A Phase III trial of Avastin (bevacizumab) in breast cancer met its primary endpoint of improving progression-free survival (PFS), but analysts remained split on whether the new data would be enough to gain FDA approval.

The randomized, double-blind, placebo-controlled Phase III study - known as AVADO - 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.

Detailed PFS data likely will be presented in June at the American Society of Clinical Oncology annual meeting, as will data regarding adverse events. Genentech spokesman Ed Lang said that so far the trial hasn't turned up "anything new" in terms of adverse events.

Secondary endpoints included overall survival, response rate, time to treatment failure, quality of life and safety. Lang said top-line overall survival data are expected in mid-2009.

In the meantime, Genentech submitted the initial AVADO data to the FDA, which is scheduled to render a decision by Feb. 23 regarding the company's supplemental biologics license application for Avastin in breast cancer. Lang said the AVADO data "are not part of the sBLA at this point," and Genentech does not expect the new data to delay the agency's decision.

Instead, Genentech's sBLA is based on data from a Phase III trial known as E2100. The open-label study was investigator-sponsored rather than company-sponsored, a fact that prompted the FDA to request additional analyses and delay acceptance of the sBLA in mid-2006. Genentech resubmitted its filing in mid-2007 but ran into trouble again when the FDA's Oncologic Drugs Advisory Committee voted against approval. (See BioWorld Today, Sept. 12, 2006, and Dec. 6, 2007.)

The E2100 study compared Avastin plus paclitaxel chemotherapy to paclitaxel alone in the first-line treatment of 722 breast cancer patients.

The trial met its primary endpoint of improving PFS, with the Avastin arm achieving a median PFS of 11.3 months compared to 5.8 months for the control arm. But the ODAC reviewers voiced concerns about the lack of a statistically significant difference in median overall survival, with the Avastin group surviving 26.5 months and the control group surviving 24.8 months. Additionally, 71.1 percent of patients in the Avastin arm experienced severe adverse events, compared to 51 percent in the control arm.

The panel debated whether the improvement in PFS should be considered a direct measure of clinical benefit despite the lack of survival advantage, and whether the PFS benefit outweighed the drug's adverse event risks. Ultimately, they voted 5 to 4 against recommending approval. While the FDA isn't bound by ODAC's recommendation, it usually follows the advice of its advisory panels.

So will more PFS data help Genentech's cause?

In a research note, Lazard Capital Markets LLC analyst Joel Sendek wrote that he remains "optimistic" about the approval of Avastin in breast cancer.

Jefferies & Co. Inc. analyst Adam Walsh, however, wrote that he views approval on Feb. 23 as "unlikely." Instead, he expects an approvable letter requesting more data, which in a best-case scenario could come from the AVADO trial or an ongoing Phase III trial known as RIBBON-1.

While AVADO was sponsored by Genentech's partner F. Hoffmann-La Roche Ltd., Genentech is conducting two of its own Phase III studies of Avastin plus chemotherapy in breast cancer: RIBBON-1 in first-line treatment and RIBBON-2 in second-line treatment.

Data from RIBBON-1 on the primary endpoint of PFS are expected later this year.

For now, Avastin is FDA-approved for first-line and second-line treatment for metastatic colorectal cancer, as well as first-line treatment of non-small-cell lung cancer. In Europe, the vascular endothelial growth factor (VEGF)-targeted antibody also has approval in breast cancer and renal cell carcinoma.

U.S. sales of Avastin racked up nearly $2.3 billion in 2007, but fourth-quarter sales of $603 million disappointed analysts. The drug already is used off-label in the U.S. for breast cancer, and analysts have estimated that an approval in that indication could generate upward of $1 billion in sales.

Shares of South San Francisco-based Genentech (NYSE:DNA) rose 93 cents to close at $70.85 Wednesday.