Article

Bokemeyer C, Bondarenko I, Hartmann JT, et al. Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study

Department of Oncology, Hematology, BMT with Section Pneumology, University Hospital, Hamburg-Eppendorf, Germany.
Annals of Oncology (Impact Factor: 7.04). 06/2011; 22(7):1535-46. DOI: 10.1093/annonc/mdq632
Source: PubMed
ABSTRACT
The randomized phase II OPUS (Oxaliplatin and Cetuximab in First-Line Treatment of Metastatic Colorectal Cancer) study showed that tumor KRAS mutation status was predictive for outcome in patients receiving cetuximab plus FOLFOX-4 (oxaliplatin/5-fluorouracil/folinic acid) as first-line therapy for metastatic colorectal cancer (mCRC).
The biomarker analysis was extended through the use of additional DNA samples extracted from stained tissue sections. KRAS and BRAF tumor mutation status was determined for new (and for BRAF, existing) samples using a PCR technique. Clinical outcome was reassessed according to mutation status. Overall survival data are presented.
Of 315 KRAS evaluable patient samples (93%), 179 tumors (57%) were KRAS wild type. Eleven of 309 (4%) KRAS/BRAF evaluable tumors (all KRAS wild type) carried BRAF mutations. The addition of cetuximab to FOLFOX-4 significantly improved progression-free survival (hazard ratio 0.567, P = 0.0064) and response (odds ratio 2.551, P = 0.0027) in patients with KRAS wild-type tumors. A favorable effect on survival was also observed.
These results confirm the efficacy of cetuximab plus FOLFOX-4 in the first-line treatment of patients with KRAS wild-type mCRC and confirm KRAS mutation status as an effective predictive biomarker. The small number of tumors with BRAF mutations precluded the drawing of definitive conclusions concerning the predictive or prognostic utility of this biomarker.

Full-text

Available from: Carsten Bokemeyer, Mar 04, 2016
Annals of Oncology 22: 1535–1546, 2011
doi:10.1093/annonc/mdq632
Published online 12 January 2011
original article
Efficacy according to biomarker status of cetuximab
plus FOLFOX-4 as first-line treatment for metastatic
colorectal cancer: the OPUS study
C. Bokemeyer
1
*, I. Bondarenko
2
, J. T. Hartmann
3
, F. de Braud
4
, G. Schuch
1
, A. Zubel
5
, I. Celik
5
,
M. Schlichting
6
& P. Koralewski
7
1
Department of Oncology, Hematology, BMT with Section Pneumology, University Hospital, Hamburg-Eppendorf, Germany;
2
City Clinical Hospital #4, Dnepropetrovsk
State Medical Academy, Dnepropetrovsk, Ukraine;
3
Department of Medical Oncology, Hematology, Immunology, Rheumatology, and Pulmonology, South West
German Comprehensive Cancer, University Hospital Tu¨bingen, Tu¨bingen, Germany;
4
Division of Clinical Pharmacology and New Drugs, Istituto Europeo di Oncologia,
Milan, Italy;
5
Global Clinical Development Unit–Oncology;
6
Global Biostatistics, Merck KGaA, Darmstadt, Germany;
7
Oncology, Rydygier Memorial Hospital, Krakow-
Nowa Huta, Poland
Received 4 August 2010; revised 27 September 2010; accepted 28 September 2010
Background: The randomized phase II OPUS (Oxaliplatin and Cetuximab in First-Line Treatment of Metastatic
Colorectal Cancer) study showed that tumor KRAS mutation status was predictive for outcome in patients receiving
cetuximab plus FOLFOX-4 (oxaliplatin/5-fluorouracil/folinic acid) as first-line therapy for metastatic colorectal cancer
(mCRC).
Patients and methods: The biomarker analysis was extended through the use of additional DNA samples extracted
from stained tissue sections. KRAS and BRAF tumor mutation status was determined for new (and for BRAF, existing)
samples using a PCR technique. Clinical outcome was reassessed according to mutation status. Overall survival data
are presented.
Results: Of 315 KRAS evaluable patient samples (93%), 179 tumors (57%) were KRAS wild type. Eleven of 309 (4%)
KRAS/BRAF evaluable tumors (all KRAS wild type) carried BRAF mutations. The addition of cetuximab to FOLFOX-4
significantly improved progression-free survival (hazard ratio 0.567, P = 0.0064) and response (odds ratio 2.551,
P = 0.0027) in patients with KRAS wild-type tumors. A favorable effect on survival was also observed.
Conclusions: These results confirm the efficacy of cetuximab plus FOLFOX-4 in the first-line treatment of patients
with KRAS wild-type mCRC and confirm KRAS mutation status as an effective predictive biomarker. The small number
of tumors with BRAF mutations precluded the drawing of definitive conclusions concerning the predictive or
prognostic utility of this biomarker.
Key words: BRAF, chemotherapy, epidermal growth factor receptor, KRAS, mCRC, predictive
introduction
The epidermal growth factor receptor (EGFR)-targeting
monoclonal antibody cetuximab improves overall survival
when added to standard chemotherapy used in the treatment of
metastatic colorectal cancer (mCRC) [1], non-small-cell lung
cancer [2], recurrent or metastatic squamous cell carcinoma of
the head and neck (SCCHN) [3] and when combined with
radiotherapy in the treatment of locally advanced SCCHN [4].
The randomized phase II OPUS (Oxaliplatin and Cetuximab in
First-Line Treatment of Metastatic Colorectal Cancer) study
demonstrated that the tumor mutation status of codons 12 and
13 of the KRAS gene was predictive for the activity of
cetuximab combined with oxaliplatin plus infusional 5-
fluorouracil (5-FU) and folinic acid (FOLFOX-4) in the first-
line treatment of mCRC [5].
The OPUS study therefore confirmed earlier retrospective
investigations of single-arm trials [6–9], which indicated that
cetuximab activity was limited to patients whose tumors were
KRAS wild type. It was also consistent with retrospective
analyses in other randomized studies in mCRC involving
cetuximab administered as monotherapy in patients who had
failed prior chemotherapy [10] and as first-line treatment in
combination with irinotecan and infusional 5-FU/folinic acid
(FOLFIRI) [11]. These analyses demonstrated improved
outcome for patients with KRAS wild-type mCRC who received
treatment including cetuximab, with overall survival improved
in both studies in the cetuximab arm compared with the
control arm [1, 10]. Retrospective analyses of several small
studies also suggested that the tumor mutation status of
original
article
*Correspondence to: Dr C. Bokemeyer, University Cancer Center Hamburg-Hubertus
Wald Tumorzentrum, Universita
¨
tsklinikum Hamburg-Eppendorf, Martinistrasse 52,
20246 Hamburg-Eppendorf, Germany. Tel: +49-(0)-40 428-03-2960;
Fax: +49-(0)-40-428-03-8054; E-mail: c.bokemeyer@uke.uni-hamburg.de
ª The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: journals.permissions@oup.com
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a second gene, BRAF, the product of which is a downstream
effector of KRAS in the MAPK pathway [12], may be predictive
and/or prognostic in mCRC patients receiving EGFR
monoclonal antibody treatment [13–17]. This raised the
possibility that consideration of the tumor BRAF mutational
status in patients with KRAS wild-type disease might allow the
further tailoring of cetuximab treatment.
