SAN ANTONIO – Adding adjuvant bevacizumab to chemotherapy failed to improve outcomes over chemotherapy alone in women with early-stage triple-negative breast cancer in the phase III BEATRICE trial.
The BEATRICE findings come on the heels of another negative bevacizumab (Avastin) trial, also unveiled at the annual San Antonio Breast Cancer Symposium. In the LEA (Letrozole/Fulvestrant and Avastin) trial, use of the angiogenesis inhibitor in combination with conventional hormone therapy had no benefit over hormone therapy alone in women with advanced breast cancer. These studies may well be the final two nails driven into the coffin containing the once-lively prospects for bevacizumab as an important therapy in breast cancer.
Dr. C. Kent Osborne
"The results, I would say, are disappointing, and they suggest that bevacizumab is going to have a very limited, if any, role in breast cancer," conference codirector Dr. C. Kent Osborne observed in commenting on the studies.
BEATRICE (Bevacizumab Adjuvant Therapy in Triple-Negative Breast Cancer) is an open-label study of 2,591 women with surgically resected early-stage disease. Participants were randomized to adjuvant chemotherapy plus or minus 1 year of bevacizumab. The chemotherapy regimen was left to the discretion of the patient’s oncologist but had to include a taxane and/or anthracycline for four to eight cycles total. Bevacizumab was dosed at 5 mg/kg per week for 1 year.
Dr. David Cameron reported that during a median follow up of 32 months the primary study endpoint, invasive disease-free survival, was achieved in 85.5% of the bevacizumab-plus-chemotherapy group and 84.1% of the chemotherapy-only group. This translated to a 13% relative risk reduction, which was not statistically significant (P = .18).
Invasive disease-free survival differs from disease-free survival, a more common outcome measure, in that it’s designed to capture any cancers bevacizumab might possibly be inducing at sites other than the breast, explained Dr. Cameron, professor of oncology at Edinburgh University.
All-cause mortality, a key secondary endpoint, occurred in 7.1% of the bevacizumab group compared to 8.3% of controls. The resultant 16% reduction in relative risk favoring the angiogenesis inhibitor was nonsignificant (P = .23); however, this analysis was underpowered. A more definitive analysis of overall survival will be conducted in late 2013, he continued.
Dr. David Cameron
Adverse events associated with bevacizumab were as seen in earlier trials: a relatively mild toxicity profile, with no increased risk of bone marrow suppression, a 2% incidence of proteinuria, 5% hypertension, and a 1.1% incidence of NYHA class III or IV heart failure.
A bright spot in BEATRICE was the overall 84% 3-year invasive disease-free survival rate.
"That was actually much better than we had originally planned. So when women go on the Web and look up what is a very negative image of triple-negative breast cancer, we can at least say that based on a big, worldwide, phase-III trial, outcomes actually may not be as bad as the older literature suggests," according to Dr. Cameron. "To me, this is a reflection of what we would see now in our clinics: yes, some of the women do badly, but generally they perhaps don’t do as badly as we’ve learned from the historical literature."
Dr. Osborne agreed, adding that the same phenomenon of control groups in more recent clinical trials doing better than projected is "being seen pretty much across the board" in breast cancer.
"It may reflect gradual improvements through the years in our basic, backbone treatments," he explained.
BEATRICE was the first study looking at bevacizumab in the adjuvant setting, where it really ought to shine, said Dr. Osborne, director of the Dan L. Duncan Cancer Center and the Lester and Sue Smith Breast Center at Baylor College of Medicine, Houston. "If it’s going to work, you’d think it would work in that situation. What we’re dealing with at that stage are microscopic metastases that haven’t developed a sufficient blood supply yet – and if you can prevent that blood supply from forming you might have a more dramatic effect than in an already established tumor, like in metastatic breast cancer."
BEATRICE was sponsored by Roche. Dr. Cameron is a consultant to the company.