Adv Ther (2018) 35:1497–1509

https://doi.org/10.1007/s12325-018-0791-0

REVIEW

An Update of Efficacy and Safety of Cetuximab

in Metastatic Colorectal Cancer: A Narrative Review
Giulia Fornasier . Sara Francescon . Paolo Baldo

Received: July 11, 2018 / Published online: September 14, 2018

Ó Springer Healthcare Ltd., part of Springer Nature 2018

ABSTRACT Keywords: Adverse drug reactions; BRAF;

Cetuximab; EGFR; Metastatic colorectal cancer
Colorectal cancer is the second most common
cancer, representing 13% of all diagnosed can-
cers. Cetuximab is a recombinant chimeric
INTRODUCTION
monoclonal IgG1 antibody and epidermal
The epidermal growth factor receptor (EGFR) is
growth factor receptor (EGFR) inhibitor.
a transmembrane glycoprotein and it is a
Cetuximab is approved for the first-line treat-
member of the human epidermal growth factor
ment in combination with chemotherapy or as
receptor (HER) family. EGFR and its ligands are
a single agent in patients who have failed or are
essential for regulating cell proliferation, sur-
intolerant to chemotherapy in patients with
vival and differentiation. This mechanism is
EGFR-expressing, RAS wild-type metastatic col-
due to the intracellular domain with tyrosine
orectal cancer. Cetuximab efficacy emerged
kinase activity. EGFR is overexpressed in a
from studies that were conducted to approve
number of cancer cells; this stimulates cancer
the drug. Cetuximab is well tolerated; its toxi-
cell proliferation, prolongs cancer cell survival
cities are caused by its mechanism of action and
by blocking apoptosis, and enhances cell
the most common adverse reaction is skin tox-
mobility to promote cancer invasion and
icity. The main purpose of this manuscript is to
metastasis. As a result of these mechanisms,
present an update on the evidence-based sum-
new anticancer drugs inhibiting EGFR were
mary of efficacy and safety and on the cost-ef-
discovered [1, 2]. Cetuximab is a monoclonal
fectiveness of cetuximab. Furthermore, it
antibody approved in 92 counties for the treat-
suggests a management of adverse drug reac-
ment of patients with EGFR-expressing, RAS
tions to improve the tolerability of the drug.
wild-type metastatic colorectal cancer (mCRC).
The drug is also approved for patients with
squamous cell cancer of the head and neck
Enhanced digital content To view enhanced digital
features for this article go to https://doi.org/10.6084/
(SCCHN). Cetuximab is being investigated as a
m9.figshare.7022600. treatment for different cancer (bladder cancer,
breast cancer, gastric cancer, non-small cell
G. Fornasier (&)
S. Francescon
P. Baldo lung cancer, prostate cancer and rectal cancer)
Department of Pharmacy, Centro di Riferimento [3]. A phase 3 trial evidenced the benefit of
Oncologico (CRO) di Aviano-IRCCS, National cetuximab for the treatment of advanced non-
Cancer Institute, Aviano, Italy
e-mail: [email protected]
small cell lung cancer [4].
1498 Adv Ther (2018) 35:1497–1509

This review focuses on the efficacy and safety CURRENT INDICATION

of cetuximab in colorectal cancer. The update
AND PHARMACOKINETICS
focuses primarily on BRAF mutation and it
suggests a management of adverse effects in
Cetuximab is administered intravenously with
order to help physicians involved in the treat-
an infusion pump, gravity drip or a syringe
ment of these diseases [5].
pump by a healthcare professional once a week.
The PubMed, Medline and Scopus databases
One hour before the administration of cetux-
and Cochrane Library were searched for ran-
imab, patients must receive an antihistamine
domised controlled trials in human, comparing
and a corticosteroid to avoid allergic reactions.
cetuximab vs other treatments in mCRC. Adverse
The first infusion is administered in 2 h; if the
events were also researched in the EudraVigilance
first infusion is well tolerated, the subsequent
and FDA Adverse Events Reporting System
doses are administered in 1 h. Cetuximab exhi-
(FAERS) databases. The search strategy included
bits dose-dependent pharmacokinetics at the
the terms cetuximab or ErbituxÒ, chemotherapy,
weekly dose. The initial dose is 400 mg/m2 of
colorectal cancer or neoplasm or tumour or
body surface area. All subsequent weekly doses
mCRC, adverse event(s), advanced or metastatic.
are 250 mg/m2 each. At the initial dose of
We selected only English articles. We limited the
400 mg/m2, cetuximab is distributed in the
search strategy to articles published from 2004 to
vascular space (Vd = 2–3 L/m2). It has a long
the present. This article does not contain any
half-life elimination (& 112 h). Cetuximab is
studies with human participants or animals per-
used in combination with irinotecan-based
formed by any of the authors.
chemotherapy, in first-line with folinic acid,
fluorouracil and oxaliplatin (FOLFOX), or as a
MECHANISM OF ACTION single agent in patients who have failed or are
intolerant to chemotherapy for RAS wild-type
Cetuximab is a recombinant chimeric mono- metastatic colorectal cancer. Cetuximab must
clonal IgG1 antibody produced in a mammalian be administered 1 h prior to the chemotherapy
cell line (Sp2/0). It binds to EGFR and compet- infusion. It is also used in combination with
itively inhibits the binding of epidermal growth radiotherapy for locally advanced squamous
factor (EGF) and other ligands. The binding of cell cancer of the head and neck, and in com-
cetuximab to EGFR blocks the phosphorylation bination with platinum-based chemotherapy
and activation of receptor-associated kinases for recurrent and/or metastatic squamous cell
(MAPK and PI3K/Akt), resulting in inhibition of cancer of the head and neck.
cell growth, induction of apoptosis, and pro- Cetuximab was approved by the Food and
motion of cancer invasion and metastasis Drug Administration (FDA) and the European
(Fig. 1). Cetuximab also inhibits the develop- Medicines Agency (EMA) in February and June
ment of new blood vessels by decreasing vas- 2004 respectively [7].
cular endothelial growth factor production and
activates human anti-chimeric antibody
BENEFIT ASSESSMENT
(HACA). The protein product of the proto-
oncogene RAS is a transducer of the EGFR sig- OF CETUXIMAB IN COLORECTAL
naling cascade that increases cell proliferation, CANCER
and survival, but mutations of specific RAS
genes cause an activation of RAS proteins Colorectal cancer is the second most common
independently of EGFR signaling. This leads to cancer overall, representing 13% of all diag-
cetuximab inefficacy. As a result of this cetux- nosed cancers. Among men, it is the third most
imab is indicated in the treatment of RAS wild- common (13%) after prostate and lung cancer.
type metastatic colorectal cancer. Cetuximab In women, it is the second most common
may also enhance the cytotoxicity of radiation (13%), preceded only by breast cancer. The
by blocking EGFR signaling [1, 5, 6]. incidence of colorectal cancer is high in
Adv Ther (2018) 35:1497–1509 1499

