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.