Hepatocellularcarcinoma:fromlocaltosystemictherapy

EricRaymondMD,PhDChairofMedicalOncology

@GroupeHospitalierParisSaint-JosephFrance

eraymond@hpsj.fr

Disclosures

• Genoscience• Pfizer• Novartis• EliLilly• Ipsen• AFROncology• PharmaEngine

ThankstoSandrineFaivre,MohamedBouattour,ValerieParadis,Anemilai

Tijeras-RaballandForprovidingmaterialsforthis

presentation

HCCisaworldwidemedicalneed

• ~850,000cases/peryear• ~800,000deaths/year

Hepatocellularcarcinoma

• ATwofaceddisease:– Underlyingliverdiseasescreatetheconditionsforcarcinogenesis(cirrhosis,fibrosis,steatosis,HBV-HCVinfection,hemochromatosis,etc…)andhavetheirownnaturalhistoryofevolution

– Acarcinomathathasalowpropensitytospreadtootherorgansandthusofferopportunityforlocaltherapy

• Adoublevascularization– HCCisprimarilyvascularizethroughthehepaticartery– Unlikemostotherorgans,theliverhasadualvascularization,arterialobliterationbeingpotentiallycompensatedbytheportalveinvascularization

Stage 0ECOG = 0, Child-Pugh A

Very early stage (0)1 HCC <2 cm

Carcinoma in situ

Early stage (A)1 HCC or 3 nodules≤3 cm, ECOG = 0

Advanced stage (C)Portal invasion,

N1, M1, ECOG = 1/2

Stage DChild-Pugh C, ECOG = 3-4

End stage (D)

HCC

Stage A-CECOG0,Child-PughA/B

Intermediate stage (B)Multinodular,ECOG=0

Survival=6mo (4-8mo)

Sorafenib:10.7-12.3mo &Lenvatinib:13.7moRegorafenib:10.6mo

Survival=16mo

Chemoembolization26-30mo(14-45mo)

Unmetneeds:TACE+systemictherapy?

Survival>36mo

Resection,transplantationorlocalablation>60mo

Unmetneeds:Adjuvanttherapy

1. Llovet JM. Harrison’s Principles of Internal Medicine. 20th edition. 2018. (in press).

BCLCstaging&relatedtreatmentoptions

Numberofcases

BeingsilentforlongtimesHCCareoftendiscoveredatlaterstage

Characteristicsofclinicaltrials

• ResponserateisdifficulttoconsiderincirrhoticandfibroticliverbecauseliverregenerationthatshallcompensateforHCCdestructionisunlikelytooccur

• Progression-freesurvivalisapotentialsurrogateofsurvival,althoughdecompensationoflivercirrhosismayleadtotreatmentinterruptionanddeaththatgenerateconfusion

• Thus,overallsurvivalhasalwaysbeenconsiderastheonlyreliableendpointforclinicaltrialinHCC

1. Vogelstein B et al. Science. 2013;339:1546-1558. 2. Schulze K et al. Nat Genet. 2015;47:505-511.

Genome Sequencing in HCC (N = 250)

••••••

••••

Telomerase maintenance: 60%Cell-cycle gene: 49%Wnt-B–catenin: 54%Epigenetic modifier: 32%Akt/mTOR: 51%MAPK: 43%

Signaling Pathways (Other):

NOTCH: 30%TGF-beta: 17%MET: 50%IGF signaling: 15% (IGF2 epi-driver)

2. Schulze K et al. Nat Genet. 2015;47:505-511. 2. Villanueva A et al. Gastrotenterology. 2012;143:1660-1669.3. Coulouarn C et al. Hepatology. 2008;47:2059-2067.

