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Lung Cancer
Clinical Implications of EGFR Expression in the Development and
Progression of Solid Tumors: Focus on Non-Small Cell Lung Cancer
David S. Ettinger

The Sidney Kimmel Comprehensive Cancer Center,

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Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

Key Words. EGFR • Cancer therapy • Lung cancer • Anti-EGFR agents

Learning Objectives
After completing this course, the reader will be able to:
1. Describe the EGFR signaling pathway as a target for new anticancer agents.
2. Characterize the various EGFR agents developed for the treatment of NSCLC.
3. Identify the appropriate indications for the use of these new agents.
CME Access and take the CME test online and receive 1 AMA PRA category 1 credit at CME.TheOncologist.com

Abstract
Dysregulation of the epidermal growth factor receptor
(EGFR) signaling pathway is associated with the devel-
opment and progression of malignancy, and EGFR-tar-
geted therapies offer the promise of better treatment
for many types of solid tumors, including non-small
cell lung cancer. Anti-EGFR agents include monoclo-
nal antibodies (mAbs) targeting the EGFR extracel-
lular receptor domain and small-molecule tyrosine
kinase inhibitors (TKIs) targeting the EGFR intracel-
lular kinase domain. Both mAbs and TKIs have dem-
onstrated encouraging results as monotherapies and in
combination with chemotherapy and radiotherapy. This
review provides a critical update on the status of these
novel therapeutics. The Oncologist 2006;11:358–373

Introduction This review focuses on new approaches in NSCLC

Lung cancer is a major cause of morbidity and mortality therapy using monoclonal antibodies (mAbs) and tyrosine
worldwide. In the U.S., 172,570 new cases and 163,510 kinase inhibitors (TKIs) targeting molecules involved in
related deaths were predicted for 2005, with lung cancer tumor growth and angiogenesis, including the epidermal
comprising ~29% of all cancer deaths [1, 2]. Between 80% growth factor receptor (EGFR) and vascular endothelial
and 87% of newly diagnosed lung cancers are non-small growth factor (VEGF).
cell lung cancer (NSCLC). Advanced presentation and lack
of effective treatment options afford poor prognoses [3, 4], Current Concepts in Advanced
and despite notable technological progress, improvements NSCLC Chemotherapy
in NSCLC survival over the past two decades have been Chemotherapy for advanced, inoperable NSCLC is gener-
modest [5]. ally palliative. The potential benefits of improved tumor
Correspondence: David S. Ettinger, M.D., The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medi-
cine, Bunting Blaustein Cancer Research Bldg., 1650 Orleans Street, Room G88, Baltimore, Maryland 21213-1000, USA. Telephone:
410-955-8847; Fax: 410-614-9424; e-mail: ettinda@jhmi.edu Received December 6, 2005; accepted for publication February 22, 2006.
©AlphaMed Press 1083-7159/2006/$20.00/0

The Oncologist 2006;11:358–373 www.TheOncologist.com

Ettinger
size, symptoms, and quality of life are mitigated by the dis-
advantages of increased hospitalization, inconvenience,
cost, and serious adverse events [6]. The advent of pacli-
taxel, gemcitabine, vinorelbine, irinotecan, and topotecan
and their combination with platinum drugs has modestly
improved response rates (RRs) and survival (Table 1) [3,
6]. Although cisplatin combinations with any of the newer
agents produce longer survival times than carboplatin com-
binations [7], no particular platinum-based regimen has
demonstrated superior efficacy over any other. A random-
ized, controlled study comparing paclitaxel plus carbo-
platin with vinorelbine plus cisplatin in 202 patients with
advanced NSCLC demonstrated fewer life-threatening tox-
icities and greater convenience and tolerability for paclitaxel
plus carboplatin but a similar overall RR and median sur-
vival time [8]. A randomized, controlled study evaluating
four platinum-containing regimens in 1,155 patients found
that the overall RR and survival time did not differ signifi-
cantly for paclitaxel plus cisplatin, gemcitabine plus cispla-
tin, docetaxel plus cisplatin, and paclitaxel plus carboplatin,
although paclitaxel plus carboplatin had lower toxicity [9].
Other randomized, controlled studies showed that the gem-
citabine plus cisplatin and gemcitabine plus paclitaxel did
not produce a longer overall survival time compared with
paclitaxel plus cisplatin [10] and that docetaxel plus cispla-
tin produced more favorable overall response and survival
rates than vinorelbine plus cisplatin [11]. Median survival
times for patients receiving these standard chemotherapy
regimens have generally been 8–11 months.
A triweekly docetaxel regimen is the current standard
for second-line chemotherapy in NSCLC, with an approxi-
mately 12% RR and 6–8 months median survival time
[12]. Weekly paclitaxel courses have been well received
and have resulted in an approximately 9 months’ median
survival time [13]. Pemetrexed, compared with docetaxel
as second-line treatment for NSCLC in phase III studies,
appeared to have similar efficacy but significantly fewer
adverse effects [14].
Despite these advancements, a plateau of effectiveness
appears to have been reached for the treatment of NSCLC
with standard chemotherapy [3], and substituting one agent
for another in combination chemotherapy regimens does not
necessarily guarantee a significantly better overall RR and
survival [15]. Current research efforts in both first- and sec-
ond-line treatments for NSCLC focus on a number of prom-
ising agents targeted against the EGFR signaling pathway.
EGFR Biology and Expression in NSCLC
EGFR, a member of the HER/Erb-B family of receptor
tyrosine kinases, mediates cell proliferation, differen-
tiation, survival, angiogenesis, and migration [16]. This
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359
molecule consists of an extracellular domain that binds
EGF, transforming growth factor alpha (TGF-α), and
other growth factors; a short transmembrane region; and
an intracellular tyrosine kinase domain. Ligand binding
leads to homodimerization of EGFR or heterodimerization
of EGFR with another receptor of the Erb-B family and
phosphorylation of specific EGFR tyrosine residues [16].
Tyrosine-phosphorylated receptors then recruit intracel-
lular signaling proteins, converting extracellular signals to
intracellular signal transduction events [17].
Although EGFR plays an important role in maintain-
ing normal cell function, dysregulation of EGFR signaling
pathways contributes to the development of malignancy
via effects on cell-cycle progression, inhibition of apopto-
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sis, induction of angiogenesis, and promotion of tumor-cell
motility and metastasis (Fig. 1) [18]. EGFR is known to be
expressed more abundantly in malignant than in normal tis-
sue, including 40%–80% of NSCLCs [18, 19]. Among the
various histologic types of lung cancer, increased EGFR
expression is most frequent in squamous and large-cell car-
cinomas and least frequent in small-cell carcinomas (Table
2) [20]. EGFR levels are also higher in pathological stage
IV NSCLC than in stage I and II disease and are higher in
cases with higher mediastinal involvement [21].
Mutant EGFRs, including EGFRvIII [22] and in-
frame deletions or amino acid substitutions around the
tyrosine kinase domain ATP-binding pocket [23], have
been reported. The tyrosine kinase mutants demonstrate
enhanced tyrosine kinase activation in response to EGF
and greater sensitivity to TKIs (see below).
Although EGFR expression is important in the devel-
opment and progression of malignancy, reports regarding
its prognostic significance have been conflicting. Some
studies found positive correlations among high levels of
EGFR, tumor invasiveness [24], and poorer survival [25,
26], whereas others showed no correlation between EGFR
expression and survival [27]. EGFR amplification in a
subset of patients from the Iressa NSCLC Trial Assess-
ing Combination Treatment (INTACT) study appeared to
increase progression-free survival (PFS) [28], but sample
size precluded definitive conclusions.
Anti-EGFR–Targeted Approaches to
Treatment of NSCLC
The role of EGFR in carcinogenesis led to the development
and extensive evaluation of EGFR-blocking agents for can-
cer treatment [29, 30]. Two EGFR-targeted approaches
have been explored: (a) mAbs targeting the EGFR extra-
cellular domain and (b) small-molecule TKIs targeting
the intracellular EGFR tyrosine kinase domain. The best-
studied of the anti-EGFR mAbs in NSCLC is cetuximab
360 EGFR Expression in NSCLC

