1. Take home message
Breast Cancer
Bevacizumab in MBC
Sabino De Placido 1

2. Survival of Patients with Metastatic Breast Cancer 1974 - 2000

3. 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.

4. Metastatic Breast Cancer
1/5
Take home message
Metastatic Breast Cancer
No single «gold standard» in metastatic breast cancer 4

5. Bevacizumab in first line MBC
Breast Cancer
Bevacizumab in first line MBC 5

6. Comparison of the Studies (1/2)
AVADO*
RIBBON-1*
No. of patients
722
488
1237
Geography
US (90%)
Ex-US
US (50%)
Randomization ratio (BV:PL)
1:1
2:1
Primary Endpoint
PFS†
PFS
Independent review
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.

7. Comparison of the Studies (2/2)
AVADO2
RIBBON-13
Placebo controlled No
Yes
Chemotherapy
Weekly paclitaxel
3-weekly docetaxel
Capecitabine
Taxane or anthracycline
Bevacizumab dose
10 mg/kg q2w
7.5 or 15 mg/kg q3w
15 mg/kg q3w
Key Secondary Endpoints
OS, ORR
OS, ORR, 1-yr survival
OS, ORR,
1-yr survival
1. Miller, et al. NEJM 2007; 2. Miles, et al. ASCO 2008; 3. Robert, et al. ASCO 2009

8. Metastatic Breast Cancer
2/5
Take home message
Metastatic Breast Cancer
Study Results
Remarkable consistency in all study results 8

9. Consistent Benefit with Bevacizumab-Based Therapy: Significant Improvement in PFS
AVADO
RIBBON-1 (Cape)
RIBBON-1 (Tax/Anthra)
Non-BV BV
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-values
p<0.0001
p=0.0003
p=0.0002
BV=bevacizumab, Cape=capecitabine, Tax/Anthra=taxane/anthracycline.
* 15 mg/kg cohort. 9 9

10. Consistent Benefit with Bevacizumab-Based Therapy: Significant Improvement in ORR
AVADO
RIBBON-1 (Cape)
RIBBON-1 (Tax/Anthra)
Non-BV BV
BV*
ORR (%) 23 41 46 64
23.6
35.4
37.9
51.3
p-values
p<0.0001
p=0.0003
p=0.0097
p<0.0054
BV=bevacizumab, Cape=capecitabine, Tax/Anthra=taxane/anthracycline.
* 15 mg/kg cohort. 10 10

11. No Statistically Significant Difference in OS
AVADO
RIBBON-1 (Cape)
RIBBON-1 (Tax/Anthra)
Non-BV BV
BV*
Median OS, mo
24.8
26.5
31.9
30.2
21.2
29.0
23.8
25.2
Stratified HR (95% CI)
0.87
1.03
0.85
p-values
P=0.14
P=0.85
P=0.87
P=0.83
1 year rate (%) 74 81 76 84 83
P=0.017
P=0.02
P=0.076
P=0.44
BV=bevacizumab, Cape=capecitabine, Tax/Anthra=taxane/anthracycline.
* 15 mg/kg cohort. 11 11

12. 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

13. General Study Designs E2100 Paclitaxel Optional Second-line
Chemo + BV (AVADO and RIBBON-1 only)
Chemo + No BV
Chemo + BV
Treat
until PD
RANDOMIZE
Previously Untreated MBC
RIBBON-1
Capecitabine,
Taxane, or Anthracycline
AVADO
Docetaxel
E2100 Paclitaxel 13 13 13

14. 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)
The docetaxel+BV7.5 arm in AVADO was excluded from the pooled analysis. PFS data for patients who received non-protocol anti- cancer therapies prior to disease progression were censored.
The primary analysis of PFS was based on IRF assessment for E2100 and on investigator assessment for AVADO and RIBBON-1. 14

15. 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

16. Metastatic Breast Cancer
Clinical Relevance 16

17. 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

18. Metastatic Breast Cancer
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

19. Metastatic Breast Cancer
Adverse Events 19

20. E2100, AVADO & RIBBON1 Metanalysis Grade ≥3 Selected Adverse Events (Aes)20

21. Metastatic Breast Cancer
4/5
Take home message
Metastatic Breast Cancer
Adverse Events
Well tolerated in MBC patients and AE are fairly manageable 21

22. Metastatic Breast Cancer
Improvements across key clinical subpopulations 22

27. Metastatic Breast Cancer
5/5
Take home message
Metastatic Breast Cancer
Improvements across key clinical subpopulations
The advantage may be relevant in triple negative breast cancer 27