Capucine Baldini, Loïc Verlingue, Vincent Goldschmidt, Bernard Doger de Spéville, Julia Lostes, Antoîne Italiano, Sophie Cousin, Gerald S. Falchook, Andrea Necchi, Òscar Reig, Elisa Fontana, Louise Carter, Jordi Rodón, Jason R. Brown, Leslie R. DeMars, Kate Josephs, Amy L. Dickson, Cong Xu, Justin Bader, Carly Campbell, Rajiv Sharma, Meredith McKean
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.