EntrectinibinpatientswithlocallyadvancedormetastaticROS1fusion-positivenon-smallcelllungcancer(NSCLC)

Myung-JuAhn1,ByoungChulCho2,SalvatoreSiena3,AlexanderDrilon4,FilippoDeBraud5,MatthewG.Krebs6,ThomasJohn7,ChrisKarapetis8,

AnnD.Johnson9,EdnaChow-Maneval9,PratikS.Multani9,RobertC.Doebele10

1SamsungMedicalCenter,Seoul,Korea;2YonseiUniversityCollegeofMedicine,Seoul,Korea;3NiguardaCancerCenter,GrandeOspedaleMetropolitanoNiguarda,Milan,Italy;4MemorialSloanKetteringCancerCenter,NewYork,USA;5FondazioneIRCCSIstitutoNazionaleTumori,Milan,Italy;6TheUniversityofManchesterandTheChristieNHSFoundationTrust,Manchester,UK;

7OliviaNewton-JohnCancerCentre,AustinHealth,Melbourne,Australia;8FlindersMedicalCentre,BedfordPark,Australia;9Ignyta,SanDiego,USA;10UniversityofColorado,Aurora,USA

Abstract 8564

Disclosures

§ Honoraria:AstraZeneca,BMS,BoehringerIngelheim,MSD,Novartis§ Consultantoradvisor:AstraZeneca,BMS,BoehringerIngelheim,MSD,Novartis

IASLC 18th World Conference on Lung CancerOctober 15-18, 2017 |Yokohama,Japan

EntrectinibCNS-Active,PotentandSelectiveROS1andTRKInhibitor

§ 30xmorepotentthancrizotinibagainstROS1

§ Mostpotentpan-TRKinhibitorinclinicaldevelopment;demonstratedclinicalactivityinmultipletumorhistologies

§ Designedtocrosstheblood-brainbarrier,withdemonstratedclinicalactivityinprimarybraintumorsandsecondaryCNSmetastases

Target ROS1 TRKA TRKB TRKC

IC50 (nM)a 0.2 1.7 0.1 0.1

aBasedonbiochemicalassay

IASLC 18th World Conference on Lung CancerOctober 15-18, 2017 |Yokohama,Japan

Background§ ROS1fusionsoccurin~2%ofNSCLCpatients§ CNSactivityisanimportantattributefornovelfirst-linetargetedtherapiesinROS1+NSCLC

§ ~20to40%ofpatientshaveknownCNSmetastasesatpresentation§ CNSisacommonsiteofrelapseinpatientsprogressingoncrizotinib

Methods§ 32ROS1fusion-positive,ROS1inhibitor-naïveNSCLCpatientsenrolledacrossSTARTRK-2

(Phase2),STARTRK-1(Phase1),andALKA-372-001(Phase1)studiesasof31Dec2016§ Overall,203patientshavebeentreatedattheRP2D(600mg,PO,once-daily)acrossthese3studies

(multiplebiomarkers/histologies)§ Datacutoffdate:13September2017

§ NSCLCaccountedfor>90%ofallROS1+solidtumorsenrolledinentrectinibstudies§ 6othertumortypeshavebeenstudied:appendix,GBM,melanoma,pancreas,thyroid,sarcoma

EntrectinibinROS1Fusion-PositiveNSCLC

RP2D=RecommendedPhase2Dose

IASLC 18th World Conference on Lung CancerOctober 15-18, 2017 |Yokohama,Japan

Total(N=32)

Age,years Median(range) 52(27,71)

Gender Female/Male,% 72/28

Race Asian/Non-Asian,% 38/62

ECOGPerformanceStatus 0-1/2,% 91/9

Smokingstatus,n(%) Neversmoker 23(72)

Formersmoker 8(25)

Currentsmoker 1(3)

Histology,n(%) Adenocarcinoma 29(91)

PriorSystemicTherapy*,n(%) 0-2/≥3priortherapies,% 50/50

§ Chemotherapy 27(84)

§ Targetedtherapy 7(22)

§ Immunotherapy 1(3)

CNSmetastasesatbaseline,n(%) 11(34)

BaselineCharacteristics

*Patientsmayhavehadmultipletherapies

IASLC 18th World Conference on Lung CancerOctober 15-18, 2017 |Yokohama,Japan

CNSMetastasesatBaseline

Total(N=32)

