27.2018-12-4-2018非小细胞肺癌EGFR突变：优化患者管理.ppt

Cncer de pulmn no microctico EGFR mutado:Optimizacin del manejo del paciente Manuel Cobo DolsOncologia Mdica H Regional Universitario Mlaga.IBIMA12-4-2018EGFR TKIs versus ChemotherapyEvents/N Median PFS(95%CI)12m PFS(95%CI)All 57/109 13.8 m(10.3-21.3)56.7%(46.0-66.0)T790M+15/37 16.0 m(13.1-NE)72.4%(53.4-84.7)T790M-42/72 10.5 m(9.2-16.2)49.4%(36.6-61.0)Study Design RecruitingSecondaryEndpointsStudy PeriodPrimaryEndpoint12ACCRU RC1126(NCT01532089)USAPhases IIIErlotinib+Bec vs ErlotinibEGFR Mut(+)RecruitingPFSOS ORRSafety20122017BEVERLY(NCT02633189)Italy2015 2018OSQoLORRPhases IIIErlotinib+Bec vs ErlotinibEGFR Mut(+)NEJ026(UMIN000017069)Japan20152018Phases IIIErlotinib+Bec vs ErlotinibEGFR Mut(+)ARTEMIS(NCT02759614)China20162019Phases IIIErlotinib+Bec vs ErlotinibEGFR Mut(+)RecruitingRecruiting StatusStudy No.PFSPFSPFSOS ORRSafetyOSQoLORR Ongoing Study:erlotinib+bevacizumab vs.erlotinib as first-line treatment IMPRESS.In exploratory analysis of T790M negative,there may be PFS benefit to continuation of EGFR TKISoria JC,et al.Lancet Oncol.2015;16:990-998.Erlotinib,Gefitinib,Afatinib(8-12m)PD:rebiopsyT790MOsimertinib (8-10m)EGFRdel 19L858ROtherInitial biopsyalso:liquid biopsyMok et al.,Phase III(Aura 3)(Osimertinib vs.CT)mPFS 10.1 vs.4.4 m NEJM 2016 Girard N.Future oncol 2017Plasma EGFR T790MPlasma from AURA trial sent for BEAMingPaired tumor and plasma available for 216 patientsOxnard et al,JCO,201618 T790M+in plasma,not tumor111 T790M+in tumor and plasma47 T790M+in tumor,not plasma40 patients T790M-tumor and plasma T790M+in tumor:62%RR,10m PFST790M+in plasma:63%RR,10m PFSImmunotherapy in EGFR-Mutant NSCLC*Data for the pembrolizumab doses were pooled.CheckMate 057KEYNOTE-010*OAKNivolumabDocetaxelPembrolizumabDocetaxelAtezolizumabDocetaxelReferences in slidenotes.Pts,nUnstratified HR(95%CI)821.18(0.69-2.00)3400.66(0.51-0.86)1600.74(0.51-1.06)Events/Pts,n/NHR(95%CI)46/860.88(0.45-1.70)447/8750.66(0.55-0.80)Pts,n(%)HR(95%CI)85(10)1.24(0.71-2.18)628(74)0.69(0.57-0.83)MutantNot detectedNot reportedMutantWild typeMutantWild type1.00.52.00.254.01.00.1101.00.22LBA2_PR:Osimertinib vs SoC EGFD-TKI as first-line treatment in patients with EGFRm advanced NSCLC(FLAURA)Key resultsRamalingam S et al.Ann Oncol 2017;28(suppl 5):Abstr LBA2_PRMedian PFS,months(95%CI)18.9(15.2,21.4)10.2(9.6,11.1)HR 0.46(95%CI 0.37,0.57)p0.0001OsimertinibSoCPFS1.00.60.40.20.003691215182124270.8Probability of progression-free survivalTime from randomization,monthsNo.at riskOsimertinibSoC27926223321017813907126427723919715210778371020Favours SoCSubgroupOverall(n=556)Log Rank(primary)Cox PHSex Male(n=206)Female(n=350)Age at screening65(n=298)65(n=258)RaceAsian(n=347)Non-Asian(n=209)Smoking history Yes(n=199)No(n=357)CNS metastasesYes(n=116)No(n=440)WHO performance status0(n=228)1(n=327)EGFR mutation at randomisation#Exon 19 deletion(n=349)L858R(n=207)EGFR mutation by ctDNAPositive(n=359)Negative(n=124)Centrally confirmed EGFR mutationPositive(n=500)Negative(n=6)FLAURA