In a phase III clinical trial, 706 patients with unresectable stage III/IV melanoma received pembrolizumab (anti-PD-1) with either placebo or epacadostat (IDO1 inhibitor). No significant differences in median PFS (4.9 versus 4.7 months) or median OS (endpoint not reached) were observed between placebo/pembro and epacadostat/pembro groups. Objective response was 32% and 34%, respectively, with 4% of patients in each group achieving CR. About 10% of patients in each group had serious treatment-related adverse events. Despite encouraging early-phase clinical trial results, epacadostat did not enhance the efficacy of pembrolizumab in this trial.

BACKGROUND: Immunotherapy combination treatments can improve patient outcomes. Epacadostat, an IDO1 selective inhibitor, and pembrolizumab, a PD-1 inhibitor, showed promising antitumour activity in the phase 1-2 ECHO-202/KEYNOTE-037 study in advanced melanoma. In this trial, we aimed to compare progression-free survival and overall survival in patients with unresectable stage III or IV melanoma receiving epacadostat plus pembrolizumab versus placebo plus pembrolizumab. METHODS: In this international, randomised, placebo-controlled, double-blind, parallel-group, phase 3 trial, eligible participants were aged 18 years or older, with unresectable stage III or IV melanoma previously untreated with PD-1 or PD-L1 checkpoint inhibitors, an ECOG performance status of 0 or 1, and had a known BRAF(V600) mutant status or consented to BRAF(V600) mutation testing during screening. Patients were stratified by PD-L1 expression and BRAF(V600) mutation status and randomly assigned (1:1) through a central interactive voice and integrated web response system to receive epacadostat 100 mg orally twice daily plus pembrolizumab 200 mg intravenously every 3 weeks or placebo plus pembrolizumab for up to 2 years. We used block randomisation with a block size of four in each stratum. Primary endpoints were progression-free survival and overall survival in the intention-to-treat population. The safety analysis population included randomly assigned patients who received at least one dose of study treatment. The study was stopped after the second interim analysis; follow-up for safety is ongoing. This study is registered with ClinicalTrials.gov, number NCT02752074. FINDINGS: Between June 21, 2016, and Aug 7, 2017, 928 patients were screened and 706 patients were randomly assigned to receive epacadostat plus pembrolizumab (n=354) or placebo plus pembrolizumab (n=352). Median follow-up was 12.4 months (IQR 10.3-14.5). No significant differences were found between the treatment groups for progression-free survival (median 4.7 months, 95% CI 2.9-6.8, for epacadostat plus pembrolizumab vs 4.9 months, 2.9-6.8, for placebo plus pembrolizumab; hazard ratio [HR] 1.00, 95% CI 0.83-1.21; one-sided p=0.52) or overall survival (median not reached in either group; epacadostat plus pembrolizumab vs placebo plus pembrolizumab: HR 1.13, 0.86-1.49; one-sided p=0.81). The most common grade 3 or worse treatment-related adverse event was lipase increase, which occurred in 14 (4%) of 353 patients receiving epacadostat plus pembrolizumab and 11 (3%) of 352 patients receiving placebo plus pembrolizumab. Treatment-related serious adverse events were reported in 37 (10%) of 353 patients receiving epacadostat plus pembrolizumab and 32 (9%) of 352 patients receiving placebo plus pembrolizumab. There were no treatment-related deaths in either treatment group. INTERPRETATION: Epacadostat 100 mg twice daily plus pembrolizumab did not improve progression-free survival or overall survival compared with placebo plus pembrolizumab in patients with unresectable or metastatic melanoma. The usefulness of IDO1 inhibition as a strategy to enhance anti-PD-1 therapy activity in cancer remains uncertain. FUNDING: Incyte Corporation, in collaboration with Merck Sharp & Dohme.

Author Info: (1) Melanoma Institute Australia, University of Sydney, Royal North Shore and Mater Hospitals, Sydney, NSW, Australia. Electronic address: georgina.long@sydney.edu.au. (2) Departme

Author Info: (1) Melanoma Institute Australia, University of Sydney, Royal North Shore and Mater Hospitals, Sydney, NSW, Australia. Electronic address: georgina.long@sydney.edu.au. (2) Department of Dermatology, University Hospital Zurich, Zurich, Switzerland. (3) The Angeles Clinic and Research Institute, Los Angeles, CA, USA. (4) Department of Pathology, University of Chicago Medical Center, Chicago, IL, USA. (5) Oncology Department, Clinica Alemana Santiago, Universidad del Desarrollo, Santiago, Chile. (6) Hospices Civils De Lyon, Cancer Research Center of Lyon, Claude Bernard University Lyon, Pierre Benite, France. (7) Medical Oncology, Hospital Clinic de Barcelona, Barcelona, Spain. (8) Westmead and Blacktown Hospitals, Melanoma Institute Australia, University of Sydney, Sydney, NSW, Australia. (9) Service de Dermatologie et Cancerologie Cutanee, Aix-Marseille University, Marseille, France. (10) Department of Haemato-Oncology, Seoul National University Hospital, Seoul, South Korea. (11) N N Blokhin Russian Cancer Research Center, Moscow, Russia. (12) Gustave Roussy Comprehensive Cancer Center, Villejuif, France. (13) The Royal Marsden NHS Foundation Trust, London, UK. (14) Merck & Co, Inc, Kenilworth, NJ, USA. (15) Incyte Corporation, Wilmington, DE, USA. (16) Incyte Corporation, Wilmington, DE, USA. (17) Merck & Co, Inc, Kenilworth, NJ, USA. (18) Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.