Table 1. Survival and tumor response rates in recent trials of chemotherapeutic agents in non-small cell lung cancer
Median survival 1-Year survival
Treatment No. of patients Response (%) (months) (%)
a
Paclitaxel plus cisplatin 292 21.3 7.8 31
Gemcitabine plus cisplatinb 288 21 8.1 36
Paclitaxel plus carboplatinc 290 15.3 8.2 35
Paclitaxel plus carboplatind 184 27 8 36
Vinorelbine plus cisplatine 181 27 8 33
Gemcitabine plus cisplatinf 69 40.6 8.7 NA
Paclitaxel plus carboplating 123 NA 12.3 51.3
Paclitaxel plus cisplatinh 159 31 8.1 35.5
Gemcitabine plus cisplatini 160 36 8.8 32.6
Paclitaxel plus carboplatinj NA 63 9.9 NA
Vinorelbine plus cisplatin k NA 60 9.5 NA
Vinorelbine plus cisplatinl 394 NA 9.1 42

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Irinotecan plus cisplatinm NA 29 10.6 NA
Irinotecan plus cisplatinn NA NA 10.3 36
Irinotecan plus cisplatino NA 43 11.7 47.5
Paclitaxel plus cisplatinp NA 34 11 NA
Paclitaxel plus cisplatinq NA 37 7 NA
Paclitaxel plus cisplatinr NA 32 8.4 NA
Docetaxel plus cisplatin ~400 32 11.3 21% (2-yr)
Docetaxel plus cisplatin ~150 37 11.3 24% (2-yr)
Topotecan plus cisplatins 15 31 NA NA
Topotecan plus carboplatint 47 13 >7.7 NA
Topotecan plus vinorelbineu NA 42 13 NA
Topotecan, cisplatin, and gemcitabinev 53 17 7 NA
Topotecan, cisplatin, and gemcitabinew 30 38 8.8 NA
Topotecan plus etoposidex 19 5 NA NA
Topotecan plus paclitaxely 18 28 NA NA
Topotecan plus paclitaxely 53 12 NA NA
a 2 2
ECOG study 1594; paclitaxel, 135 mg/m i.v. over 24 hours, day 1; cisplatin, 75 mg/m i.v., day 2 every 3 weeks.
b
ECOG study 1594; gemcitabine, 1,000 mg/m2, days 1, 8, and 15; cisplatin, 100 mg/m 2, day 1 every 4 weeks.
c
ECOG study 1594; paclitaxel, 225 mg/m2 i.v. over 3 hours, day 1; carboplatin, AUC 6.0, day 1 every 3 weeks.
d
SWOG study; paclitaxel, 225 mg/m2 i.v. over 3 hours, day 1; carboplatin, AUC 6.0, day 1 every 3 weeks.
e
SWOG study; vinorelbine, 25 mg/m2 i.v., weekly; cisplatin, 100 mg/m 2 i.v., day 1 every 4 weeks.
f
Gemcitabine, 1,250 mg/m2 i.v., days 1 and 8; cisplatin, 100 mg/m 2 i.v., day 1 every 3 weeks.
g
HOG study; paclitaxel, 200 mg/m2 over 3 hours, day 1 every 3 weeks; carboplatin, AUC 6.0, day 1.
h
EORTC study 08975; paclitaxel, 175 mg/m2 over 3 hours, day 1 every 3 weeks; cisplatin, 80 mg/m 2 i.v., day 1 every 3 weeks.
i
EORTC study 08975; gemcitabine, 1,250 mg/m2,days 1 and 8; cisplatin, 80 mg/m 2, day 1 every 3 weeks.
j
Italian lung cancer trial; paclitaxel, 225 mg/m2 over 3 hours, day 1; carboplatin, AUC 6.0, every 3 weeks.
k
Italian lung cancer trial; vinorelbine, 25 mg/m2 i.v., weekly every 4 weeks; cisplatin, 100 mg/m 2, day 1.
l
Tax 326 study; vinorelbine, 25 mg/m2 weekly; cisplatin, 100 mg/m 2 every 4 weeks.
m
CPT-11 Lung Cancer Study Group trial in Japan, stage IIIB/IV patients; irinotecan, 60 mg/m2 i.v., days 1, 8, and 15; cisplatin, 80
mg/m2 i.v., day 1 every 4 weeks.
n
CPT-11 Lung Cancer Study Group trial in Japan, stage IV patients only; irinotecan, 60 mg/m2 i.v., days 1, 8, and 15; cisplatin, 80
mg/m2 i.v., day 1 every 4 weeks.
o
CPT-11 Lung Cancer Study Group second trial, stage IIIB/IV patients; irinotecan, 60 mg/m2 i.v., days 1, 8, and 15; cisplatin, 80
mg/m2 i.v., day 1 every 4 weeks.
p
Paclitaxel, 100 mg/m2, carboplatin, AUC 6.0.
q
Paclitaxel, 100 mg/m2, carboplatin, AUC 2.0.
r
Paclitaxel, 150 mg/m2, carboplatin, AUC 2.0.
s
Topotecan, 0.75 mg/m2 on days 1–5 of a 21-day cycle; cisplatin, 75 mg/m2, single dose on day 1.
t
Topotecan, 0.5 mg/m2 on days 1–5 of a 21-day cycle; carboplatin, AUC 5 mg/ml per minute on day 1 of each cycle.
u
Topotecan , 0.5–1.0 mg/m2 on days 1–5 of a 21-day cycle; vinorelbine, 20–30 mg/m2 on days 1 and 5.
v
Topotecan, 1.0 mg/m2 on days 1–5 of a 28-day cycle; gemcitabine, 1,000 mg/m2 on days 1 and 15.
w
Topotecan, 0.5–2.0 mg/m2 on days 1–5 of a 28-day cycle; gemcitabine, 1,000 mg/m2 on days 1, 8, and 15 of a 28-day cycle.
x
Topotecan, 0.85 mg/m2 per day on days 1–3, and etoposide, 100 mg twice daily, on days 7–9 of a 21-day cycle.
y
Topotecan, 1.0–1.5 mg/m2 on days 1–5 of a 21-day cycle; paclitaxel, 175 mg/m2 over 3 hours on day 1.
Abbreviations: AUC, area under the concentration-versus-time curve; ECOG, Eastern Cooperative Oncology Group; EORTC,
European Organization for Research and Treatment of Cancer; HOG, Hellenic Oncology Group; NA, data not available; SWOG,
Southwest Oncology Group.
From [3, 6, 11, 115, 117].

