Immunotherapy in GI cancers

Immunotherapy in GI cancers Julien TAIEB Sorbonne Paris Cité Hopital Européen Georges Pompidou Inserm U97 J Taieb ESDO Leuven 217

How to progress in GI cancer treatment Better define subgroups With different prognostic and different treatments Find predictive markers for precision medecine Combine different targeted agents in accordance with the molecular profile of the patients tumor Induce an efficient immune response from the host against the tumor J Taieb ESDO Leuven 217

Immunité innée et adaptative Innée : - Rapide - Non spécifique Adaptative : - Plus lente - Spécifique

Immunité anti-tumorale Lyse antigens Immature DC mature DC TUMOR Peptide / MHC I Peptide / MHC II CD8 + T Lymphocyte CD4 + T Lymphocyte Terme, Taieb et al. Immunooncology 214

Major immunotherapeutic approaches Adoptive transfer Anti-cancer vaccines Checkpoint blockade J Taieb ESDO Leuven 217

Anti-CEA T cell transfer CEA decrease (maximum decline 74 99% vs baseline) Radiological response Inflammatory colitis 1. Parkhurst MR, et al. Mol Ther 211;19:62 626. J Taieb ESDO Leuven 217

Immune check points Mellman I et al., Science, 211 J Taieb ESDO Leuven 217

Immune check points Activate The activators Inhibit The inhibitors Mellman I et al., Science, 211 J Taieb ESDO Leuven 217

Immune check points. T cell regulation T cell function Pardoll DM et al., Nat Rev Cancer, 212 J Taieb ESDO Leuven 217

In 217, Efficacy in phase III Anti-CTLA4 (Ipilimumab, tremelumumab) Anti-PD(L)1 (Nivolumab, Pembro, Atezolizumab, avelumab, darvalumab ) Melanoma M+ (L1, L2) Adjuvant (st III) Ovarian 15% TNBC 2% Mel 3-4% NSCLC 15-2% SCLC 15% Melanoma M+ (L1, L2) Nivo +Ipili +++ Melanoma M+ and Lung M+ (L1 & L2) Lung M+ (L2) Nivo/Atezolizumab Kidney M+ (L2) Nivolumab Squamous Cell Cancer of the Head and Neck (L2). Nivolumab MSI High CRC 6% PD1/PD-L1 Blockade reported ORR RCC 15-2% Hodgkin 65-85% HCC 2% Gastric 2% HNSCC 15-25% Bladder 25% Bladder (phase 2: Atezolizumab)

Colon cancer

Change From Baseline in Tumor Size, % 1 Melanoma 1 1 NSCLC 2 1 H&N3 Urothelial 4 TNBC5 1 1 1 Gastric 6 1 chl 7-1 -1-1 -1-1 -1-1 1 NHL PMBCL 8 Mesothelioma 9 1 1 Ovarian 1 1 SCLC 11 1 Esophageal 12 1 NPC 13 1 Anal 14-1 -1-1 -1-1 -1-1 1 Biliary Tract 15 1 Colorectal 16 1 ER + /HER2 BC 17 Cervical 18 Thyroid 19 Salivary 2 1 1 1-1 -1-1 -1-1 -1

J Taieb ESDO Leuven 217

Checkpoint blockers Efficacy signal in MSI-H colorectal cancer Treatment with pembrolizumab (anti-pd-1 antibody) (n=11 mismatch repair-deficient CRC, n=21 mismatch-repair proficient CRC, n=9 mismatch-repair deficient non-crc) Radiographic responses* OS in CRC Immune-related ORR in mismatch-repair deficient vs proficient CRC: 4% vs % Adjusted OS HR for mismatch-repair deficient vs proficient CRC:.18, P =.5 *RECIST-based radiographic response **Adjusted for elapsed time since the initial diagnosis Le DT, et al. N Engl J Med. 215;372(26):259-252 J Taieb ESDO Leuven 217

Response to Pembrolizumab for MSI-H/dMMR 11 patients achieved a CR and were taken off therapy after 2 years of treatment. No evidence of cancer PD has been observed in those patients with a median time off therapy of 8.3 months. Le DT, Science 217

Pembrolizumab for MSI-H/dMMR CRC and Non-CRC Best response MSI-H CRC N = 61 a MSI-H Non-CRC N = 77 b n % (95% CI) n % (95% CI) ORR (95% CI), % 17 28% (17-41) 29 38% (27-49) Complete response 2 3% (-9) Partial response 17 28% (17-41) 27 35% (25-47) Stable disease 14 23% (13-36) 16 21% (12-32) Progressive disease 28 46% (33-59) 24 31% (21-43) DCR (CR+PR+SD) 31 51% (38-64) 45 58% (47-7) Median duration of response (range), months c Not reached (2.9+ to 12.5+) Not reached (2.4+ to 9.2+) Median time to response (range), months 4. (2-1) 2.1 (1-4) Diaz LA, ASCO 217, J Clin Oncol 35l(suppl 15), 3618 J Taieb ESDO Leuven 217

ASCO update Keynote 16 Tolerability : Rash prurit 25% Diarrhea/Colitis 11% Arthralgia 15% Thyroïditis/Hypothyroïdia 11%, Fatigue 9% grade 3-4 toxicities : 14% including pancreatitis 4% and diarrhea /colitis / thrombocytopenia / leucopenia /anemia in 2% each Efficacy : MSI : RR 28% with 11%CR ; DCR 51% MSS : RR % ; DCR 16% KEYNOTE 164 is ongoing in MSI-H (phase II, 12 pretreated pts) Le DT et al., ASCO 216, CSS 13 J Taieb ESDO Leuven 217

May 23, 217 FDA GRANTS ACCELERATED APPROVAL TO PEMBROLIZUMAB FOR FIRST TISSUE/SITE-AGNOSTIC INDICATION Adult and pediatric patients with unresectable or metastatic, MSI-H or dmmr solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options or with MSI-H or dmmr colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan Non MSI GI cancer will be treatable by anti-pd1 in the future => MSI testing has to be performed in daily practice J Taieb ESDO Leuven 217

Phase 2 CheckMate 142 Study Design: MSI-H Cohort MSI-H mstage 1 Responses a mstage 2 7/19 Nivo 3 mg/kg (Q2W) Second-line colon MSI-H 1 prior treatment for metastatic disease 1 target lesion ECOG PS of -1 Nivo 3 mg/kg (Q2W) Responses a 3 6/19 cstage 1 Nivo 3 mg/kg + Ipi 1 mg/kg (Q3W x 4 doses) Then Nivo 3 mg/kg (Q2W) Responses a 7/19 cstage 2 b Nivo 3 mg/kg + Ipi 1 mg/kg (Q3W x 4 doses) Then Nivo 3 mg/kg (Q2W) a In patients with centrally confirmed MSI-H status b Currently enrolling cstage 1 = combination therapy stage 1; cstage 2 = combination therapy stage 2; Ipi = ipilimumab; mstage 1 = monotherapy stage 1; mstage 2 = monotherapy stage 2; Nivo = nivolumab; Q2W = every 2 weeks; Q3W = every 3 weeks 19 J Taieb ESDO Leuven 217

Patient Demographics and Disease Characteristics Overman M, Lancet Oncol 217

Overall Response and Disease Control CheckMate 142 Nivolumab alone Median time to response is 2,8 (1,4-3,2) Only 3 patients with ORR experiencing progression Median duration of response are not yet reached and are responder are alive at the time of analysis Overman M, Lancet Oncol 217

