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