The X-ACT trial: a breakthrough for the adjuvant treatment of colon cancer

1. The X-ACT trial: a breakthrough for the adjuvant treatment of colon cancer Jean-Yves Douillard Centre René Gauducheau/CHU LaennecNantes, France

2. X-ACT trial in adjuvant treatment of stage III colon cancer Xeloda 1250mg/m2 twice daily, days 1–14, q21d (n=1004) Recruitment 1998–2001 • 1° endpoint: disease-free survival (DFS) • 2° endpoints • relapse-free survival (RFS) • overall survival • tolerability (NCIC CTG) • pharmacoeconomics • quality of life 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)

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 hazard ratio (HR) <1.20 then primary endpoint met • analysis in per-protocol and ITT populations • Secondary analyses • tests for superiority • DFS, RFS, overall survival • multivariate and subgroup analyses • All analyses shown were prospectively planned Cassidy J et al. J Clin Oncol Proc ASCO Late-breaking Abstract Book 2004;23:14 (Abst 3509)

4. X-ACT treatment arms were balanced Cassidy J et al. J Clin Oncol Proc ASCO Late-breaking Abstract Book 2004;23:14 (Abst 3509)

5. Other prognostic factors were balanced Cassidy J et al. J Clin Oncol Proc ASCO Late-breaking Abstract Book 2004;23:14 (Abst 3509)

6. DFS: primary endpoint clearly met (ITT) Estimated probability Xeloda (n=1004) 5-FU/LV (n=983) 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 0 1 2 3 4 5 6 Years Cassidy J et al. J Clin Oncol Proc ASCO Late-breaking Abstract Book 2004;23:14 (Abst 3509)

7. Absolute difference at 3 years: 3.6% Trend to superior DFS with Xeloda (ITT) Estimated probability 3-year DFS Xeloda (n=1004) 64.2% 5-FU/LV (n=983) 60.6% 1.0 0.8 0.6 0.4 p=0.0528 0 1 2 3 4 5 6 Years Cassidy J et al. J Clin Oncol Proc ASCO Late-breaking Abstract Book 2004;23:14 (Abst 3509)

8. Xeloda showed trend to improved overall survival (ITT) Estimated probability Xeloda (n=1004) 5-FU/LV (n=983) 3-year 81.3% 77.6% 1.0 0.8 0.6 0.4 Absolute difference at 3 years: 3.7% p=0.0706 0 1 2 3 4 5 6 Years Cassidy J et al. J Clin Oncol Proc ASCO Late-breaking Abstract Book 2004;23:14 (Abst 3509)

9. Xeloda versus 5-FU/LV: consistent benefit in all efficacy parameters Betterthan5-FU/LV Same as5-FU/LV Worsethan5-FU/LV Primary endpoint DFS p=0.0528 Secondary endpoints RFS Overall survival p=0.0407 p=0.0706 0.6 0.8 1.0 1.2 1.4 1.6 Upper margin forsuperiority Upper margin for equivalence in DFS Cassidy J et al. J Clin Oncol Proc ASCO Late-breaking Abstract Book 2004;23:14 (Abst 3509)

10. Multivariate analysis shows Xeloda significantly improved DFS, RFS and overall survival • Factors considered: age, gender, lymph nodes, time from surgery to randomization, baseline CEA, country • Consistent 20% reduction in risk with Xeloda Cassidy J et al. J Clin Oncol Proc ASCO Late-breaking Abstract Book 2004;23:14 (Abst 3509)

11. Xeloda consistently better than 5-FU/LV in subgroup analysis for DFS Xeloda better Bolus 5-FU/LV better 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 1074 912 76 1543 396 1389 593 1672 155 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 Cassidy J et al. J Clin Oncol Proc ASCOLate-breaking Abstract Book 2004;23:14 (Abst 3509) Hazard ratio and 95% CI

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

13. 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 diarrhea, stomatitis, nausea, vomiting, alopecia, hand-foot syndrome, neutropenia McKendrick J et al. Ann Oncol 2004;15(Suppl. 3):iii73 (Abstract 276PD)

14. Adjuvant Xeloda improves safety versus bolus 5-FU/LV • Significantly less: • diarrhea, nausea/vomiting, stomatitis, alopecia • grade 3/4 neutropenia and neutropenic fever/sepsis • early severe toxicity • Later onset of grade 3/4 toxicities • Improved safety profile maintained in older patients • Hand-foot syndrome higher incidence, but manageable Scheithauer W et al. Ann Oncol 2003;14:1735–43

15. Adjuvant chemotherapy needs active management Cassidy J et al. J Clin Oncol Proc ASCO Late-breaking Abstract Book 2004;23:14 (Abst 3509)

16. = visit to hospital/clinic for i.v. administration = administration of oral tablet at home; point at which dose modification can occur Xeloda: 28 opportunities for modifying dose per cycle Dose modification = interrupt, delay or reduce 5-FU/LV 425/20mg/m2(i.v. bolus) Day 1 8 15 21 28 Repeat cycle at day 28 Xeloda1250mg/m2 twice daily(oral) Days 1–14 Rest am Repeat cycle at day 21 pm

17. Xeloda dose modification reduces the recurrence of adverse events Cycles (%) 20 Grade 2 Grade 3 Grade 4 15 10 5 0 Before After Before After Before After Hand-foot syndrome Diarrhea Stomatitis F. Hoffmann-La Roche, data on file

18. Xeloda efficacy maintained with appropriate dose reduction: DFS Estimated probability 1.0 0.8 0.6 0.4 0.2 0.0 Xeloda dose intensity >90% (n=532) 60–90% (n=343) 0 12 24 36 48 60 72 Months F. Hoffmann-La Roche, data on file

19. Summary: Xeloda at least as effective as 5-FU/LV in adjuvant setting • X-ACT trial showed that adjuvant Xeloda is at least as effective as 5-FU/LV • strong trend toward superior DFS • Fewer serious grade 3/4 toxicities and later onset of serious toxicity • More convenient and flexible than 5-FU/LV • Xeloda should replace 5-FU/LV in adjuvant treatment of colorectal cancer