Changes in Tumor Burden CheckMate 142 Nivolumab alone Median TTR: 2.8 (1.1 14.) months Median DOR: not reached 85% (39/46) of responses ongoing Tt discontinuations 38 pts( 51%) : 27 (36%) for PD 6 (8%) Toxicity 5 (7%) other Overman M, Lancet Oncol 217

Progression-Free Survival Median PFS, mo 14,3 months PFS rate, % (95% CI) 12 months 5 % (38, 61) CheckMate 142 Nivolumab alone Overall Survival Median OS, mo (95% CI) OS rate, % (95% CI) NR (18, NE) 12 months 73% (62, 82) 36 investigator assessed PD 23 death/74 patients Median Follow up 12 months Overman M, Lancet Oncol 217

Investigator-assessed ORR and disease control (n=74) CheckMate 142 Nivolumab alone Overman M, Lancet Oncol 217

Safety Summary CheckMate 142 Nivolumab alone dmmr/msi-h per Local Assessment (N = 74) a Patients, n (%) Grade 1 or 2 Grade 3 or 4 Any Event 36 (49%) 15 (21%) TRAE reported in 1% of patients Fatigue Diarrhea Pruritus Hypothyroidism Lipase increased Rash Colitis Adrenal insufficiency Increase ASAT/ALAT 16 (22.%) 15 (2%) 1 (14%) 7 (1%) 3 (4%) 8 (11%) 5 (7%) 1 (1%) 1 (1%) 6 (8%) 1 (1%) 1(%) 1 (1%). Overman M, Lancet Oncol 217

Conclusions CheckMate 142: nivolumab alone Nivolumab monotherapy provided durable responses and disease control in patients with dmmr/msi-h CRC Responses and disease control were observed regardless of tumor PD-L1 expression, BRAF or KRAS mutation status, or a clinical history of Lynch syndrome Patient-reported outcome analyses showed clinically meaningful improvements in functioning, symptoms, and QOL Patients who continued treatment for 19 weeks attained a level of health that would be considered as equal to or exceeding the general health of many populations Nivolumab was well tolerated with no new safety signals observed These results suggest that nivolumab could be considered a new standard of care for patients with dmmr/msi-h CRC and warrants further investigation in patients with other dmmr/msi-h tumors Overman M, Lancet Oncol 217

FDA grants nivolumab accelerated approval for MSI-H or dmmr colorectal cancer On July 31, 217, the U.S. Food and Drug Administration granted accelerated approval to nivolumab (OPDIVO, Bristol-Myers Squibb Company) for the treatment of patients 12 years and older with mismatch repair deficient (dmmr) and microsatellite instability high (MSI-H) metastatic colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. The approval was based on data from Study CA29142 (CHECKMATE 142; NCT 26188)

Combination of nivolumab (NIVO) + ipilimumab (IPI) in the treatment of patients (pts) with deficient DNA mismatch repair (dmmr)/high microsatellite instability (MSI-H) metastatic colorectal cancer (mcrc): CheckMate 142 Study André T et al; ASCO 217; abst 3531

Study Design: CheckMate 142 Study Patients Stage 1 Stage 2 Histologically confirmed metastatic/ recurrent CRC MONOTHERAPY ARM NIVO 3 mg/kg Q2W If 7/19 confirmed responders, continue enrollment NIVO 3 mg/kg Q2W n = 74 pts dmmr/msi-h per local laboratory 1 prior line of therapy COMBINATION ARM NIVO 3 mg/kg + IPI 1 mg/kg Q3W (4 doses and then NIVO 3 mg/kg Q2W) If 7/19 confirmed responders, continue enrollment NIVO 3 mg/kg + IPI 1 mg/kg Q3W (4 doses and then NIVO 3 mg/kg Q2W) n = 84 pts Primary endpoint: ORR per investigator assessment (RECIST v1.1) Current analysis included all patients (n=84) who received their first dose 6 months prior to the data cut-off Median (range) time from first dose to data cut-off: 8.6 (6.3 19.4) months André T et al; ASCO 217, Abst 3531

Patient Demographics and Disease Characteristics CheckMate 142 Study: nivolumab + ipilimumab Age Median (range), years < 65 years, n (%) ECOG performance status, n (%) 1 dmmr/msi-h (n = 84) 57 (21-81) 61 (73) 31 (37) 53 (63) Mutation status, n (%) BRAF/KRAS wild type BRAF mutated KRAS mutated Prior lines of therapy, n (%) 1 2 3 4 22 (26) 21 (25) 3 (36) 1 (1) 17 (2) 31 (37) 23 (27) 12(14) Prior radiotherapy, n (%) 17 (2) André T et al; ASCO 217, Abst 3531

Overall Response and Disease Control: CheckMate 142 Study: nivolumab + ipilimumab ORR, n (%) [95% CI] Best overall response, n (%) CR PR SD PD ND/reported NIVO + IPI (n = 84) Investigator- Assessed 46 (55) [43.5, 65.7] 2 (2) 44 (52) 26 (31) 9 (11) 3 (4) NIVO Monotherapy 1 (n = 74) Investigator-Assessed 23 (31) [2.8, 42.9] 23 (31) 29 (39) 18 (24) 4 (5) Disease control for 12 weeks, n (%) a 66 (79) 51 (69) a Patients with CR, PR, or SD for 12 weeks André T et al; ASCO 217, Abst 3531 Overman M, Lancet Oncol 217

Best Reduction From Baseline in Target Lesion (%) Best Reduction From Baseline in Target Lesion (%) Best Change in Target Lesion Size NIVO + IPI (n = 84) NIVO Monotherapy 1 (n = 74) 8% of patients had reduction in tumor burden from baseline 62% of patients had reduction in tumor burden from baseline 1 1 75 75 5 5 25 25-25 -25-5 -5-75 -75-1 Confirmed CR or PR per investigator % Change truncated at 1 André T et al; ASCO 217, Abst 3531 Overman M, Lancet Oncol 217-1

Best reduction from baseline in target lesion (%) Results Figure 2. Association of best reduction in target lesion size (B) BRAF and KRAS mutation status in patients with dmmr/msi-h mcrc treated with NIVO + IPI B 1 8 6 4 2 2 4 6 8 1 KRAS/BRAF wild type BRAF mutation KRAS mutation Unknown 34

Best reduction from baseline in target lesion (%) Results Figure 2. Association of best reduction in target lesion size with (C) Lynch syndrome in patients with dmmr/msi-h mcrc treated with NIVO + IPI C 1 8 6 4 2 2 4 6 8 1 Lynch syndrome (Yes) Lynch syndrome (No) Unknown 35

Change in target lesion from baseline, (%) Changes in Tumor Burden CheckMate 142 Study: nivolumab + ipilimumab 1 75 5 Median TTR: 2.8 (1.1 14.) months Median DOR: not reached 85% (39/46) of responses ongoing On treatment CR or PR 1 st occurrence of new lesion 25-25 -5-75 -1 6 12 18 24 3 36 42 48 54 6 66 72 78 84 9 Time since start of treatment (week) André T et al; ASCO 217, Abst 3531 Overman M, Lancet Oncol 217

Probability of Progression-Free Survival Progression-Free Survival CheckMate 142 Study: nivolumab + ipilimumab 1..9.8.6.5.4.3.2 Median PFS, mo (95% CI) NR (11.5, NE) PFS rate, % (95% CI) 6 months 77 (66.5, 85.1) 9 months 77 (66.5, 85.1).1. 3 6 9 Time (months) 12 15 18 21 No. at Risk 84 65 35 17 13 8 1 NE = not estimable; NR = not reached André T et al; ASCO 217, Abst 3531

