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6 Waterhouseetal,Science1995
PD-1deficiencypredisposestoautoimmunediseases
Nishimuraetal,Science2001andImmunity1999
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Generalrules:managementofimmune-relatedadverseevents
Grade Management Con4nuethedrug?
Low DelaythedoseResume
whenAEsresolvetograde≤1orbaseline
Moderate∼High
AdministerCoracosteroids±Immunosuppressants
(ana-TNF,mycophenolate,etc)
Disconanuedrugpermanently(Delayinsomesituaaons)
KI*,$!(`*'*-1$
SkinToxicity
GradeofRash
(NCICTCAEv4)Management Follow-up
Grade1-2• Erymthaousand/
ormaculopapular(10-30%BSA)• Dryskin
• Pruritus,localizedordiffuse
intermident• Vi4ligo(nointerven4onindicated)
IfimprovestoGrade1:• Tapersteroidsoveratleast1monthandaddprophylac4can4bio4csforopportunis4cinfec4ons
• Resumetherapy
Grade3-4• Erythematourrash(>30%BSA))
• Pruritus,diffuseandconstant• Blisters,ulcera4on,
bullae,necro4corhemorrhagic
lesions• Toxicepidermal
necrolysis
Ifpersists>1-2weeksorrecurs:• Considerskinbiopsy• Delaytherapy• Consider0.5-1.0mg/kg/daymethylprednisoloneIVororalequivalent.Onceimproving,tapersteroidsoveratleast1month,considerprophylac4can4bio4csforopportunis4cinfec4ons,andresumetherapy
Ifworsens:• TreatasGrade3-4
• Symptomytherapy(e.g.an4histamines,topicalsteroids)
• Con4nuetherapy
• Delayordiscon4nuetherapy• Considerskinbiopsy• Dermatologyconsult• 1.0-2.0mg/kg/dayIVmethylprednisoloneIVorIVequivalent
B*/.."(#$/,:$'(7*4%$
20*7*+&+/9H$X$Y$C@gh$ >,1$6./:#H$,Vb[ ^./:#$M?@$Vb[ ^./:#$\$Vb[ _)<$$6%< QQU'cOfe GLU'cMEJe L
=9")a,' GKL'cHELe fU'cUEJe G'cgLEGe X*3(7&+/9H$X$Y$MQ@$ >,1$6./:#H$,Vb[ ^./:#$M?@$Vb[ ^./:#$\$Vb[ _)<$$6%< OM'cGKe O'cGe L =9")a,' L L K'cgGe
Diarrhoeandcoli4s
GradeofDiarrhea/Coli4s
(NCICTCAEv4)
Grade1Diarrhea:<4stools/day;Coli4s:asymptoma4c
Grade2Diarrhea:4-6stoolsperday
IVfluidsindicated<24hrs
Coli4s:abdominalpain;bloodinstool
Grade3-4Diarrhea(G3):≥7stoolsperday
incon4nence;IVfluidsindicated≥24hrs;
Coli4s(G3):severeabdominalpain,medicalinterven4onindicated,
peritonealsignsG4:life-threatening,perfora4on
• Con4nuetherapy• Symptoma4ctreatment
Management
• Delaytherapy• Symptoma4ctreatment
• Discon4nuetherapy• 1.0to2.0mg/kg/daymethylprednisoloneIVorIVequivalent
• Addprophylac4can4bio4csforopportunis4cinfec4ons
• Considerlowerendoscopy
Follow-up
• Closemonitoringforworseningsymptoms.• Educatepa4enttoreportworseningimmediatelyIfworsens:• Treatasgrade2or3/4
Ifimprovestograde1:• Resumetherapy• Ifpersists>5-7daysorrecur:• 0.5-1.0mg/kg/daymethylprednisoloneororalequivalent• Whensymptomsimprovetograde1,tapersteroidsoveratleast1month,considerprophylac4can4bio4csforopportunis4cinfec4ons,andresumetherapy
Ifworsensorpersists>305dayswithoralsteroids:• Treatasgrade3/4
Ifimproves:• Con4nuesteroidsun4lgrade1,thentaperoveratleast1month
Ifpersists>3-5days,orrecursalerimprovement:• Addinfliximab5mg/kg(ifnocontraindica4on).Note:Infliximabshouldnotbeusedincasesofperfora4onorsepsis
19.12.2014 • Diarrhea,nausea,andemesisbegan
