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Erlotinib in Non-Small Cell Lung Cancer Treatment: Current Status
and Future Development
CESARE GRIDELLI,a MARIA ANNA BARESCHINO,b CLORINDA SCHETTINO,b ANTONIO ROSSI,a
PAOLO MAIONE,a FORTUNATO CIARDIELLOb
aDivision of Medical Oncology, S.G. Moscati Hospital, Avellino, Italy; bDivision of Medical Oncology,
Department of Clinical and Experimental Medicine and Surgery F. Magrassi and A. Lanzara, Second
University of Naples, School of Medicine, Naples, Italy
Key Words. NSCLC EGFR pathways Erlotinib EGFR gene alteration
LEARNING OBJECTIVES
After completing this course, the reader will be able to:
1. Describe the molecular mechanism of action of erlotinib.
2. Define clinical and molecular predictors of response to erlotinib.
3. Describe the clinical trials performed with erlotinib in NSCLC and underline future clinical development of thisdrug in the treatment of NSCLC.
Access and take the CME test online and receive 1 AMA PRA Category 1 Credit at CME.TheOncologist.comCMECME
ABSTRACT
Non-small cell lung cancer (NSCLC) is the leading cause
of cancer-related mortality worldwide. Standard treat-
ment approaches such as chemotherapy, radiotherapy,
and surgery have reached a plateau in this disease.
Therefore, alternatives to conventional treatment, such
as new molecular-targeted therapies, are needed. Tar-
geting the epidermal growth factor receptor (EGFR)
has played a central role in advancing NSCLC research,
treatment, and patient outcome over the last several
years. There are two EGFR tyrosine kinase inhibitors
approved for the treatment of advanced NSCLC: ge-
fitinib and erlotinib. Of these, erlotinib has shown a sig-
nificant improvement in median survival, quality of life,
and related symptoms in an unselected population of
advanced and metastatic NSCLC patients in the second-
or third-line setting. Furthermore, erlotinib has signifi-
cant antitumor activity in first-line treatment. More-
over, factors that predict the efficacy of erlotinib,
including clinical, pathologic, and molecular features,
have been investigated. A series of studies is planned to
contribute to our understanding of the role of erlotinib
in NSCLC treatment. Major areas of clinical research
are the assessment of erlotinib: in adjuvant treatment,
combined with chemotherapy and/or radiotherapy in
locally advanced disease, in the first-line therapy of ad-
vanced disease, and in combination and/or sequence
with cytotoxic treatments and/or other molecular target
agents. The Oncologist 2007;12:840849
Disclosure of potential conflicts of interest is found at the end of this article.
Correspondence: Cesare Gridelli, M.D., Division of Medical Oncology, S.G. Moscati Hospital, Citta Ospedaliera, Contrada Amoretta,83100 Avellino, Italy. Telephone: 39-0825-203573; Fax: 39-0825-203556; e-mail: [email protected], website: www.gridelli.it Re-ceived March 7, 2007; accepted for publication April 24, 2007. AlphaMed Press 1083-7159/2007/$30.00/0 doi: 10.1634/theoncolo-
gist.12-7-840
TheOncologistLung Cancer
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INTRODUCTION
Non-small cell lung cancer (NSCLC) is the most frequent
cause of cancer death in the world, yet progress with che-
motherapeutic agents in this disease has reached a plateau[1, 2]. Therefore, new treatment approaches are needed.
Targeting the epidermal growth factor receptor (EGFR) has
played a central role in advancing NSCLC research, treat-
ment, and patient outcome over the last several years.
The EGFR is a member of the ErbB family of cell mem-
brane receptors that are important mediators of cell growth,
differentiation, and survival. The EGFR (also known as
ErbB-1/HER-1) is a 170-kDa transmembrane glycoprotein,
which consists of an extracellular domain that recognizes
and binds to specific ligands, a hydrophobic transmem-
brane domain involved in interactions between receptorswithin the cell membrane, and an intracellular domain that
contains the tyrosine kinase enzymatic activity. The ErbB
family cell-signaling process uses EGF-like ligands that in-
clude transforming growth factor (TGF-), amphiregu-
lin, heparin-binding EGF, epiregulin, heregulin,
neuregulins [3, 4], and betacellulin [3]. EGFR is known to
bind with high affinity to several ligands, including EGF,
amphiregulin, and TGF-.
Dimer formation activates the intracellular tyrosine ki-
nase (TK) domain. This triggers autophosphorylation of
various tyrosine residues in the catalytic C-terminal domainof the TK. These phosphorylated tyrosine residues bind to
recruitment proteins that serve as substrates for EGFR-
mediated signal transduction. These link the EGFR to var-
ious downstream effector pathways such as the RasRaf
mitogen-activated protein kinase (MAPK) pathway, which
activates cell proliferation, or the phosphatidylinositol-3-
kinaseAkt pathway, which is associated with cell survival
and inhibition of apoptosis [5, 6].
It is recognized that the EGFR-dependent autocrine
pathway plays an important role in the development and
progression of human epithelial cancers, including
NSCLC.
EGFR INHIBITORS IN NSCLC TREATMENT
NSCLC is among the epithelial cancers that are character-
ized by generally high expression levels of members of the
EGFR family of ligands and receptors [3]. Overexpression
of EGFR has also been demonstrated in bronchial prema-
lignant lesions, suggesting that the EGFR-mediated path-
way might play an important role in lung carcinogenesis
[7].