OTncologist
he ®
Ettinger
Figure 1. Epidermal growth factor receptor (EGFR) signaling
pathways. Abbreviations: MAPK, mitogen-activated protein
kinase; PI3K, phosphatidylinositol 3ʹ kinase; STAT, signal
transducer and activator of transcription.
(Erbitux®; ImClone Systems, Inc., New York), although oth-
ers—such as panitumumab (ABX-EGF) and matuzumab
(EMD72000)—are currently in early phases of investigation
[31–34]. Among the small-molecule TKIs, the best-studied
are gefitinib (Iressa®; AstraZeneca Pharmaceuticals, Wilm-
ington, DE) and erlotinib (Tarceva®; Genentech, Inc., South
San Francisco, CA). Both mAbs and TKIs generally have
milder toxicity than conventional drugs, which are cytotoxic.
Because they target cellular processes associated with tumor
resistance to radiation (e.g., proliferation and angiogenesis),
antibodies and TKIs have the potential to be combined effec-
tively with radiotherapy in the treatment of NSCLC [35].
Anti-EGFR mAbs
Antibodies generally have the advantages of less frequent
administration, induction of receptor downregulation, the
potential to engage the host immune response in direct
tumor cell cytotoxicity, and a favorable toxicity profile
(notably the absence of gastrointestinal adverse effects).
Antibodies specific for EGFR are among the first targeted
therapies to demonstrate effectiveness in treating cancer,
including NSCLC.
Cetuximab
Cetuximab, a chimeric human-murine IgG1 mAb, blocks
ligand binding to EGFR, thereby diminishing receptor
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361
Table 2. Frequency of high epidermal growth factor
receptor (EGFR) expression in lung cancer by histologic
characterization
Histology EGFR expression, % (n)
Small cell 0 (19)
Adenocarcinoma 65 (563)
Large cell 68 (72)
Squamous 84 (754)
Reprinted from Bunn PA Jr, Franklin W. Epidermal growth
factor receptor expression, signal pathway, and inhibitors
in non-small cell lung cancer. Semin Oncol 2002;29(suppl
14):38–44, with permission from Elsevier.
dimerization and autophosphorylation, and induces EGFR
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receptor downregulation, reducing the number of receptors
on the cell surface. The immunoglobulin IgG1 isotype of
cetuximab may also engage host immune functions, such as
antibody-dependent cellular cytotoxicity (ADCC) [36].
Preclinical studies with cetuximab showed that it
enhanced the activity of cytotoxic drugs [37–39] and radio-
therapy [39–41]. This may be related to its ability to block
the nuclear import of EGFR and activation of DNA-depen-
dent kinase (DNA-PK) necessary for the repair of radia-
tion- and chemotherapy-induced DNA damage [42].
Early clinical studies in advanced NSCLC have reported
promising responses for cetuximab administered as mono-
therapy or in combination with chemotherapy in chemo-
therapy-naïve and previously treated patients (Table 3).
Monotherapy. A phase II study of cetuximab monother-
apy in recurrent or metastatic EGFR-detectable NSCLC
patients with one or more prior chemotherapy regimens
demonstrated 2 of 29 (6.9%) partial responses (PRs) and 5
patients (17.2%) with stable disease [43]. Similar RRs (3.3%
PR [2/60 patients], 25% stable disease [15/60 patients])
were shown in a subsequent phase II trial in patients with
stage IIIB/IV recurrent or metastatic disease [44]. These
studies showed that cetuximab is well tolerated, with rash
as the most common toxicity. It is encouraging that recent
phase II monotherapy data in advanced colorectal cancer
(CRC) showed consistent RRs regardless of the number of
prior lines of therapy (3–8) or sequence of prior agents [45].
Combination with Chemotherapy Regimens. The effi-
cacy of cetuximab plus chemotherapy has been examined.
In a phase I study in advanced tumors including NSCLC,
2 of 19 patients (10.5%) receiving multiple doses of cetux-
imab plus cisplatin had PRs [46]. A randomized, controlled
trial in chemotherapy-naïve patients with advanced, EGFR-
expressing NSCLC showed a higher RR for the cetuximab
plus vinorelbine plus cisplatin regimen than for vinorelbine
362 EGFR Expression in NSCLC

Table 3. Results of clinical trials with cetuximab in patients with advanced NSCLC (chemotherapy-naïve and treatment-
refractory/resistant patients)
Partial response, Stable disease,
Description of study n n (%) n (%)
Monotherapy
Phase II, monotherapy; patients with recurrent or metastatic disease; ≥1 prior 29 2 (6.9%) 5 (17.2%)
therapy [43]
Combination therapy
Phase I study, various advanced tumors including lung cancer; combination 19 2 (10.5%) 11 (58%)
therapy of cetuximab with cisplatin; evaluation at 4 weeks [46]
Phase II randomized, controlled trial, chemotherapy-naïve, advanced, EGFR+, 41 13 (31.7%) 18 (43.9%)
NSCLC; combination therapy of vinorelbine/cisplatin with cetuximab [47]
Phase II study, chemotherapy-refractory/resistant patients with advanced 47 13 (27.7%) 8 (17%)
NSCLC; combination therapy of cetuximab and docetaxel [48]
Phase I/II study, chemotherapy-naïve, stage IV NSCLC patients; paclitaxel plus 31 9 (29%) 11 (35.5%)
carboplatin and cetuximab [118]

