Elsevier

The Lancet

Volume 368, Issue 9544, 14–20 October 2006, Pages 1329-1338
The Lancet

Fast track — Articles
Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial

https://doi.org/10.1016/S0140-6736(06)69446-4Get rights and content

Summary

Background

No effective therapeutic options for patients with unresectable imatinib-resistant gastrointestinal stromal tumour are available. We did a randomised, double-blind, placebo-controlled, multicentre, international trial to assess tolerability and anticancer efficacy of sunitinib, a multitargeted tyrosine kinase inhibitor, in patients with advanced gastrointestinal stromal tumour who were resistant to or intolerant of previous treatment with imatinib.

Methods

Blinded sunitinib or placebo was given orally once daily at a 50-mg starting dose in 6-week cycles with 4 weeks on and 2 weeks off treatment. The primary endpoint was time to tumour progression. Intention-to-treat, modified intention-to-treat, and per-protocol analyses were done. This study is registered at ClinicalTrials.gov, number NCT00075218.

Findings

312 patients were randomised in a 2:1 ratio to receive sunitinib (n=207) or placebo (n=105); the trial was unblinded early when a planned interim analysis showed significantly longer time to tumour progression with sunitinib. Median time to tumour progression was 27·3 weeks (95% CI 16·0–32·1) in patients receiving sunitinib and 6·4 weeks (4·4–10·0) in those on placebo (hazard ratio 0·33; p<0·0001). Therapy was reasonably well tolerated; the most common treatment-related adverse events were fatigue, diarrhoea, skin discolouration, and nausea.

Interpretation

We noted significant clinical benefit, including disease control and superior survival, with sunitinib compared with placebo in patients with advanced gastrointestinal stromal tumour after failure and discontinuation of imatinab. Tolerability was acceptable.

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%

References (37)

  • E Tamborini et al.

    A new mutation in the KIT ATP pocket causes acquired resistance to imatinib in a gastrointestinal stromal tumor patient

    Gastroenterology

    (2004)
  • E Wardelmann et al.

    Acquired resistance to imatinib in gastrointestinal stromal tumours caused by multiple KIT mutations

    Lancet Oncol

    (2005)
  • M Miettinen et al.

    Gastrointestinal stromal tumors—definition, clinical, histological, immunohistochemical, and molecular genetic features and differential diagnosis

    Virchows Arch

    (2001)
  • JP Pierie et al.

    The effect of surgery and grade on outcome of gastrointestinal stromal tumors

    Arch Surg

    (2001)
  • RP DeMatteo et al.

    Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival

    Ann Surg

    (2000)
  • BE Plaat et al.

    Soft tissue leiomyosarcomas and malignant gastrointestinal stromal tumors: differences in clinical outcome and expression of multidrug resistance proteins

    J Clin Oncol

    (2000)
  • S Hirota et al.

    Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors

    Science

    (1998)
  • MC Heinrich et al.

    Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor

    J Clin Oncol

    (2003)
  • Cited by (2262)

    View all citing articles on Scopus
    View full text