Latest Advances in the Systemic Treatment of Melanoma

Latest Advances in the Systemic Treatment of Melanoma Luis de la Cruz Merino Hospital Universitario Virgen Macarena

OUTLINE GENERAL OVERVIEW OF MELANOMA SYSTEMIC TREATMENT IMMUNOTHERAPY * ANTI-CTLA4 * ANTI-PD1 AND COMBOS * IMMUNOVIROTHERAPY TARGETED THERAPIES * BRAFi, MEKi, COMBOS COMBINATIONS OF INMUNOTHERAPY AND TARGETED THERAPIES 2017 ALGORITHMS CONCLUSIONS AND FUTURE PERSPECTIVES

SYSTEMIC MELANOMA TREATMENTS ALONG THE TIME Surgery 1846 Radiation Therapy 1901 Chemotherapy 1946 Immunotherapy Interferon-α 1995 a Interleukin-2 1998 a Immuno-Oncology Ipilimumab 2011 a Nivolumab 2014 a Pembrolizumab 2014 a Nivolumab+ Ipilimumab 2015 a Targeted Therapy Vemurafenib 2011 a Trametinib 2013 a Dabrafenib 2013 a Dabrafenib + trametinib 2014 a Vemurafenib + Cobimetinib 2015 a Date of first approval in the United States or European Union. IPI, ipilimumab; NIVO, nivolumab. 1. DeVita VT Jr, et al. Cancer Res. 2008;68:8643-8653. 2. American Cancer Society. The history of cancer. http://www.cancer.org/cancer/cancerbasics/thehistoryofcancer/. 3. Finn OJ. Ann Oncol. 2012;23(suppl 8):viii6-viii9. 4. Mansh M. Yale J Biol Med. 2011;84:381-389. 5. Kirkwood JM, et al. CA Cancer J Clin. 2012;62:309-335. 6. NCI Cancer Drug Information. Vemurafenib. http://www.cancer.gov/cancertopics/druginfo/vemurafenib. 7. NCI Cancer Drug Information. Dabrafenib. http://www.cancer.gov/cancertopics/druginfo/dabrafenib. 8. NCI Cancer Drug Information. Trametinib. http://www.cancer.gov/cancertopics/druginfo/trametinib. 9. FDA Press Release. December 22, 2014 http://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm427807.htm accessed 9 March, 2015. 10. FDA. Approved drugs: pembrolizumab. September 4, 2014. http://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm412861.htm; 11. ASCO press release 10 Jan, 2014. 12. BMS Press Release 1 October, 2015.

MEDIAN OVERALL SURVIVAL, HISTORICAL DATA

Melero I. Nat Rev 2014 Targets for immunotherapy

CTLA-4 AND PD1/PD-L1 AXIS

ANTI-CTLA4: PHASE 3 CLINICAL TRIALS Franklin EJSO 2016

Ipilimumab 3mg/kg + gp100/placebo HR 0.68/0.66 mos 10 vs 6.4m Ipilimumab 10mg/kg + DTIC HR 0.72 mos 11.2 vs 9.1m 2nd line 1st line

OVERALL SURVIVAL AND SAFETY RESULTS FROM A PHASE 3 TRIAL OF IPILIMUMAB AT 3 MG/KG VS10 MG/KG IN PATIENTS WITH METASTATIC MELANOMA Ascierto PA, 1 Del Vecchio M, 2 Robert C, 3 Mackiewicz A, 4 Chiarion Sileni V, 5 Arance AM, 6 Schmidt H, 7 Lebbé C, 8 Bastholt L, 9 Hamid O, 10 Rutkowski P, 11 McNeil C, 12 Garbe C, 13 Loquai C, 14 Dreno B, 15 Thomas L, 16 Grob J-J, 17 Hennicken D, 18 Qureshi A, 18 Maio M 19 1 Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy; 2 Medical Oncology, National Cancer Institute, Milan, Italy; 3 Institute Gustave, Roussy, Villejuif, France; 4 Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, Poznan Medical University, Poznan, Poland; 5 Istituto Oncologico Veneto, Padova, Italy; 6 Hospital Clinic, Barcelona, Spain; 7 Aarhus University Hospital, Aarhus, Denmark; 8 AP-HP Dermatology CIC Departments, Saint-Louis Hospital, INSERM U976, Université Paris Diderot, Paris, France; 9 Odense University Hospital, Odense, Denmark; 10 The Angeles Clinic and Research Institute, Los Angeles, CA, USA; 11 Maria Sklodowska-Curie Memorial Cancer Center, Warsaw, Poland; 12 Chris O'Brien Lifehouse and Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia and Melanoma Institute Australia, Sydney, New South Wales, Australia; 13 University Hospital Tübingen, Tübingen, Germany; 14 University Medical Center, Mainz, Germany; 15 Department of Oncodermatology, INSERM Research Unit 892, University Hospital, Nantes, France; 16 Department of Dermatology, Centre Hospitalier Lyon Sud, Pierre-Bénite Cedex, France; 17 Aix-Marseille University, APHM Timone, France; 18 Bristol-Myers Squibb, Princeton, NJ, USA; 19 University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy 12

