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Small-Molecule Epidermal Growth Factor Receptor
Tyrosine Kinase Inhibitors
MAARTEN L. JANMAAT, GIUSEPPE GIACCONE
Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands
Key Words. EGFR · ZD1839 · Iressa · OSI-774 · Tarceva
A BSTRACT
The growth and proliferation of cells are usually
tightly regulated processes that are activated by stimuli
from their environment. Epidermal growth factor
(EGF)-related peptides represent a class of molecules
that can trigger cell proliferation, among several cellular
processes, such as differentiation, migration, and survival. Binding of EGF-like peptides to the EGF receptor
(EGFR) at the cell surface leads to a cascade of intracellular reactions that transduce signals to the nucleus,
resulting in particular gene expression patterns.
However, in many tumor cells, the regulation of EGFR
activity is lost, due to increased or aberrant expression of
the receptor or its ligands, and this contributes to many
processes important for tumor growth, including cell
proliferation, survival, angiogenesis, invasion, and metastasis. Many strategies have been developed that specifically target the EGFR and inhibit its activity. Of these,
small-molecule tyrosine kinase inhibitors represent one
of the most promising classes of anticancer agents. Here,
we describe the status of small-molecule EGFR tyrosine
kinase inhibitors in preclinical and clinical development.
The Oncologist 2003;8:576-586
THE EPIDERMAL GROWTH FACTOR RECEPTOR
PATHWAY
The epidermal growth factor receptor (EGFR) (ErbB-1 or
HER-1) is a member of the ErbB family of receptor tyrosine
kinases (RTKs) that also includes the closely related ErbB-2
(HER-2/Neu), ErbB-3 (HER-3), and ErbB-4 (HER-4) receptors [1]. The EGFR is a 170-kDa protein located at the cell surface, consisting of an extracellular ligand-binding domain, a
single transmembrane region, and an intracellular domain with
tyrosine kinase activity. Activation of the receptor occurs
when a ligand, such as transforming growth factor-α or EGF,
binds to the ectodomain of the receptor, resulting in receptor
dimerization with either another EGFR protein or another
ErbB receptor; ErbB-2 is the preferred dimerization partner [2,
3]. The dimerization triggers activation of the intracellular
kinase domain of the receptor, autophosphorylation of tyrosine
residues in the intracellular domain, and subsequent recruitment and activation of downstream signaling molecules. Two
important signaling routes that are activated by the EGFR
involve the Ras-Raf-MEK-ERK and the PI3K-PDK1-Akt
kinase pathways, which are implicated in cell proliferation,
survival, and gene expression [1] (Fig. 1). Alternatively, the
EGFR can be activated by stimuli that do not directly bind the
receptor, such as hormones, lymphokines, and stress factors
[4]. This transactivation of the EGFR appears to be essential
for several mitogenic responses induced by the various stimuli,
as suggested by the results of experiments using dominant
negative EGFR mutants and specific kinase inhibitors [4].
Of note, Gilmore et al. recently demonstrated that insulinlike growth factor (IGF) transactivates the EGFR and that
therapeutic inhibition of the EGFR by gefitinib (Iressa®,
ZD1839; Astra Zeneca, Inc.; London, UK; http://www.
astrazeneca.com) counteracts IGF-mediated inhibition of
the proapoptotic protein BAD, resulting in cell death [5].
Activation of the EGFR can, thus, induce many different
cellular responses. The actual physiological response
Correspondence: Giuseppe Giaccone, M.D., Ph.D., Department of Medical Oncology, VU University Medical Center, De
Boelelaan 1117, PO Box 7057, MB 1007 Amsterdam, The Netherlands. Telephone: 31-20-444-4340; Fax: 31-20-444-3844;
e-mail: [email protected] Received March 14, 2003; accepted for publication August 18, 2003. ©AlphaMed Press
1083-7159/2003/$12.00/0
The Oncologist 2003;8:576-586 www.TheOncologist.com
Small-Molecule EGFR-TKIs
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Figure 1. The EGFR signaling pathway. Upon binding of a ligand, the
EGFR dimerizes, resulting in the activation of the intracellular kinase (K)
domain and subsequent autophosphorylation of tyrosine residues. This leads to
the activation of intracellular kinase
pathways such as the Ras-Raf-MEKERK and the PI3K-PDK1-AKT
pathways, which, in turn, activate transcription factors in the nucleus. Several
known biological responses to EGFR
activation are shown. Two successful
strategies to block the EGFR are
depicted. EGFR-specific monoclonal
antibodies, which compete with ligands
for receptor binding thereby preventing
EGFR kinase activation and EGFRTKIs that directly interact with the
EGFR tyrosine kinase domain and
inhibit its activity.
