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REVIEW
The impact of panitumumab treatment on survival
and quality of life in patients with RAS wild-type
metastatic colorectal cancer
This article was published in the following Dove Press journal:
Cancer Management and Research
Francesca Battaglin
1
Alberto Puccini
2
Selma Ahcene Djaballah
3
Heinz-Josef Lenz
1
1
Division of Medical Oncology, Norris
Comprehensive Cancer Center, Keck
School of Medicine, University of
Southern California, Los Angeles, CA
90033, USA;
2
Medical Oncology Unit 1,
IRCCS Ospedale Policlinico San Martino,
Genova, Italy;
3
Medical Oncology Unit 1,
Clinical and Experimental Oncology
Department, Veneto Institute of
Oncology IOV - IRCCS, Padua 35128,
Italy
Abstract: Panitumumab is a fully human monoclonal antibody targeting the epidermal
growth factor receptor (EGFR). It is currently approved for the treatment of RAS wild-type
(WT) metastatic colorectal cancer (mCRC) in combination with chemotherapy in first- and
second-line and as monotherapy in chemorefractory patients. This review will provide an
overview of main efficacy data on panitumumab from its early development up to latest
evidences, including novel perspectives on predictive biomarkers of anti-EGFRs efficacy and
mechanisms of secondary resistance. Quality of life (QoL) related issues and panitumumab
safety profile will be addressed as well.
Keywords: panitumumab, colorectal cancer, EGFR, RAS, biomarker, quality of life
Introduction
Colorectal cancer (CRC) is the third most frequently diagnosed malignancy both in
men and in women and represents one of the leading causes of cancer-related
mortality worldwide.
1
In recent years, an extended molecular characterization of
CRC has led to a deeper understanding of the mechanisms of development and
heterogeneity of this disease. Novel targeted agents including vascular endothelial
growth factors (VEGF)-, epidermal growth factor receptor (EGFR)- and more
recently immune checkpoints-inhibitors have become available for the treatment
of mCRC, adding to standard chemotherapy with 5-fluorouracil, oxaliplatin and
irinotecan.
2
The improvement in medical treatments, together with enhanced locor-
egional and surgical approaches, has translated into a longer median overall survi-
val (OS) of patients with mCRC which has surpassed 30 months in modern day
practice.
3
The EGFR signaling pathway plays a critical role in CRC development and
EGFR inhibitors are well established therapeutic agents in mCRC treatment.
Panitumumab is a fully human monoclonal antibody (mAb) which targets with
high affinity the extracellular domain of EGFR, competitively inhibiting the binding
of other ligands and thus preventing the activation of the EGFR downstream
signaling cascade (Figure 1).
4
In malignant cells the activation of EGFR promotes
cell proliferation through the KRAS/RAF/MAPK and the PI3K/AKT/mTOR axes.
5
EGFR blockade by panitumumab results in inhibition of cell growth, induction of
apoptosis, decreased of proinflammatory cytokines and VEGF production, and
EGFR downregulation through receptor internalization.
6,7
Over time, the clinical
Correspondence: Heinz-Josef Lenz
Division of Medical Oncology, Norris
Comprehensive Cancer Center, Keck
School of Medicine, University of
Southern California, 1441 Eastlake
Avenue, Suite 3456, Los Angeles, CA
90033, USA
Tel +1 323 865 3967
Email lenz@med.usc.edu
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http://doi.org/10.2147/CMAR.S186042
efficacy of panitumumab in mCRC has been proven by
several randomized trials across different treatment lines,
however since early studies it was clear that not all
patients benefit from this treatment. Hence, the identifica-
tion of predictive biomarkers has been paramount in pani-
tumumab studies, paving the way to the discovery of rat
sarcoma (RAS) mutations as negative predictive biomar-
kers for anti-EGFRs activity.
8
In this review, we will provide an overview of panitu-
mumab activity across different treatment scenarios and
treatment lines in mCRC. We will also address the impact
of panitumumab treatment on patients’quality of life
(QoL) and discuss novel perspectives on patient selection
and primary and secondary resistance mechanisms to anti-
EGFR agents.
Regulatory approval and molecular
patient selection
Panitumumab is currently approved by the Food and Drug
Administration (FDA) and European Medicines Agency
(EMA) for the treatment of RAS wild-type (WT) mCRC in
combination with FOLFOX (5-fluorouracil, leucovorin
and oxaliplatin) or FOLFIRI (5-fluorouracil, leucovorin
and irinotecan) in the first-line setting; in combination
with FOLFIRI in the second-line setting; and as mono-
therapy following disease progression after prior che-
motherapy treatment (fluoropyrimidine-, oxaliplatin- and
irinotecan-containing regimens).
4
Regulatory Agencies have also provided recommenda-
tions on validated laboratory techniques and accreditation
criteria for RAS mutation testing, which should be performed
only in highly qualified and certified laboratories. In 2017,
the American Society of Clinical Oncology (ASCO) in col-
laboration with the Association for Molecular Pathology, the
College of American Pathologists, and the American Society
for Clinical Pathology, published a set of dedicated guide-
lines on the evaluation of molecular biomarkers in CRC.
9
According to the current standard of practice every patient
being considered for anti-EGFR treatment must receive RAS
mutational testing and the analysis should include KRAS and
NRAS codons 12, 13 of exon 2; 59, 61 of exon 3; and 117 and
146 of exon 4.
8
More recently, several other tumor molecular features
and mutations in genes involved in EGFR-related path-
ways have been shown to play a role in anti-EGFRs
resistance mechanisms. The V-Raf murine sarcoma viral
oncogene homolog B1 (BRAF) V600E mutation is one of
these, and growing evidence supports the use of BRAF as a
negative predictive biomarker in clinical practice. An
overview of novel biomarkers of primary and acquired
resistance mechanisms is provided in the next sections.
Clinical efficacy
Panitumumab monotherapy
The open label phase III 408 trial was the first study to
demonstrate a progression-free survival (PFS) benefit,
although small, with single agent panitumumab compared
to best supportive care (BSC) in unselected pre-treated
mCRC (8 versus 7.3 weeks, hazard ratio (HR) 0.54; 95%
confidence interval (CI), 0.44–0.66; P<0.0001).
10
Later on,
a retrospective biomarker analysis from this study shed
light on the predictive role of KRAS exon 2 mutation on
panitumumab efficacy, demonstrating a clear improvement
in PFS for patients with WT tumors (12.3 versus 7.3 weeks,
HR 0.45; 95% CI, 0.34–0.59; P<0.0001), while no benefit
was observed in patients with mutated tumors (PFS 7.4
versus 7.3 weeks for panitumumab versus BSC, HR 0.99;
95% CI, 0.73–1.36).
11
These findings opened a new era for
biomarker discovery and molecular patient selection, lead-
ing the restriction of the use of anti-EGFR agents to KRAS
exon 2 (codon 12 and 13) WT tumors in 2008.
PI3K
PTEN
AKT
mTOR
RAS
RAF
MEK
ERK
EGFR
Panitumumab
Cell survival, proliferation, angiogenesis,
metastatic spread
Figure 1 Panitumumab, a fully humanized monoclonal IgG2 antibody, inhibits the
EGFR pathway.
Abbreviations: AKT, AKT8 virus oncogene cellular homolog; EGFR, epidermal
growth factor receptor; ERK, extracellular signal–regulated kinase; MEK, mitogen-
activated protein kinase kinase; mTOR, mammalian target of rapamycin; PI3K,
phosphatidyilinositol 3-kinase; PTEN, phosphatase and tensin homolog; RAF, v-Raf
murine sarcoma viral oncogene homolog; RAS, rat sarcoma viral oncogene
homolog.
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The activity of panitumumab monotherapy has been
compared to that of cetuximab, the first approved anti-
EGFR agent, in an open-label randomized phase III trial
in patients with chemotherapy-refractory KRAS exon
2 WT mCRC.
12
Panitumumab was non-inferior to cetux-
imab in terms of OS, PFS, and objective response rate
(ORR), with reported OS of 10.4 months and 10 months,
respectively (HR 0.97, 95% CI 0.84–1.11, P=0.0007).
Combination therapy
Shortly after the 408 study, several trials evaluated the
efficacy of panitumumab in association with chemotherapy
doublets, showing significant benefit from the addition of
panitumumab compared to chemotherapy alone in KRAS
exon 2 WT patients, both in first- and in second-line
settings (efficacy data of main trials are summarized in
Table 1).
The phase III randomized 181 trial compared second-
line treatment with panitumumab-FOLFIRI to FOLFIRI
alone.
13
The study was later amended to prospectively
evaluate KRAS exon 2 status as a predictor of panitumu-
mab efficacy. In the KRAS WT population, a significant
improvement in PFS was observed when panitumumab
was added to chemotherapy (median PFS 5.9 versus
3.9 months, HR 0.73; 95% CI, 0.59–0.90; P=0.004);
response rate was also improved to 35% versus 10% by
the addition of panitumumab. A non-significant trend
toward increased OS was observed for the panitumumab
arm: median OS 14.5 versus 12.5 months, HR 0.85, 95%
CI, 0.70–1.04; P=0.12. Conversely, no benefit was
observed in patients whose tumors harbored a KRAS
mutation.
