Clinical Pharmacokinetics and Pharmacodynamics of the Epidermal Growth Factor Receptor Inhibitor Panitumumab in the Treatment of Colorectal Cancer

Abstract

Despite progress in the treatment of metastatic colorectal cancer (mCRC) in the last 15 years, it is still a condition with a relatively low 5-year survival rate. Panitumumab, a fully human monoclonal antibody directed against the epidermal growth factor receptor (EGFR), is able to prolong survival in patients with mCRC. Panitumumab is used in different lines of therapy in combination with chemotherapy, and as monotherapy for the treatment of wild-type (WT) RAS mCRC. It is administered as an intravenous infusion of 6 mg/kg every 2 weeks and has a t½ of approximately 7.5 days. Elimination takes place via two different mechanisms, and immunogenicity rates are low. Only RAS mutations have been confirmed as a negative predictor of efficacy with anti-EGFR antibodies. Panitumumab is generally well tolerated and has a manageable toxicity profile, despite a very high prevalence of dermatologic side effects. This article presents an overview of the clinical pharmacokinetics and pharmacodynamics of panitumumab, including a description of the studies that led to its approval in the different lines of therapy of mCRC.

Full text

REVIEW ARTICLE
Clinical Pharmacokinetics and Pharmacodynamics
of the Epidermal Growth Factor Receptor Inhibitor
Panitumumab in the Treatment of Colorectal Cancer
Sander Ketzer
1
•Kirsten Schimmel
1
•Miriam Koopman
2
•Henk-Jan Guchelaar
1
ÓThe Author(s) 2017. This article is an open access publication
Abstract Despite progress in the treatment of metastatic
colorectal cancer (mCRC) in the last 15 years, it is still a
condition with a relatively low 5-year survival rate. Pani-
tumumab, a fully human monoclonal antibody directed
against the epidermal growth factor receptor (EGFR), is
able to prolong survival in patients with mCRC. Panitu-
mumab is used in different lines of therapy in combination
with chemotherapy, and as monotherapy for the treatment
of wild-type (WT) RAS mCRC. It is administered as an
intravenous infusion of 6 mg/kg every 2 weeks and has a
t

of approximately 7.5 days. Elimination takes place via
two different mechanisms, and immunogenicity rates are
low. Only RAS mutations have been confirmed as a nega-
tive predictor of efficacy with anti-EGFR antibodies.
Panitumumab is generally well tolerated and has a man-
ageable toxicity profile, despite a very high prevalence of
dermatologic side effects. This article presents an overview
of the clinical pharmacokinetics and pharmacodynamics of
panitumumab, including a description of the studies that
led to its approval in the different lines of therapy of
mCRC.
Key Points
Panitumumab, a fully human monoclonal antibody
directed against the epidermal growth factor
receptor, is used in all lines of therapy in the
treatment of metastatic colorectal cancer. Its place in
therapy relative to other biological agents is still
unclear.
Pantitumumab is administered as an intravenous
infusion of 6 mg/kg over 60 min, and it has dual
clearance mechanisms.
Panitumumab treatment is only indicated for patients
with wild-type RAS tumors. Much research is
directed at identifying other biomarkers with the
potential of predicting efficacy benefits.
1 Introduction
Colorectal cancer (CRC) is a common form of cancer and it
is estimated that there are 95,270 new cases of colon cancer
and 39,220 new cases of rectum cancer annually in the US
[1]. In Europe and Australia, the incidence rates are even
higher [2]. With 49,190 deaths per year in the US, CRC is
the third most frequent (8% of all cancer cases) and third
most lethal form of cancer [1].
Surgical resection is an essential part of therapy for
localized CRC with curative intention. In metastatic col-
orectal cancer (mCRC) without the option of resection of
disease, systemic chemotherapy is indicated as palliative
&Henk-Jan Guchelaar
h.j.guchelaar@lumc.nl
1
Department of Clinical Pharmacy and Toxicology, Leiden
University Medical Center, P.O. Box 9600, 2300 RC Leiden,
The Netherlands
2
Department of Medical Oncology, University Medical Center
Utrecht, Utrecht, The Netherlands
Clin Pharmacokinet
DOI 10.1007/s40262-017-0590-9

treatment with the aim of prolonging survival, improving
quality of life, and reducing and controlling symptoms.
As first-line therapy, a cytotoxic doublet; 5-fluorouracil
with folinic acid plus oxaliplatin (FOLFOX), capecitabine
plus oxaliplatin (CAPOX) or 5-fluorouracil with folinic
acid plus irinotecan (FOLFIRI), or the triplet consisting of
5-fluorouracil with folinic acid, oxaliplatin and irinotecan
(FOLFOXIRI), could be combined with bevacizumab. In
patients unfit for these combination therapies, or in patients
who are asymptomatic or have low disease activity, a flu-
oropyrimidine plus bevacizumab is the preferred choice of
treatment. Another option is combining an epidermal
growth factor receptor (EGFR) antibody with FOLFOX or
FOLFIRI. To date, there is no unequivocal evidence for the
superiority of one of these options in first-line treatment of
patients with RAS wild-type (WT) mCRC, with the
exception of right-sided tumors, because recent studies
show that right-sided RAS WT patients do not benefit from
anti-EGFR therapy [3–5]. In second-line treatment,
aflibercept or ramucirumab could also be considered, while
regorafenib and trifluridine/tipiracil are available for third-
line treatment of mCRC.
The EGFR antibodies target the EGFR, also known as
ErbB-1 or HER1. EGFR is a receptor on the cell surface
where members of the epidermal growth factor (EGF)
family of extracellular protein ligands can bind. Various
ligands can activate these receptors, including EGF,
transforming growth factor (TGF)-a, heparin-binding EGF
(HB-EGF), amphiregulin, betacellulin, epigen and epireg-
ulin [6]. Upon activation, EGFR undergoes transition from
an inactive monomeric form to an active homodimer or
heterodimer (with another member of the ErbB family).
EGFR dimerization stimulates its catalytic intracellular
protein tyrosine kinase activity, and, as a result,
autophosphorylation of several tyrosine residues occurs
and elicits downstream activation and signaling by several
other proteins that associate with the phosphorylated tyr-
osines. These downstream signaling proteins initiate sev-
eral signal transduction cascades, including the RAS/RAF/
MAPK, P13K/AKT, and STAT pathways, leading to
increased cell proliferation, increased angiogenesis,
migration, metastasis, and increased cell survival by
blocking apoptosis (Fig. 1)[6–9].
There are two classes of drugs in clinical use that target
the EGFR. The monoclonal antibodies (mAbs) bind on the
extracellular site of the EGFR, thereby blocking the ligand-
binding region and preventing activation, whereas the
tyrosine kinase inhibitors compete intracellularly with
adenosine triphosphate (ATP) for the binding spot and
inhibit autophosphorylation [8].
Cetuximab was the first EGFR-targeting mAb available
for the treatment of mCRC, with panitumumab following a
few years later. Panitumumab is a fully human mAb of the
immunoglobulin (Ig) G2 subtype specific to EGFR.
In September 2006, the US FDA authorized the intro-
duction of panitumumab into the US market. This drug is
indicated as first-line therapy in combination with FOL-
FOX, or in third and subsequent lines of therapy as
monotherapy for the treatment of chemofractory mCRC
after disease progression on or following irinotecan-, flu-
oropyrimidine- and oxaliplatin-containing chemotherapy
regimens. Panitumumab is contraindicated in patients with
an RAS-mutated mCRC or if the RAS mCRC status is
unknown. Marketing authorization was approved by the
European Medicines Agency (EMA) in Europe in
December 2007. The EMA registered panitumumab for the
treatment of adults with WT RAS mCRC as first-line
treatment in combination with FOLFOX or FOLFIRI, as
second-line therapy in combination with FOLFIRI for
patients who have received first-line fluoropyrimidine-
based chemotherapy (excluding irinotecan), and as a single
agent after the failure of chemotherapy regimens contain-
ing irinotecan, fluoropyrimidine, and oxaliplatin.
In this paper, we present an overview of the pharma-
cokinetics (PK) and pharmacodynamics (PD) of panitu-
mumab, and provide an up-to-date overview of the current
position of panitumumab in the treatment of mCRC. In
recent years, results from pivotal studies have been pub-
lished, and research on biomarkers has advanced progres-
sively, justifying the need for this review.
2 Pharmacokinetics
The recommended dose of panitumumab is 6 mg/kg of
bodyweight administered once every 2 weeks [10,11].
A phase I dose-finding study found no difference in
panitumumab trough concentrations for this dose regimen
compared with two other schedules: 2.5 mg/kg weekly and
9 mg/kg every 3 weeks [12]. Steady-state was reached
after 6 weeks for all cohorts, and safety profiles were also
similar. The maximum tolerated dose was not reached.
The three dose regimens were also examined in a phase I
trial in Japanese patients [13], and a similar PK and safety
profile was found in both Japanese and non-Japanese patients.
The recommended time of infusion is 60 min [10,11],
although an infusion time of 30 min could be recom-
mended if the first dose administered over 60 min was well
tolerated. A phase I study compared these infusion dura-
tions and found maximum concentration (C
max
) values
were the same for infusions of 6 mg/kg every 2 weeks
administered over 60 and 30 min [14]. No differences in
safety were noted for these two infusion durations. This can
be explained because distribution, in particular the
S. Ketzer et al.