LandscapeofMutationsinHCC

Signaling Pathways (Mut)

CharacteristicsofHepatocellularCarcinomaMicroenvironment

• Likelytovaryaccordingtothetypeoftumorcarcinogenesis– Alcohol– ViralhepatitisB/Cinducedinflammation– NASH– Others

• Likelytobeinfluencedbyfocalhypoxia– Tumorangiogenesisbeinggenuineorinducedbysorafenib– Inductionofmesenchymaldifferentiation– Inductionoflacticacidmetabolism– Facilitatetheoccurrencesofspecificoncogenicmutations

• Associatedwithlocalimmunosuppression– InhibitionofT-cellfunctions(PD1/PDL1,CTLA4)

‘Epigenetic’changesmaybefocalaccountingfortumorheterogeneityanddriftoccurringovertimefacilitatingresistancetosingleagenttherapy,pledgingforcombinations

MolecularsubtypesofHCC:Clinicaloutcome

Zucman-RossiJetal.Gastroenterology.2015;149:1226-1239

Highproliferationclass

Nonproliferationclass

Cellular&MolecularComponentsoftheHepatocellularCarcinomaMicroenvironment

EndothelialcellsPericytesVEGFR-PDGFR

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

DendriticcellsPDL1-PD1-MSHII-CD80/86

TumorassociatedmacrophagesCXCR4-TGFβR

TumorcellsTGFβR-MET-PDL1

FibroblastsFGFR

TGFβHGFFGF19IL8IL10

SDF1/CXCL12

VEGFR &PDGFRasAnti-angiogenicTargetsforHepatocellularCarcinoma

NewTargetsandNewAgentsinHepatocellularCarcinoma

EndothelialcellsPericytesVEGFR-PDGFR

1. Llovet JM et al. N Engl J Med. 2008;359:378-390.

Stratification:• Macroscopic vascular invasion (portal vein)

••

Sorafenib 400 mgPO BID (n = 299)

and/or extrahepatic spreadECOG PSGeographical region

Randomization(N = 602)

Placebo2 tablets PO 2x/d

continuousdosing (n = 303)

SHARPtrial

Learningfrom7YearsofExperiencewithSorafenibinAdvancedhepatocellularcarcinoma

SorafenibBetterthanSorafenib

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

SORAFENIBADJUVANTSPACEOverallSurvivalevaluation

1. Lencioni R et al. J Hepatol. 2016;64:1090-1098.

HR = 0.898 (95% CI, 0.606-1.33); P = .295SorafenibMedian: NR95% CI, 554-NR

PlaceboMedian: NR95% CI, 562-NR

REFLECTPhase3Trial:Lenvatinib vs SorafenibintheFirstLine

1. Cheng A-L et al. ASCO 2017. Abstract 4001.

••

Lenvatinib Sorafenib Sunitinib Cediranib

FGFR 1-4, VEGFR 1-3RET, c-KIT, PDGFR

Lenvatinib Structure

••••

OS: 13.6 vs 12.3 months, HR = 0.92 (0.79-1.06)PFS: 7.4 vs 3.7months, HR = 0.66 (0.57-0.77)TTP: 8.9 vs 3.7 months, HR = 0.63 (0.53-0.73)ORR: 24% vs 9%

••

Primary endpoint: OSSecondary endpoints: PFS, TTP, ORR bymRECIST

•••••

≥1 measureable lesionBCLC stage B, CChild–Pugh class AECOG PS ≤1No prior systemic therapy

N = 954

Outcomes

Lenvatinib12 mg/day (≥60 kg body weight)8 mg/day (<60 kg body weight)

n = 478

Sorafenib400 mg twice daily

n = 476

Noninferiority Trial

2:1

R

New application to the FDA accepted

Endpoints

1. Oikonomopoulos G et al. Future Oncol. 2016;12:465-476.

REFLECTTrial:OverallSurvival

1. Cheng A-L et al. ASCO 2017. Abstract 4001.

HR (95% CI): 0.92 (0.79-1.06)

Lenvatinib isequipotent

Regorafenib aMutikinase Inhibitor

F

phaseIIIRESORCEtrial

Regorafenib(n=379)

Placebo(n=194)

Events 232(61%) 140(72%)

Censored 147(39%) 54(28%)

MedianOS,mo(95%CI) 10.6(9.1-12.1) 7.8(6.3-8.8)

HR(95%CI) 0.63(0.50-0.79);P<.0001(2-sided)

RESORCETrial:OverallSurvival

Based on mRECIST.

