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Second- and Third-Line Treatment

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Gastrointestinal Stromal Tumor

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Abstract

Sunitinib (sunitinib malate; SU11248) is a novel oral multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenic activities. Sunitinib has been identified as a potent inhibitor of VEGFR-1, VEGFR-2, fetal liver tyrosine kinase receptor 3 (FLT3), KIT (stem-cell factor [SCF] receptor), PDGFRα, and PDGFR. Regorafenib is a small molecule inhibitor of multiple membrane-bound and intracellular kinases involved in normal cellular functions and in pathologic processes such as oncogenesis, tumor angiogenesis, and maintenance of the tumor microenvironment. Regorafenib blocks the activity of several protein kinases involved with angiogenesis (vascular endothelial growth factor [VEGF] receptors 1–3 and TIE2), oncogenesis (KIT, RET, RAF1, B-RAF, and B-RAF V600E), and the tumor microenvironment (platelet-derived growth factor receptor [PDGFR] and fibroblast growth factor receptors [FGFR]). Sunitinib and Regorafenib are two targeted agents with worldwide approval for second- and third-line treatment, respectively, in metastatic GIST.

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References

  1. Mendel DB, Laird AD, Xin X, et al. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res. 2003;9(1):327–37.

    CAS  PubMed  Google Scholar 

  2. Izzedine H, Buhaescu I, Rixe O, Deray G. Sunitinib malate. Cancer Chemother Pharmacol. 2007;60(3):357–64.

    Article  CAS  Google Scholar 

  3. Bello CL, Garrett M, Sherman L, Smeraglia J, Ryan B, Toh M. Pharmacokinetics of sunitinib malate in subjects with hepatic impairment. Cancer Chemother Pharmacol. 2010;66(4):699–707.

    Article  CAS  Google Scholar 

  4. Houk BE, Bello CL, Poland B, Rosen LS, Demetri GD, Motzer RJ. Relationship between exposure to sunitinib and efficacy and tolerability endpoints in patients with cancer: results of a pharmacokinetic/pharmacodynamic meta-analysis. Cancer Chemother Pharmacol. 2010;66(2):357–71.

    Article  CAS  Google Scholar 

  5. Bello CL, Sherman L, Zhou J, et al. Effect of food on the pharmacokinetics of sunitinib malate (SU11248), a multi-targeted receptor tyrosine kinase inhibitor: results from a phase I study in healthy subjects. Anti-Cancer Drugs. 2006;17(3):353–8.

    Article  CAS  Google Scholar 

  6. Ikezoe T, Yang Y, Nishioka C, et al. Effect of SU11248 on gastrointestinal stromal tumor-T1 cells: enhancement of growth inhibition via inhibition of 3-kinase/Akt/mammalian target of rapamycin signaling. Cancer Sci. 2006;97(9):945–51.

    Article  CAS  Google Scholar 

  7. Demetri GD, Heinrich MC, Fletcher JA, et al. Molecular target modulation, imaging, and clinical evaluation of gastrointestinal stromal tumor patients treated with sunitinib malate after imatinib failure. Clin Cancer Res. 2009;15(18):5902–9.

    Article  CAS  Google Scholar 

  8. Shirao K, Nishida T, Doi T, et al. Phase I/II study of sunitinib malate in Japanese patients with gastrointestinal stromal tumor after failure of prior treatment with imatinib mesylate. Investig New Drugs. 2010;28(6):866–75.

    Article  CAS  Google Scholar 

  9. Demetri GD, Huang X, Garrett CR, et al. Novel statistical analysis of long-term survival to account for crossover in a phase III trial of sunitinib (SU) vs. placebo (PL) in advanced GIST after imatinib (IM) failure. J Clin Oncol. 2008;26(15S):10524.

    Article  Google Scholar 

  10. Demetri GD, Reichardt P, Kang Y-K, et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumors after failure of imatinib and sunitinib (GRID): an international, multicenter, randomized, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):295–302.

    Article  CAS  Google Scholar 

  11. 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 randomized controlled trial. Lancet. 2006;368(9544):1329–38.

    Article  CAS  Google Scholar 

  12. Demetri GD, Garrett CR, et al. Complete longitudinal analyses of the randomized, placebo-controlled, phase III trial of sunitinib in patients with gastrointestinal stromal tumor following imatinib failure. Clin Cancer Res. 2012;18(11):3170–9.

    Article  CAS  Google Scholar 

  13. George S, Blay JY, Casali PG, et al. Clinical evaluation of continuous daily dosing of sunitinib malate in patients with advanced gastrointestinal stromal tumour after imatinib failure. Eur J Cancer. 2009;45(11):1959–68.

    Article  CAS  Google Scholar 

  14. Reichardt P, Kang Y-K, Rutkowski P, et al. Clinical outcomes of patients with advanced gastrointestinal stromal tumors: safety and efficacy in a world- wide treatment-use trial of sunitinib. Cancer. 2015;121(9):1405–13.

    Article  CAS  Google Scholar 

  15. Lee JL, Kim MK, Park I, et al. Randomized phase II trial of Sunitinib four weeks on and two weeks off versus two weeks on and one week off in metastatic clear-cell type REnal cell carcinoma: RESTORE trial. Ann Oncol. 2015;26(11):2300–5.

