ECHO-301/KEYNOTE-252: Addition of Epacadostat to Pembrolizumab in Unresectable or Metastatic Melanoma


Key Points

  • The addition of epacadostat to pembrolizumab did not improve progression-free or overall survival in unresectable stage III or stage IV melanoma.
  • Median progression-free survival was 4.7 months with epacadostat/pembrolizumab vs 4.9 months with placebo/pembrolizumab.

As reported in The Lancet Oncology by Long et al, the phase III ECHO-301/KEYNOTE-252 trial showed no improvement in progression-free or overall survival with the addition of the IDO1 inhibitor epacadostat to pembrolizumab in unresectable stage III or stage IV melanoma.

Study Details

In the double-blind trial, 706 patients from 118 sites in 23 countries were randomly assigned between June 2016 and August 2017 to receive epacadostat plus pembrolizumab (n = 354) or placebo plus pembrolizumab (n = 352). Treatment consisted of epacadostat 100 mg twice daily plus pembrolizumab 200 mg every 3 weeks, or placebo plus pembrolizumab for up to 2 years. Patients could not have previously received programmed cell death protein 1 (PD-1) or programmed cell death ligand-1 (PD-L1) inhibitors. No previous treatment for advanced or metastatic disease was permitted, except for BRAF or MEK inhibitors for BRAF V600–mutant disease.  

The primary endpoints were progression-free survival and overall survival in the intention-to-treat population.

Treatment Outcomes

The study was stopped after the second interim analysis. Median follow-up was 12.4 months.

Median progression-free survival was 4.7 months in the combination group vs 4.9 months in the pembrolizumab group (hazard ratio [HR] = 1.00, P = .52). Median overall survival was not reached in either group, with death occurring in 30% of the combination group vs 28% of the pembrolizumab group at the time of progression-free survival analysis (HR = 1.13, P = .81). No differences in outcome were observed according to PD-L1, IDO1, or BRAF mutation status.

Adverse Events

The most common grade ≥ 3 treatment-related adverse event was increased lipase, which occurred in 4% of the combination group vs 3% of the pembrolizumab group. Treatment-related serious adverse events occurred in 10% vs 9% of patients. No treatment-related deaths were observed in either group.

The investigators concluded, “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.”

Georgina V. Long, PhD, of the Melanoma Institute Australia, University of Sydney, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Incyte Corporation, in collaboration with Merck Sharp & Dohme. For full disclosures of the study authors, visit

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