Kinase Mutations and Imatinib Response in Patients With Metastatic Gastrointestinal Stromal Tumor.

Purpose: Most gastrointestinal stromal tumors (GISTs) express constitutively activated mutant isoforms of KIT or kinase platelet-derived growth factor receptor alpha (PDGFRA) that are potential therapeutic targets for imatinib mesylate. The relationship between mutations in these kinases and clinical response to imatinib was examined in a group of patients with advanced GIST.

Patients And Methods: GISTs from 127 patients enrolled onto a phase II clinical study of imatinib were examined for mutations of or . Mutation types were correlated with clinical outcome.

Results: Activating mutations of or were found in 112 (88.2%) and six (4.7%) GISTs, respectively. Most mutations involved exon 9 (n = 23) or exon 11 (n = 85). All KIT mutant isoforms, but only a subset of PDGFRA mutant isoforms, were sensitive to imatinib, in vitro. In patients with GISTs harboring exon 11 mutations, the partial response rate (PR) was 83.5%, whereas patients with tumors containing an exon 9 mutation or no detectable mutation of or had PR rates of 47.8% ( = .0006) and 0.0% ( < .0001), respectively. Patients whose tumors contained exon 11 mutations had a longer event-free and overall survival than those whose tumors expressed either exon 9 mutations or had no detectable kinase mutation.

Conclusion: Activating mutations of or are found in the vast majority of GISTs, and the mutational status of these oncoproteins is predictive of clinical response to imatinib. mutations can explain response and sensitivity to imatinib in some GISTs lacking mutations.