Ripretinib for the treatment of advanced, imatinib-resistant gastrointestinal stromal tumors

Discovery of constitutive activation of KIT/PDGFRA tyrosine kinases in gastrointestinal stromal tumors (GISTs) leads to the development of the targeted drug imatinib. However, the inevitable development of imatinib resistance remains a major issue. Ripretinib is a novel targeted drug that inhibits the activities of a broad spectrum of drug-resistant KIT/PDGFRA mutants. It was approved in 2020 and is currently recommended by major international guidelines as the fourth-line and beyond therapy for advanced GISTs. Emerging evidence shows that ripretinib is superior to sunitinib as a second-line treatment for KIT exon 11-mutated GISTs due to its activity against highly heterogeneous frequently occurring secondary mutations. This review summarizes current data on the use of ripretinib to treat advanced imatinib-resistant GISTs. We also propose future research directions to improve the targeted GIST treatment. Ripretinib is a novel switch-control tyrosine kinase inhibitor that is currently recommended as fourth- and later-line therapy for advanced gastrointestinal stromal tumors (GISTs). Recent clinical trials have demonstrated that ripretinib is clinically superior to the standard second-line drug sunitinib for advanced GISTs with exon 11 KIT mutations. As such, ripretinib holds promise as new option for the second-line treatment of advanced GISTs with exon-11 KIT mutations. mPFS, median progression-free survival; NR, not reached; ORR, objective response rate; RCT, randomized controlled trial; TKI, tyrosine kinase inhibitor.image