5、消化系统肿瘤消化系统肿瘤 (13).pdf

《5、消化系统肿瘤消化系统肿瘤 (13).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 (13).pdf（10页珍藏版）》请在淘文阁 - 分享文档赚钱的网站上搜索。

1、RamucirumabPlusPembrolizumabinPatientswithPreviouslyTreatedAdvancedorMetastaticBiliaryTractCancer:Nonrandomized,Open-Label,PhaseITrial(JVDF)HENDRIK-TOBIASARKENAU,a,bJUANMARTIN-LIBERAL,c,dEMILIANOCALVO,eNICOLASPENEL,fMATTHEWG.KREBS,gROYS.HERBST,hRICHARDA.WALGREN,iRYANC.WIDAU,iGUMI,iJINJIN,jDAVIDFERRY

2、,jIANCHAUkaDrug Development Unit,Sarah Cannon Research Institute UK,London,United Kingdom;bCancer Institute,University College London,London,United Kingdom;cVall dHebron Institute of Oncology,Barcelona,Spain;dCatalan Institute of Oncology(ICO),Barcelona,Spain;eEarly Clinical Drug Development Program

3、,START Madrid-HM CIOCC,Centro Integral Oncol?ogico Clara Campal,Madrid,Spain;fCentreOscar Lambret,Lille,France;gThe Christie NHS Foundation Trust and The University of Manchester,Manchester,United Kingdom;hYale University School of Medicine,Yale Cancer Center,New Haven,Connecticut,USA;iEli Lilly and

4、 Company,Indianapolis,Indiana,USA;jEli Lilly and Company,New York,New York,USA;kRoyal Marsden Hospital,Sutton,United KingdomDisclosures of potential conflicts of interest may be found at the end of this article.TRIALINFORMATIONClinicalTrials.gov Identifier:NCT02443324Sponsors:Eli Lilly and Company i

5、n collaboration withMerck&Co.,Inc.Principal Investigator:Roy S.HerbstIRB Approved:YesLESSONSLEARNEDRamucirumab plus pembrolizumab revealed no unexpected safety findings in patients with advanced or metastatic biliarytract cancer,which is consistent with reports ofother tumor cohorts within this phas

6、e Ia/b trial.Ramucirumab plus pembrolizumab did not demonstrate an improvement in overall survival when compared with histori-cal controls in biomarker unselected,heavily pretreated patients with advanced or metastatic biliary tract cancer.Patients with programmed death-ligand 1(PD-L1)-positive tumo

7、rs had improved overall survival compared with patientswith PD-L1-negative disease.ABSTRACTBackground.Few treatment options exist for patients withadvanced biliary tract cancer(BTC)following progression ongemcitabine-cisplatin.Preclinical evidence suggests that simulta-neous blockade of vascular end

8、othelial growth factor receptor 2(VEGFR-2)and programmed death 1(PD-1)or programmeddeath-ligand 1(PD-L1)enhances antitumor effects.We assessedthesafetyandefficacyoframucirumab,anIgG1 VEGFR-2antago-nist,withpembrolizumab,anIgG4 PD-1 antagonist,inbiomarker-unselected patients with previously treated a

9、dvanced or meta-staticBTC.Methods.Patients had previously treated advanced or meta-static adenocarcinoma of the gallbladder,intrahepatic andextrahepatic bile ducts,or ampulla of Vater.Ramucirumab8 mg/kg was administered intravenously on days 1 and 8 withintravenous pembrolizumab 200 mg on day 1 ever

10、y 3 weeks.The primaryendpoint was safety and tolerability of the combi-nation.Secondary endpoints included objective response rate(ORR),progression-free survival(PFS),and overall survival(OS).Results.Twenty-six patients were treated at 12 centers in fivecountries.Hypertension was the most common gra

11、de 3treatment-related adverse event(TRAE),occurring in fivepatients.One patient experienced a grade 4 TRAE(neutrope-nia),and no treatment-related deaths occurred.Objectiveresponse rate was 4%.Median progression-free survival andoverallsurvivalwere1.6monthsand6.4months,respectively.Conclusion.Ramucir

12、umab-pembrolizumab showed limited clini-cal activity with infrequent grade 34 TRAEs in patients with bio-marker-unselectedprogressiveBTC.TheOncologist2018;23:110DISCUSSIONBTCs are highly aggressive with poor prognosis and few treat-ment options following progression on gemcitabine-cisplatinCorrespon

