast cancer (TNBC), multiple myeloma (MM), etc. Some tumor targets are<br />
immunogenic but are not relevant for tumor survival such as CEA, CA-125, CA-19-9,<br />
etc. and have failed in vaccines clinical trials. Only a few studies focus on the biological<br />
and clinical relevance <strong>of</strong> tumor antigens such as MUC1, Her-2, etc. Aberrant<br />
up-regulation <strong>of</strong> some proteins that are involved in cancer relapse has shown to be a<br />
mechanism by which some auto-proteins become immunogenic and potentially targets<br />
<strong>of</strong> both humoral and cellular adaptive immune response. We evaluated whether<br />
putative relevant proteins that are found in high incidence <strong>of</strong> several cancers and<br />
associated with poor prognosis could be recognized by the humoral immune response.<br />
We further interrogate if the humoral immune response against these proteins may<br />
predict relapse and overall survival.<br />
Methods: Four broad-spectrum proteins known to be overexpressed in several tumors<br />
and associated with early relapse were identified by systematic reviews. Indirect peptide<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw385 | vi467
abstracts<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
ELISA was used to evaluate humoral immune response using all predicted peptides<br />
from these proteins. 50 stage IV cancer patients and 50 age-matched controls were<br />
studied. We identified those MHC-I and MHC-II peptides using computer-based<br />
algorithms from Ape-1, Fascin, RCAS1 and VCP.<br />
Results: Fascin and VCP peptide mixes are immunogenic in all cancer-interrogated<br />
patients and in some controls. Antibody responses were significantly elevated in cancer<br />
patient’s sera when compared to controls (Ape-1 p = ns, Fascin p = 0.0016, RCAS1<br />
p = ns and VCP p < 0.0013). Patients with an average OD > 0.38 against at least 2<br />
peptides for 2 proteins had better overall survival (p = 0.005).<br />
Conclusions: Discussion: All tumors studied reacted by peptide indirect ELISA at least<br />
against 2 peptides <strong>of</strong> overexpressed proteins involved in important biologic pathways<br />
and this is the first approach to design a broad spectrum multi-peptide vaccine to<br />
prevent relapse. Humoral immune response may also predict the clinical outcomes in<br />
malignancies that tend to relapse in short period <strong>of</strong> time.<br />
Legal entity responsible for the study: Centro de Investigación de Cáncer en Sonora<br />
Funding: Centro de Investigación de Cáncer en Sonora<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1348P Malignancy registered in Babylon <strong>Oncology</strong> Center (1990 -<br />
2015)<br />
S.F. Abood 1 , A. Al-Timimi 2 , H.O.M. Al-Dahmoshi 3 , R.M. Alwash 4 , A. Helmi 5 ,<br />
Y.Q. Alwash 4 , W. Abdul Ameir 4<br />
1 Babylon <strong>Oncology</strong> Center, Merjan Medical City, Hillah, Iraq, 2 Pathology<br />
Department, Al-Qasim University –Babylon, Hillah, Iraq, 3 Biology Department,<br />
Babylon University, Science Faculty, Hillah, Iraq, 4 Cancer Registry Center, Babylon<br />
Cancer Registry Center Directorate, Hillah, Iraq, 5 Department <strong>of</strong> Medicine, Babylon<br />
<strong>Oncology</strong> Center, <strong>Oncology</strong> Center-Marjan Hospital, Hillah, Iraq<br />
Background: During this period (1990 – 2015 ) 15283 cases <strong>of</strong> malignancy were<br />
reported. 7119 (46.55%) cases were male and 8164 (53.45%) cases were female with the<br />
ratio <strong>of</strong> M: F equal to 1:1.28. It is concluded that the incidence <strong>of</strong> cancer is increasing in<br />
alarming way in the last (25) years. It is mainly due to the effect <strong>of</strong> air, water and earth<br />
pollution by the previous wars in Iraq. This increasing incidence <strong>of</strong> cancer is associated<br />
with a younger age group especially with regard to breast and colonic carcinoma.<br />
Methods: Data <strong>of</strong> malignant cases were obtained from cancer <strong>Oncology</strong> center, Merjan<br />
Teaching Hospital during the last 25 years from 1990 to 2015 were the information <strong>of</strong><br />
different malignant patient register in files in it all investigations, histology report,<br />
surgeon refereed report address, family report, past medical & surgical history report <strong>of</strong><br />
the patient. All these data analyzed and grouped in tables and drown in figures and<br />
histogram to show the significance <strong>of</strong> increased number <strong>of</strong> malignancy per years from<br />
1990 upward.<br />
Results: A total <strong>of</strong> 15283 malignant cases have studied, 7119 (46.55%) cases were male<br />
and 8164 (53.45%) cases were female with he ratio <strong>of</strong> M: F equal to 1:1.28. Table shows<br />
the annual no. <strong>of</strong> new cancer cases registered in Babylon during 1990-2015. There is a<br />
significant relationship exist between years and no. <strong>of</strong> cancer cases registered in<br />
Babylon, r (correlation coefficient ) = 0.842 (P < 0.001).<br />
Years<br />
No. <strong>of</strong> registered<br />
cases<br />
Table: 1348P<br />
Male<br />
(No.)<br />
Male<br />
(%)<br />
Female<br />
(No.)<br />
Female<br />
(%)<br />
1990 82 43 52.4 39 47.6<br />
1991 160 98 61.25 62 38.75<br />
1992 250 133 53.2 117 46.8<br />
1993 333 172 51.56 161 48.34<br />
1994 337 179 53.11 158 46.88<br />
1995 300 157 52.48 143 47.52<br />
1996 346 181 52.29 165 47.71<br />
1997 339 176 51.92 163 48.08<br />
1998 350 182 51.92 168 48.98<br />
1999 378 194 51.28 184 48.72<br />
2000 415 224 53.97 191 46.03<br />
2001 447 241 53.91 206 46.09<br />
2002 300 155 52 145 48<br />
2003 378 167 44.2 211 55.8<br />
2004 594 311 52.00 283 48.00<br />
2005 678 288 42.00 390 58.00<br />
2006 983 420 47.60 563 52.40<br />
2007 1025 427 42.00 598 58.00<br />
2008 911 403 44.20 508 45.80<br />
2009 936 406 43.40 530 46.60<br />
2010 979 434 44.30 545 45.70<br />
2011 996 453 45.5 543 54.5<br />
2012 921 396 43.0 525 57.0<br />
2013 931 409 44 522 56<br />
2014 850 370 43 480 57<br />
2015 1064 500 48 564 52<br />
Sum 15283 7119 46.55 8164 53.45<br />
Conclusions: It is concluded that the incidence <strong>of</strong> malignancy is increasing in alarming<br />
way in the last 25 years. It is mainly due to the effect <strong>of</strong> environmental Pollution (i.e.<br />
Air, Water and Earth Pollution ) from the previous Wars in Iraq. This increasing<br />
incidence <strong>of</strong> cancer is associated with a younger age group especially with regard to<br />
Breast and GIT malignancies; however, high percentage <strong>of</strong> those malignant patients got<br />
good benefit by treatment with chemotherapy and or Hormonal therapy in Babylon<br />
<strong>Oncology</strong> Center and R.T. in Baghdad Radiotherapy Center.<br />
Legal entity responsible for the study: Babylon Health Directorate<br />
Funding: Sharif Abood<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
vi468 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong> 27 (Supplement 6): vi469–vi473, 2016<br />
doi:10.1093/annonc/mdw386<br />
psycho-oncology<br />
1349PD<br />
Unsung heroes <strong>of</strong> lung cancer: Perspectives from<br />
caregivers in the lung cancer Canada survey<br />
M. Doherty 1 , C. Sit 2 , N. Leighl 1 , P. Wheatley-Price 3<br />
1 Medical <strong>Oncology</strong>, Princess Margaret Hospital, Toronto, ON, Canada, 2 Lung<br />
Cancer Canada, Lung Cancer Canada, Toronto, ON, Canada, 3 Dept <strong>of</strong> Medical<br />
<strong>Oncology</strong>, The Ottawa Hospital Regional Cancer Centre, Ottawa, ON, Canada<br />
Background: Lung cancer (LC) is a major cause <strong>of</strong> cancer death, morbidity and loss <strong>of</strong><br />
function. Caregivers (CGs) <strong>of</strong> patients (pts) with LC provide emotional, physical, and<br />
financial support, but their contribution is under-reported. The Lung Cancer Canada<br />
Survey aimed to study the impact <strong>of</strong> LC diagnosis and treatment on pts and CGs.<br />
Methods: This online survey for pts and CG was conducted in August 2015. The<br />
questionnaire covered demographics, emotional issues and stigma, symptom burden,<br />
quality <strong>of</strong> life, treatment experiences, and unmet needs. Anonymously collected results<br />
were collated by Lung Cancer Canada.<br />
Results: 91 pts and 72 CG completed 163 interviews. Most CGs were partners (54%) or<br />
parents (38%). 60% were the primary CG, and 79% were former CGs: 68% <strong>of</strong> their care<br />
receivers had died. Most CGs coped well (79%), but stressors included care-receiver’s<br />
declining health, their own emotions, and balancing responsibilities. Fatigue,<br />
depression, and respiratory complaints were the most challenging symptoms for CGs<br />
and pts. CGs reported more negative feelings than pts: anxious/stressed 61%v42%,<br />
depressed/hopeless 32%v11%, cared for 13%v38%, encouraged 11%v25%. CGs felt less<br />
support than pts from their healthcare team (75%v92%) and family/friends (65%<br />
v87%). Treatment satisfaction was lower among CGs: only 58% felt very/somewhat<br />
satisfied (v 82% <strong>of</strong> pts). 68% <strong>of</strong> CGs reported a negative stigma attached to LC, 35% felt<br />
there was less empathy toward LC than other cancers, and 38% felt they had to<br />
advocate harder for LC than other cancers. Notably, some CGs (8%) and pts (5%)<br />
reported a lack <strong>of</strong> compassion from medical pr<strong>of</strong>essionals after a LC diagnosis. 50% <strong>of</strong><br />
CGs reported a negative household financial impact: 69% reduced working hours, and<br />
8% quit their jobs. More empathy, support services and financial resources were<br />
suggested to help alleviate CG burden.<br />
Conclusions: This is the most detailed report on the experience <strong>of</strong> CGs <strong>of</strong> pts with LC,<br />
and highlights their reactions to the illness, and the associated prejudice and stigma. It<br />
also led to opportunities for Lung Cancer Canada to decrease CG burden through<br />
support initiatives such as CG-specific educational materials and the inclusion <strong>of</strong> CGs<br />
through peer-to-peer support programs.<br />
Legal entity responsible for the study: Lung Cancer Canada<br />
Funding: Lung Cancer Canada<br />
Disclosure: P. Wheatley-Price: Advisory Boards for Merck, Lilly, Boehringer Ingelheim<br />
and AstraZeneca. All other authors have declared no conflicts <strong>of</strong> interest.<br />
depression and pr<strong>of</strong>essional ineffectiveness (p = 0.0007), disillusion (p = 0.001) and<br />
psychophysical exhaustion (p = 0.0007). CBAVE highlighted high anxiety levels in<br />
24% <strong>of</strong> the operators, low well-being in 14% and psychological suffering in 14%.<br />
According to the STAXI 2, 15% had a high expression <strong>of</strong> aggressiveness, 10% was<br />
over-controlled. The aggressiveness was statistically related to depression (p = 0.001)<br />
evaluated by BDI, disillusion (p = 0.01), relational decline (P = 0.04) and<br />
psychophysical exhaustion (p = 0.002) measured by LBQ. An individual and group<br />
support path will be carried out for 37 operatives.<br />
Conclusions: This study showed that aggressiveness, depression and anxiety play an<br />
essential role and need to be taken into account together with burn out in screening the<br />
psychological discomfort among oncology operatives. Re-tests will be administered to<br />
evaluate the effectiveness <strong>of</strong> the interventions.<br />
Legal entity responsible for the study: Marco Romeo <strong>Oncology</strong><br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1351P<br />
Psychosocial quality <strong>of</strong> life in 30 survivors <strong>of</strong> bilateral<br />
retinoblastoma<br />
A. Batra 1 , D. Dhawan 1 , S. Bakhshi 2<br />
1 Medical <strong>Oncology</strong>, All India Institute <strong>of</strong> Medical Sciences, New Delhi, India,<br />
2 Medical <strong>Oncology</strong>, All India Institute <strong>of</strong> Medical Sciences, New Delhi, India<br />
Background: Retinoblastoma (Rb) is the most common intraocular tumor in<br />
childhood. Approximately one-third <strong>of</strong> the cases are bilaterally affected. The cure rates<br />
have improved but the data on psychosocial quality <strong>of</strong> life are limited.<br />
Methods: We analyzed the psychosocial domain quality <strong>of</strong> life (QOL) in 30 survivors<br />
<strong>of</strong> bilateral Rb using PedsQL TM 4.0 generic core scale in local language, which has been<br />
validated in the Indian population. The self-reported questionnaire was filled in by<br />
children <strong>of</strong> more than 5 years <strong>of</strong> age who had completed treatment for more than 12<br />
months. The psychosocial aspect is represented by social, emotional and school<br />
domains <strong>of</strong> QOL. The QOL was compared with 25 siblings using student’s t-test.<br />
Factors predicting QOL were assessed.<br />
Results: The median age <strong>of</strong> Rb survivors was 86 (range, 61-190) months and male:<br />
female ratio was 3:1. The median age at diagnosis was 12 (range, 1-16) months. 83%<br />
(25/30) underwent enucleation <strong>of</strong> the worst eye, whereas both eyes could be preserved<br />
in 5 patients. All the patients received VEC (Vincristine, Etoposide and Carboplatin)<br />
based chemotherapy and the median number <strong>of</strong> chemotherapy cycles was 6 (range,<br />
6-12). Radiotherapy was given in 8/30 (26%) patients. The psychosocial QOL was<br />
significantly worse in Rb survivors compared with controls. The emotional health<br />
domains <strong>of</strong> QOL (fear, anger and sleeping) were significantly lower in Rb survivors.<br />
Difficulties in maintaining friendships and competing were reported in the social<br />
health domain. In school health domain, there was significantly higher absenteeism<br />
due to sickness and hospital visits among Rb survivors. Age, sex, IRSS stage and<br />
previous radiotherapy did not affect the psychosocial QOL.<br />
abstracts<br />
1350PD<br />
Psychological discomfort among operatives in oncology:<br />
Can burn-out be considered the main issue?<br />
Table: 1351P Comparison <strong>of</strong> psychosocial QOL <strong>of</strong> survivors <strong>of</strong><br />
bilateral retinoblastoma and their siblings<br />
M. Romeo, R. Giampieri, T. Meletani, S. Formentini, M. De Lisa, M.G. Baleani,<br />
R. Berardi<br />
<strong>Oncology</strong>, AOU Ospedali Riuniti Ancona Università Politecnica delle Marche,<br />
Ancona, Italy<br />
Background: Several trials have underlined the significant impact <strong>of</strong> burn out on the<br />
operatives’ quality <strong>of</strong> life in oncology, whilst others pointed out a feeling <strong>of</strong> poor<br />
psychological training. The aim <strong>of</strong> this study was to screen the personnel (including<br />
physicians and nurses) working in our Institution in order to draw paths for training<br />
and psychological support.<br />
Methods: Four Evaluation tools, including Link Burn Out Questionnaire (LBQ), Beck<br />
Depression Inventory II (BDI), STAXI 2, CBA-VE have been administered to all the<br />
operatives (Physicians, Nurses and Healthcare Assistants) working at the Department<br />
<strong>of</strong> Medical <strong>Oncology</strong> <strong>of</strong> Ancona.<br />
Results: 72 operatives out <strong>of</strong> 75 have been included in our analysis. Male/female ratio<br />
was 19/56; median age was 37 years (range 20-62); 32 were physicians (17 oncologists<br />
and 15 fellows), 28 nurses, 12 Healthcare Assistants. Regarding the LBQ, 7% <strong>of</strong> them<br />
were in burn-out (3 person according to the Relational Deterioration scale and 2<br />
according to the Disillusion scale). Regarding the BDI, 11% <strong>of</strong> the operatives showed<br />
depression; furthermore 57% had sleep problems, 15% low self-exteem issues and 33%<br />
excessive self-criticism. Depression was not related to age, years <strong>of</strong> work and<br />
pr<strong>of</strong>essional role and relational decline, while there was an association between<br />
Health Domain Rb Survivors (n = 30) Healthy Siblings (n = 25) P-value<br />
Social 74.7 ± 10.1 83.9 ± 6.6 0.0003<br />
Emotional 76.3 ± 9.6 82.5 ± 7.8 0.01<br />
School 70.2 ± 11.2 84 ± 4.9
abstracts<br />
1352P<br />
Empowerment in adolescents and young adults (AYA) with<br />
cancer and its association with health-related quality <strong>of</strong> life<br />
S. Kaal 1 , O. Husson 2 , S. van Duivenboden 1 , R. Jansen 3 , E. Manten-Horst 3 , S. van<br />
den Berg 2 , J.B. Prins 2 , W.T. van der Graaf 4<br />
1 Medical <strong>Oncology</strong>, Radboud University Medical Centre Nijmegen, Nijmegen,<br />
Netherlands, 2 Medical Psychology, Radboud University Medical Centre Nijmegen,<br />
Nijmegen, Netherlands, 3 Department <strong>of</strong> Medical <strong>Oncology</strong>/452, Radboud<br />
University Medical Centre Nijmegen, Nijmegen, Netherlands, 4 Medical <strong>Oncology</strong>,<br />
Royal Marsden Hospital NHS Foundation Trust, London, UK<br />
Background: Cancer challenges the abilities <strong>of</strong> AYA cancer patients to achieve<br />
developmental milestones such as completing education, getting an intimate<br />
relationship, pursuing gainful employment or having children. Problems concerning<br />
self-esteem, autonomy, body image, fertility and sexuality may have a negative impact<br />
on health-related quality <strong>of</strong> life (HRQoL) <strong>of</strong> AYA cancer patients. A construct that may<br />
be associated with HRQoL is empowerment, defined in the cancer setting as feelings <strong>of</strong><br />
being able to manage the challenges <strong>of</strong> the cancer experience and having a sense <strong>of</strong><br />
control over one’s life. The aims <strong>of</strong> this study were to assess the levels and associated<br />
factors <strong>of</strong> empowerment among AYA cancer patients and its relationship with HRQoL.<br />
Methods: Patients 18-35 years old at time <strong>of</strong> cancer diagnosis and visiting the AYA<br />
clinic <strong>of</strong> Radboud university medical center Nijmegen were invited to fill in<br />
questionnaires about empowerment, potential associated factors<br />
(autonomy-connectedness, coping, social support and psychological distress) and<br />
HRQoL (physical, psychological, social, religious functioning and total QoL). T-tests<br />
and linear regression analyses were performed.<br />
Results: Eighty-five AYA patients completed the questionnaire (response 29%). The<br />
mean age at diagnosis was 27.5 years (SD = 4.6). A third <strong>of</strong> the AYA patients were high<br />
empowered. Moderate empowered AYA patients were more <strong>of</strong>ten female, had lower<br />
levels <strong>of</strong> autonomy, received less social support meeting their needs, had more coping<br />
problems and higher levels <strong>of</strong> psychological distress compared to their high empowered<br />
counterparts (all p < 0.05). Regression analyses showed that psychological<br />
empowerment was independently associated with physical (Beta = 0.33), psychological<br />
(Beta = 0.50), social (Beta = 0.40) and religious functioning (Beta = 0.32) and total<br />
HRQoL (Beta = 0.52; all p < 0.01).<br />
Conclusions: Empowerment is an important factor related to HRQoL. Intrapersonal<br />
(autonomy, coping) and interpersonal (social support) factors were strongly associated<br />
with empowerment and therefore may serve as components for developing age specific<br />
empowerment interventions among AYA cancer patients to improve HRQoL.<br />
Legal entity responsible for the study: N/A<br />
Funding: Radboudumc<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1353P<br />
Pr<strong>of</strong>essional reintegration after cancer treatment: factors<br />
influencing return to work<br />
N. Adam 1 , P. van Aalderen 2 , L. van Hulle 3 , E. Smeyers 4 , T. Van Keymeulen 4 ,<br />
A. Roelstraete 5<br />
1 Physical Medicine, A-Z-St-Augustinus, Antwerp, Belgium, 2 Psycho - oncology,<br />
A-Z-St-Augustinus, Antwerp, Belgium, 3 Psycho oncology, A-Z-St-Augustinus,<br />
Antwerp, Belgium, 4 Psycho- oncology, Onze Lieve Vrouw Ziekenhuis Aalst, Aalst,<br />
Belgium, 5 Radiotherapy, Onze Lieve Vrouw Ziekenhuis Aalst, Aalst, Belgium<br />
account both physical and psychosocial factors. The results also contributed to the<br />
development <strong>of</strong> a hospital-wide health care program in cooperation with government<br />
authorities for employment.<br />
Legal entity responsible for the study: Dr. Nathalie Adam<br />
Funding: Stichting tegen Kanker<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1354P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Cancer occurrence and cure: the power <strong>of</strong> the mind<br />
F. Eisinger 1 , X. Pivot 2 , L. Greillier 3 , C. Touboul 4 , J-Y. Blay 5 , S. Couraud 6 ,<br />
C. Lhomel 7 , A.B. Cortot 8 , J-F. Morère 9 , J. Viguier 10<br />
1 Cancer Control, Institute Paoli Calmettes, Marseille, France, 2 Service Oncologie<br />
Medicale, CHU Besançon, Hôpital Jean Minjoz, Besançon, France,<br />
3 Multidisciplinary <strong>Oncology</strong> and Therapeutic Innovations, Hopital Nord, Marseille,<br />
France, 4 Statistics, KantarHealth, Paris, France, 5 Medical <strong>Oncology</strong>, Centre Léon<br />
Bérard, Lyon, France, 6 Respiratory Diseases and Thoracic <strong>Oncology</strong>, Centre<br />
Hospitalier Lyon Sud, Pierre Bénite, France, 7 <strong>Oncology</strong>/Hematology Institutionnal,<br />
Roche, Boulogne-Billancourt, France, 8 Pneumology and thoracic oncology, DRC /<br />
CHRU <strong>of</strong> Lille, Lille, France, 9 Medical <strong>Oncology</strong>, Hopital Paul Brousse, Villejuif,<br />
France, 10 Medical <strong>Oncology</strong>, CHRU Bretonneau, Tours, France<br />
Background: Making sense <strong>of</strong> illness, and cancer in particular, is a long-standing<br />
quest. In addition to scientific explanations (cancerogenesis), a layperson’s outlook on<br />
the natural history <strong>of</strong> the disease is a complex mix <strong>of</strong> “how?” and “why?”. Psychological<br />
factors have been extensively surveyed as a potential cause for cancer in different<br />
cultural backgrounds.<br />
Methods: In 2014, we conducted two surveys in France among laypersons with no<br />
history <strong>of</strong> cancer (N = 1463, age range 40-75) and physicians (N = 301, age range<br />
27-70). Interviews were conducted between June 12 and July 10, 2014 (lay persons) and<br />
between July 9 and August 8, 2014 (physicians). Questions focused on the perceived<br />
causes <strong>of</strong> cancer and the way to achieve cure.<br />
Results: Among the general population <strong>of</strong> our survey, 7% <strong>of</strong> women declared that<br />
psychological stress is one <strong>of</strong> the five main causative factors for breast cancer; in an<br />
international survey among students in 2000, this rate was 1.7% for Koreans, 20.4% for<br />
Bulgarians and 8.3% for French women. In 2014, this factor was reported by 3% <strong>of</strong><br />
female physicians in France (Significant difference with laywomen P = 0.04). In terms<br />
<strong>of</strong> cure, 89% <strong>of</strong> laypersons (France, 2014) quoted “state <strong>of</strong> mind” as a powerful tool and<br />
73% <strong>of</strong> physicians (P < 0.01). Interestingly, laywomen who mentioned psychological<br />
status as a causative factor for breast cancer are also more likely to see it as a curative<br />
tool (P < 0.01).<br />
Conclusions: It therefore appears that in 2014, psychological factors are considered<br />
more as a tool to help cure cancer than as a risk to be controlled. Laypersons saw<br />
psychological factors as playing a far more important role in both the origin and the<br />
cure <strong>of</strong> cancer than physicians did. There is also a statistical correlation between these<br />
two viewpoints.<br />
Legal entity responsible for the study: Edifice surveys were funded by Roche S.A.<br />
Funding: Edifice surveys were funded by Roche S.A.<br />
Disclosure: F. Eisinger, X. Pivot, L. Greillier, J.-Y. Blay, S. Couraud, A.B. Cortot, J.-F.<br />
Morère: Honorarium fees from Roche. C. Lhomel: Employee <strong>of</strong> Roche. All other<br />
authors have declared no conflicts <strong>of</strong> interest.<br />
Background: The majority <strong>of</strong> patients treated for cancer face the complex challenge <strong>of</strong><br />
reintegrating themselves pr<strong>of</strong>essionally, during or after cancer treatment. There is an<br />
obvious need for interventions that facilitates pr<strong>of</strong>essional reintegration. This study is a<br />
quantitative analysis <strong>of</strong> factors associated with probability to return to work, as a basis<br />
for guidelines for interventions in this respect.<br />
Methods: A multicenter questionnaire study was initiated in two cancer centers<br />
enabling the recruitment <strong>of</strong> 104 patients (NOLVAalst = 39; NGZA Antwerp= 65; sexe:<br />
male = 12, female = 92; M Age = 48.41). Pr<strong>of</strong>essionally active patients were selected<br />
between 18 and 58 years <strong>of</strong> age, 8-10 months after cancer diagnosis with curative<br />
purpose and without signs <strong>of</strong> relapse. Through binary logistic regression the predictive<br />
value <strong>of</strong> work attitude, the experienced support from colleagues and supervisors,<br />
self-efficacy, perceived positive and negative social interactions, fatigue, anxiety and<br />
depression on whether or not to work 8 to 10 months after diagnosis were examined.<br />
Statistical analyzes were made with SPSS 21.<br />
Results: From the results the imported model shows a significant predictive value (χ2<br />
(12) = 64.56, p
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
1355P<br />
Stoicism and its relation with clincal-pathological variables in<br />
patients with resected cancer undergoing adjuvant<br />
chemotherapy treatment<br />
A. Ramchandani Vaswani 1 , C. Calderon Garrido 2 , P. Jimenez Fonseca 3 ,<br />
A. Carmona-Bayonas 4 , E. Llabrés Valentí 5 , C. Beato Zambrano 6 , T. García 4 , M.D.<br />
M. Muñoz 7 , B. Castelo 8 , E. Martinez de Castro 9 , J. Rogado Revuelta 10 ,M.<br />
D. Fenor 11 , M. Mangas Izquierdo 12 , M.Á. Vicente 4 , O. Higuera 13 ,P.De<br />
La Morena 4 , M.D.L.N. Gomez Camacho 14 , S. Fernández Arrojo 3 , M.D.<br />
M. Soriano 7 , C. Jara 15<br />
1 Dept. <strong>of</strong> Medical <strong>Oncology</strong>, Hospital Universitario Insular de Gran Canaria, Las<br />
Palmas, Spain, 2 Personality, Assessment and Psychological Treatment, Universitat<br />
de Barcelona, Barcelona, Spain, 3 Medical <strong>Oncology</strong>, Hospital Universitario Central<br />
de Asturias, Oviedo, Spain, 4 Medical <strong>Oncology</strong>, Hospital Universitario Morales<br />
Meseguer, Murcia, Spain, 5 Medical <strong>Oncology</strong>, Hospital Universitario Insular de<br />
Gran Canaria, Las Palmas, Spain, 6 Medical <strong>Oncology</strong>, Hospital Nisa Castilleja de<br />
la Cuesta, Seville, Spain, 7 Medical <strong>Oncology</strong>, Hospital General "Virgen de la Luz<br />
(Hospital Virgen de la Cruz de Cuenca), Cuenca, Spain, 8 MEdical <strong>Oncology</strong>,<br />
Hospital Universitario La Paz, Madrid, Spain, 9 Medical <strong>Oncology</strong>, Hospital<br />
Universitario Marques de Valdecilla, Santander, Spain, 10 MEdical <strong>Oncology</strong>,<br />
Hospital Universitario de La Princesa, Madrid, Spain, 11 Medical <strong>Oncology</strong>,<br />
Hospital Universitario de La Princesa, Madrid, Spain, 12 Medical <strong>Oncology</strong>,<br />
Hospital Galdakao Usansolo, Vizcaya, Spain, 13 Medical <strong>Oncology</strong>, Hospital<br />
Universitario La Paz, Madrid, Spain, 14 Medical <strong>Oncology</strong>, Hospital Universitario de<br />
Canarias, San Cristobal De La Laguna, Spain, 15 Medical <strong>Oncology</strong>, Hospital Sur<br />
de Alcorcón, Madrid, Spain<br />
Background: The objective <strong>of</strong> this study is to analyze the relationship between<br />
stoicism, gender, age, location and stage <strong>of</strong> the tumor, and compare the scores with two<br />
international samples.<br />
Methods: A multicentre, prospective, observational study that uses a website to gather<br />
clinical data and questionnaires that are given before and after adjuvant chemotherapy<br />
for patients with non metastatic resected cancer. The Liverpool Stoicism Scale (LSS)<br />
was applied to assess stoicism and Student’s t contrast was used to analyze it according<br />
to gender, age, location and state <strong>of</strong> the cancer.<br />
Results: A total <strong>of</strong> 243 patients were recruited in 11 centers. Mean age <strong>of</strong> the patients<br />
was 59 years, and 58% were male. The most frequent tumors were colon (41%), breast<br />
(35%), and stomach (10.8%), in stage III (38.5%). The significantly higher Stoicism<br />
scores were obtained in: men (p < .001), over 55 years old (p < .001), patients with<br />
colon cancer (p < .001), and in stage III (p = .010). The mean <strong>of</strong> Stoicism score was<br />
56.2 (SD 7.7, range from 31 to 80), higher than the original stoicism scale in the British<br />
sample (t = 6.590, p 65 years <strong>of</strong> age) and 26 (41.9%) nonelderly patients.<br />
Informed consent was obtained from each participant. The day before discharge after<br />
surgery, all patients were asked to report their functional limitations and health-related<br />
status by filling the following sections <strong>of</strong> the MOS-SF-36 (No. <strong>of</strong> items): bodily pain<br />
(2), emotional role functioning (3), general health perceptions (5), mental health (5),<br />
physical functioning (10), physical role functioning (4), social role functioning (2),<br />
vitality (4).<br />
Results: The results are reported in the Table. In general, the health-related QoF after<br />
surgery was similar in both groups. However, the scores related to bodily pain<br />
(64.3 ± 21.2 vs. 53.1 ± 16.3, p = 0.03), physical functioning (66.3 ± 18.2 vs. 56.3 ± 11.7,<br />
p = 0.02) and vitality (56.7 ± 13.6 vs. 50.1 ± 8.7, p = 0.03) reported by younger patients<br />
were higher than that reported by the elderly.<br />
Table: 1356P<br />
Parameters ≤65 years >65 years p-value<br />
Number <strong>of</strong> patients 36 (58.1%) 26 (41.9%) -<br />
Median age (range) 59 (35-65) 67 (66-77) -<br />
Bodily pain 64.3 ± 21.2 53.1 ± 16.3 0.03<br />
Emotional role functioning 62.7 ± 18.4 60.5 ± 12.3 0.59<br />
General health perceptions 61.6 ± 12.3 58.3 ± 11.4 0.29<br />
Mental health 59.3 ± 16.4 57.1 ± 18.6 0.62<br />
Physical functioning 66.3 ± 18.2 56.3 ± 11.7 0.02<br />
Physical role functioning 72.3 ± 18.3 66.7 ± 15.4 0.21<br />
Social role functioning 61.6 ± 19.3 59.3 ± 14.1 0.61<br />
Vitality 56.7 ± 13.6 50.1 ± 8.7 0.03<br />
Conclusions: The elderly are more sensitive to physical pain and exhibit a reduced<br />
vitality after surgery than younger patients. It can be hypothesized that they are<br />
worried by the problems that will occur after discharge.<br />
Legal entity responsible for the study: University <strong>of</strong> Padua<br />
Funding: University <strong>of</strong> Padua<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1357P<br />
Psychometric properties <strong>of</strong> the functional assessment for<br />
chronic illness therapy-spiritual wellbeing (FACIT-Sp) and its<br />
relationship wtih quality <strong>of</strong> Life on patients with<br />
non-metastatic resected cancer<br />
C. Beato Zambrano 1 , C. Calderón 2 , P. Jimenez Fonseca 3 , A. Carmona-Bayonas 4 ,<br />
T. García 4 , A. Ramchandani 5 , M.D.M. Muñoz 6 , B. Castelo 7 , E. Martinez de<br />
Castro 8 , M.D. Fenor 9 , J. Rogado Revuelta 9 , M. Mangas Izquierdo 10 ,M.<br />
Á. Vicente 4 , I. Ghanem 7 , A. Fernández 4 , A. Padilla 5 , M.P. Solis Hernandez 3 ,<br />
O. Donnay 11 , M.D.M. Soriano 6 , C. Jara 12<br />
1 Medical <strong>Oncology</strong>, Clínica Sagrado Corazón, Seville, Spain, 2 Personality<br />
Assessment and Psichological Treatment, Universitat de Barcelona, Barcelona,<br />
Spain, 3 Medical <strong>Oncology</strong>, Hospital Universitario Central de Asturias, Oviedo,<br />
Spain, 4 Medical <strong>Oncology</strong>, Hospital Universitario Morales Meseguer, Murcia,<br />
Spain, 5 Medical <strong>Oncology</strong>, Hospital Universitario Insular de Gran Canaria, Las<br />
Palmas, Spain, 6 Medical <strong>Oncology</strong>, Hospital General "Virgen de la Luz(Hospital<br />
Virgen de la Cruz de Cuenca), Cuenca, Spain, 7 MEdical <strong>Oncology</strong>, Hospital<br />
Universitario La Paz, Madrid, Spain, 8 Medical <strong>Oncology</strong>, Hospital Universitario<br />
Marques de Valdecilla, Santander, Spain, 9 MEdical <strong>Oncology</strong>, Hospital<br />
Universitario de La Princesa, Madrid, Spain, 10 Medical <strong>Oncology</strong>, Hospital<br />
Galdakao Usansolo, Vizcaya, Spain, 11 Medical <strong>Oncology</strong>, Hospital Universitario de<br />
La Princesa, Madrid, Spain, 12 Medical <strong>Oncology</strong>, Hospital Sur de Alcorcón,<br />
Madrid, Spain<br />
Background: In recent years, there has been a growing interest in evaluating the<br />
relationship between spiritual wellbeing and health in cancer patients. Our goal is to<br />
analyse the trustworthiness and validity <strong>of</strong> the spiritual wellbeing scale (FACIT-Sp),<br />
and the link between the three factors <strong>of</strong> the scale and the Quality <strong>of</strong> Life (QoL) in a<br />
sample <strong>of</strong> cancer patients.<br />
Methods: NEOCOPING* is a prospective, multi-centre study. A total <strong>of</strong> 297 patients<br />
from 13 centers were checked and 195 were finally admitted, 33 were rejected because<br />
they did not match the inclusion criteria and 69 were excluded because they had not<br />
completed all the protocol at the time <strong>of</strong> the analysis. All the patients had a<br />
non-metastatic resected cancer with intention to cure and were candidates to adjuvant<br />
chemotherapy. The variables included in this study were sociodemographic, clinical,<br />
pathological and psycho-social, and the questionnaires used were FACIT-Sp scales and<br />
EORT-QLQ-C30.<br />
Results: Mean age <strong>of</strong> the patients was 58.3 years (SD = 12.2), and 60% were women.<br />
The main cancers were: colon (41.5%) and breast (34.4%). The results show that<br />
FACIT-Sp gives an excellent internal consistency (α = 0.901). Statistician<br />
Kaiser-Meyer-Okin (KMO)= .734 and Barlett’s sphericity test (χ2 = 2174.643, p < .001)<br />
were adequate. The factorial structure <strong>of</strong> FACIT-SP showed a tridimensional solution<br />
that explained a 76.7% variance, similar to the original version. The three factors were<br />
Meaning <strong>of</strong> life, Peace and Faith. The Meaning <strong>of</strong> Life and Peace were closely correlated<br />
and also with the QoL factors. Peace was the factor that best predicted functionality,<br />
symptoms, global health and QoL (p < .001).<br />
Conclusions: FACIT-Sp is a trustworthy and reliable tool to evaluate spiritual<br />
wellbeing in cancer patients with non-metastatic resected cancer, and it’s a useful and<br />
interesting concept for future investigations in oncology.<br />
Legal entity responsible for the study: Sociedad Española de Oncología Médica<br />
Funding: Sociedad Española de Oncología Médica<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw386 | vi471
abstracts<br />
1358P<br />
Evaluation <strong>of</strong> burnout syndrome and personalized<br />
intervention in the medical oncology unit <strong>of</strong> the Second<br />
University <strong>of</strong> Naples (SUN)<br />
F. Fiore 1 , L. Gargiulo 1 , C. Cardone 2 , M.M. Laterza 2 , M. Fasano 2 , F. De Vita 2 ,<br />
F. Ciardiello 1<br />
1 Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale, AOU<br />
Seconda Università degli Studi di Napoli (AOU-SUN), Naples, Italy, 2 Medical<br />
<strong>Oncology</strong>, AOU Seconda Università degli Studi di Napoli (AOU-SUN), Naples, Italy<br />
Background: Burnout and stress occur frequently among oncology healthcare workers.<br />
These syndromes affect quality <strong>of</strong> life with detrimental effect on personal wellness and<br />
patient–physician relationship. The objective <strong>of</strong> our research was to estimate the levels<br />
<strong>of</strong> stress and burnout among the healthcare workers <strong>of</strong> the oncology department <strong>of</strong><br />
SUN and to evaluate the possible effects on personal and pr<strong>of</strong>essional life in order to<br />
organize an useful therapeutic approach.<br />
Methods: Burnout and stress levels were measured among 35 oncology healthcare<br />
workers (9 physicians, 19 residents, 6 nurses) at our institution.Burnout levels were<br />
assessed by using the “Link Burnout Questionnaires” (LBQ),consisting <strong>of</strong> 24 items,<br />
scored with Likert scale (0 – 6). Stress levels were analysed by using the “Health<br />
Pr<strong>of</strong>essions Stress and Coping Scale” (HPSCS)”, a self-report questionnaire. We<br />
calculated three severity levels (low, medium and high) for burnout (0-8; 9-24; 25-36)<br />
and stress (1540), according to the score intervals obtained in each<br />
section.<br />
Results: Questionnaires were administered in March 2016. Median age <strong>of</strong> our<br />
population was 30 years (25 – 65) and 77% were females. Total burnout level was<br />
scored as medium in the overall population, with no major differences among<br />
physicians, residents and nurses. Total stress level was found medium-high in the<br />
overall population with no difference among the three groups. Stress and burnout levels<br />
were correlated with age, sex, years <strong>of</strong> service and working hours in the overall<br />
population and among the three pr<strong>of</strong>essional groups: in LBQ test, IP level (Pr<strong>of</strong>essional<br />
Ineffectiveness) was more prevalent among residents (p: 40 h per week - - - - 60 69.8 - -<br />
Mean visit duration - - - -<br />
< 20 min - - - - 28 80 0.033 0.861<br />
≥ 20 min - - - - 42 59.2 - -<br />
Physical Activities - - - -<br />
≤ 2 h per week - - - - 42 82.4 2 h per week - - - - 28 50 - -<br />
Conclusions: Burnout Syndrome is a condition highly frequent among Brazilian<br />
physicians. We could not identify relevant factors influencing its high prevalence in<br />
this setting.<br />
Legal entity responsible for the study: Centro Oncológico Antonio Ermírio de<br />
Moraes, IRB<br />
Funding: Personal funds from the authors<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
vi472 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
1361P<br />
Effect <strong>of</strong> mindfulness training on quality <strong>of</strong> life and distress in<br />
early breast cancer patients treated with endocrine therapy<br />
J. Mebis 1 , S. Censabella 2 , N. Cardinaels 2 , G. Orye 3 , S. Marquette 3 , L. Noe 2 ,<br />
A. Maes 2 , P. Bulens 2<br />
1 Division <strong>of</strong> Medical <strong>Oncology</strong>, Jessa Hospital, Hasselt, Belgium, 2 Limburg<br />
<strong>Oncology</strong> Center, Jessa Hospital, Hasselt, Belgium, 3 Gynecology, Jessa Hospital,<br />
Hasselt, Belgium<br />
Background: Endocrine therapy (ET) prescribed in breast cancer can cause side effects<br />
that mimic menopausal symptoms and can thereby affect patients’ quality <strong>of</strong> life.<br />
Mindfulness-Based Stress Reduction (MBSR) is a structured group intervention based<br />
on meditation and its application in daily life. It has been shown effective in improving<br />
quality <strong>of</strong> life (QoL) and reducing psychological distress in cancer patients but not<br />
specifically in patients receiving ET, which was the aim <strong>of</strong> this study.<br />
Methods: Newly diagnosed breast cancer patients scheduled for (any) ET and/ or<br />
radio- but no chemotherapy were recruited to participate in a standardized, 8-week<br />
MBSR program provided by a certified trainer (one 3h-session/ week). Clinical<br />
outcomes were general QoL and distress measured through the short World Health<br />
Organisation Quality <strong>of</strong> Life scale (WHOQOL-Bref) and the short revised Depression<br />
Anxiety Stress Scales (DASS-21-R) before the start, at the end, and 6 months after the<br />
end <strong>of</strong> MBSR.<br />
Results: Twenty breast cancer patients, all receiving tamoxifen (11 had also<br />
radiotherapy), completed the study. Mean age was 57.5 ± 7.4 years. At the start <strong>of</strong><br />
MBSR, 11 were postmenopausal, mean time since diagnosis was 157 ± 65 days and<br />
mean time on ET was 99 ± 68 days. As shown in Table 1, the WHOQOL-Bref total<br />
score did not improve after MBSR. In contrast, there was a significant decrease <strong>of</strong> the<br />
DASS-21-R total score, though only the comparison <strong>of</strong> scores before the start vs after 6<br />
months reached significance (p = 0.023, two-tailed paired Wilcoxon tests; scores before<br />
vs after MBSR: p = 0.186).<br />
Table: 1361P Mean scores for global QOL and psychological distress<br />
<strong>of</strong> patients treated with tamoxifen receiving MBSR<br />
Outcome<br />
WHOQO-Bref<br />
total score<br />
DASS-21-R Total<br />
score<br />
Before<br />
start <strong>of</strong><br />
MBSR<br />
At end<br />
<strong>of</strong> MBSR<br />
6-month after<br />
end <strong>of</strong> MBSR<br />
97.4(10) 96.4(8.3) 98.9(10.4) 0.170<br />
28(14.8) 22.5<br />
(13.4)<br />
abstracts<br />
19.5(17.4) 0.030<br />
P (Friedman<br />
ANOVA, two<br />
tailed)<br />
Conclusions: MBSR did not improve global QoL in breast cancer patients treated with<br />
tamoxifen. Given their rather high QoL MBSR might not have been <strong>of</strong>fered at an<br />
appropriate time. Still, MBSR was beneficial as it significantly lowered their<br />
psychological distress (up to at least 6 months).<br />
Legal entity responsible for the study: Jeroen Mebis<br />
Funding: VZW Think Pink<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw386 | vi473
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong> 27 (Supplement 6): vi474–vi482, 2016<br />
doi:10.1093/annonc/mdw387<br />
abstracts<br />
public health<br />
1363PD<br />
EMA support for early access for oncology products<br />
S. Thirstrup<br />
NDA Advisory Board, NDA Advisory Services Ltd, Leatherhead, UK<br />
Background: Access to new, innovative, medicines potentially fulfilling unmet medical<br />
needs are <strong>of</strong> paramount importance to patients. European patients will on average have<br />
to wait 6 to12 months as compared to their US counterparts to get access to new<br />
anti-cancer products. While the US FDA have introduced a number <strong>of</strong> procedures to<br />
shorten the review time, the European Medicines Agency has only recently embarked<br />
upon such efforts.<br />
Methods: Following years <strong>of</strong> discussion on what has been termed ’adaptive licensing’,<br />
the European Medicines Agency (EMA) launched a new process in March 2016 to<br />
support development, and potentially faster regulatory review and approval time was<br />
introduced by the EMA. The process has been termed PRIME (PRIority MEdicine)<br />
and contains a number <strong>of</strong> changes to the traditional sponsor-agency relationship.<br />
Results: PRIME includes early access to EMA scientific advice as well as early<br />
appointment <strong>of</strong> the future EU rapporteur who will be leading the regulatory review <strong>of</strong><br />
any future marketing authorisation. For small/medium size companies as well as<br />
academic institutions developing new medicines, access to scientific advice (at reduced<br />
or fully waived fee) will be possible at the stage <strong>of</strong> ’pro<strong>of</strong> <strong>of</strong> principle’ (i.e. prior to Phase<br />
1) whereas large pharma can enter the scheme at the stage <strong>of</strong> ’pro<strong>of</strong> <strong>of</strong> concept’ (i.e.<br />
around Phase 2).<br />
Conclusions: The PRIME scheme was launched in spring 2016 and a number <strong>of</strong><br />
projects were selected as appropriate for inclusion. Whether this process will lead to<br />
earlier access to new, innovative medicines for patients with clear unmet medical need<br />
is too early to say. At any rate, this process is the first attempt by EU regulators to<br />
optimise the use <strong>of</strong> the current medicines legislation to foster innovation and hopefully<br />
improve review time for medicines in areas with high unmet medical needs such as<br />
oncology.<br />
Legal entity responsible for the study: N/A<br />
Funding: NDA Advisory Services Ltd<br />
Disclosure: S. Thirstrup: I work as a full-time employee for NDA Advisory Services<br />
Ltd, which is a global scientific and regulatory consultancy firm for the pharmaceutical<br />
industry. I do not receive any direct payment for my work from pharmaceutical<br />
developers and/or manufacturers.<br />
1365PD<br />
Do contemporary randomized controlled trials meet ESMO<br />
thresholds for clinically meaningful benefit?<br />
J.C. Del Paggio 1 , B. Azariah 2 , R. Sullivan 3 , W. Hopman 1 , F.V. James 2 , S. Roshni 2 ,<br />
I. Tannock 4 , C. Booth 1<br />
1 Medicine, NCIC Clinical Trials Group, Cancer Research Institute, Kingston, ON,<br />
Canada, 2 Clinical <strong>Oncology</strong>, Regional Cancer Centre Thiruvananthapuram/<br />
Trivandrum, Thiruvananthapuram (Trivandrum), India, 3 Cancer Epidemiology &<br />
Population Health, King’s College Hospital, London, UK, 4 Medical <strong>Oncology</strong>,<br />
Princess Margaret Hospital, Toronto, ON, Canada<br />
Background: ESMO has developed a framework for evaluating the magnitude <strong>of</strong><br />
clinical benefit (ESMO-MCBS) <strong>of</strong> new cancer therapies. We evaluate the extent to<br />
which contemporary randomized controlled trials (RCTs) are designed to detect<br />
differences in outcome that meet the proposed ESMO thresholds for clinically<br />
meaningful benefit (CMB).<br />
Methods: All RCTs evaluating systemic therapy for breast, non-small cell (NSCLC),<br />
colorectal (CRC), and pancreas cancer published 2011-2015 were reviewed. Two<br />
authors abstracted data regarding trial characteristics and applied the ESMO-MCBS to<br />
study results. Data from the statistical methods section were used to determine if the<br />
RCT was powered to detect an effect that would meet CMB.<br />
Results: 277 eligible RCTs were included (40% breast, 31% NSCLC, 22% CRC, 6%<br />
pancreas). Median sample size was 532 and 83% were funded by industry. Among the<br />
225 RCTs in which an ESMO design score could be assigned, 69% were powered to<br />
detect an effect size that would not meet the threshold for CMB. Factors associated<br />
with being powered for small effect size included disease (79% lung, 71% GI, 61%<br />
breast, p = 0.038), treatment intent (82% palliative, 37% curative, p < 0.001), therapy<br />
(molecular 76%, cytotoxic/hormone 61%, p = 0.015), primary endpoint (OS 77%,<br />
survival surrogate 61%, p = 0.001), and funding (72% industry, 50% non-industry,<br />
p = 0.014). On adjusted analysis, only treatment intent remained significant. Among all<br />
277 RCTs, the experimental therapy was statistically superior to the control arm in 143<br />
trials; the results <strong>of</strong> 29% <strong>of</strong> these trials met the ESMO threshold for CMB. Factors<br />
associated with meeting the CMB threshold included disease (40% breast, 29% lung,<br />
14% GI, p = 0.018), treatment intent (56% curative, 20% palliative, p < 0.001), and<br />
primary endpoint (37% survival surrogate, 24% OS, p = 0.013). On adjusted analysis<br />
only treatment intent and GI cancer remained significant.<br />
Conclusions: Less than one-third <strong>of</strong> RCTs with statistically significant results meet<br />
ESMO thresholds for clinically meaningful benefit, and this represents only 15% <strong>of</strong> all<br />
published trials. Investigators and funding agencies should adopt more stringent<br />
thresholds for meaningful benefit in the design <strong>of</strong> future RCTs.<br />
Legal entity responsible for the study: Queen’s University<br />
Funding: Kingston General Hospital<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1366PD<br />
Factors affecting job retention amongst cancer survivors<br />
five years after diagnosis: evidence from the French VICAN<br />
survey<br />
C. Alleaume 1 , A-D. Bouhnik 1 , M.K. Bendiane 2 ,D.Rey 2 , V. Seror 1 , P. Peretti-Watel 1<br />
1 UMR 912 INSERM - IRD - AMU, SESSTIM, Marseille, France, 2 ORS PACA,<br />
SESSTIM-INSERM UMR912- IRD - AMU, Marseille, France<br />
Background: Each year, 355,000 new individuals are diagnosed with cancer in France,<br />
nearly half <strong>of</strong> them are in working age and most <strong>of</strong> them interrupt their pr<strong>of</strong>essional<br />
occupation during their treatment. Drawing on these findings, this study aims to<br />
investigate factors associated with job retention amongst cancer survivors.<br />
Methods: VICAN is a French national survey on life conditions <strong>of</strong> cancers survivors<br />
diagnosed in 2010. Patient questionnaires were administered 2 and 5 years after<br />
diagnosis. The questionnaire dealt with access to healthcare, recovery after treatments<br />
and impact <strong>of</strong> the disease on personal and pr<strong>of</strong>essional life in the two and five years<br />
following diagnosis, respectively (VICAN national surveys 2012 and 2015). Medical<br />
data were collected from a questionnaire completed by the physician who initiated<br />
cancer treatment, and information from the national medicoadministrative database on<br />
reimbursement data and hospital discharge records. A multinomial logistic regression<br />
was used to identify factors associated with job retention rather than switching or<br />
losing the job held before the diagnosis.<br />
Results: Among the 1,139 cancer survivors aged 17- 58 at diagnosis, 982 (86%) were<br />
employed at the time <strong>of</strong> diagnosis in 2010 whereas 78% <strong>of</strong> them had a pr<strong>of</strong>essional<br />
activity five years later: 60% remained in the same job than five years ago and 18% have<br />
been in another occupation. The following factors are positively associated with the job<br />
retention during five years after a cancer diagnosis: educational level above high school<br />
graduation, open-ended job at the time <strong>of</strong> diagnosis, working in public sector and<br />
having had a working time reduction in the two years following cancer diagnosis. The<br />
medical factors identified were adverse evolution <strong>of</strong> cancer and being treated with<br />
radiotherapy, which negatively affect return to work.<br />
Conclusions: National guidelines are needed to better take in consideration cancer<br />
survivors with no university degree and private employees in order to help them to<br />
return to work. Improving information on working conditions is necessary to get better<br />
understanding <strong>of</strong> the pr<strong>of</strong>essional issues faced by individuals with cancer.<br />
Legal entity responsible for the study: UMR 912 SESSTIM INSERM - IRD -AMU<br />
Funding: National Institut <strong>of</strong> Cancer (Institut National du Cancer, INCa)<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1367PD<br />
Second cancer screening among 5-years women cancer<br />
survivors (French National Survey VICAN5)<br />
M.K. Bendiane 1 , A-D. Bouhnik 2 , A. Monet 2 , I. Chatta 2 ,D.Rey 1<br />
1 ORS PACA, SESSTIM-INSERM UMR912-IRD - AMU, Marseille, France,<br />
2 INSERM UMR912, SESSTIM-INSERM UMR912-IRD-AMU, Marseille, France<br />
Background: Cancer survivors have an increased risk (36%) to develop cancer<br />
compared to the non-cancer population. Improvement in cancer detection and<br />
treatment has led to an important increase <strong>of</strong> the number <strong>of</strong> long-term cancer<br />
survivors, many <strong>of</strong> them being at risk <strong>of</strong> second cancer. Face to the lack <strong>of</strong> information<br />
on cancer screening practices in this population, we decided to study such practices<br />
among women cancer survivors using the VICAN5 data. We selected women because<br />
in France, organised breast cancer screening program has been implemented<br />
(mammography) since 2004 (every 2 years between 50 and 74 years) and national<br />
recommendations exist for cervical cancer screening (Pap smear) (every 3 years<br />
between 25 and 65 years).<br />
© European Society for Medical <strong>Oncology</strong> 2016. Published by Oxford University Press on behalf <strong>of</strong> the European Society for Medical <strong>Oncology</strong>.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com.
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Methods: VICAN5 is the first national French survey on life conditions, prevention<br />
practices and medical follow-up <strong>of</strong> cancer survivors five years after diagnosis. Data has<br />
been collected from patient questionnaire, personal medical file and medical insurance<br />
databases. Patient questionnaire includes questions on new cancer screening before<br />
interview. Univariates and multivariate analyses have been performed to compare<br />
cancer women to French non-cancer women regarding their screening practices.<br />
Results: VICAN5 surveyed 1149 women including 654 (60%) women with non-breast<br />
cancer and 1011 (88%) with non-cervical cancer. We found an underutilization <strong>of</strong><br />
mammography screening in the non-breast cancer group compared with women in the<br />
general population (78% vs 87%).Concerning report <strong>of</strong> Pap smear in the 3 past years,<br />
no significantly differences were found between non-cervical cancer survivors and the<br />
general population (83% vs 81%). Use <strong>of</strong> a Pap smear test is strongly associated with<br />
having had a screening mammography. Several associated factors with tertiary<br />
prevention practices was found such as psychological state (anxiety level), physical<br />
characteristics (BMI) and life style (tobacco use).<br />
Conclusions: Survivorship care plans are needed to improve information <strong>of</strong> survivors,<br />
and to increase physicians’ awareness <strong>of</strong> the importance <strong>of</strong> tertiary prevention,<br />
especially among the cancer survivors who are at high risk to develop a second cancer.<br />
Legal entity responsible for the study: French National Institute <strong>of</strong> Health and<br />
Medical Research (Inserm)<br />
Funding: French National Institute for Cancer (INCA)<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
abstracts<br />
pr<strong>of</strong>essional medical writers (n = 5) different versions <strong>of</strong> lay summaries were written<br />
and each version was reviewed and critiqued. After revision each version was tested for<br />
readability using health literacy principles and the Flesh Reading Ease score. The<br />
presentation <strong>of</strong> the information followed the “inverse pyramid principle” that provides<br />
overview information first and then the details. For the development <strong>of</strong> the template we<br />
also used guidance documents from MRCT, HRA, EFPIA and TransCelerate.<br />
Accordingly, lay summary should be written for a reading level <strong>of</strong> 11 to 12 years <strong>of</strong> age.<br />
We hypothesized that lay summaries should short to facilitate comprehension and<br />
reduce reading load.<br />
Results: The main issues for the development <strong>of</strong> a lay summaries were: the need for a<br />
lay title, the description <strong>of</strong> the study design (using graphics), choice <strong>of</strong> the most<br />
important in- and exclusion criteria, presentation <strong>of</strong> primary efficacy endpoint along<br />
with statistical measures, the description <strong>of</strong> safety data (lay term and CTCAE term),<br />
and the overall conclusion on the study. The final template arranged the information in<br />
10 paragraphs with each one being introduced by a question. The amount <strong>of</strong> white<br />
space and the use <strong>of</strong> graphics and tables was optimised for lay readers.<br />
Conclusions: The final template allowed the presentation <strong>of</strong> oncology clinical study<br />
results for laypersons. However, the intended target reading level (11- 12 years <strong>of</strong> age)<br />
could not be achieved.<br />
Legal entity responsible for the study: Boehringer Ingelheim Pharma GmbH&CoKG<br />
Funding: Boehringer Ingelheim Pharma GmbH&CoKG<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1368P Access to cancer drugs in Europe years 2005-2014<br />
N. Wilking 1 , P. Lindgren 2 , U. Wilking 1 , B. Jönsson 3<br />
1 <strong>Oncology</strong> Pathology, Karolinska Institutet, Stockholm, Sweden, 2 LIME, Karolinska<br />
Institutet, Stockholm, Sweden, 3 Economics, Stockholm School <strong>of</strong> Economics,<br />
Stockholm, Sweden<br />
Background: Cancer drugs are fundamental in precision medicine. The cost <strong>of</strong> cancer<br />
drugs has increased over the last 10-20 years. This study investigates the spending and<br />
access to cancer drugs in Europe 2005-14 and the impact <strong>of</strong> prices and indicators <strong>of</strong><br />
clinical value for variations in access.<br />
Methods: Sales data from IMS Health standardized to population, incidence and/or<br />
mortality <strong>of</strong> specific cancers for comparisons between countries. Listed prices are used<br />
(no discounts). Determinants <strong>of</strong> variations in access are investigated with statistical<br />
methods.<br />
Results: Cancer drugs sales in Europe were € 7.4 billion in 2005 and € 19.5 billion in<br />
2014. Eight countries (Austria, Belgium, France, Germany, Italy, Netherlands, Spain,<br />
UK) accounted for > 80% <strong>of</strong> sales in both 2005 and 2014. France used most in 2005 but<br />
was passed by Germany in 2014; 25% <strong>of</strong> cancer drug sales in the EU-28. Two <strong>of</strong> the top<br />
5 drugs in 2005 were not in the top 10 in 2014 (docetaxel and oxaliplatin) and one<br />
(paclitaxel) was last on the list. Trastuzumab had doubled as No1 selling drug, and<br />
several new agents are listed, e.g. bevacizumab and lenalidomide. Among the top 5 drugs<br />
in 2014, 3 have recently lost exclusivity or will in the near future (trastuzumab, rituximab<br />
and imatinib). Cancer drugs’ share <strong>of</strong> direct costs for cancer care has doubled and was<br />
21% in 2014. The newest drugs make up only 8% <strong>of</strong> total sales, varying between 4% and<br />
11% per year in different countries, with the higher share in richer countries. Countries<br />
in Eastern and Southern Europe with low GDP/capita have a usage that is 1/3 <strong>of</strong><br />
countries in Western Europe, and this has not changed between 2005 and 2014.<br />
Conclusions: Access to cancer drugs varies in Europe and relates to the countries’<br />
economic status. There are also significant variations in access between countries <strong>of</strong><br />
similar economic power, indicating opportunities for improvement through policies<br />
aimed at evidence based and cost-effective precision cancer medicine.<br />
Legal entity responsible for the study: Swedish Institute for Health Economics<br />
Funding: Novartis, Roche, BMS, Jansen, MSD<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1369P<br />
Not at all simple: The lay language summary <strong>of</strong> oncology<br />
clinical trials results. Challenges in implementing the new EU<br />
regulation (536/2014)<br />
A. Nottbohm 1 , C. Weiss-Haljiti 2 , T.M. Schindler 1<br />
1 Medical Writing Europe, Boehringer Ingelheim Pharma GmbH&CoKG, Biberach,<br />
Germany, 2 Medical Writing Europe, Boehringer-Ingelheim Pharma GmbH&CoKG,<br />
Biberach, Germany<br />
Background: The new EU clinical trial regulation (536/2014) mandates that for every<br />
clinical study conducted in the EU, a summary <strong>of</strong> the results "that is understandable for<br />
laypersons" needs to be developed. At the time <strong>of</strong> abstract writing (May 2016), the<br />
regulatory guidance for the content <strong>of</strong> these lay summaries is limited to a 10 bullet<br />
point list in Annex V <strong>of</strong> the EU-regulation. Therefore sponsors <strong>of</strong> clinical studies need<br />
to develop their own approach to the writing <strong>of</strong> these documents.<br />
Methods: The objective was to develop a template for lay summaries for oncology<br />
clinical trials. We decided that the content <strong>of</strong> the lay summary should not exceed the<br />
data provided in the synopsis <strong>of</strong> the clinical study report. In a small team <strong>of</strong><br />
1370P<br />
An observational study on the chronological efficiency <strong>of</strong> a<br />
short cancer lecture for senior elementary school children<br />
K. Miyazato, K. Kurashita, A. Shinzato<br />
4-16-1 Iso, Urasoe General Hospital, Urasoe, Japan<br />
Background: Cancer is common and the leading cause <strong>of</strong> death worldwide, but lack <strong>of</strong><br />
interest or irrational fear is deterring acquisition <strong>of</strong> useful knowledge. Delay in hospital<br />
visits and job loss may result from lack <strong>of</strong> the correct understanding in those<br />
concerned. Cancer education is important in providing accurate information for<br />
prevention and early detection <strong>of</strong> the disease. Cancer education will eventually lead to<br />
cancer incidence decline, and preservation <strong>of</strong> the work force. Unfortunately, cancer<br />
checkup rate is still low in Japan. To assess the effectiveness <strong>of</strong> cancer education in<br />
senior elementary school children, we examined the change <strong>of</strong> the educational effect<br />
over time.<br />
Methods: We gave a lecture about cancer to 5 th grade elementary school children age<br />
10-11, separately in four groups <strong>of</strong> 32 students. We taught about cancer incidence,<br />
cancer prevention and the effect <strong>of</strong> medical checkup in 15 minutes. Each group (T1 was<br />
at 7 days after the lecture, T2 after 28 days, T3 after 49 days and T4 after 147 days) was<br />
queried just once. As a control, 71 students not receiving the lecture (C) were queried<br />
similarly. We assessed the memory <strong>of</strong> the lecture in groups T1 to T4 concerning cancer<br />
incidence, the impression <strong>of</strong> cancer and health checkup in groups T1 to T4 and C.<br />
Results: Retention <strong>of</strong> the memory <strong>of</strong> the lecture was self reported on a five score scale<br />
from 1 for poor to 5 for complete memorization. The average scores were 4.2: 3.9: 3.7:<br />
3.6, for T1: T2: T3: T4, respectively, (T1 vs. T4, p = 0.041). Concerning cancer<br />
incidence, the percentage <strong>of</strong> correct answers were 37.5: 53.1: 25.0: 12.5: 9.9 for T1: T2:<br />
T3: T4: C, respectively. The average scores for fear <strong>of</strong> cancer, 1 weak to 5 strong, were<br />
4.5: 4.4: 4.4: 4.3: 4.5 for T1: T2: T3: T4: C, respectively. About the eagerness to have<br />
health checkup as adults, 1 less to 5 more, 4.8: 4.4: 4.4: 4.1: 4.4, for T1: T2: T3: T4: C,<br />
respectively (T1 vs. T4, p = 0.01).<br />
Conclusions: The cancer lecture for senior elementary school children was effective in<br />
spite <strong>of</strong> its brevity. However, the memory and the awareness for cancer declined with<br />
time. The impression <strong>of</strong> cancer was almost stable. Repeating the cancer education is<br />
important.<br />
Legal entity responsible for the study: Keiko Miyazato<br />
Funding: Urasoe General Hospital<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1371P<br />
PREDIT model: PRognostic factor <strong>of</strong> Early Death In phase II<br />
Trials or the end <strong>of</strong> ‘sufficient life expectancy’ as an inclusion<br />
criterion?<br />
T. Grellety 1 , S. Cousin 1 , L. Letinier 1 , P. Bosco-Levy 1 , S. Hoppe 1 ,D.Joly 1 ,<br />
N. Penel 2 , S. Mathoulin-Pelissier 1 , A. Italiano 1<br />
1 Medical <strong>Oncology</strong>, Institute Bergonié, Bordeaux, France, 2 Medical <strong>Oncology</strong>,<br />
Centre Oscar Lambret, Lille, France<br />
Background: ‘Life expectancy’ is a frequent inclusion criterion in phase II trials, a<br />
measure that is subjective and difficult to estimate. The aim <strong>of</strong> this study was to identify<br />
factors associated with early death in patients included in phase II trials.<br />
Methods: We retrospectively collected medical records <strong>of</strong> patients with advanced solid<br />
tumors included in phase II trials in two French Comprehensive Cancer Centers<br />
(Bordeaux, first set; Lille, second set). We analyzed patients’ baseline characteristics.<br />
Predictive factors associated with early death (mortality at three months) were<br />
Volume 27 | Supplement 6 | 2016<br />
doi:10.1093/annonc/mdw387 | vi475
abstracts<br />
identified by logistic regression. We built a model (PREDIT, PRognostic factor <strong>of</strong> Early<br />
Death In phase II Trials) based on prognostic factors isolated from the final<br />
multivariate model.<br />
Results: First and second sets included 303 and 227 patients, respectively. Patients<br />
from the first and second sets differed in tumor site (urological (25.7% vs 15.4%) and<br />
gastrointestinal (17.8% vs 27.8%)) and in lung metastasis incidence (9.9% vs 48.9%).<br />
Overall survival (OS) at three months was 87.8% (95%CI [83.5; 91.0], first set) and<br />
91.2% (95%CI [86.7; 94.2], second set). Presence <strong>of</strong> a ‘life expectancy’ inclusion<br />
criterion did not improve the 3-month OS (HR 0.6, 95%CI [0.2; 1.2], p = 0.2325).<br />
Independent factors <strong>of</strong> early death were an ECOG score <strong>of</strong> 2 (OR 13.3, 95%CI [4.1;<br />
43.4]), hyperleukocytosis (OR 5.5, 95%CI [1.9; 16.3]) and anemia (OR 2.8, 95%CI [1.1;<br />
7.1]). Same predictive factors but with different association levels were found in the<br />
second set. Using the first set, ROC analysis shows a good discrimination to predict<br />
early death (AUC: 0.89 at 3 months and 0.86 at 6 months). In the overall population,<br />
patients with 0, 1, 2 and 3 risk factors had a rate <strong>of</strong> a 3-month early-death <strong>of</strong> 2.4% (7/<br />
292), 13.7% (24/175), 37.7% (20/53) and 60% (6/10) and a rate <strong>of</strong> 6-month early-death<br />
<strong>of</strong> 6.5% (19/292), 28% (49/175), 47.2% (25/53) and 70% (7/10), respectively.<br />
Conclusions: Risk modeling in two independent cancer populations based on 3 simple<br />
clinical parameters allows identifying patients who may not benefit from a phase II<br />
trial investigational drug and may, therefore, represent a helpful tool to select patients<br />
for phase II trial entry.<br />
Legal entity responsible for the study: Institut Bergonié Comprehensive Cancer<br />
Center<br />
Funding: Institut Bergonié Comprehensive Cancer Center<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1372P<br />
Risks and benefits <strong>of</strong> phase 1 oncology trials in the era <strong>of</strong><br />
personalized medicine<br />
C. Chakiba, T. Grellety, S. Cousin, A. Italiano<br />
Medical <strong>Oncology</strong>, Institute Bergonié, Bordeaux, France<br />
Background: Although crucial to developing new anti-cancer treatments, phase I trials<br />
in oncology can be considered as ethically controversial. Critics argue that they have no<br />
therapeutic intent and <strong>of</strong>fer participants no reasonable prospect <strong>of</strong> benefit. However,<br />
early access to potentially effective new drugs especially targeted therapies can be an<br />
opportunity for patients.<br />
Methods: We reviewed all non-pediatric phase 1 oncology trials published in English<br />
in 2014 and 2015. Characteristics <strong>of</strong> trials and patients were retrieved from the<br />
publications. We assessed the rates <strong>of</strong> response to treatment, stable disease, serious<br />
adverse events and treatment-related deaths. Presence <strong>of</strong> the definition <strong>of</strong> the<br />
Maximum Tolerated Dose (MTD), as well as biomarker presence and type at inclusion<br />
were also collected.<br />
Results: We analyzed 236 trials involving 8267 participants, all <strong>of</strong> whom were assessed<br />
for toxicity and 7218 (87%) <strong>of</strong> whom were assessed for a response to therapy. 107 trials<br />
(45%) focused on a specific population (tumor type and/or molecular pr<strong>of</strong>ile) and 29<br />
trials (13%) required a positive biomarker as an inclusion criterion. The MTD was<br />
reached in only 114 studies (48%). Of 3868 participants for whom data on SAE were<br />
available, 22.6% had at least one SAE. The overall rate <strong>of</strong> death due to toxic events was<br />
0.53%. The overall response rate, ORR (i.e., for both complete and partial responses),<br />
was 19.3%. and was significantly higher in clinical trials focusing on a specific<br />
population than in “all comers” one (30 vs 6.5%, p < 0.0001). Monoclonal antibodies<br />
targeting growth factor receptors were less likely to induce objective response than<br />
tyrosine kinase inhibitors, cytotoxic or immune-modulating agents. An additional<br />
35.7% <strong>of</strong> participants had stable disease or a less-than-partial response.<br />
Conclusions: Rates <strong>of</strong> response vary among the various types <strong>of</strong> phase 1 oncology<br />
trials. However, overall response rates among modern phase 1 oncology trials is<br />
significantly higher than previously reported. This is related to the increasing<br />
sophistication <strong>of</strong> trial design through the use <strong>of</strong> targeted and biological therapies in<br />
selected patients.<br />
Legal entity responsible for the study: Institut Bergonié, Bordeaux Comprehensive<br />
Cancer Center<br />
Funding: Institut Bergonié, Bordeaux Comprehensive Cancer Center<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1373P<br />
Causes <strong>of</strong> death among cancer patients as a function <strong>of</strong><br />
calendar year, age, and time after diagnosis<br />
N.G. Zaorsky, T. Churilla, B.L. Egleston, S.G. Fisher, J.A. Ridge, E.M. Horwitz,<br />
J.E. Meyer<br />
Radiation <strong>Oncology</strong>, Fox Chase Cancer Center, Philadelphia, PA, USA<br />
Background: Our objectives are to characterize the causes <strong>of</strong> death among cancer<br />
patients as a function <strong>of</strong>: (I) calendar year, (II) patient age, and (III) time after<br />
diagnosis. The results would: (1) characterize patient risk to die <strong>of</strong> cancer- and<br />
non-cancer-death; (2) identify those who might pr<strong>of</strong>it from intense screening for<br />
second cancers; and (3) identify cancers that would most benefit from further research.<br />
Methods: We used death certificate data in SEER Stat 8.2.1 to categorize cancer patient<br />
death as being due to index-cancer, non-index-cancer, and non-cancer cause, in the<br />
USA from 1973 to 2012. In addition, data were characterized with standardized<br />
mortality ratios (SMRs), which provide the relative risk <strong>of</strong> death as compared to all<br />
persons in the USA. A total <strong>of</strong> 28 cancers and 13 non-cancer causes <strong>of</strong> death were<br />
analyzed. A minimum <strong>of</strong> 1,000 person-years-at-risk were necessary for analysis <strong>of</strong> each<br />
disease site.<br />
Results: With respect to objective I, there were 1,895,788 deaths: 1,065,324 due to<br />
index-cancer, 204,453 due to non-index-cancer, and 626,011 not due to cancer. Over<br />
the entire time period, the greatest relative decrease in index-cancer death (generally<br />
from > 60% to < 30%) was among those with cancers <strong>of</strong> the testis, kidney, bladder,<br />
endometrium, breast, cervix, prostate, ovary, anus, colorectum, melanoma, and<br />
lymphoma. Index-cancer deaths (typically > 40%) were stable among patients with<br />
cancers <strong>of</strong> the liver, pancreas, esophagus, and lung, and brain. Non-cancer causes <strong>of</strong><br />
death were highest in patients with cancers <strong>of</strong> the colorectum, bladder, kidney,<br />
endometrium, breast, prostate, testis; >40% <strong>of</strong> deaths were from heart disease. For<br />
objectives II/III, the cancers with high SMRs tended to be <strong>of</strong> immunologic/hematologic<br />
origin; and lung cancer. The highest SMRs were from non-bacterial infections,<br />
particularly among < 50 year olds (e.g. SMR > 1,000, p 2-10 years, prostate cancer patients had increasing SMRs from<br />
Alzheimer’s disease, as did testicular patients from suicide.<br />
Conclusions: The risk <strong>of</strong> death from index- and non-index-cancers varies widely<br />
among primary sites. Risk <strong>of</strong> non-cancer deaths now surpasses that <strong>of</strong> cancer deaths,<br />
particularly for young patients in the year after diagnosis.<br />
Legal entity responsible for the study: N/A<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1374P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Socioeconomic position and mortality among patients with<br />
prostate cancer: influence <strong>of</strong> mediating factors<br />
S.B. Larsen 1 , K. Brasso 2 , J. Christensen 3 , C. Johansen 1 , A. Tjønneland 4 , S. Friis 3 ,<br />
P. Iversen 2 , S.O. Dalton 1<br />
1 Survivorship, Danish Cancer Society Research Center, Copenhagen, Denmark,<br />
2 Copenhagen Prostate Cancer Center, dept. <strong>of</strong> urology, Rigshospitalet,<br />
Copenhagen University Hospital, Copenhagen, Denmark, 3 Statistics,<br />
Bioinformatics and Registry, Danish Cancer Society Research Cener,<br />
Copenhagen, Denmark, 4 Diet, Genes and Environment, Danish Cancer Society<br />
Research Center, Copenhagen, Denmark<br />
Background: Men with low socioeconomic position experience higher mortality after a<br />
prostate cancer diagnosis compared with men with higher socioeconomic position,<br />
however, the specific mediators <strong>of</strong> this association are unclear. We therefore evaluated<br />
the influence <strong>of</strong> potential mediators on the association between socioeconomic<br />
position, and prostate cancer specific and all-cause death in prostate cancer patients.<br />
Methods: We conducted a cohort study <strong>of</strong> prostate cancer patients in the Danish Diet,<br />
Cancer and Health study. All patients completed questionnaires and anthropometric<br />
measurements at enrollment. Information on vital status, educational level, income,<br />
and comorbidity was obtained by linkage to Danish nationwide registries. Clinical data<br />
and anthropometric measures were collected from medical records at diagnosis. Cox<br />
proportional hazard models were used to compute hazards ratios for all-cause and<br />
prostate cancer specific death according to socioeconomic position and potential<br />
mediators.<br />
Results: We included 953 prostate cancer patients identified among 27,179 male<br />
participants in the Diet, Cancer and Health study who were followed for a median <strong>of</strong><br />
6.5 years (interquartile range, 6.4-11.2 years). Patients with low education were more<br />
<strong>of</strong>ten overweight or obese at baseline. The likelihood <strong>of</strong> aggressive cancer was almost<br />
equally distributed between educational levels. Obesity at baseline, but not at diagnosis,<br />
was associated with increased prostate cancer specific and death <strong>of</strong> all causes. Low<br />
socioeconomic position was associated with increased prostate cancer specific and<br />
all-cause death. The increased mortality could largely be explained by tumor<br />
aggressiveness, comorbidity, treatment, and metabolic indicators, except for patients in<br />
the lowest income group.<br />
Conclusions: Our study confirmed the a priori assumption that socioeconomic<br />
position is associated with increased mortality after prostate cancer. The increased<br />
mortality could largely be explained by lifestyle and clinical parameters.<br />
Legal entity responsible for the study: The study was approved by the regional ethical<br />
committees on human studies in Copenhagen and Aarhus ( jr.nr.(KF)11–037/01) and<br />
by the Danish Data Protection Agency.<br />
Funding: The present study is supported by The Danish Council for Independent<br />
Research – Medical Science [Grant No. 271-07-0609], The Scientific Committees <strong>of</strong> the<br />
Danish Cancer Society [Grant No. 225 06 055] and The Health Insurance Foundation<br />
[Grant No. 2006B095].<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
vi476 | abstracts Volume 27 | Supplement 6 | 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
1375P<br />
Acute diagnostic oncology clinic: tackling emergency<br />
presentations <strong>of</strong> cancer<br />
T. Newsom-Davis, J. Simmons, M. Bower, S. Cox, A. Gill, L. Hennah,<br />
A. Robinson, K. Richmond, R. Sharkey<br />
<strong>Oncology</strong>, Chelsea and Westminster Hospital - NHS Trust, London, UK<br />
Background: A significant proportion <strong>of</strong> cancer patients across Europe are diagnosed<br />
with their disease as the result <strong>of</strong> an emergency presentation (EP) to acute secondary<br />
care services. This route to diagnosis is associated with poorer survival and worse<br />
patient experience. Previous work has shown that EP patients usually describe a long<br />
history <strong>of</strong> symptoms (>12 weeks), and that 70% had seen their general practitioner<br />
(GP) in the days and weeks prior to presentation. Tackling EP <strong>of</strong> cancer is important<br />
when improving the outcomes <strong>of</strong> patients across Europe. In the majority <strong>of</strong> cases there<br />
are opportunities for earlier diagnosis and hence prevention <strong>of</strong> EP.<br />
Methods: We ran a 1-year pilot <strong>of</strong> a nurse-led Acute Diagnostic <strong>Oncology</strong> Clinic<br />
(ADOC) in a district general hospital. Based in the oncology department with<br />
consultant supervision <strong>of</strong> every case, the service was targeted at primary care. Referral<br />
criteria: age >18 years, clinical or radiological suspicion <strong>of</strong> cancer, clinically unable to<br />
wait 2 weeks for a standard urgent suspected cancer referral. Patient demographics,<br />
clinic activity, investigations and diagnoses were recorded. Formal patient and GP<br />
feedback was sought from all users.<br />
Results: Seventy-seven referrals were received, <strong>of</strong> which 46 (60%) fulfilled the criteria<br />
and were accepted. All were seen within 24 hours <strong>of</strong> referral. Median time from referral<br />
to definitive diagnostic test was 7.4 days (range 1-19), and 22 patients (48%) were<br />
diagnosed with cancer. Eleven patients (24%) required non-elective hospital admission.<br />
An average <strong>of</strong> 1.43 radiological and 0.20 endoscopic investigations were undertaken per<br />
patient, <strong>of</strong> which 58% were completed at the first clinic visit. A wide range <strong>of</strong> cancer<br />
diagnoses were made, including lung, myeloma, gastrointestinal, breast and lymphoma.<br />
Two patients declined or were too unwell to undergo biopsy. Patient and GP feedback<br />
showed a high level <strong>of</strong> user satisfaction.<br />
Conclusions: ADOC is a novel, effective and efficient pathway for patients who might<br />
otherwise be diagnosed as part <strong>of</strong> EP. This pilot shows the feasibility <strong>of</strong> a nurse-led<br />
service based in an oncology department, and a high level <strong>of</strong> user satisfaction. This<br />
model <strong>of</strong> acute diagnostic oncology clinic should be considered as an addition to<br />
existing outpatient cancer diagnostic pathways.<br />
Legal entity responsible for the study: Chelsea & Westminster Hospital NHS Trust<br />
Funding: Cancer Research UK Macmillan NHS England<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1376P<br />
Pr<strong>of</strong>ile <strong>of</strong> cancer patients who visit a specialized emergency<br />
room in São Paulo, Brazil<br />
M.M. Rapozo 1 , V.M. Hatanaka 2 , M.C. Bernardes 2 , G.M. Albuquerque 2 , M.D.P.<br />
E. Diz 2<br />
1 Medicine, Faculdade de Medicina da Universidade de São Paulo - FMUSP, Sao<br />
Paulo, Brazil, 2 Radiology and <strong>Oncology</strong>, ICESP - Instituto do Câncer do Estado de<br />
São Paulo, Sao Paulo, Brazil<br />
Background: Instituto do Câncer do Estado de São Paulo (ICESP) is a Brazilian<br />
university hospital dedicated to cancer treatment. Since there are about 19,000<br />
outpatient appointments, 4,300 chemotherapy sessions and 5,400 radiotherapy sessions<br />
monthly, a focused emergency room (ER) has been created, so as to support ICESP<br />
patients. This study describes the main reasons that lead patients to ER, in order to<br />
improve medical assistance.<br />
Methods: We performed a descriptive and retrospective cohort study, using medical<br />
records <strong>of</strong> all patients attended at the ER from 01/24/16 to 02/07/16, excluding ones<br />
referred from the day hospital unity. A two-way ANOVA (α = 0.05) was followed by a<br />
Fischer’s LSD test to assess the prevalence <strong>of</strong> different cancer sites between regular<br />
appointments and ER visits.<br />
Results: In the period, 900 patients totalized 933 visits to the ER. The most frequent<br />
affections were pain (36.4%), fever (10.3%), muscle weakness (7.2%), dyspnea (6.5%),<br />
bleeding (4.5%) and swelling (4.0%). Most common ER patients cancer sites were<br />
colorectal (14.4%), breast (13.4%), head & neck (10.4%), hematological (10.3%),<br />
esophagus/ stomach (8.8%), lungs (7.2%), prostate (7.1%), urinary tract (6.0%) and<br />
liver/ bile ducts/ pancreas (5.7%), uterus (3.3%) and skin (2.9%). From 05/2008 to 08/<br />
2013, the most frequent diagnoses in ICESP were: prostate (14.8%), colorectal (12.5%),<br />
breast (12.1%), head & neck (9.2%), skin (8.4%), esophagus/ stomach (7.9%), lungs<br />
(6.5%) and hematological (6.0%). The most common cancer types treated in ICESP are<br />
also the ones most <strong>of</strong>ten seen in ER patients, but for prostate (p = 0.0082) and skin<br />
cancer (p = 0.0460), significantly less common in the ER than in regular appointments.<br />
Surprisingly, colorectal and breast cancer were the most frequent among patients in our<br />
ER, while most <strong>of</strong> them were under chemotherapy and so, visited the outpatient unity<br />
frequently during the same period. Initial tests did not exact link between complaints<br />
and tumor site.<br />
Conclusions: Our study shows the most frequent complaints <strong>of</strong> cancer patients who<br />
visit our specialized ER and demand intervention for treatment or diagnosis. A deep<br />
analysis <strong>of</strong> final ER diagnoses is required, so that multidisciplinary, educative and<br />
preventive actions should be taken, in order to avoid visits to the ER.<br />
Legal entity responsible for the study: ICESP - Instituto do Câncer do Estado de São<br />
Paulo<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1377P<br />
Highlighting differences in education satisfaction and<br />
pr<strong>of</strong>essional development between medical and clinical<br />
oncologists in Europe. A European survey conducted by the<br />
Hellenic Group <strong>of</strong> Young Oncologists (HeGYO)<br />
E. Aravantinou Fatorou, G. Papaxoinis, K. Kamposioras, A. Korogiannos,<br />
V. Papadopoulos, G. Lazaridis, M. Nikolaou, E. Voulgaris, E. Bournakis,<br />
K. Tsigaridas, M. Liontos, E. Pantavou, N. Chatzifoti, P. Zaxaropoulou, I. Varthalitis,<br />
A. Athanasiadis, N.G. Tsoukalas<br />
Under the auspices <strong>of</strong> the Hellenic Society <strong>of</strong> Medical <strong>Oncology</strong> (HeSMO), Hellenic<br />
Group <strong>of</strong> Young Oncologists (HeGYO), Athens, Greece<br />
Background: Advances in <strong>Oncology</strong> research and the increasing knowledge <strong>of</strong> cancer<br />
therapeutics render continuous education an absolute necessity for oncologists. Aim <strong>of</strong><br />
this study was to reveal any differences between Medical and Clinical Oncologists in<br />
educational opportunities and continuous pr<strong>of</strong>essional development.<br />
Methods: Residents and specialized medical (MedOncs) and clinical oncologists<br />
(ClinOncs) from Europe were invited to complete a comprehensive forty<br />
multiple-choice web-questionnaire between February 20015 and January 2016. The<br />
study was kindly endorsed by scientific organizations such as ESMO YOC, ECCO, ESO<br />
and HeSMO.<br />
Results: These are the final results <strong>of</strong> a subanalysis from 226 participants. (69%<br />
MedOncs, 31% ClinOncs). More MedOncs compared to ClinOncs choose their<br />
specialty because they consider it challenging and more available for training (85.3 vs.<br />
68.6%, p = 0.006 and 22.9 vs. 10.9%, p = 0.025 respectively). MedOncs reported being<br />
more frequently completely satisfied (19.2 vs. 14.3%) and satisfied (35.3 vs. 24.3%) with<br />
the accordance <strong>of</strong> their training to the global curriculum (p = 0.002). More ClinOncs<br />
compared to MedOncs are completely satisfied from the academic tasks and<br />
opportunities provided by their National <strong>Oncology</strong> Society (24.3 vs. 11.5%, p = 0.011).<br />
MedOncs reported higher participation in scientific activities such as co-authoring in a<br />
medical book (43.6 vs. 22.9%, p = 0.003), participating in an Editorial Board (18.6 vs.<br />
7.1, p = 0.027), giving lectures in congresses (53.2 vs. 24.3%, p < 0.001), participating in<br />
translational research (41.0 vs. 25.7%, p = 0.036), in clinical trials (64.7 vs.44.3%,<br />
p = 0.005), or in fellowships (32.1 vs. 18.6%, p = 0.038).<br />
Conclusions: It is apparent that oncologists are highly thriving for education. More<br />
educational activities and career opportunities should be <strong>of</strong>fered for both Medical and<br />
Clinical Oncologists. The differences highlighted in this survey need to be validated in a<br />
bigger cohort <strong>of</strong> oncologists.<br />
Legal entity responsible for the study: Hellenic Group <strong>of</strong> Young Oncologists<br />
(HeGYO, http://www.hesmo.gr/en/gyon/group), under the auspices <strong>of</strong> the Hellenic<br />
Society <strong>of</strong> Medical <strong>Oncology</strong> (HeSMO, http://www.hesmo.gr/en)<br />
Funding: Hellenic Group <strong>of</strong> Young Oncologists (HeGYO, http://www.hesmo.gr/en/<br />
gyon/group), under the auspices <strong>of</strong> the Hellenic Society <strong>of</strong> Medical <strong>Oncology</strong> (HeSMO,<br />
http://www.hesmo.gr/en)<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1378P<br />
abstracts<br />
Education in oncology and career development in the<br />
web-era technology: a European survey conducted by the<br />
Hellenic Group <strong>of</strong> Young Oncologists (HeGYO)<br />
N.G. Tsoukalas, K. Kamposioras, G. Papaxoinis, E. Aravantinou-Fatorou,<br />
A. Korogiannos, V. Papadopoulos, G. Lazaridis, M. Nikolaou, E. Voulgaris,<br />
E. Bournakis, K. Tsigaridas, M. Liontos, E. Papageorgiou, N. Chatzifoti,<br />
P. Zaxaropoulou, A. Athanasiadis, I. Varthalitis<br />
Hellenic Group <strong>of</strong> Young Oncologists (HeGYO, http://www.hesmo.gr/en/gyon/<br />
group), Under the auspices <strong>of</strong> the Hellenic Society <strong>of</strong> Medical <strong>Oncology</strong> (HeSMO,<br />
http://www.hesmo.gr/en), Athens, Greece<br />
Background: New technologies, especially internet, promote not only cancer research<br />
but also education and career development. The aim <strong>of</strong> this study was to reveal if<br />
European oncologists are familiar and satisfied with these new technologies in the<br />
current Web-Era.<br />
Methods: Residents and specialized medical, clinical and surgical oncologists from<br />
Europe were invited to complete a comprehensive forty multiple-choice<br />
web-questionnaire. The study was kindly endorsed by scientific organizations such as<br />
ESMO YOC, ECCO, ESO and HeSMO.<br />
Results: These are the final results from 234 participants (61% males). 70% are from<br />
Greece and 30% from 16 other European countries. 57.3% are 30-40 years old, 67.5%<br />
are medical oncologists while 37.2% are residents. 59.8% are ESMO and 30.3% ASCO<br />
members. 28.6% have ESMO accreditation, 30.3% GCP and 32.9% PhD degree. 44% <strong>of</strong><br />
the responders tend to attend 1-3 national congresses and 70.5% 1-3 international<br />
congresses per year which they find beneficial for their continuous education (94%).<br />
Volume 27 | Supplement 6 | 2016<br />
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abstracts<br />
More than 50% consider ASCO and ESMO website/newsletters useful. The more useful<br />
sections <strong>of</strong> ESMO “<strong>Oncology</strong>Pro” are considered the “Guidelines and Practice” (66%)<br />
and the “<strong>Oncology</strong> news” (49%). Nearly 50% have participated in ESMO fellowships/<br />
educational activities and 50% are planning to participate in some <strong>of</strong> them. 39% <strong>of</strong><br />
oncologists are satisfied with ESMO fellowships and 83% are satisfied with ESMO<br />
educational activities. 55% use LinkedIn, 42% ResearchGate, 18% Facebook and 7%<br />
Twitter, while 15% have their own Personal website. For search engine 28% use<br />
GoogleScholar, 14% PubFacts and 15% SlideShare. Lack <strong>of</strong> time and financial issues are<br />
considered as the main problems for continuous pr<strong>of</strong>essional development while<br />
clinical practice and on-line medical resources are considered the most effective ways to<br />
achieve continuous medical education.<br />
Conclusions: The majority <strong>of</strong> oncologists are well informed about the educational<br />
opportunities in their countries and in Europe. An increasing number <strong>of</strong> oncologists<br />
gets familiar and satisfied with the new technologies in the Web-Era and use them for<br />
their continuous oncology education and career development.<br />
Legal entity responsible for the study: Hellenic Group <strong>of</strong> Young Oncologists<br />
(HeGYO, http://www.hesmo.gr/en/gyon/group), under the auspices <strong>of</strong> the Hellenic<br />
Society <strong>of</strong> Medical <strong>Oncology</strong> (HeSMO, http://www.hesmo.gr/en)<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1379P<br />
Clinicians identify high need to increase their genomic<br />
literacy to applied cancer genomics<br />
J. Laskin 1 ,D.Ha 2 , T. Chan 1 ,A.Fok 3 , K.A. Gelmon 1 , A. Charters 2 , R. Yoshizawa 2 ,<br />
S. Struve 2 ,C.Ho 1 , D. Renouf 1 , H. Lim 1 , C. Simmons 1 , S. Taylor 4 , A. Tinker 1 ,<br />
J-P. McGhie 5 , S. Jones 3 , M. Marra 3 , P. Chow-White 2<br />
1 Medical <strong>Oncology</strong>, British Columbia Cancer Agency, Vancouver, BC, Canada,<br />
2 School <strong>of</strong> Communications, Simon Fraser, Vancouver, BC, Canada, 3 Canada’s<br />
Michael Smith Genome Sciences Centre, British Columbia Cancer Agency,<br />
Vancouver, BC, Canada, 4 Medical <strong>Oncology</strong>, BC Cancer Agency, Kelowna, BC,<br />
Canada, 5 Medical <strong>Oncology</strong>, British Columbia Cancer Agency-Vancouver Island<br />
Centre, Victoria, BC, Canada<br />
Background: This study is the first survey <strong>of</strong> the genomic literacy <strong>of</strong> medical<br />
oncologists as co-investigators on a trial using medical genomic “big data”. The<br />
Personalized Onco-Genomics Program (POG) conducts whole genome DNA and<br />
RNA sequencing and in-depth bioinformatic analyses on patients with metastatic<br />
cancers to identify somatic variants and gene expression changes that may be targetable<br />
cancer “drivers”. Aberrant pathways are matched to drug databases and this data is<br />
reported to the clinician for each individual patient.<br />
Methods: We conducted a survey <strong>of</strong> medical oncologists based at the six tertiary care<br />
cancer hospitals <strong>of</strong> the BC Cancer Agency (n = 31, 52.5% response rate) who enroll<br />
patients into POG. We measured oncologists’ level <strong>of</strong> genomic knowledge and their<br />
experience and attitudes about genomic science and technologies.<br />
Results: We found a low to moderate level <strong>of</strong> genomic literacy amongst the oncologists<br />
as 48% reported having little knowledge about newer genetic/genomic technologies.<br />
Clinicians outside <strong>of</strong> the Vancouver area (the major urban centre) reported having less<br />
knowledge about new genetics technologies compared to those located in the<br />
Vancouver area (26.7% vs 73.3%, P < 0.07, Fisher exact test). 42% <strong>of</strong> all clinicians think<br />
medical education programs do not <strong>of</strong>fer enough genomics training. The majority <strong>of</strong><br />
the respondents envision that in the next 5-years genomic technologies will have a<br />
major impact on drug discovery (67.7%) and on assisting in treatment selection (58%).<br />
The three top concerning issues pertaining to the application <strong>of</strong> genomics science and<br />
technologies into clinical practices were: cost (61.3%), patients’ genomic literacy<br />
(48.3%), and clinical utility <strong>of</strong> genomic data (42%).<br />
Conclusions: The data suggests a high need to increase genomic literacy amongst<br />
oncologists beginning in medical school and with ongoing educational tools. Although<br />
these oncologists had variable experiences with POG directly informing treatment<br />
decisions; there was overall agreement that genomics and big data will play an<br />
increasingly important role in cancer care decision-making.<br />
Legal entity responsible for the study: BC Cancer Agency<br />
Funding: BC Cancer Foundation<br />
Disclosure: J. Laskin: Academic talk honoraria: AZ, Roche. Research grants to<br />
institution from: BI, Lilly and Roche. C. Ho: Honoraria AZ, Bayer, BMS, BI, Pfizer,<br />
Lilly, Roche. Research grants BI, Genzyme. Travel grant BI. D. Renouf: Honoraria from<br />
Celgene. H. Lim: Honoraria/Consulting/Research Funding: Eli Lilly, Leo, Bayer, Ipsen,<br />
Amgen. All other authors have declared no conflicts <strong>of</strong> interest.<br />
1380P<br />
Elicitation <strong>of</strong> public preferences for lung cancer screening<br />
using three screening modalities<br />
M. Ijzerman 1 , H. Broekhuizen 1 , C. Groothuis-Oudshoorn 1 , R. Vliegenthart 2 ,<br />
H. Groen 3<br />
1 Health Technology & Services Research, University <strong>of</strong> Twente, Enschede,<br />
Netherlands, 2 Radiology, University Hospital Groningen (UMCG), Groningen,<br />
Netherlands, 3 Department <strong>of</strong> Pulmonary Diseases, University Hospital Groningen<br />
(UMCG), Groningen, Netherlands<br />
Background: Since early detection <strong>of</strong> lung cancer can substantially increase overall<br />
cancer survival, there is increasing attention for lung cancer screening. This study aims<br />
to identify public preferences for lung cancer screening and to identify subgroups with<br />
distinct preferences.<br />
Methods: The study was designed as a multi-attribute elicitation experiment using<br />
swing weighting. Attributes were selected using interviews with three clinicians and a<br />
panel session with eight representative respondents. Included attributes were<br />
sensitivity, specificity, radiation load, duration <strong>of</strong> screening procedure, time until<br />
results, mode <strong>of</strong> screening (CT scan, breath or blood test) and location <strong>of</strong> screening<br />
(GP or hospital). A hierarchical clustering method was used to identify subgroups in<br />
the preference weights.<br />
Results: In total, 1034 respondents from a representative Dutch panel aged between 40<br />
and 80 completed the questionnaire. Respondents preferred breath analysis (45%) to<br />
blood samples (31%) or the CT-scanner (24%). 59% would prefer to be screened at<br />
their GP instead <strong>of</strong> the hospital. The three most important attributes were location <strong>of</strong><br />
screening (0.18, SD = 0.16), mode <strong>of</strong> screening (0.17, SD = 0.14), and sensitivity (0.16,<br />
SD = 0.13). There was a distinction between preferences <strong>of</strong> subgroups focusing on<br />
organization <strong>of</strong> the screening service and preferences <strong>of</strong> subgroups focusing on clinical<br />
benefits <strong>of</strong> screening. Respondents with a low education where more likely to belong to<br />
subgroups found organization <strong>of</strong> the services most important, while respondents with a<br />
higher education were more likely to find clinical benefit important (P < 0.01). There<br />
were no significant between-cluster differences with regard to gender, age, smoke<br />
status, self-perceived risk, or 5-year lung cancer risk.<br />
Conclusions: Our results indicate that that there is great potential for new screening<br />
technologies that can be used at a primary care facility, and that a one-size-fits-all<br />
approach for lung cancer screening is unlikely to provide the best value for the<br />
screening population.<br />
Legal entity responsible for the study: Maarten IJzerman<br />
Funding: University <strong>of</strong> Twente<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1381P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Current or former smokers: Who wants to be screened?<br />
S. Couraud 1 , L. Greillier 2 , X. Pivot 3 , L. Guibaudet 4 , J-Y. Blay 5 , C. Lhomel 6 ,<br />
J. Viguier 7 , J-F. Morère 8 , F. Eisinger 9 , A.B. Cortot 10<br />
1 Respiratory Diseases and Thoracic <strong>Oncology</strong>, Centre Hospitalier Lyon Sud, Pierre<br />
Bénite, France, 2 Multidisciplinary <strong>Oncology</strong> and Therapeutic Innovations, Hopital<br />
Nord, Marseille, France, 3 Service Oncologie Medicale, CHU Besançon, Hôpital<br />
Jean Minjoz, Besançon, France, 4 Statistics, KantarHealth, Paris, France, 5 Medical<br />
<strong>Oncology</strong>, Centre Léon Bérard, Lyon, France, 6 <strong>Oncology</strong>/Hematology<br />
Institutionnal, Roche, Boulogne-Billancourt, France, 7 Medical <strong>Oncology</strong>, CHRU<br />
Bretonneau, Tours, France, 8 Medical <strong>Oncology</strong>, Hopital Paul Brousse, Villejuif,<br />
France, 9 Cancer Control, Institute Paoli Calmettes, Marseille, France,<br />
10 Pneumology and thoracic oncology, DRC / CHRU <strong>of</strong> Lille, Lille, France<br />
Background: Lung cancer screening (LCS) with annual low-dose CT scans reduced<br />
specific and overall mortality in a selected population (age 55-74 yrs, current or former<br />
[quit < 15 yrs ago] smokers [> 30 pack-years]). Participation is key to successful<br />
screening programs. We assessed smokers’ intention to take part in a hypothetical LCS<br />
program for smokers.<br />
Methods: The EDIFICE French nationwide observational surveys assess behavior<br />
related to cancer screening programs. EDIFICE 4 was conducted from June 12 to July<br />
10 2014 by phone interviews <strong>of</strong> a representative sample <strong>of</strong> 1602 subjects (age 40-75 yrs)<br />
using the quota method. To identify explanatory factors associated with the intention<br />
to take part in a LCS program, we performed 2 comprehensive multivariate stepwise<br />
logistic regression analyses: (i) in current and (ii) in former cigarette smokers (who<br />
quit < 15 yrs ago).<br />
Results: Among those with no personal history <strong>of</strong> cancer (N = 1463), 263 current and<br />
170 former cigarette smokers were analyzed in the 2 regression models; 36.4% and<br />
26.3% respectively, intended taking part in a LCS program. In current cigarette<br />
smokers, the following were explanatory factors <strong>of</strong> the intention to take part: have been<br />
already screened for lung cancer (OR = 2.81; 95% CI [1.37-5.91]; P < 0.01);<br />
smokers < 30 pack-years (OR = 2.69 [1.21-6.30], P = 0.02); intention to stop smoking<br />
(OR = 1.96 [1.04-3.75], P = 0.04); low EPICE score (no precarity) (OR = 2.15; 95% CI<br />
[1.16-4.08], P = 0.02). In contrast, women (OR = 0.28; 95% CI [0.15-0.52], P < 0.01)<br />
were less inclined to undergo screening. Participation in other cancer screening<br />
programs, the Fagerström score, use <strong>of</strong> e-cigarettes, previous attempts to quit, and<br />
eligibility for screening were not significantly explanatory factors. Among former<br />
cigarette smokers, those with no comorbidities were less inclined to participate<br />
vi478 | abstracts Volume 27 | Supplement 6 | 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
(OR = 0.31; 95% CI [0.11-0.74], P = 0.01) while other variables were not explanatory.<br />
Again, eligibility for screening was not significantly explanatory.<br />
Conclusions: Intending to take part in LCS programs is a complex decision.<br />
Explanatory factors differ between current and former smokers but usual eligibility<br />
criteria are not significantly explanatory. Among current smokers, intended<br />
participation is strongly associated with the intention to quit smoking.<br />
Legal entity responsible for the study: The EDIFICE surveys are funded by Roche<br />
Funding: The EDIFICE surveys are funded by Roche<br />
Disclosure: S. Couraud, L. Greillier, X. Pivot, J.-Y. Blay, J-F. Morère, F. Eisinger,<br />
A. B. Cortot: Honorarium fees from Roche. C. Lhomel: Employee <strong>of</strong> Roche. All other<br />
authors have declared no conflicts <strong>of</strong> interest.<br />
1382P<br />
Long-term explerience in the management <strong>of</strong> adolescents<br />
and young adults with cancer referred to a regional tertiary<br />
center for multidisciplinary care<br />
M. Melián Sosa, R. Díaz, E. Navarro, J.A. Mendez, M.E. Medina, A. Torres,<br />
E. García, D. Akhoundova, J. Aparicio<br />
Medical <strong>Oncology</strong>, Hospital Universitari i Politècnic La Fe, Valencia, Spain<br />
Background: Adolescents and Young Adults (AYA) with cancer constitute a<br />
heterogeneous group in which improvements in survival rates (OS) have not kept pace<br />
with those achieved in younger patients.<br />
Methods: Retrospective review <strong>of</strong> AYA (15-29 years) patients with cancer, except<br />
leukemias, referred for multidisciplinary treatment (1992-2014). Baseline<br />
characteristics, pathological type and stage, 1 st -line treatments and OS were reviewed.<br />
Differences between three age groups (15-19, 20-24, 25-29 years) assessed with<br />
Chi-square and log-rank tests. A p-value < 0.05 was considered significant.<br />
Results: 286 patients. Median age 23 years (15-29); 33.1% (15-19 years), 23.6% (20-24<br />
years) and 43.3% (25-29 years). Tumour types (% in age-groups): Paediatric-bone<br />
tumours 15.7% (28.7-13.4-7.3), germ-cell tumours (both sexes) 15.5% (11.7-17.9-17.1),<br />
adult-type epithelial tumours 14.1% (6.4-10.4-22.0), Hodgkin lymphoma 12%<br />
(11.7-11.9-12.2), non-rhabdomyosarcoma s<strong>of</strong>t-tissue tumours 9.5 % (4.3-10.4-13.0),<br />
glial-derived brain tumours 7.7% (9.6-7.5-6.5), paediatric-type brain tumours 7.7%<br />
(8.5-9.0-6.5), non-Hodgkin lymphoma 4.9% (5.3-6-4.1%), endocrine tumours 2.8%<br />
(3.2-1.5-3.3), paediatric-type solid tumours 2.1% (4.3-3.0-0.0), other bone tumours<br />
2.1% (0-4.5.0-2.4), melanoma 2.1% (1.1-1.5-3.3), liver tumours 1.8% (1.1-1.5-2.4) and<br />
rhabdomyosarcoma 1.8% (4.3-1.5-0.0). Locally advanced or metastases: 43.7%<br />
(45.8-37.3-45.6). 1 st -line treatment: 62.5% surgery, 73.7% chemotherapy and 32.5%<br />
radiotherapy; 2.1% included in clinical trials. Median follow-up: 110 months (6-314<br />
months). 5 and 10-year OS: 64 and 57%. No differences between age-groups in<br />
treatment patterns and pathology, except in incidence <strong>of</strong> paediatric bone tumours and<br />
adult-type epithelial tumours. There was a trend for worse OS in the 25-29 age group; 5<br />
and 10-year OS were 68 and 64%, 66 and 53% and 56 and 36%, respectively (p 0.06).<br />
Conclusions: Patients in the 25-29 years-group fared worse than younger patients.<br />
More biologically aggressive presentations and a higher rate <strong>of</strong> adult-type epithelial<br />
neoplasms could justify these findings. Inclusion in clinical trials remains<br />
disappointingly low.<br />
Legal entity responsible for the study: Hospital Universitario La Fe<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1383P<br />
Toxoplasmosis: an overlooked infection in cancer patients<br />
R.M. Wassef 1 , R.R. Abdel Malek 2 , E.M. Rizk 3 , A.M. Boghdady 3<br />
1 Medical Parasitology, National Institute for Hepatology and Tropical Medicine,<br />
Cairo, Egypt, 2 Clinical <strong>Oncology</strong>, Faculty Of Medicine Kasr Al Ainy - Cairo<br />
University, Cairo, Egypt, 3 Medical Parasitology, Faculty <strong>of</strong> Medicine Kasr Al Ainy -<br />
Cairo University, Cairo, Egypt<br />
Background: Toxoplasmosis is a widespread disease caused by the Apicomplexan,<br />
coccidian protozoan Toxoplasma gondii (T. gondii). Human prevalence rates for<br />
toxoplasmosis vary greatly in different parts <strong>of</strong> the world ranging from 0% in North<br />
Alaska and Canada to 94% in Costa Rica and Guatemala. Once the host acquires the<br />
infection by ingestion, T. gondii crosses the intestinal epithelium, disseminates into the<br />
deep tissues and traverses biological barriers to reach sites where it causes severe<br />
pathology. Normally, the immune response efficiently prevents the dissemination <strong>of</strong><br />
the parasite. In immunocompromised hosts, however, such reactivation may be more<br />
frequent, leading to a massive and potentially fatal recrudescence. Studies <strong>of</strong> prevalence<br />
<strong>of</strong> Toxoplasmosis in patients with neoplasms are scarce. This report represents the first<br />
prevalence study <strong>of</strong> Toxoplasmosis in cancer patients in Egypt.<br />
Methods: Blood samples were collected from 150 immunocompromised patients<br />
having different types <strong>of</strong> malignancies as well as 50 immunocompetent individuals as a<br />
control group, to assess the seroprevalence <strong>of</strong> anti-T.gondii antibodies. The “CTK<br />
biotech Onsite Toxo IgG/IgM Rapid Test Cassettes” was used according to the<br />
manufacturer’s enclosed manual for the detection <strong>of</strong> infection.<br />
Results: In our study, 34 cases <strong>of</strong> toxoplasmosis were detected. Toxoplasmosis was<br />
higher in patients’ group than in control group. Among cancer patients, prevalence <strong>of</strong><br />
T.gondii was significantly higher (20% & 4% for IgG and IgM respectively) compared<br />
with control (8% and 2%) (p = 0.003). Toxoplasmosis was higher in patients having<br />
solid organ tumors (24%) than in patients with haematological malignancies (12%)<br />
(p = 0.06). On the other hand, the type <strong>of</strong> treatment doesn’t seem to affect the<br />
prevalence <strong>of</strong> T.gondii. The prevalence in patients treated with chemotherapy was equal<br />
to the prevalence in those treated with irradiation (20% both).<br />
Conclusions: T. gondii is an opportunistic parasite that remains a serious cause <strong>of</strong><br />
morbidity and mortality in immunocompromised patients. However, screening for this<br />
parasite is usually omitted in non-HIV immunocompromised persons such as patients<br />
having malignancy. Proper diagnosis and treatment <strong>of</strong> these patients before starting<br />
treatment is mandatory as it can save their lives.<br />
Legal entity responsible for the study: Faculty <strong>of</strong> Medicine, Cairo University<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1384P<br />
Evaluation <strong>of</strong> clinical outcomes <strong>of</strong> her2/neu positive breast<br />
cancer patients treated with adjuvant trastuzumab in two<br />
oncology centers from middle income coutries<br />
H.A. Perroud 1 , C.M. Alasino 2 , A. Eniu 3 , N. Antone 3<br />
1 Institute <strong>of</strong> Experimental Genetics, School <strong>of</strong> Medical Sciences, National<br />
University <strong>of</strong> Rosario, Rosario, Argentina, 2 Clincal <strong>Oncology</strong> Department, Italian<br />
Hospital <strong>of</strong> Rosario, Rosario, Argentina, 3 Department <strong>of</strong> Breast Tumors, Ion<br />
Chiricuta <strong>Oncology</strong> Institute-IOCN, Cluj Napoca, Romania<br />
Background: Adjuvant Trastuzumab dramatically reduces the risk <strong>of</strong> relapse for Her2<br />
positive breast cancer patients (BCP). However, in middle income countries, such as<br />
Romania (Ro) and Argentina (Ar), the treatment <strong>of</strong> HER2 + BCP remains under the<br />
constraints <strong>of</strong> health care resources and poses unique challenges due to lack <strong>of</strong><br />
resources. The aim <strong>of</strong> this work is to compare time <strong>of</strong> initiation <strong>of</strong> Trastuzumab (TIT)<br />
in HER2 + BCP and its correlation with clinical outcome at 5 years in two medical<br />
centers: Institute <strong>of</strong> <strong>Oncology</strong> "Ion Chiricuta" Cluj-Napoca [Ro] and Hospital Italiano<br />
de Rosario [Ar].<br />
Methods: This was an observational, retrospective study based on medical records <strong>of</strong><br />
primary BCP (Hormone receptor [HR], Her2/Neu+) and included 43 patients (n = Ar:<br />
25; Ro: 18) with at least 5 years <strong>of</strong> follow up from both institutions. According to their<br />
clinical outcome (CO) at 5 years <strong>of</strong> the primary treatment, each patient was classified<br />
in two primary groups: disease free or relapsed.<br />
Results: Mean age <strong>of</strong> patients was 54 (range: 33-91) and mean stage <strong>of</strong> disease was II<br />
(range: I-III). Nonstatistical differences according to age and disease stage were found<br />
between groups. The most frequent histology was ductal invasive carcinoma (Ar: 12/25;<br />
Ro: 18/18; p = 0.007).All patients received surgery as primary treatment. Fourteen (14)<br />
patients received neo-adjuvant treatment (Ar: 7/25; Ro: 7/18; p = 0.167) and twenty<br />
two (22) patients received radiotherapy (Ar: 18/25; Ro: 4/18; p = 0.002). Most patients<br />
received adjuvant chemotherapy based on anthracyclines schemes (p = 0.139) and all<br />
patients received Trastuzumab. Median TIT was 8 months (range: 2-18) [Ar: 7 (range:<br />
2-17); Ro: 11 (range: 4-18), p = 0.001]. At 5 years <strong>of</strong> follow-up 18 patients relapsed (Ar:<br />
8/25; Ro: 10/18; p = 0.148). There were no association between CO and TIT in both<br />
group <strong>of</strong> patients.<br />
Conclusions: The delay on initiation <strong>of</strong> Trastuzumab, in our limited series, did not<br />
prove to interfere in the risk <strong>of</strong> relapse in HR-HER2 + BCP. Larger studies are needed<br />
to address this issue.<br />
Legal entity responsible for the study: N/A<br />
Funding: Institute <strong>of</strong> Experimental Genetics, National University <strong>of</strong> Rosario,<br />
Argentina; Italian Hospital <strong>of</strong> Rosario, Argentina; and Institute <strong>of</strong> <strong>Oncology</strong> "Ion<br />
Chiricuta" Cluj-Napoca, Romania.<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1385P<br />
abstracts<br />
Breast cancer demographics, screening and survival<br />
outcome at a regional Australian cancer centre:<br />
a retrospective study<br />
H.A. Mandaliya 1 , C. Oldmeadow 2 , T. Evans 3 ,P.Troke 4 , M. George 1<br />
1 Medical <strong>Oncology</strong>, North West Cancer Center, Tamworth, Australia, 2 Clinical<br />
Research Design, Information Technology and Statistical Support (CReDITSS),<br />
Hunter Medical Research Institute, Newcastle, Australia, 3 School <strong>of</strong> Medicine and<br />
Public Health, Faculty <strong>of</strong> Health, University <strong>of</strong> Newcastle, Newcastle, Australia,<br />
4 Cancer Information, Hunter New England Clinical Cancer Registry, Newcastle,<br />
Australia<br />
Background: Breast cancer is the third most commonly diagnosed cancer in Australia<br />
and the fourth most common cause <strong>of</strong> death from cancer. This study aimed to describe<br />
patient demographics and estimate survival for patients treated at a regional Australian<br />
cancer centre.<br />
Volume 27 | Supplement 6 | 2016<br />
doi:10.1093/annonc/mdw387 | vi479
abstracts<br />
Methods: A retrospective cohort study was conducted <strong>of</strong> breast cancer patients who<br />
had been treated at North West Cancer Centre from the period <strong>of</strong> 2008 to 2015.<br />
Demographic variables were summarised and estimates <strong>of</strong> Kaplan-Meier survival for<br />
the cohort and breast cancer subtypes were generated. Cox models were used to<br />
investigate time to breast cancer-related death for cancer stage, grade, age and distance<br />
from the treatment centre. Hazards <strong>of</strong> death associated with time from diagnosis until<br />
treatment and surgery were also assessed.<br />
Results: The cohort comprised <strong>of</strong> 285 patients that were treated at North West Cancer<br />
Centre. Mean and median age was 60 years (range 35-95); three were males. One<br />
hundred and twenty-six (44%) patients had screen-detected breast cancer. One<br />
hundred and fifty-two (53%) patients had breast conservative surgeries and 117 (41%)<br />
underwent mastectomies. Intrinsic histology subtypes Luminal A, Luminal B HER2<br />
positive, Luminal B HER2 negative, HER2 over-expression and triple negative<br />
(basal-like) were 75 (29%), 37 (14%), 98 (37%), 12 (4.6%) and 41 (16%) respectively.<br />
One hundred and fifty-six (55%) patients received adjuvant chemotherapy, 189 (66%)<br />
patients has been on adjuvant endocrine therapy and 149 (52%) patients had adjuvant<br />
radiotherapy. Five-year observed survival was 86.9% (95% CI 80.7 - 91.3). Adjusted<br />
analyses indicated that increasing stage and age were significantly associated with<br />
greater hazard <strong>of</strong> death (P < 0.001). There was insufficient evidence to suggest<br />
increasing time from diagnosis until surgery and treatment were associated with hazard<br />
<strong>of</strong> death.<br />
Conclusions: Survival outcome <strong>of</strong> breast cancer at our regional centre is relatively<br />
comparable to Australia wide breast cancer survival. Increasing age and breast cancer<br />
stage were associated with a greater hazard <strong>of</strong> death in adjusted analyses.<br />
Legal entity responsible for the study: Hunter New England Human Research Ethics<br />
Committee<br />
Funding: North West Cancer Centre, Tamworth, NSW 2340 Australia<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1386P<br />
Breast cancer fast-track programme - Evolution and<br />
guidelines to prioritize patient referral<br />
M.T.M. Martinez 1 , I. Chirivella Gonzalez 1 , K. Pinilla 1 , A. Fernandez 1 , A. Viala 1 ,<br />
A. Iranzo 1 , A. Caballero 2 , J. Calvete 2 , A. Sanmartin 3 , J. Navarro 3 , B. Bermejo 1 ,<br />
A. Lluch-Hernandez 1<br />
1 Hematology and Medical <strong>Oncology</strong>, Hospital Clinico Universitario de Valencia,<br />
Valencia, Spain, 2 Department <strong>of</strong> Surgery, Senology, Hospital Clinico Universitario<br />
de Valencia, Valencia, Spain, 3 Hospital Clinico Universitario de Valencia, Valencia,<br />
Spain<br />
Background: In our country there are a breast cancer (BC) Screening (45-70) but<br />
actually some patients are diagnosted out <strong>of</strong> it so Breast cancer fast-track program<br />
(BCFP) has proved to be an effective system to efficiently assess symptomatic women to<br />
prompt diagnose. The aim <strong>of</strong> this study is to develop a clinical prediction rule in order<br />
to better identify BC to reduce time interval between patient referral by the primary<br />
care (PC) physician to the specialist, diagnosis <strong>of</strong> BC, and start treatment.<br />
Methods: From 2009 to 2015 we analyzed retrospectively all proposals sent from PC<br />
with suspected BC to the oncology coordinator at the Clinico-Malvarrosa Health<br />
Department in Valencia. We studied the different variables for which patients were<br />
referred to BCFP and analyzed if any <strong>of</strong> them could be related to increased chance <strong>of</strong><br />
developing BC. Variables recorded include the presence/absence <strong>of</strong> lump,<br />
inflammation, pain, ulceration, skin change, nipple changes and secretion <strong>of</strong> the<br />
nipple, nodularity and family history. To investigate a grade <strong>of</strong> association we<br />
performed a Pearson Chi Square test using STATA program.<br />
Results: 810 patients were considered for the study. 156 were diagnosed with BC (19,<br />
3%). The mean <strong>of</strong> age was 65, 6 years ( 27- 94). 55 patients were between 45 and 70<br />
years and 34 out <strong>of</strong> them were going regularly screening. 78, 2%, were diagnosed with<br />
localized stage. Above the patients diagnosed with BC, mean <strong>of</strong> time till specialist<br />
assessment was 16,8 days (Standard Deviation, SD 10,9); 11,5 days (SD 13,7) were<br />
needed for histopathological diagnosis, and first treatment was administered after 26,5<br />
days (SD 18,2). Among the evaluated variables four were identified to be highly<br />
associated with BC: fixed chest lesion [Odds ratio, OR 12,7: IC 95% 7,8-20,7], lump<br />
lesion in women older than 50 years [OR 8.9: IC 95% 6,1-13,2], > 3 cm breast nodule<br />
[OR 8,2: IC 95% 5,3-12,8] and nipple secretion and retraction [OR 2,1: IC 95%<br />
1,3-3,1].<br />
Conclusions: The results show that the implementation <strong>of</strong> BCFP has managed to<br />
increase cooperation between the different healthcare pr<strong>of</strong>essionals involved in BC<br />
leading to a faster diagnosis <strong>of</strong> BC. We have identified four variables that are<br />
significantly associated with BC, aiming to decrease the evaluation time by the<br />
specialist and start earlier the treatment.<br />
Legal entity responsible for the study: N/A<br />
Funding: INCLIVA<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1387P<br />
Pain management nursing in oncologic hospital in Albania<br />
S. Enkelejda 1 , S. Diamant 2 , B. Maksim 3 , P. Edmond 4<br />
1 Public Health, Tirana University Faculty <strong>of</strong> Medicine, Tirana, Albania, 2 Pediatrics<br />
department, QSUT Mother Teresa Hospital Center. Qendra Spitalore Universitare<br />
"Nënë Tereza", Tirana, Albania, 3 Diagnostic and Imaging department, QSUT<br />
Mother Teresa Hospital Center. Qendra Spitalore Universitare "Nënë Tereza",<br />
Tirana, Albania, 4 Department <strong>of</strong> Diagnostics and Rehabilitation Medicine, Tirana<br />
University Faculty <strong>of</strong> Medicine, Tirana, Albania<br />
Background: Cancer pain management is still unsatisfactory, although some<br />
guidelines exist. This study aimed to evaluate knowledge, practices and perceived<br />
barriers regarding cancer pain management among nurses in oncologic hospital in<br />
Albania<br />
Methods: This was a cross-sectional study comprised <strong>of</strong> a questionnaire survey that<br />
was administered to nurses involved in the care <strong>of</strong> cancer patients. Questionnaire items<br />
covered pain assessment and documentation practices, knowledge regarding cancer<br />
pain management, the perceived barriers to cancer pain control, and processes<br />
perceived as the major causes <strong>of</strong> delay in opioid administration.<br />
Results: A total <strong>of</strong> 361 nurses participated in the study (9.97% (36) from them were<br />
males and 90.03% (325) were females). It was noticed a very strong significant<br />
correlation among the level <strong>of</strong> education that the nurses possess and the <strong>of</strong>fer <strong>of</strong> health<br />
care to cancer patients provide (OR = 3.1, 95%CI 1.5 – 6.1 p < 0.01). Only 9.41% <strong>of</strong> the<br />
nurses has answered correctly that the best way <strong>of</strong> administration <strong>of</strong> opioids in cancer<br />
patients is the oral way (The value <strong>of</strong> chi square test χ 2 = 1454.5 p < 0.01). It is reported<br />
that the majority <strong>of</strong> the participants (57%) have replied incorrectly that only the slight<br />
pain is treated with skin stimulation with a statistically significant change with the<br />
other categories <strong>of</strong> nurses’ answers (the value <strong>of</strong> chi square test is χ 2 = 208.6 p < 0.01).<br />
Conclusions: This study has provided a forecast over the knowledge, the approaches<br />
and the pain management <strong>of</strong> nurses that work in the oncologic hospital <strong>of</strong> Tirana,<br />
Albania. The results <strong>of</strong> the study have verified enormous information deficiencies and<br />
multiple barriers that nurses face while giving health care to cancer patients which may<br />
have negative impacts in the distribution <strong>of</strong> health care and poor quality <strong>of</strong> life. An<br />
effective educational policy for cancer ache management is required so as to develop<br />
nurses’ comprehension and clinical practices.<br />
Legal entity responsible for the study: N/A<br />
Funding: University <strong>of</strong> Medicine, Tirana, Albania<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1388P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Competencies <strong>of</strong> physicians in management and leadership<br />
for a better palliative care treatment<br />
O. Pampuri 1 , H. Zotaj 2<br />
1 Psychology, University <strong>of</strong> Tirana, faculty <strong>of</strong> social science, Tirana, Albania,<br />
2 Paliative care oncology, <strong>Oncology</strong> university center hospital, Tirana, Albania<br />
Background: • Assess current level <strong>of</strong> leadership and managerial competencies <strong>of</strong><br />
public health pr<strong>of</strong>essionals in our country, and; • Evaluation <strong>of</strong> the level <strong>of</strong> competence<br />
required (desired) governance and management <strong>of</strong> public health pr<strong>of</strong>essionals in our<br />
country. The current level <strong>of</strong> competence refers to the knowledge, skills and leadership<br />
skills and managerial control <strong>of</strong> public health pr<strong>of</strong>essionals.<br />
Methods: This international scientific study was conducted in three phases: •<br />
Exhaustive review <strong>of</strong> scientific literature; • Panel consensus (consensus development<br />
panel); • Delphi study type (Delphi survey). First, atransversal (cross-sectional) study<br />
was undertaken to enable pre-testing (piloting) <strong>of</strong> the instrument <strong>of</strong> international<br />
standardized assessment <strong>of</strong> competencies <strong>of</strong> leadership and management in a practical<br />
sample <strong>of</strong> public health pr<strong>of</strong>essionals in Tirana.<br />
Results: The average age in the group <strong>of</strong> male (N = 62) public health pr<strong>of</strong>essionals<br />
nationwide in this sample was 44.9 ± 10.6 years, while in women (N = 105) te average<br />
age <strong>of</strong> public health pr<strong>of</strong>essionals was 44.4 ± 9.9 years. The average value <strong>of</strong> the output<br />
aggregate full-scale instrument consisting <strong>of</strong> 52 questions was lower for the current<br />
level <strong>of</strong> power management compared to the level necessary (desired) powers in<br />
leading public health pr<strong>of</strong>essionals involved in this study nationwide in our country<br />
(138.4 ± 11.2 vs. 159.7 ± 25.3, respectively; P
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
effectively and efficiently. For this reason, education and competency-based training<br />
should definitely be included in all programs <strong>of</strong> continuing pr<strong>of</strong>essional development<br />
in our country. Results <strong>of</strong> the current study will enable comparability studies.<br />
Legal entity responsible for the study: The University <strong>of</strong> Medicine Tirana, Albania<br />
Funding: The study has been founded by my private grants.<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1390P<br />
Changing trends in HIV and cancer<br />
A. Fernández Ruiz 1 , R. Lastra del Prado 2 , P. Iranzo Gomez 2 , A. Rodrigo 2 ,<br />
A. Callejo Perez 2 , E. Quilez Bielsa 2 , M. Cruellas Lapeña 2 , M.J. Crusells Canales 3 ,<br />
A. Yubero Esteban 2 , N. Galan Cerrato 2 , J.J. Lambea Sorrosal 2 , L. Murillo Jaso 2 ,<br />
R. Andres Conejero 2 , P. Escudero Emperador 2 , E. Pujol Obis 2 , A. Saenz Cusi 2 ,<br />
D. Isla Casado 2<br />
1 Medical <strong>Oncology</strong>, Hospital Clinico Universitario Lozano Blesa, Zaragoza, Spain,<br />
2 Medical <strong>Oncology</strong>, Hospital Clinico Universitario Lozano Blesa, Zaragoza, Spain,<br />
3 Infectious Disease, Hospital Clinico Universitario Lozano Blesa, Zaragoza, Spain<br />
Background: New anti-retroviral therapies have changed the natural history <strong>of</strong> HIV.<br />
Oncological disease increases its role against infectious complications. Currently, they<br />
are one <strong>of</strong> the main reasons for death and hospitalization. AIDS-defining cancers<br />
(ADCs) are Kaposi’s sarcoma, non-Hodgkin lymphoma (NHL) and cervical<br />
carcinoma. The other cancers are non-AIDS defining (NADCs).<br />
Methods: An observational, retrospective study <strong>of</strong> a cohort <strong>of</strong> patients (p) with<br />
HIV-controlled in an Infectious Diseases unit and / or Medical <strong>Oncology</strong> for 11 years<br />
(2004 -2014) was conducted. ADCs and NADs are included, prognostic variables and<br />
epidemiological data were analyzed in relation to HIV and tumoral pathology.<br />
Results: Of 780 p HIV, 101 tumors were diagnosed in 91 p (12%). Males 71%. Mean<br />
age 46 years. In order <strong>of</strong> frequency: NHL 21 p (23%), lung carcinoma 13 p (14%),<br />
Kaposi’s sarcoma 9 p (10%), hepatocellular carcinoma 7p (8%). Second malignancy<br />
was targeted in 10 p (11%). Since 2009 diagnosis <strong>of</strong> NADCs, it has increased 54 p<br />
(65%) opposite to ADCs 37 p (40%) (p 0.027). 30 p (33%) have achieved complete<br />
response <strong>of</strong> the oncological pathology, 9p (11%) progression and 52 p (56%) death. 42<br />
p (46.2%) had viral load undetectable tumor diagnosis and 30p (33%) CD4 count> 500<br />
/ mm3. Of the 91 p, 48 p (53%) had HCV coinfection, 9p (10%) EBV or HPV and 50 p<br />
(54%) HBsAg positive. 57 p (63%) smokers> 20 cigarettes / day, 26 p (29%) habitual<br />
consumption alcohol. 40 p (44%) had diagnosed > 10 years with HIV and 20 p (22%)<br />
HIV diagnosis was made simultaneously to the tumor. SG from HIV diagnosis to<br />
exitus in ADCs was 2 years (CI 0- 6,597) and NADCs was 14 years (CI 12,7 - 15.3) (p<br />
0.007 0.397 HR CI 0.204 to 0.773).<br />
Conclusions: Our study confirms the appearence <strong>of</strong> malignancies earlier than in the<br />
general population and a significant increase in males not present in other studies. In<br />
relation to previous studies, we targeted the change <strong>of</strong> trend in the complications <strong>of</strong> p<br />
HIV. NADCs prevalence is progressively higher than the ADCs. In our series, it was<br />
observed a reduction risk <strong>of</strong> death 60,3 % for the patients with HIV infection and<br />
NADCs against the ADCs. It has also increased the prevalence <strong>of</strong> secondary tumors.<br />
Legal entity responsible for the study: N/A<br />
Funding: Department <strong>of</strong> Medical <strong>Oncology</strong><br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1391P<br />
Oral health disparities among privileged and underprivileged<br />
tribes <strong>of</strong> South India - a study on precancerous oral lesions<br />
prevalence<br />
K. Thiyyakandy<br />
Dentistry, Meethal Medical Sciences, Calicut, India<br />
Background: The tribal populations throughout India have remained socially and<br />
culturally alienated from mainstream Indian society until developmental and<br />
conservation activities in tribal areas forced interactions between them. Precancerous<br />
oral lesion is a major public health problem among South Indian tribes in Kerala state.<br />
The aim <strong>of</strong> this study was to explore oral health disparities among the underprivileged<br />
Paniya and the privileged Kurichiya tribes <strong>of</strong> Wayanad, South India from the<br />
Precancerous oral lesions perspective.<br />
Methods: A cross sectional survey was done among 600 Kurichiya and 400 Paniya<br />
tribal populations <strong>of</strong> Wayanad District, India from January 2013 to June 2013 after<br />
approval from the Institutional ethical committee. A pretested structured questionnaire<br />
was used to collect data regarding study variables. Oral health survey form was used to<br />
record the oromucosal status <strong>of</strong> the study population after obtaining informed consent.<br />
Results: In this study Precancerous oral lesions was found to be far more prevalent<br />
among the underprivileged Paniyas than among the privileged Kurichiyas (P < 0.0001).<br />
The prevalence <strong>of</strong> leukoplakia was found to be 42% amongst the Paniyas. This was<br />
much higher than the 2% found among the Kurichiyas.Among the Paniyas a<br />
statistically significant relationship was observed between Precancerous oral lesions and<br />
poor access to oral health care (P< 0.001).<br />
Conclusions: Oral cancer and precancerous oral lesions were at a very high among<br />
underprivileged Paniya community.Prevalence <strong>of</strong> precancerous oral lesions in the<br />
study population was due to tobacco usage and alcohol consumption and lack <strong>of</strong><br />
awareness regarding the deleterious effects <strong>of</strong> the products used. Regular oral<br />
examination by dental pr<strong>of</strong>essionals, dental health education and motivation to<br />
maintain oral hygiene should be insisted to improve the oral health status <strong>of</strong> this<br />
community.<br />
Legal entity responsible for the study: Khadeeja<br />
Funding: Meethal Dental Clinic<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1392P<br />
Geographical differences in preventable cancers in Turkey<br />
D. Yuce 1 ,M.Hayran 1 , S. Eser 2 , S. Uner 2<br />
1 Preventive <strong>Oncology</strong>, Hacettepe University Cancer Institute, Ankara, Turkey,<br />
2 Epidemiology, Hacettepe University Public Health Institute, Ankara, Turkey<br />
Background: Carcinogenic changes occur due to interactions between genetic,<br />
lifestyle-related, and environmental factors. Anti-cancer efforts should evaluate<br />
preventable risk factors to maintain a healthy life. Tobacco and obesity are the major<br />
preventable causes <strong>of</strong> cancer. We aimed to evaluate the contribution <strong>of</strong> them on cancer<br />
burden in Turkey.<br />
Methods: Population-attributable fractions were calculated according to Peto-Lopez,<br />
and Comparative Risk Assessment Collaborative Group Methods. Geographical<br />
distributions <strong>of</strong> PAFs were analyzed with ArcMap 10.4 GIS s<strong>of</strong>tware. Tobacco- and<br />
obesity-related cancers were determined according to IARC, and WCRF reports,<br />
respectively. Sex-specific relative risks were obtained from CPS-II, and standardized<br />
meta-analysis estimates and the Continuous Update Project. National cancer<br />
incidences in 2013 were used for calculating PAF cases. Since a 10-years <strong>of</strong> lag time was<br />
considered for the progression <strong>of</strong> cancer for obesity, prevalence rates were obtained<br />
from National Burden <strong>of</strong> Diseases and Cost-Effectiveness-Turkey 2003 Study. Duration<br />
from tobacco exposure to cancer is higher, but no previous qualified data was present,<br />
and same study was used to obtain smoking prevalence.<br />
Results: PAFs for tobacco and obesity were 60.4% (59.6-62.7%), and 11% (9.8-13.7%),<br />
respectively. Site-specific PAFs ranged between 29.8-91.7% and 2.2-67.9% for tobacco;<br />
and between 5.7-13.1% and 3.0-25.9% for obesity in males and females, respectively.<br />
PAFs showed geographical distribution variations. Western and southern parts <strong>of</strong><br />
Turkey were found to have greater numbers <strong>of</strong> preventable cancers. PAFs <strong>of</strong> tobaccoand<br />
obesity-related cancers<br />
Tobacco<br />
(PAF %)<br />
Table: 1392P<br />
abstracts<br />
Obesity<br />
(PAF %)<br />
M F M F<br />
Oral cavity 83.00 41.78 Colon 10.96 5.98<br />
Oesophageus 73.99 54.28 Rectum 5.69 3.01<br />
Stomach 32.16 5.96 Gall bladder 12.43 13.07<br />
Pancreas 39.28 18.02 Pancreas 7.35 5.98<br />
Larynx 87.04 67.89 Kidney 13.05 17.21<br />
Lung 91.66 67.28 Postmenopausal - 7.72<br />
breast<br />
Kidney 45.93 4.85 Endometrium - 25.88<br />
Bladder 52.85 17.67 Ovary - 3.59<br />
Leukemia 29.81 2.24<br />
Cervix - 9.40<br />
Conclusions: Determining possible interactions between geographical factors,<br />
distribution <strong>of</strong> risk factors, and prevalent cancers should guide preventive tasks against<br />
this important public health problem. According to our results western and southern<br />
parts <strong>of</strong> Turkey have the largest preventable numbers <strong>of</strong> tobacco and obesity related<br />
cancers.<br />
Legal entity responsible for the study: N/A<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
Volume 27 | Supplement 6 | 2016<br />
doi:10.1093/annonc/mdw387 | vi481
abstracts<br />
1393P<br />
Capecitabine/oxaliplatin (XELOX) versus XELOX plus<br />
bevacizumab (XELOX + bev) cost-effectiveness for metastatic<br />
colorectal cancer (mCRC) in first line treatment: a Brazilian<br />
public hospital analysis<br />
F.M. Peria 1 , A.Q. Ungari 1 , F.N. Dos Santos 1 , T. Lins-Almeida 2 , A.A. Nunes 1<br />
1 Internal Medicine Division <strong>of</strong> <strong>Oncology</strong>, HCRP Hospital das Clinicas Faculdade<br />
Medicina Universidade de Sao Paulo, Ribeirao Preto, Brazil, 2 Internal Medicine,<br />
HCRP Hospital das Clinicas Faculdade Medicina Universidade de Sao Paulo,<br />
Ribeirao Preto, Brazil<br />
Background: In the last decade there has been a significant improvement in response<br />
rates, progression-free survival and overall survival in metastatic colorectal cancer, a<br />
result <strong>of</strong> the development <strong>of</strong> new standard chemotherapy combinations and<br />
appearance <strong>of</strong> target-specific drugs, such as bevacizumab. Given the high cost <strong>of</strong> this<br />
therapy and since the resources available for health care are increasingly limited, this<br />
study aimed to carry out a cost-effectiveness analysis <strong>of</strong> XELOX protocol plus<br />
bevacizumab in first line treatment for patients with metastatic colorectal cancer from<br />
the perspective <strong>of</strong> a public hospital focused on care and education.<br />
Methods: The economic assessment employed a simple decision associated with<br />
Markov model, where costs are expressed in local currency (R$) and outcomes in<br />
months <strong>of</strong> life gained (MVG). This model used the TreeAge Pro 2013® s<strong>of</strong>tware. It has<br />
crafted a model <strong>of</strong> Markov state transition in time horizon <strong>of</strong> 60 months, each model<br />
cycle corresponded to three months. The cost data were collected retrospectively by<br />
micro-costing, and obtained through the internal electronic data system <strong>of</strong> Clinical<br />
<strong>Oncology</strong> Division.<br />
Results: The data effectiveness and the transition probabilities between the states health<br />
were calculated using data from clinical studies selected by systematic review. The<br />
difference improvement in months <strong>of</strong> life gained was 2.25 for an extra cost <strong>of</strong> R$<br />
47,833.57, which resulted in an increased cost-effectiveness ratio <strong>of</strong> R$ 21,231.43 per<br />
month gain life. In the sensitivity analysis, the variable that had the greatest impact was<br />
the effectiveness for clinical support health in XELOX. When this parameter was<br />
inserted in the model with the minimum value, the cost-effectiveness ratio increased R<br />
$ 7,814.47 and based on the maximum value that was for R$-29,614.12, meaning that<br />
in this scenario the XELOX + Bev has become dominated by XELOX.<br />
Conclusions: Considering the World Health Organization cost-effectiveness threshold<br />
(three times the value <strong>of</strong> GDP per capita), the XELOX + bev protocol it was not<br />
considered cost-effective.<br />
Clinical trial identification: This study was approved by the Research Ethics<br />
Committee <strong>of</strong> HCFMRP- USP identified as No. 956/2013.<br />
Legal entity responsible for the study: Ribeirao Preto Medical School - University <strong>of</strong><br />
Sao Paulo<br />
Funding: Ribeirao Preto Medical School - University <strong>of</strong> Sao Paulo<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1394P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Changing treatment patterns in advanced & metastatic<br />
melanoma towards targeted therapies in EU5 countries from<br />
2011 to 2015<br />
M. Bernhardt, N. Schmidt, K. Acker<br />
IMS Global <strong>Oncology</strong>, IMS Health GmbH & Co. OHG, Frankfurt, Germany<br />
Background: Real world data on treatment (TX) patterns in advanced and metastatic<br />
melanoma is <strong>of</strong> great value to demonstrate the use <strong>of</strong> novel therapy options. We<br />
provide an overview about changes in the melanoma TX patterns in regard to novel<br />
targeting drugs that recently entered the market.<br />
Methods: This study is based on IMS <strong>Oncology</strong> Analyzer, a quarterly physician<br />
panel survey including anonymous retrospective patient (PT) data about disease and<br />
TX history, across all cancer types. Melanoma PTs treated within 2011, 2013 and 2015<br />
in EU5 countries (France, Germany, Italy, Spain and UK) were analyzed.<br />
Results: The percentage <strong>of</strong> chemotherapy (CT) receiving PTs decreased from to 68.4%<br />
in 2011, 43.3% in 2013 to 9.0% in 2015. In contrast, targeted therapies against members<br />
<strong>of</strong> the MAPK pathway increased from 5.3% in 2011, to 37.9% in 2013 and to ∼45.0% in<br />
2015. In parallel, diagnostic test rates for BRAF increased to 94% in 2015. The number<br />
<strong>of</strong> PTs receiving immuno-oncology therapies as CTLA-4 inhibitors increased from<br />
∼10% in 2011 and 2013 to ∼32% in 2015. In Addition, inhibitors <strong>of</strong> PD-1/PD-L1<br />
entered the market in 2015 and gained market shares <strong>of</strong> 9.0%.<br />
Table: 1394P TX landscape <strong>of</strong> stage III/IV melanoma PTs *PTs<br />
included in a clinical trial or don’t receiving a systemic therapy were<br />
not considered<br />
TX regimens 2011 2013 2015<br />
Base (number <strong>of</strong> sample<br />
PTs)<br />
All PTs*<br />
(244)<br />
All PTs*<br />
(346)<br />
All PTs*<br />
(587)<br />
MEK&BRAF 5.3% 37.9% 44.8%<br />
CTLA-4 10.7% 10.1% 31.9%<br />
PD1/PD-L1 - - 9.0%<br />
CT 68.4% 43.3% 9.0%<br />
Others 15.6% 8.7% 5.3%<br />
Share <strong>of</strong> BRAF tested PTs - 87.6% 94.2%<br />
Conclusions: This study indicates a switch towards targeted therapies accounting for<br />
more than 80% <strong>of</strong> the melanoma treatments in 2015. Two particular classes <strong>of</strong><br />
therapies, small molecules targeting the MAPK signaling pathway and<br />
immune-oncology agents replace conventional CTs. Besides MEK&BRAF inhibitors<br />
that already showed significant market shares in 2013, particularly antibodies against<br />
CTLA-4 or the PD-1/PD-L1 pathway are more commonly used in the TX <strong>of</strong> melanoma<br />
PTs. However, a population <strong>of</strong> 6% is still not tested for BRAF mutations. Therefore,<br />
further research is necessary to understand a missing uptake <strong>of</strong> novel TX options in the<br />
clinical practice.<br />
Legal entity responsible for the study: IMS Health GmbH & Co. Ohg<br />
Funding: IMS Health GmbH & Co. Ohg<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
vi482 | abstracts Volume 27 | Supplement 6 | 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong> 27 (Supplement 6): vi483–vi492, 2016<br />
doi:10.1093/annonc/mdw388<br />
sarcoma<br />
1395O<br />
Randomized phase 3, multicenter, open-label study<br />
comparing ev<strong>of</strong>osfamide (Evo) in combination with<br />
doxorubicin (D) vs. D alone in patients (pts) with advanced<br />
s<strong>of</strong>t tissue sarcoma (STS): Study TH-CR-406/SARC021<br />
1396O<br />
Results <strong>of</strong> a prospective randomized phase III T-SAR trial<br />
comparing trabectedin vs best supportive care (BSC) in<br />
patients with pretreated advanced s<strong>of</strong>t tissue sarcoma<br />
(ASTS)<br />
W. Tap 1 , Z. Papai 2 , B. van Tine 3 , S. Attia 4 , K. Ganjoo 5 , R.L. Jones 6 , S. Schuetze 7 ,<br />
D. Reed 8 , S.P. Chawla 9 , R. Riedel 10 , A. Krarup-Hansen 11 , A. Italiano 12 ,<br />
P. Hohenberger 13 , G. Grignani 14 , L. Cranmer 15 , T. Alcindor 16 , A. Lopez-Pousa 17 ,<br />
T. Pearce 18 , S. Kroll 18 , P. Sch<strong>of</strong>fski 19<br />
1 <strong>Oncology</strong>, Memorial Sloan-Kettering Cancer Center, New York, NY, USA,<br />
2 <strong>Oncology</strong>, Semmelweis University Kutvolgyi Clinical Center, Budapest, Hungary,<br />
3 Division <strong>of</strong> <strong>Oncology</strong>, Washington University School <strong>of</strong> Medicine, St Louis, MO,<br />
USA, 4 Hematology/<strong>Oncology</strong>, Mayo Clinic, Jacksonville, FL, USA, 5 <strong>Oncology</strong>,<br />
Stanford University Medical Center, Stanford, CA, USA, 6 Medical <strong>Oncology</strong>, Royal<br />
Marsden Hospital, London, UK, 7 <strong>Oncology</strong>, University <strong>of</strong> Michigan, Ann Arbor, MI,<br />
USA, 8 Pediatrics, H. Lee M<strong>of</strong>fitt Cancer Center University <strong>of</strong> South Florida, Tampa,<br />
FL, USA, 9 Med. <strong>Oncology</strong>, Sarcoma <strong>Oncology</strong> Center, Santa Monica, CA, USA,<br />
10 <strong>Oncology</strong>, Duke University Medical Center, Durham, NC, USA, 11 Clinical<br />
Medicine, Herlev, Gent<strong>of</strong>te, Denmark, 12 Medical <strong>Oncology</strong>, Institute Bergonié,<br />
Bordeaux, France, 13 Dept. <strong>of</strong> Surgery, Universitätsklinikum Mannheim, Mannheim,<br />
Germany, 14 <strong>Oncology</strong>, Istituto di Candiolo-IRCCS-Fondazione Piemontese per la<br />
Ricerca sul Cancro-Onlus, Candiolo, Italy, 15 <strong>Oncology</strong>, Fred Hutchinson Cancer<br />
Research Center, Seattle, WA, USA, 16 <strong>Oncology</strong>, McGill University Health Center<br />
The Montreal General Hospital, Montreal, QC, Canada, 17 Research, Hospital de la<br />
Santa Creu i Sant Pau, Barcelona, Spain, 18 Clinical Development, Threshold<br />
Pharmaceuticals, Inc., South San Francisco, CA, USA, 19 General Medical<br />
<strong>Oncology</strong>, University Hospitals Leuven - Campus Gasthuisberg, Leuven, Belgium<br />
A. Le Cesne 1 , J-Y. Blay 2 , D. Cupissol 3 , A. Italiano 4 , C. Delcambre 5 , N. Penel 6 ,<br />
N. Isambert 7 , C. Chevreau 8 , E. Bompas 9 , F. Bertucci 10 , L. Chaigneau 11 ,<br />
S. Piperno-Neumann 12 , S. Salas 13 , M. Rios 14 , C. Guillemet 15 , J-O. Bay 16 ,I.<br />
L. Ray-Coquard 17 , O. Mir 1 , L. Haddag 1 , S. Foulon 1<br />
1 Medicine, Institut de Cancérologie Gustave Roussy, Villejuif, France, 2 University<br />
Claude Bernard Lyon I, Centre Léon Bérard, Lyon, France, 3 Medicine, Clinique Val<br />
d’Aurelle, Montpellier, France, 4 Medical <strong>Oncology</strong>, Institute Bergonié, Bordeaux,<br />
France, 5 Medicine, Centre Francois Baclesse, Caen, France, 6 Medical <strong>Oncology</strong>,<br />
Centre Oscar Lambret, Lille, France, 7 Medicine, Centre Georges-François Leclerc<br />
(Dijon), Dijon, France, 8 <strong>Oncology</strong>, Centre Claudius-Regaud, Toulouse, France,<br />
9 Department <strong>of</strong> Medical <strong>Oncology</strong>, Institut de Cancérologie de l’Ouest - René<br />
Gauducheau, Saint-Herblain, France, 10 Oncologie Médicale, Institute Paoli<br />
Calmettes, Marseille, France, 11 Medicine, CHU Besançon, Hôpital Jean Minjoz,<br />
Besançon, France, 12 Medicine, Institut Curie, Paris, France, 13 Medicine, CHU La<br />
Timone Adultes, Marseille, France, 14 Medecine, Institut de Cancérologie de<br />
Lorraine, Nancy, France, 15 Medecine, Centre Henri Becquerel, Rouen, France,<br />
16 Medecine, CHU Estaing, Clermont-Ferrand, France, 17 Département<br />
d’Oncologie Médicale Adulte, Centre Léon Bérard, Lyon, France<br />
abstracts<br />
© European Society for Medical <strong>Oncology</strong> 2016. Published by Oxford University Press on behalf <strong>of</strong> the European Society for Medical <strong>Oncology</strong>.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com.
