The addition of bevacizumab (Avastin) to standard adjuvant therapy for HER2-positive breast cancer failed to improve invasive disease-free survival (iDFS) in a randomized clinical trial.
Patients treated with chemotherapy plus trastuzumab (Herceptin) had 92% iDFS with or without the bevacizumab. Subgroup analysis did not identify any group of patients that benefited from the addition of the angiogenesis inhibitor.
Added to negative outcomes in several other studies, the results could spell the end of clinical investigation of anti-angiogenesis inhibitors in breast cancer, Dennis Slamon, MD, PhD, of the University of California Los Angeles, said here at the San Antonio Breast Cancer Symposium.
"All these anti-angiogenic strategies have really not impacted survival in breast cancer," said Slamon. "There may still be something there if we were able to find the right markers, but, so far, they have all come out negative for any impressive survival advantage.
"The challenge in terms of the safety issues is that if you're not getting a lot of benefit and you're adding safety concerns, you have to wonder whether it's going to be worthwhile pursuing that much further. Unless there is a new drug or new strategy to define the subgroup, I think this is not going anywhere."
Slamon reported findings from the multicenter BETH trial (Bevacizumab and Trastuzumab in HER2-Positive Breast Cancer). The study involved 3,500 patients with early-stage HER2-positive, node-positive breast cancer or high-risk node-negative disease.
Patients received either non-anthracycline or anthracycline-containing chemotherapy and trastuzumab and were randomized to bevacizumab or no additional therapy. The primary endpoint was iDFS, and secondary endpoints included DFS, overall survival, recurrence-free interval, distant recurrence-free interval, and toxicity.
The patients had a median age of 51, almost half were node negative, half had tumors ≤2 cm, and 59% were hormone-receptor positive.
When the trial ended after a median follow-up of 33 months, it had not met the primary endpoint. Overall survival was 96% to 97% in both treatment groups. Analysis of iDFS according to chemotherapy regimen showed no difference between groups.
The addition of bevacizumab increased the toxicity burden. Patients treated with bevacizumab had a 27% incidence of grade 3/4 adverse events of interest, as compared with 8% in patients who did not receive the angiogenesis inhibitor.
The bevacizumab group had significantly higher rates of hypertension (19% versus 4%, P<0.0001), bleeding (2% versus <1%, P<0.0001), heart failure (2.1% versus <1%, P=0.021), proteinuria (21 cases versus 1, P<0.0001), and gastrointestinal perforation (11 cases versus 1, P<0.031).
Slamon showed results from previous studies to emphasize the progress in breast cancer survival. With surgery alone, long-term DFS was 26%. The introduction of adjuvant therapy increased DFS to 32%, and anthracyline-based therapy added another 4%.
With the introduction of the taxanes, DFS increased to 62%, and then to 67% with dose-dense therapy and 84% with the introduction of targeted therapy. The BETH trial demonstrated iDFS of 92% in both groups.
"We have very little room at the top to think about new strategies for those patients who are not getting the benefit that we had hoped they would with targeted therapy," said Slamon.
The results leave little doubt that angiogenesis inhibitors do not have a role in breast cancer -- HER2-positive disease in this case, said Jennifer Litton, MD, of the University of Texas MD Anderson Cancer Center in Houston.
"This study asked a question that has been ongoing for several years: Whether anti-angiogenesis -- and specifically bevacizumab in this case -- is going to add anything to the current treatment strategies," said Litton, who was not involved in the study. "I feel that Dr. Slamon and his group have definitively answered this in the HER2 question. Bevacizumab adds really significant toxicity and no benefit."
The BETH trial was sponsored by the National Surgical Adjuvant Breast and Bowel Project, the Cancer International Research Group, Hoffmann-LaRoche, and Genentech.
Slamon reported no relevant disclosures.
Source: San Antonio Breast Cancer Symposium
Reference: Slamon D, et al "BETH: A randomized phase III study evaluating adjuvant bevacizumab added to trastuzumab/chemotherapy for treatment of HER2+ early breast cancer" SABCS 2013; Abstract S1-03.
Citation: "Avastin Misses Mark Again in Breast Cancer" MedPage Today December 11, 2013
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