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Avastin® (bevacizumab)

United States Food and Drug AdministrationOncologic Drugs Advisory Committee

December 5, 2007

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Overview

David Schenkein, MD

Senior VP, Clinical Hematology/OncologyGenentech, Inc.

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Overview Topics

• Indication statement

• Avastin Overview

• E2100 Summary

• Today’s Agenda

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Indication Statement

Avastin®, in combination with paclitaxel, for the treatment of patients who have not received chemotherapy for their locally recurrent or metastatic HER2-negative breast cancer.

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Avastin Overview

• Monoclonal antibody specific for VEGF ligand

• Validated antiangiogenesis in cancer therapy

– > 200,000 patients treated worldwide with Avastin

• Clinical validation in numerous settings

– Avastin approved

• Colorectal cancer and non-small cell lung cancer (worldwide)

– Progression-free and overall survival

• Metastatic breast cancer (ex-US)

– Progression-free survival (PFS)

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Avastin Milestone Developments in Metastatic Breast Cancer

E2100 1st-line MBC

2002 20041989 1997 2000 2005

VEGF-A cloned

IND for Avastin

AVF0776 Phase I/II MBC

AVF21192nd/3rd-line MBC

2001

GNE/NCI Clinical

Research Agreement

Avastin Approved Colorectal

Cancer

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ECOG Study E2100—Regulatory Milestones

2002 2005 2006 2007 2008

GNE/FDAPresubmission

Meeting

E2100 Ph III FL MBC

First Interim

Agency Request

for More Data

E2100 BLA SupplementResubmitted

E2100 BLA SupplementSubmitted

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Key Agreements With FDA to Support Resubmission (1)

• Independent Review Facility (IRF) assessment of all 722 patients

• Primary endpoint PFS by IRF review

• Data cut-off in line with ECOG interim analysis applied to final clean database

• Mature survival data

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Key Agreements With FDA to Support Resubmission (2)

Studies included in sBLA

Efficacy Safety Patient population

E2100 1st-line MBC

AVF2119 Prior anthracycline and taxane treated

AVF0776 Relapsed MBC

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Study E2100 Summary

• Avastin + paclitaxel associated with compelling treatment effect

• PFS appropriately measured

– Consistency across subsets

– Sensitivity analyses retained benefit

• Objective Response Rate (ORR) improved

• Overall Survival (OS) improved

• Favorable benefit/risk ratio

– No new safety signals observed

• Important advance for women with breast cancer

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Avastin in Metastatic Breast Cancer

• E2100 demonstrates a robust and clinically meaningful PFS treatment effect

• A PFS effect of this magnitude represents clinical benefit

• Genentech has committed to a full understanding of Avastin’s role in breast cancer

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David Schenkein, MDGenentech, Inc.

Overview

Kathy Miller, MDIndiana University

Study E2100: Design, Efficacy

Barbara Klencke, MDGenentech, Inc.

Study E2100: Safety

Eric Winer, MDDana-Farber Cancer InstituteHarvard Medical School

MBC and Bevacizumab:Placing ECOG Study 2100 in Context

Chris Bowden, MDGenentech, Inc.

Concluding Remarks

Today’s Agenda

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ECOG Study E2100:Avastin Added to Weekly Paclitaxel as Initial Chemotherapy for Patients

With Metastatic Breast Cancer

Kathy Miller, MD

Associate ProfessorIndiana University School of Medicine

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Topics

• Metastatic Breast Cancer Treatment Landscape

• E2100 Study Design Rationale

• E2100 Efficacy Data

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Metastatic Breast Cancer

• Overt metastatic disease is generally incurable

• Goal of therapy

– Live longer and prosper

• Chemotherapy

– Drug resistance is common

– Substantial toxicity

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Treatment Landscape 2001

0 5 10 15 20 25 30 35

Months

PFS OS

VATH/CMFVP1

FEC2

Paclitaxel3

EM4

Docetaxel5

DV6

Doxorubicin7

1Aisner. JCO. 1995; 2Brufman. Ann Oncol. 1997; 3Bishop. Sem Oncol. 1997; 4Pacini. Eur J Cancer. 2000; 5Chan. JCO. 1999; 6Norris. JCO. 2000; 7Parideans. JCO. 2000.

