Hepatocellularcarcinoma:fromlocaltosystemictherapy
EricRaymondMD,PhDChairofMedicalOncology
@GroupeHospitalierParisSaint-JosephFrance
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/