Zelenectide pevedotin plus pembrolizumab shows promising anti-tumor activity in mUC

First-line zelenectide pevedotin (previously BT8009) plus pembrolizumab (Keytruda) demonstrated encouraging anti-tumor activity in cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma (la/mUC), according to preliminary data from an expansion cohort of the phase 1/2 Duravelo-1 trial (NCT04561362).¹

Safety data were consistent with the known profiles for each agent.

According to the authors, zelenectide pevedotin is a “highly selective Bicycle Toxin Conjugate targeting Nectin-4 and conjugated to MMAE.” Findings on the agent were recently presented at the 2025 American Society for Clinical Oncology Annual Meeting in Chicago, Illinois.

In total, the expansion cohort included 22 patients with la/mUC who received 5 mg/m2 of zelenectide on days 1, 8, and 15 plus 200 mg of pembrolizumab on day 1 of a 21-day cycle. The median age of participants was 77 years, and 46% of patients had an ECOG Performance Status of 2.

The median time on treatment was 22.9 weeks. At the time of data report, 12 patients remained on study treatment. Twenty patients were eligible for the efficacy analysis.

In these patients, the objective response rate (ORR) was 65% (95% CI, 40.8 to 84.6). This included 5 patients with a complete response (25%; 4 confirmed), 8 patients with a partial response (40%; 6 confirmed), and 5 patients with stable disease (25%). The disease control rate was 90%.

At a median follow-up of 7.1 months (range, 1 to 13.2), the median duration of response had not been reached.

Regarding safety, data were consistent with the known safety profiles for each agent.

The most common grade 3 or higher treatment-related adverse events (TRAEs) included increased ALT and neutropenia in 13.6% of patients each as well as diarrhea, asthenia, hypomagnesemia, and pneumonia in 9.1% of patients each. Treatment-related peripheral neuropathy occurred in 50% of patients, comprised of 27.3% grade 1, 13.6% grade 2, and 9.1% grade 3.

Serious TRAEs were reported in 9.1% of patients.

Additional TRAEs of special interest included skin reactions (4.5% Gr≥3), hyperglycemia (0.0% Gr≥3), and eye disorders (0.0% Gr≥3). According to the authors, “All cases of grade 3 TRAEs of clinical interest were reversible.”

No grade 4 or 5 TRAEs of special interest were reported, nor any treatment-related deaths.

The authors concluded, “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.”

Duravelo-2 trial

The combination of zelenectide pevedotin plus pembrolizumab in la/mUC is being further evaluated in the ongoing phase 2/3 Duravelo-2 trial (NCT06225596).² In total,the global, multicenter, randomized, open-label trial plans to enroll approximately 956 patients with la/mUC. Zelenectide pevedotin is being assessed as both a monotherapy and in combination with pembrolizumab.

The study will include 2 cohorts. Cohort 1 will include patients who have not received any prior systemic therapy for la/mUC and are eligible to receive platinum-based chemotherapy. Cohort 2 will enroll patients who have received at least 1 prior systemic agent for la/mUC.

The primary end points include progression-free survival in cohort 1 and ORR in cohort 2. Secondary end points in both cohorts include overall survival, duration of response, disease control rate, and safety.

Completion of the trial is expected in December 2030.

REFERENCES

1. Giannatempo P, Galsky MD, Duran I, et al. 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. J Clin Oncol. 2025;43(suppl 16):4567. doi:10.1200/JCO.2025.43.16_suppl.4567

2. Study BT8009-230 in participants with locally advanced or metastatic urothelial cancer (Duravelo-2). ClinicalTrials.gov. Last updated June 22, 2025. Accessed July 2, 2025. https://clinicaltrials.gov/study/NCT06225596