4564 Background: Zelenectide pevedotin (zele, formerly BT8009) is a highly selective Bicycle Drug Conjugate (BDC) targeting Nectin-4 and conjugated to MMAE. Zele has a lower molecular weight (4.2 kDa) and a shorter plasma half-life (< 1 hour) than antibody drug conjugates (ADCs), with potential to rapidly penetrate solid tumors and minimize healthy tissue exposure. Preliminary results of zele + pembrolizumab (pembro) in previously untreated, cisplatin-ineligible locally advanced/metastatic urothelial carcinoma (la/mUC) patients (pts) (expansion cohort B7, NCT04561362; Duravelo-1), showed promising antitumor activity and a generally tolerable safety profile (Giannatempo et al., 2025). Here, we present updated results with extended follow-up and further efficacy data. Methods: Cisplatin-ineligible pts by Galsky criteria who had received no prior systemic anticancer treatment for la/mUC were eligible. Pts received IV zele 5 mg/m 2 on Days (D)1/8/15 + pembro 200 mg on D1 of a 21-D cycle. The primary endpoint was confirmed objective response rate (cORR) per Investigator using RECIST v1.1. Secondary endpoints included safety and additional efficacy endpoints. Treatment-related adverse events (TRAEs) were determined for all pts who received at least one dose of study drugs. Results: As of July 1, 2025, 22 pts were treated: median age 77 years, 45% had ECOG performance status (PS) of 2, and 45% had creatinine clearance < 60 mL/min. Median duration of treatment for zele and pembro was 23.4 weeks (range 1.0–84.1) and 26.9 weeks (range 3.0–85.9), respectively. Median follow-up was 11.8 months (range 1.0–19.4); 14 pts remained on study at the time of data analysis. Median progression-free survival (mPFS) was 13.0 months (95% CI 3.8–NE). cORR was 50% (n = 11/22), and disease control rate was 82% (n = 18/22), including 5 complete responses and 6 partial responses (PR); 2 additional pts had unconfirmed PRs. Median duration of response (mDOR) was not mature. The most common Gr ≥3 TRAEs included ALT increase (18%) and neutropenia and asthenia (14% each). Of AEs of clinical interest (AECIs), treatment-related Gr 3 events included peripheral neuropathy (14%; leading to drug withdrawal in 2 pts) and skin reactions (9%; these events were not serious and did not lead to withdrawal); no Gr 4 or 5 treatment-related AECIs occurred. Conclusions: Treatment with zele + pembro has promising clinical benefits in pts with la/mUC and a historically poor prognosis with first-line therapies (~50% ECOG PS of 2), including: mPFS of 13.0 months, 50% cORR, and mDOR not reached. Additionally, zele + pembro demonstrates a safety profile with the potential to differentiate from ADC combinations, including no skin-related serious AEs. These data support the Phase 2/3 study of zele as monotherapy and in combination with pembro versus chemotherapy in pts with la/mUC (NCT06225596; Duravelo-2). Clinical trial information: NCT04561362 .
Duran et al. (Wed,) studied this question.