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

作者：Toshio Shimizu, John D. Powderly, Albiruni Abdul Razak, Patricia LoRusso, Kathy D. Miller, Steven Kao, Sarah Kongpachith, Catherine Tribouley, Michelle Graham, Brian R. Stoll, Maulik Patel, Mohammad Sahtout, Martha Blaney, Rachel S. Leibman, Talia Golan, Anthony W. Tolcher · 发表于：Frontiers in Oncology · 年份：2024 · DOI：10.3389/fonc.2024.1376551 · 被引用次数：12 · 研究领域：TGF-β signaling in diseases、Cancer Immunotherapy and Biomarkers、Colorectal and Anal Carcinomas

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 patie...