全球精準(zhǔn)腫瘤治療報告 -Supporting Precision Oncology -IQVIA正式版

SupportingPrecisionOncology

TARGETEDTHERAPIES,IMMUNO-ONCOLOGY,ANDPREDICTIVEBIOMARKER-BASEDMEDICINES

AUGUST

2020

Introduction

Precisiononcologyofferstotransformcancercarewithmedicinestailoredtoeachpatientbytargetingspecificbioprocesses,geneticmutations,orbypreciselyenhancingtheindividual’simmunesystem.Precisiononcologyapproachesstartedinthe1970swiththelaunchoftamoxifen,thefirsttargetedtherapy

tointerferewithspecificcellularprocesseswithinatumor.Thisadvancementwasfollowedbyregulatoryapprovalforimmunotherapiesinthe1990sthatharnesstheimmunesystemtodestroytumorcells.Finally,precisiononcologymedicinesbecamemorepersonalizedinthe2000’sandbeyondwiththeapprovalofpredictivebiomarker-basedtreatments,whichareeffectiveintumorswithspecificmolecularprofiles,andcellulartherapiesthataregeneticallyprogramedtofightcancerwithinindividualpatients.Leapsintheunderstandingofcancerarepushingtreatmentsevenfurtherawayfromthesystemicchemotherapiesofthepastandprovidingbenefitstobothpatientsandhealthsystems.

Thisyear’soncologyreporttakesacloselookatthenumberofnoveloncologymedicineslaunchedintheUnitedStatesin2019,aswellaspatientaccesstothesemedicinesandtheuseofkeydrugclassesinprecisiononcology.Thisyear’sreporttakesalookattheimmuno-oncologypipeline,clinicaltrialactivity,andshiftsinclinicaldevelopmenttoNext-GenerationTherapeutics,suchastheCART-celltherapies.

ThereportalsoprovidesinsightintotheapplicationofbiomarkertestinginclinicalcarewithintheUnitedStatesandEurope.Clinicaldevelopmentofoncologytherapeuticsisespeciallycomplex,andthereportalsoexaminestheroleofbiomarkersandnoveltrialdesignswithinthisspace.

ThestudywasproducedindependentlybytheIQVIAInstituteforHumanDataScienceasapublic

service,withoutindustryorgovernmentfunding.ThecontributionstothisreportofCarolineAnger,PatCustis,HeenaDarira,JeffreyHodge,YaseminKaranis,MichaelKleinrock,ChrisLearn,FilManuguid,KimberlyMehle,ElyseMu?oz,DeannaNass,NitinPatel,ShivikaRastogi,DurgeshSoni,DanWinkelman,anddozensofothersatIQVIAaregratefullyacknowledged.

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MURRAYAITKEN

ExecutiveDirector

IQVIAInstituteforHumanDataScience

?2020IQVIAanditsaffiliates.Allreproductionrights,quotations,broadcasting,publicationsreserved.Nopartofthispublicationmaybereproducedortransmittedinanyformorbyanymeans,electronicormechanical,includingphotocopy,recording,oranyinformationstorageandretrievalsystem,withoutexpresswrittenconsentofIQVIAandtheIQVIAInstitute.

SupportingPrecisionOncology:TargetedTherapies,Immuno-Oncology,andPredictiveBiomarker-basedMedicines

Overview

Markettrendsforprecisiononcologytherapies

++ThecancertreatmentlandscapeintheUnitedStateshascontinuedtoevolvesince2015andnowincludesnewmedicinestargeting24differentcancertypes.

Themajorityaretargetedtherapies,drugsthatblockthegrowthofcancerbyinterferingwithspecificbiologicalprocesses,and58%requireorrecommendtestingforpharmacogenomicbiomarkersprior

touse,singlingoutwhichpatientsaremostlikelytorespondtoatreatmentbasedonthegenomicfingerprintoftheirtumor.

++TheEuropeanMedicinesAgency(EMA)approvedninenewactivesubstances(NAS)inoncologyin2019,ofwhichfiveareassociatedwithapredictivebiomarkerandtwohaveanapprovedcompaniondiagnostic.Amongtheseisthefirstapprovalintheregionforatissue-agnosticagent,larotrectinib,forthetreatmentofsolidtumorswithaNTRKgenefusion—twoyearsaftertheFDAgranteditsfirstapprovalofatissue-agnosticagent,pembrolizumab.

