Fluorouracil, Leucovorin, and Oxaliplatin With and
Without Cetuximab in the First-Line Treatment of
Metastatic Colorectal Cancer
Carsten Bokemeyer, Igor Bondarenko, Anatoly Makhson, Joerg T. Hartmann, Jorge Aparicio,
Filippo de Braud, Serban Donea, Heinz Ludwig, Gunter Schuch, Christopher Stroh, Anja H. Loos,
Angela Zubel, and Piotr Koralewski
From the University Hospital, Hamburg-
Eppendorf; South West German
Comprehensive Cancer, University
Hospital Tu¨ bingen, Tu¨ bingen; Merck
Serono, Darmstadt Germany; State
Medical Academy, City Clinical Hospital
#4, Dnepropetrovsk, Ukraine; Moscow
City Oncology Hospital #62, Moscow
Area, Russian Federation; Hospital
Universitario La Fe, Valencia, Spain; Isti-
tuto Europeo di Oncologia, Milan, Italy;
Institutul Oncologic “Prof. Dr. Al. Tres-
tioreanu” Bucuresti, Bucharest, Roma-
nia; Wilhelminenspital der Stadt Wien,
Vienna, Austria; and Wojewo´ dzki Szpital
Specjalistyczny Oddzia Chemioterapii,
Krakow, Poland.
Submitted October 31, 2008; accepted
November 25, 2008; published online
ahead of print at www.jco.org on
December 29, 2008.
Presented at the 43rd Annual Meeting
of the American Society of Clinical
Oncology, June 1-5, 2007, Chicago, IL;
14th European Cancer Conference,
September 23-27, 2007, Barcelona,
Spain; 44th Annual Meeting of the
American Society of Clinical Oncology,
May 30-June 3, 2008, Chicago, IL; and
The ESMO International Symposium:
10th World Congress on Gastrointesti-
nal Cancer, June 25-28, 2008, Barce-
lona, Spain.
Authors’ disclosures of potential con-
flicts of interest and author contribu-
tions are found at the end of this
article.
Clinical Trials repository link available on
JCO.org.
Corresponding author: Carsten
Bokemeyer, MD, Universita¨tsklinikum
Hamburg-Eppendorf, Martinistrasse
52, 20246 Hamburg-Eppendorf, Germa-
ny; e-mail: c.bokemeyer@uke.uni-
hamburg.de.
The Appendix is included in the
full-text version of this article,
available online at www.jco.org.
It is not included in the PDF version
(via Adobe® Reader®).
© 2008 by American Society of Clinical
Oncology
0732-183X/09/2705-663/$20.00
DOI: 10.1200/JCO.2008.20.8397
ABSTRACT
Purpose
This randomized study assessed whether the best overall response rate (ORR) of cetuximab combined
with oxaliplatin, leucovorin, and fluorouracil (FOLFOX-4) was superior to that of FOLFOX-4 alone as
first-line treatment for metastatic colorectal cancer. The influence of KRAS mutation status
was investigated.
Patients and Methods
Patients received cetuximab (400 mg/m
2
initial dose followed by 250 mg/m
2
/wk thereafter) plus
FOLFOX-4 (oxaliplatin 85 mg/m
2
on day 1, plus leucovorin 200 mg/m
2
and fluorouracil as a 400
mg/m
2
bolus followed by a 600 mg/m
2
infusion during 22 hours on days 1 and 2; n ⫽ 169) or
FOLFOX-4 alone (n ⫽ 168). Treatment was continued until disease progression or unacceptable
toxicity. KRAS mutation status was assessed in the subset of patients with assessable tumor
samples (n ⫽ 233).
Results
The confirmed ORR for cetuximab plus FOLFOX-4 was higher than with FOLFOX-4 alone (46% v
36%). A statistically significant increase in the odds for a response with the addition of cetuximab
to FOLFOX-4 could not be established (odds ratio ⫽ 1.52; P ⫽ .064). In patients with KRAS
wild-type tumors, the addition of cetuximab to FOLFOX-4 was associated with a clinically
significant increased chance of response (ORR ⫽ 61% v 37%; odds ratio ⫽ 2.54; P ⫽ .011) and
a lower risk of disease progression (hazard ratio ⫽ 0.57; P ⫽ .0163) compared with FOLFOX-4
alone. Cetuximab plus FOLFOX-4 was generally well tolerated.
