EGFR-directed therapies to treat non-small-cell lung cancer

Review

10.1517/13543780903066772 © 2009 Informa UK Ltd ISSN 1354-3784 1133All rights reserved: reproduction in whole or in part not permitted

EGFR-directedtherapiestotreatnon-small-celllungcancerCheryl Ho† & Janessa LaskinBritish Columbia Cancer Agency, Medical Oncologist, 600 W 10th Avenue, Vancouver, BC V5Z 4E6, Canada

Lung cancer is the leading cause of cancer death in men and women. In 2008, in the US > 200,000 patients were diagnosed with lung cancer and > 160,000 died from their disease. Over 80% of lung cancers are of the non-small cell type, for which chemotherapy has demonstrated modest survival benefits at all stages of disease. Agents that alter critical molecular cell growth pathways are a growing area of research and development includ-ing targeted therapies directed at the EGFR. Downstream effects of EGFR dimerization and activation include cell proliferation, differentiation and angiogenesis, key events in the malignant process. Two main classes of drugs have been developed, small molecule tyrosine kinase inhibitors (TKIs) and monoclonal antibodies directed against the extracellular domain of the receptor. This review discusses clinical studies with several new therapies and the plans for drug development.

Keywords: EGFR, monoclonal antibody, predictive marker, tyrosine kinase inhibitor

Expert Opin. Investig. Drugs (2009) 18(8):1133-1145

1. ThebiologyoftheEGFR

EGFR has been identified as an important therapeutic target in the treatment of NSCLC. EGFR (HER1) is a member of the HER/erbB family of transmembrane receptors that include HER2/neu, HER3 and HER4. (Figure 1) [2,3]. These receptors are characterized by a ligand binding N-terminal extracellular domain, hydrophobic transmembrane domain and a tyrosine kinase (TK) cytoplasmic domain. Located on chromosome 7p22-p12, EGFR is a 170 kDa membrane protein. Known ligands include EGF, TGF-α, amphiregulin, β-cellulin, epiregulin and heparin-binding EGF-like growth factor. Ligand binding results in receptor homo or hetero-dimerization, auto-phosphorylation of the TK domain and downstream signaling.

EGFR serves an important role in day to day cellular function; however, deregulation can result in malignant transformation. GFR TKs can become onco-genic by several different mechanisms: overexpression of receptor ligand, muta-tional activation of receptor, overexpression of receptor or transactivation by other receptor or non-receptor TKs. EGFR deregulation leads to a signaling cascade promoting cell proliferation and survival.

EGFR signals through several downstream pathways including ras/raf/MAPK, phospholipase C, PI3-K/Akt and JAK/STAT (signal transducers and activators of transcription; Figure 2) [4]. Ras is a signal transduction G protein that transmits information from cell surface receptors to the nucleus. On activation, ras releases GDP and binds GTP, which then initiates a cascade of cell signaling through MEK/MAPK. Ras activation leads to phosphorylation of nuclear transcription factors and cellular survival and proliferation. PTEN (phosphatase and tensin homologue) is a negative regulator of the ras pathway. Phospholipase C activates PKC which, like ras, leads to activation of the MEK/MAPK pathway and cell proliferation. PI3K and Akt are involved in the cell survival/apoptosis pathway. Activation of these proteins leads to cell survival through expression of antiapoptotic proteins

1. The biology of the EGFR

2. EGFR targeted agents: TKIs and

monoclonal antibodies

3. Predictive markers for anti-EGFR

therapy

4. Targeting EGFR: TKIs

5. Targeting EGFR: monoclonal

antibodies

6. Summary

7. Expert opinion

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EGFR-directedtherapiestotreatnon-small-celllungcancer

1134 ExpertOpin.Investig.Drugs(2009) 18(8)

TKI

Proliferation Invasion Inhibition ofapoptosis

Metastasis Angiogenesis

Monoclonalantibody

Figure1.TheEGFRandinhibitionstrategies.

EGF

Ras PI3K Jak PLC

AKTRaf

MAPK

PKC

PKC

STAT

EGF receptor

NF-κB

Survival

Cell cycle progression

Survival

Proliferation

Figure2.TheEGFRsignalingpathway.

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ExpertOpin.Investig.Drugs(2009) 18(8) 1135

such as Bcl-XL, caspase inhibitors and mTOR (mammalian target of rapamycin). JAK/STAT stimulates transcription of nuclear factors that promote cell survival. Transcription of target genes by aberrant EGFR signaling leads to cell proliferation, evasion of apoptosis, invasion and angiogenesis promoting tumor growth and metastasis.

An understanding of EGFR as an oncogene and the pathways that it triggers facilitates targeted drug develop-ment. TKIs block ligand-independent catalytic activity of EGFR. Antibodies directed against the extracellular domain of EGFR inhibit ligand binding and receptor dimerization. Downstream activators of this pathway have also been the focus of drug development including agents directed against ras, Akt, PTEN and mTOR. Research activity in this area may lead to more treatment options for a difficult disease.

2. EGFRtargetedagents:TKIsandmonoclonalantibodies

EGFR TKIs are small molecules that traverse the cellular membrane and bind the ATP binding site on the receptor. This prevents phosphorylation of downstream targets and blocks the signaling pathway. Blockade of EGFR at this level causes G1 cell cycle arrest. Two agents have been well developed in NSCLC, gefitinib and erlotinib. Other agents are currently being investigated and include BIBW 2992, canertinib, EKB 569, lapatinib, neratinib and XL 647.