Monoclonal
antibodies
(e.g. C225)
Ligand
Tyrosine
kinase
inhibitors
(e.g. Iressa™)
EGFR
KK
Ras
Grb2
SOS SHC
P13K
Raf
PDK1
Signal
transduction
MEK
AKT
Erk
Gene
transcription
PP
cyclin D1
myc
Cyclin D1
DNA
Jun Fos
Myc
depends on the cell context [1] as
well as the particular ligand that is
bound, which, in turn, regulates
the dimer formation and subsequent signaling pathways that are
activated [6, 7].
Adhesion
Proliferation
EGFR AS A TARGET FOR ANTICANCER
THERAPEUTICS
EGFR activity is essential for embryonic development, as
null mutations in genetically modified mice are lethal [8-10].
More specifically, EGFR is involved in organogenesis of
many mesoderm- and ectoderm-derived organs, such as the
brain, heart, and lung [8-10]. In contrast to its critical role in
embryogenesis, the EGFR lacks an essential physiological
role in the adult organism, although ErbB receptors are
involved in the development of the mammary gland [11].
However, it has become clear that the EGFR has a role in the
development and progression of cancer, since increased or
aberrant expression of the EGFR or its ligands are frequent
in many types of tumors and correlate with a more aggressive disease and poorer prognosis [12-14]. In contrast, a discrepancy exists in the literature about the role of EGFR
(over)expression as a prognostic factor in some tumor types,
in a large part because of the wide variety in detection methods and cutoffs used to define overexpression [15].
Although EGFR expression is a strong prognostic factor in
some tumors, such as head and neck, ovarian, breast,
esophageal, bladder, and cervical cancers, it will be important to introduce a widely accepted standard test to evaluate
EGFR expression levels in tissues. Amplification of the
gene for the EGFR is most frequently detected in human
Migration
Survival
Differentiation
gliomas (40%) and is often associated with gene rearrangements [16]. In many cases, exon 2-7 is deleted, yielding a
constitutively active receptor that is truncated and lacks
most of the extracellular domain. This so-called EGFRvIII
mutant has also been detected in medulloblastomas, breast
and ovarian cancer, and non-small cell lung cancer
(NSCLC) [17], though the impact of this mutant on tumor
progression is not clear in these types of carcinomas.
In addition to high expression levels and/or mutations,
other potential mechanisms can induce aberrant EGFR kinase
activity, such as ligand overexpression, heterodimerization
with other ErbB members, in particular HER-2, and transactivation by heterologous signaling networks. Uncontrolled
EGFR activity has been implicated in many aspects of tumor
growth, including the promotion of cell proliferation, angiogenesis, invasion and metastasis, and survival [13, 14, 18].
Together, this provides a rationale for the inhibition of the
EGFR as anticancer therapy, as suggested by Dr. Mendelsohn
in the early 1980s [19-21]. Indeed, many agents have been
developed that specifically target the receptor, ranging from
toxin-conjugated anti-EGFR antibodies or ligands to antisense
oligonucleotides [18, 22]. Among these, monoclonal antibodies directed against the ectodomain of the receptor and smallmolecule tyrosine kinase inhibitors (TKIs) are the most
advanced in clinical development (Table 1), and the latter class
of agents is discussed below.
Janmaat, Giaccone
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Table 1. EGFR-TKIs, their specificities, reversibilities, and development stages
Class of compound
Quinazolines
Name
Specificity
Reversible
Highest development stage
gefitinib
EGFR
Yes
Approved for third-line treatment of NSCLC in Japan and the U.S.
