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  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 Xeloda 1 250mg/m 2 twice daily, days 1–14, q21d (n=1 004) Bolus 5-FU/LV 5-FU 425mg/m 2 plus LV 20mg/m 2, days 1–5, q28d (n=983) Recruitment 1998– weeks

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

Primary endpoint clearly met: trend to superior DFS with Xeloda (ITT) Estimated probability Absolute difference at 3 years: 3.6% Test for superiority p= Xeloda (n=1 004) 5-FU/LV (n=983) Years HR=0.87 (95% CI: 0.75–1.00) Compared to HR upper limit 1.20, p< Twelves C et al. N Engl J Med 2005;352:2696–704 3-year DFS 64.2% 60.6%

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

Xeloda consistently better than 5-FU/LV in subgroup analysis for DFS Hazard ratio and 95% CI Xeloda betterBolus 5-FU/LV better ITT population Male Female <40 40–69 years old  70 N1 (1–3 nodes) N2 (  4 nodes) Baseline CEA <ULN Baseline CEA >ULN n Twelves C et al. N Engl J Med 2005;352:2696–704

What’s the difference between RFS and DFS? In patients with documented relapse RFS Relapse New colon cancer DFS Relapse New colon cancer In patients without relapse, death due to Colon cancer Treatment toxicity Colon cancer Treatment toxicity Other causes

Xeloda versus bolus 5-FU/LV: significantly superior RFS (ITT) Estimated probability Absolute difference at 3 years: 3.6% Years HR=0.86 (95% CI: 0.74–0.99) p= year Xeloda (n=1 004) 65.5% 5-FU/LV (n=983) 61.9% Cassidy J et al. J Clin Oncol 2004;22:247s (Abst 3509)

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

Xeloda showed trend to improved overall survival (ITT) Estimated probability Years Absolute difference at 3 years: 3.7% year Xeloda (n=1 004) 81.3% 5-FU/LV (n=983) 77.6% HR=0.84 (95% CI: 0.69–1.01) p= Twelves C et al. N Engl J Med 2005;352:2696–704

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

Xeloda versus 5-FU/LV: consistent benefit in all efficacy parameters Worse than 5-FU/LV Better than 5-FU/LV Upper margin for equivalence in DFS DFS Overall survival Upper margin for superiority Same as 5-FU/LV p= p= p= Twelves C et al. N Engl J Med 2005;352:2696–704 RFS Risk reduction (%)

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)

Xeloda has a favourable safety profile

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

 Grade 3 / 4 diarrhoea, stomatitis, nausea, vomiting, alopecia, hand-foot syndrome, neutropenia Estimated probability of a grade 3 / 4 adverse event Months 5-FU/LV Xeloda p<0.001 Fewer and later onset of key grade 3 / 4 adverse events with Xeloda versus 5-FU/LV Twelves C et al. N Engl J Med 2005;352:2696–704

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

Adjuvant Xeloda: improved safety profile versus bolus 5-FU / LV (grade 3 / 4) * * DiarrhoeaStomatitisHand-footNeutropenia † Nausea / Neutropenic syndromevomitingfever/sepsis Patients (%) * * *p<0.001 † Laboratory value Scheithauer W et al. Ann Oncol 2003;14:1735–43 Xeloda (n=993) Bolus 5-FU/LV (n=974)

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

Oral Xeloda enables active management Patients (%) Xeloda (n=995) Bolus 5-FU/LV (n=974) Completed full course of treatment 8488 Needed dose reduction4244 Needed interruption15 5 Needed delay4629 Needed dose reduction, interruption or delay5752 F. Hoffmann-La Roche, data on file

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

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

Xeloda has improved convenience: only nine ambulatory consultations vs 30 with 5-FU/LV Mean visits per patient Xeloda (n=995) 5-FU/LV (n=974) AE treatmentDrug administrationTotal McKendrick JJ et al. J Clin Oncol 2004;23:264s (Abst 3578; poster update)

Net costs per patient versus 5-FU/LV (£) Replacement of 5-FU/LV with Xeloda is net cost saving: travel costs Total TravelTravel time –2 000 –4 000 Cassidy J et al. Submitted

Fewer outpatient visits for chemotherapy administration with Xeloda versus 5-FU/LV Mean number per 100 patients Xeloda (n=995)5-FU/LV (n=974) Cassidy J et al. Submitted

Fewer hospitalisations for adverse events (AEs) with Xeloda versus 5-FU/LV Mean number per 100 patients AdmissionsTotal days Xeloda (n=995) 5-FU/LV (n=974) Cassidy J et al. Submitted

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

Net costs per patient versus 5-FU/LV (£) –1 000 –2 000 –3 000 –4 000 –5 000  €5 810 saved per patient Xeloda is a uniquely ‘dominant’ treatment in cancer chemotherapy: UK, Italy, USA DrugsAdministrationHospitalMedications Consultations use Total Cassidy J et al. Br J Cancer. In press

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

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

Xeloda-based combinations in the adjuvant treatment of colon cancer

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

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

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 XELOX 24 weeks Bolus 5-FU/LV Mayo Clinic or Roswell Park 24 or 32 weeks Chemotherapy-naive s tage III colon cancer n=1 886

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

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

Adjuvant evaluations of Xeloda combinations in colon cancer

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 treatment of colon cancer