# Clinical Efficacy and Toxicity of Anti-EGFR Therapy in Common Cancers

Authors: Amir Harandi; Aisha S. Zaidi; Abigail M. Stocker; Damian A. Laber
Journal: Journal of Oncology
 (2009)

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## Abstract

Epidermal growth factor receptor (EGFR) is a cell surface molecule and member of the ErbB family of receptor tyrosine kinases. Its activation leads to proliferation, antiapoptosis, and metastatic spread, making inhibition of this pathway a compelling target. In recent years, an increasing number of clinical trials in the management of solid malignancies have become available indicating the clinical efficacy of anti-EGFR monoclonal antibodies and oral small molecule tyrosine kinase inhibitors (TKIs). This review addresses frequently used EGFR inhibitors, summarizes clinical efficacy data of these new therapeutic agents, and discusses their associated toxicity and management.


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## Body

## 1. Introduction

Epidermal growth factor receptor
(EGFR), a member of the ErbB family of receptor tyrosine kinases, is a cell
surface molecule whose activation leads to an intracellular signaling cascade
affecting invasion, apoptosis, and angiogenesis [1, 2]. Members of the EFGR
family receptors (erb1/EFGR, erb2/HER2, erb3/HER3, and erb4/HER4) are composed of
extracellular ligand binding domains. When ligands bind to these domains,
receptor dimerization and autophosphorylation of intracellular tyrosine kinase
domains occur. Autophosphorylation activates the downstream signaling pathways
ras, raf, mitogen-activated protein kinase (MAPK), phosphatidylinositol
3-kinase (Pl3K), Akt, and the signal transduction and activator of
transcription (STAT) pathways. This downstream signaling leads to activation of
cell growth, proliferation, and survival of cells [3, 4]. Binding of the EGFR
by inhibitors leads to a disruption in proliferation resulting in apoptosis.
Immunological effects, such as cell-dependent cytotoxicity (CDC) and
antibody-dependent cell-mediated cytotoxicity (ADCC), also contribute to their mechanism
of action [5].Drugs targeting EGFR in malignancies
were initially developed in the 1980s, which lead to the development of
anti-EGFR monoclonal antibodies and small molecule EGFR tyrosine kinase
inhibitors (TKIs) [6–9]. EGFR is overexpressed in many solid tumors and this
over expression correlates to advanced stage and a worse prognosis [10]. In the
last few years, numerous clinical trials have proven the clinical efficacy of
EGFR-targeted therapies in the management of several cancers, including breast,
colon, pancreas, head and neck, renal, gastrointestinal stromal tumors (GISTs),
and lung carcinomas. Since these agents are now commonly used, clinical
presentation of associated toxicities and their management are important to
recognize. Therefore, this review discusses commonly used EFGR inhibitors
currently approved by the US Food and Drug Administration (FDA). A summary of
clinical data in support of these agents and commonly encountered toxicities
and management are discussed.


## 2. Anti-EGFR Agents Efficacy

### 2.1. Erlotinib

Erlotinib is an oral agent that
reversibly binds to the intracellular tyrosine kinase domain of the HER1/EGFR
thus blocking phosphorylation and inhibiting signal transduction [11].
Initially studied in nonsmall cell lung cancer (NSCLC), phase II data showed a
response rate (RR) of 12% in patients previously treated with platinum-based
chemotherapy [12, 13]. The National Cancer Institute of Canada Clinical Trials
Group (NCICCTG) then developed a phase III trial comparing erlotinib to placebo
in patients with advanced NSCLC who had prior failure of first- or second-line
chemotherapy. This study showed that erlotinib when compared to placebo had a
higher overall (O)RR, median duration of response, progression-free survival
(PFS), and overall survival (OS) (Table 1). There was also a greater reduction
in cancer-related pain, cough, and dyspnea as well as improvement in physical
function in those treated with erlotinib [14]. As a result, erlotinib is a
useful treatment option presently utilized in the management of NSCLC. In
another large phase III randomized trial of previously untreated advanced
NSCLC, the combination of carboplatin and paclitaxel with or without erlotinib
was evaluated. The results were not as favorable and showed no difference in
ORR or OS [11]. EGFR gene mutations are being investigated as a predictor of
efficacy with erlotinib in NSCLC. Recently presented at the American Society of
Clinical Oncology (ASCO) Annual Meeting, a phase II trial of erlotinib in
previously untreated NSCLC patients with mutations of the tyrosine kinase
domain of EGFR was evaluated. In this trial, 37 of 297 tumors screened had
mutations in the tyrosine kinase domain (25 with exon 19 deletion, 11 with
L858R mutation). Responses occurred in 100% of exon 19 deletions and in 75% of
those with the L858R mutation [15].Table 1
Selected clinical
trials of erlotinib.NSCLC, Non-small
cell lung cancer; OS, overall survival; ORR, overall response
rate.
MalignancyRegimenNumber of  patientsResultsCommentsNSCLCErlotinib vs. placebo
[14]731 pts
Stage IIIB/IV NSCLC after
failure with first-line or second-line chemotherapyErlotinib: ORR (8.9%)
OS (6.7 mo) Placebo:
ORR (<1%) OS (4.7 mo)Significant improvement in OS
(P<.001)NSCLCCarboplatin, Paclitaxel +/−
Erlotinib
[11]1059 pts
Previously untreated stage
IIIB/IV NSCLCErolotinib: ORR (21.5%)
OS (10.6 mo) Placebo:
ORR (19.3%) OS (10.5 mo)No difference in ORR or OS
with the combination of Erlotinib and chemotherapyPancreatic cancerGemcitibine, Erlotinib vs.
placebo
[15]569 pts
Unresectable, locally advanced
or metastatic pancreatic cancerErlotinib:  OS (6.2 mo)
Placebo:  OS (5.9 mo)One year survival was greater
with erlotinib plus gemcitabine (23% vs. 17%;P=.023)HER1/EGFRs are also overexpressed in
pancreatic tumors conferring a worse prognosis. This led to an NCIC trial
comparing gemcitabine in combination with erlotinib or placebo in patients with
locally advanced or metastatic pancreatic adenocarcinomas. This trial showed a
minimal but statistically significant increase in OS favoring the
gemcitabine/erlotinib combination. Although statistically significant, the
absolute increase in median survival was only 2 weeks [16].


### 2.2. Gefitinib

Gefitinib, an orally bioavailable
EGFR TKI, was the first targeted drug to be approved for NSCLC. The Iressa Dose
Evaluation in Adjuvant Lung Cancer (IDEAL1 and IDEAL2) trials were phase II
nonrandomized studies investigating the efficacy of gefitinib monotherapy in
NSCLC patients previously treated with a platinum agent [17, 18]. Based on
objective responses, stable disease, and symptomatic improvement, gefitinib
received accelerated approval by the FDA in 2003. In 2005, the Iressa Survival
Evaluation in Lung Cancer (ISEL) trial, a phase III randomized study, evaluated
gefitinib versus placebo in previously treated NSCLC [19]. Although there was a
significantly higher response rate seen with gefitinib, the study did not show
a significant difference in OS. As a result, the FDA restricted the use of
gefitinib to patients enrolled in clinical trials or deriving benefit from
ongoing treatment. Other randomized phase III trials, assessing gefitinib given
concurrently with chemotherapy as well as gefitinib maintenance did not show
improvements in OS [20–22]. Recently, the 33rd European
Society for Medical Oncology Congress released results of a large-scale
randomized phase III trial (IRESSA Pan-Asia study [IPASS]) [23]. In 1,217
patients, the study compared gefitinib monotherapy to carboplatin/paclitaxel
(C/P) in chemonaive never- or light-exsmokers with advanced NSCLC with
adenocarcinoma histology (Table 2). Gefitinib was superior in PFS, ORR,
toxicity, and quality of life (QOL) compared to combination chemotherapy.
However, OS and symptom improvement were similar between the two groups. PFS was longer for gefitinib than C/P in EGFR mutation
positive patients and longer with C/P in mutation-negative patients.Table 2
Selected clinical
trials of gefitinib.NSCLC, Non-small
cell lung cancer; OS, overall survival; ORR, overall response
rate; C/P, carboplatin/paclitaxel; PFS, progression free survival; EGFR, epidermal growth factor receptor.
MalignancyRegimenNumber of patientsResultsCommentsNSCLCGefitinib vs. placebo
[19]1692 pts
Second-line or third-line
treatment for patients with locally advanced or metastatic NSCLCGefitinib:  OS (5.6 mo)
Placebo:  OS (5.1 mo)No significant improvement in
OS (P=.087)
Subgroup analysis showed
significantly longer survival in never-smokers and Asian patientsNSCLCGefitinib vs.
Carboplatin/paclitaxel (C/P)
[23]1,217 pts
Previously untreated stage
IIIB/IV NSCLC, never- or light ex-smokers, adenocarcinoma histologyGefitinib: ORR (43%)
OS (18.6 mo) C/P:
ORR (32%) OS (17.3 mo)P = .0001No OS difference
PFS longer for gefitinib than
C/P in EFGR mutation positive patients (P<.0001)
PFS longer with C/P in
mutation negative patients (P<.0001)


