Phase III study data show that sunitinib lengthens survival of patients with gastrointestinal stromal tumors that have become resistant to imatinib, the first time one targeted therapy has been shown to be effective against tumors resistant to an agent that targets a different signaling pathway, according to a presentation at the 2006 Gastrointestinal Cancers Symposium.

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 is a rare tumor that arises in organs of the digestive tract. Although imatinib is highly effective in initial treatment of GIST, more than half of patients develop resistance to the drug after about two years.

In the study, the American research team compared overall survival and duration of tumor control in two groups of imatinib-resistant GIST patients: a 207-member group who received sunitinib and a 105-member group who received a placebo. (A placebo was used because no standard therapy is known to be effective after imatinib fails.)

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 relative risk of death. The benefits of sunitinib held steady regardless of the dose or duration of imatinib 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 placebo be allowed to take sunitinib, said Demetri, who is an associate professor of medicine at Harvard Medical School.