Despite a negative recommendation from the Oncologic Drugs Advisory Committee, Genentech Inc.'s Avastin (bevacizumab) gained accelerated approval from the FDA for use in combination with paclitaxel chemotherapy for the first-line treatment of metastatic HER2-negative breast cancer.

The approval came as somewhat of a surprise, considering that the FDA usually follows the advice of its advisory panels. Although the ODAC vote on Avastin in breast cancer had been close, at 5 to 4, the panel had raised concerns about trial design, toxicity and survival data.

Given the uncertainty, shares of South San Francisco-based Genentech (NYSE:DNA) remained relatively steady ahead of the news on Friday, closing down 15 cents at $71.75. In aftermarket trading, the shares initially jumped up more than $6.

Avastin is already Genentech's biggest revenue generator. With FDA approvals in first-line and second-line metastatic colorectal cancer (CRC), as well as first-line non-small-cell lung cancer (NSCLC), the drug pulled in U.S. sales of nearly $2.3 billion in 2007. That's a 32 percent increase over the previous year, which seems impressive until you consider the 54 percent year-over-year growth in 2006 and the 108 percent year-over-year growth in 2005.

Cowen and Co. analyst Eric Schmidt said Avastin's deceleration isn't necessarily due to competitive threats in CRC or NSCLC, but that the drug needs a new market to continue to achieve Wall Street's high expectations.

Approval in breast cancer provides exactly that. Although Avastin had previously gained some drug compendia listings that allowed certain insurance companies to reimburse off-label use in breast cancer, Schmidt predicted that the FDA approval could eventually translate into annual breast cancer sales between $1 billion and $2 billion.

Additionally, the approval is exciting because there "really aren't any targeted agents for HER2-negative" breast cancer patients, even though they account for about 75 percent of the patient pool, Schmidt said. Genentech's long-time blockbuster Herceptin (trastuzumab), which generated $1.3 billion in 2007, is approved for HER2-positive patients. Ditto for GlaxoSmithKline plc's Tykerb (lapatinib), which was approved last March.

Avastin already is approved for breast cancer in Europe, where it is marketed by Genentech's partner F. Hoffmann-La Roche Ltd. But the path to U.S. regulatory approval proved to be far more difficult.

In May 2006, Genentech submitted a supplemental biologics license application to the FDA seeking approval of Avastin in breast cancer. But the FDA raised concerns about the underlying data, which had not come from a traditional double-blind, placebo-controlled, company-sponsored Phase III trial. Instead, the sBLA was based on an open-label study, known as E2100, conducted by the National Institutes of Health-affiliated Eastern Cooperative Oncology Group. In September 2006, the agency delivered a complete response letter asking Genentech to audit the E2100 data in the same manner expected of a company-sponsored trial. (See BioWorld Today, Sept. 12, 2006.)

Genentech did as the FDA asked, resubmitting the revised sBLA in August 2007. But a second setback occurred in December, when ODAC narrowly voted against approval. (See BioWorld Today, Dec. 6, 2007.)

E2100 had randomized 722 previously untreated breast cancer patients to receive Avastin plus paclitaxel chemotherapy or paclitaxel alone. The study met its primary endpoint of improving progression-free survival (PFS): patients receiving Avastin achieved a median PFS of 11.3 months compared to 5.8 months for the control arm. However, there was no statistically significant difference in median overall survival, with the Avastin group surviving 26.5 months and the control group surviving 24.8 months, leading ODAC to debate the clinical merits of PFS.

The panel also raised questions about the design of E2100 once again and voiced concerns about adverse events. Six deaths were found to be 'definitely or probably' caused by toxicity related to Avastin, and 71.1 percent of patients in the Avastin arm experienced severe adverse events, compared to 51 percent in the control arm.

But between ODAC's negative decision and the FDA's positive one, data from a new Phase III trial became available. Known as AVADO, the trial was sponsored by Roche and properly designed. The randomized, double-blind, placebo-controlled Phase III study compared Avastin plus docetaxel chemotherapy to placebo plus docetaxel in the first-line treatment of 736 patients with locally recurrent or metastatic HER2-negative breast cancer. Avastin was administered at 15 mg/kg or 7.5 mg/kg every three weeks, and both doses resulted in a statistically significant improvement in PFS. (See BioWorld Today, Feb. 14, 2008.)

Although the AVADO data were not officially included in the Avastin sBLA, Genentech submitted them to the FDA for consideration. That may have helped to sway the agency's decision to go ahead and grant accelerated approval.

In its news release, Genentech said that converting its accelerated approval into a full approval will be dependent on an FDA review of the full AVADO data as well as data from a Genentech-sponsored Phase III trial known as RIBBON I. Initial RIBBON I data are expected later this year, while overall survival data from AVADO are expected around mid-2009.Genentech also plans to provide the FDA with data from three additional randomized trials that are either ongoing or planned.