### 2.3. Cetuximab

Cetuximab is a chimeric monoclonal
IgG1 antibody that binds to the EGFR subsequently blocking phosphorylation of
the receptor [24]. Cetuximab, initially approved for the treatment of
metastatic colon cancer, has made a significant difference in the management of
patients with this disease. A phase III trial comparing cetuximab monotherapy
to best supportive care (BSC) showed improved OS and QOL in patients with
colorectal cancer who had previously failed or had contraindications to
fluoropyrimidine-, irinotecan-, and oxaliplatin-based therapies (Table 2) [25].
A subsequent randomized phase III trial compared cetuximab monotherapy to
cetuximab plus irinotecan in refractory metastatic colorectal cancer (mCRC).
This study was reserved for patients who had documented disease progression on
a prestudy irinotecan regimen. The combination therapy arm showed
significantly improved ORR, median time to progression (TTP), and disease
control [26]. Another similar randomized phase III trial evaluated irinotecan
monotherapy to cetuximab plus irinotecan in patients with mCRC previously
failing oxaliplatin and/or a fluoropyrimidine who were irinotecan naïve. The
combination therapy arm yielded improved ORR, PFS, and QOL, but similar OS to
the cetuximab-only treated patients. This lack of OS difference may have been
due to posttrial therapy since a large number of patients assigned to
irinotecan eventually received cetuximab [27]. Most recently, the combination
of irinotecan and 5-fluorouracil (FOLFIRI) with or without cetuximab in the
first-line treatment of mCRC was evaluated. Cetuximab in combination with
FOLFIRI significantly increased ORR and PFS [28].The combination of EGFR and vascular
endothelial growth factor-(VEGF-) targeted agents was also evaluated in a randomized
phase III study of capecitabine/oxaliplatin (CapOx) plus bevacizumab with or
without cetuximab in mCRC. Unfortunately, the combination chemotherapy,
bevacizumab, and cetuximab resulted in a significant decrease in PFS compared
to bevacizumab and CapOx alone with no difference in OS [29]. Therefore, it was
concluded that cetuximab and bevacizumab should not be used concomitantly with
chemotherapy.At last year's ASCO annual meeting,
data revealed that KRAS gene mutation conferred resistance to treatment with
cetuximab and panitunimab. In contrast, “wild-type” or normal KRAS mutation
status was found to be a predictive marker for cetuximab and panitumumab
efficacy. In a retrospective analysis of 5-fluorouracil/leucovorin/oxaliplatin
(FOLFOX) in combination with cetuximab, KRAS wild-type status was found to be
associated with a significantly higher ORR and longer PFS when compared to
mutant KRAS in EGFR-positive patients [29]. Similarly, when EGFR-positive
patients with untreated mCRC were treated with FOLFIRI with or without
cetuximab, KRAS mutational status was predictive of response; wild-type KRAS
was associated with improved ORR and prolonged PFS. Based on these studies as
well as data with panitumumab, KRAS testing and verification of wild-type status
are now required before treatment with these agents in colorectal cancer
[29–31].EGFR is also  upregulated in squamous
cell carcinoma (SCC) of the head and neck. The use of cetuximab to treat this
disease has significantly benefited these patients. Initial phase II data
revealed activity of single agent cetuximab in recurrent and/or metastatic SCC
of the head and neck in those failing to respond to platinum-based therapy. As
a single agent, the RR was 13% with a disease control rate of 46% [32]. The combination
of cetuximab with chemotherapy has also been found to be effective.
Platinum-based chemotherapy, fluorouracil, with or without cetuximab as
first-line treatment of metastatic or recurrent SCC of the head and neck showed
that the cetuximab combination yielded a higher ORR and OS [33]. A similar
phase III trial was conducted addressing PFS with cisplatin monotherapy versus
cisplatin with cetuximab in patients with recurrent and/or metastatic SCC of
the head and neck. This included patients with documented progression during
prior cisplatin therapy. This study did not show a significant difference in
PFS or OS; however, there was a significant difference in RR favoring the
cetuximab/cisplatin arm [34]. Cetuximab with radiotherapy versus radiotherapy alone
was also studied in a separate phase III trial. The addition of cetuximab to
radiotherapy significantly prolonged PFS, median OS, and duration of
locoregional control in patients with locoregionally advanced head and neck
cancer [35].In pancreatic adenocarcinoma, trials
with cetuximab have not shown significant clinical benefit. Cetuximab with
gemcitabine or gemcitabine alone was evaluated in a large multi-institutional
phase III trial in pancreatic adenocarcinoma. The addition of cetuximab did not
significantly improve ORR, PFS, or OS [36–38].At the plenary session of ASCO 2008,
data was released on the treatment of NSCLC with cetuximab in combination with
cisplatin/vinorelbine (CV) compared to CV alone. Only patients with EGFR
detectable by immunohistochemistry (IHC) were randomized. Cetuximab plus CV
demonstrated an OS advantage. A modest survival benefit of one-to-two month(s)
was seen depending on histology. This was the first trial to demonstrate an OS advantage
of an EGFR-targeted agent in combination with platinum-based chemotherapy in
NSCLC [39].EGFR gene copy number detected by
fluorescent in situ hybridization (FISH) has been shown to be useful in
selecting NSCLC patients for treatment with cetuximab. Patients with advanced-stage NSCLC were enrolled into a phase II trial evaluating sequential or
concurrent chemotherapy (carboplatin plus paclitaxel) with cetuximab. The ORR,
disease control rate, PFS, and OS were significantly higher in the
FISH-positive versus FISH-negative patients [40]. Further investigation on the
accuracy of FISH-positive EGFR status is needed to evaluate its prognostic
value in NSCLC.


### 2.4. Panitumumab

In contrast to cetuximab, panitumumab
is the first fully human EGFR monoclonal antibody. It is an immunoglobulin
(Ig)G2 antibody that binds to the extracellular portion of the EGFR thus
inhibiting phosphorylation and activation of the intracellular kinases [41].
Efficacy of panitumumab has been evaluated in EGFR-expressing metastatic
colorectal adenocarcinomas with disease progression following oxaliplatin,
irinotecan, and fluropyrimidine-containing chemotherapy regimens. An initial
phase II multicenter trial included patients with progressive mCRC treated with
panitumumab monotherapy; patients were stratified into two groups based on  EGFR
staining intensity. As a single agent, panitumumab response and disease
stabilization were seen irrespective of EGFR staining intensity [42]. This led
to a phase III trial comparing panitumumab monotherapy to BSC alone. Efficacy
was evaluated in patients with 1% or greater EGFR tumor staining by IHC and
disease progression while on or within 6 months of the most recent
chemotherapy. Panitumumab yielded a significant reduction in PFS when compared
to BSC; however, there was no significant difference in OS (Table 3) [43].
Patients in the BSC arm were subsequently allowed to crossover to the
panitumumab arm if disease progression was documented during the study. The
crossover patient population yielded comparable results with prolonged PFS
after panitumumab treatment [44]. This has led to the approval of panitumumab
for treatment of EGFR-positive, metastatic colorectal carcinoma with disease
progression following chemotherapy [41]. As mentioned earlier, wild-type KRAS
is required for panitumumab efficacy in patients with mCRC [31].Table 3
Selected clinical
trials of cetuximab.EGFR, epidermal
growth factor receptor; BSC, best supportive care; OS, overall
survival; PFS, progression free survival; ORR, overall response
rate; mCRC, metastatic colorectal cancer; FOLFIRI, 5
Flourouracil/Folinic Acid and Irinotecan; CapOx,
capecitabine/oxaliplatin; SCC, squamous cell carcinoma; IHC,
Immunohistochemistry; CR, complete response; PR, partial
response; FISH, fluorescent in situ hybridization.
MalignancyRegimenNumber of  patientsResultsCommentsmCRCCetuximab vs. BSC
[17]572 pts
IHC EGFR+ mCRC  Previously
treated with chemotherapyCetuximab:  PR (8%)
SD (31.4%)  BSC:
PR (0%)  SD (10.9%)Cetuximab was associated with
a significant improvement in OS (P<.001)
Cetuximab: OS (6.1 mo), BSC:
OS (4.6 mo)mCRCCetuximab, Irinotecan vs.
Cetuximab monotherapy
[18]329 pts
mCRC with progression after
Irinotecan-based chemotherapyCetuximab, Irinotecan:  ORR (22.9%)
Cetuximab:  ORR (10.8%)No difference in OS Median time to progression:
Cetuximab, Irinotecan (4.1 mo), Cetuximab (1.5 mo)mCRCCetuximab, Irinotecan vs.
Irinotecan
[19]1298 pts
EGFR+ mCRCCetuximab, Irinotecan:
ORR (16.4%)  PFS (4.0 mo)
Cetuximab:  ORR (4.2%)
PFS (2.6 mo)No significant difference in
OS, but large number of pts receiving Irinotecan eventually got cetuximabmCRCFOLFIRI +/− Cetuximab
[20]1,217 pts
EGFR+ mCRC First-line treatmentFOLFIRI + Cetuximab:  PFS (8.9 mo)
ORR (46.9%)  FOLFIRI alone:
PFS (8 mo)  ORR (38.7%)15% relative risk reduction of
progressionmCRCCapOx, bevacizumab +/−
Cetuximab
[21]775 pts
Previously untreated mCRCCapOx, bevacizumab:
ORR (40.6%)  PFS (10.7 mo)
Cetuximab arm: ORR (43.9%)
PFS (9.8 mo)Cetuximab combination was
worse in PFS
No difference in OSmCRCFOLFOX +/− Cetuximab [22]337 pts  134 pts wild-type KRAS
99 pts mutant KRASWild-type KRAS response with
FOLFOX + Cetuximab (ORR 61%, PFS 7.7 mo)
Mutant KRAS response with
FOLFOX + Cetuximab (ORR 33%, PFS 5.5 mo)Cetuximab only benefits
patients with wild-type KRAS (HR 0.448,P=.0009)mCRCFOLFIRI +/− Cetuximab [23]1,217 pts
348 pts wild-type KRAS  192 pts mutant KRASWild-type KRAS response with
FOLFIRI + Cetuximab (ORR 59%, PFS 9.9 mo)
Mutant KRAS response with
FOLFIRI + Cetuximab (ORR 36%, PFS 7.6 mo)Cetuximab only benefits
patients with wild-type KRAS and reduced risk for disease progression by 32%
(P=.017)SCC of the Head and NeckPlatinum (cisplatin or
carboplatin), fluorouracil +/− Cetuximab
[25]442 pts
Untreated recurrent or
metastatic SCC of the head and neckPlatinum, fluorouracil,
Cetuximab:
ORR (36%)  PFS (5.6 mo)
Platinum, fluorouracil:  ORR (20%)
PFS (3.3 mo)Median OS was significantly
improved in the Cetuximab arm (10.1 mo vs. 7.4 mo),P=.04SCC of the Head and NeckCisplatin, Cetuximab vs.
Cisplatin
[26]117 pts
Recurrent/metastatic SCC of
the head and neckCisplatin, Cetuximab:  ORR (26%) Cisplatin  ORR (10%)No significant improvement in
OS or PFS
Enhanced response for patients
with EGFR staining less than 80% by IHCSCC of the Head and NeckRadiation, Cetuximab vs.
Radiation alone
[27]424 pts
Locoregionally advanced SCC of
the head and neckRadiation, Cetuximab:  PFS (17.1 mo)
OS (49 mo)  Radiation alone:
PFS (12.4 mo)  OS (29.3 mo)OS benefit favoring Cetuximab
arm (P=.03)
Incidence in grade 3 or higher
side effects, including mucositis, did not differ significantly between the
groupsPancreatic cancerCetuximab, Gemcitabine vs.
Gemcitabine alone
[30]735 ptsCetuximab, Gemcitabine:  ORR (14%)
PFS (3.5 mo)  OS (6.4 mo)
Gemcitabine alone: ORR (12%)
PFS (3 mo)  OS (5.9 mo)The addition of Cetuximab did
not significantly improve ORR, PFS, or OSNSCLCCisplatin, Vinorelbine +/−
Cetuximab
[31]1,125 pts
Only pts with EGFR detected by
IHC were randomizedCisplatin, Vinorelbine,
Cetuximab:
Median OS (11.3 mo) Cisplatin, Vinorelbine:
Median OS (10.1 mo)OS significantly improved in
Cetuximab arm (P=.04)NSCLCSequential or concurrent
carboplatin and paclitaxel with cetuximab
[32]229 pts
EGFR by FISH assessable in 76 pts (positive in 59%)FISH-positive: CR/PR (81%)
Median PFS (6 mo) FISH-negative:
CR/PR (55%) Median PFS (3 mo)Median OS superior in
FISH-positive (15 mo vs. 7 mo),P=.04The combination of EGFR- and
VEGF-targeting antibodies was also found to lack benefit in the case of
panitumumab. In the Panitumumab Advanced Colorectal Cancer Evaluation (PACCE)
study, patients with untreated mCRC were randomized to FOLFOX or FOLFIRI based
on investigator or patient choice. This combination was given with panitumumab
plus bevacizumab or bevacizumab alone. The combination of
FOLFOX/panitumumab/bevacizumab resulted in higher mortality compared to
FOLFOX/bevacizumab alone. The primary endpoint of median PFS was also shorter
in the panitumumab arm. Based on the results of the interim analysis, the study
was stopped and panitumumab was discontinued in both the FOLFOX and FOLFIRI
arms [45]. Similar to cetuximab, this trial with panitumumab argues against the
combined use of these agents with bevacizumab in mCRC.


