1. Thymidine phosphorylase (TP) upregulation Dose- and time-dependent upregulation of TP in human colon cancer xenografts 20 15 10 5 0 20 15 10 5 0 PaclitaxelDocetaxel 0246810 Days after administration TP (unit/mg protein) Sawada N et al. Clin Cancer Res 1998;4:1013–9 No treatment Vehicle Paclitaxel 15mg/kg Paclitaxel 100mg/kg No treatment Vehicle Docetaxel 3.75mg/kg Docetaxel 15mg/kg *p<0.05 * * * * * * ** * * * TP (unit/mg protein)

2. Xeloda ® plus taxanes Activity of the combination of Xeloda and taxanes against MX-1 carcinoma xenografts 6.0 5.0 4.0 3.0 2.0 1.0 0 –1.0 141822263034384246 6.0 5.0 4.0 3.0 2.0 1.0 0 –1.0 Tumour volume change (cm 3 ) Xeloda 5-FU Sawada N et al. Clin Cancer Res 1998;4:1013–9 ControlDocetaxelXelodaDocetaxel + Xeloda Docetaxel + 5-FU 5-FU * * * * * Days *p<0.05 Tumour volume change (cm 3 )

3. Xeloda ® plus docetaxel: rationale in breast cancer  Xeloda and docetaxel have considerable single-agent activity in breast cancer  Xeloda and docetaxel have distinct mechanisms of action and no overlap of key toxicities  Synergistic interaction between Xeloda and docetaxel mediated by further taxane-induced upregulation of TP

4. Xeloda ® plus docetaxel: phase I study summary  Two dose regimens were shown to be feasible – 75mg/m 2 docetaxel + 1,250mg/m 2 Xeloda twice daily – 100mg/m 2 docetaxel + 825mg/m 2 Xeloda twice daily  No evidence of a pharmacokinetic interaction between docetaxel and Xeloda Pronk L et al. Br J Cancer 2000;83:22–9

5. Xeloda ® plus docetaxel: phase III study design Randomisation (3-weekly cycles) Xeloda 1,250mg/m 2 twice daily, days 1–14 docetaxel 75mg/m 2, day 1 Docetaxel 100mg/m 2, day 1  Patients responding or with stable disease after 6 weeks of treatment continued until disease progression or unacceptable toxicity O’Shaughnessy J et al. San Antonio Breast Cancer Symposium 2000 (Abst 381)

6. Xeloda ® plus docetaxel: study objectives  Primary –time to disease progression *  Secondary –objective response rate –overall survival –safety profile –quality of life (EORTC QLQ-C30 and QLQ-BR23) –medical care utilisation * or deathO’Shaughnessy J et al. San Antonio Breast Cancer Symposium 2000 (Abst 381)

7. Xeloda ® plus docetaxel: baseline characteristics O’Shaughnessy J et al. San Antonio Breast Cancer Symposium 2000 (Abst 381) KPS = Karnofsky Performance Status

8. Xeloda ® plus docetaxel: chemotherapy pretreatment O’Shaughnessy J et al. San Antonio Breast Cancer Symposium 2000 (Abst 381)

9. Xeloda ® plus docetaxel: overall tumour response O’Shaughnessy J et al. San Antonio Breast Cancer Symposium 2000 (Abst 381)

10. Xeloda ® plus docetaxel : duration of response Time (months) 1.0 0.8 0.6 0.4 0.2 0 Xeloda/docetaxel7.2 Docetaxel6.9 Estimated probability 0510152025 6.97.2 Median (months) O’Shaughnessy J et al. San Antonio Breast Cancer Symposium 2000 (Abst 381)

11. Xeloda ® plus docetaxel: time to disease progression 4.26.1 Xeloda/docetaxel Docetaxel Hazard ratio = 0.643 (0.536–0.770) Log-rank p=0.0001 Median (CI) 6.1 (5.4–6.5) 4.2 (3.4–4.5) 1.0 0.8 0.6 0.4 0.2 0 Estimated probability 0510152025 Time (months) O’Shaughnessy J et al. San Antonio Breast Cancer Symposium 2000 (Abst 381)

12. Xeloda ® plus docetaxel: overall survival* 1.0 0.8 0.6 0.4 0.2 0.0 Estimated probability 02468101214161820222426 Time (months) Median (CI)Events Xeloda/docetaxel14.5 (12.3–16.3)72% Docetaxel 11.5 (9.8–12.7) 79% 11.514.5 Hazard ratio = 0.775 Log-rank p=0.0126 *Minimum follow up of 15 months (4-month safety update)

13. Xeloda ® plus docetaxel : post-study treatment O’Shaughnessy J et al. San Antonio Breast Cancer Symposium 2000 (Abst 381)

14. Xeloda ® plus docetaxel: quality of life (global health status) 80 70 60 50 40 Global health status 0612182430364248 Time (weeks) Xeloda/docetaxel n=219187127975741312113 Docetaxel n=22419013385422014125 0 O’Shaughnessy J et al. San Antonio Breast Cancer Symposium 2000 (Abst 381)

