Contribution of encorafenib and binimetinib combination therapy in patients with V600 BRAF mutation of metastatic melanoma

06/2019

MUDr. Eugen Kubala

Onkologická klinika 1. LF UK a Thomayerovy nemocnice, Praha

SUMMARY

Treatment of patients with advanced and metastatic melanoma with BRAF V600 mutation has been enriched with new combination therapy with BRAF and MEK inhibitors encorafenib and binimetinib. Pharmacological inhibition of the mitogen-activated protein kinase (MAPK) signaling pathway has brought significant progress in the treatment of metastatic melanoma. A key role is played by the product of the mutated BRAF V600E kinase¹ gene, which is part of the MAPK signaling pathway. Encorafenib is an ATP competitive inhibitor of BRAF kinase that is able to block several mutated forms of BRAF kinase (e.g. V600E, V600D and V600K) in tumor melanoma cells with much greater efficacy - up to ten times higher half-life, i.e. more than 30 hours longer effect of either dabrafenib (2 hours) or vemurafenib (0,5 hours). The COLUMBUS study has achieved its primary goal of increasing the median progression free survival (PFS) of combination therapy with encorafenib and binimetinib for 14,9 months comparing to vemurafenib treatment with 7,3 months PFS. Significant is the comparison of the two BRAF inhibitors encorafenib and vemurafenib, which indicated a higher efficacy of encorafenib over vemurafenib - PFS median 9,6 versus 7,3 months (HR 0,68; 95% CI 0,52-0,88; p = 0,0038 The combination of the BRAF inhibitor encorafenib and the MEK inhibitor binimetinib significantly shifted the PFS median to 16,4 months and the median overall survival to 33,6 months without increasing toxicity against the established combinations of BRAF and MEK inhibitors that we use in the treatment of BRAF V600 mutated melanoma.

Key words

melanoma, encorafenib, binimetinib, COLUMBUS study