Background: The aim of neo-adjuvant therapy in locally advanced or oligometastatic melanoma is to facilitate radical resection, improve outcomes and undertake research to identify biomarkers of response and resistance. The optimal schedule to balance efficacy vs toxicity in dual PD1/CTLA4 blockade regimens remains a matter of debate. We initiated an open- label, single arm study to investigate the Nivo 3/ Ipi 1 schedule as primary treatment of locally advanced or oligometastatic melanoma patients (pts). Methods: Treatment schedule consists in 4 neoadjuvant cycles of Ipilimumab 1 mg/kg and Nivolumab 3 mg/kg every 3 weeks, followed by surgery and adjuvant Nivolumab 480 mg every 4 weeks for 6 cycles. Primary objective is pathological complete remission (pCR) rate, according to Neoadjuvant Melanoma Consortium criteria. Secondary objectives are: safety, feasibility and efficacy; QoL; identification of molecular and immunological biomarkers of response and resistance (somatic genetic drivers, tumor mutational burden, mutational signatures, predicted neoantigens, germline HLA typing, somatic HLA mutations and liquid biopsy); degree of immune activation; evaluation of microbioma Results: From March 2019 to April 2021, 35 pts were included within the trial. All pts completed the treatment program. 6 pts (17%) developed immune-related (IR) G3-4 adverse events (AE): 3 transaminitis, 1 pneumonitis, 1 myocarditis and 1 CPK increase; all of them but one underwent surgery after toxicity resolution. 4 pts (11%) experienced G3-4 non-IR AE. 31 pts underwent surgery after neoadjuvant phase: pCR, near pCR, pathological partial remission (pPR) and pathological no response (pNR) were achieved in 18 (58%), 2 (7%), 4 (13%) and 7 (22%) cases, respectively. 2 pts progressed before surgery and 8 pts progressed during/after adjuvant phase (6/8 in NR at surgery). 4 pts died, 3 after disease progression and 1 for ischemic stroke 5 months after the end of therapy. At 18 months, progression free survival (PFS) and overall survival (OS) were 80 and 85%, respectively (median follow-up: 23 months); non responders (pNR) have a higher risk of relapse or death vs responders (pCR+near pCR+pPR) [HR= 4.11, 95%CI (0.96 -17) adjusted for age, p=0.06]. Conclusions: Our study lends further support to the adoption of the Nivo 3/ Ipi 1 schedule as primary treatment for locally advanced/oligometastatic melanoma, as this regimen achieved a pCR/near pCR rate of 65% with a rate of severe IR-AEs (17%) lower than previously reported in CheckMate 511 trial (34%) using Nivo3/Ipi1 schedule. Available translational data on potential genomic biomarkers of response, gut microbiome and systemic inflammatory landscape evaluated longitudinally during therapy on each patient will be presented. Clinical trial information: 2018-002172-40.