UPDATEONRECOMMENDATIONSANDGUIDELINESJenniferN.Choi,MDAssociateProfessorofDermatologyChief,DivisionofOncodermatologyRobertH.LurieComprehensiveCancerCenterNorthwesternFeinbergSchoolofMedicinejennifer.choi@northwestern.eduJune28,2018

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

AnnalsofOncology27:559–574,2016

5PillarsofImmunotherapyToxicityManagement

AnnalsofOncology27:559–574,2016

AnnalsofOncology27:559–574,2016

AnnalsofOncology27:559–574,2016

AnnalsofOncology27:559–574,2016

Ifadverseevent,consider3potenZaleZologies:1.diseaseprogression2.fortuitousevent3.treatment-relateddysimmunetoxicity

AnnalsofOncology27:559–574,2016

GeneralPrinciplesofManagement

• Organspecialistorinternalreferralneededfor2reasons:- 1.Oncologiststolearnpropermanagementofspecificimmune-relatedadverseevents- 2.Organspecialiststoincreasetheirknowledgeaboutthesedrug-mediatedtoxiciZes

• OncologistsshoulddefinetheirlocalorganspecialistteambasedontheirinterestandexperZseonthetopic,aswellasavailabilityandresponsivenesstosolicitaZon.

• OrganspecialistsupportshouldbesoughtassoonasthediagnosisandtreatmentofirAEsbecomedifficult(i.e.>grade1).SpecialistexperZseisobenneededforpropermonitoringoverZme.

GeneralPrinciplesofManagement

• Guidelinesarebasedonexpertopinion.• NoprospecZvetrialsyetontreatmentofimmunotherapy-relatedAEs.

• Grades3-5irAEsoccurwithgreaterfrequencywithCTLA-4inhibitorsthanwithPD-1orPD-L1inhibitors.

• ToxicitymoreseverewithcombinaZonsofCTLA-4andPD-1/PD-L1inhibitorsthanwitheitherclassalone.

•  Ifaserioustoxicityoccurs,thecheckpointinhibitorshouldbestoppedunZlthetoxicityresolvesorimproves.

• StudiesofoutcomesinpaZentswhodisconZnuetherapyduetoAEsshownostaZsZcallysignificantdifferenceinprogression-freeandoverallsurvival.

PrinciplesofImmunosuppression•  CorZcosteroidsaremainstayoftreatmentofmostirAEs.•  EarlyintervenZonwithcorZcosteroidsiskeygoalofmanagement•  UseofcorZcosteroidstotreatirAEshasnotbeenshowntoreduceanZ-tumorefficacy.-  BUTrouZnepremedicaZonwithcorZcosteroidsfornauseaandinfusion

reacZonsisnotrecommendedunlessindicated•  Longersteroidtapers(>4weeks,someZmes6-8weeksorlonger)topreventrecurrentirAEs

•  Prophylaxis:-  PneumocysZsjirovecipneumonia(PJP)ifprednisone>20mgQDx4or

moreweeks-  FungalinfecZons(e.g.fluconazole)ifprednisone>20mgQDx6-8or

moreweeks-  PPIorH2blockersifhigherriskofgastriZs(e.g.NSAIDuse,

anZcoagulaZon)forduraZonofsteroidtherapy-  Iflongtermsteroiduse,givevitaminD+calciumsupplementaZonto

preventosteoporosis.

•  AnZ-TNFα agents(e.g.infliximab)areeffecZveinmanagementofsomeirAEs,especiallycoliZsandinflammatoryarthriZs.-  TestforviralhepaZZsBandCprior-  Monitorcarrierscarefully-  Testforlatent/acZveTB

•  IfsevereirAEsnotresponsivetosteroidswithin48-72hours,early(72hrs)iniZaZonofanZ-TNFαtherapymaybewarranted.

