Melanoma: novità ESMO 2017

Transcription

1 Melanoma: novità ESMO 2017 Vincenzo Picone Istituto dermopatico dell Immacolata (IDI)

2 AGENDA Metastatico CheckMate 067 Adiuvante LBA7_PR - BRIM8: a randomized, double-blind, placebo-controlled study of adjuvant vemurafenib in patients (pts) with completely resected, BRAFV600+ melanoma at high risk for recurrence. K. Lewis et al. LBA6_PR COMBI-AD: Adjuvant dabrafenib (D) plus trametinib (T) for resected stage III BRAF V600E/K mutant melanoma. A. Hauschild et al. LBA8_PR - Adjuvant therapy with nivolumab () versus ipilimumab () after complete resection of stage III/IV melanoma: A randomized, double-blind, phase 3 trial (CheckMate 238). J. Weber

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4 CheckMate 067: Phase III Trial of Nivo + Ipi vs Nivo vs Ipi for First-line Treatment of Mel Stratified by PD-L1 expression (< 5% vs 5%), BRAF status, and AJCC M stage Previously untreated pts with unresectable stage III/IV melanoma and ECOG PS 0-1 (N = 945) Nivo 1 mg/kg + Ipi 3 mg/kg q3w for 4 doses, then Nivo 3 mg/kg q2w (n = 314) Nivo 3 mg/kg q2w + Placebo (n = 316) Until disease progression or unacceptable toxicity Ipi 3 mg/kg q3w for 4 doses + Placebo (n = 315) Coprimary endpoints: PFS, OS Secondary endpoints: ORR, tumor PD-L1 expression and efficacy, safety Wolchok JD, et al. ASCO Abstract LBA1; Larkin j,et al. N Engl J Med 2015;373:23-34

5 CheckMate 067: Pt Population Baseline Characteristics Characteristic Nivo + Ipi (n = 314) Nivo (n = 316) Ipi (n = 315) Median age, yrs (range) 61 (18-88) 60 (25-90) 62 (18-89) Male, % ECOG PS 0, % AJCC M1c stage, % LDH, % > ULN 2 x ULN Brain metastases, % PD-L1 expression* 5% BRAF V600 mutant *PD-L1 expression measured by IHC using a validated automated assay with the PD-L1 clone 28-8.

6 CheckMate 067: ORR and PFS for Nivo + Ipi and Nivo Alone vs Ipi Alone The study was not powered for a comparison between the + and arms, but descriptive analyses are presented at ESMO congress Madrid 2017

7 CheckMate 067: OS for Nivo + Ipi and Nivo Alone vs Ipi Alone *Stratified log-rank P < vs Ipi. Exploratory endpoint. Study not powered to detect a statistical difference between Nivo + Ipi and Nivo.

8 CheckMate 067: Subsequent Therapies and Safety Subsequent Therapies Subsequent systemic therapies were received by: 32% in the + arm, 46% in the arm, and 63% in the arm The median time to subsequent systemic therapy was not reached for the + arm, 25.5 months for the arm, and 8.1 months for the arm Safety summary The majority of + treatment-related grade 3/4 select (immune-mediated) AEs resolved within 3 to 4 weeks of intervention, using established safety guidelines

9 CheckMate 067: conclusions + and significantly improved OS vs in patients with untreated MEL In descriptive analyses performed at 3 years, + demonstrated numerically higher efficacy than alone, with a 15% relative reduced risk of death, with the median DOR not reached Based on descriptive analyses, difference in OS and PFS favoring + vs alone was observed across clinically relevant subgroups, including M1c disease, elevated lactate dehydrogenase (LDH), and those with PD-L1-expressing and -non-expressing tumors Safety profile of + was consistent with earlier experience and, similar to both the and arms, the majority of treatment-related grade 3/4 select AEs with + resolved within 3 to 4 weeks of intervention using established safety guidelines Based on available data, + continues to offer unsurpassed OS and PFS benefit over other available first-line agents, with the potential for patients to remain treatment-free after discontinuation of therapy

10 AGENDA Metastatico CheckMate 067 Adiuvante LBA7_PR - BRIM8: a randomized, double-blind, placebo-controlled study of adjuvant vemurafenib in patients (pts) with completely resected, BRAFV600+ melanoma at high risk for recurrence. K. Lewis et al. LBA6_PR COMBI-AD: Adjuvant dabrafenib (D) plus trametinib (T) for resected stage III BRAF V600E/K mutant melanoma. A. Hauschild et al. LBA8_PR - Adjuvant therapy with nivolumab () versus ipilimumab () after complete resection of stage III/IV melanoma: A randomized, double-blind, phase 3 trial (CheckMate 238). J. Weber

