Dabrafenib

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]

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
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

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. "Tafinlar EPAR". European Medicines Agency (EMA). Retrieved 10 April 2020.
  7. 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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