Presentation is loading. Please wait.

Presentation is loading. Please wait.

IRESSA Dr Rose McCormack Personalised Healthcare AstraZeneca A Presentation for the Translational Genomics Meeting Royal College of Physicians, London.

Similar presentations


Presentation on theme: "IRESSA Dr Rose McCormack Personalised Healthcare AstraZeneca A Presentation for the Translational Genomics Meeting Royal College of Physicians, London."— Presentation transcript:

1 IRESSA Dr Rose McCormack Personalised Healthcare AstraZeneca A Presentation for the Translational Genomics Meeting Royal College of Physicians, London 15 th January 2013 A Case Study in Personalised Medicine

2 AN OVERVIEW

3 THE DRUG

4 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

5 THE BIOMARKERS AND CLINICAL TRIALS

6 DNA mRNA Protein Chromosome Gene Copy Number (FISH) Gene Copy Number (FISH) DNA Mutation Analysis (e.g. ARMS) DNA Mutation Analysis (e.g. ARMS) Expression Analysis (e.g. Array, RT-PCR etc) Expression Analysis (e.g. Array, RT-PCR etc) Protein Expression Analysis (e.g. IHC) Pao & Miller 2005 Tumour cell proliferation Tumour cell survival Lessons in Biomarker Analysis PI3K MAPK Akt mTOR STAT 3/5 Grb-2 SOS Ras Raf MEK PTEN

7 The Trials: A Brief History IRESSA registration Japan ISEL INTEREST ISEL, INTEREST: Unselected trials in pre-treated setting 2003 EGFR protein expression EGFR gene copy number

8 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: ) 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: ) Activating Mutations in the Epidermal Growth Factor Receptor Underlying Responsiveness of Non-Small-Cell Lung Cancer to Gefitinib Paez et al 2004 (Science 304: ) EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy Paez et al 2004 (Science 304: ) EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy Mitsudomi T et al: J Clin Oncol 23 (11), 2005: 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: 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.

9 The Trials: A Brief History IRESSA registration Japan ISEL INTEREST IPASS 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

10 Gefitinib 250 mg/day Docetaxel 75 mg/m 2 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

11 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 Months Probability of survival Months Probability of progression- free survival Gefitinib Docetaxel Kim 2008

12 INTEREST: Summary of key subgroup analyses ORR (%) Gefitinib v. Docetaxel 9.1 v. 7.6 Overall Ever smoker Never smoker 19.7 v. 8.7Asian 6.2 v. 7.3Non-Asian 13.0 v. 7.4EGFR FISH+ 7.5 v. 10.1EGFR FISH v. 21.1EGFR Mutation+ 6.6 v. 9.8EGFR 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 HR (Gefitinib vs docetaxel) and 95% CI Overall SurvivalProgression-free Survival Kim 2008; Douillard 2010

13 INTEREST: Overlap of biomarkers EGFR expression + n=189 EGFR FISH + n=117 EGFR mutation + n= patients evaluable for EGFR expression, FISH and mutations +++ n= n=16 n=73 n=84 n=8 --- n=37 13 Douillard 2010

14 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 yrs Carboplatin/paclitaxel was offered to IRESSA patients upon progression PS, performance status; EGFR, epidermal growth factor receptor Gefitinib 250 mg/day Carboplatin AUC 5 or 6 and Paclitaxel 200mg/m 2 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 15 IPASS: Progression Free Survival (74.4%) (81.7%) N Events HR (95% CI) = (0.651, 0.845) p< 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-free 6 months progression-free 12 months progression-free % 48% 25% % 48% 7% Months Probability of PFS At risk : Objective response rate 43% vs 32% p= Mok 2009

16 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< EGFR M- HR=2.85, 95% CI 2.05, 3.98 p< Time from randomisation (months) Probability of 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< Mok 2009

17 IPASS: PFS by Biomarkers (ITT) Treatment-by-subgroup interaction test p-value p= for EGFR gene copy number p= for EGFR expression p< 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 Hazard Ratio (Gefitinib : Carboplatin / Paclitaxel) and 95% CI Fukuoka JCO 2011

18 IPASS: Overlap of biomarkers N=329 with known biomarker status for all 3 biomarkers --- = 31 EGFR Mutation+ n=261 EGFR FISH+ n= = EGFR expression + n=266 Fukuoka JCO 2011

19 DNA mRNA Protein Chromosome EGFR Gene Copy Number EGFR Gene Copy Number EGFR Mutation Analysis EGFR Mutation Analysis EGFR Expression Analysis EGFR Expression Analysis EGFR Protein Expression Analysis Pao & Miller 2005 Tumour cell proliferation Tumour cell survival 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

20 683 provided samples (56%) 565 histology 118 cytology 1038 biomarker 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 20 Mok 2009, Fukuoka 2009

21 IMPLICATIONS FOR DIAGNOSTICS

22

23 Getting the right treatment to the right patient All 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 Test sensitivity Test ease of use Interpretation of results Test Turnaround time Affected by..... Easily accessible testing Easily accessible testing High quality testing (high detection rates) High quality testing (high detection rates) Access to suitable samples Access to suitable samples Reasonable Test Turnaround Time Reasonable Test Turnaround Time Easily accessible testing Easily accessible testing High quality testing (high detection rates) High quality testing (high detection rates) Access to suitable samples Access to suitable samples Reasonable Test Turnaround Time Reasonable Test Turnaround Time Needs..... Positive

24 EGFR mutation testing: diversity in 2009 Centralised lab network Testing reimbursed High level of patients tested Tests used: CLAMP INVADER Sequencing Cycleave 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 De- centralised lab network Testing not reimbursed Low level of patients tested Tests used: TheraScreen Sequencing Pyrosequencing JapanJapanUKUK

25 Understanding and Supporting the Dx Environment Patient Physician (respiratory, surgeon, oncologist) Lab service provider/Molecular Biologist Lab service provider/Molecular Biologist Sample Test result Diagnostic company/ies Platform provider Pathologist egfr-mutation.com egfr-test.com

26 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 results ChallengesChallenges Challenges associated with a PHC approach

27 OUR EXPERIENCE AND LEARNINGS

28 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

29 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

30 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

31 31 Author | 00 Month YearSet area descriptor | Sub level 1 Confidentiality Notice This file is private and may contain confidential and proprietary information. If you have received this file in error, please notify us and remove it from your system and note that you must not copy, distribute or take any action in reliance on it. Any unauthorized use or disclosure of the contents of this file is not permitted and may be unlawful. AstraZeneca PLC, 2 Kingdom Street, London, W2 6BD, UK, T: +44(0) , F: +44 (0) ,


Download ppt "IRESSA Dr Rose McCormack Personalised Healthcare AstraZeneca A Presentation for the Translational Genomics Meeting Royal College of Physicians, London."

Similar presentations


Ads by Google