Treatment of molecular resistance and rare GIST subtypes in 2023

Gastrointestinal stromal tumors (GIST) have an incidence of 12/106/year in France and include different molecular subtypes. Mutations in KIT, PDGFRA, SDH, NF1, and other genes are mutually exclusive. Surgery is the treatment of choice in the localized phase, where it is most often curative. GIST with mutations in the KIT or PDGFRA genes at high risk of relapse have improved survival with adjuvant treatment with imatinib 400 mg/day for 3 years. In advanced disease, median overall survival has increased from 18 months before imatinib to more than 70 months since the introduction of tyrosine kinase inhibitors (TKIs). The treatment of resistant forms of GIST is evolving rapidly. Resistance to TKIs in advanced disease results mainly from the selection of resistant clones carrying resistance mutations to TKIs on KIT or PDGFRA, when they are the molecular “drivers”. Imatinib-resistant GIST respond to second-line sunitinib, third-line regorafenib, fourth-line ripretinib, and avapritinib for D842V PDGFRA point mutations. The rare molecular forms of GIST, with inactivation of NF1, mutation or loss of expression of SDH, mutations of BRAF or translocations of NTRK, generally show primary resistance to these TKIs but have specific inhibitors for certain subtypes. Several novel TKI agents blocking a broad panel of KIT and PDGFRA mutations are currently in clinical evaluation.