Thissiteisintendedforhealthcareprofessionals

MalignantMelanomaTreatment&Management
TREATMENT

ApproachConsiderations
Surgeryisthedefinitivetreatmentforearlystagemelanoma.Widelocalexcisionwithsentinellymph
nodebiopsyand/orelectivelymphnodedissection(LND)isconsideredthemainstayoftreatmentfor
patientswithprimarymelanoma.Inpatientswithsolitaryoracutelysymptomaticbrainmetastases,
surgicalmanagementmayalleviatesymptomsandprovidelocalcontrolofdisease.[24]
Becausethedefinitivetreatmentofcutaneousmelanomaissurgery,medicalmanagementisreserved
foradjuvanttherapyofpatientswithadvancedmelanoma.Lessthanonehalfofpatientswithdeep
primaries(>4mm)orregionallymphnodeinvolvementhavelongtermdiseasefreesurvival
consequently,thesepatientsareclassifiedashighriskandshouldbeconsideredforadjuvanttherapy.
Interferonalfaisapprovedforadjuvanttreatmentafterexcisioninpatientswhoarefreeofdiseasebut
areathighriskforrecurrence.Currently,therearenostandardsystemictherapeuticregimensthat
offersignificantprolongationofsurvivalformostpatientswithmetastaticmelanomawithoutsignificant
riskoftoxicities.InpatientswithBRAFV600wildtypeunresectableormetastaticmelanoma,however,
theintroductionofimmunebasedtherapyhasresultedinimprovedsurvival.
AlsoseeLentigoMalignaMelanoma,OralMalignantMelanoma,andHeadandNeckMucosal
Melanomas.

AdjuvantTherapy
GouldRothbergetaldevelopedandvalidatedamultimarkerprognosticassayfordeterminingsurvival
instageIImelanoma,whichtheseresearcherssuggestmightbebeneficialinimprovingtheselection
ofpatientsforadjuvanttherapy.[25]Multipleiterationsofageneticalgorithmusingtheautomated
quantitativeanalysis(AQUA)methodforimmunofluorescencebasedimmunohistochemistryon246
serialprimarymelanomasyieldedaconsistentfivemarkersolution.Afavorableprognosiswas
predictedbythefollowingcriteria:
ATF2ln(nonnuclear/nuclearAQUAscoreratio)greaterthan0.052
p21(WAF1)nuclearcompartmentAQUAscoregreaterthan12.98
p16(INK4A)ln(nonnuclear/nuclearAQUAscoreratio)0.083orless
BetacatenintotalAQUAscoregreaterthan38.68
FibronectintotalAQUAscore57.93orless
Primarytumorsthatmetatleastfourofthesefiveconditionswereconsideredlowrisk.Validationof
thescoreshowedthattumorsinthehighriskgroup(thosethatmetthreeorfewerconditions)were
associatedwithsignificantlyreducedsurvival(hazardratio,2.7295%confidenceinterval,1.126.58
P=0.027).

