National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
November 29, 2011 • Volume 8 / Number 23

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FDA Update

FDA Commissioner Revokes Approval of Bevacizumab for Metastatic Breast Cancer

On November 18, Food and Drug Administration (FDA) Commissioner Dr. Margaret Hamburg announced her decision to revoke the agency’s approval of the drug bevacizumab (Avastin) for the treatment of metastatic breast cancer. The FDA Center for Drug Evaluation and Research (CDER) granted bevacizumab accelerated approval for this indication in February 2008 with the condition that Genentech, the drug’s manufacturer, perform two confirmatory clinical trials.

“Unfortunately, the additional studies failed to confirm Avastin’s initial promise,” said Dr. Hamburg at a press briefing explaining the revocation. The two trials showed that bevacizumab delayed tumor growth slightly but did not improve survival or patients’ quality of life.

Based on these findings, CDER’s Oncologic Drugs Advisory Committee (ODAC) voted 12 to 1 in July 2010 to recommend that the FDA withdraw its accelerated approval for metastatic breast cancer. Following an appeal from Genentech in July of this year, ODAC upheld its recommendation to withdraw approval for the indication.

“Sometimes, despite the hopes of investigators, patients, industry, and even the FDA itself, the results of rigorous testing can be disappointing,” said Dr. Hamburg at the press briefing. “This is the case with Avastin when used for the treatment of metastatic breast cancer.”  In light of the potentially severe side effects of bevacizumab, including heart attack or heart failure, severe high blood pressure, and bleeding or hemorrhaging, “it is clear there is no proof of a benefit in breast cancer patients that would justify those risks,” Dr. Hamburg explained.

Bevacizumab is still approved for the treatment of metastatic colorectal cancer and kidney cancer, advanced non-small cell lung cancer, and glioblastoma. Dr. Hamburg stressed that the “FDA doesn’t regulate the practice of medicine,” so a final decision on whether to use bevacizumab for metastatic breast cancer will be up to a patient and her doctors. “I urge women who are currently taking the drug for breast cancer to discuss the risks and benefits…with their oncologist,” she added.

Future studies may identify subsets of patients with metastatic breast cancer who would benefit from bevacizumab. “I would really be very pleased to see Genentech pursue those studies, and we would of course be very open to the submission of a new application that would include additional data, including support for the notion of a subset of responders to the use of Avastin,” Dr. Hamburg concluded.

Further Reading: “Progression-free Survival: Patient Benefit or Lower Standard?

New Form of Asparaginase Approved to Treat Acute Lymphoblastic Leukemia

On November 18, the Food and Drug Administration (FDA) approved Erwinaze, an alternate form of asparaginase that is derived from the bacterium Erwinia chrysanthemi, to treat acute lymphoblastic leukemia (ALL) in patients who have become allergic (hypersensitive) to other forms of asparaginase derived from the bacterium Escherichia coli.

Asparaginase kills leukemia cells by breaking down the amino acid asparagine in the plasma. Asparagine depletion is selectively toxic to leukemia cells, which, unlike normal cells, cannot synthesize asparagine. The level of asparaginase activity is known to correlate with leukemia control and survival.

The FDA approval was based on the results of a single-arm trial involving 58 patients between the ages of 2 and 18 and a safety analysis of 574 patients between the ages of 1 and 66 who participated in a program to expand access to the drug. Patients in both studies had developed allergic reactions to asparaginase and pegaspargase, another modified form of asparaginase, both of which are derived from E. coli.

In the single-arm trial, the main outcome measure was the proportion of patients in whom a prespecified threshold level of asparaginase activity was maintained at 48 or 72 hours after dosing. All evaluable patients in the trial achieved this outcome.

Erwinaze is given as an injection three times per week. Side effects associated with Erwinaze treatment include serious allergic reactions, inflammation of the pancreas, high blood levels of liver enzymes, blood clotting, bleeding, nausea, vomiting, and high blood sugar.

Erwinaze has been designated as an orphan drug, a designation given to drugs for the treatment of diseases affecting fewer than 200,000 people in the United States.

Ruxolitinib Approved to Treat the Bone Marrow Disease Myelofibrosis

On November 16, the Food and Drug Administration (FDA) approved ruxolitinib (Jakafi) for patients with intermediate- or high-risk myelofibrosis. Ruxolitinib is the first drug approved specifically to treat patients with this bone marrow disease.

In patients with myelofibrosis, fibrous tissue replaces the bone marrow, causing blood cells to be made in organs such as the liver and the spleen. This disease is marked by an enlarged spleen, anemia, and decreased numbers of white blood cells and platelets. Symptoms include fatigue, abdominal discomfort, pain under the ribs, feelings of fullness, muscle and bone pain, itching, and night sweats.

Myelofibrosis and other myeloproliferative disorders are associated with the increased activity of tyrosine kinase enzymes called JAK 1 and 2, which play key roles in a signaling pathway that is involved in cell proliferation and growth, hematopoiesis, and the immune response. Ruxolitinib, a pill taken twice daily, binds to and inhibits JAK 1 and 2, which may lead to reduced inflammation and cell proliferation.

The safety and effectiveness of ruxolitinib were evaluated in two clinical trials with a total of 528 patients. Patients in both trials had myelofibrosis that was resistant or refractory to available myelofibrosis therapy or ineligible for allogeneic bone marrow transplantation. All patients had enlarged spleens and needed treatment for disease-related symptoms. Patients in one study received ruxolitinib or the best available therapy; in the other study patients received ruxolitinib or a placebo. The primary endpoint in both trials was the proportion of patients whose spleen size was reduced by at least 35 percent.

In both studies, a significantly higher proportion of patients taking ruxolitinib saw their spleen shrink by 35 percent or more—29 percent of patients receiving ruxolitinib compared with zero percent of those receiving the best available therapy, and 42 percent of patients taking the drug compared with 1 percent of those taking the placebo. In the placebo-controlled study, a greater proportion of patients receiving ruxolitinib than receiving the placebo had their myelofibrosis-related symptoms reduced by 50 percent.

The most serious side effects seen in patients treated with ruxolitinib include low blood platelet levels, anemia, fatigue, diarrhea, shortness of breath, headache, dizziness, and nausea.

Ruxolitinib was reviewed under FDA’s priority review program, an expedited 6-month review of drugs that may offer significant advances in treatment over available therapy or that provide a treatment when no adequate therapy exists.

The treatment has been designated an orphan drug, a designation given to drugs for the treatment of diseases affecting fewer than 200,000 people in the United States.

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