黑色素瘤治療進展保守估計，美國每年約新增7.5萬人，中國每年新增2萬人2010年晚期黑色素瘤治療情況VernonKSondak.Discussion:Ipilimumab:Thelightattheendofthetunnel?2010,ASCOplenarysession晚期黑色素瘤治療2008ASCO900例黑色素瘤肝轉(zhuǎn)移手術(shù)VS未手術(shù)OS29mVS7m5年OS33%VS5%RibasA.NEnglJMed.2012;366:2517-2519.Copyright?2012MassachusettsMedicalSociety.ReprintedwithpermissionfromMassachusettsMedicalSociety.CTLA-4andPD-1/L1CheckpointBlockadeforCancerTreatmentCTLA4PD-1T細胞表達時間抗原接觸后48h抗原長期接觸后產(chǎn)生配體表達由抗原提呈細胞表達CD80

(B7.1)/CD80

(B7.2)

腫瘤或炎性組織表達PD-L1

(B7-H1)

抗原提成細胞表達PD-L2

(B7-DC)

小鼠相關(guān)基因敲除由于自身免疫反應導致迅速死亡由于自身免疫反應導致慢性死亡阻斷后反應抗腫瘤T細胞特異性弱抗腫瘤T細胞特異性強阻斷CTLA4/B7

與阻斷

PD-1/PD-L1之區(qū)別里程碑：Ipilimumab

2013年全球銷售額高達5.77億美元1.HodiFS,etal.NEnglJMed.2010;363:711-723.2.RobertC,etal.NEnglJMed.2011;364:2517-2526.Ipi+gp100

Ipi

gp100Median

OS,Mos10.0

10.1

6.4HR0.68

0.66PValue<.001

.003Ipi+D

Placebo+DMedian

OS,Mos11.2

9.1HR0.72P

Value<.001Est1,2,3-YrSurvival,%47.3,28.5,20.8

36.3,17.9,12.2Ipilimumab+gp100vsgp100[1]IpilimumabvsPlacebo[2]OS(%)Mos001004880604020403224168565244362820124PatientsSurvival(%)Mos00100806040203220482816444408122436Ipilimumab+dacarbazinePlacebo+dacarbazineIpilimumab：30余年來首個藥物證實改善晚期黑色素瘤總生存PreviouslyTreatedPatientsPreviouslyUntreatedPatientsO’DaySatalJCO2010;28:18s(Abstract4)免疫相關(guān)毒性irAEEvolutionofResponse:PatientExampleScreeningWeek12Initialincreaseintotaltumourburden(mWHOPD)Week16RespondingWeek72Durable&ongoingresponse

withoutsignsofIRAEsCourtesyofK.Harmankaya抗PD-1抗體

Keytruda(pembrolizumab,MK3475)

9月4日美國FDA批準

Opdivo（nivolumab）日本已經(jīng)上市

NivolumabActivity(ORR)[1]

Melanoma:28%

NSCLC:18%

RCC:27%MK-3475Activity(ORR)[2]

Melanoma:38%

Highestdose:52%

(assessedbyRECIST1.1withconfirmationbyICR)1.TopalianSL,etal.NEnglJMed.2012;366:2443-2454.Copyright?2012MassachusettsMedicalSociety.ReprintedwithpermissionfromMassachusettsMedicalSociety.2.HamidO,etal.NEnglJMed.2013;369:134-144.ActivityofAnti-PD-1AgentsinSolidTumors81%ofptswithresponsestillontreatmentattimeofanalysis(medianfollowup:11mos)PatientwithmetastaticmelanomaPembrolizumab(MK-3475)inAdvancedMelanoma:PhaseITrialMelanomaexpansion

cohortofphaseIKEYNOTE-001studyAdvanced,unresectablediseasewithECOGPS0-1Ipilimumab-treatedpatientsmusthavePDwithresolutionofrelatedAEsRibasA,etal.ASCO2014.LBA9000.IPINaive10mg/kgq2w

