DERMATOLOGICTOXICITIESASSOCIATEDWITHIMMUNOTHERAPIESANDMANAGEMENTSTRATEGIESJenniferN.Choi,MDAssociateProfessorofDermatologyChief,DivisionofOncodermatologyRobertH.LurieComprehensiveCancerCenterNorthwesternFeinbergSchoolofMedicinejennifer.choi@northwestern.eduJune30,2018

DISCLOSURE OF RELATIONSHIPS WITH INDUSTRY

Jennifer N. Choi, MD

DISCLOSURES Biotest AG: Consultant – Honoraria

Bayer: Speaker – Honoraria Incyte: Principal Investigator – Research

Veloce Pharmaceuticals: Principal Investigator – Research

Spectrumofimmune-relatedAdverseEvents(irAEs)

AnnalsofOncology27:559–574,2016

SuozziKC,etal.JAADCaseRep.2016Jul14;2(3):264-8HofmannL,etal.EuroJCancer.60(2016):190-209

30-40%

6-16%

1-8%

DermatologicAdverseEventstoAnb-PD-1TherapiesAdverseEvent Percent(Grade3-4)

Rash 34-39%(2%)

Pruritus 17-21%(0.5-1%)

Vibligo 9-11%(0%)

NEnglJMed.2013Jul;369(2):134-44NEnglJMed.2015Jan;372(4):320-330JClinOncol2015;33NEnglJMed.2015;372:2521-2532

DermatologicAdverseEventstoAnb-PD-1TherapiesAdverseEvent Percent(Grade3-4)

Rash 34-39%(2%)

Pruritus 17-21%(0.5-1%)

Vibligo 9-11%(0%)

AdverseEvent Percent(Grade3-4)

Rash 44-65%(6-7%)

Pruritus 17-65%(0%)

Nivolumab+Ipilimumab

NEnglJMed.2013Jul11;369(2):122-33

NEnglJMed.2013Jul;369(2):134-44NEnglJMed.2015Jan;372(4):320-330JClinOncol2015;33NEnglJMed.2015;372:2521-2532

Rash

Medianbmetoonset=4-6weeks

Interface,perivascularandperiadnexallymphocybcdermabbsFewplasmacellsandeosinophils

Eczema

HwangS,etal.JAmAcadDermatol.2016Mar;74(3):455-461ShiVJ,etal.JAMADermatology.2016;152(10):1128-1136SibaudV,etal.CurrOpinOncol2016,28:254-263HofmannL,etal.EuropJCancer.2016,60:190-209BelumVR,etal.EuropJCancer.2016,60:12-25

Lichenoiddermabbs

Band-likelymphocybcinfiltratealongDEJVacuolarinterfaceCoexisbngspongiosis

Eczematous/spongiobcdermabbs

BelumVRetal.EurJCancer2016June;60:12-25.

Eczematous•  Generalized•  Localized

Eczematous•  Generalized•  Localized

Eczematous•  Generalized•  Localized

ClinicalPakernsofLichenoidDermabbs

DiscreteLocalizedInverseGeneralizedPalmoplantarMucosal

CD4 CD8

Lichenoid:Discrete

Lichenoid:Discrete

JAMA Dermatol. 2015;151(11):1206-1212.

Lichenoid:Localized

Lichenoid:Localized•  Inverse

JAAD Case Rep. 2017 Jan; 3(1): 7–9.

Lichenoid:Generalized

Lichenoid:Generalized

Lichenoid:Palmoplantar

Lichenoid:Mucosal

• 20pabents• Timetoonset:3daysto13months• 16/20(80%):erythematouspapuleswithscale- 11/20(55%):Localizedontrunkorextremibes- 9/20(45%):Generalizeddistribubon

• 16/17(94%):lichenoidhistology• 8/16(50%):lichenoid+spongiobchistology• 4/20(20%):peripheraleosinophilia• 16/20(80%)onconcurrentmedicabonspreviouslyreportedtocauselichenoiddrugerupbons

JAMADermatology.2016;152(10):1128-1136

Association of Dermatitis after PD-1/PD-L1 Inhibitor Therapy and Progression Free Survival and Overall Survival

