Download AIO KRK 0604

Waterfall plot analysis of XELOX or XELIRI
with cetuximab or bevacizumab
in pts with advanced colorectal cancer (ACRC).
Combined analysis of two randomized
1st line phase II trials if the AIO CRC study group.
Dirk Arnold1, Axel Hinke2, Anke Reinacher-Schick3, Wolff Schmiegel3,
Ullrich Graeven4, Stefan Kubicka5, Ludwig Fischer von Weikersthal6,
Nicolas Moosmann7, Hans-Joachim Schmoll1, Volker Heinemann7
1Martin
Luther University, Halle; 2WiSP, Langenfeld; 3Ruhr University, Bochum;
4Maria Hilf Hospital, Mönchengladbach, 5Medizinische Hochschule, Hannover;
6Klinikum St. Marien, Amberg; 7Ludwig Maximilian University, München; all: Germany
Working Group for Medical Oncology from the German Cancer Society
Gastrointestinal Tumor Study Group
Arnold et al., ASCO 2008 abstr. 4067
AIO GI Cancer Study Group
Introduction
The Response Evaluation Criteria in Solid Tumors (RECIST) or World Health
Organization (WHO) criteria can be used to assess the treatment response rate (RR) in
patients with advanced colorectal cancer (ACRC).
Owing to the methodology used, RR measures the percentage of patients with relevant
tumor shrinkage rather than the magnitude of response or the time until maximal
response. Both of these parameters could be relevant for ACRC treatment strategies.
Waterfall plots have commonly been used to capture the anti-tumor efficacy of biologic
agents that mainly exhibit a cytostatic effect. Thus far, only one waterfall analysis has
been conducted to investigate the use of conventional chemotherapy in patients with
ACRC.1
In order to assess the activity of different compounds used in the treatment of ACRC,
waterfall plot analyses were performed on two similarly designed, randomized, first-line,
phase II trials:
AIO KRK 0104: XELOX-cetuximab vs. XELIRI-cetuximab)
(Fischer von Weikersthal et al., ESMO 20062; update ASCO 2008: #4033 )
AIO KRK 0604: XELOX-bevacizumab vs. XELIRI-bevacizumab
(Schmiegel et al., ASCO 20073; Reinacher-Schick et al., update ASCO 2008: #4030)
Arnold et al., ASCO 2008 abstr. 4067
AIO GI Cancer Study Group
Method of the analysis
Using RECIST, the percentage change from baseline in tumor volume was evaluated when
“best response” to treatment was obtained.
A time window of assessment from 6 to 21 weeks (wks) was thereby used throughout the
analysis.
Average reduction in tumor burden (ARTB)
was calculated as difference in waterfall area under curve (AUC) divided by the number of
pts., capturing the average reduction in tumor burden.
Median reduction in tumor burden (MRTB)
captures median tumor size regression from baseline.
From the 4 treatment arms, pooled 2x2 analysis was performed to compare
XELOX vs. XELIRI
(independent from biologic agent)
bevacizumab (B) vs. cetuximab (C)
(independent from chemotherapy backbone).
Arnold et al., ASCO 2008 abstr. 4067
AIO GI Cancer Study Group
Patient population
Data were available from eligible patients with measurable disease
and at least one restaging (taken at “best response”):
Pts. (total)
Pts. herein
% of all pts.
AIO KRK 0104:
XELOX-cetuximab vs.
XELIRI-cetuximab
185
92
93
122
56
66
69
AIO KRK 0604:
XELOX-bevacizumab vs.
XELIRI-bevacizumab
255
127
128
199
100
99
78
total
440
321
73
Arnold et al., ASCO 2008 abstr. 4067
AIO GI Cancer Study Group
Combined analysis - I
Best response
XELOX
arms
N=156
XELIRI
arms
N=165
5
5
90
6
7
87
6
7
87
6
5
89
MRTB (%)
33
31
30
35
ARTB (%)
34.7
31.2
29.2
38.9
(compared with baseline)
Tumor growth (% of pts)
No Change (% of pts)
Tumor shrinkage
(% of pts)
p
(Wilcoxon Mann Whitney Test)
0.29
Bevacizumab Cetuximab
arms
arms
N=199
N=122
0.009
MRTB = median reduction in tumor burden
ARTB = avarage reduction in tumor burden
Arnold et al., ASCO 2008 abstr. 4067
AIO GI Cancer Study Group
Combined analysis - II
% of pts. (at best response) / % from baseline (ARTB)
100
90
80
70
60
50
p=0.29
40
p=0.009
30
20
10
0
XELOX
XELIRI
Tm Growth
with Bevacizumab with Cetuximab
No Change Tm Shrinkage
ARTB
Wilcoxon Mann Whitney Test
Arnold et al., ASCO 2008 abstr. 4067
AIO GI Cancer Study Group
Waterfall plot analysis of the treatment arms
CIOX / XELOX + Cetuximab: Best Response
100
n = 56
AIO 0104:
XELOXcetuximab
% change
50
0
-50
-100
-150
Arnold et al., ASCO 2008 abstr. 4067
AIO GI Cancer Study Group
Waterfall plot analysis of the treatment arms
CIOX / XELIRI + Cetuximab: Best Response
100
n = 66
AIO 0104:
XELIRIcetuximab
% change
50
0
-50
-100
-150
Arnold et al., ASCO 2008 abstr. 4067
AIO GI Cancer Study Group
Waterfall plot analysis of the treatment arms
KRK 0604 / XELOX + Bevacizumab: Best Response
100
n = 100
AIO 0604:
XELOXbevacizumab
% change
50
0
-50
-100
-150
Arnold et al., ASCO 2008 abstr. 4067
AIO GI Cancer Study Group
Waterfall plot analysis of the treatment arms
KRK 0604 / XELIRI + Bevacizumab: Best Response
100
n = 99
AIO 0604:
XELIRIbevacizumab
% change
50
0
-50
-100
-150
Arnold et al., ASCO 2008 abstr. 4067
AIO GI Cancer Study Group
Conclusion
• Waterfall plot analysis was successfully used to evaluate the results of
the AIO KRK 0104 and the AIO KRK 0604 clinical trials.
• Waterfall analyses could be used to examine the results of other CRC
trials using chemotherapy and targeted agents.
• Additional information on the rates of tumor reduction may be obtained
by ARTB and MRTB.
• Our analysis suggests a larger degree of benefit for cetuximab containing
combinations. However, the results should be interpreted with caution
due to the limited sample sizes and the retrospective and unpreplanned
character of the analysis.
• ARTB and MRTB should be validated in future trials and in relation to
parameters like secondary metastasis resection, but also to clinically
proven time-to-event-endpoints, like progression free survival and overall
survival.
Arnold et al., ASCO 2008 abstr. 4067
AIO GI Cancer Study Group