PrecisionMedicineand

ClinicalPracticeCuncaiZhou,ProfessorAffiliatedLungHospitalofTongjiUniversity,ShanghaiTherapiddevelopmentoftumorgenomicsThediscoverywasthatgeneticmaterialincancercellsisabnormal,whichlatersuggestedthatcancerwasacloneofsomatic

cellchange.EnsuringDNAisageneticmaterialDescribingthedoublehelixstructureofDNAThefirstrepetitivechromosomerearrangementincancerDiscoveringtheearliestsomaticmutationsandtheearliestgenesforcancerHumangenomesequenceSecondgenerationsequencingtechnologyTheearliestsequenceofallexonsofcancerThefirstcompletesequenceofcancergenomes400known

cancergenesThousandsofcompletesequencesofcancergenesThecancergenomesequenceasaconventionaldiagnosticmethod?Whatisprecisiononcology?IndividualizedcancermedicaltreatmentbasedonmolecularspectrumanalysisisthenewstandardAccordingtotheindividualcharacteristicsofeachpatient,individualizedmedicaltreatmentisgivenTreatmentinterventionsfocusonpatientswhoareexpectedtobenefit,andavoidthecostsandsideeffectsofpatientswhomay/probablynotbenefitThesuccessofindividualizedmedicinedependsonaccuratediagnostictestsandidentifyingpatientswhocanbenefitfromtargetedtherapyRightpatient,therightdrug,therighttimeMilestoneofLungcancerprecisionmedicine2000 Doublechemotherapy2000 Docetaxelisasecond-linetreatment2002 Gefitinib

data2004 Adjuvantchemotherapybasedoncisplatin

2005 EGFRmutationwasfound2005 ReportthewildtypedataofGefitinib2005 Pemetrexed,Erlotinib2009-2013 AccordingtotheE4599studyresults,

bevacizumabwasapprovedformarketing2011 EGFRmutationdetectionwasapplied

toclinicalpractice2013 ALKinhibitorswasapprovedformarketing2013 Afatinibwasapprovedformarketing2015 T790M2015 Nivolumab2016 Pembrolizumabasafirst-linetreatmentOverviewofLungcancermutation:ClassificationfromhistologytodrivinggenesClassificationof

TumorHistologyClassificationofdrivinggenesTimesofimmunotherapyTherewasstilloverlappedbetweenPD-L1andothergenephenotypesKRAS25%EGFR(Sensitizing)17%ALK8%NootherOncogenicDriversdetected36%MEK1<1%NRAS1%MET1%PIK3CA1%BRAF2%HER23%>1

mutantgenes3%EGFR(others)4%ECOG1594:

Fourfirst-linedual-drugchemotherapyregimensforadvancedNSCLCRevaluingthemeaningofECOG1594Nodifferenceinhistologicaleffectsbetweennon-squamouscarcinomaandsquamouscarcinoma;Therapeuticeffectofthedrugisnotverygood;Convenientfordoctorstocarryoutchemotherapyprogrammemory;Tellthedoctorthat"usinganydual-drugchemotherapyregimenyouwant".Cisplatin/PaclitaxelCisplatin/GemcitabineCisplatin/DocetaxelCarboplatin/PaclitaxelLCMC:Benefitinoverallsurvival

forpersonalizedtreatmentKrisetal.,ASCO2011,#7506,Krisetal.,JAMA2014PrecisionMedicineinAdvancedNSCLCTargettherapy

(1st,2nd,and3rdgeneration)NewtargetsIncreaseofbiomarkertestingNoactionabledrivermutationAvastin＋ChemoNon-squamousNSCLCAdenoCaSquamousCa.SCLCNOSLargecellClinicalLungCancerGenomeProjectandNetworkGenomicMedicine,ScienceTransl.Med.2013Immunotherapy

PD-L1TPS>50%Mutationload>200SquamousCarcinomaSmokingadenocarcinomaOncogenicdrivers+Oncogenicdriver-RandomizedphaseIIItrialson