There are two classes of anti-EGFR agents that have
shown clinical activity in NSCLC. These are monoclonal
antibodies (mAbs) directed at the extracellular domain of
the EGFR and low molecular weight tyrosine kinase inhib-
itors (TKIs) that inhibit the tyrosine kinase activity of
EGFR, generally by competing with ATP for the ATP-binding site. Based on their mechanism of action, small-
molecule EGFR TKIs can be distinguished as reversible or
irreversible TKIs and as selective for the EGFR or also ac-
tive against other members of the EGFR family.
The mechanisms of action and the biologic effects of
mAbs and small-molecule TKIs may differ (route of admin-
istration, biodistribution, induction of EGFR downregula-
tion, potential activation of immune functions), and this
could be clinically relevant. However, the antitumor effects
of EGFR inhibition in human cancer models are: inhibition
of cancer cell proliferation with G0/G1 cell cycle arrest and,in some cases, induction of apoptosis; antiangiogenesis
through inhibition of angiogenic growth factor production;
inhibition of invasion and metastasis; and potentiation of
antitumor activity of cytotoxic drugs and radiotherapy [3].
There are two anti-EGFR molecular-targeted agents ap-
proved for the treatment of advanced NSCLC: gefitinib
(Iressa; AstraZeneca, Wilmington, DE) and erlotinib
(Tarceva; Genentech, South San Francisco, CA). In May,
2003, with an accelerated approval procedure by the U.S.
Food and Drug Administration (FDA), gefitinib was ap-
proved as salvage third-line therapy for NSCLC. However,the FDA, in June 2005, restricted the use of gefitinib to only
those patients participating in open clinical trials or con-
tinuing to benefit from treatment already initiated. There-
fore, gefitinib was removed from the U.S. market; it is
registered in several other countries worldwide. Erlotinib
was approved by the FDA in November 2004, and by the
European Medicinal Evaluation Agency (EMEA) in Octo-
ber 2005, for the treatment of chemotherapy-resistant ad-
vanced NSCLC patients.
ERLOTINIB IN NSCLC TREATMENT
Phase III Studies
Erlotinib has dose-dependent pharmacokinetics. Daily dos-
ing does not result in drug accumulation. Erlotinib at 150
mg/day was determined to be the maximum-tolerated dose
at which biologically relevant plasma levels were achieved,
and this dose was recommended for phase II trials [8]. A
phase II trial was conducted to evaluate erlotinib in ad-
vanced refractory NSCLC [9]. Results of that phase II trial
in 52 patients showed complete responses in two patients
(4%), partial responses (PRs) in five patients (9%), and pro-
longed stable disease (SD) in 22 patients (39%). The me-
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dian survival time (MST) was 8.4 months. Lung cancer
symptoms (fatigue, dyspnea, cough) improved with erlo-
tinib use.
Erlotinib as a single agent has also been tested as first-
line treatment in advanced NSCLC patients [10]. Fifty-
three chemotherapy-naive patients with stage IIIB/IV
NSCLC received oral erlotinib (150 mg/day). The overall
rate of nonprogression at 6 weeks was 52.8% (28 of 53 pa-
tients). The objective response (OR) rate was 22.7%, and
the MST was 391 days.
Responses were more common in women than in men
and occurred mostly in those with adenocarcinoma (includ-
ing bronchioloalveolar carcinoma histology) and in non-
smokers. However, responses were also observed in
patients with other tumor histology and in former or current
smokers.
A similar phase II study was conducted to evaluate er-lotinib as first-line monotherapy in 80 chemotherapy-naive
elderly (70 years of age) patients with stage III/IV disease
[11]. There were eight PRs (10%), and 33 patients (41%)
experienced SD for 2 months or longer. The MST was 10.9
months. The 1- and 2-year survival rates were 46% and
19%, respectively. The toxicity of erlotinib in this popula-
tion compares favorably with that seen in other studies per-
formed in patients with NSCLC 70 years of age.
Phase III Studies
In advanced NSCLC, chemotherapy offers symptomatic re-lief and a modest improvement in survival. Second-line
chemotherapy with docetaxel [12, 13] can prolong survival
after platinum-based therapy. Furthermore, pemetrexed has
been approved for second-line treatment, because it was
demonstrated that pemetrexed is not inferior, in terms of
clinical efficacy, to docetaxel, but with significantly fewer
side effects [14]. In contrast, few options are available for
the treatment of patients with progressive disease after fail-
ure of second-line therapies [15]. To evaluate whether er-
lotinib clinical activity in chemotherapy-refractory NSCLC
patients could also be effective in prolonging survival, the
National Cancer Institute of Canada Clinical Trials Group
conducted a phase III randomized trial, named BR.21, in
which erlotinib was compared with placebo in stage III/IV
NSCLC patients who had failed first- or second-line che-
motherapy [16]. A total of 731 patients was randomized in
a 2:1 ratio to receive either erlotinib at 150 mg/day or pla-
cebo. Those patients had metastatic NSCLC that had previ-
ously been treated with one standard chemotherapy
regimen (50% of patients) or with two chemotherapy regi-
mens (50% of patients). Almost all patients received plati-
num-based chemotherapy. The OR rate was 8.9% in the
erlotinib arm and1% in the placebo group (p .001). The
median durations of response were 7.9 months and 3.7
months, respectively. The MST was 6.7 months for those in
the erlotinib regimen compared with 4.7 months for those in
the placebo arm (p .001; hazard ratio [HR], 0.7; 95% con-
fidence interval [CI], 0.580.85). ORs were more frequent
in women (14% versus 6%; p .0065), in patients with ad-
enocarcinoma, as compared with other histotypes (14%
versus 4.1%;p0.0001), and in patients without a smoking
history (25% versus 4%; p .0001).
