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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 Studies Indicated for Biomarker+ The reality Broad population? Biomarker targeted drug Studies Clinical characteristics? Biomarker(s)? Which biomarker? What cut-off? Indicated for Biomarker+ IRESSA - May 2001 “Dramatic” Tumour shrinkage in patient with metastatic NSCLC IDEAL 1&2 – NSCLC Phase II non-comparative - 2002 Response rate, % 30 25 20 15 18 19 250 mg 500 mg 12 9 10 5 0 250 mg 500 mg IDEAL 2 – USA IDEAL 1 – Japan and Europe Vertical bars represent 95% CI. Kris 2003, Fukuoka 2003 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 platinumbased 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 diseaserelated 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 TTF HR (95% CI) =0.82 (0.73, 0.93) p=0.0006 n=1316, progressions=1137 1.0 1.0 0.8 0.8 Proportion without treatment failure Proportion surviving 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] 0.6 0.4 IRESSA Placebo 0.2 0.6 0.4 0.2 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 Rate 8.0% vs 1.3%, p<0.0001 Thatcher 2005 ISEL OS subgroups by smoking status and histology Proportion surviving Treatment by smoking interaction test p=0.047 Never smoked (n=375) 1.0 Ever smoked (n=1317) HR 0.67; 95% CI 0.49, 0.92; p=0.012 0.8 HR 0.92; 95% CI 0.79, 1.06; p=0.242 IRESSA Placebo 0.6 0.4 0.2 0.0 0 2 4 6 8 10 12 14 16 0 2 4 6 8 10 12 14 16 Proportion surviving Treatment by race interaction test p=0.043 Asian origin (n=342) 1.0 HR 0.66; 95% CI 0.48, 0.91; p=0.010 0.8 Non-Asian origin (n=1350) HR 0.92; 95% CI 0.80, 1.07; p=0.294 0.6 0.4 0.2 0.0 0 2 4 6 8 10 12 14 16 0 2 4 Cox regression analysis Time (months) 6 8 10 12 14 16 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 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 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 EGFR mutations IPASS: Clinically selected trial in first line setting ISEL: OS by EGFR gene copy number Treatment by gene copy number interaction test p=0.047 High (+) Low (-) N=114, E=68 Cox HR=0.61 (0.36, 1.04) p=0.07 N=256, E=157 Cox HR=1.16 (0.81, 1.64) p=0.42 Percent 1.0 surviving 0.8 1.0 IRESSA Placebo 0.8 0.6 0.6 0.4 0.4 0.2 0.2 0.0 0.0 0 2 4 6 8 10 12 14 Time (months) IRESSA Placebo 16 0 2 4 6 8 10 12 14 Time (months) 16 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 INTEREST: Phase III study of IRESSA vs docetaxel in pre-treated NSCLC Endpoints Primary Patients • Progressive or recurrent disease following CT IRESSA 250 mg/day • Considered candidates for further CT with docetaxel •1 or 2 CT regimens (≥1 platinum) • PS 0-2 1:1 randomization Docetaxel 75 mg/m2 every 3 weeks • 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 • 1466 patients amodified Hochberg procedure applied to control for multiple testing CT, chemotherapy; PS, performance status; EGFR, epidermal growth factor receptor • Biomarkers •EGFR mutation •EGFR protein expression •EGFR gene copy number •K-Ras mutation Kim 2008 INTEREST: OS and PFS and ORR OS: NI margin 1.154, PP population PFS: EFR population HR (96% CI) =1.020 (0.905, 1.150) n=1433, deaths=1169 Median survival: IRESSA 7.6m, Docetaxel 8.0m HR (95% CI) =1.04 (0.93, 1.18), p=0.466 n=1316, progressions=1137 Median PFS: IRESSA 2.2m, Docetaxel 2.7m 1.0 Probability of progressionfree survival Probability of survival 1.0 IRESSA Docetaxel 0.8 0.6 0.4 0.2 0.0 IRESSA Docetaxel 0.8 0.6 0.4 0.2 0.0 0 4 8 12 16 20 Months 24 28 32 36 40 0 4 8 12 16 20 24 28 32 36 Months ORR [EFR population]: 9.1% IRESSA, 7.6% Docetaxel; p=0.3257 Kim 2008 40 INTEREST: Summary of key subgroup analyses INTEREST Overall Survival Overall ORR (%) IRESSA v. Docetaxel 9.1 v. 7.6 Ever smoker Never smoker Asian Non-Asian Progression-free Survival Overall Overall Ever smoker Ever smoker Never smoker Never smoker 19.7 v. 8.7 Asian Asian 6.2 v. 7.3 Non-Asian Non-Asian EGFR FISH+ 13.0 v. 7.4 EGFR FISH+ EGFR FISH+ EGFR FISH- 7.5 v. 10.1 EGFR FISH- EGFR FISH- EGFR Mutation+ 42.1 v. 21.1 EGFR Mutation+ EGFR Mutation+ EGFR Mutation- 6.6 v. 9.8 EGFR Mutation- 0 0.5 1.0 1.5 2.0 HR (IRESSA vs docetaxel) and 95% CI Unadjusted analysis PP population for clinical factors ITT population for biomarker factors EGFR Mutation- 0 0.5 1.0 1.5 2.0 2.5 HR (IRESSA vs docetaxel) and 95% CI EFR population Adjusted EFR analysis population Kim 2008; Douillard 2010 IPASS: Phase III study of IRESSA versus doublet chemotherapy in first line NSCLC Endpoints Patients • Adenocarcinoma histology • Never smokers or light ex-smokers* • PS 0-2 Primary IRESSA 250 mg/day Secondary 1:1 randomization • Provision of tumour sample for biomarker analysis strongly encouraged • Progression free survival (non-inferiority) Carboplatin AUC 5 or 6 and Paclitaxel 200mg/m2 3 wkly • 1217 patients from East Asian countries • 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 *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 Mok 2009 18 IPASS reports September 2008, partway through the European MAA review of INTEREST 