Full text of DOI:10.1053/sonc.2002.31525

Epidermal Growth Factor Receptors as a Target for Cancer
Treatment: The Emerging Role of IMC-C225 in the Treatment
of Lung and Head and Neck Cancers
Roy S. Herbst and Corey J. Langer
Epidermal growth factor receptor is one of four re-
ceptors critical to cellular proliferation, differentia-
RADITIONAL cytotoxic therapies, chemo-
therapy and radiation therapy (RT), used in
T
tion, and survival, and is widely expressed in malig-
nant tissue, particularly in squamous cell carcinoma
of the head and neck. Expression has been associated
with malignant progression, inhibition of apoptosis,
neoplastic angiogenesis, enhanced metastatic poten-
tial, and both chemoresistance and radioresistance.
IMC-C225 is a chimeric monoclonal antibody that
targets extracellular epidermal growth factor recep-
tor; it has shown both in vitro and in vivo antitumor
activity in tumor cells lines expressing epidermal
growth factor receptor, including heightened radia-
tion response in vitro in cultured human squamous
cell carcinoma and enhancement of taxane- and plat-
inum-induced cytotoxicity in non–small cell lung can-
cer xenografts. In A431 head and neck squamous cell
xenografts, IMC-C225 administered both before and
after radiation therapy yields a radiation enhance-
ment factor of 3.62, attributable to both tumor ne-
crosis and antiangiogenesis. In phase I pharmacoki-
netic studies, IMC-C225 has a long half-life, lending
itself to convenient weekly administration. It has
shown a favorable toxicity profile, limited primarily
to allergic and dermatologic reactions, the latter
characterized by a self-limited, sterile, acneiform
rash. Anaphylaxis is rare. Standard treatment entails
a loading dose of 400 mg/m2 at week 1, followed by a
maintenance dose of 250 mg/m2 weekly. An ongoing
phase III international multicenter, randomized
study in locally advanced squamous cell carcinoma of
the head and neck is evaluating therapeutic radiation
therapy, either alone or in conjunction with IMC-
C225. In a pilot trial, six of nine patients with plati-
num-exposed squamous cell carcinoma of the head
and neck exhibited objective response. In an ongoing
phase II trial in patients with stable or progressive
disease on platinum-based therapy, the preliminary
response rate is approximately 20%, far higher than
one would expect with standard salvage regimens.
The Eastern Cooperative Oncology Group has com-
pleted a placebo-controlled phase III registration
trial assessing cisplatin 100 mg/m2 every 4 weeks
with or without IMC-C225. Three separate phase II
trials in non–small cell lung cancer have been
launched: one trial tests IMC-C225 in combination
with standard paclitaxel/carboplatin; another inte-
grates IMC-C225 into the gemcitabine/carboplatin
combination in treatment-naive patients; and a third
trial evaluates IMC-C225 in combination with do-
cetaxel 75 mg/m2 every 3 weeks in the second-line
setting.
the management of solid tumors are associated
with significant therapeutic and safety limitations.
The successful administration of cytotoxic therapy
can be limited by nonspecific toxicities sustained
by healthy tissues. These limitations can result in
poor outcomes in terms of disease control and overall
survival, thus emphasizing the need for treatment
approaches that demonstrate efficacy in targeting
tumor cells while limiting damage to healthy cells.
There is increasing evidence that newer biologic
agents targeting cellular protein receptors or other
components of the tumor microenvironment may
work synergistically with conventional cytotoxics.
Many of these targeted agents have been considered
cytostatic, but there are emerging data to suggest that
they may be cytotoxic as well.
Treatment targeted to growth factor receptors
has shown promise in the management of solid
tumors. Growth factor receptors are important in
regulating cellular processes such as proliferation,
differentiation, and survival (Fig 1). There are four
related growth factor receptors that share similar-
ities in structure and function: HER1 (epidermal
growth factor receptor [EGFR] or c-erbB-1), HER2
(c-erbB-2), HER3 (c-erbB-3), and HER4 (c-erbB-
4).1-3 The EGFR is a 170-kd transmembrane gly-
coprotein that is encoded by the c-erbB-1 proto-
oncogene.4,5 Epidermal growth factor receptor and
c-erbB-2 proteins show 82% homology in the ty-
From the Departments of Thoracic Head and Neck Medical
Oncology and Cancer Biology, The University of Texas M.D.