At the time of initial reporting, overall survival data were not
available for the OPUS study [5]. In addition, KRAS tumor
mutation data were only available for 69% of patients in the
intention-to-treat (ITT) population. Although comparison of
the baseline characteristics and efficacy data suggested that the
KRAS population was essentially representative of the ITT
population, it was believed that the accuracy and strength of the
conclusions would be increased if tumor KRAS mutation status
could be determined for a higher proportion of patient
samples. The current manuscript therefore reports an updated
analysis based on the consideration of overall survival and other
end points in an increased population of patients for which
tumor KRAS mutation status has been determined.
patients and methods
key eligibility criteria
Eligibility criteria have previously been described [5]. The study was carried
out in accordance with the Declaration of Helsinki. All patients provided
written informed consent for the initial clinical study.
study design and treatment
As reported [5], patients were randomly assigned to receive FOLFOX-4
(oxaliplatin 85 mg/m
2
; folinic acid 200 mg/m
2
, followed by 5-FU, as a 400
mg/m
2
intravenous bolus then a 600 mg/m
2
infusion over 22 h, days 1 and
2 of a 14-day cycle) with or without cetuximab (initial dose 400 mg/m
2
and
250 mg/m
2
/week thereafter), until the occurrence of progressive disease or
unacceptable toxicity, as first-line treatment for mCRC. Response was
assessed radiologically, every 8 weeks.
The primary end point was response, as evaluated by an independent
review committee according to modified World Health Organization criteria.
Secondary end points included progression-free survival (PFS), overall
survival and safety. Retrospective subgroup analyses investigated associations
between study end points and KRAS and BRAF tumor mutation status.
KRAS and BRAF mutation analysis
DNA was extracted from formaldehyde-fixed paraffin-embedded (FFPE)
tumor tissue and from tissue recovered from stained slides previously used
to evaluate tumor EGFR expression. The mutation status of codons 12 and
13 of exon 2 of the KRAS gene was assessed using a PCR clamping and
melting curve technique, as previously described [5]. BRAF mutation status
(V600E) was analyzed using a similar approach (BRAF V600E kit; TIB
MOLBIOL, Berlin, Germany).
statistical methods and considerations
The primary efficacy analysis was carried out on the ITT population [5]. The
prespecified analyses for the ITT population were repeated by KRAS
mutation status in those ITT patients whose tumors were available and
provided an evaluable DNA sample (KRAS population). With a new clinical
cut-off date of 30 November 2008 and a new biomarker cut-off date of 12
August 2009, this updated retrospective analysis comparatively investigated
efficacy in patient subgroups defined according to KRAS and BRAF tumor
mutation status. For tumor response, treatment groups were compared using
a stratified Cochran–Mantel–Haenszel (CMH) test. PFS and overall survival
times were analyzed by the Kaplan–Meier method [18] and stratified log-
rank test. The presented efficacy analyses were of an exploratory nature and P
values were therefore not adjusted for the multiplicity of statistical tests.
Further exploratory analyses of baseline variables of potential prognostic
value were carried out in subgroups of those patients with KRAS wild-type
tumors. Hazard and odds ratios are presented within the different patient
populations for cetuximab plus FOLFOX-4 versus FOLFOX-4 alone or
KRAS wild type versus mutant. Multivariate regression analyses of best
overall response (logistic regression model), PFS and overall survival (Cox
regression models) were conducted to explore whether the treatment effect
varied significantly according to tumor KRAS mutation status in order to
evaluate its predictive utility in this study.
Adverse events (AEs) occurring up to 30 days after the end of the last
administration of study treatment were analyzed using the Medical
Dictionary for Regulatory Activities (MedDRA) version 10.0, with special
emphasis on grade 3 and 4 toxic effects according to the National Cancer
Institute—Common Toxicity Criteria, version 2.0. Cardiac events were
evaluated by compiling specific Maintenance and Support Services
Organization, Chantilly, Virginia preferred terms of related medical
concepts, including arrhythmia, congestive heart failure, infarction-
ischemia and sudden death (see supplemental Methods, available at
Annals of Oncology online for full list).
results
patients and samples
The OPUS ITT population comprised 337 eligible, randomly
assigned and treated patients: 169 receiving cetuximab plus
FOLFOX-4 and 168 receiving FOLFOX-4 alone. The safety
population (n = 338) included one additional patient who was
erroneously randomized in the interactive voice-response
system and was consequently excluded from the ITT
population. Subsequent to the initial published analysis, the
number of patients in the KRAS population was increased from
233 (69%) to 315 (93%) through the use of tumor DNA
extracted from FFPE slide-mounted tissue sections previously
used for the immunohistochemical evaluation of EGFR
expression. The baseline characteristics according to the
treatment arm of the expanded KRAS population matched
closely those of the ITT population (Table 1). BRAF mutation
status (V600E) was evaluable in tumor DNA samples from 309
of 315 patients in the KRAS population.
treatment compliance
Exposure to cetuximab was similar in the ITT and KRAS
populations, with 84% and 85% of patients, respectively,
having a relative dose intensity (RDI) of 80% (Table 2). RDIs
for oxaliplatin and 5-FU were also comparable between the
treatment arms of the ITT and KRAS populations of patients.
In the KRAS population, exposure to cetuximab was similar for
patients whose tumors were KRAS wild type and mutant, with
79% and 91% of patients, respectively, achieving an RDI of
80%. RDIs for oxaliplatin and 5-FU were also comparable
between the treatment arms for patients whose tumors were
KRAS wild type and KRAS mutant and were similar for patients
with or without mutation, according to the treatment arm
(Table 2). Post-study therapies were comparable between the
treatment groups with the exception of EGFR-targeting agents,
which were more commonly administered as post-study
original article
Annals of Oncology
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anticancer therapy to patients in the FOLFOX-4 arm than in
the cetuximab plus FOLFOX-4 arm of the ITT population
(23% versus 9% of patients). Small discrepancies were apparent
in the biomarker subpopulations (Table 2).
efficacy in the ITT and KRAS populations
As previously reported, there was no significant difference
in relation to response or PFS between patients in the ITT
population receiving cetuximab plus FOLFOX-4 compared
with FOLFOX-4 alone. At the cut-off date of 30 Novem ber
2008, ther e were 124 deaths reported (73% of patients) in
the cetuxi mab plus FOLFOX-4 group and 125 (74% of
patients) in the FOLFOX-4 alone group. For the ITT
population, overall survival was not significantly different
between the treatment arms, with the hazard ratio (HR) fo r
death 1.015 (95% CI 0.7 91–1.303), P = 0.91, and median
survival of 18.3 months for patients receiving cetuximab
plus FOLFOX -4 versus 18.0 months for FOLFOX-4 alone.
Similarly, there was no significant difference b etween the
treatment groups in the enlarged KRAS evaluable
population in relation to response, PFS or survival
(Table 3).
