Highlight
The phase III PIVOTAL trial confirms that neoadjuvant intralesional Daromun (L19IL2/L19TNF) significantly improves recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) in patients with fully resectable stage III melanoma compared to upfront surgery alone. Updated analysis at a median follow-up of 36.8 months strengthens the original findings with consistent event-free survival (EFS) benefits and no new safety concerns.
Study Background
Melanoma, particularly in stage III with regional lymph node involvement, poses substantial morbidity and mortality risks despite surgical resection. Recurrence rates remain high, prompting investigation into neoadjuvant therapies that might reduce residual microscopic disease and improve long-term outcomes. The biotherapeutic agent Daromun, a combination of immunocytokines L19IL2 and L19TNF, targets tumor vasculature and stimulates local immune responses when administered intralesionally. The PIVOTAL Phase III trial was designed to evaluate whether neoadjuvant Daromun, followed by surgery, could improve recurrence-free survival compared with the standard upfront surgery approach in patients with fully resectable stage III melanoma.
Study Design
The PIVOTAL trial (ClinicalTrials.gov: NCT02938299) is a randomized, controlled, Phase III study enrolling 256 patients with resectable stage III melanoma across European centers. Participants were randomized to receive either neoadjuvant intralesional Daromun followed by surgery or upfront surgery alone. Key endpoints included recurrence-free survival (primary), distant metastasis-free survival, event-free survival, and safety. The population consisted of two clinically distinct subgroups: patients with de novo metastatic disease (13%) and patients with recurrent melanoma after prior surgery, with or without radiotherapy and/or adjuvant systemic therapies (87%). The updated analysis presents long-term efficacy and safety outcomes at a median follow-up of 36.8 months (database cut-off November 28, 2025).
Key Findings
The updated analysis of the PIVOTAL trial confirms that neoadjuvant Daromun leads to a statistically and clinically meaningful improvement in recurrence-free survival compared to upfront surgery. The reported hazard ratio (HR) of 0.59 (P = .005) at a median follow-up of 21 months was maintained and reinforced at 36.8 months. This reduction in risk of recurrence is substantial, reflecting a 41% relative reduction in recurrence or death events.
In addition, the analysis demonstrates significant improvement in distant metastasis-free survival, indicating that neoadjuvant Daromun not only delays local relapse but potentially reduces systemic disease spread. Post hoc sensitivity analyses of event-free survival, encompassing both the overall study population and the recurrent subgroup (including those with prior systemic therapies), further validate the robustness of the treatment effect. These findings suggest that neoadjuvant Daromun is effective across clinically heterogeneous patient subsets.
Fig 2. (A) Kaplan-Meier estimates of RFS in the ITT population. Shown are estimates of RFS for 256 patients in the study (ITT population) stratified by treatment group. The median RFS was 6.5 months in the surgery arm and 23.8 months in the daromun + surgery arm. The 1-year, 2-year, and 3-year RFS rates were 38.6%, 25.5%, and 16.6% in the surgery arm and 63.5%, 49.2%, and 35.7% in the daromun + surgery arm, respectively. (B) Kaplan-Meier estimates of DMFS in the ITT population stratified by treatment group. The median DMFS was 14.0 months in the surgery arm and 38.7 months in the daromun + surgery arm. The 1-year, 2-year, and 3-year DMFS rates were 57.2%, 39.3%, and 28.7% in the surgery arm and 76.3%, 68.3%, and 51.2% in the daromun + surgery arm, respectively. (C) Kaplan-Meier estimates of EFS in the ITT population stratified by treatment group. The median EFS was 6.1 months in the surgery arm and 16.1 months in the daromun + surgery arm. The 1-year, 2-year, and 3-year EFS rates were 36.6%, 24.1%, and 15.7% in the surgery arm and 53.6%, 41.6%, and 30.1% in the daromun + surgery arm, respectively. The results were assessed by retrospective BICR. Tick marks show data censored at the time of last disease assessment. BICR, blinded independent central review; DMFS, distant metastasis-free survival; EFS, event-free survival; HR, hazard ratio; ITT, intention to-treat; RFS, recurrence-free survival.
The safety profile remains favorable with no new signals of concern emerging during extended follow-up. The intralesional route may confer localized immunological activation with limited systemic toxicity, supporting the therapeutic rationale for Daromun in this setting. Adverse events previously reported were manageable and consistent with the known mechanisms of action of the immunocytokine combination.
Expert Commentary
The updated PIVOTAL results provide compelling evidence that incorporating Daromun as a neoadjuvant immunotherapy in resectable stage III melanoma can significantly improve patient outcomes beyond surgery alone. The dual targeting of tumor-associated extracellular matrix and immune stimulation through IL-2 and TNF cytokines represents a promising strategy to enhance antitumor immunity and surgical efficacy. These data align with emerging paradigms favoring neoadjuvant immunotherapy in melanoma, where early immune priming may eradicate micrometastatic disease more effectively than adjuvant approaches.
Nevertheless, the study population mainly derived from European centers and included a majority of recurrent melanoma cases, which may affect generalizability to broader global populations or earlier stage disease. Future trials might explore combinations of Daromun with checkpoint inhibitors or other systemic agents to optimize immune response and long-term disease control. Longitudinal biomarker analyses could elucidate predictors of response and resistance mechanisms.
Conclusion
The PIVOTAL Phase III trial update firmly establishes neoadjuvant intralesional Daromun as an efficacious and safe approach to improve recurrence-free and distant metastasis-free survival in fully resectable stage III melanoma patients. These findings support the integration of Daromun into treatment protocols aiming at improved surgical outcomes and long-term disease control. Further research is warranted to explore combination regimens and to characterize patient subgroups that derive maximal benefit.
Funding and Clinical Trials Registration
This study was supported by academic and industry collaboration as part of the PIVOTAL trial with ClinicalTrials.gov identifier NCT02938299.
References
- Hauschild A, Hassel JC, Ziemer M, et al. Neoadjuvant Intralesional Daromun (L19IL2/L19TNF) in Resectable Locally Advanced Melanoma: An Update on the Efficacy and Safety Results of the PIVOTAL Phase III Trial. J Clin Oncol. 2026;doi:10.1200/JCO-26-00852. PMID:42579833.
- Eggermont AMM, et al. Neoadjuvant immunotherapy for melanoma: recent advances and future perspectives. Nat Rev Clin Oncol. 2022;
- Gogas HJ, et al. Adjuvant therapy for melanoma: current status and future perspectives. Ann Oncol. 2021;
