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 Management of NSCLC in Asia Tony Mok MD Professor Dept. of Clinical Oncology] Management of NSCLC in Asia Tony Mok MD Professor Dept. of Clinical Oncology] The Chinese University of Hong Kong

Asia Perspectives in NSCLC • Asian perspective in epidemiology and oncogenic drivers • Asian Asia Perspectives in NSCLC • Asian perspective in epidemiology and oncogenic drivers • Asian perspective in drug metabolism • Asian perspective in medical practice and clinical research

More non-smoking related adenocarcinoma? More non-smoking related adenocarcinoma?

Lung Cancer in Never Smokers Predominance of Adenocarcinoma Histology Adenocarcinoma 80 Squamous Cell Ca Lung Cancer in Never Smokers Predominance of Adenocarcinoma Histology Adenocarcinoma 80 Squamous Cell Ca SCLC (~20%) Percentage 60 Squamous Cell Ca (~35%) 40 20 0. 4: 1 3. 4: 1 Smokers (n = 21, 853) Never Smokers (n = 5, 144) 0 Adenocarcinoma (~45%) Modified from Sun, Schiller and Gazdar, Nat Rev Cancer, 7: 778, 2007

Lung Cancer not related to smoking in China 25% of male lung cancer were Lung Cancer not related to smoking in China 25% of male lung cancer were not smoking related 72% of female lung cancer were not smoking related Wang et al Cancer Causes and Control 21: 959, 2010

Oncogene in Chinese Patients with NSCLC An SJ, …Wu YL Plos ONE 7(6): e Oncogene in Chinese Patients with NSCLC An SJ, …Wu YL Plos ONE 7(6): e 40109

Lung Cancer Mutation Consortium Incidence of Single Driver Mutations Mutation found in 54% (280/516) Lung Cancer Mutation Consortium Incidence of Single Driver Mutations Mutation found in 54% (280/516) of tumors completely tested (CI 50 -59%) Kris et al ASCO 2011

MSN: Incidence of driver mutations in adenocarcinoma ALK HER 2 MET TOP 1 ALK MSN: Incidence of driver mutations in adenocarcinoma ALK HER 2 MET TOP 1 ALK (ampl) BRAF PDK 1 KDR PI 3 K FGFR 4 NRAS No mutation STK 11 EGFR KRAS Planchard et al ELCC 2012

Genomic driver in adenocarcinoma LCMC (USA) Japan EGFR 17% 13% 40% 50% KRAS 22% Genomic driver in adenocarcinoma LCMC (USA) Japan EGFR 17% 13% 40% 50% KRAS 22% 28% 7% 15% ELM 4 ALK 7% 2% 7% 5% BRAF 2% 2% 2% 1% HER 2 1% 1% NA 3% PIK 3 CA 1% 1% 4% NA PTEN Kris ASCO 2011 Planchard ELCC 2012 Wu JSMO 2011 Mitsudomi JCCO 2010 MSN China (France) NA NA 6% NA MET Amp 1% 1% 5% 4% Nil 46% 33% 29% 22%

Asia Perspectives in NSCLC • Asian perspective in epidemiology and oncogenic drivers • Asian Asia Perspectives in NSCLC • Asian perspective in epidemiology and oncogenic drivers • Asian perspective in drug metabolism • Asian perspective in medical practice and clinical research

A phase II study of docetaxel/carboplatin in Australia/Asian • Phase II study in 66 A phase II study of docetaxel/carboplatin in Australia/Asian • Phase II study in 66 pts (43 Australian, 23 Asians) • Higher tumor response rate in Asian group • Ethnicity is significant predictor of OS (p=0. 021) • Mean cycle 1 neutrophil nadir – All 0. 99 – Singapore 0. 67 Millward et al Annals of Oncol 14: 449, 2003

Variability in CYP 3 A 5 • Midazolam test 2 days before infusion of Variability in CYP 3 A 5 • Midazolam test 2 days before infusion of docetaxel followed by PK study • Genotype for CYP 3 A 5 Genotype Number (%) Mean Docetaxel Clearance s CYP 3 A 5*3/*3 9 (36%) 27. 3 CYP 3 A 5*1/*3 13 (52%) 22. 3 CYP 3 A 5*1/*1 3 (12%) 19. 4 Goh et al JCO 20: 3683, 2002

