There are now five drugs that are FDA-approved for kidney cancer: Nexavar (2005), Sutent (2006), Torisel (2007), Afinitor (2009) and Interleukin-2 (1992). There are also other targeted agent drugs in the pipeline that will likely be approved in 2010. It remains to be seen if the availability of therapies will have an impact on the number of patients who enter clinical trials, where new drugs are developed. Currently only 3% of kidney cancer patients enter clinical trials.
In December 2005 and January 2006, the U.S. Food and Drug Administration approved Nexavar and Sutent, respectively. Nexavar is jointly manufactured by Bayer and Onyx, while Sutent is manufactured by Pfizer. They were the first kidney cancer drugs approved by the FDA since 1992, when it approved Interleukin-2 (IL-2). The FDA fast tracked the review of these drugs and signed off on them within 6 months. In May 2007, the FDA approved the Wyeth drug Torisel for kidney cancer. Nexavar, Sutent, Torisel, and Afinitor are called targeted therapies in that they ‘target’ certain proteins for inhibition to staunch the growth of tumors. How effective are they? For summaries of trial results involving most of these drugs refer to Report from ASCO 2007 and Report from ASCO 2006. What follows are the data the drug companies provided to gain FDA approval.
The FDA approved Nexavar based on clinical trial results showing 167 days of progression-free survival (the period before the tumors start growing again) – twice the time experienced by patients taking placebo, but an actual improvement over the placebo by fewer than three months. Increase in survival data was not available at the time of application, although Bernard Escudier, the principal investigator for Nexavar, from the Institut Gustave-Roussy in Paris, reported at the European Cancer Conference in November 2005 a 39% improvement in survival.
The FDA approved Sutent based on its ability to shrink tumors. The trial for which it was approved showed partial shrinkage of the tumors in 40% of the patients and stable disease in another 28% with progression-free survival of 8.7 months. Median survival was 16.4 months.
Both Nexavar and Sutent inhibit the vascular endothelial growth factor receptor (VEGFR) and the platelet derived growth factor receptor (PDGFR). Blocking VEGFR and PDGFR is thought to have an inhibitory effect on angiogenesis (growth of new blood vessels to the tumor) and tumor cell proliferation.
The gold standard result or endpoint for cancer drug approval is increase in patient survival. However, the FDA approved these drugs based on progression-free survival (Nexavar) and tumor shrinkage (Sutent). Perhaps the FDA accepted these surrogate endpoints because IL-2, previously the only other approved treatment for metastatic kidney cancer, is highly toxic and is not suitable for the majority of patients. IL-2 therapy, which stimulates the immune system, produces a response in just 15% of those who undergo treatment with 7% of the patients experiencing a remission that lasts five years or more.
The FDA approved Torisel, based on a median survival of 10.9 months for patients with poor prognosis taking Torisel versus 7.3 months for similar type patients taking Interferon, or an increase in overall survival of 3½ months favoring Torisel. Torisel has a different target than Nexavar and Sutent, namely mTOR, which is a protein that is a factor in cell growth, proliferation, and survival.
The FDA approved Afinitor (everolimus) based on its efficacy on patients who failed either Sutent or Nexavar. In a randomized trial testing Afinitor versus a placebo with median progression-free survival (PFS) as the primary endpoint of the trial, Afinitor patients had a PFS of 4.9 months versus 1.9 months for the placebo.
When first approved, FDA officials called Nexavar “a major advance” in treating kidney cancer. But unlike Interleukin-2, none of the four targeted agents have yet been shown to be curative. They do not have the toxicity of IL-2, and most patients are able to tolerate them reasonably well. However, also unlike IL-2, they must be taken continuously, since a cessation of treatment will lead to a return of tumor growth. Among other effects, they work by inhibiting the growth of new blood vessels, which feed the tumors, in a process called “angiogenesis.” So far, anti-angiogenesis drugs have only been shown to have “cytostatic” activity, not “cytotoxic” action (rather than killing the cancer, they stabilize it or inhibit the disease’s progression). And after some time, the cancer develops resistance to the new drugs.
Although Nexavar, Sutent, Torisel, and Afinitor are a step forward in the fight against kidney cancer, it seems likely that patients will need a combination of therapies similar to the AIDS cocktail to either cure patients or turn kidney cancer into a chronic, but manageable disease. These drugs themselves are being tested in combinations, a couple with Avastin and IL-2 and even as adjuvant therapies in early stage kidney cancer. But to achieve real progress, the United States needs more investment in research to develop a treatment that will prolong survival in terms of years, not months. That will be a “major advance” in the treatment of kidney cancer.