Lighting the way ahead: novel approaches to breast cancer treatment with Xeloda

1. Lighting the way ahead:novel approaches to breast cancer treatment with Xeloda Miguel Martin Hospital Universitario San CarlosMadrid, Spain

2. Novel treatment approaches with Xeloda Metastatic breast cancer • Sequential monotherapy • All-oral regimens • Novel schedules of administration Adjuvant/neoadjuvant trials • Combined with taxanes and anthracyclines • Replacing anthracyclines in adjuvant treatment • Maintenance chemotherapy post adjuvant • Elderly patients

3. MOSG study design: first-line Xeloda and taxanes in combination and sequence RANDOMI ZAT ION n=345 XT: Xeloda 825mg/m2 b.i.d., d1–14 Taxotere 75mg/m2 on day 1, q21d (n=71) XP: Xeloda 825mg/m2 b.i.d., d1–14 paclitaxel 175mg/m2 on day 1, q21d (n=73) docetaxel 100mg/m2q3w (n=21) Xeloda1250mg/m2 b.i.d.d1–14, q21d (n=62) PD paclitaxel 175mg/m2q3w (n=4) PD = disease progression MOSG = Mexican Oncology Study Group Torrecillas L et al. Breast Cancer Res Treat 2004;88(Suppl. 1):S200 (Abst 5048)

4. Patient characteristics:baseline metastases Torrecillas L et al. Breast Cancer Res Treat 2004;88(Suppl. 1):S200 (Abst 5048)

5. First-line Xeloda: highly effective in combination and sequence with taxanes *Includes only responses achieved after Xeloda monotherapy†Time to PD on Xeloda if no further treatment given or time to PD on sequential taxane treatment Torrecillas L et al. Breast Cancer Res Treat 2004;88(Suppl. 1):S200 (Abst 5048)

6. Proposed CASCADE study evaluating Xeloda in sequence with a taxane in first-line MBC 3-weekly docetaxel 60–100mg/m2 or weekly paclitaxel 80mg/m2 Xeloda1250mg/m2 b.i.d.d1–14, q21d RANDO MIZATION PD n=700 1st-line MBC: HER2-negative ³12 months, post adjuvant treatment 3-weekly docetaxel 100mg/m2 or weekly paclitaxel 80mg/m2 Xeloda1250 or 1000mg/m2b.i.d., d1–14, q21d PD • Primary endpoint: time to second-line treatment failure (PD, death, withdrawal for any reason)

7. All-oral regimens

8. Phase I/II trials investigating Xeloda in all-oral combinations 1Findlay MP et al. Proc Am Soc Clin Oncol 2002;21:85b (Abst 2151) 2Chan S-C et al. Proc Am Soc Clin Oncol 2002;21:53b (Abst 2023) 3Nole F. Eur J Cancer 2003;1(Suppl. 5):S174 (Abst 575) 4Delacambre C et al. Ann Oncol 2004;15(Suppl. 3):iii42 (Abst 158P)

9. CYCLOX2: phase II New Zealand study evaluating Xeloda plus oral cyclophosphamide in MBC RANDO MI ZATION Xeloda 665mg/m2 b.i.d.continuously + oral cyclophosphamide 100mg/m2d1–14, q28d n=80 £1 prior regimen for advanced breast cancer Prior adjuvant chemotherapy allowed Xeloda 665mg/m2 b.i.d. continuously • Primary endpoint: response rate

10. Novel schedules of administration

11. Building upon experience in colorectal cancer with alternative schedules • Standard Xeloda dosing: 1250mg/m2 b.i.d. d1–14, q21d, selected over continuous administration • favorable safety and TTP1 • small sample size (<40 patients in each arm) • applicable to breast cancer? • Alternative schedules evaluated in colorectal cancer • fixed daily dose of Xeloda (750 or 1000mg/m2 b.i.d., continuous administration) is feasible and well tolerated2 1Van Cutsem E et al. J Clin Oncol 2000;18:1337–45 2Lokich J et al. Cancer Invest 2004;22:713–7

12. Spanish phase II trial:continuous versus standard Xeloda RANDO MIZATION n=80 (initial phase) Xeloda 1250mg/m2 b.i.d. d1–14, q3w (standard arm) MBC HER-2 negative up to 2 prior lines Xeloda 800mg/m2 b.i.d. d1–21, q3w (continuous arm) • Primary endpoint: incidence of HFS (H1: 50% vs 35%) • Secondary endpoints: RR, TTP • Similar dose intensities and cumulative doses

13. Intensive evaluation in the adjuvant treatment of early BC (N=21244)

14. Intensive ongoing evaluation of Xeloda as primary systemic therapy (PST) for BC

15. GEPARQUATTRO: German cooperative group neoadjuvant study • Primary endpoint: 5-year disease-free survival • Herceptin given concomitantly in HER-2 positive patients for eight or 12 cycles (and up to 1 year postoperatively) n=1600 RANDO MIZATION T100 x4 24 weeks EC x4 24 weeks T75/X1800x4 T75 x4 36 weeks X1800 x4

16. MINDACT: optimizing decision-making for adjuvant chemotherapy 1st randomization Assess clinical and genomic risk Clinical and genomic BOTH HIGH RISK DISCORDANTclinical and genomic risks Clinical and genomic BOTH LOW RISK RANDOMIZE decision-making Use clinical risk Use genomic risk High risk High risk Low risk Low risk Chemotherapy No chemotherapy MINDACT = Microarray In Node Negative Disease May Avoid Chemotherapy

17. Adjuvant XT as a replacement for anthracycline-based chemotherapy 2nd randomization High-risk patients RANDOMIZE type of chemotherapy Anthracycline based treatment Xeloda/Taxotere (XT)

18. GEICAM-CIBOMA trial: maintenance Xeloda after adjuvant chemotherapy RANDO MIZATION Xeloda 1000mg/m2 d1–14q3w x 8 cycles n=3538 Operable breast cancer Node+ ER/PR– Completed six cycles adjuvant anthracycline-based chemotherapy Observation • Primary endpoint: 5-year disease-free survival (DFS); 14.18% relative increase (59.77–64.30%; HR 0.8582)

19. Ongoing trials evaluating Xeloda as adjuvant treatment for elderly patients XN = Xeloda plus vinorelbine

20. Xeloda: improving the management of breast cancer through novel approaches • As a highly effective and well-tolerated agent, Xeloda is enabling new treatment approaches for both metastatic and early breast cancer • Novel approaches under investigation will provide further options for tailoring treatment and improving outcomes