Background: Standard of care (SOC) for resectable, macroscopic stage III melanoma is therapeutic lymph node dissection (TLND) followed by adjuvant (adj) therapy with nivolumab (NIVO), pembrolizumab (PEM) or, in BRAFmut melanoma, dabrafenib + trametinib (DAB/TRAM). The recent phase 2 SWOG S1801 trial showed superior event-free survival (EFS) of neoadjuvant (neoadj) + adj PEM as compared to adj PEM (estimated 2y-EFS 72% vs 49%). Additional phase 2 trials demonstrated safety and high efficacy (77-80% 2y-EFS) of neoadj ipilimumab (IPI) 1 mg/kg + nivolumab (NIVO) 3 mg/kg, providing the rationale for testing neoadj IPI + NIVO against SOC in a phase 3 trial. Methods: In this investigator initiated, international phase 3 trial, resectable, macroscopic, nodal stage III melanoma pts, naive to ICI and BRAFi/MEKi, were randomized to receive 2 cycles of neoadj IPI 80mg + NIVO 240mg (q3w) followed by TLND, and in case of not achieving a major pathologic response (MPR) adj DAB/TRAM (150mg BID/2mg QD; 46 wks) or 11 cycles of adj NIVO (480mg; q4w; if BRAFwt) versus TLND followed by 12 cycles of adj NIVO (480mg; q4w). The primary endpoint EFS is defined as time from randomization until progression, recurrence or death due to melanoma or treatment, and was assessed using a Cox regression model. An interim analysis using a 2-sided alpha of 0.1% (Haybittle-Peto stopping rule) was planned per protocol after completing recruitment. Results: Between Aug 2021 and Dec 2023, 423 pts were randomly assigned; 212 pts to the neoadj arm and 211 to the adj arm. At data cutoff on January 12, 2024, with a median FU of 9.9 mos, significantly less events occurred in the neoadj arm vs the adj arm (28 vs 72), with HR 0.32 (99.9% CI 0.15-0.66, p<0.0001) and estimated 12-mo EFS rates of 83.7% (99.9% CI 73.8-94.8) vs 57.2% (99.9% CI 45.1-72.6) favoring the neoadj arm. In the subgroup of BRAFmut melanoma, estimated EFS rates were 83.5% and 52.1%, and in BRAFwt 83.9% and 62.4% for neoadj versus adj respectively. 58.0% of pts in the neoadj arm had an MPR, 8.0% a path partial-response (pPR), 26.4% a path non-response (pNR), 2.4% had progression before surgery and 5.2% were not reported (95% centrally reviewed). The 12-mo RFS rates according to path response were 95.1% for MPR, 76.1% for pPR and 57.0% for pNR. Systemic treatment related adverse events (AE) grade ≥3 were seen in 29.7% and 14.7% in the neoadj and adj arm; 1 pt died due to toxicity in adj arm (pneumonitis). Surgery related grade ≥3 AEs were reported in 14.6% and 14.4% respectively. Conclusions: NADINA is the first phase 3 trial that evaluates neoadj immunotherapy against SOC in melanoma, and is also the first phase 3 trial in oncology evaluating a neoadj regimen consisting of immunotherapy alone. Neoadj IPI+NIVO followed by response-driven adj treatment results in statistically significant improved EFS compared to adj NIVO and should be considered a new SOC treatment in macroscopic stage III melanoma. Clinical trial information: NCT04949113.