subgroup analysis of efficacy according to tumor
KRAS mutations status
KRAS tumor mutational status was assessed for an additional
82 patients in the ITT population, representing an increase in
the overall ascertainment rate from 69% (233/315) of patients
Table 1. Patient and disease characteristics at baseline in the intention-to-treat and biomarker populations
Characteristic
ITT population
(n = 337)
Biomarker populations
KRAS population
(n = 315)
KRAS wild-type
population (n = 179)
KRAS/BRAF wild-type
population (n = 164)
KRAS mutant population
(n = 136)
FOLFOX-4
(n = 168)
Cetuximab
+FOLFOX-4
(n = 169)
FOLFOX-4
(n = 156)
Cetuximab
+ FOLFOX-4
(n = 159)
FOLFOX-4
(n = 97)
Cetuximab
+ FOLFOX-4
(n = 82)
FOLFOX-4
(n = 92)
Cetuximab
+ FOLFOX-4
(n = 72)
FOLFOX-4
(n = 59)
Cetuximab
+ FOLFOX-4
(n = 77)
Gender, n (%)
Male 92 (55) 89 (53) 86 (55) 82 (52) 55 (57) 42 (51) 51 (55) 38 (53) 31 (53) 40 (52)
Female 76 (45) 80 (47) 70 (45) 77 (48) 42 (43) 40 (49) 41 (45) 34 (47) 28 (47) 37 (48)
Age (years)
Median (range) 60 (30–82) 62 (24–82) 60 (30–82) 62 (24–82) 59 (36–82) 62 (24–75) 59 (37–82) 63 (24–75) 61 (30–76) 60 (34–82)
<65, n (%) 109 (65) 96 (57) 101 (65) 91 (57) 63 (65) 46 (56) 60 (65) 39 (54) 38 (64) 45 (58)
65, n (%) 59 (35) 73 (43) 55 (35) 68 (43) 34 (35) 36 (44) 32 (35) 33 (46) 21 (36) 32 (42)
Region, n (%)
Eastern Europe 93 (55) 97 (57) 88 (56) 93 (58) 58 (60) 48 (59) 56 (61) 46 (64) 30 (51) 45 (58)
Western Europe
a
75 (45) 72 (43) 68 (44) 66 (42) 39 (40) 34 (41) 36 (39) 26 (36) 29 (49) 32 (42)
ECOG PS at baseline, n (%)
0 75 (45) 65 (39) 70 (45) 61 (38) 38 (39) 32 (39) 36 (39) 27 (38) 32 (54) 29 (38)
1 76 (45) 89 (53) 70 (45) 86 (54) 49 (51) 44 (54) 47 (51) 39 (54) 21 (36) 42 (55)
2 17 (10) 15 (9) 16 (10) 12 (8) 10 (10) 6 (7) 9 (10) 6 (8) 6 (10) 6 (8)
Disease duration (months)
Median (Q1–Q3),
CRC
2.2 (1.3–17.6) 2.1 (1.2–9.8) 2.1 (1.3–16.4) 2.1 (1.2–10.8) 2.6 (1.3–19.5) 2.1 (1.1–14.3) 2.8 (1.4–20.3) 2.1 (1.2–14.2) 2.1 (1.2–13.5) 2.3 (1.4–9.0)
Median (Q1–Q3),
mCRC
1.5 (1.1–2.3) 1.4 (0.9–2.3) 1.5 (1.1–2.3) 1.4 (0.9–2.4) 1.6 (1.1–2.3) 1.3 (0.9–2.3) 1.6 (1.1–2.2) 1.3 (0.9–2.3) 1.4 (1.1–2.1) 1.6 (1.0–2.4)
Liver metastasis only, n (%)
Yes 39 (23) 50 (30) 38 (24) 48 (30) 23 (24) 25 (30) 23 (25) 23 (32) 15 (25) 23 (30)
No 129 (77) 119 (70) 118 (76) 111 (70) 74 (76) 57 (70) 69 (75) 49 (68) 44 (75) 54 (70)
Organs with metastases, n (%)
01
b
(0.6) 0 0 0 0 0 0 0 0 0
1 69 (41) 74 (44) 64 (41) 72 (45) 38 (39) 41 (50) 38 (41) 37 (51) 26 (44) 31 (40)
2 63 (38) 60 (36) 60 (38) 55 (35) 37 (38) 26 (32) 36 (39) 23 (32) 23 (39) 29 (38)
3 18 (11) 22 (13) 16 (10) 21 (13) 12 (12) 11 (13) 9 (10) 9 (13) 4 (7) 10 (13)
4 17 (10) 13 (8) 16 (10) 11 (7) 10 (10) 4 (5) 9 (10) 3 (4) 6 (10) 7 (9)
Prior therapy
c
Surgery 152 (91) 137 (81) 141 (90) 131 (82) 90 (93) 63 (77) 86 (93) 56 (78) 51 (86) 68 (88)
Adjuvant chemotherapy 36 (21) 21 (12) 32 (21) 21 (13) 21 (22) 13 (16) 21 (23) 12 (17) 11 (19) 8 (10)
Radiotherapy 23 (14) 18 (11) 21 (14) 18 (11) 15 (15) 9 (11) 15 (16) 9 (13) 6 (10) 9 (12)
a
Figure for Western Europe includes patients previously classified as from Southern Europe or rest of the world [5].
b
Patient enrolled in violation of protocol.
c
A patient may have received more than one prior therapy.
ECOG PS, Eastern Cooperative Oncology Group performance status; CRC, colorectal cancer; mCRC, metastatic colorectal cancer; Q1–Q3, interquartile
range.
Annals of Oncology
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Table 2. Exposure to study treatment and post-study anticancer therapy in the intention-to-treat and biomarker populations
Exposure
to treatment
Safety population
(n = 338)
Biomarker populations
KRAS population (n = 315) KRAS wild-type
population (n = 179)
KRAS/BRAF
wild-type population (n = 164)
KRAS mutant
population (n = 136)
FOLFOX-4
(n = 168)
Cetuximab
+ FOLFOX-4
(n = 170)
FOLFOX-4
(n = 156)
Cetuximab
+ FOLFOX-4
(n = 159)
FOLFOX-4
(n = 97)
Cetuximab
+ FOLFOX-4
(n = 82)
FOLFOX-4
(n = 92)
Cetuximab +
FOLFOX-4
(n = 72)
FOLFOX-4
(n = 59)
Cetuximab +
FOLFOX-4
(n = 77)
Duration of cetuximab treatment (weeks)
Median (Q1–Q3) 24 (14–38) 24 (13–38) 25 (19–45) 25 (19–44) 18 (10–29)
Duration of oxaliplatin treatment (weeks)
Median (Q1–Q3) 24 (16–30) 23 (15–31) 24 (16–30) 23 (14–31) 24 (16–29) 24 (16–32) 24 (17–29) 24 (17–33) 25 (18–32) 21 (12–28)
Duration of 5-FU treatment (weeks)
Median (Q1–Q3) 24 (16–32) 24 (14–36) 24 (16–32) 24 (13–36) 24 (16–32) 24 (17–41) 24 (17–33) 24 (17–40) 25 (18–33) 21.0 (11.9–32.0)
Cumulative dose of cetuximab (mg/m
2
)
Median (Q1–Q3) 5412 (3377–8247) 5405 (3146–8143) 6123 (4165–9181) 6144 (4247–9401) 4155 (2416–6655)
Cumulative dose of oxaliplatin (mg/m
2
)
Median (Q1–Q3) 883 (561–1094) 820 (514–1043) 897 (583–1101) 820 (512–1050) 879 (564–1095) 850 (596–1104) 897 (606–1098) 908 (627–1171) 922 (593–1180) 765 (425–1043)
Cumulative dose of 5-FU (mg/m
2
)
Median (Q1–Q3) 21 354 (12 793–
27 888)
19 854 (11 982–
29 960)
21 571 (13 387–
28 054)
19 527 (11 566–
29 887)
20 779 (13 606–
27 932)
21 104 (13 936–
32 715)
21 823 (14 218–
28 054)
21 104 (13 949–
32 806)
23 755 (13 168–
29 779)
16 129 (9968–26 336)
Relative dose intensity of cetuximab
a
, n (%)
<60% 3 (2) 3 (2) 2 (2) 1 (1) 1 (1)
60%–<80% 24 (14) 21 (13) 15 (18) 10 (14) 6 (8)
80%–<90% 40 (24) 38 (24) 23 (28) 22 (31) 15 (20)
90% 100 (60) 94 (60) 42 (51) 39 (54) 52 (70)
Relative dose intensity of oxaliplatin, n (%)
<60% 2 (1) 4 (2) 1 (0.6) 3 (2) 1 (1) 2 (2) 1 (1) 0 0 1 (1)
60%–<80% 31 (18) 38 (22) 27 (17) 37 (23) 16 (16) 21 (26) 14 (15) 18 (25) 11 (19) 16 (21)
80%–<90% 53 (32) 53 (31) 50 (32) 48 (30) 33 (34) 31 (38) 33 (36) 29 (40) 17 (29) 17 (22)
90% 82 (49) 75 (44) 78 (50) 71 (45) 47 (48) 28 (34) 44 (48) 25 (35) 31 (53) 43 (56)
Relative dose intensity of 5-FU, n (%)
<60% 8 (5) 10 (6) 6 (4) 8 (5) 4 (4) 4 (5) 4 (4) 2 (3) 2 (3) 4 (5)
60%–<80% 42 (25) 45 (26) 38 (24) 44 (28) 23 (24) 21 (26) 21 (23) 18 (25) 15 (25) 23 (30)
80%–<90% 39 (23) 48 (28) 36 (23) 43 (27) 27 (28) 29 (35) 27 (29) 25 (35) 9 (15) 14 (18)
90% 79 (47) 67 (39) 76 (49) 64 (40) 43 (44) 28 (34) 40 (44) 27 (38) 33 (56) 36 (47)
Post-study anticancer treatments
b
, n (%)
EGFR-targeting agents 38 (23) 15 (9) 35 ( 22) 12 (8) 17 (18) 8 (10) 16 (17) 5 (7) 18 (31) 4 (5)
VEGF-targeting agents 33 (20) 29 (17) 31 (20) 26 (16) 18 (19) 13 (16) 17 (18) 11 (15) 13 (22) 13 (17)
Cetuximab 35 (21) 15 (9) 32 (21) 12 (8) 16 (16) 8 (10) 15 (16) 5 (7) 16 (27) 4 (5)
Bevacizumab 33 (20) 29 (17) 31 (20) 26 (16) 18 (19) 13 (16) 17 (18) 11 (15) 13 (22) 13 (17)
Irinotecan 79 (47) 74 (44) 74 (47) 69 (43) 47 (48) 37 (45) 45 (49) 32 (44) 27 (46) 32 (42)
Oxaliplatin 19 (11) 21 (12) 18 (12) 20 (13) 9 (9) 15 (18) 9 (10) 12 (17) 9 (15) 5 (6)
Capecitabine 37 (22) 44 (26) 36 (23) 41 (26) 20 (21) 22 (27) 20 (22) 20 (28) 16 (27) 19 (25)
5-FU/FA 78 (46) 66 (39) 73 (47) 64 (40) 43 (44) 34 (41) 41 (45) 29 (40) 30 (51) 30 (39)
Other 26 (15) 27 (16) 26 (17) 24 (15) 13 (13) 14 (17) 13 (14) 12 (17) 13 (22) 10 (13)
a
n = 167, n = 156 and n = 74 for cetuximab plus FOLFOX4 arm of the ITT, KRAS evaluable and KRAS mutant populations, respectively.
