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Review Article
The role of epidermal growth factor receptor tyrosine kinase inhibitors in the treatment of advanced stage non-small cell lung cancer
1Department of Hematology-Oncology, National University Cancer Institute, National University Health System, Singapore; 2Division of Medical Oncology, Yonsei Cancer Center, Seoul, South Korea; 3Cancer Science Institute of Singapore, Singapore
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Abstract
The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) like erlotinib and gefitinib have
been extensively studied. Multiple randomized trials have evaluated the role of EGFR TKIs in advanced stage
non-small cell lung cancer (NSCLC) as a monotherapy in the first line, or subsequent lines of therapy, and in the
first line in the maintenance setting or in combination with chemotherapy. Most of these trials showed positive
results in particular for selected patients with specific clinical characteristic and somatic activating mutation of
EGFR. A further understanding of the mechanism of primary and secondary resistance has led to the development
of promising novel agents designed to overcome resistance to EGFR.
Key words
non-small cell lung cancer; epidermal growth factor receptor; tyrosine kinase inhibitors; Gefitinib; Erlotinib
J Thorac Dis 2010;2:144-153. DOI: 10.3978/j.issn.2072-1439.2010.02.03.6
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Introduction
Lung cancer is one of the leading causes of death worldwide with
the majority of patients presenting with advanced unresectable
or metastatic non-small cell lung cancer (NSCLC). Despite the
advances in palliative chemotherapy, the survival for patients
with advanced disease treated with chemotherapy remains poor
with a median survival of 8-10 months (1). The development of
the specific molecular-targeted therapeutic agents has provided
more treatment options to improve survival. One such molecular
target is the epidermal growth factor receptor (EGFR). EGFR
is an attractive target for various antitumor strategies including
small-molecule agents that selectively inhibit the intracellular
tyrosine kinase activity and anti-EGFR monoclonal antibody
which inhibit extracellular ligand-induced phosphorylation and
receptor degradation (2). This review will further discuss on the
role of EGFR tyrosine inhibitors (TKIs) in the management of
advanced stage NSCLC.
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EGFR pathway in NSCLC
EGFR is one of the four members of the human epidermal
growth factor receptor (HER) family of tyrosine kinase.
Structurally, EGFR consist of an extracellular ligand binding
domain, a transmembrane domain and an intracellular tyrosine
kinase domain (3). Dimerization of the EGFR occurs after
stimulation by a ligand such as epidermal growth factor (EGF).
This results in autophosphorylation and downstream increased
of cell proliferation, inhibition of apoptosis, activating invasion
and metastasis (2).
Aberrant tyrosine kinase activity is a hallmark of malignant
cells in particular for NSCLC. Overexpression of EGFR is
reported to occur in 60% of metastatic NSCLC cases and
correlates with poor disease prognosis and reduced survival (5).
Apart from EGFR overexpression, NSCLC also produce EGF
and transforming growth factor-alpha. Both of these growth
factors induce autocrine stimulation for EGFR. The inhibition
of EGFR signaling with small molecule inhibitors for tyrosine
kinase domain of EGFR on malignant cells can be effective and
potentially less toxic (6).
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Pharmacology of EGFR TKIs
Small-molecule EGFR tyrosine kinase inhibitors, such as
gefitinib and erlotinib, are orally active low molecular weight
compound (40-600kD) that reversibly compete with ATP
to bind to the intracellular catalytic domain of EGFR. This inhibits autophosphorylation and downstream signaling
cascades of RAS-RAF-MEK-MAPK (gene transcription, cell
cycle progression, and cell proliferation) and PI3K-Akt pathway
(antiapoptotic and prosurvival) (7).
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Determinants of response to EGFR
TKI
Whilst EGFR TKIs are active in unselected patients with
NSCLC, differences in response rates were observed in certain
patient subgroups. Retrospective analysis have suggested certain
clinical characteristics such as female gender, adenocarcinoma
histology, Asian ethnicity and a history of never/ light smoking
were associated with increased response to EGFR TKIs.
