OVERVIEW

Introduction

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.

Background

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.

Hepatotoxicity

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.

Drug Class: Antineoplastic Agents, Protein Kinase Inhibitors; see also Trametinib

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Dabrafenib – Tafinlar®

DRUG CLASS

Antineoplastic Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

ANNOTATED BIBLIOGRAPHY

References updated: 28 June 2018

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    (Among 125 patients with malignant melanoma and brain metastases [with BRAF V600 mutation] treated with dabrafenib and trametinib, intracranial response were achieved in 44-59% and the most common adverse events were fever and headache; while ALT elevations occurred in 12 patients [10%], none were above 5 times ULN).
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    (Further follow up of patients enrolled in a long term extension of a trial of dabrafenib monotherapy vs combination with trametinib [Long 2014] showed continued benefit of the combination with a survival of 44% vs 32% at 3 years, with ALT elevations in 13% vs 6% which rose above 5 times ULN in 2% vs <1%; no mention of clinically apparent liver injury).
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    (Among 36 patients with metastatic NSCLC treated with dabrafenib and trametinib, the objective response rate was 64% and all patients had at least one adverse event including 6 [17%] with ALT elevations which were above 5 times ULN in 4 [11%], but none were associated with jaundice or symptoms).
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    (Among 135 patients with metastatic melanoma treated with dabrafenib and trametinib in a Spanish open access program, the overall response rate was 68% and adverse events included skin reactions [42%], fever, weakness, arthralgia and diarrhea; no mention of ALT elevations or hepatotoxicity).
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  • Amaria RN, Prieto PA, Tetzlaff MT, Reuben A, Andrews MC, Ross MI, Glitza IC, et al. Neoadjuvant plus adjuvant dabrafenib and trametinib versus standard of care in patients with high-risk, surgically resectable melanoma: a single-centre, open-label, randomised, phase 2 trial. Lancet Oncol 2018; 19: 181-93. [PubMed: 29361468]
    (Among 17 patients with surgically resected melanoma given adjuvant dabrafenib and trametinib or standard of care treatment, progression free survival was greater with the kinase inibitors [20 vs 3 months] and adverse events were mostly fever, fatigue, headache and diarrhea; ALT or AST elevations occurred in only 3 patients [23%] which were all below 5 times ULN).