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Lung Cancer 69 (2010) 1–12
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Lung Cancer
journal homepage: www.elsevier.com/locate/lungcan
Review
New strategies to overcome limitations of reversible EGFR tyrosine kinase
inhibitor therapy in non-small cell lung cancer
Robert C. Doebele ∗ , Ana B. Oton, Nir Peled, D. Ross Camidge, Paul A. Bunn Jr.
University of Colorado Cancer Center, Division of Medical Oncology, Aurora, CO, United States
a r t i c l e
i n f o
Article history:
Received 9 September 2009
Received in revised form
10 December 2009
Accepted 11 December 2009
Keywords:
NSCLC
EGFR
HER
T790M
Irreversible
TKI
Antibody
a b s t r a c t
The epidermal growth factor receptor (EGFR), a member of the HER family of receptors, has become a
well-established target for the treatment of patients with non-small cell lung cancer (NSCLC). Several
EGFR-targeted agents produce objective responses in a minority of unselected patients, but a majority
of those with EGFR-activating mutations; however, all responders eventually develop resistance. The
modest activity of agents that target only EGFR may be due, in part, to the complexity and interdependency of HER family signaling. The interdependent signaling that occurs between EGFR and HER2
provides a rationale for the simultaneous inhibition of these receptors with reversible and irreversible
inhibitors. Several agents with activity against both EGFR and HER2 are currently under development.
Irreversible EGFR/HER2 tyrosine kinase inhibitors (TKIs) (e.g., BIBW 2992, HKI-272) and pan-HER TKIs
(e.g., PF00299804) comprise a novel class of agents in clinical development that may prevent and
overcome inherent and acquired resistance to first-generation reversible EGFR TKIs. Other agents in
development include the monoclonal antibody pertuzumab, and XL-647, which inhibits EGFR and HER2,
as well as multiple vascular endothelial growth factor receptor family members. Here we briefly review
the currently available EGFR-targeted agents, discuss the rationale for extending inhibition to other HER
family members, weigh the merits of irreversible HER family inhibition, and summarize preclinical and
clinical data with EGFR/HER2 and pan-HER inhibitors under clinical development.
© 2009 Elsevier Ireland Ltd. All rights reserved.
1. Introduction
Lung cancer is the leading cause of cancer death in the United
States and worldwide, claiming the lives of approximately 162,000
Americans and 1.4 million people around the world in 2008 [1–3].
Lung cancer is divided into 4 histologic subtypes according to
the World Health Organization (WHO) classification: adenocarcinoma, squamous carcinoma, large-cell carcinoma, and small-cell
carcinoma. Because the first 3 have similar treatment and staging paradigms, they are frequently grouped together as non-small
cell lung cancer (NSCLC). The NSCLC histologies represent approximately 85% of all lung cancers [4]. Most patients with NSCLC are
diagnosed with advanced-stage disease (stages IIIB and IV) requiring systemic therapy [5]. Unfortunately, the prognosis for such
patients is poor, with 5-year survival rates of 8% and 2% associated with stages IIIB and IV disease, respectively [6]. Median overall
survival (OS) ranges from approximately 7.4 to 12.3 months with
first-line chemotherapy [7–15], and from 6.7 to 8.4 months with
salvage therapy [16–20].
The epidermal growth factor receptor (EGFR) mediates several cell functions, including proliferation, migration, and survival
[21]. Its dysregulation triggers different mechanisms that contribute to the development of lung cancer. EGFR is overexpressed
in several malignancies, occurring in 40–80% of NSCLCs, which
has made it the focus of many new treatment strategies [22]. The
currently available EGFR-targeted agents have provided benefit to
certain subpopulations of patients with NSCLC. However, the efficacy of these agents in the general population has been modest
and limited by resistance in patients who initially respond. Several
compounds that simultaneously target EGFR and other members
of the HER/ErbB family are currently in clinical development for
NSCLC and may have the potential for overcoming the limitations of
reversible inhibitors that solely target EGFR. Here we briefly review
the currently available EGFR-targeted agents, discuss the rationale
for the irreversible inhibition of EGFR and other HER family members, and summarize preclinical and clinical data with EGFR/HER2
and pan-HER inhibitors that are currently in clinical development
for the treatment of patients with NSCLC.
2. HER family
∗ Corresponding author at: RC1-South Tower, Mail Stop 8117, 12801 E. 17th Ave.,
Aurora, CO 80045-0511, United States. Tel.: +1 3037242980; fax: +1 3037243889.
E-mail address: [email protected] (R.C. Doebele).
0169-5002/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.lungcan.2009.12.009
The EGFR, also known as HER1 and ErbB1, was the first described
for a family of receptor tyrosine kinases (TKs) that also includes
2
R.C. Doebele et al. / Lung Cancer 69 (2010) 1–12
Fig. 1. EGFR and downstream signaling. (A) Schematic representation of the structure of EGFR. The locations and regions of commonly occurring mutations in the EGFR TK
domain are shown in the exon boundary map. (B) Ligand-bound receptors form functionally active homodimers or heterodimers, resulting in the activation of downstream
signaling pathways that promote cellular proliferation and survival. No known ligand exists for HER2, and HER3 has no functional TK activity. Other receptor TKs (e.g., IGF-1R,
MET) can modulate EGFR downstream pathways. Note: EGFR, epidermal growth factor receptor; HB-EGF, heparin-binding epidermal growth factor; IGF-1R, insulin-like
growth factor receptor-1; NRG, neuregulin; RTK, receptor tyrosine kinase; TK, tyrosine kinase. (Panel A adapted from Kumar et al. [23]; panel B adapted from Ciardiello and
Tortora [26].)
