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

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 Hoff P et al. J Clin Oncol Van Cutsem E, et al. J Clin Oncol Schmöll HJ, et al. J Clin Oncol 2005 (Abst 3523)

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:

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

Logistic regression SO 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/ –2.31<0.001 Grade – Grade 3/4 GI –2.36<0.001 Serious AE – Grade 3/4 neutropenia – Grade 3/4 lab neutrophils – Dose reductions –2.25<0.001 Discontinuations –2.65<0.001

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 – – Grade 4US Rest of World Asia – – Grade 3/4 GIUS Rest of World Asia – –3.77 <0.001 Serious AEUS Rest of World Asia – –

Adverse event Adjusted relative risk Overall p-value for region effect Relative risk95% CI Grade 3/4 US neutropeniaRest of World Asia – – Grade 3/4 US laboratory Rest of World neutrophils Asia – – Dose US reductions Rest of World Asia – – DiscontinuationUS Rest of World Asia – –1.28 <0.001 Logistic regression NO16968: comparison US vs. RoW vs. Asia (2)

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

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