11 ADJUVANT: BACKGROUND The 5y recurrence rate for resected stage IIIB melanoma is 68% and for stage IIIC is 89% 1 Despite the high rate of recurrence, more than two-thirds of patients do not receive adjuvant therapy for resected stage III melanoma 2,3 Interferon is approved in both the USA and the EU as adjuvant therapy for resected highrisk melanoma, but it is not widely used 4 The absolute differences in EFS at 5 and 10 years were 3.5% and 2.7%, and for OS were 3.0% and 2.8% respectively in favour of IFN-α. 6 Ipilimumab at 10 mg/kg was approved in the USA in 2015 for adjuvant therapy of resected stage III melanoma based on an improvement in RFS vs placebo in a randomized, phase 3 trial (EORTC 18071) 4 5 yrs OS 65,4% vs 54,4% (HR = 0.72, P = 0.001) 5 5 yrs RFS 40.8% vs 30.3% (HR, 0.76; P<0.001) However, >50% of patients treated experienced a grade 3/4 adverse event 5 There is a need to improve the risk-benefit ratio of adjuvant treatment given the toxicity observed with the approved ipilimumab adjuvant regimen of 10 mg/kg, 4,5 1. Romano E et al. J Clin Oncol. 2010;28: Harlan LC et al. Melanoma Res. 2011;21: Mohr P (discussant). Presented at ASCO Eggermont AMM et al. Lancet Oncol. 2015;16: Eggermont AMM et al. N Engl J Med. 2016;375: ; 6. Natalie j et al. Eur J Canc Sept 2017

12 STUDY RATIONALE: MELANOMA V600+ Oncogenic BRAF mutations are found in 40% of melanomas and cause constitutive activation of the MAPK pathway 1,2 In phase 3 trials (COMBI-d and COMBI-v), treatment with the BRAF inhibitor dabrafenib plus the MEK inhibitor trametinib improved survival in patients with unresectable or metastatic BRAF V600E/K mutant melanoma 3,4 Dabrafenib plus trametinib is approved for this patient population in many countries MAPK Pathway RAS mutbraf MEK perk Proliferation, Survival, Invasion, Metastasis Dabrafenib vemurafenib Trametinib cobimetinib MAPK, mitogen-activated protein kinase; mut, mutated. 1. Long GV, et al. J Clin Oncol. 2011;29: ; 2. Jakob JA, et al. Cancer. 2012;118: ; 3. Long GV, et al. N Engl J Med. 2014;371: ; 4. Robert C, et al. N Engl J Med. 2015;372:30-39.

13 A Phase III, Randomized, Double-Blind, Placebo-Controlled Study of Vemurafenib (RO ) Adjuvant Therapy in Patients With Surgically Resected, Cutaneous BRAF-Mutant Melanoma at High Risk for Recurrence (BRIM8) Karl Lewis, 1 Michele Maio, 2 Lev Demidov, 3 Mario Mandalà, 4 Paolo A. Ascierto, 5 Christopher Herbert, 6 Andrzej Mackiewicz, 7 Piotr Rutkowski, 8 Alexander Guminski, 9 Grant Goodman, 10 Brian Simmons, 10 Chenglin Ye, 10 Yibing Yan, 10 Dirk Schadendorf 11 1 University of Colorado Comprehensive Cancer Center, Aurora, CO, USA; 2 Division of Medical Oncology and Immunotherapy, Center for Immuno- Oncology, University Hospital of Siena, Siena, Italy; 3 N N Blokhin Russian Cancer Research Center, Ministry of Health, Moscow, Russia; 4 Department of Oncology and Haematology, Papa Giovanni XXIII Cancer Center Hospital, Bergamo, Italy; 5 Melanoma Unit, Cancer Immunotherapy and Innovative Therapies, Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy; 6 Bristol Haematology and Oncology Centre, Bristol, UK; 7 Department of Cancer Immunology, Poznan University for Medical Sciences, Med-POLONIA, Poznan, Poland; 8 Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Institute Oncology Center, Warsaw, Poland; 9 Melanoma Translational Research Group, Melanoma Institute Australia, Wollstonecraft, NSW, Australia; 10 Genentech, Inc., South San Francisco, CA, USA; 11 Department of Dermatology, University Hospital Essen, Essen, Germany; German Cancer Consortium, Heidelberg, Germany

