Debaters For The Evening:

Transcription

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2 Your Debaters For The Evening:

3 Current State of Immune Checkpoint Blockade in Selected Types of Solid Tumors Jeffery Weber, MD, PhD Naiyer A. Rizvi, MD

4 Current State of ICI in Melanoma and Bladder Cancers Jeffrey S. Weber, MD, PhD Laura and Isaac Perlmutter Cancer Center NYU Langone Medical Center

5 Current US/EU Approval Status of ICIs US EU PD-1 PD-L1 CTLA-4 Combo Pembrolizumab Nivolumab Atezolizumab Durvalumab Avelumab Ipilimumab Nivo + ipi Line 1L+ 2L+ 1L+ 2L+ 1L+ 2L+ 2L+ 1L+ 2L+ 1L+ 1L+ mmelanoma NSCLC chl arcc mscchn muc Merkel cell MSI-H chl=classical Hodgkin lymphoma; arcc=advanced renal cell carcinoma; mscchn=metastatic head and neck squamous cell carcinoma; muc=metastatic urothelial cancer; MSI-H=microsatellite instability-high solid tumors Product Prescribing Information Current as of June 2017

6 Should Immunotherapy be the First-line Therapy in all Stage IV Patients?

7 Overall Survival (%) Immune Checkpoint Inhibitors Provide Durable Long-term Survival for Pts with Advanced Melanoma Front-line OS = >50% for Nivolumab N=210 IPI (Pooled Analysis) NIVO Monotherapy (Phase 1 CA ) NIVO Monotherapy (Phase 3 Checkmate-066) N=107 N= Years Schadendorf D, et al. J Clin Oncol. 2015; Hodi S, et al. ASCO. 2016; Atkinson V, et al. Presented at: SMR 2015; November 6-9, 2015; Boston, MA.

8 Long-term Outcomes with Single Agent Pembrolizumab in KEYNOTE mo OS rate was 50% in the pooled pembrolizumab arms (n=556) 33-mo PFS rate was 31% and ORR was 42% Median duration of response was not reached for pembro (range 1.0+ to mo) Responses were durable in pts who completed pembro; 9.7 mo after completion of pembro with estimated PFS (95% CI) 91% (80-96) in 104 pts Pembro front-line responses were durable! Robert C, et al. ASCO

9 First-line Single Agent vs. Concurrent vs. Sequential Immunotherapy?

10 Updated Survival Data in BMS-067 Trial of IPI vs. NIVO vs. IPI/NIVO Median OS, months (95% CI) HR (99.5% CI) vs. IPI HR (99.5% CI) vs. NIVO NIVO + IPI (N=314) NIVO (N=316) IPI (N=315) NR 0.55 ( )* 0.88 ( ) NR (29.1-NR) 0.63 ( )* 20 ( ) *P<.0001 Larkin J, et al. AACR Database lock: September 13, Minimum follow-up of 28 months

11 How Toxic is Combination Checkpoint Blockade? With an additional 19 months of follow-up, safety was consistent with the initial report 1 Patients Reporting Event, % Treatment-related adverse event (AE) Treatment-related AE leading to discontinuation NIVO + IPI (N=313) NIVO (N=313) IPI (N=311) Any Grade Grade 3-4 Any Grade Grade 3-4 Any Grade Grade Treatment-related death 2 (0.6) a 1 (0.3) b 1 (0.3) b a Cardiomyopathy (NIVO+IPI, N=1); Liver necrosis (NIVO+IPI, N=1). Both deaths occurred >100 days after the last treatment. b Neutropenia (NIVO, N=1); Colon perforation (IPI, N=1) 1 Most select AEs were managed and resolved within 3-4 weeks (85-100% across organ categories) ORR was 70.7% for patients who discontinued NIVO+IPI due to AEs, with median OS not reached 1 Larkin J, et al. N Engl J Med. 2015; Larkin J, et al. AACR

12 Toxicity of Immune Checkpoint Blockade Major side effects of immunotherapy are related to development of autoimmunity Immune-related adverse events, also known as immune-mediated adverse events (iraes, imaes), may occur in any organ system Certain events may be life threatening or fatal Prompt recognition of potentially severe iraes improves outcomes Early diagnosis and aggressive systemic corticosteroids are key to prevent lifethreatening consequences Combining checkpoint inhibitors with agents such as CTLA-4 inhibitors, significantly increases iraes

13 First-line Therapy for Melanoma is Immunotherapy for Most Patients Hard to beat the front-line median OS of 30+ months for nivolumab or pembrolizumab alone and 40+ estimated OS for IPI/NIVO 2 year OS for IPI/NIVO concurrent or sequential = 62% is unmatched by any targeted phase III trial Robert C, et al. ASCO. 2017; Larkin J, et al. AACR. 2017; Schadendorf D, et al. J Clin Oncol. 2015; Hodi S, et al. ASCO. 2016; Atkinson V, et al. Presented at: SMR 2015; November 6-9, 2015; Boston, MA.

14 What Should be the First Choice for Adjuvant Therapy in High-risk Melanoma?

15 Overall Survival: Ipilimumab Adjuvant Therapy Eggermont AMM, et al. N Engl J Med

16 Dosing of Ipilimumab as Adjuvant Therapy: 3 vs. 10 mg/kg in E1609 Accrual was 1,670 including 511 IPI10, 636 HDI and 523 IPI3 pts Grade 3+ AEs were seen in 57% of IPI10 and 36% IPI3 pts; discontinuation in 53.8% at IPI10 and 35.2% at IPI3 At a median follow-up of 3.1 years, unplanned RFS analysis showed 3-year RFS of 54% (95% CI: 49, 60) at IPI10 and 56% (50, 61) at IPI3 Tarhini A, et al. ASCO

17 Checkpoint Blockade for Bladder Cancer

18 Efficacy of PD-1 or PD-L1 Immune Checkpoint Inhibitors in Advanced Bladder Cancer Study Previous Platinum? Comparator Drug PD-L1 Assay PD-L1 (+) Expression Cutoff ORR Time to Response (mo) OS (mo) Atezolizumab (IMvigor 210) N=310 Yes No SP142 IC0: <1% (n=103) IC1: 1-5% (n=108) IC2/3: >5% (n=100) All: 15%, IC0: 8% IC1: 10%, IC2/3: 26% 2.1 (95% CI: 2-2.2) All: 7.9 Atezolizumab (IMvigor 210) N=119 No, firstline** No SP142 IC0: <1% (n=39) IC1: 1-5% (n=48) IC2/3: >5% (n=32) All: 19% IC1/2/3: 19% IC2/3: 22% Not Published All: 10.6 Avelumab (JAVELIN) N=241 Yes No Clone >5% (n=81) PD-L1 (-): 14.7% PD-L1 (+): 25% ~2.6 PD-L1 (-) 6 month OS: 52.7% PD-L1 (+) 6 month OS: 61.2% Durvalumab (Study 1108) N=103 Yes No SP263 >25% (n=61) PD-L1 (-): 5.1% PD-L1 (+): 31.1% All: 1.41 PD-L1 (-): 2.05 PD-L1 (+): 1.41 Not Published Nivolumab (CheckMate-275) N=265 Yes No 28-8 pharmdx >1% (n=122) >5% (n=81) All: 19.6%, PD-L1 (-): 16.1% PD-L1 >1%: 23.8% PD-L1 >5%: 28.4% 1.87 (95% CI: ) All: 8.74 PD-L1 (-): PD-L1 >1%: 11.3 Nivolumab (CheckMate-032) N=78 Yes No 28-8 pharmdx <1% (n=42) >1% (n=25) All: 24.4% PD-L1 (-): 26.2% PD-L1 (+): 24% 1.5 (95% CI: ) All: 9.7 PD-L1 (-): 9.9 PD-L1 (+): 16.2 Pembrolizumab (KEYNOTE-045) N=542 Yes Paclitaxel, docetaxel or vinflunine 22C3 pharmdx >10% (n=164)* All: 21.1 vs. 11.4% PD-L1 (+): 21.6 vs. 6.7% 2.1 All: 10.3 vs. 7.4 PD-L1 (+): 8 vs. 5.2 Pembrolizumab (KEYNOTE-052) N=100/374 No, firstline** Gill DM, et al. Immunotherapy No 22C3 pharmdx >10% (n=30) All: 24% PD-L1 (+): 37% 2 (95% CI: 0.2-5) 6 month OS: 67% *Cisplatin ineligible patients; **PD-L1 expression included percentage of tumor and infiltrating immune cells with PDL1 expression

