5、消化系统肿瘤消化系统肿瘤 (4).pdf
《5、消化系统肿瘤消化系统肿瘤 (4).pdf》由会员分享,可在线阅读,更多相关《5、消化系统肿瘤消化系统肿瘤 (4).pdf(7页珍藏版)》请在得力文库 - 分享文档赚钱的网站上搜索。
1、APhase2Multi-institutionalStudyofNivolumabforPatientsWithAdvancedRefractoryBiliaryTractCancerRichardD.Kim,MD;VincentChung,MD;OlatunjiB.Alese,MD;BassellF.El-Rayes,MD;DanengLi,MD;TaymeyahE.Al-Toubah,BS;MichaelJ.Schell,PhD;Jun-MinZhou,BS;AmitMahipal,MD;BaekHuiKim,MD;DaeWonKim,MDIMPORTANCECurrently,ther
2、eisnoestablishedsecond-linesystemictreatmentforbiliarytractcancer(BTC).Preclinicaldatahavedemonstratedthatthepresenceoftumor-infiltratingCD8Tcellsandprogrammedcelldeath1ligand1expressingtumorcellsinthetumormicroenvironmentofBTCsupportstherationaleofusingprogrammedcelldeath1proteinblockadeimmunothera
3、pyinBTC.OBJECTIVEToevaluateanticanceractivityofnivolumabinpatientswithadvancedrefractoryBTC.DESIGN,SETTING,AND PARTICIPANTSInthissingle-group,multicenterphase2studyofnivolumab,54patientswithhistologicallyconfirmedBTCwhosediseaseprogressedwhileundergoingtreatmentwithatleast1linebutnomorethan3linesofs
4、ystemictherapywereenrolledbetweenOctober5,2016,andDecember26,2018.Analysiswasperformedonanintention-to-treatbasis.INTERVENTIONSNivolumab,240mg,wasdeliveredintravenouslyevery2weeksfor16weeks,andthen480mgwasdeliveredintravenouslyevery4weeksuntildiseaseprogressionorunacceptabletoxiceffectsoccurred.MAIN
5、 OUTCOMES AND MEASURESTheprimaryendpointwasinvestigator-assessedobjectiveresponserate,andthesecondaryendpointswereprogression-freesurvival,overallsurvival,andincidenceofadverseevents.RESULTSAtotalof54patients(27menand27women;medianage,65yearsrange,28-86years)enrolled,and46(22menand24women;medianage,
6、65yearsrange,28-86years)wereexaminedforobjectiveresponsewithradiologicimaging.Theinvestigator-assessedobjectiveresponseratewas22%(10of46),including1unconfirmedpartialresponse,withadiseasecontrolrateof59%(27of46).Centralindependentreviewfoundanobjectiveresponserateof11%(5of46),including1unconfirmedpa
7、rtialresponse,withadiseasecontrolrateof50%(23of46).Allpatientswhorespondedtotreated(hereafterreferredtoasresponders)hadmismatchrepairproteinproficienttumors.Themediandurationofinvestigator-assessedresponsewasnotreached,withamedianfollow-upof12.4months.Amongtheintention-to-treatpopulation,medianprogr
8、ession-freesurvivalwas3.68months(95%CI,2.30-5.69months)andmedianoverallsurvivalwas14.24months(95%CI,5.98monthstonotreached).Programmedcelldeath1ligand1expressionintumorswasassociatedwithprolongedprogression-freesurvival(hazardratio,0.23;95%CI,0.10-0.51;P .001).Themostcommontreatment-relatedgrade3or4
9、toxiceffectswerehyponatremia(3of546%)andincreasedalkalinephosphatase(2of544%).CONCLUSIONS AND RELEVANCEThisstudyfoundthatnivolumabwaswelltoleratedandshowedmodestefficacywithdurableresponseinpatientswithrefractoryBTC.Furtherstudiesarewarrantedtoverifythefindingsandevaluatebiomarkersforimprovedtreatme
10、ntselectionforpatients.TRIAL REGISTRATIONClinicalTrials.govIdentifier:NCT02829918JAMAOncol.doi:10.1001/jamaoncol.2020.0930PublishedonlineApril30,2020.SupplementalcontentAuthorAffiliations:Authoraffiliationsarelistedattheendofthisarticle.CorrespondingAuthor:RichardD.Kim,MD,DepartmentofGastrointestina
11、lOncology,H.LeeMoffittCancerCenter,12902MagnoliaDr,FOB-2,Tampa,FL33612(richard.kimmoffitt.org).ResearchJAMAOncology|OriginalInvestigation(Reprinted)E1 2020 American Medical Association.All rights reserved.Downloaded From:https:/ a Shanghai Jiaotong University User on 05/14/2020Biliary tract cancers(
12、BTCs)comprise malignant intra-hepaticandextrahepaticcholangiocarcinomasandgall-bladder cancers.They are uncommon malignant neo-plasms:an estimated 12360 patients received a diagnosis ofextrahepatic cholangiocarcinoma and gallbladder cancer in2019 in the United States.1The exact incidence of intrahe-
13、paticcholangiocarcinomaisunknownsinceitisgroupedwithprimary liver cancer.The prognosis of BTCs is dismal,with a5-yearsurvivalrateofonly10%.2Surgicalresectionistheonlycurative modality for localized disease.The treatment ofunresectable,recurrent,or metastatic disease remains chal-lenging.Although gem
