UpToDate
Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Tyrosine kinase inhibitor therapy for advanced gastrointestinal stromal tumors

Author
Jeffrey Morgan, MD
Section Editors
Kenneth K Tanabe, MD
Robert Maki, MD, PhD
Deputy Editor
Diane MF Savarese, MD

INTRODUCTION

Stromal or mesenchymal neoplasms affecting the gastrointestinal (GI) tract have undergone a striking evolution in how they are perceived and classified over the last 30 years. A significant breakthrough occurred with the identification of near-universal expression of the CD117 antigen by these tumors (now called gastrointestinal stromal tumors, or GISTs). The other group of spindle cell neoplasms arising in the GI tract (which are analogous to soft tissue tumors throughout the rest of the body and include lipomas, schwannomas, hemangiomas, usual leiomyomas and the malignant counterpart, leiomyosarcomas) is typically CD117-negative [1].

The CD117 molecule is part of the KIT (c-kit) receptor, a membrane tyrosine kinase (TK) that is a product of the KIT protooncogene. In 80 percent of cases, KIT overexpression is the result of an activating mutation in the KIT protooncogene. Although the majority of GISTs are KIT positive, some KIT negative GISTs have activating mutations in a related TK receptor, platelet-derived growth factor receptor alpha (PDGFRA). The current view is that the overwhelming majority of GI tract mesenchymal tumors fall into the GIST category; they are identifiable by KIT immunoreactivity or the presence of activating mutations in KIT or PDGFRA. (See "Epidemiology, classification, clinical presentation, prognostic features, and diagnostic work-up of gastrointestinal mesenchymal neoplasms including GIST", section on 'Classification and molecular pathogenesis'.)

Prior to the year 2000, there was no known effective therapy for unresectable or metastatic GISTs. It has long been appreciated that GI tract sarcomas have lower response rates to chemotherapy than other sites of soft tissue sarcomas, indicating a higher rate of primary resistance to chemotherapy in these tumors [2-4].

Treatment of GISTs was revolutionized by the finding that mutational activation of KIT or PDGFRA stimulated growth of these cancer cells. This led to effective systemic therapies in the form of small molecule inhibitors of the receptor TKs. Imatinib (Gleevec), the prototype drug, was originally approved for the treatment of chronic myeloid leukemia (CML), a disorder in which an aberrant TK results from molecular rearrangement. (See "Initial treatment of chronic myeloid leukemia in chronic phase".)

It subsequently became evident that molecularly targeted therapy with imatinib induced dramatic, rapid, and sustained clinical benefit in GISTs as well. These agents block signaling via KIT or PDGFRA by binding to the ATP-binding pocket required for phosphorylation and activation of the receptor. Other TK inhibitors (TKIs) have been identified that block several TK targets, including KIT (referred to as multitargeted TKIs). Some data suggest an anti-GIST immune response is associated with good clinical outcomes in patients with GIST on imatinib [5].

                           

Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Nov 2016. | This topic last updated: Thu Jun 23 00:00:00 GMT+00:00 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
References
Top
  1. Rubin BP, Fletcher JA, Fletcher CD. Molecular Insights into the Histogenesis and Pathogenesis of Gastrointestinal Stromal Tumors. Int J Surg Pathol 2000; 8:5.
  2. Demetri GD, Elias AD. Results of single-agent and combination chemotherapy for advanced soft tissue sarcomas. Implications for decision making in the clinic. Hematol Oncol Clin North Am 1995; 9:765.
  3. Plaat BE, Hollema H, Molenaar WM, et al. Soft tissue leiomyosarcomas and malignant gastrointestinal stromal tumors: differences in clinical outcome and expression of multidrug resistance proteins. J Clin Oncol 2000; 18:3211.
  4. Edmonson JH, Marks RS, Buckner JC, Mahoney MR. Contrast of response to dacarbazine, mitomycin, doxorubicin, and cisplatin (DMAP) plus GM-CSF between patients with advanced malignant gastrointestinal stromal tumors and patients with other advanced leiomyosarcomas. Cancer Invest 2002; 20:605.
  5. Balachandran VP, Cavnar MJ, Zeng S, et al. Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido. Nat Med 2011; 17:1094.
  6. Joensuu H, Roberts PJ, Sarlomo-Rikala M, et al. Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med 2001; 344:1052.
