泌尿系统肿瘤免疫治疗新进展

泌尿系统肿瘤免疫治疗新进展,DocumentNumberESF-02272ExpirationDate1/2/2020,3,已有多个免疫检查点抑制剂被获批治疗膀胱癌或正处于研发阶段，为该领域带来了重大突破1,1.MoralesA,etal.JUrol.1976:116(2):180-183.2.FDABCGapproval.1998.3.Hematology/Oncology(Cancer)ApprovalsDDMVAC=剂量密集的甲氨蝶呤、长春碱、多柔比星和顺铂;GC=吉西他滨/顺铂;JPN=Japan;MIBC=肌层浸润膀胱癌;mUC=转移性尿路上皮癌;NMIBC=非肌层浸润膀胱癌;PD-1=程序性死亡受体-1;PD-L1=程序性死亡配体-1;RT=放疗;SOC=标准治疗;TURBT=经尿道膀胱肿瘤切除术;US/EU=美国/欧盟.1.NCCNClinicalPracticeGuidelines.BladderCancerV5.2017..AccessedAugust22,2017.2.EAUGuidelinesonNon-muscle-invasiveBladderCancer./guideline/non-muscle-invasive-bladder-cancer/#7.AccessedAugust22,2017.3.EAUGuidelinesonMuscle-invasiveBladderCancer./guideline/bladder-cancer-muscle-invasive-and-metastatic/#7AccessedAugust22,2017.4.Bellmuntetal.AnnOncol2014;25:iii40-iii48,不适合接受顺铂治疗PembroAtezo,Pembrolizumab、Nivolumab膀胱癌适应症未在中国大陆地区获批Atezolizumab、Durvalumab、Avelumab未在中国大陆上市地区获批上市,目前已制定了强有力的临床研究计划以评价Pembrolizumab在早期和晚期膀胱癌中的应用,Cis=原位癌;NMIBC=非肌层浸润膀胱癌;ORR=客观缓解率;OS=总生存;PFS=无进展生存;RFS=无复发生存;SD=疾病稳定;TURBT=经尿道膀胱肿瘤切除术.NotesviewshowsNCTnumbersorlatestdatapresentations.,低风险NMIBC,中-高风险NMIBC(包括CIS),局部晚期MIBC,2线/复发转移性KN-045III期IMvigor210c2II期IMvigor211III期CM-032CM-275DurvaI/II期AvelumabI期,TURBT+单药,围手术期,膀胱内化疗,1线治疗(卡介苗),维持治疗(卡介苗),卡介苗难治性KN-057II期AtezoI/II期,新辅助治疗,辅助治疗KN-123III期IMvigor010III期CM-274III期DurvaIII期,适合接收顺铂治疗,不适合接受顺铂治疗KN-052II期IMvigor210C1II期,在获得缓解/SD后给予维持治疗JAVELINBladder100III期,膀胱切除术,非肌层浸润膀胱癌,肌层浸润膀胱癌,转移性膀胱癌,适合接受顺铂治疗：PFS7个月、OS14个月、ORR43%50%不适合接受顺铂治疗：当前的标准治疗：PFS6个月,OS9个月,ORR40%当前的2线Atezolizumab标准治疗：PFS2.1-2.6个月、OS7.9个月、ORR16%当前的2线Pembrolizumab标准治疗：PFS2.1个月、OS10.3个月、ORR21.1%,辅助治疗:当前的标准治疗：3年RFS率为40%50%,OS为6.4年,卡介苗难治性：目前的标准治疗：对卡介苗治疗失败的患者经2线化疗后，RFS100%,新病灶停药,IC2/3PR/CR,Atezolizumab未在中国大陆地区获批上市,是否考虑应用irRECIST?,能否找到某种优于PD-L1IHC的生物标记物？,PD-L1阳性细胞(肿瘤,炎症细胞),KEYNOTE052(发现集)1,KEYNOTE045(验证集)2,采用PD-L122C3IHC分析方法测得的CPS,BalarAV,etal.LancetOncol.2017;18:1483-1492.2.BellmuntJ,etal.NEnglJMed.2017;376:1015-1026.,敏感性,1.0,0.8,0.6,0.4,0.2,0,0,1.0,0.8,0.6,0.4,0.2,特异性,经证实或未经证实的最佳总缓解,ROCAUC:0.62(95%CI:0.49-0.75),1.000(0.377-0.739),5.000(0.638-0.565),10.000(0.754-0.522),ORR(%;95%CI),0,5,10,15,20,25,30,35,40,Pembrolizumab(N=270),Pembrolizumab(N=74),总体人群,CPS10%的人群,14.1,14.9,7.0,6.8,21.1%,21.6%,CR,PR,CR,PR,Pembrolizumab膀胱癌适应症未在中国大陆地区获批,何种亚组患者对抗PD-1/L1治疗反应最佳？尚无定论,50,25,0,75,100,患者(%),Luminal2(Cluster2)n=55,Basal1(Cluster3)n=23,Basal2(Cluster4)n=33,Luminal1(Cluster1)n=66,Atezolizumab2,Nivolumab1,Luminal,Basal,1.GalskyJ,etal.ESMO2016.AbstractLBA31_PR.2.RosenbergJE,etal.Lancet.2016;387:1909-1920.,60.6,24.2,15.1,30.4,39.1,21.7,8.7,41.8,59.1,30.9,22.7,25.4,16.6,50,25,0,75,100,患者(%),TCGA亚型,Luminal,Basal,ClusterI,ClusterII,ClusterIII,ClusterIV,TCGA亚型患者的肿瘤缓解,n=72,n=50,n=38,n=35,Atezolizumab未在中国大陆上市地区获批上市Nivolumab膀胱癌适应症未在中国大陆地区获批,与对于接受