Probability of Survival Overall Survival CheckMate 142 Study: nivolumab + ipilimumab 1..9.8.7.6.5.4.3.2.1 Median OS, mo (95% CI) NR (NE, NE) OS rate, % (95% CI) 6 months 89 (8.2, 94.2) 9 months 88 (78.1, 93.1). 3 6 9 12 15 18 21 Time (months) No. at Risk NE = not estimable; NR = not reached 84 77 73 4 22 19 13 André T et al; ASCO 217, Abst 3531

Event, n (%) Checkmate 142 Treatment-Related Adverse Events in 15% of Patients With MSI-H Nivolumab 3 mg/kg (n = 7) Nivolumab 3 mg/kg + Ipilimumab 1 mg/kg (n = 3) Any grade Grade 3 4 Any grade Grade 3 4 Any event 41 (58.6) a 1 (14.3) 25 (83.3) 8 (26.7) Fatigue 13 (18.6) 1 (1.4) 6 (2.) Diarrhea 1 (14.3) 1 (1.4) 13 (43.3) Pruritus 8 (11.4) 5 (16.7) 1 (3.3) Nausea 5 (7.1) 6 (2.) Pyrexia 3 (4.3) 7 (23.3) Any event leading to discontinuation 4 (5.7) 2 (2.9) 4 (13.3) 4 (13.3) a One Grade 5 event of sudden death J Taieb ESDO Leuven 217 39

Safety Check Mate 142 Study: nivolumab + ipilimumab No treatment-related deaths were reported NIVO + IPI (n = 84) Patients, n (%) Any Grade Grade 3 or 4 Any TRAE 57 (68) 24 (29) Serious TRAEs 15 (18) 14 (17) Discontinuation due to TRAEs 11 (13) 8 (9) TRAEs reported in 1% of patients Diarrhea 2 (24) 1 (1) Fatigue 14 (17) 1 (1) Aspartate aminotransferase increase 14 (17) 8 (9) Pyrexia 13 (16) Pruritus 13 (16) 2 (2) Alanine aminotransferase increase 12 (14) 7 (8) Nausea 12 (14) Hyperthyroidism 11 (13) Hypothyroidism 11 (13) André T et al; ASCO 217, Abst 3531

Conclusions Check Mate 142 Study: nivolumab + ipilimumab NIVO + IPI provided durable responses, sustained disease control, and encouraging survival data in pretreated patients with dmmr/msi-h mcrc ORR of 55%, with 79% of patients achieving disease control for 12 weeks 85% of responses ongoing, and the median DOR was not yet reached 88% of patients alive at 9 months, 77% without progression NIVO + IPI demonstrated a manageable safety profile; 29% of patients had grade 3/4 TRAEs This trial is ongoing and patients will continue to be followed for survival 41 patients in this study were treated in St Antoine hospital and translational research are planned (we have primary and metastatic tissue for all) A French study will began in Septempter 217 (GERCOR group) with nivolumab and ipilumumab (55 patients) in the same population and we will collect archival tissue for all patients

dmmr/ MSI-H COL-11 Reproduced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Colon Cancer V.2.217. 217 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines and illustrations herein may not be reproduced in any form for any purpose without the express written permission of NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. The NCCN Guidelines are a work in progress that may be refined as often as new significant data becomes available. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

Summary of Efficacy in Patients With MSS Nivolumab ± Ipilimumab in Metastatic CRC Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg (n = 1) Nivolumab 3 mg/kg + Ipilimumab 1 mg/kg (n = 1) ORR, n (%) 1 (1) Median PFS, mo (95% CI) 2.28 (.62, 4.4) 1.31 (.89, 1.71) Median OS, mo (95% CI) 11.53 (.62, NE) 3.73 (1.22, 5.62) vs NR OS and 14 PFS in MSI-H pts treated with nivolumab alone vs median not reached in MSI-H pts treated with the combo NE = not estimable 43

Change in sum of longest diameters from baseline, % Phase Ib: Atezolizumab + cobimetinib in MSS pretreated mcrc Tolerability : No DLT, Diarrhea : 7%, rash: 4%, Fatigue : 52% Grade 3-4 toxicities : 34% incl. diarrhea : 9% Efficacy : Response 17% (4 OR, 5 SD) : 3 MSS/1 statut MSI ukn, 4 to 7 mo 1 9 8 7 6 5 4 3 2 1-1 -2-3 -4-5 -6-7 -8-9 -1 Tumor Biopsy : no correlation with PDL1 at D 1 2 3 4 5 6 7 8 9 1 11 12 13 14 15 16 17 18 19 2 21 22 23 Time on study (mo) PD SD PR/CR Discontinued atazolizumab New lesion Bendell JVC. et al., ASCO 216, OS 352

Conclusion Trials are ongoing in mcrc and in the adjuvant setting (soon) Colon cancer probably less easy than others MSI-H tumors : a good target Others may be: PolE, PolD, MSS with immune infiltrates Combination with targeted agents: + chemotherapy, sequence? + radiotherapy? + targeted agents: anti-angiogenics; MEK? J Taieb ESDO Leuven 217

After ASCO: even more trials for colorectal cancer Anti-CTLA-4 or anti-pd-1 or anti-pd-l1 Ipilimumab (BMS): anti-ctla-4 Nivolumab (ONO/BMS): anti-pd-1 Pembrolizumab (MSD): anti-pd-1 Perioperative First-line Second-line KEYNOTE-177 Ph III Pembro vs CT MSI-H Third-line + refractory to standard Durvalumab (AZ): anti-pd-l1 Atezolizumab (Roche): anti-pd-l1 Phase III Adjuvant NCI FOLFOX 6 m +/- atezo 1y MSI-H Ph III FOLFOX+B Vs Atezo Vs Atezo+FOLFOX+B MSI-H Phase III Atezo+ cobimetinib vs Atezo vs regorafenib MSS Avelumab (Merck/Pfizer) anti-pd-l1 SAMCO R Phase II Avelumab vs CT MSI-H 1. Study designs available at: www.clinicaltrials.gov (accessed September 217). Agents have not yet received EMA approval for treatment of indication listed

Gastric cancer

Cumulative survival Rationale for immuno-oncology in GC Pathology of GC associated with immune system evasion PD-L1 in gastric carcinoma 5 Immunosuppressive proteins expressed on immune cells in patients with GC patients, including key checkpoint inhibitors: 1 4 Cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) PD-1 1..8.6.4 PD-L1 Negative (n=65).2 PD-L1 Positive (n=67). 24 48 72 96 12 144 168 Overall survival 1. Kim JW et al. Gastric Cancer 216;19:42 2; 2. Böger C et al. Oncotarget 216;7:24269 83; 3. Saito H et al. J Surg Oncol 213;17:517 22; 4. Takano S et al. Surg Today 216;46:1341 7; 5. Zhang L et al. Int J Clin Exp Pathol. 215;8:1184 91.

