Meta-analysis confirms small PFS advantage but no OS advantage for high-dose imatinib in patients with advanced GIST

A meta-analysis performed by the MetaGIST consortium compared two doses of imatinib, 400 mg once daily versus 400 mg twice daily, in 1640 patients with advanced gastrointestinal stromal tumors (GIST). [1] The analysis confirms a small progression-free survival (PFS) advantage of the 400 mg twice daily dose of imatinib, but no overall survival (OS) advantage was observed.  The PFS advantage was mainly seen in patients with KIT exon 9 mutations.

GISTs are the most common mesenchymal neoplasms of the gastrointestinal tract, and surgery is the primary treatment for localized forms of GISTs, because they have proven to be insensitive to chemotherapy and radiotherapy. Imatinib is a small-molecule tyrosine kinase inhibitor active against BCR-ABL, KIT, and PDGFRa, and KIT is expressed in the vast majority of GISTs and is frequently mutated, which leads to constitutive activation in these tumors. The phase I EORTC trial 62001 identified the highest feasible dose of imatinib to be 400 mg twice daily and indicated extensive activity in GIST. Phase II studies (US and EORTC) showed activity at all doses tested, from 400 mg to 800 mg.

Two large, randomized, phase III studies were subsequently conducted to compare the outcome of patients treated with a daily dose of 400 mg once daily and 400 mg twice daily for unresectable or metastatic GIST. One of these studies, EORTC trial 62005, was conducted jointly in Europe and Australia by the EORTC, the Italian Sarcoma Group, and the Australasian Gastro-Intestinal Trials Group. The other study, trial S0033, was conducted in the United States and Canada by the Southwest Oncology Group, the Cancer and Leukemia Group B, the National Cancer Institute of Canada, and the Eastern Cooperative Oncology Group.

At a median follow-up of 45 months, a small but significant PFS advantage was documented for patients receiving twice daily 400 mg doses of imatinib: the risk of progression or relapse was reduced by 11% and the benefit was limited to the first two years of therapy. OS was identical for patients receiving either 400 mg imatinib doses either once or twice daily. Patients with wild type, KIT exon 9 mutations, or other mutations had worse prognoses with respect to PFS and OS than did patients with KIT exon 11 mutations. Mutation status was the only predictive factor for PFS benefit attributed to the twice daily 400 mg imatinib treatment that resulted in significantly longer PFS (42% reduction in the risk of progression), and higher objective response rate, for patients with KIT exon 9 mutations.

Martine Van Glabbeke and John Bean

[1] From the Gastrointestinal Stromal Tumor Meta-Analysis Group (MetaGIST). The members and affiliations of the writing committee are listed in the online-only Appendix. Comparison of Two Doses of Imatinib for the Treatment of Unresectable or Metastatic Gastrointestinal Stromal Tumors: A Meta-Analysis of 1,640 Patients. J Clin Oncol 28(7):1247-1253, 2009.


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