22.12.2014 Work-upiniaated:• CTscanofabd/pelvis:milddistensionofsmallbowelbutnoevidenceofmechanicalobstrucaon,freeair,masslesion,orcolonicthickness/edema
• Stool:Fecalleukocytespresent• TreatedwithIVfluidsandanaemeacbutsymptomsworsened
25.12.2014
GIToxicityCaseStudy:71yroldfemale,melanoma,stageIV
• Hospitalizedwithseverenausea,vomiang,intractablediarrhea(grade3),anddehydraaon‒ RepeatCTscan:subtledilataaonoftheduodenum;noevidenceof
mechanicalbowelobstrucaon‒ Labtests:Stoolhemoccultmildlyposiave,stoolcxnegaave‒ Colonoscopy:abnormalmucosa‒ Colonbiopsy:benigncolonicmucosa
• Beganhighdosedexamethasoneandmetronidazoleforpresumedcolias‒ Alsoreceivedomeprazole,ondansetronandIVfluids
• Received7dosesipilimumab(3mg/kg)9/14–12/14
TPCPTQC\$ C@?*D9?,'$%D+$/%&'&+$)/:',D%$9)&'D<*%$'^)D69+D'$%56<""%/:%'9#'/)Y9"+?<3'>/5"+&%&'Y9?)a/:N'^<D%$@',D99",'c+*'D9'GLI&<@eN')/D%$?)T%/D'+**%$'<3&9?)/<"'*<)/'•! 5#0#/-$'(7(,(%'(01h''<3/9$?<"'59"9/'</&'59")a,'•! 5#0#/-$'(7(,$9*(0%1h'')/j<??<a9/'c/%^'l/&)/:e'•! m*6"$:(%#$%-#.(*:%$.#?%-/.-#:H$C`$5#+*'/:#$V2,J*`*+/9[$\$+6NI6$
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>?*$9Y%?%/D'D9':$<&%'KN'&%k<?%D6<,9/N',D<$D'D<*%$)/:'MCPCTPTQC@$
Whatarethelessonslearned?
§ Iniaatetreatmentearly
§ Useresultsofdiagnosacevaluaaontoguidemanagement
§ Anegaavediagnosacevaluaaonmayneedtoberepeated
§ Ifsteroidsarebegun,taperslowly
GIToxicityCaseStudy:71yroldfemale,melanoma,stageIV
Pneumoni4s
Incidence
InfrequentAllgrades:3%Grades3-4:1%,deathsassociatedwithpulmonarytoxicity
Riskfactor
§ Nounderlyingfactoridenafiedtodate§ Noapparentrelaaonshiptotumourtype
→ Casesobservedinmulapletumourtypes(Melanoma,RCC,NSCLC,etc)
Symptom § Cough,SOB/dyspnea(restorexeraon),fever§ Asymptomaacradiographicchanges
Assessment § Pulseoximetry(restandexeraon)§ CT§ Indoubtorfordifferenaaaonperformbronchoscopy
Management
§ Delaydosing§ Coracosteroids
→ ifnotimproving48hrsorworsening,addimmunosuppressants§ Bronchoscopy/BAL
Pneumoni4s
GradeofPneumoni4s
(NCICTCAEv4)
Management Follow-up
• Re-imageatleastevery3weeksIfworsens:• TreatasGrade2or3-4
Grade1Radiographicchangesonly
• Considerdelayoftherapy• Monitorforsymptomsevery2-3days• ConsiderPulmonaryandInfec4ousDisease(ID)consults
Grade2Mildtomoderatenew
symptoms
• Re-imageevery1-3daysIfimproves:• Whensymptomsreturntonearbaseline,tapersteroidsoveratleast1monthandthenresumetherapyandconsiderprophylac4can4bio4cs
Ifnotimprovingaler2weeksorworsening:• TreatasGrade3-4
• Delaytherapy• PulmonaryandIDconsults• Monitorsymptomsdaily,considerhospitaliza4on
• 1.0mg/kg/daymethyl-prednisoloneIVororalequivalent
• Considerbronchoscopy,lungbiopsy
Grade3-4Severenewsymptoms;New/worseninghypoxia;
Life-threatening
Ifimprovestobaseline:• Tapersteroidsoveratleast6weeksIfnotimprovingaler48hoursorworsening:• Addaddi4onalimmunosuppression(e.g.infliximab,cyclophosphamide,intravenousimmunoglobulin(IVIG),ormycophenolatemofe4l)
• Delaytherapy• Hospitalize• PulmonaryandIDconsults• 2-4mg/kg/daymethylprednisoloneIVorIVequivalent