Molecular predictors of EGFR TKIs sensitivity include somatic
activating mutations in exon 18-21 of EGFR (commonly exon
19 deletions and L858R point mutation in exon 21) (8-10) and
account for 80% to 95% of the EGFR mutations in NSCLC (9).
Such mutations are present predominantly in patients with the
clinical features mentioned previously (10). Other molecular
determinants of EGFR TKIs response include KRAS mutations
and EGFR gene copy number detected by fluorescence in situ
hybridization (FISH) (11).
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Single agent EGFR TKIs in pretreated
patients
The efficacy of erlotinib and gefitinib were initially evaluated in
the second- or third-line setting in several phase II and phase III
studies (Table 1). In two randomized phase II studies, the Iressa
Dose Evaluation in Advanced Lung Cancer (IDEAL) studies I
and II, patients with pre-treated NSCLC were randomized to
gefitinib at 250 mg or 500 mg daily. In IDEAL-1 where patients who received one or two lines of chemotherapy, a similar
response rate of 18.4% and 19% was seen patients receiving
gefitinib 250mg daily or 500mg daily respectively. In addition,
the disease control rate (54.4% vs. 51.4%), progression-free
survival (PFS) (2.7 months vs. 2.8 months), median overall
survival (7.6 months vs. 8 months), and 1-year survival (35%
vs. 29%) were also similar. Subset analysis showed that Japanese
patients had a better response rate compared to non-Japanese
(27.5% vs. 10.4%; P = 0.002) (12).
In IDEAL-2, a multicentre US study, patients with advanced
NSCLC treated with two or more regimens, including a
platinum agent and docetaxel were randomised to gefitinib at
250mg or 500mg daily. The response rate was 12% vs. 10%,
and the median survival was 7 vs. 6 months for 250 mg and
500 mg daily respectively (13). Treatment was well tolerated
in both IDEAL-1 and -2, with skin rash the most common side
effect. The 250mg daily was selected for further trials as the
efficacy was similar between the two doses and as grade 3-4
toxicity was more frequent in patients receiving 500 mg daily.
Clinical predictors for response included Japanese patients,
women, adenocarcinoma histology, never smokers, and good
performance status (0 or 1). Based on these results, gefitinib
received accelerated Food and Drug Administration (FDA)
approval in 2003 as monotherapy for patients with advanced
stage NSCLC after progression with platinum-based therapy
and docetaxel (14).
The efficacy of erlotinib in pre-treated advanced NSCLC
was established in a phase III study, BR21. Patients with
NSCLC who had received one or two prior chemotherapy
regimens were randomized to erlotinib or best supportive
care. A significant improvement in median survival was seen in
patients receiving erlotinib compared with placebo (6.7 months
vs. 4.7 months, HR 0.70; 95% CI 0.58-0.85). In addition, a significant improvement in response rate and progression free
survival was also seen in the erlotinib arm. In the BR21 study,
subset analyses reported female gender, adenocarcinoma,
Asian ethnicity and a history of never smoking were clinical
indicators of increased survival (15). Additional biomarker
studies were also reported in this study. Erlotinib treatment was
associated with prolonged survival when EGFR overexpressed
by immunohistochemistry (HR 0.68; 95% CI 0.49-0.95) or by
polysomy or amplification of EGFR gene number (HR 0.44;
95% CI 0.23-0.82). EGFR mutational status had no significant
effect on survival (16).
