Maura N Dickler1, William T Barry2, Constance T Cirrincione2, Matthew J Ellis2, Mary Ellen Moynahan2, Federico Innocenti2, Arti Hurria2, Hope S Rugo2, Diana E Lake2, Olwen Hahn2, Bryan P Schneider2, Debasish Tripathy2, Lisa A Carey2, Eric P Winer2, Clifford A Hudis2. 1. Maura N. Dickler, Mary Ellen Moynahan, Diana E. Lake, and Clifford A. Hudis, Memorial Sloan Kettering Cancer Center, New York, NY; William T. Barry, Dana-Farber Cancer Institute; Eric P. Winer, Dana-Farber/Partners Cancer Care, Boston, MA; Constance T. Cirrincione, Duke University, Durham, NC; Matthew J. Ellis, Baylor College of Medicine; Debasish Tripathy, The University of Texas MD Anderson Cancer Center, Houston, TX; Federico Innocenti and Lisa A. Carey, University of North Carolina at Chapel Hill, Chapel Hill, NC; Arti Hurria, City of Hope, Duarte; Hope S. Rugo, University of California at San Francisco, San Francisco, CA; Olwen Hahn, Alliance for Clinical Trials in Oncology, Chicago, IL; and Bryan P. Schneider, Indiana University School of Medicine, Indianapolis, IN. dicklerm@mskcc.org. 2. Maura N. Dickler, Mary Ellen Moynahan, Diana E. Lake, and Clifford A. Hudis, Memorial Sloan Kettering Cancer Center, New York, NY; William T. Barry, Dana-Farber Cancer Institute; Eric P. Winer, Dana-Farber/Partners Cancer Care, Boston, MA; Constance T. Cirrincione, Duke University, Durham, NC; Matthew J. Ellis, Baylor College of Medicine; Debasish Tripathy, The University of Texas MD Anderson Cancer Center, Houston, TX; Federico Innocenti and Lisa A. Carey, University of North Carolina at Chapel Hill, Chapel Hill, NC; Arti Hurria, City of Hope, Duarte; Hope S. Rugo, University of California at San Francisco, San Francisco, CA; Olwen Hahn, Alliance for Clinical Trials in Oncology, Chicago, IL; and Bryan P. Schneider, Indiana University School of Medicine, Indianapolis, IN.
Abstract
PURPOSE: To investigate whether anti-vascular endothelial growth factor therapy with bevacizumab prolongs progression-free survival (PFS) when added to first-line letrozole as treatment of hormone receptor-positive metastatic breast cancer (MBC). PATIENTS AND METHODS: Women with hormone receptor-positive MBC were randomly assigned 1:1 in a multicenter, open-label, phase III trial of letrozole (2.5 mg orally per day) with or without bevacizumab (15 mg/kg intravenously once every 3 weeks) within strata defined by measurable disease and disease-free interval. This trial had 90% power to detect a 50% improvement in median PFS from 6 to 9 months. Using a one-sided α = .025, a target sample size of 352 patients was planned. RESULTS:From May 2008 to November 2011, 350 women were recruited; 343 received treatment and were observed for efficacy and safety. Median age was 58 years (range, 25 to 87 years). Sixty-two percent had measurable disease, and 45% had de novo MBC. At a median follow-up of 39 months, the addition of bevacizumab resulted in a significant reduction in the hazard of progression (hazard ratio, 0.75; 95% CI, 0.59 to 0.96; P = .016) and a prolongation in median PFS from 15.6 months with letrozole to 20.2 months with letrozole plus bevacizumab. There was no significant difference in overall survival (hazard ratio, 0.87; 95% CI, 0.65 to 1.18; P = .188), with median overall survival of 43.9 months with letrozole versus 47.2 months with letrozole plus bevacizumab. The largest increases in incidence of grade 3 to 4 treatment-related toxicities with the addition of bevacizumab were hypertension (24% v 2%) and proteinuria (11% v 0%). CONCLUSION: The addition of bevacizumab to letrozole improved PFS in hormone receptor-positive MBC, but this benefit was associated with a markedly increased risk of grade 3 to 4 toxicities. Research on predictive markers will be required to clarify the role of bevacizumab in this setting.
RCT Entities:
PURPOSE: To investigate whether anti-vascular endothelial growth factor therapy with bevacizumab prolongs progression-free survival (PFS) when added to first-line letrozole as treatment of hormone receptor-positive metastatic breast cancer (MBC). PATIENTS AND METHODS: Women with hormone receptor-positive MBC were randomly assigned 1:1 in a multicenter, open-label, phase III trial of letrozole (2.5 mg orally per day) with or without bevacizumab (15 mg/kg intravenously once every 3 weeks) within strata defined by measurable disease and disease-free interval. This trial had 90% power to detect a 50% improvement in median PFS from 6 to 9 months. Using a one-sided α = .025, a target sample size of 352 patients was planned. RESULTS: From May 2008 to November 2011, 350 women were recruited; 343 received treatment and were observed for efficacy and safety. Median age was 58 years (range, 25 to 87 years). Sixty-two percent had measurable disease, and 45% had de novo MBC. At a median follow-up of 39 months, the addition of bevacizumab resulted in a significant reduction in the hazard of progression (hazard ratio, 0.75; 95% CI, 0.59 to 0.96; P = .016) and a prolongation in median PFS from 15.6 months with letrozole to 20.2 months with letrozole plus bevacizumab. There was no significant difference in overall survival (hazard ratio, 0.87; 95% CI, 0.65 to 1.18; P = .188), with median overall survival of 43.9 months with letrozole versus 47.2 months with letrozole plus bevacizumab. The largest increases in incidence of grade 3 to 4 treatment-related toxicities with the addition of bevacizumab were hypertension (24% v 2%) and proteinuria (11% v 0%). CONCLUSION: The addition of bevacizumab to letrozole improved PFS in hormone receptor-positive MBC, but this benefit was associated with a markedly increased risk of grade 3 to 4 toxicities. Research on predictive markers will be required to clarify the role of bevacizumab in this setting.
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