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Key Words

Kidney cancer, clear cell renal cell carcinoma, sorafenib ³ (Nexavar®), targeted therapy. (Definitions of many terms related to cancer can be found in the Cancer.gov Dictionary ⁴.)

Summary

Early analysis of a phase III clinical trial demonstrated that treatment with sorafenib (Nevaxar®) prolonged progression-free survival in patients with metastatic kidney cancer. An updated analysis now shows that sorafenib also prolonged overall survival, but the improvement was not statistically significant.

Source

New England Journal of Medicine, January 11, 2007 (see the journal abstract ⁵). Updated results were published online May 18, 2009, in the Journal of Clinical Oncology (see the journal abstract ⁶).

Background

Most people with kidney cancer have an aggressive form of the disease called clear cell renal cell cancer. If caught early, it can be cured by surgery. However, once the cancer has spread (metastasized), the five-year survival rate is less than 10 percent.

Patients with clear cell renal cell cancer often have increased levels of vascular endothelial growth factor (VEGF) and other proteins that encourage the growth of tumor blood vessels. Sorafenib (Nevaxar®) is a targeted drug that interferes with blood vessel growth and is a member of a class of drugs called angiogenesis inhibitors.

The Study

Between November 2003 and March 2005, in a double-blinded phase III clinical trial, researchers enrolled 903 patients from 117 medical centers in 19 countries, including the United States. 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.

The patients were randomly assigned to treatment with sorafenib or a matching placebo: 451 received sorafenib pills twice a day, and 452 received placebo pills. The main goal (primary endpoint) of the trial was to see if those taking sorafenib lived longer. Researchers also planned a mid-trial (January 2005) analysis to see if sorafenib helped to slow cancer progression (measured by the trial's secondary endpoint, called progression-free survival).

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 early review of progression-free survival in January 2005 showed a statistically significant benefit for sorafenib over the placebo. 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 the rate of disease progression for the sorafenib group.

Because sorafenib was so clearly beneficial, patients in the placebo group were offered the option of switching to sorafenib starting in May 2005. A total of 216 patients from the placebo group crossed over and began taking sorafenib.

The final analysis of overall survival occurred in September 2006, 16 months after cross over to sorafenib. By that time, 561 patients had died; those taking sorafenib had lived a median of 17.8 months, 3.4 months longer than those on placebo. This difference was not statistically significant, most likely because so many patients had crossed over from placebo to sorafenib. When the patients in the placebo group who had crossed over to sorafenib were excluded from the analysis, the researchers found that sorafenib treatment was associated with a statistically significant improvement in overall survival.

Sorafenib was generally well tolerated, although adverse reactions included rash, diarrhea, fatigue, nausea, and hair loss. Seventeen percent of sorafenib patients had elevated blood pressure, and five percent had more serious heart problems. Some other angiogenesis inhibitors have also been found to have potential cardiovascular toxicity.

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 publication of the initial results. Newer targeted therapies such as sorafenib, sunitinib ⁷ (Sutent®), temsirolimus, and bevacizumab ⁸ (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.

Bhupinder Mann, M.B.B.S., who oversees the renal cancer portfolio at the National Cancer Institute's Cancer Therapy Evaluation Program, agrees. He stated that in addition to further improving treatment of metastatic disease, now the trials were also evaluating if treating patients early after curative surgery (adjuvant treatment) would reduce the risk of relapse. For example, ECOG-E2805 ⁹ is an ongoing national trial for patients who have undergone nephrectomy but have a high risk of relapse. The study is asking if postoperative sorafenib or sunitinib can decrease the risk of relapse and thus increase the number of patients who are cured, compared with treatment with surgery alone (the current standard). Due to the high interest shown by both the patients and physicians, this trial is accruing patients rapidly. As more drugs demonstrate benefit to the patients, further studies of comparative efficacy will be conducted, hopefully leading to approval of more efficacious drugs with lesser toxicity and lower cost.

Glossary Terms

Additional cancer treatment given after the primary treatment to lower the risk that the cancer will come back. Adjuvant therapy may include chemotherapy, radiation therapy, hormone therapy, targeted therapy, or biological therapy.

A substance that may prevent the formation of blood vessels. In anticancer therapy, an angiogenesis inhibitor may prevent the growth of new blood vessels that tumors need to grow.

A substance that is made by cells of the immune system. Some cytokines can boost the immune response and others can suppress it. Cytokines can also be made in the laboratory by recombinant DNA technology and used in the treatment of various diseases, including cancer.

A clinical trial in which the medical staff, the patient, and the people who analyze the results do not know the specific type of treatment the patient receives until after the clinical trial is over.

A statistics term. The middle value in a set of measurements.

Surgery to remove a kidney or part of a kidney. In a partial nephrectomy, part of one kidney or a tumor is removed, but not an entire kidney. In a simple nephrectomy, one kidney is removed. In a radical nephrectomy, an entire kidney, nearby adrenal gland and lymph nodes, and other surrounding tissue are removed. In a bilateral nephrectomy, both kidneys are removed.

The percentage of people in a study or treatment group who are alive for a certain period of time after they were diagnosed with or treated for a disease, such as cancer. The overall survival rate is often stated as a five-year survival rate, which is the percentage of people in a study or treatment group who are alive five years after diagnosis or treatment. Also called survival rate.

A study to compare the results of people taking a new treatment with the results of people taking the standard treatment (for example, which group has better survival rates or fewer side effects). In most cases, studies move into phase III only after a treatment seems to work in phases I and II. Phase III trials may include hundreds of people.

An inactive substance or treatment that looks the same as, and is given the same way as, an active drug or treatment being tested. The effects of the active drug or treatment are compared to the effects of the placebo.

The length of time during and after treatment in which a patient is living with a disease that does not get worse. Progression-free survival may be used in a clinical study or trial to help find out how well a new treatment works. Also called PFS.

The return of signs and symptoms of cancer after a period of improvement.

Describes a mathematical measure of difference between groups. The difference is said to be statistically significant if it is greater than what might be expected to happen by chance alone. Also called significant.

A type of treatment that uses drugs or other substances, such as monoclonal antibodies, to identify and attack specific cancer cells. Targeted therapy may have fewer side effects than other types of cancer treatments.

A drug used to treat advanced renal cell carcinoma (a type of kidney cancer). It is also being studied in the treatment of other types of cancer. Temsirolimus blocks a protein involved in cell division, and may kill cancer cells. It is a type of rapamycin analog and a type of serine/threonine kinase inhibitor. Also called CCI-779 and Torisel.