Development of selective inhibitors of BRAF has improved the survival of patients with BRAF-mutant
melanoma. The progression-free survival
after treatment with a BRAF inhibitor is modest, however, and BRAF inhibitors induce cutaneous toxicity, likely due to paradoxical activation of the
mitogen-activated protein kinase pathway. Combining selective BRAF and
MEK inhibition, such as the BRAF inhibitor
dabrafenib and the
MEK inhibitor
trametinib, has been shown to improve the response rate and progression-free survival in patients with advanced
melanoma while significantly alleviating the paradoxical activation of
mitogen-activated protein kinase. This combination treatment results in a reduction in skin toxicity relative to that seen with a BRAF inhibitor alone; however, addition of the
MEK inhibitor adds other toxicities, such as
pyrexia and gastrointestinal or
ocular toxicity. While combined BRAF-
MEK inhibition appears primed to become a standard molecular approach for BRAF-mutant
melanoma, the utility of the combination has to be considered in the rapidly changing landscape of immunotherapeutics, such as
immune checkpoint blockade using anti-cytotoxic T lymphocyte antigen-4 and anti-programmed death-1/programmed death-L1
antibodies. Here we review the development of the
dabrafenib plus
trametinib combination, the characteristics of each
drug and the combination, and the role of this combination in the management of patients with BRAF-mutant
melanoma.