HER2/neu (ErbB2), HER3 (ErbB3), and HER4 (ErbB4). EGFR is a 170kDa transmembrane protein that is widely expressed in several
malignancies (e.g., lung, breast, colon, esophageal). The HER (ErbB)
family of receptors share important structural similarities across 4
extracellular domains (I through IV), a transmembrane domain, and
intracellular domains consisting of a kinase domain and tyrosine
phosphorylation sites in the carboxy-terminal tail (Fig. 1A) [23].
However, HER2 lacks a ligand-binding domain and HER3 is devoid
of functional kinase activity [24,25].
Multiple ligands bind to this family of receptors with varying specificity (Fig. 1B) [26]. Ligand binding induces HER receptor
homodimerization (e.g., EGFR–EGFR) or heterodimerization (e.g.,
R.C. Doebele et al. / Lung Cancer 69 (2010) 1–12
EGFR–HER2) [21]. HER2 has no known ligand, but is the preferred
binding partner of EGFR and the other HER family members [27].
EGFR containing activating mutations in the kinase domain
(exons 18–21) were initially identified in patients with significant
responses to gefitinib [28,29]. EGFR harboring deletions in exon
19 (del19), substitution mutations in exon 21 (L858R), or less common mutations (e.g., G719S, L861Q) enables constitutive activation
of the kinase function in the absence of ligand stimulation by causing a shift in the equilibrium between active and inactive states of
the kinase domain to favor the active state (Fig. 1A) [23,30]. These
activating mutations confer hypersensitivity to TK inhibitors (TKIs),
but not inhibition by monoclonal antibodies, because the mutations
decrease the affinity of the EGFR for adenosine triphosphate (ATP),
thus improving competitive binding by the inhibitors [31].
Receptor dimerization is a required step in HER family signal
transduction. This results in the transphosphorylation of specific
tyrosine residues within the intracellular domain and leads to the
activation of downstream signaling events that modulate cellular
processes, such as those involved in cellular proliferation and survival (Fig. 1B) [26]. The type and duration of cellular response to HER
family signaling is dependent on the specific HER dimer formed.
For example, heterodimeric receptor pairs have a greater mitogenic and transforming effect than the corresponding homodimers
[32–34].
3. Blocking EGFR in NSCLC
Given the important role of EGFR in NSCLC, several EGFRtargeted agents have been developed, including small-molecule
TKIs that bind with the intracellular TK domain (e.g., erlotinib,
gefitinib) and monoclonal antibodies directed to the extracellular
receptor domain (e.g., cetuximab).
4. Reversible EGFR TKIs (gefitinib and erlotinib)
Gefitinib and erlotinib are orally administered reversible EGFR
TKIs. Gefitinib (Iressa® ; Table 1) was the first EGFR-targeted agent
approved by the US Food and Drug Administration (FDA) for the
second- and third-line treatment of patients with NSCLC [35]. The
initial approval was based largely on the data from the phase I/II
IDEAL 1 and IDEAL 2 studies [36,37]. However, gefitinib failed to
show an OS benefit in a confirmatory phase III trial (ISEL) designed
to evaluate gefitinib against placebo [38], which prompted a change
in the US label restricting gefitinib use to patients with NSCLC
who currently or who had previously derived benefit from treatment. More recently, gefitinib showed noninferiority in OS and
more favorable tolerability compared with docetaxel in the phase
III INTEREST trial of patients with previously treated NSCLC [39].
Erlotinib (Tarceva® ; Table 1) is currently the only EGFR inhibitor
approved by the FDA for the treatment of patients with NSCLC [40].
This agent has shown survival benefit in previously treated patients
with NSCLC. In the BR.21 trial, 731 patients were randomized in a
2:1 ratio to receive erlotinib 150 mg/day or placebo [16]. Improved
OS was observed with erlotinib (7.9 months vs. 3.7 months; hazard
ratio [HR], 0.7; p < 0.001). In the phase III SATURN trial, erlotinib
was shown to produce prolonged progression-free survival (PFS)
(HR, 0.71) and OS (HR, 0.81) when compared with placebo in the
maintenance (immediate second-line therapy) setting after firstline chemotherapy [41]. The improvements were most striking in
patients with EGFR-activating mutations.
While it is clear that EGFR TKIs can provide clinical benefits to patients with NSCLC, early clinical studies showed that
only ∼10% of unselected patients respond to EGFR TKIs (Table 2)
[16,17,36–39,42–50]. Retrospective analyses from phase II studies
of EGFR TKIs identified certain clinical characteristics associated
3
with objective responses to treatment, including Asian ethnicity, female gender, adenocarcinoma histology, and never-smoking
history [17,36,37,51,52]. However, the predictive value of these
demographic and clinical markers is not consistently reliable
[16,38].
Several molecular biomarkers have also been identified that
may be more effective predictors of response to EGFR TKI therapy. The most effective marker appears to be the presence of
somatic gain-of-function (activating) mutations in the kinase
domain of EGFR (Fig. 1A) [23]. Activating mutations are present
in ∼10% of American and European patients and 25–50% of Asian
patients with NSCLC [53]. Activating EGFR mutations are more
frequently associated with a never-smoking history, adenocarcinoma histology, and bronchoalveolar features [42]. About 90% of
EGFR-activating mutations are clustered in exons 19 and 21 [42].
Patients with del19 mutations demonstrate a higher response rate
and longer survival with EGFR TKI therapy than patients with
point mutations in exon 21 [43,54,55]. Response rates among
patients with activating mutations are approximately 20–90%,
compared with 10–20% in unselected patients (Tables 2 and 3)
[16,17,36–38,43–47,49,50,56–66]. Results from a subanalysis of
437 never-smoking Asian patients from the IPASS trial, which compared first-line gefitinib with chemotherapy, showed that PFS was
significantly longer following the administration of gefitinib to
patients with EGFR mutations (HR, 0.48; p < 0.0001). Conversely, in
patients with wild-type EGFR, PFS was longer following chemotherapy (HR, 2.85; p < 0.0001) [63]. These data were confirmed in other
randomized trials [67,68] and in large phase II trials [69,70].
