# Update in Antiepidermal Growth Factor Receptor Therapy in the Management of Metastatic Colorectal Cancer

Authors: Herbert H. Loong; Brigette B. Ma; Anthony T. C. Chan
Journal: Journal of Oncology
 (2009)

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## Abstract

The approval of anti-epidermal growth factor receptor (EGFR) monoclonal antibodies in the treatment of metastatic colorectal cancer (CRC) has expanded the armamentarium against this disease.
This paper will review the historical progress and recent clinical developments of anti-EGFR therapies in the treatment of metastatic CRC. Novel strategies of targeting the EGFR pathway to improve efficacy as well as ongoing research in identifying specific molecular predictors of response will be discussed.


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## Body

## 1. Introduction

A decade ago, the
systemic treatment of colorectal cancer (CRC)
consisted only of fluoropyrimidine-based chemotherapy administered alone or in
combination with either oxaliplatin or irinotecan in an empirical fashion,
guided by serial measurements of radiological response. Owing to the remarkable
advances in our understanding of the molecular mechanisms of carcinogenesis,
target-based therapies are now commonly used as in the treatment of many types
of cancer, including CRC. Cetuximab
and panitumumab are monoclonal antibody against the epidermal growth factor
receptor (EGFR) that has been approved for the treatment of patients with metastatic CRC [1, 2]. The optimal
clinical application of anti-EGFR agents in the management of CRC patients and the identification of predictive
markers are the main focus of research in recent years. This article will
concentrate on the developments and controversies of anti-EGFR therapy in the
management of CRC.


## 2. EGFR as a Target in Colorectal Cancer

The concept of
manipulation of EGFR in the treatment of epithelial malignancies such as
colorectal and lung cancers has actually been envisaged since the mid 1960s [1, 2]. It was during that period that the EGFR protein was first isolated,
characterized, and recognized as a potential therapeutic target. Throughout the
last 40 years, advances made in basic and clinical research have enhanced our
understanding of this target, and many different classes of EGFR inhibitors are
now at various stages of clinical development.EGFR is a 170 kD member of the ErbB receptor tyrosine
kinase family of signaling proteins, and its ligands include epidermal growth
factor (EGF), transforming growth factor-α  (TGF-α), heparin-binding EGF
(HB-EGF), and amphiregulin (AR). Ligand binding, dimerization, and
phosphorylation of EGFR lead to activation of downstream proteins, leading to a
cascade mediating cell growth and survival [3]. Two different anti-EGFR
strategies are currently available in the therapeutic armamentarium: (1) monoclonal
antibodies that prevent EGFR ligand binding and (2) tyrosine-kinase inhibitors (TKIs) that block phosphorylation of the intracellular tyrosine kinase component
of the EGFR. Both of these strategies dampen signal transduction through some
of the downstream pathways such as RAS/RAF/mitogen-activated
protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)-AKT cascades, thus
limiting cell growth, proliferation, invasion, angiogenesis, and metastasis [3, 4].


## 3. Anti-EGFR Monoclonal Antibodies

Cetuximab (chimeric
IgG1 monoclonal antibody) and panitumumab (fully humanized IgG2 monoclonal
antibody) are two anti-EGFR monoclonal antibodies currently approved in the
treatment of metastatic CRC. The
structural difference between the IgG-1-based cetuximab and IgG-2-based
panitumumab is believed to have implications on their mechanisms of action.
Preclinical studies have suggested that the cetuximab molecule is able to
induce antibody-dependent cell-mediated cytotoxicity (ADCC)
[4, 5], where natural killer cells, monocytes, and eosinophils are recruited to
lyse the targeted cells (i.e., tumor cells). Being a chimeric antibody,
cetuximab is also associated with a slightly higher incidence of
hypersensitivity and infusional reactions when compared with fully humanized panitumumab
(see Table 1).Table 1
Comparison between cetuximab and panitumumab.
CetuximabPanitumumabStructureChimeric IgG-1,Fully humanized: IgG-230% murineHypersensitivity reaction3%1%Half life5 days7.5 daysTreatment schedule1-2 weekly2-weeklyAntibody-dependent cellYesNo ADCC reportedmediated cytotoxicityFc Domain(ADCC)of IgG-1


### 3.1. Cetuximab

Pharmacokinetics
studies have shown that cetuximab’s binding affinity for EGFR was shown to be
one log higher than its natural ligand and its mechanism of action is thought
to be competitive inhibition of ligand binding to EGFR. Cetuximab alone
resulted in in vitro and in vivo growth inhibition in multiple
tumor types, including CRCs [4, 5]. Cetuximab was able to enhance the
antitumor effect of irinotecan, as evident from an experiment on the HT-29 CRC xenograft model, where cetuximab and irinotecan
given in combination resulted in a greater degree of tumor growth delay than
when either agent was given alone [5]. Furthermore, cetuximab has been shown to
overcome acquired resistance against irinotecan in vivo. This was shown as an experiment  where the addition of cetuximab resulted in shrinkage of tumor
xenografts which were otherwise progressing after previous treatment with irinotecan.The landmark BOND trial [2] randomized 329 patients with
metastatic CRC which were EGFR-positive
and refractory to irinotecan, to either cetuximab alone  or in combination with
irinotecan in a 2 : 1 ratio. EGFR positivity was defined as 1+ staining by
immunohistochemistry, and “irinotecan-refractory” status was defined as disease
progression on or within 3 months of irinotecan-based therapy. Cross-over was
allowed from the monotherapy arm to the combination arm upon disease
progression. Objective response rate (ORR) was significantly in favor of the
combination arm (22.9% versus 10.8%, P =   .007). Fifty-six patients who were
randomized to cetuximab alone eventually crossed over to the combination arm,
while 3.6% and 35.7% of these patients achieved partial response and stable
disease,  respectively. This study led to the US Food Drug Administration (FDA)
approval of cetuximab in patients with irinotecan-refractory meta static CRC. Subsequently, the NCIC-CO.17 study randomized
patients who had failed at least 2 lines of prior therapies, to either
supportive care or cetuximab alone [6]. In this study where no cross-over was
allowed, there was a statistically significant advantage in median overall
survival (OS) favoring the cetuximab arm (6.1 months) compared with supportive
care (4.6 months). Partial responses occurred in 23 patients (8.0%) in the cetuximab
group but none in the group assigned to supportive care alone (P < .001).Cetuximab has also
been investigated in the first-line setting. The “CRYSTAL” [7] study is a
multicentre phase III trial which
randomized more than 1000 patients with metastatic CRC,
to either the “FOLFIRI”
regimen alone  (Irinotecan, infusional 5-fluorouracil and leucovorin in a 2-weekly schedule), or in combination with cetuximab at a weekly schedule. The
primary endpoint (progression-free survival (PFS)) was met in the study, where
patients randomized to the combination arm had a significantly longer progression-free
survival (8.9 months versus 8.0 months; P = .036) than the chemotherapy alone
arm, but there was no difference in overall survival in the initial
intention-to-treat analysis. Response rate was also significantly better in the
combination arm (46.9% versus 38.7%; P = .005), resulting in a larger number of
patients being down staged enough to undergo resection of liver metastases
(9.8% versus 4.5%). The “OPUS”
study [8] is another first-line randomized phase II study, which randomized 337
chemotherapy-nave patients with metastatic CRC,
to either the FOLFOX-4 regimen or in combination with cetuximab in a 1:1
fashion. The overall RR was 45.6% in the combination arm versus 35.7% in
FOLFOX-4 alone arm. In the “ACROBAT” study, Tabernero et al. reported on 42
patients who were treated with FOLFOX-4 plus cetuximab, showing a confirmed ORR
of 81% [9]. Encouragingly, 10 patients (23%) underwent resection of previously
unresectable metastases, 8 of them had liver metastases. The resection with
curative intent rate of 23% achieved in this study is therefore comparable with
the highest reported for unselected patients.