Monoclonal antibodies directed against EGFR prevent ligand binding to the receptor, prevent receptor dimerization and induce receptor degradation. In addition to inhibiting the signaling of EGFR, monoclonal antibodies also activate immune mechanisms including antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity and complement-dependent cell mediated cytotoxicity. Cetuximab has undergone the most clinical evaluation in NSCLC. Other antibodies that target EGFR are also being explored in lung cancer including matuzumab, nimotuzumab, panitumumab, pertuzumab and zalutumumab. The focus of this review is to discuss therapeutic advances made in targeting EGFR.

3. Predictivemarkersforanti-EGFRtherapy

With the development of EGFR targeted therapy, the iden-tification of predictive markers for outcomes has become increasingly important. Most work has been concentrated on EGFR TKIs. Several potential markers have been explored including EGFR mutations, immunohistochemis-try, overexpression by fluorescence in situ hybridization (FISH) and k-ras mutations among others. So far, no marker has been consistent or common enough to be a clinically useful predictor of response and none is used to direct therapeutic choices outside of a clinical trial. EGFR mutations have been recognized as a positive predictive marker; however, these are only found in 20% of patients.

Many biomarker studies are underway and it is hoped that a marker or perhaps a cluster of markers will soon be identified.

In early studies with EGFR TKIs, it was recognized that certain clinical characteristics predicted for response: female gender, adenocarcinoma, never or light smoking history and Asian ethnicity. Dramatic responses were seen in this popu-lation prompting a search for an associated biological marker. Two groups simultaneously identified mutations in the ATP binding cleft of the EGFR sequence (exons 18 – 21) that correlated with this clinical response [5,6]. These mutations result in a constitutively active receptor, a perfect target for drug therapy. The most frequently found EGFR mutations were deletions in exon 19 and L858R (leucine to arginine) in exon 21, the former being associated with better response and survival compared to other mutations (Table 1) [7]. EGFR mutations are felt to be both prognostic and predic-tive; patients with the mutation live longer in comparison to those who do not and mutations are predictive of response to EGFR TKIs. It seems that these mutations are more common in Asian populations, in part explaining why the response rate to EGFR TKIs is higher in this group. A resis-tance mutation to EGFR TKIs has also been identified, T790M (threonine to methionine) [8,9]. This mutation in exon 20 probably modifies the structure of the TK domain such that EGFR TKIs are no longer able to bind and inhibit pathway signaling.

EGFR expression by immunohistochemistry has been explored as a potential marker for EGFR TKI therapy. Sev-eral retrospective studies have attempted to establish a link between protein expression and drug response with conflict-ing results [10-15]. Possible explanations include differences in technique and/or the fact that most of these studies have been done retrospectively and the use of archival tissue that may not reflect the status of the tumor at progression. A lack of consistent association with treatment outcomes renders immunohistochemistry a less useful tool in therapy decision making.

EGFR gene copy number by FISH holds more promise as a predictive indicator for EGFR TKIs and monoclonal antibodies. The generally accepted definition of EGFR FISH-positive status is high polysomy (≥ 4 copies in ≥ 40% of cells) or gene amplification (presence of tight gene clus-ters, a gene:chromosome ratio of per cell of ≥ 2 or ≥ 15 copies of EGFR per cell in ≥ 10% of cells analyzed) [12]. Retrospective studies have shown a more consistent associa-tion with improved survival and EGFR FISH-positive status than other markers. In both BR21 and Iressa Survival Evalu-ation in Lung cancer (ISEL), Phase III trials of erlotinib and gefitinib, respectively, versus placebo, FISH-positive patients treated with the EGFR TKI had higher response rates and survival compared to FISH-positive patients who receive placebo [11,16]. In contrast, FISH-negative patients did not achieve a benefit with the drug compared to placebo. Prospective studies need to be conducted, however; high

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EGFR copy number may be useful to identify a subpopula-tion of patients who would benefit from EGFR TKIs. The utility of EGFR FISH for predicting outcomes with mono-clonal antibodies has been evaluated in a retrospective fash-ion. Hirsch et al. performed EGFR gene copy number analysis by FISH on tissue samples from patients with advanced NSCLC enrolled on a Phase II selection trial eval-uating sequential or concurrent chemotherapy (carboplatin/pacli-taxel) with cetuximab [17]. Of 229 patients, 76 had accessible, suitable tumor tissue. The response rate tended towards improvement in FISH-positive versus -negative patients and the disease control rate was statistically significantly better (81 versus 55%, p = 0.02). Progression-free survival (PFS) and overall survival favored the FISH-positive group. This suggests a correlation between FISH status and benefit from EGFR monoclonal antibody therapy. In contrast, data from a Phase I/II study of matuzumab and paclitaxel did not dem-onstrate a correlation between response and FISH amplifica-tion, among other markers; however, this exploratory analysis may have been hampered by small numbers (n = 14) [18]. Similar to the TKIs, EGFR FISH evaluation holds promise as a predictive marker for monoclonal antibody therapy; however, prospective assessment is needed.

