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 Discovery of cisplatin 1965 Discovery of paclitaxel 1967

Ciardiello F and Tortora G., NEJM 2008 TKI EGFR TKI blocks ATP binding and prevents activation of TK domain 1.Dimerisation of ligand- bound receptors 3.Activation of two major intracellular signalling pathways 4.Cellular response to signals 2.ATP binding and phosphorylation of tyrosine-kinase domain

T Lynch et al, NEJM 2004

I Okamoto, FEBSJ 2010

M Kris et al, P ASCO 2011

AF Gadzar Oncogene 2009

E Laack et al, Lung Cancer 2010

IDEAL 1&2 Fukuoka, JCO 2003 Kris, JAMA 2003 IDEAL 1&2 Fukuoka, JCO 2003 Kris, JAMA 2003 INTACT 1&2 Giaccone, JCO 2004 Herbst, JCO 2004 INTACT 1&2 Giaccone, JCO 2004 Herbst, JCO 2004 INTEREST Kim, Lancet 2008 Unselected population FIRST-SIGNAL Han, JCO 2012 FIRST-SIGNAL IPASS Mok, NEJM 2009 WJTOG 3405 Mitsudomi, Lancet 2010 NEJ 002 Maemondo, NEJM 2010 NEJ 002 Maemondo, NEJM 2010 Molecular target Clinical/Histological selection INVITE Crinò, JCO 2008 ISEL Thatcher, Lancet 2005 TRIBUTE Herbst, JCO 2005 EURTAC Rosell, Lancet Oncol 2012 OPTIMAL Zhou, Lancet Oncol 2011 OPTIMAL Zhou, Lancet Oncol 2011 BR 21 Shepherd, NEJM 2005 TALENT Gatzmeier, JCO 2007 TALENT Gatzmeier, JCO 2007 Phase I-II Perez-Soler, JCO 2004 Phase I-II Perez-Soler, JCO 2004 SATURNCappuzzo, Lancet Oncol 2010 SATURNCappuzzo, TRUST Reck, JTO 2010 TRUST

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

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

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

T Mok et al, NEJM ms 6.3 ms Gefitinib Carbo / pac p=0.0001

GefitinibCarboplatin / paclitaxel S Thongprasert et al, JTO 2011

* 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 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

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

M Maemondo et al, NEJM 2010 HR= 0.30 ( ) p value <.001 HR= 0.30 ( ) p value < ms 5.4 ms

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JY Douillard et al, JCO 2010

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

T Mok, PeerVoice 2011

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

*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 Lee, et al. WCLC 2009; 6 Mitsudomi, et al. Lancet Oncol 2010; 7 Maemondo, et al. NEJM 2010; 8 Rosell, Lancet Oncol 2012

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) AUC 0–24 (nghour/mL)

F de Marinis et al, P ESMO 2011