In a multicentre phase III study Iressa Survival Evaluation
in Lung Cancer (ISEL) assessing the benefit of gefitinib in
the second or third line setting, patients with advanced stage
NSCLC refractory to or intolerant to their chemotherapy were
randomized to gefitinib 250mg daily or placebo. No significant
difference in median survival was seen with 5.6 vs. 5.1 months
respectively (HR 0.89; 95% CI 0.77-1.02). A superior response
rate (8% vs. 1%) and time to treatment failure (3 vs. 2.6 months)
was seen in gefitinib compared with placebo. Pre-planned subset
analysis showed an improvement in overall survival for gefitinib
compared with placebo in never smokers (8.9 months vs. 6.1
months; HR 0.67; 95% CI 0.49-0.92) and patients of Asian
origin (9.5 months vs. 5.5 months; HR 0.66; 95% CI 0.48-0.91)
(17). Exploratory subset analyses found an increased response
rate in patients with EGFR mutations compared with wild-type
(37.5% vs. 2.6%). In addition, EGFR gene copy number was a
borderline predictor survival for patients treated with gefitinib
with HR 0.61 95% CI 0.36-1.04 for high copy number and HR
1.16; 95% CI 0.81-1.64 for low copy number. A comparison of
high vs. low EGFR copy number hazard ratio was significant (P
= 0.045).
Based on the results from the ISEL study, gefitinib was
withdrawn in the US and European Union. The contrast in the
lack of survival benefit with gefitinib in the ISEL study compared
with the BR21 study may possibly be due to the large number
of patients refractory to chemotherapy in the ISEL study (90%)
as these patients represent a population who are difficult to treat
and have a poor prognosis.
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Second-line EGFR TKI compared to
chemotherapy
In a phase III global study Iressa in NSCLC Trial Evaluating
Response and Survival vs. Taxotere (INTEREST), patients with
NSCLC previously treated with platinum based chemotherapy
were randomized to gefitinib or docetaxel. The primary
endpoint of non-inferiority in terms of overall survival was
met. The median survival (HR 1.02; 96% CI 0.905-1.15) and
response rate (9.1% vs. 7.6%) for gefitinib vs. docetaxel. The coprimary
endpoint of superiority in patients with high EGFR gene-copy number was not met (HR 1.09; 95% CI 0.78-1.51;
median survival 8.4 months vs. 7.5 months). An improvement in
quality of life was seen in patients receiving gefitinib. Additional
treatment administered post study were well balanced between
the arms. In the gefitinib group, 54% received no systemic
therapy apart from further EGFR tyrosine kinase inhibitor, 31%
received docetaxel, and 15% received other chemotherapy only.
In the docetaxel arm, 53% received no systemic therapy apart
from further docetaxel, 37% received an EGFR tyrosine kinase
inhibitors, and 10% received other chemotherapy only (18).
Biomarker analysis showed no differences in survival between
gefitinib and docetaxel irrespective of EGFR protein expression,
EGFR gene mutation or KRAS gene mutation status.
In another phase III study V-15-32, Japanese patients
with pre-treated advanced stage NSCLC were randomized to
gefitinib or docetaxel. The median survival was 11.5 months
vs. 14 months respectively (HR 1.12; 95.24% CI 0.89-1.40). In
contrast to the INTEREST study, non-inferiority of survival for
gefitinib however was not met according to the pre-specified
criteria of upper confidence interval 19).
In a Korean phase III study Iressa as Second Line Therapy
in Advanced NSCLC-Asia (ISTANA), gefitinib and docetaxel
was compared in patients with advanced stage NSCLC. An
improvement in the progression free-survival (HR 0.73; 90% CI
0.533-0.998) and response rate (28% vs. 7.6%, P 20).
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First-line EGFR TKI in advanced stage
NSCLC
Several trials have examined the role of EGFR TKIs administered
concurrently with cytotoxic chemotherapy in the first line
treatment of advanced stage NSCLC or as maintenance therapy
following cytotoxic chemotherapy.
In INTACT-1 (Iressa NSCLC Trial Assessing Combination
Treatment), patients were randomized to three treatment
arms: gemcitabine and cisplatin and placebo or to the same
chemotherapy in combination with gefitinib at 250mg daily
or gefitinib 500mg daily. The median survival was similar in
the three arms at 10.9 months, 9.9 months and 9.9 months
respectively. Time to progression and response rates were also
similar (21). INTACT-2 was a three-arm phase III study with
similar design to INTACT-1. Standard chemotherapy in this
study was paclitaxel and carboplatin. The median overall survival was 9.9 months, 9.8 months and 8.7 months for placebo, gefitinib 250mg
daily and gefitinib 500mg daily respectively (22).
