I tumori gastrointestinali

Transcription

1 I tumori gastrointestinali Carmine Pinto Clinical Cancer Centre Oncologia Medica IRCCS-Arcispedale S.Maria Nuova Reggio Emilia

2 Agenda Mutation burden and Immunogenicità Immunonoterapia nel carcinoma gastrico Immunonoterapia nel carcinoma colo-rettale

3 Mutation burden vs response to PD-1/PD-L1 blockade Slide 18

4 Potential Immuno-Oncology Targets We can modulate immune response to restore the ability of effector cells to traffic to the tumor to detect and destroy cancer cells Activate T effector cells GITR ICOS OX4 CD27 CD137 IL-2 2 Block or deplete immune regulators IDO CD73 CSF1R Glutaminase CTLA-4-NF CTLA-4-Probody Enhance NK-cell activity KIR SLAMF7 6 CCR4 TGFß Optimize antigen presentation Radiation Chemotherapy Vaccines Viruses CD4 4 EFFECTOR CELL 3 Inhibit/target tumor cell pathways BCR-ABL DR5 TKIs PD-1 TIM-3 LAG-3 CTLA-4 TIGIT CXCR4 BET ADCs Block tumor inhibition/checkpoints 5 Block inhibitory stromal effects CCR2/5 IL-8 ADCs, antibody drug conjugates; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; CXCR4, chemokine CXC motif receptor 4; GITR, glucocorticoid-induced tumor necrosis factor receptor-related protein; IDO, indoleamine 2, 3- dioxygenase; KIR, killer cell immunoglobulin-like receptor; LAG3, lymphocyte-activation gene 3; NK, natural killer; PD-1, programmed death receptor-1; PD-L1, programmed death ligand 1; SLAMF7, signaling lymphocytic activation molecule family member 7.Chen DS, Mellman I. Immunity.213; 39:1-1.

5 Potential Immuno-Oncology Targets in GI Cancers 1 Activating receptors* Inhibitory receptors* CD27 OX4 CD137 CTLA-4 PD-1 TIM-3 LAG-3 Tumors may exploit immune checkpoint signals to evade immune detection 2 *The image shows only a selection of the receptors/pathways involved. 2 CD137, cluster of differentiation 137; CD27, cluster of differentiation 27; CTLA-4, cytotoxic T-lymphocyte antigen-4; LAG-3; lymphocyte activation gene-3; PD-1, programmed death receptor-1; TIM-3, T-cell immunoglobulin and mucin domain Clinicaltrials.gov. Accessed July 16, Pardoll DM. Nat Rev Cancer. 212;12(4):

6 Predictive/prognostic biomarkers in GI cancers (Hot vs Cold tumors) Activity of checkpoint inhibitors in MSI-high metastatic colorectal cancer Similar activity in MSI-high non-colorectal GI cancers (gastric cancer) NGS provides information about tumor mutational burden Activity of checkpoint inhibitors and HBV status (gastric cancer) Immune signatures (Asian vs non-asian populations in gastric cancer; Immunoscore in colon cancer)

7 6/9 Gastro-Intestinal cancers

8 Signaling mechanisms of PD-1 and PD-L1 inhibition of PD-1 signaling in H-MSI cancers Lemery et al, NEJM 217

9 Meta-analysis on PD-L1 prognostic and predictive value in GI cancers Results for Overall Survival Dai et al, OncoTargets Ther, 217

10 Agenda Mutation burden and Immunogenicità Immunonoterapia nel carcinoma gastrico Immunonoterapia nel carcinoma colo-rettale

11 Classificazione su base molecolare 31%

12 Sottotipi di carcinoma gastrico Sottotipo Incidenza (%) Caratteristiche patologiche e cliniche EBV 9 Maschi 81% Fondo/corpo Estensiva DNA metilazione MSI 22 Età mediana 72 aa Moderata DNA metilazione Instabilità cromosomiale Genoma stabile 5 Giunzione esofago-gastrica Sottoistotipo intestinale 2 Sottoistotipo diffuso Età più precoce mediana 59 aa Casratteristiche molecolari PIK3CA m 8% PD- L1-2 iperespressione EBV-CIMP CDKN2A silenziamento Segnali di citochine alterate Ipermutazioni CIMP-gastrico MLH1 silenziamento Variazione di pathways mitotiche TP53 RTK-RAS attivazione CDH1 e RHOA mutazioni CLDN18-ARHGAP fusione Adesione cellulare

13 Prognosis associated with subtypes Sohnet al, Clin Cancer Res 217

14 Br J Surg, 217 Forest plot for the effect of microsatellite instability (MSI) status on overall survival

15 Br J Surg, 217

16 Cumulative Survival PD-L1 Status and Outcome in Gastric Cancer PD-L1 Expression 1..8 Negative Positive Negative-censored Positive-censored PD-L1 Negative (n=65) PD-L1 Positive (n=67) Time After Surgery (months) PD-L1 is associated with poor prognosis in gastric cancer patients 1 Overexpression of PD-L1 in about 25% 65% of gastric cancer patients suggests that immune checkpoint inhibition may be an effective therapy 2 PD-L1, programmed death ligand Zhang L et al. Int J Clin Exp Pathol. 215;8(9): Zhang M, et al. Sci Rep. 216;6:1-92.

17 Elevated PD-L1 and PD-L2 Expression in EBV+ Gastric Cancer

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19 Slide 23

20 Neo- /Adj 1L+ 2L+ 3L+ Immuno-Oncology Studies Monotherapy Combination Therapy KEYNOTE-59*: Ph 2 Pembrolizumab JAVELIN Gastric 1*: Ph 3 1L Mnt: Avelumab vs oxaliplatin + FP KEYNOTE-585*: Ph 3 Pembrolizumab + (cisplatin + 5-FU/cape) vs PBO + (cisplatin + 5-FU/cape) KEYNOTE-59*: Ph 2 Pembrolizumab ± (cisplatin + 5-FU/cape) Checkmate 649*: Ph 3 Nivolumab + ipilimumab/xelox/folfox vs XELOX/FOLFOX PLATFORM*: Ph2 1L Mnt: Durvalumab/capecitabine NCT *: Ph 1 Pembrolizumab + ramucirumab ATTRACTION-5* (ONO ): Ph 3 Nivolumab + S-1/CapeOx vs PBO + S-1/CapeOx KEYNOTE-62*: Ph 3 (PD-L1+) Pembrolizumab ± (cisplatin + 5-FU/cape) vs PBO + (cisplatin + 5-FU/cape) ATTRACTION-4* (ONO ): Ph 2/3 Nivolumab + SOX/CapeOX vs PBO + SOX/CapeOX KEYNOTE-61*: Ph 3 Pembrolizumab vs paclitaxel Checkmate 32*: Ph 1/2 Nivolumab ± ipilimumab NCT234975*: Ph 1/2 Tremelimumab ± durvalumab JAVELIN Solid Tumor*: Ph 1 Avelumab NCT *: Ph 2 Nivolumab ± andecaliximab ECHO-23: Ph 1/2 Durvalumab ± epacadostat ATTRACTION-2* (ONO ): Ph 3 Nivolumab vs PBO LEGEND Monotherapy clinical trials JAVELIN Gastric 3*: Ph 3 Avelumab + BSC vs BSC ± chemo I-O/I-O combination clinical trials I-O/non I-O combination clinical trials KEYNOTE-59*: Ph 2 Pembrolizumab I-O/I-O & I-O/non-I-O combinations trial *Clinical trial includes patients with gastroesophageal junction cancer. 1L, first-line; 2L, second line; 3L, third line; 5FU, 5-florouracil; adj, adjuvant; BSC, best supportive care; cape, capecitabine; CapeOX, capecitabine + oxaliplatin; chemo, chemotherapy; FOLFOX, oxaliplatin + leucovorin + fluorouracil; FP, fluoropyrimidine; GEJ, gastroesophageal junction; I-O, immuno-oncology; PBO, placebo; PD-L1, programmed death ligand 1; S-1, tegafur-gimeracil-oteracil potassium; SOX, tegafur/gimeracil /oteracil potassium + oxaliplatin; XELOX, oxaliplatin + capecitabine. 1. Clinicaltrials.gov. Accessed June 29, Ohashi S et al. Gastroenterology. 215;149(7): Lote H et al. Cancer Treat Rev. 215;41(1):

21 KEYNOTE-59: Pembrolizumab Phase 2 Multicohort Study of Pembrolizumab for G/GEJ Adenocarcinoma Cohort 1 2 prior lines of CT n=259 1 Pembrolizumab 2 mg q3w Cohort 2 No prior therapy Cohort 3 No prior therapy PD-L1 positive n=25 2 n=31 3 Pembrolizumab 2 mg q3w + Cisplatin 8 mg/m 2 q3w + 5-FU 8 mg/m 2 q3w or Capecitabine 1 mg/m 2 q3w* Pembrolizumab 2 mg q3w For 24 months or until progression, intolerable toxicity, or other reason Follow-up for survival by telephone until death, withdrawal, or study end Primary Endpoints: ORR by RECIST v1.1, safety and tolerability Secondary Endpoint: DOR by central review, PFS, OS Exploratory Biomarker Endpoints: Efficacy by microsatellite instability and gene expression profile *Capecitabine was used in place of 5-FU only in Japan. 5-FU, 5-fluorouracil; CT, chemotherapy; DOR, duration of response; G, gastric; GEJ, gastro-esophageal junction; ORR, objective response; OS, overall survival; PD-L1, programmed death ligand 1; PFS, progression-free survival; q3w, every 2 weeks; RECIST, Response Evaluation Criteria In Solid Tumours. 1. Fuchs C, et al. ASCO 217. Abstract Bang et al. ASCO 217. Abstract Catenacci DV et al. World GI 217. Abstract LBA-9.

