{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T09:31:11Z","timestamp":1790847071359,"version":"4.1.0"},"reference-count":10,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2022,9,26]],"date-time":"2022-09-26T00:00:00Z","timestamp":1664150400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,11,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>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 \u226510.0% of patients. One treatment-related death was reported. The ORR was 31.4% across all treatment groups.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>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).<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/oncolo\/oyac174","type":"journal-article","created":{"date-parts":[[2022,9,26]],"date-time":"2022-09-26T13:30:07Z","timestamp":1664199007000},"page":"905-e848","source":"Crossref","is-referenced-by-count":29,"title":["Epacadostat Plus Pembrolizumab and Chemotherapy for Advanced Solid Tumors: Results from the Phase I\/II ECHO-207\/KEYNOTE-723 Study"],"prefix":"10.1093","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7608-0380","authenticated-orcid":false,"given":"John D","family":"Powderly","sequence":"first","affiliation":[{"name":"Cancer Research Clinic, Carolina BioOncology Institute , Huntersville , NC , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel J","family":"Klempner","sequence":"additional","affiliation":[{"name":"Department of Medicine, Massachusetts General Hospital and Harvard Medical School , Boston, MA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aung","family":"Naing","sequence":"additional","affiliation":[{"name":"Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center , Houston, TX , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna","family":"Bendell","sequence":"additional","affiliation":[{"name":"Drug Development Unit, Sarah Cannon Research Institute, Tennessee Oncology , Nashville, TN , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ignacio","family":"Garrido-Laguna","sequence":"additional","affiliation":[{"name":"Division of Oncology, University of Utah School of Medicine, Huntsman Cancer Institute , Salt Lake City, UT , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel V T","family":"Catenacci","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Chicago , Chicago, IL , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew H","family":"Taylor","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Earle A. Chiles Research Institute, Providence Cancer Institute , Portland, OR , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James J","family":"Lee","sequence":"additional","affiliation":[{"name":"Cancer Therapeutics Program, UPMC Hillman Cancer Center , Pittsburg , PA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fred","family":"Zheng","sequence":"additional","affiliation":[{"name":"Incyte Corporation , Wilmington, DE , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Zhou","sequence":"additional","affiliation":[{"name":"Incyte Corporation , Wilmington, DE , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohua","family":"Gong","sequence":"additional","affiliation":[{"name":"Incyte Corporation , Wilmington, DE , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hema","family":"Gowda","sequence":"additional","affiliation":[{"name":"Incyte Corporation , Wilmington, DE , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory L","family":"Beatty","sequence":"additional","affiliation":[{"name":"Department of Medicine, Abramson Cancer Center and Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,9,26]]},"reference":[{"issue":"8","key":"2022110514281105400_CIT0001","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1016\/S1470-2045(19)30274-8","article-title":"Epacadostat plus pembrolizumab versus placebo plus pembrolizumab in patients with unresectable or metastatic melanoma (ECHO-301\/KEYNOTE-252): A phase 3, randomised, double-blind study","volume":"20","author":"Long","year":"2019","journal-title":"Lancet Oncol"},{"issue":"1","key":"2022110514281105400_CIT0002","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1146\/annurev-cancerbio-030419-033635","article-title":"Is there a clinical future for IDO1 inhibitors after the failure of epacadostat in melanoma?","volume":"4","author":"Van den Eynde","year":"2020","journal-title":"Ann Rev Cancer Biol"},{"issue":"Suppl 3","key":"2022110514281105400_CIT0003","first-page":"A15","article-title":"Retrospective pooled analysis of epacadostat clinical studies identifies doses required for maximal pharmacodynamic effect in anti-PD-1 combination studies","volume":"8","author":"Smith","year":"2020","journal-title":"J ImmunoTher Cancer"},{"key":"2022110514281105400_CIT0004","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/2051-1426-2-3","article-title":"Mechanism of tumor rejection with doublets of CTLA-4, PD-1\/PD-L1, or IDO blockade involves restored IL-2 production and proliferation of CD8(+) T cells directly within the tumor microenvironment","volume":"2","author":"Spranger","year":"2014","journal-title":"J ImmunoTher Cancer"},{"issue":"3","key":"2022110514281105400_CIT0005","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1038\/nm1196","article-title":"Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy","volume":"11","author":"Muller","year":"2005","journal-title":"Nat Med"},{"issue":"7","key":"2022110514281105400_CIT0006","doi-asserted-by":"crossref","first-page":"1389","DOI":"10.1084\/jem.20130066","article-title":"Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4","volume":"210","author":"Holmgaard","year":"2013","journal-title":"J Exp Med"},{"issue":"13","key":"2022110514281105400_CIT0007","doi-asserted-by":"crossref","first-page":"3269","DOI":"10.1158\/1078-0432.CCR-16-2272","article-title":"First-in-human phase I study of the oral inhibitor of indoleamine 2,3-dioxygenase-1 epacadostat (INCB024360) in patients with advanced solid malignancies","volume":"23","author":"Beatty","year":"2017","journal-title":"Clin Cancer Res"},{"issue":"2","key":"2022110514281105400_CIT0008","doi-asserted-by":"crossref","first-page":"e000870","DOI":"10.1136\/jitc-2020-000870","article-title":"Preclinical investigations and a first-in-human phase I trial of M4112, the first dual inhibitor of indoleamine 2,3-dioxygenase 1 and tryptophan 2,3-dioxygenase 2, in patients with advanced solid tumors","volume":"8","author":"Naing","year":"2020","journal-title":"J ImmunoTher Cancer"},{"issue":"32","key":"2022110514281105400_CIT0009","doi-asserted-by":"crossref","first-page":"3223","DOI":"10.1200\/JCO.2018.78.9602","article-title":"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)","volume":"36","author":"Mitchell","year":"2018","journal-title":"J Clin 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