Pharmacokinetics and bioavailability of pembrolizumab with berahyaluronidase alfa for subcutaneous administration in participants with advanced or metastatic solid tumors: The phase 1 study 3475A-C18
- PMID: 40957773
- DOI: 10.1016/j.ejca.2025.115709
Pharmacokinetics and bioavailability of pembrolizumab with berahyaluronidase alfa for subcutaneous administration in participants with advanced or metastatic solid tumors: The phase 1 study 3475A-C18
Abstract
Background: MK-3475A is pembrolizumab with berahyaluronidase alfa for subcutaneous administration (pembrolizumab SC). The phase 1 study 3475A-C18 (NCT05017012) assessed the pharmacokinetic and safety profiles of pembrolizumab SC.
Methods: The study had 4 arms that enrolled participants with unresectable or advanced melanoma (arms 1, 2, and 4), metastatic NSCLC (arms 1-3), or advanced or metastatic RCC (arms 1 and 2). Participants received pembrolizumab SC 650 mg Q6W at solution strengths of 165 mg/mL (arms 1 and 3), 130 mg/mL (arm 2), or pembrolizumab SC 395 mg Q3W at 165 mg/mL (arm 4). Key endpoints included pembrolizumab SC bioavailability, pharmacokinetics, immunogenicity, and safety and tolerability.
Results: 140 participants received study treatment. Across all arms, mean bioavailability of pembrolizumab SC was 61 % (95 % CI, 58 %64 %; CV%, 22.4 %) and absorption rate was 0.30/day (95 % CI, 0.28-0.32/day; CV%, 43.7 %). Pharmacokinetic exposure, bioavailability, and absorption rate did not differ meaningfully with pembrolizumab SC by solution strength. Treatment-emergent anti-drug antibodies against pembrolizumab and berahyaluronidase occurred in 1 % and 2 % of participants, respectively. Injection site AEs with pembrolizumab SC occurred in 16 % of participants; all were grade 1/2 in severity. Immune-mediated AEs occurred in 41 % of participants in arms 1-3 and 18 % of participants in arm 4.
Conclusion: Results from study 3475A-C18 informed selection of pembrolizumab SC 790 mg Q6W at 165 mg/mL for further clinical development to ensure that all patients have the appropriate pembrolizumab exposure to derive expected clinical benefit. Arm 4 results provided key clinical data supporting the pembrolizumab SC 395 mg Q3W dosing regimen.
Trial registration: ClinicalTrials.gov, NCT05017012.
Keywords: antiPD-1; immunotherapy; pembrolizumab; pharmacokinetics; subcutaneous administration.
Copyright © 2025 The Authors. Published by Elsevier Ltd.. All rights reserved.
Conflict of interest statement
Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: All authors from participating clinical sites received research funding from Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, for the conduct of this study. Graham L. Cohen: None declared. Corlia Coetzee: received support for meeting attendance and/or travel from MSD. Cathryn A. Walton: None declared. Òscar Reig Torras: received consulting fees from Ipsen and MSD; payments or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Astellas Pharma, Bayer, BMS, Ipsen, Janssen-Cilag, MSD, Pfizer, and Sanofi; support for meeting attendance and/or travel from Ipsen and MSD; disclosed participation on a data safety monitoring board or an advisory board for Bicycle Therapeutics (unpaid); and stock or stock options from BMS, MSD, and Pfizer. Byoung Chul Cho: received research funding from AstraZeneca, Champions Oncology, CJ Bioscience, Cyrus, Dong-A ST, GI Innovation, ImmuneOncia, Janssen, JINTSbio, MSD, Therapex, Vertical Bio AG, and Yuhan; royalties from licensing contracts with Champions Oncology, Crown Bioscience, Imagen, and Pearl River Bio GmbH; consulting fees from Amgen, AnHeart