Neoadjuvant intralesional targeted immunocytokines (daromun) in stage III melanoma.

BACKGROUND: This phase III trial assessed daromun, a combination of two fibronectin-targeting immunocytokines (L19IL2 and L19TNF), as a neoadjuvant treatment for patients with clinically detectable stage IIIB/C melanoma [American Joint Committee on Cancer (AJCC) version 7]. PATIENTS AND METHODS: Patients were randomized to weekly intralesional daromun administrations (13 million IU of L19IL2 and 400 μg of L19TNF) for 4 weeks followed by surgery, or upfront surgery. Pretreatment with approved adjuvant agents was allowed. The primary endpoint was recurrence-free survival (RFS): events were disease recurrence or death from any cause after complete surgical tumor resection (ClinicalTrials.gov NCT02938299). RESULTS: A total of 246 patients were randomized and included in the intention-to-treat analysis: 74% had undergone two or more prior surgical resections and 35% had received prior systemic therapy. At a median follow-up of 21 months, the neoadjuvant group (n = 122) had a significantly longer RFS than the upfront surgery group (n = 124), with a median RFS of 16.7 months and 6.8 months, respectively [hazard ratio (HR) 0.59, 95% confidence interval (CI 0.41-0.86), P = 0.005, log-rank test]. The risk of distant recurrence was reduced by 40% in the neoadjuvant arm (HR 0.60, 95% CI 0.37-0.95, P = 0.029). Grade ≥3 treatment-related adverse events (TRAEs) were 6.7% in the surgery-alone arm and 27.1% in the daromun arm, mostly injection site reactions. CONCLUSIONS: Neoadjuvant daromun resulted in a significantly longer RFS than upfront surgery in patients with locally advanced melanoma. TRAEs were transient and manageable. Neoadjuvant daromun is a new therapeutic option for patients with stage III melanoma, including those with locoregional recurrence after surgery and previous adjuvant therapy.