22 KEYNOTE-59 Cohort 1: 3L+ Pembrolizumab Monotherapy Respons e* ORR (CR + PR) Objective Response All Patients 1 (N=259) Third Line 2 (n=134) Fourth Line+ (n=125) % 95% Cl % 95% Cl % 95% Cl CR PR SD NR NR PD NR NR DCR Median (range) follow-up in cohort 1 (all patients): 5.6 months ( ) 1 Median (range) follow-up in cohort 1 (3L and 4L+ patients): 5.8 months ( ) 2 *Only confirmed responses were included. CR + PR + SD 2 months CI, confidence interval; CR, complete response; DCR, disease control rate; ORR, objective response rate; PD, progressive disease; PR, partial response; SD, stable disease. 1. Adapted from Wainberg ZA, et al Oral presentation at ESMO 217. Abstract LBA Adapted from Fuchs C et al. Oral presentation at ASCO 217. Abstract 43.

23 Progression-Free Survival, (%) KEYNOTE-59 Cohort 1: 3L+ Pembrolizumab Monotherapy Overall Survival, (%) PFS and Overall Survival in All Patients 1 Median (95% CI) 6-month rate 1 Median (95% CI) 6-month rate 9 2. (2.-2.1) mos 14.6% ( ) mos 45.7% No. at Risk Time (months) No. at Risk Time (months) CI, confidence interval; mos, months; no, number; OS, overall survival; PFS, progression free survival. Wainberg ZA, et al Oral presentation at ESMO 217. Abstract LBA28. Data cutoff: April 21, 217.

24 KEYNOTE-59 Cohort 1: 3L+ Pembrolizumab Monotherapy 18-Gene T-cell inflamed GEP Score Objective Response by Biomarker Expression Response PD-L1 Expression 1 MSI Status 2 PD-L1 Positive (n=148) PD-L1 Negative (n=19) MSI-High (n=7) Non MSI-High (n=167) % 95% CI % 95% CI % 95% CI % 95% CI 18-Gene T-cell inflamed GEP Score 2.5. ORR CR PR SD NR NR PD NR NR -.5 DCR Nonresponder Responder 57% of patients were PD-L1 positive as determined by CPS Responses observed regardless of PD-L1 status, although numerically higher in PD-L1+ patients 57.1% ORR in MSI-H patients (n=7) versus 9.% in non-msi-h (n=167) T-cell inflamed GEP score significantly associated (P=.14) with improved response to pembrolizumab *Only confirmed responses were included. CR + PR + SD 2 months. Positivity based on PD-L1 expression on tumour cells, lymphocytes and macrophages. CI, confidence interval; CPS, combined positive score;cr, complete response; DCR, disease control rate; GEP, gene expression profile; MSI, microsatellite instable; MSI-H, microsatellite instable high; NR, not reported; ORR, objective response rate; PD-L1, programmed death-ligand 1; PD, progressive disease; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumours; SD, stable disease. 1. Adapted from Wainberg ZA, et al Oral presentation at ESMO 217. Abstract LBA Adapted from Fuchs C et al. Oral presentation at ASCO 217. Abstract 43.

25 KEYNOTE-59 Cohort 1: 3L+ Pembrolizumab Monotherapy 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 2 (1) 1 (1) 1 (1) Median (range) duration of exposure was 2.1 (.-23.7) months a Abnormal hepatic function, bile duct stenosis, encephalitis, increased blood bilirubin level, hyperglycemia, acute kidney injury, and pneumonitis. AE, adverse event. Wainberg ZA, et al Oral presentation at ESMO 217. Abstract LBA28. Data cutoff: April 21, 217.

26 Progression-Free Survival, % Overall Survival, % KEYNOTE-59 Cohort 2: 1L Pembrolizumab + Cisplatin + 5-FU/Capecitabine Response b Efficacy Endpoints All Patients N=25 PD-L1 Positive a n=16 PD-L1 Negative n=8 % (95% CI b ) % (95% CI b ) % (95% CI b ) ORR 6 (39-79) 69 (41-89) 38 (9-76) DCR c 8 (59-93) 75 (48-93) 75 (35-97) 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) Median (range) follow-up in cohort 2: 13.8 ( ) mos No. at Risk Progression-Free Survival (total population) Median (95% CI) 6.6 ( ) mo Time (months) 6-mo rate 68.% Median (95% CI) 13.8 (8.6-NR) mo Overall Survival (total population) 6-mo rate 76.% Time (months) % (n=3) of patients discontinued because of chemotherapy-related AEs (stomatitis, hypoacusis, and increased creatinine level) a PD-L1 positive was defined as combined positive score (CPS) 1 (previously reported as and equivalent to CPS 1%), where CPS = number of PD-L1 positive cells (tumor cells, lymphocytes, and macrophages) divided by the Data total cutoff: number April of tumor 21, 217. cells x 1. b Only confirmed responses were included. c CR + PR + SD 6 months. AE, adverse event; CI, confidence interval; CR, complete response; DCR, disease control rate; mo, month; NR, not reached; ORR, objective response rate; OS, overall survival; PD, progressive disease; PD-L1, programmed death ligand 1; PFS, progressionfree survival; PR, partial response; SD, stable disease. Adapted from Wainberg ZA, et al Oral presentation at ESMO 217. Abstract LBA28.

27 KEYNOTE-59 Cohort 3: 1L Pembrolizumab in PD-L1+ Patients Overall Survival, % Outcomes in 1L PD-L1+ Patient Population Confirmed Response a N=31 % 95% CI ORR (CR + PR) CR PR SD PD DCR b Median (Range) DOR, months 9.6 ( ) Median (95% CI) PFS, months 3.3 (2.-6.) PFS, 6-month rate 34.9% Median follow-up:17.5 months (range: ) No. at risk Overall Survival Median (95% CI) 2.7 mo ( ) 6-mo rate 72.9% Time (months Safety was consistent with previous reports, with no new signals identified a Only confirmed responses were included. b CR + PR + SD 6 months. 1L, first line; CI, confidence interval; CR, complete response; DCR, disease control rate; DOR, duration of response; NE, not estimable; NR, not reported; ORR, objective response rate; OS, overall survival; PD, progressive disease; PD-L1, programmed death ligand 1; PFS, progression-free survival; PR, partial response; SD, stable disease; TTR, time to tumour response. Adapted from Wainberg ZA, et al Oral presentation at ESMO 217. Abstract LBA28. Data cutoff: April 21, 217.

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29 ATTRACTION-2 (ONO ): Nivolumab in Asian Patients Randomization Study Design Phase 3 randomized, multicenter, double-blinded trial of nivolumab in patients with unresectable advanced gastric or gastroesophageal junction cancer refractory to or intolerant of standard therapy Nivolumab 3 mg/kg IV Q2W Key eligibility criteria: Unresectable advanced or recurrent gastric or gastroesophageal junction cancer Refractory to/intolerant of 2 standard therapy regimens ECOG PS of or 1 2:1 Stratification: Country (Japan vs South 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: PD-L1 tumor expression a 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 Retrospective determination of tumor PD-L1 expression, defined as staining in 1% (or 5%) of tumor cells, was performed in a central laboratory using immunohistochemistry (28-8 pharmdx assay) for patients with available tumor samples AEs, adverse events; 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; PD-L1, programmed death ligand 1; PFS, progression-free survival; Q2W, every two weeks; R, randomization; TTR, time to treatment response. Boku N et al. Oral presentation at ESMO 217. Abstract 617O.

