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Xeloda for the adjuvant treatment of stage III colon cancer

Xeloda for the adjuvant treatment of stage III colon cancer. Chris Twelves University of Leeds and Bradford NHS Trust UK. X-ACT trial in adjuvant treatment of stage III colon cancer. Xeloda 1 250mg/m 2 twice daily, days 1 – 14, q21d (n=1 004). Recruitment 1998–2001. Chemonaïve

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Xeloda for the adjuvant treatment of stage III colon cancer

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  1. Xeloda for the adjuvant treatment of stage III colon cancer Chris Twelves University of Leeds and Bradford NHS TrustUK

  2. X-ACT trial in adjuvant treatment of stage III colon cancer Xeloda 1250mg/m2 twice daily, days 1–14, q21d (n=1 004) Recruitment 1998–2001 Chemonaïve Stage III, resection £8 weeks 24 weeks Bolus 5-FU/LV 5-FU 425mg/m2 plus LV 20mg/m2, days 1–5, q28d (n=983) • 1° endpoint: disease-free survival (DFS) • 2° endpoints: relapse-free survival (RFS); overall survival; tolerability (NCIC CTG); pharmacoeconomics; quality of life

  3. X-ACT powered to establish at least equivalence of Xeloda to 5-FU/LV • Primary endpoint DFS • timing of analysis driven by number of events • 80% power for at least equivalence • if upper limit of 95% CI for HR <1.25, then primary endpoint met • Secondary analyses • tests for superiority • DFS, RFS, overall survival • multivariate, subgroup • All analyses shown were prospectively planned Twelves C et al. N Engl J Med 2005;352:2696–704

  4. Xeloda (n=1004) 5-FU/LV (n=983) Absolute difference at 3 years: 3.6% Primary endpoint clearly met: trend to superior DFS with Xeloda (ITT) Estimated probability 3-year DFS 64.2% 60.6% 1.0 0.8 0.6 0.4 HR=0.87 (95% CI: 0.75–1.00) Compared to HR upper limit 1.20, p<0.0001 Test for superiorityp=0.0528 0 1 2 3 4 5 6 Years Twelves C et al. N Engl J Med 2005;352:2696–704

  5. Xeloda reduces risk of relapse versus bolus 5-FU/LV (DFS) Decreased risk Increased risk 0.4 0.6 0.8 1.0 1.2 1.4 1.6 Hazard ratio and 95% CI 13% absolute risk reduction HR=0.87 (95% CI: 0.75–1.00) p=0.0528 Twelves C et al. N Engl J Med 2005;352:2696–704

  6. n ITT population Male Female <40 40–69 years old ³70 N1 (1–3 nodes) N2 (³4 nodes) Baseline CEA <ULN Baseline CEA >ULN 1987 1073 914 76 1514 397 1391 596 1669 159 Xeloda consistently better than 5-FU/LV in subgroup analysis for DFS Xeloda better Bolus 5-FU/LV better 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 Hazard ratio and 95% CI Twelves C et al. N Engl J Med 2005;352:2696–704

  7. What’s the difference between RFS and DFS?

  8. Absolute difference at 3 years: 3.6% Xeloda versus bolus 5-FU/LV: significantly superior RFS (ITT) Estimated probability 3-year Xeloda (n=1004) 65.5% 5-FU/LV (n=983) 61.9% 1.0 0.8 0.6 0.4 HR=0.86 (95% CI: 0.74–0.99)p=0.0407 0 1 2 3 4 5 6 Years Cassidy J et al. J Clin Oncol 2004;22:247s (Abst 3509)

  9. Xeloda reduces risk of relapse versus bolus 5-FU/LV (RFS) Decreased risk Increased risk 0.4 0.6 0.8 1.0 1.2 1.4 1.6 Hazard ratio and 95% CI 14% absolute risk reduction HR=0.86 (95% CI: 0.74–0.99) p=0.0407 Twelves C et al. N Engl J Med 2005;352:2696–704

  10. Absolute difference at 3 years: 3.7% Xeloda showed trend to improved overall survival (ITT) Estimated probability 3-year Xeloda (n=1004) 81.3% 5-FU/LV (n=983) 77.6% 1.0 0.8 0.6 0.4 HR=0.84 (95% CI: 0.69–1.01)p=0.0706 0 1 2 3 4 5 6 Years Twelves C et al. N Engl J Med 2005;352:2696–704

  11. Xeloda reduces risk of death versus bolus 5-FU/LV (overall survival) Decreased risk Increased risk 0.4 0.6 0.8 1.0 1.2 1.4 1.6 Hazard ratio and 95% CI 16% absolute risk reduction HR=0.84 (95% CI: 0.69–1.01) p=0.0706 Twelves C et al. N Engl J Med 2005;352:2696–704

