Interim analysis results from Duravelo-2: Zelenectide pevedotin (zele; BT8009) + pembrolizumab in patients (pts) with previously untreated locally advanced/metastatic urothelial carcinoma (la/mUC).

4516 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 + pembrolizumab (pembro) dosage selection from the Phase 2/3 Duravelo-2 study (NCT06225596/BT8009-230) in previously untreated (untx) pts with la/mUC. Methods: Adults with la/mUC were enrolled into 2 cohorts: previously untx pts eligible for platinum-based chemotherapy (Cohort [Co]1) or pts with ≥1 prior systemic therapy (Co2). IA was conducted to determine the optimized dosage of zele + pembro (Co1) or zele monotherapy (Co2). Herein, we report IA results from Co1. Pts in Co1 were randomized 1:1:1 to: zele 5 mg/m 2 on Days [D]1/8/15 + pembro 200 mg on D1; or zele 6 mg/m 2 on D1/8 + pembro 200 mg on D1; or gemcitabine + cisplatin/carboplatin ± avelumab on a 21-D cycle. Dosage optimization included safety, efficacy, and pharmacokinetic data in pharmacometric 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 6.21 months. Confirmed ORRs by BICR among randomized, dosed pts with measurable disease at baseline were 55% (16/29; 7 complete responses [CR], 9 partial responses [PR]; 95% CI 35.7–73.6) and 58% (15/26; 8 CR, 7 PR; 95% CI 36.9–76.6) with zele 5 mg/m 2 and 6 mg/m 2 , respectively. Zele-related adverse events (AEs) were reported in 97% (47% Gr ≥3) of pts at 5 mg/m 2 and 90% (40% Gr ≥3) at 6 mg/m 2 . Gr ≥3 zele-related AEs for 6 mg/m 2 (≥5% pts) included neutropenia (10%), neutrophil count decreased (7%), and anemia (7%). AEs related to pembro were reported in 80% (37% Gr ≥3) and 53% (13% Gr ≥3), respectively. 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 the 6 mg/m 2 dosage. Zele dose reductions and discontinuations due to zele-related AEs occurred in 20% and 3%, respectively, for 6 mg/m 2 . At Week 27, >50% of pts remained on tx. Conclusions: Zele at 5 mg/m 2 on D1/8/15 + pembro and 6 mg/m 2 on D1/8 + pembro on a 21-D cycle demonstrate encouraging response rates and safety profiles with the potential to differentiate from ADCs in previously untx pts. The 6 mg/m 2 D1/8 regimen demonstrated a more favorable benefit-risk profile to meet the need for safer and more tolerable treatments, with substantially reduced toxicity, better tolerability, improved potential for combinability, and enhanced convenience, leading to fewer discontinuations. Clinical trial information: NCT06225596 . Zele-related AECIs in pts with previously untx la/mUC treated with zele 6 mg/m 2 on D1/8 + pembro (N=30). AECI, n (%) Any Grade Grade ≥3 Peripheral neuropathy 11 (37) 1 (3) Skin reactions 5 (17) 0 Eye disorders 3 (10) 0 Hyperglycemia 0 0