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)
Open accessAbstract
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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Published modeling of IDO inhibition reaches only approximately 50-70% at the 100 mg dose.
“This point of the most appropriate dose is debated however particularly given that published modeling of IDO inhibition only reaches approximately 50–70% at the 100 mg dose (60).”
From Reimagining IDO Pathway Inhibition in Cancer Immunotherapy via Downstream Focus on the Tryptophan–Kynurenine–Aryl Hydrocarbon Axis (2019) · cites this paper as [60]
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References 29 · Cited by 388
- Authors
- 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.
- Affiliations
- Fox Chase Cancer Center (US)
- Corresponding author
- Mitchell, Tara C.
- ORCID
- Venue
- Journal of Clinical Oncology
- Published
- 2018-11-10
- Volume
- 36
- Issue
- 32
- Pages
- 3223-3230
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- PMC
- PMC6225502
- OpenAlex
- W2894313087
- Cited by
- 388
- References
- 29
- Citations by year
- 2026: 26 · 2025: 42 · 2024: 47 · 2023: 45 · 2022: 47 · 2021: 72 · 2020: 54 · 2019: 52 · 2018: 3
- FWCI
- 17.10
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- Journal of Clinical Oncology (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Amgen
- Bristol-Myers Squibb
- Eli Lilly and Company
- Pfizer
- AstraZeneca
- Bayer
- GlaxoSmithKline
- Sanofi
- Biogen
- University of Pennsylvania
- OncoMed Pharmaceutical
- Array BioPharma
- University of Chicago
- University of Connecticut
- Regeneron Pharmaceuticals
- Exelixis
- Celldex Therapeutics
- Deciphera Pharmaceuticals
- Mirati Therapeutics
- Incyte
- Moderna
- G1 Therapeutics
- Kyowa Hakko Kirin
- Astellas Pharma
- Genentech
- EMD Serono
- Takeda Oncology
- Ignyta
- Loxo Oncology
- Principia Biopharma
- Daiichi Sankyo Europe
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Keywords
- epacadostat, pembrolizumab, IDO1 inhibition, PD-1 inhibitors, immune checkpoint blockade, advanced solid tumors, maximum tolerated dose, treatment-related adverse events, pharmacokinetics, melanoma, non-small cell lung cancer, renal cell carcinoma, urothelial carcinoma, head and neck squamous cell carcinoma, endometrial adenocarcinoma, anticancer activity
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