Clinical activity of afatinib (BIBW 2992) in patients with lung adenocarcinoma with mutations in the kinase domain of HER2/neu.

ContentslistsavailableatSciVerseScienceDirect

Lung

Cancer

jo u rn al h om epa g e :w w w . e l s e v i e r . c o m / l o c a t e / l u n g c a n

Case

report

Clinical

activity

of

afatinib

(BIBW

2992)

in

patients

with

lung

adenocarcinoma

with

mutations

in

the

kinase

domain

of

HER2/neu

夽,夽夽

J.

De

Grève

_,

_E.

_Teugels

_,

_C.

_Geers

_,

_L.

_Decoster

_,

_D.

_Galdermans

_,

_J.

_De

_Mey

_,

_H.

_Everaert

_,

_I.

_Umelo

_,

P.

In’t

Veld

_,

_D.

_Schallier

a_{OncologischCentrumUZBrussel,Brussels,Belgium}

b_{ZNAMiddelheim,Antwerp,Belgium}

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received13May2011

Receivedinrevisedform13January2012

Accepted15January2012

Keywords:

Non-smallcelllungcancer(NSCLC)

Epidermalgrowthfactorreceptor(EGFR)

Humanepidermalgrowthfactorreceptor2

(HER2) Afatinib Adenocarcinoma Mutation

a

b

s

t

r

a

c

t

Humanepidermalgrowthfactorreceptor(HER)2/neukinasedomainmutationsarefoundin approxi-mately1–4%oflungadenocarcinomaswithasimilarphenotypetotumorswithepidermalgrowthfactor receptor(EGFR)mutations.AfatinibisapotentirreversibleErbBfamilyblocker.Wedeterminedthe tumorgenomicstatusoftheEGFRandHER2genesinnon-orlightsmokerswithlungadenocarcinoma inpatientswhowereenteredintoanexploratoryPhaseIIstudywithafatinib.Fivepatientswitha non-smokinghistoryandmetastaticlungadenocarcinomasbearingmutationsinthekinasedomainofHER2 genewereidentified,threeofwhichwereevaluableforresponse.Objectiveresponsewasobservedin allthreepatients,evenafterfailureofotherEGFR-and/orHER2-targetedtreatments;thecasehistories ofthesepatientsaredescribedinthisreport.Thesefindingssuggestthatafatinibisapotentialnovel treatmentoptionforthissubgroupofpatients,evenwhenotherEGFRandHER2targetingtreatments havefailed.

© 2012 Elsevier Ireland Ltd.

1. Introduction

The presence of activatingmutations in the tyrosinekinase domain of the human epidermal growth factor receptor 1 (EGFR/HER1/erbB1) in non-small cell lung cancer (NSCLC) cor-relates with a clinical phenotype of adenocarcinoma in never orlightsmokers,andrendersthetumorexquisitelysensitiveto EGFRtyrosinekinaseinhibitors(TKIs)[1–3].Theintroductionof targeted drugs for the treatmentof NSCLCwith EGFR-directed small-moleculeTKIs [3] and monoclonal antibodies[4] has led toasignificantbutrelativelysmalloverallimprovementin clini-caloutcomeofunselectedpatientswithadvanceddisease.EGFR mutations and increased EGFR copy number by fluorescence

夽 Previouspublications:Inabstractandposterformatthe4thLatinAmerican

ConferenceonLungCancer(LALCA)2010,inabstractandposterformat2nd

Euro-peanLungCancerConference(ELCC)2010,inabstractformattheWorldConference

onLungCancer(WCLC)2009andtheCongressoftheEuropeanCancer

Organisa-tionand34thCongressoftheEuropeanSocietyforMedicalOncology(ECCO-ESMO)

2009.

夽夽 Clinical trial details:Registry name: Single-arm Trialof BIBW 2992 in

DemographicallyandGenotypicallySelectedNSCLCPatients.Registrationnumber:

NCT00730925.

