Targeting BRAF & MEK - Treatment of Melanoma

BRAF-MEK combination double survival in advanced melanoma with V600E and V600K mutations

by C.H. Weaver M.D. Medical Editor 8/1/2018

Patients with advanced melanoma lived twice as long without disease progression when they were treated with a combination of new targeted therapies compared to treatment with a single agent.1

The combination of a novel BRAF inhibitor encorafenib (LGX 818) with a MEK inhibitor binimetinib (ARRY 162) significantly delayed cancer recurrence compared to treatment with Zelboraf (vemurafenib) alone. Zelboraf was the first BRAF inhibitor approved for treatment of advanced melanoma, and represented a breakthrough by significantly improving survival compared with chemotherapy, replaced the latter as a treatment option.2

BRAF & MEK Kinase Inhibitors

The BRAF and MEK genes are known to play a role in cell growth, and mutations of these genes are common in several types of cancer. Approximately half of all melanomas carry a specific BRAF mutation known as V600E. This mutation produces an abnormal version of the BRAF kinase that stimulates cancer growth. Some melanomas carry another mutation known as V600K. BRAF and MEK inhibitors block the activity of the V600E and V600K mutations respectively.2-6

BRAF inhibitors

  • Zelboraf®(vemurafenib) BRAF V600E kinase inhibitor
  • Tafinlar®(dabrafenib) BRAF V600E kinase inhibitor

MEK inhibitors

  • Mekinist®(trametinib) MEK V600 kinase inhibitor
  • Cotellic® (cobimetinib) MEK V600 kinase inhibitor

Combination Therapy

Combination of a BRAF and a MEK inhibitor appears to decrease the emergence of disease resistance that occurs in patients treated with BRAF inhibition alone. The combination of Taflinar plus Mekinist significantly improves survival compared to treatment with single agent Taflinar, and the combination of Zelboraf and Cotellic appear to delay cancer recurrence when compared to Tafinlar.6

The multicenter COLUMBUS study was an open-label, phase III clinical trial that compared two newer kinase inhibitors. The encorafenib-binimetinib combination was compared to single-agent vemurafenib or encorafenib in 577 patients with locally advanced, unresectable, or metastatic melanoma. Approximately a third of the patients had prior immunotherapy, and 5% had received a checkpoint inhibitor.

The overall response to treatment was 63% with the combination, 51% with encorafenib, and 40% with vemurafenib. After a median follow-up of 16.7 months, there was a 7.6-month absolute difference in favor of the combination compared to treatment with vemurafenib alone.

Development of novel precision cancer medicines targeting specific genomic abnormalities continues to expand treatment options and improve outcomes for individuals diagnosed with advanced melanoma. The encorafenib-binimetinib combination appears very promising and further studies will determine whether it offers an advantage to existing combination therapies.


  1. [Dummer R et al “Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with]( [BRAF-mutant melanoma (COLUMBUS): A multicenter, open-label, randomized phase III trial”]( [Lancet Oncol2018; DOI:10.1016/S1470-2045(18)30161-X.](
  2. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. New England Journal of Medicine. 2011;364(26):2507-16. doi: 10.1056/NEJMoa1103782.
  3. Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicenter, open-label, phase 3 randomized controlled trial. Lancet. 2012;380(9839):358-65. doi: 10.1016/S0140-6736(12)60868-X.
  4. Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. New England Journal of Medicine. 2012;367(2):107-14. doi: 10.1056/NEJMoa1203421.

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