abstracts<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
1397O<br />
The nationwide cohort <strong>of</strong> 26,883 patients with sarcomas<br />
treated in NETSARC reference network between 2010 and<br />
2015 in France: major impact <strong>of</strong> multidisciplinary board<br />
presentation prior to 1st treatment<br />
J-Y. Blay 1 , A. Le Cesne 2 , N. Penel 3 , E. Bompas 4 , C. Chevreau 5 , F. Duffaud 6 ,<br />
M. Rios 7 , P. Kerbrat 8 , D. Cupissol 9 , P. Anract 10 , J-E. Kurtz 11 , C. Lebbe 12 ,<br />
F. Bertucci 13 , S. Piperno-Neumann 14 , P. Rosset 15 , N. Isambert 16 ,<br />
P. Dubray-Longeras 17 , F. Ducimetière 1 , J-M. Coindre 18 , A. Italiano 19<br />
1 University Claude Bernard Lyon I, Centre Léon Bérard, Lyon, France, 2 Medicine,<br />
Institut de Cancérologie Gustave Roussy, Villejuif, France, 3 Medical <strong>Oncology</strong>,<br />
Centre Oscar Lambret, Lille, France, 4 Department <strong>of</strong> Medical <strong>Oncology</strong>, Institut de<br />
cancérologie de l’Ouest - René Gauducheau, Saint-Herblain, France, 5 Medical<br />
<strong>Oncology</strong>, Institut Universitaire du Cancer -Toulouse- Oncopole, Toulouse,<br />
France, 6 Medical <strong>Oncology</strong>, Centre Hospitalier Universitaire Timone, Marseille,<br />
France, 7 <strong>Oncology</strong>, Institut de Cancérologie de Lorraine - Alexis Vautrin,<br />
Vandoeuvre Les Nancy, France, 8 Medical <strong>Oncology</strong>, Centre Eugene - Marquis,<br />
Rennes, France, 9 Medicine, ICM Regional Cancer Institute <strong>of</strong> Montpellier,<br />
Montpellier, France, 10 Orthopedic surgery, Assistance Publique Hôpitaux de Paris,<br />
Hôpital Cochin, Paris, France, 11 Medical <strong>Oncology</strong>, C.H.U. Hautepierre,<br />
Strasbourg, France, 12 Dermatology, Assistance Publique Hôpitaux de Paris,<br />
Hôpital Saint-Louis, Paris, France, 13 Medical <strong>Oncology</strong>, Institute Paoli Calmettes,<br />
Marseille, France, 14 Medicine, Institut Curie, Paris, France, 15 Orthopedic surgery,<br />
CHRU Trousseau, Tours, France, 16 Medicine, Centre Georges-François Leclerc<br />
(Dijon), Dijon, France, 17 Medical <strong>Oncology</strong>, Centre Jean Perrin, Clermont-Ferrand,<br />
France, 18 Pathology, Institute Bergonié, Bordeaux, France, 19 Medical <strong>Oncology</strong>,<br />
Institute Bergonié, Bordeaux, France<br />
Methods: Seven in vitro LPS cell line models <strong>of</strong> differentiation were established.<br />
Forty-nine patient samples derived from primary and matching recurrent,<br />
retroperitoneal WDLPS and DDLPS samples, were identified through a search <strong>of</strong> the<br />
Royal Marsden Hospital LPS database. Gene expression pr<strong>of</strong>iling <strong>of</strong> the LPS cell lines<br />
and their differentiated counterparts, the patient samples and adipose tissue acting as<br />
control, was performed. Differentially expressed genes linked to the differentiation<br />
process were identified through bioinformatics analyses, including comparisons with<br />
publically available expression data for LPS.<br />
Results: The enhancer <strong>of</strong> zeste homolog 2 (EZH2) was found to be differentially<br />
expressed between WDLPS and DDLPS (higher expression in DDLPS). This<br />
differential expression was confirmed at RNA (qRT-PCR) and protein (western blot)<br />
levels. Transient reduction <strong>of</strong> EZH2 levels in LPS cell lines using RNA interference, in<br />
combination with a cocktail <strong>of</strong> agents known to cause differentiation, including steroids<br />
and insulin, led to a more differentiated phenotype, which was beyond the level<br />
achieved by the differentiation medium alone. The small molecule EZH2 inhibitor<br />
(EZH2i) GSK343 decreased cell line growth that was associated with reduction <strong>of</strong> the<br />
histone mark H3K27me3. Combining EZH2i with the differentiation medium resulted<br />
in both enhanced differentiation and growth inhibition.<br />
Conclusions: For the first time we demonstrate that inhibition <strong>of</strong> the epigenetic target<br />
EZH2 in WD/DD LPS leads to both enhanced differentiation and growth inhibition in<br />
vitro. The efficacy <strong>of</strong> this dual action is currently being evaluated clinically, in a number<br />
<strong>of</strong> Phase I/ II trials, recruiting patients with solid tumours including those with<br />
DDLPS.<br />
Legal entity responsible for the study: The Institute <strong>of</strong> Cancer Research<br />
Funding: Wellcome Trust UK<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1399PD<br />
PD1 and PDL1 expression, tumoral microenvironment (TME)<br />
characterization and clinical implication in localized<br />
osteosarcoma<br />
E. Palmerini 1 , C. Agostinelli 2 , P. Picci 1 , S. Pileri 3 , P. Lollini 4 , K. Scotlandi 1 ,<br />
M.S. Benassi 1 , S. Ferrari 1<br />
1 Muscoloskeletal <strong>Oncology</strong>, Istituto Ortopedico Rizzoli, Bologna, Italy,<br />
2 Hematology, Policlinico S. Orsola-Malpighi, Bologna, Italy, 3 Haematopathology<br />
Unit, European Institute <strong>of</strong> <strong>Oncology</strong>, Milan, Italy/Bologna; University School <strong>of</strong><br />
Medicine, Bologna, Italy, 4 Cancerology, Policlinico S.Orsola-Malpighi-"Giorgio<br />
Prodi" - C.I.R.C., Bologna, Italy<br />
Background: PD1/PDL1 immune checkpoint blockade provides clinical benefits in a<br />
variety <strong>of</strong> solid tumors. Scarce are data on PD1/PDL1 pathway and immunological<br />
infiltrates in osteosarcoma. We hypothesized that immune infiltrates were associated<br />
with superior survival, and examined a primary osteosarcoma tissue microarrays<br />
(TMA) to test this hypothesis.<br />
Methods: Biopsies from 129 pts, prospectively treated from 04/2001 to 11/2006<br />
(protocol ISG-OS1), were analyzed. TMA from representative areas were assembled.<br />
Clinical and pathological characteristics at diagnosis, immunological characterization<br />
(CD8, CD4, CD3, FOXP3, CD20, CD68) <strong>of</strong> TME, PD-1 expression on TME, and<br />
PD-L1 both on tumor (t) cells and TME were correlated with pts outcome.<br />
Results: 86/129 pts had adequate staining for all markers. Median age: 16 (range 4-39);<br />
high LDH: 36/86; high alkaline phosphatase (AP): 18/86. All pts underwent<br />
neoadjuvant chemotherapy and surgery. A good pathologic response (≥90% necrosis)<br />
was achieved by 45/86 pts. The IHC results are reported in the table.<br />
1398PD<br />
Epigenetic modulation in well differentiated (WD) and<br />
dedifferentiated (DD) liposarcoma (LPS): a novel therapeutic<br />
approach<br />
PDL1<br />
(t)<br />
PD1<br />
(TME)<br />
Table: 1399PD<br />
PDL1<br />
(TME)<br />
CD8 CD3 FOXP3 CD20 CD68<br />
Pos 0 19 12 74 77 28 25 85<br />
Neg 86 67 74 12 9 56 61 1<br />
A. Constantinidou 1 , J. Selfe 1 , T. Khin 2 , S. Popov 1 , E. Missiaglia 3 , E. Aladowicz 1 ,<br />
R. Al-Saadi 1 , D. Olmos 4 , R.L. Jones 5 , D.C. Strauss 6 ,A.Hayes 6 , W. van der Graaf 5 ,<br />
I. Judson 5 , J. Shipley 1<br />
1 Molecular Pathology, Institute <strong>of</strong> Cancer Research ICR, London, UK,<br />
2 Histopathology, Royal Marsden Hospital NHS Foundation Trust, London, UK,<br />
3 Swiss Institute <strong>of</strong> Bioinformatics, Swiss Institute <strong>of</strong> Bioinformatics, Lausanne,<br />
Switzerland, 4 Prostate Cancer Clinical Research Unit, Spanish National Cancer<br />
Research Centre, Madrid, Spain, 5 Sarcoma Unit, Royal Marsden Hospital,<br />
London, UK, 6 Melanoma/Sarcoma Unit, Department <strong>of</strong> Surgery, The Royal<br />
Marsden Hospital, London, UK<br />
Background: Therapeutic options for advanced LPS, particularly WD and/or DD LPS<br />
remain extremely limited. The aim <strong>of</strong> this study was to identify novel therapeutic<br />
targets for WDLPS and DDLPS with the working hypothesis that gene products<br />
involved in maintaining the undifferentiated phenotype <strong>of</strong> LPS are potential targets for<br />
therapy.<br />
With a median follow-up <strong>of</strong> 8 years (range 1-13), the 5-year overall survival (5-yr OS)<br />
was 74% (95% CI 64-85). Univariate analysis showed better 5-yr OS for: a) good<br />
responders (good 89% vs poor 57%, p = 0.0001); b) pts with CD8 tumoral infiltrates<br />
(CD8+ 78% vs CD8- 50%, p = 0.003); c) pts with normal AP (AP normal 85% vs AP<br />
high 44%, p = 0.04). A non-significant inferior 5-yr OS was found in PDL1 (TME)<br />
positive cases (PDL1+ 58% vs PDL1- 77%, p = 0.14). No statistically significant<br />
difference in 5-yr OS according to PD1, FOXP3, CD68, CD20, age, gender or LDH.<br />
After multivariate analysis, good histologic response (p = 0.002) and CD8 infiltration<br />
(p = 0.02) were independently correlated with better survival.<br />
Conclusions: While this study confirms the importance <strong>of</strong> good pathologic response,<br />
our findings support the hypothesis that CD8+ T effector cells presence in TME at<br />
diagnosis confers superior survival for pts with localized osteosarcoma.<br />
Legal entity responsible for the study: Emanuela Palmerini<br />
Funding: Bologna University<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
vi484 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
1400PD<br />
Anti-PD1 therapy with nivolumab in sarcoma<br />
L. Paoluzzi 1 , A. Cacavio 1 , M. Ghesani 2 , A. Karambelkar 2 , A. Rapkiewicz 3 ,<br />
G. Rosen 1<br />
1 Medicine, New York University, New York, NY, USA, 2 Radiology, New York<br />
University, New York, NY, USA, 3 Pathology, New York University, New York, NY,<br />
USA<br />
Background: Manipulation <strong>of</strong> immune checkpoints such as CTLA4 or PD-1 with<br />
targeted antibodies, has recently emerged as an effective anticancer strategy in multiple<br />
malignancies. Sarcomas are a heterogeneous group <strong>of</strong> diseases in need <strong>of</strong> more effective<br />
treatments. Different subtypes <strong>of</strong> s<strong>of</strong>t tissue and bone sarcomas have been shown to<br />
express the PD-1 ligand.<br />
Methods: We retrospectively analyzed a cohort <strong>of</strong> patients (pts) with relapsed<br />
metastatic sarcomas, who were treated with nivolumab provided under a patient<br />
assistance program from the manufacturer. Pts underwent CT or PET/CT imaging at<br />
baseline and after at least 4 doses <strong>of</strong> nivolumab; RECIST criteria were used for response<br />
assessment.<br />
Results: Twenty-five pretreated pts with metastatic s<strong>of</strong>t tissue (STS, N = 22) or bone<br />
sarcoma (N = 3), received IV nivolumab 3mg/kg every 2 weeks. Median age was 58<br />
(24-78), male:female was 11:14; ECOG PS was 0-1 in 21 pts, 2 in 4 pts; the median<br />
number <strong>of</strong> previous treatments was three (0-6); the median number <strong>of</strong> nivolumab<br />
cycles was eight; seventeen pts concomitantly received the tyrosine kinase inhibitor<br />
pazopanib at 800mg daily. The most common side effect was grade 1 or 2 LFT<br />
elevations (10 pts, 8 <strong>of</strong> them receiving pazopanib); grade 3-4 toxicity occurred in 6 pts<br />
and included grade 4 pneumonitis, grade 3 colitis, grade 3-4 LFT elevations and grade 3<br />
anemia. Twenty pts receiving at least 4 cycles thus far were evaluable for response. We<br />
observed three partial responses (PR): one dedifferentiated chondrosarcoma, one<br />
proximal epithelioid sarcoma (on pazopanib) and one osteosarcoma <strong>of</strong> the maxillary<br />
sinus (on pazopanib); eight pts had stable disease (SD): one intimal sarcoma, one<br />
synovial sarcoma, one alveolar s<strong>of</strong>t part sarcoma, one osteosarcoma, on malignant<br />
peripheral nerve sheet tumor and three leiomyosarcoma; eight pts had progression <strong>of</strong><br />
disease (PD): three leiomyosarcoma, one synovial sarcoma, one mesenchymal<br />
chondrosarcoma, one dedifferentiated liposarcoma, one desmoplastic small round cell<br />
tumor and one undifferentiated pleomorphic sarcoma . Clinical benefit (PR + SD) was<br />
observed in 11 pts.<br />
Conclusions: Collectively, our data provide a rationale for further exploring the efficacy<br />
<strong>of</strong> nivolumab and other checkpoint inhibitors in s<strong>of</strong>t tissue and osteosarcoma.<br />
Legal entity responsible for the study: Luca Paoluzzi<br />
Funding: New York University<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1401PD<br />
Subgroup analysis <strong>of</strong> leiomyosarcoma (LMS) patients (pts)<br />
from a phase 3, open-label, randomized study <strong>of</strong> eribulin<br />
(ERI) versus dacarbazine (DTIC) in pts with advanced<br />
liposarcoma (LPS) and LMS<br />
J-Y. Blay 1 , P. Sch<strong>of</strong>fski 2 , S. Bauer 3 , A. Krarup-Hansen 4 , C. Benson 5 ,<br />
D.R. D’Adamo 6 ,M.Guo 6 , R. Maki 7<br />
1 Université Claude Bernard, Centre Léon Bérard, Lyon, France, 2 Department <strong>of</strong><br />
General Medical <strong>Oncology</strong>, University Hospitals Leuven, Leuven, Belgium, 3 West<br />
German Cancer Center, University <strong>of</strong> Duisburg-Essen, Essen, Germany,<br />
4 Department <strong>of</strong> <strong>Oncology</strong>, Herlev Hospital-University <strong>of</strong> Copenhagen, Herlev,<br />
Denmark, 5 Sarcoma Unit, Royal Marsden Hospital NHS Foundation Trust,<br />
London, UK, 6 Eisai, Inc., Woodcliff Lake, NJ, USA, 7 Tisch Cancer Institute, Mount<br />
Sinai Medical Center, New York, NY, USA<br />
Background: A phase 3 study (Schöffski et al. Lancet 2016) comparing ERI with DTIC<br />
in pts with advanced LPS or LMS, showed significant improvement in overall survival<br />
(OS) for the ERI arm with a manageable toxicity pr<strong>of</strong>ile. This subgroup analysis<br />
evaluated the efficacy and safety <strong>of</strong> ERI in LMS pts.<br />
Methods: Pts aged ≥18 yrs with histologically confirmed, advanced LMS, and from 3<br />
geographic regions, were included. Pts with ECOG status ≤2 and ≥2 prior systemic<br />
treatment regimens, including an anthracycline, were randomized 1:1 to ERI (1.4 mg/<br />
m 2 , IV, on Day [D] 1 and D8) or DTIC (850, 1000, or 1200 mg/m 2 , IV, on D1) every<br />
21D until disease progression. OS, progression free survival (PFS), and safety were<br />
analyzed in the LMS subgroup.<br />
Results: 309 Pts with LMS (81% female; 80% 2 prior regimens (146 pts; 12.6 vs 11.5 mo,<br />
respectively, HR = 0.77 [95% CI 0.53–1.13]), with non-uterine disease (177 pts; 14.4 vs<br />
13.2 mo respectively, HR = 0.77 [95% CI 0.54–1.09]), and enrolled in geographic region<br />
1 (USA & Canada; 123 pts; 15.3 vs 13.0 mo, respectively, HR = 0.71 [95% CI 0.47–<br />
1.09]). PFS in LMS pts for ERI vs DTIC was similar (2.2 vs 2.6 mo, HR = 1.07, [95% CI<br />
0.84–1.38]). In the LMS subgroup, response rates were 5.1% and 7.2% in the eribulin<br />
and DTIC arms, respectively. In the ERI and DTIC arms, 99% and 98% <strong>of</strong> LMS pts<br />
had adverse events (AEs). Most frequent AEs in the ERI arm were neutropenia (46%),<br />
fatigue (46%), nausea (41%), and alopecia (33%). In the ERI and DTIC arms, 40% and<br />
38% had grade (G) 3 AEs, 25% and 18% had G4 AEs, and 5% and 2% had G5 AEs.<br />
Conclusions: In LMS pts, ERI was associated with activity comparable to the active<br />
drug DTIC. Outcome heterogeneity within the LMS subgroup may represent random<br />
variation or biologic differences in this sarcoma subtype.<br />
Clinical trial identification: NCT01327885<br />
Legal entity responsible for the study: Eisai Inc<br />
Funding: Eisai Inc<br />
Disclosure: J-Y. Blay: Honoraria: Novartis, GSK, Bayer, Roche, Pharmamar.<br />
Consulting/Advisory Role: Novartis, GSK, Bayer, Roche, Pharmamar. Research<br />
Funding: Novartis, GSK, Roche, Pharmamar. P. Sch<strong>of</strong>fski: Consulting: Swedish Orphan<br />
Biovitrium, Blueprint Medicines, Bayer, Boehringer Ingelheim, Piqur Therapeutics,<br />
Eisai, Eli Lilly, Adaptimmune, AstraZeneca, Philogen, Amcure, Novartis, Cristal<br />
Therapeutics. S. Bauer: Membership on an advisory board or Board <strong>of</strong> Directors:<br />
Blueprint Medicine, Lilly, Novartis, Pfizer, Bayer Corporate-sponsored research:<br />
Novartis, Ariad. C. Benson: Corporate-sponsored research: Investigator on company<br />
sponsored trials including Novartis, PharmaMar, Lilly. D.R. D’Adamo: Employment:<br />
Eisai Inc. Travel/Accommodations: Eisai Inc. M. Guo: Employment: Eisai Inc. Stock<br />
Ownership: Amgen Travel: Eisai Inc. R. Maki: Research Funding, Honoraria,<br />
Consulting: Eisai/Morphotek. All other authors have declared no conflicts <strong>of</strong> interest.<br />
1402PD<br />
abstracts<br />
Exposure-response <strong>of</strong> olaratumab for survival outcomes<br />
and safety when combined with doxorubicin in s<strong>of</strong>t tissue<br />
sarcoma (STS) patients<br />
R. Jones 1 ,G.Mo 2 , J.R. Baldwin 2 , R.D. Nichols 2 , R.L. Ilaria 2 , I. Conti 2 ,<br />
D.M. Cronier 3 , W.D. Tap 4<br />
1 <strong>Oncology</strong>, Fred Hutchinson Cancer Research Center, Seattle, WA, USA,<br />
2 <strong>Oncology</strong>, Eli Lilly and Company, Indianapolis, IN, USA, 3 <strong>Oncology</strong>, Eli Lilly and<br />
Company, Windlesham, UK, 4 <strong>Oncology</strong>, Memorial Sloan-Kettering Cancer Center,<br />
New York, NY, USA<br />
Background: Olaratumab (Olara), a recombinant human IgG1 monoclonal antibody,<br />
selectively binds human PGDFRα. Olara plus doxorubicin (Dox) improved survival vs<br />
Dox in a Phase 2 sarcoma trial (NCT01185964). We characterized the<br />
exposure-response relationship <strong>of</strong> Olara for progression free survival (PFS), overall<br />
survival (OS) and safety.<br />
Methods: PFS/ OS, pharmacokinetic (PK) and safety data from the 66 patients who<br />
received Olara on the phase 2 study were analyzed. The effect <strong>of</strong> Olara serum levels was<br />
explored using average serum concentration (Cavg) and trough serum concentration<br />
after cycle 1 (Cmin1). The PFS/OS data were analyzed using a matched case-control<br />
(MCC) analysis across quartiles <strong>of</strong> Olara serum levels and a time-to-event (survival)<br />
model with a constant baseline hazard and a Hill function to describe the effect <strong>of</strong><br />
Olara. The rate <strong>of</strong> treatment-emergent adverse events (TEAEs) was compared across<br />
quartiles <strong>of</strong> Olara exposure.<br />
Results: The MCC analysis using both Cavg and Cmin1 showed a benefit in PFS above<br />
the median Olara exposure (Cavg ≥ 175.2 µg/mL; Cmin1 ≥86.9 µg/mL), with patients<br />
progressing earlier in the lowest quartile (Cavg < 134.4 µg/mL; Cmin1 < 62.8 µg/mL). A<br />
consistent OS benefit was observed across the 3 upper quartiles. The survival models<br />
for PFS/OS yielded similar findings. The Olara half-maximum effective concentration<br />
estimates (PFS, ECavg50 + ECmin150 = 179 and 82.0 µg/mL; OS, 134 and 66.1 µg/mL)<br />
reflected the greater OS benefit. ECavg50 and ECmin150 corresponded to the median<br />
Cavg and Cmin1 for PFS and to the 25 th percentile <strong>of</strong> Cavg and Cmin1 for OS. The<br />
maximum predicted improvement in the hazard ratio for OS and PFS was 75% and<br />
65%, respectively. There was no increase in TEAEs with increasing Olara serum levels.<br />
Conclusions: Cmin1 and Cavg showed a similar predictive role for Olara effect. PFS/<br />
OS benefits occurred without a rate change in TEAEs across quartiles. The MCC and<br />
modeling analyses showed consistent results with maximum apparent/predicted<br />
benefit in OS achieved in the upper 3 quartiles and a risk <strong>of</strong> early progression in the<br />
lower quartile <strong>of</strong> Olara serum exposure. These results prompted a loading dose strategy<br />
in the ongoing phase 3 STS trial.<br />
Clinical trial identification: NCT01185964<br />
Legal entity responsible for the study: Eli Lilly and Company<br />
Funding: Eli Lilly and Company<br />
Disclosure: R. Jones, R.L. Ilaria: IMClone- Grant Consulting role with Eisai,<br />
Pharmamar, Merck, Adaptimmune, Immune design, Immodulon, Daiichi, Lilly, and<br />
Pfizer. G. Mo, J.R. Baldwin, R.D. Nichols, D.M. Cronier: Lilly – Employee. I. Conti:<br />
Lilly - Employee, Shareholder, Honorarium. W.D. Tap: Honorarium - Lilly, Plexxikon,<br />
Advaxis, Ariad, Boehringer Ingelheim, EMD Serono, Daiichi Sankyo, and Morphotek.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw388 | vi485
abstracts<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Table: 1403PD<br />
Characteristics Imatinib (n = 70) Sunitinib (n = 12) Pazopanib (n = 27) Total (n = 109)<br />
Drug levels (n) 290 75 31 396<br />
Drug levels per patient median (range) 3 (2-13) 2 (2-8) 3 (2-3) 3 (2-13)<br />
C min Measurement First Last First Last First Last First Last<br />
Adequate C min n (%) 29 (41) 42 (60) 7 (26) 20 (74) 5 (42) 8 (67) 41 (38) 70 (64)<br />
Patients with interventions n (%) 20 (29) 17 (63) 4 (33) 41 (38)<br />
Patients with adequate C min after intervention n (%) 19 (95) 13 (76) 3 (75) 35 (85)<br />
1403PD<br />
Optimizing the dose in cancer patients treated with<br />
imatinib, sunitinib and pazopanib<br />
N. Lankheet 1 , I.M. Desar 2 , S.F. Mulder 2 , D.M. Burger 1 , C.M.L. van Herpen 2 , W.T.<br />
A. van der Graaf 3 , N.P. van Erp 1<br />
1 Pharmacy, Radboud University Medical Centre Nijmegen, Nijmegen,<br />
Netherlands, 2 Medical <strong>Oncology</strong>, Radboud University Medical Centre Nijmegen,<br />
Nijmegen, Netherlands, 3 Medical <strong>Oncology</strong>, Royal Marsden NHS Foundation<br />
Trust, London, UK<br />
Background: Oral oncolytics imatinib (IMN), sunitinib (SNN) and pazopanib (PZN)<br />
show a high interpatient variability in pharmacokinetics. For IMN, SNN and PZN a<br />
relationship between plasma exposure and treatment outcome has been established,<br />
which supports the rationale for dose optimization <strong>of</strong> these drugs. The aim <strong>of</strong> this<br />
study was to monitor how many patients reached adequate trough levels (C min ) after<br />
dose optimization in daily practice.<br />
Methods: An observational study was performed in a cohort <strong>of</strong> patients treated with<br />
IMN, SNN or PZN <strong>of</strong> whom multiple drug levels were measured between August 2012<br />
and April 2016. Patients’ characteristics were collected by reviewing medical records.<br />
Drug levels were measured using LC-MS/MS and C min were estimated using the<br />
algorithm <strong>of</strong> Wang et al.<br />
Results: 396 trough levels were determined in 109 patients. Median sample frequency<br />
per patient was 3. During the first measurement only 38% <strong>of</strong> patients showed C min<br />
within the predefined target ranges: 52% <strong>of</strong> the patients showed a drug level below and<br />
10% above target range. Dose interventions were proposed in 72 (66%) patients and<br />
implemented in 41 (38%) patients. In 35 out <strong>of</strong> 41 patients (85%) dose interventions<br />
led to an adequate C min . Eventually, 64% <strong>of</strong> the total cohort reached an adequate C min .<br />
Conclusions: This study shows that dose optimization is an effective tool to reach<br />
adequate C min for patients treated with IMN, SNN and PZN. Initially, only 38% <strong>of</strong><br />
patients had an adequate C min . Of the patients undergoing dose intervention 85%<br />
reached an adequate C min . Plasma exposure awareness might add to the improvement<br />
<strong>of</strong> efficacy and toxicity <strong>of</strong> patients treated with IMN, SNN and PZN.<br />
Legal entity responsible for the study: Radboudumc<br />
Funding: Radboud University Medical Center<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1404PD<br />
Regorafenib (R) versus placebo (P) in s<strong>of</strong>t tissue sarcomas<br />
(STS): analysis <strong>of</strong> genetic prognostic and predictive factors<br />
T. Brodowicz 1 , B. Liegl-Atzwanger 2 , E. Tresch-Bruneel 3 , E. Bogart 3 , O. Mir 4 ,<br />
J-Y. Blay 5 , K. Kash<strong>of</strong>er 2 , A. Le Cesne 6 , R. Hamacher 1 , N. Penel 7<br />
1 Medical <strong>Oncology</strong>, Vienna General Hospital (AKH) - Medizinische Universität<br />
Wien, Vienna, Austria, 2 Pathology, Medical University Graz, Graz, Austria, 3 Unité<br />
de Méthodologie et Biostatistiques, Centre Oscar Lambret, Lille, France,<br />
4 Department <strong>of</strong> Medical <strong>Oncology</strong>, Institut Gustave Roussy, Villejuif, France,<br />
5 University Claude Bernard Lyon I, Centre Léon Bérard, Lyon, France, 6 Medical<br />
<strong>Oncology</strong>, Institut de Cancérologie Gustave Roussy, Villejuif, France, 7 Medical<br />
<strong>Oncology</strong>, Centre Oscar Lambret, Lille, France<br />
Background: REGOSARC, a double-blind randomized phase II trial compared the<br />
activity and safety <strong>of</strong> R vs P in four STS cohorts: liposarcoma, leiomyosarcoma,<br />
synovial sarcoma and other sarcomas. In non-adipocytic sarcomas, PFS/OS were 4.0<br />
[95%-CI: 2.6-5.5]/13.4 months [8.6-17.3] vs 1.0 [1.0-1.8]/9.0 months [6.8-12.5]<br />
(HR = 0.36 [0.26-0.53]/ = 0.67 [0.44-1.02] in R and P, respectively. R had no efficacy in<br />
the adipocytic cohort. Herein, we report the analysis <strong>of</strong> potential genetic prognostic<br />
and predictive factors <strong>of</strong> PFS and OS.<br />
Methods: Genetic changes were investigated by Ion Torrent Next Generation<br />
Sequencing to detect hotspot mutations in 50 genes frequently mutated in cancer (Ion<br />
AmpliSeq CancerHotspot Panel v2, CHP2) as well as mutations in the full coding<br />
sequence <strong>of</strong> VEGFR1-3, FGFR1, KIT, PDGFRB, RAF1, RET1, TIE2 and TP53.<br />
Prognostic factors (independent to treatment effect) and predictive factors (with<br />
positive interaction with treatment effect) have been identified using Kaplan-Meier<br />
method and Cox models.<br />
Results: The study population consisted <strong>of</strong> 134 patients (pts) (71 in R-/63 in P-arm).<br />
The most frequent gene alterations were: CHP2 genes alterations (42, 31%), TP53<br />
mutations (35, 26%), PDGFRB mutations (7, 5%), VEGFR1 (5, 4%), VEGFR2 (6, 4 %)<br />
and VEGFR3 mutations (5, 4%). Median OS was 12.0 months [7.2-16.6] vs 9.0<br />
[7.5-12.8], in the R and P arm, respectively. Only the KIT mutation was found to be<br />
prognostic (HR = 35.9 [4.0-324.0], p = 0.001, only 1 mutated tumor). No gene<br />
alteration was found to be predictive for OS. The median PFS was 3.7 months [2.1-5.4]<br />
vs 1.3 [1.0-1.8], respectively in the R- and P-arm. One prognostic factor for PFS was<br />
detected: FGFR1 mutations (HR = 18.0 [4.0-81.0], p < 0.001, gene mutated in 2 cases).<br />
No predictive factor was identified.<br />
Conclusions: Regorafenib is an active drug. None <strong>of</strong> the tested genes (VEGFR1,<br />
VEGFR2, VEGFR3, FGFR1, KIT, PDGFRB, RAF1, RET1, TIE2, TP53 and CHP2<br />
genes) was found to be predictive for PFS or OS. Combinatorial analysis and further<br />
subgroup testing is currently ongoing.<br />
Clinical trial identification: EudraCT 2012-005743-24<br />
Legal entity responsible for the study: Sarcoma Platform Austria & French Sarcoma<br />
Study Group<br />
Funding: Bayer<br />
Disclosure: T. Brodowicz: Lecture fee: Roche, Amgen, Bayer, Novartis, PharmaMar,<br />
Eisai Advisory Board: Amgen, Bayer, Novartis, Eisai. O. Mir: Consultant for:<br />
Astra-Zeneca, Amgen, Bayer, BMS, Novartis, Pfizer and Roche. J-Y. Blay: Advisory<br />
Board: Roche, Novartis, Bayer, MSD, Lilly, PharmaMar, Deciphera<br />
Corporate-sponsored Research: Roche, Novartis, Bayer, MSD, Lilly, PharmaMar. A. Le<br />
Cesne: Honoraria: Novartis, PharmaMar, Lilly, Pfizer. N. Penel: Research grant from<br />
Bayer HealthCare. All other authors have declared no conflicts <strong>of</strong> interest.<br />
1405PD<br />
Circulating vascular endothelial growth factor (VEGF) as<br />
prognostic factor <strong>of</strong> progression-free survival in patients<br />
with advanced chordoma receiving sorafenib: An analysis<br />
from a phase II trial <strong>of</strong> the French Sarcoma Group (GSF/<br />
GETO)<br />
L. Lebellec 1 , F. Bertucci 2 , E. Tresch-Bruneel 3 , E. Bompas 4 , Y. Toiron 5 , L. Camoin 5 ,<br />
O. Mir 6 , V. Laurence 7 , S. Clisant 8 , E. Decoupigny 3 , J-Y. Blay 9 , A. Gonçalves 2 ,<br />
N. Penel 1<br />
1 Medical <strong>Oncology</strong>, Centre Oscar Lambret, Lille, France, 2 Oncologie Médicale,<br />
Institute Paoli Calmettes, Marseille, France, 3 Clinical Research and Methodological<br />
Platform, Centre Oscar Lambret, Lille, France, 4 Department <strong>of</strong> Medical <strong>Oncology</strong>,<br />
Institut de cancérologie de l’Ouest - René Gauducheau, Saint-Herblain, France,<br />
5 Department <strong>of</strong> Molecular Pharmacology, Institute Paoli Calmettes, Marseille,<br />
France, 6 Department <strong>of</strong> Medical <strong>Oncology</strong>, Institut Gustave Roussy, Villejuif,<br />
France, 7 Medical <strong>Oncology</strong>, Institut Curie, Paris, France, 8 Clinical Research Unit,<br />
Centre Oscar Lambret, Lille, France, 9 Medical <strong>Oncology</strong>, Centre Léon Bérard,<br />
Lyon, France<br />
Background: Patients with advanced chordoma are <strong>of</strong>ten treated with tyrosine kinase<br />
inhibitors without any predictive factor to guide decision. We report herein the<br />
ancillary analysis <strong>of</strong> the predictive values <strong>of</strong> circulating pro/antiangiogenic biomarkers<br />
among patients included in the Angionext phase II trial and treated with sorafenib<br />
(NCT 00874874).<br />
Methods: Patients were treated with sorafenib 800 mg/day for 9 months, unless earlier<br />
occurrence <strong>of</strong> progression or toxicities. Six biomarkers (sE-Selectin, VEGF, VEGF-C,<br />
placental growth factor (PlGF), Thrombospondin, Stem Cell Factor (SCF)) were<br />
measured in 2 blood samples at baseline (day 1: D1) and day 7 (D7). Changes in levels<br />
<strong>of</strong> circulating biomarkers were analyzed with paired Student t-test. Prognostic value <strong>of</strong><br />
biomarkers for progression-free survival (PFS) was analyzed using univariate Cox<br />
model.<br />
Results: From May 2011 to January 2014, 26 out <strong>of</strong> 27 patients included in the original<br />
study were sampled, including 17 men and 9 women, with a median age <strong>of</strong> 64 years.<br />
The primary sites were sacrum (20, 78%), mobile spine and skull base (3 each, 11%).<br />
50% <strong>of</strong> patients had metastatic disease (13/26). After central radiological review, the<br />
9-month PFS rate was 72.9% (95%-CI: 45.9-87.9). During sorafenib treatment, a<br />
significant increase in PlGF (18.4 vs 43.8 pg/mL, p < 0.001) was noted along with a<br />
non-significant increase in VEGF (0.7 vs 1.0 ng/mL, p = 0.07). There was no significant<br />
change for the 4 other biomarkers. VEGF at D1 >1.04 ng/mL (HR = 12.5, 95%-CI:<br />
1.37-114, p = 0.025) and VEGF at D7 >1.36 ng/mL (HR = 10.7, 95%-CI: 1.16-98,<br />
p = 0.037) were associated with shorter PFS. The 9-month PFS rate was 92.3%<br />
(95%-CI: 56.6-98.9) when VEGF at D1 was ≤1.04 ng/mL versus 23.3% (95%-CI:<br />
1.0-63.2) when >1.04 ng/mL. The 9-month PFS rates was 91.7% (95%-CI: 53.9-98.8)<br />
when VEGF at D7 was ≤1.36 ng/mL versus 27.8% (95%-CI: 1.3-68.4) when >1.36 ng/<br />
mL. The serum levels <strong>of</strong> five other biomarkers were not associated with PFS.<br />
vi486 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Conclusions: High levels <strong>of</strong> VEGF at D1 and D7 were associated with poor outcome in<br />
advanced chordoma receiving sorafenib.<br />
Clinical trial identification: NCT00874874<br />
Legal entity responsible for the study: Centre Oscar Lambret<br />
Funding: Institut National du Cancer (PHRC-2009/Grant) and Bayer HealthCare<br />
France.<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1406P<br />
Update <strong>of</strong> the T-DIS randomized phase II trial: Trabectedin<br />
rechallenge versus continuation in patients (pts) with<br />
advanced s<strong>of</strong>t tissue sarcoma (ASTS)<br />
N. Kotecki 1 , A. Le Cesne 2 , E. Tresch-Bruneel 3 , O. Mir 4 , C. Chevreau 5 , F. Bertucci 6 ,<br />
C. Delcambre 7 , E. Saada-Bouzid 8 , S. Piperno-Neumann 9 , J-O. Bay 10 ,I.<br />
L. Ray-Coquard 11 , T. Ryckewaert 1 , N. Isambert 12 , A. Italiano 13 , S. Clisant 14 ,<br />
J-Y. Blay 15 , N. Penel 1<br />
1 Medical <strong>Oncology</strong>, Centre Oscar Lambret, Lille, France, 2 Medical <strong>Oncology</strong>,<br />
Institut de Cancérologie Gustave Roussy, Villejuif, France, 3 Clinical Research and<br />
Methodological Platform, Centre Oscar Lambret, Lille, France, 4 Department <strong>of</strong><br />
Medical <strong>Oncology</strong>, Institut Gustave Roussy, Villejuif, France, 5 <strong>Oncology</strong>, Centre<br />
Claudius-Regaud, Toulouse, France, 6 Oncologie Médicale, Institute Paoli<br />
Calmettes, Marseille, France, 7 Medicine, Centre Francois Baclesse, Caen, France,<br />
8 Medical <strong>Oncology</strong>, Centre Antoine Lacassagne, Nice, France, 9 Medicine, Institut<br />
Curie, Paris, France, 10 Oncohematology, CHU Estaing, Clermont-Ferrand, France,<br />
11 Département d’Oncologie médicale adulte, Centre Léon Bérard, Lyon, France,<br />
12 Medicine, Centre Georges-François Leclerc (Dijon), Dijon, France, 13 Medical<br />
<strong>Oncology</strong>, Institute Bergonié, Bordeaux, France, 14 Clinical Research Unit, Centre<br />
Oscar Lambret, Lille, France, 15 University Claude Bernard Lyon I, Centre Léon<br />
Bérard, Lyon, France<br />
Background: Trabectedin (T) maintenance beyond 6 cycles (cy) <strong>of</strong> treatment in<br />
responding pts with ASTS is associated with improved progression-free survival (PFS)<br />
vs T discontinuation (Le Cesne, Lancet Oncol 2015). The impact <strong>of</strong> T rechallenge after<br />
progressive disease (PD) was prospectively analyzed by the French Sarcoma Group in<br />
the national randomized phase II trial (T-DIS; NCT01303094).<br />
Methods: After the initial 6 cy <strong>of</strong> T (1.5 mg/m 2 as 24-h infusion every 3 weeks) pts free<br />
<strong>of</strong> PD were randomly assigned either to continuous treatment with T (C arm;<br />
immediate 7 th cy) or therapy interruption (I arm). Pts allocated to the I arm could<br />
restart T in case <strong>of</strong> PD (7 th cy at the time <strong>of</strong> PD). Here we report updated outcomes in<br />
both arms obtained either from randomization or from the 7 th cy date.<br />
Results: From 2/2011 to 3/2013, 178 pretreated pts have been enrolled. Median age and<br />
performance status were 57 years (range 19-82) and 1 (range 0-3), respectively. Most<br />
pts had leiomyosarcoma (30.0%), liposarcoma (18.0%) or synovial sarcoma (12.0%).<br />
53/178 (29.7%) non progressive patients were eligible for randomization after 6 cy <strong>of</strong> T,<br />
27 and 26 non progressive pts were randomized to C and I arms, respectively. T has<br />
been restarted in 22/26 progressive pts in I arm whereas 25 out <strong>of</strong> 27 pts <strong>of</strong> the C arm<br />
immediately continued T. Median number <strong>of</strong> cy after randomization was similar in<br />
both arms (5 vs 6 cy, p = 0.96). From the date <strong>of</strong> randomization the median PFS was<br />
5.3 vs 3.5 months (p = 0.019) in the C and I arm, respectively, and 6-month PFS was<br />
48.2 vs 19.2%. From the date <strong>of</strong> the 7 th cy comparable median PFS (4.2 vs 4.8 months,<br />
p = 0.88) and 6-m rates <strong>of</strong> PFS (45.8% vs 34.7%) were observed in C and I arm,<br />
respectively. From the 7 th cycle, a favorable trend in longer median OS was observed in<br />
C arm (26.0 vs 14.9 months), which did not reach the level <strong>of</strong> significance (log-rank<br />
test p = 0.14) due to the small sample size. Grade ≥3 toxicity rates were not<br />
significantly different between the two arms (36.0% vs 38.1%) after T rechallenge<br />
(p = 0.88).<br />
Conclusions: Though T remains an active agent at rechallenge, we do not recommend<br />
trabectedin discontinuation in pts experiencing stable disease or partial response since<br />
interruption <strong>of</strong> T resulted in a rapid PD in most pts.<br />
Clinical trial identification: EudraCT NCT01303094<br />
Legal entity responsible for the study: Centre Oscar Lambret<br />
Funding: Centre Oscar Lambret<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1407P<br />
First line therapy with aldoxorubicin and 14 days continuous<br />
infusion <strong>of</strong> ifosfamide/mesna in metastatic or locally<br />
advanced sarcomas: a phase I-II study<br />
S.P. Chawla 1 , K. Sankhala 1 , S. Chawla 2 , V. Chua 1 , E.M. Gordon 1 , N. Chawla 1 ,<br />
K. Sung 3 , D. Quon 1 , K. Kim 1 , L. Fernandez 1 , B. Leong 1 , S. Wieland 3 , D. Levitt 4<br />
1 Med. <strong>Oncology</strong>, Sarcoma <strong>Oncology</strong> Center, Santa Monica, CA, USA, 2 Clinical<br />
Development, CytRx Corporation, Los Angeles, CA, USA, 3 Clinical Operations,<br />
CytRx Corporation, Los Angeles, CA, USA, 4 Clinical, CytRx Corporation, Los<br />
Angeles, CA, USA<br />
linker which rapidly binds in vivo to albumin after iv administration. We studied the<br />
combination <strong>of</strong> A administered on Day 1 with continuous infusion (CI) <strong>of</strong> ifosfamide/<br />
Mesna (I-M) days 1-14, in patients with sarcomas to evaluate efficacy and toxicity.<br />
Methods: 27 patients entered the study at one <strong>of</strong> 2 dose levels <strong>of</strong> A:170 or 250 mg/m2<br />
(125 or 185 mg/m2 D equiv) administered on Day 1. I-M (1 g/m2 <strong>of</strong> each per day) was<br />
given up to 14 days as a CI via an out-patient portable pump. Chemotherapy cycles<br />
were repeated at 28 day interval. I-M was limited to a maximum <strong>of</strong> 6 cycles to avoid<br />
cumulative marrow toxicity, but A was continued in responding patients for clinical<br />
benefit. Subjects were followed for tumor response by CT scans and echocardiogram<br />
for cardiac toxicity every 8 weeks along with standard labs.<br />
Results: Of the 27 patients enrolled as <strong>of</strong> May 1, 2016, the results <strong>of</strong> 24 evaluable<br />
patients are presented here. Twenty <strong>of</strong> the 24 patients had s<strong>of</strong>t tissue sarcoma, 2 had<br />
metastatic osteosarcoma and 2 had dedifferentiated chondrosarcoma. Eight <strong>of</strong> 24<br />
patients (33%) had a partial response (PR), 15/24 (62%) had stable disease (SD) and<br />
only 1/24 (5%) had progressive disease with over all disease control rate <strong>of</strong> 95%<br />
(PR + SD). Eleven <strong>of</strong> 24 (46%) patients had received at least 6 cycles <strong>of</strong> A (cumulative D<br />
equivalent more than 1000 mg/m2). Four patients were considered surgically resectable<br />
after 6 cycles <strong>of</strong> chemotherapy with percent <strong>of</strong> tumor necrosis <strong>of</strong> 95% and 90% in one<br />
patient each and 80% in two patients. Median duration <strong>of</strong> PFS was 6+ (2-19+) months.<br />
The most prevalent toxicity was gr 3 or 4 neutropenia. Four patients had SAEs <strong>of</strong><br />
febrile neutropenia. There was no clinical cardiac toxicity/ congestive heart failure. No<br />
patient had LVEF < 50% on echocardiograms at any time.<br />
Conclusions: The combination <strong>of</strong> A + I-M appears to be superior in anti-tumor<br />
efficacy to D/I-M with durable responses. A + I-M combination is quite tolerable with<br />
expected reversible hematologic toxicity. Of the 46% patients who received more than<br />
1000 mg /m2 <strong>of</strong> D equivalent; no cardiac toxicity was observed.<br />
Clinical trial identification: NCT02235701<br />
Legal entity responsible for the study: CytRx Corporation<br />
Funding: CytRx Corporation<br />
Disclosure: S.P. Chawla: Research support from CytRx Corporation. S. Chawla,<br />
K. Sung, S. Wieland, D. Levitt: Employee <strong>of</strong> CytRx Corporation. All other authors have<br />
declared no conflicts <strong>of</strong> interest.<br />
1408P<br />
A phase II trial <strong>of</strong> pazopanib in patients with metastatic<br />
alveolar s<strong>of</strong>t part sarcoma<br />
M. Kim, T.M. Kim, B. Keam, D-W. Kim, D.S. Heo<br />
Internal medicine, Seoul National University Hospital, Seoul, Republic <strong>of</strong> Korea<br />
Background: Alveolar s<strong>of</strong>t part sarcoma (ASPS) is a rare mesenchymal malignant<br />
tumor, accounting for 0.5 to 1.0% <strong>of</strong> s<strong>of</strong>t tissue sarcomas. Cytogenetically, ASPS is<br />
characterized by the translocation, t (X;17)(p11.2;q25), which leads to the fusion <strong>of</strong><br />
ASPSCR1 to the TFE3 transcription factor. Few treatment options exist for patients<br />
with metastatic ASPS due to resistance to conventional chemotherapy. Considering<br />
up-regulation <strong>of</strong> several transcripts associated with angiogenesis in ASPS,<br />
anti-angiogenic drugs have been studied. Although cediranib showed a substantial<br />
activity against metastatic ASPS, there are few studies <strong>of</strong> efficacy <strong>of</strong> other<br />
anti-angiogenic drugs for ASPS.<br />
Methods: This open-label, single-arm, phase II trial evaluated efficacy and safety <strong>of</strong><br />
pazopanib (800mg once daily) in patients with metastatic ASPS. TFE3 overexpression<br />
was confirmed by immunohistochemistry in all patients. The primary endpoint was<br />
overall response rate (ORR), and secondary endpoints were toxicity, progression-free<br />
survival (PFS) and overall survival (OS).<br />
Results: A total 6 patients with metastatic ASPS were enrolled between Dec 2013 and<br />
Nov 2014. The planned sample size was not reached due to low accrual rate. The<br />
median age was 29.5 years (range, 23 - 36 years). Among six patients, one achieved<br />
partial response (ORR 16.7%) and five patient showed stable disease. One patient with<br />
stable disease received ongoing treatment for more than 18 month. With a median<br />
follow-up <strong>of</strong> 19.2 months (range, 18.4 - 22.3 months), median PFS was 5.5 months<br />
(95% confidence interval, 2.5-8.6 months) and median OS has not been reached. There<br />
were no grade 3/4 treatment-related toxicities. The most common grade 1/2 toxicities<br />
were diarrhea (100%) and hair discoloration (83%). Two patients required one dose<br />
reduction due to toxicities.<br />
Table: 1408P<br />
abstracts<br />
Characteristics No. <strong>of</strong> patients (%)<br />
Total no. <strong>of</strong> patient 6<br />
Sex Male Female 3 (50%) 3 (50%)<br />
Primary site Extremities Visceral Bone 4 (66.6%) 1 (16.7%) 1<br />
(16.7%)<br />
ECOG PS 0 1 2 (33.3%) 4 (66.7%)<br />
Number <strong>of</strong> prior chemotherapy regimen 01<br />
2<br />
4 (66.6%) 1 (16.7%) 1<br />
(16.7%)<br />
Sites <strong>of</strong> metastases Lung Bone Liver Brain 5 2 1 1<br />
Background: Aldoxorubicin (A) has demonstrated superior anti-tumor efficacy and<br />
lack <strong>of</strong> cumulative cardiac toxicity in multiple studies. A is doxorubicin (D) with a<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw388 | vi487
abstracts<br />
Conclusions: Pazopanib showed a modest anti-tumor activity with manageable<br />
toxicities for patients with metastatic ASPS. Further prospective studies with a larger<br />
sample size are warranted to validate our results.<br />
Clinical trial identification: NCT02113826<br />
Legal entity responsible for the study: Seoul National University Hospital<br />
Funding: GSK (GlaxoSmithKline)<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1409P<br />
Tolerability <strong>of</strong> modified gemcitabine/docetaxel (split-dose) in<br />
patients with advanced s<strong>of</strong>t tissue sarcomas<br />
R.G.M.V.D. Azevedo 1 , N. Fraile 1 , E. Saadi Neto 1 , R.V.M. Lopez 2 , D. Toloi 1 ,P.<br />
M. H<strong>of</strong>f 1 , O. Feher 1 , V.P.D. Camargo 1 , R. Munhoz 1<br />
1 Medical <strong>Oncology</strong>, Instituto do Câncer do Estado de São Paulo, São Paulo,<br />
Brazil, 2 Statistics Department, Instituto do Câncer do Estado de São Paulo, São<br />
Paulo, Brazil<br />
Background: S<strong>of</strong>t tissue sarcomas (STS) encompass a wide group <strong>of</strong> malignancies that<br />
pose a therapeutic challenge when diagnosed at advanced stages. The combination <strong>of</strong><br />
gemcitabine/docetaxel (GD) has shown meaningful activity in this setting and is<br />
considered a valid therapeutic option. Nevertheless, GD is associated with significant<br />
toxicities and modifications are frequently used in clinical practice in an attempt to<br />
enhance the tolerability.<br />
Methods: We assembled a retrospective cohort <strong>of</strong> patients (pts) with advanced STS<br />
treated with the conventional GD (cGD): gemcitabine (900-1000mg/m 2 ) given on day<br />
1 and day 8 + docetaxel (75mg/m 2 ) given on day 8 only or modified GD (mGD) with<br />
“split-dose” docetaxel (30-37.5mg/m 2 ) given on days 1 and 8. The primary endpoint<br />
was to compare the incidence <strong>of</strong> grade 3/4 adverse events (AE) and use <strong>of</strong> G-CSF;<br />
additional outcomes included rate <strong>of</strong> admission to the hospital, progression free<br />
survival (PFS) and overall survival (OS). Survival curves were estimated using the<br />
Kaplan-Meier method. The association <strong>of</strong> clinical/pathological or treatment variables<br />
and survival was investigated.<br />
Results: We identified 76 pts treated with cGD (n = 32; 42.1%) or mGD (n = 44;<br />
57.9%). Sixty-nine pts (90.8%) had high grade tumors and most frequent histologies<br />
were leiomyosarcoma (n = 20; 26.3%) and undifferentiated pleomorphic sarcoma<br />
(n = 21; 27.6%). Pts receiving mGD were more likely to have and ECOG ≥2 (p= 0.05).<br />
Grade 3/4 AE occurred in 13 (40.6%) <strong>of</strong> pts treated with cGD and 21 (47.7%) <strong>of</strong> pts<br />
treated with mGT (p = 0.539). Use <strong>of</strong> G-CSF occurred in 28 pts (87.5%) treated with<br />
cGD and 23 pts (52.3%) treated with mGD (p= 0.001). Rates <strong>of</strong> admission to the<br />
hospital and dose reductions were similar between groups (p = 0.107 and p = 0.941,<br />
respectively). Survival intervals were comparable between groups: median PFS was 2<br />
months (mo) for pts treated with cGD and 3 mo for mGD (p= 0.8); median OS was 13<br />
mo and 11 mo, respectively (p= 0.9).<br />
Conclusions: Despite being used for patients with poorer performance status, mGD<br />
resulted in similar efficacy, incidence <strong>of</strong> grade 3/4 AE and lower G-CSF use in<br />
comparison to cGD. This finding is particularly relevant for cost contingency in<br />
settings with limited resources.<br />
Legal entity responsible for the study: Instituto do Câncer do Estado de São Paulo<br />
Funding: Instituto do Câncer do Estado de São Paulo<br />
Disclosure: P.M. H<strong>of</strong>f: Consulting or Advisory Role - AstraZeneca (immediate family<br />
member); Bayer (immediate family member) Research funding - Roche/Genentch. V.P.<br />
D. Camargo: Speakers Bureau - BMS Travel, accomodation, expenses - BMS, MSD. R.<br />
Munhoz: SpeakerśBureau - BMS Research funding - ELI - LILLY Travel,<br />
accomodations, expenses - BMS, MSD. All other authors have declared no conflicts <strong>of</strong><br />
interest.<br />
1410P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Pazopanib in advanced vascular sarcomas: an EORTC S<strong>of</strong>t<br />
Tissue and Bone Sarcoma Group retrospective analysis<br />
A. Kollar 1 , R.L. Jones 2 , S. Stacchiotti 3 , H. Gelderblom 4 , M. Guida 5 , P. Boccone 6 ,<br />
N. Steeghs 7 ,A.Safwat 8 ,D.Katz 9 , F. Duffaud 10 , S. Sleijfer 11 , W. van sder Graaf 12 ,<br />
N. Touati 13 , S. Litière 14 , S. Marreaud 13 , A. Gronchi 15 , B. Kasper 16<br />
1 Medizinische Onkologie, Inselspital - Universitätsspital Bern, Bern, Switzerland,<br />
2 Medical <strong>Oncology</strong>, Royal Marsden Hospital, London, UK, 3 Department <strong>of</strong> Cancer<br />
Medicine, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy, 4 Clinical<br />
<strong>Oncology</strong>, Leiden University Medical Center (LUMC), Leiden, Netherlands,<br />
5 Medical <strong>Oncology</strong>, Istituto Tumori Giovanni Paolo II, Bari, Italy, 6 Medical<br />
<strong>Oncology</strong>, Candiolo Cancer Institute, Turin, Italy, 7 Clinical <strong>Oncology</strong>, The<br />
Netherlands Cancer Institute Antoni van Leeuwenhoek Hospital, Amsterdam,<br />
Netherlands, 8 Department <strong>of</strong> <strong>Oncology</strong>, Aarhus University Hospital, Aarhus,<br />
Denmark, 9 <strong>Oncology</strong>, Hadassah Ein Kerem, Jerusalem, Israel, 10 Medical<br />
<strong>Oncology</strong>, Centre Hospitalier Universitaire Timone, Marseille, France, 11 Medical<br />
<strong>Oncology</strong>, Erasmus MC Daniel den Hoed Cancer Center, Rotterdam, Netherlands,<br />
12 Medical <strong>Oncology</strong>, Institute <strong>of</strong> Cancer Research and the Royal Marsden NHS<br />
Fondation Trust, London, UK, 13 EORTC Headquarters, European Organisation for<br />
research and treatment <strong>of</strong> Cancer (EORTC), Brussels, Belgium, 14 EORTC<br />
Headquarters, European Organisation for Research and Treatment <strong>of</strong> Cancer<br />
(EORTC AISBL), Brussels, Belgium, 15 Surgery, Fondazione IRCCS Istituto<br />
Nazionale dei Tumori, Milan, Italy, 16 Interdisziplinäres Tumorzentrum Mannheim<br />
(ITM), Universitätsklinikum Mannheim, Mannheim, Germany<br />
Background: Pazopanib is a multitargeted tyrosine kinase inhibitor approved for the<br />
treatment <strong>of</strong> adult patients with selective subtypes <strong>of</strong> advanced s<strong>of</strong>t-tissue sarcoma who<br />
have previously received standard chemotherapy including anthracyclines or were unfit<br />
for anthracyclines. Data on its efficacy in vascular sarcomas are limited. The main<br />
objective <strong>of</strong> this study was to investigate the activity <strong>of</strong> pazopanib in vascular sarcomas.<br />
Methods: Clinical data <strong>of</strong> patients with advanced vascular sarcomas, including<br />
angiosarcoma (AS), hemangioendothelioma (HE) and intimal sarcoma (IS) treated<br />
with pazopanib in a real-life setting were retrospectively collected from EORTC center<br />
records. Additionally, patients treated within the EORTC 62043 and 62072 trials were<br />
included in the analysis. Patient and tumor characteristics were documented. Response<br />
was assessed according to RECIST 1.1. and survival analysis was performed. Disease<br />
control rate was the total rate <strong>of</strong>: complete response, partial response and stable disease.<br />
Results: Out <strong>of</strong> 52 patients, 40 (76.9%), 10 (19.2%) and 2 (3.8%) patients suffered from<br />
AS, HE, IS, respectively. Patient and tumor characteristics are illustrated in Table 1. The<br />
response rate was 8 (20%), 2 (20%) and 2 (100%) in the AS, HE and IS subtypes,<br />
respectively. Disease control rate was 37.5% and 60% in AS and HE, respectively. There<br />
was no difference in response rate <strong>of</strong> cutaneous AS and non-cutaneous AS (p = 0.86)<br />
and radiation-associated vs non-radiation-associated AS (p = 0.81). Median PFS and<br />
median OS (from commencing pazopanib) were 3 months (95% Cl: 2.1-4.4) and 9.9<br />
months (95% Cl: 6.5-11.3) in AS, respectively.<br />
Table: 1410P Patient and tumor characteristics <strong>of</strong> vascular sarcomas<br />
Angiosarcoma Hemangioendothelioma Intimal<br />
sarcoma<br />
N=40 N=10 N=2<br />
N (%) N (%) N (%)<br />
Median<br />
age (years) 62.4 yrs 47.2 yrs 67.2 yrs<br />
Gender<br />
Female 15 (37.5%) 4 (40%) 1 (50%)<br />
Male 20 (62.5%) 6 (60%) 1 (50%)<br />
Disease stage<br />
Locally advanced 8 (20%) 2 (20%) 1 (50%)<br />
Metastatic 32 (80%) 8 (80%) 1 (50%)<br />
Site <strong>of</strong> primary<br />
tumor<br />
Breast 15 (37.5%) 0 (0%) 0 (0%)<br />
Scalp/Head 6 (15%) 1 (10%) 0 (0%)<br />
Abdomen 8 (20%) 4 (40%) 0 (0%)<br />
Thorax 7 (17.5%) 4 (40%) 1 (50%)<br />
Extremity 4 (10%) 1 (10%) 1(50%)<br />
Localization<br />
Skin 15 (37.5%) 0 (0%) 0 (0%)<br />
Non-skin 24 (60%) 10 (100%) 2 (100%)<br />
unknown 1 (2.5%) 0 (0%) 0 (0%)<br />
Radiation-induced<br />
Yes 14 (35%) 0 (0%) 0 (0%)<br />
No 26 (65%) 10 (100%) 2 (100%)<br />
Conclusions: Pazopanib demonstrated a degree <strong>of</strong> clinical efficacy in angiosarcoma,<br />
HE and IS. In AS patients, no difference in response rate was observed between<br />
cutaneous/ non-cutaneous and radiation-associated/ non radiation-associated tumors.<br />
Legal entity responsible for the study: EORTC S<strong>of</strong>t Tissue and Bone Sarcoma Group<br />
Funding: EORTC<br />
vi488 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
Disclosure: A. Kollar: Advisory Board for Novartis. S. Stacchiotti: Reserach funding:<br />
Glaxo and Novartis. W. van der Graaf: Research grants from Novartis and GSK. B.<br />
Kasper: Honoraria from Novartis. All other authors have declared no conflicts <strong>of</strong><br />
interest.<br />
1411P<br />
Patient perspective <strong>of</strong> the diagnostic sarcoma pathway;<br />
results from a national sarcoma patient survey in England<br />
E. Younger 1 , J. Whelan 2 , R.L. Jones 1 , L. Bennister 1 , W.T. van der Graaf 1<br />
1 Sarcoma, Royal Marsden Hospital NHS Foundation Trust, London, UK,<br />
2 Sarcoma, University College London Hospital, London, UK<br />
Conclusions: High TIL counts before start <strong>of</strong> NAC are associated with poor tumor<br />
differentiation in STS. Neoadjuvant treatment increases TILs and leads to significant<br />
changes in the distribution <strong>of</strong> T-cell subsets within the tumor. High TIL counts in<br />
response to therapy may be predictive for local control and survival in STS.<br />
Clinical trial identification: NCT00003052 (clinicalTrials.gov)<br />
Legal entity responsible for the study: EORTC S<strong>of</strong>t-Tissue-Bone-Sarcoma-Group,<br />
European Society for Hyperthermic <strong>Oncology</strong><br />
Funding: Deutsche Krebshilfe (M99/94/Wi II, 70-I702-Wi II), Helmholtz Association<br />
(VH-VI-140), EORTC 62961, ESHO RHT-95, and NIH P01 CA42745<br />
Disclosure: R. Issels: honorary fee and travel support by PharmaMar and Pyrexar. All<br />
other authors have declared no conflicts <strong>of</strong> interest.<br />
Background: Sarcomas are rare and heterogeneous malignancies that can occur at any<br />
age and arise at any anatomic site. In comparison with other common cancers, patients<br />
with sarcoma report a significantly poorer experience <strong>of</strong> their patient journey.<br />
Understanding the patients’ perspective <strong>of</strong> diagnosis, treatment and follow-up will<br />
influence management and outcomes for future sarcoma patients.<br />
Methods: Questionnaires were designed by Quality Health in conjunction with<br />
Sarcoma UK, the only all sarcoma charity in the UK, patient advocates and sarcoma<br />
clinicians. In England, questionnaires were dispatched by post to a sample <strong>of</strong> 900<br />
patients drawn from respondents to National Cancer Patient Experience Surveys<br />
2010-14 (fieldwork January-March 2015). Here we focus on the diagnostic pathway.<br />
Results: Response rate was 64% (558 respondents; 418 s<strong>of</strong>t tissue, 140 bone). Most<br />
common presenting symptoms were painless lump 41% (n = 229), ‘something else’<br />
31% (n = 173) and lump increasing in size 30% (n= 166). 31% (n = 44) <strong>of</strong> bone<br />
sarcoma patients presented with bone pain. Younger patients (16-34 years) were more<br />
likely to report painful lumps; older patients (85+ years) reported increasing size. Of all<br />
patients, 18% (n = 96) presented >6 months after first noting symptoms, 24% <strong>of</strong> bone<br />
sarcoma vs 16% <strong>of</strong> s<strong>of</strong>t tissue sarcomas; 17% <strong>of</strong> bone sarcomas waited >1 year. General<br />
Practitioners (GP) referred 34% for tests and 33% to hospital specialists. Of all<br />
respondents who visited their GP, 9% were treated for another condition, and 18% were<br />
told their symptoms were not serious and to come back (9%) or not come back (9%) if<br />
symptoms persisted. Of patients attending Accident & Emergency departments, 25%<br />
were not treated appropriately; 10% <strong>of</strong> patients (younger more than older) were treated<br />
for another condition.<br />
Conclusions: Delay in presentation is a significant factor, which may adversely impact<br />
long-term outcome and quality <strong>of</strong> life. Additionally, frequent misdiagnosis highlights<br />
the low level <strong>of</strong> suspicion, education and knowledge in primary and secondary<br />
healthcare. These data will encourage initiatives to improve awareness among the<br />
public and healthcare pr<strong>of</strong>essionals.<br />
Legal entity responsible for the study: Sarcoma UK: The bone and s<strong>of</strong>t tissue cancer<br />
charity<br />
Funding: Sarcoma UK: The bone and s<strong>of</strong>t tissue cancer charity<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1412P<br />
Dissecting the role <strong>of</strong> tumor-infiltrating lymphocytes (TIL) in<br />
patients with high-risk s<strong>of</strong>t-tissue sarcoma (STS) receiving<br />
neo-adjuvant chemotherapy (NAC) with regional<br />
hyperthermia (RHT)<br />
R. Issels 1 , V. Büclein 1 , E. Kampmann 1 , T. Knösel 2 , E. Nössner 3 , M. Subklewe 1 ,<br />
L. Lindner 1<br />
1 Department <strong>of</strong> Internal Medicine III, Klinikum der Universität München, Munich,<br />
Germany, 2 Pathologisches Institut der LMU, Ludwig-Maximilians-Universität<br />
München, Munich, Germany, 3 Institut für Molekulare Immunologie, Helmholtz<br />
Zentrum München, Munich, Germany<br />
Background: In recent years, the immune system has been shown to play an important<br />
role in the development and progression <strong>of</strong> cancer. In various malignancies, the<br />
prognostic relevance <strong>of</strong> TILs has been shown. STS are a heterogeneous group <strong>of</strong> rare<br />
mesenchymal malignancies. Known prognostic factors for STS include size,<br />
localization and grading. The aim <strong>of</strong> the study was to evaluate the prognostic<br />
significance <strong>of</strong> TILs and different T-cell subsets for survival.<br />
Methods: Tissue microarrays (TMA) <strong>of</strong> tumor samples <strong>of</strong> STS patients, treated in the<br />
EORTC 62961 Phase III trial (Lancet Oncol. 2010), were assessed for TILs, counted in<br />
standard HE stainings. Additionally, immuno-stainings for CD3 (pan-T-cell marker),<br />
CD8 (cytotoxic T cells), FOXP3 (regulatory T cells) and PD-1 (T-cell activation/<br />
exhaustion) were evaluated. For 109 patients, 137 biopsies were available before (84<br />
samples) or after (53 samples) NAC ± RHT. Paired tumor samples (before and after<br />
NAC ± RHT), were available for 28 patients. Outcome was compared using<br />
Kaplan-Meier and Cox estimations.<br />
Results: Before initiation <strong>of</strong> NAC, TIL counts were significantly higher in poorly<br />
differentiated G3 than in G2 tumors. However, NAC lead to a significant increase in<br />
TIL counts, and the association with grading was no longer evident after NAC ± RHT.<br />
FOXP3 cell counts were significantly decreased after NAC ± RHT. Local<br />
progression-free survival (LPFS) and disease-free survival (DFS) were significantly<br />
enhanced for patients with high TIL counts (>5/TMA) after completion <strong>of</strong><br />
NAC ± RHT. Differences in tumor infiltration <strong>of</strong> CD3, CD8, FOXP3, and PD-1 positive<br />
cells were not associated with significant differences in LPFS or DFS.<br />
1413P<br />
ATRX-associated alternative lengthening <strong>of</strong> telomere (ALT)<br />
may be correlated with chemotherapy response in<br />
leiomyosarcoma (LMS)<br />
P-H. Huang 1 , R-L. Hong 1 , Y-M. Jeng 2 , J-Y. Liau 2 , W-W.T. Chen 1<br />
1 Department <strong>of</strong> <strong>Oncology</strong>, National Taiwan University Hospital, Taipei, Taiwan,<br />
2 Department <strong>of</strong> Pathology, National Taiwan University Hospital, Taipei, Taiwan<br />
Background: Response to systemic chemotherapy in LMS varies and no predictive<br />
biomarker exists. ALT, a common mechanism to maintain telomere in sarcoma, is<br />
associated with altered DNA repair mechanism. Loss <strong>of</strong> a chromatin modifier<br />
α-thalassemia/mental retardation syndrome X-linked (ATRX) has been implicated as<br />
one <strong>of</strong> the factors leading to ALT. We aimed to determine the relationship between<br />
ALT, ATRX and chemotherapy response in patients with advanced LMS.<br />
Methods: Histology-proven advanced LMS patients (pts) treated with systemic<br />
chemotherapy in National Taiwan University Hospital from January 1995 to<br />
December 2014 were selected. Patient demographic data and clinical outcomes<br />
including tumor response, progression-free survival and overall survival were recorded.<br />
We used formalin-fixed paraffin-embed tumor samples for ALT and ATRX status<br />
assessment by telomere-specific fluorescence in situ hybridization and<br />
immunohistochemistry, respectively.<br />
Results: 30 pts with advanced LMS treated with systemic chemotherapy were<br />
identified. Table 1 summarizes the clinicopathological information. 21 pts received<br />
anthracycline-based first line chemotherapy. 20 pts (67%) were ALT-positive (ALT+).<br />
10 pts (33%) were ATRX-negative (ATRX-), among which all but 1 were also ALT+.<br />
ALT positivity was not correlated with chemotherapy response (odds ratio = 1.25,<br />
p = 0.7844). In the 9 ALT + /ATRX- patients, a lower odds, albeit non-significant, <strong>of</strong><br />
response to chemotherapy was noted compared to non ALT + /ATRX- patients (11.3%<br />
vs 42.9%, odds ratio = 0.17, 95% CI = 0.01-1.58, p = 0.11). PFS was significantly shorter<br />
in ALT + / ATRX- patients (median 2.0 mos vs 7.7 mos, p < 0.001, hazard ratio 6.5,<br />
95% CI 2.4-17.7). No significant difference in OS was noted (median 11.7 mos vs 23.9<br />
mon, p = 0.314) between ALT + /ATRX- and non-ALT + /ATRX- pts.<br />
Table: 1413P Patient demographics and clinicopathological features<br />
n = 30 (%)<br />
Age, median (range) 51 (28-67)<br />
Sex<br />
- Male 2 (7)<br />
- Female 28 (93)<br />
Tumor Origin<br />
- Uterus 22 (73)<br />
- Retroperitoneum/intra-abdomen 3 (10)<br />
- Others 5 (17)<br />
Metastatic site<br />
- Lung 25 (83)<br />
- Liver 14 (47)<br />
- Bone 7 (23)<br />
- Intra-abdomen (excluding liver) 7 (23)<br />
Cell Morphology<br />
- Spindle 19 (63)<br />
- Epithelioid/pleomorphic 11 (37)<br />
FNCLCC Grade<br />
- Grade 1/2 12 (40)<br />
- Grade 3 18 (60)<br />
ALT FISH<br />
- Positive 20 (67)<br />
- Negative 10 (33)<br />
ATRX Expression<br />
- Present 20 (67)<br />
- Loss 10 (33)<br />
1st-line Chemotherapy<br />
- Anthracycline-based 21 (70)<br />
- Nonanthracycline-based 9 (30)<br />
Conclusions: ALT+ with ATRX- may predict poorer response to chemotherapy in<br />
advanced LMS.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw388 | vi489
abstracts<br />
Legal entity responsible for the study: Po-Hsiang Huang<br />
Funding: Department <strong>of</strong> <strong>Oncology</strong>, National Taiwan University Hospital<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1414P<br />
Possible prognostic value <strong>of</strong> local immunity cellular factors in<br />
primary and recurrent s<strong>of</strong>t tissue sarcomas<br />
E. Zlatnik 1 , O. Kit 2 , I. Novikova 1 , T. Aliev 3 , E. Nepomnyashchaya 1 , T. Ausheva 3 ,<br />
O. Selyutina 1 , I. Dashkova 3 , L. Vashchenko 3 , E. Andreyko 3 , E. Kechedzhieva 3 ,<br />
I. Sidorenko 3 , E. Velieva 3 , L. Vladimirova 4<br />
1 Laboratory <strong>of</strong> Immunophenotyping <strong>of</strong> Tumors, Rostov Research Institute <strong>of</strong><br />
<strong>Oncology</strong>, Rostov-on-Don, Russian Federation, 2 Surgical Department, Rostov<br />
Research Institute <strong>of</strong> <strong>Oncology</strong>, Rostov-on-Don, Russian Federation, 3 Department<br />
<strong>of</strong> S<strong>of</strong>t Tissue Tumors, Rostov Research Institute <strong>of</strong> <strong>Oncology</strong>, Rostov-on-Don,<br />
Russian Federation, 4 Department <strong>of</strong> Chemotherapy, Rostov Research Institute <strong>of</strong><br />
<strong>Oncology</strong>, Rostov-on-Don, Russian Federation<br />
Background: The purpose <strong>of</strong> the study was to analyze prognostic value <strong>of</strong> some cellular<br />
factors <strong>of</strong> immunologic microenvironment in s<strong>of</strong>t tissue sarcomas (STS) for the<br />
development <strong>of</strong> an effective response to treatment for primary and recurrent tumors.<br />
Methods: 24 patients (13 women and 11 men aged 35 years and older) with primary<br />
(12) and recurrent (12) s<strong>of</strong>t tissue sarcomas (G1-G4T2BN0M0, mostly poorly<br />
differentiated G3 tumors) underwent surgical removal <strong>of</strong> tumors with the following<br />
adjuvant chemotherapy and radiotherapy. Tissues <strong>of</strong> tumors and peritumoral area<br />
obtained during the surgery were homogenized; percentage <strong>of</strong> lymphocytes (T-, B-,<br />
NK, NKT, DP, DN, T-regs) was determined using FACSCantoII (BD) flow cytometer.<br />
Results: Patients were divided into 4 groups according to the results <strong>of</strong> clinical<br />
observation: group A – primary tumors, marked treatment effect; group B – primary<br />
tumors, no treatment effect; group C – recurrent tumors, marked treatment effect; and<br />
group D - recurrent tumors, no treatment effect. Retrospective assessment <strong>of</strong> local<br />
immunity statuses <strong>of</strong> patients revealed a number <strong>of</strong> differences in lymphocyte content.<br />
Patients with primary STS showed significant prognostic value <strong>of</strong> CD16/56+ level in<br />
tumor tissue: 12.2 ± 1.6% in marked treatment effect and 6.1 ± 1.2% without an effect<br />
(p < 0.05). Levels <strong>of</strong> NK- and NKT-cells were twice higher in peritumoral tissues in<br />
group A compared to group B. Absence <strong>of</strong> treatment effect in recurrent STS was<br />
associated with an increased content <strong>of</strong> DN cells in tumor tissue (9.3 ± 2.2% in group D<br />
vs. 5.5 ± 0.8% in group C; p < 0.05).<br />
Conclusions: A high local level <strong>of</strong> DN-lymphocytes, especially in recurrent tumors,<br />
and decreased content <strong>of</strong> NK-cells in primary tumors can be considered as prognostic<br />
factors for effectiveness <strong>of</strong> treatment for s<strong>of</strong>t tissue sarcomas.<br />
Legal entity responsible for the study: Rostov Research Institute <strong>of</strong> <strong>Oncology</strong><br />
Funding: Ministry <strong>of</strong> Health <strong>of</strong> the Russian Federation<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1415P<br />
Long-term safety <strong>of</strong> regorafenib (REG) in advanced<br />
gastrointestinal stromal tumors (GIST): updated safety data<br />
<strong>of</strong> the phase 3 GRID trial<br />
G.D. Demetri 1 , P. Reichardt 2 , Y-K. Kang 3 , J-Y. Blay 4 , H. Joensuu 5 , C. Kappeler 6 ,<br />
C. Wuchter-Czerwony 7 , J. Chung 8 , A. Wagner 9 , P.G. Casali 10<br />
1 Dana-Farber Cancer Institute and Ludwig Center, Harvard Medical School,<br />
Boston, MA, USA, 2 Department <strong>of</strong> Hematology, <strong>Oncology</strong>, and Palliative<br />
Medicine, Helios Klinikum Berlin Buch, Berlin, Germany, 3 Department <strong>of</strong><br />
<strong>Oncology</strong>, Asan Medical Center, University <strong>of</strong> Ulsan College <strong>of</strong> Medicine, Seoul,<br />
Republic <strong>of</strong> Korea, 4 University Claude Bernard, Centre Léon Bérard, Lyon, France,<br />
5 Department <strong>of</strong> <strong>Oncology</strong>, Helsinki University Central Hospital, Helsinki, Finland,<br />
6 Clinical Statistics Europe, Bayer Pharma AG, Berlin, Germany,<br />
7 Pharmacovigilance, Bayer Pharma AG, Berlin, Germany, 8 Clinical Development<br />
<strong>Oncology</strong>, Bayer HealthCare Pharmaceuticals, Whippany, NJ, USA, 9 Clinical<br />
Development <strong>Oncology</strong>, Bayer Pharma AG, Berlin, Germany, 10 Adult Sarcoma<br />
Medical <strong>Oncology</strong> Unit, Istituto Nazionale Tumori, Milan, Italy<br />
Background: The GRID trial showed that REG improves progression-free survival<br />
(primary endpoint; data cut<strong>of</strong>f January 2012) versus placebo in patients (pts) with<br />
advanced GIST after failure <strong>of</strong> imatinib and sunitinib (Lancet 2013; 381: 295). At<br />
progression, placebo pts could cross over to REG treatment and pts randomized to<br />
REG could continue. We present an updated safety analysis <strong>of</strong> pts in GRID who were<br />
treated with REG at any time (any REG; AR) and <strong>of</strong> the subgroup who had long-term<br />
REG (LTR) treatment (>1 year).<br />
Methods: Of the 199 randomized pts (n = 133 REG; n = 66 placebo), 58 placebo pts<br />
crossed over to REG. At the time <strong>of</strong> this analysis (June 2015), a total <strong>of</strong> 190 pts (95%)<br />
were treated with AR and 75 (38%) had LTR. Starting dose was REG 160 mg once daily<br />
for the first 3 weeks <strong>of</strong> each 4-week cycle.<br />
Results: The LTR group tended to have a better ECOG status (PS0: AR 57%/LTR 69%;<br />
PS1: AR 43%/LTR 31%). A similar proportion were ≥65 yrs <strong>of</strong> age (AR 32%; LTR 31%)<br />
and treated in the third-line (56%; 61%) or fourth-line and higher settings (44%; 39%).<br />
Median (range) treatment duration was 8.8 months (0.02– 48.4) for AR and 22.7<br />
months (12.0 – 48.4) for LTR. Median daily dose was 146.7 mg (AR) and 121.8 mg<br />
(LTR). All pts had an NCI-CTCAE (v4.0) treatment-emergent adverse event (TEAE),<br />
with the majority occurring in the first months <strong>of</strong> treatment and significantly lower<br />
rates in subsequent months. Most common REG-related grade ≥3 TEAEs included<br />
(AR; LTR): hand–foot skin reaction (20.5%; 28.0%); hypertension (24.2%; 34.7%);<br />
diarrhea (7.4%; 13.3%); fatigue (4.7%, 4.0%); and oral mucositis (2.1%, 2.7%).<br />
Although rates <strong>of</strong> treatment modifications due to REG-related TEAEs were higher in<br />
the LTR group (66.8% AR; 82.7% LTR), discontinuation rates due to REG-related<br />
TEAEs were similar (8.9% AR; 10.7% LTR), with the majority <strong>of</strong> events leading to<br />
discontinuation reported only once. There were no additional REG-related deaths since<br />
the primary analysis.<br />
Conclusions: Patients who had LTR tended to have a better ECOG status. The updated<br />
safety pr<strong>of</strong>ile <strong>of</strong> GIST pts treated with REG in GRID is consistent with the pr<strong>of</strong>ile<br />
reported at primary study completion. For pts treated with REG >1 year, no<br />
unexpected safety findings were observed.<br />
Clinical trial identification: NCT01271712<br />
Legal entity responsible for the study: Bayer<br />
Funding: Bayer<br />
Disclosure: G.D. Demetri: Stock ownership: Kolltan Pharmaceuticals, Blueprint<br />
Medicines, G1 Therapeutics, Caris, Champions <strong>Oncology</strong>, Bessor Pharmaceuticals.<br />
Advisory board: Bayer, Novartis, Pfizer, Lilly, EMD-Serono, San<strong>of</strong>i <strong>Oncology</strong>, Janssen<br />
<strong>Oncology</strong>, GlaxoSmithKline, Daiichi-Sankyo, Ariad, AstraZeneca, WIRB Copernicus<br />
Group, ZioPharm, Polaris Pharmaceuticals, Kolltan Pharmaceuticals, Blueprint<br />
Medicines, G1 Therapeutics, Caris, Champions <strong>Oncology</strong>, Bessor Pharmaceuticals.<br />
Board <strong>of</strong> directors: Blueprint Medicines Board <strong>of</strong> Directors. Corporate-sponsored<br />
research: Bayer, Novartis, Pfizer, EMO-Serono, San<strong>of</strong>i <strong>Oncology</strong>, Janssen <strong>Oncology</strong>,<br />
Glaxo-Smith-Kline (all to Dana-Farber). P. Reichardt: Advisory board: Amgen;<br />
ARIAD; Bayer; GlaxoSmithKline; Novartis; Pfizer; PharmaMar Corporate sponsored<br />
research: Novartis. Y-K. Kang, J-Y. Blay: Advisory board: Bayer, Novartis. H. Joensuu:<br />
Stock ownership: Orion Pharma Advisory board: Blueprint Medicines, Ariad. C.<br />
Kappeler, A. Wagner: Other substantive relationships: Bayer (employment). C.<br />
Wuchter-Czerwony, J. Chung: Other substantive relationships: Bayer employment. P.<br />
G. Casali: Advisory board: Amgen Dompé, ARIAD, Bayer, Blueprint Medicines, Eisai,<br />
GSK, Lilly, Merck SD, Merck Serono, Novartis, Pfizer, PharmaMar<br />
Corporate-sponsored research: Amgen Dompé, Bayer, Eisai, GSK SK, Novartis, Pfizer,<br />
PharmaMar (all institution).<br />
1416P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Predictive factors for toxicity and survival <strong>of</strong> second line<br />
sunitinib in advanced gastrointestinal stromal tumours (GIST)<br />
D. Den Hollander 1 , W.T.A. van der Graaf 2 , I.M. Desar 1 , O. Mir 3 , S. Dumont 3 ,A.Le<br />
Cesne 3<br />
1 Medical <strong>Oncology</strong>, Radboud University Medical Centre Nijmegen, Nijmegen,<br />
Netherlands, 2 Medical <strong>Oncology</strong>, Royal Marsden NHS Foundation Trust, London,<br />
UK, 3 Medical <strong>Oncology</strong>, Institut de Cancérologie Gustave Roussy, Villejuif, France<br />
Background: Sunitinib is standard second-line treatment in advanced GIST. Predictive<br />
factors for grade 3-4 toxicity, progression-free survival (PFS) and overall survival (OS)<br />
for patients treated outside clinical studies, but in sarcoma reference centers, are not<br />
well defined. Demographic and clinical features, tumour characteristics and biological<br />
parameters were investigated.<br />
Methods: A retrospective analysis was performed <strong>of</strong> patients treated in two European<br />
Comprehensive Cancer Centers (Gustave Roussy and Radboudumc) between January<br />
2005 and December 2015. Only patients with sufficient data before and during<br />
sunitinib treatment were analyzed. Logistic regression models were used to find factors<br />
associated with grade 3-4 toxicity. To identify predictive factors for PFS and OS,<br />
variables that were statistically significant in univariate analysis were used in the<br />
multivariate Cox proportional hazards model.<br />
Results: Of 238 patients who received second-line sunitinib, 91 patients were included<br />
in this analysis. Fifty six per cent <strong>of</strong> patients experienced a grade 3- 4 toxicity during<br />
sunitinib, most frequently diarrhea, neutropenia and asthenia. Age > 60 years (HR 4.9,<br />
p = 0.006) and body weight ≤ 70 kgs (HR 4.7, p = 0.009) were predictive factors for<br />
grade 3-4 toxicity. When divided into two categories, non hematological grade 3-4<br />
toxicity could be predicted by age > 60 years (HR 3.8, p = 0.012) and body weight ≤ 70<br />
kgs (HR 3.3, p = 0.025) whereas hematological toxicity was predicted by elevated serum<br />
level <strong>of</strong> LDH (HR 15.9, p = 0.03) and low albumin (HR 7.7, p = 0.03). Median PFS and<br />
OS were 7.6 months and 19.9 months, respectively, with 77 progressions (84.6%) and<br />
52 (57.1%) deaths. Less than six months use <strong>of</strong> imatinib (HR 0.2, p = 0.016) and<br />
metastatic disease (HR 0.2, p = 0.001) were predictive for longer PFS. Elevated<br />
neutrophil (HR 3.1, p = 0.04) and platelet count (HR 2.4, p = 0.046) predicted lower<br />
OS.<br />
Conclusions: In advanced GIST patients treated with second line sunitinib, older and<br />
low-weight patients are at risk for grade 3-4 toxicity. Both clinical(prior imatinib use<br />
and metastatic disease) and biological (neutrophil and platelet count) characteristics<br />
independently predict PFS and OS.<br />
Legal entity responsible for the study: Radboud University Medical Centre Nijmegen<br />
Funding: N/A<br />
Disclosure: W.T.A. van der Graaf: Research grants from Novartis and GSK. O. Mir:<br />
Consultant/speaker for Astra-Zeneca, Bayer, GSK, Novartis, Pfizer, Roche and Servier.<br />
vi490 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
A. Le Cesne: Honoraria from PharmaMar, Novartis, Lilly, Merck and Pfizer. All other<br />
authors have declared no conflicts <strong>of</strong> interest.<br />
1417P<br />
Prediction <strong>of</strong> long-term survival in metastatic<br />
gastrointestinal stromal tumour: analysis <strong>of</strong> a large,<br />
single-institution patient cohort<br />
I. Hompland 1 , Ø.S. Bruland 1 , J.P. Poulsen 1 , S. Stoldt 2 , T. Hølmebakk 2 , K.S. Hall 1 ,<br />
K. Boye 1<br />
1 Department <strong>of</strong> <strong>Oncology</strong>, Norwegian Radium Hospital, Oslo University Hospital,<br />
Oslo, Norway, 2 Department <strong>of</strong> Abdominal and Paediatric Surgery, Norwegian<br />
Radium Hospital, Oslo University Hospital, Oslo, Norway<br />
Background: Treatment <strong>of</strong> metastatic gastrointestinal stromal tumour (GIST) has<br />
improved considerably after the introduction <strong>of</strong> imatinib. A subset <strong>of</strong> patients become<br />
long-term survivors, and a more precise outcome prediction could improve clinical<br />
decision-making.<br />
Methods: Patients diagnosed with metastatic GIST from 1995 to 2013 were identified<br />
from the sarcoma database at Oslo University Hospital. Clinical data were<br />
prospectively registered in the database and supplemented with retrospective review <strong>of</strong><br />
medical records. Factors associated with survival were analysed using Kaplan-Meier<br />
curves, log-rank test and uni- and multivariate Cox regression analysis.<br />
Results: One-hundred thirty-three patients with metastatic GIST were identified, and<br />
115 were included in the final study cohort. First-line treatment with imatinib was<br />
given to 111 patients, two received nilotinib and two never received systemic treatment.<br />
Second-line treatment was administered to 35 patients and third-line therapy to 19<br />
patients. Median overall survival (OS) was 6.9 years (95 % Cl 5.6-8.3). After a median<br />
follow-up <strong>of</strong> 9.0 years 52 patients (43 %) were still alive. Factors associated with<br />
long-term survival in univariate analysis were good baseline performance status<br />
(ECOG ≤1; p < 0.001), young age (p = 0.022), oligometastatic disease (≤3 metastases;<br />
p < 0.001), maximum tumour diameter
abstracts<br />
or metastatic STS (≥16 years; ECOG performance status ≤1; naïve to therapy with<br />
study drugs; not amenable to curative treatment with surgery or radiotherapy; ≤2 prior<br />
lines <strong>of</strong> systemic therapy for advanced or metastatic disease). The Phase 1b part <strong>of</strong> the<br />
study consists <strong>of</strong> an open-label, single-arm, dose-escalation assessment <strong>of</strong> the safety<br />
and tolerability <strong>of</strong> olaratumab administered at 15 mg/kg (Days 1 and 8) or 20 mg/kg<br />
(Days 1 and 8) with gemcitabine (900 mg/m 2 [fixed dose rate: 10 mg/m 2 /minute] Days<br />
1 and 8) and docetaxel (75 mg/m 2 Day 8) in a 21-day cycle. The primary objective is to<br />
determine a dose <strong>of</strong> olaratumab that may be safely administered in combination with<br />
gemcitabine and docetaxel in patients with advanced or metastatic STS. Secondary<br />
objectives are to evaluate the safety and toxicity pr<strong>of</strong>ile, pharmacokinetics, and<br />
immunogenicity <strong>of</strong> olaratumab in combination with gemcitabine and docetaxel; and to<br />
document any antitumor activity. After the optimal dose <strong>of</strong> olaratumab in combination<br />
with gemcitabine and docetaxel has been determined, the Phase 2, randomized,<br />
double-blind, placebo-controlled part <strong>of</strong> the study will open to enrolment (in<br />
approximately December 2016). The study began in March 2016; planned enrollment<br />
for the 1b phase is approximately 30 patients.<br />
Clinical trial identification: NCT02659020<br />
Legal entity responsible for the study: Eli Lilly and Company<br />
Funding: Eli Lilly and Company<br />
Disclosure: C. Valverde Morales: Honoraria from Eli Lilly and Company as advisor for<br />
educational activities. J.A. Lopez-Martin: Eli Lilly and Company: advisory board,<br />
clinical research grants. MSD, BMS, Novartis, GSK, Roche: advisory board, clinical<br />
research grants. PharmaMar: former employee, stocks. G. Honigschmidt, Y. Zeng,<br />
J. Chen, D.F. Tai, G. Mo, R. Ilaria Jr, N.S. Pillay, N. Drove, M. Jamarik: Employee <strong>of</strong> Eli<br />
Lilly and Company. All other authors have declared no conflicts <strong>of</strong> interest.<br />
1421TiP<br />
A randomized double-blind phase II study evaluating the<br />
role <strong>of</strong> maintenance therapy with cabozantinib in high grade<br />
undifferentiated uterine sarcoma (HGUS) after stabilization<br />
or response to doxorubicin +/- ifosfamide following surgery<br />
or in metastatic first line treatment<br />
I.L. Ray-Coquard 1 , A.P. Dei Tos 2 , C. Coens 3 , M. Huizing 4 , A. Casado Herraez 5 ,A.<br />
M. Westermann 6 , E. Bompas 7 , H. Earl 8 , M.L. Hensley 9 , A. Negrouk 10 , N. Reed 11<br />
1 Département d’Oncologie médicale adulte, Centre Léon Bérard, Lyon, France,<br />
2 Department <strong>of</strong> Pathology, Ospedale Regionale Ca’ Foncello, Treviso, Italy,<br />
3 Quality <strong>of</strong> Life Department, European Organisation for Research and Treatment <strong>of</strong><br />
Cancer, Brussels, Belgium, 4 MOCA, U.Z.A. University Hospital Antwerp, Edegem,<br />
Belgium, 5 Department <strong>of</strong> Medical <strong>Oncology</strong>, Hospital Clinico Universitario San<br />
Carlos, Madrid, Spain, 6 Medical <strong>Oncology</strong> F4-224, Academic Medical Center<br />
(AMC), Amsterdam, Netherlands, 7 4-Department <strong>of</strong> Medical <strong>Oncology</strong>, Institut de<br />
cancérologie de l’Ouest - René Gauducheau, Saint-Herblain, France, 8 <strong>Oncology</strong>,<br />
Addenbrooke’s Hospital University <strong>of</strong> Cambridge Hospitals, Cambridge, UK,<br />
9 Medical <strong>Oncology</strong>, Memorial Sloan Kettering Cancer Center, New York, NY, USA,<br />
10 International Regulatory and Intergroup Unit, European Organisation for<br />
Research and Treatment <strong>of</strong> Cancer (EORTC), Brussels, Belgium, 11 Beatson<br />
<strong>Oncology</strong> Centre, Gartnavel General Hospital, Glasgow, UK<br />
Background: HGUS accounts for 6% <strong>of</strong> all uterine sarcomas and has a very poor<br />
prognosis. Most patients (pts) die <strong>of</strong> recurrent disease within 1 year <strong>of</strong> diagnosis.<br />
Treatment recommendations for advanced stage include chemotherapy with<br />
anthracyclines +/- ifosfamide, although data for the efficacy <strong>of</strong> these agents in this<br />
histologic subtype are very limited. Recently vascular invasion reported to be a driver <strong>of</strong><br />
the progression for such sarcoma subtype suggesting anti-angiogenics and so<br />
cabozantinib (VEGFR2/c-MET inhibitor) potentially active for HGUS.<br />
Trial design: This randomized phase II double-blinded trial aims to measure the role<br />
<strong>of</strong> maintenance therapy with cabozantinib in HGUS after stabilization (SD) or<br />
response (Complete Response (CR) + Partial Response (PR)) to doxorubicin-based<br />
chemotherapy following surgery or in metastatic 1 st line treatment. The main objective<br />
<strong>of</strong> the trial is to assess the efficacy <strong>of</strong> maintenance treatment with cabozantinib<br />
compared with placebo. Approximately 54 pts will be randomized, after central<br />
pathological review, to cabozantinib 60 mg once daily or placebo for up to 24 months,<br />
to detect an improvement in progression free survival (PFS) rate at 4 months from 50%<br />
to 80% with a one-sided 15% significance level. Pts randomized to the placebo arm<br />
may cross-over to cabozantinib at the time <strong>of</strong> progression. This trial is a cooperation<br />
between European Organisation for Research and Treatment <strong>of</strong> Cancer (EORTC),<br />
Cancer Research UK (CRUK) and National Cancer Institute (NCI, US) and is part <strong>of</strong><br />
the International Rare Cancers Initiative (IRCI). Primary objective: PFS rate at 4<br />
months according to RECIST 1.1 Secondary objectives: PFS, Overall Survival, Safety,<br />
Response Rate and duration <strong>of</strong> response Study status: The first pts from EORTC (6<br />
participating countries) was randomized in Feb 2015. As <strong>of</strong> 6 May 2016, 15 and 5 pts<br />
have been registered and randomized after central pathology confirmation <strong>of</strong> HGUS,<br />
respectively. CRUK has started recruitment in May 2016 and NRG <strong>Oncology</strong> in US is<br />
expected to start in October 2016.<br />
Clinical trial identification: NCT number: NCT01979393; EudraCT: 2013-000762-11<br />
Legal entity responsible for the study: European Organisation for Research and<br />
Treatment <strong>of</strong> Cancer (EORTC)<br />
Funding: European Organisation for Research and Treatment <strong>of</strong> Cancer (EORTC)<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1422TiP<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Phase II, singlearm, nonrandomized, and multicenter<br />
clinical trial <strong>of</strong> regorafenib (REG) as a single agent in the<br />
firstline setting for patients with metastatic and/or<br />
unresectable KIT/PDGFR wild-type GIST. A GEIS and ISG<br />
study<br />
J. Martín Broto 1 , E. Fumagalli 2 , V. Martínez 3<br />
1 Medical <strong>Oncology</strong>, Hospital Universitario Virgen del Rocio, Seville, Spain,<br />
2 Medical <strong>Oncology</strong>, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy,<br />
3 Medical <strong>Oncology</strong>, Hospital Universitario La Paz, Madrid, Spain<br />
Background: Approximately 10-15% <strong>of</strong> adults with GIST lack KIT or PDGFRA<br />
mutations. This KIT/PDGFRA wild-type (wt) GIST is considered a separate<br />
pathological entity and is highly clinically heterogeneous. Because most KIT/PDGFRA<br />
wt-GISTs do not respond to imatinib, new treatment approaches are needed. REG is an<br />
oral multikinase inhibitor that has been shown to improve progression-free survival<br />
(PFS) and disease control rate (DCR) vs placebo in patients with advanced GIST<br />
progressing after failure <strong>of</strong> imatinib and sunitinib (Demetri et al. Lancet 2013). This<br />
study was designed to assess the effectiveness <strong>of</strong> REG in patients with metastatic and/or<br />
unresectable KIT/PDGFR wt-GIST in the first-line setting.<br />
Trial design: Patients ≥18 years <strong>of</strong> age with histologically confirmed unresectable and/<br />
or metastatic KIT/PDGFR wt-GIST (lack <strong>of</strong> mutations in KIT exons 11,9,13,17 and<br />
PDGFR exons 12,18 confirmed by next-generation sequencing) are eligible. Other<br />
inclusion criteria include ≥1 measurable lesion (RECIST v1.1), ECOG PS 0-1, adequate<br />
bone marrow, liver, and renal function, not fulfilling any exclusion criteria, and written<br />
informed consent. FFPE-tumor blocks are to be provided. Collection <strong>of</strong> blood and<br />
fresh tumor samples for a translational substudy is optional. REG 160 mg will be<br />
administered once daily in a 3-weeks on, 1-week <strong>of</strong>f schedule until disease progression,<br />
unacceptable toxicity, or investigator/patient decision to withdraw. Thirtythree patients<br />
(+ 20%) are to be recruited according to Simon Minmax 2stage Phase II design. Main<br />
endpoint is DCR relative to the historical control <strong>of</strong> imatinib in wt-GIST. Hypothesis 0:<br />
p0 = 73% (0% CR + 23% PR + 50% SD). Hypothesis 1: achieving a DCR <strong>of</strong> p1 = 90%<br />
with REG. Using error rates <strong>of</strong> a = 0.05 and b = 0.20, the first-stage sample size is 31<br />
patients, with 26 patients as the upper limit for firststage drug rejection. Secondary<br />
outcomes include PFS, overall survival, response (CHOI criteria), correlation with<br />
translational research, early metabolic response by PETscan, and safety (CTCAE 4.03).<br />
Clinical trial identification: EudraCT Number: 2015-001048-12<br />
Legal entity responsible for the study: Grupo Español de Investigación en Sarcomas<br />
(GEIS)<br />
Funding: Bayer<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
vi492 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong> 27 (Supplement 6): vi493–vi496, 2016<br />
doi:10.1093/annonc/mdw389<br />
SCLC<br />
1423O<br />
Randomized phase 2 study <strong>of</strong> investigational aurora A kinase<br />
(AAK) inhibitor alisertib (MLN8237) + paclitaxel (P) vs<br />
placebo + P as second line therapy for small-cell lung cancer<br />
(SCLC)<br />
T.K. Owonikoko 1 , K. Nackaerts 2 , T. Csoszi 3 , G. Ostoros 4 , C. Baik 5 , Z. Mark 6 ,<br />
E. Sheldon-Waniga 7 , D. Huebner 8 , E.J. Leonard 9 , D.R. Spigel 10<br />
1 Hematology/Medical <strong>Oncology</strong>, Emory University, Atlanta, GA, USA, 2 Respiratory<br />
Diseases, Respiratory <strong>Oncology</strong> Unit, KU Leuven, University Hospitals Leuven,<br />
Leuven, Belgium, 3 Onkologiai Kozpont, Hetenyi G Korhaz, Szolnok, Hungary, 4 VIII.<br />
Tudobelosztaly, Orszagos Koranyi TBC es Pulmonologiai Intezet, Budapest,<br />
Hungary, 5 Thoracic/Head and Neck <strong>Oncology</strong>, University <strong>of</strong> Washington<br />
Seattle Cancer Care Alliance, Seattle, WA, USA, 6 3th, Tudogyogyintezet<br />
Torokbalint, Törökbálint, Hungary, 7 <strong>Oncology</strong> Statistics, Millennium<br />
Pharmaceuticals, Inc., a wholly owned subsidiary <strong>of</strong> Takeda Pharmaceutical<br />
Company Limited, Cambridge, MA, USA, 8 <strong>Oncology</strong> Clinical Research, Millennium<br />
Pharmaceuticals, Inc., a wholly owned subsidiary <strong>of</strong> Takeda Pharmaceutical<br />
Company Limited, Cambridge, MA, USA, 9 Clinical Science, Millennium<br />
Pharmaceuticals, Inc., a wholly owned subsidiary <strong>of</strong> Takeda Pharmaceutical<br />
Company Limited, Cambridge, MA, USA, 10 Sarah Cannon Research Institute,<br />
Tennessee <strong>Oncology</strong>, Nashville, TN, USA<br />
1424O<br />
Small cell lung carcinoma harbors targetable alterations<br />
including MYCL1 fusions responding to aurora kinase<br />
inhibitor<br />
S. Ali 1 , B. Kolla 2 , M. Bailey 1 , A.B. Schrock 3 , S.J. Klempner 4 , G.M. Frampton 5 ,D.<br />
A. Fabrizio 6 , S-H.I. Ou 7 ,J.He 8 , J. Suh 9 , J.S. Ross 10 , P. Stephens 11 , V. Miller 1 ,<br />
M. Patel 12<br />
1 Clinical Development, Foundation Medicine, Inc., Cambridge, MA, USA, 2 Internal<br />
Medicine, University <strong>of</strong> Minnesota, Minneapolis, MN, USA, 3 Clinical Development,<br />
Foundation Medicine, Inc., Cambridge, MA, USA, 4 Medical <strong>Oncology</strong>, The<br />
Angeles Clinic and Research Institute, Los Angeles, CA, USA, 5 Research &<br />
Development, Foundation Medicine, Inc., Cambridge, MA, USA, 6 Research and<br />
Development, Foundation Medicine, Cambridge, MA, USA, 7 Department <strong>of</strong><br />
Medicine, Division <strong>of</strong> Hematology <strong>Oncology</strong>, UC Irvine School <strong>of</strong> Medicine, Irvine,<br />
CA, USA, 8 Clinical Genomics, Foundation Medicine, Inc., Cambridge, MA, USA,<br />
9 Pathology, Foundation Medicine, Inc., Cambridge, MA, USA, 10 Pathology, Albany<br />
Medical Center, Albany, NY, USA, 11 Research and Development, Foundation<br />
Medicine, Inc, Cambridge, MA, USA, 12 Medical <strong>Oncology</strong>, University <strong>of</strong><br />
Minnesota, Minneapolis, MN, USA<br />
abstracts<br />
© European Society for Medical <strong>Oncology</strong> 2016. Published by Oxford University Press on behalf <strong>of</strong> the European Society for Medical <strong>Oncology</strong>.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com.
