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Consistent OS with placebo in BR.21 and ISEL demonstrates similar study populations Summary of search strategy Summary of data included Median PFS from individual studies90% accuracy intervals (any line of therapy) EGFR mutation-positive disease:efficacy of therapeutic options SATURN study design Stratification factors: EGFR IHC (positive vs negative vs indeterminate) Stage (IIIB vs IV) ECOG PS (0 vs 1) CT regimen (cis/gem vs carbo/doc vs others) Smoking history (current vs former vs never) Region All Non-Squamous cell ca SATURN - OS WJTOG0203: Hazard Ratios for Death according to the Subgroup Analysis 0.4 0.6 0.8 1.0 1.2 Favourserlotinib Favoursplacebo HR Male Female Caucasian Asian Adenocarcinoma Squamous-cell Never smoker Former smoker Current smoker HR (95% CI) n 0.88 (0.74–1.05) 659 0.64 (0.46–0.91) 230 0.86 (0.73–1.01) 746 0.66 (0.42–1.05) 131 0.77 (0.61–0.97) 403 0.86 (0.68–1.10) 360 0.69 (0.45–1.05) 152 0.75 (0.56–1.00) 244 0.88 (0.72–1.08) 493 SATURN: OS subgroup analyses by clinical characteristics All 0.81 (0.70–0.95) 889 Proportion surviving 1.0 0.8 0.6 0.4 0.2 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 Time (months) Placebo (BR.21)1 Placebo (ISEL)2 1Shepherd FA, et al. N Engl J Med 2005;353:123–32 2Thatcher N, et al. Lancet 2005;366:1527–37 Why Gefitinib Failed? BR21 vs ISEL Drug dosing Erlotinib and GefitinibSimilar structures, Different activity? Structural differences may affect plasma, tumour and normal tissue distribution metabolism in-vitro activity clinical efficacy and toxicity Erlotinib Gefitinib O O O O NH N N CI F N O NH N O O NH O O N MW 429.2 MW 446.9 Erlotinib is less lipophilic than gefitinib cLogP = 3.30 cLogP = 3.87 Three-fold difference in lipophilicity Greater susceptibility to metabolism Increased biliary elimination Increased protein binding Reduced free drug plasma concentration Erlotinib Gefitinib O O O O NH N N CI F N O NH N O O NH O O N MW 429.2 MW 446.9 Differences in activity of major metabolite