iressa (gefitinib) the journey - european...

Anne De Bock

Portfolio Leader, Oncology/Infection

European Regulatory Affairs

AstraZeneca

IRESSA (Gefitinib) The Journey

Overview

The DrugThe Biomarker

and Clinical Trials

SamplingLessons Learned

The Drug


and Clinical Trials


IRESSA™ (Gefitinib): A Brief Overview

IRESSA (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 and is now approved

in >70 countries worldwide.

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 26 June 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.

The Biomarker and Clinical Trials


and Clinical Trials


The Journey

Isolation of human EGF from

human urine by Cohen;Identification of EGF receptor by Cohen

Mendelsohn

proposes EGFR as anticancer target; Human EGFR cloned and sequenced

Early 1980s

First clinical trial of anti-EGFR

agent (mAb) confirms MOA

Late 1980s

1960s

Early 1990s

2000

Accumulating evidence that EGFR is

associated with tumour progression and EGFR kinase activity can be inhibited in vitro by small molecules

1994

Expanded access

programme starts in parallel with Phase II/III trials (IDEALs/ INTACTs)

Cohen’s discovery of epidermal

growth factor (EGF) in mice in 1962 pioneers major progress in cell growth/differentiation

research

1970s

Discovery of new

class of EGFR-TKIs Phase II IDEAL 1 and 2

studies report: gefitinib effective at 250 mg/day (JCO 2003; JAMA 2003)

Gefitinib Phase I trials:

favourable tolerability and good responses in NSCLC1998

2001

Publication of IDEAL 1 and 2

The Trials: A Brief History

IRESSA

registration Japan

ISEL

INTEREST

2002 200920072005

ISEL, INTEREST: Unselected

trials in pre-treated setting

2003EGFR protein expression

EGFR gene copy number

2004 2006 2008

EGFR Mutations: First Observed in 2004Lynch et al 2004 (New Eng J Med 350:2129- 2139)

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

Mitsudomi et al 2005 (JCO, vol. 23 no. 11 2513-2520, 2005 )

DNA mRNA ProteinChromosome

Gene

Copy

Number

(FISH)

DNA

Mutation

Analysis

(e.g.

ARMS)

Expression

Analysis

(e.g. Array,

RT-PCR etc)

Protein

Expression

Analysis

(e.g. IHC)

Pao & Miller 2005

Tumour cellproliferation

Tumour cellsurvival

Choosing Relevant Biomarkers

PI3K

MAPK

Akt

mTOR STAT 3/5

Grb-2

SOS

Ras

Raf

MEK

PTEN

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

2003EGFR protein expression

EGFR gene copy number

EGFR mutations

2004 2006 2008

INTEREST: Phase III Study of IRESSA vs Docetaxel in Pre-Treated NSCLC

Gefitinib

250 mg/day

Docetaxel

75 mg/m2 every

3 weeks

1:1 randomization

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 ResultsOS: 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

bilit

y o

f

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

MonthsP

rob

ab

ilit

y o

f

pro

gre

ss

ion

-fre

e

su

rviv

al

Gefitinib

DocetaxelGefitinib

Docetaxel

Kim 2008

INTEREST: Summary of Key Subgroup AnalysesORR (%)

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% CI0 0.5 1.0 1.5 2.52.0

Overall Survival Progression-free Survival

Kim 2008; Douillard 2010

INTEREST: Overlap of Biomarkers

249 patients

evaluable for EGFR expression,

FISH and mutations

EGFR

expression +

n=189

EGFR FISH +

n=117

EGFR mutation +

n=39

+++ n=24

4

3

n=16

n=73

n=84

n=8

--- n=37

14

Douillard 2010

IPASS: Phase III Study of Gefitinib versus

Doublet Chemotherapy in First-Line NSCLC

PS, performance status – EGFR, epidermal growth factor receptor

*Never smokers:<100 cigarettes in lifetime; light ex-smokers: stopped 15 years ago and smoked 10 pack yrs

Carboplatin / paclitaxel was offered to gefitinib patients upon progression

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 et al 200915

Primary Cox analysis and logistic regression with covariates; ITT population

HR <1 implies a lower risk of progression on gefitinib

24

609

453 (74.4%)

608

497 (81.7%)

n

Events

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

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

5.761%48%25%

5.874%48%7%

Carboplatin /

paclitaxel

Gefitinib 609 212 76 24 5 0608 118 22 3 1 0

363412

0 4 8 12 16 20 Months0.0

0.2

0.4

0.6

0.8

1.0

Pro

ba

bilit

y o

f P

FS

At risk :

ORR 43% vs 32% p=0.0001 Mok et al 2009

IPASS: Progression-Free Survival (ITT)

0 4 8 12 16 20 24

Time from randomization (months)

0.0

0.2

0.4

0.6

0.8

1.0P

rob

ab

ilit

y o

f P

FS

Gefitinib EGFR M+ (n=132)

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

EGFR M+

HR (95% CI) = 0.48 (0.36, 0.64)

p<0.0001

EGFR M-

HR (95% CI) = 2.85 (2.05, 3.98)

p<0.0001

M+, mutation positive;

M-, mutation negative

Treatment

by subgroup interaction

test, p<0.0001

IPASS: Comparison of PFS by Mutation Status within

Treatment Arms (ITT)

Mok et al 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 4.0

Hazard Ratio (Gefitinib : Carboplatin / Paclitaxel) and 95% CI

Fukuoka ASCO 2009

The Diagnostic


and Clinical Trials


683

provided samples

(56%)

1038

biomarker consent

(85%)

Evaluable for:

EGFR mutation: 437 (36%)

EGFR gene copy number:

406 (33%)

EGFR expression: 365 (30%)

1217

randomised

patients (100%)

Reasons for samples not evaluable:

Sample not available, insufficient

quantity to send, cytology only,

sample at another site

Fukuoka et al 2009

IPASS biomarker sampling

Lessons Learned


and Clinical Trials


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. disease segment, clinical characteristics, different biomarkers, techiniques, cut-offs etc.

What patients do you intend to target?

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 FutureIressa experience

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

Took ~4.5 further years retrospective research to show significant increase in 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

§ Early engagement with payers and health authorities ensures that drug is targeted to patients likely to respond

§ Clinical programme prospectively selects biomarker eligible patients,

§ Co-development of drug and diagnostic

§ Drug launched globally, linked to diagnostic

Summary Gefitinib is approved in Europe for a biomarker targeted

population

But it took a long time to get there

In future, pharmaceutical companies are unlikely to be able or willing

to follow a similar development path for new agents

Pharmaceutical companies and regulators are learning about this

together

Engage early

Considerable challenges on both sides

Opportunity for collaboration

Learning from our Experience•Pragmatic interpretation of regulatory guidelines

• Understand and quite often late-breaking science

•Innovative medicines to patients

•Often smaller populations with orphan prevalence

•Innovative drug development•Translation of pre-clinical models into

clinical benefit

•Clinical trial design

•Europe-wide biobanking

•Quality assurance, e.g. EUROGAPP

•Biomarker-based indications

Learning from our Experience

•Opportunities for collaboration•Consortia for challenging science

•(European equivalent of NCI?)

•Safety biomarkers

•Serious/ resistant infection

•Diagnostic partnerships

•Challenges of drug-diagnostic reimbursement

•Adoption of drug diagnostic as important as the drug

itself

•Academic-industry exchange fellowships

Integrated but Sustainable Drug (Development) Model!!!

Ultimately what we need is an

THANK YOU!!

iressa (gefitinib) the journey - european...

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