AVADO PFS Analysis (ITT Population)

All P values vs. placebo

Adapted from Miles et al. ASCO 2008, abstract LBA 1011.

AVADO: Response (patients with measurable disease), %

†mg/kg q3w

Adapted from Miles et al. ASCO 2008, abstract LBA 1011.

E2100 and AVADO Serious Adverse Events (%)

*ATE: arterial thromboembolic events. No increase in venous thromboembolic events was observed with bevacizumab in either study

1. Adapted from Miller et al. N Engl J Med 2007;357-2666-76.2. Adapted from Miles et al. ASCO 2008, abstract LBA 1011.

E2100 Study Design: Randomized, double-blind, placebo-controlled, multicentre, phase III trial

• Primary end point: progression-free survival (PFS)

• Secondary end points: overall response rate, overall survival, quality of life

Previously untreated MBC

(n=722)

Paclitaxel 90 mg/m2 qw for 3 weeks of a

4-week cycle(n=354)

Paclitaxel + bevacizumab10 mg/kg q2w

(n=368)

Progressive disease (PD)*

PD

*No crossover permitted

Adapted from Miller et al. N Engl J Med 2007;357:2666-76.

0.0

0.2

0.4

0.6

0.8

1.0

Months

PF

S p

ropo

rtio

n

0 6 12 18 24 30

E2100 Trial: PFS Results

HR=0.51 (0.43-0.62)

Log rank test P<0.0001

Paclitaxel/bevacizumab: 11.4 months

Paclitaxel: 6.11 months

484 events reported (89% of required events)

6.11 11.4

Adapted from Miller et al. N Engl J Med 2007;357:2666-76.

E2100 Trial: Overall Response Rate

Ove

rall

resp

onse

rat

e (%

)

339 341 262 236

P<0.0001

P<0.0001

Paclitaxel

Paclitaxel/bevacizumab

13.8

29.9

16.0

37.7

0

10

20

30

40

All patients Measurable disease

Adapted from Miller et al. N Engl J Med 2007;357:2666-76.

AVADO Study Design: Randomized, double-blind, placebo-controlled, multicentre, phase III trial

Primary end point: PFS

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

Previously untreated MBC

(n=705)

Docetaxel 100 mg/m2 q3w+

placeboPD

Docetaxel + bevacizumab7.5 mg/kg q3w

Docetaxel + bevacizumab15 mg/kg q3w

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

PD

PD

Adapted from Miles et al. ASCO 2008, abstract LBA1011.

All patients were given the option

to receive bevacizumab

with second line chemotherapy

Adapted from Miles et al. ASCO 2008, abstract LBA1011.

AVADO: Response (patients with measurable disease), %

Placebo+ docetaxel

(n=207)

Bev 7.5†

+ docetaxel (n=201)Bev 15†

+ docetaxel (n=206)

Overall response rate

P value (vs. control)

44

-

55

0.0295

63

0.0001

Best responseCR 1 3 1PR 44 52 62SD 39 35 25

PD 12 5 4

†mg/kg q3w

Adapted from Miles et al. ASCO 2008, abstract LBA1011.

AVADO: Safety Summary

%

Placebo+ docetaxel

(n=233)

Bev 7.5†

+ docetaxel (n=250)

Bev 15†

+ docetaxel (n=247)

Any adverse events (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‡ of

Docetaxel 24.0 20.8 24.3

Bevacizumab or placebo 11.2 8.0 11.7

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

Adapted from Miles et al. ASCO 2008, abstract LBA1011.

AVADO: Grade ≥3 Adverse Events of Special Interest,* %

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

Venous thromboembolism 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

Congestive heart failure 0 0.8 0

ATE 0.4 0 0

Proteinuria 0 0 0.4

RPLS** 0 0 0

*Protocol-defined; †mg/kg q3w; **RPLS=reversible posterior leuko encephalopathy syndrome

Ongoing RIBBON 1 Phase IIITrial Study Design

Primary end point: hierarchical PFS

Anthracycline-based combination chemotherapy, Q3w taxane (docetaxel or protein-bound paclitaxel) or capecitabine as determined by investigator prior to randomization † Chemotherapy regimen at investigator discretion

Chemotherapy*+ bevacizumabi.v. 15mg/kg q3w

Chemotherapy* + placebo

(i.v. on day 1 of 21-day cycle)

Previously untreated MBC

(n=950), 2:1 Randomization

PD

PD

Chemotherapy† + bevacizumab i.v. 15mg/kg q3w or 10

mg/kg q2w

Adapted from Albain K. ASCO 2008.

Chemotherapy†

+ crossover to bevacizumab

15mg/kg q3w or 10 mg/kg q2w