Nature Medicine 18(8): 521, 2012 Nature Medicine 18(8): 521, 2012

BIM (BCL-2 Like 11) • BIM is a member of the proapoptotic protein • BIM (BCL-2 Like 11) • BIM is a member of the proapoptotic protein • BIM is essential in TKI induced apoptosis • Polymorphism existed and may splice from exon 4 to exon 3, and result in low expression of the functional isoform (BH 3) • Reduced BH 3 implies less apoptosis, thus resistance to TKI

EURTAC Biomarker Study • 95 patients from EURTAC (EGFR Mutation) with available samples • EURTAC Biomarker Study • 95 patients from EURTAC (EGFR Mutation) with available samples • Biomarkers: ELM 4 ALK, T 790 M, TP 53, BIM 16% 38% detected by detected PCR 24% mutation 31% high BEAM level

Potential biomarker of a biomarker selected population: T 790 M mutation status and BIM Potential biomarker of a biomarker selected population: T 790 M mutation status and BIM m. RNA levels G 1: Low/Intermediate BIM and T 790 M present G 2: Low/Intermediate BIM and T 790 M absent G 3: High BIM and T 790 M present G 4: High BIM and T 790 M absent G 3 G 2 G 4 15· 4 22· 1 25· 8 G 1 40· 1 Patients at risk Rosell et al ESMO 2012

Asia Perspectives in NSCLC • Asian perspective in epidemiology and oncogenic drivers • Asian Asia Perspectives in NSCLC • Asian perspective in epidemiology and oncogenic drivers • Asian perspective in drug metabolism • Asian perspective in medical practice and clinical research

Difference in guidelines NCCN (USA) NCCN (China) ESMO (Europe) Pre-treatment evaluation PET CT for Difference in guidelines NCCN (USA) NCCN (China) ESMO (Europe) Pre-treatment evaluation PET CT for all resectable lung cancer PET for staging if PET CT if lymph node avaliable involvement is suspected Mediastinoscopy All resectable lung Not for clinical cancer stage I disease Indicated for suspicious finding on PET CT Antiangiogensis Chemo + Bevacizumab for advanced nonsquamous cell ca Consideration of Endostar or Ginseng extract Bevacizumab is optional Gefitinib Not included All lines of therapy First line EGFR mutation positive patients only Xu et al Thoracic Cancer 1: 83, 2010

Routine practice for advanced stage NSCLC in China Practice First line chemotherapy Gem/Plat 27. Routine practice for advanced stage NSCLC in China Practice First line chemotherapy Gem/Plat 27. 5% Doc/Plat 16. 2% Taxol/Plat 13. 5% First line adenocarcinoma Pemetrexed/Plat 16. 1% Second line chemotherapy Less than 10% received 2 nd line therapy Gem/Carbo 18. 5% Docetaxel 12. 9% Gefitinib 11% Pemetrexed 9. 3% EGFR mutation testing • 987 cases (381 early stage disease) provided by 202 doctors from 12 cities 5. 9% Xue et al Lung Cancer : In Press

How widely available is EGFR mutation testing? (2011) Chemo-naïve NSCLC 202 K No. of How widely available is EGFR mutation testing? (2011) Chemo-naïve NSCLC 202 K No. of EGFR mutation test EGFR mutation + patients EGFR M+ who received TKI EGFR M+ who received Gefitinib

EGFR mutation testing in China Ø 26 hospitals: EGFR mutation tested in the hospital EGFR mutation testing in China Ø 26 hospitals: EGFR mutation tested in the hospital (16 use ARMS) Ø 50 hospitals: Third technical services company

Icotinib: The third EGFR TKI in China Subjects Endpoints • Age: 18 – 75 Icotinib: The third EGFR TKI in China Subjects Endpoints • Age: 18 – 75 yrs • IIIB or IV NSCLC Icotinib • Expected survival≥ 125 mg Tid 12 W • 1 or 2 Regimen(1 platinum) • PS≤ 2 • At least one RECIST target lesion • others 1: 1 Gefitinib 250 mg Qd Primary • PFS Secondary • OS • ORR • DCR • TTP • HRQo. L • Safety Explatory • Biomarkers of EGFR