30 ATTRACTION-2 (ONO ): Nivolumab in Asian Patients Baseline Characteristics 79.1%

31 Overall Survival (%) ATTRACTION-2 (ONO ): Nivolumab in Asian Patients Placebo Nivolumab Overall Survival Median follow-up*: 15.7 months (range, ) Median OS, months (95% CI) Nivolumab 5.3 ( ) Placebo 4.1 ( ) month OS rate 27% 12% Hazard ratio,.62 (95% CI:.5.76) P <.1 24-month OS rate 12% 5% No. at Risk Months Nivolumab Placebo Compared to placebo, treatment with nivolumab resulted in a 38% reduction in risk of death *Time from first dose to data cut-off for surviving patients. CI, confidence interval; OS, overall survival. Boku N et al. Oral presentation at ESMO 217. Abstract 617O.

32 OS (%) OS (%) OS (%) PD-(L)1 Inhibition Demonstrated Long-Term OS Benefits Across Tumor Types OS (%) OS (%) OS (%) Checkmate 25: Nivo Monotherapy in 2L+ RCC 1 HR=.73 (98.5% CI:.57.93) Time (months) Nivolumab Everolimus Checkmate 57: Non-squamous NSCLC 2 2 Nivolumab Docetaxel Time (months) HR=.75 (95% CI:.63.91) Checkmate 17: Squamous NSCLC 2 Checkmate 141: Nivolumab in R/M SCCHN After Platinum Therapy HR=.62 (95% CI:.47.8) Nivolumab Docetaxel Time (months) HR=.7 (95% CI:.51.96) Nivolumab Investigators Choice Time (months) OAK: 2L+ NSCLC (ITT population) 4 Time (months) HR=.73 (95% CI:.62.87) KN-1: 1% PD-L1 2L+ NSCLC 5 6 Pembro 1 4 Atezolizumab Pembro 2 Docetaxel 2 Docetaxel Time (months) Pembro 2: HR=.72 (95% CI:.6.86) Pembro 1: HR=.6 (95% CI:.49.72) 2L, second line; CI, confidence interval; HR, hazard ratio; ITT, intent-to-treat; KN, KEYNOTE; Nivo, nivolumab; NSCLC, non-small cell lung cancer; OS, overall survival; PD-L1, programmed death ligand 1; RCC, renal cell carcinoma; R/M, recurrent or metastatic; SCCHN, squamous cell carcinoma of the head and neck. 1. Adapted from Motzer RJ et al. N Engl J Med. 215;373(19): Adapted from Borghaei H et al. Poster presentation at ASCO Adapted from Ferris RL et al. Oral presentation at ASCO Adapted from Rittmeyer A et al. Lancet. 217;389: Adapted from Herbst RS et al. Oral presentation at WCLC

33 Overall Survival (%) ATTRACTION-2 (ONO ): Nivolumab in Asian Patients Overall Survival by PD-L1 Expression Level Overall Survival (%) 26/192 patients were determined to be PD-L1 positive as detected by DAKO 28-8 of tumor cells only PD-L1 <1% PD-L1 1% 1 9 Median OS, months (95% CI) 1 9 Median OS, months (95% CI) ONO Nivolumab (n=114) Placebo (n=52) 6.1 ( ) 4.2 (3. 6.9) Hazard ratio:.71 (95% CI:.5 1.1) Nivolumab (n=16) Placebo (n=1) 5.2 ( ) 3.8 (.8 5.) Placeb o Hazard ratio:.58 (95% CI: ) No. at Risk Nivolumab Months Placebo No. at Risk Months Nivolumab Placebo Survival advantage was observed for nivolumab versus placebo regardless of PD-L1 expression *n=192 PD-L1 evaluable patients. CI, confidence interval; OS, overall survival; PD-L1, programmed death ligand 1. Boku N et al. Oral presentation at ESMO 217. Abstract 617O.

34 ATTRACTION-2 (ONO ): 2L+ Nivolumab Monotherapy ORR, n (%) 95% CI P value Best Overall Response, n (%) Nivolumab 3 mg/kg (n = 268) 31 (12) 8 16 P<.1 Placebo (n = 131) CR PR 31 (12) 2.8 SD 77 (29) 33 (25) PD 124 (46) 79 (6) NE 36 (13) 19 (15) DCR, n (%) 95% CI P value Efficacy 18 (4) P= (25) Median TTR*, mos (range) 1.6 (1.4 7.) Median DOR*, mos (95% CI) 9.8 ( ) *n=31 patients. 2L, second line; CI, confidence interval; CR, complete response; DCR, disease control rate; DOR, duration of response; mos, months; NE, not evaluable; ORR, objective response rate; PD, progressive disease; PR, partial response; RECIST, Response Evaluation Criteria In Solid Tumours; SD, stable disease; TTR, time to tumour response. Adapted from Boku N et al. Oral presentation at ESMO 217. Abstract 617O.

35 ATTRACTION-2 (ONO ): Nivolumab in Asian Patients Safety Summary Patients, n (%) Nivolumab 3 mg/kg n = 33 Any Grade 3 Grade 4 Placebo n = 161 Any Grade 3 Grade 4 Any treatment-related AE 142 (43) 36 (11) 43 (27) 7 (4) Serious treatment-related AEs 35 (11) 23 (7) 8 (5) 4 (2) Treatment-related AEs leading to discontinuation 9 (3) 4 (1) 4 (2) 3 (2) Treatment-related AEs leading to dose delay 29 (9) 16 (5) 2 (1) 1 (<1) Treatment-related deaths 5 (2) 2 (1) Treatment-related AEs (>2%) Pruritus Diarrhea Rash Fatigue Decreased appetite Nausea Malaise AST increased Hypothyroidism Pyrexia ALT increased 3 (9) 23 (7) 21 (6) 18 (5) 16 (5) 15 (5) 13 (4) 11 (3) 11 (3) 9 (3) 8 (2) 2 (<1) 2 (<1) 4 (1) 2 (<1) 1 (<1) 1 (<1) 9 (6) 3 (2) 5 (3) 9 (6) 7 (4) 4 (2) 6 (4) 3 (2) 1 (<1) 3 (2) 1 (<1) 2 (1) 1 (<1) AE, adverse events; ALT, alanine aminotransferase; AST, aspartate aminotransferase. Adapted from Boku N et al. Oral presentation at ESMO 217. Abstract 617O.

36 Checkmate 32: 2L+ Nivolumab ± Ipilimumab in Western Patients Study Design Western patients with advanced/metastatic EG cancer with progression on 1 prior chemotherapy N = 16 Nivolumab 3 mg/kg IV Q2W (NIVO 3) n=59 Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg IV Q3W* (NIVO 1 + IPI 3) n=49 Nivolumab 3 mg/kg + Ipilimumab 1 mg/kg IV Q3W* (NIVO 3 + IPI 1) n=52 Median (range) follow-up, mo : 28 (17 to 35) 24 (21 to 33) 22 (19 to 25) Primary endpoint: Secondary endpoints: Exploratory endpoint: ORR per RECIST v1.1 OS PFS Time to response Duration of response Safety PD-L1 tumor expression (Dako 28-8 pharmdx assay) ORR and OS by MSI status *Nivolumab + ipilimumab combination treatment administered for 4 cycles followed by nivolumab 3 mg/kg IV Q2W. Time from first dose to data cut-off; follow-up was shorter for patients who died prior to data cut-off. 1L, first line; EG, esophagogastric (included gastric/esophageal/gastroesophageal junction cancer), ORR, objective response rate; OS, overall survival; PD L1, programmed death-ligand 1; PFS, progression-free survival; Q2W, once every two weeks; Q3W, once every 3 weeks; RECIST, Response Evaluation Criteria In Solid Tumours. Janjigian Y et al. Oral presentation at ASCO 217. Abstract 414.

