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Addition of IDO1 Inhibitor to Immunotherapy in Melanoma


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As reported in The Lancet Oncology by Georgina V. Long, PhD, and colleagues, 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.

Georgina V. Long, PhD

Georgina V. Long, PhD

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.” ■

Long GV, et al: Lancet Oncol. June 17, 2019 (early release online).


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