IRESSA: A journey of experience from broad to biomarker populations

Claire Watkins

Global Product Statistician, AstraZeneca

EFSPI meeting on Oncology

Basel, 24th June 2010

Outline

• A brief history of IRESSA (gefitinib)

• Lessons learned

• Looking to the future of biomarker targeted drug development

What is IRESSA and how does it work?

http://www.egfr-info.com/EGFR-lung-cancer/

European Indication – approved June 2009

IRESSA is indicated for the treatment of adult patients with locally advanced

or metastatic non‑small cell lung cancer (NSCLC) with activating

mutations of EGFR‑TK.

The ideal

Biomarker targeted drug

Indicated for Biomarker+

Studies

The reality

Biomarker targeted drug

Indicated for Biomarker+

Broad population?

Clinical characteristics?

Biomarker(s)?

Which biomarker?

What cut-off?

Studies

“Dramatic” Tumour shrinkage in patient with metastatic NSCLC

IRESSA - May 2001

IDEAL 1&2 – NSCLC Phase II non-comparative - 2002

1918

912

0

5

10

15

20

25

30

Res

po

nse

rat

e, %

500 mg250 mg

Vertical bars represent 95% CI.

500 mg250 mg

IDEAL 1 – Japan and EuropeIDEAL 2 – USA

Kris 2003, Fukuoka 2003

Japan and US approvals

• Japan – full approval granted July 2002Indication: Inoperable or recurrent non small cell lung cancer.Precautions related to Indication 1. Efficacy and safety of IRESSA in patients without

previous chemotherapy regimens have not been established. 2. Efficacy and safety of IRESSA in post-operative adjuvant therapy have not been established.

• US – accelerated approval granted May 2003:IRESSA is indicated as monotherapy for the treatment of patients with locally

advanced or metastatic non-small cell lung cancer after failure of both platinum-based and docetaxel chemotherapies.

The effectiveness of IRESSA is based on objective response rates. There are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival.

• US – Phase III post approval pre-treated commitment studies including:• ISEL – OS superiority vs placebo• INTEREST – OS non-inferiority vs docetaxel• IBREESE – Symptom improvement superiority vs placebo• Question – what is needed from these studies to lift the conditional approval?

ISEL – reports December 2004

OS

HR (95% CI) =0.89 (0.77, 1.02) p= 0.0871 by primary stratified log rank test

n=1692, deaths=976

[Adjusted Cox analysis HR 0.86 (0.76-0.99) p=0.0299]

TTF

HR (95% CI) =0.82 (0.73, 0.93) p=0.0006

n=1316, progressions=1137

0.0

0.2

0.4

0.6

0.8

1.0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

IRESSAPlacebo

Months

Pro

po

rtio

n s

urv

ivin

g

0.0

0.2

0.4

0.6

0.8

1.0

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

Months

Pro

po

rtio

n w

ith

ou

t tr

ea

tme

nt

fail

ure

0

Objective Response Rate8.0% vs 1.3%, p<0.0001

Thatcher 2005

ISEL OS subgroups by smoking status and histology

IRESSAPlacebo

Pro

po

rtio

n s

urv

ivin

g

0 2 4 6 8 10 12 14 160.0

1.0

0.8

0.6

0.4

0.2

0 2 4 6 8 10 12 14 16

Time (months)

Never smoked (n=375) Ever smoked (n=1317)HR 0.92; 95% CI

0.79, 1.06; p=0.242HR 0.67; 95% CI 0.49, 0.92;

p=0.012

Pro

po

rtio

n s

urv

ivin

g

0.0

1.0

0.8

0.6

0.4

0.2

0 2 4 6 8 10 12 14 16 0 2 4 6 8 10 12 14 16

Asian origin (n=342) Non-Asian origin (n=1350)

HR 0.92; 95% CI 0.80, 1.07; p=0.294

HR 0.66; 95% CI 0.48, 0.91; p=0.010

Cox regression analysis

Treatment by race interaction test p=0.043

Treatment by smoking interaction test p=0.047

Thatcher 2005, Chang 2006

Regulatory reactions

• MHLW open public mtg 17th Jan 05• FDA Advisory committee 4th March 05• MHLW open public mtg (2) 10th March 05• MHLW open public mtg (3) 17th March 05• MHLW open public mtg (4) 24th March 05

