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Management of NSCLC in Asia

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Presentation on theme: "Management of NSCLC in Asia"— Presentation transcript:

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

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

3 More non-smoking related adenocarcinoma?

4 Lung Cancer in Never Smokers
Predominance of Adenocarcinoma Histology SCLC (~20%) Percentage 20 40 60 80 Smokers (n = 21,853) Never Smokers (n = 5,144) Adenocarcinoma Squamous Cell Ca Modified from Sun, Schiller and Gazdar, Nat Rev Cancer, 7:778, 2007 Squamous Cell Ca (~35%) Adenocarcinoma (~45%) 0.4:1 3.4:1

5 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

6 Oncogene in Chinese Patients with NSCLC
An SJ,…Wu YL Plos ONE 7(6):e40109

7 Incidence of Single Driver Mutations
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 7

8 MSN: Incidence of driver mutations in adenocarcinoma
MET TOP1 ALK (ampl) HER2 FGFR4 BRAF KDR PI3K PDK1 NRAS ALK No mutation STK11 EGFR KRAS Planchard et al ELCC 2012

9 Genomic driver in adenocarcinoma
LCMC (USA) MSN (France) China Japan EGFR 17% 13% 40% 50% KRAS 22% 28% 7% 15% ELM4-ALK 2% 5% BRAF 1% HER2 NA 3% PIK3CA 4% PTEN 6% MET Amp Nil 46% 33% 29% Kris ASCO 2011 Planchard ELCC 2012 Wu JSMO 2011 Mitsudomi JCCO 2010

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

11 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

12 Variability in CYP3A5 Midazolam test 2 days before infusion of docetaxel followed by PK study Genotype for CYP3A5 Genotype Number (%) Mean Docetaxel Clearances CYP3A5*3/*3 9 (36%) 27.3 CYP3A5*1/*3 13 (52%) 22.3 CYP3A5*1/*1 3 (12%) 19.4 Goh et al JCO 20:3683, 2002

13 Nature Medicine 18(8):521, 2012

14 BIM (BCL-2 Like 11) BIM is a member of the pro-apoptotic 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 (BH3) Reduced BH3 implies less apoptosis, thus resistance to TKI

15 EURTAC Biomarker Study
95 patients from EURTAC (EGFR Mutation) with available samples Biomarkers: ELM4 ALK, T790M, TP53, BIM 16% detected by PCR 38% detected 24% mutation 31% high BEAM level

16 Potential biomarker of a biomarker selected population:
T790M mutation status and BIM mRNA levels G1: Low/Intermediate BIM and T790M present G2:Low/Intermediate BIM and T790M absent G3: High BIM and T790M present G4:High BIM and T790M absent 40·1 22·1 15·4 25·8 G3 G4 G2 G1 Patients at risk Rosell et al ESMO 2012

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

18 Difference in guidelines
NCCN (USA) NCCN (China) ESMO (Europe) Pre-treatment evaluation PET CT for all resectable lung cancer PET for staging if lymph node involvement is suspected PET CT if avaliable Mediastinoscopy All resectable lung cancer Not for clinical stage I disease Indicated for suspicious finding on PET CT Antiangiogensis Chemo + Bevacizumab for advanced non-squamous 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

19 Routine practice for advanced stage NSCLC in China
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 2nd line therapy Gem/Carbo 18.5% Docetaxel 12.9% Gefitinib 11% Pemetrexed 9.3% EGFR mutation testing 5.9% 987 cases (381 early stage disease) provided by 202 doctors from 12 cities Xue et al Lung Cancer :In Press

20 How widely available is EGFR mutation testing?(2011)
No. of EGFR mutation test EGFR mutation + patients EGFR M+ who received TKI EGFR M+ who received Gefitinib Chemo-naïve NSCLC 202K 6% 30% 65% 75%

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

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

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

24 PFS is determined according to EGFR mutation status: ICOGEN data
Mutant Icotinib Gefitinib N ORR /29(58.6%) /39(53.8%) Cox analysis with covariates HR (95% CI) = 0.743( ) Median Time Log Rank P-Value : p=0.5551 1.0 0.8 0.6 Icotinib (mutation) Probability of PFS Gefitinib (Mutation) 0.4 Icotinib(wild type) 0.2 Gefetinib (wild type) 50 400 100 150 200 250 300 350 Days PFS, progression-free survival

