Washington Editor

While the addition of Genentech's Avastin (bevacizumab) to the chemotherapy agent paclitaxel slowed the progression of tumors in women with metastatic breast cancer, it did not prolong the patients' overall survival and increased their risk of adverse events and death, drug regulators said.

Experts on the FDA's Oncologic Drugs Advisory Committee (ODAC) will meet in Gaithersburg, Md., Wednesday to decide whether the benefits of Avastin's improved progression-free survival (PFS) in patients with metastatic breast cancer outweigh the drug's toxic risks.

The panel of outside experts also must determine whether the significant improvement in PFS, in the absence of an improvement in overall survival, is a measure of direct clinical benefit that supports approval of Avastin plus paclitaxel to treat breast cancer.

The FDA is not obligated to accept its advisory panels' recommendations, but typically does.

South San Francisco-based Genentech Inc. is seeking approval of an expanded indication for Avastin, which already is approved as a therapy for metastatic colorectal and non-small-cell lung cancers, to be used in combination with paclitaxel for the first-line treatment of locally recurrent or metastatic breast cancer.

Genentech based its supplemental biologics license application for the breast cancer indication for Avastin, a highly specific, recombinant, humanized monoclonal antibody that selectively binds to and neutralizes the biologic activity of human vascular endothelial growth factor, primarily on the results of a Phase III study, known as E2100.

The study was an open-label, randomized trial that enrolled 722 patients who had not received prior chemotherapy for their locally recurrent or metastatic breast cancer.

In the E2100 trial, the Avastin-paclitaxel combination added 5.5 months to median progression-free survival for patients with metastatic breast cancer, with the combination group achieving a median of 11.3 months before the cancer progressed or the patient died compared with 5.8 months for the group that received paclitaxel alone.

However, FDA reviewers said in briefing documents that there was no statistically significant difference in the median overall survival in the combination group, 26.5 months, compared with the paclitaxel arm, 24.8 months.

In addition, the reviewers said, 71.1 percent of patients in the combination group experienced severe adverse events, including hypertension, proteinuria, arterial and venous thrombosis, congestive heart failure, bowel perforation and death, compared with 51 percent in the paclitaxel arm.

The FDA's efficacy requirements for marketing approval for oncology drugs, based on earlier recommendations by the ODAC, requires demonstration of clinical benefit, specifically, prolongation of life or better quality of life.

However, established surrogate endpoints, such as durable complete remission in acute leukemias and disease-free survival in adjuvant therapy for breast cancer, have been accepted to support drug approvals, the briefing documents noted.

In addition, the FDA has created a guidance document that describes when PFS can be used as an endpoint for regulatory approval.

In its briefing documents, Genentech argued that the PFS results from study E2100 met the FDA's PFS endpoint criteria.

In addition, the firm maintained, only a small number of the randomized, Phase III clinical trials conducted in patients with newly diagnosed metastatic breast cancer conclusively demonstrated a survival benefit.

The results of study E2100, Genentech argued, supported the conclusion that Avastin "provides a consistent and clinically significant benefit" when added to paclitaxel for breast cancer patients.

The FDA reviewers made no recommendation in the briefing documents about the approval for the expanded indication for Avastin, stating only that they were deferring any such suggestions "pending advice of the ODAC."