abstracts<br />
1425PD<br />
Clinical activity, safety and predictive biomarkers results<br />
from a phase Ia atezolizumab (atezo) trial in extensive-stage<br />
small cell lung cancer (ES-SCLC)<br />
L.V. Sequist 1 , A. Chiang 2 , J. Gilbert 3 , M. Gordon 4 , P.R. Conkling 5 , D. Thompson 6 ,<br />
J.P. Marcoux 7 , S.J. Antonia 8 , B. Liu 9 , D.S. Shames 10 , A. Lopez-Chavez 9 ,<br />
C. O’Hear 11 , M. Fasso 11 , S. Gettinger 2<br />
1 Center for Thoracic Cancers, Massachusetts General Hospital, Boston, MA,<br />
USA, 2 Yale Cancer Center, Yale School <strong>of</strong> Medicine, New Haven, CT, USA,<br />
3 <strong>Oncology</strong>, Vanderbilt University School <strong>of</strong> Medicine, Nashville, TN, USA, 4 Division<br />
<strong>of</strong> Arizona Center for Cancer Care, Pinnacle <strong>Oncology</strong> Hematology, Scottsdale,<br />
AZ, USA, 5 Virginia <strong>Oncology</strong> Associates, US <strong>Oncology</strong> Research, Norfolk, VA,<br />
USA, 6 <strong>Oncology</strong>, Sarah Cannon Research Institute, Nashville, TN, USA, 7 Thoracic<br />
<strong>Oncology</strong>, Dana Farber Cancer Institute, Boston, MA, USA, 8 Department <strong>of</strong><br />
Thoracic <strong>Oncology</strong>, M<strong>of</strong>fitt Cancer Center, Tampa, FL, USA, 9 Product<br />
Development <strong>Oncology</strong>, Genentech, Inc., South San Francisco, CA, USA,<br />
10 <strong>Oncology</strong> Biomarker Department, Genentech, Inc., South San Francisco, CA,<br />
USA, 11 Product Development <strong>Oncology</strong>, Genentech Inc, A Member <strong>of</strong> the Roche<br />
Group, South San Francisco, CA, USA<br />
Background: Most patients (pts) with ES-SCLC receive platinum-based chemotherapy<br />
with etoposide, however median survival is
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
first-in-class fully human IgG1 monoclonal antibody with enhanced ADCC that<br />
specifically binds to Fuc-GM1, for the treatment <strong>of</strong> SCLC.<br />
Methods: Patients (pts) with relapsed/refractory SCLC after at least one line <strong>of</strong> prior<br />
therapy were enrolled. BMS-986012 was administered IV at flat doses <strong>of</strong> 70, 160, 400,<br />
and 1000 mg every 3 weeks (wk) during dose escalation. Pharmacokinetics (PK) and<br />
anti-drug antibodies (ADA) were assessed during cycle 1.<br />
Results: Twenty-nine pts were treated across all doses. Median age was 63 yr (range:<br />
26–81); 55% were female; 95% had a smoking history. Pts had received up to five lines<br />
<strong>of</strong> prior therapy; 52% had one prior line; 48% had 2 or more two prior lines. Nine pts<br />
were platinum refractory (≤3 mo from end <strong>of</strong> first line therapy to progression). No<br />
dose limiting toxicities or treatment-related grade 4 or 5 adverse events occurred.<br />
Treatment-related adverse events occurring in >10% <strong>of</strong> pts were pruritus, decreased<br />
appetite, and rash. Preliminary PK analysis suggests a linear dose-exposure relationship<br />
(Table). No ADAs were detected.<br />
Table: 1427PD Summary <strong>of</strong> Single Dose Exposures <strong>of</strong> BMS-986012<br />
70 mg 160 mg 400 mg 1000 mg<br />
AUC (0–504 hr), ug*hr/mL Geom. 4434 (31) 8544 (23) 19642 (47) 44677 (23)<br />
Mean (CV), %<br />
Cmax, ug/mL Geom. Mean (CV), % 28 (28) 74 (125) 145 (26) 348 (23)<br />
Geom. = Geometric; CV = coefficient <strong>of</strong> variation<br />
One confirmed complete response (CR; duration 53 wk; 70 mg dose level) and one<br />
confirmed partial response (PR; duration 17 wk; 400 mg dose level) were observed.<br />
Stable disease (SD) was reported in 4 pts. The CR and 2 SD occurred among the 9<br />
platinum refractory pts.<br />
Conclusions: BMS-986012 demonstrates a manageable safety pr<strong>of</strong>ile and resulted in<br />
objective responses in relapsed SCLC, including platinum refractory pts. Preliminary<br />
PK analysis showed dose-proportional and linear increase in exposure with moderate<br />
to high variability. Dose expansion is currently enrolling at 400 and 1000 mg.<br />
Clinical trial identification: NCT02247349<br />
Legal entity responsible for the study: Sponsored by Bristol-Myers Squibb<br />
Funding: Sponsored by Bristol-Myers Squibb<br />
Disclosure: Q.S-C. Chu: Personal fees from BMS and Lilly (advisory boards), Novartis<br />
(advisory board and consultancy), and Astra Zeneca, Merck (advisory and<br />
consultancy). Grants and personal fees from BI (Research Grant and advisory board).<br />
L. Krug: Grants from Bristol-Myers Squibb, during the conduct <strong>of</strong> the study; other<br />
from Bristol-Myers Squibb, outside the submitted work. C. Rudin: Personal fees from<br />
Bristol Myers Squibb, Celgene, Novartis, Medivation, and Merck, outside the<br />
submitted work. D. Lathers: Employee & Shareholder at BMS. P. Basciano: Personal<br />
fees from Bristol-Meyers Squibb, outside the submitted work as a Study Sponsor. P.M.<br />
Fracasso: Employee <strong>of</strong> BMS. P. Phillips: Employee <strong>of</strong> Bristol-Myers Squibb. N. Ready:<br />
Personal fees from Bristol Myers Squibb, Celgene, Novartis, Medivation, and Merck,<br />
outside the submitted work. All other authors have declared no conflicts <strong>of</strong> interest.<br />
1428P<br />
Phase I/II study <strong>of</strong> induction chemotherapy using carboplatin<br />
plus irinotecan and sequential thoracic radiotherapy (TRT)<br />
for elderly patients with limited-stage small-cell lung cancer<br />
(LD-SCLC): The final results <strong>of</strong> TORG 0604<br />
Y. Misumi 1 , H. Okamoto 1 , K. Naoki 2 , Y. Hosomi 3 , T. Ogura 4 , N. Masuda 5 ,<br />
K. Minato 6 , T. Yokoyama 7 , K. Kishi 8 , M. Nishikawa 9 , T. Kato 10 , N. Seki 11 , I. Goto 12 ,<br />
K. Watanabe 1<br />
1 Department <strong>of</strong> Respiratory Medicine, Yokohama Municipal Citizen’s Hospital,<br />
Yokohama, Japan, 2 Department <strong>of</strong> Respiratory Medicine, Keio University School<br />
<strong>of</strong> Medicine, Tokyo, Japan, 3 Department <strong>of</strong> Thoracic <strong>Oncology</strong> and Respiratory<br />
Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome<br />
Hospital, Tokyo, Japan, 4 Respiratory medicine, Kanagawa Cardiovascular and<br />
Respiratory Center, Yokohama, Japan, 5 Respiratory medicine, Kitasato University<br />
Hospital, Sagamihara, Japan, 6 Department <strong>of</strong> Respiratory Medicine, Gunma<br />
Prefectural Cancer Center, Ota, Japan, 7 Department <strong>of</strong> Respiratory Medicine,<br />
Kyorin university Hospital, Mitaka, Japan, 8 Dept. <strong>of</strong> Respiratory Medicine,<br />
Toranomon Hospital, Tokyo, Japan, 9 Department <strong>of</strong> Respiratory Medicine,<br />
Fujisawa Municipal Hospital, Fujisawa, Japan, 10 Department <strong>of</strong> Respiratory<br />
Medicine, Kanagawa Cancer Center, Yokohama, Japan, 11 Department <strong>of</strong> Medical<br />
<strong>Oncology</strong>, Teikyo University, Tokyo, Japan, 12 Department <strong>of</strong> Respiratory Medicine,<br />
Osaka Medical College, Takatsuki, Japan<br />
AUC <strong>of</strong> 4 and 5 (levels 1 and 2, respectively), with a fixed irinotecan dose (50 mg/m2).<br />
Primary objectives <strong>of</strong> the phase II study were efficacy, adverse events, and feasibility.<br />
Results: Forty-one patients were enrolled (median age75 years [range 70-86 years);<br />
males 31; PS 0/1/2, n = 22/18/1]. The number <strong>of</strong> patients with carboplatin<br />
dose-limiting toxicities at levels-1 (n = 6) and -2 (n = 6) were 1(grade 3 hypertension)<br />
and 2 (grade 4 thrombocytopenia), respectively. The phase II trial was expanded to 29<br />
additional patients receiving the level 1 carboplatin dose. The median number <strong>of</strong><br />
chemotherapy cycles was 4 (range 1-4), and the median radiation dose was 54Gy<br />
(range 36-60).Toxicities were generally mild. There were 5 complete and 30 partial<br />
responses (response rate 90%).With a median follow-up <strong>of</strong> 80.4 months (n = 41), the<br />
median progression-free and overall survival times were 12.5 and 27.5 months,<br />
respectively.<br />
Conclusions: Induction chemotherapy <strong>of</strong> carboplatin plus irinotecan and sequential<br />
TRT was well tolerated and effective for elderly patients with LD-SCLC. Additional<br />
confirmatory studies are warranted.<br />
Legal entity responsible for the study: Thoracic <strong>Oncology</strong> Reserch Group (TORG)<br />
Funding: Nippon Kayaku, Taiho, Lilly, San<strong>of</strong>i, Chugai, Astra Zeneca, Daiichi Sankyo,<br />
Shionogi<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1429P<br />
abstracts<br />
The humanistic burden <strong>of</strong> small cell lung cancer (SCLC):<br />
a systematic review <strong>of</strong> health-related quality <strong>of</strong> life (HRQoL)<br />
literature<br />
C. Panter 1 , B. Bennett 1 , Y. Yuan 2 , J. Penrod 2<br />
1 PCO, Adelphi Values Ltd, Bollington, UK, 2 World Wide Health Economics and<br />
Outcomes Research, Bristol-Myers Squibb, Princeton, NJ, USA<br />
Background: SCLC accounts for approximately 15% <strong>of</strong> all lung cancers and has a<br />
poorer prognosis and more aggressive course than other lung carcinomas. However,<br />
little is known about the humanistic burden <strong>of</strong> SCLC, specifically the impact on<br />
HRQoL. The objective <strong>of</strong> this study was to explore the impact <strong>of</strong> SCLC on HRQoL.<br />
Methods: A systematic literature review was conducted using specific search terms in<br />
Medline® in process (PubMed), Embase, and PsycINFO. Searches were limited to<br />
human studies and the past 10 years (2005–March 2016). Additional pragmatic<br />
searches were conducted <strong>of</strong> oncology organisation websites and conference<br />
proceedings. A total <strong>of</strong> 373 articles were retrieved. Two reviewers independently<br />
screened titles and abstracts for eligibility. Fifty-eight articles were selected for full-text<br />
review, with 27 <strong>of</strong> these being deemed eligible for inclusion (clinical trials [n = 18],<br />
observational studies [n = 7], and qualitative studies [n = 2]).<br />
Results: Most articles provided data on limited and extensive stage SCLC. The most<br />
commonly used patient-reported outcomes (PROs) to assess SCLC impact on HRQoL<br />
were the EORTC QLQ-C30 (n = 15), <strong>of</strong>ten supplemented by the lung or brain cancer<br />
module (n = 7), and the Lung Cancer Symptom Scale (n = 5). SCLC patients had<br />
significantly impacted overall HRQoL, which was lower than normative reference<br />
values. HRQoL deteriorated further as disease progressed. Specific HRQoL domains<br />
most commonly reported included activities <strong>of</strong> daily living (ADL; n = 11), and physical<br />
(n = 10), emotional (n = 10), and cognitive functioning (n = 9). Differential impacts on<br />
each <strong>of</strong> these domains were noted, with ADL being the most severely impacted and<br />
emotional and cognitive functioning being the least. There was a difference in HRQoL<br />
between clinical trial and real world studies. Not all therapies provided improved or<br />
stable HRQoL, which may be due to tolerability differences.<br />
Conclusions: These findings show that SCLC progression and treatment have a<br />
substantial impact on overall HRQoL and some <strong>of</strong> the HRQoL subdomains. Further<br />
research on the impact on specific HRQoL domains is required. Capturing HRQoL<br />
data in SCLC may help patients and clinicians make informed treatment choices.<br />
Legal entity responsible for the study: N/A<br />
Funding: Bristol-Myers Squibb<br />
Disclosure: C. Panter, B. Bennett: Research was sponsored by BMS. Y. Yuan, J. Penrod:<br />
Research was sponsored by BMS, co-author is an employee <strong>of</strong> BMS.<br />
Background: The role <strong>of</strong> irinotecan for elderly patients with LD-SCLC has been<br />
unclear, and the timing <strong>of</strong> TRT combined with chemotherapy has not been fully<br />
evaluated.<br />
Methods: Patients aged > 70 years with untreated, measurable, LD-SCLC, performance<br />
status (PS) 0-2, and adequate organ function were eligible. Treatment consisted <strong>of</strong><br />
induction with carboplatin on day 1 and irinotecan on days 1 and 8, every 21 days for 4<br />
cycles, and sequential TRT (54Gy in 27 fractions). Carboplatin doses were based on<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw389 | vi495
abstracts<br />
1430TiP<br />
STIMULI: A randomised open-label phase II trial <strong>of</strong><br />
consolidation with nivolumab and ipilimumab in<br />
limited-stage SCLC after standard <strong>of</strong> care<br />
chemo-radiotherapy conducted by ETOP and IFCT<br />
D. De Ruysscher 1 , J-L. Pujol 2 , S. Popat 3 , M. Reck 4 , C. Le Pechoux 5 , A. Liston 6 ,<br />
D. Speiser 7 , G. Coukos 8 , R. Kammler 9 , O. Dafni 10 , Z. Tsourti 10 , H. Roschitzki 9 ,<br />
M. Finlayson 9 , A-C. Piguet 9 , B. Ruepp 9 , R. Maibach 9 , R.A. Stahel 11 , S. Peters 8<br />
1 Department <strong>of</strong> Radiation <strong>Oncology</strong>, Maastro Clinic, Maastricht, Netherlands,<br />
2 Thoracic <strong>Oncology</strong> Unit, Hopital Arnaud de Villeneuve, Montpellier, France,<br />
3 Medicine, Royal Marsden Hospital, London, UK, 4 Thoracic <strong>Oncology</strong>, Lung Clinic<br />
Grosshansdorf, Airway Research Center North (ARCN), member <strong>of</strong> the German<br />
Center for Lung Research (DZL), Grosshansdorf, Germany, 5 Departement de<br />
Radiotherapie, Institut Gustave Roussy, Villejuif, France, 6 Department <strong>of</strong><br />
Microbiology and Immunology, University Hospitals Leuven - Campus<br />
Gasthuisberg, Leuven, Belgium, 7 Department <strong>of</strong> Fundamental <strong>Oncology</strong>,<br />
University <strong>of</strong> Lausanne, Lausanne, Switzerland, 8 Department <strong>of</strong> <strong>Oncology</strong>, Centre<br />
Hospitalier Universitaire Vaudois - CHUV, Lausanne, Switzerland, 9 Coordinating<br />
Office, European Thoracic Oncolocy Platform, Bern, Switzerland, 10 Biostatistics,<br />
Frontier Science Foundation – Hellas, Athens, Greece, 11 Clinic <strong>of</strong> <strong>Oncology</strong>,<br />
University Hospital Zürich, Zurich, Switzerland<br />
Background: Preliminary results from trial CheckMate 032, targeting two distinct<br />
inhibitory immune checkpoints combining nivolumab, an anti-PD1 IgG1 monoclonal<br />
antibody and ipilimumab, an anti-CTLA4 IgG1 monoclonal antibody, demonstrate<br />
very promising 31% objective response rate (ORR) and 48% one-year overall survival<br />
(OS) in pre-treated advanced SCLC. This treatment option will be explored in a<br />
consolidation setting after curative-intent chemotherapy, chest radiotherapy (RT) and<br />
prophylactic cranial irradiation (PCI) for LD-SCLC.<br />
Trial design: STIMULI is an open-label, randomised, two-arm, phase II clinical trial.<br />
Inclusion is restricted to stage I-IIIB untreated LD-SCLC patients (pts) with adequate<br />
organ and pulmonary function, and no history <strong>of</strong> auto-immune disease. Hyper- or<br />
conventionally fractionated chest RT is administered concomitantly to 4 cycles <strong>of</strong> Cis-/<br />
carboplatin plus etoposide, followed by PCI. After completion <strong>of</strong> this standard<br />
treatment, non-progressing pts are randomised 1:1 to consolidation (induction and<br />
maintenance) or observation. Induction consists <strong>of</strong> four 3-week cycles <strong>of</strong> ipilimumab<br />
3mg/kg plus nivolumab 1mg/kg, and is followed by maximally 12 months <strong>of</strong><br />
nivolumab 240mg every 2 weeks. OS and progression-free survival (PFS) are<br />
co-primary endpoints. ORR, time to treatment failure and tolerability are secondary<br />
endpoints. A total <strong>of</strong> 325 pts are expected to be enrolled in the standard treatment<br />
phase, in order for 260 pts to be randomised, with a target hazard ratio <strong>of</strong> .70 for OS<br />
and .57 for PFS. The overall one-sided significance level <strong>of</strong> .05 is split to .04 for OS and<br />
.01 for PFS, with power 78% for OS and 80% for PFS. A safety evaluation for<br />
pneumonitis will take place after the first 30 patients reach the 12 weeks follow-up on<br />
the experimental arm. Safety will be monitored by the Independent Data Monitoring<br />
Committee every 3 months. Translational research will be done on formalin-fixed,<br />
paraffin-embedded tumour tissue, PBMCs, whole blood and serum samples at the<br />
Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland. Up to April 2016, 7<br />
pts have been randomised, and enrolment is ongoing.<br />
Clinical trial identification: EudraCT number: 2013-002609-78<br />
Legal entity responsible for the study: European Thoracic <strong>Oncology</strong> Platform ETOP<br />
Funding: Bristol-Myers Squibb<br />
Disclosure: S. Popat: Consultant to BMS. M. Reck: Honoraria for consultancy and lectures<br />
from: H<strong>of</strong>fmann-La Roche, Lilly, BMS, MSD, AstraZeneca, Boehringer-Ingelheim, Pfizer,<br />
Celgene. All other authors have declared no conflicts <strong>of</strong> interest.<br />
1431TiP<br />
A Phase III study <strong>of</strong> atezolizumab with carboplatin plus<br />
etoposide in patients with extensive-stage small cell lung<br />
cancer (IMpower133)<br />
L. Horn 1 , M. Reck 2 , T.S.K. Mok 3 , M. Johnson 4 , D. Waterkamp 5 , S. Lam 5 ,<br />
X. Tang 6 , A. Sandler 5 , A. Lopez-Chavez 5 , G. Giaccone 7 , S.V. Liu 7<br />
1 Department <strong>of</strong> Medicine, Vanderbilt Ingram Cancer Center, Nashville, TN, USA,<br />
2 Thoracic <strong>Oncology</strong>, Lung Clinic Grosshansdorf, Airway Research Center North<br />
(ARCN), member <strong>of</strong> the German Center for Lung Research (DZL), Grosshansdorf,<br />
Germany, 3 <strong>Oncology</strong>, Chinese University <strong>of</strong> Hong Kong, Hong Kong, China,<br />
4 <strong>Oncology</strong>, Sarah Cannon Research Institute/Tennessee <strong>Oncology</strong>, Nashville, TN,<br />
USA, 5 Product Development <strong>Oncology</strong>, Genentech, Inc., South San Francisco,<br />
CA, USA, 6 PDBB, F. H<strong>of</strong>fmann-La Roche Ltd, Shanghai, China, 7 <strong>Oncology</strong>,<br />
Lombardi Comprehensive Cancer Center, Georgetown University, Washington,<br />
DC, USA<br />
Background: The current standard first-line treatment for the majority <strong>of</strong> patients<br />
(pts) with extensive-stage small cell lung cancer (ES-SCLC) is platinum-based<br />
chemotherapy with etoposide. Despite initial response rates ranging from 50% to 70%,<br />
median survival remains < 1 year. Atezolizumab (atezo) is an anti-PD-L1 agent that<br />
inhibits PD-L1/PD-1 signaling and restores anti-tumor T-cell activity. Atezo<br />
monotherapy has shown promising efficacy and safety in many tumor types, including<br />
SCLC (ORR by RECIST v1.1, 6% [1/17]; ORR by irRC, 24% [4/17]; Sequist et al.<br />
ESMO 2016, pending). In addition, pre-clinical and Phase I data indicate that atezo<br />
given with platinum-based chemotherapy in non-small cell lung cancer may be<br />
synergistic and results in durable responses that may translate into improved survival.<br />
(Camidge et al. WCLC 2015). Together, these findings provide a rationale to assess<br />
whether atezo combined with carboplatin + etoposide (CE) results in improved<br />
survival vs CE alone in the first-line treatment <strong>of</strong> ES-SCLC.<br />
Trial design: IMpower133 is a randomized, Phase III, multicenter, double-blinded,<br />
placebo-controlled study evaluating the efficacy and safety <strong>of</strong> atezo + CE vs<br />
placebo + CE in treatment-naive pts with ES-SCLC. Pts will be enrolled regardless <strong>of</strong><br />
PD-L1 expression status. Pts with untreated CNS metastases, autoimmune disease or<br />
prior anti-cancer therapy for ES-SCLC will be excluded. Eligible pts will be stratified by<br />
sex, ECOG PS and presence <strong>of</strong> brain metastases, and randomized 1:1 to treatment<br />
arms. The induction phase <strong>of</strong> the study will consist <strong>of</strong> four 21-day cycles <strong>of</strong> atezo (1200<br />
mg IV) or placebo with CE (C AUC 5, day 1 + E 100 mg/m 2 , days 1-3) followed by<br />
maintenance atezo or placebo until PD per RECIST v1.1. Treatment can be continued<br />
until persistent radiographic PD or symptomatic deterioration. Investigator-assessed<br />
PFS per RECIST v1.1 and OS are the co-primary endpoints. Secondary endpoints<br />
include ORR, DOR, quality <strong>of</strong> life, safety/tolerability and pharmacokinetics.<br />
Approximately 400 pts will be enrolled globally.<br />
Clinical trial identification: NCT: available on poster<br />
Legal entity responsible for the study: F. H<strong>of</strong>fmann-La Roche Ltd<br />
Funding: F. H<strong>of</strong>fmann-La Roche Ltd<br />
Disclosure: L. Horn: Research: AZ Consulting: Bayer, BI, BMS, Genentech, Lilly,<br />
Merck and Xcovery. M. Reck: Consulting/Advisory role and Speaker Bureau for Roche,<br />
lIlly, BMS, MSD, AshaZ Zeneca, Pfizer, Boehringer Ingeleim, Celgene. T.S.K. Mok:<br />
Leadership/Stocks: Sanomics Ltd Honoraria/Consulting/Research includes: AZ, Roche,<br />
Lily, Merck, MSD, BMS, BI, Novartis, Clovis Onc, Amgen, Janssen, AVEO, Biodesix,<br />
Prime <strong>Oncology</strong>, ACEA Biosciences, Vertex, SFJ, GSK, Biomarin, Pfizer.<br />
D. Waterkamp: Roche/Genentech employee and stock. S. Lam, A. Sandler: Genentech<br />
employee, Roche stock. X. Tang: Roche employee. A. Lopez-Chavez: Genentech<br />
employee. G. Giaccone: Consulting or Advisory Role: Clovis, Boehringer- Ingelheim,<br />
Celgene Research grants: Karyopharm, Astra-Zeneca; Eli-Lilly. S.V. Liu: Consulting or<br />
Advisory Role: Genentech, Boehringer Ingelheim, Ariad, Biodesix, Perthera. All other<br />
authors have declared no conflicts <strong>of</strong> interest.<br />
1432TiP<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Immune surveillance reactivation to improve overall survival<br />
in small cell lung cancer (SCLC): The randomized IMPULSE<br />
study<br />
M. Thomas 1 , R. Carter 2 , S. Ponce Aix 3 , J. Riera-Knorrenschild 4 ,<br />
A. Navarro Mendivil 5 , M. Domine 6 , J. Kollmeier 7 , P. Sadjadian 8 , R.M. Huber 9 ,<br />
M. Wolf 10<br />
1 Internistische Onkologie der Thoraxtumoren, Thoraxklinik Heidelberg, Heidelberg,<br />
Germany, 2 MOLOGEN AG, MOLOGEN AG, Berlin, Germany, 3 Servicio de<br />
Oncologia Medica, University Hospital 12 De Octubre, Madrid, Spain, 4 Klinik für<br />
Innere Medizin, Klinikum der Philipps Universität Marburg, Marburg, Germany,<br />
5 Medical <strong>Oncology</strong>, Vall d’Hebron University Hospital Institut d’Oncologia,<br />
Barcelona, Spain, 6 <strong>Oncology</strong>, University Hospital "Fundacion Jimenez Diaz",<br />
Madrid, Spain, 7 Klinik für Pneumologie, HELIOS Klinikum Emil von Behring GmbH,<br />
Berlin, Germany, 8 Onkologie und Hämatologie, Johannes Weseling klinikum,<br />
Minden, Germany, 9 Thoracic <strong>Oncology</strong> Centre Munich, LMU Klinikum der<br />
Universität München, Munich, Germany, 10 Dept. <strong>of</strong> Hemato/<strong>Oncology</strong>, Klinik<br />
Kassel, Kassel, Germany<br />
Background: The immune surveillance reactivator lefitolimod (MGN1703), a<br />
DNA-based Toll-like receptor 9 (TLR9) agonist, was compared to placebo in metastatic<br />
CRC (mCRC) patients with disease control after standard induction chemotherapy in<br />
the double-blind randomized phase 2 IMPACT study. Lefitolimod showed a superior<br />
effect over placebo in exploratory analyses <strong>of</strong> pretreatment characteristics that identified<br />
patients most likely to benefit from lefitolimod. A study in small cell lung cancer<br />
(SCLC) patients, IMPULSE, was designed to confirm this preliminary evidence <strong>of</strong><br />
efficacy in a new, high-mortality-and-unmet-need indication.<br />
Trial design: Trial characteristics: IMPULSE is a randomized, international,<br />
multicenter, open-label trial to assess the effect <strong>of</strong> TLR9-mediated immune surveillance<br />
reactivation on overall survival (OS) in extensive-disease (ED) SCLC patients.<br />
Secondary endpoints include PFS, response rates, safety, and quality <strong>of</strong> life (QOL). The<br />
baseline stratification factors neuron-specific enolase (NSE) and activated NKT cells<br />
are prospectively assessed. 103 patients with objective tumor response following 4<br />
cycles <strong>of</strong> platinum-based first-line induction therapy were randomized to receive either<br />
lefitolimod switch-maintenance therapy or local standard <strong>of</strong> care in a 3:2 ratio. Upon<br />
relapse, patients are receiving appropriate second-line therapy. All patients take part in<br />
a comprehensive immune monitoring plan that will evaluate cytokines and<br />
chemokines in serum, and the activation status <strong>of</strong> various immune cell populations.<br />
Demographic characteristics: Out <strong>of</strong> 103 patients, 62 patients were allocated to the<br />
treatment arm; 41 to standard <strong>of</strong> care (control). Median age was 63 years (MGN1703)<br />
and 64 years (control). Male/female distribution was 39/22 and 29/12, respectively.<br />
Distribution <strong>of</strong> baseline stratification factors NKT activation (≧3.5%/ < 3.5%) between<br />
treatment and control arms was 41/20 and 26/15, for NSE levels (>20/≦20) 11/50 and<br />
8/33, respectively. The figures show that patients have been adequately distributed and<br />
balanced between the two treatment arms.<br />
Clinical trial identification: 2013-003503-19<br />
Legal entity responsible for the study: MOLOGEN AG<br />
Funding: MOLOGEN AG<br />
Disclosure: R. Carter: Employee at MOLOGEN AG. All other authors have declared<br />
no conflicts <strong>of</strong> interest.<br />
vi496 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong> 27 (Supplement 6): vi497–vi521, 2016<br />
doi:10.1093/annonc/mdw390<br />
supportive care<br />
1433O<br />
Phase 3 efficacy and safety trial <strong>of</strong> proposed pegfilgrastim<br />
biosimilar MYL-1401H vs EU-neulasta® in the prophylaxis <strong>of</strong><br />
chemotherapy-induced neutropenia<br />
C.F. Waller 1 , C. Blakeley 2 , E. Pennella 3 , M. Bronchud 4 , O. Berzoy 5 , N. Voitko 6 ,<br />
H. Adamchuk 7 , Z. Zautashvili 8 , Y. Vinnyk 9 , G. Nemsadze 10 , G. Dzagnidze 11 ,<br />
Y. Shparyk 12 , I. Lytvyn 13 , A. Rusyn 14 ,V.Popov 15 , I. Lang 16 , R. Sharma 17 ,<br />
M. Baczkowski 18 , M. Kothekar 19 , A. Barve 3<br />
1 Department <strong>of</strong> Haematology, <strong>Oncology</strong> and Stem Cell Transplantation, University<br />
Medical Centre Freiburg and Faculty <strong>of</strong> Medicine, University <strong>of</strong> Freiburg, Freiburg,<br />
Freiburg, Germany, 2 Medical and Scientific Affairs, Worldwide Clinical Trials,<br />
London, UK, 3 Global Clinical Research, Mylan, Canonsburg, PA, USA, 4 Clinical<br />
<strong>Oncology</strong>, Instituto Universitario USP Dexeus, Barcelona, Spain, 5 Mammology<br />
Center, Odessa Regional Hospital, Odessa, Ukraine, 6 Chemotherapy II, Kyiv City<br />
Clinical Oncological Centre, Kiev, Ukraine, 7 Chemotherapy, Kryviyi Rih <strong>Oncology</strong><br />
Dispensary <strong>of</strong> Dnipropetrovsk Regional Council, Kryvyi Rih, Ukraine, 8 Research<br />
Institute <strong>of</strong> Clinical Medicine, Research Institute <strong>of</strong> Clinical Medicine, Tbilisi,<br />
Georgia, 9 Department <strong>of</strong> General <strong>Oncology</strong> Surgery #2, Municipal Institution <strong>of</strong><br />
Healthcare “C”, Kharkiv, Ukraine, 10 Mammological center, Konstantine Madichi<br />
Mammalogy Center, Tbilisi, Georgia, 11 Breast Unit, S.Khechinashvili Hospital,<br />
Tbilisi, Georgia, 12 Department <strong>of</strong> Chemotherapy, Lviv State Regional Treatment<br />
and Diagnostics <strong>Oncology</strong> Center, Lviv, Ukraine, 13 Department <strong>of</strong> Chemotherapy,<br />
Dnipropetrovsk Regional Clinical <strong>Oncology</strong> Center, Dnepropetrovsk, Ukraine,<br />
14 Department <strong>of</strong> Chemotherapy, Transkarpathian Regional University <strong>Oncology</strong><br />
Clinic, Uzhgorod, Ukraine, 15 Department <strong>of</strong> Medical <strong>Oncology</strong> and Palliative Care,<br />
SHATOD Dr. Marko Аntonov Markov - Varna EOOD, Varna, Bulgaria, 16 Dept. Med.<br />
<strong>Oncology</strong> and Clin. Pharmacology B, National Institute <strong>of</strong> <strong>Oncology</strong>, Budapest,<br />
Hungary, 17 Global Product safety and Risk Management, Mylan, Hatfield, UK,<br />
18 Product Safety and Risk Management, Mylan, Morgantown, WV, USA, 19 Clinical<br />
Research, Biocon Research Limited, Bangalore, India<br />
1434O<br />
ONO-7643/anamorelin for the treatment <strong>of</strong> patients with<br />
non-small cell lung cancer and cachexia: results from phase<br />
2 study with Japanese patients<br />
J. Uchino 1 , N. Katakami 2 , T. Yokoyama 3 , T. Naito 4 , M. Kondo 5 , K. Yamada 6 ,<br />
H. Kitajima 7 , K. Yoshimori 8 ,K.Sato 9 , Y. Takiguchi 10 , K. Takayama 11 , K. Eguchi 12<br />
1 Department <strong>of</strong> respiratory medicine, Fukuoka University School <strong>of</strong> Medicine,<br />
Fukuoka, Japan, 2 Division <strong>of</strong> Integrated <strong>Oncology</strong>, Institute <strong>of</strong> Biomedical<br />
Research and Innovation, Kobe, Japan, 3 Department <strong>of</strong> Respiratory Medicine,<br />
Kyorin university Hospital, Mitaka, Japan, 4 Division <strong>of</strong> Thoracic <strong>Oncology</strong>, Shizuoka<br />
Cancer Center, Shizuoka, Japan, 5 Respiratory medicine, Nagoya University,<br />
Graduate School <strong>of</strong> Medicine, Nagoya, Japan, 6 Department <strong>of</strong> Thoracic <strong>Oncology</strong>,<br />
Kanagawa Cancer Center, Yokohama, Japan, 7 Department <strong>of</strong> Respiratory<br />
Medicine, Shikoku Cancer Center, Matsuyama, Japan, 8 Department <strong>of</strong> Clinical<br />
<strong>Oncology</strong>, Japan Anti-Tuberculosis Association, Fukujuji Hospital, Kiyose, Japan,<br />
9 Respiratory medicine, Nagaoka Red Cross Hospital, Nagaoka, Japan, 10 Dept. <strong>of</strong><br />
Medical <strong>Oncology</strong>, Chiba University, School <strong>of</strong> Medicine, Chiba, Japan,<br />
11 Department <strong>of</strong> Respiratory Medicine, Kyoto Prefectural University <strong>of</strong> Medicine,<br />
Kyoto, Japan, 12 Health Science on Supportive Medicine for Intractable Diseases,<br />
Teikyo University, Tokyo, Japan<br />
abstracts<br />
© European Society for Medical <strong>Oncology</strong> 2016. Published by Oxford University Press on behalf <strong>of</strong> the European Society for Medical <strong>Oncology</strong>.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com.
abstracts<br />
1435O<br />
Exploration <strong>of</strong> the heterogeneity <strong>of</strong> moderately emetogenic<br />
chemotherapy on response to fosaprepitant in a randomized<br />
phase 3 trial<br />
C. Weinstein 1 , K. Jordan 2 , S. Green 1 , E. Camacho 3 , S. Khanani 4 ,<br />
E. Beckford-Brathwaite 1 , W. Vallejos 1 , L.W. Liang 1 , S.J. Noga 5 , B.L. Rapoport 6<br />
1 Department <strong>of</strong> Clinical Research, Merck & Co., Inc., Kenilworth, NJ, USA,<br />
2 Department <strong>of</strong> Hematology and <strong>Oncology</strong>, Martin Luther University<br />
Halle-Wittenberg, Halle, Germany, 3 Department <strong>of</strong> Hematology and Medical<br />
<strong>Oncology</strong>, Comprehensive Cancer Center at the Desert Regional Medical Center,<br />
Palm Springs, CA, USA, 4 Department <strong>of</strong> Hematology/<strong>Oncology</strong>, Reliant Medical<br />
Group, Worcester, MA, USA, 5 Department <strong>of</strong> <strong>Oncology</strong>, Weinberg Cancer<br />
Institute, Baltimore, MD, USA, 6 Department <strong>of</strong> Medical <strong>Oncology</strong>, Medical<br />
<strong>Oncology</strong> Center <strong>of</strong> Rosebank, Johannesburg, South Africa<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Results: Of 471 studies identified, a total <strong>of</strong> 12 phase 3 RCTs involving 6,797 solid<br />
cancer patients comparing sorafenib with control met the eligibility criteria and<br />
included in this meta-analysis. 8 RCTs compared sorafenib alone with a placebo and 4<br />
RCTs compared sorafenib plus chemotherapy with chemotherapy plus placebo. The<br />
RCTs involved Hepatocellular carcinoma (HCC, n = 5), Melanoma (n= 2), non-small<br />
cell lung cancer ( n = 2), pancreatic cancer, renal cell carcinoma and thyroid cancer (<br />
n = 1 each). The overall incidence <strong>of</strong> SAEs and FAEs with sorafenib were 24.5% (95%<br />
CI: 16.0%-35.5%) and 1.6% (95% CI: 0.7%- 3.3%) respectively. Compared with control,<br />
sorafenib use significantly increased the risk <strong>of</strong> both SAEs ( RR : 1.51, 95% CI:<br />
1.20-1.92, P < 0.001) and FAEs ( RR : 1.84, 95% CI: 1.29-2.64, P = 0.001). This<br />
association varied significantly with cancer types ( P = 0.001) and approval status (<br />
P = 0.018) for SAEs but no evidence for heterogeneity was found for FAEs. The risk for<br />
SAEs was significantly higher for HCC (RR: 2.20, 95%CI: 1.18-4.10, P = 0.013) and<br />
non-approved use <strong>of</strong> sorafenib (RR: 1.68, 95% CI: 1.24-2.29, P = 0.001).<br />
Conclusions: This meta-analysis <strong>of</strong> phase 3 RCTs demonstrates an increased risk <strong>of</strong><br />
SAEs and FAEs with sorafenib use in patients with solid cancers. Special vigilance is<br />
recommended while using sorafenib in non-approved settings.<br />
Legal entity responsible for the study: N/A<br />
Funding: N/A<br />
Disclosure: Y. Ando: San<strong>of</strong>i, Torii, Mitsubishi Tanabe, Mochida, Chugai, Takeda,<br />
DaiichiSankyo, Kyowa Kirin, Eisai,Taiho, Nippon Kayaku, Yakult Honsya, Merck Serono,<br />
Hisamitsu, Ono, Eli Lilly, Pfizer, Novartis, Janssen, AstraZeneca, GSK,Terumo, Bayel,<br />
Boehringer Ingelheim,BMS. All other authors have declared no conflicts <strong>of</strong> interest.<br />
1437PD<br />
Pooled analysis <strong>of</strong> treatment-related hypothyroidism with<br />
anti-PD-1/PD-L1 therapies in cancer patients<br />
S. Hong, W. Fang, L. Zhang<br />
State Key Laboratory <strong>of</strong> <strong>Oncology</strong> in South China, Sun Yat-sen University Cancer<br />
Center, Guangzhou, China<br />
Background: Blockade <strong>of</strong> programmed death 1 (PD-1), or its ligand, PD-L1, could<br />
restore T-cell immunity. Anti-PD-1/ or anti-PD-L1 antibodies have demonstrated<br />
promising efficacy in the treatment <strong>of</strong> cancer patients. The toxicity spectrum <strong>of</strong> PD-1/<br />
PD-L1 blockers is distinct from chemotherapy or other target agents. This study aims<br />
to investigate the overall incidence <strong>of</strong> treatment-related hypothyroidism with<br />
anti-PD-1/PD-L1 therapies in cancer patients.<br />
Methods: A systematic search <strong>of</strong> literature up to January 2016 was performed in<br />
EDLINE, EMBASE, and Cochrane databases to identify relevant clinical trials. Paired<br />
reviewers independently selected articles for inclusion and extracted data. Pooled<br />
incidence was calculated using Comprehensive Meta-analysis using fixed or random<br />
effects model depending the heterogeneity <strong>of</strong> the included studies.<br />
Results: A total <strong>of</strong> 23 clinical trials with 5290 patients were included. The overall<br />
incidence <strong>of</strong> all- and high-grade hypothyroidism in cancer patients receiving<br />
anti-PD-1/PD-L1 therapies were 7.3% (95% CI, 5.9% to 9.1%) and 0.4% (95% CI, 0.2%<br />
to 0.7%), respectively. Adding anti-CTLA-4 antibodies to PD-1/PD-L1 blockers led to<br />
increased incidence <strong>of</strong> all-grade fatigue (16.4% vs. 6.4%, p < 0.001), but not high-grade<br />
fatigue (0.3% vs. 0.4%). When stratified by cancer type, trial phase, drug category or<br />
drug dosage, no notably differences in the incidence <strong>of</strong> hypothyroidism were seen.<br />
Conclusions: Hypothyroidism is commonly seen with anti-PD-1/PD-L1 therapies in<br />
cancer patients. Early and appropriate management is required to avoid unnecessary<br />
dose reductions and transitory or definitive treatment discontinuations.<br />
Legal entity responsible for the study: Sun Yat-sen University Cancer Center<br />
Funding: National Natural Science Funds <strong>of</strong> China (Grant No: 81372502)<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1436PD<br />
Risk <strong>of</strong> serious adverse events (SAEs) and fatal adverse<br />
events (FAEs) with sorafenib use in patients with solid<br />
cancers: a meta-analysis <strong>of</strong> phase 3 RCTs<br />
B. Gyawali, T. Shimokata, K. Honda, Y. Ando<br />
Clinical <strong>Oncology</strong> and Chemotherapy, Nagoya University, Graduate School <strong>of</strong><br />
Medicine, Nagoya, Japan<br />
Background: Sorafenib is a commonly used vascular endothelial growth<br />
factor-tyrosine kinase inhibitor in a variety <strong>of</strong> cancers. There are concerns about the<br />
increased risk <strong>of</strong> SAEs and FAEs with sorafenib. We performed an up-to-date<br />
meta-analysis <strong>of</strong> all phase 3 randomized controlled trials (RCTs) <strong>of</strong> sorafenib to<br />
quantify the increased risk <strong>of</strong> SAEs and FAEs.<br />
Methods: We carried out a systematic search on PubMed for studies published in<br />
English. Eligibility criteria included phase 3 RCTs <strong>of</strong> solid tumors comparing<br />
sorafenib, alone or in combination with non-targeted chemotherapy (Sorafenib arm)<br />
versus placebo or non-targeted chemotherapy (control arm). Data on SAEs and FAEs<br />
for both the arms were extracted from each study and pooled to determine the overall<br />
incidence, relative risks (RRs) and 95% Confidence Intervals (CIs).<br />
1438PD<br />
Identifying cancer patients at high risk for<br />
chemotherapy-induced nausea and vomiting (CINV): the<br />
development <strong>of</strong> a prediction tool<br />
G. Dranitsaris 1 , A. Molasiotis 2 , M. Clemons 3 , E. Roeland 4 , L. Schwartzberg 5 ,<br />
D. Warr 6 , K. Jordan 7 , P. Dielenseger 8 , M.S. Aapro 9<br />
1 Outcomes Research, Augmentium Pharma Consulting Inc, Toronto, ON,<br />
Canada, 2 School <strong>of</strong> Nursing, Hong Kong Polytechnic University, Hong Kong,<br />
China, 3 Division <strong>of</strong> Medical <strong>Oncology</strong>, The Ottawa Hospital Regional Cancer<br />
Centre, Ottawa, ON, Canada, 4 Hematology & <strong>Oncology</strong>, Moores UCSD Cancer<br />
Center, La Jolla, CA, USA, 5 Hematology & <strong>Oncology</strong>, The West Clinic, Memphis,<br />
TN, USA, 6 Hematology and Medical <strong>Oncology</strong>, Princess Margaret Cancer Centre,<br />
Toronto, ON, Canada, 7 Medical <strong>Oncology</strong> & Hematology, Martin Luther University<br />
<strong>of</strong> Halle, Halle, Germany, 8 Drug Development, Institut de Cancérologie Gustave<br />
Roussy, Villejuif, France, 9 Division <strong>of</strong> Medical <strong>Oncology</strong>, Clinique de Genolier,<br />
Genolier, Switzerland<br />
Background: Nausea and vomiting (N&V) remain among the most feared side effects<br />
<strong>of</strong> chemotherapy (CT). In addition to type <strong>of</strong> CT, several patient risk factors for CINV<br />
have been consistently reported in the literature. A large dataset was assembled to<br />
develop a repeated measures cycle based model that would accurately predict the risk<br />
<strong>of</strong> ≥ grade 2 CINV (≥3 vomiting episodes) over 5 days post CT.<br />
vi498 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
Methods: CINV outcomes and risk factor data were obtained from 1198 patients<br />
enrolled in 1 <strong>of</strong> 5 non-interventional prospective cohort studies. For the cycle-based<br />
risk model, disease and treatment factors that were potential predictors <strong>of</strong> CINV were<br />
identified at baseline and after each cycle <strong>of</strong> CT. Factors with a p-value < 0.05 following<br />
a CT cycle were retained and included in a generalized estimating equations (GEE)<br />
regression analysis. A risk scoring algorithm (range: 0-32) derived from the final model<br />
coefficients was then developed. As a final step, the predictive accuracy <strong>of</strong> the algorithm<br />
was assessed via a receiver operating characteristic curve (ROC) analysis.<br />
Results: Over 4197 cycles <strong>of</strong> CT, 42.2% <strong>of</strong> patients experienced ≥ grade 2 CINV. Ten risk<br />
factors were retained in the final model (eg, age
abstracts<br />
Disclosure: K. Jordan: Consulting or Advisory Role: Merck, MSD, Helsinn Healthcare,<br />
Tesaro. B.L. Rapoport: Consulting or Advisory Role: Tesaro, Merck; Speakers’ Bureau:<br />
Tesaro, Merck; Travel, Accommodations, Expenses: Tesaro, Merck; Honoraria: Tesaro,<br />
Merck. I. Schnadig: Advisory Board: Tesaro. S. Arora, D. Powers: Employment: Tesaro.<br />
L. Schwartzberg: Consulting or Advisory Role: Eisai, Teva, Amgen, Genentech,<br />
Bristol-Myers Squibb; Leadership: Vector <strong>Oncology</strong>; Speakers’ Bureau: Genentech,<br />
Novartis, Bristol-Myers Squibb; Stock and Other Ownership Interests: Vector<br />
<strong>Oncology</strong>; Research Funding: Eisa. All other authors have declared no conflicts <strong>of</strong><br />
interest.<br />
1441P<br />
Efficacy and safety <strong>of</strong> rolapitant in the prevention <strong>of</strong><br />
chemotherapy-induced nausea and vomiting (CINV) in elderly<br />
patients<br />
M.S. Aapro 1 ,S.Arora 2 , D. Powers 3<br />
1 <strong>Oncology</strong>, IMO Clinique de Genolier, Genolier, Switzerland, 2 Biostatistics,<br />
TESARO, Inc., Waltham, MA, USA, 3 Medical Affairs, TESARO, Inc., Waltham, MA,<br />
USA<br />
Background: Although older patients (pts) may have less CINV compared with<br />
younger ones, preventative treatments with a good safety pr<strong>of</strong>ile are needed. This<br />
analysis evaluates the efficacy and safety <strong>of</strong> the long-acting neurokinin-1 receptor<br />
antagonist (RA) rolapitant according to pt age (
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Legal entity responsible for the study: TESARO, Inc.<br />
Funding: TESARO, Inc.<br />
Disclosure: L. Schwartzberg: Consulting or Advisory Role: Eisai, Teva, Amgen,<br />
Genentech, Bristol-Myers Squibb; Leadership: Vector <strong>Oncology</strong>; Speakers’ Bureau:<br />
Genentech, Novartis, Bristol-Myers Squibb; Stock and Other Ownership Interests:<br />
Vector <strong>Oncology</strong>; Research Funding: Eisai. K. Jordan: Consulting or Advisory Role:<br />
Merck, MSD, Helsinn Healthcare, Tesaro. B.L. Rapoport: Consulting or Advisory Role:<br />
Tesaro, Merck; Speakers’ Bureau: Tesaro, Merck; Travel, Accommodations, Expenses:<br />
Tesaro, Merck; Honoraria: Tesaro, Merck. I. Schnadig: Advisory Board: Tesaro. S.<br />
Arora, D. Powers: Employment: Tesaro, Inc. All other authors have declared no<br />
conflicts <strong>of</strong> interest.<br />
1443P<br />
Systematic review <strong>of</strong> the efficacy and safety <strong>of</strong> neurokinin-1<br />
receptor antagonists for chemotherapy-induced nausea and<br />
vomiting: identification <strong>of</strong> the relevant clinical trials<br />
G. Lyman 1 , D. King 2 , O. Evuarhehe 2 , D. Powers 3 , B. Harrow 4<br />
1 Medicine, Fred Hutchinson Cancer Research Center, Seattle, WA, USA,<br />
2 HealthScience, Oxford PharmaGenesis Ltd, Oxford, UK, 3 Medical Affairs,<br />
TESARO, Inc., Waltham, MA, USA, 4 Health Economics and Outcomes Research,<br />
TESARO, Inc., Waltham, MA, USA<br />
Background: Chemotherapy-induced nausea and vomiting (CINV) is a common<br />
debilitating side-effect <strong>of</strong> chemotherapy. Antiemesis guidelines recommend<br />
combinations <strong>of</strong> neurokinin-1 receptor antagonists (NK-1RAs), dexamethasone and<br />
serotonin receptor antagonists (5-HT 3 RAs) to prevent CINV in patients receiving<br />
highly emetogenic chemotherapy (HEC) and select patients receiving moderately<br />
emetogenic chemotherapy (MEC). Here, we report a systematic review aimed to assess<br />
the availability <strong>of</strong> direct or indirect evidence for safety and efficacy <strong>of</strong> rolapitant versus<br />
other NK-1RAs.<br />
Methods: A systematic review was conducted to identify randomized control trials<br />
(RCTs) comparing NK-1RAs with any comparator via MEDLINE, Embase, Cochrane<br />
databases, meeting proceedings, ClinicalTrials.gov, World Health Organization, clinical<br />
trials registry platform, FDA.gov and European Union Clinical trials register websites.<br />
We followed prespecified inclusion and exclusion criteria, screened eligible studies<br />
using the 2009 Preferred Reporting Items for Systematic Reviews and Meta-Analyses<br />
(PRISMA) guidelines, and assessed the quality <strong>of</strong> the evidence using a checklist<br />
recommended by NICE for RCT quality assessment.<br />
Results: 29 publications (22 articles; 7 abstracts) on 29 RCTs met the inclusion criteria.<br />
Complete response (no vomiting, no use <strong>of</strong> rescue medication) in the overall, delayed,<br />
and acute phase was a primary outcome in eleven, seven, and three RCTs, respectively.<br />
Rolapitant in combination with 5-HT 3 RA/dexamethasone was compared with<br />
5HT 3 RA/dexamethasone in three RCTs, in patients undergoing HEC or MEC. No<br />
RCT compared rolapitant with other NK-1RAs; however, 19 RCTs were relevant for<br />
indirect comparison.<br />
Conclusions: We identified the RCTs evaluating NK-1RAs for CINV prevention in<br />
patients undergoing HEC or MEC. The lack <strong>of</strong> direct comparison between rolapitant<br />
and other NK-1RAs suggests the need for an indirect comparison via a network<br />
meta-analysis. Results for the indirect comparison for the outcomes complete response,<br />
no vomiting, and no nausea during the delayed and overall phases will be available at<br />
the time <strong>of</strong> the presentation.<br />
Legal entity responsible for the study: TESARO, Inc.<br />
Funding: TESARO, Inc.<br />
Disclosure: G. Lyman: Research Grant: Amgen. D. Powers, B. Harrow: Employment:<br />
Tesaro, Inc. All other authors have declared no conflicts <strong>of</strong> interest.<br />
1444P<br />
Impact <strong>of</strong> chemotherapy-induced nausea and vomiting (CINV)<br />
on emergency department (ED) visits and disruption <strong>of</strong><br />
chemotherapy: results <strong>of</strong> a survey <strong>of</strong> oncology nurses<br />
C. Rittenberg 1 , R. Clark-Snow 2 , M.L. Affronti 3<br />
1 Medical <strong>Oncology</strong>, Rittenberg <strong>Oncology</strong> Consulting, Metairie, LA, USA, 2 Medical<br />
<strong>Oncology</strong>, University <strong>of</strong> Kansas Cancer Center, Westwood, KS, USA, 3 School <strong>of</strong><br />
Nursing, Duke University, Durham, NC, USA<br />
Background: Prevention <strong>of</strong> CINV is possible in most patients undergoing emetogenic<br />
chemotherapy with the current antiemetic armamentarium. Because nurses play a<br />
critical role in symptom management and supportive care, a survey <strong>of</strong> oncology nurses<br />
was conducted to (1) assess practice patterns <strong>of</strong> antiemetic use for prevention <strong>of</strong> CINV,<br />
(2) determine adherence to guideline recommendations and (3) query barriers to<br />
adherence. Estimates <strong>of</strong> CINV control rates and proportions <strong>of</strong> patients having<br />
chemotherapy postponed/stopped/changed or requiring ED/hospital visits due to<br />
CINV was also evaluated and is the focus <strong>of</strong> this abstract.<br />
Methods: In Sept 2015, 531 US-based oncology nurses participated in an online survey<br />
administered and analyzed by ONS:Edge.<br />
Results: The majority <strong>of</strong> respondents were staff nurses (73%) working in the outpatient<br />
setting (64%) with >5 years <strong>of</strong> oncology experience (70%). Practice patterns <strong>of</strong> antiemetic<br />
use revealed low adherence to antiemetic guidelines, particularly during the delayed<br />
(25-120h) phase following highly emetogenic chemotherapy, where only 25% <strong>of</strong> nurses<br />
reported administration <strong>of</strong> guideline-recommended agents. Only 17% reported most<br />
(>75%) <strong>of</strong> their patients having CINV optimally controlled; 39% reported between<br />
6-20% <strong>of</strong> patients have an alteration in their chemotherapy due to CINV, and reports <strong>of</strong><br />
ED/hospital visits due to poorly controlled CINV were high (Table).<br />
Response Options<br />
Table: 1444P<br />
% Patients with Complete Response (No Emesis/<br />
Rescue Use) 30%<br />
Any Patients Requiring Emergency Visits or<br />
Hospitalization Due to Poorly Controlled CINV<br />
Yes No Unsure<br />
Percentage Total<br />
Respondents<br />
11% 34% 38% 17%<br />
14% 37% 26% 13%<br />
5% 4%<br />
61% 22% 17%<br />
Conclusions: This nursing survey revealed poor adherence to antiemetic guideline<br />
recommendations, low CINV control rates and a surprisingly high proportion <strong>of</strong><br />
patients having changes made to their cancer treatment or ED/hospital visits due to<br />
poorly controlled CINV. There is a critical need to address barriers interfering with use<br />
<strong>of</strong> guideline-recommended antiemetics in order to optimize CINV control for patients<br />
undergoing emetogenic chemotherapy.<br />
Legal entity responsible for the study: ONS: Edge<br />
Funding: Eisai, Inc.<br />
Disclosure: C. Rittenberg: Stock in Amgen, Abbott labs, Abbie Vie, Biogen, Celgene, J<br />
& J, Novartis, Eli Lily, Gilead, Merck, Pfizer; Consultant for Heron. R. Clark-Snow:<br />
Honoraria received from Merck and Tesaro Consutant/Advisor for Merck and Tesaro<br />
Speaker’s Bureau for Merck. M.L. Affronti: Research funding from Eisai, Merck and<br />
Amgen for investigator-initiated trials.<br />
1445P<br />
abstracts<br />
Efficacy <strong>of</strong> rikkunshito, a Japanese herbal medicine, on<br />
nausea, vomiting and anorexia in patients with uterine<br />
cervical or corpus cancer treated with cisplatin and<br />
paclitaxel –A randomized phase II study<br />
S. Ohnishi 1 , H. Watari 2 , M. Kanno 3 ,Y.Oba 4 , S. Takeuchi 5 , T. Miyaji 6 ,<br />
S. Oyamada 7 , E. Nomura 3 ,H.Kato 4 , T. Sugiyama 5 , M. Asaka 8 , N. Sakuragi 2 ,<br />
T. Yamaguchi 9 , Y. Uezono 10 , S. Iwase 11<br />
1 Department <strong>of</strong> Gastroenterology and Hepatology, Hokkaido University Hospital,<br />
Sapporo, Japan, 2 Department <strong>of</strong> Obstetrics and Gynecology, Hokkaido University<br />
Hospital, Sapporo, Japan, 3 Department <strong>of</strong> Obstetrics and Gynecology, Oji General<br />
Hospital, Tokamkomai, Japan, 4 Division <strong>of</strong> Gynecologic <strong>Oncology</strong>, Hokkaido<br />
Cancer Center, Sapporo, Japan, 5 Department <strong>of</strong> Obsterics and Gynecology,<br />
Iwate Medical University School <strong>of</strong> Medicine, Morioka, Japan, 6 Department <strong>of</strong><br />
Clinical Trial Data Management, The University <strong>of</strong> Tokyo Graduate School <strong>of</strong><br />
Medicine, Tokyo, Japan, 7 Department <strong>of</strong> Biostatistics, Japanese Organisation for<br />
Research and Treatment <strong>of</strong> Cancer, Tokyo, Japan, 8 Department <strong>of</strong> Cancer<br />
Preventive Medicine, Hokkaido University Graduate School <strong>of</strong> Medicine, Sapporo,<br />
Japan, 9 Clinical Research Data Center, Tohoku University Graduate School <strong>of</strong><br />
Medicine, Sendai, Japan, 10 Division <strong>of</strong> Cancer Pathophysiology, National Cancer<br />
Center Research Institute, Tokyo, Japan, 11 Palliative medicine, University <strong>of</strong><br />
Tokyo-Research hospital,The Institute <strong>of</strong> Medical Science, Tokyo, Japan<br />
Background: Although antagonists for 5-HT3 and NK-1 receptors and corticosteroids<br />
are used for the treatment <strong>of</strong> chemotherapy-induced nausea and vomiting (CINV), this<br />
treatment is still insufficient. Rikkunshito (RKT), a Japanese herbal medicine, is widely<br />
prescribed in Japan to treat various gastrointestinal disorders, and has been reported to<br />
recover the decreases in food intake and serum ghrelin levels caused by cisplatin<br />
(CDDP) in animal models (Gastroenterology 2008;134:2004-13). We thus investigated<br />
whether RKT could improve CINV in patients receiving CDDP and paclitaxel (PTX).<br />
Methods: Patients with histologically diagnosed uterine cervical or corpus cancer who<br />
were planned to receive CDDP and PTX as first-line chemotherapy were included.<br />
Patients were randomly assigned to the RKT group receiving oral administration <strong>of</strong><br />
RKT 7.5 g/day for 14 days with standard antiemetics (granisetron, aprepitant and<br />
dexamethasone), or the control group receiving only standard antiemetics. The<br />
primary endpoint was complete control rate (CCR) in the overall phase (0-120 hours<br />
after CDDP administration), and secondary endpoints were complete response rate<br />
(CRR), total control rate, time to treatment failure, appetite and nausea assessed by<br />
VAS, FAACT anorexia and cachexia subscale scores, EORTC-QLQ-C30 scores, grade<br />
<strong>of</strong> appetite/nausea/vomiting by CTCAE v4.0, and serum level <strong>of</strong> ghrelin. Two-sided P<br />
value
abstracts<br />
(24-120 hours after CDDP administration) and CRR in overall and delayed phases<br />
were also significantly higher in the RKT group than control group (63.2% vs 35.3%,<br />
P = 0.095; 84.2% vs 52.9%, P = 0.042; 84.2% vs 52.9%, P = 0.042, respectively).<br />
Conclusions: The primary endpoint CCR in the overall phase was achieved, and RKT<br />
would improve CINV, especially in the delayed phase.<br />
Clinical trial identification: UMIN000011227<br />
Legal entity responsible for the study: Japanese Organisation for Research and<br />
Treatment <strong>of</strong> Cancer<br />
Funding: The Third-term Comprehensive 10-year Strategy for Cancer Control<br />
(H22-General-035) from the Ministry <strong>of</strong> Health, Labour and Welfare, Japan<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1446P<br />
Anamorelin in cachectic patients with non-small cell lung<br />
cancer (NSCLC) and acute phase protein reaction (APPR):<br />
Pooled analysis <strong>of</strong> two phase 3 trials (ROMANA 1 and<br />
ROMANA 2)<br />
D. Currow 1 , J. Temel 2 , A. Abernethy 3 , J. Friend 4 , R. Giorgino 5 , K.C. Fearon 6<br />
1 Discipline <strong>of</strong> Palliative and Supportive Services, Flinders University, Adelaide,<br />
Australia, 2 Hematology/<strong>Oncology</strong>, Massachusetts General Hospital Cancer<br />
Center, Boston, MA, USA, 3 Flatiron Health, New York, NY, USA, 4 R&D, Helsinn<br />
Therapeutics (US), Inc, Iselin, NJ, USA, 5 R&D, Helsinn Healthcare SA,<br />
Pambio-Noranco, Switzerland, 6 Surgery, Royal Infirmary, Edinburgh, UK<br />
Background: Cancer anorexia-cachexia frequently occurs in NSCLC patients, may be<br />
accompanied by systemic inflammation, and results in reduced muscle/lean body mass<br />
(LBM) and decreased appetite. The randomized, phase 3, double-blind ROMANA 1<br />
(NCT01387269; N = 484) and ROMANA 2 (NCT01387282; N = 495) trials in<br />
cachectic NSCLC patients demonstrated that the ghrelin receptor agonist anamorelin<br />
improved LBM, body weight, fat mass (FM), and symptom burden compared with<br />
placebo, and was well tolerated. This analysis compared the efficacy <strong>of</strong> anamorelin in<br />
patients with or without an APPR (C-reactive protein [CRP] >10 or ≤10 mg/L,<br />
respectively).<br />
Methods: Patients with stage III/IV NSCLC and cachexia (≥5% weight loss during<br />
prior 6 months or body mass index 25kg/m 2 , while only<br />
4.6% had visible malnutrition (BMI < 18.5kg/m 2 ). 36% <strong>of</strong> patients had lost >5% body<br />
weight in 6 months, 44% had CC, 40% were sarcopenic, 47% had myosteatosis, 24%<br />
had both. In terms <strong>of</strong> QOL, weight loss >5% and cancer cachexia were significantly<br />
associated with a poorer global QOL score, as well as worse physical, role, emotional<br />
and social function scores (all p < 0.005) and higher symptoms such as fatigue, nausea<br />
and vomiting, pain, appetite and diarrhoea (all p < 0.05). Sarcopenia, myosteatosis and<br />
CC were all significantly associated with reduced survival, with the highest risk <strong>of</strong><br />
mortality seen in those with both myosteatosis and sarcopenia. Median survival was<br />
583 days (95% CI 391-774 days) vs. 1001 days in those without both conditions (95%<br />
CI 746-1256 days; log rank p =
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
1449P<br />
Phase II study <strong>of</strong> pregabalin for the prevention <strong>of</strong><br />
chemotherapy induced nausea and vomiting<br />
C.S. Rossi 1 , F.M. Cruz 2 , A. del Giglio 2 , C.M. Rodrigues 1 , S.N. Castro 1<br />
1 <strong>Oncology</strong>, IBCC Instituto Brasileiro de Controle do Cancer, Sao Paulo, Brazil,<br />
2 <strong>Oncology</strong>, Faculdade de Medicina do ABC, Santo André, Brazil<br />
Background: Previous studies showed that anticonvulsants might improve the<br />
prevention <strong>of</strong> chemotherapy-induced nausea and vomiting (CINV). Pregabalin is a<br />
structural derivative <strong>of</strong> the inhibitory neurotransmitter γ-aminobutyric acid. It binds<br />
potently to the calcium channels, resulting in a reduction in the release <strong>of</strong> several<br />
neurotransmitters including glutamate, noradrenaline, serotonin, dopamine, and<br />
substance P. Some <strong>of</strong> these transmitters are involved on the physiophathology <strong>of</strong><br />
nausea and vomiting. To our knowledge, the antiemetic role <strong>of</strong> pregabalin hasn’t been<br />
investigated yet.<br />
Methods: We performed a phase II randomized, double-blind, placebo-controlled trial<br />
to investigate if pregabalin could improve the complete control <strong>of</strong> nausea and vomiting<br />
(primary end point). We enrolled eighty two chemotherapy-naive patients, scheduled<br />
to receive moderately and highly emetogenic chdmotherapy. All patients received IV<br />
ondansetron 8 mg, dexamethasone 10 mg and ranitidine 50 mg before chemotherapy<br />
on day 1 and oral dexamethasone 4 mg, bd, on days 2 and 3. Patients were randomly<br />
assigned to take pregabalin 75 mg or placebo, bd, from the night before chemotherapy<br />
to day 5. All patients received a diary to record the moment <strong>of</strong> failure, considered in<br />
this study as any episode <strong>of</strong> emesis, moderate or severe nausea or use <strong>of</strong> rescue<br />
medication. We used chi2 test to evaluate the difference <strong>of</strong> proportions between groups.<br />
Results: The overall complete response were 53.7 vs.48.8% respectively in the<br />
pregabalin and control group (p = 0.65). There was also no significant difference<br />
during the acute phase(first 24h) or delayed phase (24-120h): 80.5% vs 82.9%<br />
(p = 0.77), 53.7 vs 51.2% (p = 0.82).<br />
Conclusions: There is no role for pregabalin in the prevention <strong>of</strong> chemotherapy<br />
induced nausea and vomiting.<br />
Clinical trial identification: CAAE 49488915.1.0000.0072 Date 08/20/2015<br />
Legal entity responsible for the study: IBCC Instituto Brasileiro de Controle do<br />
Cancer<br />
Funding: IBCC Instituto Brasileiro de Controle do Cancer<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1450P<br />
Transdermal granisetron for the prevention <strong>of</strong><br />
chemotherapy-induced nausea and vomiting in metastatic<br />
colorectal cancer patients with high risk <strong>of</strong> bowel obstruction<br />
treated with temozolomide<br />
M.A. Calegari 1 , S. Monterisi 1 , A. Orlandi 1 , A. Inno 2 , R. Barile 1 , S. Corallo 1 ,C.Di<br />
Dio 1 , V. Zurlo 1 , M. Basso 1 , A. Cassano 1 , C. Barone 1<br />
1 Medicina Interna - U.O.C. di Oncologia Medica, Policlinico Universitario<br />
A. Gemelli, Rome, Italy, 2 Medical <strong>Oncology</strong>, Ospedale S.Cuore, Negrar, Italy<br />
Background: Temozolomide (TMZ) showed efficacy in patients with refractory<br />
metastatic colorectal cancer (mCRC) and MGMT promoter methylation. As<br />
moderately emetogenic chemotherapy, TMZ requires administration <strong>of</strong> 5HT3<br />
antagonists for chemotherapy-induced nausea and vomiting (CINV) prevention. Both<br />
TMZ and 5HT3 antagonists could cause constipation; besides mCRC patients might<br />
have a high risk <strong>of</strong> bowel obstruction due to disease features (adhesions, local relapses<br />
and peritoneal carcinomatosis) and use <strong>of</strong> opioids. In an ongoing phase II trial we<br />
performed an exploratory analysis to compare efficacy and safety <strong>of</strong> two antiemetic<br />
regimens with different risk <strong>of</strong> constipation.<br />
Methods: 32 patients with refractory MGMT hypermethylated mCRC receiving TMZ<br />
(200 mg/m 2 /day on days 1-5 every 4 weeks) were assigned with a ratio <strong>of</strong> 2:1 to oral<br />
metoclopramide (10 mg PO TID on days 1-5) or transdermal granisetron (Sancuso®)<br />
(3.1 mg/24 h on days 1-7). Patient filled in a diary reporting nausea, emetic episodes<br />
and constipation. Adverse events were recorded and scored according to CTCAE. A<br />
two-sided Fisher’s exact test was used to evaluate differences in nausea, vomiting,<br />
constipation and bowel obstruction (p-value
abstracts<br />
1452P<br />
Risk model for clinically relevant neutropenic event among<br />
patients with non hematological tumors receiving<br />
chemotherapy regimens not classified as high-risk for febrile<br />
neutropenia: results from a multicenter prospective cohort<br />
study (NEURISK)<br />
J. Muñoz-Langa 1 , P. Borrega 2 , J.M. García-Bueno 3 , P. Purificación Martínez del<br />
Prado 4 , J.M. Campos 5 , M. Quindos 6 , R. López Castro 7 , V. Valentí Moreno 8 ,<br />
E. Jiménez Orozco 9 , M. Lazaro 10<br />
1 Medical <strong>Oncology</strong>, Hospital Universitari i Politècnic La Fe, Valencia, Spain,<br />
2 Medical <strong>Oncology</strong>, Hospital San Pedro Alcántara, Alcántara, Spain, 3 Medical<br />
<strong>Oncology</strong>, Complejo Hospitalario Universitario de Albacete, Albacete, Spain,<br />
4 Medical <strong>Oncology</strong>, Hospital de Basurto, Bilbao, Spain, 5 Medical <strong>Oncology</strong>,<br />
Hospital Arnau de Vilanova, Valencia, Spain, 6 Medical <strong>Oncology</strong>, Complejo<br />
Hospitalario Arquitecto Marcide-Pr<strong>of</strong>. Novoa Santos, A Coruna, Spain, 7 Medical<br />
<strong>Oncology</strong>, University Hosptial de Valladolid, Valladolid, Spain, 8 Medical <strong>Oncology</strong>,<br />
Hospitasl Santa Tecla, Tarragona, Spain, 9 Medical <strong>Oncology</strong>, Hospital de Jerez,<br />
Jerez De La Frontera, Spain, 10 Medical <strong>Oncology</strong>, Complejo Universitario<br />
Hospitalario De Vigo, Vigo, Spain<br />
Background: Primary prophylaxis with G-CSF is not indicated in patients with solid<br />
tumors treated with chemotherapy with low or intermediate risk (
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
leukopenia and renal dysfunction. To avoid them, dose reduction <strong>of</strong> TMP-SMX could<br />
be considerable. Rituximab plus CHOP therapy (R-CHOP) is a standard treatment for<br />
B-cell lymphoma. Since rituximab is immunosuppressive, prophylaxis <strong>of</strong> PCP is widely<br />
introduced. In our institute, low-dose TMP-SMX has been employed in such<br />
situations. To assess the efficacy and tolerability <strong>of</strong> the regimen, retrospective analysis<br />
was performed.<br />
Methods: We reviewed patients with newly diagnosed B-cell lymphoma who<br />
completed 6 to 8 cycles <strong>of</strong> R-CHOP in our institute. In all patients, low-dose<br />
TMP-SMX consisting <strong>of</strong> 1 tablet twice a day, twice a week (4 tablets/week) was started<br />
simultaneously with R-CHOP. To improve medication adherence, administration day<br />
was fixed on Tuesday and Friday.<br />
Results: From January 2009 to September 2014, 292 patients with a median age <strong>of</strong> 67<br />
(21-89) were treated. They included diffuse large B-cell lymphoma (n = 213), follicular<br />
lymphoma (n = 65), mantle cell lymphoma (n = 6) and others (n = 8). The median<br />
length <strong>of</strong> prophylaxis from the last day <strong>of</strong> R-CHOP was 5.7 (0.6-16.6) months. The<br />
median lymphocyte count decreased from 1.1 (0.07-19.2) to 0.4 (0.03-1.4) x 10 9 /L<br />
during treatment. Of 292 patients, 291 showed no evidence <strong>of</strong> PCP. Although 1 patient<br />
developed PCP, the diagnosis was given on day 12 <strong>of</strong> the first cycle indicating that the<br />
patient already had PCP before the initiation <strong>of</strong> prophylaxis. In the other 291 patients,<br />
TMP-SMX was well tolerated and no related adverse event was observed.<br />
Conclusions: Four tablets <strong>of</strong> TMP-SMX a week may be sufficient to prevent PCP<br />
during R-CHOP. In addition, minimum toxicities are expected by this method. As<br />
demonstrated in our study, the elderly patients who need R-CHOP are increasing. In<br />
this context, our data provide a valuable insight into the total strategy <strong>of</strong> lymphoma<br />
treatment.<br />
Legal entity responsible for the study: Chiba Cancer Center<br />
Funding: Chiba Cancer Center<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1456P<br />
Underutilization <strong>of</strong> G-CSF in elderly cancer patients – an<br />
issue that needs to be urgently addressed<br />
M. Saar 1 , I-I. Sei 2 , J. Jaal 3<br />
1 Pharmacy, Tartu University Hospital, Tartu, Estonia, 2 Pharmacy Institute, Tartu<br />
University, Tartu, Estonia, 3 Hematology-<strong>Oncology</strong> Clinic, Tartu University Hospital,<br />
Tartu, Estonia<br />
Background: Chemotherapy-induced febrile neutropenia (FN) is a potentially<br />
life-threatening side-effect <strong>of</strong> chemotherapy. Prophylactic use <strong>of</strong> granylocyte colony<br />
stimulating factors (G-CSF) reduces the risk <strong>of</strong> FN. G-CSFs also appear to reduce cost<br />
and improve patients’ quality <strong>of</strong> life. The aim <strong>of</strong> our study was to assess the use <strong>of</strong><br />
G-CSF among elderly cancer patients (≥70 years), i.e. in a group <strong>of</strong> patients with<br />
shortest survival rates.<br />
Methods: We conducted a retrospective medical record review in tertiary hospital. A<br />
total <strong>of</strong> 176 chemotherapy order forms from January to February 2015 were analyzed.<br />
The use <strong>of</strong> G-CSF was compared to European Organization for Research and<br />
Treatment <strong>of</strong> Cancer and National Comprehensive Cancer Network guidelines.<br />
Results: Out <strong>of</strong> 176 patients, 82 were male and 94 female. The patients were 70 to 93<br />
years old (average 76.4). The most common diagnose among men was colorectal<br />
cancer (n = 31) and among women breast cancer (n = 36). Chemotherapy regimens<br />
with high risk <strong>of</strong> FN were prescribed to 13 (4.2%) and with intermediate risk to 13<br />
(4.2%) patients. According to the guidelines, prophylactic use <strong>of</strong> G-CSF is indicated for<br />
all patients with high risk regimens and for selected patients (with additional risk<br />
factors, including age >65) with intermediate risk regimens. Our study revealed that<br />
none <strong>of</strong> the elderly patients in intermediate risk chemotherapy group received G-CSF.<br />
Moreover, most <strong>of</strong> these elderly patients had 1 or more additional risk factors (female<br />
gender, previous chemotherapy/radiation, previous neutropenia, recent surgery, poor<br />
performance status, poor renal and liver function), due to which the prophylactic use<br />
<strong>of</strong> G-CSF would have been indicated. Most importantly, we found that none <strong>of</strong> patients<br />
in high risk chemotherapy group received G-CSF which poses serious risk <strong>of</strong><br />
developing FN leading to treatment failure.<br />
Conclusions: Our study indicated a significant underutilization <strong>of</strong> G-CSF in elderly<br />
cancer patients, especially in those receiving regimens with high risk <strong>of</strong> FN. Latter may<br />
be one <strong>of</strong> the reasons <strong>of</strong> worse outcome <strong>of</strong> cancer therapy and thereby shorter survival<br />
seen in this age-group. Underutilization <strong>of</strong> G-CSF in elderly is an issue that needs to be<br />
urgently addressed.<br />
Legal entity responsible for the study: Tartu University Hospital<br />
Funding: Tartu University Hospital<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1457P<br />
Prophylaxis <strong>of</strong> chemotherapy-induced neutropenia with<br />
lipegfilgrastim in patients with breast cancer: results from an<br />
interim analysis <strong>of</strong> the non-interventional study NADIR<br />
C.M. Kurbacher 1 , T. Fietz 2 , T. Trarbach 3 , C. Salat 4 , M. Rezai 5 , A. Lorenz 6 ,<br />
B. Niemeier 7<br />
1 Gynäkologie I (SP Gynäkologische Onkologie), Medizinisches Zentrum<br />
Bonn-Friedensplatz, Bonn, Germany, 2 Schwerpunktpraxis für Hämatologie und<br />
Internistische Onkologie, Gastroenterologie, Gastroenterologie Onkologie<br />
Bodensee, Singen, Germany, 3 Medical Department, IOMEDICO AG, Freiburg,<br />
Germany, 4 Innere Medizin, Hämatologie und internistische Onkologie,<br />
Hämato-Onkologische Schwerpunktpraxis, Munich, Germany, 5 Brustzentrum,<br />
Luisenkrankenhaus GmbH & Co. KG, Düsseldorf, Germany, 6 Onkologie,<br />
Gesundheitsforum für Frauenheilkunde, Hämatologie und Onkologie,<br />
Hildburghausen, Germany, 7 Clinical Operations, IOMEDICO AG, Freiburg,<br />
Germany<br />
Background: Anthracycline and/or taxane-based (A/T) chemotherapies (CTx) are<br />
among the most effective treatments in breast cancer (BC). Many modern A/T<br />
regimens used in BC including dose-dense (dd) protocols with treatment intervals<br />
<strong>of</strong> ≤ 2 weeks are associated with a significant incidence <strong>of</strong> febrile neutropenia (FN) thus<br />
forcing a primary prophylaxis using granulocyte colony-stimulating factors (G-CSF).<br />
Lipegfilgrastim (LIP) is a glyco-pegylated G-CSF approved to reduce the duration <strong>of</strong><br />
neutropenia and the incidence <strong>of</strong> FN. In 2014, a large-scaled non-interventional study<br />
(NIS) was initiated to obtain detailed information on the value <strong>of</strong> LIP in order to<br />
prevent both FN and severe neutropenia. Here we report on results from an interim<br />
analysis <strong>of</strong> the NIS NADIR focusing on the subset <strong>of</strong> pts with BC.<br />
Methods: The prospective multicenter NIS NADIR is conducted in 270 outpatient<br />
centers and hospitals across Germany aiming to collect data on prophylactic LIP use in<br />
2500 pts with different tumor entities subjected to CTx in the clinical routine. The<br />
objective <strong>of</strong> the study is to assess the effectiveness <strong>of</strong> LIP by determining the incidence<br />
<strong>of</strong> neutropenia grade 3/4 and FN.<br />
Results: At the time <strong>of</strong> data cut-<strong>of</strong>f (3/2016), 2422 pts were enrolled by 198 sites. 1556<br />
pts were evaluable; 741 pts were diagnosed with BC, <strong>of</strong> whom 274 were treated with dd<br />
regimens. Mean age was 54.6/ 51.4 years for all BC pts and pts with dd regimens,<br />
respectively. In 89.0/ 96.7% <strong>of</strong> pts, CTx was applied in an adjuvant setting. Overall<br />
96.1% <strong>of</strong> pts were treated with regimens containing A/T. 94.6/ 96.1% <strong>of</strong> documented<br />
CTx cycles were supported by LIP. Neutropenia grade 3/4 occurred in 29.4/ 33.9% <strong>of</strong><br />
pts, 2.2/ 1.8% developed FN. Dose reductions were reported in 5.5%/ 4.2% <strong>of</strong> cycles, in<br />
0.7%/ 0.6% <strong>of</strong> cases due to CTx-induced neutropenia. For 26.7/ 34.3% <strong>of</strong> pts,<br />
LIP-related adverse events (AE) were reported. The most frequent LIP-related AE was<br />
bone pain (11.1/ 18.6%). LIP-related serious adverse events were reported for 2.6/ 3.3%<br />
<strong>of</strong> pts.<br />
Conclusions: LIP was effective and well tolerated in BC pts treated with A/T as well as<br />
in the subgroup <strong>of</strong> pts with dd regimen. The low incidence <strong>of</strong> neutropenia grade 3/4<br />
and FN was comparable to previous publications.<br />
Clinical trial identification: Study Protocol No.: TV44689-ONC-40004<br />
Legal entity responsible for the study: Ethikkommission der Landesärztekammer<br />
Baden-Württemberg<br />
Funding: TEVA GmbH<br />
Disclosure: C.M. Kurbacher: Membership on an advisory board / expert reviewer:<br />
TEVA GmbH; Remuneration (for membership on an advisory board / expert review):<br />
TEVA GmbH; Sponsored research: TEVA GmbH. T. Fietz: Remuneration: TEVA<br />
GmbH; Other Financial Relationships: Compensation for travel expenses by TEVA<br />
GmbH. All other authors have declared no conflicts <strong>of</strong> interest.<br />
1458P<br />
Development <strong>of</strong> a prognostic system to predict the response<br />
to treatment <strong>of</strong> neutropenic fever<br />
H. Zawam, A. Selim, R. Salama, N. Hanna, W. Edesa<br />
Clinical oncology department, Cairo University, Cairo, Egypt<br />
abstracts<br />
Background: Febrile neutropenia (FN) remains one <strong>of</strong> the most commonly<br />
encountered oncologic emergencies in patients (pts) with hematological malignancies.<br />
Development <strong>of</strong> a prognostic system will help to improve the outcome in those pts.<br />
Methods: This is a prospective observational study including 142 pts with<br />
haematological malignancies who presented to Kasr Al Ainy Center <strong>of</strong> Clinical<br />
<strong>Oncology</strong> during the period 1st <strong>of</strong> June 2014 to October 2015. This group <strong>of</strong> pts<br />
suffered from 270 episodes. According to the MASCC score, high risk pts were treated<br />
inpatients. All admitted pts were subjected to blood, sputum, stool and urine cultures<br />
withdrawal and Galactomann test. PCR (polymerase chain reaction) <strong>of</strong> sepsis and BAL<br />
(broncho-alveloar lavage ) were done in certain cases. Empirical antibiotics were<br />
started immediately, antifungal and antiviral tretements were recieved according to the<br />
guidelines.<br />
Results: The different diagnostic modalities were analysed in addition to the results <strong>of</strong><br />
treatment by different classes <strong>of</strong> antibiotics. The most frequent diagnosis in our study<br />
were AML (55 pts), followed by ALL (27pts), NHL (35 pts).The disease status was<br />
found to be highly significant and affects the control <strong>of</strong> neutropenic fever episode. The<br />
more the patient developed neutropenic episodes the more the risk <strong>of</strong> mortality. In our<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw390 | vi505
abstracts<br />
study, the MASCC score was highly significant. 62% <strong>of</strong> the identified pathogens were<br />
gram positive detected by blood culture, while gram negative bacteria were the<br />
commonest pathogens identified by other diagnostic modalities.<br />
1460P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
A multi-centre study to investigate the natural history <strong>of</strong><br />
taxane acute pain syndrome (TAPS) in patients receiving<br />
taxane-based chemotherapy for breast or prostate cancer<br />
Variable<br />
Table: 1458P Multivariate analysis to determine pretreatment<br />
variables <strong>of</strong> independent prognostic value<br />
odds<br />
ratio<br />
95% CI P-value Weighted partial<br />
score<br />
Previous FN episode 1.47 0.307 7.023 0.63 -<br />
Disease burden 3.677 1.2 11.265 0.023 2<br />
Hypotension 5.609 1.711 18.392 0.004 3<br />
Prevoius fungal 1.905 0.407 8.91 0.413 -<br />
infection<br />
Uncontrolled disease 4.222 1.019 17.493 0.047 2.5<br />
The sum <strong>of</strong> the weighted partial scores <strong>of</strong> the three significant variables resulted in a<br />
prognostic score ranging from 0 (best prognosis) to 7.5 (worst prognosis). Cut<strong>of</strong>f value<br />
<strong>of</strong> 4.5 was determined and it divides patients into two groups, ≤4.5 vs. >4.5<br />
Conclusions: Many risk factors affect the outcome <strong>of</strong> FN and should be taken into<br />
consideration for every pt.<br />
Legal entity responsible for the study: Hamdy Zawam<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1459P<br />
Use <strong>of</strong> lipegfilgrastim in clinical practice for the prophylaxis<br />
<strong>of</strong> chemotherapy-induced neutropenia: interim results <strong>of</strong><br />
pan-European non-interventional study<br />
P. Pichler 1 , N. Claes 2 , P. Mazza 3 , B. Zurawski 4 , P. Potocki 5 , E. Petru 6 ,M.Šedivá 7 ,<br />
J. Katolicka 8 , F. Lanza 9 , C. Fontaine 10<br />
1 Department <strong>of</strong> Internal Medicine, University Clinic, St. Pölten, Austria,<br />
2 Department <strong>of</strong> <strong>Oncology</strong>, AZ St-Jan, Brugge, Belgium, 3 Hematology Unit, SS<br />
Annunziata Hospital, Taranto, Italy, 4 Chemotherapy Unit, <strong>Oncology</strong> Center,<br />
Bydgoszcz, Poland, 5 Department <strong>of</strong> Clinical <strong>Oncology</strong>, University Hospital,<br />
Krakow, Poland, 6 Department <strong>of</strong> Obstetrics and Gynaecology, Medical University<br />
Graz, Graz, Austria, 7 Department <strong>of</strong> <strong>Oncology</strong>, Nemocnice Na Bulovce, Prague,<br />
Czech Republic, 8 Department <strong>of</strong> <strong>Oncology</strong>, Nemocnice U sv. Anny, Brno, Czech<br />
Republic, 9 Hematology Unit, Istituti Ospitalieri, Cremona, Italy, 10 Department <strong>of</strong><br />
<strong>Oncology</strong>, UZ, Brussels, Belgium<br />
Background: Lipegfilgrastim (Lonquex®) is a long-acting glycopegylated G-CSF that<br />
was proven to be non-inferior with regards to duration <strong>of</strong> severe neutropenia compared<br />
with pegfilgrastim in breast cancer patients. The objective <strong>of</strong> this study was to evaluate<br />
effectiveness <strong>of</strong> lipegfilgrastim in everyday clinical practice in adult patients with<br />
different tumor types who are treated with cytotoxic chemotherapy.<br />
Methods: This is a prospective non-interventional study. Patients with different tumor<br />
types treated with cytotoxic chemotherapy (CT), who received lipegfilgrastim in<br />
primary (PP) or secondary prophylaxis (SP) are included in this study. CT dose<br />
modifications and neutropenic and neutropenia-related events are recorded and<br />
analyzed. Evaluation <strong>of</strong> effectiveness following the first lipegfilgrastim-supported<br />
treatment cycle is presented here.<br />
Results: At the time <strong>of</strong> analysis (March 2016), a total <strong>of</strong> 621 patients have been<br />
included. Mean age <strong>of</strong> included patients was 59.2 ± 13.2 and 67.6% were female. Most<br />
patients had breast cancer (39.8%) and lymphoma (24.0%). Exposure to lipegfilgrastim<br />
has been documented for 507 patients. Data on CT dose modifications and<br />
neutropenic events following the first lipegfilgrastim-supported cycle were available for<br />
409 and 448 patients, respectively. CT dose omissions were observed in 0.3% patients<br />
when lipegfilgrastim was applied in PP. No omissions were observed when it was<br />
applied in SP. CT dose delays were observed in 10.3% (PP) and 15.0% (SP) <strong>of</strong> patients<br />
and CT dose reductions in 5.2% (PP) and 7.5% (SP) <strong>of</strong> patients. Febrile neutropenia<br />
was recorded in 1.4% (PP) and 1.2% (SP) <strong>of</strong> patients, whereas severe neutropenia was<br />
recorded in 1.9% (PP) and 4.7% (SP) <strong>of</strong> patients. A total <strong>of</strong> 89 (17.6%) patients exposed<br />
to lipegfilgrastim reported at least one adverse drug reaction (ADR). The most<br />
common ADRs were myalgia, bone pain, and headache. Serious ADRs were reported<br />
by 25 (4.9 %) patients.<br />
Conclusions: Lipegfilgrastim is effective and well tolerated in the real world setting<br />
administered either in PP or SP. Both effectiveness and safety data obtained in this<br />
study are in line with published data for lipegfilgrastim.<br />
Clinical trial identification: N/A<br />
Legal entity responsible for the study: Teva Pharmaceuticals<br />
Funding: Teva Pharmaceuticals<br />
Disclosure: E. Petru: Honoraria from Teva, Roche, Amgen, Sandoz. All other authors<br />
have declared no conflicts <strong>of</strong> interest.<br />
R. Fernandes 1 , S. Mazzarello 2 , M.F. Ibrahim 1 , J. Hilton 1 , A. Joy 3 ,M.Ong 1 ,<br />
B. Hutton 4 , L. Vandermeer 2 , M. Clemons 1<br />
1 Department <strong>of</strong> Medicine, Division <strong>of</strong> Medical <strong>Oncology</strong>, The Ottawa Hospital<br />
Regional Cancer Centre, Ottawa, ON, Canada, 2 Ottawa Hospital Research<br />
Institute, University <strong>of</strong> Ottawa Faculty <strong>of</strong> Medicine, Ottawa, ON, Canada,<br />
3 Department <strong>of</strong> <strong>Oncology</strong>, Division <strong>of</strong> Medical <strong>Oncology</strong>, University <strong>of</strong> Alberta<br />
Cross Cancer Institute, Edmonton, AB, Canada, 4 Department <strong>of</strong> Epidemiology<br />
and Community Medicine, University <strong>of</strong> Ottawa Faculty <strong>of</strong> Medicine, Ottawa, ON,<br />
Canada<br />
Background: Taxane acute pain syndrome (TAPS) is characterized by myalgia and<br />
arthralgia starting 24-48 hours after taxane-based chemotherapy and lasting up to 7<br />
days. Despite its negative impact on patient quality <strong>of</strong> life, its characteristics and natural<br />
history remain poorly defined. This study evaluates persistence, severity and the impact<br />
<strong>of</strong> TAPS on quality <strong>of</strong> life (QoL).<br />
Methods: Eligible patients with breast or prostate cancers commencing taxane-based<br />
chemotherapy completed the Functional Assessment <strong>of</strong> Cancer Therapy-Taxane<br />
(FACT-T), Brief Pain Inventory (BPI) questionnaires and a pain medication diary daily<br />
for 1 week after each chemotherapy infusion. TAPS was defined through myalgias and<br />
arthralgias on questionnaires.<br />
Results: From March to December 2015, <strong>of</strong> 52 patients enrolled 25 completed the<br />
study. 66% <strong>of</strong> breast patients reported TAPS. TAPS started 24-72 (range 24-96) hours<br />
after treatment infusion reaching a peak by day 3 (range 1-5). TAPS was more common<br />
in the legs and back. Dose reductions, delays or treatment discontinuation were not<br />
required due to TAPS. Medications used to treat TAPS included opioids (n = 5) and<br />
NSAIDs (n = 9). There was negative effect <strong>of</strong> pain on QoL in pain scores at baseline in<br />
comparison with the final infusion cycle (mean change in “BPI worst pain” score was<br />
+1.61 and FACT-T score was -6.9, with p-values 0.014 and 0.017, respectively).<br />
Table: 1460P TAPS characteristics<br />
TC<br />
(n = 10)<br />
FEC-D<br />
(n = 2)<br />
Single agent<br />
Palcitaxel(N = 9)<br />
AC-P or<br />
AC-D<br />
(n = 3)<br />
TAPS Incidence 80% 50% 22% 100%<br />
Growth factor use (n) 7 1 0 1<br />
Taxane Dosing at 100 mg/m 2 No Yes No Yes<br />
Oral Steroids use (n) 8 1 0 2<br />
TC - cyclophosphamide plus docetaxel; FEC-D - 5-fluorouracil-epirrubicincyclophosphamide<br />
followed by docetaxel; AC-D - doxorubicin-cyclophosphamide<br />
followed by docetaxel; AC-T - doxorubicin-cyclophosphamide followed by<br />
paclitaxel<br />
Conclusions: TAPS is a common toxicity and associated with a negative impact on<br />
QoL. Further data will help define predisposing risk factors. Prospective patient<br />
reported outcome assessments are crucial to individualize treatment strategies and to<br />
improve management <strong>of</strong> TAPS.<br />
Clinical trial identification: NCT02362087<br />
Legal entity responsible for the study: Ottawa Hospital Regional Cancer Centre<br />
Funding: Ottawa Hospital Regional Cancer Centre (Internal)<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1461P<br />
Effect <strong>of</strong> solution pre-warming, hot compress, plus pH<br />
adjustment by combination with dexamethasone on venous<br />
pain in cancer patients receiving oxaliplatin via a peripheral<br />
vein<br />
S. Sumikawa 1 , H. Kawazoe 1 , K. Nakauchi 2 , Y. Yakusijin 3 , A. Tanaka 1 , H. Araki 1<br />
1 Division <strong>of</strong> pharmacy, Ehime University Hospital, Ehime, Japan, 2 Division <strong>of</strong><br />
Nursing, Ehime University Hospital, Ehime, Japan, 3 Cancer center, Ehime<br />
University Hospital, Ehime, Japan<br />
Background: Central venous port-free administration <strong>of</strong> oxaliplatin in combination<br />
with an oral fluoropyrimidine improves patient satisfaction; however, pain provoked by<br />
peripheral intravenous administration <strong>of</strong> oxaliplatin may reduce compliance. There are<br />
recent reports that pH adjustment by combination with dexamethasone, pre-warming<br />
<strong>of</strong> the solution, or a hot compress over the peripheral catheterization site, reduces<br />
peripheral venous pain. To date, the therapeutic benefit <strong>of</strong> the combination <strong>of</strong> these<br />
interventions has not been established. The aim <strong>of</strong> this study was to clarify the efficacy<br />
<strong>of</strong> this combination for venous pain in cancer patients receiving oxaliplatin through a<br />
peripheral vein.<br />
Methods: We treated all outpatients with the above combination after April 2012. The<br />
venous pain was defined as grade ≥2, according to the Common Terminology Criteria<br />
vi506 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
for Adverse Events version 4.0. We retrospectively reviewed the electronic medical<br />
records from cancer patients who had received oxaliplatin via a peripheral vein<br />
between December 2009 and June 2014. The study protocol was approved by the Ethics<br />
Committee <strong>of</strong> Ehime University Hospital (approval number: 1602007).<br />
Results: We evaluated 271 treatment courses in 59 patients. Venous pain occurred in<br />
42 courses (15.5 %) among 26 patients. Multivariate logistic regression analysis<br />
revealed that female sex and body mass index ≧25 were significantly associated with an<br />
increased risk <strong>of</strong> venous pain during all courses (adjusted odds ratio [OR]: 3.18, 95 %<br />
confidence interval [CI]: 1.35–7.92; p = 0.008 and adjusted OR: 3.37, 95 % CI: 1.27–<br />
9.40; p = 0.015, respectively). Combination <strong>of</strong> pre-warming the solution, use <strong>of</strong> a hot<br />
compress, plus pH adjustment by combining with dexamethasone were significantly<br />
associated with a reduced risk <strong>of</strong> venous pain during all courses (adjusted OR: 0.11, 95<br />
% CI: 0.02–0.44; p = 0.002).<br />
Conclusions: This is believed to be the first study to establish the analgesic effect <strong>of</strong><br />
combination <strong>of</strong> pre-warming the solution, use <strong>of</strong> a hot compress, plus pH adjustment<br />
by combining with dexamethasone on venous pain in cancer patients receiving<br />
oxaliplatin through a peripheral vein.<br />
Legal entity responsible for the study: Ehime University Hospital<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1462P<br />
Opiophobia – knowledge, attitudes and concerns about<br />
opioid medicines among Polish society, cancer patients,<br />
families and pr<strong>of</strong>essionals – the first wave <strong>of</strong> a survey<br />
A. Kieszkowska-Grudny 1 , J. Jarosz 2 , J. Grudny 3 , A. Siwy-Hudowska 4 ,<br />
D. Jasinska 2<br />
1 The Psychotheraphy and <strong>Oncology</strong> Centre, Minds <strong>of</strong> Hope, Warsaw, Poland,<br />
2 The Mazovian Pain Treatment Cluster, The Oncological Hospice Foundation,<br />
Warsaw, Poland, 3 Third Department <strong>of</strong> Lung Diseases, National Institute <strong>of</strong><br />
Tuberculosis and Lung Diseases, Warsaw, Poland, 4 The Individual’s Differences<br />
Department, University <strong>of</strong> Social Sciences and Humanities, Warsaw, Poland<br />
Background: Opiophobia is one <strong>of</strong> the major issues limiting cancer and chronic pain<br />
treatment in Poland. This study is the first stage <strong>of</strong> national survey addressing the issue<br />
<strong>of</strong> opiophobia among pr<strong>of</strong>essionals and others.<br />
Methods: The study included a total <strong>of</strong> 1248 people, in that 141 doctors (age 24 to 84y;<br />
M = 44.29; SD = 13.28), 95 nurses (age 29 to 61y; M = 45.47; SD = 8.94), 167 cancer<br />
patients/pts (age 20 to 100y; M = 59.11; SD = 21.27), 131 members <strong>of</strong> pts families (age<br />
16 to 99y; M = 52,15; SD = 19.85), 312 students (age from 18 to 56y; M = 24.55;<br />
SD = 5.41), and 402 others people (age 16 to 99y; M = 3.85;SD = 16.04), defined as a<br />
society. Internet or paper version <strong>of</strong> the questionnaires, which included 8 categories <strong>of</strong><br />
questions for pr<strong>of</strong>essionals, 4 for others, including: demographic, job experience with<br />
opioids, prescribed painkillers, knowledge about opioids, difficulties and concerns, etc.<br />
Results: 65-89% <strong>of</strong> study participants had experienced cancer in their family, but only<br />
50% identified relatives suffering chronic pain. Despite each Polish physician having<br />
the right to prescribe opioid medicines, just 1/5 <strong>of</strong> them were convinced they have no<br />
rights to do this, and 1/3 had never applied to the NHF for special prescriptions for<br />
opioids. Approximately 70% <strong>of</strong> pysicians and 30% <strong>of</strong> nurses felt qualified in opioid<br />
treatment. Fentanyl and buprenorphine patches, as well as morphine tablets were most<br />
<strong>of</strong>ten the treatment option for chronic pain. Physicians (M = 14.02; max = 20; p < .05)<br />
and nurses (M = 12.15, p < 0.05) had better knowledge about opioids than other<br />
groups. The worst knowledge was among cancer pts (M = 9.89), and their relatives<br />
(M = 10.16). The biggest concerns within pr<strong>of</strong>essionals were: the words "morphine"<br />
(M = 4.03;max = 5), and patients’ fear <strong>of</strong> opioid addiction (M = 3,96). Among<br />
nonpr<strong>of</strong>essionals, most common opinions were: over usage <strong>of</strong> painkillers, chronic pain<br />
treatment on lower level than in western EU, opioids addiction in Poland is a big<br />
problem, etc.<br />
Conclusions: Opiophobia is still a big problem among pr<strong>of</strong>essionals and<br />
nonpr<strong>of</strong>essionals in Poland. However, doctors and nurses are qualified to use these<br />
medicines on a daily basis, but they limit prescriptions fearing restrictions from the<br />
NHF under pressure from family and patient expectations.<br />
Legal entity responsible for the study: Mossakowski Research Centre; Polish Academy<br />
<strong>of</strong> Sciences<br />
Funding: Mossakowski Medical Research Centre; Polish Academy <strong>of</strong> Sciences<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1463P<br />
Denosumab for the prevention <strong>of</strong> symptomatic skeletal<br />
events (SSEs) in patients with bone-metastatic breast<br />
cancer: A comparison with skeletal-related events (SREs)<br />
J-J. Body 1 , R. von Moos 2 , A. Lipton 3 , M. Martin 4 , I. Diel 5 , G. Steger 6 , K. Tonkin 7 ,<br />
R. de Boer 8 , H-S. Radcliffe 9 , D. Niepel 10 , A.T. Stopeck 11<br />
1 Head <strong>of</strong> Medicine - Geriatrics, CHU Brugmann (ULB), Brussels, Belgium,<br />
2 Department <strong>of</strong> <strong>Oncology</strong>/Hematology, Kantonsspital Graubünden, Chur,<br />
Switzerland, 3 Department <strong>of</strong> Medical <strong>Oncology</strong> and Hematology, Penn State<br />
Hershey Medical Center, Hershey, PA, USA, 4 Medical <strong>Oncology</strong>, Hospital General<br />
Universitario Gregorio Marañon, Madrid, Spain, 5 Gynäkologische Onkologie,<br />
SPGO Mannheim, Mannheim, Germany, 6 Department <strong>of</strong> Internal Medicine,<br />
Medical University <strong>of</strong> Vienna, Vienna, Austria, 7 Medical <strong>Oncology</strong>, University <strong>of</strong><br />
Alberta Cross Cancer Institute, Edmonton, AB, Canada, 8 Department <strong>of</strong> Medical<br />
<strong>Oncology</strong>, Royal Melbourne Hospital, Parkville, Australia, 9 Biostatistics, Amgen<br />
Ltd., Uxbridge, UK, 10 Medical Development, Amgen (Europe) GmbH, Zug,<br />
Switzerland, 11 Department <strong>of</strong> Medical <strong>Oncology</strong>, Stony Brook Cancer Center,<br />
Stony Brook, NY, USA<br />
Background: A randomised controlled phase 3 trial <strong>of</strong> patients with breast cancer and<br />
bone metastases demonstrated denosumab was superior to zoledronic acid in reducing<br />
bone complications (SREs, defined as pathological fracture, surgery or radiation to<br />
bone, or spinal cord compression) (Stopeck AT, et al. J Clin Oncol 2010;28:5132–39).<br />
