Binimetinib Explained

Binimetinib, sold under the brand name Mektovi, is an anti-cancer medication used to treat various cancers.[1] Binimetinib is a selective inhibitor of MEK, a central kinase in the tumor-promoting MAPK pathway.[2] Inappropriate activation of the pathway has been shown to occur in many cancers. 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.[3] [4] In October 2023, it was approved by the FDA for treatment of NSCLC with a BRAF V600E mutation in combination with encorafenib.[5] It was developed by Array Biopharma.

Mechanism of action

Binimetinib is an orally available inhibitor of mitogen-activated protein kinase kinase (MEK), or more specifically, a MAP2K inhibitor.[6] MEK is part of the RAS pathway, which is involved in cell proliferation and survival. MEK is upregulated in many forms of cancer.[7] 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.[8] 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.[9] 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.[10] 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.

Development

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

In December 2015, the company announced that the mutant-NRAS melanoma trial was successful.[11] 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.[12] NDA submitted Jun 2016,[13] and the FDA should decide by 30 June 2017.[14]

In April 2016, it was reported that the phase III trial for low-grade ovarian cancer was terminated due to lack of efficacy.[15]

In 2017, the FDA informed Array Biopharma that the phase III trial data was not sufficient and the New Drug Application was withdrawn.[16]

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. 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. The trial was conducted at 162 sites in Europe, North America, and various countries around the world.

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.

Notes and References

  1. Web site: Array Biopharma . Binimetinib . 6 April 2015 . 4 June 2019 . https://web.archive.org/web/20190604043216/http://www.arraybiopharma.com/product-pipeline/binimetinib/ . live .
  2. Koelblinger P, Dornbierer J, Dummer R . A review of binimetinib for the treatment of mutant cutaneous melanoma . Future Oncology . 13 . 20 . 1755–1766 . August 2017 . 28587477 . 10.2217/fon-2017-0170 . free .
  3. FDA approves encorafenib and binimetinib in combination for unresectable or metastatic melanoma with BRAF mutations . U.S. Food and Drug Administration (FDA) . 27 June 2018 . https://web.archive.org/web/20191219041947/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-encorafenib-and-binimetinib-combination-unresectable-or-metastatic-melanoma-braf . 19 December 2019 . live . 17 July 2018.
  4. Web site: Drug Trial Snapshot: Mektovi . U.S. Food and Drug Administration (FDA) . 19 December 2019 . https://web.archive.org/web/20191219042036/https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trial-snapshot-mektovi . 19 December 2019 . live . 19 December 2019.
  5. Web site: 11 October 2023 . FDA approves encorafenib with binimetinib for metastatic non-small cell lung cancer with a BRAF V600E mutation . 11 October 2023 . U.S. Food and Drug Administration.
  6. Wu PK, Park JI . MEK1/2 Inhibitors: Molecular Activity and Resistance Mechanisms . Seminars in Oncology . 42 . 6 . 849–62 . December 2015 . 26615130 . 4663016 . 10.1053/j.seminoncol.2015.09.023 .
  7. Web site: Binimetinib . PubChem . 26 January 2017 . 6 January 2021 . https://web.archive.org/web/20210106092525/https://pubchem.ncbi.nlm.nih.gov/compound/mek162 . live .
  8. Ascierto PA, Schadendorf D, Berking C, Agarwala SS, van Herpen CM, Queirolo P, Blank CU, Hauschild A, Beck JT, St-Pierre A, Niazi F, Wandel S, Peters M, Zubel A, Dummer R . 3 . 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 . March 2013 . 23414587 . 10.1016/S1470-2045(13)70024-X .
  9. Mehdizadeh A, Somi MH, Darabi M, Jabbarpour-Bonyadi M . 3 . Extracellular signal-regulated kinase 1 and 2 in cancer therapy: a focus on hepatocellular carcinoma . Molecular Biology Reports . 43 . 2 . 107–16 . February 2016 . 26767647 . 10.1007/s11033-016-3943-9 . 15113957 .
  10. Woodfield SE, Zhang L, Scorsone KA, Liu Y, Zage PE . 3 . Binimetinib inhibits MEK and is effective against neuroblastoma tumor cells with low NF1 expression . BMC Cancer . 16 . 172 . March 2016 . 26925841 . 4772351 . 10.1186/s12885-016-2199-z . free .
  11. Web site: Austen . Hufford . vanc . Array BioPharma Has Successful Trial for Cancer Drug Binimetinib . December 2015 . Wall Street Journal . 5 March 2017 . 6 January 2021 . https://web.archive.org/web/20210106144100/https://www.wsj.com/articles/array-biopharma-has-successful-trial-for-cancer-drug-binimetinib-1450274949 . live .
  12. Web site: Array BioPharma announces Phase 3 binimetinib trial meets primary endpoint for NRAS-mutant melanoma . Metro Denver . December 2015 . 14 March 2016 . 7 January 2021 . https://web.archive.org/web/20210107001850/http://www.metrodenver.org/news/news-center/2015/12/array-biopharma-announces-phase-3-binimetinib-trial-meets-primary-endpoint-for-nras-mutant-melanoma . dead .
  13. Web site: Array Bio submits marketing application in U.S. for lead product candidate in certain type of melanoma. June 2016 . 5 July 2016 . 15 August 2016 . https://web.archive.org/web/20160815061552/http://seekingalpha.com/news/3191356-array-bio-submits-marketing-application-u-s-lead-product-candidate-certain-type-melanoma . live .
  14. Web site: Douglas W. . House . vanc . FDA accepts Array Bio's NDA for binimetinib, action date June 30 . 1 September 2016 . Seeking Alpha . 6 September 2016 . 19 September 2016 . https://web.archive.org/web/20160919020200/http://seekingalpha.com/news/3206604-fda-accepts-array-bios-nda-binimetinib-action-date-june-30-shares-5-percent-premarket . live .
  15. Web site: Douglas W. . House . vanc . Array bags Phase 3 study of binimetinib in ovarian cancer; shares down 4% . Seeking Alpha . 1 April 2016 . 3 April 2016 . 6 December 2016 . https://web.archive.org/web/20161206080851/http://seekingalpha.com/news/3170946-array-bags-phase-3-study-binimetinib-ovarian-cancer-shares-4-percent . live .
  16. Web site: Losing Nemo: Array pulls skin cancer NDA for binimetinib . Ben . Adams . vanc . 20 March 2017 . Fierce Biotech . 2 May 2017 . 6 January 2021 . https://web.archive.org/web/20210106145144/https://www.fiercebiotech.com/biotech/losing-nemo-array-pulls-skin-cancer-nda-for-binimetinib . live .

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