b
Commonly administered therapeutic agents given as second- or subsequent-line anticancer treatments. A patient may have received more than one of these agents.
Q1–Q3, interquartile range; 5-FU, 5-fluorouracil; EGFR, epidermal growth factor receptor; VEGF, vascular endothelial growth factor; FA, folinic acid.
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Table 3. Efficacy data in the intention-to-treat and biomarker populations
Parameter ITT population
(n = 337)
Biomarker populations
KRAS population (n = 315) KRAS wild-type
population (n = 179)
KRAS/BRAF
wild-type population (n = 164)
KRAS mutant
population (n = 136)
FOLFOX-4
(n = 168)
Cetuximab
+ FOLFOX-4
(n = 169)
FOLFOX-4
(n = 156)
Cetuximab
+ FOLFOX-4
(n = 159)
FOLFOX-4
(n = 97)
Cetuximab
+ FOLFOX-4
(n = 82)
FOLFOX-4
(n = 92)
Cetuximab
+ FOLFOX-4
(n = 72)
FOLFOX-4
(n = 59)
Cetuximab
+ FOLFOX-4
(n = 77)
Best overall response
a
, n (%)
Complete response 1 (0.6) 2 (1) 3 (2) 3 (2) 1 (1) 3 (4) 1 (1) 3 (4) 2 (3) 0
Partial response 59 (35) 75 (44) 61 (39) 70 (44) 32 (33) 44 (54) 32 (35) 40 (56) 29 (49) 26 (34)
Stable disease 76 (45) 67 (40) 63 (40) 60 (38) 42 (43) 24 (29) 41 (45) 20 (28) 21 (36) 36 (47)
Progressive disease 21 (13) 18 (11) 20 (13) 18 (11) 15 (15) 5 (6) 13 (14) 3 (4) 5 (8) 13 (17)
Not evaluable 11 (7) 7 (4) 9 (6) 8 (5) 7 (7) 6 (7) 5 (5) 6 (8) 2 (3) 2 (3)
Best overall response rate
b
(%)
All patients (95% CI) 36 (29–44) 46 (38–53) 41 (33–49) 46 (38–54) 34 (25–44) 57 (46–68) 36 (26–47) 60 (48–71) 53 (39–66) 34 (23–46)
Odds ratio (95% CI) 1.516 (0.975–2.355) 1.199 (0.764–1.882) 2.551 (1.380–4.717) 2.649 (1.390–5.048) 0.459(0.228–0.924)
P value (stratified CMH test) 0.064 0.43 0.0027 0.0029 0.0290
Disease control rate
c
(%)
(95% CI)
81 (74–87) 85 (79–90) 81 (74–87) 84 (77–89) 77 (68–85) 87 (77–93) 80 (71–88) 88 (78–94) 88 (77–95) 81 (70–89)
PFS
Median (months) (95% CI) 7.2 (6.0–7.8) 7.2 (5.6–7.7) 7.2 (6.0–7.8) 7.3 (5.6–7.8) 7.2 (5.6–7.4) 8.3 (7.2–12.0) 7.2 (5.6–7.4) 8.3 (7.3–12.7) 8.6 (6.5–9.4) 5.5 (4.0–7.3)
Hazard ratio (95% CI) 0.931 (0.705–1.230) 0.938 (0.703–1.252) 0.567 (0.375–0.856) 0.556 (0.358–0.864) 1.720 (1.104–2.679)
P value (stratified log-rank
test)
0.62 0.67 0.0064 0.0083 0.0153
PFS rates (%) (95% CI)
3 months 85 (79–90) 83 (78–89) 84 (78–90) 83 (77–89) 81 (73–89) 91 (85–97) 83 (75–91) 93 (87–99) 90 (82–97) 75 (65–85)
6 months 59 (51–68) 53 (45–61) 59 (51–68) 54 (45–62) 55 (44–65) 66 (54–77) 56 (45–67) 65 (53–77) 67 (54–80) 42 (30–53)
9 months 34 (26–43) 34 (26–43) 34 (24–43) 35 (26–43) 29 (18–40) 49 (36–61) 30 (19–42) 50 (36–64) 41 (25–57) 21 (10–32)
12 months 12 (3–20) 24 (15–33) 11 (3–19) 22 (12–32) 11 (1–21) 31 (14–48) 12 (2–23) 36 (18–53) 11 (0–24) 12 (2–22)
Survival
Median (months) (95% CI) 18.0 (16.7–21.8) 18.3 (14.8–20.4) 18.5 (16.7–21.8) 18.3 (14.8–20.4) 18.5 (16.4–22.6) 22.8 (19.3–25.9) 19.5 (17.0–23.8) 22.8 (19.3–25.8) 17.5 (14.7–24.8) 13.4 (10.5–17.7)
Hazard ratio (95% CI) 1.015 (0.791–1.303) 1.032 (0.797–1.336) 0.855 (0.599–1.219) 0.894 (0.615–1.301) 1.290 (0.873–1.906)
P value (stratified log-rank
test)
0.91 0.81 0.39 0.56 0.20
Survival rates (%) (95% CI)
3 months 95 (92–98) 91 (87–95) 95 (92–99) 91 (87–96) 95 (90–99) 95 (90–100) 97 (93–100) 96 (91–100) 97 (92–100) 87 (79–95)
6 months 90 (86–95) 86 (80–91) 90 (86–95) 87 (81–92) 88 (81–94) 93 (87–98) 91 (85–97) 93 (87–99) 95 (89–100) 80 (71–89)
12 months 73 (66–80) 69 (62–76) 73 (66–80) 68 (61–76) 73 (64–82) 77 (68–86) 77 (68–85) 80 (70–89) 73 (62–85) 59 (48–70)
24 months 35 (28–43) 36 (28–43) 35 (27–43) 36 (29–44) 33 (23–43) 47 (36–58) 35 (25–45) 46 (33–58) 38 (25–51) 25 (15–35)
Best overall response on the ITT population was based on data available at the a priori fixed time of the confirmatory analysis.
a
As assessed by independent review.
b
Best overall response rate = (complete response + partial response).
c
Disease control rate = (complete response + partial response + stable disease).
