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Oral mucositis associated with targeted therapy and immunotherapy: what’s old is new againNathanielTreister,DMD,DMScAssociateSurgeonBrighamandWomen’sHospitalAssociateProfessorHarvardSchoolofDentalMedicine
Faculty Disclosure
Company Name Honoraria/ Expenses
Consulting/ Advisory Board
Funded Research
Royalties/ Patent
Stock Options
Ownership/ Equity
Position Employee Other
(please specify)
Midatech Pharma US x
Dermtreat ApS x
No, nothing to disclose X Yes, please specify:
Outline
• Targetedtherapies– mTORinhibitors– MEKinhibitors– PI3Kinhibitors– an;-VEGFTKIs– EGFRinhibitors– BRAFinhibitors
• Immunecheckpointinhibitors– CTLA4inhibitors– PD-1/PDL-1inhibitors
HanahanD,WeinbergA.Hallmarksofcancer.Cell2011;144:646-74
mTORinhibitor-associatedstoma;;s• mTORpathway
– PI3K/AKT/mTORfrequentlyupregulated,prolifera;on
– sirolimus,temsirolimus,everolimus• Clinicalfeatures
– aphthous-likeulcers– acuteonset,daystoweeks– recurrent,diminishwith;me– dosedependent
• Management– topicalsteroids– pallia;vecare– dosemodifica;on
SonisS,etal.Cancer2010;116:210–5;Mar;nsF,etal.OralOncology2013;49:293–298;ShameemR,etal.CancerInves;ga;ons2015;33:70-7
mIASmanagementw/cor;costeroids• Retrospec;ve,openlabelphase1/2trials
– 17cancerpa;ents,everolimus/ridaforolimus– 10daysmedianonset(4–25)
• medianpain=7/10• 5dosereduc;ons,1DLT
– improvementin~90%w/steroidtherapy• topical(15),intralesional(5),systemic(1)• pallia;vetreatmentsw/limitedbenefit
• SWISHtrial(n=92),openlabelphase2– advancedHR+/HER2+breastca– EVE10mg/EXE25mg– dexamethasone0.5mg/5mL,2min,s/s,QID– incidenceof≥grade2stoma;;sat8wks
comparedw/BOLERO-2:• 2.4%vs.33%(p<0.001),21.2%vs.67%allgrades
deOliveiraMA,etal.OralOncology2011;47:998–1003;RugoH,etal.LancetOncol2017;18:654-662
Aphthousstoma;;sw/othertargetedtherapies?• PI3Kinhibitors
– idelalisib• mul;plephase1and2studies,nomucosi;s
– copanlisib• phase1,6/57(11%)w/“oralcavitymucosi;s”,table,no
descrip;onPatnaikA,etal.AnnalsOncol2016;27:1928–40
• MEKinhibitors– trame;nib(selume;nib,cobime;nib)– “mucosi;s”/”mucosalinflamma;on”reported
infrequently(2-36%),aphthous-like?nodescrip;on…InfanteJ,etal.LancetOncol2012;13:773–81FalchookG,etal.LancetOncol2012;13:782–9Abdel-RahmanO,etal.ExpertRevGastroenterolHepatol2015;9:1433–45
– acneformrashcommonAnforthR,etal.AustralasianJDermatol2014;55:250-4
TaylorB,etal.NatRevCancer2011;11:541-7
MEKinhibitors
idelalisib(PI3Kinhibitor)
MEK+PI3Kinhibitor
Oraldysesthesiaassociatedw/TKIs• Mul;-targetedtyrosinekinase
inhibitors– an;-VEGF– suni;nib,sorafebib,others
• Clinicalfeatures– poorlydescribedinliterature– normalappearingmucosa– oral/tonguesensi;vity,dysesthesia,taste
changes– associa;onw/hand-and-footskin
reac;on,increasingseverity• Management?
