CI-1 IRESSA ® (ZD1839) Monotherapy for Non-Small Cell Lung Cancer (NSCLC) Oncologic Drugs Advisory Committee Meeting September 24, 2002 Oncologic Drugs

CI-1

IRESSA®

(ZD1839) Monotherapy for Non-Small Cell

Lung Cancer (NSCLC)

IRESSA®

(ZD1839) Monotherapy for Non-Small Cell

Lung Cancer (NSCLC)

Oncologic Drugs

Advisory Committee Meeting September 24, 2002

Oncologic Drugs

Advisory Committee Meeting September 24, 2002

ONCOLOGY

CI-2

IRESSA® IntroductionIRESSA®

Introduction

George Blackledge, MD

Clinical Vice President, Oncology

AstraZeneca Pharmaceuticals

George Blackledge, MD

Clinical Vice President, Oncology

AstraZeneca Pharmaceuticals

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IRESSA® Agenda for Today’s Meeting

IRESSA® Agenda for Today’s Meeting

Introduction George Blackledge, MD

Refractory NSCLC Frances A. Shepherd, MD

Clinical efficacy Ronald B. Natale, MD

Safety profile Alan B. Sandler, MD

Summary George Blackledge, MD

Introduction George Blackledge, MD

Refractory NSCLC Frances A. Shepherd, MD

Clinical efficacy Ronald B. Natale, MD

Safety profile Alan B. Sandler, MD

Summary George Blackledge, MD

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Experts Available for Q&AExperts Available for Q&A

Jose Baselga, MDChairman, Medical OncologyVall d'Hebron University HospitalBarcelona, Spain

David Cella, PhDDirector, Center on OutcomesResearch and Education Northwestern UniversityEvanston, IL

Gary Donaldson, PhDProfessor, Department of AnesthesiologyUniversity of Utah School of MedicineSalt Lake City, UT

Jose Baselga, MDChairman, Medical OncologyVall d'Hebron University HospitalBarcelona, Spain

David Cella, PhDDirector, Center on OutcomesResearch and Education Northwestern UniversityEvanston, IL

Gary Donaldson, PhDProfessor, Department of AnesthesiologyUniversity of Utah School of MedicineSalt Lake City, UT

Mark Kris, MDChief, Thoracic OncologyMemorial Sloan-Kettering Cancer CenterNew York, NY

Thomas Lynch, MDAssociate Professor of MedicineMassachusetts General HospitalBoston, MA

Mark Kris, MDChief, Thoracic OncologyMemorial Sloan-Kettering Cancer CenterNew York, NY

Thomas Lynch, MDAssociate Professor of MedicineMassachusetts General HospitalBoston, MA

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Experts Available From AstraZeneca Experts Available From AstraZeneca

Steve Averbuch, MDAndrea Kay, MDDavid McKillop, PhDJudith Ochs, MDGraham Richmond, MScMark Scott, PhDMark Steinberg, MDHelen Swaisland, BScAlan Wakeling, PhDMichael Wolf, MSc

Steve Averbuch, MDAndrea Kay, MDDavid McKillop, PhDJudith Ochs, MDGraham Richmond, MScMark Scott, PhDMark Steinberg, MDHelen Swaisland, BScAlan Wakeling, PhDMichael Wolf, MSc

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IRESSA® for 3rd-Line NSCLCIRESSA® for 3rd-Line NSCLC

High unmet need

– Thousands of patients each year

– Disease of symptoms

IRESSA

– Unprecedented activity in target population

– Symptom control

– Excellent tolerability

High unmet need

– Thousands of patients each year

– Disease of symptoms

IRESSA

– Unprecedented activity in target population

– Symptom control

– Excellent tolerability

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Demonstration of the Role of IRESSA®Demonstration of the Role of IRESSA®

IRESSA® 250 mg po daily can be used

in the 3rd-line treatment of patients

with locally advanced or metastatic

non-small cell lung cancer.

