NeratinibinHER2- orHER3-mutantsolidtumors:SUMMIT,aglobal,multi-histology,open-label,phase2‘basket’studyDavidM.Hyman,1 SarinaPiha-Paul,2 JordiRodon,3 CristinaSaura,3 GeoffreyI.Shapiro,4 DavidI.Quinn,5VictorMoreno, 6 IngridMayer,7CarlosArteaga,7 ValentinaBoni,8 EmilianoCalvo,8 ShereneLoi,9 A.CraigLockhart,10 LillianM.Smyth,1 JosephErinjeri,1MaurizioScaltriti,1 FJavierCarmona,1 GaryUlaner,1 JeanTorrisi,1 Juber Patel,1 Jiabin Tang,1 Fanli Meng,1 Duygu Selcuklu,1HelenWon,1 NancyBouvier,1MichaelF.Berger,1 RichardE.Cutler,Jr.,11 FengXu,11 AnnaButturini,11 LisaD.Eli,11 GraceMann,11CynthiaFarrell,11Alshad S.Lalani,11 RichardBryce,11 Funda Meric Bernstam,2 JoséBaselga,1 DavidB.Solit1

1MemorialSloanKetteringCancerCenter,NewYork,NY,USA;2MDAndersonCancerCenter,Houston,TX,USA;3Valld’Hebron UniversityHospital,Barcelona,Spain; 4DanaFarberCancerInstitute,Boston,MA,USA;5USCNorrisComprehensiveCancerCenter,LosAngeles,CA,USA;6STARTMadridFundación JímenezDíaz,Madrid,Spain;7Vanderbilt-IngramCancerCenter,Nashville,TN,USA;8STARTMadridGroup,Madrid,Spain 9PeterMacCallumCancerCentre,Melbourne,Victoria,Australia;10WashingtonUniversityinSt.LouisSchoolofMedicine,St.Louis,MO,USA;11PumaBiotechnologyInc,LosAngeles,CA,USA

OralCT001

HER2(ERBB2)mutations• SubsetsofsomaticHER2mutationsareseenatrelativelylowfrequenciesacrossmultipletumortypes

• Activating HER2mutationsresultinconstitutivekinasesignaling,activationofgrowthpromoting/survivalpathways,oncogenictransformationandenhancedtumorgrowthinpreclinicalmodels

2cBioportal.orgaccessedon16March2017

HER2mutations

Activationofdownstreamsignaltransductionpathwaysandtumorgrowthsurvival

P P

NeratinibinHER2-mutant cancer• Neratinibisanoral,irreversiblepan-HERtyrosinekinaseinhibitor• Neratinibleadstopotentinhibitionofintracellularsignaling,cellproliferationandcolonyformation

ofHER2-mutanttumorcelllinesinvitro1,2

• HER2-mutantalleleshavedistinctdifferentialsensitivitytoneratinib

1Boseetal.CancerDiscovery2013:3;224–2372Carmonaetal.CancerRes2016:76(14Suppl);abst 298 3

-3-2-10

0

5 0

1 0 0

H K I-2 7 2 c o n c e n tra t io n (L o g µ M )

Cel

l via

bilit

y (%

)

Neratinib(LogµM)

-3-2-10

0

5 0

1 0 0

H E R 2 V 7 7 7 L

W T

H K I-2 9 2 c o n c e n tra t io n (L o g µ M )

Cel

l via

bilit

y (%

)

H E R 2 L 7 5 5 S

Y V M A in s

D 7 6 9 HI7 6 7 M

Sensitivity

0 –1 –2 –3

100

50

0

Cellviab

ility(%

)

AmplifiedwildtypeD769HI767ML755SV777LYVMAins

2500

2000

1500

1000

500

0WT V777L D769H V8421 L755Sdel.755–9 R678Q G309A

Meancolonyco

unt

VehicleLapatinibNeratinib

SUMMIT‘basket’studydesign

4

Solidtumors(NOS)

Endometrial

Gastroesophageal

Ovarian

Colorectal

Bladder/urinary tract

Solidtumors(NOS)

Neratinibmonotherapy

HER2 orHER3mutations(documentedbylocaltesting)

Primaryendpoint• Objectiveresponserateatweek8(ORR8)

Secondaryendpoints• ORR(confirmed)• Clinicalbenefitrate(CBR)• Progression-freesurvival(PFS)• Safety• Biomarkers

Simon2-stagedesign• If≥1responseinfirstevaluable7patients,expandcohorttoStage2(N=18)• If≥4responsesinStage2,expandorbreakout

Tumorassessments• RECISTv1.1(primarycriteria)• PETresponse

Statisticalmethods• ORR8,ORR,CBR:associated95%CI• MedianPFS:Kaplan-Meierestimatewith95%CI

