Optimizing the dose of imatinib for treatment of gastrointestinal stromal tumours: Lessons from the phase 3 trials

Abstract

Imatinib therapy for unresectable or metastatic gastrointestinal stromal tumour (GIST) is typically initiated at a dosage of 400 mg/d. Two phase 3 studies investigated whether the higher dose of 800 mg/d – administered initially or upon progression on the 400-mg dose – would improve outcomes. Both the studies confirmed the 400 mg/d starting dose for most patients. However, two groups benefited from the treatment with 800 mg/d of imatinib: patients with disease progression on standard-dose therapy, and patients whose tumour harbours an exon 9 mutation in KIT. Initial treatment with 800 mg/d of imatinib (400 mg BID) should be considered for patients with KIT exon 9–mutant GIST. In unselected patients, dose optimisation to 800 mg/d may be warranted as a first step in managing progressive disease; such patients should be closely monitored.

Introduction

Gastrointestinal stromal tumour (GIST) is the most common mesenchymal tumour of the gastrointestinal tract, occurring principally in the stomach or small intestine, and occasionally in the colon, rectum or oesophagus.¹ GIST accounts for 2% of all gastric tumours, 14% of tumours in the small intestine and 0.1% of those in the colon.² The annual incidence of GIST estimated from recent population-based studies is 10–15 cases per million persons.3, 4, 5

Approximately 95% of GISTs express KIT (CD117) – a transmembrane tyrosine kinase.⁶ Under normal circumstances, binding of its ligand (stem-cell factor) promotes KIT dimerisation, enables tyrosine kinase activity, and activates various downstream signalling pathways. Activating KIT gene mutations are present in the large majority of GISTs (80–86%), most commonly (66% of cases) in the juxtamembrane domain (exon 11) of KIT, less frequently (13%) in the extracellular domain (exon 9) and rarely (1%) in the kinase 1 domain (exon 13) or (<1%) activation loop (exon 17).⁶ These gain-of-function mutations in GISTs lead to ligand-independent constitutive activation of the KIT receptor. In the subset of GISTs without KIT mutations, approximately one-third have activating mutations of the platelet-derived growth factor receptor alpha gene (PDGFRA, encoding PDGFRα).⁷ These KIT and PDGFRA mutations are mutually exclusive, but they have similar consequences, causing constitutive activation of the expressed tyrosine kinase, thereby driving intracellular pathways involved in cell proliferation and survival.7, 8

The clinical outcome of patients with advanced GIST was historically poor because this tumour is characteristically resistant to conventional chemotherapy and radiation therapy. In a cohort of 288 patients, median survival was 1.4 years for those with metastatic GIST and 3.4 years for those with primary tumours, classified as high-risk disease according to the National Institutes of Health consensus risk stratification.⁵ Since the introduction of targeted therapy with imatinib, overall survival (OS) of patients with metastatic or unresectable GIST has increased markedly, reaching a median of 4.8 years in a pivotal phase 2 study of imatinib therapy for advanced GIST with 64 months of follow-up.⁹ Imatinib is a small-molecule tyrosine kinase inhibitor with a potent and specific activity against KIT and PDGFRα.¹⁰

Imatinib is the recommended first-line agent for treatment of unresectable or metastatic GIST and recurrent disease.11, 12, 13 The usual recommended starting dose is 400 mg/d. However, the clinical activity of imatinib in patients with advanced GIST was initially demonstrated in phase 1 and phase 2 studies at doses ranging from 400 mg/d to 1000 mg/d.14, 15, 16, 17 In the phase 1 study, dose-limiting toxicities were noted at the highest dose of 1000 mg/d, the lowest effective dose was 400 mg/d and the recommended dose for phase 2 studies was 800 mg/d. Two intergroup phase 3 studies investigated whether an imatinib dose of 800 mg/d, given initially or upon disease progression on the 400 mg/d dose, would further improve outcomes in patients with unresectable or metastatic GIST.