Innovative Immunotherapy Combo Tests IDO Inhibitor in Melanoma Trial

OncologyLive, Vol. 18/No. 16, Volume 18, Issue 16

Investigators are looking into a novel immunotherapy combination that pairs the first-in-class IDO1 inhibitor epacadostat (INCB024360) with the checkpoint blockade agent pembrolizumab (Keytruda) in patients with unresectable or metastatic melanoma.

Omid Hamid, MD

Investigators are looking into a novel immunotherapy combination that pairs the first-in-class IDO1 inhibitor epacadostat (INCB024360) with the checkpoint blockade agent pembrolizumab (Keytruda) in patients with unresectable or metastatic melanoma.

The phase III KEYNOTE-252/ECHO-301 trial, which is enrolling at more than 120 locations, will randomize 600 patients in a 1:1 ratio to either epacadostat combined with pembrolizumab or pembrolizumab plus placebo (NCT02752074). (Figure)

Figure. Epacadostat Combination in Melanoma

CT indicates computed tomography; ECOG, Eastern Cooperative Oncology Group; MRI, magnetic resonance imaging; ORR, objective response rate; OS, overall survival; PFS, progression-free survival.

The study is open to adult patients with unresectable stage III or stage IV melanoma not amenable to local treatment. Patients who have received prior systemic treatment for their disease, particularly therapy directed at the PD-1/PD-L1 pathway, CD137, or IDO1 are excluded from the trial. Anti-CTLA-4 therapy is permitted in the adjuvant setting.

In pairing the PD-1 inhibitor pembrolizumab with epacadostat, investigators are hoping to improve upon the 21% to 33% overall response rates that pembrolizumab monotherapy demonstrated in the pivotal clinical trials that led to FDA approvals in melanoma settings.1

“Combination is the next step for immune therapy. We’ve had some combinations that are showing efficacy but higher toxicity, so we’re looking for something that does better,” said Omid Hamid, MD, director of Melanoma Therapeutics and chief of Translational Research and ImmunoOncology at The Angeles Clinic and Research Institute in Los Angeles. Hamid has conducted early-stage research into epacadostat and is serving as an investigator on the trial.

Epacadostat, which is administered orally, is an inhibitor of indoleamine 2,3-dioxygenase 1, a tryptophan-catabolizing enzyme secreted into the tumor microenvironment of many cancers. IDO1 functions as an immune suppressive; when the enzyme is inhibited, the patient’s immune cells may remain active and target the tumor.

In a phase I study that tested the combination of epacadostat and pembrolizumab, 11 of 19 evaluable treatment-naïve patients achieved an objective response (58%), including 5 patients (26%) with a complete response (CR) and 6 participants (32%) with a partial response (PR).2 The disease control rate, which consisted of CRs, PRs, and stable disease, was 74% (14 patients).

Responses were observed in all sites of target lesions, including liver, lung, and lymph nodes, and regardless of PD-L1 expression status. After a median follow-up of more than 56 weeks, the median progression-free survival (PFS) had not been reached at the time updated study results were reported at the 2016 ESMO conference in October. The PFS rate was 74% at 6 months and 57% at 12 months.

Among an additional 3 patients who were previously treated for advanced melanoma, the combination resulted in 1 patient each with a CR, a PR, and progressive disease. Overall, 55% of the patients with melanoma in the study had M1c stage disease and 55% were PD-L1—positive at baseline.

“The regimen showed excellent efficacy… with no evidence of synergistic or additional toxicity from the combination” and is among the exciting potential options under study for patients with melanoma, said Tara C. Mitchell, MD, an assistant professor at the Hospital of the University of Pennsylvania in Philadelphia, and a lead investigator of the phase I study.

“We saw responses in all dose cohorts and all tumor sites, and in previously treated patients with melanoma, so it’s a well-tolerated regimen, and it’s a combination that makes sense,” said Hamid. The patients with melanoma in the phase I study were among a larger group of participants with advanced solid malignancies including non—small cell lung cancer, renal cell carcinoma, and endometrial adenocarcinoma. In all, 62 patients were enrolled in that portion of the study; they received epacadostat at doses of 25 mg, 50 mg, 100 mg, or 300 mg twice daily.

In the phase III trial, epacadostat is being administered at 100 mg twice daily. Pembrolizumab is administered to both arms of the trial intravenously every 3 weeks starting at day 1 on the first week. Regarding safety, there were no increased toxicities with the combination compared with pembrolizumab alone across the phase I study population. The most common treatment-related adverse events (AEs) of all grades among all trial participants were fatigue (29%), rash (29%), pruritus (23%) arthralgia (19%), and diarrhea (18%). Increased aspartate aminotransferase levels were seen especially in patients taking higher doses of epacadostat, according to Hamid.

Should the phase III trial prove as successful as the earlier study, it will set the stage for further investigations into the efficacy of the pembrolizumab and epacadostat combination. “The next steps are that we’re looking at this combination in other solid tumors, including lung, head and neck, and renal, showing that it’s tolerable and that it has benefit, then moving to other tumor types,” said Hamid.

The KEYNOTE-252/ECHO-301 trial is being conducted by Incyte Corporation, which is developing the drug.

Omid Hamid, MD, can be reached through Twitter @OmidHamidMD or through The Angeles Clinic (


  1. Keytruda [pembrolizumab]. Whitehouse Station, NJ: Merck & Co, Inc; 2016.
  2. Gangadhar TC, Hamid O, Smith DC, et al. Epacadostat plus pembrolizumab in patients with advanced melanoma and select solid tumors: updated phase 1 results from ECHO-202/KEYNOTE-037. Presented at: 2016 European Society for Medical Oncology Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract 1110PD. Available at Incyte Corporation website,