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Phase IB/IIA study, chemotherapy-naïve, stage IV NSCLC patients; combina- 33 8 (24.2%) 14 (42.4%)
tion therapy of cetuximab with gemcitabine plus carboplatin [50, 119]
Phase II study, stage IIIB/IV, recurrent or metastatic NSCLC with at least one 60 2 (3.3%) 15 (25%)
prior platinum, EGFR+ or EGFR−; cetuximab monotherapy [44]
Phase II study, stage IIIA/B NSCLC; cetuximab plus radiation, carboplatin, and 34 NA (toxicity study in progress)
paclitaxel; end points are safety and compliance (RTOG 0324 triala) [120]
a
Study is ongoing.
Abbreviations: EGFR, epidermal growth factor receptor; NA, not available; NSCLC, non-small cell lung cancer; RTOG, Radia-
tion Therapy Oncology Group.

plus cisplatin alone (31.7% vs. 20.0%) [47]. Other studies
of cetuximab combinations have reported similar RRs.
Cetuximab combined with docetaxel in chemotherapy-
refractory/resistant NSCLC resulted in a 28% (13/47) PR
rate and 17% (8/47) stable disease rate [48]. Cetuximab
added to paclitaxel plus carboplatin or to gemcitabine plus
carboplatin in chemotherapy-naïve NSCLC led to RRs of
26% (n = 31) and 28.6% (n = 35), respectively [49, 50].
Combination with Radiotherapy Regimens. To date,
cetuximab studies in lung cancer have focused on tumor
responses as endpoints and have not been designed to dem-
onstrate significant survival benefits. However, longer
survival has been shown in studies on other tumor types.
A recent phase III international trial comprising 424
patients with locally-advanced squamous-cell carcinoma
of the head and neck (SCCHN), a difficult-to-treat popula-
tion, demonstrated the first significant survival benefit for
a targeted therapy, cetuximab, in combination with high-
dose radiation, compared with radiation alone. Patients
receiving radiation therapy without cetuximab showed
a median survival of 28 months, and patients receiving
radiation with cetuximab showed a median survival of 54
months [51]. The 2-year and 3-year survival times were
also significantly longer in the cetuximab-treated popu-
lation. Currently, cetuximab is the only EGFR-targeted
agent shown to improve survival significantly in a cura-
tive setting in SCCHN.
Cetuximab has been well tolerated in all clinical trials
conducted. The most common treatment-related adverse
effect, which occurs in most patients, is a self-limiting acne-
iform rash generally occurring in the first 2–3 weeks. The
rash stabilizes or resolves with continued therapy and disap-
pears completely without scarring once treatment is stopped
[15, 52]. The occurrence of rash with cetuximab reflects the
widespread distribution of EGFR in epithelial tissue, and a
number of studies have reported a correlation between rash
and response to cetuximab [45, 52, 53]. A current clinical
trial (EVEREST, a phase II trial using cetuximab in esca-
lating doses combined with irinotecan to achieve higher
rates of skin rash and response in patients with metastatic
colorectal cancer previously treated with irinotecan) is
exploring dose-to-rash treatment strategies. Less com-
monly (1.5% reported in the U.S., data on file), infusion
reactions have occurred in some patients. These reactions
generally respond to treatment with corticosteroids, anti-
histamines, and bronchodilators administered alone or in
combination [52] and are rarely fatal (<1 in 1,000).
Important questions remain regarding the relevance of
EGFR detection as a requirement for cetuximab therapy.
A retrospective analysis of cetuximab for EGFR-undetect-
able CRC (as determined by immunohistochemistry [IHC])
showed four PRs (25%; 95% confidence interval [CI], 4%–
46%), and 7 of 16 EGFR-undetectable patients achieved
some degree of tumor control [54]. In an analysis of EGFR
staining intensity versus RR or survival in cetuximab-

OTncologist
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Ettinger 363

treated CRC patients, the RRs for 1+, 2+, and 3+ tumors
were uncorrelated [55]. These findings suggest that, aside
from EGFR detection by IHC, evaluation of other markers
such as activated, nonphosphorylated, and mutated recep-
tors, EGFR ligands, and downstream effector molecules
may lead to more accurate prognostic indicators of cetux-
imab responsiveness.
Matuzumab
Matuzumab (EMD 72000) is a humanized anti-EGFR
mAb currently in phase II trials for gastric, esophageal,
and lung cancers [4]. One of these trials is investigating the
effect of matuzumab in combination with the chemotherapy
agent pemetrexed as a second-line therapy in patients with
advanced NSCLC [57].

Panitumumab EGFR TKIs

Panitumumab (ABX-EGF) is a human IgG2mAb that targets
EGFR and, unlike cetuximab, mediates its effect through
mechanisms other than ADCC. In a phase I study of 88
renal cancer patients, three patients had PRs, two had minor
responses, and 44 (50%) had stable disease after 8 weeks of
Small-molecule TKIs are another class of EGFR-targeted
agents. TKIs can be orally administered, have a rapid onset
of action, and potentially have better tumor penetration than
mAbs [15]. Among drugs of this class, the two most exten-
sively evaluated in NSCLC are gefitinib and erlotinib. Both

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treatment with panitumumab [31, 42]. The frequency of an
acneiform skin rash was also directly proportional to the
dose of panitumumab and was associated with longer PFS.
Panitumumab is being evaluated as monotherapy for
patients with metastatic CRC and advanced solid tumors,
and also in combination with chemotherapy for unresect-
able or recurrent colorectal, lung, breast, bladder, and ovar-
ian cancer [56].
have demonstrated single-agent activity in NSCLC, and
greater sensitivity to either gefitinib or erlotinib has been
correlated with somatic mutations in the receptor kinase
domain and/or increased EGFR gene copy number [58]
(see below). Other TKIs undergoing testing in early-phase
clinical trials include PKI 166, GW 572016, EKB 569, and
CI-1033 [59]. In preclinical studies, all these agents inhib-
ited the growth of EGFR-expressing human cancer cell