Fig. 1 Cetuximab mechanism of action and organs with epidermal grow factor receptor (EGFR)

Australia, New Zealand, Europe and North overall survival (OS) (HR 0.77, 95% CI 0.67,
America, as a result of diet, environmental 0.88) using an EGFR monoclonal antibody [12].
exposures and genetic predisposition. Gener- Cetuximab should not be used in patients
ally, CRC is common (85%) after the age of 40 with any RAS mutation [13].
and it is often asymptomatic and in an Some patients do not respond to EGFR
advanced stage at diagnosis [8, 9]. inhibitors even though they have RAS wild-type
The benefit of cetuximab in cancer with an mCRC. Therefore, BRAF status was investigated;
overexpression of EGFR is well documented. 8–9% of patients with CRC present BRAF
Furthermore, it is proved that the efficacy of mutation and most of them present mutation
cetuximab in metastatic colorectal cancer in in BRAFV600E allele, which leads to the progres-
combination with chemotherapy is higher in sion and survival of tumour cells. BRAF muta-
patients without any RAS mutations. tion status seems to predict the lack of response
In the randomised controlled studies, an to EGFR inhibitors. Thus, it is reasonable to
analysis of KRAS exon 2 mutation and RAS investigate the status of BRAF before using
mutation (NRAS and KRAS other than KRAS cetuximab [14–16].
exon 2) was performed. The status of KRAS exon Several studies highlight that the primary
2 predicts the efficacy of the treatment with tumour location is important as a positive or
cetuximab [8–11]. Furthermore, the absence of a negative prognosis in colorectal cancer. The
mutation of the RAS gene (NRAS and KRAS) also colorectal cancer is usually classified by its
determines a positive effect of the treatment location as left-sided and right-sided. Left-sided
with cetuximab. Patients with RAS wild type tumours come from the splenic flexure,
have an improvement of progression-free sur- descending colon and sigmoid colon; right-
vival (PFS) (HR 0.60, 95% CI 0.48, 0.75) and sided tumours originate in the caecum,
1500 Adv Ther (2018) 35:1497–1509

ascending colon, hepatic flexure and colon cetuximab vs bevacizumab in combination with
transversum [17]. chemotherapy in patients with KRAS wild-type
Patients with left-sided RAS wild-type mCRC metastatic colorectal cancer. The study showed
(LC) showed a better PFS, OS and response rate a difference in OS in patients with FOLFOX plus
(RR) with EGFR inhibitors than patients with cetuximab, but not with FOLFIRI. Furthermore,
right-sided mCRC (RC) [18–20]. RC generally the CALGB/SWOG 80405 trial did not confirm
activates RAS and BRAF mutations, which the advantage of cetuximab vs bevacizumab in
results in a worse prognosis and therapy with OS in KRAS wild-type patients [28].
cetuximab [21]. On the other hand, LC appears A randomised study with 329 chemorefrac-
to closely correlate to the activation of EGFR. tory patients (218 with cetuximab and irinote-
Therefore, patients with left-sided RAS wild-type can vs 111 with cetuximab monotherapy)
mCRC should be preferentially treated with an showed a higher RR in patients treated with
anti-EGFR antibody [20]. irinotecan and cetuximab than in patients in
monotherapy with cetuximab (22.9%; 95% CI
Cetuximab Plus Irinotecan 17.5, 29.1% vs 10.8%; 95% CI 5.7, 18.1%;
P = 0.007). Also, the median survival time was
The CRYSTAL study (randomised phase III 8.6 months in the combination-therapy group
study) analysed the efficacy of cetuximab in and 6.9 months in the monotherapy group
combination with FOLFIRI as the first-line (P = 0.48) [29].
treatment for metastatic colorectal cancer. The
results showed an improvement in OS time Cetuximab Plus FOLFOX
from 20.0 months to 23.5 months (HR 0.796;
95% CI 0.670, 0.947; P = 0.0093) in patients The COIN trial involved 2445 patients assigned
treated with chemotherapy plus cetuximab in to three different arms (continuous
KRAS wild-type patients. Also, PFS and RR were chemotherapy, continuous chemotherapy with
increased. The study involved 1198 patients cetuximab, and intermittent chemotherapy).
(559 patients in each arm) [11, 22, 23]. This The results showed an increased RR in KRAS
study is used for registration of cetuximab plus wild-type patients treated with cetuximab (64%
irinotecan-based chemotherapy as first-line vs 57%, OR 1.35; 95% CI 1.00, 1.82; P = 0.049),
therapy in mCRC in Europe. A recent analysis but OS and PFS were not significantly different.
by van Brummelen et al. highlighted that BRAF An explorative analysis showed an improve-
mutation caused a lack of treatment benefit of ment in PFS in patients KRAS wild-type treated
anti-EGFR mAbs [24]. An analysis of the CRYS- with cetuximab in combination with FOLFOX
TAL study showed that KRAS wild-type patients (HR 0.72; 95% CI 0.53, 0.98; P = 0.037), but not
that receive cetuximab in combination with in patients treated with XELOX. Patients with at
FOLFIRi had a higher response if the early most one metastasis had an improvement of
tumour shrinkage was greater than 20%, while PFS, while patients with more metastasis did not
patients with early tumour shrinkage less than [26, 27, 30, 31]. The study showed the impor-
20% had an inferior OS (28.3 months vs tance of the mode of administration of 5-fluo-
19.6 months, HR 0.814, 95% CI 0.626, 1.059; rouracil; infusion is recommended, but bolus
P = 0.125) [25]. The study FIRE-3 compared administration is not [28]. A meta-analysis
cetuximab with bevacizumab in combination confirmed the efficacy of FOLFOX plus cetux-
with FOLFIRI in patients with wild-type KRAS imab with infusional fluorouracil [32]. The
showed a benefit in OS of cetuximab CELINE trial showed that the combination of
(28.7 months vs 25 months, HR 0.77; 95% CI biweekly cetuximab with FOLFOX had the same
0.62, 0.96; P = 0.017), while the PFS showed no efficacy as the weekly cetuximab administra-
significant difference [26]. The randomised tion, was well tolerated and provided more
clinical trial by Venook et al. [27] (n = 1137) treatment flexibility [33]. The OPUS study
compared the OS in patients treated with compared FOLFOX plus cetuximab and
Adv Ther (2018) 35:1497–1509 1501