    Article  CAS  Google Scholar 

  16. Bracarda S, Iacovelli R, Boni L, et al. Sunitinib administered on 2/1 schedule in patients with metastatic renal cell carcinoma: the RAINBOW analysis. Ann Oncol. 2015;26(10):2107–13.

    Article  CAS  Google Scholar 

  17. Khosravan R, Motzer RJ, Fumagalli E, Rini BI. Population pharmacokinetic/pharmacodynamic modeling of sunitinib by dosing schedule in patients with advanced renal cell carcinoma or gastrointestinal stromal tumor. Clin Pharmacokinet. 2016;55(10):1251–69.

    Article  CAS  Google Scholar 

  18. de Wit D, van Erp NP, Khosravan R, et al. Effect of gastrointestinal resection on sunitinib exposure in patients with GIST. BMC Cancer. 2014;14(1):575.

    Article  Google Scholar 

  19. Tielen R, Verhoef C, van Coevorden F, et al. Surgery after treatment with imatinib and/or sunitinib in patients with metastasized gastrointestinal stromal tumors: is it worthwhile? World J Surg Oncol. 2012;10:111.

    Article  Google Scholar 

  20. Raut CP, Wang Q, Manola J, et al. Cytoreductive surgery in patients with metastatic gastrointestinal stromal tumor treated with sunitinib malate. Ann Surg Oncol. 2010;17(2):407–15.

    Article  Google Scholar 

  21. Nishida T, Takahashi T, Nishitani A, et al. Sunitinib-resistant gastro- intestinal stromal tumors harbor cis-mutations in the activation loop of the KIT gene. Int J Clin Oncol. 2009;14(2):143–9.

    Article  CAS  Google Scholar 

  22. Rutkowski P, Bylina E, Klimczak A, et al. The outcome and predictive factors of sunitinib therapy in advanced gastrointestinal stromal tumors (GIST) after imatinib failure – one institution study. BMC Cancer. 2012;12(1):107.

    Article  CAS  Google Scholar 

  23. Heinrich MC, Maki RG, Corless CL, et al. Primary and secondary kinase genotypes correlate with the biological and clinical activity of sunitinib in imatinib-resistant gastrointestinal stromal tumor. J Clin Oncol. 2008;26(33):5352–9.

    Article  CAS  Google Scholar 

  24. Liegl B, Kepten I, Le C, et al. Heterogeneity of kinase inhibitor resistance mechanisms in GIST. J Pathol. 2008;216(1):64–74.

    Article  CAS  Google Scholar 

  25. Gajiwala KS, Wu JC, Christensen J, et al. KIT kinase mutants show unique mechanisms of drug resistance to imatinib and sunitinib in gastrointestinal stromal tumor patients. Proc Natl Acad Sci U S A. 2009;106(5):1542–7.

    Article  CAS  Google Scholar 

  26. 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.

    Article  CAS  Google Scholar 

  27. 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.

    Article  CAS  Google Scholar 

  28. Casali PG, Reichardt P, Kang Y, et al. Clinical benefit with Regorafenib across subgroups and post-progression in patients with advanced gastrointestinal stromal tumor (Gist) after progression on Imatinib and Sunitinib: phase 3 Grid trial update. Ann Oncol. 2012;23:478–9.

    Article  Google Scholar 

  29. Bauer S, Joensuu H, Casali P, et al. Results from a phase III trial (GRID) evaluating regorafenib in metastatic gastrointestinal stromal tumour (GIST): subgroup analysis of outcomes based on pretreatment characteristics. Onkologie. 2013;36:180–1.

    Google Scholar 

  30. Blay J, Casali P, Reichardt P, et al. Time course of adverse events in the phase III GRID study of regorafenib in patients with metastatic gastrointestinal stromal tumors (GIST). Eur J Cancer. 2013;49:S884.

    Article  Google Scholar 

  31. Reichardt P, Demetri G, Kang YK, et al. Randomized phase 3 trial of regorafenib in patients (pts) with metastatic and/or unresectable gastrointestinal stromal tumor (GIST) progressing despite prior treatment with at least imatinib (IM) and sunitinib (SU)-GRID trial. Onkologie. 2012;35:168.

    Google Scholar 

  32. Joensuu H, Casali PG, Reichardt P, et al. Results from a phase III trial (GRID) evaluating regorafenib (REG) in metastatic gastrointestinal stromal tumour (GIST): subgroup analysis of outcomes based on pretreatment characteristics. J Clin Oncol. 2013;31:10551.

    Google Scholar 

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Authors and Affiliations

  1. Department of Gastroenterology, The Cancer Institute Hospital of JFCR, Tokyo, Japan

    Masato Ozaka

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  1. Masato Ozaka
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Correspondence to Masato Ozaka .

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Editors and Affiliations

  1. Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan

    Yukinori Kurokawa

  2. Department of Cancer Chemotherapy, Hokkaido University Hospital Cancer Center, Sapporo, Hokkaido, Japan

    Yoshito Komatsu

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Ozaka, M. (2019). Second- and Third-Line Treatment. In: Kurokawa, Y., Komatsu, Y. (eds) Gastrointestinal Stromal Tumor. Springer, Singapore. https://doi.org/10.1007/978-981-13-3206-7_9

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  • DOI: https://doi.org/10.1007/978-981-13-3206-7_9

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  • Publisher Name: Springer, Singapore

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  • Online ISBN: 978-981-13-3206-7

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