Lee CK et al. JAAD May 2018

ManagementofRashbyImmuneCheckpointBlockade

Grade Invesbgabons Management Follow-Up

1Macules/papules

covering<10%BSA**Asymptomabcorwithsymptoms

2Macules/papules

covering10-30%BSA**Asymptomabcorwith

symptoms

*Limibngself-careADLs

3-4Macules/papules

covering>30%BSA**Asymptomabcorwith

symptoms*Severe/life-threatening

symptoms*Generalizedexfoliabve/

ulcerated/bullousrash

•  Repeatskinexam•  Ifdevelops

symptoms,treatashighergrade

•  Ifimprovesto<Grade1,resumeimmunotherapy

•  Aoersymptomsimprove,tapersteroidsover>1month

•  Ifimprovesto<Grade1,tapersteroidsover>1month

•  Ifworsensin48hours,consideraddibonalimmunosuppression(infliximab,cyclophosphamide,MMF)orsupporbvemeasures

•  Ifnoimprovement>12weeksfromlastdoseoftherapy,disconbnueimmunotherapy

•  Mucocutane-ousclinicalexam

•  Serumtesbngforliver,kidneyfuncbon

•  Considerdermatologyconsult

•  Considerskinbiopsy

•  Conbnueimmunotherapy•  Topicalcorbcosteroids

(intermediatetohighpotency)

•  Oralanbhistaminesforpruritus

•  Oralprednisone1mg/kg/dayorequivalent

•  Oralanbhistaminesforpruritus

•  Holdimmunotherapy•  Oralprednisone1mg/

kg/dayorequivalent•  Oralanbhistamines

forpruritus

Naidooetal.AnnOncol2015Sept14

Treatment of the Immune-Related Adverse Effects of Immune Checkpoint Inhibitors: A Review

Friedman CF, et al. JAMA Oncol. 2016;2(10):1346-1353.

TreatmentofSevereandSteroid-RefractoryImmune-RelatedAdverseEvents

PabentCourse

• Startedonprednisone80mgdailywith3-4weektaper• ClobetasolointmentBIDx2weekstogenitalareaandoralulcerabon;resolvedanddidnotrecur

• Aoerprednisonedosereached10mgQD,rashandpruritusalwaysrecurred.

• StartednarrowbandultravioletBphototherapy2-3bmesaweek–treatedfor3months

• Abletostopphototherapyandwasmaintainedonprednisone4mgdaily,thendisconbnuedprednisonecompletely2monthslater.

• Sbllonpembrolizumabwithstabledisease.• Norecurrenceofrashorpruritusforpast12months.

Anb-PD-1CutaneousErupbonsSevere/life-threatening

TEN-likereacbonassociatedwithnivolumabfollowingipilimumab

JImmunother2016,39(3):149-152

TENduetonivolumabJCutanPathol2017;00:1–4

•  Diffusemorbilliformerupbon->slowprogressionoverweekstomonths

•  MarkedincreaseinPD-L1stainingexpressioninepidermis

•  Pembrolizumab:8SJS,2TEN

•  50yowoman,metastabcmelanoma•  3monthspriortoadmission,startedipilimumab+nivolumabx1cycle->diffusemorbilliform,grade2.

•  Ipilimumabstopped.•  2morecyclesofnivolumab->slowprogression.Shortcourseofsystemicsteroidsaoereachdosewithsomeimprovement.Aoer3rddosenivolumab,treatmentheld.Startedprednisone1mg/kg.

•  Biopsy:mildinterfacedermabbswithrarenecrobckerabnocytes.PD-L1staininginfewscakeredkerabnocytesandweakexpressionalongepidermis.

•  Onadmission,90%BSAwith10%Nikolskysign.Extensiveconjuncbval,oral,andgenitaldesquamabon.ImmunohistochemicalanalysisdemonstratedCD8+cellsaggregatedatthedermal-epidermaljuncbonandepidermalexocytosisofCD8+cells.PD-L1expressionwasmarkedlyincreasedintheepidermis.Directimmunofluorescencewasnegabve.Dx:TEN.

