Combination dabrafenib and trametinib in the management of advanced melanoma with BRAFV600 mutations

ABSTRACT

Introduction: In the 40–50% of advanced melanoma patients with tumors harboring BRAF V600E and V600 K mutations, BRAF inhibitors such as dabrafenib are a highly effective treatment. However, most patients develop resistance after several months on treatment. The addition of a MEK inhibitor, such as trametinib, to BRAF inhibition mitigates one key pathway of resistance, further increasing response rates and improving survival.

Areas covered: This article summarizes the mechanism of action of the combination of dabrafenib and trametinib, its evolution through Phase I, II and III clinical trials and discusses its current use in the management of patients with advanced melanoma.

Expert opinion: Combination therapy with dabrafenib and trametinib improves response rate, progression-free survival and overall survival when compared to dabrafenib or vemurafenib alone. The addition of trametinib to dabrafenib changes the adverse event profile, making hyperkeratosis and cutaneous squamous cell carcinomas less common but side effects such as fever and nausea more common. How dabrafenib/trametinib is best sequenced with other effective treatments such as immune checkpoint blockade remains uncertain.

KEYWORDS:

• Dabrafenib
• trametinib
• BRAF mutation
• MAPK pathway
• advanced melanoma
• toxicity

Box 1. Drug summary

Declaration of interest

J Larkin is a non-remunerated consultant for Novartis, Pfizer, Bristol-Meyers Squibb, MSD and Roche/Genentech and receives institutional research support from Pfizer, Bristol-Meyers Squibb, Novartis and MSD. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed