iressa dr rose mccormack personalised healthcare astrazeneca a presentation for the translational...
TRANSCRIPT
IRESSA
Dr Rose McCormackPersonalised HealthcareAstraZeneca
A Presentation for the Translational Genomics MeetingRoyal College of Physicians, London15th January 2013
A Case Study in Personalised Medicine
AN OVERVIEW
THE DRUG
Gefitinib (IRESSA™): A brief overview
• 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
• 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 1st July 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
• Gefitinib is currently approved for the treatment of 1st line EGFR M+ advanced NSCLC patients in 85 countries worldwide
THE BIOMARKERS AND CLINICAL TRIALS
DNA mRNA ProteinChromosome
GeneCopy
Number(FISH)
DNA Mutation Analysis
(e.g. ARMS)
ExpressionAnalysis (e.g. Array, RT-PCR etc)
Protein Expression Analysis (e.g. IHC)
Pao & Miller 2005Tumour cellproliferation
Tumour cellsurvival
Lessons in Biomarker Analysis
PI3K
MAPK
Akt
mTOR STAT 3/5
Grb-2
SOS Ras
Raf
MEK
PTEN
The Trials: A Brief History
IRESSA registration
Japan
ISEL
INTEREST
2002 200920072005
ISEL, INTEREST: Unselected trials in pre-treated setting
2003
EGFR protein expression
EGFR gene copy number
2004 2006 2008
Reprinted with permission. © 2005 American Society of Clinical Oncology. All rights reserved.
Reprinted with permission. © 2005 American Society of Clinical Oncology. All rights reserved.
EGFR mutations: First observed in 2004
Lynch et al 2004 (New Eng J Med 350:2129- 2139)
Activating Mutations in the Epidermal Growth Factor Receptor Underlying Responsiveness of Non-Small-Cell Lung Cancer to Gefitinib
Lynch et al 2004 (New Eng J Med 350:2129- 2139)
Activating Mutations in the Epidermal Growth Factor Receptor Underlying Responsiveness of Non-Small-Cell Lung Cancer to Gefitinib
Paez et al 2004 (Science 304:1497-1500)
EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy
Paez et al 2004 (Science 304:1497-1500)
EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy
Mitsudomi T et al: J Clin Oncol 23 (11), 2005: 2513-2520
Mutations of the epidermal growth factor receptor gene predict prolonged survival after gefitinib treatment in patients with non-small-cell lung cancer with postoperative recurrence.
Mitsudomi T et al: J Clin Oncol 23 (11), 2005: 2513-2520
Mutations of the epidermal growth factor receptor gene predict prolonged survival after gefitinib treatment in patients with non-small-cell lung cancer with postoperative recurrence.
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
2003
EGFR protein expression
EGFR gene copy number
EGFR mutations
2004 2006 2008
Gefitinib 250 mg/day
Docetaxel75 mg/m2 every
3 weeks
1:1 randomization
INTEREST: Phase III study of gefitinib vs docetaxel in pre-treated NSCLC
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 Results
OS: 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
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
Gefitinib Docetaxel
Gefitinib Docetaxel
Kim 2008
INTEREST: Summary of key subgroup analyses
ORR (%)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% CI 0 0.5 1.0 1.5 2.52.0
Overall Survival Progression-free Survival
Kim 2008; Douillard 2010
INTEREST: Overlap of biomarkers
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
13
Douillard 2010
14
IPASS: Phase III study of gefitinib versus doublet chemotherapy in first line NSCLC
*Never smokers:<100 cigarettes in lifetime; light ex-smokers: stopped 15 years ago and smoked 10 pack yrsCarboplatin/paclitaxel was offered to IRESSA patients upon progressionPS, performance status; EGFR, epidermal growth factor receptor
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 2009
15
IPASS: Progression Free Survival
609453 (74.4%)
608497 (81.7%)
NEvents
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
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
16
IPASS: EGFR mutation is a strong predictor for differential PFS benefit between gefitinib 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
1.0
Probabilityof PFS
Gefitinib EGFR M+ (n=132)Gefitinib EGFR M- (n=91)Carboplatin / paclitaxel EGFR M+ (n=129)Carboplatin / paclitaxel EGFR M- (n=85)
