Phase I/IIa Trial of BMS-986148, an Anti-mesothelin Antibody-drug Conjugate, Alone or in Combination with Nivolumab in Patients with Advanced Solid Tumors

Sylvie Rottey, Jeffrey Clarke, Kyaw Aung, Jean Pascal Machiels, Ben Markman, Kimberley M. Heinhuis, Michael Millward, Martijn Lolkema, Sandip Pravin Patel, Paul De Souza, Matteo Duca, Giuseppe Curigliano, Armando Santoro, Takafumi Koyama, Michelle Brown, Heather Vezina, Chunsheng He, Quincy Siu-Chung Chu*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Purpose: To assess the safety and tolerability of BMS-986148, a mesothelin-directed antibody-drug conjugate (ADC)±nivolumab, in patients with selected tumors. Patients and Methods: In an international phase I/IIa study [NCT02341625 (CA008-002)], patients received BMS-986148 monotherapy (0.1-1.6 mg/kg intravenously (i.v.) every 3 weeks or 0.4 or 0.6 mg/kg i.v. once weekly; n=96) or BMS-986148 0.8 mg/kg nivolumab 360 mg i.v. every 3 weeks (n = 30). The primary endpoint was safety and tolerability. Results: In CA008-002, the most common (≥ 10%) treatmentrelated adverse events (TRAEs) included increased aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase. Grade 3/4 TRAEs occurred in 42 patients (49%) receiving BMS-986148 every 3 weeks monotherapy, three (25%) receiving BMS-986148 once-weekly monotherapy, and 10 (33%) receiving BMS-986148 + nivolumab every 3 weeks. Overall, 17 of 126 patients (13%) discontinued because of a TRAE. The MTD of BMS-986148 was 1.2 mg/kg i.v. every 3 weeks. The safety profile of BMS-986148 nivolumab was similar to that of BMS-986148 monotherapy (0.8 mg/kg). Active ADC exposures increased in a dose-proportional manner with both dosing regimens (every 3 weeks and once weekly). Preliminary clinical activity was observed with BMS-986148 ± nivolumab. No association between mesothelin expression and response was detected. Conclusions: BMS-986148 _ nivolumab demonstrated a clinically manageable safety profile and preliminary evidence of clinical activity, supporting additional studies combining directed cytotoxic therapies with checkpoint inhibitors as potential multimodal therapeutic strategies in patients with advanced solid tumors.

Original languageEnglish
Pages (from-to)95-105
Number of pages11
JournalClinical Cancer Research
Volume28
Issue number1
DOIs
Publication statusPublished - 1 Jan 2022

Bibliographical note

Funding Information:
We thank the patients and their families who made this study possible and the clinical study teams who participated in this study. We thank Filippo De Braud (University of Milan; Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy) for his contributions to the study. This study was supported by Bristol Myers Squibb (Princeton, NJ) and ONO Pharmaceutical Company Ltd. (Osaka, Japan). This study was funded by Bristol Myers Squibb. All authors contributed to and approved the work presented here; writing and editorial assistance was provided by Brittany L. Phillips, PhD, and Alex L. Loeb, PhD, CMPP, of Chrysalis Medical Communications, Inc. (Hamilton, NJ) and funded by Bristol Myers Squibb. This study is financially supportted by Bristol Myers Squibb.

Funding Information:
Bristol Myers Squibb, Ellipsis, Gilead, and Seagen outside the submitted work. A. Santoro reports other support from AbbVie, Amgen, Arqule, AstraZeneca, Bayer, Bristol Myers Squibb, Celgene, Eisai, Gilead, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sandoz, Sanofi, Servier, and Takeda during the conduct of the study. T. Koyama reports other support from Sysmex and Chugai outside the submitted work. H. Vezina reports other support from Bristol Myers Squibb outside the submitted work. C. He reports other support from Bristol Myers Squibb outside the submitted work. Q.S.-C. Chu reports personal fees from AbbVie, Amgen, Astellas, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, and Takeda; grants and personal fees from AstraZeneca; grants from Exactis; personal fees and other support from Merck KGaA outside the submitted work. M. Brown is an employee and stock owner of Bristol Myers Squibb. H. Vezina is an employee and stock owner of Bristol Myers Squibb. C. He is an employee and stock owner of Bristol Myers Squibb. No disclosures were reported by the other authors.

Funding Information:
S. Rottey reports other support from Pfizer, Ipsen, and Bayer, and grants and other support from Roche outside the submitted work. J. Clarke reports grants from Bristol Myers Squibb during the conduct of the study; grants from Bristol Myers Squibb, Spectrum, Adaptimmune, Bayer, Medpacto, AbbVie, Moderna, Glaxo-SmithKline, Array, Grid Therapeutics, and Cellular Biomedical Group (CBMG); grants and personal fees from Genentech, AstraZeneca, and Merck; and personal fees from Pfizer, NGM Pharmaceuticals, and G1 Therapeutics outside the submitted work. J.-P. Machiels reports other support from Pfizer, Roche, AstraZeneca, Bayer, Innate, Merck Serono, Boerhinger, Janssen, Bristol Myers Squibb, Novartis, Incyte, Cue Biopharma, ALX Oncology, iTEOS, eTheRNA, NEKTAR, Amgen, MSD, and Psioxus during the conduct of the study. B. Markman reports personal fees from Amgen, Merck, and Bristol Myers Squibb outside the submitted work. M. Millward reports other support from Bristol Myers Squibb during the conduct of the study; personal fees from Merck Sharp & Dohme, Takeda, Roche, Pfizer, and Novartis; and personal fees and other support from Bristol Myers Squibb and AstraZeneca outside the submitted work. M. Lolkema reports grants and personal fees from Astellas, Sanofi, Janssen, and MSD; personal fees from Incyte, Amgen, Bayer, Servier, Roche, Pfizer, AstraZeneca, Novartis, and Julius Clinical outside the submitted work. S.P. Patel reports other support from Bristol Myers Squibb during the conduct of the study; other support from Amgen, AstraZeneca/MedImmune, Bristol Myers Squibb, Certis, Eli Lilly, Fate Therapeutics, Genentech, Genocea, Illumina, Iovance, Merck, Pfizer, Roche/Genetech, Rakuten, and Tempus outside the submitted work. P. de Souza reports personal fees from Eisai outside the submitted work. G. Curigliano reports personal fees from Roche, Pfizer, AstraZeneca, Lilly, Novartis, Daichii Sankyo, Sanofi,

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© 2022 American Association for Cancer Research Inc.. All rights reserved.

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