CA184-169: STUDY DESIGN Initial treatment phase Re-treatment phase a Previously Treated/Untreated IPI 10 mg/kg Metastatic MEL b Q3W 4 (N = 727) (n = 365) Stratification M0 + M1a + M1b vs M1c without brain metastases vs IPI 3 mg/kg M1c with brain Q3W 4 metastases (n = 362) Prior treatment (y/n) ECOG PS (0/1) Week 1 Week 24 Randomize 1:1 IPI 10 mg/kg Q3W 4 (n = 23) IPI 3 mg/kg Q3W 4 (n = 32) Enrollment period: March 2012 to August 2012 No crossover allowed between treatment arms a After initial response (or stable disease 3 months) and subsequent progressive disease in the absence of intolerable toxicity. b Patients could not be treated with BRAF/PD-1 therapy. ECOG PS = Eastern Cooperative Oncology Group performance status; Q3W = every 3 weeks.

BASELINE CHARACTERISTICS IPI 10 mg/kg n = 365 IPI 3 mg/kg n = 362 Age, median (range), years 62 (19-88) 62 (23-89) Male, % 60 64 BRAF mutated, % 22 22 LDH >ULN, % 36 38 LDH >2 ULN, % 9 13 AJCC disease stage IV, % 90 90 M1c without brain metastases, % 45 44 M1c with brain metastases, % 18 17 ECOG PS 0, % 72 70 Any prior systemic therapy, a % 56 57 a Patients could not receive prior anti-braf or anti-pd-1 therapy. AJCC = American Joint Committee on Cancer; LDH = lactate dehydrogenase; ULN = upper limit of normal.

Alive (%) 100 90 80 70 60 50 40 30 20 10 IPI 10 mg/kg IPI 3 mg/kg OS IPI 10 mg/kg n = 365 IPI 3 mg/kg n = 362 Events (%) 262 (72) 279 (77) Median (95% CI), mo 15.7 (11.6, 17.8) 11.5 (9.9, 13.3) HR (95% CI) 0.84 (0.70, 0.99) Log-rank P value 0.04 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 Time (Months) IPI 10 m g/kg 365 306 253 217 196 181 161 151 137 126 120 118 111 105 94 16 0 IPI 3 mg/kg 362 310 253 205 168 146 131 118 107 95 87 83 80 76 71 8 0 Number of patients at risk 54% 48% 38% 31% 31% 23% Minimum OS follow-up: ~43 mo

PFS (%) 100 90 80 70 60 50 40 30 IPI 10 mg/kg n = 365 IPI 3 mg/kg n = 362 PFS Events (%) 328 (90) 330 (91) Median (95% CI), mo 2.8 (2.8, 3.0) 2.8 (2.8, 2.8) HR (95% CI) 0.89 (0.76, 1.04) Log-rank P value 0.16 ORR % (95% CI) 15 (12, 20) 12 (9, 16) DCR % (95% CI) 32 (27, 37) 28 (23, 33) 20 10 IPI 10 mg/kg IPI 3 mg/kg 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 Number of patients at risk Time (Months) IPI 10 mg/kg 365 160 89 69 52 46 43 38 38 33 33 31 29 23 11 2 0 IPI 3 mg/kg 362 138 79 60 49 39 35 32 29 27 25 23 22 19 8 0 0

SAFETY SUMMARY: TREATED PATIENTS IPI 10 mg/kg n = 364 IPI 3 mg/kg n = 362 AEs during initial treatment phase Any grade Grades 3-5 Any grade Grades 3-5 AEs, % 95 59 93 52 Treatment-related AEs, % 79 34 63 19 Serious AEs, % 64 53 51 43 AEs leading to discontinuation, % 31 26 19 16 Immune-related AEs, % 74 30 54 14 During the entire study period, study-drug toxicity led to death in 4 patients (1%) in the 10 mg/kg arm Diarrhea leading to general deterioration, fulminant colitis, multi-organ failure, bowel perforation 2 patients (<1%) in the 3 mg/kg arm Multifocal colon perforation, myocardial infarction from complications of diarrhea and colitis