++CancerpatientsintheUnitedStatesgainaccesstonovelcancertherapiesonaveragefivemonthsearlierthanpatientsinEuropedue,inpart,toastricterreimbursementenvironmentfornewcancertherapiesaspartofHealthTechnologyAssessmentproceduresinEurope.Foroncologymedicinesthatrequirepharmacogenomictestingpriortouse,thosethatlaunchintheUnitedStatesfirstreach

Europeonaveragealmostninemonthslater,inpart,duetovariablediagnosticinfrastructureandlimitedawarenessoftheseproductsbyhealthcarestakeholders,allofwhichaddsadditionalchallengesforthelaunchoftheseproductsintheregion.

++Usingdefineddailydoses(DDD)toassesschangesintheuseofmedicinesshowsthatcheckpointinhibitorusehasgrownsharplyintheUnitedStatessince

2014atacompoundannualgrowthrate(CAGR)of

111.4%andreached2,783DDDsper100,000peopleinDecember2019.AlthoughEuropeanmarketssawsimilargrowth,theirusewasapproximatelyhalfat1,470DDDsper100,000people.

++IntheUnitedStates,threetherapieshaveregulatoryapprovalfortissue-agnosticindications.Pembrolizumab(Keytruda)receivedthefirsttissue-agnosticapprovalforpatientswithunresectableormetastatic,microsatelliteinstability-high(MSI-H)ormismatchrepairdeficient(dMMR)solidtumorsin2017,andby2019,11%ofpembrolizumab-treatedpatientshadtumortypeswheretreatmentisinformedbyMSI-H/dMMRalterations,demonstratingtheimpactthattissue-agnosticbiomarkershaveonpatientuptake,despitebarriersaroundtherarityofeligiblepatientsandaccesstothenecessarytestingforuseoftissue-agnostictherapies.

Clinicalapplicationsofbiomarkers

++Thenumberofclinicaltrialsincorporatingpharmacogenomicand/orpharmacogeneticanalysistostratifypatientsforpredictiveresponse,safety,ordosing,hasmorethandoubledsince2010andrepresents42%ofoncologytrialsin2019.

++Inoncology,thetotalnumberoftrialswithinnovativetrialdesigns,whichincludeadaptative,umbrella,andbaskettrials,hasmorethantripledsince2010.Theutilityofnoveltrialdesignssupportstheclinicaldevelopmentofprecisionmedicinesbyallowingthetestingofmultipleagentsorinvestigationofmultiple

|1

Overview

hypotheseswithinasingletrial.Theyalsodelivergreaterflexibilityaroundthenumberofenrolledpatients,doseselection,andtheabilitytoquicklyidentifyanddiscontinueunsuccessfultrials.

++Despitesomechallenges,therehavebeenincreasesintheuseofbiomarkertestsinroutinecareforcertaintumortypesacrosstheUnitedStatesandEurope.Thecurrentandfutureuseofprecisiononcologytherapieswilldependoncontinueduptakeofbiomarkertesting.

++Incolorectalcancer,wheretheuseofcertainbiomarkertestsincreasedbetween13–19%since

2017,therehasbeenanincreaseintheuseofthesetestsintheclinicaldecision-makingprocess,especiallyaroundthetargetedtherapieswithbiomarkersthatpredictdrugresponse.

++Oneuniversalchallengearoundbiomarkertestinghastodowiththepatientburdenoftesting.Asmorebiomarkertestsbecomerecommendedorrequiredpriortouseoftherapyacrosscancertypes,theamountoftissueavailableforaccuratetestingwillfurthergrowasanissue,pavingthewayformorenovelmethodsofbiomarkertesting,suchastheuseofliquidbiopsies.

Pipelineforimmuno-oncologyandtissue-agnosticproducts

++Immuno-oncologyagentshaveshownsignificantantitumoractivityacrossmultipletumortypes.Thishasinfluencedtheirdevelopmentandcreatedarobustnewproductpipelinewithover700immuno-oncologytherapiescurrentlyindevelopmentacrossallphases.

