MovingTowardsaMolecularly‐BasedDefinitionofLungCancer

RobertC.Doebele,MD,PhDThoracicMalignanciesProgramDivisionofMedicalOncology

March10,2010

Disclosures

•  ImCloneSystems–ResearchGrant

•  Iwillbediscussingoff‐labelandinvesHgaHonaluseofproducts

2009EstimatedUSCancerCases*

*Excludesbasalandsquamouscellskincancersandinsitucarcinomasexcepturinarybladder.Source:AmericanCancerSociety,2009.

Men766,130

Women713,220

2009EstimatedUSCancerDeaths*

ONS=Othernervoussystem.Source:AmericanCancerSociety,2009.

Men292,540

Women269,800

LungCancerStaging

Stage5yearsurvivalI 68%

II 50%

III 10‐30%

IV <5%

DeOerbecketal.Chest2009

LungCancerTreatmentbyStage

•  I‐Surgery•  II–Surgery+AdjuvantChemotherapy

•  III–Chemotherapy,RadiaHon,Surgery

•  IV–Systemictherapy

(i.e.chemotherapyorbiologictherapy)

LungCancer:morethanonedisease

Mesothelioma 3%

Carcinoid 1%

Non‐smallcelllungcancer(NSCLC):acancerdefinedbywhatitisnot

NSCLC Histologies

MolecularlyDefinedLungCancer:anewparadigmforclassificationandtreatment?

RandomizedTrialsofDoublets+/‐TargetedRX

Neg=16withavg.of1,000paYents

CasePresentation•  72yomale,formersmoker(50packyears)

•  IniHallypresentedin2008aYertraumaHcinjurywhenasmallnodulewasdetectedandfollowedbyCTwithsignificantgrowthin5/09

•  PET/CTrevealedFDG‐aviddiseaseinLULnodule,leYhilum,APwindowandleY7thrib

•  BiopsyperformedatSt.Mary’sinGrandJuncHonandpaHentreferredhereforpossibleradiaHontherapy

•  Biopsywasreviewedandconfirmedadenocarcinoma•  MoleculartesHngperformedbyColoradoMOlecular

COrrelateslab(CMOCO)

•  PaHentreferredtomedicaloncologist–whatdidIrecommendfor1stlinetreatment?

MolecularlyDefinedLungCancer:EGFRleadstheway

ClinicalpredictorsofobjecHveresponseratetoEGFRTKI

•  Subgroupanalysisdemonstratedthatseveralgroupshadahigherlikelihoodoftumorresponse:–  Femalegender

– Asianethnicity– Never‐smokingstatus– Adenocarcinoma

DramaticresponsesinpatientstreatedwithEGFRTKI

pre‐treatment

Lynchetal.NEJM,2004

6weekstreatment

BiomarkersforresponsetoEGFRTKItherapy

•  8of9paHentswhoexperiencedtumorresponsedemonstratedmutaHonsinExon18,19,and21ofEGFRgene

BiomarkersforresponsetoEGFRTKItherapy,cont.

•  SomaHcmutaHonsinthekinasedomainofEGFRoccurin~10%ofUSpopulaHon,but30‐50%inAsianpopulaHon

•  90%ofthesemutaHonsclusterinexon19andexon21

CMOCOReportTissueProcessing:Formalinfixed,paraffinembeddedSpecimenType:LungCollecHonProcedure:LeYupperlobeDateofCollecHon:06/17/10HistologicDiagnosisSummary:AdenocarcinomaFISHREPORTUsingafluorescenceinsituhybridizaHon(FISH)technique,paraffinsecHonsarehybridizedwithmulHcolored

probesagainstthemarkersnotedbelow.Resultsareasfollows:‐ALK:NegaHveforALKrearrangement(<15%ofcellswithsplitsignals,50cellsscored)