Anderson Cancer Center, Houston, TX; and the Department of
Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA.
Dr Langer has received research grant support from ImClone,
Bristol-Myers Squibb, Aventis, Eli lilly, Intrabiotics, Genentech,
Pharmacia, AstraZeneca, Vertex, OrthoBiotech, and Amgen.
Address reprint requests to Roy S. Herbst, MD, PhD, Thoracic
Head and Neck Medical Oncology, The University of Texas M.D.
Anderson Cancer Center, 1515 Holcombe Blvd, Box 432, Hous-
ton, TX 77030-4009.
Copyright 2002, Elsevier Science (USA). All rights reserved.
0093-7754/02/2901-0407$35.00/0
doi:10.1053/sonc.2002.31525
Semin Oncol 29 (suppl 4):27-36. Copyright 2002,
Elsevier Science (USA). All rights reserved.
Seminars in Oncology, Vol 29, No 1, Suppl 4 (February), 2002: pp 27-36
27

28
HERBST AND LANGER
Fig 1. Epidermal growth factor receptor (EGFR) pathways. EGFR regulates cellular processes via multiple mechanisms. (Reprint-
ed with permission from Harari PM, Huang S-M: Modulation of molecular targets to enhance radiation. Clin Cancer Res 6:323-325,
2000. Copyright © 2000 by the American Association for Cancer Research.)
rosine kinase domain, and cross-reactivity appears
to exist between the EGFR and HER2 receptors.6,7
Epidermal growth factor receptor inhibitors block
the HER1 receptor.
correlated with various processes that contribute
to the development of malignancy, such as effects
on cell cycle progression, inhibition of apoptosis,
angiogenesis, tumor cell motility, and metastasis.
The EGFR pathway is important in controlling
cell cycle events that affect survival. There is in
vivo and in vitro evidence that numerous growth
factors, including EGF and transforming growth
factor alpha, possess angiogenic activity.12 The
EGFR pathway has been shown to regulate tumor
cell motility and metastasis in a variety of stud-
ies.13-16 Given the role of the EGFR pathways in
cell cycle progression and tumor proliferation, it
has been proposed that combining anti-EGFR
therapy with chemotherapy or RT may result in
synergistic antitumor activities by inhibiting vari-
ous processes that contribute to tumor growth.17-20
Epidermal growth factor receptor is expressed
on healthy cells that originate from all three germ
cell layers, particularly those of epithelial origin
(eg, skin, liver, and gastrointestinal tract) as well
as on malignant tissues.8-11 There are a number of
endogenous ligands for the EGFR including epi-
dermal growth factor (EGF), transforming growth
factor alpha, amphiregulin, heparin-binding EGF,
and betacellulin.1 Epidermal growth factor and
transforming growth factor alpha are the most
important stimulatory ligands for the EGFR. After
ligands bind to the EGFR, the receptor undergoes
dimerization, followed by internalization of the
receptor/ligand complex and autophosphoryla-
tion.2 Finally, the tyrosine kinase signal transduc-
tion pathways that control cellular proliferation,
differentiation, and survival are activated.3
EPIDERMAL GROWTHFACTOR
RECEPTOR EXPRESSION AND
MALIGNANCY
Epidermal growth factor receptor is important
in the maintenance of normal cellular function
and survival, and EGFR expression contributes to
the growth and survival of tumor cells (Fig 1). The
EGFR signal transduction pathways have been
Epidermal growth factor receptor expression on
normal cells ranges from 40,000 to 100,000 recep-
tors per cell.2 Expression of EGFR has been doc-
umented extensively on a wide variety of ma-
lignant cells including colon, head and neck,

IMC-C225 IN LUNG AND HEAD & NECK CANCER
29
pancreatic, non–small cell lung, breast, kidney,
ovarian, glioma, and bladder cancers both in vitro
and in vivo. In many cases, the number of EGFRs
expressed on malignant cells is greater than on
normal cells; up to 2 million EGFRs per cell have
been seen in some breast cancers.21-23 The per-