•  TNFα agentsshouldbeavoidedinpaZentswithimmune-relatedhepaZZs-  Canconsidervedolizumab(alpha-4beta-7integrininhibitor)ifboth

hepaZZsandcoliZs

PrinciplesofImmunosuppression

•  PaZentswithpre-exisZngautoimmunecondiZonsororgantransplantrecipientsmaybecandidatesforimmunecheckpointblockade.-  HigherriskofexacerbaZngbaselineautoimmunecondiZonswithanZ-

CTLA-4-  OpZmizeimmunosuppressionforpre-exisZngautoimmunecondiZons

(goalforprednisone

• PaZentswithpriorallogeneicstemcelltransplantmaybecandidatesforimmunotherapy.-  Increasedriskoftransplant-relatedcomplicaZons,includingGVHD(canbefatal).

• PaZentswithhistoryofHIVorviralhepaZZsmaybecandidates.

• VaccinesthatareinacZvatedorkilledarepermissible.- Lessclarityregardinglivevaccineuse

PrinciplesofImmunosuppression

ImmunotherapyPaZentEducaZon

•  DocumentanyunderlyingmedicalcondiZon,includingautoimmunediseases

•  RecordallmedicaZons,includingover-the-counterandherbalsupplements

•  PaZentsmustuseeffecZvebirthcontrolduringandforatleast5monthsaberfinaldoseofimmunotherapy

•  Breasmeedingiscontraindicatedduringandforatleast5monthsaberfinaldoseofimmunotherapy

•  SupporZvecare:-  Monitorbloodglucoselevels-  PPIorH2blockers-  AnZmicrobialandanZfungalprophylaxis-  VitaminD+calciumsupplementaZon

PaZentEducaZonToMonitorandBePrepared•  ImportanceforpaZentstoself-monitorsymptoms:-  SeverefaZgue-  Headache-  Rash-  Cough-  Shortnessofbreath-  Chestpain-  AbdominalbloaZng-  Changeinbowelpanern-  Weightloss-  Visionchangesoreyepain-  Severemuscleweakness-  Severemuscleorjointpains-  Moodchanges

•  Symptomscanoccurearly,late,oraberdisconZnuaZonofimmunotherapy.•  PaZentsshouldmonitorsymptomsforatleast1yearfollowingconclusionofimmunotherapy.

PaZentEducaZon•  ImportanceforpaZentstoself-monitorsymptoms:-  SeverefaZgue-  Headache-  Rash-  Cough-  Shortnessofbreath-  Chestpain-  AbdominalbloaZng-  Changeinbowelpanern-  Weightloss-  Visionchangesoreyepain-  Severemuscleweakness-  Severemuscleorjointpains-  Moodchanges

•  Symptomscanoccurearly,late,oraberdisconZnuaZonofimmunotherapy.•  PaZentsshouldmonitorsymptomsforatleast1yearfollowingconclusionofimmunotherapy.

PrinciplesofImmunotherapyRechallenge

• CauZonwhenresumingimmunotherapy->verycarefulmonitoring

• ResumpZonofimmunotherapyfollowinggrade2irAEscanbeconsidereduponresoluZonto<grade1.

•  Ifre-challengedandtoxicityreturns,permanentlydisconZnueclassofimmunotherapy.

• Canconsiderswitchingtootherclassofimmunotherapy- E.g.ifpaZentexperiencesgrade3or4toxicityfromipilimumab-containingregimen,canconsiderlatertherapywithaPD-1orPD-L1monotherapyaberresoluZonofearliertoxicity.

GeneralPrincipleUpdates• NowavailablearemulZdisciplinaryguidelinesofmanagementofirAEsbasedonexpertopinion.-  ASCO- NCCN

• As#ofpaZentstreatedgofromhundredstothousands,moreirAEswillbefoundandreported,andincidenceratesmaychange.

•  Importanceof:-  Carefulmonitoring;consideralldifferenZaldiagnoses-  EarlyintervenZon- DonothesitatetousecorZcosteroidswhenindicated- Useprophylaxis-  Followguidelinesformanagementandrechallenge- UZlizeorganspecialists/disease-specificspecialZes

ResearchonBiomarkersforResponse

• Sofar,resultshavebeenlimited.

• HightumormutaZonalburdenplusPD-L1expression->durableclinicalbenefitmorelikely

ThankYoujennifer.choi@northwestern.edu