Neoadjuvant Therapy in Resectable Advanced Melanoma: Swiss Real-World Data

Background/Objectives: Neoadjuvant and perioperative treatment regimens for melanoma have demonstrated significantly longer event-free survival (EFS) compared with adjuvant therapy in the NADINA and SWOG S1801 trials. While these studies yielded promising results, real-world effectiveness and safety remain to be clarified. Methods: We performed a retrospective, real-world study of all patients with advanced, resectable cutaneous or mucosal melanoma stage III/IV who received neoadjuvant treatment at the Department of Dermatology, University Hospital Zurich, Switzerland between April 2023 and September 2025. Primary endpoints were pathologic and radiologic response, EFS, recurrence-free survival (RFS), and safety. Results: In total, 31 patients were analyzed (52% female; median age 65 years), including 5 patients without lymph node involvement. Eighteen patients (58%) with cutaneous melanoma received neoadjuvant immunotherapy according to the NADINA protocol, three patients (10%) with mucosal melanoma received ipilimumab (1 mg/kg) and nivolumab (3 mg/kg), and ten patients (32%) were treated according to the SWOG S1801 protocol. A major pathologic response (MPR) was achieved in 12 of 31 patients (38%) overall, including 5 of 18 (28%) in the NADINA cohort, 6 of 10 (60%) in the SWOG S1801 cohort, and 1 of 3 (33%) in the mucosal cohort. We observed a pathologic partial response (pPR) in 7 of 31 patients (23%) overall, including 6 of 18 (33%) in the NADINA cohort and 1 of 3 (33%) in the mucosal cohort. A pathologic non-response (pNR) was seen in 9 of 31 patients (29%) overall, including 5 of 18 (28%) in the NADINA cohort, 3 of 10 (30%) in the SWOG S1801 cohort, and 1 of 3 (33%) in the mucosal cohort. Among all patients without lymph node involvement, 1 of 5 achieved MPR (20%), 2 had pPR (40%), and 2 showed pNR (40%). At data cutoff (median follow-up, 9.2 months), the 9-month EFS was 77% in the NADINA cohort, 74% in the SWOG S1801 cohort, and 33% in the mucosal cohort. In the whole cohort, 6-month RFS for the subgroups of MPR, pPR and pNR was 72.9%, 85.7% and 72.9%. Radiologic response evaluation with FDG-PET/CT after neoadjuvant therapy correlated significantly with pathologic response (p = 0.02). No patient with complete metabolic response (CMR) or partial metabolic response (PMR) recurred until data cutoff. In total, 6 of 31 patients (19%) showed stable metabolic disease (SMD), and 8 of 31 patients (26%) showed progressive metabolic disease (PMD). The 6-month RFS in the subgroups of SMD and PMD was 62.5% in each case. Adverse events (AEs) of grade 3 or higher were reported in 13 of 31 patients (42%) in the total real-world cohort, 8 of 18 in the NADINA cohort (44%), 2 of 10 (20%) in the SWOG S1801 cohort (20%), and 3 of 3 (100%) in the mucosal cohort. The most frequent grade 3/4 toxicities were immune-related (ir) Colitis (n = 3, 10%), irHepatitis (n = 2, 6%) and irMyocarditis (n = 2, 6%). Conclusions: Neoadjuvant immunotherapy is effective in real-world practice with a similar safety profile as shown in the clinical studies. Nevertheless, MPR rates in the NADINA real-world cohort were lower compared to the phase III trial. Larger multicenter studies are needed to validate our findings and to better understand response patterns, even in patients without lymph node involvement and in rare melanoma subtypes.