EGFRTKIvschemotherapyStudiesArmsN

(EGFRm+)ORR(%)ORRPvaluePFS(months)PFSPvalueIPASSGefitinibTaxol/carbo13212971.247.30.00019.5

6.30.0001First-SIGNALgefitinibGem/cis261684.637.50.0028.06.30.086WJOG3405GefitinibDox/Cis868662.132.10.00019.66.60.001NEJ002GefitinibTaxol/Carbo11411473.730.70.00110.85.40.001OPTIMALErlotinibGem/Carbo827283360.000113.14.60.0001ENSUREErlotinibGem/Cis11010762.733.60.000111.05.50.0001EURTACErlotinibDoublets86875815NA9.75.20.0001CONVINECIcotinibPem/CisorCarbo

14814864.833.8ＮＡ9.77.20.001RossiA,etal.CancerTreatmentReviews2013;39:489-497.ZhouCC,etal.LancetOncol2011;12:735–42.WuYL,etal.

AuunalofOnco2015.HanJY,etal.JClinOncol2012;30:1122-1128.PatientswithEGFRmutationneed

afirst-lineuseofEGFRTKI

asearlyaspossible00.20.40.60.8010201.04030Time

(Months)OSEGFR-TKI

+Chemotherapy(n=94):30.39

MOnlyEGFR-TKI(n=33):20.67

MOnlyChemotherapy(n=21):

11.70MEGFR-TKI+Chemotherapy

vs.

OnlyChemotherapy:P=0.0001OnlyEGFR-TKIvs.OnlyChemotherapy:P=0.057OPTIMALStudyBothTKIandchemotherapyshouldbeused,theOSbenefitedmostEGFRTKIshouldbeusedassoonaspossibleZhouCC,etal.2012ASCOAbstract7520.LUX-Lung7:PFSafatinib(N=160)Gefitinib(N=159)PFS(month)11.010.9HR(95%Cl)0.74(0.57-0.95)PValue0.01781.00.80.60.40.2003691215182124273033363942Time(months)PFSParkKCetal.LancetOncol2016;17:577–89.ARCHER1050

Nobrainmetastases,accompaniedby

advancedNSCLCwithEGFRsensitivitymutationMokT,etal.2017ASCOAbstractLBA9007.1.00.80.60.40.20.006121824303642monthsPFSPFS

rate30.6%vs9.6%Daco(N=227)Gef(N=225)NumberofEvernts,n(%)136(59.9%)179(79.5%)Median

PFS(95%CI)14.7(11.1-16.6)9.2(0.1-11.0)HR(95%CI)0.59(0.47-0.74)P<0.0001CrizotinibinALKpositiveNSCLCPhaseIIItrialscomparingcrizotinibwithchemotherapyinALK+lungcancer(PROFILE1007and1014)Shawetal.NEnglJMed2013.Solomonetal.NEnglJMed2014.0510152025020406080100051015202502040608010030352ndlinePROFILE10071stlinePROFILE1014Time(months)Time(months)PFS(%)PFS(%)Median(mo)HR(95%CI)PCRZ7.70.49(0.37-0.4)<0.001CTx3.0Median(mo)HR(95%CI)PCRZ10.90.45(0.35-0.60)<0.001CTx7.0AlectinibvsCrizotinibin

treatment-na?veadvancedALK+NSCLC:

GlobalphaseIIIALEXstudyPrimaryendpoint:PFS,investigator-assessedCrizotinib(n=151)Alectinib(n=152)Patientswithevents(%)6841Median

PFS,

months(95%CI)11.1(9.1-13.1)NR(17.7-NR)HR(95%CI);

P-value(log-ranktest)0.47(0.34-0.65);P<0.000102040608010013691215182124273011.1monthsPFS(%)MonthsDayAlectinib

(n=151)Crizotinib(n=152)NRShawA,etal.2017ASCOAbstractLBA9008.AlectinibvsCrizotinibin

treatment-na?veadvancedALK+NSCLC:

GlobalphaseIIIALEXstudySecondaryendpoint:PFS,IRC-assessedCrizotinib(n=151)Alectinib(n=152)Patientswithevents(%)6141Median

PFS,

months(95%CI)10.4(7.7-14.6)25.7(19.9-NR)HR(95%CI);

P-value(log-ranktest)0.50(0.36-0.70);P<0.000102040608010013691215182124273010.4

monthsPFS(%)monthsDayAlectinib

(n=151)Crizotinib(n=152)NRShawA,etal.2017ASCOAbstractLBA9008.PFS1+PFS2ofcrizotinib+

ceritinibwithnobrainmetsatbaseline

(ALEX+ASCEND-5)ALEXCrizotinibMedianPFS=14.8mCeritinib(ASCEND-5)MedianPFS=4.4mPatientswithbrainmetsatprogressiononcrizotinibTotalPFS=19.2monthsPatientswithoutbrainmetsatprogressiononcrizotinibTotalPFS=21.7monthsCeritinib(ASCEND-5)MedianPFS=6.9mALEXCrizotinibMedianPFS=14.8mALEXAlectinibMedianPFS=25.7mAlectinibvs.CrizotinibcureALK+NSCLC

patients,whowereinitiallytreated

byALKinhibitor:Alexia,Asianmulti-centerLeadingPI:CaicunZhou,LiZhangStratificationfactors:Clinicalstaging(IIIB/IVvsrecurrence)Previouschemotherapy(0vs1)ECOGPS(0/1vs2)R1：1*IRF獨(dú)立審核機(jī)構(gòu)KeyinclusioncriteriaPhaseIIIB/IVorrecurrentALKpositiveNSCLCALKcentralizeddetection(IHCandFISHorRT-PCR)ECOGPS0-2≥1measurablenidus(evaluatedbyresearchers)Allowingtreated/Nosymptomforbrainmetastasis≤1previouschemotherapyAlectinib600mgBIDPO28dayisonecycle(N=100)Crizotinib

250mgBIDPO28dayisonecycle(N=100)EndpointPrimaryPFSevaluatedbyIRFSecondaryOSORRPKQOLCNSPFSSafety3rdGenerationALK:LoratinibEfficacyresultsforALK+patientsSolomonBJ,etal.2016ASCOAbstract9009.NORR(%)(95%CI)PFS(mo)(95%CI)1priorALKTKI1457(29-82)13.5(6-NR)≥2priorALKTKI2642(23-63)9.2(1.5-NR)TotalALK4146(31-63)11.4(3.4-16.6)0102030-10-20-30-40-50-60-70-80-90-100ORR46%Bestchangefrombaseline(%)1priorTKI≥2priorTKI13.5mo9.2mo02468101214161820020406080100PFS(%)13579111315171921Time(months)Halfofthesepatientswillberesistant

toEGFR-TKIsafter8-10monthsAfatinib

(n=230)Cis/pem

(n=115)PFSevent,n(%)152(66)69(60)MedianPFS(months)11.16.9HR(95%CI)0.58(0.43–0.78)

p=0.0004100806040200 0 3 6 9 12 15 18 21 24 27Progression-freesurvival(%)100806040200月Progression-freesurvival(%)100806040200 0 10 20 30 40Proportionwithoutprogression(%)100806040200 0 3 6 9 12 15 18 21 24 27Progression-freesurvival(%) Median(95%CI)

progression-freeGefitinib (n=86) 9.2months

(8.0–13.0)Cisplatinand (n=86) 6.3monthsdocetaxel (5.8–7.8)Gefitinib(n=114)Standardchemotherapy(n=110)p<0.001p<0.001Erlotinib(n=86)Chemotherapy(n=87)HR0.37(95%CI0.25–0.54)22%47%月 0 3 6 9 12 15 18 21 24 27月月Maemondoetal.,NewEnglJMed2010;362:2380–2388.Yangetal.,JClinOncol2012;30(suppl):AbstractLBA7500.