In a phase III study of patients randomized to either gemcitabine and
cisplatin and placebo or same chemotherapy in combination with erlotinib
(Tarceva Lung Cancer Investigation [TALENT]), no differences in time
to progression, response rate or survival were seen. The median survival
was 43 weeks vs. 44.1 weeks for erlotinib and placebo respectively (23). In
a multi-center US phase III study, Tarceva responses in conjunction with
paclitaxel and carboplatin (TRIBUTE), patients were randomly assigned
to erlotinib or placebo in combination with carboplatin and paclitaxel.
Similar to the other studies, there were no difference in survival, response
rate and time to progression. Median survival for was 10.6 months and
10.5 months for patients treated with erlotinib and placebo respectively
(HR 0.99; 95% CI 0.86- 1.16) (24).
Taken together, these results indicate there is no clinical benefit with
the addition of an EGFR TKI given concurrently with chemotherapy
(Table 2). Other approaches administering EGFR TKI with chemotherapy
in the first line setting have been used such as sequential administration of
chemotherapy followed by EGFR TKI or administration of maintenance
EGFR TKI after the completion of all chemotherapy treatment. Using the
first approach, in a multicenter, phase II study, First-Line Asian Sequential
Tarceva and Chemotherapy Trial (FAST-ACT), patients were randomized
to erlotinib or placebo on days 15-28 of a 4-week cycle of a platinum and
gemcitabine regimen. Whilst the primary endpoint of non progression rate
at 8 weeks was not met, 80.3% vs. 76.9% for erlotinib and chemotherapy
vs. placebo and chemotherapy respectively, a significant improvement in
progression free survival of 29.4 weeks vs. 23.4 weeks (adjusted HR 0.47;
95% CI 0.33 to 0.68) was reported (25). Based on these promising results,
a phase III study is ongoing using this treatment strategy (26).
Two recent studies have used the latter approach (Table 3). The
West Japan Thoracic Oncology Group conducted a Phase III study
(WJTOG0203) of maintenance gefitinib therapy following first
line chemotherapy. Patients were randomized to a platinum doublet
(carboplatin/paclitaxel, cisplatin/irinotecan, cisplatin/gemcitabine) for up
to six cycles (arm A) or platinum-doublet chemotherapy for three cycles
followed by gefitinib 250 mg orally daily, until disease progression (arm
B). An improvement in progression-free survival was reported in patients
on arm B compared with arm A, 4.6 months vs. 4.3 months respectively
(HR 0.68; 95% CI 0.57-0.80) but the primary endpoint of overall survival
results did not reach statistical significance with a median survival of 12.9
months for chemotherapy alone and 13.7 months with chemotherapy
followed by gefitinib (HR 0.86; 95% CI 0.72-1.03). Exploratory subset
analysis of overall survival by histologic group showed patients in arm B
with adenocarcinoma did significantly better than patients in arm A with
adenocarcinoma with a median survival of 12.9 and 13.7 months for arm A
and B respectively (HR 0.79; 95% CI 0.65-0.98) (27).
In a second study, the phase III Sequential Tarceva in Unresectable
Lung Cancer (SATURN), patients were initially treated with four cycles
of platinum based chemotherapy. Patients without disease progression
were randomized to erlotinib or placebo. Progression free survival (PFS)
was significantly longer for erlotinib compared to placebo at 12.3 weeks and 11.1 weeks respectively (HR 0.71; 95% CI 0·62-0·82). A
secondary endpoint of overall survival was significantly longer in
patients receiving erlotinib compared with placebo at 12 months
and 11 months respectively (HR 0.81, 95% CI 0.70-0.95). The
co-primary endpoint of PFS in EGFR immunohistochemistry
positive tumors was also met with a median PFS of 12.3 weeks
vs. 11.1 weeks (HR 0.69; 95% CI 0.58-0.82). EGFR mutation
status showed that erlotinib improved PFS in patients with EGFR
activating mutations (HR 0.10; 95% CI 0.04-0.25) and EGFR
wild-type (HR 0.78; 95% CI 0.63-0.96) (28).
