Fast track — ArticlesEfficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial
Introduction
Gastrointestinal stromal tumours are a form of sarcoma and the most common mesenchymal tumour of the gastrointestinal tract, distinguishable from other soft-tissue neoplasms by histology and immunohistochemistry.1 The tumour probably arises from mutations in precursor cells that normally give rise to the interstitial cells of Cajal. Like these cells, most gastrointestinal stromal tumours express the protein product of the KIT proto-oncogene, a transmembrane receptor tyrosine kinase for which activity would normally be regulated by binding of its ligand. A subset of these tumours are overtly malignant, and greater than 40% are thought to be metastatic.1, 2, 3, 4 About 85–90% of gastrointestinal stromal tumours are associated with gain-of-function KIT gene mutations that lead to constitutive activation of KIT kinase activity.5, 6, 7 A much smaller proportion (5%) are associated with analogous gain-of-function mutations in PDGFRA, the gene encoding platelet-derived growth factor receptor α (PDGFRα); less than 10% contain no identified receptor tyrosine kinase mutations.5, 6, 7 Activating mutations of KIT and PDGFRA have been defined as the driving force behind development and maintenance of the malignant phenotype in most cases of gastrointestinal stromal tumours.
Understanding the molecular pathophysiology of this condition has allowed rational development of agents that target these signalling aberrations in the cancer cell. Traditional cytotoxic treatment is ineffective.8, 9 Imatinib mesylate, a selective inhibitor of the kinase activities of KIT and PDGFR, has substantially improved clinical outcomes for patients with advanced disease.10, 11, 12 However, in a pivotal study of imatinib in advanced gastrointestinal stromal tumour, 5% of patients showed primary resistance to imatinib and another 14% developed early resistance.11 Secondary or acquired resistance develops after a median of about 2 years of treatment with the drug.12 Such resistance can develop through various mechanisms, the most common being secondary KIT mutations in clonally expanded cancer cells.13, 14, 15 Since its approval in 2002, imatinib has been the only effective treatment for advanced gastrointestinal stromal tumour. Effective alternative treatments for use after failure of imatinib therapy were therefore an important unmet medical need justifying the development of alternative agents.
Sunitinib malate (SUTENT, previously known as SU11248; Pfizer, New York, USA) is an oral multitargeted receptor tyrosine kinase inhibitor that has shown antiangiogenic and antitumour activities in several in-vitro and in-vivo tumour models.16, 17, 18, 19, 20, 21 These effects were associated with the blockade of receptor tyrosine kinase signalling by KIT, PDGFRs, all three isoforms of the vascular endothelial growth factor receptors (VEGFR-1, VEGFR-2, VEGFR-3), Fms-like tyrosine kinase-3 receptor (FLT3), and the receptor encoded by the ret proto-oncogene (RET;16, 17, 18, 19, 20, 21 and unpublished data, Pfizer, 2006). Although both sunitinib and imatinib bind within the ATP-binding domain of both KIT and PDGFRs, they are members of different chemical classes and presumably have different binding characteristics and affinities. Additionally, sunitinib inhibits the VEGFR kinases, which are important in tumour-related angiogenesis, a property not shared by imatinib. Because of these differences, we postulated that sunitinib might yield clinical benefit in patients with gastrointestinal stromal tumour who were resistant to imatinib. Results from a phase I/II study22 showed that sunitinib induced promising clinical activity in patients with imatinib-resistant disease, although rates of tumour regression (and therefore, the rates of objective antitumour response) were low, despite a clinically significant rate of stable disease. Additionally, no second-line treatments have proven efficacy after failure of imatinib therapy. Therefore, a prospective, placebo-controlled, randomised clinical trial, with a crossover option available for patients assigned initially to placebo, was designed to test the clinical worth of sunitinib. The objectives were to assess the efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure and withdrawal of imatinib because of resistance or intolerance.
Section snippets
Patients and study design
Patients were eligible if they had histologically proven malignant gastrointestinal stromal tumour that was not amenable to surgery, radiation, or a combination of different approaches with curative intent, and confirmed objective failure of previous imatinib therapy. Criteria for inclusion were evidence of disease that was unidimensionally measurable with CT or MRI; failure of treatment with imatinib—based either on progression of disease (according to Response Evaluation Criteria in Solid
Patients
Between December, 2003, and January, 2005, 312 patients were enrolled from 56 centres in 11 countries and were randomised to receive blinded sunitinib (n=207) or placebo (n=105). Figure 1 shows the trial profile. Baseline characteristics and history of disease and treatment are summarised in table 1. All characteristics were well balanced between the groups. The most common metastatic sites were the liver, peritoneum, and mesentery. The sunitinib and placebo groups were also similar in terms of
Discussion
Time to tumour progression, progression-free survival, overall survival, and other measures of tumour response were significantly greater in patients treated with sunitinib than in those in the placebo group in a population with advanced gastrointestinal stromal tumour in which treatment with another tyrosine kinase inhibitor had failed. Median time to tumour progression with sunitinib was more than four times greater than with placebo, reducing the relative risk of progression or death by 67%
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