MUTATIONALANALYSISDNAisextractedfroma1mmtumor‐enrichedcoreofparaffin‐embeddedHssue,amplified,anddirectly

sequencedforseveralsomaHcmutaHonsthatmaybeofpredicHvevalue.Resultsareasfollows:‐KRAS,exon2:wildtype‐EGFR,exon18:wildtype‐EGFR,exon19:wildtype‐EGFR,exon20:wildtype‐EGFR,exon21:mutaYonpresent(L858R,CTG?CGG,2573T?TG)‐TP53,exon5:wildtype‐TP53,exon6:wildtype‐TP53,exon7:wildtype‐TP53,exon8:wildtype

INTERPRETATIONThepresenceofamutaHonintheusual858RcodonsuggeststhatthistumorwillrespondfavorablytoEGFRblockade.ClinicalcorrelaHonissuggested.

ClinicalHistory:Requestreviewofoutsidecytologytoconfirmdiagnosis/CMOCO.TobepresentedatLungTumorBoard07/12/10.Seventy‐twoyearoldmaleformersmokerwithnonsmallcellcarcinoma,consistentwithadenocarcinoma.

Interpretedby:_____ELECTRONICALLYSIGNED______WilburFranklin,M.D.Pathologist‐2059Date:___07/22/2010______

CasePresentation:PatientOutcome

•  ErloHnibiniHatedat150mgPOoncedailyasfirstlinetherapyforstageIVBlungadenocarcinoma

•  Ribpainresolvedwithin3‐4days•  FirstPET/CTat6weeksshoweddecreasedPETacHvityinalllesionsanddecreaseinLULnodulesize

•  RashanddiarrheanecessitatedsupporHvecareanddosereducHonto100mgPOoncedaily

IPASS:StudyDesign

GefiYnib(250mg/day)

CarboplaYn(AUC5or6)/paclitaxel

(200mg/m2)3weekly#

*Neversmokers,<100cigarefesinlifeYme;lightex‐smokers,stopped≥15yearsagoandsmoked≤10packyears;#limitedtoamaximumof6cyclesCarboplaYn/paclitaxelwasofferedtogefiYnibpaYentsuponprogressionPS,performancestatus;EGFR,epidermalgrowthfactorreceptor

PaYents• Chemonaïve

• Age≥18years

• Adenocarcinomahistology

• Neverorlightex‐smokers*

• Lifeexpectancy≥12weeks

• PS0‐2

• MeasurablestageIIIB/IVdisease

Primary• Progression‐freesurvival(non‐inferiority)

Secondary• ObjecYveresponserate• Overallsurvival• Qualityoflife• Disease‐relatedsymptoms• Safetyandtolerability

Exploratory• Biomarkers

• EGFRmutaYon• EGFR‐gene‐copynumber• EGFRproteinexpression

• 

Endpoints

Moketal.,NEJM2009

IPASS:PatientswithEGFRactivatingmutationsbenefitfrom1stlineEGFRTKI

GefiYnib(n=132)CarboplaYn/paclitaxel(n=129)

GefiYnib(n=91)CarboplaYn/paclitaxel(n=85)

EGFRmutaYonposiYve

ObjectiveresponserateinEGFRmutationpositiveandnegativepatients

0

10

20

30

40

50

60

70

80

WhichgrouphastheEGFRmutations?

•  66 yo African-American woman, adenocarcinoma, never smoker

•  70 yo Caucasian woman, adenocarcinoma, former smoker (40-50 py)

•  55 yo Asian woman, adenocarcinoma never smoker

•  70 yo Caucasian woman, adenocarcinoma, never smoker

PatientsWITHOUTEGFRmutations

•  46 yo Polynesian man, adenocarcinoma, never smoker

•  46 yo Caucasian woman, adenocarcinoma, never smoker

•  60 yo African man, adenocarcinoma, never smoker

•  42 yo Hispanic woman, adenocarcinoma, light smoker (4 py)

WhoshouldbetestedforEGFRmutations?

