1. Xeloda ® plus oxaliplatin: rationale in colorectal cancer (CRC)  Oxaliplatin is active in CRC, especially when combined with 5-FU/leucovorin (LV)  Superior response rate and time to disease progression observed with the addition of oxaliplatin to 5-FU/leucovorin  Synergistic activity of fluoropyrimidines and oxaliplatin can partly overcome clinical resistance to fluoropyrimidines  No overlap in key toxicities

2. Xeloda ® plus oxaliplatin phase I study: DLTs by dose level *The first six patients were enrolled for determination of the maximum tolerated dose (MTD) and a total of eight patients were treated at this dose level DLT = dose-limiting toxicity Evans J et al. Ann Oncol 2000;11(Suppl. 4):51 (Abst 222)

3. Xeloda ® plus oxaliplatin phase I study: most common treatment-related, clinical adverse events (all cycles) Patients (%) Nausea Paraesthesia VomitingDysaesthesiaDiarrhoeaAsthenia Evans J et al. Ann Oncol 2000;11(Suppl. 4):51 (Abst 222)

4. Xeloda ® plus oxaliplatin phase I study: efficacy in CRC patients (n=9) Evans J et al. Ann Oncol 2000;11(Suppl. 4):51 (Abst 222)

5. Xeloda ® plus oxaliplatin phase I study: summary  Xeloda/oxaliplatin combination therapy is feasible and exhibited promising antitumour activity in patients with CRC  The MTD is Xeloda 1,250mg/m 2 twice daily (days 1–14) with i.v. oxaliplatin 130mg/m 2 (day 1), every 21 days  The recommended dosing schedule is oral Xeloda 1,000mg/m 2 twice daily (days 1–14) with i.v. oxaliplatin 130mg/m 2 (day 1), every 21 days  Xeloda/oxaliplatin combination therapy is being evaluated as first-line CRC therapy in phase II studies Evans J et al. Ann Oncol 2000;11(Suppl. 4):51 (Abst 222)

6. Xeloda ® plus irinotecan: rationale in CRC  Single-agent antitumour efficacy of Xeloda and irinotecan as first-line chemotherapy  Superior response rate, time to disease progression and survival observed with the addition of irinotecan to 5-FU/LV  Efficacy of irinotecan in 5-FU-resistant patients  Different mechanisms of action  Partial overlap of key toxicities  In preclinical studies, Xeloda plus irinotecan demonstrated at least additive efficacy

7. Xeloda ® plus irinotecan phase I study: treatment schedule 181522293649 Irinotecan 70/80/90mg/m 2 as a 30-minute i.v. infusion Oral Xeloda 1,000/1,250mg/m 2 twice daily Repeat cycle at day 50 Days 1–14RestDays 22–35Rest Tewes M et al. Proc Am Assoc Cancer Res 2001;42 (Abst 3752) Day

8. Xeloda ® plus irinotecan phase I study: DLTs by dose level Tewes M et al. Proc Am Assoc Cancer Res 2001;42 (Abst 3752)

9. Xeloda ® plus irinotecan phase I study: preliminary antitumour activity  Among 19 evaluable patients –tumour responses (CR/PR) occurred in 42% of patients (95% CI: 20–67) –disease was stabilised in an additional 53% of patients (95% CI: 30–76) Tewes M et al. Proc Am Assoc Cancer Res 2001;42 (Abst 3752)

10. Xeloda ® plus irinotecan phase I study: conclusions  The predominant DLTs were diarrhoea and neutropenia  The MTD was identified as irinotecan 80mg/m 2 with Xeloda 1,250mg/m 2  DLTs occurred in five of 15 evaluable patients (33%) treated with irinotecan 70mg/m 2 plus Xeloda 1,250mg/m 2 twice daily  Dose level 1 (irinotecan 70mg/m 2 plus Xeloda 1,000mg/m 2 twice daily) is currently being evaluated in an extension of the trial  Based on preliminary data, the combination of Xeloda and irinotecan has significant antitumour activity Tewes M et al. Proc Am Assoc Cancer Res 2001;42 (Abst 3752)

