Zelenectide Pevedotin (Nectin-4 BTC) + Pembrolizumab Delivers 65% ORR (25% CR) in First-Line Cisplatin-Ineligible Urothelial Cancer

Zelenectide pevedotin is a “Bicycle” toxin conjugate that targets Nectin-4 and releases MMAE. When combined with a PD-1 blockade, it aims to rapidly induce cytotoxicity while also priming the immune system. In advanced/metastatic urothelial cancer, Nectin-4 is expressed in 97% of bladder (urothelial) cancer patients. In the Phase 1/2 Duravelo-1 Cohort B7 study (NCT04561362), 22 patients with locally advanced or metastatic urothelial carcinoma who were ineligible for cisplatin and had not been previously treated received zelenectide at a dose of 5 mg/m² on days 1, 8, and 15, alongside pembrolizumab every 3 weeks. Among 20 efficacy-evaluable patients, the ORR was 65% (25% CR; 40% PR) with a 90% disease-control rate. The median follow-up 7.1 months and the median DoR had not yet been reached. Grade ≥3 TRAEs were mainly ALT elevation and neutropenia (14% each). Peripheral neuropathy was observed in 50%, but was grade 3 in only 9% of cases. No grade ≥4 TRAEs, ocular toxicity, or treatment-related deaths were seen. For comparison, first-line pembrolizumab monotherapy in the KEYNOTE-052 study achieved a 29% ORR in a similar cisplatin-ineligible population and in the EV-103 study, a combo of enfortumab and pembro in first line patients achieved a 73% ORR, but with a higher incidence of grade ≥3 TRAEs including lipase (17.8%), maculopapular rash, fatigue (11.1% each), and one treatment related death.