### 3.2. Panitumumab

The US FDA approval
of panitumumab was based on a pivotal multinational phase III study that involved over 400 patients [10].
This study compared panitumumab versus best supportive care (BSC), allowing cross-over from the BSC arm to panitumumab upon disease progression.
The median PFS time was 8 weeks for panitumumab and 7.3 weeks for BSC. After a 12-month followup period, response rates
were 10% for panitumumab and 0% for BSC (P <  .0001). The lack of difference in OS (hazard ratio HR 1.00; 95%
confidence interval, CI 0.82 to 1.22) maybe attributed to the cross-over
design, where 76% of patients in the BSC arm subsequently received panitumumab. As expected with anti-EGFR therapies,
skin-related toxicities occurred in 90% of patients in the panitumumab group
but no patients had grade 3 or 4 infusional reactions.


### 4. EGFR Tyrosine Kinase Inhibitors

Although not approved for the treatment of CRC, small molecule inhibitors of the EGFR tyrosine
kinase (TKI) have been shown to have meaningful activity in different tumor
types such as lung and pancreatic cancer. In contrast to EGFR monoclonal
antibodies, the site of action of these drugs is  intracellular at the
ATP-binding site of the EGFR TK domain. Compared with monoclonal antibodies,
TKIs may potentially inhibit multiple targets and tend not to induce receptor
downregulation.


#### 4.1. Gefitinib

Gefitinib is a
low-molecular-weight competitive inhibitor of ATP-binding pocket of the EGFR TK
domain [11], which is approved for the treatment of nonsmall cell lung cancer.
Clinical trials of gefitinib as a single agent in CRC reported no objective tumor responses [12–14] however, a sizable proportion of
patients did have disease stabilization. A  phase II trial which compared the
250 mg versus a 500 mg daily dosing of gefitinib [15], reported 1 partial
response in a patient who received the 500 mg dose. Paired biopsies pre- and
posttreatment biopsies performed in 28 patients showed that 84% had no change
or increase in the expression level of phosphorylated EGFR, MAP kinase, and Ki67 after treatment. Gefitinib and
chemotherapy in combination have also been investigated in several trials, where
the response rates seemed to be superior to the historically reported rates of
chemotherapy alone [16–18]. However, there were significantly more toxicities
particularly with respect to neutropenia and diarrhea with the combination.
Studies combining gefitinib with irinotecan also resulted in greater toxicity,
with some trials requiring early termination.


#### 4.2. Erlotinib

Erlotinib has also
been studied in advanced CRC.
There have been mixed reports of some clinical activity when used as a single
agent. As with gefitinib, erlotinib produced a higher response rate when
combined with chemotherapy. High incidence of toxicity was noted when given in
combination with systemic chemotherapy, especially in two trials where
erlotinib was given in combination with FOLFOX and bevacizumab [19, 20], with
the latter trial having prematurely closed due to toxicity.


#### 5. Incidence and Implications of Skin Rash

Anti-EGFR monoclonal
antibodies and EGFR TKIs are associated with a distinctive skin rash. The rash
is characterized histologically as a neutrophilic infiltrate in perifollicular
areas within the basal layer of the skin, which is different from that seen in
typical acne. Skin toxicity is generally observed within 2 to 3 weeks after
the start of treatment and gradually resolves in most patients, even when anti-EGFR
treatment is continued. In the BOND study, the most frequently observed adverse
event to cetuximab was the skin rash, and in the panitumumab study, Hecht et
al. [21] reported a 95% incidence of acneiform skin rash of any grade. Grade 3 rash
occurred in 3% of patients and none experienced grade 4 skin toxicities. An
association between the severity of acneiform rash and efficacy to cetuximab
has been well described. Retrospective analysis of the BOND data showed a clear
association between higher grades of skin reaction with RR and time to
progression (TTP) [2]. This
association is also seen with panitumumab [10] and seems to hold true in the
treatment of tumors of other sites with this class of agents.The “EVEREST” study
[22] was a phase I/II dose-escalation study, where patients who were receiving
cetuximab were randomized at 22 days, to either standard dose of weekly
(250 mg/m2/week) cetuximab  or an escalating dose of cetuximab until the
development of grade 3 toxicity, with a maximum ceiling dose of 500 mg/m2/week.
Skin and tumor biopsies were obtained. Preliminary report suggested that the
PFS in standard-dose arm was 3.9 months  and 4.8 months in the dose-escalated
arm. Dose-related increases in pharmacokinetic parameters (e.g.,  Cmax, AUC) were
observed in the escalated arm. The authors concluded that cetuximab dose
escalation up to 500 mg/m2/w may improve ORR in patients who experienced no or
slight skin reactions on standard-dose cetuximab.