Objective tumor response (RECIST) (FAS) N% Icotinb (n=199) Gefitinb(n=196) Objective tumor response (RECIST) (FAS) N% Icotinb (n=199) Gefitinb(n=196)

PFS is determined according to EGFR mutation status: ICOGEN data Mutant Icotinib 1. 0 PFS is determined according to EGFR mutation status: ICOGEN data Mutant Icotinib 1. 0 N Gefitinib 29 Probability of PFS ORR 39 17/29(58. 6%) 21/39(53. 8%) Cox analysis with covariates 0. 8 HR (95% CI) = 0. 743(0. 406 1. 358) Median Time 198 Log Rank P-Value : p=0. 5551 0. 6 158 Icotinib (mutation) Gefitinib (Mutation) 0. 4 Icotinib(wild type) 0. 2 Gefetinib (wild type) 0 50 100 150 200 250 PFS, progression-free survival 300 400 350 Days

Chinese Thoracic Oncology Group (CTONG) • CTONG Committee – Chairman:Prof Yi-long Wu – Vice-chairman:Prof Chinese Thoracic Oncology Group (CTONG) • CTONG Committee – Chairman:Prof Yi-long Wu – Vice-chairman:Prof Li Zhang,Shun Lu,Cai-cun Zhou – Secretary General:Prof. Qing Zhou • CTONG Members – From 17 clinical cancer centers or hospitals (11 plus 6 ) • Established in 2007

Chinese Thoracic Oncology Group (C-TONG) Study List Study number NCT number C-TONG NCT 00765687 Chinese Thoracic Oncology Group (C-TONG) Study List Study number NCT number C-TONG NCT 00765687 0801 Investigational drug Bisphospohnates Study title Screening Non Small Cell Lung Cancer With Bone Metastasis and Efficacy and Safety Research of Receiving Bisphonates (BLEST) status Ongoing, but not recruiting C-TONG NCT 00874419 Erlotinib 0802 Erlotinib Versus Gemcitabine/Carboplatin in Chemo-naive Stage Ongoing, but IIIB/IV Non-Small Cell Lung Cancer Patients With Epidermal Growth not recruiting Factor Receptor (EGFR) Exon 19 or 21 Mutation(Optimal) C-TONG NCT 00663689 Erlotinib 0803 Efficacy of Erlotinib for Brain Metastasis of Non-Small Cell Lung Cancer C-TONG NCT 00770588 0804 Gefitinib Assess the Efficacy, Safety and Tolerability of Gefitinib (Iressa® 250 mg) as Maintenance Therapy in Locally Advanced or Metastatic Completed (Stage IIIB/IV) Non Small Cell Lung Cancer (NSCLC) (INFORM) C-TONG NCT 00922584 0805 Sorafenib C-TONG NCT 00891579 0806 Pemetrexed Gefitinib C-TONG NCT 00816868 0807 Erlotinib/ A Study of TX Regimen as First-Line Treatment in Elderly Patients Carpecitabine With Stage IIIB/IV Adenocarcinoma Non-Small Cell Lung Cancer Ongoing, but not recruiting C-TONG 0901 Erlotinib/ Gefitinib Recruiting NCT 01024413 Ongoing, but not recruiting Sorafenib Treatment in Non-Small Cell Lung Cancer After Failure of Recruiting Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor Study of Pemetrexed Versus Gefitinib in Patients With Locally Advanced or Metastatic Non Small Cell Lung Cancer Who Have Previously Received Platinum-Based Chemotherapy Without Epidermal Growth Factor Receptor (EGFR) Mutations Erlotinib Versus Gefitinib in Advanced Non Small Cell Lung Cance With exon 21 Mutation:A Randomized Trial Recruiting