  7. van Oosterom AT, Judson I, Verweij J, et al. Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: a phase I study. Lancet 2001; 358:1421.
  8. Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 2002; 347:472.
  9. van Oosterom AT, Judson IR, Verweij J, et al. Update of phase I study of imatinib (STI571) in advanced soft tissue sarcomas and gastrointestinal stromal tumors: a report of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 2002; 38 Suppl 5:S83.
  10. Verweij J, Casali PG, Zalcberg J, et al. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet 2004; 364:1127.
  11. Blanke CD, Rankin C, Demetri GD, et al. Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol 2008; 26:626.
  12. von Mehren M, Heinrich MC, Joensuu H, et al. Follow-up results after 9 years (yrs) of the ongoing, phase II B2222 trial of imatinib mesylate (IM) in patients (pts) with metastatic or unresectable KIT+ gastrointestinal stromal tumors (GIST) (abstract 10016). J Clin Oncol 2011; 29:609s. Abstract available online at: http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=102&abstractID=82574 (Accessed on July 19, 2011).
  13. Demetri GD, Rankin CJ, Benjamin RS, et al. Long-term disease control of advanced gastrointestinal stromal tumors with imatinib: 10-year otcoms from SWOG phase III intergroup trial S0033 (abstract). J Clin Oncol 32:5s (suppl; abstract 10508). Abstract available online at: http://meetinglibrary.asco.org/content/134128-144 (Accessed on July 07, 2014).
  14. Blanke CD, Demetri GD, von Mehren M, et al. Long-term results from a randomized phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. J Clin Oncol 2008; 26:620.
  15. Van Glabbeke M, Verweij J, Casali PG, et al. Initial and late resistance to imatinib in advanced gastrointestinal stromal tumors are predicted by different prognostic factors: a European Organisation for Research and Treatment of Cancer-Italian Sarcoma Group-Australasian Gastrointestinal Trials Group study. J Clin Oncol 2005; 23:5795.
  16. Rutkowski P, Nowecki ZI, Debiec-Rychter M, et al. Predictive factors for long-term effects of imatinib therapy in patients with inoperable/metastatic CD117(+) gastrointestinal stromal tumors (GISTs). J Cancer Res Clin Oncol 2007; 133:589.
  17. Armbrust T, Sobotta M, Gunawan B, et al. Does imatinib turn recurrent and/or metastasized gastrointestinal stromal tumors into a chronic disease? - single center experience. Eur J Gastroenterol Hepatol 2009; 21:819.
  18. Kristensen CA, Eigtved A, Bjerregard B, et al. FDG-PET versus spiral CT for evaluation of STI571 treatment of gastrointestinal stromal tumors (abstract). Proc Am Soc Clin Oncol 2003; 22:824a.
  19. Stroobants S, Goeminne J, Seegers M, et al. 18FDG-Positron emission tomography for the early prediction of response in advanced soft tissue sarcoma treated with imatinib mesylate (Glivec). Eur J Cancer 2003; 39:2012.
  20. Antoch G, Kanja J, Bauer S, et al. Comparison of PET, CT, and dual-modality PET/CT imaging for monitoring of imatinib (STI571) therapy in patients with gastrointestinal stromal tumors. J Nucl Med 2004; 45:357.
  21. Van den Abbeele AD. The lessons of GIST--PET and PET/CT: a new paradigm for imaging. Oncologist 2008; 13 Suppl 2:8.
  22. Van den Abbeele AD, Gatsonis C, de Vries DJ, et al. ACRIN 6665/RTOG 0132 phase II trial of neoadjuvant imatinib mesylate for operable malignant gastrointestinal stromal tumor: monitoring with 18F-FDG PET and correlation with genotype and GLUT4 expression. J Nucl Med 2012; 53:567.
  23. Shankar LK, Hoffman JM, Bacharach S, et al. Consensus recommendations for the use of 18F-FDG PET as an indicator of therapeutic response in patients in National Cancer Institute Trials. J Nucl Med 2006; 47:1059.
  24. Boellaard R, Delgado-Bolton R, Oyen WJ, et al. FDG PET/CT: EANM procedure guidelines for tumour imaging: version 2.0. Eur J Nucl Med Mol Imaging 2015; 42:328.
  25. O JH, Lodge MA, Wahl RL. Practical PERCIST: A Simplified Guide to PET Response Criteria in Solid Tumors 1.0. Radiology 2016; 280:576.
