Neoadjuvant plus adjuvant bevacizumab in early breast cancer (NSABP B-40 [NRG Oncology]): Secondary outcomes of a phase 3, randomised controlled trial

Harry D. Bear, Gong Tang, Priya Rastogi, Charles E. Geyer, Qing Liu, André Robidoux, Luis Baez-Diaz, Adam M. Brufsky, Rita S. Mehta, Louis Fehrenbacher, James A. Young, Francis M. Senecal, Rakesh Gaur, Richard G. Margolese, Paul T. Adams, Howard M. Gross, Joseph P. Costantino, Soonmyung Paik, Sandra M. Swain, Eleftherios P. MamounasNorman Wolmark

Research output: Contribution to journalArticle

82 Citations (Scopus)

Abstract

Background: NSABP B-40 was a 3×2 factorial trial testing whether adding capecitabine or gemcitabine to docetaxel followed by doxorubicin plus cyclophosphamide neoadjuvant chemotherapy would improve outcomes in women with operable, HER2-negative breast cancer and whether adding neoadjuvant plus adjuvant bevacizumab to neoadjuvant chemotherapy regimens would also improve outcomes. As reported previously, addition of neoadjuvant bevacizumab increased the proportion of patients achieving a pathological complete response, which was the primary endpoint. We present secondary patient outcomes, including disease-free survival, a specified endpoint by protocol, and data for distant recurrence-free interval, and overall survival, which were not prespecified endpoints but were collected prospectively. Methods: In this randomised controlled trial (NSABP B-40), we enrolled women aged 18 years or older, with operable, HER2-non-amplified invasive adenocarcinoma of the breast, 2 cm or greater in diameter by palpation, clinical stage T1c-3, cN0, cN1, or cN2a, without metastatic disease and diagnosed by core needle biopsy. Patients received one of three docetaxel-based neoadjuvant regimens for four cycles: docetaxel alone (100 mg/m<sup>2</sup>) with addition of capecitabine (825 mg/m<sup>2</sup> oral twice daily days 1-14, 75 mg/m<sup>2</sup> docetaxel) or with addition of gemcitabine (1000 mg/m<sup>2</sup> days 1 and 8 intravenously, 75 mg/m<sup>2</sup> docetaxel), all followed by neoadjuvant doxorubicin and cyclophosphamide (60 mg/m<sup>2</sup> and 600 mg/m<sup>2</sup> intravenously) every 3 weeks for four cycles. Those randomly assigned to bevacizumab groups were to receive bevacizumab (15 mg/kg, every 3 weeks for six cycles) with neoadjuvant chemotherapy and postoperatively for ten doses. Randomisation was done (1:1:1:1:1:1) via a biased-coin minimisation procedure to balance the characteristics with respect to clinical nodal status, clinical tumour size, hormone receptor status, and age. Intent-to-treat analyses were done for disease-free survival and overall survival. This study is registered with ClinicalTrials.gov, number NCT00408408. Findings: Between Jan 5, 2007, and June 30, 2010, 1206 patients were enrolled in the study. Follow-up data were collected from Oct 31, 2007 to March 27, 2014, and were available for overall survival in 1186 patients, disease-free survival in 1184, and distant recurrence-free interval in 1181. Neither capecitabine nor gemcitabine increased disease-free survival or overall survival. Median follow-up was 4·7 years (IQR 4·0-5·2). The addition of bevacizumab significantly increased overall survival (hazard ratio 0·65 [95% CI 0·49-0·88]; p=0·004) but did not significantly increase disease-free survival (0·80 [0·63-1·01]; p=0·06). Four deaths occurred on treatment due to vascular disorder (docetaxel plus capecitabine followed by doxorubicin plus cyclophosphamide group), sudden death (docetaxel plus capecitabine followed by doxorubicin plus cyclophosphamide group), infective endocarditis (docetaxel plus bevacizumab followed by doxorubicin plus cyclophosphamide and bevacizumab group), and visceral arterial ischaemia (docetaxel followed by doxorubicin plus cyclophosphamide group). The most common grade 3-4 adverse events in the bevacizumab group were neutropenia (grade 3, 99 [17%]; grade 4, 37 [6%]), hand-foot syndrome (grade 3, 63 [11%]), and hypertension (grade 3, 60 [10%]; grade 4, two [<1%]) and in the non-bevacizumab group were neutropenia (grade 3, 98 [16%]; grade 4, 36 [6%]), fatigue (grade 3, 53 [9%]), and hand-foot syndrome (grade 3, 43 [7%]). Interpretation: The addition of gemcitabine or capecitabine to neoadjuvant docetaxel plus doxorubicin plus cyclophosphamide does not seem to provide any benefit to patients with operable breast cancer, and should not change clinical practice in the short term. The improved overall survival with bevacizumab contradicts the findings of other studies of bevacizumab in breast cancer and may indicate the need for additional investigation of this agent. Funding: National Institutes of Health, Genentech, Roche Laboratories, Lilly Research Laboratories, and Precision Therapeutics.

