CHICAGO—The benefit of bevacizumab in metastatic breast cancer was made clear in a meta-analysis of key trials presented by Joyce O’Shaughnessy, MD, of Baylor-Sammons Cancer Center and US On cology, during the 2010 annual meeting of the American Society of Clinical Oncology.
Three randomized trials—E2100, AVADO, and RIBBON-1—that in - clude a total of 2447 patients have demonstrated significantly improved progression-free survival (PFS) for bevacizumab combined with different chemotherapy regimens for frontline treatment of metastatic breast cancer. In the pooled analysis, median PFS improved by 2.5 months when bevacizumab was combined with chemo - therapy compared with chemotherapy alone, regardless of hormone receptor status, sites of metastasis, disease-free interval, or prior adjuvant taxane use, O’Shaughnessy said.
The chemotherapy regimens for metastatic breast cancer included weekly paclitaxel; every-3-week docetaxel; and capecitabine, docetaxel or nanoparticle albumin-bound (nab)-paclitaxel, and doxorubicin or epirubicin. Ap proxi - mately 50% had received adjuvant therapy. Median follow-up was 23 months to 35 months. An overview of efficacy is shown in the Table.
O’Shaughnessy and colleagues pooled the individual results and arrived at an overall PFS of 9.2 months with bevacizumab versus 6.7 months with chemo - therapy alone, for a 36% reduction in risk. All subgroups derived benefit from bevacizumab, including patients with adverse prognostic features. Response rates increased by an absolute 17% versus controls.
Overall survival (OS), however, was not significantly improved in either the individual trials or the pooled analysis. In the pooled population, OS was 26.7 months with bevacizumab and 26.4 months with chemotherapy alone; 1- year survival rates were 82% and 77%, respectively. There were no survival differences by subsets.
“But in general, patients received multiple treatments upon progression,” O’Shaughnessy noted, which has a wellknown effect on survival and thus makes it very difficult to show survival differences between arms.
In the nonbevacizumab arms, 71% of patients received additional chemo therapy after the study, as did 65% of pa tients in the bevacizumab arm. O’Shaugh nessy pointed out that 50% of the chemotherapy- alone arm re ceived bevacizumab. An additional four anticancer agents were given to 25% of patients.
Bevacizumab use has been proved safe, with treatment-related deaths reported for 2.1% of patients. Grade 3 or higher adverse events included neutropenia, sensory neuropathy, and hypertension in approximately 10% of patients; febrile neutropenia in 6.5% of patients; venous thromboembolism in 2.8% of patients; and proteinuria in 2.3% of patients.
OS benefit uncertain
Hope Rugo, MD, of the University of California, San Francisco, posed some reasons for the lack of OS benefit shown in the trials. “Line of therapy is important,” she pointed out. Studies are less likely to show a survival benefit in the first-line unselected population, whose biology is “extremely heterogeneous.” Late-line studies are more likely to enroll a more homogeneous group of patients who have likely responded to prior treatments, have a good performance status, and have tumors associated with rapid relapse, which makes development of resis tance less likely, she said.
In addition, observation of an OS benefit is dependent on survival time postprogression, and short follow-up as well as crossover treatments (50% of the control group received bevacizu - mab) make it highly unlikely for this to be observed.
Rugo said the future studies need to hone in on which patients are more likely to benefit from taking bevacizumab. “Collaborative research and tumor biopsies are required to answer the critical question of which patients benefit most from antiangiogenic therapy,” she concluded.