Interferonalfa

Alargemulticenterstudyusinghighdoseinterferon(IFN)alfa2b,EasternCooperativeGroup
(ECOG)1684,showedimprovementindiseasefreesurvivalandsurvivalbenefit(timetoprogression
improvementof8months,witha1yearsurvivalbenefit).[26]OnthebasisofECOG1684,theUS
FoodandDrugAdministration(FDA)approvedIFNasadjuvanttreatmentafterexcisioninpatients
whoarefreeofdiseasebutareathighriskforrecurrence.
Apooledanalysisof1016patientsand716observationalcontrolsfromallECOGtrialsshoweda
significantincreaseinrelapsefreesurvival(P=0.006)butnotoverallsurvival(P=0.42).[27]
Concernsabouttoxicityassociatedwithhighdoseadjuvantinterferonalfahavepromptedseveral
investigatorstotestlowerdosesofthedrug.Lowerdoseadjuvantinterferonalfahasdemonstrated
lesstoxicitythanhighdoseinterferonalfabutalsolessefficacyindelayingprogression,withno
survivaladvantage.
ToinvestigatethepossibilitythatthesurvivalbenefitseeninECOG1684hadtodowithits
incorporationofaninductionphaseofmaximallytolerateddosagesofIFNgivenintravenouslyforthe
initial4weeks,Pectasidesetalconductedaprospective,randomizedstudyin364patientswithstage
IIB,IIC,orIIImelanomawhohadundergonecurativesurgery.Patientswererandomlyassignedto
receiveIFNalpha2bIVfor5/7daysweeklyfor4weeks(armA)versusthesameinductionregimen
followedbyIFNalpha2badministeredsubcutaneously3timesaweekfor48weeks(armB).Ata
medianfollowupof63months,therewerenosignificantdifferencesinoverallsurvivalandrelapse
freesurvivalbetweenthe2arms,andpatientsinarmBhadmoregrade1to2hepatotoxicity,
nausea/vomiting,alopecia,andneurologictoxicity.[28]
Ontheotherhand,Hauschildetalfoundthattheadditionofa4weekmodifiedhighdoseIFNalpha
inductionphasetoa2yearlowdoseadjuvantIFNalpha2btreatmentscheduledidnotimprovethe
clinicaloutcome.Intheirprospective,randomized,multicentertrialin674lymphnodenegative
patientswithresectedprimarymalignantmelanomaofmorethan1.5mmtumorthickness,therewas
nosignificantdifferencein5yearrelapsefreesurvivalandoverallsurvivalbetweenpatientswho
receivedaninductionphase(IFNalpha2b5timesweeklyIVfor2wkand5timesweekly
subcutaneouslyforanother2wk)followedby23monthsoflowdoseIFNalpha2b,andpatientswho
receivedlowdosesubcutaneoustreatment3timesaweekfor24months.[29]
HauschildetalalsostudiedoptimaldurationoftreatmentofmalignantmelanomawithlowdoseIFN
alfa2aandconcludedthatprolongingtreatmentwithconventionallowdoseIFNalfa2afrom18to60
monthsshowednoclinicalbenefitinpatientswithintermediateandhighriskprimarymelanoma.
Patientswithresectedcutaneousmelanomaofatleast1.5mmtumorthicknessandlymphnode
negativewereincludedinthisprospective,randomized,multicentertrial(n=850).Patientswere
randomlyassignedtoreceive3MUIFNalfa2aSC3times/wkforeither18or60months.Median
followupwas4.3years.Relapsefreesurvivalanddistantmetastasisfreesurvivaldidnotdiffer
betweenthe2groups.[30]
Metaanalysisdatashowsthatulcerationandtumorstageareimportantpredictorsofresponseto
interferonalfa/pegylatedinterferon.[31]
Peginterferonalfa2bisanimmunomodulatorycytokinethatenhancesphagocyteandlymphocyte
activity.ItwasapprovedbytheFDAinMarch2011asadjuvanttherapyfollowingdefinitivesurgical
resection,includingcompletelymphadenectomy.
Thedrugsapprovalwasbasedona5year,openlabel,multicentertrialinwhichcancerrecurrence
wasdelayedabout9monthslongerinpatientswhotookpeginterferonalfa2bthanitwasinpatients
whodidnottakethedrug.[3]

Granulocytemacrophagecolonystimulatingfactor
Granulocytemacrophagecolonystimulatingfactor(GMCSF)hasbeenusedintheadjuvantsettingto
treathighriskmelanoma.Inastudyof46patientswithresectedstageIIIorIVmelanomatreatedwith
asubcutaneousdoseof125mg/m2for2weeksonand2weeksoffforayear,progressionfree
survivalwas37months,vs12monthsinhistoricalcontrols.[32]
However,asubsequentdoubleblind,placebocontrolledtrialthatcomparedtheeffectofGMCSFand
peptidevaccination(PV)onrelapsefreesurvival(RFS)andoverallsurvival(OS)in815patientswith
resectedhighriskmelanoma(locallyadvancedand/orstage4)foundthatneitheradjuvantGMCSF
norPVsignificantlyimprovedRFSorOS.ExploratoryanalysesdidshowatrendtowardimprovedOS
inGMCSFtreatedpatientswithresectedvisceralmetastases.[33]

TreatmentofAdvancedStageMelanoma(StageIV)
Treatmentofpatientswithadvancedstagemelanoma(stageIV)hascontinuedtoimprovedespitethe
challenges.
Nocombinationchemotherapyregimenhasproventobesignificantlybetterthansingleagent
dacarbazine(DTIC),whichyieldsonlya1015%responserate.[34]
Twocombinationregimenscommonlyareusedinthetreatmentofpatientswithadvancedstage
melanoma.Thefirstregimenisthecisplatin,vinblastine,andDTIC(CVD)regimen.Thesecond
commonlyusedregimenistheDartmouthregimen,whichisacombinationofcisplatin,DTIC,
carmustine,andtamoxifen.However,ametaanalysisfoundthatthestrengthofevidencedoesnot
supporttheadditionoftamoxifentocombinedchemotherapyregimens.[35]
Biologictherapiesnowarebeingusedaloneandwithchemotherapyregimensinthetreatmentof
patientswithadvancedstagemelanoma.Todate,studiesdonotshowthatinterferonandinterleukin
2(IL2)addedtoDTICisbetterthanDTICalone.

