New Oral Agent Approved for Kidney Cancer and GIST

The US Food and Drug Administration (FDA) recently approved sunitinib malate (Sutent) capsules for two types of cancer: advanced renal cell carcinoma and malignant gastrointestinal stromal tumor (GIST), after disease progression on or intolerance to the frontline drug imatinib mesylate (Gleevec). Originally called SU11248, sunitinib is an oral therapy belonging to a new class of multikinase inhibitors that attack cancer by inhibiting both tumor growth and blood supply. The FDA granted the drug priority review in October 2005.

Recently Reported Findings

At the recent American Society of Clinical Oncology (ASCO) 2006 Gastrointestinal Cancers Symposium in San Francisco, researchers from Dana-Farber Cancer Institute in Boston reported on a phase III clinical trial in which sunitinib was given to control GIST in patients whose tumors had become resistant to imatinib. In addition to confirming the safety and efficacy of sunitinib, the findings illustrated 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 and associate professor of medicine at Harvard Medical School. “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.”

Study Details

In the study, the research team led by Dr. Demetri compared overall survival and duration of tumor control in two groups of imatinib-resistant GIST patients-207 received sunitinib, and 105 received a placebo. 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% reduction in the relative risk of death compared to their counterparts.

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 the placebo group be allowed to take sunitinib, said Dr. Demetri.

The approval for advanced renal cell carcinoma was based on partial response rates and duration of responses. There have been no randomized trials of sunitinib demonstrating clinical benefit such as increased survival or improvement in disease-related symptoms in renal cell carcinoma patients.

Warnings and Precautions

In trials of sunitinib, the most common adverse events included fatigue, diarrhea, nausea, mucositis/stomatitis, dyspepsia, altered taste, abdominal pain, anorexia, and skin discoloration. Women of child-bearing age who are (or become) pregnant during therapy should be informed of the potential for fetal harm while on sunitinib.

Decrease in left-ventricular ejection fraction to below the lower limit of normal have been observed. Patients with concomitant cardiac conditions should be carefully monitored for clinical signs and symptoms of congestive heart failure. Patients should be monitored for hypertension and treated as needed with standard antihypertensive therapy. Complete blood counts with platelet count and serum chemistries should be performed at the beginning of each treatment cycle for patients receiving treatment with sunitinib.