OSI-774
EGFR
Yes
Phase III
CI-1033
pan-ErbB
No
Phase II
EKB-569
EGFR
No
Phase I
PD-183805
pan-ErbB
No
Phase I
Pyridopyrimidines
PD-158780
pan-ErbB
Yes
Preclinical
Pyrrolopyrimidines
PKI-166
EGFR/ErbB-2
Yes
Phase I, discontinued
Other compounds
GW-572016
EGFR/ErbB-2
Yes
Phase II
AG-1478
EGFR
Yes
Preclinical
PRECLINICAL STUDIES WITH EGFR-TKIS
The finding that mutations in the ATP-binding site of the
intracellular domain of the EGFR disable ligand-induced
responses [23-25] indicates that that part of the receptor is
essential for EGFR tyrosine kinase activity and downstream
signaling. In order to specifically inhibit EGFR kinase activity, hundreds of natural and synthetic compounds that compete with ATP for EGFR binding were screened. Many
compounds of different chemical classes that effectively
inhibit EGFR kinase activity have been identified, some of
which are in late clinical development (Table 1). These molecules generally differ in their abilities to bind the EGFR
ATP-binding pocket—either reversibly or irreversibly—or
in their capacities to additionally inhibit other members of
the ErbB family of receptors [26]. Many of these agents
have been investigated in preclinical studies; of these, gefitinib and OSI-774 (erlotinib, Tarceva™; OSI Pharmaceuticals; Tarrytown, NY; http://www.osip.com) have been most
extensively studied [27].
Gefitinib
Gefitinib is an orally active, selective, and reversible
EGFR-TKI that chemically belongs to the class of anilinoquinazolines [27]. Similar to the effects initially found
with EGFR-blocking monoclonal antibodies [19-21], in
vitro effects of gefitinib as a single agent were mainly
cytostatic [28], although cytotoxic effects have been
observed in a few cases [5, 29]. It has been suggested that
gefitinib favors several proapoptotic mechanisms involving Bcl-2 family members, as the proapoptotic protein
BAD is activated by gefitinib in breast cancer cells [5],
while, conversely, overexpression of the apoptosis-suppressor Bcl-2 reverts gefitinib-induced cell death of vulval
carcinoma cells [29].
Gefitinib is active against a wide variety of tumor cell
lines [28, 29, 30-33], and the sensitivity of cells to gefitinib is
likely to be affected by multiple factors, as the EGFR is part
of a large signaling network [1]. Several cellular factors have
been investigated that may be implicated in the sensitivity of
cells to gefitinib. EGFR expression levels were initially found
to be unrelated to response to gefitinib, since xenografts
expressing high, moderate, and low amounts of EGFR all
showed growth inhibition upon gefitinib treatment [28, 30],
while later publications showed a correlation between the two
in some cases [31]. In contrast to expression levels, EGFR
activity status may be more important [15]. EGFR activity
can be modulated by several mechanisms, for example,
increased ligand expression or heterodimerization with ErbB2. Importantly, cells expressing high levels of ErbB-2 have
been shown to be particularly sensitive to gefitinib [29, 32,
33], although no direct evidence has demonstrated an association between ErbB-2 levels and anti-EGFR response.
Gefitinib-like agents may additionally inhibit ErbB-2 activity
by the sequestering of ErbB-2 through the induction of signaling-inactive EGFR-ErbB-2 heterodimers [34, 35].
Furthermore, it has been established that proteins that are
involved in cell cycle progression, in particular p27kip1 and
cyclin D, play essential roles in the G1-phase cell cycle arrest
observed in many cells treated with anti-EGFR agents [36,
37]. Finally, we and others have suggested that intrinsic and
persistent activity of kinase pathways downstream of EGFR,
such as the Ras-Raf-MEK-ERK and the PI3K-PDK1-Akt
pathways, may provide a mechanism of resistance to gefitinib
[5, 31, 32, 36].
Gefitinib has been combined with a variety of cytotoxic
agents, resulting in enhanced antitumor effects in cultured
cells and in vivo models, except in combination with gemcitabine [28, 30]. In addition, gefitinib treatment resulted in
synergistic effects in combination with radiation [38-40].
