Daromun plus surgery improves survival in patients with resectable melanoma

Use of neoadjuvant daromun in addition to surgery is safe and provides survival benefits in patients with resectable, locally advanced melanoma, results of the PIVOTAL study have shown.

“Treatment with daromun resulted in a clinically meaningful and statistically significant longer relapse-free survival (RFS) … and distant metastasis-free survival (DMFS) compared to surgery alone in potentially pretreated locally advanced melanoma patients,” said lead author Dr Axel Hauschild from the University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.

PIVOTAL is an open-label, randomized, multicentre, phase III trial that assessed daromun as a neoadjuvant intralesional therapy for resectable, locally advanced stage III melanoma at 22 sites in four EU countries.

In the study, Hauschild and his team randomized patients 1:1 to receive either four weekly intratumoural injections of daromun followed by surgery (week 5 to 8; treatment arm; n=127) or surgery alone within 4 weeks from randomization (control arm; n=129) between July 2016 and August 2023. Each weekly administration of daromun was distributed among all injectable tumour lesions.

RFS, as assessed by the investigators and confirmed by retrospective Blinded Independent Central Review (BICR) of PET/CT scans, was the primary endpoint.

Patients with cutaneous melanoma were included in the study if they had skin or lymph node metastases amenable to complete surgical resection. The investigators allowed prior antitumour treatments, such as surgery, radiation therapy (RT), and systemic therapies, as well as any approved adjuvant treatment postsurgery during follow-up.

On the other hand, patients with uveal or mucosal melanoma, metastatic melanoma with unknown primary, or distant metastases at screening (ruled out by PET/CT) were excluded from the analysis.

Prolonged survival

Several eligible patients both in the treatment and control arms had received previous treatments, including surgery (90.5 percent vs 92.3 percent), systemic therapy (5.5 percent vs 3.1 percent), or RT (33.9 percent vs 32.8 percent). [ASCO 2024, abstract LBA9501]

Both the treatment and control arms showed improvements in RFS, with a hazard ratio [HR] of 0.59 (95 percent confidence interval [CI], 0.41‒0.86; log-rank p=0.005) as per BICR assessment and 0.61 (95 percent CI, 0.41‒0.92; p=0.018) as per investigator assessment (power=85 percent; two-sided α=0.05).

Notably, RFS was significantly longer in the treatment arm than in the control arm as per BICR assessment (median, 16.7 vs 6.9 months). Daromun also improved DMFS significantly (HR, 0.60, 95 percent CI, 0.37‒0.95; p=0.029). In addition, 21 percent of patients in the treatment arm achieved pathological complete response (pCR).

In terms of safety, patients on neoadjuvant daromun reported low-grade, local adverse events (AEs; 14 percent grade 3). Systemic AEs were limited and of low grade, and there were no records of autoimmune treatment-emergent AEs and drug-related deaths.

“The analysis of the primary efficacy endpoint RFS and of secondary endpoints DMFS, pCR, and safety show that neoadjuvant daromun is an effective and safe therapeutic option for resectable, locally advanced melanoma patients,” Hauschild said.

Daromun is a combination of two antibody-cytokine fusions (L19IL2 and L19TNF).

The current study received funding from Philogen SpA.