∗ Correspondingauthorat:MedicalOncology,OncologischCentrum,UZBrussel,

Laarbeeklaan101,1090Brussels,Belgium.Tel.:+3224776415;fax:+3224776210.

E-mailaddress:Jacques.degreve@uzbrussel.be(J.DeGrève).

insituhybridization(FISH)arepredictivebiomarkersthatidentify patientswhoaremostsensitivetoTKIs[5,6].

HER2kinasedomainmutationsarerareinNSCLC,andarefound inapproximately1–4%oflungadenocarcinomaswithasimilar phe-notypeastumorswithEGFRmutations[7–9].In229patientswith adenocarcinomaofthelung,withalittleornosmokinghistory,we identifiedaHER2mutationinthetumortissueoffivepatients(2%), whichis10-foldrarerthanthefrequencyofEGFRmutationsinthe samecohortofpatients[10].Inothercohortswithpotentially dif-feringphenotypicselectioncriteria,theHER2mutationratewas evenlower:intumorsfrom830patientsanalyzedwithintheNCI’s LungCancerMutationConsortium(LCMC)[11]aHER2mutation wasfoundinonlythreecases(1%)comparedto98caseswithan EGFRmutation.In552samplesanalyzedatMassachusettsGeneral Hospital,onlyonepatientwitha HER2mutationwasidentified

[12].TheHER2mutationsfoundinclinicalsamplessofarareallin exon20.

Afatinibisapotent,irreversibleErbBfamilyblockerwith pre-clinicalactivityinBa/F3cellsexpressinganartificialHER2mutant andinahumanlungcancercelllinewithaninsertionalmutation atcodon776[13].

We determinedthe tumor genomic status of theEGFR and HER2genesinnon-orlightsmokerswithlungadenocarcinoma bydenaturinggradientgelelectrophoresis(DGGE)/DNA sequenc-ingofNSCLCtumortissueorincreasedcopynumberoftheEGFR gene,asdeterminedbyFISHanalysis.HER2FISHwasnotrequired

0169-5002© 2012 Elsevier Ireland Ltd.

doi:10.1016/j.lungcan.2012.01.008

Open access under CC BY-NC-ND license.

124 J.DeGrèveetal./LungCancer76 (2012) 123–127

Fig.1.ExamplesofHER2exon20mutations.

forentryintothestudyandthereforenotsystematically under-taken.InCase2,HER2FISHwasperformedlongbeforeinclusion intothecurrentstudy.Patientswereenteredintothisexploratory PhaseIIstudywithafatinib,which,amongothers,includedacohort ofpatientswithHER2kinasedomainmutations[14].Therewere norestrictionsinpriortherapyforpatientswithHER2mutations, althoughpatientshadtohaveatleastonemeasurabletumorlesion thatcouldbeaccuratelymeasuredbycomputedtomography(CT) scanormagneticresonanceimaging[14].Here,wereportthefirst therapeuticactivityofafatinibinthreepatientswithlung adeno-carcinomaanda non-smoking history,whose tumors exhibited activatingHER2 mutationsin exon 20 (Fig.1). Treatmentwith afatinibresultedin anobjectiveremission in allthree patients, evenafterfailureofotherEGFR-and/orHER2-targetedtreatments. Followingdiseaseprogression,therewasanoptiontocombinea lowerlevelofafatinibwithweeklypaclitaxelat80mg/m2 _ona

3/4-weekschedule.Fivepatientsweretreatedinthisstudy;two patientswerenotevaluableduetoearlytreatmentdiscontinuation. ThestudywasapprovedbytheEthicalCommitteeofthe Univer-sitairZiekenhuis Brussel and participatingcentersand patients provided informedconsent. Here we reportonthree evaluable patients.

