As reported by Mitchell et al in the Journal of Clinical Oncology, the combination of the oral indoleamine 2,3-dioxygenase 1 (IDO1) enzyme inhibitor epacadostat and the anti–programmed cell death protein 1 (PD-1) therapy pembrolizumab (Keytruda) showed activity in advanced solid tumors in the phase I portion of the phase I/II ECHO-202/KEYNOTE-037 study. Upregulation of the IDO1 enzyme may allow tumors to evade immune surveillance.
The multicenter trial enrolled 62 patients who received study treatment in the phase I portion between July 2014 and October 2015. The most common tumor types were melanoma (22 patients), non–small cell lung cancer (NSCLC, 12 patients), and renal cell carcinoma (RCC, 11 patients).
Patients received escalating doses of epacadostat (25, 50, 100, or 300 mg) twice per day plus pembrolizumab at 2 mg/kg or 200 mg every 3 weeks. During the safety expansion, patients received epacadostat at 50, 100, or 300 mg twice per day plus pembrolizumab at 200 mg every 3 weeks.
Toxicity and Tumor Responses
The maximum tolerated dose of epacadostat in combination with pembrolizumab was not reached. The most common treatment-related adverse events of any grade were fatigue (36%), rash (36%), arthralgia (24%), pruritus (23%), and nausea (21%), with adverse events leading to discontinuation of treatment in 11%. Treatment-related grade 3 or 4 adverse events occurred in 24% of patients, with the most common being rash (8%) and increased lipase (8%); no treatment-related deaths were observed. Epacadostat at 100 mg twice per day plus pembrolizumab at 200 mg every 3 weeks was recommended for phase II study.
Objective responses on Response Evaluation Criteria in Solid Tumors, version 1.1, occurred in 25 (40%) of 62 patients, including complete response in 8 patients; 13 patients (21%) had stable disease. At data cutoff, 17 of 25 responses were ongoing. Responses were observed in 12 of 22 patients with melanoma and were also observed in patients with NSCLC (5 of 12), RCC (2 of 11), endometrial adenocarcinoma, urothelial carcinoma, and squamous cell carcinoma of the head and neck.
The investigators concluded, “Epacadostat in combination with pembrolizumab [was] generally well tolerated and had encouraging antitumor activity in multiple advanced solid tumors.”
The study was supported by Incyte and Merck & Co.
Tara C. Mitchell, MD, of the Abramson Cancer Center, University of Pennsylvania, is the corresponding author for the Journal of Clinical Oncology article.
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