# 666
Trial-level association between response-based endpoints and progression-free/overall survival
in 1st-line therapy for metastatic colorectal cancer in the ARCAD database
Elisabeth Coart1, Everardo D. Saad1,2, Qian Shi3, Dirkje W. Sommeijer4,5, John R. Zalcberg6, Tim Maughan7, Richard M. Goldberg8, Hans-Joachim Schmoll9, Cornelis J. A. Punt5, Eric Van Cutsem10, Jean-Yves Douillard11, Paulo M. Hoff12,
Niall C. Tebbutt13, Charles S. Fuchs14, Alfredo Falcone15, Christophe Tournigand16, Aimery De Gramont17, Daniel J. Sargent3, Tomasz Burzykowski1, Marc Buyse1, for the ARCAD Group
1International
Drug Development Institute, Louvain-la-Neuve, Belgium; 2Dendrix Research, São Paulo, Brazil; 3Mayo Clinic, Rochester, MN; 4NHMRC Clinical Trials Centre, Sydney; 5 Academic Medical Centre, Amsterdam, The Netherlands; 6School of Public Health, Monash University, Melbourne, Australia; 7CRUK/MRC Oxford Institute for
Radiation Oncology, Oxford, United Kingdom; 8Ohio State University Medical Center, Columbus, OH; 9University Clinic Halle (Saale), Department of Internal Medicine IV, Halle, Germany; 10Leuven Cancer Institute (LKI), Leuven, Belgium; 11Centre René Gauducheau, Nantes, France; 12Instituto do Câncer do Estado de São Paulo, Universidade de
São Paulo, São Paulo, Brazil; 13Austin Health, Melbourne, Australia; 14Dana-Farber Cancer Institute, Boston, MA; 15Oncologia Medica 2, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy; 16Hôpital Henri Mondor, UPEC, Creteil, France; 17Hôpital Saint Antoine, Paris, France.
METHODS
ABSTRACT
RESULTS
Early tumor shrinkage (≥20% decrease from baseline)
and early objective tumor response (CR/PR by
RECIST) are associated with improved progressionfree (PFS)/overall survival (OS) to a similar extent
than best overall response, confirmed response and
early non-progression rate (CR/PR/SD by RECIST) at
the individual level in 1st-line metastatic colorectal
cancer (mCRC). We now assess these response-based
endpoints (RBEs) at the trial level.
Methods
Data were available on 12,167 pts enrolled in a total
of 17 randomized trials of chemotherapy alone or with
targeted agents. ETS, EOTR and eNPR were assessed
at 6/8/9 and 12 weeks (wks), whereas BOR and
ConfR were ascertained within 26 wks from
randomization. Correlations between treatment effects
on RBEs and on PFS/OS were assessed by
coefficients of determination (R2, adjusted for
estimation errors) using a copula model.
Results
None of the RBEs had consistently strong correlations
with PFS or OS (Table 2). The number of trials was
insufficient to obtain reliable estimates for
antiangiogenics and anti-EGFR agents separately.
Trial and Patient Features (Table 1)
• 12,167 patients from 17 trials were included, with
median follow-up of 15.7 months.
Definitions of response based endpoints: Table 2
Long-term Outcomes
• Overall survival (OS): time from randomization to
death from any cause
• Progression-free survival (PFS): time from
randomization to 1st progressive disease (PD) or death
from any cause
Statistical Methods
• The relationship between RBE and PFS or OS was
evaluated by a meta-analytic approach using R2
statistics from weighted least squares regression of
trial-specific estimates of odds ratios and hazard ratios
using Cox, logistic and Copula models. When possible,
reported R2 values are adjusted for estimation errors.3,4
• The meta-analytic unit for surrogacy was the
comparison between two arms (experimental vs
control), nested within trials. Pts of control groups were
randomly divided for trials with more than one
comparison.
• R2, the coefficient of determination, ranges from 0 to 1,
with higher values indicating stronger correlation.
