Final overall survival results and effect of prolonged (≥1 year) first-line bevacizumab-containing therapy for metastatic breast cancer in the ATHENA trial

Abstract

The ATHENA study expanded on the safety and efficacy data derived from first-line trials of bevacizumab combined with standard chemotherapy for locally recurrent/metastatic breast cancer (LR/mBC). In ATHENA, 2,264 patients received first-line bevacizumab-containing therapy in routine oncology practice. Overall survival (OS) data are now mature; additional analyses from this large data set can provide insights into treatment duration and the effect of prolonged bevacizumab exposure, where data are currently limited. Patients with HER2-negative LR/mBC received first-line bevacizumab with standard chemotherapy until disease progression, unacceptable toxicity, or physician/patient decision. We performed subgroup analyses on data from patients treated for ≥12 months and those who continued single-agent bevacizumab after stopping chemotherapy. After median follow-up of 20.1 months, median OS was 25.2 months (95% confidence interval [CI] 24.0-26.3 months) in the entire population. Median OS was 30.0 months (95% CI 28.5-32.7 months) in 1,205 patients who continued bevacizumab after discontinuation of chemotherapy and 18.4 months (95% CI 17.2-19.7 months) in 1,058 patients who discontinued bevacizumab before or at the same time as stopping chemotherapy. Bevacizumab treatment was continued for ≥12 months in 473 patients (21%). In most, bevacizumab was administered as monotherapy for extended periods after stopping chemotherapy. In the subgroup of patients treated for ≥12 months, the median time to onset of grade 3-5 adverse events was 5.0 months. There was no evidence that first onset of adverse events of special interest, except for proteinuria, was more common in later than earlier cycles. No relationship was detected between development of hypertension and OS. Findings from these analyses suggest that patients with LR/mBC can receive bevacizumab for prolonged periods without major toxicity or progression of disease. In the absence of progression, continuation of single-agent bevacizumab appears to be a reasonable approach, with minimal toxicity and the possibility of long-term disease control.

Use of Bevacizumab as a First-Line Treatment for Metastatic Breast Cancer

“…Hypertension seems to be an early adverse event, typically observed during the first year of treatment 46 . However, in our experience, hypertension is also likely to occur over the long term in treated patients, and in comparing earlier cycles with later cycles, the athena study demonstrated no difference in the first onset of hypertension 40 . Blood pressure should be monitored regularly during bevacizumab treatment.…”

“…More frequently, its presence in association with other indications, such as ovarian cancer, can be explained by a longer duration of bevacizumab treatment in those settings. In the athena study, the first onset of grade 3 or 4 proteinuria was consistently more frequent after 1 year of figure 4 Grade 3 or greater adverse events (aes) treatment than during the 1st year 40 . To monitor proteinuria in patients undergoing treatment with bevacizumab, a dipstick urinalysis is recommended every 3-4 weeks.…”

“…On the contrary, long-term treatment with bevacizumab seems to improve survival outcomes in the clinical setting a,b . In the athena observational study, median os was 30 months (95% ci: 28.5 to 32.7 months) in patients who continued treatment with bevacizumab after discontinuation of chemotherapy (n = 1205); those who discontinued bevacizumab at the same time as chemotherapy (n = 1058) experienced reduced os (median: 18.4 months; 95% ci: 17.2 to 19.7 months) 40 . More recently, the lorena study found that long-term treatment with bevacizumab (>15 months) was significantly associated with longer pfs 41 .…”

“…In clinical practice, long-term treatment does not seem to increase the risk of adverse events 40 . In the athena observational study, a higher incidence of grades 3-5 adverse events was initially observed among patients treated for more than 1 year (65.8% vs. 57.6% in the overall population), but after accounting for the varied durations of treatment exposure, the mean number of such adverse events was lower for patients treated for more than 1 year (1.26 events per treatment-year) than for those treated for less than 1 year (4.13 events per treatment-year) 40 .…”

Pre-Existing Antihypertensive Treatment Predicts Early Increase in Blood Pressure during Bevacizumab Therapy: The Prospective AVALUE Cohort Study

“…However, there is considerable ongoing debate as to whether there are risk factors for the development of hypertension in patients receiving anti-VEGF-A therapy and whether hypertension during bevacizumab treatment might predict response. Some studies have shown no correlation between the development of hypertension and overall survival [6], while others have demonstrated early hypertension with bevacizumab therapy to predict a favorable response [7]. To date, the predictive role of hypertension during anti-VEGF therapy is still under scientific debate.…”