(UroToday.com) The 2025 ASCO annual meeting featured a urothelial carcinoma trials in progress session and a presentation by Dr. Yohann Loriot discussing Duravelo-2, a phase 2/3 study of bicycle toxin conjugate zelenectide pevedotin (BT8009) targeting nectin-4 in patients with locally advanced or metastatic urothelial cancer. Bicycle drug conjugates area a new class of investigational anticancer agents that allow targeted delivery of cytotoxic payloads to tumors. They are synthetic, highly constrained, tumor-targeted bicyclic peptides linked to cytotoxic payloads and enable payload release into the tumor microenvironment. Additionally, they are small, with a molecular weight ~40 times less than antibody drug conjugates, are rapidly distributed, and have a short half life to limit exposure.
Nectin-4 is a cell adhesion molecule that is overexpressed in multiple cancers, including locally advanced and metastatic urothelial carcinoma.1 Zelenectide pevedotin (BT8009) is a bicycle toxin conjugate, comprising a highly selective bicyclic peptide targeting Nectin-4 linked to the cytotoxin MMAE via a cleavable linker. Zelenectide pevedotin has a low molecular weight and short plasma half-life, with the potential to rapidly penetrate solid tumors and reduce toxicity by minimizing exposure to normal tissue:
Results from the ongoing phase 1/2 clinical trial of zelenectide pevedotin (NCT04561362) indicate preliminary antitumor activity and a tolerable safety profile in patients with advanced malignancies, including urothelial carcinoma. This global, open label, phase 2/3 multicenter adaptive study aims to evaluate the safety and efficacy of zelenectide pevedotin as monotherapy, or combined with pembrolizumab, versus chemotherapy in patients with locally advanced or metastatic urothelial cancer.
The Duravelo-BT8009-230 trial will enroll n ≤956 adult patients in 2 cohorts. Cohort 1 will include n ≤641 previously untreated patients eligible for platinum-based chemotherapy. Cohort 2 will include n ≤315 patients with ≥1 prior systemic therapy, excluding enfortumab vedotin or other MMAE-based therapy. Patients must have locally advanced or metastatic urothelial cancer of the renal pelvis, ureter, bladder, or urethra, ECOG performance status ≤2 (Cohort 1) or ≤1 (Cohort 2), and adequate organ function. The full inclusion and exclusion criteria are as follows:
Cohort 1 will be randomized 1:1:1 to receive:
- Zelenectide pevedotin 5 mg/m2 on days 1, 8, and 15 + pembrolizumab 200 mg on day 1
- Zelenectide pevedotin 6 mg/m2 on day 1 and 8 + pembrolizumab 200 mg on day 1
- Chemotherapy: gemcitabine + cisplatin / carboplatin, followed by avelumab maintenance in appropriate patients
Cohort 2 will be randomized 1:1 to receive:
- Zelenectide pevedotin 5 mg/m2 on days 1, 8, and 15
- Zelenectide pevedotin 6 mg/m2 on days 1 and 8
Cycle lengths will be 21 days (28 days for avelumab). After 30 patients in each dose arm have 9-week follow up, an interim analysis will determine the optimal dose of zelenectide pevedotin + pembrolizumab (Cohort 1) or zelenectide pevedotin monotherapy (Cohort 2) to be used for the rest of the study:
An additional Cohort 2 arm, optimal dose of zelenectide pevedotin + pembrolizumab, will open after completion of the interim analysis. Treatment discontinuation criteria include planned completion of therapy, progressive disease, and intolerable toxicity. The primary endpoints are progression free survival (Cohort 1) and objective response rate (Cohort 2), assessed by blinded independent central review. Secondary endpoints are objective response rate (Cohort 1), progression free survival (Cohort 2), overall survival, duration of response, disease control rate, safety/tolerability, and health-related quality of life (Cohorts 1 and 2). Pharmacokinetics, incidence/titers of antidrug antibodies, and tumor/peripheral biomarkers are exploratory endpoints.
This study opened in the first quarter of 2024 and is actively recruiting.
Presented by: Yohann Loriot, MD, PhD, Gustave Roussy Institute, University Paris-Saclay, Villejuif, France
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the American Society of Clinical Oncology (ASCO) 2025 Annual Meeting, Chicago, IL, Fri, May 30 – Tues, Jun 3, 2025.
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