19 % Efficacy of PD-1 or PD-L1 Inhibitors in 2 nd Line Metastatic Bladder Cancer Objective Response Rate 19.6% 20.4% 17.6% 21.1% % Historic control with chemotherapy 12% 5 0 Atezolizumab N=310 Loriot ESMO 16 Nivolumab N=265 Sharma Lancet Oncol 17 Durvalumab N=103 Powles ASCO GU 17 Avelumab N=153 Patel ASCO GU 17 Pembrolizumab N=270 Bellmunt New Engl J Med 17 Black P. Presented at AUA 2017 (Adapted from Plimack ASCO 2016).

20 % ICI Response According to PD-L1 Expression in Advanced Bladder Cancer PD-L1 Positive PD-L1 Negative Atezolizumab N=310 Loriot ESMO 16 Nivolumab N=265 Sharma Lancet Oncol 17 Durvalumab N=103 Powles ASCO GU 17 Avelumab N=153 Patel ASCO GU 17 Pembrolizumab N=270 Bellmunt New Engl J Med 17 Adapted from Black P. Presented at AUA 2017.

21 % Grade >3 Adverse Events from ICIs in Advanced Bladder Cancer 20 (2 nd line Metastatic Trials) % 18% 15% 8 7.5% 4 5.2% 0 Atezolizumab N=310 Loriot ESMO 16 Nivolumab N=265 Sharma Lancet Oncol 17 Durvalumab N=103 Powles ASCO GU 17 Avelumab N=153 Patel ASCO GU 17 Pembrolizumab N=270 Bellmunt New Engl J Med 17 Adapted from Black P. Presented at AUA 2017.

22 KEYNOTE-045 Study (NCT ) Overall Survival: Total 43.9% 30.7% Events, n HR (95% CI) P Pembro ( ) Chemo 179 Pembrolizumab Chemotherapy Median (95% CI) 10.3 mo ( ) 7.4 mo ( ) Bellmunt J, et al. N Engl J Med No. at risk

23 Long-term Survival Follow-up of the Phase I Atezolizumab Trial Median and Landmark OS by PD-L1 Status IC0/1 (N=44) IC2/3 (N=51) All Pts* (N=95) Median OS (95% CI) 7.6 mo (4.7, 13.9) 11.3 mo (7.8, NE) 10.1 mo (7.3, 17) 1-year OS rate (95% CI) 40% (25, 56) 50% (36, 64) 46% (35, 56) 2-year OS rate (95% CI) 14% (2, 26) 43% (29, 57) 30% (20, 40) NE=Not estimable; *Efficacy-evaluable population with >12 wk f/u - A trend toward longer survival in pts with higher PD-L1 status was observed. Petrylak D, et al. Presented at ASCO GU With extended follow-up, single-agent atezolizumab continues to be well-tolerated in this phase Ia study muc cohort Most AEs were grade 1-2, and no treatment-related deaths occurred. Incidence declined substantially (including grade 3-4) after the first year. Clinical benefit was observed in a heavily pre-treated muc population Confirmed, ORs were durable (40% ongoing), with a median DOR of 22 mo and DOR up to 33+ mo observed Median OS was ~10 mo, with 46% and 30% of patients alive after 1 and 2 years, respectively (median survival follow-up duration, ~29 mo) Supports a role for atezolizumab as new standard of care in previously treated muc Phase III study IMvigor211 (NCT ) is ongoing, with enrollment completed and data expected later this year.

24 Atezolizumab was not Superior to Chemotherapy in Cisplatin-resistant Bladder Cancer?? IMvigor211 Study Design (NCT ) Urothelial Cancer Progression or recurrence of urothelial cancer following a first-line platinumcontaining regimen Randomization N=932 Estimated Completion: Nov 2017 Atezolizumab SOC: Docetaxel, Paclitaxel or Vinflunine Primary Endpoints OS Secondary Endpoints ORR PFS DOR Safety Primary efficacy endpoint, OS, was to be tested in a successive fashion in study populations defined by PD-L1 expression. The first population tested was people with the highest levels of PD-L1 expression (IC2/3), followed by those with any level of PD-L1 expression (IC1/2/3), and followed by the overall study population (ITT). Statistical significance needed to be achieved in the IC2/3 population in order to evaluate the IC1/2/3 population for statistical significance, and similarly achieved in the IC1/2/3 population in order to evaluate the overall study population for statistical significance.

25 Is PD-L1 Staining Associated with Clinical Outcome in Bladder Cancer? Study Agent Companion IHC Antibody Threshold for Positivity Target Cells Assay Associated w/ Response? Powles T, et al. Nature Atezolizumab Proprietary 5% TILs Yes Rosenberg JE, et al. Lancet Atezolizumab SP142 5% TILs Yes Balar AV, et al. Lancet (platinum ineligible) Atezolizumab SP142 5% TILs No Massard C, et al. J Clin Oncol Durvalumab SP263 25% TILs & TCs Yes Sharma P, et al. Lancet Oncol Nivolumab Dako % TCs No Sharma P, et al. Lancet Oncol Nivolumab Dako % TCs Yes Plimack ER, et al. Lancet Oncol Pembrolizumab 22C3 1% TILs & TCs TILs only Bellmunt J, et al. N Engl J Med (chemo vs immuno 2 nd line) Pembrolizumab 22C3 10% TILs & TCs No

26 Checkpoint Inhibitor Adverse Events (occurring in 10% of those with urothelial cancer that has progressed on platinum-containing regimen) Avelumab Atezolizumab Durvalumab Nivolumab Pembrolizumab Adverse Event, (%) All Grades Grades 3-4 All Grades Grades 3-4 All Grades Grades 3-4 All Grades Grades 3-4 All Grades Grades 3-4 Gen - Fatigue Gen - Periph edema Gen - Pyrexia GI - Constipation GI - Nausea GI - Vomiting GI Abdominal pain GI Diarrhea/colitis Resp - Cough Resp - Dyspnea Skin - Rash GU - UTI GU - Hematuria Musculoskeletal pain Reduced appetite U.S. FDA Prescribing Information

27 Conclusions: Checkpoint Blockade for Bladder Cancer Checkpoint inhibitors blocking the PD-1/PD-L1 axis including avelumab, nivolumab, pembrolizumab, durvalumab, and atezolizumab are well tolerated and active in metastatic bladder cancer Five drugs are approved in second-line bladder cancer; two of those are also approved first-line if cisplatin-ineligible PD-L1 staining is a poor biomarker for outcome, but may be associated with survival in some studies New immunotherapy combinations merit testing

28 Immunotherapy Advances in NSCLC Naiyer A. Rizvi, MD Price Family Chair, Clinical Translational Medicine Professor of Medicine Director, Thoracic Oncology Co-Director, Cancer Immunotherapy Columbia University Medical Center

29 OS (%) CA Five-Year Update: Phase I Nivolumab in Advanced NSCLC Median OS (95% CI), mo Overall (N=129) 9.9 (7.8, 12.4) y OS, 42% 2 y OS, 24% 3 y OS, 18% 5 y OS, 16% No. at Risk Years Brahmer J, et al. AACR

30 KEYNOTE-024 Study Design Key Eligibility Criteria Untreated stage IV NSCLC PD-L1 TPS 50% Pembrolizumab 200 mg IV Q3W (2 years) ECOG PS 0-1 No activating EGFR mutation or ALK translocation No untreated brain metastases No active autoimmune disease requiring systemic therapy R (1:1) N=305 Platinum-Doublet Chemotherapy (4-6 cycles) PD Pembrolizumab 200 mg Q3W for 2 years Key Endpoints Primary: PFS (RECIST v1.1 per blinded, independent central review) Secondary: OS, ORR, safety Exploratory: DOR Reck a To be eligible M, et for al. crossover, N Engl PD J Med. had to 2016; be confirmed by blinded, independent central NCT radiology review and all safety criteria had to be met.

