Encorafenib

Encorafenib, sold under the brand name Braftovi, is a medication for the treatment of certain melanoma cancers. It is a small molecule BRAF inhibitor [2] that targets key enzymes in the MAPK signaling pathway. This pathway occurs in many different cancers including melanoma and colorectal cancers.[3] The substance was being developed by Novartis and then by Array BioPharma. In June 2018, it was approved by the FDA in combination with binimetinib for the treatment of patients with unresectable or metastatic BRAF V600E or V600K mutation-positive melanoma.[4][5]

Encorafenib
Clinical data
Trade namesBraftovi
Other namesLGX818
AHFS/Drugs.comMonograph
MedlinePlusa618040
License data
Routes of
administration		By mouth
Drug classAntineoplastic agents
ATC code
Legal status
Legal status
Identifiers
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
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
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

The most common (≥25%) adverse reactions include fatigue, nausea, diarrhea, vomiting, abdominal pain, and arthralgia.[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.[2]

Clinical trials

Several clinical trials of LGX818, either alone or in combinations with the MEK inhibitor MEK162,[8] are being run. As a result of a successful Phase Ib/II trials, Phase III trials are currently being initiated.[9]

History

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.[4] Patients 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.[4] Treatment continued until disease progression or unacceptable toxicity.[4]

The major efficacy measure was progression-free survival (PFS) using RECIST 1.1 response criteria and assessed by blinded independent central review.[4] 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).[4] The trial was conducted at 162 sites in Europe, North America and various countries around the world.[5]

References
  1. "Summary Basis of Decision (SBD) for Braftovi". Health Canada. Retrieved 29 May 2022.
  2. 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.
  3. Burotto M, Chiou VL, Lee JM, Kohn EC (November 2014). "The MAPK pathway across different malignancies: a new perspective". Cancer. 120 (22): 3446–56. doi:10.1002/cncr.28864. PMC 4221543. PMID 24948110.
  4. "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. This article incorporates text from this source, which is in the public domain.
  5. "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. This article incorporates text from this source, which is in the public domain.
  6. 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. S2CID 2550254.
  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. "18 Studies found for: LGX818". Clinicaltrials.gove.
  9. 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.
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