Conclusion
KRAS mutational status was shown to be a highly predictive selection criterion in relation to the
treatment decision regarding the addition of cetuximab to FOLFOX-4 for previously untreated
patients with metastatic colorectal cancer.
J Clin Oncol 27:663-671. © 2008 by American Society of Clinical Oncology
INTRODUCTION
The epidermal growth factor receptor (EGFR) is a
clinically validated anticancer molecular target that
is expressed in the majority of colorectal tumors.
1-5
Cetuximab (Erbitux, developed by Merck KGaA
[Darmstadt, Germany], under license from Im-
clone New York, NY]) is an immunoglobulin
G1 monoclonal antibody that specifically targets
EGFR with high affinity, competitively inhibit-
ing endogenous ligand binding and ligand-
dependent downstream signaling.
6,7
Binding to
the tumor cell also initiates antibody-dependent
cell-mediated cytotoxicity.
8-10
Randomized phase
II and III metastatic colorectal cancer (mCRC)
studies have demonstrated the efficacy and toler-
ability of cetuximab, as monotherapy
2,11
or in
combination with irinotecan,
2,12
after the failure
of previous chemotherapy regimens including
irinotecan and/or oxaliplatin. Furthermore, in
the first-line setting, building on promising phase
II data,
13
the phase III Cetuximab Combined
With Irinotecan in First-Line Therapy for Meta-
static Colorectal Cancer (CRYSTAL) study has
shown that the addition of cetuximab to infu-
sional fluorouracil (FU)/leucovorin (LV)/irino-
tecan (FOLFIRI) significantly improves the
progression-free survival (PFS) time, response rate,
and R0 resection rate in mCRC patients, compared
with FOLFIRI alone.
14
JOURNAL OF CLINICAL ONCOLOGY
ORIGINAL REPORT
VOLUME 27 䡠 NUMBER 5 䡠 FEBRUARY 10 2009
© 2008 by American Society of Clinical Oncology
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Phase II studies examining the activity and tolerability of cetux-
imab combined with oxaliplatin and FU/LV (FOLFOX-4) have pro-
vided encouraging results.
15,16
To further evaluate this combination,
the Oxaliplatin and Cetuximab in First-Line Treatment of mCRC
(OPUS) study compared the efficacy and safety of cetuximab plus
FOLFOX-4 with FOLFOX-4 alone as first-line therapy for mCRC.
The definition of relevant molecular characteristics of an in-
dividual tumor (biomarker evaluation) will increasingly enable the
selection of patients most likely to benefit from particular treat-
ments.
17
A recent subgroup analysis of a randomized phase III
study of the immunoglobulin G2 EGFR-targeting monoclonal an-
tibody panitumumab in patients with chemotherapy-refractory
mCRC suggested a lack of clinical activity in patients whose tumors
had activating mutations at codon 12 or 13 of the KRAS gene.
18
Small retrospective studies in chemotherapy-refractory patients
have also suggested that clinical responses to cetuximab are con-
fined to those mCRC patients (approximately 55% to 70%) whose
tumors are wild type for KRAS.
19-22
This assertion has recently
been confirmed in subgroup analyses of the randomized phase III
CRYSTAL and CO.17 studies.
23,24
A subgroup analysis of the OPUS
study therefore investigated whether tumor KRAS mutation status
was predictive of a clinical response to cetuximab plus FOLFOX-4.
PATIENTS AND METHODS
Patient Eligibility
Patients were eligible for inclusion if they were ⱖ 18 years old; had a
histologically confirmed, first-occurrence of a nonresectable, EGFR-
expressing mCRC with at least one radiologically measurable lesion; a life
expectancy of ⱖ 12 weeks; an Eastern Cooperative Oncology Group Perfor-
mance Status (ECOG PS) ⱕ 2; and adequate hepatic, renal, and bone marrow
function. Patients were ineligible if they were pregnant, had a history of
previous exposure to EGFR-targeted therapy or previous chemotherapy (ex-
cept adjuvant treatment) for mCRC, or had uncontrolled severe organ or
metabolic dysfunction. The study was approved by relevant ethics committees
and was conducted inaccordance with the Declaration of Helsinki. All patients
provided written, informed consent.
Study Design
This was an open-label, randomized, multicenter phase II study compar-
ing the efficacy and safety of cetuximab combined with FOLFOX-4 versus
FOLFOX-4 alone in the first-line treatment of EGFR-expressing mCRC.
