Pembrolizumab as First-line Therapy in Cisplatin-ineligible Advanced Urothelial Cancer (KEYNOTE-052): Outcomes in Older Patients by Age and Performance Status

Pembrolizumab

as

First-line

Therapy

in

Cisplatin-ineligible

Advanced

Urothelial

Cancer

(KEYNOTE-052):

Outcomes

in

Older

Patients

by

Age

and

Performance

Status

Petros

Grivas

*

,

Elizabeth

R.

Plimack

,

Arjun

V.

Balar

,

Daniel

Castellano

,

Peter

H.

O’Donnell

,

Joaquim

Bellmunt

,

Thomas

Powles

,

Noah

M.

Hahn

,

Ronald

de

Wit

,

Dean

F.

Bajorin

,

Misoo

C.

Ellison

,

Tara

L.

Frenkl

,

James

L.

Godwin

,

Jacqueline

Vuky

a_{UniversityofWashington,FredHutchinsonCancerResearchCenter,SeattleCancerCareAlliance,Seattle,WA,USA;}b_{FoxChaseCancerCenter,Philadelphia,PA,USA;} c_{PerlmutterCancerCenter,NYULangoneHealth,NewYork,NY,USA;}d_{HospitalUniversitario12deOctubre,Madrid,Spain;}e_{TheUniversityofChicago,Chicago,IL,}

USA;f_{BethIsraelDeaconessMedicalCenter,HarvardMedicalSchool,Boston,MA,USA;}g_{BartsCancerInstitute,QueenMaryUniversityofLondon,London,UK;}h_Johns

HopkinsUniversitySidneyKimmelComprehensiveCancerCenter,Baltimore,MD,USA;i_{ErasmusMCCancerInstitute,Rotterdam,TheNetherlands;}j_{MemorialSloan}

KetteringCancerCenter,NewYork,NY,USA;k_{Merck&Co.,Inc.,Kenilworth,NJ,USA;}l_{OregonHealth&ScienceUniversity,Portland,OR,USA}

a v ai l a b l e a t w w w . s c i e n c e d i r e c t . c o m

j o u r n al h o m e p a g e : e u o n c o l o g y . e u r o p e a n u r o l o g y. c o m

Articleinfo Articlehistory:

Received15October2019 Receivedinrevisedform 23January2020 AcceptedFebruary26,2020 AssociateEditor: GianlucaGiannarini Keywords: Aged Bladdercancer Checkpointinhibitor Cisplatinineligible Immunotherapy Programmeddeath1 Pembrolizumab Platinumineligible Poorperformancestatus Urothelialcarcinoma

Abstract

Background: Patientswithtreatment-naiveadvancedurothelialcancer(UC)ineligible forcisplatin-basedchemotherapyaretypicallyolderandhavecomorbidities, represent-ingadifficult-to-treatpopulation.

Objective: Toevaluatethesafetyandantitumoractivityoffirst-linepembrolizumabin subgroupsofcisplatin-ineligibleolderpatients(aged65and75yr)withadvancedUC inKEYNOTE-052(NCT02335424),includingthosewithpoorperformancestatus (East-ernCooperativeOncologyGroupperformancestatusscore2[ECOGPS2]).

Design, setting, and participants: Patients were cisplatinineligible, had treatment-naive,histologically/cytologicallyconfirmed,locallyadvanced/metastaticUCwith measur-abledisease(ResponseEvaluationCriteriainSolidTumorsversion1.1[RECISTv1.1]),and hadECOGPS0–2.Patientsubgroupsanalyzedwereaged65yr(n=302),75yr(n=179), 65yrwithECOGPS2(65yr+ECOGPS2;n=119),and75yr+ECOGPS2(n=78).

Intervention: All patientsreceivedpembrolizumab 200mgintravenously every3 wk untilconfirmedprogression,intolerabletoxicity,patientwithdrawal,or24mooftherapy.

Outcomemeasurementsandstatisticalanalysis: Theprimaryendpointwas objec-tiveresponserate(ORR)asperRECISTv1.1.Thekeysecondaryendpointswereoverall survival(OS),durationofresponse(DOR),andsafety.

Resultsandlimitations: ORRsforthe65yr,75yr,65yr+ECOGPS2,and75yr +ECOGPS2subgroupswere29%,27%,29%,and31%,respectively;ratesofcompleteand partialresponsesweresimilaracrosssubgroups(9%,5%,6%,and6%,and20%,22%,23%, and24%,respectively).MedianDORandOSwerealsoconsistentacrossthe65yrand 65yr+ECOGPS2subgroupsandthe75yrand75yr+ECOGPS2subgroups.Study limitationsincludedopen-labeldesign,lackofacomparatorgroup,andnatureofpost hocexploratoryanalysis.

