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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.


Drug Class:  Antineoplastic Agents, Protein Kinase Inhibitors


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Regorafenib – Stivarga®


Antineoplastic Agents



Product labeling at DailyMed, National Library of Medicine, NIH


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Regorafenib 755037-03-7 C21-H15-Cl-F4-N4-O3 Regorafenib chemical structure

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References updated: 6 August 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 regorafenib).

  2. DeLeve LD. Cancer chemotherapy. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 541-67.  (Review of hepatotoxicity of cancer chemotherapeutic agents; imatinib, gefitinib, erlotinib and crizotinib are discussed, but not regorafenib).

  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. Eisen T, Joensuu H, Nathan PD, Harper PG, Wojtukiewicz MZ, Nicholson S, Bahl A, et al. Regorafenib for patients with previously untreated metastatic or unresectable renal-cell carcinoma: a single-group phase 2 trial. Lancet Oncol 2012; 13: 1055-62. PubMed Citation  (Among 49 patients with metastatic or unresectable renal cell cancer treated with regorafenib for 1 to 34 months, 40% had a partial response and side effects were common [98%], often severe [71%] and occasionally fatal [4%]; no mention of ALT elevations or hepatotoxicity).

  5. George S, Wang Q, Heinrich MC, Corless CL, Zhu M, Butrynski JE, Morgan JA, et al. Efficacy and safety of regorafenib in patients with metastatic and/or unresectable GI stromal tumor after failure of imatinib and sunitinib: a multicenter phase II trial. J Clin Oncol 2012; 30: 2401-7. PubMed Citation  (Among 34 patients with GIST and progression despite imatinib and sunitinib therapy, 4 had a partial response to regorafenib and common side effects were hand-foot syndrome [85%], fatigue [79%], hypertension [67%], diarrhea [61%] and hoarseness [46%]; no mention of ALT elevations or hepatotoxicity).

  6. 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).

  7. Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, Humblet Y, et al.; CORRECT Study Group. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 2013; 381 (9863): 303-12. PubMed Citation  (Among 760 patients with metastatic colorectal cancer, overall median survival was 6.4 months with regorafenib therapy vs 5.0 months with placebo, and side effects were frequent [93%] and often severe [55%]; no mention of ALT elevations or hepatotoxicity).

  8. Waddell T, Cunningham D. Evaluation of regorafenib in colorectal cancer and GIST. Lancet 2013; 381 (9863): 273-5. PubMed Citation  (Editorial accompanying clinical trials of Demetri [2013] and Grothey [2013] mentions that the clinical benefits were modest, but that "the case for routine use of regorafenib ... is strong, despite the apparent absence of a benefit in terms of overall survival").

  9. 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).

  10. Bruix J, Tak WY, Gasbarrini A, Santoro A, Colombo M, Lim HY, Mazzaferro V, et al. Regorafenib as second-line therapy for intermediate or advanced hepatocellular carcinoma: multicentre, open-label, phase II safety study. Eur J Cancer 2013; 49: 3412-9. PubMed Citation  (Among 36 patients with advanced hepatocellular carcinoma who were treated for 2-103 weeks with regorafenib, 3% had a partial response and 69% had stable disease with a median survival of 13.8 months; side effects were common [97%], often severe [58%], and 2 patients died of hepatic failure, but the complication was judged to be unrelated to therapy).

  11. 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; regorafenib therapy is accompanied by ALT or AST elevations in 45-65% of patients [≥5 times ULN in 6%] generally during the first 2-6 weeks of therapy, and linked to rare cases of clinically apparent hepatitis and to instances of hepatic failure and death).

  12. Iacovelli R, Palazzo A, Procopio G, Santoni M, Trenta P, De Benedetto A, Mezi S, et al. Incidence and relative risk of hepatic toxicity in patients treated with anti-angiogenic tyrosine kinase inhibitors for malignancy. Br J Clin Pharmacol 2014; 77: 929-38. PubMed Citation  (Systematic review of liver toxicity reported in controlled trials of kinase inhibitors used to treat solid tumors identified 6 articles with 3691 patients, among whom 34% had ALT elevations with kinase inhibitor therapy compared to 24% of controls [≥5 times ULN in 5.2% vs 1.4%], with highest rates for sorafenib and pazopanib).

  13. 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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  1. PubMed logoRecent References on Regorafenib

  2. Clinical Trials logoTrials on Regorafenib

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