Trametinib is a dual-kinase inhibitor that is used in the treatment of advanced malignant melanoma. Trametinib therapy is associated with transient elevations in serum aminotransferase and alkaline phosphatase levels during therapy, but has yet to be linked cases of clinically apparent acute liver injury.
Trametinib (tra me’ ti nib) is an orally available, small molecule inhibitor of the mitogen activated extracellular signal regulated kinases 1 and 2 (MEK1 and MEK2), which are important components of the kinase cascade in the mitogen activated protein kinase (MAPK) pathway (RAS-RAF-MEK-ERK). Components of the MAPK pathway are frequently mutated in patients with malignant melanoma, particular the RAF isoform BRAF. These mutations cause a constitutive activation of the MAPK pathway, resulting in unregulated cell growth and proliferation. Clinical trials of trametinib in patients with metastatic malignant melanoma have shown that it prolongs progression free and overall survival, but the effect seemed to be limited to patients with the BRAF mutations. Trametinib was approved for use in the United States in 2013. Current indications are for therapy of unresectable or metastatic malignant melanoma with BRAF V600E or V600K mutations either alone or in combination with dabrafenib (a BRAF kinase inhibitor). Trametinib is available in tablets of 0.5, 1.0 and 2.0 mg under the brand name Mekinist. The typical dose is 2 mg orally once daily. Common side effects include skin rash (57%), diarrhea (43%), fatigue (26%), peripheral edema (21%), and hypertension (15%). Uncommon, but potentially severe adverse reactions include cardiomyopathy, interstitial pneumonitis, ocular toxicity, retinal vein occlusion and severe skin reactions.
In large clinical trials, abnormalities in routine liver tests were common with serum aminotransferase elevations occurring in 39% to 60% and alkaline phosphatase in 24% to 67% of patients treated with trametinib. However, elevations in ALT above 5 times the ULN were uncommon, occurring in 0% to 5% of patients and generally resolving rapidly with temporary discontinuation or dose adjustment. In the prelicensure controlled trials of trametinib with or without dabrafenib, no cases of clinically apparent acute liver injury or hepatic failure were reported. There have yet to be published cases of clinically apparent hepatotoxicity attributed to trametinib. However, it has been used for a short time only.
Mechanism of Injury
The cause of serum enzyme elevations during trametinib therapy is not known. Trametinib is metabolized in the liver largely through the cytochrome P450 system, predominantly CYP 3A4 and CYP 2C8. Potent inducers or inhibitors of these P450 enzymes can alter serum levels of trametinib and serious drug-drug interactions can occur if trametinib is administered with other agents that are metabolized by CYP 3A4 or 2C8.
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 trametinib and other kinase inhibitors and, in some situations, switching to another kinase inhibitor may be appropriate.
REPRESENTATIVE TRADE NAMES
Trametinib – Mekinist®
Product labeling at DailyMed, National Library of Medicine, NIH
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References updated: 25 July 2014
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 trametinib).
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 trametinib).
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).
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 322 patients with metastatic melanoma and V600E or V600K BRAF mutations, trametinib therapy was associated with improved overall survival compared to conventional chemotherapy [81% vs 67% at 6 months], and common adverse events were rash [57%], diarrhea [43%], fatigue [26%] and peripheral edema [26%], while less common events were ocular toxicity [9%] and cardiac dysfunction [7%]; no mention of hepatotoxicity or ALT elevations).
Falchook GS, Lewis KD, Infante JR, Gordon MS, Vogelzang NJ, DeMarini DJ, Sun P, et al. Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial. Lancet Oncol 2012; 13: 782-9. PubMed Citation (Among 97 patients with malignant melanoma treated with escalating doses of trametinib, highest rates of response occurred in patients with BRAF mutations; no mention of ALT elevations or hepatotoxicity).
Infante JR, Fecher LA, Falchook GS, Nallapareddy S, Gordon MS, Becerra C, DeMarini DJ, et al. Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial. Lancet Oncol 2012; 13: 773-81. PubMed Citation (Among 206 patients with various advanced solid tumors treated with various doses and regimens of trametinib, the optimal dose was 2 mg daily, but the object response rate was only 10%; common side effects were rash [80%] and diarrhea [42%]; no mention of ALT elevations or hepatotoxicity).
Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, Demidov LV, et al.; METRIC Study Group. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med 2012; 367: 107-14. 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; no mention of ALT elevations or clinically apparent acute liver injury).
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 trametinib with or without dabrafenib for metastatic melanoma shortly after its approval in the US; no mention of ALT elevations or hepatotoxicity).
Wright CJ, McCormack PL. Trametinib: first global approval. Drugs 2013; 73: 1245-54. PubMed Citation (Review of the structure, mechanism of action, pharmacodynamics, efficacy and safety of trametinib and current status of its evaluation in other solid tumors and hematologic malignancies; no discussion of hepatotoxicity or ALT elevations).
Kim KB, Kefford R, Pavlick AC, Infante JR, Ribas A, Sosman JA, Fecher LA, et al. Phase II study of the MEK1/MEK2 inhibitor Trametinib in patients with metastatic BRAF-mutant cutaneous melanoma previously treated with or without a BRAF inhibitor. J Clin Oncol 2013; 31: 482-9. PubMed Citation (Among 97 patients with metastatic melanoma and BRAF mutations treated with trametinib, responses occurred largely in patients with no previous therapy with BRAF inhibitors [dabrafenib, vemurafenib] and all patients had at least one adverse event, the most common being rash [75%], diarrhea [52%] and nausea [30%]; 2 patients had ALT elevations above 5 times ULN, but this was reversible in all and there was no mention of clinically apparent hepatotoxicity).
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).
Salama AK, Kim KB. Trametinib (GSK1120212) in the treatment of melanoma. Expert Opin Pharmacother 2013; 14: 619-27. PubMed Citation (Review of the mechanism of action, pharmacology, efficacy and safety of trametinib in therapy of melanoma; no mention of ALT elevations or hepatotoxicity).
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; trametinib is not discussed).
Infante JR, Somer BG, Park JO, Li CP, Scheulen ME, Kasubhai SM, Oh DY, Liu Y, et al. A randomised, double-blind, placebo-controlled trial of trametinib, an oral MEK inhibitor, in combination with gemcitabine for patients with untreated metastatic adenocarcinoma of the pancreas. Eur J Cancer 2014; 50: 2072-81. PubMed Citation (Among 160 patients with pancreatic cancer treated with gemcitabine combined with trametinib or placebo, there was no difference in overall or progression free survive with or without trametinib; discussion of side effects did not mention ALT elevations or hepatotoxicity).
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