* Corresponding author. Department of Medicine, Division of Oncology, Genitourinary Cancers Program, University of Washington, Seattle, WA, USA, Clinical Research Division, Fred Hutchinson CancerResearchCenter,SeattleCancerCareAlliance,1144EastlakeAveE.LG-465,Seattle,WA98109, USA. Tel. +1-206-606-1943, Fax: +1-206-606-2042.

E-mail address: pgrivas@uw.edu(P. Grivas).

https://doi.org/10.1016/j.euo.2020.02.009

2588-9311/©2020TheAuthors.PublishedbyElsevierB.V.onbehalfofEuropeanAssociationofUrology.Thisisanopenaccessarticle under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction

Urothelialcancers(UCs)comprisearangeoftumorsarising from the urinary tract, including the bladder, which accountsfor>90%ofallurothelialtumorsintheUSAand Europe[1].Bladdercancerranks10thintheworldregarding incidence, with >500 000 casesestimated to have been diagnosedin2018[2].Diagnosispeaksafterage70yr,and approximately20%ofpatientsareolderthan80yr[3].

Approximately half of patients with newly diagnosed, advanced UC are ineligible for first-line cisplatin-based combination chemotherapy, in part because of age-related decline inperformance statusand the presenceofmedical comorbidities that can impact treatment-related toxicity

[3–5]. Indeed, onecriterion used to establisheligibility for cisplatin-based therapy is Eastern Cooperative Oncology Groupperformancestatus(ECOGPS)<2[4].Comorbidities inolderpatientsincluderenalfunctionimpairment(chronic kidney disease with creatinine clearance level <50–60ml/ min), grade2 hearingloss or neuropathy,and New York HeartAssociation(NYHA)classIII–IVcardiacfailure[4,6–8]

.TreatmentofUCinolderpatientsmayalsobeaffectedby potentialinteractionsamong drugsusedtotreat comorbid-itiesandchemotherapy[7].Survivalwithnon–cisplatin-based therapiesisusuallyshort,withmedianprogression-free(PFS) andoverall(OS)survivalof4–5and8–10mo,respectively[7]. Clinicalbenefit hasbeennoted withgemcitabine plus carboplatin (GCa) as a first-line treatment; alternatives include gemcitabine or carboplatin monotherapy and gemcitabine plus paclitaxel [7,9]. However, shorter OS andseveretoxicityinpatientswithbothpoorperformance statusandrenalimpairment (estimatedglomerular filtra-tionrate<60ml/min)comparedwiththosewhohadonly oneofthesefactorswerereportedwithGCa[10].Moreover, chemotherapy is not administered to approximately 20– 52% of patients with UC, including those with advanced disease, because of the presence of comorbidities, poor overallhealthstatus,andconcernsregarding chemothera-py-associated toxicities [3,9,11]; these untreatedpatients generallyfareworsethanthosewhoreceivechemotherapy andusuallypursueonlybestsupportiveandpalliativecare

[3]. The good tolerability profile ofcheckpoint inhibitors representsanewopportunityfortherapeuticintervention inolderpatientswhoarechemotherapyineligible.

Immunecheckpointblockade(anti–programmeddeath 1 [PD-1]/anti–programmed death ligand 1 [PD-L1]/anti-cytotoxic T-lymphocyte–associated protein 4) has demon-strated efficacy fora variety ofmalignancies, includingUC

[12,13].ThePD-1inhibitorpembrolizumabisapprovedinthe USA and Europeas first-linetherapy forcisplatin-ineligible patientswithUC,basedonavailableefficacyandsafetydata fromtheopen-label,single-arm,phase2KEYNOTE-052trial (ClinicalTrials.gov,NCT02335424)evaluatingtheefficacyand safety of first-line pembrolizumab in cisplatin-ineligible patientswithadvancedUC[14–16].A2018revisionofthese approvals for first-line pembrolizumab limited its use to cisplatin-ineligiblepatientswithtumorsexhibitinghighPD-1 expression based on the companion assay (22C3; Agilent Technologies, Carpinteria,CA,USA)orpatientsineligiblefor any platinum (cisplatin or carboplatin)-containing chemo-therapyregardlessofPD-L1status[14,15].Theserevisionsare basedonanearlyinterimanalysisthatfoundthatsurvivalwas shorter inpatientswithadvanced UCandtumorswithlow PD-L1expressionwhoreceivedpembrolizumabthaninthose whoreceivedchemotherapyaloneinanongoingphaseIIItrial (KEYNOTE-361,ClinicalTrials.gov,NCT02853305)[17].

