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H. Wilke* Eric Van Cutsem, Sang Cheul Oh, György Bodoky,

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H. Wilke* Eric Van Cutsem, Sang Cheul Oh, György Bodoky,

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  1. RAINBOW: A Global, Phase 3, Randomized, Double-Blind Trial of Ramucirumab and Paclitaxel (PTX) Versus Placebo and PTX in the Treatment of Metastatic Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma Following Disease Progression on First-Line Platinum- and Fluoropyrimidine-Containing Combination Therapy H. Wilke* Eric Van Cutsem, Sang Cheul Oh, György Bodoky, Yasuhiro Shimada, Shuichi Hironaka, Naotoshi Sugimoto, Oleg Lipatov, Tae You Kim, David Cunningham, Atsushi Ohtsu, Philippe Rougier, Michael Emig, Roberto Carlesi, Kumari Chandrawansa, Kei Muro *On behalf of the RAINBOW Investigators

  2. Conflictof Interest DisclosureConsultant or Advisory Role • Amgen • Bristol Myers • Lilly/ImClone • Merck KGaA • Roche Pharma

  3. Background • Second-line treatments confer a median overall survival of approximately 5 months in GC (including GEJC) after progression on 1st line platinum and fluoropyrimidine-based chemotherapy 1-3. New and effective treatments are needed. • Angiogenesis-linked growth factor receptors such as VEGF Receptor-2 and its ligands likely contribute to GC pathogenesis and may represent important therapeutic targets in GC 4. • RAINBOW assessed the efficacy of ramucirumab (RAM; a human IgG1 monoclonal antibody VEGF Receptor-2 antagonist) plus paclitaxel as 2nd-line treatment for GC patients. • Weekly paclitaxel was chosen based on available data indicating similar efficacy but more favorable toxicity/safety compared to other second-line agents (irinotecan; docetaxel); supported recently in a randomized study 5. (1) Thuss-Patience, EJC 2011; (2) Kang, JCO 2012; (3) Ford, Lancet Oncol 2013; (4) Clarke, Expert OpinBiolTher 2013; (5) Hironaka, JCO 2013

  4. RAINBOW: Study Design 1:1 Ramucirumab 8 mg/kg day 1&15 + Paclitaxel80 mg/m2day 1,8 &15 of a 28-day cycle N = 330 R A N D O M I Z E Treat until disease progression or intolerable toxicity • Survival and safety follow-up S C R E EN Placebo day 1&15 + Paclitaxel 80 mg/m2 day 1,8 &15 N = 335 • Important inclusion criteria: • - Metastatic or loc. adv. unresectable gastric or GEJ* adenocarcinoma • - Progression after 1st line platinum/fluoropyrimidine based chemotherapy • Stratification factors: • - Geographic region, • - Measurable vs non-measurable disease, • - Time to progression on 1st line therapy (< 6 mos vs. ≥ 6 mos) * GEJ=gastroesophageal junction; gastric and GEJ will be summarized under the term GC

  5. RAINBOW: Geographic Regions Region 1: N=398 Australia (41), Austria (6), Belgium (26), Bulgaria (12), Estonia (10), France (34 ), Germany (40), Great Britain (15), Hungary (29), Israel (30), Italy (28), Lithuania (12), Poland (33), Portugal (2), Romania (14), Russia (21), Spain (21), USA (24) Region 3: N=223 Hong Kong (3), Japan (140), Korea (45), Singapore (5), Taiwan (30) Region 2: N=44 Argentina (1), Brazil (35), Chile (4), Mexico (4) • Global: 170 study centers in 27 countries (Region 1 (18); Region 2 (4); Region 3 (5))

  6. RAINBOW: Patient Eligibility • Key Inclusion Criteria • Histologically or cytologically confirmed gastric / GEJ adenocarcinoma • Disease progression during first-line therapy or ≤ 4 mos after last dose of 1st -line therapy with any platinum/fluoropyrimidine doublet with or without an anthracycline • ECOG PS score 0-1 • Adequate hepatic, hematologic, coagulation, and renal function • Key Exclusion Criteria • No prior treatment with an anti-angiogenic agents • GI perforation and/or fistulae within 6 mos prior to randomization • Significant GI bleeding within 3 mos prior to randomization • Venous thromboembolic event within 3 mos, or arterial thromboembolic event within 6 mos prior to randomization

