4566 Background: Zele is a highly selective Bicycle Drug Conjugate (BDC) targeting Nectin-4, a protein overexpressed in la/mUC. There remains an unmet need in la/mUC for safer and more tolerable treatments. Here, we report an interim analysis (IA) for zele monotherapy dosage selection from the Phase 2/3 Duravelo-2 study (NCT06225596/BT8009-230) in previously treated pts with la/mUC. Methods: Adults with la/mUC were enrolled into 2 cohorts: previously untreated pts eligible for platinum-based chemotherapy (Cohort Co1) or pts with ≥1 prior systemic therapy (Co2). IA was conducted to determine the optimized dosage of zele + pembrolizomab (Co1) or zele monotherapy (Co2). Herein, we report IA results from Co2. Pts in Co2 were randomized 1:1 to zele 5 mg/m 2 on Days D1/8/15 or zele 6 mg/m 2 on D1/8 on a 21-D cycle. Dosage optimization included safety, efficacy, and pharmacokinetic data in pharmacometrics and utility score analyses to quantify benefit-risk. Results: IA was performed at 27 weeks of follow-up (N=30 each zele dose group). Median zele treatment (tx) duration was 4.80 months. Confirmed ORRs by BICR among randomized, dosed pts with measurable disease at baseline were 28% (8/29; 2 complete responses CR, 6 partial responses PR; 95% CI 12.7–47.2) and 30% (8/27; 3 CR, 5 PR; 95% CI 13.8–50.2) with zele 5 mg/m 2 and 6 mg/m 2 , respectively. Zele-related adverse events (AEs) were reported in 93% (47% Gr ≥3) of pts at 5 mg/m 2 and 93% (52% Gr ≥3) at 6 mg/m 2 . Gr ≥3 zele-related AEs for 6 mg/m 2 (≥5% pts) included neutrophil count decreased and neutropenia (10% each) and anemia, asthenia, and ALT increase (7% each). No zele-related Gr 5 AEs were reported at either dosage. Zele-related AEs of clinical interest (AECIs) for 6 mg/m 2 are summarized in the Table. Notably, no zele-related severe skin reactions of any Gr were reported at either dosage. Zele dose reductions and discontinuations due to zele-related AEs occurred in 24% and 0%, respectively, for 6 mg/m 2 . At Week 27, a third of pts remained on tx. Conclusions: Zele monotherapy at 5 mg/m 2 on D1/8/15 and 6 mg/m 2 on D1/8 on a 21-D cycle demonstrate encouraging response rates and safety profiles with the potential to differentiate from ADCs in previously treated pts. The 6 mg/m 2 D1/8 regimen provides a more favorable benefit-risk profile to meet the need for safer and more tolerable treatments, with enhanced potential for combinability and convenience, leading to fewer discontinuations. Clinical trial information: NCT06225596 . Zele-related AECIs in pts with previously treated la/mUC treated with zele 6 mg/m 2 on D1/8 (N=30). AECI, n (%) Any Grade Grade ≥3 Peripheral neuropathy 11 (38) 1 (3) Skin reactions 8 (28) 0 Eye disorders 3 (10) 0 Hyperglycemia 1 (3) 1 (3)
Petrylak et al. (Wed,) studied this question.