Elsevier

The Lancet Oncology

Volume 20, Issue 8, August 2019, Pages 1083-1097
The Lancet Oncology

Articles
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

https://doi.org/10.1016/S1470-2045(19)30274-8Get rights and content

Summary

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 BRAFV600 mutant status or consented to BRAFV600 mutation testing during screening. Patients were stratified by PD-L1 expression and BRAFV600 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.

Introduction

Advances in the development of immunotherapies, particularly immune checkpoint inhibitors that target PD-1, PD-L1, and CTLA-4, have greatly changed the treatment of advanced melanoma.1, 2, 3, 4, 5 Ipilimumab, a CTLA-4 inhibitor, was the first checkpoint inhibitor to show improved overall survival in advanced melanoma.3 However, the safety and tolerability profile of ipilimumab is not ideal, with approximately 60% of patients having immune-related adverse events.3 Following this, two PD-1 inhibitors, pembrolizumab and nivolumab, showed improved survival benefits, durable responses, and a lower incidence of grade 3 or worse adverse events compared with that of ipilimumab,2, 4 and have been approved for use in advanced melanoma globally.

Research in context

Evidence before this study

We searched PubMed on Aug 14, 2018, using the following search terms: (PD-1 OR “programmed death 1” OR PD-L1 OR “programmed death ligand” OR lambrolizumab OR pembrolizumab OR MK-3475 OR keytruda OR nivolumab OR BMS-936558 OR opdivo OR atezolizumab OR MPDL3280A OR JS-001 OR spartalizumab) AND (IDO1 OR IDO-1 OR IDO OR INDO OR indoleamine 2,3-dioxygenase OR epacadostat OR indoximod OR PF-06840003 OR KHK 2455 OR navoximod OR GED 0919 OR BMS-986205) AND melanoma. The search was limited to clinical trial publications, but no filters were set for date or language. No publications were identified reporting data from clinical studies of PD-1–PD-L1 and IDO1 inhibitor combinations in patients with advanced melanoma. However, before this phase 3 study, an open-label, phase 1–2 study (ECHO-202/KEYNOTE-037) assessing the efficacy and safety of epacadostat (25, 50, 100, or 300 mg twice daily doses in phase 1; 100 mg twice daily in phase 2) plus pembrolizumab (2 mg/kg or 200 mg every 3 weeks in phase 1; 200 mg once every 3 weeks in phase 2) in patients with various tumours, including advanced melanoma, was done in the USA. Although missing a comparator group, the results of this phase 1–2 study suggested that epacadostat plus pembrolizumab combination therapy was well tolerated, with 56% of patients with treatment-naive advanced melanoma (n=54) achieving an objective response, and might be a promising treatment for advanced melanoma.

Added value of this study

Our results showed no clinical benefit of epacadostat plus pembrolizumab compared with placebo plus pembrolizumab. To our knowledge, this was the first large randomised study across the field of immuno-oncology showing no further benefit from the addition of an immune agent other than anti-CTLA-4 to anti-PD-1 checkpoint inhibition.

Implications of all the available evidence

Epacadostat at the doses and schedule tested (100 mg twice daily) in this trial does not enhance the efficacy of pembrolizumab treatment alone.

Because tumour cells can use multiple mechanisms to evade immunosurveillance, combination treatment strategies targeting these mechanisms might be more effective at restoring immune function and improving clinical outcomes in patients with metastatic cancer. In patients with advanced melanoma,4, 5 combination treatment with nivolumab and ipilimumab was shown to improve objective response, progression-free survival, and overall survival compared with either ipilimumab or nivolumab alone. However, immune-related adverse events and systemic toxic effects were markedly higher with the combination therapy than with either monotherapy. Therefore, the need remains for an alternative treatment combination that improves overall survival without the burden of increased drug-related toxic effects.

