1. 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

2. 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

3. 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

4. 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 (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 (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

5. 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 (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 (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

6. 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

7. 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

8. 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

9. 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, %
75 25
78 22
CEA, % normal 92 93
Cr clearance (mL/min), % 30– – >80
ITT population

10. 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)

11. 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

12. 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

13. 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)

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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

20. 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

21. 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

22. 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

23. 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)