31 PFS, % KEYNOTE-024: Progression Free Survival No. at risk Reck M, et al. N Engl J Med % 50% Events, n Median, mo HR (95% CI) P Pembro Chemo ( ) Time, months % 15% Pembrolizumab Chemotherapy <.001 Assessed per RECIST v1.1 by blinded, independent central review. Data cut-off: May 9, 2016.

32 O S, % No. at risk KEYNOTE-024: Overall Survival 80% 72% Time, months Reck M, et al. N Engl J Med Data cut-off: May 9, % 54% Events, n Median, mo HR (95% CI) P Pembro 44 NR 0.60 Chemo 64 NR ( ) Pembrolizumab Chemotherapy.005

33 Key Eligibility Criteria: Stage IV or recurrent NSCLC No prior systemic therapy for advanced disease No EGFR/ALK mutations sensitive to available targeted inhibitor therapy 1% PD-L1 expression CheckMate-026 Study Design Nivolumab vs. Chemotherapy in First-line NSCLC (Phase III) R 1:1 Stratification Factors at Randomization: PD-L1 Expression (<5% vs. 5%) Histology (squamous vs. non-squamous) Socinski M, et al. ESMO. 2016; Nivolumab 3 mg/kg Q2W N=271 Chemotherapy (histology dependent) Maximum of six cycles N=270 Tumor scans Q6W until week 48 then Q12W Disease Progression or Unacceptable Toxicity Disease Progression Crossover Nivolumab (optional) Primary Endpoint: PFS per BIRC ( 5% PD-L1 +) Secondary Endpoints: PFS per BIRC ( 1% PD-L1 +) OS ORR Exploratory Objective: Predictive biomarkers for outcomes with nivolumab

34 PFS (%) CheckMate-026: Primary Endpoint PFS per IRRC in (>5% PD-L1+) Median PFS, months (95% CI) Nivolumab n= (3.0, 5.6) Chemotherapy n= (5.4, 6.9) 1-year PFS rate, % HR=1.15 (95% CI: 0.91, 1.45), P= Nivolumab No. of patients at risk: Nivolumab Chemotherapy Socinski M, et al. ESMO Months Chemotherapy All randomized patients ( 1% PD-L1+): HR = 1.17 (95% CI: 0.95, 1.43)

35 PFS (%) CheckMate-026: TMB Analysis High TMB Low/Medium TMB Median PFS, months (95% CI) Nivolumab Chemotherapy n=47 n= (5.1, NR) 5.8 (4.2, 8.5) Median PFS, months (95% CI) Nivolumab Chemotherapy n=111 n= (2.8, 5.4) 6.9 (5.5, 8.6) HR = 0.62 (95% CI: 0.38, 1.00) HR = 1.82 (95% CI: 1.30, 2.55) Nivolumab Chemotherapy Chemotherapy Nivolumab No. at Risk Nivolumab Chemotherapy Adapted from Peters, et al. AACR Months Months

36 PACIFIC Study: Durvalumab Monotherapy in NSCLC Phase 3, randomized, double-blind, placebo-controlled, multicenter, global study (26 countries) Patients with locally advanced unresectable NSCLC (Stage III) in a consolidation setting (N=702) Arm 1 (n=468): Durvalumab IV 10 mg/kg Q2wks for up to 12 months Absence of progression following at least 2 cycles of platinum-based chemotherapy concomitant with radiation therapy Primary endpoints PFS, OS Secondary endpoints ORR, DoR, DSR Safety/tolerability PK, immunogenicity, QOL R 2:1 Arm 2 (n=234): Placebo IV Q2wks Est. completion: 2017 FPD: Q2 14 LPCD: Q NCT ; Creelan B, et al. Ann Oncol

37 Response Rate (%) Ipilimumab and Nivolumab: First-line NSCLC Unselected >1% PD-L1 >50% PD-L1 6 CRs CM-012 mono (1L) CM-012 combo (1L) Hellmann, et al. Lancet Oncol

38 Antonia S, et al. Lancet Oncol Durvalumab and Tremelimumab in NSCLC

39 KEYNOTE-021: Cohort G Key Eligibility Criteria Untreated stage IIIB or IV nonsquamous NSCLC No activating EGFR mutation or ALK translocation Provision of a sample for PD-L1 assessment a ECOG PS 0-1 No untreated brain metastases No ILD or pneumonitis requiring systemic steroids R (1:1) a N=123 End Points Primary: ORR (RECIST v1.1 per blinded, independent central review) Key secondary: PFS Other secondary: OS, DOR, safety Exploratory: Relationship between antitumor activity and PD-L1 TPS Pembrolizumab 200 mg Q3W for 2 years + Carboplatin AUC 5 mg/ml/min + Pemetrexed 500 mg/m 2 Q3W for 4 cycles b Carboplatin AUC 5 mg/ml/min + Pemetrexed 500 mg/m 2 Q3W for 4 cycles b PD Pembrolizumab 200 mg Q3W for 2 years Langer, et al. Lancet Oncol. 2016; NCT a Randomization was stratified by PD-L1 TPS <1% vs 1%. b Indefinite maintenance therapy with pemetrexed 500 mg/m 2 Q3W permitted.

40 Randomized Phase II: Carbo/Pemetrexed +/- Pembrolizumab PF S, % % 63% 13.0 mo 8.9 mo Chemo Time, months No. at risk PFS Pembro + Chemo Δ26% P=.0016 Events, n HR (95% CI) Pembro + chemo ( ) Chemo alone 33 P=.0102 Langer, et al. Lancet Oncol Pembro + Chemo Chemo Alone

41 Objective Response by PD-L1 TPS Langer, et al. Lancet Oncol <1% n=21 1% n=39 1%-49% n=19 50% n=20 Pembrolizumab + Chemotherapy <1% n=23 1% n=40 1%-49% n=23 Chemotherapy Alone 50% n=17 Horizontal dotted lines represent the ORR in the total population. Assessed per RECIST v1.1 by blinded, independent central review. Data cut-off: August 8, 2016.

