Attending Physician, Member Memorial Sloan-Kettering Cancer Center Management of Metastatic Esophagogastric Cancer: Novel Biologic + / - Chemo David H. Ilson, M.D., Ph.D. Attending Physician, Member Memorial Sloan-Kettering Cancer Center New York, NY

Advanced Esophagogastric Cancer Chemotherapy: What Regimen to Use? Oxali: EOX or EOF Cape: ECX or EOX XP FLO FOLFIRI FUFIRI S-1 Cis DCF ECF Pts 489 513 160 109 209 170 305 221 126 %RR 44% 45% 41% 34% 39% 32% 54% 36% TTP, months 6.7 6.5 5.6 5.5 5.3 5.0 6.0 7.4 OS, months 10.9 10.4 10.5 10.7 9.5 9.0 13.0 9.2 8.9 Cunningham NEJM 358:36;2008, Kang Annals Oncol 20:666;2009, Al-Batran JCO 26:1435;2008, Dank Annals Oncol 19:450;2008 Koizumi Lancet Oncol 9:215;2008, Van Cutsem JCO 24:4991;2006, Webb JCO 15:61;1997

Second Line Chemo Gastric Cancer Phase III Trials  Improved Survival Docetaxel vs BSC Docetaxel or Irinotecan vs Paclitaxel vs Irinotecan Patients 84 133 69 111 112 RR % 7% -- 11% 8% 21% 14% PFS 12.2 wks NS 3.6 mo 2.3 mo OS 5.2 mo 5.3 mo (5.2-6.5) 3.8 mo 9.5 mo 8.4 mo Significance HR 0.67 P = 0.01 HR 0.657 P = 0.007 Ford H Lancet Oncol 15:78; 2014; Kang JH J Clin Oncol 30:1513; 2012 Hironaka JCO 31: 4438; 2013

Second Line Chemo Gastric Cancer Phase III Trials  Improved Survival Docetaxel/Irinotecan vs BSC Docetaxel vs BSC Ford H Lancet Oncol 15:78; 2014; Kang JH J Clin Oncol 30:1513; 2012

FIRST LINE SECOND LINE THIRD LINE

VEGFr2: Ramucirumab in Gastric Cancer: REGARD Trial Gastric/GEJ Cancer with POD on FU or Platinum Based Chemo RANDOMIZATION, 355 patients BSC + Placebo BSC + Ramucirumab 8 mg/kg q 2 weeks Fuchs CS, et al. Lancet. 2014;383(9911):31-39

Time Since Randomization, Months Time Since Randomization, Months REGARD Trial: Results OS PFS 20 HR (95% CI) = 0.483 (0.376-0.620) Log-rank P value (stratified) <.0001 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 40 60 80 100 PFS, % 238 117 Number at risk Ramucirumab Placebo 213 92 113 27 65 61 45 30 18 Time Since Randomization, Months Ramucirumab (n = 238) Placebo (n = 117) Censored 27 HR (95% CI) = 0.776 (0.603-0.998) Log-rank P value (stratified) =.047 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 26 28 40 60 80 100 OS, % 238 117 Number at risk Ramucirumab Placebo 154 66 92 34 49 Ramucirumab (n = 238) Placebo (n = 117) Censored Time Since Randomization, Months Fuchs CS, et al. Lancet. 2014;383(9911):31-39.

Median OS in Randomized Second-Line Gastric Cancer Studies Presented/Published in 2009-2013 Ramucirumab vs PBO (BSC) (N = 355) 5.2 3.8 Docetaxel vs ASC (N = 131) 5.2 3.6 Docetaxel or Irinotecan vs BSC (N = 202) 5.3 Irinotecan vs BSC (N = 40) Ford HER, et al. The Lancet Oncology. 2014;15(1):78-86. Kang JH, et al. J Clin Oncol. 2012;30(13):1513-1518. Thuss-Patience PC, et al. Eur J Cancer. 2011;47(15):2306-2314.

VEGFr2: RAINBOW: Second Line 1:1 Ramucirumab 8 mg/kg day 1&15 + Paclitaxel 80 mg/m2 day 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) Wilke GI Symposium 2014 LBA 7

Comprehensive Molecular Characterization The Cancer Genome Atlas Research Network, Nature. 2014;513(7517):202-209.

(cytokines, lysis, proliferation, migration to tumor) Blocking CTLA-4 and PD-1 Tumor Microenvironment Activation (cytokines, lysis, proliferation, migration to tumor) TCR TCR MHC MHC + + + + + + Dendritic cell B7 CD28 Tumor cell + + + T cell T cell B7 - - - PD-1 PD-L1 CTLA-4 - - - anti-PD-1 anti-CTLA-4 PD-1 PD-L2 - - - anti-PD-1 CTLA-4 Blockade (ipilimumab) PD-1 Blockade (nivolumab) Highly Confidential

Trials of Targeted Agents Second Line Regimen Number Status mTOR Everolimus AIOST00111 Pac + / - Evero 665 Ongoing HER2 TDM-1 GATSBY Pac vs TDM-1 412 Completed MM-111 NCT01774851 Pac + Tras + MM 120 Afatinib NCT01522768 Trastuz + Afat 40 NCT02274012 Pac + Afat 36 MET AMG337 NCT02016534 AMB337 140 EGFr Nimotuzumab NCT01813253 Irino + / - Nimo 400 PARP Olaparib NCT01924533 Pac + / - Olap FGFr Nindetanib NCT PDL-1 Pembrolizumab KEYNOTE 59 Pembro monotherapy 270 FRFr2 Dovitinib NCT01719549 Dovit (FGFR2 amplified) 31 FGFr2 NCT01921673 Doce + Dovit 59

Esophagogastric Cancer: Novel Biologic Second Line + / - Chemo Modest improvements with doce/paclitaxel or irinotecan vs BSC Expected toxicities of chemotherapy Targeted therapies VEGFR2 now a validated target Ramucirumab achieves similar PFS and OS benefits as chemo Less toxicity Targeted agent + Chemo Ramucirumb plus paclitaxel enhances RR, PFS, and OS New care standard for second line therapy Minimal increase in toxicity (HTN, neutropenia) Future directions Ongoing trials in HER2 + Evaluation of immunotherapy