data cut-off:12 June 2017Hazard ratio 1 implies a lower risk of progression on osimertinib 80 mg.Size of circle is proportional to the number of events*By Investigator assessment;#Local or central test;Result missing for 36 patients in the osimertinib arm and 37 patients in the SoC arm;Result missing for 21 patients in the osimertinib arm and 29 patients in the SoC arm;Subgroup categories with less than 20 events were excluded from the analysisCNS,central nervous system;ctDNA,circulating tumour DNA;EGFR,epidermal growth factor receptor;PFS,progression-free survival;SoC,standard-of-care;WHO,World Health Organization.Ramalingam et al.Presented at:ESMO Congress Sep 8-12,2017;Madrid,Spain.PFS*across subgroups0.10.20.30.40.60.8Hazard ratio(95%confidence interval)0.46(0.37,0.57)0.46(0.37,0.57)0.58(0.41,0.82)0.40(0.30,0.52)0.44(0.33,0.58)0.49(0.35,0.67)0.55(0.42,0.72)0.34(0.23,0.48)0.48(0.34,0.68)0.45(0.34,0.59)0.47(0.30,0.74)0.46(0.36,0.59)0.39(0.27,0.56)0.50(0.38,0.66)0.43(0.32,0.56)0.51(0.36,0.71)0.44(0.34,0.57)0.48(0.28,0.80)0.43(0.34,0.54)NC(NC,NC)2.0PFS hazard ratio and 95%confidence interval1.0Favours osimertinib10.025Objective response rate*FLAURA data cut-off:12 June 2017Tick marks indicate censored data*By investigator assessment#Analysis performed using a logistic regression stratified by race(Asian versus Non-Asian)and mutation type(Exon 19 deletion versus L858R);Response did not require confirmation;Calculated using Kaplan-Meier approachCI,confidence interval;DoR,duration of response;ORR,objective response rate;SoC,standard-of-care.Ramalinagm et al.Presented at:ESMO Congress Sep 8-12,2017;Madrid,Spain.Duration of responseMedian DoR,months(95%CI)17.2(13.8,22.0)8.5(7.3,9.8)Probability of remaining in response1.00.90.80.70.60.50.40.30.20.10.00369121518212427Time from first response(months)No.at riskOsimertinibSoC2232102051801811361609512869823940171440001Osimertinib(n=279)SoC(n=277)ORR(95%CI)80%(75,85)76%(70,81)Odds ratio#(95%CI)1.28(0.85,1.93);p=0.2335Complete response,n(%)Partial response,n(%)Stable disease 6 weeks,n(%)Progression,n(%)Not evaluable,n(%)7(3)216(77)47(17)3(1)6(2)4(1)206(74)46(17)14(5)7(3)Estimated remaining in response,(95%CI)12 months18 months64%(58,71)49%(41,56)37%(31,44)19%(13,26)OsimertinibSoC26Key results(cont.)Ramalingam S et al.Ann Oncol 2017;28(suppl 5):Abstr LBA2_PRNo.at riskOsimertinibSoC279276269253243232015487427726325223721820012664102924OS interim analysis1.00.60.40.20.003691215182124270.830Probability of overall survivalTime from randomization,monthsHR 0.63(95%CI 0.45,0.88)p=0.0068A p-value of 0.0015 was required forstatistical significance at current maturityMedian overall survivalNot reachedOsimertinibSoCNot reachedLBA2_PR:Osimertinib vs SoC EGFD-TKI as first-line treatment in patients with EGFRm advanced NSCLC(FLAURA)Girard N.Future oncol 2017PacienteTumorEdadPSComorbilidadCercana domicilo a hospitalApoyo familiarSintomtica/asintomticoCarga tumoralLocalizacin/N mtsPosibilidad antiangiognicos?Mts SNCSubtipo