#### 6. Combining Targeted Therapies in Colorectal Cancer

Combinations of
multiple targeted agents with or without the additional of chemotherapy have
also been investigated. The BOND-2 trial [23] randomized irinotecan-refractory
patients to either 2 drugs (bevacizumab and cetuximab) or 3 drugs (bevacizumab,
cetuximab and irinotecan). The results were encouraging, with the 3-drug arm
resulting in a better TTP and ORR
than the 2-drug arm. This study also showed for the first time that monoclonal
antibodies in combination could induce an ORR of 20% in the absence of
chemotherapy. Nonstatistical comparison with result of the BOND-1 study
suggested that bevacizumab may enhance the effects of irinotecan-cetuximab
combination, with an ORR of 37% as compared to 23% reported for the
cetuximab/irinotecan arm [2, 23] (see Table 2). Subsequent to the
BOND-2 study, 3 other randomized trials have been reported on the feasibility
of combining monoclonal antibodies in the treatment of CRC.
The PACCE study [24] randomized 824 treatment-nave patients with metastatic CRC to oxaliplatin-based chemotherapy plus
bevacizumab, with or without panitumumab, and 230 patients to irinotecan-based
chemotherapy plus bevacizumab with or without panitumumab. The study was
terminated at a preplanned interim analysis after 231 events were reported in
patients who received oxaliplatin-based therapy, where a statistically
significant increase in PFS was reported in the arm without panitumumab. In
contrast, the Dutch CAIRO-2 trial [25] has a similar study design to the PACCE
trial and involved over 700 patients. Patients received capecitabine,
oxaliplatin, and bevacizumab with or without additional cetuximab. As expected,
preliminary result reported a significantly higher incidence of grade 3-4 skin
rash in the cetuximab-containing arm, without a statistically significant
difference in mortality in either arm. The CALGB/SWOG 80405 intergroup trial
was a 3-arm study, which randomized patients with metastatic CRC to chemotherapy and cetuximab, chemotherapy and
bevacizumab, or chemotherapy plus cetuximab and bevacizumab. This study has
been suspended following a decision by the CALGB Data and Safety Monitoring
Board as from June 2008, pending a protocol revision in view of the data on
KRAS mutation (see below) [26]. The reason why the PACCE study failed to
demonstrate a survival advantage in the panitumumab-bevacizumab arm remains
unclear. It is possible that the dose of the antibodies was inappropriate
leading to excessive toxicity and reduced efficacy. Patient selection has also
proven critical in the optimal use of anti-EGFR antibodies as the use of EGFR
staining to predict response and outcome has been severely challenged. Thus, a
combination approach of targeted agents in metastatic CRC remains controversial and it is the consensus among gastrointestinal
oncologists that such an approach remains experimental.Table 2
Nonstatistical comparison of the results of the
BOND-2 [23] and BOND-1 study [1].
BOND2BOND2BOND1BOND1Cetuximab, irinotecan, and bevacizumabCetuximab and bevacizumabCetuximab and irinotecanCetuximab aloneNo. of Patients4340218111Prior treatment with oxaliplatin (%)87896264Response rates (%)37202311Time to progression (months)7.34.94.11.5Median overall survival (months)14.511.48.66.9


#### 7. EGFR Expression in Colorectal Cancer

EGFR as determined
by immunohistochemical (IHC) methods was the first biomarker investigated as a
potential predictor of response. It is overexpressed in over 80% of colorectal
cancers [27]. However, EGFR expression as measured by immunohistochemistry does
not predict clinical benefit [28, 29]. Initial observations in a small
retrospective series by Lenz et al. [30] noted that more than 20% of
EGFR-negative patients developed major objective responses. An extensive
retrospective analysis was reported in 2005 by Chung et al. [29]. They reported
a response rate of 25% in EGFR-negative patients (4 out of 16) given cetuximab
and irinotecan. This was comparable and indistinguishable from the response
rate of 23% seen in two separate clinical trials with EGFR-positive patients
[1, 31]. Given this data, immunohistochemical (IHC) demonstration of EGFR
expression is no longer required before starting cetuximab therapy in practice.
Similarly, in the  phase II trial, the response to treatment with panitumumab in
patients with metastatic CRC was
similar, irrespective of the level of EGFR protein expression assessed by IHC
analysis [32].


#### 8. Potential Predictors of Response to Anti-EGFR Therapy

##### 8.1. Activating EGFR Gene Mutations

There has been much
interest in determining whether EGFR gene mutations may play a role in
affecting response to cetuximab or panitumumab. Previous research in nonsmall
cell lung cancer [33] has shown that EGFR TK mutations predict benefit from
EGFR TKIs. However, several retrospective studies on tumor biopsies and cell
lines found that EGFR gene mutations in CRC are extremely rare [34, 35]. No significantly different gene mutations were
found between responders and nonresponders to treatment.


##### 8.2. EGFR Gene Amplification

It has been hypothesized that
DNA is a more stable molecule than
a protein and thus EGFR gene copy number maybe more accurate reflection of the
EGFR status than IHC expression [36]. In a cohort of patients treated with
cetuximab or panitumumab, EGFR gene amplification with increased copy number
has been shown to significantly correlate with objective response to treatment
[36]. This raises the possibility that patients with high EGFR copy number may
be more likely to respond to treatment with anti-EGFR therapies.


##### 8.3. KRAS Gene Mutation

KRAS is a guanosine
triphosphate (GTP)-binding protein that acts as a critical on-off switch in
cellular growth and survival pathways. It plays a key role in the RAS/MAPK signally pathway located downstream of
many growth factor receptors, including EGFR, and involved in carcinogenesis.
Mutations of KRAS that result in the constitutive activation of MAPK pathway
downstream occurs in about 40% of colorectal cancers [37]. A retrospective
analysis reported by Lièvre et al. [38] analyzed tumor samples from 30 patients
treated with cetuximab. A KRAS mutation was found in 13 tumors (43%) and was
significantly associated with absence of response to cetuximab. None of the
patients with response to cetuximab harbored a KRAS mutation. The overall
survival of patients without KRAS mutation was significantly higher compared
with those patients with a mutated tumor (P = .016; median survival 16.3 versus
6.9 months). An increase in EGFR copy number was also significantly associated
with objective tumor response.It has been hypothesized that
irrespective of the level of EGFR expression, the presence of a KRAS mutation
is associated with a constitutive activation of the RAS/MAPK
pathway, leading to cell proliferation which cannot be significantly inhibited
by cetuximab. KRAS mutations have also been implicated in resistance against
EGFR TKIs in lung adenocarcinomas [39].Large scale retrospective
reviews retrieved archived tumor tissue from prior cetuximab and panitumumab
trials. KRAS mutation analysis was performed tested in tumor samples collected
from over 1000 participants of the “CRYSTAL” [8], “OPUS”
[40], NCIC-CO.17 trial [41] and panitumumab trials [42]. Beneficial effects of
anti-EGFR antibodies were limited to a subgroup of patients with wild-type KRAS
tumors. This has led to the recommendation that all patients with advanced CRC who are being considered for cetuximab or
panitumumab should undergo KRAS testing, and if the cancer bears a mutated KRAS
gene, they should not receive an antibody that targets EGFR.