Recently, a composite endpoint <strong>of</strong> SSEs (symptomatic fracture, surgery or radiation to<br />
bone, or spinal cord compression) has been introduced as an alternative measurement<br />
<strong>of</strong> clinically relevant skeletal morbidity.<br />
Methods: Eligible patients had confirmed breast cancer, evidence <strong>of</strong> ≥1 bone<br />
metastasis and had received no prior intravenous (IV) bisphosphonates. Patients were<br />
randomised double-blind to subcutaneous (SC) denosumab 120mg/IV placebo or IV<br />
zoledronic acid 4mg (adjusted for creatinine clearance)/SC placebo every 4 weeks.<br />
Daily oral calcium and vitamin D supplements were recommended. This post-hoc SSE<br />
analysis <strong>of</strong> the patient population includes symptomatic pathologic fractures (per<br />
investigators’ judgement), spinal cord compressions and the requirement for<br />
preventative or corrective surgery or palliative radiation to bone.<br />
Results: As previously reported, fewer patients who received denosumab than<br />
zoledronic acid had confirmed first and subsequent SREs (Table). Similarly, fewer<br />
patients who received denosumab versus zoledronic acid had confirmed first and<br />
subsequent symptomatic events (SSEs). The median (95% CI) estimate <strong>of</strong> time to first<br />
SSE for both denosumab and zoledronic acid was not reached (HR = 0.76 [0.61, 0.93]<br />
P < 0.01).<br />
Number <strong>of</strong> Confirmed<br />
Events<br />
Denosumab<br />
(N = 1,026)<br />
Table: 1463P<br />
ZA<br />
(N = 1,020)<br />
Hazard or Rate Ratio (95%<br />
CI)<br />
First SSE, n (%) 156 (15.2) 198 (19.4) HR = 0.76 (0.61, 0.93)<br />
P < 0.01<br />
First SRE, n (%) 315 (30.7) 372 (36.5) HR = 0.82 (0.71, 0.95)<br />
P < 0.01 (Superiority)*<br />
First and subsequent SSEs 197 268 RR = 0.73 (0.59, 0.90)<br />
P < 0.01<br />
First and subsequent SREs 474 608 RR =0.77 (0.66, 0.89)<br />
P < 0.001 (Superiority)*<br />
*Adjusted for multiplicity<br />
Conclusions: Denosumab reduced the risk <strong>of</strong> skeletal events in patients with<br />
bone-metastatic breast cancer to a similar extent regardless <strong>of</strong> whether the endpoint<br />
was defined as SRE or SSE. The risk <strong>of</strong> developing first and subsequent SSEs was<br />
reduced by up to 27% when comparing denosumab with zoledronic acid.<br />
Clinical trial identification: NCT00321464<br />
Legal entity responsible for the study: Amgen<br />
Funding: Amgen<br />
Disclosure: J-J. Body: Lecture and consulting fees for Amgen. R. von Moos: Advisory<br />
Board: Amgen, Bayer, GSK, Novartis & Roche Research Grant: Bayer. M. Martin:<br />
Advisory Boardwalk, Novartis & AMGEN; Research funding Novartis. G. Steger:<br />
Honoraria from Amgen; Travel support and honoraria from Novartis. R. de Boer:<br />
Received honorarium/speakers fees from Amgen Australia. H-S. Radcliffe, D. Niepel:<br />
Employee <strong>of</strong> Amgen and holds Amgen stock. A.T. Stopeck: Received honorarium/<br />
consulting: Amgen; consulting: Pfizer, Sandoz, Biomarin, Peregrine. All other authors<br />
have declared no conflicts <strong>of</strong> interest.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw390 | vi507
abstracts<br />
1464P<br />
Comparison <strong>of</strong> the systemic and local pharmacokinetics,<br />
safety and tolerability <strong>of</strong> clonidine mucoadhesive buccal<br />
tablets with reference clonidine oral tablets in healthy<br />
volunteers<br />
B. Petre-Lazar1 1 , G. Sharma 2 , S. Hutchings 3 , H. Goodwin 4 , N. Yesiltas Emul 5 ,<br />
G. Dixon 1 , B. Vasseur 1<br />
1 Clinical Department, Onxeo, Paris, France, 2 Clinical Pharmacology, Simbec<br />
Research Ltd, Merthyr Tydfil, UK, 3 Scientific & Regulatory Affairs, Simbec<br />
Research Ltd, Merthyr Tydfil, UK, 4 Biometrics, Simbec Research Ltd, Merthyr<br />
Tydfil, UK, 5 Pharmaceutical Department, Onxeo, Paris, France<br />
Background: Clonidine Mucoadhesive Buccal Tablet (MBT) is a novel delivery system<br />
resulting in high and sustained concentrations <strong>of</strong> clonidine in the oral cavity. In a phase<br />
2 clinical trial, clonidine MBT reduced the incidence <strong>of</strong> severe oral mucositis (OM)<br />
compared to placebo in head and neck cancer patients undergoing chemoradiation.<br />
This study compared the pharmacokinetics (PK), safety and tolerability <strong>of</strong> clonidine<br />
MBT with a reference oral tablet (OT).<br />
Methods: This was a randomized, 3 period single dose crossover study in 36 healthy<br />
subjects aged 18-50 yr. Eligibility was assessed within 14 d <strong>of</strong> the first dose. IMP was<br />
administered in the fasted state on Day 1 <strong>of</strong> each treatment period. PK samples were<br />
collected up to 24 h (saliva) / 96 h (blood) for measurement <strong>of</strong> clonidine concentration.<br />
Safety and tolerability were evaluated at specified times throughout the study. A<br />
washout period <strong>of</strong> at least 7 d was observed between administrations.<br />
Results: There were 13 and 15 adverse events (AEs) considered at least possibly related<br />
to IMP following 50 µg and 100 µg MBT, respectively, compared to 26 following 100<br />
µg clonidine OT. All AEs were either mild or moderate in severity. No Serious AEs<br />
were reported. Dry mouth and fatigue were reduced in clonidine MBT 50 µg and 100<br />
µg versus clonidine OT respectively 28-29% vs 71% for dry mouth and 0% vs 23% for<br />
fatigue. Peak mean reductions in systolic/diastolic blood pressure were 5.7/3.7 and 7.1/<br />
4.2 mmHg for clonidine MBT 50 µg and 100 µg, respectively, compared with 13.4/7.8<br />
mmHg for clonidine OT. Mean (SD) maximum saliva and plasma concentration and<br />
exposure data is presented below:<br />
Table: 1464P<br />
PLASMA PLASMA SALIVA PLASMA<br />
C max (pg/<br />
mL)<br />
AUC 0-t (h*pg/<br />
mL)<br />
C max (pg/<br />
mL)<br />
AUC 0-t (h*pg/<br />
mL)<br />
100 µg clonidine OT 399 (86.1) 5640 (1390) 2630 (2140) 14600 (6820)<br />
100 µg clonidine MBT 222 (59.3) 4790 (1220) 387000<br />
(148000)<br />
2920000<br />
(1730000)<br />
50 µg clonidine MBT 104 (29.6) 1660 (720) 209000<br />
(132000)<br />
1440000<br />
(890000)<br />
Conclusions: Clonidine MBT is well tolerated and exhibits proportional saliva and<br />
plasma PK over the 50 - 100 µg dose level. The MBT results in higher saliva<br />
concentrations and lower systemic exposure than OT, which was associated with a<br />
trend towards fewer adverse events, less dry mouth, fatigue and hypotensive effect.<br />
Clinical trial identification: EudraCT NUMBER: 2015-001836-40 Protocol v2 dated<br />
29 June 2015<br />
Legal entity responsible for the study: Study sponsor/legal entity: Onxeo Study<br />
Contract Research Organisation responsible for coordination and running <strong>of</strong> the study:<br />
Simbec Research Dtd<br />
Funding: Onxeo<br />
Disclosure: B. Petre-Lazar1, N. Yesiltas Emul, G. Dixon, B. Vasseur:<br />
Corporate-sponsored research. G. Sharma, S. Hutchings, H. Goodwin: Simbec<br />
Research Ltd is a commercial Contract Research Organisation contracted by Onxeo to<br />
perform this Phase I clinical study.<br />
1465P<br />
Symptomatic skeletal events (SSEs) versus skeletal-related<br />
events (SREs) in patients with advanced cancer and bone<br />
metastases treated with denosumab or zoledronic acid<br />
R. von Moos 1 , L.A.M. Costa 2 , G. Scagliotti 3 , H. Sleeboom 4 , F. Goldwasser 5 ,<br />
V. Hirsh 6 , A. Spencer 7 , H-S. Radcliffe 8 , D. Niepel 9 , D.H. Henry 10<br />
1 Department <strong>of</strong> <strong>Oncology</strong>/Hematology, Kantonsspital Graubünden, Chur,<br />
Switzerland, 2 Department <strong>of</strong> <strong>Oncology</strong>, Serviço de Oncologia do Hospital de<br />
Santa Maria, Lisbon, Portugal, 3 Department <strong>of</strong> Clinical and Biological Sciences,<br />
University <strong>of</strong> Turin, Turin, Italy, 4 <strong>Oncology</strong>, Haga Teaching Hospital, The Hague,<br />
Netherlands, 5 Medical <strong>Oncology</strong>, Groupe hospitalier Cochin, Paris, France,<br />
6 Department <strong>of</strong> <strong>Oncology</strong>, McGill University Health Centre, Montreal, QC, Canada,<br />
7 Department <strong>of</strong> Clinical Haematology, Alfred Hospital, Melbourne, Australia,<br />
8 Biostatistics, Amgen Ltd., Uxbridge, UK, 9 Medical Development, Amgen (Europe)<br />
GmbH, Zug, Switzerland, 10 Department <strong>of</strong> Medicine, Joan Karnell Cancer Center,<br />
Philadelphia, PA, USA<br />
Background: An analysis <strong>of</strong> patients with advanced solid tumours (excluding breast<br />
and prostate) and bone metastases included in a randomised, double-blind, phase 3<br />
study found that denosumab reduced the occurrence <strong>of</strong> bone complications (SREs;<br />
pathological fracture, surgery or radiation to bone, or spinal cord compression) versus<br />
zoledronic acid (Henry D, et al. Support Care Cancer 2014;322:679–87). An alternative<br />
clinically relevant composite endpoint <strong>of</strong> SSEs (symptomatic fracture, surgery or<br />
radiation to bone, or spinal cord compression) has recently been introduced to also<br />
measure skeletal morbidity.<br />
Methods: Adult patients with solid tumours, evidence <strong>of</strong> ≥1 bone metastasis and no<br />
prior intravenous (IV) bisphosphonates were randomised to receive either<br />
subcutaneous (SC) denosumab 120mg/IV placebo or IV zoledronic acid 4mg (adjusted<br />
for creatinine clearance)/SC placebo every 4 weeks. Patients were recommended to take<br />
daily oral calcium and vitamin D supplementation. This post-hoc SSE analysis includes<br />
symptomatic pathologic fractures (investigator decision), spinal cord compressions and<br />
the requirement for palliative or corrective surgery or radiation to bone.<br />
Results: Fewer patients who received denosumab than zoledronic acid had confirmed<br />
first and subsequent SREs, this was also the case when the definition <strong>of</strong> SSE was<br />
applied (Table). The median (95% CI) estimate <strong>of</strong> time to first SSE for denosumab was<br />
not reached (not estimable [NE], NE) and for zoledronic acid it was 21.8 (19.0, NE)<br />
months (HR = 0.81 [0.66, 0.99]; P = 0.04).<br />
Number <strong>of</strong><br />
Confirmed Events<br />
Denosumab<br />
(N = 800)<br />
Table: 1465P<br />
ZA<br />
(N = 797)<br />
Hazard or Rate Ratio<br />
(95% CI)<br />
First SSE, n (%)* 181 (22.7) 211 (26.5) HR = 0.81 (0.66,<br />
0.99) P = 0.04<br />
First SRE, n (%) 236 (29.5) 277 (34.8) HR = 0.81 (0.68,<br />
0.96) P = 0.02<br />
First and subsequent 234 264 RR = 0.86 (0.71,<br />
SSEs*<br />
First and subsequent<br />
SREs<br />
1.04) P = 0.11<br />
328 374 RR = 0.85 (0.72,<br />
1.00) P = 0.05<br />
*SSE analysis is based on actual stratum versus SRE analysis based on<br />
randomised stratum thus for SSE analysis N = 799<br />
Conclusions: Skeletal morbidity improved with denosumab versus zoledronic acid,<br />
regardless <strong>of</strong> whether the endpoint was defined as SRE or SSE. The risk <strong>of</strong> developing<br />
first and multiple SSEs was reduced by up to 14% when comparing denosumab with<br />
zoledronic acid.<br />
Clinical trial identification: NCT00330759<br />
Legal entity responsible for the study: Amgen<br />
Funding: Amgen<br />
Disclosure: R. von Moos: Advisory Boards: Amgen, Bayer, GSK, Novartis, Roche,<br />
Research Grant: Bayer. G. Scagliotti: Consultant for Eli Lilly; Received honoraria from<br />
AstraZeneca, Roche, Pfizer, Eli Lilly and Clovis <strong>Oncology</strong>. V. Hirsh: Honoraria for<br />
Advisory Boards: Amgen, Novartis, Roche, Pfizer, Astra Zeneca, Merck, Eli Lilly, BMS.<br />
H-S. Radcliffe: Employee <strong>of</strong> Amgen and holds Amgen stock. D. Niepel: Amgen<br />
employee and holds Amgen stock. D.H. Henry: Research grant from Amgen Inc. and<br />
was a consultant to and/or participated in an advisory board for Amgen Inc. All other<br />
authors have declared no conflicts <strong>of</strong> interest.<br />
1466P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Treatment <strong>of</strong> opioid-induced constipation with naldemedine<br />
in patients with cancer: onset <strong>of</strong> action in a randomized<br />
phase 3 trial<br />
T. Murata 1 , N. Katakami 2 , T. Harada 3 , K. Shinozaki 4 , M. Tsutsumi 5 , T. Yokota 6 ,<br />
M. Arai 6 , Y. Suzuki 6 , M. Narabayashi 7 , N. Boku 8<br />
1 Department <strong>of</strong> Breast <strong>Oncology</strong>, Aichi Cancer Center - Aichi Hospital, Okazaki,<br />
Japan, 2 Division <strong>of</strong> Integrated <strong>Oncology</strong>, Institute <strong>of</strong> Biomedical Research and<br />
Innovation, Kobe, Japan, 3 Center for Respiratory Diseases, JCHO Hokkaido<br />
Hospital, Sapporo, Japan, 4 Department <strong>of</strong> Clinical <strong>Oncology</strong>, Hiroshima<br />
Prefectural Hospital, Hiroshima, Japan, 5 Department <strong>of</strong> Urology, Hitachi General<br />
Hospital, Hitachi, Japan, 6 Global Development, Shionogi & Co., Ltd., Osaka,<br />
Japan, 7 Department <strong>of</strong> palliative therapy, Cancer Institute Hospital <strong>of</strong> JFCR, Tokyo,<br />
Japan, 8 Gastrointestinal Medical <strong>Oncology</strong> Division, National Cancer Center<br />
Hospital, Tokyo, Japan<br />
Background: Opioid analgesics are widely administered to treat patients with cancer<br />
pain; however, many patients suffer from opioid-induced constipation (OIC) as a side<br />
effect. Naldemedine (NAL), a peripherally-acting μ-opioid receptor antagonist<br />
(PAMORA), is being developed for the treatment <strong>of</strong> patients with OIC. The aim <strong>of</strong> this<br />
analysis was to assess the onset <strong>of</strong> action <strong>of</strong> NAL in the context <strong>of</strong> primary efficacy and<br />
safety results previously reported.<br />
Methods: The study was a double-blind, randomized, placebo-controlled phase 3 trial<br />
in Japan. Cancer patients with OIC, defined as having ≤ 5 spontaneous bowel<br />
movements (SBMs) during the 2-week qualification period, were evenly assigned to<br />
either oral NAL 0.2 mg QD or placebo (PBO). The primary efficacy endpoint was SBM<br />
responder rate (percentage <strong>of</strong> patients with ≥ 3 SBMs/week and an increase from<br />
baseline <strong>of</strong> ≥ 1 SBM/week) during the 2-week treatment period. To assess the onset <strong>of</strong><br />
action, 1) time to the first SBM, 2) proportion <strong>of</strong> patients with at least 1 SBM at several<br />
vi508 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
time points after initial dose and 3) change in frequency <strong>of</strong> SBMs/week from baseline<br />
to first week were evaluated.<br />
Results: A total <strong>of</strong> 193 patients were randomized (NAL: 97, PBO: 96). The SBM<br />
responder rate <strong>of</strong> NAL was significantly larger than that <strong>of</strong> PBO (71.1% vs 34.4%,<br />
respectively; P < 0.0001). Besides, the time to onset <strong>of</strong> action <strong>of</strong> NAL was shorter than<br />
that <strong>of</strong> PBO with a shorter median time to the first SBM after the initial dose (NAL:<br />
4.67, PBO: 26.58 hrs). The differences between the two groups in the proportion <strong>of</strong><br />
patients with at least one SBM were statistically significant at all assessed time points<br />
(up to 4 hrs: 48.5% vs 7.3%, 8 hrs: 60.8% vs 14.6%, 12 hrs: 71.1% vs 25.0%, 24 hrs:<br />
77.3% vs 47.9%, P < 0.0001 for all). The change in the frequency <strong>of</strong> SBMs per week<br />
from baseline to the first week with NAL was significantly greater than that with PBO<br />
(5.70 vs 1.73, P < 0.0001). The overall incidences <strong>of</strong> adverse events reported during the<br />
treatment period were 44.3% and 26.0% for NAL and PBO, respectively. Only diarrhea<br />
was reported for ≥ 5% <strong>of</strong> patients (19.6% vs 7.3%). However, the most cases were<br />
reported as mild and recovered.<br />
Conclusions: Treatment with NAL led to timely improvement <strong>of</strong> OIC in patients with<br />
cancer and was generally well tolerated.<br />
Clinical trial identification: JapicCTI-132340, 15 November 2013<br />
Legal entity responsible for the study: Shionogi & Co., Ltd.<br />
Funding: Shionogi & Co., Ltd.<br />
Disclosure: N. Katakami: Speakers Bureau Dainippon Sumitomo, Chugai, Boehringer,<br />
AZ, Lilly, Taiho, Janssen, Novartis, Pfizer, Ono, Daiichi Sankyo Research Fund AZ,<br />
Eisai, Ono, Kyowa Hakko Kirin, Shionogi, Daiichi Sankyo, Taiho, Chugai, Lilly,<br />
Boehringer, Merck Serono. T. Harada: Honoraria Chugai Pharma, Taiho<br />
Pharmaceutical, Ono Pharmaceutical, AstraZeneca KK, Novartis, Boehringer<br />
Ingelheim. K. Shinozaki: Honoraria Takeda, Merck Serono, GSK, AstrZeneca,<br />
Novartis, Chugai, Daiichi Sankyo, Mochida, Taiho, Ono, Otsuka, Yakult. T. Yokota,<br />
M. Arai, Y. Suzuki: Employee <strong>of</strong> Shionogi and have stock <strong>of</strong> Shionogi. N. Boku:<br />
Honoraria Taiho, Merck Senoro, Ono, Shionogi, Chugai, Yakult, Daiichi Sankyo, Lilly,<br />
Takeda Research Funding Taiho, Chugai. All other authors have declared no conflicts<br />
<strong>of</strong> interest.<br />
1467P<br />
L-carnosine for prevention <strong>of</strong> oxaliplatin-induced neuropathy<br />
in colorectal cancer patients (pts)<br />
A.S.T. Saad 1 , R.M. Yehia 2 , S.S. Mostafa 3 , H.S. Elabhar 3 , M.F. Schaalan 2<br />
1 Clinical oncology department, Ain Shams university Faculty <strong>of</strong> medicine, Cairo,<br />
Egypt, 2 Clinical pharmacy department, Misr international university, faculty <strong>of</strong><br />
pharmacy, Cairo, Egypt, 3 Clinical pharmacology department, Cairo university,<br />
faculty <strong>of</strong> pharmacy, Giza, Egypt<br />
Background: The study aims at investigating the use <strong>of</strong> anti-oxidant L-carnosine for<br />
prevention <strong>of</strong> acute oxaliplatin neurotoxicity in colorectal cancer pts and to observe<br />
L-carnosine effect on Tumor necrosis factor alpha (TNF α) as a neuro-inflammatory<br />
cytokine.<br />
Methods: This is a pilot study that recruited 60 pts using prospective randomized<br />
controlled design. Eligible Pts (non-diabetic) were randomly assigned to two arms.<br />
Arm A (30 pts) received FOLFOX-6 regimen (oxaliplatin, 5FU & leucovorin) and Arm<br />
B (30 pts) received FOLFOX-6 regimen and oral L-carnosine 1000 mg daily all along<br />
the treatment. All recruited pts were followed for three months, then both arms were<br />
analyzed for neuropathy incidence/grade and any additional toxicities according to<br />
NCI-CTC version 4. Pre-treatment and after 3 months TNF α serum levels were<br />
collected and tested.<br />
Results: No neuropathy were detected in 35.3% <strong>of</strong> pts in Arm B compared to only 3.3%<br />
in Arm A. Also 50 % <strong>of</strong> pts in Arm B developed grade I neuropathy compared to 36.7%<br />
in Arm A and only 2.9% <strong>of</strong> Arm B pts developed grade II neuropathy compared to 60<br />
% <strong>of</strong> arm A pts. Regarding TNF α serum levels, Arm B and Arm A at base line had<br />
comparable mean serum levels (0.04ng/ml & 0.03ng/ml) however the percentage<br />
reduction <strong>of</strong> Arm B serum level was higher than Arm A (0.02ng/ml & 0.001ng/ml,<br />
respectively p value = 0.0001). No toxicities were observed due to L-carnosine addition.<br />
Table: 1467P Arm A and Arm B regarding the neuropathy grade and<br />
TNF before/after 3 months <strong>of</strong> treatment<br />
Arm A (Control<br />
group) N = 30<br />
Arm B (Test group)<br />
N=30<br />
P-value<br />
Neuropathy grade 0 1 2 Drop out 1 (3.3%) 11 (36.7%) 18 12 (35.3%) 17 (50.0%) 0.0002<br />
(60.0%) 0 (0.0%) 1 (2.9%) 4 (11.8%)<br />
TNF before start <strong>of</strong> treatment 0.03 ± 0.01 0.021 – 0.04 ± 0.01 0.02 – 0.06 0.664<br />
(ng/ml) Mean ± SD Range 0.06<br />
TNF after 3 months <strong>of</strong> treatment<br />
(ng/ml) Mean ± SD Range<br />
0.03 ± 0.01 0.016 –<br />
0.044<br />
0.02 ± 0.01 0.01 – 0.04 0.0001<br />
Conclusions: L-carnosine reduced the incidence <strong>of</strong> acute oxaliplatin induced<br />
neuropathy, delayed the onset <strong>of</strong> chronic neuropathy and decreased TNF α serum<br />
levels without additional toxicities. Further studies are warranted to examine the full<br />
potential <strong>of</strong> L-carnosine in chemotherapy induced neuropathy.<br />
Clinical trial identification: Local registry: CairoUniv 387658<br />
Legal entity responsible for the study: Faculty <strong>of</strong> Medicine, Ain Shams University<br />
Funding: Faculty <strong>of</strong> Medicine, Ain shams university Misr international university<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1468P<br />
An integrated analysis <strong>of</strong> hyponatremia in cancer patients<br />
receiving platinum-based chemotherapy in clinical trials<br />
(JCOG1405-A)<br />
Y. Ezoe 1 , J. Mizusawa 2 , K. Takizawa 3 , H. Katayama 2 , K. Kataoka 2 , K. Tobinai 2 ,<br />
M. Muto 1<br />
1 Department <strong>of</strong> Therapeutic <strong>Oncology</strong>, Kyoto University-Graduate school <strong>of</strong><br />
medicine, Kyoto, Japan, 2 JCOG Data Center/Operations Office, National Cancer<br />
Center, Tokyo, Japan, 3 Division <strong>of</strong> Endoscopy, Shizuoka Cancer Center, Shizuoka,<br />
Japan<br />
Background: Hyponatremia is one <strong>of</strong> the most common electrolyte abnormalities in<br />
cancer patients who receive chemotherapy. However, its actual incidence and risk<br />
factors remain unknown. Among anti-cancer agents, platinum-based agent (platinum)<br />
is reported to cause chemotherapy-induced hyponatremia. Our aim is to evaluate the<br />
pr<strong>of</strong>ile <strong>of</strong> chemotherapy-induced hyponatremia by integrated analysis from completed<br />
clinical trials.<br />
Methods: The present study is an epidemiological study based on the integrated<br />
analysis <strong>of</strong> clinical trials performed by Japan Clinical <strong>Oncology</strong> Group (JCOG). We<br />
included clinical trials <strong>of</strong> systemic chemotherapies for solid cancers (lung, esophageal,<br />
gastric, colorectal, biliary tract, breast, ovarian, cervical, bladder, and head and neck<br />
cancers), which were approved by the JCOG Protocol Review Committee after January<br />
2000 and <strong>of</strong> which the patient recruitment was completed by January 2014. The<br />
incidences <strong>of</strong> hyponatremia and the patient/treatment pr<strong>of</strong>iles in the latest analysis<br />
reports <strong>of</strong> each trial were used. The associations between hyponatremia and the<br />
following factors were investigated: platinum use (yes/no), platinum regimens<br />
(Cisplatin/Carboplatin), administration methods (bolus/split), the number and types <strong>of</strong><br />
concomitant medications, and planned administration dose.<br />
Results: Twenty-nine trials (4313 patients) were included. Incidence <strong>of</strong> Grade 3/4<br />
hyponatremia in patients with platinum administration was 11.9%, which was<br />
significantly higher than those without platinum (3.8%, p < 0.0001). Grade 3/4<br />
hyponatremia incidence in Cisplatin group was significantly higher than Carboplatin<br />
group (13.5% vs. 7.6%, p < 0.0001). Platinum based 3-drug combination regimens and<br />
2-drug combination regimens with irinotecan or amrubicin exhibited higher incidence<br />
<strong>of</strong> hyponatremia. Administration methods and planned administration dose were not<br />
associated with the incidence <strong>of</strong> Grade 3/4 hyponatremia.<br />
Conclusions: Our study revealed that platinum agent administration was associated<br />
with chemotherapy induced hyponatremia regardless <strong>of</strong> administration method and<br />
planned dose. Careful monitoring <strong>of</strong> sodium level is needed when platinum is<br />
administered.<br />
Legal entity responsible for the study: Japan Clinical <strong>Oncology</strong> Group (JCOG)<br />
Funding: 1. Ministry <strong>of</strong> Health, Labour and Welfare, Japan 2. Japan Agency for<br />
Medical Research and Development (AMED)<br />
Disclosure: Y. Ezoe, J. Mizusawa, K. Takizawa, H. Katayama, K. Kataoka, M. Muto:<br />
Grants from Ministry <strong>of</strong> Health, Labour and Welfare, Japan, grants from Japan Agency<br />
for Medical Research and Development (AMED). K. Tobinai: Grants from Japan<br />
AMED, during the conduct <strong>of</strong> the study; grants and personal fees from Eisai, Takeda,<br />
Mundipharma, Janssen, grants from Chugai, Kyowa Kirin, Ono, Celgene, GSK,<br />
SERVIER, Abbvie, outside the submitted work.<br />
1469P<br />
abstracts<br />
Impact <strong>of</strong> hyponatremia in a tertiary cancer center:<br />
a one-year-survey at National Cancer Institute <strong>of</strong> Milan<br />
F. Agustoni, G. Fucà, G. Corrao, C. Vernieri, S. Cavalieri, A. Raimondi, G. Peverelli,<br />
M. Prisciandaro, P. Indelicato, K. Dotti, F. Morano, G. Lo Russo, D. Signorelli,<br />
C. Proto, M. Vitali, M. Imbimbo, N. Zilembo, M. Garassino, F.G.M. De Braud,<br />
M. Platania<br />
<strong>Oncology</strong> Department, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan,<br />
Italy<br />
Background: Hyponatremia (HN), defined as a serum sodium lower than 135 mmol/l,<br />
is the most common electrolyte disorder in hospitalized patients. Etiology is<br />
heterogeneous and a large difference exists in terms <strong>of</strong> symptoms and treatments. The<br />
aim <strong>of</strong> this study is to determine the incidence <strong>of</strong> HN in a Tertiary Cancer Center<br />
evaluating possible influence in terms <strong>of</strong> prognosis and length <strong>of</strong> hospitalization.<br />
Methods: This study includes all cancer patients hospitalized at our Institution from<br />
January 2015 to December 2015 for all causes otherwise than HN. We analyzed<br />
retrospectively data regarding HN and correlation to age, sex, staging, histology.<br />
Survival distribution was estimated by Kaplan-Meyer method, differences in<br />
probability <strong>of</strong> surviving were evaluated by chi-square test.<br />
Results: A total <strong>of</strong> 1.071 patients were included in the analysis. 243 (22.7%) presented<br />
at least one episode <strong>of</strong> HN; 197 (81.1%) showed mild hyponatriemia (135-130 mmol/<br />
l), 44 (18.1%) moderate (130-125 mmol/l), 2 (0.8%) severe (< 125 mmol/l). Patients<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw390 | vi509
abstracts<br />
were affected by lung cancer in 21.7%, breast cancer in 19.5%, colorectal cancer in<br />
13.0% (others in 45.8%). Most patients had Stage IV disease (93.4%), male 44.7%,<br />
female 54.3%. Median age was 62.9 years. Concomitant diagnosis <strong>of</strong> SIADH was<br />
performed in 4 patients (8.8%). Resolution <strong>of</strong> HN after specific treatments was<br />
observed in 19 patients (41.3%), without significant differences about length <strong>of</strong><br />
hospitalization between patients with normal and abnormal value at discharge. OS was<br />
lower in patients with moderate/severe HN versus mild (2.72 vs 6.81 months).<br />
Mortality rate was significantly lower in patients with corrected HN compared to not<br />
(52.6 vs 81.5%; p: 0.08), while no statistically significant difference was observed in OS<br />
(2.89 vs 2.63 months; p: 0.85).<br />
Conclusions: HN represents a frequent occasional finding in hospitalized cancer<br />
patients, although in most cases it’s <strong>of</strong> mild degree. SIADH represents a small<br />
percentage <strong>of</strong> cases. In our experience HN is not associated to discharge delays.<br />
Independently by the underlying disease, moderate and severe HN identify a particular<br />
group <strong>of</strong> patients with poor prognosis, probably reflecting very advanced disease and<br />
palliative care needs.<br />
Legal entity responsible for the study: Francesco Agustoni<br />
Funding: Fondazione IRCCS Istituto Nazionale dei Tumori<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1470P<br />
Estimation <strong>of</strong> glomerular filtration rate in patients with<br />
abnormal body composition and relation with carboplatin<br />
toxicity<br />
M. Bretagne, A. Jouinot, J-P. Durand, C. Tlemsani, J. Arrondeau, O. Huillard, P.<br />
Boudou Rouquette, F. Goldwasser, J. Alexandre<br />
Department <strong>of</strong> Medical <strong>Oncology</strong>, Cochin Hospital, Paris Descartes University,<br />
APHP, CARPEM, CERTIM, Hôpital Cochin, Paris, France<br />
Background: Carboplatin clearance is correlated with Glomerular Filtration Rate<br />
(GFR), which is usually evaluated with creatinine clearance using Cockcr<strong>of</strong>t-Gault<br />
(CG) formula. Because serum creatinine (sCR) level is related to total muscle mass, we<br />
hypothesized that an abnormal body composition with a low lean body mass (LBM)<br />
percentage (LBM / weight) may result in GFR overestimation and inadequate<br />
carboplatin dose calculation by using CG formula. Serum cystatin C (sCY) is an<br />
alternative marker <strong>of</strong> GFR which is not affected by muscle mass. We aimed to correlate<br />
GFR creatinine (GFR Cr ) and cystatin C (GFR Cy ) to LBM percentage and the risk <strong>of</strong><br />
toxicity. A high GFR Cr /GFR Cy ratio might estimate the miscalculation <strong>of</strong> GFR with<br />
sCR.<br />
Methods: sCR and sCY were prospectively measured in consecutive cancer patients<br />
(pts) before chemotherapy. GFR Cr and GFR Cy were calculated with CG and GRUBB<br />
formula, respectively. The LBM was assessed using CT-scan. Febrile neutropenia and<br />
grade 3-4 thrombocytopenia were analysed in a subgroup <strong>of</strong> pts treated with<br />
carboplatin AUC 5 +/- paclitaxel.<br />
Results: In 134 cancer pts (males 51%), median age was 63.7 (20 – 89). In 128 pts<br />
without severe renal insufficiency, sCR was correlated with LBM (r = 0.30, Pearson<br />
correlation coefficient, p 1.4.<br />
Conclusions: Pts with a low LBM percentage (sarcopenic overweight pts) are at high<br />
risk <strong>of</strong> inadequate calculation <strong>of</strong> renal function, over dosage <strong>of</strong> carboplatin and<br />
increased acute limiting toxicity. High GFR Cr /GFR Cy ratio allows to identify these pts.<br />
Legal entity responsible for the study: J. Alexandre<br />
Funding: Fondation Martine Midy<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1471P<br />
Mannitol dosing and cisplatin-induced acute nephrotoxicity<br />
P. Dhillon, E. Amir, M. Lo, A. Kitchlu, C. Chan, P. Yip, S. Cochlin, E. Chen, R. Lee,<br />
P. Ng<br />
Pharmacy, Princess Margaret Hospital, Toronto, ON, Canada<br />
Background: Nephrotoxicity is a dose-limiting adverse effect <strong>of</strong> cisplatin. Mannitol is<br />
an osmotic diuretic given routinely as part <strong>of</strong> cisplatin regimens to prevent<br />
nephrotoxicity. There are limited data on the ideal dose <strong>of</strong> mannitol. At our centre, 3<br />
different doses are used: 12 g, 20 g, and 40 g /cycle for cisplatin doses <strong>of</strong> ≥ 50 mg/m 2 .<br />
Methods: A case-control study was performed. Electronic records <strong>of</strong> 1462 sequential<br />
outpatients who received cisplatin at ≥ 50 mg/m 2 /cycle from 2010 to 2014 were<br />
reviewed. Patients experiencing acute nephrotoxicity <strong>of</strong> any grade within 30 days <strong>of</strong> last<br />
cisplatin dose (as defined by the National Cancer Institute Common Terminology<br />
Criteria for Adverse Effects version 4) were matched to a minimum <strong>of</strong> 2 and maximum<br />
<strong>of</strong> 5 controls based on the following criteria: age +/- 5 years; baseline estimated<br />
glomerular filtration rate (eGFR) +/- 10 mL/min/1.73m 2 ; cisplatin dose per cycle; and<br />
presence <strong>of</strong> diabetes. Conditional logistic regression was used to identify baseline<br />
predictors <strong>of</strong> cisplatin-induced acute nephrotoxicity.<br />
Results: Of the 1245 included patients, 237 had nephrotoxicity and 1008 were matched<br />
controls. Median baseline eGFR for cases and controls were 83 and 80 mL/min/1.73m 2 ,<br />
respectively. 3.8% <strong>of</strong> cases experienced ≥ grade 3 nephrotoxicity. Univariable analysis<br />
showed that diabetes, baseline eGFR, and baseline magnesium level were significantly<br />
associated with nephrotoxicity, whereas mannitol dosing did not show any association<br />
(odds ratio [OR] 1.08, p = 0.29). In multivariable analysis, diabetes (OR 1.86, p = 0.004)<br />
retained statistical significance, but baseline eGFR (OR 1.01, p = 0.06) and baseline<br />
magnesium level (OR 0.25, p = 0.08) showed non-significant associations with<br />
nephrotoxicity. Age, diabetes, cisplatin dose per cycle, mannitol dose per cycle, baseline<br />
eGFR, and baseline magnesium level were not predictors for severity <strong>of</strong> nephrotoxicity.<br />
Conclusions: Cisplatin-induced acute nephrotoxicity remains common despite<br />
preventive measures in patients with good baseline renal function. Diabetes is a<br />
predictor <strong>of</strong> nephrotoxicity, whereas mannitol dosing has no significant influence,<br />
suggesting that doses may be standardized across cisplatin regimens.<br />
Legal entity responsible for the study: University Health Network<br />
Funding: University Health Network<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1472P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Chemotherapy in cancer patients undergoing hemodialysis:<br />
A multicenter study<br />
T. Funakoshi 1 , T. Horimatsu 1 , M. Nakamura 2 , K. Suyama 3 , T. Mizukami 4 , S. Arita 5 ,<br />
Y. Ozaki 6 , H. Yasui 7 , H. Satake 8 , M. Toyoda 9 , S. Yazumi 10 , T. Kirishima 11 ,<br />
A. Nozaki 12 , A. Yoshioka 13 , T. Matsubara 14 , M. Yanagita 14 , S. Fukuhara 15 ,<br />
M. Muto 1<br />
1 Therapeutic <strong>Oncology</strong>, Kyoto University-Graduate school <strong>of</strong> medicine, Kyoto,<br />
Japan, 2 Gastroenterology, Sapporo City General Hospital, Sapporo, Japan,<br />
3 Cancer Center, Kumamoto Univercity Hospital, Kumamoto, Japan, 4 Clinical<br />
<strong>Oncology</strong>, St. Marianna University School <strong>of</strong> Medicine, Kawasaki, Japan,<br />
5 Comprehensive Clinical <strong>Oncology</strong> Faculty <strong>of</strong> Medical Sciences, Kyusyu University,<br />
Fukuoka, Japan, 6 Medical <strong>Oncology</strong>, Toranomon Hospital, Tokyo, Japan,<br />
7 Medical <strong>Oncology</strong>, Kyoto Medical Center, Kyoto, Japan, 8 Medical <strong>Oncology</strong>,<br />
Kobe City Medical Center General Hospital, Kobe, Japan, 9 Medical <strong>Oncology</strong>/<br />
Hematology, Kobe University Graduate School <strong>of</strong> Medicine, Kobe, Japan,<br />
10 Digestive Disease Center, Kitano Hospital, Osaka, Japan, 11 Gastroenterology,<br />
Kyoto City Hospital, Kyoto, Japan, 12 Medical <strong>Oncology</strong>, Kyoto Miniren Chuo<br />
Hospital, Kyoto, Japan, 13 Medical <strong>Oncology</strong>, Mitsubishi Kyoto Hospital, Kyoto,<br />
Japan, 14 Nephrology, Kyoto University-Graduate school <strong>of</strong> medicine, Kyoto,<br />
Japan, 15 Healthcare Epidemiology, Kyoto University-Graduate school <strong>of</strong> medicine,<br />
Kyoto, Japan<br />
Background: Cancer is a major cause <strong>of</strong> death among patients undergoing<br />
hemodialysis (HD). However, little is known about the actual clinical practice <strong>of</strong><br />
chemotherapy in cancer patients undergoing HD. Therefore, we conducted a<br />
nationwide questionnaire survey on chemotherapy for HD patients with cancer.<br />
Methods: This retrospective study included patients undergoing HD who were<br />
subsequently diagnosed with cancer from January 2010 to December 2012. We<br />
reviewed the clinical courses <strong>of</strong> the patients who underwent chemotherapy. The<br />
questionnaires that were sent to 20 institutions, members <strong>of</strong> the Onconephrology<br />
Consortium, consisted <strong>of</strong> the following sections: (1) patient characteristics; (2) regimen,<br />
dosing, and timing <strong>of</strong> chemotherapy; and (3) outcome.<br />
Results: Overall, 675 patients were registered and the most frequent primary cancer<br />
sites were kidney, colorectum, stomach, lung, bladder, liver, breast, and pancreas. Of<br />
these patients, 74 received chemotherapy (44 as palliative chemotherapy, 30 as<br />
perioperative chemotherapy). The primary causes <strong>of</strong> renal failure were chronic<br />
glomerulonephritis (23 patients) and diabetic nephropathy (17 patients). The most<br />
commonly used cytotoxic drugs were fluoropyrimidine (15 patients) and platinum<br />
(eight patients), and the dosing and timing <strong>of</strong> these drugs differed between institutions;<br />
however, the dosing <strong>of</strong> molecular targeting drugs (24 patients) and hormone therapy<br />
drugs (15 patients) was consistent. The median survival time <strong>of</strong> patients undergoing<br />
palliative chemotherapy was 13.0 months (0.1–60.3 months). Of these, three patients<br />
(6.8%) died from treatment-related causes and eight patients (18%) died <strong>of</strong> causes<br />
other than cancer. A high proportion <strong>of</strong> the patients who had diabetic nephropathy<br />
died <strong>of</strong> causes other than cancer including two treatment-related causes. Of 30 patients<br />
who received perioperative chemotherapy, six (20%) died <strong>of</strong> causes other than cancer<br />
within three years after the initiation <strong>of</strong> chemotherapy.<br />
Conclusions: Among HD patients with cancer who received chemotherapy, the rates<br />
<strong>of</strong> mortality from causes other than cancer might be high for both palliative and<br />
perioperative chemotherapy. The indications for chemotherapy in HD patients,<br />
particularly those with diabetes, should be carefully considered.<br />
Legal entity responsible for the study: Kyoto University<br />
Funding: Japanese association <strong>of</strong> Dialyisis Physicians<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
vi510 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
1473P<br />
The effect <strong>of</strong> rikkunshito, a traditional Japanese herbal<br />
medicine, on food intake and plasma acylated ghrelin levels<br />
in lung cancer patients treated with platinum-based<br />
chemotherapy<br />
Table: 1474P Incidence <strong>of</strong> radiotherapy-induced moist desquamation<br />
(RIMD)<br />
T. Yoshiya 1 , M. Ito 1 , K. Misumi 1 , H. Hanaki 1 , Y. Tsutani 1 , K. Satoh 2 , Y. Miyata 1 ,<br />
M. Okada 1<br />
1 Surgical <strong>Oncology</strong>, Hiroshima University, Hiroshima, Japan, 2 Environmetrics and<br />
Biometrics, Hiroshima University, Hiroshima, Japan<br />
Background: Platinum-based agents are key chemotherapeutic drugs for lung cancer<br />
patients. Although considerable progress has been made in supportive therapy for<br />
chemotherapy-induced nausea and vomiting (CINV), its preventive effect for<br />
delayed-onset CINV has not been always satisfactory. We aimed to evaluate whether<br />
rikkunshito (RKT), a traditional herbal medicine <strong>of</strong> Japan, improves CINV-induced<br />
anorexia and increases plasma acylated ghrelin (AG) levels, an orexigenic gut hormone<br />
known to alleviate CINV, in lung cancer patients receiving chemotherapy.<br />
Methods: From July 2013 to March 2016, 40 lung cancer patients undergoing<br />
cisplatin-based chemotherapy were enrolled and randomized to group A (1st course<br />
with RKT (7.5 g/day on days 1-14), 2nd course without RKT (control)) or group B (1st<br />
course without RKT (control), 2nd course with RKT) in a prospective crossover study.<br />
All patients were administered cisplatin on day 1 and treated with 5HT3 and NK1<br />
receptor antagonists and steroids throughout the study. Mean food intake during 1st<br />
and 2nd courses from days 3 to 5 were compared with baseline food intake (day 1).<br />
Fasting blood samples were obtained on days 1, 3 and 5, and plasma AG levels (fmol/<br />
mL) were measured by enzyme-linked immunosorbent assay methods. The primary<br />
endpoint was food intake and secondary endpoint was plasma AG levels.<br />
Results: Thirty-nine patients (male/female, 35/4; median age, 67 years) were included<br />
in the analysis. A decreasing rate <strong>of</strong> the food intake in the control course was<br />
significantly higher than that in the RKT course (control, 25%; RKT, 18%; p = 0.025). A<br />
significant drop in plasma AG levels from day 1 to day 3 was initially noted (RKT, 11.9,<br />
7.3, p < 0.001; control, 13.3, 7.7, p < 0.001), followed by a marked increase from days 3<br />
to 5 in the RKT course (7.3, 8.3, respectively, p = 0.020), but not in the control course<br />
(8.8, 7.7, respectively, p = 0.13).<br />
Conclusions: RKT administration improves delayed-onset CINV-induced anorexia<br />
and increases plasma AG levels in lung cancer patients undergoing highly emetogenic<br />
chemotherapy.<br />
Clinical trial identification: UMIN000010748<br />
Legal entity responsible for the study: N/A<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1474P<br />
Hydroactive colloid gel vs historical controls for the<br />
prevention <strong>of</strong> radiotherapy-induced moist desquamation in<br />
breast cancer patients: preliminary results<br />
S. Censabella 1 , S. Claes 2 , M. Orlandini 2 , R. Braekers 3 , P. Bulens 2<br />
1 Division <strong>of</strong> Medical <strong>Oncology</strong>, Jessa Hospital, Hasselt, Belgium, 2 Limburg<br />
<strong>Oncology</strong> Center, Jessa Hospital, Hasselt, Belgium, 3 CENSTAT, Interuniversity<br />
Institute for Biostatistics and Statistical Bioinformatics, Hasselt, Belgium<br />
Background: Radiotherapy-induced moist desquamation (RIMD) is a painful side<br />
effect that might jeopardize radiotherapy outcomes. Previously, we found that the<br />
curative use <strong>of</strong> a hydroactive colloid gel, compared with dexpanthenol, significantly<br />
reduced the incidence <strong>of</strong> RIMD. In the present study, we investigated the efficacy <strong>of</strong> this<br />
same hydrogel in the prevention <strong>of</strong> RIMD.<br />
Methods: Breast cancer patients scheduled for radiotherapy post-lumpectomy applied<br />
the hydroactive colloid gel from start to end <strong>of</strong> radiotherapy (Preventive Hydrogel<br />
group). They were compared with two groups <strong>of</strong> matched historical controls: One<br />
group applied a dexpanthenol cream throughout radiotherapy, the other replaced<br />
dexpanthenol with the hydrogel from day 11-14 <strong>of</strong> therapy (Curative Hydrogel Group).<br />
Eligibility and radiotherapy fractionation (25#2 Gray [Gy] followed by a 8#2-Gy boost)<br />
regimen were the same for the three groups. The incidence <strong>of</strong> RIMD was analysed<br />
through two-sample proportion tests (two-tailed) and logistic regressions.<br />
Results: Overall, the incidence <strong>of</strong> RIMD was the lowest in the Preventive Hydrogel<br />
group (see Table 1). Although the difference with the Curative Hydrogel group did not<br />
reach significance when taking breast size into account, logistic regressions confirmed<br />
that patients in the Preventive Hydrogel group were at lowest risk <strong>of</strong> developing RIMD,<br />
irrespective <strong>of</strong> breast size (chi-square = 39.59, p < 0.0001, odds ratios = 0.18 for the<br />
Dexpanthenol group and 3.99, p = 0.046; odds ratios = 0.54 for the Curative Hydrogel<br />
group).<br />
% with RIMD 1. Preventive<br />
Hydrogel<br />
(N = 258)<br />
2. Dexpanthenol<br />
(N = 147)<br />
1 vs 2 p* 3. Curative<br />
Hydrogel<br />
(N = 119)<br />
1vs3<br />
p*<br />
Small breasts 4.2% 14.3% 0.031 10% 0.23<br />
Large breasts 14.7% 51% < 0.0001 23.6% 0.08<br />
Total 10.9% 38.8% < 0.0001 20.2% 0.02<br />
* Two-sample proportion tests (two-tailed). Note. Small/ Large breasts = diameter (i.e.,<br />
distance between the two entrance points <strong>of</strong> the beams) < or ≥ 20 cm.<br />
Conclusions: These findings confirm and extend previous results: Applying the<br />
hydroactive colloid gel from the start <strong>of</strong> breast cancer radiotherapy, rather than after<br />
fraction 11-14 or than dexpanthenol, significantly reduces the risk <strong>of</strong> developing<br />
RIMD.<br />
Legal entity responsible for the study: Jessa Hospital<br />
Funding: Jessa Hospital, Hasselt<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1475P<br />
Photobiomodulation for the prevention <strong>of</strong> radiodermatitis:<br />
Preliminary results <strong>of</strong> a randomized controlled clinical trial in<br />
breast cancer patients<br />
J. Robijns 1 , S. Censabella 2 , S. Claes 3 , L. Bussé 1 , N. Hellings 1 , I. Lambrichts 1 ,<br />
A. Timmermans 4 , A. Maes 3 , P. Bulens 3 , V. Somers 1 , J. Mebis 2<br />
1 Faculty <strong>of</strong> Medicine & Life Sciences, Hasselt University, Hasselt, Belgium,<br />
2 Division <strong>of</strong> Medical <strong>Oncology</strong>, Jessa Hospital, Hasselt, Belgium, 3 Limburg<br />
<strong>Oncology</strong> Center, Jessa Hospital, Hasselt, Belgium, 4 Division <strong>of</strong> Dermatology,<br />
Jessa Hospital, Hasselt, Belgium<br />
Background: The aim <strong>of</strong> our study was to investigate the efficacy <strong>of</strong><br />
photobiomodulation therapy (PBMT) for the prevention <strong>of</strong> radiodermatitis (RD) in<br />
breast cancer patients.<br />
Methods: This is a randomized controlled, patient-blinded study with breast cancer<br />
patients that underwent an identical radiotherapy (RT) regime post-lumpectomy. A<br />
total <strong>of</strong> 57 patients were enrolled and randomly assigned to the intervention group to<br />
receive laser therapy (LT, n = 30) or the control group to receive a sham treatment<br />
(n = 27). LT or sham was applied two days a week, immediately after the RT session,<br />
starting at the first day <strong>of</strong> RT. LT was delivered using a class IV MLS® laser that<br />
combines two synchronized laser diodes in the infrared range (808-905 nm) with a<br />
fixed energy density (4 J/cm 2 ). There were no significant differences between the two<br />
groups with respect to patient- and treatment-related characteristics. The skin reactions<br />
were evaluated by trained, blinded nurses at fraction 20 and at the end <strong>of</strong> RT (fraction<br />
33) according to the criteria <strong>of</strong> the Radiation Therapy <strong>Oncology</strong> Group (RTOG).<br />
Results: At fraction 20 <strong>of</strong> RT the distribution <strong>of</strong> the RTOG grades was comparable<br />
between both groups (p= .238), with most <strong>of</strong> the patients presenting RTOG grade 1. At<br />
the end <strong>of</strong> RT, the severity <strong>of</strong> RD significantly differed between the two groups (p=<br />
.035), with a greater proportion <strong>of</strong> patients experiencing RD grade 2 or higher in the<br />
control group (30% vs. 7%, for the control and LT group, resp.). The skin reactions <strong>of</strong><br />
the patients in the control group aggravated (p= .006), while they remained stable in<br />
the LT group (p= .205).<br />
Table: 1475P<br />
Control group (n = 27) LT group (n = 30)<br />
Fraction 20 <strong>of</strong> RT End <strong>of</strong> RT p* Fraction 20 <strong>of</strong> RT End <strong>of</strong> RT p*<br />
RTOG grade N (%) N (%) .006 N (%) N (%) .205<br />
0 1 (4) 0 3 (10) 0<br />
1 26 (96) 19 (70) 25 (83) 28 (93)<br />
2 0 7 (26) 2 (7) 2 (7)<br />
3 0 1 (4) 0 0<br />
*Chi-square test or Fisher’s exact test (two-tailed).<br />
Conclusions: In the control group the skin reactions developed into more severe forms<br />
(e.g. moist desquamation) towards the end <strong>of</strong> RT, whereas in the LT group the skin<br />
reactions remained stable. Results <strong>of</strong> this study show that PBMT is able to prevent<br />
aggravation <strong>of</strong> acute skin reactions <strong>of</strong> breast cancer patients undergoing RT.<br />
Clinical trial identification: NCT02443493<br />
Legal entity responsible for the study: Hasselt University<br />
Funding: Hasselt University, Limburg Sterk Merk, Province <strong>of</strong> Limburg, Jessa<br />
Hospital, Flemish Government, Limburgs Kankerfonds, ASA srl<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw390 | vi511
abstracts<br />
1476P<br />
Comparison <strong>of</strong> the usage <strong>of</strong> granulocyte colony-stimulating<br />
factors (G-CSF) in the Baltic and Nordic countries in<br />
2011-2014<br />
E. Vettus 1 , K. Kurvits 2 , K. Oselin 1<br />
1 Department <strong>of</strong> Chemotherapy, North Estonia Medical Centre, Tallinn, Estonia,<br />
2 Department <strong>of</strong> Post-Authorisation Safety, State Agency <strong>of</strong> Medicines, Tartu,<br />
Estonia<br />
Background: We aimed to analyse the use <strong>of</strong> G-CSF in the Nordic and Baltic countries<br />
and to compare the use <strong>of</strong> short- (filgrastim and its analogs) and long-acting<br />
(pegfilgrastim) G-CSFs in three cancer centres in Estonia with similar patient pr<strong>of</strong>ile<br />
and identical reimbursement system.<br />
Methods: G-CSFs were classified according to the Anatomical Therapeutic Chemical<br />
(ATC) classification (2015), the number <strong>of</strong> defined daily doses (DDD) per 1000<br />
inhabitants per day was used as a measurement (DDD is 350 mcg for filgrastim and<br />
300 mcg for pegfilgrastim). National consumption data (based on wholesale data) <strong>of</strong><br />
G-CSF in the Nordic and Baltic countries were obtained from the Estonian Agency <strong>of</strong><br />
Medicines. Dispensed G-CSF in three cancer centres in Estonia was obtained from<br />
hospital pharmacies. Number <strong>of</strong> patients and chemotherapy courses delivered per year<br />
per hospital were retrieved from the Estonian Health Insurance Fund and were<br />
compared with the dispensed G-CSF in each hospital.<br />
Results:<br />
Table: 1476P The use <strong>of</strong> G-CSF in the Nordic and Baltic countries in<br />
2011-2014 using DDD/1000 inhabitants/day<br />
Year Finland Norway Sweden Denmark Lithuania Latvia Estonia EE-1* EE-2* EE-3*<br />
2011 0.2 0.1 0.04 0.1 0.04 0.07 0.03 0.37 0.67 0.12<br />
2012 0.19 0.11 0.03 0.1 0.06 0.08 0.04 0.43 0.77 0.10<br />
2013 0.16 0.12 0.03 0.2 0.07 0.1 0.05 0.57 1.0 0.13<br />
2014 0.16 0.14 0.03 0.2 0.08 0.1 0.06 0.64 1.0 0.20<br />
*Dispensed G-CSF (0,3mg) per chemotherapy courses in three cancer centres<br />
in Estonia In 2014 the consumption <strong>of</strong> G-CSF in Sweden was 85% lower than<br />
in Denmark, Denmark and Finland using only pegfilgrastim. Latvia has used<br />
the most G-CSF when compared to other Baltics and in 2013 their use <strong>of</strong><br />
long-acting G-CSF was 8 times higher than in Lithuania. Filgrastim was the<br />
most used G-CSF in Estonia, G-CSF consumption varied 5 fold between<br />
cancer centres.<br />
Conclusions: According to the national medicines use data the overall consumption <strong>of</strong><br />
G-CSFs is highly variable in the Nordic and Baltic countries despite clear and updated<br />
guidelines by ESMO and ASCO. Consumption <strong>of</strong> G-CSFs has steadily increased in the<br />
three Baltic countries, most likely due to the availability <strong>of</strong> filgrastim biosimilars. The<br />
observed remarkable differences between use <strong>of</strong> G-CSF in the Nordic countries are<br />
difficult to explain.<br />
Legal entity responsible for the study: North Estonia Medical Centre, Tallinn, Estonia<br />
Funding: North Estonia Medical Centre, Tallinn, Estonia<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1477P<br />
Observational data on the clinical benefit <strong>of</strong> epoetin beta in<br />
cancer patients with anemia<br />
J-P. Spano 1 , F. Barlesi 2 , K. Pestel 3 ,D.Pau 4 , C. Dauriac 5<br />
1 Medical <strong>Oncology</strong>, Pitié-Salpêtrière Hospital, Paris, France, 2 Multidisciplinary<br />
<strong>Oncology</strong> and Therapeutic Innovations, Aix Marseille University; Assistance<br />
Publique Hôpitaux de Marseille, Marseille, France, 3 Medical Affairs, Roche S.A.S.,<br />
Boulogne-Billancourt, France, 4 Clinical Operations, Roche S.A.S.,<br />
Boulogne-Billancourt, France, 5 Hematology, Pontchaillou Hospital, Rennes,<br />
France<br />
Background: Anemia is a frequent complication <strong>of</strong> chemotherapy that can reduce<br />
quality <strong>of</strong> life as well as the anti-cancer efficacy <strong>of</strong> treatment.<br />
Methods: Two prospective observational studies have investigated, in a real-life setting,<br />
the efficacy and safety <strong>of</strong> epoetin beta in treatment <strong>of</strong> chemotherapy-induced anemia.<br />
The FAST study (ML22733 [NCT01168349]) included patients in France receiving<br />
chemotherapy for solid tumors or hematologic malignancies for whom the treating<br />
physician had prescribed epoetin beta, with 24–28-week follow-up. The ML25362<br />
study (NCT01716559) included patients in Hungary receiving chemotherapy for<br />
non-myeloid malignancies and presenting with symptomatic anemia, with 16-week<br />
follow-up.<br />
Results: In the FAST study, 1055 patients were enrolled and 979 (528 [54%] female,<br />
mean age 65 years) were evaluable for efficacy, including 677 with solid tumors and 302<br />
with hematologic malignancies. The starting dose <strong>of</strong> epoetin beta was 30,000 IU in<br />
>90% <strong>of</strong> patients. Mean hemoglobin (Hb) was 9.7 ± 0.9 g/dL at the start <strong>of</strong> treatment,<br />
rising to 11.5 ± 1.5 g/dL by week 24–28. In patients with solid tumors, mean Hb<br />
increased from 9.8 ± 0.8 g/dL to 11.3 ± 1.4 g/dL and in those with hematologic<br />
malignancies from 9.5 ± 1.1 g/dL to 11.8 ± 1.6 g/dL. The proportion <strong>of</strong> patients<br />
experiencing at least one physical sign <strong>of</strong> anemia reduced from 95% to 77% (solid<br />
tumors) and from 97% to 70% (hematologic malignancies) during the study, the<br />
proportion reporting fatigue decreasing from 91% to 68% (solid tumors) and 87% to<br />
66% (hematologic malignancies). 186 patients (19%) received at least one red blood cell<br />
transfusion. Thromboembolic events were seen in 13 patients (1%) (5 deep vein<br />
thrombosis, 7 pulmonary embolism, 1 arterial thrombosis). In ML25362, 160 patients<br />
(87 [54%] female, mean age 63 years) were treated with a starting dose <strong>of</strong> 30,000 IU<br />
epoetin beta. Mean Hb increased from 9.1 ± 0.1 g/dL at baseline to 10.7 ± 0.2 g/dL at<br />
week 8 and 10.8 ± 0.2 g/dL at week 16. 38 patients (24%) received at least one red blood<br />
cell transfusion. In both studies, safety was consistent with the known pr<strong>of</strong>ile <strong>of</strong> epoetin<br />
beta in this population.<br />
Conclusions: The data from both studies confirm the efficacy and safety <strong>of</strong> epoetin<br />
beta in the treatment <strong>of</strong> chemotherapy-induced anemia in a real-world setting.<br />
Clinical trial identification: NCT01168349, NCT01716559<br />
Legal entity responsible for the study: Roche S.A.S.<br />
Funding: F. H<strong>of</strong>fmann-La Roche<br />
Disclosure: J-P. Spano: Consultancy and Advisory Board membership for<br />
F. H<strong>of</strong>fmann-La Roche. K. Pestel, D. Pau: Employed by Roche S.A.S. All other authors<br />
have declared no conflicts <strong>of</strong> interest.<br />
1478P<br />
Risk factors for upper limb deep venous thrombosis (DVT)<br />
associated with peripherally inserted central catheters<br />
(PICCs) in cancer patients<br />
A.J. Lee, B.P. Fairfax<br />
<strong>Oncology</strong>, Oxford Cancer and Haematology Centre, Churchill Hospital, Oxford, UK<br />
Background: Peripherally inserted central catheters (PICCs) are associated with an<br />
increased risk <strong>of</strong> upper limb deep vein thrombosis (DVT). In Oxford University<br />
Hospitals, PICCs are widely used for the delivery <strong>of</strong> chemotherapy in cancer patients.<br />
We aimed to investigate the incidence and risk factors for PICC-associated DVT in<br />
cancer patients.<br />
Methods: This was a single centre study at a tertiary centre in Oxford. We obtained details<br />
<strong>of</strong> all patients who had PICCs inserted in 2015 under the vascular access department in the<br />
hospital. Gender, Body Mass Index (BMI), cancer type and chemotherapy regime were<br />
matched to these patients. A diagnosis <strong>of</strong> upper limb DVT was confirmed from diagnostic<br />
imaging. Retrospective analysis on the data was performed.<br />
Results: 454 oncology patients had PICCs inserted in 2015. 18 patients (4%) developed<br />
a DVT. Gender proportions were similar between the DVT and non-DVT cohorts<br />
(72% female vs 73% female, p = 0.95). Median BMI was 27.43kg in those with DVTs<br />
and 26.84 in those without DVTs (p = 0.65). Breast cancer and colorectal cancer were<br />
the most common cancer types in the DVT cohort and breast cancer was<br />
over-represented whilst colorectal cancer under-represented compared to the non-<br />
DVT cohort (Table 1) (p = 0.59). A higher proportion <strong>of</strong> patients with DVTs received<br />
FEC-T chemotherapy compared to patients without DVTs (39% vs 25%, p = 0.20).<br />
Table: 1478P Cancer types in patients with DVTs and without DVTs<br />
DVT (%) No DVT (%)<br />
Breast cancer 8 (44) 165 (38)<br />
Colorectal cancer 4 (22) 123 (28)<br />
Other 6 (33) 148 (34)<br />
Conclusions: Other studies have extensively analysed risk factors for PICC thrombosis<br />
but have not focused on types <strong>of</strong> cancer or chemotherapy. In our study, breast cancer<br />
and FEC-T chemotherapy appeared to be over-represented in the DVT cohort,<br />
however this did not reach statistical significance. We are currently performing further<br />
work using data from previous years to see if this trend continues.<br />
Legal entity responsible for the study: Oxford University Hospitals<br />
Funding: Oxford University Hospitals<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1479P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Predictive factors for use <strong>of</strong> parenteral versus oral<br />
anticoagulants in the treatment <strong>of</strong> venous thromboembolism<br />
in patients with active cancer<br />
A. Katholing 1 , K. Folkerts 2 ,M.Bach 3 , C. Martinez 1<br />
1 Epidemiology, Institute for Epidemiology, Statistics and Informatics GmbH,<br />
Frankfurt am Main, Germany, 2 Global Market Access GHEOR GM, Bayer Pharma<br />
AG, Wuppertal, Germany, 3 Global Medical Affairs, Bayer Pharma AG, Berlin,<br />
Germany<br />
Background: In patients with active cancer, the risk <strong>of</strong> venous thromboembolism<br />
(VTE) is up to five times higher. Anticoagulants (ACs) reduce the risk <strong>of</strong> VTE. We<br />
vi512 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
explored predictors for parenteral versus oral ACs in patients with cancer-associated<br />
VTE (Ca-VTE).<br />
Methods: Patient data were retrieved from general practices in England contributing to<br />
the Clinical Practice Research Datalink (CPRD) with additional hospital discharge and<br />
cause <strong>of</strong> death data. The study cohort consisted <strong>of</strong> patients with a specified cancer<br />
recorded within the 90 days before or after the first VTE between 2008 and 2014, and<br />
with a subsequent record <strong>of</strong> either LMWH or fondaparinux defined as parenteral ACs<br />
(PACs), <strong>of</strong> vitamin K antagonists (VKA) or non-VKA oral ACs (NOACs). To allow for<br />
transition from PACs to VKAs, PAC only treatment was defined as initial PAC<br />
treatment without any VKA within the first 15 days. In a case-control analysis, cases<br />
were VKA users and controls PAC only users, matched 1:1 on the date <strong>of</strong> the Ca-VTE.<br />
Adjusted incidence rate ratios were estimated from the odds ratios (ORs) using<br />
conditional logistic regression for matched case–control data. Adjustment included<br />
age, gender, tumour type, cancer therapy, lifestyle factors and comorbidities.<br />
Results: The study cohort consisted <strong>of</strong> 5419 patients with a Ca-VTE. Of those, 34.5%<br />
were given PACs (mean age 66.5), 22.7% VKAs (mean age 70.2), 0.6% NOACs (mean<br />
age 67.6), and 42.1% received no ACs. A total <strong>of</strong> 1228 PAC users were matched to 1228<br />
VKA users. With prostate cancer as the reference group, all other types <strong>of</strong> cancer were<br />
associated with preferential use <strong>of</strong> PACs. Pancreatic cancer (OR 7.69, 3.85-14.3),<br />
stomach cancer (OR 7.14; 3.70-14.3) and ovarian cancer (OR 6.67, 3.57–12.5) were the<br />
strongest predictors for initiation <strong>of</strong> PAC only therapy. History <strong>of</strong> diabetes (OR 1.37,<br />
1.03-1.81) also predicted preferential PAC use. Predictors for preferential use <strong>of</strong> VKAs<br />
were age ≥80 compared with age 60-69 (OR 1.48, 1.08 –2.03) and radiation therapy<br />
compared with chemotherapy (OR 1.63, 1.02–2.60).<br />
Conclusions: Treatment with only PACs depends on the primary tumour and is more<br />
likely in patients with a history <strong>of</strong> diabetes. However, advanced age, and radiation<br />
therapy are predictors <strong>of</strong> VKA use.<br />
Legal entity responsible for the study: Institute for Epidemiology, Stastistics and<br />
Informatics GmbH<br />
Funding: Bayer Pharma AG<br />
Disclosure: A. Katholing: Grants from Bayer Pharma AG and grants from BMS/Pfizer<br />
outside the submitted work. K. Folkerts, M. Bach: Employee <strong>of</strong> the sponsor <strong>of</strong> this<br />
study. C. Martinez: Personal fees from Boehringer Ingelheim, grants from CSL<br />
Behring, grants from Bayer Pharma AG, grants from BMS-Pfizer, outside the<br />
submitted work.<br />
1480P<br />
A risk assessment model for predicting venous<br />
thromboembolic events in chemotherapy-treated germ-cell<br />
cancer<br />
M.I. Luengo 1 , D. Hervás 2 , N. Sobrevilla 3 , X. Garcia del Muro 4 , J. Guma I Padro 5 ,<br />
D. Castellano 6 , J. Aparicio 7 , A. Sánchez Muñoz 8 , E. Buxo 9 , A. Saenz 10 ,J.<br />
L. Aguilar 3 , C. Valverde Morales 11 , A. Fernández Aramburu 12 , P. Maroto 13 ,<br />
M. Espinosa 14 , P. Jimenez Fonseca 15 ,S.Ros 16 , M. Margeli 4 , J. Sastre 17 ,<br />
E. Gonzalez-Billalabeitia 1<br />
1 Hematology and Clinical <strong>Oncology</strong>, Hospital Universitario Morales Meseguer,<br />
Murcia, Spain, 2 Bioestadística, Instituto de Investigación Sanitaria La Fe, Valencia,<br />
Spain, 3 Medical <strong>Oncology</strong>, Instituto Nacional de Cancerología (INCAN), Mexico,<br />
Mexico, 4 Medical <strong>Oncology</strong>, Institut Català d’Oncologia Hospital Duran i Reynals,<br />
Barcelona, Spain, 5 <strong>Oncology</strong> Service, University Hospital St. Joan de Reus, Reus,<br />
Spain, 6 Medical <strong>Oncology</strong>, University Hospital 12 De Octubre, Madrid, Spain,<br />
7 Medical <strong>Oncology</strong>, Hospital Universitari i Politècnic La Fe, Valencia, Spain,<br />
8 Servicio de Oncología Médica, Hospital Universitario Virgen de la Victoria,<br />
Malaga, Spain, 9 Medical <strong>Oncology</strong>, Hospital Clinic y Provincial de Barcelona,<br />
Barcelona, Spain, 10 Clinical <strong>Oncology</strong>, Hospital Clinico Universitario Lozano Blesa,<br />
Zaragoza, Spain, 11 Oncologia Médica, Vall d’Hebron University Hospital Institut<br />
d’Oncologia, Barcelona, Spain, 12 Clinical <strong>Oncology</strong>, Complejo Hospitalario<br />
Universitario de Albacete, Albacete, Spain, 13 Dept. <strong>of</strong> Medical <strong>Oncology</strong>, Hospital<br />
de la Santa Creu i Sant Pau, Barcelona, Spain, 14 Clinical <strong>Oncology</strong>, Hospital<br />
Universitario Virgen del Rocio, Seville, Spain, 15 Medical <strong>Oncology</strong>, Hospital<br />
Universitario Central de Asturias, Oviedo, Spain, 16 Clinical <strong>Oncology</strong>, Hospital<br />
Universitario Virgen de la Arrixaca, Murcia, Spain, 17 <strong>Oncology</strong> Department, Clínico<br />
San Carlos Hospital, Madrid, Spain<br />
Background: Germ-cell cancer patients (GCC) treated with chemotherapy are at high<br />
risk <strong>of</strong> developing venous thromboembolic events (VTE). Several single parameters<br />
have been proposed for risk prediction, but no risk assessment model (RAM) is<br />
currently available.<br />
Methods: All previously reported variables related with venous thrombosis in GCC<br />
were included. The association <strong>of</strong> these predictors with the development <strong>of</strong> VTEs was<br />
assessed using an Elastic Net penalized logistic regression model. The selection <strong>of</strong> the<br />
penalization factor lambda for the Elastic Net analysis was performed using 10-fold<br />
cross-validation. The adjusted model was validated using an external and independent<br />
cohort. As a measure <strong>of</strong> performance <strong>of</strong> the model the AUC (area under ROC curve)<br />
was used. The training dataset consisted <strong>of</strong> all consecutive chemotherapy-treated GCC<br />
patients recruited by 13 hospitals in the Spanish Germ-Cell Cancer Group (SGCCG)<br />
registry between 2004 and 2014. The validating dataset consisted <strong>of</strong> an external and<br />
independent cohort <strong>of</strong> patients treated at 4 independent hospitals.<br />
Results: The training subset included 513 patients, with a VTE rate <strong>of</strong> 9% (N = 44).<br />
Our penalized logistic regression model included 4 predictors: Large retroperitoneal<br />
mass (N3), presence <strong>of</strong> liver, bone or brain metastasis (LBB), IGCCC poor prognosis<br />
(IGCCCPoor) and haemoglobin basal level (HBB), which were able to predict the<br />
− 2.33 +0.16*N3+0.27*LBB<br />
probability <strong>of</strong> an event following the equation: P(event) = e +0.19*ICCCCPoor-0.003*HBB /(1 + e − 2.33+0.16*N3+ 0.27*LBB+0.19*ICCCCPoor - 0.003*HBB ). This<br />
model resulted in an area under the ROC curve <strong>of</strong> 0.83 (95% CI: 0.76-0.90). The<br />
validation subset included 325 patients with a VTE rate <strong>of</strong> 13% (N = 42). The area<br />
under the curve in the validation sample was 0.73 (95% CI, 0.65, 0.83).<br />
Conclusions: We report a risk assessment model able to predict the probability <strong>of</strong> VTE<br />
in chemotherapy-treated GCC. This model may guide patient selection in studies <strong>of</strong><br />
thromboprophylaxis in this population.<br />
Legal entity responsible for the study: Spanish Germ Cell Cancer Group<br />
Funding: Spanish Germ Cell Cancer Group<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1481P<br />
abstracts<br />
Outpatient management <strong>of</strong> cancer-associated pulmonary<br />
embolism (PE): analysis <strong>of</strong> lung carcinoma (LC) cohort from<br />
the Epiphany study<br />
C. Beato 1 , L. Faez 2 , A. Carmona-Bayonas 3 , M.D. Mediano 4 , C. Font 5 ,<br />
D. Calvo-Temprano 6 , P. Jimenez Fonseca 6 , A. Dominguez 4 , M.P.<br />
Solis Hernandez 6 , M. Biosca 7 , I. de la Haba 5 , M. Antonio 8 , O. Madriano 9 ,<br />
A. Ramchandani 10 , E. Castanon Alvarez 11 , M.J. Martinez 12 , J.A.<br />
Virizuela Echaburu 13 , R. Otero 4<br />
1 Medical <strong>Oncology</strong> Unit, Hospital Nisa Castilleja de la Cuesta, Seville, Spain,<br />
2 Medical <strong>Oncology</strong> Unit, Hospital Universitario Central de Asturias, Oviedo, Spain,<br />
3 Medical <strong>Oncology</strong>, Hospital Universitario Morales Meseguer, Murcia, Spain,<br />
4 Medical <strong>Oncology</strong>, Hospital Universitario Virgen del Rocio, Seville, Spain,<br />
5 Medical <strong>Oncology</strong>, Hospital Clinic y Provincial de Barcelona, Barcelona, Spain,<br />
6 Medical <strong>Oncology</strong>, Hospital Universitario Central de Asturias, Oviedo, Spain,<br />
7 Medical <strong>Oncology</strong> Unit, Vall d’Hebron University Hospital Institut d’Oncologia,<br />
Barcelona, Spain, 8 Medical <strong>Oncology</strong>, Institut Catala de Oncologia, L’Hospitalet<br />
de Llobregat, Barcelona, Spain, 9 Medical <strong>Oncology</strong> Onit, Hospital Infanta S<strong>of</strong>ia,<br />
Madrid, Spain, 10 Medical <strong>Oncology</strong> Unit, Hospital Universitario Insular de Gran<br />
Canaria, Las Palmas, Spain, 11 <strong>Oncology</strong> Department, Clinica Universitaria de<br />
Navarra, Pamplona, Spain, 12 Medical <strong>Oncology</strong> Unit, Hospital Universitario Santa<br />
Lucia, Cartagena, Spain, 13 Medical <strong>Oncology</strong>, Hospital Universitario Virgen<br />
Macarena, Seville, Spain<br />
Background: Clinical guidelines suggest that outpatient management <strong>of</strong> PE is an<br />
appropriate alternative in low-risk selected patients. However, this population is not<br />
adequately defined and the evidence is limited in cancer patients. Primary endpoint<br />
was the rate <strong>of</strong> success in outpatient PE management. Secondary endpoints included<br />
the analysis <strong>of</strong> complications and causes <strong>of</strong> readmission and mortality, re-thrombosis<br />
and major bleeding at 15, 30 and 90 days.<br />
Methods: Epiphany is a Spanish multicenter ambispective and non-interventional<br />
study. It includes patients with cancer-associated PE, symptomatic and incidentally<br />
diagnosed, between October 2008 and October 2014. Patients were treated according to<br />
current international guidelines, and followed for at least 90-days. We present data<br />
from the cohort with LC.<br />
Results: We included 1033 patients with cancer and PE <strong>of</strong> whom 797 were diagnosed<br />
as outpatients. Of these, 210 had LC and 72 (34.3%) were discharged in the first<br />
24-hours. 95.8% were incidental diagnoses and 83.3% did not show specific symptoms.<br />
The following features were associated with the last group (p
abstracts<br />
1482P<br />
Concerns <strong>of</strong> young women with breast cancer and theirs<br />
partners from chemotherapy to follow-up: a cross-sectional<br />
study<br />
L. Vanlemmens 1 , A. Congard 2 , C. Duprez 3 , A-S. Baudry 3 , A. Lesur 4 , C. Loustalot 5 ,<br />
C. Guillemet 6 , M. Leclercq 7 , C. Levy 8 , D. Carlier 9 , C. Lefeuvre-Plesse 10 ,<br />
H. Simon 11 , J-S. Frenel 12 , P. Antoine 3 , V. Christophe 3<br />
1 Breast Cancer Department, Centre Oscar Lambret, Lille, France, 2 Centre de<br />
Recherche PsyCLÉ (EA 3273), Aix-Marseille Université, Aix-en-Provence, France,<br />
3 SCALab UMR CNRS 9193, Université de Lille, Villeneuve d’Ascq, France, 4 Breast<br />
Cancer Department, Institut de Cancérologie de Lorraine, Nancy, France,<br />
5 Surgical Department, Centre Georges-François Leclerc (Dijon), Dijon, France,<br />
6 Medical <strong>Oncology</strong>, Centre Henri Becquerel, Rouen, France, 7 Marcq En Baroeul,<br />
France, 8 <strong>Oncology</strong>, Centre Francois Baclesse, Caen, France,<br />
9 Radio-chemotherapy, Clinique d’Imagerie du Pont Saint Vaast, Douai, France,<br />
10 Breast and Gynecologic <strong>Oncology</strong>, Centre Eugene - Marquis, Rennes, France,<br />
11 Medical <strong>Oncology</strong>, C.H.U. Brest - Hôpital Morvan, Brest, France, 12 Medical<br />
<strong>Oncology</strong>, ICO Institut de Cancerologie de l’Ouest René Gauducheau,<br />
St. Herblain, France<br />
Background: Better understanding the concerns <strong>of</strong> couples facing cancer appears<br />
crucial for care quality. This study aims to clarify the subjective experience in couples<br />
in which the woman is diagnosed with early breast cancer at a young age ( 61% pts by 15%, and 21–60% by 56%, with the main goals<br />
QOL (69%), anticancer treatment completion (52%), and fast recovery (50%). Main<br />
nutritional care barriers were lack <strong>of</strong> assessment/monitoring tools (61%), costs <strong>of</strong><br />
supplements (42%), no clear guidelines (29%), and lack <strong>of</strong> time (28%). Approaches to<br />
minimize weight loss were antiemetic therapy (56%), appetite stimulation (48%), and<br />
other anticachexia drugs (43%), more effective anticancer treatment (47%), and<br />
lowering the anticancer treatment dose (11%). 78% apply nutritional measures for<br />
cancer cachexia pts, but 9% were unaware <strong>of</strong> the cancer cachexia concept.<br />
Conclusions: A small majority <strong>of</strong> HCPs recognise the negative impact <strong>of</strong> malnutrition<br />
and cachexia on cancer care outcomes, but a minority routinely apply nutritional<br />
assessment and care. Clinical practice tools, education, and guidelines are needed to<br />
improve nutritional care practice in cancer supportive and palliative care.<br />
Legal entity responsible for the study: Nutricia<br />
Funding: Nutricia<br />
Disclosure: F. Strasser: Advisory board: Acacia, ACRAF, Amgen, Baxter, Celgene,<br />
Danone, Fresenius, GlaxoSmithKline, Grunenthal, Helsinn, Isis, Global, Millennium/<br />
Takeda, Mundipharma, Novartis, Novelpharm, Nycomed, Obexia, Ono, Otsuka,<br />
Pfizer, Pharm-Olam, PsiOxus, PrIME, Santhera, Sunstone, Teva, Vifor.<br />
Corporate-sponsored research: Novartis. Industry grants for clinical research: Celgene,<br />
Fresenius, Helsinn. R. Audisio: Corporate-sponsored research: Honoraria for<br />
independent presentations at meetings sponsored by industry (Nutricia and Roche). N.<br />
Georgiou: Corporate-sponsored research Employee <strong>of</strong> Nutricia Advanced Medical<br />
Nutrition. All other authors have declared no conflicts <strong>of</strong> interest.<br />
1484P<br />
Vaccination perception and attitudes among patients with<br />
cancer receiving chemotherapy<br />
S. Akin 1 , O. Dizdar 2 , Y. Karakas 1 , L. Ozisik 3 , M. Durusu Tanriover 3 , S. Kamisli 2 ,<br />
M. Erman 2 ,M.Hayran 2<br />
1 Medical <strong>Oncology</strong>, Hacettepe University Faculty <strong>of</strong> Medicine, Ankara, Turkey,<br />
2 Preventive <strong>Oncology</strong>, Hacettepe University Faculty <strong>of</strong> Medicine, Ankara, Turkey,<br />
3 Internal Medicine, Hacettepe University Faculty <strong>of</strong> Medicine, Ankara, Turkey<br />
Background: Immunization against vaccine preventable diseases is an essential but<br />
mostly overlooked issue in oncology practice. Despite the presence <strong>of</strong> several<br />
guidelines, vaccination coverage rates among cancer patients are quiet low. We aimed<br />
to investigate the utilization <strong>of</strong> adult immunization recommendations and the<br />
perception <strong>of</strong> the patients with cancer receiving chemotherapy on immunization.<br />
Methods: A 15-item questionnaire about immunization in adults with cancer<br />
diagnosis was administered to patients with various cancers treated in daycare<br />
chemotherapy unit <strong>of</strong> Hacettepe University Cancer Institute.<br />
Results: Total <strong>of</strong> 229 patients completed the survey. 74.7% <strong>of</strong> the patients agreed that<br />
people over 18 years <strong>of</strong> age must be vaccinated, and 54% <strong>of</strong> patients were vaccinated at<br />
least once, most commonly against influenza (25.3%) and tetanus (22.3%) over 18<br />
years old. Higher rate <strong>of</strong> participants was opposed to vaccination <strong>of</strong> patients with<br />
cancer diagnosis compared with those who was opposed to vaccination <strong>of</strong> healthy<br />
adults (p < 0.001). The most frequent reason was the concerns <strong>of</strong> being harmful (40%).<br />
Vaccination was never recommended in 93% <strong>of</strong> the participants. Only 9% <strong>of</strong> patients<br />
(n = 21) were shot after cancer diagnosis, most commonly with influenza. There was a<br />
strong association between doctor’s advice and vaccination status. Twelve <strong>of</strong> 15 patients<br />
(80%) who were recommended to be vaccinated did so whereas only 9 <strong>of</strong> 214<br />
remaining patients (4.2%) were vaccinated (p < 0.001). Among those not vaccinated<br />
after diagnosis <strong>of</strong> cancer, most frequent reason was; not recommended by the doctor<br />
(59%). Neither vaccination rates nor perceptions on adult immunization differed by<br />
age, gender, marital status, presence <strong>of</strong> co-morbidity or type <strong>of</strong> cancer. Interestingly,<br />
patients who had higher educational status had higher rate <strong>of</strong> opposition to vaccination<br />
after the diagnosis <strong>of</strong> cancer compared with those with lower educational status<br />
(p = 0.03).<br />
Conclusions: Among adult patients with cancer and receiving chemotherapy,<br />
immunization rates were found to be very low. Main reason was the lack <strong>of</strong><br />
recommendation by the primary physician involved in the treatment, mostly the<br />
oncologist. Awareness on this issue in physicians, particularly oncologists, may increase<br />
vaccination rates.<br />
Legal entity responsible for the study: N/A<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1485P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Medical oncologists’ attitudes towards vaccination in<br />
oncology practice<br />
A. Alkan 1 , E. Karcı 1 ,A.Yaşar 1 , G. Tuncay 2 , M. Ürün 1 , E.B. Köksoy 1 , Y. Ürün 1 ,F.<br />
Çay Sȩnler 1 , G. Utkan 1 , A. Demirkazık 1 , H. Akbulut 1<br />
1 Medical <strong>Oncology</strong>, Ankara University School <strong>of</strong> Medicine, Ankara, Turkey,<br />
2 Internal Medicine, Ankara University School <strong>of</strong> Medicine, Ankara, Turkey<br />
Background: Despite <strong>of</strong> vaccination is a highly effective way <strong>of</strong> preventing certain<br />
infections and widely recommended in patients’ with cancer, vaccination rate are not<br />
high enough. The purpose <strong>of</strong> this study was to evaluate the attitude <strong>of</strong> medical<br />
vi514 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
oncologists towards vaccination in their daily practice and predictors <strong>of</strong> vaccination<br />
practice in oncology.<br />
Methods: A structured questionnaire is formed to evaluate the daily practice <strong>of</strong><br />
vaccination. Medical oncologists actively working in Turkey were invited to study by<br />
emails, SMS messages and direct phone calls. Questionnaires were filled and the data<br />
were stored with an online survey platform<br />
Results: 273 medical oncologists participated the survey. Influenza, Pneumococcus and<br />
hepatitis B were the most commonly recommended vaccines (87.1%, 72.8%, 67.0%,<br />
respectively) in daily practice. Lung, lymphoma and breast cancer are the pathologies to<br />
which medical oncologists give priority while recommending vaccination (68.1%,<br />
68.1%, 24.6%, respectively. Participants prefer to recommend vaccination to patients in<br />
remission/follow-up (68.4%) or before starting therapy 64.1%. Patients’ age and<br />
comorbidities were not related with rate <strong>of</strong> vaccination. Only 23.4% <strong>of</strong> the participants<br />
thought that their recommendations on vaccination were efficient and satisfying. Lack<br />
<strong>of</strong> time during outpatient clinic visit and lack <strong>of</strong> knowledge or experience about<br />
vaccination are the most common limitations during recommending vaccination.<br />
There is a positive correlation between experience in the field and evaluating patients<br />
for vaccination (r = 0.390, p < 0.001), on the other hand, there is negative correlation<br />
between number <strong>of</strong> patients daily cared and evaluating patients for vaccination (r=<br />
-0.080, p = 0.18). Experience with autologous or allogeneic bone marrow transplant<br />
patients is related with more tendency to evaluate patients for vaccination (p < 0.001).<br />
Conclusions: Status <strong>of</strong> experience in oncology, especially in bone marrow transplant<br />
units and total number <strong>of</strong> patients exposed daily are important predictors <strong>of</strong><br />
vaccination practice in oncology. Similar with the data in other fields, there is also a<br />
huge heterogeneity in medical oncologists’ attitude towards vaccination.<br />
Legal entity responsible for the study: N/A<br />
Funding: Ankara University School <strong>of</strong> Medicine, medical oncology- Medical<br />
Oncologists<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1486P<br />
Efficacy <strong>of</strong> influenza vaccine (FluVax) in patients on<br />
chemotherapy (POCT): final data analysis from South<br />
Australia<br />
A. Ayoola 1 , S. Sukumaran 2 , R. Kumar 1 , D. Gordon 3 ,A.Roy 2 , S. Vantandoust 1 ,<br />
B. Koczwara 2 , G. Kichenadasse 2 , C. Karapetis 2<br />
1 Department <strong>of</strong> Medical <strong>Oncology</strong>, Flinders Medical Center, Bedford Park,<br />
Australia, 2 Medical <strong>Oncology</strong>, Flinders Medical Centre and Flinders University,<br />
Adelaide, Australia, 3 Department <strong>of</strong> Microbiology and Infectious Diseases, Flinders<br />
Medical Center, Bedford Park, Australia<br />
Background: Influenza (flu) virus infection has a significant morbidity and mortality<br />
in excess <strong>of</strong> 5-10% especially in patients with medical co-morbidities who are also<br />
immune-suppressed. Influenza vaccination decreases all-cause mortality by about<br />
30-50%. Patients undergoing chemotherapy along with the general public are<br />
vaccinated annually; there has been no study to assess the efficacy <strong>of</strong> influenza<br />
vaccination in these groups (patients on chemotherapy- POCT).<br />
Methods: This is a prospective single arm, phase II open label study. 53 POCT with<br />
non-haematological cancers were recruited between 2011 and 2012 influenza seasons.<br />
POCT vaccinated in the current influenza season were excluded. Participants had one<br />
dose <strong>of</strong> 2011/2012 trivalent FluVax containing strains A/California/7/2009(H1N1); A/<br />
Perth/16/2009 (H3N2); B/Brisbane/60/2008 at least 3 days before chemotherapy.<br />
Primary endpoint was early seroconversion (SC) rate at 3weeks; other end-points were<br />
late SC rate at 6weeks; sustained SC and sero-protection (SP) at 24 weeks.<br />
Haem-agglutination inhibition (HAI) titres in serum were measured at baseline, 3, 6<br />
and 24 weeks. Endpoint defined as SP (HAI ≥ 40); SC (≥4-fold increase titre).<br />
Results: 53 patients; mean (sd) age 58.3(10.5) years; n(%) <strong>of</strong> Females 31(58.5). The<br />
results are displayed in the table below.<br />
Table: 1486P<br />
Proportion N (%)<br />
Baseline 3weeks 6weeks 6months<br />
Seroconversion<br />
A/California/7/2009 (H1N1) 0 14 (35%) 14 (31.8%) 3 (7.5%)<br />
A/Perth/16/2009(H3N2) 0 12 (30%) 12 (27.3%) 7 (17.5%)<br />
B/Brisbane/60/2008 0 9 (22.5%) 8 (18.2%) 3 (7.5%)<br />
Seroprotection<br />
A/California/7/2009 (H1N1) 23 (47.9%) 30 (75%) 33(75%) 16 (40%)<br />
A/Perth/16/2009(H3N2) 19 (39.58%) 26 (65%) 26 (59.1%) 21 (52.5%)<br />
B/Brisbane/60/2008 17 (42.5%) 17 (42.5%) 14 (31.8%) 8 (20%)<br />
Conclusions: POCT might have sub-optimal response to the FluVax. Our findings<br />
should be confirmed in a larger patient population and warrants further research into a<br />
more effective strategy in this patient group.<br />
Clinical trial identification: ACTRN:12611000306910<br />
Legal entity responsible for the study: Southern Adelaide Health Network Inc<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1487P<br />
Immune-related and adverse events following low versus<br />
high initial dose <strong>of</strong> Viscum album L. in cancer patients<br />
M.L. Steele 1 , F. Schad 2<br />
1 Forschungsinstitut Havelhöhe, Gemeinschaftskrankenhaus Havelhöhe, Berlin,<br />
Germany, 2 Gastroenterlogie-Visceralzentrum, Gemeinschaftskrankenhaus<br />
Havelhöhe, Berlin, Germany<br />
Background: Viscum album L. (VA, European mistletoe) is frequently used as an<br />
immunomodulatory agent alongside conventional therapies in cancer patients in<br />
Europe. VA has been associated with improvement in health-related quality <strong>of</strong> life and<br />
a reduction in chemotherapy-related adverse drug reactions (ADRs). Mixed findings<br />
have been published regarding effects on overall survival. Beneficial effects <strong>of</strong> VA are<br />
believed to be related to its immunomodulatory properties. Recent evidence regarding<br />
immunotherapy in oncology has suggested an association between immune-related<br />
ADRs and beneficial outcomes. We investigated the immune-related events and ADR<br />
pr<strong>of</strong>iles related to VA therapy commencing with a low or high dose.<br />
Methods: The medical records <strong>of</strong> 2393 cancer patients treated between 2000 and 2013<br />
were assessed. Patients were retrospectively divided into two groups based on if their<br />
first VA application was low or high according to the appropriate Summary <strong>of</strong> Product<br />
Characteristics. Groups were compared by demographic, disease characteristics, details<br />
<strong>of</strong> treatment and ADRs.<br />
Results: 967 patients received a low dose <strong>of</strong> VA on their first ever application and 1426<br />
patients received a high dose. Groups did not differ by age, but significant differences<br />
were observed for gender, type and stage <strong>of</strong> cancer, type and administration <strong>of</strong> VA.<br />
Commencing VA therapy with a high dose was associated with a higher incidence <strong>of</strong><br />
ADRs compared to commencing with a low dose (12.6% versus 0.7%). Adjusting for<br />
age, tumour site and stage produced an odds ratio <strong>of</strong> 36.8 (95% CI = 15.4-120.6,<br />
p < 0.001). Almost all ADRs, irrespective <strong>of</strong> dose, were <strong>of</strong> mild or moderate intensity<br />
(low: 100%, high: 94%). The majority <strong>of</strong> ADRs were immune-related, general disorders<br />
and administration site conditions (low: 80%, high: 92%), many <strong>of</strong> which were desired<br />
reactions, such as pyrexia and local reactions.<br />
Conclusions: Commencing VA therapy with a high dose was highly associated with<br />
ADRs compared to a low dose, however, nearly all ADRs were expected, <strong>of</strong> mild to<br />
moderate intensity and most were desired reactions. Future research will investigate<br />
whether higher incidences <strong>of</strong> immune-related events are indicators <strong>of</strong> beneficial<br />
immunomodulation and thus better clinical outcomes.<br />
Legal entity responsible for the study: Forschungsinstitut Havelhöhe,<br />
Gemeinschaftskrankenhaus Havelhöhe<br />
Funding: Helixor, Abnoba<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1488P<br />
abstracts<br />
Analysis <strong>of</strong> cancer outcomes after desensitization protocols<br />
in patients with metastatic disease<br />
C. Pulido 1 , J. Caiado 2 , A.R. Ferreira 1 , I. Vendrell 1 , A.L. Costa 1 , A. Mendes 2 ,M.<br />
E. Pedro 2 , N. Fernandes 2 , L. Pestana 2 , P.L. Almeida 2 , C. Pinto 1 , A. Quintela 1 ,<br />
L. Ribeiro 1 , I.C. Fernandes 1 , P. Filipe 1 , R. Sousa 1 , C. Abreu 1 , D. Macedo 1 ,M.<br />
P. Barbosa 2 , L.A.M. Costa 1<br />
1 Serviço de Oncologia Médica, Centro Hospitalar Lisboa Norte - Hospital Sta<br />
Maria (HSM-CHLN), Lisbon, Portugal, 2 Serviço de Imuno-Alergologia, Clínica<br />
Universitária de Imuno-Alergologia, Centro Hospitalar Lisboa Norte - Hospital Sta<br />
Maria (HSM-CHLN), Lisbon, Portugal<br />
Background: Cancer chemotherapy and targeted therapy agents carry a potential risk<br />
for sensitization and induction <strong>of</strong> hypersensitivity reactions (HSR). It is widely<br />
unknown if patients who had drug reactions and underwent desensitization have<br />
different cancer outcomes, since the drug infusion time is largely extended. With this<br />
study we aim to describe patterns <strong>of</strong> HSR and overall survival (OS) rates for patients<br />
with metastatic cancer undergoing desensitization.<br />
Methods: This is a single center retrospective observational cohort study. Primary<br />
endpoint was OS. All patients with stage IV colorectal (CRC), breast (BC) and ovarian<br />
cancer (OC) undergoing desensitization from 2008 to 2013 at our institution were<br />
included. All patients with mild to severe HSR (Brown’s classification) were<br />
desensitized at the Immunoallergology Unit using a 12-step protocol (6-hour<br />
infusion). Clinicopathological characteristics were tabulated according to type <strong>of</strong><br />
primary. Proportion <strong>of</strong> patients alive at time points were obtained. Time to event<br />
outcomes were analyzed using Kaplan-Meier methods.<br />
Results: 50 patients were included (14 BC, 17 CRC, 19 OC), 38 female and 12 male, the<br />
majority 50 years or older (n = 36, 72%) and with good performance status (Eastern<br />
Cooperative <strong>Oncology</strong> Group grade ≤ 1 in 94.6%, n = 35). Median follow-up time from<br />
diagnosis <strong>of</strong> metastatic disease was 40 months for BC (interquartile range [IQR]<br />
31.3-67.8), 41.8 months for CRC (IQR 29.3-68.1) and 33.3 months for OC (IQR<br />
25.7-56.9). Implicated agents were platinum salts (n = 32), taxanes (n = 15) and<br />
targeted therapy agents (n = 3), used mostly after second line <strong>of</strong> therapy (n = 29, 58%).<br />
Nine patients had mild HSRs (18%), 23 moderate (46%) and 18 had severe HSRs<br />
(36%). A total <strong>of</strong> 284 desensitizations were performed (median <strong>of</strong> 5 cycles/patient).<br />
Median OS was 47.3 months for BC (11 events, IQR 31.9-92.1), 37.2 months for CC<br />
(13 events, IQR 28.3—78.6) and 33.3 months for OC (16 events, IQR 25.7-56.9).<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw390 | vi515
abstracts<br />
Conclusions: In the absence <strong>of</strong> prospective randomized studies, for ethical reasons, the<br />
experience <strong>of</strong> our institution suggests that administration <strong>of</strong> cancer therapy through<br />
desensitization protocols is feasible and patients’ outcomes seem adequate for the<br />
overall anticipated outcomes in this group <strong>of</strong> patients.<br />
Legal entity responsible for the study: Serviço de Oncologia Médica, CHLN<br />
Funding: Serviço de Oncologia Médica, CHLN<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1489P<br />
Compliance with oral cancer medications when dispensed in<br />
the oncology clinic vs. when provided directly by healthcare<br />
payers: a prospective multicenter study by the Oncoclinicas<br />
Group<br />
F.F. Gomes 1 , E.M. Sobrinho 2 , R. Miranda 3 , L. Mercurio 4 , M. Dias 5 ,<br />
K. Nascimento 1 , A. Alves 6 , E. Tavares 7 , L. Teixeira 7 , O. Silva 1 , P. Fernandes 4 ,<br />
F. Reis 1 , T. Rios 8 , C. Silva 1 , G. Lopes, Jr 9<br />
1 Pharmacy, Nucleo de Oncologia da Bahia-nob, Salvador, Brazil, 2 <strong>Oncology</strong>,<br />
Nucleo de Oncologia da Bahia-nob, Salvador, Brazil, 3 Pharmacy, Oncocentro<br />
Sete Lagoas, Sete Lagas, Brazil, 4 Pharmacy, Centro Paulista de Oncologia, Sao<br />
Paulo, Brazil, 5 Pharmacy, Oncocentro Itabira, Itabira, Brazil, 6 Pharmacy,<br />
Oncocentro Uberlandia, Uberlandia, Brazil, 7 Pharmacy, Centro de Excelencia<br />
Oncológica, Rio De Janeiro, Brazil, 8 Nutrition, Nucleo de Oncologia da Bahia-nob,<br />
Salvador, Brazil, 9 Oncologia Clínica, Grupo Oncoclínicas do Brasil, Sao Paulo,<br />
Brazil<br />
Background: The use <strong>of</strong> oral cancer medicines is rising. In Brazil, after coverage was<br />
mandated in January 2014, oral cancer medications can be dispensed in the clinic<br />
where a patient is treated or directly by the healthcare payer (or by a payer-designated<br />
third-party).<br />
Methods: We conducted an observational prospective multicenter study to compare<br />
compliance (primary endpoint) between patients who received their oral medications<br />
in oncology clinics versus those who received them directly from healthcare payers.<br />
Patients 18 years <strong>of</strong> age or older, receiving oral cancer treatment prescribed in any <strong>of</strong><br />
the group’s 34 clinics were eligible. Patients filled in an anonymous questionnaire.<br />
Respondents were classified as "compliant" when they answered "always", "<strong>of</strong>ten" or<br />
"frequently" to the question: "Do you take this medication everyday at the right time?”.<br />
Those who replied "sometimes", "rarely" or "never" were classified as "non-compliant".<br />
Further questions assessed different aspects related to adherence, including whether<br />
patients received their medication in a timely manner. Study protocol was approved by<br />
an independent ethics committee. Pearson chi-square was used to evaluate statistical<br />
significance with a 5% level.<br />
Results: Between April 2015 and May 2016, 396 patients from 7 clinics entered the<br />
study. 236 (59.6%) received their medication at a cancer clinic and 160 (40.4%) directly<br />
from a payer. Median age was 57 years in both groups. Most patients were female and<br />
receiving hormone therapy. Non-compliance was higher in the group that received<br />
their medication directly from payers (19 patients, 11.9%, vs. 7 patients, 3.0%) when<br />
compared with those who received it in the clinic (p = 0.001). Moreover, 35% vs. 4.2%<br />
(p < 0.001) reported difficulties in acquiring their medicines, and 21.9% vs. 11.4%<br />
(p = 0.005) reported other difficulties related to their treatment.<br />
Conclusions: In this study, patients who received their oral cancer medications in an<br />
