Safety and efficacy of imatinib (ST1571) in metastatic gastrointestinal stromal tumours: a phase I study

Background Gastrointestinal stromal tumours (GISTs) are rare tumours of the gastrointestinal tract characterised by cell-surface expression of the tyr osine kinase KIT (CD117). No effective systemic treatment is available. Ima tinib (ST1571) inhibits a similar tyrosine kinase, BCR-ABL, leading to resp onses in chronic myeloid leukaemia, and has also been shown to inhibit KIT. We did a phase I study to identify the dose-limiting toxic effects of imat inib in patients with advanced soft tissue sarcomas including GISTs. Methods 40 patients (of whom 36 had GISTs) received imatinib at doses of 40 0 mg once daily, 300 mg twice daily, 400 mg twice daily, or 500 mg twice da lly. Toxic effects and haematological, biochemical, and radiological measur ements were assessed during 8 weeks of follow-up. (18)Fluorodeoxyglucose po sitron-e mission tomography (PET) was used for response assessment in one c entre. Findings Five patients on 500 mg imatinib twice daily had dose-limiting tox ic effects (severe nausea, vomiting, oedema, or rash). Inhibition of tumour growth was seen in all but four patients with GISTs, resulting in 19 confi rmed partial responses and six as yet unconfirmed partial responses or more than 20% regressions. 24 of 27 clinically symptomatic patients showed impr ovement, and 29 of 36 were still on treatment after more than 9 months. PET scan responses predicted subsequent computed tomography responses. Interpretation Imatinib at a dose of 400 mg twice daily is well tolerated d uring the first 8 weeks, side-effects diminish with continuing treatment, a nd it has significant activity in patients with advanced GISTs. Our results provide evidence of a role for KIT in GISTs, and show the potential for th e development of anticancer drugs based on specific molecular abnormalities present in cancers.