CS-1 Results of the Phase 3 Clinical Trials of Abraxane vs. Taxol in Metastatic Breast Cancer William J. Gradishar, MD, FACP Professor of Medicine Northwestern

CS-1

Results of the Phase 3 Clinical Trials of Abraxane vs. Taxol in Metastatic Breast Cancer

William J. Gradishar, MD, FACP

Professor of Medicine

Northwestern University

In Metastatic Breast Cancer Abraxane Has Greater Anti-tumor Activity Than Taxol

CS-2

Removal of Cremophor Resulted in Superior Anti-tumor and Intratumor Paclitaxel Concentrations in Preclinical Models

CS-3

Desai N, et al. Clin Cancer Res 2006;12(4), 1317-24

Athymic mice with human xenografts (n = 10 per group; daily administration for 5 days)

Breast MX-1 tumor modelequidose paclitaxel comparison

0 10 20 30 40 50 60 70 80 90 100 1100

250

500

750

1000

1250

1500

1750

2000 Control

ABI-007 30 mg/kg/dose

Taxol 30 mg/kg/dose

Days postimplant

Tum

or v

olum

e (m

m3 )

0 10 20 30 40 50 60 70 80 90 100 1100

250

500

750

1000

1250

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2000 Control


Taxol 30 mg/kg/dose

Days postimplant

Tum

or v

olum

e (m

m3 )

Abraxane 30 mg/kg/dose

Taxol 30 mg/kg/dose

0 10 20 30 40 50 60 70 80 90 100 1100

250

500

750

1000

1250

1500

1750

2000 Control


Taxol 30 mg/kg/dose

Days postimplant

Tum

or v

olum

e (m

m3 )

0 10 20 30 40 50 60 70 80 90 100 1100

250

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1250

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Taxol 30 mg/kg/dose

Days postimplant

Tum

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olum

e (m

m3 )

0 10 20 30 40 50 60 70 80 90 100 1100

250

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750

1000

1250

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1750

2000 Control


Taxol 30 mg/kg/dose

Days postimplant

Tum

or v

olum

e (m

m3 )

0 10 20 30 40 50 60 70 80 90 100 1100

250

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750

1000

1250

1500

1750

2000 Control


Taxol 30 mg/kg/dose

Days postimplant

Tum

or v

olum

e (m

m3 )

Abraxane 30 mg/kg/dose

Taxol 30 mg/kg/dose

Preclinical Finding: Replacing Cremophor with Albumin Enhanced the Efficacy of Paclitaxel in Breast Cancer

CS-4

Abraxane Results in Higher Intra-tumoral Concentration of Paclitaxel Compared to Taxol

ABI-007 = 1.33 X Taxol

Desai et al. Clin Can Res, 2006.

Intratumor paclitaxel levels following equal doses ABI-007 and Taxol in nude mice bearing MX-1 human breast cancer xenografts

CS-5

Lung H522 (equitoxic dose comparison)

Abraxane30 mg/kg/dose

Control

Taxol13.4 mg/kg/dose

0 25 50 750

200

400

600

800

1000

1200

Days postimplant

Tu

mo

r vo

lum

e (m

m3)


Control



Control


0 25 50 750

200

400

600

800

1000

1200

Days postimplant

Tu

mo

r vo

lum

e (m

m3)

0 25 50 750

200

400

600

800

1000

1200

Days postimplant

Tu

mo

r vo

lum

e (m

m3)

Prostate PC3 (equitoxic dose comparison)Ovarian SKOV3 (equitoxic dose comparison)

0 25 50 750

500

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1500

Days postimplant

Tu

mo

r v

olu

me

(m

m3 )


Control


0 25 50 750

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1500

Days postimplant

Tu

mo

r v

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(m

m3 )


Control



Control


Desai N, et al. Clin Cancer Res 2006;12(4), 1317-24

Athymic mice with human xenografts (n = 10 per group; daily administration for 5 days)

Preclinical Superiority of Abraxane over Taxol: Anti-tumor Activity Predicted Results in the Clinic

0 10 20 30 40 50 60 700

500

1000

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ABI-007 30mg/kg/doseTaxol 13.4mg/kg/dose

Control

Days postimplant

Tum

or vo

lum

e (m

m3)

Nano 30 mg/kg/dose

Cremo 13.4 mg/kg/dose

0 10 20 30 40 50 60 700

500

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Control

Days postimplant

Tum

or vo

lum

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m3)

Nano 30 mg/kg/dose


0 10 20 30 40 50 60 700

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Control

Days postimplant

Tum

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e (m

m3)

Nano 30 mg/kg/dose

Cremo 13.4 mg/kg/dose0 25 50 75

0

500

1000

1500

Days postimplant

Tu

mo

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m3 )


Control


0 25 50 750

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1500

Days postimplant

Tu

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m3 )


Control



Control


0 10 20 30 40 50 60 700

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Control

Days postimplant

Tum

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m3)

Nano 30 mg/kg/dose


0 10 20 30 40 50 60 700

500

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2500


Control

Days postimplant

Tum

or vo

lum

e (m

m3)

Nano 30 mg/kg/dose


0 10 20 30 40 50 60 700

500

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2500


Control

Days postimplant

Tum

or vo

lum

e (m

m3)

Nano 30 mg/kg/dose

Cremo 13.4 mg/kg/dose0 25 50 75

0

500

1000

1500

Days postimplant

Tu

mo

r vo

lum

e (m

m3 )


Control


0 25 50 750

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Days postimplant

Tu

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m3 )


Control



Control


Colon HT29 (equitoxic dose comparison)