13、dence:Hendrik-Tobias Arkenau,M.D.,Ph.D.,Drug Development Unit,Sarah Cannon Research Institute,93 Harley St.,London,EnglandW1G6AD,United Kingdom.Telephone:020-3219-5200;e-mail:tobias.arkenauhcahealthcare.co.ukReceived April 6,2018;accepted forpublication May 14,2018.OcAlphaMed Press;the data publishe

14、d online to support this summary are the property of the authors.http:/dx.doi.org/10.1634/theoncologist.2018-0044TheOncologist 2018;23:111 www.TheOOcAlphaMed Press 2018Clinical Trial ResultsPublished Ahead of Print on May 31,2018 as 10.1634/theoncologist.2018-0044.by guest on June 6,2018http:/theonc

15、ologist.alphamedpress.org/Downloaded from chemotherapy.Preclinical evidence suggests that simultaneousblockade of VEGFR-2 and PD-1 or PD-L1 induces additive anti-tumoreffects 13.This isthe first study to combine an antian-giogenic agent(ramucirumab,an IgG1 VEGFR-2 antagonist)with an immune checkpoin

16、t inhibitor(pembrolizumab,an IgG4PD-1 antagonist)to simultaneously target both processes inpatients with previouslytreated advanced BTC.Twenty-six patients received at least one dose of ramuciru-mab and pembrolizumab.Baseline demographics and charac-teristics were as expected for an advanced,previou

17、sly treatedpopulation.The majority of patients had intrahepatic(42.3%)or extrahepatic(34.6%)cholangiocarcinoma.Median therapyduration was 9 weeks with ramucirumab and 9.3 weeks withpembrolizumab.Median follow-up duration was 15.7(95%confidenceinterval CI 10.317.0)months.TRAEs occurred in most patien

18、ts and were predominantlyof grade 12 severity.The most frequently reported TRAEs(anygrade)were fatigue,hypertension,nausea,diarrhea,and hypo-thyroidism.Nine(34.6%)patients experienced a grade 3 TRAE.One patient experienced grade 4 treatment-related neutrope-nia.Serious adverse events(AEs)were report

19、ed for 15(57.7%)patients;these were deemed related to treatment by theinvestigator in seven(26.9%)patients.One patient discontin-ued treatment due to treatment-related elevation of transami-nases.There wereno treatment-related deaths.Reduction in tumor size from baseline in target lesions wasobserve

20、d in 9(37.5%)of 24 patients;two patients were notevaluable due to no postbaseline tumor assessment(Fig.1).One(3.8%)patient had a partial response,nine(34.6%)hadstable disease,and 13(50%)had progressive disease as theirbest response to treatment.Disease control occurred in 10(38.5%)patients;median du

21、ration of stable disease was 3.9months.Median PFS was 1.6 months.Median PFS in patientswith PD-L1-positive(n512)and-negative(n512)tumorswas 1.5 months and 1.6 months,respectively.Limited analysesof efficacy by primary tumor site and line of therapy did notdemonstrate any clear trends.Median OS was 6

22、.4 months.Median OS in patients with PD-L1-positive and-negativetumors was 11.3 months and 6.1 months,respectively.Onepatient remained on treatment.Of the seven(26.9%)patientswho received postdiscontinuation systemic anticancer therapy,six were PD-L1 positive and one was PD-L1 negative.Althoughthe c

23、hemotherapy-free combination in our study reported atolerable toxicity profile,ramucirumab plus pembrolizumab didnot demonstrate an improvement in survival when comparedwith historical controls in biomarker-unselected,heavily pre-treated patients with advancedor metastatic BTC.TRIALINFORMATIONDiseas

24、eBiliary tract:gallbladder cancer and cholangiocarcinomaStage of Disease/TreatmentMetastatic/advancedPrior Therapy12 prior regimensType of Study-1Phase IPrimary EndpointSafety and tolerabilitySecondary EndpointProgression-free survival,overall survival,objective responserate,disease control rate,dur

25、ation of response,time toresponse,and pharmacokinetics of ramucirumabAdditional Details of Endpoints or Study DesignPhase I,multicohort,nonrandomized,open-label study.Patients?18 years of age were eligible for enrollment if they hadhistologically or cytologically confirmed biliary tract adenocarcino