elimination phase, takes significantly more time than the
length of the infusion. For doses exceeding 1000 mg, an
infusion time of 90 min is advised [10,11].
The PK of panitumumab is best described with a
model that includes both linear and nonlinear clearance
mechanisms [15]. Concentrations of panitumumab
increase nonlinearly with the administered dose at doses
of 0.75–2 mg/kg, but at doses [2 mg/kg the area under
the concentration–time curve (AUC) increases propor-
tionally with the dose [10,11,13,15]. Clearance
decreased with an increase in dose, due to the dual
elimination mechanisms, as is also seen with other mAbs
that target membrane-bound antigens. The binding of
panitumumab to EGFR results in nonlinear elimination
because the mAb target complex is internalized and
degraded. This process is known as target-mediated drug
disposition (TMDD). Since the available number of EGF
receptors is limited, this is a saturable and dose-depen-
dent process of elimination. Clearance depends on the
plasma concentration, and, as with higher concentra-
tions, clearance via TMDD decreases. Additionally, the
number of receptors affects the clearance of panitu-
mumab. This mechanism plays an important role in the
clearance of panitumumab from the systemic circulation.
Nonspecific linear clearance takes place via the reticu-
loendothelial system. With doses of 2.5 mg/kg, full
receptor occupation was achieved, based on a 100% skin
rash incidence at this dose level [15,16].
A PK population model of panitumumab, based on
data from 1200 patients with solid tumors from 14 dif-
ferent studies, confirmed that disposition is best descri-
bed using a two-compartment model with parallel linear
and nonlinear clearance mechanisms [17]. For a typical
male patient (60 years of age, 80 kg) with CRC, this
model provides the following PK parameters: a linear
clearance of 0.273 L/24h, a maximum nonlinear clear-
ance of 28.4 L/24 h, a central and peripheral volume of
distribution of 3.95 and 2.59 L, respectively, and a
Michaelis–Menten constant of 0.426 lg/mL. The maxi-
mum nonlinear clearance is much higher than that of
cetuximab (1.42 L/24 h), which could be the result of the
higher affinity of panitumumab for EGFR [18]. The
small volume of distribution is primarily the conse-
quence of the large molecular weight of panitumumab.
Its volume of distribution is predominantly restricted to
vascular and interstitial spaces. Furthermore, the total
volume of distribution is less than half of the total
extracellular water volume because extracellular matrix
proteins and other constituents prevent panitumumab
from distributing into the entire compartment. The
Michaelis–Menten constant is the panitumumab con-
centration at which the elimination rate is half its
Fig. 1 EGFR signaling
pathways. Upon binding of a
ligand, EGFR undergoes
transition from an inactive
monomeric form (A)toan
active dimer or heterodimer.
EGFR dimerization stimulates
its catalytic intracellular protein
tyrosine kinase activity (B) and
elicits downstream activation
and signaling. EGFR epidermal
growth factor receptor,
Pphosphorylated, PI3K
phosphatase and tensin
homolog, mTOR mechanistic
target of rapamycin, JAK janus
kinase, STAT signal transducer
and activator of transcription,
SHC src homology 2 domain
containing, GRB2 growth factor
receptor-bound protein 2, SOS
son of sevenless, MEK MAPK/
ERK kinase, MAPK mitogen-
activated protein kinase
Clinical Pharmacokinetics and Pharmacodynamics of Panitumumab in Colorectal Cancer

maximum (V
max
). At doses [2 mg/kg, when the AUC
increases proportionally with the dose, it can be assumed
that V
max
is reached and EGFR is assumed to be satu-
rated at these doses. No clinical benefit is to be expected
at doses higher than the registered dose of 6 mg/kg of
bodyweight.
The manufacturer reports the following data: at steady
state, the mean peak concentration was 213 lg/mL [stan-
dard deviation (SD) 59] and the mean trough level was
39 lg/mL (SD 14) [10,11]. The corresponding AUC was,
on average, 1306 lg*day/mL (SD 374) and the mean
clearance was 4.9 mL/kg/day (SD 1.4). The elimination
half-life (t

) varied from 3.6 to 10.9 days (mean 7.5 days).
This long t

is the result of panitumumab being a fully
human antibody with the ability to bind to the neonatal Fc
receptor (FcRn) with the Fc domain. Binding of panitu-
mumab within endomes to the FcRn protects it from
lysosomal degradation as only the free fraction is catabo-
lized in lysosomes. In this way, a large portion of panitu-
mumab is recycled back into circulation. Antibodies with
more murine material have less binding capacity to the
FcRn, and, moreover, a greater number of anti-drug anti-
bodies are formed.
Panitumumab exposure was found to be most influenced
by body weight and, to a much smaller extent, by age, sex
and cancer type [17]. PK were unaffected by race, con-
comitant chemotherapy, and baseline tumor EGFR
expression. A population PK analysis reported by the
manufacturer confirms these findings [10,11]. Results
suggest that sex, age (21–88 years), race, renal and hepatic
function, chemotherapeutic agents, and EGFR membrane
staining intensity in tumor cells did not significantly alter
the PK of panitumumab. These data substantiate that dos-
ing based on body weight is the best way to achieve similar
exposure in patients.
No PK interactions of panitumumab with other drugs
have been reported to date due to its endogenous elimi-
nation not being mediated by transporters, such as P-gly-
coprotein, and enzymes, such as cytochrome P450, and/or
by renal and biliary excretion. Second, changes in TMDD
due to down- or upregulation of EGFR by other drugs are
not to be expected.
The possible influence of coadministration of panitu-
mumab with irinotecan has been the subject of study.
Nineteen patients received irinotecan (180 mg/m
2
intra-
venously) and panitumumab (6 mg/kg intravenously) [19].
In cycle 1, panitumumab was administered 3 days after
irinotecan administration, while in cycle 2, panitumumab
administration was directly followed by the administration
of irinotecan. No influence of panitumumab coadminis-
tration on irinotecan PK was found.
3 Pharmacodynamics
Panitumumab was generated using XenoMouse
TM
technol-
ogy; human immunoglobulin genes were introduced in
genetically engineered mice which had no functional
mouse immunoglobulin expression. For production of
panitumumab, genetically engineered Chinese hamster
ovary cells are used. Panitumumab, an IgG2 mAb, was
shown to bind EGFR with high affinity;
K
D
=5910
-11
M[20]. The affinity of panitumumab for
EGFR is higher than that of cetuximab, with reported K
D
values of 15–39 910
-11
M[21,22]. This strong affinity
for EGFR is the consequence of fast association rates
combined with slow dissociation rates [23]. Panitumumab
can bind bivalenty to two EGFRs. By binding to the
extracellular domain of this receptor, panitumumab does
not activate the receptor but prevents binding of endoge-
nous ligands [20,23]. As a result, these ligands cannot
activate the receptor and subsequent dimerization and
autophosphorylation will not take place. When panitu-
mumab is bound to EGFR, the receptor is incapable of
dimerization [23], which results in decreased proliferation,
decreased angiogenesis, and apoptosis of tumor cells.
Furthermore, the binding of panitumumab results in inter-
nalization of EGFR in tumor cells [20].
Antibody-dependent cell-mediated cytotoxicity (ADCC)
and complement-dependent cytotoxicity (CDC) are often
part of the mechanism of action of therapeutic mAb’s.
ADCC involves binding of the antibody coupled to the
target cell to an Fccreceptor on an effector cell of the
immune system, mainly natural killer cells. The target cell
is then lysed by the effector cell. With CDC, the antibody
binds to complement components, which can have an
antitumor effect via membrane attack complexes. As pan-
itumumab is a fully human antibody of the IgG2 isotype,
ADCC and CDC were not expected to play a major role
because the ability of IgG2 to bind Fccreceptors and
complement components is very limited. The IgG2 subtype
has the least potential for induction of ADCC of the four
IgG subtypes, and IgG1 and IgG3 are much stronger
inducers of CDC than IgG2. Almost all therapeutic anti-
bodies in clinical use are of the IgG1 isotype because this
isotype is known to be very effective in triggering ADCC
and CDC.
In squamous cell head and neck carcinomas, in vitro
panitumumab was able to provoke ADCC in concentrations
similar to those found in patients [24]. Panitumumab was
also shown to be effective in recruiting ADCC by myeloid
effector cell-mediated ADCC, but not in recruiting ADCC
by natural killer cells [25]. The contribution of ADCC to
the efficacy of panitumumab is unclear, which is in contrast
S. Ketzer et al.