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First line monotherapy
The Iressa Pan-Asia Study (IPASS), a randomized phase III
conducted in Asia where patients were selected by clinical
characteristics for EGFR mutation (never/ light smoker,
adenocarcinoma subtype), were randomised to gefitinib or
carboplatin and paclitaxel. A superior PFS favoring gefitinib
(HR 0.74; 95% CI 0.65-0·85) was seen. Furthermore, in patients
receiving gefitinib, higher response rates (43% vs. 32.2%) and
superior quality of life were reported. In the IPASS study, in preplanned
subset analysis, patients with EGFR mutations had a
prolonged PFS with gefitinib compared with chemotherapy (HR
0.48; 95% CI 0.36-0.64) whilst patients without EGFR mutation
had a poorer PFS with gefitinib (HR 2.85; 95% CI 2.05-3.98).
Response rate for EGFR mutation positive and negative patients
was 71.7% and 1.1%, respectively (29). Based on these analyses,
gefitinib is a novel treatment option for patients with EGFR
mutations and but should not be offered to patients without the
mutation (Table 4).
The role of monotherapy erlotinib in the first line setting in
unselected patients has been reported in several phase II studies.
Response rates and survival were comparable with results from
cytotoxic chemotherapy (30, 31). Based on these phase II
studies, several phase III studies have been initiated. The Tarceva
or Chemotherapy (TORCH) study, designed to evaluate
the efficacy of erlotinib and chemotherapy in an unselected
population has been completed and results are awaited (32).
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First-line EGFR TKI in advanced
stage NSCLC in patients with EGFR
mutations
As EGFR mutations are associated with greater sensitivity to
EGFR TKIs, investigators have examined the efficacy of EGFR
TKI compared with chemotherapy in this molecularly selected
patient group in the first line setting (Table 4). In an open label
phase III Japanese study (WJTOG3405), chemo-naïve patients
with advanced stage NSCLC or postoperative recurrence with
an EGFR mutation (exon 19 deletion or L858R point mutation)
were randomized to gefitinib or cisplatin/docetaxel. An
improvement in PFS of 9.2 months vs. 6.3 months was seen in
patients receiving gefitinib compared with chemotherapy (HR
0.489; 95% CI 0.336-0.71). Response rates were 62.1% and 32.2
% for gefitinib and chemotherapy respectively (33).
In a more recent Japanese study, chemo naïve patients with
sensitizing EGFR mutations were randomly assigned to gefitinib
or carboplatin/paclitaxel. The PFS was longer in the gefitinib
arm compared to the chemotherapy arm at 10.8 months and 5.4
months respectively (HR 0.30; 95% CI 0.22-0.41) whilst the
response rates were 73.7% and 30.7% respectively. No difference
in overall survival was seen (30.5 months vs. 23.6 months) (34).
Results from the above Japanese studies, together with the
EGFR mutation subset analysis from the IPASS study (Table
4), suggest that first line gefitinib is superior to cytotoxic
chemotherapy in patients with advanced stage NSCLC harbouring
sensitive EGFR mutations on the basis of improved PFS with
acceptable toxicity. Furthermore, the European Medicines Agency
has approved the use of gefitinib for the treatment of patients with
locally advanced or metastatic NSCLC with activating mutations
of EGFR (35). We recommend that the selection of patients for
first line treatment of patients with advanced stage NSCLC should
be based on EGFR mutation status.
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EGFR TKIs in poor performance
patients
Concern of potential chemotherapy related toxicities have deprived many poor performance patients with advanced NSCLC from
deriving benefits from palliative chemotherapy. The oral administration
and potential better toxicity profile of TKIs may offer some advantages for
chemotherapy-naive poor performance status patients.
