First-in-Human Phase I/II Study of INCAGN01876, a Glucocorticoid-Induced Tumor Necrosis Factor Receptor Agonist, in Patients with Advanced or Metastatic Solid Tumors

PURPOSE: Glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) agonism in T cells may potentiate antitumor immune responses to immune checkpoint blockade therapy. This first-in-human, phase I/II dose escalation/expansion study assessed INCAGN01876, a humanized GITR-targeting agonistic mAb, for advanced solid tumors (NCT02697591). PATIENTS AND METHODS: Dose was escalated by 0.03 to 20 mg/kg every 2 weeks; flat doses of 400 mg every 4 weeks and 300 mg every 2 weeks were also evaluated. The primary objective was safety/tolerability; secondary objectives were pharmacokinetics and preliminary efficacy; and exploratory objectives were immunogenicity, GITR occupancy, and immune biomarker assessment. RESULTS: Among 100 patients enrolled [prior anti-PD-1/PD-L1 therapy, 47%; most common tumors: colorectal (19%) and melanoma (14%)], 2% had one dose-limiting toxicity (grade 4 hypoxia and grade 3 pleurisy). The MTD was not reached. Treatment-related adverse events (TRAE) occurred in 69% of patients, most frequently fatigue (17%) and pruritus (14%); 10% had grade ≥3 TRAEs, most commonly fatigue (3%); and 23% reported immune-related adverse events, most frequently generalized pruritus and generalized rash (7% each). Doses ≥5 mg/kg every 2 weeks resulted in full receptor occupancy at trough. INCAGN01876 elicited changes in immune parameters in some patients, including variable peripheral regulatory T-cell depletion and cytokine upregulation. Two patients achieved confirmed partial responses: one with appendiceal mucinous carcinoma and another with melanoma previously treated with pembrolizumab and glembatumumab; 36% of patients had disease control. CONCLUSIONS: INCAGN01876 was generally well tolerated; fatigue was the most frequent TRAE. INCAGN01876 elicited transient and variable regulatory T-cell depletion and limited antitumor activity. Future studies will explore combinatorial approaches.