Importantly, sequence-dependent effects were reported in
cells treated with combinations of gefitinib with radiation or
chemotherapy (cisplatin and/or 5-fluorouracil), with the best
results observed when gefitinib was given before radiation
and before or during chemotherapeutic treatments; whereas
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some antagonistic effects were observed when gefitinib was
given after cytotoxic treatments [38]. These data suggest the
need for caution in the design of clinical trials using combinations of gefitinib and cytotoxic agents. A relatively new
development is the preclinical evaluation of treatment with
gefitinib combined with other novel, biological agents, such
as the ErbB-2 monoclonal antibody trastuzumab [29, 32, 41].
ErbB-2 is the preferred dimerization partner for EGFR, and
EGFR/ErbB-2 dimers are thought to induce more potent signals [2, 3]. Simultaneous inhibition of the EGFR and ErbB-2
resulted in additive or synergistic effects in ErbB-2-overexpressing breast cancer cells [29, 32, 41]. Those preclinical
data initiated a currently ongoing phase II trial combining
trastuzumab with gefitinib in breast cancer patients [42].
In addition to the often limited antiproliferative effects
observed in vitro, several mechanisms of action that are
only active in vivo, such as inhibition of angiogenesis and
invasion and metastasis, have been attributed to gefitinib
[40, 43-46]. The antiangiogenesis effect of gefitinib has
been proposed to be the result of reduced secretion of
angiogenesis factors [43, 44], while gefitinib can also
directly inhibit the growth and cell-cell interactions of
endothelial cells [40, 45]. Furthermore, the combination of
gefitinib with a cytotoxic treatment, such as paclitaxel or
radiation, potentiated the antiangiogenesis effect [40, 43].
OSI-774
OSI-774 is an EGFR-specific quinazoline derivative that
inhibits the activity of purified EGFR in intact cells at
nanomolar concentrations (50% inhibitory concentrations of
2 nM and 20 nM, respectively). An initial report showed that
OSI-774 induced apoptosis and growth inhibition in several
tumor cell lines in vitro, which was associated with the
induction of p27kip1 expression and blockade in the G1 phase
of the cell cycle [47]. The upregulation of p27kip1 and, possibly, restoration of Rb function are required for the antitumor
action of EGFR inhibitors, including OSI-774 [37]. Moreover, OSI-774 has shown a substantial effect on the tumor
growth of human HN5 xenografts growing in athymic mice
[48] and on pancreas-derived xenografts, which was associated with a decrease in phosphorylation of ERK but not of
Akt [49]. In skin and tumor biopsy specimens, phosphorylated forms of EGFR, Akt, and ERK were lower after treatment with OSI-774 [50, 51]. Synergistic effects were
observed when OSI-774 was combined with cisplatin in preclinical models [48]. In addition, an enhancement of cytotoxic effects was reported when OSI-774 was combined with
doxorubicin and gemcitabine, among other cytotoxic agents
[52]. Moreover, OSI-774 selectively inhibited molecular
effectors involved in the invasion of human glioblastoma cell
lines expressing the EGFRvIII mutant [53]. This mutant
Small-Molecule EGFR-TKIs
receptor cannot be recognized by EGFR-specific monoclonal
antibodies such as cetuximab, illustrating one of the advantages of EGFR-TKIs over monoclonal antibodies. OSI-774 is
currently being tested in advanced clinical trials in various
human malignancies (Table 1).
Other Small-Molecule EGFR-TKIs
Many other small-molecule inhibitors have been investigated in preclinical studies, some of which inhibit other ErbB
kinases in addition to the EGFR. Several of these inhibitors
are currently being tested in the clinic and are discussed here.
PD-183805 and its water-soluble analog, CI-1033, are
irreversible inhibitors of all ErbB receptors (Table 1). These
agents have exhibited in vitro and in vivo antitumor activities
as single agents and in combination with cytotoxic drugs in
several tumor models [54-57]. Interestingly, Erlichman et al.
