肿瘤免疫治疗超进展

HPDinICIsandOtherTherapies内容ICIs治疗HPD其他治疗HPD（类似症状）ICIs治疗的阿克琉斯之踵？PresentedByChristopheLeTourneauat2018ASCOAnnualMeeting真实的存在，还是假象？超进展的定义其他参数：TTF<2month>50%TBincreaseB>=1.4or(1.2+newlesion)B>=1.5withR/MA=B=体积直径PresentedByChristopheLeTourneauat2018ASCOAnnualMeeting超进展的发生率YearJournalFirstAuthorTumorNo.DrugTG（volorpace）TTPRateNote2017ClinCancerResStephaneChampiatmulti131PD1/PD-L1>=29%2017ClinCancerResShumeiKatomulti155CTLA-4,PD-1/PD-L1>=2<=2month4%Allhyperprogressorsweretreatedwithanti-PD1/PDL1monotherapy.Patientswhoreceivedananti-CTLA-4(aloneorcombinedwithanti-PD1/PDL1)weresignificantlylesslikelytohaveaTTFlessthantwomonths,andnonewerehyperprogressors2017AnnOncologyE.Saâda-BouzidR/MHNSCC34PD1/PD-L1TGKR≥2斜率29%2017IASLCG.Martinez-BernalNSCLC333≥216%ID102222018ASCOYadaKanjanapanmulti182≥27%3063.TherewasnoassociationbetweenHPDandCSAEs,age,tumourtypeortypeofIOtherapy.2018ASCOIgnacioMatosmulti214PD1/PD-L1>=1.4or(1.2+newlesion)<2month15%3032.HPDwasnotassociatedwithage,tumortype,ICIregimens,previousICIormetastaticsite(Fishertest).超进展发生预测不同研究结果不一致超进展（Hyperprogression，HP）定义1.在免疫检查点抑制剂治疗后第一次评估时即进展，

或TTF<2个月2.肿瘤体积增大超过50%3.肿瘤增长速度2倍易发生超进展的相关基因扩增11q13（CCND1,FGF3,FGF4以、FGF19）扩增MDM2/MDM4扩增EGFR扩增ClinCancerRes.2017Apr15;23(8):1920-1928.ClinCancerRes.2017Aug1;23(15):4242-4250AnnalsofOncology.201728(suppl_5):v403-v427.10.1093/annonc/mdx3764例MDM2amp患者超进展发生预测ICBsIFNJAK-STATIRF8MDM2/4P53EGFRPD-L11.2.代偿3.免疫治疗超进展可能机制根据CCR（ShumeiKatoetal.2017）研究，EGFR扩增而非突变是出现HP的可能原因免疫检查点抑制剂可以导致IFN-γ上调，通过激活JAK-STAT通路诱导干扰素调节因子-8（IRF-8）的表达，结合于MDM2的启动子诱导MDM2表达，抑制p53基因。目前推测，当MDM2没有扩增时，这种级联反应没有显著影响；当MDM2扩增时，HP就发生了。免疫治疗药物阻滞了PD-1/PD-L1信号通路之后，其它信号通路得以异常激活，从而导致肿瘤快速生长。ClinCancerRes.2017Apr15;23(8):1920-1928.ClinCancerRes.2017Aug1;23(15):4242-4250面临的问题标准不统一；没有对照组；没有未治疗的肿瘤生长数据。本研究中超进展定义：Thetumorgrowthrate(TGR)beforeandduringtreatmentandvariationpermonth(ΔTGR)werecalculated.HyperprogressivediseasewasdefinedasdiseaseprogressionatthefirstevaluationwithΔTGRexceeding50%.本研究定位：ThepresentstudyisthelargestanalysisexploringHPDtodateandisthefirstconductedinadedicatedNSCLCpopulation.Inaddition,webelievethatthisistheonlystudytoincludeacontrolcohortofchemotherapytreatedpatients.JAMAOncol.PublishedonlineSeptember6,2018.doi:10.1001/jamaoncol.2018.3676解决对照组问题P：406eligiblepatientstreatedwithPD-1/PD-L1inhibitors；

59eligiblepatientstreatedwithchemotherapy,I：PD-1/PD-L1inhibitorsC：chemotherapyO：HPD至少3次CT：治疗前，基线，治疗中间隔至少2weeks研究设计JAMAOncol.PublishedonlineSeptember6,2018.doi:10.1001/jamaoncol.2018.3676年龄无关超进展发生相关性研究JAMAOncol.PublishedonlineSeptember6,2018.doi:10.1001/jamaoncol.2018.3676EGFR无关超进展发生相关性研究JAMAOncol.PublishedonlineSeptember6,2018.doi:10.1001/jamaoncol.2018.3676超进展发生相关性研究治疗前转移数相关JAMAOncol.PublishedonlineSeptember6,2018.doi:10.1001/jamaoncol.2018.3676超进展在ICIs治疗和化疗中发生的比例13.8%5.1%JAMAOncol.PublishedonlineSeptember6,2018.doi:10.1001/jamaoncol.2018.3676ICIs治疗HPD组OS差化疗HPD组OS无差异JAMAOncol.PublishedonlineSeptember6,2018.doi:10.1001/jamaoncol.2018.3676JO论文小结：ICIs治疗HPD发生率13.8%，化疗HPD发生率5.1%；ICIs治疗HPD与OS相关，变差；ICIs治疗HPD与年龄无关，与EGFR无关；ICIs治疗HPD与免疫治疗前的转移个数相关。JAMAOncol.PublishedonlineSeptember6,2018.doi:10.1001/jamaoncol.2018.3676ICIs治疗HPD现有数据讨论：解决对照问题；评估标准不统一；没有无干扰状态肿瘤的生长数据；ICIs治疗HPD发生率可能更高，早期死亡事件没有计入；机制不清楚；mPFS不是ICIs治疗的好终点。其他治疗类似HPDDiseaseflarewasdefinedashospitalizationordeathattributabletodiseaseprogressionduringthewashoutperiod.Fourteenof61patients(23%;95%CI:14–35)experiencedadiseaseflare.ClinCancerRes.2011Oct1;17(19):6298-303.DiseaseflarewasdefinedashospitalizationordeathattributabletotumorprogressionafterstoppingtheTKIandbeforeinitiationofsubsequenttherapy;thewashoutintervalwas≤21days.Twentyof227(8.8%)patientsweredefinedasdiseaseflareafterEGFRTKIcessationPatholOncolRes.2013Oct;19(4):833-8.Diseaseflarewasdefinedasunexpectedinterventions(e.g.radiationtherapyorpleuraldrainage),hospitalizatio