A quality of life (QoL) evaluation, defined as the time to
clinically significant deterioration in three common lung
cancer symptoms, showed that patients receiving erlotinib
had a significantly longer median time to deterioration for
all three symptoms: 4.9 versus 3.7 months for cough (p
.04), 4.7 versus 2.9 months for dyspnea (p .04), and 2.8
versus 1.9 months for pain (p .03). QoL response analy-
ses showed that 44%, 34%, and 42% of patients receivingerlotinib had improvement in these three symptoms, re-
spectively. This was accompanied by significantly greater
improvements in physical function (31% for erlotinib ver-
sus 19% for placebo; p .01) and global QoL (35% versus
26%; p .0001) [17]. The QoL analysis supports the true
palliative benefit of erlotinib in improving not only survival
but also symptoms.
Erlotinib in combination with chemotherapy for the
first-line treatment of NSCLC has been evaluated in two
large multicenter, randomized, placebo-controlled clinical
trials. Two platinum-based doublets (carboplatin plus pac-litaxel or cisplatin plus gemcitabine) were evaluated in
combination with erlotinib in the Tarceva Responses in
Conjunction with Paclitaxel and Carboplatin (TRIBUTE)
and Tarceva Lung Cancer Investigation (TALENT) trials,
respectively [18, 19]. In the TRIBUTE study, 1,000 pa-
tients with untreated advanced stage IIIB/IV NSCLC were
enrolled. The MST for patients treated with erlotinib was
10.6 months, versus 10.5 months for those treated with pla-
cebo (HR, 0.99; p .95; 95% CI, 0.861.16); the OR rates
were similar in the erlotinib and placebo arms (21.5% ver-
sus 19.3%, respectively; p .36). Also, in the TALENT
trial, there was no statistically significant difference in any
outcome, with an MST of 301 versus 309 days, respec-
tively. Therefore, there was no clinical benefit in either
trial, and currently concurrent use of erlotinib with chemo-
therapy is not recommended in the first-line treatment of
NSCLC. There was also no clinical benefit when gefitinib
was combined with chemotherapy in either of two similar
trialsIressa NSCLC Trial Assessing Combination Ther-
apy (INTACT)-1 (cisplatin plus gemcitabine) and IN-
TACT-2 (carboplatin plus paclitaxel) [20, 21]. Table 1
summarizes the results of phase III trials employing erlo-
tinib in the treatment of advanced NSCLC.
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COMBINATION STUDIES OF ERLOTINIB AND OTHER
TARGETED AGENTSThe development of molecular-targeted therapy has opened
new avenues for combining different drugs that block key
molecular pathways for cancer growth and progression. A
rational approach is the combination of anti-EGFR and an-
tiangiogenic agents. A large body of experimental evidence
suggests relevant functional crosstalk, that is, a pathway
signal disrupts the signal in the adjacent pathway and can
cause the signals to become confused and cross over each
other, between the EGFR and vascular endothelial growth
factor (VEGF) pathways [22].
A phase I/II trial examined the safety and efficacy ofcombining erlotinib and bevacizumab therapy in patients
with advanced nonsquamous NSCLC. Data on antitumor
activityfrom 40 patients are encouraging: ORs were seen in
20% of the patients and 65% had SD; time to progression
was 7 months with an MST of 12.6 months. The results of
this phase I/II study show that this combination is well tol-
erated and active in NSCLC [23].
A phase II, multicenter, randomized clinical trial was
conducted to evaluate the efficacy and safety of bevaci-
zumab in combination with chemotherapy or erlotinib. One
hundred twenty advanced nonsquamous NSCLC patients,
previously treated with a platinum-based regimen, were
randomized to receive docetaxel or pemetrexed plus pla-
cebo (arm 1), docetaxel or pemetrexed plus bevacizumab
(arm 2), or bevacizumab plus erlotinib (arm 3). The overall
rate of nonprogression was 39% in arm 1, compared with
52.5% in arm 2 and 51.3% in arm 3. The percentage of pa-
tients free from progression at 6 months was 21.5% versus
30.5% versus 33.6%, respectively (arm 1 versus arm 2 plus
arm 3 was 21.5% versus 31.8%). The 6-month survival rate
was 62.4% versus 72.1% versus 78.3%, respectively (arm 1
versus arm 2 plus 3 was 62.4% versus 74.7%). The data re-
ported in this trial seem to favor the addition of bevaci-
zumab to either chemotherapy or erlotinib over single-
agent chemotherapy alone [24].A phase I trial of sorafenib, a potent inhibitor of Raf-1,
which is alsoactive against VEGF-2, VEGF-3, and platelet-
derived growth factor receptor, plus erlotinib has recently
documented that this combination is feasible at the full rec-
ommended doses of both agents with acceptable toxicity
[25]. In that study promising clinical activity was also ob-
served in several tumor types.
CLINICAL AND MOLECULAR PREDICTORS OF
RESPONSE TO ERLOTINIB
Clinical Predictors
In clinical trials with the other EGFR TKI, gefitinib, it was
shown that the clinicalbenefit appears to be limited to a spe-
cific subgroup of patients, namely, women, never-smokers,
patients with adenocarcinoma, and patients of Asian ethnic-
ity. Smoking status seems to be the strongest predictor, with
patients who are never-smokers having the greatest likeli-
hood of a clinical response to gefitinib [26]. These clinical
predictors of response were confirmed in a randomized,
placebo-controlled, phase III clinical trial, Iressa Survival
Evaluation in Lung Cancer (ISEL), that investigated the ef-
fect of gefitinib on survival in chemotherapy-refractory
stage IIIB/IV NSCLC patients. Treatment with gefitinib did
not improve survival (MST, 5.6 versus 5.1 months) for the
total patient population. However, based on a preplanned
subgroup analysis, gefitinib treatment resulted in signifi-
cantly longer survival among never-smokers and patients of
Asian origin [27].
