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NBCC reports from ASCO: The debate continues on bevacizumab (Avastin®)

June 16, 2010

When the US Food and Drug Administration (FDA) approved bevacizumab (Avastin®) and paclitaxel (Taxol®) as a first-line treatment for patients with metastatic breast cancer, the National Breast Cancer Coalition (NBCC) raised serious objections with the agency's action.  At the time, the Oncology Drug Advisory Committee (ODAC) decided on a 5-4 vote that available data were not sufficient to establish a favorable risk/benefit analysis for the use of bevacizumab plus paclitaxel for first-line treatment of patients with metastatic breast cancer.  The ODAC based its decision on the results of two Phase III randomized clinical trials (i.e., AVF 2119g and E2100).  Both trials did not demonstrate improvement in overall survival with bevacizuamb.  The FDA went against the recommendation of ODAC and approved the treatment.

In a formal letter to the FDA, NBCC urged the agency to not weaken the standard for approval of drugs in first-line treatment of metastatic breast cancer. 

The debate on bevacizumab has continued at this year's annual meeting of the American Society of Clinical Oncology (ASCO).  Presentations were given on results of the RIBBON2-phase III trial and the meta-analysis of overall survival data of the three phase III trials (i.e., E2100, AVADO, and RIBBON-1). 

E2100, AVADO, and RIBBON-1 trials evaluated bevacizumab plus chemotherapy (e.g., taxanes, anthracyclines, or capecitabine) as a first-line treatment for metastatic breast cancer patients.  Each trial showed improvement in progression-free survival (PFS) with the addition of bevacizumab.  But none of the trials were designed to show a benefit in overall survival, which was the secondary endpoint in the three trials.  To further explore the overall survival data, investigators conducted a meta-analysis in 2,247 patients from these trials. 

The meta-analysis of pooled PFS data demonstrated that bevacizumab combined with first-line chemotherapy resulted in statistically significant improvements in PFS.  But again, a statistically significant difference was not seen for overall survival.

The RIBBON-2 phase III trial evaluated bevacizumab combined with various chemotherapies (e.g., vinorelbine, taxanes, capecitabine, and gemcitabine) as a second-line treatment for metastatic breast cancer patients.  The study population consisted of 684 patients, and primary endpoint of the trial was PFS.  The investigators found that the addition of bevacizumab improved median PFS from 5 months to 7 months.  The subgroup analysis suggested that patients with estrogen receptor (ER) negative or triple negative cancers had better improvement in PFS by adding bevacizumab to their treatment regimen compared to ER-positive patients.  But the trial could not definitively answer who should receive bevacizumab and which chemotherapy regimen would be best.  Overall survival data was not presented. 

At the ASCO meeting, those in the oncology community voiced objections about using PFS as an endpoint for FDA approval of bevacizumab in breast cancer.  They argued that drugs should demonstrate overall survival benefit as well as a better quality of life, with the often high cost of new drugs, especially bevacizumab (about $60,000 per year).  On July 20th, ODAC will revisit the approval of bevacizumab based on PFS endpoint. 

NBCC believes that statistically significant improvement in overall survival is fundamental to achieving meaningful progress in the treatment of breast cancer and should be the cornerstone of drug approval in this and most other settings.  Lowering the standard for drug approval will undermine the quest for advancement in treatment and for cures, as the ability to determine whether a new treatment truly saves lives will be lost. 

Only when PFS is a demonstrated surrogate endpoint for overall survival, it would be an adequate endpoint for drug approval in first-line treatment of metastatic breast cancer.  In advanced disease settings, PFS may be an adequate endpoint provided that the treatment is safer relative to evidence-based alternatives and offers a significant improvement in the patient's quality of life.  But strong limitations, which need to be addressed, exist both to the assessment of disease progression and the evaluation of quality of life.