Mitsudmoietal.,LancetOncol2010;11:121–128;Rosellatal.,LancetOncol2012;13:239–246Intra-tumoralheterogeneity

inALK/EGFRco-alteredLADCCaiW,etal.JCO.

2015Nov33(32);3701-3709.PFS:patientswithlowabundance

ofEGFRmutations19DelL858RXFLi,etal.JTO2017PrecisionMedicineinAdvancedNSCLCTargettherapy

(1st,2nd,and3rdgeneration)NewtargetsIncreaseofbiomarkertestingNoactionabledrivermutationAvastin＋ChemoNon-squamousNSCLCAdenoCaSquamousCa.SCLCNOSLargecellClinicalLungCancerGenomeProjectandNetworkGenomicMedicine,ScienceTransl.Med.2013Immunotherapy

PD-L1TPS>50%Mutationload>200SquamousCarcinomaSmokingadenocarcinomaOncogenicdrivers+Oncogenicdriver-BEYOND:Bevacizumab+

ChemotherapyinChineseNSCLCPlaceboStagedIIIB/IV,Chemonaive,Non-squamousNSCLC,aged≥18ECOGPS0-1n=276Avastin15mg/kgd1CarboAUC6d1Taxol175mg/m2d1Q3w,n=138Upto6cyclesRPD*Placebod1+Carbo/Taxol,q3w,n=1381:1PDAvastinmaintBaseline

CharacteristicsBev+CP(n=138)Pl+CP(n=138)ECOGPS,n(%)034(25)27(20)1104(75)111(80)Histology,n(%)

Adenocarcinoma137(99)136(98)Stage,n(%)

Recurrent

4(3)3(2)IIIB8(6)9(7)IV126(91)125(91)

Unknows0(0.0)1(1)EGFR

status*,n(%)8566EGFRmutant,n(%)23(27)17(26)EGFRwild-type,n(%)62(73)50(74)1stendpoint:PFS2ndendpoints:OS,ORR,Durationofresponse,safety,exploratorybiomarkers(VEGF-A,VEGFR-2)ZhouC,etal.JClinOncol2015;33:2197-2204.ZhouC,etal.JClinOncol2015;33:2197-2204.BEYOND:PFS&OSPFSMedianPFS9.2mvs6.5mHR0.40(95%CI0.29–0.54)p<0.0011.00.80.60.40.206121824Avstin+Chemo(n=138)Placebo_chemo(n=138)Time(m)9.2m

6.5m2.7Time(m)1.00.80.60.40.2061218243036OSAvastin+chemo(n=138)Placebo+Chemo(n=138)MedianOS24.3mvs6.5mHR0.68(95%CI0.50–0.93)p=0.015424.3m17.7m6.6Bev+CP

(n=136)Pl+CP

(n=133)ORR,%(95%CI)54(45.4–62.9)26(19.2–34.8)P<0.0001DCR,%(95%CI)95(89.3–97.7)89(81.8–93.3)Median,月m(95%CI)8.0(6.9–9.4)5.3(4.4–6.0)Immunotherapy:second-line

treatment,forallpopulationDatacut-offsof*August2015,

§December2014,?June2015,∥July2015or**March2015;

§§PhaseIIIdose:2mg/kgQ3Wand10mg/kgQ3W

??Tumourproportionscore(TPS)istheproportionofviabletumourcellsshowingpartialorcompletemembranePD-L1expression1.FabriceBarlesi,etal.ESMO2016;2.Reckamp,etal.WCLC2015;3.Brahmer,etal.NEnglJMed2015;4.Borghaei,etal.NEnglJMed2015;5.Herbst,etal.Lancet2015.OAK(PhIII)12/3Latezovsdoc(n=850)CheckMate017(PhIII)2,32Lnivovsdoc