##### 9. Conclusion

Throughout the last decade,
significant advancement in our understanding of the molecular mechanisms of
metastatic CRC has been made.
Anti-EGFR monoclonal antibodies approved for use in the metastatic setting have
broadened the therapeutic armamentarium in the treatment of metastatic CRC. The most effective sequence and combinations
of anti-EGFR therapy with chemotherapy and, or bevacizumab in order to achieve
cytotoxic potentiation with limited toxicity need to be addressed. Advances
made in the identification of predictive biomarkers such as KRAS mutations
allow us to select distinct groups of patients who are most likely to benefit
from cetuximab therapy.


## 3.1. Cetuximab

Pharmacokinetics
studies have shown that cetuximab’s binding affinity for EGFR was shown to be
one log higher than its natural ligand and its mechanism of action is thought
to be competitive inhibition of ligand binding to EGFR. Cetuximab alone
resulted in in vitro and in vivo growth inhibition in multiple
tumor types, including CRCs [4, 5]. Cetuximab was able to enhance the
antitumor effect of irinotecan, as evident from an experiment on the HT-29 CRC xenograft model, where cetuximab and irinotecan
given in combination resulted in a greater degree of tumor growth delay than
when either agent was given alone [5]. Furthermore, cetuximab has been shown to
overcome acquired resistance against irinotecan in vivo. This was shown as an experiment  where the addition of cetuximab resulted in shrinkage of tumor
xenografts which were otherwise progressing after previous treatment with irinotecan.The landmark BOND trial [2] randomized 329 patients with
metastatic CRC which were EGFR-positive
and refractory to irinotecan, to either cetuximab alone  or in combination with
irinotecan in a 2 : 1 ratio. EGFR positivity was defined as 1+ staining by
immunohistochemistry, and “irinotecan-refractory” status was defined as disease
progression on or within 3 months of irinotecan-based therapy. Cross-over was
allowed from the monotherapy arm to the combination arm upon disease
progression. Objective response rate (ORR) was significantly in favor of the
combination arm (22.9% versus 10.8%, P =   .007). Fifty-six patients who were
randomized to cetuximab alone eventually crossed over to the combination arm,
while 3.6% and 35.7% of these patients achieved partial response and stable
disease,  respectively. This study led to the US Food Drug Administration (FDA)
approval of cetuximab in patients with irinotecan-refractory meta static CRC. Subsequently, the NCIC-CO.17 study randomized
patients who had failed at least 2 lines of prior therapies, to either
supportive care or cetuximab alone [6]. In this study where no cross-over was
allowed, there was a statistically significant advantage in median overall
survival (OS) favoring the cetuximab arm (6.1 months) compared with supportive
care (4.6 months). Partial responses occurred in 23 patients (8.0%) in the cetuximab
group but none in the group assigned to supportive care alone (P < .001).Cetuximab has also
been investigated in the first-line setting. The “CRYSTAL” [7] study is a
multicentre phase III trial which
randomized more than 1000 patients with metastatic CRC,
to either the “FOLFIRI”
regimen alone  (Irinotecan, infusional 5-fluorouracil and leucovorin in a 2-weekly schedule), or in combination with cetuximab at a weekly schedule. The
primary endpoint (progression-free survival (PFS)) was met in the study, where
patients randomized to the combination arm had a significantly longer progression-free
survival (8.9 months versus 8.0 months; P = .036) than the chemotherapy alone
arm, but there was no difference in overall survival in the initial
intention-to-treat analysis. Response rate was also significantly better in the
combination arm (46.9% versus 38.7%; P = .005), resulting in a larger number of
patients being down staged enough to undergo resection of liver metastases
(9.8% versus 4.5%). The “OPUS”
study [8] is another first-line randomized phase II study, which randomized 337
chemotherapy-nave patients with metastatic CRC,
to either the FOLFOX-4 regimen or in combination with cetuximab in a 1:1
fashion. The overall RR was 45.6% in the combination arm versus 35.7% in
FOLFOX-4 alone arm. In the “ACROBAT” study, Tabernero et al. reported on 42
patients who were treated with FOLFOX-4 plus cetuximab, showing a confirmed ORR
of 81% [9]. Encouragingly, 10 patients (23%) underwent resection of previously
unresectable metastases, 8 of them had liver metastases. The resection with
curative intent rate of 23% achieved in this study is therefore comparable with
the highest reported for unselected patients.


## 3.2. Panitumumab

The US FDA approval
of panitumumab was based on a pivotal multinational phase III study that involved over 400 patients [10].
This study compared panitumumab versus best supportive care (BSC), allowing cross-over from the BSC arm to panitumumab upon disease progression.
The median PFS time was 8 weeks for panitumumab and 7.3 weeks for BSC. After a 12-month followup period, response rates
were 10% for panitumumab and 0% for BSC (P <  .0001). The lack of difference in OS (hazard ratio HR 1.00; 95%
confidence interval, CI 0.82 to 1.22) maybe attributed to the cross-over
design, where 76% of patients in the BSC arm subsequently received panitumumab. As expected with anti-EGFR therapies,
skin-related toxicities occurred in 90% of patients in the panitumumab group
but no patients had grade 3 or 4 infusional reactions.


## 4. EGFR Tyrosine Kinase Inhibitors

Although not approved for the treatment of CRC, small molecule inhibitors of the EGFR tyrosine
kinase (TKI) have been shown to have meaningful activity in different tumor
types such as lung and pancreatic cancer. In contrast to EGFR monoclonal
antibodies, the site of action of these drugs is  intracellular at the
ATP-binding site of the EGFR TK domain. Compared with monoclonal antibodies,
TKIs may potentially inhibit multiple targets and tend not to induce receptor
downregulation.