showed synergistic effects of combinations of CI-1033 with
the topoisomerase inhibitors SN-38 and topotecan in cells
expressing the drug transporter breast cancer resistance protein (BCRP) [55]. A possible explanation for these results is
that CI-1033 is a substrate of the BCRP pump and competes
with SN-38 and topotecan for binding places, leading to an
increased intracellular accumulation of the topoisomerase
inhibitors. Recently, Schuetz et al. showed that gefitinib
potently reversed BCRP-mediated resistance to topoisomerase inhibitors in vitro, resulting in synergistic antitumor
effects in xenograft models, which were attributed to dramatic increases in the bioavailability of the topoisomerase
inhibitors in mice [58]. Although the precise mechanism of
BCRP inhibition by EGFR-TKIs is not known, it could be an
important factor in the design of clinical combination studies
with EGFR-TKIs. Synergistic apoptotic responses were
found when cells were treated with combinations of CI-1033
and gemcitabine [57]. In that study, phosphorylation of ERK
and Akt was inhibited, similar to observations with other
EGFR-targeted agents, while concurrent activation of the
p38 stress pathway was reported, together contributing to the
apoptotic response.
PKI-166 is a dual EGFR/ErbB-2 inhibitor that induces
growth inhibition in several tumor-derived cell lines expressing high levels of EGFR and/or ErbB-2 [59] and exhibits
antitumor activity against several human tumor models in
mice, commonly associated with antiangiogenesis and antiinvasion effects [60-64]. Interestingly, when compared with
an EGFR-specific kinase inhibitor (CGP-59326), PKI-166
was more efficient at inhibiting the in vitro growth of tumor
cells in the presence of EGF-related ligands [59], suggesting
greater antitumor effects for inhibitors that target both the
EGFR and ErbB-2 compared with EGFR-specific agents.
Similar results have been published with several other
small-molecule EGFR-TKIs in preclinical studies. Of note,
Janmaat, Giaccone
GW-572016 is a novel dual EGFR/ErbB-2 kinase inhibitor
that is currently being tested in the clinic and has been
demonstrated to be active against in vitro and in vivo human
tumor models [65, 66]. EKB-569 is an irreversible inhibitor
of EGFR activity that potently inhibits the growth of cells
overexpressing EGFR or ErbB-2 but has little effect on cells
with low expression levels of these receptors [67, 68]. In
summary, the mechanism of action of the small-molecule
EGFR-TKIs involves the direct inhibition of EGFR activity
and/or the activities of other ErbB members. Inhibition of
downstream Ras/ERK and PI3K/Akt kinase pathways has
been linked, in many studies, with the antiproliferative and,
sometimes, proapoptotic effects of the EGFR-TKIs. In addition, p27kip1 upregulation appears to be essential for the
growth delay induced by these agents, while expression levels of EGFR seem to be of minor importance. In animal models, EGFR-TKIs have been shown to be potent inhibitors of
tumor growth, antiangiogenesis agents, and inhibitors of
invasion and metastasis of tumor cells when given as a
single drug or in combination with a cytotoxic treatment.
CLINICAL STUDIES WITH EGFR-TKIS
Gefitinib
Gefitinib is the EGFR-TKI that is the furthest advanced
in clinical development, and registration was obtained in
Japan in July 2002 and in the U.S. in May 2003 for third-line
therapy of advanced NSCLC. The results of three phase I
studies in patients with advanced solid tumors have been
published [69-71]. This was one of the first targeted agents
that was clinically tested, and the goals were clearly different
from trials with cytotoxic agents. Instead of the maximum
tolerated dose, one goal was to determine the optimal biological dose. Moreover, the common expression of the EGFR
in solid tumors and preclinical evidence suggested a broad
antitumor activity, leading to the inclusion of multiple tumor
types and no selection of patients based on EGFR expression
in their tumors. Other goals were to establish pharmacokinetic and pharmacodynamic relationships. Across the dose
range tested (50-1,000 mg/day), the most frequent adverse
events were dose-dependent acneiform skin rash and grade 1
or 2 diarrhea. The latter was dose limiting, being severe and
frequent in patients given doses over 600 mg/day. Other toxicities that were observed include nausea and transient and
asymptotic transaminitis. All of these side effects were
manageable and reversible on cessation of treatment.