In contrast, although female gender, adenocarcinoma,
Asian ethnicity, and a never-smoking history predicted re-
sponse to erlotinib in the BR.21 study, erlotinib had a sig-
nificant effect on survival in all subgroups of patients [17].
In fact, even though male smokers with squamous cell car-
Table 1. Phase III randomized trials with erlotinib in advanced non-small cell lung cancer
Trial (year) Setting Treatmentn ofpatients
RR(%)
OS(months) p-value
TALENT (2004) [19] First line CDDP GEM placebo 536 29.9 10.3 .48
CDDP GEM erlotinib 533 31.5 10.0TRIBUTE (2005) [18] First line CBDCA TAX placebo 540 19.3 10.5 .95
CBDCA TAX erlotinib 539 21.5 10.6
BR.21 (2005) [16] Second and third line Placebo 243 1 4.7 .001
erlotinib 488 8.9 6.7
Abbreviations: BR.21, National Cancer Institute of Canada Clinical Trials Group BR.21 trial; CBDCA, carboplatin; CDDP,cisplatin; GEM, gemcitabine; OS, overall survival; RR, response rate; TALENT, Tarceva Lung Cancer Investigation;TRIBUTE, Tarceva Responses in Conjunction with Paclitaxel and Carboplatin; TAX, paclitaxel.
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cinoma are not considered ideal candidates for treatment
with erlotinib, in this group, the MST was significantly
longer in patients receiving erlotinib (n 100) than in pa-
tients with similar characteristics in the placebo arm (n
57) (HR, 0.66; 95% CI, 0.47 0.92; p .016). This differ-
ence resulted in MSTs of 5.5 months in the erlotinib and 3.4
months in the placebo arm [28].
The effect of smoking was also examined in the TRIB-
UTE phase III trial. Despite a lack of benefit in the overall
patient population, when the analysis was confined to those
who had never smoked cigarettes, erlotinib seemed to con-
fer a survival benefit (MSTs of 10 and 22.5 months, for
smokers and never-smokers, respectively; p .01) [18].
Skin rash is a common adverse effect observed in all
clinical trials with EGFR-targeting agents. It is generally
localized on the upper torso, face, and neck, and occurs af-
ter approximately 1 week of treatment and reaches a maxi-mum intensity after 23 weeks. The incidence of rash was
higher with erlotinib than with gefitinib in phase II and III
studies [29], and may be a result of the lower plasma con-
centration of gefitinib compared with erlotinib when ad-
ministered at the recommended doses of 250 mg/day and
150 mg/day, respectively. Data from phase I dose escala-
tion trials indicate that the rash is dose dependent [30]. The
positive relationship between the development of rash and
response and/or survival, which has been shown in both the
erlotinib and cetuximab clinical trials, makes the occur-
rence of skin reactions a potential surrogate marker for anti-EGFR drug efficacy. In fact, in some trials of erlotinib in
patients with advanced NSCLC, head and neck squamous
cell carcinoma, and advanced ovarian cancer, there was a
significant correlation between rash and survival, with rash
severity correlating with greater duration of survival [31].
Furthermore, in the phase III TRIBUTE and TALENT tri-
als, a subanalysis showed that patients who developed rash
survived longer than those who did not. Finally, it was re-
cently shown that susceptibility to rash and clinical activity
of EGFR-targeting agents could be linked to polymorphic
variations in theEGFR gene [32]. The relationship between
the development of rash and survival is currently being
evaluated further and the results should help to guide the
use of EGFR-targeted therapy.
Molecular Predictors
EGFR Mutations
The exciting discovery that certain somatic mutations
within the TK ATP-binding domain of the EGFR gene are
associated with OR to EGFR TKIs brought new interest in
the molecular selection of patients to treat with these drugs
[3336]. Approximately 90% ofEGFR gene mutations af-
fect a small region of the gene within exons 1824, which
code for the TK domain. The more common mutations are
an in-frame deletion in exon 19 around codons 746750
(45%50% of all somatic EGFR mutations) and a missense
mutation leading to a leucine to arginine substitution at
codon 858 (L858R) in exon 21 (35%45% of mutations)
[35]. Somatic EGFR mutations, however, are rare events in
other tumor types. SomaticEGFR gene mutations are found
in approximately 5%15% of unselected NSCLC patients
of white ethnicity and in approximately 25%35% of
NSCLC patients of Asian ethnicity. Somatic mutations in
the EGFR gene are most frequently detected in a subpopu-
lation of NSCLC patients with characteristics associated
with a better treatment outcome, including adenocarcinoma
histology and, in particular, bronchioloalveolar carcinoma,
nonsmoking status, Asian ethnicity, and female gender [36,
37].
Available tumor samples from the BR.21 study were an-
alyzed in the search for EGFR gene mutations. Of 731 pa-
tients studied, 197 specimens were analyzed for EGFR
gene mutations, which were most commonly identified in
exons 19 and 21 [38]. A total of 45 EGFR mutations was
identified in 23% of the analyzed samples. Twenty-one mu-
tations were either deletions in exon 19 or the exon 21
L858R mutation, whereas 24 were novel mutations. Pa-
tients who had a mutation achieved a higher response rate,
although this was not statistically significant. There was no
significant difference in survival benefit seen between the
erlotinib group and the placebo group in patients with an
exon 19 deletion or exon 21 L858R mutation (p .39; HR
for death, 0.65; 95% CI, 0.261.75) or in patients with
novel mutations (p .41; HR, 0.67; 95% CI, 0.61.75)
[38].