K-ras mutations have been associated with resistance to EGFR TKIs. As k-ras is downstream in the EGFR signaling cascade, it can independently activate mechanisms that pro-mote cell proliferation and survival. Mutations in codon 12 and 13 prevent the GTPase-activating proteins from acting on GTPase, thus, blocking GTP hydrolysis, resulting in a constitutively “on” protein. K-ras mutations are primarily found in adenocarcinomas but overall ∼ 30% of NSCLC have a k-ras mutation. Of interest, it seems that k-ras and EGFR mutations are mutually exclusive, which may suggest that these cancers evolved through independent biological pathways. A meta-analysis of 17 studies of k-ras in NSCLC found that k-ras mutations were highly specific negative pre-dictors of response to single agent EGFR TKIs [19]. However, analysis of k-ras mutations and survival do not demonstrate

Table1.EGFRmutations.

Mutation Frequency

Associatedwithresponse

Exon 19 deletion 44%

Exon 21 L585R 41%

Exon 18-21 rare missense mutations

6%

Exon 20 insertion 5%

Exon 18 G719A/C or S 4%

Associated with resistance

T790M -

Adapted from [7].

the same trend; k-ras mutations do not seem to impact sur-vival outcomes in EGFR TKI treated patients. While this marker is helpful for guiding EGFR targeted monoclonal antibody-based therapy in other disease sites such as colorectal cancer, the utility of k-ras in NSCLC remains to be seen.

The field of biological predictive markers is young. With the increasing number of treatment options for NSCLC, intense research is being focused in this area to provide patients with the best treatment options and to spare them unnecessary toxicity.

4. TargetingEGFR:TKIs

4.1 ErlotinibErlotinib is an oral, reversible and selective EGFR TKI. It received FDA approval based on the National Cancer Institute of Canada trial, BR21, a Phase III trial of erlotinib in second- and third-line stage IIIB or IV NSCLC patients (Table 2) [20]. Over 700 patients were randomized in a 2:1 fashion to erlotinib 150 mg orally daily or placebo. Patient characteristics were median age 62 years, 65% male, adeno-carcinoma was the dominant pathological subtype and 50% of the patients had one previous line of therapy. The response rate with erlotinib was low, 8.9%; however, the disease con-trol rate (complete response + partial response + stable disease) was 45%. BR21 demonstrated a significant improve-ment in overall survival; erlotinib 6.7 months compared to placebo 4.7 months (p < 0.0001). Quality of life studies also indicated an improvement in the median time to deteriora-tion with cough, dyspnea and pain. Based on these data, erlotinib received FDA approval and exploration of its use in other clinical settings began.

In first-line metastatic disease, erlotinib has been evalu-ated in combination with chemotherapy. Erlotinib or placebo was administered concurrently with cisplatin/gem-citabine or carboplatin/paclitaxel in TALENT and TRIB-UTE, respectively [21,22]. These large Phase III trials failed to demonstrate a survival advantage of erlotinib with chemo-therapy over chemotherapy alone. Hypotheses to explain this finding include lack of patient selection and potential antagonistic effects of concurrent EGFR TKIs and chemotherapy with respect to cell cycle targeting.

The role of single agent erlotinib in the first-line setting is being tested in Tarceva OR Chemotherapy trial (TORCH) [23]. This non-inferiority trial randomizes patients to first-line erlotinib followed at progression by cisplatin/gemcitabine versus the current standard treatment sequence, cisplatin/gemcitabine followed by erlotinib at progression. This international trial is actively accruing and will be instrumental in determining the optimum sequence of treatment in advanced NSCLC.

Previous studies of chemotherapy in advanced disease have indicated that maintenance chemotherapy may improve PFS but has no impact on overall survival. However, with the availability of less toxic, well-tolerated agents such as EGFR TKIs, this option has been revisited. SATURN is a

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Table2.PhaseIIItrialsinvolvingEGFRTKIs.

Treatmentsetting

Drug Trial Outcome/questionbeingaddressed

StageI–III

Adjuvant Erlotinib RADIANT Does adjuvant erlotinib improve DFS after surgical resection?

Gefitinib BR 19 Does adjuvant gefitinib improve OS and DFS after surgical resection? Study terminated before completion due to concerns in BR15 about gefitinib toxicity

StageIII

Maintenance Erlotinib Dartmouth Hitchcock

Does erlotinib improve PFS after combined chemoradiotherapy and consolidation chemotherapy for stage III disease?

Gefitinib BR15 Study closed early owing to interim analysis that demonstrated an HR for death of 0.63 in favor of the placebo. Decreased survival analysis demonstrated that it was due to death not toxicity, reason for imbalance unknown

StageIV

First line Erlotinib TALENT/TRIBUTE No survival benefit for erlotinib in combination with carboplatin/paclitaxel or cisplatin/gemcitabine

TORCH Is first-line erlotinib followed by cisplatin/gemcitabine at progression non-inferior to cisplatin/gemcitabine followed by erlotinib at progression?