### 2.5. Sorafenib

Sorafenib is a novel multikinase
inhibitor with antiangiogenic and proapoptotic activity targeting EGFR as well as multiple kinases including Raff/MAPK-ERK kinase, VEGFR-2, VEGFR-3, and PDGFR-β
[39]. It is approved for use in the treatment of renal cell carcinoma (RCC) and
hepatocellular carcinoma (HCC).RCC is characterized by the loss of
the von hippel landau (VHL) gene, which leads to dysregulation of the VEGFR,
PDGFR-β, transforming growth factor-alpha (TGF-) α, EGFR, and Raf pathways promoting
angiogenesis, lymphangiogenesis, tumor cell growth, and survival. Furthermore,
RCC frequently displays EGFR immunoreactivity. Membranous and/or cytoplasmic
EGFR immunostaining in RCC was present in 123 of 132 (93%) primary and 49 of 53
(92%) metastatic samples with extensive immunoreactivity present in 83% of
primary and 74% of metastatic tumors [46].In previously treated patients with
metastatic RCC, the activity of sorafenib was demonstrated in two randomized
trials. In the largest of these studies, a randomized phase III trial of
metastatic cytokine refractory RCC, significant response and improvement in PFS
was demonstrated (Table4). At ASCO 2007, a final analysis of survival was
presented. There was no statistically significant improvement in OS; survival
benefit was likely obscured since one half of the patients originally assigned
to placebo had switched to sorafenib [47].Table 4
Selected clinical
trials of panitumumab.mCRC, metastatic
colorectal cancer; BSC, best supportive care; OS, overall survival; PFS, progression free survival; ORR, overall response rate; SD, stable disease; FOLFOX, 5 Flourouracil/Folinic Acid and oxaliplatin; FOLFIRI, 5 Flourouracil/Folinic Acid and Irinotecan.
MalignancyRegimenNumber of patientsResultsCommentsmCRCPanitumumab vs. BSC
[35]463 pts
Pts with progression after
standard chemotherapyPanitumumab:  ORR (10%)
PFS (13.8 weeks)  BSC:
ORR (0%)  PFS (8.5 weeks)No significant improvement in
OSmCRCPanitumumab monotherapy after
disease progression with BSC
[36]176 pts
Pts with progression of
disease in BSC arm of Panitumumab vs. BSC trial [35]Panitumumab:  ORR (11.6%)
SD (33%)  Median PFS of 9.4 weeksResults comparable to initial
studymCRCFOLFOX or FOLFIRI with
Bevacizumab +/− Panitumumab
[37]823 ptsFOLFOX, Bevacizumab,
Panitumumab:
Median PFS (9.5 mo)  OS (19.3 mo)
FOLFOX, Bevacizumab:  Median PFS (11 mo)
OS (20.6 mo)Panitumumab in combination
with FOLFOX and bevacizumab was associated with a shorter PFS and increased
toxicityEGFR is frequently expressed in human
hepatoma cells; in fact, EGF is one of the mitogens required for the growth of
hepatoma cells. At the ASCO meeting in 2007, data was released showing the
efficacy of sorafenib in HCC. The Sorafenib HCC Assessment Randomized Protocol
(SHARP) Trial was a large phase III double-blind placebo-controlled study
evaluating the efficacy of sorafenib versus BSC in patients with advanced HCC
who had not received previous chemotherapy. Patients receiving sorafenib had a
three-month median survival benefit compared to placebo. Importantly, sorafenib was
the first active treatment that has been proven to confer a survival benefit
and to show promise as a standard treatment for advanced HCC [48]. In another
phase III randomized trial of sorafenib in Asia-Pacific patients with HCC,
results mirrored those of the SHARP trial. Despite Asia-Pacific patients having
more advanced disease based on the Eastern Cooperative Oncology Group
performance status (ECOG PS), a significant OS advantage with sorafenib was
confirmed [49]. A North American phase II randomized trial of doxorubicin with
sorafenib versus doxorubicin with placebo in 96 Child-Pugh A patients was
published in abstract form and presented at the 2007 European Cancer
Organization Conference (ECCO). Median TTP was two months longer in the
combination arm, but did not reach statistical significance. However, OS was
significantly longer for the combination of sorafenib/doxorubicin compared to
the doxorubicin only arm (13.7 vs. 6.5 mo) [50].Sorafenib has also recently
demonstrated significant activity in the treatment of iodine-refractory thyroid
carcinoma. In a phase II trial of 30 subjects, most of the patients (80%)
showed a clinical benefit from this agent. Ninety-five percent of individuals
with available thyroglobulin levels showed a rapid response in thyroglobulin
levels with a mean decrease of 70%. These results represent a significant
advance in both response and PFS over studies in the past utilizing
chemotherapy [51].


### 2.6. Sunitinib

Like sorafenib, sunitinib is an oral small
molecule TKI that inhibits cellular signaling by targeting EGFR, VEGFR, PDGFR-β,
fetal liver tyrosine kinase receptor (FLT-3), and c-Kit, a stem cell factor
receptor [52]. This ultimately targets both angiogenesis and tumor cell
proliferation causing tumor shrinkage and cell death. Sunitinib is currently
approved for the treatment of RCC as well as  gastrointestinal stromal tumors  GISTs. Like RCC, EGFR expression
in GISTs had been validated in a recent article in which tissue microarray
samples of 33 GISTs were surveyed by IHC. EGFR expression was identified in 8
of those samples [53].The antitumor activity of sunitinib
was initially shown in two phase II trials of metastatic RCC patients who had
failed previous cytokine therapy [54, 55]. This led to a large phase III trial
comparing sunitinib to interferon-alpha (IFN-α) as first-line therapy (Table 5). Sunitinib showed superior activity in ORR and in PFS, including patients
with good, intermediate, and poor risk features. Furthermore, OS was
significantly longer in the sunitinib arm, despite significant patient crossover
from the IFN-α arm to sunitinib [56]. Sunitinib was also found to be superior
in QOL compared to IFN-α [57].Table 5
Selected clinical
trials of sorafenib.PFS,
progression free survival; OS, overall survival; PR, partial
response; CR, complete response; HCC, hepatocellular carcinoma; RCC,
renal cell carcinoma; TBRR, Tumor burden reduction rate.
MalignancyRegimenNumber of patientsResponse rateCommentsRCCSorafenib vs. placebo
[41]903
Resistant to standard therapySorafenib:
Median PFS (5.5 mo)  PR (10%)
Placebo:  Median PFS (2.8 mo)P<0.01  PR (2%)The OS showed reduced risk of
death compared with placebo but the results were not statistically
significantHCCSorafenib vs. placebo
[42]602 pts
No previous therapySorafenib:
Median OS (10.7 mo)  Placebo:
Median OS (7.9 mo)The median OS was
significantly longer in patients who received Sorafenib
HR (0.69),P=.0006Metastatic thyroid carcinomaSorafenib monotherapy [45]36 pts
Metastatic, iodine-refractory
thyroid carcinomaPR in 7 pts (21%)  SD in 20 pts (59%)Significant anti-tumor
activity with overall clinical benefit rate (PR + SD) of 80%Sunitinib has also shown significant
activity in metastatic and/or unresectable GIST following imatinib failure. In
a phase III randomized trial comparing sunitinib to placebo in imatinib
refractory GIST patients, time to tumor progression and PFS was 4-fold longer
in patients on sunitinib compared to placebo; partial response (PR) and stable
disease (SD) were also significantly longer in the sunitinib arm. Patients in
the placebo arm were subsequently allowed to crossover to the Sunitinib arm if
disease progression was documented during the study. The crossover patient
population yielded comparable results. Despite the crossover, OS favored patients
initially treated with sunitinib [58].


### 2.7. Lapatinib

Activation and overexpression of
oncogenes encoding trans-membrane receptor tyrosine kinases of the EGFR family,
including EGFR (ErbB1) and HER2/neu (ErbB2), play an important role in the
development of breast cancer [58]. Lapatinib is an orally active
4-anilinoquinazoline TKI of both HER2/neu (ErbB2) and EGFR (ErbB1). It inhibits
the autophosphorylation sites on the receptors, thereby blocking the downstream
signaling pathways of HER2 and EGFR.Lapatinib has shown activity for the
treatment of advanced HER2/neu positive metastatic breast cancer refractory to
trastuzumab (Table6). Unlike trastuzumab, lapatinib seems to have activity
against brain metastases [59–61]. Primary and secondary resistances have been
seen in patients with HER2-positive breast cancers who had been treated with
trastuzumab both in the metastatic and adjuvant settings
[53, 62–65]. Potential
mechanisms of resistance may be related to signaling through other receptors
such as EGFR or IGFR-1 [66]. Lapatinib, being a small molecule TKI, interacts
with intercellular domains and does not require full receptor activity. In a
phase III study of HER2-positive advanced or metastatic breast cancer
refractory to anthracyclines, taxanes, and trastuzumab, lapatinib plus
capecitabine showed a significant advantage over capecitabine monotherapy with
respect to ORR and PFS with a nonsignificant trend toward longer OS [67]. In
another phase III randomized trial, the combination of paclitaxel with lapatinib
compared to paclitaxel monotherapy in patients with HER2-positive cancer was
evaluated. Patients in this trial were not treated with prior trastuzumab. The
study showed a statistically significant advantage in ORR and TTP, but not in
OS. Enrollment for this study came from countries with limited HER2 testing.
Only 91 of 580 patients were HER2-positive on central testing, with
retrospective analysis revealing benefit limited to FISH-positive or IHC 3+
tumors [68].Table 6
Selected clinical
trials of sunitinib.GIST, gastrointestinal
stromal tumor; PFS, progression free survival; OS, overall
survival; PR, partial response; CR, complete response; TTP, time
to progression;  m RCC, metastatic renal cell carcinoma; QOL, quality
of life.
MalignancyRegimenNumber of patientsResponse rateCommentsRCCInterferon vs. Sunitinib
[48]750 pts
Previously untreated mRCCSunitinib:
Median PFS (11 mo)  ORR (31%)
OS (26.4 mo),P = 0.051  Interferon:
Median PFS (5 mo)  ORR (6%)
OS (21.8 mo)Sunitinib provides superior
QOL compared with IFN-α in mRCC patients.GISTSunitinib vs. placebo [50]312 pts  After progression or
intolerance to imatinibSunitinib: TTP(6.3 mo)
Placebo:  TTP(1.5 month)Sunitinib significantly
improved TTP with a 67% reduced risk of progression.