++ThePhaseIandPhaseIIimmuno-oncologypipelineincludes675productswithover102differentmechanismsofaction,andby2019,theearly-stagepipelinehasstartedtoshiftawayfromcheckpointinhibitorstowardsanincreasingnumberofCARcelltherapyproducts.ThenumberoftrialsforCARcelltherapyproductshasgrown38%since2015,withthesuccessofCART-celltherapyinB-cellcancersspurringdevelopmentintootherhematologicmalignanciesaswellassolidtumors.

++Thenumberoflate-stagemoleculesforimmuno-oncologyin2019increasedby65%since2018,from23to38,andrepresent14mechanismsofaction.ThecheckpointinhibitorPD-1/PD-L1modulators,whichremainamongthemostefficaciousimmuno-oncologytherapies,madeup47%ofthelate-stagepipelinein2019.Improvementsinformulationsorcombinationswithothertargetedtherapiesmayleadtobreakthroughs.Atthesametime,thenumberofcheckpointinhibitortrialshasdoubledsince2015.

++In2019,therewereover20tissue-agnostictherapiesindevelopmentacross28uniqueindications.Developmentisfocusedonsolidtumors,butdevelopmentforotherindicationsoftenoccurssimultaneouslyorinparallel,suggestingthatmanufacturershaveanoverlappingfocusonhistology-dependentandtissue-agnosticindications.

2|SupportingPrecisionOncology:TargetedTherapies,Immuno-Oncology,andPredictiveBiomarker-basedMedicines

Markettrendsforprecisiononcologytherapies

U.S.ANDE.U.ACCESSTOINNOVATION

Innovationinoncologycontinuestogrowduetoincreasingcontributionsfromprecisiononcologytherapies.Precisiononcologyoffersmedicinestailoredtoeachpatient,bytargetingspecificbioprocessesorgeneticmutationsorbypreciselyenhancingtheindividual’simmunesystem.Thenumberanduseoftheseagentscontinuetogrow.Overall,thecancertreatmentlandscapeintheUnitedStatesfrom2015–2019included60uniquenewactivesubstance(NAS)medicinestargeting24differentcancertypes(seeExhibit1).Thesemedicinessaw115newindicationapprovalsintotalduringthisperiod,withmanyofthesedrugsapprovedformorethanoneindication.OfthetotaluniqueNASmoleculesbetween2015and2019,93%weretargetedtherapies;drugsthatinterferewithspecificmoleculesinvolvedinthegrowth,progression,andspreadofcancer.

In2019alone,12therapies—eleventargetedagentsandonediagnosticagent—werelaunchedintheUnitedStates.Predictivebiomarkerswereassociatedwith25%(n=3)oftheseoncologyNASs,andtwowereapprovedwithacompaniondiagnostic.TwooftheNASswereimmuno-oncologyantibody-drugconjugates(ADC)thatselectivelybindproteinsfoundinspecificcancers:enfortumabvedotin(Padcev)andpolatuzumabvedotin(Polivy).Enfortumabvedotintargetsnectin-4,acellsurfaceproteinthatisexpressedonbladdercancercells,whilepolatuzumabvedotinselectivelytargetsCD79b,

aproteinreceptorexpressedonthemajorityofB-cells.Enfortumabvedotinandpolatuzumabvedotinarebothfirst-in-classADCsfortheirspecificproteintarget.

Eightofthe12NAStherapiesaredeliveredinanoralformulation,decreasingthepatientburdenofreceivingcareataninfusioncenterorhospital.SevenofthetherapiesreceivedabreakthroughtherapydesignationfromtheFDA,sixreceivedacceleratedapproval,ninewereapprovedbasedonasingletrial,andeightcited

PhaseIorPhaseIItrialsaspartoftheirapprovals.Takentogether,thesefourattributessupporttheongoingtrendaroundtheurgencyoftheFDAtobringinnovativeoncologytherapiestopatients.

