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IRESSA: A journey of experience from broad to biomarker populations

IRESSA: A journey of experience from broad to biomarker populations. Claire Watkins Global Product Statistician, AstraZeneca EFSPI meeting on Oncology Basel, 24 th June 2010. Outline. A brief history of IRESSA (gefitinib) Lessons learned

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IRESSA: A journey of experience from broad to biomarker populations

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  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. 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? http://www.egfr-info.com/EGFR-lung-cancer/

  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. The ideal Biomarker targeted drug Studies Indicated for Biomarker+

  6. The reality Biomarker targeted drug Broad population? 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

  8. IDEAL 1&2 – NSCLC Phase II non-comparative - 2002 250 mg 500 mg 250 mg 500 mg 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 2004 1.0 1.0 0.8 0.8 0.6 0.6 Proportion without treatment failure Proportion surviving 0.4 0.4 IRESSA 0.2 0.2 Placebo 0.0 0.0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Months Months Objective Response Rate8.0% 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 0 2 4 6 8 10 12 14 16 0 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 Proportion surviving 0.4 0.2 0.0 0 2 4 6 8 10 12 14 16 0 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. 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. IRESSA IRESSA Placebo Placebo 0.2 1.0 0.2 0.4 0.6 0.8 0.6 1.0 0.8 0.4 0.0 0.0 12 16 16 14 12 10 10 14 8 2 4 6 0 4 6 0 2 8 ISEL: OS by EGFR gene copy number Treatment by gene copy number interaction test p=0.047 High (+) Low (-) N=114, E=68Cox HR=0.61 (0.36, 1.04)p=0.07 N=256, E=157Cox HR=1.16 (0.81, 1.64)p=0.42 Percent surviving 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 IRESSA250 mg/day 1:1 randomization Docetaxel75 mg/m2 every3 weeks Endpoints • 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 • Patients • Progressive or recurrent disease following CT • Considered candidates for further CT with docetaxel • 1 or 2 CT regimens(≥1 platinum) • PS 0-2 • 1466 patients amodified Hochberg procedure applied to control for multiple testingCT, chemotherapy; PS, performance status; EGFR, epidermal growth factor receptor Kim 2008

  16. INTEREST: OS and PFS and ORR 1.0 1.0 IRESSADocetaxel IRESSADocetaxel 0.8 0.8 0.6 0.6 Probability of progression-free survival Probability of survival 0.4 0.4 0.2 0.2 0.0 0.0 0 4 8 12 16 20 24 28 32 36 40 0 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

  17. INTEREST: Summary of key subgroup analyses INTEREST Overall Survival Progression-free Survival ORR (%) IRESSA v. Docetaxel Overall Ever smoker Never smoker Asian Non-Asian EGFR FISH+ EGFR FISH- EGFR Mutation+ EGFR Mutation- 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- 0 0.5 1.0 1.5 2.5 0 0.5 1.0 1.5 2.0 2.0 HR (IRESSA vs docetaxel) and 95% CI HR (IRESSA vs docetaxel) and 95% CI EFR population Adjusted analysis EFR population Unadjusted analysis PP population for clinical factors ITT population for biomarker factors Kim 2008; Douillard 2010

  18. IPASS: Phase III study of IRESSA versus doublet chemotherapy in first line NSCLC IRESSA250 mg/day 1:1 randomization Carboplatin AUC 5 or 6 and Paclitaxel 200mg/m2 3 wkly 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 • 1217 patients from East Asian countries *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 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) = 0.741 (0.651, 0.845) p<0.0001 IRESSA demonstrated superiority relative to carboplatin / paclitaxel in terms of PFS 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

  21. IPASS: Superior PFS and ORR with IRESSA vs doublet chemotherapy; PFS effect not constant over time Probabilityof PFS Carboplatin / paclitaxel 1.0 IRESSA N Events 609 453 (74.4%) 608 497 (81.7%) 0.8 HR (95% CI) = 0.741 (0.651, 0.845) p<0.0001 0.6 5.874%48%7% Median PFS (months)4 months progression-free6 months progression-free12 months progression-free 5.761%48%25% 0.4 Primary objective exceeded: IRESSA demonstrated superiority relative to carboplatin / paclitaxel in terms of PFS 0.2 0.0 0 4 8 12 16 20 24 Months At risk : IRESSA 609 363 76 24 5 0 212 Carboplatin / paclitaxel 608 412 118 22 3 1 0 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

  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) Probabilityof PFS 1.0 EGFR M+HR=0.48, 95% CI 0.36, 0.64 p<0.0001 0.8 0.6 0.4 Objective response rate71.2% vs 47.3% p=0.0001 0.2 0.0 0 4 8 12 16 20 24 Time from randomisation (months) Mok 2009 M+, mutation positive 22

  23. 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) Probabilityof PFS 1.0 EGFR M- HR=2.85, 95% CI 2.05, 3.98 p<0.0001 0.8 0.6 0.4 Objective response rate1.1% vs 23.5% p=0.0013 0.2 0.0 0 4 8 12 16 20 24 Time from randomisation (months) Mok 2009 M-, mutation negative 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) Probabilityof PFS 1.0 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 0.8 Treatment by subgroup interaction test, p<0.0001 0.6 0.4 0.2 0.0 0 4 8 12 16 20 24 Time from randomisation (months) Mok 2009 M+, mutation positive; M-, mutation negative 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 4 3 n=8 EGFR mutation + n=39 --- 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. INTEREST: EGFR mutation appeared to be associated with some clinical characteristics 60 % ofsamplesEGFRmutation positive 50 40 30 20 10 0 Male PS 2 Female Asian PS 0-1 Third-line Non-Asian Second-line Ever-smoked Never-smoked Adenocarcinoma Non- adenocarcinoma Overall EGFR mutation positive rate 14.8% (44/297) Douillard 2010

  35. K-Ras and EGFR mutations rarely co-existin the same tumour 5 incidences across 19 studies totalling around 3300 patients K-Ras mutations EGFR mutations 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 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 randomisedpatients (100%) Reasons for samples not evaluable: Sample not available, insufficient quantity to send, cytology only, sample at another site 1038biomarker consent (85%) • 683provided samples • (56%) • 565 histology • 118 cytology Evaluable for: EGFR mutation: 437 (36%) EGFR gene copy number: 406 (33%) EGFR expression: 365 (30%) Mok 2009, Fukuoka 2009 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 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

  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 290:2149-2158, 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

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