Anti-IDO1/PD-L1 Combination Active in Advanced Urothelial Carcinoma

Charles Bankhead

Bladder Cancer

Chicago, IL—The activity of pembrolizumab (Keytruda) in advanced urothelial cancer appeared to get a boost with the addition of the indoleamine 2,3-dioxygenase (IDO1) inhibitor epacadostat, results of a preliminary clinical study suggested.

The combination led to an objective response rate of 35%, increasing to 38% in patients who had received 1 or no previous regimen. Approximately 66% of patients with PD-L1–positive tumors responded to the combination of pembrolizumab and epacadostat.

Among responding patients, the activity had a median duration of 30.6 weeks, David C. Smith, MD, Professor, Medical Oncology, Michigan Medicine Urology Oncology Clinic, University of Michigan, Ann Arbor, reported at the 2017 ASCO annual meeting.

“These results suggest that epacadostat plus pembrolizumab is active in patients with advanced urothelial carcinoma. Epacadostat plus pembrolizumab was generally well-tolerated. The efficacy of epacadostat plus pembrolizumab in urothelial carcinoma patients with 0 to 1 previous lines of treatment supports phase 3 investigation of this combination in urothelial carcinoma,” said Dr Smith.

Pembrolizumab and other PD-1 and PD-L1 inhibitors have demonstrated encouraging activity in advanced urothelial carcinoma. Pembrolizumab received accelerated approval from the FDA as first-line therapy for patients who are ineligible for cisplatin on the basis of data showing an objective response rate of 29% and a median duration of response of 1.4 to 17.8 months, Dr Smith noted. Nonetheless, the prognosis for advanced urothelial cancer remains unfavorable, and novel combinations are needed to improve efficacy with limited additional toxicity.

Tumors may evade immunosurveillance by a number of mechanisms, including the upregulation of IDO1. Induced by interferon-gamma, IDO1 catalyzes the first and rate-limiting step of tryptophan degradation in the kynurenine pathway, said Dr Smith. Tryptophan depletion and production of kynurenine and other metabolites shift the immune microenvironment to an immunosuppressive state.

By specific inhibition of IDO1, epacadostat blocks tryptophan metabolism and augments immunosurveillance in the tumor microenvironment. Epacadostat and a checkpoint inhibitor constitute a rational combination that might improve patient outcomes.

The combination was evaluated in a phase 1/2 clinical trial involving cohorts of patients with various types of solid tumors. Dr Smith reported findings from a group of 40 patients with advanced urothelial cancer. All patients received epacadostat 100 mg twice daily and pembrolizumab 200 mg every 3 weeks.

The patients had a median age of 67 years, men accounted for 75% of the group, and lymph nodes (58%) and lung (40%) were the most common metastatic sites. Eight patients had received ≥2 previous regimens, all the patients had previous platinum therapy, and 25% had previous radiotherapy. With respect to PD-L1 status (combined expression), 11 (≥1%) patients had PD-L1–positive tumors, 8 (<1%) had PD-L1–negative tumors, and 21 had unknown PD-L1 expression status.

Dr Smith reported that 3 patients achieved complete responses with the combination and 11 others attained partial responses. All but 2 objective responses (including all 3 complete responses) occurred in patients who had received <2 previous lines of therapy. An additional 7 patients had stable disease, resulting in a disease control rate of 53% for the entire cohort, and 59% in the subgroup of patients with 0 or 1 previous line of therapy.

Assessment of response by PD-L1 status showed that 7 of 11 (64%) patients with ≥1% staining had objective responses (all partial responses) versus 1 of 8 patients with <1% staining.

Approximately 75% of the patients had some degree of tumor shrinkage.

“The majority of patients with response had less than 2 prior lines of therapy, and the majority of these responses were durable and occurred early in the course of treatment. The majority of responses occurred in PD-L1–positive patients, and again, the responses occurred early and were durable,” said Dr Smith.

Grade 3/4 treatment-related adverse events occurred in 9 (23%) patients, consisting of rash in 3 patients, hyperglycemia in 2, and 1 case each of fatigue, elevated alanine aminotransferase, and elevated lipase. The only grade 3/4 treatment-related adverse event of special interest (immune-related) was skin reaction, occurring in 3 patients.