To evaluate the effect of gefitinib on EGFR-TK activity,
biopsies of the skin, which are known to express the EGFR,
were analyzed for known, EGFR-dependent molecular
markers and downstream effects on proliferation before and
after 28 days of treatment. These studies showed inhibition
580
of EGFR-regulated signaling in patients treated with gefitinib consistent with the proposed mechanism of action, with
downregulation of activated EGFR, mitogen-activated protein kinase, and the proliferation marker Ki67 and upregulation of p27kip1, phosphorylated signal transducer and activator
of transcription 3, and apoptotic cells [70, 72]. In those phase
I studies, promising antitumor activities were observed in
patients with NSCLC, and head and neck, ovarian, colorectal,
prostate, and breast cancers [69-71, 73].
The promising phase I results prompted the rapid initiation of phase II studies in pretreated patients with NSCLC,
and prostate, breast, colorectal, and head and neck cancers.
Currently, data are available from two large randomized
phase II studies in pretreated NSCLC patients randomized to
receive either a 250-mg or a 500-mg daily dose of gefitinib,
doses that achieved sufficient blood concentrations to inhibit
EGFR activation in preclinical models. One study, the Iressa
Dose Evaluation in Advanced Lung Cancer 1 (IDEAL1)
trial, included 210 patients who had received one prior
chemotherapy regimen, which included a platinum drug [74].
The response rate was 18.5%, while approximately 40% of
patients experienced symptom improvements. The other
study (IDEAL2) included 216 patients who had received two
or more chemotherapy regimens, which included a platinum
drug and docetaxel. In that study, the response rate was 10%
[75]. In both studies, withdrawals and grade III-IV adverse
events were more frequent in patients receiving the higher
dose, while the response rates were comparable, indicating
that activity achieved at doses of 250 mg and higher doses
did not generate better efficacy but only greater toxicities
[76]. As a result of those studies, gefitinib was approved for
the third-line treatment of NSCLC in Japan and, recently, in
the U.S. as well; whereas approval in the rest of the world is
being assessed at this time. Other phase II studies with gefitinib as monotherapy or in combination with other therapies
are under way for hormone-refractory prostate cancer,
advanced breast cancer, advanced colorectal cancer, head
and neck cancer, esophageal cancer, ovarian cancer, and
glioblastomas, among others. Preliminary data indicate that
gefitinib is generally well tolerated in combination with several cytotoxic therapies, and promising results have been
observed, including those from a phase II monotherapy trial
in recurrent or metastatic head and neck cancer [77] and in
patients with advanced breast cancer [78]. In the latter report,
low levels of phosphorylated Akt (pAkt) were indicative of
tumor response, suggesting low pAkt as a prognostic factor
for response.
At the same time, two very large randomized studies with
gefitinib and combination chemotherapy were concluded, and
preliminary results were presented recently [79, 80]. In those
studies, chemotherapy-naïve patients with advanced NSCLC
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were randomized to receive chemotherapy with either
placebo or two different doses of gefitinib (250 or 500 mg). In
the Iressa NSCLC Trial Assessing Combination Treatment 2
(INTACT2) trial, chemotherapy consisted of carboplatinpaclitaxel, which is standard in North America, and in the
INTACT1 trial, chemotherapy consisted of cisplatin-gemcitabine, which is more frequently employed in Europe.
Unfortunately, both studies failed to reach the major end
point, which was improvement in survival by the addition of
gefitinib, or any of the other end points, which included progression-free survival time, time to worsening of symptoms,
objective tumor response, and quality of life. As the studies
were robust and well designed, it should be concluded that
these efficacy results are definitive. However, the studies did
confirm the safety and tolerability of gefitinib, with comparable toxicity profiles in the control and the gefitinib treatment
arms, with the exceptions of an expected dose-dependent skin
toxicity and diarrhea in patients treated with gefitinib and
two- to threefold more drug-related withdrawals in the 500
mg/day gefitinib arm in both studies. Although the results are
disappointing, the high expectations may have been too optimistic for several reasons. One of these reasons may be the
lack of patient selection, which may have diluted a possible
beneficial effect of the addition of gefinitib to combination
chemotherapy. The impact of EGFR expression levels on sensitivity is still an issue, even though preclinical data point to
the lack of an effect. Other markers that may be used for
selection are activated forms of EGFR and downstream effectors. Recently, the expression of EGFR (HER-2/Neu) was
tested in 43 patients with advanced NSCLC who received 250
mg/day of gefinitib. No correlation with response or survival
was observed [81]. Similarly, there was no correlation
between response and the EGFR immunohistochemical
results in patients who were entered in the IDEAL phase II
studies [82]. It is theoretically possible that tumors pretreated
with chemotherapy are more sensitive to EGFR-TKIs than
chemotherapy-naïve tumors, which would be consistent with
the positive results seen in the IDEAL1 and IDEAL2 trials.
