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Lighting the way with XELOX (Xeloda plus oxaliplatin)

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  1. Lighting the way with XELOX (Xeloda plus oxaliplatin) Josep Tabernero Vall d’Hebron University HospitalBarcelona, Spain

  2. Xeloda + 3-weekly oxaliplatin: rigorous preclinical and clinical development program Preclinical:evidence of synergy1 Phase I:recommended regimen identified2 Phase II:highly effective and well tolerated first-line treatment for metastatic colorectal cancer (MCRC)1 Phase III: adjuvant and metastatic settings 1Cassidy J et al. J Clin Oncol 2004;22:2084–91 2Díaz-Rubio E et al. Ann Oncol 2002;13:558–65

  3. Supra-additive activity of XELOX in human colon cancer CXF280 xenografts Tumor volume (cm3) 10 5 1 0.5 0.1 Control Xeloda (2/3 MTD) Oxaliplatin (2/3 MTD) Combination (both 2/3 MTD) 1 11 21 31 41 51 Days after drug treatment *p<0.05 vs both single agentsMTD = maximum tolerated dose Cassidy J et al. J Clin Oncol 2004;22:2084–91

  4. 1 8 15 21 Day Oxaliplatin130mg/m2 (2-hour infusion) Xeloda1000mg/m2 twice daily Day 1 (pm)–15 (am) Rest Repeat cycle at day 22 XELOX international phase II trial:first-line in MCRC (n=96) Regimen recommended from phase I trial1 • Male/female (%) = 64 / 36; median age = 64 years2 • 28% prior (neo)adjuvant therapy 1Díaz-Rubio E et al. Ann Oncol 2002;13:558–65 2Cassidy J et al. J Clin Oncol 2004;22:2084–91

  5. First-line XELOX produces consistently high response rates across subgroups Patients (%) 80 60 40 20 0 61 60 60 56 55 55 55 54 53 50 Overall Liver Lung Yes No £80 >80 <60 ³60 Metastases (Neo)adjuvant KPS Age chemotherapy KPS = Karnofsky performance status Cassidy J et al. J Clin Oncol 2004;22:2084–91

  6. XELOX: median progression-freesurvival (PFS) of 7.7 months (n=96) Estimated probability 1.0 0.8 0.6 0.4 0.2 0.0 Median: 7.7 months(95% CI: 6.4–8.6) 0 2 4 6 8 10 12 14 16 18 20 22 Months Cassidy J et al. J Clin Oncol 2004;22:2084–91

  7. XELOX: median overall survival of 19.5 months (n=96) Estimated probability 1.0 0.8 0.6 0.4 0.2 0.0 19.5 months (95% CI: 15.3–21.6) 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 Months Cassidy J et al. J Clin Oncol 2004;22:2084–91

  8. XELOX: favorable safetyprofile compared with FOLFOX4 1Cassidy J et al. J Clin Oncol 2004;22:2084–912Goldberg R et al. J Clin Oncol 2004;22:23–303de Gramont A et al. J Clin Oncol 2000;18:2938–47

  9. Medical cost savings associated with XELOX versus FOLFOX Net costs per patient versus FOLFOX ($) 4000 2000 0 –2000 –4000 –6000 –2043 –2571 –4614 Total Savings Drug and Treatment of administration adverse events Chu E et al. Proc Am Soc Clin Oncol 2003;22:269 (Abst 1080)

  10. Large phase II–III trial program of Xeloda + oxaliplatin in MCRC ORR = overall response rateTTP = time to progression

  11. Ongoing phase III trial: XELOX ± Avastin versus FOLFOX4 ± Avastin (XELOX1*) • 2x2 factorial, randomized phase III trial Avastin 5mg/kg every 2 weeks (n=330) PD FOLFOX4 (n=300) Previously untreated patients with MCRC(n=1920) Placebo (n=330) PD Avastin 7.5mg/kg every 3 weeks (n=330) PD XELOX (n=300) Placebo (n=330) PD • Primary objectives • at least equivalent TTP with XELOX (± Avastin) versus FOLFOX4 (± Avastin) • superior TTP with Avastin + XELOX/FOLFOX versus XELOX/FOLFOX PD = disease progression *Roche registration study

  12. Randomized TREE study comparing Xeloda and 5-FU/LV + oxaliplatin (n=223) (n=150) TREE1 TREE2: + Avastin (B) RAN D O M I Z A T I O N FOLFOX(infusional 5-FU/LV + oxaliplatin) FOLFOX-B bFOL(bolus 5-FU/LV + oxaliplatin) Stage IV disease First line bFOL-B XELOX XELOX-B • Equivalent safety profile • Equivalent activity • Avastin significantly improved ORR Hoechster HS et al. Proc ASCO GI 2005 (Abst 241)

  13. First-line XELOX versus infused 5-FU + oxaliplatin: Spanish phase III trial • 1º objective • TTP XELOX Xeloda 1000mg/m2 day 1 (pm)–15 (am) Oxaliplatin 130mg/m2, day 1 First-line MCRCn=348 5-FU (TTD) + oxaliplatin 48-hour 5-FU 2250mg/m2, weekly + oxaliplatin 85mg/m2, every 2 weeks Aranda E et al. Ann Oncol 2004;15(Suppl. 3):iii82 (Abst 307P)

