1. Xeloda and Xeloda-based combinations for the first-line treatment of MCRC Chris Twelves University of Leeds and Bradford NHS Trust UK

2. HER tyrosine- kinase inhibitors Tarceva TM, gefitinib Targeting dysregulated pathways with novel agents Apoptosis Ras signalling VEGF signalling HER signalling TP Apoptotic agents Farnesyl-transferase inhibitors R115777, SCH66336, BMS 214662 Anti-HER2 MAbs Herceptin ®, Omnitarg TM Tumour-activated chemotherapy Xeloda ® Anti-VEGF MAbs Avastin ®

3. 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)

4. More 5-FU in the tumour with TP-activated Xeloda Schüller J et al. Cancer Chemother Pharmacol 2000;45:291–7 x3.2* Tumour tissue *Ratio of median values Normal tissuePlasma 5-FU x21.4* 5-FU

5. Pooled data of two identical phase III trials in first-line MCRC  Endpoints –response rate –progression-free and overall survival –tolerability –pharmacoeconomics First-line MCRC Prior adjuvant >6 months ago Xeloda (n=603) 1 250mg/m 2 twice daily, days 1–14, every 21 days Bolus 5-FU/LV (n=604) LV 20mg/m 2, bolus 5-FU 425mg/m 2 days 1–5, every 28 days Van Cutsem E et al. Br J Cancer 2004;90:1190–7

6. Significantly superior response rate with Xeloda in first-line MCRC Van Cutsem E et al. Br J Cancer 2004;90:1190–7

7. Consistently superior response rates with first-line Xeloda *p<0.05 † Predominant site of metastases Response rate (%) PriorNo priorLiver † Lung † Single Multiple adjuvantadjuvantmetastaticmetastatic sitesites * * * * * * 40 35 30 25 20 15 10 5 0 Xeloda (n=603) 5-FU/LV (n=604) Van Cutsem E et al. Br J Cancer 2004;90:1190–7

8. First-line Xeloda monotherapy: equivalent TTP to i.v. 5-FU/LV 0510152025 4.64.7 1.0 0.8 0.6 0.4 0.2 0.0 Estimated probability Hazard ratio = 0.997 Xeloda (n=603) 5-FU/LV (n=604) Months Van Cutsem E et al. Br J Cancer 2004;90:1190–7

9. First-line Xeloda monotherapy: equivalent overall survival to i.v. 5-FU/LV 12.812.9 051015202530354045 Months 1.0 0.8 0.6 0.4 0.2 0.0 Hazard ratio = 0.96 Survival probability Van Cutsem E et al. Br J Cancer 2004;90:1190–7 Xeloda (n=603) 5-FU/LV (n=604)

10. Xeloda (n=596) 5-FU/LV (n=593) Patients (%) *p<0.0001 * * * Favourable safety profile of first-line Xeloda in MCRC: grade 3/4 AEs * 40 30 20 10 0 Neutropenia Neutropenic fever + sepsis Vomiting Nausea Hand-foot syndrome Stomatitis Diarrhoea Cassidy J et al. Ann Oncol 2002;13:566–75

11. Incidence of grade 3/4 diarrhoea versus Mayo Clinic regimen *p<0.05 Xeloda Mayo Clinic UFT/LV de Gramont EORTC AIO Mayo Clinic

12. Incidence of grade 3/4 stomatitis versus Mayo Clinic regimen *p<0.001 Xeloda Mayo Clinic UFT/LV de Gramont EORTC AIO Mayo Clinic

13. Incidence of grade 3/4 neutropenia † versus Mayo Clinic regimen *p<0.001 † Data for EORTC AIO regimen show leucopenia not neutropenia Xeloda Mayo Clinic UFT/LV de Gramont EORTC AIO Mayo Clinic

14. Reduced hospitalisations for key AEs with Xeloda in first-line MCRC Xeloda (n=596) 5-FU/LV (n=593) Diarrhoea Vomiting Stomatitis Neutropenic fever + sepsis Overall No. of patients hospitalised Hand-foot syndrome Infections *p<0.05 * * * 120 100 80 60 40 20 0 Cassidy J et al. Ann Oncol 2002;13:566–75

