GAITHERSBURG, Maryland—By a 5-4 vote, the Oncology Drugs Advisory Committee failed to recommend that FDA approve Avastin (bevacizumab, Genentech) in combination with paclitaxel as a first-line treatment for locally recurrent or metastatic, HER2-negative breast cancer.
The narrow margin represented a major policy disagreement among ODAC members about progression-free survival (PFS) as an endpoint, as well as differing opinions about the quality of the data presented to support the new indication for Avastin.
Genentech based its efficacy argument on a single international phase III, open-label trial, conducted at 258 centers and designated E2100; more than 90% of the 722 patients were treated in the United States. Patients were randomized to Avastin plus paclitaxel or paclitaxel alone.
The study achieved its primary endpoint of PFS, but failed to show a statistically significant increase in overall survival, a secondary endpoint. The sponsor also presented safety data from a second study that compared Avastin plus capecitabine (Xeloda) to capecitabine alone in 462 patients with progressive metastatic breast cancer. That study found no difference in PFS or survival.
Avastin is currently approved for treating first- and second-line metastatic colorectal cancer in combination with 5-FU-based chemotherapy, and as a first-line therapy for unresectable or metastatic nonsquamous non-small-cell lung cancer in combination with carboplatin and paclitaxel. Both indications received approval based on overall survival.
Endpoint advice sought
In June 1999, ODAC recommended that FDA refuse to accept time to progression (TTP) as a primary endpoint for clinical trials in first-line metastatic breast cancer. The latest ODAC meeting became a reprise of that debate focused on a similar endpoint—PFS.
In his opening remarks, Richard Pazdur, MD, director of FDA's Office of Oncologic Drug Products, stressed that the agency sought the committee's advice on the use of PFS as an acceptable endpoint for regular approval, as well as its approval recommendation.