1. LUNG CANCER: ASCO 2006 TOPICS Adjuvant therapy Clinical studies Meta-analysis ChemoXRT for stage III disease Advances in stage IV NSCLC New agents Predictive tests

2. Time from Randomization (Mo) Probability of Survival 0405060708090102030 0.0 0.2 0.4 0.6 0.8 1.0 Adjuvant CT Control P=0.56 Keller et al. NEJM 343:1217, 2000 0.0 0.2 0.4 0.6 0.8 1.0 01234 5 Probability of Survival Time from Randomization (Yr) Adjuvant CT Control P=0.589 Adjuvant CT in NSCLC E3590 & ALPI Survival Time from Randomization (Mo) Probability of Survival 0405060708090102030 0.0 0.2 0.4 0.6 0.8 1.0 Adjuvant CT Control P=0.56 0.0 0.2 0.4 0.6 0.8 1.0 01234 5 Probability of Survival Time from Randomization (Yr) Adjuvant CT Control P=0.589 M. Tonato et al. PASCO 21:290a, 2002

3. ADJUVANT CHEMOTHERAPY NCI-C BR-10 No. Pts. 459 Stage IB-II Survival* Observation 54 Adj. Chemotx 69 HR (95% C.I.) 0.69 (0.52-0.92) P-value 0.012 * 5 year survival

4. ANITA RESULTS Cis + VNR Observation p value No. pts. 4074330.002 RFS (months) 38.3 20.7 0.002 M.S.T. (months) 65.8 43.70.013 5 year surv. 51.% 43% *Douillard JY, et al.: Proc ASCO 23:624, 2005

5. UPDATE OF CALGB 9633: STAGE IB NSCLC Initiated in 1996 with accrual target of 500 Positive study when first reported

6. CALGB 9633: FAILURE-FREE SURVIVAL adjuvant chemo controlP valueHazard Ratio [90% CI] population173171 recurrence or death 74 (42.8%) 89 (52.0%) 0.030 0.74 [0.57 – 0.96] 1-year FFS 85% (80%, 89%) 81% (76%, 86%) 0.16 2-year FFS 75% (70%, 81%) 69% (63%, 75%) 0.12 3-year FFS 66% (60%, 72%) 57% (51%, 64%) 0.047 4-year FFS 61% (51%, 67%) 52% (46%, 59%) 0.07 5-year FFS 52% (45%, 59%) 48% (41%, 55%) 0.21

7. CALGB 9633: OVERALL SURVIVAL adjuvant chemo controlP valueHazard Ratio [90% CI] population173171 died from any cause64 (37.0%) 73 (42.7%) 0.100.80 [0.60 – 1.07] 1-year survival 94% (91%, 97%) 94% (91%, 97%) 0.500 2-year survival 90% (86%, 94%) 84% (79%, 89%) 0.050 3-year survival 79% (74%, 84%) 71% (65%, 77%) 0.043 4-year survival 69% (63%, 75%) 61% (55%, 68%) 0.081 5-year survival59% (52%, 66%) 57% (50%, 64%) 0.375

8. CALGB 9633: OVERALL SURVIVAL ChemotherapyObservation median95 months78 months P value0.10 HR (90% CI)0.80 (0.60-1.07)

9. OVERALL SURVIVAL THEN AND NOW ASCO: 2004 ASCO: 2006 HR=0.62; 90% CI: 0.44- 0.89 p=0.01 HR=0.80; 90% CI: 0.60-1.07 p=0.10

10. INFLUENCE OF AGE ON SURVIVAL WITH ADJUVANT THERAPY: NCI-C BR 10* Overall Survival similar: –Age > 65: 66% vs. 46% favoring chemo (N = 155) –Age < 65:70% vs. 58% favoring chemo (N = 327) –Age > 75: HR 2.35 favoring observation Only 23 patients in this analysis, however * Pepe C, et al.: Proc ASCO 24:2006

11. LUNG ADJUVANT CISPLATIN EVALUATION (LACE)* Individual patient data from ALPI, ANITA, BLT, IALT and JBR10 Median F/U 5.1 years Survival benefit 3.9% at 3 years and 5.3% at 5 years H.R. 0.89 (0.82 – 0.96; p = 0.03) Improved DFS H.R. 0.84 (0.78 – 0.90; p < 0.001) Results by surgical stage StageH.R. (95% C.I.) IA1.41 (0.96 – 2.09) IB0.92 (0.78 – 1.10) II0.83 (0.73 – 0.95) III0.83 (0.73 – 0.95) *Pignon JP, et al.: Proc ASCO 24:366, 2006

