May 16, 2005
New targeted therapy helps patients once Gleevec fails in gastrointestinal cancer
George Demetri, MD
Patients with a digestive-tract cancer known as Gastrointestinal Stromal Tumor (GIST) whose disease progresses after successful treatment with the drug Gleevec™ (Imatinib) can significantly slow the disease and prolong their survival by taking the new targeted oral drug called SU11248, according to the results of an international clinical trial presented this weekend at the American Society of Clinical Oncology's annual meeting in Orlando, Fla.
The Phase III trial, led by investigators at Dana-Farber Cancer Institute in Boston, found that treatment with SU11248 increased by more than 400 percent the time that the disease could be controlled (median of one-and-a-half months to tumor progression for patients taking a placebo, or inert pill, to more than six months for those taking SU11248). This resulted in a highly significant improvement in overall survival for these patients who previously had no effective therapy available for their disease. The study, which involved more than 300 patients from 11 countries around the world, found that SU11248 was generally well tolerated.
"The results show convincingly that SU11248 can be an effective treatment for GIST patients who are resistant to or intolerant of Gleevec," says the study's lead author, George Demetri, MD, of Dana-Farber. "This represents an extremely hopeful outcome for cancer patients in general, and GIST patients in particular. By inhibiting these abnormal signals with new rationally-designed drugs, we can offer patients the benefits of disease control and longer survival."
Demetri, who is also an associate professor of medicine at Harvard Medical School, says that these findings prove that Gleevec was not an unusual "lucky break." "The ability to prove the clinical value of SU11248 for patients is an important validation of the concept that our field can now target drugs at specific genetic mutations that keep cancer cells growing," he adds.
GIST, a form of sarcoma, strikes an estimated 5,000 to 10,000 Americans each year, usually originating in the stomach or small intestine. Prior to the development of Gleevec, GIST was rapidly fatal in virtually all patients whose tumor could not be entirely removed by surgery. Gleevec, which was originally tested as a treatment for a form of leukemia known as CML, works by blocking the signaling activity of highly specific enzymes involved in cell growth called tyrosine kinases. In CML, a genetic error in the BCR-ABL enzyme causes an uncontrollably active signal to generate the runaway growth and accumulation of cancerous white blood cells.
In 2000, researchers led by Demetri and his team demonstrated that Gleevec could also be effective against GIST, which harbors a mutation in different tyrosine kinases known either as KIT or PDGFRA. Gleevec inhibits all three kinases (BCR-ABL, KIT, and PDGFRA). This work led to the FDA approval of Gleevec as the first effective systemic therapy for GIST in 2002. However, though Gleevec controls GIST in the vast majority of patients, resistance to the drug emerges after an average of 18 to 26 months, and patients then had no other effective options for therapy.
Resistance to Gleevec occurs when the kinases that were initially blocked by the drug develop additional mutations that enable them to avoid the cancer-controlling effects of the drug. SU11248 was designed to block a broader range of kinases in an effort to provide more control once Gleevec failed. Additionally, SU11248 is a powerful anti-angiogenesis drug that can block the signals that tumors send to the body to grow abnormal blood vessels to feed the tumor growth. SU11248 is one of the next generation of anti-angiogenesis drugs that work when taken orally.
The results of the new study were so significant that the study closed far ahead of schedule so that patients who were initially assigned to receive the placebo were able to change to the active SU11248 drug, as Demetri will report. Many patients worldwide are continuing to receive treatment as part of this trial.
Dana-Farber Cancer Institute 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.
