Pfizer Confidential 1

希少フラクションの臨床開発Clinicaldevelopmentfor

rarefrac1oncancerファイザー株式会社 クリニカルリサーチ統括部　オンコロジー領域部

廣橋　朋子 Tomoko Hirohashi, PhD

Director, Clinical research, Oncology, Pfizer Japan 杉田　潤子（薬事部門）

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Agenda

•  Background•  Successfulfactorstoenhancedrugdevelopmentforararefrac1oncancer

•  DrugdevelopmentplaninJapanforrarefrac1onofcancer

•  Summary

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Precisionmedicineforrarefrac1oncancer

TakedaM.etal.,AnnOncol.2015Dec;26(12):2477-82

Driver geneに対する分子標的治療薬の高い有効性

Difficult to initiate clinical study for rare fraction cancer

Driver gene

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Pointstobeconsideredtopursueclinicaldevelopmentforrarefrac1oncancer

Largescalescreening,longtermenrollment

StudyCost(inc.Humanresources) EAP

Cost

CoDx　Developme

nt

Unclearregulatory

path

Limitedindica1on

(LCP)

Expectedlargeeffect

size

HighmedicalneedsForthepa1ents

Transla1onisgoodfromanimaltohuman

PosiBveNegaBve

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Rarefrac1oncancer

5%

1~2%

2~3%

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General Basket Trial (In case of G-FIH study)

Dose escalation Expansion A Mutation A (ALK)

Expansion B Mutation B (ROS1)

Expansion C Mutation C (MET)

Expansion D Mutation D

US NDA

US NDA

AA

FULL

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RareFrac1onCancer

5%

2~3%

1~2%FULLPFESponsored(intheworld)

UnderdiscussionMixedModel?

The3rdPartySponsored（Asiaonly）

The3rdPartySponsored:InvesBgatoriniBatedclinicaltrial(IICT)orExternalfunding

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Successfulfactors

•  Focusedonofapar1cularcompound(anchordrug)orinapar1culararea(homeground)

•  Efficientdrugdevelopmentstrategywasavailable

•  Flexibleconceptdrugapprovalisexisted(Pinksheet)

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Efficientdrugdevelopmentstrategy

NSCLCALK

～5％

NSCLCROS1

～1~2%

NSCLCMET

～2~3%

ORR ORR ORR

•  Largeeffectsizeisexpectedfrompreclinicaldata(alltargetsare“drivergene”,KEYfactor)

•  ORRcanbeaprimaryendpoint•  Baskettrialiseasilyavailable•  NGSwillresolvetheissueofmul1pleCoDx

Thesamecompound

CoDxforALK CoDxforROS1 CoDxforMET

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Efficientdrugdevelopmentstrategy

NSCLCALK

～5％

NSCLCROS1

～1~2%

NSCLCMET

～2~3%

Forwhile20%ifapopula1onofthepa1entswithacommontumortypesmaycon1nuetorepresentarela1velylargepa1entgroupsuchthatitisrealis1callypossibletoconduct“transi1onal”regulatoryagency-mandatedrandomizedtrial(M.Maurieet.al.Oncology2016;91:299-301)

ORR ORR ORR

•  Norandomizedtrialsforeachindica1onarerequiredBEFOREapproval

Thesamecompound

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Efficientdrugdevelopmentstrategy

NSCLCALK

～5％

NSCLCROS1

～1~2%

NSCLCMET

～2~3%

ORR（AA） ORR（FULL） ORR（FULL？）

•  Norandomizedtrialsforeachindica1onarerequiredfrom2ndindica1on

Thesamecompound

RandomizedtrialG-P3wasrequiredforfullapproval

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FlexibledrugapprovalconceptintheUS

TheNextPhaseInOncology:FDA’sPazdurHasNewVisionForDrugDevelopment-November11201312:00AM

Execu1veSummaryFDA’stopcancerdrugreviewerhastakentothepodiumtopaintapictureofthenextphaseincancerdrugdevelopment,whichincludesnewbusinessmodels,areturntosingle-armtrialsandanewemphasisonsafety.

“ThePinkSheet”

RichardPazdur:FDAOfficeofHematologyandOncologyProductsDirector

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FlexibledrugapprovalconceptintheUS

…SoprofoundthatFDA’sprimaryadvocateforrandomizedtrialsin

oncologynowacknowledgesthatrandomizedtrialsmaybeunnecessary,ifnotimpossible,giventhedrama1cresponseratesshownbysomeofthesetargetedagents.

前例のない効果が示された場合は、

必ずしもP3が必要であるとは限らない。

(特に希少の場合)

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FlexibledrugapprovalconceptintheUS

•  Pazdurexplainedthatmanycancerpa1entsenrollinrandomizedtrialstocrossovertotheexperimentaldrugatthe1meofdiseaseprogression.Thatsuggestsa“lossofequipoiseandclearlythetrialshouldnothavebeendone.”

•  “Single-armtrialsdonotgiveuscompara1vesafetydata.Theygiveusasnapshotin1meofthesafetyofapar1cularpopula1onoradverseeventsthatoccur.Butonedoesn’tknowwhethertheseareassociatedwiththedrug,onedoesn’tknowwhethertheyareassociatedwiththeunderlyingdisease,”heexplained.

