1 Caroline Laboulle Alexandra Mascret Valerio Pilato

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3 Lung cancers = A need !!!!!

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5  Lung cancer murderer as 27,000 deaths /year  Incidence in women increases steadily  Incidence increasing linked to smoking 85% attributable to tobacco  Causes 5% of cases Occupational exposure (Such as Asbestos, arsenic, chromic acid, nickel oxide, iron,....)

 80% NSCLC - 20% SCLC (histological distinction)  Relatively insensitive to chemotherapy contrary to SCLC Squamous cells carcinoma 40%  3 types Adenocarcinoma 40%  Strategy depends on TNM Classification  Stage I-II : Surgery => Only Curable  Stage III-IV: Chemotherapy and/or Radiotherapy For Locally advanced and Metastasis 6 Large cell carcinoma 20%

 Current firstline therapeutic option  A platinum (cisplatin or carboplatin) + 3 rd -generation agent  Second line therapy  Docetaxel Mechanism of oncogeneseMolecular approach MAB Anti-EGFR : Cetuximab MAB Anti-VEGF: Bevacizumab TK Inhibitor : Erlotinib, Gefitinib, Sorafenib. Limits :Selectivity, IV administration,…..

The story so far 8

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2003 US Approval 2002 Japan Approval 2002 Phase III INTACT 1& Phase II IDEAL 1& Phase I 1994 Preclinical studies IRESSA Development

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ZD-1839 (Iressa) : p.o. drug quinazoline derivative selectively inhibits the EGFR tyrosine kinase Antiproliferative activity 12 Steady-state plasma [ ] : 7-10 days t 1/2 = 48h (37-65h) Pharmacokinetic:

EGFR Signaling pathway

14  Highly specific inhibition of cell lines expressing EGFR  CI50= 0,2-0,4 μM  Competitive inhibitor of ATP (type I)  Cytostatic effect dose proportional

 Dose-dependent supra-additive effect  Increase of growth inhibition EGF = survival factor for tumors cells treated by classical cytotoxics 15  Gefitinib  Docetaxel  Carboplatin BUT no clinical interaction Anticancer activity by supressing survival factors Gefitinib + Cytotoxic: Inhibitors of CYP3A4 and CYP2D6

2003 US Approval 2002 Japan Approval 2002 Phase III INTACT 1& Phase II IDEAL 1& Phase I 1994 Preclinical studies IRESSA Development

OPEN, MULTICENTER, NON-RANDOMIZED, DOSE-ESCALATING STUDIES 17

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19 1 st causes DLTs

-250mg/d > Lowest dose level tumor regression - 500mg/d < Highest dose well tolerated chronically DLT > Therapeutic dose

2003 US Approval 2002 Japan Approval 2002 Phase III INTACT 1& Phase II IDEAL 1& Phase I 1994 Preclinical studies IRESSA Development

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Monotherapy

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Symptom improvement benefits by tumor response

27  250mgAE profile

= Accelerated approval based on: – a surrogate endpoint or – an effect on a clinical endpoint – other than survival or irreversible morbidity. But with requirement that sponsor: – study the drug further, – to verify and describe its clinical benefit, or the observed clinical benefit to ultimate outcome.

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2003 US Approval 2002 Japan Approva l 2002 Phase III INTACT 1& Phase II IDEAL 1& Phase I 1994 Preclinical studies IRESSA Development

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Kaplan-Meier estimates of overall survival in each treatment group. (P=0.4560) 33

 Antagonism or Drug interactions ?  No preselection EGFR dependant cells  Naïve tumors are not sensitive Only EGFR dependant cells could be sensitive to EGFR TK inhibitor 34

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2003 US Approval 2002 Japan Approval 2002 Phase III INTACT 1& Phase II IDEAL 1& Phase I 1994 Preclinical studies IRESSA Development

Approval: 07/09/2002 to treat NSCLC EVEN known Failed in INTACT 1 and 2 Few months later… : 25,000 >200 >60 Ministery : 12/ Same incidence Placebo groups Same incidence in Iressa ® & Placebo groups ILDDeath rate guidelines (03/2005)01/2005

2003 US Approval 2002 Japan Approval 2002 Phase III INTACT 1& Phase II IDEAL 1& Phase I 1994 Preclinical studies IRESSA Development

Yes, but:  Controlled study vs placebo to verify Iressa's clinical benefit; 39 INTACT1&2: Failed survival IDEAL 1&2: Tumor shrinkage Few treatments available → 21,000 patients treated ( Expanded Acess Programme) ODAC

2008 Phase III: IPASS Research biomarkers 2004 Discover EGFR mutations 2004 ISEL US approval IRESSA Development

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All hypothesis do not lead to explanations So… We have to search elsewhere

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…Everybody get busy Research potential biomarkers: 2 ways: EGFR expression (Gene copy nb) EGFR mutation Prospective studies: INTEREST; V15-32 ONCOBELL IPASS Never smokers High gene copy number

During this time Decision of treatment… IRESSA still available for responsive patients Physicians should consider other treatment options

ISEL failed to demonstrate an OS Pulmunory toxicity Restriction in the use of gefitinib in USA and in other countries AstraZeneca does not pursue licensing in Europe 49

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Retrospective study of ISEL :  It seems to be potential biomarker Prospective study INTEREST( Iressa in NSCLC Trial Evaluating Response and Survival versus Taxotere):  Comparaison of OS for Gefitinib and Docetaxel in patients with high EGFR gene copy number Enrollment

In patients with high EGFR gene copy number, survival was not longer with Gefitinib than Docetaxel

2008 Phase III: IPASS Research biomarkers 2004 Discover EGFR mutations 2004 ISEL US approval IRESSA Development

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Increase amount & duration of ligand-dependent activation

Increase amount & duration of ligand-dependent activation

Increase amount & duration of ligand-dependent activation

Increase amount & duration of ligand-dependent activation

EXON 20 In frame duplication/insertion EXON 19 In frame deletions EXON 21: L858R Single missense mutation 59 % 41 % Leu WT L858R Arg

EGFR GENEEGFR GENE TKDOMAINTKDOMAIN

65 mutant kinase = active conformation WT Conformation

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An alternative binding mode of gefitinib 68

69 Higher affinity for gefitinib in the L858R mutant Greater efficacy in treatment of NSCLC patients carrying this mutation “addicted” to the activated EGFR for survival

Same mutational patterns FEMALES ADENOCARCINOMA ASIATICS (30-40%NSCLC) NEVER SMOKERS

So, we‘ll keep going on with clinical selection…

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2008 Phase III: IPASS Research biomarkers 2004 Discover EGFR mutations 2004 ISEL US approval IRESSA Development

recruted from 2006 to % of tumor EGFR M+

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Predictive value of -Ethnic origin, -Smoking status, -Histologic findings for responsiveness

Predictive value of EGFR mutations for responsiveness to Gefitinib Objective response rate (%)

Importance of preselection of patients Oral agent: Good efficacy, More favourable tolerability profile, Better quality of life Gefitinib = Valid treatment option for pretreated advanced NSCLC.

2008 Phase III: IPASS Research biomarkers 2004 Discover EGFR mutations 2004 ISEL7 IRESSA Development 2009 Label in EU

Iressa is indicated for the treatment of adult patients with locally advanced or metastatic non small cell lung cancer (NSCLC) with activating mutations of EGFR TK To help diagnostic: EGFR mutation database: (by City of Hope Molecular Diagnostic Laboratory ) LABEL: