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

PURPOSE Zelenectide pevedotin (BT8009) is a Bicycle Drug Conjugate comprising a highly selective Nectin-4–targeting Bicycle peptide, linked to monomethyl auristatin E. We report monotherapy dose-escalation results from Duravelo-1 (Phase I/II; ClinicalTrials.gov identifier: NCT04561362 ). METHODS Adults with advanced/metastatic solid tumors associated with Nectin-4 expression received zelenectide pevedotin intravenously at 2.5, 5.0, or 7.5 mg/m 2 once weekly on a 28-day cycle; or 7.5 mg/m 2 on days 1 and 8 of a 21-day cycle; or 7.5 or 10.0 mg/m 2 once every 2 weeks on a 28-day cycle. Primary objectives were to evaluate safety and tolerability; antitumor activity and pharmacokinetic characterization were secondary objectives. RESULTS Forty-nine patients, most with urothelial carcinoma (UC; 25 of 49), received three previous lines of therapy (median). Common treatment-related adverse events (TRAEs) included nausea (49% [grade 3/4 2%]), likely because of a lack of prophylactic antiemetics during the dose-limiting toxicity period, and fatigue (39% [grade 3/4 6%]). The most common TRAEs of clinical interest were peripheral neuropathy (33% [grade 3/4 2%]), neutropenia (22% [grade 3/4 16%]), and skin reactions (22% [grade 3/4 2%]). The maximum tolerated dose was 7.5 mg/m 2 once every 2 weeks; the recommended phase 2 doses were 5.0 mg/m 2 once weekly and 7.5 mg/m 2 on days 1 and 8 of a 21-day cycle. Across doses (efficacy-evaluable; all tumor types), the objective response rate (ORR) was 24% and the clinical benefit rate (CBR) was 48% (n = 10 of 42; 95% CI, 12.1 to 39.5); the ORR was 38% and the CBR was 57% for patients with UC (n = 8 of 21; 95% CI, 18.1 to 61.6). The median duration of response and the median follow-up for all patients were 11.1 and 7.4 months, respectively. CONCLUSION Zelenectide pevedotin monotherapy demonstrated a generally well-tolerated safety profile and preliminary efficacy, particularly in UC, supporting investigation of UC and non-UC populations in the expansion phase.