NCCN Guidelines® Insights: Gastrointestinal Stromal Tumors, Version 2.2022

Featured Updates to the NCCN Guidelines

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Margaret von Mehren Fox Chase Cancer Center;

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John M. Kane III Roswell Park Comprehensive Cancer Center;

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Richard F. Riedel Duke Cancer Institute;

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Jason K. Sicklick UC San Diego Moores Cancer Center;

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Seth M. Pollack Robert H. Lurie Comprehensive Cancer Center of Northwestern University;

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Mark Agulnik City of Hope National Medical Center;

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Marilyn M. Bui Moffitt Cancer Center;

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Janai Carr-Ascher UC Davis Comprehensive Cancer Center;

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Edwin Choy Massachusetts General Hospital Cancer Center;

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Mary Connelly The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute;

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Sarah Dry UCLA Jonsson Comprehensive Cancer Center;

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Kristen N. Ganjoo Stanford Cancer Institute;

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Ricardo J. Gonzalez Moffitt Cancer Center;

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Ashley Holder O’Neal Comprehensive Cancer Center at UAB;

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Jade Homsi UT Southwestern Simmons Comprehensive Cancer Center;

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Vicki Keedy Vanderbilt-Ingram Cancer Center;

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Ciara M. Kelly Memorial Sloan Kettering Cancer Center;

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Edward Kim Fred Hutchinson Cancer Center;

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David Liebner The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute;

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Martin McCarter University of Colorado Cancer Center;

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Sean V. McGarry Fred & Pamela Buffett Cancer Center;

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Nathan W. Mesko Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute;

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Christian Meyer The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins;

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Alberto S. Pappo St. Jude Children’s Research Hospital/University of Tennessee Health Science Center;

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Amanda M. Parkes University of Wisconsin Carbone Cancer Center;

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Ivy A. Petersen Mayo Clinic Cancer Center;

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Matthew Poppe Huntsman Cancer Institute at the University of Utah;

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Scott Schuetze University of Michigan Rogel Cancer Center;

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Jacob Shabason Abramson Cancer Center at the University of Pennsylvania;

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Matthew B. Spraker Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine;

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Melissa Zimel UCSF Helen Diller Family Comprehensive Cancer Center; and

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Mary Anne Bergman National Comprehensive Cancer Network.

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Hema Sundar National Comprehensive Cancer Network.

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Lisa E. Hang National Comprehensive Cancer Network.

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Gastrointestinal stromal tumors (GIST) are the most common type of soft tissue sarcoma that occur throughout the gastrointestinal tract. Most of these tumors are caused by oncogenic activating mutations in the KIT or PDGFRA genes. The NCCN Guidelines for GIST provide recommendations for the diagnosis, evaluation, treatment, and follow-up of patients with these tumors. These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines, including revised systemic therapy options for unresectable, progressive, or metastatic GIST based on mutational status, and updated recommendations for the management of GIST that develop resistance to specific tyrosine kinase inhibitors.

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    Ma GL, Murphy JD, Martinez ME, et al. Epidemiology of gastrointestinal stromal tumors in the era of histology codes: results of a population-based study. Cancer Epidemiol Biomarkers Prev 2015;24:298302.

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  • 3.

    Tran T, Davila JA, El-Serag HB. The epidemiology of malignant gastrointestinal stromal tumors: an analysis of 1,458 cases from 1992 to 2000. Am J Gastroenterol 2005;100:162168.

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    Dematteo RP, Heinrich MC, El-Rifai WM, et al. Clinical management of gastrointestinal stromal tumors: before and after STI-571. Hum Pathol 2002;33:466477.

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    Heinrich MC, Corless CL, Demetri GD, et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 2003;21:43424349.

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  • 9.

    Casali PG, Zalcberg J, Le Cesne A, et al. Ten-year progression-free and overall survival in patients with unresectable or metastatic GI stromal tumors: long-term analysis of the European Organisation for Research and Treatment of Cancer, Italian Sarcoma Group, and Australasian Gastrointestinal Trials Group intergroup phase III randomized trial on imatinib at two dose levels. J Clin Oncol 2017;35:17131720.

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    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;23:53575364.