IRESSA® 250 mg po daily can be used

in the 3rd-line treatment of patients

with locally advanced or metastatic

non-small cell lung cancer.

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How Did We Get Here? IRESSA®

How Did We Get Here? IRESSA®

Molecular targeted agents 1990 discovery program

ZD1839 molecule discovered 1994

Healthy volunteer trials 1997

Molecular targeted agents 1990 discovery program

ZD1839 molecule discovered 1994

Healthy volunteer trials 1997

myc cyclin D1

Jun Fos

RRRR

RRRR

EGFR Signal Transduction in Tumor Cells EGFR Signal Transduction in Tumor Cells

K K

KK

Gene transcription and cell cycle progression


CI-9

MetastasisAngiogenesis

myc cyclin D1

Jun Fos

RRRR

EGFR Signal Transduction in Tumor Cells EGFR Signal Transduction in Tumor Cells

K KRR

K

RR

K



MAPKMAPK

MEKMEK

RASRAS RAFRAF

SOSSOS

GRB2GRB2

Proliferation

PI3-KPI3-K

AKTAKT

Inhibition of apoptosis

PPPP

PPPP

PPPP

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CI-11

IRESSA® Non-Clinical SummaryIRESSA® Non-Clinical Summary

IC50 (µM)

Selective enzyme inhibition

– EGFR (ErbB-1): 0.033

– Other cellular kinases > 3

EGFR autophosphorylation < 1 inhibition in tumor cell lines

Tumor cell growth inhibition

– EGF stimulated 0.054

– Basal 8.8

IC50 (µM)

Selective enzyme inhibition

– EGFR (ErbB-1): 0.033

– Other cellular kinases > 3

EGFR autophosphorylation < 1 inhibition in tumor cell lines

Tumor cell growth inhibition

– EGF stimulated 0.054

– Basal 8.8

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8060402000

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

Day

Mea

n t

um

or

volu

me,

cm

3IRESSA® Inhibits Growth of

A549 Xenograft Tumors (NSCLC)IRESSA® Inhibits Growth of

A549 Xenograft Tumors (NSCLC)

IRESSA 200 mg/kg, po days 10 - 72IRESSA 200 mg/kg, po days 10 - 30Vehicle

CI-13

Clinical Pharmacokinetics (N = 535)

Clinical Pharmacokinetics (N = 535)

Bioavailability ~ 60%

No clinically significant effect of food

Mean t½ = 41 hours

Steady state achieved within 7 to 10 days

Bioavailability ~ 60%

No clinically significant effect of food

Mean t½ = 41 hours

Steady state achieved within 7 to 10 days

Daily oral dosing administration scheduleDaily oral dosing administration schedule

CI-14

Phase I clinical trials 1998

3rd-line monotherapy 2000(Trials 39 and 16)§

1st-line combination therapy 2000(Trials 14 and 17)§

Expanded Access Program (EAP) 2000





IRESSA® Clinical Development ProgramIRESSA® Clinical Development Program

§Separate Fast Track designations by FDA§Separate Fast Track designations by FDA

Phase I clinical trials

1998

Phase I clinical trials

1998

CI-15

IRESSA® Phase I Safety and Activity (N = 289)

IRESSA® Phase I Safety and Activity (N = 289)

Safety profile

– Grade 1 - 2 skin, GI toxicity common

– Dose-limiting toxicity: reversible Grade 3 diarrhea at 800 to 1,000 mg daily

Striking symptom improvement in NSCLC Antitumor activity in NSCLC

– 10 objective responses in 100 patients

– 17 on study ≥ 6 months

Safety profile

– Grade 1 - 2 skin, GI toxicity common

– Dose-limiting toxicity: reversible Grade 3 diarrhea at 800 to 1,000 mg daily

Striking symptom improvement in NSCLC Antitumor activity in NSCLC

– 10 objective responses in 100 patients

– 17 on study ≥ 6 months

CI-16

Prior to treatmentPrior to treatment After 14 days treatmentAfter 14 days treatment