• FDA restricts labellingIRESSA is indicated as monotherapy for the continued treatment of

patients with locally advanced or metastatic non-small cell lung cancer after failure of both platinum-based and docetaxel chemotherapies who are benefiting or have benefited from IRESSA

• Japan – no change to labelling

EGFR biomarkers

IRESSA registration

Japan

ISEL

INTEREST

IPASS

2002 200920072005

IPASS: Clinically selected trial in first line setting

ISEL, INTEREST: Unselected trials in pre-treated setting

EGFR protein expression

EGFR gene copy number

EGFR mutations

ISEL: OS by EGFR gene copy number

Time (months)

0.0

N=256, E=157Cox HR=1.16 (0.81, 1.64)

p=0.42

Low (-)

0.2

0.4

0.6

0.8

1.0

0 2 4 6 8 10 12 14 16

IRESSAPlacebo

Percent surviving

Time (months)

0.0

N=114, E=68Cox HR=0.61 (0.36, 1.04)

p=0.07

High (+)

0.2

0.4

0.6

0.8

1.0

0 2 4 6 8 10 12 14 16

IRESSAPlacebo

Treatment by gene copy number interaction test p=0.047

OS could not be analysed by EGFR mutation status as there were only 5 mutation positive patients on placebo. The ORR was 38% in the 21 mutation positive patients treated with IRESSA

Hirsch 2006

IRESSA250 mg/day

Docetaxel75 mg/m2 every

3 weeks

1:1 randomization

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

amodified Hochberg procedure applied to control for multiple testingCT, chemotherapy; PS, performance status; EGFR, epidermal growth factor receptor

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 analysesa 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: OS and PFS and ORR

OS: NI margin 1.154, PP population

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

n=1433, deaths=1169

Median survival: IRESSA 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: IRESSA 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

IRESSADocetaxel

IRESSADocetaxel

ORR [EFR population]: 9.1% IRESSA, 7.6% Docetaxel; p=0.3257 Kim 2008

INTEREST: Summary of key subgroup analyses

ORR (%)IRESSA 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-

INTEREST

0 0.5 1.0 1.5 2.0

HR (IRESSA vs docetaxel) and 95% CI

Unadjustedanalysis

PP populationfor clinical factors

ITT population for biomarker factors

HR (IRESSA vs docetaxel) and 95% CI 0 0.5 1.0 1.5 2.5

Adjustedanalysis

EFRpopulation

2.0

Overall Survival Progression-free Survival

EFR population

Kim 2008; Douillard 2010

18

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

IRESSA250 mg/day

Carboplatin AUC 5 or 6 and Paclitaxel 200mg/m2 3 wkly

1:1 randomization

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

Carboplatin/paclitaxel was offered to IRESSA patients upon progression

PS, performance status; EGFR, epidermal growth factor receptor

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

IPASS reports September 2008, partway through the European MAA

review of INTEREST

20

IPASS: Exceeded primary objective and demonstrated superior PFS for IRESSA versus doublet chemotherapy

HR, hazard ratio; CI, confidence interval; PFS, progression-free survival

Primary Cox analysis with covariates; ITT populationHR <1 implies a lower risk of progression on IRESSA

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

IRESSA demonstrated superiority relative to carboplatin / paclitaxel in terms of PFS

609453 (74.4%)

608497 (81.7%)

NEvents

IRESSA Carboplatin /

paclitaxel

Mok 2009

21

IPASS: Superior PFS and ORR with IRESSA vs doublet chemotherapy; PFS effect not constant over time

609453 (74.4%)

608497 (81.7%)

NEvents

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

IRESSA

Primary objective exceeded: IRESSA demonstrated superiority relative to carboplatin /

paclitaxel in terms of PFS

Primary Cox analysis and logistic regression with covariates; ITT populationHR <1 implies a lower risk of progression on IRESSA

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

22

IPASS: Superior progression-free survival and response rate for IRESSA in EGFR mutation positive patients

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

p<0.0001

0 4 8 12 16 20 24

Time from randomisation (months)

0.0

0.2

0.4

0.6

0.8

1.0Probabilityof PFS

IRESSA EGFR M+ (n=132)

Carboplatin / paclitaxel EGFR M+ (n=129)

