PowerPoint Presentation ` mCSCC (n=10) Locally advanced CSCC (n=16) Overall (N=26) Median age, years (min–max) 71 (56–86) 73 (56–88) 73 (56–88) Males, n (%) 8 (80.0) 13 (81.3) 21 (80.8) ECOG performance status, n (%) 0 4 (40.0) 6 (37.5) 10 (38.5) 1 6 (60.0) 10 (62.5) 16 (61.5) Primary CSCC site, n (%) Head/neck 5 (50.0) 13 (81.3) 18 (69.2) Extremity 3 (30.0) 2 (12.5) 5 (19.2) Trunk 1 (10.0) 1 (6.3) 2 (7.7) Genital 1 (10.0) 0 1 (3.8) Any prior systemic therapy, n (%) 9 (90.0) 6 (37.5) 15 (57.7) Any prior radiation therapy, n (%) 6 (60.0) 14 (87.5) 20 (76.9) Number of doses of cemiplimab, median, (min–max) 12.5 (3–23) 10.0 (2–24) 11.0 (2–24) Months of follow up, median, (min–max) 7.3 (1.6–13.8) 6.6 (1.1–13.3) 6.9 (1.1–13.8) Presented at the 13th Winter Clinical Dermatology Conference, January 12–17, 2018, Lahaina, HI, USA (encore of ASCO 2017 oral presentation) Cemiplimab (REGN2810), A Fully Human Anti-PD-1 Monoclonal Antibody, for Patients with Unresectable Locally Advanced or Metastatic Cutaneous Squamous Cell Carcinoma (CSCC): Initial Safety and Efficacy from Expansion Cohorts of Phase 1 Study Kyriakos P. Papadopoulos,1 Taofeek K. Owonikoko,2 Melissa L. Johnson,3 Irene Braňa,4 Marta Gil-Martin,5 Raymond P. Perez,6 Victor Moreno,7 April K. Salama,8 Emiliano Calvo,9 Nelson S. Yee,10 Howard Safran,11 Antonio González-Martín,12 Raid Aljumaily,13 Daruka Mahadevan,14 Kosalai K. Mohan,15 Jingjin Li,16 Elizabeth Stankevich,15 Israel Lowy,15 Matthew G. Fury,15 Jade Homsi17 1South Texas Accelerated Research Therapeutics, San Antonio, TX, USA; 2Emory Winship Cancer Institute, Atlanta, GA, USA; 3Sarah Cannon Research Institute, Nashville, TN, USA; 4Vall D’Hebron Institute of Oncology, Barcelona, Spain; 5Institut Català d'Oncologia, Barcelona, Spain; 6Unversity of Kansas, Fairway, KS, USA; 7START Madrid Fundacion Jimenez Diaz, Madrid, Spain; 8Duke University Medical Center, Durham, NC, USA; 9START Madrid, Hospital Madrid Norte Sanchinarro, Madrid, Spain; 10Penn State Cancer Institute, Hershey, PA, USA; 11Miriam Hospital, Providence, RI, USA; 12Formerly of MD Anderson International España, Madrid, Spain; 13University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; 14Formerly of University of Arizona Cancer Center, Tucson, AZ, USA; 15Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA; 16Regeneron Pharmaceuticals Inc., Basking Ridge, NJ; 17Formerly of Banner MD Anderson Cancer, Gilbert, AZ, USA. • Selected inclusion criteria include: – Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. – Measureable disease by RECIST 1.1. – Adequate organ function (bone marrow, kidney, liver). – mCSCC (M1): Expansion Cohort 7. – Unresectable locally and/or regionally advanced CSCC (M0): Expansion Cohort 8: • Acceptable reasons for surgery to be deemed inappropriate are: – Recurrence of CSCC after 2 or more surgical procedures and an expectation that curative resection would be unlikely, and/or; – Substantial morbidity or deformity anticipated from surgery. • Selected exclusion criteria: – Autoimmune disease within 5 years. – Active brain metastases. – Other invasive malignancy within 5 years (no exclusion for tumors considered cured by localized treatment). – Immunosuppressive doses of steroids (>10 mg prednisone daily or equivalent). – Systemic antitumor treatment within 4 weeks of initial dose of cemiplimab. – History of solid organ transplant. – Tumors