GIST genotyping

Imatinib (Glivec) is the standard therapy for gastrointestinal stromal tumours (GISTs), and a Phase III trial —reported recently at the 2005 Annual Meeting of the American Society of Clinical Oncology in Orlando, Florida — shows that kinase genotyping can predict the likelihood and duration of response to the drug.

Most patients with metastatic GISTs eventually develop resistance to imatinib and often acquire secondary mutations in the genes that encode kinases, such as platelet-derived growth factor α-polypeptide (PDGFA) or the oncogenic tyrosine kinase KIT. The results of the trial, which were presented at the meeting by Michael Heinrich, showed that most GISTs (324 of 332 patients in the study) express constitutively activated mutant isoforms of KIT. Although the overall frequency of KIT mutations is the same for GISTs that express KIT and those that do not, the researchers found that patients who express KIT isoforms with mutations in exon 11 of the gene had a better objective response (OR) to imatinib (OR = 67%) than patients with mutations in exon 9 of the gene (OR = 40%) or patients who had no KIT mutation (OR = 39%).

In fact, when Heinrich and colleagues examined the effects of age, sex, imatinib dose and the KIT mutations, multivariate analysis showed that the presence or absence of mutations in exon 11 was the best predictor of treatment response. Furthermore, the time to treatment failure for patients with mutations in exon 11 of KIT was longer (576 days) than for patients with mutations in exon 9 (308 days) or those with no mutations (251 days).

There was also an indication that patients with GISTs that had exon 11 mutations had better survival than those with exon 9 mutations or no mutations, although this trend was not statistically significant. Heinrich concluded that GISTs with different KIT kinase mutations are biologically different and that the differences are reflected in clinical outcome. The authors hope that the results will drive the development of therapeutic strategies that are tailored to patients whose GISTs do not express the exon 11 mutant KIT.

Curiously, in another presentation at the same meeting, Robert Maki explained that the outcome of treatment with the tyrosine-kinase inhibitor SU11248 was more effective in patients with KIT mutations in exon 9 than in exon 11. This study showed that SU11248 — which blocks several kinases including KIT and PDGFA and has anti-angiogenic and antitumour activity — is a promising clinical therapy for imatinib-resistant tumours.

Together, the studies indicate that GISTs must respond differently to imatinib and SU11248, although it is not clear why. As one participant at the meeting, Charles Sawyers (University of California, Los Angeles), mentioned, the results of this trial emphasize the importance of testing combinations of kinase inhibitors that bind targets in different conformations. ORIGINAL RESEARCH PAPERS Heinrich, M. C. et al. Correlation of target kinase genotype with clinical activity of imatinib mesylate (IM) in patients with metastatic GI stromal tumors (GISTs) expressing KIT (KIT+). J. Clin. Oncol. (Suppl.) 23, A7 (2005) Maki, R. G. et al. Results from a continuation trial of SU11248 in patients (pts) with imatinib (IM)-resistant gastrointestinal stromal tumour (GIST). J. Clin. Oncol. (Suppl.) 23, A9011 (2005).