ORLANDOIn a phase II study, 63% of patients with unresectable and/or metastatic gastrointestinal stromal tumors (GISTs) responded to treatment with imatinib(Drug information on imatinib) mesylate (Gleevec), and after a median of 15 months of follow-up, 73% of patients remain in the study, Margaret von Mehren, MD, reported at the 38th Annual Meeting of the American Society of Clinical Oncology (abstract 1608). Results at 9 months of follow-up were recently published (N Engl J Med 347:472-478, 2002).
GISTs are the most common mesenchymal tumor of the gut. Most arise in the stomach, and they are characterized by the expression of the KIT tyrosine kinase receptor, the product of the C-KIT proto-oncogene. Dr. von Mehren, a medical oncologist at Fox Chase Cancer Center, said that GISTs are resistant to standard systemic agents. Surgery is used for initial therapy. Conventional chemotherapy has a 5% response rate in recurrent/metastatic disease.
Imatinib mesylate is an ATP binding inhibitor that blocks the activity of tyrosine kinase. It has been shown to be safe and highly effective in patients with chronic myelogenous leukemia (CML) and GISTs at 400 to 600 mg daily. Dr. von Mehren said that studies evaluating doses of 800 mg in GIST are ongoing.
Between July 2000 and April 2001, 147 patients with metastatic and/or unresec-table GISTs with expression of KIT were enrolled. The median age was 54. Most patients had previous surgery, and more than half had prior systemic chemotherapy. Patients were randomized to 400 mg or 600 mg of imatinib once daily. Patients receiving the 400 mg dose were eligible to cross over to 600 mg at the time of tumor progression. Patients remained on study until disease progression (at 600 mg for crossover patients).
Dr. von Mehren said that the drug was well tolerated, with only about 20% of patients experiencing serious drug-related side effects.
"Of note, we did not observe any thrombocytopenia and had a less than 10% incidence of neutropenia. This is in contrast to the phase I study in patients with CML, where there was a 6% incidence of grade 3-4 thrombocytopenia and neutropenia at doses of 350 to 500 mg, and a 24% incidence at doses of 600 to 1,000 mg," Dr. von Mehren said.
A few patients had grade 3-4 GI bleeding localized to a tumor mass. These bleeding episodes were associated with tumor response in some patients and with irritation of the gut in others. "This contrasts with the patients who had CML, where there was only one report of a gastric hemorrhage," Dr. von Mehren said.