with cetuximab, an IgG1 mAb, where ADCC was
demonstrated to be part of its mechanism of action.
3.1 Immunogenicity
Since panitumumab is a fully human mAb, immuno-
genicity is expected to be very low; however, panitumumab
could still be recognized as nonself by the human immune
system because of unique sequences in the DNA structure,
e.g. in the complementarity-determining regions. The
development of anti-panitumumab antibodies could
potentially lead to altered PK and efficacy and a different
safety profile. To detect anti-panitumumab antibodies, two
different screening assays have been used—an enzyme-
linked immunosorbent assay (ELISA) and a biosensor
immunoassay (BIAcore assay). The biosensor immunoas-
say detects both low- and high-affinity antibodies, whereas
ELISA detects mainly high-affinity antibodies. A biologi-
cal assay can be used to identify if these antibodies have
neutralizing capacities.
With regard to patients treated with panitumumab
monotherapy, the product information states that the inci-
dence of binding antibodies was \1% as detected by
ELISA, and 3.2% (US) to 3.8% (Europe) as detected by the
BIAcore assay (excluding predose and transient positive
patients); neutralizing antibodies were seen in \1% of
cases [10,11]. Lofgren et al. reported comparable results
[26]. Overall, 0.3% (2 of 612) of patients treated with
panitumumab developed nontransient anti-panitumumab
antibodies detected with ELISA, one of which proved to be
neutralizing antibodies. With the BIAcore assay, 4.1% (25
of 604) of patients treated with panitumumab were found to
have developed nontransient anti-panitumumab antibodies;
1.3% (8 of 604) of this population tested positive for
neutralizing antibodies.
No relationship between the presence of anti-panitu-
mumab antibodies and PK, efficacy, or safety has been
observed [10,11,17].
In combination with chemotherapy, the incidences of
binding antibodies are also low. In the trial by Weeraratne
et al., 1.8% of 1124 patients developed binding antibodies
and 0.2% developed neutralizing antibodies against pani-
tumumab when combined with oxaliplatin or irinotecan
[27]. The manufacturer reports even lower incidences of
binding antibodies (B1%) in this specific population
[10,11]; therefore, the emergence of immunogenicity is
also infrequent in this population, and comparable with
patients treated with monotherapy. KRAS status did not
influence the development of antibodies [27]. Population
PK analysis showed that PK were similar in patients who
were both positive and negative for anti-panitumumab
antibodies [10,11]. The safety profile did not appear to be
altered in patients who developed antibodies.
4 Efficacy
Panitumumab has been approved for use in first-, second-
and third-line treatment of mCRC. In this section, the
available evidence that led to and supports the application
of panitumumab in these lines of therapy is presented.
4.1 First-Line Therapy
The most important results of clinical studies that investi-
gated panitumumab as part of first-line treatment are
summarized in Table 1.
The PRIME study was the pivotal phase III trial where
panitumumab was investigated as first-line therapy in
mCRC. Overall, 1183 chemotherapy-naive patients were
randomly assigned to panitumumab plus FOLFOX4 (arm
A) or FOLFOX4 alone (arm B) [28]. KRAS status was
determined as patients were included in the study, and the
following outcomes only relate to the 656 patients with WT
KRAS mutation status. The objective response rate (ORR)
was higher in arm A (57 vs. 48%). Median progression-free
survival (PFS) was 10.0 months in arm A and 8.6 months
in arm B [hazard ratio (HR) 0.80, 95% confidence interval
(CI) 0.67–0.95, p=0.01] [29], while median overall sur-
vival (OS) was also significantly longer in arm A compared
with arm B, i.e. 23.8 months and 19.4 months, respectively
(HR 0.83, 95% CI 0.70–0.98, p=0.03). In patients with
baseline liver metastases only, the complete resection rate
in arm A was 28% compared with 18% in arm B. Patients
with mutant (MT) KRAS mCRC had significantly shorter
PFS (9.2 vs. 7.3 months; HR 1.27, 95% CI 1.04–1.55,
p=0.02) and shorter OS if treated with panitumumab plus
FOLFOX4 versus FOLFOX4 alone, which was ascribed to
a PD interaction with oxaliplatin in MT KRAS subjects. A
higher response rate (RR) and longer PFS and OS were
seen in patients who developed grade 2–4 skin toxicity
versus patients with only grade 0–1 skin toxicity. Despite
the large number of grade 3 or higher skin toxicity, pani-
tumumab had no negative effect on overall quality of life
(assessed using the EuroQol 5-domain health state index
and overall health) [30,31]. A quality-adjusted time
without symptoms of disease or toxicity of treatment (Q-
twist) was performed to provide an integrated measure of
clinical benefit [32]. The quality-adjusted survival in arm A
was significantly longer than in arm B, i.e. 20.5 and
18.2 months, respectively.
Another first-line phase III trial (PACCE) resulted in a
negative recommendation for the addition of panitumumab
(6 mg/kg every 2 weeks) to bevacizumab (10 mg/kg every
2 weeks) with chemotherapy [33]. In this randomized trial,
patients received panitumumab plus bevacizumab and
chemotherapy or only bevacizumab with chemotherapy. As
Clinical Pharmacokinetics and Pharmacodynamics of Panitumumab in Colorectal Cancer

chemotherapy regimens, two irinotecan-containing regi-
mens and six different oxaliplatin-containing regimens
were allowed. The study was prematurely closed when the
interim efficacy analysis showed inferior PFS and greater
toxicity in the panitumumab-containing treatment arm. The
risk of death was higher in this arm (9 vs. 4%) and patients
experienced more grade 3–4 adverse events (87 vs. 72%)
[33,34]. The negative effect of panitumumab on median
PFS and OS was seen in both irinotecan- and oxaliplatin-
containing regimens, but because of the small sample size
of the irinotecan-containing regimens, the pvalue was not
significant in this stratum. Furthermore, the outcomes were
independent of KRAS mutation status. At the time the study
was initiated, no efficacy and tolerability data were avail-
able from phase II studies that tested this combination of
drugs.
Panitumumab as first-line therapy was also the subject
of multiple phase II studies. In one of the first phase II
trials, panitumumab (2.5 mg/kg weekly) was administered
with IFL (irinotecan, leucovorin and bolus injections of
5-fluorouracil) or FOLFIRI [35]. The panitumumab plus
IFL regimen was not well tolerated, with 59% grade 3–4
diarrhea compared with a rate of 25% with panitumumab
plus FOLFIRI, and had shorter PFS and OS compared with
panitumumab combined with FOLFIRI. IFL is currently
considered as an inferior schedule compared with FOL-
FIRI. Ko
¨hne et al. also concluded that panitumumab in
combination with FOLFIRI represents an effective first-
line treatment option for treatment of WT KRAS mCRC
[36]. The randomized phase II PEAK trial showed that
mFOLFOX6 with panitumumab resulted in longer OS
compared with mFOLFOX6 with bevacizumab as first-line
treatment in patients with unresectable WT KRAS exon 2
mCRC [37]. A single-arm, phase II trial demonstrated that
panitumumab monotherapy may also be a treatment option
for the ‘frail elderly’, who are unable to receive
chemotherapy [38]. In 33 patients with a mean age of
81 years who were unfit for chemotherapy, monotherapy
with panitumumab resulted in a median PFS of 4.3 months
and OS of 7.1 months. There were no grade 4 adverse
events or deaths related to panitumumab. The results were
confirmed in an observational study with a comparable
cohort of 40 ‘frail elderly’ patients with RAS-BRAF WT
mCRC [39].
4.2 Second-Line Therapy
Table 2gives an overview of the most substantial evidence
for application of panitumumab as part of second-line
treatment of mCRC.
Peeters et al. executed a randomized, phase III study of
panitumumab with FOLFIRI versus FOLFIRI as second-
line therapy for mCRC [40], and all of the 1186 included
patients had disease progression during or within 6 months
of prior fluoropyrimidine-containing chemotherapy. WT
KRAS was not an inclusion criterion but the results pre-
sented here are only from the WT KRAS subpopulation
(55% of 91% of patients with available KRAS status) as
there was no effect of the addition of panitumumab on the
co-primary endpoints, PFS, and OS in patients with MT
KRAS tumors. The ORR was 36% in the panitumumab–
FOLFIRI arm compared with 10% in the FOLFIRI-only
arm [41]. The addition of panitumumab significantly
improved PFS (6.7 vs. 4.9 months; HR 0.82, 95% CI
0.69–0.97, p=0.023), and, for OS (14.5 vs. 12.5 months;
HR 0.92, 95% CI 0.78–1.10, p=0.366), a positive trend
Table 1 Efficacy data of first-line panitumumab trials
Study KRAS
status
Treatment arm No. of
patients
Median PFS
(months)
HR
(pvalue)
Median OS
(months)
HR
(pvalue)
ORR
(%)
OR
(pvalue)
PRIME
[28,29]
WT KRAS P?FOLFOX4 325 10.0 0.80 (0.01) 23.8 0.83 (0.03) 57 1.47 (0.02)
FOLFOX4 331 8.6 19.4 48
MT KRAS P?FOLFOX4 221 7.4 1.27 (0.02) 15.5 1.16 (0.16) 40 0.98 (0.98)
FOLFOX4 219 9.2 19.2 41
Berlin et al.
[35]
Unselected P ?IFL 19 5.6 17 47
P?FOLFIRI 24 10.9 22.5 33
Ko
¨hne et al.
[36]
WT KRAS P?FOLFIRI 86 8.9 0.5 56 2.1
MT KRAS P?FOLFIRI 59 7.2 38
PEAK [37]WTKRAS P?mFOLFOX6 142 10.9 0.87
(0.353)
34.2 0.62 (0.009) 57.8
WT KRAS B?mFOLFOX6 143 10.1 24.3 53.5
WT wild-type, MT mutated, Ppanitumumab, FOLFOX folinic acid/infusional 5-fluorouracil/oxaliplatin, IFL irinotecan/bolus 5-fluorouracil/folinic acid, FOLFIRI
folinic acid/infusional 5-fluorouracil/irinotecan, mFOLFOX modified FOLFOX, Bbevacizumab, PFS progression-free survival, HR hazard ratio, OS overall
survival, ORR objective response rate, OR odds ratio
S. Ketzer et al.

