Binimetinib

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Binimetinib
File:Binimetinib.svg
Clinical data
Trade namesMektovi
Other namesMEK162, ARRY-162, ARRY-438162
AHFS/Drugs.comMonograph
MedlinePlusa618041
License data
Drug classAntineoplastic agent
ATC code
Legal status
Legal status
Identifiers
  • 5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzo[d]imidazole-6-carboxamide
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
E number{{#property:P628}}
CompTox Dashboard (EPA)
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Chemical and physical data
FormulaC17H15BrF2N4O3
Molar mass441.233 g·mol−1
3D model (JSmol)
  • Cn1cnc2c(F)c(Nc3ccc(Br)cc3F)c(C(=O)NOCCO)cc21
  • InChI=1S/C17H15BrF2N4O3/c1-24-8-21-16-13(24)7-10(17(26)23-27-5-4-25)15(14(16)20)22-12-3-2-9(18)6-11(12)19/h2-3,6-8,22,25H,4-5H2,1H3,(H,23,26)
  • Key:ACWZRVQXLIRSDF-UHFFFAOYSA-N

Binimetinib, sold under the brand name Mektovi, is an anti-cancer medication used to treat various cancers.[5] Binimetinib is a selective inhibitor of MEK, a central kinase in the tumor-promoting MAPK pathway.[6] Inappropriate activation of the pathway has been shown to occur in many cancers.[6] In June 2018 it was approved by the FDA in combination with encorafenib for the treatment of patients with unresectable or metastatic BRAF V600E or V600K mutation-positive melanoma.[7][8] In October 2023, it was approved by the FDA for treatment of NSCLC with a BRAF V600E mutation in combination with encorafenib.[9] It was developed by Array Biopharma.

Mechanism of action

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Binimetinib is an orally available inhibitor of mitogen-activated protein kinase kinase (MEK), or more specifically, a MAP2K inhibitor.[10] MEK is part of the RAS pathway, which is involved in cell proliferation and survival. MEK is upregulated in many forms of cancer.[11] Binimetinib, uncompetitive with ATP, binds to and inhibits the activity of MEK1/2 kinase, which has been shown to regulate several key cellular activities including proliferation, survival, and angiogenesis.[12] MEK1/2 are dual-specificity threonine/tyrosine kinases that play key roles in the activation of the RAS/RAF/MEK/ERK pathway and are often upregulated in a variety of tumor cell types.[13] Inhibition of MEK1/2 prevents the activation of MEK1/2 dependent effector proteins and transcription factors, which may result in the inhibition of growth factor-mediated cell signaling.[14] As demonstrated in preclinical studies, this may eventually lead to an inhibition of tumor cell proliferation and an inhibition in production of various inflammatory cytokines including interleukin-1, -6 and tumor necrosis factor.[14]

Development

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In 2015, it was in phase III clinical trials for ovarian cancer,[15] BRAF mutant melanoma,[16] and NRAS Q61 mutant melanoma.[17]

In December 2015, the company announced that the mutant-NRAS melanoma trial was successful.[18] In the trial, those receiving binimetinib had a median progression-free survival of 2.8 months versus 1.5 months for those on the standard dacarbazine treatment.[19] NDA submitted Jun 2016,[20] and the FDA should decide by 30 June 2017.[21]

In April 2016, it was reported that the phase III trial for low-grade ovarian cancer was terminated due to lack of efficacy.[22]

In 2017, the FDA informed Array Biopharma that the phase III trial data was not sufficient and the New Drug Application was withdrawn.[23]

In June 2018, it was approved for the treatment of certain melanomas by the U.S. Food and Drug Administration (FDA) in combination with encorafenib.[7] The FDA approved binimetinib based primarily on evidence from one clinical trial (NCT01909453) of 383 patients with BRAF V600 mutation-positive melanoma that was advanced or could not be removed by surgery.[8] The trial was conducted at 162 sites in Europe, North America, and various countries around the world.[8]

In October 2023, the US Food and Drug Administration approved encorafenib with binimetinib for adults with metastatic non-small cell lung cancer (NSCLC) with a BRAF V600E mutation, as detected by an FDA-approved test.[9]

References

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  15. ^ Clinical trial number NCT01849874 for "A Study of MEK162 vs. Physician's Choice Chemotherapy in Patients With Low-grade Serous Ovarian, Fallopian Tube or Peritoneal Cancer" at ClinicalTrials.gov
  16. ^ Clinical trial number NCT01909453 for "Study Comparing Combination of LGX818 Plus MEK162 Versus Vemurafenib and LGX818 Monotherapy in BRAF Mutant Melanoma (COLUMBUS)" at ClinicalTrials.gov
  17. ^ Clinical trial number NCT01763164 for "Study Comparing the Efficacy of MEK162 Versus Dacarbazine in Unresectable or Metastatic NRAS Mutation-positive Melanoma" at ClinicalTrials.gov
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