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LUNG CANCER

LUNG CANCER. ASCO 2007. 100. 90. 1 year: 27.1% vs. 13.3% HR: 0.68 (0.52-0.88) p=0.003. 80. 70. 60. 50. 40. 30. PCI. 20. Control. 10. (months). 0. 0. 4. 8. 12. 16. 20. 24. 28. 32. 36. Months from moment of randomization. PCI - Overall Survival.

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LUNG CANCER

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  1. LUNG CANCER ASCO 2007

  2. 100 90 1 year: 27.1% vs. 13.3% HR: 0.68 (0.52-0.88) p=0.003 80 70 60 50 40 30 PCI 20 Control 10 (months) 0 0 4 8 12 16 20 24 28 32 36 Months from moment of randomization PCI - Overall Survival PCI reduces the risk of symptomatic BMet , HR 0.27 p<0.0001 Risk of symptomatic BMet reduced to 15% vs 40% at 1 yr Slotman et al. ASCO 2007 Abstract #4

  3. Phase III of irinotecan +carboplatin vs. etoposide + carboplatin in ED SCLC Carboplatin AUC 4 Irinotecan 175 mg/m² day 1 every 3 weeks Pt no. 105 ED SCLC Stratification PS 012, 34 18-70, >70yr Institution MS mos. 1 Yr % CbIr 8.5 34 CbE 7.1 24 p=0.02 Carboplatin AUC 4 Etoposide 120 mg orally d1-5 every 3 weeks Pt no. 104 Hermes et al ASCO 2007 Abstract# 7523

  4. Pre-Op Chemotherapy in Pts with Resectable NSCLC: MRC LU22/NVALT/EORTC 08012 Overall Survival 1.00 0.75 0.50 Proportion alive and progression free 0.25 HR 1.02 95% CI 0.80, 1.31 p = 0.86 0 At risk: S 261: 214 167 114 65 39 213 160 113 64 31 CT-S 258: 0 1 2 3 4 5 Years from Randomization Nicholson et al. ASCO 2007, Abstract #7518 Gilligan et al Lancet 2007

  5. Concurrent CT/RT +/-consolidation docetaxelHOG LUN 01-24/USO-023 Hanna N, et al. ASCO 2007 Abstract #7512

  6. Bevacizumab 7.5 mg/kg vs. 15 mg/kg AVAiL study Manegold et al. ASCO 2007 Abstract # LBA7514

  7. Randomized Phase III Trial of Gefitinib vs Docetaxel in Japanese Patients Overall Survival (ITT) Probabilityof Survival 1.00 0.75 0.50 0.25 0.00 Months 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 At Risk: Gefitinib: 245 226 197 169 148 127 98 77 63 47 35 29 25 18 9 5 4 1 0 Docetaxel: 244 233 214 189 173 140 105 87 69 44 35 25 18 14 10 7 6 3 0 Niho et al. ASCO 2007 Abstract # LBA7509

  8. Platinum withheld RRM1 Expression High Low Docetaxel + Navelbine Gemcitabine + Docetaxel THE ALGORITHM ERCC 1 Expression ERCC1 mRNA Treatment with Platinum RRM1 Expression High Low Carboplatin + Docetaxel Carboplatin + Gemcitabine Simon et al ASCO 2007 # 7502

  9. HEAD & NECK CANCER ASCO 2007

  10. The EXTREME Trial Group A Cetuximab 400 mg/m2 initial dose then 250 mg/m2 weekly + EITHER carboplatin (AUC 5, d1) OR cisplatin (100 mg/m2 IV, d1) + 5-FU (1000 mg/m2 IV, d1-4): 3-week cycles Group B EITHER carboplatin (AUC 5, d1) OR cisplatin (100 mg/m2 IV, d1) + 5-FU (1000 mg/m2 IV, d1-4): 3-week cycles Randomized 6 chemotherapy cycles maximum Cetuximab Notreatment Progressive disease or unacceptable toxicity

  11. 10.1 mo 7.4 mo

  12. Cetuximab And Weekly Paclitaxel • Eligibility: • KPS  70% • Prior Systemic Chemotherapy Is Only Allowed If Given As Part Of A Multimodal Treatment For Locally Advanced Disease Which Was Completed > 6 Months Prior To Study Entry • Dosing Schedule Up To PD/Toxicity: • Paclitaxel 80 Mg/M2 IV Weekly • Cetuximab 400/250 Mg/M2 IV Weekly • Response Assessment (RECIST): • CT/MRI Every 6 Weeks

  13. Cetuximab And Weekly Paclitaxel

  14. Final Results of a Phase II Study of Erlotinib, Docetaxel and Cisplatin in Patients with Recurrent/Metastatic Head and Neck Cancer