11. Xeloda ® plus radiotherapy: rationale in rectal cancer  Xeloda mimics continuous infusion 5-FU which as a partner for radiotherapy prolongs survival compared with bolus 5-FU 1  Radiotherapy upregulates thymidine phosphorylase in tumour cells but not in healthy tissue 2  Xeloda/radiotherapy treatment demonstrated highly enhanced activity compared with either treatment alone, whereas radiotherapy plus 5-FU showed no clear additive effects 2 1 O’Connell MJ et al. N Engl J Med 1994;331:502–7 2 Sawada N et al. Clin Cancer Res 1999;5:2948–53

12. Xeloda ® plus radiotherapy phase I study: dosing schedule  Radiotherapy –1.8 Gray/day –5 days/week up to 50.4 Gray plus boost S2–S5 5.4 Gray  Oral Xeloda –first day until last day of radiotherapy –dose levels: 250, 375, 500, 650, 825 and 1,000 mg/m 2 twice daily Reese T et al. Int J Radiat Oncol Biol Phys 2000;48(3 Suppl.):120 (Abst 20)

13. Xeloda ® plus radiotherapy phase I study: DLTs by dose level *Developing on days 22 and 30 of treatment, respectively Reese T et al. Int J Radiat Oncol Biol Phys 2000;48(3 Suppl.):120 (Abst 20)

14. Xeloda ® plus radiotherapy phase I study: incidence of adverse events (all grades) by dose level These adverse events were all grade 1/2, except one case of grade 3 local skin toxicity (650mg/m 2 dose level) and one case of grade 3 diarrhoea (1,000mg/m 2 dose level) LeucopeniaLocal skin toxicityDiarrhoea 100 80 60 40 20 0 250mg/m 2 375mg/m 2 500mg/m 2 650mg/m 2 825mg/m 2 1,000mg/m 2 Incidence (% of cohort) Reese T et al. Int J Radiat Oncol Biol Phys 2000;48(3 Suppl.):120 (Abst 20)

15. Xeloda ® plus radiotherapy phase I study: incidence of adverse events (all grades) by dose level (cont’d) All episodes of these three adverse events were grade 1/2 NauseaConstipationAbdominal pain 100 80 60 40 20 0 Incidence (% of cohort) 250mg/m 2 375mg/m 2 500mg/m 2 650mg/m 2 825mg/m 2 1,000mg/m 2 Reese T et al. Int J Radiat Oncol Biol Phys 2000;48(3 Suppl.):120 (Abst 20)

16. Xeloda ® plus radiotherapy phase I study: summary of safety  The majority of adverse events were mild to moderate  Grade 1/2 leucopenia was the most common toxicity  There was no significant decrease in haemoglobin concentrations  Hand-foot syndrome was dose-limiting at Xeloda 1,000mg/m 2  The only other grade 3 adverse events were rash/itch (375mg/m 2 ), local skin toxicity (650mg/m 2 ) and diarrhoea* (1,000mg/m 2 ) (one patient each)  There were no grade 4 toxicities *which resolved to grade 1/2 within 2 days Reese T et al. Int J Radiat Oncol Biol Phys 2000;48(3 Suppl.):120 (Abst 20)

17. Xeloda ® plus radiotherapy phase I study: efficacy  Ten patients were treated in the neo-adjuvant setting with three patients too early for evaluation  Preliminary data from seven patients indicate that –tumours were down-staged in six patients –there was one pathologically confirmed complete response Reese T et al. Int J Radiat Oncol Biol Phys 2000;48(3 Suppl.):120 (Abst 20)

18. Xeloda ® plus radiotherapy phase I study: conclusions  MTD is Xeloda 1,000mg/m 2 twice daily in combination with radiotherapy  The recommended dose for further phase II evaluation is Xeloda 825mg/m 2 twice daily in combination with radiotherapy  Xeloda simplified chemoradiotherapy and was highly appealing to the patients  In combination with radiotherapy, Xeloda offers the potential to replace bolus or continuous infusion 5-FU as the standard treatment for rectal cancer Reese T et al. Int J Radiat Oncol Biol Phys 2000;48(3 Suppl.):120 (Abst 20)