Trametinib

Trametinib

Clinical data
Trade names	Mekinist, Spexotras
Other names	GSK1120212
AHFS/Drugs.com	Monograph
MedlinePlus	a613040
License data	US DailyMed: Trametinib
Routes of administration	By mouth
ATC code	L01EE01 (WHO)
Legal status
Legal status	AU: S4 (Prescription only)[1] CA: ℞-only[2][3] US: ℞-only[4] EU: Rx-only[5][6][7]
Identifiers
IUPAC name N-(3-{3-Cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)acetamide
CAS Number	871700-17-3
PubChem CID	11707110
DrugBank	DB08911
ChemSpider	9881833
UNII	33E86K87QN
KEGG	D10175
ChEBI	CHEBI:75998
ChEMBL	ChEMBL2103875
CompTox Dashboard (EPA)	DTXSID901007381
ECHA InfoCard	100.158.135
Chemical and physical data
Formula	C26H23FIN5O4
Molar mass	615.404 g·mol^−1
3D model (JSmol)	Interactive image
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
InChI InChI=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) Key:LIRYPHYGHXZJBZ-UHFFFAOYSA-N

Trametinib, sold under the brand name Mekinist among others, is an anticancer medication used for the treatment of melanoma^[4][5] and glioma.^[6][7] It is a MEK inhibitor drug with anti-cancer activity.^[8] It inhibits MEK1 and MEK2.^[8] It is taken by mouth.^[4][5]

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).^[5] When taken in combination with dabrafenib the most common side effects include fever, tiredness, nausea, chills, headache, diarrhea, vomiting, joint pain and rash.^[5]

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.^[5]

Medical uses

Trametinib, as monotherapy or in combination with dabrafenib is indicated for the treatment of melanoma and glioma.^[4][5][6][7]

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.^[11] 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).^[15] The applicant for this medicinal product is Novartis Europharm Limited.^[15] Spexotras was approved for medical use in the European Union in January 2024.^[6][7]

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]

References

1. "Prescription medicines: registration of new chemical entities in Australia, 2014". Therapeutic Goods Administration (TGA). 21 June 2022. Archived from the original on 10 April 2023. Retrieved 10 April 2023.
2. "Product monograph brand safety updates". Health Canada. February 2024. Retrieved 24 March 2024.
3. "Regulatory Decision Summary for Mekinist". Drug and Health Products Portal. 24 July 2023. Retrieved 2 April 2024.
4. "Mekinist- trametinib tablet, film coated". DailyMed. 22 June 2022. Archived from the original on 26 November 2022. Retrieved 3 January 2023.
5. "Mekinist EPAR". European Medicines Agency. 17 September 2018. Archived from the original on 9 August 2021. Retrieved 27 February 2023. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
6. "Spexotras Product information". Union Register of medicinal products. 8 January 2024. Retrieved 14 January 2024.
7. "Spexotras EPAR". European Medicines Agency. 9 November 2023. Retrieved 14 January 2024.
8. "Trametinib". NCI Drug Dictionary. U.S. Department of Health and Human Services, National Institutes of Health, National Cancer Institute. Archived from the original on 3 January 2023. Retrieved 28 February 2023. This article incorporates text from this source, which is in the public domain.
9. "Drug Approval Package: Mekinist (trametinib) Tablets NDA #204114". U.S. Food and Drug Administration (FDA). 8 July 2013. Archived from the original on 27 October 2022. Retrieved 27 February 2023.
10. "GSK melanoma drugs add to tally of U.S. drug approvals". Reuters. 30 May 2013. Archived from the original on 24 September 2015. Retrieved 5 July 2021.
11. Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, et al. (November 2012). "Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations". The New England Journal of Medicine. 367 (18): 1694–703. doi:10.1056/NEJMoa1210093. PMC 3549295. PMID 23020132.
12. "Dabrafenib/Trametinib Combination Approved for Advanced Melanoma". OncLive. 9 January 2014. Archived from the original on 25 January 2014. Retrieved 20 January 2014.
13. Long GV, Hauschild A, Santinami M, Atkinson V, Mandalà M, Chiarion-Sileni V, et al. (November 2017). "Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma" (PDF). The New England Journal of Medicine. 377 (19): 1813–1823. doi:10.1056/NEJMoa1708539. PMID 28891408. S2CID 205102412. Archived (PDF) from the original on 29 August 2021. Retrieved 1 October 2019.
14. "FDA Approves Adjuvant Combo for BRAF+ Melanoma". www.medscape.com. WebMD LLC. Archived from the original on 6 May 2018. Retrieved 2 May 2018.
15. "Spexotras: Pending EC decision". European Medicines Agency (EMA). 10 November 2023. Retrieved 5 December 2023.^{[permanent dead link‍]} 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, et al. (31 January 2017). "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)". Journal of Clinical Oncology. 30 (18_suppl): LBA8509. doi:10.1200/jco.2012.30.18_suppl.lba8509.
17. Leegaard A, Gregersen PA, Nielsen TØ, Bjerre JV, Handrup MM (November 2022). "Successful MEK-inhibition of severe hypertrophic cardiomyopathy in RIT1-related Noonan Syndrome" (PDF). European Journal of Medical Genetics. 65 (11): 104630. doi:10.1016/j.ejmg.2022.104630. PMID 36184070.
18. Bergqvist C, Wolkenstein P (March 2021). "MEK inhibitors in RASopathies". Current Opinion in Oncology. 33 (2): 110–119. doi:10.1097/CCO.0000000000000711. PMID 33395032. S2CID 230661909.