Correlation of target kinase genotype with clinical activity of imatinib mesylate (IM) in patients with metastatic GI stromal tumors (GISTs) expressing KIT (KIT+)

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Abstract
7 Background: Most GISTs express constitutively activated mutant isoforms of the KIT or PDGFRA tyrosine kinases that are therapeutic targets for IM (Gleevec). The relationship between mutations in these two kinases and IM activity was examined in a group of patients (pts) treated with IM for advanced KIT+ GIST as part of a randomized phase III study comparing 400 vs. 800 mg daily doses (CALGB 150105/SWOG S0033). Methods: Pre-treatment GIST samples from 324 pts were examined for baseline mutations of KIT or PDGFRA. Results: For the 324 eligible pts with a confirmed diagnosis of KIT+ GIST, we found KIT mutations in 280 pts (86.4%) and PDGFRA mutations in 3 pts (1%) for an overall mutation frequency of 87.3%. Pts whose tumor expressed an exon 11 KIT mutant isoform were more likely to have a objective response (OR) to IM therapy (OR=67%) than pts whose tumor expressed a KIT exon 9 mutant isoform (OR=40%) or had no kinase mutations (OR=39% p=0.0022). There was no significant effect of IM dose on the likelihood of clinical response among pts with KIT exon 11 mutant, exon 9 mutant, or no mutation GISTs. Among patients with exon 11 mutations, there was no significant difference in clinical response between patients whose tumors had point mutations versus deletions. In a multivariate analysis, KIT exon 11 genotype was the single best predictor of objective response. Pts with a KIT exon 11 mutant tumor had a significantly longer median TTF (576 days) than pts whose tumor expressed either an exon 9 KIT mutant isoform (308 days) or had no detectable kinase mutation (251 days, p=0.0012). There was a trend toward increased overall survival for pts with KIT exon 11 mutant GISTs when compared to pts with any other KIT mutation or wild-type GISTs, but this difference was not statistically significant (p=0.04, NS adjusted for multiple comparisons). Conclusions: Activating mutations of KIT or PDGFRA are found in the vast majority of KIT+ GISTs and KIT exon 11 tumor genotype correlates with the most favorable clinical responses and TTF. New therapeutic strategies may further improve these results, especially for those patients whose GISTs do not express the exon 11 mutant KIT isoform.

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