  7. RAINBOW: Study Endpoints • Primary endpoint • Overall survival (OS) • Secondary endpoints • Progression-free survival (PFS) • Time to progression (TTP) • Objective response rate (ORR) • Safety assessment • Quality of life (Assessed by EORTC-QLQ-C30 & EQ-5D) • Pharmacodynamic and immunogenicity profile • Pharmacokinetics

  8. RAINBOW: Statistical Considerations • Sample size • 510 events from 663 patients at 90% power, based on assumed HR=0.75 • Anticipated median OS 9.33 months (RAM + PTX), 7.0 months (Placebo [PBO] + PTX) • 665 patients were randomized (Dec2010 - Sep2012) • Data cut-off on 12 July 2013 after observation of 516 OS events; database lock occurred 05 Sept 2013 • Primary analysis • Stratified log-rank test with 2-sided α=0.05

  9. RAINBOW: Baseline Demographics & Patient Characteristics

  10. RAINBOW: Baseline Tumor Characteristics

  11. RAINBOW: Overall Survival Δ mOS = 2.3 months Censored No. at risk

  12. Forest Plot of Overall Survival by Subgroups -Stratified Analysis 0.2 0.5 1 2 a Region 1: Europe, United States, and Australia; Region 2: Brazil, Chile, Mexico, and Argentina; Region 3: Japan, South Korea, Hong Kong, Taiwan, and Singapore. Favors RAM+PTX Favors PBO+PTX

  13. RAINBOW: Post-discontinuation Treatment *Patients may have received more than one regimen. PDT = Post-discontinuation Treatment

  14. RAINBOW: Progression-free Survival & Response Rates Censored No. at risk

  15. Forest Plot of Progression-Free Survival by Subgroups - Stratified Analysis 0.2 0.5 1 2 a Region 1: Europe, United States, and Australia; Region 2: Brazil, Chile, Mexico, and Argentina; Region 3: Japan, South Korea, Hong Kong, Taiwan, and Singapore. Favors RAM+PTX Favors PBO+PTX

  16. RAINBOW: Efficacy by Geographic Region *Accrual: Asia n=223; EU/NA/AUS n=398; Central / South America n=44

  17. Treatment-Emergent Adverse Events Occurring in ≥ 20% of Patients and ≥ 5% Higher in the RAM + PTX Arm †Consolidated AE terms are comprised of synonymous MedDRA preferred terms: fatigue includes asthenia; neutropenia includes neutrophil count decreased; neuropathy includes peripheral sensory neuropathy; paraesthesia; neuropathy peripheral, polyneuropathy; hypoasethesia, neuralgia, dysaesthesia; abdominal pain includes abdominal pain upper and abdominal pain lower; leukopenia includes white blood cell decreased; hypertension includes blood pressure increased, hypertensive cardiomyopathy, procedural hypertension, systolic hypertension.

  18. Adverse Events of Special Interest †Each AESI category is comprised of consolidated synonymous MeDRA preferred terms.

  19. Safety Summary • Treatment-emergent adverse events grade ≥ 3 occurred at a greater frequency in the RAM + PTX arm (82% vs 63%): • Grade ≥3 TEAEs occurring in more than 10% of patients and at a higher incidence in the ram + PTX arm were neutropenia, leukopenia, hypertension, and fatigue. • Neutropenia Grade 3 (22% vs 16%) and 4 (19% vs 3%) were reported with a higher incidence in the RAM + PTX arm. • The incidence of febrile neutropenia was low and similar in both treatment arms: RAM + PTX 3.1% vs PBO + PTX 2.4%. • The incidence of deaths on study due to AEs determined by investigator as the primary cause of death was similar between arms: RAM + PTX 4.0% vs PBO + PTX 4.6%.

  20. Efficacy Summary A consistent additive effect of RAM in combination with paclitaxel was observed across all efficacy endpoints

  21. RAINBOW: Results and Conclusions • RAINBOW met the primary endpoint • RAM + PTX conferred a statistically significant and clinically meaningful OS benefit of > 2 months (median); risk reduction of death by 19% • Significant benefits in PFS and ORR were observed • RAINBOW and the recently published REGARD trial demonstrate that ramucirumab is an effective new drug for the treatment of patients with metastatic or locally advanced unresectable gastric and GEJ cancer after prior chemotherapy • This largest gastric cancer 2nd line trial clearly underlines that effective second line therapy improves survival of patients with metastatic or locally advanced unresectable gastric cancer

  22. Acknowledgements We thank the patients and their caregivers for participating in this trial. We thank the investigators and their support staff who generously participated in this work.