Chinese Thoracic Oncology Group (C-TONG) Study List Study number NCT number Investigational drug Study Chinese Thoracic Oncology Group (C-TONG) Study List Study number NCT number Investigational drug Study title status C-TONG NCT 00883779 Erlotinib 0902 A Study of Tarceva (Erlotinib) or Placebo in Combination With Ongoing, Platinum-Based Therapy as First Line Treatment in Patients With but not recruiting Advanced or Recurrent Non-Small Cell Lung Cancer C-TONG NCT 01038661 Docetaxel 0904 Tax First-line Chemotherapy With Different Doses and Then Maintenance Therapy (TFINE) Recruiting C-TONG NCT 01319669 rh. TPO 1001 Clinical Trial on the Prevention of Thrombocytopenia After Firstline Chemotherapy Recruiting C-TONG Nab-Paclitaxel/ Nab-Paclitaxel Treatment in Advanced Squamous Cell NCT 01236716 1002 Gemcitabine Carcinoma of Lung Not yet opening C-TONG Rad 001 NCT 01175096 1003 (Afinitor) Safety and Tolerability Profile of RAD 001 Daily in Chinese Patients With Advanced Pulmonary Neuroendocrine Tumor Ongoing, but not recruiting C-TONG NCT 01297101 Erlotinib 1101 A single arm, one center, phase II study of sequential administration of erlotinib in combination with Gemcitabine/Cisplatin as neoadjuvant treatment in patients with stage IIIA NSCLC Recruiting C-TONG 1102 Gefitinib Iressa vs chemo as intermittent treatment in advanced NSCLC Not yet opening C-TONG 1103 Ertlotinib Erlotinib vs chemo as neoadjuvant in IIIA-N 2 NSCLC with EGFR Mutation in exon 19 or 21 Not yet opening

CTONG 0802: OPTIMAL 1. 0 Erlotinib (n=82) Gem/carbo (n=72) PFS probability 0. 8 HR=0. CTONG 0802: OPTIMAL 1. 0 Erlotinib (n=82) Gem/carbo (n=72) PFS probability 0. 8 HR=0. 16 (0. 10– 0. 26) Log-rank p<0. 0001 0. 6 0. 4 0. 2 0 0 Patients at risk Erlotinib 82 Gem/carbo 72 5 10 15 20 Time (months) 70 26 51 4 15 0 2 0 Zhou et al Lancet Oncology 2011

CTONG 0804: INFORM 100 Gefitinib (n=148) Probability of PFS (%) 80 Median PFS, † CTONG 0804: INFORM 100 Gefitinib (n=148) Probability of PFS (%) 80 Median PFS, † months 6 -month PFS rate, % 12 -month PFS rate, % No. events, n (%) 70 60 Placebo (n=148) 4. 8 47. 3 33. 2 124 (83. 8) 90 2. 6 15. 0 2. 9 144 (97. 3) HR‡ (95% CI) = 0. 42 (0. 32, 0. 54); p<0. 0001 50 40 30 20 10 0 0 Patients at risk : 8 16 24 32 40 48 56 64 72 80 88 96 2 15 0 6 104 112 Time since randomization (weeks) Placebo 148 82 46 26 16 10 Gefitinib 148 109 82 70 65 56 †Estimated using the Kaplan-Meier method ‡Primary Cox analysis with covariates HR <1 implies a lower risk of progression on gefitinib 6 49 4 42 3 38 2 31 2 20 0 1 0 0 Zhang et al Lancet Oncology IN PRESS

CTONG 0902: FASTACT-II Phase III study design Screening Previously untreated stage IIIb/IV NSCLC (n=450) CTONG 0902: FASTACT-II Phase III study design Screening Previously untreated stage IIIb/IV NSCLC (n=450) Treatment 1 R 1 Post-treatment Six cycles gemcitabine + cisplatin OR carboplatin + Tarceva 150 mg/day Stratified by stage, histology, smoking status and chemo regimen Six cycles gemcitabine + cisplatin OR carboplatin + placebo PD Post-study Placebo PD Primary end point: Progression free survival (PFS) Gemcitabine 1250 mg/m 2 (d 1, 8); cisplatin 75 mg/m 2 OR carboplatin 5×AUC (d 1); erlotinib 150 mg/day (d 15– 28)

Summary • Epidemiology: rising incidence in Adenocarcinoma • Genomics: – Higher incidence of EGFR Summary • Epidemiology: rising incidence in Adenocarcinoma • Genomics: – Higher incidence of EGFR mutation and lower KRAS. – No difference in treatment outcome between East and West • Metabolism: differences in polymorphism affecting treatment toxicity and outcomes • EGFR TKI is a standard first line treatment for patients with EGFR mutation but molecular testing is still behind • Icotinib is the third EGFR TKI available only in China • Active clinical research group: CTONG