Background: Combination D+T improves the overall survival (OS) of patients (pts) with V600 BRAF-mutation positive advanced melanoma. D+T is currently being explored in an adjuvant study of pts with resected stage III melanoma (NCT01682083). We sought to explore neoadjuvant D+T for pts with bulky but resectable stage III melanoma (NCT01972347). Methods: In this phase 2 study, all pts received D (150 mg twice daily) + T (2 mg once daily) for 12 wks prior to complete resection of the pre-therapy tumour bed (RES), then 40 wks of further D+T. Eligible pts were ≥ 18 yrs, ECOG PS ≤ 1 with histologically confirmed resectable bulky stage IIIB/C BRAF V600E/K mutant melanoma. CT and PET scans were performed at baseline and 12 wks just prior to RES for RECIST and metabolic complete response (rCR and mCR respectively). CT monitoring was continued 12 wkly thereafter to 2 yrs then 6 mnthly to 3 yrs. Biopsies were taken at baseline and wk 1. The primary endpoints were the complete pathological response (pCR) and RECIST response rate (rRR) at wk 12. Secondary endpoints were surgical morbidity, mCR, relapse free survival (RFS), OS, toxicity and translational endpoints. Results: At data cut 4 Jan 2016, 19 had commenced D+T. 14 had reached RES (10 stage IIIC [2 in-transit only], 4 IIIB; 12 V600E, 1 V00K, 1 V600). At RES, 6/14 (43%) had pCR, 5/14 (36%) had rCR (rRR 93%), and 7/14 (50%) had mCR. All 6 pts with pCR had mCR, but 2 did not have rCR. No pt progressed during neoadjuvant treatment. 2/14 pts recurred in the resected field 12 and 36 wks after RES on D+T. These pts had the highest ctDNA at baseline. 8/14 (57%) had ≥ 1 surgical complication post RES; 8 had a wound infection requiring antibiotics, 5 had a seroma, 2 bled (1 wound evacuation). 11/14 had a post RES drain (median drain time 27d). 12/14 (86%) interrupted D+T in the first 12 wks for a median of 7d, 9 due to pyrexia ( ≥ 38.5^oC). 1 pt ceased D+T at wk 28 due to renal failure. Conclusions: A high rate of pCR was observed with neoadjuvant D+T for resectable stage III melanoma. pCR correlated with mCR, but not rCR. Surgical complication rates were consistent with historic controls and stage of disease. The trial and translational research is ongoing, and ease of resection, RFS and OS data are being collected. Clinical trial information: NCT01972347