1. Taxane-pretreated metastatic breast cancer (MBC): investigational agents TTP = median time to disease progression OS = median overall survival

2. Phase II trials of Xeloda ® monotherapy in MBC  Xeloda in patients pretreated with paclitaxel (n=163)  Xeloda in patients pretreated with paclitaxel or docetaxel (n=75 and n=100)  Xeloda versus paclitaxel in patients pretreated with anthracyclines (n=42)  Xeloda versus CMF as first-line treatment in women  55 years (n=95)

3. Phase II trial in paclitaxel-pretreated MBC  Large, multicentre, phase II trial (n=163*)  All patients were heavily pretreated –100% had received prior paclitaxel –91% had received prior anthracyclines –82% had received prior 5-FU –mean number of agents per patient = 4.7  Xeloda 1,250mg/m 2 twice daily for 14 days, followed by a 7-day rest period Blum JL et al. J Clin Oncol 1999;17:485–93 *One patient withdrew prior to receiving treatment

4. Efficacy: phase II trial in paclitaxel-pretreated MBC Blum JL et al. J Clin Oncol 1999;17:485–93  20% objective tumour response –29% tumour response in 42 patients refractory to both paclitaxel and anthracyclines  43% stable disease  Median duration of response = 7.9 months  Median time to disease progression* = 3.0 months  Median survival = 12.6 months *or death

5. Clinical Benefit Response: mean pain for pain responders over time 40 35 30 25 20 15 10 5 0 024681012141618202224 Pain score (mm) Time (weeks) Blum JL et al. J Clin Oncol 1999;17:485–93 47% of the 51 patients with considerable pain at baseline experienced a durable 50% reduction in pain intensity

6. Survival: phase II trial in paclitaxel-pretreated MBC 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0246810121416 Estimated probability 12.6 Time (months) Blum JL et al. J Clin Oncol 1999;17:485–93

7. Survival: phase II trial in paclitaxel-pretreated MBC (cont’d) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0246810121416 Responder Stable disease Progressive disease Time (months) Estimated probability Blum JL et al. J Clin Oncol 1999;17:485–93

8. Safety: phase II trial in paclitaxel-pretreated MBC  Most frequent grade 3/4 treatment-related adverse events were diarrhoea and hand-foot syndrome  Only 4% experienced grade 4 adverse events  Myelosuppression and alopecia were rare  No treatment-related deaths Blum JL et al. J Clin Oncol 1999;17:485–93

9. Impact of Xeloda ® dose modification on efficacy  The Xeloda dose modification scheme (treatment interruption or dose reduction) was implemented in the event of grade 2–4 side effects  A Cox regression analysis confirmed that the risk of disease progression* was not significantly increased in patients requiring Xeloda dose reduction for side effects compared with patients who received the standard dose –hazard ratio = 1.07 (Wald test p=0.73) *or death

10. Summary of phase II trial in paclitaxel-pretreated MBC  Xeloda is an effective agent for paclitaxel- pretreated MBC  20% of patients had an objective response; an additional 43% had stable disease  Median survival was 12.6 months  Toxicities were manageable with dose interruption or, where necessary, dose adjustment without compromising efficacy Blum JL et al. J Clin Oncol 1999;17:485–93

11. Phase II trial of Xeloda ® in taxane-pretreated MBC  Multicentre, phase II, confirmatory, US trial  75* MBC patients  Xeloda 1,250mg/m 2 twice daily for 14 days followed by a 7-day rest period  All patients had received two to three prior chemotherapy regimens and were pretreated with paclitaxel or docetaxel *One patient withdrew prior to receiving treatment Blum JL et al. (submitted)

12. Ongoing phase II trial of Xeloda ® in taxane-pretreated MBC  Ongoing multicentre, phase II, German trial  131 taxane-pretreated MBC patients to be enrolled  Xeloda 1,250mg/m 2 twice daily for 14 days followed by a 7-day rest period  Preliminary efficacy (100 patients) and safety (105 patients) data have been reported Reichardt P et al. Breast Cancer Res Treat 2000;64:83 (Abst 331)

13. Efficacy of Xeloda ® in taxane-pretreated MBC: summary 1 Blum JL et al. J Clin Oncol 1999;17:485–93 2 Blum JL et al. (submitted) 3 Reichardt P et al. Breast Cancer Res Treat 2000;64:83 (Abst 331) TTP = time to disease progression

14. Xeloda ® versus paclitaxel in anthracycline- pretreated patients: randomised, phase II trial  42* patients with anthracycline-pretreated MBC were randomised to either –Xeloda (1,250mg/m 2 twice daily intermittent schedule, 14 days on treatment, 7 days off) –paclitaxel (175mg/m 2 on day 1 every 21 days) O’Reilly SM et al. (submitted) *One patient in the paclitaxel group withdrew prior to receiving treatment