14 BRIM8: Study Design Phase III, international, multicenter, double-blind, randomized, placebo-controlled study Cohort 1 = 314 (Stage IIC, IIIA a, IIIB) Stratified by disease stage and geographic region Cohort 2 = 184 (Stage IIIC) Stratified by geographic region 1:1 1:1 Placebo x 52 weeks (n=157) Vemurafenib 960 mg BID x 52 weeks (n=157) Placebo x 52 weeks (n=91) Vemurafenib 960 mg BID x 52 weeks (n=93) Primary endpoint DFS Secondary endpoints DMFS OS Safety HRQoL A two cohort design was implemented to address the concern that the IIIc patients would drive the analysis as they would have faster events than the other stage patients At data cutoff, median follow up was 31 months in Cohort 1 and 34 months in Cohort 2 BID, twice daily; DFS, disease-free survival; DMFS, distant metastasis-free survival; HRQoL. Health-related quality of life; OS, overall survival. Patients with stage IIIA melanoma were eligible if they had one or more nodal metastasis >1 mm in diameter.

15 Patients Alive and Disease-Free (%) BRIM8: Primary DFS endpoint (Cohort 1, stage IIC IIIB) One year of adjuvant vemurafenib results in 46% DFS risk reduction in stage IIC-IIIB BRAF V600 melanoma, demonstrating a substantial clinical benefit vs placebo Vemurafenib (n = 157) Placebo (n = 157) Events, n (%) 45 (29) 72 (46) Median DFS, months (95% CI) NE 36.9 (21.4 NE) Hazard ratio (95% CI) log-rank P-value 0.54 (0.37 to 0.78) p = a Patients at risk, n 0 + Vemurafenib Placebo 84.3% Censored 66.2% 72.3% 56.5% Time (months) Vemurafenib Placebo a Cannot be considered significant because primary endpoint was not met in Cohort 2. CI, confidence interval; DFS, disease-free survival; HR, hazard ratio, NE, not estimable.

16 Patients Alive and Disease-Free (%) BRIM8: Primary DFS endpoint (Cohort 2, stage IIIC) One year of adjuvant vemurafenib increased median DFS vs placebo in stage IIIc BRAF V600 melanoma demonstrating a biologic effect, however it did not significantly reduce DFS risk Patients at risk, n Vemurafenib Placebo 78.9% Censored 58.0% Time (months) CI, confidence interval; DFS, disease-free survival; HR, hazard ratio, NE, not estimable Vemurafenib (n = 93) Placebo (n =91) Events, n (%) 52 (56) 53 (58) Median DFS, months (95% CI) 23.1 ( ) 15.4 ( ) Hazard ratio (95% CI) log-rank P-value 0.80 (0.54 to 1.18) p = % 47.5% Vemurafenib Placebo

17 Patients Alive and Without Distant Metastasis (%) Patients Alive and Without Distant Metastasis (%) BRIM8: Distant metastasis-free survival (DMFS) Secondary endpoint of DMFS is consistent with the primary endpoint in both cohorts Patients at risk, n Cohort 2 (stage IIIC) Vemurafenib 83.2% 57.5% Placebo 77.0% 62.4% + Censored Time (months) Vemurefenib Placebo Patients at risk, n Cohort 1 (stage IIC IIIB) 20 Vemurafenib 88.9% 81.0% Placebo 79.5% 66.9% + Censored Time (months) Vemurafenib Placebo Cohort 2 (IIIC) Vemurafenib (n = 93) Placebo (n = 91) Events, n (%) 38 (41) 37 (41) Median DMFS, months (95% CI) 37.2 (22.1 NE) 30.7 (24.5 NE) Hazard ratio (95% CI) 0.91 (0.57 to 1.44) p = a log-rank P-value Cohort 1 (IIC IIIB) Vemurafenib (n = 157) Placebo (n = 157) Events, n (%) 34 (22) 52 (33) Median DMFS, months (95% CI) NE NE (36.9 NE) Hazard ratio (95% CI) 0.58 (0.37 to 0.90) p = a log-rank P-value a Cannot be considered significant because primary endpoint was not met in Cohort 2.