P < 0.05 for bold values.
ITT, intention-to-treat; CI, confidence interval; CMH, Cochran–Mantel–Haenszel; PFS progression-free survival.
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in the initial published analysis to 93% (315/337) in this final
analysis. KRAS mutations were detected in the tumor tissue of
136 of 315 patients (43%). Mutations were detected more
frequently in the tumor tissue of patients who received
cetuximab plus FOLFOX-4 (77/159, 48%) compared with
FOLFOX-4 alone (59/156, 38%).
Significant interactions of treatment and KRAS tumor
mutation status were noted for best overall response (P < 0.001)
and PFS (P < 0.001) but not for overall survival (P = 0.1235).
The basis of the observed heterogeneity in treatment effect
dependent on KRAS mutation status was therefore further
explored.
Patients whose tumors were wild type for KRAS who received
cetuximab plus FOLFOX-4 had a 2.6-fold increased odds of
response (57% versus 34%; odds ratio 2.551, P = 0.0027) and
a 43% reduction in the risk of disease progression (median PFS
time 8.3 versus 7.2 months; HR 0.567, P = 0.0064) compared
with those who received FOLFOX-4 alone (Table 3). The
benefit in relation to these end points was apparent for almost
all patient subgroups (Figure 1). Survival was also improved by
the addition of cetuximab to FOLFOX-4 for patients in this
group (Figure 2A and E), but this difference was not statistically
significant (median survival time 22.8 versus 18.5 months; HR
0.855, P = 0.39). Conversely, patients whose tumors carried
mutations in KRAS who received cetuximab plus FOLFOX-4
had a decreased odds of response (34% versus 53%; odds ratio
0.459, P = 0.0290) and a higher risk of disease progression
(median PFS time 5.5 versus 8.6 months; HR 1.720, P = 0.0153)
compared with those who received FOLFOX-4 alone. Survival
time was also prolonged for patients in this group who received
FOLFOX-4 alone, but this difference was not statistically
significant (median survival time 17.5 versus 13.4; HR 1.290,
P = 0.20, Figure 2B and E).
For patients r eceiving cetuximab plus FOLFOX-4, survival
time was significantly prolonged for those whose t umors
were KRAS wild type compared with those whose tumors
carried KRAS mutations (Figure 2C and E; m edian survival
time 22.8 versus 13.4 months; HR 0 .632, P = 0.013).
Conversely, overall survival was similar for those patients
receiving FOLFOX-4, regardless of whether their tumors
were KRAS wild type or KRAS mutant (Figure 2D and E;
median survival time 18.5 versus 17.5 mo nths; H R 0.92 8,
P = 0.70). For patients whose tumors were KRAS wild type,
rates of metastatic surgery were significantly higher in those
who received cetuximab plus FOLFOX-4 (10/82, 12%)
compared with those who received FOLFOX-4 alone (3/97,
3%); CMH test , P = 0.02 42; although caution should be
exercised in the interpretation of these figures, given the
small number of patients involved.
BRAF mutation analysis
BRAF mutations were detected in the tumor tissue of 11 of 309
patients (4%): 6 of whom received cetuximab plus FOLFOX-4
and 5 of whom received FOLFOX-4 alone. All BRAF mutations
were detected in tumors that were wild type for KRAS (11/175
samples evaluable for both genes. Of the 11 patients with BRAF
mutations, 2 patients, who received cetuximab plus FOLFOX-4,
had a partial response to treatment. Efficacy was subsequently
analyzed according to the treatment arm for evaluable patients
in the KRAS population whose tumors were either wild type or
mutant for BRAF. Results for the KRAS wild-type/BRAF wild-
type population were very similar to those for the KRAS wild-
type population with the addition of cetuximab to FOLFOX-4
associated with significant improvements in response and PFS
(Table 3). In the small number of patients whose tumors were
KRAS wild-type/BRAF mutant (n = 11), overall survival was
prolonged in those receiving cetuximab plus FOLFOX-4
compared with FOLFOX-4 alone (median 20.7 versus 4.4
months). This difference should be interpreted cautiously,
given the small sample size.
safety
As reported previously, the most common grade 3/4 AE in the
safety population was neutropenia, which occurred in 30% of
patients receiving cetuximab plus FOLFOX-4 and 34% of those
receiving FOLFOX-4 alone (Table 4). The incidence of grade
3/4 cardiac events was higher in patients receiving cetuximab
plus FOLFOX-4 (8/170, 5%) compared with those receiving
FOLFOX-4 alone (0/168). The safety profile in both treatment
arms was comparable for patients with KRAS wild-type and
mutant tumors (Table 4).
discussion
Knowledge of how the specific molecular characteristics of
a tumor affect the clinical activity of particular treatment agents
will increasingly allow for the tailoring of anticancer therapy on
an individual patient basis [19–21]. This has been exemplified,
in the case of mCRC, by the demonstration of the differential
efficacy of EGFR-targeting agents according to whether tumors
carry mutations in the KRAS gene [5, 10, 11, 22–24]. Using
improved ascertainment approaches, the fraction of OPUS
study patients for whom tumor KRAS mutation status could be
determined was increased from 69% to 93%. Updated analyses
of response and PFS and a new analysis of overall survival
according to the treatment group and KRAS tumor mutational
status were therefore carried out. Also included was an
assessment of the predictive utility of BRAF tumor mutation
status in patients with KRAS wild-type disease.
The updated analyses confirmed that tumor KRAS mutation
status was predictive for clinical outcome in patients receiving
cetuximab plus FOLFOX-4 as first-line treatment for mCRC.
In relation to the primary end point, in patients whose tumors
were KRAS wild type, the addition of cetuximab to FOLFOX-4
significantly increased the odds of response. Conversely, in
patients whose tumors carried mutations in KRAS, the
addition of cetuximab to FOLFOX-4 significantly decreased
the odds of response. Similarly, the addition of cetuximab to
FOLFOX-4 was associated with a significant reduction in the
risk of disease progression for patients with KRAS wild-type
tumors but a significant increase in the risk of disease
progression for patients whose tumors carried KRAS
mutations.