Study Design and Endpoints Key eligibility criteria: Age 2 years Unresectable advanced or recurrent gastric or gastroesophageal junction cancer Histologically confirmed adenocarcinoma Prior treatment with 2 regimens and refractory to/intolerant of standard therapy ECOG PS of or 1 R 2:1 Stratification based on: Nivolumab 3 mg/kg IV Q2W Country (Japan vs Korea vs Taiwan) ECOG PS ( vs 1) Number of organs with metastases (< 2 vs 2) Primary endpoint: OS Secondary endpoints: Efficacy (PFS, BOR, ORR, TTR, DOR, DCR) Safety Exploratory endpoint: Biomarkers Placebo Patients were permitted to continue treatment beyond initial RECIST v1.1 defined disease progression, as assessed by the investigator, if receiving clinical benefit and tolerating study drug BOR, best overall response; DCR, disease control rate; DOR, duration of response; ECOG PS, Eastern Cooperative Oncology Group performance status; IV; intravenous; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; Q2W, every 2 weeks; R, randomization; RECIST, Response Evaluation Criteria In Solid Tumors; TTR, time to tumor response. ASCO GI 217 Kang et al. ASCO GI 217 49

Probability of Survival (%) Overall Survival 1 9 8 7 6 5 4 3 2 1 Patients, n Events, n Median OS [95% CI], months Hazard ratio,.63 (95% CI,.5.78) P <.1 12-Month OS Rate [95% CI], % Nivolumab 33 225 5.32 [4.63 6.41] 26.6 [21.1 32.4] Placebo 163 141 4.14 [3.42 4.86] 1.9 [6.2 17.] 2 4 6 8 1 12 14 16 18 2 22 At risk: Time (months) Nivolumab 33 275 193 142 95 57 39 19 1 5 3 Placebo 163 121 82 53 32 16 1 4 3 3 1 ASCO GI 217 Kang et al. ASCO GI 217 5

Overall Survival by Subgroup Subgroup Hazard Ratio [95% CI] All.64 [.52.8] Country Japan Korea Taiwan Age, years < 65 65 Sex Male Female ECOG PS 1 Prior gastrectomy No Yes Primary sites Gastric (fundus, corpus, antrum, and pylorus) Gastroesophageal junction Unknown.63 [.46.85].7 [.51.96].46 [.23.92].75 [.57.98].53 [.38.74].58 [.45.75].83 [.56 1.23].59 [.4.87].67 [.52.86].69 [.49.98].6 [.46.79].69 [.55.87].44 [.2.97].52 [.26 1.6] Subgroup Histological type (Lauren classification) Intestinal type Diffuse type Mixed Unknown Number of organs with metastasis < 2 2 Peritoneal metastasis No Yes Liver metastasis No Yes Measurable lesion No Yes Number of previous regimens 2 3 4 Hazard Ratio [95% CI].59 [.41.85].82 [.57 1.17].37 [.13 1.4].56 [.37.84].7 [.46 1.8].61 [.48.78].63 [.5.81].74 [.48 1.15].63 [.5.8].67 [.42 1.7].7 [.43 1.14].63 [.5.8].82 [.5 1.35].87 [.61 1.22].44 [.31.61] 1 2 3 Favors nivolumab Favors placebo Hazard ratio [95% CI] 1 2 3 Favors nivolumab Favors placebo Hazard ratio [95% CI] ASCO GI 217 Kang et al. ASCO GI 217 51

Maximum Reduction From Baseline in Target Lesions (%) Maximum Reduction in Tumor Burden From Baseline 1 a Nivolumab 1 a Placebo 8 8 6 4 6 Patients with Tumor reduction: 37.3% Patients with Tumor reduction: 12.4% 4 2 2-2 -2-4 -4-6 -6-8 -8-1 -1 a Patients with a change in tumor burden that exceeds 1%. 31% ORR ASCO GI 217 Kang et al. ASCO GI 217 52

Probability of Survival (%) Probability of Survival (%) No strong signal for PDL1 predictive value Overall survival by PD-L1 expression <1% vs 1% PD-L1 <1% PD-L1 1% 1 9 8 Median OS, months (95% CI) Nivolumab (n=114) 6.1 (4.8 8.6) Placebo (n=52) 4.2 (3. 6.9) 1 9 8 Median OS, months (95% CI) ONO-4538 Nivolumab (n=16) 5.2 (2.8 9.4) Placebo Placebo (n=1) 3.8 (.8 5.) 7 7 6 5 4 Hazard ratio,.71 (95% CI,.5 1.1) 6 5 4 Hazard ratio,.58 (95% CI,.24 1.38) 3 3 2 2 1 1 2 4 6 8 1 12 14 16 18 2 22 24 26 28 2 4 6 8 1 12 14 16 18 2 22 24 26 28 No. at Risk Nivolumab Placebo Months Months 114 1 75 56 49 42 37 24 15 11 7 4 3 1 16 15 1 7 5 4 4 2 2 52 4 27 22 16 14 11 6 5 4 3 2 2 2 1 8 4 2 1 1 1 PD-L1 evaluable patients (N=192) 53

Methods Figure 1. ATTRACTION-4 study design (part 1) a IV oxaliplatin 13 mg/m 2 on day 1 followed by 2 days off and oral S-1 or oral capecitabine twice daily for 14 days followed by 7 days off. S-1 initial dose was 4 mg/m 2 /dose. Capecitabine initial dose was 1, mg/m 2 /dose ECOG PS = Eastern Cooperative Oncology Group performance status; IV = intravenous; Q3W = every 3 weeks; RECIST = Response Evaluation Criteria in Solid Tumors 54

Results Table 2. Summary of treatment-related adverse events 55

Results Figure 3. Best reduction in tumor burden 56

Authors Conclusions Part 1 of this two-part randomized study met its primary and secondary endpoints; nivolumab + chemotherapy regimens (SOX or CapeOX) had manageable safety profiles and demonstrated clinically meaningful antitumor activity Discontinuations due to treatment-related AEs were low ( 1% of patients) and no treatment-related deaths were reported The incidence and type of treatment-related AEs were consistent with AEs known to be associated with chemotherapy regimens and with nivolumab 5 9 Objective responses were observed in more than two-thirds of patients, occurred early, and were durable, with encouraging PFS No substantial differences in clinical activity and safety were observed between the nivolumab + SOX and nivolumab + CapeOX treatment regimens These results suggest that nivolumab in combination with SOX or CapeOX chemotherapy in patients with unresectable advanced or recurrent gastric or gastroesophageal junction cancer may be a first-line therapy option Part 2 of this study is currently recruiting patients 57

414: Nivolumab ± ipilimumab in pts with advanced (adv)/metastatic chemotherapy-refractory (CTx-R) gastric (G), esophageal (E), or gastroesophageal junction (GEJ) cancer: CheckMate 32 study Study objective To evaluate the long-term survival, efficacy, and safety of nivolumab alone and in combination with ipilimumab in the oesophagogastric cohort of the CheckMate 32 study Key patient inclusion criteria Advanced/metastatic oesophagogastric cancer Progression on 1 prior chemotherapy Western population (n=16) Nivolumab 3 mg/kg IV q2w (n=59) Nivolumab 1 mg/kg + ipilimumab 3 mg/kg IV q3w* (n=49) PD/death/ toxicity PD/death/ toxicity Nivolumab 3 mg/kg + ipilimumab 1 mg/kg IV q3w* (n=52) PD/death/ toxicity PRIMARY ENDPOINT ORR (RECIST v1.1) SECONDARY ENDPOINTS OS, PFS, TTR, DoR, safety, PD-L1 tumour expression *Administered for 4 cycles followed by nivolumab 3 mg/kg IV q2w Janjigian YY, et al. J Clin Oncol 217;35(Suppl):Abstr 414

