Phase 1/2 study of INCAGN01876, an anti-GITR agonist monoclonal antibody, plus immunotherapy for advanced cancers

BACKGROUND: Modulating tumor-mediated immunosuppression with immunotherapies is an effective therapeutic approach for solid tumors. INCAGN01876 is a humanized IgG1 anti-glucocorticoid-induced tumor necrosis factor receptor (GITR) monoclonal antibody. This phase 1/2 trial evaluated INCAGN01876 plus nivolumab and/or ipilimumab for advanced malignancies. METHODS: In phase 1 (dose escalation), patients received various INCAGN01876 plus nivolumab and/or ipilimumab regimens. In phase 2 (dose expansion), patients with select tumors received INCAGN01876 plus ipilimumab (treatment group [TG] C2) or INCAGN01876 plus nivolumab (TGF). Primary endpoints: safety (phase 1), objective response rate (ORR; phase 2). RESULTS: Overall, 145 patients were enrolled: 51 and 94 in phases 1 and 2, respectively (TGC2, n = 8; TGF, n = 86 [squamous cell carcinoma of the head and neck, SCCHN, n = 46]). Four patients had dose-limiting toxicities; maximum tolerated dose was not reached; INCAGN01876 300 mg Q2W was selected as the recommended phase 2 dose based on safety with nivolumab and/or ipilimumab and safety and pharmacokinetic/pharmacodynamic monotherapy data from the INCAGN 1876-101 phase 1 study. INCAGN01876-related treatment-emergent adverse events (TEAEs) occurred in 62.8% of patients (most commonly pruritus, 16.6%); grade ≥3, 13.8%. Immune-related TEAEs occurred in 31.0% of patients (most frequently pruritus, 11.7%), most were (75.6%) grade 1/2 events. Antitumor activity was observed in TGF cohorts with SCCHN or cervical cancer (ORR 23.9% and 16.7%, respectively). CONCLUSION: INCAGN01876 plus nivolumab and/or ipilimumab was generally well tolerated, with a safety profile consistent with previous reports. This observation, along with encouraging antitumor activity in SCCHN and cervical cancer, supports development of INCAGN01876 combined with immune checkpoint inhibitors.