Epacadostat Plus Pembrolizumab versus Placebo Plus Pembrolizumab in Patients with Unresectable or Metastatic Melanoma: Results of the Phase 3, Randomised, Double-Blind Echo-301/Keynote-252 Study

Background: Immunotherapy combination treatments may improve patient outcomes. Epacadostat, an indoleamine 2,3-dioxygenase 1 (IDO1) selective inhibitor, and pembrolizumab, a programmed death protein (PD)-1 inhibitor, showed promising antitumour activity in the phase 1/2 ECHO-202/KEYNOTE-037 advanced melanoma study. Methods: In the phase 3 ECHO-301/KEYNOTE-252 (NCT02752074) study, patients with unresectable stage III or IV melanoma previously untreated with checkpoint inhibitors were stratified by PD-ligand-1 expression and BRAF mutation status, and randomised (1:1) to epacadostat 100 mg twice-daily (BID) plus pembrolizumab 200 mg every 3 weeks (Q3W) or placebo plus pembrolizumab 200 mg Q3W for up to 2 years. Primary endpoints were progression-free survival (PFS) per modified Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 and overall survival (OS). Secondary endpoints included objective response rate (ORR) per modified RECIST v1.1, duration of response (DOR), and safety. We report PFS final and OS interim analyses. Findings: 706 patients were randomised (n=354 epacadostat plus pembrolizumab, n=352 placebo plus pembrolizumab). Median follow-up was 12·4 months. No significant difference was found between epacadostat plus pembrolizumab versus placebo plus pembrolizumab for PFS (median 4·7 vs 4·9 months, respectively; HR=1·00; CI, 0·83-1.21; one-sided p=0·517) or OS (HR=1·13; 95% CI 0·86 1·49; one-sided p=0·807). Twelve-month OS rate was 74% (both groups). ORR was 34·2% (epacadostat plus pembrolizumab) and 31·5% (placebo plus pembrolizumab). Median DOR was not reached (both groups). Grade ≥3 treatment-related adverse events were reported in 21·8% of patients receiving epacadostat plus pembrolizumab; 17·0% receiving placebo plus pembrolizumab. Interpretation: Epacadostat 100 mg BID plus pembrolizumab did not improve PFS or OS versus pembrolizumab alone in unresectable or metastatic melanoma patients. Utility of IDO1 inhibition as a strategy to enhance anti-PD-1 therapy activity in cancer remains uncertain. Funding: Incyte Corporation (Wilmington, DE, USA) in collaboration with Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Declaration of Interest: GVL has served as a consultant/advisor for Amgen, Array, Bristol-Myers Squibb, Incyte, Merck Sharp and Dhome, Novartis, Pierre Fabre, and Roche; has received honoraria from Bristol-Myers Squibb, Incyte, Merck Sharp and Dhome, Novartis, and Roche; and personal fees for travel to conferences from Merck Sharp and Dhome and Roche. RD has served as a consultant/advisor for Amgen, Bristol-Myers Squibb, Merck Sharp and Dhome, Novartis, Pierre Fabre, Roche, Sanofi, Sun Pharma, and Takeda. OH has served as a consultant/advisor for and/or received honoraria from Amgen, Bristol-Myers Squibb, Incyte, Merck, Novartis, and Roche; served on speakers bureau for Amgen, Array, Bristol-Myers Squibb, Genentech, Novartis, and Sanofi; and his institution has received research funding from AstraZeneca, Bristol-Myers Squibb, Celldex, Genentech, Immunocore, Incyte, Merck, Merck Serono, Medimmune, Novartis, Pfizer, and Rinat. TFG has served on advisory boards for Merck and his institution has received research grants from Merck and Incyte. CC has served as a consultant for AstraZeneca, Bayer, Bristol-Myers Squibb, and Merck Sharp and Dhome; served on speakers bureau for Bayer, Bristol-Myers Squibb, Eli Lilly, and Merck Sharp and Dhome; received personal fees and for travel and non-financial support from Boehringer Ingelheim and Bristol-Myers Squibb; and has received research grants from Astellas Pharma, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Medivation, Merck Sharp and Dhome, and Roche. SD received personal fees from Sanofi; non-financial support for travel and research from Bristol-Myers Squibb and Merck Sharp and Dhome; and research grant from Bristol-Myers Squibb. AA has served as a consultant and on speakers bureau for Bristol-Myers Squibb, Merck Sharp and Dhome, Novartis, and Roche. MSC has served as a consultant for Amgen, Bristol-Myers Squibb, Merck Sharp and Dhome, Novartis, and Pierre Fabre. J-JG has served as a consultant/advisor for and/or received honoraria from Amgen, Bristol-Myers Squibb, Incyte, Merck/Pfizer, Merck Sharp and Dhome, Novartis, Pierre Fabre, Roche, Sanofi, and Sun Pharma; has served on speakers bureau for Novartis; and received other support for travel from Amgen, Bristol-Myers Squibb, Merck Sharp and Dhome, Pierre Fabre, and Roche. TMK declares no competing interests. LD has served as a consultant for and received honoraria and research grants from Bristol-Myers Squibb, Merck Sharp and Dhome, Novartis, and Roche. CR has served as a consultant/advisor for and received honoraria from Amgen, Bristol-Myers Squibb, Merck, Novartis, Pierre Fabre, and Roche. JL has served as a consultant for Achilles, AstraZeneca, Boston Biomedical, Bristol-Myers Squibb, Eisai, EUSA Pharma, GlaxoSmithKline, Ipsen, Imugene, Incyte, iOnctura, Kymab, Merck Serono, Merck Sharp and Dhome, Nektar Therapeutics, Novartis, Pierre Fabre, Pfizer, Roche/Genentech, Secarna, and Vitaccess; his institute has received grants from Achilles Therapeutics, Aveo, Bristol-Myers Squibb, Covance, Immunocore, Merck Sharp and Dhome, Nektar Therapeutics, Novartis, Pfizer, Pharmacyclics, and Roche; and has received non-financial support from NIHR RM/ICR Biomedical Research Centre for Cancer. JRA is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. JM and MJ are employees and stockholders of Incyte. SJD is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA and stockholder of Merck & Co., Inc., Kenilworth, NJ, USA. TCM has served as a consultant/advisor for Bristol-Myers Squibb, Incyte, Merck, and Novartis. Ethical Approval: The study was conducted in accordance with the protocol, Declaration of Helsinki, and International Council for Harmonisation guidelines for Good Clinical Practice. The protocol and amendments were approved by the institutional review boards or independent ethics committees of participating institutions. All patients provided written informed consent.