Breast Cancer Bevacizumab in MBC

Take home message

Sabino De Placido 1

Survival of Patients with Metastatic Breast Cancer 1974 - 2000

1.0

30

.8

25

1995-2000

20

1990-1994 .6

15

.4

1985-1989 1980-1984

10 5

.2

1974-1979

0 1950s 1960s 1970s 1980s 1990s

0.0

0 12 24 36 48 60 Months

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.

Take home message

1/5 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

722 US (90%) 1:1 PFS † Retrospective

AVADO*

488 Ex-US 1:1 PFS No

RIBBON-1*

1237 US (50%) 2:1 PFS 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) E2100 1 AVADO 2 RIBBON-1 3

Placebo controlled Chemotherapy No Weekly paclitaxel Yes 3-weekly docetaxel Bevacizumab dose Key Secondary Endpoints 10 mg/kg q2w 7.5 or 15 mg/kg q3w OS, ORR OS, ORR, 1-yr survival Yes 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

Take home message

2/5 Metastatic Breast Cancer Study Results

Remarkable consistency in all study results

8

Consistent Benefit with Bevacizumab-Based Therapy: Significant Improvement in PFS E2100 Non BV BV AVADO Non BV BV* RIBBON-1 (Cape) Non BV BV

Median PFS, mo Stratified HR (95% CI) p-values 5.8

11.3

0.48

(0.39

–0.61) p<0.0001

7.9

0.62

(0.48

8.8

–0.79) p=0.0003

5.7

0.69

(0.56

BV=bevacizumab, Cape=capecitabine, Tax/Anthra=taxane/anthracycline.

* 15 mg/kg cohort.

8.6

–0.84) p=0.0002

RIBBON-1 (Tax/Anthra) Non BV BV

8.0

9.2

0.64

(0.52

–0.80) p<0.0001

Consistent Benefit with Bevacizumab-Based Therapy: Significant Improvement in ORR

ORR (%) p-values

E2100 Non BV

23

BV

41 p<0.0001

AVADO Non BV

46

BV*

64 p=0.0003

RIBBON-1 (Cape) Non BV BV

23.6

35.4

p=0.0097

RIBBON-1 (Tax/Anthra) Non BV BV

37.9

51.3

p<0.0054

BV=bevacizumab, Cape=capecitabine, Tax/Anthra=taxane/anthracycline.

* 15 mg/kg cohort.

No Statistically Significant Difference in OS

Median OS, mo Stratified HR (95% CI) p-values 1 year rate (%) p-values

E2100 Non BV

24.8

BV

26.5

AVADO Non BV

31.9

BV*

30.2

RIBBON-1 (Cape) Non-BV BV

21.2

29.0

RIBBON-1 (Tax/Anthra) Non-BV BV

23.8

25.2

0.87

P=0.14

74 81 P=0.017

1.03

P=0.85

76 P=0.02

84 0.85

P=0.87

74 P=0.076

81 1.03

P=0.83

83 P=0.44

81 BV=bevacizumab, Cape=capecitabine, Tax/Anthra=taxane/anthracycline.

* 15 mg/kg cohort.

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

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

Progression-Free Survival, Pooled Population Median, mo HR (95% CI) Non-BV (n=1008) 6.7

BV (n=1439) 9.2

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 ?

Bevacizumab + Paclitaxel vs Paclitaxel Anthracyclines + Taxanes vs Taxanes Capecitabine + Docetaxel vs Docetaxel Gemcitabine + Paclitaxel vs Paclitaxel PFS 2.5 mos 0.8 mos 1.9 mos 2.1 mos

Take home message

3/5 Metastatic Breast Cancer Clinical Relevance

The improvement in PFS is similar to that of most other first line studies

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Metastatic Breast Cancer Adverse Events 19

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

Take home message

4/5 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

Take home message

5/5 Metastatic Breast Cancer Improvements across key clinical subpopulations

The advantage may be relevant in triple negative breast cancer

27