TREATMENT-RELATED AES IN 5% PATIENTS: INITIAL TREATMENT PHASE IPI 10 mg/kg n = 364 IPI 3 mg/kg n = 362 Any grade Grade 3/4 Any grade Grade 3/4 Any treatment-related AE, % 79 34 63 18 Diarrhea 37 10 23 6 Rash 26 1 14 <1 Pruritus 23 <1 22 <1 Fatigue 11 <1 9 <1 Colitis 10 5 5 3 Asthenia 9 1 5 <1 Hypophysitis 7 3 3 2 Increase in ALT 7 3 1 <1 Increase in AST 7 2 <1 <1 Nausea 6 <1 7 0 Pyrexia 6 <1 5 0 Headache 6 1 4 0

Eggermont, NEJM 2016

EORTC 18071/CA184-029: STUDY DESIGN Randomized, double-blind, phase 3 study evaluating the efficacy and safety of ipilimumab in the adjuvant setting for high-risk melanoma High-risk, stage III, completely resected melanoma N = 951 R N = 475 N = 476 INDUCTION Ipilimumab 10 mg/kg Q3W 4 INDUCTION Placebo Q3W 4 MAINTENANCE Ipilimumab 10 mg/kg Q12W up to 3 years MAINTENANCE Placebo Q12W up to 3 years Week 1 Week 12 Week 24 Treatment up to a maximum of 3 years, or until disease progression, intolerable toxicity, or withdrawal Stratification factors Stage (IIIA vs IIIB vs IIIC 1-3 positive lymph nodes vs IIIC 4 positive lymph nodes) Regions (North America, European countries, and Australia) Enrollment Period: June 2008 to July 2011 Q3W = every 3 weeks; Q12W = every 12 weeks; R = randomization.

Baseline Patient Characteristics Ipilimumab (n = 475) Placebo (n = 476) Median age, years 51 52 Male, % 62 62 ECOG PS 0/1, % 94/6 94/6 Stage, % IIIA 21 18 IIIB 45 43 IIIC with 1-3 positive LN 15 17 IIIC with 4 positive LN 20 21 1 vs 2-3 vs 4 positive LN, % 46 vs 34 vs 20 46 vs 33 vs 21 LN involvement, % Microscopic 44 41 Macroscopic 56 59 Ulceration of primary, % 41 43 ECOG PS = Eastern Cooperative Oncology Group performance status; LN = lymph node.

Patient Disposition and Treatment Ipilimumab (n = 471) Placebo (n = 474) Discontinuation, % 100 100 Reasons for discontinuation, % Normal completion (received study drug for entire 3 years) 13.4 30.2 Disease recurrence 28.7 59.5 AE related to study drug 49.7 1.9 Other reasons a 8.2 8.4 Median doses, per patient, n 4.0 8.0 Receiving 1 maintenance dose, % 42.0 70.0 Receiving 7 doses (1 year of therapy), % 28.9 56.8 a Includes AE unrelated to study drug, both related and unrelated to study drug, patient request, poor/noncompliance, death, pregnancy, patient no longer eligible, other.

100 Ipilimumab Placebo Patients Alive (%) 90 80 70 60 50 40 30 65% 54% Death/patients 162/475 214/476 HR (95% CI) a 0.72 (0.58, 0.88) Log-rank P value a 0.001 a Stratified by stage provided at randomization. 20 10 0 0 1 2 3 4 5 6 7 8 O N Number of patients at risk 162 475 431 369 325 290 199 62 4 214 476 413 348 297 273 178 58 8 Years Ipilimumab Placebo 23

Patients Alive (%) 100 90 80 70 60 50 40 65% 54% Ipilimumab Placebo Death/patients 162/475 214/476 HR (95% CI) a 0.72 (0.58, 0.88) Log-rank P value a 0.001 a Stratified by stage provided at randomization. 30 KIRKWOOD PFS 5 y OS 5 y 20 IFN alpha 2b 37% 46% 10 0 Placebo 26% 37% 0 1 2 3 4 5 6 7 8 Years O N Number of patients at risk 162 475 431 369 325 290 199 62 4 Ipilimumab 214 476 413 348 297 273 178 58 8 Placebo 24

Patients Alive and Without Recurrence (%) 100 90 80 70 60 50 40 30 20 10 41% 30% Ipilimumab Placebo Events/patients 264/475 323/476 HR (95% CI) a 0.76 (0.64, 0.89) Log-rank P value a 0.0008 Median RFS, months (95% CI) 0 0 1 2 3 4 5 6 7 8 Years O N Number of patients at risk 264 475 283 217 184 161 77 13 1 Ipilimumab 323 476 261 199 154 133 65 17 0 Placebo 27.6 (19.3, 37.2) 17.1 (13.6, 21.6) a Stratified by stage provided at randomization. CI = confidence interval.