Investigator-Assessed,n(%) 11(34)

PriorTreatment,n(%)

§ None 4(36)

§ Wholebrainradiationtherapy(WBRT) 4(36)

§ WBRT+Stereotacticradiosurgery(SRS) 3(27)

TimingofPriorWBRT/SRS,n(%) n=7

§ <4weeks 1(14)

§ ≥4weeksto<6months 5(71)

§ ≥6months 1(14)

IASLC 18th World Conference on Lung CancerOctober 15-18, 2017 |Yokohama,Japan

EntrectinibSafetySummaryMostCommon(≥10%)Treatment-RelatedAdverseEvents, n(%)

PatientstreatedattheRP2D(N=203)

AllGrades Grade3 Grade4*

Dysgeusia 78(38) 1(1) --

Fatigue 59(29) 6(3) --

Constipation 47(23) 1(1) --

Dizziness 46(23) 1(1) --

Weightincreased 39(19) 10(5) --

Diarrhea 35(17) 1(1) --

Nausea 33(16) -- --

Paresthesia 32(16) -- --

Myalgia 27(13) 1(1) --

Peripheraledema 25(12) -- --

Anemia 23(11) 9(4) --

Bloodcreatinineincreased 22(11) 1(1) --

Vomiting 22(11) -- --

Arthralgia 21(10) 1(1) --

Datacutoffdate:13September2017RP2D=RecommendedPhase2Dose

§ 203patientshavebeentreatedattheRP2Dacross3clinicalstudies

§ MostadverseeventswereGrade1-2andreversible

§ Treatment-RelatedAdverseEvents(TRAEs):§ Leadingtodoseinterruption:32%§ Leadingtodosereduction:19%§ SeriousAdverseEvents:9%§ Leadingtodiscontinuationfromstudytreatment:3%

*TherewerenoGrade4eventsoccurringin>1%ofpatients;noGrade5TRAEswerereported

IASLC 18th World Conference on Lung CancerOctober 15-18, 2017 |Yokohama,Japan

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BestResponsetoEntrectinibinROS1Fusion-Positive,Inhibitor-NaïveNSCLC25outof32patientshadconfirmedRECIST1.1responsesbyInvestigator,forORRof78%

PRSDv

Threeoutof32patientshadnopost-baselinescansandwerenon-evaluable

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Datacutoffdate:13September2017

IASLC 18th World Conference on Lung CancerOctober 15-18, 2017 |Yokohama,Japan

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BestResponsetoEntrectinibinROS1Fusion-Positive,Inhibitor-NaïveNSCLC34%(11outof32)ofthepatientshadCNSdiseaseatbaseline

PRSDv

Datacutoffdate:13September2017

CNSMetastasesatBaselineThreeoutof32patientshadnopost-baselinescansandwerenon-evaluable

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IASLC 18th World Conference on Lung CancerOctober 15-18, 2017 |Yokohama,Japan

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BICR=blindedindependentcentralreviewDatacutoffdate:13September2017

BestResponsetoEntrectinibinROS1Fusion-Positive,Inhibitor-NaïveNSCLC22outof32patientshadconfirmedRECIST1.1responsesbyBICR,forORRof69%

CNSMetastasesatBaselineFiveoutof32patientshadnopost-baselinescans(3)orweredeemednon-measurable(2)byBICR

v 0%change

IASLC 18th World Conference on Lung CancerOctober 15-18, 2017 |Yokohama,Japan

IntracranialResponse (IC)MeasurableLesions(N=6)

Measurable andNon-MeasurableLesions

(N=7)

CNSResponders 5/6 5/7

IC-ORR(95%CI) 83.3%(35.9,99.6) 71.4%(29.0,96.3)

CNSObjectiveResponseRate(byBICR)

Baseline Cycle253F,ROS1+NSCLC,Asian,neversmoker

BICR=blindedindependentcentralreviewDatacutoffdate:13September2017

§ May2014:Lobectomy,adjuvantchemotherapy§ May2015:RecurrenceinmultipleLNsin

mediastinum/abdomen,pleuraseedingandbrainmetastasis.Startedpem+cisfollowedbymaintenancepemetrexedchemotherapy