  26. National Comprehensive Cancer Network (NCCN). NCCN Clinical practice guidelines in oncology. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp (Accessed on February 27, 2016).
  27. Bechtold RE, Chen MY, Stanton CA, et al. Cystic changes in hepatic and peritoneal metastases from gastrointestinal stromal tumors treated with Gleevec. Abdom Imaging 2003; 28:808.
  28. Linton KM, Taylor MB, Radford JA. Response evaluation in gastrointestinal stromal tumours treated with imatinib: misdiagnosis of disease progression on CT due to cystic change in liver metastases. Br J Radiol 2006; 79:e40.
  29. LeCesne A, van Glabbeke M, Verweij J, et al. Is stable disease according to RECIST criteria a real stable disease in GIST patients treated with imatinib mesylate included in the intergroup EORTC/ISG/AGITG trial? (abstract). J Clin Oncol 2006; 24:522s.
  30. Le Cesne A, Van Glabbeke M, Verweij J, et al. Absence of progression as assessed by response evaluation criteria in solid tumors predicts survival in advanced GI stromal tumors treated with imatinib mesylate: the intergroup EORTC-ISG-AGITG phase III trial. J Clin Oncol 2009; 27:3969.
  31. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45:228.
  32. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000; 92:205.
  33. Shankar S, vanSonnenberg E, Desai J, et al. Gastrointestinal stromal tumor: new nodule-within-a-mass pattern of recurrence after partial response to imatinib mesylate. Radiology 2005; 235:892.
  34. Dileo P, Randhawa R, Vansonnenberg E, et al. Safety and efficacy of percutaneous radio-frequency ablation in patients with metastatic gastrointestinal stromal tumors (GIST) with clonal evolution of lesions refractory to imatinib mesylate (abstract). Proc Am Soc Clin Oncol 2004; 22:820a.
  35. Choi H, Charnsangavej C, Faria SC, et al. Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria. J Clin Oncol 2007; 25:1753.
  36. Benjamin RS, Choi H, Macapinlac HA, et al. We should desist using RECIST, at least in GIST. J Clin Oncol 2007; 25:1760.
  37. Gastrointestinal Stromal Tumor Meta-Analysis Group (MetaGIST). Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors: a meta-analysis of 1,640 patients. J Clin Oncol 2010; 28:1247.
  38. Demetri GD, Wang Y, Wehrle E, et al. Imatinib plasma levels are correlated with clinical benefit in patients with unresectable/metastatic gastrointestinal stromal tumors. J Clin Oncol 2009; 27:3141.
  39. Yoo C, Ryu MH, Kang BW, et al. Cross-sectional study of imatinib plasma trough levels in patients with advanced gastrointestinal stromal tumors: impact of gastrointestinal resection on exposure to imatinib. J Clin Oncol 2010; 28:1554.
  40. Eechoute K, Sparreboom A, Burger H, et al. Drug transporters and imatinib treatment: implications for clinical practice. Clin Cancer Res 2011; 17:406.
  41. Judson I, Ma P, Peng B, et al. Imatinib pharmacokinetics in patients with gastrointestinal stromal tumour: a retrospective population pharmacokinetic study over time. EORTC Soft Tissue and Bone Sarcoma Group. Cancer Chemother Pharmacol 2005; 55:379.
  42. Eechoute K, Fransson MN, Reyners AK, et al. A long-term prospective population pharmacokinetic study on imatinib plasma concentrations in GIST patients. Clin Cancer Res 2012; 18:5780.
  43. Heinrich MC, Corless CL, Demetri GD, et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 2003; 21:4342.
  44. Debiec-Rychter M, Dumez H, Judson I, et al. Use of c-KIT/PDGFRA mutational analysis to predict the clinical response to imatinib in patients with advanced gastrointestinal stromal tumours entered on phase I and II studies of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 2004; 40:689.
  45. Corless CL, Schroeder A, Griffith D, et al. PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib. J Clin Oncol 2005; 23:5357.
  46. Heinrich MC, Owzar K, Corless CL, et al. Correlation of kinase genotype and clinical outcome in the North American Intergroup Phase III Trial of imatinib mesylate for treatment of advanced gastrointestinal stromal tumor: CALGB 150105 Study by Cancer and Leukemia Group B and Southwest Oncology Group. J Clin Oncol 2008; 26:5360.