Atezolizumab治疗的患者，较高的突变负荷与ORR和OS改善相关,这种相关性具有统计学意义，并且独立于其他预测疗效的因子,所有患者(n=150),肿瘤突变负荷/MB,0,10,20,30,40,获得缓解的患者未获得缓解的患者,100,75,50,25,0,100,75,50,25,0,P=.0012*,P=.0079*,Q4,Q4,0,200,400,600,0,200,400,600,队列2铂类治疗失败的mUC患者的二线治疗,队列1不适合接受顺铂治疗的mUC患者的一线治疗,天,天,*Q4vsQ1,Q2,Q3.,OS概率(%),OS概率(%),中位肿瘤突变负荷四分位数(范围)Q4(16.0-62.2)Q3(8.1-16.0)Q2(5.4-8.1)Q1(0.9-5.4),中位肿瘤突变负荷四分位数(范围)Q4(13.5-46.8)Q3(9.0-13.5)Q2(5.4-9.0)Q1(0-5.4),RosenbergJE,etal.ASCO2016.Abstract104.,Atezolizumab未在中国大陆地区获批上市,小结,对于不适合接受顺铂治疗的患者，免疫治疗（Pembrolizumab或Atezolizumab）可作为一线治疗选择；尚无与卡铂进行头对头比较的研究数据对于铂类治疗失败的患者，各种抗PD-1免疫检查点抑制剂的疗效均相似ORR约为20%，某些患者获得了完全缓解和持久缓解总体毒性低于化疗极少发生治疗相关死亡（与KEYNOTE-045试验化疗组相似）患者可能无需接受长期治疗在停药后，患者获得的肿瘤缓解仍可持续存在；患者停药后再次给予免疫治疗仍能获得缓解免疫治疗的最佳疗程尚不确定在对患者进行选择时，PD-L1检测（无论采用何种方法）并非是一种有效的手段正在开展关于替代生物标记物的研究,Pembrolizumab、Nivolumab膀胱癌适应症未在中国大陆地区获批Atezolizumab、Durvalumab、Avelumab未在中国大陆上市地区获批上市,PD-1抑制剂在晚期肾癌的应用二线,在晚期肾细胞癌（aRCC）患者中比较分析纳武单抗与依维莫司的疗效与患者总生存（OS）的相关性：来自CheckMate025III期临床研究的结果,Correlationofresponsewithoverallsurvival(OS)fornivolumabvseverolimusinadvancedrenalcellcarcinoma(aRCC):ResultsfromthephaseIIICheckMate025studyMotzerRJ,etal.2016ASCOAnnualMeeting.June3-72016,abstractno.4552PosterSession(Board#174),Checkmate-025研究设计,研究背景CheckMate025是一项随机、III期临床研究。研究已经达到主要终点，证实纳武单抗（NIVO）的生存获益显著优于依维莫司（EVE）研究目的旨在评估CheckMate025研究中肿瘤的缓解情况与两个治疗组（NIVOvsEVE）OS获益之间的相关性,MotzerRJ,etal.2016ASCOAnnualMeeting.June3-72016,abstractno.4552PosterSession(Board#174),亚组：根据随机后4个月时的最佳缓解评估（BOR）将患者分组完全/部分缓解（缓解者）疾病稳定（SD）疾病进展（PD）中断治疗、死亡或治疗4个月时疗效无法评估的患者不纳入亚组分析,Checkmate-025研究结果,MotzerRJ,etal.2016ASCOAnnualMeeting.June3-72016,abstractno.4552PosterSession(Board#174),Checkmate-025研究结果,MotzerRJ,etal.2016ASCOAnnualMeeting.June3-72016,abstractno.4552PosterSession(Board#174),PFS无差异，但是免疫治疗的拖尾效应导致OS获益显著,PD-1抑制剂在晚期肾癌的应用一线,一线研究汇总,*Thistrialalsoincludesasecondinvestigationalarmoflenvatinib+everolimus.C/NCT02420821.C/NCT02684006.C/NCT02853331.C/NCT02811861.C/NCT02231749.,IMmotion151Atezolizumab+贝伐株单抗vs舒尼替尼治疗晚期/转移性初治RCC的III期临床研究,Atezolizumab+bevacizumabispendingapprovalintheEU.*1%IC:40%prevalenceusingSP142IHCassay.Nodosereductionforatezolizumaborbevacizumab.C.NCT02420821.AccessedSeptember13,2018.MotzerRJetal.OralpresentationatASCOGU2018.Abstract578.,IMmotion151PD-L1+人群的PFS*(最短随访12个月),Atezo+bev,AdaptedwithpermissionfromMotzeretal,2018.,Atezolizumab+bevacizumabispendingapprovalintheEU.*PFSassessedbyinvestigators.Minimumfollow-up,12mo.Medianfollow-up,15mo.ThePFSanalysispassedthepre-specifiedp-valueboundaryofalpha=0.04.MotzerRJetal.OralpresentationatASCOGU2018.Abstract578.,IMmotion151ITT人群的OS*(最短随访12个月),No.atrisk,1.0,0.9,0.8,0.7,0.6,0.5,0.4,0.3,0.2,0.1,0,0,3,6,9,12,15,18,21,24,27,Time(months),OverallSurvival,454,428,398,371,341,246,141,69,18,461,422,384,357,331,227,126,65,15,Atezo+bev,Sunitinib,OSdataareimmature;29%ofpatientshadanOSeventatdatacutoff,AdaptedwithpermissionfromMotzeretal,2018.,Atezolizumab+bevacizumabispendingapprovalintheEU.