2. Case1

A72-year-old,non-smokingfemalewasdiagnosedwithastage IIIlungadenocarcinoma (rightlower lobe)in May2007. Treat-ment withfour cyclesof carboplatin/gemcitabine resultedin a partialremission. Followingprogressive disease(PD)inJanuary 2008,administrationofanadditionalfourcyclesofreduceddose carboplatin/gemcitabineresulted in stable disease(SD).In May 2008,thepatientwasfoundtohavePDinthelung,with symp-toms of mildly productive cough. An exon 20 HER2 mutation (p.Tyr772Ala775dup;Fig.1)wasfoundinthetumorDNAextracted fromtheoriginaldiagnosticbiopsyinMay2007.

Treatmentwithafatinib(50mg/day)startedinJuly2008.After8 days,positronemissiontomography-CT(PET-CT)imagingshowed a radiological partial response (PR) and a metabolic complete responsethatwasmaintainedfor3months(Fig.2A).Treatment wasinterruptedthreetimesduetosideeffects(diarrhea, dysgeu-siaandskinadverseevents[AEs];allCommonTerminologyCriteria forAdverseEvents[CTCAE]Grade2)andpromptedsuccessivedose reductionsto30mg/day. Thepatientwasdeemed tohave pro-gressionafter3monthsbasedonanapproximate20%increasein

targetlesionsabovethenadir,althoughthetotaltumorburdenwas belowbaselineandthepatientcontinuedtoreceivemonotherapy withafatinib.FollowingfurtherprogressioninMay2009,afatinib wascombinedwithpaclitaxel,butthepatientshowedprogression solelyduetotheoccurrenceofbrainmetastasesshortlyafterwards anddiedonemonthaftergoingoffstudywithouthavingreceived anysubsequenttherapy.Thepatientwastreatedwithafatinibfor atotalof9monthsandsurvivedoneyearfromstudyentry.

3. Case2

A62-year-old,non-smokingfemalewithadenocarcinomaofthe rightlung wasinitially diagnosedin 2002.Hertumorcells had increasedEGFR/HER1copynumber,asassessedbyFISH,aswell asmutationsintheEGFRkinasedomain(exon21:p.Ala859Thr) andinHER2(exon20:p.Gly776Leu).Sheunderwentalobectomy forapT2N1adenocarcinomaandreceivedadjuvantchemotherapy withcisplatin/gemcitabine,followedbyradiotherapy.Arelapsein thelung andmediastinallymphnodesinJuly2003wastreated withfourcyclesofthesamechemotherapy,resultinginSD.From 2004through2008,PDwastreated sequentiallywithdocetaxel (sixcycles;SD),gefitinib(PD),trastuzumabwithpaclitaxel(PR), lapatinib,gemcitabineandvinorelbine.

Atinclusioninthecurrentstudy,thispatientsufferedfrom dys-pneaandretrosternalandrightchestwallpainrequiringnarcotic painrelief,aswellasfacialandcervicalsoft-tissuecongestion.Her EasternCooperativeOncologyGroup(ECOG)performancestatus (PS)was2.

From July 2008, this patient was treated with afatinib (50mg/day). Within 2 weeks, the cervical soft-tissue swelling decreased withmarked improvement in her general condition (ECOG PS: 1). On Day 15, a metabolic response was observed ina PET-CT scan (Fig.2B). Treatment-relatedAEsincludedskin reactions,diarrhea,intermittentnauseaandvomiting,pyrosisand epigastricpain,fatigue,mucositis,sialorrhea, hairthinning,nail changesandfissuresofthenailbedandfingertip.After2monthsof treatment(August2008),aPRwasobservedbyCTscan.Treatment wasinterruptedduetotheassociateddiarrhea,andthedosewas reducedsuccessivelyto40mg/dayand30mg/day(October2008). Atthattime,thepatientwasprogressivecomparedtothenadir ofresponse,butstillhadatumorburdenreduction(20%decrease intargetlesions)byCTscan,comparedtobaseline.Thetimeto progressiononsingle-agentafatinibwas4months;inDecember 2008,shedevelopedfurtherPDintheliverandmediastinallymph

