The Oncologist 2007 Erlotinib Lung

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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

The Oncologist 2007;12:840 849 www.TheOncologist.com


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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-

841Gridelli, Bareschino, Schettino et al.

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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.

842 Erlotinib in 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.

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