Probability of survival Probability of progression-free survival 414: Nivolumab ± ipilimumab in pts with advanced (adv)/metastatic chemotherapy-refractory (CTx-R) gastric (G), esophageal (E), or gastroesophageal junction (GEJ) cancer: CheckMate 32 study Janjigian YY, et al 1. OS 1. PFS.8.8.6.6.4.4.2.2 3 6 9 12 15 18 21 24 27 3 33 Time, months mos, months OS rate, % (95%CI) 12-month 18-month Nivolumab 3 mg/kg 6.2 (3.4, 12.4) 39 25 Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg Nivolumab 3 mg/kg + Ipilimumab 1 mg/kg 6.9 (3.7, 11.5) 35 28 4.8 (3., 8.4) 24 13 3 6 9 12 15 18 21 24 27 3 Time, months mpfs, months PFS rate, % (95%CI) 6-month 12-month Nivolumab 3 mg/kg 1.4 (1.2, 1.5) 17 8 Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg Nivolumab 3 mg/kg + Ipilimumab 1 mg/kg 1.4 (1.2, 3.8) 24 17 1.6 (1.4, 2.6) 12 1 Janjigian YY, et al. J Clin Oncol 217;35(Suppl):Abstr 414

Best reduction from baseline in target lesions, % 414: Nivolumab ± ipilimumab in pts with advanced (adv)/metastatic chemotherapy-refractory (CTx-R) gastric (G), esophageal (E), or gastroesophageal junction (GEJ) cancer: CheckMate 32 study Janjigian YY, et al Key results (cont.) Best reduction in target lesions Nivolumab 3 mg/kg PD-L1-evaluable patients, 38 of 53 Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg PD-L1-evaluable patients, 38 of 42 Nivolumab 3 mg/kg + Ipilimumab 1 mg/kg PD-L1-evaluable patients, 34 of 41 1 1 1 75 75 75 5 5 5 25 25 25-25 -25-25 -5 * * * * -5 * * * * * * * -5 * * * * * * PD-L1 <1% PD-L1 1% PD-L1 not evaluable/missing * * Janjigian YY, et al. J Clin Oncol 217;35(Suppl):Abstr 414

KEYNOTE-59: Efficacy and Safety of Pembrolizumab Alone or in Combination With Chemotherapy in Patients With Advanced Gastric or Gastroesophageal Cancer Study Design Cohort 1 2 prior lines of chemotherapy PD-L1 positive or negative Pembrolizumab 2 mg Q3W Cohort 2 No prior therapy PD-L1 positive or negative Pembrolizumab 2 mg Q3W + Cisplatin 8mg/m 2 Q3W + 5-FU 8 mg/m 2 Q3W or Capecitabine 1 mg/m 2 BID Q3W a Treat for up to 35 cycles ( ~ 2 years), or until progression or intolerable toxicity Follow-up for survival by telephone until death, withdrawal, or study end Cohort 3 No prior therapy PD-L1 positive Pembrolizumab 2 mg Q3W Response assessment per RECIST v1.1: First scan 9 weeks after cycle 1, then every 6 weeks for year 1 and every 9 weeks thereafter Primary end points: Safety (all cohorts); ORR by central review per RECIST v1.1 (cohort 1: all patients and patients with PD-L1-positive expression); ORR by central review per RECIST v1.1 (cohort 3) PD-L1 positive: combined positive score (CPS) 1 (previously reported as and equivalent to CPS 1%), where CPS=number of PD-L1-positive cells b (tumor cells, lymphocytes, and macrophages) divided by the total number of tumor cells x 1 Wainberg et al., Abstract LBA28, ESMO 217 a Capecitabine was administered only in Japan b PD-L1 IHC 22C3 pharmadx (Agilent Technologies, Carpinteria, CA,USA)

KEYNOTE-59 cohort 1: Efficacy and safety of pembrolizumab monotherapy in patients with previously treated advanced gastric cancer. Study Design Cohort 1 2 prior lines of chemotherapy PD-L1 positive or negative Pembrolizumab 2 mg Q3W Cohort 2 No prior therapy PD-L1 positive or negative Pembrolizumab 2 mg Q3W + Cisplatin 8mg/m 2 Q3W + 5-FU 8 mg/m 2 Q3W or Capecitabine 1 mg/m 2 BID Q3W a Treat for up to 35 cycles ( ~ 2 years), or until progression or intolerable toxicity Follow-up for survival by telephone until death, withdrawal, or study end Cohort 3 No prior therapy PD-L1 positive Pembrolizumab 2 mg Q3W Data cutoff: April 21, 217 Wainberg et al., Abstract LBA28, ESMO 217 a Capecitabine was administered only in Japan

KEYNOTE-59 cohort 1: Efficacy and safety of pembrolizumab monotherapy in patients with previously treated advanced gastric cancer. Baseline Characteristics Characteristic N=259 Median age (range), years 62 (24-89) Male, n (%) 198 (76) Race, n (%) White Asian Other ECOG, n (%) 1 Number of prior therapies, n (%) 2 3 4 Data cutoff: April 21, 217 Wainberg et al., Abstract LBA28, ESMO 217 2 (77) 41 (16) 7 (3) 17 (41) 151 (58) 134 (52) 75 (29) 5 (19) Characteristic N=259 Location of primary tumor, n (%) GEJ Gastric Prior gastrectomy, n (%) Total Partial No PD-L1 expression, n (%) Positive Negative Unknown HER2 status, n (%) Positive Negative Intermediate 134 (52) 124 (48) 49 (19) 17 (7) 193 (75) 148 (57) 19 (42) 2 (1) 63 (24) 194 (75) 2 (1)

KEYNOTE-59 cohort 1: Efficacy and safety of pembrolizumab monotherapy in patients with previously treated advanced gastric cancer. Response Response b All Patients N = 259 PD-L1 Positive a N = 148 PD-L1 Negative N = 19 % 95% CI % 95% CI % 95% CI ORR 12 8-17 16 11-23 6 3-13 DCR c 27 22-33 34 26-42 19 12-28 DOR CR 3 1-6 3 1-8 3 1-8 PR 9 6-13 13 8-19 4 1-9 SD 16 12-21 18 12-25 15 9-23 PD 56 49-62 53 44-61 6 5-69 Median (range) follow-up: 5.6 (.5-24.7) months 134 patients received pembrolizumab as third-line therapy; ORR was 16%, and DCR was 31% 125 patients received pembrolizuman as fourth plus-line therapy; ORR was 7%, and DCR was 23% Data cutoff: April 21, 217 Wainberg et al., Abstract LBA28, ESMO 217 a CPS 1 b Only confirmed responses were included c CR + PR + SD 2 months

KEYNOTE-59 cohort 1: Efficacy and safety of pembrolizumab monotherapy in patients with previously treated advanced gastric cancer. Best Percentage Change and Longitudinal Change in Target Lesion Size Data cutoff: April 21, 217 Wainberg et al., Abstract LBA28, ESMO 217 a Only patients with measurable disease per RECIST v1.1 by central review at baseline who had 1 postbaseline assessment were included (n=223); assessment was nonevaluable in 1 patient b Longitudinal change in the sum of the longest target lesion diameters from baseline in responders (n=31) +No progressive disease at last disease assessment

KEYNOTE-59 cohort 1: Efficacy and safety of pembrolizumab monotherapy in patients with previously treated advanced gastric cancer. PFS and OS in All Patients Data cutoff: April 21, 217 Wainberg et al., Abstract LBA28, ESMO 217