Fig.2.(A)Case1– responsetosingle-agentafatinib.PanelsA1andA3arethebaselinePET-CTandCTscans,respectively.PanelsA2andA4arethepost-treatmentPET-CTand

CTscansshowingtheearlyresponsetoafatinib.(B)Case2–responsetosingle-agentafatinib.PanelB1isabaselinePET-CTimage.PanelsB2andB3arethepost-treatment

PET-CTscansshowingmetabolicresponseonDay15oftreatmentandpartialremissionafter2months,withdiseaseprogressionat4months(PanelB4).(C)Case3–response

tosingle-agentafatinibandincombinationwithpaclitaxel.PanelC1isabaselinePET-CTimage,panelC2showstheimportantresponseinpleuralandliverdisease.Panel

126 J.DeGrèveetal./LungCancer76 (2012) 123–127 nodes.Weeklypaclitaxelwasaddedandthedoseofafatinibwas

reducedto20mg.ThepatienthadSDoverall,butwithametabolic andradiologicalresponseintheliverfor9monthsuntilApril2009, afterwhichsheprogressed.Thetimetoprogressionafterpaclitaxel wasaddedtoafatinibwas4months.ThepatientdiedinSeptember 2009,atotalof14monthsfromstudyentry.

4. Case3

InMarch2006,a49-year-oldCaucasian,non-smokingwoman wasdiagnosedwithstageIVrightupper-lobelungadenocarcinoma withdiffusepleural,liverand soft-tissuemetastases.Thetumor cells hadan increasedEGFRgene copynumber, asassessed by FISH,witha wild-typesequence.Thispatientreceivedfirst-line treatmentwitherlotinibat150mg/day,butclinicaland radiolog-icalprogressionoccurredwithin3months.FromJune2006,she wastreatedwithcisplatin/gemcitabine,withanobjectivetumor response,buttreatmentwasinterruptedduetocumulative toxic-ity.Shethenreceived,sequentially,gemcitabine(PD),carboplatin (transient response, but hematological intolerance), vinorelbine (PD),pemetrexed(transientresponse)andweeklycisplatin (symp-tomatic and objective response; treatment stopped because of intolerance).Additionalgenomicanalysisrevealedaninsertional duplication(p.Gly778Pro780dup)in exon20 oftheHER2 gene (Fig.1).AtinclusioninthecurrentstudyinJune2008[14],the patientwasseverelysymptomatic,withpainintherightchest, righthypochondriumandrightshoulder,andanorexiaandfatigue. Shehadalsodevelopedasymptomaticbonemetastasesandhadan ECOGPSof1.

Within2 weeks of starting afatinib(50mg/day), thepatient hadarapid clinicaland symptomaticresponse,with disappear-anceofalldisease-relatedsymptoms,aswellasoverallSDwith aradiologicalresponseinliverandpleura,whichwasmaintained for3months(Fig.2C).Treatmentwithafatinib(50mg/day)was associated withskin-relatedAEs, diarrhea and mucosal inflam-mationwithintermittentepistaxis, aphthousstomatitisand dry eyes.

Thetimetoprogressiononsingle-agentafatinibwas4months; following PD in October 2008, the patient received afatinib (40mg/day)combinedwithweekly paclitaxel(80mg/m2_).After

onecycle,disease-relatedsymptomsdisappearedandadramatic partialremissionwasseen.AsofJuly2009,thispatienthadanECOG PSof0,adiseasevolumeoflessthanthatatherremissionafter first-linecisplatin-basedchemotherapy2.5yearsearlier(Fig.2C). Sustainedcontrolofcarcinoembryonicantigen(CEA)tumormarker levelswasalsoachievedduringafatinibtreatment.Therewasan increaseinCEAlevelsduringineffectivepriorchemotherapy treat-mentandCEAlevelsdeclinedrapidlytonormalaftercombination ofafatinibandweeklypaclitaxel.Afatinibtreatmentwascontinued foratotalof15months,11ofwhichwereincombinationwith pacli-taxel,afterwhichtimethepatientdevelopedabrainmetastasis withoutconcurrentprogressionattheotherdiseasesites.Adverse eventswithafatinibandweeklypaclitaxelweremildandincluded skinreaction,diarrhea,fatigueandhematologicalAEs.