WhiletheFDAapproved12NASsin2019forhematologicmalignanciesandsolidtumors,theEMAapprovednine.AllnineEMA-approvedNAStreatmentsin2019weretargetedtherapies.Fiveoftheninetherapieswereassociatedwithapredictivebiomarker,andofthese,twohaveapprovalforacompaniondiagnostic.In2019,theEMAgrantedapprovalforthefirsttissue-agnosticagentintheregion,larotrectinib,forthetreatmentofsolidtumorswithanNTRKgenefusion.LiketheFDA,theEMAisbalancingregulatoryprocesseswiththepressingneedtobringinnovativeoncologytherapiestopatientsthroughactionssuchasacceptingdatafromPhaseIandPhaseIItrials(n=4)andthroughconditionalmarketingapprovals(n=4).1Ofnote,polatuzumabvedotinreceivedPRIMEdesignationstatusfromtheEMA,aschemedesigned

tosupportthedevelopmentofmedicinesthattargetanunmetneedbyacceleratingtheassessmentofthedrug.

CancerpatientsintheUnitedStatesgainaccesstonovelcancerNASsonaveragefivemonthsearlierthanpatientsinEuropedue,inpart,toastricterenvironmentforreimbursementofnewcanceragentsaspartoftheHealthTechnologyAssessmentproceduresinEurope(seeExhibit2).In2019,thereisalargedifference,inmonths,betweenthetimeaproductlaunchesintheUnitedStatesandEurope.Thisdifferenceisdueinlargeparttoonenoveldiagnosticagent,Ga-68-DOTATOC,whichlaunchedinFrancein2016forusewithpositronemissiontomography(PET)forlocalizationofsomatostatinreceptorpositiveneuroendocrinetumors(NETs).

Foroncologymedicinesthatrequirepharmacogenomicbiomarkertestingpriortouse,thosethatlaunchintheUnitedStatesfirstreachEurope,onaverage,almostninemonthslater,inpartduetovariablediagnosticinfrastructureandlimitedawarenessoftheseproductsbyhealthcarestakeholders,allofwhichaddsadditionalchallengesforthelaunchoftheseproductsintheregion.

