January 27, 2006
Sunitinib controls tumors and lengthens survival of patients with
gastrointestinal stromal tumor that is resistant to Gleevec, study finds
Findings indicate that therapies targeting multiple signals inside cancer cells are an effective approach
George Demetri, MD
At this week's American Society of Clinical Oncology (ASCO) 2006 Gastrointestinal Cancers Symposium, researchers from Dana-Farber Cancer Institute in Boston will report on a Phase III clinical trial in which the targeted drug sunitinib (originally called SU11248 and now known as Sutent™) was given to control gastrointestinal stromal tumors (GIST) in patients whose tumors had become resistant to the frontline drug imatinib (Gleevec™).
In addition to confirming the safety and efficacy of sunitinib, the findings illustrate that therapies targeting several signaling pathways inside cancer cells may be an effective treatment approach that may also be applicable to other difficult-to-treat cancers, including kidney cancer.
"Sunitinib is the first molecularly-targeted therapy proven to work against a cancer after another targeted therapy has failed," said the study's principal investigator, George Demetri, MD, director of the Center for Sarcoma and Bone Oncology at Dana-Farber. "These findings are highly significant because they show sunitinib can control tumors and improve survival rates of patients with this condition. Although GIST is relatively uncommon, our understanding of it at the molecular level — down to specific mutations in DNA — has made this disease a proving ground for new therapies that could be useful for treating other cancers."
GIST, a type of sarcoma (or cancer of the body's connective tissue), is a rare tumor that arises in organs of the digestive tract. Although Gleevec is highly effective in the initial treatment of GIST, more than half of patients develop resistance to the drug after about two years. Sunitinib, a capsule taken orally once a day, blocks the action of several "kinase" enzymes that send signals that enable cancer cells to grow. These enzymes, which serve as on-off signals for cell functions, play a crucial role in the uncontrolled growth of tumors and of blood vessels that feed them.
In the study, the research team led by Demetri compared overall survival and duration of tumor control in two groups of Gleevec-resistant GIST patients: a 207-member group who received sunitinib, and a 105-member group who received a placebo, or inert pill. (A placebo was used because there is no standard therapy known to be effective after Gleevec fails in GIST.)
The time that elapsed before tumor growth was more than four times longer in the sunitinib group (27.3 weeks) than in the placebo group (6.4 weeks). Sunitinib-treated patients also had a 50 percent reduction in the relative risk of death than their counterparts. The benefits of sunitinib held steady regardless of the dose or duration of Gleevec therapy that patients previously had received. Sunitinib was generally well tolerated, with side effects such as mild to moderate fatigue, diarrhea, nausea, mouth sores, and skin discoloration, which rarely interfered with the patients' ability to continue taking the drug.
The results were so striking, even at the first interim data analysis, that the independent data-monitoring committee recommended that patients initially assigned to the placebo group be allowed to take sunitinib, said Demetri, who is also an associate professor of medicine at Harvard Medical School.
The study was funded in part by grants from Pfizer, which manufactures sunitinib, and the Ludwig Trust for Cancer Research at Dana-Farber.
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.