M+, mutation positive

Objective response rate71.2% vs 47.3%

p=0.0001

Mok 2009

23

IPASS: Superior progression-free survival and response rate for doublet chemotherapy in EGFR mutation negative patients

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

1.0Probabilityof PFS

IRESSA EGFR M- (n=91)

Carboplatin / paclitaxel EGFR M- (n=85)

M-, mutation negative

Objective response rate1.1% vs 23.5%

p=0.0013

Mok 2009

24

IPASS: EGFR mutation is a strong predictor for differential PFS benefit between IRESSA 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

1.0Probabilityof PFS

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

M+, mutation positive; M-, mutation negative

Treatment by

subgroup interaction

test, p<0.0001

Mok 2009

European Indication – approved June 2009

IRESSA is indicated for the treatment of adult patients with locally advanced

or metastatic non‑small cell lung cancer (NSCLC) with activating

mutations of EGFR‑TK.

Lessons learned

• Understand the biology• Make friends with your translational scientists

• Determine whether to go down the targeted biomarker route as early as possible

• “The tissue is the issue” – collect as many samples as you can• No sample = no biomarker• Pathologists are key• Conflict between push for faster studies and push for targeted

healthcare• Fast recruiters are not often the most experienced at sample collection

• A targeted drug is useless without a diagnostic• Co-development has its own unique challenges

• Ensure an understanding of prognostic vs predictive• A predictive factor cannot be identified from a single arm study• A poor prognostic factor can be a good predictive factor for a new

agent

Prognostic vs Predictive

Not prognostic Prognostic

No

t pre

dic

tive

Pre

dict

ive

0

2

4

6

8

10

12

HRD+ HRD- 0

2

4

6

8

10

12

HRD+ HRD-

0

2

4

6

8

10

12

HRD+ HRD-

0

2

4

6

8

10

12

HRD+ HRD-

+ -

+

+

+-

-

-

Blue=Experimental, Purple=comparator

Lessons learned

• It matters• What you measure

• How you measure it

• How you define positive (cut-off)

MAGIC ALGORITHM!

Biomarker status

Positive or negative

Tissue sample

Diagnostic test

It matters what you measure

Protein expression

Gene mutation

Gene copy

number

EGFR

It matters how you measure it

Protein expression

Gene mutation

Gene copy

number

EGFR

IHC

FluorescenceFISH

CISH

Sequencing

ARMs

PNA-LNA PCR clamp

It matters how you define positive (cut-off)

Protein expression

Gene mutation

Gene copy

number

EGFR

IHC

FluorescenceFISH

CISH

Sequencing

ARMs

PNA-LNA PCR clamp

Staining intensity

Staining percentage

# of copies

Pattern of

copies

Type of mutation

New diagnostics may use more than one biomarker to define positivity

INTEREST: Overlap of biomarkers (EGFR gene copy number by FISH, EGFR expression by IHC, EGFR mutation)

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

32Douillard 2010

Lessons learned

• It matters• What you measure

• How you measure it

• How you define positive (cut-off)

• Consider if there is a surrogate for the biomarker e.g. clinical characteristics, another marker

MAGIC ALGORITHM!

Biomarker status

Positive or negative

Tissue sample

Diagnostic test

INTEREST: EGFR mutation appeared to be associated with some clinical characteristics

Adenoca

rcin

oma

Non- aden

ocarc

inom

a

PS 0-1 PS

2

Never

-sm

oked

Ever-s

moke

d

Second-li

ne

Third-li

ne

Mal

e

Femal

e

Asian

Non-Asi

an

% ofsamplesEGFRmutation positive

60

50

40

30

20

10

0

Overall EGFR mutation positive rate 14.8% (44/297)

Douillard 2010

K-Ras and EGFR mutations rarely co-existin the same tumour

5 incidences across 19 studies totalling around 3300 patients

Study

AstraZeneca studies

INTEREST

ISEL

INVITE

Literature

Wu et al 2008

Yamamoto et al 2008

Zhu et al 2008

Do et al 2008

Sasaki et al 2008

Na et al 2007

Massarelli et al 2007

Bae et al 2007

Hirsch et al 2006

van Zandwijk et al 2007

Yokoyama et al 2006

Suzuki et al 2006

Tam et al 2006

Tomizawa et al 2005

Shigematsu et al 2005

N evaluable

275

152

90

237

86

206

200

190

133

70

115

152

349

150

215

120

617

N (%) K-Ras+

49 (17.8)

