Phase III trial evaluating letrozole as first-line endocrine therapy with or without bevacizumab for the treatment of postmenopausal women with hormone receptor-positive advanced-stage breast cancer

CALGB 40503 (Alliance)

Maura N. Dickler, William T. Barry, Constance T. Cirrincione, Matthew J. Ellis, Mary Ellen Moynahan, Federico Innocenti, Arti Hurria, Hope S. Rugo, Diana E. Lake, Olwen Hahn, Bryan Schneider, Debasish Tripathy, Lisa A. Carey, Eric P. Winer, Clifford A. Hudis

Research output: Contribution to journalArticle

34 Citations (Scopus)

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, openlabel, 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.

Original languageEnglish (US)
Pages (from-to)2602-2609
Number of pages8
JournalJournal of Clinical Oncology
Volume34
Issue number22
DOIs
StatePublished - Aug 1 2016

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letrozole
Hormones
Breast Neoplasms
Disease-Free Survival
Therapeutics
Survival
Bevacizumab
Proteinuria

ASJC Scopus subject areas

  • Medicine(all)
  • Oncology
  • Cancer Research

Cite this

Phase III trial evaluating letrozole as first-line endocrine therapy with or without bevacizumab for the treatment of postmenopausal women with hormone receptor-positive advanced-stage breast cancer : CALGB 40503 (Alliance). / Dickler, Maura N.; Barry, William T.; Cirrincione, Constance T.; Ellis, Matthew J.; Moynahan, Mary Ellen; Innocenti, Federico; Hurria, Arti; Rugo, Hope S.; Lake, Diana E.; Hahn, Olwen; Schneider, Bryan; Tripathy, Debasish; Carey, Lisa A.; Winer, Eric P.; Hudis, Clifford A.

In: Journal of Clinical Oncology, Vol. 34, No. 22, 01.08.2016, p. 2602-2609.

Research output: Contribution to journalArticle

Dickler, MN, Barry, WT, Cirrincione, CT, Ellis, MJ, Moynahan, ME, Innocenti, F, Hurria, A, Rugo, HS, Lake, DE, Hahn, O, Schneider, B, Tripathy, D, Carey, LA, Winer, EP & Hudis, CA 2016, 'Phase III trial evaluating letrozole as first-line endocrine therapy with or without bevacizumab for the treatment of postmenopausal women with hormone receptor-positive advanced-stage breast cancer: CALGB 40503 (Alliance)', Journal of Clinical Oncology, vol. 34, no. 22, pp. 2602-2609. https://doi.org/10.1200/JCO.2015.66.1595
Dickler, Maura N. ; Barry, William T. ; Cirrincione, Constance T. ; Ellis, Matthew J. ; Moynahan, Mary Ellen ; Innocenti, Federico ; Hurria, Arti ; Rugo, Hope S. ; Lake, Diana E. ; Hahn, Olwen ; Schneider, Bryan ; Tripathy, Debasish ; Carey, Lisa A. ; Winer, Eric P. ; Hudis, Clifford A. / Phase III trial evaluating letrozole as first-line endocrine therapy with or without bevacizumab for the treatment of postmenopausal women with hormone receptor-positive advanced-stage breast cancer : CALGB 40503 (Alliance). In: Journal of Clinical Oncology. 2016 ; Vol. 34, No. 22. pp. 2602-2609.
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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, openlabel, 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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AU - Barry, William T.

AU - Cirrincione, Constance T.

AU - Ellis, Matthew J.

AU - Moynahan, Mary Ellen

AU - Innocenti, Federico

AU - Hurria, Arti

AU - Rugo, Hope S.

AU - Lake, Diana E.

AU - Hahn, Olwen

AU - Schneider, Bryan

AU - Tripathy, Debasish

AU - Carey, Lisa A.

AU - Winer, Eric P.

AU - Hudis, Clifford A.

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N2 - 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, openlabel, 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.

AB - 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, openlabel, 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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