•  Infliximab,prednisone1mg/kg.2dayslater,startedIVIGx3doses.Developedsepbcshockandmulborganfailure.Diedonhospitalday6.

JCutanPathol2017;00:1–4

*Abilityofanb-PD-1anbbodiestoinduceTENwithouttheclassicclinicalmorphologyorbmecourseofthedisease

Immunotherapy-InducedPruritus

• Approximately30%ofpabents• Associatedwithrashandxerosis• Enhancedimmunesystemacbvabonintheskin

• Adverselyaffectsqualityoflife

76-year-oldJapanesewomanAdvancedNSCLCwithnivolumabSevererashwithmucosalinvolvementàSJSOralprednisolone1mg/kgRashresolved,butpruritusunremitngwithemollients,anbhistamines,steroidsAprepitant80mgQDx5days

80mgQDx3-5days;120mg,80mg,80mg

Vibligo• 8-25%vibligo• 52to453daystoonset

JAMADermatol.2016Jan1;152(1):45-51.

HofmannL,etal.EuropJCancer.2016,60:190-209

Association of Cutaneous AE and Vitiligo With Tumor Response in Patients With Metastatic Melanoma Treated With Pembrolizumab

OR(completeorparbal)associatedwithahigheroccurrenceofvibligo:71%vs28%

JAMA Dermatol. 2016;152(1):45-51JAMA Dermatol. 2015 Nov;151(11):1206-12

Vibligoinnon-melanomacancerpabents

SOX-10

75yearoldwomanStageIVNSCLCCarboplabn+pemetrexed4monthslater,startedonnivolumab8monthsaoernivolumabinibabon:Patchofdepigmentabononrighthand

Vibligoinnon-melanomacancerpabents•  75yomanwithstage4NSCLC,treatedwithdocetaxel.Startednivolumab3monthslaterduetoprogressivedisease.

•  6dayslater,vibligoappearedonback,chest,abdomen,andextremibes

•  66yomanwithAMLinremissionaoerchemotherapyandNSCLCpreviouslytreatedwithchemotherapyandlocalradiabon

• OnnivolumabaspartofphaseIIclinicaltrialforprevenbonofAMLrecurrence

•  Depigmentabonstarbng4monthsaoernivolumabinibabon:arms,chest,face,neck

LungCancer.2017Jul;109:42-44JAAD Case Reports 2017;3:90-2

Vibligoinnon-melanomacancerpabents

•  Cross-reacbonwithmelanocytedifferenbabonanbgens:gp100,MelanA/MART-1,tyrosinase?

•  AnothersharedanbgenbetweenNSCLCandmelanocytes?

JAMADermatol.2017Jul12.

•  13/14pabentswithlungcancer•  4=squamouscelllungcancer•  10=lungadenocarcinoma•  13/14completehairrepigmentabontobaselinehaircolor

•  Nivolumab(n=11)•  Pembrolizumab(n=1)•  Atezolizumab(n=2)•  13/14parbalresponseorstabledisease

JAMADermatol.2017Jul12.

JAmAcadDermatol2017;76:863-70

•  8pabentsonanb-PD1therapyvs30vibligocontrols•  Photoexposedareaswithspecificdepigmentabonpakernconsisbngofmulbplefleckedlesions•  Nopersonalorfamilyhistoryofvibligo,thyroidibs,orotherautoimmuned/o•  Bloodandskinsamples:

•  IncreasedCXCmobfligand10levelsinserum•  SkininfiltrabonofCD8TcellsexpressingCXCmobfreceptor3andproducingelevatedlevelsofIFN-γandTNF-α

•  MeanBSA4.25%(1-9%)

JAmAcadDermatol2017;76:863-70

RepigmentabonofVibligoAssociatedwithMelanomaRelapse

NakamuraYetal.JAMADermatol.2017Sep1;153(9):942-944

Case• 83yearoldCaucasianwomanwithmetastabcmelanomatolungandspine

• Pembrolizumab2mg/kgIVevery3weeks• 2monthhistoryofworseningvaginalandinterglutealerupbon

• Onsetbetweencycles2and3• Empiricsystemicanb-fungalandanbbacterialtherapywithminimalresponse

