new targets & new drugs in hepatocellular carcinoma

NewTargetsandNewAgentsinHepatocellularCarcinoma

EricRaymondMD,PhDChairofMedicalOncology

@GroupeHospitalierParisSaint-JosephFrance

[email protected]

Disclosures

•  ConsulEngrole:– Pfizer– NovarEs– EliLilly–  Ipsen

Normaliza9onofTumorMicroenvironmentinHepatocellular

CarcinomaEricRaymondMD,PhD

ChairofMedicalOncology@GroupeHospitalierParisSaint-Joseph

[email protected]

Cellular&MolecularComponentsoftheHepatocellularCarcinomaMicroenvironment

EndothelialcellsPericytesVEGFR-PDGFR

Tcells(CD4-Treg)CD4:PD1-CTLA4-CD28Treg:CD73-CD39

Dendri9ccellsPDL1-PD1-MSHII-CD80/86

TumorassociatedmacrophagesCXCR4-TGFβR

TumorcellsTGFβR-MET-PDL1

FibroblastsFGFR

TGFβHGFFGF19IL8IL10

SDF1/CXCL12

Characteris9csofHepatocellularCarcinomaMicroenvironment

•  Likelytovaryaccordingtothetypeoftumorcarcinogenesis–  Alcohol–  ViralhepaEEsB/CinducedinflammaEon–  NASH–  Others

•  Likelytobeinfluencedbyfocalhypoxia–  Tumorangiogenesisbeinggenuineorinducedbysorafenib–  InducEonofmesenchymaldifferenEaEon–  InducEonoflacEcacidmetabolism–  FacilitatetheoccurrencesofspecificoncogenicmutaEons

•  Associatedwithlocalimmunosuppression–  InhibiEonofT-cellfuncEons(PD1/PDL1,CTLA4)

‘Epigene(c’changesmaybefocalaccoun(ngfortumorheterogeneityanddri9occurringover(mefacilita(ngresistancetosingleagenttherapy,pledgingforcombina(ons

VEGFR&PDGFRasAn9-angiogenicTargetsforHepatocellularCarcinoma



Learningfrom7YearsofExperiencewithSorafenibinAdvancedhepatocellularcarcinoma

SorafenibBe>erthanSorafenib

2005

2006

2007

2008

2009

2010

2011

2012

5

10

15

Med

ian

over

al s

urvi

val

of s

oraf

enib

(mon

th)

Lag times of accrual

SHARP

SUNITINIB

GIDEON

BRISK

ASIAN-PACIFICSUNITINIB

BRISKPlacebo SHARP

Placebo ASIAN-PACIFIC

Non-Asian patients

Asian patients

FaivreS,deGramontA,RaymondE.TargetOncol.2016

SofarnodrughasbeenabletocompetewithsorafenibasfirstlinetherapyinHCC

RegorafenibaMu9kinaseInhibitor

F

phaseIIIRESORCEtrial

RegorafenibaMu9kinaseInhibitor

Regorafenibwasannouncedtoprovideoverallsurvivalbenefitoverplaceboinsecondlineinpa9entswhohavefailedsorafenibfirstline(DatapresentedatthisWORLDGI2016)

PD1&PDL1asTargetsforHepatocellularCarcinoma



Dendri9ccellsPDL1-PD1-MSHII-CD80/86


MHC

PD-L1

PD-1

PD-1

T-cellreceptor

PD-L2

Tcell

NFκB

Other

PI3K

Tumorcell

IFNγ

IFNγR

Shp-2

Nivolumab

ImmuneCheckpointInhibi9onbyNivolumab

•  NivolumabisafullyhumanIgG4anE-PD-1monoclonalanEbodythatselecEvelyblockstheinteracEonbetweenPD-1andPD-L1/PD-L2,1restoringT-cellimmuneacEvitydirectedagainstthetumorcell

1.  TopalianSL,etal.NEnglJMed.2012;366:2443-2454

CA209-040:StudyDesign

•  PaEentsreceivednivolumabQ2Wforupto2years(maximumof48doses),dependingonresponse–  Imagingfordiseaseassessmentperformedevery6weeks