  23. Japan YoshitoKomatsu Etsuko Warita Hirofumi Fujii Toshihiko Doi KenseiYamaguchi Ken Shimada Shuichi Hironaka Yasuhiro Shimada Yasushi Omuro Hirofumi Yasui KeiMuro Naotoshi Sugimoto FumioNagashima Masahiro Gotoh Shinya Ueda KazumasaFujitani TomohiroNishina Sojiro Morita TaitoEsaki Yoshinori Hirashima Romania MihaiVoiculescu Cornelia Toganel ConstantinVolovat DumitruFilip Belgium VeerleMoons Jean-Luc van Laethem Alain Hendlisz JorisArts Eric Van Cutsem Marc Peeters Estonia TiitSuuroja Australia Winston Liauw VinodGanju Walter CosoloLara Lipton DusanKotasek Ray AsghariWengNg Marco Matos Philip Clingan SumitraAnanda Hong Kong Kent Man Chu Sing Hung Lo Hungary JuditKocsis Dank Magdolna JózsefCseh BélaPiko LászlóMangel György Bodoky BalázsPécsi Russia Irina Davidenko Oleg Lipatov Sergey Tjulandin Sergey Orlov France Jean Francois Seitz Marian Gil Delgado Christophe Borg Jean Marc Phelip EmanuelleSamalin Denis Pezet Jean Marc Gornet Philippe Rougier Jean-Philippe Metges Argentina Guillermo Lerzo Spain Carlos GarcíaGirón HerminiManzano CarlesPericay José Alés David Vicente Maria Limón Mirón EncarnaciónJiménez Antonio Sánchez José López Martín Austria HellmutSamonigg ReinhardZiebermayr Israel Ayala Hubert Alexander Beny Alexander Gluzman RavitGeva Dan Aderka Natalya Karminsky Baruch Brenner Brazil Giuliano Borges Luis AntônioPires Renata Garcia Marcelo Tanaka Alberto Nogueira Rodrigo Guimarães Roberto Rocha Leonardo Lobato Fernando Vieira Gustavo Girotto GuilhermeLuizPereira Leandro Brust Luis Schlittler Gilberto Schwartsmann Fabio Franke Germany SeverinDaum MeinholfKarthaus Jens Siveke Florian Weissinger Stefan Zeuzem HansjochenWilke Gunnar Folprecht Hans-Georg Kopp VolkmarBoehme Stefan Kasper CarstenGrüllich Markus Möhler Friedrich Overkamp BurkhardSchmidt Salah-eddinAl-batran Peter Thuss-Patience Taiwan Chia-Jui Yen Yee Chao Chang-Fang Chiu Yen-Yang Chen Cheng-Shyong Chang Chien-Liang Lin Poland Jerzy Tujakowski Maria Blasinska-Morawiec DariuszSawka ElzbietaStaroslawska Tomasz Sarosiek ZbigniewNowecki ElzbietaWojcik Italy DavidePastorelli Roberto Bordonaro Gabriella Farina Stefano Cascinu LiberoCiuffreda Alfredo Falcone Alberto Sobrero Nicola Silvestris United States BasselEl-Rayes Edward Lin Zev Wainberg Troy Guthrie Yehuda Patt Andrew Ko Gabriel Domenech JitendraGandhi Peter Rosen JafferAjani Portugal Margarida Damasceno Nuno Bonito Paula Ferreira Korea Sang Cheul Oh Hoon-KyoKim KeunWookLee Dong Bok Shin SeokYun Kang Bulgaria Galina Kurteva ViolinaTaskova Singapore Peter Cher Siang Ang Akhil Chopra Chile Pamela Boghikian Eugenia Loredo Great Britain Gary Middleton David Cunningham David Ferry Lithuania AlvydasCesas AudriusIvanauskas Mexico F. Gutierrez-Delgado Estonia KristiinaOjamaa

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