The tyrosine kinase inhibitor, imatinib (Gleevec) has been a standard therapy for patients with KIT and most PDGFRA mutant GISTs. Approximately 10 percent of GISTs have primary resistance to imatinib, due to the absence of KIT or PDGFRA mutation. Platelet-derived growth factor receptor alpha (PDGFRA) mutations occur in approximately 10-20% of patients with GIST, especially in those tumours that are KIT negative. The presence of PDGFRA D842V mutation on exon 18, however, confers resistance to imatinib. Avapritinib may be considered for such cases. GIST patients with KIT exon 9 mutation also require higher dose of imatinib (800mg). Some KIT and PDGFRA wild-type tumours have mutations of the succinate dehydrogenase (SDH) complex and are resistant to imatinib. Sunitinib or regorafenib may be considered for such patients. In the event of failure of first line imatinib, sunitinib, regorafenib, or a second-generation tyrosine kinase inhibitor, nilotinib may be considered. These have shown efficacy in some imatinib-refractory cases.