Gefitinib INTACT 1 and 2 No survival benefit for gefitinib in combination with carboplatin/paclitaxel or cisplatin/gemcitabine

IPASS Gefitinib improved PFS (HR 0.741) compared to carboplatin/paclitaxel in an Asian clinically selected population (adenoca, never or light smokers) in the first-line setting. OS was similar in both groups

Maintenance Erlotinib SATURN Maintenance erlotinib following platinum doublet therapy improves PFS in all patients and EGFR IHC + patients

Gefitinib WJTOG 0203 OS was not improved with addition of maintenance gefitinib after 3 cycles of chemotherapy compared to 3 – 6 cycles of chemotherapy alone. In pre-planned subgroup analysis of patients with adenocarcinoma, OS was improved with gefitinib

Second line Erlotinib BR 21 Erlotinib results in a 2-month improvement in OS compared to placebo

TITAN Does erlotinib improve OS compared to pemetrexed or docetaxel as a second-line treatment?

BETA The addition of bevacizumab to second-line erlotinib does not improve OS

Gefitinib ISEL Gefitinib did not improve survival compared to placebo in patients with refractory (progressed in 3 months of first-line chemotherapy) NSCLC

INTEREST Gefitinib was non-inferior to docetaxel with respect to OS in a global population

V15-32 Gefitinib did not improve OS compared to docetaxel in a Japanese patient population

DFS: Disease-free survival; HR: Hazard ratio; IHC: Immunohistochemistry; OS: Overall survival; PFS: Progression-free survival; TKI: Tyrosine kinase inhibitor.

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placebo-controlled, randomized, double-blind, study that enrolled 889 patients with advanced NSCLC [24]. Treatment with at least four cycles of standard first-line platinum-based chemotherapy was followed by randomization to Tarceva or placebo if there was no evidence of progression. The study met its primary end point of improving PFS. The full data from this study are anticipated in 2009. A second study will compare maintenance chemotherapy with single-agent gem-citabine to sequential treatment with erlotinib given imme-diately after the end of first-line chemotherapy [25]. A third trial, ATLAS, randomizes patients without progression after treatment with at least four cycles of first-line platinum che-motherapy with bevacizumab to bevacizumab/placebo or bevacizumab/erlotinib until progressive disease [26]. This study has completed accrual but is continuing with a pro-jected date of presentation in 2009. The role of bevacizumab with first-line platinum chemotherapy in metastatic NSCLC remains controversial in light of the conflicting results of ECOG 4599, which demonstrated a survival benefit and AVastin in Lung trial (AVAIL), which did not [27,28]. It will be interesting to contrast the results of SATURN and ATLAS to assess the influence of bevacizumab on outcomes.

Erlotinib is an accepted standard of care for second- and third-line NSCLC. However, currently there is an open-label randomized study being conducted to evaluate the effect of erlotinib on survival compared to standard chemotherapy (pemetrexed or docetaxel) in patients with advanced, recur-rent or metastatic NSCLC experiencing disease progression after failure of platinum-based chemotherapy (TITAN) [29]. This trial will help determine whether erlotinib or chemo-therapy is preferable in the second-line setting. Patients are currently enrolling and completion is anticipated in 2014. Second-line erlotinib has also been evaluated with bevaci-zumab in the Bevacizumab and Tarceva trial (BETA) [30]. Patients were randomized to erlotinib +/- bevacizumab. The primary end point, median survival, was similar in both groups. PFS and response rate were improved with the addition of bevacizumab and continuing analyses evaluate the impact of subsequent therapies on the results.

Erlotinib has been evaluated in early stage NSCLC. RADI-ANT is a study of erlotinib after surgery with or without adjuvant chemotherapy in NSCLC patients who have EGFR-positive tumors [31]. This Phase III trial opened in September 2006 and is currently enrolling patients. Patients must have completely resected NSCLC, up to four cycles of adjuvant chemotherapy and EGFR positivity by immunohistochemis-try or FISH. Patients will receive erlotinib or placebo for a 2 year period. The primary end point of this trial is disease free survival with results anticipated in the fall of 2009.

In stage III NSCLC, the Dartmouth-Hitchcock Medical Center is conducting a national, randomized, double-blind study to determine whether 5 years of erlotinib compared to placebo improves PFS for patients following concurrent doc-etaxel, carboplatin and thoracic radiotherapy [32]. The hypothesis is that the introduction of erlotinib following concurrent

chemoradiation and before the emergence of drug resistance will prolong the PFS by 40% from 10 months to 14 months. The concurrent chemotherapy backbone selected for this trial is not the most commonly used combination. Nonetheless, the question of erlotinib maintenance in stage III disease remains interesting particularly in light of the results from SATURN (as above).

4.2 GefitinibGefitinib received accelerated FDA approval in 2003 on the basis of Phase II data from Iressa Dose Evaluation in Advanced Lung cancer (IDEAL) 1 and 2 trials [33-35]. These trials, conducted in Asia and the US respectively, enrolled > 400 patients who failed first- or second-line chemotherapy. A response rate ranging from 9 to 19% was observed and based on the clinical benefit, the FDA recommended approval for single agent treatment for patients with advanced NSCLC whose cancer has continued to progress despite treatment with platinum-based and docetaxel che-motherapy. This approval, however, was contingent on the post marketing study commitments to complete several trials including the Iressa Survival Evaluation in Lung cancer trial (ISEL) [16]. A randomized Phase III survival study, ISEL compared gefitinib plus best supportive care versus placebo plus best supportive care in subjects with advanced NSCLC who have received one or two previous regimens and were refractory (progressed in 3 months of first-line therapy) or intolerant to their most recent regimen. The results of this study were surprisingly negative; there was no improvement in survival (5.6 versus 5.1 months) in the overall population or in the patients with adenocarcinoma (6.3 versus 5.4 months). Issues have been raised regarding the dose of gefi-tinib used (250 versus 500 mg) and the refractory patient population selected, which may have negatively affected the study outcome. The FDA indication for gefitinib changed to reflect this data and was restricted to patients who were currently or previously on the agent and achieving a benefit. In spite of the turn of events, gefitinib was felt to be active in NSCLC and continued to be tested in several settings.