Table 4. Results of clinical trials with gefitinib in patients with advanced NSCLC (chemotherapy-naïve and treatment-
refractory/resistant patients)
No. of patients
evaluable for Partial Stable disease,
Description of study response response, n (%) n (%)
Monotherapy
Randomized, placebo-controlled, multicenter phase III trial 959 77 (8%) 304 (31.7%)
(ISEL) [69]; 250 mg/day
Randomized, double-blind, parallel-group, multicenter phase II
trial (IDEAL-1) [63]
250 mg/day 103 18 (17.5%) 37 (35.9%)
500 mg/day 105 19 (18.1%) 34 (32.4%)
Randomized, double-blind, phase II trial (IDEAL-2) [62, 64]
250 mg/day 102 12 (12%) 32 (31.4%)
500 mg/day 114 10 (8.8%) 30 (26.3%)
Open-label, expanded-access program; 250 mg/day [65] 172 7 (4.1%) 60 (34.9%)
Open-label, expanded-access program; 250 mg/day [67] 60 2 (3.3%) 23 (38.3%)
Compassionate use in patients for whom prior chemotherapy 33 3 (9%) 14 (42%)
failed; 250 mg/day [68]
Expanded-access program; 250 mg/day [121] 120 8 (7%) 46 (38%)
Chemotherapy-naïve patients; 250 mg/day [122] 18 0 11 (61%)
Compassionate use program in Israel; 250 mg/day [123] 181 22 (12.2%) 40 (22.1%)
Phase II study, chemotherapy-naïve patients; 250 mg/day [124] 40 12 (30%) 16 (40%)
Expanded-access program, London; 250 mg/day [125] 124 7 (6%) 68 (55%)
Patients for whom chemotherapy had failed, at least one of which 66 3 (4.5%) 26 (39.4%)
was platinum-based; 250 mg/day [126]
Patients with advanced bronchioalveolar lung cancer; 500 mg/day 69 (chemother- 9 (13%) 21 (30%)
[70] apy-naïve)
22 (chemother- 2 (9%) 8 (36%)
apy-pretreated)
(continued)

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364 EGFR Expression in NSCLC

Table 4. (continued)
Other monotherapy studies n Response rate Criteria
Patients pretreated with at least one course of platinum-contain- 41 Median, 85 days Time to
ing chemotherapy; 250 mg/day [127] progression
Median, 96 days Overall survival
Compassionate use in patients who were able to tolerate chemo- 21,064 29.9% (comparable 1-year survival
therapy; 250 mg/day [66] (failed with second-line rate
chemotherapy) chemotherapy)
A community practice experience; maintenance on 250 mg/day 100 28% Disease control
[89] compared with IDEAL-2 (vs. IDEAL-2, rate
42%)
Partial response, Stable disease,
Combination therapy n n (%) n (%)
Phase I/II study in combination with rofecoxib; 250 mg/day [128] 33 2 (6.1%) 9 (27.3%)
Randomized, double-blind, placebo-controlled, multicenter
phase III trial, INTACT-1; cisplatin and gemcitabine plus gefi-
tinib [72]

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250 mg/day 336 161 (47.9%) NA
500 mg/day 330 159 (48.2%)
0 mg/day 324 150 (46.3%)
Randomized, double-blind, placebo-controlled, multicenter No difference in survival/response rate
phase III trial, INTACT-2; paclitaxel and carboplatin plus gefi-
tinib at
250 mg/day 9.8 months
500 mg/day 8.7 months
0 mg/day [73, 74] 9.9 months
Phase II study with gefitinib and docetaxel in patients that have 21 (13 evaluated) 3 (23%) 9 (69%)
failed or are unsuitable for platinum chemotherapy [129]
Phase I study; radiation therapy (60 Gy/30 fractions/6 weeks), 14 9 (64.3%) a 0
with gefitinib at dose 1, paclitaxel added at dose levels 2, 3, and 4 6 (42.3%) b
[75]
Randomized, noncomparative phase II study in elderly patients;
gefitinib 250 mg/day plus vinorelbine 24 3 (12.5%) 7 (29.2%)
and gemcitabine [76] 35 3 (8.6%) 13 (37.1%)
Phase II trial, first-line therapy of elderly patients; docetaxel plus
gefitinib, 250 mg/day [77] 10 5 (50%) 3 (30%)
a
Assessed by computerized tomography scan.
b
Assessed by 18Fluorodeoxyglucose-positron emission tomography scan.
Abbreviations: IDEAL, Iressa Dose Evaluation in Advanced Lung Cancer; INTACT, Iressa NSCLC Trial Assessing Combina-
tion Treatment; ISEL, Iressa Survival Evaluation in Lung Cancer; NA, not available.

lines and showed additive or synergistic growth inhibitory
effects when combined with chemotherapeutic agents or
radiotherapy [20, 60–62].
Gefitinib
Gefitinib, an anilinoquinazoline, was the first TKI selec-
tive for EGFR evaluated in NSCLC. It is orally active and
given once daily. Studies conducted on gefitinib in NSCLC
are summarized in Table 4.
Monotherapy. Two randomized, double-blind trials of
gefitinib monotherapy in daily doses of 250 mg or 500 mg
given to patients with advanced NSCLC who had previ-
ously received chemotherapy regimens—the Iressa Dose
Evaluation in Advanced Lung Cancer (IDEAL)-1 and
IDEAL-2—recorded objective RRs of 10% –19% [63,
64]. In both studies, symptoms improved in 35%–43% of
patients. Although no significant differences in efficacy
were found between the 250- and 500-mg daily doses of
gefitinib, adverse effects occurred more frequently with the
higher dosage [63, 64]. In the first study, greater efficacy
was found in Japanese than in non-Japanese patients (27.5%
vs. 10.4%, p = .0023) [63].
Results from three institutional studies of single-agent
gefitinib therapy used on a compassionate basis in patients
with advanced NSCLC for whom standard treatment had
failed or who were not suitable for systemic chemotherapy
were recently presented (Table 4) [65–68]. In the largest
of these studies, involving 21,064 patients with stage III/
IV NSCLC who received one or more doses of gefitinib,
median survival was 5.3 months, and the 1-year survival
rate was 29.9% [66]. These results are comparable with
those obtained with chemotherapy in a second-line clini-
cal setting.

