A Meta-Analysis of Overall Survival Data from Three Trials of Bevacizumab and First-Line Chemotherapy as Treatment for Patients with Metastatic Breast Cancer Baylor-Sammons Cancer Center, Texas Oncology, US Oncology, Dallas, TX; Mount Vernon Cancer Centre, London, England; Dana-Farber Cancer Institute, Boston, MA; Institut Curie, Paris, France; Mayo Clinic, Jacksonville, Florida; Michiana Hematology Oncology, South Bend, IN; Vall d'Hebron University Hospital, Barcelona, Spain; BioOncology, Genentech, S San Francisco, CA; Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN Joyce O’Shaughnessy, David Miles, Robert Gray, Véronique Diéras, Edith A. Perez, Robin Zon, Javier Cortés, Xian Zhou, See-Chun Phan, Kathy Miller ASCO, 2010
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A Meta-Analysis of Overall Survival Data from Three Trials of Bevacizumab and First-Line Chemotherapy as Treatment for Patients with Metastatic Breast.
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A Meta-Analysis of Overall Survival Data from Three Trials of Bevacizumab and First-Line
Chemotherapy as Treatment for Patients with Metastatic Breast Cancer
Baylor-Sammons Cancer Center, Texas Oncology, US Oncology, Dallas, TX; Mount Vernon Cancer Centre, London, England; Dana-Farber Cancer Institute, Boston, MA; Institut Curie, Paris, France; Mayo Clinic, Jacksonville, Florida; Michiana Hematology Oncology, South Bend, IN; Vall d'Hebron University Hospital, Barcelona, Spain; BioOncology, Genentech, S San Francisco, CA;
Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN
Joyce O’Shaughnessy, David Miles, Robert Gray, Véronique Diéras, Edith A. Perez, Robin Zon, Javier Cortés,
Xian Zhou, See-Chun Phan, Kathy Miller
ASCO, 2010
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Introduction
• Bevacizumab (BV), a monoclonal antibody, inhibits vascular endothelial growth factor (VEGF), a key mediator of angiogenesis.
• 3 randomized trials (E2100, AVADO, RIBBON-1) have demonstrated significantly improved progression-free survivial (PFS) for BV combined with different chemotherapies as first-line metastatic breast cancer (MBC) treatment.
• PFS improved when BV combined with chemotherapy regardless of hormone receptor status, sites of metastases, disease-free interval (DFI), or prior adjuvant taxane use.
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General Study Designs
OptionalSecond-
line Chemo +
BV(AVADO and
RIBBON-1 only)
Chemo +No BV
Chemo +BV
Treat untilPD
RA
ND
OM
IZE
Previously Untreated
MBC
RIBBON-1Capecitabine,
Taxane,or
Anthracycline
AVADODocetaxel
E2100Paclitaxel
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BV=bevacizumab, PL=placebo, PFS=progression-free survival, ORR=objective response rate, OS=overall survival.* Permitted continuing on BV or crossing over to BV.† Analyses based on IRF assessments. ‡ 15 mg/kg cohort.
Comparison of the Studies
E2100 AVADO* RIBBON-1*
No. of patients 722 488‡ 1237
Geography US (90%) Ex-US US (50%)
Randomization ratio (BV:PL)
1:1 1:1 2:1
ChemotherapyPaclitaxel
weeklyDocetaxel
Capecitabine,Docetaxel/nab-Paclitaxel,
Doxorubicin/Epirubicin
Primary Endpoint PFS† PFS PFS
Key Secondary Endpoints
OS, ORROS, ORR,
1-yr survivalOS, ORR,
1-yr survival
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Overview of Efficacy Results from the Individual Studies in the Pooled Analysis
• To quantify treatment benefit of BV in combination with first-line chemotherapy for MBC patients by analyzing patient data from 3 randomized controlled trials in a pooled fashion
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Statistical Methods
• Efficacy and safety data were pooled from the studies E2100, AVADO, RIBBON-1: Cape, and RIBBON-1: Tax/Anthra.
• PFS was defined in the primary analysis of the individual study statistical analysis plans.
• Stratified HR estimate from Cox model used the individual studies (E2100, AVADO, RIBBON-1: Cape, RIBBON-1: T/Anth) as the only stratification factor.
• Kaplan–Meier curves were used to determine duration of PFS and OS.
• Median OS followup:
Study Median OS followup (mo)
E2100 35
AVADO 29
RIBBON-1: Cape 23
RIBBON-1: Tax/Anthra 26
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Patient Characteristics, Pooled Population
Non-BV(n1008)
BV(n1439)
Age, median 55 yr 56 yr
Triple-negative disease, % 26 25
Disease-free interval (≤24 mo), % 39 37
Prior adjuvant chemo, % 64 62
Taxane 22 24
Anthracycline 52 48
Visceral disease, % 71 69
≥3 metastatic sites, % 38 41
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Progression-Free Survival, Pooled Population
Non-BV(n=1008)
BV(n=1439)
Median, mo 6.7 9.2
HR (95% CI) 0.64 (0.57–0.71)
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Analysis of PFS by Subgroups
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Objective Response Rate*
*Includes only patients with measurable disease at baseline.
Non-BV(n=788)
BV(n=1105)
50
0
45
40
35
30
25
20
15
10
5
32
49
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Overall Survival, Pooled Population
Non-BV(n=1008)
BV(n=1439)
Median, mo 26.4 26.7
HR (95% CI) 0.97 (0.86–1.08)
1-yr survival rate (%)
77 82
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Analysis of OS by Subgroups
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Use of Subsequent Systemic Therapies in AVADO and RIBBON-1 Studies*
%Non-BV(n654)
BV(n1071)
Any chemotherapy 71 65
Bevacizumab 51 40
Any hormonal therapy 25 23
# of subsequent anti-cancer agents
≥4 27 23
3 15 12
2 27 26
1 10 15
*Data not available from E2100.
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Safety, Causes of Death*
%Non-BV(n982)
BV(n1679)
Total deaths 55.8 51.3
MBC 51.5 47.4
Treatment-related 1.8 2.1
Other 1.4 1.5
Missing 1.0 0.3
*Safety evaluable patient population.
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Grade ≥3 Selected Adverse Events (AEs), Pooled Population