26、ma(gallbladder,intrahepatic and extrahepatic cholangiocarci-noma,or ampulla of Vater);unresectable,recurrent,or metastatic disease extent;and progression on 12 lines of priorchemotherapy or biological therapy.Prior therapy for advanced disease must have included gemcitabine and cisplatin.Priortherap

27、y in an adjuvant or neoadjuvant setting was not considered a prior line of systemic chemotherapy,unless the patient hadrapidly progressed,as defined by there having been?6 months since the last dose of chemotherapy.Furthermore,patients wererequired to have an Eastern Cooperative Oncology Group(ECOG)

28、performance status of 0 or 1,measurable disease(RECIST;version 1.1),adequate organ function,and baseline tumor tissue for biomarker analysis.PD-L1 expression was assessed using aprovisional cutoff by immunohistochemistry with an investigational version of the PD-L1 IHC 22C3 pharmDx(Agilent,Carpinter

29、ia,CA).The“combined positive score”(CPS)is the number of staining tumor and immune cells relative to total tumor cells.PD-L1status was classified by using CPS as positive(?1%)or negative(Color by:PD-L1NegativeNot reportedPositiveOn TreatmentFigure 1.Maximum change in tumor size from baseline.Abbrevi

30、ation:PD-L1,programmed death-ligand 1.2Ramucirumab-Pembrolizumab in Biliary Tract CancerOcAlphaMed Press 2018Published Ahead of Print on May 31,2018 as 10.1634/theoncologist.2018-0044.by guest on June 6,2018http:/theoncologist.alphamedpress.org/Downloaded from study treatment during this period.Stud

31、y treatment was to be discontinued if the repeat scan confirmed progression.Followingdiscontinuation,patients were followed up for survival every 90 days.Safety was assessed and graded throughout the study and for30 days after treatment discontinuation.AEs were graded using the National Cancer Insti

32、tute Common Terminology Criteria forAdverse Events,version 4.0,and judged by the investigator to be related or nonrelated to study treatment.The study planned toenroll approximately 2530 patients.The sample size was selected to allow adequate assessment of safety at the recommendeddoses for ramuciru

33、mab and pembrolizumab.The exact binomial test was used in the power analysis:Assuming a 10%15%increasebetween the null and target response rate,and the target treatment effect on ORR is between 20%and 30%,a sample size of2530 will provide approximately 60%80%power with a one-sided a level of 0.20.Da

34、ta cutoff for the current analysis wasFebruary 1,2018.Other disease cohorts from this same trial(NCT02443324)will be published separately.Investigators AnalysisManageable safety profile with limited clinical activityDRUGINFORMATIONDrug 1Generic/Working NameRamucirumabTrade NameCyramzaCompany NameEli

35、 Lilly and CompanyDrug TypeAntibodyDrug ClassAntiangiogenic:anti-VEGFR-2Dose8 mg/kgRouteIVSchedule of AdministrationRamucirumab days 1 and 8 every 3 weeks until diseaseprogression or other discontinuation criteria met.Drug 2Generic/Working NamePembrolizumabTrade NameKeytrudaCompany NameMerck and Co.

36、,Inc.Drug TypeAntibodyDrug ClassImmunotherapy:anti-PD-1Dose200 mg per flat doseRouteIVSchedule of AdministrationPembrolizumab day 1 every 3 weeks until disease progressionor other discontinuation criteria met.PATIENTCHARACTERISTICS FORPHASEI EXPERIMENTALNumber of Patients,Male8Number of Patients,Fem

37、ale18StageNonresectable,recurrent,or metastaticAgeMedian(range):63(3678)Number of Prior Systemic TherapiesMedian(range):1(13)Performance Status:ECOG0 121 14OtherComplete baseline demographic and disease characteristicsare presented in Table 1PRIMARYASSESSMENTMETHODTitleTotal patient populationNumber

38、 of Patients Screened33Number of Patients Enrolled26Number of Patients Evaluable for Toxicity26Number of Patients Evaluated for Efficacy26Evaluation MethodRECIST 1.1Response Assessment CRn50(0%)Response Assessment PRn51(4%)Response Assessment SDn59(35%)Response Assessment PDn513(50%)Arkenau,Martin-L

