Zelenectide pevedotin (BT8009) monotherapy in previously treated metastatic urothelial carcinoma (mUC): Update on Duravelo-1.

Abstract

4563 Background: Zelenectide pevedotin (zele, formerly BT8009) is a highly selective Bicycle Drug Conjugate (BDC) targeting Nectin-4, a protein that is overexpressed in mUC and other cancers. 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. Here, we present updated safety and efficacy results of zele monotherapy in enfortumab vedotin (EV)–naïve patients with mUC from the Phase 1/2 Duravelo-1 study (NCT04561362). Methods: Eligible patients had previously treated unresectable mUC, creatinine clearance ≥50 mL/min, prior anti-PD-1/PD-L1 exposure, had progressed on or were ineligible for platinum-based chemotherapy, and had not received EV. All patients treated with the recommended Phase 2 dose of zele monotherapy 5 mg/m 2 once weekly across the dose-escalation and dose expansion phases were included in the analysis. Results: As of July 1, 2025, 53 patients with a median age of 63 years (range 25–84) and a median of 2 (range 1–7) prior lines of therapy were included. Median time on treatment was 4.4 months and maximum duration was 24.9 months, and median follow-up time was 9.9 months (range 0.5–43.9). Median progression-free survival was 5.4 months (95% CI 2.3–7.1). Confirmed objective response rate (cORR) in all patients was 32% (n=17/53), and disease control rate (DCR) was 66% (n=35/53), including 2 complete responses and 15 partial responses (PR); 3 additional patients had unconfirmed PR. Of the 13 patients who had received prior taxane therapy, cORR was 31% and DCR was 69%, including 4 PR and 5 with stable disease. Median duration of response was 10.0 months (95% CI 5.3–16.6) among patients with confirmed responses (n=17). Nausea (36%), asthenia (28%), and diarrhea (28%) were the most common treatment-related adverse events (TRAEs). TRAEs of Grade ≥3 occurred in 25% of patients and serious TRAEs occurred in 9%. TRAEs led to treatment withdrawal in 4% of patients. Grade 3 TRAEs of clinical interest (AECIs) were single reports of skin reaction and hyperglycemia (n=1 each, 2%). Grade 1–2 treatment-related AECIs of peripheral neuropathy were reported in 47% of patients and were all sensory-based, with 1 patient requiring treatment withdrawal. Grade 1–2 treatment-related skin reaction and eye disorder AECIs were reported in 15% and 13%, respectively. Conclusions: Zele monotherapy at 5 mg/m 2 once weekly continues to demonstrate an encouraging efficacy profile and a promising safety profile with the potential to differentiate from ADCs in EV-naïve patients with mUC. Antitumor activity was preserved in patients with exposure to taxanes. Treatment withdrawal resulting from zele-related AECIs was uncommon. A Phase 2/3 study of zele in patients with locally advanced or mUC (NCT06225596; Duravelo-2) is currently active. Clinical trial information: NCT04561362 .