EGFR expression was determined using a DakoCytomation pharmDx immu-
nohistochemistry kit (Dako, Glostrup, Denmark), with one tumor cell stain-
ing to any intensity being the minimum criterion required to confirm
expression. Randomization (1:1) was carried out using a stratified permuted-
block procedure, with ECOG PS (0 and 1 v 2) as a stratification factor.
On day 1 of a 14-day treatment cycle, patients received cetuximab
(initial dose 400 mg/m
2
infused during 2 hours, and 250 mg/m
2
weekly
during 1 hour thereafter) followed after 1 hour by FOLFOX-4 (oxaliplatin
85 mg/m
2
on day 1, infused during 2 hours; LV 200 mg/m
2
, infused during
2 hours, followed by FU as a 400 mg/m
2
intravenous bolus then a 600
mg/m
2
infusion during 22 hours on days 1 and 2) or FOLFOX-4 alone,
until the occurrence of progressive disease (PD) or unacceptable toxicity.
In the case of unacceptable toxicity or intolerance to FU/LV, oxaliplatin, or
cetuximab, the agent responsible could be stopped and the patient could
continue with the other study medication(s). Radiologic assessment of re-
sponse was carried out every 8 weeks until PD or withdrawal for any reason.
The primary objective was to assess whether the best confirmed
overall response rate of cetuximab plus FOLFOX-4 was superior to that of
FOLFOX-4 alone. Tumor response including disease progression was as-
sessed by an independent review committee according to modified WHO
criteria. The independent review committee conducted a blinded review of
images and clinical data using a common set of prespecified criteria. The
data cutoff for the primary analysis of response was chosen to be 20 weeks
after the last randomly assigned patient started study treatment (August 4,
2006) so that all patients could have at least two 8-week evaluations.
Secondary objectives included treatment comparisons of the rate of cura-
tive metastatic surgery, duration of response, disease control rate, PFS
time, OS time, and safety, all of which were based on data from a longer
follow-up time (March 1, 2007). A retrospective subgroup analysis inves-
tigated associations between PFS and response rate and the KRAS muta-
tion status of tumors.
Statistical Methods and Considerations
The primary efficacy analysis was performed on the intention-to-
treat (ITT) population, defined as all randomly assigned patients who
received at least one dose of study treatment. Assuming a difference in the
rate of best confirmed response of at least 20% between the two treatments
(ie, approximately 70% with cetuximab plus FOLFOX-4 and 50% with
FOLFOX-4 alone for the stratum with ECOG PS 0 to 1, and 66% and 45%,
respectively, for the ECOG PS 2 stratum), the Cochran-Mantel-Haenszel
(CMH)
25,26
odds ratio (OR) over the strata was expected to be 2.33. A
sample size of approximately 146 patients per group was therefore calcu-
lated as necessary to detect an odds ratio of 2.33 at level
␣
⫽ .05, with a
Screened at baseline
(n = 364)
Prescreened
(n = 629)
Screened for tumor EGFR expression
(n = 607)
Randomly assigned
(n = 341)
(plus 3 not eligible)
Randomly assigned
(n = 344)
Treated
(n = 338)
Cetuximab + FOLFOX-4
(n = 170)
(ITT population: n = 169)
Main reason for end of treatment
Progressive disease n = 87
Stable disease n = 3
Adverse event n = 12
Death n = 9
Noncompliance n = 7
Withdrew consent n = 19
Other n = 7
FOLFOX-4
(n = 168)
(ITT population: n = 168)
Main reason for end of treatment
Progressive disease n = 92
Stable disease n = 5
Adverse event n = 26
Death n = 5
Noncompliance n = 5
Withdrew consent n = 18
Other n = 5
Not eligible
for study
(n = 23)
Not treated
(n = 6)
Not eligible
for baseline
screening
(n = 265)
Fig 1. Disposition of subjects at the time of the data cutoff March 1, 2007.
EGFR, epidermal growth factor receptor; FOLFOX-4, oxaliplatin, leucovorin, and
fluorouracil; ITT, intention to treat.
Bokemeyer et al
664
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power of 90%. With the exception of the test of the null hypothesis of
OR ⫽ 1 over the entire sample population, all further efficacy analyses were
exploratory and P values were not adjusted for the multiplicity of statistical
tests. Time-to-event data were analyzed using the Kaplan-Meier method.