oncology clinic were more compliant and reported fewer difficulties than those who<br />
received their treatment directly from a healthcare payer.<br />
Legal entity responsible for the study: N/A<br />
Funding: Oncoclinicas Group<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1490P<br />
Impact <strong>of</strong> incoming phone calls on oncology departments in<br />
oral therapies era: a large national prospective survey<br />
F. Joly Lobbedez 1 , A. Guillot 2 ,Y.Vano 3 , D. Spaeth 4 , D. Topart 5 , P. R<strong>of</strong>fet 6 ,R.El<br />
Amarti 7 , A. Hasbini 8 , A. Flechon 9<br />
1 Medocal oncology, Centre Francois Baclesse, Caen, France, 2 Medical <strong>Oncology</strong>,<br />
Institut de Cancérologie de la Loire, Saint Priest En Jarez, France, 3 <strong>Oncology</strong>,<br />
European Georges Pompidou Hospital, Paris, France, 4 <strong>Oncology</strong>, Centre<br />
d’Oncologie de Gentilly, Nancy, France, 5 34, Hopital Saint-Eloi (Montpellier),<br />
Montpellier, France, 6 75, Pfizer, Paris, France, 7 76, Hopital Jacques Monod, Le<br />
Havre, France, 8 Medical <strong>Oncology</strong>, Clinique Pasteur, Brest, France, 9 Medical<br />
<strong>Oncology</strong>, Centre Léon Bérard, Lyon, France<br />
Background: Oral therapies, and an increase <strong>of</strong> patient involvement have shifted the<br />
follow-up <strong>of</strong> patients with cancer from hospital to home. As a consequence, the<br />
number <strong>of</strong> incoming phone calls (IPC) has increased. To understand the source,<br />
reasons, management and burden <strong>of</strong> IPC, we underwent a French national survey. The<br />
objective was to describe IPC and to understand the way they are managed in oncology<br />
departments.<br />
Methods: The study was a prospective survey in a representative sample <strong>of</strong> 51 French<br />
oncology specialists (Sp) treating patients with oral therapies. Data on all IPC was<br />
collected during a one-week period in 2014. Characteristics <strong>of</strong> centers were also<br />
registered.<br />
Results: Among 51 participating onco/radiotherapy departments, 86% <strong>of</strong> Sp were<br />
oncologists or hematologists and 14% radiation oncologists. 80% were from public<br />
centers and 20% from private ones. 41%, 39% and 20% treated less than 250, 251 to<br />
1000 and more than 1000 new metastatic patients per year, respectively. The number <strong>of</strong><br />
IPC/week was 17 to 64, 65 to 130 and over 130 for respectively 33%, 35% and 31% <strong>of</strong><br />
centers (mean = 119/week). 66% <strong>of</strong> IPC were from patients and families and 23% from<br />
general practitioners. Upon IPC reception by the secretaries, half <strong>of</strong> them correspond<br />
to a medical question. A majority (65%) <strong>of</strong> centers did not have an established specific<br />
procedure and 70% <strong>of</strong> responders did not specifically train their teams (secretaries and<br />
nurses) to address the management <strong>of</strong> IPC. 65% <strong>of</strong> the sp spent more than 30 min/day.<br />
Most <strong>of</strong> them considered it disturbing medical activities. 66% <strong>of</strong> patients IPC were<br />
related to adverse effects (AE) <strong>of</strong> treatments. 22% <strong>of</strong> Sp declared at least one severe AE<br />
linked to some misinterpretation <strong>of</strong> an IPC. Centers with IPC procedures and outgoing<br />
systematic phone calls had much less IPC.<br />
Conclusions: With the increase <strong>of</strong> oral therapies, incoming phone calls in French<br />
oncology centers (mainly patient calls who need exchanging information on AE)<br />
represent an important burden <strong>of</strong> work. To improve IPC management,<br />
recommendations are produced including dedicated procedures, trained telephone<br />
triage personnel (secretaries and dedicated nurses), standardized management <strong>of</strong> AE<br />
and documentation <strong>of</strong> answers.<br />
Legal entity responsible for the study: Pfizer France<br />
Funding: Pfizer France<br />
Disclosure: F. Joly Lobbedez, A. Guillot, Y. Vano, D. Spaeth, D. Topart, P. R<strong>of</strong>fet, R. El<br />
Amarti, A. Hasbini, A. Flechon: Pfizer.<br />
1491P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Decreased body mass index (BMI) associates with impaired<br />
survival from diagnosis <strong>of</strong> brain metastases in lung cancer<br />
patients: analysis <strong>of</strong> 624 patients<br />
E.K. Masel 1 , A.S. Bergh<strong>of</strong>f 2 , G. Widhalm 3 , U. Dieckmann 4 , B. Gatterbauer 3 ,<br />
P. Birner 5 , R. Bartsch 2 , S. Schur 1 , H.H. Watzke 1 , C. Zielinski 6 , M. Preusser 6<br />
1 Clinical Division <strong>of</strong> Palliative Care, Medizinische Universitaet Wien (Medical<br />
University <strong>of</strong> Vienna), Vienna, Austria, 2 Department <strong>of</strong> <strong>Oncology</strong>, Medizinische<br />
Universitaet Wien (Medical University <strong>of</strong> Vienna), Vienna, Austria, 3 Department <strong>of</strong><br />
Neurosurgery, Medizinische Universitaet Wien (Medical University <strong>of</strong> Vienna),<br />
Vienna, Austria, 4 Department <strong>of</strong> Radiotherapy, Medizinische Universitaet Wien<br />
(Medical University <strong>of</strong> Vienna), Vienna, Austria, 5 Department <strong>of</strong> Pathology,<br />
Medizinische Universitaet Wien (Medical University <strong>of</strong> Vienna), Vienna, Austria,<br />
6 Clinical Division <strong>of</strong> <strong>Oncology</strong>, Medizinische Universitaet Wien (Medical University<br />
<strong>of</strong> Vienna), Vienna, Austria<br />
Background: Body Mass Index (BMI) has been documented as a prognostically<br />
relevant factor in several cancer types including lung cancer, but has not been<br />
investigated in brain metastases (BM). We investigated prognostic relevance <strong>of</strong> BMI in<br />
a large institutional cohort <strong>of</strong> patients with newly diagnosed lung cancer BM.<br />
Methods: Patients with newly diagnosed BM from lung cancer treated at the Medical<br />
University <strong>of</strong> Vienna between 1990 and 2013 were identified from a BM database. BMI<br />
at diagnosis <strong>of</strong> BM was calculated by the formula body weight in kilogram/body height<br />
in m 2 and defined as underweight (BMI < 18.50), weight within normal range (BMI<br />
18.50-24.99), and overweight (BMI ≥ 25.00) according to the World Health<br />
Organization (WHO). Clinical characteristics were retrieved by chart review. Graded<br />
prognostic assessment (GPA) was calculated as published previously.<br />
Results: 624 patients (male 401/624 (64.3%); female 223/624 (35.7%); median age <strong>of</strong> 61<br />
(range 33-88) were available for further analysis. Lung cancer subtype was non-small<br />
cell lung cancer (NSCLC) in 17/622 (66.8%), small cell lung cancer (SCLC) in 205/624<br />
(32.9%) and unknown in 2/624 (0.3%) patients. 313/624 (50.2%) patients had normal<br />
BMI, 272/624 (43.5%) patients were overweight and 39/624 (6.3%) patients were<br />
underweight. Underweight patients had significantly shorter median overall survival<br />
times (3 months) compared to patients with normal BMI (7 months) and overweight<br />
patients (8 months; p < 0.001; log rank test). At multivariate analysis, GPA class (HR<br />
1.430; 95% CI 1.279-1.598; p < 0.001; Cox regression model), lung cancer subtype (HR<br />
1.310; 95% CI 1.101-1.558) and presence <strong>of</strong> underweight (HR 1.845; 95% CI<br />
1.317-2.585 p = 0.014; Cox regression model) retained statistical significance as<br />
independent prognostic factors.<br />
Conclusions: Underweight is infrequent at diagnosis <strong>of</strong> BM in lung cancer patients,<br />
but strongly and independently associates with an unfavourable prognosis. Our data<br />
highlight the importance <strong>of</strong> addressing cachexia in the palliative treatment <strong>of</strong> patients<br />
with lung cancer BM. Specific interventions may help to improve patient outcomes.<br />
Legal entity responsible for the study: Medical University <strong>of</strong> Vienna<br />
Funding: Medical University <strong>of</strong> Vienna<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
vi516 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
1492P<br />
Prevention <strong>of</strong> chemotherapy-induced alopecia in patients<br />
with breast or female genital tract cancer using<br />
sensor-controlled scalp-cooling<br />
C.M. Kurbacher 1 , S. Herz 1 , G. Kolberg 1 , N. Kettelhoit 1 , A.T. Kurbacher 1 ,<br />
C. Schweitzer 1 , K. Monreal 1 , J.A. Kurbacher 2<br />
1 Gynecologic <strong>Oncology</strong>, Gynecologic Center Bonn-Friedensplatz, Bonn,<br />
Germany, 2 General Gynecology and Obstetrics, Gynecologic Center<br />
Bonn-Friedensplatz, Bonn, Germany<br />
Background: Chemotherapy (Ctx)-induced alopecia (CIA), produces a deep<br />
psychological impact in many women involved. Although sensor-controlled scalp<br />
cooling (SCSC) is effective in preventing CIA, it is infrequently used in many countries<br />
due to physicianś concerns regarding both safety and feasibility. This retrospective<br />
analysis was initiated to obtain detailed information about the effectiveness and safety<br />
<strong>of</strong> SCSC using the Paxman system (Paxman, Huddersfield, UK) in female patients<br />
(pts) exposed to CIA-inducing Ctx for breast cancer (BC) or genital tract malignancies<br />
in the clinical routine.<br />
Methods: 87 pts who underwent SCSC alongside Ctx from 2014-2016 were identified<br />
from our database: BC, 68; epithelial ovarian carcinoma, 14; others, 5; premenopausal,<br />
42; postmenopausal, 45. 63 pts were treated in a curative intent, 24 were treated in a<br />
palliative setting; 57 pts were Ctx-naïve, 30 pts had a history <strong>of</strong> prior Ctx. The following<br />
Ctx regimens were used: anthracycline-based (A), 4; taxane-based (T), 21; AT-based,<br />
48; others, 14. Pts were subjected to SCSC during each Ctx cycle. CIA was quantified<br />
according to the Dean score (DS) determined 3 wks after the last Ctx cycle. Data were<br />
analyzed regarding feasibility indicated by the SCSC completion rate, quality <strong>of</strong> hair<br />
preservation (success: DS 0-2, failure: DS 3-4), reasons <strong>of</strong> SCSC discontinuation, and<br />
safety.<br />
Results: 57 pts (64.5%) completed SCSC, with 47 (53.0%) experiencing complete hair<br />
preservation (DS 0), and 10 (11.5%) showing partial success (DS 1-2). 30 pts (35.5%)<br />
discontinued SCSC, with CIA being the main reason in 21 pts (24.1%). Headache was<br />
reported in 4 (5.0%), and local discomfort ("feeling cold") in 3 pts (3.4%). In 2 pts<br />
(2.3%), the reason <strong>of</strong> discontinuation remained unclear. Side effects were all not severe<br />
and resolved completely after cessation <strong>of</strong> SCSC.<br />
Conclusions: In the clinical routine, SCSC using the Paxman system is feasible, safe<br />
and effective in order to prevent CIA in pts with BC and female genital tract<br />
carcinomas. The treatment success rate in our study is in good agreement with<br />
previous reports on SCSC although more pts in the palliative setting or with a history<br />
<strong>of</strong> prior Ctx have been included.<br />
Legal entity responsible for the study: N/A<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1493P<br />
Survival and functional outcomes <strong>of</strong> patients with metastatic<br />
solid organ cancer admitted to the intensive care unit <strong>of</strong> a<br />
general tertiary centre<br />
F.J. Ha 1 , A.J. Weickhardt 1 , S. Parakh 1 , N.J. Glassford 2 , S. Warrillow 2 , D. Jones 2<br />
1 Department <strong>of</strong> Medical <strong>Oncology</strong>, Olivia Newton-John Cancer and Wellness<br />
Centre, Austin Hospital, Melbourne, Australia, 2 Department <strong>of</strong> Intensive Care<br />
Medicine, Austin Hospital, Melbourne, Australia<br />
Background: Studies <strong>of</strong> survival outcomes in metastatic solid organ cancer patients<br />
admitted to the intensive care unit (ICU) are limited, with no documentation <strong>of</strong><br />
functional status following discharge. Furthermore, despite the poor long term<br />
outcome, documentation <strong>of</strong> advance care planning, including goals-<strong>of</strong>-care (GOC), is<br />
<strong>of</strong>ten sub-optimal.<br />
Methods: We retrospectively assessed outcomes from patients with incurable<br />
metastatic solid organ malignancies non-electively admitted to a tertiary hospital ICU<br />
from January 2010 - June 2015. Patient demographics were collected and survival rates<br />
analysed and correlated with potential prognostic factors. Post-discharge living<br />
arrangements and functional status as assessed by Eastern Cooperative Group<br />
performance scores (ECOG) at 1- and 3-months were collected. GOC documentation<br />
specifying resuscitation status were collected.<br />
Results: 101 patients were treated in the ICU during the study period, with cancer<br />
treatment-related complications being the most common reason for admission (47%).<br />
The ICU, hospital, 30 day and 12 month mortality rates were 16%, 35%, 41% and 76%,<br />
respectively. On multiple-variable analysis, predictors <strong>of</strong> 30 day mortality were albumin<br />
abstracts<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Table: 1495P The relation between quality-<strong>of</strong>-life subscale/scale score<br />
and severity <strong>of</strong> breast cancer-related lymphedema<br />
Quality <strong>of</strong> Life Scale Lymphedema grade p value<br />
0 1 2 3<br />
n = 41 n = 20 n = 32 n = 9<br />
Mean (± standard deviation)<br />
FACT-G 84 (17) 79 (16) 75 (11) 66 (23) 0.028<br />
BCS 36 (8) 36 (8) 28 (9) 27 (14) 0.001<br />
TOI 76 (15) 72 (12) 62 (19) 56 (25) 0.001<br />
FACT-B + 4 120 (22) 114 (19) 103 (27) 94 (34) 0.004<br />
Conclusions: The results <strong>of</strong> the current study illustrated a significant relationship<br />
between the severity <strong>of</strong> BCRL and QoL. This suggests that studies investigating the QoL<br />
<strong>of</strong> breast cancer patients should not only include BCRL as a dichotomous (absent/<br />
present) variable, but patients should be stratified according to the severity <strong>of</strong> BCRL as<br />
well.<br />
Legal entity responsible for the study: Kasr Al-Ainy School <strong>of</strong> Medicine, Cairo<br />
University<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1496P<br />
Cancer-related fatigue in breast cancer survivors: more<br />
evidence for a physiological substrate<br />
J. Ramos 1 , B. Cantos 1 , C. Maximiano 1 , H. Cebolla 2 , C. Fiuza-Luces 3 ,<br />
L. Gutierrez 1 , P. Osorio 4 , J. Cerrato 4 , J.L. Sanchez 4 , B. Nuñez 1 , A. Garate 4 ,<br />
I. Pagola 5 , L.B. Alejo 4 , A. Lucia 3 , A. Ruiz-Casado 1<br />
1 Medical <strong>Oncology</strong>, Hospital Universitario Puerta de Hierro, Madrid, Spain,<br />
2 Estructura Social, Universidad Nacional Eduación a Distancia, Madrid, Spain,<br />
3 Biomedicine, Universidad Europea de Madrid, Madrid, Spain, 4 Master AF y<br />
Salud, Universidad Europea de Madrid, Madrid, Spain, 5 Motricidad, Universidad<br />
Europea de Madrid, Madrid, Spain<br />
Background: Cancer-related fatigue (CRF) is a complex multi-dimensional construct<br />
related to reduced physical function and health-related quality <strong>of</strong> life. This symptom is<br />
under-reported by patients and and undertreated by clinicians. Recent reviews have<br />
concluded that exercise reduces cancer-related fatigue. The NCCN recommends that all<br />
cancer patients should be screened for fatigue regularly. As management <strong>of</strong> CRF is<br />
currently suboptimal, a change <strong>of</strong> approach is required.<br />
Methods: Breast cancer survivors who had finished their treatments in the last 6<br />
months, did not have any evidence <strong>of</strong> disease and were able to manage the<br />
accelerometer were <strong>of</strong>fered to participate in a cross sectional study. CRF was evaluated<br />
through PERFORM, a questionnaire developed and validated in Spanish speakers.<br />
Weekly moderate-vigorous physical activity (WMVA) was objectively evaluated with<br />
accelerometers. Physical condition was evaluated through the one mile-walk test,<br />
hand-held dynamometer and sit to stand test.<br />
Results: 96 women with a history <strong>of</strong> breast cancer were recruited between March -2014<br />
and April-2016. Age 52 (29-78), BMI 26 (18-41), waist 86 cm (65-116). 72% had<br />
received anthracyclines, 17% Herceptin, 70% radiotherapy. Basal heart rate 74 bpm<br />
(56-102); Final heart rate (after walking one mile) 107 bpm (68-159); Estimated<br />
VO 2max 27,7 ml/kg/min (7,7-47); Strength right upper extremity was 26 Kg (10-40). Sit<br />
to stand test 7,4 (4,1-18,4) s. WMVPA was 231 min (69,5-424,5). Median PERFORM<br />
score was 46 (12-60). There were not any significant correlations for previous<br />
treatments, physical condition, anthropometry or physical activity with fatigue score.<br />
Heart rate (both basal and final) were significantly associated to fatigue (p < 0.05).<br />
Conclusions: Despite <strong>of</strong> meeting international recommendations for physical activity,<br />
this sample exhibited a poor cardiorespiratory fitness and cardiometabolic pr<strong>of</strong>ile.<br />
Basal and post exercise heart rate were the only predictors <strong>of</strong> fatigue in our series.<br />
Neither previous treatments nor physical condition or adiposity signs had a definitive<br />
relationship with fatigue. Other authors have suggested that fatigue is associated with a<br />
maladaptive autonomic pr<strong>of</strong>ile. Further research studying heart rate variability is<br />
warranted.<br />
Legal entity responsible for the study: Hospital Universitario Puerta de<br />
Hierro-Majadahonda<br />
Funding: Hospital Universitario Puerta de Hierro-Majadahonda<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1497P<br />
Impact <strong>of</strong> cognitive functions on oral anticancer therapies<br />
adherence<br />
M. Dos Santos 1 , M. Lange 2 , B. Clarisse 2 , M. Barillet 2 , F. Joly 1<br />
1 Medical <strong>Oncology</strong>, Centre Francois Baclesse, Caen, France, 2 Clinical Research<br />
Department, Centre Francois Baclesse, Caen, France<br />
Background: Oral anticancer therapies have now an important place in the therapeutic<br />
arsenal, but factors influencing adherence to oral treatment are poorly documented in<br />
oncology. The objective <strong>of</strong> this study was to assess the relationship between cognitive<br />
functions and oral medication adherence in order to identify patient pr<strong>of</strong>iles that are more<br />
likely to be non-adherents, with a focus on the elderly population particularly at risk.<br />
Methods: This prospective pilot study included patients initiating a first exclusive oral<br />
therapy. Before initiation <strong>of</strong> treatment, we performed a standardized<br />
neuropsychological test battery and an assessment <strong>of</strong> autonomy, depression and<br />
anxiety. Information on socio-demographic conditions was collected. Adherence to<br />
oral therapy was evaluated by two self-assessment questionnaires and an observance<br />
sheet at 1 and 3 months after start <strong>of</strong> treatment. We present here only the results at 1<br />
month.<br />
Results: Among 126 patients enrolled, 111 (88%) completed the adherence<br />
questionnaires at 1 month with an adherence rate <strong>of</strong> 90% and a median age at baseline<br />
<strong>of</strong> 70. Global cognitive impairment was observed in 50% with the Montreal Cognitive<br />
assessment (MoCA). Working memory disorders and depression were significantly<br />
associated with non-adherence: [1.38 (1.03-1.85); P= 0.0326] and [4.67 (1.11-19.59);<br />
P= 0.0352] respectively. A relationship was found between age and MoCA score and<br />
also with working memory impairement, with for both <strong>of</strong> them a higher impact above<br />
70 years (P< 0.005).<br />
Conclusions: Working memory dysfunctions and depression appear as predictors <strong>of</strong><br />
non-adherence. Focusing on cognitive functions before initiation <strong>of</strong> oral anticancer<br />
therapy is therefore relevant to identify patient pr<strong>of</strong>iles more likely to fail<br />
self-management <strong>of</strong> oral anticancer therapy and therefore help decision-making,<br />
particularly in elderly.<br />
Clinical trial identification: N° ID-RCB: 2011-A00907-34<br />
Legal entity responsible for the study: Pr<strong>of</strong>essor Florence Joly<br />
Funding: Programme Hospitalier de Recherche Clinique, PHRC<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1498P<br />
Evaluation <strong>of</strong> an interactive electronic patient reported<br />
outcome (e-PRO) system in outpatient with oral<br />
chemotherapy<br />
M. Rasschaert 1 , K. Papadimitriou 1 , S. Altintas 1 , M. Huizing 1 , J. Van den Brande 1 ,<br />
T. Van den Mooter 1 , P.M.C. Specenier 2 , C.D. Rolfo 1 , S. De Keersmaecker 1 ,I.Van<br />
Brussel 3 , J. Ravelingien 4 , M. Peeters 1<br />
1 MOCA, U.Z.A. University Hospital Antwerp, Edegem, Belgium, 2 Medical<br />
<strong>Oncology</strong>, U.Z.A. University Hospital Antwerp, Edegem, Belgium, 3 Project<br />
Manager, Remedus, Aartselaar, Belgium, 4 Management, Remedus, Aartselaar,<br />
Belgium<br />
Background: Health Information Technology (HIT) is increasingly integrated in<br />
clinical cancer care. Simultaneously routine assessment <strong>of</strong> patient reported outcomes<br />
(PROs) has been shown to reliably improve symptom management, identification <strong>of</strong><br />
psychosocial problems and patient-provider communication.<br />
Methods: This study is a single center experience <strong>of</strong> a multicenter randomized study<br />
for the development and validation <strong>of</strong> an interactive e-PRO tool (RemeCoach). After<br />
obtaining informed consent, outpatients, using oral anti-cancer treatment, recorded<br />
their medication intake and 17 clinical parameters using this E-PRO tool. The device<br />
allowed real time data collection and communication with other care providers via a<br />
central platform. The registered data were processed by an algorithm, this algorithm<br />
stratifies the data into different grades according to international standards <strong>of</strong> care<br />
(CTCAE v4.0) and clinical importance. Patient clinical and demographic information<br />
is collected from medical records and analyzed using descriptive statistics.<br />
Results: 37 Patients were included, 59% male, mean age 59,2 (range 38-79). 35% Of<br />
patients used capecitabine, 43% regorafenib, 5% pazopanib, 5% everolimus and 5%<br />
sunitinib. Most common symptoms cited were fatigue, cutaneous toxicity, myalgia and<br />
joint pain and cough. Out <strong>of</strong> 19 patients that stopped therapy, one (5%) dropped out <strong>of</strong><br />
the study, 1 switched therapy due to progressive disease, 8 (42%) patients died, 9 (48%)<br />
terminated prescribed treatment. The RemeCoach was well adopted: > 75% patients<br />
registered > 75% <strong>of</strong> clinical outcomes.<br />
Conclusions: This study confirms the feasibility <strong>of</strong> the program, in an outpatient<br />
setting. This e-tool provides a means to register compliance, early symptoms <strong>of</strong> disease<br />
and toxicity <strong>of</strong> treatment.The compliance to the e-PRO tool will be confirmed, with<br />
further development <strong>of</strong> this program in a multicenter, randomized design. Evaluation<br />
<strong>of</strong> quality <strong>of</strong> life PRO-measurements and further exploration <strong>of</strong> the relationship<br />
between optimal pharmacovigilance and improvement <strong>of</strong> patient’s outcome will ensue.<br />
Legal entity responsible for the study: University Hospital Antwerp<br />
Funding: University Hospital Antwerp<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
vi518 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
1499P<br />
Evaluation <strong>of</strong> a clinical decision support system (CDSS) to<br />
optimize cytotoxic drug dosing in cancer patients with renal<br />
insufficiency<br />
L. Krens, M. Damh<strong>of</strong><br />
Clinical Pharmacy, Ziekenhuisgroep Twente, Hengelo, Netherlands<br />
Background: The incidence <strong>of</strong> renal insufficiency is ever increasing in cancer patients,<br />
since patients are getting older and more aggressive treatments become available. For<br />
those drugs in which renal excretion is an important determinant <strong>of</strong> elimination, dose<br />
adjustment is <strong>of</strong>ten required if renal function is impaired. “CS rules” is a cognitive<br />
clinical decision support system (CDSS) designed to assist clinical pharmacists in<br />
making dosing decisions for individual patients. Recommendations on<br />
chemotherapeutic dosing are consistent with the established guidelines and published<br />
evidence.<br />
Methods: From September 2015 until January 2016 a pilot with the CDSS was<br />
performed in the ZGT Hospital in the Netherlands. Clinical rules were defined for18<br />
cytotoxic drugs used in our hospital, for which dose reduction is required if renal<br />
function is impaired. The CDSS was run overnight and generated alerts on all newly<br />
prescribed chemotherapeutics. Alerts were analyzed by the clinical pharmacist. If a<br />
dose reduction seemed necessary, the oncologist was contacted by the pharmacist and<br />
the necessity <strong>of</strong> dose reduction was discussed.<br />
Results: During the pilot period a total <strong>of</strong> 2681 chemotherapeutics were prescribed, the<br />
18 active rules generated 112 alerts. Overall, 18.8 % <strong>of</strong> the generated clinical alerts<br />
resulted in an intervention by the clinical pharmacist about dose reduction. In table 1 a<br />
more detailed overview is given for the included cytotoxic drugs and the generated<br />
number <strong>of</strong> alert and interventions.<br />
Table: 1499P Detailed overview <strong>of</strong> number <strong>of</strong> prescription, alerts and<br />
interventions per cytostatic drug<br />
Cytotoxic drug Prescriptions Alerts Interventions<br />
n n % a n % b<br />
Bortezomib 452 14 3.1 4 28.6<br />
Cisplatin 133 27 20.3 5 18.5<br />
Cyclophospamide 482 3 0.62 0 0<br />
Capecitabine 429 22 5.1 4 18.2<br />
Dacarbazine 20 0 0 0 0<br />
Doxorubicin 395 0 0 0 0<br />
Epirubicin 64 0 0 0 0<br />
Etoposide 285 13 4.6 1 7.7<br />
Fludaribine 1 4 c 400 0 0<br />
Ifosfamide 0 0 0 0 0<br />
Hydroxycarbamide 0 0 0 0 0<br />
Irinotecan 96 0 0 0 0<br />
Lomustine 0 0 0 0 0<br />
Melphalan 54 0 0 0 0<br />
Mercaptopurine 0 0 0 0 0<br />
Methotrexate 56 16 28.6 0 0<br />
Pemetrexed 214 13 6.1 6 46.1<br />
Procarbazine 0 0 0 0 0<br />
Total 2681 112 4.1 21 18.8<br />
a as a percentage <strong>of</strong> number <strong>of</strong> prescriptions<br />
b as a percentage <strong>of</strong> alerts C 4 alerts were generated after a single prescription<br />
<strong>of</strong> fludarabin<br />
Conclusions: CDSS can effectively be used in daily hospital pharmacy practice to select<br />
patients at risk <strong>of</strong> cytotoxic drug overdose due to renal impairment. The identification<br />
<strong>of</strong> patients at risk helps the clinical pharmacist and oncologist to optimize drug therapy<br />
in cancer in patient with renal dysfunction.<br />
Legal entity responsible for the study: ZGT Hospital<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1500P<br />
Drug-drug interactions in cancer patients: a prospective<br />
study <strong>of</strong> medication surveillance on cytotoxic agents<br />
A.E. Ramos-Esquivel 1 , A. Viquez-Jaikel 2 , C. Fernandez 2 , Z. Zeledon 1 , F. Jimenez 3 ,<br />
M. Juarez 1 , L. Corrales 1 , I. Gonzalez-Herrera 1<br />
1 Oncologia Medica, Hospital San Juan de Dios, San Jose, Costa Rica,<br />
2 Pharmacy, Hospital San Juan de Dios, San Jose, Costa Rica, 3 Hematology,<br />
Hospital San Juan de Dios, San Jose, Costa Rica<br />
Methods: A sample size <strong>of</strong> 149 subjects was calculated based on an expected<br />
percentage <strong>of</strong> 11% <strong>of</strong> patients with clinically relevant DDIs. Patients starting a new<br />
anticancer therapy were asked to participate in this trial. Information <strong>of</strong> the use <strong>of</strong><br />
concomitant medications with antineoplastic agent(s), including over-the-counter<br />
drugs, was collected by the oncologist through a structured interview. DDIs were<br />
identified using the LexiComp Handbook and a s<strong>of</strong>tware programme available at www.<br />
drugs.com. If a clinically relevant DDI was recognized by the clinical pharmacist, a<br />
recommendation was sent to the prescribing oncologist who decided whether to carry<br />
out the suggested intervention or not.<br />
Results: The mean age <strong>of</strong> the patients was 57.5 ± 13.6 years, and 74.5% (n = 111) <strong>of</strong><br />
them were female. The majority <strong>of</strong> patients had solid tumours (98.6%), specifically:<br />
breast (53.7%), followed by gastrointestinal (23.5%) and genitourinary malignancies<br />
(6.7%). Seventy-two patients (47.7%) had an underlying comorbidity other than<br />
cancer, mainly high blood pressure (n = 52) and diabetes mellitus (n = 23). The median<br />
number <strong>of</strong> medications per patients was 3 (range: 0 – 12). A total <strong>of</strong> 37 clinically<br />
relevant interactions were detected in 26 patients (17.4%; 95% Confidence Interval:<br />
14.3 – 20.5). Of these interactions, 11 (29.7%) were considered <strong>of</strong> high risk (category<br />
D), leading to therapy modifications in 100% <strong>of</strong> cases, as suggested by the clinical<br />
pharmacist. The principal mechanism <strong>of</strong> DDIs was pharmacokinetic (70.3%), followed<br />
by pharmacodynamic (19%), and unknown in the remaining cases (10.7%).<br />
Conclusions: Clinically relevant DDIs were frequently detected in this prospective<br />
study. A multidisciplinary approach is required to identify and avoid potentially<br />
harmful DDIs.<br />
Legal entity responsible for the study: University <strong>of</strong> Costa Rica. Caja Costarricense de<br />
Seguro Social.<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1501P<br />
abstracts<br />
Impact <strong>of</strong> adjuvant anthracycline-based and taxane-based<br />
chemotherapy on plasma VEGF levels and cognitive function<br />
in early-stage breast cancer patients<br />
R. Ng 1 , X.Y. Phey 2 ,T.Ng 2 , H.L. Yeo 2 , M. Shwe 2 , Y.X. Gan 3 , H.K. Ho 2 , A. Chan 2<br />
1 Medical <strong>Oncology</strong>, National Cancer Center, Singapore, 2 Pharmacy, National<br />
University <strong>of</strong> Singapore, 3 Pharmacy, National Cancer Center, Singapore<br />
Background: Vascular endothelial growth factor (VEGF) has been shown to induce<br />
neurogenesis in the brain and yield neuroprotective effects. It is hypothesized that<br />
adjuvant chemotherapy containing doxorubicin or taxane, reduces circulating VEGF<br />
levels and, in turn, leads to cognitive decline in cancer patients who receive<br />
chemotherapy. This multicenter, longitudinal study was designed to evaluate the<br />
impact <strong>of</strong> chemotherapy on VEGF levels and the association between VEGF levels and<br />
cognitive function.<br />
Methods: One hundred and forty-six early-stage breast cancer patients were recruited<br />
and assessed at three time points: before chemotherapy (T1), during chemotherapy<br />
(T2) and at the end <strong>of</strong> chemotherapy (T3). At each time point, we quantified plasma<br />
VEGF levels using a multiplex immunoassay (Luminex®). Self-perceived cognitive<br />
functioning was assessed using the Functional Assessment <strong>of</strong> Cancer<br />
Therapy-Cognitive Function Version, and objective cognitive functioning was assessed<br />
using Headminder. Plasma VEGF levels were quantified using a multiplex<br />
immunoassay (Luminex®).<br />
Results: The average age <strong>of</strong> this cohort was 50.5 ± 9.2 years, with the majority being<br />
Chinese (82.9%), and diagnosed with Stage II breast cancer (56.2%). Forty-one (28.3%)<br />
patients reported self-perceived cognitive impairment at the end <strong>of</strong> chemotherapy, with<br />
impairment in the attention (7.2%) and memory (11.0%) domains detected using<br />
Headminder. Among the patients who received an anthracycline-based<br />
chemotherapy regimen, the median plasma VEGF levels were significantly higher at T2<br />
(T2: 37.0 pg/ml vs T1: 21.2 pg/ml; p < 0.001) and T3 (T3: 36.4 pg/ml vs T1: 21.2 pg/ml;<br />
p < 0.001) than at baseline. Among the patients who received taxane-based<br />
chemotherapy, there were no significant differences in VEGF levels between the time<br />
points. Plasma VEGF levels were not associated with chemotherapy-associated<br />
cognitive impairment.<br />
Conclusions: Breast cancer patients experience dysregulation in plasma VEGF levels<br />
during chemotherapy, and the regimen types may have a differential impact on<br />
circulating VEGF levels. However, changes in plasma VEGF levels during<br />
chemotherapy were not associated with cognitive impairment.<br />
Legal entity responsible for the study: Singhealth CIRB; National Cancer Centre<br />
Singapore<br />
Funding: National Medical Research Council Singapore<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
Background: Cancer patients are <strong>of</strong>ten treated with numerous concomitant<br />
medications other than antineoplastic agents. Recent studies have shown a high<br />
prevalence <strong>of</strong> drug-drug interactions (DDIs) among these patients, some <strong>of</strong> them<br />
considered as clinically relevant due to potential changes on the efficacy and toxicity <strong>of</strong><br />
the anticancer therapy. We aimed to determine clinically relevant DDIs leading to<br />
pharmaceutical intervention in ambulatory cancer patients treated at our centre.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw390 | vi519
abstracts<br />
1502P<br />
Insomnia prevalence in an oncology patient population: an<br />
Irish tertiary referral centre experience<br />
E.C. Harrold 1 , A.F. Idris 2 , N.M. Keegan 3 , L. Corrigan 4 , M.Y. Teo 5 , S.T. Lim 6 ,<br />
E. Duff 6 , M. O Donnell 6 , J. Kennedy 4 ,D.O’Donnell 7 , S. Sukor 4 , C. Grant 4 ,<br />
D. Gallagher 4 , S. Collier 2 , T. Kingston 2 , A.M. O’Dwyer 2 , S. Cuffe 4<br />
1 Dept Medical <strong>Oncology</strong>, Mater Hospital, Dublin, Ireland, 2 Department <strong>of</strong> Medical<br />
<strong>Oncology</strong>, St James’s Hospital, Dublin, Ireland, 3 Medical <strong>Oncology</strong>, Beaumont<br />
Hospital, Dublin, Ireland, 4 Medical <strong>Oncology</strong>, St James’s Hospital, Dublin, Ireland,<br />
5 Medical <strong>Oncology</strong>, Memorial Sloan Kettering Cancer Center, New York, NY, USA,<br />
6 Medicine, Trinity College Dublin, Dublin, Ireland, 7 Haematology <strong>Oncology</strong> Day<br />
Care Centre, St James’s Hospital, Dublin, Ireland<br />
Background: NCCN survivorship guidelines recommend dedicated sleep assessment<br />
reflecting its association with increased symptom distress scores and mortality<br />
Reported insomnia prevalence in the general Irish population is 15%; reported<br />
prevalence internationally amongst new or recently diagnosed cancer patients varies<br />
from 23-50%. Insomnia prevalence has not been quantified in an Irish oncology<br />
cohort.<br />
Methods: With ethical approval an 8 page questionnaire was prospectively<br />
administered to ambulatory cancer patients aged ≥ 18 attending a tertiary referral<br />
centre. Pre-specified criteria for insomnia syndrome (IS) combined those <strong>of</strong><br />
International Classification <strong>of</strong> Sleep Disorders and DSM-IV. The Hospital Anxiety and<br />
Depression scale (HADS-D/A) was used to screen for depression and anxiety as<br />
confounding variables. Logistical regression model was used for analysis.<br />
Results: Response rate was 87% (294/337). Median respondent age was 55-64.80% were<br />
female. Breast (37%), colorectal (13%) and lung (12.2%) were the most common cancer<br />
subtypes. 62% reported sleep disturbance after diagnosis.33% met IS criteria. 60%<br />
reported moderate/severe insomnia related distress, 23% a significant impact on<br />
physical function. 45% who did not meet criteria had ≥1 <strong>of</strong> 4 critical features. On<br />
univariate analysis female sex, age 0.05).<br />
Conclusions: In Eastern societies, diagnosis <strong>of</strong> cancer is commonly preferred to be<br />
hidden from the patients, otherwise patients should have serious pshyciatric problems<br />
according to their relatives’ thoughts. We found that, anxiety and depression scores <strong>of</strong><br />
informed and non-informed patients did not show statistically significant difference.<br />
We think that decreased anxiety <strong>of</strong> informed patients may be caused by the acceptance<br />
<strong>of</strong> the cancer and preperation to the difficult treatment, and the increased anxiety and<br />
depression <strong>of</strong> non-informed patients may be caused by the expectation <strong>of</strong> bad news.<br />
Clinical trial identification: Local ethical commitee accepted.<br />
Legal entity responsible for the study: Gaziantep University/ Gaziantep/ Turkey<br />
Funding: M.E. Kalender<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1505TiP<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
The prospective study <strong>of</strong> relation between 5-HIAA/<br />
substance P and nausea/vomiting in patients receiving<br />
moderately emetogenic chemotherapy<br />
T. Muranaka 1 , Y. Komatsu 1 , S. Ohnishi 2 , K. Sawada 2 , K. Harada 1 , Y. Kawamoto 1 ,<br />
H. Nakatsumi 1 , S. Yuki 2 , M. Yagisawa 3 , M. Nakamura 3 , Y. Kobayashi 4 ,<br />
S. Sogabe 4 , T. Miyagishima 4 , N. Sakamoto 2<br />
1 Cancer Center, Hokkaido University Hospital, Sapporo, Japan, 2 Department <strong>of</strong><br />
Gastroenterology and Hepatology, Hokkaido University Hospital, Sapporo, Japan,<br />
3 Gastroenterology, Sapporo City General Hospital, Sapporo, Japan, 4 Medical<br />
<strong>Oncology</strong>, Kushiro Rosai Hospital, Kushiro, Japan<br />
Background: The use <strong>of</strong> antagonists <strong>of</strong> the NK1 and/or 5-HT3 receptor is<br />
recommended for the patients receiving high emetogenic chemotherapy (HEC) in<br />
order to prevent chemotherapy-induced nausea and vomiting (CINV). Although we<br />
widely use them for the patients receiving moderately emetogenic chemotherapy<br />
(MEC), supporting evidence is insufficient. We therefore planned to measure the blood<br />
concentration <strong>of</strong> 5-HIAA and substance P in patients receiving MEC, and investigate<br />
the relation between their levels and CINV.<br />
Trial design: This is a multicenter exploratory observational research in Japanese<br />
patients receiving chemotherapy for gastrointestinal cancer. The key eligibility criteria<br />
are as follows: 1) Diagnosed gastrointestinal cancer; 2) Planned to receive high dose<br />
cisplatin (for five patients in cohort 1, for validation <strong>of</strong> measurement), oxaliplatin or<br />
irinotecan (for 45 patients in cohort 2); 3) 20 years <strong>of</strong> age or older; 4) ECOG PS <strong>of</strong> 0, 1<br />
or 2; 5) Keeping adequate major organ function. By sampling the patients’ blood before<br />
and 4, 24, 48, 72 and 96 hours after HEC/MEC administration, we measure the<br />
vi520 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
changes in blood concentration <strong>of</strong> substance P and 5-HIAA after chemotherapy, and<br />
survey the relevance <strong>of</strong> blood concentrations <strong>of</strong> substance P and 5-HIAA and CINV<br />
measured by visual analogue scale. This trial is recruiting the patients from 3 institutes<br />
from February 2016 to October 2017, and registered as UMIN000021072.<br />
Clinical trial identification: The trial information <strong>of</strong> this study was registered as<br />
UMIN000021072 and released 18th February 2016.<br />
Legal entity responsible for the study: Hokkaido University Hospital<br />
Funding: Ono Pharmaceutical Co., Ltd.<br />
Disclosure: Y. Komatsu: Yoshito Komatsu received honoraria from Ono<br />
Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co. Ltd., Yakult Pharmaceutical<br />
Industry Co. Ltd., Daiichi–Sankyo Ltd. and Bristol–Myers Squibb. M. Nakamura:<br />
Takeda, Chugai Pharma, Bayer Yakuhin, Yakult Honsha, Taiho Pharmaceutical, Lilly<br />
Japan, and Kirin Pharmaceuticals. N. Sakamoto: Bristol Myers Squibb and Gilead<br />
sciences. All other authors have declared no conflicts <strong>of</strong> interest.<br />
1506TiP<br />
Quality <strong>of</strong> life, efficacy, and patient-reported outcome with<br />
NEPA as antiemetic prophylaxis in patients receiving highly<br />
or moderately emetogenic chemotherapy<br />
M. Karthaus 1 , J. Rauh 2 , D. Guth 3 , V. Heilmann 4 , J. Schilling 5<br />
1 Klinik für Hämatologie, Onkologie und Palliativmedizin, Städtisches Klinikum<br />
München - Harlaching, Munich, Germany, 2 Fachinternistische<br />
Gemeinschaftspraxis, Dr. Rauh, Witten, Germany, 3 Gynäkologische Praxis, Dr.<br />
Guth, Plauen, Germany, 4 Praxis Günzburg, Dr. Heilmann, Günzburg, Germany,<br />
5 Dr. Schilling, Gynäkologisch-Onkologische Schwerpunktpraxis, Berlin, Germany<br />
Background: The combination <strong>of</strong> 5-HT 3 - and NK 1 -receptor-antagonists (RA) and<br />
dexamethasone is recommended by international guidelines for patients receiving<br />
highly emetogenic (HEC) and anthracycline / cyclophosphamide (AC) containing<br />
chemotherapy as well as for patients receiving certain moderately emetogenic<br />
chemotherapy (MEC) regimens for the prevention <strong>of</strong> chemotherapy-induced nausea<br />
and vomiting (CINV). NEPA (Akynzeo®) is a fixed combination capsule that combines<br />
the new NK 1 -RA netupitant and the 5-HT 3 -RA palonosetron. It has been approved for<br />
the prevention <strong>of</strong> acute and delayed CINV in adult cancer patients receiving<br />
cisplatin-based HEC or MEC. The objective <strong>of</strong> the study is to evaluate the quality <strong>of</strong> life<br />
<strong>of</strong> adult cancer patients undergoing MEC or HEC and receiving NEPA for CINV<br />
prophylaxis and to investigate the efficacy and safety <strong>of</strong> NEPA under real life<br />
conditions.<br />
Trial design: This non interventional study is planned to evaluate 2500 patients<br />
receiving single day or two day MEC or HEC (10-20 patients / participating center)<br />
treated in > 100 German centers (min. 125, max. 250 centers). NEPA is prescribed in<br />
accordance with the terms <strong>of</strong> the marketing authorisation. The primary endpoint is the<br />
patientś quality <strong>of</strong> life as recorded by FLIE questionnaires. Secondary endpoints<br />
include complete response (CR, no vomiting, no rescue medication), additional<br />
medication, safety data and AEs as documented by online questionnaire and patient<br />
diary. 3 consecutive chemotherapy cycles will be documented. For documentation<br />
treating physicians use the ODM QuaSi® online documentation system. All<br />
specifications in the online documentation system must be verifiable by patient records<br />
or medical test records. The trial is in ongoing. At the time <strong>of</strong> abstract submission, 178<br />
patients treated in 129 centers (69 gynaecologic oncology, 58 medical oncology, 2<br />
urologic oncology) had been included. The majority <strong>of</strong> patients (118) had breast<br />
cancer. Data on quality <strong>of</strong> life, efficacy and toxicity as available at the cut-<strong>of</strong>f date May<br />
2016 will be presented at the meeting.<br />
Clinical trial identification: DRKS00009316<br />
Legal entity responsible for the study: Riemser Pharma GmbH<br />
Funding: Riemser Pharma GmbH<br />
Disclosure: M. Karthaus: Consultant for Helsinn Healthcare, Riemser Pharma.<br />
J. Schilling: Consultant <strong>of</strong> Riemser Pharma. All other authors have declared no<br />
conflicts <strong>of</strong> interest.<br />
1507TiP<br />
abstracts<br />
Validation <strong>of</strong> a risk-assessment score for prediction <strong>of</strong><br />
venous thromboembolism in cancer outpatients receiving<br />
active treatments: ONKOTEV-2 trial<br />
C.A. Cella 1 , F. Lordick 2 , N. Fazio 3<br />
1 Gastrointestinal Tumors and Neuroendocrine Tumors Unit, Istituto Europeo di<br />
Oncologia, Milan, Italy, 2 University Cancer Center Leipzig, University Clinic Leipzig,<br />
Leipzig, Germany, 3 Gastrointestinal and NET Unit, Istituto Europeo di Oncologia,<br />
Milan, Italy<br />
Background: Venous thromboembolism (VTE) risk assessment is an outstanding area<br />
<strong>of</strong> investigation. In a previous large prospective study, involving more than 800<br />
ambulatory cancer patients from two European academic institutions, we pioneered an<br />
extensive screening with a upper and lower limbs ultrasound to all patients to have the<br />
most precise incidence <strong>of</strong> VTE in cancer outpatients (ONKOTEV trial - data under<br />
submission). We investigated several risk factors potentially associated to a increased<br />
risk <strong>of</strong> thrombosis and tested the efficacy <strong>of</strong> Khorana score in preventing VTE events.<br />
We finally constructed a four-cathegory risk model score, improving the predictability<br />
<strong>of</strong> VTE in cancer outpatients. The four variables included in the ONKOTEV score are<br />
the following: the presence <strong>of</strong> metastases, a positive history <strong>of</strong> previous VTE, the<br />
macroscopic compression <strong>of</strong> vessels or lymphnodes by tumor mass and a Khorana<br />
score point <strong>of</strong> 2 or more. The validation <strong>of</strong> this new risk assessment model is the goal<br />
<strong>of</strong> the further prospective trial, ONKOTEV 2.<br />
Trial design: ONKOTEV 2 trial is an observational, multicentric, no-pr<strong>of</strong>it study,<br />
endorsed by EORTC Young Investigator Program, and aims to validate the ONKOTEV<br />
score as novel easy-to-use tool for the prediction <strong>of</strong> VTE in ambulatory cancer patients<br />
starting a new antitumoral treatment (chemotherapy, endocrine therapy, radiation<br />
therapy or surgery). The study will be based on clinical, laboratory and imaging data<br />
collection, which will allow to calculate the ONKOTEV score in each patient at<br />
baseline. The patient will be clinically monitored for 8 months, in order to detect any<br />
thromboembolic event during the trial. The duration <strong>of</strong> the study will be approximately<br />
20 months. It will be a first analysis at the time <strong>of</strong> the visit inclusion (T0), a control visit<br />
at 8 months (T8). The median period <strong>of</strong> observation will be 8 months. It is expeted to<br />
enroll 465 patients.<br />
Legal entity responsible for the study: Study coordination: European Institute <strong>of</strong><br />
<strong>Oncology</strong><br />
Funding: EORTC<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw390 | vi521
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong> 27 (Supplement 6): vi522–vi525, 2016<br />
doi:10.1093/annonc/mdw391<br />
thoracic malignancies, other<br />
1509PD<br />
Quality <strong>of</strong> resection and outcome in stage III thymic<br />
epithelial tumors (TET): A retrospective analysis <strong>of</strong> 150<br />
cases from the national network RYTHMIC experience<br />
abstracts<br />
1508PD<br />
Patient-reported outcomes (PROs) and impact <strong>of</strong> lactate<br />
dehydrogenase (LDH) levels on outcomes in a phase 3 trial<br />
(NGR015) with best investigator choice (BIC) plus or minus<br />
NGR-hTNF in previously treated patients with malignant<br />
pleural mesothelioma (MPM)<br />
V. Gregorc 1 , A. Bulotta 1 , M.G. Viganò 1 , G. Citterio 1 , G. Petrella 1 , E. Brioschi 1 ,<br />
M. Ducceschi 1 , L. Gianni 1 , S. Colombi 2 , G. Rossoni 2 , G. Salini 2 , V. Savia 2 ,<br />
A. Lambiase 2 , C. Bordignon 2<br />
1 Department <strong>of</strong> <strong>Oncology</strong>, San Raffaele Scientific Institute, Milan, Italy, 2 Clinical<br />
Development, MolMed, Milan, Italy<br />
Background: NGR-hTNF selectively binds to CD13-expressing blood vessels. CD13 is<br />
upregulated by tumor hypoxia/angiogenesis, which are associated with high LDH<br />
serum levels. Patients (pts) failing a 1st-line pemetrexed-based regimen were<br />
randomized in NGR015 trial to weekly NGR-hTNF (N; n = 200) or placebo (P;<br />
n = 200) both given with BIC, including gemcitabine, vinorelbine or doxorubicin (95%<br />
<strong>of</strong> pts) or supportive care (5%).<br />
Methods: PROs were assessed with the MPM-LCSS questionnaire, based on a 100-mm<br />
visual analog scale (with 0 as best rating) for 5 major symptoms (appetite loss, fatigue,<br />
cough, dyspnea and pain) and 3 summary items (total distress, activity and quality <strong>of</strong><br />
life [QoL]). PROs measures were time to symptomatic deterioration (TSD; ≥ 25%<br />
increase) and responder analysis (≥ 10% decrease). We explored also the predictivity <strong>of</strong><br />
baseline LDH (median 274 U/L; IQR 196 to 388) for N benefit.<br />
Results: At baseline, PROs completion rate (88% vs 92%) and scores (median 36 vs 36)<br />
were balanced between N and P arms, respectively. Scores inversely correlated with OS<br />
(p < .0001). By ITT analyses, TSD (HR = 1.01; p = .97) and OS (HR = 0.94; p = .61) did<br />
not differ between arms. Predefined OS analyses indicated an interaction only between<br />
treatment and treatment-free interval (TFI) from end <strong>of</strong> 1st-line to start <strong>of</strong> 2nd-line<br />
therapy (HR = 0.54; p = 0.008). In pts with short TFI (< median, 4.8 months; n = 198),<br />
there was improved OS (HR = 0.69; median, 9.0 vs 6.3 months; p = .02) and slightly<br />
longer TSD (HR = 0.66; median, 3.3 vs 2.8 months) for N vs P, respectively. The rate <strong>of</strong><br />
pts with a decrease ≥ 10% was 49% vs 37%, with median OS <strong>of</strong> 15.6 vs 8.4 months,<br />
respectively. In the ITT population, LDH levels were inversely related to TFI<br />
(p < .0001) and higher in short than long TFI subsets (p < .0001). In the short TFI<br />
subset, the HR for PFS was 0.56 (p = .001) with LDH ≥ 1st quartile and 0.36 (p = .001)<br />
with LDH ≥ 3rd quartile and the increase in median OS was 3.7 and 7 months,<br />
respectively.<br />
Conclusions: NGR-hTNF has improved OS in MPM pts rapidly progressing after<br />
front-line therapy, without altering QoL and with increasing effects noted with<br />
increasing LDH levels.<br />
Clinical trial identification: NCT01098266<br />
Legal entity responsible for the study: N/A<br />
Funding: MolMed<br />
Disclosure: S. Colombi, G. Rossoni, G. Salini, V. Savia, A. Lambiase, C. Bordignon:<br />
Employee <strong>of</strong> MolMed.All other authors have declared no conflicts <strong>of</strong> interest.<br />
M.V. Bluthgen 1 , E. Dansin 2 ,D.Ou 3 , H. Lena 4 , J. Mazieres 5 , E. Pichon 6 , F. Thillays 7 ,<br />
G. Massard 8 , X. Quantin 9 , Y. Oulkhouir 10 , T. Nguyen Tan Hon 11 , L. Thiberville 12 ,<br />
C. Clement-Duchene 13 , C. Lindsay 1 , P. Missy 14 , T. Molina 15 , N. Girard 16 ,<br />
B. Besse 1 , P. Thomas 17<br />
1 Cancer Medicine, Institut Gustave Roussy, Villejuif, France, 2 Medical <strong>Oncology</strong><br />
Department, Centre Oscar Lambret, Lille, France, 3 Department <strong>of</strong> Radiation<br />
<strong>Oncology</strong>, Institut Gustave Roussy, Villejuif, France, 4 Medical <strong>Oncology</strong><br />
Department, Centre Hospitalier Universitaire de Rennes, Rennes, France, 5 Medical<br />
<strong>Oncology</strong> Department, CHU Toulouse, Hôpital de Larrey, Toulouse, France,<br />
6 Service de pneumologie et d’explorations fonctionnelles, CHRU de Tours, Tours,<br />
France, 7 Service de radiothérapie, ICO Institut de Cancerologie de l’Ouest René<br />
Gauducheau, St. Herblain, France, 8 Department <strong>of</strong> Thoracic Surgery, C.H.U.<br />
Strasbourg-Nouvel Hopital Civil, Strasbourg, France, 9 Respiratory Disease<br />
Department, CHU Montpellier, Montpellier, France, 10 Service de pneumologie et<br />
oncologie thoracique, Hôpital de la Côte-de-Nacre, Caen, France, 11 Medical<br />
<strong>Oncology</strong> Department, Centre Francois Baclesse, Caen, France, 12 Medical<br />
<strong>Oncology</strong> Department, Rouen University Hospital, Rouen, France, 13 Chest<br />
Department, University Medical Center Nancy, Nanacy, France, 14 Epidemiology,<br />
Intergroupe Francophone de Cancérologie Thoracique, Paris, France,<br />
15 Department <strong>of</strong> Pathology, GH Necker - Enfants Malades, Paris, France,<br />
16 Department <strong>of</strong> Respiratory Medicine, Louis Pradel Hospital, Lyon, France,<br />
17 Department <strong>of</strong> Thoracic Surgery, Hôpital Nord-APHM, Marseille, France<br />
Background: Stage III TET represents a heterogeneous population and their optimal<br />
approach remains unclear; most <strong>of</strong> the available literature is composed <strong>of</strong> small series<br />
spanned over extended periods <strong>of</strong> time. RYTHMIC (Réseau tumeurs THYMiques et<br />
Cancer) is a French nationwide network for TET with the objective <strong>of</strong> territorial<br />
coverage by regional expert centers and systematic discussion <strong>of</strong> patients management<br />
at national tumor board. We reviewed our experience in stage III thymic tumors in<br />
order to evaluate the value <strong>of</strong> tumor board recommendations and multidisciplinary<br />
approach.<br />
Methods: We conducted a retrospective analysis <strong>of</strong> patients (pts) with stage III TET<br />
discussed at the RYTHMIC tumor board from January 2012 to December 2015.<br />
Clinical, pathologic and surgical data were prospectively collected in a central database.<br />
Survival rates were based on Kaplan-Meier estimation. Cox proportional hazard<br />
models were used to evaluate prognostic factors for disease free survival (DFS) and<br />
overall survival (OS).<br />
Results: 150 pts were included in the analysis. Median age was 64 years [18 – 91], 56%<br />
males, thymoma A-B2/ B3-thymic carcinoma in 52% and 47% respectively; 12%<br />
presented with autoimmune disorder (76% myasthenia). Local treatment was surgery<br />
in 134 pts (90%) followed by radiotherapy (RT) in 90 pts; 26 pts received preoperative<br />
chemotherapy (CT). Complete resection rate (R0) was 53%. Among 38 pts considered<br />
non-surgical candidates at diagnosis, 26 pts became resectable after induction CT with<br />
a R0 rate <strong>of</strong> 58%; 12 pts received CT-RT and/or CT as primary treatment. Recurrence<br />
rate was 38% (n = 57), first sites were pleural (n = 32) and lung (n = 12). The 5-year OS<br />
and DFS were 88% and 32% respectively. Gender (p = 0.04), histology (p = 0.02) and<br />
surgery (p < 0.001) as primary treatment modality were significant prognostic factors<br />
for OS in multivariate analysis. Histology (p = 0.02) and adjuvant RT (p = 0.05) were<br />
significantly associated with DFS. Completeness <strong>of</strong> resection was not associated with<br />
survival in our cohort.<br />
Conclusions: Surgery followed by radiotherapy improves outcome irrespectively <strong>of</strong> R0.<br />
Stage III TET not candidate to surgery should be reassessed for resection after<br />
induction chemotherapy.<br />
Legal entity responsible for the study: N/A<br />
Funding: RYTHMIC<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
© European Society for Medical <strong>Oncology</strong> 2016. Published by Oxford University Press on behalf <strong>of</strong> the European Society for Medical <strong>Oncology</strong>.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com.
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
1510PD<br />
Pathological central review <strong>of</strong> 400 thymic epithelial tumors<br />
(TET): The national network RYTHMIC experience<br />
T. Molina 1 , M.V. Bluthgen 2 , L. Chalabreysse 3 , V. De Montpréville 4 , A. De Muret 5 ,<br />
V. H<strong>of</strong>man 6 , S. Lantuejoul 7 , M. Parrens 8 , I. Rouquette 9 , V. Secq 10 , N. Girard 11 ,<br />
A. Marx 12 , B. Besse 2<br />
1 Department <strong>of</strong> Pathology, GH Necker - Enfants Malades, Paris, France, 2 Cancer<br />
Medicine, Institut Gustave Roussy, Villejuif, France, 3 Service d’anatomie<br />
pathologique, Hôpital Louis-Pradel, Lyon, France, 4 Service d’anatomie<br />
pathologique, Centre chirurgical Marie-Lannelongue, Le Plessis-Robinson,<br />
France, 5 Service d’anatomie pathologique, CHU de Tours, Tours, France, 6 Service<br />
d’anatomie pathologique, Hôpital Pasteur, Nice, France, 7 Service d’anatomie<br />
pathologique, CHU de Grenoble, Grenoble, France, 8 Service d’anatomie<br />
pathologique, CHU de Bordeaux, Bordeaux, France, 9 Service d’anatomie<br />
pathologique, Institut Universitaire du Cancer -Toulouse- Oncopole, Toulouse,<br />
France, 10 Service d’anatomie pathologique, Hopital Nord, Marseille, France,<br />
11 Department <strong>of</strong> Respiratory Medicine, Louis Pradel Hospital, Lyon, France,<br />
12 Pathology, Universitätsklinikum Mannheim, Mannheim, Germany<br />
Background: RYTHMIC (Réseau tumeurs THYMiques et Cancer) is a nationwide<br />
network for TET appointed in 2012 by the French National Cancer Institute. The<br />
objectives <strong>of</strong> the network are management <strong>of</strong> clinical tumor board and central<br />
pathologic review <strong>of</strong> all cases. RYTHMIC Tumor Board is based on initial<br />
histopathological diagnosis.<br />
Methods: Pathological central review <strong>of</strong> patients diagnosed with TET from January<br />
2012 to May 2016 was made by a panel <strong>of</strong> 10 expert pathologists from the working<br />
group. Assessment <strong>of</strong> agreement or disagreement between the initial institution and<br />
the panel review was made according the WHO 2004/2015 and new ITMIG proposals<br />
for histologic typing and staging. Discordances were classified as “major” when they<br />
would have changed the therapy or management <strong>of</strong> patients according to the<br />
RYTHMIC guidelines.<br />
Results: A total <strong>of</strong> 400 specimens were reviewed. Considering either histological<br />
subtype and/or staging, a total <strong>of</strong> 172 discordances in 157 patients (39%) were<br />
identified as follow: 111 concerning histological diagnosis and 61 regarding stage. A<br />
total <strong>of</strong> 31 major discordances in 29 patients (7%) were identified: 18 patients for<br />
whom post-surgical treatment recommendation concerning adjuvant radiotherapy<br />
would have been changed and 11 patients for whom management <strong>of</strong> disease should<br />
have been modified. The most frequent disagreement was the sub-diagnosis <strong>of</strong> stage III<br />
reflecting the underlying difficulty in pericardial and/or mediastinal pleura histological<br />
invasion. Additionally, major disagreement between the initial and panel pathology’s<br />
stage and subsequent interpretation by the working group at national tumor board was<br />
found in 4 patients, enhancing the importance <strong>of</strong> an expert pathologist at the<br />
RYTHMIC network committee.<br />
Conclusions: The RYTHMIC experience confirms the relevance <strong>of</strong> an expert<br />
histopathological panel diagnosis <strong>of</strong> thymic malignancies and for better<br />
decision-making in particular concerning post-operative radiotherapy to avoid over- or<br />
under-treatment <strong>of</strong> the patients.<br />
Legal entity responsible for the study: N/A<br />
Funding: RYTHMIC<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1511P<br />
TKIs in first-line for advanced NSCLC with activating<br />
EGFR-mutations: The European Society for Medical<br />
<strong>Oncology</strong> Magnitude <strong>of</strong> Clinical Benefit Scale (ESMO-MCBS)<br />
applied to pivotal phase III randomized controlled trials<br />
J. Giuliani, A. Bonetti<br />
Dept. <strong>Oncology</strong>, Ospedale di Legnago, Legnago, Italy<br />
Background: In light <strong>of</strong> results <strong>of</strong> pivotal phase III randomized controlled trials<br />
(RCTs) concerning the effect <strong>of</strong> first-line tyrosine kinase inhibitor (TKIs) in first-line<br />
for advanced non-small cell lung cancer (NSCLC) with activating epidermal growth<br />
factor receptor (EGFR)-mutations, it might be interesting to examine the magnitude <strong>of</strong><br />
the clinical benefit from TKIs in this setting <strong>of</strong> patients.<br />
Methods: European Society for Medical <strong>Oncology</strong> Magnitude <strong>of</strong> Clinical Benefit Scale<br />
(ESMO-MCBS) was applied to pivotal phase III RCTs in first-line for advanced<br />
NSCLC with activating EGFR-mutations, to derive a relative ranking (from grade 1 to<br />
grade 5) <strong>of</strong> the magnitude <strong>of</strong> clinically meaningful benefit that can be expected from<br />
TKIs (erlotinib, gefitinib and afatinib) in this subset <strong>of</strong> patients.<br />
Results: Our study evaluated 8 phase III RCTs (including 1710 patients). The main<br />
reported outcomes <strong>of</strong> the considered pivotal phase III RCTs in first-line for advanced<br />
NSCLC with activating EGFR-mutations and the corresponding ESMO-MCBS score<br />
are reported in Table 1.<br />
Legend: N= number; OS= overall survival; PFS= progression free survival; *= referring<br />
to PFS; HR= hazard ratio; 95% C.I.= 95% Confidence Interval; NR= not reached; NS=<br />
not significant; **= referring to the primary endpoint; ESMO-MCBS= European<br />
Society for Medical <strong>Oncology</strong>-Magnitude <strong>of</strong> Clinical Benefit Scale (from grade 1 to<br />
grade 5).<br />
Conclusions: The ESMO-MCBS reached high grade (grade 4) for all TKIs treatments<br />
with at least a phase III RCT. Combining pharmacological costs <strong>of</strong> drugs with the<br />
measure <strong>of</strong> efficacy represented by the PFS, it is evident that afatinib is the most<br />
cost-effective, with the lowest difference in costs per month-PFS gained (1682.3 €,data<br />
derived from literature) and a comparable high grade <strong>of</strong> magnitude <strong>of</strong> clinical benefit.<br />
Legal entity responsible for the study: N/A<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1512P<br />
abstracts<br />
Prognostic value <strong>of</strong> FGFR1 overexpression and amplification<br />
in esophageal squamous cell carcinoma patients:<br />
a combined analysis from TCGA database<br />
B. Chen, S. Liu, J. Wang, B. Hu, H. Xu, R. Tong, X. Hu, J. Xue, Y. Lu<br />
Department <strong>of</strong> Thoracic <strong>Oncology</strong>, Cancer Center, West China Hospital, Sichuan<br />
University, Chengdu, China<br />
Background: To explore the clinical and prognostic value <strong>of</strong> fibroblast growth factor<br />
receptor 1 (FGFR1) mRNA expression and amplification in patients with esophageal<br />
squamous cell carcinoma (ESCC).<br />
Methods: FGFR1 mRNA expression was measured by quantitative RT-PCR in tumor<br />
tissue <strong>of</strong> 145 Chinese patients with ESCC who underwent surgery during January 2009<br />
and December 2010 in West China Hospital. Pooled data about FGFR1 mRNA<br />
expression, amplification and survival <strong>of</strong> 186 patients with Esophageal Carcinoma was<br />
extracted from TCGA database (TCGA, Provisional). Log rank and Cox proportional<br />
hazards regression were conducted to analyze the correlation between survival and<br />
FGFR1 mRNA expression or amplification.<br />
Table: 1511P Main outcomes <strong>of</strong> the considered pivotal phase III RCTs in first-line for advanced NSCLC with activating EGFR-mutations and the<br />
corresponding ESMO-MCBS score<br />
Authors/Trial Comparative Regimens N° <strong>of</strong><br />
patients<br />
Zhou et al, 2011 OPTIMAL carboplatin + gemcitabine erlotinib 72<br />
82<br />
Primary endpoint<br />
PFS<br />
OS<br />
(months)<br />
NR<br />
NR<br />
PFS<br />
(months)<br />
4.6<br />
13.1<br />
p-Value*<br />
PFS/OS gain<br />
(months)**<br />
PFS/OS HR (95%<br />
C.I.)**<br />
< 0.001 8.5 0.16 (0.10-0.26) 4<br />
ESMO-MCBS<br />
Rosell et al, 2012 EURTAC<br />
cisplatin + docetaxel/gemcitabine<br />
erlotinib<br />
129<br />
132<br />
PFS (crossover<br />
allowed)<br />
21.6<br />
21.9<br />
6.3<br />
9.5<br />
< 0.001 3.2 0.48 (0.36-0.64) 4<br />
Maemondo et al, 2010<br />
NEJ2002<br />
carboplatin + paclitaxel gefitinib 110<br />
114<br />
Mitsudomi et al, 2010 cisplatin + docetaxel gefitinib 86<br />
WJTOG3405<br />
86<br />
Han et al, 2012<br />
cisplatin + gemcitabine gefitinib 26<br />
First-SIGNAL<br />
22<br />
Sequist et al, 2013<br />
cisplatin + pemetrexed afatinib 111<br />
LUX-Lung 3<br />
229<br />
Wu et al, 2014 LUX-Lung 6 cisplatin + gemcitabine afatinib 122<br />
242<br />
PFS 23.6<br />
30.5<br />
PFS 30.9<br />
NR<br />
OS 22.9<br />
22.3<br />
PFS (crossover NR<br />
allowed) NR<br />
PFS<br />
NR<br />
NR<br />
5.5<br />
10.4<br />
6.3<br />
9.2<br />
6.3<br />
8.0<br />
6.9<br />
11.1<br />
5.6<br />
11.0<br />
< 0.001 4.9 0.36 (0.25-0.51) 3<br />
< 0.001 2.9 0.49 (0.37-0.71) 3<br />
NS −0.6 0.93 (0.72-1.21) 1<br />
< 0.001 4.9 0.49 (0.37-0.65) 4<br />
< 0.001 5.4 0.28 (0.20-0.39) 3<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw391 | vi523
abstracts<br />
Results: Univariate analysis showed ESCC patients with higher FGFR1 mRNA<br />
expression had significantly shorter overall survival (OS: 22.00 vs 33.00 months; P<br />
=0.038) than those with lower FGFR1 mRNA expression. Multivariate modeling<br />
confirmed that patients with higher FGFR1 mRNA expression had a significantly<br />
greater risk <strong>of</strong> death than those with lower FGFR1 mRNA expression after adjusting for<br />
pathologic stage (hazard ratio [HR]= 1.54, 95 % confidence interval [CI] = 1.03–2.30,<br />
P = 0.037). However, the analysis <strong>of</strong> pooled data from TCGA indicates there is no<br />
significant association between FGFR1 mRNA expression and OS in ESCC patients<br />
(25.10 vs 25.07 months; P =0.477). Either in our local or TCGA data sets, no<br />
significantly correlation between FGFR1 mRNA expression and disease free survival<br />
(DFS) was found (21.10 vs 39.00 months, P =0.1413; 18.10 vs 21.22 months; P =0.334).<br />
Pooled analysis <strong>of</strong> TCGA datasets showed FGFR1 amplification was found in 13/186<br />
(6.98 %) <strong>of</strong> all patients and was more frequent but without significant difference in<br />
squamous cell carcinoma than that in adenocarcinoma (10.31 % vs 3.37 %; P = 0.064).<br />
Survival analysis showed ESCC with FGFR1 amplification had no significantly<br />
difference in OS (25.47 v 35.80 months; P =0.499) than those without FGFR1<br />
amplification.<br />
Conclusions: Our analyses results support FGFR1 mRNA expression but not<br />
amplification could be an independent prognostic biomarker in patients with surgically<br />
resected ESCC.<br />
Legal entity responsible for the study: Jianxin Xue<br />
Funding: West China Hospital<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1513P<br />
Wait times for diagnosis and treatment <strong>of</strong> lung cancer:<br />
a single centre experience<br />
C. Labbe, M. Anderson, S. Simard, L. Tremblay, F. Laberge, R. Vaillancourt<br />
Department <strong>of</strong> Respirology, Institut Universitaire de Cardiologie et de Pneumologie<br />
de Québec (IUCPQ), Quebec City, QC, Canada<br />
Background: Multiple clinical practice guidelines recommend rapid evaluation <strong>of</strong><br />
patients with suspected lung cancer. It is uncertain if delays in diagnosis and<br />
management have a negative effect on outcomes.<br />
Methods: This retrospective review included 551 patients diagnosed with lung cancer<br />
through the Rapid Diagnostic Assessment Program at Institut Universitaire de<br />
Cardiologie et de Pneumologie de Québec between September 2013 and March 2015.<br />
Median wait times between initial referral, diagnosis and first treatment were calculated<br />
and compared with recommended targets. Analyses were performed for effect <strong>of</strong> delays<br />
on the outcomes <strong>of</strong> progression-free survival (PFS) and overall survival (OS).<br />
Results: Most patients were investigated and treated within recommended targets, as<br />
shown in Table 1. Among the entire cohort, 379 patients were treated at our<br />
institution. Of these, 289 (76%) commenced their treatment within recommended<br />
targets. When comparing patients meeting targets with patients not meeting targets,<br />
the only statistically significant difference was treatment modality. Patients meeting<br />
targets were more likely to be treated with surgery, as opposed to radiation or<br />
chemotherapy. PFS on first treatment modality was influenced by TNM stage and<br />
diagnostic method. There was also a trend for improved PFS if the treatment was<br />
commenced within targets (HR 0.85, CI 0.58-1.24, p = 0.07). OS was influenced by<br />
TNM stage and first treatment modality, but was not affected by delays (HR 0.84, CI<br />
0.56-1.27, p = 0.41).<br />
Table: 1513P – Median wait times for investigation and treatment<br />
Relative wait times from:<br />
Recommended<br />
target, days<br />
Median<br />
time, days<br />
(IQR)<br />
Patients<br />
within<br />
target, No.<br />
(%)<br />
Investigation (n = 551)<br />
Referral to first appointment (n = 551) 14 6 (4-10) 461 (84%)<br />
Referral to chest computed tomography scan 14 5 (1-7) 174 (92%)<br />
(n = 189)<br />
Biopsy to pathology result (n = 551) 14 3 (2-4) 550 (99.8%)<br />
Request for EGFR and ALK testing to result<br />
14 5 (3-6) 169 (98%)<br />
(n = 172)<br />
Treatment (n = 379)<br />
Respirology consultation to time <strong>of</strong> surgery (n = 210) 56 59 (41-80) 100 (48%)<br />
Operative decision to time <strong>of</strong> surgery (n = 210) 28 8 (2-21) 180 (86%)<br />
Surgery to commencing adjuvant chemotherapy 120 44 (36-55) 41 (98%)<br />
(n= 42)<br />
RO referral to RO consultation (n = 211) 7 4 (2-7) 166 (79%)<br />
RO referral to commencing definitive radiation 28 26 (22-35) 42 (63%)<br />
(n = 67)<br />
Diagnosis to commencing definitive chemoradiation 180 27 (13-34) 48 (100%)<br />
(n = 48)<br />
RO referral to commencing palliative radiation 14 8 (6-16) 69 (72%)<br />
(n = 96)<br />
Decision for chemotherapy to commencing<br />
chemotherapy (n = 117)<br />
7 6 (4-8) 79 (68%)<br />
IQR: interquartile range; EGFR: epidermal growth factor receptor; ALK:<br />
anaplasic lymphoma kinase; RO: radiation oncology<br />
Conclusions: Recommended targets for wait times in the investigation and treatment<br />
<strong>of</strong> lung cancer can be achieved with a Rapid Diagnostic Assessment Program. Patients<br />
treated with surgery, as compared to radiation or chemotherapy, are more likely to be<br />
treated within targets. Shorter delays might have a favorable influence on PFS, but has<br />
no effect on OS.<br />
Legal entity responsible for the study: Institut Universitaire de Cardiologie et de<br />
Pneumologie de Québec<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1514P<br />
Preoperative diffusing capacity correlates with tumor<br />
malignant grade and surgical outcome in clinical stage I lung<br />
cancer<br />
Y. Miyata 1 , T. Mimura 2 , Y. Tsutani 3 , H. Hanaki 3 , K. Misumi 3 , M. Okada 3<br />
1 Surgical <strong>Oncology</strong> Dept., Hiroshima University, Hiroshima, Japan, 2 Surgical<br />
oncology, Hiroshima University, Hiroshima, Japan, 3 Surgical <strong>Oncology</strong>, Hiroshima<br />
University, Hiroshima, Japan<br />
Background: Diffusing capacity <strong>of</strong> the lung for carbon monoxide (DLCO) is a<br />
predictor <strong>of</strong> complications after resection for lung cancer. This study aimed to<br />
determine the association between DLCO and tumor aggressiveness and survival in<br />
clinical stage I non-small cell lung cancer (NSCLC) patients.<br />
Methods: We retrospectively examined 437 consecutive patients with clinical stage IA<br />
NSCLC who underwent complete resection between January 2009 and December 2014<br />
at our institution. Patients were divided into 2 groups according to preoperative DLCO<br />
value. Several potential prognostic factors including DLCO were analyzed with respect<br />
to outcomes.<br />
Results: The median follow-up periods after the operations were 39.0 months (1.0–<br />
99.0 months). Total 53 patients with 50% or less <strong>of</strong> DLCO and 384 patients with more<br />
than 50% <strong>of</strong> DLCO were compared. Patients with low DLCO were more male (77% vs<br />
58%), higher age (73.5 ± 8.0 vs 66.7 ± 9.8), higher smoking history (93% vs 52%)<br />
compared with patients with high DLCO. The incidence <strong>of</strong> adenocarcinoma was low in<br />
patients with low DLCO (51% vs 84%), whereas the incidence <strong>of</strong> squamous cell<br />
carcinoma was high (40% vs 9%) compared to patients with high DLCO. 19% <strong>of</strong><br />
adenocarcinoma patients with low DLCO were lepidic predominant, whereas 31% with<br />
high DLCO. The OS and DFS decreased to 68.3% and 63.7% at 5 years in patients with<br />
low DLCO, compared with 92.3% and 85.2% in patients with high DLCO (P < 0.001,<br />
P < 0.001, log-lank, respectively). Multivariate survival analysis using Cox’s regression<br />
model revealed that less than 50% <strong>of</strong> DLCO was an independent predictor for OS<br />
(hazard ratio 4.21, P = 0.001) and DFS (hazard ratio 3.44, P = 0.001).<br />
Conclusions: Preoperative DLCO correlated with tumor malignant grade and was an<br />
independent determinant <strong>of</strong> long-term survival in patients with clinical stage I NSCLC<br />
who were amenable to curative surgery.<br />
Legal entity responsible for the study: N/A<br />
Funding: Hiroshima University<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1515P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Frequency, patterns and prognostic impact <strong>of</strong> distant<br />
metastases in a large mono-institutional series <strong>of</strong> malignant<br />
pleural mesothelioma (MPM): Not necessarily bad news<br />
F. Grosso 1 , A. Roveta 1 , G. Gallizzi 1 , A. Muzio 2 , S. Zai 1 ,F.Ugo 1 , A. Aurelio 3 ,<br />
R. Libener 4 , M. Mancuso 5 , G. Ferretti 6 , P. Franzone 7 , M. Pastormerlo 8 ,<br />
E. Piccolini 9 , D. Degiovanni 10 , G. Numico 1<br />
1 <strong>Oncology</strong>, AO SS Antonio e Biagio e C Arrigo, Alessandria, Italy, 2 <strong>Oncology</strong>,<br />
Ospedale Santo Spirito, Casale Monferrato, Italy, 3 Radiology, AO SS Antonio e<br />
Biagio e C Arrigo, Alessandria, Italy, 4 Pathological Anatomy, AO SS Antonio e<br />
Biagio e C Arrigo, Alessandria, Italy, 5 Thoracic Surgery, AO SS Antonio e Biagio e<br />
C Arrigo, Alessandria, Italy, 6 Pneumonology, AO SS Antonio e Biagio e C Arrigo,<br />
Alessandria, Italy, 7 Radiotherapy, AO SS Antonio e Biagio e C Arrigo, Alessandria,<br />
Italy, 8 Pathological Anatomy, Ospedale Santo Spirito, Casale Monferrato, Italy,<br />
9 Pneumonology, Ospedale Santo Spirito, Casale Monferrato, Italy, 10 Palliative<br />
Care, Ospedale Santo Spirito, Casale Monferrato, Italy<br />
Background: MPM is a deadly cancer whose lethality is almost invariably due to<br />
thoracic loco regional progression, whereas distant metastasis (mets) are rarely<br />
reported and their prognostic impact remains unclear. The aim <strong>of</strong> this study is to<br />
describe the incidence and patterns <strong>of</strong> metastatization and to explore their potential<br />
prognostic role in a large series <strong>of</strong> MPM patients (pts) in the highly asbestos polluted<br />
area <strong>of</strong> Casale Monferrato, in the North <strong>of</strong> Italy.<br />
Methods: Data from a dedicated MPM database were retrieved and analyzed with<br />
MedCalc Statistical S<strong>of</strong>tware version 16.1.<br />
Results: From 2009/1 to 2016/1, 368 pts (118 females, 250 males), median age 70.5<br />
(range 28 – 91, IQR 63 – 77) were treated at our institution. Pts characteristics were as<br />
follows: asbestos exposure certain pr<strong>of</strong>essional in 147 (40%), certain domestic in 51<br />
(14%), environmental in 170 (56%); PS 0 in 239 (75%), 1 in 95 (26%), ≥ 2 in 34 (9%);<br />
vi524 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
histology epithelioid in 271 (74%), biphasic in 50 (14%), sarcomatoid in 46 (12%);<br />
stage at diagnosis I – II in 147 (40%), III – IV in 221 (60%). With a median 30 months<br />
(mths) follow up, overall survival (OS) was 14.5 mths (95% CI 13.2 – 16.6). Sixty-eight<br />
pts (18%, 24 females, 44 males), 51 epithelioid, 11 biphasic and 6 sarcomatoid, had<br />
distant mets, <strong>of</strong> which 13 already had mets at diagnosis (3.5%). The other 55 patients<br />
developed mets at a median time-interval <strong>of</strong> 10 mths (95% CI 7.1 – 12.4) from<br />
diagnosis. The most common sites <strong>of</strong> mets were: lung in 26 pts (7%), peritoneum in 23<br />
(6%), liver in 19 (5%), and bone in 16 (4%). Median OS in mets pts (n = 68) was 19<br />
mths (95% CI 16 – 21.8). Median OS in non-distant mets pts (n = 300) was 13.4 mths<br />
(95% CI 11.7 – 15.5).<br />
Conclusions: Eighteen % <strong>of</strong> pts in this series had distant mets, mainly in lung, liver,<br />
peritoneum and bone. Distant mets are rarely found at diagnosis (3.5%) but usually are<br />
a late event and develop at approximately two-thirds <strong>of</strong> the natural history <strong>of</strong> MPM.<br />
Acknowledging the limits <strong>of</strong> the small numbers, our results suggest that distant disease<br />
likely does not negatively affect OS compared with loco-regional progression. The<br />
longer OS <strong>of</strong> distant mets patients may indeed suggest a better controlled or a less<br />
aggressive thoracic disease.<br />
Legal entity responsible for the study: General Director <strong>of</strong> "SS. Antonio e Biagio e<br />
C. Arrigo" Hospital, dr Giovanna Baraldi<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1516P<br />
Phase II trial <strong>of</strong> S-1 plus cisplatin combined with<br />
bevacizumab for advanced non-squamous non-small cell<br />
lung cancer (TCOG LC-1202)<br />
K. Kubota 1 , A. Miyanaga 1 , Y. Hosomi 2 , Y. Okuma 2 , K. Minato 3 , S. Fujimoto 3 ,<br />
Y. Takiguchi 4 , H. Okamoto 5 , Y. Hattori 6 , H. Isobe 7 , H. Aono 8<br />
1 Pulmonary Medicine and <strong>Oncology</strong>, Nippon Medical School, Tokyo, Japan,<br />
2 Department <strong>of</strong> Thoracic <strong>Oncology</strong> and Respiratory Medicine, Tokyo Metropolitan<br />
Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan,<br />
3 Department <strong>of</strong> Respiratory Medicine, Gunma Prefectural Cancer Center, Ota,<br />
Japan, 4 Medical <strong>Oncology</strong>, Chiba University, School <strong>of</strong> Medicine, Chiba, Japan,<br />
5 Department <strong>of</strong> Respiratory Medicine, Yokohama Municipal Citizen’s Hospital,<br />
Yokohama, Japan, 6 Thoracic <strong>Oncology</strong>, Hyogo Cancer Center, Akashi, Japan,<br />
7 Medical <strong>Oncology</strong>, KKR Sapporo Medical Center, Sapporo, Japan, 8 Respiratory<br />
Medicine, Mitsui Memorial Hospital, Tokyo, Japan<br />
Background: S-1 plus Cisplatin is a standard chemotherapy regimen for advanced<br />
non-small cell lung cancer (NSCLC) (Ann Oncol. 2015; 26:1401-8). Bevacizumab<br />
significantly improved overall survival (OS) in patients with advanced<br />
non-squamous (NSq) NSCLC who received carboplatin plus paclitaxel, however<br />
failed to show OS advantage in patients who received cisplatin plus gemcitabine.<br />
Few studies <strong>of</strong> bevacizumab evaluated quality <strong>of</strong> life (QOL) in patients with<br />
NSq-NSCLC.<br />
Methods: Chemotherapy-naïve patients with stage IIIB, IV, or recurrent NSq-NSCLC,<br />
ECOG PS 0-1, age 20-74 years old, and measurable lesions were treated with a 3-week<br />
cycle <strong>of</strong> S-1 40 mg/m 2 twice a day on days 1-14, cisplatin 60 mg/m 2 on day 8 and<br />
bevacizumab 15 mg/kg on day 8 for 4-6 cycles. Patients without progressive disease<br />
received maintenance bevacizumab 15 mg/kg on day 1 with a 3-week cycle and S-1 40<br />
mg/m 2 twice a day on every other day. Primary endpoint was progression-free survival<br />
(PFS) and secondary endpoints were objective response (OR), OS, toxicity pr<strong>of</strong>ile and<br />
QOL.<br />
Results: From June 2013 to January 2015, 39 evaluable patients were enrolled from 8<br />
institutions. Patient characteristics were: Male/Female 29/10; median age 65 years old<br />
(range 38-74); Performance status 0/1 22/17; IIIB/IV/recurrence 1/35/3; adeno/large<br />
cell/other 35/1/3. 31 patients (80%) completed 4 cycles <strong>of</strong> induction chemotherapy and<br />
23 patients (59%) started maintenance chemotherapy. Median PFS, OS and OR were<br />
7.3 months, 21.4 months and 64%, respectively. Worst hematologic and<br />
non-hematologic toxicities (%): grade 3/4 leukopenia (13/0); neutropenia (18/5);<br />
thrombocytopenia (0/0); anemia (0/0); neutropenic fever (3/0); hypertension (28/0);<br />
diarrhea (3/0).<br />
Conclusions: The trial met the primary endpoint. S-1 plus cisplatin combined with<br />
bevacizumab is well tolerated and highly active in patients with advanced NSq-NSCLC.<br />
QOL data will be presented at the meeting.<br />
Clinical trial identification: UMIN000009476<br />
Legal entity responsible for the study: N/A<br />
Funding: The Tokyo Cooperative <strong>Oncology</strong> Group (TCOG)<br />
Disclosure: K. Kubota: Honoraria from Taiho, Chugai, Eli-Lilly, Daiichi-Sankyo.Y.<br />
Hosomi: Speaker Fees as honoraria from Chugai, Eli Lilly Japan, AstraZeneca, Taiho<br />
and Ono, outside the submitted work.Y. Takiguchi: Lecture fee from Taiho<br />
pharmaceutical co., and Chugai Pharmaceutical Co.H. Okamoto: Corporate-sponsored<br />
research: Takeda, MSD, Ono, Astrazeneca, Merck, Chugai, Taiho, Bristol, Eli Lilly,<br />
Parexel.All other authors have declared no conflicts <strong>of</strong> interest.<br />
1517P<br />
Cisplatin-raltitrexed vs cisplatin-pemetrexed in the<br />
treatment <strong>of</strong> advanced pleural mesothelioma. Final results <strong>of</strong><br />
a network meta-analysis<br />
L.A. Lazzari Agli, C. Cherubini, M. Papi, C. Santelmo, S.V.L. Nicoletti, E. Bianchi,<br />
M. Fantini, C. Ridolfi, L. Stocchi, E. Tamburini, D. Tassinari<br />
<strong>Oncology</strong>, Ospedale Infermi, Rimini, Italy<br />
Background: To compare efficacy and safety <strong>of</strong> cisplatin-pemetrexed and<br />
cisplatin-raltitrexed in the treatment <strong>of</strong> advanced pleural mesothelioma.<br />
Methods: An indirect comparison <strong>of</strong> efficacy and safety <strong>of</strong> cisplatin-pemetrexed and<br />
cisplatin-raltitrexed was performed. The indirect comparison and the network meta-analysis<br />
were performed on data extracted from cisplatin-pemetrexed vs cisplatin, and<br />
cisplatin-raltitrexed vs cisplatin comparisons in the treatment <strong>of</strong> metastatic pleural<br />
mesothelioma. The Odds Ratios <strong>of</strong> 10, 15, and 20 month survival rate and response rate were<br />
assumed as indexes <strong>of</strong> efficacy; the Odds Ratio <strong>of</strong> grade III-IV side effects, and the absolute<br />
risk <strong>of</strong> overall, hematologic and non-hematologic toxicity, were assumed as indexes <strong>of</strong> safety.<br />
Results: The outcome <strong>of</strong> 352 patients were analyzed. 226 patients were treated with<br />
cisplatin-pemetrexed and 126 with cisplatin-raltitrexed. The Odds Ratios and 95%<br />
Confidence Interval (95% CI) <strong>of</strong> 10, 15, and 20 months survival rate and response rate<br />
were 1.204 (95% CI 0.646-2.244, p = 0.559), 1.022 (95% CI 0.492-2.123, p = 0.953),<br />
1.127 (95% CI 0.437-2.907, p = 0.805) and 0.559 (95% CI 0.258-1.212, p = 0.141),<br />
respectively. An absolute increased risk <strong>of</strong> grade III-IV side effects was observed for<br />
cisplatin-pemetrexed: 5.8% (95% CI 2.6%-9%, p < 0.001), 9% (95% CI 2.3%-15.7%,<br />
p = 0.008) and 2.8% (95% CI 0.2%-5.4%, p = 0.035) for overall toxicity, hematological<br />
toxicity and non-hematological toxicity, respectively.<br />
Conclusions: Cisplatin-pemetrexed and cisplatin-raltitrexed can be considered<br />
comparable in terms <strong>of</strong> efficacy in the treatment <strong>of</strong> metastatic pleural mesothelioma,<br />
with a modest increased risk <strong>of</strong> grade III-IV side effects for cisplatin-pemetrexed. The<br />
comparability in terms <strong>of</strong> efficacy and safety <strong>of</strong> the two schedules may support<br />
clinicians in decision making at the time <strong>of</strong> planning strategies against metastatic<br />
pleural mesothelioma.<br />
Legal entity responsible for the study: N/A<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1518P<br />
abstracts<br />
Malignant pleural effusion (MPE) characterized with<br />
11C-Methionine PET/CT before and after talc pleurodesis:<br />
interim evaluation <strong>of</strong> a prospective clinical trial<br />
E. Lopci 1 , P. Zucali 2 , G. Ceresoli 3 , A. Testori 2 , E. Voulaz 4 , K. Marzo 1 , L. Leonardi 1 ,<br />
M. Rodari 1 , L. Olivari 1 , G. Ferraroli 4 , E. Bottoni 4 , M. Perrino 2 , A. Crepaldi 4 ,<br />
A. Galeassi 5 , L. Gurrieri 5 , G. Veronesi 4 , M. Alloisio 4 , A. Santoro 2 , A. Chiti 1<br />
1 Nuclear Medicine, Humanitas Research Hospital, Milan, Italy, 2 Medical <strong>Oncology</strong>,<br />
Humanitas Research Hospital, Milan, Italy, 3 Medical <strong>Oncology</strong>, Humanitas<br />
Gavazzeni, Bergamo, Italy, 4 Surgical <strong>Oncology</strong>, Humanitas Research Hospital,<br />
Milan, Italy, 5 Medical <strong>Oncology</strong>, Humanitas Mater Domini, Castellanza, Italy<br />
Background: Malignant pleural effusion (MPE) is one the most frequent signs <strong>of</strong><br />
mesothelioma presentation. 18F-FDG PET/CT has proved to be useful in detecting pleural<br />
lesions, although unreliable results have been reported in patients receiving talc pleurodesis<br />
due to induced inflammatory reaction. In this study we aimed to define the role <strong>of</strong><br />
11C-methionine PET/CT in the characterization <strong>of</strong> MPE before and after talc pleurodesis.<br />
Methods: From September 2014 to February 2016 30 consecutive patients referred to<br />
our Institution for MPE were prospectively enrolled. Patients were evaluated at baseline<br />
and after pleurodesis with two consecutive PET investigations: 11C-methionine<br />
(experimental) and 18F-FDG (standard). Semi-quantitative PET parameters were<br />
defined for both examinations: i.e. SUVmax, SUVmean, metabolic tumor volume<br />
(MTV) and metabolic tumor burden (MTB = MTVxSUVmean), and statistically<br />
compared to pathological findings at videothoracoscopy.<br />
Results: The interim analysis was completed in 15 patients (M:F = 13:2; mean age 73<br />
years) affected by malignant mesothelioma (12 epithelioid, 3 non-epithelioid). All<br />
tumors showed increased uptake <strong>of</strong> 11C-methionine at baseline: median SUVmax,<br />
SUVmean, MTV and MTB were 4.7 (range 3-10.1), 2.8 (range 1.5-4.6), 19.5 (range<br />
0.9-464.3) and 45.2 (range 2-2052.2), respectively. MTV and MTB were significantly<br />
higher in non-epithelioid tumors compared to other histotype (p = 0.022 and 0.03,<br />
respectively). For 11C-methionine PET the median percentage <strong>of</strong> variation before and<br />
after talc pleurodesis was 12.8 for SUVmax (%ΔSUV) and 29.9 for MTB (%ΔMTB).<br />
Compared to 18F-FDG, the percentage <strong>of</strong> variation for MTB resulted significantly<br />
lower for 11C-methionine (p < 0.001), but not for SUVmax. Interestingly, there was an<br />
inverse linear correlation between MTV for 18F-FDG PET at baseline and %ΔSUV or<br />
%ΔMTB after pleurodesis (p < 0.01), whereas for 11C-methionine only for%ΔSUV.<br />
Conclusions: 11C-methionine PET/CT appears able to characterise malignant pleural<br />
effusion. This preliminary analyses shows that it might be less influenced by<br />
inflammatory reaction related to talc pleurodesis compared to 18F-FDG.<br />
Clinical trial identification: NCT02519049<br />
Legal entity responsible for the study: IRCCS Istituto Clinico Humanitas -<br />
Humanitas Mirasole SPA<br />
Funding: IRCCS Istituto Clinico Humanitas - Humanitas Mirasole SPA<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw391 | vi525
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong> 27 (Supplement 6): vi526–vi544, 2016<br />
doi:10.1093/annonc/mdw392<br />
translational research<br />
1520O<br />
Lurbinectedin (PM01183) exhibits antitumor activity in<br />
PARP-inhibitor resistant germline BRCA PDX and lacks<br />
cross-resistance with cisplatin<br />
1519O<br />
Availability <strong>of</strong> tumour gene expression data facilitates clinical<br />
decision-making for patients with advanced cancers<br />
J. Laskin 1 ,C.Ho 1 , Y. Shen 2 , M. Jones 3 , K.A. Gelmon 1 , H. Lim 1 , D.J. Renouf 1 ,<br />
S. Yip 4 , A. Tinker 1 , K. Khoo 5 , C. Lohrisch 1 , S. Chia 1 , B. Deol 1 , K. Schrader 6 ,<br />
Y. Ma 3 , R. Moore 3 , A. Mungall 3 , S. Jones 3 , M. Marra 3<br />
1 Medical <strong>Oncology</strong>, British Columbia Cancer Agency, Vancouver, BC, Canada,<br />
2 Canada’s Michael Smith Genome Sciences Centre, British Columbia Cancer<br />
Agency, Vancouver, BC, Canada, 3 Canada’s Michael Smith Genome Sciences<br />
Centre, British Columbia Cancer Agency, Vancouver, BC, Canada, 4 Pathology,<br />
BC Cancer Agency, Vancouver General Hospital University <strong>of</strong> British Columbia,<br />
Vancouver, BC, Canada, 5 Medical <strong>Oncology</strong>, BC Cancer Agency, Kelowna, BC,<br />
Canada, 6 Hereditary Cancer Program, British Columbia Cancer Agency,<br />
Vancouver, BC, Canada<br />
C. Cruz 1 , G. Caratu 2 , A. Llop-Guevara 3 , M. Castroviejo 3 , S. Gutierrez-Enriquez 4 ,<br />
B. Morancho 5 , E. Álvarez de la Campa 6 , L. Prudkin 7 , P. Nuciforo 7 , J. Arribas 5 ,<br />
A. Vivancos 2 , X. de la Cruz 6 , C. Galmarini 8 , P.M. Avilés 9 , C. Saura 1 , O. Díez 4 ,<br />
V. Serra 3 , J. Balmaña 1<br />
1 Medical <strong>Oncology</strong>, Hospital Vall d’Hebron and Vall d’Hebron Institute <strong>of</strong><br />
<strong>Oncology</strong>, Barcelona, Spain, 2 Cancer Genomics Group, Vall d’Hebron Institute <strong>of</strong><br />
<strong>Oncology</strong>, Barcelona, Spain, 3 Experimental Therapeutics Group, Vall d’Hebron<br />
Institute <strong>of</strong> <strong>Oncology</strong>, Barcelona, Spain, 4 Oncogenetics Group, Vall d’Hebron<br />
Institute <strong>of</strong> <strong>Oncology</strong>, Barcelona, Spain, 5 Growth Factors Laboratory, Vall<br />
d’Hebron Institute <strong>of</strong> <strong>Oncology</strong>, Barcelona, Spain, 6 Translational Bioinformatics<br />
and Computational Biology, Vall d’Hebron Institute <strong>of</strong> Research, Barcelona, Spain,<br />
7 Molecular <strong>Oncology</strong> Group, Vall d’Hebron Institute <strong>of</strong> <strong>Oncology</strong>, Barcelona,<br />
Spain, 8 Cell Biology and Pharmacogenomics, PharmaMar S.A., Madrid, Spain,<br />
9 Non Clinical Toxicology and Pharmacology, PharmaMar S.A., Madrid, Spain<br />
abstracts<br />
1521PD<br />
Clinical evaluation <strong>of</strong> the utility <strong>of</strong> a liquid biopsy (circulating<br />
tumoral cells and ctDNA) to determine the mutational<br />
pr<strong>of</strong>ile (EGFR, KRAS, ALK, ROS1 and BRAF) in advanced<br />
NSCLC patients<br />
L. Barrera 1 , E. Montes-Servin 2 , J.R. Borbolla 3 , L. Arnold 4 , J. Poole 4 , V. Alexiadis 4 ,<br />
V. Singh 5 , B. Gustafson 6 , O. Arrieta 2<br />
1 Onoclogy Business Unit, AstraZeneca, Mexico City, Mexico, 2 Clinical Research,<br />
Instituto Nacional de Cancerologia (INCan), Mexico City, Mexico, 3 Medical Affairs,<br />
AstraZeneca, Luton, UK, 4 Research & Development, Biocept, Inc, San Diego, CA,<br />
USA, 5 Medical Affairs, Biocept, Inc, San Diego, CA, USA, 6 Business Development,<br />
Biocept, Inc, San Diego, CA, USA<br />
Background: Circulating tumor DNA (ctDNA) has emerged as a specific and sensitive<br />
blood-based biomarker for detection <strong>of</strong> several mutations in non–small-cell lung<br />
cancer (NSCLC). Other clinical applications include serial monitoring <strong>of</strong> biomarker<br />
status or the development <strong>of</strong> resistance mutations.<br />
Methods: Forty patients with advanced NSCLC who either had a new diagnosis (group<br />
1) or had developed acquired resistance to an EGFR kinase inhibitor (group 2) were<br />
analyzed with the highly sensitive Biocept, Inc Target-Selector TM Real-Time PCR<br />
based plasma assays genotyping for the detection <strong>of</strong> EGFR mutations L858R, Del19<br />
© European Society for Medical <strong>Oncology</strong> 2016. Published by Oxford University Press on behalf <strong>of</strong> the European Society for Medical <strong>Oncology</strong>.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com.
