Background: Both anti-PD-1 antibodies and BRAK/MEK inhibitors (BRAF/MEKi) reduce the risk of recurrence for patients with resected stage III melanoma. For patients with V600 BRAF-mutated melanoma who recur with resectable disease on or after adjuvant, many may be suitable for ‘second adjuvant' treatment after surgery. We sought to examine the efficacy and safety of ‘second adjuvant’ BRAF/MEKi in patients who recurred despite adjuvant PD-1 based immunotherapy. Methods: Patients with V600 BRAF-mutated melanoma treated with adjuvant PD-1 based immunotherapy for resected stage III/IV disease who recurred, underwent resection of recurrence and were then treated with adjuvant BRAF/MEKi were identified retrospectively from 13 centres. Demographics, disease characteristics, treatment details, and outcome data were examined. Results: 55 patients were included; median age at commencement of PD-1 was 53y, most were V600E (91%) and had IIIB (42%) or IIIC (44%) melanoma. PD-1 based adjuvant therapy included nivolumab (71%), nivolumab plus ipilimumab (14%), pembrolizumab (13%) and pembrolizumab plus mRNA-4157 vaccine (2%). Patients had initial recurrence after mean 8.4 months (95% CI 7.4-10.6), mainly while on treatment (65%), in regional nodes (42%), in-transit metastases (ITMs; 38%), both regional nodes and ITMs (7%) and distant metastases (13%). Surgical management included CLND (36%), selected nodal resection (11%), ITM resection (33%) and resection of distant metastasis (13%). A minority had adjuvant radiotherapy (17%). Stage at start of second adjuvant BRAF/MEKi included IIIB (29%), IIIC (53%) IIID (4%) and IV (15%). Patients received dabrafenib and trametinib (95%, N = 52) and encorafenib and binimetinib (5%, N = 3). After a median follow up of 21.4 months (19.7-25.4), 17 (31%) patients have recurred again. Mean duration of treatment was 9 months (95% CI 7.4-10.6); 20% ceased for toxicity, 7% for recurrence and 35% were on treatment at last follow up. The most common toxicity was pyrexia (43%) and 21% patients experienced a severe (G3-4) adverse event. Median RFS was 33.4 months (14.3.7-NR) and median DMFS was not reached. At 12 months, 72% (59-88) of patients were recurrence free and 90% (81-100) were free of distant recurrence. For those whose disease recurred again, most recurred after cessation of second adjuvant BRAF/MEKi (13/17, 76%). 7 (41%) recurred locally and 8 (47%) recurred with new metastatic disease but none had brain metastases. Conclusions: This is the first study examining outcomes of patients receiving second adjuvant targeted therapy for melanoma, after failure of adjuvant PD-1 based immunotherapy. While RFS appears shorter compared to first line trials, second adjuvant treatment with BRAF/MEKi appears safe and active in preventing further recurrence. Further data on sequencing adjuvant therapies are needed.