NO16968: XELOXAAdjuvant 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)
Chemo/radiotherapy-naive
stage III colon ≤8 weeks since resection
N=1886
• Primary endpoint: superiority of DFS
• Secondary endpoints: RFS, OS, tolerability
n=944
n=942
RANDO MISATION
Adjuvant XELOX vs 5-FU/LV: NO16968 (XELOXA) Phase III trial
Bolus 5-FU/LV (6 months) Mayo Clinic [n=664]
orRoswell Park [n=278]
XELOX (6 months) capecitabine 1000mg/m2 bid d1–14
oxaliplatin130mg/m2 d1 q3w
8 cycles
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
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 93/7Cr clearance (mL/min) (%) 30–50 50–80 >80
340 57
34256
ITT population
Patient demographics
Safety
Grade 3/4 AEs (%)XELOXn=938
5-FU/LVn=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 0.6
Neurosensory 11.4 0.1
Schmoll et al. JCO 2007
Cross-trial comparison with MOSAIC
Schmoll et al. JCO 2007*MOSAIC trial: André et al. NEJM 2004
Grade 3/4 AEs (%)XELOXn=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
Efficacy Results
Primary endpoint met:superior DFS with XELOX
HR=0.80 (95% CI: 0.69–0.93)p=0.0045
ITT population
1.0
0.0
0.2
0.4
0.6
0.8
0 1 2 3 4 5 6
Years
XELOX 5-FU/LV
3-year DFS:benefit with XELOX maintained and increased over time
XELOX 5-FU/LV 1.0
0.0
0.2
0.4
0.6
0.8
0 1 2 3 4 5 6
Years
ITT population
Δ at 3 years: 4.5%
70.9%
3-yearDFS
66.5%
4-year DFS:benefit with XELOX maintained and increased over time
XELOX 5-FU/LV 1.0
0.0
0.2
0.4
0.6
0.8
0 1 2 3 4 5 6
Years
ITT population
Δ at 4 years: 6.1%
Δ at 3 years: 4.5%
70.9% 68.4%
3-yearDFS
66.5% 62.3%
4-yearDFS
5-year DFS:benefit with XELOX maintained and increased over time
XELOX 5-FU/LV 1.0
0.0
0.2
0.4
0.6
0.8
0 1 2 3 4 5 6
Years
ITT population
Δ at 4 years: 6.1% Δ at 5 years: 6.3%
Δ at 3 years: 4.5%
70.9% 68.4%
3-yearDFS
66.5% 62.3%
4-yearDFS
5-yearDFS
59.8%66.1%
DFS across stratification factors
All
Positive lymph nodes
CEA baseline value
5-FU/LV regimen
n CI HR
1886 0.69–0.93 0.80
1222664
0.59–0.900.71–1.11
0.730.89
1401724
0.56–1.320.66–0.92
0.860.78
1331
555
0.64–0.92
0.64–1.17
0.77
0.87
HR
4
≤3≥4
AbnormalNormal
Mayo
Roswell
10.60.40.2 2
ITT population
53
Favours XELOX Favours 5-FU
Superior RFS with XELOX(excludes all non-cancer-related mortality)
ITT population
1.0
0.0
0.2
0.4
0.6
0.8
0 1 2 3 4 5 6
XELOX 5-FU/LV
72.1% 69.7%
3-yearRFS
67.5% 63.3%
4-yearRFS
5-yearRFS
60.9%67.8%
HR=0.78 (95% CI: 0.67–0.92)p=0.0024
Δ at 4 years: 6.4% Δ at 5 years: 6.9%
Δ at 3 years: 4.6%
Years
Trend to improved OS with XELOX
ITT population
1.0
0.0
0.2
0.4
0.6
0.8
0 1 2 3 4 5 6
XELOX 5-FU/LV
Δ at 5 years: 3.4%
HR=0.87 (95% CI: 0.72–1.05)p=0.1486
Years
77.6%
5-yearOS
74.2%
Years
2 4 6
0.4
0.6
0.8
1.0
0
0.4
0.6
0.8
1.0
Years
1. André et al. JCO 2009
8 2 4 60 8
Cross-trial comparison of MOSAICand XELOXA: OS in stage III disease
XELOX
5-FU/LV
FOLFOX4
LV5FU2
XELOXA(57 mo) MOSAIC1
(81.9 mo)
ITT population
1.0
0.6
0.8
1. André et al. JCO 2009
1 2 3 4 5 6 7 8
Cross-trial comparison of MOSAICand XELOXA: OS in stage III disease
Years
XELOX (n=944)
FOLFOX4 (n=672) –
5-yr OS 6-yr OS
72.9%
77.6%
NO16968 (XELOXA)*
MOSAIC1**
–
*Median observation time: 57.0 months**Median follow-up: 81.9 monthsITT population
0.4
0
• 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
NO16968 (XELOXA): conclusions
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