KEYNOTE-029 Expansion Cohort: Pembrolizumab + Ipilimumab Safe, Active in Advanced Melanoma CCO Independent Conference Coverage* of the 2016 ASCO Annual Meeting, June 3-7, 2016 *CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs. This activity is supported by educational grants from Amgen, Ariad, Bayer Healthcare Pharmaceuticals, Celgene Corporation, Genentech, Incyte, Merck, and Taiho Pharmaceuticals.

KEYNOTE-029: Pembrolizumab + Ipilimumab in Advanced Melanoma: Background Rationale for CTLA-4 and PD-1/PD-L1 blockade in melanoma well established[1] CTLA-4 inhibition (eg, by ipilimumab) effective during priming phase PD-1/PD-L1 inhibition (eg, by pembrolizumab, nivolumab) effective at tumor bed during effector phase Pembrolizumab and nivolumab demonstrate improved survival outcomes vs ipilimumab[2,3] Nivolumab 1 mg/kg + ipilimumab 3 mg/kg in combination improved PFS, ORR vs either as monotherapy, but with increased toxicity[3,4] KEYNOTE-029 expansion cohort study evaluated safety, efficacy of pembrolizumab 2 mg/kg + ipilimumab 1 mg/kg in pts with advanced melanoma[5] 1. Ribas A. N Engl J Med. 2012;366:2517-2519. 2. Robert C, et al. N Engl J Med. 2015;372:2521-2532. 3. Larkin J, et al. N Engl J Med. 2015;373:23-34. 4. Postow MA, et al. N Engl J Med. 2015;372:2006-2017. 5. Long GV, et al. ASCO 2016. Abstract 9506. Slide credit: clinicaloptions.com

KEYNOTE-029: Study Design Phase I trial Dose Run-In (Phase Ia)[1] Dose Expansion (Phase Ib)[2] Pts with advanced melanoma, ≥ 0 prior therapies OR pts with advanced RCC, ≥ 1 prior therapy Pts with advanced melanoma; ECOG PS 0-1; ≥ 0 prior therapies, no prior PD-1, PD-L1, or anti–CTLA-4 (N = 153) Pembrolizumab 2 mg/kg Q3W, ≤ 24 mos + Ipilimumab 1 mg/kg Q3W x 4 doses Dose run-in (phase Ia): dose determined to be tolerable, active based on DLT rate[1] Dose expansion (phase Ib)[2] Primary endpoint: safety Secondary endpoints: DoR, ORR, OS, PFS DLT, dose-limiting toxicity; DoR, duration of response; ECOG, Eastern Cooperative Oncology Group; PS, performance score; RCC, renal cell carcinoma; 1. Atkins MB, et al. ASCO 2016. Abstract 3013. 2. Long GV, et al. ASCO 2016. Abstract 9506. Slide credit: clinicaloptions.com

KEYNOTE-029: Baseline Characteristics Pembrolizumab + Ipilimumab (N = 153) Median age, yrs (range) 60 (22-82) Male, % 66 ECOG PS 0, % 74 LDH level elevated, % 24 BRAFV600 mutant, % 36* PD-L1 positive, % 83† M1c disease, % 56 No previous therapy, % 87 ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase; PS, performance status. *13 pts with prior BRAF ± MEK inhibitor therapy. †2 pts with tumors not evaluable for PD-L1 expression. PD-L1 positivity defined as ≥ 1% staining in tumor, adjacent immune cells by IHC (22C3 antibody). Slide credit: clinicaloptions.com Long GV, et al. ASCO 2016. Abstract 9506.

KEYNOTE-029: Adverse Events Category, % Treatment Related (N = 153) Immune Mediated* Any grade 95 58 Grade 3/4 42 25 Led to death Led to ipilimumab discontinuation only 10 8 Led to pembrolizumab discontinuation† 7 4 Led to ipilimumab and pembrolizumab discontinuation‡ *Regardless of investigator attribution. †After discontinuation or completion of ipilimumab. ‡Includes 1 pt who discontinued ipilimumab (due to colitis) and then pembrolizumab (due to increased lipase). 72% of pts received all 4 doses of ipilimumab Slide credit: clinicaloptions.com Long GV, et al. ASCO 2016. Abstract 9506.

KEYNOTE-029: Adverse Events Treatment-Related AEs (> 15% Pts), % Any Grade (N = 153) Grade 3/4 Fatigue 46 Pruritus 39 Rash 3 Diarrhea 24 < 1 Lipase increased 18 14 Vitiligo Dry mouth 16 Nausea Hypothyroidism Immune-Mediated AEs per Pt, % Any Grade (N = 153) Grade 3/4 42 75 1 31 22 2 19 3 7 4 < 1 Most common immune-mediated AEs: hypothyroidism, hyperthyroidism, hypophysitis, pneumonitis, hepatitis, colitis, and skin reactions 145 total events were managed with systemic treatment* with corticosteroids (57%), infliximab (7%), or other (4%) 76% of any grade AEs and 81% of grade 3/4 AEs had resolved† at data cutoff AE, adverse event. * ≥ 1 systemic treatments allowed. †Excluding endocrinopathies. Slide credit: clinicaloptions.com Long GV, et al. ASCO 2016. Abstract 9506.

Pembrolizumab + Ipilimumab (N = 153) KEYNOTE-029: Response Characteristic Pembrolizumab + Ipilimumab (N = 153) ORR, % (95% CI) 57 (49-65) DCR, % (95% CI) 78 (71-85) Best overall response, % CR 10 PR 47 SD 22 PD 20 No assessment 2 DCR, disease control rate; PD, progressive disease; SD, stable disease. 81% of pts experienced some tumor reduction; median change: -54.5% Tumor response in both PD-L1–positive or PD-L1–negative status 98% of responders maintained response at time of data cutoff Robust responses experienced in all subgroups Slide credit: clinicaloptions.com Long GV, et al. ASCO 2016. Abstract 9506.

KEYNOTE-029: PFS and OS 70% of pts progression free at 6 mos Events: 49 (32%) Median PFS: NR 93% of pts alive at 6 mos Median OS: NR Median follow-up: 10.0 mos (range: 0.8-14.1 mos) NR, not reached. Slide credit: clinicaloptions.com Long GV, et al. ASCO 2016. Abstract 9506.

KEYNOTE-029: Conclusions Combination of pembrolizumab 2 mg/kg + ipilimumab 1 mg/kg appears to have manageable toxicity profile 72% of pts received all 4 doses of ipilimumab Grade 3/4 immune-mediated AEs: 25% No treatment-related deaths Pembrolizumab 2 mg/kg + ipilimumab 1 mg/kg produces robust, durable responses in pts with advanced melanoma ORR: 57% ORR similar across key subgroups Durable response in 98% of pts DoR: 6+ to 43+ wks; 6-mo PFS: 70% AE, adverse event; DoR, duration of response. Slide credit: clinicaloptions.com Long GV, et al. ASCO 2016. Abstract 9506.

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