Safety, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy from a First-in-Human Study of Volrustomig, a Novel PD-1/CTLA-4 Bispecific Antibody

PURPOSE: Volrustomig is an IgG1 monovalent bispecific antibody engineered to preferentially target cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) on programmed cell death protein 1 (PD-1)-positive T cells while providing adequate and durable PD-1 inhibition. The aim of this phase I, first-in-human study (NCT03530397) is to evaluate the safety, tolerability, pharmacokinetics, immunogenicity, pharmacodynamics, and antitumor activity of volrustomig. This article reports findings for the dose-exploration and immunotherapy-naïve expansion cohorts. PATIENTS AND METHODS: Patients aged ≥18 years who had histologically or cytologically confirmed advanced cancer, measurable disease, a performance status of 0 or 1, and adequate organ and marrow function received volrustomig 2.25 to 2,500 mg intravenously every 3 weeks until confirmed disease progression, initiation of alternative cancer therapy, unacceptable toxicity, or consent withdrawal. The primary objective in the dose-exploration phase was to evaluate safety and tolerability, describe dose-limiting toxicities, and determine the maximum tolerated dose. Secondary objectives included the assessment of preliminary antitumor activity and volrustomig pharmacokinetics. RESULTS: Eighty-six patients received volrustomig treatment in the dose-exploration and immunotherapy-naïve expansion cohorts; 78 (90.7%) patients were immunotherapy-naïve. Common treatment-related adverse events (TRAE) were pruritus (30.2%), hypothyroidism (26.7%), hyperthyroidism (24.4%), and rash (24.4%). TRAEs led to treatment discontinuation in 33.7% of patients and one death. At doses ≥500 mg, volrustomig demonstrated robust peripheral and intratumoral T-cell activation and proliferation at levels greater than those seen with approved PD-1/CTLA-4 regimens. Seventeen (19.8%) patients had objective responses, including 2 (2.3%) complete responses; the median response duration was 17.5 months. CONCLUSIONS: These results support further development of volrustomig as monotherapy and in combination regimens, with phase III trials ongoing. See related commentary by Park and Gainor, p. 2803.