  47. Patrikidou A, Domont J, Chabaud S, et al. Long-term outcome of molecular subgroups of GIST patients treated with standard-dose imatinib in the BFR14 trial of the French Sarcoma Group. Eur J Cancer 2016; 52:173.
  48. Debiec-Rychter M, Sciot R, Le Cesne A, et al. KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours. Eur J Cancer 2006; 42:1093.
  49. Van Glabbeke MM, Owzar K, Rankin C, et al. Comparison of two doses of imatinib in the treatment of unresectable or metastatic gastrointestinal stromal tumors (GIST): a meta-analysis based on 1,640 paitnets (abstract). J Clin Oncol 2007; 25:546s.
  50. Casali PG, Jost L, Reichardt P, et al. Gastrointestinal stromal tumours: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol 2009; 20 Suppl 4:64.
  51. Demetri GD, Benjamin RS, Blanke CD, et al. NCCN Task Force report: management of patients with gastrointestinal stromal tumor (GIST)--update of the NCCN clinical practice guidelines. J Natl Compr Canc Netw 2007; 5 Suppl 2:S1.
  52. Medeiros F, Corless CL, Duensing A, et al. KIT-negative gastrointestinal stromal tumors: proof of concept and therapeutic implications. Am J Surg Pathol 2004; 28:889.
  53. Hirota S, Ohashi A, Nishida T, et al. Gain-of-function mutations of platelet-derived growth factor receptor alpha gene in gastrointestinal stromal tumors. Gastroenterology 2003; 125:660.
  54. Cassier PA, Fumagalli E, Rutkowski P, et al. Outcome of patients with platelet-derived growth factor receptor alpha-mutated gastrointestinal stromal tumors in the tyrosine kinase inhibitor era. Clin Cancer Res 2012; 18:4458.
  55. Yoo C, Ryu MH, Jo J, et al. Efficacy of Imatinib in Patients with Platelet-Derived Growth Factor Receptor Alpha-Mutated Gastrointestinal Stromal Tumors. Cancer Res Treat 2016; 48:546.
  56. Farag S, Somaiah N, Chooi H, et al. Clinical characteristics and treatment outcome in a large multicenter observational cohort of pdgfra exon 18 mutated gastrointestinal stromal tumor (GIST) patients (abstract). J Clin Oncol 34, 2016 (suppl; abstr 11011). Abstract available online at http://meetinglibrary.asco.org/content/164473-176 (Accessed on June 16, 2016).
  57. https://clinicaltrials.gov/ct2/show/NCT01243346?term=GIST+and+D842V+mutation&rank=1 (Accessed on December 07, 2015).
  58. https://clinicaltrials.gov/ct2/show/NCT02508532?term=GIST+and+PDGFRA+mutations&rank=4 (Accessed on December 07, 2015).
  59. Trent JC, et al. A phase II study of dasatanib for patients with imatinib-resistant gastrointestinal stromal tumor (GIST) (Abstract 10006). J Clin Oncol 2011; 29:604s. Abstract available online at http://meetinglibrary.asco.org/content/79120-102 (Accessed on July 19, 2011).
  60. von Mehren M, Tetzlaff ED, MAcaraeg M, et al. Dose escalating study of crenolanib besylate in advanced GIST patients with PDGFRA D842V activating mutations (abstract). J Clin Oncol 34, 2016 (suppl; abstr 11010). Abstract available online at http://meetinglibrary.asco.org/content/170566-176 (Accessed on June 16, 2016).
  61. Boikos SA, Pappo AS, Killian JK, et al. Molecular Subtypes of KIT/PDGFRA Wild-Type Gastrointestinal Stromal Tumors: A Report From the National Institutes of Health Gastrointestinal Stromal Tumor Clinic. JAMA Oncol 2016; 2:922.
  62. Mussi C, Schildhaus HU, Gronchi A, et al. Therapeutic consequences from molecular biology for gastrointestinal stromal tumor patients affected by neurofibromatosis type 1. Clin Cancer Res 2008; 14:4550.
  63. Blay JY, Le Cesne A, Ray-Coquard I, et al. Prospective multicentric randomized phase III study of imatinib in patients with advanced gastrointestinal stromal tumors comparing interruption versus continuation of treatment beyond 1 year: the French Sarcoma Group. J Clin Oncol 2007; 25:1107.
