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The Oncologist, Vol. 12, No. 7, 840-849, July 2007; doi:10.1634/theoncologist.12-7-840
© 2007 AlphaMed Press

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Lung Cancer

Erlotinib in Non-Small Cell Lung Cancer Treatment: Current Status and Future Development

Cesare Gridellia, Maria Anna Bareschinob, Clorinda Schettinob, Antonio Rossia, Paolo Maionea, 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

Correspondence: Cesare Gridelli, M.D., Division of Medical Oncology, "S.G. Moscati" Hospital, Città Ospedaliera, Contrada Amoretta, 83100 Avellino, Italy. Telephone: 39-0825-203573; Fax: 39-0825-203556; e-mail: cgridelli{at}libero.it website: www.gridelli.it

Received March 7, 2007; accepted for publication April 24, 2007.


   Learning Objectives
Top
 Learning Objectives
Abstract
 Introduction
 EGFR Inhibitors in NSCLC...
 Erlotinib in NSCLC Treatment
 Combination Studies of Erlotinib...
 Clinical and Molecular...
 Future Development
 Disclosure of Potential...
 References
 
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 this drug in the treatment of NSCLC.

Access and take the CME test online and receive 1 AMA PRA Category 1 CreditTM at CME.TheOncologist.com


   ABSTRACT
Top
 Learning Objectives
 Abstract
Introduction
 EGFR Inhibitors in NSCLC...
 Erlotinib in NSCLC Treatment
 Combination Studies of Erlotinib...
 Clinical and Molecular...
 Future Development
 Disclosure of Potential...
 References
 
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide. Standard treatment 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. Targeting 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: gefitinib and erlotinib. Of these, erlotinib has shown a significant 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 significant antitumor activity in first-line treatment. Moreover, 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 advanced disease, and in combination and/or sequence with cytotoxic treatments and/or other molecular target agents.

Disclosure of potential conflicts of interest is found at the end of this article.


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
EGFR Inhibitors in NSCLC...
 Erlotinib in NSCLC Treatment
 Combination Studies of Erlotinib...
 Clinical and Molecular...
 Future Development
 Disclosure of Potential...
 References
 
Non-small cell lung cancer (NSCLC) is the most frequent cause of cancer death in the world, yet progress with chemotherapeutic 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, treatment, and patient outcome over the last several years.

The EGFR is a member of the ErbB family of cell membrane 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 transmembrane domain involved in interactions between receptors within 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 include transforming growth factor {alpha} (TGF-{alpha}), amphiregulin, 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-{alpha}.

Dimer formation activates the intracellular tyrosine kinase (TK) domain. This triggers autophosphorylation of various tyrosine residues in the catalytic C-terminal domain of the TK. These phosphorylated tyrosine residues bind to recruitment proteins that serve as substrates for EGFR-mediated signal transduction. These link the EGFR to various downstream effector pathways such as the Ras–Raf–mitogen-activated protein kinase (MAPK) pathway, which activates cell proliferation, or the phosphatidylinositol-3'-kinase–Akt 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
Top
 Learning Objectives
 Abstract
 Introduction
 EGFR Inhibitors in NSCLC...
Erlotinib in NSCLC Treatment
 Combination Studies of Erlotinib...
 Clinical and Molecular...
 Future Development
 Disclosure of Potential...
 References
 
NSCLC is among the epithelial cancers that are characterized 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 premalignant lesions, suggesting that the EGFR-mediated pathway 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 inhibitors (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 active 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 administration, biodistribution, induction of EGFR downregulation, 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 approved 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 approved 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 continuing to benefit from treatment already initiated. Therefore, 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 October 2005, for the treatment of chemotherapy-resistant advanced NSCLC patients.


   ERLOTINIB IN NSCLC TREATMENT
Top
 Learning Objectives
 Abstract
 Introduction
 EGFR Inhibitors in NSCLC...
 Erlotinib in NSCLC Treatment
Combination Studies of Erlotinib...
 Clinical and Molecular...
 Future Development
 Disclosure of Potential...
 References
 
Phase I–II Studies
Erlotinib has dose-dependent pharmacokinetics. Daily dosing 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 advanced 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 prolonged stable disease (SD) in 22 patients (39%). The median survival time (MST) was 8.4 months. Lung cancer symptoms (fatigue, dyspnea, cough) improved with erlotinib 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 patients). 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 (including bronchioloalveolar carcinoma histology) and in nonsmokers. 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 erlotinib 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 population compares favorably with that seen in other studies performed in patients with NSCLC >70 years of age.