27
All analyses were repeated by KRAS mutation status in those ITT patients
whose tumors were available and provided an assessable DNA sample
(KRAS population).
KRAS Mutation Detection
Tumor DNA was extracted from formaldehyde-fixed paraffin-embedded
tissues, and screened for the presence of KRAS codon 12 and 13 mutations
using a polymerase chain reaction (PCR) clamping and melting curve tech-
nique adapted from Chen et al
28
(full methods information is listed in the
Appendix, online only). Briefly, a one-step Lightcycler PCR reaction (Light-
Mix, k-ras Gly12; TIB MOLBIOL, Berlin, Germany) incorporated a codon 12
Table 1. Patient and Disease Characteristics at Baseline
Characteristic
ITT Population (n ⫽ 337) KRAS Population (n ⫽ 233) KRAS Wild Type (n ⫽ 134) KRAS Mutant (n ⫽ 99)
FOLFOX-4
(n ⫽ 168)
Cetuximab ⫹
FOLFOX-4
(n ⫽ 169)
FOLFOX-4
(n ⫽ 120)
Cetuximab ⫹
FOLFOX-4
(n ⫽ 113)
FOLFOX-4
(n ⫽ 73)
Cetuximab ⫹
FOLFOX-4
(n ⫽ 61)
FOLFOX-4
(n ⫽ 47)
Cetuximab ⫹
FOLFOX-4
(n ⫽ 52)
No. of
Patients %
No. of
Patients %
No. of
Patients %
No. of
Patients %
No. of
Patients %
No. of
Patients %
No. of
Patients %
No. of
Patients %
Sex
Male 92 55 89 53 66 55 57 50 44 60 30 49 22 47 27 52
Female 76 45 80 47 54 45 56 50 29 40 31 51 25 53 25 48
Age, years
Median 60 62 60 59 59 59 61 60
Range 30-82 24-82 30-82 24-82 36-82 24-74 30-75 41-82
⬍ 65 109 65 96 57 77 64 70 62 46 63 39 64 31 66 31 60
ⱖ 65 59 35 73 43 43 63 43 38 27 37 22 36 16 34 21 40
Region
Eastern Europe 93 55 97 57 71 59 70 62 45 62 38 62 26 55 32 62
Western Europe 49 29 45 27 49 41 43 38 28 38 23 38 21 45 20 38
Southern Europe 25 15 27 16 0 0 0000
ROW 110000000
ECOG PS at baseline
0 7545 6539 5042 34302737193123491529
1 7645 8953 5647 70623751376119403363
2 17 10 15 9 14 12 9 8 9 12 5 8 5 11 4 8
Disease duration, months
Median, CRC 2.2 2.1 2.1 2.2 2.0 2.1 2.1 2.3
Q1-Q3 1.3-17.6 1.2-9.8 1.3-14.4 1.4-10.7 1.3-15.0 1.2-9.4 1.2-7.8 1.6-10.7
Median, mCRC 1.5 1.4 1.6 1.4 1.6 1.3 1.4 1.6
Q1-Q3 1.1-2.3 0.9-2.3 1.1-2.3 1.0-2.4 1.2-2.2 0.9-2.4 1.1-2.3 1.0-2.4
Tumor site
Colon 89 53 92 54 66 55 61 54 41 56 31 51 25 53 30 58
Rectum 79 47 75 44 54 45 51 45 32 44 30 49 22 47 21 40
Colon ⫹ rectum 0 2 1 0 1 1 00012
Metastatic sites
Liver 146 87 149 88 108 90 101 89 65 89 54 89 43 91 47 90
Lung 65 39 64 38 44 37 45 40 27 37 16 26 17 36 29 56
Bone 4 2 9 5 3 3 4 4 3 4 1 2 0 3 6
Lymph node 45 27 41 24 32 27 25 22 19 26 15 25 13 28 10 19
Other 27 16 25 15 17 14 17 15 12 16 9 15 5 11 8 15
Organs with metastases
01
ⴱ
0.60000000
1 6941 7444 5243 50443142325221451835
2 6338 6036 4134 38342433172817362140
3 18 11 2213 1513 1614 12 16 9 15 3 6 7 13
ⱖ 4 17 10 13 8 12 10 9 8 6 8 3 5 6 13 6 12
Prior therapy†
Surgery 152 91 137 81 108 90 100 88 67 92 50 82 41 87 50 96
Adjuvant chemotherapy 36 21 21 12 19 16 14 12 12 16 8 13 7 15 6 12
Radiotherapy 23 14 18 11 13 11 13 12 9 12 5 8 4 9 8 15
Abbreviations: ITT, intention to treat; FOLFOX-4, oxaliplatin, leucovorin, and fluorouracil; ROW, rest of the world; ECOG PS, Eastern Cooperative Oncology Group
performance status; CRC, colorectal cancer; mCRC, metastatic colorectal cancer; Q1-Q3, interquartile range.
