TY - JOUR
T1 - First-in-human, open-label, phase 1/2 study of the monoclonal antibody programmed cell death protein-1 (PD-1) inhibitor cetrelimab (JNJ-63723283) in patients with advanced cancers
AU - Felip, Enriqueta
AU - Moreno, Victor
AU - Morgensztern, Daniel
AU - Curigliano, Giuseppe
AU - Rutkowski, Piotr
AU - Trigo, José Manuel
AU - Calvo, Aitana
AU - Kowalski, Dariusz
AU - Cortinovis, Diego
AU - Plummer, Ruth
AU - Maio, Michele
AU - Ascierto, Paolo A.
AU - Vladimirov, Vladimir I.
AU - Cervantes, Andres
AU - Zudaire, Enrique
AU - Hazra, Anasuya
AU - T’jollyn, Huybrecht
AU - Bandyopadhyay, Nibedita
AU - Greger, James G.
AU - Attiyeh, Edward
AU - Xie, Hong
AU - Calvo, Emiliano
N1 - Funding Information:
Enriqueta Felip declares advisory board participation for AbbVie, Amgen, AstraZeneca, Bayer, Beigene, Blue Print Medicines, Boehringer Ingelheim, BMS, Lilly, GSK, Janssen, Medical Trends, Merck KGaA, Merck Sharp and Dohme, Novartis, Peptomyc, Pfizer, Puma Biotechnology, Regeneron, Roche, Sanofi Genzyme, Syneos Health, Takeda, Grifols; speaker bureau participation for AstraZeneca, Boehringer Ingelheim, BMS, Lilly, Merck Sharp and Dohme, Novartis, Peervoice, Pfizer, prIME Oncology, Roche, Takeda, Touchmedical, CME Outfitters; research funding from Fundación Merck Salud and a grant for oncology innovation; and is an Independent Member of the Board at Grifols. Victor Moreno declares consulting fees from Basilea, Bayer, BMS, Roche, and Janssen; and honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Bayer, BMS, and Janssen. Daniel Morgensztern declares consulting fees from AbbVie, Gilead, G1 Therapeutics, Lilly, PharmaMar, and Takeda; and participation on a data safety monitoring board or advisory board for BMS. Giuseppe Curigliano declares personal fees from Astra Zeneca, BMS, Boehringer Ingelheim, Daiichi Sankyo, Foundation Medicine, GSK, Lilly, Novartis, Pfizer, Roche, Samsung, and Seagen; non-financial support from Pfizer and Roche; grants from Merck; and other conflicts of interest/competing interests outside the submitted work from Ellipsis. Piotr Rutkowski declares payment or honoraria from BMS, Merck, MSD, Novartis, Pierre Fabre, and Sanofi; and participation on a data safety monitoring board or advisory board for Blueprint Medicines, BMS, Merck, MSD, Philogen, Pierre Fabre, and Sanofi. Diego Cortinovis declares speaker bureau participation for AstraZeneca, BMS, Boehringer Ingelheim, and MSD; and consultancy fees for Amgen, Novartis, and Roche. Ruth Plummer declares institutional grants for clinical trial costs from Janssen. Michele Maio declares consulting fees, travel reimbursement, participation in a data safety monitoring board or advisory board, and honoraria from Alfasigmal, Amgen, AstraZeneca, BMS, GSK, Incyte, Lilly, Merck, MSD (consulting fees only), Pierre-Fabre, Roche, Sanofi, and Sciclone; and owns stocks or stock options from Epigen Therapeutics and Theravance. Paolo A. Ascierto declares consulting fees from 4SC, AstraZeneca, BMS, Boehringer-Ingelheim, Daiichi, Eisai, Idera, Immunocore, Italfarmaco, iTeos, Lunaphore, Merck Serono, Merck Sharpe and Dohme, Nektar, Nouscom, Novartis, Oncosec, Pfizer, Pierre-Fabre, Regeneron, Roche/Genentech, Sandoz, Sankyo, Sanofi, Seagen, and Sun Pharma; and institutional grants from BMS, Pfizer, Roche/Genentech, and Sanofi. Enrique Zudaire, Anasuya Hazra, Huybrecht T’jollyn, James G. Greger, Edward Attiyeh, Nibedita Bandyopadhyay, and Hong Xie are employees of Janssen and may own stocks or shares. Emiliano Calvo declares advisory board participation (financial interest) for Adcendo, Alkermes, Amunix, Anaveon, Amcure, AstraZeneca, BMS, Janssen, MonTa, MSD, Nanobiotix, Nouscom, Novartis, OncoDNA, PharmaMar, Roche/Genentech, Sanofi, Servier, SyneosHealth, TargImmune, and T-knife; research grants for Achilles and BeiGene; steering committee (financial interest) and IDMC participation for BeiGene (IDMC steering committee), EORTC IDMC chair (non-financial interest), MedSIR (steering committee), and Novartis (steering committee); honoraria for scientific board participation for Adcendo, Chugai Pharmaceuticals, and PsiOxus Therapeutics; employment at HM Hospitals Group and START Program of Early Phase Clinical Drug Development in Oncology, START corporation, Oncoart Associated, and International Cancer Consultants; and is the founder and president of the not-for-profit Investigational Therapeutics in Oncological Sciences (INTHEOS) Foundation. Aitana Calvo, Andres Cervantes, Dariusz Kowalski, José Manuel Trigo, and Vladimir I. Vladimirov have no relevant disclosures to declare.