14
In the first-line setting, the phase III randomized
PRIME study demonstrated the benefit of combining pani-
tumumab with FOLFOX-4 compared to FOLFOX-4 alone
in KRAS exon 2 WT mCRC.
15,16
Further efficacy analysis
of this study, based on a more extensive patient molecular
selection after the emerging evidence on the role of rare
RAS activating mutations (KRAS exon 3 and 4, NRAS exon
2, 3 and 4) and BRAF mutations in anti-EGFRs
resistance,
17
proved for the first time a striking advantage
from panitumumab treatment in the extended RAS WT
population and lack of efficacy in RAS-mutated tumors.
Notably, in 446 RAS/BRAF WT patients, panitumumab
was shown to confer a greater magnitude of OS benefit
compared to KRAS exon 2 WT, with an impressive
7.4 months improvement over chemotherapy alone (28.3
versus 20.9 months, HR 0.74; 95% CI, 0.57–0.96;
P=0.02).
18
The presence of a BRAF mutation was also
confirmed as an independent negative prognostic factor
both for PFS and OS, irrespective of treatment.
Similar results were obtained from updated molecular
analyses of randomized first-,
19
second-
14
and third-line
20
trials. A meta-analysis also confirmed the presence of
extended RAS mutations as negative predictive biomarkers
for anti-EGFRs activity in mCRC, with no difference
between KRAS exon 2 mutations and other KRAS or
NRAS mutations.
21
These data led to the FDA restriction
for the use of panitumumab to extended KRAS and NRAS
WT mCRC. More recently, evidence on the role of
BRAFV600E mutation as a biomarker of resistance to
anti-EGFR agents has been confirmed by large meta-ana-
lyses showing a lack of treatment benefit from anti-EGFR
mAbs, both in terms of PFS and OS, for BRAF-mutated
mCRC.
22–24
Both anti-EGFRs and anti-VEGF agents are approved
for the first-line treatment of RAS WT mCRC in associa-
tion with chemotherapy and have recently been compared
in different head-to-head randomized trials. The phase II
PEAK study investigated the addition of panitumumab
versus bevacizumab to FOLFOX chemotherapy in the
first-line setting.
25
Although not designed to prove the
superiority of one treatment over the other, this study
showed a significant improvement in PFS (13.1 versus
10.1 months, HR 0.61; 95% CI, 0.42–0.88; P=0.0075),
and a trend towards OS (41.3 versus 28.9 months, HR
0.70; 95% CI, 0.48–1.04; P=0.08) from panitumumab
versus bevacizumab in the extended RAS/BRAF WT popu-
lation, suggesting a survival benefit from first-line use of
panitumumab in association to chemotherapy in these
patients.
26
A recent exploratory pooled analysis evaluating
the effect of sequence of biological therapies on OS in
patients with RAS or RAS/BRAF WT mCRC treated with
panitumumab across the PRIME, PEAK and 181 trials,
confirmed a trend towards improved OS for first-line pani-
tumumab plus chemotherapy followed by second-line
VEGF inhibitors, compared with first-line bevacizumab
followed by second-line anti-EGFRs.
27
Large prospective
randomized trials are warranted to further evaluate the
optimal first-/second-line targeted treatment sequence in
RAS WT mCRC. Of interest, the ongoing CR-
SEQUENCE trial from the Spanish Cooperative Group
for the Treatment of Digestive Tumors (TTD), evaluating
the efficacy of FOLFOX plus panitumumab followed by
FOLFIRI plus bevacizumab (Sequence 1) versus FOLFOX
plus bevacizumab followed by FOLFIRI plus
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Table 1 Efficacy results from main panitumumab trials
Trial (phase)
Ref
Treatment
Arms (n.)
Treatment
Line
Primary
Endpoint
ORR (%) PFS OS
KRAS ex
2WT
RAS WT KRAS ex
2WT
RAS WT KRAS ex
2WT
RAS WT
408 (III)
NCT00113763
10,11,20
Panitumumab
(n.231)
BSC (n.232)
3rd/+ PFS 17%
0%
17%
0%
2.87 m
(n.124)
1.7 m
(n.119)
[HR 0.45;
P<0.0001]
HR 0.39;
95% CI,
0.27–0.56;
P<0.001
8.1 m
(n.124)
7.6 m
(n.119)
[HR 0.99;
95% CI,
0.75–1.29]
Not
reported
0007 (III)
NCT01412957
80
Panitumumab
(n.189)
BSC (n.188)
3rd/+ OS 27%
1.6%
[P<0.0001]
31%
2.3%
[P<0.0001]
3.6 m
(n.189)
1.7 m
(n.188)
[HR 0.51;
P<0.0001]
5.2 m
(n.142)
1.7 m
(n.128)
[HR 0.46;
P<0.0001]
10 m
(n.189)
7.4 m
(n.188)
[HR 0.73;
P=0.0096]
10 m
(n.142)
6.9 m
(n.128)
[HR 0.70;
P=0.0135]
ASPECCT (III)
NCT01001377
12
Panitumumab
(n.499)
Cetuximab
(n.500)
3rd/+ OS 22%
20%
NE 4.1 m
(n.499)
4.4 m
(n.500)
[HR 1.00;
95% CI,
0.88–
1.14]
NE 10.4 m
(n.499)
10 m
(n.500)
[HR 0.97;
Z-score
−3.19;
P=0.0007]
NE
PRIME (III)
NCT00364013
15,16
FOLFOX +
Panitumumab
(n.593)
FOLFOX
(n.590)
1st PFS 57%
48%
[P=0.02]
Not
reported
10.0 m
(n.325)
8.6 m
(n.331)
[HR 0.80;
P=0.01]
10.1 m
(n.259)
7.9 m
(n.253)
[HR 0.72;
P=0.004]
23.8 m
(n.325)
19.4 m
(n.331)
[HR 0.83;
P=0.03]
25.8 m
(n.259)
20.2 m
(n.253)
[HR 0.77;
P=0.009]
314 (II)
NCT00508404
19,47
FOLFIRI +
Panitumumab
(n.154)
1st ORR 56% 59% 8.9 m
(n.86)
11.2 m
(n.68)
Not
Reported
Not
reported
PEAK (II)
NCT00819780
25,26
FOLFOX +
Panitumumab
(n.142)
FOLFOX +
Bevacizumab
(n.143)
1st PFS 57.8%
53.5%
65%
60%
10.9 m
(n.142)
10.1 m
(n.143)
[HR 0.87;
P=0.35]
12.8 m
(n.88)
10.1 m
(n.82)
[HR 0.68;
P=0.029]
34.2 m
(n.142)
24.3 m
(n.143)
[HR 0.62;
P=0.009]
36.9 m
(n.88)
28.9 m
(n.82)
[HR 0.76;
P=0.15]
PLANET-TTD
(II)
NCT00885885
28
FOLFOX +
Panitumumab
(n.38)
FOLFIRI +
Panitumumab
(n.39)
1st ORR 74%
67%
78%
73%
13 m
(n.38)
14 m
(n.39)
[HR 0.90;
P=0.728]
13 m (n.27)
15 m (n.26)
[HR 0.70;
P=0.307]
37 m (n.38)
41 m (n.39)
[HR 1.0;
P=0.966]
39 m
(n.27)
49 m
(n.26)
[HR 0.9;
P=0.824]
(Continued)
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panitumumab (Sequence 2) in untreated patients with
unresectable RAS WT left-sided mCRC (NCT03635021).
Of note, panitumumab treatment was consistently asso-
ciated with higher early tumor shrinkage (ETS) rates and
greater depth of response (DpR) in a large retrospective
analysis of patients with RAS WT mCRC from the rando-
mized first-line PRIME, PEAK and PLANET
28
trials.
Irrespective of treatment, ETS and DpR were associated
with improved PFS, OS and resection rates in this analy-
sis, suggesting that achieving these endpoints during first-
line treatment is linked with favorable outcomes.
29
In the third-line setting, regorafenib and trifluridine/tipir-
acil are recommended after progression to standard cytotoxic
and targeted treatments. However, in RAS WT patients not
previously treated with anti-EGFR antibodies, cetuximab in
combination with irinotecan or panitumumab monotherapy
may be considered as a third-line. Of interest, in the context
of the continuum of care of mCRC patients, several studies
and case reports have reported data about different treatment
strategies in second- or third-line, including the reintroduc-
tion or re-challenge with cetuximab or panitumumab in
patients who have been previously treated with anti-EGFR
drugs as a first-line.
30,31
Despite promising results, further
perspective trials are warranted to establish the role of this
strategy in the third-line setting in RAS WT mCRC patients
(see paragraph 6).
32
Combination with intensified
chemotherapy
Panitumumab has also been tested in combination with the
triple chemotherapy regimen FOLFOXIRI in several small
studies.
