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Prognostic value of early objective tumor response (EOTR) to
systemic therapy in metastatic colorectal cancer (mCRC)
Individual patient data (IPD) meta-analysis of randomized trials from the ARCAD database
Dirkje W Sommeijer1, Qian Shi2, Jeffrey P Meyer2, Katrin M Sjoquist1, Paulo M Hoff 3, Matthew T Seymour4, James Cassidy5, Richard Goldberg6, Jean-Yves Douillard7, J. Randolph Hecht8,
Herbert Hurwitz9, Christophe Tournigand10, Niall C Tebbutt11, Enrique Aranda12, John Souglakos13, Fairooz F Kabbinavar8, Benoist Chibaudel15, Aimery de Gramont15, Daniel J Sargent2, John Zalcberg16 –For the ARCAD Group
1AGITG
and NHMRC Clinical Trials Centre, University of Sydney, Sydney, Australia; 2 Mayo Clinic, Rochester, MN, USA; 3Centro de Oncologia, Hospital Sirio-Lianes-Sao Paulo, Sao Paulo, Brazil; 4Cancer Research UK Clinical Centre, Leeds, UK; 5Hoffmann La Roche, Nutley, UK; 6Ohio State
University Comprehensive Cancer Center, Columbus, USA; 7ICO Centre René Gauducheau, St Herblain, France; 8David Geffen School of Medicine at UCLA, Los Angeles, USA; 9Duke University Medical Center, Durham, USA; 10Hospital Henri Mondor, UPEC, Creteil, France; 11Austin Health and
University of Melbourne, Heidelberg, Australia; 12Medico Oncolo, Córdoba, Spain; 13Medico Oncolo, Córdoba, Spain; 14University of Crete, School of Medicine, Heraklion, Greece; 15Hospital Saint Antoine, Paris, France; 16 Peter McCallum Hospital, Melbourne, Australia
ABSTRACT
METHODS
Background
EOTR has been suggested as a potential surrogate for overall
survival (OS) in patients (pts) with mCRC1-6 and allows early
assessment of treatment efficacy, facilitating adaptive trial design. We
assessed at the individual patient level, the correlation between
EOTR (complete or partial response) at 6, 8 and 12 weeks (wk), OS
and progression free survival (PFS) in pts with mCRC treated with
1stline chemotherapy with or without a targeted agent as a first step in
a surrogacy demonstration.
Patient Characteristics
• 13,949 patients from 15 trials were included
• Age: 14% < 50; 27% 50 – 59; 34% 60 – 69;
25% ≥ 70
• ECOG PS: 52% 0; 43% 1; 5% 2+
• Gender: 61% male; 39% female
• 37% lung involvement; 79% Liver
involvement
• Regimen: 43% targeted; 57% non-targeted
• Median follow: 16.6 months
Methods
IPD from 13,949 pts enrolled on 15 randomized Phase III trials in
1stline mCRC were used; 8 trials included targeted (anti-angiogenic
and anti-EGFR) agents. EOTR prognostic value was assessed by
landmark analyses using Cox models stratified by treatment
assignment. P-values <0.01 were considered statistically significant
to account for multiple comparisons.
Results
Of 13,949 pts, 11,987 had sufficient response data to be included in
the analysis. Median OS was 21.7 months (mo) in pts with an EOTR
vs. 16.5 mo without EOTR at 6 wk (p<.0001, Hazard Ratio [HR]
0.64, 95% confidence interval [CI] 0.58-0.70, c statistic [c] 0.55).
HRs were similar whether pts were treated with targeted therapies
(p<.0001, HR 0.66, 95% CI 0.56-0.78, c 0.55) or non-targeted
therapies (p<.0001, HR 0.63, 95% CI 0.56-0.70, c 0.55). Median PFS
was 8.4 mo in pts with EOTR at 6 wk vs. 7.0 mo in pts without
EOTR (p<.0001, HR 0.79, 95% CI 0.73-0.85). EOTR at 8 and 12
wks were also significantly associated with longer OS and PFS. The
prognostic value of EOTR at 6, 8 and 12 wks remained significant
(p<0.0001) after adjusting for age, gender, performance status and
location of metastatic disease (lung or liver). Overall tumor response
(to 26 wk) however provided superior OS prediction (p<.0001, HR
0.51, 95% CI, 0.48-0.54, CS 0.60) vs. EOTR.
Conclusions
Early response measured at 6, 8 or 12 wk after starting 1st line
treatment was a strong and independent predictor of both OS and
PFS in patient with mCRC and warrants further consideration as a
potential endpoint for future trials, particularly randomized phase II
trials.
OBJECTIVES
• To determine, at the individual patient level,
the correlation between early tumor response
and long-term outcomes in patients with
mCRC treated with 1st line chemotherapy with
or without a targeted agent.
• This analysis will be the first step in the
surrogacy evaluation of early tumor response
endpoints in patients with mCRC.
Response Endpoints
• EOTR (Primary) –any objective response (CR
or PR) at 6, 8, and 12 weeks from
randomization
• EOTR endpoints at different time points, i.e.
