Neoadjuvant Intralesional Daromun (L19IL2/L19TNF) in Resectable Locally Advanced Melanoma: An Update on the Efficacy and Safety Results of the PIVOTAL Phase III Trial

Daromun (L19IL2/L19TNF) was investigated as a neoadjuvant, intralesional therapy for patients with fully resectable stage III melanoma in the phase III PIVOTAL trial (ClinicalTrials.gov identifier: NCT02938299 ). The trial enrolled 256 patients in the European Union and met its primary end point, demonstrating a statistically significant improvement in recurrence-free survival (RFS; hazard ratio, 0.59; P = .005) for daromun followed by surgery versus up-front surgery, at a median follow-up (FU) of 21 months from random assignment. PIVOTAL included two clinically distinct subgroups, namely, patients with de novo diagnosed metastatic disease (n = 34; 13%) and patients with recurrence(s) after surgery with or without radiotherapy and/or adjuvant systemic therapies (n = 222; 87%). Here, we present an updated analysis of the primary and secondary end points, including safety data, at a median FU of 36.8 months from random assignment (database cutoff: November 28, 2025), alongside new sensitivity analyses of event-free survival (EFS). The updated analysis confirms the clinically and statistically meaningful improvements in RFS and distant metastasis-free survival recorded in the neoadjuvant daromun versus control arm. The EFS post hoc analysis, conducted in both the overall population and the recurrent patient subgroups (with or without prior systemic therapies), provides consistency and robustness to the benefit of neoadjuvant daromun observed for the primary efficacy end point. No new safety signals of concern were recorded.