Patients Alive and Without Recurrence (%) 100 90 80 70 60 Ipilimumab Placebo Events/patients 264/475 323/476 HR (95% CI) a 0.76 (0.64, 0.89) Log-rank P value a 0.0008 Median RFS, months (95% CI) 27.6 (19.3, 37.2) 17.1 (13.6, 21.6) 50 41% 40 30 30% KIRKWOOD PFS 5 y OS 5 y 20 IFN alpha 2b 37% 46% 10 0 Placebo 26% 37% 0 1 2 3 4 5 6 7 8 Years O N Number of patients at risk 264 475 283 217 184 161 77 13 1 Ipilimumab 323 476 261 199 154 133 65 17 0 Placebo a Stratified by stage provided at randomization. CI = confidence interval.

Safety Summary Ipilimumab (n = 471) Placebo (n = 474) Any Grade Grade 3/4 Any grade Grade 3/4 Any AE, % 98.7 54.1 91.1 26.2 Treatment-related AE, % 94.1 45.4 59.9 4.0 Treatment-related AE leading to discontinuation, % 48.0 32.9 1.5 0.6 Any immune-related AE, % 90.4 41.6 39.7 2.7 No new deaths due to drug-related AEs compared with the primary analysis 5 patients (1.1%) in the ipilimumab group 3 patients with colitis (2 with gastrointestinal perforations) 1 patient with myocarditis 1 patient had multiorgan failure with Guillain-Barré syndrome No deaths related to study drug in the placebo group Secondary endpoint

Safety: Immune-Related Adverse Events (%) Ipilimumab (n = 471) Placebo (n = 474) All grades Grade 3 Grade 4 Grade 5 All grades Grade 3 Grade 4 Any irae 90.4 35.9 5.7 1.1 39.7 2.5 0.2 Dermatologic 63.3 4.2 0 0 20.9 0 0 Rash 34.2 1.1 0 0 11.0 0 0 Gastrointestinal 46.1 14.9 1.3 0.6 17.9 0.6 0.2 Diarrhea 41.2 9.8 0 0 16.9 0.4 0 Colitis 15.1 6.6 0.8 0.6 1.3 0.2 0 Endocrine 37.8 7.2 0.6 0 8.0 0.2 0 Hypophysitis 16.3 4.2 0.2 0 0.2 0 0 Hepatic 24.4 8.1 2.8 0 4.2 0.2 0 LFT increase 18.6 3.0 1.3 0 3.8 0 0 Neurologic 4.5 1.1 0.8 0 1.9 0 0 Other 23.6 7.2 0.4 0.4 4.9 1.7 0 LFT = liver function test.

ANTI-PD1 PHASE 3 TRIALS Franklin EJSO 2016

CA209-067: Study Design 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 for 4 doses then NIVO 3 mg/kg Q2W Unresectable or Metatastic Melanoma Previously untreated 945 patients 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 + IPI-matched placebo Treat until progression or unacceptable toxicity N=315 IPI 3 mg/kg Q3W for 4 doses + NIVO-matched placebo Database lock: Sept 13, 2016 (median follow-up ~30 months in both NIVO-containing arms) *The study was not powered for a comparison between NIVO and NIVO+IPI 39

Updated Response To Treatment NIVO+IPI (N=314) NIVO (N=316) IPI (N=315) ORR, % (95% CI)* 58.9 (53.3 64.4) 44.6 (39.1 50.3) 19.0 (14.9 23.8) Best overall response % Complete response 17.2 14.9 4.4 Partial response 41.7 29.7 14.6 Stable disease 11.5 9.8 21.3 Progressive disease 23.6 38.6 51.1 Unknown 6.1 7.0 8.6 Median duration of response, months (95% CI) NR (NR NR) 31.1 (31.1 NR) 18.2 (8.3 NR) *By RECIST v1.1; NR = not reached. At the 18-month DBL, the CR rate for NIVO+IPI, NIVO and IPI was 12.1%, 9.8% and 2.2%, respectively Database lock: Sept 13, 2016, minimum f/u of 28 months 40

Updated Progression-Free Survival 100 90 80 Median PFS, mo (95% CI) HR (95% CI) vs. IPI NIVO+IPI (N=314) NIVO (N=316) IPI (N=315) 11.7 (8.9 21.9) 0.42 (0.34 0.51) 6.9 (4.3 9.5) 0.54 (0.45 0.66) 2.9 (2.8 3.2) -- Progression-free Percentage Survival of PFS (%) 70 60 50 40 30 20 10 0 NIVO+IPI NIVO IPI 50% 43% 18% HR (95% CI) vs. NIVO 0 3 6 9 12 15 18 21 24 27 30 33 36 Months 0.76 (0.62 0.94) 43% 37% 12% -- -- Patients at risk: NIVO+ IPI 314 218 176 156 137 132 125 118 110 104 71 16 NIVO 316 178 151 132 120 112 107 103 97 88 62 16 0 0 IPI 315 136 77 58 46 43 35 33 30 27 16 5 0 Database lock: Sept 13, 2016, minimum f/u of 28 months 8