• Addprophylac4can4bio4csforopportunis4cinfec4ons
• Considerbronchoscopy,lungbiopsy
PulmonaryToxicityCaseStudy#1
• 66yofemalewithmetastaacNSCLC,4priorsystemictherapies• Pasthxofasthma,pulmonaryembolism,25packyeartobaccouse(quitin1990)§ medicaaon:salmeterol/fluacasoneandsalbutamolinhaler
2.2015-8.2015 Received14dosesNivolumab(3mg/kg)
2.9.2015 • Serialrestagingrevealedparaalremission• Radiographicappearanceofgroundglassopaciaesnotconsistentwithmetsorinfecaon
• Subjectwasasymptomaac,deniedcoughorworseneddyspnea
• O2sat95%(92%withprolongedambulaaon)
5.9.2015 Bronchoscopy:noinfecaouseaology,reacavechangesandinflammaaononBAL
7.9.2015 • Steroidtherapywasiniaatedon8/17/10,withsubsequentslowtaper(6wks)• Scansimproved• Subjectrechallengedoncesteroidstapered,withnorecurrenceofpneumonias
!! QJ'@9'?<"%'^)D6'?%"</9?<'!! 7/,%Dh'_<@'HJ'cO'&<@,'<r%$'fD6'&9,%'9#'m_G'
<3e'!! =6%,D'*<)/I,69$D/%,,'9#'3$%<D6'!! X$%<D%&'^)D6',D%$9)&,'9/'_<@'JJ''!! >/j)k)?<3'c&<@'GLUe'</&'?@59*6%/9"<D%'c_<@'
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A&7+(,/.1$!(`*'*-1$</%#$K-&:1$nT$
Pneumoni4s
Whatarethelessonslearned?
• Pulmonarytoxicitymaypresentwithclinicalsymptomsormaybeanincidentalfindingonscans
• Subjectshavebeensuccessfullytreatedwithsteroids• Subjectswithlow-gradepnemoniasmaybere-challenged
withstudydrugoffofsteroids
Endocrinopathies
Incidence • Allgrades:6%• Grade3/4:1%
Involvedorgans• Hypothyroidism/hyperthyroidism• Hypophysias• Adrenalinsufficiency,secondaryadrenocoracalinsufficiency
‒Morethanoneendocrineorganmaybeinvolved
Onset• Withinweeks∼mayoccurmanymonths
‒ Typicallyidenafiedthroughrouaneperiodicmonitoringor‒ Partofworkupofassociatedsymptoms
Symptom• Non-specificsymptoms
‒ Headache,faague,weakness,memoryloss,impotence,personalitychanges,andvisual-fieldimpairment
• Whenencounteringnon-specificsymptoms,thinkofendocrinopathies
Management• Nivolumabmaybeconanuedonceappropriatehormonereplacementiniaated
• Subjectswithendocrinopathymayrequirereplacementdosesteroidsratherthanhigh-dosesteroids
EndocrinopathyCaseStudy
• 72yomalewithmalignantmelanomawithmulaplesites,1stlinechemotherapy• Pasthistoryofhypertension,insulin-dependentdiabetesmellitustype2,
hypercholesterolemia,andbenignprostatehypertrophy• Conmeds:glyburide/meuormin,atenolol,hydrochlorothiazide,aspirin,rosuvastaan,insulin,
finasteride,lisinopril,lorazepam,prochlorperazine,andamlodipine4-7.2014 Received4cyclesofipilimumab(3mg/kg)
3.8.2014 Presentedtoclinicwithprofoundfaague,bodyaches,andlegweakness• Labs:undetectableserumcorasollevel,elevatedLH13.6mIU/mL(ref1.7-8.6),otherwiseWNL
• BrainMRI:Nosignsofanymasslesions;CXR:mildlyenlargedheart
8.8.2014Admidedtohospitalon8.8.2014• OrthostaacwithSBPin60’suponstanding• ACTH:<5pg/ml(RR7-50)• ACTHsamtest:pre-samcorasol0.9ug/dL,post-samcorasol8.6ug/dL@30min,10.8ug/dL@60min
• Endocrineconsult:primaryhypophysias• HypoadrenalstateduetoprimaryACTHdeficiency• TreatedwithIVFandreplacementdosesteroids
