Binimetinib

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Binimetinib
Binimetinib.svg
Clinical data
Trade names Mektovi
Other namesMEK162, ARRY-162, ARRY-438162
AHFS/Drugs.com Monograph
MedlinePlus a618041
License data
Drug class Antineoplastic Agents
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
CompTox Dashboard (EPA)
ECHA InfoCard 100.167.617 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C17H15BrF2N4O3
Molar mass 441.233 g·mol−1
3D model (JSmol)
  • CN1C=NC2=C1C=C(C(=C2F)NC3=C(C=C(C=C3)Br)F)C(=O)NOCCO
  • 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. [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.

Contents

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]

Related Research Articles

<span class="mw-page-title-main">Melanoma</span> Cancer originating in melanocytes

Melanoma is the most dangerous type of skin cancer; it develops from the melanin-producing cells known as melanocytes. It typically occurs in the skin, but may rarely occur in the mouth, intestines, or eye. In women, melanomas most commonly occur on the legs; while in men, on the back. Melanoma is frequently referred to as malignant melanoma. However, the medical community stresses that there is no such thing as a 'benign melanoma' and recommends that the term 'malignant melanoma' should be avoided as redundant.

<span class="mw-page-title-main">Targeted therapy</span> Type of therapy

Targeted therapy or molecularly targeted therapy is one of the major modalities of medical treatment (pharmacotherapy) for cancer, others being hormonal therapy and cytotoxic chemotherapy. As a form of molecular medicine, targeted therapy blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth, rather than by simply interfering with all rapidly dividing cells. Because most agents for targeted therapy are biopharmaceuticals, the term biologic therapy is sometimes synonymous with targeted therapy when used in the context of cancer therapy. However, the modalities can be combined; antibody-drug conjugates combine biologic and cytotoxic mechanisms into one targeted therapy.

<span class="mw-page-title-main">Sorafenib</span> Chemical compound

Sorafenib, sold under the brand name Nexavar, is a kinase inhibitor drug approved for the treatment of primary kidney cancer, advanced primary liver cancer, FLT3-ITD positive AML and radioactive iodine resistant advanced thyroid carcinoma.

<span class="mw-page-title-main">KRAS</span> Protein-coding gene in humans

KRAS is a gene that provides instructions for making a protein called K-Ras, a part of the RAS/MAPK pathway. The protein relays signals from outside the cell to the cell's nucleus. These signals instruct the cell to grow and divide (proliferate) or to mature and take on specialized functions (differentiate). It is called KRAS because it was first identified as a viral oncogene in the KirstenRAt Sarcoma virus. The oncogene identified was derived from a cellular genome, so KRAS, when found in a cellular genome, is called a proto-oncogene.

<span class="mw-page-title-main">Tremelimumab</span> Monoclonal antibody

Tremelimumab, sold under the brand name Imjudo, is a fully human monoclonal antibody used for the treatment of hepatocellular carcinoma. Tremelimumab is designed to attach to and block CTLA-4, a protein that controls the activity of T cells, which are part of the immune system.

<span class="mw-page-title-main">BRAF (gene)</span> Protein-coding gene in the species Homo sapiens

BRAF is a human gene that encodes a protein called B-Raf. The gene is also referred to as proto-oncogene B-Raf and v-Raf murine sarcoma viral oncogene homolog B, while the protein is more formally known as serine/threonine-protein kinase B-Raf.

<span class="mw-page-title-main">Axitinib</span> Chemical compound

Axitinib, sold under the brand name Inlyta, is a small molecule tyrosine kinase inhibitor developed by Pfizer. It has been shown to significantly inhibit growth of breast cancer in animal (xenograft) models and has shown partial responses in clinical trials with renal cell carcinoma (RCC) and several other tumour types.

<span class="mw-page-title-main">Vemurafenib</span> Targeted cancer drug

Vemurafenib (INN), sold under the brand name Zelboraf, is a medication used for the treatment of late-stage melanoma. It is an inhibitor of the B-Raf enzyme and was developed by Plexxikon.

<span class="mw-page-title-main">Selumetinib</span> Chemical compound

Selumetinib (INN), sold under the brand name Koselugo, is a medication for the treatment of children, two years of age and older, with neurofibromatosis type I (NF-1), a genetic disorder of the nervous system causing tumors to grow on nerves. It is taken by mouth.

<span class="mw-page-title-main">Nivolumab</span> Cancer drug

Nivolumab, sold under the brand name Opdivo, is a medication used to treat a number of types of cancer. This includes melanoma, lung cancer, malignant pleural mesothelioma, renal cell carcinoma, Hodgkin lymphoma, head and neck cancer, urothelial carcinoma, colon cancer, esophageal squamous cell carcinoma, liver cancer, gastric cancer, and esophageal or gastroesophageal junction (GEJ) cancer. It is administered intravenously.

<span class="mw-page-title-main">Trametinib</span> Anticancer medication

Trametinib, sold under the brand name Mekinist among others, is an anticancer medication used for the treatment of melanoma and glioma. It is a MEK inhibitor drug with anti-cancer activity. It inhibits MEK1 and MEK2. It is taken by mouth.

A MEK inhibitor is a chemical or drug that inhibits the mitogen-activated protein kinase kinase enzymes MEK1 and/or MEK2. They can be used to affect the MAPK/ERK pathway which is often overactive in some cancers.

