CR-1

Actions Ongoing Clinical Development

Actions Ongoing Clinical Development

Judith S. Ochs, MDJudith S. Ochs, MD

CR-2

Immediate Actions Agreed With FDAImmediate Actions Agreed With FDA

● Communicate rapidly and extensively• Enable informed physician decision making • Reduce the numbers of patients receiving

IRESSA® for the first time• Provide FDA with prescription data q 2 wk

● Maintain IRESSA® availability

● Rapidly provide full data to FDA for review

● Communicate rapidly and extensively• Enable informed physician decision making • Reduce the numbers of patients receiving

IRESSA® for the first time• Provide FDA with prescription data q 2 wk

● Maintain IRESSA® availability

● Rapidly provide full data to FDA for review

CR-3

Communications—December 17, 2004Communications—December 17, 2004

AstraZeneca actions

● Press release

● ~ 141,000 Dear Doctor Letters (DDL)

● Sales force distribution of DDL

● DDL posted to Web sites

● Patient advocate groups notified

● Clinical trial investigators, NCI notified

● Promotional activity suspended

External actions

● ASCO e-mail from FDA

● Information posted on FDA Web site

AstraZeneca actions

● Press release

● ~ 141,000 Dear Doctor Letters (DDL)

● Sales force distribution of DDL

● DDL posted to Web sites

● Patient advocate groups notified

● Clinical trial investigators, NCI notified

● Promotional activity suspended

External actions

● ASCO e-mail from FDA

● Information posted on FDA Web site

CR-4

Further Communications Further Communications

● Presentation at ODAC

● Communications to healthcare professionals• Journal placement of DDL• AACR, WCLC abstracts• Manuscript in preparation

● Presentation at ODAC

● Communications to healthcare professionals• Journal placement of DDL• AACR, WCLC abstracts• Manuscript in preparation

CR-5

CR-6

Feb/March Journal PlacementFeb/March Journal Placement

● American Journal Oncology Reviews● Clinical Lung Cancer● Clinical Advances in Hematology & Oncology● Hematology/Oncology Today● JAMA Oncology Subscriber● Journal of Clinical Oncology● New England Journal Oncology Subscriber● Oncology● Oncology Times● The Oncologist

● American Journal Oncology Reviews● Clinical Lung Cancer● Clinical Advances in Hematology & Oncology● Hematology/Oncology Today● JAMA Oncology Subscriber● Journal of Clinical Oncology● New England Journal Oncology Subscriber● Oncology● Oncology Times● The Oncologist

CR-7

Impact on IRESSA® UsageImpact on IRESSA® Usage

● Total and new prescriptions for IRESSA® have significantly decreased

• Total prescriptions are 49% lower

• New prescriptions are 58% lower

● Market research

• 78% clinical oncologists aware of DDL content

• 86% modifying treatment practice

● Total and new prescriptions for IRESSA® have significantly decreased

• Total prescriptions are 49% lower

• New prescriptions are 58% lower

● Market research

• 78% clinical oncologists aware of DDL content

• 86% modifying treatment practice

CR-8

Clinical Implications andNext Steps

Clinical Implications andNext Steps

CR-9

Pertinent Questions to AskPertinent Questions to Ask

● Why did this result occur?• How does this result compare to other data

on IRESSA® in NSCLC?• The play of chance?• Dose selection strategy?• Trial population and geography?

● What biologic data may be available to better understand the outcomes?

● What other relevant clinical data are expected?

● Why did this result occur?• How does this result compare to other data

on IRESSA® in NSCLC?• The play of chance?• Dose selection strategy?• Trial population and geography?

● What biologic data may be available to better understand the outcomes?

● What other relevant clinical data are expected?

CR-10

0.4 0.6 0.8 1 1.5

Adenocarcinoma

All patients

Female

PS 0,1

1 prior chemo

Refractory

Never smoked

Non-adenocarcinoma

Ever smoked

Intolerant

2 prior chemos

PS 2,3

Male

Hazard ratio and 95% CI

Favors IRESSA® Favors placebo

11.4

7.7

14.0

8.3

7.4

7.8

17.2

4.6

5.2

7.2

8.0

6.6

4.9

Response rate, %Trial 709 Phase II

Survival

Consistency of Outcome Between Trial 709 and Phase II Data (1)

Consistency of Outcome Between Trial 709 and Phase II Data (1)

13.813.8

10.210.2

20.720.7

10.410.4

26.826.8

5.35.3

7.17.1

10.510.5

9.89.8

4.44.4

NANANANA

9.39.3

CR-11

0.4 0.6 0.8 1 1.5

Prior docetaxel

All patients

Asian ethnicity

Time since Dx: >12 mo

Time since Dx: <6 mo

<65 yr

No prior docetaxel

≥65 yr

Time since Dx: 6-12 mo

Non-Asian ethnicity

Hazard ratio and 95% CIFavors IRESSA® Favors placebo

Prior chemo response: PD/NE

Prior chemo response: CR/PRPrior chemo response: SD

10.3

7.7

12.0

9.3

6.8

7.1

6.7

8.7

6.9

6.5

7.0

8.98.0

Survival

Consistency of Outcome Between Trial 709 and Phase II Data (2)