centage of tumors that express EGFR varies by
tumor type; for example, for some cancers such as
squamous cell carcinomas of the head and neck
and lung, EGFR is expressed on the majority of
tumors (Table 1). Several studies have shown that
EGFR expression correlates with reduced disease-
free and overall survival, poor prognosis, increased
risk of recurrence, advanced tumor stage, and in-
creased risk of metastasis, although others report
conflicting results.1,24,25
Given the role of EGFR in contributing to the
development of malignancy and the presence of
EGFR on numerous cancer cell types (and, in
some cases, at increased frequency), there is an
opportunity to target and block the EGFR path-
ways to treat tumors that express EGFR. The spec-
ificity of EGFR blockade by monoclonal antibod-
ies results in a favorable safety profile that differs
from that of chemotherapy and RT.
immunoconjugates, and antisense oligonucleo-
tides. Small molecules that target the intracellular
tyrosine kinase signaling pathways, such as the
tyrosine kinase inhibitors, can inhibit the EGFR
pathway.26-29 Anti-EGFR monoclonal antibodies
target the extracellular receptor and thus are able
to effectively block the EGFR pathways in a highly
specific manner. They have been shown to suc-
cessfully target malignant cells.30 However, anti-
EGFR monoclonal antibodies do not exclusively
target tumor cells; they will also affect normal
tissues. The effects of anti-EGFR monoclonal an-
tibodies on normal tissues are minimal, because
many healthy cells expressing the EGFR do not
turn over rapidly.
The intestinal epithelium is a notable exception
because it is in a constant state of self-renewal.
The newly formed epithelial cells that originate
from the crypt epithelium express EGFR, which is
important for maintaining normal structure and
function. While tyrosine kinase inhibitors, which
are given orally, are associated with intestinal ep-
ithelial toxicity, anti-EGFR antibodies, which are
given intravenously, are not associated with these
effects. It has been speculated that the oral deliv-
ery directly exposes the intestinal epithelium to
the toxic effects of the agent while intravenous
delivery makes direct access to the epithelium
from the systemic circulation more difficult. In
addition, the larger IgG molecule might not pen-
etrate the crypts to have this effect.
ANTIEPIDERMAL GROWTHFACTOR
RECEPTOR TARGETED APPROACHES
Numerous EGFR blockers have been investi-
gated including anti-EGFR monoclonal antibod-
ies, tyrosine kinase inhibitors, ligand conjugates,
A number of anti-EGFR monoclonal antibodies
have been tested in vitro and in vivo using animal
models, and a few have entered clinical trials.
Examples of those that have undergone or are
currently in clinical testing are IMC-C225, a chi-
meric monoclonal antibody; EMD 55900 (mono-
clonal antibody 425), a murine anti-EGFR mono-
clonal antibody31-33; ICR 62, a rat monoclonal
antibody32,34; and ABX-EGF, a fully human anti-
EGFR antibody.35 IMC-C225, as an example, is an
anti-EGFR monoclonal antibody currently in
phase II and III trials. Studies include colorectal
carcinoma,36 pancreatic carcinoma,37 breast carci-
noma,11 prostatic carcinoma,38 renal cell carci-
noma,39 as well as squamous cell carcinoma of the
head and neck (SCCHN).40
Table 1. Solid Tumor Epidermal Growth Factor
Receptor Expression Shown by Primary Tumor Site
Primary Tumor
Site
U.S. Annual
Incidence*
% of Tumors
Expressing EGFR
Head and neck
Colorectal
Pancreatic
Lung
30,200
130,200
28,300
164,000
12,300
31,200
180,400
53,200
48,900
23,100
184,200
80% to 100%
25% to 77%
30% to 50%
40% to 80%
43% to 89%
50% to 90%
65%
Esophageal
Renal cell
Prostate
Bladder
31% to 48%
90%
Cervical/uterus
Ovarian
35% to 70%
14% to 91%
Breast
EMERGENCE OF IMC-C225
Abbreviation: EGFR, epidermal growth factor receptor.
