Evan J. Lipson, M.D.

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1 Update on treatment for Merkel cell, cutaneous squamous cell and basal cell cancers Evan J. Lipson, M.D. The Johns Hopkins University School of Medicine Bloomberg~Kimmel Institute for Cancer Immunotherapy Sidney Kimmel Comprehensive Cancer Center October 14, 2017

2 Disclosure Information Evan J. Lipson, MD I have the following financial relationships to disclose: Consultant/Advisor: Bristol-Myers Squibb, EMD Serono, Merck, Novartis Grant/Research Funding: AstraZeneca, Genentech, Merck -and- I will discuss the off-label use of drugs and the experimental use of agents that have not been approved by the FDA.

3 Objectives Describe the immunogenic nature of Merkel cell, cutaneous squamous cell and basal cell carcinomas (MCC, cscc, BCC) Explain the rationales for treatment of MCC, cscc and BCC with immunotherapy Discuss the anti-tumor activity of PD-1/L1 antibodies in patients with advanced MCC, cscc and BCC

4 Background: Merkel cell carcinoma Rare (~2000 new cases per year in U.S.) Lethal (5-year MCC-specific survival ~60%) Standard therapy for patients with advanced disease: platinum + etoposide (small cell regimen) initial responses common (55%), rarely durable Majority (~80%) of cases associated with Merkel cell polyomavirus; remaining are associated with UV damage and a high genetic mutation burden

5 Avelumab (anti-pd-l1) in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, openlabel, phase 2 trial (JAVELIN Merkel 200 trial) Avelumab: PD-L1 blocking antibody administered at 10 mg/kg IV every 2 weeks, premedication with antihistamine and acetaminophen 88 patients, median follow-up = 16.4 months Objective response rate = 33% (10 CR, 19 PR) 74% have a duration of response of one year or more Overall survival rate at one year = 52% Responses observed in pts regardless of PD-L1 expression or presence of Merkel cell polyomavirus. Kaufman et al, Lancet Oncology, 2016 AACR Annual Mtg, April 2017

6 American Association for Cancer Research Annual Meeting April 1-5, 2017 Progression-free survival at 1 year of follow-up compared with historical chemotherapy trial results Progression-free survival, % Cowey et al. Value Health, 2016 Becker et al. Ann Oncol, 2016 Iyer et al. Cancer Med, Months from start of systemic therapy Avelumab Cowey 2016 Becker 2016 Iyer 2016

7 First FDA-approved drug for Merkel cell carcinoma March 2017: FDA grants accelerated approval of avelumab for the treatment of patients 12 yrs with metastatic MCC

8 First-line avelumab treatment in patients with metastatic Merkel cell carcinoma (mmcc): preliminary data from an ongoing study Preliminary data among 25 patients with >6 weeks of follow-up demonstrated an unconfirmed ORR of 64% D Angelo et al, ESMO 2017

9 Non-comparative, Open-label, Multiple Cohort, Phase 1/2 Study to Evaluate Nivolumab in Patients With Virus-associated Tumors (CheckMate 358): Merkel Cell Carcinoma Cohort Twenty-five patients with advanced Merkel cell carcinoma Merkel cell polyomavirus (MCPyV)-positive and negative Rx: nivolumab (anti-pd-1) 240mg q2weeks All-treated (N=25) Treatment-naïve (n=15) 1-2 prior therapies (n=10) ORR, % (95% CI)* 64 (43 82) 73 (45 92) 50 (19 81) Complete response, % (n) 32 (8) 47 (7) 10 (1) Partial response, % (n) 32 (8) 27 (4) 40 (4) Stable disease, % (n) 12 (3) 20 (3) 0 Progressive disease, % (n) 12 (3) 7 (1) 20 (2) Unable to determine, % (n) 12 (3) 0 30 (3) *By RECIST v1.1, investigator assessed. Median follow-up 51 weeks; range: 5-63 weeks. Topalian et al, AACR Annual Mtg, April

10 Characteristics of Tumor Response Best Reduction from Baseline in Target Lesions (%) PD-L1 status (n=22) Positive Negative Unknown Patients Topalian et al, AACR Annual Mtg, April

11 Characteristics of Tumor Response Best Reduction from Baseline in Diameters of Target Lesions (%) PD PD SD At a median follow up of 51 weeks, 75% of responses (12/16) are ongoing SD SD PR PD PR CR PR PR CR CR PR PR Tumor MCPyV status (n=22) PR CR CR Positive Negative Unknown CR PR CR CR Patients Topalian et al, AACR Annual Mtg, April

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13 Pembrolizumab in advanced MCC Single arm, open label, phase II trial of first systemic therapy Unresectable or metastatic MCC No systemic immunosuppression or active autoimmune disease Pembrolizumab (anti-pd-1) 2 mg/kg IV every three weeks for up to 2 years Primary endpoint: objective response rate (CR + PR per RECIST)

Percent change in SLD of target lesions Percent Change in Target Lesions -100-80 -60-40 -20 0 20 40 60 80 100 120 140 160 Responses in virus-pos & virus-neg MCCs ORR: 56% Viral Status

