IRESSA

Dr Rose McCormackPersonalised HealthcareAstraZeneca

A Presentation for the Translational Genomics MeetingRoyal College of Physicians, London15th January 2013

A Case Study in Personalised Medicine

AN OVERVIEW

THE DRUG

Gefitinib (IRESSA™): A brief overview

• Gefitinib is a once-daily 250mg oral medication that targets and blocks the activity of the EGFR-TK

• Gefitinib was the first EGFR-TK inhibitor to be approved for use in non-small cell lung cancer

• Gefitinib has demonstrated longer progression-free survival, better tolerability and quality of life compared with doublet chemotherapy (carboplatin/paclitaxel) in first-line treatment for EGFR mutation-positive advanced NSCLC.

• On the 1st July 2009 the European Commission granted marketing authorisation for gefitinib for the treatment of adults with locally advanced or metastatic NSCLC with activating mutations of EGFR-TK across all lines of therapy

• Gefitinib is currently approved for the treatment of 1st line EGFR M+ advanced NSCLC patients in 85 countries worldwide

THE BIOMARKERS AND CLINICAL TRIALS

DNA mRNA ProteinChromosome

GeneCopy

Number(FISH)

DNA Mutation Analysis

(e.g. ARMS)

ExpressionAnalysis (e.g. Array, RT-PCR etc)

Protein Expression Analysis (e.g. IHC)

Pao & Miller 2005Tumour cellproliferation

Tumour cellsurvival

Lessons in Biomarker Analysis

PI3K

MAPK

Akt

mTOR STAT 3/5

Grb-2

SOS Ras

Raf

MEK

PTEN

The Trials: A Brief History

IRESSA registration

Japan

ISEL

INTEREST

2002 200920072005

ISEL, INTEREST: Unselected trials in pre-treated setting

2003

EGFR protein expression

EGFR gene copy number

2004 2006 2008

Reprinted with permission. © 2005 American Society of Clinical Oncology. All rights reserved.

Reprinted with permission. © 2005 American Society of Clinical Oncology. All rights reserved.

EGFR mutations: First observed in 2004

Lynch et al 2004 (New Eng J Med 350:2129- 2139)

Activating Mutations in the Epidermal Growth Factor Receptor Underlying Responsiveness of Non-Small-Cell Lung Cancer to Gefitinib

Lynch et al 2004 (New Eng J Med 350:2129- 2139)

Activating Mutations in the Epidermal Growth Factor Receptor Underlying Responsiveness of Non-Small-Cell Lung Cancer to Gefitinib

Paez et al 2004 (Science 304:1497-1500)

EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy

Paez et al 2004 (Science 304:1497-1500)

EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy

Mitsudomi T et al: J Clin Oncol 23 (11), 2005: 2513-2520

Mutations of the epidermal growth factor receptor gene predict prolonged survival after gefitinib treatment in patients with non-small-cell lung cancer with postoperative recurrence.

Mitsudomi T et al: J Clin Oncol 23 (11), 2005: 2513-2520

Mutations of the epidermal growth factor receptor gene predict prolonged survival after gefitinib treatment in patients with non-small-cell lung cancer with postoperative recurrence.

The Trials: A Brief History

IRESSA registration

Japan

ISEL

INTEREST

IPASS

2002 200920072005

IPASS: Clinically selected trial in first line setting

ISEL, INTEREST: Unselected trials in pre-treated setting

2003

EGFR protein expression

EGFR gene copy number

EGFR mutations

2004 2006 2008

Gefitinib 250 mg/day

Docetaxel75 mg/m2 every

3 weeks

1:1 randomization

INTEREST: Phase III study of gefitinib vs docetaxel in pre-treated NSCLC

Patients• Progressive or recurrent disease following CT

• Considered candidates for further CT with docetaxel

• 1 or 2 CT regimens(≥1 platinum)

• PS 0-2

Primary• Overall survival•(co-primary analyses of non-inferiority in all patients and superiority in patients with high EGFR gene copy number)

Secondary• Progression-free survival• Objective response rate• Quality of life• Disease related symptoms• Safety and tolerability

Exploratory• Biomarkers

•EGFR mutation•EGFR protein expression•EGFR gene copy number•K-Ras mutation

Endpoints

• 1466 patients

Kim 2008

INTEREST Results

OS: NI margin 1.154, PP population

HR (96% CI) =1.020 (0.905, 1.150)