|3

Exhibit1:U.S.NewActiveSubstancesinOncologybyYearofIndicationApproval,2015–2019

atezolizumab*

avelumab

durvalumab

erdafitinib*

enfortumabvedotin-ejfv

nivolumab

pembrolizumab*

entrectinib*

larotrectinib*

pembrolizumab*

lenvatinib

Bladder

nivolumab

pembrolizumab

Tissue

ramucirumab*

acalabrutinib

regorafenib

Agnostic

daunorubicin+cytarabine

duvelisib

enasidenib*

Liver

fedratinib

dabrafenib*

gilteritinib*

lenvatinib

glasdegib

trametinib*

ibruntinib*

inotuzumabozogamicin

ivosidenib*

Thyroid

midostaurin*

moxetumomabpasudotox-tdfk

venetoclax*

tagraxofusp-erzs

tisagenlecleucel**

Leukemia

BPDCN

alectinib*

Myelofibrosis

atezolizumab*

brigatinib*

dabrafenib*

dacomitinib*

durvalumab*

Lung

entrectinib*

getfitinib*

lorlatinib*

necitumumab

nivolumab

osimertinib*

Neuroblastoma

pembrolizumab*

trametinib*

dinutuximab

Sarcoma

eribulinmesylate

andSoft

Tissue

olaratumab

Sarcoma

trabectedin

Multiple

daratumumab

Myeloma

elotuzumab

Prostate

ixazomib

panobinostat

selinexor

avelumab

abemaciclib*

cabozantinib

atezolizumab*

ipilimumab

alpelisib*

nivolumab

lenvatinib

neratinib*

nivolumab

avelumab

pembrolizumab*

olaparib*

pembrolizumab

palbociclib*

binimetinib*

ribociclib*

cemiplimab-rwlc

talazoparib*

cobimetinib*

Head

encorafenib*

Renal

pembrolizumab*

andNeck

sonidegib

ipilimumab*

Breast

talimogenelaherparepvec***

nivolumab*

ramucirumab

trifluridine/tipiracil*

Skin

acalabrutinib

axicabtagene**

ciloleucel

copanlisib

Colorectal

duvelisib

ibrutinib*

Cancer

mogamulizumab

nivolumab

obinutuzumab

pembrolizumab

Lymphoma

polatuzumab

vedotin-piiq

tisagenlecleucel**

zanubrutinib

irinotecanliposome

Pancreatic

olaparib*

niraparib*

Ovarian

olaparib*

rucaparib*

Cervical

pembrolizumab*

Endometrial

lenvatinib*

pembrolizumab*

TSGCT

Gastric Esophagus pexidartinib

*

**

***

apalutamide

pembrolizumab*

darolutamide

ga-68-dotatoc

Targetedtherapy

lutetiumLu177dotatate*

pembrolizumab*

Non-targetedtherapy

trifluridine/tipiracil*

PGXtesting

CAR-T

Oncolyticvirus

Source:Publiclyavailablesources,including:NIH.TargetedCancerTherapies.AccessedMar2020.Availablefrom:/about-cancer/treatment/types/targeted-therapies/targeted-therapies-fact-sheet;PharmGKB.AccessedApr2020./labelAnnotations.IQVIAInstitute,Jun2020

Notes:Exhibitshowsinitialandsubsequentapprovalsforoncologicagentswithintheperiodof2015through2019.Excludessupportivecare.

Targetedtherapiesblockthegrowthandspreadofcancerbyinterferingwithspecificmoleculesinvolvedinthegrowth,progression,andspreadofcancer.Predictivemedicinesareflaggedforspecifictumortype.Ga-68-DOTATOCisadiagnosticagentforlocalizationofsomatostatinreceptorpositiveneuroendocrinetumors(NETs).Skincancerincludesmelanoma,Merkelcellcarcinoma,cutaneoussquamouscellcarcinomaandbasalcellcarcinoma;BPDCN=Blasticplasmacytoiddendriticcellneoplasms;TSGCT=tenosynovialgiantcelltumor.

4|SupportingPrecisionOncology:TargetedTherapies,Immuno-Oncology,andPredictiveBiomarker-basedMedicines

Exhibit2:DifferenceinU.S.andEuropeanAccesstoNovelOncologyTherapies,2015–2019

DifferencebetweenU.S.andEuropelaunchinmonths

Differenceinlaunch,inmonths,fortherapies

launchedinU.S.priortoEurope

First

15

N=14

4

11

11

5

U.S.Launch

10

0

First

-5

Launch

-10

Europe

-15

2015

2016

2017

2018

U.S.LaunchDate

Averagedifferenceinmonths

Source:IQVIAAnalyticsLink;IQVIAInstitute,Jun2020

2

2019

Average

15.0

First

5.0

U.S.Launch

10.0

0.0

-5.0

First

Launch

-10.0

-15.0

Europe

N=13

3

9

10

1

15

15.0

10

10.0

5

5.0

0

0.0

-5

-5.0

-10

-10.0

-15

-15.0

2015

2016

2017

2018

2019

U.S.LaunchDate

Doesnotrequirebiomarkertesting

Requiresbiomarkertesting

Averagedifferencefordrugs

thatrequirebiomarkertesting

Notes:DifferenceinmonthswascalculatedasU.S.minusEuropeanlaunchdate.Thischartincludesalldrugsthatlaunchedfirstin2015andbeyondineitherU.S.orEuropeangeographies.Thisanalysisexcludesdrugsthatdidnotlaunchinbothgeographieswithinthistimeperiod.Numbersabovethex-axisreflectlaunchfirstintheUnitedStatesandbelowtheaxisreflectlaunchfirstinEurope.Thenegativevaluein2019isinfluencedbythedifferenceinlaunchmonthsfromonedrug,Ga-68-DOTATOC,whichlaunchedinFrancein2016.

DEFININGPRECISIONONCOLOGYTREATMENTS

Precisiononcologyincludesmedicinestargetingspecificbioprocessesorgeneticmutationsorthatpreciselyenhancetheindividual’simmunesystem.Precisiononcologyincludestargetedtherapies,immuno-oncologytherapies,aswellastherapiesassociatedwithpredictivebiomarkers.Specifically,

Targetedtherapiesblockthegrowthandspreadofcancerbyinterferingwithspecificmoleculesinvolvedinthegrowth,progression,andspreadofcancer.2

Immuno-oncologytherapieshelpapatient’simmunesystemfightcancer.Theyincludeabroadrangeoftreatmentssuchasmonoclonalantibodies,checkpointinhibitors,andimmunesystemmodulators.3Inaddition,clinicalresearchisprogressingonpersonalizedcellularproducts,includingnovelCARproducts.