18 BRIM8: Adjuvant vemurafenib was tolerable and had a manageable safety profile The majority of patients in both cohorts received their planned treatment Vemurafenib (n = 247) Placebo (n = 247) Dose intensity, median % Treatment duration, median days Any grade AEs, n (%) 246 (100) 219 (89) Grade 3-4 AEs, n (%) 141 (57) 37 (15) Grade 5 AEs, n (%) 1 (<1) a 0 Treatment discontinuation for AEs, n (%) 49 (20) b 5 (2.0) b a Refers to a case of a patient who died 2 months after hospitalization for hypertension; brain imaging revealed haemorrhage in a cerebral lesion consistent with metastasis. The patient had surgery for the cerebral hemorrhage and was subsequently discharged. The death was not considered to be related to the study drug. b Treatment discontinuation for AEs by cohort, n (%) C2: 13 (14%) vemurafenib, vs 0 placebo ; C1: 34 (22%) vemurafenib, vs 5 (3%) placebo.

19 BRIM8: conclusions One year of adjuvant vemurafenib provided a substantial DFS benefit (46% reduction vs placebo) in patients with stage IIC-IIIB BRAF V600+ melanoma In stage III C BRAF V600+ melanoma adjuvant vemurafenib increased median DFS demostrating a biological effect, but did not significantly reduce DFS risk Secondary endpoints and subgroup analyses were consistant with the primary endpoint in both cohorts Adjuvant vemurafenib was tolerable and had a manegeable safety profile consistent with that previously observed in clinical studies The incidence of cuscc/ka is consistent with the known safety profile for vemurafenib No non-cuscc or GI malignancies were reported OS data were immature and furter follow up is ongoing cuscc, cutaneous squamous cell carcinoma;dfs, disease-free survival; GI, gastrointestinal; KA, keratoacanthoma; OS, overall survival.

20 AGENDA Metastatico CheckMate 067 Adiuvante LBA7_PR - BRIM8: a randomized, double-blind, placebo-controlled study of adjuvant vemurafenib in patients (pts) with completely resected, BRAFV600+ melanoma at high risk for recurrence. K. Lewis et al. LBA6_PR COMBI-AD: Adjuvant dabrafenib (D) plus trametinib (T) for resected stage III BRAF V600E/K mutant melanoma. A. Hauschild et al. LBA8_PR - Adjuvant therapy with nivolumab () versus ipilimumab () after complete resection of stage III/IV melanoma: A randomized, double-blind, phase 3 trial (CheckMate 238). J. Weber

21 COMBI-AD: ADJUVANT DABRAFENIB PLUS TRAMETINIB FOR RESECTED STAGE III BRAF V600 MUTANT MELANOMA Axel Hauschild, Mario Santinami, Georgina V. Long, Victoria Atkinson, Mario Mandalà, Vanna Chiarion-Sileni, James Larkin, Marta Nyakas, Caroline Dutriaux, Andrew Haydon, Caroline Robert, Laurent Mortier, Jacob Schachter, Ran Ji, Pingkuan Zhang, Bijoyesh Mookerjee, Jeff Legos, Richard Kefford, Reinhard Dummer, John M. Kirkwood

22 COMBI-AD: STUDY DESIGN Key eligibility criteria Completely resected, high-risk stage IIIA (lymph node metastasis > 1 mm), IIIB, or IIIC cutaneous melanoma BRAF V600E/K mutation Surgically free of disease 12 weeks before randomization ECOG performance status 0 or 1 No prior radiotherapy or systemic therapy Stratification BRAF mutation status (V600E, V600K) Disease stage (IIIA, IIIB, IIIC) R A N D O M I Z A T I O N N = 870 1:1 Treatment: 12 months a Dabrafenib 150 mg BID + trametinib 2 mg QD (n = 438) 2 matched placebos (n = 432) Followup b until end of study c Primary endpoint: RFS d Secondary endpoints: OS, DMFS, FFR, safety BID, twice daily; DMFS, distant metastasis free survival; ECOG, Eastern Cooperative Oncology Group; FFR, freedom from relapse; OS, overall survival; QD, once daily; RFS, relapse-free survival. a Or until disease recurrence, death, unacceptable toxicity, or withdrawal of consent; b Patients were followed for disease recurrence until the first recurrence and thereafter for survival; c The study will be considered complete and final OS analysis will occur when 70% of randomized patients have died or are lost to follow-up; d New primary melanoma considered as an event.