• Consultedaoeradmissiontohospitalforrash

Anb-PD-1CutaneousErupbons

• Exacerbabonofpsoriasis• Psoriasiformerupbons

JEurAcadDermatolVenereol.2015Sep21

ActaDermVenereol.2015Aug13

JAMADermatol.2015Jul;151(7):797-9CurrOpinOncol2016,28:25-263

JEurAcadDermatolVenereol.2016Oct14JAMADermatol.2016May1;152(5):590-2

CurrentProbCancer.2017;41:407-412

Anb-PD-1InducedPsoriasis•  21pabents•  86%male•  71%withhistoryofpsoriasis•  Meanbmeofonsetbetweenanb-PD1inibabonandpsoriasisflare:50days-  Denovopsoriasis:90days-  Preexisbngpsoriasis:33days

•  95%developedplaquepsoriasis-  +gukate:n=6-  +palmoplantar:n=4-  +pustularpalmoplantar:n=1

•  81%topicaltreatment•  10%systemicsteroids•  5%acitrebn(5/17pabentsrequiredacitrebnassecond-linetx)•  5%phototherapy•  91%controlledbytreatment;9%worsened

BonigenJetal.Oct2016doi:10.1111/jdv.14011

•  Ifknownhistoryofpsoriasis,makesurepabentsarefollowedcarefullyduringimmunotherapy.•  Inibatetopicalsteroidtreatmentearlyonwithamaintenanceregimen:

E.g.TopicalsteroidsBIDx2weeks,thentopicalcalcipotrienecream/ointmentQD-BIDduringonweekdaysandtopicalsteroidsQD-BIDonweekends

•  Lowthresholdtoaddonphototherapywhileonimmunotherapy.•  Canconsideraddibonaltherapy:acitrebn,low-dosemethotrexate

Feb May Aug Oct

Anb-PD-1CutaneousErupbons

• Autoimmunebullousskindisorders- Bullouspemphigoid

CancerImmunolRes.2016Feb29.MelanomaRes.2015Jun;25(3):265-8.IntlJDermatolo.2018;57:664-669.

•  Atleast21casesreported:pembro,nivo,durvalumab,atezolizumab•  Pruritus:prominentfeature,precedingorconcurrent•  Meanbmetopruritus:17weeks•  Timetodevelopmentofbullae:6to80weeks(median24weeks)•  Metastabcmelanoma,head/neckSCC,lungadenocarcinoma,lung

SCC,NSCLC,renalcellcarcinoma,urothelialcarcinoma•  Meanage:71years•  6/21pabents=29%hadoralmucosalinvolvement

•  Topicalsteroidmonotherapy•  Oralsteroids+topicalsteroids•  Doxycycline+niacinamide:n=1;+oralandtopicalsteroids:n=3•  Rituximab:n=1•  Omalizumab:n=1•  3/21pabents:prolongedcoursesofBPfor3-12monthsaoer

disconbnuabonofcheckpointinhibitor•  Disconbnuabonnecessaryin16/21cases=76%•  7/19pabents=37%hadcancerprogressionorpabentdeathshortly

aoerBPdiagnosisandcheckpointinhibitordisconbnuabon

•  2theories:•  AlteredregulabonofT-cellstargebngcollagenXVII/

BP180•  IncreasedautoanbbodyproducbonagainstBP180

•  Inpabentswithpersistentorunusualpruritus,considersubclinicalBP.

•  Cantakemonthstoresolveduetoautoimmuneacbvabon

Otherreportedcutaneoussideeffectstocheckpointinhibitors

•  Acneiformerupbon•  Acbnickeratosis•  Acutegeneralizedexanthematouspustulosis(AGEP)•  Annulargranuloma•  Alopeciaareata,universalis•  Basalcellcarcinoma•  Dermalhypersensibvityreacbon(DHR)•  Dermabbsherpebformis•  Dermatomyosibs•  Drugrashwitheosinophiliaandsystemicsymptoms(DRESS)•  Erupbvekeratoacanthoma•  Erythema•  Erythema-nodosum-likepanniculibs•  Exfoliabvereacbon•  Grover’sdisease•  Hyperhidrosis