42 Overall Survival % 92% 75% 72% O S, % Papadimitrakopoulou, et al. ASCO (Abstract 9094) Updated HR: 0.69 No. at risk Langer, et al. Lancet Oncol Time, months

43 Phase III First-line Combination Trials in Advanced NSCLC Treatment N Arms CheckMate Nivolumab, Ipilimumab Nivolumab MYSTIC 1092 KEYNOTE Impower Durvalumab, Tremelimumab Pembrolizumab, Pemetrexed, Carboplatin Atezolizumab, Paclitaxel/Carboplatin, Bevacizumab Durvalumab Atezolizumab, Paclitaxel/ Carboplatin Platinum-doublet Chemotherapy SOC Platinum-based Chemotherapy Pemetrexed, Carboplatin Paclitaxel/Carboplatin

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45 Current Status and Future Prospects for Development of Robust Prognostic and Predictive Biomarkers of Response in Selected Types of Solid Tumors

46 POINT: PD-L1 Staining by IHC is Generally a Useful Marker for the Benefit of PD-1 Blockade Joaquim Bellmunt, MD, PhD Associate Professor of Medicine Director, Bladder Cancer Center Dana-Farber Cancer Institute Boston, MA

47 The Rationale for PD-L1 Testing in Cancer PD-L1 Expression as a Predictive Biomarker Are tumors with high PD-L1 expression more sensitive to immune-mediated approaches compared with tumors that have low or no PD-L1 expression? The Prognostic Value of PD-L1 Expression Are tumors with high PD-L1 expression associated with better or worse prognosis compared with tumors that have low or no PD-L1 expression?

48 High PD-L1 Expression May Be Associated with Poor Prognosis Wu P, et al. PLoS ONE

49 Zhao T, et al. PLoS ONE

50 Considerations for PD-L1 Expression as a Predictive Biomarker and PD-L1 Testing Tumor Type PD-L1 Expression Level Cell Types That Express PD-L1 Variability Across PD-L1 Assays

51 PD-L1 Expression Can Vary Between Primary And Metastasis, Different Metastases, and Within One Tissue Sample Variation of PD-L1 Expression Within One Single NSCLC Tissue Sample 1 : Variation of PD-L1 Expression Between Primary Tumor Metastases 2 : Primary Melanoma Lymph Node Metastasis Brain Metastasis In 20 NSCLC samples tested with the anti PD-L IHC assay, discordant PD-L1 results were observed in 30% of the matched primary versus metastatic cases 3 1 McLaughlin J, et al. JAMA Oncol. 2016; 2 Madore J, et al. Pigment Cell Melanoma Res. 2015; 3 Phillips T, et al. Appl Immunohistochem Mol Morphol

52 PD-L1 Expression May Predict Sensitivity to Immune-Mediated Approaches Study Cancer Type Level of PD-L1 Expression ORR, % (vs. control) Fehrenbacher NSCLC TC3 or IC3* TC2 or IC2* TC1 or IC1* TC0 or IC0* 37.5 (13.0) 7.7 (15.6) 14.0 (19.1) 7.8 (9.8) Massard Bladder PD-L1 positive** PD-L1 negative** TC IC TC or IC Borghaei Non-squamous NSCLC PD-L1 10% PD-L1 5% PD-L1 1% 37 (13) 36 (13) 31 (12) Ferris SCCHN PD-L1 10% PD-L1 5% PD-L1 1% 27.9 (2.9) 22.2 (2.3) 17.0 (1.6) Rosenberg Bladder IC2/3 IC1/2/3 All IC=immune cells; IHC=immunohistochemistry; TC=tumor cells *TC3 50%, TC2 5% and <50%, TC1 1% and <5%, and TC0 <1%; IC3 10%, IC2 5% and <10%, IC1 1% and <5%, and IC0 <1% **PD-L1 positive: either TC or IC 25%, PD-L1 negative: both TC and IC <25% 1 Fehrenbacher L, et al. Lancet. 2016; 2 Massard C, et al. J Clin Oncol. 2016; 3 Borghaei H, et al. N Engl J Med. 2015; 4 Ferris RL, ASCO 2016; 5 Rosenberg JE, et al. Lancet

53 Advances in Other Treatment Settings in Advanced NSCLC: Pembrolizumab Immunotherapy (KEYNOTE 010 & 024) Pembrolizumab treatment setting: Indicated for first-line treatment for patients with metastatic NSCLC whose tumors express PD-L1 in 50% of cells and who do not have EGFR- or ALK-positive tumor mutations. Also indicated for patients with locally advanced or metastatic NSCLC progressing after 1 prior chemotherapy regimen and whose tumors express PD-L1 with 1% of cells. Patients with EGFR- or ALK-positive tumor mutations should also have received targeted therapy prior to treatment with pembrolizumab 1 Results from a randomized Phase III clinical trial: 2 Median OS TPS 50% 3,a Pembrolizumab 10 mg/kg (n=346) Pembrolizumab 2 mg/kg (n=345) Docetaxel (n=343) HR (95% CI) 0.38 (0.38, 0.77) P= (0.36, 0.7) P<.0001 Median OS a 4,a Median PFS (0.58, 0.88) P=.0008 p= (0.74, 1.05) P= (0.49, 0.75) P< (0.66, 0.94) P=.004 a Primary endpoint Time (months) 1 FDA Prescribing Information; 2 Herbst RS, et al. Lancet 2016; 3 Reck M, et al. N Engl J Med

54 Summary of FDA-Approved and Investigational PD-L1 Assays in Urothelial Carcinoma* Ab clone/ epitope Pembrolizumab 1 22C3 Atezolizumab 2,3 SP142 Nivolumab Durvalumab 5 SP263 Avelumab Cell type scored TCs and ICs ICs TCs TCs or ICs TCs Scoring method FDA status for urothelial carcinoma PD-L1 thresholds under evaluation CPS: % of PD-L1 positive TCs and ICs relative to the total number of tumor cells NA 1% 10% % of PD-L1 expressing ICs Complementary IC2/3 ( 5%), IC1 ( 1% but <5%), IC0 (<1%) % of PD-L1 expressing TCs NA 1% 5% % of PD-L1 expressing TCs or ICs NA 25% % of PD-L1 expressing TCs NA 5% * No head-to-head studies have been conducted and direct comparisons cannot be made between these studies. 1 Bellmunt J, et al. N Engl J Med. 2017; 2 Loriot Y, et al. Poster presentation at ESMO Abstract 83P; 3 Ventana. Roche receives FDA Approval for novel PD-L1 biomarker assay [press release]. May 18, 2016; 4 Sharma P, et al. Lancet Oncol. 2017; 5 Powles T, et al. Poster presentation at ASCO GU Abstract 286; 6 Patel M, et al. Poster presentation at ESMO Abstract 777PD.

55 Rosenberg JE, et al. Lancet PD-L1 Antibody Atezolimumab in Cisplatin-resistant Bladder Cancer

56 Phase II CheckMate 275 Study in Chemo-resistant Bladder Cancer: Nivolumab is Active All PD-L1 <1% PD-L1 1% PD-L1<5% PD-L1 5% Outcome, % N=265 n=143 n=122 n=184 n=81 Confirmed ORR by BIRC a % CI Median PFS in months (95% CI) 2.00 ( ) 1.87 ( ) 3.55 ( ) Median OS in months (95% CI) 8.74 (6.05 NR) 5.95 ( ) (8.74 NR) Responders (N=52) Time to response: 1.9 months ( ) Duration of response: NR (7.4-NR) Ongoing responders at time of response: 40/52 (77%) Safety: No new safety profile compare to prior reports a BIRC, blinded independent review committee Sharma P, et al. Lancet Oncol

57 Clinical Response to Durvalumab Monotherapy in UC Correlates with PD-L1 Expression Antitumour Activity of Durvalumab per BICR in the Primary Efficacy Population of the UC Cohort, including the Second-line or Greater ( 2L) Post-platinum Subgroup ORR, n (%) (95% CI) ORR, n (%) (95% CI) Total PD-L1 High PD-L1 Low/Neg ORR by BICR assessment Primary Efficacy Population (103pts, 13 weeks follow-up) N=103 N=61 N=39 21 (20.4) (13.1, 29.5) 19 (31.1) (19.9, 44.3) ORR by BICR assessment ( 2L) post-platinum subgroup 2 (5.1) (0.6, 17.3) N=94 N=58 N=33 19 (20.2) (12.6, 29.8) 18 (31.0) (19.5, 44.5) 1 (3.0) (0.1, 15.8) Clinical activity seen in all patient subgroups Greater efficacy occurred in patients with PD-L1 high expression Efficacy is still observed in the PD- L1 low/neg group consistent with the level seen with SoC PD-L1 SP263 assay is especially helpful in informing patients on the likelihood of response to durvalumab Powles, et al. Presented at 2017 ASCO GU.

