Sunitinib and Temsirolimus: Two New Targeted Drugs for Advanced Kidney CancerKey Words
Kidney cancer, sunitinib (Sutent®), temsirolimus (Torisel®), targeted drugs. (Definitions of many terms related to cancer can be found in the Cancer.gov Dictionary.)
Summary
In separate clinical trials, two new targeted drugs—sunitinib (Sutent®) and temsirolimus (Torisel®)—showed positive results in patients with advanced kidney cancer, offering new options for treatment.
Source
New England Journal of Medicine, January 11, 2007 (see the journal abstract). Updated results were published in the Journal of Clinical Oncology online ahead of print, June 1, 2009 (see the journal abstract).
New England Journal of Medicine, May 31, 2007 (see the journal abstract).
Background
An estimated 58,000 Americans will be diagnosed with kidney cancer in 2009, and about 13,000 people are expected to die of the disease. When diagnosed before the disease has spread to other organs, kidney cancer may be cured by surgery to remove all or part of the affected kidney along with surrounding tissues and, in some cases, nearby lymph nodes. In 25 to 30 percent of cases, however, the disease has spread to other organs (metastatic) by the time it is diagnosed and cannot be cured with surgery.
For many years the standard treatment for metastatic kidney cancer was one of two biological therapies, interferon alpha (IFN) or interleukin-2. Both of these agents stimulate the body's immune system; the idea is that growth of the cancer may be slowed by strengthening the body's immune defenses. However, only a few patients benefit from these therapies. About 10 percent of patients with metastatic kidney cancer who are treated with a biological therapy survive for five years.
Out-of-control growth of tumor blood vessels is a characteristic of kidney cancer. Sunitinib is a targeted drug that inhibits several cellular proteins that promote the growth of tumor blood vessels. The U.S. Food and Drug Administration (FDA) approved sunitinib to treat metastatic kidney cancer in January 2006 after preliminary studies suggested that the drug could shrink tumors and delay disease recurrence in patients previously treated with biological therapy. Sunitinib is taken as a pill on an outpatient basis.
The drug temsirolimus targets another cellular protein, mTOR, which regulates the growth of tumor cells and blood vessels. Preliminary studies in patients with advanced kidney cancer that had stopped responding to other therapies showed that temsirolimus could slow or stop further tumor growth and sometimes shrank tumors. Temsirolimus is given as a once-weekly intravenous infusion.
Study 1 (Sunitinib)
In the sunitinib study, 750 patients with a type of kidney cancer called clear cell renal cell carcinoma that had spread beyond the kidney were randomly assigned to receive either IFN or sunitinib. (More than 90 percent of kidney cancers are renal cell carcinomas, and 80 percent of these are clear cell carcinomas.) Most of the patients had had surgery to remove the primary tumor and the affected kidney. None had had previous biological therapy, and most had a good to moderate prognosis.
The study was designed primarily to measure how long treatment delayed growth in patients' tumors (progression-free survival). Determining whether treatment extended patients' lives was a secondary goal. The lead author of the study was Robert J. Motzer, M.D., of Memorial Sloan-Kettering Cancer Center in New York.
Study 1 Results
Median progression-free survival for sunitinib patients was 11 months, compared with five months for those treated with IFN. Tumors shrank in 31 percent of sunitinib patients, compared with six percent of IFN patients. Sunitinib patients lived for a median of 26.4 months, compared with 21.8 months for IFN patients, although the difference was of borderline statistical significance.
Patients treated with sunitinib were somewhat more likely to experience diarrhea, high blood pressure, and "hand-foot syndrome" (tenderness and sensitivity in the hands and feet). Rates of fatigue and weakness were higher in patients who received IFN. Other side effects occurred at similar rates in both groups of patients.
Study 2 (Temsirolimus)
This study enrolled 626 patients with renal cell carcinoma that had spread beyond the kidney. All of the patients were deemed to have a poor prognosis. Patients were assigned at random to one of three groups:
- One group was treated with IFN alone;
- The second group was treated with temsirolimus alone;
- The third group received a lower dose of temsirolimus in combination with IFN.
