Slide 1. Slide 2. Slide 3. Individualized Therapy in Lung Cancer : Where are we in 2011? Notable Advances in Cancer Research in the last 2 years

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1 Slide 1 Individualized Therapy in Lung Cancer : Where are we in 2011? Giorgio V. Scagliotti University of Torino Department of Clinical & Biological Sciences giorgio.scagliotti@unito.it Slide 2 Notable Advances in Cancer Research in the last 2 years Farrel A. Nat. Med. 2011; 17: Slide 3 Progress in the treatment of metastatic lung cancer Pao W. et al. Nat. Rev. Cancer 2010; 10;760

2 Slide 4 Twenty-Two Years of Phase III Trials for Patients With Advanced NSCLC 33 phase III trials were initiated between 1973 and Five trials (15%) showed a statistically significant difference in survival, with a median prolongation of the survival of 2 months. Conclusion : Analysis of past trials in North America shows that the prolongation in median survival between two arms of a randomized study was rarely in excess of 2 months. Techniques for improved use of patient resources and appropriate trial design for phase III randomized therapeutic trials with patients with advanced NSCLC need to be developed. Breathnach OS et al. J. Clin. Oncol. 2001; 19: 1734 Slide 5 Progress in the treatment of metastatic lung cancer Pao W. et al. Nat. Rev. Cancer 2010; 10;760 Slide 6 Efficacy by Histology in Pemetrexed Studies First-line Second-line Pem/Cis Maintenance NSCLC Pem vs. Docetaxel vs. Gem/Cis Pem vs. Placebo Histologic Group Pem Doc Cis/Pem Cis/Gem Pem Placebo Non-squamous n=205 n=194 n=618 n=634 n=325 n=156 Median OS, months Adjusted HR (95% CI) 0.78 ( ) 0.84 ( ) 0.70 ( ) P value Squamous n=78 n=94 n=244 n=229 n=116 n=66 Median OS, months Adjusted HR (95% CI) 1.56 ( ) 1.23 ( ) 1.07 ( ) P value Non-squamous = adenocarcinoma, large cell carcinoma, and other/indeterminate NSCLC histology Scagliotti GV et al. Oncologist 2009

3 Slide 7 Cancer Research at the roundabout 1. Cancer is a genetic somatic disease (5% inherited) 2. (Very likely) originates from stem cells 3. It is caused by genetic alterations of a handful of genes (Oncogenes or Driver genes ) 4. It is often possible to identify these genetic lesions by molecular diagnosis 5. Targeted Therapy is only effective when aimed at the alteration of the driver gene(s): Oncogenic Addiction Slide 8 Randomized Trials with CT+/- Targeted Therapies in Treatment-naive NSCLC TRIAL TARGET CT GROUP COMMENT INTACT-1 EGFR GC AstraZeneca Closed, no benefit INTACT-2 EGFR PC AstraZeneca Closed, no benefit TRIBUTE EGFR PC Genentech/OSI Closed, no benefit TALENT EGFR GC Genentech/OSI Closed, no benefit ABXEGFR EGFR PC Amgen Closed, no benefit AG3340 MMP PC Agouron Closed, no benefit AG3340 MMP GC Agouron Closed, no benefit BMS MMP PC BMSO Closed, no benefit Lonafarnib FT (ras) PC Schering Closed, no benefit ISIS 3521 PKC PC ISIS Closed, no benefit Targretin RXR PC Ligand Closed, no benefit Sorafenib raf-kinase,vegfr2 PC Bayer Closed, no benefit Figitumumab IGFR-1 PC Pfizer Closed, no benefit AZ2171 VEGFR PC Astra Zeneca Closed, no benefit ASA-404 VDA PC Novartis Closed, no benefit Slide 9 Progress in the treatment of metastatic lung cancer Pao W. et al. Nat. Rev. Cancer 2010; 10;760

4 Slide 10 Slide 11 EGFR or K-RAS Mutations According to Ethnicity and Smoking Status Suda K. et al. Cancer Metastasis Rev. 2010; 29:49 Slide 12 EGFR-TKIs and EGFR Mutation -Directed Front - Line Studies Study Entry Criteria HR for PFS (EGFR mut +) IPASS Mok NEJM 2009 First SIGNAL Proc. IASLC 2009 Asiatic, never- & light smokers, adenocarcinoma (EGFR mut %) Adenocarcinoma, Neversmokers (EGFR mut + 44%) 0.48 ( ) 0.61 ( ) HR for OS (EGFR mut +) 0.91 * ( ) *overall population 0.82 ( )

