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 I study

Presenters: Papadopoulos KP¹,Owonikoko TK², Johnson ML³, Bra?a I⁴, Gil-Martin M⁵, Perez RP⁶, Moreno V⁷, Salama AK⁸, Calvo E⁹,Yee NS¹⁰, Safran H¹¹, González-Martín A¹², Aljumaily R¹³, Mahadevan D¹⁴, Mohan KK¹⁵, Li J¹⁶, Stankevich E¹⁵, Israel Lowy I¹⁵, Fury MG¹⁵, Homsi J¹⁷

Affiliations: ¹South Texas Accelerated Research Therapeutics, San Antonio, TX; ²Emory Winship Cancer Institute, Atlanta, GA; ³Sarah Cannon Research Institute, Nashville, TN; ⁴Vall D’HebronInstitute of Oncology, Barcelona, Spain; ⁵InstitutCatalàd’Oncologia, Barcelona, Spain; ⁶Unversity of Kansas, Fairway, KS; ⁷START Madrid Fundacion Jimenez Diaz, Madrid, Spain; ⁸Duke University Medical Center, Durham, NC; ⁹START Madrid, Hospital Madrid Norte Sanchinarro, Madrid, Spain; ¹⁰Penn State Cancer Institute, Hershey, PA; ¹¹Miriam Hospital, Providence, RI; ¹²Formerly of MD Anderson International España, Madrid, Spain; ¹³University of Oklahoma Health Sciences Center, Oklahoma City, OK; ¹⁴Formerly of University of Arizona Cancer Center, Tucson, AZ; ¹⁵Regeneron Pharmaceuticals Inc., Tarrytown, NY; ¹⁶Regeneron Pharmaceuticals Inc., Basking Ridge, NJ; ¹⁷Formerly of Banner MD Anderson Cancer, Gilbert, AZ.

Background/Objective: Cemiplimab (REGN2810) is a human immunoglobulin G4 monoclonal antibody directed against PD-1.1. Phase I results from the first 60 patients with advanced solid tumors showed no dose-limiting toxicities. The most common treatment-related adverse events (AEs) in these patients were fatigue (28%), arthralgia (12%), and nausea(12%); the overall response rate was 18 percent. Cemiplimab 3mg/kg every two weeks (Q2W) was selected for further study in Expansion Cohorts. As of April 27, 2017, 392 patients have been enrolled in the Phase I study. The coprimary objectives of the CSCC Expansion Cohorts of this Phase I open-label study were to characterize the safety and tolerability of intravenous cemiplimab 3mg/kg and to evaluate the efficacy of cemiplimab by measuring overall response rate (ORR).

Methods: 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. All patients received cemiplimab 3mg/kg Q2W for up to 48 weeks (if no progression or intolerance), followed by post-treatment follow-up. There was an option for re-treatment for patients who experienced disease progression during post-treatment follow-up, but no CSCC patients required this re-treatment option at the time of this study. All patients underwent tumor imaging every eight weeks, and response assessments were per RECIST 1.1. Research biopsies were performed at baseline and at Day 29. Subjects included scored a 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Status, had a measurable disease by RECIST 1.1, had adequate organ function (bone marrow, kidney, liver), were in the mCSCC(M1): Expansion Cohort 7 and/or the unresectablelocally and/or regionally advanced CSCC (M0): Expansion Cohort 8. Exclusion criteria included presence of an autoimmune disease within five years, active brain metastases, or other invasive malignancy within five years (no exclusion for tumors considered cured by localized treatment), immunosuppressive doses of steroids (>10mg prednisone daily or equivalent), systemic antitumor treatment within four weeks of initial dose of cemiplimab, history of solid organ transplant, and tumors of lip or eyelid not eligible for CSCC cohorts.

Results: Investigator-assessed preliminary ORR (complete response [CR] + partial response [PR] + one unconfirmed PR) by RECIST 1.1 was 46.2 percent (12/26 patients; 95% confidence interval [CI]: 26.6–66.6; intent-to-treat [ITT] population). Disease control rate (DCR = ORR + stable disease [SD]) was 69.2 percent (18/26 patients; 95% CI: 48.2–85.7). Cemiplimab also produced rapid, deep, and durable tumor reductions in target lesions in both cohorts. 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. A total of 17 of 21 evaluated tumors (81%) were positive (?1%) for tumor expression of PD-L1 by immunohistochemistry. There was no apparent association between PD-L1 immunohistochemistry results and objective responses. The most common treatment-emergent adverse event (AEs) were fatigue, occurring among six patients. Two patients discontinued study treatment after treatment-related AEs: an 86-year-old woman developed a Grade 3 rash after three doses (she continued post-treatment follow-up) and an 88-year old male withdrew consent following Grade 3 transaminase elevation and Grade 2 fatigue after six doses. There were two deaths within 30 days of last dose of study drug, both considered unrelated to study drug.

Conclusion: 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 II study is ongoing in patients with unresectablelocally advanced and mCSCC(NCT02760498).

Funding/Disclosures: This study was funded by Regeneron Pharmaceuticals Inc, and Sanofi. Dr. Papadopoulos has received institutional research funding from Regeneron and Sanofi. Taofeek Owonikoko holds a consulting/advisory role for Regeneron. Melissa Johnson receives research funding from Regeneron. Raymond Perez receives institutional research funding from Regeneron. Emiliano Calvo receives institutional research funding from Sanofi. Nelson Yee receives institutional research funding from Regeneron. Kosalai Mohan, Jingjin Li, Elizabeth Stankevich, Israel Lowy, Matthew Fury, are stockholders and employees of Regeneron Pharmaceuticals, Inc. Matthew Fury also receives research funding, institutional patents, royalties, and other intellectual property from Regeneron. Jade Homsi receives research funding from Regeneron.