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MalignantMelanomaMedication
MEDICATION

MedicationSummary
Highdoseinterferon(IFN)alfa2bistheonlyadjuvanttherapyapprovedbytheUSFoodandDrug
Administration(FDA)forhighriskresectedmelanoma,definedasdeepprimariesgreaterthan4mm
inBreslowdepth(AJCCstageIIB)andregionallymphnodemetastasis(stageIII).Varioustrialsof
lowdoseIFNhaveshownnobenefitindiseasefreerelapseoroverallsurvival(OS)rates.[82]
Similarly,multiplemelanomavaccinetrialsareinprogress,predominantlyforstageIIIandIVdisease,
buttheyhavenotdemonstratedanOSadvantagetodate.
Ipilimumab,aCTLA4blocker,enhancestheTcellresponseinHLA2positivepatientsand
demonstratesremarkablepromiseinpatientswithmetastaticmelanoma.Itisbeingstudiedbyitself
andincombinationwithotherimmunotherapiesandvaccines.[60]

AntineoplasticAgents
ClassSummary
Theseagentsinhibitcellgrowthanddifferentiation.Chemotherapeuticagentsusedtotreatmelanoma
includedacarbazine,cisplatin,vinblastine,carmustine,andtamoxifen.

Dacarbazine
Viewfulldruginformation
Althoughthemechanismofactionfordacarbazineisunknown,possibleactionsincludealkylating
agent,purinemetabolite,orinteractionwithsulfhydrylgroups.TheendresultisinhibitionofDNA,
ribonucleicacid(RNA),andproteinsynthesis.

Cisplatin
Viewfulldruginformation
CisplatinisanalkylatingagentthatinhibitsDNAsynthesisand,thus,cellproliferationbycausingDNA
crosslinksanddenaturationofthedoublehelix.

Vinblastine
Viewfulldruginformation

Vinblastineinhibitsmicrotubuleformation,whichdisruptsformationofthemitoticspindle,causingcell
proliferationtoarrestatmetaphase.ItisacomponentoftheCVDregimen.

Ipilimumab(Yervoy)
Viewfulldruginformation
AnticytotoxicTlymphocyteassociatedprotein4(CTLA4)isahumanizedantibodythatovercomes
CTLA4mediatedTcellsuppressiontoenhancetheimmuneresponseagainsttumors.Themarker
CTLA4isassociatedwithpromotingaregulatoryresponsebytheimmunesystem.Thisregulatory
responsehasadampeningeffectontheimmunesystem.Ipilimumabisabletoinhibittheeffectsof
CTLA4onTcellsandallowstheexpansionofnaturallydevelopedmelanomaspecificcytotoxicT
cells.Thisagentisthefirstnewagenttobeapprovedformelanomainoveradecade.
Itisindicatedforthetreatmentofunresectableormetastaticmelanoma.Additionally,itisindicatedfor
theadjuvanttreatmentofpatientswithcutaneousmelanomawithpathologicinvolvementofregional
lymphnodes>1mmwhohaveundergonecompleteresection,includingtotallymphadenectomy.Itis
alsoindicatedinpreviouslyuntreatedpatientswithBRAFV600wildtype,unresectableormetastatic
melanomaincombinationwithnivolumab.

Dabrafenib(Tafinlar)
Viewfulldruginformation
DabrafenibinhibitssomemutatedformsofBRAFkinaseswithinvitroIC50valuesof0.65,0.5,and
1.84nMforBRAFV600E,BRAFV600K,andBRAFV600Denzymes,respectively.Itisindicatedfor
unresectableormetastaticmelanomawithBRAFV600EmutationconfirmedbywiththeTHxIDBRAF
mutationtest.

Trametinib(Mekinist)
Viewfulldruginformation
Trametinibisareversibleinhibitorofmitogenactivatedextracellularsignalregulatedkinase1(MEK1)
andMEK2activation,andofMEK1andMEK2kinaseactivity.Itisapprovedforunresectableor
metastaticmelanomawithBRAFV600EorV600KmutationsconfirmedbywiththeTHxIDBRAF
mutationtest.

Pembrolizumab(Keytruda)
Viewfulldruginformation
Pembrolizumabisaprogramedcelldeath1protein(PD1)inhibitor.Itisindicatedasfirstline
treatmentforunresectableormetastaticmelanoma.

Tamoxifen
Viewfulldruginformation
Tamoxifencompetitivelybindstotheestrogenreceptor,producinganuclearcomplexthatdecreases
DNAsynthesisandinhibitsestrogeneffects.ItisusedintheDartmouthregimentopossiblyabrogate
themultidrugresistancephenotype.

Vemurafenib(Zelboraf)
Viewfulldruginformation
InhibitssomemutatedformsofBRAFserinethreoninekinase,includingBRAFV600E.Thedrugis
indicatedforunresectableormetastaticmelanomawithBRAFV600mutationasdetectedbythe
cobas4800BRAFV600MutationTest(RocheMolecularSystems).Vemurafenibhasnotbeen
studiedwithwildtypeBRAFmelanoma.

