Systemic Therapy for Gastrointestinal Stromal Tumor: Current Standards and Emerging Challenges

Abstract

Gastrointestinal stromal tumor (GIST), though rare, is the most common mesenchymal tumors of the gastrointestinal tract. KIT or PDGFRα mutation plays as an oncogenic driver in the majority of GISTs. Surgical resection is the only curative treatment for localized disease. The discovery of imatinib with promising anti-tumor effect and successive tyrosine kinase inhibitors (TKI), including second-line sunitinib and third-line regorafenib, revolutionized the management of advanced and metastatic GIST over the past two decades. Recently, ripretinib and avapritinib were approved for the fourth line setting and for PDGFRA exon 18-mutant GIST in first-line setting, respectively. Despite multi-line TKIs exerted ability of disease control, drug resistance remained an obstacle for preventing rapid disease progression. Experimental TKIs or novel therapeutic targets may further improve treatment efficacy. Immune checkpoint inhibitors such as anti-programmed cell death protein-1 (PD1) and anti-CTL-associated antigen 4 (CTLA-4) showed moderate response in early phase trials composed of heavily pretreated patients. KIT/PDGFRα wild-type GISTs are generally less sensitive to imatinib and late-line TKIs. Recent studies demonstrated that targeting fibroblast growth factor receptor signaling may be a potential target for the wild-type GISTs.

Keywords: Avapritinib; Gastrointestinal stromal tumors; Imatinib; Regorafenib; Ripretinib; Sunitinib; Systemic treatment.

Fig. 1

Treatment scheme of FDA-approved tyrosine kinase inhibitors for advanced GISTs. Figure created with BioRender.com.

Fig. 2

The molecular characterization of KIT/PDGFRA wild-type (WT) gastrointestinal stromal tumor. Dashed outline indicates loss of function, and bold outline indicates activation of kinases Star symbols indicate gene mutations. SDH, succinate dehydrogenase; NF1, neurofibromin 1; RTK, receptor of tyrosine kinase; FGF, fibroblast growth factor; FGFR, fibroblast growth factor receptor; MAX, MYC Associated Factor X; MEN1, Menin 1; CHD4, Chromodomain Helicase DNA Binding Protein 4. Figure created with BioRender.com.

Fig. 3

Mechanisms of actions of approved TKI and selected investigational systemic treatments targeting GIST. *Type I TKI (targeting active formation). Figure created with BioRender.com.