0 10 20 30 40 50 60 700

500

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1500

Days postimplant

Tu

mo

r v

olu

me

(m

m3) Abraxane

30 mg/kg

Control

Taxol20 mg/kg

0 10 20 30 40 50 60 700

500

1000

1500

Days postimplant

Tu

mo

r v

olu

me

(m

m3) Abraxane

30 mg/kg

Control

Taxol20 mg/kg

Abraxane30 mg/kg

Control

Taxol20 mg/kg13.4

0 10 20 30 40 50 60 700

500

1000

1500

Days postimplant

Tu

mo

r v

olu

me

(m

m3) Abraxane

30 mg/kg

Control

Taxol20 mg/kg

0 10 20 30 40 50 60 700

500

1000

1500

Days postimplant

Tu

mo

r v

olu

me

(m

m3) Abraxane

30 mg/kg

Control

Taxol20 mg/kg

Abraxane30 mg/kg

Control

Taxol20 mg/kg13.4

CS-6

Abraxane vs. TaxolPhase 3 Clinical Trial

Journal Clin Oncology, 2005;23.

CS-7

Phase 3 Trial Design

Randomization Randomization (1:1)(1:1)

N = 460N = 460

Randomization Randomization (1:1)(1:1)

N = 460N = 460Taxol 175 mg/mTaxol 175 mg/m22

IV over 3 hrs q 3 wkIV over 3 hrs q 3 wkStandard Premedication Standard Premedication with Dexamethasone and with Dexamethasone and

Anti-histaminesAnti-histamines

Taxol 175 mg/mTaxol 175 mg/m22

IV over 3 hrs q 3 wkIV over 3 hrs q 3 wkStandard Premedication Standard Premedication with Dexamethasone and with Dexamethasone and

Anti-histaminesAnti-histamines

Abraxane 260 mg/m2Abraxane 260 mg/m2 IV over 30 min q 3 wkIV over 30 min q 3 wk

No Standard No Standard PremedicationPremedication

Abraxane 260 mg/m2Abraxane 260 mg/m2 IV over 30 min q 3 wkIV over 30 min q 3 wk

No Standard No Standard PremedicationPremedication

CS-8Investigator Response DemonstratingSuperior Efficacy Across All Lines of Therapyin Metastatic Breast Cancer

Replacement of Cremophor with albumin enhanced the efficacy of paclitaxel in metastatic breast cancer

Source: Abraxane NDA

CS-9Response Assessment Demonstrated Superiority of Cremophor-free Paclitaxel Independent of Dataset and Reviewer

Source: Abraxane NDA

Reconciled Target Lesion

Response Rate

Investigator Target Lesion

Response Rate

Blinded Radiologist Target Lesion

Response Rate

CS-10

Abraxane Response Rate (Package Insert) Statistically Significantly Higher than Taxol

Source: Abraxane Package Insert

CS-11Prolonged Time to Disease ProgressionIndependent Radiology Laboratory Response Dataset, Investigator Response Dataset, and Follow-up Disease Progression Data

0.00

0.25

0.50

0.75

1.00

0 8 16 24 32 40 48 56 64 72 80 88 96 104 112 120

Week

Note: P-value from log-rank test.Source: NDA Labeling Supplement

Abraxane (N = 233)Taxol (N = 227)P-value = 0.002Hazard Ratio = 0.721

Pro

po

rtio

n o

f n

o P

rog

ress

ion

CS-12

No Difference in Overall SurvivalAll Patients

0.00

0.25

0.50

0.75

1.00

0 8 16 24 32 40 48 56 64 72 80 88 96 104 112 120 128 136 144 152

Week

Pro

po

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n o

f n

o P

rog

ress

ion

Abraxane (N = 129)Taxol (N = 143)P-value = 0.348Hazard Ratio = 0.904

Note: P-value from log-rank test.Source: NDA Labeling Supplement

CS-13

Second Phase 3 Randomized Controlled Clinical Trial Confirms the Results from CA012

Abraxane260 mg/m2

Taxol175 mg/m2 P-value

Patients Evaluable (All) N = 81 N = 820.025

Response Rate 38% 21%

Patients Evaluable (First Line) N = 47 N = 480.005

Response Rate 47% 19%

GCP study required by the Chinese Regulatory Authorities for Approval of Abraxane in China(PI:Guan Zhong-Zen)

100 Patients per arm (Abraxane vs. Taxol)

Dose: Abraxane 260 mg/m2, Taxol 175 mg/m2 q3w

CS-14

Preliminary Progression-Free SurvivalPer-Protocol Population (Study CA201)

0.00

0.25

0.50

0.75

1.00

0 3 6 9 12 15 18

Months

Abraxane 260 mg/m2 (N = 94)Taxol 175 mg/m2 (N = 93)P-value = 0.090HR = 0.644

Pro

po

rtio

n N

ot

Pro

gre

ssed

33% of events

CS-15

Hypotheses for Increased Anti-tumor Activity

50% higher paclitaxel dose50% higher paclitaxel dose 33% higher intra-tumor paclitaxel33% higher intra-tumor paclitaxel

A Combination of Two Factors

CS-16

Summary: Abraxane is Efficacious and Well Tolerated at a Higher Paclitaxel Dose

Abraxane consistently demonstrated superioranti-tumor activity compared to Taxol in metastatic breast cancer

There is no scientific reason to believe that Abraxane would be less effective in the adjuvant setting

Documents

CS-1 Results of the Phase 3 Clinical Trials of Abraxane vs. Taxol in Metastatic Breast Cancer William J. Gradishar, MD, FACP Professor of Medicine Northwestern