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LiquidBiopsiesinOncologyDrugandDeviceDevelopmentPart2Transcript:SessionI,CancerLiquidBiopsies:StateoftheScience

PasiJanne: Getstarted.OnbehalfoftheAmericanAssociationforCancerResearch,Iwanttothankyouforjoiningustoday.MynameisPasiJanne,amemberoftheAACR'sregulatoryscienceandpolicysubcommittee.TheAACRisproudtobecosponsoringthisworkshopforthesecondstraightyearwiththeUSFoodandDrugAdministration.AlongwithmyAACRcochair,Dr.CarlosArteaga,we'rethrilledtocochairthisworkshopwithdoctorsJuliaBeaver,GideonBlumenthal,andReenaPhilip,fromtheFDA.

[00:00:30] Liquidbiopsiesareanexcitingtechnologyandholdmuchpromiseforimprovingcancerdiagnosisandmonitoring,aswellasdrugdevelopment.Thetechnologyhasuniqueregulatoryconcerns,particularlyinestablishinganalyticandclinicalvalidity.Thegoalofthisyear'sworkshopistoexploretheregulatorychallengesinadoptingthistechnologyforearlydetection,diseasemonitoring,andpotentialuseassurrogateendpointmarkersfordrugdevelopment.

[00:01:00]Theworkshopwillhavefoursessions.Thefirstsessionwillbethestateoftheartofthevarioustechnologies.Secondsessionwillexploreusingliquidbiopsiesforearlydiagnosisorresidualdiseasedetection.Thethirdsessionwillexamineliquidbiopsiesincancerdrugdevelopmentandclinicaluse.Finally,thefourthsessionwillexaminetheregulatoryconsiderationsfordevelopmentoftheseassays.

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Oneofthehallmarksoftheworkshopistheinterdisciplinaryforum,withawiderangeofperspectivesfromstakeholders,fromacademia,government,aswellasindustry.I'mhappytoreportthatasoflastnightwehaveover500peopleregisteredfortheworkshop.Inadditiontotheover200peopleregisteredtoattendtheworkshophereinDC,there'salmost300peoplewatchingthisworkshop.Wehavealivewebcast.We'dliketoexpressanoteofappreciationtoAmgenfortheirsupportoftoday'sworkshop,whichishelpingtodefraysomeoftheexpensesassociatedwithit,includingallowingthisworkshoptobebroadcastinrealtime.TheAACRiscontinuouslylookingforopportunitiestoengageonimportantregulatoryscienceissues,andtheAACRlooksforwardtoacontinued,productivepartnershipwiththeFDA.

[00:02:00] Iwanttoagainthankallofyouforjoiningustoday,andIwillnowturnitovertomyfellowworkshopcochair,Dr.GideonBlumenthalfromtheFDA,foradditionalopeningremarks.Gideon.

GideonBlumenthal:

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Hey,thanksPasi,andjustwantedtopiggybackonwhatyousaid.We'rethrilledtobehereforoursecondliquidbiopsyandoncologyworkshop,backbypopulardemand.Wehadalotofgreatinterestfromourfirstworkshop,wherewepresentedthecaseofthefirstapprovalofaliquidbiopsydevice,aplasmactDNAEGFRtesttodetectEGFRmutationsinmetastaticnonsmallcelllungcancer.Withthisworkshopwewanttocontinuethediscussion,alsofocusingonearly

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stagedisease.Wehaveagreatsessionforthat.Wealsowanttotalkaboutnovelregulatoryissues,includingusingtheseinnovativetechnologiesaspotentialsurrogateendpointsasdrugdevelopmenttoolsforregulatorydecisionmaking.Thispromisestobeagreatmeeting.Wewanttokeepthisveryinteractivewiththecrowd,sohopefullythere'llbealotoftimeforrobustdiscussionduringthepanel.Forthoseofyoulisteningviawebcast,pleasesendusyourquestionsandwe'lltrytoengagethepanelistsandspeakerswithyourquestionsaswell.

Withthat,I'llturnitovertoJuliaBeaverforsessionone.

