Phase I Dose Escalation and Cohort Expansion of Lorigerlimab, a Bispecific PD-1 × CTLA-4 DART Molecule With Focus on Metastatic Castration-Resistant Prostate Cancer

PURPOSE Dual blockade of PD-(L)1 and cytotoxic T-lymphocyte–associated protein-4 (CTLA-4) increases antitumor activity beyond checkpoint inhibitor monotherapies, but substantially increases toxicity, limiting potential for long-term outcomes and combination strategies. Lorigerlimab is an investigational bispecific PD-1 × CTLA-4 DART molecule designed to enhance CTLA-4 binding to T cells in the tumor microenvironment and limit T-cell binding in normal tissue to increase tolerability. METHODS A phase I, dose-escalation/cohort-expansion study (ClinicalTrials.gov identifier: NCT03761017 ) evaluated lorigerlimab in advanced solid tumors. Safety was the primary end point; secondary end points included antitumor activity, pharmacokinetics, immunogenicity, and pharmacodynamics. Doses evaluated during dose escalation: 0.1-10.0 mg/kg. The recommended dose for expansion (RDE) was investigated in four cohorts. Objective response was assessed per RECIST v1.1 in all cohorts, and prostate-specific antigen (PSA) response was evaluated in the metastatic castration-resistant prostate cancer (mCRPC) cohort. RESULTS Overall, 162 patients received ≥1 lorigerlimab dose, including 127 who received lorigerlimab at the RDE of 6 mg/kg IV once every 3 weeks. All-grade treatment-related adverse event (TRAEs) occurred in 85.8% of the 162 patients (139/162), with grade ≥3 TRAEs in 36.4%. Rates of immune-related adverse events (AEs) were 34.6% (all grades) and 13.4% (grade ≥3), and 24.7% of the patients experienced AEs resulting in lorigerlimab discontinuation. Objective responses were observed in all expansion cohorts: mCRPC (25.0%, 9/36); melanoma (11.9%, 5/42); checkpoint naïve non–small cell lung cancer (21.4%, 3/14); and microsatellite stable colorectal cancer (5.0%, 1/20). The PSA50 response rate in mCRPC was 28.6% (12/42). Objective responses in mCRPC were associated with increased expression of inducible costimulator in CD4 + and Ki67 in circulating T cells. CONCLUSION Lorigerlimab demonstrated a manageable safety profile for the dual PD-(L)1/CTLA-4 targeting strategy, and antitumor activity was observed in all expansion indications. Durable objective and PSA50 response rates were observed in mCRPC. A lorigerlimab phase II in mCRPC is ongoing.