Overall Survival Median OS, mo (95% CI) NIVO+IPI (N=314) NIVO (N=316) IPI (N=315) NR NR (29.1 NR) 20.0 (17.1 24.6) 100 HR (98% CI) vs. IPI 0.55 (0.42 0.72)* 0.63 (0.48 0.81)* -- Overall Percentage Survival of PFS (%) 90 80 70 60 50 40 30 73% 74% 67% HR (95% CI) vs. NIVO 64% 59% 45% 0.88 (0.69 1.12) -- -- *P<0.0001 20 10 0 NIVO+IPI NIVO IPI 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Months Patients at risk: NIVO+IPI 314 292 265 247 226 221 209 200 198 192 170 49 7 NIVO 316 292 265 244 230 213 201 191 181 175 157 55 3 IPI 315 285 254 228 205 182 164 149 136 129 104 34 4 0 0 0 Database lock: Sept 13, 2016, minimum f/u of 28 months 42

OS in Patients with BRAF Wild-type and Mutant Tumors BRAF Wild-type BRAF Mutant NIVO+IPI NIVO IPI NIVO+IPI NIVO IPI Median, mo (95% CI) NR (27.6 NA) NR (25.8 NR) 18.5 (14.8 23.0) Median, mo (95% CI) NR NR (26.4 NR) 24.6 (17.9 31.0) 100 HR (95% CI) vs NIVO 0.97 (0.74 1.28) -- -- 100 HR (95% CI) vs NIVO 0.71 (0.45 1.13) -- -- 90 90 80 80 71% 70 61% 70 OS (%) 60 50 40 57% OS (%) 60 50 40 62% 51% 30 42% 30 20 10 NIVO+IPI NIVO IPI 20 10 NIVO+IPI NIVO IPI 0 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Months Months Patients at risk: Patients at risk: NIVO+IPI 212 194 170 157 144 142 133 127 126 120 108 31 5 0 NIVO+IPI 102 98 95 90 82 79 76 73 72 72 62 18 2 0 NIVO 218 199 179 163 155 144 134 127 124 119 105 38 2 0 NIVO 98 93 86 81 75 69 67 64 57 56 52 17 1 0 IPI 215 194 166 147 134 118 106 96 87 82 67 21 3 0 IPI 100 91 88 81 71 64 58 53 49 47 37 13 1 0 43

OS by Tumor PD-L1 Expression, 5% Cutoff PD-L1 Expression Level <5% PD-L1 Expression Level 5% NIVO+IPI NIVO IPI NIVO+IPI NIVO IPI Median OS, mo (95% CI) NR (31.8 NR) NR (23.1 NR) 18.5 (13.7 22.5) Median OS, mo (95% CI) NR NR 28.9 (18.1 NR) 100 HR (95% CI) vs NIVO 0.84 (0.63 1.12) 100 HR (95% CI) vs NIVO 1.05 (0.61 1.83) 90 90 80 80 70 70 72% OS (%) 60 50 40 63% 55% OS (%) 60 50 40 68% 54% 30 41% 30 20 20 10 ORR of 56.2% for NIVO+IPI and 42.3% for NIVO 10 ORR of 73.5% for NIVO+IPI and 58.8% for NIVO 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Months Patients at risk: NIVO+IPI 210 194 178 163 146 144 139 131 130 127 116 34 7 0 NIVO 208 189 169 151 144 133 123 118 112 110 99 34 2 0 IPI 202 179 158 140 125 108 100 90 81 78 63 18 2 0 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Months Patients at risk: NIVO+IPI 68 63 56 55 52 50 45 45 45 44 35 11 0 0 NIVO 80 79 75 73 68 63 61 58 57 54 49 18 1 0 IPI 75 72 67 65 61 55 46 43 40 39 33 13 1 0 44

Safety Summary With an additional 19 months of follow-up, safety was consistent with the initial report 1 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) 95.8 58.5 86.3 20.8 86.2 27.7 Treatment-related AE leading to discontinuation 39.6 31.0 11.5 7.7 16.1 14.1 Most select AEs were managed and resolved within 3-4 weeks (85 100% across organ categories) Treatment-related death, n (%) 2 (0.6) a 1 (0.3) b 1 (0.3) b 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). 1 1. Larkin J, et al. NEJM 2015;373:23 34. 45