23 BASELINE DEMOGRAPHICS AND PATIENT CHARACTERISTICS a Dabrafenib Plus Trametinib (n = 438) Placebo (n = 432) Total (N = 870) Median age (range), years 50 (18-89) 51 (20-85) 50 (18-89) Male, n (%) 195 (45) 193 (45) 388 (45) BRAF mutation status, n (%) V600E V600K b 397 (91) 41 (9) 395 (91) 37 (9) 792 (91) 78 (9) ECOG performance status of 0, n (%) 402 (92) 390 (90) 792 (91) Disease stage, n (%) IIIA IIIB IIIC III (unspecified) N of positive lymph nodes, n (%) 1 2 or 3 4 Type of lymph involvement, n (%) Microscopic Macroscopic Not reported Primary tumour ulceration, n (%) Yes No 83 (19) 169 (39) 181 (41) 5 (1) 177 (40) 158 (36) 73 (17) 152 (35) 158 (36) 128 (29) 179 (41) 253 (58) 71 (16) 187 (43) 166 (38) 8 (2) 183 (42) 150 (35) 72 (17) 157 (36) 161 (37) 114 (26) 177 (41) 249 (58) 154 (18) 356 (41) 347 (40) 13 (1) 360 (41) 308 (35) 145 (17) 309 (36) 319 (37) 242 (28) 356 (41) 502 (58) a Reported for patients with available data; b One patient had both BRAF V600E and BRAF V600K mutations and was included in the V600K subset.

24 Proportion Alive and Relapse Free COMBI-AD: Relapse-free survival (primary endpoint) y, 88% y, 56% 2 y, 67% P = y, 58% Group Dabrafenib plus trametinib Events, n (%) 166 (38) Placebo 248 (57) Median (95% CI), mo NR (44.5-NR) 16.6 ( ) HR (95% CI) 0.47 ( ); P < y, 44% 3 y, 39% No. at Risk Dabrafenib plus trametinib Placebo Months From Randomization NR, not reached.

25 RELAPSE-FREE SURVIVAL BY SUBGROUP V600K (n = 78) V600E (n = 792) Male (n = 482) Female (n = 388) < 65 years (n = 712) 65 years (n = 158) Disease stage IIIA (n = 154) Disease stage IIIB (n = 356) Disease stage IIIC (n = 347) Micrometastasis (n = 309) Macrometastasis (n = 319) Micrometastasis and ulceration (n = 143) Micrometastasis and no ulceration (n = 165) Macrometastasis and ulceration (n = 116) Macrometastasis and no ulceration (n = 201) 1 Nodal metastatic mass (n = 360) 2 3 Nodal metastatic masses (n = 308) 4 Nodal metastatic masses (n = 145) HR Favors Dabrafenib Plus Trametinib Favors Placebo 10.00

26 Proportion With Freedom From Relapse FREEDOM FROM RELAPSE y, 88% y, 56% 2 y, 67% 3 y, 59% Group Dabrafenib plus trametinib Events, n (%) 165 (38) Placebo 247 (57) Median (95% CI), mo NR (44.5-NR) 16.6 ( ) HR (95% CI) 0.47 ( ); nominal P < y, 44% 3 y, 39% No. at Risk Dabrafenib plus trametinib Placebo Months From Randomization

27 Proportion Alive and Distant Metastasis Free DISTANT METASTASIS FREE SURVIVAL y, 91% y, 70% 2 y, 77% 2 y, 60% 3 y, 71% 3 y, 57% Group Dabrafenib plus trametinib Events, n (%) 110 (25) Placebo 152 (35) Median (95% CI), mo NR (NR-NR) NR (41.2-NR) HR (95% CI) 0.51 ( ); nominal P <.001 No. at Risk Dabrafenib plus trametinib Placebo Months From Randomization

28 Proportion Alive OVERALL SURVIVAL (FIRST INTERIM ANALYSIS) y, 94% 2 y, 91% 2 y, 83% 3 y, 86% 3 y, 77% No. at Risk Dabrafenib plus trametinib Placebo Group Dabrafenib plus trametinib Events, n (%) 60 (14) Placebo 93 (22) a Prespecified significance boundary (P = ). Median (95% CI), mo NR (NR-NR) NR (NR-NR) HR (95% CI) 0.57 ( ); P =.0006 a Months From Randomization

