FDA Commissioner Margaret A. Hamburg, M.D., this morning revoked the agency’s 2008 approval of Avastin (bevacizumab) with the chemo drug paclitaxel for the treatment of women with HER2-negative metastatic breast cancer (MBC) in the U.S., concluding that the drug had not been shown to be safe and effective for that use.
“After reviewing the available studies, it is clear that women who take Avastin for metastatic breast cancer risk potentially life-threatening side effects without proof that the use of Avastin will provide a benefit, in terms of delay in tumor growth, that would justify those risks. Nor is there evidence that use of Avastin will either help them live longer or improve their quality of life,” Dr. Hamburg said in a statement.
Dr. Hamburg’s decision comes nearly five months since an FDA Oncology Drug Advisory Committee (ODAC) sided with agency staff officials, who concluded that Avastin does not prolong overall survival in patients with breast cancer or offer a benefit in slowing the progression of the disease that outweighs the drug’s risks.
FDA conditionally approved Avastin for MBC in 2008 despite an advisory panel’s 5–4 recommendation against the drug, citing Genentech’s E2100 study. It showed a 5.5-month increase in progression free survival (PFS) from 5.8 to 11.3 months.
FDA began efforts to withdraw the MBC indication in June, citing a Center for Drug Evaluation and Research recommendation after other clinical studies combining Avastin with various chemo drugs failed to replicate or surpass the duration of PFS seen in E2100. Genentech said the later studies still showed some PFS benefit linked to Avastin use, and that the initial 5.5-month PFS was the largest in median PFS observed in a first-line MBC trial.
Genentech and the FDA have clashed over what the primary endpoint of clinical studies should be: PFS, as the drug developer is seeking, or overall survival, as the agency wants. At a two-day hearing in June, ODAC panelists and FDA staffers expressed doubt that a new study would show much better results than earlier studies.
At that hearing and again in a later submission, Genentech responded by arguing that:
- There are significant unmet medical needs in first-line MBC, for which no other medication has been approved since Avastin;
- Avastin in combination with weekly paclitaxel confers a clinically meaningful benefit in first-line MBC. The company cited findings by more than 80 regulatory agencies worldwide that Avastin’s effect varies by chemotherapy partner.
- Avastin’s safety profile supported maintaining the MBC indication. The company noted that were fewer total deaths on Avastin than with chemotherapy alone and no difference in treatment-related deaths.
“We are disappointed with this outcome. We remain committed to the many women with this incurable disease and will continue to provide help through our patient support programs to those who may be facing obstacles to receiving their treatment,” Genentech said in a statement.
Genentech also said that despite the FDA action, it will start a new Phase III study of Avastin in combination with paclitaxel in previously untreated metastatic breast cancer, and will evaluate a potential biomarker it said may help identify which people might derive a more substantial benefit from Avastin.