15.  Expensive  Painful in the short term  Associated with complications –infections –bleeding –pneumothorax –deep-vein thrombosis (DVT) –pulmonary embolism  Cumbersome for patients Risks with indwelling catheters and infusion pumps avoided with oral Xeloda

16. Patients (%) *p<0.0001 Xeloda: reduced risk of life-threatening infection NeutropeniaNeutropenic fever/sepsis Xeloda (n=596) 5-FU/LV (n=593) Cassidy J et al. Ann Oncol 2002;13:566–75 * 40 30 20 10 0 *

17. Xeloda is substantially resource-saving versus Mayo Clinic in first-line MCRC  Data prospectively collected (n=602) on drug administration, hospital admissions, drugs and consultations for AEs  Compared with 5-FU/LV, Xeloda patients required –fewer hospital visits for drug administration –fewer days in hospital for treatment-related AEs –fewer expensive drugs (antimicrobials fluconazole, 5-HT3-antagonists) for AEs –more frequent unscheduled home, day care, office and telephone consultations Twelves C et al. Eur J Cancer 2001;37:597–604

18. Patients prefer oral therapy: randomised study in first-line MCRC (n=97)  Xeloda  i.v. 5-FU/LV (Mayo Clinic, in- or out-patient de Gramont regimens) or i.v. 5-FU/LV  Xeloda  Before treatment 95% preferred oral  Most still preferred oral after treatment: 64% overall –86%, 63% and 50% in the Mayo, in- and out-patient de Gramont groups, respectively –preference strength depended on comparator i.v. regimen  Principal reasons for oral preference were –increased convenience –home-based administration –tablet formulation

19. First-line Xeloda monotherapy versus 5-FU/LV  Significantly superior response rate  Equivalent median TTP and overall survival  Favourable safety profile  More resource saving  Patient preference for oral therapy

20. Median overall survival (months) Patients should receive all proven agents in the course of their disease Grothey A et al. J Clin Oncol 2004;22:1209–14 Patients receiving 3 agents (%) 0102030405060708090 22 21 20 19 18 17 16 15 14 13

21. Xeloda is an ideal combination partner  Xeloda generates 5-FU preferentially in tumour tissue and has high single-agent, first-line activity  Synergistic antitumour activity in human colon cancer xenografts –Xeloda + oxaliplatin (XELOX) 1 –Xeloda + irinotecan (XELIRI) 2 1 Cassidy J et al. J Clin Oncol 2004;22:2084–91 2 Cao S et al. Clin Colorectal Cancer 2005;4:336–43

22. Xeloda-based combinations: XELOX

23. n=238 1 n=230 1 Response (%) 60 50 40 30 20 10 0 n=128 2 n=132 2 1 Kubicka S et al. ASCO GI 2006 (Abst 277) 2 Sastre J et al. J Clin Oncol 2005;23:252s (Abst 3524) Evidence for XELOX: response rates comparable to 5-FU-based regimens Xeloda/oxaliplatin 5-FU/oxaliplatin

24. XELOX TTP compares favourably with 5-FU-based regimens Xeloda/oxaliplatin 5-FU/oxaliplatin 1 Cassidy J et al. J Clin Oncol 2004;22:2084–91; 2 Scheithauer W et al. J Clin Oncol 2003;21:1307–12 3 Goldberg R et al. J Clin Oncol 2004;22:23–30; 4 de Gramont A et al. J Clin Oncol 2000;18:2938–47 5 Kubicka S et al. ASCO GI 2006 (Abst 277) n=96 1 n=267 3 n=45 2 n=238 5 n=230 5 n=44 2 n=210 4 Months Phase II studies

25. CAPOX versus FUFOX: similar overall survival Survival probability CAPOX (n=240) FUFOX (n=231) HR= 1.16 (90% CI: 0.95–1.41) 1.0 0.8 0.6 0.4 0.2 0.0 020406080 100 120 140160 Weeks  17.3 months Median Kubicka S et al. ASCO GI 2006 (Abst 277) 60% events