•  A3+3designwasusedinthephase1doseescalaEonphase•  Here,wereportinterimresultsfromtheongoingdoseescalaEonphaseandpartoftheexpansionphase

DoseEscala9on Expansion

Uninfectedsorafenibprogressors3mg/kg(n=50)

HCV-infectedExpandat3mg/kg

(n=50)

HBV-infectedDoseTBD(n=50)

Uninfected 0.3mg/kg 1mg/kg 3mg/kg 10mg/kg0.1mg/kg

HCV-infected 0.3mg/kg 1mg/kg 3mg/kg 10mg/kg

Uninfectedsorafenib-naïveorintolerant3mg/kg(n=50)

HBV-infected 0.3mg/kg0.1mg/kg 1mg/kg 3mg/kg 10mg/kg

AnthonyB.El-Khoueiryetal.ASCO2015

•  58-year-oldwhitemalewithHCV-infectedHCC,ECOG0,Child-PughA5•  Progressedonsorafenib

CA209-040:DurablePar9alResponsetoNivolumab

Week12 Week48Baseline

Arterial

Venous+ +

+

+

+

++

+

++


CA209-040:ResponseKine9csORR:around15%-MedianDura9onresponse17months

TimeSinceFirstDose,Months

Chan

geinTargetLesion

From

Baseline,%

180

0 3 6 9 12 15 18 21

-100

-80

-60

-40

-20

0

20

40

60

80

100

Months,range

Uninfected(n=21)

HCV(n=11)

HBV(n=10)

TotalEvaluable(n=42)

DOR 7.2*–12.5* 1.4*–8.3* 11.9 1.4*–12.5*

DuraEonofSD 1.1*–17.3* 2.9†–14.0 2.7*–6.9* 1.1*–17.3*

*Censored†Patient with resolved HCV infection First occurrence of new lesion

14

+


CA209-040:PreliminaryOverallSurvival

OverallSurvivalRate,%(95%CI)* Total(N=47)

At9months 70(52–82)

At12months 62(42–76)

*OverallsurvivalesEmatedusingKaplan-Meiermethod


MedianOS:14monthsirrespec9veofpriorsorafenibtreatmentAE>grade3:1%-Welltolerated

UpdateASCO2016

HGF&c-METInhibi9oninHepatocellularCarcinoma


HepatocytesTumorcellsTGFβR-MET-PDL1

mRNAoverexpression

Proteinoverexpression

Geneamplifica9on

Muta9on

ChronicliverinflammaEon(viral–others)

Fibroblastsandfibrosis

Localimmunosupression

GenuineHypoxia

Treatmentinducedhypoxia(embolizaEon,anE-angiogenic)

EpigeneEcchangesassociatedwithHGF/c-METacEvaEon

HGFsEmulaEonofhepatocytesandhepatocarcinomacellsharboringc-MET

c-METinhibitorsinlatestagedrugdevelopment

METIV-HCC–Tivan9nib–phase3trial

CELESTIAL–Cabozan9nib–phase3trial

•  Firstgenera(on•  Specificity?•  Resultspending

Inhibi9onofc-METWithTepo9nib

TolerabilityandAc9vityofSecond-LineTepo9nib,aPotentandHighlySelec9vec-MetInhibitor,inPa9entswithAdvancedHepatocellular

CarcinomaPreviouslyTreatedwithSorafenib

30

10

-10-20

-40-50-60B

est r

elat

ive

chan

ge in

sum

of lo

nges

t dia

met

erin

bas

elin

e (%

)

Tepotinib 300 mgDose level

Tepotinib 500 mg20

0

-30

Abstract No. 238

Faivreetal.WorldGI2016

CT after 2 cycles showed objective response by RECIST (-48%)

PET scan after 2 cycles showed significant decrease of size and metabolic activity

FGF19&FGFR4asTargetsinHepatocellularCarcinoma



FibroblastsFGFR

Inhibi9onofFGF19/FGFR4Ac9va9onWithBLU-554

TGFβ&TGFβ-RasTargetsinHepatocellularCarcinoma




TumorassociatedmacrophagesCXCR4-TGFβR


• >30TGFβmembers(TGFβ1-3,acEvins,NODAL,BMP,GDF,AMH)

