Pembrolizumab/ Epacadostat Combo Active in Urothelial Carcinoma

David C. Smith, MD

Combining the PD-1­ inhibitor pembrolizumab (Keytruda) with the IDO1 inhibitor epacadostat led to an overall response rate (ORR) of 35% in patients with advanced urothelial carcinoma, according to findings from the phase I/II ECHO-202/KEYNOTE-037 trial.

The median duration of response was 30.6 weeks (range, 9.7-93.1). Among patients who had received 0 or 1 prior lines of treatment, the ORR was 38%.

“The efficacy of epacadostat plus pembrolizumab in urothelial carcinoma patients with 0 or 1 prior lines of treatment supports phase III investigation of this combination in urothelial carcinoma,” said lead study author David C. Smith, MD, a professor of Medical Oncology and Urology at Michigan Medicine.

In the phase II part of the ECHO-202/KEYNOTE-037 trial, patients received 100 mg of epacadostat twice daily plus 200 mg of pembrolizumab every 3 weeks. Patients had a life expectancy of >12 weeks, an ECOG performance status of 0 or 1, adequate liver function, and no prior treatment with an IDO1 or PD-1 inhibitor. Patients had progressed during or after platinum-based chemotherapy in the first-line, neoadjuvant, or adjuvant setting. Response was assessed every 9 weeks.

Smith presented data for 40 patients with a median age of 67. Seventy-five percent of patients were men and 88% were white. Eleven patients (28%) had PD-L1 expression ≥1% by combined positive score (CPS; tumor and immune cell PD-L1 expression) and 8 patients (20%) had PD-L1 expression <1% by CPS. PD-L1 status was unknown for 21 patients.

Twenty-five percent of patients had prior radiation and most had prior surgery. Thirty-two (80%) patients had 0 or 1 prior lines of treatment and 8 patients had 2 or more prior lines.

At a median follow-up of 33.8 weeks, there were 14 patient responses, including 3 (8%) complete responses (CRs) and 11 (28%) partial response (PRs). The disease control rate (DCR) was 53% (n = 21).

“The majority of the responses were durable and occurred early during the course of treatment,” said Smith, adding, “The majority of the responses were seen at the first evaluation point.”

Ten of the 14 responses remained ongoing. Two patients had completed study treatment and had ongoing responses at the last follow-up, and 11 patients remained on treatment.

In the 32 patients who received 0 or 1 prior treatment lines, there were 12 responses, including 3 (9%) CRs and 9 (28%) PRs. The DCR was 59% (n = 19). In the 8 patients who received ≥2 prior treatment lines, there were 2 (25%) PRs and no CRs. In the PD-L1—positive group, the ORR was 64%, all PRs. In the PD-L1&shy;–negative group, there was 1 PR and no CRs.

Seventy percent (n = 28) of patients experienced at least 1 all-grade adverse event (AE) and grade 3/4 AEs occurred in 23% (n = 9) of patients. The most common all-grade AEs were fatigue (33%) and rash (20%). The most common grade 3/4 AEs were rash (n = 3), hyperglycemia (n = 2), fatigue (n = 1), ALT increased (n = 1), and lipase increased (n = 1).

Treatment-related AEs resulted in dose interruptions in 11 patients, dose reductions in 2 patients, and discontinuations in 3 patients.

The only grade 3/4 AE of special interest—those attributable to the immunotherapy itself or immune reactions—was severe skin reaction, which occurred in 3 patients. There were no treatment-related deaths.

In May, the FDA approved single-agent pembrolizumab for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

Smith DC, Gajewski T, Hamid O, et al. Epacadostat plus pembrolizumab in patients with advanced urothelial carcinoma: Preliminary phase I/II results of ECHO-202/KEYNOTE-037. J Clin Oncol 35, 2017 (suppl; abstr 4503).

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