U,:('.*,(0/-"1$</%#$K-&:1$
C\PhPTQC@$ _),56<$:%&'#$9?'69,*)D<"''TQPhPTQC@$ C%%/')/'5")/)5'^)D6')?*$9Y%?%/D'9#'6@*9D%/,)9/N'#<a:+%N'</&'&)00)/%,,'ThPhPTQC@$ CD%$9)&'$%*"<5%?%/D'56</:%&'#$9?'.='D9'*$%&/),9/%'cQ'?:'n)&e'
Endocrinopathies
Asymptoma4cTSHeleva4on
• Con4nuetherapy• IfTSH<0.5xLLN,orTSH>2xULN,orconsistentlyoutofrangein2subsequentmeasurements:includefT4aatsubsequentcyclesasclinicallyindicated;considerendocrinologyconsult
• Evaluateendocrinefunc4on• ConsiderpituitaryscanSymptoma4cwithabnormallab/pituitaryscan:• Delaytherapy• 1-2mg/kg/daymethylprednisoloneIVorPOequivalent• Ini4ateappropriatehormonetherapy
Noabnormallab/pituitaryMRIscanbutsymptomspersist:• Repeatlabsin1-3weeks/MRIin1month
Ifimproves(withorwithouthormonereplacement):• Tapersteroidsoveratleast1monthandconsiderprophylac4can4bio4csforopportunis4cinfec4ons
• Resumetherapy• Pa4entswithadrenalinsufficiencymayneedtocon4nuesteriodswithmineralocor4coidcomponent
• Delayordiscon4nuetherapy• Ruleoutsepsis• StressdoseofIVsteroidswithmineralocor4coidac4vity• IVfluids• Consultendocrinologist• Ifadrenalcrisisruledout,thentreatasaboveforsymptoma4cendocrinopathy
Symptoma4cendocrinopathy
Suspicionofadrenalcrisis(e.g.severedehydra4on,
hypotension,shockoutofpropor4onto
currentillness
Endocrinopathies
Whatarethelessonslearned?
• Whenencounteringnon-specificsymptoms(faague,weakness),thinkofendocrinopathies
• Considerendocrineconsulttointerpretlabresultsandguidemanagement
• Subjectwithendocrinopathymayrequirereplacementdosesteroidsratherthanhigh-dosesteroids
Renaltoxici4es
Incidence
• <1%ofsubjectstreatedwithnivolumabmonotherapyhaveexperiencedarelatedSAEofacuterenalfailure‒ 2Grade2,3Grade3‒ 2inmonotherapystudies(Mel,RCC),3incombinaaon
(Mel,NSCLC)
Onset • Median43days(6-505days)• Mostcommonlypresentwithelevaaonsinserumcreaanine
Management Steroidsgenerallyleadtoclinicalimprovement/resoluaon
Renalbiopsy Mayhelpdisanguishinflammatoryversusnon-inflammatoryeaologies
RenalToxicityCaseStudy
§ 70yomalewithmetastaacmelanoma,1stlineBRAFinhibitor,2ndlineipilimumab§ Pasthxofhypothyroidism,asthma,dvt§ Conmeds:thyroidhormonereplacement,lowmolecularweightheparin(LMWH)§ Baselinelabs:nitrogen-N6.4mmol/l,Creaanine–114micromol/l
12.2013-4.2014 Receivedpembrolizumab(3mg/kg,2doseswithprogressionofdisease,palliaaveradiotherapy,conanuaaonbeyondprogression,6dosespembrolizumab
3.5.2014 • Labs:Creaanine–increasedto273micromol/l• Presumedcontrastinducednephropathy–ReceivedIVFluids• Labs:Creaanine–decreasedto251micromol/l
26.4.2014 • Rou4neLabs:Slightlyelevatedcreaanine–150micromol/l
27.4.2014 • ScheduledCTTumorAssessmentwithIVContrast:Decreaseinmetastaacdisease(abdominalmass)
RenalToxicityCaseStudy
13.5.2014 • Labs:Creaanine–increasedto334micromol/l• HospitalizedforManagementofelevatedCr
‒ Symptoms–Drymouth,nose,throat‒ Labs-Auto-anabodiesnegaave
-Urinalysis–noproteinuriaorhematuria‒ Renalultrasound–normalsizekidneys,witholdnon-occlusivetumorthrombusintheinferiorvenacavaandrightrenalvein.