Treatment by subgroup interaction test, p<0.0001
Mok 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 4.0Hazard Ratio (Gefitinib : Carboplatin / Paclitaxel) and 95% CI
Fukuoka JCO 2011
IPASS: Overlap of biomarkers
N=329 with known biomarker status for all 3 biomarkers
--- = 31EGFR Mutation+ n=261
EGFR FISH+ n=249
+++ = 132
2551
13
28
15
34
EGFR expression +
n=266
Fukuoka JCO 2011
DNA mRNA ProteinChromosome
EGFR GeneCopy
Number
EGFR Mutation Analysis
EGFR ExpressionAnalysis
EGFR ExpressionAnalysis
EGFR Protein Expression Analysis
Pao & Miller 2005
Tumour cellproliferation
Tumour cellsurvival
Lessons in Biomarker Analysis
PI3K
MAPK
Akt
mTOR STAT 3/5
Grb-2
SOS Ras
Raf
MEK
PTEN
• What? Choose your biomarker(s) carefully
• How? •The tool that you use to measure your biomarker must be robust and reliable• The cut-offs used to define biomarker positive, negative, and unknown subgroups must be appropriate• Samples must be available
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
20Mok 2009, Fukuoka 2009
IMPLICATIONS FOR DIAGNOSTICS
Getting the right treatment to the right patient
All NSCLC patientsAll NSCLC patients
Patients tested
Test result
Treated
• Test Availability and Ease of Test Order
• Test sensitivity• Test ease of use• Interpretation of results• Test Turnaround time
Affected by.....
• Easily accessible Easily accessible testingtesting
• High quality High quality testing (high testing (high detection rates)detection rates)
• Access to suitable Access to suitable samplessamples
• Reasonable Test Reasonable Test Turnaround TimeTurnaround Time
Needs.....
Positive
EGFR mutation testing: diversity in 2009
•Centralised lab network•Testing reimbursed• High level of patients tested•Tests used:
•CLAMP•INVADER•Sequencing•Cycleave
•De- centralised lab network•Testing not reimbursed• Low level of patients tested•Tests used:
•TheraScreen•Sequencing•Pyrosequencing
JapanJapan UKUK
Understanding and Supporting the Dx Environment
Patient
Physician(respiratory,
surgeon, oncologist)
Lab service provider/Molecular Biologist
Sample
Test result
Diagnostic company/ies Platform
provider
Pathologist
egfr-mutation.com egfr-test.com
Testing reimbursement
Access to testing
Diversity of testing
methods /capabilities
across countries
Time taken to generate test
results
Availability of suitable
samples for testing
Physicians adopting a
PHC approach Multiple
individuals involved from
decision to test to getting
resultsChallengesChallenges
Challenges associated with a PHC approach
OUR EXPERIENCE AND LEARNINGS
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. molecular disease segment, clinical characteristics, different biomarkers, techniques, cut-offs etc.
28
What patients do you intend to treat?
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 future
Gefitinib experience
• Gefitinib had standard drug development
• Predictive biomarker for gefitinib discovered by external collaborator ~7 years after start of clinical trials
• Retrospective investigation was required to show the significant 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
§ Clinical programme prospectively selects biomarker eligible patients, targeted to patients most likely to respond
§ Early engagement with health authorities and payers
§ Co-development of drug and diagnostic§ Drug launched globally, linked to
diagnostic established within the diagnostic environment
Summary
• Gefitinib is approved in Europe for a biomarker targeted population- Gefitinib was developed during a time of rapid progress in the understanding of
molecular mechanisms of cancer, therefore the route to approval was not straightforward
- 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- Assess efficacy in a biomarker defined, targetted population, as early as possible- Maximise tissue samples, no sample means no biomarker result- Diagnostic test adoption is as important as the drug
• Pharmaceutical companies, Physicians, Pathologists, Academics and Regulators are learning about this together- Engage early- Considerable challenges on both sides- Opportunity for collaboration
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