FOLFOX alone. The response in RAS wild-type et al. evidenced a modest efficacy of first-line
metastatic colorectal cancer in first-line treat- monotherapy with cetuximab in patients with
ment was higher in patients treated with FOL- KRAS/RAS/BRA wild-type colorectal carcinomas
FOX plus cetuximab than in patients treated [39].
with FOLFOX alone (OS: HR 0.81; P = 0.0062)
[34]. The presence of BRAF mutation is a nega- Cetuximab Plus BRAF/MEK Inhibitors
tive result of treatment both in patients receiv-
ing chemotherapy plus cetuximab and The phase III BEACON trial is testing the effi-
chemotherapy alone. Consequently, the BRAF cacy of encorafenib, cetuximab plus or minus
tumour mutation is a negative marker of prog- binimetinib versus irinotecan/cetuximab or
nosis [34, 35]. ESMO clinical guidelines confirm FOLFIRI/cetuximab in patients with BRAFV600E-
the efficacy of cetuximab with FOLFOX in RAS mutation mCRC [3]. This study is ongoing and
wild-type colorectal cancer [36]. its expected completion date is July 2019. This
combination therapy is an innovative strategy
Cetuximab in Monotherapy to improve the prognosis of patients with BRAF-
mutation mCRC and to decrease the resistance
Cetuximab is used as monotherapy in RAS wild- to the treatment with cetuximab [14, 40, 41].
type metastatic colorectal cancer in patients An analysis of data of the BEACON trial showed
who have failed irinotecan and oxaliplatin- that the overall response rate (ORR) was 41% (1
based chemotherapy or who are intolerant to complete and 11 partial response). The analysis
irinotecan [7]. In a phase III randomised trial also highlighted that nine patients had a pro-
(n = 572), the drug was evaluated as a longation of stable disease. Furthermore, the
monotherapy in patients with metastatic col- duration of treatment was at least 5.6 months in
orectal cancer that could not use chemother- enrolled patients [42]. These promising results
apy. Cetuximab is compared with the best led to the Breakthrough Therapy designation
supportive care. The primary end point was OS. from the FDA for cetuximab in combination
The addition of cetuximab resulted in an with encorafenib and binimetinib as the third-
improvement of OS (HR for death = 0.77; 95% line treatment for patients with BRAFV600E-mu-
CI 0.64, 0.92; P = 0.005).The median survival tant mCRC [43].
was 6.1 months with cetuximab and
4.6 months in the supportive-care group. There
was also an improvement of PFS (HR for disease ADVERSE EFFECTS OF CETUXIMAB
progression or death = 0.68; 95% CI 0.57, 0.80;
P \ 0.001) with cetuximab [35]. The NORDIC- Cetuximab is generally well tolerated. The most
VII study showed a beneficial effect of cetux- common (C 10%) adverse drug reactions (ADRs)
imab monotherapy against Nordic FLOX (bolus associated with cetuximab are related to the
5-fluorouracil/folinic acid and oxaliplatin) in inhibition of EGFR and to its administration.
patients with RAS wild-type metastatic colorec- The ADRs include skin reactions, hypomagne-
tal cancer [37]. An open-label, randomised, saemia, mucositis and infusion-related reactions
multicentre, phase 3 study compared cetuximab (Table 1).
with panitumumab in monotherapy. Median Cetuximab in combination with
overall survival was 10.4 months (95% CI 9.4, chemotherapy and radiotherapy is associated
11.6) with panitumumab and 10.0 months with a higher incidence of these ADRs and with
(95% CI 9.3, 11.0) with cetuximab (HR 0.97; other ADRs such as neutropenia, diarrhoea,
95% CI 0.8, 1.11). This study showed that nausea and vomiting. In particular, cetuximab
panitumumab and cetuximab provide a similar in combination with platinum-based
overall survival benefit in patients with chemotherapy may increase the frequency of
chemotherapy-refractory metastatic colorectal severe neutropenia and leukopenia with the risk
cancer [38]. A recent analysis by Moiseyenko of infections, while cetuximab in combination
with fluoropyrimidines may cause cardiac
1502 Adv Ther (2018) 35:1497–1509