Consistency of Outcome Between Trial 709 and Phase II Data (2)

11.1

10.2

27.5

12.4

10.010.7

6.0

10.4

NA

5.3

NA

Response rate, %Trial 709 Phase II

8.0

NA

CR-12

Hazard ratio and 95% CI

Favors Active Favors Placebo

BR21709

Survival Response Rate

17%

9%

5%

8%

25%

4%

??%

??%

12%

6%

BR21709

0.40 0.60 0.80 1.00 1.25

All Patients

Never Smokers

Smokers

Asian

Non Asian

BR21709

BR21709

BR21709

Hazard ratio and 95% CI

Favors Active Favors Placebo

BR21709

Survival Response Rate

17%

9%

5%

8%

25%

4%

??%

??%

12%

6%

BR21709

0.40 0.60 0.80 1.00 1.25

All Patients

Never Smokers

Smokers

Asian

Non Asian

BR21709

BR21709

BR21709

Hazard ratio and 95% CI

Favors Active Favors Placebo

BR21709

Survival Response Rate

17%

9%

5%

8%

25%

4%

??%

??%

12%

6%

BR21709

0.40 0.60 0.80 1.00 1.25

All Patients

Never Smokers

Smokers

Asian

Non Asian

BR21709

BR21709

BR21709

Hazard ratio and 95% CI

Favors Active Favors Placebo

BR21709

Survival Response Rate

17%

9%

5%

8%

25%

4%

??%

??%

12%

6%

BR21709

0.40 0.60 0.80 1.00 1.25

All Patients

Never Smokers

Smokers

Asian

Non Asian

BR21709

BR21709

BR21709

The Play of Chance?The Play of Chance?

● Is the overall outcome in Trial 709 inconsistent with that seen in erlotinib study (BR21)?

● Is the overall outcome in Trial 709 inconsistent with that seen in erlotinib study (BR21)?

BR21Trial 709

Survival Response rate, %

Favors active agent Favors placebo

98

CR-13

Dose Selection StrategyDose Selection Strategy

● Doses up to 1000 mg explored in extensive Phase I program

● 250 mg and 500 mg compared in randomized Phase II trials in 416 patients• No difference in survival • Increased toxicity at 500 mg

● No data to suggest doses above 500 mg would achieve better outcomes but cannot be ruled out completely

● Doses up to 1000 mg explored in extensive Phase I program

● 250 mg and 500 mg compared in randomized Phase II trials in 416 patients• No difference in survival • Increased toxicity at 500 mg

● No data to suggest doses above 500 mg would achieve better outcomes but cannot be ruled out completely

CR-14

Methodologic: Areas to ExploreMethodologic: Areas to Explore

● Highly refractory population?

● Cultural or environmental differences between regions?• Smoking exposure

● Highly refractory population?

● Cultural or environmental differences between regions?• Smoking exposure

CR-15

What Does This Mean?What Does This Mean?

● IRESSA® is an active and well-tolerated agent● Data consistent with Phase II and large clinical

experience● Variability in outcome, with significant survival

increase in• Never smokers• Asian patients

● Biomarker studies from Trial 709 may help in further interpretation of results

● IRESSA® is an active and well-tolerated agent● Data consistent with Phase II and large clinical

experience● Variability in outcome, with significant survival

increase in• Never smokers• Asian patients

● Biomarker studies from Trial 709 may help in further interpretation of results

CR-16

Biomarkers of Interest in NSCLCBiomarkers of Interest in NSCLC

● EGFR expression

• Exploratory analyses from Phase II IDEAL studies

• Relationship with survival shown for erlotinib

● EGFR activating mutations

• Described in dramatic responders to IRESSA®

● Other exploratory biomarkers

• EGFR gene copy number

• HER-family dimerization patterns

● EGFR expression

• Exploratory analyses from Phase II IDEAL studies

• Relationship with survival shown for erlotinib

● EGFR activating mutations

• Described in dramatic responders to IRESSA®

● Other exploratory biomarkers

• EGFR gene copy number

• HER-family dimerization patterns

Relationship Between EGFR Expression and Survival for Erlotinib BR21

Relationship Between EGFR Expression and Survival for Erlotinib BR21

A positive EGFR expression status was defined as having at least 10% of cells staining for EGFR in contrast to the 1% cut-off specified in the DAKO EGFR pharmDx™ kit instructions. The use of the pharmDx kit has not been validated for use in Non-Small Cell Lung Cancer.