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Ettinger
A phase III randomized, multicenter study of gefitinib
in refractory advanced NSCLC, the Iressa Survival Evalu-
ation in Lung Cancer (ISEL) trial, recently concluded that
gefitinib provided no significant survival benefit over best
supportive care across the total population of patients stud-
ied [69]. However, significant survival benefit was observed
in specific subpopulations, including patients of Asian
descent (n = 342; median survival 9.5 vs. 5.5 months; p =
.01) and patients with no smoking history (n = 375; median
survival, 8.9 vs. 6.1 months; p = .012) [69].
A study in patients with advanced bronchioalveolar cell
carcinoma (BAC), a subtype of NSCLC with distinctive
clinical, pathologic, and radiographic characteristics that
is generally considered chemoresistant, found that single-
agent gefitinib therapy of 500 mg daily achieved tumor RRs
of 21% and 10% in chemotherapy-naïve and previously
treated patients, respectively. Median survival times were
12 and 10 months, respectively [70]. In this same study,
increased EGFR gene copy number, as detected by fluo-
rescence in situ hybridization (FISH), was associated with
longer survival (median survival >18 months vs. 8 months;
p = .042) [71].
Combination with Chemotherapy Regimens. Two dou-
ble-blind, placebo-controlled trials—the Iressa NSCLC
Trial Assessing Combination Therapy (INTACT)-1 and
INTACT-2 trials—evaluated whether the addition of gefi-
tinib to gemcitabine plus cisplatin or paclitaxel plus carbo-
platin provides additional clinical efficacy over chemother-
apy alone in chemotherapy-naïve patients with advanced
NSCLC. Both indicated no benefit from gefitinib in objec-
tive RR or survival [72, 73]. One potential explanation for
the failure of gefitinib to provide clinical benefit is that con-
current cytotoxic agents abrogate its efficacy by directly or
indirectly altering EGFR expression [74]. It has been sug-
gested, therefore, that sequential therapy, in which chemo-
therapy regimens are preceded or followed by gefitinib, or
intercalated therapy, in which high doses of gefitinib are
given as a bolus between chemotherapy regimens, may be
better strategies, and trials to test these hypotheses are cur-
rently in progress [15].
Preliminary results from other studies of gefitinib used
in combination with chemotherapy have provided some
encouraging results [75–77]. In one study, in which gefi-
tinib was given in combination with concurrent paclitaxel
plus carboplatin and radiation therapy in patients with stage
III NSCLC, a complete RR of 27% and a PR rate of 64%
were achieved in 11 evaluable patients [75].
The available clinical data on gefitinib indicate signifi-
cant variability in responsiveness. Recent studies suggest
that greater response to EGFR inhibitors is related to muta-
www.TheOncologist.com
365
tions in exons 18–21 of the EGFR tyrosine kinase domain,
which increase growth factor signaling (Table 5) [23, 28
,34, 63, 78–80]. Mutations were significantly associated
with adenocarcinoma, history of no smoking, and female
gender [81, 82].
On the other hand, some reports describe the existence
of tumors with a different type of EGFR mutation in this
domain—a threonine-to-methionine substitution at posi-
tion 790 (T790M)—that renders resistance instead of sen-
sitivity to gefitinib [81, 83–85]. In addition, a mutation in
the K-ras gene, which mediates EGFR signaling, may also
confer resistance to TKIs [28, 79]. If confirmed, these find-
ings suggest that screening for such mutations may identify
patients who are more, or less, likely to respond to gefitinib.
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Measurement of EGFR expression by IHC was not use-
ful for predicting responsiveness to gefitinib in the patients
enrolled in the IDEAL or INTACT studies [86, 87]. How-
ever, IHC coupled with FISH to detect increased EGFR
gene copy number may help to predict which patients are
likely to benefit from gefitinib therapy [88]. Other factors
that might be predictive of responsiveness include a better
performance status and the appearance of rash while on
gefitinib treatment [89, 90].
Gefitinib has been generally well tolerated, with skin
rash and diarrhea occurring in 40%–60% of patients. Other
less common adverse effects include nausea, vomiting,
pruritus, dry skin, and asthenia [91, 92]. Potential danger
of gefitinib-associated lung toxicity in a subset of NSCLC
patients with previous thoracic irradiation or poor perfor-
mance status has also been reported [93].
Erlotinib
Like gefitinib, erlotinib is an orally-active, EGFR-spe-
cific quinazoline TKI that demonstrated antitumor activ-
ity in xenograft models [3, 15, 19, 94]. In addition to first-
line treatment for advanced pancreatic cancer, erlotinib
is currently approved for second-line treatment of locally
advanced or metastatic NSCLC. Several clinical studies of
erlotinib in advanced NSCLC have been reported (Table 6).
Monotherapy. A phase II study of erlotinib (150 mg daily)
in 57 advanced NSCLC patients demonstrated two com-
plete responses (4%) and 5 PRs (9%). The median overall
survival time was 8.4 months, with a 40% 1-year survival
rate. Patients with skin rash survived significantly longer
than those without rash, suggesting skin rash as a potential
marker of erlotinib response [95]. Erlotinib (150 mg daily)
resulted in a 25.4% PR rate (15 of 59 evaluable patients) in
BAC patients. Greater erlotinib responsiveness was shown
in never-smoking patients (37%) and adenocarcinoma with
BAC (30%) [96].
366 EGFR Expression in NSCLC

Table 5. Epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer
Frequency
Gene Mutation Location (n/total patients) Study Effect Reference
EGFR Deletions and EGFR TK domain, 18% (14/78) IDEAL ↑ response to Lynch et al.
point mutations exons 18–21 10% (32/312) INTACT gefitinib (SD and [28]
survival)
EGFR Amplification 8% (7/90) IDEAL INTACT:↑ response
4–1000× (mean, 7% (24/312) INTACT to
8×) gefitinib (SD)
EGFR Deletions and 746–753 89% ↑ response to Lynch et al.
insertions L858R, L861Q, (8/9 responsive pts) gefitinib (PR) [23]
Substitutions G719C 80%
(2/25 untreated pts)
EGFR Deletions 746–750 (exon 19) 28.8% (17/59) ↑ response to Mitsudomi
Point mutations 858 (exon 21), other 25.4% (15/59) gefitinib (tumor et al. [130]
codons (total 56%, 33/59) response, CEA)
↑ in nonsmokers,