was observed. The latter may be the result of crossover
after progression in the FOLFIRI arm (34% of patients).
Again, PFS and OS appeared to be longer for subjects with
grade 2 or higher skin toxicity compared with patients with
grade 0–1 skin toxicity, or the FOLFIRI-only arm. No
premedication was required and very few infusion reac-
tions (0.7%) and no fatal reactions were observed. Overall
health status and health state index were measured using
the EQ-5D scales [31]. Health-related quality of life did not
differ between the treatment groups. Baseline scores were
relatively high, thus an improvement in quality of life was
probably unrealistic.
FOLFIRI with panitumumab in second-line therapy
was also examined in phase II trials. The trial by Cohn
et al. contributed to the evidence that would later result in
the exclusion of people with MT KRAS to receive pani-
tumumab-containing therapy [42]. In the STEPP study,
panitumumab was found to be more effective in WT
KRAS patients, as well as when administered concomi-
tantly with FOLFIRI or irinotecan as second-line therapy
[43,44]. In the randomized SPIRITT study, FOLFIRI plus
panitumumab had similar PFS and OS compared with
FOLFIRI plus bevacizumab for WT KRAS exon2patients
whowererefractorytofirst-line treatment with
chemotherapy containing oxaliplatin and bevacizumab
[45]. A recent, randomized, phase II trial by Shitara et al.
found comparable results in a study with a similar design
[46]. Furthermore, in another phase II trial, panitumumab
(9 mg/kg) administered every 3 weeks together with
irinotecan (350 mg/m
2
) was found to be safe, active, and
feasible [47]. In Asian patients, the combination of pan-
itumumab plus irinotecan and S-1 (a combination of
tegafur, gimericil and oteracil) showed promising efficacy
and an acceptable toxicity profile as second-line therapy
for mCRC [48]. S-1 is currently not yet registered in the
US or Europe for mCRC.
4.3 Third and Subsequent Lines of Therapy
In Table 3, the most prominent outcomes of phase II and
III trials, in which panitumumab was studied as a third or
further line of treatment, are depicted.
To fully evaluate the effect of panitumumab as
monotherapy, a randomized, open-label, phase III trial was
performed by Van Cutsem et al. [49]. In this trial, pani-
tumumab plus best supportive care (BSC) was compared
with BSC alone, with PFS as the primary endpoint. Patients
included had received at least two prior lines of treatment.
In the analysis, irrespective of KRAS mutation status, the
ORR was 10% in patients receiving panitumumab and 0%
in patients receiving only BSC. Panitumumab significantly
prolonged PFS; median PFS was 8 weeks in this arm
versus 7.3 in the BSC arm (HR 0.54, 95% CI 0.44–0.66,
p\0.0001). When only patients with a WT KRAS status
were included in the analysis, ORR was 17% and PFS was
12.3 weeks in the panitumumab arm; the results in the BSC
arm were not different from the whole cohort (HR 0.45,
95% CI 0.34–0.59, p\0.0001) [50]. It has to be noted that
Table 2 Efficacy data of second-line panitumumab trials
Study KRAS
status
Treatment arm No. of
patients
Median
PFS
HR
(pvalue)
Median OS HR
(pvalue)
ORR
(%)
OR (pvalue)
Peeters et al.
[40,41]
WT KRAS P?FOLFIRI 303 6.7 months 0.82
(0.023)
14.5 months 0.92
(0.366)
36.0 5.50
(\0.0001)
FOLFIRI 294 4.9 months 12.5 months 9.8
MT KRAS P?FOLFIRI 238 5.3 months 0.94
(0.561)
11.8 months 0.93
(0.482)
13.4 0.93 (0.89)
FOLFIRI 248 5.4 months 11.1 months 14.8
Cohn et al. [42]WTKRAS P?FOLFIRI 64 26 weeks 0.8 50 weeks 0.6 23 1.6
MT KRAS P?FOLFIRI 45 19 weeks 31 weeks 16
STEPP [43,44]WTKRAS P?FOLFIRI or
irinotecan
49 5.5 months 0.8 13.7 months 0.8 16 2.0
MT KRAS P?FOLFIRI or
irinotecan
38 3.3 months 13.1 months 8
SPIRITT [45]WTKRAS P?FOLFIRI 91 7.7 months 1.01 (0.97) 18.0 months 1.06 (0.75) 32
B?FOLFIRI 91 9.2 months 21.4 months 19
Shitara et al. [46]WTKRAS P?FOLFIRI 59 6.0 months 1.14 16.2 months 1.16 46.2
B?FOLFIRI 58 5.9 months 13.4 months 5.7
Carrato et al. [47]WTKRAS P?irinotecan 53 4.5 months 15.1 months 23
WT wild-type, MT mutated, Ppanitumumab, Bbevacizumab, FOLFIRI folinic acid/infusional 5-fluorouracil/irinotecan, PFS progression-free survival, HR hazard
ratio, OS overall survival, ORR objective response rate, OR odds ratio
Clinical Pharmacokinetics and Pharmacodynamics of Panitumumab in Colorectal Cancer

the absolute gain in PFS is fairly small in this group of
extensively pretreated patients. OS was not different
between treatment groups, probably at least partly because
patients in the BSC-alone arm were allowed to enter a
crossover study. Patients treated with panitumumab main-
tained better control over symptoms related to CRC, and
reported a better quality of life compared with patients
treated with BSC alone, assessed using the FACT
Colorectal Cancer Symptom Index and EQ-5D index,
respectively [51]. A higher health-related quality of life
was associated with absence of disease progression in the
panitumumab arm only [52]. Furthermore, longer OS and
PFS were correlated with a high grade of skin toxicity
(grade 2–4) in patients treated with panitumumab [53]. By
combining the efficacy and safety measures in a Q-twist
analysis, the quality-adjusted PFS was significantly longer
in the panitumumab arm (12.3 weeks) versus the BSC-
alone arm (5.8 weeks) [54]. In the open-label extension
study focusing on safety, 176 of the patients who had
progressive disease in the BSC arm received panitumumab
monotherapy [55]. Overall, panitumumab was well toler-
ated; 92% of patients experienced at least one adverse
event related to panitumumab, but grade 3 and 4 adverse
events were seen in 16 and 2% of patients, respectively.
Skin toxic effects were most common, and 4% of
the population discontinued therapy because of adverse
events.
The ASPECCT study was set up to test if panitumumab
was noninferior to cetuximab [56]. This randomized, open-
label, noninferiority, phase III trial compared cetuximab
monotherapy with panitumumab monotherapy in patients
with WT KRAS exon 2 mCRC. Overall, 999 patients who
had disease progression or intolerance to oxaliplatin and
irinotecan-based therapy, and had received a thymidylate
synthase inhibitor, were treated with one of these drugs in a
multinational study in 27 countries. Panitumumab was
noninferior to cetuximab with regard to OS, i.e.
10.2 months with panitumumab versus 9.9 months with
cetuximab (HR 0.94, 95% CI 0.82–1.07) [57]. Median PFS
was also comparable, i.e. 4.2 and 4.4 months with panitu-
mumab and cetuximab, respectively (HR 0.98, 95% CI
0.87–1.12). Hypomagnesia and increased skin toxicity
appeared to be predictors of longer OS for both EGFR
inhibitors. While skin toxicity rates were comparable (13%
with panitumumab, 10% with cetuximab), the cetuximab
arm experienced more infusion reactions (12.5 vs. 2.8% in
the panitumumab arm) and the panitumumab arm had a
higher incidence of hypomagnesia (7 vs. 3% in the
cetuximab arm).
Panitumumab (9 mg/kg every 3 weeks) plus irinotecan
(300–350 mg/m
2
every 3 weeks) was compared with
irinotecan alone in the PICCOLO trial [58]. KRAS WT
(codons 12, 13, and 61) patients who showed resistance to
fluoropyrimidine-containing therapy (at least one prior line
of treatment) were selected. These patients did not receive
irinotecan or EGFR-targeted therapy prior to commence-
ment of the study. In the primary analysis, 460 patients
were included. Patients treated with the combination of
irinotecan and panitumumab showed longer PFS (HR 0.78,
95% CI 0.64–0.95, p=0.015) and a higher ORR (34 and
12%), but no difference was seen in OS (HR 1.01, 95% CI
0.83–1.23, p=0.91) between treatment arms. Skin
Table 3 Efficacy data of third- and subsequent-line panitumumab trials
Study KRAS
status
Treatment arm No. of
patients
Median
PFS
HR (pvalue) Median OS
(months)
HR
(pvalue)
ORR
(%)
OR (pvalue)
Van Cutsem
[50,55]
WT KRAS P?BSC 124 12.3 weeks 0.45
(\0.0001)
8.1 0.99 17
BSC 119 7.3 weeks 7.6 0
MT KRAS P?BSC 84 7.4 weeks 0.99 4.9 1.02 0
BSC 100 7.3 weeks 4.4 0
ASPECCT
[56,57]
WT KRAS P 499 4.2 months 0.98 10.2 0.94 22 1.15
C 500 4.4 months 9.9 19.8
PICCOLO [58]WTKRAS P?irinotecan 230 0.78 (0.015) 10.4 1.01 (0.91) 34 4.12
(\0.0001)
Irinotecan 230 10.9 12
Hecht et al. [59] Unselected P (2.5 mg/kg
weekly)
148 14 weeks 9 9
Muro et al. [60] Unselected P 52 8.0 weeks 9.3 13.5
Andre et al. [61]WTKRAS P?irinotecan 65 6.3 months 11.9 35.2
WT wild-type, MT mutated, Ppanitumumab, Ccetuximab, BSC best supportive care, PFS progression-free survival, HR hazard ratio, OS overall survival, ORR
objective response rate, OR odds ratio
S. Ketzer et al.