  14. Favorable safety of XELOX in Spanish phase III trial: grade 3 / 4 adverse events (n=286) Patients (%) XELOX 48-hour 5-FU (TTD) days 1 and 8 + oxaliplatin 85mg/m2day 14, q14d 40 30 20 10 0 Nausea Anemia Diarrhea Asthenia Vomiting Anorexia Neutropenia Paresthesiae Aranda E et al. Ann Oncol 2004;15(Suppl. 3):iii82 (Abst 307P)

  15. Trials investigating other regimens combining Xeloda with oxaliplatin

  16. Standard XELOX versus dose intense Xeloda/oxaliplatin: randomized phase II • 1º objective • PFS • No prospective efficacy comparison Standard XELOX Xeloda 1000mg/m2 days 1–14 Oxaliplatin 130mg/m2, day 1, every 21 days First-line MCRCn=89 Dose-intense (DI) Xeloda + oxaliplatin Xeloda 1750mg/m2 days 1–7, 14–21 Oxaliplatin 85mg/m2, days 1, 14 every 28 days Scheithauer W et al. J Clin Oncol 2003;21:1307–12

  17. First-line CAPOX versus infused FUFOX:German phase III trial • 1º objective • PFS CAPOX Xeloda 1000mg/m2 days 1 (pm)–15 (am) Oxaliplatin 70mg/m2, days 1, 8 1st-line MCRCn=476 FUFOXOxaliplatin 50mg/m2 + LV 500mg/m25-FU 2000mg/m2 (24-hour), days 1, 8, 15, 22 every 6 weeks

  18. Favorable safety of CAPOX versus FUFOX: treatment-related grade 3/4 adverse events Patients (%) 40 30 20 10 0 CAPOX FUFOX Pain Nausea Diarrhea Infection Vomiting Hand-foot syndrome Stomatitis Neuropathy Arkenau HT et al. Proc 2005 GI Cancers Symposium 2005;197 (Abst 226)

  19. XELOX: favorable safety profile compared with 5-FU-based combinations • Safety profile of Xeloda + oxaliplatin compares favourably with 5-FU/LV + oxaliplatin • in cross-trial1–3 and direct comparison4,5 • Xeloda-based versus 5-FU/LV-based regimens associated with • similar incidence of diarrhea, nausea/vomiting, sensory neuropathy • higher incidence of hand-foot syndrome • particularly low incidence of neutropenia compared with 5-FU/LV-based regimens 1Cassidy J et al. J Clin Oncol 2004;22:2084–91; 2Goldberg R et al. J Clin Oncol 2004;22:23–30 3de Gramont A et al. J Clin Oncol 2000;18:2938–47; 4Aranda E et al. Ann Oncol 2004;15(Suppl. 3):iii82 (Abst 307P) 5Arkenau HT et al. Proc 2005 GI Cancers Symposium 2005;197 (Abst 226)

  20. XELOX: favorable safety profile compared with 5-FU-based combinations 1Cassidy J et al. J Clin Oncol 2004;22:2084–91; 2Goldberg R et al. J Clin Oncol 2004;22:1–8 3de Gramont A et al. J Clin Oncol 2000;18:2938–47; 4Aranda E et al. Ann Oncol 2004;15(Suppl. 3):iii82 (Abst 307P) 5Arkenau HT et al. Proc 2005 GI Cancers Symposium 2005;197 (Abst 226)

  21. Favorable response rates with Xeloda/oxaliplatin versus 5-FU/LV/oxaliplatin Response (%) 60 50 40 30 20 10 0 XELOX (n=96)1 XELOX (n=45)2 DI XELOX (n=44)2 FOLFOX (n=267)3 FOLFOX (n=210)4 XELOX (n=39)5 FOLFOX (n=45)5 CAPOX (n=142)6 FUFOX (n=133)6 1Cassidy J et al. J Clin Oncol 2004;22:2084–91; 2Scheithauer W et al. J Clin Oncol 2003;21:1307–12 3Goldberg R et al. J Clin Oncol 2004;22:23–30; 4de Gramont A et al. J Clin Oncol 2000;18:2938–47 5Hochster HS et al. Proc 2005 GI Cancers Symposium 2005;204 (Abst 241) 6Arkenau HT et al. Proc 2005 GI Cancers Symposium 2005;197 (Abst 226)

  22. Xeloda is an effective, well tolerated combination partner for oxaliplatin • Xeloda plus oxaliplatin is at least as effective and well tolerated compared with 5-FU/LV plus oxaliplatin • Xeloda plus oxaliplatin is a convenient schedule because it avoids the use of central venous devices and pumps • Ongoing phase III trials have been designed to establish that Xeloda is the combination partner of choice for oxaliplatin • Combination of XELOX with biological agents should further improve outcomes