  64. Patrikidou A, Chabaud S, Ray-Coquard I, et al. Influence of imatinib interruption and rechallenge on the residual disease in patients with advanced GIST: results of the BFR14 prospective French Sarcoma Group randomised, phase III trial. Ann Oncol 2013; 24:1087.
  65. Verweij J, van Oosterom A, Blay JY, et al. Imatinib mesylate (STI-571 Glivec, Gleevec) is an active agent for gastrointestinal stromal tumours, but does not yield responses in other soft-tissue sarcomas that are unselected for a molecular target. Results from an EORTC Soft Tissue and Bone Sarcoma Group phase II study. Eur J Cancer 2003; 39:2006.
  66. Van Glabbeke M, Verweij J, Casali PG, et al. Predicting toxicities for patients with advanced gastrointestinal stromal tumours treated with imatinib: a study of the European Organisation for Research and Treatment of Cancer, the Italian Sarcoma Group, and the Australasian Gastro-Intestinal Trials Group (EORTC-ISG-AGITG). Eur J Cancer 2006; 42:2277.
  67. Berman E, Nicolaides M, Maki RG, et al. Altered bone and mineral metabolism in patients receiving imatinib mesylate. N Engl J Med 2006; 354:2006.
  68. Joensuu H, Reichardt P. Imatinib and altered bone and mineral metabolism. N Engl J Med 2006; 355:628; author reply 628.
  69. Owen S, Hatfield A, Letvak L. Imatinib and altered bone and mineral metabolism. N Engl J Med 2006; 355:627; author reply 628.
  70. Ferrero D, Pogliani EM, Rege-Cambrin G, et al. Corticosteroids can reverse severe imatinib-induced hepatotoxicity. Haematologica 2006; 91:ECR27.
  71. Kerkelä R, Grazette L, Yacobi R, et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med 2006; 12:908.
  72. Verweij J, Casali PG, Kotasek D, et al. Imatinib does not induce cardiac left ventricular failure in gastrointestinal stromal tumours patients: analysis of EORTC-ISG-AGITG study 62005. Eur J Cancer 2007; 43:974.
  73. Khakoo AY, Steinert DM, Patel SR, et al. Rare incidence of congestive heart failure (CHF) in gastrointestinal stromal tumor (GIST) and other sarcoma patients receiving imatinib mesylate (IM) therapy (abstract). J Clin Oncol 2007; 25:551s.
  74. Rutkowski P, Ruka W. Emergency surgery in the era of molecular treatment of solid tumours. Lancet Oncol 2009; 10:157.
  75. Zalcberg JR, Verweij J, Casali PG, et al. Outcome of patients with advanced gastro-intestinal stromal tumours crossing over to a daily imatinib dose of 800 mg after progression on 400 mg. Eur J Cancer 2005; 41:1751.
  76. Tamborini E, Bonadiman L, Greco A, et al. A new mutation in the KIT ATP pocket causes acquired resistance to imatinib in a gastrointestinal stromal tumor patient. Gastroenterology 2004; 127:294.
  77. Chen LL, Trent JC, Wu EF, et al. A missense mutation in KIT kinase domain 1 correlates with imatinib resistance in gastrointestinal stromal tumors. Cancer Res 2004; 64:5913.
  78. Antonescu CR, Besmer P, Guo T, et al. Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation. Clin Cancer Res 2005; 11:4182.
  79. Wardelmann E, Merkelbach-Bruse S, Pauls K, et al. Polyclonal evolution of multiple secondary KIT mutations in gastrointestinal stromal tumors under treatment with imatinib mesylate. Clin Cancer Res 2006; 12:1743.
  80. Heinrich MC, Corless CL, Blanke CD, et al. Molecular correlates of imatinib resistance in gastrointestinal stromal tumors. J Clin Oncol 2006; 24:4764.
  81. Guo T, Agaram NP, Wong GC, et al. Sorafenib inhibits the imatinib-resistant KITT670I gatekeeper mutation in gastrointestinal stromal tumor. Clin Cancer Res 2007; 13:4874.
  82. Debiec-Rychter M, Cools J, Dumez H, et al. Mechanisms of resistance to imatinib mesylate in gastrointestinal stromal tumors and activity of the PKC412 inhibitor against imatinib-resistant mutants. Gastroenterology 2005; 128:270.
