1. Werner Scheithauer Professor of Internal Medicine, Cancer Center at the Vienna University Hospital, Austria

2. Capecitabine: the new standard chemotherapy in advanced gastric cancer? Werner Scheithauer University Hospital Vienna, Austria

3. Second most common cause of cancer mortality Worldwide: 934, 000 new cases and 700, 000 deaths/year Gastric cancer: a global disease www.cancer.gov Kamangar F, et al. J Clin Oncol 2006;24:2137–50  20/100,000 <10/100,000  10 to  20/100,000 Gastric cancer incidence

4. 17% 15% 68% 10–15% 25–30% 30–35% 25–30% Japan 1 Resectable Locally advanced Metastatic Western countries 2 Resectable Locally advanced Metastatic Unstaged 1 http://www.ncc.go.jp/en/ncch/annrep/2000 2 sanofi-aventis Internal Epidemiology Data Stage at diagnosis

5. Non-measurable lesions Variable study inclusion criteria Heterogeneous patient populations Inadequate number of patients Response rate rather than survival Palliative chemotherapy for advanced gastric cancer (AGC)

6. Chemotherapy improves survival in metastatic gastric cancer (MGC) Median OS (months) FAMTX 1 (n=30) BSC 1 (n=10) FEMTX 2 (n=21) BSC 2 (n=20) ELF 3 (n=31) BSC 3 (n=30) CLF 4 (n=51) BSC 4 (n=52) 1 Murad AM, et al. Cancer 1993;72:37–41; 2 Pyrhonen S, et al. Br J Cancer 1995;71:587–91; 3 Glimelius B, et al. Ann Oncol 1997;8:163–8; 4 Scheithauer W, et al. Second International Conference on Biology, Prevention and Treatment of GI Malignancy, Koln, Germany, 1995;68 (Abstract) 12 10 8 6 4 2 0 Chemotherapy Best supportive care (BSC) OS = overall survival; 5-FU = 5-fluorouracil FAMTX = 5-FU, doxorubicin, methotrexate FEMTX = 5-FU, epirubicin, methotrexate ELF = etoposide, leucovorin, 5-FU CLF = cisplatin, leucovorin, 5-FU

7. FAM = 5-FU, doxorubicin, mitomycin C FP = 5-FU, cisplatin; ECF = epirubicin, cisplatin, 5-FU BSC 1 5-FU monotherapy 2,3 FAM 2,4 FAMTX 5–7 FP 2,3,6 and ECF 5,8,9 4 months 7 months 6–7 months 7–9 months Median OS 1 Wagner AO, et al. Cochrane Database Syst Rev 2005;2:CD004064; 2 Kim NK, et al. Cancer 1993;71:3813–18 3 Ohtsu A, et al. J Clin Oncol 2003;21:54–9; 4 Wils JA, et al. J Clin Oncol 1991;9:827–31 5 Waters JS, et al. Br J Cancer 1999;80:269–72; 6 Vanhoefer U, et al. J Clin Oncol 2000;18:2648–57 7 Cocconi G, et al. Ann Oncol 2003;14:1258–63; 8 Ross P, et al. J Clin Oncol 2002;20:1996–2004 9 Webb A, et al. J Clin Oncol 1997;15:261–7 Survival has improved with conventional regimens

8. Chemotherapy in patients with MGC Conventional regimens prolong survival and achieve acceptable response rates BUT... Median OS still <12 months Complete response rate is low Response duration is short Inconvenient drug administration Regimens may be toxic No standard treatment –all options have similar survival outcomes and safety profiles –FP/ECF most common reference therapy in Europe There is a clear need for new active treatments

9. New treatment options for AGC aim to improve survival EpirubicinCisplatinFluorouracil

10. New treatment options for AGC aim to improve survival Paclitaxel Irinotecan Docetaxel Epirubicin?OxaliplatinCapecitabine, S-1

11. Capecitabine: the new standard chemotherapy in AGC?

12. FP 5-FU c.i. 800mg/m 2 day 1  5 cisplatin 80mg/m 2 day 1 every 3 weeks XP Capecitabine 1, 000mg/m 2 b.i.d. day 1  14 cisplatin 80mg/m 2 day 1 every 3 weeks AGC and/or MGC (n=316) n=156 n=160 RANDOMISATIONRANDOMISATION Primary endpoint: non-inferiority in PFS Can XP improve PFS versus FP? International phase III study in MGC (ML17032) Kang Y-K, et al. Ann Oncol 2006;17(Suppl. 6):vi19 (Abstract O-003) PFS = progression-free survival; b.i.d. = twice daily c.i. = continuous infusion

