Neoadjuvant Intralesional Daromun (L19IL2/L19TNF) in Resectable Locally Advanced Melanoma: an Update on the Primary Outcome and Sensitivity Analyses (EFS) from the PIVOTAL Phase 3 Trial.

LBA9517 Background: PIVOTAL (NCT02938299) is an open-label, randomized, multicenter, phase 3 trial evaluating daromun as a neoadjuvant intralesional (IT) therapy for resectable, locally advanced stage III melanoma. The trial enrolled 256 efficacy-evaluable patients (pts) in the EU and met its primary endpoint, demonstrating a statistically significant improvement in recurrence-free survival (RFS; HR = 0.59; p = 0.005) for daromun versus upfront surgery, at a median follow-up (FU) of 21 months from randomization (Kähler et al, Ann Onc 2025, 36, 1166). Methods: Pts with skin and/or lymph node metastatic melanoma amenable to complete surgical resection were randomized (1:1) to receive 4 weekly IT injections of daromun (13 Mio IU of L19IL2 and 400 μg of L19TNF) followed by surgery or upfront surgery alone. Prior surgery, radiotherapy (RT) and/or systemic therapies (ST) were permitted, as well as any approved adjuvant treatment post-surgery.The primary endpoint was RFS, the secondary endpoints included DMFS, OS and safety. An event-free survival (EFS) sensitivity analysis was conducted, considering progression to unresectable melanoma before surgery, recurrence of the disease, or death due to melanoma or treatment as events. Results: An updated primary outcome analysis at a median FU of over 36 months from randomization (database cut-off Nov. 29, 2025) confirmed a clinically relevant improvement in RFS (HR = 0.60; p = 0.003) for daromun versus upfront surgery. The EFS sensitivity analysis carried out in the overall population was consistent with the RFS results (HR = 0.66; 95% CI = 0.47-0.92).The PIVOTAL trial included two clinically distinct subgroups: pts with newly diagnosed disease (n = 32; 12%) and pts with recurrence(s) after surgery and/or systemic (neo)adjuvant treatment (n = 224; 88%). Among the recurrent cohort, 86 pts (38.3%) had received and failed previous ST, while 138 pts (61.6%) had only received surgery/RT. Sensitivity EFS analyses were also performed in i) the recurrent cohort (HR = 0.59; 95% CI = 0.41-0.85), ii) the subgroup of pts in the recurrent cohort who had only received previous surgeries and/or RT (HR = 0.55; 95% CI = 0.34-0.89), and iii) the pts subgroup in the recurrent cohort who received prior ST (HR = 0.63; 95% CI = 0.36-1.08 ). The rate and type of treatment-related adverse events at a longer FU were consistent with previous reports, and no new safety risks were identified. Conclusions: With longer FU the highly significant reduction in the risk of recurrence or death with neoadjuvant daromun in pts with locally advanced stage III melanoma is confirmed. The sensitivity EFS analyses provide consistent, confirmatory evidence of daromun’s efficacy across the entire trial population and, more importantly, in the subgroup of pts with recurrent disease, regardless of any prior ST. No new safety signals were reported. Clinical trial information: NCT02938299 .