Other potential biomarkers of responsiveness include increased
EGFR gene copy number as detected by fluorescence in situ
hybridization (FISH). True gene amplification or high polysomy is
defined when gene clusters are recognized and/or more than 4
EGFR gene copies exist in >40% of cells [71]. Our in vitro experience
in NSCLC cell lines showed that both EGFR gene amplification and
high copy number were significantly associated with sensitivity
to EGFR TKIs [72]. Indeed, in both the BR.21 and ISEL trials, FISHpositive patients treated with EGFR TKIs demonstrated improved
OS compared with patients receiving placebo [73,74]. EGFR protein
expression by immunohistochemistry (IHC) has a lesser degree of
predictive power [73–78]. In the BR.21 trial, IHC-positive patients
treated with erlotinib had significantly superior survival compared
with placebo-treated patients, whereas the ISEL trial showed that
gefitinib was associated with improved survival in IHC-positive
patients; however, the difference was not statistically significant
[73,77]. Combining FISH and IHC may also predict EGFR TKI benefit
[78].
Mutations in the KRAS gene, which are present in approximately 15–30% of NSCLC cases, are strongly associated with lack
of response to EGFR TKIs [74,79–81]. In contrast to colorectal
cancer, where KRAS mutation status predicts benefit from EGFR
monoclonal antibody therapy, most studies in NSCLC show no
significant association between the presence or absence of KRAS
mutations and PFS or OS after EGFR TKI or monoclonal antibody
therapy. This includes the recent SATURN trial, in which patients
received immediate second-line therapy with erlotinib or placebo
[41]. Interestingly, KRAS mutations and EGFR-activating mutations
are almost always mutually exclusive, suggesting that they play
functionally overlapping roles in NSCLC tumorigenesis [74,79,80].
Despite the clinical benefits achieved with EGFR TKIs in selected
patient populations, acquired resistance has proven to be a major
clinical issue. Nearly all patients who initially respond to EGFR TKI
treatment eventually relapse. Several underlying molecular mechanisms have been implicated in resistance to EGFR TKIs. The most
common form of resistance involves the missense mutation T790M
within the EGFR TK domain (Figs. 1A and 2) [23,82,83]. This mutation is associated with >50% of cases of acquired resistance [84].
4
R.C. Doebele et al. / Lung Cancer 69 (2010) 1–12
Table 1
EGFR, pan-HER, and EGFR/HER2 inhibitors in NSCLC.
Agents
Targets (IC50 , nM)
Phase of clinical development
First-generation reversible TKIs
Gefitinib
Erlotinib
EGFR (33), HER2 (>3500)
EGFR (0.56), HER2 (512), HER4 (790)
Restricted access in United States
FDA approved
Irreversible TKIs
BIBW 2992
HKI-272
PF00299804
EGFR (0.5), HER2 (14)
EGFR (92), HER2 (59)
EGFR (6.0), HER2 (45.7), HER4 (73.7)
III
II
II
Other reversible TKIs
Lapatinib
XL-647
EGFR (10.8), HER2 (9.2)
EGFR (0.3), HER2 (16), VEGFR-2 (1.5), VEGFR-3 (8.7), EphB4 (1.4)
II
II
Monoclonal antibodies
Cetuximab
Pertuzumab
EGFR (NA)
HER2 (NA)
III
II
Note: EGFR, epidermal growth factor receptor; FDA, US Food and Drug Administration; IC50 , maximal inhibitory concentration; NA, not applicable; NSCLC, non-small cell
lung cancer; TKI, tyrosine kinase inhibitor.
The IC50 values shown are from cell-free in vitro kinase assays of gefitinib [64], erlotinib [40], BIBW 2992 [124], HKI-272 [35], PF-299804 [40], lapatinib [126], and XL-647
[125] against wild-type HER receptors. All values are expressed in nM.
Table 2
Clinical trials evaluating the EGFR TKIs gefitinib and erlotinib in unselected patients as first-, second-, or third-line therapy in NSCLC.
EGFR TKI
Trials
Line of therapy
Na
Second, third
2618 (2339 response evaluable)
3.1–22.5
5.6–11.5
Gefitinib
IDEAL 1 [36]
IDEAL 2 [37]
ISEL [38]
INTEREST [39]
INVITE [45]
V-15-32 [44]
Second, third
880 (819 response evaluable)
8.9–28.3
6.7–14.7
Erlotinib
BR.21 [16]
Perez-Soler et al. [17]
Perng et al.b [46]
Kubota et al. [47]
Giaccone et al. [50]
SWOG 0341 [48]
Jackman et al. [43]
Lilenbaum et al. [49]
First
261
4.0–22.7
5–13
ORR, %
Median OS, mo
Note: EGFR TKI, epidermal growth factor receptor tyrosine kinase inhibitor; MS, median survival; NSCLC, non-small cell lung cancer; ORR, objective response rate; OS, overall
survival; PFS, progression-free survival; SWOG, Southwest Oncology Group.
a
Sum total number of patients treated with EGFR TKIs in all studies listed in each row (IDEAL-1 [n = 208] [36], IDEAL-2 [n = 216] [37], ISEL [n = 1129, of whom 959 were
evaluable for response] [38], INTEREST [n = 659, of whom 723 were evaluable for response] [39], INVITE [n = 97] [45], V-15-32 [n = 245, of whom 200 were evaluable for
response] [44], BR.21 [n = 488, of whom 427 for evaluable for response] [16], Perez-Soler et al. [n = 57] [17], Perng et al. [n = 273] [46], Kubota et al. [n = 62] [47], Giaccone et
al. [n = 53] [50], SWOG 0341 [n = 76] [48], Jackman et al. [n = 80] [43], Lilenbaum et al. [n = 52] [49]).
b
Median OS not evaluated in Perng et al. [46].