In 2013, a single arm phase II trial enrolled 37
patients with quadruple WT (KRAS, NRAS, HRAS,
BRAF) initially unresectable mCRC to receive treatment
with panitumumab in association to a modified
FOLFOXIRI regimen.
33
Median PFS was 11.3 months.
The ORR, primary endpoint of the study, was 89% with
one complete response, allowing 16 metastases resection,
13 of which (35%) R0. Another single arm phase II trial
assessing the efficacy of FOLFOXIRI plus panitumumab
in RAS WT tumors was published in 2016.
34
ORR was
59% (no complete responses) and 10 patients (66%)
underwent surgery and secondary R0 resection. Median
PFS was 13.3 months.
Table 1 (Continued).
Trial (phase)
Ref
Treatment
Arms (n.)
Treatment
Line
Primary
Endpoint
ORR (%) PFS OS
KRAS ex
2WT
RAS WT KRAS ex
2WT
RAS WT KRAS ex
2WT
RAS WT
VOLFI (II)
NCT01328171
35
mFOLFOXIRI
+
Panitumumab
(n.63)
mFOLFOXIRI
(n.33)
1st ORR - 87.3%
60.6%;
[P=0.0041]
- 9.7 m
(n.63)
10.1 m
(n.33)
[HR 0.92;
P=0.72]
Not
Reported
Not
Reported
181 (III)
NCT00339183
13,14,81
FOLFIRI +
Panitumumab
(n.591)
FOLFIRI
(n.595)
2nd PFS, OS 35%
10%
[P<0.0001]
41%
10%
5.9 m
(n.303)
3.9 m
(n.294)
[HR 0.73;
P=0.004]
6.4 m
(n.208)
4.6 m
(n.213)
[HR 0.70;
P=0.007]
14.5 m
(n.303)
12.5 m
(n.294)
[HR 0.85;
P=0.12]
16.2 m
(n.303)
13.9 m
(n.294)
[HR 0.81;
P=0.08]
SPIRITT (II)
NCT00418938
82
FOLFIRI +
Panitumumab
(n.91)
FOLFIRI +
Bevacizumab
(n.91)
2nd PFS 32%
19%
NE 7.7 m
(n.91)
9.2 m
(n.91)
[HR 1.01;
P=0.97]
NE 18 m (n.91)
21.4 m
(n.91)
[HR 1.06;
P=0.75]
NE
Abbreviations: BSC, best supportive care; CI, confidence interval; ex, exon; HR, hazard ratio; m, months; n, number of patients; NE, not evaluated; PFS, progression free
survival; ORR, objective response rate; OS, overall survival; Ref, reference; WT, wild-type.
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More recently, promising results were presented from
the randomized phase II VOLFI trial, which enrolled 96
patients with unresectable RAS WT mCRC to receive either
mFOLFOXIRI plus panitumumab or FOLFOXIRI alone.
35
First-line treatment with mFOLFOXIRI plus panitumumab
resulted in significantly higher ORR compared to che-
motherapy alone (87.3% versus 60.6%; OR: 4.47; 95%
CI, 1.61–12.38; P=0.0041), and higher disease control rate
(DCR) (97% versus 79%, P=0.0071). Secondary resection
rates were 33.3% in the anti-EGFR arm (61.9% R0) versus
12.1% in the chemotherapy-only arm in the overall popula-
tion, and 75% versus 36.4% in the potentially resectable
cohort. Median PFS was not significantly different between
treatment arms in the overall population.
To clarify whether the intensification of chemotherapy
treatment in combination with panitumumab may be bene-
ficial, two trials are currently ongoing. The phase III
TRIPLETE trial is testing the efficacy of FOLFOXIRI
plus panitumumab versus mFOLFOX6 plus panitumumab
in previously untreated RAS/BRAF WT mCRC
(NCT03231722). The phase II PANIRINOX trial is asses-
sing treatment with FOLFIRINOX plus panitumumab ver-
sus mFOLFOX6 plus panitumumab (NCT02980510).
Results of these trials are warranted to further evaluate the
efficacy and safety of this intensified treatment strategy.
Maintenance treatment
Maintenance treatment with the anti-VEGF bevacizumab
in combination with a fluoropyrimidine after a period of
induction therapy in patients with a good response to the
initial treatment has become a standard of care for mCRC
and is included in main international guidelines. On the
other hand, there is less evidence on maintenance strate-
gies involving anti-EGFR mAbs.
The role of continuing panitumumab as a maintenance
therapy after first-line treatment was firstly evaluated in a
retrospective analysis of patients from the PRIME and PEAK
trials receiving maintenance therapy with panitumumab plus
5-fluorouracil/leucovorin (5-FU/LV).
36
Overall, the median
duration of panitumumab maintenance was 21 weeks (inter-
quartile range: 11–41). The analysis showed an OS and PFS
benefit in continuing the administration of panitumumab in
addition to 5-FU/LV versus chemotherapy ± bevacizumab,
with PRIME patients having a median OS of 40.2 versus
24.1 months and PEAK patients a median OS of 39.1 versus
28.9 months, respectively.
More recently, the phase II VALENTINO study investi-
gated the efficacy of a maintenance treatment with 5FU/LV
plus panitumumab versus single-agent panitumumab follow-
ing first-line FOLFOX plus panitumumab in patients with RAS
WT mCRC. This study showed that maintenance with pani-
tumumab alone following induction with FOLFOX plus pani-
tumumab achieves inferior PFS than the 5FU/LV plus
panitumumab combination: 10-months PFS 52.8% versus
62.8%, median PFS 10.2 versus 13 months, respectively
(P=0.011).
37
Data from the Japanese phase II SAPPHIRE trial,
where patients not progressing after 6 cycles of
FOLFOX plus panitumumab were randomized to receive
5-FU/LV and panitumumab as maintenance therapy or to
continue induction treatment, showed similar 9-months
PFS in the two arms, thus supporting the use of panitu-
mumab plus 5-FU/LV as a maintenance treatment in order
to delay disease progression while preventing the occur-
rence of oxaliplatin-induced neuropathy.
38
Tumor sidedness in panitumumab trials
Over the past few years, several studies highlighted the
prognostic value of primary tumor location (left colon
versus right colon) and data have focused on location as
a potential predictive biomarker for anti-EGFRs activity,
especially in the first-line setting. In particular, left-sided
primary tumors have been shown to have better prognosis
and improved treatment outcomes from the use of EGFR
inhibitors in addition to combination chemotherapy.
Data from 927 patients with extended RAS WT mCRC
enrolled in three randomized trials on panitumumab
(PRIME, PEAK and 181) showed that the overall prog-
nosis was worse for right-sided tumors than for left-sided
ones, regardless of treatment. The addition of panitumu-
mab to chemotherapy led to striking PFS and OS out-
comes in left-sided tumors; conversely, patients with RAS
WT right-sided primary tumors derived no benefit from
the addition of anti-EGFRs to chemotherapy. A higher
proportion of patients with right-sided tumors harbored
BRAF mutations, thus contributing to the worse prognosis
of this group, nevertheless, similar efficacy data were also
obtained in the RAS/BRAF WT population.
39
Similar
results were found consistently across several different
trials of panitumumab in second- and later-lines of
treatment,
40
and trials investigating cetuximab-based
treatments.
41
A more recent retrospective analysis of
patients with RAS WT mCRC from the PRIME and
PEAK trials further evaluated the effects of primary
tumor location on ETS, DpR, and long-term survival.
First-line panitumumab was associated with improved
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5916
ETS (PRIME: 62% versus 36%; PEAK: 58% versus 41%)
and DpR (PRIME: 59% versus 49%; PEAK: 70% versus
48%) in patients with left-sided mCRC, and panitumumab
treatment consistently predicted long-term survival.
Notably, in the pooled analyses of the studies, more
patients with right-sided disease achieved ETS if treated
with panitumumab than comparator (39% versus 29%),
thus ETS may identify a subgroup of patients with right-
sided disease who might respond to panitumumab.
42
Large meta-analyses of first-line trials comparing che-
motherapy plus bevacizumab to chemotherapy plus anti-
EGFRs have shown a significant benefit in ORR, PFS and
OS in patients with left-sided primary tumors treated with
anti-EGFR mAbs compared to bevacizumab, whereas
right-sided tumors have been shown to be a negative
prognostic indicator for OS for all treatments and to ben-
efit more from bevacizumab treatment.
43,44
Several hypotheses have been proposed to explain
these findings, involving the role of different embryogenic
origin, the association of right-sided tumors with specific
molecular phenotypes (particularly, CMS1-immune and
CMS3-metabolic), different methylation signatures and
the distinct microbiota in right versus left colon, support-
ing the role of tumor sidedness as a surrogate for tumor
biology.
45
A limitation of these data is the unplanned retrospec-
tive nature of the abovementioned analyses, however, in
light of their consistency across a number of different
randomized trials, NCCN guidelines have recently incor-
porated into their recommendation to exclude anti-EGFR
antibodies in the first-line treatment of right-sided RAS
WT mCRC.