58 KEYNOTE-052: Pembrolizumab as 1 st -Line Therapy for Cisplatin-Ineligible Bladder Cancer Objective Response (by PD-L1 Subgroups) CPS <1% N=33 CPS 1% to <10% N=33 CPS 10% N=30 N = 100 n % (95% CI) n % (95% CI) n % (95% CI) ORR (24%) 6 18% (7-36%) 5 15% (5-32%) 11 37% (20-56%) Complete response 1 3% (0.1-16%) % (4-31%) Partial response 5 15% (5-32%) 5 15% (5-32%) 7 23% (10-42%) Stable disease 3 9% (2-24%) 5 15% (5-32%) 7 23% (10-42%) Excluding those with CPS unknown *CPS=Combined positive score for PD-L1 positive cells (tumor, immune cells) Median time to response: 2.0 months (range, ) Median duration of response : Not reached (range, 1.4+ to 9.8+ months) Duration of response rate 6 months: 83% The PD-L1 high expression cut point was determined to be CPS 10% (PD-L1 positive tumor, immune cells) and enriched for response; this cut point will be validated in the remaining patients in the cohort (n=274 additional patients) Balar A, et al. Ann Oncol Data cutoff date: June 1, 2016

59 Overall Survival, (%) Adapted from 1 Bellmunt J, et al. N Engl J Med. 2017; 2 Bellmunt J, et al. Oral presentation at SITC 2016; 3 Overall Survival, (%) KEYNOTE-045: Overall Survival* No. at Risk Pembro Chemo Overall Survival: Total Time (months) Median OS, months (95% CI) Pembrolizumab 10.3 ( ) Chemotherapy 7.4 ( ) HR: 0.73; 95% CI, ; P= No. at Risk Pembro 74 Chemo 90 Overall Survival: CPS 10% 2 Median OS, months (95% CI) Pembrolizumab 8.0 ( ) Chemotherapy 5.2 ( ) HR: 0.57; 95% CI, ; P= Time (months) *Assessed per RECIST v1.1 by blinded, independent central review. Data cutoff date: Sep 7, CPS is the % of PD-L1 positive tumor cells and tumor-infiltrating immune cells relative to the total number of tumor cells.

60 PD-L1 Expression as a Predictor of Checkpoint Blockade Sensitivity in UC Powles, et al. Nature Phase I Atezolizumab Rosenberg, et al. Lancet Phase II Atezolizumab Balar, et al. Lancet Phase II Atezolizumab Massard, et al. J Clin Oncol Phase I Durvalumab Sharma, et al. Lancet Oncol Phase I/II Nivolumab Sharma, et al. Lancet Oncol Phase I/II Nivolumab Plimack, et al. Lancet Oncol Phase I Pembrolizumab Bellmunt, et al. N Engl J Med Phase III Pembrolizumab 5/8 studies reported positive association with PD-L1 staining

61 Key Diagnostic Challenges in UC In-clinic use of PD-L1 expression is likely to differ across lines of therapy Multiple diagnostic assays & algorithms used in clinical development: confusion regarding the impact of the test used

62 UC: SP263 Uses Tumor and Immune Cell Scores Durvalumab Tumour Cell (TC) Area TC area with PD-L1 expression IC area with PD-L1 expression Immune Cell (IC) area Definition Tumour Cell: Proportion of tumour cells with membrane staining for PD-L1 at any intensity above background staining Immune Cell: Proportion of tumour associated immune cells with staining for PD-L1 at any intensity above background staining OR Assay SP263 Cut-offs for PD-L1 High TC 25% or IC 25%

63 UC: SP142 Uses Tumor and Immune Cell Scores Atezolizumab Tumour Area Definition The proportion of tumour area occupied by PD- L1 expressing tumour-infiltrating immune cells of any intensity IC area with PD-L1 expression Assay Cut-offs for PD-L1 High SP142 5%

64 UC: 22C3 Uses Combined Proportion Score Pembrolizumab Tumour Cell (TC) Area TC area with PD-L1 expression Definition The percentage of PD-L1 expressing tumour and infiltrating immune cells relative to the total number of immune cells. IC area with PD-L1 expression + Assay 22C3 10% Cut-offs for PD-L1 High

65 Overall Survival (Probability) Overall Survival (Probability) CheckMate 025: OS by PD-L1 Expression in arcc Overall Survival: PD-L1 1% Median OS, months (95% CI) Nivolumab 21.8 ( ) Everolimus 18.8 ( ) Everolimus Time (months) Nivolumab No. of patients at risk Nivolumab Everolimus Overall Survival: PD-L1 <1% Median OS, months (95% CI) Nivolumab 27.4 (21.4 NE) Everolimus 21.2 ( ) HR (95% CI): 0.79 ( ) HR (95% CI): 0.77 ( ) Everolimus Time (months) Nivolumab No. of patients at risk Nivolumab Everolimus Adapted from Motzer, et al. N Engl J Med. 2015; Sharma P, et al. Oral presentation at ESMO Abstract 3LBA. Based on data cut-off of June 2015.

66 PFS PFS IMmotion 150: IRF-Assessed PFS ITT Population 1% of IC expressing PD-L1 Atezo + bev (n=101) Atezo (n=103) Sunitinib (n=101) mpfs, mos (95% CI) Stratified HR* (95% CI) 11.7 ( ) 1.00 ( ) P= ( ) 1.19 ( ) P= ( ) -- Atezo + bev (n=50) Atezo (n=54) Sunitinib (n=60) mpfs, mos (95% CI) Stratified HR* (95% CI) 14.7 ( ) 0.64 ( ) P= ( ) 1.03 ( ) P= ( ) No. at Risk Atezo + bev Atezo Sunitinib Time (months) No. at Risk Atezo + bev Atezo Sunitinib Time (months) *Compared with sunitinib. P values for descriptive purposes only and not adjusted for multiple comparisons. Adapted from McDermott D, et al. Poster presentation at ASCO GU Abstract 431.

