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

Management of NSCLC in Asia

Tony Mok MDProfessor

Dept. of Clinical Oncology]The Chinese University of Hong Kong

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?

Lung Cancer in Never Smokers

Squamous Cell Ca (~35%)

Adenocarcinoma (~45%)

Predominance of Adenocarcinoma Histology

SCLC (~20%)

Per

cent

age

0

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

0.4:1 3.4:1

Lung Cancer not related to smoking in China

25% of male lung cancer were not smoking related

25% of male lung cancer were not smoking related

72% of female 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):e40109

Lung Cancer Mutation Consortium

Incidence of Single Driver Mutations

Mutation found in 54% (280/516) oftumors completely tested (CI 50-59%)

Kris et al ASCO 2011

No mutation detected 33%

KRAS (28%)

EGFR (13%)

STK11( 10%)

ALK -EML4 (2%)

NRAS (2%)

BRAF (2%)

PDK1 (2%)

HER2 (1%)

KDR (1%)

MET (1%)

PI3K (1%)

TOP1 (1%)

FGFR4 (1%)

ALK amplification (2%)

MSN: Incidence of driver mutations in adenocarcinoma

KRAS

EGFR

STK11

ALKNRAS

BRAF PDK1HER2

KDRMET

PI3KTOP1

FGFR4

No mutation

ALK (ampl)

Planchard et al ELCC 2012

Genomic driver in adenocarcinoma

LCMC

(USA)

MSN

(France)

China Japan

EGFR 17% 13% 40% 50%

KRAS 22% 28% 7% 15%

ELM4-ALK

7% 2% 7% 5%

BRAF 2% 2% 2% 1%

HER2 1% 1% NA 3%

PIK3CA 1% 1% 4% NA

PTEN NA NA 6% NA

MET Amp

1% 1% 5% 4%

Nil 46% 33% 29% 22%Kris ASCO 2011Planchard ELCC 2012Wu JSMO 2011Mitsudomi JCCO 2010

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 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 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

Nature Medicine 18(8):521, 2012

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

EURTAC Biomarker Study

• 95 patients from EURTAC (EGFR Mutation) with available samples

• Biomarkers: ELM4 ALK, T790M, TP53, BIM

16% detected by

PCR

16% detected by

PCR

38% detected

38% detected

24% mutation

24% mutation

31% high BEAM level31% high

BEAM level

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

40·122·115·4 25·8

G3

G4G2

G1

Patients at risk

Potential biomarker of a biomarker selected population:T790M mutation status and BIM mRNA levels

Rosell et al ESMO 2012

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 guidelinesNCCN (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

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 2nd line therapyGem/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

Chemo-naïve NSCLC

No. of EGFR mutation test

EGFR mutation + patients

EGFR M+ who received TKI

EGFR M+ who received Gefitinib

202K

How widely available is EGFR mutation testing? （ 2011）

EGFR mutation testing in China

26 hospitals: EGFR

mutation tested in the

hospital (16 use ARMS)

50 hospitals: Third

technical services

company

Gefitinib250 mg Qd

Icotinib125 mg Tid

1:1

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

Primary•PFS

Secondary• OS• ORR• DCR• TTP• HRQoL• SafetyExplatory•Biomarkers of EGFR

Endpoints

Icotinib: The third EGFR TKI in China

Objective tumor response (RECIST)(FAS)

Icotinb (n=199)

Gefitinb(n=196)

N%

PFS is determined according to EGFR mutation status: ICOGEN data

0

0.2

0.4

0.6

0.8

1.0

Probability of P

FS

50 100 150 200 250 300 350 400

DaysPFS, progression-free survival

Mutant

Icotinib Gefitinib

N 29 39 ORR 17/29 （ 58.6% ） 21/39 （ 53.8%） Cox analysis with covariates

  HR (95% CI) = 0.743(0.406 1.358)  

Median Time 198 158 Log Rank P-Value : p=0.5551

Icotinib (mutation)

Gefitinib (Mutation)

Icotinib(wild type)

Gefetinib (wild type)

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 numberInvestiga-tional drug

