1. IRESSA: A journey of experience from broad to biomarker populations
Claire Watkins
Global Product Statistician, AstraZeneca
EFSPI meeting on Oncology
Basel, 24th June 2010

2. A brief history of IRESSA (gefitinib) Lessons learned
Outline
A brief history of IRESSA (gefitinib)
Lessons learned
Looking to the future of biomarker targeted drug development

3. What is IRESSA and how does it work?

4. 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.

5. Biomarker targeted drug
The ideal
Biomarker targeted drug
Studies
Indicated for Biomarker+

6. Clinical characteristics? Which biomarker? What cut-off?
The reality
Broad population?
Biomarker targeted drug
Studies
Clinical characteristics?
Biomarker(s)?
Which biomarker? What cut-off?
Indicated for Biomarker+

7. IRESSA - May 2001
“Dramatic” Tumour shrinkage in patient with metastatic NSCLC 7

8. IDEAL 1&2 – NSCLC Phase II non-comparative - 2002
250 mg
500 mg
250 mg
500 mg
References
Kris MG et al. JAMA 2003; 290:
Fukuoka M et al. J Clin Oncol 2003; 21:
IDEAL 2 – USA
IDEAL 1 – Japan and Europe
Vertical bars represent 95% CI.
Kris 2003, Fukuoka 2003

9. Japan and US approvals Japan – full approval granted July 2002
Indication: 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?

10. ISEL – reports December 2004OS
HR (95% CI) =0.89 (0.77, 1.02) p= by primary stratified log rank test
n=1692, deaths=976
[Adjusted Cox analysis HR 0.86 ( ) p=0.0299]
TTF
HR (95% CI) =0.82 (0.73, 0.93) p=0.0006
n=1316, progressions=1137
1.0
1.0
0.8
0.8
0.6
0.6
Proportion without treatment failure
Proportion surviving
0.4
0.4
Reference
Thatcher N et al. Lancet 2005; 366:
0.2
IRESSA
0.2
Placebo
0.0
0.0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Months
Months
Objective Response Rate 8.0% vs 1.3%, p<0.0001
Thatcher 2005

11. ISEL OS subgroups by smoking status and histology
Treatment by smoking interaction test p=0.047
Never smoked (n=375)
Ever smoked (n=1317)
1.0
HR 0.67; 95% CI 0.49, 0.92; p=0.012
HR 0.92; 95% CI 0.79, 1.06; p=0.242
IRESSA
0.8
Placebo
0.6
Proportion surviving
0.4
0.2
0.0 2 4 6 8 10 12 14 16 2 4 6 8 10 12 14 16
Treatment by race interaction test p=0.043
Asian origin (n=342)
Non-Asian origin (n=1350)
1.0
HR 0.66; 95% CI 0.48, 0.91; p=0.010
HR 0.92; 95% CI 0.80, 1.07; p=0.294
0.8
0.6
References
Thatcher N et al. Lancet 2005; 366:
Chang A et al. J Thorac Oncol 2006; 1:
Proportion surviving
0.4
0.2
0.0 2 4 6 8 10 12 14 16 2 4 6 8 10 12 14 16
Time (months)
Cox regression analysis
Thatcher 2005, Chang 2006

12. 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 labelling
IRESSA 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

13. IRESSA registration Japan
EGFR biomarkers
ISEL, INTEREST: Unselected trials in pre-treated setting
ISEL
IRESSA registration Japan
INTEREST
IPASS
2002
2005
2007
2009
EGFR protein expression
EGFR gene copy number
IPASS: Clinically selected trial in first line setting
EGFR mutations

14. ISEL: OS by EGFR gene copy number
Treatment by gene copy number interaction test p=0.047
High (+)
Low (-)
N=114, E=68 Cox HR=0.61 (0.36, 1.04) p=0.07
N=256, E=157 Cox HR=1.16 (0.81, 1.64) p=0.42
Percent surviving
1.0
1.0
IRESSA
Placebo
IRESSA
Placebo
0.8
0.8
0.6
0.6
0.4
0.4
0.2
0.2
Reference
Hirsch F et al. J Clin Oncol 2006; 24:
0.0
0.0 2 4 6 8 10 12 14 16 2 4 6 8 10 12 14 16
Time (months)
Time (months)
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

15. INTEREST: Phase III study of IRESSA vs docetaxel in pre-treated NSCLC
Endpoints
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
IRESSA 250 mg/day
Docetaxel 75 mg/m2 every 3 weeks
1:1 randomization
Reference
Kim ES et al. Lancet 2008; 372:
1466 patients
amodified Hochberg procedure applied to control for multiple testing CT, chemotherapy; PS, performance status; EGFR, epidermal growth factor receptor
Kim 2008 15