Table 3
Clinical trials evaluating the EGFR TKIs gefitinib and erlotinib in selected patients as first-line therapy in NSCLC.
EGFR TKI
Trials
Gefitinib
WJTOG 0403b [59]
SWOG 0126c [65]
Sugio et al.b [58]
Sequist et al.b [57]
ONCOBELLd [61]
IPASSe [63]
Inoue [66]
Erlotinib
Paz-Ares et al.b , f [56]
Jackman et al.b , g [43]
Na
ORR, %
Median OS, mo
864
17–75
13–20
53
65–90
30f
Note: BAC, bronchioloalveolar carcinoma; EGFR TKI, epidermal growth factor receptor tyrosine kinase inhibitor; ORR, objective response rate; OS, overall survival; SWOG,
Southwest Oncology Group.
a
Sum total number of patients treated with EGFR TKIs in all studies listed in each row (WJTOG 0403 n = 28) [59], SWOG 0126 [n = 135] [65], Sugio et al. [n = 19] [58], Sequist
et al. [n = 31] [57], ONCOBELL [n = 42] [61], IPASS [n = 609] [63], Paz-Ares et al. [n = 21] [56], Jackman et al. [n = 32] [43]).
b
Somatic mutation-positive selected patients.
c
Selected by histology (BAC).
d
Selected by tobacco history (never smokers) or increased EGFR gene copy number or activation of antiapoptotic protein Akt.
e
Selected by smoking history.
f
Overall survival not reported in Paz-Ares et al.
g
Erlotinib and gefitinib.
R.C. Doebele et al. / Lung Cancer 69 (2010) 1–12
Fig. 2. Molecular surface model of the catalytic cleft of T790M-mutated EGFR in
the active conformation. T790M-mediated resistance has been attributed to steric
hindrance due to the bulky methionine side chain (red spheres) [23,82]; however,
it more likely occurs through an increased binding affinity for ATP [83]. Irreversible
inhibitors may overcome T790M-mediated resistance by covalently binding to
cysteine-797 (shown in yellow). The blue mesh represents erlotinib bound within
the catalytic cleft. Note: ATP, adenosine triphosphate; EGFR, epidermal growth factor
receptor. (Adapted from Kumar et al. [23].)
Consistent with this mutation emerging through selective pressure
during EGFR TKI treatment, a recent study using a highly sensitive
mutation-specific assay showed that low levels of T790M could be
detected in tumor samples from TKI-naïve patients [85]. Although
EGFR TKI treatment did induce response in these patients, PFS was
significantly shorter than in patients who did not harbor T790M
at baseline (7.7 months vs. 16.5 months; p < 0.001). These results
suggest that treatment with reversible EGFR TKIs may select for
pre-existing T790M clones in certain patients, resulting in relapse.
Therefore, this mutation may be a useful pretreatment biomarker to
identify patients who are likely to derive shorter periods of benefit
from erlotinib or gefitinib. Several other resistance-conferring EGFR
mutations have also been identified [42,86]. Additionally, mechanisms of acquired resistance unrelated to EGFR have also been
identified.
Amplification of the MET oncogene [87] and increased expression of insulin-like growth factor-1 receptor (IGF-1R) [88] can
circumvent EGFR inhibition through the activation of downstream
signaling pathways (Fig. 1B) [26]. Early identification of patients
at risk for relapse through the detection of biomarkers associated
with acquired resistance to EGFR TKIs (e.g., T790M, MET amplification) could help guide future treatment choices beyond the second
line.
5. Anti-EGFR monoclonal antibodies (cetuximab)
Cetuximab (Erbitux® ; Table 1) is a humanized monoclonal antibody that binds the extracellular portion of the EGFR, inducing
its internalization and blocking its downstream cellular signaling [89]. While single-agent cetuximab has minimal activity (6.9%
objective response rate [ORR]) in pretreated patients with NSCLC
[90], recent results from several phase II trials [62,91–94] and
the phase III FLEX trial suggest that this agent may increase the
effectiveness of first-line chemotherapy [7]. In the largest of these
studies, cetuximab provided an OS benefit when added to cisplatin/vinorelbine chemotherapy compared with chemotherapy
alone (11.3 months vs. 10.1 months; HR, 0.87; p < 0.044) [7]. In
another randomized phase III trial (BMS-099) designed to evaluate
first-line carboplatin/taxane chemotherapy with or without cetux-
5
imab in unselected patients, cetuximab failed to meet the primary
end point of PFS (4.40 months vs. 4.24 months; HR, 0.9; p = 0.23)
by an independent review committee; however, when assessed by
clinical investigators as a secondary end point, PFS was significantly
prolonged by the addition of cetuximab (4.4 months vs. 3.8 months;
HR, 0.79; p = 0.0036), and ORRs were also improved [95].
Cetuximab has not yet received approval from the FDA for
the treatment of patients with NSCLC. However, the National
Comprehensive Cancer Network now recommends cetuximab in
combination with cisplatin/vinorelbine as a treatment option for
patients with advanced or recurrent NSCLC who meet certain eligibility criteria (including EGFR expression as detected by IHC [≥1
positive tumor cell]) [96].