5 Slide 13 EGFR-TKIs and EGFR Mutation -Directed Front - Line Studies Study Entry Criteria HR for PFS (EGFR mut +) IPASS Mok NEJM 2009 First SIGNAL Proc. IASLC 2009 WEJGSG002 Kobayashi ASCO 2009 Asiatic, never- & light smokers, adenocarcinoma (EGFR mut %) Adenocarcinoma, Neversmokers (EGFR mut + 44%) 0.48 ( ) 0.61 ( ) EGFR Mutation + (all) 0.35 ( ) EURTAC (EU) EGFR Mutation + (all) 0.42 ( ) OPTIMAL (China) EGFR Mutation + (all) 0.16 ( ) HR for OS (EGFR mut +) 0.91 * ( ) *overall population 0.82 ( ) NA?? Slide 14 Progress in the treatment of metastatic lung cancer Pao W. et al. Nat. Rev. Cancer 2010; 10;760 Slide 15 Progress in the treatment of metastatic lung cancer Pao W. et al. Nat. Rev. Cancer 2010; 10;760

6 Slide 16 60% 40% 20% 0% -20% Comparison of Responses EGFR mutations with erlotinib vs EML4-ALK translocations with crizotinib -40% -60% -80% -100% 70% partial response rate EGFR mutant 70% partial response rate EML4-ALK translocated Jackman CCR 2009, Bang ASCO 2010 Slide 17 Status of Actionable Driver Mutations in Lung Adenocarcinoma Tumor Specimens No mutation detected KRAS (22%) EGFR (17%) EML4-ALK (7%) Double mutants (3%) BRAF (2%) AKT1 NRAS MEK1 MET AMP HER2 PIK3CA Lung Cancer Mutation Consortium (LCMC) mutation testing Performed in CLIA-certified laboratories at LCMC sites Physicians used data in real-time to guide therapeutic decisions for patients If EGFR mutation: give erlotinib If other mutation: recommend trial of agent specific for that target 54% incidence of single driver mutations among samples KRAS, EGFR, and EML4-ALK most common Kris MG, et al. ASCO Abstract CRA7506. Slide 18 Frequencies of Intrinsic Resistance to EGFR-TKIs relative to sensitivity/resistance in NSCLC

7 Slide 19 EGFR TKI + HD 2 nd -gen EGFR TKI Chemo-naïve advanced NSCLC EGFR mutant EGFR TKI + BCL-2i EGFR TKI + IGF-1Ri EGFR TKI + METi EGFR TKI + HCQ EGFR TKI (diff dosing schedules) EGFR TKI + chemo EGFR mutant NSCLC with acquired resistance* Potent 2 nd -gen EGFR TKI 2 nd -gen EGFR TKI + cetuximab Chemo EGFR TKI 2 nd -gen EGFR TKI + METi Slide 20 About the MET gene and Cancer The oncogene encodes a tyrosine-kinase receptor for HGF ( Scatter factor ) It is over-expressed in response to unfavourable micro-environmental conditions, such as hypoxia or ionizing radiations: Oncogene Expedience. It is constitutively activated in some cancers, by amplification, mutations or autocrine loops: Oncogene Addiction. It is good candidate for targeted therapies Slide 21 MET response correlates with gene amplification 200 cancer l. tested < 3 % ADDICTION Cell Line EBC-1 MKN-45 MET copy N GTL % EXPEDIENCE HS746T SNU5 NCI- H Hypoxia (or HGF) PHA PHA

8 Slide 22 MET & Lung Cancer Amplification of MET occurs in 1-7% of non-small cell lung cancer (NSCLC), associated with poor prognosis MET amplification increases up to 20% in tumors harbouring somatic EGFR mutations, with acquired resistance to EGFR inhibitors (gefitinib and erlotinib) Preclinical studies suggest the preexistence and clonal selection of MET amplification in EGFR mutant NSCLC The combination of erlotinib and a Met mab improves progression-free survival and overall survival in NSCLC patients stratified for high Met expression Slide 23 MetMAb + Erlotinib vs Erlotinib Alone in Previously Treated Advanced NCSLC HGF HGF MetMAb: monovalent antibody to Met Prevents Met activation by hepatocyte growth factor Met Growth Migration Survival MetMAb No activity Met EGFR mutations in study population Met diagnostic-positive population: imbalanced on MetMAb arm Met diagnostic-negative population: imbalanced on placebo arm Predefined Met diagnostic-positive population Tumor samples with 50% tumor cells displaying moderate or strong Met staining by IHC Spigel DR, et al. ASCO Abstract 7505 Slide 24 MetMAb + Erlotinib vs Erlotinib in Advanced NCSLC: PFS and OS No PFS or OS benefit to adding MetMAb to erlotinib in ITT population MetMAb + erlotinib associated with survival benefits in Met-positive population Outcome MetMAb + Erlotinib (n = 69) ITT Population (n = 137) Placebo + Erlotinib (n = 68) Met Diagnostic-Positive Population (n = 66) MetMAb + Erlotinib (n = 35) Placebo + Erlotinib (n = 31) Met Diagnostic-Negative Population (n = 62) MetMAb + Erlotinib (n = 31) Placebo + Erlotinib Median PFS, mos HR (95% CI) 1.09 ( ) 0.53 ( ) 1.82 ( ) P value (n = 31) Median OS, mos HR (95% CI) 0.80 ( ) 0.37 ( ) 1.78 ( ) P value Spigel DR, et al. ASCO Abstract 7505.