比較試験はむしろSafety評価として重要となる

à  最初のIndication（肺がん）でP3が実施され安全性が確認されていていれば，同一癌腫のMutation違いの場合は

P3の比較試験は必要がない

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FlexibledrugapprovalconceptintheUS

…FDAcouldapproveadrugindicatednotforapar1culartypeofcancerbutforinhibi1ngapar1cularmolecularpathway.“Thereisnothinginthelegisla1onthatwouldprohibitusfromapprovingadrugforinhibi1ngpathwayXorinhibi1ngpathwayYwithoutanyreferencetoaknownestablisheddiseasehere.Sothatisopen,wedohavethatdegreeofflexibility.”

臓器ごとの承認ではなく標的分子別の適応で

承認する可能性もある。

ALCOMAでの適応取得を支持する考え方？

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•  Ifsuccessfulfactorsareexited,drugdevelopmentforrarefrac1oncancercanbeenhancedandac1vated

HowaboutJapan?Howtoestablishdrugdevelopmentplan

inJapanforrarefrac1oncancer

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Conduct/Par1cipateintobaskettrial(G-FIH)

vsConductlocal/regionalphase2study

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Japanpar1cipa1onintobasketTrial(G-FIHstudy)

Doseescala1on

ExpansionAMuta1onA

ExpansionBMuta1onB

ExpansionCMuta1onC

ExpansionDMuta1onD

USNDAJ-NDAJapanjoin

Japanjoin

Japanjoin

Japanjoin

FoodEffectCohort

DDICohort

USNDAJ-NDA

USNDAJ-NDA

USNDAJ-NDA

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Pointstobeconsidered

•  HowtosetenoughsamplesizeofJ-ptsforeachcohortforJNDA?– Needtoshowconsistencybetweennon-JapaneseandJapaneseontheprimaryendpoint?

– Addi1onalclinicalstudyisrequired?•  FromJapanregulatoryperspec1ve,Phase1isconsideredas“forsafety”– EndpointcanbeacceptablefromJapanregulatoryauthority?

•  CanwemeetCoDxdevelopment(approvalandlaunch)?

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Flexibleac1onintheUSforCoDxapproval

hXp://www.accessdata.fda.gov/drugsa\da_docs/appleXer/2016/202570Orig1s016ltr.pdf

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Conductlocal/regionalphase2study(Concept)

Incaseofrarefrac1oncancer,“N-of-1Trial”forrarediseasecanbeapplicableif;

•  aprimaryendpointcanbeORR•  indica1onwillbeobtainedregardlessofline

A B C D

PDPD PD PD

Ifsameapproachisusedinsinglearmstudy,robustdatapackaged(comparedwithstandardofcare)canbeobtained

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SinglearmstudyhavingaSOCdataatmaximum

1stRegimen 2ndRegimen 3rdRegimen 4thRegimen

1stRegimen 2ndRegimen 3rdRegimen 4thRegimen

1

2

1stRegimen 2ndRegimen 3rdRegimen 4thRegimen3

1stRegimen 2ndRegimen 3rdRegimen 4thRegimen4

1stRegimen 2ndRegimen 3rdRegimen 4thRegimen5

1stRegimen 2ndRegimen 3rdRegimen 4thRegimen6

1stRegimen 2ndRegimen 3rdRegimen 4thRegimen7

1st regimen 2nd regimen 3rd regimen 4th regimen

50% 40% 30% 20%

70% 60% 70% 60%治験薬

SOC

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Pointstobeconsidered

•  Theregulatorysuccessratemightbehigherthanjoiningbaskettrial– Robustdatapackagescanbeobtainedsuch,includingacertainlevelofSOCdata

•  Druglagmustbeexisted•  Difficulttogetendorsementforanaddi1onalregionalstudy

(Mi1ga1onplan)– Thenthe3rdpartycollabora1on(IICTorexternalfunding)willbeeffec1velyused

–  IfSOCdatacanbeobtainedfromrealworlddata(bothsafetyandefficacy),thesamplesizecanbeminimized

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Summary•  Inglobalperspec1ve,drugdevelopmentforrarefrac1oncancer

canbeenhancedandac1vated,ifsuccessfulfactorsareexited–  Efficientdrugdevelopmentstrategyisavailable–  Flexibleconceptdrugapprovalisexisted(Pinksheet)

•  Ontheotherhand,s1llsomedifficul1esareexistedinJapan–  Lessexperiencesofthe3rdpartycollabora1on–  Regulatorypathforclinicaldevelopmentofrarefrac1oncancerhasnotbeenestablishedyet

•  Japanrequiresaregulatoryschemefordrugdevelopment/approvalforrarefrac1oncancer–  FlexibilityforbothdrugandCoDxapprovals–  Addi1onalregulatoryvalue

•  NOTE:CurrentSAKIGAKEisnotapplicableforLCM(Expansionofindica1on).

–  Effec1veuseofrealworlddata(usingpa1entregistryini1a1ve)

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