### 4.1. Gefitinib

Gefitinib is a
low-molecular-weight competitive inhibitor of ATP-binding pocket of the EGFR TK
domain [11], which is approved for the treatment of nonsmall cell lung cancer.
Clinical trials of gefitinib as a single agent in CRC reported no objective tumor responses [12–14] however, a sizable proportion of
patients did have disease stabilization. A  phase II trial which compared the
250 mg versus a 500 mg daily dosing of gefitinib [15], reported 1 partial
response in a patient who received the 500 mg dose. Paired biopsies pre- and
posttreatment biopsies performed in 28 patients showed that 84% had no change
or increase in the expression level of phosphorylated EGFR, MAP kinase, and Ki67 after treatment. Gefitinib and
chemotherapy in combination have also been investigated in several trials, where
the response rates seemed to be superior to the historically reported rates of
chemotherapy alone [16–18]. However, there were significantly more toxicities
particularly with respect to neutropenia and diarrhea with the combination.
Studies combining gefitinib with irinotecan also resulted in greater toxicity,
with some trials requiring early termination.


### 4.2. Erlotinib

Erlotinib has also
been studied in advanced CRC.
There have been mixed reports of some clinical activity when used as a single
agent. As with gefitinib, erlotinib produced a higher response rate when
combined with chemotherapy. High incidence of toxicity was noted when given in
combination with systemic chemotherapy, especially in two trials where
erlotinib was given in combination with FOLFOX and bevacizumab [19, 20], with
the latter trial having prematurely closed due to toxicity.


### 5. Incidence and Implications of Skin Rash

Anti-EGFR monoclonal
antibodies and EGFR TKIs are associated with a distinctive skin rash. The rash
is characterized histologically as a neutrophilic infiltrate in perifollicular
areas within the basal layer of the skin, which is different from that seen in
typical acne. Skin toxicity is generally observed within 2 to 3 weeks after
the start of treatment and gradually resolves in most patients, even when anti-EGFR
treatment is continued. In the BOND study, the most frequently observed adverse
event to cetuximab was the skin rash, and in the panitumumab study, Hecht et
al. [21] reported a 95% incidence of acneiform skin rash of any grade. Grade 3 rash
occurred in 3% of patients and none experienced grade 4 skin toxicities. An
association between the severity of acneiform rash and efficacy to cetuximab
has been well described. Retrospective analysis of the BOND data showed a clear
association between higher grades of skin reaction with RR and time to
progression (TTP) [2]. This
association is also seen with panitumumab [10] and seems to hold true in the
treatment of tumors of other sites with this class of agents.The “EVEREST” study
[22] was a phase I/II dose-escalation study, where patients who were receiving
cetuximab were randomized at 22 days, to either standard dose of weekly
(250 mg/m2/week) cetuximab  or an escalating dose of cetuximab until the
development of grade 3 toxicity, with a maximum ceiling dose of 500 mg/m2/week.
Skin and tumor biopsies were obtained. Preliminary report suggested that the
PFS in standard-dose arm was 3.9 months  and 4.8 months in the dose-escalated
arm. Dose-related increases in pharmacokinetic parameters (e.g.,  Cmax, AUC) were
observed in the escalated arm. The authors concluded that cetuximab dose
escalation up to 500 mg/m2/w may improve ORR in patients who experienced no or
slight skin reactions on standard-dose cetuximab.


### 6. Combining Targeted Therapies in Colorectal Cancer

Combinations of
multiple targeted agents with or without the additional of chemotherapy have
also been investigated. The BOND-2 trial [23] randomized irinotecan-refractory
patients to either 2 drugs (bevacizumab and cetuximab) or 3 drugs (bevacizumab,
cetuximab and irinotecan). The results were encouraging, with the 3-drug arm
resulting in a better TTP and ORR
than the 2-drug arm. This study also showed for the first time that monoclonal
antibodies in combination could induce an ORR of 20% in the absence of
chemotherapy. Nonstatistical comparison with result of the BOND-1 study
suggested that bevacizumab may enhance the effects of irinotecan-cetuximab
combination, with an ORR of 37% as compared to 23% reported for the
cetuximab/irinotecan arm [2, 23] (see Table 2). Subsequent to the
BOND-2 study, 3 other randomized trials have been reported on the feasibility
of combining monoclonal antibodies in the treatment of CRC.
The PACCE study [24] randomized 824 treatment-nave patients with metastatic CRC to oxaliplatin-based chemotherapy plus
bevacizumab, with or without panitumumab, and 230 patients to irinotecan-based
chemotherapy plus bevacizumab with or without panitumumab. The study was
terminated at a preplanned interim analysis after 231 events were reported in
patients who received oxaliplatin-based therapy, where a statistically
significant increase in PFS was reported in the arm without panitumumab. In
contrast, the Dutch CAIRO-2 trial [25] has a similar study design to the PACCE
trial and involved over 700 patients. Patients received capecitabine,
oxaliplatin, and bevacizumab with or without additional cetuximab. As expected,
preliminary result reported a significantly higher incidence of grade 3-4 skin
rash in the cetuximab-containing arm, without a statistically significant
difference in mortality in either arm. The CALGB/SWOG 80405 intergroup trial
was a 3-arm study, which randomized patients with metastatic CRC to chemotherapy and cetuximab, chemotherapy and
bevacizumab, or chemotherapy plus cetuximab and bevacizumab. This study has
been suspended following a decision by the CALGB Data and Safety Monitoring
Board as from June 2008, pending a protocol revision in view of the data on
KRAS mutation (see below) [26]. The reason why the PACCE study failed to
demonstrate a survival advantage in the panitumumab-bevacizumab arm remains
unclear. It is possible that the dose of the antibodies was inappropriate
leading to excessive toxicity and reduced efficacy. Patient selection has also
proven critical in the optimal use of anti-EGFR antibodies as the use of EGFR
staining to predict response and outcome has been severely challenged. Thus, a
combination approach of targeted agents in metastatic CRC remains controversial and it is the consensus among gastrointestinal
oncologists that such an approach remains experimental.Table 2
Nonstatistical comparison of the results of the
BOND-2 [23] and BOND-1 study [1].
BOND2BOND2BOND1BOND1Cetuximab, irinotecan, and bevacizumabCetuximab and bevacizumabCetuximab and irinotecanCetuximab aloneNo. of Patients4340218111Prior treatment with oxaliplatin (%)87896264Response rates (%)37202311Time to progression (months)7.34.94.11.5Median overall survival (months)14.511.48.66.9