mutacinDecisin de tratamiento en primera lnea.Factores a tener en cuenta Afatinib in NSCLC Pts With Uncommom EGFR MutationsYang JC,et al.Lancet Oncol.2015;16:830-838.OutcomeAfatinib Group 1(n=38)*Afatinib Group 2(n=14)Afatinib Group 3(n=23)ChemotherapyGroup(n=25)ORR,%(95%CI)71.1(54.1-84.6)14.3(1.8-42.8)8.7(1.1-28.0)24(9.4-45.1)Median DOR,mos(95%CI)11.1(4.1-15.2)8.2(4.1-12.4)7.1(4.2-10.1)-Disease control,%(95%CI)84.2(68.7-94.0)64.3(35.1-87.2)65.2(42.7-83.6)-Median PFS,mos(95%CI)10.7(5.6-14.7)2.9(1.2-8.3)2.7(1.8-4.2)8.2(5.2-10.8)Median OS,mos(95%CI)19.4(16.4-26.9)14.9(8.1-24.9)9.2(4.1-14.2)30.2(13.0-42.3)*Consists of pts with all point mutations or duplications in exons 18-21.Consists of pts with de novo T790M mutations.Consists of pts with exon 20 insertions.Consists of pts with mutations falling into groups 1/2/3(n=18/3/2).CohortnUncommon MutationsGroup 138Point mutations or duplications in exons 18-21(L861Q,G719S,G719A,G719C,S768I,rare others)alone or in combination with each otherGroup 214De novo T790M mutations in exon 20 alone or in combination with other mutationsGroup 323Exon 20 insertionsPacientes con PS 2 mayorJuan O.TherapeuticAdvancesinMedicalOncology2017Pacientes unfit,suelen ser 30%de los casos Ensayos con afatinib,dacometinib o osimertinib,no han reclutado pts PS 2El resto de estudios,con erlotinib y gefitinib la proporcin de pts PS 2 fue pequea(excepto en el EURTAC con erlotinib se reclutaron 14%de pts con PS 2)Rosell et al.Lancet Oncol 2012.-Pacientes PS 2:lo ms recomendado gefitinib y erlotinib.Ms datosAfatinib y dacometinib son ms txicosSlo un estudio prospectivo fase II con gefitinib que reclut 30 pts con mutacin de EGFR,inelegible para quimioterapia.22 pts de ellos tenan PS 3,y 68%de ellos,el PS regres a PS 1 en el curso de 1 mes,con una RG del&%PFS 6,5 meses y SG de 18,8 mesesTener en cuenta el tipo de comorbilidad(Ej.Problemas intestinales crnicos,TKIs 2 generacin menos recomendados.Heptica:ms toxicidad con gefitinib,etc)Erlotinib y gefitinib tienen ms interaccin farmacolgica.gefitinib y erlotinib tienen un potencial importante de interaccin con otros frmacos.Se comportan como inductores o inhibidores de enzimas relacionadas con los citocromos Juan O.TherapeuticAdvancesinMedicalOncology2017Pacientes unfit-ancianos dependientes/polimedicadosPFS benefit in AURA3 patients with CNS metastases at baselineWith CNS metastasesWithout CNS metastasesPopulation:intent-to-treatProgression-free survival defined as time from randomisation until date of objective disease progression or death.Progression included deaths in the absence of RECIST progression.Tick marks indicate censored data.CNS metastases determined programmatically from baseline data of CNS lesion site,medical history,and/or surgery,and/or radiotherapy.Probability ofprogression-free survival1.00.80.60.40.20No.at riskOsimertinibPlatinum-pemetrexed0369121518935180324692741424000MonthsOsimertinib(n=93)Platinum-pemetrexed(n=51)Median PFS,months(95%CI)8.5(6.8,12.3)4.2(4.1,5.4)HR 0.32(95%CI 