TARCEVA prolonged survival in the EGFR positive subgroup (N = 127; HR = 0.65; 95% CI = 0.43 - 0.97) (figure 3) and the subgroup whose EGFR status was unmeasured (N = 493; HR = 0.76; 95% CI = 0.61 - 0.93) (figure 5), but did not appear to have an effect on survival in the EGFR negative subgroup (N = 111; HR = 1.01; 95% CI = 0.65 - 1.57) (figure 4). However, the confidence intervals for the EGFR positive, negative and unmeasured subgroups are wide and overlap, so that a survival benefit due to TARCEVA in the EGFR negative subgroup cannot be excluded.

CR-17

CR-18

Mutation of the EGFR Tyrosine Kinase in Human Non-Small Cell Lung Carcinoma Mutation of the EGFR Tyrosine Kinase in Human Non-Small Cell Lung Carcinoma

● Mutation appears almost exclusively in NSCLC

● Mutation is activating, inATP-binding site

● Mutation more frequent in• Females• Adenocarcinomas• Never smokers

● Frequency of mutation approx. 12% in Caucasian, 26% in Asian population

● Incomplete association of mutation with response in IDEAL studies (6/14 PR in mutation+)

● Mutation appears almost exclusively in NSCLC

● Mutation is activating, inATP-binding site

● Mutation more frequent in• Females• Adenocarcinomas• Never smokers

● Frequency of mutation approx. 12% in Caucasian, 26% in Asian population

● Incomplete association of mutation with response in IDEAL studies (6/14 PR in mutation+)

Paez J, Janne, PA, Lee JC, et al. Science. April 29 2004;Lynch TJ, Bell DW, Sordella et al. N Engl J Med. April 30 2004.

CR-19

Biologic CorrelationsSummary of Currently Available Data

Biologic CorrelationsSummary of Currently Available Data

● EGFR expression appears to be associated with increased survival in BR21

● EGFR mutations appear to explain some, but not all, of the responses to IRESSA®

● Outcomes in trial 709 comparing IRESSA® to placebo will be explored in terms of EGFR expression, activating mutation and other biomarkers

• Data available in June 2005

• Results may provide further insight into clinical outcomes

● Prospective studies needed

● EGFR expression appears to be associated with increased survival in BR21

● EGFR mutations appear to explain some, but not all, of the responses to IRESSA®

● Outcomes in trial 709 comparing IRESSA® to placebo will be explored in terms of EGFR expression, activating mutation and other biomarkers

• Data available in June 2005

• Results may provide further insight into clinical outcomes

● Prospective studies needed

CR-20

Prospective Studies to Investigate Predictive Markers and Outcome in NSCLC

Prospective Studies to Investigate Predictive Markers and Outcome in NSCLC

● IRESSA® vs. doublet chemotherapy• Mandatory tissue collection to evaluate

further utility of defined biomarkers

● Targeted study population• Mutation+• Never smokers

● Specific studies in Asian population(s)

● IRESSA® vs. doublet chemotherapy• Mandatory tissue collection to evaluate

further utility of defined biomarkers

● Targeted study population• Mutation+• Never smokers

● Specific studies in Asian population(s)

CR-21

Further Studies in Advanced NSCLCFurther Studies in Advanced NSCLC

● Trial 721—IRESSA® vs. docetaxel• Post-approval commitment (n = 1440)

• Interim analysis: ~ May-June with 380 deaths

● IRESSA® vs. docetaxel• Japan post-approval commitment (n = 484)

● Phase II Trial 503: IRESSA® vs. docetaxel• Supportive of Trial 721 and dose

● Trial 721—IRESSA® vs. docetaxel• Post-approval commitment (n = 1440)

• Interim analysis: ~ May-June with 380 deaths

● IRESSA® vs. docetaxel• Japan post-approval commitment (n = 484)

● Phase II Trial 503: IRESSA® vs. docetaxel• Supportive of Trial 721 and dose

CR-22

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

Trial 503—IRESSA® 250 mg Daily vs. Docetaxel 75 mg/m2

Trial 503—IRESSA® 250 mg Daily vs. Docetaxel 75 mg/m2

IRESSA® Docetaxel

Median (mo) 7.5 7.1

HR = 0.96 (0.61, 1.52), P = .87

N = 141, 55% mortality

Time, mo

0 2 4 6 8 10 12 14

—— IRESSA®

------ Docetaxel

Pat

ien

ts s

urv

ivin

g (

%)

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

CR-23

Clinical SummaryClinical Summary

● Well-tolerated agents like IRESSA® are an accepted addition to the therapeutic armamentarium

● Clinical and translational data are pointing the way to most appropriate use

● AstraZeneca remains committed to IRESSA® and other biologically targeted agents

● Well-tolerated agents like IRESSA® are an accepted addition to the therapeutic armamentarium

● Clinical and translational data are pointing the way to most appropriate use

● AstraZeneca remains committed to IRESSA® and other biologically targeted agents