PNEUMO TRIESTE 2012

1. PNEUMO TRIESTE 2012 THE PERSONALIZED THERAPY OF NSCLC Giampietro Gasparini Oncology - San Filippo Neri Hospital Rome, Italy Trieste, 27 March 2012 www.professorgasparini.com

2. CANCER THERAPY ERAS • Locoregional treatments yrs ’40 -’50 • Chemotherapeutic- based yrs ’60 -’80 • systemic treatments • Targeted treatments current yrs • Genomic-based treatments the era is beginning

3. EVOLUTION OF SYSTEMIC THERAPY IN ADVANCED NSCLC Gefitinib 2004 Docetaxel 2003 First-line Second-line Third-line Not approved Erlotinib2005 Maintenance Pemetrexed 2004 Docetaxel 2000 Paclitaxel Gemcitabine 1998 Bevacizumab 2007 Pemetrexed 2008 Vinorelbine 1997 Gefitinib 2009 12+ Carboplatin 1989 Pemetrexed 2009 Cisplatin 1978 Median overall survival, months ~8–10 Erlotinib 2010 ~6 ~2–4 1970 1980 1990 2000 2010 Bevacizumab + PC Best supportive care Single-agent platinum Doublets Histology-direct therapy European Medicines Agency. http://www.ema.europa.eu/ema/index.jsp?curl=/pages/home/Home_Page.jsp

4. IMPACT OF SYSTEMIC THERAPY ON OS IN STAGE IV NSCLC OVER 10 YEARS PROPORTION OF PTS TREATED • at least 1 line 20% 42% 1988 2008 • 2 - 3 lines 7% 60% • SURVIVAL RATES • 1 yr survival 8% 37% • 2 yrs survival 0.3% 15% • MEDIAN OS (mos) 4,6 5,1 data from 987 pts followed at the Princess Margaret Hospital & Sannybrook Odette Cancer Ctr – Toronto. The Oncologist, 16:1307, 2011

5. NSCLCDifferenthistotypes: Differenttreatments Squamous cell ( NO Bevacizumab) Non Squamous cell (Pemetrexed)

6. CHARACTERISTICS OF THE NSCLC TUMORS ACCORDING TO THE VASCULAR PATTERNS (a vascular pattern)

7. ALVEOLAR PATTERN The onlyvesselsevident in this pattern arisefrom the alveolarsepta

8. NSCLC MAIN FEATURES ACCORDING TO THE VASCULAR PATTERNS ANGIOGENESIS PATTERNS PAPILLARY BASAL DIFFUSE ALVEOLAR Reproduced Reproduced Absent Absent MUCOSA ARCHITECTURE Destroyed Destroyed Destroyed Preserved NORMAL LUNG NEW VESSELS Present Present Present Absent Present Present Present Absent TUMOR STROMA Expected incidence NON-SMOKER PATIENTS Higher incidence Expected incidence Lower incidence Squamous Adenocarcinoma None None PREVALENT HISTOTYPE Well differentiated Poorly differentiated Poorly differentiated None PREVALENT GRADING BCL-2, laminin receptor - - BCL-2 HIGHER THAN EXPECTED BCL-2, laminin receptor BCL-2, p53, EGFR - - LOWER THAN EXPECTED Pezzella, Gasparini et al Am J Pathol 151: 1417, 1997

9. THE TUMOR OF EACH SINGLE PATIENT IS UNIQUE BECAUSE THE GENOME OF HIS/HER CANCER IS UNIQUE

10. THE SWITCH FROM HISTOLOGIC TYPE TO MOLECULAR CLINICAL ONCOLOGY:THERAPEUTIC IMPLICATIONS OLD PARADIGM NEW PARADIGM SUBCLASSIFICATION BY TARGET IDENTIFICATION DISEASE- DRIVEN THERAPY HISTOLOGY DRIVEN THERAPY HISTOLOGY DRIVEN THERAPY UNDERSTANDING THE MOLECULAR TAXONOMY: MOLECULAR DRIVEN THERAPY PRESUMED HOMOGENEOUS GROUP OF PTS PRESUMED HOMOGENEOUS GROUP OF PTS PRESUMED HOMOGENEOUS GROUP OF PTS SAME THERAPEUTIC REGIMEN SAME THERAPEUTIC REGIMEN SAME THERAPEUTIC REGIMEN PERSONALIZED THERAPY

11. THE PARADIGM OF PERSONALIZED CANCER CARE: WHAT DOES IT MEAN? THE ASPIRATION TO BASE A TREATMENT ON THE UNIQUE BIOLOGICAL FEATURES OF A PATIENT’S DISEASE THROUGH THE IDENTIFICATION OF VALIDATED TOOLS OF RESPONSE/RESISTANCE TO THERAPY AIMS • TO IMPROVE DRUG EFFICACY • TO AVOID INAPPROPRIATE DRUG EXPOSURE (PRIMARY RESISTANT TUMORS) • TO MAXIMIZE QUALITY OF LIFE • TO SPARE UNNECESSARY COSTS

12. THERAPEUTIC TARGETING OF THE HALLMARKS OF CANCER Hanahan  Weinberg, Cell, 144:646, 2011

13. MULTISTEP PATHOGENESIS OF INVASIVE LUNG ADENOCARCINOMA Invasive ADC Poor Prognosis ADC Cancer J Clinicians,61:91,2011

14. DRIVER MUTATIONS IN LUNG ADENOCARCINOMA 15% 8% EGFR Infrequent NF1 KRAS NTRK 10% 25% STK11 17% 3% BRAF ErbB2 3% 4% 5% HER-4 PIK3CA EML4-ALK 6% Paik et Al,JCO 29: 2046. 2011