Breast

Cervical

Biliarytract

Lung

Datacut-off:10-Mar-2017NOS=nototherwisespecified

• FFPEtumors(archivalorfreshpre-treatmentbiopsies)retrospectivelysequencedcentrallyusingNGS(MSK-IMPACT)• PlasmacfDNA (pre-treatment)retrospectivelysequencedcentrallyusinga HER2single-genehybridcaptureresearchassay(MSKCC)

HER2-mutanttumors

HER3-mutanttumors Closed

Open

Enrollment

EnrollmentbytumortypeNeratinib monotherapy(n=141)

HER2-mutationpositive

Lungcancer 26(18.4)

Breastcancer 25(17.7)

Bladder/urinarytractcancer 16(11.3)

Solidtumors(NOS) 15(10.6)

Colorectalcancer 12(8.5)

Biliarytractcancer 9(6.4)

Endometrialcancer 7(5.0)

Cervicalcancer 5(3.5)

Gastroesophagealcancer 5(3.5)

Ovariancancer 4(2.8)

HER3-mutationpositive

Solidtumors(NOS) 17(12.1) 5

Baselinedemographics

6

PatientcharacteristicsHER2mutant

(n=124)HER3mutant

(n=17)Total

(n=141)

AgeMedian(range),years<65years,n(%)≥65years,n(%)

61(30–83)81(64.8)43(34.7)

66(39–82)7(43.8)10(58.8)

61(30–83)88(62.4)53(37.6)

Gender,n(%)FemaleMale

79(63.7)45(36.3)

13(76.5)4(23.5)

92(65.2)49(34.8)

ECOGperformance status,n(%)012

36(29.0)83(66.9)5(4.0)

2(11.8)12(75.6)3(17.6)

38(27.0)95(67.4)8(5.7)

Priorsystemiclines,n(%)AnyNone12≥3

120(96.8)4(3.2)

33(26.4)29(23.4)58(46.4)

17(100)0(0)1(6.3)

12(70.6)4(25.0)

137(97.0)4(2.8)

34(24.1)41(29.1)62(44.0)

Mediantimefrommetastasistoenrollment,years(range) 1.02(0.0–15.0) 1.13(0.3–4.5) 1.03(0.0–15.0)

DistributionofHER2mutations

7

DistributionofHER3mutations

8

NoclinicalactivityseeninHER3-mutantcohort

Patientdisposition

9

ParameterHER2mutant

(n=124)HER3mutant

(n=17)Total

(n=141)

Patientscontinuingontreatment,n(%) 10 0 10

Treatmentdiscontinuation,n(%)DeathDiseaseprogressionAdverse eventWithdrawalofconsentInvestigatorrequestLosttofollow-upOther

114(91.9)2(1.6)

88(71.0)5(4.0)4(3.2)5(4.0)1(0.8)9(7.2)

17(100.0)1(5.9)

16(94.1)0(0.0)0(0.0)0(0.0)0(0.0)0(0.0)

131(92.9)3(2.1)

104(73.8)5(3.5)4(2.8)5(3.5)1(0.7)9(6.4)

Subjectsendedstudy,n(%)DeathWithdrawalofconsentLosttofollow-upOther

81(65.3)70(56.5)5(4.0)5(4.0)1(0.8)

15(88.2)12(70.6)2(12.5)1(6.3)0(0.0)

96(68.1)82(58.2)7(5.0)6(4.3)1(0.7)

EfficacyinHER2-mutantpatientsbytumortype

10

EfficacyinHER2-mutantpatientsbytumortype

11

EfficacyinHER2-mutantpatientsbytumortype

12

EfficacyinHER2-mutantpatientsbytumortype

13

EfficacyinHER2-mutantpatientsbytumortype

14

EfficacyinHER2-mutantpatientsbyallele

15

EfficacyinHER2-mutantpatientsbyallele

16

EfficacyinHER2-mutantpatientsbyallele

17

IntegratedefficacybytumortypeandHER2mutation

18

Efficacysummary

19

HER2mut HER3mut

Breast(n=25)

Bladder(n=16)

Lung(n=26)

Colorectal(n=12)

Biliarytract(n=9)

Cervical(n=5)

NOS(n=17)

ORRatweek8,n (%)[95%CI]

8(32.0)[14.9–53.5]

0(0.0)[0.0–20.6]

1(3.8)[0.1–19.6]

0(0.0)[0.0–26.5]

2(22.2)[2.8–60.0]

1(20.0)[0.5–71.6]

0(0.0)[0.0–20.6]

ORR,n(%)[95%CI]

6(24.0)[9.4–45.1]

0(0.0)[0.0–20.6]

1(3.8)[0.1–19.6]

0(0.0)[0.0–26.5]

0(0.0)[0.0–33.6]

1(20.0)[0.5–71.6]

0(0.0)[0.0–20.6]

Clinicalbenefitrate,n(%)[95%CI]

