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

Time from Randomization (Mo) Probability of Survival Adjuvant CT Control P=0.56 Keller et al. NEJM 343:1217, 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 Adjuvant CT Control P= Probability of Survival Time from Randomization (Yr) Adjuvant CT Control P=0.589 M. Tonato et al. PASCO 21:290a, 2002

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

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

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

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

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

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

OVERALL SURVIVAL THEN AND NOW ASCO: 2004 ASCO: 2006 HR=0.62; 90% CI: p=0.01 HR=0.80; 90% CI: p=0.10

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

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 (0.82 – 0.96; p = 0.03) Improved DFS H.R (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

Adjusted HR=0.65, 95% CI [ ], p = Adjusted HR=0.65, 95% CI [ ], p = Effect of adjuvant chemotherapy on survival in patients with ERCC1 negative tumors

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

H.O.G. LUN 01-24/USO 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 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

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%

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

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

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 – 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 to (p = 0.039) META-ANALYSIS OF CISPLATIN VERSUS CARBOPLATIN* *Ardizzoni A, et al.: Proc ASCO 24:366, 2006

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

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

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: , 1995

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METASTATIC NSCLC: NEW AGENTS Sorafenib Sunitinib ZD6474

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

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

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

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

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

Progression-Free Survival Estimated PFS Probability (%) Time (Weeks) Median PFS: 11.3 weeks (95% CI )

Overall Survival Estimated Survival Probability (%) Time (Weeks) Median Overall Survival: 23.9 Weeks (95% CI 17.0–28.3)

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

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 = Progression-free survival in Part A (months) Median PFS ZD6474 = 11.0 weeks Gefitinib = 8.1 weeks Final data cut-off, July

Median survival ZD6474 then gefitinib = 6.1 months Gefitinib then ZD6474 = 7.4 months Probability of remaining alive Secondary Endpoint: Overall Survival Time to death (months) Hazard ratio = 1.19 (95% CI = 0.84 to 1.68) Two-sided P-value = 0.34

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

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