WSMOS Fall meeting: Advances in the treatment of metastatic and - PowerPoint PPT Presentation

WSMOS Fall meeting: Advances in the treatment of metastatic and high-risk melanoma John A. Thompson MD jat@uw.edu Office: 206-288-2044

Somatic mutation frequencies observed in exomes from 3,083 tumour–normal pairs. MS Lawrence et al. Nature 000 , 1-5 (2013) doi:10.1038/nature12213

Chen DS Immunity 39:1, 2013

Mechanism ¡of ¡ac-on ¡of ¡Ipilimumab ¡and ¡Nivolumab ¡ Tumor Microenvironment Activation (cytokines, lysis, proliferation, migration to tumor) TCR TCR MHC MHC + + + + + + Dendritic Tumor ¡cell ¡ B7 CD28 cell + + + T cell T cell PD-1 PD-L1 - - - B7 CTLA-4 - - - anti-PD-1 anti-CTLA-4 PD-1 PD-L2 - - - anti-PD-1 CTLA-4 Blockade (ipilimumab) PD-1 Blockade (nivolumab)

Activity of Anti–Programmed Death 1 (PD-1) Antibody in Patients with Refractory Melanoma Complete/partial Response (CR/PR): 33/107 (31%) Stable Disease (SD): 7/107 (7%) . Topalian SL, et al. N Engl J Med 2012;366:2443-2454. Topalian SL, et al. J Clin Oncol 2014;32:1020-1030.

Immune-related adverse experiences (irAEs) www.hcp.yervoy.com/mm/resources-library Adverse reaction management guide Patient Wallet Card Skin: Endocrine § Pruritus § Fatigue § Rash § Headache § Mental status changes Gastrointestinal § Hypotension § Diarrhea § Abnl thyroid function tests/serum § Abdominal Pain chemistries § Blood in stool § Bowel perforation Neurological § Peritoneal signs § Uni- or bilateral weakness § Sensory alterations Liver: § Paresthesias § ↑ AST/ALT, Bili

CA209-­‑067 ¡Study ¡Design ¡ ¡ ¡ ¡ Randomized, ¡double-­‑blind, ¡phase ¡III ¡study ¡ to ¡compare ¡NIVO ¡+ ¡IPI ¡or ¡NIVO ¡alone ¡ ¡to ¡IPI ¡alone ¡ NIVO 1 mg/kg + IPI 3 mg/kg Q3W N=314 for 4 doses then NIVO 3 mg/kg Q2W Unresectable or Stratify by: Metatastic Melanoma Treat until • PD-L1 N=316 Randomize progression** • Previously untreated expression* NIVO 3 mg/kg Q2W + 1:1:1 or • 945 patients IPI-matched placebo • BRAF status unacceptable toxicity • AJCC M stage N=315 IPI 3 mg/kg Q3W for 4 doses + 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. 7

CA209-­‑067 ¡Study ¡PFS ¡and ¡OS ¡ ¡ ¡ ¡

CA209-­‑067 ¡Response ¡to ¡Treatment ¡ ¡ ¡ ¡ ¡ ¡

CA209-­‑067 ¡Safety ¡Summary ¡ ¡ ¡ ¡ ¡ ¡ ¡ NIVO ¡+ ¡IPI ¡(N=313) ¡ NIVO ¡(N=313) ¡ IPI ¡(N=311) ¡ PaJents ¡ReporJng ¡Event, ¡% ¡ Any ¡ Grade ¡ ¡ Any ¡ Grade ¡ ¡ Any ¡ Grade ¡ ¡ Grade ¡ 3–4 ¡ ¡ Grade ¡ 3–4 ¡ ¡ Grade ¡ 3–4 ¡ ¡ Treatment-­‑related ¡adverse ¡ 96 ¡ 55 ¡ 82 ¡ 16 ¡ 86 ¡ 27 ¡ event ¡(AE) ¡ Treatment-­‑related ¡AE ¡leading ¡ 36 ¡ 29 ¡ 8 ¡ 5 ¡ 15 ¡ 13 ¡ to ¡disconJnuaJon ¡ ¡ Treatment-­‑related ¡death* ¡ ¡ 0 ¡ 0.3 ¡ 0.3 ¡ • 67.5% of patients (81/120) who discontinued the NIVO + IPI combination due to treatment- related AEs developed a response *One reported in the NIVO group (neutropenia) and one in the IPI group (cardiac arrest)

CA209-­‑067 ¡ ¡Conclusions ¡ ¡ ¡ ¡ ¡ • NIVO alone and NIVO + IPI significantly improved PFS and ORR vs. IPI alone in patients with previously untreated melanoma – NIVO + IPI resulted in numerically longer PFS and a higher ORR vs. NIVO alone, but these results not compared statistically – In patients whose tumors have ≥ 5% PD-L1 expression , both NIVO alone and NIVO + IPI resulted in a similar prolongation in PFS, although ORR was numerically higher with NIVO + IPI • Based upon available evidence, the combination represents a means to improve outcomes vs. NIVO alone, particularly for patients whose tumors have <5% PD- L1 expression

