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Previous Volume 347:472-480 August 15, 2002 Number 7 Next

	Full Text PDF PDA Full Text PowerPoint Slide Set Perspective by Schwartz, R. Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited PubMed Citation

ABSTRACT

Background Constitutive 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.

Methods We 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.

Results A 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.

Conclusions Imatinib 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.

Source Information

From the Dana–Farber Cancer Institute and Harvard Cancer Center, Boston (G.D.D., A.D.V.A., D.A.T., S.S., M.J., J.A.F., S.G.S., C.D.M.F.); the Fox Chase Cancer Center, Philadelphia (M.M., B.E.); the Oregon Health and Science University and Portland Veterans Affairs Medical Center, Portland (C.D.B., M.C.H., B.J.D., C.C.); the University of Turku, Turku, Finland (P.J.R.); Novartis Oncology, Basel, Switzerland (S.L.S., R.C., B.K., B.P., S.D.); and the University of Helsinki, Helsinki, Finland (H.J.).

Drs. Demetri, von Mehren, Blanke, and Joensuu contributed equally to the article.

Address reprint requests to Dr. Demetri at the Center for Sarcoma and Bone Oncology, Dana–Farber Cancer Institute, SW 530, 44 Binney St., Boston, MA 02115, or at gdemetri{at}partners.org.

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