D. Haller, 1 J. Cassidy, 2 J. Tabernero, 3 J. Maroun, 4 F. de Braud, 5 T. Price, 6 E. Van Cutsem, 7 M. Hill, 8 F. Gilberg, 9 H-J. Schmoll 10 1 University of Pennsylvania, Philadelphia, USA; 2 Glasgow University, Glasgow, Scotland; 3 Vall d'Hebron University Hospital, Barcelona, Spain; 4 Ottawa Regional Cancer Centre, Ottawa, Canada; 5 Istituto Europeo di Oncologia, Milan, Italy; 6 The Queen Elizabeth Hospital, Adelaide, Australia; 7 University Hospital Gasthuisberg, Leuven, Belgium; 8 Maidstone Hospital, Maidstone, UK; 9 Hoffmann-La Roche, Basel, Switzerland; 10 Martin Luther University, Halle, Germany Phase III Trial of Capecitabine + Oxaliplatin vs Bolus 5-FU/LV in Stage III Colon Cancer (NO16968): Impact of Age on DFS and OS

2 Background 1. Sargent et al. NEJM 2001;345:1091–1097; 2. Twelves et al. NEJM 2005;352:2696– André et al. J Clin Oncol 2009;27:3109–3116; 4. McCleary et al. ASCO 2009 (poster 4010) Adjuvant 5-FU/LV demonstrated benefit in older patients compared with surgery alone 1 Oral capecitabine is at least equivalent to bolus 5-FU/LV for disease-free survival (DFS) and overall survival (OS) as adjuvant therapy in patients with stage III colon cancer 2 Older patients (≥70 years) treated with capecitabine also showed improved outcomes vs. 5-FU/LV (X-ACT) 2 Recent data from the MOSAIC trial and ACCENT database demonstrated that newer adjuvant regimens (e.g. oxaliplatin combinations) were not associated with significant efficacy benefits vs. 5-FU/LV in patients ≥65 years compared with younger patients 3,4

3 MOSAIC: DFS by age 3 MOSAIC trial demonstrated efficacy of FOLFOX4 vs. LV5FU2 is not maintained in patients ≥65 years 3. André et al. J Clin Oncol 2009;27:3109–3116 Prognostic factor (n) Hazard ratio (95% CI) FOLFOX4 better LV5FU2 better Overall Age ≥65 years (n=463) <65 years (n=884)

4 ACCENT: efficacy not maintained in patients ≥70 years of age in overall population 4 Age Endpoint HR (95% CI) Experimental vs. Control IV 5-FU/LV Deaths within 6 mo Exp vs. Control % (p-value) DFS*OS*TTR* <70 years n=10, (0.79, 0.91) 0.84 (0.79, 0.91) 0.85 (0.79, 0.91) 0.89 vs (p=0.58) ≥70 years n=2, (0.97, 1.28) 1.13 (0.96, 1.32) 1.13 (0.97, 1.32) 2.71 vs (p=0.37) Interaction of age by treatment p=0.005 p=0.004 *Values <1 favor experimental arm (oxaliplatin-based regimens) 4. McCleary et al. ASCO 2009 (poster 4010)

5 ACCENT: efficacy of oxaliplatin-based (MOSAIC/C-07) combinations by age 4 Age Endpoint HR (95% CI) Experimental vs. Control IV 5-FU/LV Deaths within 6 mo Exp vs. Control % (p-value) DFS*OS*TTR* <70 years n=3, (0.68, 0.86) 0.81 (0.71, 0.93) 0.76 (0.67, 0.86) 0.81 vs (p=1.0) ≥70 years n= (0.80, 1.35) 1.19 (0.90, 1.57) 0.92 (0.69, 1.23) 2.57 vs (p=0.25) Interaction of age by treatment p=0.016p=0.037p=0.21 *Values <1 favor experimental arm (oxaliplatin-based regimens) 4. McCleary et al. ASCO 2009 (poster 4010)

6 Chemo/radiotherapy-naïve stage III colon cancer ≤8 weeks since resection (n=1886) n=944 n=942 RANDOMIZATION NO16968 (XELOXA): trial design 5 Bolus 5-FU/LV (6 months) Mayo Clinic (n=664) or Roswell Park (n=278) XELOX (6 months) capecitabine 1000 mg/m 2 bid d1–14 oxaliplatin130 mg/m 2 d1 q3w 8 cycles 5. Haller D, et al. Eur J Cancer Suppl 2009;7:4(Abst 5LBA)

7 NO16968 (XELOXA): patient demographics Characteristic XELOX (n=944) 5-FU/LV (n=942) Male, %5453 Median age, years (range) <70 years, n (%) ≥70 years, n (%) 61 (22–83) 752 (80) 192 (20) 62 (24–82) 725 (77) 217 (23) ECOG PS, % CEA, % normal9293 Creatinine clearance, % 30–50 mL/min 50–80 mL/min >80 mL/min

