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Welcome. Chris Twelves University of Leeds and Bradford NHS Trust UK. Evolution of treatment: new opportunities for Xeloda in breast cancer (BC). Neoadjuvant BC proof of concept for model biologics and targeted therapies Adjuvant BC replace 5-FU in standard anthracycline-based regimens

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  1. Welcome Chris Twelves University of Leeds and Bradford NHS TrustUK

  2. Evolution of treatment: new opportunities for Xeloda in breast cancer (BC) • Neoadjuvant BC • proof of concept for model biologics and targeted therapies • Adjuvant BC • replace 5-FU in standard anthracycline-based regimens • as an alternative to other cytotoxics • Metastatic BC • increasing adjuvant use of anthracyclines-taxanes • need for effective, well tolerated and convenient regimens • sequential monotherapies • doublet and triplet combinations ± Herceptin • all oral combinations

  3. Evolution of treatment: new opportunities for Xeloda in colorectal cancer • Adjuvant colon cancer • introduction of chemotherapy combinations • need to select appropriate (effective, well tolerated, convenient) treatment for each patient • Metastatic colorectal cancer • increasing use of complex chemotherapy combinations ± biologicals and/or small molecules • need for effective, well tolerated and convenient regimens that are cost effective

  4. Xeloda: new evidence for a paradigm shift 19.30–20.45 • Innovations in early breast cancer management with Xeloda Heikki Joensuu • Xeloda-based regimens: expanding options for the first-line treatment of metastatic breast cancer William Gradishar • Xeloda: reaching a landmark in adjuvant colon cancer therapy Chris Twelves • Xeloda: optimizing treatment of metastatic colorectal cancer Eric Van Cutsem • Question and answerAll • CloseChris Twelves

  5. Innovations in early breast cancer (BC) management with Xeloda Heikki Joensuu Helsinki University Central Hospital Helsinki, Finland

  6. Rationale for integrating Xeloda into the treatment of early BC • High single-agent efficacy in metastatic BC (MBC) • objective response rate 15–28% in five clinical trials of pretreated MBC • median duration of response ≈8 months • Active in combination regimens • Xeloda extends overall survival when combined with Taxotere1 • interesting partner to build on improved outcomes achieved with taxanes in early BC treatment2,3 • Favorable safety profile, with minimal myelosuppression and alopecia 1O’Shaughnessy J et al. J Clin Oncol 2002;20:2812–232Bear HD et al. Breast Cancer Res Treat 2004;88(Suppl. 1):S16 (Abst 26)3Martin M et al. Breast Cancer Res Treat 2003 (Abst 43)

  7. Ongoing evaluation of Xeloda as primary systemic therapy (PST) for BC (n>5000)

  8. Several randomized studies are exploring alternative doses of XT CHAT = Capecitabine, Herceptin and Taxotere Trial (multinational);MOSG = Mexican Oncology Study Group; USO = US Oncology, USA

  9. Primary objective: pathological (pCR) and clinical complete response (cCR) of PST Phase III Korean trial: XT versus AC as PST for early BC RANDO MIZ ATION SURGERY A60C600 x4 X1000T75 x4 ECOG PS £1 Stage II/IIIbreast cancer Axillary lymph node involvement No prior treatment X1000T75 x4 A60C600 x4 *Xeloda dose: twice daily, days 1–14, every 21 days Ro J et al. Presented at St Gallen 2005

  10. PST with XT: highly effective versus AC Ro J et al. Presented at St Gallen 2005

  11. Ongoing French study evaluating PST with CEX as an alternative to FEC RANDO MIZATION SURGERY FE100C x4 Taxotere100 x4 n=200 Stage II or IIIA operablebreast cancer Taxotere100 x4 CE100X900 x4 • Primary endpoint: pCR Xeloda dose: twice daily, days 1–14, every 21 days

  12. NSABP B-40: phase III study of XT as PST for BC Taxotere100 x4 RANDO MIZ ATION RAND AC x4 X825T75 x4 n=1200 Stage II or IIIA operablebreast cancer G1000T75 x4 Taxotere100 x4 RAND AC x4 X825T75 x4 G1000T75 x4 Primary objective: pCR/cCR Xeloda dose: twice daily, days 1–14, every 21 days

  13. Intensive evaluation in the adjuvant treatment of early BC (n>20000)

  14. Registration trial evaluating benefits of addingXeloda to Taxotere in sequential adjuvant treatment RANDO MIZ ATION Taxotere100 x4 AC x4 US Oncology n=2410 N+N0, tumor >2cmN0, ER/PR– AC x4 X825 T75 x4 • Primary endpoint: disease-free survival (DFS) at 5 years • Patients with ER+ or PR+ tumors will receive tamoxifen or anastrozole for 5 years • Recruitment complete: end of 2005 Xeloda dose: twice daily, days 1–14, every 21 days

  15. Phase III adjuvant study (FinXX)of sequential Xeloda-based combinations RANDO MIZATION FE75C x3 Taxotere80 x3 n=1500 pN+ or pN0, >2cm PgR –ve X900 T60 x3 CE75X900 x3 • Primary endpoint: relapse-free survival (RFS) • Patients with ER+ or PR+ tumors will receive tamoxifen or anastrozole for 5 years • Recruitment complete: end of 2006 Xeloda dose: twice daily, days 1–14, every 21 days