(n=41)IPINaive10mg/kgq3w

(n=24)IPINaive2mg/kgq3w

(n=22)IPITreated10mg/kgq2w

(n=16)IPITreated10mg/kgq3w

(n=32)IPIRefractory10vs2mg/kgq3w

(n=173)IPINa?ve10vs2mg/kgq3w

(n=103)Nonrandomizedcohorts

(n=135)Randomizedcohorts(n=276)BaselineJanuary2012April2012HamidO,etal.NEnglJMed.2013;369:134-144.Copyright?2013MassachusettsMedicalSociety.ReprintedwithpermissionfromMassachusettsMedicalSociety.54-yr-oldmalewithdesmoplasticmelanomaafterprogressingonipilimumabClinicalActivityofMK-3475inaPatientWithMetastaticDesmoplasticMelanomaCTLInfiltratesinRegressingMetastaticMelanomaLesionAfterMK-3475TreatmentBaseline:February29,2012August20,2012RibasA,etal.ASCO2013.Abstract9009.CD8+IHCCD8+IHCPembrolizumab(MK-3475)inAdvancedMelanoma:AEs>10%IncidenceSimilarsafetyprofilesinipilimumab-naiveandipilimumab-treatedpatientsOthergrade3/4AE(<1%incidence):ALTelevation,headache,hypothyroidism,decreasedappetite,dyspneaAdverseEvent,%Total(N=411)AnyGradeGrade3/4Fatigue362Pruritus24<1Rash20<1Diarrhea16<1Arthralgia160Nausea12<1Vitiligo110RibasA,etal.ASCO2014.AbstractLBA9000.404913Pembrolizumab(MK-3475)inAdvancedMelanoma:ResponsebyPD-L1ExpressionPD-L1positivity:stainingin≥1%oftumorcells125patientsevaluableforPD-L1expressionPD-L1–PD-L1+P=.0007*KeffordR,etal.ASCO2014.Abstract3005.*1-sidedPvaluescalculatedbylogisticregression,adjustingfordose/schedule.Unselected(n=113)PD-L1+(n=83)PD-L1–(n=30)010203040506070ORR(%)Pembrolizumab(MK-3475)inAdvancedMelanoma:SurvivalbyPD-L1ExpressionPD-L1positivity:stainingin≥1%oftumorcellsPD-L1–P=.0051P=.3165OverallSurvivalProgression-FreeSurvivalKeffordR,etal.ASCO2014.Abstract3005.806040200020406080100PFS(%)WksPD-L1positivePD-L1negative806040200020406080100OS(%)WksPD-L1positivePD-L1negativePhaseINivolumabStudy:Long-termFollow-upinIPI-NaivePtsWithMelanomaPrimaryendpoints:safety,tolerabilitySecondaryendpoints:preliminaryefficacy,dose-responserelationshipsStudyamendedtocollectOSdataSubgroupanalysisofresponsebykeypatientfeaturesExploratoryPD-L1analysis:positiveiftumormembranestainedatanyintensity(cut-off:1%or5%expression)HodiFS,etal.ASCO2014.Abstract9002.Patientswithadvancedmelanoma,ECOGPS0-2,1-5linesofprevioussystemictherapy(N=107)Treatmentmax:96weeksNivolumab0.1mg/kgIVq2w(n=17)Nivolumab0.3mg/kgIVq2w(n=18)Nivolumab1mg/kgIVq2w(n=35)Nivolumab3mg/kgIVq2w(n=17)Nivolumab10mg/kgIVq2w(n=20)PhaseINivolumabStudyinAdvancedMelanoma:SelectAEsSelectAE:associatedwithpotentialimmunologicetiologiesthatrequiremorefrequentmonitoringand/oruniqueinterventionAllpatientshave≥1yroffollow-up1TopalianS,etal.JClinOncol.2014;32:1020-30TopalianS,etal.JClinOncol.2014;32:1020-1030.HodiFS,etal.ASCO2014.Abstract9002.Category,%(n)AnyGradeGrade3/4AnyselectAE54(58)5(5)

Skin36(38)0

Gastrointestinal18(19)2(2)

Endocrinopathies13(14)2(2)

Hepatic7(7)1(1)

Infusionreaction6(6)0

Pulmonary4(4)0

Renal2(2)1(1)PD-L1CutoffNPD-L1Status,nPD-L1Frequency,n/N(%)ORR,n/N(%)1%tumormembranestaining41Positive,2626/41(63)9/26(35)Negative,1515/41(37)2/15(13)5%tumormembranestaining41Positive,1818/41(44)8/18(44)Negative,2323/41(56)3/23(13)-100-50050100150200Maximum%Responsein

BaselineTargetLesions1%cutoffPositivePD-L1statusPatientPhaseINivolumabStudyinAdvancedMelanoma:ORRbyPD-L1ExpressionTumortissuecollectionretrospective;41samplesHodiFS,etal.ASCO2014.Abstract9002.Negative-100-500501001502005%cutoffPositivePD-L1statusPatientNegativePhaseINivolumabStudyinAdvancedMelanoma:ExpertPerspectiveLongestfollow-upofanyPD-1antibodystudyResponseduration64%beyond24wksMedianDoRof22.9mosSurvivaloutcomes2-yrOS:48%;3-yrOS:41%MedianOS:20.3mosat3mg/kgdoseforphaseII/IIIstudiesMedianPFS:9.7mosat3mg/kgdoseforphaseII/IIIstudiesGrade3/4irAEs:5%HodiFS,etal.ASCO2014.Abstract9002.PhaseIStudy:Nivolumab+IpilimumabinStageIII/IVMelanomaConcurrenttherapystudydesign