As compared with EGFR TKIs, fewer predictive biomarkers have
been identified for cetuximab benefit in NSCLC. In metastatic
colorectal cancer (mCRC), EGFR protein expression was required
for enrollment in the landmark trial, and the presence of KRAS
mutations predicted nonresponsiveness to cetuximab [97,98]. In
lung cancer, however, the KRAS mutation status was not a useful
biomarker for cetuximab benefit in either the FLEX or BMS-099 trial
[99–101].
Analysis of EGFR FISH in FLEX and BMS-099 also failed to
show any prediction for benefit [99,100]. However, analysis of
tumor samples from patients receiving concurrent or sequential
cetuximab in combination with chemotherapy revealed markedly
improved survival for patients who were FISH positive for EGFR
(OS, 15 months vs. 7 months for FISH-negative patients; HR, 0.83;
p = 0.065) [102]. Previous data demonstrated that FISH positivity is not a positive prognostic factor in NSCLC [103,104]. These
results provide a premise for further assessment of the predictive value of FISH, which will be tested in the Southwest Oncology
Group (SWOG) 0817 trial, a first-line study randomizing patients
to chemotherapy with or without cetuximab.
Retrospective analyses of large randomized trials such as FLEX as
well as prospective clinical studies will be required to validate KRAS
mutations, EGFR protein expression, and other molecular characteristics as predictive biomarkers for cetuximab in NSCLC.
6. Rationale for EGFR/HER2 inhibition
Although EGFR is clearly a valid target in NSCLC, the efficacy
demonstrated by EGFR-targeted agents is not as impressive as
was initially expected. However, the modest activity of agents that
solely block EGFR is not surprising given the complex nature and
interdependency of HER family signaling. One approach to improve
responsiveness to EGFR inhibitors may be to simultaneously target
multiple HER family members.
As highlighted above, HER2 is the preferred partner for all of the
HER family members, including EGFR [27]. The molecular interactions that occur between EGFR and HER2 regulate and diversify
EGFR downstream signaling, and EGFR mitotic signals can be augmented by the coexpression of HER2 [33]. For example, HER2
amplification in human mammary epithelial cell lines was found
to cause constitutive activation of HER2 and ligand-independent
activation of EGFR [105].
In preclinical studies, both EGFR and HER2 have demonstrated
the potential to facilitate transformation to a malignant phenotype independently [106] and synergistically [32]. Indeed, high
synchronous coexpression of EGFR and HER2 is associated with an
unfavorable prognosis in patients with stage I through IIIA NSCLC
[107–109]. Such synchronous overexpression may increase the formation of EGFR/HER2 heterodimers, resulting in a more aggressive
phenotype. Such a cooperative role for these receptors was supported in a recent preclinical study that showed that in NSCLC
cell lines that coexpress EGFR and HER2, knockdown of HER2
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R.C. Doebele et al. / Lung Cancer 69 (2010) 1–12
expression via RNA interference resulted in growth inhibition in
both cell culture and tumor xenograft models [110]. Interestingly,
Cappuzzo et al. showed that HER2 amplification in patients with
NSCLC, particularly in conjunction with EGFR mutations or amplification/overexpression, correlates with sensitivity to EGFR TKIs
[111].
HER2 amplification has been detected in patients with lung adenocarcinoma at a frequency of ∼10%, and overexpression of the
HER2 protein is found in a subset of NSCLCs (20–30%), mostly adenocarcinomas [111–113]. Overexpression of HER2 has been proven
to be an independent unfavorable prognostic factor in resected
NSCLC [112]. Somatic mutations of HER2 have also been identified in a small, but potentially important fraction of patients
with lung adenocarcinoma (<5%). As with activating mutations of
EGFR, the presence of HER2 mutations correlates with female gender, nonsmoking status, and Asian background in patients with
adenocarcinomas [114]. Such mutations may act to circumvent
EGFR-mediated signaling in NSCLC. In a preclinical study, transfection of bronchial epithelial cells with the G776(YVMA) HER2 kinase
domain mutation resulted in enhanced transformation compared
with cells containing wild-type HER2 [115]. HER2 YVMA was capable of transactivating EGFR both in the absence of ligand and in the
absence of EGFR kinase activity. It was also found that lung cancer cell lines harboring a G776 HER2 mutation were resistant to
erlotinib/gefitinib treatment but remained sensitive to inhibition
of both EGFR and HER2. In addition, there are limited preclinical
and clinical data suggesting that tumors with HER2 mutations may
respond to trastuzumab therapy [115,116]. Currently, a phase II
trial evaluating the efficacy of trastuzumab in patients with HER2
FISH-positive/and or HER2 mutation-positive NSCLC is recruiting
patients.
7. EGFR/HER2 inhibition in NSCLC
The role of HER2 in NSCLC and the interdependent signaling
that occurs between this receptor and the other HER family members provide a rationale for the simultaneous inhibition of EGFR
and HER2 in the treatment of NSCLC. While inhibition of EGFR
blocks only EGFR-mediated signal transduction, inhibition of EGFR
and HER2 may more effectively disrupt signaling from EGFR/HER2
heterodimers. Furthermore, activity against both EGFR and HER2
would be expected to interfere with signaling from all NSCLCrelated homodimers and heterodimers (Fig. 3). Indeed, preclinical
studies in a variety of malignant cell types, including NSCLC, have
shown that EGFR/HER2 inhibition can induce superior anti-tumor
activity compared with single-receptor targeting [112,117–123].
Several agents with activity against both EGFR and HER2 are currently in clinical development for NSCLC (Table 1) [35,40,124,125].
8. Reversible EGFR/HER2 TKIs
8.1. Lapatinib
Lapatinib (GW572016; Tykerb® ) is an oral, reversible, TKI
that targets EGFR and HER2 (Table 1) [126]. This agent was
approved by the FDA in combination with capecitabine in the treatment of patients with advanced or metastatic breast cancer with
HER2 overexpression. The use of this agent in breast cancer validates EGFR/HER2 inhibition as an effective treatment approach.