### 7. EGFR Expression in Colorectal Cancer

EGFR as determined
by immunohistochemical (IHC) methods was the first biomarker investigated as a
potential predictor of response. It is overexpressed in over 80% of colorectal
cancers [27]. However, EGFR expression as measured by immunohistochemistry does
not predict clinical benefit [28, 29]. Initial observations in a small
retrospective series by Lenz et al. [30] noted that more than 20% of
EGFR-negative patients developed major objective responses. An extensive
retrospective analysis was reported in 2005 by Chung et al. [29]. They reported
a response rate of 25% in EGFR-negative patients (4 out of 16) given cetuximab
and irinotecan. This was comparable and indistinguishable from the response
rate of 23% seen in two separate clinical trials with EGFR-positive patients
[1, 31]. Given this data, immunohistochemical (IHC) demonstration of EGFR
expression is no longer required before starting cetuximab therapy in practice.
Similarly, in the  phase II trial, the response to treatment with panitumumab in
patients with metastatic CRC was
similar, irrespective of the level of EGFR protein expression assessed by IHC
analysis [32].


### 8. Potential Predictors of Response to Anti-EGFR Therapy

#### 8.1. Activating EGFR Gene Mutations

There has been much
interest in determining whether EGFR gene mutations may play a role in
affecting response to cetuximab or panitumumab. Previous research in nonsmall
cell lung cancer [33] has shown that EGFR TK mutations predict benefit from
EGFR TKIs. However, several retrospective studies on tumor biopsies and cell
lines found that EGFR gene mutations in CRC are extremely rare [34, 35]. No significantly different gene mutations were
found between responders and nonresponders to treatment.


#### 8.2. EGFR Gene Amplification

It has been hypothesized that
DNA is a more stable molecule than
a protein and thus EGFR gene copy number maybe more accurate reflection of the
EGFR status than IHC expression [36]. In a cohort of patients treated with
cetuximab or panitumumab, EGFR gene amplification with increased copy number
has been shown to significantly correlate with objective response to treatment
[36]. This raises the possibility that patients with high EGFR copy number may
be more likely to respond to treatment with anti-EGFR therapies.


#### 8.3. KRAS Gene Mutation

KRAS is a guanosine
triphosphate (GTP)-binding protein that acts as a critical on-off switch in
cellular growth and survival pathways. It plays a key role in the RAS/MAPK signally pathway located downstream of
many growth factor receptors, including EGFR, and involved in carcinogenesis.
Mutations of KRAS that result in the constitutive activation of MAPK pathway
downstream occurs in about 40% of colorectal cancers [37]. A retrospective
analysis reported by Lièvre et al. [38] analyzed tumor samples from 30 patients
treated with cetuximab. A KRAS mutation was found in 13 tumors (43%) and was
significantly associated with absence of response to cetuximab. None of the
patients with response to cetuximab harbored a KRAS mutation. The overall
survival of patients without KRAS mutation was significantly higher compared
with those patients with a mutated tumor (P = .016; median survival 16.3 versus
6.9 months). An increase in EGFR copy number was also significantly associated
with objective tumor response.It has been hypothesized that
irrespective of the level of EGFR expression, the presence of a KRAS mutation
is associated with a constitutive activation of the RAS/MAPK
pathway, leading to cell proliferation which cannot be significantly inhibited
by cetuximab. KRAS mutations have also been implicated in resistance against
EGFR TKIs in lung adenocarcinomas [39].Large scale retrospective
reviews retrieved archived tumor tissue from prior cetuximab and panitumumab
trials. KRAS mutation analysis was performed tested in tumor samples collected
from over 1000 participants of the “CRYSTAL” [8], “OPUS”
[40], NCIC-CO.17 trial [41] and panitumumab trials [42]. Beneficial effects of
anti-EGFR antibodies were limited to a subgroup of patients with wild-type KRAS
tumors. This has led to the recommendation that all patients with advanced CRC who are being considered for cetuximab or
panitumumab should undergo KRAS testing, and if the cancer bears a mutated KRAS
gene, they should not receive an antibody that targets EGFR.


#### 9. Conclusion

Throughout the last decade,
significant advancement in our understanding of the molecular mechanisms of
metastatic CRC has been made.
Anti-EGFR monoclonal antibodies approved for use in the metastatic setting have
broadened the therapeutic armamentarium in the treatment of metastatic CRC. The most effective sequence and combinations
of anti-EGFR therapy with chemotherapy and, or bevacizumab in order to achieve
cytotoxic potentiation with limited toxicity need to be addressed. Advances
made in the identification of predictive biomarkers such as KRAS mutations
allow us to select distinct groups of patients who are most likely to benefit
from cetuximab therapy.


## 4.1. Gefitinib

Gefitinib is a
low-molecular-weight competitive inhibitor of ATP-binding pocket of the EGFR TK
domain [11], which is approved for the treatment of nonsmall cell lung cancer.
Clinical trials of gefitinib as a single agent in CRC reported no objective tumor responses [12–14] however, a sizable proportion of
patients did have disease stabilization. A  phase II trial which compared the
250 mg versus a 500 mg daily dosing of gefitinib [15], reported 1 partial
response in a patient who received the 500 mg dose. Paired biopsies pre- and
posttreatment biopsies performed in 28 patients showed that 84% had no change
or increase in the expression level of phosphorylated EGFR, MAP kinase, and Ki67 after treatment. Gefitinib and
chemotherapy in combination have also been investigated in several trials, where
the response rates seemed to be superior to the historically reported rates of
chemotherapy alone [16–18]. However, there were significantly more toxicities
particularly with respect to neutropenia and diarrhea with the combination.
Studies combining gefitinib with irinotecan also resulted in greater toxicity,
with some trials requiring early termination.


## 4.2. Erlotinib

Erlotinib has also
been studied in advanced CRC.
There have been mixed reports of some clinical activity when used as a single
agent. As with gefitinib, erlotinib produced a higher response rate when
combined with chemotherapy. High incidence of toxicity was noted when given in
combination with systemic chemotherapy, especially in two trials where
erlotinib was given in combination with FOLFOX and bevacizumab [19, 20], with
the latter trial having prematurely closed due to toxicity.


