Dabrafenib

Dabrafenib
Clinical data
Trade namesTafinlar
Other namesGSK-2118436
AHFS/Drugs.comMonograph
MedlinePlusa613038
License data
Routes of
administration		By mouth
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • US: ℞-only
  • EU: Rx-only
  • In general: ℞ (Prescription only)
Identifiers
IUPAC name
  • N-{3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard100.215.965 Edit this at Wikidata
Chemical and physical data
FormulaC23H20F3N5O2S2
Molar mass519.56 g·mol−1
3D model (JSmol)
SMILES
  • CC(C)(C)C1=NC(=C(S1)C2=NC(=NC=C2)N)C3=C(C(=CC=C3)NS(=O)(=O)C4=C(C=CC=C4F)F)F
InChI
  • 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, sold under the brand name Tafinlar & Rafinlar[1] ( both by Novartis) among others, is a medication 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.[2][3]

Approvals and indications

The US Food and Drug Administration initially approved dabrafenib as a single agent treatment for patients with BRAF V600E mutation-positive advanced melanoma on May 29, 2013.[4][5] Dabrafenib was approved for use in the European Union in August 2013.[6]

Clinical trial data demonstrated that resistance to dabrafenib and other BRAF inhibitors occurs within six to seven months.[7] To overcome this resistance, the BRAF inhibitor dabrafenib was combined with the MEK inhibitor trametinib.[7] On January 8, 2014, the FDA approved this combination of dabrafenib and trametinib for BRAF V600E/K-mutant metastatic melanoma.[8][9] 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,[10] making it the first oral chemotherapy regimen that prevents cancer relapse for node positive, BRAF-mutated melanoma.[11]

In April 2017, the European Union approved the combination of dabrafenib with trametinib for BRAF V600-positive advanced or metastatic non small-cell lung cancer (NSCLC).[12][13][6]

References

  1. ↑ "Novartis' new drug for mutated lung cancer gets insurance coverage". KBR (in Korean). 2020-02-10. Retrieved 2021-09-02.
  2. ↑ 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): 893–9. doi:10.1517/17425255.2013.794220. PMID 23621583. S2CID 207491581.
  3. ↑ 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.
  4. ↑ "Drug Approval Package: Tafinlar (dabrafenib) Capsules NDA #202806". U.S. Food and Drug Administration (FDA). 24 December 1999. Retrieved 10 April 2020.
  5. ↑ "GSK melanoma drugs add to tally of U.S. drug approvals". Reuters. May 30, 2013.
  6. 1 2 "Tafinlar EPAR". European Medicines Agency (EMA). Retrieved 10 April 2020.
  7. 1 2 Flaherty, Keith T.; Infante, Jeffery R.; Daud, Adil; Gonzalez, Rene; Kefford, Richard F.; Sosman, Jeffrey; Hamid, Omid; Schuchter, Lynn; Cebon, Jonathan; Ibrahim, Nageatte; Kudchadkar, Ragini; Burris, Howard A.; Falchook, Gerald; Algazi, Alain; Lewis, Karl; Long, Georgina V.; Puzanov, Igor; Lebowitz, Peter; Singh, Ajay; Little, Shonda; Sun, Peng; Allred, Alicia; Ouellet, Daniele; Kim, Kevin B.; Patel, Kiran; Weber, Jeffrey (November 1, 2012). "Combined BRAF and MEK Inhibition in Melanoma with BRAF V600 Mutations". New England Journal of Medicine. 367 (18): 1694–703. doi:10.1056/NEJMoa1210093. PMC 3549295. PMID 23020132.
  8. ↑ "Dabrafenib/Trametinib Combination Approved for Advanced Melanoma". OncLive. January 9, 2013.
  9. ↑ 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.
  10. ↑ 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. PMID 28891408. S2CID 205102412.
  11. ↑ "FDA Approves Adjuvant Combo for BRAF+ Melanoma". www.medscape.com. WebMD LLC. Retrieved 2 May 2018.
  12. ↑ "EU Approves Dabrafenib/Trametinib Combination in BRAF+ NSCLC". Targeted Oncology. 4 April 2017. Retrieved 10 April 2020.
  13. ↑ "Mekinist EPAR". European Medicines Agency (EMA). Retrieved 10 April 2020.

Further reading

  • "Dabrafenib". Drug Information Portal. U.S. National Library of Medicine.


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