37 Checkmate 32: 2L+ Nivolumab ± Ipilimumab Objective Response NIVO 3 n = 59 NIVO 1 + IPI 3 n = 49 NIVO 3 + IPI 1 n = 52 ORR, n (%)* 7 (12) 12 (24) 4 (8) [95% CI] [5, 23] [13, 39] [2, 19] BOR, n (%)* Complete response 1 (2) 1 (2) Partial response 6 (1) 11 (22) 4 (8) Stable disease 12 (2) 8 (16) 15 (29) Progressive disease 34 (58) 23 (47) 24 (46) Not evaluable 6 (1) 6 (12) 9 (17) DCR, n (%) 19 (32) 2 (41) 19 (37) Median TTR (range), months 1.6 (1.2 to 4.) 2.7 (1.2 to 14.5) 2.6 (1.3 to 2.8) Median DOR (95% CI), months 7.1 (3., 13.2) 7.9 (2.8, NE) NR (2.5, NE) * Investigator review. Patients with a BOR of complete response, partial response, or stable disease. 2L, second line; BOR, best objective response; CI, confidence interval; DCR, disease control rate; DOR, duration of response; IV, intravenous; NE, not estimable; NIVO 3, nivolumab 3 mg/kg IV Q2W; NIVO 1 + IPI 3, nivolumab 1 mg/kg + ipilimumab 3 mg/kg IV Q3W; NIVO3 + IPI, Nivolumab 3 mg/kg + Ipilimumab 1 mg/kg IV Q3W; NR, not reached; Q2W, once every two weeks; Q3W, once every 3 weeks; TTR, time to treatment response. Janjigian Y et al. Oral presentation at ASCO 217. Abstract 414.

38 Probability of PFS* Checkmate 32: 2L+ Nivolumab ± Ipilimumab Probability of Survival Progression-Free Survival and Overall Survival Progression-Free Survival Overall Survival mpfs (95% CI), months 6-month PFS rate, % 12-month PFS rate, % NIVO ( ) 17 8 NIVO 1 + IPI ( ) NIVO 3 + IPI ( ) mos (95% CI), months 12- month OS rate, % 18- month OS rate, % NIVO ( ) NIVO 1 + IPI 3 NIVO 3 + IPI ( ) (3. 8.4) No. at Risk: Time (months) No. at Risk: Time (months) NIVO NIVO NIVO 1 + IPI NIVO 1 + IPI NIVO 3 + IPI NIVO 3 + IPI *Investigator review. 1L, first line; CI, confidence interval; mos, median OS; mpfs, median PFS; NIVO 3, nivolumab 3 mg/kg IV Q2W; NIVO 1 + IPI 3, nivolumab 1 mg/kg + ipilimumab 3 mg/kg IV Q3W; NIVO 3 + IPI 1, Nivolumab 3 mg/kg + Ipilimumab 1 mg/kg IV Q3W; OS, overall survival; PFS, progression-free survival; Q2W, once every two weeks; Q3W, once every 3 weeks. Janjigian Y et al. Oral presentation at ASCO 217. Abstract 414.

39 Checkmate 32: 2L+ Nivolumab ± Ipilimumab Efficacy by PD-L1 Status 1 and MSI-H Status 2 NIVO 3 n=59 NIVO 1 + IPI 3 n=49 NIVO 3 + IPI 1 n=52 PD-L1 expression 1% n=16 <1% n=26 1% n=1 <1% n=32 1% n=13 <1% n=3 OS rate (95% CI), % 12 mos 34 (12 57) 45 (25 62) 5 (18 75) 32 (16 48) 23 (6 47) 25 (11 42) ORR, % MSI-H expression OS rate (95% CI), % MSI-H n = 7 Non-MSI-H n = 18 MSI-H n = 2 Non-MSI-H n = 21 MSI-H n = 2 Non-MSI-H n = mos 57 (17 84) 33 (14 54) 5 (1 91) 36 (16 56) 5 (1 91) 23 (8 43) 18 mos 29 (4 61) 17 (4 36) 5 (1 91) 3 (12 5) 5 (1 91) 6 ( 23) ORR, n (%)* 2 (29) 2 (11) 1 (5) 4 (19) 1 (5) 1 (5) DCR, n (%) 5 (71) 5 (28) 1 (5) 9 (43) 1 (5) 8 (36) mdor (95% CI), mos 1 (7 13) NR (3 NE) NR (NE NE) 5 (3 NE) NR (NE NE) 3 (NE NE) Responses were observed irrespective of PD-L1 Clinical activity and durable responses were observed in both MSI-H and non-msi-h patients *Investigator Review. Patients with a BOR of complete response, partial response, or stable disease. 2L, second line; CI, confidence interval; DCR, disease control rate; DOR, duration of response; mos, months; mdor, median duration of response; MSI-H, microsatellite instability high; NIVO 3, nivolumab 3 mg/kg IV Q2W; NIVO 3 + IPI 1, 3, nivolumab 1 mg/kg + ipilimumab 3 mg/kg IV Q3W; NIVO3 + IPI Nivolumab 3 mg/kg + Ipilimumab 1 mg/kg IV Q3W; NE, not estimable; NR, not reached; ORR, objective response rate; OS, overall survival; PD-L1, programmed death ligand Janjigian Y et al. Oral presentation at ASCO 217. Abstract Ott P et al. Poster presentation at ESMO 217. Abstract 674P.

40 Checkmate 32: 2L+ Nivolumab ± Ipilimumab Treatment-Related Adverse Events Patients, n (%) NIVO 3 n=59 Any Grade Grade 3 4 NIVO 1 + IPI 3 n=49 Any Grade Grade 3 4 NIVO 3 + IPI 1 n=52 Any Grade Grade 3 4 Any TRAE 41 (69) 1 (17) 41 (84) 23 (47) 39 (75) 14 (27) Serious TRAEs 6 (1) 3 (5) 21 (43) 17 (35) 13 (25) 9 (17) TRAEs leading to treatment discontinuation TRAEs in 15% of patients in any treatment arm 2 (3) 2 (3) 1 (2) 1 (2) 7 (13) 5 (1) ALT increased 5 (8) 2 (3) 8 (16) 7 (14) 5 (1) 2 (4) AST increased 7 (12) 3 (5) 8 (16) 5 (1) 2 (4) 1 (2) Decreased appetite 9 (15) 5 (1) 3 (6) Diarrhea 9 (15) 1 (2) 15 (31) 7 (14) 5 (1) 1 (2) Fatigue 2 (34) 1 (2) 14 (29) 3 (6) 1 (19) Pruritus 1 (17) 9 (18) 1 (2) 12 (23) Rash 5 (8) 1 (2) 8 (15) One Grade 5 TRAE was reported (tumor lysis syndrome in a patient treated with NIVO 3 + IPI 1) 2L, second line; ALT, alanine aminotransferase; AST, aspartate aminotransferase; NIVO 3, nivolumab 3 mg/kg IV Q2W; NIVO 1 + IPI 3, nivolumab 1 mg/kg + ipilimumab 3 mg/kg IV Q3W; NIVO 3 + IPI 1, Nivolumab 3 mg/kg + Ipilimumab 1 mg/kg IV Q3W; Q2W, once every two weeks; Q3W, once every 3 weeks. TRAE, treatment-related adverse event. Janjigian Y et al. Oral presentation at ASCO 217. Abstract 414.

41 ATTRACTION-4 (ONO ): 1L Nivolumab + SOX/CapeOX Study Design 1,2 Randomized, multicenter, phase 2/3 trial of nivolumab + chemotherapy as firstline treatment in patients with unresectable advanced or recurrent GC or GEJC Part 1 (n=4) Part 2 (n=~65) Key Inclusion Criteria Treatment-naïve patients Unresectable advanced or recurrent HER2-negative GC/GEJC ECOG PS 1 Neoadjuvant or adjuvant chemotherapy completed 18 days prior to recurrence R 1:1 Nivolumab 36 mg IV Q3W + SOX* Continuation to Part 2 criteria: Confirmed tolerability and safety At least 2/15 subjects had CR or PR by RECIST v1.1 Nivolumab 36 mg IV Q3W + CapeOX* R Nivolumab + SOX/CapeOX Placebo + SOX/CapeOX Start Date: March 216 Estimated Study Completion Date: NA Estimated Primary Completion Date: August 22 Status: Recruiting Study Sites: Japan, Korea, Taiwan Study Director: Ono Pharmaceutical/Bristol-Myers Squibb Primary Outcome Measures: PFS (Part 2) OS (Part 2) Secondary Outcome Measures: ORR, PFS, DOR, DCR, TTR, BOR, lesion size (Part 2) Safety (Parts 1 and 2) *IV oxaliplatin 13 mg/m 2 on day 1 followed by 2 days off and oral SOX or oral capecitabine twice daily for 14 days followed by 7 days. SOX dose was mg/m 2 /dose (body surface area <1.25 m 2, 4 mg/dose; 1.25 and <1.5 m 2, 5 mg/dose; 1.5 m 2, 6 mg/dose. Capecitabine dose was 1, mg/m 2 /dose (body surface area <1.36 m 2, 1,2 mg/dose; 1.36 and <1.66 m 2, 1,5 mg/dose; 1.66 and <1.96 m 2, 1,8 mg/dose; 1.96 m 2, 2,1 mg/dose). Treatment continued until progressive disease per RECIST v1.1, unacceptable toxicity, or withdrawal of consent. Investigator will choose SOX or CapeOX therapy, taking into account the condition of each patient. 1L, first line; BOR, best overall response; CapeOX, capecitabine, oxaliplatin; chemo, chemotherapy; CR, complete response; DCR, disease control rate; DOR, duration of response; ECOG, Eastern Cooperative Oncology Group; GC, gastric cancer; GEJC, gastroesophageal junction cancer; HER2, human epidermal growth factor receptor 2; NA, not available; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; PS, performance status; R, randomized; RECIST, Response Evaluation Criteria In Solid Tumours; SOX, tegafur, gimeracil, oteracil potassium, oxaliplatin; TTR, time to response. 1. Clinicaltrials.gov. NCT Accessed June 27, Adapted from Kang YK. Poster presentation at ESMO 217. Abstract 671P.