12. Adjusted HR=0.65, 95% CI [0.50-0.86], p = 0.002 Adjusted HR=0.65, 95% CI [0.50-0.86], p = 0.002 Effect of adjuvant chemotherapy on survival in patients with ERCC1 negative tumors

13. Adjusted HR=1.14, 95% CI [0.84-1.55], P = 0.40 Effect of adjuvant chemotherapy on survival in patients with ERCC1 positive tumors

14. H.O.G. LUN 01-24/USO 02-33 SWOG 9504, a phase II study of cisplatin + etoposide + XRT with consolidation taxotere achieved M.S.T. of 26 months and 5 yr. survival 29% in 83 patients with stage IIIB NSCLC HOG LUN 01-24, a phase III study with and without consolidation taxotere Cisplatin 50 mg/M 2 days 1, 8, 29, and 36 + etoposide 50 mg/M 2 days 1-5 and 29-33 + concurrent XRT 59.4 Gy (1.8 Gy/fraction); C.R., P.R. and stable patients randomized to docetaxel 75 mg/M 2 q 3 weeks x 3 versus observation 4 to 8 weeks after induction

15. CONSOLIDATION DOCETAXEL 33% of patients entering protocol did not randomize due to progression or toxicity from chemoXRT 22% required dose modification with cycle 2 and/or 3 Docetaxel doses: 0 cycles: 7 % 1 cycle: 34% 2 cycles: 30% 3 cycles: 29%

16. GRADE 3-4 DOCETAXEL TOXICITIES HOG LUN 01-24 N = 73 Neutropenia 23% GCP fever 8% Pneumonitis 10% Fatigue 7% 1 or more Gr 3-4 toxicity 45%

17. COMPARISON GRADE 3-4 TOXICITIES WITH DOCETAXEL SWOG 9504 SWOG 0012 HOG LUN 01-24 (N = 65) (N = 343) (N = 73) Neutropenia 57% 54% 23% Infection --- 15% 3% Pneumonitis 7% 7% 10% Therapy-related death 5% 5% 5%

18. International patient data meta-analysis of randomized first- line chemotherapy comparing cisplatin versus carboplatin based chemotherapy Nine phase III trials with 2,968 patients analyzed Higher response rate with cisplatin (33%) versus carboplatin (26%) based chemotherapy (p < 0.001) Improved survival with cisplatin, but not statistically significant (HR = 1.07; 95% C.I. 0.99 – 1.15; p = 0.1); survival was statistically superior to carboplatin when a platinum compound combined with third generation drug (taxane, vinorelbine or gemcitabine); H.R. 1,106 with 95% C.I. 1.05 to 1.106 (p = 0.039) META-ANALYSIS OF CISPLATIN VERSUS CARBOPLATIN* *Ardizzoni A, et al.: Proc ASCO 24:366, 2006

19. NEW TREATMENT NSCLC No. Pts. Resp. rate M.S.T. 17 63% Too early 54 62% 53 weeks

20. CARBOPLATIN + PACLITAXEL IN NSCLC* 1. CBDCA AUC 6 + Paclitaxel 225 mg/M 2 over 3 hours 2. 17 of 27 responses (63%) *Vafai D, Natale RB, et al.: Proc ASCO 14:353, 1995

21. PHASE II TRIAL OF PACLITAXEL PLUS CARBOPLATIN IN NSCLC* Paclitaxel 135 mg/M 2 as a 24 hr. infusion plus Carboplatin AUC 7.5 with G-CSF administered to 54 patients Courses every 3 weeks x 6; 32 (59%) completed all 6 courses If < grade 4 myelosuppression, Paclitaxel escalated to 175 mg/M 2 and 215 mg/M 2 Objective response rate 62% including 9% C.R. M.S.T. 53 weeks *Langer CJ, et al.: J Clin Oncol 13:1860-1870, 1995

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31. METASTATIC NSCLC: NEW AGENTS Sorafenib Sunitinib ZD6474

