KEYNOTE-059 (Cohort 1): Pembrolizumab Monotherapy in Previously Treated Advanced Gastric or GEJ Adenocarcinoma CCO Independent Conference Highlights* of the 2017 ASCO Annual Meeting; June 2-6, 2017; Chicago, Illinois *Clinical Care Options (CCO) is an independent medical education organization that provides conference coverage and other unique educational programs for healthcare professionals GEJ, gastroesophageal junction. This activity is supported by educational grants from AbbVie, Amgen, AstraZeneca, Celgene Corporation, Genentech, Halozyme, Incyte, and Merck & Co., Inc.

Pembrolizumab for Pretreated Advanced Gastric or GEJ Adenocarcinoma: Background PD-L1 overexpression a feature of gastric cancers[1-3] Pembrolizumab: humanized anti–PD-1 IgG4-κ mAb; blocks PD-1 interaction with its ligands PD-L1/2[4] Phase Ib KEYNOTE-012: manageable toxicity, 22% ORR in pts with advanced PD-L1+ gastric cancer[5] Current analysis reports data from phase II KEYNOTE-059 of pembrolizumab with focus on cohort 1 (pts with advanced gastric/GEJ cancer and ≥ 2 prior lines of therapy who received pembrolizumab monotherapy)[6] GEJ, gastroesophageal junction. 1. Kim JW, et al. Gastric Cancer. 2016;19:42-52. 2. Qing Y, et al. Drug Des Devel Ther. 2015;9:901-909. 3. Dong M, et al. Hum Pathol. 2016;53:25-34. 4. Pembrolizumab [package insert]. 5. Muro K, et al. Lancet Oncol. 2016;17:717-726. 6. Fuchs CS, et al. ASCO 2017. Abstract 4003. Slide credit: clinicaloptions.com

KEYNOTE-059: Study Design Open-label, multicohort phase II study Primary endpoints: ORR, safety; secondary endpoints: DoR, PFS, OS Exploratory biomarker endpoints: efficacy by MSI, GEP Cohort 1 ≥ 2 prior lines of CT Pembrolizumab 200 mg Q3W Pts with recurrent or metastatic gastric or GEJ adenocarcinoma; ECOG PS 0/1; HER2/neu negative*; no prior PD-1/PD-L1 tx, systemic steroids, autoimmune disease, ascites, or CNS mets (N = 259) Tx continued for 24 mos or until PD, intolerable toxicity, or withdrawal of consent; survival follow-up until study end, death, or withdrawal Pembrolizumab 200 mg Q3W + Cisplatin 80 mg/m2 Q3W + 5-FU 800 mg/m2 Q3W or Capecitabine 1000 mg/m2 BID Q3W Cohort 2 No prior tx Cohort 3 No prior tx, PD-L1+ Pembrolizumab 200 mg Q3W 5-FU, 5-fluorouracil; CNS, central nervous system; CT, chemotherapy; DoR, duration of response; ECOG, Eastern Cooperative Oncology Group; GEJ, gastroesophageal junction; mets, metastases; GEP, gene expression profile; MSI, microsatellite instability; PD, progressive disease; PS, performance status; tx, treatment. *HER2/neu positive allowed in cohort 1 if prior trastuzumab administered. Slide credit: clinicaloptions.com Fuchs CS, et al. ASCO 2017. Abstract 4003.

KEYNOTE-059 (Cohort 1): Baseline Characteristics All Pts (N = 259) Median age, yrs (range) 62 (24-89) Male, n (%) 198 (76.4) Geographic region, n (%) United States East Asia Other 124 (47.9) 34 (13.1) 101 (39.0) ECOG PS, n (%) 1 107 (41.3) 151 (58.3) Primary tumor location, n (%) Gastric GEJ 125 (48.3) 133 (51.4) Characteristic, n (%) All Pts (N = 259) Prior therapies 2 3 ≥ 4 134 (51.7) 75 (29.0) 50 (19.3) Prior surgery for gastric cancer 66 (25.5) HER2 positive 63 (24.3) PD-L1 expression Positive* Negative 148 (57.1) 109 (42.1) CPS, combined positive score; ECOG, Eastern Cooperative Oncology Group; GEJ, gastroesophageal junction; PS, performance status. *CPS ≥ 1% where CPS is (PD-L1 staining cells/total tumor cells) x 100. Slide credit: clinicaloptions.com Fuchs CS, et al. ASCO 2017. Abstract 4003.