Phase III Studies
In advanced NSCLC, chemotherapy offers symptomatic relief 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 failure of second-line therapies [15]. To evaluate whether erlotinib 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 chemotherapy [16]. A total of 731 patients was randomized in a 2:1 ratio to receive either erlotinib at 150 mg/day or placebo. Those patients had metastatic NSCLC that had previously been treated with one standard chemotherapy regimen (50% of patients) or with two chemotherapy regimens (50% of patients). Almost all patients received platinum-based chemotherapy. The OR rate was 8.9% in the erlotinib arm and <1% 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% confidence interval [CI], 0.58–0.85). ORs were more frequent in women (14% versus 6%; p = .0065), in patients with adenocarcinoma, as compared with other histotypes (14% versus 4.1%; p <0.0001), 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 analyses showed that 44%, 34%, and 42% of patients receiving erlotinib had improvement in these three symptoms, respectively. This was accompanied by significantly greater improvements in physical function (31% for erlotinib versus 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 paclitaxel 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 patients 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 placebo (HR, 0.99; p = .95; 95% CI, 0.86–1.16); the OR rates were similar in the erlotinib and placebo arms (21.5% versus 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, respectively. Therefore, there was no clinical benefit in either trial, and currently concurrent use of erlotinib with chemotherapy 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 trials—Iressa NSCLC Trial Assessing Combination Therapy (INTACT)-1 (cisplatin plus gemcitabine) and INTACT-2 (carboplatin plus paclitaxel) [20, 21]. Table 1 summarizes the results of phase III trials employing erlotinib in the treatment of advanced NSCLC.


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  		Table 1. Phase III randomized trials with erlotinib in advanced non-small cell lung cancer

 

   COMBINATION STUDIES OF ERLOTINIB AND OTHER TARGETED AGENTS
Top
 Learning Objectives
 Abstract
 Introduction
 EGFR Inhibitors in NSCLC...
 Erlotinib in NSCLC Treatment
 Combination Studies of Erlotinib...
Clinical and Molecular...
 Future Development
 Disclosure of Potential...
 References
 
The 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 antiangiogenic 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 of combining erlotinib and bevacizumab therapy in patients with advanced nonsquamous NSCLC. Data on antitumor activity from 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 tolerated and active in NSCLC [23].

A phase II, multicenter, randomized clinical trial was conducted to evaluate the efficacy and safety of bevacizumab 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 placebo (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 patients 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 reported in this trial seem to favor the addition of bevacizumab 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 also active against VEGF-2, VEGF-3, and platelet-derived growth factor receptor, plus erlotinib has recently documented that this combination is feasible at the full recommended doses of both agents with acceptable toxicity [25]. In that study promising clinical activity was also observed in several tumor types.


   CLINICAL AND MOLECULAR PREDICTORS OF RESPONSE TO ERLOTINIB
Top
 Learning Objectives
 Abstract
 Introduction
 EGFR Inhibitors in NSCLC...
 Erlotinib in NSCLC Treatment
 Combination Studies of Erlotinib...
 Clinical and Molecular...
Future Development
 Disclosure of Potential...
 References
 
Clinical Predictors
In clinical trials with the other EGFR TKI, gefitinib, it was shown that the clinical benefit appears to be limited to a specific subgroup of patients, namely, women, never-smokers, patients with adenocarcinoma, and patients of Asian ethnicity. Smoking status seems to be the strongest predictor, with patients who are never-smokers having the greatest likelihood 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 effect 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 significantly 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 response to erlotinib in the BR.21 study, erlotinib had a significant effect on survival in all subgroups of patients [17]. In fact, even though male smokers with squamous cell carcinoma 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 patients with similar characteristics in the placebo arm (n = 57) (HR, 0.66; 95% CI, 0.47–0.92; p = .016). This difference 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 TRIBUTE 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 confer 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 after approximately 1 week of treatment and reaches a maximum intensity after 2–3 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 concentration of gefitinib compared with erlotinib when administered at the recommended doses of 250 mg/day and 150 mg/day, respectively. Data from phase I dose escalation 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 occurrence 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 trials, a subanalysis showed that patients who developed rash survived longer than those who did not. Finally, it was recently shown that susceptibility to rash and clinical activity of EGFR-targeting agents could be linked to polymorphic variations in the EGFR 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 [33–36]. Approximately 90% of EGFR gene mutations affect a small region of the gene within exons 18–24, which code for the TK domain. The more common mutations are an in-frame deletion in exon 19 around codons 746–750 (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. Somatic EGFR 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 subpopulation 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 analyzed in the search for EGFR gene mutations. Of 731 patients 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 mutations were either deletions in exon 19 or the exon 21 L858R mutation, whereas 24 were novel mutations. Patients 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, 0.26–1.75) or in patients with novel mutations (p = .41; HR, 0.67; 95% CI, 0.6–1.75) [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 mutations 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 tumor activation profiles that lead to variations in both the natural history and clinical course after treatment with erlotinib or gefitinib. The relationship between the two most common types of somatic EGFR mutations has been evaluated.