Table 1 Most common (C 10%) adverse effects with cetuximab and their management
Most common adverse Management
effects (‡ 10%)
Skin reactions (15–88%) See Table 2
Hypomagnasaemia (6–55%) Monitor electrolytes during treatment and continue for at least 8 weeks following
completion of the treatment with cetuximab
Infusion-related reactions Patient must receive an antihistamine and corticosteroid before the infusion of cetuximab;
(18–21%) monitor patient for at least 1 h after infusion
Grade 1–2: Manage with a slow infusion rate and with symptomatic treatment
Grade 3–4: Manage with interruption of the infusion and with symptomatic treatment. If
the reactions are not severe, it is possible to resume the drug with a slow infusion and
patient monitoring
Mucositis (8–32%) Avoid cheek or lip biting, mouth breathing, spicy and highly textured foods. Avoid highly
flavoured and alcohol-containing mouthwashes
Maintain good oral hygiene, dentures by brushing daily and soaking in antimicrobial
solution or benzydamine for at least 30 min/day and by rinsing thoroughly with
physiological saline or sodium bicarbonate after every meal
Use local or systemic analgesics (ibuprofen or acetaminophen) for pain
Use nystatin for candidiasis
Grade 2: topical corticosteroids or anaesthetics
Grade 3: Clobesol ointment with systemic erythromycin or minocycline. If necessary
temporary interruption of cetuximab or lower dosage
Grade 4: Interruption of cetuximab

ischaemia including myocardial infarction and severe rash is uncommon. The most common
congestive heart failure and palmar-plantar skin reaction observed with cetuximab is
erythrodysaesthesia [2]. papulopustular rash, also called acneiform rash.
Radiation dermatitis and cardiovascular dis- This type of rash is particular, because there are
orders are important serious adverse reactions no lesions like cysts or comedones, although
associated with cetuximab plus radiotherapy the papulopustular eruption is located in seb-
[2, 19]. Also, the most common ADRs reported orrhoeic areas (face, scalp, trunk). The skin
in the EudraVigilance [44] and FAERS [45] reaction usually appears 2 weeks after the
databases show a higher incidence of skin beginning of cetuximab. The rash may be
reactions and infusion-related reactions (Fig. 2). accompanied by dry skin (xerosis), itchiness or
erythema. Xerosis can cause fissures and infec-
Skin Reactions tion. EGFR is expressed on the basal ker-
atinocytes and in hair follicles. Cetuximab
Skin toxicity with cetuximab occurs with a high regulates proliferation, differentiation, migra-
frequency (80%). It appears on the face, neck, tion and survival of the keratinocytes; in the
scalp, chest and upper back. Patients generally hair follicles, it seems to regulate the follicular
present a mild or moderate rash, while the homeostasis. The inhibition of EGFR leads to a
Adv Ther (2018) 35:1497–1509 1503

Fig. 2 Numbers of cases of ADRs reported in EudraVigilance and FEARS

skin modification and a follicular degeneration The management consists of preventive

with a consequent inflammation (Fig. 3). activities reported before. Furthermore, it is
Preventive strategies are recommended to important to maintain hygiene, use hydrogels
avoid or to decrease these reactions. In partic- for debridement of crusts and to protect the skin
ular, patients should use warm water, cleanse from the trauma it is necessary to use an
themselves with mild soap or hypoallergenic occlusive dressing. It is possible to use high-
cleaners or shower oils, use emollient-based potency topical steroids for 12 weeks. If there is
creams, avoid sun exposure and use a broad- pain, patients should use analgesics. If there is
spectrum sunscreen (SPF of 30 or more), use systemic inflammatory response syndrome
dermatologist-approved make-up and remove it (SIRS) it is necessary to take systemic antibiotics;
with a gentle, skin-friendly cleanser. Preventive before choosing the antibiotics, a culture
treatment with doxycycline 100 mg or should be done [46, 48].
minocycline 100 mg and hydrocortisone cream
0.1% can reduce the experience of severe skin Hypomagnesaemia
reactions. In Table 2, the grade of reactions and
management are summarized (NHS criteria are Hypomagnesaemia may occur days to months
used) [5, 46–50]. after initiation of treatment and may result
Radiation dermatitis can appear with cetux- from magnesium wasting through urinary
imab plus radiotherapy, usually in the first excretion (Fig. 3). The mechanism of cetux-
weeks of radiotherapy. Radiation dermatitis imab-induced hypomagnesaemia is correlated
presents erythema and dry or wet desquamation with EGFR expression in the kidney. The
and can lead to skin necrosis with ulcerations of cetuximab inhibition of EGFR interferes with
full-thickness skin with bleeding. magnesium transporters in the kidney and
1504 Adv Ther (2018) 35:1497–1509