0.21,0.49)Probability ofprogression-free survival1.00.80.60.40.20036912151818689160611163561133659100MonthsOsimertinib(n=186)Platinum-pemetrexed(n=89)Median PFS,months(95%CI)10.8(8.3,12.5)5.6(4.2,6.8)HR 0.40(95%CI 0.29,0.55)Mok et al.NEJM 2017Osimertinib(n=22)#SoC(n=19)Median best percentage change from baseline in CNS target lesion size:-64%(range-100%to+20%)Median best percentage change from baseline in CNS target lesion size:-45%(range-100%to+20%)Stable diseasePartial responseProgressive diseaseBest change from baseline in target lesion size(%)-100-80-60-40-20020-100-80-60-40-20020Best change from baseline in target lesion size(%)Not evaluableStable diseasePartial responseComplete responseFLAURA:CNS RESPONSE*:CNS EVALUABLE FOR RESPONSE SETRRRR R RRRRRRRRRRRR Prior brain radiotherapyR Prior brain radiotherapy36Presented by J Vansteenkiste at ESMO Asia 2017,1719 November 2017,Singapore Proferred Paper Session 1,Abstract LBA5.Ann Oncol 2017;28(suppl_10):mdx729.007Osimertinib aun no aprobado en 1 lnea de CPNM avanzado con mutacin EGFRFlaura.CNS PFS:CNS FULL ANALYSIS SET.Osimertinib is the recomendation in pts with SNC metastases*Progression events that did not occur within 2 scheduled visits(plus visit window)of the last evaluable assessment(or randomisation)were censored and therefore excluded in the number of events;#A p-value of 0.0015 was required for statistical significance at current maturityCI,confidence interval;CNS,central nervous system;HR,hazard ratio;NC,not calculable;PFS,progression-free survival;SoC,standard-of-careFLAURA data cut-off:12 June 2017 Median CNS PFS,months(95%CI)NC(16.5,NC)13.9(8.3,NC)HR 0.48(95%CI 0.26,0.86)p=0.014Osimertinib(n=61)SoC(n=67)Median follow-up for CNS PFS,months12.47.0Total number of events(CNS progression or death),%3045Pts with CNS progression other than death,%*2039Progression in new CNS lesions,%1230CNS PFS was nominally statistically significantCNS PFS analysis was third in the hierarchical statistical testing strategy and,as OS did not reach formal statistical significance(HR 0.63 95%CI 0.45,0.88;p=0.0068),#CNS PFS could not be formally tested for statistical significanceOsimertinib(N=61)SoC(N=67)0.20.40.60.81.00.00369121518212427Time from randomisation(months)Probability of progression-free survivalNo.at riskOsimertinibSoCPresented by J Vansteenkiste at ESMO Asia 2017,1719 November 2017,Singapore Proferred Paper Session 1,Abstract LBA5.Ann Oncol 2017;28(suppl_10):mdx729.007Osimertinib aun no aprobado en 1 lnea de CPNM avanzado con mutacin EGFRFirst lineSecond lineThird and sucessive linesFirst generation TKIErlotinib Or gefitinibSecond generation TKIAfatinib TKI+angiangiogenicErlotinib+bevacizumabThird generation TKIOsimertinibChemoterapy9-10 m15-30%no possible 2 line11-13 m AfatinSecond generation TKIDacometinib 14,7 m Dacomet16 m erl+bevE+B T790M-ultsens10 m erl+bevE+B T790M+ultsens16 m erl+bev18,9 m osimertinibOsimert T790M-ultsensOsimert T790M+ultsens?5,5-6 m25-30%T790M not detected:NotPossible