Emerging data suggest that patients with NSCLC and EGFR exon 19 deletion have a longer survival time following 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 associated 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 a slightly shorter survival time than FISH-negative patients randomized to placebo [41, 43]. In the BR.21 trial, FISH-positive patients (approximately 40%) randomized to receive 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 [44–46], suggesting that the mutant allele of the EGFR gene is selectively amplified in tumors, as has been observed in EGFR-mutant NSCLC cell lines [47].

High levels of EGFR protein expression, as determined by immunohistochemistry (IHC), were associated with response 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 signal–related kinase (ERK)-1, and ERK-2 are able to regulate gene transcription, and play an important role in cell proliferation, survival, and transformation [5, 6]. Approximately 15%–30% of lung adenocarcinomas contain activating mutations in the ras family member. EGFR mutations are common 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 history 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 associated with resistance to EGFR TKIs in NSCLC. Sixty tumor specimens obtained from lung adenocarcinoma patients, which were shown to be sensitive or refractory to single-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 mutations, 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 x 10–11). All 17 tumors with EGFR mutations responded to gefitinib or erlotinib, while all nine tumors with K-ras mutations did not (p = 3.2 x 10–7) [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 patients with known K-ras genotype, the HR in the erlotinib arm was 0.77 (95% CI, 0.57–1.06; p = .06). For the 176 K-ras wild-type patients, the univariate HR for erlotinib treatment was 0.69 (95% CI, 0.49–0.97; p = .03). In contrast, the HR for the 30 K-ras mutant patients was 1.67 (95% CI, 0.62–4.5; 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 patients with known K-ras genotype, the multivariate Cox regression 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 results need to be confirmed in other larger studies. The presence of a K-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 sensitizing EGFR 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]. The most well studied of such EGFR mutations occurs in exon 20. Acquired mutations in exon 20 of the EGFR gene change conformation of the receptor and block binding of gefitinib or erlotinib to the active site creating resistance to these EGFR TKIs.

One study described the occurrence of a secondary mutation in a patient with NSCLC following successful gefitinib treatment [55]. While the first mutation, a deletion in exon 19, conferred sensitivity to the treatment, a second point mutation in exon 20, leading to a threonine 790->methionine substitution, induced resistance to several EGFR inhibitors.

Another group identified the same threonine 790->methionine mutation in two of five patients with acquired resistance to gefitinib or erlotinib, and in a sixth patient whose tumor progressed when treated with adjuvant gefitinib after complete resection. The mutation could not be detected in untreated tumor samples [54].

Interestingly, the EGFR protein bearing the second mutation was sensitive to CL-387,785, a specific and irreversible anilinoquinazoline EGFR TKI, suggesting that second-generation EGFR TKIs might have a role in the treatment of NSCLC. In this respect, screening for agents that could 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
Top
 Learning Objectives
 Abstract
 Introduction
 EGFR Inhibitors in NSCLC...
 Erlotinib in NSCLC Treatment
 Combination Studies of Erlotinib...
 Clinical and Molecular...
 Future Development
Disclosure of Potential...
 References
 
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 advanced disease, and in combination and/or sequence with cytotoxic treatments and/or other molecular-targeted agents. Table 2 summarizes a series of ongoing phase II and III studies. Among these, an Italian–Canadian trial, Tarceva® OR Chemotherapy (TORCH), appears particularly interesting. The design of this phase III randomized, multicenter trial is based on a noninferiority survival comparison between an experimental strategy including first-line erlotinib followed at progression by chemotherapy with cisplatin and gemcitabine (PG) and a standard arm consisting of first-line PG chemotherapy followed at progression by erlotinib. Moreover, this trial will allow the evaluation of the relationship between molecular predictors, such as EGFR and K-ras mutational status, and erlotinib treatment response. The aim of the TORCH study is to evaluate, in a randomized fashion, what is the most appropriate and cost-effective sequential approach for erlotinib and chemotherapy in an unselected population of metastatic NSCLC patients.


