1. 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

2. 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)

3. 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)

4. 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

5. 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

6. 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

7. 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– – >80
ITT population

8. 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

9. 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

10. Efficacy Results

11. 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

12. 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

13. 4-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
Δ at 4 years: 6.1%
0.4
0.2
0.0 1 2 3 4 5 6
Years
ITT population

14. 5-year DFS: benefit with XELOX maintained and increased over time
70.9% %
66.1%
1.0
5-FU/LV
66.5% %
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

15. 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

16. Superior RFS with XELOX (excludes all non-cancer-related mortality)
3-year RFS
4-year RFS
5-year RFS
1.0
XELOX
72.1% %
67.8%
5-FU/LV
67.5% %
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

17. 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

18. 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

19. 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

20. 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

21. 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