Transcript NO16968 (XELOXA) Adjuvant treatment with XELOX in stage

Phase III Trial of Capecitabine +
Oxaliplatin vs Bolus 5-FU/LV in
Stage III Colon Cancer (NO16968):
Impact of Age on DFS and OS
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
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 for
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 outcomes vs. 5-FU/LV (X-ACT)2
•
Recent data from the MOSAIC trial and ACCENT database
demonstrated that newer adjuvant regimens (e.g. oxaliplatin
combinations) were not associated with significant efficacy
benefits vs. 5-FU/LV in patients ≥65 years compared with
younger patients3,4
1. Sargent et al. NEJM 2001;345:1091–1097; 2. Twelves et al. NEJM 2005;352:2696–2704
3. André et al. J Clin Oncol 2009;27:3109–3116; 4. McCleary et al. ASCO 2009 (poster 4010)
2
MOSAIC: DFS by age3
• MOSAIC trial demonstrated efficacy of FOLFOX4 vs.
LV5FU2 is not maintained in patients ≥65 years
Prognostic factor (n)
Hazard ratio (95% CI)
Overall
Age
≥65 years (n=463)
<65 years (n=884)
0.0
0.2
0.4
0.6
FOLFOX4 better
3. André et al. J Clin Oncol 2009;27:3109–3116
0.8
1.0
1.2
1.4
1.6
LV5FU2 better
3
ACCENT: efficacy not maintained in patients
≥70 years of age in overall population4
Age
Endpoint HR (95% CI)
Experimental vs. Control IV 5-FU/LV
Deaths within 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)
0.85
(0.79, 0.91)
0.89 vs. 0.79 (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. 2.11 (p=0.37)
p=0.005
p=0.005
p=0.004
Interaction of age
by treatment
*Values <1 favor experimental arm (oxaliplatin-based regimens)
4. McCleary et al. ASCO 2009 (poster 4010)
4
ACCENT: efficacy of oxaliplatin-based
(MOSAIC/C-07) combinations by age4
Age
Endpoint HR (95% CI)
Experimental vs. Control IV 5-FU/LV
Deaths within 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. 0.81 (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. 1.37
(p=0.25)
p=0.016
p=0.037
p=0.21
Interaction of age
by treatment
*Values <1 favor experimental arm (oxaliplatin-based regimens)
4. McCleary et al. ASCO 2009 (poster 4010)
5
NO16968 (XELOXA): trial design5
Chemo/radiotherapy-naïve stage III colon cancer
≤8 weeks since resection (n=1886)
RANDOMIZATION
n=944
n=942
XELOX (6 months)
Bolus 5-FU/LV (6 months)
capecitabine 1000 mg/m2 bid d1–14
oxaliplatin130 mg/m2 d1
q3w
8 cycles
Mayo Clinic (n=664)
or
Roswell Park (n=278)
5. Haller D, et al. Eur J Cancer Suppl 2009;7:4(Abst 5LBA)
6
NO16968 (XELOXA): patient demographics
XELOX
(n=944)
54
5-FU/LV
(n=942)
53
61 (22–83)
752 (80)
192 (20)
62 (24–82)
725 (77)
217 (23)
ECOG PS, %
0
1
75
25
78
22
CEA, % normal
92
93
Creatinine clearance, %
30–50 mL/min
50–80 mL/min
>80 mL/min
3
40
57
3
42
56
Characteristic
Male, %
Median age, years (range)
<70 years, n (%)
≥70 years, n (%)
7
NO16968 (XELOXA) primary endpoint met: superior DFS with
XELOX and benefit maintained and increased over time
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
XELOX
5-FU/LV
Δ at 3 years: 4.5%
0.6
Δ at 4 years: 6.1%
0.4
0.2
Δ at 5 years: 6.3%
HR=0.80 (95% CI: 0.69–0.93)
p=0.0045
0.0
0
ITT population
1
2
3
Years
4
5
6
8
NO16968 (XELOXA): trend toward
improved OS with XELOX
5-year
OS
77.6%
74.2%
1.0
0.8
XELOX
5-FU/LV
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
ITT population
1
2
3