13. Why should XP be more effective than FP? FP is a reference regimen for AGC Capecitabine monotherapy is effective and well tolerated in AGC 1–4 –ORR: 19–34%; SD: 30–56% –median TTP: 2.8–4.8 months –median OS: 8.1–10.0 months XP was effective and well tolerated in phase II study 5 –ORR: 55%; SD: 16.7% –median TTP: 5.8 months –median OS: 10.1 months 1 Hong YS, et al. Ann Oncol 2004;15:1344–7 2 Leon-Rodriguez E, et al. Ann Oncol 2002;13(Suppl. 5):191 (Abstract 708) 3 Sakamoto J, et al. Anticancer Drugs 2006;17:231–6 4 Koizumi W, et al. Oncology 2003;64:232–6 5 Kim TW, et al. Ann Oncol 2002;13:1893–8 ORR = overall response rate SD = stable disease TTP = time to progression

14. Primary endpoint met: XP improves PFS versus FP (HR=0.81 ) Per protocol HR = hazard ratio; CI = confidence interval Estimated probability HR=0.81 (95% CI: 0.63–1.04) Compared to HR upper limit 1.25, p=0.0008 02468101214161820222426 Months 1.0 0.8 0.6 0.4 0.2 0 XP (n=139) FP (n=137) 5.65.0 Kang Y-K, et al. Ann Oncol 2006;17(Suppl. 6):vi19 (Abstract O-003)

15. PFS: robust results in subgroups Kang Y-K, et al. Ann Oncol 2006; 17(Suppl. 6):vi19 (Abstract O-003) PP population Prior chemotherapy No prior chemotherapy Male Female  65 years >65 years KPS <80% KPS  80% 1 metastatic site  2 metastatic sites 276 28 248 185 91 238 38 30 246 98 178 HR (95% CI) Favours XPFavours FP 0.20.61.01.41.82.22.6 KPS = Karnofsky performance status

16. Estimated probability 02468101214161820222426283032 Months 1.0 0.8 0.6 0.4 0.2 0 HR=0.85 (95% CI: 0.64–1.13) Compared to HR upper limit 1.25, p=0.0076 10.59.3 XP (n=139) FP (n=137) XP versus FP also shows non-inferiority in OS (HR=0.85 ) Kang Y-K, et al. Ann Oncol 2006;17(Suppl. 6):vi19 (Abstract O-003) Per protocol

17. Superior response rate with XP versus FP RECIST confirmed response (%) XP (n=160) FP (n=156)p value ORR 95% CI 41 (33–49) 29 (22–37) 0.033 CR 2 30.720 PR39260.022 SD37420.421 PD10180.051 Intent-to-treat (ITT), investigators’ assessment Kang Y-K, et al. Ann Oncol 2006;17(Suppl. 6):vi19 (Abstract O-003) RECIST = Response Evaluation Criteria in Solid Tumours CR = complete response PR = partial response PD = progressive disease

18. Similar incidence of grade 3/4 adverse events: XP versus FP Grade 3/4 adverse events (AEs) Neutropenia Nausea/ vomiting Stomatitis Diarrhoea Febrile neutropenia Leucopenia HFS Kang Y-K, et al. Ann Oncol 2006;17(Suppl. 6):vi19 (Abstract O-003) Patients (%) XP (n=156) FP (n=155) 60 50 40 30 20 10 0 HFS = hand-foot syndrome

19. XP: a potential new standard chemotherapy in AGC As effective as FP Improved tolerability Avoids inconvenience and complications associated with infused 5-FU

