ESMO/ECCO Presidential Session III NO16968: XELOXA Adjuvant Treatment with Capecitabine and Oxaliplatin (XELOX) in Stage III Colon Cancer ESMO/ECCO Presidential Session III D. Haller, J. Tabernero, J. Maroun, F. de Braud, T. Price, E. Van Cutsem, M. Hill, F. Gilberg, K. Rittweger, H.-J. Schmoll

Rationale for XELOXA trial In 2002, when planning the study, the standard of care for adjuvant treatment of colon cancer was bolus 5- FU/LV (either Mayo Clinic or Roswell Park regimen) Based on upcoming results of X-ACT trial, capecitabine was expected to be at least equivalent to bolus 5-FU/LV in stage III colon cancer Two large trials were ongoing investigating the additional benefit of oxaliplatin to bolus or infusional 5-FU/LV (NSABP C-07 and MOSAIC)

Rationale for XELOXA trial In order to investigate oral fluoropyrimidines plus oxaliplatin, based on the X-ACT trial, capecitabine was chosen as a partner with oxaliplatin vs the standard of care at the time (bolus 5-FU/LV) XELOXA became the third of 3 parallel conducted studies (NSABP C-07, MOSAIC and XELOXA) investigating the role of oxaliplatin in adjuvant treatment of colon cancer In contrast to NSABP C-07 and MOSAIC, which included stage II and III patients, XELOXA investigated only stage III given the preliminary results of the X-ACT trial (stage III disease only)

Adjuvant XELOX vs 5-FU/LV: NO16968 (XELOXA) Phase III trial R A N D O M I S A T I O N XELOX (6 months) capecitabine 1000mg/m2 bid d1–14 oxaliplatin130mg/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] 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). n=942 Primary endpoint: superiority of DFS Secondary endpoints: RFS, OS, tolerability

Eligibility 18 years old, ECOG 1 Stage III colon carcinoma, 1 positive lymph node Randomised 8 weeks after surgery Informed consent Normal 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

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

Patient demographics XELOX n=944 5-FU/LV n=942 Male (%) 54 53 Age (median, range) 61 (22–83) 62 (24–82) ECOG (0/1) (%) 75/25 78/22 CEA (normal/abnormal) (%) 92/8 93/7 Cr clearance (mL/min) (%) 30–50 50–80 >80 3 40 57 3 42 56 ITT population

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

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

Efficacy Results

Primary endpoint met: superior DFS with XELOX 1.0 5-FU/LV 0.8 0.6 0.4 HR=0.80 (95% CI: 0.69–0.93) p=0.0045 0.2 0.0 1 2 3 4 5 6 Years ITT population

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

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

5-year DFS: benefit with XELOX maintained and increased over time 70.9% 68.4% 66.1% 1.0 5-FU/LV 66.5% 62.3% 59.8% 0.8 Δ at 3 years: 4.5% 0.6 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

DFS across stratification factors Favours XELOX Favours 5-FU n CI HR All 1886 0.69–0.93 0.80 Positive lymph nodes ≤3 1222 0.59–0.90 0.73 ≥4 664 0.71–1.11 0.89 Abnormal 140 0.56–1.32 0.86 CEA baseline value Normal 1724 0.66–0.92 0.78 Mayo 1331 0.64–0.92 0.77 5-FU/LV regimen Roswell 555 0.64–1.17 0.87 0.2 0.4 0.6 1 2 3 4 5 HR ITT population

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

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

Cross-trial comparison of MOSAIC and XELOXA: OS in stage III disease 1.0 1.0 XELOXA (57 mo) 0.8 0.8 MOSAIC1 (81.9 mo) 0.6 0.6 XELOX FOLFOX4 5-FU/LV LV5FU2 0.4 0.4 2 4 6 8 2 4 6 8 Years Years ITT population 1. André et al. JCO 2009

Cross-trial comparison of MOSAIC and XELOXA: OS in stage III disease 5-yr OS 6-yr OS NO16968 (XELOXA)* 1.0 XELOX (n=944) 77.6% – MOSAIC1** FOLFOX4 (n=672) – 72.9% 0.8 0.6 0.4 1 2 3 4 5 6 7 8 Years *Median observation time: 57.0 months **Median follow-up: 81.9 months ITT population 1. André et al. JCO 2009

NO16968 (XELOXA): conclusions Efficacy XELOX significantly improves DFS and RFS compared with bolus 5-FU/LV trend to improved OS with XELOX; follow-up ongoing Ease of administration fewer study visits, no pumps or catheters Favourable safety profile XELOX is a new option and a new standard for patients with stage III colon cancer

Thank you To the 1886 patients and their families To the participating 226 centres and investigators To the nurses and study coordinators To the NO16968 (XELOXA) Steering Committee And everybody else who made this contribution to the advancement of patient care possible