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    Martin-Broto J, Martinez-Marín V, Serrano C, et al. Gastrointestinal stromal tumors (GISTs): SEAP-SEOM consensus on pathologic and molecular diagnosis. Clin Transl Oncol 2017;19:536545.

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  • 13.

    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;42:10931103.

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  • 14.

    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;40:689695.

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  • 15.

    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;26:53605367.

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  • 16.

    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;52:173180.

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  • 17.

    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;28:12471253.

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  • 18.

    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;125:660667.

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  • 19.

    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;18:44584464.

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  • 20.

    Joensuu H, Wardelmann E, Sihto H, et al. Effect of KIT and PDGFRA mutations on survival in patients with gastrointestinal stromal tumors treated with adjuvant imatinib: an exploratory analysis of a randomized clinical trial. JAMA Oncol 2017;3:602609.

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  • 21.

    U.S. Food & Drug Administration. FDA approves avapritinib for gastrointestinal stromal tumor with a rare mutation. Accessed August 16, 2022. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-avapritinib-gastrointestinal-stromal-tumor-rare-mutation

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  • 22.

    Ayvakit (avapritinib) tablets, for oral use [prescribing information]. Cambridge, MA: Blueprint Medicines Corporation; 2020.

  • 23.

    Heinrich MC, Jones RL, von Mehren M, et al. Avapritinib in advanced PDGFRA D842V-mutant gastrointestinal stromal tumour (NAVIGATOR): a multicentre, open-label, phase 1 trial. Lancet Oncol 2020;21:935946.

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  • 24.

    Jones RL, Serrano C, von Mehren M, et al. Avapritinib in unresectable or metastatic PDGFRA D842V-mutant gastrointestinal stromal tumours: long-term efficacy and safety data from the NAVIGATOR phase I trial. Eur J Cancer 2021;145:132142.

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  • 25.

    Janeway KA, Kim SY, Lodish M, et al. Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations. Proc Natl Acad Sci USA 2011;108:314318.

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  • 26.

    Miettinen M, Wang ZF, Sarlomo-Rikala M, et al. Succinate dehydrogenase-deficient GISTs: a clinicopathologic, immunohistochemical, and molecular genetic study of 66 gastric GISTs with predilection to young age. Am J Surg Pathol 2011;35:17121721.

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  • 27.

    Heinrich MC, Rankin C, Blanke CD, et al. Correlation of long-term results of imatinib in advanced gastrointestinal stromal tumors with next-generation sequencing results: analysis of phase 3 SWOG intergroup trial S0033. JAMA Oncol 2017;3:944952.

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  • 28.

    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;2:922928.

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  • 29.

    Liu W, Zeng X, Wu X, et al. Clinicopathologic study of succinate-dehydrogenase-deficient gastrointestinal stromal tumors: a single-institutional experience in China. Medicine (Baltimore) 2017;96:e7668.

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  • 32.

    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;27:17941799.

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  • 33.

    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;25:236240.

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    Votrient (pazopanib) tablets, for oral use [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2021.

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    Yebra M, Bhargava S, Kumar A, et al. Establishment of patient-derived succinate dehydrogenase-deficient gastrointestinal stromal tumor models for predicting therapeutic response. Clin Cancer Res 2022;28:187200.

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  • 36.

    Lee JH, Shin SJ, Choe EA, et al. Tropomyosin-related kinase fusions in gastrointestinal stromal tumors. Cancers (Basel) 2022;14:2659.

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    Brenca M, Rossi S, Polano M, et al. Transcriptome sequencing identifies ETV6-NTRK3 as a gene fusion involved in GIST. J Pathol 2016;238:543549.

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    Shi E, Chmielecki J, Tang CM, et al. FGFR1 and NTRK3 actionable alterations in “wild-type” gastrointestinal stromal tumors. J Transl Med 2016;14:339.

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  • 43.

    Agaram NP, Wong GC, Guo T, et al. Novel V600E BRAF mutations in imatinib-naive and imatinib-resistant gastrointestinal stromal tumors. Genes Chromosomes Cancer 2008;47:853859.

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  • 44.

    Hostein I, Faur N, Primois C, et al. BRAF mutation status in gastrointestinal stromal tumors. Am J Clin Pathol 2010;133:141148.