## 2.1. Erlotinib

Erlotinib is an oral agent that
reversibly binds to the intracellular tyrosine kinase domain of the HER1/EGFR
thus blocking phosphorylation and inhibiting signal transduction [11].
Initially studied in nonsmall cell lung cancer (NSCLC), phase II data showed a
response rate (RR) of 12% in patients previously treated with platinum-based
chemotherapy [12, 13]. The National Cancer Institute of Canada Clinical Trials
Group (NCICCTG) then developed a phase III trial comparing erlotinib to placebo
in patients with advanced NSCLC who had prior failure of first- or second-line
chemotherapy. This study showed that erlotinib when compared to placebo had a
higher overall (O)RR, median duration of response, progression-free survival
(PFS), and overall survival (OS) (Table 1). There was also a greater reduction
in cancer-related pain, cough, and dyspnea as well as improvement in physical
function in those treated with erlotinib [14]. As a result, erlotinib is a
useful treatment option presently utilized in the management of NSCLC. In
another large phase III randomized trial of previously untreated advanced
NSCLC, the combination of carboplatin and paclitaxel with or without erlotinib
was evaluated. The results were not as favorable and showed no difference in
ORR or OS [11]. EGFR gene mutations are being investigated as a predictor of
efficacy with erlotinib in NSCLC. Recently presented at the American Society of
Clinical Oncology (ASCO) Annual Meeting, a phase II trial of erlotinib in
previously untreated NSCLC patients with mutations of the tyrosine kinase
domain of EGFR was evaluated. In this trial, 37 of 297 tumors screened had
mutations in the tyrosine kinase domain (25 with exon 19 deletion, 11 with
L858R mutation). Responses occurred in 100% of exon 19 deletions and in 75% of
those with the L858R mutation [15].Table 1
Selected clinical
trials of erlotinib.NSCLC, Non-small
cell lung cancer; OS, overall survival; ORR, overall response
rate.
MalignancyRegimenNumber of  patientsResultsCommentsNSCLCErlotinib vs. placebo
[14]731 pts
Stage IIIB/IV NSCLC after
failure with first-line or second-line chemotherapyErlotinib: ORR (8.9%)
OS (6.7 mo) Placebo:
ORR (<1%) OS (4.7 mo)Significant improvement in OS
(P<.001)NSCLCCarboplatin, Paclitaxel +/−
Erlotinib
[11]1059 pts
Previously untreated stage
IIIB/IV NSCLCErolotinib: ORR (21.5%)
OS (10.6 mo) Placebo:
ORR (19.3%) OS (10.5 mo)No difference in ORR or OS
with the combination of Erlotinib and chemotherapyPancreatic cancerGemcitibine, Erlotinib vs.
placebo
[15]569 pts
Unresectable, locally advanced
or metastatic pancreatic cancerErlotinib:  OS (6.2 mo)
Placebo:  OS (5.9 mo)One year survival was greater
with erlotinib plus gemcitabine (23% vs. 17%;P=.023)HER1/EGFRs are also overexpressed in
pancreatic tumors conferring a worse prognosis. This led to an NCIC trial
comparing gemcitabine in combination with erlotinib or placebo in patients with
locally advanced or metastatic pancreatic adenocarcinomas. This trial showed a
minimal but statistically significant increase in OS favoring the
gemcitabine/erlotinib combination. Although statistically significant, the
absolute increase in median survival was only 2 weeks [16].


## 2.2. Gefitinib

Gefitinib, an orally bioavailable
EGFR TKI, was the first targeted drug to be approved for NSCLC. The Iressa Dose
Evaluation in Adjuvant Lung Cancer (IDEAL1 and IDEAL2) trials were phase II
nonrandomized studies investigating the efficacy of gefitinib monotherapy in
NSCLC patients previously treated with a platinum agent [17, 18]. Based on
objective responses, stable disease, and symptomatic improvement, gefitinib
received accelerated approval by the FDA in 2003. In 2005, the Iressa Survival
Evaluation in Lung Cancer (ISEL) trial, a phase III randomized study, evaluated
gefitinib versus placebo in previously treated NSCLC [19]. Although there was a
significantly higher response rate seen with gefitinib, the study did not show
a significant difference in OS. As a result, the FDA restricted the use of
gefitinib to patients enrolled in clinical trials or deriving benefit from
ongoing treatment. Other randomized phase III trials, assessing gefitinib given
concurrently with chemotherapy as well as gefitinib maintenance did not show
improvements in OS [20–22]. Recently, the 33rd European
Society for Medical Oncology Congress released results of a large-scale
randomized phase III trial (IRESSA Pan-Asia study [IPASS]) [23]. In 1,217
patients, the study compared gefitinib monotherapy to carboplatin/paclitaxel
(C/P) in chemonaive never- or light-exsmokers with advanced NSCLC with
adenocarcinoma histology (Table 2). Gefitinib was superior in PFS, ORR,
toxicity, and quality of life (QOL) compared to combination chemotherapy.
However, OS and symptom improvement were similar between the two groups. PFS was longer for gefitinib than C/P in EGFR mutation
positive patients and longer with C/P in mutation-negative patients.Table 2
Selected clinical
trials of gefitinib.NSCLC, Non-small
cell lung cancer; OS, overall survival; ORR, overall response
rate; C/P, carboplatin/paclitaxel; PFS, progression free survival; EGFR, epidermal growth factor receptor.
MalignancyRegimenNumber of patientsResultsCommentsNSCLCGefitinib vs. placebo
[19]1692 pts
Second-line or third-line
treatment for patients with locally advanced or metastatic NSCLCGefitinib:  OS (5.6 mo)
Placebo:  OS (5.1 mo)No significant improvement in
OS (P=.087)
Subgroup analysis showed
significantly longer survival in never-smokers and Asian patientsNSCLCGefitinib vs.
Carboplatin/paclitaxel (C/P)
[23]1,217 pts
Previously untreated stage
IIIB/IV NSCLC, never- or light ex-smokers, adenocarcinoma histologyGefitinib: ORR (43%)
OS (18.6 mo) C/P:
ORR (32%) OS (17.3 mo)P = .0001No OS difference
PFS longer for gefitinib than
C/P in EFGR mutation positive patients (P<.0001)
PFS longer with C/P in
mutation negative patients (P<.0001)


## 2.3. Cetuximab

Cetuximab is a chimeric monoclonal
IgG1 antibody that binds to the EGFR subsequently blocking phosphorylation of
the receptor [24]. Cetuximab, initially approved for the treatment of
metastatic colon cancer, has made a significant difference in the management of
patients with this disease. A phase III trial comparing cetuximab monotherapy
to best supportive care (BSC) showed improved OS and QOL in patients with
colorectal cancer who had previously failed or had contraindications to
fluoropyrimidine-, irinotecan-, and oxaliplatin-based therapies (Table 2) [25].
A subsequent randomized phase III trial compared cetuximab monotherapy to
cetuximab plus irinotecan in refractory metastatic colorectal cancer (mCRC).
This study was reserved for patients who had documented disease progression on
a prestudy irinotecan regimen. The combination therapy arm showed
significantly improved ORR, median time to progression (TTP), and disease
control [26]. Another similar randomized phase III trial evaluated irinotecan
monotherapy to cetuximab plus irinotecan in patients with mCRC previously
failing oxaliplatin and/or a fluoropyrimidine who were irinotecan naïve. The
combination therapy arm yielded improved ORR, PFS, and QOL, but similar OS to
the cetuximab-only treated patients. This lack of OS difference may have been
due to posttrial therapy since a large number of patients assigned to
irinotecan eventually received cetuximab [27]. Most recently, the combination
of irinotecan and 5-fluorouracil (FOLFIRI) with or without cetuximab in the
first-line treatment of mCRC was evaluated. Cetuximab in combination with
FOLFIRI significantly increased ORR and PFS [28].The combination of EGFR and vascular
endothelial growth factor-(VEGF-) targeted agents was also evaluated in a randomized
phase III study of capecitabine/oxaliplatin (CapOx) plus bevacizumab with or
without cetuximab in mCRC. Unfortunately, the combination chemotherapy,
bevacizumab, and cetuximab resulted in a significant decrease in PFS compared
to bevacizumab and CapOx alone with no difference in OS [29]. Therefore, it was
concluded that cetuximab and bevacizumab should not be used concomitantly with
chemotherapy.At last year's ASCO annual meeting,
data revealed that KRAS gene mutation conferred resistance to treatment with
cetuximab and panitunimab. In contrast, “wild-type” or normal KRAS mutation
status was found to be a predictive marker for cetuximab and panitumumab
efficacy. In a retrospective analysis of 5-fluorouracil/leucovorin/oxaliplatin
(FOLFOX) in combination with cetuximab, KRAS wild-type status was found to be
associated with a significantly higher ORR and longer PFS when compared to
mutant KRAS in EGFR-positive patients [29]. Similarly, when EGFR-positive
patients with untreated mCRC were treated with FOLFIRI with or without
cetuximab, KRAS mutational status was predictive of response; wild-type KRAS
was associated with improved ORR and prolonged PFS. Based on these studies as
well as data with panitumumab, KRAS testing and verification of wild-type status
are now required before treatment with these agents in colorectal cancer
[29–31].EGFR is also  upregulated in squamous
cell carcinoma (SCC) of the head and neck. The use of cetuximab to treat this
disease has significantly benefited these patients. Initial phase II data
revealed activity of single agent cetuximab in recurrent and/or metastatic SCC
of the head and neck in those failing to respond to platinum-based therapy. As
a single agent, the RR was 13% with a disease control rate of 46% [32]. The combination
of cetuximab with chemotherapy has also been found to be effective.
Platinum-based chemotherapy, fluorouracil, with or without cetuximab as
first-line treatment of metastatic or recurrent SCC of the head and neck showed
that the cetuximab combination yielded a higher ORR and OS [33]. A similar
phase III trial was conducted addressing PFS with cisplatin monotherapy versus
cisplatin with cetuximab in patients with recurrent and/or metastatic SCC of
the head and neck. This included patients with documented progression during
prior cisplatin therapy. This study did not show a significant difference in
PFS or OS; however, there was a significant difference in RR favoring the
cetuximab/cisplatin arm [34]. Cetuximab with radiotherapy versus radiotherapy alone
was also studied in a separate phase III trial. The addition of cetuximab to
radiotherapy significantly prolonged PFS, median OS, and duration of
locoregional control in patients with locoregionally advanced head and neck
cancer [35].In pancreatic adenocarcinoma, trials
with cetuximab have not shown significant clinical benefit. Cetuximab with
gemcitabine or gemcitabine alone was evaluated in a large multi-institutional
phase III trial in pancreatic adenocarcinoma. The addition of cetuximab did not
significantly improve ORR, PFS, or OS [36–38].At the plenary session of ASCO 2008,
data was released on the treatment of NSCLC with cetuximab in combination with
cisplatin/vinorelbine (CV) compared to CV alone. Only patients with EGFR
detectable by immunohistochemistry (IHC) were randomized. Cetuximab plus CV
demonstrated an OS advantage. A modest survival benefit of one-to-two month(s)
was seen depending on histology. This was the first trial to demonstrate an OS advantage
of an EGFR-targeted agent in combination with platinum-based chemotherapy in
NSCLC [39].EGFR gene copy number detected by
fluorescent in situ hybridization (FISH) has been shown to be useful in
selecting NSCLC patients for treatment with cetuximab. Patients with advanced-stage NSCLC were enrolled into a phase II trial evaluating sequential or
concurrent chemotherapy (carboplatin plus paclitaxel) with cetuximab. The ORR,
disease control rate, PFS, and OS were significantly higher in the
FISH-positive versus FISH-negative patients [40]. Further investigation on the
accuracy of FISH-positive EGFR status is needed to evaluate its prognostic
value in NSCLC.