  16. Adjuvant XT: manageable incidence of adverse events Joensuu H et al. ASCO 2005 (Abst 719)

  17. Adjuvant CEX: low incidence of grade 3/4 adverse events Joensuu H et al. ASCO 2005 (Abst 719)

  18. Xeloda-based regimens: manageable incidence of grade 3/4 neutropenia Joensuu H et al. ASCO 2005 (Abst 719)

  19. Maintenance of dose intensity in adjuvant XT and CEX regimens Joensuu H et al. ASCO 2005 (Abst 719)

  20. UK adjuvant study of sequential Xeloda monotherapy (TACT2) RANDO MIZATION CMF x4 Epirubicin x4 n=4400 Medium-risk breast cancer Epirubicin x4 Xeloda x4 • Primary endpoint: 5-year DFS • 2 x 2 factorial design; accelerated epirubicin with G-CSF Xeloda dose: twice daily, days 1–14, every 21 days

  21. Microarray In Node Negative Disease May Avoid Chemotherapy (MINDACT) MINDACT: optimizing decision-makingfor adjuvant chemotherapy Assess clinical and genomic risk Clinical and genomic BOTH HIGH RISK DISCORDANTclinical and genomic risks Clinical and genomic BOTH LOW RISK 1st RANDOMIZATION decision-making Use clinical risk Use genomic risk High risk High risk Low risk Low risk Chemotherapy No chemotherapy

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

  23. GEICAM-CIBOMA trial: maintenance Xeloda after adjuvant chemotherapy RANDO MIZATION n=3538 Operable breast cancer Node+ ER/PR– Xeloda x8 Completed six cycles adjuvant anthracycline-based chemotherapy Observation • Primary endpoint: 5-year disease-free survival (DFS) Xeloda 1000mg/m2 d1–14 q3w

  24. Xeloda: potential to improve outcomes in early BC • Several multinational trials investigating potential of Xeloda to improve outcomes in early BC • pre-operative XT improves pCR rate versus AC1 • Xeloda plus Taxotere was well tolerated in the management of early BC2 • Results eagerly awaited from ongoing trials evaluating Xeloda as primary systemic and adjuvant therapy 1Ro J et al. Presented at St Gallen 20052Joensuu H et al. ASCO 2005 (Abst 719)

  25. Xeloda-based regimens: expanding options for the first-line treatment of metastatic breast cancer (MBC) William Gradishar Feinberg School of MedicineRobert H. Lurie Comprehensive Cancer CenterNorthwestern UniversityChicago, USA

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

  27. Xeloda monotherapy in patients³65 years: highly effective in first-line MBC ORR = overall response rate CR = complete response PR = partial response Bajetta E et al. J Clin Oncol 2005;23:2155–61

  28. Xeloda monotherapy in MBC: low incidenceof non-hematologic grade 3/4 events Patients (%) 40 30 20 10 0 • 713 taxane-pretreated patients • Minimal alopecia • No cumulative toxicity • No treatment-related deaths Hand-foot Diarrhea Fatigue Stomatitis Nausea Dehydration syndrome Blum JL et al. J Clin Oncol 1999;17:485–93Blum JL et al. Cancer 2001;92:1759–68; Reichardt P et al. Ann Oncol 2003;14:1227–33 Fumoleau P et al. Eur J Cancer 2004;40:536–42; Maung K. Clin Breast Cancer 2003;3:375–7

  29. Xeloda monotherapy: minimal myelosuppression Patients (%) 40 30 20 10 0 • 498 taxane-pretreated patients Grade 3 Grade 4 Leukopenia Neutropenia Anemia Thrombo- cytopenia Blum JL et al. J Clin Oncol 1999;17:485–93Blum JL et al. Cancer 2001;92:1759–68; Reichardt P et al. Ann Oncol 2003;14:1227–33 Fumoleau P et al. Eur J Cancer 2004;40:536–42

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

  31. Addition of Xeloda to Taxotere extends survival Similar survival benefit in patients relapsing £2 years after adjuvant anthracyclines ORR TTP 6.1 months 4.2 months 42% 30% XT (n=255) Taxotere (n=255) Overall population1 XT Taxotere Relapse £2 years2 Hazard ratio = 0.77 Log-rank p=0.013 11.5 14.5 2Leonard R et al. Semin Oncol 2004;31(Suppl. 10):21–8 Estimated probability 1.0 0.8 0.6 0.4 0.2 0.0 XT Taxotere 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Months 1O’Shaughnessy J et al. J Clin Oncol 2002;20:2812–23

  32. Grade 3 Grade 4 Grade 3 Grade 4 XT (n=251) Both full doses (670 cycles) Both reduced (405 cycles) Taxotere (n=255) XT: a manageable safety profile Fewer grade 3/4 adverse events afterTaxotere and Xeloda doses are reduced Patients (%) 30 20 10 0 Hand-foot syndrome Fatigue/ asthenia Diarrhea Neutropenic fever Stomatitis Nausea O’Shaughnessy J et al. J Clin Oncol 2002;20:2812–23 Leonard et al. Ann Oncol 2005; submitted

