Preliminary results were presented at the ASCO 2017 meeting for the Phase I/II ECHO-202/KEYNOTE-037 trial, investigating Incyte’s IDO inhibitor, epacadostat, in combination with Merck & Co’s PD-1 inhibitor, Keytruda, in advanced urothelial carcinoma.

This study enrolled second-line platinum failure or first-line platinum-ineligible patients, with the exception of those who had received prior checkpoint inhibitor therapy. A total of 40 patients were evaluated, with 75% being frontline or second-line. All patients in the trial had received prior platinum treatment.

The preliminary overall response rate (ORR) reported in efficacy-evaluable patients was 35%. Of the patients who responded, all were partial responses. At data cutoff, 12 of the 13 responses were ongoing. The most common treatment-related adverse events (TRAE) were fatigue, rash, and increased amylase. Grade ≥3 TRAEs occurred in 20% of patients and three patients discontinued treatment due to TRAEs. The reasons for treatment discontinuation were grade 3 rash (n=1), grade 3 COPD exacerbation (n=1), and grade 2 diarrhea (n=1).

To place this efficacy data into context, rough comparisons can be made with data from Keytruda’s pivotal Phase III KEYNOTE-045 trial as a single agent in second-line urothelial carcinoma. In this trial, the ORR was 21%, including 7% of patients who achieved complete responses. Keytruda was approved on the basis of a 3-month OS benefit over chemotherapy demonstrated in this trial, though PFS was not significantly extended with Keytruda treatment.  

Differences in clinical trial design and baseline characteristics for patients enrolled in the KEYNOTE-045 trial versus the ECHO-202/KEYNOTE-037 trial made direct comparisons difficult. Preliminarily, the ORR for epacadostat + Keytruda appears to be slightly higher than that seen with Keytruda monotherapy. However, the lack of complete responses in the combination trial could be an early hint of trouble.

PFS and biomarker analyses for ECHO-202/KEYNOTE-037 are ongoing, and it is too early to draw conclusions about whether the responses seen in the preliminary data will translate into PFS or OS benefit. In addition, Phase III data will be needed to gather data in a larger patient population, and to make direct comparisons with existing treatments. Currently, two Phase III studies evaluating epacadostat + Keytruda, one in frontline bladder cancer, and one in second-line bladder cancer, are planned.

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Smith DC, et al. (2017). Epacadostat plus pembrolizumab in patients with advanced urothelial carcinoma: Preliminary phase I/II results of ECHO-202/KEYNOTE-037. American Society of Clinical Oncology Annual Meeting, Chicago, IL. Abstract #4503.