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Vemurafenib is a selective inhibitor of BRAF kinase that is used in the therapy of metastatic and advanced malignant melanoma.  Vemurafenib therapy is commonly associated with transient elevations in serum aminotransferase during therapy and has been linked to rare, but occasionally severe cases of clinically apparent acute liver injury.



Vemurafenib (vem’ ue 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.  Vemurafenib was shown to be active against the V600E mutants of BRAF in vitro and in animal models.  Furthermore, in clinical trials vemurafenib therapy was associated with an improvement in overall survival in patients with metastatic malignant melanoma with V600E mutations.  Vemurafenib was approved for use in the United States in 2011 and current indications are for unresectable or metastatic melanoma with the BRAF V600E mutation.  Vemurafenib is available in tablets of 240 mg under the brand name Zelboraf.  The typical dose is 960 mg (4 tablets) twice daily.  Common side effects include fatigue, nausea, arthralgias, rash, alopecia, photosensitivity, pruritus, and skin papilloma.  Uncommon, but potentially severe side effects include severe skin and hypersensitivity reactions, cutaneous squamous cell carcinoma, ocular toxicity, and prolonged QTc intervals.



In large clinical trials of vemurafenib, abnormalities in routine liver tests were common and serum aminotransferase elevations occurred in up to one third of patients.  ALT and AST values greater than 5 times the upper limit of normal (ULN) occurred in 3% of patients, and rare instances of clinically apparent liver injury were reported, but the clinical features of the injury have not been described.  The onset of liver test abnormalities was typically within 3 to 6 weeks of starting vemurafenib, and the abnormalities resolved rapidly either spontaneously or with temporary drug discontinuation.


Mechanism of Injury

The mechanism of injury accounting for serum enzyme elevations during vemurafenib therapy is not known.  Vemurafenib is metabolized in the liver largely through the CYP 1A2 pathway and liver injury may be related to production of a toxic intermediate.  Vemurafenib is susceptible to drug-drug interactions with agents that inhibit or induce hepatic CYP 1A2 activity.


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 vemurafenib and other kinase inhibitors and, in some situations, switching to another BRAF inhibitor may be appropriate.


Drug Class:  Antineoplastic Agents, Protein Kinase Inhibitors


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Vemurafenib – Zelboraf®


Antineoplastic Agents



Product labeling at DailyMed, National Library of Medicine, NIH


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Vemurafenib 918504-65-1 C23-H18 Cl-F2-N3-O3-S Vemurafenib chemical structure

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References updated: 28 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 kinase inhibitors such as vemurafenib).

  2. DeLeve LD. 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 kinase inhibitors including imatinib, gefitinib, erlotinib and crizotinib, but not vemurafenib).

  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, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, O'Dwyer PJ, Lee RJ, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 2010; 363: 809-19. PubMed Citation  (Among 87 patients with metastatic melanoma treated with escalating doses of vemurafenib, objective responses occurred at doses at or above 240 mg twice daily in patients with the BRAF V600E mutation, and adverse events included squamous cell carcinoma [21%], arthralgias, rash, nausea, photosensitivity and fatigue; no mention of ALT elevations or hepatotoxicity).

  5. Vemurafenib (Zelboraf) for metastatic melanoma. Med Lett Drugs Ther 2011; 53 (1374): 77-8. PubMed Citation  (Concise description of mechanism of action, efficacy, safety and costs of vemurafenib for metastatic melanoma, does not mention ALT elevations or hepatotoxicity, but does mention Stevens Johnson syndrome, toxic epidermal necrolysis and anaphylaxis).

  6. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, et al.; BRIM-3 Study Group. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011; 364: 2507-16. PubMed Citation  (Among 675 patients with metastatic melanoma and the BRAF V600E mutation, overall survival was greater with vemurafenib than dacarbazine treatment [84% vs 64% at 6 months], and the most common adverse events were skin toxicity, arthralgias and fatigue; Alk P elevations occurred in 7% of vemurafenib treated patients; rates of ALT elevations and hepatotoxicity were not provided).

  7. Sosman JA, Kim KB, Schuchter L, Gonzalez R, Pavlick AC, Weber JS, McArthur GA, et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med 2012; 366: 707-14. PubMed Citation  (Among 132 patients with advanced melanoma with BRAF V600 mutations and previous treatment treated with vemurafenib, confirmed responses occurred in 53% and common side effects included arthralgia, rash, photosensitivity and fatigue, and elevated liver enzymes were reported in 17% of patients and were severe in 4 [3%] which led to drug discontinuation in some, but did not result in deaths).

