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Gastrointestinal Stromal Tumors Treatment (PDQ®): Treatment - Health Professional Information [NCI] - Treatment Option Overview

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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.[22] 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.[4]

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).[3] 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.

Table 6. Relationship Between Tyrosine Kinase Genotype and Response to Imatinib Therapya

European Phase I/IIb Trial, % (n)[31]B-2222 Phase IIc Trial, % (n)[32]European/Australasian Phase IIId Trial, % (n)[18]North AmericanCLB-80004Phase IIIe Trial, % (n)[33]
N = number in sample, number of observations; NR = not reported.
a Annual review of pathology by ANNUAL REVIEWS, INC. Reproduced with permission of ANNUAL REVIEWS, INC., in the format Internet posting via Copyright Clearance Center.[3]
b[Level of evidence: 1iiA, 1iiDii,1iiDiv (Phase 1) and2A; 2Div(Phase II)]
c[Level of evidence: 1iiDiv]
d[Level of evidence: 1iiAand1iiDiii]
e[Level of evidence: 1iiDiv]
f Defined as complete or partial response by Southwest Oncology Group (SWOG) criteria for B-2222 or RECIST (Response EvaluationCriteria in Solid Tumors) for all other trials; excludes nonevaluable patients.
g Statistically significant difference compared toKIT9 and wild-type (noKITorPDGFRAmutation) groups.
Study participants(N = 37)(N = 127)(N= 377)(N = 324)
Objective responsef 
KITexon 1183 (24)83g(85)70g(248)67g(211)
KIT exon 925 (4)48 (23)35 (58)40 (25)
Wild-type33 (6)0 (9)25 (52)39 (33)
Progressive disease 
KIT exon 11453NR
KIT exon 901717NR
Wild-type335619NR
1|2|3|4

WebMD Public Information from the National Cancer Institute

Last Updated: February 25, 2014
This information is not intended to replace the advice of a doctor. Healthwise disclaims any liability for the decisions you make based on this information.
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