42 Change From Baseline in the Sum of the Longest Target Lesion Diameters, (%) ATTRACTION-4 (ONO ) Part 1: 1L Nivolumab + SOX/CapeOX Change From Baseline in the Sum of the Longest Target Lesion Diameters, (%) Efficacy ORR, % (95% CI) 67 (43 85) 71 (44 9) 5 Nivo + SOX Nivolumab + SOX n=21 Tumor Reduction 5 Nivolumab + CapeOX n=17 c BOR, n (%) CR a 1 (5) PR 13 (62) 12 (71) SD 4 (19) 2 (12) PD 2 (1) 2 (12) Not evaluable 1 (5) 1 (6) DCR, b n (%) 18 (86) 14 (82) Median TTR, months (range) 2.1 ( ) 1.4 ( ) Median DOR, months (95% CI) NR (4.3 NE) 5.8 (2.8 NE) Nivo + CapeOx 25 2% Tumor Increase 25 2% Tumor Increase -25-3% Tumor Increase Discontinued On-treatment -25-3% Tumor Reduction Discontinued On-treatment Time Since Treatment Initiation (months) Time Since Treatment Initiation (months) a Defined as disappearance of all non-lymph node target lesions. Any pathological target lymph nodes must have had a reduction in the short axis to <1 mm. b Defined as the percentage of patients in whom the BOR is CR, PR, or SD. C One patient had a protocol deviation of nivolumab treatment for another study and was excluded from efficacy analyses. 1L, first line; BOR, best overall response; CapeOX, capecitabine, oxaliplatin; CI, confidence interval; CR, complete response; DCR, disease control rate; NE, not evaluable; Nivo, nivolumab; ORR, objective response rate; PD, progressive disease; PR, partial response; SD, stable disease; SOX, tegafur, gimeracil, oteracil potassium, oxaliplatin; TTR, time to treatment response. Adapted from Kang YK. Poster presentation at ESMO 217. Abstract 671P.

43 ATTRACTION-4 (ONO ) Part 1: 1L Nivolumab + SOX/CapeOX Safety n=21 Nivolumab + SOX Nivolumab + CapeOX n=18 Patients, n (%) Any grade Grade 3 4 Any grade Grade 3 4 Any treatment-related AE 21 (1) 11 (52) 18 (1) 12 (67) Treatment-related AEs leading to 2 (1) a 1 (5) discontinuation Treatment-related AEs leading to dose delay 1 (48) 5 (24) 8 (44) 4 (22) Treatment-related deaths Treatment-related AEs ( 25%) Diarrhea 13 (62) 1 (5) 8 (44) 1 (6) Peripheral sensory neuropathy 12 (57) 1 (5) 12 (67) 2 (11) Decreased appetite 11 (52) 1 (56) 2 (11) Nausea 1 (48) 9 (5) 2 (11) Decreased neutrophil count 1 (48) 3 (14) 1 (56) 1 (6) Decreased platelet count 9 (43) 4 (22) 1 (6) Fatigue 7 (3) 6 (33) 1 (6) Peripheral neuropathy 6 (29) 1 (5) 2 (11) Constipation 5 (24) 5 (28) Vomiting 5 (24) 6 (33) Peripheral edema 5 (24) 1 (6) Palmar-plantar erythrodysesthesia syndrome 8 (44) *One patient had grade 2 increased aspartate aminotransferase attributed to nivolumab and grade 2 intracranial hemorrhage attributed to SOX and one patient had grade 3 increased alanine aminotransferase attributed to nivolumab. 1L, first line; CapeOX, capecitabine, oxaliplatin; SOX, tegafur, gimeracil, oteracil potassium, oxaliplatin; TRAE, treatment-related adverse event. Adapted from Kang YK. Poster presentation at ESMO 217. Abstract 671P.

44 JAVELIN Basket Trial: Avelumab Slide 3 Chung et al, Abstract 49, ASCO 216

45 JAVELIN Basket Trial: Avelumab Slide 32 Chung et al, Abstract 49, ASCO 216

46 Interim Analysis NCT : Phase 1 Multi-Cohort Study of Ramucirumab Plus Pembrolizumab Phase 1a: DLT Assessment (n=6 to 12) Primary: Safety and tolerability Secondary: PK Schedule 1: Ram 8mg/kg, Day 1 and 8 Pembro 2 mg fixed, Day 1 Both IV every 3 weeks Schedule 2: Ram 1 mg/kg, Day 1 Pembro 2 mg fixed, Day 1 Both IV every 3 weeks Phase 1b: Cohort Expansion (n=155) a Primary: Safety and tolerability Secondary: PK and efficacy Exploratory: Biomarkers and IG Cohort A: Gastric/GEJ (2L+) Cohort A2: Gastric/GEJ (1L) Cohort B: Gastric/GEJ (2L+) Efficacy Outcomes in Evaluable Patients 2nd-Line Cohorts A/B, n= ( ) 1st-Line Cohort A2, n= ( ) All treated patients Median follow-up duration, mo (95% CI) BOR, n (%) CR PR 3 (7) 4 (14) SD 18 (44) 14 (5) PD 13 (32) 5 (18) Not Evaluable 7 (17) 5 (18) ORR 7% b 14% c DCR d 51% 64% Median DOR, mo (95% CI) Median TTR, mo (95% CI) Duration of SD, mo (95% CI) 6.7 ( ) NR 1.4 ( ) 2. ( ) 5. (4. 8.5) 5.6 ( ) The safety profile of ramucirumab combined with pembrolizumab is consistent with monotherapy treatment for each drug, with no additive toxicities a Patients may continue treatment for up to 35 cycles, until confirmed progressive disease or discontinuation for any other reason. b Objective response rate in the response evaluable population (n=34) was 9%. c Objective response rate in the response evaluable population (n=23) was 17%. d Patients with best response of CR, PR, or SD. 1L, first line; 2L, second line; BOR, best overall response; CR, complete response; DCR, disease control rate; DLT, dose-limiting toxicity; DOR, duration of response; GC, gastric cancer; GEJ, gastroesophageal junction; GEJC, GEJ cancer; IG, immunogenicity; NR, not reached; ORR, objective response rate; PD, progressive disease; PK, pharmacokinetics; PR, partial response; Pembro, pembrolizumab; Ram, ramucirumab; SD, stable disease; TTR, time to response. Adapted from Chau I et al. Poster presentation at ASCO 217. Abstract 446, showing only the GC/GEJC cohorts.

47 DLT Review NCT : A Multi-Cohort Phase 1 Study of Ramucirumab Plus Durvalumab Summary of Responses Phase 1a G/GEJ (28-day treatment cycle) Ramucirumab 8 mg/kg Q2W Durvalumab 75 mg Q2W Phase 1b Cohort Expansion a (n=~6 patients) Primary: Safety Secondary: PK, IG, preliminary efficacy Exploratory: Biomarker G/GEJ N=26 BOR, n (%) CR - PR 4 (15%) SD 8 (31%) PD 11 (42%) NE b 3 (12%) ORR, n (%) 4 (15%) c DCR (CR+PR+SD), n (%) 12 (46%) d Median DOR, mos (95% CI) 5.6 (-,-) Median TTR, mos (95% CI) 1.5 (1.3, 5.6) Combination of durvalumab and ramucirumab in patients with advanced G/GEJ adenocarcinoma did not reveal any unexpected safety signals a Patients are treated until confirmed progressive disease, or any other decision to discontinue. b Patients have not had their first scan on treatment. c Objective response rate in the response evaluable population (n=23) was 17%. d Disease control rate in the response evaluable population (n=23) was 52%. BOR, best overall response; CI, confidence interval; CR, complete response; DCR, disease control rate; DLT, dose limiting toxicities; DOR, duration of response; G, gastric; GEJ, gastroesophageal junction; IG, immunogenicity; mos, months; NE, not evaluable; ORR, objective response rate; PK, pharmacokinetics; PR, partial response; Q2W, every 2 weeks; SD, stable disease; TTR, time to response. Adapted from Golan T et al. Poster presentation at 19 th World Congress on Gastrointestinal Cancer. Abstract PD-1 to show only GC/GEJC cohorts.

