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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
2
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.
3
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
4
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
E2100 AVADORIBBON-1
(Cape)RIBBON-1
(Tax/Anthra)
Non-BV
BVNon-BV
BV*Non-BV BV
Non-BV BV
Median PFS, mo
5.8 11.3 7.9 8.8 5.7 8.6 8.0 9.2
StratifiedHR (95% CI)
0.48(0.39–0.61)
0.62(0.48–0.79)
0.69(0.56–0.84)
0.64(0.52–0.80)
p-values p<0.0001 p=0.0003 p=0.0002 p<0.0001
BV=bevacizumab, Cape=capecitabine, Tax/Anthra=taxane/anthracycline.* 15 mg/kg cohort.
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Objective
• 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
8
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)
10
Analysis of PFS by Subgroups
11
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
12
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
14
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.
15
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.
16
Grade ≥3 Selected Adverse Events (AEs), Pooled Population
%Non-BV(n982)
BV(n1679)
Neutropenia
7.1 10.0
Sensory neuropathy
8.5 9.5
Hypertension
1.2 9.0
Febrile neutropenia
3.5 6.5
Venous thromboembolic event
3.8 2.8
Proteinuria
0 2.3
Arterial thromboembolic event
0.3 1.6
Bleeding
0.4 1.5
Left ventricular systolic function
0.2 1.5
Wound dehiscence
0.3 0.8
Fistula
0.3 0.5
GI perforation
0.3 0.5
RPLS
0 <0.1
RPLS=Reversible posterior leukoencephalopathy syndrome.
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• PFS
- HR=0.64, 36% reduction in risk of PD or death
- 2.5 month improvement in median PFS
- Improvements across key clinical subpopulations
• ORR
- 17% increase vs controls
• OS
- No statistically significant difference
Summary of Pooled Efficacy Analysis
18
Conclusions
• Significant PFS advantage but no OS difference with BV across 3 first-line studies and in pooled analysis
- In MBC, the ability of Phase III trials to demonstrate treatment effect upon OS depends on the duration of survival post-progression (SPP)
- Higher chance of affecting OS in populations with short SPP (20 month SPP in these 3 first-line trials)
• Patients with adverse prognostic features benefit from BV as do patients with more indolent disease
• Low incidence of treatment-related deaths with BV
• Safety profile consistent with previous BV experienceBroglio and Berry. 2009. J Natl Cancer Inst. 101:1642-49.Saad, Katz, and Buyse. 2010. J Clin Oncol. 28:1958-62.Burzykowski, et al. 2008. J Clin Oncol. 26:1987-92.
19
Acknowledgments
• We would like to thank all of the patients and all of the investigators who participated in the E2100, AVADO, and RIBBON-1 studies from:
Australia Italy Romania Ukraine
Austria Lithuania Russia United Kingdom
Belgium Mexico Singapore USA
Brazil Netherlands South Africa Uruguay
Canada Norway South Korea
China Panama Spain
France Peru Sweden
Germany Philippines Switzerland
Greece Poland Taiwan
Guatemala Portugal Thailand
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Back-up
21
Database Cutoff Dates from First-line MBC Studies Used in Pooled Analysis
E2100 AVADO RIBBON-1
PFS
Feb, 2005(Interim analysis)
Gray, et al. JCO, 2009 (IRF results)
Oct , 2007
Miles, et al. ASCO 2008
Jul, 2008
Robert, et al. ASCO 2009
OSOct, 2006
US PI
Apr 30, 2009(Pre-specified OS update, includes exploratory PFS
update)
Miles, SABCS 2009
Feb 23, 2009(Pre-specified OS
update)
Unpublished
MBC=metastatic breast cancer, OS=overall survival, PFS=progression-free survival.