What we learned from immunotherapy in the past years

What we learned from immunotherapy in the past years Paolo A. Ascierto, MD Unit Melanoma, Cancer Immunotherapy and Innovative Therapies Istituto Nazionale Tumori Fondazione G. Pascale, Napoli, Italy

Disclosure Employment or Leadership Position: None Consultant/Advisory Role: Bristol-Meyers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Amgen, Array, Merck Serono, Pierre Fabre, Incyte, NewLink Genetics, Genmab Stock Ownership: None Research Funding: Bristol-Meyers Squibb, Roche-Genentech, Array Expert Testimony: None Other Remuneration: None

What we learned from Immuno-therapy in melanoma Immune adaptability, and memory offers the potential for long-term survival Unique MoAs offer the opportunity for combination Targeting the immune system not the tumour offers the potential for activity across multiple tumour types Potential to improve clinical outcome In various solid and haematologic malignancies Unique safety profiles Efficacy as adjuvant Dosage may makes a difference Efficacy in brain mtx

The MDX1-2 study: randomized phase III, double blinded, three arms study which compared ipilimumab + gp1 vs ipilimumab + placebo vs gp1 + placebo N. 676 pretreated advanced melanoma patients were enrolled. Randomization was 3:1:1 and the primary endpoint was OS No separation in curves for the first 3 months Separation and survival impact occurs after 3 months (~ 4 months improvement in median OS Near doubling of 1 and 2 years when we start to see durable long-term survivors Median OS ipi + gp1 = 1, mos Ipi + placebo = 1,1 mos gp1 + placebo = 6,4 mos Hodi et al New Engl J Med 21; 363:711-23

No effect in surrogate endpoints Best Overall Response Rate (BORR) ipi + gp1 = 5,7 % Ipi + placebo = 1,9 % gp1 + placebo = 1,5 % 17/1/2 17 6 Hodi et al New Engl J Med 21; 363:711-23

Progression-Free Survival (Probability) Overall Survival (Probability) Renal Cancer - CheckMate 25 Study: PFS and OS 1. 1..9.8.7.6 HR (95% CI),.88 (.75 1.3) P =.1135.9.8.7.6 HR (98.5% CI),.73 (.57.93) P =.18 Nivolumab 25. m.5.5.4.3 Nivolumab 4.6 m.4.3 Everolimus 19.6 m.2.2.1. Everolimus 4.4 m.1. No. of patients at risk 3 6 9 12 15 Months 18 21 24 27 3 Nivolumab 41 23 145 116 81 66 48 29 11 4 Everolimus 411 227 129 97 61 47 25 16 3 No. of patients at risk 3 6 9 12 15 Months 18 21 24 27 3 33 Nivolumab 41 389 359 337 35 275 213 139 73 29 3 Everolimus 411 366 324 287 265 241 187 115 61 2 2 CI, confidence interval; HR, hazard ratio; NE, not estimable; PFS, progression-free survival. Sharma P et al. Oral presentation at ESMO 215. 3LBA. Motzer RJ et al. N Engl J Med. 215 Nov 5;373(19):183-13.

Co-primary endpoint Progression-Free Survival (Probability) PFS per IRRC: IMDC intermediate/poor risk Median PFS, months (95% CI) NIVO + IPI 11.6 (8.7 15.5) 1..9.8.7.6.5.4.3.2.1. No. at Risk NIVO + IPI SUN SUN 8.4 (7. 1.8) Hazard ratio (99.1% CI),.82 (.64 1.5) P =.331 3 6 9 12 15 18 21 24 27 3 Months 425 34 233 187 163 149 118 46 17 3 422 282 191 139 17 86 57 33 11 1 Escudier B et al ESMO 217

Co-primary endpoint Overall Survival (Probability) OS: IMDC intermediate/poor risk Median OS, months (95% CI) NIVO + IPI NR (28.2 NE) 1..9.8.7.6.5.4.3.2.1 SUN 26. (22.1 NE) Hazard ratio (99.8% CI),.63 (.44.89) P <.1. No. at Risk NIVO + IPI SUN 3 6 9 12 15 18 21 24 27 3 33 Months 425 399 372 348 332 318 3 241 119 44 2 422 387 352 315 288 253 225 179 89 34 3 Escudier B et al ESMO 217