AftergoingoffstudyinSeptember2009,thepatientreceived trastuzumabsequentiallycombinedwithweeklypaclitaxelfor6 months(CEAmarkerstabilizationfor3months),liposomal dox-orubicinfor4months(markerstabilizationfor2months),weekly cisplatinforthreeadministrations,andoraletoposidefor3months withnofurtherclinicalbenefit. Inaddition, shedeveloped lep-tomeningealdiseasein June2010,whichwastreated withfour intrathecaladministrationsofdepocyteleadingtoadurable com-pletecytologicalandsymptomaticresponseofherleptomeningeal disease.ThepatientdiedinMarch2011,withanoverallsurvivalof 32monthsafterinclusioninthestudy.

5. Additionalcases

TwootherpatientswithHER2mutationswereenrolledintothe study,butbothcaseswereconsideredtobenon-evaluable.One patientwasa51-year-oldwomanwitha4pack-yearsmoking his-tory(whostoppedsmoking29yearsbeforestudyentry).Shewas treatedwithafatinibmonotherapyfor7weeksanddiscontinued treatmentduetotheoccurrenceofGrade3rash.Stabledisease wasobservedatthistime.Thepatientreceivedsubsequent peme-trexedtherapywithdiseaseprogressionaftertwocycles,followed bydocetaxelwithdiseasestabilizationfor5months,afterwhich thepatientwaslosttofollow-up.

Thesecondpatientwasa62-year-oldfemale,never smoker, whoreceivedafatinibforonly2weeksandwasdiscontinueddue toGrade3diarrheaanddeteriorationofhergeneralcondition.No tumorassessmentswereundertakenwithinthestudyafter base-line.Thepatientwassubsequentlylosttofollow-up.

6. Discussion

Wedescribe thefirstevidenceofclinicalbenefit from treat-mentwithafatinibinpatientswithanexon20HER2-mutantlung adenocarcinomawhohavepreviouslyfailedvarious chemother-apy regimens and the EGFR and/or HER2 inhibitors erlotinib, trastuzumaband lapatinib.Fivepatientswereidentified witha HER2mutation,althoughonlythreewereevaluableforresponse; mutationsinallthreepatientswereinexon20(twoinsertional duplications and one single amino-acid mutation). Analogous mutationsinEGFRinexon20arerelativelyinsensitiveto inhibi-tionbythereversibleinhibitorgefitinib[15].Intwopatients,arapid metabolicresponsewasobservedwithin1–2weeks.Twopatients hadgenomicactivationofbothEGFRandHER2.

The most striking response to single-agent afatinib was observed in Case 1, with a p.Tyr772Ala775dup mutation in HER2.Comparedwiththeothertwopatients,thispatientshowed genomicactivationofHER2only.Thismutationcausesanamino acidchange identicalto a mutation studiedin a recently pub-lishedpreclinicalmodelofmutantHER2-drivenlungcancer[16]. Inthismousemodel,theforcedexpressionofthemutantallele iscapableofinducinginvasiveadenosquamouscarcinomasthat arerestrictedtotheproximalanddistalbronchioles.Thesecancers werecompletelydependentonthepresenceofthismutationand regressedcompletelywhentheexpressionofthemutantgenewas reversed.Treatmentwithafatinibledtosignificanttumor regres-sion in this preclinical model. In two of our clinical cases,the additionofpaclitaxeltoafatinibledtoadditionaldiseasecontrol, withprolongedremissioninonepatientdespiteashortresponse tosingle-agentafatinib,raisingthepossibilityofsynergism.Ina xenograftoftheHER2mutantlungcancercelllineH1781,which containsahomozygoussingleamino-acidinsertioninexon20[8], administrationofafatinibresultedindiseasestabilization,in con-trasttothetumorregressionobservedinthepreclinicalmouse model.Takentogetherwithourclinicalexperience,thisindicates thatthehumanHER2-drivenlungcancermayhaveamorecomplex molecularpathogenesisthanthepreclinicalHER2-drivenmouse model.