Summary of iraes across clinical trials irae (%) Pembrolizumab Nivolumab Ipilimumab Nivo+Ipi Pembro+Ipi Diarrhea 14,4-16,9 11,2-19,2 22,7-33,1 44,1 12 Colitis 1,8-3,6 1,0-1,3 8,2-11,6 11,8 6 Hepatitis 1,1-1,8 3,4-6,4 1,2-7,1 30,0 30 Hypothyroidism 8,7-10,1 4,4-8,6 2,0-4,2 15,0 17 Hyperthyroidism 3,2-6,5 1,9-4,2 1,0-2,3 9,9 8 Hypophysitis <1 <1 2,3-3,9 7,7 11 Pneumonitis <1 1,9-1,3 0,4-1,6 6,4 7 Rash 13,4-14,7 9,3-21,7 14,5-20,9 28,4 53 Pruritus 14,1-14,4 16,0-18,8 24,4-35,4 33,2 28 46 Lavinia Spain, et al. Future Medicine 2015 Georgina Long SMR 2015

Immunovirotherapy: T-VEC an HSV-1-derived oncolytic immunotherapy designed to produce local and systemic effects Local effect: virus-induced tumour-cell lysis Systemic effect: antitumour immune response 1 Healthy cells 2 GM-CSF 3 Dendritic cell activated by GM- CSF CD4+ helper T cell 4 T-VEC Tumour cells Tumour cell lysis TDAs CD8+ cytotoxic T cell TDAs Distant dying tumour cell T-VEC replication in tumour tissue 1 3 Tumour cells rupture for an oncolytic effect 1 4 Systemic antitumour immune response 3,5,6 Death of distant cancer cells 5 8 1. Hawkins LK, et al. Lancet Oncol 2002;3:17 26; 2. Fukuhara H, Todo T. Curr Cancer Drug Targets 2007;7:149 55; 3. Amgen. Imlygic Summary of Product Characteristics. Section 5.1; 4. Pol JG, et al. Virus Adapt Treat 2012;4:1 21; 5. Melcher A, et al. Mol Ther 2011;19:1008 16; 6. Dranoff G. Oncogene 2003;22:3188 92; 7. Liu BL, et al. Gene Ther 2003;10:292 303; 8. Andtbacka RHI, et al. J Clin Oncol 2015;33:2780 8. Proposed mechanism of action for T-VEC. TDA, tumour-derived antigen.

Interim Efficacy and Safety of a Randomized (1:1) Open-Label Phase 2 Study of Talimogene Laherparepvec and Ipilimumab vs Ipilimumab Alone in Unresected, Stage IIIB - IV Melanoma Jason Chesney, 1 Frances Collichio, 2 Robert H.I. Andtbacka, 3 Igor Puzanov, 4 John Glaspy, 5 Mohammed Milhem, 6 Omid Hamid, 7 Lee Cranmer, 8 Yvonne Saenger, 9 Merrick Ross, 10 Lisa Chen, 11 Jenny J. Kim, 11 Howard L. Kaufman 12 1 University of Louisville, Louisville, KY, USA; 2 The University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, NC, USA; 3 Huntsman Cancer Institute, Salt Lake City, UT, USA; 4 Vanderbilt University, Nashville, TN, USA; 5 David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; 6 University of Iowa, Iowa City, IA, USA; 7 The Angeles Clinic and Research Institute, Los Angeles, CA, USA; 8 University of Arizona, Tucson, AZ, USA; 9 New York Presbyterian Hospital, Columbia University Medical Center, New York NY, USA; 10 MD Anderson Cancer Center, Houston, TX, USA; 11 Amgen Inc., Thousand Oaks, CA, USA; 12 Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA EUHQ-NP-678x-1016-038814a ESMO 2016 1108 PD

Study Schema for Phase 2 N = 200 Unresectable Stage IIIB IV Melanoma Injectable ECOG PS 0 or 1 BRAF WT: 1 prior tx allowed BRAF MT: 2 prior tx allowed (one must be BRAF inhibitor) Prior PD-1/checkpoint inhibitors allowed but not required No active CNS mets Week 1 R T-VEC Intralesional 4 ml x 10 6 PFU/mL, after 3 weeks 4 ml x 10 8 PFU/mL, Q2W thereafter 1:1 Week 6 Ipilimumab 3mg/kg IV Q3W x 4 Week 12 n = 100 Ipilimumab 3mg/kg IV Q3W x 4 Week 18 n = 100 TVEC dosing until CR, all injectable tumors disappeared, PD per irrc, or intolerance, whichever comes first Tumor assessments at baseline and Q12W thereafter by irrc (requiring confirmation 28 days from the date first documented)* Safety follow-up within 4 weeks after treatment ended; long term follow-up every 12 weeks after safety follow-up for 36 months Primary Endpoint ORR irrc per investigator (90% power to detect 21% increase in ORR assuming 15% ORR for Ipi alone) Secondary Endpoints OS, DoR, PFS, TTR *Wolchok JD et al. Clin Cancer Res. 2009;15(23):7412-7420. CR, complete response; DoR, duration of response; irrc, immune-related response criteria; IV, intravenous; ORR, objective response rate; PD, progressive disease; PFS, progression free survival; PFU, plaque-forming unit; OS, overall survival; Q2W, once every 2 weeks; Q3W, once every 3 weeks; TTR, time to treatment failure; tx, treatment 49

