A Meta-Analysis of Overall Survival Data from Three Trials of Bevacizumab and First-Line...

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

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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.

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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

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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

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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)

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Analysis of PFS by Subgroups

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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

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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

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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.

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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.

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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

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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.

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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

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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.