Original languageEnglish (US)
Article number44
Pages (from-to)1037-1048
Number of pages12
JournalThe Lancet Oncology
Volume16
Issue number9
DOIs
StatePublished - Sep 1 2015

Fingerprint

docetaxel
gemcitabine
Randomized Controlled Trials
Breast Neoplasms
Doxorubicin
Cyclophosphamide
Disease-Free Survival
Survival
Hand-Foot Syndrome
Neutropenia
Drug Therapy
Bevacizumab
Large-Core Needle Biopsy
Recurrence
Numismatics
Palpation
National Institutes of Health (U.S.)

ASJC Scopus subject areas

  • Oncology

Cite this

Neoadjuvant plus adjuvant bevacizumab in early breast cancer (NSABP B-40 [NRG Oncology]) : Secondary outcomes of a phase 3, randomised controlled trial. / Bear, Harry D.; Tang, Gong; Rastogi, Priya; Geyer, Charles E.; Liu, Qing; Robidoux, André; Baez-Diaz, Luis; Brufsky, Adam M.; Mehta, Rita S.; Fehrenbacher, Louis; Young, James A.; Senecal, Francis M.; Gaur, Rakesh; Margolese, Richard G.; Adams, Paul T.; Gross, Howard M.; Costantino, Joseph P.; Paik, Soonmyung; Swain, Sandra M.; Mamounas, Eleftherios P.; Wolmark, Norman.

In: The Lancet Oncology, Vol. 16, No. 9, 44, 01.09.2015, p. 1037-1048.