48 Future Directions in Gastric Cancer Potential for checkpoint inhibitor Ab therapy ± other I-O agents ± antiangiogenics ± cytotoxics ± other targeted therapy (Neo)Adjuvant 1 1L 1 HER2 negative Maintenance 2L 3L+ FP/Pt ± RT Pt + FP doublet- or tripletbased regimen HER2 positive Trastuzumab + cisplatin + capecitabine/5-fu 6 8 cycles or until disease progression Ramucirumab ± paclitaxel 3,4 Irinotecan, docetaxel or paclitaxel 1 No SOC 5 If prolonged progressionfree interval after 1L, can rechallenge with Pt/FP 2 May discontinue due to toxicity or infection 1L, first line; 2L, second line; 3L, third line; 5-FU, 5-fluorouracil; Ab, antibody; FP, fluoropyrimidine; HER2, human epidermal growth factor 2; I-O, immuno-oncology; Pt, platinum; RT; radiation therapy; SOC, standard of care. 1. Waddell T et al. Ann Oncol. 213;24(suppl 6):vi57-vi Hershman DL et al. J Clin Oncol. 214;32(18): Fuchs CS et al. Lancet. 214;383(9911): Wilke H et al. Lancet Oncol. 214;15(11): Smyth EC et al. Ann Oncol. 216;27(suppl 5):v38-v49.7.

49 Agenda Mutation burden and Immunogenicità Immunonoterapia nel carcinoma gastrico Immunonoterapia nel carcinoma colo-rettale

50 Molecular classification of colon cancer Slide 3 Guinney et al, Nature Medicine 215

51 Mutational load differences Slide 4

52 Histology of MSI cancers Histology of MSI Cancers

53 dmmr in colorectal cancer Slide 6 15% of colorectal carcinomas across all stages

54 Immunoscore as prognostic marker in stage I/II/III colon cancer Slide 9 Galon et al, ASCO 216

55 Immunoscore as prognostic marker in stage I/II/III colon cancer Slide 7 Galon et al, ASCO 216

56 Immunoscore as prognostic marker in stage I/II/III colon cancer Slide 8 Galon et al, ASCO 216

57 Immunoscore as prognostic marker in stage I/II/III colon cancer Slide 18 Galon et al, ASCO 216

58 Immunoscore as prognostic marker in stage I/II/III colon cancer The immunoscore study

59 Immunoscore as prognostic marker in stage I/II/III colon cancer Study implications

60 Single agent anti-pd1 in mcrc MSI-H in mcrc 4%

61 Survival Probability Proportion Without Event dmmr/msi-h Status and Outcomes in mcrc Overall Survival: Pooled Data Set 1 Median OS CALGB/SWOG dmmr BRAF mutation (n=53): 11.7 months 1. dmmr BRAF wild-type (n=1): 15. months pmmr BRAF mutation (n=197): 11.3 months.75 pmmr BRAF wild-type (n=2713): 17.3 months BRAF wt and pmmr.5 Unadjusted model HR: 1.39, P=.13 Median OS (95% CI) MSS n= months ( ) MSI-H n= months ( ).4.2 BRAF mt pmmr BRAF mt dmmr BRAF wt and dmmr P< OS (months) Time From Randomization (months) dmmr Status: Prevalence 1 dmmr, n (%) pmmr, n (%) Total, N CAIRO* 18 (5.6%) 34 (94.4%) 322 CAIRO2* 29 (5.6%) 487 (94.4%) 516 COIN 65 (4.4%) 1396 (95.6%) 1461 FOCUS 41 (5.4%) 723 (94.6%) 764 Pooled data set 153 (5.%) 291 (95.%) 363 *dmmr testing assessed by IHC, with PCR in the absence of MMR protein expression. dmmr testing assessed by PCR. dmmr testing assessed by IHC. CRC, colorectal cancer; dmmr, mismatch repair deficient; HR, hazard ratio; MSI-H, microsatellite instability high; OS, overall survival; pmmr, mismatch repair proficient. 1. Venderbosch S et al. Clin Canc Res. 214;2: Tabernero J (Venook AP). Presented at ASCO 217.

62 Checkpoint Inhibition Represents a Logical Therapeutic Target in dmmr/msi-h mcrc dmmr/msi-h tumors are highly immunogenic, which may make these tumors susceptible to immune checkpoint inhibitors 1 dmmr/msi-h mcrc tumors exhibit high mutational load, increased presence of tumor-specific neoantigens, and increased immune infiltration 1,2 Several immune checkpoint proteins,including PD-1, PD-L1 and CTLA-4, may be highly expressed 2 CTLA-4, cytotoxic T-lymphocyte antigen 4; dmmr, mismatch repair deficient; mcrc, metastatic colorectal cancer; MSI-H, microsatellite instability high; PD-1, programmed death receptor-1; PD-L1, programmed death ligand 1; TIL, tumor-infiltrating lymphocyte. 1. Llosa NJ et al. Cancer Discov. 215;5(1): Le DT et al. N Engl J Med. 215;372(26)

63 Selected Planned/Ongoing Immuno-Oncology Trials for dmmr/msi-h mcrc 1 Monotherapy Combination Therapy 1L 2L+ KEYNOTE-164: Ph 2 2L, pembrolizumab Checkmate 142: Ph 2 1L, nivolumab + ipilimumab Checkmate 142: Ph 2 2L+, nivolumab + ipilimumab Checkmate 142: Ph 2 2L+, nivolumab monotherapy NCT : Ph 2 3L+, durvalumab KEYNOTE-177: Ph 3 1L, pembrolizumab vs chemo ± bevacizumab/cetuximab COMMIT (NCT ): Ph 3 1L, FOLFOX + bevacizumab ± atezolizumab LEGEND Clinical trial is not yet opened Clinical trial is ongoing Corvus (NCT ): Ph 1 2L-6L, atezolizumab ± CPI-444 ECHO-22/KEYNOTE-37: Ph 1/2 2L+, pembrolizumab + epacadostat Checkmate 142: Ph 2 2L+, nivolumab + BMS (anti-lag3) SAMCO (NCT ): Ph 2 2L+, avelumab vs chemo ± targeted therapy* Treatment of dmmr/msi-h mcrc with immuno-oncology compounds has shown promising results 2 * Chemotherapy (standard treatment; FOLFOX or FOLFIRI) ± targeted therapy(panitumumab, cetuximab, bevacizumab, or afibercept) 1L, first line; 2L, second line; chemo, chemotherapy; dmmr, mismatch repair deficient; FOLFOX, fluorouracil + leucovorin + oxaliplatin; mfolfox, leucovorin calcium + fluorouracil + oxaliplatin; mcrc, metastatic colorectal cancer; MSI-H, microsatellite instability high. 1. Clinicaltrials.gov. Accessed June 27, Paul B et al. Immunotherapy. 216;8(6):

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65 KEYNOTE-16: Pembrolizumab Summary of Clinical Activity 1,2 Phase 2, open-label trial of pembrolizumab as monotherapy in 3 different treatment-refractory patient populations N=83 Key Inclusion Criteria dmmr CRC pmmr CRC dmmr non-crc n=28 n=25 n=3 Pembrolizumab 1 mg/kg Q2W Primary Outcome Measures: irpfs, irorr (using irrc) Secondary Outcome Measures: OS, irpfs/pfs (using irrc and RECIST 1.1), ORR, IRAEs, MSI and treatment response, markers of MSI status Response ORR, n (%) [95% CI] DCR, n (%) [95% CI] dmmr CRC n=28 16 (57%) [39 73] 25 (89%) [73 96] pmmr CRC n=25 (%) [ 13] 4 (16%) [6 35] CR, n (%) 3 (11%) (%) PR, n (%) 13 (46%) (%) SD,* n (%) 9 (32%) 4 (16%) PD, n (%) 1 (4%) 11 (44%) NE, n (%) 2 (7%) 1 (4%) PFS, mo NR 2.3 OS, mo NR 5.98 dmmr and pmmr CRC groups had received a median of 3 and 4 prior treatment regimens, respectively No new safety signal reported *At Week 12. Patients were considered not evaluable if they did not undergo a 12 week scan. CRC, colorectal cancer; CI, confidence interval; CR, complete response; DCR, disease control rate; dmmr, mismatch repair deficient; IRAE, immune-related adverse event; irorr, immune-related objective response rate; irpfs, immune-related progression-free survival; irrc, immune-related response criteria; mcrc, metastatic colorectal cancer; MSI, microsatellite instability; NE, not evaluable; NR, not reached; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; pmmr, mismatch repair proficient; PR, partial response; Q2W, every two weeks; RECIST, Response Evaluation Criteria In Solid Tumors; SD, stable disease. 1. Le DT et al. Oral presentation at ASCO Le DT et al. N Engl J Med. 215;372(26):

