1. Tolerability of fluoropyrimidines differs by region Daniel G. Haller on behalf of: Cassidy J, Clarke S, Cunningham D, Van Cutsem E Hoff P, Rothenberg M, Saltz L, Schmöll H-J, Allegra C Bertino J, Douillard J-Y, Gustavsson B, Milano G O'Connell M, Rustum Y, Tabernero J, Fagerberg J Gilberg F, Sirzen F and Twelves C

2. Hypothesis Generation IMPACT analysis and other observations suggest differences in toxicity for patients receiving adjuvant bolus 5-FU/LV in different countries. 1  Limited information available on regional differences in fluoropyrimidine tolerability There is also controversy surrounding the tolerable capecitabine dose in Europe compared to the US:  Europe-labeled dose seems acceptable  Recommended dose in US considered too high Retrospective analysis of safety data conducted from 3 phase III trials involving 5-FU, capecitabine and oxaliplatin 2–4 to investigate these differences 1. IMPACT investigators. Lancet 1995 2. Hoff P et al. J Clin Oncol 2001 3. Van Cutsem E, et al. J Clin Oncol 2001 4. Schmöll HJ, et al. J Clin Oncol 2005 (Abst 3523)

3. Two identical phase III trials (SO14796, SO14695) in first-line MCRC: Trials Analyzed Prior adjuvant therapy > 6 months ago Capecitabine (n=596) 5-FU/LV (n=593) Endpoints Progression-free survival Overall survival Tolerability Curative resection < 8 wks prior to randomization ECOG PS < 1; No prior chemo- radio- or immunotherapy XELOX (n=938) 5-FU/LV (n=926) Endpoints Progression-free survival Overall survival Tolerability One phase III trial (NO16968 XELOXA) in adjuvant stage III colon cancer:

4. Methodology for regional safety comparison Regions:  US compared to non-US (all 3 studies)  US compared to rest of the world (RoW) and East Asia (NO16968 only) Multivariate analysis (logistic regression) adjusted for: age, gender, BMI, body surface, baseline creatinine clearance, ECOG PS and treatment (bolus 5-FU/LV, capecitabine, capecitabine + oxaliplatin) Interaction term between region and treatment to assess effect modification. Interaction assessed at p=0.05. If in adjusted model the interaction term is significant, stratified relative risks by treatment are compared

5. Logistic regression SO14796 + SO14695: comparison US vs. RoW Treatment-related adverse event Relative risk adjusted for age, gender, BMI, body surface, creatinine clearance, ECOG PS and treatment Overall p-value for region effect Relative risk95% CI Grade 3/41.771.35–2.31<0.001 Grade 41.720.91–3.240.094 Grade 3/4 GI1.721.25–2.36<0.001 Serious AE1.200.85–1.700.291 Grade 3/4 neutropenia1.511.01–2.250.044 Grade 3/4 lab neutrophils1.200.78–1.840.417 Dose reductions1.721.32–2.25<0.001 Discontinuations1.831.27–2.65<0.001

6. Logistic regression NO16968: comparison US vs. RoW vs. Asia (1) Adverse event Adjusted relative risk Overall p-value for region effect Relative risk95% CI Grade 3/4US Rest of World Asia 1.85 1.29 1.00 1.21–2.83 0.93–1.79 0.013 Grade 4US Rest of World Asia 2.59 1.24 1.00 1.09–6.15 0.62–2.47 0.028 Grade 3/4 GIUS Rest of World Asia 3.62 2.38 1.00 2.11–6.20 1.50–3.77 <0.001 Serious AEUS Rest of World Asia 2.87 2.10 1.00 1.52–5.39 1.22–3.63 0.005

7. Adverse event Adjusted relative risk Overall p-value for region effect Relative risk95% CI Grade 3/4 US neutropeniaRest of World Asia 0.96 0.63 1.00 0.53–1.73 0.41–0.95 0.025 Grade 3/4 US laboratory Rest of World neutrophils Asia 1.09 0.72 1.00 0.58–2.03 0.47–1.11 0.097 Dose US reductions Rest of World Asia 0.96 0.78 1.00 0.64–1.46 0.56–1.08 0.137 DiscontinuationUS Rest of World Asia 1.84 0.87 1.00 1.14–2.96 0.59–1.28 <0.001 Logistic regression NO16968: comparison US vs. RoW vs. Asia (2)

8. General conclusions More treatment-related toxicity reported in US compared to RoW:  in 1 st line MCRC (5-FU/LV or capecitabine)  in adjuvant setting (5-FU/LV or XELOX) When comparing East Asia, RoW and US in adjuvant setting, a ‘gradient’ of fluoropyrimidine toxicity observed:  East Asia – low  US – high

9. Potential factors explaining regional differences in fluoropyrimidine tolerability Methodology  reporting in clinical trials Baseline prognostic and predictive factors Food habits  impact of dietary folate Culture  Potentially influencing drug compliance Genetic polymorphisms affecting drug metabolism