The study was designed primarily to compare survival of patients treated with temsirolimus or with temsirolimus plus IFN with survival of patients treated with IFN. The lead author of the study was Gary R. Hudes, M.D., of Fox Chase Cancer Center in Philadelphia.
Study 2 Results
Patients treated with temsirolimus survived for a median of 10.9 months and those who received temsirolimus plus IFN survived for 8.4 months, compared with 7.3 months for patients treated with IFN alone. The improved survival with temsirolimus compared to IFN was statistically significant, whereas the improvement with the temsirolimus/IFN combination was not. Typical overall survival for this high-risk group of patients with advanced kidney cancer is less than six months.
Patients who received temsirolimus had higher rates of skin rash and mouth sores, whereas rates of fatigue and weakness were higher in patients who received IFN.
The FDA approved temsirolimus for the treatment of advanced renal cell carcinoma in May 2007 based on the results of this study.
Comments
In study 1, although the improvement in progression-free survival in patients treated with sunitinib was statistically significant, the five-month improvement in median overall survival fell just short of being statistically significant. The possibility remained, therefore, that the apparent overall survival improvement could be a chance finding. However, after sunitinib was approved in 2006, when initial study results showed that the drug delayed disease progression, the study design was changed to permit patients in the IFN group to switch to sunitinib when their tumors began to grow again (a practice known as crossover). Also, some patients received other treatments (such as temsirolimus or sorafenib [Nexavar®], another new targeted drug approved for patients with advanced renal cell carcinoma) after being withdrawn from this study when their tumors began to progress.
Administration of additional active treatments makes it challenging to assess whether sunitinib truly extended patients' survival, explained Bhupinder S. Mann, M.B.B.S., of the National Cancer Institute's (NCI's) Cancer Therapy Evaluation Program. "Overall survival can be confounded by crossover to the study arm with better results - in this case to the sunitinib arm - as well as by the administration of other post-study treatments," Dr. Mann said. "These factors very likely explain the statistical findings of the study's overall survival results. Because the study showed a robust increase in progression-free survival and an improved overall survival with sunitinib treatment, the probability is low that the observed overall survival improvement is due to chance," he added.
Patients in the temsirolimus study could also receive other treatments when their disease progressed. As in the sunitinib study, the use of other treatments can complicate interpretation of the data. In addition, it is not known why temsirolimus alone improved survival compared with IFN alone whereas the combination of temsirolimus and IFN did not.
Both of these studies were initially presented at the 2006 annual meeting of the American Society of Clinical Oncology (ASCO). Asked at a press briefing to directly compare sunitinib and temsirolimus, investigators with both studies emphasized that no such comparison could be made because the two drugs had not been studied head to head.
The two studies enrolled very different patient populations, noted Dr. Hudes from the temsirolimus study. All of the patients in his trial were in poor health, were unable to work, and would not have been eligible for enrollment in the sunitinib study or in most other clinical trials of kidney cancer therapies. The sunitinib study, by contrast, was open to all patients with clear cell carcinoma that had spread beyond the kidney. Most of the patients had a favorable or intermediate progrosis, said Dr. Motzer, the lead author.
During a discussion following the ASCO presentation, Michael B. Atkins, M.D., of the Vanderbilt University Medical Center in Nashville, Tenn., said the available evidence suggested the following standard approaches to the treatment of metastatic kidney cancer:
- Sunitinib for first-line treatment of patients with a favorable or intermediate prognosis
- Temsirolimus for first-line treatment of patients with a poor prognosis
- Sorafenib—approved by the FDA in 2005 for second-line treatment of patients previously treated with biological therapy
An NCI-sponsored phase III clinical trial (E2805 - see the protocol summary) is currently testing whether sunitinib and sorafenib can improve survival for previously untreated kidney cancer patients whose tumors have been surgically removed and have not spread beyond the kidney. Preliminary results from this trial may be available in 2011.
 Back to Top |
