Efficacy, safety and factors associated with disease progression in patients with unresectable (stage III) or distant metastatic (stage IV) BRAF V600-mutant melanoma: An open label, non-randomized, phase IIIb study of trametinib in combination with dabrafenib.

Abstract

BACKGROUND\nBRAF and MEK inhibitors combination, including dabrafenib (D) and trametinib (T) have transformed the treatment of BRAF V600-mutant advanced melanoma patients, including patients with brain metastasis (BM). In a large phase IIIb, single-arm, open-label, multicenter\xa0French study, we assessed safety, response to treatment, progression-free survival (PFS) and factors associated with progression, and stratified the population into risk groups.\n\n\nMETHODS\nPatients with unresectable, advanced, BRAF V600-mutant melanoma were included, including those with the presence of BM, Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤2, elevated lactate dehydrogenase (LDH) or previous melanoma treatments. Responses were determined locally, without central review. PFS was estimated using the Kaplan-Meier analysis and modelled with multivariate Cox model. Risk subgroups were identified using a regression tree analysis.\n\n\nRESULTS\nBetween March 2015 and November 2016, 856 patients received at least one D\xa0+\xa0T dose. Overall, 92% had stage IV melanoma, 38% ECOG PS ≥1, 32% BM\xa0and 37.5% elevated LDH. Median PFS was 8.02 months (95% confidence interval [CI] 7.33-8.77). Significant factors associated with lower PFS were ECOG PS ≥1, elevated LDH, ≥3 metastatic sites\xa0and presence of BM. Patients with <3 metastatic sites, ECOG\xa0=\xa00 and no BM had the highest probability of PFS at 6 months (83%, 95% CI\xa076-87) and 12 months (56%, 95% CI\xa047-64), respectively.\n\n\nCONCLUSIONS\nThis is the largest prospective study in advanced BRAF V600-mutant melanoma patients treated with D\xa0+\xa0T, conducted in conditions close to real-world practice . We confirm previous findings that LDH, ECOG PS and ≥3 metastatic sites are associated with shorter PFS, but the real-world setting introduces BM as a major prognostic factor.