Targeting the HER1/EGFR Receptor to Improve Outcomes in Non–Small-Cell Lung Cancer

ABSTRACT: Non–small-cell lung cancer represents a growing global burden andremains a therapeutic challenge. Only small improvements in survivalhave been made with standard chemotherapeutic approaches to advanceddisease in recent history. Novel biologic targeted therapies offerthe potential of improving patient management and treatment outcomesin non–small-cell lung cancer. Prominent among these novelagents are the HER1/epithelial growth factor receptor (EGFR) inhibitors.One of these agents, gefitinib (Iressa), is already approved for usein advanced, refractory non–small-cell lung cancer. Erlotinib (Tarceva)is a promising HER1/EGFR inhibitor in phase III evaluation as firstlinetherapy combined with chemotherapy and as second-/third-linemonotherapy in advanced non–small-cell lung cancer. In addition,erlotinib is being evaluated in combination with the angiogenesis inhibitorbevacizumab (Avastin), a strategy combining two new modalitiesin cancer treatment. Results of these trials will provide importantinformation on optimal use of these new targeted therapies and mayoffer the promise of improving the treatment of non–small-cell lungcancer.

Non-small-cell lung cancer is agrowing global burden and anongoing therapeutic challenge.Despite attempts to optimizedisease management and treatment,there have been only limited advanceswith new variations on standardchemotherapeutic regimens, and overallprogress in this regard has beenpoor. There has been no substantialimprovement in patient survival overthe past 20 years. The advent of targetedcancer therapies such as thosetargeting the HER1/epidermal growthfactor receptor (EGFR) offers thepromise of improved treatment ofnon-small-cell lung cancer.Current Status ofStandard ChemotherapyLung cancer is almost uniformlyfatal, and accounts for approximately20% of all cancer deaths (excludingthose due to skin cancers) accordingto World Health Organization estimatesfor 2000.[1] In the UnitedStates, lung cancer continues to be theleading cause of cancer-related mortality.[2] Approximately 75% to 80%of lung cancers exhibit non-small-celllung cancer histology, and the major-ity of these patients present with eitherlocally advanced (stage III) ormetastatic (stage IV) disease.[3] Patientsundergoing successful surgicalresection for early (stage I/II) localizednon-small-cell lung cancer havesurvival rates of 50% to 80%. However,chemotherapy is required in themajority of non-small-cell lung cancerpatients, because the majoritypresent at advanced stages of diseaseand because many patients requirechemotherapy for relapse after surgery.[3]Chemotherapy for advanced non-small-cell lung cancer appears to havereached a plateau in terms of improvingsurvival, with slight improvementsover the past 10 years still leavingmedian survival at less than 1 year. Asdemonstrated by the recent trial bySchiller et al comparing combinationsof cisplatin with paclitaxel, docetaxel(Taxotere), or gemcitabine (Gemzar)

