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

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)

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

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

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

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)

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

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

Favorable safety of single-agent Xeloda in all patient groups

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 (%) Leonard R et al. Semin Oncol 2004;31(Suppl. 10):21–8

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

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 Grade 3/4 Grade 1/2 Patients (%; n=43)

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 (%) PhysicalRoleFunction:EmotionalSocialCognitive Maintained Improved (p<0.01)

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)

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

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)

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

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

Control XT: preclinical synergy MX-1 breast cancer xenografts – 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

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– Months Estimated probability XT Taxotere Log-rank p = Hazard ratio = 0.77 XT(n=255) Taxotere(n=255) Addition of Xeloda to Taxotere extends survival

XT: superior response rate and TTP Log-rank p= 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

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)

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

Acceptable safety of XT versus Taxotere (grade 3/4) Patients (%) 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)

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

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 (%) DiarrheaStomatitisHand-footNeutropenic syndromefever Both full dose, X 1250 T 75 (670 cycles) Both reduced dose, X 1000 T 60 (405 cycles)

Quality of life not compromised with XT Global health status Weeks XT Taxotere O’Shaughnessy J et al. J Clin Oncol 2002;20:2812–23

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

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

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)

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