Background: OpACIN-neo tested 3 dosing schemes of neoadjuvant (neoadj) IPI+NIVO and identified 2 cycles of IPI 1mg/kg + NIVO 3mg/kg (I1N3) as the most favorable with a pathologic (path) response rate (pRR) of 77% and 20% grade 3-4 irAEs. After 17.6 months median FU, 1/64 (2%) patients (pts) with path response vs 13/21 (62%) of the non-responders ( > 50% viable tumor cells; pNR) had relapsed. We hypothesized that therapeutic lymph node dissection (TLND) could be omitted in pts achieving a complete or near-complete path response (≤10% viable tumor cells; major path response, MPR) in the index node (largest LN metastasis: ILN), whereas additional adjuvant (adj) therapy might improve the outcome of pNR pts. Methods: PRADO is an extension cohort of the multi-center phase 2 OpACIN-neo study that aims to confirm the pRR and safety of neoadj I1N3 and to test response-driven subsequent therapy. Pts with RECIST 1.1 measurable clinical stage III melanoma were included to receive 2 cycles of neoadj I1N3 after marker placement in the ILN. ILN resection was planned at wk 6. Pts that achieved MPR in the ILN did not undergo TLND; pts with pPR ( > 10 –≤50% viable tumor cells) underwent TLND; and pts with pNR underwent TLND and received adj NIVO or targeted therapy (TT) for 52 wks +/- radiotherapy (RT). Primary endpoints were pRR in the ILN and 24-month RFS. Estimated toxicity rates at wk 12 were calculated using a Kaplan Meier based method. Results: Between Nov 16, 2018 and Jan 3, 2020, 99 of 114 screened pts were eligible and enrolled. So far, 86 pts had ≥12 wks FU. 70/99 pts achieved a path response in the ILN (pRR 71%, 95% CI 61% - 79%); 60 (61%) had MPR. TLND was omitted in 58 (97%) of the MPR pts. There were 28 non-responders; 7 developed distant metastasis before ILN resection. To date, 8 of the 21 pNR pts had adj NIVO, 7 had adj TT and 7 had adj RT. The estimated grade 3-4 irAE rate at wk 12 was 24%. Due to toxicity, 10 pts (10%) received only 1 cycle I1N3 and in 3 pts ILN resection was not performed: 2 of these pts underwent TLND at wk 9 and one pt was not evaluated for path response. At data cutoff, the surgery-related grade 1,2 and 3 AE rates were 29%, 10% and 0% in pts who underwent ILN resection only vs 21%, 30% and 9% in pts who underwent subsequent TLND (p = 0.004). At ASCO 2020 all pts will have reached ≥12 wks FU. Conclusions: Neoadj I1N3 treatment induced a high pRR with tolerable toxicity. TLND was omitted in a major subset of pts, reducing surgical morbidity. Longer FU is needed to report safety and RFS when TLND is omitted in MPR pts. Clinical trial information: NCT02977052