25 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

26 Chinese Thoracic Oncology Group (C-TONG) Study List
number NCT number Investiga- tional drug Study title status C-TONG 0801 NCT Bisphospoh- nates Screening Non Small Cell Lung Cancer With Bone Metastasis and Efficacy and Safety Research of Receiving Bisphosphonates (BLEST) Ongoing, but not recruiting 0802 NCT Erlotinib Erlotinib Versus Gemcitabine/Carboplatin in Chemo-naive Stage IIIB/IV Non-Small Cell Lung Cancer Patients With Epidermal Growth Factor Receptor (EGFR) Exon 19 or 21 Mutation(Optimal) 0803 NCT Efficacy of Erlotinib for Brain Metastasis of Non-Small Cell Lung Cancer 0804 NCT Gefitinib Assess the Efficacy, Safety and Tolerability of Gefitinib (Iressa® 250mg) as Maintenance Therapy in Locally Advanced or Metastatic (Stage IIIB/IV) Non Small Cell Lung Cancer (NSCLC) (INFORM) Completed 0805 NCT Sorafenib Sorafenib Treatment in Non-Small Cell Lung Cancer After Failure of Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor Recruiting 0806 NCT Pemetrexed 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 0807 NCT Erlotinib/ Carpecitabine A Study of TX Regimen as First-Line Treatment in Elderly Patients With Stage IIIB/IV Adenocarcinoma Non-Small Cell Lung Cancer 0901 NCT Erlotinib Versus Gefitinib in Advanced Non Small Cell Lung Cance With exon21 Mutation:A Randomized Trial

27 Chinese Thoracic Oncology Group (C-TONG) Study List
number NCT number Investiga- tional drug Study title status C-TONG 0902 NCT Erlotinib A Study of Tarceva (Erlotinib) or Placebo in Combination With Platinum-Based Therapy as First Line Treatment in Patients With Advanced or Recurrent Non-Small Cell Lung Cancer Ongoing, but not recruiting 0904 NCT Docetaxel Tax First-line Chemotherapy With Different Doses and Then Maintenance Therapy (TFINE) Recruiting 1001 NCT rhTPO Clinical Trial on the Prevention of Thrombocytopenia After First- line Chemotherapy 1002 NCT Nab-Paclitaxel/ Gemcitabine Nab-Paclitaxel Treatment in Advanced Squamous Cell Carcinoma of Lung Not yet opening 1003 NCT Rad001 (Afinitor) Safety and Tolerability Profile of RAD001 Daily in Chinese Patients With Advanced Pulmonary Neuroendocrine Tumor 1101 NCT 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 1102 Gefitinib Iressa vs chemo as intermittent treatment in advanced NSCLC 1103 Ertlotinib Erlotinib vs chemo as neoadjuvant in IIIA-N2 NSCLC with EGFR Mutation in exon 19 or 21

28 CTONG 0802: OPTIMAL 1.0 0.8 0.6 0.4 0.2 Erlotinib (n=82) Gem/carbo (n=72) HR=0.16 (0.10–0.26) Log-rank p<0.0001 PFS probability Time (months) Patients at risk Erlotinib Gem/carbo Zhou et al Lancet Oncology 2011

29 Time since randomization (weeks)
CTONG 0804: INFORM 100 Gefitinib (n=148) Placebo (n=148) 90 80 Median PFS,† months 6-month PFS rate, % 12-month PFS rate, % No. events, n (%) (83.8) (97.3) 70 60 HR‡ (95% CI) = 0.42 (0.32, 0.54); p<0.0001 Probability of PFS (%) 50 40 30 20 10 8 16 24 32 40 48 56 64 72 80 88 96 104 112 Time since randomization (weeks) Patients at risk : Placebo 148 82 46 26 16 10 6 4 3 2 2 2 Gefitinib 148 109 82 70 65 56 49 42 38 31 20 15 6 1 †Estimated using the Kaplan-Meier method ‡Primary Cox analysis with covariates HR <1 implies a lower risk of progression on gefitinib Zhang et al Lancet Oncology IN PRESS

30 CTONG 0902: FASTACT-II Phase III study design
Screening Treatment Post-treatment Six cycles gemcitabine + cisplatin OR carboplatin + Tarceva Tarceva 150mg/day PD Previously untreated stage IIIb/IV NSCLC (n=450) 1 Post-study R Stratified by stage, histology, smoking status and chemo regimen 1 Six cycles gemcitabine + cisplatin OR carboplatin + placebo Placebo PD Primary end point: Progression free survival (PFS) Gemcitabine 1250mg/m2 (d1,8); cisplatin 75mg/m2 OR carboplatin 5×AUC (d1); erlotinib 150mg/day (d15–28)

31 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


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