Dacarbazine
DTICwasthefirstdrugapprovedbytheUSFoodandDrugAdministration(FDA)forthetreatmentof
metastaticmelanoma.Intheinitialstudieswithdacarbazine,theoverallresponseratewas22%,with
noimpactonsurvival.InaphaseIIIstudyofdacarbazinecomparedwithtemozolomide,theresponse
ratewas12%versus13%.[36]Onthebasisofthistrial,andthegreatereaseofadministrationof
temozolomideversusdacarbazine(oralversusintravenous),mostoncologistscurrentlyuse
temozolomideastheirfirstlinedrugformelanoma.

Interleukin2
TheseconddrugapprovedbytheFDAforthetreatmentofmetastaticmelanomawasIL2,a
recombinanthormoneoftheimmunesystemoriginallydescribedasaTcellderivedgrowthfactorand
usedasalymphokineactivatedcellkillertherapy.
Apooledanalysisof270patientstreatedwithahighdoseIL2bolus(600,000720,000units/kgevery
8hoursfor5days)resultedinanobjectiveresponserateof16%(completeresponseof6%)withthe
bestresponseinpatientswithsofttissueandlungmetastases.Theoverallmediansurvivalwas11.4
months.[37]

Thetreatmentwasquitetoxic,withsomepatientsrequiringintensivecareunitsupport.Themore
commontoxicitiesincludedhypotension(45%),vomiting(37%),diarrhea(32%),andoliguria(39%).
Consequently,thistherapyisofferedonlyincentersthathaveadequatelytrainedstaffandfacilities.
Toqualifyforthistypeoftreatment,patientsmusthavenormalresultsonpulmonaryfunctiontesting,
brainMRI,andcardiacstresstesting,plusadequaterenalandhepaticfunction.

Carboplatinandpaclitaxel
CarboplatinandpaclitaxelhavebeentestedintwosmallphaseIIstudies,andwhenusedin
combinationwithsorafenib,theresponseratewas1117%.Thisregimensometimesisbeingusedby
cliniciansinclinicalpracticebecauseoflessertoxicitythandacarbazineandalsoasasecondor
thirdlineregimen.
However,arandomized,placebocontrolledphaseIIIstudybyHauschildetalfoundthattheaddition
ofsorafenibtocarboplatinandpaclitaxeldidnotimproveoutcomeinpatientswithunresectablestage
IIIorIVmelanomatheseinvestigatorsrecommendagainstthiscombinationinthesecondlinesetting
forpatientswithadvancedmelanoma.[38,39]

TreatmentofmelanomawithBRAFmutations
BRAFmutationsarepresentin60%ofmelanomas.Detectionofthismutationisimportantpriorto
startingtreatmentinanymelanomapatient.Inamulticenter,phaseI,doseescalationtrial,32patients
withmetastaticmelanomawhohadaBRAFmutationweretreatedwithvemurafenib(PLX4032).[40]
Twopatientshadacompleteresponse,and24hadapartialresponse.
FirstlinetreatmentofpatientswithBRAFV600wildtypeormutationpositive,unresectableor
metastaticmelanomaiswithnivolumabasamonotherapyorincombinationwiththeimmunotherapy
ipilimumab.[41]
Vemurafenib(Zelboraf)wasapprovedbytheFDAinAugust2011.Itisaninhibitorofsomemutated
formsofBRAFserinethreoninekinase,includingBRAFV600E.Thisagentisindicatedforthe
treatmentofunresectableormetastaticmelanomawithBRAFV600mutationasdetectedbythe
cobas4800BRAFV600MutationTest(RocheMolecularSystems).Vemurafenibhasnotbeen
studiedwithwildtypeBRAFmelanoma.
InMay2013theFDAapproveddabrafenib(Taflinar),aBRAFinhibitorinthesameclassas
vemurafenib,forpatientswithunresectableormetastaticmelanomawithBRAFV600Emutation
confirmedbytheTHxIDBRAFmutationtest.[42]Inamulticenter,openlabel,phaseIIIrandomized
controlledtrial,treatmentwithdabrafenibsignificantlyimprovedprogressionfreesurvivalinpatients
withBRAFmutatedmetastaticmelanoma,comparedwithdacarbazine(5.1vs2.7mo).[43]
PhaseIIItrialresultsfortheinvestigationalBRAFinhibitorvemurafenibincludeda63%relative
reductionintheriskofdeathaswellasa74%relativereductionintheriskoftumorprogressionin
patientswithpreviouslyuntreatedmetastaticmelanomawiththeBRAFV600Emutationcompared
withdacarbazine,theonlychemotherapeuticdrugcurrentlyapprovedbytheUSFoodandDrug
Administration(FDA)forthisdisease.[44]
Inaddition,theoverallsurvivalrateat6monthsinthevemurafenibgroupwas84%,versus64%inthe
dacarbazinegroup.[44]Despitetheshortfollowupperiod,theseresultshavesignificantclinical
implications,as,ofthepreviouslymentioned4060%ofcutaneousmelanomaswithBRAFmutations,
about90%involvetheBRAFV600Emutation.Moreover,aresponsetovemurafenibinfourof10

