Identifying optimized dosage for zelenectide pevedotin in locally advanced/metastatic urothelial carcinoma (la/mUC) using quantitative analyses.

Abstract

4567 Background: Zelenectide pevedotin (zele; BT8009) is a Bicycle Drug Conjugate (BDC) comprising a highly selective bicyclic peptide targeting Nectin-4 linked to the cytotoxin monomethyl auristatin E (MMAE) via a cleavable linker. Zele demonstrated preliminary antitumor activity and a generally tolerable safety profile in patients (pts) with la/mUC in the Phase 1/2 Duravelo-1 trial (NCT04561362) [Reig, 2024; Giannatempo, 2025]. Zele is being evaluated in a randomized Phase 2/3 study at 2 dosages, 5 mg/m 2 on Days (D)1/8/15 and 6 mg/m 2 on D1/8 of a 21-D cycle, each as monotherapy or combined with pembrolizumab (P) in pts with la/mUC (NCT06225596, Duravelo-2) [Loriot, 2025]. After 30 pts in each dosage arm had 27 weeks follow-up (N=120 total), an interim analysis was conducted to select the optimized dosage for further development. Methods: Pharmacometric (PMx) and utility score analyses were conducted to quantify the benefit-risk comprehensively. For the PMx analysis, all pharmacokinetic (PK), overall response rate [ORR, assessed by investigator (INV) and/or blinded independent central reviewer (BICR)], and adverse event (AE) data [zele-related and treatment-emergent (TE) Gr ≥3 AE, Gr ≥3 neutropenia, Gr ≥2 gastrointestinal disorders, Gr ≥2 peripheral neuropathy, any Gr skin reactions, dose modifications] from Duravelo-1 and -2 were pooled and analyzed using population PK (PopPK) and exposure-response (ORR, AE) modeling. Simulations for ORR and AE probabilities were then generated for comparing dosages with balance of relevant pt characteristics. The utility score analysis was mainly based on Gr ≥3 zele-related TEAEs and ORR by BICR regardless of confirmation in Duravelo-2, with sensitivity analyses based on alternative safety and/or efficacy endpoints (TEAEs, confirmed ORR by BICR). Results: The datasets for PopPK, ORR, and AE analysis included 434, 203 (203 INV assessed, 114 BICR assessed), and 394 pts, respectively, mostly treated at the 5 or 6 mg/m 2 dosages. Modeling of ORR did not detect a significant difference between the dosages studied. ORR was impacted positively by P combination, negatively by baseline tumor size, but not by the assessor (INV vs BICR). The AE rates were significantly correlated with exposures of zele and/or MMAE. Between 5 mg/m 2 D1/8/15 and 6 mg/m 2 D1/8, ORR did not differentiate them; safety favored 6 mg/m 2 D1/8 as its predicted AE probabilities were mostly lower. For AEs favoring 6 mg/m 2 D1/8, predicted probabilities were lower by 0.1% – 15.5% as monotherapy and by 0.1% – 19.1% in combination. The utility score analysis favored 6 mg/m 2 D1/8 consistently for zele combined with P and remained neutral between the dosages for monotherapy. Conclusions: 6 mg/m 2 D1/8 was identified as the optimized zele dosage for monotherapy and in combination with P based on the overall benefit-risk informed by the comprehensive quantitative analyses. Clinical trial information: NCT06225596 .