Multicenter phase 1 dose-escalation and cohort-expansion study of lorigerlimab in advanced solid tumors

Dual blockade of PD-(L)1 and CTLA-4 increases antitumor activity beyond checkpoint inhibitor monotherapies, but also increases toxicity. Lorigerlimab is an investigational bispecific PD-1 x CTLA-4 dual-affinity re-targeting 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. A multicenter phase 1, dose-escalation/cohort-expansion study evaluated lorigerlimab in advanced solid tumors. After dose escalation (0.1-10.0 mg/kg), 6 mg/kg once every 3 weeks was chosen as the recommended dose for expansion (RDE). Overall, 162 patients received at least 1 lorigerlimab dose, including 127 who received lorigerlimab at the RDE. All-grade treatment-related adverse events (TRAEs) occurred in 85.8% of 162 patients, with grade ≥3 TRAEs in 36.4%, and TRAEs resulting in lorigerlimab discontinuation in 24.7%. Objective responses were observed in all 4 expansion cohorts: metastatic castration-resistant prostate cancer (mCRPC; 25.0%), melanoma (11.9%), ICI-naïve non-small cell lung cancer (21.4%), and microsatellite stable colorectal cancer (5.0%). The PSA50 response rate in mCRPC was 28.6%. Objective responses in mCRPC were associated with increased expression of inducible costimulator in CD4⁺ and Ki67 in circulating T cells. The authors conclude thatlorigerlimab demonstrated a manageable safety profile, with antitumor activity in all expansion indications. A lorigerlimab phase 2 trial in mCRPC is ongoing.