Predictivebiomarker-basedtherapiespredicttumorresponsetoaspecifictherapybyinformingonwhichmolecularalterationsaredrivingcancergrowth.Predictivebiomarkerscanbeusedtoselectwhichtargetedtherapyislikelytohaveaneffect,enablingstakeholderstomakeprecisetreatmentchoices.Regulatorsrequireorrecommendpatientsbescreenedforbiomarkerstatuspriortotheuseofapredictivebiomarkertherapy.

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THERISEOFPRECISIONONCOLOGYMEDICINES

Thenumberoftargetedoncologymedicineshasgrown,andnowaccountsfor93%ofthetotaluniqueNASmoleculeslaunchingbetween2015and2019intheUnitedStates.Sotoohastheuseoftargetedoncologytherapies(asmeasuredinstandarddoseunits),which,intotal,havedoubledoverthepast10yearsacrossthedevelopedmarkets.IntheUnitedStates,theuseoftargetedtherapieshasdoubledsince2009andmorethandoubledintheEU5overall,withuseinGermanyandSpaintriplingfortargetedoncologytherapies.Similarly,inSouthKoreaandCanada,volumegrewby173%and163%,respectively.

Inadditiontotargetedtherapies,58%ofoncologymedicineslaunchedbetween2015and2019intheUnitedStatesrequireorrecommendtestingforpharmacogenomicbiomarkerspriortouse.Predictivebiomarkerscanbeusedtodeterminewhichpatientswillrespondbesttoaparticulartherapyorwhichpatientswouldbemorelikelytoexperienceapotentialadverseeventallowingforapersonalizedtreatmentselection.By2019intheUnitedStates,70productshadrequirementsorrecommendationsontheirlabelsforbiomarkertestingpriortouse,anincreaseof67%since2015(seeExhibit3).

Cancer-targetingimmuno-oncologyagentsincludethecheckpointinhibitors—therapiesthatblockimmunecheckpointsandsubsequentlyactivateapatient’simmunesystemtofighttumors—andthesedrugshaveinduceddurableresponsesinsomepreviouslyintractablecancers.Since2011,sevencheckpointinhibitorshavereceivedregulatoryapprovalintheUnitedStates:pembrolizumab,nivolumab,cemiplimab,atezolizumab,avelumab,durvalumab,andipilimumab.Theestimatedpercentageofpatientswithcancereligibleforcheckpointinhibitordrugshasincreasedfromapproximately2%in2011to44%in2018,4andthepercentageofpatientswithcancerestimatedtorespondtocheckpointinhibitordrugshasrisen,fromunder1%in2011toapproximately13%in2018.4Subsequently,thevolumeoftheseagents(instandarddoseunits)hasdoubledsince2016intheUnitedStates.

ToassesschangesinuseofcheckpointinhibitorsacrosstheUnitedStatesandEurope,adefineddailydose(DDD)metricwasusedtonormalizeuseacrosscountriesper100,000people,drivingunderstandingofusageonanormalizeddaysoftherapylevel.

Exhibit3:NumberofU.S.OncologyMedicineswithRequiredorRecommendedPredictiveBiomarkerTesting

70

63

53

47

42

36

30

25

16

17

19

20

12

13

8

10

10

7

7

5

5

6

6

5

6

4

3

2

2

2

3

1

1

1

1

4

<1998 2000 2001 2002 2004 2005 2006 2007 2009 2011 2012 2013 2014 2015 2016 2017 2018 2019

CumulativecountovertimeIndividualcountbyyear

Source:IQVIAInstitute,Jun2020

Notes:U.S.oncologymedicinesthatrecommendorrequirepharmacogenomictestingontheirprescribinglabelspriortouse.Thelistincludesoncologytherapiesthatgainedapprovalforindicationsoutsideoftheinitialregulatoryapprovalthatsubsequentlyrecommendedorrequiredabiomarkertestpriortouse.