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
and T790M. In addition, group 1 patients were analyzed for KRAS and BRAF<br />
mutations with the same methodology; ROS1 and ALK were analyzed by FISH on<br />
captured circulating tumor cells (CTCs) with the same platform before and after TKI<br />
treatment. Tumor tissue was analyzed with Real-Time PCR and FISH based assays.<br />
Results: Results showed up to 90% concordance rate <strong>of</strong> EGFR, KRAS and ALK<br />
alterations for between the tissue and blood samples. The T790M mutation appeared in<br />
50% <strong>of</strong> plasma samples analyzed in patients with clinical progression after TKI<br />
inhibitors. Group 1 paired analysis <strong>of</strong> mutations status monitoring (P= 0.016) showed<br />
that the pattern <strong>of</strong> mutant ctDNA and CTCs changed in response to systemic therapy<br />
in 83% <strong>of</strong> the cases (partial response or disease progression; R 2 = 0.808). ctDNA<br />
analysis <strong>of</strong> multiple mutations on group 1 showed: 1) 40% <strong>of</strong> patients had at least one<br />
or more new mutation different than the one detected in tissue biopsy; 2) 28% <strong>of</strong> EGFR<br />
tissue positive patients also had a KRAS mutation: 3) 75% <strong>of</strong> KRAS positive patients<br />
had a BRAF mutation. This technique may be sensitive enough to detect mutations<br />
missed by standard tissue genotyping probably due to tissue heterogeneity.<br />
Conclusions: Target-Selector TM ctDNA and CTC assays appear capable <strong>of</strong> rapidly<br />
detecting EGFR and KRAS mutations as well as ALK rearrangements. It is highly<br />
concordant with mutations present in tumor tissue. It would seem to be a viable<br />
alternative to identify secondary EGFR mutations such as T790M.<br />
Legal entity responsible for the study: National Cancer Institute. Mexico<br />
Funding: Biocept, Inc.<br />
Disclosure: L. Barrera, J.R. Borbolla: AstraZeneca full-time employee L. Arnold,<br />
J. Poole, V. Alexiadis, B. Gustafson, V. Singh: Biocept, Inc. full-time employee. All<br />
other authors have declared no conflicts <strong>of</strong> interest.<br />
1522P<br />
Mouse clinical trials <strong>of</strong> pancreatic cancer: Integration <strong>of</strong> PDX<br />
models with genomics to improve patient outcomes to<br />
chemotherapeutics<br />
A. Davies 1 , M. Hidalgo 2 , J. Stebbing 3 , D. Ciznadija 4 , A. Katz 4 , D. Sidransky 5<br />
1 Medical Affairs, Champions <strong>Oncology</strong>, Hackensack, NJ, USA, 2 CIOCC, Hospital<br />
Madrid Norte San Chinarro Centro Integral Oncologico Clara Campal, Madrid,<br />
Spain, 3 Surgery and Cancer, Imperial College London - Hammersmith Hospital,<br />
London, UK, 4 Translational <strong>Oncology</strong>, Champions <strong>Oncology</strong>, Hackensack, NJ,<br />
USA, 5 Medicine, Johns Hopkins Hospital, Baltimore, MD, USA<br />
Background: Although a number <strong>of</strong> treatments are available for pancreatic cancer,<br />
these are <strong>of</strong>ten administered in prescribed sequences, which may not represent the<br />
optimal therapeutic strategy. Technologies enabling multiple regimens to be evaluated<br />
simultaneously to identify beneficial therapies are needed. Drug screening in<br />
patient-derived xenografts (PDXs) is a potential solution. We examined whether<br />
pancreatic PDXs capture patient responses to different drugs and report performance<br />
metrics highlighting clinical utility.<br />
Methods: Pancreatic tumors from 94 patients were engrafted into immunodeficient<br />
mice to generate PDX models. Of these, 19 models were sequenced to identify key<br />
genomic alterations with therapeutic implications. Sensitivity to different therapeutics<br />
was evaluated and effects on tumor growth aligned to clinical RECIST criteria. A total<br />
<strong>of</strong> 16 PDX screening outcomes were correlated with individual clinical responses and<br />
statistical parameters such as sensitivity, specificity, and predictive values calculated.<br />
Results: Of the 94 implanted pancreatic tumors, 82 have completed the implantation<br />
process, with 72 (88%) successfully engrafting. Sequencing revealed alterations in 451<br />
common genes, including those informing treatment choices such as EGFR, KRAS,<br />
and BRCA 1/2. PDX models from 39 patients were screened in 144 drug tests<br />
employing 56 FDA-approved therapies and 9 experimental agents. In 14/16 (88%)<br />
cases with available data, a correlation between clinical and PDX outcomes was noted<br />
and from this cohort we calculated positive and negative predictive values <strong>of</strong> 82% and<br />
100% respectively.<br />
Conclusions: Using a small cohort, we showed drug responses in pancreatic PDX<br />
model correlate with clinical outcomes to the same therapy. Application <strong>of</strong> such<br />
models to guide treatment decisions for pancreatic cancer patients may help lead to<br />
better outcomes. Moreover, given the clinical relevance <strong>of</strong> these models, they could also<br />
be deployed as real-time patient surrogates during drug development and clinical trials,<br />
permitting real-time analysis <strong>of</strong> treatment responses and identification <strong>of</strong> biomarkers<br />
that predict different therapeutic outcomes.<br />
Legal entity responsible for the study: N/A<br />
Funding: Champions <strong>Oncology</strong><br />
Disclosure: A. Davies, D. Ciznadija: Employee <strong>of</strong> Champions <strong>Oncology</strong> Stockholder in<br />
Champions <strong>Oncology</strong>. M. Hidalgo, J. Stebbing: Advisory board for Champions<br />
<strong>Oncology</strong>. A. Katz: Employee <strong>of</strong> Champions <strong>Oncology</strong> Stockholder <strong>of</strong> Champions<br />
<strong>Oncology</strong>. D. Sidransky: Chairman <strong>of</strong> Board for Champions <strong>Oncology</strong> Stockholder in<br />
Champions <strong>Oncology</strong>.<br />
1523P<br />
Using mouse and human pancreatic organoids to infer<br />
resistance to targeted therapy<br />
M. Ponz-Sarvise 1 , V. Corbo 2 , K. Frese 3 , H. Tiriac 2 , D. Engle 2 , D. Filipini 2 ,<br />
K. Wright 2 ,Y.Park 2 ,K.Yu 2 , Ö. Daniel 2 , D. Tuveson 2<br />
1 Medical <strong>Oncology</strong>, Clinica Universitaria de Navarra, Pamplona, Spain, 2 Tuveson<br />
Lab, CSHL, Cold Spring Harbor, NY, USA, 3 Tuveson Lab, CRUK/MRC Oxford<br />
Institute for Radiation <strong>Oncology</strong>, Oxford, UK<br />
Background: Pancreatic ductal adenocarcinoma (PDA) is a lethal disease with a 5-year<br />
survival rate less than 6%. Novel models <strong>of</strong> PDA able <strong>of</strong> predicting resistance/<br />
sensitivity to treatment are needed. Our lab has developed a 3D culture system that<br />
enables the growth, as organoids, <strong>of</strong> both mouse and human pancreatic ducts. These<br />
organoids can be established either from healthy or neoplastic tissues, providing a<br />
platform for the therapeutics.<br />
Methods: We used the organoids to evaluate the therapeutic efficacy <strong>of</strong> the<br />
simultaneous inhibition <strong>of</strong> the kinases MEK1/2 and AKTs. Toxicity was assessed in<br />
vitro by measuring ATP content in mouse and human organoids treated with single<br />
agents or combination for 72hrs. Genetically engineered mice developing pancreatic<br />
cancer (KPC) were used for the in vivo study.KPC were randomly assigned to different<br />
treatment arms and then treated.<br />
Results: The dual inhibition <strong>of</strong> MEK1/2 and AKTs, combined with the cytotoxic drug<br />
gemcitabine, provided the longest extension in median survival, but without preventing<br />
mice to succumb <strong>of</strong> their disease. Tumor-derived organoids were highly resistant to<br />
both single agents and combination. To assess the potential mechanism <strong>of</strong> resistance<br />
we evaluated the activation <strong>of</strong> a number <strong>of</strong> receptor tyrosine kinases (RTKs) by<br />
interrogating KPC treated tissues. Members <strong>of</strong> the ERBB family were activated in mice<br />
treated with the combination compared to those treated with gemcitabine only.<br />
Accordingly, we analyzed the expression and activation <strong>of</strong> several RTKs, including the<br />
ERBB family, at baseline and after treatment in both mouse and human organoids.<br />
Dual inhibition <strong>of</strong> MEK1/2 and AKTs induced changes in the expression <strong>of</strong> ERBB<br />
receptors and ligands in both normal and tumor-derived organoids. However, only<br />
tumor organoids showed a significant increase in the expression and activation <strong>of</strong><br />
receptors upon treatment that was accompanied by the re-activation <strong>of</strong> ERK and AKT.<br />
Accordingly, the addition <strong>of</strong> an irreversible pan-ERBB inhibitor to the combination <strong>of</strong><br />
MEK1/2 and AKTs prevented the rewiring <strong>of</strong> the pathways and improved tumor<br />
sensitivity.<br />
Conclusions: Pancreatic organoids represent a system that can be used to predict drug<br />
sensitivity as well as to identify mechanism <strong>of</strong> resistance.<br />
Legal entity responsible for the study: Cold Spring Harbor Laboratory<br />
Funding: Lustgarten Foundation<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1524P<br />
abstracts<br />
Generation and characterization <strong>of</strong> a collection <strong>of</strong><br />
patient-derived xenografts (PDX) models for translational<br />
lung cancer research<br />
S. Molina-Pinelo 1 , R. Meléndez 2 , R. Suarez 1 , L. García 1 , L. Ojeda 1 , P. Yague 1 ,<br />
L. Paz-Ares 3 , I. Ferrer 1<br />
1 H12O-CNIO Lung Cancer Clinical Research Unit, University Hospital 12 De<br />
Octubre, Madrid, Spain, 2 Instituto de Biomedicina de Sevilla, Hospital Universitario<br />
Virgen del Rocio, Seville, Spain, 3 Medical <strong>Oncology</strong>, Hospital Universitario Doce de<br />
Octubre, Madrid, Spain<br />
Background: The use <strong>of</strong> good preclinical models is essential in translational cancer<br />
research. An appropriate preclinical model must be useful for drug screening,<br />
biomarker discovery and preclinical evaluation <strong>of</strong> precision therapeutic strategies.<br />
Conventional available preclinical models are not optimal to this end. Xenografts from<br />
cell lines do not reconstitute the architecture and environment <strong>of</strong> human cancer and<br />
acquire mutations not found in the original tumor. Our aim is to generate and<br />
characterize a collection <strong>of</strong> PDX models for translational lung cancer research by<br />
implantation <strong>of</strong> lung primary human tumors in mice. Mainly, this collection will be<br />
used for biomarker identification and preclinical evaluation <strong>of</strong> new therapeutic<br />
strategies targeted to bad prognostic lung tumors with suboptimal therapeutic<br />
approaches.<br />
Methods: Resected NSCLC from patients were subcutaneous xenografted and<br />
expanded in successive groups <strong>of</strong> nude mice to get a perpetual live bank <strong>of</strong> each tumor.<br />
Every tumor, which successfully grew in mice, was used to analyze the exome and<br />
transcriptome by NGS techniques. Furthermore, a bank <strong>of</strong> frozen pieces <strong>of</strong> tumor was<br />
stored in order to generate later cohorts <strong>of</strong> tumor-bearing mice suitable for preclinical<br />
drug evaluation and biomarker identification.<br />
Results: We have characterized 32 different PDX models at the genomic and<br />
transcriptomic level: 20 SCC, 10 ADC and 2 LCC. The PDX models mostly retain the<br />
principal histologic and molecular characteristics <strong>of</strong> their donors and recapitulate the<br />
heterogeneity <strong>of</strong> human lung tumors. In our PDX collection we have sufficiently<br />
represented all the NSCLC histology and the most relevant molecular alterations in<br />
lung cancer in order to perform precision medicine evaluation studies.<br />
Conclusions: We have generated and characterize a collection <strong>of</strong> PDX models <strong>of</strong><br />
NSCLC, which represents the most frequent histological and molecular subtypes <strong>of</strong> this<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw392 | vi527
abstracts<br />
type <strong>of</strong> LC. This collection will be really useful to integrate drug screening with<br />
biomarker discovery and to evaluate precision therapeutic strategies preclinically. Our<br />
future aim will be to use this collection in order to identify new effective therapeutic<br />
strategies targeted to bad prognostic subtypes <strong>of</strong> lung cancer.<br />
Legal entity responsible for the study: IF is funded by Fundacion AECC and<br />
Consejería de Salud de la Junta de Andalucía (PI-0029-2013). SMP is funded by<br />
Consejería de Salud y Bienestar Social (PI-0046-2012), and Fundación Mutua<br />
Madrileña (2014). LPA is funded by Fondo de Investigación Sanitaria (1401964) and<br />
RTICC (R12/0036/0028).<br />
Funding: None<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1525P<br />
Prevalence and clinical associations <strong>of</strong> PTEN loss in<br />
non-small cell lung carcinoma (NSCLC) patients (pts) <strong>of</strong> the<br />
European Thoracic <strong>Oncology</strong> Platform (ETOP) Lungscape<br />
cohort<br />
A. Soltermann 1 , U. Rulle 1 , O. Dafni 2 , E. Verbeken 3 , E. Thunnissen 4 , A. Warth 5 ,<br />
R. Cheney 6 , A. Sejda 7 , E-J. Speel 8 , L. Bille Madsen 9 , D. Nonaka 10 , A. Navarro 11 ,<br />
I. Sansano 12 , A. Marchetti 13 , S. Finn 14 , R. Kammler 15 , K. Schulze 16 ,<br />
L. Bubendorf 17 , R.A. Stahel 18 , O.B.O. Lungscape 19<br />
1 Pathology, Universitätsspital Zürich, Zurich, Switzerland, 2 Biostatistics, Frontier<br />
Science Foundation – Hellas, Athens, Greece, 3 Pathology, University Hospitals<br />
Leuven - Campus Gasthuisberg, Leuven, Belgium, 4 Pathology, Vrije University<br />
Medical Centre (VUMC), Amsterdam, Netherlands, 5 Pathology, University Hospital<br />
Heidelberg, Heidelberg, Germany, 6 Pathology and Laboratory Medicine, Roswell<br />
Park Cancer Institute, Buffalo, NY, USA, 7 Pathology, Medical University <strong>of</strong> Gdansk,<br />
Gdansk, Poland, 8 Pathology, Maastricht University Medical Center (MUMC),<br />
Maastricht, Netherlands, 9 Pathology, Aarhus University Hospital, Aarhus,<br />
Denmark, 10 Pathology, The Christie NHS Foundation Trust, Manchester, UK,<br />
11 Pathology, Hospital General Universitario Valencia, Valencia, Spain, 12 Pathology,<br />
Vall d’Hebron University Hospital Institut d’Oncologia, Barcelona, Spain,<br />
13 Pathology, Ospedale Clinicizzato, Chieti, Italy, 14 Cancer Molecular Diagnostics,<br />
St James’s Hospital, Dublin, Ireland, 15 Translational Research Coordination,<br />
European Thoracic Oncolocy Platform, Bern, Switzerland, 16 <strong>Oncology</strong> Biomarker<br />
Development, Genentech, San Francisco, CA, USA, 17 Institute for Pathology,<br />
Universitätsspital Basel, Basel, Switzerland, 18 Clinik and Policlinic <strong>of</strong> <strong>Oncology</strong>,<br />
Universitätsspital Zürich, Zurich, Switzerland, 19 K. Monkhorst, The Netherlands<br />
Cancer Institute Amsterdam; K.M. Kerr, Royal Infirmary Aberdeen; S. Peters,<br />
European Thoracic Oncolocy Platform, Bern, Switzerland<br />
Background: Loss <strong>of</strong> PTEN might be a prognostic biomarker in NSCLC.<br />
Methods: We explored the prevalence <strong>of</strong> PTEN loss and its association with<br />
clinico-pathologic parameters as well as patient outcome (overall survival (OS),<br />
relapse-free survival (RFS) and time to relapse (TTR)) in the ETOP Lungscape cohort<br />
<strong>of</strong> resected stages I–III NSCLC. Tumor tissue was assessed for PTEN protein<br />
expression using immunohistochemistry on tissue microarrays. All cases were locally<br />
H-scored by ETOP pathologists, after having passed a stringent External Quality<br />
Assessment, and were centrally analyzed with pixel-based Image-J computer analysis.<br />
PTEN loss was defined as H-score = 0.<br />
Results: PTEN expression in tumor tissue was evaluable in 2245 pts from 16 ETOP<br />
Lungscape centers with the following characteristics: median follow-up 4.8 years;<br />
54.3% <strong>of</strong> pts still alive; median age 66.4 years; 65.9% male; 10.6%, 53.9% and 31.5%<br />
never, former and current smokers, respectively, and 4.1% with unknown smoking<br />
status. Stage distribution was: IA 22.4%, IB 25.9%, IIA 16.8%, IIB 12.2%, IIIA 20.8%,<br />
IIIB 1.9%. Histology was 48.7 % adenocarcinoma (AC), 43.8% squamous cell<br />
carcinoma (SCC), 4.4% large cell, 3.2% other types. PTEN loss was detected in 981 pts<br />
(43.7%; 95% confidence interval (CI): 41.6%-45.8%) and was significantly associated<br />
with male sex (47.2% in men versus 36.9% in women; p < 0.001), smoking history<br />
(24.5% in never smokers versus 46.5% in current/former smokers, p < 0.001), histology<br />
(37.4% in AC versus 51.2% in SCC; p < 0.001), stage (40.4%, 45.5%, 48.3% for stage I,<br />
II, III; p = 0.007), tumor size (median 4.0 cm with versus 3.4 cm without loss,<br />
p < 0.001). For outcome, PTEN loss was significantly associated with poor OS and RFS<br />
for AC (HR = 1.20; 95% CI: 1.01-1.42) but not for SCC (adjusted interaction p = 0.022).<br />
High sensitivity and specificity was found when comparing the pathologists’ scores<br />
with the computer-based ones under various cut-<strong>of</strong>fs.<br />
Conclusions: In this large cohort <strong>of</strong> resected NSCLC, PTEN loss was present in half <strong>of</strong><br />
the SCC and in one third <strong>of</strong> AC, and associated with poorer pts’ prognosis in the latter.<br />
Computerized immunoreactivity measurements are a promising alternative to<br />
pathologists’ scorings.<br />
Clinical trial identification: ETOP Lungscape 002 PTEN<br />
Legal entity responsible for the study: European Thoracic <strong>Oncology</strong> Platform (ETOP)<br />
Funding: Genentech Inc.<br />
Disclosure: K. Schulze: Employee <strong>of</strong> Genentech Inc. 1 DNA Way, South San Francisco,<br />
CA 94080. All other authors have declared no conflicts <strong>of</strong> interest.<br />
1526P<br />
Biomarker driven combinations for synthetic lethal<br />
approaches in KRAS mutant (KRASm) lung adenocarcinoma<br />
(LAC)<br />
C. Lazzari 1 , A. Verlicchi 2 , C. Codony Servat 3 , J. Codony Servat 3 , M.A. Molina Vila 3 ,<br />
I. Chaib 4 , J.L. Ramírez Serrano 5 , N. Karachaliou 6 , F. de Marinis 1 , R. Rosell 5<br />
1 Divisione di Oncologica Toracica, Istituto Europeo di Oncologia, Milan, Italy,<br />
2 Dipartimento di Oncologia/Ematologia, Ospedale Civile di Ravenna - S.ta Maria<br />
delle Croci, Ravenna, Italy, 3 Laboratory <strong>of</strong> Cellular and Molecular Biology, Pangaea<br />
Biotech SL, IOR Quirón-Dexeus University Institute, Barcelona, Spain, 4 Laboratory<br />
<strong>of</strong> Cellular and Molecular Biology, Institut d’Investigació en Ciències Germans Trias<br />
i Pujol, Badalona, Spain, 5 Translational Research Unit, Laboratory <strong>of</strong> Molecular<br />
Biology, Catalan Institute <strong>of</strong> <strong>Oncology</strong> (ICO Badalona), Hospital Germans Trias i<br />
Pujol, Badalona, Spain, 6 Medical <strong>Oncology</strong> Service, Instituto Oncológico Dr Rosell<br />
(IOR), Hospital Universitario Quirón-Dexeus, Barcelona, Spain<br />
Background: MEK inhibition is interesting but still has modest efficacy in KRASm<br />
LAC patients. STAT3 activation and AXL mediated epithelial-to-mesenchymal<br />
transition cause resistance to MEK inhibition. p21-activated kinase 1 (PAK1) regulates<br />
ERK activation and its role in KRASm LAC warrants further investigation. YAP1<br />
suppression increases trametinib efficacy in KRASm LAC cells. We have explored the<br />
role <strong>of</strong> STAT3, AXL, PAK1 and YAP1 in KRASm LAC cells and developed a rationale<br />
for combinatorial strategies.<br />
Methods: Quantitative real-time PCR gene expression analysis was performed in 4<br />
KRASm LAC cell lines (H23, A549, H460 and Calu6). The MEK inhibitor (i)<br />
selumetinib was combined with evodiamine (STAT3i), R428 (AXLi) or ivermectin<br />
(dual YAP1-PAK1i). Cell viability was assessed by the thiazolyl blue assay and the<br />
combination index (CI) was calculated for the analysis <strong>of</strong> drug interactions.<br />
Results: We first evaluated the effect <strong>of</strong> selumetinib in the 4 KRASm LAC cell lines.<br />
H23 and H460 were less sensitive to selumetinib than A549 and Calu6. Among the cell<br />
lines examined, H23 cells had the highest STAT3 mRNA expression and the<br />
combination <strong>of</strong> selumetinib with evodiamine synergistically suppressed cell viability<br />
(CI = 0.8). The combination <strong>of</strong> R428 with selumetinib was also synergistic in H23 cells<br />
(CI = 0.58) that have moderate AXL mRNA expression. High PAK1 mRNA expression<br />
was detected in the A549 selumetinib-sensitive cell line, and the addition <strong>of</strong> the dual<br />
PAK1-YAP1i, ivermectin, to selumetinib increased the effect <strong>of</strong> MEK inhibition alone<br />
(CI = 0.17). To our surprise, the combination <strong>of</strong> ivermectin with selumetinib was not<br />
synergistic in the H23 cells that overexpress YAP1. H460 and Calu-6 cells have<br />
moderate or low STAT3, AXL, PAK1 and YAP1 expression. Further cell viability<br />
experiments as well as immunoblotting and biomarkers analysis in clinical tumor<br />
samples are ongoing.<br />
Conclusions: The heterogeneous biology <strong>of</strong> KRASm LAC may partially explain the<br />
difficulties encountered in the development <strong>of</strong> efficient therapies. Our data, until now,<br />
identify STAT3, AXL and PAK1 as potential biomarkers and the targeting <strong>of</strong> them as a<br />
potential synergistic strategy to combine with MEK inhibition.<br />
Legal entity responsible for the study: N/A<br />
Funding: This work was supported by grants from the La Caixa Foundation and Red<br />
Tematica de Investigacion Cooperativa en Cancer (RTICC; grant RD12/0036/ 0072).<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1527P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Differential expression pr<strong>of</strong>ile <strong>of</strong> lung squamous cell<br />
carcinoma (LSCC) and druggable targets to be combined with<br />
necitumumab (N)<br />
A. Verlicchi 1 , C. Lazzari 2 , C. Codony Servat 3 , M.A. Molina Vila 3 , J. Codony Servat 3 ,<br />
I. Chaib 4 , J.L. Ramírez Serrano 5 , N. Karachaliou 6 , C. Dazzi 1 , R. Rosell 5<br />
1 Dipartimento di Oncologia/Ematologia, Ospedale Civile di Ravenna - S.ta Maria<br />
delle Croci, Ravenna, Italy, 2 Divisione di Oncologica Toracica, Istituto Europeo di<br />
Oncologia, Milan, Italy, 3 Laboratory <strong>of</strong> Cellular and Molecular Biology, Pangaea<br />
Biotech SL, IOR Quirón-Dexeus University Institute, Barcelona, Spain, 4 Laboratory<br />
<strong>of</strong> Cellular and Molecular Biology, Institut d’Investigació en Ciències Germans Trias<br />
i Pujol, Badalona, Spain, 5 Translational Research Unit, Laboratory <strong>of</strong> Molecular<br />
Biology, Catalan Institute <strong>of</strong> <strong>Oncology</strong> (ICO Badalona), Hospital Germans Trias i<br />
Pujol, Badalona, Spain, 6 Medical <strong>Oncology</strong> Service, Instituto Oncológico Dr Rosell<br />
(IOR), Hospital Universitario Quirón-Dexeus, Barcelona, Spain<br />
Background: LSCC lacks effective targeted therapies. EGFR is commonly expressed in<br />
LSCC and N, an anti-EGFR monoclonal antibody (mAb), is the only approved targeted<br />
therapy that with chemotherapy provides a small (clinically irrelevant) survival benefit<br />
as 1st-line treatment in metastatic LSCC. AXL, STAT3 or YAP1 pathway activation,<br />
and hedgehog-GLI signaling have been described as mechanisms <strong>of</strong> resistance to<br />
anti-EGFR therapy. p21-activated kinase 1 (PAK1) is overexpressed in LSCC,<br />
diminishing the efficacy <strong>of</strong> anti-EGFR mAbs. Herein, we evaluate the relevance <strong>of</strong> these<br />
pathways in LSCC cell lines, illustrating the potential for synthetic lethal approaches.<br />
Methods: AXL (and its ligand GAS6), STAT3, YAP1, GLI1/2 and PAK1 mRNA<br />
expression were examined by quantitative real-time PCR in 6 LSCC cell lines: H2286,<br />
HCC366, H520, H1703, SK-MES1, and EBC1. Cell viability was assessed by the<br />
thiazolyl blue assay after treatment with evodiamine (STAT3i), R428 (AXLi),<br />
vi528 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
ivermectin (dual YAP1-PAK1i) or GANT61 and mebendazole (GLIi) alone or in<br />
combination with 25ug/ml <strong>of</strong> N.<br />
Results: EGFR was homogeneously overexpressed in all tested cell lines except H520<br />
that lacks EGFR expression. Moderate STAT3 mRNA expression was detected in<br />
SK-MES1 cells in which treatment with evodiamine synergistically increased the effect<br />
<strong>of</strong> N alone. The dual YAP1-PAK1i, ivermectin was more active (IC50 3-7uM) in the<br />
H1703 and H2286 YAP1 overexpressing cells in comparison with the rest <strong>of</strong> YAP1 low<br />
expressing cells. No correlation was found between PAK1 expression and sensitivity to<br />
ivermectin in the tested LSCC cell lines. High GLI1/2 expression and relative sensitivity<br />
to the GLI1/2i, GANT61 or mebendazole (IC50 2-3uM) were detected in the H2286<br />
cells. Among our LSCC cell lines, H2286 also had the highest AXL and GAS6 mRNA<br />
expression. Western blotting analysis, as well as further cell viability experiments with<br />
drugs alone and in combination with N, are ongoing.<br />
Conclusions: LSCC is a heterogeneous disease, in which common signaling pathways<br />
dictate distinct pathologic outputs. The awareness <strong>of</strong> these differences is necessary<br />
while planning efficient strategies to improve the scant clinical benefit with EGFR<br />
mAbs.<br />
Legal entity responsible for the study: N/A<br />
Funding: This work was supported by grants from the La Caixa Foundation and Red<br />
Tematica de Investigacion Cooperativa en Cancer (RTICC; grant RD12/0036/ 0072).<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1528P<br />
Repeated exposure to cisplatin enhances NK cell-mediated<br />
cytotoxicity via up-regulation <strong>of</strong> NKG2D ligands in non-small<br />
cell lung cancer cells<br />
R. Okita, Y. Nojima, A. Maeda, S. Saisho, K. Shimizu, M. Nakata<br />
General Thoracic Surgery, Kawasaki Medical School Hospital, Okayama, Japan<br />
Background: Cisplatin (CDDP) is one <strong>of</strong> the key drugs for non-small cell lung cancer<br />
(NSCLC) and CDDP-resistant mechanisms have been investigated, while the role <strong>of</strong><br />
immune cells on excluding CDDP-treated cancer cells is poorly understood. Here we<br />
demonstrate repeated exposure to CDDP enhances NK group 2 member D (NKG2D)<br />
ligands MHC class I-related chain A and B (MICA/B) and UL16 binding protein<br />
(ULBP)-2/5/6 in NSCLC cell lines while attenuates them in tumor tissue from patients<br />
with NSCLC.<br />
Methods: A549 cells were exposed to 10 µM <strong>of</strong> CDDP (A549-CR) at least thrice then<br />
possible influences <strong>of</strong> CDDP exposure on expressions <strong>of</strong> MICA/B and ULBP-2/5/6<br />
were investigated by flow cytometry. NK cell-mediated cytotoxicity against A549-CR<br />
cells was assessed by LDH release assay and compared with original A549 cells. The<br />
expressions <strong>of</strong> NKG2D ligands in tissue samples from NSCLC patients who received<br />
CDDP-base chemotherapy were also evaluated using immunohistochemical reactions.<br />
Results: Basal expression <strong>of</strong> MICA/B and ULBP-2/5/6 were clearly upregulated in<br />
A549-CR cells compared with original A549 cells. As expected, NK cell-mediated<br />
cytotoxicity was enhanced against A549-CR cells compared with A549 cells, and this<br />
enhancement depended on NKG2D-NKG2D ligands interaction. On the other hand,<br />
the expression <strong>of</strong> MICA/B and ULBP-2/5/6 were lower in residual tumor than in<br />
pre-treated samples from patients with NSCLC.<br />
Conclusions: Repeated CDDP exposure enhances the expression <strong>of</strong> NKG2D ligands in<br />
A549 cell line, resulted in enhanced NK cell-mediated cytotoxicity in vitro. On the<br />
other hand, repeated CDDP exposure attenuated the expression <strong>of</strong> NKG2D ligands in<br />
patients with NSCLC, suggested that the residual tumor was the result <strong>of</strong> tumor<br />
immunoescape from NK cells.<br />
Legal entity responsible for the study: Kawasaki Medical School<br />
Funding: This work was supported by the Japan Society for the Promotion <strong>of</strong> Science<br />
(JSPS) Kakenhi Grant (25462189) to R Okita. Dr. M Nakata received research funding<br />
from Kyowa Kirin for this study.<br />
Disclosure: M. Nakata: Research funding from Kyowa Kirin. All other authors have<br />
declared no conflicts <strong>of</strong> interest.<br />
1529P<br />
DLK1-DIO3 imprinted cluster in lung cancer<br />
A. Quintanal 1 , A. Salinas 2 , R. Suarez 1 , R. Meléndez 2 , A. Carnero 3 , L. Paz-Ares 1 ,<br />
S. Molina-Pinelo 1<br />
1 Medical <strong>Oncology</strong>, Hospital Universitario Doce de Octubre, Madrid, Spain,<br />
2 Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocio, Seville,<br />
Spain, 3 Molecular <strong>Oncology</strong> Laboratory, IBIS/CSIC/US, Seville, Spain<br />
small nucleolar RNAs (SNORD113 and SNORD114) and several pseudogenes.<br />
Aberrations involving some components <strong>of</strong> the DLK1-DIO3 cluster have been linked<br />
to pathological processes. The purpose <strong>of</strong> this study was to assess the role <strong>of</strong> the<br />
DLK1-DIO3 cluster in non-small cell lung cancer.<br />
Methods: DNA methylation <strong>of</strong> gene clusters was analyzed by Illumina in tumour and<br />
matched control (healthy) tissue from 47 patients with lung cancer. DNA was extracted<br />
using the QIAamp DNA Mini Kit. For each assay, 500 ng <strong>of</strong> DNA was treated with<br />
sodium bisulfate using EZ DNA Methylation Kit and cleaned with ZR-96 DNA<br />
Clean-up Kit, before standard Illumina amplification, hybridization, and imaging<br />
steps. Methylation data were processed using the RnBeads R package.<br />
Results: Patients with lung cancer showed three deregulated protein-coding genes: one<br />
was hypermethylated (DIO3) and two were hypomethylated (DLK1 and RTL1).<br />
Statistically significant differences (adjusted p-value < 0.05) were also detected in two<br />
different families <strong>of</strong> SNORDs (SNORD113 and SNORD114), with the exception <strong>of</strong><br />
SNORD114-30 that showed similar but non-significant pattern <strong>of</strong> DNA<br />
hypomethylation (p = 0.07. Similarly, two miRNA clusters and four lncRNAs (MEG3,<br />
MEG8, MEG9 and LINC00524) were found to be significantly less methylated in<br />
tumors as compared to non-tumoral tissue.<br />
Conclusions: Our results strongly imply that hypomethylation <strong>of</strong> this cluster may be a<br />
key target in unravelling <strong>of</strong> the mechanism <strong>of</strong> lung cancer.<br />
Legal entity responsible for the study: Fundación para la Investigación Biomédica del<br />
Hospital Universitario 12 de Octubre<br />
Funding: SMP is funded by Fondo de Investigación Sanitaria (CD1100153), Consejería<br />
de Salud y Bienestar Social (PI2009-0224 and PI-0046-2012), and Fundación Mutua<br />
Madrileña (2014). LPA is funded by Fondo de Investigación Sanitaria (PI1102688 and<br />
1401964) and RTICC (R12/0036/0028). IF is funded by Fundación AECC.<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1530P<br />
abstracts<br />
Serum microRNAs as potential biomarkers for lung cancer<br />
H-Y. Lee 1 , S-S. Han 2 , S-Y. Song 2<br />
1 Internal Medicine, Kangwon National University, Kangwon National University<br />
Hospital, Chuncheon, Republic <strong>of</strong> Korea, 2 Internal Medicine, Kangwon National<br />
University Hospital, Chuncheon, Republic <strong>of</strong> Korea<br />
Background: MicroRNAs are single-stranded RNA species that constitute a class <strong>of</strong><br />
non-coding RNAs, and are emerging as key regulators <strong>of</strong> gene expression. Since each<br />
miRNA is capable <strong>of</strong> regulating multiple genes, miRNAs are attractive markers for<br />
studies <strong>of</strong> coordinated gene expression. The interest in circulating RNAs as biomarkers<br />
is rapidly increasing as their potential is being realized. In this study, we investigated<br />
serum miRNA expression to compare non-small-cell lung cancer patients and controls<br />
by our previous studied miRNA pr<strong>of</strong>iles.<br />
Methods: This study involved RNA isolation from 184 sera specimens including those<br />
from lung cancer patients and age- and gender-matched controls (n = 92 each). Serum<br />
RNA was isolated with miRNeasy Serum/Plasma Kit (Qiagen), and reverse<br />
transcription was performed using the miScript II RT Kit (Qiagen) according to the<br />
manufacturer’s instructions.Real-time PCR was performed on the StepOnePlusTM<br />
Real Time PCR System (Applied Biosystems) using the miScript SYBR Green PCR Kit<br />
(Qiagen), according to the manufacturer’s instructions. The data were analyzed using<br />
the PCR array data analysis tools (Qiagen). Appropriate informed consent was<br />
obtained from the participants, and the Institutional Review Board <strong>of</strong> the Kangwon<br />
National University Hospital (Chuncheon, Korea) approved the study.<br />
Results: miR-21-5p, miR-144-5p, miR-182-5p, miR-205-5p, miR-891a-5p and<br />
miR-1246 was found to be present at substantially higher levels in lung cancer<br />
compared with control sera, as indicated by an absolute fold change ≥1.0 and P < 0.05.<br />
And miR-1246 was most significantly higher level in in lung cancer compared with<br />
control sera (fold change = 5.6, p-value < 0.05). Conversely, let-7c-5p, miR1-3p,<br />
miR-133a-3p, miR-139-5p, miR-196a-5p, miR-196b-5p, miR-210-3p, miR-301b-3p,<br />
miR-30a-3p, miR-338-3p, miR-490-3p, miR-577, miR-615-3p and miR-944 did not<br />
show significant difference between two groups.<br />
Conclusions: Differences in miRNA pr<strong>of</strong>ile identified support circulating miRNA s<br />
having potential as diagnostic biomarkers for lung cancer. More extensive studies <strong>of</strong><br />
lung cancer and control serum specimens are warranted to independently validate the<br />
potential clinical relevance <strong>of</strong> these miRNA s as minimally invasive biomarkers for<br />
lung cancer.<br />
Legal entity responsible for the study: N/A<br />
Funding: Kanhwon National University<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
Background: According to classical Mendelian laws, the majority <strong>of</strong> genes in a human<br />
cell are inherited in two functionally equivalent parental copies. However, there is a<br />
small subset <strong>of</strong> genes with one turned-<strong>of</strong>f copy in a parent-<strong>of</strong>-origin-dependent manne.<br />
This phenomenon, known as genomic imprinting, is an epigenetic process that<br />
involves monoallelic expression. Some genes are imprinted across the complete<br />
genome sequence, but the vast majority <strong>of</strong> imprinted genes are clustered. In this sense,<br />
the DLK1-DIO3 imprinted cluster is located on chromosome 14q32.2. This region<br />
includes protein-coding genes (DLK1, RTL1 and DIO3), long non-coding RNAs<br />
(MEG3, MEG8, MEG9 and LINC00524), two large clusters <strong>of</strong> miRNAs, two families <strong>of</strong><br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw392 | vi529
abstracts<br />
1531P<br />
Evaluation <strong>of</strong> the interindividual variability in plasma<br />
nivolumab level in non-small-lung cancer outpatients:<br />
preliminary results<br />
A. Puszkiel 1 , G. Noé 2 , P. Boudou-Rouquette 3 , C. Le Cossec 4 , J. Arrondeau 3 ,J.<br />
S. Giraud 1 , J. Alexandre 3 , M. Vidal 5 , F. Goldwasser 3 , B. Blanchet 1<br />
1 Functional Unit <strong>of</strong> Pharmacokinetics and Pharmacochemistry, Hôpital Cochin,<br />
Paris, France, 2 UMR 8638 CNRS, Paris Descartes University, Paris, France,<br />
3 Department <strong>of</strong> Medical <strong>Oncology</strong>, Cochin Hospital, Paris Descartes University,<br />
APHP, CARPEM, CERTIM, Hôpital Cochin, Paris, France, 4 DOMU, Assistance<br />
Publique - Hopitaux De Paris, Paris, France, 5 Functional Unit <strong>of</strong> Pharmacokinetics<br />
and Pharmacochemistry, Paris Descartes University, UMR 8638 CNRS, Hôpital<br />
Cochin, Paris, France<br />
Background: Nivolumab, an anti PD-1 inhibitor, has been approved for the treatment<br />
<strong>of</strong> previously treated advanced or metastatic non-small-cell-lung cancer (NSCLC). The<br />
response rate is about 20% with nivolumab. The inter-patient variability in clinical<br />
outcomes to nivolumab is large and could be influenced by its pharmacokinetics.<br />
However, no data is currently available about the inter-patient variability in plasma<br />
exposure to nivolumab in NSCLC outpatients. The aim was to investigate the<br />
inter-patient variability in plasma level <strong>of</strong> nivolumab from 27 NSCLC outpatients.<br />
Methods: NSCLC patients were treated with nivolumab (3 mg/kg) every two weeks.<br />
Blood samples were collected just before the infusion on days 0 (baseline), 14, 28 and<br />
42 after treatment start. Plasma trough levels (C min ) <strong>of</strong> nivolumab were assayed with<br />
home-made ELISA. Univariate linear regression models were performed in order to<br />
explain the inter-patient variability in nivolumab C min on day 42. Multivariate model<br />
included all variables which were significant at the 10% level in the univariate analyses.<br />
Results: The calibration for nivolumab assay was linear in the range 5-100 µg/mL.<br />
Intra- and interday imprecision for three internal quality controls (5, 20 and 75 µg/mL)<br />
were less than 9 and 12%, respectively. The median age <strong>of</strong> the cohort was 68 years<br />
(range 41-84) and the sex ratio (female/male) 1.27. The median dose <strong>of</strong> nivolumab was<br />
207 mg (range 147-288). No nivolumab was detected in baseline samples. The mean<br />
nivolumab C min was 17.3 ± 4.8 µg/mL (CV = 27.8%), 25.0 ± 9.7 µg/mL (CV = 38.8%)<br />
and 33.0 ± 12.9 µg/mL (CV = 39.1%) on days 14, 28 and 42, respectively. A significant<br />
variation in nivolumab C min was observed over the time (one-way Anova test,<br />
p < 0.001). In the multivariate linear regression analysis, nivolumab C min on day 42 was<br />
independently associated with IgG level (β = -3.25; p = 0.0022) and ALAT (β = 0.45;<br />
p = 0.042).<br />
Conclusions: These preliminary results highlight a large inter-patient variability in<br />
nivolumab C min in NSCLC outpatients. Further PK/PD investigations are warranted to<br />
identify the influence <strong>of</strong> this pharmacokinetic variability on clinical outcomes.<br />
Legal entity responsible for the study: N/A<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1532P<br />
New insights from KISS activity: a prognostic biomarker in<br />
malignant pleural mesothelioma<br />
V. Ciaramella, C.M. Della Corte, F. Papaccio, V. Giuseppe, G. Esposito, M. Fasano,<br />
E. Martinelli, T. Troiani, F. Ciardiello, F. Morgillo<br />
Medicina Clinica Sperimentale Magrassi Lanzara, AOU Seconda Università degli<br />
Studi di Napoli (AOU-SUN), Naples, Italy<br />
Background: The KISS1 gene (“KI”: in homage to the location <strong>of</strong> where it was<br />
discovered, Hershey, Pennsylvania, home <strong>of</strong> Hershey’s Kiss, and “SS”: Suppressor<br />
Sequence) encodes for a 145 amino acid peptide, known as kisspeptin, which is cleaved<br />
to smaller peptides <strong>of</strong> 54 amino acid, known as metastatin. KISS1 was originally<br />
isolated in melanoma as a molecule with anti-metastatic effects. Associations between<br />
loss <strong>of</strong> KISS1 expression and increased tumor progression and poor prognosis were<br />
found in various solid tumors, including lung cancer, but the precise role <strong>of</strong> KISS1<br />
expression is not well defined.<br />
Methods: The human mesothelioma H2452, H2052, H28 and MSTO cell lines were<br />
used. The mRNA and protein levels <strong>of</strong> KISS1, and its G-protein coupled receptor<br />
GPR54, were evaluated by qPCR and Western Blot analysis. In order to prove that<br />
kisspeptins regulate cell proliferation, migration, and invasion in mesothelioma cell<br />
lines via KISS/GPR54, we conducted in vitro treatments with different doses <strong>of</strong><br />
kisspeptin (Kp-10) [from Kp-10 −7 to Kp-10 −12 M] through MTT, Scratch and Boyden<br />
Chamber assays. Finally, MMPs activity (MMP-2 and MMP-9) was examined by<br />
gelatin Zymography.<br />
Results: The presence <strong>of</strong> KISS1 and GPR54 were found in all cell lines analyzed, both<br />
at mRNA and protein levels. Treatment with Kp-10, at dose from 10 −12 to 10 −10 M,<br />
significantly inhibited cell proliferation, migration and invasion <strong>of</strong> mesothelioma cell<br />
lines. In addition, Kp-10 treatment inhibited the production and activity <strong>of</strong> MMP-2<br />
and MMP-9 determining consequently a marked reduction in the invasiveness <strong>of</strong><br />
primary tumors and metastases.<br />
Conclusions: The results demonstrate a role <strong>of</strong> the KISS1/GPR54 system in malignant<br />
mesothelioma and may be used as a predictive marker <strong>of</strong> progression disease. However,<br />
further studies are required to investigate the effect <strong>of</strong> Kp-10 alone or in combination<br />
with molecular targeted agents.<br />
Legal entity responsible for the study: N/A<br />
Funding: None<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1533P<br />
First generation <strong>of</strong> a small chemical molecule ROR1 RTK<br />
tyrosine kinase inhibitor<br />
H. Mellstedt 1 , M. Hojjat-Farsangi 2 , A.H. Daneshmanesh 3 , A. Moshfegh 3 ,<br />
S. Byström 4 , M. Norin 4 , T. Olin 4 , J. Schultz 4 , J. Vågberg 4 , A. Österborg 5<br />
1 Dept <strong>of</strong> <strong>Oncology</strong>-Pathology, Karolinska Institute, Stockholm, Sweden,<br />
2 Department <strong>of</strong><strong>Oncology</strong>-Pathology, Karolinska Institute, Stockholm, Sweden,<br />
3 Department <strong>of</strong> <strong>Oncology</strong>-Pathology, Karolinska Institute, Stockholm, Sweden,<br />
4 Kancera AB, Stockholm, Sweden, 5 Department <strong>of</strong> Hematology, Karolinska<br />
University Hospital Solna, Stockholm, Sweden<br />
Background: The receptor tyrosine kinase (RTK) ROR1 is <strong>of</strong> importance during<br />
embryogenesis for the central nervous, musco-skeletal and cardio-pulmonary systems.<br />
ROR1 is practically not present in normal adult tissues. ROR1 is however re-expressed<br />
in several hematological and non-hematological malignancies and involved in tumor<br />
cell proliferation, survival, invasiveness and metastases. The unique characteristics <strong>of</strong><br />
this onco-fetal RTK should make it a suitable candidate for targeted therapy.<br />
Methods: A chemical synthesis program has been initiated based on a chemical library<br />
and phenotypic screening programme. Small molecules have been produced which<br />
specifically target the phosphorylated TK domain <strong>of</strong> ROR1. Tumor cell death in vitro is<br />
measured by Annexin V/PI and MTT. Effects on signaling molecules by WB for<br />
phosphorylated and non-phosphorylated proteins. Xenotransplanted non-scid mice<br />
and zebra fishes are used for in vivo testing <strong>of</strong> anti-tumor effects.<br />
Results: Phosphorylated ROR1 is expressed in e.g. CLL, triple negative breast cancer,<br />
pancreatic and lung cancer cells. A lead compound has been synthesized, KAN<br />
0439834. In biochemical assay IC50 is 5 nM. The compound kills specifically with high<br />
efficiency chronic lymphocytic leukemia cells, triple negative breast cancer cells,<br />
pancreatic carcinoma cells, lung cancer cells. The ligands for ROR1 is Wnt5a and 3a<br />
which both are expressed in tumor cells. The drug specifically dephosphorylated ROR1<br />
as well as downstream Wnt canonical (e.g. GSK3β) and non-canonical (e.g. PI3K,<br />
AKT, mTOR) molecules. In non-scid mice transplanted with human CLL cells a<br />
significant reduction <strong>of</strong> CLL cells was noted as well as inhibition in the zebra fish<br />
model <strong>of</strong> triple negative breast cancer cells <strong>of</strong> tumor growth and metastases. KAN<br />
0439834 is well tolerated in the mice.<br />
Conclusions: ROR1 is an activated onco-fetal RTK expressed in various malignancies.<br />
Small chemical molecules specifically targeting ROR1 could be shown in vitro and in<br />
vivo preclinical models to specifically and efficiently kill tumor cells at a low<br />
concentration. The oral available KAN 0439834 is the first generation <strong>of</strong> a ROR1 TKI<br />
with promising characteristic to be further developed for first-in-man clinical trials.<br />
Legal entity responsible for the study: Karolinska Institute, Department <strong>of</strong><br />
<strong>Oncology</strong>-Pathology and Department <strong>of</strong> Hematology.<br />
Funding: Kancera AB, Karolinska Institute Science Park<br />
Disclosure: H. Mellstedt: Co-founder <strong>of</strong> Kancera AB and member <strong>of</strong> Board <strong>of</strong><br />
Directors as well as stock owner. M. Hojjat-Farsangi, A.H. Daneshmanesh,<br />
A. Österborg: Stock owner <strong>of</strong> Kancera AB. A. Moshfegh: Employee and stock owner at<br />
Kancera. S. Byström, M. Norin, T. Olin, J. Schultz, J. Vågberg: Employee and stock<br />
owner at Kancera.<br />
1534P<br />
Effects <strong>of</strong> MRX34, a liposomal miR-34 mimic, on target gene<br />
expression in human white blood cells (hWBCs): qRT-PCR<br />
results from a first-in-human trial <strong>of</strong> microRNA cancer<br />
therapy<br />
H.J. Peltier, K. Kelnar, A.G. Bader<br />
Translational Research, Mirna Therapeutics Inc, Austin, TX, USA<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Background: Each microRNA (miRNA) modulates the expression <strong>of</strong> hundreds <strong>of</strong><br />
genes across distinct cellular pathways, giving miRNA-based therapy the potential to<br />
simultaneously repress multiple oncogenic processes in the tumor microenvironment,<br />
including growth and proliferation, resistance, cancer stem cells, metastasis, and<br />
immune evasion. The naturally occurring tumor suppressor miR-34a has been shown<br />
to down-regulate the expression <strong>of</strong> >30 oncogenes (eg, MET, MEK1, MYC, PDGFR-α,<br />
CDK4/6, BCL2, WNT 1/3, NOTCH1, CD44), as well as genes involved in tumor<br />
immune evasion (eg, PD-L1, DGKζ). MRX34, a liposome-encapsulated miR-34a<br />
mimic, is a potential first-in-class miRNA therapy for cancer.<br />
Methods: In the MRX34-101 phase I trial (NCT01829971), patients with advanced<br />
malignancies under dexamethasone premedication received IV infusions <strong>of</strong> MRX34<br />
daily for 5 d in week 1 with 2 weeks rest in 21d cycles (QDx5 schedule). Whole blood<br />
was collected pretreatment and at multiple times after the first and during subsequent<br />
infusions. Total RNA from hWBCs (LeukoLOCK method) was isolated (mirVana kit)<br />
and assessed for quality (Agilent 2100 Bioanalyzer). qRT-PCR was used to measure<br />
and compare the relative expression levels <strong>of</strong> selected direct miR-34a target genes in the<br />
RNA from pre- and post-dose samples.<br />
vi530 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Results: Expression <strong>of</strong> miR-34a target genes was repressed in hWBCs 24 hrs after the<br />
start <strong>of</strong> MRX34 dosing. The effect was dose-dependent such that the depth <strong>of</strong><br />
repression increased at higher MRX34 doses corresponding to increased exposure to<br />
and uptake <strong>of</strong> miR-34a in hWBCs. In contrast, expression <strong>of</strong> p21 (CDKN1A), a<br />
tumor-suppressor gene specifically induced by miR-34a, was increased.<br />
Conclusions: This qRT-PCR analysis <strong>of</strong> hWBC samples obtained from patients treated<br />
with MRX34 in a first-in-human clinical trial <strong>of</strong> miRNA cancer therapy showed<br />
dose-dependent modulation <strong>of</strong> expression in target genes directly regulated by<br />
miR-34a. Our work suggests that MRX34 effectively delivers active miR-34a mimics to<br />
hWBCs in pts with cancer, and provides a potentially useful method to evaluate<br />
biomarkers <strong>of</strong> response to MRX34 therapy.<br />
Clinical trial identification: NCT01829971<br />
Legal entity responsible for the study: Mirna Therapeutics Inc<br />
Funding: Mirna Therapeutics Inc<br />
Disclosure: H.J. Peltier, K. Kelnar: Employment, Mirna Therapeutics Inc. A.G. Bader:<br />
Employment, Stock Ownership, Mirna Therapeutics, Inc.<br />
1535P<br />
circular RNA: A novel regulatory non-coding RNA expressed<br />
in prostate cancer<br />
J.P. Greene 1 , G. Blackshields 1 , O. Casey 1 , L. Brady 1 , A.M. Baird 1 ,S.Gray 1 ,<br />
S. Finn 2 , R. McDermott 3<br />
1 Histopathology, Trinity College Dublin, Dublin, Ireland, 2 Cancer Molecular<br />
Diagnostics, University <strong>of</strong> Dublin Trinity College, Dublin, Ireland, 3 Dept. <strong>of</strong> Medical<br />
<strong>Oncology</strong>, AMNCH Adelaide and Meath Hospital, Dublin, Ireland<br />
Background: Recent advances in prostate cancer (PCa) have led to the development <strong>of</strong><br />
new treatments that target the androgen receptor (AR) pathway. However, some pts<br />
present with intrinsic resistance to treatment while others eventually develop acquired<br />
resistance. The mechanisms associated with the development <strong>of</strong> resistance have yet to<br />
be fully characterized. Non-coding RNAs (ncRNA) are RNA molecules, which are not<br />
translated into protein and include microRNAs (miRNA). Recently a novel type <strong>of</strong><br />
ncRNA was identified and is termed circular RNA (circRNA). circRNA appear to play<br />
a crucial role in gene expression through the regulation <strong>of</strong> miRNAs. The aim <strong>of</strong> this<br />
study is to determine the role <strong>of</strong> circRNA in enzalutamide resistance and their<br />
interaction with miRNAs associated with PCa.<br />
Methods: Total RNA was extracted from a panel <strong>of</strong> prostate cell lines, which included<br />
benign (n = 3), malignant (n = 5) and an isogenic model <strong>of</strong> enzalutamide resistance.<br />
circRNA pr<strong>of</strong>iling was performed using an Arraystar microarray platform.<br />
Differentially expressed circRNAs were ranked according to fold change between<br />
groups (FC >2; p-value < 0.05). Additionally, circRNA/miRNA interactions were<br />
predicted based on sequence pairing identified by TargetScan and verified by miRanda.<br />
Results: In total 9,757 circRNAs were classified as present across the panel <strong>of</strong> cell lines.<br />
Cell lines were stratified according to their AR status, malignancy status and resistance<br />
to enzalutamide. A number <strong>of</strong> differentially expressed circRNA were identified between<br />
the groups. The majority <strong>of</strong> circRNA were downregulated in enzalutamide resistant<br />
cells when compared with drug sensitive cells (280 upregulated v 550 downregulated).<br />
Predicted miRNA targets were determined for circRNAs with FC greater than 2. For<br />
each circRNA up and downregulated, 5 binding sites for their targeted miRNAs were<br />
identified allowing identification <strong>of</strong> circRNA/miIRNA interactions relevant to PCa.<br />
Conclusions: circRNAs are differentially expressed based on AR and malignancy<br />
status, and enzalutamide sensitivity. Binding sites for miRNA associated with PCa can<br />
be identified on circRNA. This novel type <strong>of</strong> ncRNA may have a role as biomarkers in<br />
PCa and serve as predictive markers to enzalutamide therapy.<br />
Legal entity responsible for the study: ICORG<br />
Funding: Irish Cancer Society<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1536P<br />
Description and prognostic value <strong>of</strong> the mutational load<br />
across various metastatic solid tumors in the prospective<br />
MOSCATO-01 and MATCH-R trials<br />
previous treatment, whole exome sequencing was performed on prospective samples<br />
with both high tumor cellularity (> 30%) and good DNA.<br />
Results: Mutational load from 160 patients was obtained, with 9 patients having<br />
multiple longitudinal mutational loads and 4 patients with synchronous mutational<br />
loads from different biopsies sites. Mutational load was ranging from 0.2 to 28.7 mut/<br />
Mb with 80% <strong>of</strong> patients under 5 mut/Mb. In this heterogeneous population with<br />
various preceding therapies, mutational load was not associated with overall survival.<br />
Overall survival (OS) trended to be longer in patients with mutational load under 5<br />
mut/Mb (median 18 months [95% CI n.a.] vs 12 months [95% CI 7.1-16.9], p = 0.13).<br />
Variations <strong>of</strong> mutational load highlight importance <strong>of</strong> histology and history <strong>of</strong><br />
treatment.<br />
Conclusions: Prospective evaluation <strong>of</strong> the mutational load is routinely feasible in<br />
precision medicine trials. Results were obtained within 4 weeks <strong>of</strong> tumor biopsy. In this<br />
heterogeneous population, mutational load is not prognostic. Signatures <strong>of</strong> mutational<br />
processes and neoantigens are currently being characterized in our patients.<br />
Legal entity responsible for the study: N/A<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1537P<br />
abstracts<br />
The role <strong>of</strong> PP2A in innate resistance to HER2-targeted<br />
therapy<br />
N. Conlon 1 , M. McDermott 1 , J. Crown 2 ,N.O’Donovan 1<br />
1 National Institute for Cellular Biotechnology, Dublin City University, Dublin, Ireland,<br />
2 Dept <strong>of</strong> Medical <strong>Oncology</strong>, St Vincents University Hospital, Dublin, Ireland<br />
Background: We previously identified protein phosphatase 2A (PP2A) as a potential<br />
mediator <strong>of</strong> resistance to lapatinib in cell line models <strong>of</strong> acquired lapatinib resistance<br />
(McDermott, 2014). The aim <strong>of</strong> this study was to evaluate the potential role <strong>of</strong> PP2A in<br />
innate resistance to lapatinib and/or trastuzumab in HER2-positive breast cancer.<br />
Methods: Proliferation assays were carried out to assess sensitivity to lapatinib,<br />
trastuzumab and the PP2A inhibitors, okadaic acid and LB-100, alone and in<br />
combination with lapatinib, using an acid phosphatase assay. Immunoblotting for<br />
eEF2, p-eEF2, PPP2CA, p-PPP2CA, Akt, p-Akt, ERK, p-ERK, S6K and p-S6K was<br />
performed in a panel <strong>of</strong> HER2-positive cell lines that were classified as sensitive or<br />
resistant to lapatinib (IC 50 > 1 µM lapatinib) or trastuzumab (< 20% growth inhibition<br />
at 15 µg/mL).<br />
Results: Cell lines that are innately resistant to lapatinib and/or trastuzumab were<br />
significantly more sensitivity to okadaic acid (p = 0.020, p < 0.001). In three <strong>of</strong> the four<br />
innately lapatinib/trastuzumab resistant cell lines, treatment with okadaic acid restored<br />
sensitivity to lapatinib. Sensitivity to the therapeutic PP2A inhibitor LB-100 correlated<br />
with lapatinib sensitivity and LB-100 enhanced response to lapatinib in JIMT-1 cells.<br />
Neither PPP2CA nor p-PPP2CA levels correlated with lapatinib/trastuzumab or<br />
okadaic acid sensitivity. However, higher levels <strong>of</strong> phospho-eEF2, a protein<br />
dephosphorylated by PP2A, correlated with sensitivity to lapatinib (p = 0.035) and<br />
trastuzumab (p < 0.001). Following lapatinib treatment, decreased p-Akt (p = 0.008),<br />
decreased p-S6K (p = 0.011), decreased p-ERK (p = 0.010), and increased p-eEF2<br />
(p = 0.006), correlated with response.<br />
Conclusions: In addition to its potential role as a target to overcome acquired lapatinib<br />
resistance, PP2A may be a promising target to overcome innate resistance to HER2<br />
targeted therapies in HER2-positive breast cancer. Levels <strong>of</strong> phosphorylated eEF2, the<br />
PP2A target, may be a novel predictive and pharmacodynamic biomarker <strong>of</strong> response/<br />
resistance to lapatinib.<br />
Legal entity responsible for the study: Dublin City University<br />
Funding: Irish Cancer Society and Science Foundation Ireland<br />
Disclosure: J. Crown: Research funding from Roche, GSK, Boehringer Ingelheim, Eisai<br />
and advisory/consulting role for Novartis, Eisai, Pfizer, Genomic Health, Teva, New<br />
<strong>Oncology</strong> and Bayer. N. O’Donovan: Research funding from Eisai, Boehringer<br />
Ingelheim and GSK. All other authors have declared no conflicts <strong>of</strong> interest.<br />
L. Mahjoubi 1 , M. Pedredo 2 , C. Massard 1 , E. Castanon Alvarez 1 , C. Lefebvre 2 ,<br />
L. Lacroix 3 , Y. Loriot 4 , F. André 4 , J-C. Soria 1<br />
1 Drug Development Department (DITEP), Institut Gustave Roussy, Villejuif, France,<br />
2 Plateforme de Génomique Fonctionnelle, Gustave Roussy, Institut Gustave<br />
Roussy, Villejuif, France, 3 Laboratoire de Recherche Translationnelle et Centre de<br />
Ressources Biologiques, Institut Gustave Roussy, Villejuif, France, 4 Medical<br />
<strong>Oncology</strong> Department, Institut Gustave Roussy, Villejuif, France<br />
Background: MOSCATO-01 and MATCH-R are ongoing prospective precision<br />
medicine trials (NCT01566019 and NCT02517892). They allow genomic analysis <strong>of</strong><br />
purposefully acquired tumor biopsies obtained in patients with various types <strong>of</strong><br />
metastatic solid tumors. MATCH-R encompassed whole exome sequencing (WES)<br />
since its inception, while MOSCATO incorporated WES in 2015.<br />
Methods: To describe the landscape and evaluate the prognostic impact <strong>of</strong> the<br />
mutational load in metastatic solid tumors blinded from histology and history <strong>of</strong><br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw392 | vi531
abstracts<br />
1538P<br />
Neutrophil-to-lymphocyte ratio (NLR) and<br />
platelet-to-lymphocyte ratio (PLR) as predictive biomarkers<br />
<strong>of</strong> pathologic complete response (pCR) in neoadjuvant breast<br />
cancer: an Irish Clinical <strong>Oncology</strong> Group study (ICORG 16-20)<br />
S. Rafee 1 , D.J. McHugh 2 , M. Greally 3 , O. Ayodele 4 , N. Keegan 5 , M. Lim 6 ,<br />
A. Hassan 7 ,D.O’Mahony 1 , B. Hennessy 8 , C. Kelly 6 , J. Kennedy 9 , J. Walshe 10 ,<br />
M. O’Connor 11 , G. Leonard 3 , V. Murphy 12 , V. Livingstone 1 , M. Corrigan 1 ,<br />
S. O’Reilly 1<br />
1 Medical <strong>Oncology</strong>, Cork University Hospital, Cork, Ireland, 2 Medical <strong>Oncology</strong>,<br />
Mid-Western Regional Hospital, Limerick, Ireland, 3 Medical <strong>Oncology</strong>, University<br />
College Hospital Galway, Galway, Ireland, 4 Medical <strong>Oncology</strong>, Waterford Regional<br />
Hospital, Waterford, Ireland, 5 Medical <strong>Oncology</strong>, Beaumont Hospital, Dublin,<br />
Ireland, 6 Medical <strong>Oncology</strong>, Mater Misericordiae University Hospital University<br />
College Dublin, Dublin, Ireland, 7 Medical <strong>Oncology</strong>, St Vincents University<br />
Hospital, Dublin, Ireland, 8 Medical <strong>Oncology</strong>, Royal College <strong>of</strong> Surgeons in Ireland,<br />
Dublin, Ireland, 9 Medical <strong>Oncology</strong>, St James’s Hospital, Dublin, Ireland, 10 Medical<br />
<strong>Oncology</strong> Unit, St Vincents University Hospital, Dublin, Ireland, 11 Medical<br />
<strong>Oncology</strong>, University Hospital Waterford, Waterford, Ireland, 12 Clinical Research,<br />
Irish Clinical <strong>Oncology</strong> Research Group ICORG, Dublin, Ireland<br />
Background: Over the past few years, the rapidly advancing field <strong>of</strong> cancer<br />
immunology has provided solid evidence that the systemic inflammatory response,<br />
usually measured by surrogate blood-based parameters, such as neutrophil or platelet<br />
count, has an important role in the progression <strong>of</strong> several solid tumors. In this study,<br />
we investigate the association between pre neoadjuvant therapy NLR and PLR, and<br />
pCR in breast cancer<br />
Methods: We performed a retrospective review <strong>of</strong> patients with non-metastatic breast<br />
cancer treated with neoadjuvant therapy followed by surgery in seven cancer centers<br />
across Ireland. Blood cell counts were obtained within one week before the start <strong>of</strong><br />
neoadjuvant therapy. The NLR and PLR were defined as the absolute neutrophil count<br />
and the absolute platelet count, respectively, divided by the absolute lymphocyte count.<br />
pCR was defined as the absence <strong>of</strong> residual invasive cancer in the complete resected<br />
breast specimen and all sampled regional lymph nodes following completion <strong>of</strong><br />
neoadjuvant systemic therapy. Receiver operating characteristic (ROC) curves were<br />
used to determine the optimal cut-<strong>of</strong>fs for high vs low NLR and PLR. The relationships<br />
between pCR and NLR group (high/low) or PLR group (high/low) were investigated<br />
using the chi-squared test and binary logistic regression<br />
Results: A total <strong>of</strong> 304 breast cancer patients were included in the study. The median<br />
age was 54. 28% (n = 85) <strong>of</strong> patients had pCR. Applying the ROC mentioned above, we<br />
determined cut<strong>of</strong>f values <strong>of</strong> 2.05 and 138.19 for the NLR and PLR respectively, to be<br />
optimal to discriminate between high and low groups. In the non-pCR group, 64.8%<br />
(n = 142) had a NLR ≥2.05 compared to 51.8% (n = 44) in the pCR group. Patients<br />
with high NLR were less likely to achieve pCR compared to patients with low NLR<br />
(p = .036, OR = 1.72, 95% CI: 1.03 to 2.86 ). In the non-pCR group, 58.9% (n = 129)<br />
had a PLR ≥138.19 compared to 44.7% (n = 38) in the pCR group. Patients with high<br />
PLR were less likely to achieve pCR compared to those with low PLR (p = .026, OR:<br />
1.77, 95% CI: 1.07 to 2.94)<br />
Conclusions: High NLR and PLR are independently associated with poor response to<br />
neoadjuvant therapy in breast cancer<br />
Clinical trial identification: ICORG 16-20<br />
Legal entity responsible for the study: Irish Clinical <strong>Oncology</strong> Research Group<br />
(ICORG 16-20)<br />
Funding: Irish Clinical <strong>Oncology</strong> Research Group (ICORG 16-20)<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1539P<br />
Androgen receptor and estrogen receptor beta interplay in<br />
triple negative breast carcinomas<br />
M.V. Karamouzis, A. Anestis, C. Michailidou, A.G. Papavassiliou<br />
Department <strong>of</strong> Biological Chemistry, National and Kapodistrian University <strong>of</strong><br />
Athens, Athens, Greece<br />
Background: Triple negative breast cancer (TNBC) is an aggressive breast cancer<br />
subtype. We explored the role <strong>of</strong> androgen receptor (AR) in TNBC focusing on its<br />
association with ERβ in ligand-independent AR activation.<br />
Methods: We performed in vitro experiments in breast cancer cell lines BT-20 and<br />
MDA-MB 453, which express high and low levels <strong>of</strong> AR, respectively. We have also<br />
studied PI3K/AKT pathway molecules mTOR, PTEN and AKT with immunoblot<br />
analysis and RT-PCR. Immunoblot analysis <strong>of</strong> BT-20 and MDA-MB 453 cells for ERβ<br />
following transfection with increasing amounts <strong>of</strong> ERβ was also performed. In order to<br />
test if a physical association (ERβ-AR) occurs, immunoprecipitation (IP) was<br />
performed. Τreatment with agonists and antagonists <strong>of</strong> AR and ERβ was also applied.<br />
Results: We have verified the endogenous expression <strong>of</strong> ERβ in TNBC cell lines. We<br />
have demonstrated that the cellular model that expresses only ERβ (BT-20) holds a<br />
different molecular pr<strong>of</strong>ile compared to that expressing only AR (MDA-MB 453). The<br />
presence <strong>of</strong> ERβ led to PTEN increase; subsequently, expression levels <strong>of</strong><br />
phosphorylated (p) molecules <strong>of</strong> PI3K/AKT pathway (p-mTOR, p-Akt) were reduced.<br />
Contrarily, AR (+) cellular model showed high expression levels <strong>of</strong> the same molecules,<br />
indicating the strong proliferative effect <strong>of</strong> AR in TNBC. The cellular model which<br />
expresses both AR and ERβ showed that ERβ modulates AR proliferative activity by<br />
increasing PTEN and reducing activation <strong>of</strong> downstream molecules <strong>of</strong> PI3K/AKT<br />
pathway. Agonists <strong>of</strong> both receptors (testosterone and 17β-estradiol for AR and ERβ,<br />
respectively) enhanced receptors expression, affecting the expression levels <strong>of</strong> the PI3K/<br />
AKT signaling pathway molecules. Treatment with the AR antagonist bicalutamide did<br />
not have significant impact. Using IP, a specific interaction between ERβ and AR was<br />
revealed.<br />
Conclusions: There is strong evidence that ERβ is involved in TNBC progression. Our<br />
data provide a strong anti-proliferative effect <strong>of</strong> ERβ in TNBC cells via the PI3K/AKT<br />
signaling pathway and may represent a significant therapeutic target. More detailed<br />
studies are ongoing to this concept, which may have considerable impact for the<br />
treatment <strong>of</strong> TNBC patients.<br />
Legal entity responsible for the study: N/A<br />
Funding: Department <strong>of</strong> Biological Chemistry, Medical School, National and<br />
Kapodistrian University <strong>of</strong> Athens, Athens, Greece<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1540P<br />
Implementation <strong>of</strong> an interdisciplinary molecular tumor<br />
board in managing <strong>of</strong> advanced stage breast cancer<br />
S. Armeanu-Ebinger 1 , D. Döcker 1 , A. Kopic 2 , S. Brucker 3 , D. Wallwiener 3 ,<br />
U. Martens 4 , C. Kyzirakos 1 , M. Menzel 1 , A. Rinkleb 1 , S. Biskup 1<br />
1 Tumor Diagnostics, CeGaT GmbH, Tübingen, Germany, 2 Private Oncological<br />
Daily Clinic, Stuttgart, Germany, 3 Universitäts-Frauenklinik, University Clinic<br />
Tübingen, Tübingen, Germany, 4 Klinik für Innere Medizin III: Hämatologie,<br />
Onkologie, Palliativmedizin, SLK-Kliniken Heilbronn GmbH, Heilbronn, Germany<br />
Background: Screening <strong>of</strong> somatic mutations in tumors is included in modern studies<br />
in oncology to test the efficiency <strong>of</strong> a particular drug expected to target the detected<br />
mutations. In so called “Umbrella” trials a set <strong>of</strong> preselected drugs are tested in cancer<br />
patients with different cancer types with distinct mutations. Despite <strong>of</strong> promising<br />
results <strong>of</strong> different studies based on molecular testing, the impact <strong>of</strong> comprehensive<br />
screening approaches is still underestimated. In a personalized medicine the molecular<br />
tumor analyses has to complement other diagnostics and enable up-to-date therapy<br />
such as targeted therapies, immunotherapies, and others.<br />
Methods: We compared a dataset <strong>of</strong> 25 breast cancer cases who had previously<br />
undergone CeGaT somatic tumor panel (NGS-based panel diagnostics comprising 649<br />
tumor-related genes) or tumor exome diagnostics. All cases were discussed in an<br />
interdisciplinary tumor board composed by gynecologists, oncologists, clinical and<br />
molecular geneticists. Among others, issues such as clinical relevance <strong>of</strong> the molecular<br />
report in the context <strong>of</strong> the individual clinical setting were discussed retrospectively.<br />
Results: In an adjuvant setting, standard/guideline therapies were considered the best<br />
approach. In locally advanced tumors, relapse or metastatic disease, the molecular<br />
report was considered extremely relevant, either consistent with clinical decisions or<br />
enabling new approaches, including targeted or immunologic therapies, but also<br />
selected chemotherapy. Only in 1/25 cases (4 %), no therapeutically relevant somatic<br />
mutation could be detected. We present select examples <strong>of</strong> cases, in which the<br />
therapeutic approach would be re-considered retrospectively.<br />
Conclusions: The retrospective evaluation resulted in the implementation <strong>of</strong> a<br />
monthly interdisciplinary molecular tumor board discussing current patients and<br />
prospective approaches. All patients with locally advanced tumors, relapse or<br />
metastases are <strong>of</strong>fered comprehensive molecular testing and comprehensive individual<br />
evaluation <strong>of</strong> therapeutic approaches.<br />
Legal entity responsible for the study: none<br />
Funding: CeGaT GmbH<br />
Disclosure: S. Armeanu-Ebinger, D. Döcker, C. Kyzirakos, M. Menzel, A. Rinkleb:<br />
Employed at CeGaT GmbH, which provides molecular tumor diagnostics. All other<br />
authors have declared no conflicts <strong>of</strong> interest.<br />
1541P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Presence <strong>of</strong> tumor-specific cytolytic T cells in human primary<br />
breast carcinoma: consequences for immunotherapy<br />
D. Schröder 1 , J. Carrasco 2 , O. Bricard 1 , G. Hames 1 , N. Remy 1 , K. Missault 1 ,<br />
J-L. Canon 2 , P. Vannuffel 3 , C. Galant 4 , M. Berlière 4 , P.G. Coulie 1<br />
1 Cellular Genetics Unit, De Duve Institute, Bruxelles, Belgium, 2 Department <strong>of</strong><br />
Medical <strong>Oncology</strong> / Translational Research Unit, Grand Hopital de Charleroi Site<br />
Notre Dame, Charleroi, Belgium, 3 Centre de Génétique Humaine, Institut de<br />
Pathologie et de Génétique, Gosselies, Belgium, 4 Breast Clinic, King Albert II<br />
Institute, Cliniques Universitaires St. Luc, Brussels, Belgium<br />
Background: Immunotherapy through stimulatory antibodies targeting the CTLA-4 or<br />
PD-1 pathways has a demonstrated clinical efficacy in a fraction <strong>of</strong> patients with<br />
various cancers. It is likely that the main immune effectors <strong>of</strong> these therapies are CD8 +<br />
cytolytic T lymphocytes (CTL) recognizing tumor-specific antigens. Highly antigenic<br />
tumors such as metastatic melanomas are <strong>of</strong>ten immunogenic, i.e. they stimulate<br />
spontaneous anti-tumor CTL responses. This immunogenicity, <strong>of</strong> which the presence<br />
vi532 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
<strong>of</strong> tumor-infiltrating T cells (TILs) is probably a surrogate marker, might be a<br />
predictive marker for clinical benefit to immunostimulatory antibodies. The<br />
immunogenicity <strong>of</strong> primary breast carcinomas for CD8 + T cells has not been studied,<br />
but the amounts <strong>of</strong> TILs have been positively correlated with patients’ survival. Here we<br />
wished to obtain evidence for the presence <strong>of</strong> tumor-specific CD8 + T cells in TILs from<br />
primary breast carcinomas.<br />
Methods: From 5 tumors (2 ER + /HER2 − ,2ER + /HER2 + ,1ER − /HER2 − ) we isolated<br />
TILs and derived a random set <strong>of</strong> ±100 CD8 + T cell clones that we screened for<br />
recognition <strong>of</strong> candidate tumor-specific antigenic peptides selected through tumor<br />
exome sequencing and gene expression pr<strong>of</strong>iling. These peptides were encoded either<br />
by mutated genes or by cancer-germline genes.<br />
Results: For 4 tumors, we screened 61-142 T cell clonotypes for recognition <strong>of</strong> 23-61<br />
candidate mutated peptides, without any positive result. For the last tumor (ER + /<br />
HER2 − ), 6 out <strong>of</strong> 57 T cell clonotypes recognized 4 out <strong>of</strong> 109 candidate mutated<br />
peptides but not the corresponding wild-type peptides. This tumor contained more<br />
mutations than the other four, and displayed microsatellite instability.<br />
Conclusions: Some human primary breast carcinomas are immunogenic, as one tumor<br />
contained at least 10% <strong>of</strong> tumor-specific cells among the CD8 + TILs. Our observation<br />
corroborates the association between high mutation burden and CTL response to<br />
mutated tumor antigens. The presence <strong>of</strong> tumor-specific CD8 + suggests that the<br />
corresponding patient could benefit from the currently used immunostimulatory<br />
antibodies.<br />
Clinical trial identification: code 0nco2008-01 - non interventional trial<br />
Legal entity responsible for the study: Cliniques Universitaires Saint Luc<br />
Funding: Cliniques Universitaires Saint Luc, Belgian Cancer Foundation, Fonds de la<br />
Recherche Scientifique<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1542P<br />
Exploratory analyses <strong>of</strong> candidate predictive and prognostic<br />
tissue biomarkers (BMs) in the open-label randomised phase<br />
III TANIA trial <strong>of</strong> bevacizumab (BEV) in HER2-negative locally<br />
recurrent/metastatic breast cancer (LR/mBC)<br />
C. Zielinski 1 , J. Gligorov 2 , N. Marschner 3 , F. Puglisi 4 , E. Vrdoljak 5 ,J.<br />
Cortes Castan 6 , S. de Ducla 7 , R. Deurloo 7 , V. Easton 8 , G. von Minckwitz 9<br />
1 Department <strong>of</strong> Medicine I, Comprehensive Cancer Center, Medical University<br />
Vienna and Central European Cooperative <strong>Oncology</strong> Group (CECOG), Vienna,<br />
Austria, 2 Medical <strong>Oncology</strong> Department, Assistance Publique Hôpitaux de Paris –<br />
Tenon, IUC-UPMC, Sorbonne University, Paris, France, 3 Internal Medicine /<br />
Hematology, Outpatient Cancer Center, Freiburg, Germany, 4 Department <strong>of</strong><br />
Medical and Biological Sciences, University <strong>of</strong> Udine and Department <strong>of</strong> <strong>Oncology</strong>,<br />
University Hospital <strong>of</strong> Udine, Udine, Udine, Italy, 5 Department <strong>of</strong> <strong>Oncology</strong>, Center<br />
<strong>of</strong> <strong>Oncology</strong>, Split, Croatia, 6 Medical <strong>Oncology</strong>, Ramon y Cajal University Hospital,<br />
Madrid and Vall d’Hebron Institute <strong>of</strong> <strong>Oncology</strong> (VHIO), Barcelona, Spain, 7 Pharma<br />
Development Medical Affairs, F H<strong>of</strong>fmann-La Roche Ltd, Basel, Switzerland,<br />
8 PDMA Operations (Biometrics), Stamford Consultants AG on behalf <strong>of</strong> F<br />
H<strong>of</strong>fmann-La Roche Ltd, Basel, Switzerland, 9 Department <strong>of</strong> Medical <strong>Oncology</strong>,<br />
German Breast Group, Neu-Isenburg, Germany<br />
Background: In the TANIA trial (NCT01250379), adding BEV to 2nd-line<br />
chemotherapy (CT) significantly improved 2nd-line progression-free survival (PFS,<br />
primary endpoint; hazard ratio [HR] 0.75, 95% CI 0.61–0.93; p = 0.0068) in<br />
BEV-pretreated LR/mBC. No difference in 3rd-line PFS or overall survival (OS) was<br />
observed. Post hoc analyses explored potential associations between 6 candidate BMs<br />
(based on previous results/biological hypotheses) and 2nd-line PFS and OS.<br />
Methods: Patients (pts) with BEV-pretreated HER2-negative LR/mBC were<br />
randomised to receive 2nd-line CT ± BEV until disease progression (PD), unacceptable<br />
toxicity or withdrawal. At 2nd PD, 3rd-line CT was given without BEV in the CT arm<br />
and with BEV in the BEV + CT arm. Archival primary or metastatic tumour samples<br />
collected before 2nd-line BEV from pts consenting to optional translational research<br />
were analysed by immunohistochemistry using median expression levels for each BM<br />
as the cut-<strong>of</strong>f for high vs low BM subgroups.<br />
Results: Samples (mainly primary tumour) were available from 210 (43%) <strong>of</strong> 494<br />
randomised pts. Baseline characteristics and efficacy in these pts were broadly<br />
representative <strong>of</strong> the ITT population. High CA9 and CD31 were associated with worse<br />
prognosis but larger BEV benefit, although neither was consistently predictive across<br />
endpoints (table). Pts with high CA9 had median PFS <strong>of</strong> 4.6 vs 1.9 mo with BEV + CT<br />
vs CT, respectively; pts with high CD31 had median OS <strong>of</strong> 19.3 vs 13.0 mo,<br />
respectively. No BM was associated with a detrimental BEV effect.<br />
Conclusions: Continued BEV significantly improved 2nd-line PFS irrespective <strong>of</strong> BM<br />
levels in LR/mBC. Exploratory analyses suggested potential predictive effects <strong>of</strong> CA9<br />
(PFS) and CD31 (OS), suggesting involvement <strong>of</strong> tumour and endothelium<br />
characteristics in the therapeutic concept <strong>of</strong> anti-angiogenesis.<br />
Clinical trial identification: EUDRACT 2010-020998-16<br />
Legal entity responsible for the study: F H<strong>of</strong>fmann-La Roche<br />
Funding: F H<strong>of</strong>fmann La Roche<br />
Disclosure: C. Zielinski: Honoraria (Advisory Boards): Roche J. Gligorov: Consultant<br />
for Roche/Genentech and Eisai and honoraria from Novartis/GlaxoSmithKline,<br />
Genomic Health and Teva. N. Marschner: Honoraria Roche for consultancy and<br />
advisory boards, as well as grants for scientific projects. F. Puglisi: Honoraria from<br />
AstraZeneca, Amgen, Celgene, Ipsen, Novartis, Pierre Fabre and Roche. E. Vrdoljak:<br />
Funding for clinical trials from Roche and Pfizer, and consulting honoraria from Bayer,<br />
AstraZeneca, Amgen, Merck, MSD, GlaxoSmithKline, Novartis, Pfizer and Roche. J.<br />
Cortes Castan: Consultancy fees from Roche, Celgene and AstraZeneca, and honoraria<br />
from Roche, Celgene, Novartis and Eisai. S. de Ducla, R. Deurloo: Employee <strong>of</strong> Roche<br />
and holds shares in Roche. V. Easton: Employee <strong>of</strong> Stamford Consultants AG<br />
contracted to Roche. G. von Minckwitz: Institution received research funds from Pfizer,<br />
GSK, San<strong>of</strong>i-Aventis, Amgen, Roche, Novartis, Celgene, Teva, Boehringer-Ingelheim,<br />
AstraZeneca and Myriad Genetics.<br />
1543P<br />
Old friends are better to trust: Repositioning cl<strong>of</strong>azimine and<br />
suramin against triple-negative breast cancer<br />
A. Koval, K. Ahmed, V. Katanaev<br />
Department <strong>of</strong> Pharmacology and Toxicology, University <strong>of</strong> Lausanne, Lausanne,<br />
Switzerland<br />
Background: Triple-negative breast cancer (TNBC) is the breast cancer subtype<br />
currently without targeted therapy. In our previous studies we identified that the<br />
human-use approved drugs cl<strong>of</strong>azimine and suramin have shown a pr<strong>of</strong>ound<br />
inhibitory activity towards Wnt pathway, which TNBC somatic cells use heavily. The<br />
accumulated over decades <strong>of</strong> application <strong>of</strong> these drugs will facilitate enrollment in<br />
clinical trials and repositioning as targeted treatments.<br />
Methods: We have characterized Wnt signaling status in various TNBC somatic and<br />
stem cell lines in presence <strong>of</strong> cl<strong>of</strong>azimine and suramin through WB and<br />
immun<strong>of</strong>luorescence. We have also monitored their effects on cell survival, migration<br />
and colony formation in conventional assays, as well as on apoptosis and cell cycle. We<br />
have also used two mouse xenograft models to study the effects <strong>of</strong> the drugs on tumor<br />
growth in vivo followed by IHC and WB analysis <strong>of</strong> relevant markers <strong>of</strong> Wnt signaling<br />
pathway activation.<br />
Table: 1542P<br />
BM 2nd-line PFS HR (95% CI) Interaction p-value a OS HR (95% CI) Interaction p-value a<br />
≤Median >Median ≤Median >Median<br />
CD31 No. <strong>of</strong> vessels 1.02 (0.68–1.55) 0.60 (0.39–0.93) 0.110 1.42 (0.88–2.27) 0.60 (0.37–0.99) 0.016<br />
CD31 volume fraction 0.85 (0.57–1.29) 0.74 (0.48–1.15) 0.585 1.20 (0.74–1.95) 0.75 (0.47–1.22) 0.179<br />
tVEGF-A 1.10 (0.73–1.65) 0.63 (0.41–0.95) 0.091 0.99 (0.63–1.55) 0.86 (0.53–1.38) 0.626<br />
CA9 cytoplasm H-score 0.92 (0.64–1.30) 0.49 (0.30–0.81) 0.064 0.93 (0.62–1.39) 0.93 (0.54–1.60) 0.878<br />
CA9 membrane H-score 0.90 (0.65–1.27) 0.41 (0.23–0.74) 0.017 0.99 (0.67–1.47) 0.70 (0.38–1.27) 0.258<br />
PD-L1 immune cell 0.84 (0.59–1.19) 0.61 (0.36–1.04) 0.357 1.01 (0.68–1.51) 0.68 (0.37–1.26) 0.196<br />
PD-L1 tumour cell 0.79 (0.58–1.06) 0.96 (0.17–5.38) 0.795 0.92 (0.65–1.29) 0.36 (0.04–3.16) 0.469<br />
CD8 invasive margin 0.77 (0.44–1.33) 1.07 (0.63–1.83) 0.357 0.87 (0.46–1.65) 1.35 (0.73–2.48) 0.313<br />
CD8 tumour centre 0.61 (0.40–0.93) 0.97 (0.63–1.49) 0.155 0.87 (0.55–1.37) 1.00 (0.62–1.63) 0.711<br />
CD163 invasive margin 1.00 (0.55–1.80) 0.96 (0.56–1.64) 0.891 0.76 (0.40–1.44) 1.65 (0.87–3.14) 0.094<br />
CD163 tumour centre 1.09 (0.71–1.67) 0.71 (0.47–1.06) 0.262 0.91 (0.57–1.45) 0.93 (0.58–1.48) 0.886<br />
a Not adjusted for multiplicity. CA9 = carbonic anhydrase 9; PD-L1 = programmed cell death 1 ligand 1; tVEGF-A = tumour vascular endothelial growth factor-A.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw392 | vi533
abstracts<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Results: Both drugs were found active in suppressing growth <strong>of</strong> a panel <strong>of</strong> TNBC cell<br />
lines as well as <strong>of</strong> CSC cell line in vitro, which correlates with their ability to suppress<br />
Wnt signal transduction. As expected, these drugs suppress proliferation as well as<br />
migration <strong>of</strong> the cancer cells – two processes that are governed by Wnt signaling. We<br />
have also investigated if these compounds could be used as the co-treatments by<br />
calculating their combination index. A similar trend was obtained in vivo, where<br />
suramin and cl<strong>of</strong>azimine were able to suppress growth <strong>of</strong> the tumor xenografts without<br />
inducing significant overt side effects. Our data however presumes that suramin unlike<br />
cl<strong>of</strong>azimine must be used at the doses significantly higher than those used for its<br />
intended purpose.<br />
Conclusions: This work is an attempt to translate our previous investigations on the<br />
molecular mechanisms <strong>of</strong> the cl<strong>of</strong>azimine and suramin action in Wnt pathway and<br />
bring these advances to the level <strong>of</strong> clinics. Our results show that their anti-Wnt<br />
activity results in the ability to suppress TNBC growth in vivo with few or no side<br />
effects visible in xenografted animals. Challenges remain however to establish<br />
optimized regimen for their new application in order to maximize their efficacy and to<br />
perform trials with their usage as a co-therapy.<br />
Legal entity responsible for the study: University <strong>of</strong> Lausanne<br />
Funding: Swiss National Science Foundation - SNF<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1545P<br />
The number <strong>of</strong> tumorspheres cultured from CETCs in breast<br />
cancer patients is directly related to stage <strong>of</strong> disease and<br />
administration <strong>of</strong> chemotherapy<br />
M. Pizon, D. Schott, U. Pachmann, K. Pachmann<br />
Transfusion Center Bayreuth, Transfusion Center Bayreuth, Bayreuth, Germany<br />
Background: Breast cancer is one <strong>of</strong> the leading causes <strong>of</strong> cancer death for women<br />
worldwide. Major hurdles for a successful treatment are cancer metastasis, resistance to<br />
therapy and disease recurrence. The presence <strong>of</strong> CETCs is closely related to metastasis<br />
formation, but the mechanisms through which CETCs promote recurrence <strong>of</strong> disease<br />
are still unclear. Therefore, the aim <strong>of</strong> this study was to determine the proliferative<br />
capacity <strong>of</strong> CETCs by analyzing the frequency <strong>of</strong> tumorsphere formation with<br />
subsequent phenotypic characterization <strong>of</strong> the spheres arising in breast cancer patients.<br />
Methods: CETCs were cultured under conditions favoring growth <strong>of</strong> tumorspheres<br />
from 72 patients with breast cancer, including a subpopulation <strong>of</strong> 23 patients with<br />
metastatic disease. Cell viability, stem cell marker expression and ALDH 1 activity was<br />
evaluated by fluorescence scanning microscope (Olympus Scan®R).<br />
Results: Sphere formation was observed in 79 % <strong>of</strong> patients with breast cancer. In the<br />
current study we found that the number <strong>of</strong> tumorspheres depended on stage <strong>of</strong> disease.<br />
Patients in stage IV had statistically significant more tumorspheres compared to<br />
patients in stage I (median 6 vs. 2; =0.002). The most important factor for growing <strong>of</strong><br />
tumorspheres is obtaining chemotherapy. Patients with chemotherapy treatment had<br />
lower numbers <strong>of</strong> tumorspheres compared to patients without chemotherapy (median<br />
2 vs. 5; =0.002). Interestingly, patients with HER2 positive primary tumor had higher<br />
number <strong>of</strong> tumorspheres with median 10. Analysis <strong>of</strong> surface marker expression pr<strong>of</strong>ile<br />
<strong>of</strong> tumorspheres showed that spheres cultured from CETCs had typical phenotype <strong>of</strong><br />
cancer stem cells with a high enzymatic activity for ALDH 1. There was no sphere<br />
formation in a control group with 50 healthy donors.<br />
Conclusions: This study demonstrates that a small fraction <strong>of</strong> CETCs has proliferative<br />
activity. Identifying the CETC subset with cancer stem cell properties may provide<br />
more clinically useful prognostic information. Chemotherapy is the most important<br />
component in cancer therapy because it frequently reduces the number <strong>of</strong><br />
tumorspheres.<br />
Legal entity responsible for the study: N/A<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1546P<br />
Preclinical validation <strong>of</strong> a new tumor imaging agent targeting<br />
aVb3 to detect breast tumor using NIR-light imaging<br />
F. Beurrier 1 , I. Treilleux 2 , Y. Chen 3 ,E.Froc 1 ,P.Gayet 4 , S. Guillermet 4 , P. Rizo 4 ,<br />
N. Chopin 1 , C. Faure 1 , D. Dammaco 1 , S. Klinger 1 , D. Ferraioli 1 , G. Garin 5 ,<br />
A. Dutour 3<br />
1 Surgical Oncolgoy, Centre Léon Bérard, Lyon, France, 2 Biopathology<br />
Department, Centre Léon Bérard, Lyon, France, 3 Basic REsearch Center, Centre<br />
Léon Bérard, Lyon, France, 4 Preclinical development, Fluoptics, Grenoble, France,<br />
5 Clinical Research, Centre Léon Bérard, Lyon, France<br />
Background: To date, complete tumor removal during surgery depends on surgeon’s<br />
ability to differentiate tumor from normal tissue. AngioStamp TM which binds αvβ3<br />
integrin is a new fluorescent agent for imaging during cancer surgery. It conscists <strong>of</strong> a<br />
cyclodecapeptide scaffold with 4 cyclic Arg-Gly-Asp (RGD) pentapeptide motifs on<br />
one side, and a fluorescent dye on the other side. We conducted preclinical studies to<br />
evaluate the distribution <strong>of</strong> AngioStamp TM in vivo in mouse breast tumor model and<br />
to determine the expression <strong>of</strong> αvβ3 integrin on human breast specimens.<br />
Methods: The capacity <strong>of</strong> AngioStamp TM to target αvβ3 integrin was assessed in 4T1<br />
breast tumor model. After tumor implantation, mices were injected with<br />
AngioStamp TM or a saline solution (control group). Detection <strong>of</strong> the tumors was<br />
performed at different timepoints (early, progressive and established tumors, N= 24<br />
mices/ timepoints) using near infrared (NIR) imaging system (Fluobeam TM ) to detect<br />
fluorescence in tumor tissue. In parallel, we evaluated the expression <strong>of</strong> αvβ3 integrin<br />
in normal breast tissue, benign lesions (N = 20) and various tumors subtypes (N = 120)<br />
by immunohistochemistry.<br />
Results: In mice injected with AngioStamp TM , fluorescence was observed only within<br />
the tumors with low background. AngioStamp TM labeled tumors at all timepoints. No<br />
false negative fluorescence was found as confirmed by histopathological analyses. In<br />
humans, the αvβ3 integrin are expressed in normal breast epithelial cells and benign<br />
metaplastic or proliferative epithelial lesions. However, due to the density <strong>of</strong><br />
carcinomatous cells, the level <strong>of</strong> expression was much higher in breast cancer: 94% <strong>of</strong><br />
invasive ductal carcinomas and 100% <strong>of</strong> invasive lobular carcinomas had a<br />
membranous staining (moderate to high intensity). Expression in breast cancer was not<br />
restricted to tumor subtypes neither hormone receptor expression nor SBR grade.<br />
Conclusions: Based on this preclinical demonstration, AngioStamp TM could allow a<br />
better per-operative detection <strong>of</strong> tumor bed in breast cancer, increasing the efficiency <strong>of</strong><br />
surgical procedure especially for infraclinic disease and decreasing the rate <strong>of</strong> second<br />
surgery. Preclinical development is ongoing and the first clinical trial is expected in<br />
2017.<br />
Legal entity responsible for the study: Frederic Beurrier<br />
Funding: CAnceropole Rhone Alpes Auvergne<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1547P<br />
Germline and somatic multi-gene sequencing in patients<br />
(pts) with advanced high grade serous ovarian cancer<br />
(HGSOC) and triple negative breast cancer (TNBC)<br />
N. Stjepanovic 1 , M. Wilson 1 , V. Mandilaras 1 , B. Clarke 2 , H. Berman 2 , R.H. Kim 1 ,<br />
S. Lheureux 1 , S. Randall Armel 1 , J. McCuaig 1 , A. Volenik 1 , R. Demsky 1 ,H.Chow 1 ,<br />
M. Mysura 3 , L. Siu 1 , P. Bedard 1 , S. Kamel-Reid 3 , T. Stockley 3 , A. Oza 1<br />
1 Division <strong>of</strong> Medical <strong>Oncology</strong> & Hematology, Princess Margaret Hospital,<br />
Toronto, ON, Canada, 2 Department <strong>of</strong> Pathology and Laboratory Medicine,<br />
Princess Margaret Hospital, Toronto, ON, Canada, 3 Genome Diagnostics,<br />
Laboratory Medicine Program, Princess Margaret Hospital, Toronto, ON, Canada<br />
Background: Genomic similarities <strong>of</strong> HGSOC and TNBC include germline pathogenic<br />
variants (GPV) in BRCA1/2 and somatic mutations in homologous recombination<br />
(HR) genes. Non-BRCA GPV in HGSOC and TNBC pts have also been identified<br />
through multi-gene Next Generation Sequencing (NGS). Somatic multi-gene analysis<br />
can identify pts with acquired HR mutations for trials with novel targeted drugs, like<br />
PARP inhibitors.<br />
Methods: Study cohort included HGSOC and TNBC pts unselected for family history<br />
or age at diagnosis, enrolled in an institutional molecular screening program<br />
(NCT01505400). DNA extracted from matched blood and tumor samples (FFPE) was<br />
additionally tested using a lab-developed NGS Hereditary Cancer Panel <strong>of</strong> 52 cancer<br />
predisposition genes, including 11 HR genes. Medical records were reviewed for<br />
clinical course, pathology and prior germline testing results. All pts consented for<br />
research on banked samples and return <strong>of</strong> GPV by a genetic counsellor.<br />
Results: Of 58 analyzed pts 48 (83%; 8/17 TNBC and 40/41 HGSOC) had prior<br />
germline testing, which revealed GPV in 17 pts: BRCA1 (12 pts), BRCA2 (4 pts) and<br />
PALB2 (1 pt). We identified previously unknown GPV in five pts (9%; see table) and a<br />
potentially clinically relevant RAD51 variant in a previously known germline BRCA1<br />
carrier with HGSOC.<br />
Table: 1547P<br />
Pt Cohort New GPV Prior germline testing<br />
1 TNBC BRCA2 Patient declined<br />
2 TNBC BRCA1 + CHEK2 Provincial testing criteria not met<br />
3 HGSOC CHEK2 BRCA1/2 wild type (WT)<br />
4 HGSOC PALB2 BRCA1/2 WT<br />
5 HGSOC FANCC BRCA1/2 WT<br />
Among 22 GPV carriers, three HGSOC pts (14%) also had somatic mutations in HR<br />
genes (BRCA1, FANCD2), in addition to their GPV that were present in the tumor. Of<br />
36 germline WT pts, five HGSOC pts (14%) had somatic mutations in HR genes<br />
(BRCA1/2, FANCD2), including one who achieved a partial response on a clinical trial<br />
with a PARP inhibitor.<br />
Conclusions: Comprehensive germline and tumor analysis with 52 gene panel in<br />
advanced HGSOC and TNBC found previously unidentified GPV in 9% <strong>of</strong> pts and<br />
somatic mutations in HR genes in 14% <strong>of</strong> germline WT pts. This increases options for<br />
targeted therapeutics with investigational agents, such as PARP inhibitors.<br />
Legal entity responsible for the study: Princess Margaret Cancer Centre<br />
Funding: AstraZeneca<br />
vi534 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Disclosure: M. Wilson, S. Lheureux: Consulting/Advisory for AstraZeneca. L. Siu:<br />
Consulting-Advisory: Oncoethix, Novartis, Daiichi Sankyo, Boehringer, Merck/Family<br />
Member-Leadership: Agios; Ownership Interests: Agios,Entremed/Research. Funding:<br />
Abraxis, Celgene, BMS, Genentech/Roche, GSK, Merck, Novartis, Pfizer, MedImmune,<br />
AstraZeneca, Boehringer. P. Bedard: Consulting/Advisory: Pfizer, Genentech/Roche,<br />
San<strong>of</strong>i Research Funding: Bristol-Myers Squibb, San<strong>of</strong>i, AstraZeneca, Genentech/<br />
Roche, SERVIER, GlaxoSmithKline, Oncothyreon, Novartis, SignalChem, PTC<br />
Therapeutics. A. Oza: Consulting/Advisory: Amgen, Verastem, Clovis <strong>Oncology</strong>,<br />
Immunovaccine Honoraria: WebRx Research Funding: AstraZeneca, Roche, Merck,<br />
AstraZeneca Travel, Accommodations, Expenses: AstraZeneca. All other authors have<br />
declared no conflicts <strong>of</strong> interest.<br />
1548P<br />
Organotypic slice ovarian cancer model as a platform to test<br />
novel therapeutics<br />
A. Michael 1 , G. Falgari 1 , N. Annels 1 , P. Ellis 2 , W. Ashbourne 2 , S. Butler Manuel 2 ,H.<br />
S. Pandha 1<br />
1 School <strong>of</strong> Biosciences and Medicine, Leggett Building, University <strong>of</strong> Surrey,<br />
Guildford, UK, 2 Gynaecological <strong>Oncology</strong>, Royal Surrey County Hospital,<br />
Guildford, UK<br />
Background: An effective way to test new drugs in a pre-clinical setting remains a<br />
challenging task. Ovarian cancer models are particularly difficult as the tumours are<br />
very heterogeneous and although progress has been made with testing cell lines derived<br />
from ascites- new platforms are needed. Precision cut tumour slices have been tested<br />
for many years and the technique is improving. Organotypic culture could potentially<br />
<strong>of</strong>fer an platform to test drugs without having to rely on laboratory animal models.<br />
Testing individual tumour’ sensitivity to cytotoxics would allow for a personalized<br />
approach to cancer treatment and would help to avoid some <strong>of</strong> the unnecessary<br />
toxicity. We have developed an organotypic slice ovarian cancer culture model that<br />
allows for testing cytotoxics and targeted agents on tissue taken directly from patients.<br />
Methods: Tumour tissue obtained from patients undergoing operation for ovarian<br />
cancer was biopsied using a core punch biopsy. The tumours were sliced on a vibrating<br />
microtome into 300 µm thick slices and cultivated in culture. Slices were harvested at<br />
various time points and fixed in 10% buffered formalin before embedding in paraffin.<br />
The viability, morphology, and proliferation index <strong>of</strong> the cultivated slices were analysed<br />
by immunochemistry (IHC) using H&E, ki67, cleaved Caspase 3 assay and compared<br />
to the original tumour biopsy. The cultivated tumour slices were also treated with<br />
cisplatin and saline control.<br />
Results: Core punch biopsies were obtained from 18 high grade serous ovarian tumors<br />
and one endometroid tumour and cultured for up to seven days. The tissue viability<br />
assessed using ki67 showed high proliferation rate at the start <strong>of</strong> the culture and low<br />
levels <strong>of</strong> apoptosis. The apoptosis index varied depending on the individual culture<br />
conditions and the number <strong>of</strong> necrotic cells have increased. The morphology <strong>of</strong> the<br />
tissue was retained throughout. Following administration <strong>of</strong> cisplatin we were able to<br />
observe clear signs <strong>of</strong> necrotic and apoptotic cell death. The platform is currently being<br />
used to test the effect <strong>of</strong> other cytotoxics as well as novel drugs.<br />
Conclusions: Organotypic slice ovarian cancer model is a new way <strong>of</strong> assessing<br />
sensitivity to anticancer agents and has promising potential for use in personalized<br />
cancer treatment<br />
Legal entity responsible for the study: University <strong>of</strong> Surrey<br />
Funding: Grace Charity<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1549P<br />
Response to savolitinib (AZD6094/HMPL-504, a potent and<br />
selective MET inhibitor) in a papillary renal cell carcinoma<br />
patient harbouring a novel MET activating mutation<br />
M.M. Frigault 1 , D. Stetson 1 , E. Maloney 2 , J.F. Kramkowski 3 , E. Barry 1 ,E.<br />
K. Lamberth 4 , S. Signoretti 5 ,C.D’Cruz 6 , B. Dougherty 1 , J.C. Barrett 7 ,T.<br />
K. Choueiri 8<br />
1 <strong>Oncology</strong> Translational Science, AstraZeneca PLC, Boston, MA, USA, 2 <strong>Oncology</strong><br />
Science, AstraZeneca PLC, Boston, MA, USA, 3 The Lank Center for Genitourinary<br />
<strong>Oncology</strong>, Dana-Farber Cancer Institute, Boston, MA, USA, 4 Cinical Operations,<br />
Sarah Cannon Research Institute, Nashville, TN, USA, 5 Pathology, Brigham and<br />
Women’s Hospital, Boston, MA, USA, 6 BioScience, AstraZeneca, Boston, MA,<br />
USA, 7 <strong>Oncology</strong> Translational Science, AstraZeneca PLC, Boston, MA, USA,<br />
8 Medical <strong>Oncology</strong>, Dana-Farber Cancer Institute, Boston, MA, USA<br />
Background: A 56 year old woman was enrolled on a phase II trial to evaluate the<br />
efficacy <strong>of</strong> AZD6094 (HMPL-504) in patients with papillary renal cell carcinoma<br />
(PRCC) (NCT02127710) in September 2014. A diagnostic sample was collected from<br />
the patient in December 2012 during resections <strong>of</strong> several metastatic lesions to the<br />
abdominal lymph nodes. This archival tumor sample was analyzed by central<br />
pathology demonstrating high grade, poorly differentiated PRCC Type 2. The patient<br />
started savolitinib on 9/2/14. Prior systemic therapies included suntinib and cytokines<br />
with best response being progressive disease (PD) for both prior lines <strong>of</strong> therapies.<br />
Methods: Next Generation Seqeuncing (NGS) <strong>of</strong> the diagnostic tumor sample<br />
(Foundation Medicine Inc, Cambridge, MA, USA) with a median exon coverage <strong>of</strong><br />
500x demonstrated the existence <strong>of</strong> a MET mutation MET_c.3583C > T with an allele<br />
fraction <strong>of</strong> 24%.<br />
Results: The amino acid substitution <strong>of</strong> L1195F is located in exon 18 within the kinase<br />
domain <strong>of</strong> the MET receptor tyrosine kinase and has been previously reported in<br />
papillary renal carcinoma patients (Schmidt et al Nature Genetics 1997, Albiges et al<br />
CCR 2014). We demonstrate for the first time that this MET L1195F mutant is<br />
actionable. MET L1195F is predicted as an activating mutation (PolyPhen and SIFT)<br />
and is phosphorylated in vitro when overexpressed demonstrating the activation <strong>of</strong><br />
MET. The MET L1195F mutant is demonstrated to be sensitive to savolitinib, a<br />
selective and potent MET inhibitor.<br />
Conclusions: Athough MET L1195F confers tumor control and benefit from<br />
savolitinb, after 36 weeks <strong>of</strong> treatment and 29.7% best tumor shrinkage from the<br />
baseline tumor measurement, the patient in which we found this mutation<br />
unfortunately relapsed and died shortly after. Plasma samples were collected from this<br />
subject prior to treatment, during the course <strong>of</strong> savolitinib treatment and upon relapse.<br />
NGS analysis <strong>of</strong> circulating tumor DNA (ctDNA) isolated from plasma can be used to<br />
monitor for emerging mechanisms <strong>of</strong> resistance to treatment. Characterization <strong>of</strong> the<br />
mechanisms <strong>of</strong> resistance to savolitinib will provide rationale for the management <strong>of</strong><br />
such patients going forward.<br />
Clinical trial identification: NCT02127710<br />
Legal entity responsible for the study: AstraZeneca PLC<br />
Funding: AstraZeneca PLC<br />
Disclosure: M.M. Frigault, D. Stetson, E. Maloney, E. Barry, B. Dougherty, J.C. Barrett,<br />
C. D’Cruz: Employed by AstraZeneca. All other authors have declared no conflicts <strong>of</strong><br />
interest.<br />
1550P<br />
abstracts<br />
Investigating the combination <strong>of</strong> bevacizumab and the EGF<br />
receptor inhibitor erlotinib for the treatment <strong>of</strong> metastatic<br />
renal cell carcinoma<br />
R. Grepin 1 , M. Guyot 2 , J. Durivault 1 , B. Front 1 , D. Ambrosetti 3 , G. Pagès 2<br />
1 Medical Biology, Centre Scientifique de Monaco, Monaco, Monaco, 2 CNRS UMR<br />
7284/INSERM U 1081, University Nice Sophia Antipolis, Institute for Research on<br />
Cancer and Aging, Nice, France, 3 Laboratoire central d’anatomopathologie,<br />
Hôpital Pasteur, Nice, France<br />
Background: One <strong>of</strong> the major characteristics <strong>of</strong> metastatic clear cell renal cell<br />
carcinomas (RCC) is the over-expression <strong>of</strong> the Vascular Endothelial Growth Factor<br />
(VEGF). Several treatments against this pro-angiogenic factor are usually used such as<br />
sunitinib or the anti-VEGF bevacizumab (BVZ). In a mouse experimental model <strong>of</strong><br />
RCC we have described that BVZ accelerated tumor growth. A down-regulation <strong>of</strong><br />
phospho tyrosine phosphatase receptor kappa (PTPRk) by tumor cells under the<br />
selection pressure exerted during BVZ treatment is a potential explanation for this<br />
accelerated growth. The main target <strong>of</strong> PTPRk is the Epidermal Growth Factor<br />
Receptor (EGFR). Thus, down-regulation <strong>of</strong> PTPRk leads to a constitutive activation <strong>of</strong><br />
the EGFR. According to the literature BVZ combined with ERLO does not benefit<br />
patients. However, the EGFR mutations were not checked in this clinical study.<br />
Considering these data, a combination <strong>of</strong> an inhibitor <strong>of</strong> EGFR (erlotinib/Tarceva)<br />
with the BVZ/interferon alpha (INF) treatment could be more efficient against RCC<br />
growth.<br />
Methods: Tumor cells were injected subcutaneously, bioluminescence was quantified<br />
by using an in vivo Imaging System.<br />
Results: The BVZ/INF/ERLO treatment strongly reduced tumor volume and no tumor<br />
relapse has been observed compared to the reference treatment sunitinib. The triple<br />
combination reduces the production <strong>of</strong> redundant pro-angiogenic/pro-inflammatory<br />
cytokines <strong>of</strong> the ELR + CXCL family and induces a polarization <strong>of</strong> macrophages<br />
towards the M1 phenotype. The number <strong>of</strong> lymphatic vessels is inferior in tumors<br />
receiving this combination compared to the tumors <strong>of</strong> BVZ/INF or ERLO treated mice.<br />
Although no study has shown that BVZ combined with ERLO does not benefit<br />
patients, the EGFR mutations were not checked in this clinical study. Based on cells<br />
isolated from human RCC tumors we have identified a new mutation <strong>of</strong> the EGFR in<br />
human RCC, which could discriminate sensitive and insensitive patients to ERLO.<br />
Conclusions: Together, our results indicate that BVZ/INF treatment could be more<br />
efficient in RCC if it is coupled to ERLO when a specific mutation <strong>of</strong> the EGFR is<br />
present. In conclusion BVZ/INF/ERLO is a relevant combination that deserves to be<br />
tested for the treatment <strong>of</strong> RCC.<br />
Legal entity responsible for the study: Centre Scientifique Monaco<br />
Funding: Centre Scientifique Monaco<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw392 | vi535
abstracts<br />
1551P<br />
Epithelial to mesenchymal transition induces autophagy in<br />
renal cell carcinoma: Implications in cancer therapy<br />
S. Bhattacharyya 1 , M. Singla 1 , A. Bal 2 , S.K. Singh 3 , A.K. Mandal 3<br />
1 Department <strong>of</strong> Biophysics, Post Graduate Institute <strong>of</strong> Medical Education and<br />
Research (PGIMER), Chandigarh, India, 2 Department <strong>of</strong> Histopathology, Post<br />
Graduate Institute <strong>of</strong> Medical Education and Research (PGIMER), Chandigarh,<br />
India, 3 Department <strong>of</strong> Urology, Post Graduate Institute <strong>of</strong> Medical Education and<br />
Research (PGIMER), Chandigarh, India<br />
Background: Epithelial to mesenchymal transition (EMT) contributes to the<br />
metastatic and invasive potential <strong>of</strong> tumors including renal-cell carcinoma (RCC).<br />
Various preclinical and clinical results have indicated that dysregulated elements<br />
leading to EMT can be a potential target in RCC. We assessed the expression pr<strong>of</strong>ile <strong>of</strong><br />
EMT associated genes in surgically resected tumor tissue and targeted the survival<br />
mechanism <strong>of</strong> EMT-induced cells.<br />
Methods: We studied the expression <strong>of</strong> epithelial marker (E-cadherin), mesenchymal<br />
markers (Snail, Slug, Vimentin, Twist) and cancer stem cell marker (ALDH1) in 71<br />
patients <strong>of</strong> histologically proven RCC. These were analysed in both tumor section and<br />
the adjoining normal looking parenchyma by real time PCR and Western immunoblot.<br />
In vitro studies were carried out in primary cultures and RCC cell line (A498) where<br />
EMT was induced pharmacologically using tumor growth factor-beta (TGF-β, 10ng/<br />
ml). Autophagy was assessed in EMT induced cells by acridine orange staining.<br />
Tetrazolium dye, (MTT) 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium<br />
bromide assay and propidium iodide (PI)-Annexin staining were done to evaluate<br />
post-treatment cell survival in EMT cells with temsirolimus and autophagy inhibitor,<br />
choloroquine.<br />
Results: Epithelial marker, E-cadherin was significantly down-regulated in tumor<br />
tissue while expression <strong>of</strong> mesenchymal and cancer stem cell markers increased in<br />
tumor tissue as compared to adjoining normal tissue. EMT signature proteins showed<br />
an increase in in vitro culture <strong>of</strong> primary cells from tumor tissue as well as in EMTinduced<br />
A498 cells. We also observed increased invasiveness and autophagy in EMT<br />
induced A498 cells and primary tumor cells as compared to the normal cells. It was<br />
observed that addition <strong>of</strong> autophagy inhibitor (chloroquine) with temsirolimus to<br />
EMT-induced cells decrease their viability. Annexin-PI assay showed a significant cell<br />
death in combination <strong>of</strong> chloroquine and temsirolomus on EMT induced cells.<br />
Conclusions: Our study shows that the process <strong>of</strong> EMT is involved in the metastatic<br />
spread <strong>of</strong> RCC and autophagy helps in survival <strong>of</strong> the EMT-induced cells. Thus,<br />
inhibition <strong>of</strong> autophagy might represent a future therapeutic option.<br />
Legal entity responsible for the study: Postgraduate institute <strong>of</strong> Medical Education<br />
and Research, Chandigarh, India<br />
Funding: Postgraduate institute <strong>of</strong> Medical Education and Research, Chandigarh,<br />
India<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1552P<br />
Toward therapeutic drug monitoring <strong>of</strong> everolimus? Results<br />
<strong>of</strong> an exploratory study <strong>of</strong> the dose-exposure relationships<br />
S. Falkowski 1 , M. Deppenweiler 2 , C. Monchaud 3 , F. Saint-Marcoux 3 ,<br />
M-L. Laroche 2 , N. Picard 3 , L. Venat-Bouvet 1 , N. Tubiana-Mathieu 1 , P. Marquet 3 ,<br />
J-B. Woillard 3<br />
1 Medical <strong>Oncology</strong>, CHU Limoges - Hopital Dupuytren, Limoges, France,<br />
2 Department <strong>of</strong> Pharmacology, Toxicology and Pharmacovigilance, CHU Limoges<br />
- Hopital Dupuytren, Limoges, France, 3 Department <strong>of</strong> Pharmacology, Toxicology<br />
and Pharmacovigilance; INSERM UMR 850; Univ Limoges, CHU Limoges -<br />
Hopital Dupuytren, Limoges, France<br />
Background: The efficacy <strong>of</strong> everolimus (EVR) has been demonstrated in the treatment<br />
<strong>of</strong> (i) hormone receptor-positive advanced breast cancer (ii) metastatic renal cell cancer<br />
and (iii) neuroendocrine tumours <strong>of</strong> pancreatic origin. The recommended dosage <strong>of</strong><br />
EVR is 10 mg once daily but contrary to transplantation, therapeutic drug monitoring<br />
(TDM) <strong>of</strong> EVR is not mandatory and no blood trough levels (C 0 ) have been defined.<br />
The aims <strong>of</strong> this study were (i) to determine C 0 that could predict the occurrence <strong>of</strong><br />
toxicities and (ii) to investigate the relationship between polymorphisms <strong>of</strong> candidate<br />
genes and C 0 .<br />
Methods: This monocentric retrospective observational study was carried out over 4<br />
months in 54 patients on EVR for breast, renal or neuroendocrine cancer. Clinical,<br />
biological and radiologic data were collected from the patients’ medical records.<br />
Toxicity was defined by temporary interruption and/or dose reduction <strong>of</strong> EVR.<br />
Patients’ exposure to EVR was dichotomized by ROC curve. The association between<br />
exposure and toxicity was then determined using a Cox model for repeated events. The<br />
impact <strong>of</strong> CYP3A4*22 and CYP3A5*3 SNPs on C 0 was investigated by generalized<br />
estimating equation.<br />
Results: Forty-two patients (77.8%) had breast cancer, 10 (18.5%) had renal cell cancer<br />
and 2 (3.7%) had neuroendocrine cancer. Toxicity (all grades) was reported in 75.9% <strong>of</strong><br />
the patients (EVR discontinuation in 25.9% patients). Haematological disorders were<br />
observed in the majority <strong>of</strong> toxicity cases (22%). The EVR C 0 threshold determined by<br />
ROC analysis was 26.3 µg/L (Sen = 0.38,Spe = 0.88). The risk <strong>of</strong> toxicity was increased<br />
4-fold for C 0 > 26.3 µg/L (HR= 4.12, IC95% = [1.48-11.5], p = 0.0067). C 0 was<br />
significantly lower in carriers <strong>of</strong> at least one CYP3A5*1 allele<br />
(intercept (expressors) = 10.72 ± 1.45, β non expressors = +6.32 ± 2.22, p = 0.0044). No<br />
association between carriers <strong>of</strong> CYP3A4*22 variant and blood trough C 0 was found.<br />
Conclusions: An EVR C 0 > 26.3 µg/L was associated with an increased 4-fold risk <strong>of</strong><br />
toxicity, with a specificity <strong>of</strong> 88%. The genetic polymorphism CYP3A5*3 has an<br />
important impact on EVR exposure. These results provide elements <strong>of</strong> pro<strong>of</strong> in favour<br />
<strong>of</strong> using EVR TDM in oncology.<br />
Legal entity responsible for the study: CHU Dupuytren, Limoges<br />
Funding: INSERM UMR 850; CHU Dupuytren, Limoges<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1553P<br />
The role <strong>of</strong> immune system on the efficacy <strong>of</strong> bevacizumab in<br />
patients with metastatic colorectal cancer (mCRC)<br />
H. Akbulut, M. Ocal, G. Sonugur, B. Akay, C. Babahan, S. Abdi Abgarmi,<br />
A. Demirkazik, F. Icli<br />
Medical <strong>Oncology</strong>, Ankara University School <strong>of</strong> Medicine, Ankara, Turkey<br />
Background: We aimed to investigate the role <strong>of</strong> anti-bevacizumab antibodies,<br />
regulatory T, CD4+ and CD8+ cells on the efficacy <strong>of</strong> bevacizumab plus chemotherapy<br />
combination in patients with mCRC.<br />
Methods: Thirty consecutive patients treated with bevacizumab plus either irinotecan<br />
or oxaliplatin based chemotherapy regimens were included. The levels <strong>of</strong> Tregs<br />
(CD4 + CD25(hi)FoxP3+), CD4+ and CD8+ cells from peripheral blood were assayed<br />
by flow cytometry before the onset and after 4 cycles <strong>of</strong> bevacizumab. The<br />
anti-bevacizumab antibody levels were assayed by ELISA 3 months after the onset <strong>of</strong><br />
bevacizumab.<br />
Results: The median age was 59 years. The majority <strong>of</strong> the patients had metastatic<br />
disease at the time <strong>of</strong> diagnosis. The chemotherapy backbone was FOLFIRI in 75% <strong>of</strong><br />
the patients. The median number <strong>of</strong> treatment cycles was 7. The objective response<br />
(OR) and disease stabilization rates were 30% and 73.3%, respectively. The median<br />
progression-free survival (PFS) and overall survival times were 8.0 and 16.0 months.<br />
Four patients had measurable anti-bevacizumab levels. There was no OR in patients<br />
with measurable anti-bevacizumab antibody levels. The levels <strong>of</strong> Treg cells were<br />
between 0.15 and 4.82% (median 0.40%) and the ratio <strong>of</strong> CD4 + /CD8+ cells between<br />
0.91 and 4.30 (median 1,9) on peripheral blood before the treatment. There were no<br />
significant changes in the levels <strong>of</strong> Tregs and the ratio <strong>of</strong> CD4 + cell/CD8+ cells on<br />
bevacizumab treatment. The patients with higher CD4 + /CD8+ cells before the<br />
bevacizumab had favorable PFS times (14 vs 6 mos, P = 0.065). The patients having low<br />
Treg levels after 4 cycles <strong>of</strong> bevacizumab had favorable PFS time (14 vs 7 mos,<br />
p = 0.061). The chemotherapy backbone had no significant effect on trial parameters.<br />
Conclusions: The Tregs and the ratio <strong>of</strong> CD4+ /CD8 + cells could be predictors <strong>of</strong> PFS<br />
for bevacizumab treatment in patients with mCRC. The pre-treatment ratio <strong>of</strong> CD4+<br />
/CD8+ cells, the levels <strong>of</strong> Tregs and anti-bevacizumab antibodies might influence the<br />
efficacy <strong>of</strong> long term use <strong>of</strong> bevacizumab in patients with mCRC. The improved PFS in<br />
patients having lower Tregs after bevacizumab treatment may provide a rationale for<br />
the combination <strong>of</strong> bevacizumab and immune checkpoint inhibitors.<br />
Legal entity responsible for the study: N/A<br />
Funding: TUBITAK (The Scientific and Technological Research Council <strong>of</strong> Turkey)<br />
(Grant# 114S496)<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1554P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
The role <strong>of</strong> Krüppel-like factor (KLF5) and its mechanism for<br />
treatment resistance in preoperative chemoradiation therapy<br />
for rectal cancer<br />
J.Y. Kim 1 , S.G. Park 2 , N.K. Kim 3<br />
1 Department <strong>of</strong> surgery, Hallym university College <strong>of</strong> medicine, Kungki-do,<br />
Republic <strong>of</strong> Korea, 2 Department <strong>of</strong> surgery, Hallym university, Kungki-do, Republic<br />
<strong>of</strong> Korea, 3 Department <strong>of</strong> surgery, Yonsei cancer center, Seoul, Republic <strong>of</strong> Korea<br />
Background: The aim <strong>of</strong> this study was to determine whether Krüppel-like factor 5<br />
(KLF5) expression in pre-irradiation tumor biopsies is a useful predictive marker <strong>of</strong><br />
tumor response in patients with rectal cancer<br />
Methods: This study included 60 human colon tumor pre-irradiation specimens.<br />
Expression was studied by immunohistochemistry(IHC) using scoring system(0-15).<br />
Functional roles <strong>of</strong> KLF5 were analysed by over-expression <strong>of</strong> the protein in colon<br />
cancer cell line. Protein interactions were studied by stress induction such as chemo or<br />
radiation and MTT assays.<br />
Results: Complete remission was achieved by 9(18%) patients. Tumor regression was<br />
significantly related with p53 and KLF5(p = 0.021,p = 0.004,respectfully). The KLF5<br />
IHC score significantly correlated with KRAS mutation status(5.92 ± 2.54 vs<br />
8.44 ± 1.94,p = 0.006),and pCR(4.11 ± 2.61 vs 6.68 ± 2.43,p = 0.005). In HCT 116 cell<br />
line, KLF5 protein was significantly increased after radiation therapy, suggesting that<br />
KLF5 via cyclin D1, b-catenin. HCT 116 with KLF5 overexpression exhibited<br />
significantly better cell viability compared to control cells in MTT assay.<br />
vi536 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Conclusions: Overexpression <strong>of</strong> KLF5 might be predictive <strong>of</strong> poor tumor regression<br />
after preoperative CRT. Our study suggests IHC <strong>of</strong> KLF5 as a possible biomarker to<br />
predict complete remission and T-down staging. Our study suggests KLF5 has a role to<br />
get resistance to chemo-radiation therapy in rectal cancer treated preoperative CRT.<br />
Legal entity responsible for the study: N/A<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1555P<br />
The role <strong>of</strong> p21 activated kinase (PAK) in human colorectal<br />
cancer cell lines and resistance to cetuximab<br />
A. Servetto, V. D’Amato, R. Rosa, C. Di Mauro, P. Ciciola, R.C. Orsini,<br />
R. Marciano, S. de Placido, R. Bianco<br />
Medicina Clinica e Chirurgia, University <strong>of</strong> Naples Federico II, Naples, Italy<br />
Background: The sensitivity to anti-EGFR targeted agents depends on the KRAS/<br />
NRAS mutational status in colorectal cancer (CRC). Ras mutations, by disabling its<br />
intrinsic GTPase activity, increase EGFR-independent activation <strong>of</strong> PI3K/AKT and<br />
MAPK pathways. In CRC up to 25% <strong>of</strong> patients are refractory to EGFR-based<br />
therapies, even in absence <strong>of</strong> RAS mutations. We need to identify alternative signaling<br />
pathways that sustain the constitutive/acquired resistant phenotype. p21 Activated<br />
Kinase (PAK) family proteins play an important role in many cellular processes, being<br />
involved in the context <strong>of</strong> cancer progression. We focused our attention on the role <strong>of</strong><br />
PAK signaling pathway in the onset <strong>of</strong> cetuximab resistance.<br />
Methods: We used different human colorectal cancer cell lines, with distinct KRAS/<br />
NRAS mutational status, including SW48, HT29, HCT116, LS174T, SW480, GEO,<br />
LOVO, SW620. We also generated SW48 cells stably transfected with various KRAS<br />
mutations (G12A, G12D, G12V, G13D). We tested the effects <strong>of</strong> PAK inhibition by<br />
PF-3758309 on cell survival, cell viability and intracellular signal transduction.<br />
Results: All the cell lines are sensitive to the PAK inhibitor PF-3758309, as shown by<br />
the inhibition <strong>of</strong> cell proliferation and cell viability, in both Ras wild type and Ras<br />
mutated cell lines. The treatment with PF-3758309 reduces the phosphorylation <strong>of</strong><br />
various signal transducers downstream to PAKs, such as MEK1 (Ser298), beta-Catenin<br />
(Ser675) CRAF (Ser338). Thus, we evaluated the downregulation <strong>of</strong> distinct PAK<br />
is<strong>of</strong>orms (PAK1, PAK2, PAK4). By western blot analysis we found a more specific<br />
inhibition <strong>of</strong> PAK2 phosphorylation after treatment with PF-3758309. Preliminary<br />
data suggest that combination <strong>of</strong> cetuximab and PF-3758309 enhances sensitivity to<br />
cetuximab in CRC cells, even in presence <strong>of</strong> RAS mutations.<br />
Conclusions: We demonstrated that the PAK inhibitor PF-3758309 is effective in CRC<br />
cell lines, independently from the RAS mutational pr<strong>of</strong>ile. To further study the role <strong>of</strong><br />
different PAK is<strong>of</strong>orms, we are now performing PAK RNA silencing in both RAS wild<br />
type and RAS mutant cell lines. Based on these data, we plan to investigate the role <strong>of</strong><br />
PAK signaling in the onset <strong>of</strong> cetuximab resistance, both in vitro and in vivo.<br />
Legal entity responsible for the study: Department <strong>of</strong> Clinical Medicine and Surgery,<br />
University <strong>of</strong> Naples Federico II, Naples, Italy<br />
Funding: Department <strong>of</strong> Clinical Medicine and Surgery, University <strong>of</strong> Naples Federico<br />
II, Naples, Italy<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1556P<br />
Evaluation <strong>of</strong> exposure <strong>of</strong> regorafenib and its metabolites in<br />
cancer patients with renal impairment by modelling,<br />
simulation, and clinical study<br />
M. Block 1 , B. Ploeger 2 , J. Grevel 3 , K. Schnizler 1 , M. Gerisch 4 , F-T. Hafner 4 ,<br />
S. Reschke 5 , F. Huang 6 , Z.J. Trnkova 5 , I. Sturm 5 , A. Cleton 5<br />
1 Systems Pharmacology <strong>Oncology</strong>, Bayer Technology Services GmbH,<br />
Leverkusen, Germany, 2 Clinical Pharmacometrics, Bayer Pharma AG, Berlin,<br />
Germany, 3 Clinical Pharmacokinetics, BAST Inc. Limited, Loughborough, UK,<br />
4 Drug Metabolism and Pharmacokinetics, Bayer Pharma AG, Wuppertal,<br />
Germany, 5 Clinical Pharmacology <strong>Oncology</strong>, Bayer Pharma AG, Berlin, Germany,<br />
6 Clinical Pharmacology <strong>Oncology</strong>, Bayer HealthCare Pharmaceuticals, Whippany,<br />
NJ, USA<br />
Background: Regorafenib (Stivarga®) is an oral multikinase inhibitor which targets<br />
angiogenic, stromal, and oncogenic receptor tyrosine kinases and is currently approved<br />
in metastatic colorectal cancer and advanced gastrointestinal stromal tumors.<br />
Regorafenib is predominantly metabolized in the liver by cytochrome P450 (CYP) 3A4<br />
and uridinediphosphate-glucuronosyltransferase (UGT) 1A9. As cancer patients<br />
treated with regorafenib may have varying degrees <strong>of</strong> renal impairment,<br />
physiology-based pharmacokinetic (PBPK) modeling and simulation was used to<br />
further estimate the effect <strong>of</strong> renal impairment on the pharmacokinetics (PK) <strong>of</strong><br />
regorafenib and its two pharmacologically active metabolites M-2 and M-5. A phase 1<br />
study (NCT01853046) with regorafenib in cancer patients with severe renal<br />
impairment and a control group with normal renal function or mild renal impairment<br />
was subsequently designed based on the PBPK simulations.<br />
Methods: A PBPK model using in vitro and clinical data was used to characterize the<br />
PK <strong>of</strong> regorafenib. In addition, published data on normal renal function versus<br />
pathophysiological changes typical for patients with renal impairment were integrated,<br />
including changes in CYP 3A4 activity. The impact <strong>of</strong> end-stage renal disease (ESRD;<br />
GFR level
abstracts<br />
ClearCell FX system (Clearbridge Biomedics, Singapore) uses a label-free inertial<br />
micr<strong>of</strong>luidics approach based on biomechanical properties, and is able to capture CTCs<br />
independent <strong>of</strong> EpCAM expression. We investigated tumor biology by genomic<br />
pr<strong>of</strong>iling <strong>of</strong> CTCs using next-generation sequencing (NGS).<br />
Methods: Participants in this prospective study comprised 31 patients with advanced<br />
esophageal cancer (EC), gastric cancer (GC), colorectal cancer (CRC), or head and<br />
neck cancer (HN). CTCs were collected from 5 ml <strong>of</strong> peripheral blood and NGS was<br />
performed after whole-genome amplification (WGA) <strong>of</strong> DNA extracted from CTCs.<br />
Results: Underlying pathology was EC in 8 patients, GC in 1, CRC in 11, and HN in<br />
11. CTCs were detected from peripheral blood <strong>of</strong> all patients (median number <strong>of</strong> CTCs,<br />
14.5/ml; range, 3-133/ml). The most frequently detected mutations in CTCs were to<br />
APC, EGFR, RB1 and SMAD4 (10.5%) in HN and EC, and TP53 (27.2%), MET, RB1,<br />
and SMAD4 (18.2%) in CRC. NGS was successfully performed with WGA-treated<br />
DNA from CTCs and related material.<br />
Conclusions: We were able to effectively capture CTCs from patients with HN, EC, GC<br />
and CRC, and successfully perform NGS <strong>of</strong> CTCs using a micr<strong>of</strong>luidic separation<br />
system without antibodies. The next trial is now ongoing to assess correlations between<br />
emergence <strong>of</strong> gene mutations in CTCs and changes in therapeutic effect during<br />
molecular-targeted therapy.<br />
Legal entity responsible for the study: Kazufumi Honda<br />
Funding: An Japan Agency for Medical Research and Development (AMED)<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1559P<br />
Evaluation <strong>of</strong> exposure <strong>of</strong> regorafenib (REG) and its<br />
metabolites in pediatric patients by modeling, simulation,<br />
and clinical study<br />
B. Ploeger 1 , J. Grevel 2 , M. Frede 3 , M. Block 4 , K. Schnizler 4 , M. Gerisch 5 ,<br />
F-T. Hafner 5 , Z.J. Trnkova 6 , A.C. Agostinho 7 , I. Sturm 6 , A. Cleton 6<br />
1 Clinical Pharmacometrics, Bayer Pharma AG, Berlin, Germany, 2 Clinical<br />
Pharmacometrics, BAST Inc. Limited, Loughborough, UK, 3 Clinical<br />
Pharmacometrics, Bayer Pharma AG, Wuppertal, Germany, 4 Systems<br />
Pharmacology <strong>Oncology</strong>, Bayer Technology Services GmbH, Leverkusen,<br />
Germany, 5 Drug Metabolism and Pharmacokinetics, Bayer Pharma AG,<br />
Wuppertal, Germany, 6 Clinical Pharmacology <strong>Oncology</strong>, Bayer Pharma AG, Berlin,<br />
Germany, 7 Clinical Development <strong>Oncology</strong>, Bayer HealthCare Pharmaceuticals,<br />
Whippany, NJ, USA<br />
Background: REG (Stivarga®) is an oral multikinase inhibitor which is currently<br />
approved in adult patients with metastatic CRC and GIST. A phase 1 dose-finding<br />
study in pediatric patients with solid malignant tumors (EudraCT Number:<br />
2013-003579-36) is ongoing. We used physiology-based (PBPK) and population-based<br />
PK (popPK) modeling and simulation based on knowledge about REG in adult cancer<br />
patients to simulate REG pharmacokinetics (PK) in pediatric patients, to support the<br />
clinical study design, and to evaluate the PK data <strong>of</strong> REG and its two pharmacologically<br />
active metabolites M-2 and M-5.<br />
Methods: A PBPK model, built using data from literature and clinical studies in adult<br />
cancer patients, was used for PK simulation. Then physiological changes were<br />
integrated, including data on the growth and ontogeny <strong>of</strong> PK processes relevant for<br />
REG (e.g., cytochrome P450 3A4 activity) to scale the adult model to children. REG<br />
exposure in children (6 months to 18 years) was simulated to define dosing in the<br />
clinical study. A popPK model was developed based on the PBPK simulations to define<br />
the PK sampling time-points. During the study, exposure was estimated using the<br />
popPK model and compared with the PBPK simulations.<br />
Results: Using a PBPK approach, body surface area normalized dosing was found<br />
superior compared with body weight normalized dosing. The recommended starting<br />
dose for the phase 1 study was 45 and 60 mg/m 2 for patients aged 6 to 24 months and 2<br />
to 18 years, respectively. Sparse sampling with 2–5 samples per subject allowed for<br />
accurate estimation <strong>of</strong> the apparent clearance. The PBPK predictions <strong>of</strong> REG exposure<br />
were slightly higher and that <strong>of</strong> M-2 and M-5 slightly lower compared with the<br />
observed exposure in the phase 1 pediatric study. For example, in the phase 1 trial for<br />
the dose <strong>of</strong> 72 and 82 mg/m 2 , the geometric mean <strong>of</strong> the REG AUC (0–24) based on<br />
nominal dosing was estimated to be 43.1 and 50.1 mg*h/L, respectively.<br />
Conclusions: Application <strong>of</strong> PK modeling provided an increased understanding <strong>of</strong><br />
REG PK in pediatric patients. In addition, it allowed a sparse sampling schedule to<br />
minimize the burden for the patients in the pediatric study and supported the design <strong>of</strong><br />
the clinical study.<br />
Legal entity responsible for the study: Bayer<br />
Funding: Bayer<br />
Disclosure: B. Ploeger, M. Block, K. Schnizler, F-T. Hafner, Z.J. Trnkova, A.C.<br />
Agostinho: Other substantive relationships: Bayer (employee). J. Grevel: Stock<br />
ownership: BAST. M. Frede, I. Sturm: Stock ownership: Bayer. Other substantive<br />
relationships: Bayer (employee). M. Gerisch: Stock ownership: Bayer Other substantive<br />
relationships: Bayer (employee). A. Cleton: Stock ownership: Bayer, AstraZeneca,<br />
Pfizer. Other substantive relationships: Bayer (employee).<br />
1560P<br />
Quantitative evaluation <strong>of</strong> HER2-mediated cellular uptake <strong>of</strong><br />
the HER2-targeted antibody-liposomal doxorubicin<br />
conjugate MM-302 suggests potential for treating<br />
HER2-intermediate tumors<br />
E. Geretti 1 , C. Espelin 1 , B. Adiwijaya 1 , N. Dumont 1 , S. Coma 1 , Z. Koncki 1 ,<br />
G. Garcia 1 , T. Bloom 1 , V. Rimkunas 1 , J. Reynolds 1 , K. Campbell 1 , V. Moyo 1 ,<br />
I. Molnar 1 , P. Lorusso 2 , K. Miller 3 ,C.Ma 4 , I.E. Krop 5 , P. Munster 6 , T. Wickham 1<br />
1 Development, Merrimack Pharmaceuticals, Inc., Cambridge, MA, USA, 2 Yale<br />
School <strong>of</strong> Medicine, Yale Cancer Center, New Haven, CT, USA, 3 <strong>Oncology</strong>,<br />
Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA,<br />
4 Washington University, Washington University School <strong>of</strong> Medicine, St. Louis, MO,<br />
USA, 5 Breast Cancer Treatment Center, Dana Farber Cancer Institute, Boston,<br />
