IRESSA (Gefitinib) The Journey - European...
Transcript of 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
The DrugThe Biomarker
and Clinical Trials
SamplingLessons Learned
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
The DrugThe Biomarker
and Clinical Trials
SamplingLessons Learned
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
The DrugThe Biomarker
and Clinical Trials
SamplingLessons Learned
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
The DrugThe Biomarker
and Clinical Trials
SamplingLessons Learned
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!!