Trametinib Explained

Tradename:Mekinist, Spexotras
Dailymedid:Trametinib
Routes Of Administration:By mouth
Atc Prefix:L01
Atc Suffix:EE01
Legal Au:S4
Legal Au Comment:[1]
Legal Ca:Rx-only
Legal Ca Comment:[2] [3]
Legal Us:Rx-only
Legal Us Comment:[4]
Legal Eu:Rx-only
Legal Eu Comment:[5] [6]
Cas Number:871700-17-3
Pubchem:11707110
Drugbank:DB08911
Chemspiderid:9881833
Unii:33E86K87QN
Kegg:D10175
Chembl:2103875
Chebi:75998
Synonyms:GSK1120212
Iupac Name:N-(3-phenyl)acetamide
C:26
H:23
F:1
I:1
N:5
O:4
Smiles:Ic1ccc(c(F)c1)N\C3=C\2/C(=O)N(C(=O)N(C/2=C(\C(=O)N3C)C)c4cccc(NC(=O)C)c4)C5CC5
Stdinchi:1S/C26H23FIN5O4/c1-13-22-21(23(31(3)24(13)35)30-20-10-7-15(28)11-19(20)27)25(36)33(17-8-9-17)26(37)32(22)18-6-4-5-16(12-18)29-14(2)34/h4-7,10-12,17,30H,8-9H2,1-3H3,(H,29,34)
Stdinchikey:LIRYPHYGHXZJBZ-UHFFFAOYSA-N

Trametinib, sold under the brand name Mekinist among others, is an anticancer medication used for the treatment of melanoma and glioma.[7] It is a MEK inhibitor drug with anti-cancer activity.[8] It inhibits MEK1 and MEK2. It is taken by mouth.

The most common side effects include rash, diarrhea, tiredness, peripheral edema (swelling, especially of ankles and feet), nausea and acneiform dermatitis (acne-like inflammation of the skin). When taken in combination with dabrafenib the most common side effects include fever, tiredness, nausea, chills, headache, diarrhea, vomiting, joint pain and rash.

In May 2013, trametinib was approved as a single-agent by the US Food and Drug Administration for the treatment of people with V600E mutated metastatic melanoma.[9] [10] It was approved for medical use in the European Union in June 2014.

Medical uses

Trametinib, as monotherapy or in combination with dabrafenib is indicated for the treatment of melanoma and glioma.

History

Clinical trial data demonstrated that resistance to single-agent trametinib often occurs within 6 to 7 months.[11] To overcome this, trametinib was combined with the BRAF inhibitor dabrafenib. As a result of this research, on 8 January 2014, the FDA approved the combination of dabrafenib and trametinib for the treatment of patients with BRAF V600E/K-mutant metastatic melanoma.[12] On 1 May 2018, the FDA approved the combination dabrafenib/trametinib as an adjuvant treatment for BRAF V600E-mutated, stage III melanoma after surgical resection based on the results of the COMBI-AD phase 3 study,[13] making it the first oral chemotherapy regimen that prevents cancer relapse for node positive, BRAF-mutated melanoma.[14]

Society and culture

Legal status

In November 2023, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Spexotras, intended for the treatment of low- and high-grade glioma (LGG and HGG). The applicant for this medicinal product is Novartis Europharm Limited.[15] Spexotras was approved for medical use in the European Union in January 2024.

Research

Trametinib had good results for metastatic melanoma carrying the BRAF V600E mutation in a phase III clinical trial. In this mutation, the amino acid valine (V) at position 600 within the BRAF protein has become replaced by glutamic acid (E) making the mutant BRAF protein constitutively active.[16]

Trametinib has been used off label to treat various RASopathies, including Noonan Syndrome and Primary Intestinal Lymphangiectasia.[17] [18]

