Abstract
Regorafenib (Stivarga®) is an orally administered small molecule inhibitor of multiple protein kinases, including kinases involved in oncogenesis and tumour angiogenesis. It was initially approved for use in patients with previously treated metastatic colorectal cancer. Based on the findings of the phase III GRID clinical trial, approval for regorafenib has been expanded to include the treatment of advanced gastrointestinal stromal tumours (GISTs) following the failure of imatinib and sunitinib. In the GRID trial, regorafenib significantly improved progression-free survival and was associated with a significantly higher disease control rate than placebo. No significant between-group difference was observed in overall survival (OS) in the trial; however, the high proportion of patients who crossed over from placebo to regorafenib likely impacted the OS analysis. Regorafenib has an acceptable tolerability profile, with most adverse events being manageable with dose modification and/or supportive measures. The most commonly reported drug-related adverse events among patients receiving regorafenib in the GRID trial were hand-foot skin reaction, hypertension, diarrhoea and fatigue. In conclusion, regorafenib presents a valuable new tool in the treatment of patients with advanced GISTs following the failure of imatinib and sunitinib.
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Iorio N, Sawaya RA, Friedenberg FK. Review article: the biology, diagnosis and management of gastrointestinal stromal tumours. Aliment Pharmacol Ther. 2014;39(12):1376–86.
Miettinen M, Lasota J. Gastrointestinal stromal tumors. Gastroenterol Clin North Am. 2013;42(2):399–415.
National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology (NCCN Guideline®): soft tissue sarcoma (Version 1.2015). 2015. http://www.nccn.org. Accessed 13 Apr 2015.
ESMO/European Sarcoma Network Working Group. Gastrointestinal stromal tumours: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25(Suppl 3):321–6.
Vadakara J, von Mehren M. Gastrointestinal stromal tumors: management of metastatic disease and emerging therapies. Hematol Oncol Clin North Am. 2013;27(5):905–20.
Serrano C, George S. Recent advances in the treatment of gastrointestinal stromal tumors. Ther Adv Med Oncol. 2014;6(3):115–27.
Hirota S, Isozaki K. Pathology of gastrointestinal stromal tumors. Pathol Int. 2006;56(1):1–9.
Siddiqui MAA, Scott LJ. Imatinib: a review of its use in the management of gastrointestinal stromal tumours. Drugs. 2007;67(5):805–20.
Deeks ED, Keating GM. Sunitinib. Drugs. 2006;66(17):2255–66.
Demetri GD, van Oosterom AT, Garrett CR, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet. 2006;368(9544):1329–38.
Guo T, Hajdu M, Agaram NP, et al. Mechanisms of sunitinib resistance in gastrointestinal stromal tumors harboring KITAY502-3ins mutation: an in vitro mutagenesis screen for drug resistance. Clin Cancer Res. 2009;15(22):6862–70.
US FDA. Stivarga (regorafenib): prescribing information. 2015. http://www.fda.gov. Accessed 20 Apr 2015.
European Medicines Agency. Stivarga: summary of product characteristics. 2015. http://www.ema.europa.eu. Accessed 30 Mar 2015.
Demetri GD, Reichardt P, Kang Y-K, et al. 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.
Wilhelm SM, Dumas J, Adnane L, et al. Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int J Cancer. 2011;129(1):245–55.
Schmieder R, Hoffmann J, Becker M, et al. Regorafenib (BAY 73-4506): antitumor and antimetastatic activities in preclinical models of colorectal cancer. Int J Cancer. 2014;135(6):1487–96.
Van Looy T, Gebreyohannes YK, Wozniak A, et al. Characterization and assessment of the sensitivity and resistance of a newly established human gastrointestinal stromal tumour xenograft model to treatment with tyrosine kinase inhibitors. Clin Sarcoma Res. 2014;4:10.
Abou-Elkacem L, Arns S, Brix G, et al. Regorafenib inhibits growth, angiogenesis, and metastasis in a highly aggressive, orthotopic colon cancer model. Mol Cancer Ther. 2013;12(7):1322–31.
