Safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy from a first-in-human study of volrustomig, a novel PD-1/CTLA-4 bispecific antibody

Abstract Purpose: Volrustomig is an IgG1 monovalent bispecific antibody engineered to preferentially target CTLA-4 on 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 manuscript 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, performance status of 0–1, and adequate organ and marrow function received volrustomig 2.25–2500 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 the safety and tolerability, describe dose-limiting toxicities, and determine the maximum tolerated dose. Secondary objectives included assessment of preliminary antitumor activity and volrustomig pharmacokinetics. Results:86 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 (TRAEs) 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 intra-tumoral 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; median response duration was 17.5 months. Conclusions: These results support further development of volrustomig as monotherapy and in combination regimens, with phase 3 trials ongoing.