Zelenectide pevedotin (BT8009) Nectin-4–targeted BDC + pembrolizumab hits 50% cORR and 13.0-mo mPFS in 1L cisplatin-ineligible la/mUC

Zelenectide pevedotin (zele; BT8009) is a Nectin-4–targeted Bicycle Drug Conjugate delivering MMAE (small 4.2 kDa construct with short plasma half-life), combined here with PD-1 blockade (pembrolizumab) in Duravelo-1 expansion cohort B7 (Phase 1/2; NCT04561362) for previously untreated, cisplatin-ineligible locally advanced/metastatic urothelial carcinoma (n=22; median age 77; ECOG PS 2 in 45%). At a July 1, 2025 cutoff (median follow-up 11.8 months), confirmed ORR was 50% (11/22) with 5 CRs and DCR 82%, and mPFS was 13.0 months (95% CI 3.8–NE); responses are numerically above historical pembrolizumab monotherapy in this setting (KEYNOTE-052 ORR 29% with ~9%–10% CR), though cross-trial comparisons are shaky and DOR is not mature here. Grade ≥3 TRAEs included ALT increase (18%) and neutropenia/asthenia (14% each); treatment-related Grade 3 AECIs included peripheral neuropathy (14%, leading to withdrawal in 2 patients) and skin reactions (9%) with no Grade 4/5 treatment-related AECIs—contrasting with the established Nectin-4 ADC + pembrolizumab standard (enfortumab vedotin+pembrolizumab) that delivers high responses and OS/PFS benefit in Phase 3 but is clinically limited by rash and neuropathy risk. Take Home: If durability holds up, a “fast in/fast out” Nectin-4 MMAE conjugate that can pair with pembrolizumab while keeping skin toxicity manageable could be meaningful for frail 1L cisplatin-ineligible mUC patients—but with only 22 patients and immature DOR, Duravelo-2 will need to show it can compete with (or carve out a safer niche than) EV+pembro rather than just beat historical pembro-alone.