ⴱ
Patient enrolled in violation of protocol.
†A patient may have received more than one prior therapy.
Cetuximab Plus FOLFOX-4 in the First-Line Treatment of mCRC
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to 14 spanning locked nucleic acid oligomer to suppress amplification of the
wild-type sequence.
29
Post-PCR hybridization and melting curve analysis
using fluorescently tagged oligonucleotides incorporated in the original PCR
reaction permitted the identification and discrimination of distinct KRAS
codon 12 and 13 missense mutations.
Safety Analysis
The safety population comprised all patients who received at least one
dose of study treatment. All adverse events (AEs) reported with onset on or
after the first day of study medication and captured up to 6 weeks after the end
of the last administration of study treatment were coded using the Medical
Dictionary for Regulatory Activities version 8.1 and summarized by worst
severity per patient according to the National Cancer Institute Common
Toxicity Criteria version 2.0.
RESULTS
Patient Demographics
Three hundred forty-four patients were randomly assigned
(three of them in error). Of the eligible patients, 337 received study
treatment at 79 centers. Study accrual lasted from July 2005 until
March 2006, with 169 patients receiving cetuximab plus FOLFOX-4
and 168 patients receiving FOLFOX-4 alone (Fig 1). Baseline demo-
graphic and disease characteristics were generally well balanced be-
tween the treatment groups (Table 1). DNA suitable for KRAS
mutation analysis was extracted from the tumor samples of 233
patients, 113 and 120 of whom had received cetuximab plus
FOLOFOX-4 and FOLFOX-4 alone, respectively. These patients com-
prised the KRAS population. In general, the population with tissue
available for KRAS analysis (n ⫽ 233) was considered to be represen-
tative of the overall ITT population (n ⫽ 337) in relation to demo-
graphic parameters (Table 1).
Treatment Compliance
The median duration of cetuximab treatment was 24 weeks, with
84% of patients having a relative dose-intensity (RDI) of ⱖ 80%.
Similar numbers of patients in both arms had RDIs of ⱖ 80% for
oxaliplatin (75% and 80% of patients receiving cetuximab plus
Table 2. Efficacy Data in the ITT and KRAS Populations
Characteristic
ITT Population (n ⫽ 337) KRAS Population (n ⫽ 233) KRAS Wild Type (n ⫽ 134) KRAS Mutant (n ⫽ 99)
FOLFOX-4
(n ⫽ 168)
Cetuximab ⫹
FOLFOX-4
(n ⫽ 169)
FOLFOX-4
(n ⫽ 120)
Cetuximab ⫹
FOLFOX-4
(n ⫽ 113)
FOLFOX-4
(n ⫽ 73)
Cetuximab ⫹
FOLFOX-4
(n ⫽ 61)
FOLFOX-4
(n ⫽ 47)
Cetuximab ⫹
FOLFOX-4
(n ⫽ 52)
No. of
Patients %
No. of
Patients %
No. of
Patients %
No. of
Patients %
No. of
Patients %
No. of
Patients %
No. of
Patients %
No. of
Patients %
Best overall response
ⴱ
Complete response 1 0.6 2 1 3 3 2 2 1 1 2 3 2 4 0
Partial response 59 35 75 44 47 39 52 46 26 36 35 57 21 45 17 33
Stable disease 76 45 67 40 47 39 46 41 30 41 19 31 17 36 27 52
Progressive disease 21 13 18 11 17 14 10 9 12 16 3 5 5 11 7 13
Not assessable 11 7 7 4 6 5 3 3 4 5 2 3 2 4 1 2
Best overall response
rate†, %
All patients 36 46 42 48 37 61 49 33