X-rays of NSCLC Patient Pre- and Post-Treatment With IRESSA®

(400 mg/day)

X-rays of NSCLC Patient Pre- and Post-Treatment With IRESSA®

(400 mg/day)

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Rationale for Monotherapy Rationale for Monotherapy

No approved therapy for 3rd-line NSCLC patients

Clinical need

– Objective response

– Symptom improvement

– Well-tolerated therapy

No approved therapy for 3rd-line NSCLC patients

Clinical need

– Objective response

– Symptom improvement

– Well-tolerated therapy

Trials 39 and 16

CI-19

Results Results

Response rate 10% in Trial 39 with an additional 30% stable disease

Associated symptom improvement

Similar supportive data in Trial 16

Highly acceptable safety profile

Response rate 10% in Trial 39 with an additional 30% stable disease

Associated symptom improvement

Similar supportive data in Trial 16

Highly acceptable safety profile

Trials 39 and 16

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1st-Line Combination Therapy1st-Line Combination Therapy

Rationale– Novel mechanism of action – Objective responses in Phase I– Was seen as the next logical step in improving

outcome in NSCLC Trial design

– Previously untreated patients with advanced, unresectable NSCLC

– Standard combination chemotherapy ± IRESSA®

– Primary objective: survival

Rationale– Novel mechanism of action – Objective responses in Phase I– Was seen as the next logical step in improving

outcome in NSCLC Trial design

– Previously untreated patients with advanced, unresectable NSCLC

– Standard combination chemotherapy ± IRESSA®

– Primary objective: survival

Trials 14 and 17

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1st-Line Combination Trial Results1st-Line Combination Trial Results

Both trials – Representative of typical 1st-line populations – Well-balanced baseline patient and disease

characteristics

Both trials – Representative of typical 1st-line populations – Well-balanced baseline patient and disease

characteristics No difference in overall survival across treatment

arms in both trials Analysis of response rate and time to progression

showed no additional benefit for IRESSA® added to 2-drug chemotherapy

No difference in overall survival across treatment arms in both trials

Analysis of response rate and time to progression showed no additional benefit for IRESSA® added to 2-drug chemotherapy

No additional safety issues No additional safety issues

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IRESSA® 3rd-Line Monotherapy Benefit Distinct From Combination Trial Data

IRESSA® 3rd-Line Monotherapy Benefit Distinct From Combination Trial Data

Trials 14 and 17 outcomes are not germane to results demonstrated in 3rd-line NSCLC

– Different treatment setting

– Combination with chemotherapy rather than monotherapy

Lack of survival benefit in 1st-line does not negate responses and symptom improvement in 3rd-line

Trials 14 and 17 outcomes are not germane to results demonstrated in 3rd-line NSCLC

– Different treatment setting

– Combination with chemotherapy rather than monotherapy

Lack of survival benefit in 1st-line does not negate responses and symptom improvement in 3rd-line

CI-24

“With Genentech’s anti-VEGF announcement recently, SWOG’s evidence of interference by tamoxifen in the efficacy of breast cancer adjuvant therapy, and the IRESSA® results, I think we’re seeing a pattern emerge that is really (paradoxically) quite hopeful.

We’ve said that these new therapies are dramatically unlike chemotherapy but we’ve tried to develop them as if they were.

Now we know they’re not, and IRESSA has to be used following different paradigms.”

Larry Norton, MD

“With Genentech’s anti-VEGF announcement recently, SWOG’s evidence of interference by tamoxifen in the efficacy of breast cancer adjuvant therapy, and the IRESSA® results, I think we’re seeing a pattern emerge that is really (paradoxically) quite hopeful.

We’ve said that these new therapies are dramatically unlike chemotherapy but we’ve tried to develop them as if they were.

Now we know they’re not, and IRESSA has to be used following different paradigms.”