Fig. 3 Mechanism of cetuximab inducing skin toxicity and hypomagnesaemia

blocks its reabsorption with consequent hypo- of this reaction, patients must receive an anti-
magnesaemia. Hypomagnesaemia can cause histamine and a corticosteroid. Indeed, patients
severe fatigue, irritability, paraesthesias, cramps should be monitored for at least 1 h after infu-
and hypocalcaemia. It is necessary to monitor sion. Grade 1–2 can be managed with a slow
electrolytes during treatment and continue for infusion rate and with a symptomatic treat-
at least 8 weeks following completion of the ment. Grade 3–4 can be managed with the
treatment with cetuximab. Patients can use a interruption of the infusion and with a symp-
supplementation with magnesium to reinte- tomatic treatment. If there are no severe reac-
grate this electrolyte. The loss of magnesium tions, after the resolution of symptoms, it is
can also cause diarrhoea [5, 49]. possible to resume the drug with a slow infusion
and monitoring. Furthermore, patients with a
Infusion-Related Reactions history of allergy to red meat or tick bites or
with IgE antibodies against galactose–alpha-1,3-
Infusion-related reactions are common with galactose, expressed in the Fab portion of
cetuximab (90% on the first infusion), because cetuximab, have a high risk of developing
it is a chimeric antibody, so it can activate the allergic reactions after infusion [5, 49, 51, 52].
human anti-mouse antibody. The symptoms are
flushing, rash, fever, urticaria, chills, bron- Mucositis
chospasm, dyspnoea, nausea, vomiting, blood
pressure changes, angina and myocardial Mucositis occurs in 8% to 23% of patients
infarction. To avoid or decrease the possibility treated with most EGFR inhibitors alone and up
Adv Ther (2018) 35:1497–1509 1505

Table 2 Management of skin rash

Grade Presentation Management
Mild Localized papules, pustules Preventive strategies
Few symptoms (itchiness and Hydrocortisone 1–2.5% cream or clindamycin 1% cream or topical solution
erythema)
No impact on daily activities
No sign of infection
Moderate Generalized papules, pustules Preventive strategies
Mild symptoms (itchiness and Hydrocortisone 2.5% cream or fluocinonide 0.05% cream plus clindamycin
erythema) 1% cream or topical solution
Minimal impact on daily Doxycycline 100 mg or minocycline 100 mg
activates
Severe Generalized papules, pustules Interruption and dose reduction are recommended
Severe symptoms (itchiness and Hydrocortisone 2.5% cream or fluocinonide 0.05% cream plus clindamycin
erythema) 1% cream or topical solution
Significant impact on daily doxycycline 100 mg or minocycline 100 mg
activities Oral corticosteroid
Potential for infection Analgesics for patients with pain
EGFR epidermal grow factor receptor, EGF epidermal grow factor

to 26% in patients on combination COST-EFFECTIVENESS

chemotherapy. To avoid this reaction, patients
OF CETUXIMAB
should avoid cheek or lip biting, avoid mouth
breathing, maintain good oral hygiene, main-
We searched for cost-effectiveness analyses of
tain dentures by brushing daily and soaking in
cetuximab in the literature to understand the
antimicrobial solution or benzydamine for at
cost–benefit ratio of adding cetuximab to
least 30 min/day and by rinsing thoroughly
chemotherapy or using cetuximab in
with physiological saline or sodium bicarbonate
monotherapy. Shankaran et al. [54] reported
after every meal, avoiding spicy and highly
that first-line therapy with cetuximab plus
textured foods, and avoiding highly flavoured
FOLFIRI in patients with KRAS wild-type is more
and alcohol-containing mouthwashes. If there
efficient than bevacizumab plus FOLFIRI (the
is pain, it is possible to use a local or systemic
incremental cost-effectiveness ratio (ICER) of
analgesic (ibuprofen or acetaminophen). In case
cetuximab is $86,487/life year (LY) compared
of moderate or severe mucositis it necessary to
with bevacizumab). The results of this analysis
use topical corticosteroids or anaesthetics. If
impact both clinical practice and policy for
there is a concomitant candidiasis, it is neces-
evaluating which treatment to use in patients
sary to use an antifungal medication, in partic-
with mCRC. The analysis by Park et al. [55]
ular nystatin. Patients with a grade 3 reaction
highlighted the same conclusion as Shankaran
can use clobetasol ointment with systemic ery-
et al. Furthermore, Parker et al. showed the cost-
thromycin or minocycline. If necessary, cetux-
ineffectiveness of third-line treatment of
imab may be temporarily interrupted or a lower
cetuximab plus irinotecan compared with sup-
dosage can be used. Patients with grade 4 may
portive care (definite as per Cunningham et al.
interrupt the treatment [49, 53].
1506 Adv Ther (2018) 35:1497–1509