In stage IV disease, gefitinib was evaluated as a front-line therapy in combination with chemotherapy in two large Phase III trials, INTACT 1 and 2 [36,37]. Gefitinib was com-bined with carboplatin/paclitaxel and cisplatin/gemcitabine, respectively. There was no survival advantage to concurrent EFGR TKI and chemotherapy, similar to the results found with erlotinib in TALENT and TRIBUTE.

Gefitinib as a single agent first-line treatment was evaluated in Iressa Pan ASia study (IPASS), a Phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected chemo-naive patients with advanced NSCLC [38]. Conducted in nine countries in Asia, enrollment criteria required adenocarcinoma histology and never smoker (< 100 cigarettes in lifetime) or light ex-smoker status (stopped ≥ 15 years ago and smoked ≤ 10 pack years). The intention was to select for clinical features that predict

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a response to EGFR TKIs. The study was designed to dem-onstrate non-inferiority; however, it exceeded expectations with a statistically significant improvement in PFS with gefi-tinib (hazard ratio; HR 0.741, p < 0.0001). The overall survival was not different and this may be influenced by second- and third-line treatments. EGFR mutational analy-sis was conducted in > 400 of the 1217 patients enrolled in the trial and correlated with outcomes. Over 59% of patients had an EGFR mutation, probably because of their selec-tion criteria. EGFR mutation-positive patients treated with gefitinib had an improvement in PFS compared to those treated with chemotherapy. In contrast, EGFR mutation-negative patients had an improvement in PFS with che-motherapy compared to gefitinib. The investigators noted that in the whole patient population, the PFS effect was not constant over time, initially favoring carboplatin/paclitaxel and then favoring gefitinib, potentially driven by differences in PFS outcomes for patients with EGFR muta-tion-positive (gefitinib benefit) and -negative (carboplatin/paclitaxel benefit) tumors. The results of this trial were very encouraging; however, the impact on North American clini-cal practice remains to be seen.

Maintenance gefitinib in advanced NSCLC was assessed in the West Japan Thoracic Oncology Group trial 0203 [39]. Over 600 patients were randomized to six cycles of platinum doublet chemotherapy or three cycles of platinum doublet chemotherapy followed by gefitinib until progressive disease. The chemotherapy options included carboplatin/paclitaxel or cisplatin plus a second drug: irinotecan, vinorelbine, doc-etaxel or gemcitabine. The primary end point, overall sur-vival, was not met (HR 0.86, p = 0.10), although it did demonstrate a trend towards improvement with gefitinib. A pre-planned subset analysis in patients with adenocarcinoma showed that a platinum doublet with maintenance gefitinib had a statistically superior overall survival time. Similar to the Iressa Pan ASia study, the results are difficult to translate into a non-Asian population but raise important questions regarding potential treatment options. The European Organi-zation for Research and Treatment of Cancer trial 08021 looked at a similar question and compared overall survival of patients with advanced NSCLC who did not progress on previous first-line palliative induction chemotherapy when treated with maintenance gefitinib versus placebo [40]. This trial opened in 2004 and closed in the summer of 2008 enrolling > 500 patients with results pending.

In North America, gefitinib’s indication in second- and third-line treatments was removed after the results of ISEL; however, two key studies were subsequently conducted in this setting. Both compared gefitinib to docetaxel, a standard second-line option in advanced NSCLC. The V-15-32 study conducted in Japan compared gefitinib 250 mg daily to doc-etaxel 60 mg/m2 on day 1 every 21 days in > 480 patients [41]. The primary objective, to demonstrate overall survival non-inferiority for gefitinib relative to docetaxel, was not met. The HR was 1.12 (95% CI, 0.89 – 1.40); however, no significant

difference in overall survival (p = 0.330) was apparent between treatments. Subsequent treatments may have affected the out-come as only 36% of gefitinib treated patients went on to receive docetaxel whereas 53% of docetaxel patients received gefitinib. The second trial, INTEREST, was a global study conducted in patients who were predominantly non-Asian [42]. It compared gefitinib 250 mg daily with the standard second-line docetaxel dose 75 mg/m2. A non-inferiority end point of overall survival was also adopted in INTEREST with a co-primary analysis for superiority in patients with high EGFR gene copy number. Over 1400 patients were enrolled and the study met its goal of non-inferiority with an HR of 1.020, median survival 7.6 versus 8 months. In the high EGFR gene copy number population, gefitinib was not superior, a surpris-ing outcome as previous biomarker studies had identified this as a positive predictive marker for EGFR TKI treatment. It is conceivable that the results were confounded by the prognos-tic value of EGFR overexpression. The two arms were well balanced in terms of baseline characteristics. Further treat-ments after the trial also seemed to be equal; in the gefitinib group, 54% did not receive further treatment beyond an EGFR TKI and in the docetaxel group 53% did not receive further treatment except for docetaxel. A third trial is this set-ting is underway, Iressa as Second Line Therapy in Advanced NSCLC-Asia (ISTANA) [43]. This is a randomized, open-label, parallel group, Phase III, multi-center trial comparing gefitinib to docetaxel in advanced NSCLC patients who had previously received platinum-based chemotherapy. The primary end point was PFS and the HR was 0.729 (90% CI 0.533 – 0.998), favoring gefitinib. Preliminary analysis also indicated that response rate and overall survival favored gefitinib.