In the TRIBUTE trial, EGFR mutations were found in
13% of cases and were correlated with a higher response
rate to erlotinib plus chemotherapy, 53%, compared with
EGFR wild-type cases (18%). Patients with EGFR muta-
tions also had a higher response rate to either treatment
(38%) compared with wild-type cases (23%; p .01), and
a longer survival time that was independent of treatment (8
versus 5 months for the mutation-positive and -negative
groups, respectively; p .001) [39].
Different mutations in EGFR may confer different tu-
mor activation profiles that lead to variations in both the
natural history and clinical course after treatment with er-
lotinib or gefitinib. The relationship between the two most
common types of somatic EGFR mutations has been eval-
uated.
Emerging data suggest that patients with NSCLC and
EGFR exon 19 deletion have a longer survival time follow-
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ing treatment with gefitinib or erlotinib than those with the
L858R mutation [40].
EGFR Gene Amplification and High Copy Number
The EGFR gene is rarely amplified in NSCLC. However, it
is possible to identify, by fluorescence in situ hybridization
(FISH) analysis, a higher EGFR gene copy number in a
variable proportion of cancer cells in approximately 25%
35% of unselected NSCLC patients. Several groups have
investigated the potential predictive value of EGFR gene
amplification in patients treated with gefitinib or erlotinib.
A high EGFR copy number determined by FISH was asso-
ciated with a slightly worse prognosis [41] or no difference
in survival outcome compared with a normal gene copy
number [42].
The randomized BR.21 and ISEL studies showed that
FISH-positive patients randomized to placebo had aslightly shorter survival time than FISH-negative patients
randomized to placebo [41, 43]. In the BR.21 trial, FISH-
positive patients (approximately 40%) randomized to re-
ceive erlotinib had a significantly longer survival time than
FISH-positive patients randomized into the placebo arm
(HR, 0.44; p .01). In the FISH-negative patients, there
was no significant difference in survival. Similar results
were observed in the ISEL trial in which gefitinib was used.
Interestingly, a significant correlation between the presence
of a high EGFR gene copy number and mutations was seen
[4446], suggesting that the mutant allele of the EGFRgene is selectively amplified in tumors, as has been ob-
served in EGFR-mutant NSCLC cell lines [47].
High levels of EGFR protein expression, as determined
by immunohistochemistry (IHC), were associated with re-
sponse and survival in a retrospective subset analysis of the
BR.21, the Southwest Oncology Group 0126 trial, and the
series of gefitinib treated patients reported by Cappuzzo et
al. [38, 45]. In the BR.21 trial, IHC-positive patients treated
with erlotinib had a significantly longer survival duration
than placebo-treated patients (HR, 0.68; p .02).
K-ras Mutations Predict Drug Resistance to EGFR
Inhibitors
EGFR signaling pathways include downstream GTPases
encoded by ras genes. The activation of ras determines a
multistep phosphorylation cascade that ultimately leads to
the activation of MAPKs. The MAPKs, extracellular sig-
nalrelated kinase (ERK)-1, and ERK-2 are able to regulate
gene transcription, and play an important role in cell prolif-
eration, survival, and transformation [5, 6]. Approximately
15%30% of lung adenocarcinomas contain activating mu-
tations in the ras family member.EGFR mutations are com-
mon in tumors from patients who have smoked 100
cigarettes in their lifetimes (never-smokers) [48], while
K-ras mutations commonly occur in individuals with a his-
tory of substantial cigarette use [49]. These mutations are
most frequently found in codons 12 and 13 in exon 2 of the
K-ras gene [50, 51]. K-ras mutations were found to be as-
sociated with resistance to EGFR TKIs in NSCLC. Sixty
tumor specimens obtained from lung adenocarcinoma pa-
tients, which were shown to be sensitive or refractory to sin-
gle-agent gefitinib or erlotinib, were evaluated for
mutations in the EGFR and K-ras genes. Collectively, 9 of
38 (24%) tumors refractory to either TKI had K-ras muta-
tions, while 0 of 21 (0%) drug-sensitive tumors had such
mutations (p .02). Conversely, 17 of 22 (77%) tumors
sensitive to either kinase inhibitor had EGFR mutations, in
contrast to 0 of 38 (0%) drug-resistant tumors (p 6.8
1011). All 17 tumors with EGFR mutations responded to
gefitinib or erlotinib, while all nine tumors with K-ras mu-tations did not (p 3.2 107) [52].
An exploratory analysis of K-ras mutational status in
the BR.21 trial was conducted in 206 patients; 30 (14.6%)
specimens had missense mutations in codon 12 or 13 (22 in
the erlotinib arm and 8 in the placebo arm). For all 206 pa-
tients with known K-ras genotype, the HR in the erlotinib
arm was 0.77 (95% CI, 0.571.06; p .06). For the 176
K-ras wild-type patients, the univariate HR for erlotinib
treatment was 0.69 (95% CI, 0.490.97; p .03). In con-
trast, the HR for the 30 K-ras mutant patients was 1.67
(95% CI, 0.624.5; p .31), with an interaction p-value of.09. OR rates were 5% (1 of 20) in K-ras mutant patients
and 10.2% (10 of 98) in K-ras wild-type patients. In pa-
tients with known K-ras genotype, the multivariate Cox re-
gression model showed that K-ras mutation was
significantly associated with shorter survival (HR, 1.63;
95% CI, 1.06 2.51; p .03) [53]. A subgroup analysis of
BR.21 patients indicated that patients with K-ras mutations
did not appear to derive any survival benefit from erlotinib
therapy. However, the numbers of patients are small and re-
sults need to be confirmed in other larger studies. The pres-
enceofaK-ras gene mutation is likely to constitute a useful
marker for selecting those patients who will not benefit
from anti-EGFR therapies.