## 5. Incidence and Implications of Skin Rash

Anti-EGFR monoclonal
antibodies and EGFR TKIs are associated with a distinctive skin rash. The rash
is characterized histologically as a neutrophilic infiltrate in perifollicular
areas within the basal layer of the skin, which is different from that seen in
typical acne. Skin toxicity is generally observed within 2 to 3 weeks after
the start of treatment and gradually resolves in most patients, even when anti-EGFR
treatment is continued. In the BOND study, the most frequently observed adverse
event to cetuximab was the skin rash, and in the panitumumab study, Hecht et
al. [21] reported a 95% incidence of acneiform skin rash of any grade. Grade 3 rash
occurred in 3% of patients and none experienced grade 4 skin toxicities. An
association between the severity of acneiform rash and efficacy to cetuximab
has been well described. Retrospective analysis of the BOND data showed a clear
association between higher grades of skin reaction with RR and time to
progression (TTP) [2]. This
association is also seen with panitumumab [10] and seems to hold true in the
treatment of tumors of other sites with this class of agents.The “EVEREST” study
[22] was a phase I/II dose-escalation study, where patients who were receiving
cetuximab were randomized at 22 days, to either standard dose of weekly
(250 mg/m2/week) cetuximab  or an escalating dose of cetuximab until the
development of grade 3 toxicity, with a maximum ceiling dose of 500 mg/m2/week.
Skin and tumor biopsies were obtained. Preliminary report suggested that the
PFS in standard-dose arm was 3.9 months  and 4.8 months in the dose-escalated
arm. Dose-related increases in pharmacokinetic parameters (e.g.,  Cmax, AUC) were
observed in the escalated arm. The authors concluded that cetuximab dose
escalation up to 500 mg/m2/w may improve ORR in patients who experienced no or
slight skin reactions on standard-dose cetuximab.


## 6. Combining Targeted Therapies in Colorectal Cancer

Combinations of
multiple targeted agents with or without the additional of chemotherapy have
also been investigated. The BOND-2 trial [23] randomized irinotecan-refractory
patients to either 2 drugs (bevacizumab and cetuximab) or 3 drugs (bevacizumab,
cetuximab and irinotecan). The results were encouraging, with the 3-drug arm
resulting in a better TTP and ORR
than the 2-drug arm. This study also showed for the first time that monoclonal
antibodies in combination could induce an ORR of 20% in the absence of
chemotherapy. Nonstatistical comparison with result of the BOND-1 study
suggested that bevacizumab may enhance the effects of irinotecan-cetuximab
combination, with an ORR of 37% as compared to 23% reported for the
cetuximab/irinotecan arm [2, 23] (see Table 2). Subsequent to the
BOND-2 study, 3 other randomized trials have been reported on the feasibility
of combining monoclonal antibodies in the treatment of CRC.
The PACCE study [24] randomized 824 treatment-nave patients with metastatic CRC to oxaliplatin-based chemotherapy plus
bevacizumab, with or without panitumumab, and 230 patients to irinotecan-based
chemotherapy plus bevacizumab with or without panitumumab. The study was
terminated at a preplanned interim analysis after 231 events were reported in
patients who received oxaliplatin-based therapy, where a statistically
significant increase in PFS was reported in the arm without panitumumab. In
contrast, the Dutch CAIRO-2 trial [25] has a similar study design to the PACCE
trial and involved over 700 patients. Patients received capecitabine,
oxaliplatin, and bevacizumab with or without additional cetuximab. As expected,
preliminary result reported a significantly higher incidence of grade 3-4 skin
rash in the cetuximab-containing arm, without a statistically significant
difference in mortality in either arm. The CALGB/SWOG 80405 intergroup trial
was a 3-arm study, which randomized patients with metastatic CRC to chemotherapy and cetuximab, chemotherapy and
bevacizumab, or chemotherapy plus cetuximab and bevacizumab. This study has
been suspended following a decision by the CALGB Data and Safety Monitoring
Board as from June 2008, pending a protocol revision in view of the data on
KRAS mutation (see below) [26]. The reason why the PACCE study failed to
demonstrate a survival advantage in the panitumumab-bevacizumab arm remains
unclear. It is possible that the dose of the antibodies was inappropriate
leading to excessive toxicity and reduced efficacy. Patient selection has also
proven critical in the optimal use of anti-EGFR antibodies as the use of EGFR
staining to predict response and outcome has been severely challenged. Thus, a
combination approach of targeted agents in metastatic CRC remains controversial and it is the consensus among gastrointestinal
oncologists that such an approach remains experimental.Table 2
Nonstatistical comparison of the results of the
BOND-2 [23] and BOND-1 study [1].
BOND2BOND2BOND1BOND1Cetuximab, irinotecan, and bevacizumabCetuximab and bevacizumabCetuximab and irinotecanCetuximab aloneNo. of Patients4340218111Prior treatment with oxaliplatin (%)87896264Response rates (%)37202311Time to progression (months)7.34.94.11.5Median overall survival (months)14.511.48.66.9


## 7. EGFR Expression in Colorectal Cancer

EGFR as determined
by immunohistochemical (IHC) methods was the first biomarker investigated as a
potential predictor of response. It is overexpressed in over 80% of colorectal
cancers [27]. However, EGFR expression as measured by immunohistochemistry does
not predict clinical benefit [28, 29]. Initial observations in a small
retrospective series by Lenz et al. [30] noted that more than 20% of
EGFR-negative patients developed major objective responses. An extensive
retrospective analysis was reported in 2005 by Chung et al. [29]. They reported
a response rate of 25% in EGFR-negative patients (4 out of 16) given cetuximab
and irinotecan. This was comparable and indistinguishable from the response
rate of 23% seen in two separate clinical trials with EGFR-positive patients
[1, 31]. Given this data, immunohistochemical (IHC) demonstration of EGFR
expression is no longer required before starting cetuximab therapy in practice.
Similarly, in the  phase II trial, the response to treatment with panitumumab in
patients with metastatic CRC was
similar, irrespective of the level of EGFR protein expression assessed by IHC
analysis [32].


## 8. Potential Predictors of Response to Anti-EGFR Therapy

### 8.1. Activating EGFR Gene Mutations

There has been much
interest in determining whether EGFR gene mutations may play a role in
affecting response to cetuximab or panitumumab. Previous research in nonsmall
cell lung cancer [33] has shown that EGFR TK mutations predict benefit from
EGFR TKIs. However, several retrospective studies on tumor biopsies and cell
lines found that EGFR gene mutations in CRC are extremely rare [34, 35]. No significantly different gene mutations were
found between responders and nonresponders to treatment.


