1. A paradigm shift in the treatment of advanced lung cancer: survival and symptom benefits with Tarceva Tudor-Eliade Ciuleanu Cancer Institute Ion Chiricuta and University of Medicine and Pharmacy Iuliu Hatieganu Cluj-Napoca, Romania

2. What are our therapeutic objectives in advanced NSCLC? To prolong life –improved survival –lengthened time to disease progression To maintain QoL –improved disease-related symptoms/QoL To develop better-tolerated treatment regimens QoL = quality of life

3. More effective and better tolerated second-line therapeutic strategies are needed Increasing need for second-line treatment due to greater use of first-line, platinum-based chemotherapy Many patients (e.g. elderly, poor PS) are unsuitable to receive chemotherapy due to significant toxicities Patients progressing on first-line chemotherapy may benefit from an agent with a different mechanism of action As single agents, docetaxel and pemetrexed have proven benefits in second-line NSCLC, but are limited by significant toxicities

4. Tarceva: preliminary evidence of antitumour effects and clinical benefits Objective RR = 12.3% (5.1–23.7) Median OS = 8.4 months (4.8–13.9) 1-year survival rate = 40% (28–54) Survival distribution function Time (months) 051015202530 1.00 0.75 0.50 0.25 0 Pérez-Soler R, et al. J Clin Oncol 2004;22:3238–47 Phase II trial in relapsed NSCLC: overall survival OS = overall survival RR = response rate Tarceva 150mg/day

5. BR.21, a randomised phase III trial of Tarceva (erlotinib; OSI-774) as treatment following chemotherapy in patients with advanced NSCLC: an NCIC CTG trial NCIC CTG = National Cancer Institute of Canada Clinical Trials Group

6. BR.21: study design PS = performance status; CR = complete response; PR = partial response SD = stable disease; PD = progressive disease Stratified by: Centre PS (0/1 vs 2/3) Response to prior treatment (CR/PR:SD:PD) Prior regimens (1 vs 2) Prior platinum (yes vs no) Tarceva 150mg daily Placebo 2 1 R A N D O M I S E

7. BR.21: patient characteristics

8. NCIC CTG BR.21: best response (n=638)* CI = confidence interval *Measurable disease was not an entry criterion

9. *HR and p (log-rank test) adjusted for stratification factors at randomisation and HER1/EGFR status BR.21: improvement in overall survival with Tarceva 42.5% improvement in median survival Survival distribution function Survival time (months) HR=0.73, p<0.001* 1.00 0.75 0.50 0.25 0 051015202530 Shepherd F, et al. N Engl J Med 2005;353:123–32 Tarceva Placebo

10. Forest plot of survival by subsets D-R = diagnosis to randomisation HR <1 = improved survival with Tarceva Tarceva:placebo PS 0–1 PS 2–3 Male Female <65 years  65 years Adenocarcinoma Squamous type Other histology Prior weight loss <5% Prior weight loss 5–10% Prior weight loss >10% Never-smoker Current/ex-smoker 1 prior regimen 2+ prior regimens 01230123 HR Factors Tarceva:placebo Prior platinum No prior platinum Prior taxane No prior taxane Best prior response: CR/PR Best prior response: SD Best prior response: PD D-R: <6 months D-R: 6–12 months D-R: >12 months HER1/EGFR-positive HER1/EGFR-negative HER1/EGFR-unknown Canada/USA Rest of world HR 01230123 Tarceva ® Prescribing Information. 2005. OSI Pharmaceuticals, Inc., and Genentech, Inc.

