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LUNG CANCER: ASCO 2006 TOPICS Adjuvant therapy • Clinical studies • Meta-analysis

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 . Adjuvant CT. Adjuvant CT. Adjuvant CT. Adjuvant CT. Control. Control. Control. Control. 1.0.

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LUNG CANCER: ASCO 2006 TOPICS Adjuvant therapy • Clinical studies • Meta-analysis

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  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. Adjuvant CT Adjuvant CT Adjuvant CT Adjuvant CT Control Control Control Control 1.0 1.0 1.0 1.0 0.8 0.8 0.8 0.8 0.6 0.6 0.6 0.6 Probability of Survival Probability of Survival ProbabilityofSurvival Probability of Survival 0.4 0.4 0.4 0.4 P=0.56 P=0.56 P=0.589 P=0.589 0.2 0.2 0.2 0.2 0.0 0.0 0.0 0.0 0 0 10 10 20 20 30 30 40 40 50 50 60 60 70 70 80 80 90 90 0 0 1 1 2 2 3 3 4 4 5 5 Time from Randomization (Mo) Time from Randomization (Mo) Time from Randomization (Yr) Time from Randomization (Yr) Keller et al. NEJM 343:1217, 2000 M. Tonato et al. PASCO 21:290a, 2002 Adjuvant CT in NSCLCE3590 & ALPI Survival

  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 + VNRObservationp value No. pts. 407 433 0.002 RFS (months) 38.3 20.7 0.002 M.S.T. (months) 65.8 43.7 0.013 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

  7. CALGB 9633: OVERALL SURVIVAL

  8. CALGB 9633: OVERALL SURVIVAL

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

  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 Stage H.R. (95% C.I.) IA 1.41 (0.96 – 2.09) IB 0.92 (0.78 – 1.10) II 0.83 (0.73 – 0.95) III 0.83 (0.73 – 0.95) *Pignon JP, et al.: Proc ASCO 24:366, 2006

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

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

  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/M2 days 1, 8, 29, and 36 + etoposide 50 mg/M2 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/M2 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. META-ANALYSIS OF CISPLATIN VERSUS CARBOPLATIN* • 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) *Ardizzoni A, et al.: Proc ASCO 24:366, 2006

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

  20. CARBOPLATIN +PACLITAXEL IN NSCLC* • CBDCA AUC 6 + Paclitaxel 225 mg/M2over 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/M2 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/M2 and 215 mg/M2 • 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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  30. METASTATIC NSCLC: NEW AGENTS • Sorafenib • Sunitinib • ZD6474

  31. Phase II Sorafenib in NSCLCGatzemeier 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

  32. Efficacy * By RECIST criteria †3 patients died prior to tumor measurement

  33. 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

  34. CH3 O H3C N N H CH3 F N H O N H SunitinibSocinski et al, ASCO 2006, Abstract 7001 Multi-kinase inhibitor CH3 VEGFR-1 PDGFR-a VEGFR-2 PDGFR-b VEGFR-3 RET KIT FLT-3

  35. 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

  36. Progression-Free Survival 100 90 80 70 60 50 40 30 20 10 0 Median PFS: 11.3 weeks (95% CI 10.0-15.7) Estimated PFS Probability (%) 0 5 10 15 20 25 30 35 40 Time (Weeks)

  37. Overall Survival Median Overall Survival: 23.9 Weeks (95% CI 17.0–28.3) 100 90 80 70 60 50 40 30 20 10 0 Estimated Survival Probability (%) 0 5 10 15 20 25 30 35 40 45 50 Time (Weeks)

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

  39. 1.0 0.9 0.8 0.7 Median PFS ZD6474 = 11.0 weeks Gefitinib = 8.1 weeks 0.6 0.5 0.4 0.3 0.2 0.1 0 16 17 18 12 13 14 15 0 1 2 3 4 5 6 7 8 9 10 11 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 Probability of remaining progression-free Progression-free survival in Part A (months) Final data cut-off, July 2005

  40. 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 21 22 23 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 24 16 17 18 19 20 Secondary Endpoint: Overall Survival Median survival ZD6474 then gefitinib = 6.1 months Gefitinib then ZD6474 = 7.4 months Probability of remaining alive Hazard ratio = 1.19 (95% CI = 0.84 to 1.68) Two-sided P-value = 0.34 Time to death (months)

  41. 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

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

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