10(40.0)[21.1–61.3]

3(18.8)[4.0–45.6]

11(42.3)[23.4–63.1]

1(8.3)[0.2–38.5]

3(33.3)[7.5–70.1]

3(60.0)[14.7–94.7]

2(11.8)[1.6–38.3]

MedianPFS,months(95%CI)

3.5(1.9–4.3)

1.8(1.7–3.5)

5.5(2.7–10.9)

1.8(1.4–1.9)

2.8(0.5–3.7)

20.1(0.5–NA)

1.7(1.4–2.0)

Incidenceoftreatment-emergentadverseevents(≥10%)Neratinibmonotherapy(N=141)

Adverse event,n(%) Anygrade Grade≥3

Diarrhea 104(73.8) 31(22.0)Nausea 61(43.3) 3(2.1)Vomiting 58(41.1) 3(2.1)Constipation 49(34.8) 2(1.4)Fatigue 45(31.9) 5(3.5)Decreasedappetite 40(28.4) 1(0.7)Abdominalpain 33(23.4) 7(5.0)Anemia 22(15.6) 10(7.1)Dyspnea 18(12.8) 5(3.5)Dehydration 17(12.1) 8(5.7)Aspartateaminotransferaseincreased 15(10.6) 5(3.5)Asthenia 15(10.6) 1(0.7)Weightdecreased 15(10.6) 0 20

Characteristicsofdiarrhea

Adverse event,n(%)Neratinibmonotherapy

(N=141)

Incidenceofdiarrhea,n(%)a

Anygrade 104(73.8)

Grade3 31(22.0)

Actiontakenwithneratinib,n(%)

Permanentdiscontinuation 4(2.8)

Dosereduction 2(1.4)

Temporaryhold 21(14.9)

Seriousdiarrhea(hospitalizedorimportant medicalevent) 15(10.6)

Median(range)numberofgrade3episodesofdiarrhea perpatient 1(1–12)

Median (range)timetofirstgrade3diarrhea,days 10(4–87)

Median(range)durationofgrade3diarrheaperepisode,days 2(1–18)

aNograde4/5diarrheareported 21

AgreementbetweenlocalandcentralassessmentofHER2mutations

1Chengetal.JMol Diagn 2015;17:251–642HER2 single-genehybridcaptureresearch-use-onlyassay(MSKCC)

• >98%concordancewasobservedbetweenlocalandcentralHER2mutationassaysEnrollmentassay(n=124)

Localtest(n=96)

ArchivalFFPEtumor(MSK-IMPACT1)

(n=28)

Centraltesting(retrospective)

ArchivalFFPEtumor(MSK-IMPACT1)

98%(48/49) N/A

ScreeningcfDNA(RUOassay2)

100%(60/60)

100%(20/20)

23

PlasmactDNA attimeofneratinibclinicalprogressionrevealsacquiredHER2 (T798I)gatekeepermutationthatinducesresistance

Hankeretal.AdvancedOnlinePublication;doi:10.1158/2159-8290;CancerDiscovery2017

Progressiononneratinib

Responsetocombination

FULVESTRANTNERATINIB

AROMATASEINHIBITORS

201520142013201220112010

FulvestrantaddedSUMMIT

trial

Chestwallrecurrence

Bonemets

Skinmets

ER+/HER2–diagnosed

12/2014 1/2015

Baselineskinmets

Responsetoneratinib

4/2016 6/2016

SkinmettumorFFPENGS:L869Ractivatingmutation

PlasmactDNA Guardant360T798Igatekeepermutation

PD

2016

Conclusions

24

• Neratinibactivitywasinfluencedbybothtumorlineageandmutationtype:

– Breastcancer:single-agentactivityobserved.Combinationwithfulvestrant inER+diseaseunderway

– Biliarycancerandcervicalcancer:preliminarysingle-agentactivity;enrollmentongoing

– Lungcancer:responseratelowbutpromisingprolongeddiseasestabilizationinheavily-pretreatedpatients

– Colorectalcancerandbladdercancer,andHER3 cohort:insufficientsingle-agentactivity

– Mutationclass:missensemutationsappearmoresensitivecomparedwithexon20insertions,althoughcomparisonpartiallyconfoundedbytumor-lineageassociations

• Single-agentneratinibshowsactivityinsomecohorts;combinationsmaybeneededtoimproveactivityanddurability(similartoHER2-targetedtherapyinHER2-amplifiedtumors)

• NeratinibsafetyprofileconsistentwithpreviousreportsinmetastaticHER2-amplifiedtumors

– Diarrheawasnotatreatment-limitingtoxicitywithanti-diarrhealprophylaxis

Acknowledgements

25

Theauthorswouldliketothank:

• Allofthepatientsandtheirfamilies

• SUMMITstudyinvestigatorsandclinicaltrialstaff