clinical topic updates

Resistance-Conferring Mutations With First-Generation Tyrosine Kinase Inhibitors

by Jonathan C. Trent, MD, PhD

Overview

Imatinib has revolutionized the treatment of gastrointestinal stromal tumors (GIST); however, resistance to tyrosine kinase inhibition is a continuing challenge. Newer strategies are evolving to overcome tyrosine kinase inhibitor–resistant GIST, drawing on the observed patterns of primary and acquired resistance.

Expert Commentary

Jonathan C. Trent, MD, PhD

Professor of Medicine
Associate Director for Clinical Research
Sylvester Comprehensive Cancer Center
University of Miami Miller School of Medicine
Miami, FL

“Understanding the type of GIST mutation that is present is really the key first step in determining which therapy should be used to treat the patient.”

Jonathan C. Trent, MD, PhD

GIST are generally thought to arise when an interstitial cell of Cajal acquires a mutation in KIT or its sister kinase PDGFRA. Approximately 80% of GIST harbor KIT mutations, while roughly 10% have mutations in PDGFRA. The remainder harbor various distinct mutations, including those that lead to succinate dehydrogenase (SDH) deficiency. Understanding the type of GIST mutation that is present is really the key first step in determining which therapy should be used to treat the patient.

The most common KIT-mutant GIST result from primary mutations in exons 11 and 9. First-line imatinib improves survival in most patients with GIST. Median overall survival for those diagnosed with metastatic GIST had been just 9 months in the pre-imatinib era; today, we see a median overall survival of approximately 8 years in our practice. This reflects the use of not only imatinib but also sunitinib, regorafenib, and some of the newer agents that are on the verge of becoming available.

Every patient at our GIST clinic undergoes next-generation sequencing and/or circulating tumor DNA testing to guide treatment and to help us understand the drivers of resistance. KIT inhibition by imatinib is often effective initially, but preexisting GIST clones may harbor secondary mutations that portend resistance to imatinib. Acquired resistance to imatinib typically results from the expansion of subpopulations with different KIT secondary mutations that cluster in 2 regions of the kinase: the ATP-binding pocket (which is also the site of imatinib binding) encoded by exons 13 and 14 and/or the activation loop encoded by exons 17 and 18. Shifting from an inactive state to an activated state is dependent on the interaction of 1 region of the kinase called the activation switch with another area called the switch pocket. Newer molecules, such as the switch control kinase inhibitor ripretinib, have been designed to potentially address a wider range of the known mutant, or amplified, forms of the kinase. Ripretinib was recently approved for the treatment of adults with advanced GIST who have received prior treatment with 3 or more kinase inhibitors, including imatinib. With respect to resistant GIST, sunitinib is very effective against resistant mutations that occur at exons 13 or 14 but is not very effective against exon 17– or exon 18–resistant mutations. Conversely, regorafenib is not very effective for mutations in exons 13 or 14, but some evidence supports its activity against exon 17 mutations. PDGFRA-mutant GIST represents yet another category, of which exon 18 D842V substitution is most common. This substitution activates the kinase in such a way as to render it resistant to imatinib, sunitinib, and regorafenib. There had been no treatment for PDGFRA D842V–mutant GIST; however, avapritinib was recently approved by the US Food and Drug Administration for use in adults with unresectable or metastatic GIST harboring this specific mutation.

Other important categories include SDH-deficient GIST. Unfortunately, there are no therapies available that directly target the loss of SDH. GIST caused by SDH germline mutations are clinically important in that they may be syndromic and linked to a higher risk for other malignancies. Other rare GIST mutations (eg, BRAF, NF1, NTRK) are potentially targetable and are therefore also important clinically (ie, you would not want to treat a BRAF-mutant GIST or an NTRK-mutant GIST with imatinib).

References

Arshad J, Roberts A, Ahmed J, et al. Utility of circulating tumor DNA in the management of patients with GI stromal tumor: analysis of 243 patients. JCO Precision Oncology. 2020;4:66-73.

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(7):922-928.

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):5352-5359.

Kobayashi K, Szklaruk J, Trent JC, et al. Hepatic arterial embolization and chemoembolization for imatinib-resistant gastrointestinal stromal tumors. Am J Clin Oncol. 2009;32(6):574-581.

Oppelt PJ, Hirbe AC, Van Tine BA. Gastrointestinal stromal tumors (GISTs): point mutations matter in management, a review. J Gastrointest Oncol. 2017;8(3):466-473.

Prenen H, Cools J, Mentens N, et al. Efficacy of the kinase inhibitor SU11248 against gastrointestinal stromal tumor mutants refractory to imatinib mesylate. Clin Cancer Res. 2006;12(8):2622-2627.

Serrano C, Mariño-Enríquez A, Tao DL, et al. Complementary activity of tyrosine kinase inhibitors against secondary kit mutations in imatinib-resistant gastrointestinal stromal tumours [published correction appears in Br J Cancer. 2019;121(3):281]. Br J Cancer. 2019;120(6):612-620.

Serrano C, Vivancos A, López-Pousa A, et al. Clinical value of next generation sequencing of plasma cell-free DNA in gastrointestinal stromal tumors. BMC Cancer. 2020;20(1):99.

Yeh CN, Chen MH, Chen YY, et al. A phase II trial of regorafenib in patients with metastatic and/or a unresectable gastrointestinal stromal tumor harboring secondary mutations of exon 17. Oncotarget. 2017;8(27):44121-44130.

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