KEYNOTE-059 (Cohort 1): Response Median follow-up: 5.8 mos (range: 0.5-21.6 mos) Confirmed Response, % (95% CI) All Pts (N = 259) ORR 11.6 (8.0-16.1) CR 2.3 (0.9-5.0) PR 9.3 (6.0-13.5) SD 16.2 (11.9-21.3) PD 56.0 (49.7-62.1) DCR* 27.0 (21.7-32.9) DCR, disease control rate; PD, progressive disease; SD, stable disease. *CR + PR + SD ≥ 2 mos. Slide credit: clinicaloptions.com Fuchs CS, et al. ASCO 2017. Abstract 4003.

KEYNOTE-059 (Cohort 1): Safety TRAE Occurring in > 5% of Pts, % All Pts (N = 259) Any Grade Grade 3/4 Fatigue 18.9 2.3 Pruritus 8.9 Rash 8.5 0.8 Hypothyroidism 7.7 0.4 Decreased appetite 7.3 Anemia 6.9 2.7 Nausea Diarrhea 6.6 1.2 Arthralgia 5.8 irAE Occurring in > 1% of Pts, % All Pts (N = 259) Any Grade Grade 3/4 Any 17.8 4.6 Hypothyroidism 8.9 0.4 Hyperthyroidism 3.5 Colitis 2.3 1.2 Pneumonitis 1.9 0.8 Thyroiditis 1.5 Infusion reaction Severe skin reaction* D/c, discontinued; irAE, immune-related adverse event; TRAE, treatment-related adverse event. *Includes erythema multiforme, jaundice, rash, maculopapular rash. Systemic corticosteroids for irAEs: n = 13. Treatment interruption due to irAEs: n = 10. D/c for TRAEs: abnormal hepatic function, bile duct stenosis, n = 1 each. Grade 5 TRAEs: acute kidney injury, pleural effusion, n = 1 each. Slide credit: clinicaloptions.com Fuchs CS, et al. ASCO 2017. Abstract 4003.

PD-L1 and Third Line of Therapy KEYNOTE-059 (Cohort 1): Response by PD-L1 Expression and Line of Therapy Confirmed Response, % (95% CI) PD-L1 Line of Therapy PD-L1 and Third Line of Therapy Positive (n = 148) Negative (n = 109) Third (n = 134) ≥ Fourth (n = 125) (n = 75) (n = 58) ORR 15.5 (10.1-22.4) 6.4 (2.6-12.8) 16.4 (10.6-23.8) (2.8-12.2) 22.7 (13.8-33.8) 8.6 (2.9-19.0) CR 2.0 (0.4-5.8) 2.8 (0.6-7.8) 3.0 (0.8-7.5) 1.6 (0.2-5.7) 2.7 (0.3-9.3) 3.4 (0.4-11.9) PR 13.5 (8.5-20.1) 3.7 (1.0-9.1) 13.4 (8.2-20.4) 4.8 (1.8-10.2) 20.0 (11.6-30.8) 5.2 (1.1-14.4) DCR* 33.1 (25.6-41.3) 19.3 (12.3-27.9) 31.3 (23.6-39.9) 22.4 (15.4-30.7) 38.7 (27.6-50.6) (12.5-35.3) DCR, disease control rate; SD, stable disease. *CR + PR + SD ≥ 2 mos. Slide credit: clinicaloptions.com Fuchs CS, et al. ASCO 2017. Abstract 4003.

