Sorafenib Delays Recurrence of Metastatic Kidney CancerKey Words
Kidney cancer, clear cell renal cell carcinoma, sorafenib (Nexavar®), targeted therapy. (Definitions of many terms related to cancer can be found in the Cancer.gov Dictionary.)
Summary
In this phase III clinical trial, sorafenib (Nevaxar®) prolonged progression-free survival in patients with the most aggressive form of kidney cancer who had stopped responding to other treatments.
Source
New England Journal of Medicine, January 11, 2007 (see the journal abstract).
(N Eng J Med Jan 2007; 356(2): 125-34)
Background
Most people with kidney cancer have an aggressive form of the disease called clear cell renal cell cancer. If caught early, it can often be cured or controlled by surgery. However, once the cancer has spread (metastasized), the five-year survival rate is less than 10 percent.
Researchers are testing a number of targeted drugs for effectiveness against metastatic kidney cancer, including the drug sorafenib (Nevaxar®). Sorafenib, given as a pill, interferes with the formation of blood vessels that feed tumors. Such drugs are called angiogenesis inhibitors.
The Study
In this double-blinded, phase III clinical trial, researchers enrolled 903 patients from 117 medical centers in 19 countries, including the United States. Virtually all of the patients had metastatic clear cell renal cell cancer for which they had received some form of prior treatment (nephrectomy and/or cytokine therapy) that had failed to stop the disease.
Between November 2003 and March 2005, the patients were divided randomly into two groups, with 451 receiving sorafenib twice a day, and 452 receiving a placebo. The main goal (primary endpoint) of the trial was to see if those taking sorafenib lived longer overall. Researchers also planned a mid-trial (January 2005) analysis to see if sorafenib was helping to prevent relapses (called progression-free survival, the trial’s secondary endpoint).
The study’s principal investigator was Bernard Escudier, M.D., of the Institut Gustave Roussy in Villejuif, France. Both Bayer Pharmaceuticals and Onyx Pharmaceuticals were involved in the design and support of this trial, which was known as the Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET).
Results
The planned review of progression-free survival in January 2005 showed a statistically significant benefit for sorafenib over the placebo in terms of this secondary endpoint. Those taking sorafenib (384 at the time of the mid-trial analysis) went a median of 5.5 months before their disease progressed, compared to 2.8 months for those taking placebo (385 patients). This amounted to a 56 percent reduction in risk for the sorafenib group.
Because sorafenib was so clearly beneficial, patients in the placebo group were told which pill they had been taking and were offered the option of joining the sorafenib group starting in May 2005. Of those in the placebo group, 216 crossed-over and began taking sorafenib.
The final analysis of overall survival will occur when there are a total of 540 deaths, the number required to show a reliable distinction between the two groups in terms of this primary endpoint. When survival was assessed in November 2006, 220 patients had died; at that time those taking sorafenib had lived a median of 19.3 months after joining the study, 3.4 months longer than those on placebo.
However, while these results were suggestive they were not statistically significant. The cross-over of patients from one group to the other may have compromised the data on overall survival, or it may be too soon to see an impact on survival.
Patients taking sorafenib had adverse reactions such as rash and diarrhea. Other significant events were fatigue, nausea, and hair loss. Seventeen percent of sorafenib patients had elevated blood pressure, and three percent had more serious heart problems, including two deaths.
Comments
Based on the progression-free survival benefit seen in this trial, on December 20, 2005, the U.S. Food and Drug Administration approved sorafenib for the treatment of advanced kidney cancer.
“Renal cell carcinoma is among the most resistant of tumors to therapy,” said James Brugarolas, M.D., Ph.D., from the University of Texas Southwestern Medical Center, in an editorial accompanying the results. Newer targeted therapies such as sorafenib, sunitinib (Sutent®), temsirolimus, and bevacizumab (Avastin®) “show how promising treatments can emerge from an understanding of the molecular genetics and biology of tumors,” he added, noting the need for a greater understanding of how they affect specific patients.
Alison Martin, M.D., who oversees the renal cancer portfolio at the National Cancer Institute’s Cancer Therapy Evaluation Program, agreed, saying “The next generation of trials will ask how to use these targeted therapies better.” She cited a number of ongoing and planned studies that she urged patients to consider joining.
For example, ECOG-E2805 is a national trial for patients who have undergone nephrectomy and who are considered at high risk for relapse. The study will ask if postoperative sorafenib or sunitinib, i.e., treatment given in the adjuvant setting, can increase the number of patients who are cured compared to those treated with the standard of surgery alone. Other trials, such as ECOG-E2804, are asking if combinations of angiogenesis inhibitors are more promising than treatment with a single agent.
 Back to Top |