– treataspainordysesthesia?– dietmodifica;ons
Kollmannsbergeretal.Oncologist2011;16:543-53;LeeW,etal.BrJDermatology2009;161:1045-51;YuanA,etal.OralOncology2015;51:1026–33;SchmidingerM,etal.Oncologist2017;22:1-10;GerendeshB,etal.OncotargetsandTherapy2017;10:5053-64
Suni;niboraltoxicity
• Mucosalsensi;vity– most≤grade2– <10%requireddosereduc;on
• <1%requireddiscon;nua;on
• Clinicalcourse– 7-14daysaserstart/severityincreases– resolvesduring2wkrest– recurs,severitylessens
• Clinicalfindingsnormal– singlereportof“bullousmucosi;s”(?)
Kollmannsbergeretal.Oncologist2011;16:543-53;MignognaM,etal.AnnPhamacother2009;43:546-7
Immunotherapy-associatedoralAEs• Immunecheckpointinhibitors
– blockCTLA-4,PD-1/PD-L1;Tcellac;va;on– ipilimumab,nivolumab,pembrolizumab
• Clinicalfeatures– lichenoidinflamma;on,(bullouspemphigoid)
• ~3monthsmeanonset(cutaneous);highlyvariable,casereports/series,mul;systempossible
– siccasyndrome(n=4,Hopkins,abruptonsetofseverehypofunc;on,;meframevariable)
– GVHDaseralloHSCT(relapse),poten;allysevere/refractory
• acute,overlap,chronicforms– combina;ontherapyw/higherrates
• Management– lichenoid–topicalsteroids,+/-modifica;ons– sicca–pallia;ve,sialogogues,dental– earlyrecogni;on,referral
CurryJ,etal.JCutanPathol2017;44:158-76;ShiV,etal.JAMADermatol2016;152:1128-36;CappelliLC,etal.AnnRheumDis2017;76:43–50;HaverkosB,etal.Blood.2017;130:221-8;SibaudV.AmJClinDermatol2017;SibaudV,etal.JEADV2017;31:e428-75
nivolumabx2neoadjuvantheadandneckcancerprotocol
nivolumab-associatedlichenoidinflamma;on,managedwithtopicalclobetasol0.05%solu;on
acuteGVHDerup;onfollowing1stcycleofpembrolizumabformetasta;ccoloncancer,s/pRICalloHSCTforAML
Otherreportedoraltoxici;es• Ima;nib
– lichenoidreac;ons,cheili;s,SJS• EGFinhibitors
– mucosi;s,‘whichrarelyincludesaphthousulcers’,‘withoutmucosalchanges’
• Vemurafenib– mucosalkeratosis
• symptoma;c,gingiva,palate,lineaalba,labial• regressedondiscon;nua;on
– SCC(lowerlip,n=1)• Benignmigratoryglossi;s/erythema
migrans– bevacizumab,suni;nib,sorafenib(an;-
VEGF?...)
Amitay-LaishI,etal.DermatologicTherapy2011;24:386-95;PileriA,etal.JEADV2016;30:10-25-67;MacdonaldJ,etal.JAmAcadDermatol2015;72:203-18;HidalgoM,etal.JClinOncol2001;19:3267-3279;HubicheT,etal.Oncologist2013;18:e16-e17;GavrilovicI,
etal.Oncologist2012;17:274-8;BoussemartL,etal.AnnOncol2013;24:1691-7;VigariosE,etal.BrJDermatol2015;172:1669-89
s/palloHSCT,cGVHD,s/pIL-2,mildsymptoms
s/palloHSCT,cGVHD,denovo,severesymptoms
Summary
• Novelcancertherapies,noveloraltoxici;es,butmimicothercondi;ons
• Understandrisk,recognizeearlysigns/symptoms
• Pa;enteduca;on,preven;on,awareness
• Managementdependsoncorrectdiagnosis,specialtyreferral
• Researchopportuni;esabound