SequencedtherapystudydesignPatientswithstageIII/IVmelanoma

with≤3

previous

therapiesInductionIpilimumabq3wx4cycles+Nivolumabq3wx8cyclesMaintenanceIpilimumab+Nivolumabq12wx8cyclesPatientswithstageIII/IVmelanomawith≥3previous

dosesofipilimumab(n=33)Nivolumab(1or3mg/kg)q2wuntilprogressionWolchokJD,etal.NEnglJMed.2013;369:122-133.SznolM,etal.ASCO2014.LBA9003MaintenanceNivolumab3mg/kgq2w(max48doses)Cohort8Cohorts6,7Cohort1,2,2a,3(n=53)(n=41)InductionIpilimumab1mg/kgq3wx4cycles

+Nivolumab3mg/kgq3wx4cyclesPhaseIStudyofNivolumab+IpilimumabinAdvancedMelanoma:SafetyNonewsafetysignalswith22mosoffollow-upfortheinitialconcurrentcohorts22/94(23%)patientsdiscontinuedtreatmentduetotreatment-relatedadverseevents1/94drug-relateddeathintrial;fatalmultiorganfailure(asaresultofcolitis)incohort8SznolM,etal.ASCO2014.AbstractLBA9003.AE,%ConcurrentCohorts1-3

(n=53)Cohort8

(n=41)AllConcurrent(n=94)AnyGrGr3/4AnyGrGr3/4AnyGrGr3/4AllrelatedAEs966295619662SelectAEsGastrointestinal43934203914Hepatic301512122214Skin7947315779Endocrine174222193Renal660033OtherUveitis642243Pneumonitis622242Lipaseincreased261915102115Amylaseincreased216127176PhaseIStudyofNivolumab+IpilimumabinMelanoma:ResponseCharacteristics34ptsmaintainanongoingresponsePatientscancontinuetorespondfollowingtreatmentdiscontinuationMedianfollow-upof22mosand7mosforcohorts2and8,respectivelyFor7respondingptsincohort2whodiscontinuedtherapyforreasonsotherthandiseaseprogression,86%(6/7)respondedfor

≥16wkssinceendoftherapy89%(8/9)ofptsincohort2remainedinresponse

and94%(16/17)ofcohort8remainedinresponseatthetimeofanalysisSznolM,etal.ASCO2014.AbstractLBA9003.04812162024281300102030405060708090100110120WksMosCohortNivo0.3/IPI3

Cohort1Nivo1/IPI3

Cohort2Nivo3/IPI1

Cohort2aNivo3/IPI3

Cohort3Nivo1/IPI3

Cohort8TimetoanddurationofresponsewhileontreatmentResponsedurationfollowingtreatmentdiscontinuationTimetoresponseOngoingresponseSznolM,etal.ASCO2014.AbstractLBA9003.PhaseIStudyofNivolumab+IpilimumabinMelanoma:OSforConcurrentTx1009080706050403020100Survival(%)480369121518212427303336394245MosPtsatRisk,nNivo0.3/IPI3

Nivo1/IPI3Nivo3/IPI1Nivo3/IPI3Concurrent14

17

16

6

5313

17

16

6

5211

16

15

6

4810

15

15

6

468

15

15

6

447

14

13

6

407

14

4

6

317

13

2

6

287

9

0

3

197

4

0

0

115

3

0

0

82

3

0

0

52

3

0

0

52

2

0

0

41

0

0

0

11

0

0

0

10

0

0

0

0Nivo0.3mg/kg+IPI3mg/kg

Nivo1mg/kg+IPI3mg/kg

Nivo3mg/kg+IPI1mg/kg

Nivo3mg/kg+IPI3mg/kg

ConcurrentcohortCensored2-yrOS:50%2-yrOS:79%2-yrOS:88%ConcurrentTherapyWithIpilimumabandNivolumab:ExpertPerspective42%ORRwith17%CRsand82%inremissionforallpatientsreceivingconcurrenttreatment62%rateofgrade3/4irAEsatoptimaldoses:LFTs,lipase,amylase,rash,colitisBRAFstatus,PD-L1tumorstainingnotclearlyassociatedwithresponseResponseinsequentialpatientsassociatedwithplasmaipilimumablevelspriortostartingnivolumabConcurrent2-yrOSof79%=impressiveBenefitworththetoxicity?輔助治療：高劑量干擾素1年方案FDA和EMAHDI-IIB,C和III期(高危患者）:20MIU/m2IV5x/周，4周（誘導）10MIU/m2SC3x/周，48周(維持)輔助治療：EORTC18071:AdjuvantIpilimumabvsPlaceboforResectedStageIIIDiseaseEggermontA,etal.ASCO2014.AbstractLBA9008.Primaryendpoint:RFSperIRC(timetolocal,regional,distantmetastasis,ordeath)Secondaryendpoints:OS,DMFS,AEprofile,health-relatedQoLPatientswithhigh-risk,completelyresectedstageIIImelanomaandECOGPS0/1(N=951)Ipilimumab10mg/kgq3wx4thenq12wforupto3yrs(n=475)Placeboq3wx4thenq12wforupto3yrs(n=476)Stratifiedbystage(IIIavsIIIbvsIIIcwith1-3positiveLNvsIIIcwith≥4positiveLN),region(NorthAmerica,Europe,Australia)AdjuvantIpilimumabvsPlaceboforResectedStageIIIDisease:RFSEggermontA,etal.ASCO2014.AbstractLBA9008.IpilimumabPlaceboEvents/patients234/475294/476HR(95%CI)*0.75(0.64-0.90)Log-rankPvalue*.00132-yrRFSrate,%51.543.83-yrRFSrate,%?46.534.8*Stratifiedbystage.

