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Avastin's slip on PFS

Last week's Oncologic Drugs Advisory Committee meeting produced what may be a temporary setback for Genentech Inc., but it might have a bigger impact on other developers of first-line treatments for metastatic breast cancer.

Genentech's task was to convince ODAC that Avastin bevacizumab combined with paclitaxel increases progression-free survival (PFS) in women who have metastatic breast cancer compared to paclitaxel alone. It also had to persuade the committee that the PFS increase is clinically meaningful. The company accomplished the first goal, but not the second.

Largely because of flaws in the design and conduct of the sole investigator-sponsored Phase III study submitted to support the sBLA, Genentech (DNA, South San Francisco, Calif.) was unable to convince either ODAC or FDA that it had accurately measured the magnitude of Avastin's benefit.

A parallel issue was the relevance of PFS, the primary endpoint of the Phase III trial, in the absence of a statistically significant improvement in survival. The committee concluded PFS is an acceptable endpoint for metastatic disease, but only if it is rigorously assessed and accompanied by at least neutral survival data.

Tying together the two issues, ODAC's 5-4 vote against recommending approval of the Avastin sBLA reflected its uncertainty about the size of the PFS benefit and the lack of strong confirmatory survival data.

The committee's discussion mirrored FDA's internal debates, Richard Pazdur, director of FDA's Office of Oncology Drugs, told BioCentury after the meeting. He characterized the outcome as "relatively neutral" and said the agency was "more interested in the committee's discussion than its vote."

DNA plans to discuss with FDA the possibility of approval based on data in the sBLA plus postmarket study commitments, Susan Desmond-Hellmann, president of product development, told a conference call after the meeting

The agency also could wait for data the company expects next year from two ongoing trials of Avastin as first-line treatment for metastatic disease.

In Europe, EMEA approved Avastin in March for first-line treatment of metastatic breast cancer based on the same investigator-sponsored study. Whether or not first-line metastatic breast cancer ultimately is put on Avastin's U.S. label, the panel's discussion made it clear many clinicians will continue to use the drug for this indication.

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