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Treatment Landscape 2007—Little Progress With Chemotherapy

0 5 10 15 20 25 30 35

Months

PFS OS

AT1

AT2

GT3

wkly Paclitaxel4

Docetaxel5

GET6

GV7

1Jassem. JCO. 2001; 2Sledge. JCO. 2003; 3Albain. Proc ASCO. 2004; 4Seidman. Proc ASCO. 2004; 5Jones. JCO. 2005; 6Zielinski. JCO. 2005; 7Martin. Lancet Oncology. 2007.

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Rationale for E2100

• Importance of angiogenesis

• Taxanes have antiangiogenic activity and are synergistic with Avastin

• AVF0776: Avastin activityas monotherapy

• AVF2119: Ongoing phase III trial in refractory disease

• Greater benefits expected earlier in natural history

Pragmatic

Biologic Clinical

• Intravenous placebo considered barrier to accrual

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MBC not previously treated with

chemotherapy

(N = 685)

Stratification

- Disease-free interval

- Adjuvant therapy

- ER+, ER–, unknown

- Number of metastatic sites

Paclitaxel: 90 mg/m2 IV infusion over 1 hr every wk for 3 wk followed by 1 wk of rest

Avastin: 10 mg/kg following paclitaxel treatment on Wk 1 and 3 of every cycle

R

A

N

D

O

M

I

Z

E

D

Paclitaxel: 90 mg/m2 IV infusion over 1 hr every wk for 3 wk followed by 1 wk of rest

E2100—Study Design

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E2100—Endpoints

• Primary endpoint

– Progression-free survival (PFS)

• Secondary endpoints

– Objective response rate (ORR)

– Overall survival (OS)

– Quality of life (QoL)

– Safety

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Rationale for Progression-Free Survival as the Primary Endpoint for E2100

• Important endpoint in the first-line setting

• Clinical benefit from prolonging PFS

– Maintain disease control

– Prevent symptoms of disease progression

– Prevent toxicities, psychological burden, and uncertainty of disease progression

• PFS endpoint not obscured by subsequent therapy

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Statistical Considerations

• Primary endpoint: PFS

– N = 685

– 85% power to detect a 33% improvement

• 6 vs 8 mo

– Interim analyses after 50% and 78% events

– Final analysis after 546 events

• Secondary endpoint: OS

– 15% to 25% power to detect 2- to 3-mo improvement

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E2100—Key Eligibility Criteria

• Disease setting

– Locally recurrent or metastatic breast cancer (mBC)

– HER2+ only if pretreatment with Herceptin or unsuitable

– Measurable or non-measurable disease

• Prior therapy

– No prior chemotherapy for mBC

– Adjuvant taxanes if > 12 mo prior to randomization

• Baseline requirements

– No CNS metastases

– Performance status

• ECOG 0 or 1

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Assessment Frequency (timing)

Clinical evaluation Every cycle (every 4 wk)

Safety assessment Every cycle (every 4 wk)

Tumor assessment(scan or x-ray)

Every 3 cycles (every 12 wk)Balanced assessments on both arms

QoL (FACT-B) Baseline, Wk 17, and Wk 33

E2100—Assessments

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Participating Centers

• 10 major cooperative groups participated

• 258 enrolling centers

– US, Canada, Peru, South Africa

– < 10% of patients enrolled ex-US

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ECOG Study E2100:Efficacy Results

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E2100 Baseline Characteristics—Balanced

Paclitaxel(n = 354)

Paclitaxel + Avastin(n = 368)

Median age, years (range) 55 (27 - 85) 56 (29 - 84)

≥ 65 years, % 23 23

Measurable disease at baseline, % 77 68

ER+ and/or PR+, % 64 63

HER2+, % 1.7 2.7

Disease-free interval ≤ 24 mo, % 41 41

≥ 3 metastatic sites, % 29 29

Prior adjuvant chemotherapy, % 65 66

Prior adjuvant anthracyclines, % 51 50

Prior adjuvant taxane therapy, % 19 20

Metastatic hormonal therapy, % 36 36

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Paclitaxel(n = 354)