2
It has to be noted, however, that when selecting the
optimal treatment strategy for a RAS WT mCRC patient a
comprehensive evaluation of the clinical scenario, treat-
ment goals, expected toxicities and patients’characteris-
tics and preferences must be taken into account, leading to
a personalized approach that may favor, for instance, an
anti-VEGF therapy as first-line for a left-sided RAS WT
mCRC, saving anti-EGFR agents for a later treatment line.
Quality of life, safety and tolerability
Anti-EGFR therapy frequently results in skin-related toxi-
cities (eg acneiform rash, xerosis, paronychia). These side
effects can negatively affect treatment compliance and
patients’quality of life (QoL)
46
and it is important to
evaluate how the impact of such adverse events weigh
against the benefits of panitumumab in mCRC patients.
Therefore, maintenance of QoL is an important objective
in clinical trials and patient-reported outcomes (PROs) are
a useful way of measuring the impact of treatment
on QoL.
Study 314 was a single-arm, multicenter, phase II study
evaluating the efficacy and safety of panitumumab plus
FOLFIRI as first-line treatment for patients with mCRC.
47
In this trial, QoL was measured using the EuroQoL 5-
domain (EQ-5D) and the EORTC QoL Questionnaires
(QLQ-C30) as an exploratory endpoint. Notably, panitu-
mumab plus FOLFIRI had minimal impact on patients’
QoL, as EQ-5D and QLQ-C30 scores remained stable
throughout the study despite the high incidence of skin-
related toxicity.
48
In the PRIME trial,
15
QoL was assessed as a prespeci-
fied tertiary endpoint, using the EQ-5D health state index
(HSI) and overall health rating (OHR) measures. There
were no statistically significant differences between the
panitumumab plus FOLFOX4 and FOLFOX4 arms in
HSI or OHR scores from baseline to progression or to
discontinuation.
49
Of interest, in this study the authors
assessed whether skin toxicities and early tumor shrinkage
(ETS) may have had impact on QoL. However, no sig-
nificant differences in QoL outcomes were observed
between patients with grade (G) 0–2 skin toxicity and
those with G3+ skin toxicity, as well as no difference in
QoL for those with ETS versus those without ETS.
Nonetheless, patients with tumor-related symptoms at
baseline who experienced ETS showed a statistically
meaningful improvement in QoL compared with those
who did not have ETS.
The evaluation of changes in health-related QoL
(HRQoL) using the EQ-5D was a tertiary objective also
in the second-line phase III 181 trial.
13
A total of 530
patients (263 treated with panitumumab plus FOLFIRI
and 267 with FOLFIRI) were included in the HRQoL
analysis, representing 88.8% of the overall KRAS WT
population. There were no statistically significant or clini-
cally meaningful overall differences in the change in
HRQoL when comparing treatment arms. In addition,
regardless of the severity of skin toxicity, patients treated
with panitumumab maintained a similar HRQoL.
50
Panitumumab has also been reported to provide better
control of symptoms and maintenance of HRQoL com-
pared with BSC alone in patients with chemorefractory
KRAS WT mCRC.
51
Taken together, these data suggest that the addition of
panitumumab to chemotherapy regimens as a first-,
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second- or later-line treatment of patients with RAS WT
mCRC provides improvements in survival outcomes with-
out compromising HRQoL.
Safety and tolerability data are available from clinical
trials evaluating panitumumab as a monotherapy or in
combination with chemotherapy in mCRC. Based on a
pooled analysis of patients enrolled in panitumumab trials
(n=2,224), the most commonly reported adverse reactions
(AE) are skin reactions occurring in approximately 94% of
patients, including rash (47%), dermatitis acneiform
(39%), pruritus (36%), erythema (33%), dry skin (21%),
and paronychia (20%). Other very commonly reported AE
occurring in ≥20% of patients are diarrhea (46%), nausea
(39%), vomiting (26%), constipation (23%), abdominal
pain (23%), fatigue (35%), pyrexia (21%), and decreased
appetite (30%).
52
In phase II trials, the most frequent panitumumab-
related AE involved skin (92–96%), nails (28–30%),
eyes (8–17%), hair (8%).
53
EGFR is expressed in normal
skin cells; therefore, dermatologic AE are directly linked
to EGFR blockade. Acneiform rash usually appears after
the first treatment administration, while paronychia and
desquamation usually appear by the fourth week of
treatment.
54
In a pooled analysis of 920 patients treated
with panitumumab monotherapy included in ten phase I-
III clinical trials most patients experienced G1–2 skin
toxicities that rarely resulted in treatment discontinuation.
Importantly, the development of skin toxicities ≥G2 has
been associated with improved PFS and OS;
55
therefore, it
is considered a strong predictive biomarker of clinical
benefit in patients treated with EGFR inhibitors.
Since these toxicities can result in treatment disconti-
nuation and can potentially affect the patient’s QoL,
increase patient risk for additional infections, and lead to
suboptimal anti-EGFR schedules -all of which may affect
clinical outcomes- their management should be an impor-
tant focus when administering these agents.
56
Hence,
novel strategies to reduce the incidence and the severity
of skin toxicity have been developed based on the
STEPP
54
(Skin Toxicity Evaluation Protocol with
Panitumumab) and J-STEPP
57
randomized studies. The
randomized phase II STEPP study evaluated the impact
of a pre-emptive strategy (primary prophylaxis) including
skin moisturizers, sunscreen, topical steroids, and doxycy-
cline for the duration of anti-EGFR therapy, versus a
reactive treatment after toxicity occurrence.
54
The pre-
emptive strategy significantly reduced the incidence of
≥G2 skin toxicity at 6 weeks compared to standard care
(29% versus 62%, respectively). Similarly, the Japanese
open-label, multicenter, randomized J-STEPP study
showed that the cumulative incidence of ≥G2 skin toxi-
cities in 6 weeks was 21.3% in the pre-emptive group
compared with 62.5% in the reactive group (RR=0.34;
95% CI, 0.19–0.62; P<0.001).
57
Panitumumab administration should be withheld at the
first occurrence of G3 skin toxicities. Re-introduction of
panitumumab at the original dose is recommended once
toxicity has subside, while dose reduction is recommended
upon subsequent occurrence of G3 toxicities (80% of the
original dose at the second occurrence and 60% at the third
occurrence).
4
Discontinuation of treatment is implemented
at the forth occurrence or if G3 skin toxicities do not
recover after 1–2 withheld doses.
When panitumumab is administered as monotherapy
severe diarrhea is uncommon, however its incidence
increases when panitumumab is associated with che-
motherapy. In fact, G3–4 diarrhea occurred in up to 28%
of patients in trials combining an EGFR inhibitor with
chemotherapy.
58
Another common AE that may occur during panitumu-
mab treatment is hypomagnesemia, due to the effects of
EGFR inhibition in the ascending loop of Henle and in the
distal convoluted renal tubule. Incidence of hypomagnese-
mia can be up to 28–36% and was found to be associated
with treatment duration.
59
In most cases panitumumab-
induced hypomagnesemia is asymptomatic, however for
patients who experience a symptomatic ≥G2 hypomagne-
semia, oral or intravenous replacement should be consid-
ered. Of interest, early onset of hypomagnesemia during
anti-EGFR treatment has been associated with treatment
efficacy.
60
Panitumumab is a fully human mAb, hence incidence
of infusion-related reactions is very low (1–3%). The use
of routine premedication before the administration of pani-
tumumab is recommended if a previous infusion reaction
has occurred.
4
Panitumumab in the elderly
population
Despite the high prevalence of CRC in the elderly popula-
tion, these patients have been underrepresented in clinical
trials and their optimal treatment is yet to be determined,
with only few data available on anti-EGFR treatment in
combination with chemotherapy. In the daily practice,
treatment of older cancer patients is challenging and a
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Cancer Management and Research 2019:11
5918
careful assessment of patients’performance status, comor-
bidities, age-related organ function, life expectancy, poten-
tial treatment-related toxicity and QoL issues should be
implemented in the decision making to select those
patients who could benefit from treatment.
The use of panitumumab as monotherapy in the first-
line setting in elderly and frail patients was investigated by
Sastre and colleagues, who treated 33 KRAS WT patients
over 70 years of age with an ECOG functional status up to
3 in a single arm phase II trial. Treatment with panitumu-
mab was demonstrated to be an active and safe option in
this group of patients. ORR was 9.1% with a 6-months
PFS rate of 53.3% and median OS of 12.3 months in the
extended RAS WT patients.
61
Encouraging data were also
reported in another study investigating panitumumab
monotherapy in molecularly selected RAS and BRAF WT
frail elderly patients deemed unfit for chemotherapy.
62
However, data on the adoption of chemotherapy plus
anti-EGFRs in elderly mCRC patients are scarce. In the
subgroup analysis of RAS WT patients from the PRIME
study the combination of FOLFOX-4 and panitumumab
showed a benefit over FOLFOX-4 in the subset of patients
aged more than 65 years (n=188), in terms of OS (26.6
versus 17.4 months; HR 0.78; 95% CI, 0.58–1.09), PFS
(9.7 versus 9.2 months; HR 0.88; 95% CI, 0.65–1.19) and
ORR (49% versus 42%), without raising any safety
concern.