However, clinical results with this agent in NSCLC have been disappointing. A phase II trial of lapatinib in patients with advanced
NSCLC who had either bronchoalveolar carcinoma (BAC) histology
or nonsmoking history was stopped early after failing to meet the
primary end point of response [127]. Based on the results of this
study, lapatinib is no longer in clinical development as monother-
apy for the treatment of patients with NSCLC. In weighing the
potential benefits of additional HER2 blockade, it is important to
note that the potency of lapatinib against HER2 appears to be similar to that of the irreversible inhibitors discussed below (Table 1)
[126].
9. Irreversible HER family TKIs
A newer class of small-molecule HER family inhibitors, the irreversible TKIs, has emerged in recent years (Table 1) [35,40,124].
Most of these agents are active against EGFR and HER2, and some
also inhibit HER4. Unlike reversible TKIs (e.g., erlotinib, gefitinib,
lapatinib), these agents bind covalently to the kinase domain of
their target receptors. Importantly, many of these irreversible
inhibitors have demonstrated activity in preclinical studies against
EGFR mutations that confer resistance to the reversible EGFR TKIs
gefitinib and erlotinib (e.g., T790M; Fig. 2) [23,82,83]. Additionally, preclinical studies have shown that resistance develops less
frequently with this class of agents compared with reversible
inhibitors [128]. Thus, these agents should be studied both in combination with erlotinib or gefitinib to delay the development of
resistance and prolong PFS and after progression following erlotinib
or gefinitib.
9.1. BIBW 2992
BIBW 2992 is a irreversible EGFR/HER2 inhibitor, with activity against wild-type and mutant forms of EGFR, including T790M
[124]. In preclinical cell-based assays, BIBW 2992 was more potent
than gefitinib, erlotinib, and lapatinib in inducing the cell death
of NSCLC cell lines, including those harboring wild-type EGFR,
the activating L858R mutation, and the erlotinib-resistant T790M
mutation [124]. Importantly, the half maximal inhibitory concentrations (IC50 s) for BIBW 2992 in these in vitro models were
typically substantially less than the maximum achievable drug
plasma concentration (300 nM) [129]. BIBW 2992 also demonstrated activity in cells expressing the EGFR resistance mutations
D770-771insNPG and the variant III deletion (EGFRvIII). Furthermore, BIBW 2992 effectively blocked the growth of NSCLC cell lines
(NCI-H1781) expressing a HER2 activating mutation (776insV).
Recently, Bean et al. showed that BIBW 2992 is active against a novel
secondary mutation, T854A, which is associated with acquired
resistance to reversible EGFR TKIs [130]. In both human NSCLC
tumor xenograft models and murine lung cancer models BIBW
2992 was effective in tumors harboring the L858R/T790M double
mutant.
Phase I studies of single-agent BIBW 2992 show that it exhibits
side effects characteristic of the reversible EGFR TKIs, including
cutaneous rash and gastrointestinal disturbances [131–134]. BIBW
2992 had a manageable toxicity profile when administered in a
continuous daily dosing regimen [131,134]. In one phase I study, 3
of 12 patients with NSCLC had confirmed partial responses (PRs), 2
of whom had del19 mutations. The recommended phase II dose of
50 mg once daily was well tolerated [134].
BIBW 2992 is being evaluated in the single-arm phase II
LUX-Lung 2 trial of patients with advanced lung adenocarcinoma harboring activating EGFR mutations who are chemotherapy
naïve (including patients who had received neoadjuvant/adjuvant
chemotherapy) or who had experienced failure of first-line
chemotherapy [135,136]. The initial starting dose of 50 mg/day was
reduced to 40 mg/day secondary to toxicities, and patients received
treatment until disease progression. Interim results from secondline patients treated in this study were recently presented at the
2009 Annual Meeting of the American Society of Clinical Oncology
[135]. Most patients in the second-line setting received a starting
R.C. Doebele et al. / Lung Cancer 69 (2010) 1–12
7
Fig. 3. Differential activity of sole EGFR inhibition vs. EGFR/HER2 inhibition. EGFR inhibition interferes only with EGFR-mediated signal transduction. EGFR/HER2 inhibition
blocks signal transduction from all NSCLC-related receptor pairs. It is not known whether blocking multiple HER family members will result in improved clinical efficacy in
NSCLC. Note: EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer.
dose of 50 mg/day. A total of 67 patients who had received BIBW
2992 as second-line treatment were evaluable for response. With
a median follow-up of 6.6 months, the ORR (complete response
[CR] plus PR) was 64% (43 of 67 patients) and the disease control rate (CR plus PR plus stable disease [SD]) was 96% (64 of 67
patients). PFS among patients receiving second-line BIBW 2992 was
10.2 months. No patients with the T790M resistance mutation have
yet been evaluated. Interim results from the first 53 chemotherapynaïve patients treated in this study were presented at the 2009
World Conference on Lung Cancer [136]. Thirty patients received
a starting dose of 50 mg/day and 23 received 40 mg/day. At 3.3
months of follow-up, the response rate was 63% among the 38
evaluable patients; 13 patients (34%) had SD. The most frequently
occurring side effects included skin toxicity (grade 3: first-line,
5.7%; second-line, 17.8%) and diarrhea (grade 3: first-line, 18.9%;
second-line, 16.4%) [135,136]. A randomized, double-blind, multicenter phase IIB/III trial (LUX-Lung 1) is currently in progress to
evaluate BIBW 2992 against placebo in patients with NSCLC who
experienced failure of prior erlotinib or gefitinib [137]. The phase
III LUX-Lung 3 trial also began accrual to compare BIBW 2992 with
cisplatin/pemetrexed in first-line patients with EGFR mutationpositive NSCLC.
transformed with the A775insYVMA mutation were found to be
sensitive to HKI-272 [143]. In vivo, treatment with HKI-272 resulted
in substantial anti-tumor effects in HER2- and EGFR-dependent
human tumor xenograft models [144].