  83. 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; 15:5902.
  84. 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; 26:5352.
  85. 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; 368:1329.
  86. 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; 12:107.
  87. Demetri GD, Garrett CR, Schöffski P, 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; 18:3170.
  88. Reichardt P, Kang YK, Rutkowski P, et al. Clinical outcomes of patients with advanced gastrointestinal stromal tumors: safety and efficacy in a worldwide treatment-use trial of sunitinib. Cancer 2015; 121:1405.
  89. Reichardt P, Demetri GD, Gelderblom H, et al. Correlation of KIT and PDGFRA mutational status with clinical benefit in patients with gastrointestinal stromal tumor treated with sunitinib in a worldwide treatment-use trial. BMC Cancer 2016; 16:22.
  90. Prior JO, Montemurro M, Orcurto MV, et al. Early prediction of response to sunitinib after imatinib failure by 18F-fluorodeoxyglucose positron emission tomography in patients with gastrointestinal stromal tumor. J Clin Oncol 2009; 27:439.
  91. 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; 45:1959.
  92. 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; 15:6862.
  93. Desai J, Yassa L, Marqusee E, et al. Hypothyroidism after sunitinib treatment for patients with gastrointestinal stromal tumors. Ann Intern Med 2006; 145:660.
  94. Wolter P, Stefan C, Decallonne B, et al. The clinical implications of sunitinib-induced hypothyroidism: a prospective evaluation. Br J Cancer 2008; 99:448.
  95. Chu TF, Rupnick MA, Kerkela R, et al. Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib. Lancet 2007; 370:2011.
  96. US Food and Drug Administration http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm224050.htm.
  97. Raut CP. Morgan JA, Quigley MT, et al. Perioperative sunitinib dosing around extensive resections of imatinib-resistant metastatic gastrointestinal stromal tumors (abstract 10044). J Clin Oncol 2007; 25:555s. Abstract available online at: http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=47&abstractID=36307 (Accessed on July 19, 2011).
  98. 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; 30:2401.
  99. Demetri GD, Reichardt P, Kang YK, 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; 381:295.
  100. Ben-Ami E, Barysauskas CM, von Mehren M, et al. Long-term follow-up results of the multicenter phase II trial of regorafenib in patients with metastatic and/or unresectable GI stromal tumor after failure of standard tyrosine kinase inhibitor therapy. Ann Oncol 2016; 27:1794.
  101. Dewaele B, Wasag B, Cools J, et al. Activity of dasatinib, a dual SRC/ABL kinase inhibitor, and IPI-504, a heat shock protein 90 inhibitor, against gastrointestinal stromal tumor-associated PDGFRAD842V mutation. Clin Cancer Res 2008; 14:5749.
  102. Kindler H, Campbell NP, Wroblewski K, et al. Final results of a University of Chicago phase II consortium trial of sorafenib (SOR) in patients (pts) with imatinib (IM)- and sunitinib (SU)-resistant (RES) gastrointestinal stromal tumors (GIST) (abstract). Data presented at the 2011 ASCO GI Cancers Symposium, January 20-22, San Francisco, CA. Abstract available online at http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=103&abstractID=70751 (Accessed on March 03, 2011).
  103. Park SH, Ryu MH, Ryoo BY, et al. Sorafenib in patients with metastatic gastrointestinal stromal tumors who failed two or more prior tyrosine kinase inhibitors: a phase II study of Korean gastrointestinal stromal tumors study group. Invest New Drugs 2012; 30:2377.
  104. Montemurro M, Gelderblom H, Bitz U, et al. Sorafenib as third- or fourth-line treatment of advanced gastrointestinal stromal tumour and pretreatment including both imatinib and sunitinib, and nilotinib: A retrospective analysis. Eur J Cancer 2013; 49:1027.
  105. Montemurro M, Schöffski P, Reichardt P, et al. Nilotinib in the treatment of advanced gastrointestinal stromal tumours resistant to both imatinib and sunitinib. Eur J Cancer 2009; 45:2293.
  106. Sawaki A, Nishida T, Doi T, et al. Phase 2 study of nilotinib as third-line therapy for patients with gastrointestinal stromal tumor. Cancer 2011; 117:4633.
