Bevacizumab Bombs Again in the BETH Breast Cancer Study

Kate Johnson

December 12, 2013

SAN ANTONIO, Texas — Adding the antiangiogenic bevacizumab (Avastin, Genentech) to adjuvant chemotherapy plus trastuzumab (Herceptin, Genentech) had no effect on invasive disease-free survival (IDFS) in patients with breast cancer with HER2-positive disease, according to new study results.

The results, presented here at the 36th Annual San Antonio Breast Cancer Symposium (SABCS), are "about as negative as you can get in terms of outcome, in terms of bevacizumab adding anything," said Dennis Slamon, MD, PhD, 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 the UCLA Department of Medicine.

"This trial has, for me, put the bevacizumab question to rest," added session moderator Jennifer Litton, MD, associate professor in the Department of Breast Oncology at the University of Texas M.D. Anderson Cancer Center in Houston, in an interview with Medscape Medical News.

The BETH Study (Treatment of HER2 Positive Breast Cancer With Chemotherapy Plus Trastuzumab vs Chemotherapy Plus Trastuzumab Plus Bevacizumab) included 3509 women with HER2-positive breast cancer who were either node-positive or high-risk node-negative, with the latter group making up 41% of the population.

Patients were enrolled in 1 of 2 chemotherapy regimens: 6 cycles of docetaxel/carboplatin plus trastuzumab (TCH) with or without bevacizumab (n = 3231) or an anthracycline-based regimen involving 3 cycles of docetaxel plus trastuzumab given with or without bevacizumab followed by 3 cycles of 5-fluorouracil, epirubicin, and cyclophosphamide (n = 278).

In both regimens, patients continued trastuzumab with or without bevacizumab after chemotherapy to complete 1 year of targeted therapy.

For the primary outcome of the study, which was IDFS, there was no statistically significant difference between the patients who received bevacizumab and those who did not.

At a median follow-up of 38 months, IDFS rates were 92% for both groups of the TCH cohort (ie, those treated with or without bevacizumab)

A secondary endpoint compared IDFS in patients in the anthracycline-based vs the TCH-based cohorts and also found no significant differences between the regimens, whether with or without bevacizumab. However, the study was not designed to compare these different chemotherapy approaches, and thus these results must be interpreted with caution, acknowledged Dr. Slamon.

Although the trial had a negative finding for bevacizumab, the overall results "are among the best results we have seen to date in the adjuvant treatment of HER2-positive breast cancer," said Dr. Slamon, noting in a press conference that it was a surprise to see a 92% IDFS rate next to those of his previous Breast Cancer International Research Group 006 (BCIRG006) trial ( N Engl J Med. 2011;365:1273-1283), which showed an 86% IDFS rate at the 3-year mark. "We were struck by this improvement," he said, adding that the previous trial had a slightly smaller proportion of node-negative patients.

When broken down by node status, the BETH results showed an 88% 3-year disease-free survival rate among node-positive patients treated with or without bevacizumab and a 96% rate in node-negative patients.

Overall, BETH showed that the addition of bevacizumab did not add any efficacy "but clearly added a greater rate of serious adverse events," said Dr. Slamon.

In terms of all grade 3 or 4 adverse events of special interest, hypertension was much higher in the bevacizumab group (19% vs 4%; P < .001). "[T]his is an on-target known effect of antiangiogenic therapy, and we certainly saw it here," Dr. Slamon said.

There was also a trend for more congestive heart failure with bevacizumab (2.1% vs <1%; P = .0621), "and clearly a difference in bleeding" (2% vs <1%; P < .0001).

Proteinuria and gastrointestinal perforations were also more common in the bevacizumab group (1% vs <1% [P < .0001]; and 11 cases vs 1 case [P = .0031]).

"All of these antiangiogenic strategies have really not impacted survival," said Dr. Slamon. "The challenge in terms of safety issues is if you're not getting a lot of benefit and you're adding safety concerns, you have to wonder if it's going to be worthwhile pursuing it much further.... [U]nless there's a new drug or a new strategy to define a subgroup, I think this is not going anywhere."

On the basis of the BETH and BCIRG006 results, Dr. Slamon said there is no reason to consider the use of anthracyclines anymore, but Dr. Litton cautioned that the BETH results do not shed light on this issue.

"We shouldn't say all anthracyclines should go away," she said. Furthermore, she noted, "it's very important to understand that the BETH trial specifically asked the question whether bevacizumab adds anything, and the answer is quite clearly no. BETH was not a trial that was planned to compare anthracycline- vs nonanthracycline-based therapy and was not designed with any significant power to compare these 2 arms."

Gary Lyman, MD, who also heard Dr. Slamon's presentation, told Medscape Medical News that he agrees with Dr. Litton.

"For me, there are few surprises related to the primary objectives of the study; ie, no additional efficacy and considerably greater toxicity in this setting with the addition of bevacizumab," said Dr. Lyman, professor of medicine and director, Comparative Effectiveness and Outcomes Research Program, Duke University School of Medicine and Duke Cancer Institute, Durham, North Carolina.

The trial was clearly not designed to address the question related to anthracyclines. Thus, any conclusions related to the role of anthracycline vs nonanthracycline chemotherapy in this setting cannot be made, he added.

The study was sponsored by the National Surgical Adjuvant Breast and Bowel Project. Dr. Slamon has financial relationships with Novartis, Sanofi, and Amgen Inc. Dr. Litton has disclosed no relevant financial relationships.

36th Annual San Antonio Breast Cancer Symposium (SABCS): Abstract S1-03. Presented December 11, 2013.

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