Two phase II trials from North America and Europe reported no benefit
with the use of EGFR TKIs compare with either chemotherapy or best
supportive care in this group of patients (36, 37). However, these two trials
were conducted in unselected patients. In contrast, in a Japanese study of
patients with untreated, advanced stage NSCLC with sensitising EGFR
mutations treated with gefitinib, the response rate was 66% (90% CI,
51%-80%) and was associated with an improvement in performance status
(38).
In a recent phase III trial, the Tarceva Or Placebo In Clinically Advanced
Lung Cancer (TOPICAL) study, patients with chemo-naïve advanced stage
NSCLC with a poor performance (ECOG PS 2/3 or PS 0/1 and unfit for
platinum chemotherapy) were randomized to erlotinib or placebo. Preliminary
results presented in abstract form reported no difference in overall survival
(HR 0.98; 95% CI 0.82-1.15). In pre-specified subgroup analysis, erlotinib use
in females improved overall survival (HR 0.75; 95% CI 0.57-0.99) and PFS
(HR 0.64; 95% CI 0.49-0.83) (39).
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Toxicity of EGFR TKIs
EGFR TKIs are generally well tolerated. The two most common toxicities
include dermatologic and gastrointestinal side effects. High levels of EGFR
expression in the basal layer of the epidermis is thought to be the cause of the
dermatologic toxicity (40). In BR21, erlotinib was found to cause rash in 76%
overall and 9% of grade ≥ 3 toxicity (15). The efficacy of the drug has been
correlated with the occurrence and severity of the skin adverse event (40, 41).
However, conflicting evidence has been shown in IDEAL-2 study where the
presence of skin toxicities did not correlate with tumour response to gefitinib
and was not a marker for antitumor activity (13).
In addition, diarrhea is also a common side effect of erlotinib (<1%-4% for
grade ≥ 3 toxicity) (15, 30) and gefitinib (2-5% for grade ≥3 toxicity) (17, 18,
29). Cases of gastrointestinal perforation, some of which were fatal, have also
been reported in patients receiving erlotinib (42).
Reports of severe or fatal drug-related interstitial lung disease associated
with the EGFR TKIs had been reported in particularly Japanese patients with
a prevalence of 3.5% and mortality of 1.6% (43). However, other clinical
trial including placebo control trial with erlotinib (15) and trials combining
EGFR TKIs with chemotherapy, mainly conducted in non-Asian populations,
the incidence of interstitial lung disease was similar across the groups
(approximately 1% in all groups) (21-24).
Hepatic toxicity has been observed in erlotinib use and caution need to be
exercised for patients with liver impairment.
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Mechanism of resistance of EGFR TKIs
Resistance of EGFR TKIs can be divided into primary or secondary (acquired)
resistance. Preexisting somatic mutations in KRAS are associated with primary
resistance to EGFR TKIs (44). KRAS and EGFR mutations are usually mutually exclusive and are rarely found in the same tumour.
Activating mutations of KRAS occur in about 13-30% of lung
adenocarcinomas (44-46). A meta-analysis suggests KRAS
mutations are negative predictors for response of EGFR TKIs
(47).
Insertion mutations in the exon 20 in EGFR TK domain also
has been found to cause primary resistance by reducing efficacy
of the TKIs. It reduces the inhibitory activity of TKIs 100 fold
but is rare and is not a predominant cause of primary TKIs
resistance (48).
Despite initial good response to EGFR TKIs, almost all
patients will subsequently develop acquired resistance. Multiple
acquired resistance mechanisms have been implicated. One of
the mechanisms extensively studied is a secondary mutation
of EGFR at exon 20 involving substitution of methionine
for threonine at 790 (T790M). This mutation is present in
approximately 50% of patients with acquired resistance to EGFR
TKIs (49, 50). The mechanism of this resistance is unclear with
hypothesis that T790M are usually present in small fraction
of tumour cell before treatment with EGFR TKIs and clonal
selection after the treatment has resulted in this resistance (51).