patientswiththeBRAFV600Kmutationwasnoted,suggestingsensitivityofthismutationvariantto
vemurafenib.[44]
Vemurafenibwasgenerallywelltolerated,withcutaneousevents(squamouscellcarcinoma,
keratoacanthoma,orbothallweretreatedwithsimpleexcision),arthralgia,fatigue,and
photosensitivitythemostcommonadverseeventssucheventsledtodosemodificationor
interruptionin38%ofpatients.[44]Adverseeventsseenwithdacarbazinewereprimarilyfatigue,
nausea,vomiting,andneutropeniaandledtodosemodificationorinterruptionin16%ofpatients.
Dabrafenibwasshowntosignificantlyimproveprogressionfreesurvivalcomparedwithdacarbazine
(5.1vs2.7mo)inpatientswithBRAFmutatedmetastaticmelanomainamulticenter,openlabel,
phaseIIIrandomizedcontrolledtrial.[45]
Trametinib(Mekinist)isamitogenactivated,extracellularsignalregulatedkinase(MEK)inhibitorthat
wasapprovedbytheFDAinMay2013forunresectableormetastaticmelanomawithBRAFV600Eor
V600KmutationsconfirmedbytheTHxIDBRAFmutationtest.[42]ApprovalwasbasedonaphaseIII
openlabeltrialinwhichmedianprogressionfreesurvivalwas4.8monthswithtrametinibversus1.5
monthsinpatientsreceivingdacarbazineorpaclitaxel.At6months,therateofoverallsurvivalwas
81%inthetrametinibgroupand67%inthechemotherapygroupdespitecrossover(hazardratiofor
death,0.5495%confidenceinterval[CI],0.32to0.92).[46]
InJanuary2014,theFDAapprovedtrametinibforuseincombinationwithdabrafenibfortreating
patientswithunresectableormetastaticmelanomawithBRAFV600EorV600Kmutations.Approval
wasbasedonthedemonstrationofresponserateandmediandurationofresponseinaphaseI/II
study.Medianprogressionfreesurvivalinthecombinationfulldose150mg/2mggroupwas9.4
monthscomparedwith5.8monthsinthedabrafenibmonotherapygroup(hazardratioforprogression
ordeath,0.3995%CI,0.25to0.62).Therateofcompleteorpartialresponsewithcombination
therapywas76%comparedwith54%withmonotherapy.Improvementindiseaserelatedsymptoms
oroverallsurvivalhasnotbeendemonstratedforthiscombination.[47,48,49]
InNovember2015,theFDAapprovedcobimetinib,anMEK1andMEK2inhibitor,forunresectableor
metastaticmelanomainpatientswithaBRAFV600EorV600Kmutation,incombinationwith
vemurafenib.Approvalwasbasedonresultsin495patientswithadvancemelanomafromthephase
3coBRIMstudy,inwhichmedianprogressionfreesurvivalwaslongerwithcobimetinibplua
vemiurafenibthanwithvemurafenibmonotherapy(12.3vs7.2monthshazardratio,0.5895%
confidenceinterval,0.460.72).Additionally,theobjectiveresponseratewashigherwiththe
combinationthanwithvemurafenibalone(70%vs50%P<0.0001).[50]