  107. Cauchi C, Somaiah N, Engstrom PF, et al. Evaluation of nilotinib in advanced GIST previously treated with imatinib and sunitinib. Cancer Chemother Pharmacol 2012; 69:977.
  108. Kanda T, Ishikawa T, Takahashi T, Nishida T. Nilotinib for treatment of gastrointestinal stromal tumors: out of the equation? Expert Opin Pharmacother 2013; 14:1859.
  109. Ganjoo KN, Villalobos VM, Kamaya A, et al. A multicenter phase II study of pazopanib in patients with advanced gastrointestinal stromal tumors (GIST) following failure of at least imatinib and sunitinib. Ann Oncol 2014; 25:236.
  110. Mir O, Cropet C, Toulmonde M, et al. Pazopanib plus best supportive care versus best supportive care alone in advanced gastrointestinal stromal tumours resistant to imatinib and sunitinib (PAZOGIST): a randomised, multicentre, open-label phase 2 trial. Lancet Oncol 2016; 17:632.
  111. Garner AP, Gozgit JM, Anjum R, et al. Ponatinib inhibits polyclonal drug-resistant KIT oncoproteins and shows therapeutic potential in heavily pretreated gastrointestinal stromal tumor (GIST) patients. Clin Cancer Res 2014; 20:5745.
  112. Heinrich MC, vonMehren M, Demetri GD, et al. A phase 2 study of ponatinib in patients (pts) with advanced gastrointestinal stromal tumors (GIST) after failure of tyrosine kinase inhibitor (TKI) therapy: Initial report. Ann Oncol 2014; 24(Suppl 4):iv494.
  113. Cortes JE, Kim DW, Pinilla-Ibarz J, et al. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med 2013; 369:1783.
  114. Blay JY, Shen L, Kang YK, et al. Nilotinib versus imatinib as first-line therapy for patients with unresectable or metastatic gastrointestinal stromal tumours (ENESTg1): a randomised phase 3 trial. Lancet Oncol 2015; 16:550.
  115. Demetri GD, Casali PG, Blay JY, et al. A phase I study of single-agent nilotinib or in combination with imatinib in patients with imatinib-resistant gastrointestinal stromal tumors. Clin Cancer Res 2009; 15:5910.
  116. Reichardt P, Blay JY, Gelderblom H, et al. Phase III study of nilotinib versus best supportive care with or without a TKI in patients with gastrointestinal stromal tumors resistant to or intolerant of imatinib and sunitinib. Ann Oncol 2012; 23:1680.
  117. Kim KP, Ryu MH, Yoo C, et al. Nilotinib in patients with GIST who failed imatinib and sunitinib: importance of prior surgery on drug bioavailability. Cancer Chemother Pharmacol 2011; 68:285.
  118. Kang YK, Ryu MH, 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; 14:1175.
  119. 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:iii21.
  120. Consensus-based guidelines from the National Comprehensive Cancer Network (NCCN) available online at http://www.nccn.org/professionals/physician_gls/f_guidelines.asp (Accessed on November 02, 2015).
  121. von Mehren M. Imatinib-refractory gastrointestinal stromal tumors: the clinical problem and therapeutic strategies. Curr Oncol Rep 2006; 8:192.
  122. Sawaki A, Yamao K. Imatinib mesylate acts in metastatic or unresectable gastrointestinal stromal tumor by targeting KIT receptors--a review. Cancer Chemother Pharmacol 2004; 54 Suppl 1:S44.
  123. Schnadig ID, Blanke CD. Gastrointestinal stromal tumors: imatinib and beyond. Curr Treat Options Oncol 2006; 7:427.
  124. Pierie JP, Choudry U, Muzikansky A, et al. The effect of surgery and grade on outcome of gastrointestinal stromal tumors. Arch Surg 2001; 136:383.
  125. Corbin KS, Kindler HL, Liauw SL. Considering the role of radiation therapy for gastrointestinal stromal tumor. Onco Targets Ther 2014; 7:713.
  126. Cuaron JJ, Goodman KA, Lee N, Wu AJ. External beam radiation therapy for locally advanced and metastatic gastrointestinal stromal tumors. Radiat Oncol 2013; 8:274.
  127. Joensuu H, Eriksson M, Collan J, et al. Radiotherapy for GIST progressing during or after tyrosine kinase inhibitor therapy: A prospective study. Radiother Oncol 2015; 116:233.