[56]) in patients with mCRC. The economic evaluate the relevance of BRAF mutation. A
probabilistic sensitivity analyses by Huxley et al. recent analysis showed that cetuximab plus
reported that cetuximab plus chemotherapy FOLFIRI is more cost-effective than beva-
(FOLFIRI or FOLFOX) in patients with RAS wild- cizumab plus FOLFIRI in patients with KRAS
type mCRC is more effective than chemother- wild-type. On the contrary, use of cetuximab in
apy alone, but that cetuximab is unlikely to be monotherapy was not cost-effective in the
more cost-effective in accordance with UK cri- treatment of mCRC [58].
teria than chemotherapy alone (FOLFOX or
FOLFIRI) because of its high cost compared with
the QALY gained (* £30,000 per QALY gained) ACKNOWLEDGEMENTS
[57].
Monotherapy with cetuximab demonstrated
clinically and more statistically significant Funding. No sources of funding were used in
improvement than treatment with supportive the preparation of this review. The article pro-
care alone in patients with RAS wild-type mCRC cessing charges were funded by the author.
that progressed after chemotherapy [29]. The
cost-effectiveness analysis by Carvalho et al. Editorial and Other Assistance. Literature
proved that both cetuximab and panitumumab search strategy was performed by Laura Ciolfi, a
in monotherapy are less cost-effective in RAS biomedical librarian of the Unit of Scientific
wild-type metastatic colorectal cancer com- and Patients’ Library at CRO Aviano IRCCS.
pared with supportive care [58].
Authorship. All named authors meet the
International Committee of Medical Journal
CONCLUSION Editors (ICMJE) criteria for authorship for this
article, take responsibility for the integrity of
The addition of EGFR MAb to either the work as a whole, and have given their
chemotherapy or best supportive care improves approval for this version to be published.
progression-free survival, overall survival and
tumour response rate, but may increase toxicity Disclosures. Giulia Fornasier, Sara Frances-
in people with KRAS exon 2 wild-type or con and Paolo Baldo have nothing to disclose.
extended RAS wild-type metastatic colorectal
cancer. There are improvements in progression- Compliance with Ethics Guidelines. This
free survival (HR 0.70, 95% CI 0.60–0.82), article does not contain any studies with
overall survival (HR 0.88, 95% CI 0.80–0.98) human participants or animals performed by
and response rate (OR 2.41, 95% CI 1.70–3.41). any of the authors.
The ADRs are manageable, and it possible to
reduce the risk of developing severe adverse Data Availability. The datasets during and/
effects with preventive activity. In patients with or analysed during the current study are avail-
RAS wild-type population (no mutations in able from the corresponding author on reason-
KRAS or NRAS), the addition of EGFR MAb able request.
improved progression-free survival (HR 0.60,
95% CI 0.48–0.75), overall survival (HR 0.77,
95% CI 0.67–0.88) and response rate (OR 4.28,
95% CI 2.61–7.03) [36, 59]. The most common REFERENCES
ADR reported with cetuximab is skin toxicity,
and the preventive strategies are recommended 1. Lenz H-J. Anti-EGFR mechanism of action: antitu-
mor effect and underlying cause of adverse events.
to avoid or to decrease this reaction. The
Oncol (Williston Park). 2006;20:5–13.
investigation of BRAF mutation may be signifi-
cant to predict the lack of response to EGFR 2. ERBITUX (cetuximab). https://www.erbitux.com/.
inhibitors. More studies are necessary to Accessed 3 Apr 2018.
Adv Ther (2018) 35:1497–1509 1507

3. ClinicalTrials.gov. https://clinicaltrials.gov/. Acces- 15. Corcoran RB, André T, Atreya CE, et al. Combined
sed 3 Apr 2018. BRAF, EGFR, and MEK inhibition in patients with
BRAFV600E-mutant colorectal cancer. Cancer Dis-
4. Pirker R, Pereira JR, von Pawel J, et al. EGFR cov. 2018;8:428–43.
expression as a predictor of survival for first-line
chemotherapy plus cetuximab in patients with 16. ASCO Daily News. ASCO Annu. Meet. https://am.
advanced non-small-cell lung cancer: analysis of asco.org/daily-news. Accessed 17 May 2018.
data from the phase 3 FLEX study. Lancet Oncol.
2012;13:33–42. 17. Modest DP, Stintzing S, von Weikersthal LF, et al.
Exploring the effect of primary tumor sidedness on
5. Lenz H-J. Cetuximab in the management of col- therapeutic efficacy across treatment lines in
orectal cancer. Biol Targ Ther. 2007;1:77–91. patients with metastatic colorectal cancer: analysis
of FIRE-3 (AIOKRK0306). Oncotarget.
6. Vincenzi B, Schiavon G, Silletta M, Santini D, 2017;8:105749–60.
Tonini G. The biological properties of cetuximab.
Crit Rev Oncol Hematol. 2008;68:93–106. 18. Cao D-D, Xu H-L, Xu X-M, Ge W. The impact of
primary tumor location on efficacy of cetuximab in
7. European Medicines Agency (EMA)—Erbitux. metastatic colorectal cancer patients with different
http://www.ema.europa.eu/ema/index.jsp?curl=pa Kras status: a systematic review and meta-analysis.
ges/medicines/human/medicines/000558/human_ Oncotarget. 2017;8:53631–41.
med_000769.jsp&mid=WC0b01ac058001d124.
Accessed 3 Apr 2018. 19. Tejpar S, Stintzing S, Ciardiello F, et al. Prognostic
and predictive relevance of primary tumor location
8. I numeri del cancro in Italia—2016, AIRTUM. in patients with RAS wild-type metastatic colorectal
http://www.registri-tumori.it/cms/it/node/4572. cancer: retrospective analyses of the CRYSTAL and
Accessed 3 Apr 2018. FIRE-3 trials. JAMA Oncol. 2017;3:194–201.

