Background: Patients with advanced melanoma who progress on 1^st line TT and 2^nd line IT have limited treatment options. We explored the safety and efficacy of re-treatment with 3^rd line TT. Methods: was pooled from 6 centers in Australia from 2009-2018. Eligible patients with BRAF V600 mutant melanoma had 1^st line therapy with a BRAF/MEK inhibitor, 2^nd line IO and were re-challenged with a BRAF/MEK inhibitor. Results: 90 patients were included; median age 61 years, 78% BRAF V600E, 89% ECOG 0-1 at baseline. 1^st line TT was combination BRAF/MEK inhibitors in 80%, predominately dabrafenib/trametinib. Response to 1st line therapy was CR 20%, PR 41%, SD 17% and PD 13% and median duration of therapy was 7.2 months (0-33 months). 70% stopped for progressive disease, 9% toxicity and 16% had a planned switch to immunotherapy. For 2^nd line IT, 49% had PD-1 alone, 33% had PD-1+CTLA-4, 14% had CTLA-4 alone. Only median duration on IT was 67 days (0-23 months), 81% ceased for PD, 14% for toxicity. Of patients who had a planned switch to IO before 1^st line TT progression, one patient responded to second line IO with SD as BORR, there were no other responses to 2^nd line IO in the planned switch group. At 3^rd line TT re-challenge, 54% were AJCC stage IVd, 34% IVc, 51% had elevated LDH, 59% ECOG 0-1. 47% were re-challenged with dabrafenib/trametinib, 33% vemurafenib/cobimetinib, 11% encorafenib/binimetinib. BORR was 28%, with median duration on 3^rd line TT 81 days. The OS was 1.7 years, with 34% alive at time of analysis. Conclusions: Despite progression on 1^st line TT and 2^nd line IT, patients may experience meaningful response and on re-challenge TT.