NCCN Guidelines® Insights: Gastrointestinal Stromal Tumors, Version 2.2022

Featured Updates to the NCCN Guidelines

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  • 1 Fox Chase Cancer Center;
  • | 2 Roswell Park Comprehensive Cancer Center;
  • | 3 Duke Cancer Institute;
  • | 4 UC San Diego Moores Cancer Center;
  • | 5 Robert H. Lurie Comprehensive Cancer Center of Northwestern University;
  • | 6 City of Hope National Medical Center;
  • | 7 Moffitt Cancer Center;
  • | 8 UC Davis Comprehensive Cancer Center;
  • | 9 Massachusetts General Hospital Cancer Center;
  • | 10 The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute;
  • | 11 UCLA Jonsson Comprehensive Cancer Center;
  • | 12 Stanford Cancer Institute;
  • | 13 O’Neal Comprehensive Cancer Center at UAB;
  • | 14 UT Southwestern Simmons Comprehensive Cancer Center;
  • | 15 Vanderbilt-Ingram Cancer Center;
  • | 16 Memorial Sloan Kettering Cancer Center;
  • | 17 Fred Hutchinson Cancer Center;
  • | 18 University of Colorado Cancer Center;
  • | 19 Fred & Pamela Buffett Cancer Center;
  • | 20 Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute;
  • | 21 The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins;
  • | 22 St. Jude Children’s Research Hospital/University of Tennessee Health Science Center;
  • | 23 University of Wisconsin Carbone Cancer Center;
  • | 24 Mayo Clinic Cancer Center;
  • | 25 Huntsman Cancer Institute at the University of Utah;
  • | 26 University of Michigan Rogel Cancer Center;
  • | 27 Abramson Cancer Center at the University of Pennsylvania;
  • | 28 Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine;
  • | 29 UCSF Helen Diller Family Comprehensive Cancer Center; and
  • | 30 National Comprehensive Cancer Network.

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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    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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    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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    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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    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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    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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    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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    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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    Stivarga (regorafenib) tablets, for oral use [prescribing information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc.; 2020.

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    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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    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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    Vitrakvi (larotrectinib) capsules, for oral use [prescribing information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals, Inc.; 2022.

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    Rozlytrek (entrectinib) capsules, for oral use [prescribing information]. South San Francisco, CA: Genentech, Inc.; 2021.

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

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    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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    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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    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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    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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    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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    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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    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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    Schöffski P, Mir O, Kasper B, et al. Activity and safety of the multi-target tyrosine kinase inhibitor cabozantinib in patients with metastatic gastrointestinal stromal tumour after treatment with imatinib and sunitinib: European Organisation for Research and Treatment of Cancer phase II trial 1317 ‘CaboGIST’. Eur J Cancer 2020;134:6274.

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    Schöffski P, Reichardt P, Blay JY, et al. A phase I-II study of everolimus (RAD001) in combination with imatinib in patients with imatinib-resistant gastrointestinal stromal tumors. Ann Oncol 2010;21:19901998.

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    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;14:57495758.

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    Trent JC, Wathen K, von Mehren M, et al. A phase II study of dasatinib for patients with imatinib-resistant gastrointestinal stromal tumor (GIST) [abstract]. J Clin Oncol 2011;29(Suppl):Abstract 10006.

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    Smith BD, Kaufman MD, Lu WP, et al. Ripretinib (DCC-2618) is a switch control kinase inhibitor of a broad spectrum of oncogenic and drug-resistant KIT and PDGFRA variants. Cancer Cell 2019;35:738751.e9.

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    Alkhuziem M, Burgoyne AM, Fanta PT, et al. The call of “the wild”-type GIST: it’s time for domestication. J Natl Compr Canc Netw 2017;15:551554.

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    Kato S, Adashek JJ, Shaya J, et al. Concomitant MEK and cyclin gene alterations: implications for response to targeted therapeutics. Clin Cancer Res 2021;27:27922797.

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