Immunoterapia e melanoma maligno metastatico: siamo partiti da li. Vanna Chiarion Sileni Istituto Oncologico Veneto

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1 Immunoterapia e melanoma maligno metastatico: siamo partiti da li Vanna Chiarion Sileni Istituto Oncologico Veneto Vanna.chiarion@iov.veneto.it

Metastatic Melanoma Available Treatment: 197 217 Zelboraf

dual therapy Feb 212 Aug 215 DTIC-Dome (dacarbazine) 197s

Zelboraf + Cotellic (vemurafenib + cobimetinib) dual

5% Yervoy (ipilimumab) Jul 211 Opdivo (nivolumab) June 215

2 Metastatic Melanoma Available Treatment: Zelboraf (vemurafenib) Tafinlar + Mekinist (dabrafenib + trametinib) dual therapy Feb 212 Aug 215 DTIC-Dome (dacarbazine) 197s Tafinlar (dabrafenib) Aug 213 Mekinist (trametinib) Jun 214 Zelboraf + Cotellic (vemurafenib + cobimetinib) dual therapy Nov IntronA (interferon alfa-2b) 2 Median OS: 6.2 months 1-year survival: 25.5% Yervoy (ipilimumab) Jul 211 Opdivo (nivolumab) June 215 Keytruda (pembrolizumab) July 215 Imlygic (T-VEC) (talimogene laherparepvec) Dec 215 Opdivo (nivolumab) + Yervoy (ipilimumab) May 216

3 Akbani et al Cell Press 215

4 Tumours Use Various Mechanisms to Escape the Immune System Immune escape mechanisms are complex and frequently overlapping A. Ineffective presentation of tumour antigens to the immune system VEGF APC B. Recruitment of immunosuppressive cells (Tregs, MDSCs, others) CD8 + T cell TCR MHC MDSC Treg CTLA-4 Tumour cells PD-L1 PD-L1 PD-1 PD-1 TGF-β IDO IL-1 TGF-β IL-1 TGF-β ARG1 inos CD8 + T cell D. T cell checkpoint CD4 + T cell C. Secretion of immunosuppressive factors Vesely MD, et al. Ann Rev Immunol 211;29:235 71

5 Subset Ipilimumab OS Analyses by Prior Therapy (N=1861)* Presented By Axel Hauschild at 214 ASCO Annual Meeting

6 Alive (%) OS: Randomized Patients Number of patients at risk IPI 1 mg/kg IPI 3 mg/kg 54% 48% OS Time (Months) IPI 1 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).84 (.7,.99) Log-rank P value.4 38% 31% 31% 23% IPI 1 mg/kg IPI 3 mg/kg CI = confidence interval. Minimum OS follow-up: ~43 mo

7 Safety Summary: Treated Patients IPI 1 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, % Treatment-related AEs, % Serious AEs, % AEs leading to discontinuation, % Immune-related AEs, % 74 3 a During the entire study period, study-drug toxicity led to death in 4 patients (1%) in the 1 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 a No grade 5 immune-related AEs in the IPI 1 mg/kg group. AEs = adverse events.

9 O v e ra ll S u rv iv a l, % O v e ra ll S u rv iv a l, % 3-Year OS For Pts With Advanced Melanoma Treated With Pembrolizumab in KEYNOTE-1 Caroline Robert, 1 Antoni Ribas, 2 Omid Hamid, 3 Adil Daud, 4 Jedd D. Wolchok, 5 Anthony M. Joshua, 6 Wen-Jen Hwu, 7 Jeffrey S. Weber, 8 Tara C. Gangadhar, 9 Richard Joseph, 1 Roxana Dronca, 11 Amita Patnaik, 12 Hassane Zarour, 13 Richard Kefford, 14 Peter Hersey, 15 Xiaoyun Nicole Li, 16 Scott J. Diede, 16 Scot Ebbinghaus, 16 F. Stephen Hodi Pts, N Events, n (55%) Median (95% CI) 24.4 mo ( ) Treatment Naive a Pts, N Events, n (47%) Median (95% CI) 32.2 mo (27.2-NR) N o. a t r is k T im e, m o n th s 5 % 4 % N o. a t r is k T im e, m o n th s 6 1 % 4 5 %

2 ULN N = 7 Bar height represents ORR. Error bars represent the 95% CI.

10 Rate (95% CI), % ORR: LDH 1 vs >1 2 vs >2 ULN (RECIST v1.1, Central Review) % % 26% 2 7% 1 Total N = ULN N = 333 >1 2 ULN N = ULN N = 7 Bar height represents ORR. Error bars represent the 95% CI. Data shown for patients with known LDH and centrally evaluable disease at baseline. Data cutoff date: Sep 18, 215 (median follow-up, 32 months).