15. Xeloda ® plus docetaxel: most common treatment- related clinical adverse events (all grades) Xeloda/docetaxel (n=251) Docetaxel (n=255) Diarrhoea Stomatitis HFS Nausea Fatigue/ asthenia NF VomitingAlopeciaPyrexiaMyalgia Arthralgia HFS = hand-foot syndrome; NF = neutropenic fever 70 60 50 40 30 20 10 0 Patients (%) O’Shaughnessy J et al. San Antonio Breast Cancer Symposium 2000 (Abst 381)

16. Xeloda ® plus docetaxel: most common (>5%) grade 3/4 treatment-related toxicities 30 25 20 15 10 5 0 Patients (%) Xeloda/docetaxel (n=251) Diarrhoea Stomatitis HFS* Nausea Fatigue/ asthenia NF Docetaxel (n=255) Grade 3 Grade 4 Grade 3 Grade 4 *Grade 4 not applicable; NF = neutropenic fever O’Shaughnessy J et al. San Antonio Breast Cancer Symposium 2000 (Abst 381)

17. Xeloda ® plus docetaxel: grade 3/4 treatment-related adverse events over time 100 80 60 40 20 0 Adverse events (%) 061218243036424854 Time (weeks) Xeloda/docetaxel Docetaxel O’Shaughnessy J et al. San Antonio Breast Cancer Symposium 2000 (Abst 381)

18. Xeloda ® plus docetaxel: most common grade 3/4 * laboratory abnormalities *NCIC common toxicity criteria; ULN = upper limit of normal O’Shaughnessy J et al. San Antonio Breast Cancer Symposium 2000 (Abst 381)

19. Xeloda ® plus docetaxel: dose reductions O’Shaughnessy J et al. San Antonio Breast Cancer Symposium 2000 (Abst 381)

20. Xeloda ® plus docetaxel: summary of safety  Treatment with oral Xeloda plus docetaxel compared with docetaxel alone leads to –more gastrointestinal side effects and hand-foot syndrome –less myalgia, arthralgia and grade 4 neutropenia with associated complications (neutropenic fever/sepsis) O’Shaughnessy J et al. San Antonio Breast Cancer Symposium 2000 (Abst 381)

21. Xeloda ® plus docetaxel: conclusions  The addition of oral Xeloda to docetaxel leads to –superior response rates –superior time to disease progression –superior overall survival with a manageable safety profile  Xeloda plus docetaxel is the first and only cytotoxic combination to improve survival over docetaxel monotherapy in anthracycline-pretreated patients O’Shaughnessy J et al. San Antonio Breast Cancer Symposium 2000 (Abst 381)

22. Xeloda ® plus paclitaxel: phase II trial  Ongoing study evaluating a 21-day cycle of –Xeloda 1,000mg/m 2 twice daily, days 1–14 –i.v. paclitaxel 175mg/m 2, day 1  All patients had anthracycline-pretreated advanced/metastatic breast cancer  62% objective response rate including 16 complete responses (23%) in 71 evaluable patients  8.6 months median time to disease progression  Favourable safety profile, with a low incidence of severe toxicities Pérez-Manga G et al. Breast Cancer Res Treat 2000;64:125 (Abst 535)

23. Xeloda ® plus docetaxel plus epirubicin  Phase I study in 23 patients with advanced breast cancer  Principal dose-limiting toxicity was neutropenia, non-haematological toxicities were rare  Recommended regimen is a 21-day cycle of –Xeloda 985mg/m 2 twice daily, days 1–14 –i.v. docetaxel 75mg/m 2, day 1 –i.v. epirubicin 75mg/m 2, day 1  Objective responses occurred in 21 of 23 patients enrolled (91%) Angiolini C et al. Breast Cancer Res Treat 2000;64:123 (Abst 529)

24. Xeloda ® plus vinorelbine: phase I study  40 pretreated patients with advanced/metastatic breast cancer received a 21-day cycle of –Xeloda 500–1,250mg/m 2 twice daily, days 1–14 –i.v. vinorelbine 12.5–22.5mg/m 2, days 1 and 3  Maximum tolerated dose not yet defined  48% response rate in 33 evaluable patients treated at all dose levels  Minimal toxicity Nolè F et al. Breast Cancer Res Treat 2000;64:125 (Abst 539)

25. Xeloda ® plus weekly docetaxel: phase I/II study  12 patients with anthracycline-pretreated MBC have been treated in an ongoing phase I/II study  Recommended dose identified as intermittent Xeloda 900mg/m 2 twice daily plus weekly docetaxel 30mg/m 2  Feasible safety profile with a low incidence of severe myelosuppression –only one grade 4 adverse event (neutropenia) –most common (>10%) grade 3 adverse events were asthenia (five patients) and nail toxicity (four patients)  Objective tumour responses in six of 11 evaluable patients Mackey J. 2nd International Breast Cancer International Research Group Conference, Edmonton, Canada, June 26–28, 2000

26. Ongoing Xeloda ® combination trials Additional trials are investigating Xeloda plus  Weekly paclitaxel/docetaxel  Vinorelbine (three studies exploring different schedules)  Docetaxel/epirubicin in untreated advanced breast cancer  Cyclophosphamide/epirubicin as neo-adjuvant therapy (EORTC)  Idarubicin  Cyclophosphamide all-oral regimens