  15. EfficacyN = 48 Complete Response 4 Pts (8%) Partial Response 28 Pts (58%) Stable Disease 13 Pts (25%) Overall Response Rate 66% Disease Control Rate 91% Only 3 Pts Progressed After 2 Cycles Of Treatment

  16. Intratumoral EGFR Antisense DNA in Recurrent SCCHN: A Phase I Trial

  17. Clinical Response17 Evaluable for Response Complete Response CR 2 Partial Response PR 3 Stable Disease SD 2 Progressive Disease PD 10 Response Rate: 5/17 (29%) DCR: 7/17 (41%) Pre-Treatment Post-Treatment

  18. A Phase 2 Study Of Axitinib (AG-013736), A Potent Inhibitor Of VEGFRs, In Patients With Advanced Thyroid Cancer 18

  19. Tight Fit Of Axitinib In The Kinase Domain Of VEGFR-2 Receptor Protein Backbone Axitinib Receptor Protein Surface Target VEGFR-1 VEGFR-2 VEGFR-3 Cellular IC50(nM) 0.1* 0.20.1 – 0.3

  20. Best Response by Histology* *Excludes 9 Indeterminate Assessments And 1 Ineligible Patient

  21. Human Papillomavirusand Oropharyngeal Cancer: A Growing EpidemicA Therapeutic Target

  22. Oropharynx Cancer and HPV-2007 Population At Risk Increasing Numbers of Oropharynx Cancer 40-70% Of New Oropharynx Cases are HPV+ Advanced Stage At Diagnosis Sexually Transmitted Younger, Less Alcohol, Less Tobacco, Both Sexes Preventive Vaccine Available Different Prognosis, Different Biology More Responsive To Radiotherapy?, Chemotherapy?

  23. GASTRO-INTESTINAL CANCER ASCO 2007

  24. Perioperative CT in liver metastasesEORTC Intergroup phase III study 40983 Randomize FOLFOX4 Surgery FOLFOX4 6 cycles (3 months) 6 cycles (3 months) Surgery N=364 patients Primary endpoint: demonstrate an improvement in progression-free survival with peri-operative FOLFOX4 compared to surgery alone Secondary endpoints : overall survival, tumor resectability, tumor response, safety B Nordlinger et al., ASCO 2007, A5 (LBA5)

  25. Progression-free survival in eligible pts EORTC Intergroup phase III study 40983 HR= 0.77; CI:0.60-1.00, p=0.041 100 90 +8.1%At 3 years Periop CT 80 70 60 50 36.2% 40 Surgery only 30 28.1% 20 10 0 (years) 0 1 2 3 4 5 6 O N Number of patients at risk : 125 171 83 57 37 22 8 115 171 115 74 43 21 5

  26. CRYSTAL study :cetuximab : 1rst line in mCRC ! Phase III : international => 1217 patients FOLFIRI R FOLFIRI + Cetuximab (400 mg/m² puis 250 mg/m²hebdo) Primary endpoint : PFS secondary : OS, Responses , toxicity E. Van Cutsem, ASCO 2007, Abstract 4000

  27. CRYSTAL study :cetuximab : 1rst line in mCRC ! Cetuximab added to FOLFIRI significantly increases RR and PFS OR progression : 0.85 Toxicity idem apart cutaneous rash (19% gr 3-4) E. Van Cutsem, ASCO 2007, Abstract 4000

  28. …cetuximab : 2d line in mCRC ! EPIC study (1) Phase III: international ; 1298 pts mCRC progressing under oxaliplatine EGFR + in IHC irinotécan 350 mg/m²/3s + cetuximab(400 mg/m² then 250 mg/m² hebdo) R irinotécan Main endpoint : Overall Survival C.Eng et al., ASCO 2007, Abstract 4003

  29. … …cetuximab : 2d line in mCRC ! EPIC study (2) No difference in overall survival Increased PFS (HR 0.69, p<0.0001) Higher RR: 16.4% vs 4.2%, (p<0.0001) Better QoL Cross-over may explain the absence of OS advantage ? C.Eng et al., ASCO 2007, Abstract 4003

  30. NO 16966 :Oxaliplatin +/- beva in 1rst line CCRM: Non inferiority Xelox vs FOLFOX 4 International Phase III First part, 634 pts FOLFOX 4 R XELOX After 2003 : factorial design 2X2, 1400 pts FOLFOX 4+/- beva (5mg/kg/2s ou 7.5 mg/kg/3s) R XELOX +/- Beva idem L. Saltz, J Cassidy, ASCO 2007, Abstract 4030