EOTR6, EOTR8, and EOTR12, were
analyzed using protocol-specified tumor
assessment frequency
• Overall tumor response (Secondary)
• Best objective response –CR or PR within
initial 26 weeks treatment
• Confirmed response –CR or PR which was
confirmed at least 4 weeks later during
treatment up to 26 weeks
RESULTS
*Not included in EOTR endpoints, but
included in overall response endpoints
**EOTR12 studies included 5 EOTR6
studies and 1 EOTR8 study (OPTIMOX2,
see Table 1)
Statistical Methods
• Univariate and multivariate Cox model,
stratified by treatment arms with landmark
approach was used to assess the prognostic
values of response endpoints in terms of longterm outcomes
• C statistics were reported for model prediction
comparisons among response endpoints
*
**
• Median OS and PFS were significantly longer in
patients with an EOTR at 6, 8, and 12 weeks as
compared to patients without an EOTR (Figure 1)
• Hazard ratios for survival were similar whether
patients were treated with targeted or nontargeted therapies in univariate models (Figure 2)
• The prognostic value of EOTR at 6, 8, an 12
weeks remained significant after adjusting for
age, gender, performance status and lung/liver
metastatic disease
• Overall tumor response however provided better
prediction of OS at the individual patient level
Table 1: Studies Included
Study [Year]
N9741 [1999]
OPTIMOX1 [2000]
Treatment assignments at
randomization*
Sample
size
519
383
468
621
1413
353
352
105
104
411
402
110
145
136
Regimen type
NT
NT
NT
NT
NT
NT
NT
NT
ANG
NT
ANG
ANG
NT
NT
FOLFOX/CAPOX+placebo
358
NT
FOLFOX/CAPOX+Cediranib20mg
502
ANG
FOLFOX/CAPOX+Cediranib30mg
216
115
115
115
114
668
667
349
350
ANG
NT
NT
NT
NT
NT
NT
ANG
ANG
202
NT
410
202
135
115
58
49
156
157
158
480
589
325
221
704
705
192
ANG
ANG + EGFR
ANG + EGFR
ANG
ANG + EGFR
ANG + EGFR
NT
ANG
ANG
ANG
NT
EGFR
EGFR
ANG
ANG
ANG
Tumor measurement
frequency#
6 weeks
IFL/rIFL
IROX
8 weeks
FOLFOX
FOLFOX
FU
FOCUS [2000]
12 weeks
AVF2192g [2000]
8 weeks
AVF2107g [2000]
6 weeks
HORG [2000]
HORIZON II
[2005]
FOCUS2 [2004]
Long-term outcomes
• OS – Time from randomization to death due to
any cause
• PFS – Time from randomization to 1st PD or
death due to any cause.
Figure 1: Kaplan-Meier Estimates for OS and PFS by EOTR at 6, 8 and 12 weeks
CONSORT Diagram
FINDINGS
12 weeks##
6 weeks
12 weeks
FU+IRI
FU+OX
5FULV+Placebo
5FULV+Bev
IFL+Placebo
IFL+Bev
5FULV+Bev
FOLFIRI
FOLFOXIRI
5FULV
5FULV+OX
Cap
Cap+OX
FOLFOX4+/-placebo
NO16966 [2003]
6 weeks
XELOX+/-placebo
FOLFOX4+Bev
XELOX+Bev
OPTIMOX2 [2004]
8 wks, then 12 wks mFOLFOX7
Bev+OX
PACCE [2005]
12 weeks
Bev+OX+Pmab (KRAS WT)
Bev+OX+Pmab (KRAS MT)
Bev+IRI
Bev+IRI+Pmab (KRAS WT)
Bev+IRI+Pmab (KRAS MT)
Cap
MAX [2005]
6 weeks
Cap+Bev
Cap+Bev+Mitomycin
Macro [2006]
9 weeks
XELOX+Bev
FOLFOX4
PRIME [2006]
8 weeks
FOLFOX4+Pmab (KRAS WT)
FOLFOX4+Pmab (KRAS MT)
HORIZON III
[2006]
mFOLFOX6+Bev
8 weeks
mFOLFOX6+Cediranib20mg
mFOLFOX6+Cediranib30mg
Abbreviations: IRI, irinotecan; OX, oxaliplatin; LV, leucovorin; Bev, bevacizumab; Cap, capecitabine; Pmab,
Pamtumumab; WT, wild type; MT, mutated; NT, non-targeted; ANG, Anti-angiogenic regimen; EGFR, Anti-EGFR
regimen; #.Protocol-specified tumor measurement frequency.## HORG: Publication indicates every 8 weeks, however, data
shows every 12 weeks; *Treatment grouping was according to the 1st cycle of the treatment
Figure 2: Association between Response Endpoints and Outcomes
DISCUSSION
• EOTR warrants further consideration as a
potential surrogate endpoint to detect early
signals for future trials, particularly randomized
phase II studies
• The second step in the surrogacy evaluation of
EOTR in patients with mCRC will be the
assessment of correlation between EOTR and
OS/PFS at trial level7
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