toxicity, grade 3 or higher diarrhea, infection, lethargy, and
hematological toxicity were more frequently reported in
the combined treatment arm.
The first phase II trial that showed response to panitu-
mumab (2.5 mg/kg) as monotherapy included patients with
mCRC refractory to therapies with fluoropyrimidine and
oxaliplatin or irinotecan, or both [59]. Muro et al. also
found panitumumab monotherapy to be effective in Japa-
nese patients who developed progressive disease during or
after at least two previous lines of therapy containing
irinotecan, oxaliplatin, and fluoropyrimidine [60]. In the
study by Andre et al., the combination of panitumumab
with irinotecan also appeared active in patients with WT
KRAS mCRC refractory to standard chemotherapy [61].
Another single-arm, phase II trial found limited efficacy of
irinotecan plus panitumumab as salvage therapy in WT
KRAS patients refractory to treatment with irinotecan,
oxaliplatin, and fluoropyrimidine [62]. Only 8 of 35
patients showed partial response and six had stable disease.
With an ORR of 23% and a PFS of 2.7 months, response is
limited. It has to be noted that 15 patients received a low
irinotecan dose (100–120 mg/m
2
). In patients who received
normal doses of irinotecan (150–180 mg/m
2
), the RR was
30%.
5 Biomarkers
Much research dedicated to finding and confirming
biomarkers such as RAS,BRAF and EGFR and its ligands
to predict the efficacy of panitumumab in certain subpop-
ulations has been performed.
5.1 RAS
Ras proteins play an important role in the signal trans-
duction cascade of EGFRs. Depending on whether they are
bound to GDP (guanosine diphosphate) or GTP (guanosine
triphosphate), they are either in an inactive or active state,
respectively. Mutations in RAS (KRAS,NRAS and HRAS)
result in a reduction of hydrolysis of ATP bound to Ras,
facilitated by GTPase activating proteins (GAPs). Conse-
quently, Ras proteins are in a hyperactive state in patients
with mutated RAS [63]. Ras proteins can be activated by
other growth factor receptors, therefore when the Ras
proteins are in a hyperactive state, blocking the receptor
with panitumumab will not result in a significant reduction
in signal transduction because Ras proteins will stay active
independently of the binding of ligands to EGFR. Single
mutations, typically at codons 12, 13, and 61, can result in
an aberrant Ras function.
In the last few years, the indication of panitumumab
treatment has been amended to patients with a confirmed
WT RAS tumor status exclusively, where, initially, only
WT KRAS was required.
The evidence responsible for limitation of the use of
panitumumab to patients with WT KRAS tumors comes
from earlier pivotal trials. The extended analysis of the
study by Van Cutsem et al. was the first to address this
issue. Patients with MT KRAS treated with panitumumab
had comparable PFS as those patients treated with BSC
(7.4 vs. 7.3 weeks) [50]. Additionally, no responses were
observed in the MT KRAS population. The results from the
PRIME study and the trial by Peeters et al. confirmed that
patients with an MT KRAS status did not benefit from
panitumumab treatment. In the PRIME study, FOLFOX4
therapy shows even significantly longer PFS than panitu-
mumab with FOLFOX4 in the MT KRAS population (9.2
vs. 7.4 months; HR 1.27, 95% CI 1.04–1.55, p=0.02). In
the trial by Peeters et al., panitumumab combined with
FOLFIRI resulted in similar PFS as therapy with FOLFIRI
alone in MT KRAS patients (5.3 and 5.4 months; HR 0.94,
95% CI 0.78–1.14, p=0.561).
Peeters and colleagues retrospectively showed that
individual mutations in KRAS codons 12 or 13 have no
consistent prognostic or predictive value [64]. They used
data from three phase III trials with different treatment
regimens containing panitumumab. With this retrospective
analysis, it was confirmed that panitumumab should
exclusively be used in patients with WT KRAS tumors.
Doi et al. executed an exploratory analysis on data from
two studies in Japanese patients to examine whether the
association between MT KRAS tumors and worse outcome
was similar in this population [65]. In Japanese patients,
MT KRAS status was also associated with a lack of
response to panitumumab therapy. There was no objective
response in 10 patients with MT KRAS tumors, and median
PFS was 7.3 weeks, compared with 13.2 weeks in patients
with WT KRAS tumors.
The limitations were later extended to WT RAS tumors
only, including KRAS exons 2, 3, and 4 and NRAS exons 2,
3, and 4. The evidence for this requirement to initiate
panitumumab therapy is primarily derived from extended
analyses of previous described phase II and III trials,
especially the PRIME study and the trial by Peeters et al. A
summary of the published evidence can be found in
Table 4.
The extended RAS analyses of the PRIME trial, the
study by Peeters et al. and the trial by Van Cutsem et al. all
showed significant longer PFS and OS in the treatment arm
that contained panitumumab in WT RAS patients [66–68].
In the MT RAS population, no improvement in survival, or
even shorter survival, was seen if panitumumab was
combined with FOLFIRI, BSC, or FOLFOX4.
Furthermore, Peeters et al. examined samples from the
phase III trial that compared panitumumab plus BSC with
Clinical Pharmacokinetics and Pharmacodynamics of Panitumumab in Colorectal Cancer