(n=272)CheckMate057(PhIII)42/3Lnivovsdoc(n=582)KEYNOTE-010(PhII/III)5≥2Lpembro§§vsdoc(n=1033)TypeoftissueNotlimitedSquamouscarcinomaNonsquamouscarcinomaNotlimitedPD-L1optionNoNoNoYes(TPS??≥1%)ORR,%Atezo14%vsdoc13%Nivo20%vsdoc9%§Nivo19%vsdoc12%**Pembro2mg/kg18%vs

pembro10mg/kg18%vsdoc9%AEG3-4treatmentrelatedAEs:15vs43%G3-4treatmentrelated

AEs:8vs56%?G3-4treatmentrelatedAEs:10vs54%**G3-5treatmentrelatedAEs:

13%pembro2mg/kgvs16%pembro

10mg/kgvs35%docHR0.62

(p=0.0004)*HR0.63

(p=0.0008)*HR0.72

(p<0.001)∥HR0.73

(p=0.0003)HR0.95

HR0.92

(p=0.39)**HR0.61(p<0.0001)HR0.79(p=0.004)Nivo

OSDoc

OSPembro

2mg/kg

OSAtezo

OSNivo

PFSDoc

PFSNivo

OSDoc

OSNivo

PFSDoc

PFSDoc

OSAtezo

PFSDoc

PFSDoc

OSPembro

10mg/kg

OSPembro

2mg/kg

PFSDoc

PFSPembro

10mg/kg

PFSHR0.71(p=0.0008)HR0.88(p=0.07)13.89.64.02.89.26.03.52.89.412.22.34.210.412.78.53.94.04.0CriticalStudyonfirst-line

treatmentwiththecheckpoint

inhibitors:KM024vs.CM026SocinskiMA,etal.2016ESMOAbstractLBA7.ReckM,etal.2016ESMOAbstractLBA8.CheckMate026KEYNOTE-024Keyinclusioncriteria:StageIVorrecurrentNSCLCNoprevioussystemictreatmentforadvanceddiseaseNoavailabletargetedinhibitorsforsensitiveEGFR/ALKmutations≥1%ofPD-L1expressionAllowingCNStransfertreatedfullyatleasttwoweekspriortoRandomgroupingNivolumab3mg/kgIVQ2Wn=271Chemotherapy(histologicaldependence)Maximumtreatmentcyclen=270DiseaseprogressionorunacceptabletoxicityProgressionCrossedoverto(selectable)ThetumorwasscannedforQ6Wevery12weeksuntilthe48thweekStratifiedfactorsinrandomization:PD-L1expression(<5%vs≥5%)Histology(squamouscarcinomavs.non-squamouscarcinoma)Primaryendpoint:PFS(≥5%PD-L1*)Secondaryendpoint:PFS(≥1%PD-L1*)OSORRKeyinclusioncriteria:UntreatedPhaseIVNSCLCPD-L1TPS5%orhigherECOGPS0-1NoactivatedEGFRmutationorALKtranslocationNountreatedbrainmetastasesAutoimmunediseasewhichdoesnotrequiresystemictreatmentPembrolizumab200mgIVQ3W(2years)Platinum-baseddoubletchemotherapy(4-6cycles)Pembrolizumab200mgQ3W×2

yearsPD*CriticalendpointPrimary:PFS(RECISTv1.1Blindmethod(Independentcentralizedevaluation)Secondary:OS,ORR,safetyExploratoryendpoint:DORR(1:1)N=305CheckMate026vs.KEYNOTE-024:OS*＞30Gyofpreviousradiotherapy,whichconducted6monthspriortothe

firstadministrationisnotallowedinthestudy..SocinskiMA,etal.2016ESMOAbstractLBA7.ReckM,etal.2016ESMOAbstractLBA8.AggarwalC,etal.2016ESMOAbstract1060P.100806040200036912152130Nivolumabn=211Chemotherapyn=21218242714.4(11.7,17.4)56.313.2(10.7-17.1)53.6MedicanOSmo(95%CI)OSratein1yearHR=1.02(95%CI:0.80,1.30)ChemotherapyNivolumabMonth70%54%100806040200036912151821PembroChemotherapy4464Events,nNRNRmedican,mo0.60(0.41-0.89)HR(95%CI)0.005PTime(month)PembroChemotherapyKEYNOTE024(PD-L1+≥50%)CheckMate026(PD-L1+≥5%)

