At a median follow-up of 22.2 months in the neoadjuvant daromun plus surgery arm (arm 1; n = 122) and 20.2 months for the upfront surgery arm (arm 2; n= 124), the RFS was significantly longer in arm 1 compared with arm 2. Specifically, the median RFS was 16.7 months vs 6.8 months in arm 1 vs arm 2, respectively. The estimated 2-year RFS rates were 41.6% (95% CI, 31.4%-55.1%) and 23.6% (95% CI, 15.4%-36.2%) in the respective arms (HR, 0.59; 95% CI, 0.41-0.86; log-rank P = .005).
“Despite the more advanced patient population, [data from the] PIVOTAL [trial] showed a significant improvement in RFS with a 41% reduction in the risk of recurrence or death in patients treated with daromun,” Katherina C. Kähler, MD, of the University Hospital Schleswig-Holstein in Germany, and colleagues wrote in the study. “In the prespecified analysis of [distant metastasis–free survival (DMFS)], daromun significantly reduced the risk of distant metastasis by 40% compared with the control arm. These findings suggest that daromun triggers a systemic immune response, even when administered locally.”
What Were the Background, Design, and Baseline Patient Characteristics of the PIVOTAL Study?
The neoadjuvant treatment with intratumoral daromun demonstrated a statistically and clinically meaningful improvement in RFS vs surgery alone in patients with locally advanced, fully resectable melanoma, meeting the primary end point of PIVOTAL.2
The open-label, controlled, multicenter study included patients at least 18 years of age with locally advanced melanoma with measurable disease and were eligible to receive intralesional therapy with at least 1 injectable skin or nodal melanoma lesion of at least 10 mm in longest diameter or multiple injectable lesions with a combined longest diameter of at least 10 mm.1 Additionally, patients included on the study were allowed to have received prior anticancer therapy, including surgery, radiotherapy, and approved systemic treatment consisting of adjuvant immune checkpoint inhibitors and BRAK/MEK inhibitors. Patients were also required to have an ECOG performance status of 0 or 1 and a life expectancy of at least 24 months.
Of note, patients were randomly assigned 1:1 to receive either neoadjuvant daromun followed by surgery or upfront surgery. Those in arm 1 were treated with daromun injected once a week for up to 4 weeks, which was followed by surgery within 4 weeks after the last treatment. Patients in arm 2 underwent surgical resection of all melanoma tumor lesions within 4 weeks of random assignment.
The primary end point of the study was RFS per blinded independent central review (BICR); secondary end points included overall survival, DMFS, and pathologic response.
In the intention-to-treat population (n = 246), the median age was 64.0 years (range, 22.0-91.0), more than half were male (56.1%), and most had an ECOG performance status of 0 (94.7%). Furthermore, most patients had normal lactate dehydrogenase levels (83.7%), and more than half had stage IIIC disease (American Joint Committee on Cancer [AJCC] 7th version, 51.6%; AJCC 8th version, 69.9%). Regarding BRAF mutation status, 35.8% of patients had BRAF mutations, 37.4% had wild-type, and 26.8% had an unknown status. Notably, more than half of patients (56.5%) had 1 melanoma metastasis at study entry, and the most common location of melanoma metastases included the skin (55.3%) and lymph nodes (52.4%). Additionally, no surgery, 1 prior surgery, 2 prior surgeries, and 3 prior surgeries were reported in 8.1%, 17.9%, 34.6%, and 39.4% of patients; 95.5% of patients had not previously received radiotherapy; and 65% had not received prior systemic therapy.
What Were the Additional Efficacy and Safety Data?
The investigator-assessed RFS data were consistent with those from the primary analysis per BICR. Of note, the median investigator-assessed RFS was 24.2 months in arm 1 and 10.7 months in arm 2, demonstrating a 39% reduction in the risk of recurrence or death in patients treated with daromun (HR, 0.61; 95% CI, 0.41-0.92; log-rank P = .018).
The benefit of neoadjuvant daromun was also observed in terms of DMFS; the estimated DMFS rate at 2 years was 59.4% (95% CI, 48.0%-73.6%) in arm 1 vs 38.8% (95% CI, 26.9%-56.0%) in arm 2. Of note, the median time to distant metastases was 28.0 months (95% CI, 22.1- not reached) and 17.7 months (95% CI, 11.2-30.1) in arms 1 vs 2, respectively (HR, 0.60; 95% CI, 0.37-0.95; P = .029).
Regarding safety, grade 3 or greater adverse effects (AEs) of any cause were observed in 31.3% of patients in arm 1 (n = 37 of 118) and in 10.9% in arm 2 (n = 13 of 119). Grade 3 treatment-related AEs (TRAEs) occurred in 26.3% of patients in arm 1 compared with 6.7% in arm 2. The most common grade 3 TRAE was injection site reaction among patients in arm 1. Moreover, 3 grade 1 immune-related AEs were observed in arm 1, and no treatment-related deaths were reported.
“Neoadjuvant daromun represents a well-tolerated and effective therapeutic option for patients with pretreated, recurrent stage III melanoma,” the study authors wrote in their conclusion. “Its favorable safety profile and clinical efficacy support its potential role as a complementary or alternative strategy to systemic immunotherapy, particularly in high-risk patients or those ineligible for immune checkpoint inhibitors.”
References
- Kähler KC, Hassel JC, Ziemer M, et al. Neoadjuvant intralesional targeted immunocytokines (daromun) in stage III melanoma. Ann Oncol. 2025;36(10):1166-1177. doi:10.1016/j.annonc.2025.06.014
- Ryan C. Neoadjuvant daromun elicits RFS benefit in locally advanced, fully resectable melanoma. OncLive. October 16, 2023. Accessed October 1, 2025. https://www.onclive.com/view/neoadjuvant-daromun-elicits-rfs-benefit-in-locally-advanced-fully-resectable-melanoma
