1. Giorgio Mustacchi NSCLC: Targeting angiogenesis

2. NON-SMALL CELL LUNG CANCER

3. Fry WA, et al. Cancer. 1996;77:1953. Years NON-SMALL CELL LUNG CANCER Survival by stage

4. Key targets for novel anticancer agents Angiogenesis/ vasculature G1 M G0 S G2 Signal transduction Cell cycle Invasion MetastasisApoptosis

5. Extracellular Intracellular Rini BI, Small EJ. J Clin Oncol 23: 1028-1043, 2005.

7. Molecular-targeted agents under investigation in lung cancer Phase I Phase II Phase III Approved AZD2171 Vandetanib Motesanib Sorafenib Avastin Sunitinib VEGF TRAP Vatalanib Angiogenesis inhibitors Gefitinib Tarceva Bortezomib Matuzumab Cetuximab Bexarotene Imatinib AZD6244 Tipifarnib Talabostat PF-3512676 Celecoxib AS1404 Lapatinib RAD001 CP-751871 ABT-751 Panitumumab EGFR/HER inhibitors Other molecular- targeted therapies HKI-272

8. 1. Johnson DH, et al. J Clin Oncol. 2004;22:2184-2191. *Bevacizumab was given until disease progression or unacceptable toxicity. After disease progression, patients in the control arm of AVF0757g had the option to receive single-agent bevacizumab 15 mg/kg Q3W. TrialPhasePatientsTreatment Arms* AVF0757g [1] II 98 PC  6 Bevacizumab 7.5 mg/kg Q3W + PC  6 Bevacizumab 15 mg/kg Q3W + PC  6 Bevacizumab in Advanced NSCLC: Clinical Trial Evidence In Squamous cell type life-threatening or fatal hemoptysis in 4/13 pts

9. Alan Sandler, M.D., Robert Gray, Ph.D., Michael C. Perry, M.D., Julie Brahmer, M.D., Joan H. Schiller, M.D., Afshin Dowlati, M.D., Rogerio Lilenbaum, M.D., and David H. Johnson, M.D. N Engl J Med Volume 355(24):2542-2550 December 14, 2006 Paclitaxel-Carboplatin +/- Bevacizumab in NSCLC FDA Registrative ECOG Trial

10. Study design Randomized Phase III Open Label Multicenter Trial Chemonaive pts, Stage III/IV NSCLC PS < 2 Excluded: Squamous, CNS M1, hemoptysis No Bevacizumab crossover permitted Pacli/Carbo +/- Bevacizumab

11. E4599 Trial: Addition of Bevacizumab improves RR, PFS and Overall Survival Months Probability HR: 0.79 (95% CI: 0.67-0.92; P =.003) 10.312.3 Sandler A, et al. N Engl J Med. 2006;355:2542-2550. 0 0.2 0.4 0.6 0.8 1.0 0123648186243042 CP CP + bevacizumab RR %Survival, % P<.00112 Months24 Months CP + bevacizumab 355123 CP154415

12. Sandler A et al. N Engl J Med 2006;355:2542-2550 HR for Death (Subgroups Analysis)

13. Sandler A et al. N Engl J Med 2006;355:2542-2550 Causes of Death (85.2%)(89.8%) (4.5%)(0.6%)

14. Adverse Events, According to Treatment Sandler A et al. N Engl J Med 2006;355:2542-2550

15. Adverse Events According to Treatment and age 70 Ramalingam, JCO Jan 2008

16. PFS according to age 70 Ramalingam, JCO an 2008 In older pts Bevacizumab is more toxic without > in survival

17. AVAil: 1°-Line Chemotherapy +/- Bevacizumab

18. AVAiL: Efficacy Results Rack, WCLC 2007, Abs C1-06

20. The benefit is significant, but… In ~ 60 % of NSCLC there is a contraindication : »Age over 70 »Squamous Cell Lung cancer »Anti-coagulation therapy »Brain metastasis »History of hemoptysis »PS > 1

21. Inhibitory spectrum of multi-kinase targeting TKIs 1 Wedge SR, et al. Cancer Res 2002;62:4645–55; 2 Carlomagno F, et al. Cancer Res 2002;62:7284–90; 3 Mendel DB, etal.ClinCancer Res 2003;9:327–37; 4 Abrams TJ, et al. Mol Cancer Ther 2003;2:471–8; 5 Wilhelm SM, et al. CancerRes2004;64:7099109; 6 Carlomagno F, et al. J Natl Cancer Inst 2006;98:326–34 IC 50 (nm)* VEGFR-1VEGFR-2VEGFR-3PDGFREGFRRAFc-KitRET Vandetanib 1,2 (ZD6474)–40110–500––100 Sunitinib 3,4 (SU11248)– 9– 8–– 10– Sorafenib 5,6 (BAY43-9006)–90 20 57–6 68 50 *Biochemical IC 50 values were determined using slightly different methods between the studies. Cut-off of 1,000nM used

22. Sunitinib in platinum-failing NCSLC Open Phase II trial Median PSF (weeks) % RR % SD N = 6312 (95% CI: 10 to 16.1) 11.128.6 Socinski, JCO Feb 2008 Median Overall Survival : 23.4 weeks (95% CI: 17 to 28.3)