Gefitinib as an adjuvant therapy was evaluated by a National Cancer Institute of Canada Clinical Trials Group trial, BR 19 [44]. The objective was to compare whether adjuvant treatment with gefitinib for 2 years was superior to placebo in patients with completely resected stage IB, II and IIIA NSCLC in terms of overall survival and disease-free survival. The trial opened in 2002; however, accrual was suspended in 2005 based on the recommendations of the data safety and monitoring board, in part due to the results of BR 15 (discussed below). A more detailed analysis is anticipated in 2009.

BR15/Southwestern Oncology Group 0023 was a Phase III trial of cisplatin/etoposide concurrent with radio-therapy with consolidation docetaxel followed by mainte-nance therapy with gefitinib or placebo in patients with inoperable locally advanced stage III NSCLC [45]. This study was closed early (in 2005) based on an unplanned interim analysis that suggested a possible detrimental effect of gefi-tinib on survival. In an updated analysis in 2007, the median survival was gefitinib 23 m and placebo 35 m with an HR of 0.63 (p = 0.01). Decreased survival was due to cancer and not gefitinib toxicity; however, the reason for this sig-nificant disparity was unclear. In addition, the backbone treatment for stage III disease was based on the Phase II

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data from Southwestern Oncology Group 9504, which is controversial. A Phase III trial conducted by the Hoosier Oncology Group comparing concurrent cisplatin/etoposide radiotherapy with and without consolidation docetaxel found no improvement in overall survival with the addition of docetaxel [46]. Therefore, consolidation docetaxel adds toxicity but no survival benefit in stage III disease. It is not known if the addition of docetaxel had any bearing on the results of the BR 15 study. The recommendation from BR15 was that maintenance EGFR TKIs outside the setting of a clinical trial was not advised in stage III disease.

4.3 BIBW2992Targeting both EGFR and HER2, BIBW 2992 (Tovok, Boehringer Ingelheim, Ridgefield, CT, USA) is an orally available, irreversible dual receptor TKI. A Phase I study of this agent demonstrated a response rate of 20% in the 15 (of 47) patients with advanced solid tumors [47]. The maximum tolerated dose was 50 mg daily and the dose-limiting toxicity was dyspnea with interstitial changes (n = 1) and rash (n = 2), both of which resolved with cessation of drug. Similar to current EGFR TKIs, the most common adverse event was rash and diarrhea. Of the three NSCLC patients with a partial response, two were females with adenocarcinoma and an EGFR exon 19 mutation and the third was a male non-smoker. Recognizing the importance of treatment in patients who develop resistance to erlotinib/gefitinib, a randomized, double-blind, multi-center Phase IIb/III trial study is being conducted in patients who have previously been treated with platinum-based chemotherapy and an EGFR TKI for at least 3 months and then progressed [48]. Patients will be randomized in a 2:1 fashion to BIBW 2992 or placebo. The primary end point is overall survival with secondary end points of response rate, PFS, clinical benefit, safety, quality of life and pharmacokinetics. Two Phase II studies are also underway evaluating this agent in special populations, patients with known EGFR mutations and patients with EGFR FISH-positive tumors.

4.4 CanertinibCanertinib (CI 1033, Pfizer, New York, NY, USA) is a pan-ERBB inhibitor. Janne et al. conducted a Phase II study of single agent canertinib in NSCLC patients refractory or recurrent after platinum-based chemotherapy [49]. Three 21-day dosing schedules were evaluated: 50 mg daily for 21 consecutive days, 150 mg daily for 21 consecutive days and 450 mg daily for 14 consecutive days followed by 7 days of no treatment. Over 160 patients were randomized on this trial. The third arm (450 mg) was closed early owing to tox-icity signals. The most common adverse event was diarrhea and rash. The primary end point, survival at 1 year, was 29, 26 and 29%; response rates were 2, 2 and 4%; and stable disease was confirmed in 16, 23 and 18%, respectively. A Phase I trial of canertinib was conducted in combination with carboplatin and paclitaxel in chemo-naive patients with

advanced NSCLC who had at least one elevated tumor expressing member of the erb-B family receptors [50]. The dose-limiting toxicities were diarrhea, rash, asthenia and hypotension. The maximum tolerated dose in combination with chemotherapy was 100 mg daily. A Phase II cohort was included in this study with a response rate of 26%, median PFS 5.1 months and median overall survival 12.4 months. Further Phase II testing was recommended based on these positive outcomes. The focus of future development will be on patient selection for this agent.