29 SAFETY SUMMARY AE Category, n (%) Dabrafenib Plus Trametinib (n = 435) Placebo (n = 432) Any AE 422 (97) 380 (88) AEs related to study treatment 398 (91) 272 (63) Any grade 3/4 AE 180 (41) 61 (14) Any SAE 155 (36) 44 (10) SAEs related to study treatment 117 (27) 17 (4) Fatal AEs related to study drug 0 0 AEs leading to dose interruption 289 (66) 65 (15) AEs leading to dose reduction 167 (38) 11 (3) AEs leading to treatment 114 (26) 12 (3) discontinuation AE, adverse a event; SAE, serious adverse event. a Most common AEs leading to treatment discontinuation in the dabrafenib plus trametinib arm were pyrexia (9%) and chills (4%)

30 CONCLUSIONS This is the first randomized study of combination BRAF and MEK inhibition as melanoma adjuvant therapy Dabrafenib plus trametinib significantly reduced the risk of disease recurrence vs placebo in patients with resected high-risk, stage III, BRAF V600E/K mutant melanoma (RFS HR, 0.47 [95% CI, ]; P <.001) Estimated 1-, 2-, and 3-year RFS rates with dabrafenib plus trametinib were 88%, 67%, and 58%, respectively Similar RFS benefit was observed across patient subgroups, including all stage categories In addition to RFS, OS improvement with dabrafenib plus trametinib was demonstrated (HR, 0.57 [95% CI, ]) Similar rates of post-recurrence therapy in each arm attributes OS improvement to adjuvant dabrafenib plus trametinib treatment Manageable safety profile with combination dabrafenib and trametinib Dabrafenib plus trametinib is a novel adjuvant treatment option for BRAF V600 mutant melanoma

31 AGENDA Metastatico CheckMate 067 Adiuvante LBA7_PR - BRIM8: a randomized, double-blind, placebo-controlled study of adjuvant vemurafenib in patients (pts) with completely resected, BRAFV600+ melanoma at high risk for recurrence. K. Lewis et al. LBA6_PR COMBI-AD: Adjuvant dabrafenib (D) plus trametinib (T) for resected stage III BRAF V600E/K mutant melanoma. A. Hauschild et al. LBA8_PR - Adjuvant therapy with nivolumab () versus ipilimumab () after complete resection of stage III/IV melanoma: A randomized, double-blind, phase 3 trial (CheckMate 238). J. Weber

32 Adjuvant Therapy With Nivolumab Versus Ipilimumab After Complete Resection of Stage III/IV Melanoma: A Randomized, Double-blind, Phase 3 Trial (CheckMate 238) Jeffrey Weber, 1 Mario Mandala, 2 Michele Del Vecchio, 3 Helen Gogas, 4 Ana M. Arance, 5 C. Lance Cowey, 6 Stéphane Dalle, 7 Michael Schenker, 8 Vanna Chiarion-Sileni, 9 Ivan Marquez-Rodas, 10 Jean-Jacques Grob, 11 Marcus Butler, 12 Mark R. Middleton, 13 Michele Maio, 14 Victoria Atkinson, 15 Paola Queirolo, 16 Veerle de Pril, 17 Anila Qureshi, 17 James Larkin, 18 * Paolo A. Ascierto 19 * 1 NYU Perlmutter Cancer Center, New York, New York, USA; 2 Papa Giovanni XIII Hospital, Bergamo, Italy; 3 Medical Oncology, National Cancer Institute, Milan, Italy; 4 University of Athens, Athens, Greece; 5 Hospital Clínic de Barcelona, Barcelona, Spain; 6 Texas Oncology-Baylor Cancer Center, Dallas, Texas, USA; 7 Hospices Civils de Lyon, Pierre Bénite, France; 8 Oncology Center Sf Nectarie Ltd., Craiova, Romania; 9 Oncology Institute of Veneto IRCCS, Padua, Italy; 10 General University Hospital Gregorio Marañón, Madrid, Spain; 11 Hôpital de la Timone, Marseille, France; 12 Princess Margaret Cancer Centre, Toronto, Ontario, Canada; 13 Churchill Hospital, Oxford, United Kingdom; 14 Center for Immuno-Oncology, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy; 15 Gallipoli Medical Research Foundation and Princess Alexandra Hospital, Woolloongabba, and University of Queensland, Greenslopes, Queensland, Australia; 16 IRCCS San Martino-IST, Genova, Italy; 17 Bristol-Myers Squibb, Princeton, New Jersey, USA; 18 Royal Marsden NHS Foundation Trust, London, UK; 19 Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy; *Contributed equally to this study.

