Zelenectide Pevedotin Shows Safety, Preliminary Efficacy in Advanced Solid Tumors

Zelenectide pevedotin (BT8009) demonstrated a well-tolerated safety profile and promising antitumor activity in patients with advanced solid tumors, primarily urothelial carcinoma, according to findings from the monotherapy dose-escalation portion of the Duravelo-1 phase 1/2 clinical trial (NCT04561362).¹

A total of 49 patients were enrolled in the trial. All patients experienced at least 1 adverse event (AE), and 94% of patients experienced a treatment-related AE.

The most common treatment-related AEs of any grade were nausea (49%), fatigue (39%), diarrhea (29%), and decreased appetite (29%). Grade ≥ 3 AEs occurred in 39% of patients, with neutropenia being the most common (16%). In 63% of patients, AEs led to dose modifications. This primarily consisted of interruptions rather than reductions. Only 2 patients (4%) discontinued treatment due to AEs (idiopathic intracranial hypertension and sepsis). No fatal (grade 5) AEs were reported.

Efficacy Findings of the Duravelo-1 Trial

Zelenectide pevedotin demonstrated promising preliminary antitumor activity in a heavily pretreated population. The median duration of response was 11.1 months in the efficacy-evaluable patient population (n = 42), and 13.1 months in patients with urothelial carcinoma.

Key efficacy results in the efficacy-evaluable population (n=42) showed an overall objective response rate (ORR) of 24% and a clinical benefit rate (CBR) of 48%. Efficacy was particularly notable in patients with urothelial carcinoma (n=21), who achieved an ORR of 38% and a CBR of 57%, with a median progression-free survival (PFS) of 7.4 months, compared with a PFS of 3.6 months in the efficacy-evaluable population.

The relationship between Nectin-4 expression levels and response was not straightforward. Among patients with urothelial carcinoma, the ORR was 38% for those with medium-high expression and 33% for those with low/negative expression, suggesting the relationship requires further evaluation in larger cohorts.

Pharmacokinetics Profile

The pharmacokinetics profile supports zelenectide pevedotin’s safety observations. The drug exhibited a very short half-life (t½ of 0.42– 0.91 hours) resulting in extensive elimination within hours of administration.

Time to maximum effect occurred at approximately 2-3 hours post-infusion, with a t½ of 37 hours–50 hours. There was limited or no accumulation of monomethyl auristatin E (MMAE) in the plasma with repeat dosing.

Exposures of both zelenectide pevedotin and MMAE increased in a generally dose-proportional manner.

Study Design and Patient Characteristics

The Duravelo-1 study is a phase 1/2 open-label, multicenter trial. The primary objectives of the trial were to evaluate the safety and tolerability of zelenectide pevedotin and to determine the maximum tolerated dose and/or phase 2 dose(s). The secondary objectives were to assess the preliminary antitumor activity and characterize zelenectide pevedotin’s pharmacokinetic profile.

Zelenectide pevedotin binds to Nectin-4-expressing tumor cells, leading to the release of MMAE into the tumor microenvironment. A key feature is that this process does not necessarily require internalization into the cancer cell, which may prevent the development of certain resistance pathways.

Patients received intravenous infusions across several dosing schedules:

• Once weekly (28-day cycle): 2.5, 5.0, or 7.5 mg/m²
• Once every 2 weeks (28-day cycle): 7.5 or 10.0 mg/m²
• Days 1 and 8 (21-day cycle): 7.5 mg/m²

Two recommended phase 2 doses were identified: 5.0 mg/m² once weekly and 7.5 mg/m² on days 1 and 8 of a 21-day cycle.

The median age of the overall patients (n = 49) was 66 years (range, 35–83), and the median age of patients with urothelial carcinoma (n = 25) was 68 years (range, 47–81). The median prior lines of therapy in the total patient population and patients with urothelial carcinoma was 3 (range, 1–15 vs 1–7).

Patients with a medium-high Nectin-4 expression represented 59% (n = 29) of the total patient population, and 52% (n = 13) in patients with urothelial carcinoma.

All patients with urothelial carcinoma had previously received both platinum-based therapy and a checkpoint inhibitor. None had prior received enfortumab vedotin (Padcev).

In September, the FDA granted fast track designation to the antibody-drug conjugate CRB-701 for the treatment of recurrent or metastatic head and neck squamous cell carcinoma. CRB-701 targets Nectin-4. This designation marked Nectin-4 as an established therapeutic target for urothelial carcinoma. In 2021, the FDA approved enfortumab vedotin, a Nectin-4 directed antibody, for the treatment of patients with locally advanced or metastatic urothelial carcinoma.

“Zelenectide pevedotin represents a promising treatment option in the therapeutic pathway for this patient population and a potentially well-suited partner for combination therapies in earlier lines of treatment,” concluded Baldini et al, authors of the study. “The results presented herein are promising but must be validated in future planned prospective studies.”

A new phase 2/3 randomized study (NCT06225596) is enrolling patients to assess zelenectide pevedotin as both a monotherapy and in combination with pembrolizumab (Keytruda) vs chemotherapy in patients with locally advanced/metastatic urothelial carcinoma.

REFERENCE

1. Baldini C, Verlingue L, Goldschmidt V, et al. First-in-human, phase I/II dose escalation and expansion study of zelenectide pevedotin in patients with advanced solid tumors: Results from the monotherapy dose escalation. J Clin Oncol 0, JCO-25-00559.Published online November 6, 2025. Accessed November 10, 2025. doi:10.1200/JCO-25-00559.