66 KEYNOTE-164: Pembrolizumab Study Design 1,2 Phase 2 multicenter, multicohort trial of pembrolizumab as monotherapy in patients with previously treated, locally advanced unresectable or metastatic colorectal cancer NCT246198, N=12 Patients Locally advanced unresectable or metastatic dmmr/msi-h mcrc 2 prior therapies (must include prior fluoropyrimidine, oxaliplatin, and irinotecan) ECOG PS or 1 Measurable disease Adequate organ function 2 mg pembrolizumab IV on Day 1 Q3W for up to 35 cycles (approx 2 years) PD or intolerable toxicities Safety follow-up ( 9 days) Survival follow-up (Q9W) Primary Outcome Measures: ORR per RECIST v1.1 Secondary Outcome Measures: DOR, DCR, PFS, OS 1EP, primary endpoint; 2EP, secondary endpoint; DCR, disease control rate; DOR, duration of response; EGFR, epidermal growth factor receptor; ECOG PS, Eastern Cooperative Oncology Group performance status; IV, intravenous; Q3W, every 3 weeks; Q9W, every 9 weeks; ORR, objective response rate; RECIST, Response Evaluation Criteria In Solid Tumors; PFS, progression-free survival; OS, overall survival; VEGF, anti-vascular endothelial growth factor. 1. Diaz LA et al. Poster presentation at ASCO 217. Abstract Clinicaltrials.gov. NCT Accessed August 28, 217.

67 Change From Baseline (%) KEYNOTE-164: Pembrolizumab Results n MSI-H CRC N=61* % (95% CI) ORR 17 28% (17 41) Complete response Partial response 17 28% (17 41) Stable disease 14 23% (13 36) Progressive disease DCR (CR+PR+SD) mttr, mos (range) mdor, mos (range) mpfs, mos (95% CI) 28 46% (33 59) 31 51% (38 64) 4 (2 1) NR ( ) 2.3 ( ) 12 mos OS 72% Best Percentage Change From Baseline in Target Lesion Size (RECIST v1.1 by IRC) Prior lines of therapy, n (%) 1 6 (1%) 2 28 (46%) 3 13 (21%) 4 5 (8%) 5 6 (1%) *2 patients were nonevaluable. CI, confidence interval; CRC, colorectal cancer; CR, complete response; DCR, disease control rate; mos, months; IRC, independent central radiology review; mdor, median duration of response; mos, months; mpfs, median progressionfree survival; MSI-H, microsatellite instability high; mttr, median time to response; NR, not reached; OS, overall survival; PR, partial response; SD, stable disease. Adapted from Diaz LA et al. Poster presentation at ASCO 217. Abstract 371.

68 KEYNOTE-164: Pembrolizumab Events Safety 1 MSI-H CRC N=61, n (%) Any grade 35 (57%) Grade (15%) Led to death (Grade 5) Led to discontinuation 1 (2%) Events 1% Any grade Grade 3 4 Grade 5 Arthralgia 1 (16%) Nausea 9 (15%) Diarrhea 8 (13%) Asthenia 7 (12%) 1 (2%) Pruritus 7 (12%) Fatigue 6 (1%) 2 (3%) Pembrolizumab is approved in the US for the treatment of 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 CRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan 2 CRC, colorectal cancer; dmmr, mismatch repair deficient; MSI-H, microsatellite instability-high. 1. Diaz LA et al. Poster presentation at ASCO 217. Abstract Keytruda Prescribing information. Keytruda U.S. Product Information. Available at: docs/label/217/125514s14lbl.pdf. Accessed August 28, 217.

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70 Checkmate 142: Nivolumab ± Ipilimumab Cohorts Study Design Patients Stage 1 Stage 2 Histologically confirmed metastatic/ recurrent CRC Monotherapy Arm (n=74) Nivolumab 3 mg/kg Q2W If 7/19 confirmed responders, continue enrollment Nivolumab 3 mg/kg Q2W dmmr/msi-h per local laboratory 1 prior line of therapy Combination Arm (n=84*) Nivolumab 3 mg/kg + ipilimumab 1 mg/kg Q3W (4 doses, then nivolumab 3 mg/kg Q2W) If 7/19 confirmed responders, continue enrollment Nivolumab 3 mg/kg + ipilimumab 1 mg/kg Q3W (4 doses, then nivolumab 3 mg/kg Q2W) Primary Outcome Measures: ORR per investigator assessment (RECIST v1.1) Secondary Outcome Measures: ORR per blinded independent central review (BICR), PFS, OS, and safety Tumor imaging assessments were performed every 6 weeks for 24 weeks and thereafter every 12 weeks until disease progression or discontinuation Treatment beyond progression was permitted if the patient was determined by the investigator to be benefiting from and tolerating study therapy, and consent was provided by the patient *Number of patients from interim analysis. BICR, blinded independent committee review; CRC, colorectal cancer; dmmr, mismatch repair deficient; MSI-H, microsatellite instability high; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; Q2W, every 2 weeks; Q3W, every 3 weeks; RECIST, Response Evaluation Criteria In Solid Tumors. 1. Andre T et al. Poster presentation at ASCO 217. Abstract Overman MJ et al. Oral presentation at ASCO GI 217. Abstract GI17.

71 Checkmate 142: Nivolumab ± Ipilimumab Cohorts Disease Characteristics and Prior Therapy<br />Nivolumab ± Ipilimumab in Metastatic CRC

72 Checkmate 142: Nivolumab Monotherapy Change in Sum of Target Lesions From Baseline (%) Response Rates* Patients Objective Response, n (%) [95% CI] dmmr/msi per Local Laboratory (n=74) 23 (31.1%) [ ] 1 75 Tumor Reduction Confirmed partial response or complete response First documented occurrence of new lesion Patient off treatment % change truncated to 1% CR, n (%) PR, n (%) 23 (31%) SD, n (%) 28 (38%) PD, n (%) 19 (26%) Not determined, n (%) 4 (5%) Disease Control for 12 weeks, n (%) [95% CI] Median Duration of Response, Months (range) Median TTR, Months (IQR) 51 (69%) (57 79) NR (NE) 2.8 ( ) Weeks Symbol + indicates a censored value. January 217 data cutoff. CI, confidence interval; CR, complete response; IQR, interquartile range; NE, not evaluable; NR, not reached; PR, partial response; SD, stable disease; TTR, time to respond. Adapted from Overman MJ et al. Lancet Oncol doi:1.116/s (17)

73 Progression-Free Survival (%) Checkmate 142: Nivolumab Monotherapy Overall Survival (%) Investigator-Assessed PFS and OS Progression-free Survival Nivolumab (n=74) Overall Survival Nivolumab (n=74) mpfs, months (95% CI) 14.3 (4.3 NE) mos, months (95% CI) NR (18. NE) month rate, % (95% CI) 5% (38 61) month rate, % (95% CI) 73% (62 82) MSI-H/dMMR mcrc per Local Lab Censored observations MSI-H/dMMR mcrc per Local Lab Censored observations Number at risk (numbered censored) Time Since Start of Treatment (months) Number at risk (number censored) Time Since Start of Treatment (months) 74 () 48 (2) 41 (3) 32 (9) 17 (22) 12 (26) 12 (26) 11 (27) 6 (32) 3 (35) (38) 74 () 64 (3) 59 (3) 55 (3) 37(18) 21 (34) 19 (34) 17 (34) 11 (4) 6 (45) 1 (5) (51) CI, confidence interval; CRC, colorectal cancer; dmmr, mismatch repair deficient; mos, median overall survival; mpfs, median progression-free survival; MSI-H, microsatellite instability high; NE, not estimable; PFS, progression-free survival. Overman MJ et al. Lancet Oncol doi:1.116/s (17)