39、iberal,Calvo et al.3www.TheOOcAlphaMed Press 2018Published Ahead of Print on May 31,2018 as 10.1634/theoncologist.2018-0044.by guest on June 6,2018http:/theoncologist.alphamedpress.org/Downloaded from Response Assessment OTHERn53(12%)(Median)Duration Assessments PFS1.64 months,CI:1.382.76(Median)Dur

40、ation Assessments OS6.44 months,CI:4.1713.27(Median)Duration Assessments Response Duration6 monthsOutcome NotesFurther graphical details on maximum change in tumor sizeover time,duration of treatment,and efficacy results byPD-L1 status are presented in the extended discussion.ADVERSEEVENTSSERIOUSADV

41、ERSEEVENTSASSESSMENT,ANALYSIS,ANDDISCUSSIONCompletionStudy completed;one patient remains on study treatment.Investigators AssessmentManageable safety profile with limited clinical activityAdverse eventsGrade 1Grade 2Grade 3Grade 4Grade 5TotalFatiguea3(11.5)6(23.1)09(34.6)Hypertension03(11.5)5(19.2)0

42、08(30.8)Nausea7(26.9)007(26.9)Diarrhea4(15.4)1(3.8)0005(19.2)Hypothyroidism1(3.8)3(11.5)0004(15.4)Decreased appetite2(7.7)1(3.8)0003(11.5)Epistaxis3(11.5)00003(11.5)Infusion-related reaction1(3.8)2(7.7)0003(11.5)Pyrexia3(11.5)00003(11.5)Stomatitis2(7.7)1(3.8)0003(11.5)Rashb3(11.5)00003(11.5)Alanine

43、aminotransferaseincreased01(3.8)1(3.8)02(7.7)Aspartate aminotransferaseincreased1(3.8)01(3.8)02(7.7)Peripheral edema2(7.7)002(7.7)Gingival bleeding2(7.7)002(7.7)Pruritus1(3.8)1(3.8)02(7.7)Vomiting2(7.7)00002(7.7)Data are n(%).The table shows treatment-related adverse events occurring in at least two

44、 patients,according to preferred term or consolidatedcategory.aConsolidated category(fatigue and asthenia).bConsolidated category(rash and maculopapular rash).Abbreviation:,indicates a grade is not available per National Cancer Institute Common Terminology Criteria for Adverse Events,version 4.0.Nam

45、eGradeAttributionColitis3PossibleDuodenal ulcer3PossibleGastrointestinal inflammation3PossibleHepatocellular injury3PossibleHypertension3PossibleHypophysitis3PossibleLiver abscess3PossibleTransaminases increased3Possible4Ramucirumab-Pembrolizumab in Biliary Tract CancerOcAlphaMed Press 2018Published

46、 Ahead of Print on May 31,2018 as 10.1634/theoncologist.2018-0044.by guest on June 6,2018http:/theoncologist.alphamedpress.org/Downloaded from Biliary tract cancer(BTC)arises from the epithelial lining ofthe gallbladder,intrahepatic and extrahepatic bile ducts,andampulla of Vater.There are more than

47、 186,000 new cases ofBTC diagnosed worldwide each year 5.The incidence of BTC isincreasing in the U.S.and some European countries,largely dueto an increase in diagnosis of intrahepatic cholangiocarcinoma6,7.Lymph node involvement and distance metastases areearly characteristics of BTC,preventing up

48、to 90%of patientsfromreceivingcurativeintentsurgery8.Gemcitabine in combination with cisplatin is standard first-line palliative treatment for advanced BTC,with a median over-all survival(OS)of 11.211.7 months 9,10.There is no estab-lished standard of care following progression on gemcitabine-cispla

49、tin,and chemotherapeutic agents have modest activity inthis setting.A recent systematic review that included 14 phaseII trials indicated an objective response rate of 7.7%,meanprogression-free survival(PFS)of 3.2 months,and mean OS of7.2 months with second-line therapy 11.Outcomes are sub-optimal,an

50、d a substantial unmet need persists to improve out-comes forpatients with advanced BTC.Antiangiogenic therapies have several noted immunostimu-latory effects including increased trafficking of T cells intotumors as well as reduction of immunosuppressive cytokinesand Tregulatory cells,suggesting anti