TreatmentofBRAFV600wildtypemelanoma
FirstlinetreatmentofpatientswithBRAFV600wildtypeormutationpositive,unresectableor
metastaticmelanomaiswithnivolumabasamonotherapyorincombinationwiththeimmunotherapy
ipilimumab.
TheNovember2015approvalfornivolumabmonotherapyisbasedondatafromtherandomized
phase3CheckMate066trial,whichcomparednivolumabmonotherapywithdacarbazineinthefirst
linetreatmentof418patientswithadvancedBRAFwildtypemelanoma.Inaninterimanalysis,
nivolumabdemonstratedsuperioroverallsurvival,whichwastheprimaryoutcome.Theoverall
survivalrateat1yearwas72.9%(95%CI,65.5to78.9)inthenivolumabgroupand42.1%(95%CI,
33.0to50.9)inthedacarbazinegroup.Asignificantbenefitwithrespecttooverallsurvivalwas
observedinthenivolumabgroup,ascomparedwiththedacarbazinegroup(hazardratiofordeath,

0.4299.79%CI,0.25to0.73P<0.001).Medianprogressionfreesurvivalwasalsoimprovedinthe
nivolumabtreatedpatientscomparedwithdacarbazine(5.1vs2.2monthsHR,0.43P<0.001).[51]
TheFDAapprovedthecombinationregimenofnivolumabplusipilimumabonSeptember30,2015in
previouslyuntreatedpatientswithBRAFV600wildtypeunresectableormetastaticmelanoma.
Approvalwasbasedonresultsfromthephase2CheckMate069studyOfthe142patientsenrolled,
109hadbothBRAFwildtypeandBRAFmutationpositivemelanoma.Theprimaryendpointwas
objectiveresponserate(ORR)inpatients.InpatientswithBRAFwildtypemelanomatreatedwiththe
combinationregimen,theoverallresponseratewas61%(95%CI:4871)comparedto11%(95%CI:
325)inpatientsgivenipilimumabmonotherapy(P<0.001).
Additionalanalysisshowedthatcompleteresponseswereseenin22%ofpatients.Partialresponses
wereseenin43%ofthecombinationgroupand11%oftheipilimumabmonotherapygroup.The
combinationgrouphada60%reductionintheriskofprogressioncomparedwithipilimumabalone
(HR=0.4095%CI:0.220.71P<0.002).MedianPFSwas8.9monthswiththecombination(95%CI:
7.0,NA)and4.7monthswithipilimumabalone(95%CI:2.85.3).[52]
InJanuary2016,thisindicationwasexpandedtoincludemutationpositivemelanoma,making
nivolumabeffectiveacrossBRAFstatus.[41].

Vaccines
Melanomavaccinesandgenetherapyaretwoadditionaltreatmentoptionsthatmaybecome
available.[53]
A2007reviewfoundnoclearevidencethattheadditionofimmunotherapytochemotherapy
increasessurvivalinmetastaticmelanomaandrecommendedthatcombinedimmunotherapyand
chemotherapybelimitedtoclinicaltrials.[54]Becausenumerousprotocolsforpatientswithadvanced
stagemelanomaexist,eligiblepatientsshouldbereferredtoanoncologycenterparticipatinginthese
studies.Vaccineshavenotbeensuccessfulasatreatmentformetastaticmelanomabutarestilla
reasonableareaofresearchintheadjuvantsetting.[33]

Externalbeamradiation
Thebrainisacommonsiteofmetastasisinmalignantmelanoma.Brainmetastasesareassociated
withapoorprognosis.Managementofbrainmetastasescanbedifficultduetorapidprogressionof
diseaseandresistancetoconventionaltherapies.Stereotacticradiosurgeryisusedincreasinglyin
patientswithalimitednumberofmetastasesitislessinvasivethancraniotomy.Externalbeam
radiationaloneappearseffectiveinpalliatingsymptoms.Chemotherapyaloneisrelativelyineffective,
althoughthecombinationofchemotherapywithexternalbeamradiationisbeinginvestigated.[24]

Futuretherapies
InamulticenterphaseIItrial,targetedtherapywithimatinibwasaneffectivetreatmentoptionin
patientswithadvancedmelanomaharboringmutationsoramplificationoftheKITprotooncogene.[55,
56,57] Of50patientswithmelanomasarisingfromacral,mucosal,orchronicallysundamagedsites
withKITalterations,24evaluablepatientswithKITmutant(n=8),KITamplifiedmelanoma(n=11),
orboth(n=5)weretreatedwithimatinib.Sevenofthese24patientsachievedapartialresponseto

therapy,withfivepatients'responsesconfirmedonsubsequentimagingstudies,foranoverall
confirmedresponserateof21%.[55,56]
Thesefindingsreinforcesimilarfindingsintwoearlierstudies.[1,58]