MA, USA, 6 Helen Diller Family Comprehensive Cancer Center, Helen Diller Family<br />
Comprehensive Cancer Center, San Francisco, CA, USA<br />
Background: MM-302 is a HER2-targeted antibody–liposomal doxorubicin conjugate<br />
designed to target doxorubicin to HER2-expressing tumor cells. MM-302 showed an<br />
acceptable safety pr<strong>of</strong>ile and promising activity in a Phase I study in HER2-positive<br />
metastatic breast cancer (NCT01304797), and it is now being evaluated in a Phase II<br />
trial in the same setting (NCT02213744). The goal <strong>of</strong> this work is to determine the<br />
correlation between single-cell HER2 expression and liposome uptake on MM-302<br />
patient biopsies as well as on preclinical tumor models.<br />
Methods: Frozen biopsies were collected 3 days post infusion <strong>of</strong> MM-302 (8-50 mg/m 2 ;<br />
alone or in combination with trastuzumab, with or without cyclophosphamide), and<br />
stained for PEG (surrogate for MM-302), HER2 and cytokeratin, side-by-side with two cell<br />
standard arrays: A PEG array, obtained by cell incubation with increasing amounts <strong>of</strong><br />
MM-302, and a HER2 array, containing a panel <strong>of</strong> cell lines at various HER2 levels. The<br />
HER2 expression and liposome uptake in individual tumor cells <strong>of</strong> the human samples<br />
was quantified based on the PEG and HER2 fluorescent intensities <strong>of</strong> the standards.<br />
MM-302 cellular delivery was investigated in vivo in IHC 0, 1 + , 2+ and 3+ tumor models.<br />
Results: Uptake <strong>of</strong> MM-302 into HER2-expressing cells was detected in ∼80% <strong>of</strong><br />
patient biopsies. Interestingly, HER2 expression within individual samples was found<br />
to be heterogeneous, ranging from ∼1X10 5 to over 1 X 10 6 HER2 receptors per cell.<br />
Evaluation <strong>of</strong> cellular HER2 expression and MM-302 uptake within the same sample<br />
revealed that the magnitude <strong>of</strong> MM-302 tumor cell uptake was comparable across the<br />
range <strong>of</strong> HER2 expression from ∼1X10 5 to over 1 X 10 6 HER2 receptors per cell.<br />
These findings were in line with preclinical in vivo studies showing HER2-mediated<br />
delivery <strong>of</strong> MM-302 to IHC 1 + , 2 + , and 3+ tumors but not to IHC 0 tumors.<br />
Conclusions: Our data suggest that MM-302 effectively targets tumor cells expressing<br />
various levels <strong>of</strong> HER2 in patients’ tumors. Hence, in addition to treating<br />
HER2-positive patients, MM-302 may be a promising agent for treating patients with<br />
intermediate HER2 expression (HER2 IHC 1 + /2 + , FISH-negative).<br />
Clinical trial identification: NCT01304797<br />
Legal entity responsible for the study: Merrimack Pharmaceuticals, Inc.<br />
Funding: Merrimack Pharmaceuticals, Inc.<br />
Disclosure: E. Geretti, C. Espelin, B. Adiwijaya, N. Dumont, S. Coma, G. Garcia,<br />
T. Bloom, V. Rimkunas, J. Reynolds, K. Campbell, V. Moyo, I. Molnar, T. Wickham:<br />
Stocks ownership from Merrimack Pharmaceuticals, Inc. I.E. Krop: Employment,<br />
Leadership, Stock and Other Ownership Interests: immediate family member (Vertex)<br />
Consulting or Advisory Role: Amgen Research Funding: Genentech Travel,<br />
Accomodations, Expenses: Bayer. All other authors have declared no conflicts <strong>of</strong> interest.<br />
1561P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Survival is associated with circulating cytokine levels in<br />
metastatic testicular germ cell tumors<br />
D. Svetlovska 1 , V. Miskovska 2 , D. Cholujova 3 , P. Gronesova 3 , S. Cingelova 4 ,<br />
M. Chovanec 5 , Z. Sycova-Mila 5 , J. Obertova 6 , P. Palacka 6 , J. Rajec 6 ,<br />
K. Kalavska 7 , V. Usakova 8 , J. Luha 9 , D. Ondrus 2 , S. Spanik 10 , J. Mardiak 6 ,<br />
M. Mego 11<br />
1 Clinical Trials; Translational Research Unit, National Cancer Institute; Faculty <strong>of</strong><br />
Medicine, Comenius University, Bratislava, Slovak Republic, 2 1st Department <strong>of</strong><br />
<strong>Oncology</strong>, Faculty <strong>of</strong> Medicine and St. Elisabeth Cancer Institute, Bratislava,<br />
Slovak Republic, 3 Laboratory <strong>of</strong> Tumor Immunology, Cancer Research Institute,<br />
Slovak Academy <strong>of</strong> Sciences, Bratislava, Slovak Republic, 4 Oncohematology<br />
Clinic, National Cancer Institute, Bratislava, Slovak Republic, 5 Clinical <strong>Oncology</strong>,<br />
National Cancer Institute, Bratislava, Slovak Republic, 6 Clinical <strong>Oncology</strong>; 2nd<br />
Department <strong>of</strong> <strong>Oncology</strong>, National Cancer Institute; Faculty <strong>of</strong> Medicine, Comenius<br />
University, Bratislava, Slovak Republic, 7 Translational Research Unit, Faculty <strong>of</strong><br />
Medicine, Comenius University, Bratislava, Slovak Republic, 8 Internal Medicine,<br />
St. Elisabeth Cancer Institute, Bratislava, Slovak Republic, 9 Institute <strong>of</strong> Medical<br />
Biology, Genetics and Clinical Genetics, Faculty <strong>of</strong> Medicine, Comenius University,<br />
Bratislava, Slovak Republic, 10 1st Department <strong>of</strong> <strong>Oncology</strong>; Internal Medicine,<br />
Faculty <strong>of</strong> Medicine and St. Elisabeth Cancer Institute; St. Elisabeth Cancer<br />
Institute, Bratislava, Slovak Republic, 11 Clinical <strong>Oncology</strong>; Translational Research<br />
Unit; 2nd Department <strong>of</strong> <strong>Oncology</strong>, National Cancer Institute; Faculty <strong>of</strong> Medicine,<br />
Comenius University, Bratislava, Slovak Republic<br />
Background: Cytokines are the communicators <strong>of</strong> immune system and are involved in<br />
almost all immune responses. They have an important role in cancer pathogenesis. The<br />
aim <strong>of</strong> this study was to investigate the association between plasma cytokines and<br />
vi538 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
patient’s/tumor characteristics and prognosis in metastatic chemonaive testicular germ<br />
cell tumors (TGCTs).<br />
Methods: The study population consisted <strong>of</strong> 92 chemonaive metastatic TGCTs<br />
patients, enrolled between July 2010 and March 2014. We analyzed 51 plasma<br />
cytokines at baseline before chemotherapy administration (n = 92) and on cycle 1 day<br />
22 (n = 55) using multiplex bead arrays. Patients were treated with at least one cycle <strong>of</strong><br />
cisplatin-based chemotherapy. Circulating cytokine levels were correlated with tumor<br />
characteristics, progression-free and overall survival as well.<br />
Results: Median age was 32.4 (range 18.4-65.4) years, median follow up was 33.2<br />
month (range 0.1-54.8). Disease progression experienced 10.9 % and 7.6 % <strong>of</strong> patients<br />
died. Several baseline cytokines positively correlated with histology, disease stage,<br />
localization <strong>of</strong> metastases. Elevated baseline levels <strong>of</strong> IFN-alpha 2, IL-2R alpha, IL-16,<br />
HGF, MCP-3 significantly correlated with worse progression-free survival (PFS) and<br />
overall survival (OS) as well, SCGF-beta only with worse OS. Higher levels <strong>of</strong> IL-12p40<br />
measured on day 22 cycle 1 correlated with shorter PFS and OS.<br />
Conclusions: The present study found out significant associations between circulating<br />
cytokines and prognosis and tumour/patient’s characteristics in metastatic TGCTs.<br />
Our findings suggest, that plasma cytokines could be considered as biomarker for<br />
identification <strong>of</strong> high risk patients. In addition, new treatment approaches targeted for<br />
relevant cytokine should be investigated.<br />
Legal entity responsible for the study: National Cancer Institute, Bratislava, Slovak<br />
Republic<br />
Funding: Slovak Research and Development Agency<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
abstracts<br />
<strong>of</strong> patients harbour FGFR1 amplification. However, its role in lung cancer has not yet<br />
been thoroughly described.<br />
Methods: Several lung cell lines with different genetic backgrounds were transfected<br />
with plasmids to either overexpress or silence FGFR1. In these models, several<br />
tumorigenic abilities were tested in vitro and in vivo. Besides, mRNA from<br />
formalin-fixed paraffin-embedded tissue <strong>of</strong> a cohort <strong>of</strong> lung cancer patients was<br />
extracted and FGFR1 expression levels, as well as other histology-specific differentially<br />
expressed genes, were measured and related to clinical characteristics.<br />
Results: FGFR1 increases oncogenic properties in SCC cell lines, but exerts the<br />
opposite effects in several lung ADC cell lines. This behaviour is a consequence <strong>of</strong><br />
differentially expressed genes between these two histologies in the cell lines under<br />
study. According to this, analysis <strong>of</strong> FGFR1 mRNA expression, along with the above<br />
mentioned differentially expressed genes, in a cohort <strong>of</strong> lung cancer patients, reinforced<br />
our in vitro results. In this patient cohort, high FGFR1 mRNA expression was<br />
associated to a shorter overall survival (OS) and progression free survival (PFS) in lung<br />
SCC patients. However, a trend for longer OS was observed for the ADC patients with<br />
higher FGFR1 mRNA expression.<br />
Conclusions: We provide evidence that FGFR1 oncogenic role is dependent <strong>of</strong> its<br />
molecular context, resulting in a differential role for this gene in tumorigenesis. This<br />
involves a differential prognostic role <strong>of</strong> this gene in the two main lung cancer<br />
histologies. The characterization <strong>of</strong> this molecular context may be <strong>of</strong> interest in order<br />
to decide the suitability for a patient to receive anti-FGFR therapy.<br />
Legal entity responsible for the study: CNIO<br />
Funding: ISCIII<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1562P<br />
Mechanisms <strong>of</strong> acquired resistance to the fibroblast growth<br />
factor receptor (FGFR) inhibitor BGJ398 in FGFR driven<br />
bladder cancer<br />
1564P<br />
FGFR4 exerts differential roles in tumorigenesis through a<br />
mechanism <strong>of</strong> cooperation<br />
M. Hodgson-Garms, J. Mariadason, A. Weickhardt<br />
Olivia Newton-John Cancer Research Institute, Latrobe University School <strong>of</strong><br />
Cancer Medicine, Melbourne, Australia<br />
Background: Mutations and fusions <strong>of</strong> the FGFR3 gene occur in 10-20% <strong>of</strong> metastatic<br />
urothelial carcinoma (mUC), and recent in-vitro work demonstrates that these<br />
alterations confer sensitivity to FGFR inhibitors such as BGJ398 (Novartis). Based on<br />
these findings a phase I/II clinical trial <strong>of</strong> BGJ398 in patients with mUC harboring<br />
FGFR3 mutations and fusions is underway. The objective <strong>of</strong> this study was to assess<br />
potential mechanisms <strong>of</strong> acquired resistance to FGFR inhibition in order to develop<br />
rational combination therapies to enhance the efficacy <strong>of</strong> these agents.<br />
Methods: Acquired resistance to the FGFR inhibitor BGJ398 was generated by<br />
continuous exposure <strong>of</strong> the FGFR3 fusion harboring cell lines RT4 and SW780 cells to<br />
increasing concentrations <strong>of</strong> BGJ398. Alterations in cell signaling components and<br />
gene expression between parental and resistant cells were assessed by western blots,<br />
phospho-kinome arrays, and qRT-PCR. Reversal <strong>of</strong> drug resistance was assessed by<br />
withdrawal <strong>of</strong> drug from resistant lines and monitoring <strong>of</strong> cell proliferation.<br />
Results: Acquired resistance to BGJ398 in RT4 and SW780 was associated with<br />
morphological changes consistent with epithelial to mesenchymal transition.<br />
Consistent with these changes, increased mRNA expression <strong>of</strong> the mesenchymal<br />
markers Vimentin and ZEB1 and loss <strong>of</strong> expression <strong>of</strong> the epithelial marker<br />
E-Cadherin was observed in resistant cell lines. In both cell lines resistance was<br />
accompanied by an increase in pErbB3 and a corresponding increase in expression <strong>of</strong><br />
the ErbB3 ligand, NRG1. Additionally, resistant cell lines demonstrated an increase in<br />
pAXL levels and increased expression <strong>of</strong> Fra1 mRNA, a transcriptional activator <strong>of</strong><br />
AXL and known EMT driver. Resistant cell lines were cross resistant to alternative<br />
FGFR inhibitors such as PD173074 (Pfizer). Resistant cell lines rapidly regained<br />
sensitivity to BGJ398 after drug withdrawal <strong>of</strong> 1 month.<br />
Conclusions: Acquired resistance to BGJ398 is associated with acquisition <strong>of</strong> an EMT<br />
phenotype, increased pErbB3 and NRG1 expression, and increased expression <strong>of</strong> the<br />
EMT drivers Fra1 and pAXL. Preclinical study <strong>of</strong> concurrent inhibition <strong>of</strong> these<br />
pathways is underway to assess potential strategies to overcome resistance to FGFR<br />
inhibition.<br />
Legal entity responsible for the study: N/A<br />
Funding: Grant funding from Pfizer. BGJ398 provided by Novartis<br />
Disclosure: A. Weickhardt: BGJ398 provided by Novartis. Research grant funding<br />
provided by Pfizer. All other authors have declared no conflicts <strong>of</strong> interest.<br />
A. Quintanal-Villalonga 1 , I. Ferrer 1 , Á. Marrugal 1 , L. Ojeda-Márquez 1 ,<br />
L. García-Redondo 1 , R. Suarez 1 , J. Zugazagoitia 2 , A. Carnero 3 , L. Paz-Ares 2 ,<br />
S. Molina-Pinelo 1<br />
1 H120-CNIO Lung Cancer Clinical Research Unit, CNIO- Spanish National Cancer<br />
Center, Madrid, Spain, 2 Medical <strong>Oncology</strong>, University Hospital 12 De Octubre,<br />
Madrid, Spain, 3 Molecular <strong>Oncology</strong> Laboratory, IBIS/CSIC/US, Seville, Spain<br />
Background: FGFR4 has been thoroughly described as an oncogene in many types <strong>of</strong><br />
tumors, including colorectal and hepatocellular carcinoma. In lung adenocarcinoma,<br />
this receptor tyrosine kinase has been found to be one <strong>of</strong> the most mutated genes.<br />
Nonetheless, little work has been done to unravel its role in lung tumorigenesis so far.<br />
Methods: Several lung cell lines, harbouring different genetic driver alterations with<br />
relevance in lung cancer, were transfected with plasmids to either overexpress or silence<br />
FGFR4. In these genetically engineered models several tumorigenic abilities were tested<br />
in vitro and in vivo. Besides, mRNA from paraffin-embedded tissue <strong>of</strong> a cohort <strong>of</strong> lung<br />
cancer patients was extracted and FGFR4 expression levels, as well as other genes found<br />
relevant, were measured and related to clinical characteristics.<br />
Results: FGFR4 increases oncogenic properties in SCC cell lines, but its effects in lung<br />
ADC cell lines are context-depended. This differential role <strong>of</strong> FGFR4 in tumorigenesis<br />
is due to differentially expressed genes between these two histologies in the cell lines<br />
under study, involving a molecular cooperation in some cases. The analysis <strong>of</strong> FGFR4<br />
mRNA expression, together with the aforementioned differentially expressed genes, in<br />
a cohort <strong>of</strong> lung cancer patients, provided further support to our in vitro and in vivo<br />
results. High FGFR4 mRNA expression correlated with a shorter overall survival (OS)<br />
and progression free survival (PFS) in lung SCC patients. Nonetheless, longer OS and<br />
PFS were reported for the ADC patients with higher FGFR4 mRNA expression.<br />
Conclusions: Our results show that FGFR4 oncogenic role is context-dependent and<br />
that in some cases it depends on a molecular cooperation. At a clinical level, FGFR4<br />
mRNA expression could have a biomarker role in patient outcome. This potential<br />
prognostic role seems to be differential in the two main lung cancer histologies. The<br />
study <strong>of</strong> the molecular context <strong>of</strong> FGFR4, involving the presence <strong>of</strong> molecules with<br />
which FGFR4 is able to cooperate, could be <strong>of</strong> interest in determining the eligibility <strong>of</strong> a<br />
patient to receive FGFR-targeted therapy, or even in designing new therapeutic<br />
approaches.<br />
Legal entity responsible for the study: CNIO-Hospital 12 Octubre<br />
Funding: ISCIII<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1563P<br />
The oncogenic role <strong>of</strong> FGFR1 depends on the molecular<br />
context<br />
A. Quintanal 1 , I. Ferrer 1 , L. Ojeda-Márquez 1 , Á. Marrugal 1 , R. Suarez 1 ,<br />
L. García-Redondo 1 , A. Carnero 2 , L. Paz-Ares 3 , S. Molina-Pinelo 1<br />
1 H120-CNIO Lung Cancer Clinical Research Unit, CNIO- Spanish National Cancer<br />
Center, Madrid, Spain, 2 Molecular <strong>Oncology</strong> Laboratory, IBIS, Seville, Spain,<br />
3 Medical <strong>Oncology</strong>, Hospital Universitario Doce de Octubre, Madrid, Spain<br />
Background: The FGFR protein family has been extensively related to oncogenesis in<br />
several types <strong>of</strong> tumors, including lung cancer. In squamous cell lung carcinoma, 20%<br />
1565P<br />
Impact <strong>of</strong> a salvage chemotherapy with carboplatin plus<br />
docetaxel on testosterone levels in metastatic castration -<br />
and docetaxel-resistant prostate cancer (mDRPC)<br />
C.W.M. Reuter, V. Grünwald, P. Ivanyi, A. Ganser<br />
Hematology, Hemostaseology, <strong>Oncology</strong> and Stem Cell Transplantation,<br />
Hannover Medical School, Hannover, Germany<br />
Background: Recent data suggest that carboplatin plus docetaxel (DC) may be effective<br />
in mDRPC. Platinum(II)-complexes interfere with steroid biosynthesis by inhibiting<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw392 | vi539
abstracts<br />
the cholesterol side chain cleavage enzyme (CYP11A1), 3β-hydroxysteroid<br />
dehydrogenase (HSD3B1,2) and 17α hydroxylase/C17,20-lyase (CYP17A1).<br />
Methods: Docetaxel failure/resistance was defined according to the Prostate Cancer<br />
Working Group (PCWG2 2007) criteria. Treatment consisted <strong>of</strong> at least two cycles <strong>of</strong><br />
carboplatin AUC5 iv for 30 min on day 1 every 4 weeks, docetaxel at a dose <strong>of</strong> 35 mg/<br />
m2 iv for one hour on days 1, 8, 15 plus prednisone 2x5mg/day orally after receiving<br />
informed consent until disease progression or occurrence <strong>of</strong> intolerable adverse effects.<br />
Efficacy measures were done following PCWG2 recommendations. Testosterone/<br />
androgene levels were measured before (n = 73) and during carboplatin/docetaxel<br />
chemotherapy (n = 63).<br />
Results: Of the 96 pts. treated since February 2005, 95.8% had bone, 42.7% lymph<br />
node, 26.0% liver and 19.8% lung involvement. At the current analysis, the median<br />
follow-up time was 14.6 months, 86 pts. had died and 90 had progressive disease. The<br />
objective response rate was 22/59 (37.3%). Response <strong>of</strong> prostate-specific antigen<br />
(≥50%) was observed in 48/96 (50%) patients. Median progression-free survival (PFS)<br />
was 7.2 months (CI 95% 6.3, 8.1) and median OS was 15.6 months (CI 95% 11.6, 19.7).<br />
The most common reversible grade 3/4 toxicity was leukopenia/ neutropenia (39.6/<br />
33.3%). Median free testosterone levels were 0.63 pg/ml before and
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
tested. These magnets will also be used in the mice studies with laser-driven protons<br />
and for experimental gantry design studies at conventional therapy beamlines.<br />
Conclusions: Substantial progress has been made towards clinical application <strong>of</strong><br />
promising laser-driven proton therapy although further development is required.<br />
Legal entity responsible for the study: Technical University Dresden<br />
Funding: German Government: BMBF, nos. 03ZIK445, 03Z1N511, 03Z1O511 and<br />
03Z1H531.<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1569P<br />
Time structure influence on the radiobiological response to<br />
MeV electron beams<br />
E. Beyreuther 1 , M. Gotz 2 , L. Karsch 2 , E. Lessmann 1 , M. Schürer 2 , J. Pawelke 2<br />
1 Radiation Physics, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany,<br />
2 OncoRay, University Hospital - TU Dresden, Dresden, Germany<br />
Background: In current clinical radiotherapy electron, photon and ion beams are<br />
delivered (quasi-) continuously with typical dose-rates <strong>of</strong> a few Gy/min. Recent<br />
developments in dose delivery like IMRT and respiratory-gated treatment as well as<br />
accelerator techniques like flattening filter free Linacs and laser-based particle<br />
accelerators are driven towards intermittent irradiation with higher dose rates.<br />
Compared to continuous dose delivery these new techniques differ not only in dose<br />
rate, but also in the temporal sequence <strong>of</strong> pulse delivery, i.e. pulse lengths and pulse<br />
intervals. Previous studies on the influence <strong>of</strong> high dose rates were focussed on single<br />
pulse electron exposure and vary in energy, pulse duration and cell line; the impact <strong>of</strong><br />
intermittent irradiation was rarely investigated. In the present work, the influence <strong>of</strong><br />
dose rates <strong>of</strong> up to 10 12 Gy/min and <strong>of</strong> intermittent irradiation with pulse lengths and<br />
pulse intervals in the range <strong>of</strong> seconds were studied.<br />
Methods: The radiation source ELBE (Electron Linac for beams with high Brilliance<br />
and low Emittance) was used to mimic intermittent irradiation with asymmetric<br />
split-doses, separated by pulse intervals in the range <strong>of</strong> 10 ms to 90 s, and the<br />
quasi-continuous electron beam <strong>of</strong> a clinical LINAC. Using the HNSCC line SQ20B<br />
the impact <strong>of</strong> pulse structure was analyzed by clonogenic survival assay. Moreover, the<br />
LINAC-like electron beam and electron pulses with pulse dose rates <strong>of</strong> up to 10 12 Gy/<br />
min were used to measure the kinetics <strong>of</strong> g-H2AX/53BP1 foci disappearance up to 24 h<br />
after treatment as a surrogate marker for DNA double-strand break complexity in the<br />
normal human breast epithelial cell line 184A1.<br />
Results: In general, the radiation response was found to be independent from electron<br />
pulse structure for the two endpoints under investigation.<br />
Conclusions: These results reveal that ultra-high pulse dose rates <strong>of</strong> 10 12 Gy/min and<br />
pulse intervals <strong>of</strong> 10 ms to 90 s between two pulses have no significant influence on the<br />
radiobiological effectiveness <strong>of</strong> megavoltage electrons.<br />
Legal entity responsible for the study: Helmholtz-Zentrum Dresden-Rossendorf<br />
Funding: BMBF<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1570P<br />
‘Research’ vs ‘real world’ patients: the representativeness <strong>of</strong><br />
clinical trial participants<br />
Y.B. Karanis 1 , F.A. Bermudez Canta 1 , L. Mitr<strong>of</strong>an 2 , H. Mistry 1 , C. Anger 1<br />
1 Global <strong>Oncology</strong>, IMS Health, London, UK, 2 Global <strong>Oncology</strong>, IMS Health, La<br />
Defence, France<br />
Background: Randomized Clinical Trials (RCTs) are the gold standard in assessing the<br />
efficacy <strong>of</strong> new treatments as they allow for the analysis <strong>of</strong> a homogenous study<br />
population. However restricting the eligibility criteria may result in cherry-picking<br />
RCT participant thus compromising the generalisability. We have investigated<br />
differences in certain prognostic factors between trial and non-trial patients to see if<br />
this has an effect on how long patients stay on cytotoxic or targeted treatments.<br />
Methods: IMS Health <strong>Oncology</strong> Analyzer, a patient database collected through a<br />
quarterly physician panel survey was used. Data includes Stage IV, NSCLC, Colorectal<br />
(CRC) and Pancreatic Cancer (PC) patients within EU5 (France, Germany, Italy,<br />
Spain, UK) reported between 2013 and 2015. For the initial analysis the prognostic<br />
factors compared are ECOG, Co-morbidities and Age. For the secondary analysis<br />
cytotoxic and targeted treatments were grouped and the average duration <strong>of</strong> treatments<br />
(DOTs) were compared.<br />
Results: Based on the results displayed above, patients enrolled in clinical trials are<br />
more likely to be Younger (1), Fitter (2) and with No-Comorbidities (3) versus ‘Real<br />
World’ patients. Similar DOTs (4) were observed for the two patient groups in CRC<br />
and NSCLC. Sample number for PC patients with DOT information were too low to<br />
analyse.<br />
Table: 1570P<br />
NSCLC CRC PC<br />
Non-Trial<br />
n = 10,534<br />
Trial<br />
n = 439<br />
Non-Trial<br />
n = 6,260<br />
Trial<br />
n = 265<br />
Non-Trial<br />
n = 4,081<br />
Trial<br />
n=41<br />
(1) Age<br />
65 Years <strong>of</strong> age 46% 39% 54% 45% 55% 39%<br />
(2) Performance Status<br />
ECOG 0-1 78% 85% 84% 89% 66% 71%<br />
ECOG 2-4 22% 15% 16% 11% 34% 29%<br />
(3) Co-Morbidities<br />
No Co-morbidities 40% 55% 49% 64% 39% 66%<br />
4) Average DOT (months)<br />
Cytotoxic Treatments 3.7 3.8 6.3 6.4 4.8 -<br />
Targeted Treatments 7.6 7.3 7.6 7.2 6.4 -<br />
Conclusions: Our data supports the existence <strong>of</strong> prognostic differences between ‘Trial’<br />
and ‘Real World’ patients. Even though we have not observed an effect <strong>of</strong> this on DOT,<br />
further analysis is required to study the array <strong>of</strong> clinical and survival outcomes that<br />
prognostic differences are likely to impact. The next step is a comparison <strong>of</strong> parameters<br />
such as response to therapy, adverse events and Progression Free Survival to further<br />
analyse the representativeness <strong>of</strong> RCTs.<br />
Legal entity responsible for the study: IMS Health<br />
Funding: IMS Health<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1571P<br />
Reliability <strong>of</strong> apparent diffusion coefficient assessments<br />
according to the QIBA guideline<br />
H. Beaumont 1 , B. Moreau 2 , C. Hoog 2 , E. Oubel 1 , A. Iannessi 2<br />
1 Sciences, MEDIAN Technologies, Valbonne, France, 2 Radiology, Centre Antoine<br />
Lacassagne, Nice, France<br />
Background: Apparent Diffusion Coefficient (ADC) is an emerging quantitative<br />
imaging biomarker in oncology obtained from MR imaging. This index might predict<br />
tumor aggressiveness and therapy response at baseline. The Quantitative Imaging<br />
Biomarkers Alliance (QIBA) published a guideline to assess the reliability <strong>of</strong> ADC. Our<br />
study aims at testing the implementation <strong>of</strong> QIBA guidelines and confirm the expected<br />
results. This is a first step before assessing response thresholds <strong>of</strong> ADC for patient<br />
monitoring.<br />
Methods: An ice–water phantom was scanned on an Optima MR 450W 1,5T (GE)<br />
following the QIBA quality control protocol. The diffusion weighted MRI images were<br />
obtained using a multislice SS-EPI sequence with b-values 0, 100, 600 and 800 s/mm 2 .<br />
Mean ADC and standard deviation ADC were measured over a spherical volume <strong>of</strong><br />
interest (diameter: 4cm) placed at the center <strong>of</strong> the 0°C water cylinder (Diameter: 5<br />
cm). To assess the spatial dependence, another acquisition was performed with the<br />
phantom in a different orientation. ADC bias error, ADC random error, ADC b-value<br />
dependence, ADC signal to noise ratio and ADC spatial dependence were assessed as<br />
defined into the QIBA guideline and were compared to the QIBA tolerances,<br />
respectively 10%, 5%, 2%, 75:1 and 5%.<br />
Results: The ADC bias error was about 6%, meaning the ADC measured is close to the<br />
theoretical value <strong>of</strong> 1.1*10 −3 mm 2 /s for the 0°C water. ADC b-value dependence and<br />
ADC spatial dependence were respectively 0.5% and 3% and passed the test. With<br />
about 10%, the random error was out <strong>of</strong> the tolerance. The ADC signal to noise ratio<br />
was about 2:1, below QIBA expectations.<br />
Conclusions: The obtained results do not perfectly fit with the QIBA expectations.<br />
Therefore, these data deserve further analysis and the QIBA guidelines likely to be<br />
discussed. Even if the clinical value <strong>of</strong> ADC has been put in evidence by several groups,<br />
the process <strong>of</strong> qualification <strong>of</strong> the biomarker and its performances need to be more<br />
documented.<br />
Legal entity responsible for the study: N/A<br />
Funding: Centre Antoine Lacassagne, Nice, FRANCE<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1572P<br />
Current and future next generation sequencing usage in<br />
European molecular oncology diagnostics<br />
C.M. Whitten, A. Thum, T. Blass<br />
IVD, Dii Healthcare, Leipzig, Germany<br />
abstracts<br />
Background: The integration <strong>of</strong> next generation sequencing (NGS) into clinical<br />
molecular diagnostic (MolDx) laboratories has been growing and continues to expand<br />
into new applications for molecular oncology, but is hampered by technical challenges.<br />
In order to better meet the needs <strong>of</strong> diagnostic testing, it is necessary to understand the<br />
current and planned adoption <strong>of</strong> NGS systems as kits, both commercial and laboratory<br />
developed, must be optimized for specific machines.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw392 | vi541
abstracts<br />
Methods: We surveyed >3000 labs throughout Western Europe and will here focus on<br />
NGS usage in general and overall molecular methods for BRCA, BRAF, RAS, and<br />
EGFR in Germany (DE), Italy (IT), and the UK. Telephone interviews were conducted<br />
in 2015 and 2016 with data collected on technologies, systems and kits used, test<br />
volumes, and planned NGS systems and markers in the next 5 years.<br />
Results: Usage <strong>of</strong> NGS systems is increasing, though this varies by country, with DE<br />
being slowest to adopt where only 7% <strong>of</strong> MolDx labs have an NGS and 50% <strong>of</strong> systems<br />
used for oncology MolDx are still Sanger sequencers. Most molecular oncology done in<br />
IT is on RT-PCR (51%) systems, followed by NGS (34%). The UK has the highest NGS<br />
usage for oncology (52% <strong>of</strong> systems). Overall, ∼17% <strong>of</strong> MolDx labs in Europe have an<br />
NGS machine and, <strong>of</strong> those not currently running NGS, another 21% plan to acquire it<br />
in the next 5 years. Sixty-five percent <strong>of</strong> those reporting a preference chose Illumina<br />
systems. There is a growing focus on benchtop sequencers seen in the dominant<br />
presence <strong>of</strong> Illumina’s MiSeqs (35%) and Thermo Fisher Ion sequencers (29%) out <strong>of</strong><br />
all current NGS systems and future planned systems (90% reporting intent to acquire<br />
Illumina systems stated this would be a MiSeq).<br />
Conclusions: Current top molecular oncology testing includes EGFR, BRAF, RAS, and<br />
BRCA and these will remain widely tested in the near future along with increasing use<br />
<strong>of</strong> multi-gene panels. The popularization <strong>of</strong> smaller and easier to use NGS systems will<br />
help grow clinical NGS usage as they’re cheaper and faster but there is still a need for<br />
increased automation, more panels, and easier result reporting. As NGS usage in labs<br />
becomes standardized and more requested by oncologists, this will push payers to<br />
improve reimbursement strategies allowing for improved clinical patient care.<br />
Legal entity responsible for the study: dii Healthcare GmbH: a consulting and market<br />
research firm operating solely in the area <strong>of</strong> in-vitro diagnostics<br />
Funding: dii Healthcare GmbH: a consulting and market research firm operating<br />
solely in the area <strong>of</strong> in-vitro diagnostics<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1573P<br />
A candidate gene study for oxaliplatin induced chronic<br />
peripheral neuropathy (OICPN) based on a prior genome wide<br />
association study (GWAS)<br />
J.R. Cliff 1 , D.F. Carr 2 , R.H. Lord 1 , A.L. Jorgensen 3 , M. Pirmohamed 2<br />
1 Medical <strong>Oncology</strong>, Clatterbridge Cancer Center, Wirral, UK, 2 Molecular and<br />
Clinical Pharmacology, University <strong>of</strong> Liverpool, Liverpool, UK, 3 Biostatistics,<br />
University <strong>of</strong> Liverpool, Liverpool, UK<br />
Background: Peripheral neuropathy complicates oxaliplatin therapy and occurs in two<br />
forms; a transient cold-induced neuropathy and a chronic form which requires dose<br />
reduction, early cessation, or causes long term morbidity in a proportion <strong>of</strong> patients.<br />
Various studies have suggested a complex pharmacogenetic susceptibility may exist to<br />
account for inter-individual variation in occurrence and severity <strong>of</strong> OICPN, but results<br />
are frequently contradictory or unvalidated. We performed a systematic review <strong>of</strong> the<br />
literature which identified two East Asian studies suggesting a role for three SNPs;<br />
ACYP2 (rs843748), FARS2 (rs171401290), and TAC1 (rs10486003), based on GWAS<br />
and subsequent replication in a candidate gene study. We attempted to replicate these<br />
findings in a Caucasian population.<br />
Methods: A combined population from a prospective cohort study and retrospective<br />
case-control study was included for genotyping. All patients were <strong>of</strong> European<br />
ancestry, had no pre-existing symptomatic peripheral neuropathy and received<br />
oxaliplatin with a fluoropyrimidine. They were assessed specifically for this study and<br />
categorised as ‘cases’ or ‘controls’ based on the presence and severity <strong>of</strong> OICPN using<br />
NCI CTC criteria. Cases experienced grade 3-4 neuropathy or grade 2 neuropathy<br />
resulting in adjustment or cessation <strong>of</strong> oxaliplatin. Controls experienced a maximum <strong>of</strong><br />
grade 1 neuropathy with no treatment adjustments required due to OICPN. Minimum<br />
cumulative dose criteria were applied to inclusion <strong>of</strong> controls. Blood or saliva samples<br />
were collected, DNA extracted and genotyped for the selected SNPs using the TaqMan<br />
allelic discrimination methodology.<br />
Results: After quality control, 119 <strong>of</strong> 120 eligible recruited patients were included in<br />
the final genotyping results comprising 51 controls and 68 cases. None <strong>of</strong> the three<br />
SNPs were found to be associated with development <strong>of</strong> OICPN on univariate analysis<br />
or after adjustment for potentially relevant clinical factors (P > 0.05).<br />
Conclusions: Our findings do not support the suggested relationship between the<br />
included SNPs and development <strong>of</strong> clinically important OICPN in European patients.<br />
Clinical trial identification: NIHR CRN: 8630<br />
Legal entity responsible for the study: University <strong>of</strong> Liverpool and Clatterbridge<br />
Cancer Centre NHS Foundation Trust<br />
Funding: Uinversity <strong>of</strong> Liverpool, North West Cancer Research and Clatterbridge<br />
Cancer Charity<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1574P<br />
Differential regulation <strong>of</strong> pr<strong>of</strong>ibrotic genes responsible for<br />
cardiotoxicity after experimental anticancer treatments<br />
M. Gyongyosi, K. Zlabinger, D. Lukovic, A. Spannbauer, G. Maurer,<br />
J. Bergler-Klein<br />
Cardiology, Medizinische Universitaet Wien (Medical University <strong>of</strong> Vienna), Vienna,<br />
Austria<br />
Background: Transcriptomic analysis <strong>of</strong> the myocardial samples aimed to search genes<br />
responsible for myocardial fibrosis and development <strong>of</strong> heart failure induced by<br />
anticancer therapy under experimental setting.<br />
Methods: Domestic pigs (38 ± 3 kg) received 3 cycles <strong>of</strong> cytostatic treatment <strong>of</strong> human<br />
dose with either doxorubicin (DOX, n = 6) or liposomal encapsulation <strong>of</strong><br />
doxorubicin-citrat complex (Myocet® MYO, n = 9), or epirubicin (EPI, n = 9) or<br />
physiologic saline (Controls, CO, n = 6). Left (LV) and right ventricular (RV) ejection<br />
fraction (EF) was assessed after the application <strong>of</strong> the last dose by cardiac magnetic<br />
resonance imaging. LV and RV myocardial fibrosis was quantified by picrosorius-red<br />
staining. mRNAs <strong>of</strong> myocardial samples from the LV and RV were isolated. The gene<br />
expression pr<strong>of</strong>ile was analyzed by next generation sequencing (NGS) followed by<br />
post-hoc RT-PCR <strong>of</strong> selected genes.<br />
Results: Five, 6 and 2 animals survived the treatment in DOX, MYO and EPI groups,<br />
respectively, thus EPI was excluded from the functional analysis. Both MYO and DOX<br />
resulted in decrease <strong>of</strong> LV EF (56.4 ± 5.6% vs 41.9 ± 13.5%, p < 0.05) and RV EF<br />
(42.1 ± 2.8% vs 28.9 ± 8.9%, p < 0.05) in MYO vs DOX, resp., with a trend towards less<br />
myocardial fibrosis in MYO-treated animals. The cardiac muscle contraction gene<br />
myozenin was significantly (p < 0.05) down-regulated in group DOX as compared to<br />
group MYO (0.12 ± 0.09 vs 1.13 ± 0.06 log fold changes /LFC/). EMILIN and<br />
SERPINH1 genes (both are involved in biosynthetic pathway <strong>of</strong> collagen and elastin)<br />
were significantly overexpressed in LV and RV samples <strong>of</strong> both DOX and MYO groups.<br />
Besides activations <strong>of</strong> tumor-repressors, both DOX and MYO treatments led to<br />
up-regulation <strong>of</strong> several proto-oncogenes, such as JUNB (LV: 1.68 ± 0.3 and<br />
1.65 ± 0.23; RV:1.71 ± 0.13 and 1.98 ± 0.93 LFC, resp.) or BCL3 (LV: 2.97 ± 0.34 and<br />
2.96 ± 0.79; RV: 6.34 ± 0.61 and 4.81 ± 1.01 LFC, resp.).<br />
Conclusions: Myocet® proved to be less cardiotoxic as compared with DOX, resulting<br />
in better cardiac function and less fibrosis. However, both cytostatic treatments led to<br />
overexpression <strong>of</strong> collagen-associated genes and proto-oncogenes, which might explain<br />
the development <strong>of</strong> myocardial fibrosis and secondary malignancies.<br />
Legal entity responsible for the study: Mariann Gyongyosi<br />
Funding: TEVA ratiopharm provided the Department <strong>of</strong> Cardiology, Medical University<br />
<strong>of</strong> Vienna, with NPL-doxorubicin and an unrestricted grant, but was not involved in the<br />
study protocol, data acquisition, data analysis or the writing <strong>of</strong> the abstract.<br />
Disclosure: M. Gyongyosi: Funding: TEVA ratiopharm provided the Department <strong>of</strong><br />
Cardiology, Medical University <strong>of</strong> Vienna, with NPL-doxorubicin and an unrestricted<br />
grant, but was not involved in the study protocol, data acquisition, data analysis or the<br />
writing <strong>of</strong> the abstract. All other authors have declared no conflicts <strong>of</strong> interest.<br />
1575P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
5-Fluorouracil (5FU) intratumoural pharmacokinetics: Rapid<br />
uptake in cells and in spheroids (SPH)<br />
M. Jove 1 , P. Loadman 2 , J. Wicks 2 , J. Spencer 2 ,A.Race 2 , R. Salazar 3 ,C.<br />
J. Twelves 4<br />
1 Medical <strong>Oncology</strong>, The Leeds Teaching Hospital NHS Trust St. James University<br />
Hospital, Leeds, UK, 2 Drug and Metabolism Pharmacokinetics, Institute Cancer<br />
Therapeutics, Bradford, UK, 3 Medical <strong>Oncology</strong>, Catalan Institute <strong>of</strong> <strong>Oncology</strong>, L<br />
´ Hospitalet, Spain, 4 Medical <strong>Oncology</strong>, Leeds Institute <strong>of</strong> Cancer & Pathology,<br />
Leeds ECMC, Leeds, UK<br />
Background: Limited data are available on 5FU intratumoral pharmacokinetics.<br />
Previous studies with radiolabeled 5FU showed homogeneous uptake in spheroids<br />
within a few minutes (Cancer Chemother Pharmacol. 1984;13(2):131-5) but no<br />
quantification was done. We present data on intracellular and intra-spheroidal 5FU<br />
uptake; drug efflux experiments are on-going and results will be presented.<br />
Methods: MCF-7 and HCT-116 cells were used for cellular and spheroid experiments.<br />
Spheroid growth was optimized to produce a spheroid <strong>of</strong> 300-400 µm diameter at day<br />
4. Treatment: 1x10 6 cells or 30 spheroids/time point were exposed to 10 µM (1300ng/<br />
mL) 5FU at
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Table: 1575P 5FU uptake ng/g Mean [range]<br />
Min HCT-116 cells MCF-7 cells HCT-116 spheroids<br />
abstracts<br />
Results: In transduced cells, TRAIL mRNA levels were 40.000 fold higher with a<br />
concurrent 5 fold higher protein expression. TRAIL mRNA and protein levels<br />
increased when the cells were co-cultured with U266 cells, or in presence <strong>of</strong> IL-1α and<br />
IL-1β, whereas the MM cell apoptosis after 48 hrs was 70,3 ± 3,5% compared to<br />
20,5 ± 2,3% <strong>of</strong> control UC-MSCs. Significant reduction <strong>of</strong> MM tumor masses were<br />
detected in mice injected with TRAIL + -UC-MSCs, as compared to control mice<br />
(p < 0.05).<br />
Conclusions: Our data support the TRAIL + -UC-MSCs approach to treat MM in<br />
NOD-SCID mice. Besides their migratory property to the MM microenvironment,<br />
TRAIL + -UC-MSCs reinforce their constitutive anti-MM activity by TRAIL<br />
over-expression.<br />
Legal entity responsible for the study: Pr<strong>of</strong>. Franco Silvestris<br />
Funding: AIRC (Associazione Italiana per la Ricerca sul Cancro)<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1580P<br />
A multicellular 3D cell culture model for investigation <strong>of</strong><br />
endothelial cell migration<br />
A. Amann 1 , M. Zwierzina 2 , G. Gamerith 3 , S. Koeck 3 , E. Lorenz 4 , H. Zwierzina 3 ,<br />
J. Kern 4<br />
1 Innere Medizin, Medizinische Universität Innsbruck, Innsbruck, Austria,<br />
2 Department <strong>of</strong> plastic, reconstructive and aesthetic surgery, Austria, Medizinische<br />
Universität Innsbruck, Innsbruck, Austria, 3 Haematology and <strong>Oncology</strong>,<br />
Medizinische Universität Innsbruck, Innsbruck, Austria, 4 Oncotyrol - Center for<br />
Personalized Cancer Medicine, Oncotyrol - Center for Personalized Cancer<br />
Medicine, Innsbruck, Austria<br />
Background: We are experiencing a transition from disease to target-oriented therapy<br />
due to the increasing understanding <strong>of</strong> the mechanisms relevant to the genesis <strong>of</strong><br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
cancer. One major hurdle for the development <strong>of</strong> these targeted therapeutic regimens,<br />
however, is the limited availability <strong>of</strong> predictive in vitro models. We present data that<br />
highlights the differences <strong>of</strong> RNA expression <strong>of</strong> in vivo like 3D microtissues consisting<br />
<strong>of</strong> tumour cells, fibroblasts and two different endothelial cell lines compared to normal<br />
2D cell culture conditions.<br />
Methods: 96-well hanging drop microtiter plates (InSphero AG, Zürich, Switzerland)<br />
were applied for the production <strong>of</strong> 3D mono-, co- and tri-cultures including the<br />
human lung cancer cell lines A549 or Colo699 alone or in combination with a human<br />
lung fibroblast cell line (SV-80) and either a human umbilical vein endothelial cell line<br />
(HUVEC) or the primary human lung microvascular endothelial cell line (HMVEC-L).<br />
Tumour endothelial spheroid aggregation was displayed immunohistochemically<br />
(IHC) by protein expression <strong>of</strong> e-cadherin, CD31, von Willebrand factor (vWF) and<br />
α-muscle actin (α-SMA). RNA expression pr<strong>of</strong>iling by Affymetrix chip analysis was<br />
performed for multicellular 3D microtissues and 2D cultured cell lines. Bevacizumab<br />
was added in different doses and inhibition <strong>of</strong> endothelial cell migration and drug<br />
related toxicity was displayed either by flow cytometry or IHC.<br />
Results: In microtissues, endothelial cells aggregated in coherent tube-like structures<br />
preferentially in the fibroblast consisting core <strong>of</strong> all microtissues. However, inhibition<br />
<strong>of</strong> vascular endothelial growth (VEGF) factor by bevacizumab led to an in part<br />
blockade <strong>of</strong> endothelial cell migration into the microtissues. Nevertheless, no toxic<br />
effect <strong>of</strong> this drug was displayed either on tumour cells, fibroblasts or endothelial cells.<br />
RNA expression pr<strong>of</strong>iles revealed a high number <strong>of</strong> regulated genes in tri-cultures<br />
when compared to microtissues only consisting <strong>of</strong> mono- or co-cultures or to<br />
traditional 2D cultivated cells.<br />
Conclusions: In this work, we demonstrate a functional multicellular model consisting<br />
<strong>of</strong> tumour cells, fibroblasts and endothelial cells that allows the investigation <strong>of</strong><br />
anti-angiogenic drugs.<br />
Legal entity responsible for the study: Medical University Innsbruck Tirol Kliniken<br />
Funding: Medical University Innsbruck Tirol Kliniken<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
vi544 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong> 27 (Supplement 6): vi545–vi551, 2016<br />
doi:10.1093/annonc/mdw393<br />
tumour biology and pathology<br />
1581PD<br />
Copenhagen prospective personalized oncology (CoPPO):<br />
Genomic pr<strong>of</strong>iling to select patients for phase 1 trials<br />
I.V. Tuxen 1 , C.W. Yde 2 , M. Mau-Sørensen 1 , E. Santoni-Rugiu 3 , U. Lassen 1 ,F.<br />
C. Nielsen 2<br />
1 Department <strong>of</strong> <strong>Oncology</strong>, Rigshospitalet, Copenhagen University Hospital,<br />
Copenhagen, Denmark, 2 Department <strong>of</strong> Genomic medicine, Rigshospitalet,<br />
Copenhagen University Hospital, Copenhagen, Denmark, 3 Dept. <strong>of</strong> Pathology,<br />
Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark<br />
Background: Advanced technologies can be used to portray genomic alterations (GA)<br />
that potentially drive tumor growth. We have established a sequencing and array based<br />
pipeline to identify GA to select patients (pts) who might benefit from novel targeted<br />
treatments and to enrich the population in phase 1 trials with pts that harbor specific<br />
targets. A total <strong>of</strong> 300 pts are referred annually based on 25 ongoing phase 1 trials.<br />
Methods: Adults with advanced solid tumors referred to a dedicated Phase 1 Unit were<br />
<strong>of</strong>fered biopsy for mapping <strong>of</strong> GA. Three fresh tumor 18 G needle biopsies were taken,<br />
two were stored in RNAlater® (Life Technologies) for RNA expression analyses and<br />
DNA gene mutation analyses, while one biopsy was formalin-fixed and<br />
paraffin-embedded for histopathological analyses to confirm suitability <strong>of</strong> the material,<br />
including the presence <strong>of</strong> min. 100 tumor cells. SNP-array from tumor and whole<br />
exome sequencing (WES) from DNA (tumor and blood) were performed using<br />
sequence capture and Illumina sequencing to call tumor specific mutations. WES from<br />
blood was used to subtract germline polymorphisms. Expression levels <strong>of</strong> therapeutic<br />
targets were revealed by expression Array and RNA-seq from tumor RNA. A tumor<br />
board reviewed results. Pts with specific GA that could be targeted with drugs in<br />
development were enrolled in phase 1 trials. Individualized treatment with marketed<br />
drugs (Off-label) or non-approved drugs (Named pt program) were <strong>of</strong>fered according<br />
to level <strong>of</strong> existing evidence.<br />
Results: Between May 2013 and April 2016, we screened 366 heavily pretreated pts<br />
with solid tumors. In 297 pts (81%) a biopsy was taken. In 283 (77%) we achieved<br />
sufficient tumor tissue to perform a full genomic pr<strong>of</strong>ile. An actionable target was<br />
identified in 215 pts (75%) out <strong>of</strong> 283 pts. Mean time from biopsy to reporting <strong>of</strong><br />
results was 36 days. 153 pts with an actionable target were eligible for treatment. 57 pts<br />
(20%) were treated according to the findings <strong>of</strong> either mutations or RNA expression<br />
levels <strong>of</strong> treatment targets in phase 1 trials (N = 39) or Off-label treatment/Named pt<br />
program (N = 18).<br />
Conclusions: Establishing sequencing and array-based pipeline for enrichment <strong>of</strong><br />
patients to phase 1 trials is feasible in a Phase 1 Unit.<br />
Clinical trial identification: NCT02290522<br />
Legal entity responsible for the study: Rigshospitalet, Copenhagen<br />
Funding: Region H<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1582P<br />
Analysis <strong>of</strong> circulating cell-free DNA in plasma shows a<br />
higher detection rate <strong>of</strong> EGFR mutations in patients with<br />
extrathoracic disease progression<br />
Y. Seki 1 , Y. Fujiwara 2 , T. Kohno 1 , Y. Goto 2 , H. Horinouchi 2 , S. Kanda 2 ,<br />
H. Nokihara 2 , N. Yamamoto 2 , K. Kuwano 3 ,Y.Ohe 2<br />
1 Division <strong>of</strong> Genome Biology, National Cancer Center Research Institute, Tokyo,<br />
Japan, 2 Department <strong>of</strong> Thoracic <strong>Oncology</strong>, National Cancer Center Hospital,<br />
Tokyo, Japan, 3 Division <strong>of</strong> Respirology, Department <strong>of</strong> Internal Medicine, Jikei<br />
University School <strong>of</strong> Medicine, Tokyo, Japan<br />
Background: Noninvasive monitoring <strong>of</strong> EGFR mutations conferring sensitivity (i.e.,<br />
L858R and various types <strong>of</strong> exon 19 deletion mutations) and resistance (i.e., T790M<br />
and C797S) to tyrosine kinase inhibitors (TKIs) is vital for efficient therapy <strong>of</strong> lung<br />
adenocarcinoma (LADC) with conventional and/or new generation EGFR-TKIs.<br />
Although plasma cell-free DNA (cfDNA) is detectable at an early stage, the size <strong>of</strong> the<br />
tumors does not significantly correlate with cfDNA concentration. We explored clinical<br />
features <strong>of</strong> patients with LADC whose cfDNA examination was useful.<br />
Methods: Forty-four plasma samples from 37 LADC patients receiving EGFR-TKI<br />
therapy, including 20 who developed resistance, were prospectively subjected to droplet<br />
digital PCR-cfDNA analysis to determine the fraction <strong>of</strong> cfDNA with EGFR mutations,<br />
and analyzed according to clinical features. The factors subjected to analysis were age,<br />
sex, ECOG PS, sites <strong>of</strong> metastatic disease, and sites <strong>of</strong> recent progressive disease.<br />
Results: cfDNA samples from 19 (95%) <strong>of</strong> the 20 resistant patients were positive for<br />
TKI-sensitive mutations as previously reported. Also, 26 (84%) <strong>of</strong> 31 patients with<br />
extrathoracic disease progression, and 24 (86%) <strong>of</strong> 28 with regional lymph node<br />
metastases, were similarly positive. cfDNA analysis from patients with these features<br />
correlated with a high detection rate <strong>of</strong> TKI-sensitive mutations (acquired resistance:<br />
risk ratio: 2.073, 95% CI: 1.326-3.239; extrathoracic disease progression: risk ratio:<br />
2.726, 95% CI: 1.189-6.250; lymph node metastases: risk ratio: 2.095, 95% CI:<br />
1.052-4.174). Presence and cites <strong>of</strong> metastatic diseases were not correlated with<br />
detection rate significantly.<br />
Conclusions: EGFR mutation detection from cfDNA is useful in EGFR-TKI-resistant<br />
patients, especially those with extrapleural disease progression. One possible<br />
explanation for this difference is that migration potency <strong>of</strong> tumor cells might increase<br />
the amount <strong>of</strong> plasma cfDNA by promoting the dissemination <strong>of</strong> tumor cells into<br />
plasma. Further analysis <strong>of</strong> cfDNA from patients with these features may be useful for<br />
tumor molecular pr<strong>of</strong>iling and treatment modification.<br />
Clinical trial identification: The study was registered in the University Hospital<br />
Medical Information Network Clinical Trial Registry (UMIN 000017581).<br />
Legal entity responsible for the study: Yutaka Fujiwara<br />
Funding: The Ministry <strong>of</strong> Health Labour and Welfare, Japan<br />
Disclosure: Y. Goto: Eli Lilly, Boehringer Ingelheim (Consulting, Honoraria received),<br />
AstraZeneca (Honoraria received). H. Horinouchi: Corporate-sponsored research:<br />
Taiho, Merck Serono, MSD, Astellas, Novartis. H. Nokihara: Merck Serono, Pfizer,<br />
Eisai, Chugai Pharma, Novartis, Daiichi Sankyo, GlaxoSmithKline, Yakult, Quintiles,<br />
Astellas, (Research funding), San<strong>of</strong>i (Honoraria received), Taiho, Eli Lilly, Boehringer<br />
Ingelheim, AstraZeneca, Ono (Honoraria & funding). N. Yamamoto: Quintiles,<br />
Astellas, Chugai, Esai, Taiho, BMS, Pfizer, Novartis, Daiichi-Sankyo, Boehringer<br />
Ingelheim, Kyowa-Hakko Kirin (Research funding), AstraZeneca, Pfizer, Eli Lilly,<br />
Chugai(Honoraria received). Y. Ohe: AstraZeneca, Chugai, Taiho Pharmaceutical,<br />
Ono, Bristol-Myers Squibb,(Research funding)(Honoraria received) Sumitomo<br />
Dainippon, Kyorin,(Research funding;) Lilly, Pfizer, Boehringer Ingelheim, (Honoraria<br />
received). All other authors have declared no conflicts <strong>of</strong> interest.<br />
1583P<br />
Unsupervised latent class analysis <strong>of</strong> adult glioma variant<br />
pr<strong>of</strong>iles reveals biologically and clinically relevant subclasses<br />
M. Chang 1 , S. Ramkissoon 2 , H. Bokhari 3 , A. Fichtenholtz 1 , S. Ali 4 , J.S. Ross 2 ,<br />
E. Neumann 1<br />
1 Knowledge Informatics, Foundation Medicine, Cambridge, MA, USA, 2 Pathology,<br />
Foundation Medicine, Inc., Cambridge, MA, USA, 3 Computational Biology, Cornell<br />
University, Ithaca, NY, USA, 4 Clinical Development, Foundation Medicine, Inc.,<br />
Cambridge, MA, USA<br />
Background: Adult gliomas represent a diverse group <strong>of</strong> tumors characterized by<br />
differing genetic signatures and clinical presentations. Using unsupervised latent class<br />
analysis (LCA) <strong>of</strong> glioma somatic variants (independent <strong>of</strong> diagnosis), we identified<br />
biologically and clinically relevant subclasses associated with distinct clinical outcomes<br />
while highlighting the landscape <strong>of</strong> glioma driver events.<br />
Methods: LCA was performed on somatic variants from 765 adult glioma patients<br />
(grade II-IV, TCGA dataset) using expectation-maximization and Newton-Raphson<br />
algorithms to determine maximum likelihood estimates <strong>of</strong> model parameters. Survival<br />
outcomes per class were generated using Kaplan–Meier and COX proportional hazard<br />
analysis.<br />
Results: LCA revealed seven distinct classes <strong>of</strong> gliomas. Classes 1 and 2 were defined by<br />
IDH1/2 mutations. Class 1 showed co-occurring CIC mutations and 1p/19q<br />
co-deletion (oligodendroglial lineage) whereas Class 2 enriched for co-occurring TP53<br />
and ATRX mutations (astrocytic lineage). Class 3 was characterized by dysregulated<br />
cell cycle signaling largely due to alterations in MDM2/CDK4 whereas Class 4 enriched<br />
for activation <strong>of</strong> PI3K signaling mediated through alterations in NF1, PIK3CA, and<br />
PTEN. Receptor tyrosine kinase activation including EGFR and PDGFRA/KDR/KIT<br />
defined Class 5 and 7, respectively. Class 6 enriched for gliomas with gains <strong>of</strong> chr 7 but<br />
without PTEN alterations. Median survival was greatest for classes defined by IDH1/2<br />
(2907 days Class 1, 2000 days Class 2) and poorest for Class 4 (383 days).<br />
Conclusions: LCA <strong>of</strong> glioma somatic variants reveal biologically and clinically relevant<br />
classes independent <strong>of</strong> diagnosis that are associated with significant differences in<br />
patient survival. The genomic classes seem to involve different underlying molecular<br />
mechanisms that can become altered in gliomas. These findings suggest that<br />
LCA-based glioma classification may serve as a primary predictor for clinical outcomes<br />
and provide objective data to be used in clinical management and trial design.<br />
Legal entity responsible for the study: Foundation Medicine<br />
Funding: Foundation Medicine<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
abstracts<br />
© European Society for Medical <strong>Oncology</strong> 2016. Published by Oxford University Press on behalf <strong>of</strong> the European Society for Medical <strong>Oncology</strong>.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com.
abstracts<br />
1584P<br />
Germline genetic background contribution to metastatic<br />
dissemination in breast cancer extreme phenotype patients<br />
A. Santonja 1 , B. Pajares 2 , B. Jiménez-Rodríguez 2 , C. Fernández-De Sousa 2 ,<br />
N. Ribelles 2 , A. Lluch-Hernandez 3 , I. Catoira 3 , E. Perez-Ruiz 4 , M. Martin 5 , M. Del<br />
Monte-Millan 5 , A. Gonzalez-Neira 6 , G. Pita 6 , M.A. Pujana 7 , M. Ruiz 8 , N. Bonifaci 7 ,<br />
J. De la Haba 9 , P. Sanchez-Rovira 10 , E. Alba 2 , A. Romero 11<br />
1 Instituto de Investigacion Biomedica de Malaga (IBIMA), Hospital Universitario<br />
Regional y Virgen de la Victoria, Malaga, Spain, 2 Hospital Universitario Regional y<br />
Virgen de la Victoria, Instituto de Investigacion Biomedica de Malaga (IBIMA),<br />
Malaga, Spain, 3 Hematology and Medical <strong>Oncology</strong>, Hospital Clinico Universitario<br />
de Valencia, Valencia, Spain, 4 Medical <strong>Oncology</strong>, Hospital Costa del Sol, Marbella,<br />
Spain, 5 Medical <strong>Oncology</strong>, Hospital General Universitario Gregorio Marañon,<br />
Madrid, Spain, 6 Spanish National Cancer Research Centre (CNIO), CNIO- Spanish<br />
National Cancer Center, Madrid, Spain, 7 Breast Cancer and Systems Biology Unit,<br />
Catalan Institute <strong>of</strong> <strong>Oncology</strong> (ICO), Bellvitge Institute for Biomedical Research<br />
(IDIBELL), Barcelona, Spain, 8 Medical <strong>Oncology</strong>, Hospital Universitario Virgen del<br />
Rocio, Seville, Spain, 9 Medical <strong>Oncology</strong>, Hospital Provincial de Córdoba,<br />
Cordoba, Spain, 10 Medical <strong>Oncology</strong>, Complejo Hospitalario de Jaen Universidad<br />
de Jaen, Jaen, Spain, 11 Medical <strong>Oncology</strong>, Hospital Clinico San Carlos, Madrid,<br />
Spain<br />
Background: Previous studies suggest that breast cancer dissemination is not only<br />
driven by the tumor somatic alterations but also by the host’s genetic background. The<br />
main objective <strong>of</strong> this study is to identify germinal genetic variations predictive <strong>of</strong><br />
metastatic dissemination in breast cancer patients.<br />
Methods: Breast cancer patients with discordant extreme phenotypes were selected for<br />
a genome-wide association study (GWAS): low risk patients (10 positive lymph nodes) without relapse. Patients were distributed in a<br />
discovery set including controls (low risk without relapse and high risk with relapse)<br />
and a validation set. Around 4.3 million SNPs were genotyped with the<br />
HumanOmni5-Quad Beadchip (Illumina) from peripheral blood DNA. Data analysis<br />
was performed as an individual association analysis using Plink s<strong>of</strong>tware,<br />
GenomeStudio (Illumina) and snpMatrix package from R and a pathways analysis with<br />
GSA-SNP (http://gsa.muldas.org).<br />
Results: We successfully genotyped 145 patients, 95 in the discovery set (47 cases and<br />
48 controls) and 50 cases in the validation set. In the individual association analysis,<br />
the strongest associations were located in SNPs in/close to genes related with metastatic<br />
dissemination. One <strong>of</strong> the top SNPs was rs28452734 (p = 3.43x10 −5 , OR = 9.86 in<br />
discovery set; p = 2.96x10 −3 , OR = 4.3 in validation set). This SNP is located near<br />
XYTL1, a gene involved in the biosynthesis <strong>of</strong> glycosaminoglycan chains which form<br />
the extracellular matrix. XYLT1 has been previously associated with adhesion,<br />
proliferation, angiogenesis and metastasis. In turn, the pathways analysis identified an<br />
enrichment <strong>of</strong> genes from KEGG pathways including ECM-receptor interaction and<br />
cell adhesion and in three pathways previously published in association with metastasis<br />
1) PIK3CA multipotent genetic program 2) early-stage metastatic disease or low<br />
burden signature 3) exosomal integrins and organ-specific metastasis.<br />
Conclusions: These results suggest that there may be an association between patient’s<br />
germline genetic background and breast cancer prognosis, independently or in<br />
conjunction with intrinsic tumor alterations.<br />
Legal entity responsible for the study: FIMABIS (Fundacion Publica Andaluza para la<br />
Investigacion de Malaga en Biomedicina y Salud)<br />
Funding: Instituto de Salud Carlos III (Fondos de Investigacion Sanitaria ISCIII-FIS)<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1585P<br />
Differences in incidence and biological characteristics<br />
between Roma and non-Roma women with breast cancer in<br />
Slovakia<br />
M. Reckova 1 , J. Mardiak 2 , L. Plank 3 , M. Vulevova 4 , S. Cingelova 2 , M. Mego 2<br />
1 <strong>Oncology</strong>, POKO Poprad, Poprad, Slovak Republic, 2 Medical <strong>Oncology</strong>, National<br />
Cancer Institute(Národný Onkologický Ustav), Bratislava, Slovak Republic,<br />
3 Pathology, Comenius University in Bratislava, Jessenius Faculty <strong>of</strong> Medicine,<br />
Martin, Slovak Republic, 4 Faculty <strong>of</strong> Pharmacy, Comenius University Bratislava,<br />
POKO Poprad, Bratislava, Slovak Republic<br />
Background: Roma (Gypsies) constitute the largest ethnic minority in Slovakia. They<br />
originally came from Northern India. There are some data about higher prevalence <strong>of</strong><br />
communicable diseases and higher infant and childhood mortality in Roma (R). Data<br />
about non-communicable diseases are very sparse and data about cancer in R are<br />
practically non-existent. The aim <strong>of</strong> this study was to compare differences in incidence<br />
and pathological characteristics between R and non-Roma (non-R) breast cancer<br />
patients (pts) in Slovakia.<br />
Methods: Roma and non-Roma breast cancer (BC) pts were identified using Slovak<br />
HER2 Registry that contains pathological data <strong>of</strong> all BC pts diagnosed in Slovakia from<br />
2003. Database from the last Census <strong>of</strong> Slovakia in 2011 (C/2011) was matched by<br />
gender, date <strong>of</strong> birth and residency with HER2 Registry from 2011 to 2013. Based on<br />
the match, R and non-R breast cancer pts were identified. Age-distribution and<br />
pathological characteristics were compared between R and non-R BC pts.<br />
Results: There were 10,344 pts registered in the HER2 Registry from 2011 to 2013, and<br />
151,128 people identified themselves as to have Roma nationality or to speak Roma<br />
language based on the C/2011. By matching the C/2011 and HER2 Registry, 32 and<br />
5,775 women with BC were identified as R and non-R, respectively. Median age <strong>of</strong> R<br />
pts was statistically significantly lower compared to non-R (49 vs. 61 years <strong>of</strong> age,<br />
P < 0.00001). The age-standardized breast cancer incidence rate was 5.88 times higher<br />
in R compared to non-R pts (246 vs. 42 per 100,000 people). Roma pts had more triple<br />
negative (28.1% vs. 12.3%, P = 0.01), and hormone receptor negative tumors (34.3% vs.<br />
18.1%, P = 0.03) when compared with non-Roma and and these differences remained<br />
statistically significant in multivariate analysis.<br />
Conclusions: We, for the first time, revealed differences in incidence and biological<br />
characteristics <strong>of</strong> Roma women with BC when compared to non-Roma. Roma patients<br />
are younger at diagnosis, have higher age-standardized breast cancer incidence rate and<br />
more aggressive tumors when compared to non-Roma. Further trials are needed to<br />
identify the factors responsible for our observation.<br />
Legal entity responsible for the study: 2nd <strong>Oncology</strong> Clinic, Faculty <strong>of</strong> Mediciine<br />
Comenius University Bratislava<br />
Funding: 2nd <strong>Oncology</strong> Clinic, Faculty <strong>of</strong> Mediciine Comenius University Bratislava<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1586P<br />
Different breast tumor morphological structures reflect<br />
specific EMT states and contribute to cancer metastasis<br />
T. Gerashchenko 1 , E. Denisov 2 , D. Pautova 3 , M. Zavyalova 4 , N. Cherdyntseva 1 ,<br />
V. Perelmuter 4<br />
1 Molecular <strong>Oncology</strong> and Immunology, Tomsk Cancer Research Institute, Tomsk,<br />
Russian Federation, 2 Translational Cellular and Molecular Biomedicine, Tomsk<br />
State University, Tomsk, Russian Federation, 3 Cytology and Genetics, Tomsk<br />
State University, Tomsk, Russian Federation, 4 Pathological Anatomy and Cytology,<br />
Tomsk Cancer Research Institute, Tomsk, Russian Federation<br />
Background: Epithelial-mesenchymal transition (EMT) is an obligatory event during<br />
invasion and metastasis and contributes to tumor progression. Intratumor<br />
morphological heterogeneity <strong>of</strong> invasive carcinoma no special type (IC NST),<br />
represented by five types <strong>of</strong> morphological structures: tubular, trabecular, solid,<br />
alveolar structures, and discrete groups <strong>of</strong> tumor cells, is associated with tumor<br />
progression. The presence <strong>of</strong> alveolar structures in the tumors <strong>of</strong> untreated patients is<br />
linked with lymph node metastasis (Zavyalova et al., 2013), however the mechanism <strong>of</strong><br />
this fact is unknown. The aim <strong>of</strong> this work was to estimate the association between<br />
morphological structures and metastasis frequency in the chemotherapy treated<br />
patients and to study gene expression pr<strong>of</strong>ile <strong>of</strong> the structures.<br />
Methods: 438 IC NST patients (mean age 50, T 1-4 N 0-3 M 0-1 ) treated with neoadjuvant<br />
chemotherapy have been enrolled. SurePrint G3 v2 8x60K gene expression arrays were<br />
used to analyze transcriptome <strong>of</strong> morphological structures, isolated from fresh tumors<br />
(n = 3) by laser microdissection.<br />
Results: Patients with alveolar or trabecular structures or discrete group <strong>of</strong> cells in breast<br />
tumors more frequently displayed lymph node metastasis than cases without these<br />
morphological variants (65.3% vs. 33.2%, р < 0.0001; 58.7% vs. 36.3%, р < 0.0001; 59.4%<br />
vs. 41.3%, р = 0.0002, respectively). The presence <strong>of</strong> alveolar or trabecular structures was<br />
associated with high frequency <strong>of</strong> distant metastasis in comparison with cases without<br />
these structures (42.8% vs. 27.3%, p = 0.0036; 41.9% vs. 20.7%, p = 0.0005, respectively).<br />
Cluster analysis <strong>of</strong> morphological structures showed the following phylogeny: alveolar<br />
and tubular – solid – trabecular – discrete groups <strong>of</strong> tumor cells. Furthermore, different<br />
structures showed specific set <strong>of</strong> epithelial (E) (EpCAM, CDH1, CLDN3) and<br />
mesenchymal (M) (Vim, MMP2, CDH11, CDH2) markers with prevalence <strong>of</strong> E in<br />
alveolar structures and M in discrete groups <strong>of</strong> tumor cells.<br />
Conclusions: Five types <strong>of</strong> morphological structures <strong>of</strong> IC NST may represent different<br />
EMT states and thus contribute to tumor metastasis. Research is supported by Russian<br />
Science Foundation Grant: No. 14-15-00318<br />
Legal entity responsible for the study: Tomsk Cancer Research Institute<br />
Funding: Russian Science Foundation Grant: No. 14-15-00318<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1587P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Tumor infiltrating lymphocytes and tertiary lymphoid<br />
structures in paired primary tumors and metastases from<br />
breast cancer patients<br />
C. Solinas 1 , A. Boisson 1 , D. Brown 2 ,R.deWind 3 , G. van den Eynden 1 ,<br />
S. Garaud 1 , L. Buisseret 1 , C. Naveaux 1 , C. Sotiriou 2 , D. Larsimont 3 , M. Piccart 4 ,<br />
K. Willard-Gallo 1<br />
1 Molecular Immunology Unit, Institute Jules Bordet, Brussels, Belgium, 2 BCTL -<br />
Breast Cancer Translational Research Laboratory, Institute Jules Bordet, Brussels,<br />
Belgium, 3 Department <strong>of</strong> Pathology, Institute Jules Bordet, Brussels, Belgium,<br />
4 Medicine Department, Institute Jules Bordet, Brussels, Belgium<br />
Background: In primary tumors (P), infiltrating lymphocytes (TIL) and tertiary<br />
lymphoid structures (TLS) have been associated with better clinical outcomes, in HER2<br />
vi546 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
+ and triple negative breast cancer (BC). The temporal and spatial heterogeneity <strong>of</strong> TIL<br />
and TLS between P and their matched metastases (M) is currently unknown.<br />
Methods: We analyzed formalin fixed paraffin embedded tissue samples from a<br />
retrospective cohort <strong>of</strong> BC patients who underwent adjuvant surgery for the P and<br />
metastasectomy or biopsy for their metachronous M at a distant site(s) (n = 51).<br />
Immunohistochemistry stained sections using anti-CD3 (T cells) and anti-CD20 (B cells)<br />
antibodies in a double stain were scored by two trained pathologists blinded to the clinical<br />
data. TIL were scored as the percent (%) <strong>of</strong> stroma plus tumor surface area infiltrated with<br />
CD3 + plus CD20 + cells. The number <strong>of</strong> TLS were normalized to the tumor area.<br />
Results: The extent <strong>of</strong> TIL in P (range 1-35%) was significantly higher with respect to<br />
the corresponding M (p = 0.04). Interestingly, when the extent <strong>of</strong> TIL in P was ≥10%<br />
(=TIL+) there was a significant decrease in the %TIL detected in M (p < 0.0001,<br />
n = 20). Alternatively, when TIL infiltration in the P was C]) homozygotes and heterozygotes in breast cancer<br />
patients: a clinicopathological analysis<br />
J. Huszno 1 , E. Grzybowska 2 , Z. Kolosza 3 , M. Nycz Bochenek 4 , J. Pamula Pilat 5 ,<br />
K. Tecza 5 , E. Nowara 1<br />
1 Clinical and Experimental <strong>Oncology</strong> Departament, Maria Sklodowska Curie MSC<br />
Memorial Cancer Institute in Gliwice, Gliwice, Poland, 2 Cwnter fot Translational<br />
Research and Molecular Biology <strong>of</strong> Cancer, Maria Sklodowska Curie MSC<br />
Memorial Cancer Institute in Gliwice, Gliwice, Poland, 3 Department <strong>of</strong><br />
Epidemiology and Silesia Cancer registry, Maria Sklodowska Curie MSC Memorial<br />
Cancer Institute in Gliwice, Gliwice, Poland, 4 Genetic Outpatient Clinic, Maria<br />
Sklodowska Curie MSC Memorial Cancer Institute in Gliwice, Gliwice, Poland,<br />
5 Canter fot Translational Research and Molecular Biology <strong>of</strong> Cancer, Maria<br />
Sklodowska Curie MSC Memorial Cancer Institute in Gliwice, Gliwice, Poland<br />
Background: TP53 is a tumor suppressor gene which participates in regulation <strong>of</strong> cell<br />
cycle check points, DNA repair, and apoptosis. Somatic mutations <strong>of</strong> TP53 are more<br />
frequent in advanced stage or in cancer subtypes with aggressive behavior (such as<br />
triple negative or HER2-amplified breast cancers). The aim <strong>of</strong> this study was to<br />
compare TP53 germline gene polymorphisms (c.[215G > C]) wild – type homozygotes<br />
GG with heterozygotes GC according to clinicopathological factors.<br />
Methods: We reviewed the medical records <strong>of</strong> 65 (29% TP53 gene homozygotes and<br />
71% heterozygotes) breast cancer patients who were diagnosed and treated in COI in<br />
Gliwice. Mutation pr<strong>of</strong>ile was assessed by RFLP-PCR technique. We evaluated the<br />
presence <strong>of</strong> polymorphism TP53 (c.[215G > C]). Statistical analysis was carried out<br />
using STATISTICA 7 s<strong>of</strong>tware.<br />
Results: The median age <strong>of</strong> patients was 51 years (range from 32 to 77). There was no<br />
difference according to median age between TP53 gene homozygotes and<br />
heterozygotes (51 vs. 52 years, p = 0.903). Lobular invasive carcinoma was observed<br />
insignificantly more frequently in TP53 gene homozygotes in comparison to<br />
heterozygotes (21% vs. 9%, p = 0.218). Tumor size (T3-T4) was detected in 15% <strong>of</strong> pts.<br />
Pts being TP53 gene heterozygotes had larger tumor size (T > 2) than homozygotes<br />
(20% vs. 5%, p = 0.258). Ki67 > 20% was detected in 56% <strong>of</strong> tumors and was more <strong>of</strong>ten<br />
reported in TP53 gene homozygotes (75% vs. 46%, p = 0.157). There was observed<br />
tendency to the presence <strong>of</strong> lymph node metastases (53% vs. 35%, p = 0.266) and triple<br />
negative breast cancer (16% vs. 7%, p = 0.347) in patients with TP53 gene homozygotes<br />
in comparison to heterozygotes (53% vs. 35%, p = 0.266). There were no associations<br />
between type <strong>of</strong> TP53 gene polymorphisms (homozygotes vs. heterozygotes) and<br />
steroid receptor status (68% vs. 74%, p = 0.762), higher histological grade (G > 2) (38%<br />
vs. 35%, p = 1.00) or HER2 overexpression (26% vs. 21%, p = 0.761).<br />
Conclusions: TP53 gene homozygotes were characterized by lymph node metastases,<br />
lobular histological type, triple negative breast cancer and higher Ki67 (>20%). In<br />
contrary, larger tumor size (T > 2) was mostly presented in TP53 gene heterozygotes.<br />
Legal entity responsible for the study: Clinical and Experimental <strong>Oncology</strong><br />
Department MSC Memorial Cancer Center and Institute <strong>of</strong> <strong>Oncology</strong>, Gliwice Branch<br />
Funding: Center for Translational Research and Molecular Biology <strong>of</strong> Cancer Clinical<br />
and Experimental <strong>Oncology</strong> Department MSC Memorial Cancer Center and Institute<br />
<strong>of</strong> <strong>Oncology</strong>, Gliwice Branch<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1589P<br />
Prognostic impact <strong>of</strong> tumor-infiltrating lymphocytes (TILs) in<br />
male breast cancer<br />
S. Abdeljaoued 1 , I. Bettaieb 1 , O. Adouni 1 , A. Goucha 1 , O. El Amine 1 ,<br />
A. Chabchoub 2 , H. Bouzaiene 2 , J. Ben Hassouna 2 , R. Makhlouf 1 , T. Ben Dhiab 2 ,<br />
H. Boussen 3 , K. Rahal 2 , A. Gamoudi 1<br />
1 Histo-Pathology, Institut Salah Azaïz, Tunis, Tunisia, 2 Carcinologic Surgery,<br />
Institut Salah Azaïz, Tunis, Tunisia, 3 Medical <strong>Oncology</strong>, Abderrahmen Mami<br />
Hospital, Ariana, Tunisia<br />
Background: The presence <strong>of</strong> tumor-infiltrating lymphocytes (TILs) has been shown<br />
to have significant prognostic relevance for certain subtypes <strong>of</strong> female breast cancer.<br />
However, whether TILs have any indication for prognosis in male breast cancer (MBC)<br />
patients remains unknown. The aim <strong>of</strong> this study was to evaluate the prognostic value<br />
<strong>of</strong> TILs in MBC.<br />
Methods: We retrospectively identified 120 male breast cancer patients diagnosed<br />
between 2000 and 2013 at Salah Azaïz National Cancer Institute. Two pathologists<br />
independently evaluated TIL levels using H&E-stained slides following 2014<br />
International TILs Working Group guidelines. Samples were classified as: low-TILs (≤<br />
5), intermediate-TILs (10-50) and Lymphocyte Predominant Breast Cancer (LPBC) (≥<br />
60%). Prognostic significance <strong>of</strong> TILs and overall survival (OS) was assessed by<br />
Kaplan-Meier analysis and log-rank test. Subtyping revealed 51 Luminal A (42.5%), 57<br />
Luminal B (47.5%), 2 HER2-enriched (1.7%) and 10 TNBC tumors (8.3%).<br />
Results: The median for presence <strong>of</strong> stromal TILs (sTILs) was 10.8% (1%-40%). 63<br />
(52.5%) had low sTILs and 57 (47.5%) had moderate sTILs. No LPBC were identified.<br />
TNBC subtype (13.1% [5%-25%]) and HER2-enriched tumors (14% [13%-15%])<br />
compared with Hormone receptor-positive tumors (10.0% [5.0%-22.5%]) had higher<br />
median levels <strong>of</strong> TILs at diagnosis. On univariate analysis, higher levels <strong>of</strong> TILs were<br />
associated with better OS (p = 0.04) and HER2 (p = 0.05). There was no significant<br />
difference between levels <strong>of</strong> TILs according to lymph node status (p = 0.39), tumor size<br />
(p = 0.16) or grade (p = 0.77). Multivariate analyses indicated that Higher levels <strong>of</strong><br />
TILs were an independent prognostic factor for OS (p = 0.05).<br />
Conclusions: High TILs is a favorable prognostic factor in MBC patients. Low-TILs<br />
seemed to be associated with worst overall survival suggesting a more aggressive<br />
phenotype in MBC patients. These results show that TILs may represent a novel MBC<br />
marker with prognostic significance that could be included into the limited marker<br />
panels for MBC.<br />
Legal entity responsible for the study: Salah Azaïz Cancer Institute<br />
Funding: Salah Azaïz Cancer Institute<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1590P<br />
abstracts<br />
The prognostic impact <strong>of</strong> the putative primary site <strong>of</strong> breast<br />
and ovarian cancers in an unfavorable subset <strong>of</strong> cancer <strong>of</strong><br />
unknown primary site<br />
M. Kodaira 1 , K. Yonemori 2 , T. Shimoi 2 , A. Shimomura 2 , M. Yunokawa 2 ,<br />
C. Shimizu 2 , Y. Fujiwara 2 , K. Tamura 2<br />
1 Medical <strong>Oncology</strong>, JIKOKAI Kodaira Hospital, Toda, Japan, 2 Breast and Medical<br />
<strong>Oncology</strong>, National Cancer Center Hospital, Tokyo, Japan<br />
Background: Specific patient subsets with breast and ovarian cancer contributed to the<br />
improved survival <strong>of</strong> the group in which the primary tumor was found. However, the<br />
outcome <strong>of</strong> presuming primary site <strong>of</strong> breast and ovarian cancer in patients with CUP<br />
is not clear.<br />
Methods: Patients who were diagnosed with an unfavorable subset <strong>of</strong> CUP and who<br />
underwent chemotherapy after referral to the National Cancer Center Hospital from<br />
April 2007 to March 2015 were enrolled in this study. The presumed primary site <strong>of</strong><br />
breast and ovarian cancer was based on the information about histology,<br />
immunohistochemistry, and pattern <strong>of</strong> metastasis. We retrospectively assessed the<br />
clinical outcomes <strong>of</strong> patients with the unfavorable subset <strong>of</strong> CUP with a putative<br />
primary site <strong>of</strong> breast and ovarian cancer (P-CUP) and the patients with the<br />
unfavorable subset <strong>of</strong> CUP (U-CUP).<br />
Results: A total <strong>of</strong> 409 patients were diagnosed with CUP and 343 patients were<br />
categorized as having the unfavorable subset <strong>of</strong> CUP. A clinicopathological<br />
examination revealed that 40 (11.7%) <strong>of</strong> the 343 patients had P-CUP and the<br />
remaining 303 (88.3%) patients had U-CUP. One hundred thirty-six patients received<br />
chemotherapy (22 with P-CUP, and 113 with U-CUP). Regarding the initial treatment,<br />
among the 22 patients with P-CUP, 3 received hormonal therapy for breast cancer, and<br />
the remaining 19 patients received chemotherapy based on the presumed primary<br />
organ (breast, 4; ovaries, 15). One hundred and five patients with U-CUP were treated<br />
with conventional platinum-based chemotherapy, and 8 patients received<br />
non-platinum drug treatment. The objective response rates were 61.1% for P-CUP<br />
(95% confidence interval [CI]: 38.6–83.6) and 41.1% for CUP (95% CI: 31.8–50.4). The<br />
median overall survival was 50.0 months for patients with P-CUP and 16.9 months for<br />
patients with U-CUP (hazard ratio: 0.32, 95% CI: 0.14–0.69, P =0.004).<br />
Conclusions: In this study, patients with a putative primary site <strong>of</strong> breast and ovaries<br />
had higher response rates and a better prognosis compared with the patients with the<br />
unfavorable subset <strong>of</strong> CUP. It might be reasonable to classify this subset as a new<br />
category <strong>of</strong> the favorable subset in CUP.<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw393 | vi547
abstracts<br />
Legal entity responsible for the study: National Cancer Center Hospital, Japan<br />
Funding: National Cancer Center Hospital, Japan<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1591P<br />
Primordial germ cell as potent cell <strong>of</strong> origin <strong>of</strong> mucinous<br />
cystic neoplasms <strong>of</strong> the pancreas and mucinous ovarian<br />
tumors<br />
I. Labidi-Galy 1 , K.M. Elias 2 , P. Tsantoulis 1 , A. Vitonis 2 , L. Doyle 3 , J. Hornick 3 ,D.<br />
W. Cramer 2 , M. Goggins 4 , C.L. Kerr 5 , M. Birrer 6 , M. Hirsch 3 , R. Drapkin 7<br />
1 Department <strong>of</strong> <strong>Oncology</strong>, Hôpitaux Universitaires de Genève - HUG, Geneva,<br />
Switzerland, 2 Department <strong>of</strong> Obstetrics and Gynecology, Brigham and Women’s<br />
Hospital, Boston, MA, USA, 3 Department <strong>of</strong> pathology, Brigham and Women’s<br />
Hospital, Boston, MA, USA, 4 Department <strong>of</strong> pathology, Johns Hopkins University,<br />
Baltimore, MD, USA, 5 Department <strong>of</strong> Biology, University <strong>of</strong> Maryland School <strong>of</strong><br />
Medicine, Baltimore, MD, USA, 6 Hematology/<strong>Oncology</strong>, Massachusetts General<br />
Hospital, Boston, MA, USA, 7 Department <strong>of</strong> Obstetrics and Gynecology, Penn<br />
Ovarian Cancer Research Center, Philadelphia, PA, USA<br />
Background: Mucinous ovarian tumors (MOT) are among the rarest and least studied<br />
epithelial ovarian neoplasms. Teratoma-associated MOT have been shown to be <strong>of</strong><br />
germ cell origin. However, the pathogenesis <strong>of</strong> MOT not associated with teratoma<br />
remains unclear. Recent exome sequencing studies revealed similarities between MOT<br />
and mucinous cystic neoplasms (MCN) <strong>of</strong> the pancreas with frequent mutations in<br />
KRAS and RNF43.<br />
Methods: Here we investigated the clinical characteristics <strong>of</strong> a series <strong>of</strong> 23 MCN and<br />
287 MOT, which included age at diagnosis, sex, stage and exposure to smoking. We<br />
compared the immunohistochemical patterns <strong>of</strong> 23 MCN and 18 MOT (CK7, CK20,<br />
CDX2, MUC2, PAX8, SMAD4 and β-catenin). We analyzed the gene expression<br />
pr<strong>of</strong>ile (GEP) <strong>of</strong> 19 normal pancreatic tissues, 36 pancreatic ductal adenocarcinomas<br />
(PDAC), 6 MCN, 8 MOT, 27 normal fallopian tubes (FT), 13 high-grade serous<br />
ovarian carcinomas (HGSOC), 6 ovarian surface epithelium (OSE), 2 human PGCs<br />
and single cell RNA-sequencing <strong>of</strong> 5 primordial germ cells (PGC).<br />
Results: We observed that both MOT and MCN occur mainly in young women that<br />
have been exposed to smoking and they are frequently diagnosed at early stages. Both<br />
tumors have similar immunohistochemical phenotype, mainly<br />
CK7 + CK20-MUC2-CDX2-. Thus, we hypothesize that MCN and MOT would share a<br />
common cell <strong>of</strong> origin, primordial germ cells (PGCs) that stopped in the dorsal<br />
pancreas during their descent to gonads during early human embryogenesis. We<br />
compared GEP <strong>of</strong> MOT, HGSOC, OSE, FT and PGCs. Alterations in MOT correlated<br />
more with PGCs whereas HGSOC correlated with OSE or FT. We also compared GEP<br />
<strong>of</strong> normal pancreatic tissue, PDAC, pancreatic MCN and PGCs. Molecular alterations<br />
in pancreatic MCN correlated more with PGCs whereas PDAC relied on normal<br />
pancreatic tissue.<br />
Conclusions: These finding support a common molecular pathway for the<br />
development <strong>of</strong> MCN and MOT and suggest that both tumors can derive from PGCs.<br />
Pancreatic MCN would arise from embryological remnants <strong>of</strong> PGCs that stop in the<br />
pancreas during early developement. In the ovaries, MOT can develop from PGCs that<br />
would not undergo oogonia.<br />
Legal entity responsible for the study: N/A<br />
Funding: Fondation de France, Arthur Sachs/Harvard<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1592P<br />
Comprehensive molecular and immunological analysis to<br />
assess the tumor immune contexture in stage II and III<br />
colorectal cancer<br />
K. Silina 1 , U. Petrausch 2 , F. Posch 3 , S. Leibl 4 , A. Mündlein 5 , H. Moch 4 ,<br />
A. Siebenhüner 6 , R. Stupp 6 , J. Riedl 3 , B.C. Pestalozzi 6 , P. Schraml 4 , A. Gerger 3 ,<br />
T. Winder 6<br />
1 Institute <strong>of</strong> Experimental Immunology, University <strong>of</strong> Zurich, Zurich, Switzerland,<br />
2 Swiss Tumor Immunology Institute, OnkoZentrum Zürich, Zurich, Switzerland,<br />
3 Department <strong>of</strong> Internal Medicine, Medical University Graz, Graz, Austria,<br />
4 Department <strong>of</strong> Pathology, University Hospital Zürich, Zurich, Switzerland, 5 VIVIT,<br />
Vorarlberg Institute for Vascular Investigation and Treatment, Feldkirch, Austria,<br />
6 <strong>Oncology</strong>, Universitätsspital Zürich, Zurich, Switzerland<br />
Background: Tumor immune infiltrates play a critical role in CRC. The neutrophil to<br />
lymphocyte ratio (NLR), microsatelite instability (MSI-H), and tertiary lymphoid<br />
structures (TLS) have shown independent prognostic value in several cancer types. In<br />
this study, we performed molecular, tissue and liquid testing in stage II and III<br />
colorectal cancer to link molecular and immunological findings aiming to predict<br />
tumor immune infiltrates.<br />
Methods: For this retrospective, exploratory study we analyzed prospectively collected<br />
archival tissue samples <strong>of</strong> 111 patients with stage II and III CRC. To quantify TLS/mm<br />
at tumor invasive front we performed multispectral microscopy after<br />
immun<strong>of</strong>luorescent co-staining <strong>of</strong> CD21/CD23. BRAF mutation was determined by<br />
allele-specific PCR. MSI was assessed by immunohistochemistry for the mismatch<br />
repair proteins MLH1, MSH2, PMS2, MSH6. NLR was defined by absolute peripheral<br />
blood neutrophil count divided by the absolute peripheral blood lymphocyte count.<br />
Results: BRAF V600E and MSI-H status were highly associated with each other: 5<br />
(50%) out <strong>of</strong> the 10 CRC patients with MSI-H had a BRAF mutation (p < 0.0001).<br />
MSI-H and/or BRAF mutant CRC showed a significantly higher median total number<br />
<strong>of</strong> TLS/mm than patients without these molecular phenotypes (1.22 vs. 0.9, p = 0.04),<br />
suggesting the concept that these tumors induce a distinct local immune response.<br />
Further, we were able to demonstrate a negative correlation between high NLR and a<br />
low number <strong>of</strong> TLS (Spearman’s rho = -0.26, p = 0.007) suggesting an impact <strong>of</strong><br />
neutrophils on the generation <strong>of</strong> structured lymphoid aggregates in the tumor<br />
microenvironment.<br />
Conclusions: We discovered NLR as a peripheral blood surrogate to identify TLS as<br />
part <strong>of</strong> the tumor immune contexture. For the first time, we linked NLR with<br />
immune-related genomic alterations and immune-cell infiltration in stage II and III<br />
colorectal cancer.<br />
Legal entity responsible for the study: N/A<br />
Funding: University Hospital Zurich<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1593P<br />
The colorectal cancer (CRC) tumour microenvironment<br />
recruits and polarises two distinct populations <strong>of</strong> myeloid<br />
cells with unique regulatory pr<strong>of</strong>iles<br />
L.A. Elliott 1 , K. Sheahan 2 , G. Doherty 2 , D. Fennelly 3 , E. Ryan 2<br />
1 ERC, St.Vincent’s University Hospital, Dublin City University, Dublin, Ireland,<br />
2 Centre for Colorectal Disease, St Vincents University Hospital, Dublin, Ireland,<br />
3 <strong>Oncology</strong>, St Vincents University Hospital, Dublin, Ireland<br />
Background: Tumor resident myeloid cells (MCs) are instrumental to cancer<br />
progression and are emerging as a potential therapeutic target in many cancers. The<br />
mechanisms by which tumours regulate MCs remain poorly defined. We investigated<br />
how the CRC tumour microenvironment (TME) impacts on MCs recruitment and<br />
function.<br />
Methods: Patients with Stage II/III CRC undergoing surgical resection were recruited<br />
(n = 21). Fresh samples <strong>of</strong> tumour and uninvolved tissue were obtained and digested to<br />
a single cell suspension. MCs were phenotyped using multi-parameter flow cytometry.<br />
We generated tumor (TCM) and normal (NCM) conditioned media from a further<br />
cohort (n = 40) and assessed levels <strong>of</strong> 16 cytokines using a multiplex assay. Finally, we<br />
designed a MC:Cell line co-culture model to investigate the molecular mechanisms that<br />
control MC function.<br />
Results: We found two distinct MC subsets, HLA-DR hi CD11c hi and CD11b hi CD15 hi ,<br />
unique to the tumor tissue, dominated the CD45+ compartment. Further analysis<br />
showed that the HLA-DR hi CD11c hi and the CD11b hi CD15 hi were <strong>of</strong> monocyte and<br />
neutrophil origin, respectively. In support <strong>of</strong> their potential immune-regulatory and<br />
proangiogenic function, we showed that the HLA-DR hi CD11c hi subset expressed ILT4,<br />
PDL1 and Tie-2. The CD11b hi CD15 hi subset exhibited high levels <strong>of</strong> arginase, an<br />
enzyme involved in T cell suppression. Interestingly, both cell subsets displayed an<br />
altered chemokine receptor pr<strong>of</strong>ile compared to their blood counterparts. Accordingly,<br />
we were able to confirm the upregulated expression <strong>of</strong> inflammatory mediators, CXCL1<br />
(p < 0.0001), CXCL5 (p < 0.0198), CCL5 (p < 0.0001), CCL4 (p < 0.0074), IL-8<br />
(p < 0.0127), and IL-1β (p < 0.0001) in TCM compared to NCM. Finally, we found<br />
several genes upregulated (IDO1, CSF1, IL1A, IL-1B) in monocytes exposed to tumour<br />
conditioned media whereas the genes IGF1, FASLG, CCR4 were under expressed.<br />
Conclusions: This study identifies two MC subsets in patients with CRC. We<br />
demonstrate that the TME recruits these cells via a complex chemokine-chemokine<br />
receptor network subsequently transforming them into a highly activated but<br />
immune-regulatory cell that favors tumor growth.<br />
Legal entity responsible for the study: Louise Elliott<br />
Funding: Merck Serono<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1594P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Qualitative and quantitative differences in a set <strong>of</strong> criteria for<br />
histological grading <strong>of</strong> colorectal cancer<br />
T. Savchyn 1 , S.A. Antoniuk 2 , A.N. Grabovoy 2<br />
1 ESC “Institute <strong>of</strong> Biology”, Taras Shevchenko National University <strong>of</strong> Kyiv, Kyiv,<br />
Ukraine, 2 Department <strong>of</strong> Pathologic Anatomy, National Cancer Institute <strong>of</strong> the<br />
MPH Ukraine, Kiev, Ukraine<br />
Background: Colorectal cancer grading still remains semiquantitative and subjective.<br />
The aim <strong>of</strong> this study was to estimate the differences between G1, G2 and G3 tumor<br />
grades using quantitative methods and build objective tests for tumor grading.<br />
Methods: Samples were collected from 114 patients with colorectal cancer. The tissue<br />
slices were stained with Einarson’s gallocyanin chrome alum stain for the NA content<br />
detection. Immunohistochemical reactions were conducted using monoclonal<br />
antihuman Ki-67, Bcl-2 and p53 antibodies. Silver nitrate impregnation was used for<br />
nucleolus organizer regions (NORs) detection. Regression analysis was conducted<br />
vi548 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
abstracts<br />
using logistic model. Cox and Snell’sR 2 (R 2 CS), Nagelkerke’sR 2 (R 2 N), Bayesian<br />
information criterion (BIC) and ROC curves (AUC values) were used for assessing the<br />
fitting ability <strong>of</strong> obtained models.<br />
Results: Two strategies for multiclass classification were used. One-vs.-one (OvO)<br />
compares grades pairwise and then builds binary classifier for each grade. One-vs.-all<br />
(OvA) strategy involves training classifier based on comparing the grade to the set <strong>of</strong><br />
others. Logistic regression model was selected as binary classifier. As a result large<br />
varieties <strong>of</strong> models were built including different set <strong>of</strong> predictors. Models with the best<br />
accuracy were selected for each strategy (Table). G2 vs. G3 includes such predictors as<br />
tumor expression rate <strong>of</strong> Bcl-2 and p53. And these predictors are included in G3 vs.<br />
All. Pointing that the main effect induced by G2 and G3. But G2 vs. G3 has better<br />
accuracy (AUC = 0.8). G1 vs. G2 includes number <strong>of</strong> NORs total volume <strong>of</strong> NORs and<br />
average DNA content in the cells. G1 vs. All includes the same predictors too but<br />
shows better accuracy (AUC = 0.74).<br />
Table: 1594P<br />
χ 2 df p R 2 CS R 2 N BIC AUC<br />
OvO G1 vs. G2 15.38 3 0.002 0.15 0.22 124 0.72<br />
G2 vs. G3 14.82 4 0.005 0.17 0.29 91 0.80<br />
G3 vs. G1 19.52 3 0.0002 0.39 0.54 53 0.89<br />
OvA G1 vs. All 18.61 3 0.0003 0.16 0.24 130 0.74<br />
G2 vs. All 7.23 2 0.03 0.07 0.09 154 0.64<br />
G3 vs. All 13.91 4 0.008 0.12 0.23 103 0.78<br />
Conclusions: Therefore, models from different strategies can be combined into a novel<br />
one. In our case G1 vs. All and G2 vs. G3 may be used together for colorectal tumor<br />
grading in an hierarchical manner. First <strong>of</strong>f G1 separates from group <strong>of</strong> G2 and G3<br />
with the following G2 and G3 separation.<br />
Legal entity responsible for the study: National Cancer Institute, Department <strong>of</strong><br />
Pathologic Anatomy; 33/43, Lomonosova str., Kyiv, 03022, Ukraine<br />
Funding: Ministry <strong>of</strong> Healthcare <strong>of</strong> Ukraine<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1595P<br />
MicroRNAs as biomarkers <strong>of</strong> resistance to HER2 inhibitors in<br />
combination with chemotherapy in gastro-oesophageal<br />
cancer cell lines<br />
H. Lote 1 , D. Zito 1 , R. Burke 2 , E. Smyth 3 , C. Braconi 4 , D. Cunningham 3 , N. Valeri 5<br />
1 Laboratory <strong>of</strong> Gastrointestinal Cancer Biology and Genomics, Division <strong>of</strong><br />
Molecular Pathology, The Institute <strong>of</strong> Cancer Research ICR, Sutton, UK, 2 Cancer<br />
therapeutics, Institute <strong>of</strong> Cancer Research ICR, London, UK, 3 Department <strong>of</strong><br />
<strong>Oncology</strong>, The Institute <strong>of</strong> Cancer Research/Royal Marsden NHS Foundation<br />
Trust, Sutton, UK, 4 Signal Transduction and Molecular Pharmacology, The<br />
Institute <strong>of</strong> Cancer Research ICR, Sutton, UK, 5 Laboratory <strong>of</strong> Gastrointestinal<br />
Cancer Biology and Genomics, Division <strong>of</strong> Molecular Pathology, The Institute <strong>of</strong><br />
Cancer Research/Royal Marsden NHS Foundation Trust, Sutton, UK<br />
Background: MicroRNAs (miRs) may be involved in primary resistance to HER2<br />
inhibitors and represent a clinically useful biomarker for gastro-oesophageal cancer<br />
(GOC) patients with HER2 amplified disease. Identification <strong>of</strong> miRs responsible for<br />
resistance to HER2 inhibitors may allow us to develop a novel, reproducible,<br />
non-invasive and cost-effective tool for GOC patient stratification. Defining predictive<br />
biomarkers <strong>of</strong> resistance to HER2 inhibitors would enable patient selection, minimise<br />
chances <strong>of</strong> severe toxicity in those less likely to respond, and may define novel<br />
strategies to restore drug sensitivity.<br />
Methods: A high-throughput large-scale RNA interference screen in the<br />
HER2-amplified GOC cell line NCI-N87 and the HER2-non-amplified cell line FLO-1<br />
was performed in order to discover novel miRs involved in sensitivity and resistance to<br />
trastuzumab. Cells were transfected using a library <strong>of</strong> 1015 miR mimics, control miRs<br />
and siRNAs, and siPLK1 positive control. They were treated 48 hours later with<br />
cisplatin + 5FU + trastuzumab based on IC50 data previously obtained. Cell viability<br />
was analysed after 72 hrs <strong>of</strong> continuous drug treatment by fluorescence-based assay<br />
(Cell Titer Blue® and EnVision). Data from 3 biological replicates was analysed and<br />
shortlisting <strong>of</strong> significant hits was based on the concordance among data from different<br />
replicates. miRs were considered significant if they caused >40% decrease in cell<br />
viability with a t-test p value <strong>of</strong> 40% decrease in cell viability and were associated<br />
with a p value <strong>of</strong> 40% decrease<br />
in cell viability and were associated with a p value <strong>of</strong>
abstracts<br />
Conclusions: Our findings collectively indicate that NEK2 modulates hepatoma cell<br />
functions, including growth, drug resistance, metastasis and angiogenesis.<br />
Legal entity responsible for the study: N/A<br />
Funding: Chang-Gung Memorial Hospital, Taiwan<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1598P<br />
Characteristics and prognostic potential <strong>of</strong> tertiary lymphoid<br />
structures in oral tongue squamous cell carcinoma<br />
X. Liu 1 , Y. Wang 2 , J. Fang 2 , J. Song 2 , Y. Chen 2 ,T.Wu 2 , J. Wang 2 , B. Cheng 2 ,<br />
Z. Wang 2<br />
1 Department <strong>of</strong> oral and maxill<strong>of</strong>acial surgery, Guanghua School <strong>of</strong> Stomatology,<br />
Hospital <strong>of</strong> Stomatology, Sun Yat-Sen University, Guangzhou, China, 2 Department<br />
<strong>of</strong> oral medicine, Guanghua School <strong>of</strong> Stomatology, Hospital <strong>of</strong> Stomatology, Sun<br />
Yat-Sen University, Guangzhou, China<br />
Background: Recently, tertiary lymphoid structures (TLSs) have been reported in<br />
melanoma, NSCLC, breast cancer, colorectal cancer and so on. They are considered to<br />
drive local adaptive immune responses against tumors and considered as important<br />
sites <strong>of</strong> extranodal T cell priming and epitope spreading in the responder T cell<br />
repertoire. In terms <strong>of</strong> prognostic value, TLS is the factory for immune response.<br />
Therefore TLS act as a favorable clinical outcome for patients. But TLS was seldom<br />
reported on oral tongue squamous cell carcinoma. To identify and evaluate the<br />
presence <strong>of</strong> tertiary lymphoid structures in oral tongue squamous cell carcinomas<br />
(OTSCC). If present, we would study the prognostic values <strong>of</strong> TLSs in OTSCC and<br />
analyze whether they are related to the survival <strong>of</strong> OTSCC.<br />
Methods: The expression <strong>of</strong> PNAd + HEV, CD20 + B cells, CD3 + T cells was examined<br />
to record the quantity <strong>of</strong> TLSs, using immunohistochemistry (IHC) in<br />
paraffin-embedded tissue samples from 168 OTSCC patients. Overall Survival (OS)<br />
and disease-free survival (DFS) were estimated using the Kaplan-Meier method, with a<br />
log-rank test. Multivariate survival analysis was done using the Cox proportional<br />
hazards model. Variables that were statistically significant in the univariate analysis<br />
were entered into multivariate Cox regression analyses to indentify its independent<br />
value.<br />
Results: TLS was a well-organized structure composed <strong>of</strong> a specific indicator <strong>of</strong> HEV<br />
and distinct B cell aggregates and T cell area. TLSs were found in about 26.5% <strong>of</strong><br />
OTSCC patients. Among clinicopathological data [including gender, age, smoking<br />
history, alcohol consumption, tumor differentiation, TNM stage and TILs (tumor<br />
infiltrating lymphocyte)], TLSs were associated with TILs (p < 0.05). Log-rank test<br />
showed that presence <strong>of</strong> TLS affect the relapse and 5 year overall survival rates <strong>of</strong><br />
OTSCC (both p < 0.05). In multivariate analyses, TLS was the independent factor <strong>of</strong><br />
relapse and 5 year overall survival rates <strong>of</strong> OTSCC (both p < 0.05).<br />
Conclusions: The presence <strong>of</strong> TLS in OTSCC was identified. TLS is associated with<br />
adverse prognosis in patients with OTSCC. It may play important roles in preventing<br />
the recurrence <strong>of</strong> OTSCC.<br />
Legal entity responsible for the study: Guanghua School <strong>of</strong> Stomatology, Hospital <strong>of</strong><br />
Stomatology, Sun Yat-sen University, Guangdong Provincial Key Laboratory <strong>of</strong><br />
Stomatology<br />
Funding: National Natural Science Foundations <strong>of</strong> China (No. 81272954, 81472524)<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1599P<br />
Management optimization <strong>of</strong> non small cell lung cancer<br />
(NSCLC) specimens. A single institution experience with a<br />
multiplexed mass spectrometry approach<br />
G. De Maglio 1 , A. De Pellegrin 1 , A. Follador 2 , S. Distefano 3 , G. Morana 3 , P. Vailati 3 ,<br />
N. Bergamin 1 , S. Ciani 1 , E. Poletto 2 , E. De Carlo 2 , G. Pelizzari 2 , M. Cattaneo 2 ,<br />
E. Lugatti 3 , G. Fasola 2 , S. Pizzolitto 1<br />
1 SOC Anatomia Patologica, Azienda Sanitaria Universitaria Integrata Udine, Udine,<br />
Italy, 2 Dipartimento di Oncologia, Azienda Sanitaria Universitaria Integrata Udine,<br />
Udine, Italy, 3 SOC Pneumologia, Azienda Sanitaria Universitaria Integrata Udine,<br />
Udine, Italy<br />
Background: Molecular characterization <strong>of</strong> NSCLC has improved significantly in the<br />
last few years and multigenes diagnostic platforms spread in clinical molecular<br />
laboratories for the advantage <strong>of</strong> their multiplexed approach added to the requirement<br />
<strong>of</strong> a very low amount <strong>of</strong> DNA, compared to conventional methods. The main goal for<br />
NSCLC sampling management is the optimization <strong>of</strong> either cytological and histological<br />
specimens to guarantee immunophenotyping <strong>of</strong> the tumour with all genomic data for<br />
targeted therapies. However, DNA yield is <strong>of</strong>ten very critical and low tumour cells<br />
enrichment requires high analytical sensitivities.<br />
Methods: In the period January 2014-March 2016, we genotyped 438 NSCLC by<br />
multiplexed mass spectrometry on Agena MassARRAY® System (Agena Bioscience)<br />
with CE-IVD Myriapod® Lung status kit (Diatech Pharmacogenetics), a target assay<br />
that investigates more than 230 mutations on 10 genes involved in NSCLC, with a<br />
DNA amount <strong>of</strong> at least 40 ng. In 35% <strong>of</strong> cases, cytological samples were the only<br />
available diagnostic material.<br />
Results: In 102 (23.3%) samples the amount <strong>of</strong> DNA extracted would have been<br />
insufficient for EGFR testing by RealTime PCR or pyrosequencing, and they would had<br />
been classified as “not adequate”. We processed these cases by mass spectrometry<br />
observing EGFR and KRAS mutations in 12 (11.8%) and 30 (29.4%) cases, respectively.<br />
Among all cases we observed 12 (2.7%) tumours with neoplastic cell content lower<br />
than 30% that didn’t revealed any mutation in EGFR/KRAS. We classified these<br />
patients as “inadequate for molecular testing”, recommending a retest on a more<br />
representative sampling <strong>of</strong> the lesion.<br />
Conclusions: Combining a sensitive multiplexed mass spectrometry approach with an<br />
efficient management <strong>of</strong> the sample, the diagnostic accuracy was 97.3%. This value<br />
would had been decreased to 76.7% if only Real Time or sequencing methods were<br />
available. Considering the generally mutual presence <strong>of</strong> EGFR/KRAS mutations and<br />
ALK rearrangements we avoid a further diagnostic bronchoscopic exam to 42 patients.<br />
Cooperation between pneumologist, pathologist, molecular biologist and oncologist is<br />
essential for the management <strong>of</strong> NSCLC patients.<br />
Legal entity responsible for the study: N/A<br />
Funding: N/A<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1600P<br />
Typing <strong>of</strong> non-small cell lung carcinoma and investigation <strong>of</strong><br />
enteric differentiation in small biopsy specimens<br />
A. Erol 1 , S. Perçinel 1 , A. Demirkazik 2<br />
1 Pathology, Ankara University School <strong>of</strong> Medicine, Ankara, Turkey, 2 Medical<br />
<strong>Oncology</strong>, Ankara University School <strong>of</strong> Medicine, Ankara, Turkey<br />
Background: The development <strong>of</strong> targeted therapy has led to the need for subtyping <strong>of</strong><br />
non-small cell lung carcinomas (NSCLC). The aim <strong>of</strong> this study was to assess the utility<br />
<strong>of</strong> immunohistochemical (IHC) markers in subtyping particularly poorly differentiated<br />
NSCLC in small biopsy specimens and also investigate NSCLC for enteric<br />
differentiation.<br />
Methods: A: total <strong>of</strong> 760 small lung biopsies diagnosed as NSCLC between 2001-2011<br />
were re-evaluated for tumor typing morphologically. Among these, 126 cases [108<br />
NSCLC-not otherwise specified (NOS), 11 squamous cell carcinoma (SCC), 7<br />
adenocarcinoma (ADC) and 1 adenosquamous carcinoma (ADSC)] were selected for<br />
IHC examination. These cases were stained for thyroid transcription factor-1<br />
(TTF-1) + Napsin A and p63 + CK5/6 using a double IHC staining method and stained<br />
for desmoglein-3 (DSG-3), CK7, CK20 and CDX2 using a conventional IHC method.<br />
Diagnostic concordance between 40 resection specimens and their corresponding<br />
biopsy specimens were also compared.<br />
Results: 366 (50.6%) <strong>of</strong> 724 cases diagnosed as NSCLC were morphologically typed<br />
and 358 (49.4%) <strong>of</strong> them were classified as NSCLC-NOS. After IHC examination,<br />
while 74 (69%) <strong>of</strong> 108 NSCLC-NOS cases could be typed, 34 (31%) <strong>of</strong> cases could not<br />
be classified in spite <strong>of</strong> IHC examination. TTF-1 expression in 100% <strong>of</strong> ADC and 7% <strong>of</strong><br />
SCC, Napsin A expression in 77% <strong>of</strong> ADC and 2% <strong>of</strong> SCC, p63 expression in 93% <strong>of</strong><br />
SCC and 28% <strong>of</strong> ADC, CK5/6 expression in 96% <strong>of</strong> SCC and 9% <strong>of</strong> ADC, DSG-3<br />
expression in 21% <strong>of</strong> SCC and none <strong>of</strong> ADC and CK7 expression in 89% <strong>of</strong> ADC and<br />
30% <strong>of</strong> SCC were observed. CDX2 positivity was detected in 14.3% <strong>of</strong> ADC, 17.9% <strong>of</strong><br />
SCC and 29.4% <strong>of</strong> NSCLC-NOS cases. 5.6% <strong>of</strong> NSCLC-NOS cases expressed CK20.<br />
Diagnostic concordance compared between biopsy and resection specimens in 40 cases<br />
was found to be 65% (100% with respect to SCC).<br />
Conclusions: A panel <strong>of</strong> TTF-1, p63 and CK5/6 allows to reliably classify 70% <strong>of</strong><br />
poorly differentiated NSCLC cases in small biopsy specimens.<br />
Legal entity responsible for the study: N/A<br />
Funding: Ankara University Scientific research foundation<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1601P<br />
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
Genomic DNA from HT29 cells and its modified forms<br />
influence in vitro survival <strong>of</strong> the same tumor cells via TLR9-<br />
and autophagy signaling<br />
G. Műzes 1 , Z. Tulassay 1 , A. L. Kiss 2 , F. Sipos 1<br />
1 2nd Department <strong>of</strong> Medicine, Semmelweis University, Budapest, Hungary,<br />
2 Department <strong>of</strong> Anatomy, Histology and Embryology, Semmelweis University,<br />
Budapest, Hungary<br />
Background: The interrelated role <strong>of</strong> TLR9 and autophagy signaling in cancer has not<br />
yet been clarified. In our previous study incubation <strong>of</strong> HT29 cancer cells with modified<br />
self-DNAs resulted in different effects on TLR9-signaling and cell differentiation. This<br />
study was designed to assess the TLR9-related activities <strong>of</strong> self-DNA sequences on cell<br />
survival and autophagy response in HT29 cells.<br />
Methods: HT29 cells were incubated for 72 h with intact genomic (g), and arteficially<br />
hypermethylated (m), fragmented (f), and hypermethylated/fragmented (m/f) tumoral<br />
self-DNAs. Cell viability was measured by MTT assay, while induction <strong>of</strong> apoptosis by<br />
TUNEL. Cell proliferation was estimated by Ki67 immunocytochemistry.<br />
Transcriptional changes <strong>of</strong> TLR9- and autophagy pathways were assayed by qRT-PCR<br />
and immunocytochemistry. Morphologic features <strong>of</strong> apoptosis and autophagy were<br />
vi550 | abstracts Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> <strong>of</strong> <strong>Oncology</strong><br />
examined by transmission electron microscopy (TEM). The number <strong>of</strong><br />
colonosphere-positive wells was also determined.<br />
Results: Following incubation with g-, m/f-, and mainly with m-DNAs viability and<br />
proliferation rate <strong>of</strong> HT29 cells decreased, while percentage <strong>of</strong> apoptotic cells increased.<br />
F-DNA resulted in an enhanced cell survival. Methylation <strong>of</strong> self-DNA decreased<br />
TLR9 expression, but it did not influence the positive effect <strong>of</strong> DNA fragmentation on<br />
MyD88 and TRAF6 overexpression, and TNFα downregulation. Fragmentation <strong>of</strong><br />
DNA abrogated the effect <strong>of</strong> methylation on IRAK2, NFκB and IL8 mRNA<br />
upregulations. Regarding autophagy g- and f-DNAs caused significant upregulation <strong>of</strong><br />
Beclin1, Atg16L1, and LC3 mRNAs, while m- and m/f-DNAs resulted in rather modest<br />
expressions, verified by immunocytochemistry, as well. According to TEM in each<br />
group <strong>of</strong> tumor cells varying degree <strong>of</strong> autophagy was observed. Incubation with<br />
m-DNA suppressed tumor cell survival by inducing apoptotic death, and activated<br />
mitophagy. F-DNA enhanced cell survival, and activated both macroautophagy and<br />
lipophagy. CD133+ colonospheres were detected after m-DNA incubation.<br />
Conclusions: Our study provided evidence for a close interplay between<br />
TLR9-signaling and autophagy with remarkable influences on survival <strong>of</strong> HT29 cells<br />
subjected to intact or modified self-DNA treatments.<br />
Legal entity responsible for the study: Ferenc Sipos<br />
Funding: Hungarian Scientific Research Fund (OTKA-K111743)<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1602P<br />
Syndecan-1 up-regulates microRNA-331-3p and mediates<br />
epithelial-to-mesenchymal transition in prostate cancer<br />
T. Fujii 1 , K. Shimada 1 , Y. Tatsumi 1 , N. Tanaka 2 , K. Fujimoto 2 , N. Konishi 1<br />
1 Pathology, Nara Medical University, Nara, Japan, 2 Urology, Nara Medical<br />
University Hospital, Kashihara, Japan<br />
Background: Syndecan-1 is an important regulator, and may contribute to various<br />
mechanisms in the progression <strong>of</strong> prostate cancer, such as cell growth, and<br />
epithelial-to-mesenchymal transition (EMT), through regulation <strong>of</strong> microRNAs<br />
(miRNAs). We recently found that miR-331-3p is down-regulated by syndecan-1<br />
silencing in PC3 cells, based on an miRNA expression array and quantitative RT-PCR<br />
assay. The aim <strong>of</strong> the present study was to investigate whether syndecan-1-regulated<br />
miR-331-3p expression positively affects EMT.<br />
Methods: The expression <strong>of</strong> miR-331-3p, E-cadherin, and vimentin was detected in<br />
twenty-three prostate cancer tissues with in situ hybridization and<br />
immunohistochemistry. For functional analysis <strong>of</strong> miR-331-3p and syndecan-1,<br />
miR-331-3p precursor or syndecan-1 siRNA was transfected into PC3 cell lines. Cell<br />
proliferation and migration were evaluated with MTS assay and wound healing assay,<br />
respectively. For bioinformatics prediction, quantitative RT-PCR and luciferase assay<br />
were used to identify the target <strong>of</strong> the miRNA.<br />
Results: In situ hybridization and immunohistochemistry <strong>of</strong> radical prostatectomy<br />
samples revealed miR-331-3p expression in cancer cells with high Gleason patterns,<br />
and EMT was demonstrated by decreased E-cadherin and increased vimentin staining.<br />
Overexpression <strong>of</strong> miR-331-3p up-regulated mesenchymal markers such as vimentin,<br />
N-cadherin, and Snail, and down-regulated epithelial markers such as E-cadherin and<br />
desmoplakin in the prostate cancer cell line PC3. We identified Neuropilin 2 (NRP2)<br />
and nucleus accumbens-associated protein 1 (NACC1) as putative target molecules in<br />
silico, as they were closely associated with the expression <strong>of</strong> miR-331-3p and TGF-β/<br />
Smad 4 signals. Syndecan-1 gene silencing decreased the levels <strong>of</strong> Dicer, which is<br />
involved in miRNA maturation.<br />
Conclusions: miR-331-3p can suppress tumor growth and the migration <strong>of</strong> prostate<br />
cancer cells by targeting NRP2 and NACC1, which may provide a potential therapeutic<br />
target for prostate cancer treatment. Moreover, syndecan-1-mediated miRNA<br />
maturation by Dicer and miR-331-3p-mediated EMT via effects on TGF-β/Smad 4<br />
signaling are essential for the development <strong>of</strong> prostate cancer.<br />
Legal entity responsible for the study: Nara Medical University School <strong>of</strong> Medicine,<br />
Nara, Japan<br />
Funding: Grant-in-Aid from the Ministry <strong>of</strong> Educaion, Culture, Sports, Science and<br />
Technology, Japan (26462424)<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1604P<br />
Tyrosine kinase inhibitors targeted therapy and the<br />
AKT-m-TOR pathway in kidney cancer tissues<br />
the study is investigation <strong>of</strong> AKT-m-TOR pathway components in kidney cancer<br />
tissues before and after TKI-targeted therapy.<br />
Methods: The study included 30 patients with metastatic clear cell kidney cancers. The<br />
treatment <strong>of</strong> these men consisted <strong>of</strong> pre-operational sorafinib targeted therapy in dose<br />
<strong>of</strong> 400 mg every day during the two months. Then the radical nephrectomy was<br />
performed. Content <strong>of</strong> phospho-PTEN, AKT (pan), phospho-AKT (T308),<br />
phospho-AKT (S473), phospho-GSK-3-beta (Ser9), phospho-PDK1 (Ser241),<br />
phospho-c-Raf (Ser259), m-TOR, phospho-mTOR (Ser2448), phospho-p70 S6<br />
(Ser371), phospho-p70 S6 (T389) phospho-4E-BP1 (Thr37/46) was determined by<br />
western blotting analysis in tissues before and after targeted therapy.<br />
Results: We have revealed the increased content <strong>of</strong> total AKT (pan),<br />
phospho-GSK-3-beta, phospho-PDK1, phospho-c-Raf in 91.0; 67.4; 46.0% and 69.0%<br />
in cancer tissues, respectively, compared with unaltered ones. The m-TOR, its<br />
phosphorylated form and phospho-4E-BP1 in kidney cancers were increased 76.1%;<br />
67.2% and 78.7%, respectively, in comparison to normal tissues. We found the reduced<br />
level <strong>of</strong> phospho-PTEN in 1.7 fold after treatment. It was also noted that the decrease<br />
in the amount <strong>of</strong> phosphorylated AKT (T308) was 1.5-fold compared with that before<br />
the treatment. The phospho-p70 S6 (S371) kinase expression was increased 1.9-fold in<br />
patients receiving TKI-targeted therapies.<br />
Conclusions: TKI-targeted therapy was associated with the reduction <strong>of</strong> AKT signaling<br />
pathway activation. The fall <strong>of</strong> PTEN and gain <strong>of</strong> p70 S6 kinase levels during treatment<br />
were observed Acknowledgments.<br />
Legal entity responsible for the study: Tomsk Cancer Research Institute<br />
Funding: President Grant №MD-3637.2015<br />
Disclosure: All authors have declared no conflicts <strong>of</strong> interest.<br />
1605P<br />
abstracts<br />
Preclinical animal data <strong>of</strong> the SM88 tyrosine isomer<br />
G.H. Sokol 1 , R. Dickey, IV 2 , G. Del Priore 2 , D. Garzon 3 , S. H<strong>of</strong>fman 2<br />
1 Uniformed Services University <strong>of</strong> the Health Sciences, Bethesda, MD, USA,<br />
2 Research, Tyme Inc, New York, NY, USA, 3 Research, ITR labs, Montreal, Canada<br />
Background: SM88, a combination therapy including tyrosine isomers, has<br />
demonstrated anti-cancer activity with low toxicity when administered together [J Clin<br />
Oncol 31, 2013 (suppl; abstr e22095)]. We now report preclinical toxicology data.<br />
Methods: 7 day escalating dose, 28 day repeat dose in rats/dogs using the tyrosine<br />
agent <strong>of</strong> SM88. Test and control/vehicle items were administered qd or 3x/wk over 4<br />
wks at dose levels <strong>of</strong> 25, 75 and 150mg/kg. Study parameters compared pretreatment as<br />
well as day 29 (main and recovery animals) and day 55 (recovery animals). Blood was<br />
collected days 1 and 27 at 8 time points for toxicokinetics.<br />
Results: All animals demonstrated consistent organ and cell volume decrease and<br />
reduced concentration <strong>of</strong> zymogenous vacuoles in the pancreas. Changes were<br />
reversible upon discontinuation <strong>of</strong> the SM88 agent. There were no changes: in other<br />
organ weights, body weight, food consumption, ECGs, ocular findings, hematology,<br />
coagulation, clinical chemistry/urinalysis, and no macroscopic or microscopic findings<br />
that could be attributed to the tyrosine at up to 150 mg/kg. Consequently the No<br />
Observed Effect Level (NOEL) was determined to be 150 mg/kg. Day 27 plasma Cmax<br />
values at 150 mg/kg were 41.7 ug/ml and 41.36 ug/ml for males and females<br />
respectively. AUC 0-Tlast values were 717.7 (males) and 724.8 (females) hr*ug/ml. The<br />
difference in combined tyrosine isomer concentrations in plasma between Day 1 and<br />
27, show that the systemic exposures to tyrosine generally increased dose-dependently,<br />
and in a slightly less than dose-proportional manner. The maximum concentration<br />
levels (C max ) were reached at 2-6.7 hours post-dosing. After T max , the plasma<br />
concentrations declined gradually at a mean estimated T 1/2 value <strong>of</strong> 7.9-9.3 hrs on Day<br />
1 and from 8.4 -9.6 hrs on Day 27. There were no sex-related differences with sex ratios<br />
between 0.3 and 1.8 for all measured parameters. Over the 4-week treatment period,<br />
AUC 0-Tlast and AUC INF (C max ) accumulation ratios (Day 27/Day 1) ranged from<br />
0.6-1.8 (0.8 to 1.6) with 25, 75 and 150 mg/kg, suggesting no accumulation when<br />
administered three (3) times per week over a 27 day period.<br />
Conclusions: Pancreas changes suggest possible mechanisms and therapeutic insights<br />
to explain SM88’s clinical activity, supporting clincal trials.<br />
Legal entity responsible for the study: Steve H<strong>of</strong>fman, CEO, Tyme Inc<br />
Funding: Tyme Inc<br />
Disclosure: G.H. Sokol: Board position at Tyme Inc. R. Dickey IV, G. Del Priore,<br />
D. Garzon, S. H<strong>of</strong>fman: Stock ownership, membership on an advisory board or board<br />
<strong>of</strong> directors, corporate-sponsored research, or other substantive relationships.<br />
L.V. Spirina 1 , E. Usynin 2 , I. Kondakova 1 , Z. Yurmazov 2 , E. Slonimskaya 3 ,<br />
E. Kolegova 1<br />
1 Laboratory <strong>of</strong> Tumor Biochemistry, Tomsk Cancer Research Institute RAMS,<br />
Tomsk, Russian Federation, 2 <strong>Oncology</strong>, Tomsk Cancer Research Institute, Tomsk,<br />
Russian Federation, 3 Department <strong>of</strong> General <strong>Oncology</strong>, Tomsk Cancer Research<br />
Institute RAMS, Tomsk, Russian Federation<br />
Background: Modifications <strong>of</strong> molecular features by the action <strong>of</strong> tyrosine kinase<br />
inhibitors (TKIs) in tumors are the basis <strong>of</strong> anticancer treatment efficacy. The aim <strong>of</strong><br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw393 | vi551
drug index<br />
<strong>Annals</strong> Of <strong>Oncology</strong> 27 (Supplement 6): vi552–vi555, 2016<br />
doi:10.1093/annonc/mdw398<br />
drug index<br />
7A7 (EGFR monoclonal antibody): 11P<br />
AAV (adeno-associated virus vector): 11P<br />
AAV-7A7 (gene therapy targeting EGFR): 11P<br />
ABBV-399: 371P<br />
Abemaciclib: LBA12, LBA13, LBA18, 314TiP,<br />
1297TiP<br />
Abiraterone acetate: LBA29, LBA33_PR, 59P,<br />
718O, 727PD, 728PD, 730PD, 731PD, 736P,<br />
737P, 738P, 740P, 741P, 743P, 744P, 745P, 746P,<br />
747P, 748P, 752P, 758P, 761P, 764TiP, 766TiP<br />
ABTL0812 (novel regulator <strong>of</strong> Akt/mTOR axis):<br />
378P<br />
ABT-414: 326PD<br />
AC0010 (EGFR inhibitor): 359O<br />
ACT (Adoptive cell therapy): 1065P, 1080P,<br />
1088P, 1094P, 1095P<br />
Ad-RTS-hIL-12 (veledimex; gene therapy<br />
candidate): 280P<br />
Adv-FZ33 (adenovirus vector): 1567P<br />
Afatinib: LBA43, 8P, 10P, 12P, 13P, 26P, 110P,<br />
122P, 229PD, 351P, 408TiP, 1189P, 1230P,<br />
1236P, 1238P, 1241P, 1244P, 1254P, 1259P,<br />
1276P, 1273P, 1284P, 1286TiP, 1511P<br />
Aflibercept: 498P, 551P, 552P, 554P, 604TiP,<br />
1275P<br />
Aldoxorubicin: 1407P<br />
Alectinib: 1209PD, 1263P, 1290TiP<br />
Alisertib (MLN8237; aurora A kinase inhibitor):<br />
LBA29, 1423O, 1424O<br />
ALK inhibitor: 410TiP, 1060P, 1207PD, 1208O,<br />
1263P, 1289P<br />
ALM201 (23-amino acid peptide derived from<br />
FKPB-L): 143TiP<br />
Akt inhibitor: 33P, 375P, 718O<br />
Alpelisib (BYL719): 311TiP, 375P<br />
ALW-II-41-27: 1O<br />
AM0010 (PEGylated human IL-10): 364PD<br />
Amrubicin: 448P<br />
Anamorelin (ONO-7643): 1434O, 1446P<br />
Androgen deprivation therapy (ADT): 720PD,<br />
723PD, 740P, 735P, 742P, 746P, 747P, 749P,<br />
760P, 761P, 762P, 764TiP, 767TiP, 769TiP,<br />
770TiP, 771TiP<br />
ANG1005 (taxane derivative): 324O<br />
Anastrozole: LBA13, LBA14_PR, LBA18, 250P,<br />
263P<br />
Anthracycline: LBA6_PR, 153PD, 194P, 208P,<br />
220TiP, 221TiP, 246P, 279P, 290P, 299P, 315TiP,<br />
709TiP, 942TiP, 1073P, 1073P, 1410P, 1413P,<br />
1457P, 1492P, 1496P, 1501P, 1506TiP<br />
Anti-androgen: 747P<br />
Anti-angiogenic: 628P, 829P, 920P, 1073P, 1275P<br />
Anti-CD20 monoclonal antibody therapy:<br />
945TiP<br />
Anti-coagulants: 1479P<br />
Anti-CTLA4: LBA36, 846TiP, 1120P, 1130P<br />
Anti-EGFR: LBA20_PR, 1O, 9P, 15P, 18P, 56PD,<br />
62P, 63P, 89P, 94P, 99P, 166P, 455O,<br />
457O,461O, 464PD, 465PD, 472P, 478P, 480P,<br />
498P, 499P, 522P, 526P, 528P, 529P, 533P, 535P,<br />
540P, 541P, 569P, 571P, 598TiP, 605TiP, 606TiP,<br />
696P, 959P, 993P, 995P, 1002P, 1093P, 1175P,<br />
1189P, 1256P, 1260P, 1527P, 1555P<br />
Anti-emetics: 1029P, 1440P, 1441P, 1442P, 1443P,<br />
1453P<br />
Anti-estrogen: 1285TiP<br />
Anti-infectives: 1220P<br />
Anti-metabolites: 1073P<br />
Anti-microtubule agents: 1073P<br />
Anti-neoplastic agents: 865P, 868P, 932P, 1208O<br />
Anti-PD-1/PD-L1 antibodies: LBA38, LBA41_PR,<br />
17P, 82P, 92P, 221TiP, 389P, 479P, 613O, 719O,<br />
775PD, 777PD, 786P, 818P, 842TiP, 844 TiP,<br />
847TiP, 949O, 955PD, 956PD, 957PD, 978P,<br />
1027P, 1050PD, 1055O, 1057P, 1062P, 1063P,<br />
1066P, 1067P, 1068P, 1072P, 1073P, 1074P,<br />
1084P, 1086P, 1092P, 1102TiP, 1104TiP,<br />
1105TiP, 1111O, 1113PD, 1114PD, 1116PD,<br />
1119P, 1120P, 1123P, 1124P, 1126P, 1130P,<br />
1133P, 1150P, 1212PD, 1216PD, 1221P, 1237P,<br />
1260P, 1296TiP, 1400PD, 1430TiP, 1431P,<br />
1437PD<br />
Anti-VEGF therapy: LBA20_PR, 498P, 533P,<br />
552P, 636P, 824P, 844TiP, 859P, 1550P<br />
Apalutamide (ARN-509): 769TiP, 771TiP<br />
Apatinib: 373P<br />
APG101 (CD95-IgG fusion protein): 133P<br />
APO010 (hexameric FAS-ligand): 134P<br />
APR-246: 386P<br />
Aromatase Inhibitors: 862P, 884P, 888P<br />
ASG-15ME (antibody-monomethyl auristatin E<br />
conjugate): 780PD<br />
ASG-22CE (ASG-22ME; enfortumab vedotin):<br />
788P<br />
Aspirin: 1342P<br />
Atezolizumab: 77P, 82P, 229PD, 358O, 389P,<br />
470P, 782PD, 783P, 871P, 1068P, 1089P,<br />
1105TiP, 1109PD, 1171P, 1181P, 1222P, 1223P,<br />
1271P, 1294TiP, 1425PD, 1431TiP<br />
Atorivastatin: 354P<br />
Atrasentan: 754P<br />
Avelumab (MSB0010718C; anti-PD-L1): 775PD,<br />
775PD, 777PD, 818P, 842TiP, 844TiP, 1271P<br />
Axitinib: 476P, 773PD, 775PD, 804P, 808P, 813P,<br />
818P, 820P, 825P, 827P, 828P, 844TiP, 851TiP,<br />
961P, 1035P<br />
AZD0530 (SFK inhibitor): 1188P<br />
AZD1775, (WEE1 kinase inhibitor): 1146P<br />
AZD2014 (mTORC1/mTORC2 inhibitor): 29P,<br />
362PD<br />
AZD4547 (FGFR inhibitor): 28P<br />
AZD5069: 1049PD<br />
AZD6244: 632P<br />
AZD8931: 509P<br />
AZD9150: 1049PD<br />
AZD9291: 1189P<br />
Bacillus Calmette-Guerin (BCG): 1036P<br />
Bavituximab: LBA45<br />
BAX69 (Imalumab): 365PD<br />
BAY 1163877: 360O_PR<br />
Bendamustine: 239P<br />
BEP regimen: 882P<br />
Bevacizumab: LBA21, LBA22, 53PD, 56PD, 101P,<br />
118P, 124P, 135P, 206P, 235P, 237P, 241P,<br />
328PD, 391P, 393P, 442P, 457O, 462PD, 463PD,<br />
466PD, 476P, 487P, 489P, 490P, 493P, 494P,<br />
498P, 501P, 503P, 517P, 534P, 539P, 546P, 551P,<br />
557P, 804P, 822P, 824P, 851TiP, 857PD, 859PD,<br />
860PD, 863P, 867P, 868P, 877P, 895P, 904TiP,<br />
1196P, 1197P, 1273P, 1197P, 1275P, 1277P,<br />
1286TiP, 1294TiP, 1303P, 1304P, 1364O_PR,<br />
1368P, 1393P, 1516P, 1542P, 1550P, 1552P<br />
BGJ398: 1562P<br />
BI 836845: 374P<br />
Bicalutamide: 733P, 759P<br />
Biosimilar bevacizumab: 1196P<br />
Biosimilar filgrastim: (myl-1401H): 14476P,<br />
1433O, 1450P<br />
Biosimilar peg-filgrastim: 1433O, 1451P<br />
Biosimilar rituximab (PF-05280586): 946TiP<br />
Biosimilar trastuzumab: (BCD-022): 224PD<br />
Bisphosphonate(s): 750P, 829P, 1463P<br />
BKM120: 959P<br />
Bleomycin: 276P, 837P, 838P, 932P<br />
BMS-986012 (antibody with enhanced ADCC<br />
that binds Fuc-GM1): 1427PD<br />
Bortezomib: 906O, 941TIP, 1499P<br />
BRAF inhibitor: 1149P, 1150P, 1156TiP, 1174P,<br />
1268P<br />
Brentuximab vedotin: 947TiP<br />
Brigatinib (BRG): 1207PD, 1289TiP<br />
Bulparlisib (BKM120): 335P, 959P<br />
Cabazitaxel: LBA9_PR, 721PD, 722PD, 743P,<br />
744P, 745P, 746P, 753P, 755P, 766TiP, 820P<br />
Cabozantinib: LBA30_PR, 229PD, 774PD, 787P,<br />
814P, 815P, 816P, 818P, 820P, 1275P, 1421TiP<br />
Calcium gluconate: 504P<br />
Camptothecin: 389P, 864P<br />
Capecitabine: LBA21, LBA26, 53PD, 86P, 101P,<br />
135P, 204P, 205P, 239P, 240P, 243P, 273P, 278P,<br />
312TiP, 392P, 446P, 447P, 467PD, 469PD, 478P,<br />
489P, 490P, 493P, 496P, 504P, 544P, 551P, 582P,<br />
594P, 599TiP, 600TiP, 602TiP, 614O, 645P, 649P,<br />
680P, 681P, 690P, 974P, 1393P, 1498P, 1499P<br />
CapeOX: 504P<br />
CAR-T: 943TiP, 945TiP, 1048O, 1064P, 1083P<br />
CAR-NK: 1083P<br />
Carboplatin: LBA8, 113P, 118P, 153PD, 187PD,<br />
188P, 190P, 208P, 241P, 294P, 372P, 379P, 386P,<br />
387P, 414TiP, 505P, 798P, 801P, 834P, 835P,<br />
842TiP, 857PD, 859PD, 860PD, 861P, 863P,<br />
867P, 877P, 896P, 967P, 1016TiP, 1033P, 1178O,<br />
1193P, 1199P, 1256P, 1269P, 1278P, 1279P,<br />
1280P, 1281P, 1294TiP, 1298TiP, 1299TiP,<br />
1351P, 1426PD, 1428P, 1430TiP, 1431TiP,<br />
1435O, 1440P, 1453P, 1470P, 1511P, 1516P,<br />
1565P<br />
Carfilzomib: 929P, 941TIP<br />
L-carnosine: 1467P<br />
Catumaxomab: 1303P<br />
CVA21 (CAVATAK TM , immunotherapeutic<br />
strain <strong>of</strong> Coxsackievirus A21): 1051PD,<br />
1054PD, 1104TiP, 1157TiP<br />
CD3ζ: 943TiP, 945TiP, 1048O<br />
CEA-IL2v (RG7813; cergutuzumab<br />
amunaleukin): 358O<br />
Cediranib: 328PD, 1408P<br />
Ceritinib: LBA42_PR, 410TiP, 1205PD, 1208O,<br />
1273P<br />
Cetuximab: LBA4, LBA36, LBA37, 1O, 2PD, 9P,<br />
10P, 13P, 15P, 95P, 139P, 457O, 461O, 462PD,<br />
468PD, 484P, 491P, 495P, 496P, 497P, 498P,<br />
508P, 510P, 521P, 525P, 527P, 533P, 540P, 541P,<br />
548P, 574P, 578P, 580P, 588P, 598P, 600TiP,<br />
606TiP, 957PD, 959P, 967P, 967P, 971P, 974P,<br />
975P, 977P, 991P, 993P, 994P, 995P, 1002P,<br />
1003P, 1007P, 1015P, 1016TiP, 1017TiP,<br />
1019TiP, 1205PD, 1555P<br />
Ch1N11 (PS-targeting antibody): 1074P<br />
Cilengitide: 328PD<br />
Cisplatin (CDDP): LBA8, LBA26, LBA32_PR,<br />
10P, 87P, 93P, 204P, 387P, 446P, 610O, 616P,<br />
630P, 633P, 640P, 645P, 664P, 667P, 676P, 681P,<br />
698P, 702P, 711TiP, 712TiP, 756P, 782PD, 792P,<br />
795P, 796P, 797P, 798P, 799P, 801P, 837P, 838P,<br />
839P, 842TiP, 845TiP, 850TiP, 893P, 964P, 967P,<br />
970P, 973P, 974P, 980P, 981P, 989P, 990P, 994P,<br />
995P, 996P, 998P, 1000P, 1003P, 1007P, 1010P,<br />
1012P, 1015P, 1016TiP, 1018TiP, 1019TiP,<br />
1033P 1183P, 1187PD, 1190P, 1192P, 1193P,<br />
1195P, 1197P, 1199P, 1200P, 1201O, 1229P,<br />
1256P, 1259P, 1269P, 1282P, 1287TiP,<br />
1294P,1298TiP, 1303P, 1426PD, 1430TiP, 1440P,<br />
1445P, 1471P, 1473, 1499P, 1499P, 1506TiP,<br />
1511P, 1516P, 1517P, 1520O, 1521P, 1528P,<br />
1548P, 1557P,1558P, 1595P<br />
Clarithromycin: 907O<br />
Cl<strong>of</strong>azimine: 1543P<br />
Clonidine: 1464P<br />
© European Society for Medical <strong>Oncology</strong> 2016. Published by Oxford University Press on behalf <strong>of</strong> the European Society for Medical <strong>Oncology</strong>.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com.