?Dataarenotyetmature.100806040200PatientsAliveWithoutRelapse(%)Median:26.1mosMedian:17.1mosIpilimumab10mg/kg

Placebo60012243648MosPatients

atRisk,n

Ipilimumab

PlaceboO

234

294N

475

476276

260205

19367

625

40

0EggermontA,etal.ASCO2014.AbstractLBA9008.Events/PatientsIpilimumabPlaceboHR(CI*)

(Ipilimumab:Placebo)AJCC2002(CRF)

StageIIIA

StageIIIB

StageIIICTypeofLN+Microscopic

MacroscopicUlcerationNo

Yes

UnknownTotal*95%CIfortotal,99%CIelsewhere.

?Unstratifiedanalysis.34/98

99/213

101/16436/88121/207137/18183/210

151/265108/193

186/283116/257

106/197

12/21131/244

146/20317/29234/475

(49.3%)294/476

(61.8%)0.76(0.64-0.91)?0.84(0.61-1.17)

0.67(0.48-0.93)1.08(0.40-2.87)0.68(0.47-0.99)

0.83(0.63-1.10)0.91(0.49-1.68)

0.77(0.54-1.08)

0.73(0.52-1.02)0.250.51.02.04.0Ipilimumab

betterPlacebo

betterTreatmenteffectP<.01Adj.IpilimumabvsPlaceboforResectedStageIIIDisease:RFSbySubgroupPatients,%Ipilimumab(n=471)Placebo(n=474)AllGradesGrade3Grade4AllGradesGrade3Grade4AnyirAE90.436.55.538.62.30.2Dermatologic

Rash63.3

34.44.5

1.30020.9

11.00

00

0Gastrointestinal

DiarrheaColitis*46.3

41.4

15.914.9

9.6

6.81.1

0

0.817.7

16.7

1.30.6

0.4

0.20.2

0

0Endocrine

HypophysitisHypothyroidism37.6

18.3

8.97.9

4.7

0.20.6

0.4

06.5

0.4

0.80

0

00

0

0Hepatic

LFTincrease25.1

19.77.9

3.82.8

1.54.4

4.00.2

00

0Neurologic4.51.10.81.900Other23.67.40.44.41.70AdjuvantIpilimumabvsPlaceboforResectedStageIIIDisease:irAEsEggermontA,etal.ASCO2014.LBA9008.AdjuvantIpilimumabinStageIIIMelanoma:ExpertPerspectiveMedianRFSinresectedstageIIIa-cmelanoma:

17moswithplaceboto26moswithipilimumab(HR:0.75;P=.0013)Improvementseenforallstages,ulceratedprimaryornot,microscopicormacroscopicLNburdenGrade3/4irAErate:42%Isthebenefitworththetoxicity?局部免疫治療：OncolyticVirus

T-vecOPTiM:TalimogeneLaherparepvecinStageIIIB/IVMelanoma(PhaseIIIStudy)Talimogenelaherparepvec:anoncolyticimmunotherapycomprisingaHSV-1virusbackbonecontainingthegeneforGM-CSF,apotentimmunestimulator

Primaryendpoint:durableresponserate(CRorPRfor≥6mos)Secondaryendpoints:OS,ORR,TTF,safetyPatientswithstageIIIb,IIIc,orIVunresectablemelanoma,

ECOGPS0-1(N=436)Every2wksforupto2yrsUpto3yrsoffollow-upaftertreatmentT-Vecupto4mL

(108pfu/mLperinjection)

intralesionallyq2w*

(n=295)GM-CSF125μg/m2SCdailyfor2wks,then2wksoff

(n=141)ClinicalT.NCT00769704.KaufmanHL,etal.ASCO2014.Abstract9008a.Randomized2:1*Initialdose106pfu/mLwith3wks

