AVADO

David Miles

Mount Vernon Cancer Centre, Middlesex,United Kingdom

A randomized, double-blind study of bevacizumab in combination with docetaxel as first-line treatment of patients with HER2-negative locally recurrent or metastatic breast cancer: efficacy and safety

On behalf of the AVADO investigators

Disclosure

ASCO General COI

Yes, I have Consultant or Advisory Role to disclose

– Roche

Yes, I have Honoraria to disclose

– Roche

Introduction

Bevacizumab is a monoclonal antibody to vascular endothelial growth factor (VEGF) that inhibits tumor angiogenesis

In a phase III trial (E2100) the addition of bevacizumab to first-line paclitaxel significantly increased progression-free survival (PFS) in patients with metastatic breast cancer (mBC)1

Docetaxel is a widely used and active taxane in mBC

AVADO was designed to investigate the addition of bevacizumab to docetaxel in first-line mBC

1. Miller et al. N Engl J Med 2007;357:2666–76

Docetaxel* 100mg/m2 + placebo q3w

Docetaxel* + bevacizumab 7.5mg/kg q3w

Docetaxel* + bevacizumab 15mg/kg q3w

*Docetaxel was administered for a maximum of nine cycles, but earlier discontinuation was permitted

AVADO: double-blind, placebo-controlled trial

Primary endpoint: progression-free survival

Secondary endpoints: overall response rate, duration of response, time to treatment failure, overall survival, safety, quality of life

All patientsgiven optionto receive

bevacizumabwith 2nd-line

chemotherapy

1st-line locally recurrentor mBC (n=705)

Stratification factors:• region• prior taxane/time to

relapse since adjuvant chemo

• measurable disease• hormone receptor

status

Treat withplacebo/

bevacizumabto disease

progression

AVADO: key eligibility criteria

Women aged ≥18 years

ECOG PS 0–1

No prior chemotherapy for locally recurrent or mBC

Prior adjuvant chemotherapy permitted if relapse ≥6 months since last dose (≥12 months if taxane-based)

HER2-negative

AVADO: statistical design

Sample size assumptions were based upon

– 80% power to detect PFS hazard ratio of 0.7• median 6.0 vs 8.6 months

– 705 patients required

Planned analyses were

– to compare PFS between each bevacizumab-containing arm versus control using a closed-test procedure (unstratified test)

– to investigate PFS with censoring for non-protocol antineoplastic therapy given prior to progression (stratified test)

AVADO: results

736 patients recruited from 104 sites in 26 countries between March 2006 and April 2007

Data cut-off 31 October 2007

Median follow-up = 10.2 months (range 0–17.5)

Analysis

– intent-to-treat population (all randomized patients), n=736

– safety population (patients receiving at least one dose of study therapy), n=730

AVADO: patient characteristics(ITT population), %

Placebo +docetaxel(n=241)

Bev 7.5†

+ docetaxel(n=248)

Bev 15† + docetaxel

(n=247)

Median age, years (range)

55.0 (29–83)

54.0 (26–83)

55.0 (27–76)

ECOG PS 0/1 62/38 61/39 61/39

ER/PgR positive 78 78 76

DFI ≥12 months 82 75 81

Adjuvant chemotherapyTaxaneAnthracycline

651555

651553

681755

≥3 metastatic sites 41 49 49

SitesBoneLiverLung

595038

604042

554648

Measurable disease 86 81 83

†mg/kg q3w; DFI = disease-free interval

Bev 15† +docetaxel (n=247)

HR + 95% CI (unstratified)

Bev 7.5† +docetaxel (n=248)

1.0

0.8

0.6

0.4

0.2

0

Months

PFS estimate

0 6 12 18

1.0

0.8

0.6

0.4

0.2

0

Months0 6 12 18

AVADO: progression-free survival(ITT population)

†mg/kg q3w;

HR + 95% CI (stratified*) 0.69 (0.54–0.89)p=0.0035

0.79 (0.63–0.98)p=0.0318

Placebo +docetaxel (n=241)

Median 8.78.0

HR + 95% CI (stratified*) 0.61 (0.48–0.78)p<0.0001

Median 8.88.0

0.72 (0.57–0.90)p=0.0099

HR + 95% CI (unstratified)

Placebo +docetaxel (n=241)