* American Cancer Society, 2000.
Much of the data regarding the efficacy and
safety of anti-EGFR monoclonal antibody in solid

30
HERBST AND LANGER
tumors come from clinical experience with IMC-
C225. IMC-C225 is a human:murine chimeric
anti-EGFR IgG monoclonal antibody that has
demonstrated both in vitro and in vivo antitumor
activity in tumor cell lines expressing the EGFR.
Treatment of cultured human squamous cell car-
cinoma cells with C225 has been shown to
heighten radioresponse in vitro. In vitro studies
have also shown cell growth inhibition and, in
some cases, cytotoxicity. IMC-C225 enhances the
cytotoxic effect of chemotherapeutics, like taxanes
and platinum, and radiation in human non–small
cell lung cancer (NSCLC) xenograft models.41,42
In vitro and in vivo studies have confirmed the
antitumor activity of IMC-C225. Treatment of a
human colorectal carcinoma cell line, DiFi, with
IMC-C225 resulted in G1 cell cycle arrest and
induction of apoptosis as evidenced by reduction
in cell volume and DNA fragmentation.43 IMC-
C225 has been shown to inhibit cellular prolifer-
ation of a number of squamous cell carcinoma
head and neck cell lines in vitro.19 Renal cell
carcinoma cell lines treated with IMC-C225
showed dose-dependent inhibition of DNA syn-
thesis resulting in inhibition of cellular prolifera-
tion.44 Human prostatic carcinoma cell lines
DU145 treated with IMC-C225 showed effects on
cell cycle progression.45 There was an increased
G1/G0 peak in comparison with control cells and a
decreased number of cells in the S phase. IMC-
C225 showed significant inhibitory effects in the
athymic nude mice inoculated with the human
prostatic cell lines DU145 and PC-3 in compari-
son with control mice.
Fig 2. The effect of C225 antibody on tumor angiogenesis is
shown. Mice were given intradermal inoculation of 106 A431
tumor cells, and the number of vessels at the injection site was
determined in C225-treated (}) and control (F) mice. Tumor
volumes in C225-treated ({) and control (E) mice were also
plotted. Treatment with C225 (1 mg intraperitoneally) was
given 1 day after tumor cell inoculation. (Reprinted with per-
mission.47
)
IMC-C225 and radiation appear synergistic. A
number of putative mechanisms of action have
been postulated, including: (1) induction of G1
cell cycle arrest, (2) inhibition of cellular prolifer-
ation, (3) promotion of radiation-induced apopto-
sis, (4) inhibition of radiation-induced damage
repair, and (5) inhibition of tumor angiogene-
sis.41,42,45,47
Blockade of EGFR by IMC-C225 has shown in
vitro inhibition of growth in multiple human squa-
mous cell carcinoma cell lines, including A431,
UMSCC-1, and UM-SCC-6. IMC-C225 produces
apoptosis, which appears to be independent of
cellular exposure time when given alone. How-
ever, exposure of tumor cells to radiation following
IMC-C225 yields synergistic apoptosis, which in-
creases with exposure time to IMC-C225. This is
associated with a corresponding decrease in acti-
vated STAT-3 (signal transduction and transcrip-
tion activation) proteins. In vivo studies of A431
xenografts implanted in nude mice corroborate in
vitro work.49
IMC-C225 has also been shown to inhibit neo-
angiogenesis. A study by Perrotte et al46 of IMC-
C225 showed inhibition of messenger RNA and
protein production of vascular endothelial growth
factor in human bladder cancer xenografts in nude
mice. Milas et al47 showed significant inhibition of
new vessels at the site of A531 inoculation and
tumor xenografts (Fig 2); furthermore, angiogene-
sis inhibition was associated with significant tumor
growth delay.
