• George D Demetri, Margaret von Mehren, Charles D Blanke, Annick D Van den Abbeele, Burton Eisenberg, Peter J Roberts, Michael C Heinrich, David A Tuveson, Samuel Singer, Milos Janicek, Jonathan A Fletcher, Stuart G Silverman, Sandra L Silberman, Renaud Capdeville, Beate Kiese, Bin Peng, Sasa Dimitrijevic, Brian J Druker, Christopher Corless, Christopher D M Fletcher, and Heikki Joensuu.
• Dana-Farber Cancer Institute and Harvard Cancer Center, Boston, MA 02115, USA.
• N. Engl. J. Med. 2002 Aug 15; 347 (7): 472-80.

BackgroundConstitutive activation of KIT receptor tyrosine kinase is critical in the pathogenesis of gastrointestinal stromal tumors. Imatinib mesylate, a selective tyrosine kinase inhibitor, has been shown in preclinical models and preliminary clinical studies to have activity against such tumors.MethodsWe conducted an open-label, randomized, multicenter trial to evaluate the activity of imatinib in patients with advanced gastrointestinal stromal tumor. We assessed antitumor response and the safety and tolerability of the drug. Pharmacokinetics were assessed in a subgroup of patients.ResultsA total of 147 patients were randomly assigned to receive 400 mg or 600 mg of imatinib daily. Overall, 79 patients (53.7 percent) had a partial response, 41 patients (27.9 percent) had stable disease, and for technical reasons, response could not be evaluated in 7 patients (4.8 percent). No patient had a complete response to the treatment. The median duration of response had not been reached after a median follow-up of 24 weeks after the onset of response. Early resistance to imatinib was noted in 20 patients (13.6 percent). Therapy was well tolerated, although mild-to-moderate edema, diarrhea, and fatigue were common. Gastrointestinal or intraabdominal hemorrhage occurred in approximately 5 percent of patients. There were no significant differences in toxic effects or response between the two doses. Imatinib was well absorbed, with pharmacokinetics similar to those reported in patients with chronic myeloid leukemia.ConclusionsImatinib induced a sustained objective response in more than half of patients with an advanced unresectable or metastatic gastrointestinal stromal tumor. Inhibition of the KIT signal-transduction pathway is a promising treatment for advanced gastrointestinal stromal tumors, which resist conventional chemotherapy.Copyright 2002 Massachusetts Medical Society

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