The following background information was prepared by Musa Mayer, AdvancedBC at the request of Research Advocacy Network. Thanks, Musa for your help!

Three documents are being made available to you as background before this call:

• Paul Goldberg’s write-up of the meeting, in The Cancer Letter of December 14, is entitled “Avastin Vote Puts Focus on FDA Criteria in First-Line Metastatic Breast Cancer.” This succinctly written article reports on the dynamics of the ODAC meeting, and clarifies the complex regulatory history and background so essential for understanding the issues.

• The FDA Briefing Document details FDA’s concerns about the safety and efficacy of Avastin for this indication, and raises questions about the research and the endpoint of progression-free survival (PFS) supporting it. FDA briefing documents: http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4332b1-01-FDA.pdf

“The key issue of this application is whether the significant improvement in PFS, in the absence of an improvement in overall survival, is a measure of direct clinical benefit that supports regular approval of bevacizumab plus paclitaxel for 1st-line treatment of patients with metastatic breast cancer.”

The improvement of PFS, in the absence of an improvement in overall survival in breast cancer patients, must be weighted against the increased toxicity, including deaths associated with the administration of bevacizumab. The absence of activity of bevacizumab in the second and third line setting for breast cancer as evident in the results of the AVF2119g study must be taken into consideration.”

• The Genentech Briefing Document includes the company (sponsor) presentation of the evidence for safety and efficacy from E2100 and other clinical trials of Avastin in breast cancer. Genentech briefing documents: http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4332b1-03-Genentech.pdf

“The addition of bevacizumab to first-line paclitaxel resulted in a statistically significant and clinically meaningful improvement in the primary endpoint, progression-free survival (PFS) based on an independent review of radiographs (hazard ratio [HR] of 0.483; p < 0.0001), with a 5.5-month increase in median PFS (from 5.8 to 11.3 months).

“The safety profile for bevacizumab in Study E2100 was consistent with the profile established in previous trials in this and other indications. Thus, the risk-benefit profile was highly favorable in the MBC setting.

“Regulatory precedence for PFS as an endpoint for approval in breast cancer has been established, as PFS has served as the primary endpoint for the approval of most of the chemotherapy agents and hormonal agents currently and recently approved for use in MBC.”

As Paul Goldberg’s article reflects, for this meeting FDA posed two issues for consideration that were discussed at length by ODAC members:

1. In the E2100 study, PFS is clearly not a surrogate endpoint for survival in first-line breast cancer. Can PFS be considered a measure of direct clinical benefit in initial treatment of metastatic breast cancer?

2. Is an estimated 5.5 month improvement in median PFS, with no improvement in survival, at a cost of increased toxicity and death, sufficient to establish a net clinical benefit in support of approval of bevacizumab for the initial treatment of patients with metastatic breast cancer?

The split vote at ODAC indicates that there is real disagreement on these issues. In holding this teleconference, we aren’t expecting to resolve these disagreements, of course, but simply to educate advocates more fully on the issues and their implications for drug development.