JuliaBeaver: Thanks,Gideon.So,sessiononewillbeanupdateofthestateofthescienceofliquidbiopsieswithtalksoncirculatingcellfreetumorDNA,exosomes,andcirculatingtumorcells.

[00:00:30] Thesetalkswillgointoupdatesoneachbiomarker,techniquestodetectcurrentusesandfuturedirections.Eachtalkwillbeapproximately20minutes.Followedby5minutesofquestionsfromtheaudiencetoeachoftheconsecutivespeakers.Weareluckytohavethreeexpertspeakersintheirfields,whoIwillnowintroducecollectively.

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ThefirsttalkwillbeonnewdevelopmentsandanalysisofcirculatingtumorDNAgivenmyDr.MaxDiehn.Dr.DiehnisanAssistantProfessorofRadiationOncologyatStanfordUniversity,wherehisresearchisfocusedonthoracicmalignanciesanddevelopmentandapplicationofmethodsfordetectionofcirculatingtumorDNA.

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Thenexttalkwillbeonstrategytoexploitthebiologyofexosomesfordiagnosisandtreatmentofcancer;givenbyDr.RaghuKalluri.Dr.KalluriisaProfessorandChairmanoftheDepartmentofCancerBiologyandtheDirectoroftheMetastasisResearchCenteratMDAndersonCancerCenter.Hisresearchinterestsincludethestudyofcelltissuemicroenvironmentandit'simpactoncancerprogressionandmetastasis.

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ThelasttalkofthesessionwillbegivenbyDr.DanielHaberonnewstrategiesforquantificationofcirculatingtumorcells.Dr.HaberisDirectoroftheMassachusetsGeneralHospitalCancerCenter,andtheKurtJ.IsselbacheratHarvardMedicalSchoolProfessorofOncologyatHarvardMedicalSchool.Hisresearchhasfocusedontheareaofcancergeneticsanddevelopmentofnoveltechnologiesforquantifyingandpurifyingcirculatingtumorcells.

ThankyouforcomingandIwillturnthepodiumovertoDr.Diehn.

MaxDiehn:

Great.Well.Thankyouverymuch,pleasuretobeheretodaytospeaktoyouaboutcirculatingtumorDNAandsomeofourwork.It'salittlebitearlyforawestcoastperson,it'sabout5:45inthemorning,soifIfallasleepsomeonekickmeplease.Herearemydisclosures.TodayI'llcoverafewitemsinthis20minutetalk.FirstisabriefbackgroundoncirculatingtumorDNA,whichIassumethe

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[00:00:30] vastmajorityhereandonlinearefamiliarwith.Then,brieflytalkabouthowwearealreadyusingthisbiomarkerinthecliniccurrently,withafocusonlungcancer,whichiswhatIspecializeinclinicallyaswellaswhatmyresearchareais.ThenkindofspendmosttimeonthreeemergingapplicationsorfuturedirectionsrelatedtodetectionofheterogeneityoftriculresistancemutationsusingcirculatingtumorDNA,minimalresistancediseasedetection,andearlydetection.

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CirclingtumorDNAofcoursereferstosmallfragmentsoftumorDNAthatoriginateintumorsthatarefoundinthecirculationofcancerpatients.WeallhavecirculatingcellfreeDNAinourplasma,butinpatientsthatdon'thavecancerthatcomesofcoursefromthehealthycellsthatareturningovereverydaywhereasinpatientswhohavecancer,thereissomeDNAfromthetumoraswellasalargebackgroundofDNAfromtheirhealthycellsthataredyingeachday.Wecanisolatethisanolytethroughroutineblooddrawsandthenanalyzeitinavarietyofways.There'sbeenalotofinterestinthisareainthelastfiveorsoyears.We'veknownaboutthisbiomarkerforatleast60yearsbutthetechniquesneededtosensitivelyandspecificallydetectithavenotbeenwidelyavailableuntilthelastfiveorsoyears.That'sreallywhat'sledtotheexplosionofinterestinthisfield.