15. Efficacy of Xeloda ® versus paclitaxel: randomised, phase II trial O’Reilly SM et al. (submitted)

16. Safety of Xeloda ® versus paclitaxel: randomised, phase II trial  Alopecia, paraesthesias and neutropenia were more common with paclitaxel  Nausea, vomiting, diarrhoea and hand-foot syndrome were more common with Xeloda O’Reilly SM et al. (submitted)

17. Xeloda ® versus CMF: randomised, phase II trial  Xeloda versus CMF as first-line treatment for MBC (patients who had received prior hormonal treatment for MBC were eligible)  95* women  55 years of age received either –Xeloda 1,250mg/m 2 twice daily intermittent schedule –CMF (cyclophosphamide 600mg/m 2, methotrexate 40mg/m 2, 5-FU 600mg/m 2 ) every 21 days  Median age of 69 and 70 years, respectively O’Shaughnessy J et al. Ann Oncol (in press) *One patient in each group withdrew prior to receiving treatment

18. Efficacy of Xeloda ® versus CMF: randomised, phase II trial O’Shaughnessy J et al. Ann Oncol (in press) *Upper limit not yet reached

19. Xeloda ® versus CMF: time to disease progression Xeloda (n=61) CMF (n=32) 1.0 0.8 0.6 0.4 0.2 0.0 0246810121416 Estimated probability Time (months) 4.13.0 O’Shaughnessy J et al. Ann Oncol (in press)

20. Xeloda ® versus CMF: survival Xeloda (n=61) CMF (n=32) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 024681012141618202224 Estimated probability Time (months) 17.219.6 O’Shaughnessy J et al. Ann Oncol (in press)

21. Safety of Xeloda ® versus CMF: randomised, phase II trial  Nausea, vomiting, stomatitis and fatigue had similar incidences with CMF and Xeloda  Diarrhoea and hand-foot syndrome were more common with Xeloda  Alopecia and neutropenia were more common with CMF O’Shaughnessy J et al. Ann Oncol (in press)

22. Most frequent (>20%) treatment-related adverse events: safety pop ulation (n=319) 60 50 40 30 20 10 0 Grade 1/2 Grade 3 Grade 4 DiarrhoeaHand-footNauseaVomiting syndrome* Patients (%) *Grade 4 not applicable

23. Grade 3/4 haematological events: safety population (n=319) Grade 3 Grade 4 10 8 6 4 2 0 Patients (%) LeucopeniaAnaemiaNeutropeniaThrombocytopenia

24. Patient education  Patient education is essential for the management of Xeloda side effects  Patients should be educated to –recognise the symptoms and severity of side effects –interrupt treatment upon the development of moderate or more severe side effects –contact their oncology team (physician, nurse or pharmacist) for further advice

25. Conclusions: phase II Xeloda ® monotherapy trials in MBC  Xeloda is a highly active treatment for MBC  Clinically meaningful response rates (18–26%) in heavily pretreated patients  Response rates of 30–36% as first- and second-line treatment in two randomised, phase II studies  Acceptable side-effect profile with adverse events manageable by dose titration in patients who develop toxicity while maintaining efficacy

26. Phase III first-line trial Xeloda 1,000mg/m 2 b.i.d. days 1–14 q21d Continuous Xeloda 666mg/m 2 b.i.d. Classical Bonadonna CMF q28d RANDOMISATIONRANDOMISATION RANDOMISATIONRANDOMISATION Preferred Xeloda regimen CMF ANZBCTG Stage 1Stage 2 1° endpoint: QoL-adjusted survival

27. RANDOMISATIONRANDOMISATION Xeloda 1,250mg/m 2 b.i.d. intermittent 3-weekly cycle x 8 Epirubicin 60mg + paclitaxel 175mg 3-weekly cycle x 8 Epirubicin 90mg 3-weekly cycle x 4 followed by paclitaxel 90mg weekly x 12 Xeloda monotherapy Epirubicin or paclitaxel monotherapy Second-line therapy Xeloda monotherapy German AGO phase III trial First-line therapy 1° endpoint: covariate TTP and overall survival

28. Xeloda ® as adjuvant treatment for high-risk, node-negative breast cancer: CALGB trial  Randomised trial of adjuvant chemotherapy in women >65 years of age with early-stage breast cancer  Comparison of Xeloda versus CMF or AC  5-year relapse-free survival as 1° endpoint  2° endpoints: overall survival, QoL, physical function  Assessment of treatment adherence, tolerance to treatment, biological markers of response