### 8.2. EGFR Gene Amplification

It has been hypothesized that
DNA is a more stable molecule than
a protein and thus EGFR gene copy number maybe more accurate reflection of the
EGFR status than IHC expression [36]. In a cohort of patients treated with
cetuximab or panitumumab, EGFR gene amplification with increased copy number
has been shown to significantly correlate with objective response to treatment
[36]. This raises the possibility that patients with high EGFR copy number may
be more likely to respond to treatment with anti-EGFR therapies.


### 8.3. KRAS Gene Mutation

KRAS is a guanosine
triphosphate (GTP)-binding protein that acts as a critical on-off switch in
cellular growth and survival pathways. It plays a key role in the RAS/MAPK signally pathway located downstream of
many growth factor receptors, including EGFR, and involved in carcinogenesis.
Mutations of KRAS that result in the constitutive activation of MAPK pathway
downstream occurs in about 40% of colorectal cancers [37]. A retrospective
analysis reported by Lièvre et al. [38] analyzed tumor samples from 30 patients
treated with cetuximab. A KRAS mutation was found in 13 tumors (43%) and was
significantly associated with absence of response to cetuximab. None of the
patients with response to cetuximab harbored a KRAS mutation. The overall
survival of patients without KRAS mutation was significantly higher compared
with those patients with a mutated tumor (P = .016; median survival 16.3 versus
6.9 months). An increase in EGFR copy number was also significantly associated
with objective tumor response.It has been hypothesized that
irrespective of the level of EGFR expression, the presence of a KRAS mutation
is associated with a constitutive activation of the RAS/MAPK
pathway, leading to cell proliferation which cannot be significantly inhibited
by cetuximab. KRAS mutations have also been implicated in resistance against
EGFR TKIs in lung adenocarcinomas [39].Large scale retrospective
reviews retrieved archived tumor tissue from prior cetuximab and panitumumab
trials. KRAS mutation analysis was performed tested in tumor samples collected
from over 1000 participants of the “CRYSTAL” [8], “OPUS”
[40], NCIC-CO.17 trial [41] and panitumumab trials [42]. Beneficial effects of
anti-EGFR antibodies were limited to a subgroup of patients with wild-type KRAS
tumors. This has led to the recommendation that all patients with advanced CRC who are being considered for cetuximab or
panitumumab should undergo KRAS testing, and if the cancer bears a mutated KRAS
gene, they should not receive an antibody that targets EGFR.


### 9. Conclusion

Throughout the last decade,
significant advancement in our understanding of the molecular mechanisms of
metastatic CRC has been made.
Anti-EGFR monoclonal antibodies approved for use in the metastatic setting have
broadened the therapeutic armamentarium in the treatment of metastatic CRC. The most effective sequence and combinations
of anti-EGFR therapy with chemotherapy and, or bevacizumab in order to achieve
cytotoxic potentiation with limited toxicity need to be addressed. Advances
made in the identification of predictive biomarkers such as KRAS mutations
allow us to select distinct groups of patients who are most likely to benefit
from cetuximab therapy.


## 8.1. Activating EGFR Gene Mutations

There has been much
interest in determining whether EGFR gene mutations may play a role in
affecting response to cetuximab or panitumumab. Previous research in nonsmall
cell lung cancer [33] has shown that EGFR TK mutations predict benefit from
EGFR TKIs. However, several retrospective studies on tumor biopsies and cell
lines found that EGFR gene mutations in CRC are extremely rare [34, 35]. No significantly different gene mutations were
found between responders and nonresponders to treatment.


## 8.2. EGFR Gene Amplification

It has been hypothesized that
DNA is a more stable molecule than
a protein and thus EGFR gene copy number maybe more accurate reflection of the
EGFR status than IHC expression [36]. In a cohort of patients treated with
cetuximab or panitumumab, EGFR gene amplification with increased copy number
has been shown to significantly correlate with objective response to treatment
[36]. This raises the possibility that patients with high EGFR copy number may
be more likely to respond to treatment with anti-EGFR therapies.


## 8.3. KRAS Gene Mutation

KRAS is a guanosine
triphosphate (GTP)-binding protein that acts as a critical on-off switch in
cellular growth and survival pathways. It plays a key role in the RAS/MAPK signally pathway located downstream of
many growth factor receptors, including EGFR, and involved in carcinogenesis.
Mutations of KRAS that result in the constitutive activation of MAPK pathway
downstream occurs in about 40% of colorectal cancers [37]. A retrospective
analysis reported by Lièvre et al. [38] analyzed tumor samples from 30 patients
treated with cetuximab. A KRAS mutation was found in 13 tumors (43%) and was
significantly associated with absence of response to cetuximab. None of the
patients with response to cetuximab harbored a KRAS mutation. The overall
survival of patients without KRAS mutation was significantly higher compared
with those patients with a mutated tumor (P = .016; median survival 16.3 versus
6.9 months). An increase in EGFR copy number was also significantly associated
with objective tumor response.It has been hypothesized that
irrespective of the level of EGFR expression, the presence of a KRAS mutation
is associated with a constitutive activation of the RAS/MAPK
pathway, leading to cell proliferation which cannot be significantly inhibited
by cetuximab. KRAS mutations have also been implicated in resistance against
EGFR TKIs in lung adenocarcinomas [39].Large scale retrospective
reviews retrieved archived tumor tissue from prior cetuximab and panitumumab
trials. KRAS mutation analysis was performed tested in tumor samples collected
from over 1000 participants of the “CRYSTAL” [8], “OPUS”
[40], NCIC-CO.17 trial [41] and panitumumab trials [42]. Beneficial effects of
anti-EGFR antibodies were limited to a subgroup of patients with wild-type KRAS
tumors. This has led to the recommendation that all patients with advanced CRC who are being considered for cetuximab or
panitumumab should undergo KRAS testing, and if the cancer bears a mutated KRAS
gene, they should not receive an antibody that targets EGFR.


## 9. Conclusion

Throughout the last decade,
significant advancement in our understanding of the molecular mechanisms of
metastatic CRC has been made.
Anti-EGFR monoclonal antibodies approved for use in the metastatic setting have
broadened the therapeutic armamentarium in the treatment of metastatic CRC. The most effective sequence and combinations
of anti-EGFR therapy with chemotherapy and, or bevacizumab in order to achieve
cytotoxic potentiation with limited toxicity need to be addressed. Advances
made in the identification of predictive biomarkers such as KRAS mutations
allow us to select distinct groups of patients who are most likely to benefit
from cetuximab therapy.



---

*Source: 967920-2009-04-09.xml*