Zelenectide Pevedotin Shows Promise in Urothelial Carcinoma Treatment
核心洞察
Zelenectide pevedotin, a novel bicycle toxin conjugate, targets Nectin-4 (搜索) and is being evaluated for metastatic urothelial carcinoma (搜索).
Early data from the Duravelo-1 trial show a 45% objective response rate in patients who had not received enfortumab vedotin.
The ongoing Duravelo-2 trial is assessing zelenectide pevedotin as monotherapy and in combination with pembrolizumab.
Zelenectide pevedotin (formerly BT8009), a first-in-class bicycle toxin conjugate (BTC), is under investigation as a potential treatment for metastatic urothelial carcinoma (搜索). The agent targets Nectin-4 (搜索), similar to the antibody-drug conjugate enfortumab vedotin, but utilizes a novel small molecule approach. Early data from the phase 1/2 Duravelo-1 trial (NCT04561362) have shown promising efficacy and tolerability in patients who had not previously received enfortumab vedotin. The ongoing phase 2/3 Duravelo-2 trial (NCT06225596) is further evaluating zelenectide pevedotin as a monotherapy and in combination with pembrolizumab.
Duravelo-1 Trial Results
In the Duravelo-1 trial, efficacy-evaluable patients (n = 38) with recurrent, unresectable metastatic urothelial carcinoma (搜索) who received zelenectide pevedotin at 5 mg/m2 weekly achieved an objective response rate (ORR) of 45%, with a median duration of response (DOR) of 11.1 months (95% CI, 3.9-not reached). One patient experienced a complete response, and 16 achieved partial responses. The clinical benefit rate was 61%. The median time on treatment was 16.1 weeks (range, 1.0-101.4).
Safety and Tolerability
The most common treatment-related adverse effects (TRAEs) observed in Duravelo-1 were nausea (33%), asthenia (22%), pyrexia (20%), fatigue (20%), and diarrhea (18%). Grade 3 or higher TRAEs occurred in 22% of patients, and grade 3 or higher treatment-emergent AEs (TEAEs) occurred in 53%. TEAEs led to dose interruption (53%), reduction (27%), and discontinuation (4%). No treatment-related deaths occurred. TRAEs of specific monitoring related to the therapy included peripheral neuropathy (36%), skin reactions (18%), and hyperglycemia/diabetes mellitus (7%).
Novel Mechanism of Action
BTCs like zelenectide pevedotin differ from antibody-drug conjugates (ADCs) due to their pharmacokinetic properties, which are more akin to small molecules. Bicycles are chemically synthesized molecules that are significantly smaller than antibodies, allowing for optimization of affinity, stability, and solubility. Zelenectide pevedotin has a molecular weight of 4.2 kDa and comprises a nectin-4 (搜索)-targeted bicyclic peptide linked to the cytotoxin MMAE.
Duravelo-2 Trial Design
The Duravelo-2 trial is enrolling adult patients with locally advanced or metastatic urothelial carcinoma (搜索). Cohort 1 includes patients with previously untreated disease and is comprised of three arms: zelenectide pevedotin plus pembrolizumab, zelenectide pevedotin plus pembrolizumab with a different dosing schedule and gemcitabine plus cisplatin or carboplatin. Cohort 2 includes patients with previously treated disease and is comprised of three arms: zelenectide pevedotin, zelenectide pevedotin with a different dosing schedule and zelenectide pevedotin plus pembrolizumab.
Expert Commentary
Terence W. Friedlander, MD, chief of Hematology-Oncology at Zuckerberg San Francisco General, UCSF, noted that the BTC molecule may penetrate the tumor microenvironment better and be less persistent in circulation, potentially leading to reduced toxicity. Srikala Sridhar, MD, MSc, FRCPC, a clinician investigator at Princess Margaret Cancer Centre in Toronto, Canada, highlighted that the Duravelo-2 trial will provide crucial information about dosing and efficacy of this new bicycle toxin conjugate.