and carboplatin (Paraplatin)/paclitaxel, there are no survival differencesamong standard regimens, with1-year survival rates being 35% to40%.[4] Apart from the limited survivalbenefit with traditional chemotherapy,such treatment often is associatedwith toxicity that cannot be toleratedby patients already debilitatedfrom major surgery, concomitant morbiditiesin older age, prior chemotherapy,or symptoms of late-stage disease.In brief, therapeutic needs innon-small-cell lung cancer includeimproved survival and prolonged timeto disease progression, improvementin disease-related symptoms and otheraspects of quality of life, and bettertolerated regimens for patients whoare not candidates for standardcombinations.Targeted Treatment:HER1/EGFR InhibitorsNewer, molecular-targeted approachesto treatment offer the potentialfor improving tumor responses andreducing treatment-associated toxicities.A variety of classes of these newbiologic agents that target cell signalingpathways may find roles in treatmentof non-small-cell lung cancer(Table 1): HER1/EGFR targetedagents, including EGFR tyrosine kinaseinhibitors and monoclonal anti-antibodies;angiogenesis inhibitors; signaltransduction inhibitors, cyclooxygenase-2 inhibitors, and other inhibitorsof cell survival pathways.HER1/EGFR inhibition is an attractivetarget in non-small-cell lung cancer;exploitation of this approach hasproduced a number of novel agentsthat are well along in clinical developmentand investigation. HER1/EGFR is pivotal in regulating a numberof functions that determine tumorcell proliferation and survival and appearsto have no critical function inhealthy tissue. Overexpression/dysregulation of the receptor is commonin non-smal-cell lung cancer,having been identified in 76% of squamouscell carcinomas, 47% of adenocarcinomas,and 43% of large cell carcinomas,and there is evidence thatoverexpression/dysregulation is associatedwith poor prognosis[5-8]; thereis also evidence that the EGFRvIIImutant is associated with progressionof non-small-cell lung cancer.[9]Early investigation of this targetshowed no evidence of severe toxicitywith its inhibition in vivo and demonstratedthat inhibition in vitro resultedin blocking of downstream cellactivation.A wide range of uses of HER1/EGFR inhibitors can be conceived innon-small-cell lung cancer, includingin the settings of neoadjuvant or adjuvanttherapy, as first- or second-linetherapy in combination with standardchemotherapeutic agents in patientswith advanced disease or as first-linetreatment in those who are not suitablecandidates for standard chemotherapy,and as palliative therapyaimed at maintaining/improving qualityof life. In addition, such agents mayeventually be targeted to specific subgroupsof patients based on molecularprofiling of disease.Erlotinib (Tarceva) is a promisingHER1/EGFR-targeting agent. Thisagent exhibits highly selective, potent,and reversible inhibition of HER1/EGFR tyrosine kinase phosphorylation,resulting in inhibition of tumorcell proliferation and induction of cellapoptosis, and has been found to inhibitthe EGFR mutant EGFRvIII. Intumor models, erlotinib has beenshown to have at least additive antitu-mor effects when combined with cytotoxicagents with no increase incellular toxicity and to result in stasisor regression of tumor growth in non-small-cell lung cancer and other humantumor xenografts. The agent isorally available, and is well toleratedin human subjects.Erlotinib is currently being evaluatedin a number of phase III and phaseII trials in advanced non-small-celllung cancer (Table 2). These includethe phase III TRIBUTE trial evaluatingthe effects of adding erlotinib tocarboplatin/paclitaxel in first-linetherapy and the phase III TALENTtrial evaluating the addition of erlotinibto cisplatin/gemcitabine in first-linetherapy. Recent final results haveshown that these trials did not meettheir primary end points of improvingoverall survival. Further studies willattempt to detect a survival advantagefor erlotinib use as a single agent insecond- and third-line treatment. In addition,the phase III BR.21 trial willprovide important information on theeffects of erlotinib alone in advanceddisease.Ongoing phase II trials include anevaluation of the combination oferlotinib with the angiogenesis inhibitorbevacizumab (Avastin), a humanizedmonoclonal antibody directedagainst vascular endothelial growthfactor (VEGF); VEGF plays a centralrole in tumor angiogenesis and maintenanceof established blood vessels.Bevacizumab has been shown to improvesurvival in colorectal cancer by30% as first-line therapy, and is currentlybeing investigated in non-small-cell lung cancer and small-celllung cancer. The prospect of combiningHER1/EGFR-inhibitory andantiangiogenesis effects with theerlotinib/bevacizumab combination ishighly attractive.Select pivotal studies with otheragents targeting HER1/EGFR in advancednon-small-cell lung cancer areshown in Table 3. These include thephase III INTACT 1 and 2 trials of theHER1/EGFR tyrosine kinase inhibitorgefitinib (Iressa) in combinationwith standard chemotherapy as firstlinetreatment; results of these trialsshowed no benefit of adding gefitinibto chemotherapy in this setting. How

ever, positive results of the IDEAL 1and 2 trials[10,11] resulted in US Foodand Drug Administration approval ofuse of this agent for treatment of advanced,refractory non-small-cell lungcancer. The anti-HER1/EGFR monoclonalantibody cetuximab (Erbitux)is being evaluated in combination withchemotherapy as first-or second-linetreatment in a number of phase II trials;the phase II randomized trial ofcisplatin/vinorelbine (Navelbine) withor without cetuximab has shown amarkedly higher response rate with thecetuximab-including regimen. In addition,a phase II trial of the monoclonalantibody ABX-EGF combinedwith chemotherapy in patients withtumors shown to overexpress HER1/EGFR is under way.ConclusionFigure 1 provides some idea of thecurrent status of attempting to improvetreatment and outcomes in advancednon-small-cell lung cancer. As noted,gefitinib is now available for treatmentof advanced, refractory disease. Theantifolate agent pemetrexed wasshown to be as effective as docetaxeltherapy in recurrent lung cancer. Thehypoxic cell cytotoxin tirapazamineshowed no additional benefits whenadded to chemotherapy in two largerandomized trials. The outcomes of thephase III TRIBUTE, TALENT, andBR.21 trials of erlotinib are eagerlyawaited.There are a number of challengesto be met in defining the role and optimizingthe benefits of HER1/EGFRtargetedtherapy in non-small-celllung cancer. It should be determinedwhether HER1/EGFR overexpression/activation is predictive of response toinhibitors and whether there are otherpredictive markers that could permiteffective patient targeting. Surrogatemarkers of activity may be useful inassessing whether subpopulations ofpatients respond to these treatments.Optimal doses of these agents for effectiveinhibition of their target and forinhibition of downstream pathwaysremain to be elucidated. Likewise,optimal doses and schedules of theseagents when used alone or in combinationwith chemotherapy remain tobe determined, and optimal combinationswith chemotherapeutic agentsand/or other biologic agents remain tobe identified.Evaluation of use of these therapiesat each stage of non-small-celllung cancer is ongoing. It is hoped thatin the near future, the classical optionsof surgery, radiation therapy, and cytotoxicchemotherapy in non-smallcelllung cancer will be joined byHER1/EGFR inhibition and angiogenesisinhibition as modalities thatimprove overall patient managementand outcomes of treatment in thisdisease.

Disclosures:

The author(s) have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

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