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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