Phase 1/2 Duravelo-1 study: Preliminary results of nectin-4–targeting zelenectide pevedotin (BT8009) plus pembrolizumab in previously untreated, cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer.

4567 Background: Effective and tolerable therapies for patients (pts) with locally advanced or metastatic urothelial cancer (la/mUC) in the first-line setting are needed. Zelenectide pevedotin (zele, previously BT8009) is a highly selective Bicycle Toxin Conjugate (BTC) targeting Nectin-4 and conjugated to MMAE, and has shown an objective response rate (ORR) of 45% and a generally tolerable safety profile as monotherapy in previously treated, enfortumab vedotin-naïve pts with mUC in the ongoing Phase 1/2 study (NCT04561362, Duravelo-1; Reig et al., 2024). Here, we present preliminary data from expansion Cohort B7 of Duravelo-1, investigating zele + pembrolizumab (pembro) in pts with previously untreated, cisplatin-ineligible, la/mUC. Methods: Pts who were cisplatin-ineligible by Galsky criteria (Galsky et al., 2011) received zele 5 mg/m 2 on D1, D8, D15 plus pembro 200 mg D1, every 21 days. The primary endpoint was ORR as assessed by investigator per RECIST v1.1. Secondary endpoints included safety and disease control rate (DCR). Treatment-related adverse events (TRAEs) were determined for all pts who received at least one dose of study drugs. Results: As of 3 Jan 2025, 22 pts were enrolled from Nov 2023 to Jul 2024 with a median time on treatment of 22.9 weeks and 12 pts still receiving study treatment. Median age was 77 years; 46% of pts had an ECOG performance status (PS) of 2; 55% with CrCl < 60 mL/min. With 20 efficacy evaluable pts, the ORR is 65.0% (95% CI, 40.8, 84.6), including 5 CRs (25.0%; 4 confirmed), 8 PRs (40.0%; 6 confirmed) and 5 SD (25.0%). Median follow-up was 7.1 mo (range 1.0 – 13.2) and median duration of response was not reached. DCR is 90.0%. The most common grade (Gr) ≥3 TRAEs included ALT increased and neutropenia (13.6% each), and diarrhea, asthenia, hypomagnesemia, and pneumonia (9.1% each). Serious TRAEs related to zele or zele + pembro occurred in 9.1%. Treatment-related peripheral neuropathy occurred in 50.0% (27.3% Gr1, 13.6% Gr2, 9.1% Gr3). Other TRAEs of clinical interest included skin reactions (4.5% Gr≥3), hyperglycemia (0.0% Gr≥3), and eye disorders (0.0% Gr≥3). All cases of grade 3 TRAEs of clinical interest were reversible. There were no grade 4/5 TRAEs of clinical interest and no treatment related deaths. Conclusions: Zelenectide pevedotin + pembro shows promising anti-tumor activity as a first-line treatment in a cohort of cisplatin-ineligible pts with la/mUC including a large proportion of pts with PS = 2. The combination of zele + pembro was generally tolerable and broadly consistent with the existing safety profiles of each respective agent. No new safety signals were observed with the combination. Zele + pembro combination therapy is being investigated in previously untreated la/mUC pts in the ongoing Phase 2/3 Duravelo-2 study (NCT06225596). Clinical trial information: NCT04561362 .