NSQ NSCLC - CheckMate 57: PFS and OS mpfs Nivolumab 2.3 months Docetaxel 4.2 months HR =.92; (95% CI,.77-1.11); P =.39 mos Nivolumab 12,2 months Docetaxel 9.4 months HR =.73; (95% CI,.59.89); P =.2 Horn et al, ESMO 215

Head & Neck - CheckMate 141: PFS and OS Checkmate 141. AACR 216

No effect in surrogate endpoints Two main reasons: 1) Slow action 2) Possible fake progressions 17/1/2 17 12

Anti-PD-1s in melanoma have an effect on surrogate endpoints as well Pembrolizumab Keynote 6 Nivolumab Checkmate 66

Overall Survival (%) Immune Checkpoint Inhibitors Provide Durable Long-term Survival for Patients with Advanced Melanoma 1 IPI (Pooled analysis) 1 9 NIVO Monotherapy (Phase 1 CA29-3) 2 NIVO Monotherapy (Phase 3 Checkmate 66) 3 8 PEMBRO Monotherapy (Phase 1 Keynote-1) 4 Naïve Patients 7 6 5 4 3 2 ~ 6% 5% N=278 N=21 45% 4% N=655 N=152 N=17 35% N=1,861 4% 2% PEMBRO Monotherapy (Phase 1 Keynote-1) 4 Pretreated and Naïve Patients PEMBRO Monotherapy (Phase 3 Keynote-6) 7 Study mos (mos) 1-yrs OS% 2-yrs OS% 3-yrs OS% 5-yrs OS% CA29-3 2,3 65% 47% 41% 35% CA29-66 NR 7,7% 57,7% NA NA Keynote-1 All Pts 24,4 66% 5 5% 4% NA Keynote-6 32,3 ~7% 55% 5% 7 NA 1 1 2 3 4 5 6 7 8 9 1 Years PA Ascierto Keynote-1 Naive Pts 1. Schadendorf et al. J Clin Oncol 215;33:1889-1894; 2. Current analysis; 2. Hodi FS. AACR 216 3. Poster presentation by Dr. Victoria Atkinson at SMR 215 International Congress. 4. Robert et al. Oral presentation ASCO 216 5. Daud et al. Oral presentation ASCO 215 6. Larkin et al NEJM 215 7. Robert et al. ASCO 217 32,2 73% 5 61% 45% NA

Targeting CTLA-4 and PD-1 pathways Periphery Tumour microenvironment Activation (cytokines, lysis, proliferation, migration to tumour) Dendritic cell MHC B7 TCR CD28 +++ +++ B7 CTLA-4 - - - Anti-CTLA-4 T cell T cell +++ - - - - - - TCR MHC PD-1 PD-L1 Anti-PD-1/PD-L1 PD-1 PD-L2 Anti-PD-1 Tumour cell CTLA-4 pathway PD-1 pathway Wolchock J, et al. JCO 213 Volume 31, Issue 15_suppl ; abstr 912^

OS (INTENT-TO-TREAT) Subsequent therapy 32% 46% 63% Wolchok et al NEJM 217 Hoeller ESMO 217 8

Overall Survival (%) Immune Checkpoint Inhibitors Provide Durable Long-term Survival for Patients with Advanced Melanoma 1 IPI (Pooled analysis) 1 9 NIVO Monotherapy (Phase 1 CA29-3) 2 NIVO Monotherapy (Phase 3 Checkmate 66) 3 8 PEMBRO Monotherapy (Phase 1 Keynote-1) 4 Naïve Patients 7 6 5 4 3 2 ~ 6% 5% N=278 N=21 N=314 58% 45% 4% N=655 N=152 N=17 35% ~ 45-5% ipi/nivo N=1,861 4% 2% PEMBRO Monotherapy (Phase 1 Keynote-1) 4 Pretreated and Naïve Patients PEMBRO Monotherapy (Phase 3 Keynote-6) 7 Study mos (mos) 1-yrs OS% 2-yrs OS% 3-yrs OS% 5-yrs OS% CA29-3 2,3 65% 47% 41% 35% CA29-66 NR 7,7% 57,7% NA NA Keynote-1 All Pts 24,4 66% 5 5% 4% NA Keynote-6 32,3 ~7% 55% 5% 7 NA 1 1 2 3 4 5 6 7 8 9 1 Years PA Ascierto Keynote-1 Naive Pts 1. Schadendorf et al. J Clin Oncol 215;33:1889-1894; 2. Current analysis; 2. Hodi FS. AACR 216 3. Poster presentation by Dr. Victoria Atkinson at SMR 215 International Congress. 4. Robert et al. Oral presentation ASCO 216 5. Daud et al. Oral presentation ASCO 215 6. Larkin et al NEJM 215 7. Robert et al. ASCO 217 32,2 73% 5 61% 45% NA