Paclitaxel + Avastin

(n = 368)

Patients with an event, n (%) 184 (52) 173 (47)

Stratified analysis

HR 0.483

95% CI (0.385, 0.607)

p value

Log-rank 0.0001

PFS, mo

Median 5.8 11.3

95% CI (5.36, 8.15) (10.45, 13.27)

E2100—PFS by Independent Radiology Facility (IRF)

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0.8

0.6

0.4

0.2

0.0

1.0

3630241260

Pro

port

ion

with

out

even

t

HR = 0.483 (0.385, 0.607)

Log-rank test, p ≤ 0.0001

Paclitaxel (n = 354)

Paclitaxel + Avastin (n = 368)

18

Time, mo

E2100—PFS by IRF (Kaplan-Meier)

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Exploratory Analyses of PFS

1. PFS in key subsets

2. IRF vs Investigator-assessed progression

3. Sensitivity analyses

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All Patients Age < 40 yr

Age 40 - 64 yr

Age ≥ 65 yr

< 3 Metastatic sites

≥ 3 Metastatic sites

Measurable disease at baseline

Non-measurable disease at baseline No prior adjuvant chemotherapy Prior adjuvant chemotherapy Prior adjuvant TAXANE therapy

ER+

ER–

E2100—PFS Consistent Across Subgroups

Paclitaxel betterPaclitaxel + Avastin better

0.50.2 521Hazard ratio

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Exploratory Analyses of PFS

1. PFS in key subsets

2. IRF vs Investigator-assessed progression

3. Sensitivity analyses

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11.3

0.8

0.6

0.4

0.2

0.0

1.0

18 3630241260

Pro

port

ion

with

out

even

t

HR = 0.483

PAC

PAC + AVA

PFS by IRF

E2100—PFS Consistent Between IRF and Investigator

5.8

11.4

HR = 0.421

PAC

PAC + AVA

PFS by investigator

5.8

Months

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Exploratory Analyses of PFS

1. PFS in key subsets

2. IRF vs Investigator-assessed progression

3. Sensitivity analyses

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Median PFS

PFS analysis variationPAC

(n = 354)

PAC + AVA

(n = 368) HR p value

Primary analysis 5.8 11.3 0.48 < 0.0001

Investigator Progression not confirmed by IRF:

• Paclitaxel alone: Censor

• Avastin arm: Assume progression

5.8

9.2 0.60 < 0.0001

Sensitivity Analyses—Significant Benefit Retained Even if Avastin Arm Penalized

CSR Table 15

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Secondary Analyses

• Objective Response Rate

• Overall Survival

• Quality of Life

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0

10

20

30

40

50

60

CR PR SD PD UE

PAC

PAC + AVA

* Stratified analysis of CR + PR comparison, p < 0.0001

0%

22%

50%*

44%

34%

26%

12%Be

st r

esp

onse

, %Best Overall Response by IRFPatients With Measurable Disease at Baseline

9%5%

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0

10

20

30

40

50

60

CR + PR CR + PR

Be

st r

esp

onse

, %

E2100—Objective Response by Investigators and IRFPatients With Measurable Disease at Baseline

Investigator assessment IRF assessment

50%

22%23%

48%

PACPAC + AVA

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Paclitaxel(n = 354)

Paclitaxel + Avastin

(n = 368)

Patients who died, n (%) 238 (67.2) 243 (66)

Stratified analysis

HR 0.869

95% CI (0.722, 1.046)

p value

Log-rank 0.1374

Overall survival, mo

Median 24.8 26.5

95% CI (21.39, 27.37) (23.72, 29.21)

Note: Data are based on a 21 October 2006 cutoff.