Ipilimumab
AnticytotoxicTlymphocyteassociatedprotein4(CTLA4)isahumanizedantibodydirectedata
downregulatoryreceptoronactivatedTcells.[59]Theproposedmechanismofactionisinhibitionof
Tcellinactivation,allowingexpansionofnaturallydevelopedmelanomaspecificcytotoxicTcells.
Ipilimumab,aCTLA4blocker,hasdemonstratedremarkablepromiseinpatientswithmetastatic
melanoma.Clinicaltrialsformonotherapyandincombinationwithotherimmunotherapiesand
vaccineshavebeenconcludedorarecurrentlyunderway.[60]IpilimumabwasapprovedbytheFDA
inMarch2011forunresectableormetastaticmelanoma.
Hodietalreportedimprovedsurvivalwithipilimumabinpatientswithmetastaticmelanoma.
IpilimumabblocksCTLA4toapotentiateTcellresponse.Inaphase3study,676patientswithHLA2
positivepatientswithunresectablestageIIIorIVmelanomawhodiseaseprogressedwhilereceiving
therapyformetastaticdiseasewererandomlyassignedina3:1:1ratiotoipilimumabplusgp100,
ipilimumab,orgp100alone.Ipilimumabwasgivenatadoseof3mg/kgandwasadministeredwithor
withoutgp100every3weeksforupto4treatmentssubsequently,patientswouldreceivereinduction
therapy.Themedianoverallsurvivalwas10monthsamongpatientsreceivingipilimumabplusgp100,
comparedwith6.4monthsinthosereceivinggp100alone.Therewasnodifferenceinsurvivalinthe
otheripilimumabarmcomparedwiththeipilimumabplusgp100arm.Becauseofthesefindings,
ipilimumabhasbeenapprovedasatreatmentformetastaticmelanoma.[60]
Inaphase3studyofipilimumabanddacarbazinecomparedwithdacarbazineandplacebo,survival
amongpatientswithmetastaticmelanomawasimprovedby2months(11movs9mo)inthe
ipilimumabarmhowever,theyhadmoregrade3and4toxicity.[61]
IntheMDX01020trial,researchersevaluatedimmunerelatedadverseevents(AEs)in676patients
previouslytreatedformetastaticmelanomawhowererandomlyassignedtoreceive1ofthefollowing
3treatmentregimens(ina3:1:1ratio):(1)ipilimumabplusglycoprotein100melanomaantigen
vaccine(gp100)(2)ipilimumabplusplaceboor(3)gp100plusplacebo.[62,63]Mostoftheimmune
relatedAEsdevelopedwithin12weeksofinitialdosing,typicallyresolvingin68weeks.Fewerthan
10%ofpatientsreceivinganyipilimumabtreatmentexperiencedanimmunerelatedAEmorethan70
daysaftertheirlastdrugdose,andalloftheseAEsweregrade1or2inseverity.Mostimmune
relatedAEs,evengrade3/4events,werereadilymanagedwithmonitoringandearlycorticosteroid
therapyonly5patientsneededinfliximabforgastrointestinalAEs,andall5subsequentlyimproved.
[62,63]

TheFDAapprovedthecombinationregimenofnivolumabplusipilimumabonSeptember30,2015in
previouslyuntreatedpatientswithBRAFV600wildtypeunresectableormetastaticmelanoma.[52]
Additionally,itisindicatedfortheadjuvanttreatmentofpatientswithcutaneousmelanomawith
pathologicinvolvementofregionallymphnodes>1mmwhohaveundergonecompleteresection,
includingtotallymphadenectomy.[64]
Theuseofimmunecheckpointinhibitorsforthetreatmentofadvancedmelanomahasevolved
beyondmonotherapiestocombinationstrategies.Thiscombinationapproachresultsinresponse
ratesaround60%andsuperiorprogressionfreesurvivalcomparedwithipilimumabmonotherapy
(median11.5versus2.9months).[65]