beforesubsequentdosing.OPTiMStudyofT-VecinStageIIIB/IVMelanoma:Response(ITTPopulation)DRR:16.3%withT-Vecvs2.1%withGM-CSF(P<.0001)ResponsesinbothlocalanddistantlesionsKaufmanHL,etal.ASCO2014.Abstract9008a.AndtbackaRH,etal.ASCO2013.AbstractLBA9008.Response,%DRRORRCRPRGM-CSF(n=141)2.15.70.75.0T-Vec(n=295)16.326.410.815.6OPTiMStudyofT-VecinStageIIIB/IVMelanoma:OSSurvival,%T-VecGM-CSFDifference,%(95%CI)12mos73.769.14.6(-4.7to13.8)24mos49.840.39.5(-0.5to19.6)36mos38.630.18.5(-1.2to18.1)48mos32.621.311.3(1.0to21.5)Events/N(%)Median(95%CI)inMosT-Vec189/295(64)23.3(19.5-29.6)GM-CSF101/141(72)18.9(16.0-23.7)HR:0.79(95%CI:0.62-1.00;unadjustedlog-rankP=.051)KaufmanHL,etal.ASCO2014.Abstract9008a.100806040200OS(%)600101520525303540455055PtsatRisk,n

T-Vec

GM-CSF295

141269

124230

100187

83159

63145

52125

4695

3666

2736

1516

52

00

0T-VecinStageIIIB/IVMelanoma(OPTiMStudy):ExpertPerspectiveT-Vecisaneffectivelocalintralesionaltherapywithresponseratesatinjectedlesionsof64%24-wkDRRendpointmet:16%withT-Vecvs2%withGM-CSF(P<.0001)ToxicitieswereminimalOS:borderlinesignificantimprovementwithT-Vec

(HR:0.79;P=.051)T-Vechaslocoregionalactivityandmodestsystemiceffects,wellsuitedforcombinationwithcheckpointproteininhibitorsasanimmune-primingagent*OnlypatientswhoreceivedbothT-VecandIPI.CR,CRu,andPDincluded.?1patientwithPDnotshownintheplotbecausetumorburdencouldnotbeaccuratelycalculated(missingpostbaselinedata).?Percentagechangefrombaseline:538§Percentagechangefrombaseline:265Investigator-AssessedResponses,n(%)(N=18*)Overallresponse10(56)(95%CI:31-79)CR6(33)PR4(22)SD3(17)PD5(28)–100–5002550100200PercentageChangeFromBaseline?Patients(N=17)?StageIVM1c(n=4)StageIVM1b(n=5)StageIVM1a(n=4)StageIIIc(n=3)StageIIIb(n=1)§PuzanovI,etal.ASCO2014.Abstract9029.T-Vec+IPIinUnresectedStageIIIB-IVMelanoma:MaxChangeinTumorBurdenT-Vec+IPIinUnresectedStageIIIB-IVMelanoma:ExpertPerspective18patientstreatedwithT-VecplusIPIORR:56%(4CR,6PR)plus3SDOnly3grade3/4irAEsfromIPIMelan-A–targetingTcellsincreasedintheperipheralbloodaftercombinationtherapyImpressiveearlyresultsaddressingthehypothesisthat

T-VecmayprimeanimmuneresponseamplifiedbyIPI靶向治療：

伊馬替尼、恩度、威羅菲尼、達拉菲尼、達拉菲尼聯(lián)合曲美替尼C-KIT突變患者格列衛(wèi)治療有效

中國人約10.8%C-kit突變501patientsscreened.43ptstreatedandevaluatedResponse:(23.3%)10PRand13SD.Noresponsein15doseescalation(600-800mg/day)ptsThemedianPFS:3.5m(15weeks)TheOS:14m(60weeks),1-yearOS51%Guo,etal.JClinOncol.2011恩度+DTICvsDTIC恩度+DTICvsDTICEndostarplusDacarbazineimprovemPFSvs.Dacarbazinealoneasthe1stlinetherapyEstimated1-and2-yrsurvivalrates1yr:26.7%vs.56.3%，2yr:12.7%vs.22.6%Mightbeanewregimenfortheuntreatedptswithadvancedmelanoma.靶向BRAF突變、MEK

BRAF突變率：中國人：20.6%，西方：50%威羅菲尼：BRIM3試驗腫瘤迅速縮小大于80%迅速緩解癥狀中位PFS7個月與DTIC比較早期即有生存獲益BREAK3：達拉非尼VsDTIC達拉非尼187入組150mgbidDTIC63入組1g/m2PFS達拉非尼VsDTIC6.9mvs2.7m達拉非尼OS大于18m

MEK抑制劑：曲美替尼177BRAF突變患者接受達拉非尼聯(lián)合78既往未使用BRAF抑制劑PFS11mORR63-76%69既往使用BRAF抑制劑PFS3.6mORR9-15%PhaseIIStudy:CombinedBRAFandMEKInhibitioninBRAFV600-PositiveMelanomaPrimaryendpoints:cuSCC,PFS,ORR,DoR,safetySecondaryendpoints:populationPKparameters,OS*Crossovertocombinationdabrafenib+trametinib150/2afterprogressionallowed.Patientswithmetastaticmelanoma,BRAFV600E/Kmutations,ECOGPS0-1,nopreviousBRAFi/MEKi(N=162)Dabrafenib150mgBID*(n=54)Dabrafenib150mgBID