9.6.2014 • Labs:Creaanine–nadiredtobaselineat123miromol/l
15.5.2014 • KidneyBiopsy:AcuteIntersaaalNephrias• Labs:Creaanine–308miromol/l• Treatment:Oral70mgBIDprednisone• wasstarted,creaaninedecreasedTreatment:Prednisonetaperedover3weeks
anddisconanuedon6/9/2012.
14.6.2014to18.6.2014
• Labs:Creaanine–increasedto141micromol/lthen159micromol/l
18.6.2014 • Treatment:10mgPODailyPrednisonestarted
21.6.2014 • Labs:Creaanine–decreasedto130micromol/l
Renaltoxici4es
Grade1Crea4nine>ULNand>thanbaselinebut≤1.5x
baseline
GradeofCrea4nineEleva4on
(NCICTCAEv4)
Grade2-3Crea4nine>1.5xbaseline
to≤6xULN
Grade4Crea4nine>6xULN
Management
• Con4nuetherapy• Monitorcrea4nineweekly
• Delaytherapy• Monitorcrea4nineevery2-3days• 0.5to1.0mg/kg/daymethylprednisoloneIVororalequivalent
• Considerrenalbiopsy
• Discon4nuetherapy• Monitorcrea4ninedaily• 1.0-2.0mg/kg/daymethylprednisoloneIVorIVequivalent
• Consultnephrologist• Considerrenalbiopsy
Follow-up
Ifreturnstobaseline:• Resumerou4necrea4ninemonitoringperprotocolIfworsens:• TreatasGrade2or3/4
IfreturnstoGrade1:• Tapersteroidsoveratleast1month,considerprophylac4can4bio4csforopportunis4cinfec4ons,andresumetherapyandrou4necrea4ninemonitoringperprotocol
Ifeleva4onspersist>7daysorworsen:• TreatasGrade4
IfreturnstoGrade1:Tapersteroidsoveratleast1monthandaddprophylac4can4bio4csforopportunis4cinfec4ons
Renaltoxici4es
WhatAreTheLessonsLearned?
• Steroidsgenerallyledtoclinicalimprovement
• Renalbiopsygenerallyshowesevidenceofkidneyinflammaaon
• Noclearassociaaonwithtumortype,noincreasedriskapparentinRCC
Hepatotoxici4es
Incidence Hepaaasisrare
DiagnosisConsiderimmune-relatedcauseevenifconfoundingfactors(conmeds;relevantmedicalhx)arepresent
Onset Median89days(range:13-140days)
Management Longsteroidtaperisindicated,evenifimprovementoccursrapidly
Outcomes• Nofatalcase• Mostcasesweremanagedwithcoracosteroidswitheventresoluaon
HepatotoxicityCaseStudy
§ 60yomalewithstageIVNSCLCmetastaac,severalpalliaaveradiotherapiesand4priorsystemicregimens
§ Pasthistoryofalcoholuse(4-6beers/day),GERD§ Nopasthxofliverdisease§ Conmeds:atenolol,alprazolam,andpantoprazole
1.15-7.2015 • Received16dosesNivolumab(3mg/kg)
24.8.2015 Rou4nelabs:• AST(38)andALT(38)• Tbili(0.5)• AlkPhos(74)• LDH(221)
27.7.2015 • Iniaatedatovaquone/proguanilforMalariaprophylaxis
31.8.2015 • CTscan:nolivermasses
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Hepatotoxici4es
GradeofLiverTestEleva4on
(NCICTCAEv4)
Grade1ASTorALT>ULNto3.0orULNand/
orT.bili>-1.5XULN
Grade2ASTorALT>3.0to≤5xULNand/orT.bili>1.5to≤3xULN
Grade3-4ASTorALT>5xULN
and/orT.bili>3xULN
• Con4nuetherapy
Management
• Delaytherapy• Increasefrequencyofmonitoringtoevery3days
• Discon4nuetherapy*• Increasefrequencyofmonitoringtoevery1-2days
• 1.0to2.0mg/kg/daymethylprednisoloneIVorIVequivalent**
• Addprophylac4can4bio4csforopportunis4cinfec4ons
• Consultgastroenterologist
Follow-up
• Con4nueLFTmonitoringperprotocolIfworsens:• Treatasgrade2or3-4
