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

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Presentation on theme: "Management of NSCLC in Asia Tony Mok MD Professor Dept. of Clinical Oncology] The Chinese University of Hong Kong."— 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 Squamous Cell Ca (~35%) Adenocarcinoma (~45%) Predominance of Adenocarcinoma Histology SCLC (~20%) Percentage Smokers (n = 21,853) Never Smokers (n = 5,144) Adenocarcinoma Squamous Cell Ca Modified from Sun, Schiller and Gazdar, Nat Rev Cancer, 7:778, :13.4:1

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 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

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

9 Genomic driver in adenocarcinoma LCMC (USA) MSN (France) ChinaJapan EGFR17%13%40%50% KRAS22%28%7%15% ELM4- ALK 7%2%7%5% BRAF2% 1% HER21% NA3% PIK3CA1% 4%NA PTENNA 6%NA MET Amp 1% 5%4% Nil46%33%29%22% 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 GenotypeNumber (%) Mean Docetaxel Clearance s CYP3A5*3/*39 (36%)27.3 CYP3A5*1/*313 (52%)22.3 CYP3A5*1/*13 (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 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 40·122·115·425·8 G3 G4 G2 G1 Patients at risk Potential biomarker of a biomarker selected population: T790M mutation status and BIM mRNA levels 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 MediastinoscopyAll resectable lung cancer Not for clinical stage I disease Indicated for suspicious finding on PET CT AntiangiogensisChemo + Bevacizumab for advanced non- squamous cell ca Consideration of Endostar or Ginseng extract Bevacizumab is optional GefitinibNot includedAll 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 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 5.9% 987 cases (381 early stage disease) provided by 202 doctors from 12 cities Xue et al Lung Cancer :In Press

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

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

22 Gefitinib 250 mg Qd Icotinib 125 mg Tid 1:1 Subjects Age 18 –75 yrs III B or IV NSCLC Expected survival 12 W 1 or 2 Regimen 1 platinum PS2 At least one RECIST target lesion others Primary PFS Secondary OS ORR DCR TTP HRQoL Safety Explatory Biomarkers of EGFR Endpoints Icotinib: The third EGFR TKI in China

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

24 PFS is determined according to EGFR mutation status: ICOGEN data Probability of PFS Days PFS, progression-free survival Mutant Icotinib Gefitinib N ORR 17/ % 21/ % Cox analysis with covariates HR (95% CI) = 0.743( ) Median Time Log Rank P-Value : p= Icotinib (mutation) Gefitinib (Mutation) Icotinib(wild type) Gefetinib (wild type)

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 Study number NCT number Investiga- tional drug Study titlestatus 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 C-TONG 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) Ongoing, but not recruiting C-TONG 0803 NCT Erlotinib Efficacy of Erlotinib for Brain Metastasis of Non-Small Cell Lung Cancer Ongoing, but not recruiting C-TONG 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 C-TONG 0805 NCT Sorafenib Sorafenib Treatment in Non-Small Cell Lung Cancer After Failure of Epidermal Growth Factor Receptor-Tyrosine Kinase InhibitorRecruiting C-TONG 0806 NCT Pemetrexed Gefitinib 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 Recruiting C-TONG 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 Ongoing, but not recruiting C-TONG 0901 NCT Erlotinib/ Gefitinib Erlotinib Versus Gefitinib in Advanced Non Small Cell Lung Cance With exon21 Mutation A Randomized Trial Recruiting

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

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

29 CTONG 0804: INFORM Estimated using the Kaplan-Meier method Primary Cox analysis with covariates HR <1 implies a lower risk of progression on gefitinib HR (95% CI) = 0.42 (0.32, 0.54); p< Gefitinib (n=148) Placebo (n=148) Median PFS, months 6-month PFS rate, % 12-month PFS rate, % No. events, n (%) (83.8) (97.3) Gefitinib Placebo Probability of PFS (%) Patients at risk : Time since randomization (weeks) Zhang et al Lancet Oncology IN PRESS

30 CTONG 0902: FASTACT-II Phase III study design Placebo Tarceva 150mg/day Previously untreated stage IIIb/IV NSCLC (n=450) R 1 1 PD Six cycles gemcitabine + cisplatin OR carboplatin + placebo Six cycles gemcitabine + cisplatin OR carboplatin + Tarceva PD Stratified by stage, histology, smoking status and chemo regimen TreatmentPost-treatmentScreening Post-study Gemcitabine 1250mg/m 2 (d1,8); cisplatin 75mg/m 2 OR carboplatin 5×AUC (d1); erlotinib 150mg/day (d15–28) Primary end point: Progression free survival (PFS)

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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