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.