Encorafenib

Encorafenib, sold under the brand name Braftovi, is an anti-cancer medication used for the treatment of certain melanoma cancers. It is a small molecule BRAF inhibitor [4] that targets key enzymes in the MAPK signaling pathway. This pathway occurs in many different cancers including melanoma and colorectal cancers.[5]

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

Encorafenib was developed by Novartis and Array BioPharma. In June 2018, it was approved by the FDA in combination with binimetinib for the treatment of people with unresectable or metastatic BRAF V600E or V600K mutation-positive melanoma.[6][7]

Medical uses

Encorafenib is indicated in combination with binimetinib, for the treatment of people with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test;[2] in combination with cetuximab, for the treatment of adults with metastatic colorectal cancer with a BRAF V600E mutation, as detected by an FDA-approved test, after prior therapy;[2] in combination with binimetinib, for the treatment of adults with metastatic non-small cell lung cancer with a BRAF V600E mutation, as detected by an FDA-approved test.[2][8]

Encorafenib is not indicated for treatment of people with wild-type BRAF melanoma, wild-type BRAF CRC, or wild-type BRAF NSCLC.[2]

In December 2024, the FDA granted accelerated approval to encorafenib with cetuximab and mFOLFOX6 (fluorouracil

Pharmacology

Encorafenib acts as an ATP-competitive RAF kinase inhibitor, decreasing ERK phosphorylation and down-regulation of CyclinD1.[10] This arrests the cell cycle in G1 phase, inducing senescence without apoptosis.[10] Therefore, it is only effective in melanomas with a BRAF mutation, which make up 50% of all melanomas.[11] The plasma elimination half-life of encorafenib is approximately 6 hours, occurring mainly through metabolism via cytochrome P450 enzymes.[4]

History

Approval of encorafenib in the United States was based on a randomized, active-controlled, open-label, multicenter trial (COLUMBUS; NCT01909453) in 577 participants with BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma.[6] Participants 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.[6] Treatment continued until disease progression or unacceptable toxicity.[6]

The major efficacy measure was progression-free survival (PFS) using RECIST 1.1 response criteria and assessed by blinded independent central review.[6] The median PFS was 14.9 months for participants 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).[6] The trial was conducted at 162 sites in Europe, North America, and various countries around the world.[7]