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  		Table 2. Ongoing phase II and III studies employing erlotinib in the treatment of NSCLC

 
Another possible approach to improving clinical outcome in the metastatic setting is multitargeted inhibition that combines blockade of angiogenesis, Ras–Raf–ERK, 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 clinical 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 erlotinib treatment by clarifying the relationship between EGFR expression and response to treatment, and to define the predictive potential of EGFR mutation expression and EGFR copy number for response to erlotinib.


   DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
Top
 Learning Objectives
 Abstract
 Introduction
 EGFR Inhibitors in NSCLC...
 Erlotinib in NSCLC Treatment
 Combination Studies of Erlotinib...
 Clinical and Molecular...
 Future Development
 Disclosure of Potential...
References
 
C.G. and F.C. have acted as consultants for and have financial interests in Roche. P.M. has acted as a consultant for Roche.


   REFERENCES
Top
 Learning Objectives
 Abstract
 Introduction
 EGFR Inhibitors in NSCLC...
 Erlotinib in NSCLC Treatment
 Combination Studies of Erlotinib...
 Clinical and Molecular...
 Future Development
 Disclosure of Potential...
 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 results. J Clin Oncol 2001;19:1734–1742.[Abstract/Free Full Text]
  2. Schiller JH, Harrington D, Belani CP et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002;346:92–98.[Abstract/Free Full Text]
  3. Normanno N, Bianco C, De Luca A et al. Target-based agents against ErbB receptors and their ligands: A novel approach to cancer treatment. Endocr Relat Cancer 2003;10:1–21.[Abstract]
  4. Mendelsohn J. Blockade of receptors for growth factor: An anticancer therapy – the fourth annual Joseph H Burchenal American Association of Cancer Research Clinical Research Award Lecture. Clin Cancer Res 2000;6:747–753.[Free Full Text]
  5. Olayioye MA, Neve RM, Lane HA et al. The ErbB signaling network: Receptor heterodimerization in development and cancer. EMBO J 2000;19:3159–3167.[CrossRef][Medline]
  6. Yarden Y, Sliwkowski MX. Untangling the ErbB signaling network. Nature Rev Mol Cell Biol 2001;2:127–137.[CrossRef][Medline]
  7. Kurie JM, Shin HJ, Lee JS et al. Increased epidermal growth factor receptor expression in metaplastic bronchial epithelium. Clin Cancer Res 1996;2:1787–1793.[Abstract]
  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 patients with advanced solid malignancies. J Clin Oncol 2001;19:3267–3279.[Abstract/Free Full Text]
  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;22:3238–3247.[Abstract/Free Full Text]
  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.[Abstract/Free Full Text]
  11. Jackman DM, Yeap BY, Lindeman NI et al. Phase II clinical trial of chemotherapy-naïve patients ≥ 70 years of age treated with erlotinib for advanced non-small-cell lung cancer. J Clin Oncol 2007;25:760–766.[Abstract/Free Full Text]
  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 Oncol 2000;18:2095–2103.[Abstract/Free Full Text]
  13. Fossella FV, DeVore R, Kerr RN et al. Randomized phase III trial of docetaxel 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 Cell Lung Cancer Study Group. J Clin Oncol 2000;18:2354–2362.[Abstract/Free Full Text]
  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;22:1589–1597.[Abstract/Free Full Text]
  15. Massarelli E, Andre F, Liu DD et al. A retrospective analysis of the outcome of patients who have received two prior chemotherapy regimens including platinum and docetaxel for recurrent non-small-cell lung cancer. Lung Cancer 2003;39:55–61.[CrossRef][Medline]
  16. Shepherd FA, Rodrigues Pereira J, Ciuleanu T et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005;353:123–132.[Abstract/Free Full Text]
  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 Cancer Institute of Canada Clinical Trials Group Study BR.21. J Clin Oncol 2006;24:3831–3837.[Abstract/Free Full Text]
  18. Herbst RS, Prager D, Hermann R et al. TRIBUTE: A phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol 2005;23:5892–5899.[Abstract/Free Full Text]
  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 advanced 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 trial–INTACT 1. J Clin Oncol 2004;22:777–784.[Abstract/Free Full Text]
  21. Herbst RS, Giaccone G, Schiller JH et al. Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: A phase III trial–INTACT 2. J Clin Oncol 2004;22:785–794.[Abstract/Free Full Text]
  22. Ciardiello F, Bianco R, Damiano V et al. Antiangiogenic and antitumor activity of anti-epidermal growth factor receptor C225 monoclonal antibody in combination with vascular endothelial growth factor antisense oligonucleotide in human GEO colon cancer cells. Clin Cancer Res 2000;6:3739–3747.[Abstract/Free Full Text]
  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;23:2544–2555.[Abstract/Free Full Text]
