Tumour growth is angiogenesis dependent Judah Folkman 1971
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Meta-analyses confirm survival benefit with chemotherapy 1990s. Tumour growth is angiogenesis dependent Judah Folkman 1971. Routine identification of EGFR mut+ve & TKIs therapy 2010-11. Discovery of cisplatin 1965. Discovery of paclitaxel 1967. VEGF gene identified - PowerPoint PPT Presentation
Transcript of Tumour growth is angiogenesis dependent Judah Folkman 1971
Tumour growth is angiogenesis dependent
Judah Folkman1971 VEGF gene
identifiedand EGFR isolated
1980s
Meta-analyses confirm
survival benefit withchemotherapy
1990sBevacizumab / TKIs improve
survival in mol. unselected NSCLC2000s
Routine identification of EGFR mut+ve &
TKIs therapy2010-11
Discoveryof cisplatin
1965Discovery
of paclitaxel 1967
Ciardiello F and Tortora G. , NEJM 2008
TKI TKI
EGFR TKI blocks ATP binding and prevents activation of TK domain
1. Dimerisation of ligand-bound receptors
3. Activation of two major intracellular signalling pathways4. Cellular response
to signals
2. ATP binding and phosphorylation of tyrosine-kinase domain
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
GEFITINIB/ERLOTINIB CLINICAL DEVELOPMENT
IDEAL 1&2 Fukuoka, JCO 2003
Kris, JAMA 2003
INTACT 1&2Giaccone, JCO 2004
Herbst, JCO 2004
INTEREST Kim, Lancet
2008
Unselected population
FIRST-SIGNALHan, JCO 2012
IPASS Mok, NEJM
2009 WJTOG 3405 Mitsudomi,
Lancet 2010
NEJ 002Maemondo, NEJM 2010
Molecular targetClinical/Histological selection
2000 2003 2004 2005 2007 2008 2009 2010 2011 2012
INVITE Crinò, JCO
2008
ISEL Thatcher, Lancet 2005
TRIBUTE Herbst, JCO 2005
EURTAC Rosell,
Lancet Oncol 2012
OPTIMALZhou, Lancet Oncol 2011
BR 21 Shepherd, NEJM 2005
TALENT Gatzmeier,
JCO 2007
Phase I-IIPerez-Soler, JCO 2004
SATURN Cappuzzo,
Lancet Oncol 2010
TRUST Reck, JTO 2010
GEFI
TIN
IBER
LOTI
NIB
AsiaIPASS,2009
OPTIMAL, 2011First-SIGNAL, 2012
JapanWJTG, 2010
NEJSG, 2010
USASequist, 2008CALGB, 2011
EuropeSLCG, 2009FIELT, 2011
EURTAC, 2012
Gefitinib250 mg/day
Carboplatin AUC 5/6 Paclitaxel
200mg/m2 3 wkly
1:1 randomization
*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
Patients•Age ≥18 years • Life expectancy≥ 12 weeks
•Adenocarcinoma histology
•Never smokers or light ex-smokers*
•PS 0-2•Stage IIIB/IV•Measurable disease
Primary• 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
Endpoints
T Mok et al, NEJM 2009
IRESSA PAN ASIA STUDY DESIGN
T Mok et al, NEJM 2009
EGFR mutation by PCR sequencing
437 samples (36%)
261 positive (60%)
T Mok et al, NEJM 2009
9.5 ms6.3 ms
Gefitinib Carbo / pac
p=0.0001
Gefitinib Carboplatin / paclitaxel S Thongprasert et al, JTO 2011
* Gemcitabine+Cisplatin Dose: Same as in INTACT-1 and TALENT
Gefitinib 250 mg/day P.O. daily,
Gemcitabine 1250 mg/m2 (D1 & D8) Cis-
platin 80 mg/m2 (D1)q 3 weeks x 9 cycles
Patients
• Chemo-naïve• Age 18-75 years• Adenocarcinoma • Never smoker • ECOG PS 0-2• Stage IIIB or IV
Female vs. Male PS 0, 1 vs. 2 Stage IIIb vs. IV
PD
R
1
1
PD
Primary Endpoint: OS
J-Y Han et al, JCO 2012
J-Y Han et al, JCO 2012
T Mitsudomi et al, Lancet 2009
9.2 ms
6.3 ms
HR= 0.49, p <.001
M Maemondo et al, NEJM 2010
HR= 0.30 (0.22-0.41)p value <.001
10.8 ms
5.4 ms
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
T Mok, PeerVoice 2011 (modified)
73.0*
* Measurable Disease
*
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 20095Lee, et al. WCLC 2009; 6Mitsudomi, et al. Lancet Oncol 2010; 7Maemondo, et al. NEJM 2010; 8 Rosell, Lancet Oncol 2012
TK-Is AND DIFFERENT EXPOSURE
MTD ~MTD
Standard dosing
1Hidalgo M, et al. J Clin Oncol 2001;19:3267–792Ranson M, et al. J Clin Oncol 2002;20:2240–50
Cmax = maximum plasma concentrationAUC = area under the curve
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
F de Marinis et al, P ESMO 2011