Changes in Target Lesions: Comparing Nivolumab Alone and in Combination Change in target lesions from baseline (%) Change in target lesions from baseline (%) Nivolumab monotherapy Nivolumab + ipilimumab 3 1 mg/kg nivolumab + 3 mg/kg ipilimumab 1 8 6 4 3 mg/kg 1st occurrence of new lesion 2 1 8 6 4 First occurrence of new lesion 2 2 2 2 4 4 6 6 8 8 1 1 2 3 4 5 6 7 8 9 1 11 12 13 14 15 1 1 2 3 4 5 6 7 8 9 1 11 Weeks since treatment initiation Weeks since treatment initiation Horizontal line at 3% = threshold for defining objective response (partial tumour regression) in absence of new lesions or non-target disease according to RECIST Wolchok JD, et al. J Clin Oncol 213;31(suppl): abstract 912^; Sznol M, et al. J Clin Oncol 213;31(suppl): abstract CRA96^

Treatment decision based on patient's characteristic Patient history (eg, autoimmune disease) Organ system function, especially cardiac function Patient s wishes and lifestyle factors Mutational status Performance status Brain mtx Tumor burden LDH level Disease Tempo Ascierto ESMO 216

Is OS still the most important endpoint? Yes, of course. But.

% Overall Survival OS curves form the most important study with ipilimumab 1 Study mos (mos) 1-yrs OS% 2-yrs OS% 3-yrs OS% CA29-69 NR 65% 54% NA Keynote-6 NR 59% 43% NA CA184-169 Ipi 1 mg/kg CA184-169 Ipi 3 mg/kg 15,7 54% 38% 31% 11,5 48% 31% 23% CA29-66 8,8 ~4% ~25% NA 5 Pooled analysis 11,4 ~45% ~25% 22% 1 2 3 4 5 Years

% Progression-Free PFS curves may predict long-term benefit higher and faster responses 1 durable responses Drug A 5 mpfs Drug A mpfs Drug B 1-yr PFS Drug A Drug B 1-yr PFS Drug B 2-yrs PFS Drug A 2-yrs PFS Drug B 1 2 Years Ascierto PA & Long GV. Lancet Oncol. 216;17:137-139.

Patients alive (%) EORTC 187: Overall Survival 1 9 8 7 Ipilimumab Placebo Deaths/patients 162 / 475 214 / 476 Hazard ratio (95.1% CI)*.72 (.58 -.88) Log-rank P value*.1 *Stratified by stage at randomization 6 5 4 65% 54% 3 2 1 CI = confidence interval; NR = not reached. 5-year difference 11% 1 2 3 4 5 6 7 8 O N Number of patients at risk : 162 475 431 369 325 29 199 62 4 214 476 413 348 297 273 178 58 8 Years Ipilimumab Placebo Eggermont et al. NEJM 216

RFS (%) Checkmate 238: Primary Endpoint: RFS NIVO IPI 1 Events/patients 154/453 26/453 9 Median (95% CI) NR NR (16.6, NR) HR (97.56% CI).65 (.51,.83) 8 Log-rank P value <.1 7 6 5 71% 61% 66% 53% 4 3 2 1 Number of patients at risk NIVO IPI NIVO IPI 3 6 9 12 15 18 21 24 27 Months 453 399 353 332 311 291 249 71 5 453 364 314 269 252 225 184 56 2 Weber et al. NEJM 217

