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

Survival of Patients with Metastatic Breast Cancer 1974 - 2000

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.

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

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

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.

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

Metastatic Breast Cancer 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 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

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

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

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

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

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

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

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

Metastatic Breast Cancer Adverse Events 19

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

Metastatic Breast Cancer 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

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