63
Positive results in terms of tolerability and
efficacy were also recently reported in a retrospective
study of 100 patients aged over 70 years (95.4% ECOG
performance status 0–1) treated with doublet chemother-
apy plus panitumumab, with a median PFS of 9.4 months
(95% CI, 7.8–11.0) and a median OS of 23.0 months (95%
CI, 20.6–25.3).
64
To clarify the safety and efficacy of panitumumab in
association with chemotherapy in the elderly population a
dedicated trial, the phase II PANDA study (NCT02904031),
is currently ongoing, enrolling patients over 70 years of age
with an ECOG performance status 1 or 2 if aged 70 to
75 years and an ECOG performance status 0 or 1 if aged
>75 years. In this study elderly patients with a diagnosis of
RAS and BRAF WT mCRC are randomized to a first-line
treatment with panitumumab in combination with FOLFOX
or 5FU/LV. Of note, secondary endpoints of the study
include the evaluation of the prognostic role of geriatric
assessment tools and toxicity risk scores to aid patient
selection in the elderly population. Safety and efficacy
results of this trial are warranted to inform targeted treat-
ment choices in elderly patients.
Novel mechanisms of resistance and
future perspectives
Several additional mechanisms of primary resistance to
anti-EGFRs have been identified in RAS WT mCRC so
far, based on preclinical data and retrospective evaluations.
However, the routine use of these biomarkers in clinical
practice is not recommended at present, and further pro-
spective validation is warranted. These include HER2
amplification, PIK3CA mutations (exon 9 and 20), MET
amplification, FGFR1 and PDGFRA mutations and loss of
PTEN function.
65
HER2 amplification, in particular, has
recently gained attention as a promising druggable target
in mCRC. Based on a strong pre-clinical rationale,
66
the
proof-of-concept phase II HERACLES trial has shown
promising activity of a combined HER2 blockade with
trastuzumab and lapatinib in treatment-refractory HER2-
positive mCRC.
67
Notably, all patients enrolled in the trial
received previous EGFR inhibitors and none of those
evaluable for response achieved an objective response to
either panitumumab or cetuximab, supporting the role of
HER2 amplification as a resistance mechanism to anti-
EGFRs. Several trials are currently investigating HER2
blockade strategies in HER2-amplified mCRC, opening
new perspectives for this subset of patients. Other novel
treatment strategies combining EGFR inhibitors with dif-
ferent targeted agents (ie panitumumab plus the mTOR
inhibitor everolimus;
68
or panitumumab plus BRAF and
MEK inhibition in BRAFV600E-mutant tumors
69
), aiming
to overcome primary resistance to anti-EGFR agents, are
also under investigation.
More recently, a panel of multiple combined genomic
alterations comprising activating mutations of the
MAPKs or PI3K/AKT axis, NTRK/ROS1/ALK/RET rear-
rangements, HER2 amplification or mutations, and MET
amplification (the PRESSING panel), has been shown to
be able to predict primary resistance to anti-EGFRs in
RAS/BRAF WT mCRCs.
70
Additionally, a right-sided pri-
mary tumor location was found to be associated with
resistance to anti-EGFRs, confirming previous literature
evidence. Overall, the combined evaluation of the
PRESSING panel and primary tumor location demon-
strated the best predictive accuracy. These results open
novel perspectives on the clinical application of a more
comprehensive molecular characterization of RAS/BRAF
WT mCRCs to further improve and refine patient selec-
tion for anti-EGFR treatment and possibly tailor persona-
lized targeted approaches.
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Clonal selection induced by treatment pressure is often
responsible for the development of secondary resistance to
EGFR inhibitors, and emerging mutations in the RAS/
RAF/MAPK pathway can be identified in tumor samples
at progression in patients previously diagnosed with a RAS
WT tumors.
71
Several trials are investigating different
approaches to multiple target inhibition based on the emer-
gence of different resistance drivers. In this setting, the use
of liquid biopsies and the analysis of circulating tumor
DNA (ctDNA) are being evaluated as a less invasive and
more comprehensive approach to pharmacogenomic pro-
filing and biomarkers monitoring in mCRC patients.
72
These techniques might play, in the near future, a pivotal
role in improving patient selection and targeted treatment
strategies by implementing early detection of the emer-
gence of treatment resistance and allowing a dynamic
molecular profiling.
73
Indeed, repeated ctDNA analyses
have been able to capture the emergence of resistant clones
during treatment with panitumumab or cetuximab in RAS
WT patients, showing that this phenomenon is closely
related to treatment exposure, with a dynamic increase
during anti-EGFRs administration followed by a rapid
decline at withdrawal.
74,75
In a recent biomarker analysis
from a second-line phase II trial of panitumumab in asso-
ciation with irinotecan in KRAS WT mCRC, plasma test-
ing of cell-free DNA revealed a mutant RAS emergence
rate of 36.7% (n=39), and first detected emergence of RAS
mutations preceded progression by a median of 3.6 months
(range, 0.3–7.5).
76
However, patients who had emergent
RAS mutations at progression had similar median PFS to
those who remained WT and a mutant RAS allele fre-
quency threshold that could predict near-term outcomes
was not identified, thus calling for further evaluation of the
clinical value of this approach. Interestingly, recently pub-
lished results from retrospective analyses evaluating emer-
gent mutations in circulating cell-free DNA in patients
treated with panitumumab in the ASPECCT study showed
that patients with a higher RAS mutant allele frequency at
baseline had worse clinical outcomes than those with a
lower frequency (P<0.001). However, extended RAS muta-
tion, by itself, did not preclude clinical responses to pani-
tumumab in this setting and emergent ctDNA RAS
mutations were not associated with less favorable patient
outcomes in panitumumab-treated patients.
77,78
Further
research is needed to identify a clinically relevant thresh-
old for baseline and emergent ctDNA RAS mutations.
Of note, focusing on the issue of analytical sensitivity in
evaluating predictive biomarkers to anti-EGFR treatments,
the phase II ULTRA trial investigated a high-sensitivity
tumor tissue genotyping technique of KRAS, NRAS, BRAF
and PIK3CA to ultra-select irinotecan-resistant mCRC
patients for panitumumab plus FOLFIRI treatment.
Results from this study identify the optimal RAS/BRAF
mutational threshold for outcome prediction to be 5%,
suggesting that the biological and clinical implications of
mutation frequencies below this cut-off still warrant further
investigations.
79
Finally, re-challenge strategies after treatment breaks in
patients with RAS WT tumors that demonstrated a pre-
vious response to anti-EGFR agents are currently under
study. The phase II CHRONOS study (NCT03227926)
aims to investigate a re-challenge strategy with panitumu-
mab as third-line treatment after a first-line treatment with
anti-EGFRs in RAS/BRAF WT mCRC, with a molecular
follow-up based on ctDNA. In this study liquid biopsies
for ctDNA testing are prospectively collected during the
first-line and the re-challenge phases to test the correlation
between circulating ctDNA biomarkers and treatment
response. Interestingly, the possibility of continuing pani-
tumumab beyond progression is also being investigated in
a multicenter single-arm phase II Japanese clinical trial of
second-line FOLFIRI plus panitumumab after first-line
treatment with FOLFOX plus panitumumab in initial
RAS WT mCRC (UMIN000026817). Mutational status
using ctDNA will be prospectively assessed at multiple
time-points during this study as one of the planned sec-
ondary endpoints.
Conclusions
Panitumumab in association with chemotherapy is a valu-
able first- or second-line treatment option in patients with
RAS WT mCRC, as well as a monotherapy option in
advanced lines for chemorefractory patients. The toxicity
profile of panitumumab is manageable and this agent has a
favorable impact on patient’s QoL, showing positive
results also in the population of frail and elderly mCRC
patients. Novel treatment scenarios are opening for pani-
tumumab including combinations with intensified che-
motherapy regimens to implement conversion to
resectability in initially unresectable patients and mainte-
nance treatment strategies. The development of panitumu-
mab has significantly added to the treatment options for
RAS WT mCRC, and has contributed to expanding the
horizons of mCRC molecular profiling.
Current efforts are directed to dissect the mechanisms
of primary resistance beyond RAS status and the
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Cancer Management and Research 2019:11
5920
mechanisms of acquired resistance to panitumumab (and
more generally anti-EGFRs), which entails a more com-
prehensive molecular characterization of RAS WT tumors,
the assessment of additional mutational and clinico-patho-
logical features, ie BRAF status and tumor sidedness, and
the development of novel technologies to capture the
dynamic heterogeneity of the genomic landscape displayed
by mCRC under targeted treatment pressure. Recent
advancements in this field warrant a prospective validation
of new predictive biomarkers in RAS WT mCRC, in order
to further refine patient selection and develop novel mole-
cularly-tailored treatment strategies to optimize outcomes
and patients benefit.