  • 45.

    Maertens O, Prenen H, Debiec-Rychter M, et al. Molecular pathogenesis of multiple gastrointestinal stromal tumors in NF1 patients. Hum Mol Genet 2006;15:10151023.

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    Belinsky MG, Rink L, Cai KQ, et al. Somatic loss of function mutations in neurofibromin 1 and MYC associated factor X genes identified by exome-wide sequencing in a wild-type GIST case. BMC Cancer 2015;15:887.

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  • 47.

    Burgoyne AM, De Siena M, Alkhuziem M, et al. Duodenal-jejunal flexure GI stromal tumor frequently heralds somatic NF1 and Notch pathway mutations. JCO Precis Oncol 2017;1:112.

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  • 48.

    Charo LM, Burgoyne AM, Fanta PT, et al. A novel PRKAR1B-BRAF fusion in gastrointestinal stromal tumor guides adjuvant treatment decision-making during pregnancy. J Natl Compr Canc Netw 2018;16:238242.

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    NCI Staff. Dabrafenib-trametinib combination approved for solid tumors with BRAF mutations. Accessed August 16, 2022. Available at: https://www.cancer.gov/news-events/cancer-currents-blog/2022/fda-dabrafenib-trametinib-braf-solid-tumors

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  • 50.

    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;26:53525359.

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  • 51.

    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;11:41824190.

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  • 52.

    Heinrich MC, Corless CL, Blanke CD, et al. Molecular correlates of imatinib resistance in gastrointestinal stromal tumors. J Clin Oncol 2006;24:47644774.

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    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;12:17431749.

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    Desai J, Shankar S, Heinrich MC, et al. Clonal evolution of resistance to imatinib in patients with metastatic gastrointestinal stromal tumors. Clin Cancer Res 2007;13:53985405.

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    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;41:17511757.

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    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;368:13291338.

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    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;45:19591968.

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    Patel S, Zalcberg JR. Optimizing the dose of imatinib for treatment of gastrointestinal stromal tumours: lessons from the phase 3 trials. Eur J Cancer 2008;44:501509.

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    Goodman VL, Rock EP, Dagher R, et al. Approval summary: sunitinib for the treatment of imatinib refractory or intolerant gastrointestinal stromal tumors and advanced renal cell carcinoma. Clin Cancer Res 2007;13:13671373.

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    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 USA 2009;106:15421547.

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    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;15:68626870.

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    Nishida T, Takahashi T, Nishitani A, et al. Sunitinib-resistant gastrointestinal stromal tumors harbor cis-mutations in the activation loop of the KIT gene. Int J Clin Oncol 2009;14:143149.

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  • 63.

    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;381:295302.

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    Blay JY, Serrano C, Heinrich MC, et al. Ripretinib in patients with advanced gastrointestinal stromal tumours (INVICTUS): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol 2020;21:923934.

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    Zalcberg JR, Heinrich MC, George S, et al. Clinical benefit of ripretinib dose escalation after disease progression in advanced gastrointestinal stromal tumor: an analysis of the INVICTUS study. Oncologist 2021;26:e20532060.

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    Kindler HL, Campbell NP, Wroblewski K, et al. Sorafenib (SOR) in patients (pts) with imatinib (IM) and sunitinib (SU)-resistant (RES) gastrointestinal stromal tumors (GIST): final results of a University of Chicago phase II consortium trial [abstract]. J Clin Oncol 2011;29(Suppl):Abstract 10009.

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    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;30:23772383.

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    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;49:10271031.

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    Kefeli U, Benekli M, Sevinc A, et al. Efficacy of sorafenib in patients with gastrointestinal stromal tumors in the third- or fourth-line treatment: a retrospective multicenter experience. Oncol Lett 2013;6:605611.

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  • 71.

    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;15:59105916.

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  • 72.

    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;45:22932297.

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  • 73.

    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;117:46334641.

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    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;23:16801687.

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  • 75.

    Cauchi C, Somaiah N, Engstrom PF, et al. Evaluation of nilotinib in advanced GIST previously treated with imatinib and sunitinib. Cancer Chemother Pharmacol 2012;69:977982.

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  • 76.

    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;16:550560.

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  • 77.

    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;17:632641.

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