Years
4
5
6
9
NO16968 (XELOXA): subgroup analysis
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 findings from ACCENT meta-analysis
also apply to XELOX regimen
• Determine relapse-free survival (RFS) overall and
according to age
10
NO16968 (XELOXA): subgroup
analysis of DFS by age
Age group
3-year DFS
XELOX
5-FU/LV
Hazard ratio
(95% CI)
<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 years (n=1477)
72%
69%
0.79 (0.66–0.94)
≥70 years (n=409)
66%
60%
0.87 (0.63–1.18)
<70 vs. ≥70 years
Interaction of age
by treatment*
*Multiple Cox regression
ITT population
p=0.6222
This non-significant p-value indicates that
XELOX efficacy is positive, irrespective of age
11
NO16968 (XELOXA): subgroup
analysis of OS by age
Age group
5-year OS
XELOX
5-FU/LV
Hazard ratio
(95% CI)
<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 years (n=1477)
80%
76%
0.86 (0.69–1.08)
≥70 years (n=409)
69%
67%
0.94 (0.66–1.34)
<70 vs. ≥70 years
Interaction of age
by treatment*
*Multiple Cox regression
ITT population
p=0.7065
This non-significant p value indicates that
XELOX efficacy is positive, irrespective of age
12
NO16968 (XELOXA): subgroup
analysis of RFS by age
Age group
Overall (n=1886)
3-year RFS
XELOX
5-FU/LV
Hazard ratio
(95% CI)
72%
67%
0.78 (0.67–0.92)
<70 years (n=1477)
73%
69%
0.78 (0.65–0.93)
≥70 years (n=409)
69%
61%
0.83 (0.60–1.15)
<70 vs. ≥70 years
ITT population
13
Comparison with ACCENT analysis
Hazard ratio (95% CIs)*
DFS
OS
ACCENT analysis4†
<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)
p=0.016
p=0.037
<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)
p=0.6222
p=0.7065
Interaction of age by treatment
NO16968 (XELOXA)
Interaction of age by treatment
*Values <1 favor oxaliplatin-based therapy vs. 5-FU/LV; †Data for oxaliplatin-based regimens
4. McCleary et al. ASCO 2009 (poster 4010)
14
NO16968 (XELOXA): safety by age
XELOX
Grade 3/4 AEs, %
5-FU/LV
<70 years ≥70 years <70 years
(n=748)
(n=190)
(n=711)
≥70 years
(n=215)
All grade 3/4 AEs
57
70
51
60
Diarrhea
18
26
19
25
Nausea/vomiting
8
11
6
5
Stomatitis
<1
1
9
8
Neutropenia*
9
10
16
17
Febrile neutropenia
<1
<1
4
4
Hand-foot syndrome
6
4
<1
<1
Neurosensory
11
11
<1
0
*Includes granulocytopenia
Safety population
15
NO16968 (XELOXA): conclusions
•
XELOX results in superior DFS compared with bolus 5-FU/LV as
adjuvant treatment for patients with stage III colon cancer
•
These findings confirm the benefits previously demonstrated
with the addition of oxaliplatin to 5-FU in stage III patients
•
Efficacy benefits are maintained in patients ≥65 and ≥70 years in
contrast to results from ACCENT and MOSAIC in which no
significant benefit is shown with FOLFOX in this age group:
– reasons for this apparent difference are unknown
•
OS data thus far indicate a trend toward superior survival with
XELOX
•
XELOX is an effective adjuvant therapy and should be
considered for all eligible patients, without an arbitrary upper
age limit
16
Acknowledgments
• 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
17
References
1.
Sargent et al. NEJM 2001;345:1091–1097
2.
Twelves et al. NEJM 2005;352:2696–2704
3.
André et al. J Clin Oncol 2009;27:3109–3116
4.
McCleary et al. J Clin Oncol 2009;27(15S):4010
5.
Haller D, et al. Eur J Cancer Suppl 2009;7:4(Abst 5LBA)
18