Best Overall Response: Confirmed T-VEC + Ipi N = 42 Confirmed a n (%) Ipi N = 40 ORR n (%) (95% CI) 15 (35.7) (21.6, 52.0) 7 (17.5) (7.3, 32.8) CR 4 (9.5) 4 (10.0) PR 11 (26.2) 3 (7.5) SD 13 (31.0) 11 (27.5) PD 6 (14.3) 5 (12.5) UE b 5 (11.9) 13 (32.5) Odds ratio (95% CI) for ORR 2.6 (0.9, 7.3) DCR n (%) (95% CI) 28 (66.7) (50.5, 80.4) 18 (45.0) (29.3, 61.5) Odds ratio (95% CI) for DCR 2.4 (1.0, 6.0) a Confirmation of initial CR/PR/PD by subsequent assessment by 4 w apart. A CR/PR without confirmation is classified as SD. There is no confirmation required for UE or SD, however, SD duration must be > 77 days. b Unconfirmed PD is classified as UE CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease; UE = unable to evaluate; DCR = disease control rate (SD or better). 50

Percentage Change from Baseline Best Change in Overall Tumor Area From Baseline 600 400 200 100 75 50 25 0 25 50 75 100 600 400 200 100 75 50 25 0 25 50 75 100 Talimogene Laherparepvec + Ipilimumab (N = 38) Stage IIIb (N = 1) Stage IIIc (N = 8) Stage IV M1a (N = 8) Stage IV M1b (N = 11) Stage IV M1c (N = 10) Ipilimumab (N = 33) Stage IIIb (N = 5) Stage IIIc (N = 7) Stage IV M1a (N = 8) Stage IV M1b (N = 2) Stage IV M1c (N = 11)

1 st LINE Unresectable melanoma Rapidly progressive, high LDH/tumor burden BRAF STATUS BRAF WT IMMUNOTHERAPY Keynote 006 (pembro vs Ipi 1ª/2ª líne) Checkmate 066 (nivo vs QT BRAF WT) Checkmate 067 (nivo or ipi/nivo vs ipi) Checkmate 067 (nivo o ipi/nivo vs ipi) Keynote 029 (phase II, ipi LOW DOSE/pembro) Optim (T-VEC vs G-CSF) No rapidly progressive, - IIIB/C, M1a low LDH/tumor burden Ipilimumab/nivolumab + Anti PD1 +++ TVEC (IIIB-M1A) + 2 nd LINE CT/ clinical trial Ipilimumab/clinical trial CT/clinical Trial Eva M Couselo (VHIO) L de la Cruz (HUVM) 3 rd LINE CT/Clinical trial if previous ipilimumab 2ª line: anti-ctla4 after anti- PD1? anti-pd1 after ibraf/imek?

Druggable mutations in melanoma

BRAFi (dabrafenib) PFS HR, 0.37 vs DTIC 1 Hyperproliferative skin AEs BRAFi (vemurafenib) PFS HR, 0.38 vs DTIC 2 Hyperproliferative skin AEs RAS mutbraf BRAFi + MEKi ph 3 studies Dabrafenib + trametinib PFS HR, 0.67 vs dabrafenib 4 OS HR, 0.71 vs dabrafenib 4 PFS HR, 0.56 vs vemurafenib 5 OS HR, 0.69 vs vemurafenib 5 NP4: 1606042435 MEKi (trametinib) PFS HR, 0.45 vs chemotherapy 3 MEK perk Proliferation, Survival, Invasion, Metastasis Vemurafenib + cobimetinib PFS HR, 0.58 vs vemurafenib 6 OS HR, 0.70 vs vemurafenib 6 Decreased hyperproliferative skin AEs 4,5,6 AE, adverse event; BRAF, v-raf murine sarcoma viral oncogene homolog B; BRAFi, BRAF inhibitor; DTIC, dacarbazine; HR, hazard ratio; MEK, mitogen-activated protein kinase kinase; MEKi, MEK inhibitor; mut, mutant; OS, overall survival; perk, phospho-extracellular signal-regulated kinase; PFS, progression-free survival; ph, phase. 1. Hauschild A, et al. Lancet 2012;380:358; updated in J Clin Oncol. 2013 (suppl) [abstract 9013]; 2. McArthur GA, et al. Lancet Oncol. 2014;15:323-332; 3. Flaherty KT, et al. N Engl J Med. 2012;367:107-114; 4. Long GV, et al. Lancet. 2015;386:444-451; 5. Robert C, et al. N Engl J Med. 2015;372:30-39; 6. Atkinson V, et al. SMR. 2015. Adapted from Keith T. Flaherty, MD. ASCO 2016

