FDA Issues Complete Response Letter for Bevacizumab in Metastatic Breast Cancer

Genentech, Inc, recently announced that it received a Complete Response Letter from the US Food and Drug Administration (FDA) for a supplemental Biologics License Application (sBLA) for bevacizumab (Avastin) with chemotherapy in first-line metastatic breast cancer. The FDA has requested a substantial safety and efficacy update from the E2100 trial, including an independent review of patient scans for progression-free survival, the study's primary endpoint. Issuance of the Complete Response Letter satisfies the FDA's product review performance goals specified under the Prescription Drug User Fee Act. A new 6-month review period will begin once the additional information requested is submitted to the FDA.

New Requirements

The sBLA submitted to the FDA on May 23, 2006 was based on interim data from the E2100 trial. The study was sponsored by the National Cancer Institute (NCI) under a Cooperative Research and Development Agreement between NCI and Genentech and was conducted by a network of researchers led by the Eastern Cooperative Oncology Group (ECOG). The FDA has notified Genentech that they now expect the information from this cooperative group trial to be audited and summarized in a manner typically used for a company-sponsored trial. This expectation is different from the understanding that Genentech had when the sBLA was submitted and will require the recollection of information from ECOG study sites.

"We are disappointed that this will cause a delay in the review of our application, as there is a great unmet medical need for women with metastatic breast cancer. Based on the scope of this request, we anticipate we will be able to resubmit the application to the FDA by mid-2007," said Hal Barron, Genentech senior vice president, development, and chief medical officer. "We believe E2100 demonstrates significant clinical benefit, and we will work with ECOG and the FDA to help bring Avastin to patients with metastatic breast cancer."

Genentech is pursuing a broad development program for bevacizumab that currently includes 130 clinical trials across 25 different types of cancer. As part of this program, Genentech is conducting two phase III studies of bevacizumab plus chemotherapy in both first- and second-line metastatic breast cancer (RIBBON-1 and RIBBON-2). A third phase III trial (AVADO) in first-line metastatic breast cancer is being conducted by Roche.

About E2100

Patients enrolled in E2100 were randomized to receive weekly treatment with paclitaxel, with or without bevacizumab administered every 2 weeks. In addition to patients with HER2-negative metastatic breast cancer, patients with HER2-positive tumors were enrolled in the study only if they had received prior treatment with trastuzumab (Herceptin) or were unable to receive treatment with trastuzumab. Patients who had received adjuvant paclitaxel within the previous 12 months, patients with a prior history of blood clots or who were receiving blood thinners, and patients with brain metastases were excluded from the study.

Results from the E2100 trial were first presented at the 2005 American Society of Clinical Oncology annual meeting. In the study, adverse events were similar to those seen in previous trials of bevacizumab plus chemotherapy. No new toxicities were identified as being associated with with the drug.

Bevacizumab, in combination with intravenous 5-FU-based chemotherapy, is indicated for first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum. The FDA first approved bevacizumab on February 26, 2004, as a first-line treatment for metastatic colorectal cancer in combination with intravenous 5-FU-based chemotherapy.