1. Xeloda and Xeloda-based combinations in the treatment of MBC Steffan Kahlert Insert affiliation

2. Intestine Liver Xeloda 5'-DFCR 5'-DFUR CyD 5'-DFCR 5'-DFUR 5-FU Tumour >> healthy tissue Xeloda CyD CE 5'-DFCR = 5'-deoxy-5-fluorocytidine; 5'-DFUR = 5'-deoxy-5-fluorouridine; CyD = cytidine deaminase; CE = carboxylesterase Tumour/TP-activated oral Xeloda Thymidine phosphorylase (TP)

3. Patient and disease characteristics influence treatment decisions Sequence versus combination Prior adjuvant chemotherapy Cumulative dose of anthracyclines Cardiac impairment Increasing use of taxanes Long-term side effects Disease-free interval Disease characteristics Sites of metastases Tumor biology Tumor burden Patient characteristics Age Performance status Preference Comorbidities e.g. diabetes, impaired cardiac function Trial vs clinic patients

4. Xeloda monotherapy: highly active first-line therapy for MBC 1 Talbot D et al. Br J Cancer 2002;86:1367–72 2 O’Shaughnessy J et al. Ann Oncol 2001;12:1247–54 CMF = cyclophosphamide, methotrexate, 5-fluorouracil TTP = time to progression

5. Xeloda monotherapy in patients ≥65 years: highly effective in first-line MBC Bajetta E et al. J Clin Oncol 2005;23:2155–61

6. First-line Xeloda: similar high activity to anthracyclines and taxanes in MBC 1 Leonard R et al. Semin Oncol 2004;31(Suppl. 10):21–8 2 Reynoso N et al. Breast Cancer Res Treat 2005;94(Suppl. 1):S219 (Abst 5039) 3 Paridaens R et al. J Clin Oncol 2000;18:724–33; 4 Alexandre J et al. J Clin Oncol 2000;18:562–73 5 Sjöström J et al. Eur J Cancer 1999;35:1194–201 ; 6 Dieras V et al. Semin Oncol 1995;22(Suppl. 8):33–9 7 Nabholtz J et al. J Clin Oncol 1996;14:1858–67; 8 Miller KD et al. Breast Cancer Res Treat 2005;94:S6 (Abst 3)

7. Large body of evidence with Xeloda in taxane-pretreated MBC  Five trials in 730 patients evaluated Xeloda monotherapy 1 –pivotal USA (n=163) –confirmatory US/French (n=75) –German (n=136) –French (n=126) –US Xeloda ± Avastin (n=462)  Xeloda dose in all trials was 1 250mg/m 2 twice daily for 14 days, followed by a 7-day rest period Leonard R et al. Semin Oncol 2004;31(Suppl. 10):21–8

8. Xeloda: consistently high activity in taxane-pretreated MBC  Xeloda is more effective than other monotherapies, p=0.005 2 1 Leonard R et al. Semin Oncol 2004;31(Suppl. 10):21–8 2 Miles D et al. Clin Breast Cancer 2004;5:273–8

9. Favorable safety of single-agent Xeloda in all patient groups

10. Xeloda monotherapy in MBC: low incidence of grade 3 / 4 adverse events (n=713)  Minimal alopecia and myelosuppression  No cumulative toxicity  No treatment-related deaths Hand-footDiarrhoeaFatigue StomatitisNauseaDehydration syndrome Patients (%) 40 30 20 10 0 Leonard R et al. Semin Oncol 2004;31(Suppl. 10):21–8

11. Xeloda monotherapy: minimal myelosuppression (n=498) Patients (%) Leukopenia Neutropenia Anemia Thrombo- cytopenia 40 20 0 Grade 3 Grade 4 Leonard R et al. Semin Oncol 2004;31(Suppl. 10):21–8

12. Xeloda 1 000mg/m 2 twice daily in patients ≥65 years  Grade 3/4 diarrhea: 13% with 1 250mg/m 2, 2% with 1 000mg/m 2  Efficacy of the two starting doses was similar (n=73) Bajetta E et al. J Clin Oncol 2005;23:2155–61 FatigueHFSNauseaDiarrheaStomatitisNeutropenia 80 60 40 20 0 Grade 3/4 Grade 1/2 Patients (%; n=43)

13. Xeloda treatment improves QoL in women with MBC (n=1 125)  Overall QoL stable or improved in >70% of patients Segalla J et al. Eur J Cancer Suppl 2005;3:115 (Abst 410) Patients (%) 0 20 40 60 80 PhysicalRoleFunction:EmotionalSocialCognitive Maintained Improved (p<0.01)

14. MOSG: first-line Xeloda sequence or combination? X 1250 (n=62) PD T 100 (n=21) P 175 (n=4) X 825 T 75 (n=71) RANDOMIZATIONRANDOMIZATION X 825 P 175 (n=73) PD = disease progression MOSG = Mexican Oncology Study Group n=345 Reynoso N et al. Breast Cancer Res Treat 2005;94(Suppl. 1):S219 (Abst 5039)

15. First-line Xeloda sequence compares favourably with combinations Reynoso N et al. Breast Cancer Res Treat 2005;94(Suppl. 1):S219 (Abst 5039)

16. Sequential Xeloda and taxanes is cost-saving  Xeloda followed by a taxane is cost-saving with similar efficacy to the combinations Reynoso N et al. Breast Cancer Res Treat 2005;94(Suppl. 1):S219 (Abst 5039)