TARGETED THERAPY: cobrim (vemu/cobi vs vemu) COMBI-D (dabra(trame vs dabra) COMBI V (dabra/trame vs vemu) 1 st LINE Rapidly progressive, high LDH/tumor burden Unresectable melanoma BRAF STATUS BRAF MUTATED No rapidly progressive, low LDH/tumor burden IMMUNOTHERAPY: Keynote 006 (pembro vs Ipi 1ª/2ª linea) - 35% BRAF mut - 17% ibraf treated Checkmate 067 (nivo o ipi/nivo vs ipi) - 1st Line - ibraf/imek naive - 31 5% BRAF mut Optim (T-VEC vs G-CSF) - IIIB/C, M1a Ipilimumab/nivolumab inh BRAF/MEK Anti PD1 inh BRAF/MEK TVEC (IIIB-M1A) 2 nd LINE 3 rd LINE Eva M Couselo (VHIO) L de la Cruz (HUVM) BRAF/MEK inh CT/Clinical trial Anti PD1 BRAF/MEK inh Ipilimumab/clinical trial Anti PD1 CT/ clinical trial 2nd Line: anti-ctla4 after anti- PD1? anti-pd1 after ibraf/imek? (BRAF+) ibraf/imek after anti- PD1/anti-CTLA4? (BRAF+)

Targeted therapies: MAPKi in melanoma BRAF mut Dual MAPK pathway inhibition PD-L1 inhibition MAPK Inhibitor-Induced Changes 1,2 Increased melanoma antigen expression Decreased immunosuppressive cytokine production Increased CD8+ T-cell infiltration Increased T-cell clonality a Increased PD-L1 expression Class I MHC upregulation CD8+ T cell per Tumor Cell ND MEKi 1. Frederick D et al. CCR 2013. 2. Ebert P et al. Immunity 2016.

Phase III Study of Atezo + Cobi + Vem in BRAF V600 Mutant Melanoma (NCT02908672) A Phase III study evaluating atezo + cobi + vem vs placebo + cobi + vem in patients with BRAF V600 mutant advanced melanoma is planned Previously Untreated Advanced Melanoma Vem 960mg BID a Cobi 60mg QD b Atezo 840mg q2w Vem 720mg BID + Vem Placebo 240mg BID Cobi 60mg QD b BRAF V600 mutation ECOG PS 0-1 Measurable disease No significant history of liver disease N = 500 R Vem 960mg BID a Cobi 60mg QD b Treatment until PD or toxicity Placebo q2w Vem 960mg BID Cobi 60mg QD b Key study objectives Primary: investigator-assessed PFS Secondary: PFS (IRF-assessed), OS, ORR, DOR, Safety, PK a Vemurafenib dose will decrease to 720 mg BID + placebo 240 mg BID beginning day 22 of vem + cobi doublet treatment phase. b Cobimetinib administered on 21 days on/7 days off schedule. IRF, independent review facility; PK, pharmacokinetics.

CONCLUSIONS AND FINAL REMARKS MELANOMA SYSTEMIC TREATMENT HAS DRAMATICALLY CHANGED UPFRONT HAS TO BE DETERMINED: * BRAF STATUS * CLINICAL STATUS, DISCARD/CONFIRM RAPIDLY PROGRESSIVE DISEASE IMMUNOTHERAPY MUST BE BASED ON ANTI-P1 AND TARGETED THERAPIES ON ibraf+imek COMBOS COMBINATIONS OF INMUNOTHERAPY AND TARGETED THERAPIES, CLINICAL TRIALS ONGOING CHALLENGES IN CLINICAL RESEARCH: BRAIN METS, AUTOIMMUNE DISORDERS (IT), DURATION OF THERAPIES (IT), POST-PROGRESSION TX, RECHALLENGE WITH IT/TARGETED TX, BIOMARKERS (IT)... STILL MANY QUESTIONS TO BE ANSWERED THROUGH TRANSLATIONAL RESEARCH