1. Bruix J et al. Lancet. 2017;389:56-66.

FDA Approved

PD1&PDL1asTargetsforHepatocellularCarcinoma

NewTargetsandNewAgentsinHepatocellularCarcinoma

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

DendriticcellsPDL1-PD1-MSHII-CD80/86

TumorcellsTGFβR-MET-PDL1

MHC

PD-L1

PD-1

PD-1

T-cellreceptor

PD-L2

Tcell

NFκB

Other

PI3K

Tumorcell

IFNγ

IFNγR

Shp-2

Nivolumab

ImmuneCheckpointInhibitionbyNivolumab

• Nivolumab isafullyhumanIgG4anti-PD-1monoclonalantibodythatselectivelyblockstheinteractionbetweenPD-1andPD-L1/PD-L2,1 restoringT-cellimmuneactivitydirectedagainstthetumorcell

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

1. El-Khoueiry AB et al. Lancet. 2017. pii: S0140-6736(17)31046-2.

NivolumabinPatientsWithAdvancedHCCCheckMate 209-040

APhase1/2TrialofSafetyandAntitumorActivityofNivolumab

September 22, 2017

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

CA209-040:DurablePartialResponsetoNivolumab

Week12 Week48Baseline

Arterial

Venous+ +

+

+

+

++

+

++

AnthonyB.El-Khoueiry etal.ASCO2015

CA209-040:Activity

Activityreportedacrosssubgroups

MedianOS:around14monthsirrespectiveofpriorsorafenibtreatment

AE> grade3:1%- Welltolerated

Summary

1. El-Khoueiry AB et al. Lancet. 2017. S0140-6736(17)31046-2.

SurvivalUpdateBasedonSorafenibExposure

a Kaplan-Meier method; closed circles denote censored patients.

1. Crocenzi T et al, J Clin Oncol. 2017:35 (suppl; abstr 4013)

HGF&c-METInhibitioninHepatocellularCarcinoma

NewTargetsandNewAgentsinHepatocellularCarcinoma

HepatocytesTumorcellsTGFβR-MET-PDL1

mRNAoverexpression

Proteinoverexpression

Geneamplification

Mutation

Chronicliverinflammation(viral– others)

Fibroblastsandfibrosis

Localimmunosupression

GenuineHypoxia

Treatmentinducedhypoxia(embolization,anti-angiogenic)

EpigeneticchangesassociatedwithHGF/c-METactivation

HGFstimulationofhepatocytesandhepatocarcinoma cellsharboringc-MET

Bouattour et al. Hepatology 2017, in press

c-METinhibitorsinlatestagedrugdevelopment

METIV-HCC– Tivantinib– phase3trial

CELESTIAL– Cabozantinib– phase3trial

• Firstgeneration• Specificity?

Bouattour et al. Hepatology 2017, in press

Tivantinib Placebo

MedianOS,mo 8.4 9.1

Patients 226 114

Events 180 94

HR(95%CI) 0.97(0.75-1.25);P=.81

Tivantinib - METIVTrial:OverallSurvival

1. Rimassa L et al. ASCO Annual Meeting. 2017. Abstract 4000.

Inhibitionofc-METWithTepotinib

TolerabilityandActivityofSecond-LineTepotinib,aPotentandHighlySelectivec-MetInhibitor,inPatientswithAdvancedHepatocellular

CarcinomaPreviouslyTreatedwithSorafenib

30

10

-10-20

-40-50-60Be

st re

lativ

e ch

ange

in s

umof

long

est d

iam

eter

in b

asel

ine

(%)

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

NewTargetsandNewAgentsinHepatocellularCarcinoma

TumorcellsTGFβR-MET-PDL1

FibroblastsFGFR

InhibitionofFGF19/FGFR4ActivationWith BLU-554

Baseline Week16

0 8 16 24 32

-26%SD -44%PR -45%PR PD

Week

Baseline

IHC+

FISH-

Radiographicresponseinpost-sorafenib,non-viralHCC

KimRetal.ILCA2017

*4confirmedresponses

IHC-positivityenrichesforradiographictumorreductionandresponse

KimRetal.ILCA2017

TGFβ&TGFβ-RasTargetsinHepatocellularCarcinoma

NewTargetsandNewAgentsinHepatocellularCarcinoma

EndothelialcellsPericytesVEGFR-PDGFR

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

TumorassociatedmacrophagesCXCR4-TGFβR

TumorcellsTGFβR-MET-PDL1

Galunisertib:TGF-βRIInhibitorinHepatocellularCarcinoma

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

Exvivo ProliferationControl TGFb inh.