9 Slide 25 MetMAb: Safety and Met Expression as a Prognostic Factor AE profile in MetMAb + erlotinib arm similar to placebo + erlotinib Higher frequency of peripheral edema in MetMAb arm Met expression associated with worse outcome in placebo + erlotinib arm 52% of tissue samples found to be Met diagnostic positive Outcome Met Diagnostic Positive (n = 66) Placebo + Erlotinib Met Diagnostic Negative (n = 62) Median PFS, mos HR (95% CI) 1.71 ( ) P value.06 Median OS, mos HR (95% CI) 2.61 ( ) P value.004 Spigel DR, et al. ASCO Abstract Slide 26 Squamous Cell Carcinoma of the Lung Detailed genomic analysis of squamous cell lung cancers has identified several new potential therapeutic targets Gene Event Type Frequency FGFR1 Amplification 20-25% FGFR2 Mutation 5% PIK3CA Mutation 9% PTEN Mutation/Deletion 18% CCND1 Amplification 8% CDKN2A Deletion/Mutation 45% PDGFRA Amplification/Mutation 9% EGFR Amplification 10% MCL1 Amplification 10% BRAF Mutation 3% DDR2 Mutation 4% ERBB2 Amplification 2% In 63% of lung SCCs we can now identify a possible therapeutic target Targets will need to be validated in pre-clinical models FGFR1/2, PIK3CA and DDR2 inhibitor trials are planned or ongoing Hammerman P. et al. Proc. IASLC 2011 Slide 27 Targeting stem cell self-renewal pathways Alison MR et al. J. Pathol. 2011; 223:147

10 Slide 28 Current Concept of Pharmacogenomics Roden DM et al. Ann Intern Med 2006; 145: Slide 29 Predictive Molecular Markers for Response to Chemotherapy in NSCLC Gene Abnormality Drug Response p53 Mutation Multiple KRAS Mutation Platinum -tubulin Increased isotype 3 Taxanes RRM1 Increased expression Gemcitabine ERCC1 Increased expression Platinum BRCA1 Increased expression Platinum Thymidylate synthase Increased expression Antifolates EGFR mutation Present Platinum Slide 30 ITACA Adjuvant Trial Pharmacogenomics: Yes or No? ERCC1 High Low TS TS High Low High Low Profile 4 Profile 3 Profile 2 Profile 1 Taxanes Control Pem Control Cis/Gem Control Cis/Pem Control Control = investigators choice of cisplatin-based doublet Primary endpoint = 30% increase in OS; Trial Status as July 2011= 265/700 patients

11 Slide 31 Phase II Study of Preoperative Cis/Pem in Stage IIIa N2 non-squamous NSCLC N=33 Stage IIIa N2 by Med (+CT Scan + PET) Cis 75 mg/ m2 & Pem 500 mg/m2 x 3 q3wks Restaging by CT scan and PET Surgery Biomarker Assessment TS, TTF-1, E2F1, ERCC1, BRCA1 (Functional Imaging Changes) Primary end point : ORR Secondary end points :pcr,pfs,os, tumor downstaging, toxicity Slide 32 EPIC Trial Elderly Patients Individualized Chemotherapy Trial Individualized Arm 2:1 Randomization Control Arm EGFR Mut + Yes Squamous Cell Carcinoma Treatment based on Investigators Preference Yes No EGFR Mut + Yes Off Study ERCC1 low ERCC1 high ERCC1 low ERCC1 high RRM1 high RRM1 low RRM1 low RRM1 high No Carboplatin Gemcitabine Carbo/Gem Taxane ERCC1 low ERCC1 high ERCC1 low TS high TS low TS low Carboplatin Pemetrexed Carbo/Pem ERCC1 high TS high RRM1 low RRM1 high PIs : G. Simon & G. Scagliotti University of South Carolina (Hollings Cancer Center) & University of Torino Gemcitabine Taxane Slide 33 Summary EGFR-TKIs should be the preferred first line treatment choice for patients with tumours harbouring EGFR sensitizingmutations. ALK inhibitors under investigations. In more than 60% of squamous cell carcinoma of the lung a potential therapeutic target has been identified. Need to be verified in preclincal models. Therapeutic choices based on histology are the current standard of care for the majority of our patients The definition of homogeneous genetic subgroups of tumors and the search for individualized approaches is the way to substiantially increase survival expectancy in this disease.

12 Slide 34 If I saw further than other men, it was because I stood on the shoulders of giants If I have ever made any valuable discoveries, it has been due more to patient attention, than to any other talent