Evaluation of Systemic Treatment Options for Gastrointestinal Stromal Tumours

SIMPLE SUMMARY: This review summarises the systemic treatment options available for patients with gastrointestinal stromal tumours (GIST). While surgical treatment is recommended for most localised GIST, pre- or post-operative therapy with imatinib is indicated in patients with a high risk of disease recurrence. For most patients with inoperable or metastatic GIST, imatinib is the first-line therapy. Sunitinib, regorafenib, and ripretinib are licensed as second-, third-, and fourth-line therapy, respectively. However, patients with GIST harbouring specific mutations could be imatinib-resistant and follow different therapeutic schemes. This review evaluates potential medication options for each line of systemic treatment and examines the possibility of personalised treatment. The focus is placed on the tumour mutational profile, treatment-related adverse effects, and patient characteristics. Finally, a multidisciplinary approach is crucial, as combining systemic therapy with surgery, radiotherapy, interventional radiology, and radionuclide therapy can improve outcome. ABSTRACT: Gastrointestinal stromal tumours (GIST) are the most common mesenchymal tumours of the gastrointestinal tract. Surgical treatment is recommended for the majority of localised GIST, while systemic treatment is the cornerstone of management for metastatic or unresectable disease. While a three-year regimen of imatinib is the standard of care in the adjuvant setting, there is no precise recommendation for the duration of neoadjuvant treatment, where imatinib is usually given between 4 and 12 months. Continuous treatment with imatinib at a dose of 400 mg once per day is recommended for most patients with unresectable or metastatic GIST in the first line. An exception is represented by patients with tumours harbouring the imatinib-insensitive PDGFRA D842V mutation who would be better treated with avapritinib. Targeted therapies are also recommended in the presence of NTRK rearrangements and BRAF mutations, although limited data are available. While an increase in the dose of imatinib to 800 mg is an option for the second line, sunitinib is usually considered the standard of care. Similar outcomes were reported for ripretinib in patients with tumours harbouring KIT exon 11 mutation, with significantly fewer side effects. Regorafenib and ripretinib are the standards of care in the third and fourth lines, respectively. The recent development of various systemic treatment options allows for a more personalised approach based on the molecular profile of the GIST, patient characteristics, and the profile of medications’ adverse events. A multidisciplinary approach is paramount since combining systemic treatment with locoregional treatment options and supportive care is vital for long-term survival.