  31. Interest of Beva : Beva +CT > Placebo +CT SSP SG HR = 0.83 [97.5% CI 0.72–0.95] (ITT) p = 0.0023 HR = 0.89 [97.5% CI 0.76–1.03] p = 0.0769 PFS estimée Survie 1.0 0.8 0.6 0.4 0.2 0 1.0 0.8 0.6 0.4 0.2 0 XELOX/FOLFOX+bevacizumabN=699 ; 420 évènements FOLFOX+bevacizumab/XELOX+bevacizumab N=699;513 évènements XELOX/FOLFOX+placebo N=701 ; 455 évènements FOLFOX+placebo/XELOX+placebo N=701;547 évenements 19.9 21.3 8.0 9.4 0 5 10 15 20 25 0 6 12 18 24 30 36 Mois Mois L. Saltz et al., ASCO 2007, Abstract 238 actualized

  32. EVEREST :final results Randomized Phase I/II (multicentric) Bras A CAMPTO +ERBITUX « classic » 166 Patients CCRm +; EGFR + OMS 0-1 Progressiveunder CPT11 Bras B CAMPTO + ERBITUX Dose escalation: 50 mg/m²/s until 500mg/m² CAMPTO+ERBITUX 21 days R J22 Bras C non eligibles pts For randomisation because Tox > gr 2 cut Tox > gr 1 S. Tejpar et al, ASCO 2007, Abstract 4037

  33. EVEREST :final results S. Tejpar et al, ASCO 2007, Abstract 4037

  34. Metastatic colorectal cancer: circulating tumoral cells (CTC) are predictive for survival ! N = 456 mCRC L1, L2, L3 7,5 ml blood samples- immunomagnetic separation cytokeratine-PE, CD45-APC, DAPI.=> initial level and during treatment Changes in CTC status at 3 &t 5 weeks influence overall survival P = 0.002 P = 0.0002 N.J. Meropol et al., ASCO 2007, Abstract 4010

  35. 1.0 0.9 0.8 0.7 0.6 0.5 Probability FOLFOX4 stage II LV5FU2 stage II FOLFOX4 stage III LV5FU2 stage III 0.4 0.3 0.2 0.1 0 MOSAIC:Overall Survival: Stage II and Stage III p=0.996 0.1% 4.4% p=0.029 HR [95% CI] Stade II 1.00 [0.71–1.42] Stade III 0.80 [0.66–0.98] 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 Mois Data cut-off: January 2007 A. de Gramont et al., ASCO 2007, Abstract 4007 actualisé

  36. Adenocarcinoma from stomach and low esophagus FFCD-FNLCC Accord 07 trialNeoadjuvant Chemotherapy vs surgery alone 00.5 0 1 1 2 2 3 3 4 4 5 5 6 6 7 7 PFS Overall survival Logrank p value = 0.021 Hazard Ratio = 0.69 (95% CI 0.50-0.95) Logrank p value = 0.0033 Hazard Ratio = 0.65 (95% CI 0.48-0.89) 1.00 1.00 0.80 0.80 CT + surgery 0.60 0.60 CT + surgery 0.40 0.40 surgery 0.20 0.20 surgery 0.0 0.0 Years Years => Neoadjuvant FU-P is a new standard in resectable gastric and esophageal adenocarcinoma => Confirmation of the MAGIC trial V. Boige et al., ASCO 2007, Abstract 4510 actualized

  37. S1 seul vs S1-cisplatine in 1srt line Avanced Gastric Cancers: SPIRITS study S-140 mg/m2 2 fois/j 28j - repos 14 j Etude phase III 305 ptsnon résécablesou récidivants L1 R S-140 mg/m2 2 fois/j 21 j - repos 14 j CDDP60 mg/m2 J8 Objectif principal = SG H. Narahara et al., ASCO 2007, Abstract 4514 actualisé

  38. S1 seul vs S1-cisplatine in 1srt line Avanced Gastric Cancers: SPIRITS study H. Narahara et al., ASCO 2007, Abstract 4514 actualisé

  39. Pancreatic Cancer

  40. 1.0 0.8 0.6 0.4 0.2 0.0 0 5 10 15 20 25 0 5 10 15 20 25 Gemcitabine (G) + bevacizumab (B)vs G + placebo (P) 1rst line palliative : phase III (double blind CALGB 80303) (525 advanced pancreatic cancer) PFS OS Bevacizumab 4.9 mo Placebo 4.7 mo HR = 1.00 P = 0.99 Bevacizumab 5.8 moPlacebo 6.1 mo HR = 1.03 P = 0.78 1.0 0.8 HR=1.00 p=0.99 0.6 Survie Survie 0.4 0.2 0.0 Mois Mois H.L. Kindler et al., ASCO 2007, Abstract 4508