NeuzilletC.,Pharmacol.Ther.(2015)WakefieldLM.,Nat.Rev.Cancer(2013)

CanonicalandNon-CanonicalTGFβPathway

Galuniser9b:TGF-βRIInhibitorinHepatocellularCarcinoma

TumoralExplant Slicing

Control

DrugA

DrugB

CultureanddrugtesEng

O2

CO2

O2/CO2/T°monitor

Evalua9on of Drugs in Ex Vivo Organotypic Culture Assays From SurgicalSpecimensofHumanHepatocellularCarcinoma:StudyingtheTumorCells inTheirGenuineStroma

BySerovaetal,Oncotarget2015

Exvivo Prolifera9onControl TGFβinh.

Apoptosis

P-SMAD2/3(PDbiomarker)

(13pts)

(13pts)

(11pts)

TGFβRIInhibi9onInducedbyGaluniser9binHumanHepatocellularCarcinomaExplants

BySerovaetal,Oncotarget2015

A Phase 2 Study of a Second Line Galunisertib in Patients With Advanced Hepatocellular Carcinoma

StudyDesignforPartAandPartB

Screening Patients with

Child Pugh A or B7 Hepatocarcinoma

who progress Under sorafenib

Galunisertib 160 mg/day


R A N D O M I Z E


Part A AFP ≥1.5 ULN

Part B AFP <1.5 ULN

Abbreviation: ULN, upper limit of normal.

CourtesyofFaivreS.etal.Pres.ASCOGI2014andASCO2016

Galuniser9b(TGFβRIInhibitor)inPa9entsWithHepatocellularCarcinoma

n/N (%) Median AFP responders 25/103 (24%) 21.4 mo AFP non-responders 78/103 (76%) 6.8 mo

Overallsurvival

AFPresponders=paEentswhodecreasedcirculaEngAFPlevelsby>20%

AFPnonresponders

AFPresponders

CourtesyofFaivreS.etal.Pres.ASCOGI2014andASCO2016

Part A AFP ≥1.5 ULN

Part B AFP <1.5 ULN

ArmanddeGramontunpublished

PD-L1ExpressioninHepatocellularCarcinoma

Tumorboundary

CD3

PD-L1

Combina9onwithPD-L1inhibitors

T-cells

Cancercells

InvivotransgenicC57B16/ASB-Bmicemodel

Galuniser9binCombina9onWithSorafenibInvivotransgenicC57B16/ASB-Bmicemodel

At12weeks

Randomization N = 32

Transgenic C57Bl6/ASV-B Mice; age 8 weeks

Placebo N = 8

Sorafenib + galunisertib

N = 8

Echo-Doppler Every 4 weeks

Sorafenib (30 mg.kg-1)

N = 8

Galunisertib (100 mg.kg-1)

N = 8

Rijeras-Raballanetal.Unpublisheddata


Sorafenib(1stline)

Regorafenib(2ndline)

Tumorangiogenesis

Galuniser9b(TGFβ-RI)

Tepo9nib(c-MET)

BLU‑554

(FGF19/FGFR4)

Microenvironmentsignaling

NivolumabPembrolizumab

(PD-L1)

IpilimumabTremelimumab

(CTLA4)

Immunestroma

ç Combina9onsè

Conclusions•  Variouscomponentsoftumormicroenvironmentcouldbeusedastargetstocontroltumorgrowthinhepatocellularcarcinoma

•  Inhibi9onoftumorangiogenesis,microenvironmentsignalingandlocalimmunosuppressionappearaspromisingop9onsfortumorgrowthcontrol

•  Combina9ontherapiesnormalizingthemicroenvironmentofferpromiseforop9malcontrolofhepatocellularcarcinogenesis

Thanksforyouraoen9on

EricRaymondMD,PhDChairofMedicalOncology

@GroupeHospitalierParisSaint-JosephFrance

[email protected]

new targets & new drugs in hepatocellular carcinoma

Health & Medicine