Study title status

C-TONG 0801

NCT00765687Bisphospoh-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

NCT00874419 ErlotinibErlotinib 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

NCT00663689 ErlotinibEfficacy of Erlotinib for Brain Metastasis of Non-Small Cell Lung Cancer

Ongoing, but not recruiting

C-TONG 0804

NCT00770588 GefitinibAssess 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

NCT00922584 SorafenibSorafenib Treatment in Non-Small Cell Lung Cancer After Failure of Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor Recruiting

C-TONG 0806

NCT00891579Pemetrexed 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

NCT00816868Erlotinib/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

NCT01024413Erlotinib/Gefitinib

Erlotinib Versus Gefitinib in Advanced Non Small Cell Lung Cance With exon21 Mutation ： A Randomized Trial

Recruiting

Chinese Thoracic Oncology Group (C-TONG) Study List

Study number

NCT numberInvestiga-tional drug

Study title status

C-TONG 0902

NCT00883779 ErlotinibA 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

NCT01038661 DocetaxelTax First-line Chemotherapy With Different Doses and Then Maintenance Therapy (TFINE)

Recruiting

C-TONG 1001

NCT01319669 rhTPOClinical Trial on the Prevention of Thrombocytopenia After First-line Chemotherapy

Recruiting

C-TONG 1002

NCT01236716 Nab-Paclitaxel/Gemcitabine

Nab-Paclitaxel Treatment in Advanced Squamous Cell Carcinoma of Lung

Not yet opening

C-TONG 1003

NCT01175096Rad001(Afinitor)

Safety and Tolerability Profile of RAD001 Daily in Chinese Patients With Advanced Pulmonary Neuroendocrine Tumor

Ongoing, but not recruiting

C-TONG 1101

NCT01297101 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

Gefitinib Iressa vs chemo as intermittent treatment in advanced NSCLC Not yet opening

C-TONG 1103

ErtlotinibErlotinib vs chemo as neoadjuvant in IIIA-N2 NSCLC with EGFR Mutation in exon 19 or 21

Not yet opening

CTONG 0802: OPTIMALP

FS

pro

bab

ility

1.0

0.8

0.6

0.4

0.2

0

HR=0.16 (0.10–0.26)Log-rank p<0.0001

Time (months)

0 5 10 15 20

Patients at riskErlotinib 82 70 51 15 2

Gem/carbo (n=72)Erlotinib (n=82)

Gem/carbo72 26 4 0 0

Zhou et al Lancet Oncology 2011

CTONG 0804: INFORM

†Estimated using the Kaplan-Meier method‡Primary Cox analysis with covariatesHR <1 implies a lower risk of progression on gefitinib

HR‡ (95% CI) = 0.42 (0.32, 0.54); p<0.0001

Gefitinib(n=148)

Placebo(n=148)

Median PFS,† months6-month PFS rate, %12-month PFS rate, %No. events, n (%)

4.847.333.2

124 (83.8)

2.615.02.9

144 (97.3)

GefitinibPlacebo

0 16 40 56 72 96 1120

10

40

60

80

100P

rob

abil

ity

of

PF

S (

%)

Patients at risk :

20

30

50

70

90

8 24 32 48 64 80 88 104

148 46 10 4 2 0 082 26 16 6 3 2 2 0148 82 56 42 31 6 0109 70 65 49 38 20 15 1

Time since randomization (weeks)

Zhang et al Lancet Oncology IN PRESS

CTONG 0902: FASTACT-II Phase III study design

Placebo

Tarceva 150mg/day

Previously untreated

stage IIIb/IV NSCLC (n=450)

R

1

1

PDSix cycles gemcitabine

+ cisplatin OR carboplatin + placebo

Six cycles gemcitabine + cisplatin OR

carboplatin + TarcevaPD

Stratified by stage, histology, smoking status and chemo regimen

Treatment Post-treatmentScreening

Post-study

Gemcitabine 1250mg/m2 (d1,8); cisplatin 75mg/m2 OR carboplatin 5×AUC (d1); erlotinib 150mg/day (d15–28)

Primary end point: Progression free survival (PFS)

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