Data evaluated by an independent review committee from the phase III, randomized AVEREL trial showed that the addition of bevacizumab to trastuzumab and docetaxel significantly improves the progression-free survival of women with HER2-positive breast cancer, despite findings from an investigator assessment that this progression-free survival improvement was present but statistically non-significant. These interesting data were presented by Luca Gianni, MD (San Raffaele Cancer Center, Milano, Italy) during the 2011 CTRC-AACR San Antonio Breast Cancer Symposium. The AVEREL study was designed to evaluate the combination of bevacizumab with trastuzumab and docetaxel as first-line therapy for HER2-positive, locally recurrent/metastatic breast cancer. As such, AVEREL was the first randomized trial of bevacizumab in this type of breast cancer, according to the researchers.
In order to be allowed to the study, patients needed to have measurable or evaluable HER2-positive, locally recurrent/metastatic breast cancer and ECOG performance status 0/1. Patients with metastases in the central nervous system were excluded from the study. In total, 424 patients from 60 centers were enrolled in the study of whom 421 received treatment. These patients were randomly assigned to a treatment with trastuzumab (8mg/kg6mg/kg q3w) and docetaxel (100mg/m2 q3w) (N=208) or trastuzumab and docetaxel combined with bevacizumab (15mg/kg q3w) (N=216).
After a median follow-up period of 26 months, the investigator assessment revealed a non-significant reduction in the risk of progression of 18% when bevacizumab was added to trastuzumab and docetaxel (HR[95%CI]: 0.82[0.65-1.02]; p=0.0775). However, a second independent review committee analysis did find a significant 28% reduction in the risk for progression or death with the addition of bevacizumab (0.72[0.54-0.94]; p= 0.0162). Overall, median progression-free survival increased by 2.8 and 2.9 months with bevacizumab according to investigator analysis and independent review committee analysis, respectively. The overall response rate by investigator assessment in the study was 69.9% for the trastuzumab plus docetaxel arm vs. 74.3% when bevacizumab was added (p=0.3492). In the independent review committee assesment however, a significant difference in overall response rate was demonstrated in favor of the patients receiving bevacizumab (65.9% vs. 76.5%; p=0.0265).
“Because there are effective treatments for women with HER2-positive breast cancer, researchers are now examining the precise role of an anti-angiogenic drug in combination with existing therapy” Gianni said. “The concept of this trial was a test for the benefit observed in early phase 1 and phase 2,” Gianni continued. “In a way, we confirmed that combining an anti-angiogenic drug with another treatment is a good idea. But now, we have to search the subset of women who have the characteristics associated with benefit from the addition of an anti-angiogenic. The key element is looking for a restricted indication that might have a longer-lasting effect than what has been observed in AVEREL.”