9. Global Burden of Disease Cancer Collaboration, 20. Holch JW, Ricard I, Stintzing S, Modest DP, Heine-
Fitzmaurice C, Allen C, et al. Global, regional, and mann V. The relevance of primary tumour location
national cancer incidence, mortality, years of life in patients with metastatic colorectal cancer: a
lost, years lived with disability, and disability-ad- meta-analysis of first-line clinical trials. Eur J Can-
justed life-years for 32 cancer groups, 1990 to 2015: cer. 1990;2017(70):87–98.
a systematic analysis for the global burden of dis-
ease study. JAMA Oncol. 2017;3:524–48. 21. Missiaglia E, Jacobs B, D’Ario G, et al. Distal and
proximal colon cancers differ in terms of molecular,
10. De Roock W, Claes B, Bernasconi D, et al. Effects of pathological, and clinical features. Ann Oncol.
KRAS, BRAF, NRAS, and PIK3CA mutations on the 2014;25:1995–2001.
efficacy of cetuximab plus chemotherapy in
chemotherapy-refractory metastatic colorectal can- 22. Van Cutsem E, Köhne C-H, Láng I, et al. Cetuximab
cer: a retrospective consortium analysis. Lancet plus irinotecan, fluorouracil, and leucovorin as first-
Oncol. 2010;11:753–62. line treatment for metastatic colorectal cancer:
updated analysis of overall survival according to
11. Van Cutsem E, Köhne C-H, Hitre E, et al. Cetux- tumor KRAS and BRAF mutation status. J Clin
imab and chemotherapy as initial treatment for Oncol. 2011;29:2011–9.
metastatic colorectal cancer. N Engl J Med.
2009;360:1408–17. 23. Van Cutsem E, Lenz H-J, Köhne C-H, et al. Fluo-
rouracil, leucovorin, and irinotecan plus cetuximab
12. Karapetis CS, Khambata-Ford S, Jonker DJ, et al. treatment and RAS mutations in colorectal cancer.
K-ras mutations and benefit from cetuximab in J Clin Oncol. 2015;33:692–700.
advanced colorectal cancer. N Engl J Med.
2008;359:1757–65. 24. van Brummelen EMJ, de Boer A, Beijnen JH,
Schellens JHM. BRAF mutations as predictive bio-
13. Sorich MJ, Wiese MD, Rowland A, Kichenadasse G, marker for response to anti-EGFR monoclonal
McKinnon RA, Karapetis CS. Extended RAS muta- antibodies. Oncologist. 2017;22:864–72.
tions and anti-EGFR monoclonal antibody survival
benefit in metastatic colorectal cancer: a meta- 25. Piessevaux H, Buyse M, Schlichting M, et al. Use of
analysis of randomized, controlled trials. Ann early tumor shrinkage to predict long-term out-
Oncol. 2015;26:13–21. come in metastatic colorectal cancer treated with
cetuximab. J Clin Oncol. 2013;31:3764–75.
14. Zhao B, Wang L, Qiu H, et al. Mechanisms of
resistance to anti-EGFR therapy in colorectal can- 26. Heinemann V, von Weikersthal LF, Decker T, et al.
cer. Oncotarget. 2016;8:3980–4000. FOLFIRI plus cetuximab versus FOLFIRI plus
1508 Adv Ther (2018) 35:1497–1509

bevacizumab as first-line treatment for patients 37. Guren TK, Thomsen M, Kure EH, et al. Cetuximab
with metastatic colorectal cancer (FIRE-3): a ran- in treatment of metastatic colorectal cancer: final
domised, open-label, phase 3 trial. Lancet Oncol. survival analyses and extended RAS data from the
2014;15:1065–75. NORDIC-VII study. Br J Cancer. 2017;116:1271–8.

27. Venook AP, Niedzwiecki D, Lenz H-J, et al. Effect of 38. Price TJ, Peeters M, Kim TW, et al. Panitumumab
first-line chemotherapy combined with cetuximab versus cetuximab in patients with chemotherapy-
or bevacizumab on overall survival in patients with refractory wild-type KRAS exon 2 metastatic col-
KRAS wild-type advanced or metastatic colorectal orectal cancer (ASPECCT): a randomised, multi-
cancer: a randomized clinical trial. JAMA. centre, open-label, non-inferiority phase 3 study.
2017;317:2392–401. Lancet Oncol. 2014;15:569–79.

28. Tveit KM, Guren T, Glimelius B, et al. Phase III trial 39. Moiseyenko VM, Moiseyenko FV, Yanus GA, et al.
of cetuximab with continuous or intermittent flu- First-line cetuximab monotherapy in KRAS/NRAS/
orouracil, leucovorin, and oxaliplatin (Nordic BRAF mutation-negative colorectal cancer patients.
FLOX) versus FLOX alone in first-line treatment of Clin Drug Investig. 2018;38:553–62.
metastatic colorectal cancer: the NORDIC-VII
study. J Clin Oncol. 2012;30:1755–62. 40. Ursem C, Atreya CE, Van Loon K. Emerging treat-
ment options for BRAF-mutant colorectal cancer.
29. Cunningham D, Humblet Y, Siena S, et al. Cetux- Gastrointest Cancer Targ Ther. 2018;8:13–23.
imab monotherapy and cetuximab plus irinotecan
in irinotecan-refractory metastatic colorectal can- 41. Lam M, Pant S, Yap TA. Combination drug devel-
cer. N Engl J Med. 2004;351:337–45. opment in BRAF mutant colorectal cancer. Onco-
science. 2018;5:51–3.
30. Maughan TS, Adams RA, Smith CG, et al. Addition
of cetuximab to oxaliplatin-based first-line combi- 42. Van Cutsem E, Cuyle P-J, Huijberts S, et al. BEACON
nation chemotherapy for treatment of advanced CRC study safety lead-in (SLI) in patients with
colorectal cancer: results of the randomised phase 3 BRAFV600E metastatic colorectal cancer (mCRC):
MRC COIN trial. Lancet. 2011;377:2103–14. efficacy and tumor markers. J Clin Oncol.
2018;36:627.
31. Sotelo MJ, Garcı́a-Paredes B, Aguado C, Sastre J,
Dı́az-Rubio E. Role of cetuximab in first-line treat- 43. Array BioPharma. Array BioPharma receives FDA
ment of metastatic colorectal cancer. World J Gas- Breakthrough Therapy Designation for Braftovi in
troenterol. 2014;20:4208–19. combination with Mektovi and cetuximab for BRAF
V600E-mutant metastatic colorectal cancer. http://
32. Chan DL, Pavlakis N, Shapiro J, et al. Does the www.arraybiopharma.com/. Accessed 24 Aug 2018.
chemotherapy backbone impact on the efficacy of
targeted agents in metastatic colorectal cancer? A 44. EudraVigilance database. https://bi.ema.europa.eu/
systematic review and meta-analysis of the litera- analyticsSOAP/saw.dll?PortalPages. Accessed 29
ture. PLoS One. 2015;10:e0135599. May 2018.

