First-in-Human Phase 1/2 Study of INCAGN01876, a Glucocorticoid-Induced Tumor Necrosis Factor Receptor Agonist, in Patients with Advanced or Metastatic Solid Tumors

Background: Glucocorticoid-induced tumor necrosis factor receptor–related protein (GITR) agonism in T cells may potentiate antitumor immunity responses to immune checkpoint blockade therapy. This first-in-human, phase 1/2 dose escalation/expansion study assessed INCAGN01876, a humanized GITR targeting agonistic monoclonal antibody, for advanced solid tumors (NCT02697591). Methods: Dose was escalated 0.03 to 20 mg/kg Q2W; flat doses of 400 mg Q4W and 300 mg Q2W were also evaluated. The primary objective was safety/tolerability; secondary objectives were pharmacokinetics and preliminary efficacy; 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%]; melanoma [14%]); 2% had one dose-limiting toxicity (grade 4 hypoxia; grade 3 pleurisy). Maximum tolerated dose was not reached. Treatment-related adverse events (TRAEs) occurred in 69% of patients, most frequently fatigue (17%) and pruritus (14%); 10% had grade ≥3 TRAEs, most commonly fatigue (3%); 23% reported immune-related AEs, most frequently generalized pruritus and generalized rash (7% each). Doses ≥5 mg/kg Q2W resulted in full receptor occupancy at trough. INCAGN01876 elicited changes in immune parameters in some patients, including variable peripheral regulatory T-cell (Treg) 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. Conclusion: INCAGN01876 was generally well tolerated; fatigue was the most frequent TRAE. INCAGN01876 elicited transient and variable Treg depletion and limited antitumor activity. Future studies will explore combinatorial approaches.