Acquired Resistance to Anti-EGFR Agents Resulting
from Secondary Mutations
In addition to primary resistance to anti-EGFR therapies,
resistance eventually develops in most NSCLC patients
who initially respond to gefitinib or erlotinib who harbor
sensitizingEGFR mutations, leading to disease progression
during treatment. In these cases, acquired resistance to
EGFR inhibitors has been shown to be associated with the
occurrence of an additional EGFR gene mutation [54, 55].
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have a broader spectrum of activity for EGFR family members
has identified three drugs (EKB-569, HKI-272, and CI-1033)
that have shown activity against the resistant mutant [56].
FUTURE DEVELOPMENT
A series of studies is planned to contribute to our under-standing of the role of erlotinib in NSCLC treatment. Major
areas of clinical research are the assessment of erlotinib: in
adjuvant treatment, combined with chemotherapy and/or
radiotherapy in locally advanced disease, in the first-line
therapy of advanced disease, and in combination and/or se-
quence with cytotoxic treatments and/or other molecular-
targeted agents. Table 2 summarizes a series of ongoing
phase II and III studies. Among these, an ItalianCanadian
trial, Tarceva OR Chemotherapy (TORCH), appears par-
ticularly interesting. The design of this phase III random-
ized, multicenter trial is based on a noninferiority survival
comparison between an experimental strategy including
first-line erlotinib followed at progression by chemother-
apy with cisplatin and gemcitabine (PG) and a standard arm
consisting of first-line PG chemotherapy followed at pro-
gression by erlotinib. Moreover, this trial will allow the
evaluation of the relationship between molecular predic-
tors, such as EGFR and K-ras mutational status, and erlo-
tinib treatment response. The aim of the TORCH study is to
evaluate, in a randomized fashion, what is the most appro-
priate and cost-effective sequential approach for erlotinib
and chemotherapy in an unselected populationof metastatic
NSCLC patients.
Another possible approach to improving clinical out-
come in the metastatic setting is multitargeted inhibition
that combines blockade of angiogenesis, RasRafERK,
and EGFR. In this context, an interesting multitargeted
agent with a low toxicity profile is sorafenib. Our group is
currently starting a phase II, randomized, multicenter clin-
ical trial to investigate if the combination of erlotinib and
sorafenib or the combination of a standard chemotherapy
regimen, gemcitabine, plus sorafenib could be active and
tolerated in NSCLC patients who are elderly or who have a
performance status score of 2, who are generally less likely
than other patients to tolerate standard-dose platinum-based
doublet chemotherapy.
In conclusion, it is of importance to define the patient
population who will derive the most benefit from erlotinibtreatment by clarifying the relationship between EGFR ex-
pression and response to treatment, and to define the pre-
dictive potential of EGFR mutation expression and EGFR
copy number for response to erlotinib.
DISCLOSURE OF POTENTIAL CONFLICTS
OF INTEREST
C.G. and F.C. have acted as consultants for and have finan-
cial interests in Roche. P.M. has acted as a consultant for
Roche.
REFERENCES
1 Breathnach OS, Freidlin B, Conley B et al. Twenty-two years of phase III
trials for patients with advanced non-small-cell lung cancer: Sobering re-
sults. J Clin Oncol 2001;19:17341742.
2 Schiller JH, Harrington D, Belani CP et al. Comparison of four chemother-
apyregimensfor advanced non-small-cell lung cancer. N Engl J Med2002;
346:9298.
3 NormannoN, BiancoC, De Luca A et al.Target-based agentsagainst ErbB
receptors and their ligands: A novel approach to cancer treatment. Endocr
Relat Cancer 2003;10:121.
4 Mendelsohn J. Blockade of receptorsfor growthfactor: An anticancer ther-
apy the fourth annual Joseph H Burchenal American Association of Can-cer Research Clinical Research Award Lecture. Clin Cancer Res 2000;6:
747753.
5 Olayioye MA, Neve RM, Lane HA et al. The ErbB signaling network: Re-
ceptor heterodimerization in development and cancer. EMBO J 2000;19:
31593167.
6 Yarden Y, Sliwkowski MX. Untangling the ErbB signaling network. Na-
ture Rev Mol Cell Biol 2001;2:127137.
7 Kurie JM,Shin HJ,Lee JS et al.Increased epidermalgrowth factorreceptor
expression in metaplastic bronchial epithelium. Clin Cancer Res 1996;2:
17871793.
8 Hidalgo M, Siu LL, Nemunaitis J et al. Phase I and pharmacologic study of
OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in pa-
tients with advanced solid malignancies. J Clin Oncol 2001;19:32673279.
9 Perez-Soler R, Chachoua A, Hammond LA et al. Determinants of tumor
response and survival with erlotinib in patients with non-small-cell lung
cancer. J Clin Oncol 2004;22:32383247.
10 Giaccone G, Gallegos Ruiz M, Le Chevalier T et al. Erlotinib for frontline
treatment of advanced non-small cell lung cancer: A phase II study. Clin
Cancer Res 2006;12:6049 6055.
11 Jackman DM, Yeap BY, Lindeman NI et al. Phase II clinical trial of che-
motherapy-nave patients 70 years of age treated with erlotinib for ad-
vanced non-small-cell lung cancer. J Clin Oncol 2007;25:760766.