PFS estimate

*Data censored for non-protocol therapy before PD

Bev 7.5†

Baseline risk factor n HR

All patients 489 0.79

ER/PgR combined

Negative

Positive

105

382

0.76

0.78

Prior adjuvant chemotherapy

Yes

No

318

171

0.67

1.04

Prior taxane therapy

Yes

No

73

416

0.59

0.84

Measurable disease at baseline Yes

No

408

81

0.76

1.14

0.25 0.5 1 2 4

Favors bevacizumab

Favors placebo

AVADO: PFS subgroup analysis(ITT population)

Bev 15†

n HR

488 0.72

111

376

0.60

0.73

323

165

0.65

0.85

77

411

0.42

0.77

413

75

0.70

0.89

†mg/kg q3w

AVADO: response(patients with measurable disease), %

Placebo + docetaxel

(n=207)

Bev 7.5† + docetaxel

(n=201)

Bev 15† + docetaxel

(n=206)

Overall response rate 44 55 63

p value (vs control) – 0.0295 0.0001

Best responseCR

PR

SD

PD

1

44

39

12

3

52

35

5

1

62

25

4

†mg/kg q3w

AVADO: overall survival* (ITT population)

Placebo + docetaxel

(n=241)

Bev 7.5† + docetaxel

(n=248)

Bev 15† + docetaxel

(n=247)

Deaths, n (%) 50 (21) 49 (20) 37 (15)

Median overall survival, months

Hazard ratio

(95% CI)

NR

–

NR

0.92

(0.62–1.37)

NR

0.68

(0.45–1.04)

1-year survival, %

Patients still at risk, n

73

63

78

73

83

79

*Unstratified analysis; †mg/kg q3w; NR = not reached

Cut-off for final survival analysis 24 months after last patient recruited (April 2009)

AVADO: safety summary

%

Placebo + docetaxel

(n=233)

Bev 7.5† + docetaxel

(n=250)

Bev 15† + docetaxel

(n=247)

Any AE 99.6 100.0 99.6

Any grade ≥3 AE 67.0 74.8 74.1

AEs leading to death* 2.6 1.6 1.6

AEs leading to discontinuation‡ ofDocetaxelBevacizumab or placebo

24.011.2

20.8 8.0

24.311.7

†mg/kg q3w; *during study phase; ‡not mutually exclusive

AVADO: selected key grade ≥3 adverse events,* %

Adverse event, %Placebo +

docetaxel (n=233) Bev 7.5† +

docetaxel (n=250)Bev 15† +

docetaxel (n=247)

Diarrhea 3.4 6.8 6.9

Fatigue 5.2 8.4 6.5

Palmar-plantar erythema 0.9 5.2 6.1

Mucosal inflammation 0.4 4.0 4.9

Peripheral sensory

neuropathy 1.7 3.2 4.5

Stomatitis 0.4 2.8 3.2

Myalgia 0.9 1.2 3.6

Skin exfoliation 0 2.4 1.2

Anemia 2.6 0.4 1.2

Infection 3.0 0.8 0.4

*With a ≥2% difference in incidence between study arms; †mg/kg q3w

AVADO: grade ≥3 adverse events of special interest,* %

*Protocol-defined; †mg/kg q3w; RPLS = reversible posterior leukoencephalopathy syndrome;ATE = arterial thromboembolic event; VTE = venous thromboembolic event

Adverse event, %Placebo +

docetaxel (n=233)Bev 7.5† +

docetaxel (n=250)Bev 15† +

docetaxel (n=247)

All 31.3 35.2 36.4

Neutropenia 17.2 19.2 19.8

Febrile neutropenia 12.0 15.2 16.6

VTE 3.4 1.2 1.2

Hypertension 1.3 0.4 3.2

Bleeding 0.9 1.2 1.2

Wound-healing complication 0.9 0.4 0.4

GI perforation 0.9 0.4 0.4

CHF 0 0.8 0

ATE 0.4 0 0

Proteinuria 0 0 0.4

RPLS 0 0 0

AVADO: conclusions

Double-blind, placebo-controlled trial AVADO confirms the clinical benefit of combining first-line bevacizumab with taxane chemotherapy for patients with HER2-negative mBC

Both the 7.5 and 15mg/kg doses significantly increase PFS and response rate compared with placebo

Overall survival data are not yet mature

No new safety signals were detected and bevacizumab had limited impact on the toxicity profile of docetaxel 100mg/m2

