腫瘤免疫治療超進(jìn)展

HPDinICIsandOtherTherapies內(nèi)容ICIs治療HPD其他治療HPD（類(lèi)似癥狀）ICIs治療的阿克琉斯之踵？PresentedByChristopheLeTourneauat2018ASCOAnnualMeeting真實(shí)的存在，還是假象？超進(jìn)展的定義其他參數(shù)：TTF<2month>50%TBincreaseB>=1.4or(1.2+newlesion)B>=1.5withR/MA=B=體積直徑PresentedByChristopheLeTourneauat2018ASCOAnnualMeeting超進(jìn)展的發(fā)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.Saada-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).超進(jìn)展發(fā)生預(yù)測(cè)不同研究結(jié)果不一致超進(jìn)展（Hyperprogression，HP）定義1.在免疫檢查點(diǎn)抑制劑治療后第一次評(píng)估時(shí)即進(jìn)展，

或TTF<2個(gè)月2.腫瘤體積增大超過(guò)50%3.腫瘤增長(zhǎng)速度2倍易發(fā)生超進(jìn)展的相關(guān)基因擴(kuò)增11q13（CCND1,FGF3,FGF4以、FGF19）擴(kuò)增MDM2/MDM4擴(kuò)增EGFR擴(kuò)增ClinCancerRes.2017Apr15;23(8):1920-1928.ClinCancerRes.2017Aug1;23(15):4242-4250AnnalsofOncology.201728(suppl_5):v403-v427.10.1093/annonc/mdx3764例MDM2amp患者超進(jìn)展發(fā)生預(yù)測(cè)ICBsIFNJAK-STATIRF8MDM2/4P53EGFRPD-L11.2.代償3.免疫治療超進(jìn)展可能機(jī)制根據(jù)CCR（ShumeiKatoetal.2017）研究，EGFR擴(kuò)增而非突變是出現(xiàn)HP的可能原因免疫檢查點(diǎn)抑制劑可以導(dǎo)致IFN-γ上調(diào)，通過(guò)激活JAK-STAT通路誘導(dǎo)干擾素調(diào)節(jié)因子-8（IRF-8）的表達(dá)，結(jié)合于MDM2的啟動(dòng)子誘導(dǎo)MDM2表達(dá)，抑制p53基因。目前推測(cè)，當(dāng)MDM2沒(méi)有擴(kuò)增時(shí)，這種級(jí)聯(lián)反應(yīng)沒(méi)有顯著影響；當(dāng)MDM2擴(kuò)增時(shí)，HP就發(fā)生了。免疫治療藥物阻滯了PD-1/PD-L1信號(hào)通路之后，其它信號(hào)通路得以異常激活，從而導(dǎo)致腫瘤快速生長(zhǎng)。ClinCancerRes.2017Apr15;23(8):1920-1928.ClinCancerRes.2017Aug1;23(15):4242-4250面臨的問(wèn)題標(biāo)準(zhǔn)不統(tǒng)一；沒(méi)有對(duì)照組；沒(méi)有未治療的腫瘤生長(zhǎng)數(shù)據(jù)。本研究中超進(jìn)展定義：Thetumorgrowthrate(TGR)beforeandduringtreatmentandvariationpermonth(ΔTGR)werecalculated.HyperprogressivediseasewasdefinedasdiseaseprogressionatthefirstevaluationwithΔTGRexceeding50%.本研究定位：ThepresentstudyisthelargestanalysisexploringHPDtodateandisthefirstconductedinadedicatedNSCLCpopulation.Inaddition,webelievethatthisistheonlystudytoincludeacontrolcohortofchemotherapytreatedpatients.JAMAOncol.PublishedonlineSeptember6,2018.doi:10.1001/jamaoncol.2018.3676解決對(duì)照組問(wèn)題P：406eligiblepatientstreatedwithPD-1/PD-L1inhibitors；

59eligiblepatientstreatedwithchemotherapy,I：PD-1/PD-L1inhibitorsC：chemotherapyO：HPD至少3次CT：治療前，基線，治療中間隔至少2weeks研究設(shè)計(jì)JAMAOncol.PublishedonlineSeptember6,2018.doi:10.1001/jamaoncol.2018.3676年齡無(wú)關(guān)超進(jìn)展發(fā)生相關(guān)性研究JAMAOncol.PublishedonlineSeptember6,2018.doi:10.1001/jamaoncol.2018.3676EGFR無(wú)關(guān)超進(jìn)展發(fā)生相關(guān)性研究JAMAOncol.PublishedonlineSeptember6,2018.doi:10.1001/jamaoncol.2018.3676超進(jìn)展發(fā)生相關(guān)性研究治療前轉(zhuǎn)移數(shù)相關(guān)JAMAOncol.PublishedonlineSeptember6,2018.doi:10.1001/jamaoncol.2018.3676超進(jìn)展在ICIs治療和化療中發(fā)生的比例13.8%5.1%JAMAOncol.PublishedonlineSeptember6,2018.doi:10.1001/jamaoncol.2018.3676ICIs治療HPD組OS差化療HPD組OS無(wú)差異JAMAOncol.PublishedonlineSeptember6,2018.doi:10.1001/jamaoncol.2018.3676JO論文小結(jié)：ICIs治療HPD發(fā)生率13.8%，化療HPD發(fā)生率5.1%；ICIs治療HPD與OS相關(guān)，變差；ICIs治療HPD與年齡無(wú)關(guān)，與EGFR無(wú)關(guān)；ICIs治療HPD與免疫治療前的轉(zhuǎn)移個(gè)數(shù)相關(guān)。JAMAOncol.PublishedonlineSeptember6,2018.doi:10.1001/jamaoncol.2018.3676ICIs治療HPD現(xiàn)有數(shù)據(jù)討論：解決對(duì)照問(wèn)題；評(píng)估標(biāo)準(zhǔn)不統(tǒng)一；沒(méi)有無(wú)干擾狀態(tài)腫瘤的生長(zhǎng)數(shù)據(jù)；ICIs治療HPD發(fā)生率可能更高，早期死亡事件沒(méi)有計(jì)入；機(jī)制不清楚；mPFS不是ICIs治療的好終點(diǎn)。其他治療類(lèi)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