Drug dose and schedule
A patient with unresectable or metastatic GIST may be treated with an initial dose of 400 mg imatinib mesylate daily, with therapeutic effects monitored by 18 fluoro-deoxyglucose-positron emission tomography (18 FDG-PET) or computed tomography; dose escalation to 400 mg twice a day may be appropriate for patients with progressive disease, although it is unlikely to help patients who progress within 2 months of initiation of imatinib therapy.[4,15,16,17] An initial dose of 800 mg daily may be appropriate for patients with GIST harboring KIT exon 9 mutations. Resistance to imatinib may be primary with rapid progression of disease despite an increase in the imatinib dose, although this appears to occur in fewer than 20% of patients; some investigators have speculated that GIST with primary resistance to imatinib have mutations in other oncogenic signaling pathways that do not involve KIT.[1,19,20]
The majority of patients treated with imatinib ultimately experience disease progression after an initial response because of the development of delayed imatinib resistance. In most cases, delayed resistance is associated with secondary mutations in a separate portion of the KIT-coding sequence.[20,21]
The oral TKI sunitinib malate is generally given to patients with unresectable disease who progress on higher-dose imatinib, although individuals with localized progression may be candidates for resection. Less specific than imatinib, sunitinib inhibits vascular endothelial growth factor receptors (VEGFR 1-3), Fms-like tyrosine kinase-3 (FLT3), colony-stimulating factor 1 receptor (CSF-1R), and RET as well as KIT and PDGFR and displays antiangiogenic activity.[23,24,25] A number of other targeted therapeutics for the treatment of GIST are in development, including a variety of other kinase inhibitors, heat-shock protein 90 (Hsp90) inhibitors such as IPI-504, the mTOR inhibitor RAD001, and histone deacetylase inhibitors.[3,26]
Treatment with imatinib or sunitinib may be continued for as long as the patient appears to be deriving clinical benefit or has disease stability.
Response to kinase inhibitors
KIT- and PDGFRA-mutational analysis may be of help in predicting responses to kinase inhibitors for patients with unresectable, metastatic, or recurrent GIST who are undergoing therapy with selective TKIs.[18,27,28,29,30] However, the data are preliminary and mutational analysis for treatment decisions is not routine. There is currently no evidence that basing treatment decisions on mutational analysis improves OS. Four trials involving 768 patients and imatinib doses ranging from 400 mg to 800 mg per day have correlated tumor genotypes and complete and partial objective responses (see Table 6). For these 768 genotyped GIST, the objective response for KIT exon 11 mutant, KIT exon 9 mutant, and wild-type (no KIT or PDGFRA mutation) GIST were 71%, 38%, and 28% (weighted averages), respectively; rates of primary resistance to imatinib therapy were 5%, 16%, and 23%, respectively.