Ifreturnstobaseline:• Resumerou4nemonitoring,resumeI-OtherapyperprotocolIfeleva4onspersist>5-7daysorworsen:• 0.5-1mg/kg/daymethylprednisoloneororalequivalentandwhenLFTreturnstograde1orbaseline,ortapersteroidsoveratleast1month,considerprophylac4can4bio4csforopportunis4cinfec4ons,andresumeI-Otherapyperprotocol
Ifreturnstograde2:• Tapersteroidsoveratleast1month
Ifdoesnotimprovein>3-5days,worsensorrebounds• Addmycophenolatemofe4l1gBID• Ifnoresponsewithinanaddi4onal3-5days,considerotherimmunosuppressantsperlocalguidelines
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Prevent-1
• Knowtheimmune-toxicityspectrum->considerrareirAE:• Nervoussystem(e.gPN,meningites/encepahalias,Guillan-Barresyndrome)• Hematology(e.g.hemolyacanemia,thrombocyto-,neutro-,pancytopenia)• Musculo-aracularsystem(e.g.arthrias,myopathies)• Heart(e.g.pericardias,myocardias)• Eyes(e.g.uveias,conjuncavias,blepharias,reanias,orbitalmyosias)
• Tumoralinfiltra4on->pulmonarylymphangias,carcinomatousmeningiasé
• Opportunis4cpathogens
->considerhistoryofpreviousinfecaonsandriskforviralinfecaons(e.g.HIV,viralhepaaas)
• Co-medica4ons
->anaarrhythmics,anahypertensives,anabioacs,anaconvulsantsoranapsychoacs
Prevent-2
• Iden4fydys-immunityriskfactors->personalandfamiliarhistoryofautoimmunediseases• digesave(Crohn’sdisease,ulceraavecolias,celiacdisease)• skin(psoriasis)• rheumaac(spondyloarthraas,rheumatoidarthrias,lupus)• endocrine(diabetes,thyroidias)• respiratory(intersaaalpneumonias,sarcoidosis)• pancreaac(pancreaaas)• kidney(nephrias)• hematological(hemolyacanemia,immunologicthrombocytopenicpurpura)• neurological(myasthenia,mulaplesclerosis)• eye(uveias,sclerias,reanias)• cardiovascular(heartfailure,lerventricularsystolicdysfuncaon,myocardias)
Prevent-3
• Informpa4entsandtheirhealthcareproviders->avoidself-management->newsymptomshouldberapidlyreportedwithoutdelay->reacaonsmayoccuratanyame•Digesave:diarrhea,bloodormucusinthestool,severeabdominalpain•Endocrine:faague,weightloss,nausea,vomiang,thirstorappeateincrease,polyuria•Skin:extensiverash,severepruritus•Respiratory:shortnessofbreath,coughing•Neurological:headache,confusion,muscleweakness,numbness•Arthralgiaorswellingjoints•Myalgia•Unexplainedfever•Hemorrhagicsyndrome•Severelossofvisioninoneorbotheyes
Prevent-4
• Pa4entswithspecificcondi4ons• Elderly
->nodifferenceinsafety(>65yrs,nodoseadjustment)• Renalandhepa9cimpairment
->nodata,nodoseadjustment(ie.>30ml/min,bilirubin>ULNto1.5N)• Pregnancyandbreast-feeding
->maycausefetalharmincludingaboraon,sallbirthorprematuredelivery• Paaentswithhistoryofchronicinfecaon
->limiteddata,hepaactoxicityincreased• Pa9entswithhistoryofauto-immunediseases
->limiteddata,monitorcloselyandwithinaninterdisciplinaryteam
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An4cipate
• ImmunotherapybaselinechecklistPhysicalexamina4on:•performancestatus,weight,size,BMI•heartrate&bloodpressure•generalsymptoms•pre-exisangsymptoms:intesanaltransit,dyspnea/coughing,rash,nausea,headaches,signsofmotororsensoryneuropathyandarthralgia•historyoffeverorrecentinfecaon•baselineelectrocardiogram
Laboratorytest:•CompleteCBC,Serumelectrolytes•Totalbilirubin,AST,ALT,GGT,PAL•Albuminemia,CRP•TSH,T4•(Corasol,ACTH,LH,FSH,estradioltestosterone)•(Proteinuria,Urinarysediment)•(Virology,Auto-anabodies)Imaging:• CTscan(e.g.thorax)