95% CI 29-44 38-53 33-51 38-57 26-49 47-73 34-64 20-47
Odds ratio 1.516 1.312 2.544 0.507
95% CI 0.975-2.355 0.779-2.208 1.238-5.227 0.223-1.150
P (stratified CMH test) .064 .307 .011 .106
Disease control rate‡, % 81 85 81 89 78 92 85 85
95% CI 74-87 79-90 73-87 81-94 67-87 82-97 72-94 72-93
PFS time, months
Median 7.2 7.2 7.2 7.3 7.2 7.7 8.6 5.5
95% CI 6.0-7.8 5.6-7.7 6.0-7.9 5.6-8.1 5.6-7.4 7.1-12.0 6.5-9.5 4.0-7.4
Hazard ratio 0.931 0.928 0.570 1.830
95% CI 0.705-1.230 0.665-1.295 0.358-0.907 1.095-3.056
P (log-rank test) .6170 .6609 .0163 .0192
PFS rates, %
3 months 85 83 82 86 78 93 87 78
95% CI 79-90 78-89 75-89 80-93 69-88 87-100 77-97 67-90
6 months 59 53 60 54 54 66 69 39
95% CI 51-68 45-61 50-69 44-64 42-66 53-79 54-83 25-54
9 months 34 34 33 35 27 47 42 20
95% CI 26-43 26-43 23-43 25-45 15-39 33-62 24-61 7-33
12 months 12 24 13 20 13 30 14 6
95% CI 3-20 15-33 4-23 8-32 2-24 10-49 0-30 0-16
NOTE. P ⬍ 0.05 for bold values.
Abbreviations: ITT, intention to treat; FOLFOX-4, oxaliplatin, leucovorin, and fluorouracil; CMH, Cochran-Mantel-Haenszel; PFS, progression-free survival.
ⴱ
As assessed by independent review. Best overall response on the ITT population was based on data available at the a priori fixed time of the confirmatory analysis.
†Complete response ⫹ partial response.
‡Complete response ⫹ partial response ⫹ stable disease.
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FOLFOX-4 and FOLFOX-4, respectively) and FU (67% and 70% of
patients, respectively). Reductions and delays in cetuximab dosing
were primarily because of skin reactions, and delays in chemotherapy
dosing were because of hematologic, GI, or neurologic reactions. In
the KRAS population, comparable levels of exposure were reached;
86% of patients who received cetuximab had a RDI ⱖ 80%. RDIs of
ⱖ 80% were also reported for 73% and 81% of patients receiving
oxaliplatin and for 65% and 72% of patients receiving FU in the
cetuximab plus FOLFOX-4 and FOLFOX-4 arms, respectively.
Efficacy
Efficacy data are summarized in Table 2. The best confirmed
overall response rate in the cetuximab plus FOLFOX-4 group was
46%, and in the FOLFOX-4–alone group, this value was 36%. The
comparison between the two treatment groups resulted in a com-
mon ECOG PS–adjusted OR of 1.52 (95% CI, 0.98 to 2.36), indi-
cating an increase in the chance of a response in the cetuximab plus
FOLFOX-4 arm by 52%. This increase was not statistically signifi-
cant at the 5% level (ECOG PS–adjusted CMH test, P ⫽ .064). A
slightly greater treatment effect was observed in the group of par-
ticipants (n ⫽ 153 v 152) with ECOG PS 0 to 1 (OR ⫽ 1.65; 95% CI,
1.04 to 2.60; CMH test, P ⫽ .032). Regarding the secondary efficacy
end points, although a marked benefit in relation to PFS time
was not detected (Table 2; Fig 2A), the addition of cetuximab to
FOLFOX-4 was associated with an approximate doubling of the R0
resection rate from 2.4% (four of 168 patients) forFOLFOX-4 alone
to 4.7% (eight of 169 patients) for cetuximab plus FOLFOX-4. The
median duration of response was also longer in the cetuximab group
(9.0 v 5.7 months).