The proto-oncogene c-Met has been implicated in causing
acquired resistance to EGFR TKIs. MET amplification activates
EGFR independent PI3K/AKT pathway through HER-3
dependent activation (52).
Other mechanisms of acquired resistance that have been
intensively looked into include epithelial-to-mesenchymal
transition (EMT), downregulation of PTEN pathways and
Insulin-like Growth Factor-1 (53, 54, 55, 56). Further studies are
needed to establish the clinical significance of these resistance
mechanisms.
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Novel agents
Despite the efficacy the current EGFR TKIs, novel agents
are needed to improve the efficacy as well as to overcome the
resistance to EGFR TKIs. These therapies are broadly divided
into irreversible TKIs and multikinase inhibitors.
In preclinical studies, irreversible EGFR TKIs have
demonstrated potential of overcoming the resistance conferred
by T790M (57). Most of these agents have activities not only
against EGFR but also other Erb/Her family and most of them
are undergoing phase II and III studies. One of the promising
agents is BIBW 2992 that has both irreversible binding to EGFR
and Her2. It has showed activity in patients who have developed
resistance to erlotinib (58). Currently, this agent is being tested
in randomized studies comparing with placebo or cytotoxic
chemotherapy after encouraging results in phase II studies (59,
60).
A recent phase II study of the irreversible pan-EGFR TKIs,
HKI-272 (neratinib) in patients of advanced stage NSCLC with or without prior TKIs showed only low activity with a
response rate of 0-3% (61). Other similar agents that potentially
overcome resistance conferred by T790M mutation are currently
undergoing clinical trials. These include PF00299804 and
EKB-569 (62, 63).
The multikinase inhibitor vandetanib is an orally active low
molecular weight inhibitor of EGFR, VEGFR and RET receptor.
Several phase II trials of vandetanib have shown an improvement
in PFS when combined with chemotherapy or as monotherapy.
However, phase III trials of vandetanib in combination with
docetaxel or permetrexed or as monotherapy have shown
only modest activity. A randomized, double-blind phase III
trial of second line therapy with permetrexed with or without
vandetanib (ZEAL), a positive trend was seen for vandetanib
with pemetrexed for PFS (HR 0.86; 97.58% CI 0.69-1.06) (64).
Another randomized phase III study comparing vandetanib
vs. erlotinib after failure of the cytotoxic therapy also did not
meet its primary objective of PFS prolongation with vandetanib
(HR 0.98; 95.22% CI 0.87-1.10) (65). In a recently published
randomized phase III trial (ZODIAC) with combination of
docetaxel and vandetanib compared with docetaxel alone
showed a minor improvement in PFS in patients with advanced
NSCLC after progression following first-line therapy with a
median survival of 4 months vs. 3.2 months (HR 0·79; 97·58%
CI 0.70-0.90) (66).
BMS-690514, another orally active multikinase inhibitor
of EGFR, Her-2, VEGFR-2 and VEGFR-3 also has shown
promising activity in both erlotinib-naive and erlotinib failure
patients (67).
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Summary
The development of the EGFR TKIs in NSCLC have expanded
treatment options in the treatment of advanced stage NSCLC.
However, these agents are associated with response and
improvement in survival for selected patients with specific
clinical and molecular characteristics. Further evaluation of
the best strategies especially in terms of molecular assays in
identifying and selecting these favourable patients are crucial in
ensuring the success of these agents. As resistance to gefitinib
and erlotinib will occur with time, an understanding of the
mechanisms of resistance and further development of novel
agents are needed.
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References
Cite this article as: Voon PJ, Cho BC, Yeo WL, Soo RA. The role of epidermal growth factor receptor tyrosine kinase inhibitors in the treatment of advanced stage non-small cell lung cancer. J Thorac Dis 2010;2(3):144-153. doi: 10.3978/j.issn.2072-1439.2010.02.03.6
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