15. PERSONALIZED THERAPY: EGFR NSCLC

16. IPASS TRIAL Eligibility Criteria • ≥ 18 years of age • Stage IIIB/IV NSCLC • ADC/Bronchoalveolar • Non/light smokers • No prior systemic Tx • Measurable disease by RECIST • ECOG PS of 0 or 1 • Adequate organ function GEFITINIB 250 mg PO daily (n=607) Primary Endpoint : PFS RANDOM I Z A T I ON Secondary Endpoints : OS, RR, QoL, Safety, EGFR status CARBOPLATIN/TAXOL (6 cycles) (N=1217) (n=589) WJTOG0203 TRIAL PLATINUM-DOUBLETS (6 cycles) Primary Endpoint : OS Eligibility Criteria • ≥ 18 years of age • Stage IIIB/IV NSCLC • No prior systemic Tx • Measurable disease by RECIST • ECOG PS of 0 or 1 • Adequate organ function (n=301) Secondary Endpoints : PFS, RR, QoL, Safety (N=604) GEFITINIB 250 mg PO daily RANDOM I Z A T I ON PLATINUM-DOUBLETS (3 cycles) (n=302) Takeda K, et al. J Clin Oncol; 28 (5):753-60, 2010 Mok TS, et al. N Engl J Med; 361 (10):947-57, 2009

17. WJTOG0203 TRIAL IPASS TRIAL P:NS P:NS P < 0.001 P < 0.001 Takeda K, et al. J Clin Oncol; 28 (5):753-60, 2010 Mok TS, et al. N Engl J Med; 361 (10):947-57, 2009

19. EGFR-TKIs AND EGFR MUTATION -DIRECTED FRONT - LINE STUDIES

20. PROGRESS IN THE TREATMENT OF METASTATIC LUNG CANCER Pao W. et al. Nat. Rev. Cancer 2010; 10;760

21. THERAPEUTIC RESISTANCE TO KINASE INHIBITORS Gatekeeper mutations near to kinase active site • Additional mutations in the target oncogene • Gene amplification • Upstream mutations activating the target oncoproteins • Bypass mechanisms involving alterations that dysregulate a cellular effector acting in parallel to the drug target Wagle et al, JCO;29:3085, 2011

22. FREQUENCIES OF INTRINSIC RESISTANCE TO EGFR-TKIS RELATIVE TO SENSITIVITY/RESISTANCE IN NSCLC

23. DIAGNOSTIC FEATURES OF EML4-ALK-POSITIVE NSCLC FISH H&E ALK HIC • The frequency of EML4-ALK ranges from 1.5% - 6.7% (Asian) to 13% (White) to 33% • (never/light smokers without EGFR mutation) • EML4-ALK pts are more likely to be men (23% vs 9%) • EML4-ALK pts are significantly younger than EGFR or WT/WT pts • EML4-ALK–positive tumors appear histologically distinct from EGFR mutant and WT/WT tumors Shaw, AT, et al. J Clin Oncol; 27:4247-53 2009

24. PERSONALIZED THERAPY: EMLA4-AKT NSCLC

25. NSCLC (Adenocarcinoma histology): Suggested algorithm for molecular testing before treatment with oral TKIs (*) "Other" includes BRAF, MEK1, AKT1, PIK3CA… Horn L, et al. J Clin Oncol, 27 (26):4232-5, 2009

26. BEVACIZUMAB IN NON SQUAMOUS NSCLCKEY RESULTS Sandler A, et al. N Engl J Med. 2006;355(24):2542-2550. Reck M, et al. J ClinOncol. 2009;27(8):1227-1234.

27. SQUAMOUS CELL CARCINOMA OF THE LUNG 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

28. WHICH STRATEGY FOR SEQUENTIAL TREATMENTS TO MAKE A TUMOR A CHRONIC DISEASE

29. STEPS FOR MATCHING EACH CANCER WITH INDIVIDUALLY TARGETED THERAPY Haber et al, Cell, 145: 19, 2011

30. SEQUENTIAL THERAPY OF ADVANCED DISEASE EMPIRIC APPROACH PHARMACOGENOMIC APPROACH Use presumednon-cross resistant cytotoxic agents Biopsy-obtained updated genomic characterization (eg, secondary mutations, gene amplification, epigenetic alterations, …) NSCLC 1st line Cisplatinum-based Therapy 1st line Gefinitib/Erlotinib in EGFR m tumors • 2nd line Therapy • Docetaxel • Pemetrexed • Vinorelbine 2nd line Therapy Selective agents to T790 mutation-WZ4002 c-MET inhibitors Irreversible anti-EGFR agents

31. THE BATTLE TRIAL: PERSONALIZING THERAPY FOR LUNG CANCER – STUDY DESIGN Kim et al, Cancer Discovery, 1:43, 2011

32. THE BATTLE TRIAL: PERSONALIZING THERAPY FOR LUNG CANCER – RESULTS

33. PHARMACOGENETICS and clinical utility Genetics Individualized drug Minimize Toxicity PHARMACOGENETICS AIM Maximize Efficacy Pharmacology Individualized dosing

34. A FLIGHT ON FUTURE YEARS • NEW STRATEGIES FOR KILLING CANCER STEM CELLS 1 • ULTRA-SELECTIVE ANTICANCER DRUG DELIVERY BY NANOTECHNOLOGIES (Nanoporous particle-supported by lipid bilayers) 2 • NEW COMPREHENSIVE CLASSIFICATION OF NSCLC BASED ON GENOMIC ABNORMALITIES ACCOUNTING FOR ALL THE MUTATED CANCER GENES PRESENT IN A SINGLE TUMOR • PIVOTAL TRIALS IN GENOTYPE – DEFINED SUBGROUPS 1 Lang, Cancer Cell, 20: 341,2011 2 Ashley, Nature Materials,10: 389, 2011