1) The document discusses several studies evaluating different adjuvant chemotherapy regimens for stage III colon cancer. 2) The X-ACT trial found that capecitabine (Xeloda) resulted in superior disease-free survival and a trend towards improved overall survival compared to bolus 5-FU/LV, with a better safety profile. 3) The MOSAIC trial showed that adding oxaliplatin (FOLFOX) to 5-FU/LV improved overall survival compared to 5-FU/LV alone in stage III colon cancer patients. 4) The XELOXA trial found that capecitabine plus oxaliplatin (XELOX) resulted in

1. The evolving landscape of adjuvant treatment of colon cancer

2. Colon cancer survival rate *SEER database – O’Connell et al. J Natl Cancer Inst 2004 † US National Cancer Database – Greene et al. Ann Surg 2002 Eligible for adjuvant treatment Eligible for adjuvant treatment No adjuvant treatment? 27 † – 44* IIIc = Tx, N2 42 † – 64* IIIb = T3 or T4, N1 60 † – 83* IIIa = T1 or T2, N1 72* IIb = T4, N0 85* IIa = T3, N0 93* I = T1 or T2, N0 5-year survival (%) Stage (AJCC 6 th Edition)

7. X-ACT: trend to superior DFS with Xeloda 0.4 Xeloda (n=1 004) 5-FU/LV (n=983) Years 5-year DFS (%) 60.8 56.7 0.6 0.8 1.0 1 2 3 4 5 6 7 8 Absolute difference at 5 years: 4.1% 0 Estimated probability ITT population HR=0.88 (95% CI: 0.77–1.01) p=0.0682 Twelves et al. ASCO GI 2008

8. X-ACT: trend to superior OS with Xeloda Years 1 2 3 4 5 6 7 8 0 0.4 0.6 0.8 1.0 Estimated probability Absolute difference at 5 years: 3.1% HR=0.86 (95% CI: 0.74–1.01) p=0.0600 Xeloda (n=1 004) 5-FU/LV (n=983) 5-year OS (%) 71.4 68.4 ITT population Twelves et al. ASCO GI 2008

9. X-ACT: improved safety with Xeloda Neutropenia Nausea/ vomiting Stomatitis Diarrhoea Febrile neutropenia HFS Patients (%) Scheithauer et al. Ann Oncol 2003 * * * * *p<0.001 Xeloda (n=993) 5-FU/LV (n=974) Grade 3 / 4 AEs

12. MOSAIC – superior OS with adjuvant oxaliplatin in stage III patients 4 6 2 8 0 0.0 0.2 0.4 0.6 0.8 1.0 Estimated probability FOLFOX4 (n=672) LV5FU2 (n=675) 6-year OS (%) 73.0 68.6 HR=0.80 (95% CI: 0.66–0.98) p=0.029 Absolute difference at 6 years: 4.4% André et al. J Clin Oncol 2009 Years

16. Safety Schmoll et al. JCO 2007 0.1 11.4 Neurosensory 15.9 8.8 Neutropenia 4.2 0.4 Febrile neutropenia 0.6 5.4 HFS 3.3 6.2 Vomiting 4.5 5.2 Nausea 8.9 0.6 Stomatitis 20.2 19.4 Diarrhoea 5-FU/LV n=926 XELOX n=938 Grade 3/4 AEs (%)

17. Cross-trial comparison with MOSAIC Schmoll et al. JCO 2007 *MOSAIC trial: André et al. NEJM 2004 12.4 11.4 Neurosensory 41.1 8.8 Neutropenia 1.8 0.4 Febrile neutropenia 2.0 5.4 HFS 5.8 6.2 Vomiting 5.1 5.2 Nausea 2.7 0.6 Stomatitis 10.8 19.4 Diarrhoea FOLFOX4 (MOSAIC)* n=1108 XELOX n=938 Grade 3/4 AEs (%)

18. Superior RFS with XELOX (excludes all non-cancer-related mortality) ITT population 1.0 0.0 0.2 0.4 0.6 0.8 0 1 2 3 4 5 6 XELOX 5-FU/LV 72.1% 69.7% 3-year RFS 67.5% 63.3% 4-year RFS 5-year RFS 60.9% 67.8% HR=0.78 (95% CI: 0.67–0.92) p=0.0024 Δ at 4 years: 6.4% Δ at 5 years: 6.9% Δ at 3 years: 4.6% Years

19. Immature Data: Trend to improved OS with XELOX ITT population 1.0 0.0 0.2 0.4 0.6 0.8 0 1 2 3 4 5 6 XELOX 5-FU/LV Δ at 5 years: 3.4% HR=0.87 (95% CI: 0.72–1.05) p=0.1486 Years 77.6% 5-year OS 74.2%

20. Cross-trial comparison of MOSAIC and XELOXA: OS in stage III disease Years 2 4 6 0.4 0.6 0.8 1.0 0 0.4 0.6 0.8 1.0 Years 1. André et al. JCO 2009 8 2 4 6 0 8 XELOX 5-FU/LV FOLFOX4 LV5FU2 XELOXA (57 mo) MOSAIC 1 (81.9 mo) ITT population

21. Cross-trial comparison of MOSAIC and XELOXA: OS in stage III disease 1.0 0.6 0.8 1. André et al. JCO 2009 1 2 3 4 5 6 7 8 Years XELOX (n=944) FOLFOX4 (n=672) – 5-yr OS 6-yr OS 72.9% 77.6% NO16968 (XELOXA)* MOSAIC 1 ** – *Median observation time: 57.0 months ** Median follow-up: 81.9 months ITT population 0.4 0

22. Adjuvant XELOX: favourable toxicity compared with FOLFOX4 and FLOX Grade 3 / 4 AEs Patients (%) XELOX 1 (n=938) FOLFOX4 2 (n=1 108) FLOX 3 (n=1 200) Cross-trial comparison † Not reported Neutropenia Nausea Stomatitis Diarrhoea Febrile neutropenia HFS Vomiting Neurosensory † † 1. Schmoll et al. J Clin Oncol 2007 2. André et al. N Engl J Med 2004; 3. Kuebler et al. J Clin Oncol 2007 0 10 20 30 40 50