2 BR.21 Study Design R Stratified by: Centre Erlotinib* 150mg/day PS, 0/1 vs 2/3Response to prior Rx(CR/PR:SD:PD)Prior regimens,(1 vs 2)Prior platinum,(Yes vs no)Erlotinib* 150mg/dayR*2:1 RandomizationPlacebo “150 mg” dailyBR 21Shepherd et al. N Engl J Med. 2005;353:2
3 BR.21 Progression-Free Survival ___ Erlotinib, _____ Placebo2.2 mos mos*HR 0.61, p <0.0001*Adjusted for stratification factors (except centre) AND EGFR statusBR 21MonthsShepherd et al. N Engl J Med. 2005;353:
4 Survival time (months) BR.21: Overall Survival1.000.750.500.25HR=0.70 (95% CI, ); P < 0.001**HR and P-value adjusted for stratification factors at randomization plus HER1/EGFR status.Survival distribution function31%42.5% improvement in median survivalPre-specified analyses in the statistical analysis plan for study BR.21 included stratifications on the basis of performance status, prior therapy (including platinum therapy), responsiveness to prior therapy, and HER1/EGFR status.Treatment of NSCLC patients with erlotinib resulted in a statistically significant improvement in the primary endpoint of overall survival versus placebo.In a univariate analysis of all patients, the hazard ratio was 0.72 (ie, patients treated with erlotinib had a 28% better chance of survival compared with placebo)Patients treated with erlotinib (median survival=6.7 months) survived 30% longer than placebo-treated patients (median survival=4.7 months).One-year survival rates were increased 48% by treatment with erlotinib.Erlotinib is the only HER1/EGFR inhibitor proven to prolong the survival of patients with advanced, refractory NSCLC.ErlotinibPlacebo21%Survival time (months)Shepherd et al. N Engl J Med. 2005;353:44
5 IPASS Study Design R Primary endpoint: PFS Gefitinib 250mg/dayChemonaïve advanced NSCLCAdenocarcinomaNon-smoker or light smokerN = 1217RPaclitaxel (200 mg/m2, IV, d1) plus carboplatin (AUC=5 or 6 mg/min) repeated every 3 weeks up to 6 cyclesPrimary endpoint: PFSSecondary endpoints: ORR, OS, QoL and safetyMok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, Nishiwaki Y, Ohe Y, Yang JJ, Chewaskulyong B, Jiang H, Duffield EL, Watkins CL, Armour AA, Fukuoka M. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med Sep 3;361(10):Mok TS, et al. N Engl J Med Sep 3;361(10):5
6 IPASS: PFS and OS by Known EGFR Mutation Status 1.01.0Gefitinib EGFR M+Gefitinib EGFR M-C / P EGFR M+C / P EGFR M-48162412200.80.8Mutation +0.60.6Probability of survival0.40.4Probability of progression-free survival0.20.2Mutation -0.00.04812162024283236IPASS404448Time from randomisation (months)Time from randomisation (months)52Patients at risk excludes censored patients and those who have experienced an eventYang CH et al. ESMO 2010666
7 INTEREST Study Design Endpoints Patients IRESSA 250 mg/day Age ≥18 yearsLife expectancy ≥8 weeksProgressive or recurrent disease following CTConsidered candidates for further CT with docetaxel1 or 2 CT regimens (≥1 platinum)PS 0-2PrimaryOverall survival (co-primary analysesa of non-inferiority in all patients and superiority in patients with high EGFR gene copy number)SecondaryProgression-free survivalObjective response rateQuality of lifeDisease-related symptomsSafety and tolerabilityExploratoryBiomarkersIRESSA250 mg/day1:1 randomizationDocetaxel74 mg.m2 every 3 weeksINTEREST was an international, multicenter, randomized, open-label, parallel-group, Phase III study of IRESSA (gefitinib) versus docetaxel in patients with locally advanced or metastatic recurrent NSCLC who were pre-treated with platinum-based chemotherapy.Eligible patients were at least 18 years of age with NSCLC that had progressed or recurred following one or two prior therapies (at least one platinum based) and with a performance status of 0 to 2 and a life expectancy of >8 weeks.Patients were randomized to receive either IRESSA (250 mg/day orally) or docetaxel (1-hour 75 mg/m2 infusion every 3 weeks).The primary endpoint was overall survival using co-primary analyses of non-inferiority in all patients and superiority in patients with high epidermal growth factor receptor (EGFR) gene copy number.Secondary endpoints compared progression-free survival, objective response rate, quality of life, disease-related symptoms and safety and tolerability for IRESSA and docetaxel.Exploratory endpoints included the efficacy outcomes in biomarker subgroups defined by EGFR expression by immunohistochemistry (IHC), EGFR mutation and K-RAS mutation status.aModified Hochberg procedure applied to control for multiple testing CT: chemotherapy; PS: performance statusKim ES, et al. Lancet Nov 22;372(9652):77