KN024CM026TumorbiopsyDiagnosistobetransferedWithin6monthsPD-L1threshold50%(22C3clone)5%(28-8clone)IntervalforradiologicalexaminationEvery9weeksEvery6weeksforthefirst48weeksPrimaryendpointPFS(RECIST)PFS(IRRC)Never-smokers(PD-1)3%11%Histologywassquamouscellcarcinoma19%24%Timefromdiagnosistotreatment?2monthsPreviousradiotherapy?*37.6%CheckMate026PotentialImbalancebetweenpotentialgroups?Nivolumab(n=271)化療(n=270)Female,%32.145.2Partialmetastaticsite(nidus),liver%19.913.3PD-L1expression,≥5%%≥25%≥50%≥75%76.848.732.520.777.860.746.727.4Kaplan-MeierEstimateofPFS2Events,nHR(95%CI)Pembrolizumab(n=154)740.54(0.40-0.72)P<0.001Chemotherapy

(n=151)110Median(95%CI)18.3mo(12.7-NE)8.4mo(6.8-9.8)59.7%38.5%036912151821Time,months020406080100PFS2,%51.0%24.6%24PFS2BrahmerJR,etal.2017ASCOAbstract9000.Kaplan-MeierEstimateofOSBrahmerJR,etal.2017ASCOAbstract9000.Events

,nHR(95%CI)Pembrolizumab(n=154)630.63(0.46-0.88)P=0.003Chemotherapy(n=151)84Median(95%CI)NR(19.4-NE)14.5mo(9.8-19.6)70.3%54.8%036912151821Time,months020406080100OS,%51.2%43.0%24OSKEYNOTE-021:Response*ParientswithTPS≥50%Gadgeel,etat.ASCO2016CohortA:Pembrolizumab+carboplatin+paclitaxel(n=25)CohortB:Pembrolizumab+carboplatin+paclitaxel+bevacizumab(n=25)CohortC:Pembrolizumab+carboplatin+pemetrexed(n=25)KEYNOTE-021CohortGStudyDesignKeyEligibilitycriteriaUntreatedstageIIIBorIVnon-squamousNSCLCECOGPS0-1ProvisionofasampleforPD-L1

assessmentNoactivatingEGFRmutationorALKtranslocationNountreatedbrainmetastasesNoILDorpneumonitisrequiringsystemicsteroidsPembrolizumab200mgIVQ3W(2y)+ACQ3W*4ACQ3W*4bPembrolizumab200mgQ3W2

yeatsPD*R(1:1)aN=12351%crossoverinITTpopulation73%crossoverexcludingongoingptsaRandomizationwasstratifiedbyPD-L1TPS<1%vs≥1%bIndefinitemaintenancetherapywithpemetrexed500mg/m2Q3Wpermitted.SoriaJC.Presentedat2016ESMO.Keyend-pointsPrimary：ORR(RECISTv1.1perblinded,independentcentralreview)Keysecondary：PFSOthersecondary：OS、safetyExploratory：RelationshipbetweenantitumoractivityandPD-L1TPSKEYNOTE-021CohortGOverall

ResponseandbyPD-L1TPSPembro+chemoResponders(n=33)ChemoAloneResponders

(n=18)TTR,

median

(mo)(range)1.5(1.2-12.3)2.7(1.1-4.7)DOR,

median

(mo)(range)NR(1.4+-13.0+)NR(1.4+-15.2+)Ongoingresponse,

n

(%)29

(58)14

(78)ObjectiveResponse55%29%020406080100Pembro+ChemoChemoAloneORR,%(95%CI)ObjectiveResponsebyPD-L1TPS57%54%20%80%13%38%39%35%0%20%40%60%80%100%<1%n=21≥1%n=291%-49%n=19≥50%n=20<1%n=21≥1%n=40n=23≥50%n=171%-49%Pembro+ChemoChemoAloneORRnearlydoubledwithKEYTRUDAcombovs.chemoaloneSignificantORRbenefitwithKEYTRUDAcomboinPD-L1negativeandPD-L1positivepatientsSoriaJC.Presentedat2016ESMO.KEYNOTE-021CohortGProgression

