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BR.21 Study Design *2:1 Randomization R Stratified by: Centre PS, 0/1 vs 2/3 Response to prior Rx (CR/PR:SD:PD) Prior regimens, (1 vs 2) Prior platinum,

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Presentation on theme: "BR.21 Study Design *2:1 Randomization R Stratified by: Centre PS, 0/1 vs 2/3 Response to prior Rx (CR/PR:SD:PD) Prior regimens, (1 vs 2) Prior platinum,"— Presentation transcript:

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2 BR.21 Study Design *2:1 Randomization R Stratified by: Centre PS, 0/1 vs 2/3 Response to prior Rx (CR/PR:SD:PD) Prior regimens, (1 vs 2) Prior platinum, (Yes vs no) Placebo 150 mg daily Erlotinib* 150mg/day Shepherd et al. N Engl J Med. 2005;353:

3 BR.21 Progression-Free Survival *Adjusted for stratification factors (except centre) AND EGFR status Months ___ Erlotinib, _____ Placebo 2.2 mos 1.8 mos *HR 0.61, p < Shepherd et al. N Engl J Med. 2005;353:

4 21% 31% *HR and P-value adjusted for stratification factors at randomization plus HER1/EGFR status. BR.21: Overall Survival 42.5% improvement in median survival Survival time (months) Erlotinib Placebo HR=0.70 (95% CI, ); P < 0.001* Survival distribution function Shepherd et al. N Engl J Med. 2005;353:

5 IPASS Study Design Primary endpoint: PFS Secondary endpoints: ORR, OS, QoL and safety Gefitinib 250mg/day Chemonaïve advanced NSCLC Adenocarcinoma Non-smoker or light smoker N = 1217 Paclitaxel (200 mg/m 2, IV, d1) plus carboplatin (AUC=5 or 6 mg/min) repeated every 3 weeks up to 6 cycles R Mok TS, et al. N Engl J Med Sep 3;361(10):

6 IPASS: PFS and OS by Known EGFR Mutation Status Probability of progression-free survival Time from randomisation (months) PFS (2008) Gefitinib EGFR M+ Gefitinib EGFR M- C / P EGFR M+ C / P EGFR M Time from randomisation (months) Probability of survival OS (2010) Mutation + Mutation - Patients at risk excludes censored patients and those who have experienced an event Yang CH et al. ESMO 2010

7 INTEREST Study Design a Modified Hochberg procedure applied to control for multiple testing CT: chemotherapy; PS: performance status Patients Age 18 years Life expectancy 8 weeks 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 a 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 Endpoints IRESSA 250 mg/day IRESSA 250 mg/day Docetaxel 74 mg.m 2 every 3 weeks Docetaxel 74 mg.m 2 every 3 weeks 1:1 randomization Kim ES, et al. Lancet Nov 22;372(9652):

8 INTEREST: Gefitinib vs. Docetaxel in NSCLC After Chemotherapy OS in overall study population Gefitinib demonstrated non-inferior survival compared with docetaxel Kim ES, et al. Lancet Nov 22;372(9652): Months Probability of survival HR (96% CI) = (0.905, 1.150) OS in patients with high EGFR gene copy number 20 Gefitinib Docetaxel 0 40 Months 20 HR (95% CI) = 1.09 (0.78, 1.51) P =

9 SATURN Study Design Primary endpoint: PFS in all patients; PFS in patients with EGFR IHC- positive tumours Secondary endpoints: OS in ITT and EGFR-positive tumours, PFS in EGFR-negative tumours, time to progression, tumour response, QoL Erlotinib 150mg/day Run-in Period: Patients with advanced NSCLC Treatment with four cycles of platinum- doublet chemo N = 1949 Placebo R Eligibility: No progressive disease N = 889 Cappuzzo F, et al. Lancet Oncol Jun;11(6):521-9.

10 SATURN: Erlotinib vs. Placebo in NSCLC After Chemotherapy Probability Time (weeks) PFS OS Time (weeks) Erlotinib (n=438) Placebo (n=451) Erlotinib (n=437) Placebo (n=447) HR=0.71 (0.62–0.82) Log-rank p< HR=0.81 (0.70–0.95) Log-rank p= Cappuzzo F, et al. Lancet Oncol Jun;11(6):521-9.

11 SATURN: EGFR Activating Mutations Time (weeks) Probability HR=0.10 (0.04–0.25) Log-rank p< PFS 1 Erlotinib (n=22) Placebo (n=27) Time (months) HR=0.83 (0.34–2.02) Log-rank p= Erlotinib (n=22) Placebo (n=27) OS Cappuzzo F, et al. Lancet Oncol Jun;11(6): Brugger, et al. J Thorac Oncol 2009;4 (Suppl. 1):S348–9 (Abs. B9.1)

12 PFS: Overall Population Overall population Progression-free survival probability (%) Time (weeks) Unstratified analysis: Hazard ratio = (95% CI: 0.490–0.945) Log-rank P-value = PF (n=94) Median: 12.4 weeks (95% CI: 8.3–16.1) Erlotinib (n=94) Median: 8.3 weeks (95% CI: 8.0–11.4) CI = confidence interval Post-baseline tumor assessments were initiated at week 8 and conducted every 4 weeks thereafter. Boyer et al ASCO Abstract LBA7523. Dacomitinib versus Erlotinib Phase ll

13 AFATINIB: PRECLINICAL ACTIVITY DrugIC50 (nM) WTL858RExon 19 DelL858R/T790M Afatinib Erlotinib >4,000 Gefitinib 3, >4,000 PF Oncogene 2008;27: Cancer Res 2006;66: Science 2004;304: JNCI 2005;97: Cancer Res 2007; 67:

14 PFS by independent review Statistically significant across almost all subgroups


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