11. Survival benefit with erlotinib according to HER1/EGFR biomarker status nHRCIp* p†p† Mutation status Wild-type1370.730.49–1.100.13 Mutant 400.770.40–1.500.45 EGFR expression (IHC) IHC+1840.680.49–0.950.02 IHC–1410.930.63–1.360.70 Gene copy Number (FISH) Low690.860.48–1.510.59 High560.440.2–0.82 0.008 *p value for subgroup compared with placebo † p value for interaction 0.97 Tsao M-S, et al. N Engl J Med 2005;353:133–44 0.25 0.10

12. Progression-free survival HR=0.61, p<0.001* 25% 10% Survival distribution function Survival time (months) 1.00 0.75 0.50 0.25 0 051015202530 Tarceva Placebo Shepherd F, et al. N Engl J Med 2005;353:123–32 *HR and p (log-rank test) adjusted for stratification factors at randomisation and HER1/EGFR status

13. Efficacy of current treatment options in the second-line setting* *Survival cannot be compared directly because of different patient populations † n=156 (T) and 82 (BSC); ‡ n=253 1 Tarceva product information; 2 OSI and Roche data on file 3 Pemetrexed product information; 4 Docetaxel product information 5 Hanna N, et al. J Clin Oncol 2004;22:1589–97 Tarceva vs BSC 1,2 Docetaxel (75mg/m 2 ) vs pemetrexed 3 Docetaxel (75mg/m 2 ) vs BSC 4 T (n=488) BSC (n=243) D (n=288) P (n=283) D (n=55) BSC (n=100) PS (%) 0/1 2 3 65 26 9 68 23 9 88 12 0 89 11 0 75 25 0 75 25 0 Prior regimens (%) 1  2 50 100 0 0 80 20 76 24 Median survival (months)* 6.7 4.7 7.9 8.3 7.5 4.6 1-year survival (%) 31.2 21.5 29.7 37 19 Median survival in PS 0/1 patients with one prior regimen 9.42 † 6.72 † 9.15 9.45 ‡5 – –

14. Score Bezjak A, et al. J Clin Oncol 2005;23(Suppl. 16 Pt I):625s (Abs. 7018) BR.21: QoL impairments at baseline – mainly due to fatigue, cough, dyspnoea and pain 100 80 60 40 20 0 GlobalRolePhysicalFatigueCoughDyspnoeaPain

15. BR.21: time to deterioration of QoL symptoms *Median † Adjusted log-rank Bezjak A, et al. J Clin Oncol 2005;23(Suppl. 16 Pt I):625s (Abs. 7018)

16. BR.21: change in symptoms *  10 point change from baseline at any time †  2 Bezjak A, et al. J Clin Oncol 2005;23(Suppl. 16 Pt I):625s (Abs. 7018)

17. BR.21: change in QoL domains (EORTC QLQ-C30) Improved* (%) Stable (%) Worse* (%) VariableTarceva Placebo Global QoL † 35 26 16 28 49 46 Physical function † 31 19 18 24 51 57 Role function 39 32 14 20 47 47 Social function 39 37 21 19 39 44 Emotional function † 39 30 24 36 37 35 *  10 point change from baseline at any time (clinically significant) † p<0.01 Bezjak A, et al. J Clin Oncol 2005;23(Suppl. 16 Pt I):625s (Abs. 7018)

18. BR.21: adverse events (%) Tarceva (n=485)Placebo (n=242) AnyGrade 3, 4AnyGrade 3, 4 Rash75 917 0 Diarrhoea54 618<1 Nausea33 324 2 Vomiting23 219 2 Stomatitis17<1 3 0 Fatigue52184520 Ocular (all)27 1 9<1 Anorexia52 938 5 Infection24 415 2

19. Tolerability of second-line therapies: haematological toxicities Shepherd F, et al. N Engl J Med 2005;353:123–32 Hanna N, et al. J Clin Oncol 2004;22:1589–97 Serious haematological toxicities may require hospitalisation and blood transfusions The most common non-haematological side effects were rash and diarrhoea (mainly mild to moderate)

20. Conclusions: Tarceva in NSCLC NSCLC has a high incidence and mortality Standard cytotoxic regimens offer clinical benefits, but are limited by substantial toxicities Tarceva is a new treatment option that has equivalent efficacy to approved chemotherapy options for second-line treatment, but is not associated with the side effects of chemotherapy Tarceva is a valuable new treatment option for patients with advanced NSCLC