Take home message
Breast Cancer
Bevacizumab in MBC
Sabino De Placido
1
Survival of Patients with Metastatic
Breast Cancer 1974 - 2000
1.0
30
.8
No. Drugs Available
25
1995-2000
1990-1994
.6
1985-1989
.4
1980-1984
20
15
10
5
.2
1974-1979
0
1950s 1960s 1970s 1980s 1990s
0.0
0
12
24
36
Months
48
60
International Guidelines for Management of Metastatic
Breast Cancer: Combination vs Sequential Single-Agent
Chemotherapy
Fatima Cardoso , Philippe L. Bedard , Eric P. Winer , Olivia Pagani , Elzbieta Senkus-Konefka , Lesley
J. Fallowfield , Stella Kyriakides , Alberto Costa , Tanja Cufer , Kathy S. Albain ; on behalf of the
ESO-MBC Task Force
J Natl Cancer Inst 2009;101:1174–1181
In the absence of evidence to guide daily clinical decision making in MBC,
both combination and sequential single agent chemotherapy are reasonable
options as first-line systemic therapy.
An important question for future research is the clear definition of patients
who may benefit from a combination approach.
Until such data are available, the ESO-MBC Task Force believes that
sequential single-agent therapy should be the preferred choice for most
MBC patients, in the absence of rapid clinical progression, life-threatening
visceral metastases, or the need for rapid symptom and/or disease control.
These recommendations reflect consensus expert opinion and represent
level 5 clinical evidence.
1/5
Take home message
Metastatic Breast Cancer
No single «gold standard» in
metastatic breast cancer
4
Breast Cancer
Bevacizumab in first line MBC
5
Comparison of the Studies (1/2)
No. of patients
Geography
Randomization
ratio (BV:PL)
Primary Endpoint
Independent
review
E2100
AVADO*
RIBBON-1*
722
488
1237
US (90%)
Ex-US
US (50%)
1:1
1:1
2:1
PFS†
PFS
PFS
Retrospective
No
Prospective
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.
Comparison of the Studies (2/2)
Placebo
controlled
Chemotherapy
Bevacizumab
dose
Key Secondary
Endpoints
E21001
AVADO2
RIBBON-13
No
Yes
Yes
Weekly
paclitaxel
3-weekly
docetaxel
10 mg/kg q2w 7.5 or 15 mg/kg q3w
OS, ORR
OS, ORR,
1-yr survival
Capecitabine
Taxane or
anthracycline
15 mg/kg q3w
OS, ORR,
1-yr survival
1. Miller, et al. NEJM 2007; 2. Miles, et al. ASCO 2008; 3. Robert, et al. ASCO 2009
2/5
Take home message
Metastatic Breast Cancer
Study Results
Remarkable consistency in all
study results
8
Consistent Benefit with Bevacizumab-Based
Therapy: Significant Improvement in PFS
E2100
AVADO
RIBBON-1
(Cape)
RIBBON-1
(Tax/Anthra)
NonBV
BV
NonBV
BV*
NonBV
BV
NonBV
BV
Median PFS,
mo
5.8
11.3
7.9
8.8
5.7
8.6
8.0
9.2
Stratified
HR (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<0.0001
p=0.0003
p=0.0002
p<0.0001
p-values
BV=bevacizumab, Cape=capecitabine, Tax/Anthra=taxane/anthracycline.
* 15 mg/kg cohort.
Consistent Benefit with Bevacizumab-Based
Therapy: Significant Improvement in ORR
E2100
ORR (%)
p-values
AVADO
RIBBON-1
(Cape)
RIBBON-1
(Tax/Anthra)
NonBV
BV
NonBV
BV*
NonBV
BV
NonBV
BV
23
41
46
64
23.6
35.4
37.9
51.3
p<0.0001
p=0.0003
p=0.0097
BV=bevacizumab, Cape=capecitabine, Tax/Anthra=taxane/anthracycline.
* 15 mg/kg cohort.
p<0.0054
No Statistically Significant Difference in OS
E2100
Median OS,
mo
RIBBON-1
(Tax/Anthra)
BV
NonBV
BV*
Non-BV
BV
Non-BV
BV
24.8
26.5
31.9
30.2
21.2
29.0
23.8
25.2
p-values
p-values
RIBBON-1
(Cape)
NonBV
Stratified
HR (95% CI)
1 year rate
(%)
AVADO
74
0.87
1.03
0.85
1.03
P=0.14
P=0.85
P=0.87
P=0.83
81
P=0.017
76
84
P=0.02
74
81
P=0.076
BV=bevacizumab, Cape=capecitabine, Tax/Anthra=taxane/anthracycline.
* 15 mg/kg cohort.
83
81
P=0.44
A Meta-Analysis of Overall Survival Data from
Three Trials of Bevacizumab and First-Line
Chemotherapy as Treatment for Patients with
Metastatic Breast Cancer
Joyce O’Shaughnessy, David Miles, Robert Gray,
Véronique Diéras, Edith A. Perez, Robin Zon, Javier Cortés,
Xian Zhou, See-Chun Phan, Kathy Miller
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
ASCO, 2010
E2100
Paclitaxel
Previously
Untreated
MBC
AVADO
Docetaxel
RIBBON-1
Capecitabine,
Taxane,
or
Anthracycline
RANDOMIZE
General Study Designs
Chemo +
No BV
Chemo +
BV
Treat
until
PD
Optional
Second-line
Chemo +
BV
(AVADO and
RIBBON-1
only)
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)
Summary of Pooled Efficacy Analysis
• 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
Metastatic Breast Cancer
Clinical Relevance
16
Clinical Relevance
• Is 2.5 month improvement in median PFS a
clinically relevant result ?
PFS
Bevacizumab + Paclitaxel vs Paclitaxel
2.5 mos
Anthracyclines + Taxanes vs Taxanes
0.8 mos
Capecitabine + Docetaxel vs Docetaxel
1.9 mos
Gemcitabine + Paclitaxel vs Paclitaxel
2.1 mos
3/5
Take home message
Metastatic Breast Cancer
Clinical Relevance
The improvement in PFS is
similar to that of most other
first line studies
18
Metastatic Breast Cancer
Adverse Events
19
E2100, AVADO & RIBBON1 Metanalysis
Grade ≥3 Selected Adverse Events (Aes)
20
4/5
Take home message
Metastatic Breast Cancer
Adverse Events
Well tolerated in MBC patients
and AE are fairly manageable
21
Metastatic Breast Cancer
Improvements across key clinical subpopulations
22
5/5
Take home message
Metastatic Breast Cancer
Improvements across key clinical subpopulations
The advantage may be relevant
in triple negative breast cancer
27