12 Shepherd FA, Dancey J, Ramlau R et al. A prospective randomized trial of
docetaxel versus best supportive care in patients with non-small-cell lung
cancer previously treated with platinum-based chemotherapy. J Clin Oncol2000;18:20952103.
13 Fossella FV, DeVore R, Kerr RN et al. Randomized phase III trial of do-
cetaxel versus vinorelbine or ifosfamide in patients with advanced non-
small-cell lung cancer previously treated with platinum-containing
chemotherapy regimens. The TAX 320 Non-Small CellLung Cancer Study
Group. J Clin Oncol 2000;18:23542362.
14 Hanna N, Shepherd FA, Fossella FV et al. Randomized phase III trial of
pemetrexed versus docetaxel in patients with non-small-cell lung cancer
previously treated with chemotherapy. J Clin Oncol 2004;22:15891597.
15 Massarelli E, Andre F, Liu DD et al. A retrospective analysis of the out-
come of patients who have received two prior chemotherapy regimens in-
cluding platinum and docetaxel for recurrent non-small-cell lung cancer.
Lung Cancer 2003;39:5561.
847Gridelli, Bareschino, Schettino et al.
www.TheOncologist.com
7/28/2019 The Oncologist 2007 Erlotinib Lung
10/12
16 Shepherd FA, Rodrigues Pereira J, Ciuleanu T et al. Erlotinib in previously
treated non-small-cell lung cancer. N Engl J Med 2005;353:123132.
17 Bezjak A, Tu D, Seymour L et al. Symptom improvement in lung cancer
patients treated with erlotinib: Quality of life analysis of the National Can-
cer Institute of Canada Clinical Trials Group Study BR.21. J Clin Oncol
2006;24:38313837.
18 Herbst RS, Prager D, Hermann R et al. TRIBUTE: A phase III trial of er-
lotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel
chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol 2005;
23:58925899.
19 Gatzemeier U, Pluzanska A, Szczesna A et al. Results of a phase III trial of
erlotinib (OSI-774) combined with cisplatin and GC chemotherapy in ad-
vanced non-small cell lung cancer (NSCLC). J Clin Oncol 2004;22(suppl
14):619s.
20 Giaccone G, Herbst RS, Manegold C et al. Gefitinib in combination with
gemcitabine and cispatin in advanced non-small-cell lung cancer: A phase
III trialINTACT 1. J Clin Oncol 2004;22:777784.
21 Herbst RS, Giaccone G, Schiller JH et al. Gefitinib in combination with
paclitaxel and carboplatinin advanced non-small-cell lung cancer: A phaseIII trialINTACT 2. J Clin Oncol 2004;22:785794.
22 Ciardiello F, Bianco R, Damiano V et al. Antiangiogenic and antitumor ac-
tivity of anti-epidermal growth factor receptor C225 monoclonal antibody
in combination with vascular endothelial growth factor antisense oligonu-
cleotide in human GEO colon cancer cells. Clin Cancer Res 2000;6:3739
3747.
23 Herbst RS, Johnson DH, Mininberg E et al. Phase I/II trial evaluating the
anti-vascular endothelial growth factor monoclonal antibody bevacizumab
in combination with the HER-1/epidermal growth factor receptor tyrosine
kinase inhibitor erlotinib for patients with recurrent non-small-cell lung
cancer. J Clin Oncol 2005;23:25442555.
24 Fehrenbacher L, O Neill V, Belani CP et al. A phase II, multicenter, ran-
domized clinical trial to evaluate the efficacy and safety of bevacizumab incombination with either chemotherapy (docetaxel or pemetrexed) or erlo-
tinib hydrochloridecomparedwith chemotherapyalonefor treatmentof re-
current or refractory nonsmallcelllung cancer. J Clin Oncol 2006;24(suppl
18):379s.
25 Duran I, Hotte S, Chen E et al. Dual inhibition of the MAPK pathway by
combination targeted therapy: A phase I trial of sorafenib (SOR) and erlo-
tinib (ERL) in advanced solid tumors. Eur J Cancer Suppl 2006;4:167.
26 Miller VA, Kris MG, Shah N et al. Bronchioloalveolar pathologic subtype
and smoking history predict sensitivity to gefitinib in advanced non-small-
cell lung cancer. J Clin Oncol 2004;22:11031109.
27 Thatcher N, Chang A, Parikh P et al. Gefitinib plus best supportive care in
previously treated patients with refractory advanced non-small-cell lung
cancer: Results from a randomised, placebo-controlled, multicentre study(Iressa Survival Evaluation in Lung Cancer). Lancet 2005;366:15271537.
28 Clark GM, Cameron T, Das Gupta A et al. Clinical benefit of erlotinib in
male smokers in squamous cell NSCLC. J Clin Oncol 2006;24(suppl 18):
405s.
29 Perez-Soler R, Saltz L. Cutaneous adverse effects with HER1/EGFR-
targeted agents: Is there a silver lining? J Clin Oncol 2005;23:52355246.
30 Roskos L, Lohner M, Osborn K et al. Low pharmacokinetic variability fa-
cilitates optimal dosing of ABX-EGF in cancer patients. Proc Am Soc Clin
Oncol 2002;21:91a.
31 Soulieres D, Senzer NN, Vokes EE et al. Multicenter phase II study of er-
lotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor,
inpatientswith recurrentor metastatic squamouscell cancerof theheadand
neck. J Clin Oncol 2004;22:7785.
32 Amador ML, Oppenheimer D, Perea S et al. An epidermal growth factor
receptor intron 1 polymorphism mediates response to epidermal growth
factor receptor inhibitors. Cancer Res 2004;64:91399143.
