LY4101174 (Nectin-4–targeted exatecan ADC) shows 18% ORR post-enfortumab vedotin in mUC—but with heavy hematologic toxicity

LY4101174 is a next-generation anti–Nectin-4 antibody-drug conjugate delivering the topoisomerase I inhibitor exatecan (DAR 8; maleimide–β-glucuronide poly-sarcosine linker) being evaluated in the EXCEED Phase 1 dose-escalation study (NCT06238479) in heavily pretreated locally advanced/metastatic urothelial carcinoma and selected solid tumors. As of December 3, 2025, 143 patients were treated; among 66 efficacy-evaluable mUC patients receiving 2.4–4.0mg/kg Q3W (92% EV-pretreated; median 4 prior lines), ORR was 18% (12/66; 12 PRs) and DCR was 70% (46/66), with short median follow-up (4.9 months). Toxicity was dominated by cytopenias (grade≥3 anemia 47%, neutropenia 29%, thrombocytopenia 21%, febrile neutropenia 10%), including DLTs at 3.2mg/kg Q2W prompting a move to Q3W dosing; G-CSF prophylaxis was required at 4.0mg/kg Q3W, while TRAEs drove dose reductions in 24% and discontinuations in 2%—a tolerability profile that looks at least as myelosuppressive as other topo-I ADCs and contrasts with 1L EV+pembrolizumab efficacy benchmarks (EV-302 ORR ~68%, mPFS 12.5 months), though that’s a very different (frontline) population.