Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: a phase I study

Summary

Background

Gastrointestinal stromal tumours (GISTs) are rare tumours of the gastrointestinal tract characterised by cell-surface expression of the tyrosine kinase KIT (CD117). No effective systemic treatment is available. Imatinib (STI571) inhibits a similar tyrosine kinase, BCR-ABL, leading to responses 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 imatinib in patients with advanced soft tissue sarcomas including GISTs.

Methods

40 patients (of whom 36 had GISTs) received imatinib at doses of 400 mg once daily, 300 mg twice daily, 400 mg twice daily, or 500 mg twice daily. Toxic effects and haematological, biochemical, and radiological measurements were assessed during 8 weeks of follow-up.¹⁸ Fluorodeoxy-glucose positron-emission tomography (PET) was used for response assessment in one centre.

Findings

Five patients on 500 mg imatinib twice daily had dose-limiting toxic effects (severe nausea, vomiting, oedema, or rash). Inhibition of tumour growth was seen in all but four patients with GISTs, resulting in 19 confirmed partial responses and six as yet unconfirmed partial responses or more than 20% regressions. 24 of 27 clinically symptomatic patients showed improvement, 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 during the first 8 weeks, side-effects diminish with continuing treatment, and 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 the development of anticancer drugs based on specific molecular abnormalities present in cancers.

Introduction

Gastrointestinal stromal tumours (GISTs) arise from mesenchymal stem cells thought to share common ancestry with the interstitial cells of Cajal within the gastrointestinal tract. GISTs are generally thought to be malignant, but have different degrees of aggressiveness, resulting in varying times to the development of metastases.¹ The median survival of patients with unresectable or metastatic soft-tissue sarcomas including GISTs has been estimated at 53 weeks,² and conventional chemotherapy is ineffective with regard to survival.³

Mutations in the cellular proto-oncogene KIT that lead to constitutive activation of the KIT tyrosine kinase (CD117) have been described in most human GISTs.⁴ KIT is thought to promote tumour growth or prevent apoptosis in this disease. Imatinib (Glivec, previously called STI571) is an orally bioavailable, small-molecule inhibitor of some tyrosine kinases involved in cell signalling, including KIT, platelet-derived growth-factor receptor (PDGFr), and BCR-ABL fusion protein.5, 6 Imatinib has already shown substantial activity in patients with chronic myeloid leukaemia at doses of 300–1000 mg.7, 8 It causes 50% inhibition of KIT at about 100 nmol/L—similar to the concentration required for inhibition of BCR-ABL.⁹ These and other data¹⁰ justify studying imatinib as a targeted antineoplastic agent in KIT-driven GISTs. We therefore did a dose-finding study of imatinib in advanced soft-tissue sarcomas including GISTs.