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]
The most common (≥25%) adverse reactions include fatigue, nausea, diarrhea, vomiting, abdominal pain, and arthralgia.[4]
Medical uses
In October 2023, the US
Food and Drug Administration approved encorafenib with binimetinib for adults with metastatic non-small cell lung cancer (NSCLC) with a BRAF V600E mutation, as detected by an FDA-approved test.[6]
Pharmacology
Encorafenib acts as an ATP-competitive RAF kinase inhibitor, decreasing
ERK phosphorylation and down-regulation of
CyclinD1.[7] This arrests the cell cycle in
G1 phase, inducing
senescence without
apoptosis.[7] Therefore, it is only effective in melanomas with a BRAF mutation, which make up 50% of all melanomas.[8] 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,[9] are being run. As a result of a successful Phase Ib/II trials, Phase III trials are currently being initiated.[10]
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]
^
abLi 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.
PMID26586345.
S2CID2550254.
^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