## 2.4. Panitumumab

In contrast to cetuximab, panitumumab
is the first fully human EGFR monoclonal antibody. It is an immunoglobulin
(Ig)G2 antibody that binds to the extracellular portion of the EGFR thus
inhibiting phosphorylation and activation of the intracellular kinases [41].
Efficacy of panitumumab has been evaluated in EGFR-expressing metastatic
colorectal adenocarcinomas with disease progression following oxaliplatin,
irinotecan, and fluropyrimidine-containing chemotherapy regimens. An initial
phase II multicenter trial included patients with progressive mCRC treated with
panitumumab monotherapy; patients were stratified into two groups based on  EGFR
staining intensity. As a single agent, panitumumab response and disease
stabilization were seen irrespective of EGFR staining intensity [42]. This led
to a phase III trial comparing panitumumab monotherapy to BSC alone. Efficacy
was evaluated in patients with 1% or greater EGFR tumor staining by IHC and
disease progression while on or within 6 months of the most recent
chemotherapy. Panitumumab yielded a significant reduction in PFS when compared
to BSC; however, there was no significant difference in OS (Table 3) [43].
Patients in the BSC arm were subsequently allowed to crossover to the
panitumumab arm if disease progression was documented during the study. The
crossover patient population yielded comparable results with prolonged PFS
after panitumumab treatment [44]. This has led to the approval of panitumumab
for treatment of EGFR-positive, metastatic colorectal carcinoma with disease
progression following chemotherapy [41]. As mentioned earlier, wild-type KRAS
is required for panitumumab efficacy in patients with mCRC [31].Table 3
Selected clinical
trials of cetuximab.EGFR, epidermal
growth factor receptor; BSC, best supportive care; OS, overall
survival; PFS, progression free survival; ORR, overall response
rate; mCRC, metastatic colorectal cancer; FOLFIRI, 5
Flourouracil/Folinic Acid and Irinotecan; CapOx,
capecitabine/oxaliplatin; SCC, squamous cell carcinoma; IHC,
Immunohistochemistry; CR, complete response; PR, partial
response; FISH, fluorescent in situ hybridization.
MalignancyRegimenNumber of  patientsResultsCommentsmCRCCetuximab vs. BSC
[17]572 pts
IHC EGFR+ mCRC  Previously
treated with chemotherapyCetuximab:  PR (8%)
SD (31.4%)  BSC:
PR (0%)  SD (10.9%)Cetuximab was associated with
a significant improvement in OS (P<.001)
Cetuximab: OS (6.1 mo), BSC:
OS (4.6 mo)mCRCCetuximab, Irinotecan vs.
Cetuximab monotherapy
[18]329 pts
mCRC with progression after
Irinotecan-based chemotherapyCetuximab, Irinotecan:  ORR (22.9%)
Cetuximab:  ORR (10.8%)No difference in OS Median time to progression:
Cetuximab, Irinotecan (4.1 mo), Cetuximab (1.5 mo)mCRCCetuximab, Irinotecan vs.
Irinotecan
[19]1298 pts
EGFR+ mCRCCetuximab, Irinotecan:
ORR (16.4%)  PFS (4.0 mo)
Cetuximab:  ORR (4.2%)
PFS (2.6 mo)No significant difference in
OS, but large number of pts receiving Irinotecan eventually got cetuximabmCRCFOLFIRI +/− Cetuximab
[20]1,217 pts
EGFR+ mCRC First-line treatmentFOLFIRI + Cetuximab:  PFS (8.9 mo)
ORR (46.9%)  FOLFIRI alone:
PFS (8 mo)  ORR (38.7%)15% relative risk reduction of
progressionmCRCCapOx, bevacizumab +/−
Cetuximab
[21]775 pts
Previously untreated mCRCCapOx, bevacizumab:
ORR (40.6%)  PFS (10.7 mo)
Cetuximab arm: ORR (43.9%)
PFS (9.8 mo)Cetuximab combination was
worse in PFS
No difference in OSmCRCFOLFOX +/− Cetuximab [22]337 pts  134 pts wild-type KRAS
99 pts mutant KRASWild-type KRAS response with
FOLFOX + Cetuximab (ORR 61%, PFS 7.7 mo)
Mutant KRAS response with
FOLFOX + Cetuximab (ORR 33%, PFS 5.5 mo)Cetuximab only benefits
patients with wild-type KRAS (HR 0.448,P=.0009)mCRCFOLFIRI +/− Cetuximab [23]1,217 pts
348 pts wild-type KRAS  192 pts mutant KRASWild-type KRAS response with
FOLFIRI + Cetuximab (ORR 59%, PFS 9.9 mo)
Mutant KRAS response with
FOLFIRI + Cetuximab (ORR 36%, PFS 7.6 mo)Cetuximab only benefits
patients with wild-type KRAS and reduced risk for disease progression by 32%
(P=.017)SCC of the Head and NeckPlatinum (cisplatin or
carboplatin), fluorouracil +/− Cetuximab
[25]442 pts
Untreated recurrent or
metastatic SCC of the head and neckPlatinum, fluorouracil,
Cetuximab:
ORR (36%)  PFS (5.6 mo)
Platinum, fluorouracil:  ORR (20%)
PFS (3.3 mo)Median OS was significantly
improved in the Cetuximab arm (10.1 mo vs. 7.4 mo),P=.04SCC of the Head and NeckCisplatin, Cetuximab vs.
Cisplatin
[26]117 pts
Recurrent/metastatic SCC of
the head and neckCisplatin, Cetuximab:  ORR (26%) Cisplatin  ORR (10%)No significant improvement in
OS or PFS
Enhanced response for patients
with EGFR staining less than 80% by IHCSCC of the Head and NeckRadiation, Cetuximab vs.
Radiation alone
[27]424 pts
Locoregionally advanced SCC of
the head and neckRadiation, Cetuximab:  PFS (17.1 mo)
OS (49 mo)  Radiation alone:
PFS (12.4 mo)  OS (29.3 mo)OS benefit favoring Cetuximab
arm (P=.03)
Incidence in grade 3 or higher
side effects, including mucositis, did not differ significantly between the
groupsPancreatic cancerCetuximab, Gemcitabine vs.
Gemcitabine alone
[30]735 ptsCetuximab, Gemcitabine:  ORR (14%)
PFS (3.5 mo)  OS (6.4 mo)
Gemcitabine alone: ORR (12%)
PFS (3 mo)  OS (5.9 mo)The addition of Cetuximab did
not significantly improve ORR, PFS, or OSNSCLCCisplatin, Vinorelbine +/−
Cetuximab
[31]1,125 pts
Only pts with EGFR detected by
IHC were randomizedCisplatin, Vinorelbine,
Cetuximab:
Median OS (11.3 mo) Cisplatin, Vinorelbine:
Median OS (10.1 mo)OS significantly improved in
Cetuximab arm (P=.04)NSCLCSequential or concurrent
carboplatin and paclitaxel with cetuximab
[32]229 pts
EGFR by FISH assessable in 76 pts (positive in 59%)FISH-positive: CR/PR (81%)
Median PFS (6 mo) FISH-negative:
CR/PR (55%) Median PFS (3 mo)Median OS superior in
FISH-positive (15 mo vs. 7 mo),P=.04The combination of EGFR- and
VEGF-targeting antibodies was also found to lack benefit in the case of
panitumumab. In the Panitumumab Advanced Colorectal Cancer Evaluation (PACCE)
study, patients with untreated mCRC were randomized to FOLFOX or FOLFIRI based
on investigator or patient choice. This combination was given with panitumumab
plus bevacizumab or bevacizumab alone. The combination of
FOLFOX/panitumumab/bevacizumab resulted in higher mortality compared to
FOLFOX/bevacizumab alone. The primary endpoint of median PFS was also shorter
in the panitumumab arm. Based on the results of the interim analysis, the study
was stopped and panitumumab was discontinued in both the FOLFOX and FOLFIRI
arms [45]. Similar to cetuximab, this trial with panitumumab argues against the
combined use of these agents with bevacizumab in mCRC.


