TY - JOUR
T1 - First-In-Human Study of Cemiplimab Alone or in Combination with Radiotherapy and/or Low-dose Cyclophosphamide in Patients with Advanced Malignancies
AU - Papadopoulos, Kyriakos P.
AU - Johnson, Melissa L.
AU - Lockhart, Albert C.
AU - Moore, Kathleen
AU - Falchook, Gerald S.
AU - Formenti, Silvia C.
AU - Naing, Aung
AU - Carvajal, Richard D.
AU - Rosen, Lee S.
AU - Weiss, Glen J.
AU - Leidner, Rom S.
AU - Li, Jingjin
AU - Paccaly, Anne
AU - Feng, Minjie
AU - Stankevich, Elizabeth
AU - Lowy, Israel
AU - Fury, Matthew G.
AU - Crittenden, Marka R.
N1 - Funding Information:
K.P. Papadoulos is an employee/paid consultant for Bayer, reports receiving commercial research grants from ADC Therapeutics, Amgen, ARMO, Bayer, Merck Serono, Incyte, F-Star, Jounce, Medimmune, Regeneron Pharmaceuticals, Inc., MABSpace Biosciences, 3D Medicines. M.L. Johnson is an employee/paid consultant for Genentech/Roche, Celgene, Boehringer Ingelheim, Sanofi, Mirati, LOXO, Calithera, AstraZeneca, Merck, Araxes Pharma, Mersana Therapeutics, BeiGene, Incyte, Pfizer, Guardant Health, Bristol Myers Squibb, Ribon Therapeutics, and reports receiving commercial research grants from BerGenBio, Lilly, EMD Serono, Janssen, Mirati, Genmab, Pfizer, AstraZeneca, Genentech/Roche, Stemcen-trix, Novartis, Checkpoint Therapeutics, Array, Regeneron Pharmaceuticals, Inc., Apexigen, Abbvie, Tarveda, AdaptImmune, Syndax, Neovia, Boehringer Ingelheim, Sanofi, Hengrui, Merck, Daiichi Sankyo, Lycera, G1 Therapeutics, Dynavax, LOXO, CytomX, BeiGene, Birdie, Corvus, Incyte, Genocea, Gritstone, Amgen, Bristol Myers Squibb, Kadmon, Clovis, Acerta, OncoMed, Guardant Health, Takeda, Shattuck Labs, GlaxoSmithKline, and reports receiving other remuneration from Abbive, Astellas, AstraZeneca, Boehringer Ingelheil, Clovis, Daiichi Sankyo, EMD Serono, Bristol Myers Squibb, Exelixis, Genentech, Incyte, Merck, Pfizer, Sysmex Inostics, Vapotherm. K Moore reports receiving other commercial research support from PTC Therapeutics, is an advisory board member/unpaid consultant for AstraZeneca, Aravive, Clovis, GlaxoSmithKline/Tesaro, Immunogen, Genentech/Roche, Cue, and OncoMed, and reports receiving other remuneration from Research to Practice, PRIME and Curio. G.S. Falchook is an employee/paid consultant for Fujifilm and EMD Serono, reports receiving commercial research grants (paid to institution) from 3-V Biosciences, Abbvie, ADC Therapeutics, Aileron, American Society of Clinical Oncology, Amgen, ARMO, AstraZeneca, BeiGene, Bioatla, Biothera,Celldex, Celgene, Ciclomed, Curegenix, Curis, Cyteir, DelMar, eFFECTOR, Eli Lilly, EMR Serono, Exelixis, Fujifilm, Genman, GlaxoSmithKline, Hutchison MediPharma, Ignyta,Incyte, Jacobio, Jounce, Kolltan, Loxo, MedImmune, Millennium, Merck, miRNA, National Institutes of Health, Novartis, OncoMed, Oncothyreon, Precision Oncology, Regen-eron Pharmaceuticals, Inc., Rgenix, Ribbon, Stategia, Syndax, Taiho, Takeda, Tarveda, Tesaro, Tocagen, Turning Point Therapeutics, U.T. MD Anderson Cancer Center, Vegenics, Xencor, reports receiving speakers bureau honoraria from Total Health Conferencing, and reports receiving other remuneration from Wolters Kluwer, Bristol-Myers Squibb, EMD Serono, Fujifilm, Millennium, and Sarah Cannon Research Institute. S.C. Formenti is an employee/paid consultant for Pfizer, reports receiving