Overall Survival

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E2100—Overall Survival

PAC+AVA 104103

00

58

2319

344307PAC

4848

193165

No. of patients at risk

249215

368354

297258

HR = 0.869 (0.722, 1.046)

Log-rank test, p = 0.1374

PAC (n = 354): Median OS 24.8 mo

PAC + AVA (n = 368): Median OS 26.5 mo0.8

0.6

0.4

0.2

0.0

1.0

543630 6048420

Pro

por

tion

surv

ivin

g

18 24126

0.8

0.6

0.4

0.2

0.0

1.0

543630 6048420 18 24126

* Post-hoc

Months

p = 0.017*

74.0%

81.4%

50.1%

55.0%

p = 0.191*

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E2100—Quality of Life: Primary Analysis Favors Avastin Therapy

-24.6

-15.9

-12.7

-6.6

-30

-25

-20

-15

-10

-5

0

Baseline Wk 17 Wk 33

PAC

PAC + AVADecline

Change from baseline for Trial Outcome Index-Breast

Patients with QoL data

PAC N =

PAC + AVA N =

327

347

290

318

296

292

p = 0.0069

p = 0.0002

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E2100—Efficacy Conclusions for Avastin + Paclitaxel

• Clinically meaningful improvement in PFS

– Magnitude of PFS benefit consistent for all patient subgroups

– Similar PFS results based on IRF or investigator assessments validates ECOG review process

– Robust PFS result verified by sensitivity analyses

• Doubling of ORR, with improvement in 1-year survival and no additional QoL burden

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ECOG Study E2100:Safety

Barbara Klencke, MD

Associate Group Medical DirectorGenentech, Inc

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Paclitaxel(n = 342)

Paclitaxel + Avastin (n = 358)

Cycles* received per patient

Median 6 10

Range 1 - 26 1 - 38

25th - 75th percentile 3 - 9 6 - 15

*1 cycle = 4 weeks.

E2100—Treatment Received 

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Status and reason for discontinuation

Paclitaxel(n = 354)

(%)

Paclitaxel + Avastin(n = 368)

(%)

Total(N = 722)

(%)

Not treated 2.3 0.5 1.4

Treatment ongoing 2 11 7

Discontinued protocol therapy 96 89 92

Disease progression 55 45 50

Toxicity/side effects/complications 19 20 20

Death 1.4 1.6 1.5

Other 20 22 21

Reasons for Treatment Discontinuation

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Paclitaxel(n = 348)

%

Paclitaxel +Avastin

(n = 363)%

Death events 73.6 70.2

Due to MBC 69.3 66.9

Due to protocol therapy 0.3 0.0

Due to other cause 2.0 2.5

Unknown 2.0 0.8

E2100: Investigator-Reported Cause of Death in Safety Population

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Deaths

Paclitaxel(n = 348)

n (%)

Paclitaxel +Avastin

(n = 363)n (%)

All deaths 256 (73.6) 255 (70.2)

Due to protocol therapy Not assessable by

Genentech6 (1.7)

E2100—Causes of Death:Comprehensive Genentech Clinical Review

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NCI-CTCAE Term Grade ≥ 3

Paclitaxel (n = 348)

(%)

Paclitaxel + Avastin

(n = 363)(%)

Patients with ≥ 1 event 50.6 71.1

Neuropathy 18.1 25.3

Hypertension 1.4 16.0

Fatigue 5.2 10.7

Infection without neutropenia 4.6 9.1

Neutropenia (Grade 4) 3.2 5.8

Vomiting 2.3 5.5

Grade 3-5 nonhematologic and Grade 4-5 hematologic events included.

Most Frequent Grade 3-5 Adverse Events by Category and Preferred Term (≥ 5% Incidence)

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Paclitaxel(n = 348)

Paclitaxel + Avastin(n = 363)

Grade 3-5

1.4 16.0

0 3.6

0 3.0

0.3 2.2

0.3 2.2

0 0.6

Gr 3 Gr 4 Gr 5

15.4 0.6 0

1.1 1.9 0.6

1.9 1.1 0

1.7 0.6 0

1.9 0.3 0

0 0 0.6

Selected adverse events

Hypertension

Arterial thromboembolism

Proteinuria

Hemorrhage

Left ventricular dysfunction

GI perforations

E2100—Grade 3-5 Adverse Events: Categories of Special Interest (%) by Grade

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E2100—Safety Summary for Avastin + Paclitaxel