  41. Phase III SHARP TrialOverall survival (Intention-to-treat) 1.00 PlaceboMedian: 34.4 weeks (95% CI: 29.4, 39.4) 0.75 0.50 0.25 0 Patients at riskSorafenib: 299 274 241 205 161 108 67 38 12 0 0 303 276 224 179 126 78 47 25 7 2 0 Placebo: SorafenibMedian: 46.3 weeks(95% CI: 40.9, 57.9) Survival Probability Hazard ratio (S/P): 0.69 (95% CI: 0.55, 0.88) P=0.00058* Weeks 0 8 16 24 32 40 48 56 64 72 80 *O’Brien-Fleming threshold for statistical significance was P=0.0077.

  42. GENITOURINARY CANCERS ASCO 2007 Presentation Title l l 45

  43. International Kidney Cancer Working Group : Prognostic Factors for Survival1 Prognostic Factors Risk Groups : Survival GroupMed. OS Good Risk 27.8 mos Interm Risk 11.4 mos Poor Risk 4.1 mos • 3748 untreated RCC patients from 11 centers in US and Europe 1 IKCWG, ASCO, 2007 Presentation Title l l 46

  44. Renal Cell Carcinoma ASCO 2005 to 2007 • A series of phase 3 clinical trials presented which have defined a new treatment approach for renal cell carcinoma Trial Prior Rx Clear Cell 2005 : TARGETs trial (sorafenib) Yes Yes 2006 : Sunitinib vs IFNα No Yes Temsirolimus ± IFNα No No 2007 : IFNα ± Bevacizumab No Yes Presentation Title l l 47

  45. AVOREN Trial: B017705: study design Bevacizumab + IFN-α2a (n=327) PD RCC patients (n=649) 1:1 IFN-α2a + placebo (n=322) PD Bevacizumab/placebo 10mg/kg i.v. q 2w until progression IFN-2a 9MIU s.c. three times/week (maximum of 52 weeks) (dose reduction allowed) P.I. Bernard Escudier Presentation Title l l 48

  46. Progression-free survival (investigator assessed) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 HR=0.63, p<0.0001 Median progression-free survival: Bevacizumab + IFN = 10.2 months Placebo + IFN = 5.4 months Probability of being progression-free 5.4 10.2 0 6 12 18 24 Time (months) Presentation Title l l 49

  47. RCC Treatment Alogrithm : 2007 * Regimen Setting Therapy Options HD IL-2 ? Sorafenib MSK Risk : Good or Intermediate Sunitinib ? Bevacizumab ± IFNα Treatment Naïve Patient MSK Risk : Poor Temsirolimus Sunitinib ?Sorafenib Cytokine Refractory Sorafenib Sunitinib Treatment Refractory Patient (≥ 2nd Line) Refractory to VEGF/VEGFR or mTOR Inhibitors ?Sequential TKI’s or VEGF Inhibitor ?Investigational Presentation Title l l 50 *Adapted from M Atkins, ASCO 2006

  48. EORTC/Intergroup Study 30987 T4bN0M0 or TxN2-3 or M1 TCC of Urothelium No prior Chemo RANDOMIZE Gemcitabine 1000 mg/m2 days 1, 8 & 15 Cisplatin 70 mg/m2 day 2 Arm 1 is given as a 4 week cycle (28 days) Þ Every 21 days if d15 is withheld or missed Paclitaxel 80mg/ m2 on days 1 and 8 Cisplatin 70 mg/m2 on day 1 Gemcitabine 1000 mg/m2 on days 1 and 8 Arm 2 is given as a 3 week cycle (21 days) Opened in May 2001. Closed in June 2004 Presentation Title l l 51

  49. Overall Survival Gem/Cis 247/315 12.8 mo 1 Pac/Cis/Gem 239/312 15.7 mo 0.86 (0.72-1.03) 0.10 14% improvement (n.s.) Presentation Title l l 52

  50. Sternberg et al (abst. 5019): Satraplatin vs. Prednisone • SPARC trial – Satraplatin, oral platinum compound • Regimen: (patients failed prior chemotherapy) • Satraplatin 80 mg/m2/day x 5 q 5 weeks + Prednisone • Placebo + Prednisone • 950 patients, 9/2004 – 1/2006 • Satraplatin wins? • PSA response: 25% vs. 12% • Pain response 24% vs. 14% • Progression-free survival p< 0.00000003 • Time to pain progression • OVERALL SURVIVAL??????? Presentation Title l l 53

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