33. Kotake M, Aoyama T, Munemoto Y, et al. Multi- 45. FDA Adverse Events Reporting System (FAERS)
center phase II study of infusional 5-fluorouracil (5- public dashboard—FDA adverse events reporting
FU), leucovorin, and oxaliplatin, plus biweekly system (FAERS) public dashboard. https://fis.fda.
cetuximab as first-line treatment in patients with gov/sense/app/777e9f4d-0cf8-448e-8068-
metastatic colorectal cancer (CELINE trial). Oncol f564c31baa25/sheet/45beeb74-30ab-46be-8267-
Lett. 2017;13:747–53. 5756582633b4/state/analysis. Accessed 28 May
2018.
34. Bokemeyer C, Köhne C-H, Ciardiello F, et al. FOL-
FOX4 plus cetuximab treatment and RAS mutations 46. Pinto C, Barone CA, Girolomoni G, et al. Manage-
in colorectal cancer. Eur J Cancer. ment of skin toxicity associated with cetuximab
1990;2015(51):1243–52. treatment in combination with chemotherapy or
radiotherapy. Oncologist. 2011;16:228–38.
35. Jonker DJ, O’Callaghan CJ, Karapetis CS, et al.
Cetuximab for the treatment of colorectal cancer. 47. Potthoff K, Hofheinz R, Hassel JC, et al. Interdisci-
N Engl J Med. 2007;357:2040–8. plinary management of EGFR-inhibitor-induced
skin reactions: a German expert opinion. Ann
36. Van Cutsem E, Cervantes A, Nordlinger B, Arnold Oncol. 2011;22:524–35.
D, ESMO Guidelines Working Group. Metastatic
colorectal cancer: ESMO Clinical Practice Guideli- 48. Lacouture ME, Anadkat MJ, Bensadoun R-J, et al.
nes for diagnosis, treatment and follow-up. Ann Clinical practice guidelines for the prevention and
Oncol. 2014;25(Suppl 3):iii1–9. treatment of EGFR inhibitor-associated
Adv Ther (2018) 35:1497–1509 1509

dermatologic toxicities. Support Care Cancer. treatment for metastatic colorectal cancer in the
2011;19:1079–95. United States. Am J Clin Oncol. 2018;41:65–72.

49. Hofheinz R-D, Segaert S, Safont MJ, Demonty G, 55. Park T, Choi C, Choi Y, Suh D-C. Cost-effectiveness
Prenen H. Management of adverse events during of cetuximab for colorectal cancer. Expert Rev
treatment of gastrointestinal cancers with epider- Pharmacoecon Outcomes Res. 2016;16:667–77.
mal growth factor inhibitors. Crit Rev Oncol
Hematol. 2017;114:102–13. 56. Cunningham D, Pyrhönen S, James RD, Punt CJ,
Hickish TF, Heikkila R, et al. Randomised trial of
50. NHS. Guidelines for cetuximab induced rashes. irinotecan plus supportive care versus supportive
NHS. February 2015. (http://www.kentmedwaycanc care alone after fluorouracil failure for patients with
erguide.nhs.uk/EasySiteWeb/GatewayLink.aspx?al metastatic colorectal cancer. Lancet. 1998;
Id=419417). 352:1413–8.

51. Roselló S, Blasco I, Garcı́a Fabregat L, Cervantes A, 57. Huxley N, Crathorne L, Varley-Campbell J, Tikho-
Jordan K, ESMO Guidelines Committee. Manage- nova I, Snowsill T, Briscoe S, et al. The clinical
ment of infusion reactions to systemic anticancer effectiveness and cost-effectiveness of cetuximab
therapy: ESMO Clinical Practice Guidelines. Ann (review of technology appraisal no. 176) and pani-
Oncol. 2017;28:100–18. tumumab (partial review of technology appraisal
no. 240) for previously untreated metastatic col-
52. Chung CH, Mirakhur B, Chan E, et al. Cetuximab- orectal cancer: a systematic review and economic
induced anaphylaxis and IgE specific for galactose- evaluation. Health Technol Assess. 2017;21:1–294.
alpha-1,3-galactose. N Engl J Med. 2008;358
:1109–17. 58. Carvalho AC, Leal F, Sasse AD. Cost-effectiveness of
cetuximab and panitumumab for chemotherapy-
53. Peterson DE, Boers-Doets CB, Bensadoun RJ, refractory metastatic colorectal cancer. PLoS One.
Herrstedt J, ESMO Guidelines Committee. Man- 2017;12:e0175409.
agement of oral and gastrointestinal mucosal
injury: ESMO clinical practice guidelines for diag- 59. Chan DLH, Segelov E, Wong RS, et al. Epidermal
nosis, treatment, and follow-up. Ann Oncol. growth factor receptor (EGFR) inhibitors for meta-
2015;26(Suppl 5):v139–51. static colorectal cancer. Cochrane Database Syst
Rev. 2017;6:CD007047.
54. Shankaran V, Ortendahl JD, Purdum AG, et al.
Cost-effectiveness of cetuximab as first-line