  8. Wenk KS, Pichard DC, Nasabzadeh T, Jang S, Venna SS. Vemurafenib-induced DRESS. JAMA Dermatol 2013; 149: 1242-3. PubMed Citation  (80 year old woman with melanoma developed generalized fever and skin rash 3 weeks after starting vemurafenib [eosinophils 26%, ALT 132 U/L, bilirubin and Alk P not given], resolving within 6 weeks on corticosteroids).

  9. Tsai KY, Nowroozi S, Kim KB. Drug safety evaluation of vemurafenib in the treatment of melanoma. Expert Opin Drug Saf 2013; 12: 767-75. PubMed Citation  (Review of safety of vemurafenib focusing on skin toxicity and secondary malignancies, mentions that grade 3 liver test abnormalities are reported in 0-6% of treated patients).

  10. Anker CJ, Ribas A, Grossmann AH, Chen X, Narra KK, Akerley W, Andtbacka RH, et al. Severe liver and skin toxicity after radiation and vemurafenib in metastatic melanoma. J Clin Oncol 2013; 31: e283-7. PubMed Citation  (15 year old girl with melanoma metastatic to brain, bone and liver developed fatal intrahepatic hemorrhage after vemurafenib and radiation therapy, and was found to have melanoma lined cysts with hemorrhage and acute hepatic necrosis on autopsy).

  11. Ribas A, Hodi FS, Callahan M, Konto C, Wolchok J. Hepatotoxicity with combination of vemurafenib and ipilimumab. N Engl J Med 2013; 368: 1365-6. PubMed Citation  (In a pilot study of the combination of vemurafenib and ipilimumab in 10 patients with metastatic melanoma, serum ALT or AST elevations ≥5 times ULN arose within 13-36 days of starting therapy in 6 patients, all of which were asymptomatic and reversible, which resolved within 4-12 days with corticosteroid therapy, recurring in one patient on restarting ipilimumab).

  12. da Rocha Dias S, Salmonson T, van Zwieten-Boot B, Jonsson B, Marchetti S, Schellens JH, Giuliani R, et al. The European Medicines Agency review of vemurafenib(Zelboraf®) for the treatment of adult patients with BRAF V600 mutation-positive unresectable or metastatic melanoma with BRAF V600 mutations: summary of the scientific assessment of the Committee for Medicinal Products for Human Use. Eur J Cancer 2013; 49: 1654-61. PubMed Citation  (Report of regulatory review of vemurafenib including for clinical safety in 866 patients, mentions one case of Stevens Johnson syndrome and that liver test abnormalities occurred in 18% of patients, usually arising after 3-6 weeks and usually mild [< grade 3]).

  13. Muluneh B, Buie LW, Collichio F. Vemurafenib-associated pancreatitis: case report. Pharmacotherapy 2013; 33: e43-4. PubMed Citation  (49 year old man developed epigastric pain 2 weeks after starting vemurafenib for metastatic melanoma [lipase 1544 U/L, no other laboratory results provided], which resolved upon stopping and recurred within two days of restarting vemurafenib).

  14. Degen A, Völker B, Kapp A, Gutzmer R. Erythema nodosum in a patient undergoing vemurafenib therapy for metastatic melanoma. Eur J Dermatol 2013; 23: 118. PubMed Citation

  15. 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).

  16. 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; aminotransferase elevations occurred in 35-38% of patients in registration trials of vemurafenib, were above 5 times ULN in 3% and cases of clinically apparent liver injury, but not hepatic failure, have been reported).

  17. Larkin J, Del Vecchio M, Ascierto PA, Krajsova I, Schachter J, Neyns B, Espinosa E, et al. Vemurafenib in patients with BRAF (V600) mutated metastatic melanoma: an open-label, multicentre, safety study. Lancet Oncol 2014; 15: 436-44. PubMed Citation  (Among 3222 patients with metastatic melanoma with BRAF V600 mutations enrolled in an open label safety study of vemurafenib, liver test abnormalities arose in 13% [≥grade 3 in 5%], including ALT elevations in 2.9% [≥5 times ULN in 1.6%] and Alk P elevations in 3.1% [≥3 times ULN in 1.1%], but no deaths were attributed to hepatic failure).

  18. McArthur GA, Chapman PB, Robert C, Larkin J, Haanen JB, Dummer R, Ribas A, et al. Safety and efficacy of vemurafenib in BRAF (V600E) and BRAF (V600K) mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. Lancet Oncol 2014; 15: 323-32. PubMed Citation  (Among 675 patients with metastatic melanoma with BRAF V600 mutations, median overall survival was longer in those treated with vemurafenib than dacarbazine [36.5 vs 9.7 months], and 31% on vemurafenib developed abnormal liver tests [which were ≥grade 3 in 11%] compared to 6% [with 2% ≥grade 3] on dacarbazine).

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  1. PubMed logoRecent References on Vemurafenib

  2. Clinical Trials logoTrials on Vemurafenib

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