12 (7.9)

24 (26.7)

9 (3.8)

26 (30.2)

30 (14.6)

25 (12.5)

21 (11.1)

17 (12.8)

16 (22.9)

6 (5.2)

12 (7.9)

21 (6.0)

6 (4.0)

21 (9.8)

4 (3.3)

50 (8.1)

N evaluable

297

215

65

235

86

204

200

195

133

71

115

215

41

349

150

241

120

519

N (%) M+

44 (14.8)

26 (12.1)

6 (9.2)

96 (40.9)

10 (11.6)

34 (16.7)

73 (36.5)

82 (42.1)

32 (24.1)

7 (9.9)

20 (17.4)

26 (12.1)

13 (31.7)

102 (29.2)

38 (25.3)

116 (48.1)

29 (24.2)

120 (23.1)

Number

K-Ras+/M+

1

0

1

0

0

3

0

0

0

0

0

0

0

0

0

0

0

0

K-Ras mutations EGFR mutations

35

Lessons learned

• Engage with regulators early• Everyone is learning as they go along

• FDA in particular has stated positions that may not be practical in all cases

• >90% evaluable samples • Prove don’t work in –ve

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

37Mok 2009, Fukuoka 2009

Lessons learned

• Engage with regulators early• Everyone is learning as they go along

• FDA in particular has stated positions that may not be practical in all cases

• >90% evaluable samples • Prove don’t work in –ve

• Don’t want to do a repeat of Phase IIIs

• Issues of generating a strong signal in a small early study

• Payers are key stakeholders• Randomised Phase IIs• Keep an eye to the future

• New or revised tests, markers, tissue types

• Flexible consent

• Be aware that science will move on as your study is ongoing

Personalised Healthcare development today and in the future

Today

• 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

2013

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

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

§ Clinical programme prospectively tailored for responders, used for co-development of drug and diagnostic

§ Drug launched globally, linked to diagnostic

Summary

• IRESSA 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

• There are several useful learnings for future biomarker targeted products• Understand the science

• Maximise tissue samples

• Diagnostic is as important as the drug

• Pharmaceutical companies and regulators are learning about this together• Engage early

• Considerable challenges on both sides

• Opportunity for collaboration

References

• Kris MG, Natale RB, Herbst RS, et al: Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: A randomized trial. JAMA 290:2149-2158, 2003

• Fukuoka M, Yano S, Giaccone G, et al: Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer. J Clin Oncol 21:2237-2246, 2003

• Thatcher N, Chang A, Parikh P, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 366: 1527–37, 2005

• Chang A, Parikh P, Thongprasert S, et al: Gefitinib (IRESSA) in Patients of Asian Origin with Refractory Advanced Non-small Cell Lung Cancer: Subset Analysis from the ISEL Study. J Thoracic Oncol 1: 8: 847-855, 2006

• Hirsch FR, Varella-Garcia M, Bunn PA, et al. Molecular predictors of outcome with gefitinib in a Phase III placebo-controlled study in advanced non-small-cell lung cancer. J Clin Oncol 24: 5034-5042, 2006

• Kim ES, Hirsch V, Mok T, et al: Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet 372:1809-1818, 2008

• Douillard JY, Hirsch V, Mok T, et al: Molecular analyses from a phase III trial comparing gefitinib with docetaxel in previously treated non-small-cell lung cancer (INTEREST). J Clin Oncol 26 (May 20 Suppl): Abstract 8001, 2008

• Mok T, Wu Y, Thongprasert S, et al: Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma NEJM 361: 947-957, 2009

• Douillard J, Hirsh V, Mok T, et al: Molecular predictors of outcome with gefitinib and docetaxel in previously treated non-small-cell lung cancer: data from the randomised phase III INTEREST trial J Clin Oncol 5:744-752, 2010

• Fukuoka M, Wu Y, Thongprasert S, et al. Biomarker analyses from a phase III, randomized, open-label, first-line study of gefitinib (G) versus carboplatin/paclitaxel (C/P) in clinically selected patients (pts) with advanced non-small cell lung cancer (NSCLC) in Asia (IPASS). J Clin Oncol 27 (15s suppl): Abstract 8006, 2009