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women, pts with
adenocarcinomas
EGFR Substitution T790M 2/6 pts Pao et al.
[84]
EGFR Substitution T790M 1 pt ↑ resistance to Kobayashi
gefitinib; pt relapsed et al. [83]
EGFR Substitution L858R (exon 21) 2 pts ↑ resistance to Toyooka et
and T790M gefitinib al. [85]
EGFR Deletions Exon 19 19 (exon 19) ↑ response to Toyooka et
Missense Exon 21 18 (exon 21) gefitinib (survival; al. [85]
mutations Total: 32% (38/120) 25.1 vs. 14.0 months)
EGFR Transversions 719 and 858 18% (12/64) SWOG Response to Gumerlock
Deletions S0126 gefitinib (survival) et al. [79]
K-ras Transversions 12 (exon 2) 30% (19/63) SWOG Resistance to
(smokers) S0126 gefitinib
Transitions (1/19 responded)
(nonsmokers)
EGFR + See above See above 6% (4/63) SWOG (No response to
K-ras S0126 gefitinib)
EGFR + Not specified in EGFR exons 18–21; 24% (9/37) Phase II All responded to Kris et al.
K-ras abstract K-ras exon 2 12% (4/34) erlotinib erlotinib [101]
study None responded
EGFR + Not specified in EGFR exons 18–21; 7.8% (15/191) TALENT No significant Gatzemeier
K-ras abstract K-ras exons 2 & 3 14.7% (24/163) correlations with et al. [100]
response
EGFR Not specified EGFR, PI3K 0% (0/15) 1 responder Giaccone et
K-ras K-ras 53.3% (8/15) Not specified al. [131]
(abstract)
EGFR Deletions 746–750 (exon 19) 40% (111/277) Not known Kosaka et
Point mutations 858 (exon 21) and ↑ in nonsmokers, al. [81]
719 (exon 18) females, patients
Duplications/ Exon 20 with adenocarci-
insertions nomas
Abbreviations: CEA, carcino-embryonic antigen; IDEAL, Iressa Dose Evaluation in Advanced Lung Cancer; INTACT, Iressa
NSCLC Trial Assessing Combination Treatment; PI3K, phosphatidylinositol 3ʹ kinase; PR, partial response; pt, patient; SD,
stable disease; SWOG, Southwest Oncology Group; TALENT, a phase III study of gemcitabine plus cisplatin with or without
erlotinib in advanced NSCLC; TK, tyrosine kinase.

A recent double-blind, placebo-controlled phase III
study comparing erlotinib with placebo in patients (n = 731)
with stage IIIB/IV NSCLC and one to two prior chemother-
apy regimens—the National Cancer Institute of Canada
Clinical Trials Group (NCIC CTG) trial BR.21—reported
the first evidence of an EGFR inhibitor prolonging sur-
vival in chemotherapy-refractory NSCLC [97, 98]. Patients
receiving erlotinib (n = 488) at 150 mg daily demonstrated
significantly longer overall survival (6.7 months vs. 4.7
months) and PFS (2.2 months vs. 1.8 months) than those

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Ettinger 367

Table 6. Results of clinical trials with erlotinib (150 mg daily) in patients with advanced non-small cell lung cancer (NSCLC)
Partial Overall survival 1-Year
Study response (%) (months) survival
Monotherapy
Placebo-controlled, randomized, phase III trial with patients for whom
first- or second-line therapy failed [98]
Erlotinib, n = 488 6.7
Placebo, n = 243 4.7
Phase II, open-label, chemotherapy-naïve patients aged ≥70 years [132] 4/30 (13.3%)
Phase II open-label trial of patients previously treated with platinum- 8.4 40%
based chemotherapy [95]
Phase II open-label trial, BAC patients [96]
Total 15/59 (25%)
Never smoked 7/19 (37%) 58%
Smoke ≤5 pack-years 3/7 (43%)
Smoke ≥6 pack-years 5/33 (15%)

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Phase II, chemotherapy-naïve, stage IIIB/IV, PS 0–2, NSCLC patients; 12/53 (23%)
150 mg/day erlotinib for 6 weeks [131]; nonprogression rate, 55% (mostly
in women, adenocarcinomas/BAC, and nonsmokers)
Combination therapy
TRIBUTE study: phase III, prospective, placebo-controlled, randomized,
previously untreated patients; erlotinib or placebo, with six cycles of car-
boplatin plus paclitaxel and maintenance monotherapy [102]
Erlotinib, n = 526 10.8
Placebo, n = 533 10.6
TRIBUTE study, subgroup analysis: patients that have never smoked
[102, 103]
Erlotinib, n = 69 23
Placebo, n = 44 10
TALENT study: Phase III, prospective, placebo-controlled, untreated
patients; erlotinib or placebo, with six cycles of gemcitabine and cisplatin,
followed by maintenance monotherapy [104]
Erlotinib 9.9 41%
Placebo 10.1 42%
Abbreviations: BAC, bronchioalveolar carcinoma; PS, performance status score; TRIBUTE, a phase III study of gemcitabine
plus cisplatin with or without erlotinib in advanced NSCLC.

receiving placebo. The overall erlotinib RR was 8.9%.
The median response duration was 34.2 weeks. RRs were
higher among specific subpopulations, including women,
Asians, nonsmokers, and patients with adenocarcinoma,
reminiscent of similar results with gefitinib [98]. Response
was associated with higher EGFR gene copy number, but no
survival advantage was seen in patients with higher EGFR
expression or mutations in exons 19 and 21 [99]. Mutation
frequency in EGFR or K-ras was not correlated with tumor
sensitivity or responsiveness to erlotinib in one study [100];
in another study, 9 of 37 patients with EGFR mutations
responded well to erlotinib, and 4 of 34 patients with K-ras
mutations did not respond to erlotinib (Table 5) [101].
Combination with Chemotherapy Regimens. As with
the gefitinib INTACT studies [72, 73], erlotinib showed no
survival advantage when combined with a two-drug che-
motherapy regimen. In a randomized, placebo-controlled
study of 1,059 previously untreated advanced NSCLC
patients, erlotinib (150 mg daily) with six cycles of pacli-
taxel plus carboplatin followed by maintenance mono-
therapy showed no significant differences in overall RR,
response duration, median survival, or time to progres-
sion (TTP) compared with paclitaxel plus carboplatin
alone [102]. However, patients who never smoked showed
longer survival with erlotinib (23 vs. 10 months) [103]. A
placebo-controlled study of erlotinib (150 mg daily) plus
gemcitabine plus cisplatin in 1,172 patients with previously
untreated, advanced NSCLC showed no improvement in
overall survival or TTP compared with gemcitabine plus
cisplatin alone [104].
Erlotinib tolerability is similar to that of gefitinib. Skin
rash and diarrhea are the most common adverse effects [59].
Preliminary results of a study of erlotinib administered at
1,200, 1,600, or 2,000 mg weekly suggest that 1,600 mg/
week is tolerable for advanced NSCLC patients refractory
to previous chemotherapy. Weekly high-dose therapy (i.e.,
>2,000 mg) is being investigated [105].