HKI-272 was evaluated in a phase I trial of patients with
advanced EGFR/HER2 expressing solid tumors by IHC [139]. The
most common and dose-limiting adverse event (AE) was diarrhea.
Other common AEs were nausea, vomiting, fatigue, and anorexia.
No radiographic responses or PRs were achieved among the 14
patients with NSCLC enrolled in the study. However, SD for >24
weeks was observed in 6 patients with NSCLC who had previously
experienced gefitinib or erlotinib failure.
HKI-272 was evaluated in a phase II clinical trial of patients with
advanced NSCLC who had previously received up to 3 chemotherapy regimens [145]. Patients were divided into 3 groups: patients
who experienced failure of gefitinib or erlotinib and had EGFR
mutations (arm A; n = 91), patients who were mutation negative
(arm B; n = 48), and patients who did not receive prior EGFR TKIs
(arm C; n = 28). There were no significant differences among arms
A, B, and C in response rate (2%, 2%, and 4%, respectively), SD rate
(47%, 46%, and 39%, respectively), or median PFS (11.6, 14.7, and 7.4
weeks, respectively). Currently, there are no other ongoing studies
of HKI-272 in patients with NSCLC.
9.2. HKI-272
HKI-272 (neratinib) is an irreversible inhibitor of EGFR and
HER2. In preclinical studies, HKI-272 was more potent than gefitinib in suppressing ligand-induced EGFR autophosphorylation and
downstream signaling and growth-inhibiting NCI-H1975 BAC cells
harboring L858R and T790M mutations in EGFR [128,138]. However, a recent study in NSCLC cell culture models showed that
T790M-mediated resistance emerges in the presence of HKI-272 at
0.2 ␮M (111 ng/mL), similar to the maximum concentration (Cmax )
(112 ng/mL) observed in the phase I trial [139], indicating that this
agent could overcome T790M only at concentrations above those
achieved in clinical trials [140]. HKI-272 also showed activity in a
gefitinib-resistant BAC cell line (NCI-H1650) harboring an in-frame
deletion mutation of EGFR (delE746-A750) [128], and in Ba/F3 cells
transformed with the EGFRvIII mutant, which is resistant to gefitinib and erlotinib [141]. This agent has also demonstrated activity
in cells harboring various HER2 mutants. NCI-H1781 cells harboring the 776insV mutation [142] and erlotinib-resistant murine cells
9.2.1. PF00299804
PF00299804 is an orally bioavailable, irreversible pan-HER TKI.
Pan-HER inhibitors are active against EGFR, HER2, and HER4.
PF00299804 effectively inhibited the in vitro kinase activity of wildtype EGFR with a potency similar to that of gefitinib, erlotinib, and
another irreversible pan-HER inhibitor, CI-1033 [40]. In preclinical cell culture models, PF00299804 demonstrated activity in cells
containing common EGFR mutations and the EGFR L858R/T790M
double mutant at significantly lower IC50 values than gefitinib.
In addition, PF00299804 was active in NSCLC cell lines harboring
the HER2 776insV mutation and in YVMA-expressing cells. In vivo,
PF00299804 demonstrated anti-tumor activity in xenograft models
of T790M-mediated gefitinib resistance [40].
A phase I trial studying PF00299804, in which 42 patients with
NSCLC were enrolled, showed acceptable tolerability, with the most
frequently reported AEs being diarrhea (78%) and rash (65%) [146].
Among 29 patients evaluable for tumor response, 2 had a PR and
8 showed SD. Currently, none of the patients with biopsy-proven
8
R.C. Doebele et al. / Lung Cancer 69 (2010) 1–12
T790M mutations has shown response, although the number of
patients with this mutation is small. A single patient with the
T790M mutation detected in the blood had SD [146].
PF-00299804 is being evaluated in a 2-arm, phase II trial in
patients with advanced NSCLC after failure of ≥1 prior chemotherapy regimen and prior treatment with erlotinib [147]. Patients
with wild-type KRAS who had progressive disease after ≥1 prior
chemotherapy regimen and erlotinib were enrolled by histology:
adenocarcinoma (arm A) and non-adenocarcinoma (arm B). To
date, 34 patients have enrolled (arm A, n = 30; arm B, n = 4). In
a preliminary report of 20 patients evaluable for response, PRs
(unconfirmed) were observed in 2 patients and 10 patients had SD
(9 of 18 patients in arm A and 1 of 2 patients in arm B) with a median
duration of 11.5 weeks. Additionally, disease control was reported
in patients harboring T790M mutations. The most common AEs
were skin and gastrointestinal disorders (grade 3 in 19% and 13% of
patients, respectively); grade 4 pulmonary embolus/dyspnea was
reported in 2 patients.
10. Other emerging agents
10.1. Pertuzumab
Although trastuzumab has failed to show clinical activity in
NSCLC [148,149], another HER2-directed monoclonal antibody,
pertuzumab, is in clinical development for NSCLC. Pertuzumab is
a recombinant, humanized monoclonal antibody and the first in
a new class of agents known as the HER dimerization inhibitors.
While this agent is specifically directed against HER2, it binds to
a region of the extracellular domain that interferes with the heterodimerization of HER2 with other HER family members [150]. In
vitro, this agent has been shown to block HER signaling, leading to
apoptosis. Interestingly, in vivo studies suggest that the anti-tumor
activity of pertuzumab is not restricted to HER2 overexpression, in
contrast to trastuzumab [150].