26. XELOX is well tolerated versus 5-FU/oxaliplatin regimens: phase III evaluation in MCRC 1 Sastre J et al. J Clin Oncol 2005;23:252s (Abst 3524) HFS = hand-foot syndrome NR = not reported 2 Arkenau HT et al. Eur J Cancer Suppl 2005;3:168 (Abst 601) 3 Bennouna J et al. Eur J Cancer Suppl 2005;3:179 (Abst 636)

27. XELOX has less severe neutropenia than FOLFOX 1 Cassidy J et al. J Clin Oncol 2004;22:2084–91 2 Goldberg R et al. J Clin Oncol 2004;22:23–30 3 de Gramont A et al. J Clin Oncol 2000;18:2938–47 NR = not reported

28. Time to progression gained with XELOX is not lost in hospital / clinic 1 de Gramont A et al. J Clin Oncol 2000;18:2938–47 2 Cassidy J et al. J Clin Oncol 2004;22:2084–91 Days/patient 70 60 50 40 30 20 10 0 TTP gain with FOLFOXDays in hospital/clinicDays in hospital/clinic versus 5-FU/LV 1 with FOLFOX 1 with XELOX 2

29. Total cost US $42 442 US $47 056 Treatment of adverse events US $405 US $2 448 US $42 037 US $44 608 Drug and administration Total savings US $4 614 Medical cost savings associated with XELOX versus FOLFOX Chu E et al. Proc Am Soc Clin Oncol 2003;22:269 (Abst 1080) XELOX FOLFOX

30. First-line XELOX versus 5-FU-based combinations with oxaliplatin  Comparable response rates, TTP and overall survival  Favourable safety profile  More cost effective  Improved patient convenience

31. Xeloda-based combinations: XELIRI

32. Evidence for XELIRI: response rates compare favourably with 5-FU/LV/irinotecan 1 Patt YZ et al. Ann Oncol 2004;15(Suppl. 3):iii88 (Abst 238P); 2 Bajetta E et al. Cancer 2004;100:279–87 3 Borner MM et al. Ann Oncol 2005;16:282–8; 4 Ahn J et al. J Clin Oncol 2005;23:299s (Abst 3714) 5 Garcia-Alfonso P et al. Eur J Cancer Suppl 2005;3:181 (Abst 641); 6 El Rayes BF et al J Clin Oncol 2005;23:290s (Abst 3677) 7 Douillard JY et al. Lancet 2000;355:1041–7; 8 Tournigand C et al. J Clin Oncol 2004;22:229–37 60 50 40 30 20 10 0 Response (%) n=68 2 n=36 4 n=45 5 n=145 7 n=52 1 n=37 3 n=109 8 n=38 6 XELIRI FOLFIRI Phase II studies

33. TTP: XELIRI compares favourably with 5-FU/LV/irinotecan XELIRI FOLFIRI Months 1 Patt YZ et al. Ann Oncol 2004;15(Suppl. 3):iii88 (Abst 238P); 2 Bajetta E et al. Cancer 2004;100:279–87 3 Borner MM et al. Ann Oncol 2005;16:282–8; 7 Douillard JY et al. Lancet 2000;355:1041–7 8 Tournigand C et al. J Clin Oncol 2004;22:229–37 n=68 2 n=145 7 n=52 1 n=37 3 n=109 8 Phase II studies

34. Survival: XELIRI compares favourably with infused 5-FU combinations XELIRI FOLFIRI Months 1 Patt YZ et al. Ann Oncol 2004;15(Suppl. 3):iii88 (Abst 238P); 2 Borner MM et al. Ann Oncol 2005;16:282–8 3 Douillard JY et al. Lancet 2000;355:1041–7; 4 Tournigand C et al. J Clin Oncol 2004;22:229–37 n=145 7 n=52 1 n=37 3 n=109 8 Phase II studies

