Epacadostat Added to Pembrolizumab is a Promising Combination in Bladder Cancer

David C. Smith, MD

When epacadostat, an IDO1 inhibitor, was combined with pembrolizumab (Keytruda), a PD-1 inhibitor, responses were seen in 35% of patients with advanced urothelial carcinoma, according to findings presented during the 2017 ASCO Annual Meeting.

The median duration of response with the combination was 30.6 weeks (range, 9.7-93.1). Among patients who had received 0 or 1 prior lines of treatment, the overall response rate 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 &ge;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).

&ldquo;The majority of the responses were durable and occurred early during the course of treatment,&rdquo; said Smith, adding, &ldquo;The majority of the responses were seen at the first evaluation point.&rdquo;

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 &ge;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;&ndash;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&mdash;was severe skin reaction, which occurred in 3 patients. There were no treatment-related deaths. &nbsp;&nbsp;

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.

Reference:

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 Oncol35, 2017 (suppl; abstr 4503).