of lip or eyelid not eligible for CSCC cohorts. Results Patient characteristics • As of April 27, 2017 (data cut-off date), 26 patients (median age, 73 years) from the CSCC expansions cohorts have been treated with cemiplimab. • Patient characteristics and exposure to cemiplimab are summarized in Table 1. Disclosures Dr. Kyriakos Papadopoulos: institutional research funding from Abbvie, MedImmune, Daiichi Sankyo, GlaxoSmithKline, Regeneron, Sanofi, ARMO BioSciences, ArQule, Amgen, Calithera Biosciences, Curagenix, Incyte, Merck, Peloton Therapeutics, 3D Medicines, Formation Biologics, EMD Serona. Taofeek Owonikoko: consulting/advisory role for Abbvie, Celgene, Eisai, G1 Therapeutics, Genentech/Roche, Eli Lilly, Novartis, Sandoz, and Takeda; institutional research funding from Abbvie, Astellas Pharma, AstraZeneca/MedImunne, Bayer, BMS, Celgene, G1 Therapeutics, Novartis, Regeneron, Stemcentrix; institutional patents, royalties, other intellectual property from “Overcoming acquired resistance to chemotherapy treatments through suppression of STAT3; selective chemotherapy treatments and diagnostics methods related thereto”. Melissa Johnson: institutional consulting/advisory role for Astellas, BI, Celgene, Genentech/Roche, Otsuka; research funding from Array, BioPharm, AstraZeneca, BergenBio, Checkpoint Therapeutics, Inc., EMD Serono, Genentech/Roche, Genemab, Janseen, Kadmox, Lilly, Mirati Therapeutics, Inc., Novartis, OncoMed, Pfizer, Regeneron, Stementrx. Irene Braňa: no disclosures. Marta Gil Martin: no disclosures. Raymond Perez: consulting/advisory role for Pharmaceutical Research Associates; institutional research funding from Agensys, Altor BioScience, Bristol-Myers Squibb, Dompe Farmaceutici, Genentech/Roche, Immunogen, Incyte, Lilly, MedImmune, Millennium, Novartis, Onyx, Regeneron, Tetralogic Pharmaceuticals. Victor Moreno: no disclosures. April Salama: Honoraria and consulting/advisory role for BMS; institutional research funding from Abbvie, BMS, Celldex, Genentech, GSK, Immunocore, Merck, Reata Pharmaceuticals. Emiliano Calvo: Consulting/ advisory role for Astellas Pharma, GSK, Lilly/Imclone, Nanobiotix, Novartis, Pfizer, Roche/Genentech; Speakers bureau fee from Novartis; institutional research funding from Abbvie, Boehringer Ingelheim, Bristol-Myers, Squibb, Eisai, Janssen Oncology, Lilly, Merck, Millenium, Nektar, Novartis, OncoMed, Pfizer, PharmaMar, Psi Oxus, Puma Biotechnology, Roche/Genentech, Sanofi, Spectrum Pharmaceuticals. Nelson Yee: consulting/ advisory role for Bayer; institutional research funding from EMD Serono, Medpace, Momenta Pharmaceuticals, Onxeo, Pharmacycles, Regeneron. Howard Safran: no disclosures. Antonio González-Martín: consulting/advisory role for, Speakers bureau and travel/accommodations/expenses fees from Roche and PharmaMar, Speakers bureau and travel/accommodations/expenses fees from AstraZeneca. Raid Aljumaily: no disclosures. Daruka Mahadevan: no disclosures. Kosalai Mohan: stockholder and employee of Regeneron Pharmaceuticals, Inc. Jingjin Li: stockholder and employee of Regeneron Pharmaceuticals, Inc. Elizabeth Stankevich: employee of Regeneron Pharmaceuticals, Inc., stockholder at Regeneron Pharmaceuticals, Inc., BMS, Celgene, Merck. Israel Lowy: stockholder and employee of Regeneron Pharmaceuticals, Inc. Matthew Fury: stockholder and employee of Regeneron Pharmaceuticals, Inc.; consulting/advisory role for Egenix; research funding from AstraZeneca/MedImmune, Novartis, Regeneron; institutional patents, royalties, other intellectual property from Regeneron. Jade Homsi: honoraria and speakers’ bureau fees from Genentech, Merck; consulting/advisory role for Castle Biosciences, Novartis; research funding from Bristol-Myers Squibb, Regeneron; travel/accommodations/expenses from Genentech, Merck, Novartis. References 1. Papadopoulos KP et al. J Clin Oncol. 