n=1433, deaths=1169

Median survival: Gefitinib 7.6m, Docetaxel 8.0m

PFS: EFR population

HR (95% CI) =1.04 (0.93, 1.18), p=0.466

n=1316, progressions=1137

Median PFS: Gefitinib 2.2m, Docetaxel 2.7m

0 4 8 12 16 20 24 28 32 36 400.0

0.2

0.4

0.6

0.8

1.0

Months

Pro

ba

bil

ity

of

su

rviv

al

0 4 8 12 16 20 24 28 32 36 400.0

0.2

0.4

0.6

0.8

1.0

Months

Pro

ba

bil

ity

of

pro

gre

ss

ion

-fr

ee

su

rviv

al

Gefitinib Docetaxel

Gefitinib Docetaxel

Kim 2008

INTEREST: Summary of key subgroup analyses

ORR (%)Gefitinib v. Docetaxel

9.1 v. 7.6 Overall

Ever smoker

Never smoker

19.7 v. 8.7 Asian

6.2 v. 7.3 Non-Asian

13.0 v. 7.4 EGFR FISH+

7.5 v. 10.1 EGFR FISH-

42.1 v. 21.1 EGFR Mutation+

6.6 v. 9.8 EGFR Mutation-

Overall

Ever smoker

Never smoker

Asian

Non-Asian

EGFR FISH+

EGFR FISH-

EGFR Mutation+

EGFR Mutation-

Overall

Ever smoker

Never smoker

Asian

Non-Asian

EGFR FISH+

EGFR FISH-

EGFR Mutation+

EGFR Mutation-

0 0.5 1.0 1.5 2.0

HR (Gefitinib vs docetaxel) and 95% CI HR (Gefitinib vs docetaxel) and 95% CI 0 0.5 1.0 1.5 2.52.0

Overall Survival Progression-free Survival

Kim 2008; Douillard 2010

INTEREST: Overlap of biomarkers

EGFR expression +

n=189

EGFR FISH +n=117

EGFR mutation +n=39

249 patients evaluable for EGFR expression, FISH and mutations

+++ n=24

4

3

n=16

n=73

n=84

n=8

--- n=37

13

Douillard 2010

14

IPASS: Phase III study of gefitinib versus doublet chemotherapy in first line NSCLC

*Never smokers:<100 cigarettes in lifetime; light ex-smokers: stopped 15 years ago and smoked 10 pack yrsCarboplatin/paclitaxel was offered to IRESSA patients upon progressionPS, performance status; EGFR, epidermal growth factor receptor

Gefitinib 250 mg/day

Carboplatin AUC 5 or 6 and Paclitaxel

200mg/m2 3 wkly

1:1 randomization

Patients• Adenocarcinoma

histology

• Never smokers or light ex-smokers*

• PS 0-2

• Provision of tumour sample for biomarker analysis strongly encouraged

Primary• Progression free survival (non-inferiority)

Secondary• Objective response rate• Quality of life• Disease related symptoms• Overall survival• Safety and tolerability

Exploratory• Biomarkers

•EGFR mutation•EGFR gene copy number•EGFR protein expression

Endpoints

• 1217 patients from East Asian countries

Mok 2009

15

IPASS: Progression Free Survival

609453 (74.4%)

608497 (81.7%)

NEvents

HR (95% CI) = 0.741 (0.651, 0.845) p<0.0001

Gefitinib

Primary objective exceeded: Gefitinib demonstrated superiority relative to carboplatin /

paclitaxel in terms of PFS

Carboplatin /

paclitaxel

Carboplatin / paclitaxel

IRESSA

Median PFS (months)4 months progression-free6 months progression-free12 months progression-free

5.761%48%25%

5.874%48%7%

609 212 76 24 5 0608 118 22 3 1 0

363412

0 4 8 12 16 20 24 Months0.0

0.2

0.4

0.6

0.8

1.0Probabilityof PFS

At risk :

Objective response rate 43% vs 32% p=0.0001

Mok 2009

16

IPASS: EGFR mutation is a strong predictor for differential PFS benefit between gefitinib and doublet chemotherapy

EGFR M+HR=0.48, 95% CI 0.36, 0.64 p<0.0001

EGFR M-

HR=2.85, 95% CI 2.05, 3.98 p<0.0001

0 4 8 12 16 20 24

Time from randomisation (months)

0.0

0.2

0.4

0.6

0.8

1.0

Probabilityof PFS

Gefitinib EGFR M+ (n=132)Gefitinib EGFR M- (n=91)Carboplatin / paclitaxel EGFR M+ (n=129)Carboplatin / paclitaxel EGFR M- (n=85)

Treatment by subgroup interaction test, p<0.0001

Mok 2009

IPASS: PFS by Biomarkers (ITT)

Treatment-by-subgroup interaction test p-value

p=0.0437 for EGFR gene copy number

p=0.2135 for EGFR expression

p<0.0001 for EGFR mutation

Favours gefitinib Favours carboplatin / paclitaxel

Known mutation status

EGFR Mutation+

EGFR Mutation-

Known expression status

EGFR+

EGFR-

Known FISH status

EGFR FISH+

EGFR FISH-

0.25 0.5 1.0 2.0 4.0Hazard Ratio (Gefitinib : Carboplatin / Paclitaxel) and 95% CI

Fukuoka JCO 2011

IPASS: Overlap of biomarkers

N=329 with known biomarker status for all 3 biomarkers

--- = 31EGFR Mutation+ n=261

EGFR FISH+ n=249

+++ = 132

2551

13

28

15

34

EGFR expression +

n=266

Fukuoka JCO 2011

DNA mRNA ProteinChromosome

EGFR GeneCopy

Number

EGFR Mutation Analysis

EGFR ExpressionAnalysis

EGFR ExpressionAnalysis

EGFR Protein Expression Analysis

Pao & Miller 2005

Tumour cellproliferation

Tumour cellsurvival

Lessons in Biomarker Analysis

PI3K

MAPK

Akt

mTOR STAT 3/5

Grb-2

SOS Ras

Raf

MEK

PTEN

• What? Choose your biomarker(s) carefully

• How? •The tool that you use to measure your biomarker must be robust and reliable• The cut-offs used to define biomarker positive, negative, and unknown subgroups must be appropriate• Samples must be available