Larry Norton, MD

CI-25

Trial Design Randomization

3rd line Iressa vs BSC2nd line Iressa vs Taxotere

Taxotere +/- Iressa

1st line Iressa vs Navelbine(platinum-ineligible pts)Protocol final; to start 4Q02

Locally advanced Iressa vs placebo CT+RT Taxotere × 3 Randomize NCI (SWOG / Intergroup) – actively recruiting

Adjuvant Iressa vs placeboAZ (Japan) - actively recruiting NCI / NCI-C / EORTC – to start 4Q02

Randomized, Controlled Trials in NSCLCRandomized, Controlled Trials in NSCLC

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IRESSA® Expanded Access ProgramIRESSA® Expanded Access Program

Rationale– Clinical benefit in Phase I– Satisfy patient and physician demand

Developed in close collaboration with– FDA – NORD – Patient advocates – Medical ethicists

Eligible population– Patients with advanced NSCLC and

no other treatment options

Rationale– Clinical benefit in Phase I– Satisfy patient and physician demand

Developed in close collaboration with– FDA – NORD – Patient advocates – Medical ethicists

Eligible population– Patients with advanced NSCLC and

no other treatment options

CI-28

IRESSA® Expanded Access ProgramIRESSA® Expanded Access Program

Confirmed unmet need in refractory NSCLC

~ 18,000 patients worldwide (2,000 per month)

~ 40% of patients continued IRESSA beyond 6 months

Confirmed unmet need in refractory NSCLC

~ 18,000 patients worldwide (2,000 per month)

~ 40% of patients continued IRESSA beyond 6 months

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CI-30

FDA Questions (1)FDA Questions (1)

The FDA believes the relevance of the symptom improvement data discussed above cannot be adequately evaluated without a randomized, blinded study with an adequate control arm (the two doses of ZD1839 show no difference in efficacy and are thus not adequate). Do you agree?

The FDA believes the relevance of the symptom improvement data discussed above cannot be adequately evaluated without a randomized, blinded study with an adequate control arm (the two doses of ZD1839 show no difference in efficacy and are thus not adequate). Do you agree?

CI-31


Given the lack of clinical benefit in two large studies of ZD1839 in combination with standard first-line NSCLC chemotherapy, is the Study 0039 response rate of 10% in 139 patients with resistant or refractory NSCLC reasonably likely to predict ZD1839 clinical benefit in NSCLC?

Given the lack of clinical benefit in two large studies of ZD1839 in combination with standard first-line NSCLC chemotherapy, is the Study 0039 response rate of 10% in 139 patients with resistant or refractory NSCLC reasonably likely to predict ZD1839 clinical benefit in NSCLC?

CI-32


More than 12,000 NSCLC patients have received ZD1839 under an Expanded Access Protocol. Please discuss what position FDA should take on ZD1839 expanded access if marketing approval of ZD1839 is not granted at this time.

More than 12,000 NSCLC patients have received ZD1839 under an Expanded Access Protocol. Please discuss what position FDA should take on ZD1839 expanded access if marketing approval of ZD1839 is not granted at this time.

CI-33


Regardless of whether ZD1839 is granted accelerated approval for treating NSCLC, additional trials may be needed. Please discuss potential study designs to demonstrate that ZD1839 provides clinical benefit to NSCLC patients.

Regardless of whether ZD1839 is granted accelerated approval for treating NSCLC, additional trials may be needed. Please discuss potential study designs to demonstrate that ZD1839 provides clinical benefit to NSCLC patients.

CI-34

IRESSA®IRESSA®

High unmet need in target population

Consistent response rate

Correlated symptomatic benefit

Well tolerated, easily administered

High unmet need in target population

Consistent response rate

Correlated symptomatic benefit

Well tolerated, easily administered

Documents

CI-1 IRESSA ® (ZD1839) Monotherapy for Non-Small Cell Lung Cancer (NSCLC) Oncologic Drugs Advisory Committee Meeting September 24, 2002 Oncologic Drugs