KEYNOTE-052: Updated Findings on First-line Pembrolizumab in Cisplatin-Ineligible Advanced Urothelial Cancer 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 This activity is supported by educational grants from AbbVie, Amgen, AstraZeneca, Celgene Corporation, Genentech, Halozyme, Incyte, and Merck & Co., Inc.

KEYNOTE-052: Background Cisplatin-based therapy improves survival in metastatic UC[1] Alternative regimens required for pts ineligible for cisplatin-based therapy due to age-related comorbidities Available alternative chemotherapy regimens associated with poor outcomes and unfavorable toxicity[2] Phase II data on anti–PD-L1 agent atezolizumab suggested clinical activity in untreated cisplatin-ineligible pts with advanced/metastatic UC (ORR: 23%)[3] KEYNOTE-052 assessed safety, efficacy of anti–PD-1 antibody pembrolizumab in untreated cisplatin-ineligible pts with advanced UC Preliminary analysis: ORR 24% (95% CI: 16.0-33.6) after median follow-up 8 mos[4] Current analysis reports additional follow-up, median: 9.5 mos (range: 0.1-23 mos)[5] UC, urothelial cancer. 1. von der Masse H, et al. J Clin Oncol. 2005;23:4602-4608. 2. De Santis M, et al. J Clin Oncol. 2012;30:191-199. 3. Balar AV, et al. Lancet. 2017;389:67-76. 4. Balar A, et al. ESMO 2016. Abstract LBA32. 5. O’Donnell P, et al. ASCO 2017. Abstract 4502. Slide credit: clinicaloptions.com

KEYNOTE-052: Study Design Multicenter, open-label, single-arm phase II study Primary endpoint: ORR Secondary endpoints: DoR, PFS, OS, safety, PD-L1 expression Exploratory objective: assess relationship between biomarkers and response Pts with advanced UC, no previous chemotherapy for metastatic disease, ECOG PS 0-2, and ineligible for cisplatin* (N = 370) Followed for up to 24 mos of therapy, confirmed PD, intolerable toxicity, or withdrawal of consent Pembrolizumab 200 mg Q3W Biomarker assessment conducted on pretreatment samples. Data cutoff: 3/9/17 CrCl, creatinine clearance; DoR, duration or response; ECOG, Eastern Cooperative Oncology Group; NYHA, New York Heart Association; PD, progressive disease; PS, performance status; UC, urothelial cancer. *Cisplatin ineligibility: CrCl < 60 mL/min, ECOG PS 2, grade ≥ 2 neuropathy or hearing loss, NYHA class III heart failure. Slide credit: clinicaloptions.com O’Donnell P, et al. ASCO 2017. Abstract 4502.

KEYNOTE-052: Baseline Characteristics Pembrolizumab (N = 370) Median age, yrs (range) Age ≥ 80 yrs, n (%) 74 (34-94) 107 (29) Male, n (%) 286 (77) ECOG PS, n (%) 1 2 80 (22) 134 (36) 155 (42) Primary tumor location Upper tract Lower tract 69 (19) 300 (81) Liver metastases, n (%) 77 (21) Characteristic Pembrolizumab (N = 370) Metastases location, n (%) Lymph node only Visceral disease 51 (14) 315 (85) Previous adj/neo-adj platinum-based chemotherapy, n (%) 37 (10) Cisplatin ineligibility, n (%) Renal dysfunction ECOG PS 2 ECOG PS 2 and renal dysfunction Other 183 (50) 120 (32) 34 (9) 33 (9) adj, adjuvant; ECOG, Eastern Cooperative Oncology Group; neo-adj, neo-adjuvant; PS, performance status. Slide credit: clinicaloptions.com O’Donnell P, et al. ASCO 2017. Abstract 4502.

KEYNOTE-052: Confirmed ORR (Primary Endpoint) Response Pembrolizumab (N = 370) n* % 95% CI ORR 108 29 25-42 CR 27 7 5-10 PR 81 22 18-27 SD 67 18 14-22 PD 155 42 37-47 DoR, duration of response; NR, not reached; PD, progressive disease; SD, stable disease; TTR, time to response. *No assessment in 31 pts; 9 pts were not evaluable ORR increased 5% with longer follow-up: CR in 10 additional pts, PR in 9 additional pts 58% pts had reduction in tumor size Median TTR: 2 mos (range: 1-9 mos); median DoR: NR (95% CI: 12 mos to NR) Slide credit: clinicaloptions.com O’Donnell P, et al. ASCO 2017. Abstract 4502.