Funding Information:
This work was supported by Janssen Research & Development. Writing assistance was provided by Ann C. Sherwood, PhD, of Janssen; and by Sarika Sharma, PhD, Russell Craddock, PhD, and Benjamin Ricca, PhD, of Parexel. Writing assistance was funded by Janssen Research and Development.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/4
Y1 - 2022/4
N2 - Purpose: To assess the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of cetrelimab (JNJ-63723283), a monoclonal antibody programmed cell death protein-1 (PD-1) inhibitor, in patients with advanced/refractory solid tumors in the phase 1/2 LUC1001 study. Methods: In phase 1, patients with advanced solid tumors received intravenous cetrelimab 80, 240, 460, or 800 mg every 2 weeks (Q2W) or 480 mg Q4W. In phase 2, patients with melanoma, non-small-cell lung cancer (NSCLC), and microsatellite instability–high (MSI-H)/DNA mismatch repair-deficient colorectal cancer (CRC) received cetrelimab 240 mg Q2W. Response was assessed Q8W until Week 24 and Q12W thereafter. Results: In phase 1, 58 patients received cetrelimab. Two dose-limiting toxicities were reported and two recommended phase 2 doses (RP2D) were defined (240 mg Q2W or 480 mg Q4W). After a first dose, mean maximum serum concentrations (Cmax) ranged from 24.7 to 227.0 µg/mL; median time to Cmax ranged from 2.0 to 3.2 h. Pharmacodynamic effect was maintained throughout the dosing period across doses. In phase 2, 146 patients received cetrelimab 240 mg Q2W. Grade ≥ 3 adverse events (AEs) occurred in 53.9% of patients. Immune-related AEs (any grade) occurred in 35.3% of patients (grade ≥ 3 in 6.9%). Overall response rate was 18.6% across tumor types, 34.3% in NSCLC, 52.6% in programmed death ligand 1–high (≥ 50% by immunohistochemistry) NSCLC, 28.0% in melanoma, and 23.8% in centrally confirmed MSI-H CRC. Conclusions: The RP2D for cetrelimab was established. Pharmacokinetic/pharmacodynamic characteristics, safety profile, and clinical activity of cetrelimab in immune-sensitive advanced cancers were consistent with known PD-1 inhibitors. Trial registrations: NCT02908906 at ClinicalTrials.gov, September 21, 2016; EudraCT 2016–002,017-22 at clinicaltrialsregister.eu, Jan 11, 2017.
AB - Purpose: To assess the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of cetrelimab (JNJ-63723283), a monoclonal antibody programmed cell death protein-1 (PD-1) inhibitor, in patients with advanced/refractory solid tumors in the phase 1/2 LUC1001 study. Methods: In phase 1, patients with advanced solid tumors received intravenous cetrelimab 80, 240, 460, or 800 mg every 2 weeks (Q2W) or 480 mg Q4W. In phase 2, patients with melanoma, non-small-cell lung cancer (NSCLC), and microsatellite instability–high (MSI-H)/DNA mismatch repair-deficient colorectal cancer (CRC) received cetrelimab 240 mg Q2W. Response was assessed Q8W until Week 24 and Q12W thereafter. Results: In phase 1, 58 patients received cetrelimab. Two dose-limiting toxicities were reported and two recommended phase 2 doses (RP2D) were defined (240 mg Q2W or 480 mg Q4W). After a first dose, mean maximum serum concentrations (Cmax) ranged from 24.7 to 227.0 µg/mL; median time to Cmax ranged from 2.0 to 3.2 h. Pharmacodynamic effect was maintained throughout the dosing period across doses. In phase 2, 146 patients received cetrelimab 240 mg Q2W. Grade ≥ 3 adverse events (AEs) occurred in 53.9% of patients. Immune-related AEs (any grade) occurred in 35.3% of patients (grade ≥ 3 in 6.9%). Overall response rate was 18.6% across tumor types, 34.3% in NSCLC, 52.6% in programmed death ligand 1–high (≥ 50% by immunohistochemistry) NSCLC, 28.0% in melanoma, and 23.8% in centrally confirmed MSI-H CRC. Conclusions: The RP2D for cetrelimab was established. Pharmacokinetic/pharmacodynamic characteristics, safety profile, and clinical activity of cetrelimab in immune-sensitive advanced cancers were consistent with known PD-1 inhibitors. Trial registrations: NCT02908906 at ClinicalTrials.gov, September 21, 2016; EudraCT 2016–002,017-22 at clinicaltrialsregister.eu, Jan 11, 2017.
KW - Colorectal cancer
KW - Melanoma
KW - Microsatellite instability–high
KW - Monoclonal antibody PD-1 inhibitor efficacy
KW - Non-small-cell lung cancer
KW - Pharmacokinetics/pharmacodynamics
UR - http://www.scopus.com/inward/record.url?scp=85126487408&partnerID=8YFLogxK
U2 - 10.1007/s00280-022-04414-6
DO - 10.1007/s00280-022-04414-6
M3 - Article
C2 - 35298698
AN - SCOPUS:85126487408
SN - 0344-5704
VL - 89
SP - 499
EP - 514
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
IS - 4
ER -