KEYNOTE-059 (Cohort 1): Maximum Change From Baseline in Target Lesion Size 120 PD-L1 positive PD-L1 negative PD-L1 expression unknown Pts With Reduction, % All pts* 42.4 PD-L1 positive 47.3 PD-L1 negative 36.3 100 80 60 *Included pts with measurable disease at BL and ≥ 1 post-BL assessment (n = 223). 40 20 Change From BL (%) -20 BL, baseline -40 -60 -80 -100 Slide credit: clinicaloptions.com Fuchs CS, et al. ASCO 2017. Abstract 4003. Reproduced with permission.

KEYNOTE-059 (Cohort 1): Depth and Duration of Response Treatment Exposure and Duration of Response Longitudinal Change From BL in Tumor Size Among Responders (n = 30) 20 Treatment discontinued Treatment ongoing -20 Change From BL (%) Confirmed Responders (n = 30) -40 CR PR PD Death Ongoing pembrolizumab treatment -60 -80 BL, baseline; DoR, duration of response; PD, progressive disease. -100 2 4 6 8 10 12 14 16 18 20 22 24 2 4 6 8 10 12 14 16 18 20 22 24 Mos Since First Dose Mos Since Treatment Initiation Outcome All Pts* PD-L1+ PD-L1- Median DoR, mos (95% CI) 8.4 (1.6+† to 17.3+) 16.3 (1.6+ to 17.3+) 6.9 (2.4 to 7.0+) *Included pts with measurable disease at BL and ≥ 1 post-BL assessment (n = 30). †No PD at last disease assessment. Slide credit: clinicaloptions.com Fuchs CS, et al. ASCO 2017. Abstract 4003. Reproduced with permission.

KEYNOTE-059 (Cohort 1): Survival OS PFS All Pts (N = 259) Median OS, mos (95% CI) 5.6 (4.3-6.9) 12-mo OS rate, % 23.4 All Pts (N = 259) Median PFS, mos (95% CI) 2.0 (2.0-2.1) 100 100 80 80 60 60 OS (%) PFS (%) 40 40 20 20 2 4 6 8 10 12 14 16 18 20 22 2 4 6 8 10 12 14 16 18 20 22 Mos Mos Pts at risk, n Pts at risk, n 259 199 144 112 87 51 27 22 12 7 2 259 136 51 34 22 17 4 2 2 2 Slide credit: clinicaloptions.com Fuchs CS, et al. ASCO 2017. Abstract 4003. Reproduced with permission.

KEYNOTE-059 (Cohort 1): Exploratory Analyses Confirmed Response, % (95% CI) MSI-High (n = 7) Non–MSI-High (n = 167) ORR 57.1 (18.4-90.1) 9.0 (5.1-14.4) CR 14.3 (0.4-57.9) 2.4 (0.7-6.0) PR 42.9 (9.9-81.6) 6.6 (3.3-11.5) DCR* 71.4 (29.0-96.3) 22.2 (16.1-29.2) 0.5 0.0 18-Gene T-Cell−Inflamed GEP Score -0.5 Nonresponder Responder *CR + PR + SD ≥ 2 mos. DCR, disease control rate; GEP, gene expression profile; MSI, microsatellite instability; SD, stable disease. MSI assessed in 174 pts MSI-high: 4.0% 18-gene T-cell–inflamed GEP score, assessed in 144 pts, associated with significantly improved response to pembrolizumab (P = .014) Slide credit: clinicaloptions.com Fuchs CS, et al. ASCO 2017. Abstract 4003. Reproduced with permission.

KEYNOTE-059 (Cohort 1): Conclusions In pts with advanced gastric/GEJ cancer and ≥ 2 prior therapies, pembrolizumab well tolerated with promising antitumor activity, durable responses ORR: 11.6%; higher in PD-L1+ vs PD-L1- tumors (15.5% vs 6.4%) and MSI-high vs non–MSI-high tumors (57.1% vs 9.0%) Study investigators suggest pembrolizumab as potential therapeutic option for this pt population Pembrolizumab in earlier-line therapy and in chemotherapy combinations under investigation for advanced gastric/GEJ cancer in ongoing randomized trials GEJ, gastroesophageal junction; MSI, microsatellite instability. Slide credit: clinicaloptions.com Fuchs CS, et al. ASCO 2017. Abstract 4003.

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