33 CA : CA : Study Design Patients with high-risk, completely resected stage IIIB/IIIC or stage IV melanoma Stratified by: 1:1 n = 453 n = 453 1) Disease stage: IIIB/C vs IV M1a-M1b vs IV M1c 2) PD-L1 status at a 5% cutoff in tumor cells 3 mg/kg IV Q2W and placebo IV Q3W for 4 doses then Q12W from week mg/kg IV Q3W for 4 doses then Q12W from week 24 and placebo IV Q2W Follow-up Maximum treatment duration of 1 year Enrollment period: March 30, 2015 to November 30, 2015

34 At least 15 years of age Key Eligibility Criteria Eastern Cooperative Oncology Group performance status score of 0 or 1 Histologically confirmed melanoma metastatic to regional lymph nodes or with distant metastases surgically rendered free of disease Stage IIIB, IIIC, or stage IV melanoma by the American Joint Committee on Cancer 2009 classification, 7th edition Complete regional lymphadenectomy or resection was required within 12 weeks of randomization Patients with ocular/uveal melanoma, systemic corticosteroid use >10 mg/day of prednisone or equivalent, or previous systemic therapy for melanoma were excluded Acral and mucosal melanoma were allowed

35 Study Overview Primary endpoint RFS: time from randomization until first recurrence (local, regional, or distant metastasis), new primary melanoma, or death Secondary endpoints OS Safety and tolerability RFS by PD-L1 tumor expression HRQoL Current interim analysis Primary endpoint (RFS), safety, and HRQoL DMFS (exploratory) Duration of follow-up: minimum 18 months; 360 events DMFS = distant metastasis-free survival; HRQoL = health-related quality of life

36 Baseline Patient Characteristics (n = 453) (n = 453) Median age, years Male, % Stage, IIIB+IIIC, % Macroscopic lymph node involvement (% of stage IIIB+IIIC) Ulceration (% of stage IIIB+IIIC) Stage IV, % M1c without brain metastases (% stage IV) PD-L1 expression 5%, % BRAF mutation, % LDH ULN, % Most of the patients had cutaneous melanoma (85%), and 4% had acral and 3% had mucosal melanoma All 905 patients are off treatment; median doses were 24 (1-26) in the group and 4 (1-7) in the group 397 patients completed 1 year of treatment (61% of the group and 27% of the group)

37 RFS (%) Primary Endpoint: RFS 100 Events/patients 154/ / Median (95% CI) NR NR (16.6, NR) 80 HR (97.56% CI) 0.65 (0.51, 0.83) Log-rank P value < % 61% 66% 53% Number of patients at risk Months

38 RFS (%) RFS (%) Subgroup Analysis of RFS: PD-L1 Expression Level PD-L1 Expression Level <5% PD-L1 Expression Level 5% Events/patients 114/ /286 Events/patients 31/152 57/154 Median (95% CI) NR 15.9 (10.4, NR) Median (95% CI) NR NR 100 HR (95% CI) 0.71 (0.56, 0.91) 100 HR (95% CI) 0.50 (0.32, 0.78) % % % % Number of patients at risk Months Number of patients at risk Months

39 RFS (%) RFS (%) Subgroup Analysis of RFS: Disease Stage Stage III Stage IV Events/patients 120/ /366 Events/patients 33/82 43/87 Median (95% CI) NR NR (16.6, NR) Median (95% CI) NR (15.9, NR) 16.8 (8.5, NR) 100 HR (95% CI) 0.65 (0.52, 0.83) 100 HR (95% CI) 0.70 (0.45, 1.10) % % % 50 58% Months Months Number of patients at risk Number of patients at risk

40 RFS (%) RFS (%) Subgroup Analysis of RFS: BRAF Mutation Status BRAF Mutant BRAF Wild type Events/patients 63/187 84/194 Events/patients 67/ / Median (95% CI) NR NR (16.1, NR) HR (95% CI) 0.72 (0.52, 1.00) Median (95% CI) NR 16.6 (12.3, NR) HR (95% CI) 0.58 (0.43, 0.79) % % % % Number of patients at risk Months Number of patients at risk Months