Pietanzaetal.,ASCO2010,Abstr#10538

Chmielecki and Pao AACR 2009; Oxnard et al., ASCO 2010 #7520

2ndgenerationEGFRinhibition:Pan‐HER,irreversibleTKIs

•  SeveraldrugsindevelopmentasnextgeneraHoninhibitors–  BindandinhibitotherHERfamilymembers

–  Irreversible(covalentbinding)

ComparisonofEGFRTKIs

AdaptedfromDoebeleetal.,LungCancer2010

PF299804vs.Erlotinib:Progression‐freeSurvival*fortheOverallPopulation

Overall population

100 90 80 70 60 50 40 30 20 10 0

Prog

ress

ion-

free

su

rviv

al p

roba

bilit

y (%

)

0 5 10 15 20 25 30 35 40 45 50 55 60 Time (weeks)

Unstratified analysis: Hazard ratio = 0.681 (95% CI: 0.490–0.945) Log-rank P-value = 0.019

PF299804 (n=94) Median: 12.4 weeks (95% CI: 8.3–16.1)

Erlotinib (n=94) Median: 8.3 weeks (95% CI: 8.0–11.4)

CI = confidence interval *Post-baseline tumor assessments were initiated at week 8 and conducted every 4 weeks thereafter.

PF299804activityafterchemotherapyandEGFRTKIfailure

Campbell et al., ASCO 2010, Abstr 7596

EGFRinNSCLC•  EveryoneshouldbetestedotherwisetoomanypaHentsdeniedmoreeffecHve,moretolerabletherapy

•  PaHentsinevitablydevelopresistance–  50%becauseofsecondT790MmutaHon

–  20%secondarytoMEToverexpression

•  NextgeneraHonofEGFRinhibitorsareindevelopment

ALK:Arapidfollow‐uptothesuccessofEGFRTKIinEGFRmutantpatients

ALK:AnoveloncogeneidentifiedinNSCLC

AnaplasYcLymphomaKinase:

•  IniHallyidenHfiedinAnaplasHcLargeCellLymphoma(ALCL)–  2;5translocaHonfusingNPMto

ALK

•  PointmutaHonsinneuroblastoma

•  NovelfusionidenHfiedin2007inNSCLC–  EML4‐ALK

Sodaetal.,Nature2007

Critozitinib(PF‐02341066)Anoral,selecHveinhibitorofMetandALKkinases

Solomonetal.,JTO2009

PatientwithALKpositiveNSCLC

Pre‐Treatment(FLT‐PET)

AYer4weeksofcrizoHnib

WhoshouldbetestedforALK?

•  EnrichmentstrategyoftesHngonly:–  adenocarcinoma

–  <10pysmokinghistory–  EGFRwild‐type–  KRASwild‐type

•  yields45%ALK+rate(comparedto3‐5%inunselectedpopulaHons)

Camidgeetal.,ClinCanRes,inpress

AssociationofClinicalandHistologicfeaturesinALK+patients

Doebeleetal.,submi3ed

ClinicalandhistologiccharacteristicsofALKpositivepatients

Doebeleetal.,submi3ed

* Detected by High-resolution melting analysis (HRMA)

MolecularcharacteristicsofALKpositivepatients

Doebeleetal.,submi3ed

EML4/ALK+ Med. Age

Male Female Never** Smoker

Smoker† Adeno‡ Non- Adeno

129/3933 (3.3%)

59 56/1451 3.9%

51/1017 5.0%

83/762 10.8%

36/1534 2.3%

118/2168 5.4%

8/870 0.9%

WhoshouldbetestedforALK?

•  All patients with NSCLC

•  Other technologies such as IHC or RT-PCR – cheaper – more widely available – RT-PCR gives more detailed

information – Not yet validated

BIBF‐1120

Conclusions:

•  RaHonallydesigned,targetedtherapiessuccessfullyimpacHngdifficult‐to‐treatdiseases

•  TesHngofBiomarkersinNSCLCcanhelpguidetherapytoappropriatepaHentpopulaHonsattherightHme

•  NoclinicalcharacterisHcscandisHnguishwhowillhaveafavorable(e.g.,targetable)biomarkers

UniversityofColoradoThoracicOncologyProgram