FreeSurvivalandOverallSurvivalEvents

,nHR(95%CI)Pembro+chemo

(n=48)230.53(0.31-0.91)P=0.0102Chemoalone(n=33)33051015206Time,monthsPFS(%)010203040506070809010077%63%PFS13.0mo8.9mo051015206Time,monthsOS(%)010203040506070809010092%92%75%72%12OS47%riskreductionofdiseaseprogressionMedianPFS=13.0months51%crossoverinITTpopulation73%crossoverexcludingongoingptsSoriaJC.Presentedat2016ESMO.First-linetreatmentstudydesignfor

Shr-12110combinationchemotherapyStudygroup:Confirmedbypathologicalhistologyorcytologicalexamination,thesubjectsshouldbenonsquamouscarcinomasandnon-smallcelllungcancer,EGFR/ALKwild-type,advancedormetastatic(PhaseIIIB/IV),maleorfemale,18to70yearsold,ECOGPS0-1scores,notreceivedsystemicchemotherapyforadvanced/metastaticdisease.About412subjectswereexpectedtobeenrolled.Layering:gender,smokinghistoryHistologicalorcytologicaldiagnosisofIIIBorIVnon-squamousNSCLC;Unsystematictreatment;ExcludedEGFRpositiveandALKpositivepatients;ECOGscoreislessthanorequalto1ExcludingactivebrainmetastasesR(1:1)N=350SHR-1210200mg，IV,Q3W(Untilthediseaseprogression)SHR-1210200mg+carboplatinAUC5mg/ml/min+Pemetrexed500mg/m2,IV,Q3W,4-6courseoftreatmentMaintenancetreatment:SHR-1210200mg+Pemetrexed500mg/m2,IV,Q3W,￡2years,untildiseaseprogressesCarboplatinAUC5mg/ml/min+Pemetrexed500mg/m2

IV,Q3W,4-6courseoftreatmentMaintenancetreatment:Pemetrexed500mg/m2,IV,Q3W,￡2years,untildiseaseprogresses

Cross-over

afterPDPI:C.ZhouAnti-tumoractivityof

PD-1inhibitor+Apatinib2016WCLCOA11.07:CombiningAnti-angiogenesisandImmunotherapyenhancesantitumoreffectbypromotingimmuneresponseinlungcancer–ShaZhao.Apatinib+PD-1PhaseII

clinicalstudydesignStudydesign: Thestudyisdividedintotwophases,thefirstphaseisatwo-arm,singlecenter,opendesignstudytoobservethedosetoleranceoftwogroupsforpatientswithadvancednon-small-celllungcancer(NSCLC)andunsuccessfulpreviousstandardtreatment,andPKextensionresearchwasconducted; Thesecondstageisatwo-arm/singlearm,multicenter,opendesignstudy,accordingtothedrugtoleranceinthefirstphase,choosingoneortwogroupsofdoses,enrollingpatientswithadvancednon-smallcelllungcancerandunsuccessfulpreviousfirst-linechemotherapy,curativeeffectandsafetyinvestigationwereconducted.Leadunit: AffiliatedPulmonaryhospitalofTongjiuniversity,Shanghai About10centerswereinvolved(Tobeconfirmedafterthebeginningoffirstphase)OveralldesignofstudyAdvancedNSCLCSecond-linechemotherapyortreatmentpriortosecond-linewasfailedHavingmeasurablenidusECOG0-1SHR-1210,200mg,q2w+Apatinib,250mg，q.d.(n~12)SHR-1210,200mg,q2w+Apatinib,500mg，q.d.(n~12)ThefirstphaseThefirst-linechemotherapyfailedSHR-1210,200mg,q2w+Apatinib,500mg，q.d.(n=35)SHR-1210,200mg,q2w+Apatinib,250mg，q.d.(n=35)ThesecondphaseAbout118subjectsareenrolledPKextension(n,10~12)PKextension(n,10~12)ClinicalchallengesintumortherapyCurrentmethodsarenotsufficientfortreatmentselectionanddiseasesurveillance,anditisdifficulttooptimizetheapplicationoftargetedtherapyandimmunotherapy.TissuebiopsyTrauma,costly,andsometimesitdoesn'thappenAlackofmaterialformolecularspectrumanalysisInabilitytocapturetheheterogeneityofdiseaseNotsuitableforserialsamplingImageologyTimedelayinthedetectionofdiseaseprogressionItisdifficulttodistinguishthefalseprogressionNoinformationforthemolecularlevelPlasmaproteinbiomarkersSometimesnocorrelationwithdiseaseLowsensitivityLonghalf-lifeTheevolutionoftumortherapy

