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Epacadostat plus pembrolizumab in patients with advanced urothelial carcinoma: promising preliminary phase I/II results of ECHO-202/KEYNOTE-037

The ECHO-202/KEYNOTE-037 presented by David Smith, at ASCO2017, is an open-label, phase I/II study of epacadostat + IV pembrolizumab in patients with advanced tumors, amongst others urothelial carcinoma.The phase I/II efficacy and safety outcomes for the urothelial carcinoma cohort at an October 29, 2016 data cutoff, were presented at ASCO 2017 by David C. Smith, Professor of Internal Medicine and Professor of Urology at the University of Michigan School of Medicine, Michigan, USA. The new data in advanced urothelial carcinoma confirm earlier research that adding Incyte’s epacadostat to oncology drugs such as here, pembrolizumab, boost their effectiveness without significantly increasing side effects.

Epacadostat is a first-in-class, highly potent and selective oral inhibitor of the IDO1 enzyme that regulates the tumor immune microenvironment, thereby restoring effective anti-tumor immune responses. IDO1 overexpression is associated with tumor progression and shortened patient (pt) survival. In single-arm studies, the combination of epacadostat and immune checkpoint inhibitors has shown proof-of-concept in patients with unresectable or metastatic melanoma. In these studies, epacadostat combined with the CTLA-4 inhibitor ipilimumab or the PD-1 inhibitor pembrolizumab improved response rates compared with studies of the immune checkpoint inhibitors alone.

Adult patients with advanced UC, prior platinum therapy (adjuvant or advanced disease setting) or alternative therapy (if platinum was not appropriate),and no prior IDO-inhibitor, anti-PD-1 or anti-CTLA-4 therapies, were eligible to participate to the ECHO-202/KEYNOTE-037 study.

In phase I, patients received epacadostat (25, 50, 100, or 300 mg PO BID) + pembrolizumab (2 mg/kg or 200 mg IV Q3W); the maximum toxic dose was not exceeded. Epacadostat (100 mg BID) + pembrolizumab (200 mg Q3W) dosing was selected for phase II. Response was assessed in RECIST 1.1-evaluable patients. Safety was assessed in patients receiving ≥1 epacadostat + pembrolizumab dose. The results show that a total of 40 patients (phase I, n = 5; phase II, n = 35) were evaluated. The median age of the patients enrolled, was 67 years, 75% were men, 88% were white, 100% had prior platinum therapy, and 75% had 0–1 prior line of therapy for advanced disease.

Preliminary ORR (CR+PR) and DCR (CR+PR+SD) for all efficacy-evaluable patients were 35% (13/37; all PR) and 57% (21/37; 13 PR, 8 SD), respectively; for patients with 0–1 prior line of therapy for advanced disease, ORR and DCR were 37% (10/27) and 63% (17/27). A higher response rate was observed in PD-L1 positive patients,although responses were also observed in PD-L1 negative patients.

At data cutoff, 12/13 responses were ongoing (range, 1+ to 652+ days). De median duration of response was 30,6 or more weeks. PFS and biomarker analyses are ongoing. The most common treatment related adverse events (TRAEs; seen in ≥10% of 40 patients) were fatigue (28%), rash (18%), and increased amylase (10%; asymptomatic). Grade ≥3 TRAEs occurred in 20% of patients (rash was the only grade ≥3 TRAE to occur in > 1 pt [n = 3]). Three patients discontinued due to TRAEs (grade 3 rash [n = 1]; grade 3 COPD exacerbation [n = 1], grade 2 diarrhea [n = 1]). There were no treatment related deaths. The adverse events were manageable with supportive care. The researchers conclude that the combination of the IDO1 inhibitor epacadostat and the PD-1 inhibitor pembrolizumab was generally well tolerated and associated with increased response compared with previously reported PD-1 inhibitor monotherapy in patients with advanced urothelial cancer. The safety profile seen in this study was consistent with the previously reported phase I findings, as well as the phase 1/2 safety data in other tumor types supporting continued evaluation of the combination (see also J Clin Oncol 35, 2017;suppl; abstr 3012, presented at ASCO 2017 by Hamid O. et al).

A phase III urothelial cancer study is planned.

About ECHO clinical trial program

The ECHO clinical trial program was established to investigate the efficacy and safety of epacadostat as a core component of combination therapy in oncology. Ongoing Phase 1 and Phase 2 studies evaluating epacadostat in combination with PD-1 and PD-L1 inhibitors collectively plan to enroll over 900 patients in a broad range of solid tumor types as well as hematological malignancies. The Phase 3 ECHO-301 KEYNOTE-252 MEL study (NCT02752074), a randomized, double-blind, placebo-controlled study investigating pembrolizumab in combination with epacadostat or placebo for the treatment of patients with unresectable or metastatic melanoma, is also ongoing. Besides the studies combining epacadostat with pembrolizumab in melanoma and urothelial cancer, Incyte and Merck (MSD) are trying the cocktail in several other tumor types, including lung (NSCLC), head-and neck cancer (SCCHN) and kidney cancers (RCC).

For more information about the ECHO clinical trial program, visit and Clinical trial information:NCT02178722


Smith DC, Gajewski T, Hamid O, et al. J Clin Oncol 35, 2017 (suppl; abstr 4503). Presented at ASCO2017.

Speaker David Smith


David C. Smith, University of Michigan, Professor of Internal Medicine and Professor of Urology at the University of Michigan School of Medicine, Ann Arbor, Michigan, USA


See: Keyslides

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