41 RFS: Prespecified Subgroups Subgroup No. of events/no. of patients 3 mg/kg 10 mg/kg Unstratified HR (95% CI) Overall Overall 154/ / (0.53, 0.81) Age <65 years 106/ / (0.51, 0.84) 65 years 48/120 59/ (0.45, 0.97) Sex Male 99/ / (0.53, 0.88) Female 55/195 73/ (0.44, 0.89) Stage (CRF) Stage IIIb 41/163 54/ (0.44, 1.00) Stage IIIc 79/ / (0.49, 0.87) Stage IV M1a-M1b 25/62 35/ (0.38, 1.05) Stage IV M1c 8/20 8/ (0.37, 2.66) Not reported 1/2 0/0 Stage III: Ulceration Absent 58/201 94/ (0.42, 0.82) Stage III: Lymph node involvement Present 60/153 64/ (0.51, 1.04) Not reported 2/15 5/ (0.07, 2.00) Microscopic 41/125 55/ (0.47, 1.07) Macroscopic 72/ / (0.46, 0.84) Not reported 7/25 7/ (0.21, 1.72) Unstratified HR (95% CI) PD-L1 status <5%/indeterminate 123/ / (0.56, 0.90) BRAF mutation status 5% 31/152 57/ (0.32, 0.78) Mutant 63/187 84/ (0.52, 1.00) Wild-type 67/ / (0.43, 0.79) Not reported 24/69 17/ (0.45, 1.54) 0 1 2

42 DMFS (%) Exploratory Endpoint: DMFS for Stage III Patients % 73% Events/patients 93/ /366 Median (95% CI) NR NR HR (95% CI) 0.73 (0.55, 0.95) Log-rank P value Number of patients at risk Months

43 Safety Summary AE, n (%) (n = 452) (n = 453) Any grade Grade 3/4 Any grade Grade 3/4 Any AE 438 (97) 115 (25) C 446 (98) 250 (55) C Treatment-related AE 385 (85) 65 (14) 434 (96) 208 (46) Any AE leading to discontinuation Treatment-related AE leading to discontinuation 44 (10) 21 (5) 193 (43) 140 (31) 35 (8) C 16 (4) 189 (42) C 136 (30) There were no treatment-related deaths in the group There were 2 (0.4%) treatment-related deaths in the group (marrow aplasia and colitis), both >100 days after the last dose

44 Treatment-Related Select Adverse Events AE, n (%) (n = 452) (n = 453) Any grade Grade 3/4 Any grade Grade 3/4 Skin 201 (44.5) 5 (1.1) 271 (59.8) 27 (6.0) Gastrointestinal 114 (25.2) 9 (2.0) 219 (48.3) 76 (16.8) Hepatic 41 (9.1) 8 (1.8) 96 (21.2) 49 (10.8) Pulmonary 6 (1.3) 0 11 (2.4) 4 (0.9) Renal 6 (1.3) 0 7 (1.5) 0 Hypersensitivity/ 11 (2.4) 1 (0.2) 9 (2.0) 0 infusion reaction Endocrine Adrenal disorder 6 (1.3) 2 (0.4) 13 (2.9) 4 (0.9) Diabetes 2 (0.4) 1 (0.2) 1 (0.2) 0 Pituitary disorder 8 (1.8) 2 (0.4) 56 (12.4) 13 (2.9) Thyroid disorder 92 (20.4) 3 (0.7) 57 (12.6) 4 (0.9) Median time to onset of treatment-related select AEs was generally shorter for patients receiving (range weeks) than for those receiving (range weeks)

45 CA : Conclusions Nivolumab showed a clinically and statistically significant improvement in RFS vs the active control of high-dose ipilimumab for patients with resected stages IIIB/IIIC and stage IV melanoma at high risk of recurrence (HR = 0.65, P < ) 18-month RFS rates were 66% for nivolumab and 53% for ipilimumab Benefit for nivolumab was observed across the majority of prespecified subgroups tested, including PD-L1 and BRAF mutation status Nivolumab has a superior safety profile in comparison with ipilimumab, with fewer grade 3/4 AEs and fewer AEs leading to treatment discontinuation Nivolumab has the potential to be a new standard treatment option for patients with resected stage IIIB, IIIC, and IV melanoma regardless of BRAF mutation

46 Conclusions adjuvant TX A. Eggermont ESMO 2017 Presidential Symposium III presentation BRAFi Monotherapy: unclear future BRAFi+MEKi for BRAFmut Convenience: oral Clear RFS+DMFS+OS benefit in all stages ANTI-PD1 FOR ALL? Convenience q2wk (nivo) vs q3wk/flat dose (pembro) Pending overall survival data. Potentially their strength End of IFN Except for ROW, but Only in ulcerated melanoma PRO: Availibility/price End of adjuvant ipilimumab LIGHT is the future for ipi in combo development