## 2.5. Sorafenib

Sorafenib is a novel multikinase
inhibitor with antiangiogenic and proapoptotic activity targeting EGFR as well as multiple kinases including Raff/MAPK-ERK kinase, VEGFR-2, VEGFR-3, and PDGFR-β
[39]. It is approved for use in the treatment of renal cell carcinoma (RCC) and
hepatocellular carcinoma (HCC).RCC is characterized by the loss of
the von hippel landau (VHL) gene, which leads to dysregulation of the VEGFR,
PDGFR-β, transforming growth factor-alpha (TGF-) α, EGFR, and Raf pathways promoting
angiogenesis, lymphangiogenesis, tumor cell growth, and survival. Furthermore,
RCC frequently displays EGFR immunoreactivity. Membranous and/or cytoplasmic
EGFR immunostaining in RCC was present in 123 of 132 (93%) primary and 49 of 53
(92%) metastatic samples with extensive immunoreactivity present in 83% of
primary and 74% of metastatic tumors [46].In previously treated patients with
metastatic RCC, the activity of sorafenib was demonstrated in two randomized
trials. In the largest of these studies, a randomized phase III trial of
metastatic cytokine refractory RCC, significant response and improvement in PFS
was demonstrated (Table4). At ASCO 2007, a final analysis of survival was
presented. There was no statistically significant improvement in OS; survival
benefit was likely obscured since one half of the patients originally assigned
to placebo had switched to sorafenib [47].Table 4
Selected clinical
trials of panitumumab.mCRC, metastatic
colorectal cancer; BSC, best supportive care; OS, overall survival; PFS, progression free survival; ORR, overall response rate; SD, stable disease; FOLFOX, 5 Flourouracil/Folinic Acid and oxaliplatin; FOLFIRI, 5 Flourouracil/Folinic Acid and Irinotecan.
MalignancyRegimenNumber of patientsResultsCommentsmCRCPanitumumab vs. BSC
[35]463 pts
Pts with progression after
standard chemotherapyPanitumumab:  ORR (10%)
PFS (13.8 weeks)  BSC:
ORR (0%)  PFS (8.5 weeks)No significant improvement in
OSmCRCPanitumumab monotherapy after
disease progression with BSC
[36]176 pts
Pts with progression of
disease in BSC arm of Panitumumab vs. BSC trial [35]Panitumumab:  ORR (11.6%)
SD (33%)  Median PFS of 9.4 weeksResults comparable to initial
studymCRCFOLFOX or FOLFIRI with
Bevacizumab +/− Panitumumab
[37]823 ptsFOLFOX, Bevacizumab,
Panitumumab:
Median PFS (9.5 mo)  OS (19.3 mo)
FOLFOX, Bevacizumab:  Median PFS (11 mo)
OS (20.6 mo)Panitumumab in combination
with FOLFOX and bevacizumab was associated with a shorter PFS and increased
toxicityEGFR is frequently expressed in human
hepatoma cells; in fact, EGF is one of the mitogens required for the growth of
hepatoma cells. At the ASCO meeting in 2007, data was released showing the
efficacy of sorafenib in HCC. The Sorafenib HCC Assessment Randomized Protocol
(SHARP) Trial was a large phase III double-blind placebo-controlled study
evaluating the efficacy of sorafenib versus BSC in patients with advanced HCC
who had not received previous chemotherapy. Patients receiving sorafenib had a
three-month median survival benefit compared to placebo. Importantly, sorafenib was
the first active treatment that has been proven to confer a survival benefit
and to show promise as a standard treatment for advanced HCC [48]. In another
phase III randomized trial of sorafenib in Asia-Pacific patients with HCC,
results mirrored those of the SHARP trial. Despite Asia-Pacific patients having
more advanced disease based on the Eastern Cooperative Oncology Group
performance status (ECOG PS), a significant OS advantage with sorafenib was
confirmed [49]. A North American phase II randomized trial of doxorubicin with
sorafenib versus doxorubicin with placebo in 96 Child-Pugh A patients was
published in abstract form and presented at the 2007 European Cancer
Organization Conference (ECCO). Median TTP was two months longer in the
combination arm, but did not reach statistical significance. However, OS was
significantly longer for the combination of sorafenib/doxorubicin compared to
the doxorubicin only arm (13.7 vs. 6.5 mo) [50].Sorafenib has also recently
demonstrated significant activity in the treatment of iodine-refractory thyroid
carcinoma. In a phase II trial of 30 subjects, most of the patients (80%)
showed a clinical benefit from this agent. Ninety-five percent of individuals
with available thyroglobulin levels showed a rapid response in thyroglobulin
levels with a mean decrease of 70%. These results represent a significant
advance in both response and PFS over studies in the past utilizing
chemotherapy [51].


## 2.6. Sunitinib

Like sorafenib, sunitinib is an oral small
molecule TKI that inhibits cellular signaling by targeting EGFR, VEGFR, PDGFR-β,
fetal liver tyrosine kinase receptor (FLT-3), and c-Kit, a stem cell factor
receptor [52]. This ultimately targets both angiogenesis and tumor cell
proliferation causing tumor shrinkage and cell death. Sunitinib is currently
approved for the treatment of RCC as well as  gastrointestinal stromal tumors  GISTs. Like RCC, EGFR expression
in GISTs had been validated in a recent article in which tissue microarray
samples of 33 GISTs were surveyed by IHC. EGFR expression was identified in 8
of those samples [53].The antitumor activity of sunitinib
was initially shown in two phase II trials of metastatic RCC patients who had
failed previous cytokine therapy [54, 55]. This led to a large phase III trial
comparing sunitinib to interferon-alpha (IFN-α) as first-line therapy (Table 5). Sunitinib showed superior activity in ORR and in PFS, including patients
with good, intermediate, and poor risk features. Furthermore, OS was
significantly longer in the sunitinib arm, despite significant patient crossover
from the IFN-α arm to sunitinib [56]. Sunitinib was also found to be superior
in QOL compared to IFN-α [57].Table 5
Selected clinical
trials of sorafenib.PFS,
progression free survival; OS, overall survival; PR, partial
response; CR, complete response; HCC, hepatocellular carcinoma; RCC,
renal cell carcinoma; TBRR, Tumor burden reduction rate.
MalignancyRegimenNumber of patientsResponse rateCommentsRCCSorafenib vs. placebo
[41]903
Resistant to standard therapySorafenib:
Median PFS (5.5 mo)  PR (10%)
Placebo:  Median PFS (2.8 mo)P<0.01  PR (2%)The OS showed reduced risk of
death compared with placebo but the results were not statistically
significantHCCSorafenib vs. placebo
[42]602 pts
No previous therapySorafenib:
Median OS (10.7 mo)  Placebo:
Median OS (7.9 mo)The median OS was
significantly longer in patients who received Sorafenib
HR (0.69),P=.0006Metastatic thyroid carcinomaSorafenib monotherapy [45]36 pts
Metastatic, iodine-refractory
thyroid carcinomaPR in 7 pts (21%)  SD in 20 pts (59%)Significant anti-tumor
activity with overall clinical benefit rate (PR + SD) of 80%Sunitinib has also shown significant
activity in metastatic and/or unresectable GIST following imatinib failure. In
a phase III randomized trial comparing sunitinib to placebo in imatinib
refractory GIST patients, time to tumor progression and PFS was 4-fold longer
in patients on sunitinib compared to placebo; partial response (PR) and stable
disease (SD) were also significantly longer in the sunitinib arm. Patients in
the placebo arm were subsequently allowed to crossover to the Sunitinib arm if
disease progression was documented during the study. The crossover patient
population yielded comparable results. Despite the crossover, OS favored patients
initially treated with sunitinib [58].


## 2.7. Lapatinib

Activation and overexpression of
oncogenes encoding trans-membrane receptor tyrosine kinases of the EGFR family,
including EGFR (ErbB1) and HER2/neu (ErbB2), play an important role in the
development of breast cancer [58]. Lapatinib is an orally active
4-anilinoquinazoline TKI of both HER2/neu (ErbB2) and EGFR (ErbB1). It inhibits
the autophosphorylation sites on the receptors, thereby blocking the downstream
signaling pathways of HER2 and EGFR.Lapatinib has shown activity for the
treatment of advanced HER2/neu positive metastatic breast cancer refractory to
trastuzumab (Table6). Unlike trastuzumab, lapatinib seems to have activity
against brain metastases [59–61]. Primary and secondary resistances have been
seen in patients with HER2-positive breast cancers who had been treated with
trastuzumab both in the metastatic and adjuvant settings
[53, 62–65]. Potential
mechanisms of resistance may be related to signaling through other receptors
such as EGFR or IGFR-1 [66]. Lapatinib, being a small molecule TKI, interacts
with intercellular domains and does not require full receptor activity. In a
phase III study of HER2-positive advanced or metastatic breast cancer
refractory to anthracyclines, taxanes, and trastuzumab, lapatinib plus
capecitabine showed a significant advantage over capecitabine monotherapy with
respect to ORR and PFS with a nonsignificant trend toward longer OS [67]. In
another phase III randomized trial, the combination of paclitaxel with lapatinib
compared to paclitaxel monotherapy in patients with HER2-positive cancer was
evaluated. Patients in this trial were not treated with prior trastuzumab. The
study showed a statistically significant advantage in ORR and TTP, but not in
OS. Enrollment for this study came from countries with limited HER2 testing.
Only 91 of 580 patients were HER2-positive on central testing, with
retrospective analysis revealing benefit limited to FISH-positive or IHC 3+
tumors [68].Table 6
Selected clinical
trials of sunitinib.GIST, gastrointestinal
stromal tumor; PFS, progression free survival; OS, overall
survival; PR, partial response; CR, complete response; TTP, time
to progression;  m RCC, metastatic renal cell carcinoma; QOL, quality
of life.
MalignancyRegimenNumber of patientsResponse rateCommentsRCCInterferon vs. Sunitinib
[48]750 pts
Previously untreated mRCCSunitinib:
Median PFS (11 mo)  ORR (31%)
OS (26.4 mo),P = 0.051  Interferon:
Median PFS (5 mo)  ORR (6%)
OS (21.8 mo)Sunitinib provides superior
QOL compared with IFN-α in mRCC patients.GISTSunitinib vs. placebo [50]312 pts  After progression or
intolerance to imatinibSunitinib: TTP(6.3 mo)
Placebo:  TTP(1.5 month)Sunitinib significantly
improved TTP with a 67% reduced risk of progression.


## 3. Anti-EGFR Agent-Associated Toxicity

EGFR is expressed on nearly all
normal cells, particularly those of epithelial origin such as skin, liver, and
gastrointestinal tract, but not on hematopoietic cells [69]. As a consequence,
the most commonly encountered toxic effects from these agents are rash and
diarrhea. Along with other toxicities, recognition and management of associated
adverse effects with anti-EGFR agents will result in improved clinical
outcomes, patient compliance, and QOL.