<span class="mw-page-title-main">Dabrafenib</span> Chemical compound

Dabrafenib, sold under the brand name Tafinlar among others, is an anti-cancer medication used for the treatment of cancers associated with a mutated version of the gene BRAF. Dabrafenib acts as an inhibitor of the associated enzyme B-Raf, which plays a role in the regulation of cell growth.

<span class="mw-page-title-main">Encorafenib</span> Chemical compound

Encorafenib, sold under the brand name Braftovi, is a medication for the treatment of certain melanoma cancers. It is a small molecule BRAF inhibitor that targets key enzymes in the MAPK signaling pathway. This pathway occurs in many different cancers including melanoma and colorectal cancers. The substance was being developed by Novartis and then by Array BioPharma. In June 2018, it was approved by the FDA in combination with binimetinib for the treatment of patients with unresectable or metastatic BRAF V600E or V600K mutation-positive melanoma.

<span class="mw-page-title-main">Pembrolizumab</span> Pharmaceutical drug used in cancer treatment

Pembrolizumab, sold under the brand name Keytruda, is a humanized antibody used in cancer immunotherapy that treats melanoma, lung cancer, head and neck cancer, Hodgkin lymphoma, stomach cancer, cervical cancer, and certain types of breast cancer. It is administered by slow intravenous injection.

<span class="mw-page-title-main">Cobimetinib</span> Chemical compound

Cobimetinib, sold under the brand name Cotellic, is an anti-cancer medication used in combination with vemurafenib (Zelboraf) alone or with both vemurafenib and atezolizumab (Tecentriq) to treat melanoma. Cobimetinib is a MEK inhibitor. Cotellic, Zelboraf, and Tecentriq are all marketed by Genentech.

<span class="mw-page-title-main">Atezolizumab</span> Monoclonal anti-PD-L1 antibody

Atezolizumab, sold under the brand name Tecentriq, is a monoclonal antibody medication used to treat urothelial carcinoma, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), hepatocellular carcinoma and alveolar soft part sarcoma, but discontinued for use in triple-negative breast cancer (TNBC). It is a fully humanized, engineered monoclonal antibody of IgG1 isotype against the protein programmed cell death-ligand 1 (PD-L1).

V600E is a mutation of the BRAF gene in which valine (V) is substituted by glutamic acid (E) at amino acid 600. It is a driver mutation in a proportion of certain diagnoses, including melanoma, hairy cell leukemia, papillary thyroid carcinoma, colorectal cancer, non-small-cell lung cancer, Langerhans cell histiocytosis, Erdheim–Chester disease and ameloblastoma.

<span class="mw-page-title-main">Ribociclib</span> Chemical compound

Ribociclib, sold under the brand name Kisqali, is a medication used for the treatment of certain kinds of breast cancer. Ribociclib is a kinase inhibitor. It was developed by Novartis and Astex Pharmaceuticals.

<span class="mw-page-title-main">Avapritinib</span> Chemical compound

Avapritinib, sold under the brand name Ayvakit among others, is a medication used for the treatment of advanced systemic mastocytosis and for the treatment of tumors due to one specific rare mutation: it is specifically intended for adults with unresectable or metastatic gastrointestinal stromal tumor (GIST) that harbor a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation. Avapritinib is a kinase inhibitor.

References

  1. ↑ "Product monograph" (PDF). hres.ca. Retrieved 19 October 2023.
  2. ↑ "Summary Basis of Decision (SBD) for Mektovi". Health Canada. 23 October 2014. Retrieved 29 May 2022.
  3. ↑ "Binimetinib". Array Biopharma.
  4. 1 2 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.
  5. 1 2 "FDA approves encorafenib and binimetinib in combination for unresectable or metastatic melanoma with BRAF mutations" (Press release). U.S. Food and Drug Administration (FDA). 27 June 2018. Archived from the original on 19 December 2019. Retrieved 17 July 2018.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  6. 1 2 3 "Drug Trial Snapshot: Mektovi". U.S. Food and Drug Administration (FDA). 19 December 2019. Archived from the original on 19 December 2019. Retrieved 19 December 2019.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  7. 1 2 "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.
  8. ↑ 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.
  9. ↑ "Binimetinib". PubChem.
  10. ↑ 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.
  11. ↑ 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.
  12. 1 2 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.
  13. ↑ 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
  14. ↑ 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
  15. ↑ Clinical trial number NCT01763164 for "Study Comparing the Efficacy of MEK162 Versus Dacarbazine in Unresectable or Metastatic NRAS Mutation-positive Melanoma" at ClinicalTrials.gov
  16. ↑ Hufford A (December 2015). "Array BioPharma Has Successful Trial for Cancer Drug Binimetinib". Wall Street Journal.
  17. ↑ "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.
  18. ↑ Array Bio submits marketing application in U.S. for lead product candidate in certain type of melanoma. June 2016
  19. ↑ House DW (1 September 2016). "FDA accepts Array Bio's NDA for binimetinib, action date June 30". Seeking Alpha.
  20. ↑ House DW (1 April 2016). "Array bags Phase 3 study of binimetinib in ovarian cancer; shares down 4%". Seeking Alpha.
  21. ↑ Adams B (20 March 2017). "Losing Nemo: Array pulls skin cancer NDA for binimetinib". Fierce Biotech.
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