This hypothesis, together with the results of the INTACT
studies, suggests that sequential administration of chemotherapy followed by gefinitib may be a more effective approach.
Although no phase II studies have so far been performed for
the first-line therapy of advanced NSCLC with gefinitib
alone, data reported from the extended access program seem
to indicate definite activity in that setting. Provocative results
have been reported in the treatment of bronchioalveolar carcinoma [83]. This tumor type has a definitively different biology than the common adenocarcinomas of the lung, as it is
more frequently observed in women and nonsmokers. Female
gender and no smoking history (and Japanese race in the
IDEAL1 study) were, in fact, identified in phase II studies as
Small-Molecule EGFR-TKIs
prognostic factors for response in advanced NSCLC [74].
However, it is evident that further investigation is needed to
improve combination treatment with gefitinib in NSCLC
patients and to identify the subset of patients that benefit from
gefitinib treatment. Moreover, this drug is being investigated
in studies of a large number of other malignancies, either as a
single agent or as part of a combination therapy.
OSI-774
OSI-774 is structurally related to gefitinib and has very
similar toxicity and safety profiles, with skin rash and diarrhea as dose-limiting toxicities. Promising activity has been
seen in phase I trials, with some reports of complete
responses [84, 85]. The dose chosen for further evaluation
after phase I studies is 150 mg/day, which is just below the
maximum tolerated dose of 200 mg/day. To date, the results
of three monotherapy phase II trials have been presented. In
a study with 56 NSCLC patients, seven patients (11%)
achieved partial responses, while 19 patients (34%) had stable disease [85]. The response rate to OSI-774 in NSCLC is
similar to that obtained with gefitinib and C225, indicating
a consistent pattern of activity of this class of agents in
NSCLC. Promising phase II results have also been reported
for advanced ovarian cancer and refractory head and neck
cancer, with response rates of 8.8% and 13%, respectively,
and disease stabilization in 44% and 29% of patients,
respectively [86, 87]. Many phase I/II studies in various
malignant diseases are being carried out at this time with
OSI-774 in combination with several chemotherapeutics
and/or radiation [88]. In those studies, responses have been
reported for NSCLC, penile carcinoma, head and neck cancer, and mesothelioma, while prolonged disease stabilization was observed in NSCLC, mesothelioma, and head and
neck, bladder, ovary, stomach, and skin cancers [89-91].
Two large international studies of OSI-774 have been
concluded in the first-line treatment of advanced NSCLC in
combination with chemotherapy, versus chemotherapy
alone, with the same chemotherapy regimens used in the
gefitinib phase III studies (carboplatin-paclitaxel and cisplatin-gemcitabine). The results of those studies are
awaited with interest and some trepidation in the light of the
negative results with gefitinib.
As with the antibody C225 [92], there has been a retrospective analysis of correlation between survival and intensity
of skin rash. Across several studies and different tumor types,
there was a consistent correlation between skin toxicity and
survival [93].
Other Small Molecules
CI-1033 is an irreversible inhibitor of all four members
of the ErbB family of receptors. The data from several phase
Janmaat, Giaccone
I studies, in which several different administration schedules
were tested, have been presented. All schedules tested were
generally well tolerated. Side effects included the ones
observed with the other small molecules, with diarrhea and
skin rash as dose-limiting toxicities, as well as reports of
thrombocytopenia and allergy [94]. Unfortunately, no complete or partial responses were reported from phase I trials,
though several patients achieved stable disease [95]. Phase
II studies are under way. A large, randomized phase II trial
in patients with advanced NSCLC, who failed prior platinum-based chemotherapy, is presently testing CI-1033 in
three different schedules and doses in patients selected on
the basis of having at least one of the four HER receptors
positive.
Phase I studies with the dual EGFR/ErbB-2 inhibitor
PKI-166 have recently concluded. The major toxicities
were similar to those of the other two small molecules, but
an apparently higher incidence of liver toxicity was noted
with this agent. Therefore, further development of PKI-166
was discontinued.