Acknowledgments
This manuscript was partly supported by the National Cancer
Institute (grant number P30CA014089), the Gloria Borges
WunderGlo Foundation-The Wunder Project, the Dhont
Family Foundation, the San Pedro Peninsula Cancer Guild,
the Daniel Butler Research Fund, the Call to Cure Research
Fund, and the Fong Research Project. The content is solely
the responsibility of the authors and does not necessarily
represent the official views of the National Cancer Institute
or the National Institutes of Health. Francesca Battaglin and
Alberto Puccini are co-first authors for this study.
Author contributions
All authors contributed to data analysis, drafting and revis-
ing the article, gave final approval of the version to be
published, and agree to be accountable for all aspects of
the work.
Disclosure
FB has received travel/accommodations from Bayer and
Amgen Inc. HJL has received clinical trial financial support
from Merck Serono and Roche, honoraria for advisory
board membership and lectures from Bayer, Boehringer
Ingelheim, Genentech, Pfizer, Merck Serono and Roche,
and travel/accommodations from Bayer, Merck Serono
and Roche. The authors report no other conflicts of interest
in this work.
References
1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J
Clin.2018;68(1):7–30.
2. National Comprehensive Cancer Network. Clinical practice guidelines in
oncology. Colon Cancer. Version 1.2019. Available from: https://www.nccn.
org/professionals/physician_gls/pdf/colon.pdf Accessed April 01, 2019.
3. Cremolini C, Schirripa M, Antoniotti C, et al. First-line chemother-
apy for mCRC-a review and evidence-based algorithm. Nat Rev Clin
Oncol.2015;12(10):607–619. doi:10.1038/nrclinonc.2015.129
4. Vectibix® (Panitumumab). Thousand Oaks, CA: Amgen Inc.; 2017.
Available from: https://www.accessdata.fda.gov/drugsatfda_docs/
label/2017/125147s207lbl.pdf. Accessed January 16, 2019.
5. Citri A, Yarden Y. EGF-ERBB signalling: towards the systems level.
Nat Rev Molecular Cell Biol.2006;7(7):505–516. doi:10.1038/nrm1962
6. Yang BB, Lum P, Chen A, et al. Pharmacokinetic and pharmacody-
namic perspectives on the clinical drug development of panitumu-
mab. Clin Pharmacokinet.2010;49(11):729–740. doi:10.2165/
11535970-000000000-00000
7. Giannopoulou E, Antonacopoulou A, Matsouka P, Kalofonos HP.
Autophagy: novel action of panitumumab in colon cancer.
Anticancer Res.2009;29(12):5077–5082.
8. Allegra CJ, Rumble RB, Hamilton SR, et al. Extended RAS gene
mutation testing in metastatic colorectal carcinoma to predict
response to anti-epidermal growth factor receptor monoclonal anti-
body therapy: american society of clinical oncology provisional clin-
ical opinion update 2015. J Clin Oncol.2016;34(2):179–185.
doi:10.1200/JCO.2015.63.9674
9. Sepulveda AR, Hamilton SR, Allegra CJ, et al. Molecular biomarkers for
the evaluation of colorectal cancer: guideline from the American society
for clinical pathology, college of American pathologists, association for
molecular pathology, and American society of clinical oncology. JMol
Diagn.2017;19(2):187–225. doi:10.1016/j.jmoldx.2016.11.001
10. Van Cutsem E, Peeters M, Siena S, et al. Open-label phase III trial of
panitumumab plus best supportive care compared with best suppor-
tive care alone in patients with chemotherapy-refractory metastatic
colorectal cancer. J Clin Oncol.2007;25(13):1658–1664.
doi:10.1200/JCO.2006.08.1620
11. Amado RG, Wolf M, Peeters M, et al. Wild-type KRAS is required for
panitumumab efficacy in patients with metastatic colorectal cancer. J
Clin Oncol.2008;26(10):1626–1634. doi:10.1200/JCO.2007.14.7116
12. Price TJ, Peeters M, Kim TW, et al. Panitumumab versus cetuximab
in patients with chemotherapy-refractory wild-type KRAS exon 2
metastatic colorectal cancer (ASPECCT): a randomised, multicentre,
open-label, non-inferiority phase 3 study. Lancet Oncol.2014;15
(6):569–579. doi:10.1016/S1470-2045(14)70118-4
13. Peeters M, Price TJ, Cervantes A, et al. Randomized phase III study
of panitumumab with fluorouracil, leucovorin, and irinotecan
(FOLFIRI) compared with FOLFIRI alone as second-line treatment
in patients with metastatic colorectal cancer. J Clin Oncol.2010;28
(31):4706–4713. doi:10.1200/JCO.2009.27.6055
14. Peeters M, Oliner KS, Price TJ, et al. Analysis of KRAS/NRAS
mutations in a phase III study of panitumumab with FOLFIRI com-
pared with FOLFIRI alone as second-line treatment for metastatic
colorectal cancer. Clin Cancer Res.2015;21(24):5469–5479.
doi:10.1158/1078-0432.CCR-15-0526
15. Douillard JY, Siena S, Cassidy J, et al. Randomized, phase III trial of
panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin
(FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients
with previously untreated metastatic colorectal cancer: the PRIME study.
J Clin Oncol.2010;28(31):4697–4705. doi:10.1200/JCO.2009.27.4860
16. Douillard JY, Siena S, Cassidy J, et al. Final results from PRIME:
randomized phase III study of panitumumab with FOLFOX4 for first-
line treatment of metastatic colorectal cancer. Ann Oncol.2014;25
(7):1346–1355. doi:10.1093/annonc/mdu141
17. Therkildsen C, Bergmann TK, Henrichsen-Schnack T, Ladelund S,
Nilbert M. The predictive value of KRAS, NRAS, BRAF, PIK3CA
and PTEN for anti-EGFR treatment in metastatic colorectal cancer: a
systematic review and meta-analysis. Acta Oncol.2014;53(7):852–
864. doi:10.3109/0284186X.2014.895036
18. Douillard JY, Oliner KS, Siena S, et al. Panitumumab-FOLFOX4
treatment and RAS mutations in colorectal cancer. N Engl J Med.
2013;369(11):1023–1034. doi:10.1056/NEJMoa1305275
Dovepress Battaglin et al
Cancer Management and Research 2019:11 submit your manuscript | www.dovepress.com
DovePress 5921
19. Karthaus M, Hofheinz RD, Mineur L, et al. Impact of tumour RAS/
BRAF status in a first-line study of panitumumab + FOLFIRI in
patients with metastatic colorectal cancer. Br J Cancer.2016;115
(10):1215–1222. doi:10.1038/bjc.2016.343
20. Peeters M, Oliner KS, Parker A, et al. Massively parallel tumor
multigene sequencing to evaluate response to panitumumab in a
randomized phase III study of metastatic colorectal cancer. Clin
Cancer Res.2013;19(7):1902–1912. doi:10.1158/1078-0432.CCR-
12-1913
21. Sorich MJ, Wiese MD, Rowland A, Kichenadasse G, McKinnon RA,
Karapetis CS. Extended RAS mutations and anti-EGFR monoclonal
antibody survival benefit in metastatic colorectal cancer: a meta-
analysis of randomized, controlled trials. Ann Oncol.2015;26
(1):13–21. doi:10.1093/annonc/mdu378
22. Rowland A, Dias MM, Wiese MD, et al. Meta-analysis of BRAF
mutation as a predictive biomarker of benefit from anti-EGFR mono-
clonal antibody therapy for RAS wild-type metastatic colorectal can-
cer. Br J Cancer.2015;112(12):1888–1894. doi:10.1038/bjc.2015.173
23. Pietrantonio F, Petrelli F, Coinu A, et al. Predictive role of BRAF
mutations in patients with advanced colorectal cancer receiving
cetuximab and panitumumab: a meta-analysis. Eur J Cancer.
2015;51(5):587–594. doi:10.1016/j.ejca.2015.01.054
24. van Brummelen EMJ, de Boer A, Beijnen JH, Schellens JHM. BRAF
mutations as predictive biomarker for response to anti-EGFR mono-
clonal antibodies. Oncologist.2017. doi:10.1634/theoncologist.2017-
0031
25. Schwartzberg LS, Rivera F, Karthaus M, et al. PEAK: a randomized,
multicenter phase II study of panitumumab plus modified fluorour-
acil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus
mFOLFOX6 in patients with previously untreated, unresectable,
wild-type KRAS exon 2 metastatic colorectal cancer. J Clin Oncol.