67 Phase II Study of Atezolizumab + Bevacizumab vs. Sunitinib Phase I study: ORR 40% Phase II: PFS did not pan out but response seen in both PD-L1 high/low Overall survival a better metric Subsets of high PD-L1 cancers? McDermott D, et al. IMmotion150 biomarkers: AACR

68 PD-L1 in SCCHN Treated with Nivolumab Exploratory analysis: Patients with a tumor PD-L1 expression level of 1% or more may have a greater magnitude of effect from nivolumab therapy than those whose PD-L1 level was less than 1%. Ferris RL, et al. N Engl J Med

69 Conclusions The rationale includes potential prognostic and predictive value of PD-L1 testing PD-L1 positivity enriches for clinical benefit for selected drugs, diseases and settings IHC is unreliable for measuring PD-L1 expression Need to look beyond a single static biomarker Ergo, PD-L1 staining is not a useful helpful biomarker setting-based

70 Current Status and Future Prospects for Development of Robust Prognostic and Predictive Biomarkers of Response in Selected Types of Solid Tumors

71 COUNTERPOINT: PD-L1 Staining is Not All It s Purported to Be Jeffrey S. Weber, MD, PhD Laura and Isaac Perlmutter Cancer Center NYU Langone Medical Center

72 PD-L1 tumor staining makes little difference in melanoma, bladder, and RCC, but has some impact in lung cancer; with combined therapy, it is not useful

73 Nivolumab vs. DTIC-OS by PD-L1 Status in Front-line Melanoma Atkinson, et al. SMR

74 PD-L1 Staining is Associated with Superior OS and PFS with Pembrolizumab in Melanoma, but Does Not Rule Out Benefit PD-L1 positive PD-L1 positive PD-L1 negative PD-L1 negative No. at risk PD-L1 positive PD-L1 negative No. at risk PD-L1 positive PD-L1 negative Daud A, et al. J Clin Oncol

75 Larkin J, et al. AACR PD-L1 Staining Falls Out as a Factor with Combined Checkpoint Blockade in Melanoma

76 No Impact of PD-L1 Staining on Outcome in Squamous NSCLC Treated with Nivolumab Brahmer J, et al. N Engl J Med

77 No Impact of PD-L1 Staining on OS for Atezolizumab in Second-line NSCLC vs. Chemotherapy Rittmeyer A, et al. Lancet

78 Rizvi N, et al. J Clin Oncol No Impact of PD-L1 Expression on Outcome with Front-line NIVO + Chemotherapy in NSCLC

79 No Impact of PD-L1 Staining on Efficacy of Pembrolizumab in Refractory SCCHN PD-L1-positive patients PD-L1-negative patients PD-L1-positive patients PD-L1-negative patients Bauml J, et al. J Clin Oncol

80 Benefit of Nivolumab Compared to Everolimus in Renal Cell Cancer is Independent of PD-L1 Staining Kaplan-Meier Curve for Overall Survival, According to Programmed Death 1 Ligand (PD-L1) Expression Level Motzer R, et al. N Engl J Med

81 Little Impact of PD-L1 Staining on Survival in Renal Cell Cancer Patients Treated with Atezolizumab McDermott D, et al. J Clin Oncol

82 No Impact of PD-L1 Staining on OS in Refractory Bladder Cancer Patients Treated with Atezolimumab Balar A, et al. Lancet

83 Almost All Cells were PD-L1 Positive in Relapsed/Refractory Hodgkin s Lymphoma - Not Useful Chen, et al. J Clin Oncol

84 Presented By Noah Hahn at 2015 ASCO Annual Meeting PD-L1 Status Summary

85 What are the Facts? In non-squamous NSCLC, clear association of PD-L1 staining level and OS benefit from nivolumab versus chemotherapy 1 However, in all other histologies in phase II/III trials, there is unclear benefit of PD-L1 staining With combination immune checkpoint blockade, PD-L1 staining is not a useful biomarker The utility of a predictive biomarker is to inform who not to treat: by that criterion, PD-L1 staining falls short Choosing patients by PD-L1 staining will increase response rates PD-L1 staining can be difficult to quantitate, may vary from tumor to tumor, and may vary over time within a tumor, and is inducible Ergo, PD-L1 staining is not a useful biomarker 1 Borghaei, et al. N Engl J Med

86

87 Emerging Concepts of Combined Immune Checkpoint Blockade

88 POINT: The Efficacy of CTLA-4 + PD-1 is Superior to PD-1 Blockade Alone Robert L. Ferris, MD, PhD UPMC Endowed Professor and Chief Division of Head and Neck Surgery Associate Director for Translational Research Co-Leader, Cancer Immunology Program University of Pittsburgh Cancer Institute Pittsburgh, PA

89 Therapies to Drive an Immune Response Vaccines Adoptive T-cell therapies CAR-T TIL therapy Cytokines TLR agonists Agonist Abs (4-1BB, OX-40) Checkpoint blockade (Abs blocking CTLA4, PD-1, PD-L1)

90 Multiple Immuno-Inhibitory Pathways Regulate T-cell Tolerance and T-cell Exhaustion Potent ability to limit T-cell function Numerous therapeutic opportunities Many unanswered questions Freeman GJ, Sharpe AH. Nat Immunol Not Pictured: TIGIT, B7-H4, B7-H5/VISTA

91 Activating and Inhibitory Co-Receptors CD28 OX40 GITR CD137 CD27 Activating Receptors HVEM Inhibitory Receptors CTLA-4 LAG-3 PD-1 TIM-3 BTLA VISTA Ipilimumab Tremelimumab Pembrolizumab Nivolumab Durvalumab Mellman I, et al. Nature Agonistic antibodies T-cell stimulation Blocking antibodies

92 Proportion Alive Pooled OS Including EAP Data: 4846 pts Median OS (95% CI): 9.5 ( ) 3-year OS Rate (95% CI): 21% (20 22%) Ipilimumab CENSORED Months Patients at Risk Ipilimumab Schadendorf D, et al. J Clin Oncol

93 CheckMate-141 Study Design: Phase III Trial of Nivolumab in Recurrent/Metastatic SCCHN Key Eligibility Criteria R/M SCCHN of the oral cavity, oropharynx, larynx, or hypopharynx ECOG PS 0 1 Not amenable to curative therapy Progression 6 months of last dose of platinum-based therapy Documentation of p16 to determine HPV status No active CNS metastases Stratification factor Prior cetuximab treatment R 2:1 Randomized 360/360 Nivolumab 3mg/kg IV Q2W Investigator s Choice Methotrexate 40mg/m² IV weekly Docetaxel 30mg/m² IV weekly Cetuximab 400mg/m² IV once, then 250mg/m² weekly Primary endpoint OS Other endpoints PFS ORR Safety DOR Biomarkers Quality of life Ferris RL, et al. N Engl J Med

94 Overall Survival Overall Survival (% of patients) 100 Ferris RL, et al. N Engl J Med Nivolumab Investigator s Choice Median OS, mo (95% CI) Nivolumab (n=240) 7.5 ( ) Investigator s Choice (n=121) 5.1 ( ) HR (97.73% CI) 0.70 ( ) 1-y OS 1-y Rate OS Rate (95% (95% CI) CI) 36.0% 36.0% ( ) ( ) 16.6% ( ) Months No. at Risk Nivolumab Investigator s Choice

95 Overall Survival (% of patients) Overall Survival By PD-L1 Expression PD-L1 Expression 1% PD-L1 Expression <1% Treatment Arm Median OS, mo (95% CI) HR (95% CI) Treatment Arm Median OS, mo (95% CI) HR (95% CI) Nivolumab (n=88) 8.7 ( ) Investigator s Choice (n=61) 4.6 ( ) 0.55 ( ) Nivolumab (n=73) 5.7 ( ) Investigator s Choice (n=38) 5.8 ( ) 0.89 ( ) Nivolumab Investigator s Choice Months Nivolumab Investigator s Choice No. at Risk Nivolumab Investigator s Choice Ferris RL, et al. N Engl J Med Nivolumab Investigator s Choice Nivolumab Investigator s Choice Months

96 CheckMate-067: Study Design Randomized, double-blind, phase III study to compare NIVO + IPI or NIVO alone to IPI alone Previously untreated, unresectable or metastatic melanoma N=945 Randomize 1:1:1 N=314 Stratify by: PD-L1 expression* BRAF status AJCC M Stage N=315 N=316 *Verified PD-L1 assay with 5% expression level was used for the stratification of patients; validated PD-L1 assay was used for efficacy analyses. **Patients could have been treated beyond progression under protocol-defined circumstances. NIVO 1 mg/kg + IPI 3 mg/kg Q3W x 4 then NIVO 3 mg/kg Q2W NIVO 3 mg/kg Q2W + IPImatched placebo IPI 3 mg/kg Q3W x4 + NIVO-matched placebo Treat until progression** or unacceptable toxicity Wolchok JD, et al. ASCO

