Trametinib

Trametinib
Clinical data
Trade names	Mekinist
Other names	GSK1120212
AHFS/Drugs.com	Monograph
MedlinePlus	a613040
License data	EU EMA: by INN; US DailyMed: Mekinist;
Pregnancy; category	US: D (Evidence of risk) ;
ATC code	L01XE25 (WHO) ;
Legal status
Legal status	AU: S4 (Prescription only) ; US: ℞-only ;
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;
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 (trade name Mekinist) is a cancer drug. It is a MEK inhibitor drug with anti-cancer activity.[1]

It inhibits MEK1 and MEK2.[1]

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.[2]

In May 2013, trametinib was approved as a single-agent by the Food and Drug Administration for the treatment of patients with V600E mutated metastatic melanoma.[3] Clinical trial data demonstrated that resistance to single-agent trametinib often occurs within 6 to 7 months.[4] To overcome this, trametinib was combined with the BRAF inhibitor dabrafenib.[4] As a result of this research, on January 8, 2014, the FDA approved the combination of dabrafenib and trametinib for the treatment of patients with BRAF V600E/K-mutant metastatic melanoma.[5] On May 1, 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,[6] making it the first oral chemotherapy regimen that prevents cancer relapse for node positive, BRAF-mutated melanoma.[7]

Other uses

In a person with a sequence variant in the ARAF gene, trametinib helped the lymphatic system to remodel toward a healthier state, reducing lymphatic edema.[8] This benefit would not occur in most people because it is specific to genomes similar to the reported one, but it is potentially lifesaving for the few people with such genomes.[8] This case provides an example of what precision medicine can accomplish.[8]

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References

"Trametinib". NCI Drug Dictionary. U.S. Department of Health and Human Services, National Institutes of Health, National Cancer Institute.
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.
"GSK melanoma drugs add to tally of U.S. drug approvals". Reuters. May 30, 2013.
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.
"Dabrafenib/Trametinib Combination Approved for Advanced Melanoma". OncLive. January 9, 2014.
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.
"FDA Approves Adjuvant Combo for BRAF+ Melanoma". www.medscape.com. WebMD LLC. Retrieved 2 May 2018.
Li, Dong; March, Michael E; Gutierrez-Uzquiza, Alvaro; Kao, Charlly; et al. (2019), "ARAF recurrent mutation causes central conducting lymphatic anomaly treatable with a MEK inhibitor", Nature Medicine, 25 (7): 1116–1122, doi:10.1038/s41591-019-0479-2, PMID 31263281.

External links

"Trametinib". Drug Information Portal. U.S. National Library of Medicine.

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[nci-1] "Trametinib". NCI Drug Dictionary. U.S. Department of Health and Human Services, National Institutes of Health, National Cancer Institute.

[2] 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.

[3] "GSK melanoma drugs add to tally of U.S. drug approvals". Reuters. May 30, 2013.

[NEJM-4] 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.

[5] "Dabrafenib/Trametinib Combination Approved for Advanced Melanoma". OncLive. January 9, 2014.

[Long_et_al-6] 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.

[Medscape-7] "FDA Approves Adjuvant Combo for BRAF+ Melanoma". www.medscape.com. WebMD LLC. Retrieved 2 May 2018.

[pmid-31263281-8] Li, Dong; March, Michael E; Gutierrez-Uzquiza, Alvaro; Kao, Charlly; et al. (2019), "ARAF recurrent mutation causes central conducting lymphatic anomaly treatable with a MEK inhibitor", Nature Medicine, 25 (7): 1116–1122, doi:10.1038/s41591-019-0479-2, PMID 31263281.