74 Checkmate 142: Nivolumab Monotherapy Patients, n (%) Safety All Patients (N=74) Grade 1-2 Grade 3 Grade 4 Any TRAE* 36 (49%) 13 (18%) 2 (3%) TRAEs reported in 1% of patients Fatigue Diarrhea Pruritus Rash Nausea Hypothyroidism 16 (22%) 15 (2%) 1 (14%) 8 (11%) 7 (1%) 7 (1%) 1 (1%) 1 (1%) The most common grade 3/4 TRAEs were increased concentrations of lipase (6 [8%]) and amylase (2 [3%]) Five (7%) patients discontinued treatment due to drug-related adverse events, including increased ALT, colitis, duodenal ulcer, acute kidney injury, and stomatitis (one each) No deaths were reported due to study drug toxicity *One Grade 5 event of sudden death was reported; this death was not attributed to study drug toxicity on autopsy. AE, adverse event; ALT, alanine aminotransferase; TRAE, treatment-related adverse event. Overman M et al. Lancet Oncol. 217 Jul 19. pii: S (17)

75 Checkmate 142: Nivolumab + Ipilimumab Combination Change in Target Lesion From Baseline (%) Efficacy Investigator assessed ORR, n (%) [95% CI] Best overall response, n (%) CR PR SD PD Not determined/reported Disease control for 12 weeks, * n (%) [95% CI] dmmr/msi-h (n=84) 46 (55%) [ ] 2 (2%) 44 (52%) 26 (31%) 9 (11%) 3 (4%) 66 (79%) [ ] Median TTR, months (range) 2.8 ( ) Median DOR, months, [95% CI] NR [NE NE] On treatment 1 Off treatment 75 CR or PR 1 st occurrence of new lesion Time Since Start of Treatment (weeks) Patients with CR, PR, or SD for 12 weeks. CI, confidence interval; CR, complete response; dmmr, mismatch repair deficient; DOR, duration of response; MSI-H, microsatellite instability high; NE, not estimable; NR, not reached; ORR, objective response rate; PD, progressive disease; PR, partial response; SD, stable disease; TTR, time to response. Andre T et al. Poster presentation at ASCO 217. Abstract 3531.

76 Checkmate 142: Nivolumab + Ipilimumab Combination Best Reduction from Baseline in Target Lesion (%) Best Reduction in Target Lesion Size % of patients had a reduction in tumor burden from baseline Confirmed CR or PR per investigator. CR, complete response; PR, partial response. Andre T et al. Poster presentation at ASCO 217. Abstract 3531.

77 Probability of PFS Probability of Survival Checkmate 142: Nivolumab + Ipilimumab Combination Investigator-Assessed PFS and OS Progression-free Survival Overall Survival No. at Risk PFS rate (95% CI), % 6-month 77 ( ) 9-month 77 ( ) Median PFS (95% CI), months NR (11.5 NE) Time (months) OS rate (95% CI), % 6-month 89 ( ) 9-month 88 ( ) Median OS (95% CI), months NR (NE NE) No. at Time (months) Risk CI, confidence interval; NE, no estimatable; OS, overall survival; PFS, progression-free survival. Andre T et al. Poster presentation at ASCO 217. Abstract 3531.

78 Checkmate 142: Nivolumab + Ipilimumab Combination Safety dmmr/msi-h (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 Fatigue Aspartate aminotransferase increase Pyrexia Pruritus Alanine aminotransferase increase Nausea Hyperthyroidism Hypothyroidism 2 (24%) 14 (17%) 14 (17%) 13 (16%) 13 (16%) 12 (14%) 12 (14%) 11 (13%) 11 (13%) 1 (1%) 1 (1%) 8 (9%) 2 (2%) 7 (8%) AEs were manageable, with Grade 3/4 TRAEs reported in 29% of patients No treatment-related deaths were reported in this study *All events (ALT level increase, autoimmune hepatitis, colitis, dyspnea, necrotizing myositis, pneumonitis, immune sarcoidosis, transaminase increase, thrombocytopenia) occurred in one patient each with the exception of acute kidney injury, which was reported in 2 patients. AE, adverse event; ALT, alanine aminotransferase; dmmr, mismatch repair deficient; MSI-H, microsatellite instability high; TRAE, treatment-related adverse events. Andre T et al. Poster presentation at ASCO 217. Abstract 3531.

79 Checkmate 142: MSI-H Cohorts Overview of Ongoing dmmr/msi-h Cohorts in Checkmate 142 Cohort Disease State Regimens Endpoint(s) Monotherapy 2L+ mcrc Nivolumab Nivolumab + Ipilimumab 2L+ mcrc 3 1L mcrc 5 2L+ mcrc Nivolumab + ipilimumab Nivolumab + ipilimumab Nivolumab + anti-lag3 Primary Endpoint: ORR (investigator assessment) Secondary Endpoint: ORR (BICR) Other Endpoints: PFS, OS, biomarkers, safety, and tolerability 1L, first line; 2L, second line; BICR, blinded independent central review; dmmr, mismatch repair deficient; LAG, lymphocyte activation gene; mcrc, metastatic colorectal cancer; MSI-H, microsatellite instability high; ORR, objective response rate; OS, overall survival; PFS, progression-free survival. Clinicaltrials.gov. NCT Accessed June 21, 217.

80 Several Exploratory Immuno-Oncology Trials for non-msi-h mcrc Are Ongoing 1 Patients with MSS CRC have not been shown to benefit from single agent PD-1/PD-L1 inhibition 2 Checkmate 142: Ph 2 2L+, nivolumab + ipilimumab + cobimetinib NCT : Ph 1/2 2L+, nivolumab + varlilumab Checkmate 142: Ph 2 2L+, nivolumab + daratumumab NCT : Pilot/Ph1 1L+, pembrolizumab + CC-486, or romidepsin 1L, first line; 2L, second line; CRC, colorectal cancer; dmmr, mismatch repair deficient; MSI-H, microsatellite instability high; Ph, phase. 1. Clinicaltrials.gov. Accessed June 27, Le DT, et al. N Engl J Med. 215;372:

81 NCT : Atezolizumab Phase 1b Dose Escalation and Cohort Expansion in MSI-Unselected CRC 1,2 Phase Ib Dose Escalation and Cohort Expansion Study (NCT )

82 NCT : Atezolizumab Phase 1b Dose Escalation and Cohort Expansion in MSI-Unselected CRC 1,2 PD-L1 and MEK Inhibition: A Rational Combination

83 NCT : Atezolizumab Phase 1b Dose Escalation and Cohort Expansion in MSI-Unselected CRC 1,2 Baseline Characteristics

84 NCT : Atezolizumab Phase 1b Dose Escalation and Cohort Expansion in MSI-Unselected CRC 1,2 Baseline Characteristics (cont.)

85 NCT : Atezolizumab Phase 1b Dose Escalation and Cohort Expansion in MSI-Unselected CRC 1,2 Efficacy: Confirmed Objective Response

86 NCT : Atezolizumab Phase 1b Dose Escalation and Cohort Expansion in MSI-Unselected CRC 1,2 Efficacy: Change in Tumor Burden

87 NCT : Atezolizumab Phase 1b Dose Escalation and Cohort Expansion in MSI-Unselected CRC 1,2 Efficacy: Duration of Treatment and Response

88 NCT : Atezolizumab Phase 1b Dose Escalation and Cohort Expansion in MSI-Unselected CRC 1,2 Efficacy: Progression-Free Survival And Overall Survival

89 NCT : Atezolizumab Phase 1b Dose Escalation and Cohort Expansion in MSI-Unselected CRC 1,2 Safety: Treatment-related AEs

90 Phase 1 Combination of anti-cd27 agonist antibody varilumab with nivolumab in advanced solid tumors Baseline Patient Characteristics CRC 42 Presented By Rachel Sanborn at 217 ASCO Annual Meeting

91 Phase 1 Combination of anti-cd27 agonist antibody varilumab with nivolumab in advanced solid tumors Varlilumab & Nivolumab Combination Therapy is Well Tolerated Presented By Rachel Sanborn at 217 ASCO Annual Meeting

92 Phase 1 Combination of anti-cd27 agonist antibody varilumab with nivolumab in advanced solid tumors Tumor Response Presented By Rachel Sanborn at 217 ASCO Annual Meeting

93 Phase 1 Combination of anti-cd27 agonist antibody varilumab with nivolumab in advanced solid tumors Durable Response in MMR-proficient CRC Patient Presented By Rachel Sanborn at 217 ASCO Annual Meeting