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Doubling Dose of Gleevec to Treat GIST May Not Be Any More Beneficial

Doubling Dose of Gleevec to Treat GIST May Not Be Any More Beneficial
M. D. Anderson News Release 06/01/03

Less may be more when it comes to using Imatinib mesylate (Gleevec™) to treat advanced gastrointestinal stromal tumors (GIST), says a researcher from The University of Texas M. D. Anderson Cancer Center who presented results of a large multi-center trial testing different doses of the pill.

Studying 746 patients from 57 institutions, the research team found that a standard dose of the oral medication is as beneficial, and less toxic, than giving the same dose twice daily, that is, a total dose twice as high.

That means Imatinib is not only effective, it is efficient, says Robert Benjamin, M.D., professor and chair of the Department of Sarcoma Medical Oncology.

"There may be no need to up the dose to achieve maximum benefit for this extraordinarily effective drug," he says. "This is the best therapy, bar none, for the treatment of these tumors, even if they have metastasized."

Benjamin, the study's first author, presented the findings at the annual meeting of the American Society of Clinical Oncology. The study's senior author is George Demetri, M.D., of the Dana Farber Cancer Institute.

Imatinib, first approved for use in chronic myeloid leukemia (CML), was also found to have remarkable power in treating GIST, and was approved by the Food and Drug Administration for treatment of that cancer on the basis of a limited, 147-patient clinical trial.

The study now being reported is much larger and "confirms that GIST is remarkably sensitive to Gleevec," Benjamin says. The research is also noteworthy for the cooperation demonstrated between multiple institutions that each treated relatively small numbers of patients with the rare disease, he said.

"We all had our patients waiting in the wings for this drug to become available, and once it did, we were able to launch the dosing study very efficiently," said Benjamin.  At M. D. Anderson alone, more than 100 patients were enrolled in the study, he says.

To date, the researchers have found no survival differences or differences in time to progression between patients randomized to either a 400 milligram or an 800 milligram daily dose. They also found no significant differences in the response rate between the two arms: The response rate (tumor shrinkage of at least 30%) is 49% for patients who used 400 milligrams and 48% for the 800-milligram arm. Additionally, 27% who used 400 milligrams and 26% who used 800 milligrams had stable disease. Patients who used the double dose, however, experienced significantly more toxicity. "The bottom line is that we see no general advantage to starting with a higher dose," he says.

He also cautions that while Imatinib is powerful, not every patient is helped. In this study, cancer continued to grow in about 15% treated with the standard dose. These patients are now being treated with the higher dose to see if, individually, an increased level of drug will be beneficial.

GIST belongs to a group of cancers called soft tissue sarcomas, rare cancers that may occur anywhere in connective tissue and which are estimated to affect approximately 10,000 patients annually.

Before the use of Imatinib therapy, GIST was normally treated with surgery, but the cancer would usually return and would be unresponsive to chemotherapy agents used for other sarcomas.

In GIST, a specific change or mutation in the DNA causes a cellular enzyme, known as KIT, to be switched "on" all the time. KIT is an enzyme, called a tyrosine kinase, that is responsible for sending growth and survival signals inside the cell. Imatinib works to turn that switch off.

Patients in the trial will continue to be studied to make sure no differences in overall survival and disease control appear over time, Benjamin says. At the meeting, European investigators reported on an even larger study using the same design.  “In contrast to our findings,” Benjamin said, “the European study did show a longer time to progression in patients treated at the higher dose.  The final answer is not in, and more time will be required to determine if the higher dose has any real advantage

06/01/03


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