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Dabrafenib

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Dabrafenib
Clinical data
Trade namesTafinlar
License data
ATC code
Legal status
Legal status
Identifiers
  • N-{3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide
CAS Number
PubChem CID
ChemSpider
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.215.965 Edit this at Wikidata
Chemical and physical data
FormulaC23H20F3N5O2S2
Molar mass519.56 g/mol g·mol−1
3D model (JSmol)
  • CC(C)(C)c1nc(c(s1)c2ccnc(n2)N)c3cccc(c3F)NS(=O)(=O)c4c(cccc4F)F
  • InChI=1S/C23H20F3N5O2S2/c1-23(2,3)21-30-18(19(34-21)16-10-11-28-22(27)29-16)12-6-4-9-15(17(12)26)31-35(32,33)20-13(24)7-5-8-14(20)25/h4-11,31H,1-3H3,(H2,27,28,29)
  • Key:BFSMGDJOXZAERB-UHFFFAOYSA-N

Dabrafenib (trade name Tafinlar, GSK2118436) is a drug 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. Dabrafenib has clinical activity with a manageable safety profile in clinical trials of phase 1 and 2 in patients with BRAF(V600)-mutated metastatic melanoma.[1][2]

Approvals and indications

The Food and Drug Administration initially approved dabrafenib as a single agent treatment for patients with BRAF V600E mutation-positive advanced melanoma on May 30, 2013.[3]

Clinical trial data demonstrated that resistance to dabrafenib and other BRAF inhibitors occurs within 6 to 7 months.[4] To overcome this resistance, the BRAF inhibitor dabrafenib was combined with the MEK inhibitor trametinib.[4] On January 8, 2014, the FDA approved this combination of dabrafenib and trametinib for BRAF V600E/K-mutant metastatic melanoma.[5][6] 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,[7] making it the first oral chemotherapy regimen that prevents cancer relapse for node positive, BRAF-mutated melanoma.[8]

[April 2017] The European Union approved the combination with trametinib for BRAF V600-positive advanced or metastatic non small-cell lung cancer (NSCLC).[9]

Further reading

U.S. National Center for Biotechnology Information: Medical Genetics Summaries - Dabrafenib Therapy and BRAF and G6PD Genotype

References

  1. ^ Gibney, G. T.; Zager, J. S. (2013). "Clinical development of dabrafenib in BRAF mutant melanoma and other malignancies". Expert Opinion on Drug Metabolism & Toxicology. 9 (7): 1. doi:10.1517/17425255.2013.794220. PMID 23621583.
  2. ^ Huang, T.; Karsy, M.; Zhuge, J.; Zhong, M.; Liu, D. (2013). "B-Raf and the inhibitors: From bench to bedside". Journal of Hematology & Oncology. 6: 30. doi:10.1186/1756-8722-6-30. PMC 3646677. PMID 23617957.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  3. ^ "GSK melanoma drugs add to tally of U.S. drug approvals". Reuters. May 30, 2013.
  4. ^ a b "Combined BRAF and MEK Inhibition in Melanoma with BRAF V600 Mutations". 367 (18). New England Journal of Medicine. November 1, 2012: 1694–703. doi:10.1056/NEJMoa1210093. PMC 3549295. PMID 23020132. {{cite journal}}: Cite journal requires |journal= (help)
  5. ^ "Dabrafenib/Trametinib Combination Approved for Advanced Melanoma". OncLive. January 9, 2013.
  6. ^ Maverakis E; Cornelius LA; Bowen GM; Phan T; Patel FB; Fitzmaurice S; He Y; Burrall B; Duong C; Kloxin AM; Sultani H; Wilken R; Martinez SR; Patel F (2015). "Metastatic melanoma – a review of current and future treatment options". Acta Derm Venereol. 95 (5): 516–524. doi:10.2340/00015555-2035. PMID 25520039.
  7. ^ Long, Georgina V.; Hauschild, Axel; Santinami, Mario; Atkinson, Victoria; Mandalà, Mario; Chiarion-Sileni, Vanna; Larkin, James; Nyakas, Marta; Dutriaux, Caroline; Haydon, Andrew; Robert, Caroline; Mortier, Laurent; Schachter, Jacob; Schadendorf, Dirk; Lesimple, Thierry; Plummer, Ruth; Ji, Ran; Zhang, Pingkuan; Mookerjee, Bijoyesh; Legos, Jeff; Kefford, Richard; Dummer, Reinhard; Kirkwood, John M. (9 November 2017). "Adjuvant Dabrafenib plus Trametinib in Stage III-Mutated Melanoma". New England Journal of Medicine. 377 (19): 1813–1823. doi:10.1056/NEJMoa1708539. Retrieved 7 August 2018.
  8. ^ "FDA Approves Adjuvant Combo for BRAF+ Melanoma". www.medscape.com. WebMD LLC. Retrieved 2 May 2018.
  9. ^ Dabrafenib/Trametinib Combo Wins EU Approval for BRAF+ NSCLC. April 2017


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