Therapeutics, ArriVent, AstraZeneca, BeiGene, BMS, Boehringer-Ingelheim, CJ, Cyrus Therapeutics, Daiichi Sankyo, Eli Lilly, Gilead, GSK, Harpoon Therapeutics, Janssen, MSD, Novartis, Ono, Pfizer, Regeneron, Roche, Sanofi, Seagen, Takeda, and Yuhan; payments or honoraria for presentations from ASCO, AstraZeneca, The Chinese Thoracic Oncology Society, ESMO, Guardant, IASLC, Korean Cancer Association, Korean Cancer Study Group, Korean Society of Medical Oncology, Korean Society of Thyroid-Head and Neck Surgery, MSD, Novartis, Pfizer, Roche, and Zailab; and disclosed participation on a scientific advisory board for Bridgebio Therapeutics, Cyrus Therapeutics, Guardant Health, KANAPH Therapeutic Inc, J INTS BIO, and Therapex Co., Ltd; membership on the board of directors of J INTS BIO; stock ownership in Bridgebio Therapeutics, Cyrus Therapeutics, Gencurix Inc, Interpark Bio Convergence Corp., J INTS BIO, KANAPH Therapeutic Inc, and TheraCanVac Inc; and founding role with DAAN Biotherapeutics. Georgina McAdam: None declared. Carlos I. Rojas: None declared. Laura Medina Rodríguez: received payments or honoraria as a speaker from MSD, Novartis, and Servier; payments for expert testimony from MSD, Novartis, and Servier; and support for meeting attendance and/or travel from MSD, Novartis, and Servier. Zsuzsanna Papai: None declared. Sze W. Chan: received speaker fees from Novartis, AstraZeneca, Janssen, MSD, Boehringer Ingelheim, Takeda, Dr Reddy’s, and Pfizer; participation in advisory boards for Novartis, AstraZeneca, Roche, Pfizer, Janssen, MSD, and Dr Reddy’s; research funding from Roche, Incyte, Novartis, and Pfizer. Bernardo L. Rapoport: received consulting fees from AstraZeneca South Africa, MSD, and Roche South Africa; payments or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from AstraZeneca South Africa, MSD, and Roche South Africa; and disclosed leadership or fiduciary role in the South Africa Society of Medical Oncology. Christian Caglevic: received consulting or advisory role for Gilead Sciences, and received research funding paid to institution from MSD, AstraZeneca, Roche, Astellas Pharma, Bristol-Myers Squibb, GSK, Athenex, Sanofi, AbbVie, Amgen, Bayer HealthCare Pharmaceuticals, BioNTech SE, Daiichi Sankyo INC, Exelixis, Novartis, F. Hoffmann LaRoche, PharmaMar, Zymeworks, Cogent Biosciences, Pfizer, Dizal Pharma, Merus and Jazz Pharmaceuticals. Patricio Yañez Weber: None declared. Toshiaki Takahashi: received grants or contracts (to institution) from Amgen, AnHeart Therapeutics, AstraZeneca, Chugai Pharmaceutical Co., Eli Lilly Japan, Janssen Pharmaceutical, Merck Biopharma, MSD, and Pfizer; and payments or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Amgen, AstraZeneca, BMS Japan, Chugai Pharmaceutical Co., Eli Lilly Japan, MSD, Novartis, Ono Pharmaceutical, Pfizer Japan, and Takeda Pharmaceutical Co. Takayasu Kurata: received grants or contracts from Amgen, AstraZeneca, Bristol Myers, Chugai; Daiichi Sankyo, Janssen, and MSD; and payments or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from AstraZeneca, Bristol Myers, Chugai, Eli Lilly, MSD, Nipponkayaku, Ono, Pfizer, and Takeda. Gina Song: Employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and owns shares in Merck & Co., Inc., Rahway, NJ, USA. Julia W. Cohen: Employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and owns shares in Merck & Co., Inc., Rahway, NJ, USA. Omobolaji O. Akala: Employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and owns shares in Merck & Co., Inc., Rahway, NJ, USA. Richard Khanyile: received honoraria from AstraZeneca.
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