The addition of the anti-angiogenesis agent bevacizumab not only failed to extend disease-free or overall survival in women with breast cancer, but also significantly increased the risk of adverse events, according to data reported at the San Antonio Breast Cancer Symposium.
After 38 months of follow-up in the BETH (Bevacizumab with Trastuzumab Adjuvant Therapy in HER2+ Breast Cancer) trial, 92 percent of the women in both arms of the trial achieved invasive disease-free survival, reported Dennis J. Slamon, MD, PhD, Director of Clinical/Translational Research at UCLA's Jonsson Comprehensive Cancer Center and Professor of Medicine and Chief of Hematology/Oncology at the UCLA Department of Medicine.
“That is about as negative as you can get when it comes to bevacizumab adding anything,” he said at a news briefing where he described the results of the trial that included 3,509 women.
In the trial, there were 145 events among women who received chemotherapy plus trastuzumab, and 147 events among women who received chemotherapy, trastuzumab, and bevacizumab, he reported.
“The challenge for bevacizumab is in safety, because you are not getting a lot of benefit and you are adding safety concerns. You have to wonder if it is going to be worthwhile pursuing bevacizumab. Unless there is a new study that can define a subgroup, I don't think this is going anywhere.”
Slamon made the case that the BETH trial may have also given added weight to the use of non-anthracycline therapy in women with HER2-positive breast cancer, because the study was stratified by conventional anthracycline-based therapy and non-anthracycline therapy using a backbone of docetaxel and carboplatin. The outcomes were virtually identical, he noted.
Jennifer Litton: ‘Continues to Be Ongoing Debate’
In commenting on the study as moderator of the news briefing, Jennifer Litton, MD, Associate Professor of Medicine in the Department of Breast Medical Oncology at the University of Texas MD Anderson Cancer Center, agreed that the study showed no role for bevacizumab, but disagreed that it spelled the end of the road for anthracycline-based therapy.
“Bevacizumab adds significant toxicity and no benefit, but we could spend the next five hours debating whether to use anthracyclines—and I am clearly on the other side of the aisle,” she said.
“I think it is very important for us to understand that the BETH trial specifically asked the question of whether bevacizumab added anything, and the answer quite clearly is no. The study does not ask the question of whether we should compare the arms between an anthracycline and a non-anthracycline containing arm. That was not the design or intent of the trial. This continues to be an ongoing debate.”
In the BETH trial, Slamon and colleagues at 170 worldwide sites recruited the 3,509 participants with node-positive or high-risk node-negative HER2-positive breast cancer. The HER2-positive status was confirmed at a central testing laboratory.
“This was a large adjuvant trial that looked at the combination of chemotherapy plus trastuzumab regimens plus or minus bevacizumab,” he explained. Slamon, a key investigator who determined that the alteration in HER2 was a non-inherited but significant driver of pathogenesis among women with these cancers—and that perhaps 20 to 25 percent of the global burden of breast cancer involves the HER2 alteration. He said that since the alteration was associated with increased tumor growth and proliferation, the theory was that an attack with an anti-angiogenesis agent would improve outcomes—a finding that was observed in preclinical and small clinical trials.
In the BETH trial, researchers were permitted to select the type of chemotherapy patients would receive before they were randomized to receive either bevacizumab or no bevacizumab. “There was a robust discussion among physicians at the 170 sites over whether anthracyclines could be avoided in this disease, considering that for decades treatment with anthracyclines had been the backbone of breast cancer therapy,” Slamon said.
He and his colleagues assigned 3,231 patients to a treatment regimen with docetaxel and carboplatin plus trastuzumab. “This combination got around the one problem with trastuzumab. When anthracyclines are used in combination with trastuzumab, it can cause cardiac dysfunction,” he said. This group was divided into one group of 1,617 patients who were treated with trastuzumab and 1,614 patients who received both trastuzumab and bevacizumab.
The other group of 278 patients were treated with anthracycline-containing regimens as well as trastuzumab for a year. The patients were further divided into a group of 140 women on trastuzumab and 138 women on trastuzumab and bevacizumab.
Previous studies had not been able to show statistically significant different outcomes in disease-free survival between the anthracycline-based treatment and the anthracycline-sparing treatment, he noted, adding, though, that he was surprised that so few of his colleagues opted to include women in the anthracycline treatment arm, considering the dominant role the drugs have over decades.
Overall, the 1,757 patients treated with chemotherapy and trastuzumab and the 1,752 treated with chemotherapy, trastuzumab, and bevacizumab were well-matched: All were about 51 years old; 90 percent had ECOG performance status 0; about 48 percent had no positive lymph nodes; half the women had tumors two centimeters in diameter or less; and about 40 percent of the women opted for breast-conserving therapy.
For the secondary endpoint of overall survival, there were 62 deaths among the women on chemotherapy and trastuzumab (96 percent survival rate), compared with 54 events in the chemotherapy plus trastuzumab plus bevacizumab arm (97% survival rate). “There are very few events here, which is, again, very good news for patients,” he said.
Slamon illustrated that the subgroup analyses showed no significant differences. There was a trend for women in Latin America to do better with bevacizumab, but women in Asia did worse with bevacizumab. There were also non-significant trends that indicated that bevacizumab might be better with high-grade tumors and in women who had smaller tumors at the time of diagnosis. But none of those differences achieved statistical significance.
He noted that results comparing the type of chemotherapy—anthracycline-based or non-anthracycline-based—were not statistically different.
“The addition of bevacizumab didn't add any efficacy, but certainly added some safety concerns,” and those were significant differences, he said:
- Overall, 463 patients of the patients on bevacizumab (27% of the total) had Grade 3/4 adverse events compared with 143 patients (8% of the total) not taking the anti-angiogenesis agent;
- Hypertension was experienced by 329 women in the bevacizumab cohort (19%) compared with 78 of those not taking bevacizumab (4%)—“This is an on-target, known effect of anti-angiogenic therapy, and we certainly saw it in BETH;”
- Bleeding was experienced by 50 patients (3%) on bevacizumab compared with nine (less than 1%) of those not on the drug;
- Congestive heart failure was diagnosed in 23 women taking bevacizumab (2%) compared with 12 women (less than 1%) not on bevacizumab;
- Proteinuria was observed in 21 women (1%) on bevacizumab and in 1 one woman not on bevacizumab; and
- Eleven women on bevacizumab had gastrointestinal perforations compared with one woman not on bevacizumab.
Slamon said that in comparing BETH results with those of other large trials, it appeared that the non-anthracycline therapy “performed extremely well.” He acknowledged, though, that he was performing cross-trial comparisons, and cautioned that all the caveats of such analyses had to be considered.
In response to questions from reporters, Slamon said, “All of the anti-angiogenic strategies have really not impacted survival in breast cancer. There may still be something there if we were really able to find the right markers, but so far they have all come out negative for any kind of impressive survival advantage.”
He also said the trial probably shows that anthracyclines may not be necessary for treatment either. “We were all trained to use anthracycline in breast cancer, and the only reason we moved to non-anthracycline regimens was because of the safety signal we saw when anthracyclines were used with trastuzumab, and we observed drops in cardiac ventricular function and fourfold increases in congestive heart failure. I think there is no reason to take that risk any longer.”
This study was supported by funds from Roche/Genentech, and Slamon noted that he has served as an adviser to both companies in the past several years, including the time during which the study was conducted.
In a video interview on the iPad issue with OT reporter Dan Keller, Dr. Slamon elaborates on the clinical results of the trial.
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