Regorafenib is an oral multi-kinase inhibitor that is used in the therapy of metastatic colorectal cancer and gastrointestinal stromal tumor. Regorafenib has been associated with frequent serum aminotransferase elevations during therapy and with rare, but sometimes severe and even fatal instances of clinically apparent liver injury.
Regorafenib (re goe raf’ e nib) is an orally available, small molecule, multi-specific kinase inhibitor with activity against vascular endothelial growth factors (VEGF) receptors -1, -2 and -3, as well as against the receptor for platelet derived growth factor (PDGF) and several RAF kinases, c-Kit and TIE2. Inhibition of these kinases decreases angiogenesis, which plays an important role in the growth and spread of several forms of solid tumors. Regorafenib received approval for use in the United States in 2012 for therapy of metastatic colorectal cancer and advanced, unresectable gastrointestinal stromal tumors after failure of other antineoplastic agents. Regorafenib is available in tablets of 40 mg under the brand name Stivarga. The typical dose is 160 mg once daily for 21 days in 28 day cycles continued until there is tumor progression or unacceptable toxicity. Side effects are common and can include fatigue, diarrhea, anorexia, weight loss, nausea, abdominal pain, hand-foot syndrome, hypertension, mucositis, dysphonia, infections, rash and fever. Uncommon, but potentially severe side effects include bleeding, poor wound healing, gastrointestinal perforation and fistula, hypertension, severe skin toxicities, cardiac ischemia and reversible posterior leukoencephalopathy syndrome.
In large clinical trials of regorafenib, elevations in serum aminotransferase levels were common, occurring in 39% to 45% of patients, and were greater than 5 times the upper limit of normal (ULN) in 3% to 6%. In addition, there have been several reports of clinically apparent liver injury arising during regorafenib therapy which was often severe and occasionally fatal, estimated to occur in 0.3% of treated subjects. For these reasons, routine monitoring of liver enzymes is recommended. The clinical features of regorafenib associated liver injury have not been well described. The onset is usually within 3 to 6 weeks of starting regorafenib, and the pattern of injury was typically hepatocellular or mixed. Regorafenib, like other multi-kinase inhibitors [sunitinib, imatinib, sorafenib], has also been associated with episodes of hyperammonemic coma generally arising within a few days or weeks of starting and with rapid reversal upon stopping treatment.
Mechanism of Injury
The mechanism of injury accounting for serum enzyme elevations and liver injury during regorafenib therapy is not known. Regorafenib is metabolized in the liver largely through the CYP 3A4 pathway and liver injury may be related to production of a toxic intermediate. Regorafenib is susceptible to drug-drug interactions with agents that inhibit or induce hepatic CYP 3A4 activity.
Outcome and Management
Serum aminotransferase elevations above 5 times the upper limit of normal (if confirmed) or any elevation accompanied by jaundice or symptoms should lead to dose reduction or temporary cessation. Regorafenib has been implicated in cases of acute liver failure, but not in instances of chronic hepatitis or vanishing bile duct syndrome. There does not appear to be cross reactivity in risk for hepatic injury between regorafenib and other multi-kinase inhibitors such axitinib, sorafenib and sunitinib.
REPRESENTATIVE TRADE NAMES
Regorafenib – Stivarga®
Product labeling at DailyMed, National Library of Medicine, NIH
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References updated: 6 August 2014
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Demetri GD, Reichardt P, Kang YK, Blay JY, Rutkowski P, Gelderblom H, Hohenberger P, et al.; GRID study investigators. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 2013; 381(9863): 295-302. PubMed Citation (Among 199 patients with advanced GIST after failure of other kinase inhibitors, regorafenib therapy yielded a longer progression free survival [4.8 months] compared to placebo [0.8 months], but no change in overall survival; side effects were common [98%] and often severe [60%]; no mention of ALT elevations or hepatotoxicity).
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Regorafenib (Stivarga) for metastatic colorectal cancer and GIST. Med Lett Drugs Ther 2013; 55 (1415): e36. PubMed Citation (Concise review of the efficacy, safety and costs of regorafenib in colorectal cancer and GIST shortly after its approval for this use in the US, mentions that regorafenib can cause severe liver injury).
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Kuo JC, Parakh S, Yip D. Regorafenib-induced hyperammonemic encephalopathy. J Clin Pharm Ther 2014; 39: 446-8. PubMed Citation (61 year old man with metastatic GIST with liver involvement developed confusion 13 months after starting regorafenib that resolved rapidly with stopping and recurred rapidly on restarting regorafenib [ammonia 105
μmol/L], resolving within 4 days of stopping again).
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