33 Lynch TJ, Bell DW,SordellaR et al.Activating mutationsin theepidermal
growth factor receptor underlying responsiveness of non-small-cell lung
cancer to gefitinib. N Engl J Med 2004;350:21292139.
34 Paez JG, Janne PA, Lee JC et al. EGFR mutations in lung cancer: Correla-
tion with clinical response to gefitinib therapy. Science 2004;304:1497
1500.
35 Shigematsu H, Lin L, Takahashi T et al. Clinical and biological features
associated with epidermal growth factor receptor gene mutations in lung
cancers. J Natl Cancer Inst 2005;97:339346.
36 Janne PA, Engelman JA, Johnson BE. Epidermal growth factor receptor
mutations in non-small-cell lung cancer: Implications for treatment and tu-
mor biology. J Clin Oncol 2005;23:32273234.
37 Giaccone G. Epidermalgrowth factorreceptorinhibitors in thetreatment of
non-small-cell lung cancer. J Clin Oncol 2005;23:32353242.
38 Tsao MS, Sakurada A, Cutz JC et al. Erlotinib in lung cancer: Molecular
and clinical predictors of outcome. N Engl J Med 2005;353:133144.
39 Gandara DR,Gumerlock PH.Epidermal growthfactor receptor tyrosine ki-
nase inhibitors plus chemotherapy: Case closedor is thejurystillout? J Clin
Oncol 2005;23:58565858.
40 Jackman DM, Yeap BY, Sequist LV et al. Exon 19 deletion mutations of
epidermal growth factor receptor are associated with prolonged survival in
non-small cell lung cancer patients treated with gefitinib or erlotinib. Clin
Cancer Res 2006;12:39083914.
41 Hirsch FR, Varella-Garcia M, Bunn PA Jr et al. Epidermal growth factor
receptor in non-small-cell lung carcinomas:Correlation between gene copy
numberand protein expression andimpact on prognosis. J Clin Oncol2003;
21:37983807.
42 Dziadziuszko R, Holm B, Skov B et al. Epidermal growth factor receptorgene copy numberand protein levelare notassociatedwithoutcomeof non-
small-cell lung cancer patients treated with chemotherapy. Ann Oncol
2007;18:447452.
43 Hirsch FR, Varella-Garcia M, Bunn PA Jr et al. Molecular predictors of
outcome with gefitinib in a phase III placebo-controlled study in advanced
non small cell lung cancer. J Clin Oncol 2006;24:50345042.
44 TakanoT, OheY, Sakamoto H et al.Epidermal growthfactor receptor gene
mutations and increased copy numbers predict gefitinib sensitivity in pa-
tients with recurrent non-small-cell lung cancer. J Clin Oncol 2005;23:
68296837.
45 Cappuzzo F, Hirsch FR, Rossi E et al. Epidermal growth factor receptor
gene and protein and gefitinib sensitivity in non-small-cell lung cancer.
J Natl Cancer Inst 2005;97:643655.
46 Amann J, Kalyankrishna S, Massion PP et al. Aberrant epidermal growth
factor receptor signaling and enhanced sensitivity to EGFR inhibitors in
lung cancer. Cancer Res 2005;65:226235.
47 Tracy S, Mukohara T, Hansen M et al. Gefitinib induces apoptosis in the
EGFRL858Rnon-small-celllung cancer cell line H3255. Cancer Res2004;
64:72417244.
48 Pao W, Miller V, Zakowski M et al. EGF receptor gene mutations are com-
mon in lung cancers from never smokers and are associated with sensi-
tivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A 2004;
101:1330613311.
49 Ahrendt SA, Decker PA, Alawi EA et al. Cigarette smoking is strongly as-
sociated with mutation of the K-ras gene in patients with primary adeno-
carcinoma of the lung. Cancer 2001;92:15251530.
848 Erlotinib in NSCLC
7/28/2019 The Oncologist 2007 Erlotinib Lung
11/12
50 Rodenhuis S, Slebos RJC, Boot AJM et al. Incidence and possible clinical
significance of K-ras oncogene activation in adenocarcinoma of the human
lung. Cancer Res 1998;48:57385741.
51 Suzuki Y, Orita M, Shiraishi M et al. Detection ofras gene mutations in
human lung cancers by single-strand conformation polymorphism analysis
of polymerase chain reaction products. Oncogene 1990;5:10371043.
52 Pao W, Wang TY, Riely GJ et al. KRAS mutations and primary resistance
of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med 2005;2:e17.
53 Tsao M, Zhu C, Sakurada A et al. An analysis of the prognostic and pre-
dictive importanceof K-ras mutation statusin theNationalCancer Institute
of Canada Clinical Trials Group BR.21 study of erlotinib versus placebo in
the treatment of non-small cell lung cancer. J Clin Oncol 2006;24(suppl
18):365s.
54 Pao W, Miller VA, Politi KA et al. Acquired resistance of lung adenocar-
cinomas to gefitinib or erlotinib is associated with a second mutation in the
EGFR kinase domain. PLoS Med 2005;2:e73.
55 Kobayashi S, Boggon TJ, Dayaram T et al. EGFR mutation and resistanceof non-small-cell lung cancer to gefitinib. N Engl J Med 2005;352:786
792.
56 Carter TA, Wodicka LM, Shah NP et al. Inhibition of drug-resistant mu-
tants of ABL, KIT, and EGF receptor kinases. Proc Natl Acad Sci U S A
2005;102:1101111016.
849Gridelli, Bareschino, Schettino et al.
www.TheOncologist.com
7/28/2019 The Oncologist 2007 Erlotinib Lung
12/12
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