August 19, 2002
Gleevec shrinks tumors in over half of patients with incurable stomach cancer
George Demetri, MD
The "designer" drug Gleevec, originally developed to treat leukemia, has shown remarkable potency in a rare, fatal gastrointestinal cancer, according to data that persuaded the Food and Drug Administration to rapidly approve it for use in the disease.
In a clinical trial headed by a Dana-Farber Cancer Institute investigator, Gleevec shrank tumors in 53.7 percent of patients with advanced, inoperable forms of gastrointestinal stromal tumor (GIST). GIST is normally treated with surgery, but often returns and responds less than 5 percent of the time when treated with standard chemotherapy agents.
Although Gleevec did not eradicate the tumors in any patients, it shrank and halted the tumors' life-threatening progression in those who responded to the drug, and some patients returned to normal activities. Side effects of the oral medication were common, but were milder than those of conventional chemotherapy drugs.
A report on a multicenter clinical trial involving 147 patients is being published in the Aug. 15 issue of the New England Journal of Medicine (NEJM). Other, larger trials testing Gleevec in GIST are underway but results have yet to be released.
Some of the findings on Gleevec and GIST have been reported at meetings, but the NEJM article "is the first formal manuscript showing how these patients do," said George Demetri, MD, director of the Center for Sarcoma and Bone Oncology at Dana-Farber. Demetri, who headed the clinical study, had called for a trial of Gleevec in GIST after the drug proved highly successful in treating chronic myeloid leukemia (CML). In both cases, Gleevec blocks a cascade of signals that causes normal cells to become cancerous and to survive when they should die. The signal in GIST, carried out by a protein called KIT, is different from the one that causes CML but the mechanism is similar.
The FDA approved Gleevec for use in GIST last February, a year after it was approved for CML. About 5,000 patients in the United States have GIST. In the newest approval, the FDA acted on results from the trial being reported in today's NEJM article. In the data submitted to the FDA, however, only 35 percent of patients had confirmed responses; since then, the authors report, that rate rose to 53.7 percent in the ongoing trial. Demetri estimates that in actual practice, the rate of partial responses (percentage of patients in whom tumors shrink by 50 percent or more, but less than 100 percent) is about 65 percent.
The trial was carried out by investigators at Dana-Farber and three other academic centers - Fox-Chase Cancer Center in Philadelphia, the Oregon Health & Science University, and the University of Helsinki, Finland - in collaboration with Novartis Pharmaceuticals, the drug's manufacturer. The patients were treated beginning in 2000 and 2001.
The 147 patients were randomly assigned to one of two doses of Gleevec, 400 or 600 mg., which was taken orally each day. Overall, 79 (53.7 percent) had a partial response and in 41 patients (27.9 percent) the progression of the disease was halted.
After a median follow-up of 24 weeks, the median time-to-relapse had not been reached, according to the report. Some patients who didn't respond to the lower dose had tumor stabilization after being switched to the higher dose.
Researchers have noted that both in CML and in GIST, the tumors in some patients become resistant to Gleevec's effects. It appears that the cancer cells mutate or find another route for the abnormal growth-signaling pathways that allow the tumors to escape normal growth regulation. They are testing other drugs that might block these alternative pathways.
"We never thought this drug would be a cure," said Demetri, who is also an associate professor of medicine at Harvard Medical School. "But we have patients treated beginning in July 2000 who are still doing great."
In addition to Novartis, support for the trial was provided by the Quick Family Research Fund, the Lawrence J. and Anne Cable Rubenstein Foundation and the Abraham J. and Phyllis Katz Foundation.
Dana-Farber Cancer Institute (www.dana-farber.org) is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute.