In a separate study by Milas et al47 of A431
xenografts treated with radiation and IMC-C225
3 hours prior, 3 days after, and 6 days after RT
yielded a radiation enhancement factor of 3.62
compared with radiation alone (Table 2, Fig 3).
The primary mechanism of action appeared to be
tumor necrosis. There was abundant evidence of
antiangiogenic effect, with microscopic sections
EFFECT OF IMC-C225 AND RADIATION
IMC-C225 resulted in enhanced radiosensitiv-
ity and radiation-induced apoptosis as well as sig-
nificantly diminished cell survival.41,48 In human
squamous cell carcinoma of the head and neck,

IMC-C225 IN LUNG AND HEAD & NECK CANCER
31
Table 2. Effect of C225 on Radioresponse of A431 Tumor Xenografts in Nude Mice
Days Required for Tumors
Absolute
Normalized
Enhancement
Factor
Treatment
No treatment
to Grow from 8 mm to 12 mm
Growth Delay
Growth Delay
6.5 Ϯ 0.4
Ϯ 2.8
C225 (single)12.0
C225 (multiple)13.9
18 Gy
5.5 Ϯ 2.8
7.4 Ϯ 3.5
Ϯ 3.5
25.8 Ϯ 3.4
42.7 Ϯ 3.3
83.8 Ϯ 10.1
19.3 Ϯ 3.4
36.2 Ϯ 3.3
77.3 Ϯ 10.1
C225 single plus 18 Gy
C225 multiple plus 18 Gy
30.7 Ϯ 3.32
1.59
3.62
69.9 Ϯ 10.14
NOTE. A single dose of C225 resulted in an absolute growth delay of 5.5 Ϯ 2.8 days, and multiple doses yielded an absolute growth delay
of 7.4 Ϯ 3.5 days in the A431 tumor xenograft model. Eighteen Gy yielded an absolute growth delay of 19.3 Ϯ 3.4 days. In combination with
18 Gy, a single dose of C225 resulted in an absolute growth delay of 36.2 Ϯ 3.3 days. Normalized growth delay of 30.7 days Ϯ 3.32 was
determined by subtracting the absolute growth delay with C225 alone from that observed with combination C225 plus 18 Gy; hence, the
enhancement factor. This figure divided by absolute growth delay observed with 18 Gy alone was 1.59. Multiple doses of C225 yielded an
enhancement factor of 3.62.
Reprinted with permission.47
showing hemorrhage, vascular thrombosis, and di-
minished microvessel density. Other mechanisms
included retardation of tumor growth, with evi-
dence of terminal cell differentiation and inhibi-
tory effect on tumor cell repopulation. The inves-
tigators concluded that IMC-C225 enhances
tumor radioresponse by multiple mechanisms in-
volving both direct and indirect actions on tumor
cell survival.
relatively convenient weekly administration. It
is highly selective and specific, has a good side-
effect profile, and yields no apparent exacerba-
tion of chemotherapy or radiation toxicity.
However, several potential drawbacks exist. It
targets only one of four Erb-B family members.
The antibody appears bulky and may not neces-
sarily penetrate large tumors or into the central
nervous system. It appears to be inactive against
truncated forms of the receptor, and may induce
an immunologic response. In addition, there is
no oral formulation.