•  Nailchanges•  Necrobzingvasculibs•  Papulopustularrosacea•  Peritumoralinflammatorycellulibs•  Photosensibvityreacbon•  Pityriasislichenoides-likereacbon•  Prurigonodularis•  Pyodermagangrenosum-likeulcerabons•  Radiabon-associateddermabbs•  Regressionofmelanocybcnevi•  Sarcoidosis•  Sclerodermoidreacbon•  Seborrheickeratosis•  Sjögren’ssyndrome•  Squamouscellcarcinoma•  Sweet’ssyndrome•  Tumoralmelanosis•  Urbcaria•  Xerosis

Erupbvekeratoacanthomas

CutaneousSCCs5/82pabents=6.1%Face,chest,armsOlderpabents(73yovs60yo)Hwangetal.JAmAcadDermatol2016;74:455-61.

Erupbvekeratoacanthomas

JAMADermatology.2017May3

•  3pabentsonpembrolizumab•  Suddenonsetofmulbplelesionsonsun-exposedareasofextremibes•  Median13months(4-18mos)•  Pathology:Mulbloculated,crateriform,kerabn-filledlesionsSquamouscellsw/glassyappearingcytoplasmandminimalcytologicatypiaDisbnctlichenoidinfiltrateinunderlyingdermisw/CD3+Tcells•  IL+topicalsteroids+/-cryotherapy

Autoimmunefasciibs•  43-year-oldwomanwithmetastabcmelanoma•  Startedonnivolumab•  14monthslater:developedprogressivefabgue,widespreadmyalgiaofbilateralupperandlowerlimbs,progressivedysphagia

•  Skin-musclebiopsy:focusedfascialandperifascicularinflammatoryinfiltrate

ParkerMetal.BMJCaseRep2018;Jan8

Pembrolizumab-inducedscleroderma•  66-year-oldmanwithmetastabcmelanoma.Startedonpembrolizumab.Aoercycle13,developedfabgueandswellingofjointsandankles.Progressiontoburningandmuscleweakness.Developeddiffuseskinthickeningoverbilateralextremibesandface.

•  TreatedwithIVIG5daysweeklypermonthandmycophenolatemofebl1000mgBID.Symptomimprovement,then14weekslater,begantodeclineanddied2monthslater.

•  79-year-oldmanwithmetastabcmelanoma.Startedonpembrolizumab.Aoercycle5,severesbffnessofhandsandfeet.Pembrolizumabwasdisconbnued.

•  Treatedwithhydroxychloroquine200mgBIDandoralprednisone.Improvementinsymptoms.

Mayo Clin Proc. 2017;92(7):1158-1163

Checkpointinhibitor-induceddermatomyosibs•  Ipilimumab:n=1•  Nivolumab:n=1•  42-year-oldmanwithstageIVlungadenocarcinoma.Treatedwith4cyclesofcisplabn,pemetrexed,andbevacizumab->7cyclesofpemetrexedandbevacizumab->4cyclesofdocetaxel.Startedonnivolumab(3mg/kgQ2weeks).

•  Afewdaysaoercycle1:generalfabgueandminorproximallimbmuscleweakness•  6weekslater:clearproximalmuscleweaknessandskinfindings•  MRIlegs:abnormallyhighintensityareasinbilateraladductorandobturatormuscles;EMGshowedmyogenicconversion.

•  Treatedwithprednisolone0.6mg/kgQD->slighttemporaryimprovement•  Thendiagnosedwithspinalcordandmeningealdisseminabon10dayslater->death

Intern Med. 2018 Mar 9.

Erythemanodosum-likepanniculibs

Sarcoidosis

Immunotherapy-inducedalopeciaareata

•  1-1.6%ofpabentsonimmunotherapy•  Anb-CTLA-4,PD-1,andPD-L1inhibitors•  Scalp,face,eyebrows,eyelashes,trunk•  Areataanduniversalis•  Treatmentwithintralesionalsteroids(triamcinolone)andtopicalsteroids(clobetasol)

•  Resultantregrowthwithpoliosis

BrJDermatol.2017June;176(6):1649–1652.

ThankYoujennifer.choi@northwestern.edu