12 Pembrolizumab Versus Ipilimumab For Advanced Melanoma: Final Overall Survival Analysis of KEYNOTE-6 O S, % No. at risk Pembro Q2W Pembro Q3W Ipi % 68% 59% Arm Events, n HR (95% CI) Pembro Q2W ( ).85 Pembro Q3W ( ).83 Ipi Time, months % 55% 43% NR (22.1-NR) NR (23.5-NR) 16. ( ) P Final analysis data cutoff date: Dec 3, 215.

13 ORR (95% CI), % Similar Findings in KEYNOTE-6 (Blank et al. SMR 216, Poster 24) % Pembro Ipi 34% 17% 11% 8% 6% ULN >1 to 2 ULN >2 ULN Responders, n DOR, mo median (range) Ongoing a NR NR NR NR NR NR ( ) ( ) ( ) ( ) ( )( ) 7% 74% 74% 75% 8% 1% a Responders without subsequent PD. Blank C et al. Poster presented at SMR 216; Nov 6-9, 216; Boston, MA.

14 Overall Percentage Survival of PFS (%) Overall Survival 1 9 Median OS, months (95% CI) HR (98% CI) vs. IPI HR (95% CI) vs. NIVO NIVO+IPI (N=314) NIVO (N=316) IPI (N=315) NR.55 (.42.72)*.88 ( ) NR (29.1 NR).63 (.48.81) 2. ( ) % 7 74% 64% *P< % 59% 4 45% NIVO+IPI NIVO IPI Months Number of patients at risk: NIVO+IPI NIVO IPI Database lock: Sept 13, 216

15 Overview pooled analysis of data from patients with metastatic mucosal melanoma who had received NIVO monotherapy (3 mg/kg), NIVO (1 mg/kg) plus IPI (3 mg/kg), or IPI monotherapy (3 mg/kg) in one of six trials: Phase I: CA29-3 and CA29-38 Phase II: CheckMate 69 Phase III: CheckMate 37, CheckMate 66, and CheckMate 67 NIVO Monotherapy NIVO+IPI IPI Monotherapy Studies 3/37/38/66/67 67/69 67/69 Total patients, N Mucosal mel, n (%) 86 (1%) 35 (9%) 36 (1%) Cutaneous mel, n (%) 665 (75%) 326 (8%) 269 (75%) Acral/Ocular/Other 138 (15%) 46 (11%) 52 (15%) 15

16 Probability of Progression-Free Survival PFS Mucosal Melanoma NIVO (N=86) NIVO+IPI (N=35) IPI (N=36) Median, mos (95% CI) 3. ( ) 5.9 (2.8 NR) 2.7 ( ) HR (95% CI) vs IPI.61 (.39.96).42 (.23.75) P value vs IPI* Median follow-up, mos (range) 6.2 ( ) 8.1 ( ) 8.6 ( ) -- *Unstratified log-rank test NIVO NIVO+IPI IPI Number of Patients at Risk Months NIVO NIVO+IPI IPI

17 Probability of Progression-Free Survival PFS Cutaneous Melanoma NIVO (N=665) Median, mos (95% CI) 6.2 ( ) HR (95% CI) vs IPI.73 (.61.87) NIVO+IPI (N=326) 11.7 ( ).49 (.4.61) IPI (N=269) 3.9 ( ) P value vs IPI*.4 <.1 -- Median follow-up, mos (range) 1. ( ) 11.7 ( )** ( )** *Unstratified log-rank test. **Follow-up times are for all melanoma subtypes NIVO NIVO+IPI IPI Number of Patients at Risk Months NIVO NIVO+IPI IPI