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There'sanumberofreasonswhycirculatingtumorDNAisaveryattractivebiomarker.Ilistthreemainoneshere.ThefirstisthatoneIwillbefocusingontodayismeasuringmutations,somaticalterations,thatwecanfindincirculatingDNAthatofcourse,comefromthecancergenomesandthatarevery,veryspecifictothosecancercells.Reallynoothercancercellsinthatpatient'sbodywillhavethosemutationsandsowehaveabiomarkerthat'squitespecific.Differentthanmostproteinbasedbiomarkers,whichofcoursearealsomadebynormalcells,usually.Thesecondis,andveryimportantfromabiologystandpoint,isthatmutationsareveryimportantinthepathogenesisofthedisease,ifyouweregonnadesignabiomarkerfromthegroundupitmakessensetopicksomethingthatisreallylinkedtothedisease.Then,lastlyandveryimportantly,someofthemutationsareactionableandthatmeansnotonlycanweusethisbiomarkertotrackhowmuchcancerapatienthasintheirbody,butalsopotentiallyusetheinformationwegetfromtheseassaystodeterminewhatthebesttreatmentmightbe.

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OneoftheexcitingaspectsofcirculatingtumorDNA,butalsooneofthechallengesisthatit'sreallyapplicabletoanypartofapatient'sdiseasetrajectory.Onthisgraph,here,IshowontheYaxistumorburdenofaidealizedpatientandonthe...asthepatientgoesthroughtime,thediseaseburdengoesupordown,sointhisexamplethispatienthassomesortofprediagnosticphase,thentumorgrows,hassomelocaltreatmentthathasaresponse,recurs,getssystemictreatmentandrecursagain.We'llusethistojusttalkaboutwherewemightimagineusingcirculatingtumorDNAintheclinic.Thefirstandveryactiveareaofresearchandinterestis,ofcourse,earlydetectionorscreeningwhereonemightbeabletousethisbiomarkertoidentifypatientswhoare

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asymptomaticornotknowntohavecancer,whothencouldhavesubsequent,othertests.

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Thethingwe'realreadydoingroutinelyintheclinic,everyday,isnoninvasivetumorgenotypingmeaningidentifyingthegenotypeofthetumorfromtheplasma.Iwilltalkaboutthat.Ifapatientgetsalocaltherapywecouldimagineusingthisbiomarkertoattractresponsebecauseifatreatmentisworking,itshoulddecreasetheamountofcirculatingtumorDNA.Inaveryexcitingareaofresearchistheideaofminimalresidualdiseasesistryingtodetermineifpatientshavehadlocaltherapy,whetherornottheystillhavemicroscopicdiseaseintheirbodyornotandwe'lltalkmoreaboutthat.Wecouldenvisionusingitinsurveillance,wherewecurrentlygenerallyuseimaginginmostcancersbutmaybesomedaywecoulddothisallusingcirculatingtumorDNA.Thenifapatientrecurswithsystemicdisease,onecouldagain,usecirculatingtumorDNAtomeasuresystemictreatmentresponse.Then,veryimportantly,ifoneisonatargetedagent,wecantrytolookforresistancemutationsintheplasma,whichoftencanbefoundlongbeforeapatientactuallyhasaclinicalrecurrence.

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That'salltheexcitingstuff,butofcourse,thereremainssignificantchallenges.Oneofthemostimportantchallengesisthatthereisn'tverymuchofthisDNA,total,meaningthecombinationofthegermlineDNAandthetumorDNAistheconcentrationofthisisreally,generallyquitelow.Usuallyonlyafewnanogramspermilliliterinpatientswithearlystagediseaseorwhoareinremission.Thatmeansoneneedsassaysthatareveryefficient,wecan'tbelosingmoleculesandweneedassaysthatworkonnanograminputDNAamounts.Now,that'scompoundedbythefactthatthefractionofthissmallamountofDNAthat'sfromthetumorisusuallyverysmall.

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Eveninadvancedpatients,itmaybeinthesingledigitpercents,butinpatientswhoarerespondingtotreatmentorwhoarewithearlystag