6|SupportingPrecisionOncology:TargetedTherapies,Immuno-Oncology,andPredictiveBiomarker-basedMedicines

Exhibit4:CheckpointInhibitorsUseinDefinedDailyDosesperCapita,2011–2019

DDDper100,000population

3,000

EU5

UnitedStates

DDDsper

100Kpeople

2,500

asofDec1,2019

2,000

Drug

EU5

United

States

1,500

692.3

1,375.8

510.2

757.3

1,000

72.7

296.1

129.6

271.9

500

34.6

65.8

18.9

15.9

0

12.0

15.0

2011

2012

2013

2014

2015

2016

2017

2018

2019

2011

2012

2013

2014

2015

2016

2017

2018

2019

PembrolizumabNivolumabDurvalumabAtezolizumabIpilimumabAvelumabCemiplimab

Source:IQVIAMarketPrognosis,Sep2019;IQVIAInstitute,May2020

Notes:EU5percapitacalculationusedtheDDDsforeachtimeperioddividedbytheentireEU5populationforthatyear.

UsehasrisensharplyintheUnitedStates,growingatan111.4%CAGRsince2014,andreaching2,783DDDsper100,000peopleinDecember2019(seeExhibit4).AlthoughEuropeanmarketssawsimilargrowthataCAGRof114.9%,usewasapproximatelyhalfthatoftheUnitedStatesat1,470DDDsper100,000people

(seeAppendixonDefinedDailyDoses).DifferencesinDDDsbetweentheUnitedStatesandEuropeare,inpart,duetoahigheruseofthePD-1inhibitorpembrolizumabintheUnitedStates,alagtimeforindicationapprovalsbetweentheregions,andaffordability/reimbursementchallengesforthecheckpointinhibitorsinEurope.

TheuseofcheckpointinhibitorsacrosstheEU5varies(seeExhibit5).FranceandGermanyhavethehighestpercapitaDDDuseofcheckpointinhibitors—1,424–2,308DDDsper100,000peopleinDecember2019—inpartduetoshorter5andmorefavorableHTAassesmentsforimmunotherapymedicinesrelativetootherEuropeancountries,6andduetotheincreasingspendingoncancertherapieswithinthesecountries.7SpainhadthelowestDDDuseper100,000peopleat971followedbytheUnitedKingdomat977,inpart,duetoaccessandreimbursementchallenges.AlthoughthetotalDDDsper100,000peopleinItalyisbelowthatofGermany

andFrance,inpartduetoreimbursementchallengesaroundcemiplimabanddurvalumab,thecountry’suseofnivolumabisroughlybetweenthatofFranceandGermany,resultinginanoverallhigheruseofcheckpointinhibitorscomparedwithSpainandtheUnitedKingdom.

Exhibit5:EU5CheckpointInhibitorUseasof

December2019,DefinedDailyDosesper100KPopulation

2,308

1,424

1,321

977 971

Germany France Italy United Spain

Kingdom

Source:IQVIAMarketPrognosis,Sep2019;IQVIAInstitute,May2020

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TISSUE-AGNOSTICTRENDS

Tissue-agnosticmedicinesrepresentaparadigmshiftinthetreatmentofcancerinthattheyarehistology-independentandtargetcertaingenomicmutationsacrosstumorsratherthaninspecifichistologies.IntheUnitedStates,therearethreeoncologymedicineswithatissue-agnosticapproval:pembrolizumab,larotrectinib,andentrectinib.Amongotherindications,pembrolizumabreceivedthefirstapprovalforsolidtumorswithpositivemicrosatelliteinstability–high(MSI-H)ormismatch-repair–deficient(dMMR)statusin2017.Larotrectinibandentrectinibhaveapprovalsin

Tissue-agnosticmedicinesrepresentaparadigmshiftinthetreatmentofcancer.

solidtumorswithneurotrophicreceptortyrosinekinase(NTRK)genefusions.LarotrectinibalsoreceivedEMAapprovalinlate2019forsolidtumorswithNTRKgenefusions.IntheUnitedStates,thecombinedvolume(standarddoseunits)ofthesetherapieshasgrownbyalmostfourtimessincethefirsttissue-agnosticapprovalin2017.

MicrosatelliteinstabilitymutationsimpacttheproductionofDNAmismatchrepairenzymes,andcellsharboringthesemutationsarelessabletorepairerrorsinDNAreplication,increasingtheriskofdevelopingcancer.