ENCORAFENIB AND BINIMETINIB
Encorafenib and Binimetinib
Encorafenib is a selective inhibitor of BRAF kinase that is used in combination with binimetinib, an inhibitor of MEK, in the therapy of metastatic and advanced malignant melanoma. Encorafenib-binimetinib combination therapy is commonly associated with transient elevations in serum aminotransferase levels during therapy, but has yet to be linked to instances of clinically apparent acute liver injury.
Encorafenib (en' co raf" e nib) is an orally available, inhibitor of mutated forms of BRAF, a serine/threonine kinase that is a component of the mitogen-activated pathway (MAP) kinases, which are important intracellular signals involved in control of cell growth and proliferation. BRAF is an early step in the cascade of MAP kinases (RAS-RAF-MEK-ERK) and is frequently mutated in malignant conditions, including at least half of cases of melanoma. Binimetinib (bin' i me' ti nib) is an orally available inhibitor of MEK, mitogen-activated protein kinase kinase, another important component of the MAP kinase pathway. Encorafenib was shown to have enhanced activity against selected mutants of BRAF in vitro and in animal models. In clinical trials, the combination of encorafenib with binimetinib was associated with an improvement in overall survival in patients with metastatic malignant melanoma with V600E and V600K mutations in comparison to standard therapies. Furthermore, the combination appeared to be better tolerated than encorafenib alone. The combination of encorafenib with binimetinib was approved for use in the United States in 2018 and current indications are for unresectable or metastatic melanoma with the BRAF V600E or V600K mutations. Encorafenib is available in tablets of 50 and 75 mg under the brand name Braftovi and binimetinib as tablets of 15 mg under the brand name Mektovi. The recommended dose regimen is 450 mg of encorafenib once daily in combination with 45 mg of binimetinib twice daily (30 mg twice daily in patients with moderate or severe liver impairment). The combination should be continued until disease progression or unacceptable toxicities arise. Common side effects include fatigue, nausea, arthralgias, rash, alopecia, photosensitivity, pruritus, and skin papilloma. Uncommon but potentially severe side effects include new primary malignancies, both cutaneous and non-cutaneous, hemorrhage, uveitis and other ocular toxicities, rhabdomyolysis, prolongation of QTc intervals and embryo-fetal toxicity.
In large clinical trials of the combination of encorafenib and binimetinib, abnormalities in routine liver tests were common and serum ALT elevations occurred in 26% of patients. ALT and AST values greater than 5 times the upper limit of normal (ULN) occurred in 6% and led to dose modification or discontinuation in 3.6% of patients. However, the aminotransferase abnormalities were generally transient and asymptomatic and there were no reports of clinically apparent liver injury with jaundice reported from the prelicensure studies. Since its approval and more widespread use, there have been no published instances of clinically apparent hepatotoxicity attributed to this combination therapy, but the total experience with its use has been limited.
Likelihood score: E* (unproven but suspected rare cause of clinically apparent liver injury).
Mechanism of Injury
The mechanism of injury accounting for serum enzyme elevations during encorafenib/binimetinib therapy is not known. Encorafenib is metabolized in the liver largely through the CYP 3A4 pathway and is susceptible to drug-drug interactions with agents that inhibit or induce hepatic CYP 3A4 activity. Binimetinib is metabolized largely via UGT1A1 and to a lesser extent by CYP 1A2 and 2C19. The two kinase inhibitors do not appear to affect the metabolic disposition of each other. Discontinuation of binimetinib should lead to a reduction in the dose of encorafenib (to 300 mg daily), while discontinuation of encorafenib should trigger discontinuation of binimetinib.
Outcome and Management
Serum aminotransferase elevations above 5 times the upper limit of normal (if confirmed) or any elevations accompanied by jaundice or symptoms should lead to dose reduction or temporary cessation. There does not appear to be cross reactivity in risk for hepatic injury between encorafenib and binimetinib and other similar kinase inhibitors such as darafenib and vermurafenib and, in some situations, switching to another BRAF/MEK inhibitors may be appropriate.
Drug Class: Antineoplastic Agents, Protein Kinase Inhibitors
Encorafenib and Binimetinib
Encorafenib – Braftovi®
Binimetinib – Mektovi®
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