35. Safety of Xeloda- and 5-FU-containing combinations with irinotecan 1 Patt YZ et al. Ann Oncol 2004;15(Suppl. 3):iii88 (Abst 238P); 2 Borner M et al. Ann Oncol 2005;16:282–8 3 Garcia-Alfonso P et al. Eur J Cancer Suppl 2005;3:181 (Abst 641); 4 Ahn J et al. J Clin Oncol 2005;23:299s (Abst 3714) 5 Köhne C et al. J Clin Oncol 2005;23:252s (Abst 3525); 6 Douillard JY et al. Lancet 2000;355:1041–7

36. Sequential arm (n=194) Randomisation (n=820; 382 evaluable) Combination arm (n=188) CAIRO: phase III study of combination versus sequential therapy Punt C et al. Eur J Cancer Suppl 2005;3:168 (Abst 600) Xeloda Irinotecan XELOX XELIRI XELOX 1st-line 2nd-line 3rd-line

37. First-line MCRC: XELIRI more grade 3/4 adverse events than Xeloda Diarrhoea HFS Vomiting Nausea Febrile Cholinergic neutropenia syndrome (all grades) 50 40 30 20 10 0 Patients (%) Xeloda (n=194) XELIRI (n=188) * ** * *p<0.05; **p≤0.01 Punt C et al. Eur J Cancer Suppl 2005;3:168 (Abst 600)

38. Second-line MCRC: irinotecan more acute, XELOX more chronic grade 3/4 AEs Diarrhoea Sensory Febrile HypersensitivityCholinergic neuropathyneutropenia reactionssyndrome (all grades)(all grades) 50 40 30 20 10 0 Irinotecan (n=109) XELOX (n=79) * ** *p<0.05; **p≤0.01 Patients (%) Punt C et al. Eur J Cancer Suppl 2005;3:168 (Abst 600)

39. Sequence vs combination: similar incidence of grade 3/4 adverse events Diarrhoea Fatigue HFS Nausea Vomiting Cholinergic syndrome (all grades) 50 40 30 20 10 0 Sequential (n=194) Combination (n=188) *  60-day all-cause mortality: sequential 3%; combination 6.7% *p<0.05 Patients (%) Punt C et al. Eur J Cancer Suppl 2005;3:168 (Abst 600)

40. First-line XELIRI versus 5-FU-based combinations with irinotecan  Comparable response rates, TTP and overall survival  Favourable safety profile  Improved patient convenience

41. Oral Xeloda offers freedom without a loss of effective management  Proven compliance in clinical trials  Patients prefer oral chemotherapy  Home-based treatment: patients lead more normal life  Less time in hospital = more time with family  Patient education is a priority –time allocated before treatment begins –patients advised on side-effect management upfront –telephone follow-up  Oral Xeloda simplifies increasingly complex regimens

42. Replacing infused 5-FU/LV with Xeloda: less time wasted per patient 1 Köhne CH et al. J Clin Oncol 2003;21:3721–8 2 de Gramont A et al. J Clin Oncol 1997;15:808–15; 3 Van Cutsem E et al. Br J Cancer 2004;90:1190–7  Less time in hospital = more face-to-face time with family

43. CAPOX and CAPIRI: similar high first-line efficacy  First-line CAPIRI and CAPOX were both well tolerated Grothey A et al. J Clin Oncol 2004;22(Suppl.):253s (Abst 3534) CAPIRI: Xeloda 1000mg/m 2 bid, d1–14, q21d + irinotecan 80mg/m 2 d1, 8 CAPOX: Xeloda 1000mg/m 2 bid, d1–14, q21d + oxaliplatin 70mg/m 2 d1, 8

44. Xeloda: the backbone of first-line therapy for MCRC  Xeloda: superior response rate, similar TTP and OS, favourable safety compared with 5-FU/LV  XELOX: ideal combination, effective and well tolerated  XELIRI: effective, long-term treatment, with appropriate management of adverse events  After discontinuation of combination, Xeloda allows continued oral treatment –maximising response duration first-line –freedom from infusions, continued efficacy with minimal side effects