Epacadostat Plus Pembrolizumab in Patients With Advanced Solid Tumors: Phase I Results From a Multicenter, Open-Label Phase I/II Trial (ECHO-202/KEYNOTE-037)

Abstract

Purpose: Tumors may evade immunosurveillance through upregulation of the indoleamine 2,3-dioxygenase 1 (IDO1) enzyme. Epacadostat is a potent and highly selective IDO1 enzyme inhibitor. The open-label phase I/II ECHO-202/KEYNOTE-037 trial evaluated epacadostat plus pembrolizumab, a programmed death protein 1 inhibitor, in patients with advanced solid tumors. Phase I results on maximum tolerated dose, safety, tolerability, preliminary antitumor activity, and pharmacokinetics are reported.

Patients and methods: Patients received escalating doses of oral epacadostat (25, 50, 100, or 300 mg) twice per day plus intravenous pembrolizumab 2 mg/kg or 200 mg every 3 weeks. During the safety expansion, patients received epacadostat (50, 100, or 300 mg) twice per day plus pembrolizumab 200 mg every 3 weeks.

Results: Sixty-two patients were enrolled and received one or more doses of study treatment. The maximum tolerated dose of epacadostat in combination with pembrolizumab was not reached. Fifty-two patients (84%) experienced treatment-related adverse events (TRAEs), with fatigue (36%), rash (36%), arthralgia (24%), pruritus (23%), and nausea (21%) occurring in ≥ 20%. Grade 3/4 TRAEs were reported in 24% of patients. Seven patients (11%) discontinued study treatment because of TRAEs. No TRAEs led to death. Epacadostat 100 mg twice per day plus pembrolizumab 200 mg every 3 weeks was recommended for phase II evaluation. Objective responses (per Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) occurred in 12 (55%) of 22 patients with melanoma and in patients with non-small-cell lung cancer, renal cell carcinoma, endometrial adenocarcinoma, urothelial carcinoma, and squamous cell carcinoma of the head and neck. The pharmacokinetics of epacadostat and pembrolizumab and antidrug antibody rate were comparable to historical controls for monotherapies.

Conclusion: Epacadostat in combination with pembrolizumab generally was well tolerated and had encouraging antitumor activity in multiple advanced solid tumors.

Figures

Fig 1.

CONSORT diagram of the study design and patient disposition. (*) Patients who completed treatment either received 2 years of combination therapy or received ≥ 6 months of combination treatment and achieved a complete response with two or more doses of pembrolizumab administered beyond the date of initial complete response. Three patients with melanoma met the latter criteria for early stopping of treatment (50 mg twice per day, two patients; 100 mg twice per day, one patient).

Fig 2.

Pharmacokinetic-predicted time-averaged inhibition of indoleamine 2,3-dioxygenase 1 (IDO1) inhibition for individual patients by epacadostat dose.

Fig 3.

Change from baseline in target lesions. (A) Best percentage change from baseline in target lesions by tumor type in all patients. (B) to (D) Percentage change from baseline in target lesions over time in patients with (B) melanoma, (C) non–small-cell lung cancer (NSCLC), and (D) renal cell cancer (RCC). EA, endometrial adenocarcinoma; RECIST, Response Evaluation Criteria in Solid Tumors; SCCHN, squamous cell carcinoma of the head and neck; TNBC, triple-negative breast cancer; UC, urothelial carcinoma. (*) Progressive disease per RECIST version 1.1. (†) Partial response per RECIST version 1.1.