KEYNOTE-59 cohort 1: Efficacy and safety of pembrolizumab monotherapy in patients with previously treated advanced gastric cancer. PFS and OS by PD-L1 Expression Data cutoff: April 21, 217 Wainberg et al., Abstract LBA28, ESMO 217

KEYNOTE-59 cohort 1: Efficacy and safety of pembrolizumab monotherapy in patients with previously treated advanced gastric cancer. Treatment-Related Adverse Events Event, n (%) N = 259 Any 159 (61) Grades 3-5 Anemia, grade 3 Fatigue, grade 3 Dehydration, grade 3 46 (18) 7 (3) 6 (2) 3 (1) Serious 29 (11) Led to discontinuation a 7 (3) Led to death Acute kidney injury Pleural effusion Median (range) duration of exposure was 2.1 (.-23,7) months 2 (1) 1 (1) 1 (1) Data cutoff: April 21, 217 Wainberg et al., Abstract LBA28, ESMO 217 a Abnormal hepatic function, bile duct stenosis, encephalitis, increase blood bilirubin level, hyperglycemia, acute kidney injury, and pneumonitis

KEYNOTE-59 cohort 1: Efficacy and safety of pembrolizumab monotherapy in patients with previously treated advanced gastric cancer. Immune-Mediated Adverse Events a and Infusion-Related Reactions Event, n (%) There were no grade 4/5 immune-mediated or infusion reactions N=259 All Grades in >2 Patients Grades 3b Any 5 (19) 13 (5) Hypothyroidism 24 (9) 1 (<1) Hyperthyroidism 9 (4) Colitis 4 (2) 3 (1) Infusion-related reactions 4 (2) Pneumonitis 4 (2) 2 (1) Thyroiditis 3 (1) 1 (<1) Data cutoff: April 21, 217 Wainberg et al., Abstract LBA28, ESMO 217 a Based on a list of terms specified by the sponsor and included regardless of attribution to study treatment or immune relatedness by the investigator b 2 (1%) patients experienced grade 3 rash; 1 (<1%) patient experienced grade 3 adverse events: uveitis, hepatitis, jaundice, encephalitis, and maculopapular rash

KEYNOTE-59 Cohort 2: Safety and efficacy of pembrolizumab plus 5-fluorouracil and cisplatin for first-line treatment of advanced gastric cancer Study Design Cohort 1 2 prior lines of chemotherapy PD-L1 positive or negative Pembrolizumab 2 mg Q3W Cohort 2 No prior therapy PD-L1 positive or negative Pembrolizumab 2 mg Q3W + Cisplatin 8mg/m 2 Q3W + 5-FU 8 mg/m 2 Q3W or Capecitabine 1 mg/m 2 BID Q3W a Treat for up to 35 cycles ( ~ 2 years), or until progression or intolerable toxicity Follow-up for survival by telephone until death, withdrawal, or study end Cohort 3 No prior therapy PD-L1 positive Pembrolizumab 2 mg Q3W Data cutoff: April 21, 217 Wainberg et al., Abstract LBA28, ESMO 217 a Capecitabine was administered only in Japan

KEYNOTE-59 Cohort 2: Safety and efficacy of pembrolizumab plus 5-fluorouracil and cisplatin for first-line treatment of advanced gastric cancer Baseline Characteristics Characteristic N=25 Median age (range), years, y 64 (21-82) Male, n (%) 16 (24) Race, n (%) White Asian ECOG PS, n (%) 1 8 (32) 17 (68) 15 (6) 1 (4) Characteristic N=25 Location of primary tumor, n (%) GEJ Gastric Prior gastrectomy, n (%) Total Partial No PD-L1 expression, n (%) Positive Negative Unknown 5 (2) 2 (8) 4 (16) 1 (4) 2 (8) 16 (64) 8 (32) 1 (4) HER2 negative, n (%) 25 (1) Data cutoff: April 21, 217 Wainberg et al., Abstract LBA28, ESMO 217

KEYNOTE-59 Cohort 2: Safety and efficacy of pembrolizumab plus 5-fluorouracil and cisplatin for first-line treatment of advanced gastric cancer Response Respons e b All Patients N = 25 PD-L1 Positive a N = 16 PD-L1 Negative N = 8 % 95% CI % 95% CI % 95% CI ORR 6 39-79 69 41-89 38 9-76 DCR c 8 59-93 75 48-93 75 35-97 BOR CR 4-2 -22 13-53 PR 56 35-76 69 41-89 25 3-65 SD 32 15-54 19 4-46 5 16-84 PD 4-2 6-3 -37 Data cutoff: April 21, 217 Wainberg et al., Abstract LBA28, ESMO 217 Median (range) follow-up in cohort 2: 13.8 (1.8-24.1) months a CPS 1 b Only confirmed responses were included c CR + PR + SD 6 months

KEYNOTE-59 Cohort 2: Safety and efficacy of pembrolizumab plus 5-fluorouracil and cisplatin for first-line treatment of advanced gastric cancer Best Percentage Change and Longitudinal Change in Target Lesion Size Data cutoff: April 21, 217 Wainberg et al., Abstract LBA28, ESMO 217 a Only patients with measurable disease per RECIST v1.1 by central review at baseline who had 1 postbaseline assessment were included (n=25); assessment was nonevaluable for 1 patient b Longitudinal change in the sum of the longest target lesion diameters from baseline in patients with 1 postbaseline assessment (n=25) +No progressive disease at last disease assessment

KEYNOTE-59 Cohort 2: Safety and efficacy of pembrolizumab plus 5-fluorouracil and cisplatin for first-line treatment of advanced gastric cancer PFS and OS Data cutoff: April 21, 217 Wainberg et al., Abstract LBA28, ESMO 217

KEYNOTE-59 Cohort 2: Safety and efficacy of pembrolizumab plus 5-fluorouracil and cisplatin for first-line treatment of advanced gastric cancer Treatment-Related Adverse Events Event, n (%) N = 25 Any 25 (1) Grades 3/4 Neutropenia Stomatitis Anemia Decreased platelet count Decreased appetite Fatigue 19 (76) 6 (24) 5 (2) 2 (8) 2 (8) 2 (8) 2 (8) Led to discontinuation 3 (12) Led to death Median (range) duration of exposure was 7.1 (.8-23.8) months 3 (12%) patients discontinued treatment because of chemotherapy-related adverse events (stomatitis [grade 3], hypoacusis [grade 2], increased creatinine level [grade 1]) No patients discontinued treatment because of pembrolizumab-related adverse events Data cutoff: April 21, 217 Wainberg et al., Abstract LBA28, ESMO 217

KEYNOTE-59 Cohort 2: Safety and efficacy of pembrolizumab plus 5-fluorouracil and cisplatin for first-line treatment of advanced gastric cancer Immune-Mediated Adverse Events a Event, n (%) All Grades in >2 Patients There were no grade 4/5 immune-mediated or infusion reactions N=25 Grades 3 in All Patients Any 12 (48) 4 (16) Hyperthyroidism 4 (16) Palmar-plantar erythrodysesthesia 2 (8) 2 (8) Nephrotic syndrome 1 (4) 1 (4) Rash 1 (4) 1 (4) Maculopapular rash 1 (4) 1 (4) Data cutoff: April 21, 217 Wainberg et al., Abstract LBA28, ESMO 217 a Based on a list of terms specified by the sponsor and included regardless of attribution to study treatment or immune relatedness by the investigator

