FDA withdraws accelerated approval of bevacizumab for the treatment of metastatic breast cancer
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Mattias Neyt, Frank Hulstaert
The FDA decision
In November 2011, after hearing the industry, FDA’s Commissioner decided, based on the available evidence, to withdraw the previously granted accelerated approval of bevacizumab (Avastin®) for the treatment of metastatic breast cancer. This withdrawal came after FDA had in February 2008 granted an accelerated approval for bevacizumab on the basis of the results of the E2100 study. This study showed an improvement in progression-free survival (PFS) of 5.5 months. The 2008 approval was granted “upon the condition that the drug's sponsor must diligently conduct additional studies to confirm and describe its benefit.”1
The evidence according to FDA
Four additional studies were provided in November 2009 and “did not confirm that the increase in PFS was as substantial as the original study had suggested. On review, FDA’s Center for Drug Evaluation and Research (CDER) concluded that these studies did not verify clinical benefit, and that the available evidence indicated that the drug was not shown to be safe and effective. It therefore proposed to withdraw the breast cancer indication.”1
In total, ”there have been five studies of Avastin submitted to FDA in support of the indication for metastatic breast cancer, involving more than 3,500 patients. None of these studies has demonstrated an overall survival benefit or an improvement in quality of life, and none of the four studies, AVADO, RIBBON1, AVF2119g and RIBBON2, has come close to replicating the PFS gain shown in E2100.”1
Furthermore, as shown in Table 1, there is an increase in adverse events: “a pooled analysis of selected adverse events grade 3 and higher in the first-line trials (E2100, AVADO, and RIBBON1), prepared by Genentech, shows that there was an increase in all of these adverse events, except for one, in those receiving Avastin plus chemotherapy.”1
Consequently, FDA concludes that, because of the increased adverse events and “because the evidence demonstrates only limited activity of Avastin in tumors, and no clear clinical benefit, the risk-benefit profile of Avastin cannot be considered positive.”1
Synergy with paclitaxel or focus on subgroup of patients?
“Genentech contends that the "most plausible" explanation for the discrepancy between E2100 and the other trials is that Avastin is more effective when paired with paclitaxel than with other chemotherapy agents.”1 “CDER has conducted exploratory analysis of the AVADO and RIBBON1 data to look for evidence of interactions between Avastin and the chemotherapeutic agents.”1 It was concluded that “there are clearly no data to establish this hypothesis, and some of the data that are available are not supportive.”1 This contrasts with the position of the European Medicines Agency (EMA) that still approves Avastin in combination with paclitaxel for first-line treatment of patients with metastatic breast cancer.2
Is the effect better in patients with triple-negative breast cancer? “CDER conducted an exploratory analysis of the first-line trials Genentech has submitted, segregating the triple-negative patients from other patients, and found that the overall survival and progression-free survival results of the triple-negative breast cancer patients are similar to the results for other patients.”1
And what about the intervention’s cost-effectiveness?
In the UK, the National Institute for Health and Clinical Excellence (NICE) has evaluated the cost-effectiveness of bevacizumab in combination with a taxane for the first-line treatment of metastatic breast cancer. The taxanes are a group of drugs that includes paclitaxel (Taxol®) and docetaxel (Taxotere®). The evaluation was based on a critical appraisal of the manufacturer’s submission that focused on the combination of bevacizumab plus paclitaxel, primarily based on the E2100 trial. According to NICE’s standards, outcomes were relatively unfavourable, and “the Committee concluded that the most plausible incremental cost-effectiveness ratio (ICER) for bevacizumab plus paclitaxel versus weekly paclitaxel was between £110,000 and £259,000 per QALY gained.” In other combinations, the ICER would even be larger. “The Committee concluded that bevacizumab in combination with a taxane as a first-line treatment for metastatic breast cancer was not a cost-effective use of NHS resources.”3
1. Food and Drug Administration (FDA), Department of health and human services. Proposal to withdraw approval for the breast cancer indication for Avastin (Bevacizumab). November 18, 2011. FDA-2010-N-0621
2. Product Information as approved by the CHMP on 16 December 2010, pending endorsement by the European Commission.
3. National Institute for Health and Clinical Excellence (NICE). Bevacizumab in combination with a taxane for the first-line treatment of metastatic breast cancer. February 2011. NICE technology appraisal guidance 214