• Avastin + paclitaxel relatively well tolerated despite longer treatment

• Discontinuation for treatment toxicity equally balanced

• Safety profile consistent with known Avastin toxicity profile

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AVF2119—Study Design

Metastatic breast cancer • Measurable disease• Prior anthracycline + taxane

therapy required• HER2+ or HER2–

Primary endpoint• PFS by IRF

Stratification• ECOG performance status• Number of prior chemotherapy regimens

Capecitabine2500 mg/m2 q day × 14q 3 wk

Capecitabine2500 mg/m2 q day × 14

Avastin 15 mg/kgq 3 wk

N = 450

RANDOMIZE

1:1

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E2100 and AVF2119—Summary of Treatment

E2100 AVF2119

PAC(n = 348)

PAC + AVA(n = 363)

Cape(n = 215)

Cape + AVA(n = 229)

Median number of cycles administered

6 10 4 6

4-wk cycles 3-wk cycles

Discontinuation due to toxicity, %

19 20 12 10

Treatment-related deaths, %

Not assessable by Genentech

1.7* 0.9 0.4

*Comprehensive Genentech clinical review.

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AVF2119

Cape(n = 215)

Cape + AVA(n = 229)

0.5 20.0

0.5 0.4

0 1.3

0.5 0.4

1.0 3.5

0 0

0.9 0

E2100 and AVF2119g—Grade 3-5 Adverse Events: Categories of Special Interest (%)

Selected adverse events, Grade 3 - 5

E2100

PAC(n = 348)

PAC + AVA(n = 363)

Hypertension 1.4 16.0

Arterial thromboembolic events

0 3.6

Proteinuria 0 3.0

Hemorrhage 0.3 2.2

Left ventricular dysfunction

0.3 2.2

GI perforations 0 0.6

Neuropathy 18.1 25.3

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Avastin Safety Summary

• E2100 and AVF2119 report side effects consistent with current Avastin labeling

• Overall safety profile and QoL outcomes from E2100 support acceptability of the safety profile for Avastin + paclitaxel

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Metastatic Breast Cancer and Bevacizumab:Placing ECOG Study 2100 in Context

Eric Winer, MDDirector, Breast Oncology Center

Dana-Farber Cancer Institute

Associate Professor of Medicine Harvard Medical School

Chief Scientific AdvisorSusan G. Komen for the Cure

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Why Do We Develop New Therapies for Patients With Metastatic Breast Cancer?

• To improve treatment outcomes for women living with the disease today

• To identify promising new therapies that can be applied to the adjuvant setting

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How Do We Maximize Clinical Benefit forWomen With Metastatic Breast Cancer?

• Goals of treatment are to

– Maximize survival

• Median survival from initiation of first-line chemotherapy in HER2-negative disease is approximately 2 years

– Maintain disease control

– Minimize symptoms from disease

– Minimize toxicity from treatment

QUALITYOF LIFE

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Agents Approved for Metastatic Breast Cancer Since 2001

Drug Trial Size

Capecitabine Docetaxel + Capecitabine vs

Docetaxel

N = 511

Gemcitabine Paclitaxel + Gemcitabinevs

Paclitaxel

N = 529

Lapatinib Capecitabine + Lapatinib vs

Capecitabine

N = 324

Ixabepilone Capecitabine + Ixabepilonevs

Ixabepilone

N = 752

O’Shaughnessy. JCO. 2002; Melemed. ASCO Breast. 2007; Geyer. NEJM. 2006; Thomas. JCO. 2007.

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10 mo5 mo

MBC Tx—Recent Major Phase 3 Trials: Efficacy Results

20 mo10 mo

PFS/TTP

OS

1Miller. SABCS. 2005; 2O’Shaughnessy. JCO. 2002; 3Melemed. ASCO Breast. 2007; 4Geyer. NEJM. 2006; 5Thomas. JCO. 2007; NA: Not available.

