The Management of Unresectable, Advanced Gastrointestinal Stromal Tumours

Abstract

Gastrointestinal stromal tumours (GISTs) are the most common gastrointestinal tract mesenchymal tumours. Tyrosine kinase inhibitors (TKIs) have transformed the management of advanced GIST. Imatinib was the first TKI to gain approval as management for patients with advanced GIST, establishing a new standard of care. Since then, as a result of several trials including the GRID and INVICTUS studies, we now have five lines of approved targeted therapy, including imatinib, sunitinib, regorafenib, ripretinib and avapritinib for the treatment of unresectable, advanced GISTs. In this review, the Australasian Gastrointestinal Trials Group (AGITG) provide an overview of the key trials that have changed clinical practice, discuss the molecular drivers of GISTs, the importance of molecular testing and directing therapy according to molecular targets, as well as future strategies in the management of advanced GISTs.

Large-scale, prospective observational study of regorafenib in Japanese patients with advanced gastrointestinal stromal tumors in a real-world clinical setting

“…Oncogenic gain-of-function mutations of the genes encoding KIT and platelet-derived growth factor receptor A (PDGFRA) are the driver events for most GISTs, with activating KIT mutations present in approximately 80% of GISTs and PDGFRA mutations in 5–10% ( 3 , 4 ). Tyrosine kinase inhibitors (TKIs) are the mainstay of the treatment of advanced GISTs.…”

“…Tyrosine kinase inhibitors (TKIs) are the mainstay of the treatment of advanced GISTs. Imatinib, which inhibits signaling by KIT and PDGFRA, is generally used as first-line therapy, while sunitinib, which inhibits vascular endothelial growth factor receptors (VEGFRs) as well as KIT and PDGFRA, is used as second-line therapy ( 1 , 3 ).…”

“…In the event of disease progression due to the development of resistance to both these drugs, the multikinase inhibitor regorafenib is commonly used as third-line therapy ( 1 , 3 ). Regorafenib has activity against tyrosine kinases involved in oncogenesis (e.g., KIT, RET, and V600E-mutated BRAF), stromal maintenance (e.g.…”

Rapid Determination of 9 Tyrosine Kinase Inhibitors for the Treatment of Hepatocellular Carcinoma in Human Plasma by QuEChERS-UPLC-MS/MS

“…Their action mechanism is based on competing with adenosine triphosphate (ATP) for binding to the ATP-binding site of the kinase domain in order to block or reduce the phosphorylation of tyrosine kinase and, ultimately, exert anti-tumor effects ( Cammarota et al, 2022 ; Yang et al, 2022 ; Yao et al, 2022 ). TKIs are widely used in the treatment of small-cell lung cancer (SCLC) ( Hwang et al, 2021 ), non-small cell lung cancer (NSCLC) ( Lin et al, 2022 ; Ten et al, 2022 ), gastrointestinal mesenchymal tumor (GIST) ( Mohammadi and Gelderblom, 2021 ; Foo et al, 2022 ; Klug et al, 2022 ), hepatocellular liver cancer (HCC) ( Decraecker et al, 2021 ), renal cancer (RCC) ( Fogli et al, 2020 ; Pedersen et al, 2021 ), and other cancers owing to their high selectivity and low adverse effects when compared with those of the traditional cytotoxic anticancer drugs ( Xing et al, 2021 ). Sorafenib is the first first-line oral small molecule TKI approved by the U.S. Food and Drug Administration (FDA) for HCC, ushering in a new era of molecular targeting in HCC ( Di et al, 2013 ; Decraecker et al, 2021 ).…”

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“…PDGFR and fibroblast growth factor receptor), angiogenesis (e.g. VEGFR 1-3 and TIE2) (3,5), and tumor immunity (6). Its efficacy was demonstrated in the phase 3 GRID trial, in which it significantly improved progression-free survival (primary endpoint) and the disease control rate (DCR) compared with placebo in patients with metastatic and/or unresectable GIST that had progressed after treatment with imatinib and sunitinib (7).…”