2016:34 (suppl; abstr 3024). 2. Karia PS et al. J Am Acad Dermatol. 2013;68:957–966. 3. Stratigos A et al. Eur J Cancer. 2015;51:1989–2007. 4. Karia PS et al. J Clin Oncol. 2014;32:327–334. 5. Cranmer LD et al. Oncologist. 2010;15:1320–1328. ` Table 1. Patient characteristics and exposure to cemiplimab †5 patients not evaluated by immunohistochemistry: 1 CR, 1 PR, 2 SD, 1 PD; ‡Includes 1 unconfirmed PR. NE, not evaluable. Figure 4. Early response to cemiplimab in a 62-year old male with locally advanced CSCC Screening Response after 6 weeks of cemiplimab ` Figure 5. Durable response with cemiplimab in an 86-year old with CSCC of trunk, metastatic to bilateral axillary lymph nodes Screening >6 months after treatment discontinuation Background • Cemiplimab (REGN2810) is a human immunoglobulin G4 monoclonal antibody directed against PD-1.1 • Phase 1 results from the first 60 patients with advanced solid tumors showed no dose-limiting toxicities:1 – The most common treatment-related adverse events were fatigue (28%), arthralgia (12%), and nausea (12%). – The overall response rate was 18%. • Cemiplimab 3 mg/kg every 2 weeks (Q2W) was selected for further study in Expansion Cohorts. • As of April 27, 2017, 392 patients have been enrolled in the Phase 1 study. • Cutaneous squamous cell carcinoma (CSCC) is the 2nd most common skin cancer in US.2 • Risk factors for CSCC include ultraviolet exposure, advanced age, immunosuppression.3 – There is a predominance of males and a median age of 71 years at diagnosis.4 • CSCC has a surgical cure rate of >95% in early stage disease; however, a small percentage of patients develop unresectable locally advanced or metastatic CSCC4 – US mortality: 3,900–8,800/year.4 • There is no widely accepted standard of care systemic therapy for locally advanced or metastatic CSCC (mCSCC).5 – Conventional cytotoxic chemotherapy can induce tumor responses, but often is poorly tolerated among older patients with CSCC. – In a single arm trial with cetuximab (n=36), median overall survival was 8.1 months.6 • In Phase 1 dose escalation study of cemiplimab, a durable radiologic complete response to cemiplimab was achieved in a CSCC patient.1,7 • There is a higher mutation burden in CSCC than any tumor type in The Cancer Genome Atlas (TCGA).8 • Immunosuppression is a well-described risk factor for CSCC (especially in solid organ transplant patients).9 • Programmed death-ligand 1 (PD-L1) expression has been associated with high-risk disease10; CSCC tumors may therefore be responsive to PD-1 checkpoint blockade. Objectives • The co-primary objectives of the CSCC Expansion Cohorts of this Phase 1 open label study were to: – Characterize the safety and tolerability of intravenous cemiplimab 3 mg/kg. – Evaluate the efficacy of cemiplimab by measuring overall response rate (ORR). Methods Study design: CSCC Expansion Cohorts (NCT02383212) • Cohort 7 