Table 4 Efficacy data according to RAS and BRAF status in panitumumab trials
Study RAS/BRAF
status
Treatment arm No. of
patients
Median PFS
(months)
HR
(pvalue)
Median OS
(months)
HR
(pvalue)
ORR
(%)
OR
(pvalue)
PRIME
[28,66]
WT RAS P?FOLFOX4 259 10.1 0.72 (0.04) 25.8 0.77
(0.009)
FOLFOX4 253 7.9 20.2
WT KRAS/MT
other RAS
P?FOLFOX4 51 7.3 1.28 (0.33) 17.1 1.39
(0.12)
FOLFOX4 57 8.0 17.8
MT RAS P?FOLFOX4 272 7.3 1.31
(0.008)
15.5 1.21
(0.04)
FOLFOX4 276 8.7 18.7
WT RAS/WT
BRAF
P?FOLFOX4 228 10.8 0.68
(0.002)
28.3 0.74
(0.02)
FOLFOX4 218 9.2 20.9
WT RAS/MT
BRAF
P?FOLFOX4 24 6.1 0.58 (0.12) 10.5 0.90
(0.76)
FOLFOX4 29 5.4 9.2
Ko
¨hne et al.
[36,70]
WT RAS P?FOLFIRI 69 11.2 0.37 59 2.0
MT RAS P?FOLFIRI 74 7.3 41
WT RAS/WT
BRAF
P?FOLFIRI 60 13.2 0.25 68 3.7
MT RAS or
MT BRAF
P?FOLFIRI 83 6.9 37
PEAK [37]WTRAS P?mFOLFOX6 88 13.0 0.65
(0.029)
41.3 0.63
(0.058)
63.6
WT RAS B?mFOLFOX6 82 9.5 28.9 60.5
Peeters et al.
[40,67]
WT RAS P?FOLFIRI 208 6.4 0.70
(0.007)
16.2 0.81
(0.08)
41
FOLFIRI 213 4.6 13.9 10
WT KRAS/MT
other RAS
P?FOLFIRI 61 3.7 0.89 (0.63) 11.3 0.83
(0.40)
FOLFIRI 46 3.7 9.2
MT RAS P?FOLFIRI 299 4.8 0.86 (0.14) 11.8 0.91
(0.34)
15
FOLFIRI 294 4.0 11.1 13
WT RAS/WT
BRAF
P?FOLFIRI 186 6.9 0.68
(0.006)
18.7 0.83
(0.15)
FOLFIRI 190 5.5 15.4
WT RAS/MT
BRAF
P?FOLFIRI 22 2.5 0.69 (0.34) 4.7 0.64
(0.20)
FOLFIRI 23 1.8 5.7
Van Cutsem
et al. [55,68]
WT RAS P ?BSC 142 5.2 0.46
(\0.0001)
10.0 0.70
(0.0135)
31.0 20.00
(
\0.0001)
BSC 128 1.7 6.9 2.3
WT KRAS/
MT RAS
P?BSC 26 1.6 1.03
(0.9429)
7.6 0.99
(0.9625)
0
BSC 28 1.6 7.5 0
Shitara[46]WTRAS/WT
BRAF
P?FOLFIRI 46 18.9 1.21 7.4 1.14 52.5
WT RAS/WT
BRAF
B?FOLFIRI 44 16.1 6.7 2.6
MT RAS or
MT BRAF
P?FOLFIRI 8 5.4 0.42 3.2 0.54 0
MT RAS or
MT BRAF
B?FOLFIRI 11 8.2 3.7 18.2
Andre [61]WTRAS/WT
BRAF
P?irinotecan 41 8.7 15.8 46.3
MT RAS or
MT BRAF
P?irinotecan 19 1.9 4.6 0
WT wild-type, MT mutated, Ppanitumumab, FOLFOX folinic acid/infusional 5-fluorouracil/oxaliplatin, FOLFIRI folinic acid/infusional
5-fluorouracil/irinotecan, Bbevacizumab, BSC best supportive care, mFOLFOX modified FOLFOX, PFS progression-free survival, HR hazard
ratio, OS overall survival, ORR objective response rate, OR odds ratio
S. Ketzer et al.

BSC [69]. None of the patients (n=9) with WT KRAS
(codons 12, 13, and 61) with an NRAS mutation (codons
12, 13, and 61) responded to panitumumab. The same
applies to patients with BRAF mutations (n=13). Patients
with WT NRAS (HR 0.39, 95% CI 0.27–0.56, p\0.0001)
and WT BRAF (HR 0.37, 95% CI 0.24–0.55, p\0.001)
had longer PFS when treated with panitumumab compared
with BSC alone, but patients with MT NRAS (HR 1.94,
95% CI 0.44–8.44, p=0.379) had a comparable PFS.
In the phase II studies, comparable results were obtained
[46,61,70]. In the PEAK trial, if RAS mutation status
beyond KRAS exon 2 (KRAS exons 2, 3, and 4 plus NRAS
exons 2, 3, and 4) was taken into account, the panitu-
mumab arm had better median PFS (13.0 vs. 9.5 months;
HR 0.65, 95% CI 0.44–0.96, p=0.029) and OS (41.3 vs.
28.9 months; HR 0.63, 95% CI 0.39–1.02, p=0.058) than
the bevacizumab arm [37].
These findings confirm that chemotherapy combined
with panitumumab or panitumumab monotherapy should
not be used in patients with MT RAS tumors because there
is no survival benefit and an increase in adverse events has
been observed. In some reports, the addition of panitu-
mumab has a negative impact on survival parameters in
patients with MT RAS tumors; however, in the WT RAS
population, there is still a relevant subset of nonresponders.
Identification of additional biomarkers is necessary to
avoid treatment of patients with anti-EGFR therapy who
will not benefit from this treatment, and prevent unneces-
sary toxicity and costs.
5.2 BRAF
BRAF is the gene coding for the protein B-RAF, which
plays an important role in the signal transduction pathway
of EGFR by regulating MAP kinases and ERK signaling.
The predominant BRAF mutation is the V600E mutation.
This BRAF V600E mutation is mutually exclusive with
KRAS mutations in CRC [71].
The BRAF MT tumors have been less evaluated than
MT RAS tumors. There are fewer randomized trials where
BRAF mutation status was recorded and these studies
lacked power to show conclusive results. In a meta-anal-
yses, it has been shown that in BRAF-mutated mCRC
patients, the addition of an EGFR inhibitor to other therapy
does not increase OS, PFS, and ORR [72]. The authors
conclude that BRAF MT patients should be excluded from
therapy with anti-EGFR antibodies. In another meta-anal-
ysis by Rowland and colleagues, BRAF mutation status was
not found to be a clear predictive marker for OS and PFS
with panitumumab and cetuximab [73]. In that meta-anal-
ysis, different statistical methods are used and the inclusion
of studies also differs slightly from the meta-analysis by
Pietrantonio et al. [72].
Currently, a V600E BRAF mutation is a confirmed
worse prognostic marker, and data suggest only a small,
nonclinically relevant benefit for anti-EGFR treatment.
5.3 Epidermal Growth Factor Receptor (EGFR)
It can be hypothesized that patients with mCRC whose
tumors overexpress EGFR respond better to panitumumab
treatment. On average, 35% of patients have an increased
gene copy number (GCN) [74]. In 2005, the first associ-
ation was found between the EGFR GCN and the response
to anti-EGFR treatment in CRC [75], and, in subsequent
years, more studies followed. In 2013, all data were
combined in a meta-analysis because individual studies
lacked power. It was shown that median OS (1.61-fold
increase) and median PFS (1.54-fold increase) were higher
in patients with an increased EGFR GCN when treated
with anti-EGFR treatment. Time to progression was
unaffected [74]. Data on panitumumab were mainly
derived from one study in which patients who did not
respond to treatment with irinotecan and oxaliplatin
received panitumumab plus BSC or BSC alone [76].
Patients treated with panitumumab (n=58) with a high
GCN (defined as tumors with C43% chromosome 7
polysomy or mean C2.47 EGFR GCN per nucleus) had a
higher ORR compared with patients with a low GCN
(30–32 vs. 0%). Longer PFS (p\0.04) and OS (p\0.02)
were seen in patients with tumors with C40% chromosome
7 polysomy or mean C2.5 EGFR GCN per nucleus. For
patients treated with BSC alone (n=34), no correlation
was observed between PFS and GCN.
In contrast, Hecht and colleagues found a lack of cor-
relation between EGFR status and response to panitu-
mumab [77]. They combined data on EGFR expression in
the tumor from two different phase II studies. Low and
high EGFR expression were not associated with an altered
ORR, PFS, or OS.
In conclusion, it is not unequivocally proven that a high
GCN or high EGFR expression levels are related to a better
outcome of panitumumab treatment.
5.4 EGFR Ligands
Amphiregulin (AREG) and epiregulin (EREG) are ligands
of EGFR. Multiple studies have found indications that the
extent of expression of these ligands is related to efficacy
of anti-EGFR therapy.
High messenger RNA expression of one of these ligands
in WT RAS patients in the PICCOLO trial resulted in
longer PFS in the treatment arm with panitumumab
(8.3 months) compared with the irinotecan-alone arm
(4.4 months), with an HR of 0.38 (p\0.001), whereas for
patients with low expression levels, PFS was comparable
Clinical Pharmacokinetics and Pharmacodynamics of Panitumumab in Colorectal Cancer