RFS (%) RFS (%) Subgroup Analysis of RFS: PD-L1 Expression Level PD-L1 Expression Level <5% PD-L1 Expression Level 5% NIVO IPI NIVO IPI Events/patients 114/275 143/286 Events/patients 31/152 57/154 Median (95% CI) NR 15.9 (1.4, NR) Median (95% CI) NR NR 1 HR (95% CI).71 (.56,.91) 1 HR (95% CI).5 (.32,.78) 9 8 9 8 82% 7 6 64% 7 6 74% 5 4 54% 5 4 3 3 NIVO IPI 2 1 NIVO IPI Number of patients at risk 3 6 9 12 15 18 21 24 27 Months 275 242 24 189 171 159 129 41 3 286 219 184 153 139 124 1 31 2 Number of patients at risk NIVO IPI 2 1 NIVO IPI 3 6 9 12 15 18 21 24 27 Months 152 135 13 125 122 114 15 26 2 154 133 12 18 15 93 78 21 Weber et al. NEJM 217

RFS (%) RFS (%) Subgroup Analysis of RFS: Disease Stage Stage III Stage IV NIVO IPI NIVO IPI Events/patients 12/367 163/366 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) 1 HR (95% CI).65 (.52,.83) 1 HR (95% CI).7 (.45, 1.1) 9 9 8 7 72% 8 7 63% 6 5 62% 6 5 58% 4 4 3 3 2 1 NIVO IPI Number of patients at risk 3 6 9 12 15 18 21 24 27 Months 2 1 NIVO IPI Number of patients at risk 3 6 9 12 15 18 21 24 27 Months NIVO 367 322 29 272 257 239 23 58 3 NIVO 82 73 59 56 51 49 43 12 2 IPI 366 299 259 223 28 186 152 45 1 IPI 87 65 55 46 44 39 32 11 1 Weber et al. NEJM 217

RFS (%) RFS (%) Subgroup Analysis of RFS: BRAF Mutation Status 1 9 8 7 6 5 4 3 2 1 BRAF Mutant NIVO IPI Events/patients 63/187 84/194 Median (95% CI) NR NR (16.1, NR) HR (95% CI).72 (.52, 1.) NIVO IPI Number of patients at risk NIVO IPI 68% 63% 3 6 9 12 15 18 21 24 27 Months 187 159 142 135 126 118 12 32 2 194 155 142 118 112 1 78 26 1 1 NIVO IPI 9 8 7 6 5 4 3 2 1 BRAF Wild type NIVO IPI Events/patients 67/197 15/214 Median (95% CI) NR 16.6 (12.3, NR) HR (95% CI).58 (.43,.79) NIVO IPI Number of patients at risk 72% 57% 3 6 9 12 15 18 21 24 27 Months 197 175 154 145 137 127 18 26 2 214 174 14 122 111 96 8 22 1 Weber et al. NEJM 217

Patient Case 71 year old male with BRAF V6E-mutated MEL, ~7 brain mets, no steroids or SRT Baseline 1 year Tawbi et al ASCO 217

Ipilimumab + nivolumab in Brain Metastases Intracranial ORR: 55% Intracranial DCR: 6% Tawbi et al. ASCO 217

Ipilimumab + nivolumab in Brain Metastases Long et al. ASCO 217

Progression free survival curves from the most recent studies on advanced melanoma patients with brain metastases Ascierto and Mc Arthur JTM 217

Change From Baseline in Tumor Size, % Change From Baseline in Tumor Size, % Pembrolizumab Demonstrates Broad Antitumor Activity 1 8 Melanoma 1 (N=655) KEYNOTE-1 1 8 NSCLC 2 (N=262) KEYNOTE-1 1 8 H&N 3 (N=132) KEYNOTE-12 1 8 Urothelial 4 (N=33) KEYNOTE-12 1 8 Gastric 5 (N=39) KEYNOTE-12 6 6 6 6 6 4 4 4 4 4 2 2 2 2 2-2 -2-2 -2-2 -4-4 -4-4 -4-6 -6-6 -6-6 -8-8 -8-8 -8-1 -1-1 -1-1 1 8 6 4 2-2 -4-6 -8-1 TNBC 6 (N=32) KEYNOTE-12 1 8 6 4 2-2 -4-6 -8-1 chl 7 (N=29) KEYNOTE-13 1 8 6 4 2-2 -4-6 -8-1 Mesothelioma 8 (N=25) KEYNOTE-28 1 8 6 4 2-2 -4-6 -8-1 Ovarian 9 (N=26) KEYNOTE-28 1 8 6 4 2-2 -4-6 -8-1 SCLC 1 (N=2) KEYNOTE-28 1 Esophageal 11 (N=23) KEYNOTE-28 8 6 4 2-2 -4-6 -8-1 1. Daud A et al. 215 ASCO; 2. Garon EB et al. ESMO 214; 3. Seiwert T et al. 215 ASCO; 4. Plimack E et al. 215 ASCO; 5. Bang YJ et al. 215 ASCO; 6. Nanda R et al. SABCS 214; 7. Moskowitz C et al. 214 ASH Annual Meeting; 8. Alley EA et al. 215 AACR; 9. Varga A et al. 215 ASCO; 1. Ott PA et al. 215 ASCO; 11. Doi T et al. 215 ASCO.