Acknowledgements

All patients participating

AVADO investigators and study personnel

The study sponsor, F. Hoffmann-La Roche

BACK-UP SLIDES

1.0

0.8

0.6

0.4

0.2

00 6 12 18

Months

AVADO: progression-free survival (stratified analysis)

1.0

0.8

0.6

0.4

0.2

00 6 12 18

Months

Median 8.88.0Median 8.78.0

HR + 95% CI* 0.61 (0.48–0.78)p<0.0001

Bev 15† + docetaxel

(n=247)

Placebo + docetaxel

(n=241)

†mg/kg q3w; *Data censored for non-protocol therapy prior to PD (ITT population)

HR + 95% CI* 0.69 (0.54–0.89)p=0.0035

Bev 7.5† + docetaxel

(n=248)

Placebo + docetaxel

(n=241)

PFS estimate PFS estimate

Bev 7.5†

Baseline risk factor n HR

All patients 489 0.79

Age

<65 years

≥65 years

410

79

0.81

0.62

Disease-free interval

≤24 months

>24 months

188

301

0.70

0.83

Number of metastatic sites

<3

≥3

264

221

0.73

0.79

0.25 0.5 1 2 4

Favors bevacizumab

Favors placebo

AVADO: PFS subgroup analysis(ITT population)

Bev 15†

n HR

488 0.72

402

86

0.73

0.62

161

327

0.62

0.79

263

221

0.77

0.65

†mg/kg q3w

AVADO: patients starting docetaxel at each cycle,* %

0

20

40

60

80

100

1–3 4–6 7–9Cycle number

Placebo + docetaxelBev 7.5† + docetaxelBev 15† + docetaxel

Patients, %

*Safety population; †mg/kg q3w

AVADO: patients starting bevacizumab/placebo at each cycle,* %

0

20

40

60

80

100

1–3 4–6 7–9 10–14 15–18 10+

Patients, %

Cycle number*Safety population; †mg/kg q3w

Placebo + docetaxelBev 7.5† + docetaxelBev 15† + docetaxel

Phase III trial of bevacizumab + paclitaxel in first-line mBC (E2100)

Primary endpoint: progression-free survival – other endpoints: overall response rate, overall

survival, quality of life

Paclitaxel(n=354)

Paclitaxel + bevacizumab10mg/kg q2w

(n=368)

Treat to disease progression*

Treat to disease progression

*No cross over permitted

Paclitaxel:90mg/m2/w for 3 weeks of a 4-week cycle

Miller, et al. NEJM 2007

Previously untreated locally recurrent or mBC

(n=722)

E2100: significant progression-free survival increase

*Scans available for 90% of patients Cameron D. EJC Suppl. 2008; Avastin SmPC 2008

11.4

HR=0.48

Paclitaxel (n=354)

Bev + paclitaxel (n=368)

PFS byinvestigator

5.811.3

HR=0.42

PFS by IRF*

5.8

0 6 12 18 24 30 36 42 48 54Month

PFS estimate1.0

0.8

0.6

0.4

0.2

0

confirmed by Independent Review Facility (IRF)

E2100: objective response(patients with measurable disease)

Cameron D. EJC Suppl. 2008

Bestresponse (%)

Investigator assessment

(n=525)

IRF assessment(n=472)

50

2223

48 Paclitaxel

Bev + paclitaxel

CR + PRp<0.0001

CR + PRp<0.0001

60

50

40

30

20

10

0

E2100: no new safety signals

Miles D. EJC Suppl. 2008; Avastin SmPC 2008

Selected grade 3/4 adverse events,* %

Paclitaxel(n=348)

Bev + paclitaxel (n=363)

Grade 3 Grade 4 Grade 3 Grade 4

Sensory neuropathy 17.0 0.6 23.7 0.6

Fatigue 4.9 0.3 10.5 0.2

Infection + grade 3/4 neutropenia 1.1 0.3 2.8 0

Hypertension 1.4 0 15.4 0.6

Arterial thromboembolic events† ‡ 0 0 1.1 1.9

Venous thromboembolic events 2.3 2.0 2.8 0.3

Bleeding 0.3 0 1.7 0.6

Proteinuria 0 0 1.9 1.1

Left ventricular dysfunction† 0 0 1.9 0.3*Includes NCI AdEERS mandatory collection in the bevacizumab plus paclitaxel arm only which does not allow a valid comparison between the two arms†Events were double counted where applicable ‡Two additional patients died from myocardial infarction in the bevacizumab plus paclitaxel arm