Transcript Management of EGFR+ in Asia - Scientific Organizing Service

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 perspective in drug metabolism
• Asian perspective in medical practice and
clinical research
More non-smoking related
adenocarcinoma?
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 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) of
tumors completely tested (CI 50-59%)
Kris et al ASCO 2011
MSN: Incidence of driver mutations
in adenocarcinoma
No mutation detected 33%
KRAS (28%)
ALK
ALK (ampl)
HER2 MET TOP1
FGFR4
BRAF PDK1 KDR PI3K
NRAS
EGFR (13%)
STK11( 10%)
No mutation
ALK -EML4 (2%)
NRAS (2%)
BRAF (2%)
STK11
PDK1 (2%)
HER2 (1%)
KDR (1%)
MET (1%)
PI3K (1%)
EGFR
TOP1 (1%)
KRAS
FGFR4 (1%)
ALK amplification (2%)
Planchard et al ELCC 2012
Genomic driver in adenocarcinoma
Kris ASCO 2011
Planchard ELCC 2012
Wu JSMO 2011
Mitsudomi JCCO 2010
LCMC
(USA)
MSN
China
(France)
Japan
EGFR
17%
13%
40%
50%
KRAS
22%
28%
7%
15%
ELM4ALK
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%
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
Clearance
s
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 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 (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
38%
detected
24%
mutation
31% high
BEAM level
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
G3
G2
G4
15·4
22·1
25·8
G1
40·1
Patients at risk
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 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 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 27.5%
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
How widely available is EGFR mutation
testing?（2011）
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%
EGFR mutation testing in China
26 hospitals: EGFR
mutation tested in the
hospital (16 use ARMS)
50 hospitals: Third
technical services
company
Icotinib: The third EGFR TKI in
China
Subjects
• Age：18
• IIIB
Endpoints
–75 yrs
or IV NSCLC
• Expected
survival≥
Icotinib
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
• HRQoL
• Safety
Explatory
•Biomarkers of EGFR
Objective tumor response (RECIST)
(FAS)
N%
Icotinb (n=199)
Gefitinb(n=196)
PFS is determined according to EGFR
mutation status: ICOGEN data
Mutant
1.0
Icotinib
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 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
C-TONG
0801
NCT number
NCT00765687
Investigational drug
Study title
Bisphospohnates
Screening Non Small Cell Lung Cancer With Bone Metastasis and
Efficacy and Safety Research of Receiving Bisphosphonates
(BLEST)
status
Ongoing, but
not recruiting
C-TONG
0802
NCT00874419
Erlotinib
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
0803
NCT00663689
Erlotinib
Efficacy of Erlotinib for Brain Metastasis of Non-Small Cell Lung
Cancer
Ongoing, but
not recruiting
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
0804
NCT00770588
Gefitinib
C-TONG
0805
NCT00922584
Sorafenib
Sorafenib Treatment in Non-Small Cell Lung Cancer After Failure of
Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor
Recruiting
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
C-TONG
0806
NCT00891579
Pemetrexed
Gefitinib
C-TONG
0807
NCT00816868
A Study of TX Regimen as First-Line Treatment in Elderly Patients
Erlotinib/
Carpecitabine With Stage IIIB/IV Adenocarcinoma Non-Small Cell Lung Cancer
Ongoing, but
not recruiting
Erlotinib/
Gefitinib
Recruiting
C-TONG
0901
NCT01024413
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 number
Investigational drug
Study title
status
Ongoing,
but not recruiting
C-TONG
0902
NCT00883779 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
C-TONG
0904
NCT01038661 Docetaxel
Tax First-line Chemotherapy With Different Doses and Then
Maintenance Therapy (TFINE)
Recruiting
C-TONG
1001
NCT01319669 rhTPO
Clinical Trial on the Prevention of Thrombocytopenia After Firstline Chemotherapy
Recruiting
C-TONG
1002
NCT01236716
Nab-Paclitaxel/ Nab-Paclitaxel Treatment in Advanced Squamous Cell
Gemcitabine
Carcinoma of Lung
Not yet opening
C-TONG
1003
NCT01175096
Rad001
(Afinitor)
Safety and Tolerability Profile of RAD001 Daily in Chinese
Patients With Advanced Pulmonary Neuroendocrine Tumor
Ongoing,
but not recruiting
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
1101
NCT01297101 Erlotinib
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-N2 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=0.16 (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
90
Probability of PFS (%)
80
Median PFS,† months
6-month PFS rate, %
12-month PFS rate, %
No. events, n (%)
70
60
Gefitinib
(n=148)
Placebo
(n=148)
4.8
47.3
33.2
124 (83.8)
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
8
16
24
32
40
48
56
64
72
80
88
96
2
15
0
6
104 112
Time since randomization (weeks)
Patients at risk :
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)
Treatment
1
R
1
Post-treatment
Six cycles gemcitabine
+ cisplatin OR
carboplatin + Tarceva
Tarceva
150mg/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 1250mg/m2 (d1,8); cisplatin 75mg/m2 OR
carboplatin 5×AUC (d1); erlotinib 150mg/day (d15–28)
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