Avastin® (bevacizumab) remains on the market in the US and is FDA-approved for advanced colon and rectal cancer in combination with chemotherapy, both as first-line and second-line therapy.
The public hearing held on June 28 and 29 reviewed the process began in December, 2010 to withdraw the FDA provisional approval of Avastin for metastatic, HER-2 negative breast cancer. It did not consider or change other label indications for colorectal, kidney, or small cell lung cancers or glioblastoma.
A final decision on breast cancer will be made by the FDA Commissioner Margaret Hamburg, MD. Until then the indication for breast cancer will remain on the FDA-approved label.
What’s Behind the Hearing?
In 2008, using a procedure called accelerated approval, the FDA gave provisional approval for Avastin to be used to treat metastatic breast cancer based on a randomized clinical trial that showed it took about 5.5 months longer for tumors to get worse (progression-free survival) for women with who received Avastin in addition to chemotherapy than for those who got chemo alone.
However, the provisional approval required that Genentech, the manufacturer of Avastin, conduct further clinical studies to show that the medicine did more — that it actually improved overall survival time.
However, none of the new studies found that survival time increased with Avastin, and they found shorter progression-free survival times than the first trial. In addition, there were more serious, sometimes life-threatening, side effects associated with using the drug.
In July 2010, ODAC voted to remove the metastatic breast cancer indication from the label.
In December of 2010, FDA announced that they were beginning the process of removing the indication. Genentech objected to the decision and asked for an new ODAC hearing, which was held this week.
In an unusual step, FDA allowed testimony from advocates and breast cancer survivors at the beginning of the hearing. In a highly emotionally-charged atmosphere, some so-called “super-responders” told personal stories of successful treatment with Avastin and chemotherapy.
However, at the end of the day, ODAC voted 6-0 that the required further studies had failed to show a clinical benefit when Avastin was added to chemotherapy for metastatic breast cancer. They further voted 6-0 that the drug was not shown to be safe in those trials, with a 13% higher rate of toxic side effects.
Further written comments from Genentech, the Center for Drug Evaluation and Research, and the public will be accepted until July 28, 2011. After that the question will closed until Dr. Hamburg makes her decision.
Should the label indication be withdrawn, Avastin can still be prescribed off-label for metastatic breast cancer, but insurance reimbursements for the expensive drug may be in jeopardy.
At the end of yesterday’s hearing the FDA updated its Avastin information, writing:
Following the closing of the docket, the Center for Drug Evaluation and Research will await Commissioner Hamburg’s final decision on Avastin’s use for metastatic breast cancer. The Commissioner’s decision related to breast cancer will not affect Avastin’s approved indications for use in colon, lung, kidney, and brain cancers. That is, regardless of the final decision on metastatic breast cancer approval, Avastin will remain on the market.
What’s the Situation for Avastin and Colorectal Cancer
The ODAC decision does not affect colorectal cancer. It remains an FDA labeled indication for both first and second line treatment of metastatic (stage IV and recurrent) colorectal cancer.
Avastin was first approved in 2004 for first-line treatment of colorectal cancer when randomized studies showed that it added a median of about five months of life to irinotecan-based chemotherapy alone.
Two years later, second-line therapy for colorectal was added as an indication on the Avastin label, again based on increased survival time when added to FOLFOX chemotherapy.
What About Side Effects?
The clinical trials leading to colorectal cancer approvals found serious, but uncommon side effects, including formation of holes in the colon (gastrointestinal perforation) generally requiring surgery and sometimes leading to abdominal infections, impaired wound healing, and bleeding from the lungs or internally. More common, but less serious, side effects included high blood pressure, fatigue, blood clots, diarrhea, decreased white counts that lowered immunity to infection, mouth sores, and loss of appetite.
Genentech and the FDA also issued two safety warnings in 2004 and 2006:
- A doubling of the risk of serious arterial thromboembolic events, including strokes, heart attack, transient ischemic attacks (TIAs), and angina.
- A rare risk of reversible posterior leukoencephalopathy syndrome (RPLS), a rare brain-capillary leak syndrome.
In 2007, the FDA updated the Avastin label warning of fistula formations,in some cases with fatal outcome. Fistulas involved holes between lungs and esophagus, areas in the lungs, the vagina, bladder, and biliary tract. Events were reported throughout treatment with bevacizumab, with most events occurring within the first six months.
These adverse events and warnings are included on the Avastin label.