4.5 EKB569EKB 569 (Wyeth, Madison, NJ, USA) is a 3-cyanoquinoline pan-ErbB TKI. A Phase I study of this drug evaluated two different dosing schedules: intermittent, 14 days of a 28-day cycle or continuous, every day of a 28-day cycle. The maxi-mum tolerated dose was 75 mg daily and the dose-limiting toxicity was diarrhea. There were no responses; however, one NSCLC patient had stable disease for 33 weeks on the drug. A Phase II trial was designed to assess the efficacy of daily EKB-569 in patients previously treated with a platinum- and docetaxel-based therapy either given concurrently or as separate regimens. The study is closed to accrual with results awaited.

4.6 NeratinibNeratinib (HKI 272, Wyeth) is an oral 6,7-disubstituted- 4-anilinoquinoline-3-carbonitrile irreversible inhibitor of EGFR, HER 2 and HER 3. Preclinical work suggested that neratinib was active in patients with the T790M acquired resistance mutation to erlotinib and gefitinib [51]. A Phase I study of this agent demonstrated a maximum tolerated dose of 320 mg with diarrhea being the most common and dose-limiting toxicity [52]. Of the 72 patients enrolled, 16 had NSCLC and while there were no responses, 5 of those patients had stable disease for ≥ 24 weeks duration. Based on the preclinical data and the benefit seen in NSCLC, a Phase II trial was conducted looking at single agent neratinib [53]. There were three arms in the study; patients who had taken gefitinib or erlotinib for 3 months or greater were assessed for EGFR mutations, positive patients were allocated to Arm A, negative to Arm B and the third arm consisted of patients with adenocarcinoma, < 20 year pack history of smoking and current non-smoker status to Arm C. Accrual has been completed and the results are pending.

4.7 XL647XL 647 (Exelixis, South Francisco, CA, USA) is a reversible inhibitor of EGFR, HER2 and VEGF. Preclinical work showed efficacy in the H1975 cell line, which expresses EGFR mutations L858R and T790M; consequently, drug development has focused on special populations [54]. A Phase II study reported at the AACR-NCI-European Organization for Research and Treatment of Cancer trial

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International Conference on Molecular Targets and Cancer Therapeutics in October 2007 evaluated XL 647 in advanced NSCLC patients with adenocarcinoma, who had an activat-ing EGFR mutation or met at least one of the following criteria: female, Asian or minimal/never smokers. Thirty-seven patients enrolled and thirty-four were evaluable for response. Ten (30%) patients had a partial response; five had exon 19 deletions, one had an L858R mutation, three were wild type and one had an unknown mutation status. The most common toxicities were diarrhea, rash, fatigue and nausea. Recognizing the potential to treat patients with acquired resistance to EGFR TKIs, a second Phase II was designed to evaluate patients who have had disease progres-sion following a previous benefit from erlotinib or gefitinib or who express the T790M mutant form of EGFR.

5. TargetingEGFR:monoclonalantibodies

5.1 CetuximabTwo Phase III studies have evaluated cetuximab in first-line metastatic NSCLC patients. BMS 099 was a randomized study of taxane/carboplatin/cetuximab versus taxane/carboplatin with a primary end point of PFS. The study did not meet its pri-mary outcome with cetuximab arm having a PFS of 4.4 m compared to 4.24 m (HR 0.902, p = 0.2358) [55]. An updated analysis performed in 2008 showed a median overall survival of 9.7 months with chemotherapy + cetuximab, compared to 8.4 months with chemotherapy alone, with an HR of 0.89 (p = 0.17). While this demonstrates a trend toward improved survival, this study was not powered to show a survival differ-ence. The second trial, the First-line in Lung cancer with ErbituX study (FLEX), combined cisplatin and vinorelbine with cetuximab or placebo. Eligibility criteria required EGFR expression by immunohistochemistry (at least one cell-positive) for participation; ∼ 85% of the patients screened met this cri-terion [56]. Over 1000 patients enrolled in this large Phase III study that demonstrated a statistically significant improvement in overall survival in patients receiving cetuximab in combina-tion with vinorelbine and cisplatin compared to chemotherapy alone (11.3 versus 10.1 months) with an HR of 0.871 (p = 0.044). Based on these data, ImClone and Bristol-Myers Squibb are pursuing a regulatory filing with the FDA for the first-line treatment of patients with advanced NSCLC. Phase II studies conducted with cetuximab and other chemotherapy regimens including cisplatin/gemcitabine and carboplatin/paclitaxel have also demonstrated clinical activity and good tolerability [57-59]. In the US, the combination of carboplatin/taxol with bevacizumab is a common first-line regimen and, therefore, it is difficult to predict how the FLEX trial data will be integrated into actual clinical practice.

5.2 MatuzumabMatuzumab (EMD 72000, EMD Pharmaceuticals, Merck & Co, Whitehouse Station, NJ, USA) is a humanized monoclonal antibody that selectively binds EGFR. Several

early studies have been done with this antibody in NSCLC. A single agent Phase I study in EGFR expressing advanced solid tumors established a maximum tolerated dose of 1600 mg weekly with the most common adverse event being rash. Kollmannsberger et al. conducted a Phase I study of matuzumab weekly with paclitaxel 175 mg/m2 every 3 weeks in EGFR protein-expressing advanced NSCLC patients [60]. The maximum tolerated dose was not reached; matuzumab 800 mg weekly with paclitaxel was well toler-ated. Of 18 patients, there were 4 patients with a response, one of whom had a complete response. There is a continu-ing randomized Phase II of pemetrexed alone versus peme-trexed plus matuzumab in stage IIB/IV NSCLC patients previously treated with platinum-based therapy. Two differ-ent schedules of matumab are being evaluated, 800 mg weekly and 1600 mg every 3 weeks. The trial is closed to accrual but analysis is continuing.