IDO1 is an intracellular enzyme that catalyses the first and rate-limiting step of the tryptophan–kynurenine metabolism pathway, depleting local tryptophan concentrations and increasing concentrations of downstream metabolites, including kynurenine.6 In the tumour microenvironment, decreased tryptophan and increased tryptophan metabolites induce cell-cycle arrest and effector T-cell apoptosis and promote regulatory T-cell activity, contributing to local immunosuppression.6 IDO1 activation has been correlated with poor prognosis in patients with cancer,7 including those with melanoma,8 making it an attractive target for combination therapies using IDO1 inhibitors and PD-1 inhibitors. IDO1 and PD-L1 are commonly co-expressed in the tumour microenvironment of biopsies from patients with metastatic melanoma, with an increase in co-expression after immune therapy or targeted therapy9 indicating a possible resistance mechanism. Furthermore, tumour IDO1 expression positively correlated with PD-L1 expression by melanoma cells in primary melanoma, locoregional metastasis, and distant metastasis specimens from patients with advanced melanoma,10 supporting observations in mouse models that both proteins are upregulated by interferon gamma.11

In a preclinical melanoma mouse model,12 the combination of an IDO inhibitor with a PD-L1 inhibitor resulted in more effective reactivation of anti-tumour immunity and tumour growth inhibition compared with that of either drug alone. Previous work13 had established optimal activity of the selective IDO1 inhibitor epacadostat in in vivo models, with exposures that exceeded the half maximal inhibitory concentration at steady state, predose. These exposures were consistently reported in a phase 1 study14 assessing the effects of epacadostat doses of 100 mg and higher, administered orally twice daily in patients with advanced solid tumours. However, in that study, no objective responses were reported for epacadostat monotherapy among 52 patients with several tumour types, including six patients with advanced melanoma.14 By contrast, combination therapy with ipilimumab 3 mg/kg and epacadostat 50 mg twice daily resulted in four (22%) of 18 patients with immunotherapy-naive advanced melanoma achieving an objective response.15 Data from the phase 1 portion of the ECHO-202 study,16 assessing epacadostat and pembrolizumab in various solid tumours, reported that 11 (58%) of 19 patients with treatment-naive advanced melanoma achieved an objective response and found that this combination was well tolerated. The predominant epacadostat dose in this report was 50 mg twice daily, but doses of 25–300 mg twice daily were also assessed; a formal analysis of dose–response effects was not done. The 100 mg twice daily dose of epacadostat was selected for phase 2 assessment in the ECHO-202 study because of its preliminary antitumour activity, favourable safety profile, preliminary phase 1 activity in melanoma, previous efficacy observed in melanoma with a 50 mg twice daily dose in combination with ipilimumab, and predicted target inhibition shown in phase 1 studies.14, 15, 16 Two series of patients with melanoma treated with epacadostat and PD-1 inhibitors were subsequently reported. In two open-label, phase 1–2 studies17, 18 of patients with advanced melanoma, the combinations of epacadostat (100 mg twice daily) plus pembrolizumab (ECHO-202)17 and epacadostat (100 mg or 300 mg twice daily) plus nivolumab (ECHO-204)18 were well tolerated, with 18 (60%) of 30 (ECHO-202) and 26 (65%) of 40 (ECHO-204) patients naive to treatment achieving an objective response. The phase 3 ECHO-301/KEYNOTE-252 study was initiated to further assess the combination of epacadostat plus pembrolizumab in patients with unresectable or metastatic melanoma previously untreated with a checkpoint inhibitor. In this Article, we report efficacy and safety data from the ECHO-301 study.

Section snippets

Study design and participants

ECHO-301 was an international, randomised, placebo-controlled, double-blind, parallel-group, phase 3 trial done in 118 hospitals in 23 countries (appendix, pp 2–3). Eligible participants were aged 18 years or older who had histologically or cytologically confirmed, unresectable stage III or stage IV melanoma not amenable to local therapy; an ECOG performance status of 0 or 1; a known BRAFV600 mutation status or had consented to BRAFV600 mutation testing during screening; measurable disease in

Results

Between June 21, 2016, and Aug 7, 2017, we enrolled and randomly assigned 706 patients to treatment with epacadostat plus pembrolizumab (n=354) or placebo plus pembrolizumab (n=352; appendix p 7), from a total of 928 patients who were initially screened (figure 1). These 706 patients comprised the intention-to-treat population. Baseline characteristics were similar between treatment groups (table 1). Among all enrolled patients, the median age was 64 years (IQR 53–72). IDO1 expression was

Discussion

In the phase 3 ECHO-301/KEYNOTE-252 study, the addition of epacadostat 100 mg twice daily to pembrolizumab did not result in greater clinical benefit compared with that of pembrolizumab monotherapy in patients with unresectable or metastatic melanoma previously untreated with a checkpoint inhibitor. We observed no differences in progression-free survival, overall survival, or objective response between the two study groups. Additionally, with the caveat that the study was not formally powered

Data sharing

Access to individual patient-level data is not available for this study. The study protocol is available in the appendix (p 15).

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