Trametinib2mgQD(n=54)Dabrafenib150mgBID

Trametinib1mgQD(n=54)FlahertyKT,etal.NEnglJMed2012;367:1694-1703.BRAFandMEKInhibitioninBRAFV600-PositiveMelanoma:OSbyTreatmentArmCovariatessignificantlyassociatedwithOSMalevsfemale(HR:0.45;P=.0472)LDH≤ULNvs>ULN(HR:0.19;P<.0001)<3vs≥3diseasesites(HR:0.23;P=.0007)FlahertyKT,etal.ASCO2014.Abstract9010.TreatmentDeaths,n(%)MedianOS,Mos(95%CI)HR(95%CI)12-MoOSRate,%24-MoOSRate,%Dabrafenib(n=54)36(67)20.2(14.5-27.1)NA7044150/1

(n=54)31(57)18.7(13.7-NR)0.96(0.60-1.55)6947150/2

(n=54)32(59)25.0(17.5-NR)0.79(0.49-1.27)8051III期臨床試驗：COMBI-d:Dabrafenib+TrametinibasFirst-lineTxinBRAFV600E/KMelanomaPrimaryendpoint:PFSSecondaryendpointsinclude:OS,ORR,DoR,safetyLongGV,etal.ASCO2014.Abstract9011.PatientswithunresectablestageIIICorIVcutaneousmelanomaandBRAFV600E/Kmutation(947screened;

N=423)Dabrafenib150mgBID+Trametinib2mgQD(n=211)Dabrafenib150mgBID+Placebo(n=212)StratifiedbyLDH(>ULNvs≤ULN),andBRAFmutation(V600EvsV600K)CrossovernotpermittedDabrafenib+TrametinibasFirst-lineTxinBRAFV600E/KMelanoma(COMBI-d):PFSImprovedORRwithcombinationtherapy(67%vs51%)LongGV,etal.ASCO2014.Abstract9011.1.00.90.80.70.60.50.40.30.20.10ProportionAliveand

ProgressionFreeMosFromRandomizatioabrafenib

MedPFS:8.8mos

6-moPFS:57%Dabrafenib+Trametinib

MedPFS:9.3mos

6-moPFS:70%HR0.75(95%CI:0.57-0.99;

P=.035)Medianfollow-up:9mosDabrafenib+TrametinibasFirst-lineTxinBRAFV600E/KMelanoma(COMBI-d):OSLongGV,etal.ASCO2014.Abstract9011.*Notsignificant,didnotcrossstoppingboundaryforinterim

analysis(2-sidedα<.00028).Dabrafenib+Trametinib6monthOS:93%Died(events):40(19%)1.00.90.80.70.60.50.40.30.20.1002468101214MosFromRandomization2112122082051851741601421029011110000PtsatRisk,nDabrafenib+trametinibDabrafenibProportionAlive161820199190444120Dabrafenib6monthOS:85%Died(events):55(26%)HR:0.63(95%CI:0.42-0.94;P=.023*)Medianfollow-up:9mosDabrafenib+TrametinibinBRAFV600E/KMelanoma:ExpertPerspectiveRandomizedphaseIIstudy(n=162)MedianOS:25mosinpatientstreatedwithdabrafenib150BIDandtrametinib2mgQDPtswhofailedBRAFiwhocrossedovertodualtherapydidworsewithpoorOSFemaleshadworseoutcomesthanmalesClinicalfactorsassociatedwithpoorOS:LDH>ULNand≥3diseasesitesRandomizedphaseIIIstudy(N=423)ofdabrafenibalonevsdabrafenibplustrametinibPFSprolonged(HR:0.75;P=.035)from8.8to9.3mosDespitecrossover,OSprolonged40vs55deathswithshortmedianfollow-upof9mosWhythesmalldifferenceinmedianPFS?總結(jié)PD1抗體低毒、高效、患者總生存期長，已經(jīng)獲得FDA批準；PD1抗體聯(lián)合依匹單抗效果明顯，但是毒性也很明顯；依匹單抗對于III期黑色素瘤患者輔助治療有效；免疫治療時代必須使用免疫治療的評價標準；T-Vec局部注入有效，與依匹單抗聯(lián)用有協(xié)同作用；伊馬替尼可用于C-KIT突變的患者；DTIC聯(lián)合恩度可以作為晚期黑色素瘤的治療選擇；BRAFV600突變的黑色素瘤，威羅菲尼單藥、達拉菲尼單藥、達拉菲尼聯(lián)合曲美替尼仍是標準的治療選擇2014年胰腺癌治療進展中山大學附屬第三醫(yī)院腫瘤內(nèi)科陳展洪2014年9月22日概述——癌癥之王1.80%的患者發(fā)現(xiàn)時為晚期2.接受根治性手術(shù)的患者80%以上會復發(fā)3.手術(shù)是治愈的基礎(chǔ)4.總體人群5年生存率為4-5%5.發(fā)病率近似于死亡率2010NEJM2014年中國胰腺癌專家共識-輔助化療No.ptsCCRTChemoOS,med5-YOSGITSG1p=.012221-40/5FU-5FU1120*