OS (%) OS for BRAF-mutation positive (n=173) and BRAF wild-type (n=296) patients 1 BRAF-mutation positive (n=173) BRAF wild-type (n=296) 8 Median OS, months 1-year OS, % 2-year OS, % 11.6 48 24 8.5 39 18 6 P= NS 4 BRAF-mutation positive 2 Time (months) BRAF wild-type 6 12 18 24 3 36 Ascierto et al. J Trans Med 211

OS: Subgroup Analysis IPI 1 mg/kg IPI 3 mg/kg Hazard ratio vs events/patients events/patients (95% CI) Overall Population 262/365 279/362.84 (.7,.99) Age <65 years 15/224 158/28.78 (.62,.97) 65 years 112/141 121/154.99 (.77, 1.28) BRAF mutation status Positive 47/8 6/79.65 (.44,.96) Negative 169/225 181/237.92 (.75, 1.14) Not done 46/6 38/46.77 (.5, 1.19) M-stage M/M1a/M1b 84/136 11/142.78 (.58, 1.4) M1c no brain metastases 124/164 12/158.92 (.72, 1.18) M1c with brain metastases 54/65 58/62.71 (.49, 1.4) ECOG PS 17/262 183/253.8 (.65,.99) 1 92/13 96/19 1. (.75, 1.33) Prior systemic treatment No 19/16 113/157.85 (.65, 1.1) Yes 153/25 166/25.86 (.69, 1.7) Baseline ULN 151/222 16/219.85 (.68, 1.7) >ULN 13/133 116/136.82 (.63, 1.7) 2 ULN 223/321 233/36.84 (.7, 1.1) >2 ULN 31/34 43/49.97 (.61, 1.55) 1 2 1 mg/kg better 3 mg/kg better Ascierto et al. ESMO 216 Ascierto et al. Lancet Oncology 217

OS (%) OS (%) Checkmate 67: OS in Patients with BRAF Wild-type and Mutant Tumors BRAF Wild-type BRAF Mutant NIVO+IPI NIVO IPI NIVO+IPI NIVO IPI 1 9 Median, mo (95% CI) HR (95% CI) vs NIVO NR (27.6 NA).97 (.74 1.28) NR (25.8 NR) 18.5 (14.8 23.) -- -- 1 9 Median, mo (95% CI) HR (95% CI) vs NIVO NR.71 (.45 1.13 ) NR (26.4 NR) 24.6 (17.9 31. ) -- -- 8 7 6 5 4 61% 57% 8 7 6 5 4 71% 62% 51% 3 42% 3 Patients at risk: 2 NIVO+IPI 1 NIVO IPI 3 6 9 12 15 18 21 24 27 3 33 36 39 Months NIVO+IPI 212 194 17 157 144 142 133 127 126 12 18 31 5 NIVO 218 199 179 163 155 144 134 127 124 119 15 38 2 IPI 215 194 166 147 134 118 16 96 87 82 67 21 3 Patients at risk: 2 NIVO+IPI 1 NIVO IPI 3 6 9 12 15 18 21 24 27 3 33 36 39 Months NIVO+IPI 12 98 95 9 82 79 76 73 72 72 62 18 2 NIVO 98 93 86 81 75 69 67 64 57 56 52 17 1 IPI 1 91 88 81 71 64 58 53 49 47 37 13 1 Larkin et al. AACR 217

EGFR mutant NSCLC subjects derive less benefit from anti-pd1/pd-l1 Presented By Naiyer Rizvi at 217 ASCO Annual Meeting

Hypothetical model about how BRAFV6 mutation in melanoma cells could affect the tumor microenvironment and response to ipilimumab and combination of ipilimumab and nivolumab. Ascierto PA & McArthur JA. J Transl Med 217;15:173

