TAFINLAR + MEKINIST target two distinct points on the mitogen-activated protein kinase (MAPK) pathway to provide concomitant inhibition1,2
BRAF V600 mutations result in constitutive activation of the MAPK pathway, which plays a key role in regulating the growth, proliferation and survival of normal cells, including melanocytes, which are the cells from which melanoma originates.3,4 As many as 50% of patients with melanoma harbour mutations of the BRAF V600 gene.5
In melanoma cells with a BRAF V600 mutation, the BRAF V600 and mitogen-activated extracellular signal-regulated kinase (MEK) proteins send signals that cause melanoma cells to grow and increase uncontrollably. TAFINLAR + MEKINIST work together to block these signals.1,2
TAFINLAR, in combination with MEKINIST, is designed to target the oncogenic driver of BRAF V600-positive melanoma. TAFINLAR is an inhibitor of the mutated BRAF V600 kinase1 and MEKINIST is a reversible and highly selective inhibitor of MEK 1 and MEK 2, which sit downstream of BRAF.2 Combined inhibition of BRAF and MEK reduces extracellular signal-related kinase (ERK)-driven gene expression that can cause tumour growth.
ERK, extracellular signal-related kinase; Ligand, molecule which produces a signal by binding to a site on the target protein; MAPK, mitogen-activated protein kinase; MEK, mitogen-activated extracellular signal-regulated kinase; RAS, monomeric G protein; Receptor, protein on the surface of a cell (or inside of a cell) that selectively receives and binds to an extracellular ligand.
Further information about BRAF V600 mutations, the BRAF pathway, as well as the importance of BRAF testing in melanoma can also be found here.
Combining TAFINLAR + MEKINIST results in greater and more prolonged inhibition of tumour growth versus either drug alone in BRAF V600-mutant melanoma1,2
Blocking MEK, in addition to BRAF in BRAF V600-positive melanoma:
- Prolonged inhibition of tumour growth versus either drug alone in vitro and in vivo.1,2
- Is thought to reduce the risk of treatment resistance.1-3,6-9
- Decreases the incidence of cutaneous adverse events (such as hyperkeratosis and cutaneous squamous-cell carcinoma) that may occur with BRAF inhibitor monotherapy; however, increases in other types of adverse event have been seen when TAFINLAR and MEKINIST are used in combination.1,2,10,11
- TAFINLAR (dabrafenib) Summary of Product Characteristics.
- MEKINIST (trametinib) Summary of Product Characteristics.
- Nijenhuis CM, et al. Cancer Treat Rev 2013;39:305–312.
- Melanoma UK. What is melanoma. Available at: https://www.melanomauk.org.uk/pages/category/what-is-melanoma Accessed February 2021.
- Ascierto PA, et al. J Transl Med 2012;10:85.
- Hauschild A, et al. J Clin Oncol 2013;31(suppl): abstract number 9013.
- Robert C, et al. Pigment Cell Melanoma Res 2018;31:201.
- McArthur GA, et al. Lancet Oncol 2014; 15: 323–332.
- Greger JG, et al. Mol Cancer Ther 2012;11:909–920.
- Robert C, et al. New Eng J Med 2015;372:30–39.
- Long G, et al. New Engl J Med 2014;371:1877–1888.