Cisplatin-based combination chemotherapy remains the standard of care for locally advanced or metastatic urothelial cancer (la/mUC); however, toxicity is substantial, responses are rarely durable, and many la/mUC patients are ineligible. Enfortumab vedotin and pembrolizumab have each shown a survival benefit versus chemotherapy in UC, are not restricted by cisplatin eligibility, and warrant investigation as a first-line (1L) combination therapy in patients ineligible for cisplatin.

In this ongoing Phase 1b/2, multicenter, open-label study, 1L cisplatin-ineligible patients with la/mUC received enfortumab vedotin 1.25 mg/kg (Days 1 and 8) and pembrolizumab 200 mg (Day 1) intravenously in 3-week cycles. The primary endpoint was safety. Key secondary endpoints included confirmed objective response rate (ORR), duration of response (DOR), and overall survival (OS).

Forty-five patients received enfortumab vedotin plus pembrolizumab. The most common treatment-related adverse events (TRAEs) were peripheral sensory neuropathy (55.6%), fatigue (51.1%), and alopecia (48.9%). Twenty-nine patients (64.4%) had grade 3 or higher TRAEs; the most common were increased lipase (17.8%), maculopapular rash (11.1%), and fatigue (11.1%). One death (2.2%) was classified as a TRAE. Confirmed ORR after a median of 9 cycles was 73.3% with a 15.6% complete response rate. Median DOR and median OS were 25.6 months and 26.1 months, respectively.

Enfortumab vedotin plus pembrolizumab showed a manageable safety profile. Most patients experienced tumor shrinkage. The median DOR and median OS exceeding 2 years in a cisplatin-ineligible patient population make this a promising combination currently under investigation in a Phase 3 study (NCT04223856).(Funded by Astellas Pharma US, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Seagen Inc; EV-103/KN-869 ClinicalTrials.gov number NCT03288545).