Zelenectide Pevedotin Displays Antitumor Activity in Advanced Solid Tumors

Treatment with zelenectide pevedotin, a Nectin-4–targeting bicycle toxin conjugate (BTC), displayed antitumor activity among patients with advanced solid tumors, particularly advanced urothelial carcinoma, according to findings from the dose-expansion and dose-escalation phase 1/2 Duravelo-1 trial (NCT04561362) published in the Journal of Clinical Oncology.

The primary efficacy analysis included 42 evaluable patients across all enrolled tumor types, demonstrating a confirmed objective response rate (ORR) of 24% (n = 10; 95% CI, 12% to 40%). Among these responders, 1 patient achieved a complete response, and 9 patients achieved a partial response. The clinical benefit rate (CBR) for the overall evaluable population was 48% (n = 20). In the subset of evaluable patients with urothelial carcinoma (n = 21), the confirmed ORR reached 38% (n = 8; 95% CI, 18% to 62%), and the CBR was 57% (n = 12).

For the overall population, the median duration of response (DOR) was 11.1 months (range, 4.5 to 21.6) after a median follow-up of 7.4 months (range, 0.4-31.8). In the urothelial carcinoma population, the median DOR was 13.1 months (range, 4.5-21.6) after a median follow-up of 12.4 months (range, 0.5-28.6).

The median progression-free survival (PFS) for all patients was 3.6 months (95% CI, 1.8 to 6.5), while patients with urothelial carcinoma experienced a median PFS of 7.4 months (95% CI, 1.8 to 12.4). Investigators observed that antitumor activity was most pronounced in patients with medium-to-high Nectin-4 expression, where the ORR was 25% (n = 7/28) for the total cohort and 38% (n = 5/13) for those with urothelial carcinoma.

“[Z]elenectide pevedotin is a novel agent with a generally well-tolerated safety profile that has demonstrated preliminary efficacy, especially in patients with [urothelial carcinoma] at the [recommended phase 2 doses (RP2Ds)] of 5.0 mg/m² once weekly and 7.5 mg/m² on days 1 and 8 of a 21-day cycle,” Capucine Baldini, MD, medical oncologist in the Drug Development Department at Gustave Roussy Villejuif, wrote in the publication with study coinvestigators. “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. The results presented herein are promising but must be validated in future planned prospective studies.”

The open-label, multicenter phase 1/2 study was designed to investigate zelenectide pevedotin as a monotherapy or in combination with pembrolizumab (Keytruda). The monotherapy dose-escalation phase utilized a 3+3 design to evaluate various intravenous dosing schedules. Patients received the study drug at 2.5, 5.0, or 7.5 mg/m² once weekly for each 28-day cycle; 7.5 or 10.0 mg/m² once every 2 weeks for each 28-day cycle; or 7.5 mg/m² on days 1 and 8 for each 21-day cycle.

The maximum tolerated dose (MTD) was determined to be 7.5 mg/m² once every 2 weeks. Based on the preliminary efficacy and safety data, the investigators selected 2 RP2Ds: 5.0 mg/m² once weekly on a 28-day cycle and 7.5 mg/m² on days 1 and 8 of a 21-day cycle.

The study enrolled a total of 49 patients between September 2020 and August 2022. The median age of the patients was 66 years (range, 35 to 83), and 59% of the cohort was male. Urothelial carcinoma was the most frequent tumor type, representing 51% (n = 25) of the patients, followed by breast cancer (14%), pancreatic cancer (12%), and lung cancer (12%).

The population had a median of 3 previous lines of systemic therapy (range, 1 to 15). All patients with urothelial carcinoma had previously received both platinum-based chemotherapy and a checkpoint inhibitor. Furthermore, 59% of the total population (n = 29) had medium-high Nectin-4 expression at baseline. In terms of previous targeted therapies, 1 patient with urothelial carcinoma had received sacituzumab govitecan-hziy (Trodelvy), and none had received prior enfortumab vedotin-ejfv (Padcev) before entering the trial.

The primary end points for this portion of the study included safety and tolerability, as well as the determination of the MTD and the RP2Ds. Secondary end points consisted of ORR, CBR, DOR, and PFS according to RECIST v1.1 criteria, along with pharmacokinetic characterization of the agent and its payload, monomethyl auristatin E.

Treatment-related adverse effects (TRAEs) occurred in 94% (n = 46) of all patients, with grade 3 or higher TRAEs reported in 39% (n = 19). The most common AEs of any grade were nausea (49%), fatigue (39%), diarrhea (29%), and decreased appetite (29%). The high rate of nausea was attributed to a lack of prophylactic antiemetics during the initial dose-limiting toxicity (DLT) evaluation period.

TRAEs of clinical interest included peripheral neuropathy in 33% of all patients (grade 3/4, 2%), neutropenia in 22% (grade 3/4, 16%), and skin reactions in 22% (grade 3/4, 2%). Hyperglycemia or new-onset diabetes mellitus occurred in 20% of patients, and ocular disorders were reported in 10%.

Dose modifications were required for 63% of patients, primarily due to neutropenia (16%) and fatigue (12%). Three patients experienced DLTs, which included grade 3 asthenia, grade 3 fatigue with febrile neutropenia and decreased appetite, and grade 4 sepsis. No grade 5 TRAEs were observed during the study.

Reference

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 monotherapy dose escalation. J Clin Oncol. 2025;43(35):3728-3738. doi:10.1200/JCO-25-00559