Initial results from EXCEED, a phase 1 study of LY4101174, an antibody-drug conjugate targeting Nectin-4, in participants with advanced or metastatic urothelial carcinoma.

Abstract

4517 Background: Enfortumab vedotin plus pembrolizumab (EVP) is the current first-line standard of care for locally advanced / metastatic urothelial carcinoma (mUC). However, subsequent treatment options are limited, representing an urgent and growing unmet need. Preclinical data suggest that EV resistance may be payload mediated and consequently Nectin-4 remains a viable target for alternative therapies. LY4101174 is a next generation anti-Nectin-4 ADC comprising a humanized IgG1 antibody conjugated to the topoisomerase I inhibitor, exatecan, via a maleimide-ß-glucuronide poly-sarcosine linker and a homogeneous drug antibody ratio of 8. Here, we report the initial clinical data from the phase 1 dose escalation cohort of EXCEED (NCT06238479). Methods: Adults with locally advanced / mUC or other selected solid tumors were eligible. Participants (pts) must have received or were ineligible for available standard therapies, and have ECOG PS 0-1. Dose escalation utilized a Bayesian optimal interval design. Key endpoints were safety, PK, and antitumor activity of LY4101174 per RECIST v1.1. Results: As of 3 Dec 2025, 143 pts (86 mUC, 57 non-UC tumors) were treated across 6 dose levels (DLs) of LY4101174 (0.8-3.2 mg/kg Q2W or 2.4-4.0 mg/kg Q3W IV). Median age was 68 (range, 30-85), 60% ECOG PS 1. Median prior lines of therapy was 4 (range, 1-10), 92% of mUC pts had received prior EV (19% [15/79] had discontinued EV due to treatment-related toxicity). LY4101174 and total antibody exhibited mostly linear, dose-proportional PK up to 4.0 mg/kg, and up to 3.2 mg for exatecan. At 3.2 mg/kg Q2W, 3 of 6 pts experienced DLTs (neutropenia [grades 3 and 4], febrile neutropenia, and thrombocytopenia [both grade 3]) prompting a schedule change to 3.2 mg/kg Q3W for continued escalation. The most common treatment-emergent AEs (TEAEs) across Q3W DLs were anemia (71%), fatigue (55%), nausea (49%), neutropenia (36%), thrombocytopenia (31%), diarrhea (26%), vomiting (25%), and decreased appetite (23%). The most common grade ≥3 TEAEs were anemia (47%), neutropenia (29%), thrombocytopenia (21%), febrile neutropenia and leukopenia (10% each); prophylactic granulocyte colony stimulating factor (G-CSF) was required at DL 4.0 mg/kg Q3W. TRAEs led to dose reduction in 24% and discontinuation in 2%. In the 66 efficacy evaluable mUC pts treated with 2.4-4.0 mg/kg Q3W (92% [61/66] EV-pretreated), ORR was 18% (12/66) and DCR was 70% (46/66) with 12 PR (8 confirmed, 4 ongoing and pending confirmation) and 34 SD. Median follow-up was 4.9 months (95% CI, 1.4-NE). Conclusions: LY4101174 has demonstrated clinical activity at Q3W dose levels, including in EV pre-treated mUC, suggesting Nectin-4 remains an important therapeutic target. Dose and duration on treatment were mainly limited by grade ≥3 hematologic toxicity requiring the use of prophylactic G-CSF. Clinical trial information: NCT06238479 .