enrolled 10 patients with mCSCC and Cohort 8 enrolled 16 patients with unresectable locally and/or regionally advanced CSCC (Figure 1). Figure 1. Study design: CSCC expansion cohorts Metastatic CSCC Cohort 7 (n=10) Cemiplimab 3 mg/kg Q2W, for up to 48 weeks Response assessments every 8 weeks (RECIST 1.1)Locally and/or regionally advanced CSCC Cohort 8 (n=16) Research tumor biopsies were taken at screening and Day 29±3. RECIST, Response Evaluation Criteria In Solid Tumors. • All patients received cemiplimab 3 mg/kg Q2W for up to 48 weeks (if no progression or intolerance), followed by post-treatment follow-up. – There is an option for re-treatment for patients who experienced disease progression during post- treatment follow-up, but no CSCC patients have required this re-treatment option at this time. • All patients underwent tumor imaging every 8 weeks, and response assessments are per RECIST 1.1. • Research biopsies were performed at baseline and at Day 29. Treatment-related TEAEs of any grade occurring in ≥2 patients, or ≥Grade 3 in any patient Number of patients (%) Any grade ≥Grade 3 Fatigue 6 (23.1) 0 Arthralgia 2 (7.7) 1 (3.8) Rash, maculopapular 2 (7.7) 1 (3.8) Diarrhea 2 (7.7) 0 Nausea 2 (7.7) 0 Hypothyroidism 2 (7.7) 0 Asthenia 1 (3.8) 1 (3.8) Aspartate aminotransferase elevation 1 (3.8) 1 (3.8) Alanine aminotransferase elevation 1 (3.8) 1 (3.8) ` Table 2. Summary of treatment-related TEAEs (N=26) Immunohistochemistry • A total of 17 of 21 evaluated tumors (81%) were positive (≥1%) for tumor expression of PD-L1 by immunohistochemistry (Table 4). • There was no apparent association between PD-L1 immunohistochemistry results and objective responses. ` Table 4. Tumor PD-L1 expression by immunohistochemistry using Dako 22C3 clone Tumor PD-L1 Total CR PR SD PD NE ORR† Number of patients ≥50% 8 0 3‡ 3 2 0 38% (3/8)‡ ≥1–49% 9 1 4 0 2 2 56% (5/9) <1% 4 0 2 1 1 0 50% (2/4) Conclusions • This is the first prospective study of a PD-1 inhibitor in patients with advanced CSCC. • Cemiplimab was generally well tolerated in CSCC in this predominantly older population. • Both locally advanced and mCSCC are highly responsive to cemiplimab (combined ORR 46.2%), and durability is emerging. • Eighty-one percent of pre-treatment tumor samples were PD-L1 positive. • A unifying characteristic of cutaneous malignancies appears to be responsiveness to immune checkpoint inhibition. • A phase 2 study is ongoing in patients with unresectable locally advanced and mCSCC (NCT02760498). 6. Maubec E et al. J Clin Oncol. 2011;29:3419–3426. 7. Falchook GS et al. J Immunother Cancer. 2016;4:70. 8. Pickering CR et al. Clin Cancer Res. 2014;20:6582–6592. 9. Euvrard E et al. N Engl J Med. 2003;348:1681–1691. 10. Slater NA, Googe PB. J Cutan Pathol. 2016;43:663–670. Acknowledgments We thank the patients and their families, the investigators and study teams involved in this study. This study was funded by Regeneron Pharmaceuticals Inc, and Sanofi. We would like to acknowledge the following people from the study sponsors: Bo Gao, Frank Seebach, Laura Simpson, Ana Kostic, Usman Chaudhry, Wilson Caldwell, Minjie Feng, Dale LeSueur. Medical writing support and typesetting was provided by Prime, Knutsford, UK, funded by Sanofi and Regeneron Pharmaceuticals Inc. Treatment-emergent adverse events (TEAEs) • Treatment-related TEAEs occurring in ≥2 patients overall, or ≥Grade 