KEYNOTE-59 Cohort 3: Safety and efficacy of pembrolizumab monotherapy for first-line treatment of patients with PD-L1-positive advanced gastric/gastroesophageal cancer Study Design Cohort 1 2 prior lines of chemotherapy PD-L1 positive or negative Pembrolizumab 2 mg Q3W Cohort 2 No prior therapy PD-L1 positive or negative Pembrolizumab 2 mg Q3W + Cisplatin 8mg/m 2 Q3W + 5-FU 8 mg/m 2 Q3W or Capecitabine 1 mg/m 2 BID Q3W a Treat for up to 35 cycles ( ~ 2 years), or until progression or intolerable toxicity Follow-up for survival by telephone until death, withdrawal, or study end Cohort 3 No prior therapy PD-L1 positive Pembrolizumab 2 mg Q3W Data cutoff: April 21, 217 Wainberg et al., Abstract LBA28, ESMO 217 a Capecitabine was administered only in Japan

KEYNOTE-59 Cohort 3: Safety and efficacy of pembrolizumab monotherapy for first-line treatment of patients with PD-L1-positive advanced gastric/gastroesophageal cancer Baseline Characteristics Characteristic N=31 Median age (range), years, y 62 (32-75) Male, n (%) 19 (61) Race, n (%) White Asian ECOG PS, n (%) 1 16 (52) 15 (48) 14 (45) 17 (55) No. of prior therapies, n (%) Characteristic N=31 Location of primary tumor, n (%) GEJ Gastric Prior gastrectomy, n (%) Total Partial No 12 (39) 19 (61) 9 (29) 3 (1) 19 (61) PD-L1 positive, n (%) 31 (1) HER2 negative, n (%) 31 (1) Data cutoff: April 21, 217 Wainberg et al., Abstract LBA28, ESMO 217

KEYNOTE-59 Cohort 3: Safety and efficacy of pembrolizumab monotherapy for first-line treatment of patients with PD-L1-positive advanced gastric/gastroesophageal cancer Response Response a N = 31 % 95% CI ORR 26 12-45 DCR b 36 19-55 BOR CR 7 1-21 PR 19 8-38 SD 29 14-48 PD 39 22-58 Median (range) follow-up in cohort 3: 17.5 (1.7-2.7) months Data cutoff: April 21, 217 Wainberg et al., Abstract LBA28, ESMO 217 a Only confirmed responses were included b CR + PR + SD 6 months Data cutoff: April 21, 217

KEYNOTE-59 Cohort 3: Safety and efficacy of pembrolizumab monotherapy for first-line treatment of patients with PD-L1-positive advanced gastric/gastroesophageal cancer Best Percentage Change and Longitudinal Change in Target Lesion Size Data cutoff: April 21, 217 Wainberg et al., Abstract LBA28, ESMO 217 a Only patients with measurable disease per RECIST v1.1 by central review at baseline who had 1 postbaseline assessment were included (n=31); assessment were nonevaluable/not evailable in 3 patients b Longitudinal change in the sum of the longest target lesion diameters from baseline in patients with CR or PR (n=3) +No progressive disease at last disease assessment

KEYNOTE-59 Cohort 3: Safety and efficacy of pembrolizumab monotherapy for first-line treatment of patients with PD-L1-positive advanced gastric/gastroesophageal cancer PFS and OS Data cutoff: April 21, 217 Wainberg et al., Abstract LBA28, ESMO 217

KEYNOTE-59 Cohort 3: Safety and efficacy of pembrolizumab monotherapy for first-line treatment of patients with PD-L1-positive advanced gastric/gastroesophageal cancer Treatment-Related Adverse Events Event, n (%) N = 31 Any 24 (77) Grades 3-5 7 (23) Led to discontinuation Led to death 1 (3) Pneumonitis a 1 (3) Median (range) duration of exposure was 2.8 (.7-2.3) months 1 patient each experienced grade 3 adverse events (neutropenia, diffuse uveal melanocytic proliferation, colitis, bile duct obstruction, decreased neutrophils, dehydration, hyponatremia, and rash 1 patient died because of a treatment-related adverse events during safety follow-up (pneumonitis) Data cutoff: April 21, 217 Wainberg et al., Abstract LBA28, ESMO 217 a death occurred during safety follow-up

KEYNOTE-59 Cohort 3: Safety and efficacy of pembrolizumab monotherapy for first-line treatment of patients with PD-L1-positive advanced gastric/gastroesophageal cancer Immune-Mediated Adverse Events a Event, n (%) All Grades in >2 Patients N=31 Grades 3 Grade 5 Any 1 (32) 2 (7) 1 (3) Pneumonitis 4 (13) 1 (3) Colitis 1 (3) 1 (3) Rash 1 (3) 1 (3) Data cutoff: April 21, 217 Wainberg et al., Abstract LBA28, ESMO 217 a Based on a list of terms specified by the sponsor and included regardless of attribution to study treatment or immune relatedness by the investigator

KEYNOTE-59 Cohort 3: Safety and efficacy of pembrolizumab monotherapy for first-line treatment of patients with PD-L1-positive advanced gastric/gastroesophageal cancer Summary and Conclusion (I) Updated KEYNOTE-59 results Pembrolizumab continues to demonstrate, in patients with advanced G/GEJ cancer, Promising antitumor activity and durable response as monotherapy in patients whose disease has progressed after 2 prior lines of therapy Encouraging antitumor activity in combination with chemotherapy in previously untreated patients Encouraging antitumor activity as monotherapy in previously untreated patients with PD-L1-positive tumors Responses were regardless of PD-L1 expression, but higher in patients with PD-L1-positive tumors in cohorts 1 and 2 Safety was manageable and consistent with that previous reports: no new safety signals Wainberg et al., Abstract LBA28, ESMO 217

KEYNOTE-59 Cohort 3: Safety and efficacy of pembrolizumab monotherapy for first-line treatment of patients with PD-L1-positive advanced gastric/gastroesophageal cancer Summary and Conclusion (II) Results support further development of pembrolizumab for advanced G/GEJ cancer KEYNOTE-61 (NCT237498) is an ongoing, phase 3, randomized clinical study of pembrolizumab versus paclitaxel in patients with advanced G/GEJ cancer whose disease progressed after first-line therapy with platinum and fluoropyrimidine KEYNOTE-62 (NCT2494583) is an ongoing, phase 3, randomized clinical study of pembrolizumab alone or in combination with chemotherapy versus chemotherapy alone as first-line therapy for advanced PD-L1 positive G/GEJ cancer Wainberg et al., Abstract LBA28, ESMO 217

After ESMO: even more trials for oesophagogastric cancer Anti-CTLA-4 or anti-pd-1 or anti-pd-l1 Ipilimumab (BMS): anti-ctla-4 Nivolumab (ONO/BMS): anti-pd-1 Pembrolizumab (MSD): anti-pd-1 Durvalumab (AZ): anti-pd-l1 Atezolizumab (Roche): anti-pd-l1 Avelumab (Merck/Pfizer) anti-pd-l1 Perioperative First-line Second-line Phase III Adjuvant 577 Nivo vs placebo ESO after RCTX Phase II Adjuvant Phase II Perioperative FOLFOX/ FLOT +/- atezolizumab Phase III 649/648 Nivo Ipi vs CTX Phase III 649/648 Nivo Ipi vs CTX KEYNOTE-62 Ph III Pembro vs Pembro, Cis, 5-FU vs Cis, 5-FU Phase II Durvalumab vs placebo JAVELIN GASTRIC 1 Phase III Maintenance after FOLFOX ONO-473 Phase III Nivo vs Taxanes KEYNOTE-181 Phase III Pembro vs standard of care KEYNOTE-61 Phase III Pembro vs paclitaxel Phase Ib/II Durva vs Treme vs Durva+Treme Third-line + refractory to standard ONO-4538-7 Phase II Nivo KEYNOTE-18 Phase II Pembro Phase Ib and II Durva+Treme (Phase I) and Phase III Avelumab JAVELIN GASTRIC 3 1. Study designs available at: www.clinicaltrials.gov (accessed September 217). Agents have not yet received EMA approval for treatment of indication listed