683provided samples

(56%)

•565 histology • 118 cytology

1038biomarker consent

(85%)

Evaluable for:EGFR mutation: 437 (36%)EGFR gene copy number: 406 (33%)EGFR expression: 365 (30%)

1217 randomised

patients (100%)

IPASS: Attrition factors in biomarker analysis

Reasons for samples not evaluable: Sample not available, insufficient quantity to send, cytology only, sample at another site

20Mok 2009, Fukuoka 2009

IMPLICATIONS FOR DIAGNOSTICS

Getting the right treatment to the right patient

All NSCLC patientsAll NSCLC patients

Patients tested

Test result

Treated

• Test Availability and Ease of Test Order

• Test sensitivity• Test ease of use• Interpretation of results• Test Turnaround time

Affected by.....

• Easily accessible Easily accessible testingtesting

• High quality High quality testing (high testing (high detection rates)detection rates)

• Access to suitable Access to suitable samplessamples

• Reasonable Test Reasonable Test Turnaround TimeTurnaround Time

Needs.....

Positive

EGFR mutation testing: diversity in 2009

•Centralised lab network•Testing reimbursed• High level of patients tested•Tests used:

•CLAMP•INVADER•Sequencing•Cycleave

•De- centralised lab network•Testing not reimbursed• Low level of patients tested•Tests used:

•TheraScreen•Sequencing•Pyrosequencing

JapanJapan UKUK

Understanding and Supporting the Dx Environment

Patient

Physician(respiratory,

surgeon, oncologist)

Lab service provider/Molecular Biologist

Sample

Test result

Diagnostic company/ies Platform

provider

Pathologist

egfr-mutation.com egfr-test.com

Testing reimbursement

Access to testing

Diversity of testing

methods /capabilities

across countries

Time taken to generate test

results

Availability of suitable

samples for testing

Physicians adopting a

PHC approach Multiple

individuals involved from

decision to test to getting

resultsChallengesChallenges

Challenges associated with a PHC approach

OUR EXPERIENCE AND LEARNINGS

The Biomarker Journey

• Ideally biomarker to indication in biomarker population is a straightforward, well planned process

• In reality this is a challenging process in which your direction changes e.g. molecular disease segment, clinical characteristics, different biomarkers, techniques, cut-offs etc.

28

What patients do you intend to treat?

Do you need a diagnostic to identify those patients?

Is there an existing assay available to identify the patients?

Do you need to develop a diagnostic test suitable for selecting patients eligible for

therapy?

What are you measuring?

How are you measuring it?

How do you define your cut-offs?

Can you develop an appropriate tool that can be used to measure in a robust and reliable

way?

Patient/ Disease Biomarker/Dx Tool

Personalised Healthcare development today and in the future

Gefitinib experience

• Gefitinib had standard drug development

• Predictive biomarker for gefitinib discovered by external collaborator ~7 years after start of clinical trials

• Retrospective investigation was required to show the significant clinical benefit for those patients identified by diagnostic test

• Ultimately identified patients most likely to benefit offers an alternative treatment option to doublet chemotherapy in newly diagnosed advanced/metastatic NSCLC

Future Therapies

§ Personalised Healthcare research discovers predictive biomarker in preclinical models before start of clinical development

§ Clinical programme prospectively selects biomarker eligible patients, targeted to patients most likely to respond

§ Early engagement with health authorities and payers

§ Co-development of drug and diagnostic§ Drug launched globally, linked to

diagnostic established within the diagnostic environment

Summary

• Gefitinib is approved in Europe for a biomarker targeted population- Gefitinib was developed during a time of rapid progress in the understanding of

molecular mechanisms of cancer, therefore the route to approval was not straightforward

- In future, pharmaceutical companies are unlikely to be able or willing to follow a similar development path for new agents

• There are several useful learnings for future biomarker targeted products- Understand the science- Assess efficacy in a biomarker defined, targetted population, as early as possible- Maximise tissue samples, no sample means no biomarker result- Diagnostic test adoption is as important as the drug

• Pharmaceutical companies, Physicians, Pathologists, Academics and Regulators are learning about this together- Engage early- Considerable challenges on both sides- Opportunity for collaboration

31 Author | 00 Month Year Set area descriptor | Sub level 1

Confidentiality Notice This file is private and may contain confidential and proprietary information. If you have received this file in error, please notify us and remove it from your system and note that you must not copy, distribute or take any action in reliance on it. Any unauthorized use or disclosure of the contents of this file is not permitted and may be unlawful. AstraZeneca PLC, 2 Kingdom Street, London, W2 6BD, UK, T: +44(0)20 7604 8000, F: +44 (0)20 7604 8151, www.astrazeneca.com