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Mitchell TC, Hamid O, Smith DC, 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;36(32):3223-3230doi: 10.1200/JCO.2018.78.9602.
Mitchell, T. C., Hamid, O., Smith, D. C., Bauer, T. M., Wasser, J. S., Olszanski, A. J., Luke, J. J., Balmanoukian, A. S., Schmidt, E. V., Zhao, Y., Gong, X., Maleski, J., Leopold, L., & Gajewski, T. F. (2018). 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). Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 36(32), 3223-3230. https://doi.org/10.1200/JCO.2018.78.9602
Mitchell, Tara C, 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)." Journal of clinical oncology : official journal of the American Society of Clinical Oncology vol. 36,32 (2018): 3223-3230. doi: https://doi.org/10.1200/JCO.2018.78.9602
Mitchell TC, Hamid O, Smith DC, Bauer TM, Wasser JS, Olszanski AJ, Luke JJ, Balmanoukian AS, Schmidt EV, Zhao Y, Gong X, Maleski J, Leopold L, Gajewski TF. 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 Nov 10;36(32):3223-3230. doi: 10.1200/JCO.2018.78.9602. Epub 2018 Sep 28. PMID: 30265610; PMCID: PMC6225502.
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J Clin Oncol. 2018 Nov 10;36(32):3223-3230. doi: 10.1200/JCO.2018.78.9602. Epub 2018 Sep 28.

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).

Journal of clinical oncology : official journal of the American Society of Clinical Oncology

Tara C Mitchell, Omid Hamid, David C Smith, Todd M Bauer, Jeffrey S Wasser, Anthony J Olszanski, Jason J Luke, Ani S Balmanoukian, Emmett V Schmidt, Yufan Zhao, Xiaohua Gong, Janet Maleski, Lance Leopold, Thomas F Gajewski

Affiliations

  1. Tara C. Mitchell, University of Pennsylvania; Anthony J. Olszanski, Fox Chase Cancer Center, Philadelphia, PA; Omid Hamid and Ani S. Balmanoukian, The Angeles Clinic and Research Institute, Los Angeles, CA; David C. Smith, University of Michigan, Ann Arbor, MI; Todd M. Bauer, Tennessee Oncology, Nashville, TN; Jeffrey S. Wasser, University of Connecticut School of Medicine, Farmington, CT; Jason J. Luke and Thomas F. Gajewski, University of Chicago Medicine, Chicago, IL; Emmett V. Schmidt, Merck & Co, Kenilworth, NJ; and Yufan Zhao, Xiaohua Gong, Janet Maleski, and Lance Leopold, Incyte Corporation, Wilmington, DE.

PMID: 30265610 PMCID: PMC6225502 DOI: 10.1200/JCO.2018.78.9602

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.

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