Targeted Drugs Delay Growth of Kidney Cancer
The targeted drugs sunitinib (Sutent) and sorafenib (Nexavar) can delay the progression of kidney cancer by 3 to 6 months over existing treatments, according to the results of final-stage clinical trials in the January 11 New England Journal of Medicine (NEJM).
The results also show how a "rational" approach to developing cancer drugs can succeed over the long term. Sunitinib and sorafenib, the first new therapies for kidney cancer since the 1980s, inhibit the growth of new blood vessels (angiogenesis) that feed tumors.
Research at NCI and elsewhere in the 1990s showed that the majority of clear-cell renal cell carcinomas, the most common type of kidney cancer, have mutations in the tumor-suppressor gene VHL. These mutations can lead to the proliferation of blood vessels.
The first antiangiogenic drug tested was bevacizumab (Avastin), which blocks angiogenesis by inhibiting the vascular endothelial growth factor (VEGF). After a small study demonstrated that the concept was correct, sunitinib and sorafenib were tried.
"These trials represent a continuation of the initial approach with Avastin and a validation of the whole concept," says Dr. Ronald Bukowski of the Cleveland Clinic, who co-authored the sorafenib study.
Both sunitinib and sorafenib inhibit the receptors of several angiogenic factors, including the VEGF receptor 2. The drugs are oral medications that patients can take at home.
"The positive results from the two trials together confirm that we're on the right path to targeted therapy for kidney cancer," says Dr. Robert J. Motzer of Memorial Sloan-Kettering Cancer Center, who led the sunitinib trial.
"The sunitinib trial has changed the standard of care, and it's the first change in 20 years," says Dr. Motzer. He presented the data last June at the American Society of Clinical Oncology's annual meeting.
The trial compared sunitinib and interferon as a first-line therapy for the clear-cell type. In the sunitinib group, tumors took 11 months to grow compared with 5 months in the interferon group.
Sorafenib was compared to placebo in patients with the clear-cell type who had failed a previous therapy. The drug doubled the time to progression (5.5 months compared with 2.8 months).
While these drugs are likely to help patients live longer, it will be important to establish whether life expectancy might be affected by drug toxicities, says Dr. James Brugarolas of the University of Texas Southwestern Medical Center, who wrote an accompanying editorial in NEJM.
Both drugs are associated with side effects such as diarrhea, skin rash, and high blood pressure. In some patients the toxicities are severe.
The two trials demonstrate the benefits of rational drug design, notes Dr. Brugarolas. A better understanding of the biology of kidney cancer led to the hypothesis that inhibiting angiogenesis might affect tumor growth, and this turned out to be true.
"As a result we have three new drugs, and that is a remarkable success story," says Dr. Brugarolas, noting that a third drug, temsirolimus, is likely to win FDA approval.
The next challenge will be to learn whether patients might benefit from combinations of these drugs or from taking them in certain sequences.
"These drugs are a major advance for the disease," says Dr. Bukowski. "It is now up to us to learn how best to use them."
By Edward R. Winstead