Research output: Contribution to journalArticle

Bear, HD, Tang, G, Rastogi, P, Geyer, CE, Liu, Q, Robidoux, A, Baez-Diaz, L, Brufsky, AM, Mehta, RS, Fehrenbacher, L, Young, JA, Senecal, FM, Gaur, R, Margolese, RG, Adams, PT, Gross, HM, Costantino, JP, Paik, S, Swain, SM, Mamounas, EP & Wolmark, N 2015, 'Neoadjuvant plus adjuvant bevacizumab in early breast cancer (NSABP B-40 [NRG Oncology]): Secondary outcomes of a phase 3, randomised controlled trial', The Lancet Oncology, vol. 16, no. 9, 44, pp. 1037-1048. https://doi.org/10.1016/S1470-2045(15)00041-8
Bear, Harry D. ; Tang, Gong ; Rastogi, Priya ; Geyer, Charles E. ; Liu, Qing ; Robidoux, André ; Baez-Diaz, Luis ; Brufsky, Adam M. ; Mehta, Rita S. ; Fehrenbacher, Louis ; Young, James A. ; Senecal, Francis M. ; Gaur, Rakesh ; Margolese, Richard G. ; Adams, Paul T. ; Gross, Howard M. ; Costantino, Joseph P. ; Paik, Soonmyung ; Swain, Sandra M. ; Mamounas, Eleftherios P. ; Wolmark, Norman. / Neoadjuvant plus adjuvant bevacizumab in early breast cancer (NSABP B-40 [NRG Oncology]) : Secondary outcomes of a phase 3, randomised controlled trial. In: The Lancet Oncology. 2015 ; Vol. 16, No. 9. pp. 1037-1048.
@article{17e82d29c47d48a2bd100d70abbeb553,
title = "Neoadjuvant plus adjuvant bevacizumab in early breast cancer (NSABP B-40 [NRG Oncology]): Secondary outcomes of a phase 3, randomised controlled trial",
abstract = "Background: NSABP B-40 was a 3×2 factorial trial testing whether adding capecitabine or gemcitabine to docetaxel followed by doxorubicin plus cyclophosphamide neoadjuvant chemotherapy would improve outcomes in women with operable, HER2-negative breast cancer and whether adding neoadjuvant plus adjuvant bevacizumab to neoadjuvant chemotherapy regimens would also improve outcomes. As reported previously, addition of neoadjuvant bevacizumab increased the proportion of patients achieving a pathological complete response, which was the primary endpoint. We present secondary patient outcomes, including disease-free survival, a specified endpoint by protocol, and data for distant recurrence-free interval, and overall survival, which were not prespecified endpoints but were collected prospectively. Methods: In this randomised controlled trial (NSABP B-40), we enrolled women aged 18 years or older, with operable, HER2-non-amplified invasive adenocarcinoma of the breast, 2 cm or greater in diameter by palpation, clinical stage T1c-3, cN0, cN1, or cN2a, without metastatic disease and diagnosed by core needle biopsy. Patients received one of three docetaxel-based neoadjuvant regimens for four cycles: docetaxel alone (100 mg/m2) with addition of capecitabine (825 mg/m2 oral twice daily days 1-14, 75 mg/m2 docetaxel) or with addition of gemcitabine (1000 mg/m2 days 1 and 8 intravenously, 75 mg/m2 docetaxel), all followed by neoadjuvant doxorubicin and cyclophosphamide (60 mg/m2 and 600 mg/m2 intravenously) every 3 weeks for four cycles. Those randomly assigned to bevacizumab groups were to receive bevacizumab (15 mg/kg, every 3 weeks for six cycles) with neoadjuvant chemotherapy and postoperatively for ten doses. Randomisation