In patients with KRAS wild-type tumors, the addition of
cetuximab to FOLFOX-4 led to an improvement in median
survival time of over 4 months (18.5–22.8 months). Due to
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A
Subgroup (number of patients in Group A vs B) Number of responses OR [95%CI]
No benefit under cetuximab Benefit under cetuximabOR and 95% CI
0.01 0.02 0.05 0.1 0.2 0.5 1 2 5 10 20 50 100 200
Group A vs B
All ITT Subjects ( 82 vs 97) 47 vs 33 2.55[ 1.38, 4.72]
Age
< 65 years ( 46 vs 63) 29 vs 21 3.35[ 1.51, 7.45]
>= 65 years ( 36 vs 34) 18 vs 12 1.72[ 0.64, 4.63]
Gender
Male ( 42 vs 55) 27 vs 18 4.00[ 1.64, 9.76]
Female ( 40 vs 42) 20 vs 15 1.76[ 0.72, 4.29]
ECOG PS
0 - 1 ( 76 vs 86) 46 vs 31 2.72[ 1.44, 5.14]
2 ( 6 vs 11) 1 vs 2 0.90[ 0.06,12.58]
% EGFR positive cells
>35 % ( 7 vs 10) 5 vs 2 8.75[ 0.90,84.80]
20 % - 35 % ( 6 vs 6) 4 vs 1 10.00 [ 0.65,154.4]
>10 % - 20 % ( 8 vs 5) 5 vs 0
> 0 % - 10 % ( 61 vs 76) 33 vs 30 1.77[ 0.89, 3.55]
Number of metastatic sites
<=2 ( 67 vs 75) 42 vs 25 3.21[ 1.59, 6.52]
>2 ( 15 vs 22) 5 vs 8 0.88[ 0.22, 3.49]
Liver metastases only
Yes ( 25 vs 23) 19 vs 9 4.57[ 1.31,15.98]
No ( 57 vs 74) 28 vs 24 1.99[ 0.97, 4.08]
Leucocytes
<= 10000/mm^3 ( 64 vs 76) 39 vs 26 3.19[ 1.56, 6.52]
> 10000/mm^3 ( 16 vs 18) 8 vs 5 2.37[ 0.55,10.14]
LDH at baseline
> upper normal range ( 40 vs 33) 24 vs 7 5.15[ 1.79,14.87]
<= upper normal range ( 34 vs 55) 21 vs 24 2.22[ 0.90, 5.44]
Alkaline Phosphatase at baseline
>= 300 U/L ( 13 vs 19) 6 vs 8 1.10[ 0.25, 4.80]
< 300 U/L ( 66 vs 74) 40 vs 22 3.74[ 1.83, 7.66]
Prior adjuvant chemotherapy
Yes ( 13 vs 21) 6 vs 6 1.96 [ 0.48, 7.95]
No ( 69 vs 76) 41 vs 27 2.55 [ 1.28, 5.07]
Figure 1. (A) Forest plot of common odds ratios (adjusted for ECOG PS) for best overall response by a priori subgroups in patients with KRAS wild-type
tumors. (B) Forest plot of hazard ratios for progression-free survival time by a priori subgroups in patients with KRAS wild-type tumors. Group A received
cetuximab plus FOLFOX-4; Group B received FOLFOX-4 alone. CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance
status; EGFR, epidermal growth factor receptor; HR, hazard ratio; ITT, intention-to-treat; LDH, lactate dehydrogenase; OR, odds ratio.
Annals of Oncology
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B
Subgroup (number of patients in Group A vs B) Number of events
Group A vs B
HR [95%CI]
Benefit under cetuximab No benefit under cetuximabHR and 95% CI
0.01 0.02 0.0 5 0.1 0.2 0.5 1 2 5 10 20 50 100 200
All ITT Subjects (82 vs 97) 38 vs 62 0.57[ 0.37,0.86]
Age
< 65 years (46 vs 63) 21 vs 41 0.53[ 0.31,0.90]
>= 65 years (36 vs 34) 17 vs 21 0.70[ 0.37,1.35]
Gender
Male (42 vs 55) 20 vs 32 0.69[ 0.39,1.24]
Female (40 vs 42) 18 vs 30 0.45[ 0.25,0.83]
ECOGPS (unstratified)
0-1 (76 vs 86) 34 vs 54 0.55[ 0.35,0.85]
2 (6 vs 11) 4 vs 8 0.73[ 0.22,2.47]
%EGFR positive cells
>35% (7 vs 10) 3 vs 6 0.65[ 0.15,2.79]
20%-35%(6 vs 6) 1 vs 2 0.31[ 0.02,3.88]
>10%-20%(8 vs 5) 5 vs 5 0.18[ 0.03,0.93]
>0%-10%(61 vs 76) 29 vs 49 0.60[ 0.37,0.96]
Number of metastatic sites
<=2 (67 vs 75) 25 vs 45 0.46[ 0.28,0.76]
>2 (15 vs 22) 13 vs 17 1.31[ 0.62,2.78]
Liver metastases only
Yes (25 vs 23) 9 vs 9 0.64[ 0.23,1.79]
No (57 vs 74) 29 vs 53 0.59[ 0.37,0.93]
Leucocytes
<= 10000/mm^3 (64 vs 76) 31 vs 49 0.45[ 0.28,0.73]
> 10000/mm^3 (16 vs 18) 6 vs 12 0.82[ 0.28,2.42]
LDH at baseline
> upper normal range (40 vs 33) 21 vs 26 0.44[ 0.24,0.82]
<= upper normal range (34 vs 55) 14 vs 35 0.48[ 0.25,0.89]
Alkaline Phosphatase at baseline
>= 300 U/L (13 vs 19) 5 vs 12 0.55[ 0.19,1.63]
< 300 U/L (66 vs 74) 32 vs 49 0.53[ 0.33,0.84]
Prior adjuvant chemotherapy
Yes (13 vs 19) 5 vs 12 0.55[ 0.19,1.63]
No (66 vs 74) 32 vs 49 0.53[ 0.33,0.84]
Figure 1. Continued
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the limited sample size, this difference did not reach
statistical significance, although it would be clinically
meaningful if confirmed in an adequately powered
randomized study. The converse was true for patients w ith
KRAS mutant tumors.
A randomized phase III study prospectively investigating the
EGFR-targeting antibody, panitumumab, in combination with
FOLFOX-4 as first-line treatment in patients with KRAS wild-
type mCRC reported a significant difference between treatment
groups in PFS time, with a HR of 0.80 in favor of patients
receiving panitumumab plus FOLFOX-4 compared with
FOLFOX-4 alone (P = 0.02) [24]. As in the current study, the
converse was true for patients whose tumors carried mutations
in KRAS. Overall survival and response rate were also superior
for patients with KRAS wild-type disease in the panitumumab
plus FOLFOX-4 arm, but the differences did not reach
statistical significance. Grade 3/4 skin toxicity was particularly
common for patients in this treatment group (36%). In the
phase III Continuous Chemotherapy plus Cetuximab or
Intermittent Chemotherapy (COIN) study, patients received
A
HR [95% CI]: 0.855 [0.599-1.219]
p-value: 0.39 (log-rank)
Events
Median OS
[95% CI]
FOLFOX
(n=97)
71
18.5
[16.4-22.6]
Cetuximab + FOLFOX
(n=82)
55
22.8
[19.3-25.9]
At risk
FOLFOX
Cetuximab + FOLFOX
97 84 67 48 27 20 3
82 75 59 48 33 20 1
KRAS wild-type population
FOLFOX
Cetuximab + FOLFOX
e t a m i t s e r e i e M - n a l p a K
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Overall survival time (months)
0 6 1 2 1 8 2 4 3 0 36
B
HR [95% CI]: 1.290 [0.873-1.906]
p-value: 0.20 (log-rank)
Events
Median OS
[95% CI]
FOLFOX
(n=59)
45
17.5
[14.7-24.8]
Cetuximab + FOLFOX
(n=77)
61
13.4
[10.5-17.7]
At risk
FOLFOX
Cetuximab + FOLFOX
59 54 41 25 19 12 0
77 61 45 26 17 15 2
KRAS mutant population
FOLFOX
Cetuximab + FOLFOX
e t a
m
i
t
s
e
r
e
i e M -
n
a l p
a
K
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Overall survival time (months)
0 6 12 18 24 30 36
C
HR [95% CI]: 0.632 [0.438-0.912]
p-value: 0.013 (log-rank)
Events
Median OS
[95% CI]
KRAS mutant
(n=77)
61
13.4
[10.5-17.7]
KRAS wild type
(n=82)
55
22.8
[19.3-25.9]
At risk
KRAS mutant
KRAS wi ld ty pe
77 61 45 26 17 15 2
82 75 59 48 33 20 1
mutant
wild type
etamitsereieM-nalpaK
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Overall survival time (months)
0 6 12 18 24 30 36
Cetuximab + FOLFOX group
D
HR [95% CI]: 0.928 [0.637-1.352]
p-value: 0.70 (log-rank)
Events
Median OS
[95% CI]
KRAS mutant
(n=59)
45
17.5
[14.7-24.8]
KRAS wild ty pe
(n=97)
71
18.5
[16.4-22.6]
At risk
KRAS muta nt
KRAS wi ld ty pe
59 54 41 25 19 12 0
97 84 67 48 27 20 3
mutant
wild type
e
ta
mit
se
rei
e
M-nalp
a
K
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Overall survival time (months)
0612
18
24 30 36
FOLFOX group
E
Events
Median OS
[95% CI]
KRAS mt
(n=59)
45
17.5
[14.7-24.8]
KRAS wt
(n=97)
71
18.5
[16.4-22.6]
KRAS mt
(n=77)
61
13.4
[10.5-17.7]
KRAS wt
(n=82)
55
22.8
[19.3-25.9]
KRAS evaluable populations
FOLFOX: KRAS mutant
FOLFOX: KRAS wild type
Cetuximab + FOLFOX: KRAS mutant
Cetuximab + FOLFOX: KRAS wild type
e t a
m
i
t
s e r
e
i e
M
-
n a
l p
a
K
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Overall survival time (months)
0 6 12 18 24 30 36
FOLFOX Cetuximab + FOLFOX
Figure 2. Kaplan–Meier plots of survival time according to the treatment arm for patients whose tumors were (A) KRAS wild type and (B) KRAS mutant
and according to tumor KRAS mutation status for patients receiving (C) cetuximab plus FOLFOX-4 (D) FOLFOX-4 alone. Panel (E) shows survival
according to the treatment arm and KRAS tumor mutation status for the four subgroups of patients. CI, confidence interval; FOLFOX, FOLFOX-4; HR,
hazard ratio; mt, mutant; OS, overall survival; wt, wild type.
