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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Dabrafenib

Last Update: June 28, 2018.

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

DRUGCAS REGISTRY NO.MOLECULAR FORMULASTRUCTURE
Dabrafenib 1195765-45-7 C23-H20-F3-N5-O2-S2
Dabrafenib chemical structure

ANNOTATED BIBLIOGRAPHY

References updated: 28 June 2018

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    (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).
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    (Among 423 pateints with advanced melanoma [with BRAF V600E or V600K mutations] treated wtih dabrafenib with or without trametinib, progression free survival was slightly better with the combination [9.3 vs 8.8 months], while adverse events tended to be more common and more severe with the combination, ALT elevations occurring in 11% vs 5% and rising above 5 times ULN in 2% vs <1%; no mention of clinically apparent hepatotoxicity).
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    (49 year old woman with metastatic melanoma and liver involvement developed severe abdominal pain and hemoperitoneum from rupture of hepatic metstases after 3 doses of dabrafenib and trametinib, recovering with conservative management and able to restart the same chemotherapeutic regimen).
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    (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 49 were attributed to antineoplastic agents [5.5%], 3 of which were attributed to kinase inhibitors [imatinib, lapatinib], but none to dabrafenib or trametinib).
  • Anker CJ, Grossmann KF, Atkins MB, Suneja G, Tarhini AA, Kirkwood JM. Avoiding severe toxicity from combined BRAF inhibitor and radiation treatment: consensus guidelines from the Eastern Cooperative Oncology Group (ECOG). Int J Radiat Oncol Biol Phys 2016; 95: 632-46. [PMC free article: PMC5102246] [PubMed: 27131079]
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    (Among 59 patients with previously treated, refractory NSCLC [with BRAF V600E mutation], treated with dabrafenib and trametinib, the overall response rate was 63% and adverse events were common, but ALT elevations occurred in only 3 patients [6%] and were above 5 times ULN in only 1; there were no serious liver related adverse events).
  • Knispel S, Zimmer L, Kanaki T, Ugurel S, Schadendorf D, Livingstone E. The safety and efficacy of dabrafenib and trametinib for the treatment of melanoma. Expert Opin Drug Saf 2017: 1-15. [PubMed: 29050517]
    (Review of the structure, mechanism of action, clinical efficacy and safety of dabrafenib and its combination with trametinib as therapy for metastatic melanoma; no specific discussion of hepatotoxicity).
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    (Among 99 patients enrolled in a trial of dabrafenib and trametinib, 18 survived for at least 5 years and no new safety issues arose; no mention of ALT levels or hepatotoxicity).
  • Long GV, Hauschild A, Santinami M, Atkinson V, Mandalà M, Chiarion-Sileni V, Larkin J, et al. Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N Engl J Med 2017; 377: 1813-23. [PubMed: 28891408]
    (Among 870 patients with Stage III, resected malignant melanoma treated with dabrafenib and trametinib or placebo for at least 1 year, relapse free survival was greater with the combination therapy [58% vs 39%], although adverse events were greater and included ALT elevations in 15% vs 1% that were above 5 times ULN in only one patient on the combination therapy; no mention of serious liver related serious adverse events).
  • Davies MA, Saiag P, Robert C, Grob JJ, Flaherty KT, Arance A, Chiarion-Sileni V, et al. Dabrafenib plus trametinib in patients with BRAF (V600)-mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial. Lancet Oncol 2017; 18: 863-73. [PMC free article: PMC5991615] [PubMed: 28592387]
    (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).
  • Long GV, Flaherty KT, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, et al. Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: long-term survival and safety analysis of a phase 3 study. Ann Oncol 2017; 28: 1631-9. [PMC free article: PMC5834102] [PubMed: 28475671]
    (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).
  • Shroff RT, Yarchoan M, O'Connor A, Gallagher D, Zahurak ML, Rosner G, Ohaji C, et al. The oral VEGF receptor tyrosine kinase inhibitor pazopanib in combination with the MEK inhibitor trametinib in advanced cholangiocarcinoma. Br J Cancer 2017; 116: 1402-7. [PMC free article: PMC5520097] [PubMed: 28441383]
    (Among 25 patients with advanced, refractory cholangiocarcinoma treated with pazopanib and trametinib for an average of 12 weeks, the objective response rate was 5% and adverse events were common including elevated liver tests in 44% resulting in dose interruption in 1 patient, but without clinically apparent liver injury).
  • Planchard D, Smit EF, Groen HJM, Mazieres J, Besse B, Helland Å, Giannone V, et al. Dabrafenib plus trametinib in patients with previously untreated BRAF (V600E)-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial. Lancet Oncol 2017; 18: 1307-16. [PubMed: 28919011]
    (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).
  • Martín Algarra S, Soriano V, Fernández-Morales L, Berciano-Guerrero MÁ, Mujika K, Manzano JL, Puértolas Hernández T, et al. Dabrafenib plus trametinib for compassionate use in metastatic melanoma: A STROBE-compliant retrospective observational postauthorization study. Medicine (Baltimore) 2017; 96: e9523. [PMC free article: PMC6393118] [PubMed: 29384960]
    (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).
  • Bunchorntavakul C, Reddy KR. Drug hepatotoxicity: newer agents. Clin Liver Dis 2017; 21: 115-34. [PubMed: 27842767]
    (Review of the hepatotoxicity of recently approved medications including kinase inhibitors such as imatinib, erlotinib, lapatinib, pazopanib, ponatinib, nilotinib, sorafenib, sunitinib and regorafenib, but does not mention dabrafenib or trametinib).
  • 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).

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