5.3 NimotuzumabNimotuzumab (TheraCIM h-R3, YM Biosciences, Inc., Ontario, Canada) is a monoclonal antibody against the extracellular domain of the EGF receptor that blocks ligand binding and receptor dimerization. It is currently marketed in certain countries in combination with radiotherapy for glioma and head and neck malignancies. A Phase I/II study was conducted in combination with palliative external radia-tion in stage IIB-IV NSCLC patients unsuitable for radical radiotherapy or combined chemoradiotherapy [61]. So far, 13 patients have been treated on this protocol. Nimotuzumab administered concurrently with radiotherapy was well toler-ated at the 100 and 200 mg/week dose. Six patients had a partial response and several had a clinically meaningful improvement in their symptomatology. The drug was well tolerated and noted to have minimal side effects including absence of cutaneous manifestations. This antibody is also being evaluated with whole brain radiotherapy in NSCLC for patients with brain metastases.

5.4 PanitumumabPanitumumab (ABX EGF, Vectibix, Amgen, Thousand Oaks, CA, USA) is a fully humanized IgG2 antibody to EGFR. As an IgG2 antibody, panitumumab does not acti-vate antibody-dependent cellular cytotoxicity. Panitumumab has been evaluated in advanced NSCLC in combination with carboplatin/paclitaxel in a randomized Phase II study involving 166 patients [62]. Patients in the chemotherapy alone and chemotherapy plus panitumumab had similar outcomes with no difference in time to disease progression, response rate or overall survival. Based on the lack of benefit observed in this trial, further development of panitumumab in NSCLC is not expected.

5.5 ZalutumumabA trial involving zalutumumab (HuMax-EGFr, Genmab, Copenhagen, Denmark) and chemoradiotherapy was initiated

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in Europe in 2007. The trial purpose was to investigate if treatment with zalutumumab in combination with chemo-therapy and radiotherapy would improve overall survival in NSCLC compared to chemo-radiation alone. This study was terminated, however, due to considerations regarding the appropriate therapeutic regimen for these patients. There are no other trials currently active with this agent in NSCLC.

6. Summary

EGFR inhibition is an active area of drug development for the treatment of NSCLC. The success of erlotinib, gefitinib and cetuximab in this disease site has revolutionized the treatment of advanced NSCLC and prompted the search for other agents with greater efficacy and less toxicity. Prolonged use of erlotinib and gefitinib in responding patients has resulted in a drug-resistance phenotype and so efforts have also been focused on developing second generation EGFR TKIs that are effective in patients with acquired resistance. Several EGFR antibodies are currently under investigation, utilizing both pathway inhibition and immune mechanisms to treat NSCLC. With these agents directed against a spe-cific growth pathway, EGFR, research into biological mark-ers to identify subpopulations who stand to gain the most benefit from these agents holds promise for the future.

7. Expertopinion

NSCLC is a complicated and deadly disease. In the past 20 years, treatment has undergone significant improvements; in addition to best supportive care, there are now at least three different lines of therapy one might consider using to improve a patient’s quality of life and modestly prolong survival.

However, the benefits from cytotoxic chemotherapies have only taken us so far and there is a need for less toxic, more effective systemic strategies such as EGFR targeted therapy.

EGFR inhibitors have radically shifted how we treat NSCLC. Not only do we have a more tolerable alternative to standard chemotherapy, this class of drugs has also forced us to recognize that NSCLC represents a range of diseases. Histology and biological characteristics play an important role in deciding the most suitable therapeutic option. At this point, there is still not enough clearly defined predictive information to guide our choices for EGFR therapy, but that time is imminent. Meanwhile, there is ample clinical evidence to support the use of erlotinib and gefitinib in advanced NSCLC and these drugs have appropriately been incorporated into common practice. The evidence for the monoclonal antibodies is slightly behind, but this is another viable mechanism of receptor inhibition.

The drive to identify predictive markers for anti-EGFR agents has greatly enhanced our knowledge of tumor biol-ogy; this in turn will help define more targeted agents in the future. Targeting the EGFR pathway has been a tremendous success for some patients. Now, our challenge is to defini-tively identify the patients likely to benefit from an EGFR inhibitor and to choose the most appropriate method, TKI or monoclonal antibody or perhaps a combination. The era in which we blindly select therapies for any and all lung cancers needs to come to a close and more focused work on targeted therapy will eventually lead us in this direction.

Declarationofinterest

C Ho has received honorarium from Roche. J Laskin has received honorarium and research funding from Roche.

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AffiliationCheryl Ho† MD FRCPC & Janessa Laskin MD†Author for correspondenceClinical Assistant Professor British Columbia Cancer Agency, Medical Oncologist, 600 W 10th Avenue, Vancouver, BC V5Z 4E6, Canada Tel: +604 877 6000; Fax: +604 877 0585; E-mail: [email protected]

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Documents

EGFR-directed therapies to treat non-small-cell lung cancer