2014;32(21):2240–2247. doi:10.1200/JCO.2013.53.2473
26. Rivera F, Karthaus M, Hecht JR, et al. Final analysis of the rando-
mised PEAK trial: overall survival and tumour responses during first-
line treatment with mFOLFOX6 plus either panitumumab or bevaci-
zumab in patients with metastatic colorectal carcinoma. Int J
Colorectal Dis.2017;32(8):1179–1190. doi:10.1007/s00384-017-
2800-1
27. Peeters M, Forget F, Karthaus M, et al. Exploratory pooled analysis
evaluating the effect of sequence of biological therapies on overall
survival in patients with RAS wild-type metastatic colorectal carci-
noma. ESMO Open.2018;3(2):e000297. doi:10.1136/esmoopen-
2017-000297
28. Carrato A, Abad A, Massuti B, et al. First-line panitumumab plus
FOLFOX4 or FOLFIRI in colorectal cancer with multiple or
unresectable liver metastases: a randomised, phase II trial
(PLANET-TTD). Eur J Cancer.2017;81:191–202. doi:10.1016/j.
ejca.2017.04.024
29. Taieb J, Rivera F, Siena S, et al. Exploratory analyses assessing the
impact of early tumour shrinkage and depth of response on survival
outcomes in patients with RAS wild-type metastatic colorectal cancer
receiving treatment in three randomised panitumumab trials. J
Cancer Res Clin Oncol.2018;144(2):321–335. doi:10.1007/s00432-
017-2534-z
30. Goldberg RM, Montagut C, Wainberg ZA, et al. Optimising the use
of cetuximab in the continuum of care for patients with metastatic
colorectal cancer. ESMO Open.2018;3(4):e000353. doi:10.1136/
esmoopen-2018-000353
31. Cremolini C, Rossini D, Dell’Aquila E, et al. Rechallenge for patients
with RAS and BRAF wild-type metastatic colorectal cancer with
acquired resistance to first-line cetuximab and irinotecan: a phase 2
single-arm clinical trial. JAMA Oncol. Epub 2018 Nov 21.
32. Mauri G, Pizzutilo EG, Amatu A, et al. Retreatment with anti-EGFR
monoclonal antibodies in metastatic colorectal cancer: systematic
review of different strategies. Cancer Treat Rev.2019;73:41–53.
doi:10.1016/j.ctrv.2018.12.006
33. Fornaro L, Lonardi S, Masi G, et al. FOLFOXIRI in combination
with panitumumab as first-line treatment in quadruple wild-type
(KRAS, NRAS, HRAS, BRAF) metastatic colorectal cancer patients:
a phase II trial by the Gruppo Oncologico Nord Ovest (GONO). Ann
Oncol.2013;24(8):2062–2067. doi:10.1093/annonc/mdt165
34. Bendell JC, Zakari A, Peyton JD, et al. A phase II study of
FOLFOXIRI plus panitumumab followed by evaluation for resection
in patients with metastatic KRAS wild-type colorectal cancer with
liver metastases only. Oncologist.2016;21(3):279–280. doi:10.1634/
theoncologist.2015-0439
35. Geissler M, Klingler T, Martens UM, et al. 453PD1st-line
mFOLFOXIRI + panitumumab vs FOLFOXIRI treatment of RAS
wt mCRC: a randomized phase II VOLFI trial of the AIO (KRK-
0109). Ann Oncol.2018;29(suppl_8). doi:10.1093/annonc/mdx807
36. Modest DP, Rivera F, Bachet JB, et al. Panitumumab-based main-
tenance after oxaliplatin discontinuation in metastatic colorectal can-
cer: a retrospective analysis of two randomised trials. Int J Cancer.
2019. doi:10.1002/ijc.32110
37. Pietrantonio F, Morano F, Corallo S, et al. First-line FOLFOX plus
panitumumab (Pan) followed by 5FU/LV plus pan or single-agent pan
as maintenance therapy in patients with RAS wild-type metastatic
colorectal cancer (mCRC): the VALENTINO study. J Clin Oncol.
2018;36(15_suppl):3505. doi:10.1200/JCO.2018.36.15_suppl.3505
38. Nakamura M, Munemoto Y, Takahashi M, et al. SAPPHIRE: a
randomized phase II study of mFOLFOX6+ panitumumab versus 5-
FU/LV + panitumumab after 6 cycles of frontline mFOLFOX6+
panitumumab in patients with colorectal cancer. J Clin Oncol.
2018;36(4_suppl):729. doi:10.1200/JCO.2018.36.4_suppl.729
39. Peeters M. Outcome according to Left Vs. Right Side in the
Panitumumab Studies. Presented At: ESMO 2016 Congress, Special
Session. Copenhagen, Denmark; October 7–11, 2016.
40. Boeckx N, Koukakis R, de Beeck KO, et al. Effect of primary tumor
location on second- or later-line treatment outcomes in patients with
RAS wild-type metastatic colorectal cancer and all treatment lines in
patients with RAS mutations in four randomized panitumumab stu-
dies. Clin Colorectal Cancer.2018;17(3):170–178.e173. doi:10.1016/
j.clcc.2018.03.005
41. Tejpar S, Stintzing S, Ciardiello F, et al. Prognostic and predictive
relevance of primary tumor location in patients with RAS wild-type
metastatic colorectal cancer: retrospective analyses of the CRYSTAL
and FIRE-3 trials. JAMA Oncol.2017;3(2):194–201. doi:10.1001/
jamaoncol.2016.3797
42. Peeters M, Price T, Taieb J, et al. Relationships between tumour
response and primary tumour location, and predictors of long-term
survival, in patients with RAS wild-type metastatic colorectal cancer
receiving first-line panitumumab therapy: retrospective analyses of
the PRIME and PEAK clinical trials. Br J Cancer.2018;119(3):303–
312. doi:10.1038/s41416-018-0165-z
43. Holch JW, Ricard I, Stintzing S, Modest DP, Heinemann V. The
relevance of primary tumour location in patients with metastatic
colorectal cancer: a meta-analysis of first-line clinical trials. Eur J
Cancer.2017;70:87–98. doi:10.1016/j.ejca.2016.10.007
44. Arnold D, Lueza B, Douillard JY, et al. Prognostic and predictive
value of primary tumour side in patients with RAS wild-type meta-
static colorectal cancer treated with chemotherapy and EGFR direc-
ted antibodies in six randomised trials. Ann Oncol.2017.
doi:10.1093/annonc/mdx175
45. Stintzing S, Tejpar S, Gibbs P, Thiebach L, Lenz HJ. Understanding
the role of primary tumour localisation in colorectal cancer treatment
and outcomes. Eur J Cancer.2017;84:69–80. doi:10.1016/j.
ejca.2017.07.016
46. Wagner LI, Lacouture ME. Dermatologic toxicities associated with
EGFR inhibitors: the clinical psychologist’s perspective. Impact on
health-related quality of life and implications for clinical manage-
ment of psychological sequelae. Oncology (Williston Park).2007;21
(11 Suppl 5):34–36.
Battaglin et al Dovepress
submit your manuscript | www.dovepress.com
DovePress
Cancer Management and Research 2019:11
5922
47. Kohne CH, Hofheinz R, Mineur L, et al. First-line panitumumab plus
irinotecan/5-fluorouracil/leucovorin treatment in patients with meta-
static colorectal cancer. J Cancer Res Clin Oncol.2012;138(1):65–
72. doi:10.1007/s00432-011-1061-6
48. Thaler J, Karthaus M, Mineur L, et al. Skin toxicity and quality of
life in patients with metastatic colorectal cancer during first-line
panitumumab plus FOLFIRI treatment in a single-arm phase II
study. BMC Cancer.2012;12:438. doi:10.1186/1471-2407-12-438
49. Siena S, Tabernero J, Bodoky G, et al. Quality of life during first-line
FOLFOX4±panitumumab in RAS wild-type metastatic colorectal
carcinoma: results from a randomised controlled trial. ESMO Open.
2016;1(2):e000041. doi:10.1136/esmoopen-2016-000041
50. Bennett L, Zhao Z, Barber B, et al. Health-related quality of life in
patients with metastatic colorectal cancer treated with panitumumab
in first- or second-line treatment. Br J Cancer.2011;105(10):1495–
1502. doi:10.1038/bjc.2011.409
51. Odom D, Barber B, Bennett L, et al. Health-related quality of life and
colorectal cancer-specific symptoms in patients with chemotherapy-
refractory metastatic disease treated with panitumumab. Int J
Colorectal Dis.2011;26(2):173–181. doi:10.1007/s00384-010-1112-5
52. Vectibix. INN-panitumumab. Available from: https://www.ema.
europa.eu/en/documents/product-information/vectibix-epar-product-
information_en.pdf Accessed March 31, 2019.
