Transcript NO16968 (XELOXA) Adjuvant treatment with XELOX in stage

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 5FU/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
Chemo/
radiotherapy-naive
stage III colon
≤8 weeks since resection
N=1886
R
A
N
D
O
M
I
S
A
T
I
O
N
n=944
XELOX (6 months)
capecitabine 1000mg/m2 bid d1–14
oxaliplatin130mg/m2 d1
q3w
8 cycles
Bolus 5-FU/LV (6 months)
n=942
Mayo Clinic [n=664]
or
Roswell Park [n=278]
• 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
54
61 (22–83)
5-FU/LV
n=942
53
62 (24–82)
ECOG (0/1) (%)
75/25
78/22
CEA (normal/abnormal) (%)
92/8
93/7
3
40
57
3
42
56
Male (%)
Age (median, range)
Cr clearance (mL/min) (%)
30–50
50–80
>80
ITT population
Safety
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
0.6
Neurosensory
11.4
0.1
Grade 3/4 AEs (%)
Schmoll et al. JCO 2007
Cross-trial comparison with MOSAIC
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
Grade 3/4 AEs (%)
Schmoll et al. JCO 2007
*MOSAIC trial: André et al. NEJM 2004
Efficacy Results
Primary endpoint met:
superior DFS with XELOX
XELOX
5-FU/LV
1.0
0.8
0.6
0.4
HR=0.80 (95% CI: 0.69–0.93)
p=0.0045
0.2
0.0
0
1
2
3
Years
ITT population
4
5
6
3-year DFS:
benefit with XELOX maintained and increased over time
3-year
DFS
XELOX
5-FU/LV
1.0
70.9%
66.5%
0.8
Δ at 3 years: 4.5%
0.6
0.4
0.2
0.0
0
1
2
3
Years
ITT population
4
5
6
4-year DFS:
benefit with XELOX maintained and increased over time
XELOX
5-FU/LV
1.0
3-year
DFS
4-year
DFS
70.9%
66.5%
68.4%
62.3%
0.8
Δ at 3 years: 4.5%
0.6
Δ at 4 years: 6.1%
0.4
0.2
0.0
0
1
2
3
Years
ITT population
4
5
6
5-year DFS:
benefit with XELOX maintained and increased over time
XELOX
5-FU/LV
1.0
3-year
DFS
4-year
DFS
5-year
DFS
70.9%
66.5%
68.4%
62.3%
66.1%
59.8%
0.8
Δ at 3 years: 4.5%
0.6
Δ at 4 years: 6.1%
0.4
Δ at 5 years: 6.3%
0.2
0.0
0
1
2
3
Years
ITT population
4
5
6
DFS across stratification factors
Favours XELOX
Favours 5-FU
All
5-FU/LV
regimen
HR
0.80
1222 0.59–0.90
664 0.71–1.11
0.73
0.89
Abnormal
Normal
140 0.56–1.32
1724 0.66–0.92
0.86
0.78
Mayo
1331 0.64–0.92
0.77
≤3
≥4
Roswell
0.2
ITT population
CI
1886 0.69–0.93
Positive lymph
nodes
CEA
baseline value
n
0.4 0.6
555
1
HR
2
3 4 5
0.64–1.17
0.87
Superior RFS with XELOX
(excludes all non-cancer-related mortality)
1.0
XELOX
5-FU/LV
3-year
RFS
72.1%
67.5%
4-year
RFS
69.7%
63.3%
5-year
RFS
67.8%
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
0
1
2
3
Years
ITT population
4
5
6
Trend to improved OS with XELOX
1.0
5-year
OS
77.6%
74.2%
XELOX
5-FU/LV
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
0
1
2
3
Years
ITT population
4
5
6
Cross-trial comparison of MOSAIC
and XELOXA: OS in stage III disease
1.0
1.0
XELOXA
(57 mo)
0.8
MOSAIC1
(81.9 mo)
0.8
0.6
0.6
0.4
XELOX
FOLFOX4
5-FU/LV
LV5FU2
0
2
0.4
4
Years
ITT population
6
8
0
2
4
6
Years
1. André et al. JCO 2009
8
Cross-trial comparison of MOSAIC
and XELOXA: OS in stage III disease
NO16968 (XELOXA)*
XELOX
1.0
5-yr OS
6-yr OS
(n=944)
77.6%
–
(n=672)
–
72.9%
MOSAIC1**
FOLFOX4
0.8
0.6
0.4
0
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