ImmunotherapyTargetedtherapyChallengeCancerisaheterogeneousdiseaseThetumorchangesbecauseofselectivepressureUnsatisfiedclinicalrequirementsThemolecularmechanismrelatedto

drugresistanceofEGFR-TKIYu,ClinCancerRes2013Genealterationsatprogression

andNazartinibefficacyTanDSW,etal.2017ASCOAbstract11506.-100Best%changefrombaseline-80-60-40-2002040608010013579111315171921PFS(months)patientIDNo.EGFRmutationsOthercancer-relatedgeneticalterationsatprogressionBaselineProgression9EX19DEL,T790MEX19DELTP53R273C,CDKN24AM53BRAFrearrangement(CLDN15partner).HGFamp?,MYST3amp?11IIEX19DELEX19DELAKT2amp,ARFRP1amp,ALXamp,CCNE1amp,CDKN2AY44fs*1(130_131insA),TP53L130R8EX19DEL,T790MEX19DELPIK3CAY10211C,RB1loss,IRS2amp?3EX19DEL,T790MEX19DELTP53P278S,CDKN2A/2Bloss,EGFRamp,BRIP1truncation,ETV6truncation10L858R,T790ML858RTP35S241Y,PIK3CAP447_L455del,CCNE1amp6EX19DEL,T790MEX19DEL,T790M,C797SCTNNB1D32G,PIK3CAQ546K,CDKN2A/2Bloss,MTORA1828_1831del,PTPRDsplicesite4947+1G>T1EX19DEL,T790M?EX19DEL,T790MTP53S183*,RB1D68fs*9,EGFRamp4§EX19DEL,T790MEX19DELCTNNB1S33F5L8658R,T790ML858R,T790MPTCH1T416S,EGFRamp,MDM2amp,FRS2amp,NKX2-1amp,JUNamp?,ZNF217amp?,AURKAamp?7§EX19DEL,T790MEX19DEL

G724STP53L45fs*712EX19DEL,T790M?EX19DEL

METampBRAFrearrangement(PRKAR1Bpartner),EMSYamp,MDMZamp,FRSZamp,EGFRamp?AcquiredresistancetocrizotinibEML4ALKKinasedomainEML4ALKKinasedomainEML4ALKKinasedomainEML4ALKKinasedomainEML4ALKKinasedomainEML4ALKKinasedomain1151TinsL1152RC1156YI1171TF1174L/CL1196MG1202RF1245CG1269AEGFRIGF-1Rc-KITKRASmutMEKmutSRCAmplificationoftheALKfusionMutationintheALKkinasedomainBypasssignallingNext-generationALKinhibitorsEGFRinhibitorsIGF-1RinhibitorsKITinhibitorsSrcinhibitorsMEKinhibitorsHSP90inhibitorsHSP90Foundin~25%ofcrizotinib-resistanttumoursEML4,echinodermmicrotubule-associated

protein-like4;HSP,heat-shockprotein;IGF-1R,insulin-likegrowthfactor1receptor.AdaptedfromLovlyCM.AmSocClinOncolEducBook.2015:e165-73.AURA17study:AZD9291