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ORIGINAL RESEARCH article
Front. Oncol.
Sec. Cancer Immunity and Immunotherapy
Volume 14 - 2024 |
doi: 10.3389/fonc.2024.1376551
This article is part of the Research Topic Monoclonal Antibodies and Immune Checkpoint Inhibitors in the treatment of Cancer View all 28 articles
First-in-Human Phase 1 Dose-Escalation Results With Livmoniplimab, an Antibody Targeting the GARP:TGF-ß1 Complex, as Monotherapy and in Combination With the Anti-PD-1 Antibody Budigalimab in Patients With Advanced Solid Tumors
Provisionally accepted- 1 Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Tokyo, Japan
- 2 Department of Pulmonary Medicine and Medical Oncology, Wakayama Medical University, Wakayama, Wakayama, Japan
- 3 Carolina BioOncology Institute (CBI), Huntersville, North Carolina, United States
- 4 Cancer Clinical Research Unit, Princess Margaret Cancer Centre, Toronto, Ontario, Canada
- 5 Cancer Center, School of Medicine, Yale University, New Haven, Connecticut, United States
- 6 Melvin and Bren Simon Comprehensive Cancer Center, Department of Medicine, School of Medicine, Indiana University Bloomington, Indianapolis, Indiana, United States
- 7 Department of Medical Oncology, Chris O’Brien Lifehouse, Camperdown, New South Wales, Australia
- 8 AbbVie (United States), North Chicago, Illinois, United States
- 9 Institute of Oncology, Sheba Medical Center, Ramat Gan, Tel Aviv District, Israel
- 10 Tel Aviv University, Tel Aviv, Tel Aviv, Israel
- 11 NEXT Oncology, San Antonio, Texas, United States
Background: Transforming growth factor (TGF)-ß1 is a pleiotropic cytokine that can promote tumor growth and suppress antitumor immune responses. Latent TGF-ß1 associates with glycoprotein-A repetition predominant (GARP) on the surface of regulatory T cells prior to its activation and release. Livmoniplimab is a monoclonal antibody (mAb) that binds the GARP:TGF-ß1 complex to inhibit activation and release of TGF-ß1. It is in clinical development in combination with budigalimab, an anti-programmed cell death protein 1 Fc-modified mAb. The first-in-human, phase 1, dose-escalation results are presented herein (ClinicalTrials.gov: NCT03821935). Methods: The dose-escalation phase enrolled adult patients with advanced solid tumors. Patients received escalating doses of livmoniplimab ranging from 3mg to 1500mg, once every 2 weeks (Q2W), as monotherapy or in combination with a 500mg fixed dose of budigalimab Q4W. The primary objective of the dose escalation was to determine the recommended phase 2 dose. Secondary objectives were to assess safety and pharmacokinetics (PK), and exploratory objectives included evaluating preliminary efficacy. Results: Fifty-seven patients enrolled in the dose escalation: 23 in monotherapy cohorts and 34 in combination therapy cohorts. Dose-limiting toxicities were limited, no maximum tolerated dose was reached, and the maximum administered dose of 1500mg was selected for dose expansion. The most common adverse events reported in monotherapy-treated patients were fatigue, anemia, and nausea, and those in combination therapy-treated patients were pruritus, fatigue, nausea, and anemia. Livmoniplimab exhibited dose-proportional PK, and peripheral blood biomarker data demonstrated saturation of the GARP:TGF-ß1 complex on platelets at livmoniplimab doses within the linear PK range. No objective tumor responses were observed in the monotherapy dose escalation. However, the objective response rate was 15% in the combination dose escalation, with a median response duration of 8.4 months. Conclusions: Livmoniplimab was well-tolerated as monotherapy and in combination with budigalimab in the dose-escalation phase. Encouraging preliminary efficacy was demonstrated in the combination dose escalation in heavily pretreated patients, supporting further development of this novel drug combination in patients with advanced solid tumors.
Keywords: Advanced solid tumors, TGF-ß1, GARP, Immunotherapy, Anti-PD-1 antibody, combination drug therapy, Investigational therapies, tumor micro environment (TME)
Received: 25 Jan 2024; Accepted: 10 Sep 2024.
Copyright: © 2024 Shimizu, Powderly, Abdul Razak, Lorusso, Miller, Kao, Kongpachith, Graham, Stoll, Patel, Sahtout, Blaney, Leibman, Golan and Tolcher. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Toshio Shimizu, Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, 104-0045, Tokyo, Japan
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