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Dabrafenib is a selective inhibitor of mutated forms of BRAF kinase and is used 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 BRAF V600E mutation.  Dabrafenib was approved for use in the United States in 2013.  It 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 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 and squamous cell skin cancer.



Elevations in serum ALT levels were reported in 11% of patients treated with dabrafenib alone, but all elevations were ≤5 times ULN.  When dabrafenib was given in combination with trametinib, serum ALT elevations occurred in 35% to 42% of patients and were ≥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.


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

Serum aminotransferase elevations above 5 times the upper limit of normal (if confirmed) or 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 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


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Dabrafenib – Tafinlar®


Antineoplastic Agents



Product labeling at DailyMed, National Library of Medicine, NIH


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Dabrafenib 1195765-45-7 C23-H20-F3-N5-O2-S2 Dabrafenib chemical structure

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References updated: 25 July 2014

  1. Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999.  (Review of hepatotoxicity published in 1999 before the availability of tyrosine kinase receptor inhibitors such as dabrafenib).

  2. DeLeve LD. Erlotinib. Cancer chemotherapy. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 556. (Review of hepatotoxicity of cancer chemotherapeutic agents discusses several tyrosine kinase inhibitors including imatinib, gefitinib, erlotinib and crizotinib, but not dabrafenib).

  3. Chabner BA, Barnes J, Neal J, Olson E, Mujagic H, Sequist L, Wilson W, et al. Targeted therapies: tyrosine kinase inhibitors, monoclonal antibodies, and cytokines. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1731-54.  (Textbook of pharmacology and therapeutics).

  4. Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, Hamid O, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 2012; 367: 1694-703. PubMed Citation  (Among 247 patients with metastatic melanoma and BRAF V600 mutations, progression free survival was prolonged by the combination of trametinib and dabrafenib compared to dabrafenib alone [mean 9.2 and 9.4 months vs 5.8 months]; most side effects were more common with the combination, but cutaneous squamous cell carcinoma was less [2% and 7% vs 19%]; no mention of hepatotoxicity or ALT elevations).

  5. Long GV, Trefzer U, Davies MA, Kefford RF, Ascierto PA, Chapman PB, Puzanov I, et al. Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain(BREAK-MB): a multicentre, open-label, phase 2 trial. Lancet Oncol 2012; 13: 1087-95. PubMed Citation  (Among 255 patients with malignant melanoma metastatic to the brain, objective responses to dabrafenib occurred in 31-39% of patients with BRAF V600E, but in only 7-22% of those with V600K mutations; ALT elevations ≥3 times ULN occurred in 2-4% of dabrafenib treated subjects).

  6. Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, Rutkowski P, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 2012; 380 (9839): 358-65. PubMed Citation  (Among 250 patients with metastatic melanoma and BRAF mutations, progression free survival was longer with dabrafenib than dacarbazine therapy [5.1 vs 2.7 months], but side effects were more frequent with dabrafenib and included skin toxicity, fever, fatigue, arthralgias and headache; no mention of ALT elevations or hepatotoxicity).

  7. Falchook GS, Long GV, Kurzrock R, Kim KB, Arkenau TH, Brown MP, Hamid O, et al. Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. Lancet 2012; 379 (9829): 1893-901. PubMed Citation  (Among 184 patients with various advanced malignancies [156 with melanoma] treated with dabrafenib in varying doses, responses occurred only in patients with BRAF mutations, the optimal dose appeared to be 150 mg twice daily and dose limiting side effects include cutaneous squamous cell carcinoma [11%], fatigue and fever).

  8. Dabrafenib (Tafinlar) and trametinib (Mekinist) metastatic melanoma. Med Lett Drugs Ther 2013; 55 (1422): 62-3. PubMed Citation  (Concise review of mechanism of action, efficacy, safety and cost of dabrafenib with or without trametinib for metastatic melanoma shortly after their approval in the US; no mention of ALT elevations or hepatotoxicity).

  9. King AJ, Arnone MR, Bleam MR, Moss KG, Yang J, Fedorowicz KE, Smitheman KN, et al. Dabrafenib; preclinical characterization, increased efficacy when combined with trametinib, while BRAF/MEK tool combination reduced skin lesions. PLoS One 2013; 8: e67583. PubMed Citation  (Review of the development, mechanism of action and efficacy of dabrafenib, a specific inhibitor of V600E mutant BRAF; no discussion of hepatotoxicity).

  10. Ascierto PA, Minor D, Ribas A, Lebbe C, O'Hagan A, Arya N, Guckert M, et al. Phase II trial (BREAK-2) of the BRAF inhibitor dabrafenib (GSK2118436) in patients with metastatic melanoma. J Clin Oncol 2013; 31: 3205-11. PubMed Citation  (Among 92 patients with metastatic melanoma and BRAF mutations treated with dabrafenib, confirmed responses occurred in 59% with BRAF V600E, but only 13% with V600K; adverse events occurred in 93% of patients and included arthralgia, hyperkeratosis, fever, fatigue, headache and nausea; but no mention was made of ALT elevations or hepatotoxicity).

  11. Ballantyne AD, Garnock-Jones KP. Dabrafenib: first global approval. Drugs 2013; 73: 1367-76. PubMed Citation  (Review of the structure, mechanism of action, pharmacology, efficacy and safety of dabrafenib given alone or in combination with trametinib, mentions ALT elevations occurred in 2% and 5% of patients in one clinical study).

  12. Spraggs CF, Xu CF, Hunt CM. Genetic characterization to improve interpretation and clinical management of hepatotoxicity caused by tyrosine kinase inhibitors. Pharmacogenomics 2013; 14: 541-54. PubMed Citation  (Review of genetic associations of serum ALT and bilirubin elevations during therapy with tyrosine kinase inhibitors, focusing on lapatinib and pazopanib).

  13. Shah RR, Morganroth J, Shah DR. Hepatotoxicity of tyrosine kinase inhibitors: clinical and regulatory perspectives. Drug Saf 2013; 36: 491-503. PubMed Citation  (Review of the hepatotoxicity of 18 tyrosine kinase inhibitors approved for use in cancer in the US as of 2013; dabrafenib is not discussed).

  14. Rutkowski P, Blank C. Dabrafenib for the treatment of BRAF V600-positive melanoma: a safety evaluation. Expert Opin Drug Saf 2014: 1-10. [Epub ahead of print] PubMed Citation  (Review of the safety of dabrafenib in treatment of melanoma, lists 23 common adverse effects of dabrafenib, but not ALT elevations or hepatotoxicity).

  15. Amaria RN, Kim KB. Dabrafenib for the treatment of melanoma. Expert Opin Pharmacother 2014; 15: 1043-50. PubMed Citation  (Review of the rationale behind the development of dabrafenib, its mechanism of action, pharmacology, preclinical activity and basis for efficacy in malignant melanoma; no mention of ALT elevations or hepatotoxicity).

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  1. PubMed logoRecent References on Dabrafenib

  2. Clinical Trials logoTrials on Dabrafenib

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