was done (1:1:1:1:1:1) via a biased-coin minimisation procedure to balance the characteristics with respect to clinical nodal status, clinical tumour size, hormone receptor status, and age. Intent-to-treat analyses were done for disease-free survival and overall survival. This study is registered with ClinicalTrials.gov, number NCT00408408. Findings: Between Jan 5, 2007, and June 30, 2010, 1206 patients were enrolled in the study. Follow-up data were collected from Oct 31, 2007 to March 27, 2014, and were available for overall survival in 1186 patients, disease-free survival in 1184, and distant recurrence-free interval in 1181. Neither capecitabine nor gemcitabine increased disease-free survival or overall survival. Median follow-up was 4·7 years (IQR 4·0-5·2). The addition of bevacizumab significantly increased overall survival (hazard ratio 0·65 [95{\%} CI 0·49-0·88]; p=0·004) but did not significantly increase disease-free survival (0·80 [0·63-1·01]; p=0·06). Four deaths occurred on treatment due to vascular disorder (docetaxel plus capecitabine followed by doxorubicin plus cyclophosphamide group), sudden death (docetaxel plus capecitabine followed by doxorubicin plus cyclophosphamide group), infective endocarditis (docetaxel plus bevacizumab followed by doxorubicin plus cyclophosphamide and bevacizumab group), and visceral arterial ischaemia (docetaxel followed by doxorubicin plus cyclophosphamide group). The most common grade 3-4 adverse events in the bevacizumab group were neutropenia (grade 3, 99 [17{\%}]; grade 4, 37 [6{\%}]), hand-foot syndrome (grade 3, 63 [11{\%}]), and hypertension (grade 3, 60 [10{\%}]; grade 4, two [<1{\%}]) and in the non-bevacizumab group were neutropenia (grade 3, 98 [16{\%}]; grade 4, 36 [6{\%}]), fatigue (grade 3, 53 [9{\%}]), and hand-foot syndrome (grade 3, 43 [7{\%}]). Interpretation: The addition of gemcitabine or capecitabine to neoadjuvant docetaxel plus doxorubicin plus cyclophosphamide does not seem to provide any benefit to patients with operable breast cancer, and should not change clinical practice in the short term. The improved overall survival with bevacizumab contradicts the findings of other studies of bevacizumab in breast cancer and may indicate the need for additional investigation of this agent. Funding: National Institutes of Health, Genentech, Roche Laboratories, Lilly Research Laboratories, and Precision Therapeutics.",
author = "Bear, {Harry D.} and Gong Tang and Priya Rastogi and Geyer, {Charles E.} and Qing Liu and Andr{\'e} Robidoux and Luis Baez-Diaz and Brufsky, {Adam M.} and Mehta, {Rita S.} and Louis Fehrenbacher and Young, {James A.} and Senecal, {Francis M.} and Rakesh Gaur and Margolese, {Richard G.} and Adams, {Paul T.} and Gross, {Howard M.} and Costantino, {Joseph P.} and Soonmyung Paik and Swain, {Sandra M.} and Mamounas, {Eleftherios P.} and Norman Wolmark",
year = "2015",
month = "9",
day = "1",
doi = "10.1016/S1470-2045(15)00041-8",
language = "English (US)",
volume = "16",
pages = "1037--1048",
journal = "The Lancet Oncology",
issn = "1470-2045",
publisher = "Lancet Publishing Group",
number = "9",