97 Response to Treatment NIVO + IPI (N=314) NIVO (N=316) IPI (N=315) ORR, % (95% CI) 57.6 ( ) 43.7 ( ) 19 ( ) Two-sided P value vs IPI <.001 < Best Overall Response - % Complete Response Partial Response Stable Disease Progressive Disease Unknown Duration of Response (months) Median (95% CI) NR (13.1, NR) NR (11.7, NR) NR (6.9, NR) *By RECISTv1.1; NR, not reached Wolchok JD, et al. ASCO

98 PFS by PD-L1 Expression Level (1%) *Per validated PD-L1 immunohistochemical assay based on PD-L1 staining of tumor cells in a section of at least 100 evaluable tumor cells Wolchok JD, et al. ASCO

99 Safety Summary 67.5% of patients (81/120) who discontinued the NIVO + IPI due to treatmentrelated AEs developed a response Patients Reporting Event, % Treatment-related adverse event (AE) Treatment-related AE leading to discontinuation Treatment-related death* NIVO + IPI (N=313) NIVO (N=313) IPI (N=311) Any Grade Grade 3-4 Any Grade Grade 3-4 Any Grade Grade *One reported in the NIVO group (neutropenia) and one in the IPI group (cardiac arrest). Wolchok JD, et al. ASCO

100 CTLA4 + PD-1 Targeting in Lung Cancer: CheckMate-012 NIVO 3 mg/kg Q2W + IPI 1 mg/kg Q12W (N=38) NIVO 3 mg/kg Q2W + IPI 1 mg/kg Q6W (N=39) NIVO 3 mg/kg Q2W (N=52) Confirmed ORR, % (95% CI) 47 (31-64) 39 (23-55) 23 (13-37) Median Duration of Response, months (95% CI) Median Length of Follow-up, months (range) Best Overall Response, % NR (11.3, NR) NR (8.4, NR) NR (5.7, NR) 12.9 (0.9-18) 11.8 ( ) 14.3( ) Complete Response Partial Response Stable Disease Progressive Disease Unable to Determine Median PFS, months (95% CI) 8.1 ( ) 3.9 ( ) 3.6 (2.3, 6.6) 1-year OS rate, % (95% CI) NC 69 (52-81) 73 (59-83) Antonia SJ, et al. J Thorac Oncol. 2016; Hellmann MD, et al. Lancet Oncol NC= Not calculated (when >25% of patients are censored); NR= Not reached Combination data based on a February 2016 database lock, monotherapy data based on a March 2015 database lock except for OS data, which are based on an August 2015 database lock

101 Durvalumab (Anti PD-L1) + Tremelimumab (Anti CTLA-4) Trials in SCCHN Phase II HAWK Phase II CONDOR Setting 2L SCCHN post plat in R/M setting 2L SCCHN post plat in R/M setting Regimen PD-L1 status Rationale Durvalumab Durvalumab + Tremelimumab Durvalumab Tremelimumab + N=112 N=120 N=60^ N=60^ Accelerated approval of the Monotherapy in PD-L1+ Zandberg Accelerated approval of the Combination in PD-L1 Establishes individual component contribution to combination in PD-L1 Siu Phase III EAGLE 2L SCCHN post plat 1L pts who progressed within 6 mo of multimodal tx w/pt in the locally advanced setting Durvalumab + Tremelimumab Durvalumab SOC + N=100 + N=100 + N=100 N=140 N=Adaptive 140* N=140 Confirmatory trial Combination approval in all-comers Ferris and Licitra

102 Potential of IO Therapies: 1L Trials with IO/IO Combinations Primary Endpoints Phase III CheckMate 651 No prior systemic therapy, platinum sensitive Nivolumab + Ipilimumab SOC (EXTREME) PFS, OS Phase II CheckMate 714 No prior therapy, platinum sensitive/refractory Nivolumab + Ipilimumab Nivolumab ORR Phase III KESTREL EAGLE No prior CT/IO, platinumsensitive (KESTREL) or refractory (EAGLE) Durvalumab + Tremelimumab Durvalumab SOC (EXTREME) PFS, OS Phase III KEYNOTE-048 1L+ R/M No prior systemic therapy, platinum sensitive Pembrolizumab + Platinum/5-FU Pembrolizumab SOC (EXTREME) PFS, OS

103 Conclusions Immune checkpoint therapy, specifically anti-pd1 or -CTLA-4 monotherapy, improves survival in patients with metastatic cancers Several questions remain: Does combining two different checkpoint inhibitors add benefit? YES Do all patients benefit from combination therapy? NO Do we need to incorporate biomarkers for patient selection? YES Do we need to consider acute and chronic AE profile, and patient PS? YES

104 Emerging Concepts of Combined Immune Checkpoint Blockade

105 COUNTERPOINT: The Efficacy of CTLA-4 + PD-1 is NOT Superior to PD-1 Blockade Alone Joaquim Bellmunt, MD, PhD Associate Professor of Medicine Director, Bladder Cancer Center Dana-Farber Cancer Institute Boston, MA

106 PD-1 Blockade Alone CTLA-4 + PD-1 Slide courtesy of A. Ribas

107 PD-1 Blockade Alone Slide courtesy of A. Ribas CTLA-4 + PD-1 Matching the images using the ipi+nivo combo approach

108 Efficacy in 611 Patients in KEYNOTE 001 ORR: 33% ORR in previously untreated: 45% Pembrolizumab provided an ORR of 25% to 52% in the initial melanoma expansion cohorts of KEYNOTE-001, irrespective of dosing schedule or prior ipilimumab status. Ribas A, et al. JAMA Central radiology review by RECIST v1.1 Data as of October 18, 2014; median follow-up: 21 months

109 Pembrolizumab Treatment-related AEs with Incidence >5% Adverse Event, % Total N=411 Any Grade Grade 3/4 Fatigue 36 2 Pruritus 24 <1 Rash 20 <1 Diarrhea 16 <1 Arthralgia 16 0 Nausea 12 <1 Vitiligo 11 0 Asthenia 9 0 Cough 9 0 Similar safety profiles in IPI-N and IPI-T patients Analysis cut-off date: October 18, Adverse Event, n (%) Total N=411 Any Grade Grade 3/4 Myalgia 9 0 Headache 8 <1 Hypothyroidism 8 <1 Decreased appetite 7 <1 Dyspnea 7 <1 Chills 6 0 Pyrexia 6 0 ALT increased 5 <1 Total Ribas A, et al. JAMA. 2016

110 CheckMate-067: Study Design Randomized, double-blind, phase III study to compare NIVO + IPI or NIVO alone to IPI alone N=314 NIVO 1 mg/kg + IPI 3 mg/kg Q3W x 4 then NIVO 3 mg/kg Q2W Previously untreated, unresectable or metastatic melanoma N=945 Randomize 1:1:1 Stratify by: BRAF status AJCC M stage Tumor PD-L1 expression <5% vs 5%* N=316 NIVO 3 mg/kg Q2W + IPImatched placebo Treat until progression** or unacceptable toxicity N=315 IPI 3 mg/kg Q3W x4 + NIVO-matched placebo *Verified PD-L1 assay with 5% expression level was used for the stratification of patients; validated PD-L1 assay was used for efficacy analyses. **Patients could have been treated beyond progression under protocol-defined circumstances. Wolchok JD, et al. ASCO The study was not powered for a comparison between NIVO and NIVO+IPI

111 Overall Survival Results From a Phase III Trial of Nivolumab Combined with Ipilimumab in Treatment-naïve Patients with Advanced Melanoma CheckMate 067 NIVO+IPI and NIVO significantly improved OS and PFS vs. IPI alone in patients with untreated advanced melanoma In descriptive analyses, NIVO+IPI resulted in numerically higher OS, PFS and ORR vs. NIVO alone For NIVO+IPI, median DOR and time to subsequent therapy are still not reached Larkin J, et al. AACR Abstract CT075.