53. Mitchell EP, Piperdi B, Lacouture ME, et al. The efficacy and safety
of panitumumab administered concomitantly with FOLFIRI or
Irinotecan in second-line therapy for metastatic colorectal cancer:
the secondary analysis from STEPP (Skin Toxicity Evaluation
Protocol With Panitumumab) by KRAS status. Clin Colorectal
Cancer.2011;10(4):333–339. doi:10.1016/j.clcc.2011.06.004
54. Lacouture ME, Mitchell EP, Piperdi B, et al. Skin toxicity evaluation
protocol with panitumumab (STEPP), a phase II, open-label, rando-
mized trial evaluating the impact of a pre-emptive skin treatment
regimen on skin toxicities and quality of life in patients with meta-
static colorectal cancer. J Clin Oncol.2010;28(8):1351–1357.
doi:10.1200/JCO.2008.21.7828
55. Peeters M, Siena S, Van Cutsem E, et al. Association of progression-
free survival, overall survival, and patient-reported outcomes by skin
toxicity and KRAS status in patients receiving panitumumab mono-
therapy. Cancer.2009;115(7):1544–1554. doi:10.1002/cncr.24088
56. Lacouture ME, Anadkat M, Jatoi A, Garawin T, Bohac C, Mitchell E.
Dermatologic toxicity occurring during anti-EGFR monoclonal inhi-
bitor therapy in patients with metastatic colorectal cancer: a systema-
tic review. Clin Colorectal Cancer.2018;17(2):85–96. doi:10.1016/j.
clcc.2017.12.004
57. Kobayashi Y, Komatsu Y, Yuki S, et al. Randomized controlled trial
on the skin toxicity of panitumumab in Japanese patients with meta-
static colorectal cancer: HGCSG1001 study; J-STEPP. Future Oncol.
2015;11(4):617–627. doi:10.2217/fon.14.251
58. Fakih M, Vincent M. Adverse events associated with anti-EGFR
therapies for the treatment of metastatic colorectal cancer. Curr
Oncol.2010;17(Suppl 1):S18–S30. doi:10.3747/co.v17is1.615
59. Costa A, Tejpar S, Prenen H, Van Cutsem E. Hypomagnesaemia
and targeted anti-epidermal growth factor receptor (EGFR)
agents. Target Oncol.2011;6(4):227–233. doi:10.1007/s11523-
011-0200-y
60. Vincenzi B, Galluzzo S, Santini D, et al. Early magnesium mod-
ifications as a surrogate marker of efficacy of cetuximab-based
anticancer treatment in KRAS wild-type advanced colorectal cancer
patients. Ann Oncol.2011;22(5):1141–1146. doi:10.1093/annonc/
mdq550
61. Sastre J, Massuti B, Pulido G, et al. First-line single-agent panitu-
mumab in frail elderly patients with wild-type KRAS metastatic
colorectal cancer and poor prognostic factors: a phase II study of
the Spanish cooperative group for the treatment of digestive
tumours. Eur J Cancer.2015;51(11):1371–1380. doi:10.1016/j.
ejca.2015.04.013
62. Pietrantonio F, Cremolini C, Aprile G, et al. Single-agent panitu-
mumab in frail elderly patients with advanced RAS and BRAF
wild-type colorectal cancer: challenging drug label to light up new
hope. Oncologist.2015;20(11):1261–1265. doi:10.1634/theoncolo-
gist.2015-0171
63. Douillard J, Siena S, Peeters M, Koukakis R, Terwey J, Tabernero J.
547pimpact of baseline age on efficacy and safety of first-line pani-
tumumab (PMAB) + folfox4 vs folfox4 treatment. Ann Oncol.
2014;25(suppl_4):iv187–iv187. doi:10.1093/annonc/mdu333.49
64. Asimakopoulou N, Souglakos J, Kentepozidis N, et al. Efficacy of
panitumumab in older patients with metastatic colorectal cancer: a
retrospective analysis using the database of the Hellenic Oncology
Research Group (HORG). J Geriatr Oncol.2019;10(1):143–148.
doi:10.1016/j.jgo.2018.08.002
65. Bertotti A, Papp E, Jones S, et al. The genomic landscape of response
to EGFR blockade in colorectal cancer. Nature.2015;526(7572):263–
267. doi:10.1038/nature14969
66. Bertotti A, Migliardi G, Galimi F, et al. A molecularly annotated
platform of patient-derived xenografts (“xenopatients”)identifies
HER2 as an effective therapeutic target in cetuximab-resistant color-
ectal cancer. Cancer Discov.2011;1(6):508–523. doi:10.1158/2159-
8290.CD-11-0109
67. Sartore-Bianchi A, Trusolino L, Martino C, et al. Dual-targeted
therapy with trastuzumab and lapatinib in treatment-refractory,
KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal
cancer (HERACLES): a proof-of-concept, multicentre, open-label,
phase 2 trial. Lancet Oncol.2016;17(6):738–746. doi:10.1016/
S1470-2045(16)00150-9
68. Townsend A, Tebbutt N, Karapetis C, et al. Phase IB/II study of
second-line therapy with Panitumumab, Irinotecan, and Everolimus
(PIE) in KRAS Wild-Type Metastatic Colorectal Cancer. Clin Cancer
Res.2018;24(16):3838–3844. doi:10.1158/1078-0432.CCR-17-3590
69. Corcoran RB, Andre T, Atreya CE, et al. Combined BRAF, EGFR,
and MEK inhibition in patients with BRAF(V600E)-mutant color-
ectal cancer. Cancer Discov.2018;8(4):428–443. doi:10.1158/2159-
8290.CD-17-1226
70. Cremolini C, Morano F, Moretto M, et al. Dissecting primary resis-
tance to anti-EGFRs in RAS and BRAF wt metastatic colorectal
cancer (mCRC): a case-control study. J Clin Oncol.2017;35(suppl;
abstr 11508). doi:10.1200/JCO.2017.35.15_suppl.11508
71. Misale S, Di Nicolantonio F, Sartore-Bianchi A, Siena S, Bardelli A.
Resistance to anti-EGFR therapy in colorectal cancer: from hetero-
geneity to convergent evolution. Cancer Discov.2014;4(11):1269–
1280. doi:10.1158/2159-8290.CD-14-0462
72. Bettegowda C, Sausen M, Leary RJ, et al. Detection of circulating
tumor DNA in early- and late-stage human malignancies. Sci Transl
Med.2014;6(224):224ra224. doi:10.1126/scitranslmed.3007094
73. Siravegna G, Mussolin B, Buscarino M, et al. Clonal evolution and
resistance to EGFR blockade in the blood of colorectal cancer
patients. Nat Med.2015;21(7):795–801. doi:10.1038/nm.3870
74. Morelli MP, Overman MJ, Dasari A, et al. Characterizing the patterns
of clonal selection in circulating tumor DNA from patients with
colorectal cancer refractory to anti-EGFR treatment. Ann Oncol.
2015;26(4):731–736. doi:10.1093/annonc/mdv005
75. Parseghian CM, Loree JM, Morris VK, et al. Anti-EGFR-resistant clones
decay exponentially after progression: implications for anti-EGFR re-
challenge. Ann Oncol.2019;30(2):243–249. doi:10.1093/annonc/mdy509
76. Sartore-Bianchi A, Siena S, Bardelli A, et al. Dynamic molecular
analysis and clinical correlates of tumor evolution within a phase II
trial of panitumumab-based therapy in metastatic colorectal cancer.
Ann Oncol.2017;29(1):119–126.
77. Peeters M, Price T, Boedigheimer M, et al. Evaluation of emergent
mutations in circulating cell-free DNA and clinical outcomes in
patients with metastatic colorectal cancer treated with panitumumab
in the ASPECCT study. Clin Cancer Res.2019;25(4):1216–1225.
doi:10.1158/1078-0432.CCR-18-2072
Dovepress Battaglin et al
Cancer Management and Research 2019:11 submit your manuscript | www.dovepress.com
DovePress 5923
78. Kim TW, Peeters M, Thomas A, et al. Impact of emergent circulating
tumor DNA RAS mutation in panitumumab-treated chemoresistant
metastatic colorectal cancer. Clin Cancer Res.2018;24(22):5602–
5609. doi:10.1158/1078-0432.CCR-17-3377
79. Santos C, Azuara D, Vieitez JM, et al. Phase II study of high-
sensitivity genotyping of KRAS, NRAS, BRAF and PIK3CA to
ultra-select metastatic colorectal cancer patients for panitumumab
plus FOLFIRI: the ULTRA trial. Ann Oncol.2019;30(5):796–803.
doi:10.1093/annonc/mdz082
80. Kim TW, Elme A, Kusic Z, et al. A phase 3 trial evaluating
panitumumab plus best supportive care vs best supportive care in
chemorefractory wild-type KRAS or RAS metastatic colorectal
cancer. Br J Cancer.2016;115(10):1206–1214. doi:10.1038/
bjc.2016.309
81. Peeters M, Price TJ, Cervantes A, et al. Final results from a rando-
mized phase 3 study of FOLFIRI {±} panitumumab for second-line
treatment of metastatic colorectal cancer. Ann Oncol.2014;25
(1):107–116. doi:10.1093/annonc/mdt523
82. Hecht JR, Cohn A, Dakhil S, et al. SPIRITT: a randomized,
multicenter, phase II study of panitumumab with FOLFIRI and
bevacizumab with FOLFIRI as second-line treatment in patients
with unresectable wild type KRAS metastatic colorectal cancer.
Clin Colorectal Cancer.2015;14(2):72–80. doi:10.1016/j.
clcc.2014.12.009
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