Notes and References

  1. Web site: Prescription medicines: registration of new chemical entities in Australia, 2014 . Therapeutic Goods Administration (TGA) . 21 June 2022 . 10 April 2023 . 10 April 2023 . https://web.archive.org/web/20230410065838/https://www.tga.gov.au/resources/resource/guidance/prescription-medicines-registration-new-chemical-entities-australia-2014 . live .
  2. Web site: Product monograph brand safety updates . Health Canada . February 2024 . 24 March 2024.
  3. Web site: Regulatory Decision Summary for Mekinist . Drug and Health Products Portal . 24 July 2023 . 2 April 2024.
  4. Web site: Mekinist- trametinib tablet, film coated . DailyMed . 22 June 2022 . 3 January 2023 . 26 November 2022 . https://web.archive.org/web/20221126082029/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0002ad27-779d-42ab-83b5-bc65453412a1 . live .
  5. Web site: Mekinist EPAR . European Medicines Agency . 17 September 2018 . 27 February 2023 . 9 August 2021 . https://web.archive.org/web/20210809155109/https://www.ema.europa.eu/en/medicines/human/EPAR/mekinist . live . Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  6. Web site: Spexotras Product information . Union Register of medicinal products . 8 January 2024 . 14 January 2024.
  7. Web site: Spexotras EPAR . European Medicines Agency . 9 November 2023 . 14 January 2024.
  8. Web site: Trametinib . NCI Drug Dictionary . U.S. Department of Health and Human Services, National Institutes of Health, National Cancer Institute . 28 February 2023 . 3 January 2023 . https://web.archive.org/web/20230103070845/https://www.cancer.gov/publications/dictionaries/cancer-drug/def/trametinib-dimethyl-sulfoxide . live .
  9. Web site: Drug Approval Package: Mekinist (trametinib) Tablets NDA #204114 . U.S. Food and Drug Administration (FDA) . 8 July 2013 . 27 February 2023 . 27 October 2022 . https://web.archive.org/web/20221027052740/http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204114Orig1s000TOC.cfm . live .
  10. News: GSK melanoma drugs add to tally of U.S. drug approvals . Reuters . 30 May 2013 . 5 July 2021 . 24 September 2015 . https://web.archive.org/web/20150924181713/http://www.reuters.com/article/2013/05/30/us-glaxosmithkline-approvals-idUSBRE94S1A020130530 . live .
  11. Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, Hamid O, Schuchter L, Cebon J, Ibrahim N, Kudchadkar R, Burris HA, Falchook G, Algazi A, Lewis K, Long GV, Puzanov I, Lebowitz P, Singh A, Little S, Sun P, Allred A, Ouellet D, Kim KB, Patel K, Weber J . Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations . The New England Journal of Medicine . 367 . 18 . 1694–703 . November 2012 . 23020132 . 3549295 . 10.1056/NEJMoa1210093 .
  12. News: Dabrafenib/Trametinib Combination Approved for Advanced Melanoma . OncLive . 9 January 2014 . 20 January 2014 . 25 January 2014 . https://web.archive.org/web/20140125190539/http://www.onclive.com/web-exclusives/FDA-Approves-First-Ever-Combination-for-Metastatic-Melanoma . live .
  13. Long GV, Hauschild A, Santinami M, Atkinson V, Mandalà M, Chiarion-Sileni V, Larkin J, Nyakas M, Dutriaux C, Haydon A, Robert C, Mortier L, Schachter J, Schadendorf D, Lesimple T, Plummer R, Ji R, Zhang P, Mookerjee B, Legos J, Kefford R, Dummer R, Kirkwood JM . Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma . The New England Journal of Medicine . 377 . 19 . 1813–1823 . November 2017 . 28891408 . 10.1056/NEJMoa1708539 . 205102412 . Georgina Long . 1 October 2019 . 29 August 2021 . https://web.archive.org/web/20210829180011/https://espace.library.uq.edu.au/data/UQ_697684/UQ697684_OA.pdf?Expires=1630260097&Key-Pair-Id=APKAJKNBJ4MJBJNC6NLQ&Signature=EPxIcTSWneYoXTBn7mhDGqtfvfgtlX1dlcK8GS7IMFEOHtmsmmb10bQPl7E0M1X5LtxFHv8kttrOmDzn-Y-027A8HVX5cijl0RQEzPGsvDnVzVez-KzEEtVzFSjZDKJgKyUToW1DaQMGBsGVizvNibSu2brfR53kiBxpiZb7pzL-NeCGwLw8gGB--EIKBRLbnACKfpUz3tjs6Dlii4Y-yHd0L0SHHK14cEneQ7GZoLDgxTGACHPOsI2ys0~AYQBZpJKm9GVz4GDSQYIL4TtetnSSddgpTuImjMAPrU8LclAsHvw6lPPsYKXI2ZXPEB3e1Wiky4sJ0mXfKzBuP34urw__ . live .
  14. Web site: FDA Approves Adjuvant Combo for BRAF+ Melanoma . www.medscape.com . WebMD LLC . 2 May 2018 . 6 May 2018 . https://web.archive.org/web/20180506065323/https://www.medscape.com/viewarticle/895984 . live .
  15. Web site: Spexotras: Pending EC decision . European Medicines Agency (EMA) . 10 November 2023 . 5 December 2023 . Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  16. Robert C, Flaherty KT, Hersey P, Nathan PD, Garbe C, Milhem MM, Demidov LV, Hassel JC, Rutkowski P, Mohr P, Dummer R . METRIC phase III study: Efficacy of trametinib (T), a potent and selective MEK inhibitor (MEKi), in progression-free survival (PFS) and overall survival (OS), compared with chemotherapy (C) in patients (pts) with BRAFV600E/K mutant advanced or metastatic melanoma (MM) . 10.1200/jco.2012.30.18_suppl.lba8509 . Journal of Clinical Oncology . 30 . 18_suppl . 31 January 2017 . LBA8509 .
  17. Leegaard A, Gregersen PA, Nielsen TØ, Bjerre JV, Handrup MM . Successful MEK-inhibition of severe hypertrophic cardiomyopathy in RIT1-related Noonan Syndrome . European Journal of Medical Genetics . 65 . 11 . 104630 . November 2022 . 36184070 . 10.1016/j.ejmg.2022.104630 . free .
  18. Bergqvist C, Wolkenstein P . MEK inhibitors in RASopathies . Current Opinion in Oncology . 33 . 2 . 110–119 . March 2021 . 33395032 . 10.1097/CCO.0000000000000711 . 230661909 .

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