• Duringtreatment• CBC,renal/liverfuncaon,serumelectrolytes,glycaemia,CRP• TSH/proteinuriaevery2months• No“rouane”imaging
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Detect-1
• Ruleoutdiseaseprogression• Orenmostlikelycauseforsymptoms
• Ruleoutotherevents• e.g.infecton,paraneoplasacthrombosis
• AlwaysconsiderirAE:• Earlytoxiciaes(e.g.skin5weeks,gastrointesanal7.3weeks,hepaac7.7weeks)• Latetoxiciaes(e.g.pulmonary8.9weeks,endocrine10.4weeks,renal15.1weeks)• However:largeconfidenceintervals!!
• Considerbaselinevaluesasreference
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Treat
• Cor4costeroidmodality->ruleoutanyinfecaon->consideranabioacprophylaxisandtesangfortuberculosis->generallyapplycoracosteroidsoveraperiodofatleastonemonth,slowtapering
• Resume/terminateimmunotherapy->generallyconsiderdelayingtherapyforproperdiagnosis->definitelydisconanueincaseofadverseimmunedysfuncaon -life-threatening(Grade4) -severe(Grade3)andrecurring -moderate(Grade2)butnotresolvedinthreemonthsdespitetreatment->endocrinopathiescontrolledbyhormonereplacementtherapydonotrequireterminaaonofimmunotherapy->resumeimmunotherapy: -ifthesideeffectisstabilized≤Grade1AND -ifthesteroiddoseisreducedto≤10mg/dprednisonorequivalentAND -intheabsenceofotherimmunosuppressivedrugs
• Considerorganspecialistreferral
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Toxici4esofemergingcombina4onimmunotherapies
77
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Slide 14
Jedd Wolchok at 2015 ASCO Annual Meeting
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Slide 10
Michael Postow at 2015 ASCO Annual Meeting
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Time to Onset of Grade 3/4 Treatment-related Select AEs<br />Patients receiving nivolumab + ipilimumab or ipilimumab alone
Presented By Michael Postow at 2015 ASCO Annual Meeting
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Melanoma NSCLC RCC
Schedule
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CheckMate012I1Q6W,N3Q2W
CheckMate0164xI1N3Q3W,thenN3Q2W
ResponseRate
57.6%
39%
43%
Toxicity,AEGrade3/4
68.7%
28%
23.8%
Ipilimumab(I)Nivolumab(N)combinaaons
Ipilimumab(I)Nivolumab(N)combinaaonRCC
Hammersetal,ASCO2014
Toxici4esofcombina4onsofimmunotherapieswithtargetedtherapies
87
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Evolvingsynergis4ccombina4onsoftargetedimmunotherapies
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Response
92 PresentedbyAntoniRibasASCO2015
Select drug-related adverse events of interest
Antoni Ribas at 2015 ASCO Annual Meeting
Safety
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Bevacizumabplusipilimumabinpa4entswithmetasta4cmelanoma
Hodi, Cancer Immunol. Research 2014
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Summary-combina4ontherapies
- Highresponserates- Unexpectedtoxiciaes- Combinaaonshavetobetestedinearlyphasetrials
- Guidelinesandmanagementoftreatmentshavetobeadaptedtoeachcombinaaon
96
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