  12. Xeloda versus 5-FU/LV: consistent benefit in all efficacy parameters Betterthan5-FU/LV Same as5-FU/LV Worsethan5-FU/LV Riskreduction(%) DFS 13 p=0.0528 RFS 14 p=0.0407 Overall survival 16 p=0.0706 0.6 0.8 1.0 1.2 1.4 1.6 Upper margin forsuperiority Upper margin for equivalence in DFS Twelves C et al. N Engl J Med 2005;352:2696–704

  13. Treatment with Xeloda significantly improved DFS, RFS and OS • Consistent 20% reduction in risk with Xeloda Cassidy J et al. J Clin Oncol 2004;22:247s (Abst 3509)

  14. Xeloda has a favourable safety profile

  15. Adjuvant Xeloda has improved safety versus bolus 5-FU/LV • Significantly less • diarrhoea, nausea/vomiting, stomatitis, alopecia • grade 3/4 neutropenia and neutropenic fever/sepsis • early severe toxicity • Improved safety profile maintained in older patients • Hand-foot syndrome more common, but manageable Scheithauer W et al. Ann Oncol 2003;14:1735–43

  16. Fewer and later onset of key grade 3/4 adverse events with Xeloda versus 5-FU/LV Estimated probability of agrade 3/4 adverse event 5-FU/LV Xeloda 1.0 0.8 0.6 0.4 0.2 0.0 p<0.001 0 1 2 3 4 5 6 7 8 Months • Grade 3/4 diarrhoea, stomatitis, nausea, vomiting, alopecia, hand-foot syndrome, neutropenia Twelves C et al. N Engl J Med 2005;352:2696–704

  17. Adjuvant Xeloda: improved safety profile versus bolus 5-FU/LV (all grades) Patients (%) Treatment-related AEs 100 80 60 40 20 0 Xeloda (n=993) Bolus 5-FU/LV (n=974) * * * * * * Diarrhoea Stomatitis Hand-foot Neutropenia† Nausea/ Alopecia syndrome vomiting *p<0.001 †Laboratory value Scheithauer W et al. Ann Oncol 2003;14:1735–43

  18. Adjuvant Xeloda: improved safety profile versus bolus 5-FU/LV (grade 3/4) Patients (%) 80 70 60 50 40 30 20 10 0 Xeloda (n=993) Bolus 5-FU/LV (n=974) * * * * Diarrhoea Stomatitis Hand-foot Neutropenia† Nausea/ Neutropenic syndrome vomiting fever/sepsis *p<0.001 †Laboratory value Scheithauer W et al. Ann Oncol 2003;14:1735–43

  19. Improved safety profile of Xeloda maintained in older patients (>70 years) *Grade 3/4 laboratory abnormalities (NCI CTCAE) Díaz-Rubio E et al. J Clin Onco 2004;22:303s (Abst 3737)

  20. Oral Xeloda enables active management F. Hoffmann-La Roche, data on file

  21. Xeloda dose modification reduces the recurrence of AEs Cycles (%) 20 Grade 2 Grade 3 Grade 4 15 10 5 0 Before After Before After Before After Hand-foot syndrome Diarrhoea Stomatitis Cassidy J et al. J Clin Oncol 2004;22:247s (Abst 3509)

  22. Xeloda is more convenient and cost saving compared with 5-FU/LV

  23. Xeloda (n=995) 5-FU/LV (n=974) Xeloda has improved convenience: only nine ambulatory consultations vs 30 with 5-FU/LV Mean visitsper patient 30 20 10 0 AE treatment Drug administration Total McKendrick JJ et al. J Clin Oncol 2004;23:264s (Abst 3578; poster update)

  24. Replacement of 5-FU/LV with Xeloda is net cost saving: travel costs Net costs per patient versus 5-FU/LV (£) 4000 2000 0 –2000 –4000 TotalTravel Travel time Cassidy J et al. Submitted

  25. Fewer outpatient visits for chemotherapy administration with Xeloda versus 5-FU/LV Mean number per 100 patients 3000 2500 2000 1500 1000 500 0 2800 735 Xeloda (n=995) 5-FU/LV (n=974) Cassidy J et al. Submitted

  26. Fewer hospitalisations for adverse events (AEs) with Xeloda versus 5-FU/LV Mean number per 100 patients Xeloda (n=995) 5-FU/LV (n=974) 150 125 100 75 50 25 0 Admissions Total days Cassidy J et al. Submitted

