Dabrafenib is a selective inhibitor of mutated forms of BRAF kinase and is used alone or in combination with trametinib in the treatment of advanced malignant melanoma. Dabrafenib therapy is associated with transient elevations in serum aminotransferase during therapy, but has not been linked to instances of clinically apparent acute liver injury.
Dabrafenib (da braf’ e nib) is an orally available, small molecule inhibitor of certain mutated forms of BRAF kinase, a serine/threonine kinase that is frequently mutated in patients with malignant melanoma and other solid tumors. BRAF is an isoform of RAF, an early step in the mitogen-activated protein (MAP) kinase pathway which is an important cascade of kinases (RAS-RAF-MEK-ERK) that controls cell activation, growth and proliferation. Mutated forms of BRAF can cause dysregulation of cell growth resulting in tumor progression. Clinical trials of dabrafenib in patients with advanced melanoma have shown that it prolongs progression free survival in humans, but the effect seemed to be limited to patients with the BRAF V600E mutation. Dabrafenib was approved for use in the United States in 2013 and the combination of dabrafenib with trametinib (a inhibitor of MEK, a kinase active downstream of BRAF in the MAP kinase pathway) in 2014. Dabrafenib is currently indicated as a single agent for treatment of unresectable or metastatic melanoma with the BRAF V600E mutation, and in combination with trametinib for patients with advanced melanoma with BRAF V600E or V600K mutations. Dabrafenib is available in capsules of 50 and 75 mg under the brand name Tafinlar. The recommended dose is 150 mg orally twice daily. Common side effects include hyperkeratosis, skin rash, headache, fever, alopecia and peripheral neuropathy. Uncommon, but potentially severe side effects include serious skin toxicity including squamous cell carcinoma, venous thrombosis, cardiomyopathy, ocular toxicities and serious febrile reactions. Dabrafenib may cause a paradoxical stimulation of wild-type BRAF which may account for some of its adverse effects, including hyperkeratosis, squamous cell skin cancer and tumor progression in patients with melanoma that have BRAF-wild type mutations. The paradoxical effects of dabrafenib are less frequent when it is combined with trametinib.
Elevations in serum ALT levels were reported in 11% of patients treated with dabrafenib alone, but all elevations were above 5 times ULN. When dabrafenib was given in combination with trametinib, serum ALT elevations occurred in 35% to 42% of patients and were above 5 times ULN in 4%. Similarly, serum alkaline phosphatase elevations occurred in 26% of patients given dabrafenib alone, but in 60% to 67% given dabrafenib and trametinib. These abnormalities were largely asymptomatic and fully reversible. There were no instances of clinically apparent acute liver injury or hepatic failure reported in prelicensure studies of dabrafenib and, since its approval and more wide spread use, there have been no published reports of dabrafenib hepatotoxicity.
Likelihood score: E* (unproven but suspected cause of clinically apparent liver injury).
Mechanism of Injury
The cause of the transient serum enzyme elevations during dabrafenib therapy is not known. Dabrafenib is metabolized in the liver largely through the cytochrome P450 pathway (CYP 3A4 and 2C8) and liver injury may be related to production of a toxic intermediate. Dabrafenib also induces CYP 3A4 and 2C8 activity and is susceptible to drug-drug interactions with agents that inhibit or induce or are metabolized by these hepatic drug metabolizing enzymes.
Outcome and Management
In using kinase inhibitors for treatment of cancer, monitoring of routine liver tests before starting and during therapy is warranted. Serum aminotransferase elevations above 5 times the upper limit of normal (if confirmed) or elevations accompanied by jaundice or symptoms should lead to temporary cessation. Dabrafenib should not be restarted until the liver test abnormalities improve or resolve and then only with careful monitoring. There does not appear to be cross reactivity in risk for hepatic injury between dabrafenib and other inhibitors of the MAP kinase pathway and, in some situations, switching to another kinase inhibitor may be appropriate.
REPRESENTATIVE TRADE NAMES
Dabrafenib – Tafinlar®
Product labeling at DailyMed, National Library of Medicine, NIH
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References updated: 28 June 2018
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