Meta-analyses confirm
survival benefit with
chemotherapy
1990s
Routine identification
Tumour growth is
of EGFR mut+ve &
Discovery angiogenesis dependent
TKIs therapy
of cisplatin
Judah Folkman
2010-11
1965
1971
Discovery
VEGF gene identified
Bevacizumab / TKIs improve
of paclitaxel
and EGFR isolated
survival in mol. unselected NSCLC
1967
1980s
2000s
1.
Dimerisation of ligandbound receptors
2.
ATP binding and
phosphorylation of
tyrosine-kinase domain
EGFR TKI blocks ATP binding and
prevents activation of TK domain
3.
Activation of two
major intracellular
signalling pathways
4.
Cellular response
to signals
Ciardiello F and Tortora G. , NEJM 2008
T Lynch et al, NEJM 2004
I Okamoto, FEBSJ 2010
M Kris et al, P ASCO 2011
AF Gadzar Oncogene 2009
E Laack et al, Lung Cancer 2010
INTACT 1&2
INTEREST
Giaccone, JCO 2004
Herbst, JCO 2004
Fukuoka, JCO 2003
Kris, JAMA 2003
2000
2003
2004
IPASS
Kim, Lancet 2008
ISEL
IDEAL 1&2
NEJ 002
Thatcher,
Lancet 2005
2005
Maemondo,
NEJM 2010
Mok, NEJM 2009
WJTOG 3405
INVITE
FIRST-SIGNAL
Crinò, JCO 2008
Han, JCO 2012
2007 2008
2009
2010
Mitsudomi,
Lancet 2010
2011 2012
TRIBUTE
TALENT
SATURN
OPTIMAL
Herbst, JCO 2005
Gatzmeier,
JCO 2007
Cappuzzo,
Lancet Oncol 2010
Zhou,
Lancet Oncol 2011
Phase I-II
BR 21
TRUST
Perez-Soler, JCO 2004
Shepherd,
NEJM 2005
Reck, JTO 2010
Unselected population
Clinical/Histological selection
EURTAC
Rosell,
Lancet Oncol 2012
Molecular target
Asia
IPASS,2009
OPTIMAL, 2011
First-SIGNAL, 2012
USA
Europe
Sequist, 2008
CALGB, 2011
SLCG, 2009
FIELT, 2011
EURTAC, 2012
Japan
WJTG, 2010
NEJSG, 2010
IRESSA PAN ASIA STUDY DESIGN
Patients
•Age ≥18 years
•Life expectancy
≥ 12 weeks
•Adenocarcinoma
histology
•Never smokers or light
ex-smokers*
•PS 0-2
•Stage IIIB/IV
•Measurable disease
Endpoints
Primary
Gefitinib
250 mg/day
1:1 randomization
Carboplatin AUC 5/6
Paclitaxel 200mg/m2
3 wkly
• PFS (non-inferiority)
Secondary
• Objective response rate
• Quality of life
• Disease related symptoms
• Overall survival
• Safety and tolerability
Exploratory
• Biomarkers
•EGFR mutation
•EGFR gene copy number
•EGFR protein expression
*Never smokers:<100 cigarettes in lifetime; light ex-smokers: stopped 15 years ago and smoked 10 pack yrs
Carboplatin/paclitaxel was offered to gefitinib patients upon progression
T Mok et al, NEJM 2009
EGFR mutation by PCR sequencing
437 samples (36%)
261 positive (60%)
T Mok et al, NEJM 2009
Gefitinib
Carbo / pac
p=0.0001
9.5 ms
6.3 ms
T Mok et al, NEJM 2009
Gefitinib
Carboplatin / paclitaxel
S Thongprasert et al, JTO 2011
Gefitinib
Patients
• Chemo-naïve
250 mg/day P.O. daily,
1
• Age 18-75 years
R
• Adenocarcinoma
• Never smoker
• ECOG PS 0-2
• Stage IIIB or IV
PD
1
Female vs. Male
PS 0, 1 vs. 2
Stage IIIb vs. IV
Primary Endpoint: OS
Gemcitabine
1250 mg/m2 (D1 & D8)
Cisplatin 80
mg/m2
(D1)
PD
q 3 weeks x 9 cycles
* Gemcitabine+Cisplatin Dose: Same as in INTACT-1 and TALENT
J-Y Han et al, JCO 2012
J-Y Han et al, JCO 2012
9.2 ms
HR= 0.49, p <.001
6.3 ms
T Mitsudomi et al, Lancet 2009
HR= 0.30 (0.22-0.41)
p value <.001
10.8 ms
5.4 ms
M Maemondo et al, NEJM 2010
GY Ku et al, Lung Cancer 2011
JY Douillard et al, JCO 2010
1. P Jänne et al, WCLC 2011/2. R Rosell et al, NEJM 2009/
3. J De Grève et al, ASCO 2011
L Paz-Ares et al, J Cell Mol Med 2010
R Rosell et al, Lancet Oncol 2012
C Zhou et al, Lancet Oncology 2011
E Bria et al, Ann Oncol 2011
R Rosell et al, Lancet Oncology 2012
R Rosell et al, Lancet Oncol 2012
73.0*
*
* Measurable Disease
T Mok, PeerVoice 2011 (modified)
T Mok, PeerVoice 2011
* TKI arm ** Measurable Disease
1.Mok et al, NEJM 2009; 2.Zhou et al. Lancet Oncol 2011;
3.Rosell et al, Lancet Oncol 2012;
*For IPASS, First-SIGNAL and CALGB30406 these data are for all patients in TKI arm (not limited to EGFR MUT+ group)
ALT = alanine aminotransferase; AST = aspartate aminotransferase
1Zhou,
et al. Lancet Oncol 2011; 2Rosell, et al. NEJM 2009; 3Janne, et al. ASCO 2010; 4Mok, et al. NEJM 2009
5Lee, et al. WCLC 2009; 6Mitsudomi, et al. Lancet Oncol 2010; 7Maemondo, et al. NEJM 2010; 8 Rosell, Lancet Oncol 2012
~MTD
MTD
Erlotinib1
(150mg/day)
Gefitinib2
(225mg/day)
Gefitinib2
(525mg/day)
Gefitinib2
(700mg/day)
Cmax (ng/mL)
2.120
307
903
2.146
AUC0–24
(ng•hour/mL)
38.420
5.041
14.727
36.077
Standard dosing
Cmax = maximum plasma concentration
AUC = area under the curve
1
Hidalgo M, et al. J Clin Oncol 2001;19:3267–79
Ranson M, et al. J Clin Oncol 2002;20:2240–50
2
F de Marinis et al, P ESMO 2011