}

TY - JOUR

T1 - Neoadjuvant plus adjuvant bevacizumab in early breast cancer (NSABP B-40 [NRG Oncology])

T2 - Secondary outcomes of a phase 3, randomised controlled trial

AU - Bear, Harry D.

AU - Tang, Gong

AU - Rastogi, Priya

AU - Geyer, Charles E.

AU - Liu, Qing

AU - Robidoux, André

AU - Baez-Diaz, Luis

AU - Brufsky, Adam M.

AU - Mehta, Rita S.

AU - Fehrenbacher, Louis

AU - Young, James A.

AU - Senecal, Francis M.

AU - Gaur, Rakesh

AU - Margolese, Richard G.

AU - Adams, Paul T.

AU - Gross, Howard M.

AU - Costantino, Joseph P.

AU - Paik, Soonmyung

AU - Swain, Sandra M.

AU - Mamounas, Eleftherios P.

AU - Wolmark, Norman

PY - 2015/9/1

Y1 - 2015/9/1

N2 - Background: NSABP B-40 was a 3×2 factorial trial testing whether adding capecitabine or gemcitabine to docetaxel followed by doxorubicin plus cyclophosphamide neoadjuvant chemotherapy would improve outcomes in women with operable, HER2-negative breast cancer and whether adding neoadjuvant plus adjuvant bevacizumab to neoadjuvant chemotherapy regimens would also improve outcomes. As reported previously, addition of neoadjuvant bevacizumab increased the proportion of patients achieving a pathological complete response, which was the primary endpoint. We present secondary patient outcomes, including disease-free survival, a specified endpoint by protocol, and data for distant recurrence-free interval, and overall survival, which were not prespecified endpoints but were collected prospectively. Methods: In this randomised controlled trial (NSABP B-40), we enrolled women aged 18 years or older, with operable, HER2-non-amplified invasive adenocarcinoma of the breast, 2 cm or greater in diameter by palpation, clinical stage T1c-3, cN0, cN1, or cN2a, without metastatic disease and diagnosed by core needle biopsy. Patients received one of three docetaxel-based neoadjuvant regimens for four cycles: docetaxel alone (100 mg/m2) with addition of capecitabine (825 mg/m2 oral twice daily days 1-14, 75 mg/m2 docetaxel) or with addition of gemcitabine (1000 mg/m2 days 1 and 8 intravenously, 75 mg/m2 docetaxel), all followed by neoadjuvant doxorubicin and cyclophosphamide (60 mg/m2 and 600 mg/m2 intravenously) every 3 weeks for four cycles. Those randomly assigned to bevacizumab groups were to receive bevacizumab (15 mg/kg, every 3 weeks for six cycles) with neoadjuvant chemotherapy and postoperatively for ten doses. Randomisation was done (1:1:1:1:1:1) via a biased-coin minimisation procedure to balance the characteristics with respect to clinical nodal status, clinical tumour size, hormone receptor status, and age. Intent-to-treat analyses were done for disease-free survival and overall survival. This study is registered with ClinicalTrials.gov, number NCT00408408. Findings: Between Jan 5, 2007, and June 30, 2010, 1206 patients were enrolled in the study. Follow-up data were collected from Oct 31, 2007 to March 27, 2014, and were available for overall survival in 1186 patients, disease-free survival in 1184, and distant recurrence-free interval in 1181. Neither capecitabine nor gemcitabine increased disease-free survival or overall survival. Median follow-up was 4·7 years (IQR 4·0-5·2). The addition of bevacizumab significantly increased overall survival (hazard ratio 0·65 [95% CI 0·49-0·88]; p=0·004) but did not significantly increase disease-free survival (0·80 [0·63-1·01]; p=0·06). Four deaths occurred on treatment due to vascular disorder (docetaxel plus capecitabine followed by doxorubicin plus cyclophosphamide group), sudden death (docetaxel plus capecitabine followed by doxorubicin plus cyclophosphamide group), infective endocarditis (docetaxel plus bevacizumab followed by doxorubicin plus cyclophosphamide and bevacizumab group), and visceral arterial ischaemia (docetaxel followed by doxorubicin plus cyclophosphamide group). The most common grade 3-4 adverse events in the bevacizumab group were neutropenia (grade 3, 99 [17%]; grade 4, 37 [6%]), hand-foot syndrome (grade 3, 63 [11%]), and hypertension (grade 3, 60 [10%]; grade 4, two [<1%]) and in the non-bevacizumab group were neutropenia (grade 3, 98 [16%]; grade 4, 36 [6%]), fatigue (grade 3, 53 [9%]), and hand-foot syndrome (grade 3, 43 [7%]). Interpretation: The addition of gemcitabine or capecitabine to neoadjuvant docetaxel plus doxorubicin plus cyclophosphamide does not seem to provide any benefit to patients with operable breast cancer, and should not change clinical practice in the short term. The improved overall survival with bevacizumab contradicts the findings of other studies of bevacizumab in breast cancer and may indicate the need for additional investigation of this agent. Funding: National Institutes of Health, Genentech, Roche Laboratories, Lilly Research Laboratories, and Precision Therapeutics.

