Open Access

K. C. Kähler, J. C. Hassel, M. Ziemer, P. Rutkowski, F. Meier, L. Flatz, C. Gaudy-Marqueste, L. Zimmer, M. Santinami, F. Russano, I. von Wasielewski, T. K. Eigentler, M. Maio, I. Zalaudek, S. Haferkamp, P. Quaglino, Julia Welzel, C. Röcken, A. Enk, J.-C. Simon, T. Świtaj, M. Garzarolli, T. Amaral, N. Malissen, E. Livingstone, G. Elia, A. Covelli, K. Lorizzo, D. Neri, S. Mulatto, A. Parca, B. Pizzichi, P. A. Ascierto, C. Garbe, C. Robert, D. Schadendorf, A. Hauschild

• Background This phase 3 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 (AJCC version 7). Methods Patients were randomized to 4 weekly intralesional daromun administrations (13 Mio IU of L19IL2 and 400 μg of L19TNF) 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. Key findings 246 patients were randomized and included in the intention-to-treat analysis: 74% had undergone ≥ 2 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 and 6.8 months, respectively (HRBackground This phase 3 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 (AJCC version 7). Methods Patients were randomized to 4 weekly intralesional daromun administrations (13 Mio IU of L19IL2 and 400 μg of L19TNF) 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. Key findings 246 patients were randomized and included in the intention-to-treat analysis: 74% had undergone ≥ 2 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 and 6.8 months, respectively (HR 0.59; 95% CI 0.41 to 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.…