CLINICAL ASPECTS OF IMC-C225
IMC-C225 is characterized by a long half-life
(approximately 8 days), which lends itself to
In phase I studies, IMC-C225 has proven well
tolerated, with minimal overlapping toxicities to
conventional therapy.50 A safety review showed
that adverse events were generally mild to moder-
ate.51 The percentage of adverse events of grade 3
severity or greater was 12%. Major toxicities asso-
ciated with IMC-C225 are allergic and skin reac-
tions. Of 189 patients treated, 2% experienced
grade 3 and 2% experienced grade 4 allergic reac-
tions. Patients with low-grade allergic reactions
were successfully continued on therapy by admin-
istering prophylactic antihistamine therapy and by
slowing the infusion rate. At current phase II
dosing, nearly all patients developed some form of
dose-related acne-like rash. These sterile, suppura-
tive rashes, characterized as multiple pustular le-
sions that generally occur on the face, neck, and
upper trunk, tend to manifest during the first 2
weeks of therapy. Despite their frequent occur-
rence, the acne-like rashes did not prove to be
Fig 3. Effects of IMC-C225 and RT on A431 xenografts are
shown. Tentative synergy is observed for the combination of
IMC-C225 and radiation, and the therapeutic effect is accentu-
ated by multiple administrations of IMC-C225. (Reprinted with
permission.47
)

32
HERBST AND LANGER
dose-limiting and resolved completely without
scarring after cessation of therapy in all cases.
Given that EGFRs are expressed in epithelial tis-
sues, skin reactions are a toxicity shared by the
class of EGFR inhibitors.
Anaphylactic reactions are rare. They have
been reported in less than 2% of patients and
invariably occur during the test dose or first infu-
sion; they respond to standard treatments, includ-
ing antihistamines and corticosteroids. No fa-
talities have been associated with IMC-C225
administration.
study evaluating RT, either alone or given concur-
rently with IMC-C225 (Fig 4). Three different
forms of radiation are permitted: single daily frac-
tionation; twice a day; and concomitant boost. As
of October 2000, 178 of the 450 patients targeted
for accrual have been enrolled. The majority
(61%) have received concomitant boost RT. Eigh-
teen percent have received twice-a-day RT, and
21% have received once-daily RT. No untoward
toxicities or significant adverse events have been
observed.
IMC-C225 IN RECURRENT AND/OR
METASTATIC SQUAMOUS CELL
CARCINOMA OF THE HEAD AND NECK
ONGOING RESEARCHIN HEAD AND
NECK CANCER
Most current studies in upper aerodigestive ma-
lignancy have focused on SCCHN.52 In early-
stage squamous cell carcinoma, a “window of op-
portunity” study is assessing the role of weekly
IMC-C225 for three doses before surgery in resect-
able stage II, III, and IV disease. The primary
objectives of this effort are pharmacokinetics, tu-
mor localization, and receptor saturation. A sepa-
rate single-center study is assessing the role of
IMC-C225, in conjunction with cisplatin and
concurrent RT, with concomitant boost adminis-
tered at the end of RT, in locally advanced, unre-
sectable, newly diagnosed SCCHN. The primary
objectives in this study are response rate and
safety.
IMC-C225 has been evaluated in recurrent and
metastatic SCCHN. One of the earlier studies
combined cisplatin 100 mg/m2 every 3 weeks ϫ 3
with IMC-C225 given weekly in an escalating
dose. The primary objective of this effort was to
determine the tumor–EGFR saturating dose of
IMC-C225, to gauge the optimal biologic dose of
IMC-C225, and to establish a safety profile over a
range of dose levels in combination with cisplatin
therapy. Eligibility was restricted to patients with
locally advanced, recurrent, or metastatic EGFR-
positive head and neck cancer; measurable or
evaluable disease; tumor accessible to repeat biop-
sies for EGFR determination; up to one prior che-
motherapy regimen; acceptable performance sta-
tus; adequate renal, hepatic, and marrow function;
at least 2 months elapsed since prior surgery or
radiation; and no severe intercurrent medical ill-
The largest effort to date in locally advanced,
newly diagnosed squamous cell carcinoma is a
phase III international multicenter, randomized
Fig 4. An ongoing phase III
trial in locally advanced squa-
mous cell carcinoma of the head
and neck is testing radiation
alone versus concurrent radia-
tion and IMC-C225. Stratifica-
tions include Karnofsky perfor-
mance status, tumor and nodal
(T and N) status, and radiation
fraction (RT) and schedule. BID,
twice a day; Con Boost, concom-
itant boost; SD, standard daily;
Fx, fractionation.

