2. Tumour growth is angiogenesis dependent Judah Folkman 1971 VEGF gene identified and EGFR isolated 1980s Meta-analyses confirm survival benefit with chemotherapy 1990s Bevacizumab / TKIs improve survival in mol. unselected NSCLC 2000s Routine identification of EGFR mut+ve & TKIs therapy 2010-11 Discovery of cisplatin 1965 Discovery of paclitaxel 1967

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12. Asia IPASS,2009 OPTIMAL, 2011 First-SIGNAL, 2012 Japan WJTG, 2010 NEJSG, 2010 USA Sequist, 2008 CALGB, 2011 Europe SLCG, 2009 FIELT, 2011 EURTAC, 2012

14. Gefitinib 250 mg/day Carboplatin AUC 5/6 Paclitaxel 200mg/m 2 3 wkly 1:1 randomization *Never smokers:<100 cigarettes in lifetime; light ex-smokers: stopped  15 years ago and smoked  10 pack yrs Carboplatin/paclitaxel was offered to gefitinib patients upon progression Patients Patients Age ≥18 years Age ≥18 years Life expectancy ≥ 12 weeks Life expectancy ≥ 12 weeks Adenocarcinoma histology Adenocarcinoma histology Never smokers or light ex-smokers* Never smokers or light ex-smokers* PS 0-2 PS 0-2 Stage IIIB/IV Stage IIIB/IV Measurable disease Measurable disease Primary PFS (non-inferiority) PFS (non-inferiority)Secondary Objective response rate Objective response rate Quality of life Quality of life Disease related symptoms Disease related symptoms Overall survival Overall survival Safety and tolerability Safety and tolerabilityExploratory Biomarkers Biomarkers EGFR mutationEGFR mutation EGFR gene copy numberEGFR gene copy number EGFR protein expressionEGFR protein expression Endpoints Endpoints T Mok et al, NEJM 2009 IRESSA PAN ASIA STUDY DESIGN

15. T Mok et al, NEJM 2009 EGFR mutation by PCR sequencing 437 samples (36%) 261 positive (60%)

16. T Mok et al, NEJM 2009 9.5 ms 6.3 ms Gefitinib Carbo / pac p=0.0001

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18. * Gemcitabine+Cisplatin Dose: Same as in INTACT-1 and TALENT Gefitinib 250 mg/day P.O. daily, Gefitinib 250 mg/day P.O. daily, Gemcitabine 1250 mg/m 2 (D1 & D8) Cisplatin 80 mg/m 2 (D1) q 3 weeks x 9 cycles Patients Chemo-naïve Age 18-75 years Adenocarcinoma Never smoker ECOG PS 0-2 Stage IIIB or IV Female vs. Male PS 0, 1 vs. 2 Stage IIIb vs. IV PD R 1 1 PD Primary Endpoint: OS J-Y Han et al, JCO 2012

21. T Mitsudomi et al, Lancet 2009 9.2 ms 6.3 ms HR= 0.49, p <.001

22. M Maemondo et al, NEJM 2010 HR= 0.30 (0.22-0.41) p value <.001 HR= 0.30 (0.22-0.41) p value <.001 10.8 ms 5.4 ms

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24. JY Douillard et al, JCO 2010

26. 1. P Jänne et al, WCLC 2011/2. R Rosell et al, NEJM 2009/ 3. J De Grève et al, ASCO 2011

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34. T Mok, PeerVoice 2011 (modified) 73.0* * Measurable Disease *

35. T Mok, PeerVoice 2011

36. * TKI arm ** Measurable Disease 1.Mok et al, NEJM 2009; 2.Zhou et al. Lancet Oncol 2011; 3.Rosell et al, Lancet Oncol 2012;

37. *For IPASS, First-SIGNAL and CALGB30406 these data are for all patients in TKI arm (not limited to EGFR MUT+ group) ALT = alanine aminotransferase; AST = aspartate aminotransferase 1 Zhou, et al. Lancet Oncol 2011; 2 Rosell, et al. NEJM 2009; 3 Janne, et al. ASCO 2010; 4 Mok, et al. NEJM 2009 5 Lee, et al. WCLC 2009; 6 Mitsudomi, et al. Lancet Oncol 2010; 7 Maemondo, et al. NEJM 2010; 8 Rosell, Lancet Oncol 2012

38. MTD ~MTD Standard dosing 1 Hidalgo M, et al. J Clin Oncol 2001;19:3267–79 2 Ranson M, et al. J Clin Oncol 2002;20:2240–50 C max = maximum plasma concentration AUC = area under the curve Erlotinib 1 (150mg/day) Gefitinib 2 (225mg/day) Gefitinib 2 (525mg/day) Gefitinib 2 (700mg/day) C max (ng/mL)2.1203079032.146 AUC 0–24 (nghour/mL)38.4205.04114.72736.077

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