Binimetinib, sold under the brand nameMektovi, is ananti-cancer medication used to treat various cancers.[4] Binimetinib is a selective inhibitor of MEK, a centralkinase in the tumor-promotingMAPK pathway.[5] Inappropriate activation of the pathway has been shown to occur in many cancers.[5] In June 2018 it was approved by the FDA in combination withencorafenib for the treatment of patients with unresectable or metastatic BRAFV600E or V600K mutation-positive melanoma.[6][7] In October 2023, it was approved by the FDA for treatment of NSCLC with aBRAF V600E mutation in combination withencorafenib.[8] It was developed byArray Biopharma.
Binimetinib is an orally available inhibitor of mitogen-activated protein kinase kinase (MEK), or more specifically, aMAP2K inhibitor.[9] MEK is part of theRAS pathway, which is involved in cell proliferation and survival. MEK is upregulated in many forms of cancer.[10] 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.[11] MEK1/2 aredual-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.[12] 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.[13] 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 includinginterleukin-1,-6 andtumor necrosis factor.[13]
In December 2015, the company announced that the mutant-NRAS melanoma trial was successful.[17] In the trial, those receiving binimetinib had a medianprogression-free survival of 2.8 months versus 1.5 months for those on the standarddacarbazine treatment.[18]NDA submitted Jun 2016,[19] and the FDA should decide by 30 June 2017.[20]
In April 2016, it was reported that the phase III trial for low-grade ovarian cancer was terminated due to lack of efficacy.[21]
In 2017, the FDA informed Array Biopharma that the phase III trial data was not sufficient and theNew Drug Application was withdrawn.[22]
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.[6] 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.[7] The trial was conducted at 162 sites in Europe, North America, and various countries around the world.[7]
^"Binimetinib".PubChem.Archived from the original on 6 January 2021. Retrieved26 January 2017.
^Ascierto PA, Schadendorf D, Berking C, Agarwala SS, van Herpen CM, Queirolo P, et al. (March 2013). "MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study".The Lancet. Oncology.14 (3):249–56.doi:10.1016/S1470-2045(13)70024-X.PMID23414587.{{cite journal}}: CS1 maint: overridden setting (link)
^Mehdizadeh A, Somi MH, Darabi M, Jabbarpour-Bonyadi M (February 2016). "Extracellular signal-regulated kinase 1 and 2 in cancer therapy: a focus on hepatocellular carcinoma".Molecular Biology Reports.43 (2):107–16.doi:10.1007/s11033-016-3943-9.PMID26767647.S2CID15113957.{{cite journal}}: CS1 maint: overridden setting (link)
^Clinical trial numberNCT01849874 for "A Study of MEK162 vs. Physician's Choice Chemotherapy in Patients With Low-grade Serous Ovarian, Fallopian Tube or Peritoneal Cancer" atClinicalTrials.gov
^Clinical trial numberNCT01909453 for "Study Comparing Combination of LGX818 Plus MEK162 Versus Vemurafenib and LGX818 Monotherapy in BRAF Mutant Melanoma (COLUMBUS)" atClinicalTrials.gov
^Clinical trial numberNCT01763164 for "Study Comparing the Efficacy of MEK162 Versus Dacarbazine in Unresectable or Metastatic NRAS Mutation-positive Melanoma" atClinicalTrials.gov
This article incorporates text from this source, which is in thepublic domain.
