Phase III Trial of Capecitabine + Oxaliplatin vs Phase III Trial of Capecitabine + Oxaliplatin vs. Bolus 5-FU/LV in Stage III Colon Cancer (NO16968) Impact of Age on Disease-free Survival 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. Schmoll10 1University of Pennsylvania, Philadelphia, USA; 2Glasgow University, Glasgow, Scotland; 3Vall d'Hebron University Hospital, Barcelona, Spain; 4Ottawa Regional Cancer Centre, Ottawa, Canada; 5Istituto Europeo di Oncologia, Milan, Italy; 6The Queen Elizabeth Hospital, Adelaide, Australia; 7University Hospital Gasthuisberg, Leuven, Belgium; 8Maidstone Hospital, Maidstone, UK; 9Hoffmann-La Roche, Basel, Switzerland; 10Martin Luther University, Halle, Germany

Background Adjuvant 5-FU/LV demonstrated benefit in older patients compared with surgery alone1 Oral capecitabine is at least equivalent to bolus 5-FU/LV in disease-free survival (DFS) and overall survival (OS) as adjuvant therapy in patients with stage III colon cancer2 Older patients (≥70 years) treated with capecitabine also showed improved outcome vs. 5-FU/LV (X-ACT)2 Recent abstract presentation of the ACCENT database concluded that newer adjuvant regimens (e.g. oxaliplatin combinations) were not associated with significant efficacy benefits vs. 5-FU/LV in patients ≥70 years compared with younger patients3 1. Sargent et al. NEJM 2001;345:1091–1097; 2. Twelves et al. NEJM 2005;352:2696–2704 3. McCleary et al. J Clin Oncol 2009;27(Suppl. 15s):Abst 4010

MOSAIC: DFS by age MOSAIC trial demonstrated efficacy of FOLFOX4 vs. LV5FU2 is not maintained in patients ≥65 years4 Prognostic factor (n) Hazard ratio (95% CI) FOLFOX4 better LV5FU2 better 0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2 2.4 Overall Age ≥65 (463) <65 (884) 4. André et al. J Clin Oncol 2009;27:3109–3116

ACCENT: efficacy in overall population Age Endpoint (HR (95% CI) Experimental vs. control IV 5-FU/LV Deaths with 6 mo Exp vs. control % (p-value) DFS* OS* TTR* <70 years n=10,499 0.85 (0.79, 0.91) 0.84 (0.79, 0.91) 0.89 vs. 0.79 (p=0.58) ≥70 years n=2,170 1.11 (0.97, 1.28) 1.13 (0.96, 1.32) 1.13 (0.97, 1.32) 2.71 vs. 2.11 (p=0.37) Interaction of age by treatment, p-value 0.005 0.004 *Values <1 favor experimental arm 3. McCleary et al. J Clin Oncol 2009;27(Suppl. 15s):Abst 4010

ACCENT: efficacy of oxaliplatin-based (MOSAIC/C-07) combinations by age Endpoint (HR (95% CI) Experimental vs. control IV 5-FU/LV Deaths with 6 mo Exp vs. control % (p-value) DFS* OS* TTR* <70 years n=3,977 0.77 (0.68, 0.86) 0.81 (0.71, 0.93) 0.76 (0.67, 0.86) 0.81 vs. 0.81 (p=1.0) ≥70 years n=703 1.04 (0.80, 1.35) 1.19 (0.90, 1.57) 0.92 (0.69, 1.23) 2.57 vs. 1.37 (p=0.25) Interaction of age by treatment, p-value 0.016 0.037 0.21 *Values <1 favor experimental arm 3. McCleary et al. J Clin Oncol 2009;27(Suppl. 15s):Abst 4010

NO16968: trial design Primary endpoint: DFS R A N D O M I Z A T I O N XELOX (6 months) capecitabine 1000 mg/m2 bid d1–14 oxaliplatin130 mg/m2 d1 q3w 8 cycles n=944 Chemo/ radiotherapy-naive stage III colon ≤8 weeks since resection N=1886 Bolus 5-FU/LV (6 months) Mayo Clinic [n=664] or Roswell Park [n=278] n=942 Centres pre-specified use of Mayo Clinic or Roswell Park regimens. Mayo Clinic Leucovorin 20 mg/m2 i.v. bolus injection + 5-fluorouracil 425 mg/m2 i.v. bolus injection daily on days 1-5 of a 4 week cycle, for a total of 6 cycles (24 weeks). Roswell Park Leucovorin 500 mg/m2 by 2 hour i.v. infusion + 5-fluorouracil 500 mg/m2 i.v. bolus injection daily on Day 1 of weeks 1-6 of an 8 week cycle, for a total of 4 cycles (32 weeks). Primary endpoint: DFS Secondary endpoints: RFS, OS, tolerability

