Encorafenib

Encorafenib
Names
Trade namesBraftovi
Other namesLGX818
IUPAC name
  • Methyl [(2S)-1-{[4-(3-{5-chloro-2-fluoro-3-[(methylsulfonyl)amino]phenyl}-1-isopropyl-1H-pyrazol-4-yl)-2-pyrimidinyl]amino}-2-propanyl]carbamate
Clinical data
Drug classBRAF kinase inhibitor[1]
Main usesMelanoma, colorectal cancer[2]
Side effectsTiredness, nausea, diarrhea,, abdominal pain, rash, joint pain[2]
Routes of
use		By mouth
Typical dose300 to 450 mg OD[2]
External links
AHFS/Drugs.comMonograph
US NLMEncorafenib
MedlinePlusa618040
Legal
License data
Legal status
Chemical and physical data
FormulaC22H27ClFN7O4S
Molar mass540.01 g·mol−1
3D model (JSmol)
SMILES
  • C[C@@H](CNc1nccc(n1)c2cn(nc2c3cc(cc(c3F)NS(=O)(=O)C)Cl)C(C)C)NC(=O)OC
InChI
  • InChI=1S/C22H27ClFN7O4S/c1-12(2)31-11-16(17-6-7-25-21(28-17)26-10-13(3)27-22(32)35-4)20(29-31)15-8-14(23)9-18(19(15)24)30-36(5,33)34/h6-9,11-13,30H,10H2,1-5H3,(H,27,32)(H,25,26,28)/t13-/m0/s1
  • Key:CMJCXYNUCSMDBY-ZDUSSCGKSA-N

Encorafenib, sold under the brand name Braftovi, is a medication used to treat melanoma and colorectal cancer.[2] Specifically it is used for cases which are BRAF V600E or V600K mutation-positive that cannot be removed by surgery.[2] It is taken by mouth.[1]

Common side effects include tiredness, nausea, diarrhea,, abdominal pain, rash, and joint pain.[2] Other side effects may include bleeding, uveitis, QT prolongation, and other cancers.[2] In those with minor liver problems a lower dose should be used.[3] Use in pregnancy may harm the baby.[2] It is a kinase inhibitor that blocks the BRAF protein.[2][4]

Encorafenib was approved for medical use in the United States and Europe in 2018.[1][4] In the United Kingdom for 4 weeks it costs the NHS about £5,600 as of 2021.[3] In the United States this amount costs about 12,400 USD.[5]

Medical uses

Dosage

For melanoma it is used at a dose of 450 mg per day together with binimetinib.[2]

For colorectal cancer it is used at a dose of 300 mg per day together with cetuximab.[2]

Treatment is continued as long as it is working.[4]

Pharmacology

Encorafenib acts as an ATP-competitive RAF kinase inhibitor, decreasing ERK phosphorylation and down-regulation of CyclinD1.[6] This arrests the cell cycle in G1 phase, inducing senescence without apoptosis.[6] Therefore, it is only effective in melanomas with a BRAF mutation, which make up 50% of all melanomas.[7] The plasma elimination half-life of encorafenib is approximately 6 hours, occurring mainly through metabolism via cytochrome P450 enzymes.[8]

History

In June 2018, it was approved by the FDA in combination with binimetinib for people with unresectable or metastatic BRAF V600E or V600K mutation-positive melanoma.[9][10]

Approval of encorafenib in the United States was based on a randomized, active-controlled, open-label, multicenter trial (COLUMBUS; NCT01909453) in 577 patients with BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma.[9] People were randomized (1:1:1) to receive binimetinib 45 mg twice daily plus encorafenib 450 mg once daily, encorafenib 300 mg once daily, or vemurafenib 960 mg twice daily.[9] Treatment continued until disease progression or unacceptable toxicity.[9]

The major efficacy measure was progression-free survival (PFS) using RECIST 1.1 response criteria and assessed by blinded independent central review.[9] The median PFS was 14.9 months for patients receiving binimetinib plus encorafenib, and 7.3 months for the vemurafenib monotherapy arm (hazard ratio 0.54, 95% CI: 0.41, 0.71, p<0.0001).[9] The trial was conducted at 162 sites in Europe, North America and various countries around the world.[10]

Research

Several trials of LGX818, either alone or in combinations with the MEK inhibitor MEK162,[11] are being run. As a result of a successful Phase Ib/II trials, Phase III trials are currently being initiated.[12]

References

  1. 1 2 3 "Encorafenib Monograph for Professionals". Drugs.com. Archived from the original on 20 July 2021. Retrieved 15 December 2021.
  2. 1 2 3 4 5 6 7 8 9 10 11 "DailyMed - BRAFTOVI- encorafenib capsule". dailymed.nlm.nih.gov. Archived from the original on 21 April 2021. Retrieved 15 December 2021.
  3. 1 2 BNF 81: March-September 2021. BMJ Group and the Pharmaceutical Press. 2021. p. 1023. ISBN 978-0857114105.
  4. 1 2 3 "Braftovi". Archived from the original on 16 September 2021. Retrieved 15 December 2021.
  5. ↑ "Braftovi Prices, Coupons & Patient Assistance Programs". Drugs.com. Archived from the original on 19 April 2021. Retrieved 15 December 2021.
  6. 1 2 Li Z, Jiang K, Zhu X, Lin G, Song F, Zhao Y, Piao Y, Liu J, Cheng W, Bi X, Gong P, Song Z, Meng S (January 2016). "Encorafenib (LGX818), a potent BRAF inhibitor, induces senescence accompanied by autophagy in BRAFV600E melanoma cells". Cancer Letters. 370 (2): 332–44. doi:10.1016/j.canlet.2015.11.015. PMID 26586345.
  7. ↑ Hodis E, Watson IR, Kryukov GV, Arold ST, Imielinski M, Theurillat JP, et al. (July 2012). "A landscape of driver mutations in melanoma". Cell. 150 (2): 251–63. doi:10.1016/j.cell.2012.06.024. PMC 3600117. PMID 22817889.
  8. ↑ Koelblinger P, Thuerigen O, Dummer R (March 2018). "Development of encorafenib for BRAF-mutated advanced melanoma". Current Opinion in Oncology. 30 (2): 125–133. doi:10.1097/CCO.0000000000000426. PMC 5815646. PMID 29356698.
  9. 1 2 3 4 5 6 "FDA approves encorafenib and binimetinib in combination for unresectable or metastatic melanoma with BRAF mutations". U.S. Food and Drug Administration (FDA) (Press release). 27 June 2018. Archived from the original on 18 December 2019. Retrieved 28 June 2018. Public Domain This article incorporates text from this source, which is in the public domain.
  10. 1 2 "Drug Trial Snapshot: Braftovi". U.S. Food and Drug Administration (FDA). 16 July 2018. Archived from the original on 19 December 2019. Retrieved 18 December 2019. Public Domain This article incorporates text from this source, which is in the public domain.
  11. ↑ "18 Studies found for: LGX818". Clinicaltrials.gove. Archived from the original on 19 July 2021. Retrieved 10 August 2021.
  12. ↑ Clinical trial number NCT01909453 for "Study Comparing Combination of LGX818 Plus MEK162 and LGX818 Monotherapy Versus Vemurafenib in BRAF Mutant Melanoma (COLUMBUS)" at ClinicalTrials.gov
  • "Encorafenib". Drug Information Portal. U.S. National Library of Medicine. Archived from the original on 20 July 2021. Retrieved 10 August 2021.
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