Tissues of the body affected by autoimmune attack The clinical spectrum of IRAEs (immune-related adverse events) Festino and Ascierto. Oncoimmunology Eds 217

Most frequent iraes Grade 3-4 AEs % % of Pts who permantely discontinued for any grade Ipilimumab 3 mg/kg 1 27 15.4 Ipilimumab 1 mg/kg 1 34 31 Nivolumab 2 13 6 Pembrolizumab 2 mg/kg 3 13.5 4.5 Ipilimumab/Nivolumab 4 56.5 38.7 1. Ascierto et al. ESMO 216 2. Atkinson et al. SMR 215 3. Hamid ESMO 216 4. Wolchock et al ASCO 216

Distribution of grade I II and grade III V IRAEs for all tumour types in the main clinical trials with anti- CTLA4, anti-pd-1 or anti-pd-l1 antibodies as single therapy Michot JM et al. Eur J Cancer 216

Treatment algorithms/experience aid early diagnosis and management of immune-mediated adverse reactions Result from increased or excessive immune activity Systemic high-dose corticosteroids* may be required for severe events Unless an alternate aetiology has been identified, consider all signs and symptoms Immunemediated adverse reactions Can be severe or life-threatening; may involve various organs Early diagnosis and appropriate management essential to minimise life-threatening complications Patient education for early recognition *With or without additional immunosuppressive therapy

Time to and Durability of Response in Patients Who Discontinued Due to Toxicity NIVO+IPI NIVO IPI On treatment Off treatment First response Ongoing response 8 16 24 32 4 48 56 64 72 8 Time (weeks) 8 16 24 32 4 48 56 64 72 8 Time (weeks) 8 16 24 32 4 48 56 64 72 8 Time (weeks) Larkin J et al. ECC 215

Percentage of OS CA29-69: Overall Survival at 2 Years of Follow Up Median and 95% CI 1 All Randomized NIVO+IPI NR 9 83% Discontinued Due to AEs NIVO+IPI NR 8 All Randomized IPI 71% NR (11.9-NR) 7 73% 6 5 4 3 65% 64% 54% 2 1 3 6 9 12 15 18 21 24 27 3 Time (months) Number of patients at risk: Nivolumab + Ipilimumab Nivolumab + Ipilimumab Ipilimumab 95 35 47 82 33 41 77 32 36 74 3 33 69 29 29 67 27 27 65 26 26 63 26 25 57 24 22 6 1 3 Subsequent systemic therapies were used in 64% of IPI patients, 28% of NIVO+IPI patients and in 31% of NIVO+IPI patients who discontinued due to treatment-related AEs Hodi et al ASCO 216

Exploratory endpoint Mean FKSI-19 score (SD) scale -76 Health-related quality of life: Intention to treat 75 7 65 6 55 5 45 4 No. at Risk NIVO SUN Worse Better NIVO+IPI SUN 4 8 12 16 2 24 28 32 36 4 44 48 52 56 6 64 68 72 76 8 84 Week Minimum important difference: 3 to 5 532 52 399 35 323 298 288 188 142 19 126 118 154 118 13 114 18 14 119 89 9 13 515 52 46 42 383 294 311 169 111 215 134 98 173 13 92 156 91 71 132 82 64 16 Escudier B et al ESMO 217

Raising the bar Chemotherapy Radiotherapy Combination approaches Immunotherapy Targeted therapy Ascierto ESMO 216

What s the next NeoAdjuvant The right duration of treatments Better combos with less side effects Combination or sequencing

Progression-Free Survival, % PFS (irrc, investigator) From Last Pembrolizumab Dose to PD or Death in Patients Who Completed Protocol-Specified Time on Pembrolizumab (n = 14) 1 9 8 7 6 5 4 3 2 1 2 4 6 8 1 12 14 Time, months No. at risk 14 96 95 86 67 3 6 Patients who completed protocol-specified time on pembrolizumab, n Estimated PFS, % (95% CI) 12 (98%) patients were alive after a median of 9.7 months after completing pembrolizumab treatment Median PFS 14 91 (8-96) NR Robert C et al ASCO 217 Abstract #954 Data cutoff date: Nov 3, 216.