KRAS mutations in codons 12/13 (hereinafter called KRAS
mutations) were detected in the tumor tissue of 99 of 233 (42%)
patients, 52 of whom received cetuximab plus FOLFOX-4 and 47
of whom received FOLFOX-4 alone (Table 2). No mutations were
detected in the tumors of 134 patients (58%; hereinafter called
KRAS wild-type tumors), 61 of whom received cetuximab plus
FOLFOX-4 and 73 of whom received FOLFOX-4 alone. In patients
whose tumors were scored as KRAS wild type, the addition of
cetuximab to FOLFOX-4 was associated with a 2.54-fold increased
chance for response compared with FOLFOX-4 alone (61% v 37%;
OR ⫽ 2.54; 95% CI, 1.24 to 5.23; ECOG PS–adjusted CMH test,
P ⫽ .011). Conversely, for patients with tumor KRAS mutations,
the response rate for cetuximab plus FOLFOX-4 was lower, com-
pared with FOLFOX-4 alone (33% v 49%; OR ⫽ 0.51; 95% CI, 0.22
to 1.15; ECOG PS–adjusted CMH test, P ⫽ .106). The R0 resection
rate was more than doubled in patients with KRAS wild-type
tumors who received cetuximab plus FOLFOX-4 (six of 61 pa-
tients; 9.8%) compared with those who received FOLFOX-4 alone
(three of 73 patients; 4.1%). In contrast, in patients whose tumors
carried KRAS mutations, R0 resection rates were similar in both
treatment arms (one in 52 and one in 47 patients, respectively;
1.9% and 2.1%). However, due to the small patient numbers, these
data have to be interpreted with caution.
The risk of disease progression (Figs 2A and 2B) was similar for
both the ITT (cetuximab plus FOLFOX-4 v FOLFOX-4 alone; hazard
ratio [HR] ⫽ 0.93; log-rank test, P ⫽ .6170) and the KRAS population
(HR ⫽ 0.93; log-rank test, P ⫽ .6609), adding additional evidence
consistent with the representability of the KRAS population. A
marked risk reduction for progression was evident between the study
arms when comparing patients according to whether KRAS mutations
were detected in their tumor DNA. Specifically, as summarized in
Table 2 and Figure 3, the addition of cetuximab to FOLFOX-4 was
associated with a 43% reduction in the risk of progression in patients
with KRAS wild-type tumors (Fig 3C; HR ⫽ 0.57; log-rank test,
P ⫽ .0163). In those patients receiving cetuximab plus FOLFOX-4, the
risk of disease progression was lower for those whose tumors were wild
type for KRAS, compared with those whose tumors carried mutations
(Fig 3A; HR ⫽ 0.45; log-rank test, P ⫽ .0009). However, in patients
whose tumors carried mutations of KRAS, the risk of disease progres-
sion was found to be lower for those receiving FOLFOX-4 alone
compared with those receiving cetuximab plus FOLFOX-4 (Fig 3D;
A
0
No. of patients at risk
Cet. + FOLFOX-4 169 138 109 71 47 27 10
FOLFOX-4 168 138 112 72 35 15 4
Cet. + FOLFOX-4 FOLFOX-4
No. of patients 169 168
Progression 102 (60.4%) 102 (60.7%)
Censored 67 (39.6%) 66 (39.3%)
Median 7.2 mo. 7.2 mo.
95% CI (5.6 to 7.7) (6.0 to 7.8)
Log-rank P = .6170 HR = 0.931 (0.705 to 1.230)
Progression-Free
Survival (proportion)
Time (months)
1.0
0.8
0.6
0.4
0.2
24681012
ITT Population
Cet. + FOLFOX-4
FOLFOX-4
B
0
No. of patients at risk
Cet. + FOLFOX-4 113 97 73 48 31 19 5
FOLFOX-4 120 94 80 53 24 10 4
No. of patients
Progression
Censored
Median
95% CI
Log-rank P = .6609 HR = 0.928 (0.665 to 1.295)
Progression-Free
Survival (proportion)
Time (months)
1.0
0.8
0.6
0.4
0.2
24681012
KRAS Population
Cet. + FOLFOX-4
FOLFOX-4
Cet. + FOLFOX-4
113
69 (61.1%)
44 (38.9%)
7.3 mo.
(5.6 to 8.1)
FOLFOX-4
120
74 (61.7%)
46 (38.3%)
7.2 mo.
(6.0 to 7.9)
Fig 2. Kaplan and Meier plots for progression-free survival time for patients in each study arm in (A) the intention to treat (ITT) population and (B) the KRAS population.
Cet., cetuximab; FOLFOX-4, oxaliplatin, leucovorin, and fluorouracil; mo., months.
Cetuximab Plus FOLFOX-4 in the First-Line Treatment of mCRC
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