Chemistry:Encorafenib
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| Trade names | Braftovi |
| Other names | LGX818 |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a618040 |
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| Routes of administration | By mouth |
| Drug class | Antineoplastic agents |
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| Formula | C22H27ClFN7O4S |
| Molar mass | 540.01 g·mol−1 |
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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]
References
- ↑ "Summary Basis of Decision (SBD) for Braftovi". 23 October 2014. https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?linkID=SBD00534&lang=en.
- ↑ 2.0 2.1 "Development of encorafenib for BRAF-mutated advanced melanoma". Current Opinion in Oncology 30 (2): 125–133. March 2018. doi:10.1097/CCO.0000000000000426. PMID 29356698.
- ↑ "The MAPK pathway across different malignancies: a new perspective". Cancer 120 (22): 3446–56. November 2014. doi:10.1002/cncr.28864. PMID 24948110.
- ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 "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 19 December 2019. Retrieved 2018-06-28.
This article incorporates text from this source, which is in the public domain.
- ↑ 5.0 5.1 "Drug Trial Snapshot: Braftovi". 16 July 2018. https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trial-snapshot-braftovi. This article incorporates text from this source, which is in the public domain.
- ↑ "FDA approves encorafenib with binimetinib for metastatic non-small cell lung cancer with a BRAF V600E mutation". 11 October 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-encorafenib-binimetinib-metastatic-non-small-cell-lung-cancer-braf-v600e-mutation.
- ↑ 7.0 7.1 "Encorafenib (LGX818), a potent BRAF inhibitor, induces senescence accompanied by autophagy in BRAFV600E melanoma cells". Cancer Letters 370 (2): 332–44. January 2016. doi:10.1016/j.canlet.2015.11.015. PMID 26586345.
- ↑ "A landscape of driver mutations in melanoma". Cell 150 (2): 251–63. July 2012. doi:10.1016/j.cell.2012.06.024. PMID 22817889.
- ↑ "18 Studies found for: LGX818". Clinicaltrials.gove. https://clinicaltrials.gov/ct2/results?cond=&term=LGX818&cntry=&state=&city=&dist=.
- ↑ 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
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