When gastrointestinal stromal tumour (GIST), the most common form of sarcoma, was first recognized as a distinct pathological entity in the 1990s, patients with advanced-stage disease had a very poor prognosis owing to a lack of effective medical therapies. The discovery of KIT mutations as the first and most prevalent drivers of GIST and the subsequent development of the first KIT tyrosine kinase inhibitor (TKI), imatinib, revolutionized the treatment of patients with this disease. We can now identify the driver mutation in 99% of patients with GIST via molecular diagnostic testing, and therapies have been developed to treat many, but not all, molecular subtypes of the disease. At present, seven drugs are approved by the FDA for the treatment of advanced-stage GIST (imatinib, sunitinib, regorafenib, ripretinib, avapritinib, larotrectinib and entrectinib), all of which are TKIs. Although these agents can be very effective for treating certain GIST subtypes, challenges remain and new therapeutic approaches are needed. In this Review, we discuss the molecular subtypes of GIST and the evolution of current treatments, as well as their therapeutic limitations. We also highlight emerging therapeutic approaches that might overcome clinical challenges through novel strategies predicated on the biological features of the distinct GIST molecular subtypes.
All currently approved systemic therapies for GIST are tyrosine kinase inhibitors (TKIs); these agents can be used to treat the majority of patients with advanced-stage GIST.
TKIs have limitations, particularly in the setting of advanced-stage disease, because of secondary intra-allelic mutations that confer drug resistance, but also because of the need for indefinite treatment to control quiescent, drug-persistent tumour cells.
Understanding the underlying biology of the different molecular subtypes of GIST has presented new therapeutic approaches beyond TKIs.
TKIs remain relevant for GISTs harbouring receptor tyrosine kinase mutations or fusions, but applying them in new, more strategic ways will benefit patients.
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The work of M.C.H. has been supported by grants from the Department of Veterans Affairs (1 I01 BX005358-01A1) and the NIH National Cancer Institute (1 R21 CA263400-01), and by philanthropic donations from the GIST Cancer Research Fund and the Jonathan David Foundation.
M.C.H. has been a consultant for Blueprint Medicines, Deciphera Pharmaceuticals, Novartis and Theseus Pharmaceuticals, and has a patent for the treatment of GIST using imatinib that has been licensed by his institute to Novartis. The other authors declare no competing interests.
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Klug, L.R., Khosroyani, H.M., Kent, J.D. et al. New treatment strategies for advanced-stage gastrointestinal stromal tumours. Nat Rev Clin Oncol 19, 328–341 (2022). https://doi.org/10.1038/s41571-022-00606-4
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