  24. Fehrenbacher L, O' Neill V, Belani CP et al. A phase II, multicenter, randomized clinical trial to evaluate the efficacy and safety of bevacizumab in combination with either chemotherapy (docetaxel or pemetrexed) or erlotinib hydrochloride compared with chemotherapy alone for treatment of recurrent or refractory non small cell lung cancer. J Clin Oncol 2006;24(suppl 18):379s.[CrossRef]
  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 erlotinib (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;22:1103–1109.[Abstract/Free Full Text]
  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;366:1527–1537.[CrossRef][Medline]
  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;23:5235–5246.[Abstract/Free Full Text]
  30. Roskos L, Lohner M, Osborn K et al. Low pharmacokinetic variability facilitates 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 erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent or metastatic squamous cell cancer of the head and neck. J Clin Oncol 2004;22:77–85.[Abstract/Free Full Text]
  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;64:9139–9143.[Abstract/Free Full Text]
  33. Lynch TJ, Bell DW, Sordella R et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350:2129–2139.[Abstract/Free Full Text]
  34. Paez JG, Janne PA, Lee JC et al. EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy. Science 2004;304:1497–1500.[Abstract/Free Full Text]
  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;97:339–346.[Abstract/Free Full Text]
  36. Janne PA, Engelman JA, Johnson BE. Epidermal growth factor receptor mutations in non-small-cell lung cancer: Implications for treatment and tumor biology. J Clin Oncol 2005;23:3227–3234.[Abstract/Free Full Text]
  37. Giaccone G. Epidermal growth factor receptor inhibitors in the treatment of non-small-cell lung cancer. J Clin Oncol 2005;23:3235–3242.[Abstract/Free Full Text]
  38. Tsao MS, Sakurada A, Cutz JC et al. Erlotinib in lung cancer: Molecular and clinical predictors of outcome. N Engl J Med 2005;353:133–144.[Abstract/Free Full Text]
  39. Gandara DR, Gumerlock PH. Epidermal growth factor receptor tyrosine kinase inhibitors plus chemotherapy: Case closed or is the jury still out? J Clin Oncol 2005;23:5856–5858.[Free Full Text]
  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;12:3908–3914.[Abstract/Free Full Text]
  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 number and protein expression and impact on prognosis. J Clin Oncol 2003;21:3798–3807.[Abstract/Free Full Text]
  42. Dziadziuszko R, Holm B, Skov B et al. Epidermal growth factor receptor gene copy number and protein level are not associated with outcome of non-small-cell lung cancer patients treated with chemotherapy. Ann Oncol 2007;18:447–452.[Abstract/Free Full Text]
  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;24:5034–5042.[Abstract/Free Full Text]
  44. Takano T, Ohe Y, Sakamoto H et al. Epidermal growth factor receptor gene mutations and increased copy numbers predict gefitinib sensitivity in patients with recurrent non-small-cell lung cancer. J Clin Oncol 2005;23:6829–6837.[Abstract/Free Full Text]
  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;97:643–655.[Abstract/Free Full Text]
  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;65:226–235.[Abstract/Free Full Text]
  47. Tracy S, Mukohara T, Hansen M et al. Gefitinib induces apoptosis in the EGFRL858R non-small-cell lung cancer cell line H3255. Cancer Res 2004;64:7241–7244.[Abstract/Free Full Text]
  48. Pao W, Miller V, Zakowski M et al. EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A 2004;101:13306–13311.[Abstract/Free Full Text]
  49. Ahrendt SA, Decker PA, Alawi EA et al. Cigarette smoking is strongly associated with mutation of the K-ras gene in patients with primary adenocarcinoma of the lung. Cancer 2001;92:1525–1530.[CrossRef][Medline]
  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;48:5738–5741.
  51. Suzuki Y, Orita M, Shiraishi M et al. Detection of ras gene mutations in human lung cancers by single-strand conformation polymorphism analysis of polymerase chain reaction products. Oncogene 1990;5:1037–1043.[Medline]
  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.[CrossRef][Medline]
  53. Tsao M, Zhu C, Sakurada A et al. An analysis of the prognostic and predictive importance of K-ras mutation status in the National Cancer 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 adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2005;2:e73.[CrossRef][Medline]
  55. Kobayashi S, Boggon TJ, Dayaram T et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 2005;352:786–792.[Abstract/Free Full Text]
  56. Carter TA, Wodicka LM, Shah NP et al. Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases. Proc Natl Acad Sci U S A 2005;102:11011–11016.[Abstract/Free Full Text]



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