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2017ESMO肺癌免疫治疗进展同济大学附属上海市肺科医院陈晓霞2017.10.21，上海主要内容•惊天海啸：PACIFIC研究•又现曙光：血液肿瘤突变负荷（bTMB）研究•王者依旧：Checkmate017和Checkmate057三年随访分析esmo.orgPACIFIC研究:DURVALUMAB对照安慰剂在III期局部进展期不可切除的非小细胞肺癌同步放化疗后巩固治疗的一项双盲三期临床研究LuisPaz-Ares1,AugustoVillegas2,DaveyDaniel3,DavidVicente4,ShujiMurakami5,RinaHui6,TakashiYokoi7,AlbertoChiappori8,KiHyeongLee9,MaikedeWit10,ByoungChulCho11,MaryamBourhaba12,XavierQuantin13,TakaakiTokito14,TarekMekhail15,DavidPlanchard16,HaiyiJiang17,YifanHuang17,PhillipA.Dennis17,MustafaÖzgüroğlu18Acknowledgement:Dr.ScottJ.AntoniaofH.LeeMoffittCancerCenterandResearchInstituteistheleadauthorforthisstudy;Dr.Paz-Aresispresentingonhisbehalf1HospitalUniversitario12deOctubre,CiberOnc,UniversidadComplutenseandCNIO,Madrid,Spain;2CancerSpecialistsofNorthFlorida,Jacksonville,FL,USA;3TennesseeOncology,Chattanooga,TN,andSarahCannonResearchInstitute,Nashville,TN,USA;4HospitalUniversitarioVirgenMacarena,Seville,Spain;5KanagawaCancerCenter,Yokohama,Japan;6WestmeadHospitalandtheUniversityofSydney,Sydney,NSW,Australia;7KansaiMedicalUniversityHospital,Hirakata,Japan;8H.LeeMoffittCancerCenterandResearchInstitute,Tampa,FL,USA;9ChungbukNationalUniversityHospital,ChungbukNationalUniversityCollegeofMedicine,Cheongju,Korea;10VivantesKlinikumNeukoelln,Berlin,Germany;11YonseiCancerCenter,YonseiUniversityCollegeofMedicine,Seoul,Korea;12CentreHospitalierUniversitairedeLiège,Liège,Belgium;13CHUMontpellierandICMVald'Aurelle,Montpellier,France;14KurumeUniversityHospital,Kurume,Japan;15FloridaHospitalCancerInstitute,Orlando,FL,USA;16GustaveRoussy,Villejuif,France;17AstraZeneca,Gaithersburg,MD,USA;18IstanbulUniversityCerrahpasaSchoolofMedicine,Istanbul,Turkey背景•初诊时III期不可切除的非小细胞肺癌患者约占全部NSCLC患者的1/31•以含铂双药为基础的同步放化疗是对于状态良好的III期不可切除的非小细胞肺癌患者的标准治疗•从同步放化疗(cCRT)开始，这部分患者的中位无进展生存时间约为8-10个月，5年生存率约为15%1–6•近年来，对于进展期非小细胞肺癌患者的治疗进展缓慢7–9;III期不可切除的NSCLC患者，如何在cCRT之后应用新的治疗手段进一步改善生存获益,存在未被满足的临床需求。•PACIFIC研究是第一个在III期局部进展不可切除的患者人群中采用免疫检查点抑制剂治疗并进行疗效评估的三期随机对照研究cCRT,concurrentchemoradiationtherapy;PFS,progression-freesurvival;NSCLC,non-smallcelllungcancer;SOC,standardofcare.1.AupérinA,etal.JClinOncol2010;28:2181–90;2.YoonSM,etal.WorldJClinOncol2017;8:1–20;3.AhnJS,etal.JClinOncol2015;33:2660–6;4.FuruseJ,etal.ClinOncol1999;17:2692–9;5.BelderbosJ,etal.EurJCancer2007;43:114–21;6.ClamonG,etal.JClinOncol1999;17:4–11;7.NCCNguidelinesforNSCLCV4.2017.Availableat:(accessedJune2017);8.Vansteenkiste,J.,etal.AnnOncol2013;24(Suppl6):vi89-98;9.TsujinoK,etal.JThoracOncol2013;8:1181–9Durvalumab阻断PD-L1与PD-1和CD80的结合ImmunecellTumorcellTcellTumorantigenMHCITCRMHCIITCRPD-1PD-L1InhibitionXCD80PD-L1CD80InhibitionXActivationCD28CD80PD-1PD-L1TumorantigenDurvalumab1是人源化IgG1单克隆抗体,灭活了ADCC效应，主要作用原理是阻断PD-1/L1抑制信号通路，增强效应性T细胞的杀伤功能。