Post on 20-Mar-2018
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