commercial research grants from Bristol-Myers Squibb, Varian, Regeneron Pharmaceuticals, Inc., EISAI, Merck, and reports receiving speakers bureau honoraria from Bristol-Myers Squibb, Varian, Elekta, Janssen, Regeneron Pharmaceuticals, Inc., GlaxoSmithKline, EISAI, AstraZeneca, Merck, ViewRay, Bayer, and EMD Serono. A. Naing is an employee/paid consultant for CytomX Therapeutics and Novartis, reports receiving commercial research grants from NCI, EMD Serono, MedImmune, Healios Onc. Nutrition, Attecocor, Amplimmune, ARMO BioSciences, Karyopharm Therapeutics, Incyte, Novartis, Regeneron Pharmaceuticals, Inc., Merck, Bristol-Myers Squibb, Pfizer, CytomX Therapeutics, Neon Therapeutics, Calithera Biosciences, TopAlliance Biosciences, Eli Lilly, Kymab, PsiOxus, and Immune Deficiency Foundation, and reports receiving other remuneration from ARMO BioSciences. R.D. Carvajal is an employee/paid consultant for Array, Bristol-Myers Squibb, Castle Biosciences, Compugen, Immunocore, I-Mab, InxMed, Merck, Pierre Fabre, PureTech Health, Sanofi Genzyme, and Sorrento Therapeutics. L.S. Rosen reports receiving commercial research grants from Regeneron Pharmaceuticals, Inc. (to institution). G.J. Weiss is an employee/paid consultant for Unum Therapeutics, MiRanostics Consulting, Paradigm, Angiex, IBEX Medical Analytics, Spring Bank Pharmaceuticals, Pfizer, IDEA Pharma, GLG Council, Guidepoint Global, Ignyta, Circulogene, holds ownership interest (including patents) in Unum Therapeutics, MiRanostics Consulting and Circulogene and reports receiving other remuneration from Cambridge HealthTech, GlaxoSmithKline and Tesaro. R.S. Leidner reports receiving commercial research grants from Bristol-Myers Squibb, and is an advisory board member/unpaid consultant for Sanofi, AstraZeneca, Merck, Bristol-Myers Squibb, Oncolys Biopharma. J. Li is an employee/paid consultant for Regeneron Pharmaceuticals, Inc. A. Paccaly is an employee/paid consultant for Regeneron Pharmaceuticals, Inc., and is a former employee/paid consultant for Amgen. M. Feng and E. Stankevich are employee/paid consultant for Regeneron Pharmaceuticals, Inc. I. Lowy is an employee/paid consultant for and holds ownership interest (including patents) in Regeneron Pharmaceuticals, Inc. M.G. Fury is an employee/paid consultant for Regeneron Pharmaceuticals, Inc. M.R. Crittenden reports receiving commercial research grants from Bristol-Myers Squibb, Nanobiotix, MavuPharma, and Jounce Therapeutics. No potential conflicts of interest were disclosed by A.C. Lockhart.
Funding Information:
The study was funded by Regeneron Pharmaceuticals, Inc., and Sanofi. Medical writing support under the direction of the authors was provided by Emmanuel Ogunnowo, PhD, of Prime and funded by Regeneron Pharmaceuticals, Inc. and Sanofi according to Good Publication Practice guidelines (https://annals.org/aim/ fullarticle/2424869/good-publication-practice-communicating-company-sponsored-medical-research-gpp3). The authors wouldliketo thankthe patients,theirfamilies, all other investigators, and all investigational site members involved in this study. The authors were responsible for all content and editorial decisions, and received no honoraria related to the development of this publication.
Publisher Copyright:
© 2020 American Association for Cancer Research Inc.. All rights reserved.