§ Dec2014:CNSradiationtherapy(SRS)§ Jan2016:Startedentrectinib

IASLC 18th World Conference on Lung CancerOctober 15-18, 2017 |Yokohama,Japan

0 3 6 9 12 15 18 21 24 27 30 33 36 39Time on Study (months)

t

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CNSmetastasesatbaseline

t timetoresponseongoing

progressionbyRECISTv1.1▌

BICR=blindedindependentcentralreviewDatacutoffdate:13September2017

TimeonTreatmentwithEntrectinib(byBICR)53%ofPatientsStillonStudy

IASLC 18th World Conference on Lung CancerOctober 15-18, 2017 |Yokohama,Japan

DurabilityofEntrectinibTreatmentinROS1+NSCLCPatients(byBICR)

MedianDORof28.6months(95%CI:6.8,34.8)

MedianPFSof29.6months(95%CI:7.7,36.6)

BICR=blindedindependentcentralreviewDatacutoffdate:13September2017

Dur

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Medianfollow-up:12.9months(5.6,30.2) Medianfollow-up:8.5months(5.4,16.5)

IASLC 18th World Conference on Lung CancerOctober 15-18, 2017 |Yokohama,Japan

BestResponsebyBICR, n(%) Total(N=32)

ObjectiveResponseRate(BICR-ORR)*(95%CI) 68.8% (50.0,83.9)

§ CompleteResponse,n(%) 2(6.3)

§ Partial Response,n(%) 20(62.5)

§ StableDisease,n(%) 4(12.5)

IntracranialBICR-ORR(patientswithmeasurabledisease)(95%CI) 83.3%(35.9,99.6)

MedianDuration ofResponse(BICR-mDOR)(95%CI) 28.6months(6.8,34.8)

MedianProgression-FreeSurvival(BICR-mPFS)(95%CI) 29.6months(7.7,36.6)

EfficacyofEntrectinibinROS1+NSCLC

*Investigator-AssessedORR(95%CI)=78.1%(60.0,90.7)

BICR=blindedindependentcentralreviewDatacutoffdate:13September2017

IASLC 18th World Conference on Lung CancerOctober 15-18, 2017 |Yokohama,Japan

§ EntrectinibdemonstratesclinicallymeaningfulanddurablebenefitinROS1 NSCLC§ BICR-ORRof69%,including2completeresponses

§ Investigator-assessedORRof78%§ MedianBICR-DORof29monthsandmedianBICR-PFSof30months

§ Inaddition,entrectinibdemonstratesstrongCNSactivity:intracranialBICR-ORRof83%inpatientspresentingwithmeasurableCNSdiseaseatbaseline

§ Entrectinibiswelltolerated,includingintheCNS,in>200patientstreatedattheRP2D§ MostlyGrade1-2reversibletreatment-relatedadverseevents§ 3%patientstreatedattheRP2Ddiscontinuedentrectinibduetotreatment-relatedadverse

events

§ TheglobalPhase2study,STARTRK-2,remainsopenforenrollment§ NewDrugApplicationsforentrectinibinROS1NSCLCandTRKtissue-agnosticanticipated

in2018

Conclusions

BICR=blindedindependentcentralreviewRP2D=recommendedPhase2dose

Datacutoffdate:13September2017

Wethankthepatients,theirfamiliesandcaregivers,andparticipatingclinicalsitesAustralia§ OliviaNewton-JohnCancerResearchInstitute§ FlindersMedicalCentre

Italy§ NiguardaCancerCenter,GrandeOspedaleMetropolitanoNiguarda§ FondazioneIRCCS,IstitutoNazionaleTumori

Singapore§ NationalCancerCentre

SouthKorea§ AsanMedicalCenter§ SamsungMedicalCenter§ SeoulNationalUniversityHospital§ YonseiUniversityCollegeofMedicine

UnitedStates§ CityofHopeCancerCenter§ MassachusettsGeneralHospital§ MayoClinicArizona§ MemorialSloanKetteringCancerCenter§ UniversityCancer&BloodCenter§ UniversityofColorado,Aurora§ UniversityofMinnesota

UnitedKingdom§ SarahCannonResearchInstituteUK§ TheChristieResearchNHSFoundationTrust