PS5-09-23: A Phase 2 study of zelenectide pevedotin, a Bicycle Drug Conjugate, in patients with NECTIN4 amplified advanced breast cancer (Duravelo-3)

Abstract Background: Zelenectide pevedotin (zele; formerly BT8009) is a Bicycle® Drug Conjugate (BDC®) comprised of a highly selective bicyclic peptide targeting Nectin-4 linked to monomethyl auristatin E (MMAE) via a cleavable linker. With low molecular weight and a short plasma half-life, zele has the potential to rapidly penetrate solid tumours with minimal exposure to healthy tissue. The ongoing Phase 1/2 Duravelo-1 trial (NCT04561362; BT8009-100) has shown preliminary antitumour activity and a manageable safety profile of zele monotherapy in patients (pts) with breast cancer (BC). This open-label, multicentre, Phase 2 Duravelo-3 study (NCT06840483; BT8009-201) aims to further evaluate the efficacy and safety of zele monotherapy in pts with recurrent, unresectable, or metastatic NECTIN4 amplified (amp) BC. Trial design: The trial will enrol pts into 2 cohorts: pts with hormone receptor (HR)+/human epidermal growth factor receptor 2 (HER2)– BC who have received ≤3 prior lines of nonendocrine-based therapy in the metastatic setting (Cohort A; n≈33) and pts with triple-negative BC who have received 1–3 prior lines of systemic therapy in the metastatic setting (Cohort B; n≈33). NECTIN4 amp is defined as a NECTIN4:CEN1 ratio ≥2.0 or NECTIN4 copy number ≥6, per fluorescence in situ hybridization. All pts must have ECOG performance status 0–1 and adequate organ function. Pts previously treated with MMAE will be excluded. All pts will receive zele 6 mg/m2 IV on Days 1 and 8 of a 21-day cycle. The primary endpoint is objective response rate. Secondary endpoints are duration of response, clinical benefit rate, disease control rate, progression-free survival, overall survival, time to progression, and incidence of adverse events. Efficacy endpoints will be investigator-assessed per RECIST v1.1. Exploratory endpoints will include assessment of baseline tumour biomarkers, including Nectin-4 expression and surrogates of NECTIN4 amp, and peripheral blood biomarkers such as circulating Nectin-4 protein and tumour DNA. Pharmacokinetics, correlation of efficacy and safety with biomarkers of NECTIN4 amp, and measurement of antidrug antibody are additional exploratory endpoints. This study is actively recruiting. Citation Format: P. A. Kaufman, P. Aftimos, J. Cortes, G. Curigliano, F. Dalenc, M. Danso, K. Jhaveri, M. Rimawi, C. Saura, P. Savas, P. Schmid, J. Ricker, K. Josephs, C. Xu, E. Hamilton. A Phase 2 study of zelenectide pevedotin, a Bicycle Drug Conjugate, in patients with NECTIN4 amplified advanced breast cancer (Duravelo-3) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-09-23.