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 IPASS: Superior PFS and ORR with IRESSA vs doublet chemotherapy; PFS effect not constant over time Probability 1.0 of PFS Carboplatin / IRESSA N Events 0.8 609 453 (74.4%) paclitaxel 608 497 (81.7%) HR (95% CI) = 0.741 (0.651, 0.845) p<0.0001 0.6 5.8 74% 48% 7% Median PFS (months) 5.7 4 months progression-free 61% 6 months progression-free 48% 12 months progression-free 25% 0.4 Primary objective exceeded: IRESSA demonstrated superiority relative to carboplatin / paclitaxel in terms of PFS 0.2 0.0 At risk : IRESSA Carboplatin / paclitaxel 0 4 8 12 16 20 24 Months 609 608 363 412 212 118 76 22 24 3 5 1 0 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 IPASS: Superior progression-free survival and response rate for IRESSA in EGFR mutation positive patients IRESSA EGFR M+ (n=132) Probability of PFS 1.0 Carboplatin / paclitaxel EGFR M+ (n=129) 0.8 EGFR M+ HR=0.48, 95% CI 0.36, 0.64 p<0.0001 0.6 0.4 Objective response rate 71.2% vs 47.3% 0.2 p=0.0001 0.0 0 4 8 12 16 20 24 Time from randomisation (months) Mok 2009 M+, mutation positive 22 IPASS: Superior progression-free survival and response rate for doublet chemotherapy in EGFR mutation negative patients Probability of PFS IRESSA EGFR M- (n=91) 1.0 Carboplatin / paclitaxel EGFR M- (n=85) 0.8 0.6 EGFR M- HR=2.85, 95% CI 2.05, 3.98 p<0.0001 0.4 Objective response rate 1.1% vs 23.5% 0.2 p=0.0013 0.0 0 4 8 12 16 20 24 Time from randomisation (months) Mok 2009 M-, mutation negative 23 IPASS: EGFR mutation is a strong predictor for differential PFS benefit between IRESSA and doublet chemotherapy Probability of PFS IRESSA EGFR M+ (n=132) IRESSA EGFR M- (n=91) Carboplatin / paclitaxel EGFR M+ (n=129) Carboplatin / paclitaxel EGFR M- (n=85) 1.0 0.8 Treatment by subgroup interaction test, p<0.0001 EGFR M+ HR=0.48, 95% CI 0.36, 0.64 p<0.0001 0.6 EGFR M- HR=2.85, 95% CI 2.05, 3.98 p<0.0001 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 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 predictive Not prognostic Prognostic 12 12 10 10 8 8 Olaparib 6 Comparator Olaparib 6 Comparator 4 4 2 2 0 HRD+ + HRD- 0 - 12 HRD+ HRD- + - 12 10 10 Predictive 8 8 Olaparib 6 Comparator Olaparib 6 Comparator 4 4 2 2 0 HRD+ HRD- + - 0 HRD+ HRD- + - Blue=Experimental, Purple=comparator Lessons learned • It matters • What you measure • How you measure it • How you define positive (cut-off) Tissue sample Diagnostic test MAGIC ALGORITHM! Biomarker status Positive or negative It matters what you measure Protein expression Gene copy number EGFR Gene mutation It matters how you measure it FISH Fluorescence Gene copy number IHC Protein expression CISH EGFR Gene mutation Sequencing ARMs PNA-LNA PCR clamp It matters how you define positive (cut-off) Staining intensity Staining percentage # of copies FISH CISH Fluorescence Gene copy number IHC Protein expression New diagnostics may use more than one biomarker to define positivity Pattern of copies EGFR Gene mutation Sequencing ARMs PNA-LNA PCR clamp Type of mutation 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 4 EGFR mutation + n=39 3 n=8 --- n=37 249 patients evaluable for EGFR expression, FISH and mutations Douillard 2010 32 Lessons learned • It matters • What you measure • How you measure it • How you define positive (cut-off) Tissue sample Diagnostic test MAGIC ALGORITHM! Biomarker status Positive or negative • Consider if there is a surrogate for the biomarker e.g. clinical characteristics, another marker INTEREST: EGFR mutation appeared to be associated with some clinical characteristics % of samples EGFR mutation 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-exist in 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 K-Ras mutations N evaluable N (%) K-Ras+ EGFR mutations N evaluable N (%) M+ Number K-Ras+/M+ 275 152 90 49 (17.8) 12 (7.9) 24 (26.7) 297 215 65 44 (14.8) 26 (12.1) 6 (9.2) 1 0 1 237 86 206 200 190 133 70 115 152 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) 349 150 215 120 617 21 (6.0) 6 (4.0) 21 (9.8) 4 (3.3) 50 (8.1) 235 86 204 200 195 133 71 115 215 41 349 150 241 120 519 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) 0 0 3 0 0 0 0 0 0 0 0 0 0 0 0 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 IPASS: Attrition factors in biomarker analysis 1217 randomised patients (100%) 1038 biomarker consent (85%) Reasons for samples not evaluable: Sample not available, insufficient quantity to send, cytology only, sample at another site 683 provided 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 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 2013 • 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 § 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 codevelopment 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: 847855, 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 5:744752, 2010 Fukuoka M, Wu Y, Thongprasert S, et al. Biomarker analyses from a phase III, randomized, open-label, firstline 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