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one of two fluoropyrimidine/oxaliplatin chemotherapy
regimens with and without cetuximab as first-line treatment for
mCRC. The primary analysis demonstrated that the addition of
cetuximab to chemotherapy conferred no benefit in relation to
PFS or overall survival, irrespective of KRAS mutational status,
although response rate was significantly improved in patients
with KRAS wild-type tumors [25]. Of note, the capecitabine
dose was reduced in 19% of patients in the cetuximab arm,
from 1000 to 850 mg/m
2
bd due to safety concerns. Before the
dose reduction, patients in this arm receiving capecitabine/
oxaliplatin (XELOX) received significantly less capecitabine
and oxaliplatin than the corresponding control group (P =
0.001). The lower dose level of capecitabine subsequently
administered may also conceivably have been suboptimal for
the treatment of mCRC. Indeed, closer inspection of the
results suggested that patients with KRAS wild-type tumors
who received XELOX plus cetuximab derived no additional
benefit, whereas those who received infusional 5-FU/
oxaliplatin (OxMdG) plus cetuximab had prolonged PFS time
(HR 0.77, P = 0.056) compared with those receiving OxMdG
alone. This ef fect was more pronounced in patients with
tumors wild type for KRAS, BRAF and NRAS (HR 0.72,
P = 0.036).
The OPUS study results are consistent with updated data
from the Cetuximab Combined With Irinotecan in First-Line
Therapy for Metastatic Colorectal Cancer (CRYSTAL) study,
which demonstrated that the addition of cetuximab to FOLFIRI
as first-line therapy for patients with mCRC improved response
rate, PFS and overall survival in patients with KRAS wild-type
tumors compared with FOLFIRI alone [1]. Both studies are
entirely consistent with the revised guidance from regulatory
and advisory authorities concerning the administration of
cetuximab only to patients with KRAS wild-type mCRC [26–
29] and confirm KRAS tumor mutation status as a powerful
predictive biomarker in relation to the clinical efficacy of
cetuximab combined with standard first-line chemotherapy.
One additional candidate biomarker, BRAF tumor mutation
status, was investigated in the current study. As only a small
number of tumors with mutations in this gene were identified
(11/312), no definitive conclusions concerning possible
predictive or prognostic utility can be reached. Analyses of
larger numbers of patients will be required to fully explore the
Table 4. Incidence of grade 3/4 adverse events
a
in the intention-to-treat and biomarker populations
Adverse
event, n (%) Safety population
(n = 338)
Biomarker populations
KRAS population
(n = 315)
KRAS wild-type
population (n = 179)
KRAS/BRAF wild-type
population (n = 164)
KRAS mutant
population (n = 136)
FOLFOX-4
(n = 168)
Cetuximab
+ FOLFOX-4
(n = 170)
FOLFOX-4
(n = 156)
Cetuximab
+ FOLFOX-4
(n = 159)
FOLFOX-4
(n = 97)
Cetuximab
+ FOLFOX-4
(n = 82)
FOLFOX-4
(n = 92)
Cetuximab
+ FOLFOX-4
(n = 72)
FOLFOX-4
(n = 59)
Cetuximab
+ FOLFOX-4
(n = 77)
Any 117 (70) 129 (76) 107 (69) 119 (75) 62 (64) 67 (82) 58 (63) 58 (81) 45 (76) 52 (68)
MedDRA version 10.0 preferred term
Neutropenia 57 (34) 51 (30) 54 (35) 47 (30) 31 (32) 29 (35) 30 (33) 26 (36) 23 (39) 18 (23)
Rash 1 (0.6) 19 (11) 1 (0.6) 17 (11) 0 9 (11) 0 8 (11) 1 (2) 8 (10)
Diarrhea 12 (7) 14 (8) 12 (8) 14 (9) 5 (5) 7 (9) 5 (5) 5 (7) 7 (12) 7 (9)
Leukopenia 10 (6) 12 (7) 9 (6) 10 (6) 5 (5) 6 (7) 5 (5) 6 (8) 4 (7) 4 (5)
Fatigue 5 (3) 8 (5) 4 (3) 7 (4) 3 (3) 1 (1) 3 (3) 1 (1) 1 (2) 6 (8)
Peripheral sensory
neuropathy
12 (7) 7 (4) 12 (8) 7 (4) 8 (8) 3 (4) 8 (9) 3 (4) 4 (7) 4 (5)
Anemia 4 (2) 7 (4) 3 (2) 6 (4) 2 (2) 3 (4) 1 (1) 2 (3) 1 (2) 3 (4)
Thrombocytopenia 4 (2) 7 (4) 4 (3) 7 (4) 0 3 (4) 0 3 (4) 4 (7) 4 (5)
Hypersensitivity 2 (1) 7 (4) 2 (1) 6 (4) 1 (1) 1 (1) 1 (1) 0 1 (2) 5 (6)
Paresthesia 7 (4) 2 (1) 7 (4) 2 (1) 5 (5) 1 (1) 5 (5) 1 (1) 2 (3) 1 (1)
Palmar-plantar
erythrodysesthesia
1 (0.6) 7 (4) 1 (0.6) 7 (4) 1 (1) 3 (4) 1 (1) 3 (4) 0 4 (5)
Neuropathy 6 (4) 3 (2) 6 (4) 3 (2) 3 (3) 1 (1) 3 (3) 1 (1) 3 (5) 2 (3)
Composite categories
b
Skin reactions
c
1 (0.6) 30 (18) 1 (0.6) 25 (16) 0 15 (18) 0 12 (17) 1 (2) 10 (13)
Infusion-related
reactions
3 (2) 8 (5) 3 (2) 7 (4) 2 (2) 1 (1) 2 (2) 0 1 (2) 6 (8)
Neurotoxicity-
associated events
c
20 (12) 15 (9) 20 (13) 14 (9) 14 (14) 6 (7) 14 (15) 6 (8) 6 (10) 8 (10)
Cardiac events 0 8 (5) 0 6 (4) 0 3 (4) 0 3 (4) 0 3 (4)
Mucositis
c
2 (1) 5 (3) 2 (1) 5 (3) 2 (2) 2 (2) 2 (2) 0 0 3 (4)
a
Occurring in >3% of patients in either arm of the safety population or according to composite categories of special interest.
b
See supplemental Methods (available at Annals of Oncology online) for preferred terms included in composite adverse event categories.
c
No grade 4 events reported.
MedDRA, Medical Dictionary for Regulatory Activities.
original article
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biomarker potential of BRAF mutation status in mCRC.