*Minimumfollow-up,12mo.Medianfollow-up,15mo.Event/patientratio:27%foratezo+bev,31%forsunitinib.TheOSanalysisdidnotpassthePvalueboundaryofalpha=0.0009atthefirstinterimanalysis.MotzerRJetal.OralpresentationatASCOGU2018.Abstract578.,IMmotion151PD-L1+人群的OS*(最短随访12个月),Atezolizumab+bevacizumabispendingapprovalintheEU.*Minimumfollow-up,12mo.Medianfollow-up,15mo.Event/patientratio:27%foratezo+bev,31%forsunitinib.TheOSanalysisdidnotpassthePvalueboundaryofalpha=0.0009atthefirstinterimanalysis.MotzerRJetal.OralpresentationatASCOGU2018.Abstract578.,1.0,0.8,0.6,0.4,0.2,0,0,3,6,9,12,15,18,21,24,27,Time(months),OverallSurvival,0.9,0.7,0.5,0.3,0.1,OSdataareimmature;30%ofpatientshadanOSeventatdatacutoff,AdaptedwithpermissionfromMotzeretal,2018.,Checkmate214Nivolumab+IpilimumabVS舒尼替尼治疗晚期/转移性初治RCC的III期临床研究,Nivolumab+ipilimumabfollowedbynivolumabmaintenanceisnotyetapprovedas1LtherapyintheEU.*Patientcharacteristicsareshownfortheprimaryefficacypopulation;favourableriskpatientswereincludedinthesafetypopulation.1.C.NCT02231749.AccessedSeptember13,2018.2.MotzerRJetal.NEnglJMed.2018;378(14):1277-1290.,Checkmate214IMDC中高危人群的OS(中位随访25.2个月),Nivolumab+ipilimumabfollowedbynivolumabmaintenanceisnotyetapprovedas1LtherapyintheEU.Medianfollowup:25.2months.BasedondatacutoffofAugust7,2017.2MotzerRJetal.NEnglJMed.2018;378(14):1277-1290.,AdaptedwithpermissionfromMotzeretal,2018.,Checkmate214IMDC中高危人群的ORR,Nivolumab+ipilimumabfollowedbynivolumabmaintenanceisnotyetapprovedas1LtherapyintheEU.*IRRC-assessedORRandBORbyRECISTv1.1.P0.001forbothORRandCR.Unabletodetermine/notreported.MotzerRJetal.NEnglJMed.2018;378(14):1277-1290.,Checkmate214IMDC中高危人群的PFS*(中位随访25.2个月),Nivolumab+ipilimumabfollowedbynivolumabmaintenanceisnotyetapprovedas1LtherapyintheEU.*IRRC-assessed.MotzerRJetal.NEnglJMed.2018;378(14):1277-1290.,NumericalimprovementinPFSinIMDCintermediate/poorriskpatientsdidnotreachstatisticalsignificance,AdaptedwithpermissionfromMotzeretal,2018.,不同PD-L1表达水平的OS分析:IMDC中高危人群1,2*(中位随访25.2个月),Nivolumab+ipilimumabfollowedbynivolumabmaintenanceisnotyetapprovedas1LtherapyintheEU.*Medianfollowup:25.2months.BasedondatacutoffofAugust7,2017.1.MotzerRJetal.NEnglJMed.2018;378(14):1277-1290supplementaryappendix.2.MotzerRJetal.NEnglJMed.2018;378(14):1277-1290.,AdaptedwithpermissionfromMotzeretal,2018.,ASCO-GU更新KN-426和CM-214,Keytruda+Axitinib:ORR59.3%，OSHR0.53Nivolumab+ipilimumab：ORR41%，OSHR0.71,EAU指南对晚期RCC患者的治疗推荐更新(2018),EAU指南推荐nivolumab+ipilimumab用于治疗1L中高危患者Cabozantinib,sunitinib,或pazopanib*也被推荐用于治疗1L中高危RCC，但未列入强烈推荐Sunitinib或pazopanib依然被推荐用于治