IMC-C225 IN LUNG AND HEAD & NECK CANCER
33
nesses. Twelve patients with a variety of head and
neck primary sites were enrolled. Adverse events
included skin toxicity, fever, chills, and asthenia,
all relatively mild. There was one anaphylactic
reaction, one relatively severe episode of cytotox-
icity, and two fairly marked rashes. Of nine evalu-
able patients, two patients (both previously treated
with cisplatin) exhibited a complete response; four
other patients, all previously treated, experienced
a partial response. The overall response rate in this
small cohort was 67%. It should be noted that
response rates in this setting using conventional
therapy are generally much lower, with a median
survival of 4 to 6 months and 1-year survival rate
of 5% at best.53
This experience has given rise to an evaluation
of IMC-C225 in patients who have failed to ob-
tain partial or complete response with standard
treatment. Patients with metastatic or recurrent
SCCHN were given a choice of two different
cytotoxic regimens, either cisplatin or paclitaxel in
combination, or standard fluorouracil infusion
with cisplatin. Those with stable disease or tumor
progression after two courses of standard therapy
then proceeded to weekly IMC-C225/cisplatin
given every 3 weeks for a total of four courses. In
the absence of tumor progression, IMC-C225
alone is continued until disease progression. As of
January 2001, over 100 patients have been en-
rolled on this effort; 33 patients responded to the
primary chemotherapy and did not proceed to
IMC-C225. Of the remaining patients, 45 had
stable disease and 27 had progressive disease. The
unverified response rates in these two categories
were 20% and 21%, respectively, considerably
higher than one might expect with standard cyto-
toxic therapy alone.53
Finally, the Eastern Cooperative Oncology
Group completed a phase III registration trial as-
sessing cisplatin 100 mg/m2 every 4 weeks in com-
bination with either IMC-C225 or placebo. A
loading dose of 400 mg/m2 IMC-C225 was given
at week 1, followed by a maintenance dose of 250
mg/m2 weekly thereafter. This study targeted 114
patients for accrual and completed enrollment in
the summer of 2001.
ROLE OF IMC-C225 IN LUNG CANCER
Epidermal growth factor receptor expression is
relatively higher in squamous cell malignancy
compared with nonsquamous NSCLC. Expression
in small cell lung cancer has been low; in one
series of 37 specimens, no expression was noted.55
Preclinical work has shown an additive effect be-
tween IMC-C225 and radiation in both H226 and
A549 NSCLC cell lines, with potential synergy at
higher doses of IMC-C225. In the A549 line,
IMC-C225 showed synergy with escalating doses
of either cisplatin or vinorelbine, and an additive
effect positive/negative synergy with paclitaxel.54,56
In combination with RT, IMC-C225 also has
shown synergy or additivity with vinorelbine and
paclitaxel.56
Three separate studies in NSCLC are ongoing
for IMC-C225 (Table 3). The Colorado study
targets treatment-naive patients, and grafts full-
dose IMC-C225 onto standard paclitaxel/carbo-
platin. Eligibility stipulates chemotherapy-naive,
pathologically documented, measurable EGFR-
positive advanced NSCLC; adequate performance
status; age Ն 18 years; and adequate physiologic
indices, including an absolute neutrophil count of
1,500/mL, platelet count of Ն 100,000/mm3, bili-
rubin Յ 1.5 upper limit of normal, with transami-
Table 3. IMC-C225: Non–Small Cell Lung Cancer Studies
Setting
Target
40
Regimen
Site(s)
Colorado (Bunn)
First line
Paclitaxel 225 mg/m2 every 3 wk
Carboplatin AUC 6 every 3 wk
IMC-C225 400 mg/m2 load3 250 mg/m2 IV every wk
Gemcitabine 1000 mg/m2 days 1, 8
First line
30
50
Alabama (Robert)
Carboplatin AUC 5.5 every 3 wk
M.D. Anderson (Blumenschein)
IMC-C225 400 mg/m2 load3 250 mg/m2 IV every wk
Docetaxel 75 mg/m2 every 3 wk
Second line
M.D. Anderson (Herbst)
IMC-C225 400 mg/m2 load3 250 mg/m2 IV every wk
University of Chicago (Vokes)

34
HERBST AND LANGER
CONCLUSIONS AND UNANSWERED
QUESTIONS
nases Յ 2.5 upper limit of normal. In addition, no
other active malignancy in the past 3 years and no
evidence of grade Ն 2 neuropathy is permitted.
