Sunitinib and Temsirolimus for Kidney Cancer

by National Cancer Institute

Summary

In separate clinical trials, two new targeted drugs - sunitinib (Sutent) and temsirolimus - have shown positive results in patients with advanced kidney cancer, offering new standards of care.

Source

American Society of Clinical Oncology annual meeting, Atlanta, Georgia, June 4, 2006.

Background

An estimated 39,000 Americans will be diagnosed with kidney cancer (renal cell carcinoma) in 2006 and about 12,800 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 diseased 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 by the time it is diagnosed and becomes very difficult to treat.

Kidney cancer that has spread to other organs (metastatic) cannot be cured by surgery. The standard treatment is one of two biological therapies, interferon alpha (IFN) or interleukin-2. Both of these agents stimulate the body's immune system - the idea is to stop the cancer from growing by strengthening the body's own immune defenses. However, only a minority of patients benefit from these therapies. The estimated five-year survival rate for patients with metastatic kidney cancer is less than 10 percent.

Out-of-control growth of blood vessels that feed tumors is a characteristic of kidney cancer. Sunitinib inhibits proteins in the body's cells that promote the growth of tumor blood vessels. It was approved by the U.S. Food and Drug Administration (FDA) 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 experimental 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 could sometimes cause a tumor to shrink. In these early studies, patients with very advanced tumors and short life expectancy seemed to benefit from treatment with temsirolimus. Temsirolimus is given as a once-weekly intravenous infusion.

Study 1 (Sunitinib)

In the sunitinib study (see the meeting abstract 5), researchers enrolled 750 patients with a type of kidney cancer called clear cell carcinoma, that had spread beyond the kidney. (About 75 percent of kidney cancers are clear cell carcinomas.) Most of the patients had had surgery to remove the diseased kidney and the primary tumor. None had had previous biological therapy.

Based on a standard set of risk categories used to estimate the seriousness of a patient's kidney cancer, most patients in this trial had a favorable or intermediate outlook. The patients were randomly assigned to receive either IFN or sunitinib.

The study was primarily designed to measure the time it took for the patients' cancer to progress (time to progression); determining the survival rate 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

In patients treated with sunitinib, the median time to disease progression was 11 months, compared with five months for those treated with IFN. Tumors shrank by at least half in 31 percent of patients who received sunitinib compared with six percent of those who received IFN.

Patients treated with sunitinib were somewhat more likely to experience diarrhea, high blood pressure, and "hand-foot syndrome," a condition characterized by tenderness and sensitivity in the hands and feet. Rates of fatigue and weakness were higher in patients who received IFN. Other side effects were similar in the two groups.

Study 2 (Temsirolimus)

In the temsirolimus study (see the meeting abstract 6), researchers enrolled 626 patients with renal cell carcinoma that had spread beyond the kidney. All of the patients in the study were deemed to have a poor outlook.

The 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 primarily designed to determine which of the two approaches resulted in the longest survival. 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 alone survived for a median of 10.9 months, compared with 8.4 months for those who received temsirolimus in combination with IFN and 7.3 months for those treated with IFN alone. Median survival among patients treated with temsirolimus alone was 49 percent better than in those treated with IFN alone. Typical overall survival for this high-risk group of patients with advanced kidney cancer is less than six months. The addition of IFN to temsirolimus offered no advantage.

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.

Limitations

Patients weren't followed long enough in the sunitinib study to determine whether those who took sunitinib lived longer than those who took IFN, Motzer said. He noted that even with longer follow-up it will be difficult to assess whether the new drug extends survival because many patients in the IFN group have now switched to sunitinib, which would skew the results.

Comments

Asked at an ASCO press briefing to directly compare sunitinib and temsirolimus, investigators with both studies emphasized that no such comparison can currently be made because the two drugs have not been studied head-to-head.

The two studies enrolled very different patient populations, noted Hudes from the temsirolimus study. All 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, he said. 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 favorable or intermediate risk characteristics, said Motzer, the lead author. About 10 percent were considered poor risk.

During the discussion after the ASCO presentation, Michael B. Atkins of the Vanderbilt University Medical Center in Nashville, Tenn., noted that this and other available evidence now suggests the following standard approaches in the treatment of metastatic kidney cancer.

Sunitinib for first — line treatment of patients with favorable or intermediate outlooks

Temsirolimus for first — line treatment of patients with a poor outlook

Sorafenib (Nexavar) — approved by the FDA in 2005 - for second-line treatment of patients previously treated with biological therapy.

Future clinical trials will test whether combinations of targeted drugs will work better than single agents in patients with metastatic disease, the investigators said.

In addition, the National Cancer Institute and its cooperative groups have opened a phase III clinical trial that will test 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.

About the Author

www.nci.nih.gov
The National Cancer Institute's research programs are extensive and contain many innovative initiatives. I invite you to explore our Web site to find out more about the exciting work being conducted here at NCI and by NCI-supported scientists throughout the country.