Progression-Free Survival, % PFS (irrc, investigator) From Last Pembrolizumab Dose to PD or Death in Patients Who Completed Protocol-Specified Time on Pembrolizumab (n = 14) (cont) 1 9 8 7 6 5 4 3 2 1 No. at risk CR 24 PR 68 SD 12 2 4 6 8 1 12 14 Time, months 23 23 22 18 9 1 61 61 55 4 17 4 12 11 9 9 4 1 Best Response n Estimated PFS, % (95% CI) Median PFS CR 24 95 (69-99) NR PR 68 91 (74-97) NR SD 12 83 (48-96) NR Robert C et al ASCO 217 Abstract #954 Data cutoff date: Nov 3, 216.

Spiegel et al. ESMO 217

What s the next NeoAdjuvant The right duration of treatments Better combos with less side effects Combination or sequencing

New emerging pathways for future combination with anti-pd-1/pd-l1 compounds HDAC inhibitor (eg., entinostat [Ph 2]) IDO1 inhibitor (eg., epacadostat [Ph 3]) Anti-GITR (eg., BMS-986156 (Ph 1/2]) Anti-LAG-3 (eg., BMS-98616 [Ph 1/2]) GITR, glucocorticoid-induced TNFR-related protein; HDAC, histone deacetylases; IDO1, indoleamine 2,3-dioxygenase 1; LAG-3, lymphocyte-activation gene 3 Ascierto PA & McArthur JA. J Transl Med 217;15:173

New Emerging Pathways for Future Combination With Anti PD-1/PD-L1 Compounds: IDO1 Inhibition IDO1 inhibitor (e.g., epacadostat [Ph 3]) IDO1, indoleamine 2,3-dioxygenase 1; PD-1, programmed death receptor-1; PD-L1, programmed death ligand 1. Ascierto PA, McArthur JA. J Transl Med. 217;15:173.

Hamid et al ESMO 217

ECHO-31 (Keynote-252): Phase 3 Study of Pembrolizumab + Epacadostat or Placebo in Patients With Unresectable or Metastatic Melanoma Randomised, Phase 3, double-blind, placebo-controlled study of pembrolizumab in combination with the IDO1 inhibitor, epacadostat, or placebo in subjects with unresectable or metastatic melanoma Subjects with unresectable or metastatic MEL have baseline biopsy to identify PD-L1 status ECOG PS: or 1 Untreated for advanced or metastatic disease except for prior standard of care targeted therapy (eg, BRAF/MEK inhibitor, alone or in combination) for BRAF V6 mutant melanoma N=~6 R A N D O M I S A T I O N Pembrolizumab Q3W + Epacadostat PO daily Pembrolizumab Q3W + Placebo PO daily Co-primary endpoints: PFS OS Survival follow-up Secondary endpoints: ORR Safety and tolerability BID, twice daily; ECOG PS, Eastern Cooperative Oncology Group performance status; MEL, melanoma; ORR, overall response rate; OS, overall survival; PD-L1, programmed death ligand 1; PO, by mouth; PFS, progression-free survival; Q3W, every 3 weeks. Clinicaltrials.gov: NCT275274.

New Emerging Pathways for Future Combination With Anti PD-1/PD-L1 Compounds: Anti LAG-3 Anti-LAG-3 (e.g., relatlimab [Ph 1/2]) LAG-3, lymphocyte-activation gene 3; PD-1, programmed death receptor-1; PD-L1, programmed death ligand 1. Ascierto PA, McArthur JA. J Transl Med. 217;15:173.

Ascierto PA, et al. ESMO 217

Overall Survival (%) Raising the bar 1 9 8 7 6 5 4 3 2 ~ 6% N=21 45% 4% N=655 N=152 35% N=17 ipi/nivo 5% 4% 2% N=1,861 IPI (Pooled analysis) 1 NIVO Monotherapy (Phase 1 CA29-3) 2 PEMBRO Monotherapy (Phase 1 Keynote-1) 4 Pretreated and Naïve Patients NIVO Monotherapy (Phase 3 Checkmate 66) 3 PEMBRO Monotherapy (Phase 1 Keynote-1) 4 Naïve Patients 1 1 2 3 4 5 6 7 8 9 1 Years 1. Schadendorf et al. J Clin Oncol 215;33:1889-1894; 2. Current analysis; 2. Hosi FS. AACR 216 3. Poster presentation by Dr. Victoria Atkinson at SMR 215 International Congress. 4. Robert et al. Oral presentation ASCO 216 5. Daud et al. Oral presentation ASCO 215

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