Therapeutic Role of Ripretinib in Gastrointestinal Stromal Tumor: A Next-Generation Tyrosine Kinase Inhibitor Addressing Resistance and Mutation Diversity

This review evaluates the efficacy of ripretinib in the management of gastrointestinal stromal tumors (GISTs), rare mesenchymal neoplasms. These tumors are primarily caused by mutations in the KIT proto-oncogene (CD117) or platelet-derived growth factor receptor alpha (PDGFRA) gene. The introduction of tyrosine kinase inhibitors (TKIs) such as imatinib has improved the treatment of GIST. However, the resistance to these TKIs has become a major impediment to its clinical management, particularly due to the occurrence of secondary resistance mutations in the KIT gene. Ripretinib, a novel switch-control inhibitor, represents a new-generation TKI designed to overcome this challenge. By targeting the switch pocket and activation loop, it has been reported to inhibit various KIT mutations, including secondary resistance mutations, as well as PDGFRA mutations. Clinical trials have demonstrated that ripretinib significantly prolongs progression-free and overall survival in patients who have failed third-line or later treatments. It also improves objective response rate and durability of response, with manageable adverse effects such as alopecia and fatigue. Emerging data further suggest mutation-specific efficacy, particularly in exon 11 and exon 17/18 combinations, highlighting the potential for personalized therapy. This review highlights the development, mechanism of action, and key clinical outcomes of ripretinib, with an emphasis on its potential to overcome resistance and its role in personalized GIST therapy.