8 INTEREST: Gefitinib vs. Docetaxel in NSCLC After Chemotherapy Gefitinib demonstrated non-inferior survival compared with docetaxelOS in overall study populationOS in patients with high EGFR gene copy number1.00.8HR (96% CI) = (0.905, 1.150)HR (95% CI) = 1.09 (0.78, 1.51)P =0.6Probability of survivalGefitinibDocetaxel0.40.2Pre-treated NSCLC INTEREST STUDY (D791GC00001)INTEREST was a Phase III, randomized, open-label, parallel-group, international, multicentre trial comparing IRESSA to docetaxel in 1466 patients with locally advanced or metastatic NSCLC who had previously received platinum-based chemotherapy and were eligible for further chemotherapy. Pre-planned exploratory subgroup analysis of 44 EGFR mutation positive patients provides supportive evidence for the approved indication. For patients with EGFR mutations, IRESSA was superior to docetaxel in terms of PFS (HR 0.16, 95% CI 0.05 to 0.49, p=0.0012) and ORR (42.1% vs 21.1%, p= ).Kim ES, Hirsh V, Mok T, Socinski MA, Gervais R, Wu YL, Li LY, Watkins CL, Sellers MV, Lowe ES, Sun Y, Liao ML, Osterlind K, Reck M, Armour AA, Shepherd FA, Lippman SM, Douillard JY. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet Nov 22;372(9652):0.02036402040MonthsMonthsKim ES, et al. Lancet Nov 22;372(9652):8
9 SATURN Study Design R Erlotinib 150mg/day Placebo Run-in Period: Patients with advanced NSCLCTreatment with four cycles of platinum-doublet chemoN = 1949Erlotinib 150mg/dayEligibility:No progressive diseaseN = 889RPlaceboPrimary endpoint: PFS in all patients; PFS in patients with EGFR IHC- positive tumoursSecondary endpoints: OS in ITT and EGFR-positive tumours, PFS in EGFR-negative tumours, time to progression, tumour response, QoLCappuzzo F, et al. Lancet Oncol Jun;11(6):521-9.
10 SATURN: Erlotinib vs. Placebo in NSCLC After Chemotherapy PFSOS1.00.80.60.40.21.00.80.60.40.2Erlotinib (n=437)Placebo (n=447)Erlotinib (n=438)Placebo (n=451)HR=0.71 (0.62–0.82)Log-rank p<0.0001HR=0.81 (0.70–0.95)Log-rank p=0.0088ProbabilityCappuzzo F, Ciuleanu T, Stelmakh L, Cicenas S, Szczésna A, Juhász E, Esteban E, Molinier O, Brugger W, Melezínek I, Klingelschmitt G, Klughammer B, Giaccone G; SATURN investigators. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study. Lancet Oncol Jun;11(6):521-9.Time (weeks)Time (weeks)Cappuzzo F, et al. Lancet Oncol Jun;11(6):521-9.10
11 SATURN: EGFR Activating Mutations PFS1OS21.00.80.60.40.21.00.80.60.40.2HR=0.10 (0.04–0.25) Log-rank p<0.0001HR=0.83 (0.34–2.02) Log-rank p=0.6810ProbabilityErlotinib (n=22)Placebo (n=27)Erlotinib (n=22)Placebo (n=27)Significantly improved PFS with erlotinib vs. placebo in patients with EGFR MUT +ve diseaseOS data not yet mature (N.B. 67% of patients with EGFR MUT +ve disease in placebo arm received a second-line EGFR TKI)Cappuzzo F, Ciuleanu T, Stelmakh L, Cicenas S, Szczésna A, Juhász E, Esteban E, Molinier O, Brugger W, Melezínek I, Klingelschmitt G, Klughammer B, Giaccone G; SATURN investigators. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study. Lancet Oncol Jun;11(6):521-9.Brugger, et al. J Thorac Oncol 2009;4 (Suppl. 1):S348–9 (Abs. B9.1)Time (weeks)Time (months)1. Cappuzzo F, et al. Lancet Oncol Jun;11(6):521-9.2. Brugger, et al. J Thorac Oncol 2009;4 (Suppl. 1):S348–9 (Abs. B9.1)111111
12 PFS: Overall Population Dacomitinib versus Erlotinib Phase llOverall population100908070605040302010PF (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)Progression-free survival probability (%)Dacomitinib Phase 2Unstratified analysis: Hazard ratio = (95% CI: 0.490–0.945) Log-rank P-value = 0.019Time (weeks)CI = confidence intervalPost-baseline tumor assessments were initiated at week 8 and conducted every 4 weeks thereafter.Boyer et al ASCO Abstract LBA7523.
13 AFATINIB: PRECLINICAL ACTIVITY DrugIC50 (nM)WTL858RExon 19 DelL858R/T790MAfatinib1600.70.550Erlotinib2110403.8>4,000Gefitinib3, 415710-63PF-804529-6372-4119Afatinib1. Oncogene 2008;27: Cancer Res 2006;66: Science 2004;304: JNCI 2005;97: Cancer Res 2007; 67:
14 PFS by independent review AfatinibStatistically significant across almost all subgroups