32. Phase II Sorafenib in NSCLC Gatzemeier U et al, ASCO 2006, Abstract 7002 A multi-kinase inhibitor targeting Raf, VEGFR-1, VEGFR-2, VEGFR-3, PDGFR- , Flt-3, c-Kit, and p38  All were ECOG PS 0-2, no significant bleeding, brain mets allowed Sorafenib 400 mg BID (28 day cycles) Approximately 2/3 had 1 prior regimen while about 1/3 had 2 or more prior regimens 54% adeno, 31% squamous cell

33. Efficacy Response* (n = 51)No. of Patients (%) Stable disease30 (59) Progressive disease18 (35) Not evaluated † 3 (6) * By RECIST criteria † 3 patients died prior to tumor measurement

34. PROGRESSION-FREE AND OVERALL SURVIVAL SUMMARY Median PFS of 2.7 months overall (5.5 months in SD patients) MST 6.7 months 2 patients treated for 2 years with ongoing treatment in 1 patient

35. VEGFR-2 VEGFR-1 VEGFR-3 PDGFR-  RET KIT FLT-3 PDGFR-  Sunitinib Socinski et al, ASCO 2006, Abstract 7001 CH 3 N H O N H F H3CH3C N H O N Multi-kinase inhibitor

36. EFFICACY (RECIST) Response No. patients (%) (N = 63) PR 6 (9.5) SD 27 (42.9) PD 14 (22.2) NE * 16 (25.4) ----------------------------------------------------------------------------------------------- Median duration of response, weeks (range) 12.2 (4.3 – 30.3+)** * Patients for whom scans were not evaluable or not available for review ** One patient with ongoing tumor response at 30.3 weeks

37. Progression-Free Survival 100 90 80 70 60 50 40 30 20 10 0 Estimated PFS Probability (%) Time (Weeks) Median PFS: 11.3 weeks (95% CI 10.0-15.7) 0510152025303540

38. Overall Survival 100 90 80 70 60 50 40 30 20 10 0 Estimated Survival Probability (%) 05101520253035404550 Time (Weeks) Median Overall Survival: 23.9 Weeks (95% CI 17.0–28.3)

39. ZD6474 versus Gefitinib Natale R et al, ASCO 2006, Abstract 7000 NSCLC 2 nd /3 rd -line Gefitinib 250 mg n=85 Part A ZD6474 300 mg n=83 Disease progression or toxicity Part B Gefitinib 250 mg ZD6474 300 mg Study designed to have an 75% power to detect a 33% PFS at a significance level of p <0.2

40. Probability of remaining progression-free Primary Endpoint in Part A: Progression-Free Survival Hazard ratio = 0.69 (95% CI = 0.50 to 0.96) Two-sided P-value = 0.025 Progression-free survival in Part A (months) Median PFS ZD6474 = 11.0 weeks Gefitinib = 8.1 weeks Final data cut-off, July 2005 0.1 0.8 0.6 0.4 0.2 0.9 0.7 0.5 0.3 0 1.0 02468105319711 12141315 171618

41. Median survival ZD6474 then gefitinib = 6.1 months Gefitinib then ZD6474 = 7.4 months Probability of remaining alive Secondary Endpoint: Overall Survival 0.1 0.8 0.6 0.4 0.2 0.9 0.7 0.5 0.3 0 1.0 Time to death (months) 24 0 654128391011121314157 1617181920 2122 23 Hazard ratio = 1.19 (95% CI = 0.84 to 1.68) Two-sided P-value = 0.34

42. MOLECULAR PREDICTORS IN NSCLC Resected patients with Excision Repair Cross- Complementing 1 (ERCC-1) positive tumors do not benefit from adjuvant cisplatin-based chemotherapy EGFR exon 19 or 21 mutation predicts response and TTP, but not survival in patients with BAC treated with erlotonib K-ras mutation predicts resistance to erlotinib Improved PFS with addition of bevacizumab to carboplatin + paclitaxel occurred mainly in patients with low baseline intercellular adhesion molecule (ICAM) levels

43. CONCLUSIONS Adjuvant therapy ChemoXRT Stage IV disease Post-platinum doublet Pemetrexed, Docetaxel Erlotinib Sorafenib, Sunitinib, ZD6474 Biology – especially adjuvant therapy