TY - JOUR
T1 - Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors
AU - Demetri, George D.
AU - Von Mehren, Margaret
AU - Blanke, Charles D.
AU - Van Den Abbeele, Annick D.
AU - Eisenberg, Burton
AU - Roberts, Peter J.
AU - Heinrich, Michael C.
AU - Tuveson, David A.
AU - Singer, Samuel
AU - Janicek, Milos
AU - Fletcher, Jonathan A.
AU - Silverman, Stuart G.
AU - Silberman, Sandra L.
AU - Capdeville, Renaud
AU - Kiese, Beate
AU - Peng, Bin
AU - Dimitrijevic, Sasa
AU - Druker, Brian J.
AU - Corless, Christopher
AU - Fletcher, Christopher D.M.
AU - Joensuu, Heikki
N1 - Copyright 2002 Massachusetts Medical Society
PY - 2002/7/15
Y1 - 2002/7/15
N2 - 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.
AB - 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.
KW - Adolescent
KW - Adult
KW - Aged
KW - Aged, 80 and over
KW - Antineoplastic Agents/adverse effects
KW - Benzamides
KW - Female
KW - Gastrointestinal Neoplasms/drug therapy
KW - Humans
KW - Imatinib Mesylate
KW - Male
KW - Middle Aged
KW - Piperazines/adverse effects
KW - Protein-Tyrosine Kinases/antagonists & inhibitors
KW - Proto-Oncogene Proteins c-kit/genetics
KW - Pyrimidines/adverse effects
KW - Remission Induction
KW - Signal Transduction/drug effects
KW - Stromal Cells/pathology
KW - Survival Analysis
UR - http://www.scopus.com/inward/record.url?scp=0037103424&partnerID=8YFLogxK
U2 - 10.1056/NEJMoa020461
DO - 10.1056/NEJMoa020461
M3 - Article
C2 - 12181401
AN - SCOPUS:0037103424
SN - 0028-4793
VL - 347
SP - 472
EP - 480
JO - New England Journal of Medicine
JF - New England Journal of Medicine
IS - 7
ER -