HCC

All Patients (N = 262) CheckMate 4 Study Design Study Endpoints Dose Escalation Uninfected (n = 23) Sorafenib Experienced (2L) (n = 37) Primary Safety and tolerability (escalation).1 1 mg/kg N = 48 HCV infected (n = 1) HBV infected (n = 15) Sorafenib Naive (1L) (n = 11) Objective response rate a (expansion) Secondary Objective response rate a (escalation) Disease control rate Time to response Duration of response Overall survival Dose Expansion Uninfected (n = 113) Sorafenib Experienced (2L) (n = 145) Other Biomarker assessments 3 mg/kg HCV infected (n = 5) Patient-reported outcomes b N = 214 HBV infected (n = 51) Sorafenib Naive (1L) (n = 69) Disease assessment imaging (CT or MRI) every 6 weeks Interim analysis data cutoff date: August 8, 216 Median follow-up was 13.3 months in the dose-escalation phase and 1.5 months in the dose-expansion phase a RECIST v1.1; b Baseline and every 6 weeks through week 25 using the EQ-5D utility index and visual analog scale (VAS). ASCO GI 217 88

Safety: Dose-Expansion Phase Patients, n (%) Any Grade Uninfected (n = 113) Grade 3/4 HCV Infected (n = 5) Any Grade Grade 3/4 HBV Infected (n = 51) Any Grade Grade 3/4 All Dose Expansion (N = 214) Any treatment-related AE (TRAE) 84 (74) 22 (19) 4 (8) 15 (3) 35 (69) 3 (6) 159 (74) 4 (19) TRAEs ( 5%) Fatigue 34 (3) 2 (2) 8 (16) 1 (2) 7 (14) 49 (23) 3 (1) Pruritus 18 (16) 14 (28) 1 (2) 13 (25) 45 (21) 1 (<1) Rash 16 (14) 2 (2) 9 (18) 8 (16) 33 (15) 2 (1) Diarrhea 19 (17) 2 (2) 5 (1) 3 (6) 1 (2) 27 (13) 3 (1) Nausea 1 (9) 6 (12) 1 (2) 17 (8) Dry mouth 9 (8) 2 (4) 2 (4) 13 (6) Decreased appetite 6 (5) 2 (4) 1 (2) 3 (6) 11 (5) 1 (<1) Laboratory TRAEs ( 5%) AST increase 9 (8) 4 (4) 6 (12) 5 (1) 1 (2) 16 (7) 9 (4) ALT increase 7 (6) 2 (2) 7 (14) 3 (6) 3 (6) 17 (8) 5 (2) Any Grade Grade 3/4 ASCO GI 217 89

Time to Response and Duration of Response Sorafenib Experienced (2L) Investigator Assessment Dose Escalation Dose Expansion 3 mg/kg Uninfected (n = 3) 1 mg/kg 1 mg/kg Uninfected (n = 14) HCV (n = 2).3 mg/kg 1 mg/kg HCV (n = 7) CR PR HBV (n = 1).1 mg/kg HBV (n = 6) Last dose Last dose when off treatment Censored with ongoing response TTR, median (range), mo 1.9 (1.4 5.6) DOR, median (range), mo 17.1 (7.2 32.5+) TTR, median (range), mo 2.7 (1.2 9.6) DOR, median (range), mo NR (1.4 9.8+) NR, not reached. ASCO GI 217 9

Probability of Survival Overall Survival Sorafenib Experienced (2L) 1..9.8.7.6.5 Dose Expansion: Median OS (95% CI), mo = 13.2 (13.2 NR).4.3.2 Dose Escalation: Median OS (95% CI), mo = 15. (5. 2.2).1. 3 6 9 12 15 18 21 24 27 3 33 36 39 OS Rate (95% CI), % Dose Escalation (n = 37) Dose Expansion (n = 145) 6 months 67 (49 8) 82 (74 87) 9 months 67 (49 8) 71 (63 78) a 12 months 58 (4 72) NC 18 months 46 (29 62) NC a Data cutoff August 8, 216. NC, not available/not calculated. Months ASCO GI 217 91

Change in Target Lesion Size From Baseline (%) Response by PD-L1 Expression Sorafenib Experienced (2L) Investigator Assessment 1 Dose Escalation 1 Dose Expansion PD-L1: < 1% 1% NA PD-L1: < 1% 1% NA 5 5-5 PD-L1 < 1% PD-L1 1% -5 PD-L1 < 1% PD-L1 1% ORR, n/n (%) 95% CI, % 4/26 (15.4), 4.4 34.9 2/9 (22.2), 2.8 6 ORR, n/n (%) 95% CI, % 17/99 (17.2) 1.3 26.1 8/25 (32.), 14.9 53.5-1 Patients -1 Patients Responses were observed irrespective of PD-L1 expression on tumor cells ASCO GI 217 92

Other GI cancer

Attraction 1 trial Nivolumab monotherapy for advanced pretreated oesophageal cancer Summary of Clinical Activity (N=64): As of Nov. 17, 216 Best Overall Response/ORR Investigator Central Review Response N % (95% CI) N % (95% CI) Complete response (CR) 2 3.1 (.9, 1.7) 3 4.7 (1.6, 12.9) Partial response (PR) 12 18.8 (11.1, 3.) 8 12.5 (6.5, 22.8) Stable disease (SD) 2 31.3 (21.2, 43.4) 16 25. (16., 36.8) Progressive disease (PD) 29 45.3 29 45.3 NE 1 1.6 8* 12.5 ORR (CR+PR) 14 21.9 (13.5, 33.4) 11 17.2 (9.9, 28.2) *Including subjects who have no target lesion 64 patients were assessable for the primary endpoint as one patient was excluded due to having multiple primary cancers 1

Results Figure 2. Progression-Free Survival and Overall Survival (N=64): As of Nov. 17, 216 CI = confidence interval 95

Nivolumab in L2+ Anal cancer NCI9673: Primary Endpoint of Response Rate Lancet Oncology 217 Cathy Eng

RESULTATS Taux de réponse : 9/37 = 24% (IC95=15-33) en réponse dont 2 réponses complètes, et 1 réponse partielle chez un patient VIH 7/9 des répondeurs (78%) ont maintenu cette réponse jusqu'à l'analyse des données (temps médian 5.8mois IC95=3.9-8.1, durée la plus longue à 1.4mois) Réponse radiologique de -7% (IC95=57-9) Taux de stabilisation : 17/37 = 47% (IC95=6-63) en maladie stable, soit au total 72% (IC95=53-84) de contrôle de la maladie à la 1 ère évaluation

Bryan S. Balancing cost-effectiveness with other values: the NICE experience - Gesundheitswesen 29; 71: S3-S33

Conclusion J Taieb WCGIC Barcelona 216