for both treatment arms [78]. With regard to ORR and OS,
results were not significant.
Other studies also showed associations between
expression levels of these ligands and survival in patients
treated with panitumumab. In one trial, patients with RAS
WT tumors with high AREG expression had higher ORR
(67 vs. 38%) compared with tumors with low AREG
expression [70].
This association was also found in a smaller trial; high
expression levels of EREG (relative to nontumor tissue)
and AREG resulted in a higher OS in WT KRAS patients,
with HRs of 0.326 (p=0.011) and 0.277 (p=0.019),
respectively [79]. Furthermore, high ratios of ERBB2,
MET, and vascular endothelial growth factor receptor A
(VEGFA) between tumor and nontumor tissues were shown
to be associated with worse OS.
Similar results were found by Yoshida et al. [80].
AREG, EREG, TGFa, and HB-EGFR may be predictive
markers for successful treatment with anti-EGFR antibod-
ies. Patients with immunoreactivity to two or more of these
ligands had a significantly higher ORR (53.3 vs. 0%) and
longer PFS (231 vs. 79 days) than patients with
immunoreactivity to none or one of these ligands.
Several other biomarkers have been the subject of study,
including PTEN and PIK3CA, polymorphisms of EGFR,
telomere length, circulating tumor cells, tumor budding,
microRNA expression, and EGFR downstream phospho-
proteins. Moreover, the prognostic and predictive value of
clinical biomarkers, such as early tumor shrinkage and
depth of response, have recently been explored; however,
there is currently insufficient evidence to use these
biomarkers in decision making regarding the treatment of
patients with panitumumab.
6 Safety
In phase I studies, the most prevalent adverse events were
discerned and considered acceptable. More robust data on
safety issues were derived from phase III studies. The most
common adverse reactions were skin reactions, gastroin-
testinal disorders, fatigue, pyrexia, hypomagnesia and
paronychia.
6.1 Skin Toxicity
Skin-related toxicity is a direct result of the mechanism of
action of panitumumab, as expression of EGFR is high in
keratinocytes and hair follicles. Skin reactions are observed
in more than 90% of patients treated with panitumumab,
and the US prescribing information contains a boxed
warning regarding this cluster of adverse events.
Additional in-depth data on integument-related tolera-
bility were collected in the population of the previously
described trial of Ko
¨hne et al. Almost all patients (98% of
154) experienced skin-related toxicity, with rash (42%),
dry skin (40%), acne (36%), and alopecia (34%) being the
most prevalent [81]. Grade 3 or higher toxicities were
experienced by 36% of patients, with rash, acne, and
paronychia being the most frequent. The median time to
first integument-related toxicity was 8 days, with these
toxicities lasting for a median of 334 days. Quality of life
was assessed using two validated tools based on patient-
reported outcomes—the EORTC QLQ-C30 global health
status and the EuroQol EQ-5D health state index and
overall health. The scores on these scales were comparable
at baseline and at the end of follow-up, indicating that skin
toxicity did not have a negative impact on quality of life.
The ORR was higher in patients who had more severe
integument-related toxicity; 56% in patients with grade 2
or higher skin toxicity versus 29% with grade 0–1, indi-
cating that skin toxicity is a predictor of efficacy of
panitumumab.
Indeed, the phase III trials made it clear that patients
who develop at least grade 2 skin toxicity have better
ORR,PFS, and OS. This raises the question whether
patients receiving panitumumab with WT RAS status who
do not develop skin toxicity should receive a dose escala-
tion to induce skin toxicity or discontinuation of therapy.
More research is needed to establish the value of skin
toxicity as a prospective biomarker.
Takahashi and colleagues indicated that low serum
levels of hepatocyte growth factor, AREG, and EREG prior
to the start of treatment with anti-EGFR antibodies might
be markers for predicting a high grade of skin toxicity [82].
Additionally, these authors found a higher grade of skin
toxicity (grade 2–3 vs. grade 0–1) correlated with longer
PFS and OS.
Other studies investigated whether genetic variation
within the EGFR gene could predict EGFR inhibitor-as-
sociated skin toxicity [83,84]. Some polymorphisms and
haplotypes have been identified but have not been con-
firmed in larger RCTs.
Skin toxicity can be prevented by proactive treatment
with sunscreen, skin moisturizers, doxycycline, and topical
corticosteroids, as was observed in the STEPP trial, which
compared pre-emptive skin treatment with reactive treat-
ment [43]. Pre-emptive treatment resulted in meaning-
ful less grade 2 or higher skin toxicity, and patients with
this treatment reported better quality of life, assessed using
the Dermatology Life Quality Index. The management of
EGFR inhibitor-induced skin toxicity was also evaluated in
a systemic review [85]. As well as panitumumab, studies
on cetuximab and tyrosine kinase inhibitors were included.
S. Ketzer et al.

The prophylactic use of systemic tetracyclines was con-
sidered the most promising strategy.
6.2 Gastrointestinal Disorders
Gastrointestinal disorders seen in patients receiving pani-
tumumab therapy consisted mainly of diarrhea, nausea and
vomiting, abdominal pain, and constipation. Diarrhea
occurs in approximately 50% of cases but is most often
mild or moderate in severity. Grade 3–4 diarrhea has been
reported in approximately 2% of patients receiving
monotherapy, and, in combination with chemotherapy, a
rate of approximately 17% of individuals was observed.
6.3 Paronychia
Paronychia has been observed in approximately 20% of
patients treated with panitumumab. It is an inflammation of
the fingers and/or toes that involves swelling of the lateral
nail folds, and is considered a very cumbersome adverse
event.
6.4 Hypomagnesia
Hypomagnesia is a common adverse event, occurring in
approximately 30% of patients. Grade 3–4 hypomagnesia
has been reported in up to 7% of treated individuals.
Symptoms include seizures, tremor, nystagmus, and car-
diac arrest, therefore it is important to monitor magne-
sium levels of patients treated with panitumumab.
Hypomagnesia may be caused by EGFR inhibition in the
kidney, leading to magnesium wasting [86]. The higher
incidence in patients treated with panitumumab versus
cetuximab could be a result of the higher binding affinity
to EGFR. It has also been suggested that the occurrence of
hypomagnesia during treatment with cetuximab or pani-
tumumab is associated with higher ORR, but data are
inconclusive [87].
6.5 Interstitial Lung Disease
Interstitial lung disease (ILD) is one of the most serious
side effects of panitumumab, with most cases being
reported in the Japanese population. The reason for this is
unclear, but possible explanations could be genetic sus-
ceptibility, different clinical practices or environmental
factors, detection bias, and reporting bias. A postmarketing
analysis in Japan showed an incidence of ILD of 1.3% (39
of 3085 patients), with a high mortality rate of 51.3% (20
of 39 cases) [88]. The following risk factors for ILD were
identified: male sex, older than 65 years of age, a history of
ILD, poor general condition, and no history of previous
drug treatment for CRC (including cetuximab). Interstitial
pneumonitis or pulmonary fibrosis are contraindications for
the use of panitumumab. In patients with a history of these
conditions, the benefits of therapy versus the risk of pul-
monary complications should be carefully considered.
6.6 Infusion Reactions
Infusion-related reactions were reported in only 4% of
patients treated with panitumumab, of whom \1% were
grade 3 or higher. No premedication was required prior to
administration of panitumumab [12].
7 Discussion and Conclusions
The anti-EGFR antibody panitumumab has now been
available for more than 10 years for the treatment of RAS
WT mCRC. The PK have been well-established, with a
dual clearance mechanism, via binding to the EGFR and
via the reticuloendothelial system. The mechanism of
action depends largely on the blockade of EGFR, thereby
preventing the binding of endogenous ligands and its
effects on tumor growth, survival, and metastasis. The
immunogenicity of panitumumab is very low, a conse-
quence of panitumumab being a fully human antibody.
Panitumumab is registered and used in all lines of therapy
for the treatment of mCRC, in combination with
chemotherapy and as monotherapy. Until now, the only
(retrospectively) confirmed predictive biomarker is RAS,
but others are expected, particularly with regard to BRAF.
Anti-EGFR therapy in patients with an RAS-mutated
mCRC is detrimental for outcome. In terms of safety, the
high incidence of skin toxicity is especially notable, which
predicts a better response compared with no skin toxicity.
Overall, panitumumab is well tolerated.
Despite its mature state of clinical development, some
topics of debate, recent discoveries, and future develop-
ments regarding panitumumab are to be considered,
including its place relative to cetuximab and bevacizumab
in the treatment of mCRC, the potential combination
therapy of panitumumab and bevacizumab, and the most
effective chemotherapy backbone to combine with pani-
tumumab. These, among other matters, will be discussed
below.
The place of panitumumab relative to another available
anti-EGFR antibody, cetuximab, is still unclear. Only the
ASPECCT trial reported data on the prospective head-to-
head comparison of panitumumab and cetuximab in a
randomized clinical trial, and showed that both drugs had
similar efficacy [56,57]; however, both drugs appeared to
have a different safety profile. A higher incidence of
hypersensitivity reactions and infusion reactions was seen
with cetuximab, probably due to the fact that cetuximab is
Clinical Pharmacokinetics and Pharmacodynamics of Panitumumab in Colorectal Cancer

