Dabrafenib and Trametinib, alone and in combination for BRAF-mutant metastatic melanoma
Cet article passe en revue les essais récents ayant évalué le dabrafenib et le trametinib, seuls ou en combinaison, pour le traitement de patients atteints d'un mélanome métastatique présentant une mutation du gène BRAF
Dabrafenib and trametinib were approved for use as monotherapies in BRAF-mutant metastatic melanoma by the U.S. Food and Drug Administration (FDA) in 2013, and most recently, their use in combination has received accelerated FDA approval. Both drugs target the MAPK pathway: dabrafenib selectively inhibits mutant BRAF which constitutively activates the pathway, and trametinib selectively inhibits MEK1 and MEK2 proteins activated by RAF kinases. The phase 3 study of dabrafenib in BRAFV600E metastatic melanoma reported rapid tumour regression in most patients and a 59% objective RECIST response rate. The median progression-free survival (PFS) and overall survival (OS) were improved compared with dacarbazine. Toxicities were well-tolerated and different from those reported for vemurafenib, the first FDA-approved BRAF inhibitor. Efficacy has been demonstrated in other BRAF-mutant genotypes. The phase 3 study of trametinib in BRAF inhibitor naïve patients with BRAFV600E or BRAFV600K also showed benefit with a prolonged median PFS and OS compared with chemotherapy. Trametinib is ineffective in patients who have progressed on BRAF inhibitors. A phase 2 trial of combined dabrafenib and trametinib demonstrated higher response rates and longer median PFS than dabrafenib monotherapy, with less cutaneous toxicity. Here, we review the clinical development of both drugs as monotherapies and in combination, and discuss their role in the management of BRAF-mutant melanoma.