Adding bevacizumab to endocrine therapy as first-line therapy for women with advanced breast cancer does not impact survival
The first-efficacy results of the phase III LEA study failed to demonstrate a statistically significant increase in progression-free survival (PFS) for endocrine therapy (ET) plus bevacizumab compared with ET alone as first-line therapy for women with ER+/HER2- metastatic breast cancer.
Preclinical and retrospective clinical data suggest that high vascular endothelial growth factor (VEGF) levels in breast tumors are associated with a decreased response to ET. Furthermore, clinical data suggest that downregulation of VEGF may overcome resistance to ET and improve efficacy. This formed the rationale for the design of the phase III LEA study evaluating the safety and efficacy of first-line bevacizumab in combination with ET in endocrine responsive advanced breast cancer patients. In the LEA study, a total of 380 patients with unresectable ER+/HER2- locally advanced or metastatic breast cancer were randomized between ET alone (letrozole [91.6%] or fulvestrant [8.4%]) or ET (letrozole [89%] or fulvestrant [11%]) plus bevacizumab. The primary endpoint of the study was PFS, while secondary objectives included overall survival (OS), time to treatment failure, overall response rate (ORR) and safety.
The median PFS for patients receiving ET plus bevacizumab was 18.4 months and did not differ significantly from the 13.4 months observed for patients treated with ET alone (HR[95%CI]: 0.83[0.65-1.06]; p= 0.14). With respect to OS, a similar survival was observed for both treatment arms (42 months for ET alone vs. 41 months for ET plus bevacizumab; HR[95%CI]: 1.18[0.77-1.81]; p=0.47). The main side effects (any grade, per patient, ET + bevacizumab vs. ET) observed in the LEA study were anemia (98% vs. 100%), fatigue (50% vs. 29%), hemorrhage (19% vs. 2%), hypertension (59% vs. 16%), proteinuria (30.3% vs. 2.8%) and thrombosis (2.1% vs. 0.6%).
As such, the LEA trial failed to demonstrate a statistically significant increase in PFS by adding bevacizumab to ET in the first-line treatment of ER+/HER2- advanced breast cancer. Of note, the PFS observed in the control arm of this study was relatively high which has certainly influenced the statistics of the trials. Therefore, a small beneficial effect on PFS of adding bevacizumab to ET cannot be ruled out. With respect to OS, no effect was seen by the addition of bevacizumab. Currently, biomarker studies are underway to select subgroups of patients that might benefit from VEGF inhibition in addition to ET.
M. Martin, S. Loibl, G. von Minckwitz et al.Phase III trial evaluating the addition of bevacizumab to endocrine therapy as first-line treatment for advanced breast cancer – First efficacy results from the LEA study. Presented at SABCS 2012; Abstract S1-7.