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