Nivolumab(Opdivo)
Viewfulldruginformation
Nivolumabisamonoclonalantibodytoprogrammedcelldeath1protein(PD1).Itblocksthe
interactionbetweenPD1anditsligands,PDL1andPDL2.Itisindicatedasasingleagentfor
unresectableormetastaticmelanomaanddiseaseprogressionfollowingipilimumabtreatmentand,if
BRAFV600mutationpositive,aBRAFinhibitor.Itisalsoindicatedasasingleagentinthefirstline
treatmentofunresectableormetastaticBRAFV600wildtypeormutationpositivemelanoma.
CombinationtherapywithipilimumabfortreatmentofpatientswithBRAFV600wildtypeormutation
positiveunresectableormetastaticmelanomaissuperiortoeitherdrugalone.

Cobimetinib(Cotellic)
Viewfulldruginformation
Reversibleinhibitorofmitogenactivatedproteinkinase(MAPK)/extracellularsignalregulatedkinase1
(MEK1)andMEK2.MEKproteinsareupstreamregulatorsoftheextracellularsignalrelatedkinase
(ERK)pathway,whichpromotescellularproliferation.
CobimetinibisindicatedforunresectableormetastaticmelanomainpatientswithaBRAFV600Eor
V600Kmutationincombinationwithvemurafenib.Cobimetinibandvemurafenibtarget2different
kinasesintheRAS/RAF/MEK/ERKpathwaycomparedwitheitherdrugalone,coadministration
resultedinincreasedapoptosisinvitroandreducedtumorgrowthinmouseimplantationmodelsof
tumorcelllinesharboringBRAFV600Emutations.

BiologicalResponseModulators
ClassSummary
Immunotherapy(biotherapy)currentlyusedtotreatpatientswithmelanomaincludesIFNand
interleukin(IL)2.Anoncologistshouldadministerthesetreatments.

Interferonalfa2b(IntronA)
Viewfulldruginformation
IFNalfa2bisaproteinproductmanufacturedbyrecombinantDNAtechnology.Themechanismof
antitumoractivityisnotclearlyunderstoodhowever,directantiproliferativeeffectsagainstmalignant
cellsandmodulationofhostimmuneresponsemayplayimportantroles.Itisthedrugofchoicefor
adjuvanttherapyinpatientswithhighriskmelanoma.Itsimmunomodulatoryeffectsinclude
suppressionoftumorcellproliferation,enhancementofmacrophagephagocyticactivity,and
augmentationoflymphocytecytotoxicity.

IFNalfa2bisgenerallyinitiatedwithin56daysofsurgeryandtypicallyadministeredbymedical
oncologists.

Peginterferonalfa2b(Sylatron)
Viewfulldruginformation
Peginterferonalfa2bisanimmunomodulatorycytokinethatenhancesphagocyteandlymphocyte
activity.Alfainterferonsactthroughhighaffinitycellsurfacereceptors,which,onceactivated,are
knowntoinhibitcellulargrowth,alterthestateofcellulardifferentiation,interferewithoncogene
expression,altercellsurfaceantigenexpression,increasethephagocyticactivityofmacrophages,
andenhancethecytotoxicityoflymphocytesfortargetcells.
Acovalentattachmentofpolyethyleneglycolpolymerchainstointerferonmolecules(knownas
PEGylation)cansignificantlyincreasethetimethedrugremainsinthebloodstream,which,inturn,
canreducethefrequencyofdosingandpotentiallyreducetheseverityandfrequencyofadverse
effects.
ItwasapprovedbytheFDAinMarch2011asadjuvanttherapyfollowingdefinitivesurgicalresection,
includingcompletelymphadenectomy.Itisthefirsttherapyapprovedfortheadjuvanttreatmentof
melanomain15years.

Interleukin2(Proleukin)
Viewfulldruginformation
IL2istheonlytherapyknowntocureadvancedstagemelanoma.ItactivatesTcellsandamplifies
theirresponses.Itenhancesnaturalkillercellantitumoractivity.

OncolyticImmunotherapy
ClassSummary
Localtreatmentoflesionsornodallesionsmaybeneededfollowingresection.

Talimogenelaherparepvec(Imlygic)
Viewfulldruginformation
Theexactmechanismofactionisunknown.Talimogenelaherparepvecisageneticallymodified,live,
attenuatedherpessimplexvirusprogrammedtoreplicatewithintumorsandtoproducetheimmune
stimulatoryproteinGMCSF.Causeslysisoftumors,followedbyreleaseoftumorderivedantigens,
whichtogetherwithvirallyderivedGMCSFmaypromoteanantitumorimmuneresponse.Itisa
solutionforintralesionalinjectionthatmaybeconsideredforlocaltreatmentofunresectable
cutaneous,subcutaneous,andnodallesionsinpatientswithmelanomarecurrenceafterinitial
surgery.
WhattoReadNextonMedscape
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