LY4052031 (Nectin-4 topo1 ADC) delivers 48% ORR in metastatic urothelial cancer, including post-enfortumab activity

LY4052031 is a next-generation anti–Nectin-4 antibody-drug conjugate (ADC) with a cleavable linker and a novel topoisomerase I inhibitor payload (Camp98; DAR 8) evaluated in the NEXUS-01 Phase 1 dose-escalation study (NCT06465069) in previously treated or standard-therapy-ineligible locally advanced/metastatic urothelial carcinoma (mUC) and other solid tumors. As of Nov 25, 2025, 70 patients were treated (47 mUC), and in efficacy-evaluable mUC with CYP2D6 activity score (AS) ≥0.5 receiving 2.4–4.8mg/kg Q3W (n=21), ORR was 48% (1 CR, 9 PR) with DCR 81% and median DoR 7 months (95% CI, 2.7–NE); in prior enfortumab vedotin (EV)-treated mUC (n=15), ORR was 40% (DCR 80%), which sits above typical post-platinum/ICI benchmarks like sacituzumab govitecan’s ~27% ORR in TROPHY-U-01 (not an EV-post population, but a useful “late-line” yardstick). Safety was chemo-like and topo1-flavored (nausea 43%, alopecia 39%, fatigue 37%, mucositis 27%), with anemia the most common grade ≥3 TEAE (13%); a notable development was CYP2D6 low-AS association with increased DLTs at higher doses, prompting a protocol amendment requiring baseline CYP2D6 genotyping and dedicated dose-finding for low AS (<0.5).