mAb,monoclonalantibody;MHC,majorhistocompatibilitycomplex;PD-1,programmedcelldealth-1;PD-L1,programmedcelldeathligand-1;TCR,T-cellreceptor1.StewartR,etal.CancerImmunolRes2015;3:1052-62DurvalumabPACIFIC:研究设计三期随机双盲安慰剂对照的多中心研究*Definedasthetimefromrandomization(whichoccurredupto6weekspost-cCRT)tothefirstdocumentedeventoftumorprogressionordeathintheabsenceofprogression.ClinicalTrials.govnumber:NCT02125461BICR,blindedindependentcentralreview;cCRT,concurrentchemoradiationtherapy;DoR,durationofresponse;NSCLC,non-smallcelllungcancer;ORR,objectiveresponserate;OS,overallsurvival;PFS,progression-freesurvival;PROs,patient-reportedoutcomes;PS,performancestatus;q2w,every2weeks;RECIST,ResponseEvaluationCriteriainSolidTumors;WHO,WorldHealthOrganization•Ⅲ期局部进展期不可切除的NSCLC，经过至少2个周期的同步放化疗后没有疾病进展•18岁以上（包含）•PS评分0-1•预计生存12周以上•收集患者的组织标本Durvalumab10mg/kgq2wforupto12monthsN=476Placebo10mg/kgq2wforupto12monthsN=2372:1随机分组,分层因素：年龄、性别、吸烟史N=713次要研究终点•ORR(perBICR)•DoR(perBICR)•安全性和耐受性•PROs主要研究终点PFS(BICR应用RECISTv1.1标准)*OSRcCRT之后1-42天统计分析•计划样本量:N=702(2:1随机化)•共同主要研究终点:PFS、OS•PFS假设:研究应用双侧α0.025，对458例事件进行HR为0.67的log-rank检验，把握度≥95%•计划在~367(80%)例事件发生后进行PFS的中期分析（IA）•实际IA在371例事件后进行，并对PFS分析结果进行了报道•OS假设:研究应用双侧α0.025，对491例事件进行HR为0.73的log-rank检验，把握度≥85%•研究目前仍对OS保持盲态，对于OS的最终分析计划在目标事件数完成后开始HR,hazardratio;ITT,intention-to-treat;OS,overallsurvival;PFS,progression-freesurvival基线特征(ITT)Durvalumab(N=476)Placebo(N=237)年龄中位数(范围),年≥65岁,%64(31–84)45.264(23–90)45.1男性,%70.270.0WHOPS评分,%*0/149.2/50.448.1/51.5吸烟状态,%吸烟/曾经/从不16.6/74.4/9.016.0/75.1/8.9疾病分期,%†IIIA/IIIB52.9/44.552.7/45.1组织类型,%鳞癌/非鳞癌47.1/52.943.0/57.0PD-L1状态,%已知:TC25%/TC≥25%未知‡39.3/24.236.644.3/18.637.1既往经过化疗,%Induction/DefinitivecCRT25.8/99.828.7/99.6既往经过放疗,%*54Gy54to≤66Gy66to≤74Gy0.692.96.3091.68.0对于既往cCRT,的反应%¶CR/PR/SD/PD1.9/48.7/46.6/0.43.0/46.8/48.1/0*Notreportedormissing(durvalumab,placebo,total):WHOperformancestatus(0.4%each),priorradiotherapy(0.2%,0.4%,0.3%).†Other:durvalumab,2.5%;placebo,2.1%;total,2.4%.‡Nosamplecollectedornovalidtestresult.¶Notevaluable/notapplicable:durvalumab,2.3%;placebo,2.1%;total,2.2%.cCRT,concurrentchemoradiationtherapy;CR,completeresponse;ITT,intention-to-treat;PD,progressivedisease;PD-L1,programmedcelldeathligand-1;PR,partialresponse;SD,stabledisease;TC