Study
N pts
(N comparisons)
CT only Anti-ANG Anti-EGFR
GERCOR (C97-3)
177 (1)
CAIRO1
BICC-C
03-TTD-01
GONO
N9741
FOCUS1
FOCUS2
HORIZON II
NO16966
MAX
HORIZON III
PRIME (C203)
534 (1)
176 (2)
242 (1)
83 (1)
890 (4)
854 (2)
261 (2)
1009 (2)
897 (2)
52 (1)
All
PFS
OBJECTIVES
To assess, at the trial level, the correlation between
early response-based endpoints (RBEs) and longterm outcomes in patients with metastatic
colorectal cancer (mCRC) treated in the 1st line
This analysis is the second and final step in the
surrogacy evaluation of early RBEs in this setting
(in the first step, strong associations were shown at
the individual-patient level1,2)
Early objective tumor response
939 (3)
423 (2)
1474 (2)
CRYSTAL
COIN
PACCE (C249)
965 (2)
935 (2)
748 (4)
CAIRO2
2888 (8)
393 (2)
4156 (11)
Abbreviation
Definition
EOTR
CR or PR by RECIST at 6/8/9, and 12 weeks from
randomization
≥20% decrease from baseline in sum of longest
diameters at 6/8/9, and 12 weeks from randomization
Early tumor shrinkage
ETS
Early non-progression rate
eNPR
Best objective response
BOR
Confirmed response
ConfR
eNPR at
12 wks
BOR
ConfR
0.16
0.06
(0.00-0.57) (0.00-0.34)
0.25
0.07
0.92
0.23
0.54
0.25
0.26
0.32
(0.00-0.95) (0.00-0.49) (0.00-1.00) (0.00-0.80) (0.00-1.00) (0.00-0.57)* (0.00-0.97) (0.00-1.00)
PFS
0.42
0.17
0.56
0.05
(0.00-1.00) (0.00-0.74) (0.10-1.00)* (0.00-0.44)
OS
0.20
0.08
0.59
0.18
0.26
0.65
0.07
0.05
(0.00-0.97) (0.00-0.58) (0.16-1.00)* (0.00-0.88) (0.00-0.78)* (0.32-0.97)* (0.00-0.56) (0.00-0.54)
CR, PR, or SD by RECIST at 6/8/9, and 12 weeks
from randomization
CR or PR by RECIST within initial 26 weeks of
treatment
CR or PR by RECIST, confirmed at least 4 weeks
later, during initial 26 weeks of treatment
0.34
0.03
(0.00-1.00) (0.00-0.36)
Chemotherapy + targeted agents
PFS
0.13
0.08
0.13
0.01
(0.00-0.67) (0.00-0.72) (0.00-0.71) (0.00-0.13)*
OS
0.19
0.24
0.00
0.00
0.17
0.73
0.26
0.18
(0.00-1.00) (0.00-1.00) (0.00-0.06)* (0.00-0.02)* (0.00-1.00) (0.00-1.00) (0.00-0.66)* (0.00-0.60)*
Table 2. Definition of RBEs
Endpoint
EOTR at EOTR at
eNPR at
Overall
Survival
6/8/9
wks
12 wks
6/8/9 wks
0.25
0.01
0.31
0.01
(0.00-0.72) (0.00-0.16) (0.00-0.93) (0.00-0.14)
*Unadjusted R2
Despite their individual-level associations with PFS
and OS, RBEs do not appear to be surrogate endpoints
in 1st-line mCRC, given their poor predictive ability.
•
6/8/9 wks
ETS at
12 wks
Chemotherapy alone
1115 (1)
Totals 5123 (18)
Treatment ETS at
OS
Conclusions
•
Table 3. Adjusted R2 (95% CI)
Table 1. Trials Included
Background
MAIN FINDINGS
Figure 1.
Trial-specific
correlations
between odds
ratios for ETS
and hazard
ratios for
PFS/OS
0.13
0.17
(0.00-0.66) (0.00-0.74)
• None of the RBEs had consistently strong
correlations with PFS or OS (Table 3 and Figure 1).
This was observed in the overall analyses and in the
chemotherapy alone and chemotherapy + targeted
agents treatment classes.
• The RBEs present different levels of association
with PFS/OS, ranging from 0.01 to 0.92. The
observed width of the CIs for the R2 estimates
either indicate a high level of uncertainty in the
data or are informative and point to a rather weak
association.
• The number of treatment comparisons was
insufficient to obtain reliable separate estimates for
antiangiogenics (N=8) and anti-EGFR (N=11).
DISCUSSION
• Despite their individual-level associations with PFS
and OS, RBEs do not appear to be surrogate
endpoints in 1st-line mCRC, given their poor
predictive ability.
• This holds true for both the early RBEs (ETS,
EOTR and eNPR at 6/8/9 and 12 weeks) and the
conventional response endpoints BOR and ConfR.
• Work is ongoing to assess the role of depth of
response and other continuous endpoints as
potential surrogates for PFS and OS in 1st-line
mCRC.
REFERENCES
1. Sommeijer DW, Shi Q, Saad ED, et al. Early predictors of prolonged overall survival
(OS) in patients (pts) on first-line chemotherapy (CT) for metastatic colorectal cancer
(mCRC): An ARCAD study with individual patient data (IPD) on 10,962 pts. J Clin
Oncol 32:5s, 2014 (suppl; abstr 3538).
2. Saad ED, Coart E, Sommeijer DW, et al. Early predictors of improved long-term
outcomes in first-line antiangiogenics plus chemotherapy (anti-ANG/CT) in metastatic
colorectal cancer (mCRC): Analysis of individual patient (pt) data from the ARCAD
database. J Clin Oncol 32:5s, 2014 (suppl; abstr 3578).
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Molenberghs G, Buyse M, eds: Evaluation of Surrogate Endpoints.New York: Springer,
2005.
4. Burzykowski T, Molenberghs G, Buyse M, et al. The validation of surrogate
endpoints using data from randomized clinical trials: a case study in advanced
colorectal cancer. Journal of the Royal Statistical Society, Series A 167,103 -124,
2004.