Apoptosis

P-SMAD2/3(PDbiomarker)

(13pts)

(13pts)

(11pts)

TGFbRI InhibitionInducedbyGalunisertibinHumanHepatocellularCarcinomaExplants

BySerovaetal,Oncotarget2015

Galunisertib(TGFbRIInhibitor)inPatientsWithHepatocellularCarcinoma

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

Overall survival

AFPresponders=patientswhodecreasedcirculatingAFPlevelsby>20%

AFPnonresponders

AFPresponders

CourtesyofFaivreS.etal.Pres.ASCOGI2014andASCO2016

Part A AFP ≥1.5 ULN

Part B AFP <1.5 ULN

TACE+Sorafenib TACE+Placebo

MedianOS,d(95%CI) 631.0(473.0-879.0)

598.0(500.0-697.0)

HR(95%CI) 0.91(0.67-1.24);two-sidedP=.57

1. Meyer T et al. Lancet Gastroenterol Hepatol. 2017;2:565-575.

TACE-2:Sorafenib+TACEinUnresectable HCC

SARAHTrial:OverallSurvival

1. Vilgrain V et al. J Hepatol. 2017;66:S85-S86.

SIRTSorafenib

Intent-to-Treat PopulationN = 459

Median8.0 mo9.9 mo

SIRTSorafenib

Per-ProtocolPopulationN = 380

Median9.9 mo9.9 mo

HR = 1.15 (95% CI, 0.94-1.41)Log-rank P = .18

HR = 0.99 (95% CI, 0.79-1.24)Log-rank P = .92

••

Unresectable HCCBCLC C or

•••

BCLC A/BChild–Pugh A, or B ≤7 pts

ECOG PS 0-1

R

SIRT(yttrium-90microspheres)

Single injectionn = 237

Sorafenib400 mg twice daily

n = 222

SIRveNIB:SIRTvsSorafenib1

•

•

•

•

•

Asian patients with locallyadvanced inoperable HCC

BCLC B/C

Child–Pugh A, or B ≤7 pts

ECOG PS 0-1

No extrahepatic metastasis

N = 360

R

SIRT(yttrium-90microspheres)

Single injection

n = 182

Sorafenib400 mg twice daily

n = 178Outcomes

1. Chow P et al. ASCO 2017. Abstract 4002.

Intent-to-Treat Population Treated Population

SIRTSorafenib

SIRTSorafenib

Dropout:SIRT 28.6% (52 pts) vs sorafenib 9% (16 pts)

No OS difference in ITT or treatedpopulation

NewTargetsandNewAgentsinHepatocellularCarcinoma

Sorafenib(1st line)

Regorafenib(2nd line)

Tumorangiogenesis

Galunisertib(TGFβ-RI)

Tepotinib(c-MET)

BLU-554(FGF19/FGFR4)

Microenvironmentsignaling

NivolumabPembrolizumab

(PD-L1)

IpilimumabTremelimumab

(CTLA4)

Immunestroma

ç Combinationsè

Conclusions• Variouscomponentsoftumormicroenvironmentcouldbeusedastargetstocontroltumorgrowthinhepatocellularcarcinoma

• Inhibitionoftumorangiogenesis,microenvironmentsignalingandlocalimmunosuppressionappearaspromisingoptionsfortumorgrowthcontrol

• Combinationtherapiesnormalizingthemicroenvironmentofferpromiseforoptimalcontrolofhepatocellularcarcinogenesis

Thanksforyourattention

http://pamm-meetings.org/