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| Clinical data | |
|---|---|
| Trade names | Mektovi |
| Other names | MEK162, ARRY-162, ARRY-438162 |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a618041 |
| License data |
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| Drug class | Antineoplastic Agents |
| ATC code | |
| Legal status | |
| Legal status | |
| Identifiers | |
| |
| CAS Number | |
| ECHA InfoCard | 100.167.617 |
| Chemical and physical data | |
| Formula | C17H15BrF2N4O3 |
| Molar mass | 441.233 g·mol−1 |
| 3D model (JSmol) | |
| |
| |
Binimetinib, sold under the brand name Mektovi, is an anti-cancer medication used to treat various cancers.[3] Binimetinib is a selective inhibitor of MEK, a central kinase in the tumor-promoting MAPK pathway.[4] Inappropriate activation of the pathway has been shown to occur in many cancers.[4] 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.[5][6] In October 2023, it was approved by the FDA for treatment of NSCLC with a BRAF V600E mutation in combination with encorafenib.[7] It was developed by Array Biopharma.
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Transcription
Mechanism of action
Binimetinib is an orally available inhibitor of mitogen-activated protein kinase kinase (MEK), or more specifically, a MAP2K inhibitor.[8] MEK is part of the RAS pathway, which is involved in cell proliferation and survival. MEK is upregulated in many forms of cancer.[9] 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.[10] 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.[11] 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.[12] 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.[12]
Development
In 2015, it was in phase III clinical trials for ovarian cancer,[13] BRAF mutant melanoma,[14] and NRAS Q61 mutant melanoma.[15]
In December 2015, the company announced that the mutant-NRAS melanoma trial was successful.[16] 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.[17] NDA submitted Jun 2016,[18] and the FDA should decide by 30 June 2017.[19]
In April 2016, it was reported that the phase III trial for low-grade ovarian cancer was terminated due to lack of efficacy.[20]
Binimetinib was studied for treatment of rheumatoid arthritis, but a phase II trial did not show benefit.[medical citation needed]
In 2017, the FDA informed Array Biopharma that the phase III trial data was not sufficient and the New Drug Application was withdrawn.[21]
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.[5] 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.[6] The trial was conducted at 162 sites in Europe, North America, and various countries around the world.[6]
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.[7]
References
- ^ "Product monograph" (PDF). hres.ca. Retrieved 19 October 2023.
- ^ "Summary Basis of Decision (SBD) for Mektovi". Health Canada. 23 October 2014. Retrieved 29 May 2022.
- ^ "Binimetinib". Array Biopharma.
- ^ a b Koelblinger P, Dornbierer J, Dummer R (August 2017). "A review of binimetinib for the treatment of mutant cutaneous melanoma". Future Oncology. 13 (20): 1755–1766. doi:10.2217/fon-2017-0170. PMID 28587477.
- ^ a b This article incorporates text from this source, which is in the public domain.
- ^ a b c This article incorporates text from this source, which is in the public domain.
- ^ a b "FDA approves encorafenib with binimetinib for metastatic non-small cell lung cancer with a BRAF V600E mutation". U.S. Food and Drug Administration. 11 October 2023. Retrieved 11 October 2023.
- ^ Wu PK, Park JI (December 2015). "MEK1/2 Inhibitors: Molecular Activity and Resistance Mechanisms". Seminars in Oncology. 42 (6): 849–62. doi:10.1053/j.seminoncol.2015.09.023. PMC 4663016. PMID 26615130.
- ^ "Binimetinib". PubChem.
- ^ Ascierto PA, Schadendorf D, Berking C, 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. PMID 23414587.
- ^ Mehdizadeh A, Somi MH, Darabi M, et al. (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. PMID 26767647. S2CID 15113957.
- ^ a b Woodfield SE, Zhang L, Scorsone KA, et al. (March 2016). "Binimetinib inhibits MEK and is effective against neuroblastoma tumor cells with low NF1 expression". BMC Cancer. 16: 172. doi:10.1186/s12885-016-2199-z. PMC 4772351. PMID 26925841.
- ^ 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
- ^ 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
- ^ Clinical trial number NCT01763164 for "Study Comparing the Efficacy of MEK162 Versus Dacarbazine in Unresectable or Metastatic NRAS Mutation-positive Melanoma" at ClinicalTrials.gov
- ^ Hufford A (December 2015). "Array BioPharma Has Successful Trial for Cancer Drug Binimetinib". Wall Street Journal.
- ^ "Array BioPharma announces Phase 3 binimetinib trial meets primary endpoint for NRAS-mutant melanoma". Metro Denver. December 2015. Archived from the original on 7 January 2021. Retrieved 14 March 2016.
- ^ Array Bio submits marketing application in U.S. for lead product candidate in certain type of melanoma. June 2016
- ^ House DW (1 September 2016). "FDA accepts Array Bio's NDA for binimetinib, action date June 30". Seeking Alpha.
- ^ House DW (1 April 2016). "Array bags Phase 3 study of binimetinib in ovarian cancer; shares down 4%". Seeking Alpha.
- ^ Adams B (20 March 2017). "Losing Nemo: Array pulls skin cancer NDA for binimetinib". Fierce Biotech.
External links
- "Binimetinib". Drug Information Portal. U.S. National Library of Medicine.
This page was last edited on 11 February 2024, at 00:42