Breast Cancer Specialists Brace for FDA Word on Avastin

ABSTRACT: An advisory panel recommended revoking bevacizumab’s approval in breast cancer. Oncologists and patients express concern about what the future holds for those who do benefit from bevacizumab.

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 (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.

Taxanes take center stage in head and neck cancer

The revocation of bevacizumab in breast cancer treatment could mean a loss of about $500 million in sales in the U.S. to Roche/Genentech, but the drug continues to prove its mettle in other solid tumors.

Results from a Gynecologic Oncology Group trial (0218) indicated that bevacizumab and chemotherapy, followed by maintenance therapy with bevacizumab alone, increased PFS, compared with chemotherapy alone, in women with previously untreated advanced ovarian cancer (ASCO 2010 abstract LBA1). These data were confirmed by similar results from the unpublished ICON7 study.

Updated results from the E4599 study demonstrated that the first-line use of bevacizumab in advanced non-small-cell lung cancer led to a median 3.9-month improvement in OS compared with chemotherapy alone (J Thorac Oncol online, August 3, 2010).

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.

Avastin accelerated

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 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.

DID YOU KNOW? Bevacizumab reimbursement Patients who encounter problems with obtaining payer reimbursement for bevacizumab should contact the Genentech Access Solution Group at

www.genentechaccesssolutions.com

.

The three large randomized trials (E2100, AVADO, and RIBBON-1) evaluated bevacizumab plus first-line chemotherapy regimens (taxane-based, anthracycline-based, or 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.

Evolving data

Was the accelerated approval for bevacizumab in this setting inappropriate? No, according to the experts who spoke with Oncology News International. And it's not surprising that just as data can change over time, approval status may also shift.

ERIC WINER, MD

"The approval process doesn't have to be so conservative, and it can be flexible as the data mature," said Eric Winer, MD, professor of medicine at Harvard Medical School and chief of women's cancer at Dana-Farber Cancer Institute, both in Boston. "That is a good thing. I agree with the concept that data can evolve over time and what looks like a good choice in one year may look unfavorable in another year."

While the three studies do not show survival benefits, bevacizumab does appear to help a subset of women who may end up living longer, Dr. Winer said.

"My own preference is to have it for some patients. It should not disappear from our armamentarium," said Dr. Winer, adding that the agent does improve PFS by a small to moderate amount and helps to control cancer.

SARA HURVITZ, MD

"I think PFS is enough to get accelerated approval of the drug so it was appropriate to approve it. However, survival does remain the gold standard," said Sara Hurvitz, MD, an assistant professor of medicine and director of the breast oncology program at the University of California, Los Angeles, Jonsson Comprehensive Cancer Center

Nonetheless, Dr. Hurvitz said she hopes that women who are currently on bevacizumab, and benefiting from it, will not see an interruption in their therapy.

Financial repercussions

Obviously, neither patients nor their physicians can make any significant decisions until the FDA renders its verdict. Assuming the FDA takes the panel's advice, bevacizumab will remain on the market as an approved treatment option for colon, lung, kidney, and brain cancers (see Related Reading). While physicians could still prescribe bevacizumab for breast cancer patients as an off-label drug, obtaining reimbursement could be problematic. As an approved drug, Roche/Genentech capped yearly spending on Avastin at $57,000 for patients with incomes below $100,000. Without this cap, the wholesale price of bevacizumab could be $88,000 per breast cancer patient (New York Times, July 20, 2010).

CHARLES SHAPIRO, MD

During an interview conducted in August, Charles Shapiro, MD, director of breast medical oncology at Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute in Columbus, recommended that patients should not be started on bevacizumab unless they are in a clinical trial.

TABLE Ongoing trials of bevacizumab as adjuvant therapy for breast cancer

"Those who are benefiting are now in a bad situation, and I think special arrangements need to be made so that patients don't have to pay. We will have to see what happens, but I would make a plea to insurance companies that any patient who is responding to bevacizumab should remain on it," said Dr. Shapiro, who is also a professor of medicine at the university.

He said that ongoing clinical trials of bevacizumab in the adjuvant setting may turn in different results (see Table). Roche/Genentech said there are no plans to alter or stop the trials that are underway. However, the question remains: Will patients not in clinical trials be forced off the medication if the FDA rescinds the approval?

"It is a little early to be asking these questions," said Charlotte Arnold, a spokesperson for Roche/Genentech. "We understand that there are a lot of concerned people out there."