Not reported yet

XD2

GT3

TyX4

IxX5

XDD

GTT

TvXX

IxXX

XD2

GT3

TyX4

IxX5

XDD

GTT

TvXX

IxXX

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PFS or TTP, mo

4 6 8 120 2 10

Phase III PFS/TTP Results in First-line Metastatic Breast Cancer Trials Utilizing Taxanes

ATFACJassem 2001

APACBiganzoli 2002

ADACNabholtz 2003

Pq wPq 3wSeidmann 2004

FACMackey 2002

GTTMelemed 2007

ADFACBontenbal 2005

GETFECZielinski 2005

ECETCarmichael 2001

Luck 2000 ETEC

E2100 Paclitaxel + BevacizumabPqw

ATTASledge 2003 T

Experimental arm

Control arm

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Is Prolonging Progression-Free Survival Meaningful for Patients?

• Improvements in progression-free survival

– Delay the onset of disease-related symptoms and the side effects from a new therapy

– Avoid the psychological consequences associated with disease progression and changing therapy

– Eliminate the uncertainty as to whether new treatment will be effective

Yes, prolonging progression-free survival can be highly meaningful!

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For Progression-Free Survival to Equal Patient Benefit, Then…

• The improvement in PFS must be

– Substantial in magnitude

– Established with confidence

– Supported by other measures of efficacy

• Survival

• QoL

• Objective response rate

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Applying These Criteria to the Combination of Paclitaxel + Bevacizumab

Criteria As demonstrated in ECOG 2100

Substantial in magnitude

PFS hazard ratio: 0.48 (p < 0.0001)

Established with confidence

Agreement between investigator and independent review

Sensitivity analyses

Supported by other measures of efficacy

OS hazard ratio: 0.87 (p = 0.14)

QoL favors bevacizumab

Doubling of response rate (p < 0.0001)

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10 mo5 mo

MBC Tx—Recent Major Phase 3 Trials: Efficacy Results

20 mo10 mo

PFS/TTP

OS

1Miller. SABCS. 2005; 2O’Shaughnessy. JCO. 2002; 3Melemed. ASCO Breast. 2007; 4Geyer. NEJM. 2006; 5Thomas. JCO. 2007; NA: Not available.

Not reported yet

XD2

GT3

TyX4

IxX5

E21001 TAT

XDD

GTT

TvXX

IxXX

XD2

GT3

TyX4

IxX5

E21001 TAT

XDD

GTT

TvXX

IxXX

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Longerprogression-free

survival

Side effects/risks from treatment

FrequencySeverity

Extent of improvement

The Trade-Off

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What Side Effects and Risks Must Be Accepted With Paclitaxel and Bevacizumab?

• 20% increase in Grade 3-5 toxicity

– Asymptomatic Grade 3 hypertension and proteinuria were the most common adverse events

• Neuropathy increase due to duration of treatment

• Small increase in severe toxicity

– Arterial thrombotic events

– Congestive heart failure

– GI perforation

– Bleeding

• Added day-to-day toxicity quite limited

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In Summary

• Progression-free survival is a meaningful endpoint

• The combination of bevacizumab and paclitaxel results in

– Substantial improvement in progression-free survival

– Modest additional toxicity for the majority of patients

• Bevacizumab in combination with paclitaxel is a valuable treatment option for women with metastatic breast cancer

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Concluding Remarks

Chris Bowden, MD

Senior Group Medical DirectorGenentech, Inc.

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E2100 Summary

• Benefit

– Clinically meaningful treatment effect on progression-free survival

– PFS supported by all secondary endpoints

• Risk

– Safety profile familiar to prescribing oncologists

• Confidence

– Independent cooperative group study

– Consistency across subsets, IRF vs investigator, multiple sensitivity analyses

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Indication Statement

Avastin® in combination with paclitaxel is indicated for the treatment of patients who have not received chemotherapy for their locally recurrent or metastatic HER2-negative breast cancer.

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Avastin®

Supportive Slides

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TAX(n54)

TAX/AV(n114)

No. of patients with an objective response 54 112 a

No. of patients with an event 22 (40.7%) 56 (50.0%)

Duration of objective response (months)

Median 9.7 9.4

95% CI (7.43, 12.62) (8.38, 13.31)

Unstratified Hazard Ratio (Relative to TAX) 0.838 (0.508, 1.382)

a Two patients (21061 and 29004) have negative durations of objective response because a PD was recorded prior to a PR. For Patient 21061, the PD was retracted in the reader comments; for Patient 29004, the PD date was kept and allowed to be followed by a best response of PR since PD was not assessed as a best response.

