More to the avastin/breast cancer story?

More to the avastin/breast cancer story?

In November 2011, the FDA revoked the approval of Genentech's bevacizumab (Avastin) for the treatment of breast cancer. The somewhat controversial decision was based on lack of evidence of improved survival with the drug, even though several studies have shown improvement in progression-free survival. This has sparked a debate regarding surrogate clinical endpoints, such as progression-free survival or pathological complete response, which is the endpoint used in two new studies recently published in the New England Journal of Medicine. The first study from Germany randomly assigned 1948 women with medium-sized tumors to receive neoadjuvant epirubicin and cyclophosphamide, followed by doxetaxel with or without bevacizumab, in patients with HER2-negative breast cancers. Rates of pathological complete response were 14.9% without bevacizumab and 18.4% with the drug (odds ratio 1.29; 95% CI, 1.02 to 1.65; P = 0.04). Patients with hormone receptor-negative ("triple negative") tumors did better while patients with hormone receptor-positive tumors saw no improvement (N Engl J Med 2012;366:299-309). The other study, supported by the National Cancer Institute, looked at about 1200 patients with operable HER2-negative breast cancer. Patients were given neoadjuvant therapy with docetaxel plus capecitabine or paclitaxel plus gemcitabine followed by doxorubicin-cyclophosphamide. They were further randomized to receive bevacizumab for the first six cycles. Adding capecitabine or gemcitabine to docetaxel had no effect and increased toxicity; however, adding bevacizumab increased the rate of pathological complete reponse (28.2% without bevacizumab vs the 34.5% with bevacizumab, P = 0.02). Bevacizumab increased the rates of hypertension, left ventricular systolic dysfunction, hand-foot syndrome, and mucositis. The authors conclude that bevacizumab significantly increased the rate of pathological complete response (N Engl J Med 2012;366:310-320). An accompanying editorial points out that the ongoing controversy regarding bevacizumab for the treatment of breast cancer revolves around the issue of using surrogate endpoints in clinical trials as well as broader economic issues in the treatment of cancer. Although the study showed improvement in the surrogate endpoint of pathological complete response (defined as absence of residual tumor in the breast and nodes in the European study and a less stringent criteria of absence of residual tumor in the breast only in the American study), neither study was powered to show differences in survival — the criteria the FDA used to withdraw the approval for bevacizumab (N Engl J Med 2012;366:374-375). It is unlikely that either of these studies will influence the FDA to change its decision until more definitive survival data are available.