### 3.1. Skin Toxicity

When EGF was initially discovered, it
was named for its ability to increase growth and keratinization of skin
epithelium [69]. EGFR was found to be expressed in the human skin within
keratinocytes, the follicular epithelium, sweat and sebaceous glands, and in
capillaries of the dermis [70–73]. For this reason, the most common
toxicity of EGFR-targeted agents involves the skin and adnexal structures
resulting in a rash and less commonly nail toxicity.EGFR is expressed on hair follicles
and sebaceous glands and the binding of this receptor by inhibitors leads to a
disruption in proliferation, resulting in an immunological reaction with skin
inflammation, folliculitis, and rash [72, 73]. The most commonly seen skin
reaction with EFGR inhibitors is a follicular acneiform eruption, also termed
acne-like rash or folliculitis. EGFR-associated rash differs from acne in that
there are no comedones or blackheads. The incidence of an acneiform-like skin
rash has been reported to occur in about 85% of cetuximab-treated patients
[74, 75]. Symptoms typically appear within two weeks after starting treatment.
This is mainly located on the face (nose, cheeks, nasolabial folds, chin,
forehead, and in a perioral distribution). Other locations include the
shoulders and upper part of the back and chest. The rash tends to improve over
time even with continued use and does resolve fully after cessation of therapy.
In 35% of patients, dry itchy skin of the arms and legs can occur, which can
potentially become secondarily infected by Staphylococcus aureus or Herpes
simplex infection [76].There have been numerous studies
showing a direct correlation between  the severity of a rash with response and OS.
In fact, the  greatest benefit in survival of cetuximab-treated patients is seen
in those with a grade 3 rash [27, 75, 76]. The degree of skin toxicity has been
classified by The National Cancer Institute Common Toxicity Criteria version
3.0 (Table 7). Prospective trials are needed to further investigate the
correlation between anti-EGFR therapy and rash to elucidate the validity and
clinical implications of this association.Table 7
Selected clinical
trials of lapatinib.MBC, metastatic
breast cancer; PFS, progression free survival; OS, overall
survival; TTP, time to progression.
MalignancyRegimenNumber of patientsResponse rateCommentsMBCCapecitibine +/− Lapatinib
[59]324 pts
HER2-positive MBC that had
progressed with chemotherapy (anthracycline, a taxane, and trastuzumab)Capecitabine, Lapatinib:  TTP (6.2 mo)
ORR (24%) Capecitabine monotherapy:
TTP (4.3 mo) ORR (14%)Non-significant trend toward
improved OS favoring lapatinib
Fewer pts in the lapatinib arm
developed brain metastases as the first site of progression (13 vs. 4%)MBCLapatinib, Paclitaxel vs.
Paclitaxel monotherapy
[60]580 pts
55% received prior
chemotherapy or hormonal therapy
No pts received prior
traztuzumabLapatinib, Paclitaxel:  ORR (60%)
Median TTP (8 mo) Paclitaxel monotherapy:
ORR (36%) Median TTP (6 mo)Improved clinical outcome was
seen with the combination without a significant change in side effect profile
No difference in OS, but
majority of pts were not properly tested for HER2Recommendations in the management of
EGFR-associated rash have been limited by the lack of clinical trials
evaluating rash therapies (Table8). This has led to treatment recommendations based  on
the clinical experience of dermatologists and oncologists familiar with
EGFR-associated rash. In general, preventive measures are essential and include
avoidance of soaps, limiting shower time, use of lukewarm water, and liberal
use of skin moisturizers and emollients. Beneficial topical treatment
approaches for a grade 1 rash include the use of antibiotic agents
(metronidazole, erythromycin, and clindamycin lotion) as well as local
corticosteroid cream if an extensive inflammatory component is present. For
grade 2 reactions, anti-inflammatory oral antibiotics (minocycline or
doxycycline) should be used since secondary infections are common. In the event
of a grade 3 rash, oral corticosteroids and antibiotics should be utilized and
EGFR-targeted therapy should be held until the acute inflammatory phase has
resolved [77, 78].Table 8
Management of
anti-EGFR-associated rash and common terminology criteria for adverse events
v3.0 (CTCAE), National Cancer
Institute.
CTC GradeRashManagement1Macular or papular eruption or
erythema
AsymptomaticTopical antibiotic agents
(metronidazole, erythromycin, and clindamycin lotion)
Corticosteroid cream if an
extensive inflammatory component exists2Macular or papular eruption or
erythema
Symptomatic covering <50%
of bodyAnti-inflammatory oral
antibiotics (minocycline or doxycycline)
Corticosteroid cream if an
extensive inflammatory component exists3Macular or papular eruption or
erythema
Symptomatic covering >50%
of bodyAnti-inflammatory oral
antibiotics (minocycline or doxycycline)
Oral corticosteroids EGFR therapy should be held
until the acute inflammatory phase has resolved4Generalized exfoliative, ulcerative, or bullouis dermatitisAnti-inflammatory oral
antibiotics (minocycline or doxycycline)
Oral corticosteroids
(Medrol-dose pack)
EGFR therapy should be held
until the acute inflammatory phase has resolvedRash and hand-foot syndrome,
characterized by redness, ulceration, and dysesthesia of the palms and soles,
are the most common adverse events associated with sorafenib and sunitinib.
Hand-foot syndrome associated with these agents occurs in 20–30% of patients,
with less than 10% experiencing grade 3 or higher toxicity. It rapidly resolves
with drug discontinuation and topical emollients and moisturizers are used to
prevent and diminish toxicity. Other associated adverse events seen with
sorafenib and sunitinib include diarrhea, hypertension, fatigue, and
hematologic cytopenias [79, 80].Anti-EGFR therapy can also result in
nail toxicity, which can occur in 10–15% of patients after 4–8 weeks of
therapy. It can progress into a paronychia like cracking reaction, a painful
and difficult to treat side effect [74]. Some individuals require several
months for complete healing after cessation of therapy [71]. Hair disorders are
also commonly seen with these agents. Since EGFR signaling plays a vital role
in the initiation of hair growth, interruption of EGFR signaling can result in
disorganized hair follicles leading to follicular necrosis and alopecia
[81, 82].Nimotuzumab, which is marketed under the name
of BIOMAbegfr, is a recombinant
humanized IgG1 monoclonal antibody targeting EGFR. It has been approved for SCC
of the head and neck and glioma in a number of countries. In the clinical
trials thus far, nimotuzumab has not been associated with skin toxicity.
Further clinical trials in different cancers are currently ongoing [83].


### 3.2. Gastrointestinal Toxicity

The use of oral anti-EGFR TKIs has
been found to be strongly associated with gastrointestinal toxicities including
diarrhea and hepatotoxicity. The pathophysiology of anti-EGFR-induced diarrhea
is thought to result from excessive chloride secretion inducing a secretory
diarrhea [84]. In large randomized trials, oral TKIs erlotinib and lapatinib
have been found to cause diarrhea in 40–60% of patients with approximately 10%
experiencing grade 3 or 4 toxicity [11, 14]. The reported incidence of diarrhea
associated with sorafenib and sunitinib has been 20–40% [79, 81]. Diarrhea
induced by oral TKIs can be managed by lowering the dose and rarely involves
treatment interruption. Loperamide is a useful therapy decreasing intestinal
motility.Hepatic toxicity with asymptomatic
elevations of transaminases and hyperbilirubinemia is commonly associated with
oral TKIs. The mechanism of action is thought to be direct targeting of
hepatocytes that overexpress EGFR with potential induction of chronic hepatitis
with active necrosis. The overall incidence of hepatotoxicity with oral
anti-EGFR TKIs has been reported at around 10% (2% grade 2 or 3) [11, 14, 79, 80].
These compounds can be continued with mild hyperbilirubinemia and should be
discontinued with grade 3 or 4 toxicity. Concurrent TKIs and hepatotoxic drugs
should be used with caution.


### 3.3. Pulmonary Toxicity

Interstitial lung disease related to
gefitinib therapy has been well reported, with a worldwide incidence estimated
at 1% [85, 86]. In a small series from Japan, the incidence of ILD in 112
patients receiving gefitinib was estimated at 5.4% [87]. Four deaths occurred,
all being in current or former smokers, with pre-existing pulmonary fibrosis
being a significant risk factor. The adverse pulmonary effects of erlotinib are
less well known, but cases of fatal ILD have been reported [88, 89]. A phase 3b
trial has been initiated to examine the efficacy and safety of erlotinib in advanced
NSCLC with disease progression after chemotherapy. From a total of 229
patients, one (0.4%) interstitial lung disease-like event was reported [90].


### 3.4. Cardiac Toxicity

Cardiac toxicity with anti-EGFR TKIs
has been reported. It is clear that cardiotoxicity with TKIs is not a  “class effect,”
since it does not occur with all known agents. Sunitinib caused a decline in
left ventricular ejection fraction (LVEF) below 50% in 11% of the patients
[91]. In a phase III trial comparing sunitinib to IFN-α, 10% of patients had
declines in LVEF after a median duration treatment of 6 months [56]. Sorafenib
has induced acute coronary syndromes, including myocardial infarction. In the
RCC study comparing sorafenib to placebo, 2.9% of sorafenib-treated patients
had a myocardial infarction, compared to 0.4% in placebo-treated patients [47].
The cardiac toxicity of lapatinib was analyzed in 3.558 patients treated in 18
phase I–III clinical trials; 598 received prior anthracyclines and 759 had been
given trastuzumab in the past [92]. Lapatinib was associated with a decline in
LVEF in 1.6% of patients (58 of 3,558). The mean LVEF decrease was 18.7% and
was mostly asymptomatic (1.4% asymptomatic and 0.2% symptomatic). Of the seven
with symptomatic LVEF decrease, cardiotoxicity resolved in all but one patient.


### 3.5. Allergic Reactions

Allergic and anaphylactoid reactions
are associated with cetuximab and, less often, panitumumab administration
[26, 75]. Severe reactions are observed in approximately 3% of patients
following cetuximab administration, with a fatal outcome in 0.1% of patients
[93, 94]. Up to 90% of severe reactions associated with cetuximab occur within
the first few minutes of the first dose [95]. The decision to rechallenge or
discontinue treatment after a reaction occurs depends on the severity of the
reaction. In the case of anaphylactic reactions, further therapy with cetuximab
is contraindicated. Mild-to-moderate hypersensitivity reactions can be managed
by temporary infusion interruption and resuming at a slower infusion rate.
Management of severe reactions must include immediate interruption and
treatment with epinephrine. Corticosteroids, antihistamines, bronchodilators,
and oxygen also might be required.Hypersentivity reactions to cetuximab
might correlate with the development of specific antihuman IgE antibodies [96].
On the contrary, no antihuman antibodies have been detected with panitumumab.
The incidence of hypersensitivity reactions with panitumumab in multiple trials
has been approximately 3%, with severe reactions accounting for approximately
1% [97]. The successful use of panitumumab after severe hypersensitivity
reactions to cetuximab has been reported, but requires further investigation
[98].