Mross K, Frost A, Steinbild S, et al. A phase I dose-escalation study of regorafenib (BAY 73-4506), an inhibitor of oncogenic, angiogenic, and stromal kinases, in patients with advanced solid tumors. Clin Cancer Res. 2012;18(9):2658–67.
Strumberg D, Scheulen ME, Schultheis B, et al. Regorafenib (BAY 73-4506) in advanced colorectal cancer: a phase I study. Br J Cancer. 2012;106(11):1722–7.
European Medicines Agency. Stivarga: CHMP extension of indication variation assessment report. 2014. http://www.ema.europa.eu. Accessed 30 Mar 2015.
Sunakawa Y, Furuse J, Okusaka T, et al. Regorafenib in Japanese patients with solid tumors: phase I study of safety, efficacy, and pharmacokinetics. Invest New Drugs. 2014;32(1):104–12.
Health Canada. Stivarga (regorafenib tablets): product monograph. 2015. http://webprod5.hc-sc.gc.ca/dpd-bdpp/start-debuter.do?lang=eng. Accessed 30 Mar 2015.
George S, Wang Q, Heinrich MC, 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(19):2401–7.
Demetri GD, Reichardt P, Kang Y-K, et al. An updated overall survival analysis with correction for protocol-planned crossover of the international, phase III, randomized, placebo-controlled trial of regorafenib in advanced gastrointestinal stromal tumors after failure of imatinib and sunitinib (GRID) [abstract no. 110]. In: 2015 Gastrointestinal Cancers Symposium. 2015.
Komatsu Y, Doi T, Sawaki A, et al. Regorafenib for advanced gastrointestinal stromal tumors following imatinib and sunitinib treatment: a subgroup analysis evaluating Japanese patients in the phase III GRID trial. Int J Clin Oncol. 2015. doi:10.1007/s10147-015-0790-y.
Chang J, Casali PG, Reichardt P, et al. Health-related quality of life (HRQoL) of patients with advanced gastrointestinal stromal tumors (GIST) treated with regorafenib (REG) vs placebo (P) in the phase III GRID trial [abstract no. 3830]. In: The European Cancer Congress. 2013.
Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):303–12.
Hartmann JT, Haap M, Kopp H-G, et al. Tyrosine kinase inhibitors—a review on pharmacology, metabolism and side effects. Curr Drug Metab. 2009;10(5):470–81.
Strumberg D, Schultheis B. Regorafenib for cancer. Expert Opin Investig Drugs. 2012;21(6):879–89.
Grothey A, George S, van Cutsem E, et al. Optimizing treatment outcomes with regorafenib: personalized dosing and other strategies to support patient care. Oncologist. 2014;19(6):669–80.
Kang Y-K, Ryu M-H, Yoo C, et al. Resumption of imatinib to control metastatic or unresectable gastrointestinal stromal tumours after failure of imatinib and sunitinib (RIGHT): a randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2013;14(12):1175–82.
Yip D, Zalcberg J, Ackland S, et al. Controversies in the management of gastrointestinal stromal tumors. Asia Pac J Clin Oncol. 2014;10(3):216–27.
Disclosure
The preparation of this review was not supported by any external funding. During the peer review process, the manufacturer of the agent under review was offered an opportunity to comment on this article. Changes resulting from comments received were made by the authors on the basis of scientific and editorial merit. Matt Shirley and Gillian Keating are salaried employees of Adis/Springer.
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The manuscript was reviewed by: C. R. Garrett, Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA; P. Rutkowski, Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
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Shirley, M., Keating, G.M. Regorafenib: A Review of Its Use in Patients with Advanced Gastrointestinal Stromal Tumours. Drugs 75, 1009–1017 (2015). https://doi.org/10.1007/s40265-015-0406-x
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DOI: https://doi.org/10.1007/s40265-015-0406-x