Zelenectide pevedotin (BT8009), a novel Nectin-4-targeted bicycle drug conjugate, demonstrated a well-tolerated safety profile and promising antitumor activity in patients with advanced solid tumors, according to findings from the monotherapy dose-escalation portion of the Duravelo-1 phase 1/2 clinical trial.
The study enrolled 49 patients with advanced solid tumors, primarily urothelial carcinoma. All patients experienced at least one adverse event, with 94% experiencing treatment-related adverse events. The most common treatment-related adverse events of any grade were nausea (49%), fatigue (39%), diarrhea (29%), and decreased appetite (29%).
Safety Profile Shows Manageable Toxicity
Grade ≥3 adverse events occurred in 39% of patients, with neutropenia being the most common at 16%. Adverse events led to dose modifications in 63% of patients, primarily consisting of interruptions rather than reductions. Only 2 patients (4%) discontinued treatment due to adverse events—idiopathic intracranial hypertension and sepsis. Notably, no fatal (grade 5) adverse events were reported.
Encouraging Efficacy Results in Heavily Pretreated Population
Zelenectide pevedotin demonstrated promising preliminary antitumor activity in a heavily pretreated population. In the efficacy-evaluable patient population (n=42), the overall objective response rate was 24% with a clinical benefit rate of 48%. The median duration of response was 11.1 months.
Efficacy was particularly notable in patients with urothelial carcinoma (n=21), who achieved an overall response rate of 38% and a clinical benefit rate of 57%. These patients had a median progression-free survival of 7.4 months, compared with 3.6 months in the overall efficacy-evaluable population. The median duration of response in urothelial carcinoma patients was 13.1 months.
Nectin-4 Expression and Response Relationship
The relationship between Nectin-4 expression levels and response was not straightforward. Among patients with urothelial carcinoma, the overall response rate 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.
Unique Pharmacokinetic Profile
The pharmacokinetics profile supports zelenectide pevedotin's safety observations. The drug exhibited a very short half-life (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 half-life of 37-50 hours. There was limited or no accumulation of monomethyl auristatin E (MMAE) in the plasma with repeat dosing.
Study Design and Patient Characteristics
The Duravelo-1 study is a phase 1/2 open-label, multicenter trial evaluating the safety and tolerability of zelenectide pevedotin and determining the maximum tolerated dose and/or phase 2 dose(s). Patients received intravenous infusions across several dosing schedules, including once weekly, once every 2 weeks, and on days 1 and 8 of treatment cycles.
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 all patients was 66 years (range, 35–83), with urothelial carcinoma patients having a median age of 68 years (range, 47–81). The median prior lines of therapy was 3 in both the total patient population and patients with urothelial carcinoma. All patients with urothelial carcinoma had previously received both platinum-based therapy and a checkpoint inhibitor, though none had prior treatment with enfortumab vedotin.
Mechanism of Action and Future Directions
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.
"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 the study authors. "The results presented herein are promising but must be validated in future planned prospective studies."
A new phase 2/3 randomized study is now enrolling patients to assess zelenectide pevedotin as both a monotherapy and in combination with pembrolizumab versus chemotherapy in patients with locally advanced/metastatic urothelial carcinoma.