NO16968: eligibility 18 years old, ECOG 1 Stage III colon carcinoma, 1 positive lymph node Randomized 8 weeks after surgery Informed consent Normal renal function or mild renal impairment No seizures, CNS disorders, psychiatric disability, cardiac disease (CHF, symptomatic CAD or arrhythmias), or MI 12 months Normal neutrophils, platelets, creatinine, bilirubin, ALAT, ASAT, alkaline phosphatase

NO16968: stratification factors Patients stratified by: Geographic region Number of lymph nodes involved (≤3 vs. ≥4) Baseline CEA (normal vs. abnormal) 5-FU/LV regimen (Mayo vs. Roswell Park) Number of lymph nodes sampled per geographical region

NO16968: patient demographics XELOX (n=944) 5-FU/LV (n=942) Male, % 54 53 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, % 0 1 75 25 78 22 CEA, % normal 92 93 Cr clearance (mL/min), % 30–50 50–80 >80 3 40 57 3 42 56 ITT population

NO16968: primary endpoint met – superior DFS with XELOX (ESMO 2009) HR=0.80 (95% CI: 0.69–0.93) p=0.0045 1.0 0.8 XELOX 0.6 5-FU/LV 0.4 0.2 0.0 1 2 3 4 5 6 Years ITT population 5. Haller et al. Eur J Cancer Suppl 2009;7:4(Abst 5LBA)

NO16968: DFS benefit with XELOX maintained and increased over time 3-year DFS 4-year DFS 5-year DFS 70.9% 68.4% 66.1% 1.0 66.5% 62.3% 59.8% 0.8 Δ at 3 years: 4.5% XELOX 0.6 5-FU/LV Δ at 4 years: 6.1% Δ at 5 years: 6.3% 0.4 0.2 0.0 1 2 3 4 5 6 Years ITT population

NO16968: trend toward improved OS with XELOX 5-year OS 1.0 77.6% 74.2% 0.8 XELOX 5-FU/LV HR=0.87 (95% CI: 0.72–1.05) p=0.1486 0.6 Δ at 5 years: 3.4% 0.4 0.2 0.0 1 2 3 4 5 6 Years ITT population

Subgroup analysis of 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 ACCENT and MOSAIC findings are FOLFOX- or oxaliplatin-specific Determine relapse-free survival (RFS)

NO16968 subgroup analysis of DFS by age 3-year DFS Hazard ratio (95% CI) XELOX 5-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 0.79 (0.66, 0.94) ≥70 years, n=409 66% 60% 0.87 (0.63, 1.18) ITT population

NO16968 subgroup analysis of RFS by age 3-year RFS Hazard ratio (95% CI) XELOX 5-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 61% 0.83 (0.60,1.15) ITT population

NO16968 subgroup analysis of OS by age 5-year OS Hazard ratio (95% CI) XELOX 5-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 76% 0.86 (0.69,1.08) ≥70 years, n=409 69% 67% 0.94 (0.66,1.34) ITT population

Comparison with ACCENT analysis Hazard ratio (95% CIs)* DFS OS ACCENT analysis3† <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) NO16968 <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) *Values <1 favor oxaliplatin-based therapy vs. 5-FU/LV. †Data for oxaliplatin-based regimens. 3. McCleary et al. J Clin Oncol 2009;27(Suppl. 15s):Abst 4010

NO16968: treatment exposure by age Mean value XELOX 5-FU/LV <70 years (n=748) ≥70 years (n=190) (n=711) (n=215) Duration of therapy, days 5-FU – 175 164 Capecitabine 158 130 Oxaliplatin 154 124 Dose intensity 0.82 0.76 0.78 0.59 0.79 0.63 Safety population

NO16968: safety by age Grade 3/4 AEs, % XELOX 5-FU/LV <70 years All grade 3/4 57 70 51 60 Diarrhea 18 26 19 25 Nausea/vomiting 8 11 6 5 Stomatitis <1 1 9 Neutropenia* 10 16 17 Febrile neutropenia 4 Hand-foot syndrome Neurosensory *Includes granulocytopenia Safety population

NO16968 (XELOXA): conclusions XELOX significantly improves DFS compared with bolus 5-FU/LV as adjuvant therapy for stage III colon cancer XELOX efficacy maintained in patients ≥65 and ≥70 years Efficacy in the elderly subgroup achieved despite decreased treatment duration and dose intensity These findings differ from those of the MOSAIC study and the ACCENT analysis Reasons for this apparent difference are unknown Current analysis supports consideration of XELOX for patients with stage III colon cancer, regardless of age

Acknowledgements 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

Next steps Large pool of data from NO16968 is currently under evaluation – more analyses will be presented at future congresses in 2010 Current findings and later analyses expected to further influence treatment practice

References Sargent et al. NEJM 2001;345:1091–1097 Twelves et al. NEJM 2005;352:2696–2704 McCleary et al. ASCO 2009 (poster 4010) André et al. J Clin Oncol 2009;27:3109–116 Haller D, et al. Eur J Cancer Suppl 2009;7:4 (Abst 5LBA)