23. Sorafenib vs Placebo in Heavily pretreated NCSLC Double blind controlled Phase II trial PS < 2 At least 2 prior chemotherapy regimens (n= 342) If Response after 2 months of Sorafenib (n=97; 28.3%) Randomisation to Sorafenib or Placebo Median PSF (mos) Stable DX PD Sorafenib3.629%46% Placebo1.9 (p=.01) 5% (p=.002) 58% Schiller, ASCO 2008, Abs 8014

24. Tumour cavitation with a multi-targeting TKI PretreatmentAfter 6 weeks’ treatment with sorafenib 400mg b.i.d. Image kindly provided by Dr M Reck, Hospital Grosshansdorf, Germany

25. Sorafenib: G 3 & 4 Toxicities Hand-Foot Skin Reaction (15%); Fatigue (11%); INR abnormalities (3%) Schiller, ASCO 2008, Abs 8014 2 G5 hemoptysis

26. Docetaxel +/- Vandetanib in pretreated NCSLC Double blind controlled Phase II trial vs Placebo PS < 2 N = 127Median PSF (weeks) Vandetanib18.7 Placebo12 HR 0.64 (p=.074) Heymach, JCO 2007

27. Vandetanib +/- Carbo/Paclitaxel in 1st line NCSLC Randomized Phase II trial PS < 2 N = 181Median PSF (weeks) % RR Vandetanibna7 Van + CP2432 CP23 HR 0.76 (p=.098) 25 Heymach, ASCO 2007, Abs 7544 Discontinued MORE TOXIC

28. Tarceva and Avastin: targeting the tumour and the vasculature Tumour Tarceva Avastin Inhibits tumour cell growth and blocks synthesis of angiogenic proteins (e.g. bFGF, VEGF, TGF-  ) by tumour cells Inhibits endothelial cells from responding to the angiogenic protein VEGF bFGF VEGF TGF-  Endothelial cells

29. Phase II study of Avastin with chemotherapy or Tarceva in advanced NSCLC Previously treated advanced non-squamous NSCLC (n=120) PD Tarceva PD Tarceva Randomised, multicentre study Primary endpoint: safety and preliminary efficacy (PFS) Secondary endpoints: objective RR (+ duration); duration of survival Avastin 15mg/kg every 3 weeks; Tarceva 150mg/day orally; docetaxel 75mg/m 2 and pemetrexed 500mg/m 2 every 3 weeks PD = progressive disease Herbst R, et al. Eur J Cancer Suppl 2006;4:20 (Abs. 53) Tarceva + Avastin (n=39) Chemotherapy (n=41) Chemotherapy + Avastin (n=40)

30. Phase II study of Avastin plus chemotherapy or Tarceva in advanced NSCLC: efficacy Herbst R, et al. Eur J Cancer Suppl 2006;4:20 (Abs. 53) PFSOverall survival Progression-free survival rate 1.0 0.8 0.6 0.4 0.2 0 012345678012345678 Progression-free survival (months) Survival rate Duration of survival (months) 024681012141618202224 1.0 0.8 0.6 0.4 0.2 0 Avastin + Tarceva4.4 33.6 Avastin + CT4.830.5 CT3 21.5 Median 1-year (months) rate (%) Avastin + Tarceva13.7 57.1 Avastin + CT12.653.6 CT 8.6 34.8 Median 6-month (months) rate (%)

31. Double ‑ blind, randomised study Primary endpoint = OS Secondary endpoints: PFS, RR and duration, safety and pharmacokinetics Status: ongoing; planned n=650 OSI-3364g *No crossover permitted Phase III study of Tarceva ± Avastin in the second-line setting Previously treated advanced non- squamous NSCLC PD* PD Tarceva 150mg/day + placebo Tarceva 150mg/day + Avastin 15mg/kg every 3 weeks

32. Phase II study of first-line Tarceva + Avastin versus Avastin + chemotherapy Randomised, multicentre, open-label Primary endpoint: PFS Secondary endpoints: safety, QoL, OS, correlation of biomarkers and clinical characteristics with outcome –EGFR IHC and FISH, EGFR mutations, K-ras, pMAPK, pAKT, HER2 IHC and FISH, HER3, amphiregulin, TGF- , EGF, ICAM Status: planned; n=200 Tarceva 150mg + Avastin 15mg/kg every 3 weeks Stage IIIB/IV enlarged non- squamous NSCLC, unselected Chemotherapy + Avastin BO20571

33. ATLAS: Tarceva + Avastin following the new standard of care in first-line treatment Avastin + placebo Chemotherap y naïve stage IIIB/IV non- squamous NSCLC Tarceva Non-PD AVG3671g (phase IIIb) Avastin 15mg/kg every 3 weeks; Tarceva 150mg/day *Either carboplatin/paclitaxel, carboplatin/gemcitabine or carboplatin/docetaxel Off study Avastin + Tarceva PD Off study (n  800) PD 1:1 Avastin plus chemotherapy* PD or significant toxicity Primary endpoint = PFS Status: ongoing; planned n=1,150

34. Fry WA, et al. Cancer. 1996;77:1953. Years NSCLC: Survival by stage The best treatment: NO SMOKING