16. 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
1.0
1.0
IRESSA Docetaxel
IRESSA Docetaxel
0.8
0.8
0.6
0.6
Probability of progression-free survival
Probability of survival
0.4
0.4
Reference
Kim ES et al. Lancet 2008; 372:
0.2
0.2
0.0
0.0 4 8 12 16 20 24 28 32 36 40 4 8 12 16 20 24 28 32 36 40
Months
Months
ORR [EFR population]: 9.1% IRESSA, 7.6% Docetaxel; p=0.3257
Kim 2008 16

17. INTEREST: Summary of key subgroup analyses
Overall Survival
ORR (%)
IRESSA v. Docetaxel
Progression-free Survival
Overall
Ever smoker
Never smoker
Asian
Non-Asian
EGFR FISH+
EGFR FISH-
EGFR Mutation+
EGFR Mutation-
9.1 v 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 EGFR FISH-
42.1 v 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-
References
Kim ES et al. Lancet 2008; 372:
Douillard et al. J Clin Oncol; 26 (May 20 Suppl.): Abstract 8001.
0.5
1.0
1.5
2.0
0.5
1.0
1.5
2.0
2.5
HR (IRESSA vs docetaxel) and 95% CI
EFR population
HR (IRESSA vs docetaxel) and 95% CI
Unadjusted
analysis
PP population
for clinical factors
ITT population for biomarker factors
Adjusted
analysis
EFR
population
Kim 2008; Douillard 2010 17

18. Carboplatin AUC 5 or 6 and Paclitaxel 200mg/m2 3 wkly
IPASS: Phase III study of IRESSA versus doublet chemotherapy in first line NSCLC
Endpoints
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
IRESSA 250 mg/day
Carboplatin AUC 5 or 6 and Paclitaxel 200mg/m2 3 wkly
1:1 randomization
Reference
Mok TS et al. N Engl J Med 2009; 361:
1217 patients from East Asian countries
*Never smokers:<100 cigarettes in lifetime; light ex-smokers: stopped 15 years ago and smoked  10 pack yrs
Carboplatin/paclitaxel was offered to IRESSA patients upon progression
PS, performance status; EGFR, epidermal growth factor receptor
Mok 2009 18

19. 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
IRESSA
Carboplatin /
paclitaxel N
Events
609
453 (74.4%)
608
497 (81.7%)
HR (95% CI) = (0.651, 0.845) p<0.0001
IRESSA demonstrated superiority relative to carboplatin / paclitaxel in terms of PFS
Reference
Mok TS et al. N Engl J Med 2009; 361:
Mok 2009
Primary Cox analysis with covariates; ITT population
HR <1 implies a lower risk of progression on IRESSA
HR, hazard ratio; CI, confidence interval; PFS, progression-free survival 20 20 20

21. Objective response rate 43% vs 32% p=0.0001
IPASS: Superior PFS and ORR with IRESSA vs doublet chemotherapy; PFS effect not constant over time
Probability of PFS
1.0
Carboplatin /
paclitaxel
IRESSA N
Events
609
453 (74.4%)
608
497 (81.7%)
0.8
HR (95% CI) = (0.651, 0.845) p<0.0001
0.6
Median PFS (months) 4 months progression-free 6 months progression-free 12 months progression-free
5.7 61% 48% 25%
5.8 74% 48% 7%
0.4
Primary objective exceeded: IRESSA demonstrated superiority relative to carboplatin / paclitaxel in terms of PFS
0.2
Reference
Mok TS et al. N Engl J Med 2009; 361:
0.0 4 8 12 16 20 24
Months
At risk :
IRESSA
609
363
212 76 24 5
Carboplatin / paclitaxel
608
412
118 22 3 1
Objective response rate 43% vs 32% p=0.0001
Mok 2009
Primary Cox analysis and logistic regression with covariates; ITT population
HR <1 implies a lower risk of progression on IRESSA 21 21 21

22. IPASS: Superior progression-free survival and response rate for IRESSA in EGFR mutation positive patients
IRESSA EGFR M+ (n=132) Carboplatin / paclitaxel EGFR M+ (n=129)
Probability of PFS
1.0
0.8
EGFR M+ HR=0.48, 95% CI 0.36, 0.64
p<0.0001
0.6
0.4
Objective response rate 71.2% vs 47.3%
p=0.0001
0.2
Reference
Mok TS et al. N Engl J Med 2009; 361:
0.0 4 8 12 16 20 24
Time from randomisation (months)
Mok 2009
M+, mutation positive 22 22 22