20. Multicentre phase III REAL-2 trial: can capecitabine improve OS versus 5-FU? Locally advanced or metastatic oesophagogastric cancer (n=1,002) R A N D O M I S A T I O N Epirubicin Cisplatin Fluorouracil Epirubicin Oxaliplatin Fluorouracil Epirubicin Cisplatin Capecitabine Epirubicin Oxaliplatin Capecitabine Epirubicin 50mg/m 2 day 1 Cisplatin 60mg/m 2 vs oxaliplatin 130mg/m 2 day 1 5-FU 200mg/m 2 c.i. daily vs capecitabine 500–625mg/m 2 b.i.d. p.o. daily For 24 weeks: eight cycles every 3 weeks Cunningham D, et al. N Engl J Med 2008;358:36–46 p.o. = orally

21. Regimenn ORR (%) TTP (months) OS (months)Reference FOLFOX49456.2 8.6Louvet et al. 2002 FU(inf)/Ox55565.210.0Chao et al. 2004 FUFOX48546.511.4Dyster et al. 2005 FOLFOX461387.111.2DeVita et al. 2005 FLO41435.6 9.6Al-Batran et al. 2005 Why should EOC be more effective than ECF? Capecitabine is effective and well tolerated in AGC XP has become a new reference regimen for AGC Oxaliplatin has shown promising activity in phase II trials EOC = epirubicin, oxaliplatin, capecitabine FOLFOX = 5-FU, leucovorin, oxaliplatin; FU(inf)/Ox = 5-FU infusion, oxaliplatin FUFOX = 5-FU, oxaliplatin; FLO = 5-FU, leucovorin, oxaliplatin

22. REAL-2: can capecitabine replace 5-FU, can oxaliplatin replace cisplatin? In combination treatments of oesophagogastric cancer –can capecitabine replace 5-FU? –can oxaliplatin replace cisplatin? Primary endpoint of non-inferiority in OS for capecitabine versus 5-FU, oxaliplatin versus cisplatin (PP population) –based on ECF 1-year survival of 35%, 1,000 patients (250 per arm) needed to show non-inferiority (80% power, one-sided  =0.05) –upper limit of HR for experimental arms compared with standard arms should be <1.23 –secondary endpoint: superiority in OS among the four regimens (intent-to-treat) Cunningham D, et al. N Engl J Med 2008;358:36–46

23. HR=0.86 (95% CI: 0.80–0.99) REAL-2: primary endpoint met – non-inferior OS with capecitabine versus 5-FU Per protocol Estimated probability Capecitabine combinations (n=480) 5-FU combinations (n=484) 1.0 0.8 0.6 0.4 0.2 0 0122436486072 10.99.6 Months Cunningham D, et al. N Engl J Med 2008;358:36–46

24. Similar OS with oxaliplatin versus cisplatin HR=0.92 (95% CI: 0.8–1.1) Oxaliplatin combinations (n=474) Cisplatin combinations (n=490) 10.410.0 0122436486072 Months Estimated probability 1.0 0.8 0.6 0.4 0.2 0 Cunningham D, et al. N Engl J Med 2008;358:36–46 Per protocol

25. Superior OS with EOC versus ECF Intent-to-treat HR=0.80 (95% CI: 0.66–0.97) Log-rank p=0.02 Median OS (months) ECF (n=249) 9.9 EOC (n=239)11.2 0122436486072 Months Estimated probability 1.0 0.8 0.6 0.4 0.2 0 Cunningham D, et al. N Engl J Med 2008;358:36–46

26. Grade 3 / 4 AEs Neutropenia Nausea/ vomiting Stomatitis Diarrhoea Febrile neutropenia Thromboembolic events Cunningham D, et al. N Engl J Med 2008;358:36–46 Starling N, et al. Proc ASCO GI 2007 (Abstract 74) Patients (%) *p<0.05 compared with ECF Capecitabine-based regimens are well tolerated ECF (n=236) ECC (n=241) EOF (n=235) EOC (n=239) 60 50 40 30 20 10 0 * * * * * * * HFS

27. ORR (%) PFS* (months) OS* (months) ECC 1 466.7 9.9 ECF 1 416.2 9.9 EOC 1 487.011.2 EOF 1 426.5 9.3 XP 2 415.610.4 FP 2 295.0 8.9 REAL-2 versus ML17032: consistent efficacy with capecitabine regimens Response evaluated every 3 months in REAL-2, 1 every 1.5 months in ML17032 2 In REAL-2, 1 maximum treatment duration: 6 months 1 Cunningham D, et al. N Engl J Med 2008;358:36–46 2 Kang Y-K, et al. Ann Oncol 2006;17(Suppl. 6):vi19 (Abstract O-003) * * Intent-to-treat