KEYNOTE-052: ORR Subgroup Analyses n/N 59/191 49/179 97/330 11/40 66/214 42/156 18/69 90/300 14/77 94/293 25/51 81/315 34/120 52/183 11/34 11/33 % (95% CI) 31 (24-38) 27 (21-35) 29 (25-35) 28 (15-44) 31 (25-38) 27 (20-35) 26 (16-38) 30 (25-36) 18 (10-29) 32 (27-38) 49 (35-63) 26 (21-31) 28 (21-37) 28 (22-36) 32 (17-51) 33 (18-52) Age ECOG PS Disease location Liver metastases Metastases location Reason for cisplatin ineligibility < 75 yrs ≥ 75 yrs < 85 yrs ≥ 85 yrs 0-1 2 Upper tract Lower tract Present Absent Lymph node only Visceral disease ECOG PS 2 Renal dysfunction ECOG PS 2/renal dysfunction Other ECOG, Eastern Cooperative Oncology Group; PS, performance status. 10 20 30 40 50 60 70 ORR retained across multiple subgroups ORR, % (95% CI) Slide credit: clinicaloptions.com O’Donnell P, et al. ASCO 2017. Abstract 4502. Reproduced with permission.

KEYNOTE-052: Treatment Exposure and DoR Median TTR: 2 mos (range: 1-9 mos) Median DoR: NR (95% CI: 12 mos to NR) 67% of responses ongoing at data cutoff CR or PR PD Treatment ongoing DoR, duration or response; NR, not reached; PD, progressive disease; TTR, time to response. 8 16 24 32 40 48 56 64 72 80 88 96 Wks Slide credit: clinicaloptions.com O’Donnell P, et al. ASCO 2017. Abstract 4502. Reproduced with permission.

KEYNOTE-052: ORR by PD-L1 Expression Response PD-L1 CPS < 10% PD-L1 CPS ≥ 10% n % 95% CI Training set* (n = 66) (n = 30) ORR 11 17 9-28 37 20-56 CR 3 5 1-13 4 13 4-31 PR 8 12 5-23 7 23 10-42 SD 9 6-24 PD 35 53 40-65 Validation set* (n = 185) (n = 80) 42 17-29 41 51 40-63 1-6 14 18 10-28 20 15-27 27 34 24-45 19 14-25 15 11-29 86 47 37-54 24 15-35 CPS, combined positive score; PD, progressive disease; SD, stable disease. *Training set: threshold for high PD-L1 expression defined in first 100 enrolled pts. Validation set includes remaining evaluable pts. Slide credit: clinicaloptions.com O’Donnell P, et al. ASCO 2017. Abstract 4502.

KEYNOTE-052: TRAEs Discontinued due to AEs: 7% Any-Grade TRAEs (≥ 5% of Pts), n (%) Pembrolizumab (N = 370) Any 243 (66) Fatigue 67 (18) Pruritus 62 (17) Rash 44 (12) Decreased appetite 37 (10) Hypothyroidism 35 (10) Diarrhea 32 (9) Nausea 31 (8) Grade 3-5 TRAEs (≥ 3 Pts), n (%) Pembrolizumab (N = 370) Any 70 (19) Fatigue 8 (2) Colitis 6 (2) Muscle weakness 5 (1) Increased alkaline phosphate 5 (10 Diarrhea 4 (1) Pneumonitis Increased AST Asthenia 3 (1) Hepatitis Increased ALT ALT, alanine aminotransferase; AST, aspartate aminotransferase; irAE, immune-related adverse event; TRAE, treatment-related adverse event. Discontinued due to AEs: 7% 1 death due to TRAE (myositis) Most irAEs grade 1-2 (most common: hypothyroidism) Slide credit: clinicaloptions.com O’Donnell P, et al. ASCO 2017. Abstract 4502.

18-Gene T-Cell Inflamed GEP Score 18-gene GEP score significantly associated with response (P < .0001) Response significantly associated with all genes (P < .05) T-cell inflamed GEP score identified in 31 of 81 responders who were not identified by PD-L1 CPS testing PD-L1 and T-Cell Inflamed GEP and Response 31/81 responders 39/81 responders 1.0 0.500 0.8 0.6 0.000 Sensitivity 18-Gene GEP Score 0.4 -0.318 18-gene GEP AUC: 0.70 (95% CI: 0.63-0.77) IHC PD-L1 AUC: 0.66 (95% CI: 0.59-0.73) 1-sided P = .1288 -0.500 0.2 9/81 responders 2/81 responders AUC, area under the concentration curve; CPS, combined positive score; GEP, gene expression profile. -1.000 1.0 0.8 0.6 0.4 0.2 10 25 50 75 100 IHC PD-L1 CPS Specificity Nonresponder Responder Slide credit: clinicaloptions.com O’Donnell P, et al. ASCO 2017. Abstract 4502. Reproduced with permission.

Conclusions In untreated cisplatin-ineligible pts with advanced UC, pembrolizumab demonstrated significant clinical activity ORR: 29% (95% CI: 25-42) after median follow-up: 9.5 mos (range: 0.1-23 mos) ORR increased with longer treatment duration; median DoR: NR (95% CI: 12 mos to NR) Safety profile similar to previous data for pembrolizumab ORR increased in pts with PD-L1 expression (CPS ≥ 10%) ORR in pts with CPS ≥ 10%: 51% (validation set) T-cell inflamed GEP score identified responders not identified with PD-L1 testing CPS, combined positive score; DoR, duration of response; NR, not reached; UC, urothelial cancer; GEP, gene expression profile. Slide credit: clinicaloptions.com O’Donnell P, et al. ASCO 2017. Abstract 4502. Slide credit: clinicaloptions.com

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