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Unconventionalapproachesandnewdrugsinrectalcancer
EmmanouilFokas,MDDPhilUniversityofFrankfurt
Sharmaetal.,NatRevClinOncol2016Bristowetal.,LancetOncol2018
NewDrug–Radiotherapycombinations
Giraltetal.,RadiotherOncol2005
EGFRasPredictiveBiomarker
EGFR- EGFR+
pCR:8/35 pCR:2/5229% 4%
p=0.006
RoleofEGFRinrectalcancer
Series n Treatment pCR
Bertolini,2007 40 RT+5-FU+Cetuximab 8%
Machiels,2007 30 RT+Cape+Cetuximab 5%
Rödel2008;Fokas2014 48 RT+Capox+Cetuximab 9%
Horisberger,2009 50 RT+Capiri+Cetuximab 8%
Kim,2011 40 RT+Capiri+Cetuximab 23%
Helbling,201368KRASWT
RT+Cape+/-Panitumumab 10%vs.18%
ClinicaltrialswithEGFR-Inhibition
EXPERT-CTrial(randomizedphaseII)MRI-definedhighrisk:≤1mmtomesorectalfascia,T3≥5mm,low-lyingT3,V1,T4
R
RT50.4Gy+Capecitabine
CAPOX4#,q21
TME
CAPOX4#,q21
RT50.4Gy+Capecitabine
Cetweekly
CAPOX4#,q21
Cetweekly
TME
CAPOX4#,q21
Cetweekly
Dewdneyetal.,JClinOncol2012
EndpointCAPOX
N=81KRAS/BRAFwildtype:
n=44
CAPOX+CN=83
KRAS/BRAFwildtype:
n=46P
pCR(primaryendpoint) 7% 11% ns
PFSat3years 81% 80% ns
Relapse<6/≥6mts 18%/2% 2%/15% -
OSat3years 81% 96% 0.035
Dewdneyetal.,JClinOncol2012
EXPERT-CTrial(randomizedphaseII)
Debucquoyetal.JClinOncol,2009
Microarray:Downregulationofgenesinvolvedinproliferation/cellcycleUpregulationofinflammatorygeneexpression
K-rasstatus:Notrelatedtooutcomeparameters(TRG,DS,DFS)
N=41
N=41
Molecularprofileaftercetuximabtrt
Continuous5-FU
DAY 1 8 15 29 43 52
Bevacizumab
PhaseItrial
ClinicaltrialswithVEGF-Inhibition
Jain,Science2005 Willettetal.,NatMed2004
Willettetal.,NatMed2004
Bevacizumab+CRTinrectalcancer:PhaseI
Series n Treatment pCR TOX/Postopcomplications
Willett,2009 32 BV+RT+5-FU 16%Presacralabscess(2);Delayedhealing(2);Woundinfection(3);Hematoma(1);Ileus
(2);neurogenicbladder(1);…
Velenic,2011 61 BV+RT+Cape 13% Presacralabscess(12);Delayedhealing(18);Anastomoticleackage(7)…
Dellas,2013 70 BV+RT+CAPOX 17% Presacralabscess(1);Delayedhealing(1);Analfistula(1);…
Salazar,2015 90 BV+RT+CapevsRT+Cape
16%vs11%(p=0.5)
Grade3-4tox:16%vs13%Surgical:43%vs39%
AXEBEAMVerstraete,2015
80 BV+RT+CAPvsBV+RT+CAPOX
(n=59)11%
vs36%
Translationalstudy:DecreaseinMVD;
Smallincreaseinhypoxia;PDGFA,PDGF-BB;CA-IX,𝛂-SMAas
potentialbiomarkersforpCR
ClinicaltrialswithVEGF-Inhibition
Author/Group
ModeofAction
Drug/Schedule Comments
O‘Neil;2010 ProteasomeInhibition Bortezomib+5-FU/RT
PhaseI(n=9);(DLT:diarrhea)
Ree;2010Histone
DeactylaseInhibition
Vorinostat+palliativeRT30Gyin10#
PhaseI(n=17)(DLT:fatique,anorexia,
diarrhea)
Buijsen;2013 PI3-K/AKTInhibition Nelfinavir+Cape/RT
PhaseI(n=11)pCR27%
(DLT:cholangitis,liver-enzymes)
Moos;2014 RAF/MEK/ERKandVEGF-R Sorafenib+Cape/RT
PhaseII(n=40)pCR15%
(Grade4:3%neutropenia;Grade3:diarrhea
Czito;2017 PARPInhibition Veliparib+Cape/RT PhaseI(n=32);
pCR29%
…beyondEGFR-andVEGF-Inhibition
T-cells(immunoscore)inrectalcancer
Aniteietal,ClinCancerRes2016
RTcanactivatetheimmunesystem:complementaryroleswithimmunotherapy?
Sharabietal,LancetOncol2015
aCTLA-4andaPD-1/PD-L1Immunecheckpointinhibitors
Ribasetal,Science2018
• CTLA-4:downmodulatesT-cellactivationinalymphnode
• PD-1/PD-L1axis:limitsT-celleffectorfunctionswithintissues
PrognosticroleofPD-L1inrectalcancer• CRTupregulatedPD-L1incancercells(p<0.001)andinvasivefront(p<0.001)
• High PD-L1 expression on pre-CRT inflammatory cells (p=0.048) and post-CRT
inflammatorycells(invasivefront;p=0.010)correlatedwithimprovedoutcome
Hechtetal.,EJC2017
CRT+aPD-L1inrectalcancer
5-FU-CRT50.4GyTME
Week3 Week6 Week9 Week12 Week15
+/-Atezolizumab(ivq3w;PhaseII,randomisation2:1;n=50)
TranslationalResearch:Tumorsamplesweek-1,(3),15Bloodsamplesweek-1,every3weeks
PI:JavierCarrasco
CRT+oncolyticvirusinrectalcancerEnadenotucirev(ColoAd1):• AchimericgroupBadenovirus• Replicatesonlyintumortissueandnotwithinnormal,non-canceroustissue• Activatestheimmunesystemviareleaseofheatshockprotein70(HSP70),high-
mobilitygroupbox-1(HMGB1)andcalreticulin• Leadstodendriticcell-mediatedTcellactivation
5-FU-CRT50.4GyTME
Week3 Week6 Week9 Week12
+Enadenotucirev(weeklyiv;PhaseIvirusdose-escalationtrial;n=30)
PI:MariaHawkins
CRT+aTGF-βinrectalcancerGalunisertib(LY2157299):• AnoralsmallmoleculeinhibitoroftheTGF-βreceptorIkinase• Downregulatesphospho-SMAD2,abrogatingactivationofthecanonicalTGFpathway• Activatestheimmunesystemviadiversemechanisms(e.g.T-cells,DC,NKcells)
5-FU-CRT50.4GyTME
Week3 Week6 Week9 Week12
+Galunisertib(2x14-daycourses;startsbeforeCRT;PhaseII(pCR);n=30)
PI:ChristinaYoung
• EGRF-Inhibition:noroleintheprimarysetting!
• VEGF-Inhibition:noroleintheprimarysetting!
• Role of other targeted agents only minimally
explored
• Immunotherapiesappearpromisingbuttheirefficacy
inrectalcancerremainstobedemonstrated
• Future roleof RadiationOncology in the context of
immunotherapies:challenge!
Conclusions