28. Capecitabine plus platinum-based chemotherapy approved in Europe 1 Murad AM, et al. Cancer 1993;72:37–41 2 Vanhoefer U, et al. J Clin Oncol 2000;18:2648–57; 3 Van Cutsem E, et al. J Clin Oncol 2006;24:4991–7 4 Dank M, et al. J Clin Oncol 2005;23(Suppl. 16S):403s (Abstract 4003); 5 Cunningham D, et al. N Engl J Med 2008;358:36–46; 6 Kang Y-K, et al. Ann Oncol 2006;17(Suppl. 6):vi19 (Abstract O-003) Months BSC 1 FAMTX 2 FP 3 IF 4 EOF 5 DCF 3 ECF 5 XP 6 ECx 5 EOx 5 024681012 IF = irinotecan + 5-FU

29. Putting the evidence into practice: case study 45-year-old male; ECOG PS: 0 Chief complaint: epigastric pain No dysphagia or weight loss Gastroscopy: large ulceroinfiltrative lesion encircling the antral lumen Biopsy: tubular adenocarcinoma, M/D ECOG = Eastern Cooperative Oncology Group; PS = performance status

30. Abdomen and pelvis computed tomography (CT)

31. Patient received EOC chemotherapy Before treatment After cycle 2: PR 01 October 2004 22 August 2004 After cycle 4: ++PR After cycle 8: CR? 07 February 2005 10 November 2004

32. Upper limit of normal August 04 September 04 October 04 November 04 December 04 January 05 February 05 CEA (ng/mL) Carcinoembryonic antigen (CEA) levels 18 16 14 12 10 8 6 4 2 0

33. Patient received EOC chemotherapy Before treatmentAfter cycle 7 Biopsy: no cancer

34. Patient was in remission for 9 months without chemotherapy Chemotherapy stopped in February 2005 Patient followed-up every 3 months –abdomen and pelvis CT –gastrofiberscopy (GFS) –CEA

35. CT scans 22 September 2006 revealed disease progression

36. Patient received second-line chemotherapy Re-induction of EOC –four cycles: SD (for 4 months) Irinotecan 150mg/m 2 day 1, 14 plus mitomycin C 8mg/m 2 day 1 every 4 weeks 1,2 –four cycles: SD (for 2 months) Docetaxel 75mg/m 2 every 3 weeks 3 –three cycles: PD 1 Giuliani F, et al. Am J Clin Oncol 2005;28:581–5 2 Bamias A, et al. J Chemother 2003;15:275–81 3 Lee JL, et al. Cancer Chemother Pharmacol 2008;61:631–7

37. CEA: 20.9ng/mL 4 December 2007: patient with PD, alive no longer receiving treatment

38. What other capecitabine-based options are available?

39. Efficacy DCX 1 (n=40) DCF 2 (n=227) ORR (%) 95% CI 68 52–83 37 30–43 TTP/PFS (months)7.85.6 OS (months)16.99.2 1 Kang Y-K, et al. J Clin Oncol 2004;22(Suppl. 14S):329s (Abstract 4066) 2 Van Cutsem E, et al. J Clin Oncol 2006;24:4991–7 Integrating docetaxel in the treatment of AGC: high efficacy with capecitabine

40. TrialSettingn Advanced disease XP or FP ± trastuzumab (TOGA)HER2+ AGC 374 Capecitabine + cisplatin ± bevacizumabMGC 760 ECX  FOLFIRI vs FOLFIRI  ECX AGC/MGC 416 ECX ± panitumumab (REAL-3)AOGC 660 Operable disease Perioperative ECX ± bevacizumab (STO-3)Adjuvant1,100 XELOX vs observation (CLASSIC)Adjuvant1,024 Capecitabine: the backbone of future standards in gastric cancer HER2 = human epidermal growth factor receptor 2; AOGC = advanced oesophagogastric cancer XELOX = capecitabine + oxaliplatin

41. Capecitabine is effective and well tolerated –can replace 5-FU in current treatment regimens for AGC Further data will support the use of capecitabine in this indication Capecitabine is an effective, safe and convenient oral therapy for gastric cancer Conclusions