<strong>Annals</strong> Of <strong>Oncology</strong><br />
drug index<br />
Clopidogrel: LBA50<br />
Cobimetinib: 286P, 470P, 1109PD, 1111O, 1138P,<br />
1142P, 1156TiP<br />
Corticosteroids: 1118P, 1220P<br />
CPI-444 (small molecule inhibitor <strong>of</strong> adenosine<br />
A2A receptor): 389P, 1068P, 1105TiP<br />
CPI-613 (mitochondrial metabolism inhibitor):<br />
675P<br />
Crizotinib: LBA42_PR, 229P, 480P, 613O,<br />
1206PD, 1207PD, 1209PD, 1210PD, 1263P,<br />
1264P, 1265P, 1266P, 1273P, 1289TiP, 1290TiP,<br />
1291TiP<br />
CRLX101 (investigational nanoparticle-drug<br />
conjugate containing camptothecin): 393P,<br />
394P, 413TiP<br />
CRLX101 (NDC): 864P<br />
Custirsen: LBA9_PR<br />
Cyclophosphamide (cyclophosphan): LBA21,<br />
205P, 206P, 208P, 221TiP, 245P, 315TiP, 415TiP,<br />
902TiP, 904TiP, 943TiP, 945TiP, 982P, 1048O,<br />
1075P, 1435O, 1460P, 1499P, 1506TiP<br />
CXD101: 1578P<br />
Cytarabine: 948TiP<br />
Cytokeratin (CK): 1169P<br />
Dabrafenib: LBA19_PR, 229P, 455O, 1134P,<br />
1137P, 1135P, 1140P, 1141P<br />
Dacarbazine: LBA6_PR, 932P, 1119P, 1136P,<br />
1142P, 1401PD, 1499P<br />
Dacomitinib: 840P<br />
Dalteparin: 1040P<br />
Daratumumab: 906O<br />
Dasatinib: 328PD, 727PD<br />
Degarelix: 734P, 735P<br />
Dendritic cell vaccination: 1085P<br />
Denosumab: 750P, 829P, 1463P, 1465P<br />
Dexamethasone: 547P, 715TiP, 748P, 906O,<br />
940TiP, 941TiP, 1443P, 1449P, 1461P, 1506TiP,<br />
1534P, 1566P<br />
Digoxin: 474P<br />
DKN-01: 698P<br />
DLYE5953A (anti-Ly6E): 357O<br />
Docetaxel: LBA4, LBA6_PR, LBA9_PR, LBA16,<br />
LBA29, LBA42_PR, LBA45, LBA47_PR, LBA48,<br />
41P, 77P, 188P, 204P, 206P, 212P, 281P, 288P,<br />
293P, 399P, 413TiP, 426PD, 610O, 633P, 640P,<br />
641P, 642P, 636P, 637P, 651P, 664P, 718O,<br />
720PD, 721PD, 722PD, 723PD, 729PD, 732P,<br />
736P, 737P, 741P, 743P, 744P, 745P, 746P, 753P,<br />
754P, 755P, 756P, 761P, 766TiP, 767TiP, 771TiP,<br />
974P, 989P, 990P, 1000P, 1010P, 1011P, 1085P,<br />
1089P, 1093P, 1178O, 1190P, 1191P, 1195P,<br />
1215PD, 1217PD, 1218PD, 1219PD, 1220P,<br />
1275P, 1276P, 1290TiP, 1296TiP, 1299TiP,<br />
1368P, 1409P, 1420TiP, 1433O, 1442P, 1460P,<br />
1511P, 1565P<br />
Dovitinib: 972P<br />
Doxorubicin (Adriamycin): 53PD, 101P, 135P,<br />
205P, 217P, 243P, 382P, 792P, 932P, 1075P,<br />
1395O, 1407P, 1420TiP, 1421TiP, 1440P, 1442P,<br />
1460P, 1499P, 1508PD, 1573P, 1576P<br />
DS-8201A: LBA17<br />
Durvalumab (MED14673; ant-PD-L1<br />
antibody): 82P, 221TiP, 846TiP, 949O,<br />
955PD, 1049PD, 1050PD, 1100TiP, 1103TiP,<br />
1216PD<br />
EC1169 (PSMA-targeted tubulysin smallmolecule<br />
drug conjugate): 731P<br />
EC1456 (folic acid-tubulysin small-molecule<br />
drug conjugate): 395P<br />
EDV (EGFR-targeteding nanocells including<br />
clinician’s choice <strong>of</strong> cytotoxic drugs, siRNA or<br />
miRNA): 412TiP, 959P<br />
EGFR/ERBB inhibitors: LBA43, 27P, 62P, 119P,<br />
528P, 1060P, 1174P, 1188P, 1189P, 1257P,<br />
1274P<br />
EGFR-TKI therapy: LBA43, 1582P<br />
Enadenotucirev: 1087P<br />
Endocrine therapy: LBA1_PR, LBA12, LBA18,<br />
135P, 862P<br />
Enzalutamide: LBA29, 59P, 719O, 726PD, 728PD,<br />
731P, 737P, 738P, 739P, 743P, 744P, 745P, 746P,<br />
747P, 749P, 752P, 759P, 760P, 761P, 764TiP,<br />
766TiP, 767TiP, 770TiP, 1535P<br />
Enzastaurin: 328PD<br />
Entrectnib: 138P<br />
Epacadostat: 1110PD<br />
Epirubicin: LBA6_PR, LBA26, 206P, 221TiP,<br />
649P, 973P, 990P, 1440P, 1499P, 1573P<br />
Epoetin beta: 1477P<br />
Erdafitinib (JNJ-42756493): 781PD, 789P, 845TiP<br />
Eribulin mesylate: 31P, 33P, 235P, 238P, 244P,<br />
246P, 247P, 273P, 397P, 1030P, 1401PD<br />
Erlotinib: 351P, 363PD, 369P, 1167P, 1189P,<br />
1236P, 1238P, 1241P, 1251P, 1254P, 1258P,<br />
1262P, 1275P, 1284P, 1286TiP, 1511P, 1550P<br />
Estramustine: 723PD<br />
Estro-progestins: 862P<br />
24-ethyl-cholestane-3β,5α,6α-triol: 282P<br />
Etoposide: LBA6_PR, 382P, 837P, 838P, 948TiP,<br />
1193P, 1194P, 1200P, 1351P, 1424O, 1426PD,<br />
1430TiP, 1431TiP, 1499P<br />
Everolimus: LBA18, 6P, 29P, 222O, 227PD,<br />
229PD, 262P, 310TiP, 416O, 417O, 421PD,<br />
423PD, 436P, 437P, 443P, 444P, 445P, 471P,<br />
785P, 814P, 815P, 816P, 818P, 820P, 827P, 830P,<br />
852TiP, 1032P, 1035P, 1062P, 1081P, 1498P,<br />
1552P<br />
Evodiamine: 1527P<br />
Ev<strong>of</strong>osfamide: 1395O<br />
Exemestane: LBA18, 222O, 227PD, 263P, 277P,<br />
310TiP<br />
EZH2 inhibitor (GSK343): 1398PD<br />
F2-27 (HSV-TK): 1579P<br />
FEC-D (5-fluorouracil-epirubicincyclophosphamide<br />
followed by docetaxel):<br />
1460P<br />
Fentanyl (Transdermal; TF): 1320P<br />
FluVax: 1486P<br />
FOLFIRI: LBA22, 124P, 457O, 462P, 464PD,<br />
468PD, 539P, 540P, 548P, 551P, 552P, 554P,<br />
1552P<br />
FOLFIRINOX: 675P, 676P, 678P, 679P, 680P,<br />
682P, 683P, 690P<br />
FOLFOX: LBA22, 461O, 499P, 503P, 540P, 551P,<br />
553P, 643P, 1071P<br />
FOLFOX4: 482P, 485P, 527P, 700P<br />
FOLFOX6: 484P, 501P, 508P, 1467P<br />
mFOLFOX6: 1071P<br />
FOLFOXIRI: LBA21, LBA22, 489P, 517P<br />
Folinic acid: 633P, 664P<br />
Fludarabine: 415TiP, 943TiP, 945TiP, 948TiP,<br />
1075P, 1499P<br />
5-Fluorouracil (5FU, 5-FU, Fluorouracil): LBA37,<br />
95P, 100P, 125P, 243P, 446P, 473P, 496P, 519P,<br />
542P, 549P, 627P, 641P, 643P, 645P, 664P, 967P,<br />
680P, 700P, 839P, 973P, 989P, 990P, 993P,<br />
1000P, 1003P, 1010P, 1015P, 1016TiP, 1218PiD,<br />
1442P, 1460P, 1557P, 1575P<br />
Fluoropyrimidine: LBA20_PR, LBA21, 93P,<br />
463PD, 466PD, 472P, 505P, 551P, 557P, 575P,<br />
639P, 660P, 709TiP<br />
Flutamide: 862P<br />
Foretinib: 32P<br />
Fosaprepitant (anti-emetic): 1435O<br />
FUFIRI: 473P<br />
FU-LV (5 FU-LV): 551P, 622PD<br />
Fulvestrant: LBA14_PR, LBA18, 229PD, 250P,<br />
260P, 264P, 265P, 277P, 311TiP, 313TiP, 862P,<br />
1285TiP<br />
Gallium DOTA-PET (GaPET); used in<br />
scintigraphy and being evaluated in breast<br />
cancer management): 425PD,<br />
Galunisertib: 1102TiP<br />
Ganciclovir: 1567P<br />
Gefitinib: LBA43, 351P, 1167P, 1188P, 1189P,<br />
1201O, 1218PD, 1230P, 1231P, 1236P, 1240P,<br />
1242P, 1244P, 1245P, 1247P, 1251P, 1254P,<br />
1257P, 1258P, 1284P, 1285TiP, 1286TiP,<br />
1287TiP, 1288TiP, 1511P<br />
Gemcitabine: LBA6_PR, LBA8, 118P, 127P, 270P,<br />
367PD, 387P, 414TiP, 426PD, 621PD, 666P,<br />
676P, 678P, 681P, 683P, 684P, 690P, 691P,<br />
698P, 700P, 702P, 712TiP, 714TiP, 715TiP,<br />
842TiP, 857PD, 877P, 942TiP, 1033P, 1045P,<br />
1199P, 1256P, 1269P, 1282P, 1298TiP,<br />
1299TiP, 1409P, 1420TiP, 1508PD, 1511P,<br />
1516P, 1523P<br />
Glembatumumab vedotin (GV, CDX-011:<br />
antibody drug conjugate (ADC): 309TiP, 1147P<br />
Glucocorticoid: 550P, 928P<br />
Glutamine: 512P<br />
GnRH agonist (gonadotropin-releasing hormone<br />
agonist): 747P, 769TiP, 884P<br />
Goserelin: 735P, 723PD, 735P, 862P<br />
Granisetron: 1450P<br />
Granulocyte colony stimulating factor (G-CSF):<br />
948TiP, 1474P<br />
GSK2879552: 381P<br />
GSK 458 (dual PI3K-MAPK inhibitor): 14P<br />
hCGβ-Arg9 gene modified tumour vaccine: 38P<br />
HDACi: 1578P<br />
Hedgehog pathway inhibitor: 1153P<br />
Heparin: 695P<br />
HER2 inhibitors (HER2 targeted therapies,<br />
HER2 targeting antibody-drug conjugate,<br />
anti-HER2 therpies): LBA17, LBA18, LBA26,<br />
1595P<br />
HF10 (a replication-competent HSV-1 oncolytic<br />
virus): 1146P<br />
5-HIAA: 1505TiP<br />
Hormone (therapy): LBA33_PR, 1073P, 1482P,<br />
1489P<br />
5-HT3 antagonist: (5-HT3 RA): 1440P, 1445P,<br />
1505TiP, 1506TiP, 1443P, 1445P, 1473P,<br />
1505TiP, 1506TiP<br />
Hydroactive colloid gel: 1474P<br />
Hydroxycarbamide: 1499P<br />
Ibrutinib: 331PD, 919P, 945TiP<br />
Icotinib: 1229P<br />
Idarubicin: 948TiP<br />
Idelasib: 919P<br />
Ifosfamide: LBA6_PR, 896P, 1075P, 1407P,<br />
1421TiP, 1499P<br />
Imatinib: 936P, 937P, 1368P, 1403PD, 1416P,<br />
1418P, 1419P<br />
Immune cell therapy: 1302P<br />
Immune checkpoint therapy: 1059P, 1073P,<br />
1076P, 1077P, 1078P, 1081P, 1083P, 1097P,<br />
1084P, 1096P, 1097P, 1104TiP, 1106O, 1121P,<br />
1132P, 1144P, 1149P, 1157TiP, 1158P, 1180P,<br />
1220P, 1222P, 1223P, 1224P, 1271P, 1275P,<br />
1291TiP, 1399PD, 1400PD, 1430TiP<br />
ImmuniCell® (γδ T cells expressing chimeric<br />
antigen receptors; CARs targeting CD19):<br />
1064P<br />
Immunostimulants: 1220P<br />
drug index<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw398 | vi553
drug index<br />
<strong>Annals</strong> Of <strong>Oncology</strong><br />
drug index<br />
Immunotherapy: 16P, 17P, 52O, 57PD, 74P, 79P,<br />
82P, 111P, 221TiP, 229PD, 280P, 320P, 327PD,<br />
356TiP, 389P, 390P, 406P, 470P, 1070P, 1095P,<br />
1073P, 1132P, 1133P, 1294TiP, 1372P, 1394P<br />
Imprime PGG (I): 139P<br />
Interferon alpha: 1550P<br />
Intratumoral SD 101: 1067P<br />
Ipafricept (WNT inhibitor): 367PD<br />
Ipatasertib (GDC-0068): 718O<br />
Ipilimumab: LBA2_PR, LBA36, LBA39, 58PD,<br />
101TiP, 229PD, 478P, 479P, 756P, 774P, 784PD,<br />
846TiP, 847TiP, 897P, 921P, 922P, 954O,<br />
950PD, 964P, 1016TiP, 1017TiP, 1047O,<br />
1051PD, 1051PD, 1054PD, 1059P, 1062P,<br />
1063P, 1068P, 1071P, 1074P, 1084P, 1086P,<br />
1090P, 1091P, 1092P, 1101TiP, 1106O, 1107O,<br />
1108PD, 1112PD, 1113PD, 1115P, 11171P,<br />
1118P, 1120P, 1121P, 1122P, 1123P, 1125P,<br />
1128P, 1130P, 1131P, 1132P, 1134P, 1142P,<br />
1146P, 1150P, 1428P, 1430TiP, 1440P, 1442P,<br />
1499P<br />
Irinotecan: LBA20_PR, LBA22, LBA27, 95P, 279P,<br />
466PD, 471P, 472P, 477P, 493P, 494P, 495P,<br />
548P, 572P, 639P, 642P, 661P, 680P, 682P, 964P<br />
Ivermectin: 1527P<br />
Ixazomib: 941TiP<br />
J591: 772TiP<br />
KAN 0439834: 1533P<br />
Kisspeptin: 1532P<br />
KM-CART (concentrated ascites reinfusion<br />
therapy): 1302P<br />
Kp-10: 1532P<br />
KTE C19 CAR T- cells (anti-CD19 CAR cells):<br />
415TiP, 943TiP, 945TiP, 1048O, 1083P<br />
Lanreotide autogel/depot (LAN): 438P, 439P,<br />
440P, 449TiP, 451TiP<br />
Lanreotide LAR: 447P, 450TiP<br />
Lapatinib: LBA26, 14P, 122P, 191P, 229PD, 273P,<br />
312TiP, 1537P<br />
LDE225: 8P<br />
Lefitolimod (MGN1703; DNA-based TLR9<br />
agonist): 1432TiP<br />
Lenalidomide: 707P, 940TiP, 941TiP, 1368P<br />
Lenvatinib mesilate: 2PD, 6P, 776PD, 962P,<br />
1204PD<br />
Letrozole: LBA1_PR, LBA15, LBA18, 222O,<br />
225PD, 263P, 884P<br />
Leucovorin: 519P, 548P, 643P, 680P, 973P, 990P<br />
Leuprolide (leuprorelin; Eligard): 735P, 742P,<br />
770TiP<br />
Lipegfilgrastim ((Lonquex®); glyco-pegylated G-<br />
CSF): 1456P, 1457P, 1459P<br />
Liposomal anthracyclines: 865P<br />
Liposomal doxorubicin hydrochloride<br />
(MYOCET®): 293P, 1573P<br />
Lirilumab (NK) cell-targeted anti-KIR antibody):<br />
1086P<br />
Lomustine: 1499P<br />
LOXO-101: 407TiP, 409TiP<br />
Lumretuzumab: 369P, 372P<br />
Lurbinectedin (PM01183): 223O, 391P, 392P,<br />
901TiP, 1520O<br />
Lutathera (177Lu-dotatate.tyr-octreotate): 420PD<br />
LY3023414: 1274P<br />
Lynparza: 1103TiP<br />
Macrolides: 907O<br />
Magnesium sulphate: 504P<br />
Mannitol: 1471P<br />
Marine-derived bioactive compound (MB-E5):<br />
51P<br />
Mebendazole: 1527P<br />
MEDI0562: 1052PD<br />
MEDI0680: 1050PD, 1072P<br />
MEK inhibitor: LBA47_PR, 18P, 286P, 1149P,<br />
1150P<br />
Melphalan: 1499P<br />
Mercaptopurine: 1499P<br />
Merestinib: 712TiP<br />
Mesna: 1407P<br />
Metformin: 198P, 200P, 230PD, 302P, 303P, 353P,<br />
417O, 450TiP, 765TiP, 902TiP<br />
Methotrexate: LBA4, 245P, 331PD, 332P, 792P,<br />
908O, 990P, 1015P, 1499P<br />
Metoclopramide: 1450P<br />
mirOx: 473P<br />
Mitoxantrone: 745P, 948TiP<br />
MM-121 (Seribantumab): 1296TiP<br />
MM-2206: 733P<br />
MM-302 (HER2-antibody/liposomal/doxorubicin<br />
conjugate): 315TiP, 1560P<br />
ModraDoc006 (solid dispersion formula <strong>of</strong><br />
docetaxel): 399P<br />
Motolimod: LBA37<br />
MP0250 (multi-DARPin®): 361PD<br />
MRX34 (liposomal miR-34 mimic): 1534P,<br />
1566P,<br />
MTA (molecularly targeted agents): 1066P<br />
mTCF-dd: (taxotere cisplatin fluorouracil<br />
regimen): 633P<br />
mTOR inhibitor: 122P<br />
Multi-kinase inhibitor: 1556P<br />
mXELIRI (capecitabine/irinotecan): 493P<br />
Myl-1401O (trastuzumab biosimilar): LBA16<br />
Mytomycin C: 973P, 1054PD<br />
Nab-paclitaxel (Abraxane®): 86P, 221TiP, 236P,<br />
241P, 367PD, 414TiP, 651P, 666P, 667P, 676P,<br />
677P, 678P, 679P, 681P, 682P, 683P, 684P, 691P,<br />
700P, 714TiP, 715TiP, 1029P, 1030P, 1045P,<br />
1059P, 1278P, 1279P, 1280P, 1281P, 1294TiP,<br />
1298TiP, 1299TiP<br />
nal-IRI (MM-398; liposomal irinotecan, plus 5-<br />
FU/LV): 622PD, 693P<br />
Naldemedine: 1466P<br />
Naloxone: 1320P<br />
napabucasin (BBI608; NAPA): 454O<br />
NC-6004 (nanoparticle cisplatin): 398P<br />
Necitumumab: 1256P, 1260P, 1274P, 1297TiP,<br />
1298TiP, 1527P<br />
NEPA (NK 1 -RA netupitant plus 5-HT 3 -RA<br />
palonosetron): 1506TiP<br />
Neratinib: 229PD<br />
Neurokinin-1 receptor antagonists: 1443P<br />
NeuVax (a HER2-targeted peptide vaccine):<br />
1069P<br />
NGR-hTNF: 1508PD<br />
Nimotuzumab: 1093P<br />
Nintedanib: LBA20_PR, 472P, 859PD, 904TiP,<br />
1275P, 1276P<br />
Niraparib: LBA3_PR<br />
Nivolumab: LBA4, LBA31_PR, LBA39,<br />
LBA41_PR, 115O, 229PD, 356TiP, 479P, 774PD,<br />
784P, 852TiP, 955PD, 1016TiP, 1017TiP, 1028P,<br />
1032P, 1047O, 1059P, 1062P, 1070P, 1079P,<br />
1082P, 1084P, 1086P, 1089P, 1090P, 1091P,<br />
1098P, 1101TiP, 1102TiP, 1112PD, 1113PD,<br />
1114PD, 1116P, 1119P, 1120P, 1123P, 1124P,<br />
1125P, 1126P, 1129P, 1130P, 1215PD, 1217PD,<br />
1220P, 1222P, 1224P, 1225P, 1228P, 1229P,<br />
1271P, 1295TiP, 1400PD, 1430TiP, 1531P<br />
NK 1 -receptor-antagonists: 1506TiP<br />
NKTR-214: 1078P<br />
Non-pegylated liposomal doxorubicin (Npld,<br />
myocettm): 863P<br />
NOTCH inhibitor: 122P<br />
NOX-A12 (olaptesed pegol): 1083P<br />
NSAIDs: 531P, 1308P, 1342<br />
NVP-CGM097 (p53-HDM2 protein-protein<br />
interaction inhibitor): 380P<br />
NY-ESO-1 c259 SPEAR T-cells TM (genetically<br />
engineered NY-ESO-1 specific): 1075P<br />
Octreotide: 429P, 442P, 1303P<br />
Octreotide LAR: 438P, 446P<br />
ODM-203: 370P<br />
Okadaic acid: 1537P<br />
Olaparib (AZD2281, KU-0059436): LBA25,<br />
229PD, 720P, 901TiP, 902TiP, 903TiP, 1102TiP,<br />
1557P<br />
Olaratumab: 1402PD, 1420TiP<br />
Oncolytic adenovirus: 1080P, 1087P<br />
Ondansetron: 1449P<br />
ONT-380: 278P, 312TiP<br />
Opioids: 1308P, 1310P, 1320P, 1462P, 1466P<br />
Osimertinib (AZD9291): 8P, 12P, 13P, 1041P,<br />
1234P, 1246P<br />
OT-1 TCR transgenic T-cells: 1080P<br />
Oxaliplatin: LBA20_PR, LBA22, 95P, 124P,<br />
463PD, 464 PD, 467PD, 472P, 493P, 500P, 502P,<br />
504P, 514P, 553P, 558P, 575P, 643P, 649P, 661P,<br />
680P, 682P, 1368P, 1440P, 1461P, 1467P, 1573P<br />
Oxycodone: 1320P<br />
Paclitaxel: LBA8, LBA16, LBA25, LBA50, 31P,<br />
33P, 87P, 113P, 118P, 137P, 190P, 192P, 217P,<br />
237P, 242P, 243P, 285P, 286P, 294P, 362PD,<br />
372P, 375P, 387P, 391P, 426PD, 505P, 636P,<br />
663P, 795P, 857PD, 859PD, 860PD, 861P, 864P,<br />
867P, 877P, 896P, 991P, 993P, 1003P, 1015P,<br />
1029P, 1033P, 1193P, 1199P, 1256P, 1294TiP,<br />
1368P, 1423O, 1445P, 1460P, 1511P, 1516P<br />
Paclitaxel (nanoparticle albumin-bound<br />
paclitaxel): 663P<br />
Palbociclib: LBA15, 225PD, 229P, 260P, 261P<br />
Pancrelipase (extracted pancreatic enzyme;<br />
pancreatin): 654P<br />
Panitumumab: 9P, 471P, 455O, 471P, 482P, 485P,<br />
495P, 497P, 498P, 499P, 501P, 531P, 598TiP,<br />
600TiP, 605TiP, 606TiP, 649P<br />
Pantoprazole: 636P, 736P<br />
PARP inhibitors: LBA3_PR, LBA25, 115P, 404P,<br />
730PD, 865P, 874P, 878P<br />
Pasireotide LAR: 416O, 442P, 1148P<br />
Pazopanib: 229P, 785P, 811P, 817P, 818P, 819P,<br />
820P, 824P, 827P, 832P, 833P, 852TiP, 858PD,<br />
897P, 986P, 1034P, 1035P, 1400PD, 1403PD,<br />
1408P, 1410P, 1463PD, 1498P<br />
PD-1 inhibitor: 1090P<br />
PD1/PD-L1 inhibitor: 1181P, 1394P<br />
PD0325901 (MEK inhibitor): 480P<br />
PD173074 (FGFR inhibitor): 6P, 1562P<br />
Pegfiligrastim (EU Neulasta®; US Neulasta®):<br />
206P, 633P, 1433O, 1450P, 1459P, 1476P<br />
PEGPH20 (Pegylated recombinant human<br />
hyaluronidase): 715TiP<br />
Pegylated liposomal doxorubicin: 877P<br />
Pembrolizumab (anti-PD1): LBA8, LBA32_PR,<br />
LBA38, LBA48, 2PD, 78P, 82P, 229PD, 364PD,<br />
713TiP, 716TiP, 719O, 725PD, 773PD, 776PD,<br />
847TiP, 848TiP, 849TiP, 900TiP, 940TiP,<br />
941TiP, 944TiP, 947TiP, 955PD, 957PD, 1028P,<br />
1060P, 1067P, 1071P, 1082P, 1084P, 1089P,<br />
1090P, 1104TiP, 1107O, 1110PD, 1113PD,<br />
1114PD, 1115P, 1116P, 1120P, 1124P, 1126P,<br />
1127P, 1130P, 1157TiP, 1158TiP, 1219PD,<br />
1221P, 1222P, 1224P, 1260P, 1271P, 1291TiP<br />
Pemetrexed: LBA8, LBA42_PR, 10P, 118P, 379P,<br />
426PD, 1191P, 1197P, 1200P, 1201O, 1229P,<br />
1240P, 1259P, 1269P, 1282P, 1283P, 1286TiP,<br />
vi554 | drug index Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> Of <strong>Oncology</strong><br />
drug index<br />
1287TiP, 1290TiP, 1294TiP, 1296TiP, 1499P,<br />
1511P, 1517P<br />
Pertuzumab: 229PD, 270P, 312TiP, 315TiP<br />
PF-3758309 (PAK inhibitor): 1555P<br />
PF-04518600 (PF-8600; OX40 agonist): 1053PD<br />
PF-06647020: LBA35<br />
PI3K inhibitor: 122P<br />
Pimaserttib (MEK inhibitor): 14P, 1136P<br />
Pixantrone: 942TiP<br />
Platinum: LBA3_PR, LBA4, LBA8, LBA27,<br />
LBA29, LBA31_PR, LBA35, LBA37, LBA45,<br />
LBA48, 112P, 386P, 426PD, 448P, 505P, 624P,<br />
639P, 641P, 642P, 649P, 660P, 700P, 777PD,<br />
783P, 790P, 796P, 801P, 855O, 861P, 862P,<br />
863P, 865P, 868P, 877P, 878P, 879P, 957PD,<br />
959P, 961P, 967P, 985P, 991P, 993P, 994P,<br />
1016TiP, 1017TiP, 1043P, 1060P, 1103TiP,<br />
1200P, 1218PD, 1221P, 1259P, 1269P, 1274P,<br />
1277P, 1282P, 1286TiP, 1290TiP, 1293TiP,<br />
1423O, 1424O, 1427PD, 1431TiP, 1468P, 1473P,<br />
1565P, 1590P<br />
PLD (pegylated liposomal doxorubicin): 386P<br />
PNA (peptide nucleic acid oligonucleotide<br />
analogues; DNA binding): 368P<br />
Pomalidomide: 941TiP<br />
Ponatinb: 229P<br />
Prednisone: LBA9_PR, LBA33_PR, 718O, 738P,<br />
740P, 746P, 748P, 1303P<br />
Pregabalin (calcium channels binder): 1449P<br />
Prexasertib (CHK1/2 inhibitor; LY2606368):<br />
231PD, 855O, 1019TiP<br />
Procarbazine: 332P, 1499P<br />
Progesterone derivatives: 46P<br />
Progestins: 862P<br />
PTC596: 384P<br />
Quadramet® ( 153 Sm-EDTMP ethylene-diamintetramethylene-phosphonate):<br />
1306P<br />
Quisinostat (novel protein acetylator): 386P<br />
Quizartinib (AC220): 948TiP<br />
R-IDEA regimen: 931P<br />
R428 (AXL inhibitor): 32P<br />
Racotumomab: 1093P<br />
Radioactive iodine: 953PD; 958P, 962P<br />
Radium-223 chloride: 745P, 853TiP<br />
Radium-223 dichloride: 310TiP, 853TiP<br />
RAI-rDTC: 953PD<br />
Raloxifene: 1324PD<br />
Raltitrexed: 1517P<br />
Ramucirumab: LBA38, 592P, 617PD, 634P, 636P,<br />
663P, 710TiP, 712TiP, 1100TiP, 1275P<br />
Ranitidine: 1449P<br />
Ranolazine: 25P<br />
Refametinib ((BAY 86-9766): 15P, 32P<br />
Regorafenib: LBA20_PR, LBA28, 15P, 229P,<br />
464PD, 466PD, 472P, 474P, 478P, 505P, 506P,<br />
507P, 516P, 524, 547P, 598TiP, 603TiP, 692P,<br />
980P, 1404PD, 1409PD, 1415P, 1422TiP, 1498P,<br />
1556P, 1559P<br />
RGX: 734P<br />
Ribociclib: LBA1_PR, 1002P<br />
Rikkunshito (anti-emetic; Japanese herbal<br />
medicine): 1445P, 1473P<br />
Ritonavir: 399P<br />
Rituximab: 332P, 908O, 914P, 915P, 917P, 919P,<br />
924P, 935P, 942TiP, 946TiP, 1368P, 1455P<br />
Rivaroxaban: 695P<br />
Rociletinib: 1239P<br />
Rolapitant: 1440P, 1441P, 1442P, 1443P<br />
ROR1 TKI: 1533P<br />
Rose Bengal (PV-10): 1158TiP<br />
Rosuvastatin: 474P<br />
Rucaparib (PARP inhibitor): 219TiP, 649P, 856O<br />
RX-3117 (an oral antimetabolite): 396P<br />
RX-5902: 385P,<br />
S-1 (tegafur, gimeracil, and oteracil): LBA27,<br />
87P, 279P, 477P, 493P, 500P, 519P, 630P, 640P,<br />
661P, 667P, 702P, 709TiP, 711TiP, 1190P,<br />
1195P, 1218PD, 1516P<br />
S49076 (AXL inhibitor): 32P<br />
Savolitinib (AZD6094/HMPL-50): 1549P<br />
Selinexor: 383P, 854O<br />
Selumetinib: LBA47_PR, 13P, 376P, 1261P, 1269P,<br />
1526P<br />
Signal transduction inhibitor: 1073P<br />
SM88 tyrosine isomer- 1605P<br />
SNX-5422: 423PD<br />
Somatostatin analouges: 417O, 421PD, 422PD,<br />
425PD, 436P, 438P, 440P, 441P, 442P, 443P,<br />
443P, 446P<br />
Sonidegib: 281P<br />
Sorafenib: LBA28, 229P, 397P, 466PD, 615O,<br />
617PD, 704P, 705P, 707P, 708TiP, 710TiP,<br />
713TiP, 716TiP, 813P, 818P, 822P, 824P, 826P,<br />
827P, 833P, 953PD, 958P, 1275P, 1313P,<br />
1405PD, 1436PD<br />
Statin: 196P<br />
Steroids: 314TiP, 1030P, 1322P, 1473P<br />
Streptozocin: 446P<br />
Substance P: 1505TiP<br />
Sunitinib: LBA11_PR, LBA30_PR, 229P, 445P,<br />
727PD, 818P, 819P, 820P, 821P, 831P, 833P,<br />
843TiP, 1034P, 1035P, 1275P, 1313P, 1403PD,<br />
1416P, 1498P, 1550P<br />
Suramin: 1543P<br />
SYM004 (EGFR inhibitor): 9P<br />
TAK-228 (MLN0128): 277P, 377P<br />
Talimogene laherparepvec: 1108PD<br />
Talozoparib: 153PD<br />
Tamoxifen: LBA18, 46P, 165P, 229PD, 265P, 862P,<br />
888P, 1324PD, 1361P<br />
TAS-102 (trifluridine/tipiracil): 465P, 472P, 512P,<br />
513P, 515P, 555P, 564P, 639P<br />
Taselisib (GDC-0032; PI3-kinase (PI3K)<br />
inhibitor): 313TiP<br />
Taxane: LBA16, LBA27, 31P, 33P, 153PD, 208P,<br />
238P, 246P, 270P, 279P, 286P, 294P, 296P, 303P,<br />
312TiP, 314TiP, 324O, 627P, 639P, 709TiP,<br />
728PD, 731P, 753P, 766TiP, 795P, 801P, 839P,<br />
863P, 865P, 879P, 1029P, 1043P, 1059P,<br />
1103TiP, 1457P, 1460P, 1488P, 1492P, 1501P<br />
TDM1 (Ado/trastuzumab/emtansine antibody<br />
drug conjugate): LBA17, 24P, 25P, 269P, 275P,<br />
312TiP, 314TiP, 315TiP<br />
Tegafur-uracil: 519P<br />
Telotristat etiprate (an oral tryptophan<br />
hydroxylase inhibitor): 422PD<br />
Temozolomide: 51P, 326PD, 327PD, 333P, 337P,<br />
338P, 346P, 348P, 350P, 353P, 354P, 356TiP,<br />
446P, 451TiP, 478P, 1450P<br />
Temsirolimus: 229PD, 328PD, 824P, 833P, 930P,<br />
1035P<br />
Tepotinib: 1257P, 1287TiP, 1292TiP<br />
Thalidomide: 920P, 941TiP<br />
4’-thio-2’-deoxycytidine: 411TiP<br />
Tivantinib: 706P<br />
Tivozanib: 826P<br />
TKI (Tyrosine kinase inhibitor): 10P, 12P, 13P,<br />
26P, 60P, 61P, 62P, 118P, 359O, 373P, 720P,<br />
804P, 808P, 814P, 833P, 843TiP, 844TiP, 845TiP,<br />
851TiP, 859PD, 966P, 995P, 1096P, 1166P,<br />
1201O, 1202O, 1203PD, 1210PD, 1231P, 1233P,<br />
1234P, 1235P, 1242P, 1243P 1245P, 1246P,<br />
1247P, 1248P, 1249P, 1250P, 1251P, 1252P,<br />
1253P, 1254P, 1258P, 1266P, 1284P, 1285TiP,<br />
1286TiP, 1287TiP, 1289TiP, 1293TiP, 1295TiP,<br />
1364O_PR, 1372P, 1405PD, 1410P, 1511P,<br />
1521PD, 1533P<br />
TKI258: 732P,<br />
Tong-Luo-San (TLS, Japanese herb): 1313P<br />
Topoisomerase inhibitors: LBA17, 393P, 864P,<br />
1073P<br />
Topotecan: 857PD, 1424O<br />
TPCA-1 (STAT3 inhibitor): 1188P<br />
Trabectedin: LBA6_PR, 897P, 1396O, 1406P,<br />
1520O<br />
Trametinib: 455O, 1134P, 1135P, 1137P, 1140P,<br />
1141P, 1149P, 1167P, 1526P<br />
Trastuzumab: LBA16, LBA18, 14P, 24P, 25P, 93P,<br />
104P, 108P, 122P, 144O, 151PD, 166P, 169P,<br />
184P, 189P, 191P, 204P, 205P, 208P, 209P, 210P,<br />
211P, 212P, 224PD, 229PD, 233P, 245P, 247P,<br />
269P, 270P, 271P, 273P, 274P, 278P, 293P, 297P,<br />
304P, 312TiP, 314TiP, 315TiP, 324O, 459O,<br />
612O, 614O, 626P, 629P, 630P, 641P, 644P,<br />
672P, 674P, 1031P, 1069P, 1368P, 1384P, 1479P,<br />
1482P, 1496P, 1537P, 1560P, 1595P<br />
TRC105 (endoglin antibody): 804P, 851TiP<br />
Tremelimumab: 856TiP, 1245P<br />
Trimethoprim-sulfamethoxazole: 1455P<br />
Tumour necrosis factor-thymosin-α1: 308P<br />
UC-MSC (TRAIL-engineered umbilical cord<br />
mesenchymal stem cells): 1579P<br />
VIII (STAT Inhibitor): 39P<br />
VAL-201: 388P<br />
Vandetanib: 328PD, 1203PD, 1261P, 1275P<br />
Vantictumab (OMP-18R5): 367PD, 677P<br />
VEGF inhibitor (VEGF targeted therapy):<br />
LBA30_PR, 1196P, 1286TiP<br />
Vemurafenib: 55PD, 229P, 336P, 1109PD, 1111O,<br />
1138P, 1139P, 1141P, 1142P, 1143P, 1156TiP<br />
Vinblastine: 792P, 932P<br />
Vincristine: 332P, 964P, 1351P<br />
Vinflunine: 796P, 800P, 845TiP, 850TiP<br />
Vinorelbine: 31P, 33P, 243P, 426PD, 1187P,<br />
1284P, 1299TiP, 1508PD<br />
Virotherapy: 1080P<br />
Viscum album (European mistletoe): 1487P<br />
Vismodegib: 1152P, 1153P, 1155P<br />
Vitamin K antagonist (VKA): 1040P, 1479P<br />
VX-984 (selective DNA-dependent protein<br />
kinase): 382P<br />
X-396: 1210PD<br />
XELOX (capecitabine/oxaliplatin): 493P, 551P,<br />
553P, 660P, 1393P<br />
XELOXIRI (oxaliplatin/capecitabine/irinotecan):<br />
496P<br />
Yttrium-90 (Y-90): 803P<br />
Zoledronic acid: 20P, 672P, 677P, 1463P, 1465P<br />
drug index<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw398 | vi555
translational research index<br />
<strong>Annals</strong> Of <strong>Oncology</strong> 27 (Supplement 6): vi556–vi561, 2016<br />
doi:10.1093/annonc/mdw399<br />
translational<br />
research<br />
index<br />
10q23.3-26.3 (glioblastoma chromosomal<br />
region): 131P<br />
15-3p: 1530P<br />
4EB-P1 (4EBP-1): 28P, 29P, 33P<br />
4F2hc tumour antigen: 50P<br />
A2AR: 389P, 1068P, 1105TiP<br />
ABC: 808P<br />
ABCB1: 186P, 205P, 288P<br />
ABCB3: 205P<br />
ABCB7: 205P<br />
ABCC1: 205P<br />
ABCC2: 981P<br />
ABCC3: 981P<br />
ABCC5: 205P, 635P<br />
ABCG2: 205P, 376P, 808P<br />
ABCG4: 939P<br />
ABL: 1210PD<br />
ACTH: 1091P<br />
ACTN4: 1183P<br />
ACVR1B: 538P<br />
ACYP2: 981P, 1573P<br />
AGP (alpha-1 acid glycoprotein): 1419P<br />
AIFM3: 939P<br />
AKT: 9P, 15P, 24P, 28P, 31P, 33P, 36P, 51P, 96P,<br />
110P, 111P, 229PD, 277P, 303P, 353P, 378P,<br />
383P, 450TiP, 540P, 659P, 718O, 785P, 880P,<br />
889P, 897P, 902TiP, 924P, 959P, 980P, 1188P,<br />
1274P, 1285TiP, 1523P, 1537P, 1539P, 1555P,<br />
1604P<br />
AKT1: 119P, 894P, 897P, 1213PD<br />
AKT2: 897P<br />
AKT3: 1144P<br />
ALDH1: 965P, 1545P, 1551P<br />
ALK: LBA8, LBA42_PR, 121P, 138P, 410TiP,<br />
427PD, 665P, 897P, 1060P, 1089P, 1160P, 1181P,<br />
1206PD, 1207PD, 1208O, 1209PD, 1210PD,<br />
1211PD, 1213PD, 1214PD, 1221P, 1223P,<br />
1250P, 1263P, 1264P, 1266P, 1268P, 1272P,<br />
1289TiP, 1290TiP, 1291TiP, 1292TiP, 1295TiP,<br />
1296TiP, 1521PD<br />
ALT: 1413P<br />
AMPK: 5P, 303P, 353P, 417O,<br />
Androgen receptor (AR): LBA29, LBA33_PR,<br />
173P, 187P, 261P, 289P, 296P, 388P, 405P, 637P,<br />
719O, 727PD, 733P, 737P, 766TiP, 1535P, 1539P<br />
ANGPT2 (ANG2): 708TiP<br />
Aniopoietin-1 (Ang-1): 46P<br />
Aniopoietin-2 (Ang-2): 46P, 807P<br />
AOL (aspergillus oryzae lectin): 1328P<br />
AP: 868P<br />
APAF1: 303P<br />
APC: 7P, 54P, 418O, 458O, 523P, 538P, 620PD,<br />
899P, 964P, 1558P<br />
APLF: 7P<br />
APOC2: 635P<br />
APTX: 642P<br />
ARD1A: 458O, 697P<br />
AREG: 1006P<br />
ARID: 419O<br />
ARID1A/2: 96P, 538P, 879P, 894P<br />
AR-V7: 726PD, 728PD, 729PD<br />
Atg16L1: 1601P<br />
ATM: LBA25, 96P, 176P, 287P, 620PD, 624P,<br />
878P, 899P<br />
ATR: 96P<br />
ATRX: 96P, 418O, 1413P<br />
AURKA: LBA29<br />
Aurora A kinase (AAK): LBA29, 1423O<br />
AXL: LBA30_PR, 15P, 30P, 32P, 1210PD, 1293TiP,<br />
1526P, 1527P, 1562P<br />
B7.1: 1294TiP<br />
BAP1: 806P<br />
BART4-5p: 646P<br />
BAT25: 883P<br />
BAT26: 883P<br />
Bax: 22P<br />
Bcl-2: 22P, 33P, 46P, 58PD, 190P, 419O, 807P,<br />
913P, 923P, 1534P, 1566P, 1594P<br />
Bcl-3: 1574P<br />
Bcl-6: 923P, 924P<br />
Bcl-xl: 22P, 924P, 933P<br />
BCRP (breast cancer resistant protein): 474P,<br />
808P, 1442P<br />
BCRP-1: 808P<br />
BDNF: 701P<br />
Beclin1: 1601P<br />
Beta-Catenin/β(beta)-catenin: 4P, 21P, 385P,<br />
1555P, 1591P<br />
BIM1: 384P<br />
BMP/BMPR1A: 7P<br />
BRAC1: 874P<br />
BRAD1: 176P<br />
BRAF G469: 1212PD<br />
BRAF V600E: 55PD, 99P, 228PD, 336P, 368P,<br />
427PD, 455O, 461O, 568P, 569P, 980P, 1109PD,<br />
1111O, 1130P, 1134P, 1135P, 1137P, 1138P,<br />
1140P, 1142P, 1143P, 1145P, 1150P, 1156TiP,<br />
1176P, 1212PD, 1213PD, 1255P, 1268P, 1592P<br />
BRAF: LBA19_PR, LBA21, 9P, 55PD, 56PD, 66P,<br />
69P, 71P, 89P, 90P, 93P, 99P, 120P, 228PD,<br />
336P, 368P, 383P, 455O, 458O, 459O, 461O,<br />
462PD, 464PD, 482P, 499P, 501P, 508P, 509P,<br />
523P, 528P, 529P, 530P, 535P, 538P, 540P, 548P,<br />
560P, 563P, 565P, 568P, 569P, 620PD, 696P,<br />
897P, 954O, 980P, 1005P, 1027P, 1106O,<br />
1108PD, 1109PD, 1111O, 1116P, 1118P, 1131P,<br />
1134P, 1135P, 1137P, 1139P, 1140P, 1141P,<br />
1144P, 1145P, 1147P, 1148P, 1149P, 1166P,<br />
1168P, 1174P, 1175P, 1176P, 1213PD, 1235P,<br />
1250P, 1255P, 1268P, 1394P, 1521PD, 1572P,<br />
1592P<br />
BRAF27: 1144P<br />
BRCA: LBA3_PR, 170P, 176P, 219TiP, 223O,<br />
231PD, 538P, 855O, 856O, 865P, 874P, 876P,<br />
877P, 878P, 903TiP, 1043P, 1336P, 1337P,<br />
1547P, 1572P<br />
BRCA1: LBA34, 96P, 105P, 112P, 113P, 153PD,<br />
167P, 168P, 169P, 170P, 176P, 182P, 219TiP,<br />
223O, 272P, 287P, 401P, 620PD, 642P, 874P,<br />
875P, 878P, 886P, 894P, 903TiP, 966P, 1103TiP,<br />
1335P, 1336P, 1337P, 1522P, 1547P<br />
BRCA2: LBA34, 59P, 96P, 105P, 112P, 113P,<br />
153PD, 167P, 168P, 169P, 176P, 219TiP, 223O,<br />
287P, 401P, 418O, 458O, 620PD, 865P, 874P,<br />
875P, 878P, 886P, 894P, 903TiP, 954O, 1103TiP,<br />
1335P, 1336P, 1337P, 1522P, 1547P<br />
BRD4-NOTCH3: 1424O<br />
BRIP1: 176P, 287P<br />
BT-20: 1539P<br />
C1D15: LBA12<br />
C797S: 1582P<br />
CA 125: 857PD, 876P, 1347P<br />
CA19-9 (CA19.9): 70P, 71P, 86P, 1347P<br />
CA-9: 114P, 1542P<br />
CACNG1: 272P<br />
Cadherin (E-/VE-): 12P, 15P<br />
CagA: 933P<br />
Caireticulin: 1001P<br />
CALR: 1001P<br />
Cancer stem cells: 41P, 341P, 384P, 414TiP, 545P,<br />
804P, 965P, 1534P, 1566P<br />
CAR (chimeric antigen receptor): 943TiP, 945P<br />
Caspase 3: 33P, 36P, 172P, 1548P<br />
Caspase 5: 1056PD<br />
Caspase 6: 172P<br />
Caspase 7: 36P<br />
Caspase 8: 172P<br />
Caspase 9: 172P<br />
CCDC6-RET: 1203PD<br />
ccfDNA long fragment/β-globin Ratio (cLBR):<br />
64P<br />
CCL4: 1593P<br />
CCL5: 1593P<br />
CCND1: LBA12, LBA15, 46P, 79P<br />
CCND3: 79P<br />
CCNE1: LBA12, LBA12, 79P, 894P<br />
CCR7: 1088P<br />
CD10: 923P<br />
CD105: 804P<br />
CD11: 1593P<br />
CD127: 83P<br />
CD13: 1508PD<br />
CD133: 34P, 341P, 1601P<br />
CD134: 1053P<br />
CD137: 1064P<br />
CD138: 134P<br />
CD14: 1085P<br />
CD15: 1593P<br />
CD152: 83P<br />
CD16: 172P<br />
CD163: 81P, 1542P<br />
CD19: 415TiP, 943TiP, 945TiP, 1048O, 1064P<br />
CD20: 81P, 172P, 520P, 931P, 935P, 945TiP,<br />
946TiP, 1399PD, 1598P<br />
CD24: 964P, 965P<br />
CD25: 83P, 172P, 358O, 1088P<br />
CD274: 1076P<br />
CD28: 943TiP, 945TiP,1064P<br />
CD3: 81P, 117P, 172P, 520P, 567P, 572P, 624P,<br />
635P, 1094P, 1399PD, 1412P, 1598P<br />
CD30: 923P<br />
CD31: 807P, 1542P, 1580P<br />
CD34: 340P, 931P<br />
CD38: 906O<br />
CD3ζ: 943TiP, 945TiP, 1064P<br />
CD4: 81P, 83P, 172P, 567P, 637P, 694P, 869P,<br />
1050PD, 1052PD, 1061P, 1065P, 1081P, 1088P,<br />
1094P, 1399PD, 1552P<br />
CD44: 143TiP, 341P, 965P, 1534P, 1566P<br />
CD45: 75P, 76P, 234P, 1593P<br />
CD45FRA: 1088P<br />
CD45RO: 83P, 572P<br />
CD5/6: 289P<br />
CD56: 520P<br />
CD68: 1399PD<br />
CD73: 389P<br />
CD74: 121P<br />
CD8: 81P, 85P, 117P, 172P, 364PD, 567P, 572P,<br />
624P, 637P, 694P, 786P, 869P, 1050PD, 1052PD,<br />
1061P, 1065P, 1068P, 1078P, 1088P,<br />
1094P,1180P, 1399PD, 1412P, 1425PD, 1541P,<br />
1542P, 1552P<br />
CD80 (CD-80): 694P, 1050PD, 1103TiP<br />
CD83: 1683P<br />
CD90: 341P<br />
CD95: 133P, 134P, 172P<br />
CDC2: 46P<br />
CDH1: 182P, 523P, 635P, 1335P, 1586P<br />
CDH11: 1586P<br />
CDH2: 1586P<br />
CDK: 229PD, 538P<br />
CDK1: 303P<br />
CDK12: 292P<br />
CDK2: LBA12<br />
CDK2A: 899P<br />
© European Society for Medical <strong>Oncology</strong> 2016. Published by Oxford University Press on behalf <strong>of</strong> the European Society for Medical <strong>Oncology</strong>.<br />
All rights reserved. For permissions, please email: journals.permissions@oup.com.
<strong>Annals</strong> Of <strong>Oncology</strong><br />
translational research index<br />
CDK4: LBA1_PR, LBA12, LBA13, LBA15, LBA18,<br />
29P, 261P, 303P, 311TiP, 314TiP, 954O, 1002P,<br />
1297TiP, 1534P, 1566P, 1583P<br />
CDK6: LBA1_PR, LBA12, LBA13, LBA15, LBA18,<br />
228PD, 261P, 311TiP, 314TiP, 1002P, 1297TiP,<br />
1534P, 1566P<br />
CDKN1A: 1534P<br />
CDKN2A: LBA15, 79P, 176P, 665P, 697P, 886P,<br />
899P, 980P, 1144P<br />
CDKN2B: 79P, 176P<br />
CDX2: 34P, 561P, 1591P<br />
CEA: 71P, 358O, 1056PD, 1347P<br />
CEP9: 117P<br />
CETCs (circulating epithelial tumour cells):<br />
1545P<br />
CHEK1/2: 303P, 878P, 1547P<br />
CHK1: 231PD, 1019TiP<br />
CHK2: 231PD, 287P<br />
CHP2: 1404PD<br />
Chromosomal instability: 562P<br />
Circular RNA (circRNA): 1535P<br />
Circulating DNA (cDNA): 69P, 71P, 456O<br />
Circulating free cell DNA (cfcDNA): 64P, 525P,<br />
528P, 566P, 1582P<br />
Circulating free DNA (cfDNA): 59P, 60P, 66P,<br />
68P, 71P, 566P, 1144P, 1176P, 1247P, 1265P<br />
Circulating nucleosomes: LBA23_PR<br />
Circulating tumour cells (CTCs): 65P, 70P, 71P,<br />
72P, 73P, 76P, 232P, 234P, 456O, 518P, 753P,<br />
792P, 886P, 965P, 1160P, 1521PD, 1558P<br />
Circulating tumour DNA (ctDNA): LBA29, 59P,<br />
63P, 70P, 90P, 255P, 525P, 530P, 687P, 696P,<br />
1145P, 1159PD, 1161P, 1162P, 1293TiP, 1521PD<br />
CK: 73P, 74P<br />
CK20: 34P, 1591P<br />
CK5: 19P<br />
CK7: 1591P<br />
c-Kit (KIT, CKIT): 2PD, 620PD, 964P, 1422TiP<br />
CLDN18: 87P<br />
CLDN3: 1586P<br />
CLDN7: 939P<br />
Clusterin: LBA29<br />
c-Myc (MYC): LBA12, 4P, 924P<br />
COL3A1: 96P<br />
COMT: 981P<br />
Copy number alterations: 1182P<br />
Copy number variants: 921P, 1163P, 1164P<br />
CoREST: 381P<br />
CRAF: 1555P<br />
CREBBP: 77P<br />
CT26: 1061P, 1067P<br />
CTLA-4 (CTLA4; Cytotoxic T-lymphocyte<br />
antigen-4): LBA36, 479P, 694P, 1027P, 1055O,<br />
1057PD, 1077P, 1117P, 1118P, 1123P, 1128P,<br />
1130P, 1180P, 1245P, 1394P, 1430TiP, 1437PD,<br />
1541P<br />
CTNNB1: 119P, 618PD, 620PD, 880P, 894P, 899P,<br />
964P, 1213PD<br />
CTR1: 981P<br />
CXCL1: 1593P<br />
CXCL10: 1425PD<br />
CXCL12: 1083P<br />
CXCL14: 939P<br />
CXCL5: 1593P<br />
CXCL9: 1425PD<br />
CXCR2: 1049PD<br />
Cyclin A: 1328P<br />
Cyclin D: 314TiP, 1328P<br />
Cyclin D1: 29P, 303P, 1002P<br />
CYP: 1556P<br />
CYP17: LBA33_PR, 727PD, 738P<br />
CYP1B1: 1344P<br />
CYP2C19: 376P<br />
CYP2C8: LBA50<br />
CYP3A4: 186P, 399P, 808P<br />
CYP3A5: 936P<br />
CYSTATIN C (GFR Cy ): 1470P<br />
Cytochrome P450: 376P<br />
Cytokeratin 4 (CK4): 968P<br />
Cytokeratin: 234P, 1169P<br />
DAPI: 76P<br />
DDR2: 120P, 1213PD, 1250P<br />
Dendritic cells: LBA45<br />
DFNA5: 102P<br />
DGKζ: 1534P<br />
DH1: 349P<br />
DIO3: 1529P<br />
DKK1: 698P, 1529P<br />
DLK2: 939P<br />
DMC1: 7P<br />
dMMR (deficient mismatch repair): 567P<br />
DMNT1: 21P, 411TiP<br />
DMNT3A: 538P<br />
DNA copy number: 205P, 562P, 637P<br />
DNA damage: 756P, 1557P<br />
DNA methylation: 325O<br />
DNA repair genes: 7P, 115P, 727PD, 996P<br />
DNA repair: 96P, 107P, 356TiP, 379P, 460O, 874P,<br />
902TiP, 966P<br />
DNA: LBA23_PR, LBA25, 525P, 564P, 687P, 892P,<br />
969P, 973P, 982P, 1164P, 1166P, 1174P, 1379P,<br />
1519O, 1529P, 1599P, 1601P<br />
DNA-PK: 382P<br />
DPYD (DPD): 296P<br />
DSG2: 87P<br />
E1: 976P<br />
E17K: 119P<br />
E2F1-4: LBA12<br />
E2F3: 19P<br />
E6: 22P<br />
E7: 22P<br />
EBV: 663P, 966P, 969P, 973P, 982P<br />
E-cadherin (CDH1): 1551P, 1562P, 1580P, 1602P<br />
eEF2: 1537P<br />
EGF, EGFR (HER-1): LBA8, LBA36, LBA37,<br />
LBA43, 1O, 8P, 9P, 10P, 11P, 12P, 13P, 15P,<br />
18P, 26P, 27P, 56PD, 58PD, 60P, 61P, 62P, 66P,<br />
69P, 79P, 87P, 93P, 99P, 104P, 109P, 110P, 119P,<br />
120P, 130P, 289P, 308P, 342P 312TiP, 326PD,<br />
351P, 359O, 408TiP, 412TiP, 418O, 455O,<br />
457O, 461O, 464O, 465PD, 472P, 478P, 480P,<br />
497P, 498P, 499P, 509P, 522P, 526P, 527P, 528P,<br />
529P, 533P, 535P, 539P, 620PD, 630P, 663P,<br />
665P, 880P, 894P, 964P, 975P, 995P, 1089P,<br />
1166P 1160P, 1161P, 1168P,1175P, 1181P,<br />
1188P, 1189P, 1201O, 1202O, 1211PD, 1212PD,<br />
1213PD, 1221P, 1223P, 1226P, 1230P, 1231P,<br />
1233P, 1235P, 1236P, 1237P, 1239P, 1240P,<br />
1241P, 1242P, 1243P, 1244P, 1245P, 1248P,<br />
1249P, 1250P, 1251P, 1252P, 1253P, 1254P,<br />
1255P, 1256P, 1257P, 1258P, 1259P, 1260P,<br />
1261P, 1262P, 1266P, 1268P, 1272P, 1274P,<br />
1284P, 1285TiP, 1286TiP, 1287TiP, 1288TiP,<br />
1292TiP, 1295TiP, 1296TiP, 1297TiP, 1298TiP,<br />
1511P, 1521PD, 1522P, 1527P, 1550P, 1555P,<br />
1558P, 1572P, 1582P, 1583P, 1599P<br />
EGFL7: 537P<br />
EGFLAM: 939P<br />
EGFR del19: 1213PD, 1247P, 1259P<br />
EGFR Exon 18 1173P, 1226P<br />
EGFR Exon 19: 10P, 26P, 69P, 119P, 1173P,<br />
1189P, 1226P, 1244P, 1251P, 1252P, 1254P<br />
EGFR Exon 20: 1173P, 1226P, 1254P<br />
EGFR Exon 21: 1173P, 1226P<br />
EGFR Exons 746-750: 12P<br />
EGFR G719: 69P, 119P<br />
EGFR L858R: 8P, 13P, 69P, 1160P, 1189P 1242P ,<br />
1202O, 1213PD, 1230P, 1242P, 1244P, 1247P,<br />
1252P, 1254P, 1259P, 1582P<br />
EGFR L861Q: 1202O<br />
EGFR M: 1232P, 1234P, 1246P, 1247P<br />
EGFR rs917881: 130P<br />
EGFR T790M: 8P, 10P, 13P, 61P, 62P, 63P, 66P,<br />
69P, 359O, 1041P, 1161P, 1189P, 1201O, 1202O,<br />
1234P, 1235P, 1236P, 1237P, 1243P, 1246P,<br />
1247P, 1249P, 1257P, 1287TiP, 1582P<br />
EGFR/ALK: 1060P<br />
elF4E: 29P<br />
EML4: 121P, 1160P<br />
EML4-ALK fusion: 1161P, 1250P, 1424O<br />
EMT6: 1078P<br />
eNOS: 708TiP<br />
EOMES: 1425PD<br />
EpCAM: 76P, 341P, 792P, 1558P, 1586P<br />
EPHA2: 1O, 15P, 1210PD, 1567P<br />
EphB3: 28P<br />
Epithelial-mesenchymal transition (EMT): 12P,<br />
15P, 17P, 34P, 128P, 645P, 701P, 1551P, 1562P,<br />
1586P, 1602P<br />
ER (Estrogen receptor): LBA14_PR, LBA15, 103P,<br />
105P, 111P, 145O, 147PD, 152PD, 165P, 173P,<br />
174P, 175P, 177P, 179P, 180P, 183P, 185P, 189P,<br />
190P, 194P, 200P, 222O, 225PD, 226PD, 229PD,<br />
245P, 259, 260P, 261P, 265P, 266P, 271P, 277P,<br />
292P, 294P, 296P, 310TiP, 311TiP, 313TiP, 388P,<br />
862P, 880P, 884P, 1285TiP, 1539P, 1541P<br />
ERCC1: 186P, 294P, 620PD, 642P, 964P, 985P<br />
ERCC2: 186P<br />
ERCC3: 7P<br />
ERG: 727PD<br />
ERK: 110P, 130P, 383P, 455O, 540P, 1136P, 1188P,<br />
1526P, 1537P<br />
ERβ: 1539P<br />
ETV-NTRK (Fusion): 954O, 980P<br />
EXO1: 996P<br />
EZH2 (Enhancer <strong>of</strong> zeste homolog 2): 21P, 96P,<br />
419O, 433P, 1398PD<br />
FADD: 303P<br />
FAM: 538P<br />
FANCA: 418O<br />
FANCC: 1547P<br />
FANCD2: 1547P<br />
FARS2: 1573P<br />
FAS: 997P<br />
Fascin: 1347P<br />
FASL: 134P, 997P<br />
FAT1: 292P, 538P<br />
FBXW7: 458O, 538P, 840P, 894P, 980P<br />
FcγRIIA and IIIA: 641P<br />
FFG-1: 46P<br />
FGF: 17P, 732P<br />
FGF10: 1424O<br />
FGF19: 79P<br />
FGF2: 473P<br />
FGF23: 732P<br />
FGFR: LBA20_PR, 229PD, 370P, 732P, 781PD,<br />
785P, 789P, 845TiP, 859PD, 904TiP, 972P,<br />
1212PD<br />
FGFR1: 2PD, 6P, 370P, 472P, 665P, 845TiP,<br />
845TiP, 894P, 954O, 1213PD, 1404PD, 1512P,<br />
1563P<br />
FGFR2: 2PD, 6P, 28P, 131P, 370P, 472P, 845TiP,<br />
885P, 1214PD<br />
FGFR3: 2PD, 6P, 28P, 63P, 370P, 472P, 541P,<br />
786P, 845TiP, 899P, 1214PD, 1562P<br />
FGFR4: 2PD, 6P, 186P, 665P, 845TiP, 1564P<br />
translational<br />
research<br />
index<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw399 | vi557
translational research index<br />
<strong>Annals</strong> Of <strong>Oncology</strong><br />
translational<br />
research<br />
index<br />
FLCN: 428PD<br />
FLT: 538P, 1276P<br />
FLT3: 541P, 899P, 948TiP, 1166P<br />
FLT-ITD fusion: 948TiP, 1166P<br />
FN1: 791P<br />
Folate receptor: 395P<br />
Fos-related antigen 2 (Fra-2): 3P<br />
FOXA1: 296P<br />
FOXM1: 1011P<br />
FoxP3: 83P, 567P, 1081P, 1180P, 1412P<br />
Fra1: 1562P<br />
FT1/FTS (fused toes homolog): 49P<br />
FUCOSYL GM1: 1427PD<br />
GA: 894P, 980P<br />
Gal-1: 1061P<br />
GALNT12: 287P<br />
GAS6: 30P, 1527P<br />
GATA3: 182P, 1180P<br />
G-CSF: 181P, 1409P<br />
GDF-15: 380P<br />
GDF2: 7P<br />
GFP: 1579P<br />
GGH (gamma-glutamyl hydrolase): 519P<br />
Ghrelin: 1434O<br />
Gli1: 10P, 1527P<br />
GLI2: 1527P<br />
Glut-1: 114P<br />
GM-CSF: 1058P, 1069P, 1085P<br />
GNAQ: 1144P<br />
GNAS: 541P, 620PD, 687P, 899P<br />
GNRH: 734P, 735P<br />
GP130: 47P<br />
GPR54: 1532P<br />
GR: 727PD<br />
GSG1L: 939P<br />
GSTM: 51P<br />
GSTM1: 920P<br />
GZMA: 1425PD<br />
GZMB: 1425PD<br />
H2AFX: 576P<br />
H3K27me3: 21P<br />
hCGβ (Tumour antigen): 38P<br />
HDAC: 419O<br />
HDM2: 366PD, 380P<br />
Hedgehog: 8P, 10P, 13P, 26P, 281P, 1004P, 1152P,<br />
1153P, 1527P<br />
hENT1: 127P<br />
Hepatocyte growth factor (HGF): 787P<br />
HER (ERBB, ErbB): LBA43, 96P, 104P, 229PD,<br />
522P, 630P, 1236P, 1238P, 1523P<br />
HER2 (ERBB2, cerb-B2, HER2 neu): LBA1_PR,<br />
LBA12, LBA13, LBA15, LBA16, LBA17, LBA18,<br />
LBA26, 9P, 14P, 15P, 24P, 25P, 27P, 31P, 33P,<br />
79P, 93P, 103P, 104P, 105P, 108P, 110P, 111P,<br />
120P, 121P, 122P, 135P, 144O, 147PD, 150PD,<br />
151PD, 153PD, 162P, 163P, 165P, 169P, 171P,<br />
174P, 175P, 177P, 179P, 181P, 184P, 185P, 186P,<br />
189P, 190P, 191P, 193P, 194P, 200P, 204P, 206P,<br />
208P, 209P, 210P, 211P, 212P, 213P, 216P, 222O,<br />
224PD, 225PD, 226PD, 228PD, 230PD, 233P,<br />
235P, 237P, 238P, 239P, 245P, 246P, 247P, 248P,<br />
249P, 251P, 253P, 257P, 258P, 259, 260P, 261P,<br />
264P, 264P, 267P, 268P, 270P, 271P, 272P,<br />
273P, 274P, 275P, 276P, 277P, 278P, 283P, 284P,<br />
289P, 292P, 293P, 294P, 296P, 297P, 304P,<br />
310TiP, 311TiP, 312TiP, 313TiP, 315TiP,<br />
408TiP, 458O, 459O, 509P, 521P, 541P, 624P,<br />
624P, 641P, 644P, 663P, 665P, 672P, 673P, 674P,<br />
703P, 792P, 894P, 896P, 954O, 964P, 1030P,<br />
1031P, 1069P, 1103TiP, 1161P, 1168P, 1212PD,<br />
1213PD, 1235P, 1236P, 1250P, 1267P, 1272P,<br />
1338P, 1347P, 1384P, 1385P, 1537P, 1541P,<br />
1542P, 1545P, 1560P, 1585P, 1587P, 1588P,<br />
1595P<br />
HER3 (ErbB3): 93P, 122P, 369P, 372P, 509P, 703P,<br />
1296TiP, 1562P<br />
HER4 (ERBB4, ErbB4): 93P, 408TiP, 523P, 899P,<br />
1250P<br />
Heregulin (HRG, Hg): 369P, 372P, 1296TiP<br />
Hes1: 49P<br />
HGF: 361PD, 539P, 630P, 663P<br />
HGFR (hepatocyte-derived growth factor<br />
receptor): 34P<br />
HIC1: 124P<br />
HIF1: 114P<br />
HIF-1-alpha (HIF1α, HIF1A): 46P, 708TiP<br />
High mutation load (HML): 115P<br />
HIST1H2BD: 576P<br />
HIST1H2BJ: 576P<br />
HIST1H2BK: 576P<br />
HIST1H3F: 576P<br />
HIST1H4I: 576P<br />
HLA: 1223P<br />
HLA-A: 1056PD, 1075P<br />
HLA-A2: 1223P<br />
HLA-DR: 757P, 869P, 1088P, 1593P<br />
HMMR: 287P<br />
Homologous recombination (HR): 112P, 902TiP,<br />
966P, 1103TiP, 1547P<br />
Homologous recombination repair deficiency<br />
(HRD): LBA3_PR, 112P, 113P, 115P<br />
875P, 901TiP<br />
Hormone receptors, (hormonal receptors,<br />
steroidal receptors, steroid receptors, HR):<br />
LBA1_PR, LBA12, LBA13, LBA14_PR, LBA18,<br />
31P, 33P, 135P, 146O, 148PD, 150PD, 181P,<br />
191P, 193P, 204P, 229PD, 248P, 249P, 251P,<br />
253P, 264P, 268P, 283P, 284P, 297P, 1030 P,<br />
1384P<br />
HR23B: 1578P<br />
HRAS 3/14: 899P<br />
HRD Score: 112P, 113P<br />
HSP90: 423PD<br />
ICAM-1: 1054PD<br />
ictP: 868P<br />
IDH1: 323O, 345P, 347P, 1583P<br />
IDH2: 323O, 1583P<br />
IDO: 922P<br />
IDO1: 341P, 1110PD<br />
Interferon-gamma (IFNγ IFNg, IFN-gamma):<br />
LBA31_PR, LBA45, 37P, 1550P<br />
IGF: 303P<br />
IGF-1 (IGF1): 111P, 374P, 417O, 630P<br />
IGF1R (IGF-1R): 169P, 450TiP, 523P, 897P,<br />
902TiP<br />
IGF2 (IGF-2): 374P<br />
IGFBP-2: 964P<br />
IGFR: 1148P<br />
IL-10: 364PD<br />
IL-12: LBA45, 280P, 1063P<br />
IL-13: 1063P<br />
IL13R alpha2: 353P<br />
IL17: 327PD, 1063P<br />
IL-1β: 1085P, 1593P,<br />
IL-2: 358O, 1063P, 1078P, 1080P<br />
IL-20RB: 272P<br />
IL-4: 1063P, 1085P<br />
IL-6 (IL6): 16P, 39P, 86P, 280P, 1085P<br />
IL-8 (IL8): 539P, 280P, 663P, 1055O, 1593P, 1601P<br />
ILT4: 1593P<br />
Integrin: 1170P<br />
Interferon-alpha: 1550P<br />
Internal tandem duplications: 1166P<br />
Involucrin (IVL): 22P<br />
IRAK2: 1601P<br />
IRF7 (Interferon regulatory factor 7): 256P<br />
JAK2: 921P, 1091P<br />
JNK1/2: 36P<br />
JUNB: 1574P<br />
KDM5C: 806P<br />
KDR: 899P, 899P, 1583P<br />
KEGG: 1584P<br />
KHSRP: 939P<br />
Ki-67: LBA13, LBA15, 103P, 114P, 116P, 149PD,<br />
163P, 174P, 175P, 179P, 180P, 189P, 193P, 200P,<br />
221TiP, 289P, 294P, 296P, 340P, 436P, 446P,<br />
727PD, 1052PD, 1548P, 1588P, 1594P<br />
KIF5B-RET: 1203PD, 1204PD<br />
KIR: 1061P, 1086P<br />
KISS1: 1532P<br />
KIT: 2PD, 4P, 899P, 986P, 1005P, 1144P, 1404PD,<br />
1583P<br />
KLF5: 1554P<br />
KRAS: LBA47_PR, 3P, 54P, 56PD, 64P, 66P, 69P,<br />
70P, 71P, 89P, 91P, 92P, 94P, 95P, 98P, 99P,<br />
120P, 139P, 383P, 401P, 450TiP, 455O, 458O,<br />
461O, 466PD, 471P, 478P, 484P, 487P, 491P,<br />
495P, 496P, 497P, 499P, 506P, 508P, 509P, 510P,<br />
516P, 521P, 522P, 523P, 525P, 525P, 528P, 529P,<br />
530P, 535P, 540P, 541P, 548P, 560P, 565P, 568P,<br />
569P, 571P, 572P, 620PD, 630P, 665P, 687P,<br />
688P, 696P, 697P, 880P, 894P, 899P, 1089P,<br />
1144P, 1160P, 1161P, 1166P, 1168P, 1174P,<br />
1211PD, 1212PD, 1213PD, 1223P, 1235P,<br />
1250P, 1255P, 1271P, 1272P, 1521PD, 1522P,<br />
1526P, 1555P, 1591P, 1599P<br />
LC3-II: 1601P<br />
LEF: 4PD<br />
LEPR (leptine gene): 35P<br />
Let-7/LIN28: 166P<br />
LFC: 1574P<br />
lgG4: 1028P<br />
Lgr5: 34P<br />
LINC00524: 1529P<br />
Linear Models for Microarray Data (LIMMA):<br />
23P<br />
LKB1: 111P, 303P, 450TiP<br />
LOH (Loss <strong>of</strong> heterozygosity): 44P112P, 113P,<br />
131P, 131P, 649P<br />
LRP1B: 79P, 1424O<br />
LRRFIP2: 7P<br />
LSD1 (lysine-specific demethylase 1): 381P<br />
LTK: 1210PD<br />
Ly6E (lymphocyte antigen 6 complex locus E):<br />
541P<br />
LYN: 894P<br />
MAFA: 939P<br />
Major histocompatibility complex (MHC) class I/<br />
II: 57PD<br />
MAP: 9P<br />
MAP2K1: 120P, 1144P, 1250P<br />
MAP2K6: 98P<br />
MAP3K1: 109P<br />
MAP3K13: 79P<br />
MAPK: 15P, 18P, 24P, 30P, 33P, 36P, 96P, 228PD,<br />
272P, 455O, 618PD, 806P, 1027P, 1113PD,<br />
1149P, 1394P, 1555P<br />
MATE1: 981P<br />
MC1R: 1144P<br />
MCP-3: 539P<br />
MDA-MB 453: 1539P<br />
MDM2: 1583P<br />
MDM4: 418O<br />
MDN1: 541P<br />
MDR1: 296P, 808P, 936P<br />
MDSCs (Myeloid-derived suppressor cells): 757P<br />
vi558 | translational research index Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> Of <strong>Oncology</strong><br />
translational research index<br />
MEC: 954O<br />
MED12: 897P<br />
MEG3: 1529P<br />
MEG8: 1529P<br />
MEG9: 1529P<br />
MEK: 13P, 14P, 15P, 18P, 32P, 33P, 130P, 286P,<br />
383P, 455O, 470P, 632P, 894P, 1109PD, 1111O,<br />
1118P, 1135P, 1136P, 1141P, 1394P, 1526P<br />
MEK1: LBA47_PR, 376P, 480P, 1136P, 1261P,<br />
1523P, 1534P, 1555P, 1566P<br />
MEK2: LBA47_PR, 376P, 480P, 1111O, 1136P,<br />
1149P, 1261P, 1523P<br />
MEN1: 96P, 418O, 419O, 428PD, 434P<br />
Mesenchymal stem cells: 1579P<br />
MET (c-MET): LBA30_PR, 9P, 17P, 63P, 228PD,<br />
361PD, 371P, 417O, 450TiP, 480P, 620PD<br />
METi: 480P, 663P, 706P, 712TiP, 787P, 897P,<br />
964P, 1165P, 1549P, 1210PD, 1212PD, 1213PD,<br />
1235P, 1257P, 1287TiP, 1292TiP, 1293TiP,<br />
1534P, 1549P, 1558P, 1566P<br />
Metabolomics: 152PD<br />
Metallothionein species (MT1H): 4P<br />
MGMT: 54P, 131P, 323O, 324P, 337P, 338P, 339P,<br />
341P, 345P, 347P, 349P, 356TiP, 620PD, 1450P<br />
MHC- II: 1347P<br />
MHC-I: 1347P<br />
MIB-1: 807P<br />
MIB-1Li: 340P<br />
MICA: 1061P, 1528P<br />
MICB: 1528P<br />
microRNA (miR): 19P, 21P, 166P, 185P, 290P,<br />
412TiP, 532P, 645P, 841P, 1530P, 1534P, 1535P,<br />
1566P, 1595P, 1602P<br />
Microsatelite stable (MSS): 562P, 568P, 624P<br />
Microsatellite instability (MSI): 52O, 115P, 479P,<br />
562P, 568P, 645P, 883P, 1056PD, 1076P, 1592P<br />
miR-133a-3p: 1530P<br />
miR-139-R-196a-5p: 1530P<br />
miR-144-5p: 1530P<br />
miR-17: 125P<br />
miR-182.59: 1530P<br />
miR-192-3p: 532P<br />
miR-192-5p: 532P<br />
miR-196b-5p: 1530P<br />
miR-200c: 41P<br />
miR-205.5p: 1530P<br />
miR-21: 125P, 1530P<br />
miR-210-3p: 1530P<br />
miR-21-5p: 1530P<br />
miR-223-3P (hsa): 841P<br />
miR-224-5p (hsa): 841P<br />
miR-29a: 125P<br />
miR-30: 185P<br />
miR-301b-3p: 1530P<br />
miR-30a-3p: 1530P<br />
miR-31.3p: 457O<br />
miR-31: 542P<br />
miR-31-5p (hsa): 841P<br />
miR-331-3p: 22P, 1602P<br />
miR-34: 1534P, 1534P, 1566P<br />
miR-340: 21P<br />
miR-490-3p: 1530P<br />
miR-548I1: 575P<br />
miR-577: 1530P<br />
miR-7: 1596P<br />
miR-891a-5p: 1530P<br />
miR-92: 125P<br />
miR-944: 1530P<br />
MITF: 1111O<br />
MKI67: 131P<br />
MLH1: 7P, 563P, 620PD, 887P, 996P, 1335P<br />
MLK7-AS1: 635P<br />
MLL2: 79P, 292P, 1424O<br />
MLL3: 182P<br />
MMP: 1597P<br />
MMP1 (Matrix metalloproteinase 1): 841P<br />
MMP12: 841P<br />
MMP2: 46P, 1532P, 1586P<br />
MMP3: 4P<br />
MMP-7: 499P<br />
MMP-9: 39P, 46P, 698P, 1532P<br />
MMR: 90P, 538P, 663P, 887P, 996P, 1056PD<br />
MPO: 81P<br />
mRNA (plasma): 642P<br />
mRNA: LBA12, 30P, 296P, 341P, 372, 574P, 575P,<br />
728PD, 841P, 922P, 924P, 1085P, 1171P, 1183P,<br />
1187P, 1296TiP, 1425PD, 1512P, 1527P, 1532P,<br />
1562P, 1563P, 1564P, 1574P, 1579P, 1601P<br />
mRNA-126: 537P<br />
MRP1: 964P<br />
mrR1-3p: 1530P<br />
MSH2: 7P, 418O, 563P, 887P, 1335P<br />
MSH3: 996P<br />
MSH6: 7P, 563P, 887P, 1335P<br />
MSI-H: 458O, 479P<br />
MSR1: 287P<br />
mTOR: 14P, 28P, 29P, 33P, 51P, 104P, 109P,<br />
229PD, 277P, 303P, 311TiP, 353P, 377P, 378P,<br />
417O, 418O, 423PD, 437P, 443P, 443P, 450TiP,<br />
471P, 618PD, 785P, 806P, 810P, 824P, 833P,<br />
852TiP, 880P, 897P, 902TiP, 954O, 980P, 1035P,<br />
1081P, 1182P, 1274P, 1604P<br />
mTORC1/mTORC2: 29P, 377P<br />
MUC1: 19P, 792P, 1347P<br />
MUC2: 19P, 87P, 1591P<br />
MUC5AC: 19P<br />
MUM1: 923P<br />
MUS81: 7P<br />
Musashi-1: 34P, 341P<br />
Mutational load: 1111O, 1536P<br />
MUTYH: 7P, 176P, 287P, 1335P<br />
MYB-NFIB (gene fusion): 954O, 972P<br />
MYBPC3: 96P<br />
MYC: 292P, 665P, 894P, 913P, 1424O, 1534P,<br />
1566P<br />
MYCL1: 1424O<br />
MYCL1-JAZF1: 1424O<br />
MYCL1-MACF1: 1424O<br />
MYCL1-PABPC4: 1424O<br />
MYCN: LBA29<br />
NANOG: 19P, 341P<br />
NCOR1: 79P<br />
Nectin-4: 788P<br />
NEK2: 1597P<br />
Nestin: 341P<br />
NEU: 896P<br />
Neurokinin-1: 1440P<br />
NF1: 428PD, 894P, 897P, 954O, 980P, 1583P<br />
NFAT: 933P<br />
NF-κB (Nuclear factor kappa B): 4P, 5P, 47P,<br />
303P, 924P, 1576P, 1601P<br />
NGS (next generation sequencing): 15P, 53PD,<br />
66P, 105P, 115P, 138P, 182P, 287P, 401P,<br />
414TiP, 458O, 523P, 548P, 560P, 571P, 607TiP,<br />
612O, 618PD, 632P, 638P, 697P, 785P, 840P,<br />
874P, 878P, 899P, 966P, 1144P, 1163P, 1164P,<br />
1174P, 1182P, 1214PD, 1232P, 1255P, 1295TiP,<br />
1335P, 1404PD, 1547P, 1549P, 1566P, 1572P,<br />
1574P<br />
NK cells: LBA37, 925P, 927P, 975P, 1061P, 1083P,<br />
1086P, 1111O, 1414P, 1527P<br />
NK-1 receptors: 1445P, 1473P, 1505TiP<br />
NKT: 1432TiP<br />
N-myc: LBA29<br />
Notch: 49P<br />
Notch1: 49P, 541P, 620PD, 1534P, 1566P<br />
Notch2: 49P<br />
Notch3: 79P<br />
NQO1: 186P<br />
NR1/2: 635P<br />
NR21: 883P<br />
NR24: 883P<br />
NR27: 883P<br />
NRAS: 56PD, 66P, 69P, 89P, 93P, 99P, 120P, 383P,<br />
455O, 458O, 461O, 509P, 521P, 523P, 525P,<br />
529P, 535P, 540P, 541P, 548P, 565P, 568P, 569P,<br />
571P, 1005P, 1136P, 1144P, 1148P, 1174P,<br />
1175P, 1213PD, 1235P, 1250P, 1555P<br />
NRG1: 630P, 1562P<br />
NRP2 (Neuropilin 2): 22P, 663P<br />
NSE: 19P<br />
NTRK: 954O, 980P<br />
NTRK1: 138P, 407TiP, 409TiP, 427PD, 620PD,<br />
897P<br />
NTRK2/3: 138P, 407TiP, 409TiP, 427PD,<br />
NY-ESO-1: 1075P<br />
OCT1: 303P<br />
OCT2: 981P<br />
OCT4: 19P, 341P<br />
OX40: 1053PD<br />
p16: LBA15, 976P<br />
P1NP: 868P<br />
p21: 46P, 303P, 1555P<br />
p27: 383P<br />
p38: 30P, 36P<br />
p4EB-P1: 33P<br />
p52: 5P<br />
p53: LBA29, 3P, 19P, 22P, 46P, 59P, 116P, 174P,<br />
186P, 294P, 303P, 366PD, 380P, 386P, 806P,<br />
840P, 875P, 880P, 886P, 889P, 894P, 897P, 899P,<br />
954O, 964P, 1144P, 1232P, 1328P, 1576P, 1594P<br />
p70: 111P<br />
PAK1: 1526P, 1527P, 1555P<br />
PAK2: 1555P<br />
PAK4: 1555P<br />
pAKT: 9P, 1O, 30P, 31P, 47P, 111P<br />
PALB2: 287P, 1547P<br />
PARP: LBA3_PR, LBA25, 33P, 649P, 730PD,<br />
856O, 876P, 903TiP, 1103TiP, 1520O<br />
PARP1: LBA3_PR, 901TiP<br />
PARP2: LBA3_PR, 901TiP<br />
PARP3: 901TiP<br />
PAX8: 1591P<br />
pAXL: 30P<br />
PBRM1: 806P<br />
PD-1: LBA38, LBA41_PR, 2PD, 17P, 73P, 79P,<br />
80P, 81P, 81P, 364PD, 470P, 478P, 620PD,<br />
719O, 725PD, 773PD, 824P, 847TiP, 900TiP,<br />
944TiP, 947TiP, 949O, 955PD, 957PD, 978P,<br />
1017TiP, 1027P, 1028P, 1047O, 1050PD,<br />
1057PD, 1068P, 1072P, 1077P, 1157TiP 1088P,<br />
1103TiP, 1114PD, 1120P, 1123P, 1124P, 1126P,<br />
1128P, 1129P, 1130P, 1133P, 1180P, 1220P,<br />
1222P, 1260P, 1291TiP, 1399PD, 1412P,<br />
1430TiP, 1437PD, 1541P<br />
PDFGR: LBA20_PR, 620PD, 1422TiP<br />
PDFGRA (PDGFRα): 2PD, 450TiP, 472P, 964P,<br />
1212PD, 1402PD, 1420TiP, 1534P, 1566P,<br />
1583P<br />
PDGFR beta (PDGFRβ, PDGFR-b): 472P,<br />
1404PD<br />
PDGFR: 732P, 859PD, 904TiP, 986P<br />
PD-L1: LBA8, LBA31_PR, LBA32_PR, LBA38,<br />
LBA41_PR, LBA48, 16P, 17P, 18P, 73P, 74P,<br />
75P, 76P, 77P, 78P, 80P, 81P, 82P, 92P, 117P,<br />
221TiP, 327 PD, 470P, 620PD, 624P, 725PD,<br />
translational<br />
research<br />
index<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw399 | vi559
translational research index<br />
<strong>Annals</strong> Of <strong>Oncology</strong><br />
translational<br />
research<br />
index<br />
756P, 773PD, 775PD, 777PD, 784P, 786P, 824P,<br />
846TiP, 847TiP, 848TiP, 849TiP, 871P, 880P,<br />
900TiP, 921P, 940TIP, 944TiP, 947TiP, 949O,<br />
955PD, 965P, 978P, 1027P, 1049PD, 1050PD,<br />
1052PD, 1057PD, 1061P, 1066P, 1068P, 1072P,<br />
1077P, 1096P, 1102TiP, 1103TiP, 1109PD,<br />
1112PD, 1133P, 1157TiP, 1171P, 1213PD,<br />
1215PD, 1216PD, 1219PD, 1221P, 1223P,<br />
1224P, 1226P, 1237P, 1291TiP, 1294TiP,<br />
1425PD, 1431TiP, 1437PD, 1534P, 1542P, 1593<br />
PD-L2: 773PD, 900TiP, 921P, 947TiP, 1028P,<br />
1072P, 1076P, 1096P, 1182P, 1399PD<br />
PDLIM4: 1006P<br />
PDX models: 1522P, 1524P<br />
p-eEF2: 1537P<br />
pEPHA2: 1O, 15P, 1210PD<br />
pErbB3: 1562P<br />
pERK (p-ERK): 47P, 455O, 480P, 933P, 1537P<br />
pFGFR: 28P<br />
PGE2: 1085P<br />
PHD2 (prolyl hydroxylase 2): 27P<br />
phospho-4E-BP1: 1604P<br />
phospho-c-Raf: 1604P<br />
phospho-GSK-3-beta: 1604P<br />
phospho-mTOR: 1182P<br />
phospho-P70S6K: 889P, 1604P<br />
phospho-PDK1: 1604P<br />
PI3K alpha: 375P<br />
PI3K: 14P, 24P, 28P, 31P, 33P, 51P, 96P, 109P,<br />
229PD, 311TiP, 335P, 375P, 383P, 540P, 718O,<br />
785P, 889P, 897P, 902TiP, 959P, 980P, 1182P,<br />
1255P, 1274P, 1285TiP, 1539P, 1555P<br />
PI3KCA: 883P, 899P, 959P<br />
PIDD: 303P<br />
PIGF: 499P, 663P, 1405PD<br />
PIK3CA: 33P, 54P, 79P, 93P, 99P, 104P, 120P,<br />
182P, 272P, 277P, 292P, 303P, 311TiP, 313TiP,<br />
375P, 401P, 450TiP, 458O, 509P, 523P, 529P,<br />
538P, 548P, 560P, 569P, 618PD, 620PD, 659P,<br />
665P, 687P, 806P, 880P, 894P, 897P, 899P, 954O,<br />
980P, 1160P, 1212PD, 1213PD, 1235P, 1250P,<br />
1583P, 1584P<br />
PIK3R1: 897P<br />
PKA: 303P<br />
pKAP1: 382P<br />
PKCδ: 36P<br />
Plasma cell-free DNA (cf-DNA): 1288TiP<br />
pMAP: 1O<br />
pMAPK: 9P, 30P, 31P, 33P<br />
pMEK: 33P<br />
PMS2: 7P, 563P, 887P<br />
PNET4: 325O<br />
POLD1: 7P<br />
POLE: 7P, 460O, 966P<br />
POSTN: 791P<br />
PP2A: 1537P<br />
PPARG: 841P<br />
PPP1R14C: 635P<br />
PPP2CA: 1537P<br />
p-PPP2CA: 1537P<br />
PR (PgR, Progesterone receptor): LBA14_PR,<br />
103P, 105P, 145O, 165P, 174P, 180P, 189P, 190P,<br />
193P, 194P, 200P, 267P, 289P, 294P, 296P, 862P,<br />
880P, 884P<br />
pRb: 886P<br />
PRB2: 635P<br />
PRM 1: 620PD<br />
Prolactin (PRL-R): 1091P<br />
PS: LBA45, 1074P<br />
pS6: 31P, 33P, 889P<br />
p-S6K: 1537P<br />
pS6RP: 111P<br />
PSA (Prostate-specific antigen): LBA29, 405P,<br />
1085P, 1565<br />
p-SHP: 933P<br />
PSMA: 731P<br />
pSRC: 727PD<br />
pSTAT1: 1061P<br />
pSTAT3: 21P, 454O, 1061P<br />
pSTMN (phospho-Stathmin): 889P<br />
PTCH1: 541P<br />
PTEN: 54P, 96P, 131P, 383P, 418O, 450TiP, 538P,<br />
540P, 618PD, 620PD, 840P, 880P, 889P, 894P,<br />
897P, 899P, 903TiP, 924P, 954O, 980P, 1213PD,<br />
1274P, 1335P, 1525P, 1539P, 1583P, 1604P<br />
PTK7: LBA35<br />
PTPN11: 618PD<br />
PTPRk: 1550P<br />
RAD50: 107P, 287P<br />
RAD51C: 878P<br />
Raf: 130P, 383P, 522P, 980P<br />
RAF-1: 1404PD<br />
Ras (RAS): LBA20_PR, LBA21, LBA22, 3P, 9O,<br />
18P, 56PD, 90P, 96P, 99P, 383P, 459O, 461O,<br />
462PD, 466PD, 472P, 480P, 482P, 485P, 489P,<br />
493P, 494P, 499P, 501P, 521P, 522P, 525P, 526P,<br />
527P, 533P, 535P, 560P, 569P, 571P, 696P,<br />
1175P, 1271P, 1555P, 1572P<br />
Rb: LBA12, LBA15, 1351P, 1424O<br />
RB1: LBA12, LBA29, 894P, 1424O, 1558P<br />
RBMXL3: 541P<br />
RET: 2PD, 6P, 120P, 427PD, 428PD, 620PD,<br />
954O, 1203PD, 1204PD, 1212PD, 1214PD,<br />
1250P, 1264P, 1272P<br />
RET-1: 1404PD<br />
RHOA: 635P<br />
RICTOR: 897P, 1182P, 1424O<br />
RLF1-MYCL1: 1424O<br />
RNA: 4P, 16P, 45P, 96P, 128P, 303P, 369P, 575P,<br />
694P, 729PD, 980P, 1054PD, 1097P, 1164P,<br />
1182P, 1270P, 1379P, 1519O, 1529P, 1535P,<br />
1555P, 1557P, 1566P, 1580P, 1591P, 1595P<br />
RNF43: 1591P<br />
ROR1 RTK: 1533P<br />
ROR1 TKI: 1533P<br />
ROR2: 575P<br />
ROR-yt: 1180P<br />
ROS1: 121P, 122P, 138P, 897P, 1205PD, 1206PD,<br />
1210PD, 1214PD, 1250P, 1264P, 1265P, 1272P,<br />
1521PD<br />
ROS1-CD74: 1205PD<br />
ROS1-EZR: 1205PD<br />
ROS1-SLC34A2:1205PD<br />
RPRM: 303P<br />
RRM1: 87P, 620PD<br />
Rs28452734: 1584P<br />
RTL1: 1529P<br />
RXRA: 939P<br />
S100A10: 1006P<br />
S45F: 119P<br />
S6: 31P, 33P<br />
S6K: 28P, 353P, 1537P<br />
SCEL: 1006P<br />
SCG2 (Secretogranin II): 964P<br />
SCN9A: 137P<br />
SDF-1: 539P<br />
SDHC: 287P<br />
Serotonin: 422PD, 1443P<br />
Serum cystatin C (SCY): 1470P<br />
sE-Selectin: 1405PD<br />
SETD2: 806P<br />
SFN: 791P<br />
siRNA: 412TiP, 1602P<br />
SIRT1: 1576P<br />
SIRT3: 1576P<br />
SLITRK6: 780PD<br />
SLK: 1210PD<br />
Slug: 12P, 15P, 1551P<br />
SMAD2: 1102TiP, 1602P<br />
SMAD4: 7P, 401P, 458O, 523P, 620PD, 620PD,<br />
964P, 1558P, 1591P<br />
SMARCA: 419O<br />
SMARCA4: 806P<br />
SMARKCB1: 899P<br />
Smo: 8P, 10P, 13P, 26P, 281P<br />
S-mut (shared mutations): 875P<br />
SNAI1: 15P, 1182P<br />
SNAIL: 1551P, 1602P<br />
SNORD113: 1529P<br />
SNORD114: 1529P<br />
SNPs: 109P, 137P, 178P, 182P, 186P, 288P, 708TiP,<br />
808P, 920P, 981P, 996P, 997P, 1164P, 1573P,<br />
1581PD, 1584P<br />
SNVs: 1165P, 1174P<br />
SOX2: 19P, 58PD, 341P<br />
SOX8 939P<br />
SOX9: 458O<br />
SPARC: 296P<br />
SRC: 110P, 388P, 727PD, 1188P<br />
SSTR (Somatostatin receptor): 964P, 1148P<br />
STAT3: 39P, 123P, 454O, 1049PD, 1188P, 1526P,<br />
1527P<br />
STAT5: 1091P<br />
Stem cell support (ASCT; autologous stem cell<br />
support): 931P, 965P, 1009P<br />
Stem cells/stem cell factors: 19P, 34P, 41P, 297P,<br />
415TiP, 940TiP, 1405PD<br />
STK11: 96P, 897P, 1255P<br />
STST3: 16P<br />
Survivin: 46P, 58PD, 72P<br />
SWI: 879P<br />
Synd-1 (syndecan-1): 19P, 1602P<br />
TAC1: 1573P<br />
TAU: 296P<br />
T-bet: 1180P<br />
TBX21: 1425PD<br />
TCF4: 4P<br />
TERT: 109P, 344P<br />
TFE3: 1408P<br />
TGF-alpha (TGF-α): 9P, 630P<br />
TGF beta (TGF-β): 17P, 30P, 1102TiP, 1602P<br />
TGFBRII: 1056PD<br />
Thrombospondin: 1405PD<br />
Thymidylate synthase (TS, TYMS): 604TiP,<br />
1240P<br />
TIE2: 464PD, 1404PD, 1593P<br />
TIMP1: 87P, 630P<br />
TK1 (thymidine kinase 1): 564P<br />
TLE3: 620PD, 880P<br />
TMEM176A: 939P<br />
TMEM176B: 939P<br />
TMEM200B: 939P<br />
TNF-alpha (TNF-α, TNFA): 869P, 1080P, 1085P,<br />
1467P<br />
TNFSF10: 272P<br />
Toll-like receptor 8: LBA37<br />
Toll-like receptor 9 (TLR9): 1432TiP, 1601P<br />
TOP2A: 54P, 620PD, 880P<br />
Topoisomerase I (Topo1): 54P, 389P, 642P, 964P<br />
Topoisomerase IIα: 296P<br />
TORC1/2: 277P, 362PD<br />
TP53 c.[215G>C]): 1588P<br />
TP53: LBA29, 44P, 54P, 79P, 182P, 186P, 255P,<br />
292P, 379P, 401P, 428PD, 458O, 508P, 523P,<br />
vi560 | translational research index Volume 27 | Supplement 6 | October 2016
<strong>Annals</strong> Of <strong>Oncology</strong><br />
translational research index<br />
530P, 620PD, 647P, 687P, 697P, 840P, 894P,<br />
897P, 899P, 919P, 954O, 966P, 980P, 1111O,<br />
1213PD, 1335P, 1583, 1255P, 1271P, 1404PD,<br />
1424O, 1588P<br />
TP63: 19P<br />
TPMT: 981P<br />
TRAIL: 1579P<br />
TRAIL-UC-MSCs: 1579P, 1579P<br />
Transcribed Ultra Conserved Regions (T-UCRs):<br />
570P<br />
T-regulatory cells (TREGs): LBA36, 83P, 1081P,<br />
1553P<br />
TRIB3: 378P<br />
TRK: 407TiP<br />
TRKB: 701P<br />
TS: 296P, 642P, 880P, 1283P<br />
TSC1/2: 303P, 417O, 428PD, 897P, 897P<br />
TSH: 1091P<br />
TTF1: 76P<br />
TUBB3: 41P, 964P<br />
Tubulin beta 3: 296P<br />
Tumour infiltrating cells (TILs): 57PD, 77P,<br />
221TiP, 327PD, 572P, 1065P, 1073P, 1088P,<br />
1094P, 1095P, 1096P, 1097P, 1133P, 1181P,<br />
1294TiP, 1412P, 1541P, 1587P, 1589P<br />
Tumour microenvironment: 1399PD<br />
Tumour suppressor genes/proteins: 102P, 387P,<br />
560P, 854O, 1563P<br />
Tumourspheres: 1545P<br />
T-URC 160: 570P<br />
Twist: 1551P<br />
UCHL-1: 19P<br />
UGT: 1556P<br />
UGT1A: 808P<br />
UGT1A1: 279P, 376P<br />
USP28: P7<br />
VAF (variant allele frequency): 1174P<br />
Variants <strong>of</strong> unknown significance: 1166P<br />
Vascular endothelial growth factor (VEGF): 15P,<br />
46P, 303P, 308P, 361PD, 450TiP, 465PD, 534P,<br />
663P, 708TiP, 712TiP, 727PD, 804P, 810P, 824P,<br />
851TiP, 852TiP, 859PD, 869P, 870P, 920P,<br />
1035P, 1304P, 1405PD, 1501P, 1550P<br />
VDR (vitamin D receptor): 938P<br />
VEGFA (VEGF-A): 98P, 101P, 1542P<br />
VEGFC (VEGF-C): 698P, 1405PD<br />
VEGFR: LBA20_PR, 2PD, 361PD, 370P, 472P,<br />
708TiP, 732P, 775PD, 804P, 807P, 814P, 904TiP,<br />
986P, 1261P<br />
VEGFR1: 2PD, 6P, 472P, 1404PD<br />
VEGFR2 (VEGFR-2): LBA30_PR, LBA38, 2PD, 6P,<br />
373P, 464PD, 472P, 663P, 787P, 920P, 1404PD<br />
VEGFR3: 2PD, 6P, 464PD, 472P, 807P, 1404PD<br />
VHL: 287P, 418O, 428PD, 806P<br />
Vim: 1586P<br />
Vimentin: 12P, 15P, 1551P, 1562P, 1602P<br />
Vγ9+ γδ T cells: 1064P<br />
WEE1: 379P<br />
Werner syndrome protein (WRN): 42P<br />
WNT 1/3: 1534P, 1566P<br />
Wnt: 4P, 7P, 367PD, 575P, 677P, 1543P<br />
XPO1 (exportin): 383P, 854O<br />
XRCC6BP1: 7P<br />
YAP1: 1188P, 1526P, 1527P<br />
y-IFN: 1063P, 1550P<br />
YKL-40 (CHI3L1): 95P<br />
ZDHHC14: 87P<br />
ZEB1: 1562P<br />
β2GP1: LBA45<br />
translational<br />
research<br />
index<br />
Volume 27 | Supplement 6 | October 2016<br />
doi:10.1093/annonc/mdw399 | vi561
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