Background: Neoadjuvant D+T has a high pathologic response rate and impressive short-term survival. The NeoCombi trial (NCT01972347) enrolled 35 patients with resectable stage III melanoma, with last patient commencing treatment April 19th 2017. We report 5-year outcomes from this trial. Methods: Pts received 12 wks neoadjuvant standard dose D+T, then 40 wks adjuvant D+T. Eligible pts were ≥ 18 yrs, ECOG PS ≤ 1 with clinical stage III BRAF V600E/K melanoma. CT and PET scans were performed at baseline and prior to surgery. Pathologic response was determined as per International Neoadjuvant Melanoma Consortium (INMC) criteria and defined as complete (pCR), near complete, partial (pPR) or no response (pNR). CT monitoring was continued 12 wkly thereafter to 2 yrs, then 6 monthly to 3 yrs, then as standard care. The primary endpoints were the complete pathological response (pCR) and RECIST response rate (rRR) at wk 12. Secondary endpoints included relapse free survival (RFS), OS, and toxicity. Results: 35 pts were enrolled, 6 with IIIB, 29 IIIC (7 ITM only) disease (clinical AJCCv7). At data cut August 17th 2021, median F/U was 60 mo (95% CI 56-72). No patients progressed in the neoadjuvant phase, and (49%) had a pCR, 1 near pCR, 6 pPR, 11 pNR. 5-year RFS, DMFS and OS data are shown in the Table. The majority of recurrences occurred within the first 2 years, with no recurrences beyond 3y. 21 patients recurred; 12 (57%) had first recurrence locoregional (6/12 subsequent distant recurrence) and 9 (43%) had first recurrence in distant sites (3/9 in brain). Locoregional recurrence was managed with surgery alone in 4/12, systemic therapy alone in 2/12, or both surgery and systemic therapy in 5/12 (4/5 had adjuvant systemic therapy), 1 pt was observed until distant recurrence. Subsequent systemic therapy in the 15 patients with a distant recurrence included PD-1 based immunotherapy (N=14) and BRAF targeted therapy (N=10). Conclusions: Neoadjuvant D+T in clinical stage III melanoma has impressive early activity, however patients remain at high risk of recurrence. Pathologic response can identify patients at the highest risk of recurrence, offering a chance of alternative adjuvant therapy in non-responders. Clinical trial information: NCT01972347.