ImmuneBasedTherapy
PD1inhibitors
Programmedcelldeath1protein(PD1)andtherelatedtargetPDligand1(PDL1)areexpressedon
thesurfaceofactivatedTcellsundernormalconditions.ThePDL1/PD1interactioninhibitsimmune
activationandreducesTcellcytotoxicactivitywhenbound.Thisnegativefeedbackloopisessential
formaintainingnormalimmuneresponsesandlimitsTcellactivitytoprotectnormalcellsduring
chronicinflammation.TumorcellsmaycircumventTcellmediatedcytotoxicitybyexpressingPDL1
onthetumoritselforontumorinfiltratingimmunecells,resultingintheinhibitionofimmunemediated
killingoftumorcells.
InSeptember2014,theFDAgrantedacceleratedapprovalforpembrolizumab(Keytruda).
PembrolizumabisthefirstmonoclonalantibodyforinhibitionofPD1.[66]Itwasinitiallyindicatedfor
unresectableormetastaticmelanomaanddiseaseprogressionfollowingipilimumaband,ifBRAF
V600mutationpositive,aBRAFinhibitor.Approvalwasbasedondataincludingastudyinwhich
approximately24%ofpatientsexperiencedtumorshrinkage.[2]
InDecember2015,theFDAapprovedpembrolizumabasfirstlinetreatmentforunresectableor
metastaticmelanoma.Approvalwasbasedonthephase3KEYNOTE006trial.Patientswith
advancedmelanomawererandomizedtoreceiveeitherpembrolizumab10mg/kgevery2wkorevery
3wk,or4dosesofipilimumab(3mg/kgevery3wk).Progressionfreesurvivalforthepembrolizumab
groupswere47.3%and46.4%respectivelyand26.5%foripilimumab.Notethatthetrialuseda
higherdoseofpembrolizumabthanthedosethatisapprovedbytheFDA,whichis2mg/kgevery3
wk.[67]
Nivolumab(Opdivo),anotherPD1inhibitor,wasgrantedacceleratedapprovalinDecember2014for
unresectableormetastaticmelanomaanddiseaseprogressionfollowingipilimumabtreatmentand,if
BRAFV600mutationpositive,aBRAFinhibitor.Approvalwasbasedoninterimresultsofa
randomizedclinicaltrialinpatientswithunresectableormetastaticmelanomathathadprogressed
afteripilimumab.Interimanalysisconfirmedobjectiveresponsesin38ofthefirst120patientstreated
withnivolumab(31.7%95%confidenceinterval[CI]23.540.8)versusfiveof47patientswho
receivedinvestigator'schoiceofchemotherapy(10.6%CI,3.523.1).[4]
Nivolumabandipilimumabcombination
TheFDAapprovedthecombinationregimenofnivolumabplusipilimumabonSeptember30,2015in
previouslyuntreatedpatientswithBRAFV600wildtypeunresectableormetastaticmelanoma.
Approvalwasbasedonresultsfromthephase2CheckMate069studyin142patients,inwhich
patientswithBRAFwildtypemelanomahadantheoverallresponserateof61%withthecombination
regimen,versus11%withipilimumabmonotherapy(P<0.001).Completeresponseswereseenin
22%ofpatients.Partialresponseswereseenin43%ofthecombinationgroupand11%ofthe
ipilimumabmonotherapygroup.Riskofprogressionwas60%lowerinthecombinationgroup
comparedwithipilimumabalone(HR=0.40P<0.002).MedianPFSwas8.9monthswiththe
combinationand4.7monthswithipilimumabalone.[52]
Inpharmacovigilancestudies,myocarditisoccurredin0.27%ofpatientstreatedthecombinationof
ipilimumabandnivolumab.Johnsonetalreportedfatalmyocarditisintwopatientswithmelanoma
whowerereceivingtreatmentwithipilimumabandnivolumab.Bothpatientsdevelopedmyositiswith
rhabdomyolysis,earlyprogressiveandrefractorycardiacelectricalinstability,andmyocarditiswitha
robustpresenceofTcellandmacrophageinfiltrates.[68]

Talimogenelaherparepvec
InOctober2015,theFDAapprovedtheoncolyticimmunotherapeuticvaccinetalimogene
laherparepvec(Imlygic).Itisageneticallymodified,liveattenuatedherpessimplextypeIvirus
programmedtoreplicatewithintumorsandproducetheimmunestimulatoryproteingranulocyte
macrophagecolonystimulatingfactor(GMCSF).Inthisprocess,thegeneICP34.5isdeletedand
replacedwiththecodingsequenceforGMCSF.Itisindicatedforthelocaltreatmentofunresectable
cutaneous,subcutaneous,andnodallesionsinpatientswithmelanomarecurrenceafterinitial
surgery.Itisadministerbyinjectionintocutaneous,subcutaneous,and/ornodallesionsthatare
visible,palpable,ordetectablebyultrasoundguidance.[69]
Thestudyenrolled436patients,ofwhich295patientstreatedwithtalimogenelaherparepvecwere
comparedwith141patientstreatedwithGMCSF.Theprimaryendpointwasthedurableresponse
rate(DRR),definedastherateofcompleteresponsepluspartialresponsecontinuouslylasting6
monthsandbeginningwithinthefirst12months.Secondaryendpointsincludedoverallsurvival(OR)
andtheoverallresponserate(ORR).
TheDRRwassignificantlyhigheramongpatientswhoreceivedtalimogenelaherparepveccompared
withthosegivenGMCSF(16.3%vs2.1%oddsratio,8.9P<0.001).Ofthepatientswho
experiencedadurableresponse,29.1%hadadurablecompleteresponseand70.8%hadadurable
partialresponse.Themediantimetoresponsewas4.1(range:1.2to16.7)monthsinthearm
receivingtalimogenelaherparepvec.
ORRratewasalsohigherwithtalimogenelaherparepvec(26.4%vs5.7%P<0.001).Inall,32
(10.8%)patientsreceivingtalimogenelaherparepvecexperiencedacompleteresponse,compared
withjustone(<1%)patientreceivingGMCSF.Themediantimetotreatmentfailurewas8.2months
withtalimogenelaherparepvecand2.9monthswithGMCSF(hazardratio[HR],0.42).MedianOS
was23.3monthsand18.9months,respectively(HR,0.79P=0.051),whichjustmissedbeing
statisticallysignificant.[70]