biopsy.Liquid biopsy false negativeOsi T790M+QT T790M-9-10 m5,5 mOsi T790M+QT T790M-9-10 m5,5 mOsi T790M+QT T790M-9-10 m5,5 mOsi T790M+QT T790M-9-10 m5,5 mOsi +GefitT790M+C797Strans9-10 m QT No Mutat5,5 mQTT790M+C797SCis QT No Mutat5,5 m QT No Mutat5,5 m QT No Mutat5,5 m QT No Mutat5,5 m QT No Mutat5,5 m5,5 m Inmunoth?m Inmunoth?m Inmunoth?m Inmunoth?m Inmunoth?m Inmunoth?m Inmunoth?m Inmunoth?m Inmunoth?m Inmunoth?m Inmunoth?m sequential TKI2-4 m sequential TKI2-4 m sequential TKI2-4 m sequential TKI2-4 mNazartinib?mSequential cronogramaCRITICAL QUESTION.When appoved,Osimertinib for all patients in first line EGFR mut,OR sequence has sense in a subgroup of patients?First lineSecond lineThird and sucessive linesFirst generation TKIErlotinib Or gefitinibSecond generation TKIAfatinib TKI+angiangiogenicErlotinib+bevacizumabThird generation TKIOsimertinibChemoterapy9-10 m15-30%no possible 2 line11-13 m AfatinSecond generation TKIDacometinib 14,7 m Dacomet16 m erl+bevE+B T790M-ultsens10 m erl+bevE+B T790M+ultsens16 m erl+bev18,9 m osimertinibOsimert T790M-ultsensOsimert T790M+ultsens?5,5-6 m25-35%T790M not detected:NotPossible biopsy.Liquid biopsy false negativeSequential cronogramaWhich is the more recomendable treatment in first line EGFR mut?Is based on PFS or is based in the overall survival of the complete potential sequence?Osimertinib:up to first?Presented By Sanjay Popat at 2017 ASCO Annual Meeting.-Add median survivals:WRONGThis is not biological real.It is play with numbers.-“Osimertinib first line:no other target therapies in sucessive lines.Best,use sequence:WRONG.If the treatment is clearly benefit,this must be the first lineSubsequent therapies post-afatinib among patients with EGFRM+NSCLC in LUX-Lung 3,6 and 7Single-agent CTOther1st-gen TKI monotherapy*Any subs systemic treatmentPlatinum-based CTSecond-line treatment394(71%)252(46%)39(7%)49(9%)54(10%)Third-line treatment265(48%)48(9%)104(19%)75(14%)38(7%)Fourth-line treatment156(28%)27(5%)50(9%)49(9%)30(5%)Any-line treatment394(71%)277(50%)181(33%)186(34%)Discontinued afatinib at time of analysis Patients with common EGFR mutations randomised to afatinibn=579n=553 121(22%)*Erlotinib,gefitinib and icotinib;Includes:platinum-based,single-agent and other CT combination therapies;osimertinib,afatinib,HM61713 and rociletinib monotherapies;erlotinib-,gefitinib-,icotinib-and afatinib-containing combinations;immune checkpoint inhibitors;and other therapiesSequist L et al.,ESMO 2017 poster#1349Data cut-off(LL3&6:25 March 2016;LL7:05 December 2016)29%of patients notReceived subsequent therapy for differenten reasons:This patients loose the chance to received 2 line therapy againstT790M mutNon-Shedding DNAsShedding DNAsVessels,Tissue BarriersTissueBiopsyLiquidBiopsyTumor HeterogeneityAll EGFRmut contain actEGFRmutBut only some contain resistant T790MNot all tumor cells shed DNA to blood Presented by:James Chih-Hsin Yang,MD,PhD.National Taiwan UniversityNot always Liquid biopsy detect T790M.67-75%false negativ