112 Dr. Larkin s Comments about KEYNOTE-067 The trial isn t combined vs. sequential Just combo vs. single agents with crossover outside the study Study not designed or powered for comparison between nivo monotherapy vs. combination Number of events at this first OS analysis less then anticipated 112

113 Combination ICI Safety Summary With an additional 19 months of follow-up, safety was consistent with the initial report NIVO+IPI (N=313) NIVO (N=313) IPI (N=311) Patients reporting event, % Any Grade Grade 3-4 Any Grade Grade 3-4 Any Grade Grade 3-4 Treatment-related adverse event (AE) Treatment-related AE leading to discontinuation Treatment-related death, n (%) 2 (0.6) a 1 (0.3) b 1 (0.3) b Most select AEs were managed and resolved within 3-4 weeks (85 100% across organ categories) ORR was 70.7% for pts who discontinued NIVO+IPI due to AEs, with median OS not reached a Cardiomyopathy (NIVO+IPI, n=1); Liver necrosis (NIVO+IPI, n=1). Both deaths occurred >100 days after the last treatment. b Neutropenia (NIVO, n=1); colon perforation (IPI, n=1). Larkin J, et al. New Engl J Med 2015.

114 Progression-Free Survival (Intent-to-Treat) In the randomized phase III KEYNOTE-006 study, pembrolizumab had fewer toxicities and significantly improved overall survival compared with ipilimumab. Robert C, et al. N Engl J Med Wolchok JD, et al. ASCO

115 Checkmate 016: Phase 1b Trial of Nivolumab + Ipilimumab in Metastatic RCC N=175* Key Eligibility Criteria Advanced or metastatic clear cell RCC KPS 80% No active CNS metastases Available tumor tissue (archival or recent acquisition) For NIVO3 + IPI1 and NIVO1 + IPI3 expansion arms and NIVO3 + IPI3 addition arm: Treatment naïve Stopped due to toxicity Nivolumab 3 mg/kg (IV) + ipilimumab 1 mg kg (IV) Q3W x 4 Nivolumab 1 mg/kg (IV) + ipilimumab 3 mg/kg (IV) Q3W x 4 Nivolumab 3 mg/kg (IV) + ipilimumab 3 mg/kg (IV) Q3W x 4 Nivolumab 3 mg/kg (IV) Q2W Primary Outcome Measures: Safety and tolerability Secondary Outcome Measures: ORR, DOR *Estimated study enrollment including arm that terminated due to toxicity. There are 47 patients continuing in each remaining arm. One prior adjuvant or neoadjuvant therapy for localized or locally advanced RCC is allowed provided recurrence occurred 6 months after the last dose of the adjuvant or neoadjuvant therapy. Only prior cytokine-based treatment for metastatic RCC (eg, interferon-alpha [IFN-α] or interleukin 2 [IL-2]) as prior therapy is allowed. AEs, SAEs, and laboratory abnormalities. By RECIST v NCT ; Hammers HJ, et al. Poster presentation at ESMO Abstract 1062P.

116 Overall Survival (Probability) Overall Survival of Nivolumab + Ipilimumab in Advanced/Metastatic RCC (Checkmate 016) Median OS, months (95% CI) NIVO3 + IPI1 NR NIVO1 + IPI (25.99 NR) Time (months) Number of patients at risk NIVO3 + IPI NIVO1 + IPI Adapted from Hammers HJ, et al. Poster presentation at ESMO Abstract 1062P.

117 In Select Nivo-treated Pts, Median Survival Not Reached; How Much Crossover After Nivo? Motzer RJ, et al. N Engl J Med Escudier B, et al. Eur Urol

118 Phase II Study of Front Line Therapy With Nivolumab and Salvage Nivolumab + Ipilimumab in Patients With Advanced Renal Cell Carcinoma. HCRN: GU Nivolumab 240 mg IV Q2W x 6 then initial disease assessment PR or CR Part A Continue nivolumab 360 mg IV Q3W until PD, toxicity or 84 weeks PD or 12 months Part B Re-induce nivolumab 3 mg/kg and ipilimumab 1 mg/kg Q3W x 4 (must complete by week 16) Toxicity that requires discontinuation of study drug or 84 weeks of treatment completed continue being followed per protocol PD Evaluate for Part B Nivolumab 360 mg Q3W starting week PR, CR or SD Continue nivolumab until PD, toxicity or 48 weeks PD Off study NCT

119 DANUBE (Durvalumab +/- Tremelimumab) in 1 st Line UBC Randomization Stratification Factors 1. Cisplatin eligibility (eligible vs. ineligible) 2. PD-L1 status (positive vs. negative) 3. Visceral metastasis (presence or absence; i.e., bone, lung or liver) TCC of the urothelium (renal pelvis, ureters, urinary bladder and urethra) Treatment-naïve patients Unresectable/stage IV NCT Randomization N=650 Estimated Timelines Estimated Completion: September 2019 Estimated Primary Data: March 2018 Durvalumab + tremelimumab N=217 Durvalumab Monotherapy N=217 SOC N=217 Primary Endpoints PFS & OS (Combo vs. SOC) Secondary Endpoints PFS & OS (Single agents vs. SOC) PFS (PD-L1+ and PD-L1-) OS (Combo vs. SOC) ORR (Combo vs. SOC) FACT-BL Immunogenicity PK (C max and C trough )

120 Checkmate 032: Phase 1/2 Trial of Nivolumab vs Nivolumab + Ipilimumab in muc: Overall Survival and Progression-Free Survival Overall Survival (Probability) Progression-Free Survival (Probability) Median OS, months (95% CI) Median PFS, months (95% CI) NIVO 3 + IPI ( ) NIVO 3 + IPI ( ) NIVO 1 + IPI (4.5 NR) NIVO 1 + IPI ( ) No. at risk NIVO 1 + IPI 3 NIVO 3 + IPI Time (months) No. at risk NIVO 1 + IPI 3 NIVO 3 + IPI Time (months) Median follow-up times for NIVO 3 + IPI 1 arm is 16.7 months, and NIVO 1 + IPI 3 arm is 7.8 months Diamonds are censored patients. Sharma P, et al. Oral presentation at SITC Abstract 449.

121 KEYNOTE-045 Study (NCT ) Overall Survival: Total 43.9% 30.7% Events, n HR (95% CI) P Pembro ( ).0022 Chemo 179 Pembrolizumab Chemotherapy Median (95% CI) 10.3 mo ( ) 7.4 mo ( ) No. at risk Bellmunt J, et al. N Engl J Med

122 Can We Select Patients More Likely to Respond to PD-1/L1 Blockade? 1. Pre-existing T cell infiltration and adaptive PD-L1 expression 2. TCR clonality 4. Mutational load Rizvi, et al. Science Le, et al. NEJM Tumeh, et al. Nature Herbst, et al. Nature Tumeh, et al. Nature IFN signature by expression profiling Nonresponder Responder Best Overall Response, RECISTv1.1 Ribas, et al. ASCO Transcriptome Hugo, et al. Cell

123 Conclusions PD-1/PD-L1 blockade therapy should be used as single agent in patients who have a chance of responding to this therapy Combination therapies with PD-1/PD-L1 blockade should only be used in patients with a low likelihood of a tumor response to single agent therapy

124 Should PD-1 blockade be used alone or in combination?