PreventionofMalignantMelanoma
Thefocusofmelanomapreventionisavoidanceofsunexposure.Everyone,especiallythose
individualsathighriskofdevelopingamelanoma,shouldwearprotectiveclothing,avoidpeaksun
hours,protectchildrenagainstexposuretoultravioletradiation,avoidtanningbooths,andwear
sunscreenwithasunprotectionfactor(SPF)ofatleast15.
Thislastrecommendationisconsideredsomewhatcontroversial,becausenostudyhasshown
sunscreentoreducetheincidenceofmelanoma.[71]Moreover,asystematicreviewfoundthat
sunscreenuseleadstolongerdurationofintentionalsunexposure,andsunburnstendtobemore
frequentamongsunscreenusers.[72]
Inaddition,astudyof499whitechildrenwhowereenrolledatbirthoratage6andstratified
colorimetricallybyskintonefoundnoassociationbetweensunscreenuseandtheoverallnumberof
molesattheageof15years.Theonlysignificantassociationwasforlighterskinnedchildrenwhohad
atleastthreesunburnsat12to14yearsold,whohadfewermolesiftheyusedsunscreen.However,
eventhatassociationmighthaveoccurredbychance.[73]
Firstdegreerelativesofapatientdiagnosedwithfamilialmelanomashouldbeencouragedtohave
annualskinexaminations.

Consultations
Apatientwithasuggestivelesionshouldbereferredtoadermatologistorsurgicaloncologistfor
excisionalbiopsy.
Ifthediagnosisofmelanomaismade,thepatientshouldbereferredtoanoncologistafterdefinitive
surgeryisperformed.

LongTermMonitoring
Followupcareofapatientwithmelanomaisbasedonthestageoftheprimary.Thefollowup
examinationshouldbeperformedwiththeknowledgethatthepatienthasanincreasedriskfora
secondprimaryandthat,ofallsolitarysitesofvisceralrecurrence,thelungsarethemostfrequent.
FollowupguidelinesfromtheNationalComprehensiveCancerNetworkarelistedbelow.[18]
Followupforstage0insituisasfollows:
Atleastannualskinexaminationforlife
Educatepatientinmonthlyselfexaminationofskin
FollowupforstageIAisasfollows:
Historyandphysicalexamination(H&P)(withemphasisonnodesandskin)every312mofor5
y,thenannuallyasclinicallyindicated
Atleastannualskinexaminationforlife
Educatepatientinmonthlyselfexaminationofskinandlymphnodes
FollowupforstageIBIV(patientswithnoevidenceofdisease)isasfollows:
H&P(withemphasisonnodesandskin)every36mofor2y,thenevery312mofor2y,then
annuallyasclinicallyindicated
Chestradiography,lactatedehydrogenase(LDH)level,andcompletebloodcellcount(CBC)
every612mo(optional)
RoutineimagingisnotrecommendedforstageIBorIIAdisease
CTscanstofollowupforspecificsignsandsymptoms
ConsiderCTscanstoscreenstageIIBandhigherforrecurrent/metastaticdisease
Atleastannualskinexaminationforlife
Educatepatientinmonthlyselfexaminationofskinandlymphnodes
Guidelines
WhattoReadNextonMedscape
RelatedConditionsandDiseases

MalignantMelanomaStaging
MalignantMelanomaGuidelines
OralMalignantMelanoma
MalignantMelanomaTreatmentProtocols
Melanoma
ConjunctivalMelanoma

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