## 3.1. Skin Toxicity

When EGF was initially discovered, it
was named for its ability to increase growth and keratinization of skin
epithelium [69]. EGFR was found to be expressed in the human skin within
keratinocytes, the follicular epithelium, sweat and sebaceous glands, and in
capillaries of the dermis [70–73]. For this reason, the most common
toxicity of EGFR-targeted agents involves the skin and adnexal structures
resulting in a rash and less commonly nail toxicity.EGFR is expressed on hair follicles
and sebaceous glands and the binding of this receptor by inhibitors leads to a
disruption in proliferation, resulting in an immunological reaction with skin
inflammation, folliculitis, and rash [72, 73]. The most commonly seen skin
reaction with EFGR inhibitors is a follicular acneiform eruption, also termed
acne-like rash or folliculitis. EGFR-associated rash differs from acne in that
there are no comedones or blackheads. The incidence of an acneiform-like skin
rash has been reported to occur in about 85% of cetuximab-treated patients
[74, 75]. Symptoms typically appear within two weeks after starting treatment.
This is mainly located on the face (nose, cheeks, nasolabial folds, chin,
forehead, and in a perioral distribution). Other locations include the
shoulders and upper part of the back and chest. The rash tends to improve over
time even with continued use and does resolve fully after cessation of therapy.
In 35% of patients, dry itchy skin of the arms and legs can occur, which can
potentially become secondarily infected by Staphylococcus aureus or Herpes
simplex infection [76].There have been numerous studies
showing a direct correlation between  the severity of a rash with response and OS.
In fact, the  greatest benefit in survival of cetuximab-treated patients is seen
in those with a grade 3 rash [27, 75, 76]. The degree of skin toxicity has been
classified by The National Cancer Institute Common Toxicity Criteria version
3.0 (Table 7). Prospective trials are needed to further investigate the
correlation between anti-EGFR therapy and rash to elucidate the validity and
clinical implications of this association.Table 7
Selected clinical
trials of lapatinib.MBC, metastatic
breast cancer; PFS, progression free survival; OS, overall
survival; TTP, time to progression.
MalignancyRegimenNumber of patientsResponse rateCommentsMBCCapecitibine +/− Lapatinib
[59]324 pts
HER2-positive MBC that had
progressed with chemotherapy (anthracycline, a taxane, and trastuzumab)Capecitabine, Lapatinib:  TTP (6.2 mo)
ORR (24%) Capecitabine monotherapy:
TTP (4.3 mo) ORR (14%)Non-significant trend toward
improved OS favoring lapatinib
Fewer pts in the lapatinib arm
developed brain metastases as the first site of progression (13 vs. 4%)MBCLapatinib, Paclitaxel vs.
Paclitaxel monotherapy
[60]580 pts
55% received prior
chemotherapy or hormonal therapy
No pts received prior
traztuzumabLapatinib, Paclitaxel:  ORR (60%)
Median TTP (8 mo) Paclitaxel monotherapy:
ORR (36%) Median TTP (6 mo)Improved clinical outcome was
seen with the combination without a significant change in side effect profile
No difference in OS, but
majority of pts were not properly tested for HER2Recommendations in the management of
EGFR-associated rash have been limited by the lack of clinical trials
evaluating rash therapies (Table8). This has led to treatment recommendations based  on
the clinical experience of dermatologists and oncologists familiar with
EGFR-associated rash. In general, preventive measures are essential and include
avoidance of soaps, limiting shower time, use of lukewarm water, and liberal
use of skin moisturizers and emollients. Beneficial topical treatment
approaches for a grade 1 rash include the use of antibiotic agents
(metronidazole, erythromycin, and clindamycin lotion) as well as local
corticosteroid cream if an extensive inflammatory component is present. For
grade 2 reactions, anti-inflammatory oral antibiotics (minocycline or
doxycycline) should be used since secondary infections are common. In the event
of a grade 3 rash, oral corticosteroids and antibiotics should be utilized and
EGFR-targeted therapy should be held until the acute inflammatory phase has
resolved [77, 78].Table 8
Management of
anti-EGFR-associated rash and common terminology criteria for adverse events
v3.0 (CTCAE), National Cancer
Institute.
CTC GradeRashManagement1Macular or papular eruption or
erythema
AsymptomaticTopical antibiotic agents
(metronidazole, erythromycin, and clindamycin lotion)
Corticosteroid cream if an
extensive inflammatory component exists2Macular or papular eruption or
erythema
Symptomatic covering <50%
of bodyAnti-inflammatory oral
antibiotics (minocycline or doxycycline)
Corticosteroid cream if an
extensive inflammatory component exists3Macular or papular eruption or
erythema
Symptomatic covering >50%
of bodyAnti-inflammatory oral
antibiotics (minocycline or doxycycline)
Oral corticosteroids EGFR therapy should be held
until the acute inflammatory phase has resolved4Generalized exfoliative, ulcerative, or bullouis dermatitisAnti-inflammatory oral
antibiotics (minocycline or doxycycline)
Oral corticosteroids
(Medrol-dose pack)
EGFR therapy should be held
until the acute inflammatory phase has resolvedRash and hand-foot syndrome,
characterized by redness, ulceration, and dysesthesia of the palms and soles,
are the most common adverse events associated with sorafenib and sunitinib.
Hand-foot syndrome associated with these agents occurs in 20–30% of patients,
with less than 10% experiencing grade 3 or higher toxicity. It rapidly resolves
with drug discontinuation and topical emollients and moisturizers are used to
prevent and diminish toxicity. Other associated adverse events seen with
sorafenib and sunitinib include diarrhea, hypertension, fatigue, and
hematologic cytopenias [79, 80].Anti-EGFR therapy can also result in
nail toxicity, which can occur in 10–15% of patients after 4–8 weeks of
therapy. It can progress into a paronychia like cracking reaction, a painful
and difficult to treat side effect [74]. Some individuals require several
months for complete healing after cessation of therapy [71]. Hair disorders are
also commonly seen with these agents. Since EGFR signaling plays a vital role
in the initiation of hair growth, interruption of EGFR signaling can result in
disorganized hair follicles leading to follicular necrosis and alopecia
[81, 82].Nimotuzumab, which is marketed under the name
of BIOMAbegfr, is a recombinant
humanized IgG1 monoclonal antibody targeting EGFR. It has been approved for SCC
of the head and neck and glioma in a number of countries. In the clinical
trials thus far, nimotuzumab has not been associated with skin toxicity.
Further clinical trials in different cancers are currently ongoing [83].


## 3.2. Gastrointestinal Toxicity

The use of oral anti-EGFR TKIs has
been found to be strongly associated with gastrointestinal toxicities including
diarrhea and hepatotoxicity. The pathophysiology of anti-EGFR-induced diarrhea
is thought to result from excessive chloride secretion inducing a secretory
diarrhea [84]. In large randomized trials, oral TKIs erlotinib and lapatinib
have been found to cause diarrhea in 40–60% of patients with approximately 10%
experiencing grade 3 or 4 toxicity [11, 14]. The reported incidence of diarrhea
associated with sorafenib and sunitinib has been 20–40% [79, 81]. Diarrhea
induced by oral TKIs can be managed by lowering the dose and rarely involves
treatment interruption. Loperamide is a useful therapy decreasing intestinal
motility.Hepatic toxicity with asymptomatic
elevations of transaminases and hyperbilirubinemia is commonly associated with
oral TKIs. The mechanism of action is thought to be direct targeting of
hepatocytes that overexpress EGFR with potential induction of chronic hepatitis
with active necrosis. The overall incidence of hepatotoxicity with oral
anti-EGFR TKIs has been reported at around 10% (2% grade 2 or 3) [11, 14, 79, 80].
These compounds can be continued with mild hyperbilirubinemia and should be
discontinued with grade 3 or 4 toxicity. Concurrent TKIs and hepatotoxic drugs
should be used with caution.


## 3.3. Pulmonary Toxicity

Interstitial lung disease related to
gefitinib therapy has been well reported, with a worldwide incidence estimated
at 1% [85, 86]. In a small series from Japan, the incidence of ILD in 112
patients receiving gefitinib was estimated at 5.4% [87]. Four deaths occurred,
all being in current or former smokers, with pre-existing pulmonary fibrosis
being a significant risk factor. The adverse pulmonary effects of erlotinib are
less well known, but cases of fatal ILD have been reported [88, 89]. A phase 3b
trial has been initiated to examine the efficacy and safety of erlotinib in advanced
NSCLC with disease progression after chemotherapy. From a total of 229
patients, one (0.4%) interstitial lung disease-like event was reported [90].


## 3.4. Cardiac Toxicity

Cardiac toxicity with anti-EGFR TKIs
has been reported. It is clear that cardiotoxicity with TKIs is not a  “class effect,”
since it does not occur with all known agents. Sunitinib caused a decline in
left ventricular ejection fraction (LVEF) below 50% in 11% of the patients
[91]. In a phase III trial comparing sunitinib to IFN-α, 10% of patients had
declines in LVEF after a median duration treatment of 6 months [56]. Sorafenib
has induced acute coronary syndromes, including myocardial infarction. In the
RCC study comparing sorafenib to placebo, 2.9% of sorafenib-treated patients
had a myocardial infarction, compared to 0.4% in placebo-treated patients [47].
The cardiac toxicity of lapatinib was analyzed in 3.558 patients treated in 18
phase I–III clinical trials; 598 received prior anthracyclines and 759 had been
given trastuzumab in the past [92]. Lapatinib was associated with a decline in
LVEF in 1.6% of patients (58 of 3,558). The mean LVEF decrease was 18.7% and
was mostly asymptomatic (1.4% asymptomatic and 0.2% symptomatic). Of the seven
with symptomatic LVEF decrease, cardiotoxicity resolved in all but one patient.


## 3.5. Allergic Reactions

Allergic and anaphylactoid reactions
are associated with cetuximab and, less often, panitumumab administration
[26, 75]. Severe reactions are observed in approximately 3% of patients
following cetuximab administration, with a fatal outcome in 0.1% of patients
[93, 94]. Up to 90% of severe reactions associated with cetuximab occur within
the first few minutes of the first dose [95]. The decision to rechallenge or
discontinue treatment after a reaction occurs depends on the severity of the
reaction. In the case of anaphylactic reactions, further therapy with cetuximab
is contraindicated. Mild-to-moderate hypersensitivity reactions can be managed
by temporary infusion interruption and resuming at a slower infusion rate.
Management of severe reactions must include immediate interruption and
treatment with epinephrine. Corticosteroids, antihistamines, bronchodilators,
and oxygen also might be required.Hypersentivity reactions to cetuximab
might correlate with the development of specific antihuman IgE antibodies [96].
On the contrary, no antihuman antibodies have been detected with panitumumab.
The incidence of hypersensitivity reactions with panitumumab in multiple trials
has been approximately 3%, with severe reactions accounting for approximately
1% [97]. The successful use of panitumumab after severe hypersensitivity
reactions to cetuximab has been reported, but requires further investigation
[98].


## 4. Conclusions

Therapeutic agents in clinical
practice targeting the EGFR pathway have made great advances in the treatment
of malignancy. EGFR activation is associated with proliferation,
antiapoptosis, and metastatic spread, making this pathway a compelling target.
Numerous large clinical trials have shown clinical evidence of anticancer
activity with these new agents resulting in improved tumor response and
patients' survival. Several other anti-EGFR agents are in development, giving
hope to future advances in therapy. An awareness and proper management of
associated toxicities can increase patient compliance, QOL, and overall
treatment success. Ongoing and future research will expand the applications of
anti-EGFR therapy, elucidate optimal combinations and sequences, discover
pathways of resistance, and continue to benefit cancer patients.



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*Source: 567486-2009-05-06.xml*