8%18%EORTC2P=0.099胰頭癌亞組5460-40/5FUCI--12.617.110%20%RTOG97044#P=0.1523022150.4/5FUCI放療前后各8周5FU放療前后各8周Gem16.718.821%(3y)31%(3y)P=0.033胰頭癌亞組CONKO-15p=.005175179--Gemx620.222.8

9%21%ESPAC-13^p=.000569737572-40/5FU-40/5FU--5FU/LV5FU/LV16.913.921.6^19.911%7%29%13%ESPAC-36P=0.39551537-

-5-Fu/FAx6Gemx62323.620%(5y)22%(5y)JASPAC01187191S1GEM未達到25.570%(2y)53%(2y)關(guān)于輔助治療不得不說的幾點25-30%的患者術(shù)后化療后仍在1年內(nèi)死亡；輔助化療有效，吉西他濱及5-Fu療效相近；輔助放療地位仍有爭議；臨床試驗的患者是經(jīng)過選擇的患者，生存數(shù)據(jù)往往好于現(xiàn)實中患者?，F(xiàn)實中有四分之一的患者由于各種手術(shù)并發(fā)癥無法接受輔助治療。局部晚期：化療還是化療序貫放化療？LAP07試驗GERCORIII期臨床試驗研究終點

主要終點：

4個月誘導化療后患者腫瘤控制后評估給予CRT是否提高OS

次要終點：厄羅替尼在LAPC中的作用評估放療質(zhì)量（RTQA）對療效的影響耐受性分子標志物的預測作用，CTC流程圖PascalHammel,etal.2013ASCOAbstractLBA4003.第一、二次隨機聯(lián)合OS各組無差異PascalHammel,etal.2013ASCOAbstractLBA4003.如何解讀？？LAP

07

:進入二次隨機的患者情況Hammel

H-F,

et

al.

2014

ASCO

Abstract

4001.化療(n=101)放化療(n=81)P值3.2個?月5.2個?月0.045(0.3-22)(0.2-25.7)?無治療?生存061218240.80.60.40.20.0

治療間歇期：CRT組較CT組長l

24例(19%)在CT組和30例(27%)CRT組未接受二線治療

(p=0.1)l

在接受二線化療患者，治療間歇期的中位時間如圖

1.0

化療

(n=136)中位?治療?生存=3.7個月化放療

(n=133)中位?治療?生存=6.1個月P=0.017時間

(?月)

Hammel

H-F,

et

al.

2014

ASCO

Abstract

4001.重新引入化療的時間結(jié)論l

LAPC患者化療4個月后腫瘤控制CRT不優(yōu)于繼續(xù)化療，CRT組耐受性良好l

LAPC的標準治療仍為化療，CRT可作為化療控制腫瘤后的一個選擇l

但CRT組的PFS有改善趨勢l

在CRT組，患者達到較長的治療間歇期且較少的局部腫瘤進展l

需要整合更多的研究：更多活化系統(tǒng)治療，優(yōu)化CRT技術(shù)，生活質(zhì)量分析，成本效率評估Hammel

H-F,

et

al.

2014

ASCO

Abstract

4001.晚期胰腺癌姑息化療1.胰腺癌體能狀況評估有別于其它腫瘤，全面體能狀態(tài)評估應包括PS評分、疼痛、膽道梗阻、營養(yǎng)狀況；2.體能狀態(tài)良好具體標準如下：（１）ＰＳ評分≤２分；（２）疼痛控制良好，疼痛數(shù)字分級法（NRS）評估值≤３；（３）膽道通暢；（４）體重穩(wěn)定。2014中國專家共識MPACT：吉西他濱聯(lián)合白蛋白紫杉醇有生存優(yōu)勢ACCORD及MPACT臨床試驗數(shù)據(jù)比較二線化療方案療效一般，支持數(shù)據(jù)有限1Pelzer

JCO

2008

；2

Berk

Hepatogastroent

2012；

3

Xiong

Cacner

2008；

4,

Neuzillet

World

J

Gastroent

2012

；5

Takahara

Cancer

Chemother

Pharmacol

2013

；6

Boeck

Oncology

2007

；7

Todaka

,Jpn

就從2010;8

Ko

Br

J

Cancer

2013靶向藥物作為二線方案療效差1

Tang，

JCO

2009

;2

Kulke

JCO

2007;

3

O

Reilly

Oncoligist

2010

；4,

Ko

cancer

chemother

pharmacol

2010;

5Wolpin

JCO

2009

;6

Bodoky

invest

NEW

Drugs

2012

;7

Ko

JCO

2013

一項隨機化的ruxolitinib（RUX）或安慰

劑（PBO）聯(lián)合卡培他濱（CAPE）二線治療轉(zhuǎn)移性胰腺癌（mPC）的雙盲2期研究Herbert

Hurwitz,

et

al.

