Correlation of primary kinase genotype and clinical outcome of Imatinib and Sunitinib for treatment of advanced GIST

Background/Purpose: Most gastrointestinal stromal tumours (GISTs) harbour mutant KIT kinase, which is imatinib target. Sunitinib, which targets KIT and several other kinases, has demonstrated efficacy in patients with GIST after they experience imatinib failure. But not all patients benefit equally. We examined the impact of primary kinase genotype on imatinib and sunitinib activity.

Patients/Methods: Tumour responses were assessed radiologically in 41 patients with unresectable/metastatic GIST. KIT mutational status was retrospectively determined for all these patients by using tumour specimens obtained before first-line imatinib therapy.

Results: Among our patients with GIST, exon11 was identified as the most common site for KIT mutation (63%), exon 9-mutant GIST was assessed at 17% of our patients, while wild-type KIT/other exon mutations were observed at 20% of our patients. GIST responsiveness to first-line imatinib varied by primary KIT genotype, patients with exon 11-mutant and exon 9-mutant GISTs were more sensitive (TTP;average 32.7 months v 33.2months) than those with wild-type KIT/other exon- mutant GISTs (TTP;average 24.6 months). In terms of responsiveness to second-line sunitinib, TTP was longer for our patients with primary KIT exon 9 mutation than for those with exon 11 mutation, or wild-type KIT/other exon mutations (TTP; average 20.25 months v 10.0 months and 7.5 months, respectively).

Conclusion: Our results showed that clinical activity of both imatinib and sunitinib are influenced by primary mutations in the predominant pathogenic kinase, which has implications for optimization of the therapy of patients with GIST.