A phase II trial was conducted to evaluate the activity of pertuzumab in patients with recurrent NSCLC [151]. Patients were
treated with pertuzumab intravenously once every 3 weeks. The
primary end point was ORR. Pertuzumab was well tolerated, but
no responses were seen in the 43 patients treated. Secondary
end points, such as pharmacodynamic activity as assessed by F18-fluorodeoxyglucose positron emission tomography, correlated
with prolonged PFS in 27.3% of the patients. Currently, another
phase II study is under way to evaluate the combination of pertuzumab with erlotinib for the second-line treatment of patients
with advanced NSCLC.
10.2. ZD6474 (vandetanib, Zactima)
ZD6474 (vandetanib, Zactima) is a dual inhibitor of the EGFR and
vascular endothelial growth factor-2. Despite promising results in
vitro and in vivo that this drug could retain efficacy in the presence of acquired EGFR TKI resistance, there is no clinical evidence
that it exhibits any benefit beyond what current EGFR TKIs produce
[152,153]. A randomized phase III trial comparing vandetanib to
erlotinib showed no significant efficacy difference but toxicity was
greater with vandetanib [154]. The phase III, double-blind, placebocontrolled ZODIAC trial, which involved vandetanib in addition to
docetaxel, showed that vandetanib 100 mg significantly improved
median PFS (14.0 weeks vs. 17.3 weeks; HR, 0.79) in second-line
therapy for patients with locally advanced or metastatic NSCLC
[155]. A similar randomized trial comparing pemetrexed with
pemetrexed plus vandetanib showed no significant difference in
PFS or OS although both were numerically longer in the vandetanib
arm [156]. However, patients in the vandetanib arms of both trials
exhibited more toxicities. Unfortunately, no studies to date have
identified clinical or molecular markers that would predict benefit
from this agent [154,156]. The phase III ZEPHYR trial is comparing vandetanib with BSC in patients who have progressed under
erlotinib.
10.3. XL-647
XL-647 (EXEL-7647) is a reversible inhibitor of EGFR, HER2, vascular endothelial growth factor receptors-2 and -3, and the ephrin
type B subclass 4 receptor (EphB4) [125]. Despite the fact that this
agent is a reversible inhibitor, preclinical studies showed that XL647 had in vitro and in vivo activity against H1975 cells harboring
the double L858R/T790M resistance mutation [125]. It is unclear
which inhibitory effects of XL-647 are responsible for the activity
observed in these cells.
Preliminary results of a phase II trial of XL-647 in patients with
NSCLC who had acquired resistance to erlotinib or gefitinib (n = 23)
showed a PR in 1 patient and SD in 7 patients [157]. XL-647 was well
tolerated, and the major AEs were similar to those that occurred
with the EGFR TKIs. In another trial, XL-647 was administered to
41 patients with chemotherapy-naïve NSCLC meeting ≥1 of the following criteria: Asian ethnicity, female gender, and minimal (<15
pack-years) or no smoking history [158]. PRs were achieved in 10
(28%) of 36 evaluable patients, and 36% achieved SD for ≥3 months.
Among the patients who achieved a PR, 70% had detectable EGFR
mutations. Studies of XL-647 in NSCLC are ongoing.
11. Conclusion
EGFR is an established target for NSCLC treatment, and the currently available EGFR-targeted agents have provided significant
benefits and may have expanding indications for selected populations. However, objective responses in the general population
are uncommon with the currently available EGFR-targeted therapies, and most patients who initially respond eventually develop
acquired resistance. Preclinical evidence supports the concept that
the concurrent inhibition of multiple HER family members may
be more effective than sole EGFR inhibition. Several EGFR/HER2targeted agents and pan-HER inhibitors are in clinical development.
Although studies with the reversible EGFR/HER2 inhibitor lapatinib
have not been promising, irreversible TKIs are an emerging class
of agents that may have the potential to overcome and prevent
the emergence of acquired resistance that occurs with reversible
EGFR TKIs. It remains to be seen whether this newer generation
of agents will play a role as a superior inhibitor of EGFR by overcoming/preventing resistance or whether they will demonstrate
wider effectiveness by blocking both EGFR and HER2 signaling.
Correlation of outcomes with biomarkers such as HER2 expression
or mutation and EGFR mutation status may help discern between
these 2 characteristics of these compounds. The results from ongoing phase II and III trials of these agents in patients with NSCLC,
particularly those who are resistant to reversible EGFR TKIs, are
eagerly awaited.
Conflict of interest statement
RCD, ABO, NP have no conflicts of interest to disclose. DRC has
served on advisory boards for Boehringer Ingelheim Pharmaceuticals. PAB has served as a consultant for Boehringer Ingelheim
Pharmaceuticals, AstraZeneca, OSI/Genentech, GlaxoSmithKline,
and Bristol-Myers Squibb/ImClone.
R.C. Doebele et al. / Lung Cancer 69 (2010) 1–12
Acknowledgments
This work was supported by Boehringer-Ingelheim Pharmaceuticals, Inc. Writing and editorial assistance was provided by
Johnathan Maher, PhD, of BlueSpark Healthcare Communications,
and was contracted by Boehringer-Ingelheim Pharmaceuticals, Inc.
PAB, RCD, ABO, and NP meet criteria for authorship as recommended by the International Committee of Medical Journal Editors
(ICMJE), were fully responsible for all content and editorial decisions, and were involved in all stages of manuscript development.
PAB, RCD, ABO, and NP received honoraria for this article. The
authors take full responsibility for the content and views in this
article.
Research support: NP is supported by an IASLC Young Investigator Award and a Fulbright-Schneider Yehuda Danon Post-Doctoral
Fellowship by the United States–Israel Education Foundation.
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