Duration of Objective Response Patients with Measurable Disease at Baseline and an Objective Response

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Subgroup Analysis of PFS (1)

Baseline Risk Factor

Total n n Median

(mo) n Median (mo)

Hazard Ratio (95% Cl)

All Patients 722 354 5.8 368 11.3 0.54 (0.44-0.67)

Age (yrs)

<40 59 32 4.8 27 8.3 0.54 (0.26-1.09)

40-64 496 239 6.1 257 12.1 0.51 (0.39-0.66)

≥65 167 83 6.1 84 10.4 0.67 (0.42-1.05)

Race

White 550 266 6.0 284 12.0 0.54 (0.42-0.69)

Non-White 172 88 5.6 84 10.9 0.55 (0.36-0.86)

Region

North America 663 324 5.8 339 11.2 0.55 (0.44-0.68)

Rest of the World 59 30 6.5 29 12.5 0.43 (0.19-0.94)

Disease Status

Locally recurrent 12 4 - 8 10.9 0.83 (0.09-8.04)

Metastatic 709 349 5.8 360 11.4 0.54 (0.44-0.67)

TAX better

TAX/AV better

0.50.2 521

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Subgroup Analysis of PFS (2)

Baseline Risk Factor

Total n n Median

(mo) n Median (mo)

Hazard Ratio (95% Cl)

All Patients 722 354 5.8 368 11.3 0.54 (0.44-0.67)

Disease-free intervals (months)

≤24 months 296 146 4.9 150 10.6 0.58 (0.42-0.79)

>24 months 426 208 8.3 218 12.1 0.50 (0.38-0.67)

ER status

Positive 446 223 7.7 223 11.9 0.59 (0.44-0.78)

Negative 265 127 4.9 138 11.1 0.44 (0.31-0.61)

Unknown 11 4 21.3 7 1.70 (0.15-19.07)

ER/PR/HER2 combined

Negative 232 110 5.3 122 10.6 0.49 (0.34-0.70)

All others 490 224 7.4 246 12.5 0.57 (0.44-0.75)

HER2 status

Positive 15 6 2.4 9 11.3 0.00 (0.00- )

Negative 650 316 6.1 334 11.1 0.57 (0.45-0.71)

Unknown 57 32 7.7 25 12.5 0.42 (0.19-0.93)

TAX better

TAX/AV better

0.50.2 521

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Subgroup Analysis of PFS (3)

Baseline Risk Factor

Total n n Median

(mo) n Median (mo)

Hazard Ratio (95% Cl)

All Patients 722 354 5.8 368 11.3 0.54 (0.44-0.67)

Number of metastatic sites

<3 514 252 6.6 262 13.3 0.53 (0.41-0.69)

≥3 208 102 4.8 106 8.3 0.56 (0.38-0.81)

Measurable Disease at baseline

No 250 111 4.1 139 16.6 0.37 (0.25-0.54)

Yes 472 243 6.7 229 10.7 0.66 (0.51-0.85)

SLD of target lessions (mm)

≤Median (76.00) 238 116 8.6 122 11.1 0.72 (0.50-1.03)

>Median 234 127 5.8 107 8.6 0.63 (0.44-0.91)

Prior adjuvant hormone therapy

Yes 343 175 6.1 168 12.4 0.56 (0.41-0.77)

No 379 179 5.5 200 11.1 0.52 (0.39-0.70)

Metastatic / Recurrence hormone therapy

Yes 262 128 6.0 134 11.9 0.53 (0.37-0.77)

No 460 226 5.8 234 11.1 0.55 (0.43-0.72)

TAX better

TAX/AV better

0.50.2 521

CO-76

Reasons for PFS censoring: Patients censored more than 90 days from data cutoff (%)

TAX

(n=354) TAX/AV

(n=368) Total

(n=722)

Patients censored more than 90 days prior to data cutoff

40 35 37

No scans or pertinent clinical information submitted to IRF

6 6 6

Non-protocol Therapy 15 13 14

Investigator PD not confirmed by IRF

15 9 12

Data cutoff 3 9 5