The first phase I/II data with the dual EGFR/ErbB-2
kinase inhibitor GW-572016 reveal that the compound is
well tolerated in patients at concentrations up to 1,250
mg/day as monotherapy as well as in combination with
chemotherapeutics [96-102]. In addition to skin rash and
diarrhea, headache was one of the most common adverse
events. In one study, the inhibition of activated Akt, activated
ERK, and cyclin D protein was associated with tumor cell
apoptosis and regression of metastasis, and was predictive of
clinical response [102]. Interestingly, two trastuzumab-resistant breast cancer patients had objective responses [102],
while two gefitinib-resistant NSCLC patients achieved minor
responses [98], suggesting that the dual specificity of GW572016 may be more effective in some patients than more
specific agents. Phase II trials are under way, including ones
in patients with trastuzumab-refractory metastatic breast
cancer and metastatic colorectal cancer [99, 100].
EKB-569 is an irreversible EGFR-specific TKI that
inhibits the growth of tumor cell lines that overexpress
EGFR or ErbB-2 in vitro and in vivo [67]. The data from
three preliminary phase I trials have been presented. In those
trials, several treatment schedules were tested as monotherapy in patients with advanced-stage solid tumors [103] and in
combination with cytotoxic agents in patients with advanced
pancreatic [104] and colorectal cancers [105]. The results
again show mild diarrhea and skin rash as the major toxicities, indicating that EKB-569 was generally well tolerated.
CONCLUSIONS
The emerging clinical data in EGFR-targeted therapy
point to a role for these types of agents in the treatment of
582
cancer. However, the disappointing results of the INTACT
trials with gefitinib demonstrate that the use of these agents
in combination with chemotherapy is not straightforward
and that additional investigation of optimal treatment
schedules and sequences is warranted. The results of phase
III trials with OSI-774 in combination with chemotherapy
for NSCLC patients, which are very similar to the studies
with gefitinib, are eagerly awaited, because they might
reveal differences between the structurally related compounds. Alternative strategies may include the combination
of anti-EGFR agents with radiation or other novel, targeted
agents, such as Herceptin®, which have been demonstrated
to be effective combinations in preclinical studies [29, 32,
38-41] and are currently being tested in patients. In contrast
to combination strategies, the superior response rates for
pretreated NSCLC patients with gefitinib and OSI-774 as
single agents, along with a high rate of disease control,
symptom relief, and good tolerability, support the use of
anti-EGFR agents as monotherapy, and prospective studies
in chemotherapy-naïve patients need to be performed.
In addition to the treatment of NSCLC, various trials
have concluded or are under way to test the efficacy of
EGFR-targeted therapy against other tumor types, such as
breast, prostate, head and neck, and colon cancers, as single-agent therapy and in combination with chemotherapy.
Preliminary data show good tolerability of EGFR-TKIs in
combination treatments, and promising results with several
tumor types have been observed.
Another issue to be addressed is whether the broader
selectivity of some EGFR-TKIs impacts their antitumor efficacies. Objective and minor responses were achieved with
the EGFR/ErbB-2 inhibitor GW-572016 in patients pretreated with gefitinib or trastuzumab, indicating that a
broader selectivity may be more effective in some cases.
However, a major drawback to this is the higher toxicity
observed in patients treated with agents targeting multiple
ErbB receptors. A good alternative could be treatment with
combinations of targeted agents, such as combined treatment
with gefitinib and trastuzumab, which is being assessed at
this time in patients with advanced breast cancer [42].
The major challenge will be to identify the subset of
patients that will benefit from anti-EGFR therapy. Data from
clinical trials with anti-EGFR agents show that responders had
a higher incidence of skin rash than nonresponders [92, 93].
Although more evidence should be gathered, this suggests skin
rash as a potential surrogate marker for clinical activity.
In conclusion, EGFR-TKIs have potential antitumor activity against many types of cancer, including NSCLC. However,
more work is needed to improve their efficacy as single-agent
therapy (i.e., via patient selection) or in combination with
chemotherapy, radiotherapy, or other novel (targeted) agents.
583
Small-Molecule EGFR-TKIs
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