23. Objective response rate 1.1% vs 23.5% Time from randomisation (months)
IPASS: Superior progression-free survival and response rate for doublet chemotherapy in EGFR mutation negative patients
IRESSA EGFR M- (n=91)
Carboplatin / paclitaxel EGFR M- (n=85)
Probability of PFS
1.0
0.8
EGFR M-
HR=2.85, 95% CI 2.05, 3.98
p<0.0001
0.6
0.4
Objective response rate 1.1% vs 23.5%
p=0.0013
0.2
Reference
Mok TS et al. N Engl J Med 2009; 361:
0.0 4 8 12 16 20 24
Time from randomisation (months)
Mok 2009
M-, mutation negative 23 23 23

24. IPASS: EGFR mutation is a strong predictor for differential PFS benefit between IRESSA and doublet chemotherapy
IRESSA EGFR M+ (n=132) IRESSA EGFR M- (n=91) Carboplatin / paclitaxel EGFR M+ (n=129)
Carboplatin / paclitaxel EGFR M- (n=85)
Probability of PFS
1.0
0.8
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
Treatment by subgroup interaction test, p<0.0001
0.6
0.4
0.2
Reference
Mok TS et al. N Engl J Med 2009; 361:
0.0 4 8 12 16 20 24
Time from randomisation (months)
Mok 2009
M+, mutation positive; M-, mutation negative 24 24 24

25. 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.

26. 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

27. Prognostic vs Predictive
Not prognostic
Prognostic
Not predictive + - + -
Predictive + - + -
Blue=Experimental, Purple=comparator

28. Lessons learned It matters What you measure How you measure it
How you define positive (cut-off)
Biomarker status
Positive or negative
MAGIC ALGORITHM!
Tissue sample
Diagnostic test

29. It matters what you measure
Gene copy number
Protein expression
EGFR
Gene mutation

30. It matters how you measure it
FISH
CISH
Fluorescence
Gene copy number
IHC
Protein expression
EGFR
ARMs
Gene mutation
PNA-LNA PCR clamp
Sequencing

31. It matters how you define positive (cut-off)
Staining percentage
# of copies
Staining intensity
FISH
CISH
Fluorescence
Gene copy number
IHC
Pattern of copies
Protein expression
EGFR
ARMs
Gene mutation
New diagnostics may use more than one biomarker to define positivity
PNA-LNA PCR clamp
Sequencing
Type of mutation

32. INTEREST: Overlap of biomarkers (EGFR gene copy number by FISH, EGFR expression by IHC, EGFR mutation)
EGFR expression +
n=189
EGFR FISH +
n=117
n=73
n=16
n=84
+++ n=24
249 patients evaluable for EGFR expression, FISH and mutations
Reference
Douillard et al. J Clin Oncol 2009, in press. 4
EGFR mutation +
n=39 3
n=8
--- n=37
Douillard 2010 32

33. 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
Biomarker status
Positive or negative
MAGIC ALGORITHM!
Tissue sample
Diagnostic test

34. Overall EGFR mutation positive rate 14.8% (44/297)
INTEREST: EGFR mutation appeared to be associated with some clinical characteristics
% of samples EGFR mutation positive 60 50 40 30 20 10
Reference
Douillard et al. J Clin Oncol 2009, in press.
Male
PS 2
Female
Asian
PS 0-1
Second-line
Third-line
Non-Asian
Never-smoked
Ever-smoked
Adenocarcinoma
Non- adenocarcinoma
Overall EGFR mutation positive rate 14.8% (44/297)
Douillard 2010

35. K-Ras and EGFR mutations rarely co-exist in 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
349
150
215
120
617
K-Ras mutations
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)
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 41
349
150
241
120
519
EGFR mutations
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)
13 (31.7)
102 (29.2)
38 (25.3)
116 (48.1)
29 (24.2)
120 (23.1)
Number
K-Ras+/M+ 1 3 35

36. 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

37. IPASS: Attrition factors in biomarker analysis
1217 randomised patients (100%)
Reasons for samples not evaluable: Sample not available, insufficient quantity to send, cytology only, sample at another site
1038 biomarker consent
(85%)
683 provided samples
(56%)
565 histology
118 cytology
Evaluable for:
EGFR mutation: 437 (36%)
EGFR gene copy number: 406 (33%)
EGFR expression: 365 (30%)
Reference
Mok TS et al. N Engl J Med 2009; 361:
Mok 2009, Fukuoka 2009 37 37 37

38. 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

39. Personalised Healthcare development today and in the future
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

40. 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

41. 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: , 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: , 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: , 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: , 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: , 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: , 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: , 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