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

Abstract

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.

Figure 1.

Patient disposition. ^aTwo patients completed treatment [0.3 mg/kg every 2 weeks (Q2W) and 300 mg Q2W, respectively]. The death in the 300-mg Q2W cohort was coded as dyspnea secondary to disease progression. Reasons for patient ineligibility included meeting the following exclusion criteria: (i) laboratory and medical history parameters not within the protocol-defined range (39%; 17/44 patients); (ii) any condition that would, in the investigator’s judgment, interfere with full participation in the study (including administration of the study drug and attending required study visits), pose a significant risk to the subject, or interfere with the interpretation of study data (16%; 7/44 patients); (iii) known active central nervous system metastases and/or carcinomatous meningitis (14%; 6/44 patients); and (iv) evidence of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection or risk of reactivation (positive testing for HBV DNA and/or HCV RNA; 11%; 5/44 patients) and not meeting the following inclusion criteria: willingness to provide a written informed consent form (7%; 3/44 patients) and having Eastern Cooperative Oncology Group performance status of 0 or 1 (5%; 2/44 patients). FAS, full analysis set.

Figure 2.

A, INCAGN01876 mean (±SE) concentration–time profiles after the first dose and at steady state. B, Relationship between serum concentrations of INCAGN01876 and GITR receptor occupancy. C, Percentage of INCAGN01876 receptor occupancy vs. time. The average receptor occupancy per cohort is depicted (± SD). PK analysis includes patients with ADA-negative status at the respective visit; first visit/steady state: 0.03 mg/kg, n = 4/n = 0; 0.1 mg/kg, n = 4/n = 0; 0.3 mg/kg, n = 3/n = 1; 1 mg/kg, n = 3/n = 1; 3 mg/kg, n = 15/n = 5; 5 mg/kg, n = 16/n = 5; 10 mg/kg, n = 14/n = 4; 20 mg/kg, n = 3/n = 0; 300 mg, n = 21/n = 7; and 400 mg, n = 9/n = 3. RO, receptor occupancy.

Figure 3.

A, Frequencies of Tregs. B, Changes in central memory (CM) and EM CD4⁺ T cells.