PMID- 35298698 OWN - NLM STAT- MEDLINE DCOM- 20220411 LR - 20220512 IS - 1432-0843 (Electronic) IS - 0344-5704 (Print) IS - 0344-5704 (Linking) VI - 89 IP - 4 DP - 2022 Apr TI - 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. PG - 499-514 LID - 10.1007/s00280-022-04414-6 [doi] 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 (C(max)) ranged from 24.7 to 227.0 microg/mL; median time to C(max) 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. CI - (c) 2022. The Author(s). FAU - Felip, Enriqueta AU - Felip E AD - Thoracic Cancer Unit, Oncology Department, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Barcelona, Spain. FAU - Moreno, Victor AU - Moreno V AD - Phase 1 Trials Unit, START MADRID-FJD, Hospital Fundacion Jimenez Diaz Medical Oncology Division, Madrid, Spain. FAU - Morgensztern, Daniel AU - Morgensztern D AD - Division of Oncology, Section of Medical Oncology, Washington University School of Medicine, St. Louis, MO, USA. FAU - Curigliano, Giuseppe AU - Curigliano G AD - Division of Early Drug Development, European Institute of Oncology, IRCCS and University of Milano, Milan, Italy. FAU - Rutkowski, Piotr AU - Rutkowski P AD - Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland. FAU - Trigo, Jose Manuel AU - Trigo JM AD - Department of Medical Oncology, Hospital Universitario Virgen de La Victoria y Regional, Malaga, Spain. FAU - Calvo, Aitana AU - Calvo A AD - Oncology Service, Hospital General Universitario Gregorio Maranon, Madrid, Spain. FAU - Kowalski, Dariusz AU - Kowalski D AD - Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland. FAU - Cortinovis, Diego AU - Cortinovis D AD - Oncology Unit, San Gerardo Hospital, Monza, Italy. FAU - Plummer, Ruth AU - Plummer R AD - Sir Bobby Robson Unit, Northern Centre for Cancer Care, Newcastle Hospitals NHS Trust and Newcastle University, Newcastle, UK. FAU - Maio, Michele AU - Maio M AD - Center for Immuno-Oncology, Azienda Ospedaliera Universitaria Senese, University of Siena, Siena, Italy. FAU - Ascierto, Paolo A AU - Ascierto PA AD - Unit of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS-Fondazione Pascale, Napoli, Italy. FAU - Vladimirov, Vladimir I AU - Vladimirov VI AD - Pyatigorsky Oncology Dispensary, Pyatigorsk, Russia. FAU - Cervantes, Andres AU - Cervantes A AD - Medical Oncology Department, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain. FAU - Zudaire, Enrique AU - Zudaire E AD - Janssen Research & Development, Spring House, PA, USA. FAU - Hazra, Anasuya AU - Hazra A AD - Janssen Research & Development, Spring House, PA, USA. FAU - T'jollyn, Huybrecht AU - T'jollyn H AD - Janssen Research & Development, Beerse, Belgium. FAU - Bandyopadhyay, Nibedita AU - Bandyopadhyay N AD - Janssen Research & Development, Raritan, NJ, USA. FAU - Greger, James G AU - Greger JG AD - Janssen Research & Development, Spring House, PA, USA. FAU - Attiyeh, Edward AU - Attiyeh E AD - Janssen Research & Development, Spring House, PA, USA. FAU - Xie, Hong AU - Xie H AD - Janssen Research & Development, Spring House, PA, USA. FAU - Calvo, Emiliano AU - Calvo E AUID- ORCID: 0000-0003-4921-829X AD - Centro Integral Oncologico Clara Campal Medical Oncology Division, START Madrid-CIOCC, Sanchinarro University Hospital, Madrid, Spain. emiliano.calvo@startmadrid.com. LA - eng SI - ClinicalTrials.gov/NCT02908906 PT - Clinical Trial, Phase I PT - Clinical Trial, Phase II PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220317 PL - Germany TA - Cancer Chemother Pharmacol JT - Cancer chemotherapy and pharmacology JID - 7806519 RN - 0 (Antibodies, Monoclonal) RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Apoptosis Regulatory Proteins) RN - 0 (Immune Checkpoint Inhibitors) RN - 0 (Programmed Cell Death 1 Receptor) SB - IM MH - Antibodies, Monoclonal/adverse effects MH - Antibodies, Monoclonal, Humanized/adverse effects MH - Apoptosis Regulatory Proteins MH - *Carcinoma, Non-Small-Cell Lung/drug therapy MH - Humans MH - Immune Checkpoint Inhibitors MH - *Lung Neoplasms/drug therapy MH - *Melanoma/drug therapy MH - *Neoplasms/drug therapy/pathology MH - Programmed Cell Death 1 Receptor PMC - PMC8956549 OTO - NOTNLM OT - Colorectal cancer OT - Melanoma OT - Microsatellite instability-high OT - Monoclonal antibody PD-1 inhibitor efficacy OT - Non-small-cell lung cancer OT - Pharmacokinetics/pharmacodynamics COIS- 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 Fundacion 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, Jose Manuel Trigo, and Vladimir I. Vladimirov have no relevant disclosures to declare. EDAT- 2022/03/18 06:00 MHDA- 2022/04/12 06:00 PMCR- 2022/03/17 CRDT- 2022/03/17 17:19 PHST- 2021/09/21 00:00 [received] PHST- 2022/02/16 00:00 [accepted] PHST- 2022/03/18 06:00 [pubmed] PHST- 2022/04/12 06:00 [medline] PHST- 2022/03/17 17:19 [entrez] PHST- 2022/03/17 00:00 [pmc-release] AID - 10.1007/s00280-022-04414-6 [pii] AID - 4414 [pii] AID - 10.1007/s00280-022-04414-6 [doi] PST - ppublish SO - Cancer Chemother Pharmacol. 2022 Apr;89(4):499-514. doi: 10.1007/s00280-022-04414-6. Epub 2022 Mar 17.