18 Most Common Treatment-Related Select AEs NIVO+IPI (N = 313) NIVO (N = 313) IPI (N = 311) Any grade Grade 3-4 Any grade Grade 3-4 Any grade Grade 3-4 Skin AEs, % Rash Pruritus Gastrointestinal AEs, % Diarrhea Colitis Endocrine AEs, % Hypothyroidism Hyperthyroidism Hepatic AEs, % Elevated ALT Elevated AST Pulmonary AEs, % Pneumonitis Renal AEs, % Elevated creatinine Immune-modulating medicines were used to manage adverse events and led to resolution rates of immune mediated AEs in the vast majority (>85%) of patients Database lock Nov

19 ORR, a % (95% CI) Best Response to Treatment 1 9 NIVO+IPI NIVO IPI % % 23% 45% 31% 33% 17% 2 1% 1 n LDH ULN LDH > ULN LDH > 2x ULN a By RECIST v1.1.

20 Overall Survival (%) Immune Checkpoint Inhibitors Provide Durable Long-term Survival for Patients with Advanced Melanoma IPI (Pooled analysis) 1 NIVO Monotherapy (Phase 1 CA29-3) 2 NIVO Monotherapy (Phase 3 Checkmate 66) 3 6 N= N= N=1, Years 1. Schadendorf et al. J Clin Oncol 215;33: ; 2. Current analysis; 3. Poster presentation by Dr. Victoria Atkinson at SMR 215 International Congress.

21 IPI+NIVO: OS in 29 pts treated at the MSKCC Rosner S et al ASCO SITC, 217

22 Combining immunotherapy and. Apetoh L, Ann Oncol 215

23 Progression-Free Survival, % Primary and Acquired Resistance to PD-1 Inhibitor Based Therapy What Resistance Looks Like on a PFS Curve 1 KEYNOTE Primary resistance KN-6 PEMBRO (q2w) PEMBRO (q3w) IPI Months Schachter J, et al. J Clin Oncol. 216;34(suppl) [abstract 954]. 23

Blocking the MAPK Signaling Pathway Results in Changes in the Tumor Microenvironment

Tumor Cell Death T Cells Are Activated and Live Longer Tumor Cells Are More Visible

24 MAPK Inhibitor-Induced Changes 1,2 Increased melanoma antigen expression Decreased

T-cell clonality a Increased PD-L1 expression Class I MHC upregulation 1.

25 Blocking the MAPK Signaling Pathway Results in Changes in the Tumor Microenvironment Dual MAPK Pathway pathway inhibition Inhibition PD-L1 inhibition Inhibition Enhanced Tumor Cell Death T Cells Are Activated and Live Longer Tumor Cells Are More Visible Tumors Are More Susceptible Class I MHC P =.24 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 1. Frederick D et al. CCR Ebert P et al. Immunity 216. a Adaptive Technologies, Seattle, WA. ND MEKi CD8+ T cell per Tumor Cell ND MEKi 25

26 Progression-Free Survival, % Primary and Acquired Resistance to PD-1 Inhibitor Based Therapy What Resistance Looks Like on a PFS Curve 1 KEYNOTE Primary resistance KN-6 PEMBRO (q2w) PEMBRO (q3w) IPI Acquired resistance Months Schachter J, et al. J Clin Oncol. 216;34(suppl) [abstract 954]. 26

27 Hierarchy of Co-inhibitory Receptors Anderson AC et al. Immunity 216; 44:989

29 PL Cheng et al Cancer Discovery Aug 216

30 PD-L1,IDO,FOXP3.TIM3,LAG3 Upregolati nei tumori infiammati β-catenin, PPAR-γ FGFR3 Upregolati nei tumori non infiammati

32 KIM JM & Chen DS. Ann Oncol 216

33 Tumor Immunotherapy is a reality in the treatment of melanoma. a better understanding of all involved players will improve the results

Immunotherapy of Melanoma Sanjiv S. Agarwala, MD

Immunotherapy of Melanoma Sanjiv S. Agarwala, MD Professor of Medicine Temple University School of Medicine Chief, Oncology & Hematology St. Luke s Cancer Center, Bethlehem, PA Overview Metastatic Melanoma