CA209-­‑067 ¡PFS ¡by ¡PD-­‑L1 ¡Expression ¡Level ¡(1%) ¡ ¡ ¡ ¡ ¡ ¡ N= 490 N= 353 PD-L1 ≥ 1%* PD-L1 <1%* mPFS ¡ ¡ HR ¡ ¡ mPFS ¡ ¡ HR ¡ ¡ 1.0 1.0 Proportion alive and progression-free Proportion alive and progression-free NIVO + IPI NIVO + IPI 12.4 ¡ ¡ 0.44 ¡ 11.2 ¡ ¡ 0.38 ¡ ¡ 0.8 0.8 NIVO NIVO 12.4 ¡ ¡ 0.46 ¡ ¡ 2.8 ¡ ¡ 0.67 ¡ IPI IPI 0.6 0.6 3.9 ¡ -­‑-­‑ ¡ 2.8 ¡ -­‑-­‑ ¡ 0.4 0.4 0.2 0.2 NIVO + IPI NIVO + IPI NIVO NIVO IPI IPI 0.0 0.0 0 3 6 9 12 15 18 21 0 3 6 9 12 15 18 Months Months No. at risk No. at risk NIVO + IPI NIVO + IPI 155 113 91 78 32 4 1 123 82 65 57 26 6 0 NIVO NIVO 171 115 97 83 34 7 1 0 117 50 42 34 13 2 0 IPI IPI 164 83 47 36 16 3 113 39 19 12 5 0 *Per validated PD-L1 immunohistochemical assay with expression defined as ≥ 1% of tumor cells showing PD-L1 staining in a section of at least 100 evaluable tumor cells.

Standard dose pembrolizumab + reduced dose ipilimumab for metastatic melanoma Long GV et al Lancet Oncol 18:1202, 2017 153 Pts with metastatic melanoma Pembro 2 mg/kg + Ipi 1 mg/kg q 3 wks x 4 doses Pembro 2 mg/kg q 3 wks for up to two years or disease progression or intolerance

Standard dose pembrolizumab + reduced dose ipilimumab for metastatic melanoma Long GV et al Lancet Oncol 18:1202, 2017 Grade 3-4 immune-related toxicity 27% All (n=153) PDL-1 pos PDL-1 neg (n=127) (n=24) C R 23 (15%) 18 (14%) 4 (17%) PR 70 (46%) 61 (48%) 8 (33%)

Long GV et al Lancet Oncol 18:1202, 2017

Tumor Staining for PD-L1: Correlation with Response to Therapy with Anti-PD-1 or Anti-PD-L1 Overall Response Rate PD-L1 Positive PD-L1 Negative Topalian (NEJM 2012) 9/25 0/17 Grosso (ASCO 2013) 7/16 3/18 Herbst (ASCO 2013) 13/33 8/61 Robert (NEJM 2015) 53% 33%* *PD-L1 negative or indeterminate Topalian SL, et al. N Engl J Med 2012;366:2443-2454. Grosso J, et al. ASCO Meeting Abstracts 2013;31:3016. Herbst RS, et al. ASCO Meeting Abstracts 2013;31:3000. Robert C, et al. N Engl J Med 2015;372:320-330.

Slide 20 Presented By Michael Atkins at 2015 ASCO Annual Meeting

Hypothesis 1: Interferon- γ Response Genes Will Predict Response to Pembrolizumab Presented By Antoni Ribas at 2015 ASCO Annual Meeting

PFS and OS in Patients With Melanoma and<br />IFN γ Signature Score Above and Below the Cutoff Presented By Antoni Ribas at 2015 ASCO Annual Meeting

Presence of Tregs and expression of PD-L1 and IDO are associated with a CD8+ T cell infiltrate Presented By Thomas Gajewski at 2015 ASCO Annual Meeting

Expression of differentiation antigens and cancer-germline antigens is comparable in T cell signature-high versus -low patients Presented By Thomas Gajewski at 2015 ASCO Annual Meeting

Overall mutational load (non-synonymous mutations) is comparable in T cell signature-high versus -low samples Presented By Thomas Gajewski at 2015 ASCO Annual Meeting

48% of non-T cell-inflamed tumors show evidence of active b-catenin signaling, which inhibits immune cell recruitment into tumor site Presented By Thomas Gajewski at 2015 ASCO Annual Meeting

Genomic and transcriptomic features of response to anti-PD-1 therapy of melanoma Hugo et al Cell 165:35, 2016 Whole exome sequences from tumors from 38 pts with metastatic melanoma, and pt-matched normal tissue for germline references 21 responding pts 17 non-responding pts 14 pts with prior MAPKi therapy Median of 489 non-synonymous somatic mutations (range 73 - 3985)

Genomic and transcriptomic features of response to anti-PD-1 therapy of melanoma Hugo et al Cell 165:35, 2016 High mutational loads associated with Improved survival, … .. but were not associated with response to therapy.

Genomic and transcriptomic features of response to anti-PD-1 therapy of melanoma Hugo et al Cell 165:35, 2016 Survival of PD-1-treated pts based on Gene set variance analysis scores presence or absence of “innate anti-PD-1 resistance” (IPRES) signature ( ñ gene expression for epithelial to mesenchymal transition, angiogenesis, and wound- healing) IPRES signature was detected in residual tumor after MAPKi therapy, suggesting that induction of this signature may impair responsiveness to combined MAPKi and anti-PD-1 therapy.

Genomic and transcriptomic features of response to anti-PD-1 therapy of melanoma Hugo et al Cell 165:35, 2016