Epacadostat plus pembrolizumab achieved responses in 40% of patients with advanced solid tumors.
Major finding: Epacadostat plus pembrolizumab achieved responses in 40% of patients with advanced solid tumors.
Approach: The safety and efficacy of epacadostat plus pembrolizumab was evaluated in a phase I trial of 62 patients.
Impact: IDO1 inhibition with epacadostat is well tolerated in combination with pembrolizumab.
IDO1 is an intracellular enzyme expressed on tumor cells and cells in the tumor microenvironment that catalyzes a rate-limiting step in tryptophan metabolism. Upregulation of IDO1 in tumor cells can promote immune evasion, suggesting the potential for therapeutic blockade of IDO1 in combination immunotherapies. Epacadostat is a potent selective IDO1 inhibitor that has been shown to suppress tumor growth in combination with immune checkpoint blockade in preclinical studies, and was well tolerated as a monotherapy in phase I and II clinical trials of patients with advanced cancer. Mitchell and colleagues sought to evaluate the safety and efficacy of epacadostat in combination with the PD-1 inhibitor pembrolizumab in the phase I portion of the ECHO-202/KEYNOTE-037 open-label trial. A total of 62 patients with advanced solid tumors were enrolled and treated with epacadostat plus pembrolizumab. The primary objectives were evaluation of the dose-limiting toxicities, maximum tolerated dose, safety, and tolerability of epacadostat plus pembrolizumab. Exploratory endpoints included preliminary antitumor activity. Combination therapy was well tolerated, with 11% of patients discontinuing study treatment due to treatment-related adverse events. Overall, 84% of patients experienced treatment-related adverse events and 24% of patients experienced grade 3–4 adverse events. Objective responses occurred in 25 of 62 (40%) patients, including complete responses in 8 patients and partial responses in 17 patients. Responses were observed in 12 of 22 (55%) patients with melanoma, as well as in patients with non–small cell lung cancer, renal cell carcinoma, endometrial adenocarcinoma, urothelial carcinoma, and squamous cell carcinoma of the head and neck. Taken together, these findings indicate that epacadostat is well tolerated in combination with pembrolizumab and has antitumor activity in a variety of tumor types.
Mitchell TC, Hamid O, Smith DC, Bauer TM, Wasser JS, Olszanski AJ, et al. 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). J Clin Oncol 2018 Sep 28 [Epub ahead of print].
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