2014

ASCO

Abs

4000JAK-STAT信號通路抑制l

JAKs是一種家族激酶

包括JAK1JAK2

JAK3和

TYK2l

JAKs通過激活STAT轉(zhuǎn)錄因子介導激酶信號l

Ruxolotinib是一種JAK1和JAK2抑制劑，阻滯通過許多炎癥因子的信號通路l

Ruxolotinib可減少炎癥因子水平，在臨床試驗中改善骨髓纖維化患者的癥狀和OS2014

ASCO

Abs

4000RECAP研究設計

入組患者??

組織學確定為轉(zhuǎn)移

性PDAC??

Karnofsky

PS

≥60??

吉西他濱治療失敗

Ruxolitinib（15mg

BID,

1-21天）

卡培他濱（1000mg/m2

BID,1-14天）

安慰劑

（BID，1-21天）

卡培他濱

（1000mg/m2BID,1-14天）隨機化1:1n=64n=63??

首要終點：OS??

次要終點：臨床獲益反應（包括疼痛，Karnfsky

PS，鎮(zhèn)痛劑使用，體重），

ORR(RECIST,確定反應（4周），PFS，QoL,安全性分析計劃??

雙側(cè)α=0.2；β＜0.2??

進行亞組分析，包括CRP,白蛋白，PS評分，以這些相關(guān)因素來驗證炎癥假說??

額外的亞組分析是建立在胰腺癌患者人口統(tǒng)計和標準預后標準基礎(chǔ)上的，用來檢

驗質(zhì)量異質(zhì)性

2014

ASCO

Abs

4000OS(ITT)Ruxolitinib+卡培他濱（n=64）安慰劑+卡培他濱（n=63）中位OS,天數(shù)生存率，%3個月6個月12個月136.5644222129.5583511

2014

ASCO

Abs

4000CRP＞13mg/L患者的OS和PFS:治療組更長Ruxolitinib+卡安慰劑+卡培他培他濱（n=31）

濱（n=29）中位OS,天數(shù)83.055.0生存率，%3個月6個月12個月484211291102014

ASCO

Abs

4000Ruxolitinib+卡培他濱（n=31）安慰劑+卡培他濱（n=29）中位OS,天數(shù)生存率，%3個月6個月12個月83.048421155.029110OSPFS兩組有效率的比較2014

ASCO

Abs

4000兩組臨床獲益反應比較Ruxolitinib+卡培他濱安慰劑+卡培他濱患者人數(shù)（%）

意向人群，n

臨床獲益反應

疼痛強度

鎮(zhèn)痛劑使用

PS評分

體重CRP＞13mg/L，n臨床獲益反應

疼痛強度

鎮(zhèn)痛劑使用

PS評分

體重

l

在CRP≤13mg/L的患者中，Ruxolitinib+卡培他濱組有2例有臨床獲益反應

VS安慰劑+卡培他濱有0例

2014

ASCO

Abs

4000結(jié)論lRuxolitinib是一種JAK1/JAK2抑制劑，與卡培他濱聯(lián)合二線治療轉(zhuǎn)移性胰腺癌患者，相對于卡培他濱單藥更有臨床活性

在ITT人群中，聯(lián)合治療OS和PFS

更好，但是效應比較小

在檢測了CRP這種全身炎癥標記物的亞組中，

觀察到了OS(HR=0.47)和PFS（HR=0.62）的獲益證據(jù)2014

ASCO

Abs

4000胰腺癌藥物研發(fā)的挑戰(zhàn)??

胰腺癌中存在63類基因變異??

基因變異主要存在12條細胞

通路??

胰腺癌中間質(zhì)非常豐富

??

有利于腫瘤增長

??

對化療形成牢固的屏障未來,路在何方?1.從遺傳學角度對胰腺癌患者進行分層應該與更新的直接抑制KRAS的策略相協(xié)調(diào)。臨床前期試驗提示胰腺癌較多的基質(zhì)也是細胞毒性化療藥物進入胰腺原發(fā)腫瘤的障礙。轉(zhuǎn)移性胰腺癌中基質(zhì)的屏障功能靶向作用的程度是目前應用擾亂基質(zhì)的藥物聯(lián)合化療的臨床試驗中正在評估的問題2.免疫學治療，例如CD40激動劑和癌癥疫苗3.KRAS突變對細胞代謝的影響以及胰腺癌細胞對局部營養(yǎng)缺乏的環(huán)境的適應的性研究提示，在胰腺癌變的過程中，特殊的代謝途徑出現(xiàn)了變異。可以應用靶向藥物抑制有氧酵解、谷氨酰胺代謝或細胞轉(zhuǎn)化和癌癥進展中