What happens when a popular cancer treatment seems to fall out of favor with regulatory officials? Breast cancer specialists and their patients are about to find out.
The FDA is slated to issue a final ruling on whether to withdraw its approval of bevacizumab(Drug information on bevacizumab) (Avastin), based on an FDA advisory panel's recommendation against the continued approval of the drug for the treatment of metastatic breast cancer.
Oncology News International spoke with several oncologists as they waited for the FDA decisions, many of whom expressed concern about repercussions to their patients.
While the follow-up studies may not have delivered the data that the FDA panel was looking for, the agent does appear to benefit some women with advanced disease.
"I had a woman who had four rounds of treatment and then was finally helped by Avastin. So now I don't know if I can get the drug for her in the future, and I think there are a lot of questions," said Minetta Liu, MD, an assistant professor of medicine and oncology at Georgetown University Medical Center and the Lombardi Cancer Center in Washington, DC.
"Patients like this one are the ones that I worry about most," Dr. Liu added.
Bevacizumab, an angiogenesis inhibitor that neutralizes vascular endothelial growth factor (VEGF), received accelerated approval by the FDA in 2008 with a condition that Roche/Genentech conduct follow-up studies. Unfortunately, the ongoing studies showed that bevacizumab, when used in combination with standard chemotherapy, did not demonstrate any survival benefit. To add insult to injury, early studies showed a progression-free survival (PFS) of more than five months yet follow-up data demonstrated only about three months of PFS with bevacizumab and no overall survival (OS) benefit.
Bevacizumab was approved in combination with paclitaxel(Drug information on paclitaxel) chemotherapy for first-line treatment of advanced HER2-negative breast cancer based on results from the phase III E2100 study. In November 2009, developer Genentech, which became a subsidiary of Roche in 2009, submitted two supplemental Biologics License Applications (sBLAs) to the FDA based on the AVADO and RIBBON-1 studies as part of the company's effort to convert the accelerated approval to standard approval.
The three large randomized trials (E2100, AVADO, and RIBBON-1) evaluated bevacizumab plus first-line chemotherapy regimens (taxane-based, anthracycline-based, or capecitabine(Drug information on capecitabine) [Xeloda]-based). All three trials showed an improvement in the primary endpoint of PFS. While the trials were not designed to show an OS benefit, the latter was a secondary endpoint in all three trials.
At the American Society of Clinical Oncology (ASCO) 2010 meeting, Joyce O'Shaughnessy, MD, and colleagues presented a meta-analysis of the three trials, using complete survival data from each study. A total of 1,439 patients received bevacizumab plus chemotherapy and were compared with 1,008 controls. The overall median age of the patients was 56 years, and 73% were hormone-receptor-positive. A total of 62% had received prior adjuvant chemotherapy. The duration of follow-up ranged from 29 months (AVADO trial) to 36 months (E2100).
In the pooled analysis, the researchers found the median PFS improved from 6.7 to 9.2 months in the bevacizumab arms. However, pooled results showed no statistically significant difference between the arms for OS. The median OS was 26.4 months for the control group and 26.7 months for the patients receiving bevacizumab plus chemotherapy (ASCO 2010 abstract 1005).
SANDRA HORNING, MD
Bevacizumab is expensive and it is associated with significant adverse side effects. Common side effects that occurred in more than 10% of patients who received bevacizumab for different cancer types, and at least double the rate of the comparison group, were nosebleeds, headache, high blood pressure, inflammation of the nose, proteinuria, taste change, dry skin, rectal bleeding, tear production disorder, back pain, and exfoliative dermatitis. Across all trials, treatment with bevacizumab was permanently stopped in 8.4% to 21% of patients due to adverse events.
"We are disappointed by the committee's recommendation and believe Avastin should continue to be an option for women with this incurable disease," said Sandra Horning, MD, senior vice-president, global head, clinical development hematology/oncology for Roche. "We will continue to discuss the data from the more than 2,400 women who participated in three phase III studies with the FDA," she added in a written statement.
The FDA is expected to make a decision on the use of bevacizumab for patients with metastatic breast cancer by September 17, 2010.