SAN ANTONIO – Adjuvant bevacizumab does not further improve the already very good outcomes being achieved with contemporary therapy in high-risk HER2-positive breast cancer, according to results of the randomized, phase III BETH trial.
There was little room for improvement on chemotherapy and HER2-targeted therapy with trastuzumab as the standard of care, as an estimated 92% of patients were still alive and free of disease after a median follow-up of about 3 years, lead investigator Dr. Dennis J. Slamon reported at the San Antonio Breast Cancer Symposium.
Dr. Dennis J. Slamon
"The addition of bevacizumab didn’t add any efficacy but certainly added some safety concerns," Dr. Slamon commented in a press briefing. Increased rates of grade 3/4 adverse events, such as hypertension and bowel perforation, were associated with use of bevacizumab.
BETH thus joins a host of trials with negative results for antiangiogenic therapy in breast cancer, he said. "Unless there is a new drug or strategy where we can find the subgroup [that benefits], I think this is not going anywhere. We have gotten a pretty good effect with what we have. We have very little room at the top. We have to think about new strategies for those patients who aren’t getting the benefit that we hope they will with targeted therapy."
In other trial findings, there were consistently high rates of invasive disease–free survival regardless of whether the chemotherapy/trastuzumab regimen used (left up to the treating centers) did not contain an anthracycline (docetaxel, carboplatin, and trastuzumab [Herceptin] – TCH) or did contain an anthracycline (5-fluorouracil, epirubicin, and cyclophosphamide – FEC).
Given the known toxicity of anthracyclines and the availability of an equally effective and safer alternative, their use in HER2-positive breast cancer is no longer justified, according to Dr. Slamon, director of clinical/translational research at the University of California, Los Angeles (UCLA) Jonsson Comprehensive Cancer Center and professor of medicine and chief of the division of hematology/oncology at UCLA.
Acknowledging that the topic is intensely debated, Dr. Slamon noted that "there is no reason to take that risk now that we have more than 4,000 patients treated [with TCH] between BCIRG-006 [which first rigorously tested this regimen] and BETH that show that this gives a pretty favorable outcome. We at our institution do not use these drugs [anthracyclines]. It doesn’t mean they are not effective; they just don’t provide any incremental benefit over other drugs that would give you the same effect without the safety concerns."
While praising the trial as "exceptionally well run" and agreeing on interpretation of the bevacizumab results, press briefing moderator Dr. Jennifer Litton expressed an opposing view.
"I’m totally on the other side of the aisle, that we shouldn’t say that all anthracyclines should go away," maintained Dr. Litton, associate professor in the department of breast medical oncology at the University of Texas MD Anderson Cancer Center in Houston. "The BETH trial specifically asked the question: Does bevacizumab add anything? And the answer quite clearly is no." It did it compare an anthracycline- and a non–anthracycline-containing arm. "That was not the design or intent," she said.
Additionally, in contrast to other similar trials, almost half of the patients who participated in BETH had stage I disease, raising the possibility of selection bias for who received TCH.
"But I do feel that the Herceptin story and the combination stories to come" with lapatinib, pertuzumab, and TDM1 "are really going to also be the landscape changers in HER2 disease," Dr. Litton concluded. "And we are going to be continuing to find specific strategies and not a one-therapy-fits-all for all HER2 disease because we are learning more and more about the molecular subsets of cancer. How we have broken them up into triple receptors is really going to go by the wayside."
Dr. Jennifer Litton
Bevacizumab (Avastin) is an antibody to vascular endothelial growth factor (VEGF). It is approved for use by the Food and Drug Administration to treat colorectal cancer, glioblastoma, non–small cell lung cancer, and renal cell cancer.
The 3,509 women enrolled in BETH (Bevacizumab and Trastuzumab Adjuvant Therapy in HER2-Positive Breast Cancer) had HER2-positive, node-positive, or high-risk node-negative breast cancer; 92% received TCH as their chemotherapy.
With a median follow-up of 38 months in the trial population overall, there was no significant difference between patients randomized to receive bevacizumab and those who did not in terms of the 3-year rate of invasive disease–free survival (92% vs. 92%) and overall survival (97% vs. 96%).
The findings were consistent across subgroups stratified by a variety of patient and disease characteristics, Dr. Slamon noted.