Epacadostat Plus Pembrolizumab and Chemotherapy for Advanced Solid Tumors: Results from the Phase I/II ECHO-207/KEYNOTE-723 Study.
oregon; chiles; Humans; Kynurenine; Programmed Cell Death 1 Receptor; Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Tumor Microenvironment
BACKGROUND: Epacadostat, an oral, selective inhibitor of IDO1, has shown activity when administered with pembrolizumab. We evaluated the addition of chemotherapy to epacadostat and pembrolizumab in patients with advanced or metastatic solid tumors. One proposed mechanism of resistance to PD-1 checkpoint inhibition is through immunosuppression mediated by L-kynurenine. IDO1, indoleamine-2,3-dioxygenase 1 is the rate-limiting enzyme catalyzing the conversion of L-tryptophan to L-kynurenine. If IDO1 is a mechanism of tumor escape from checkpoint inhibition, then addition of an IDO1 inhibitor with a PD-1 checkpoint inhibitor could enable tumor response to immunotherapy.
METHODS: Patients received one of 7 tumor-appropriate chemotherapy regimens. Pembrolizumab 200 mg was infused intravenously every 3 weeks. Epacadostat 100 mg was administered orally twice daily. The primary objectives of phase I were determining safety/tolerability and defining the maximum tolerated or pharmacologically active dose of epacadostat. Phase II of the study was designed to enroll efficacy-expansion cohorts and to assess changes in the tumor and tumor microenvironment via mandatory-biopsy cohorts.
RESULTS: A total of 70 patients were enrolled. Twelve patients were enrolled in the phase II mandatory-biopsy cohorts. Due to early study closure, efficacy expansion did not enroll. Grades 3 and 4 treatment-emergent adverse events (TEAEs) occurred in 78.6% of patients. Neutropenia and disease progression were the only grades 3 and 4 TEAEs reported in ≥10.0% of patients. One treatment-related death was reported. The ORR was 31.4% across all treatment groups.
CONCLUSION: The combination of epacadostat 100 mg bid with pembrolizumab and chemotherapy had an acceptable safety profile. This regimen showed antitumor activity across multiple types of advanced or metastatic solid tumors (ClinicalTrials.gov Identifier: NCT03085914).
Earle A. Chiles Research Institute
Powderly, John D; Klempner, Samuel J; Naing, Aung; Bendell, Johanna; Garrido-Laguna, Ignacio; Catenacci, Daniel V T; Taylor, Matthew H; Lee, James J; Zheng, Fred; Zhou, Feng; Gong, Xiaohua; Gowda, Hema; and Beatty, Gregory L, "Epacadostat Plus Pembrolizumab and Chemotherapy for Advanced Solid Tumors: Results from the Phase I/II ECHO-207/KEYNOTE-723 Study." (2022). Articles, Abstracts, and Reports. 6764.