  27. Xeloda requires fewer costly medications for management of AEs Cassidy J et al. Submitted

  28. Xeloda is a uniquely ‘dominant’ treatmentin cancer chemotherapy: UK, Italy, USA Net costs per patient versus 5-FU/LV (£) 4000 3000 2000 1000 0 –1000 –2000 –3000 –4000 –5000 • €5810 saved per patient -3565 Drugs Administration Hospital Medications Consultations use Total Cassidy J et al. Br J Cancer. In press

  29. Xeloda as a dominant treatment strategy confirmed in Italian study Di Costanzo F et al. Eur J Cancer Suppl 2005;3:191 (Abst 675)

  30. Xeloda versus Mayo Clinic regimenin adjuvant treatment Benefits • At least equivalent efficacy • Trend to improved DFS and OS • Improved RFS •  toxicity • Convenience • Cost savings Risks •  hand-foot syndrome (manageable)

  31. Xeloda-based combinations in the adjuvant treatment of colon cancer

  32. 1 MOSAIC 0.77 0.91 (0.65 – 0.90) <0.001 (0.75 – 1.11) NR 2 NSABP C - 07 0.79 (0.67 – 0.93) <0.004 NR NR 3 CALGB89803 NR 0.84 NR NR 4 PETACC - 3 0.89 (0.77 – 1.11) 0.091 NR NR 3Saltz LB et al. J Clin Oncol 2004;22:245S (Abst 3500); 4Van Cutsem E et al.J Clin Oncol 2005;23:3s (Abst LBA8) Combinations in adjuvant chemotherapy: recent evidence DFS OS h azard ratio h azard ratio Oxaliplatin combinations (95% CI) p value (95% CI) p value Irinotecan combinations NR = not reported 1de Gramont A et al. J Clin Oncol 2005;23:246s (Abst 3501); 2Wolmark N et al. J Clin Oncol 2005;23:246s (Abst LBA3500)

  33. Xeloda: a replacement for 5-FU/LV in adjuvant treatment • Based on the X-ACT data, Xeloda is replacing 5-FU/LV for the adjuvant treatment of colon cancer • XELOX can optimise oxaliplatin-containing combinations • similar high efficacy and favourable safety profile compared with FOLFOX in metastatic CRC • improved convenience • simplifies increasingly complex combinations with biologics in ongoing trials

  34. XELOXA: adjuvant Xeloda + oxaliplatin (XELOX) versus 5-FU/LV • 1º endpoint: DFS – XELOX >5-FU/LV • 2º endpoints: survival; tolerability; convenience; pharmacoeconomics • Completed recruitment September 2004 XELOX24 weeks Chemotherapy-naive stage III colon cancer n=1 886 Bolus 5-FU/LV Mayo Clinicor Roswell Park 24 or 32 weeks

  35. XELOX is an ideal combination in the adjuvant setting 1 XELOXA Grade 3/4 toxicities XELOX 5 - FU/LV Diarrhoea 19 20 Stomatit i s <1 8 Nausea 5 4 Vomiting 6 3 Neurosensory 11 0 HFS 5 <1 Neutropenia 8 15 Febrile <1 4 neutropenia 1Schmoll H-J et al. Eur J Cancer Suppl 2005;3:173 (Abst 617)

  36. XELOX 19 <1 5 6 11 5 8 <1 XELOX is an ideal combination in the adjuvant setting 1 2 3 XELOXA MOSAIC NSABP C - 07 Grade 3/4 toxicities 5 - FU/LV FOLFOX FLOX Diarrhoea 20 12 36 Stomatit i s 8 3 NR Nausea 4 5 15 Vomiting 3 6 12 Neurosensory 0 12 8 HFS <1 2 NR Neutropenia 15 41 5 Febrile 4 2 NR neutropenia 1Schmoll H-J et al. Eur J Cancer Suppl 2005;3:173 (Abst 617) 2André T et al. N Engl J Med 2004;350:2343–51 3Smith R et al. Proc Am Soc Clin Oncol 2003;22:294 (Abst 1181; poster update)

  37. Adjuvant evaluations of Xeloda combinations in colon cancer

  38. Xeloda: the evidence • At least as effective as 5-FU/LV for stage III colon cancer • superior RFS, trend to superior DFS and OS • Fewer grade 3/4 toxicities than 5-FU/LV • Dosing flexibility improves side-effect management • Convenience of oral administration allows patients to lead a more normal lifestyle • Cost effective • Effective, safe and convenient combination partner, simplifying combination treatment • The fluoropyrimidine of choice in the adjuvant treatmentof colon cancer

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