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