AB - Background: NSABP B-40 was a 3×2 factorial trial testing whether adding capecitabine or gemcitabine to docetaxel followed by doxorubicin plus cyclophosphamide neoadjuvant chemotherapy would improve outcomes in women with operable, HER2-negative breast cancer and whether adding neoadjuvant plus adjuvant bevacizumab to neoadjuvant chemotherapy regimens would also improve outcomes. As reported previously, addition of neoadjuvant bevacizumab increased the proportion of patients achieving a pathological complete response, which was the primary endpoint. We present secondary patient outcomes, including disease-free survival, a specified endpoint by protocol, and data for distant recurrence-free interval, and overall survival, which were not prespecified endpoints but were collected prospectively. Methods: In this randomised controlled trial (NSABP B-40), we enrolled women aged 18 years or older, with operable, HER2-non-amplified invasive adenocarcinoma of the breast, 2 cm or greater in diameter by palpation, clinical stage T1c-3, cN0, cN1, or cN2a, without metastatic disease and diagnosed by core needle biopsy. Patients received one of three docetaxel-based neoadjuvant regimens for four cycles: docetaxel alone (100 mg/m2) with addition of capecitabine (825 mg/m2 oral twice daily days 1-14, 75 mg/m2 docetaxel) or with addition of gemcitabine (1000 mg/m2 days 1 and 8 intravenously, 75 mg/m2 docetaxel), all followed by neoadjuvant doxorubicin and cyclophosphamide (60 mg/m2 and 600 mg/m2 intravenously) every 3 weeks for four cycles. Those randomly assigned to bevacizumab groups were to receive bevacizumab (15 mg/kg, every 3 weeks for six cycles) with neoadjuvant chemotherapy and postoperatively for ten doses. Randomisation was done (1:1:1:1:1:1) via a biased-coin minimisation procedure to balance the characteristics with respect to clinical nodal status, clinical tumour size, hormone receptor status, and age. Intent-to-treat analyses were done for disease-free survival and overall survival. This study is registered with ClinicalTrials.gov, number NCT00408408. Findings: Between Jan 5, 2007, and June 30, 2010, 1206 patients were enrolled in the study. Follow-up data were collected from Oct 31, 2007 to March 27, 2014, and were available for overall survival in 1186 patients, disease-free survival in 1184, and distant recurrence-free interval in 1181. Neither capecitabine nor gemcitabine increased disease-free survival or overall survival. Median follow-up was 4·7 years (IQR 4·0-5·2). The addition of bevacizumab significantly increased overall survival (hazard ratio 0·65 [95% CI 0·49-0·88]; p=0·004) but did not significantly increase disease-free survival (0·80 [0·63-1·01]; p=0·06). Four deaths occurred on treatment due to vascular disorder (docetaxel plus capecitabine followed by doxorubicin plus cyclophosphamide group), sudden death (docetaxel plus capecitabine followed by doxorubicin plus cyclophosphamide group), infective endocarditis (docetaxel plus bevacizumab followed by doxorubicin plus cyclophosphamide and bevacizumab group), and visceral arterial ischaemia (docetaxel followed by doxorubicin plus cyclophosphamide group). The most common grade 3-4 adverse events in the bevacizumab group were neutropenia (grade 3, 99 [17%]; grade 4, 37 [6%]), hand-foot syndrome (grade 3, 63 [11%]), and hypertension (grade 3, 60 [10%]; grade 4, two [<1%]) and in the non-bevacizumab group were neutropenia (grade 3, 98 [16%]; grade 4, 36 [6%]), fatigue (grade 3, 53 [9%]), and hand-foot syndrome (grade 3, 43 [7%]). Interpretation: The addition of gemcitabine or capecitabine to neoadjuvant docetaxel plus doxorubicin plus cyclophosphamide does not seem to provide any benefit to patients with operable breast cancer, and should not change clinical practice in the short term. The improved overall survival with bevacizumab contradicts the findings of other studies of bevacizumab in breast cancer and may indicate the need for additional investigation of this agent. Funding: National Institutes of Health, Genentech, Roche Laboratories, Lilly Research Laboratories, and Precision Therapeutics.

UR - http://www.scopus.com/inward/record.url?scp=84940606731&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84940606731&partnerID=8YFLogxK

U2 - 10.1016/S1470-2045(15)00041-8

DO - 10.1016/S1470-2045(15)00041-8

M3 - Article

C2 - 26272770

AN - SCOPUS:84940606731

VL - 16

SP - 1037

EP - 1048

JO - The Lancet Oncology

JF - The Lancet Oncology

SN - 1470-2045

IS - 9

M1 - 44

ER -