8 NO16968 (XELOXA) primary endpoint met: superior DFS with XELOX and benefit maintained and increased over time Years ITT population Δ at 4 years: 6.1% Δ at 5 years: 6.3% Δ at 3 years: 4.5% 70.9% 3-year DFS 66.5% 5-year DFS 59.8% 66.1% XELOX 5-FU/LV 4-year DFS 62.3% 68.4% HR=0.80 (95% CI: 0.69–0.93) p=0.0045

9 NO16968 (XELOXA): trend toward improved OS with XELOX ITT population XELOX 5-FU/LV Δ at 5 years: 3.4% HR=0.87 (95% CI: 0.72–1.05) p= Years 77.6% 5-year OS 74.2%

10 NO16968 (XELOXA): subgroup analysis Survival outcomes by age – analysis performed to: Compare with data presented from ACCENT and MOSAIC Assess treatment effects of XELOX vs. 5-FU/LV in patients by age: –≥ 65 (planned) and ≥ 70 years (unplanned) Determine if findings from ACCENT meta-analysis also apply to XELOX regimen Determine relapse-free survival (RFS) overall and according to age

11 NO16968 (XELOXA): subgroup analysis of DFS by age Age group 3-year DFS Hazard ratio (95% CI) XELOX5-FU/LV <65 vs. ≥65 years <65 years (n=1142)72%69%0.80 (0.65–0.98) ≥65 years (n=744)68%62%0.81 (0.64–1.03) <70 vs. ≥70 years <70 years (n=1477)72%69%0.79 (0.66–0.94) ≥70 years (n=409)66%60%0.87 (0.63–1.18) Interaction of age by treatment* p= ITT population *Multiple Cox regression This non-significant p-value indicates that XELOX efficacy is positive, irrespective of age

12 NO16968 (XELOXA): subgroup analysis of OS by age ITT population Age group 5-year OS Hazard ratio (95% CI) XELOX5-FU/LV <65 vs. ≥65 years <65 years (n=1142)80%77%0.87 (0.67–1.13) ≥65 years (n=744)73%70%0.90 (0.68–1.19) <70 vs. ≥70 years <70 years (n=1477)80%76%0.86 (0.69–1.08) ≥70 years (n=409)69%67%0.94 (0.66–1.34) Interaction of age by treatment* p= *Multiple Cox regression This non-significant p value indicates that XELOX efficacy is positive, irrespective of age

13 NO16968 (XELOXA): subgroup analysis of RFS by age Age group 3-year RFS Hazard ratio (95% CI) XELOX5-FU/LV Overall (n=1886)72%67%0.78 (0.67–0.92) <70 vs. ≥70 years <70 years (n=1477)73%69%0.78 (0.65–0.93) ≥70 years (n=409)69%61%0.83 (0.60–1.15) ITT population

14 Comparison with ACCENT analysis *Values <1 favor oxaliplatin-based therapy vs. 5-FU/LV; † Data for oxaliplatin-based regimens 4. McCleary et al. ASCO 2009 (poster 4010) Hazard ratio (95% CIs)* DFSOS ACCENT analysis 4† <70 years (n=3877)0.77 (0.68–0.86)0.81 (0.71–0.93) ≥70 years (n=703)1.04 (0.80–1.35)1.18 (0.90–1.57) Interaction of age by treatmentp=0.016p=0.037 NO16968 (XELOXA) <70 years (n=1477)0.79 (0.66–0.94)0.86 (0.69–1.08) ≥70 years (n=409)0.87 (0.63–1.18)0.94 (0.66–1.34) Interaction of age by treatmentp=0.6222p=0.7065

15 NO16968 (XELOXA): safety by age *Includes granulocytopenia Safety population Grade 3/4 AEs, % XELOX5-FU/LV <70 years (n=748) ≥70 years (n=190) <70 years (n=711) ≥70 years (n=215) All grade 3/4 AEs Diarrhea Nausea/vomiting81165 Stomatitis<1198 Neutropenia* Febrile neutropenia<1 44 Hand-foot syndrome64<1 Neurosensory11 <10

16 NO16968 (XELOXA): conclusions XELOX results in superior DFS compared with bolus 5-FU/LV as adjuvant treatment for patients with stage III colon cancer These findings confirm the benefits previously demonstrated with the addition of oxaliplatin to 5-FU in stage III patients Efficacy benefits are maintained in patients ≥65 and ≥70 years in contrast to results from ACCENT and MOSAIC in which no significant benefit is shown with FOLFOX in this age group: –reasons for this apparent difference are unknown OS data thus far indicate a trend toward superior survival with XELOX XELOX is an effective adjuvant therapy and should be considered for all eligible patients, without an arbitrary upper age limit

17 Acknowledgments Thank you to the: –1886 patients and their families –226 participating centers and investigators –nurses and study coordinators –NO16968 (XELOXA) Steering Committee –others who made this contribution to the advancement of patient care possible

18 References 1.Sargent et al. NEJM 2001;345:1091– Twelves et al. NEJM 2005;352:2696– André et al. J Clin Oncol 2009;27:3109– McCleary et al. J Clin Oncol 2009;27(15S): Haller D, et al. Eur J Cancer Suppl 2009;7:4(Abst 5LBA)