Adjuvant Bevacizumab Fails in HER2-Positive Breast Cancer Trial

The addition of bevacizumab to the combination of chemotherapy and trastuzumab as adjuvant therapy did not influence invasive disease-free survival (DFS), according to study results presented at the 36th annual San Antonio Breast Cancer Symposium (SABCS) held in San Antonio, Texas.

According to results of the phase III international BETH (Bevacizumab With Trastuzumab Adjuvant Therapy in HER2-Positive Breast Cancer) study, at a median follow-up of 38 months, the invasive DFS rates for HER2-positive breast cancer patients treated with trastuzumab, docetaxel, and carboplatin were 92%-both with and without bevacizumab.

"The major takeaway is that bevacizumab does not appear to add any benefit to standard of care trastuzumab plus chemotherapy in the adjuvant setting," said Sara Hurvitz, MD, director of the Hematology/Oncology Breast Cancer Program at the UCLA Jonsson Comprehensive Cancer Center, who was not involved in the trial.

"The chemotherapy/trastuzumab regimen yielded a very high DFS rate, thus the control arm therapy is quite effective and a hard mark to beat," Hurvitz said.

“This result is about as negative as you can get in terms of bevacizumab adding anything to the outcome,” said Dennis J. Slamon, MD, PhD, of the UCLA Jonsson Comprehensive Cancer Center, who presented the data at a press briefing. “Bevacizumab did not add any efficacy but certainly added some safety concerns.”

The BETH trial set out to test whether adding bevacizumab to two separate chemotherapy-trastuzumab combination regimens would provide additional benefit in HER2-positive disease. “There is a correlation of high levels of HER2 and high levels of VEGF within the tumor and poor prognosis,” said Slamon during a press briefing. “Both are independent prognostic predictors and together these predict an even worse outcome.” A small, 50-patient phase II trial indicated that combining trastuzumab with bevacizumab with no additional chemotherapy resulted in encouraging objective responses that warranted further testing.

Dr. Slamon and his colleagues have definitively answered that bevacizumab does not provide an additional benefit to the current treatment strategies for HER2-positive breast cancer, said Jennifer Litton, MD, associate professor in the Department of Breast Oncology at the University of Texas MD Anderson Cancer Center in Houston, and moderator of the press briefing. “Bevacizumab really adds significant toxicity and no benefit.”

A total of 3,509 women with HER2-positive breast cancer who had node-positive disease or high-risk, node-negative disease were enrolled to one of two cohorts: 3,231 were enrolled in cohort 1 (docetaxel/carboplatin/trastuzumab) and 278 patients were enrolled in cohort 2 (anthracycline/trastuzumab).

Patients in cohort 1 received 6 cycles of docetaxel/carboplatin/trastuzumab with or without bevacizumab followed by trastuzumab with or without bevacizumab for the rest of the 12-month treatment.

Patients in cohort 2 received 3 cycles of trastuzumab plus docetaxel, then 3 cycles of 5-fluorouracil, epirubicin, cyclophosphamide, and finally trastuzumab with or without bevacizumab for the rest of the 12-month treatment. Within each cohort, patients were randomized 1:1 to receive the regimen either with or without bevacizumab.

The primary endpoint was invasive DFS for treatment with bevacizumab compared to treatment without bevacizumab.

This trial showed a marked improvement in invasive DFS at 3 years compared with the Breast Cancer International Research Group (BCIRG) 006 trial published in the New England Journal of Medicine in 2011, which showed an 86% invasive DFS rate for a similar patient group. “When we saw the data we were struck by the improvement,” said Slamon during the press briefing.

In a subset analysis, age, race, and geographic distribution did not result in different invasive DFS rates. All patient groups, including those with more than two positive axillary lymph nodes and those with a larger tumor burden had significant benefit from the treatment. Invasive DFS was slightly higher among patients with node-negative disease (96%) compared with node-positive patients (88%), but bevacizumab did not improve outcomes for any subgroup. In the BCIRG 006 trial, the 3-year invasive DFS rate was 85% for node-positive patients and 96% for node-negative patients.

The addition of bevacizumab resulted in higher rates of grade 3/4 adverse events. Eight percent of patients in the chemotherapy/trastuzumab treatment arms had a grade 3/4 adverse event compared with 27% of patients in the bevacizumab experimental arms (P < .0001). Hypertension, an on-target toxicity of bevacizumab, was higher among bevacizumab-treated patients, with 19% of these patients experiencing a grade 3/4 hypertension event compared with 4% of patients in the chemotherapy/trastuzumab group (P < .0001).

Bleeding, although rare, was higher among patients treated with bevacizumab (2% compared with less than 1% for patients in the non-bevacizumab arm;P < .0001). Congestive heart failure was higher in the bevacizumab treatment arm (2.1% vs less than 1%; P = .0621), as was proteinuria (1% vs less than 1%;P < .0001) and gastrointestinal perforations (11 cases vs 1 case; P < .0001).

According to Slamon, the results of the BETH trial show that the combination of docetaxel, carboplatin, and trastuzumab may be the best combination for treating women with HER2-positive breast cancer after surgery regardless of tumor size or lymph node status.

“One problem that [trastuzumab] causes for women when used in combination with anthracycline is cardiac dysfunction which occurs in a small but defined number of patients and includes congestive heart failure,” said Slamon during a press briefing. Trastuzumab plus anthracyclines result in a threefold to fivefold increase in cardiac toxicity. Substituting anthracyclines with docetaxel plus carboplatin results in similar efficacy without the toxicity.

Although the BETH trial showed that docetaxel plus carboplatin results in similar efficacy and lower toxicity compared with anthracyclines, the trial was not designed to compare the difference in outcomes of these two chemotherapy regimens when combined with trastuzumab.

Based on the BETH and 006 trial results, Dr. Slamon said that from his perspective, there is no role of anthracyclines in adjuvant therapy for HER2-positive breast cancer patients. “There is no single trial that really showed there was an incremental benefit with anthracyclines,” said Slamon. “The evidence all came from a pooled meta-analysis. It doesn’t mean [anthracyclines] are not effective, but they don’t add a clear incremental benefit,” said Slamon.

Commenting on the role of anthracyclines, Dr. Litton said that this trial result is not yet a reason to not use anthracyclines, partly because the BETH trial had almost 50% of patients enrolled as stage I patients, which is different than previous trials. “This will be an ongoing debate.”

This study did not directly address the question of whether docetaxel plus carboplatin can replace anthracyclines in adjuvant therapy for HER2-positive breast cancer patients, said Lisa Carey, MD, medical director of the University of North Carolina Breast Center and oncologist at the Lineberger Comprehensive Cancer Center in Chapel Hill, North Carolina. Carey, who was not involved in the BETH study, does not believe that this result should facilitiate a switch from anthracycline-based to docetaxel/carbolatin–based adjuvant therapy.

“There are no data at this point supporting the use of bevacizumab in early breast cancer,” said Carey.

This is the fourth study (along with BCIRG 006, TRYPHAENA, and TRIO-B07) to provide information on the DFS rate and safety of the docetaxel, carboplatin, and trastuzumab regimen in early HER2-positive breast cancer patients, Hurvitz noted. Compared with the anthracycline/trastuzumab regimen, the docetaxel, carboplatin, and trastuzumab combination used in the trial "is a less toxic regimen and appears to be equally effective," said Hurvitz. "I use it as standard of care in my patients."