17. Tailoring treatment to patients with single-agent Xeloda  First-line Xeloda is a highly active, well-tolerated, cost-effective option for patients –with slowly progressing disease / low risk –where QoL issues are paramount –who are older or less fit –after adjuvant anthracyclines and taxanes

18. First-line MBC: expanding treatment options with rationally designed Xeloda combinations XT XP± HerceptinXN Xeloda A standard of care treatment option for extending survival: fit patients with rapidly progressing disease and/or visceral metastases XT = Xeloda + Taxotere; XP = Xeloda + paclitaxel; XN = Xeloda + vinorelbine

19. Control XT: preclinical synergy MX-1 breast cancer xenografts 6.0 5.0 4.0 3.0 2.0 1.0 0.0 –1.0 1418222630343842 Tumour volume change (cm 3 ) Days p<0.05 for each arm versus XT Sawada N et al. Clin Cancer Res 1998;4:1013–9 Taxotere Xeloda XT

20. 2 Leonard R et al. Semin Oncol 2004;31(Suppl. 10):21–8 Overall population 1 Taxotere XT Relapse ≤2 years 2 Survival benefit maintained in aggressive disease 1 O’Shaughnessy J et al. J Clin Oncol 2002;20:2812–23 1.0 0.8 0.6 0.4 0.2 0.0 02468101214161820222426 Months Estimated probability XT Taxotere 11.514.5 Log-rank p = 0.013 Hazard ratio = 0.77 XT(n=255) Taxotere(n=255) Addition of Xeloda to Taxotere extends survival

21. XT: superior response rate and TTP 4.26.1 Log-rank p=0.0001 0246810121416182022242628 1.0 0.8 0.6 0.4 0.2 0.0 Months XT (n=255) 42% Taxotere (n=256)30% Response rate p=0.006 O’Shaughnessy J et al. J Clin Oncol 2002;20:2812–23 Estimated probability

22. XT significantly more active than sequential T X in first-line MBC Beslija S et al. Eur J Cancer Suppl 2005;3:118 (Abst 407)

23. Xeloda/Taxotere vs T X: survival advantage with 74% cross-over Beslija S et al. Eur J Cancer Suppl 2005;3:118 (Abst 407) 1.0 0.8 0.6 0.4 0.2 0.0 0510152025303540 Months Survival probability 1922 p = 0.006 Hazard ratio = 0.53 XT(n=50) T X(n=50)

24. Acceptable safety of XT versus Taxotere (grade 3/4) Patients (%) 40 30 20 10 0 HFS Stomatitis Diarrhea Neutropenia Neutropenic fever Fatigue Alopecia Edema Beslija S et al. Eur J Cancer Suppl 2005;3:118 (Abst 407) XT(n=50) T X(n=50)

25. O’Shaughnessy trial: XT dose reduction does not compromise efficacy – OS 1.0 0.8 0.6 0.4 0.2 0.0 05101520253035404550 Survival probability Months 15.014.6 F. Hoffmann-La Roche, data on file Cycle 2 dose Both full, X 1250 T 75 Both reduced, X 1000 T 60

26. Leonard R et al. Semin Oncol 2004;31(Suppl. 10):21–8 O’Shaughnessy trial: less grade 3/4 toxicity after XT doses reduced  The Xeloda label recommends a reduced starting dose for patients with moderate renal impairment or those aged ≥60 years at baseline Cycles (%) 20 16 12 8 4 0 DiarrheaStomatitisHand-footNeutropenic syndromefever Both full dose, X 1250 T 75 (670 cycles) Both reduced dose, X 1000 T 60 (405 cycles)

27. Quality of life not compromised with XT 80 70 60 50 40 0 Global health status 0612182430364248 Weeks XT Taxotere O’Shaughnessy J et al. J Clin Oncol 2002;20:2812–23

28. Xeloda/paclitaxel: consistent activity in MBC 1 Batista N et al. Br J Cancer 2004;90:1740–6; 2 Gradishar W et al. J Clin Oncol 2004;22:2321–7 3 Blum J et al. Breast Cancer Res Treat 2004;88(Suppl. 1):S202 (Abst 5053) 4 Susnjar S et al. J Clin Oncol 2005;23:90s (Abst 851); 5 Uhlmann C et al. Oncology 2004;67:117–22

29. Favorable safety profile of q3w XP: low incidence of grade 3/4 adverse events Gradishar W et al. J Clin Oncol 2004;22:2321–7 Batista N et al. Br J Cancer 2004;90:1740–6

30. Xeloda/vinorelbine: consistently high activity in MBC 1 Ghosn M et al. J Clin Oncol 2005;23:46s (Abst 673) 2 Stuart N et al. Proc Am Soc Clin Oncol 2003;22:46 (Abst 183) 3 Ahn J et al. Proc Am Soc Clin Oncol 2003;22:54 (Abst 216) 4 Welt A et al. Ann Oncol 2005;16:64 –9 5 Estevez L et al. Ann Oncol 2004;15(Suppl. 3):iii44 (Abst 166P)

31. Xeloda-based regimens: expanding options for the first-line treatment of MBC  Xeloda is a highly effective and well-tolerated combination partner, allowing tailoring of treatment  Xeloda should be considered a first-line agent of choice in single-agent setting XT XP± HerceptinXN Xeloda