ThetherapeuticeffectobservedinCase2wasalsoof consid-erableinterest,asthetumorshowedgenomicactivationofboth EGFRandHER2,andwaspreviouslytreatedwith,andhadbecome clinicallyresistantto,erlotinib,trastuzumabandlapatinib[17].

Althoughwe cannotexcludethat thesecondresponse, with addedpaclitaxel, resultsfromtheactivityof single-agent pacli-taxel,themagnitudeanddurationoftheresponseinpatientswith diseaseresistanttomultipleotherchemotherapiessuggeststhat

theresponsewastosomeextentachievedbythecombinationof afatinibwithpaclitaxel.

A limited number of studies in NSCLC have attempted to evaluate the activity of HER2-targeting agents, and have been summarizedbyKellyetal.[18].Thesestudiescouldnotreveala significantbenefitfromtrastuzumaborlapatinib.However,these studieswereperformedinNSCLCpatientpopulationsunselected forHER2status(HER2copynumberormutation)and primarily incombinationwithchemotherapeuticagents,andthereforewere notapttodetectclinicalbenefitinpatientswithagenomic acti-vationofHER2.Therewas,however,areportofonepatientwith aHER2FISHpositivetumor,butnoHER2orEGFRmutation,who achievedashort-livedresponse(4weeks)toapan-HERinhibitor (dacomitinib;PF-00299804)andsubsequentlyprogressed follow-ingadditionaltreatmentwithtrastuzumab,butwho responded aftervinorelbinewasadded.Furthermore,anadditionalpatient withaHER2mutationrespondedtotrastuzumabplusvinorelbine afterfailureofplatinum-basedchemotherapyandgefitinib. How-ever,thiscasedoesnotallowfortheassessmentoftheindependent activityoftrastuzumab[19].

ThisreportsuggeststhatthepresenceofHER2mutationsmay characterizeasubgroupofNSCLCthatisconstitutivelydependent ontheHER2pathway.Afatinibisapotentialnoveltreatmentoption forthissubgroupofpatients,evenwhenotherEGFRandHER2 tar-getingtreatmentshavefailed.Therateanddurationofresponse associatedwithafatinibandthecombinedactivityofafatiniband paclitaxelshouldbefurtherassessedinearlierlinesoftreatment inthisgenomicallydefinedpopulation.

Funding

ThisworkwassupportedbyBoehringerIngelheimandgrants fromtheNationalCancerPlan,Action29(grantPNC/KNP-29-011), Belgium;andtheStichtingtegenKanker,Belgium(grantnumber: SCIE2004-45).

Conflictofintereststatement

JacquesDeGrèvereceivedhonorariaandaresearchgrantfrom BoehringerIngelheim.IjeomaUmelodeclaredVUBOZRfellowship; andacollaboratorintheHER2trial.Nootherconflictsofinterestto disclose.CarolineGeers,ErikTeugels,DenisSchallier,Henrik Ever-aert,DaniellaGaldermans,LoreDecoster,JohanDeMeyandPeter In’tVeldhavenodisclosurestodeclare.

Acknowledgements

Thefirstdraftofthismanuscriptandfinalamendswere writ-tenbyJacquesDeGrève.Editorialsupportforthepreparationof thismanuscriptwasprovidedbyOgilvyHealthworldMedical Edu-cation;fundingwasprovidedbyBoehringerIngelheim.Wethank DrFedericoCappuzzoforreferralofapatientforinclusioninthis study.

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