14、citabine plus cisplatin has demon-strated significant antitumor activity as first-line therapy formetastaticBTC,3toourknowledgethereisnoestablishedsys-temictherapyafterfailureofgemcitabinepluscisplatin.Intherecent ABC-06(Advanced Biliary Cancer-06)study,FOLFOX(folinicacid,fluorouracil,andoxaliplatin
15、)wasevaluatedassec-ond-linetreatmentafterprogressionwhengivengemcitabinepluscisplatin,anditdemonstratedonlyamodest1-monthsur-vivalbenefitvsactivesymptomcontrol.4Noveleffectivethera-peutic approaches are needed for improvement in the clini-cal outcomes of patients with BTCs.Nivolumabisahumanimmunoglo
16、bulinG4monoclonalan-tibodythatblockstheligationofprogrammedcelldeath1pro-tein(PD-1)and programmed cell death 1 ligand 1(PD-L1).Pro-grammed cell death 1 protein is a transmembrane proteinexpressed on T cells,and it interacts with its ligand PD-L1 ex-pressedoncancercells,leadingtoinhibitionofT-cellpro
17、lifera-tion and activation and apoptosis of antigen-specific T cells.5With the success of PD-1 blockade immunotherapy in mela-noma,nivolumab has been extensively studied in the treat-mentofmultipletumortypes,andemergingclinicaldatahavedemonstrateddurableclinicalactivityandsafetyofnivolumabinvariousc
18、ancers.However,onlylimiteddataarereportedonthe role of immune checkpoint inhibitors in BTC owing to therarity of the disease.Programmed cell death 1 ligand 1 expres-sionandinfiltrationofCD8Tcellsinthetumormicroenviron-menthavebeenreportedaspotentialbiomarkersofPD-1block-ade immunotherapy in several
19、cancers.6,7A recent studydemonstratedthepresenceoftumor-infiltratingCD8TcellsandPD-L1expressingtumorcellsinthetumormicroenvironmentof BTC.8These data support the rationale of using PD-1 block-adeimmunotherapyinBTC.Onthebasisofpreclinicaldata,weconducted a phase 2 study to evaluate the safety and eff
20、icacyof nivolumab for patients with advanced refractory BTC.MethodsThe study was an investigator-initiated,multi-institutional(Moffitt Cancer Center,City of Hope,and Winship CancerInstituteofEmoryUniversity),open-label,single-groupphase2 study designed to evaluate the safety,tolerability,and effi-ca
21、cyofnivolumabforpatientswithadvancedBTCs,whowereenrolledbetweenOctober5,2016,andDecember26,2018.ThestudywasapprovedbytheMoffittCancerCenter,CityofHope,and Winship Cancer Institute of Emory University institu-tional review boards,and all patients provided written in-formed consent prior to enrollment
22、.This study followed theTransparent Reporting of Evaluations With NonrandomizedDesigns(TREND)reportingguideline.Thestudywasconductedin compliance with the trial protocol(Supplement 1).PatientSelectionandTreatmentPertinenteligibilitycriteriawerehistologicallyconfirmedun-resectable or metastatic chola
23、ngiocarcinoma or gallbladdercancers,refractory or intolerant to at least 1 line of systemictherapybutnomorethan3priorlinesofsystemictherapy,age18 years or older,Eastern Cooperative Oncology Group per-formance status of 0 or 1,and adequate organ function.Allpatients received a flat dose of nivolumab,
24、240 mg,intrave-nously every 2 weeks for 16 weeks and then 480 mg intrave-nously every 4 weeks until disease progression or unaccept-able toxic effects occurred.EvaluationTumor assessment was performed with computed tomogra-phy and/or magnetic resonance imaging at baseline and ev-ery8weeksuntildiseas
25、eprogressionortreatmentdiscontinu-ation.Objective response rate(ORR)was evaluated usingResponse Evaluation Criteria in Solid Tumors,version 1.1(RECIST v1.1)9and iRECIST10criteria by the local investiga-torsandcentrallyreviewedbyindependentradiologists.Sur-vival was monitored every 12 weeks after dis
- 配套讲稿:
如PPT文件的首页显示word图标,表示该PPT已包含配套word讲稿。双击word图标可打开word文档。
- 特殊限制:
部分文档作品中含有的国旗、国徽等图片,仅作为作品整体效果示例展示,禁止商用。设计者仅对作品中独创性部分享有著作权。
- 关 键 词:
- 5、消化系统肿瘤消化系统肿瘤 4 消化系统 肿瘤
限制150内