PY - 2020/3/1
Y1 - 2020/3/1
N2 - Purpose: This first-in-human study assessed the safety, tolerability, dose-limiting toxicities (DLT), antitumor activity, and pharmacokinetics of cemiplimab, a monoclonal anti-programmed cell death-1 (PD-1), as monotherapy and in combination with hypofractionated radiotherapy (hfRT) and/or cyclophosphamide (CPA) in patients with advanced solid tumors. Patients and Methods: Patients were enrolled in 1 of 10 dose escalation cohorts and received cemiplimab 1, 3, or 10 mg/kg every 2 weeks intravenously for up to 48 weeks. Depending on the cohort, patients received hfRT and/or low-dose (200 mg/m2) CPA. Safety was evaluated. Antitumor activity was assessed by Response Evaluation Criteria in Solid Tumors version 1.1. Results: Sixty patients were enrolled. The median duration of follow-up was 19.3 weeks (range, 2.3-84.3). There were no DLTs. The most common treatment-emergent adverse events (TEAEs) of any grade were fatigue (45.0%), nausea (36.7%), and vomiting (25.0%). The most common immune-related adverse events (irAEs) of any grade were arthralgia (10.0%), hypothyroidism (8.3%), and maculopapular rash (8.3%). Cemiplimab pharmacokinetic parameters increased in a close to dose-proportional manner and were similar regardless of combination therapy regimen. Two patients (one with cutaneous squamous cell carcinoma and one with cervical cancer) experienced a complete response; 7 had a partial response. Observed duration of response was ≽12 months in 6 patients. Conclusions: The safety profile of cemiplimab was comparable with other anti-PD-1 agents. Addition of hfRT and/or CPA did not appear to increase grade ≽3 irAEs, suggesting that cemiplimab can be safely administered with hfRT and/or CPA. Cemiplimab exhibited encouraging antitumor activity with 2 complete responses and 7 partial responses observed; responses were also durable.
AB - Purpose: This first-in-human study assessed the safety, tolerability, dose-limiting toxicities (DLT), antitumor activity, and pharmacokinetics of cemiplimab, a monoclonal anti-programmed cell death-1 (PD-1), as monotherapy and in combination with hypofractionated radiotherapy (hfRT) and/or cyclophosphamide (CPA) in patients with advanced solid tumors. Patients and Methods: Patients were enrolled in 1 of 10 dose escalation cohorts and received cemiplimab 1, 3, or 10 mg/kg every 2 weeks intravenously for up to 48 weeks. Depending on the cohort, patients received hfRT and/or low-dose (200 mg/m2) CPA. Safety was evaluated. Antitumor activity was assessed by Response Evaluation Criteria in Solid Tumors version 1.1. Results: Sixty patients were enrolled. The median duration of follow-up was 19.3 weeks (range, 2.3-84.3). There were no DLTs. The most common treatment-emergent adverse events (TEAEs) of any grade were fatigue (45.0%), nausea (36.7%), and vomiting (25.0%). The most common immune-related adverse events (irAEs) of any grade were arthralgia (10.0%), hypothyroidism (8.3%), and maculopapular rash (8.3%). Cemiplimab pharmacokinetic parameters increased in a close to dose-proportional manner and were similar regardless of combination therapy regimen. Two patients (one with cutaneous squamous cell carcinoma and one with cervical cancer) experienced a complete response; 7 had a partial response. Observed duration of response was ≽12 months in 6 patients. Conclusions: The safety profile of cemiplimab was comparable with other anti-PD-1 agents. Addition of hfRT and/or CPA did not appear to increase grade ≽3 irAEs, suggesting that cemiplimab can be safely administered with hfRT and/or CPA. Cemiplimab exhibited encouraging antitumor activity with 2 complete responses and 7 partial responses observed; responses were also durable.
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U2 - 10.1158/1078-0432.CCR-19-2609
DO - 10.1158/1078-0432.CCR-19-2609
M3 - Article
C2 - 31796520
AN - SCOPUS:85077564568
VL - 26
SP - 1025
EP - 1033
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 5
ER -