Patients must not have received radiation within 4
weeks of treatment and must have no clinically
significant cardiac disease, arrhythmias, or conduc-
tion deficits. The primary objective of this study is
a safety assessment, with secondary objectives in-
cluding antitumor activity (response rate and du-
ration of response) and an evaluation of the effect
of IMC-C225 on paclitaxel and carboplatin phar-
macokinetics.
The second study grafts full-dose IMC-C225
onto standard doses of gemcitabine and carbopla-
tin. This study targets 30 patients for accrual. The
assessment occurs every 6 weeks (two cycles). El-
igibility is virtually identical to the Colorado trial.
The primary objectives include safety and toxicity;
secondary objectives include response rate and
time to progression.
The EGFR pathway plays an important role in
cellular proliferation, angiogenesis, and survival.
Epidermal growth factor receptor is expressed in
approximately one third of human tumors, and
expression can affect overall prognosis and sur-
vival. Monoclonal antibodies directed at the
EGFR have been extensively studied. IMC-C225,
a human:murine chimeric anti-EGFR IgG1 mono-
clonal antibody, has shown both in vitro and in
vivo antitumor activity in tumor cell lines express-
ing the EGFR. Activity in combination with che-
motherapy has been shown in colon cancer (with
CPT-11), head and neck cancer (with cisplatin),
and in pancreatic cancer (with gemcitabine).54,57
The role (if any) of IMC-C225 in thoracic
malignancy has not yet been defined. In this re-
gard, although studies for advanced disease are
being conducted, the work in SCCHN and pre-
clinical work with radiation provides hope for a
potential role in locally advanced NSCLC that is
only beginning to be investigated. In addition, it
must be determined whether there is enhanced
treatment efficacy in tumors with high- versus
low-level EGFR expression and whether IMC-
C225 is more effective against tumors with squa-
mous cell histology compared with other NSCLC
types. The current lung cancer studies described
herein, if they show feasibility and early activity,
will constitute the cornerstone of this process.
Finally, a third study grafts full-dose IMC-C225
onto standard salvage therapy with docetaxel 75
mg/m2 every
3 weeks. Eligibility stipulates
pathologically documented, docetaxel-naive, EGFR-
positive NSCLC refractory to one prior chemo-
therapy regimen, with progressive disease occur-
ring either during treatment or within 3 months
after discontinuation of prior therapy. Patients
are required to have Karnofsky performance
score Ն 60 and adequate physiologic indices (ab-
solute neutrophil count Ն 1,500/mm3, platelets
Ն 100,000/m3, hemoglobin Ն 9 g/dL, bilirubin Յ
1.5 X upper limit of normal, alkaline phosphatase,
SGOT/SGPT Յ 5 X upper limit of normal, and
serum creatinine Յ 1.5 mg/dL). Patients must be
18 years of age or older, with no other active
invasive malignancy in the past 3 years, no che-
motherapy or radiation within 30 days of enroll-
ment, and no evidence of grade Ն 2 neuropathy.
The primary objective of this trial is response rate;
secondary objectives include safety and toxicity,
duration of response, survival, and the effect of
IMC-C225 on docetaxel pharmacokinetics. This
study targets 50 patients for accrual. If two or fewer
of the first 21 patients respond, the trial will be
closed. If, however, three or more of the first 21
patients respond, 29 additional patients will be
accrued to demonstrate whether a 25% response
rate is reached.
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