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)
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Published on: January 28, 2019
Tara C Mitchell1, Omid Hamid1, David C Smith1
1Tara 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.
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.
Insights
The combination of epacadostat, an indoleamine 2,3-dioxygenase 1 inhibitor, and pembrolizumab showed promising antitumor activity in advanced solid tumors. This novel cancer immunotherapy regimen was generally well tolerated in the phase I/II trial.
Area of Science:
- Oncology
- Immunotherapy
- Pharmacology
Background:
- Tumors can evade immune detection by increasing indoleamine 2,3-dioxygenase 1 (IDO1) enzyme activity.
- Epacadostat is a selective inhibitor targeting the IDO1 enzyme.
- Pembrolizumab is a programmed death protein 1 (PD-1) inhibitor used in cancer treatment.
Purpose of the Study:
- To evaluate the safety, tolerability, and preliminary antitumor activity of epacadostat combined with pembrolizumab.
- To determine the maximum tolerated dose (MTD) of the epacadostat and pembrolizumab combination.
- To assess the pharmacokinetics of the combination therapy in patients with advanced solid tumors.
Main Methods:
- An open-label, phase I/II trial (ECHO-202/KEYNOTE-037) enrolled patients with advanced solid tumors.
- Patients received escalating doses of oral epacadostat twice daily with intravenous pembrolizumab every 3 weeks.
- A safety expansion cohort received specific doses of epacadostat plus pembrolizumab.
Main Results:
- The maximum tolerated dose was not reached; epacadostat 100 mg twice daily with pembrolizumab 200 mg every 3 weeks was recommended for phase II.
- Treatment-related adverse events (TRAEs) occurred in 84% of patients, most commonly fatigue and rash; 11% discontinued due to TRAEs.
- Objective responses were observed in 55% of melanoma patients and in patients with other solid tumors, including NSCLC and RCC.
Conclusions:
- The combination of epacadostat and pembrolizumab was generally well tolerated in patients with advanced solid tumors.
- The regimen demonstrated encouraging antitumor activity across multiple tumor types.
- Further evaluation in phase II studies is warranted based on these promising results.
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