Drug Combination Is Effective in Urothelial Carcinoma

When combined with the IDO1 inhibitor epacadostat, Keytruda (pembrolizumab), a PD-1 inhibitor, resulted in an overall response rate (ORR) of 35 percent in patients with advanced urothelial carcinoma, according to results from the phase 1/2 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 one prior lines of treatment, the ORR was 38 percent.

“The efficacy of epacadostat plus pembrolizumab in urothelial carcinoma patients with 0 or one prior lines of treatment supports phase 3 investigation of this combination in urothelial carcinoma,” said lead study author David C. Smith, M.D., a professor of Medical Oncology and Urology at Michigan Medicine.

In the phase 2 part of the ECHO-202/KEYNOTE-037 trial, patients received 100 mg of epacadostat twice daily plus 200 mg of Keytruda every three weeks. Patients had a life expectancy of at least 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 nine weeks.

Smith presented data for 40 patients with a median age of 67. Seventy-five percent of patients were men and 88 percent were white. Eleven patients (28 percent) had PD-L1 expression 1 percent or more by combined positive score (CPS; tumor and immune cell PD-L1 expression) and eight patients (20 percent) had PD-L1 expression under 1 percent 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 percent) 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 three (8 percent) complete responses (CRs) and 11 (28 percent) partial response (PRs). The disease control rate (DCR) was 53 percent (21 patients).

“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 one prior treatment lines, there were 12 responses, including three (9 percent) CRs and nine (28 percent) PRs. The DCR was 59 percent (19 patients). In the eight patients who received two or more prior treatment lines, there were two (25 percent) PRs and no CRs. In the PD-L1—positive group, the ORR was 64 percent, all PRs. In the PD-L1­–negative group, there was 1 PR and no CRs.

Seventy percent (28 patients) of patients experienced at least one all-grade adverse event (AE) and grade 3/4 AEs occurred in 23 percent (nine patients) of patients. The most common all-grade AEs were fatigue (33 percent) and rash (20 percent). The most common grade 3/4 AEs were rash (three patients), hyperglycemia (two patients), fatigue (one patient), ALT increased (one patient) and lipase increased (one patient).

Treatment-related AEs resulted in dose interruptions in 11 patients, dose reductions in two patients, and discontinuations in three 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 Keytruda 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.