14 Percent change in SLD of target lesions Percent Change in Target Lesions Responses in virus-pos & virus-neg MCCs ORR: 56% Viral Status Negative Positive Fraction responding: 44% of virus-neg 62% of virus-pos (difference not significant) Tumor viral status negative positive n = 24 (N=24) Nghiem et al, AACR Annual Conf, 2016

15 Conclusions: PD-1/L1 blockade in MCC Anti-PD-1/PD-L1 therapy can induce durable tumor regressions in patients with advanced MCC PFS compares favorably to historical outcomes with chemotherapy ORR may depend on treatment-naïve vs treatmentexperienced Responses seen regardless of tumor MCPyV status or PD-L1 expression

16 Cutaneous Squamous Cell Ca No established standard of care for unresectable or metastatic cscc Cetuximab tested in 36 pts with cscc disease control rate (CR+PR+SD at 6 weeks) = 69% PR + CR = 28% Maubec et al., JCO, 2011

17 Cutaneous Squamous Cell Ca REGN2810 (anti-pd-1) 3 mg/kg every 2 wks for up to 48 wks 26 pts enrolled Median age: 72.5 y (range, 56-88y) ORR (PR + CR, including unconfirmed) = 52% (12/23; 4uPR, 5 PR, 2CR, 1 ucr) Papadopoulos et al, ASCO 2017

18 Cutaneous Squamous Cell Ca Disease control rate (ORR+SD) 70% (16/23, including 4SD) One patient experienced PD during REGN2810 treatment after initial response REGN2810 for patients with advanced CSCC is enrolling patients NCT Papadopoulos et al, ASCO 2017

19 Basal cell carcinoma Unresectable or metastatic basal cell carcinoma (BCC) is rare (<10,000 cases per year in the US) Standard therapy: hedgehog pathway inhibitors Commonly cause dose-limiting toxicities (e.g., dysgeusia, anorexia, muscle cramps) Response rates and durability are suboptimal Response characteristics to vismodegib (hedgehog inhibitor) Diagnosis Overall response rate Duration of response (months) Metastatic BCC 30% (n=33) 7.6 Locally-advanced BCC 43% (n=63) 7.6 Sekulic et al, NEJM, 2012

any human cancer type Commonly expresses PD-L1 (33/40 tumors (82%))

20 Scientific rationale for testing anti-pd-1 in advanced basal cell carcinoma Genetic mutational burden among the highest reported in any human cancer type Commonly expresses PD-L1 (33/40 tumors (82%)) PD-L1 PD-1 Jayaraman et al, J Invest Dermatol, 2014 Lipson et al, JITC, 2017

21 Locally advanced basal cell carcinoma: Ongoing partial response to anti-pd-1 Pre-Rx 7 months

22 Metastatic basal cell carcinoma: Partial response to anti-pd-1, ongoing at 21 months Pre-therapy 6.5 months Lipson et al, JITC, 2017

23 Clinical trial in development: immune checkpoint blockers in advanced BCC 19 patients with locally-advanced or metastatic BCC Nivolumab 480mg IV q4weeks Add ipilimumab 1mg/kg if PD after 16 weeks First-line and prior therapies allowed Primary endpoints objective response rate disease control rate (CR + PR + SD 26 wks) Interrogation of immune checkpoint expression in preand on-therapy tumor biopsies

24 Questions? Evan J. Lipson, MD

25 Impact of Treatment Breaks on Vismodegib- Associated Patient Outcomes in Advanced BCC Efficacy 0 (n = 358) Number of treatment breaks 1 (n = 72) 2 (n = 39) 3 (n = 13) Complete response 30% 33% 51% 39% Partial response 31% 32% 44% 46% Median duration of treatment days 229 days 399 days 454 days Median PFS 19.8 mo 19.0 mo NE NE Adverse events n = 368 n = 76 n = 41 n = 14 Dysgeusia 51% 58% 63% 93% Muscle spasms 59% 70% 81% 93% Alopecia 59% 63% 78% 79% Grade 3 TEAEs 39% 45% 66% 79% NE = not estimable; TEAEs = treatment-emergent adverse events Dummer R et al. ASCO 2015;Abstract 9024.

26 Treatment breaks for vismodegibassociated side effects Median duration of treatment increases with increasing # of treatment breaks (0, 1, 2 or 3) Treatment breaks did not appear to compromise antitumor impact Results support providing dose interruptions as needed

News from ASCO. Niven Mehra, Medical Oncologist. Radboud UMC Institute of Cancer Research and The Royal Marsden Hospital

News from ASCO. Niven Mehra, Medical Oncologist. Radboud UMC Institute of Cancer Research and The Royal Marsden Hospital News from ASCO Niven Mehra, Medical Oncologist Radboud UMC Institute of Cancer Research and The Royal Marsden Hospital Disclosures Speaker fees: Merck, Bayer Advisory boards: Janssen-Cilag Research and