Following a review of two clinical trials, the FDA's oncology advisory panel has voted against the use of Avastin in metastatic breast cancer, urging the regulator to revise the drug's label to exclude this patient population. While such a revision would drive down Avastin's share in what is a high-incidence indication, the move would have little impact on Avastin in the wider oncology market.
The Oncology Drugs Advisory Committee's decision comes after two Phase III trials of Avastin (bevacizumab; Genentech/Roche/Chugai) and chemotherapy failed to demonstrate any clinically relevant benefit in patients with metastatic breast cancer. The panel ruling is likely to shrink Avastin's share in the cancer market if the FDA agrees with the advisory committee and withdraws the drug for use in the high-incidence breast cancer population. The US regulator is due to make its decision on September 17, 2010.
Avastin is a humanized monoclonal antibody directed towards vascular endothelial growth factor (VEGF). VEGF plays an important role in angiogenesis, a key driver of tumor growth. The drug was approved in the US in 2004 and in the EU in 2005 for first-line metastatic colorectal cancer in combination with 5-fluorouracil-based chemotherapy. Since then, Avastin has gained approval for non-small cell lung cancer, renal cell carcinoma and glioma.
In 2008, the FDA granted Avastin accelerated approval for the first-line treatment of metastatic HER2 negative breast cancer. The FDA decision was based on findings of the E1200 trial, in which Avastin in combination with paclitaxel significantly improved progression-free survival (PFS) by 5.5 months compared to paclitaxel alone but failed to demonstrate any overall survival (OS) benefit. The FDA granted approval on the condition that Roche/Genentech provide further verification that the drug was clinically effective in this patient population.
To support the filing, Genentech recently submitted the findings of the AVADO trial, which examined Avastin with docetaxel at multiple doses, and the RIBBON-1 trial, examining Avastin in combination with either an anthracycline- or taxane-based chemotherapy or Xeloda (capecitabine; Roche/Genentech). The FDA then sought advice from its expert advisory panel to assess the benefits and risks of using Avastin based on these two trials. In both cases, the advisory panel's vote was unanimous, as the panel asserted that Avastin failed to demonstrate any clinically meaningful benefit to metastatic breast cancer patients when combined with chemotherapy.
In the three-arm AVADO trial, 736 previously untreated HER-2 negative breast cancer patients were recruited and randomized to receive docetaxel with placebo, or docetaxel with Avastin at 7.5mg/kg or 15mg/kg doses every three weeks. PFS improvements were not clinically relevant, with the addition of 7.5mg/kg of Avastin to docetaxel leading to just a 0.8 month difference in median PFS and 15g/kg to docetaxel leading to a 0.88 month difference. Objective OS was statistically insignificant for both dose groups. Furthermore, more patients in the Avastin treatment arms experienced Grade 3/4 safety events compared to the docetaxel and placebo treatment arm. As a result, the advisory panel voted unanimously that the AVADO trial failed to demonstrate that the benefits of Avastin outweighed the risks.
In the RIBBON-1 study, 1,237 HER-2 negative breast cancer patients were randomized to receive Avastin or placebo with either an anthracycline- or taxane-based chemotherapy or Xeloda every three weeks. The Avastin plus Xeloda arm showed a 2.9 month increase in median PFS, while the Avastin plus anthracycline- or taxane-based arm showed a statistically significant improvement in median PFS of 1.2 months. However, there was no OS benefit with the addition of bevacizumab to either cohort. As a result, the advisory panel voted 12 to one that the RIBBON 1 trial failed to demonstrate that the benefits of Avastin outweighed the risks.
Both the AVADO and RIBBON-1 trials overwhelmingly suggest that Avastin may be less effective in breast cancer than in other tumor types, such as colorectal cancer and non-small cell lung cancer. However, the panel ruling does not necessarily mean that the FDA will follow the recommendation. The FDA has gone against the advisory committee in the past, most notably when approving Tarceva (erlotinib; Genentech/Roche) for non-small cell lung cancer in the maintenance setting in spite of a 12 to one ruling for a negative recommendation. Indeed, this was also the case when the FDA granted accelerated approval for Avastin in breast cancer in 2008. At the time, the FDA advisory panel voted five to four against approving the drug in this indication.
Either way, the Oncology Drugs Advisory Committee's ruling will present a setback for Roche and Genentech in terms of growth opportunities for Avastin. Breast cancer incidence continues to rise in women, with an estimated 500,000 cases reported annually across the seven major markets (the US, Japan, France, Germany, Italy, Spain and the UK). Current treatment options are restricted to patients with HER2 positive metastatic breast cancer rather than HER2 negative patients, which are comparatively underserved. Even if the FDA chooses to ignore the panel's advice and allows Avastin's continued use in breast cancer, the drug's uptake is likely to be limited based on current clinical data. Nevertheless, continued success in stronghold areas such as colorectal cancer and non-small cell lung cancer should allow Avastin to retain its leading position in the oncology market, a position which provided the drug with company-reported sales of $5.4 billion in 2009.
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