  33. XT dose reduction does not compromise efficacy: TTP Estimated probability 1.0 0.8 0.6 0.4 0.2 0.0 Cycle 2: both reduced (X: 1000mg/m2, T: 60mg/m2) Cycle 4: both full (X: 1250mg/m2, T: 75mg/m2) 6.4 6.7 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Months F. Hoffmann-La Roche, data on file

  34. Xeloda plus 3-weekly paclitaxel (XP): consistently high activity in MBC 1Batista N et al. Br J Cancer 2004;90:1740–6 2Gradishar W et al. J Clin Oncol 2004;22:2321–7 *94% treated in first line

  35. European study (1st/2nd line)1 US study (>90% 1st line)2 Favorable safety profile of XP: low incidence of grade 3/4 adverse events Patients (%) 60 50 40 30 20 10 0 Fatigue Hand-footsyndrome Dyspnea Alopecia Peripheralneuropathy Neutropenia Paresthesiae 1Batista N et al. Br J Cancer 2004;90:1740–6 2Gradishar W et al. J Clin Oncol 2004;22:2321–7

  36. Xeloda plus weekly paclitaxel: a highly effective and well-tolerated combination • Recommended regimen from Swiss (SAKK) phase I trial2 • Xeloda1000mg/m2 twice daily, days 1–14 • paclitaxel 80mg/m2 days 1, 8, 15, q21d 1Blum J et al. Breast Cancer Res Treat 2004;88(Suppl. 1):S202 (Abst 5053)2Uhlmann C et al. Oncology 2004;67:117–22 *Most common (>5%)

  37. XN: consistently high activity in MBC • Recommended regimen from German phase I/II study3 • Xeloda1000mg/m2twice daily, days 1–14 • vinorelbine 25mg/m2days 1, 8, q21d 1Stuart N et al. Proc Am Soc Clin Oncol 2003;22:46 (Abst 183) 2Ahn J et al. Proc Am Soc Clin Oncol 2003;22:54 (Abst 216)3Welt A et al. Ann Oncol 2005;16:64–94Ghosn M et al. Breast Cancer Res Treat 2002;76:S133 (Abst 531)5Estevez L et al. Ann Oncol 2004;15(Suppl. 3):iii44 (Abst 166P)

  38. Grade 3 Grade 4 XN: well tolerated in pretreated patients with MBC (n=48) Patients (%) 80 60 40 20 0 Anemia Vomiting Hand-foot syndrome Leukopenia Neutropenia Constipation Welt A et al. Ann Oncol 2005;16:64–9 Estevez L et al. Ann Oncol 2004;15(Suppl. 3):iii44 (Abst 166P)

  39. XN Lebanese study update • Abstract 673; Ghosn M • Vinorelbine (N)-capecitabine (C) combinations in advanced breast cancer (ABC): long-term results of two multicentric phase II trials • Monday May 16, 2005, 14.00–18.00 • Level 2, Hall C

  40. Ongoing international phase II study evaluating Xeloda plus oral vinorelbine in first-line MBC Age <65 years Xeloda1000mg/m2 days 1–14 plus vinorelbine* 80mg/m2 orally, days 1 and 8, q3w n=55 HER2-negative MBC Prior (neo-)adjuvant chemotherapy No prior chemotherapy for MBC Xeloda750mg/m2 days 1–14 plus vinorelbine* 80mg/m2 orally, days 1 and 8, q3w Age ≥65 years • Primary endpoint: ORR *For cycle 1, oral vinorelbine 60mg/m2

  41. Xeloda + Herceptin (XH) shows at least additive activity against xenografts Tumor volume (mm3) • 1000 • 800 • 600 • 400 • 200 • 100 1000 100 10 BT474 xenograft KPL-4 xenograft 20 30 40 50 60 20 30 40 50 60 Days after inoculation Control H HT X XHT Fujimoto-Ouchi K et al. Cancer Chemother Pharmacol 2002;49:211–16Adapted from Sawada N et al. Proc Am Assoc Cancer Res 2002;43:1088 (Abst 5388) XH XT

  42. Xeloda + Herceptin (XH): high first-line activity in HER2-positive MBC • Favorable safety (n=41) • only grade 3/4 treatment-related adverse event was hand-foot syndrome (10%) Xu L et al. Ann Oncol 2004;15(Suppl. 3):iii38 (Abst 141P)

  43. Ongoing trials evaluating XH in MBC H = Herceptin; T = Taxotere; N = vinorelbine; X = Xeloda

  44. XT Xeloda XP ± Herceptin XN Xeloda-based regimens: expandingoptions 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

  45. Xeloda: reaching a landmark in adjuvant therapy Chris Twelves University of Leeds and Bradford NHS TrustUK

  46. European authorities approve Xeloda as adjuvant treatment for colon cancer • EMEA approved Xeloda (31 March 2005) . . . Xeloda is indicated for the adjuvant treatment of patients following surgery for stage III (Dukes’ stage C) colon cancer

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