www.TheOncologist.com
368
EGFR and Tumor Angiogenesis: Another
Rational Approach to NSCLC Treatment
New blood vessel formation is required for the growth and
progression of most tumors. The EGFR is also involved
in angiogenesis: the EGFR ligands—EGF and TGF-α—
induce angiogenesis, and TGF-α promotes the expression
of VEGF, which induces vascular growth and vascular
cell permeability [18, 106], providing a strong rationale
for combined anti-VEGF/anti-EGFR therapy. VEGF
expression is upregulated in many tumors, resulting in
an imbalance between pro- and antiangiogenic factors in
the tumor microenvironment, promoting vascularization
and growth [106, 107]. At least four isoforms of VEGF
exist, VEGF-A through VEGF-D, and three isoforms of
membrane-bound VEGF receptors have been identified
(VEGFR-1, VEGFR-2, and VEGFR-3), each with distinct
roles in angiogenesis [108].
Antiangiogenesis in NSCLC Treatment
Several angiogenesis inhibitors have been studied in
NSCLC [109]. They include antibodies to VEGF and
VEGFR and inhibitors of VEGFR tyrosine kinase [108].
The best-studied angiogenesis inhibitor is bevacizumab
(rHumAb-VEGF), an anti-VEGF antibody that has been
evaluated in combination with chemotherapeutic agents
and erlotinib in advanced or recurrent NSCLC. In a ran-
domized, controlled trial involving 99 patients with previ-
ously untreated stage IIIB/IV or recurrent NSCLC, beva-
cizumab added to paclitaxel plus carboplatin improved
overall response and TTP compared with paclitaxel plus
carboplatin alone. The median TTP was significantly
greater for patients receiving a high-dose (15 mg/kg) beva-
cizumab regimen than for those receiving a low-dose (7.5
mg/kg) bevacizumab regimen (7.4 vs. 4.2 months; p = .023).
In contrast, no significant difference in TTP was found for
the low-dose bevacizumab group versus paclitaxel plus car-
boplatin alone [110].
Preliminary results from a phase I/II study of bevaci-
zumab plus erlotinib in previously treated stage IIIB/IV or
recurrent NSCLC patients showed PRs in 8 of 40 (20.0%) and
stable disease in 26 of 40 (65%) patients. The median overall
survival time and TTP were 12.6 and 6.2 months, respec-
tively [111]. The recent Eastern Cooperative Oncology Group
(ECOG) E4599 trial compared paclitaxel plus carboplatin
with bevacizumab (PCB) and without bevacizumab (PC) in
advanced NSCLC [112]. This was the first phase III trial to
demonstrate a survival advantage obtained from a first-line
treatment combining a targeted biologic with chemotherapy,
reporting encouraging tumor RRs (27% for PCB vs. 10% for
PC), PFS (6.4 vs. 4.5 months) and median survival rates (12.5
vs. 10.3 months) with bevacizumab.
EGFR Expression in NSCLC
Bevacizumab appears to be generally well tolerated.
Combination with paclitaxel plus carboplatin showed mod-
est changes to the chemotherapy regimen toxicity profile
[110]. However, some bevacizumab-associated adverse
effects warrant special attention, including hypertension,
proteinuria, and hemorrhage. Most cases of hemorrhage
with bevacizumab have been minor, but some serious pul-
monary hemorrhages have occurred, which often results
from angiogenesis inhibition; also, poorly developed
neovessels in large, centrally located tumors may be more
prone to hemorrhage into the necrotic tumor cavity [110].
Eligibility restrictions in clinical trials of bevacizumab in
NSCLC have included a history of myocardial infarction
or stroke, significant peripheral vascular disease, central
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nervous system or brain metastasis, lung carcinoma of
squamous cell histology or close proximity to a major ves-
sel, and use of anticoagulants, aspirin, or nonsteroidal anti-
inflammatory drugs.
Promising results have been reported for combined anti-
EGFR and anti-VEGF therapy, notably the Bowel Oncol-
ogy with Cetuximab Antibody (BOND)-2 study, which
showed that concurrent administration of cetuximab and
bevacizumab is feasible and can result in improved RRs in
bevacizumab-naïve patients with advanced CRC [113] (see
above). In addition, ZD6474, an orally available small-mol-
ecule kinase inhibitor of both EGFR and VEGFR, is being
explored for efficacy in NSCLC and other cancers. Phase II
trials of ZD6474 in combination with standard chemothera-
pies in first- and second-line settings for advanced or meta-
static NSCLC are ongoing. Preliminary data have shown
that ZD6474 combined with docetaxel provided an 18.2%
(2/11) PR rate and a 63.4% (7/11) SD rate for ≥12 weeks in
NSCLC patients who had previously failed first-line plati-
num-based chemotherapy [114]. ZD6474 combined with
carboplatin plus paclitaxel as a first-line therapy in NSCLC
(IIIB–IV) demonstrated a 39% (7/18) PR rate in a random-
ized, double-blind trial [115].
Summary and Conclusions
Current treatments for advanced NSCLC have resulted in
only modest response rates, and drug resistance is com-
mon. Based on identification of tumor-specific molecu-
lar signaling pathways, targeted therapies offer poten-
tially greater clinical benefit. Newer therapies targeted
against the EGFR signaling pathway offer the promise
of improved NSCLC treatment, leading to longer patient
survival. Recent studies with the anti-EGFR antibody
cetuximab, the EGFR TKIs gefitinib and erlotinib, and
the anti-VEGF antibody bevacizumab have been encour-
aging. Important findings include: (a) enhanced vinorel-
bine/cisplatin efficacy by cetuximab in chemotherapy-
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Ettinger
naïve patients with advanced, EGFR-detectable NSCLC;
(b) enhanced efficacy of paclitaxel/carboplatin by bevaci-
zumab in chemotherapy-naïve patients with advanced or
recurrent NSCLC; (c) activity of the TKIs gefitinib and
erlotinib as second- or third-line monotherapy in prolong-
ing survival (erlotinib) or improving symptoms (gefitinib
and erlotinib) in advanced NSCLC patients failing prior
chemotherapy; and (d) evidence of the activity of gefitinib
and erlotinib in patients with BAC.
Despite their activity as a second- or third-line therapy
in advanced NSCLC and augmentation of chemotherapeu-
tic agent activity in preclinical studies, neither gefitinib
nor erlotinib conferred a survival advantage in previously
untreated NSCLC when administered with two-drug che-
motherapy regimens (gemcitabine plus cisplatin and pacli-
taxel plus carboplatin). The reasons for their apparent lack
of benefit when used concomitantly with platinum-contain-
ing regimens are unclear but may involve direct or indirect
alteration of EGFR expression by cytotoxins. Thus, differ-
ent administration schedules may be required (e.g., TKI
administered before or after standard chemotherapy). On
the other hand, cetuximab is well tolerated, with skin rash
as its most common toxicity, and has resulted in longer sur-
vival in patients with SCCHN when combined with radia-
tion therapy without exacerbating radiation toxicity, unlike
chemotherapeutic agents.
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Disclosure of Potential Conflicts
of Interest
Dr. Ettinger has acted as a consultant for Bristol-Myers
Squibb, AstraZeneca, and Genentech; performed con-
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