3 in any patient are summarized in Table 2. Investigator assessment mCSCC (n=10), n (%) Locally advanced CSCC (n=16), n (%) Overall (N=26), n (%) Complete response 0 2 (12.5) 2 (7.7) Partial response 6 (60.0)† 4 (25.0) 10 (38.5) Stable disease 1 (10.0) 5 (31.3) 6 (23.1) Progressive disease 2 (20.0) 4 (25.0) 6 (23.1) Not evaluated 1 (10.0) 1 (6.3) 2 (7.7) Tumor response • Tumor response by cohort are summarized in Table 3. • Investigator assessed preliminary ORR (complete response [CR] + partial response [PR] + one unconfirmed PR) by RECIST 1.1 was 46.2% (12/26 patients; 95% CI: 26.6–66.6; intention-to-treat population). • Disease control rate (DCR = ORR + stable disease [SD]) was 69.2% (18/26 patients; 95% CI: 48.2–85.7). • Clinical activity in all patients with at least 1 response evaluation of target lesions are shown in Figure 2. • Cemiplimab also produced rapid, deep and durable tumor reductions in target lesions in both cohorts (Figure 3). ` Table 3. Best overall tumor response rate by cohorts †Includes 5 confirmed partial responses and 1 unconfirmed partial response. ` Figure 3. Change in target lesion over time mCSCC (RECIST responses) *Patient progressed at subsequent assessment; however, the sum of target lesions are not evaluable. PD, progressive disease; uPR, unconfirmed partial response. 1 2 3 4 5 6 7 8 9 11 40 20 0 –20 –40 –60 –80 –100 0 P er ce nt c ha ng e in ta rg et le si on s fr om b as el in e First CR/PR First PD Months 10 12 * Locally advanced (RECIST responses) Locally advanced (SD, PD) • Figure 4 shows a case example of a CSCC patient with early response. • Figure 5 shows a case example of a patient with CSCC of trunk, metastatic to bilateral axillary lymph nodes, with durable response to cemiplimab. – Cemiplimab was discontinued due to an adverse event (rash) after 3 doses; patient continued to maintain response >6 months after discontinuation. ` Plot shows 22 patients who had at least 1 response evaluation. Not listed are 4 enrolled patients who did not have at least 1 response evaluation due to death in cycle 1 (2 patients), early clinical progression but no scans (1 patient), and end-of-cycle 1 response assessment that showed new lesions but unevaluable target lesions (1 patient). †Patient had new lesions at end of cycle 1. ‡Patients had stable disease despite large decreases in target lesions: 1 patient discontinued treatment after cycle 1 due to arthralgia, so is stable disease by RECIST; 1 patient developed new lesions during cycle 2 so is stable disease by RECIST. B es t p er ce nt c ha ng e in ta rg et le si on s fr om b as el in e Figure 2. Clinical activity in all patients with at least 1 response evaluation of target lesions Number of patients with confirmed responses = 11 One had progressive disease at 21 weeks, 10 remain in response (>8 to >40 weeks duration of responses) 40 20 0 –20 –40 –60 –80 –100 ‡‡† • Two patients discontinued study treatment after treatment-related TEAEs – 86-year old female developed Grade 3 rash after 3 doses; she continues post-treatment follow-up – 88-year old male withdrew consent following Grade 3 transaminase elevation and Grade 2 fatigue after 6 doses. • There were 2 deaths within 30 days of last dose of study drug, both considered unrelated to study drug. mCSCC (SD, PD, uPR) Progressive disease Stable disease Unconfirmed response Confirmed response Slide Number 1