Optimal Use of Targeted Agents for Advanced Gastrointestinal Stromal Tumours

Imatinib is the recommended 1st-line treatment for a KIT-positive unresectable and/or metastatic gastrointestinal stromal tumour (GIST). However, some patients experience intolerance to imatinib and most patients will eventually experience disease progression while on imatinib treatment. Sunitinib is approved for treatment of a GIST after disease progression on, or intolerance to, imatinib therapy. Progression may occur early or later on, in treatment and is determined by factors including initial GIST genotype and mutational status. GISTs with KIT exon 11 mutations appear to be sensitive to standard dose imatinib, and patients with GISTs exhibiting KIT exon 9 mutations whose disease has progressed on imatinib 400 mg/day have been shown to respond to imatinib 800 mg/day, albeit with a higher incidence of adverse events. Sunitinib has shown clinical benefit in all major GIST mutational subtypes, particularly in patients with wild-type or KIT exon 9 genotype and against GISTs with secondary KIT exon 13 or 14 mutations. The choice between higher-dose imatinib and sunitinib after progression on standard dose imatinib is unclear, and apart from the GIST primary resistance genotype and mutational status, individual patient factors such as tumour characteristics, drug pharmacokinetics, and other clinical factors may affect response to treatment. Individualisation of therapy may help to maximise clinical benefit of therapy in these patients.