Indeed, in the CRYSTAL study, BRAF tumor mutation status
was shown to be of prognostic impact for patients receiving
FOLFIRI [1]. Similarly, in the phase III CAIRO2 study, BRAF
tumor mutation was shown to be a marker of poor prognosis in
patients with mCRC receiving capecitabine, oxaliplatin and
bevacizumab either with or without cetuximab [30]. Other
candidate markers with possible application in this setting
include high-level tumor expression of the EGFR ligands
amphiregulin and epiregulin [31, 32], and tumor mutation
status of the PIK3CA gene [33].
In summary, the current study demonstrated that the
addition of cetuximab to FOLFOX-4 as first-line therapy for
mCRC improved clinical outcome compared with FOLFOX-4
alone in patients whose tumors were wild type for KRAS and
confirmed KRAS tumor mutation status as a clinically useful
predictive factor for the efficacy of cetuximab plus FOLFOX-4
in relation to response and PFS.
acknowledgements
The authors thank Christopher Stroh of Merck KGaA for his
contribution in relation to the biomarker analyses and Tobias
Haas of Merck KGaA for carrying out the KRAS and BRAF
mutation detection assays. Editorial assistance in the
preparation of this manuscript was provided by Dr Jim
Heighway, Cancer Communications and Consultancy Ltd,
funded by Merck KGaA, Darmstadt, Germany.
funding
Merck KGaA.
disclosure
CB reports participating in advisory boards for Merck Serono
and receiving honoraria for lectures. JTH reports receiving
honoraria for lectures from Merck Serono. AZ, IC and MS are
salaried employees of Merck KGaA. All other authors reported
no conflict of interest.
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    • "Oncogenomic studies have enabled a molecular taxonomy of colorectal cancer (Ana Sebio, 2015; Dienstmann, 2014), but to date, this has had only a limited impact on the clinical management of this disease. BRAF(V600E) mutations occur in about 8%–10% of CRC patients and are associated with a poor prognosis, especially in the metastatic setting (Bokemeyer et al., 2011; Van Cutsem et al., 2011; Richman et al., 2009; Tol et al., 2009). These tumors can be identified by a distinctive gene expression signature. "
    [Show abstract] [Hide abstract] ABSTRACT: BRAF(V600E) mutant colon cancers (CCs) have a characteristic gene expression signature that is also found in some tumors lacking this mutation. Collectively, they are referred to as “BRAF-like” tumors and represent some 20% of CCs. We used a shRNA-based genetic screen focused on genes upregulated in BRAF(V600E) CCs to identify vulnerabilities of this tumor subtype that might be exploited therapeutically. Here, we identify RANBP2 (also known as NUP358) as essential for survival of BRAF-like, but not for non-BRAF-like, CC cells. Suppression of RANBP2 results in mitotic defects only in BRAF-like CC cells, leading to cell death. Mechanistically, RANBP2 silencing reduces microtubule outgrowth from the kinetochores, thereby inducing spindle perturbations, providing an explanation for the observed mitotic defects. We find that BRAF-like CCs display far greater sensitivity to the microtubule poison vinorelbine both in vitro and in vivo, suggesting that vinorelbine is a potential tailored treatment for BRAF-like CCs.
    No preview · Article · Apr 2016 · Cell
  • Source
    • "Thus, it appears that EGFR expression as detected by IHC is not a requirement for the efficacy of necitumumab in combination with chemotherapy, consistent with findings from other studies evaluating cetuximab (Chung et al, 2005; Folprecht et al, 2010; Brodowicz et al, 2013; Licitra et al, 2013). The safety profile of necitumumab in combination with mFOLFOX6 was generally comparable with those reported for other EGFR mAbs when used in combination with FOLFOX regimens (Tabernero et al, 2007; Folprecht et al, 2010; Ocvirk et al, 2010; Bokemeyer et al, 2011; Brodowicz et al, 2013; Douillard et al, 2014; Wasan et al, 2014). The most common grade X3 AEs were primarily class effects reflecting exposure to this treatment combination, including gastrointestinal disorders (diarrhoea 9.1%), blood and lymphatic disorders (neutropenia, 29.5%), nervous system disorders (paraesthesia 13.6%), and skin toxicities (rash 20.5%). "
    [Show abstract] [Hide abstract] ABSTRACT: Background: This single-arm phase II study investigated the EGFR monoclonal antibody necitumumab plus modified FOLFOX6 (mFOLFOX6) in first-line treatment of locally advanced or metastatic colorectal cancer (mCRC). Methods: Patients received 800-mg intravenous necitumumab (day 1; 2-week cycles), followed by oxaliplatin 85 mg m(-2), folinic acid 400 mg m(-2), and 5-fluorouracil (400 mg m(-2) bolus then 2400 mg m(-2) over 46 h). Radiographic evaluation was performed every 8 weeks until progression. Primary endpoint was objective response rate. Results: Forty-four patients were enrolled and treated. Objective response rate was 63.6% (95% confidence interval 47.8-77.6); complete response was observed in four patients; median duration of response was 10.0 months (7.0-16.0). Median overall survival (OS) and progression-free survival (PFS) were 22.5 (11.0-30.0) and 10.0 months (7.0-12.0), respectively. Clinical outcome was better in patients with KRAS exon 2 wild type (median OS 30.0 months (23.0-NA); median PFS 12.0 (8.0-20.0)), compared with KRAS exon 2 mutant tumours (median OS 7.0 months (5.0-37.0); median PFS 7.0 (4.0-18.0)). The most common grade ⩾3 adverse events were neutropenia (29.5%), asthenia (27.3%), and rash (20.5%). Conclusion: First-line necitumumab+mFOLFOX6 was active with manageable toxicity in locally advanced or mCRC; additional evaluation of the impact of tumour RAS mutation status is warranted.British Journal of Cancer advance online publication, 14 January 2016; doi:10.1038/bjc.2015.480 www.bjcancer.com.
    Full-text · Article · Jan 2016 · British Journal of Cancer
  • Source
    • "Moreover, based on miR-31-3p or miR-31-5p expression levels we were able to discriminate 34%, respectively 40% of patients with wt-RAS status who could be considered as non-responders beside RAS mutated patients. Wt-RAS status is manifested in 60% of mCRC patients [17]. The combination of RAS mutational status with miR-31-5p/3p expression levels could be in this respect powerful tool for identification of patients who are more likely to respond to cetuximab therapy. "
    [Show abstract] [Hide abstract] ABSTRACT: The aim of our study was to investigate whether microRNAs (miRNAs) could serve as predictive biomarkers to anti-EGFR therapy (cetuximab, panitumumab) in patients with RAS wild-type (wt-RAS) metastatic colorectal cancer (mCRC). Historical cohort of 93 patients with mCRC (2006-2009) was included and further divided into exploratory and validation cohorts. MiRNAs expression profiling was performed on the exploratory cohort of 41 wt-KRAS mCRC patients treated with cetuximab to identify miRNAs associated with time to progression (TTP). The validation was performed on two independent cohorts: 28 patients of wt-RAS mCRC treated with cetuximab and 24 patients of wt-RAS mCRC treated with panitumumab. We identified 9 miRNAs with significantly different expression between responders and non-responders to cetuximab therapy (P ≤ 0.01). These 9 miRNAs were further evaluated in two independent cohorts of patients and miR-31-3p (P < 0.001) and miR-31-5p (P < 0.001) were successfully confirmed as strongly associated with TTP in wt-RAS mCRC patients treated with cetuximab but not panitumumab. When evaluated on the complete cohort of cetuximab patients (N = 69), miR-31-3p (HR, 5.10; 95% CI, 2.52-10.32; P < 0.001) and miR-31-5p (HR, 4.80; 95% CI, 2.50-9.24; P < 0.001) were correlated with TTP on the comparable level of significance. There was no difference in miR-31-5p/3p expression levels in RAS mutated and wild-type tumor samples. MiR-31-5p/3p are promising predictive biomarkers of cetuximab response in wt-RAS mCRC patients.
    Full-text · Article · Oct 2015 · Oncotarget
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