a chimeric antibody, whereas panitumumab is a fully
human antibody. Alternatively, hypersensitivity reactions
may be caused by galactose-a-1,3-galactose, a component
added during the manufacturing process of cetuximab for
post-translational modification, or by residues of murine-
derived N-glycolylneuraminic acid, which is introduced
during the manufacturing process [89,90]. In contrast,
panitumumab showed more cases of severe hypomagnesia
[56,57].
In a meta-analysis, it was shown that both drugs were
related to a significantly increased risk of grade 3–4
infections, but only cetuximab was associated with a higher
incidence of febrile neutropenia [91]. In this analysis,
studies where anti-EGFR mAbs were used for indications
other than mCRC, were also included. When the comor-
bidity and medical history of individual patients are taken
into account, these differences in adverse events could
result in the preference of one drug over the other on an
individual patient level.
The earlier-discussed higher potential of cetuximab in
triggering ADCC compared with panitumumab does not
result in increased efficacy. Panitumumab may compensate
for the lesser activation of ADCC with its higher binding
affinity to EGFR, or the effects of ADCC may play an
insignificant role compared with the receptor-blocking
action.
Treating patients with panitumumab after they received
prior cetuximab is only indicated when treatment with
cetuximab is discontinued for reasons other than disease
progression, e.g. hypersensitivity reactions [92–96].
The place of panitumumab relative to the angiogenesis
inhibitor bevacizumab, an antibody directed against
VEGFA, is another point of debate. As previously dis-
cussed, three studies investigated panitumumab versus
bevacizumab [37,45,46]. The randomized, phase II PEAK
trial found an advantage of panitumumab treatment on PFS
and OS in a subpopulation of patients with WT RAS tumors
[37]. In WT KRAS patients, only OS was significantly
improved with panitumumab plus mFOLFOX6 compared
with bevacizumab plus mFOLFOX6. In the phase II
SPIRITT study, a higher ORR was seen in favor of patients
treated with panitumumab plus FOLFIRI versus beva-
cizumab plus FOLFIRI [45]. PFS and OS were comparable
in both treatment arms. The trial conducted by Shitara et al.
also showed a trend toward improved OS in patients who
were WT RAS and BRAF in the FOLFIRI plus panitu-
mumab arm compared with the FOLFIRI plus beva-
cizumab arm [46].
In cases of cetuximab versus bevacizumab, the results
are also variable. The FIRE-3 study compared cetuximab
plus FOLFIRI with bevacizumab plus FOLFIRI as first-line
therapy of mCRC in a randomized, open-label, phase III
trial [97]. Although ORR (primary endpoint) and PFS were
similar for both regimens in WT KRAS patients, the com-
bination with cetuximab showed a significantly longer OS
(28.7 vs. 25.0 months). In the RAS WT population, the
median depth of response and frequency of early tumor
shrinkage, obtained by centralized radiological review,
were significantly better in the cetuximab arm [98]. In
contrast, the not yet published CALGB study found no
differences in survival outcomes between cetuximab versus
bevacizumab, both in combination with chemotherapy as
first-line treatment [99].
Based on the available evidence, panitumumab or
bevacizumab cannot be preferred over the other as first- or
second-line therapy in mCRC. More data are warranted to
have a better selection of patients for anti-EGFR versus
anti-VEGF treatment. Extended analysis of biomarkers
might be an important tool in selecting patients who benefit
most from panitumumab treatment.
It has recently been shown that patients with a tumor
located on the right side do not benefit from anti-EGFR
therapy. Brule
´et al. found that patients with right-sided
colon cancer did not benefit from cetuximab therapy
compared with BSC (median PFS 1.9 and 1.9 months,
respectively), while patients with left-sided colon cancer
did benefit (median PFS 5.4 and 1.8 months, respectively)
[3]. In a retrospective analysis of the FIRE-3 and CRYS-
TAL studies in the RAS WT population, patients with
right-sided tumors had markedly inferior ORR, PFS, and
OS compared with patients with left-sided tumors [4]. The
efficacy benefits relative to the comparative therapy are
much higher in patients with left-sided tumors compared
with patients with right-sided tumors. A recent meta-
analysis including the PRIME and PEAK trials confirms
that the addition of an anti-EGFR agent to chemotherapy in
first-line therapy only results in survival benefit in patients
with WT RAS left-sided tumors but not in right-sided WT
RAS tumors [5]. Additionally, anti-EGFR therapy results in
significantly longer survival in the WT RAS population
with left-sided tumors compared with bevacizumab. These
findings will affect prescription guidelines and label claims
at short notice.
The PACCE trial was the first study where panitu-
mumab and bevacizumab were combined as treatment for
mCRC; however, this combination failed as a treatment
option in the first line. A similar study was performed with
cetuximab. In the CAIRO2 trial, cetuximab was combined
with oxaliplatin, capecitabine, and bevacizumab as first-
line therapy, and then compared with the same regimen
without cetuximab [100]. The addition of cetuximab
resulted in a significantly shorter PFS (primary endpoint)
and inferior quality of life. OS and RR were not signifi-
cantly different for both treatment groups, while patients in
the treatment arm with cetuximab experienced more grade
3–4 adverse events. A recently published retrospective
S. Ketzer et al.

cohort study by Taniguchi et al. showed that a short
interval (\6 months) between bevacizumab and anti-EGFR
antibody treatment may interfere with the efficacy of the
subsequent anti-EGFR therapy [101]. Although only 14 of
114 patients (WT KRAS exon 2) received panitumumab
plus irinotecan, others received cetuximab with irinotecan.
A higher RR and longer PFS and OS were seen if the
interval between bevacizumab and anti-EGFR antibody
therapy was at least 6 months compared with a shorter
interval. However, the combination of bevacizumab and
panitumumab is still the subject of research.
A recent phase I study showed that panitumumab 6 mg/
kg every 2 weeks is the recommended dose in combination
with bevacizumab 5 mg/kg every 2 weeks [102]; no dose-
limiting toxicities were seen in three Japanese patients
receiving this regimen. Liu and colleagues provide the
most recently published evidence. In this randomized,
phase II trial, FOLFIRI was compared with FOLFIRI plus
panitumumab (4 mg/kg biweekly) and bevacizumab
(4 mg/kg biweekly) as second-line treatment [103]. Inde-
pendent of KRAS mutation status, this combination was
able to prolong PFS, OS, and RR compared with FOLFIRI
alone, at the cost of additional grade 3–4 adverse events,
but these were tolerable. This second-line therapy was first
evaluated in other phase II trials using lower doses of both
drugs [104,105]. The mechanisms of potential antagonistic
effects of combined VEGF and anti-EGFR antibodies are
still unclear. Acquired resistance to bevacizumab might be
associated with co-resistance to anti-EGFR therapy, or a
PD interaction between the two might be responsible.
Another possibility is the inclusion of oxaliplatin in the
chemotherapy backbone. In the PACCE trial, this was
mainly the case, as well as in the CAIRO2 study, which is
in contrast with more recent research where irinotecan is
used. More data are warranted to get a final answer on the
feasibility and efficacy of this combination-targeted
therapy.
Regarding the chemotherapy backbone, panitumumab
can be combined with FOLFOX and FOLFIRI; however,
the addition of FOLFOX has only been investigated as
first-line therapy, whereas FOLFIRI is not included in the
US label. On the other hand, the US label of cetuximab
only states the combination with irinotecan-containing
regimens. As no large studies have been performed with
the aim of comparing the different chemotherapy back-
bones directly, no definite conclusions can be drawn to
what the most optimal chemotherapy regimen is to com-
bine with anti-EGFR treatment. As described in the pre-
vious paragraph, the combination of bevacizumab and
panitumumab or cetuximab only seems to prolong survival
in combination with irinotecan-containing chemotherapy
schedules. The COIN trial showed that there is a lack of
benefit in the addition of cetuximab to oxaliplatin-based
chemotherapy in first-line treatment of WT KRAS mCRC
[106], although it is unclear if these findings are the result
of the inclusion of oxaliplatin in the chemotherapy back-
bone or of the use of CAPOX, which was the most com-
mon chemotherapy regimen in this study. Further study on
the most optimal chemotherapy to combine with anti-
EGFR treatment is required.
For the last few years, the use of panitumumab has
been limited to RAS WT mCRC only. However, even in
this population, there is still a substantial subgroup of
patients who have no objective response when treated
with panitumumab. Other biomarkers may be able to
predict a lack of efficacy. V600E BRAF mutation status
seems to be important, although its predictive role has not
been unequivocally established until now. There is little
evidence on the best treatment of patients with MT BRAF
tumors. A pilot trial explored whether treatment with
vemurafenibcombinedwithpanitumumabforpatients
with MT BRAF tumors is suitable [98]. Treatment was
well tolerated, but showed only modest clinical activity in
this subset of chemoresistantandhighlyaggressive
mCRC.
EGFR GCN, EGFR expression, levels of EGFR ligands,
and other potential biomarkers should be examined in this
newly defined population of patients with RAS WT tumors,
and a predictive role might become apparent. The purpose
of these studies would be to better define the population
that profits from panitumumab therapy and to further
reduce the number of patients who are unnecessarily trea-
ted with panitumumab, resulting in adverse events in the
absence of an objective response.
Overall, this review shows that panitumumab is a
valuable therapy in the treatment of left-sided mCRC in all
lines of therapy, with RAS WT as a predictive biomarker.
More research is needed to better define the subpopulation
that will benefit most from treatment with panitumumab.
The place of panitumumab in treatment, compared with
other drugs, especially bevacizumab and cetuximab, should
also be further investigated.
Compliance with Ethical Standards
Funding No sources of funding were used to assist in the preparation
of this review.
Conflict of interest Sander Ketzer, Kirsten J.M. Schimmel, Miriam
Koopman, and Henk-Jan Guchelaar declare that they have no con-
flicts of interest.
Open Access This article is distributed under the terms of the
Creative Commons Attribution-NonCommercial 4.0 International
License (http://creativecommons.org/licenses/by-nc/4.0/), which per-
mits any noncommercial use, distribution, and reproduction in any
medium, provided you give appropriate credit to the original
author(s) and the source, provide a link to the Creative Commons
license, and indicate if changes were made.
Clinical Pharmacokinetics and Pharmacodynamics of Panitumumab in Colorectal Cancer

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