In KEYNOTE-052, first-line treatment of 370 patients with pembrolizumab yielded an objective response rate (ORR)of29%,with33(9%)completeresponses(CRs)and73 (20%) partial responses (PRs) across the entire trial population[18].Responseswereusuallyrapidanddurable, and pembrolizumab was well tolerated overall. It was hypothesizedthatpembrolizumabactivityandtolerability are independent of age and performance status. An exploratory post hoc analysis of KEYNOTE-052 was con-ducted to evaluate the antitumor activity and safety of pembrolizumab in the subgroup of cisplatin-ineligible patients whowere considered older(aged 65 and 75 yr)and/orhadpoorperformancestatus(ie,ECOGPS2).

2. Patientsandmethods

2.1. Studydesignandpatientpopulation

ThisstudywasconductedinaccordancewiththeDeclaration ofHelsinkiandtheInternationalConferenceon Harmonisa-tionGoodClinicalPracticeguidelines,andincompliancewith local and institutional regulations. All patients provided written informed consent to participate. Study design and methodsaredescribedindetailelsewhere[16].Inbrief,adults with treatment-naive, histologically/cytologicallyconfirmed, locallyadvanced(unresectable)ormetastaticUCoftherenal pelvis, ureter, bladder, or urethra, who were ineligible for cisplatin-basedchemotherapy,hadcentrallyconfirmed mea-surabledisease(asperResponseEvaluationCriteriainSolid

Conclusions: Theclinicalbenefitofpembrolizumabin advancedUCappeared tobe consistentregardlessofageand/orpoorperformancestatus.

Patientsummary: Thisstudylookedatwhetherolderageand poorerperformance statusaffecthowwellpatientswithpreviouslyuntreatedadvancedurothelialcancer ineligibleforstandard-of-caretreatment respondtopembrolizumab.Outcomeswith pembrolizumabwerenotaffectedbyolderageorpoorerperformancestatus,makingit aneffectiveoption.

©2020TheAuthors.PublishedbyElsevierB.V.onbehalfofEuropeanAssociationof Urology.ThisisanopenaccessarticleundertheCCBY-NC-NDlicense( http://creati-vecommons.org/licenses/by-nc-nd/4.0/).

Tumorsversion1.1[RECISTv1.1]),andhadECOGPS0–2were enrolled.Cisplatinineligibilitywasdefinedbyhavingoneor moreofthefollowingfactors:ECOGPS2,creatinineclearance level 30–59ml/min, grade 2 neuropathy/hearing loss, or NYHAclassIIIheartfailure.

2.2. Treatmentandassessments

All enrolled patients were administered pembrolizumab 200mgintravenouslyevery3wkuntildocumenteddisease progression,intolerabletoxicity,physician/patientdecision towithdraw,orcompletionof24mooftreatment.Tumor response was assessed by computed tomography or magnetic resonanceimaging at9 wkafterthe firstdose ofpembrolizumab,every6wkthereafterforthe1styear, andthenevery12wkthroughyear2.

PD-L1 expression (assessed using the PD-L1 IHC 22C3 pharmDxassay;AgilentTechnologies)wasdeterminedusing combinedpositivescore(CPS;numberofPD-L1–positivecells [tumorcells,lymphocytes,andmacrophages]/totalnumberof tumorcells  100).A CPScutoffof10 was usedto define tumorsexpressingPD-L1andwasvalidatedbydetermining the ORR among all subsequently enrolled patients with CPS10(referredtoasthevalidationset)[16,19].

Safety was assessed by reporting adverse events (AEs) using Common Terminology Criteria for Adverse Events, version 4.0. AEs and serious AEs (SAEs) were monitored throughoutthestudyandfor30and90d,respectively,after thelastdose.

2.3. Studyendpoints

TheprimaryendpointwastheORRasperRECISTv1.1byan independent central imaging review. Secondary efficacy endpointswere durationofresponse(DOR), OS,andPFSas perRECISTv1.1by anindependent centralimagingreview. Theprimarysafetyobjectivewascharacterizationofthesafety andtolerabilityofpembrolizumab,whichwasachievedbyAE reporting, and included SAEs, fatal AEs, and immune-mediatedAEs.

2.4. Statisticalanalysis

Data for thefollowingpatient subgroups were analyzed: age65yr(65yr),age75yr(75yr),age65yrwith ECOGPS2(65yr+ECOGPS2),andage75yrwithECOG PS2(75yr+ECOGPS2).ORRwassummarizedusingpoint estimateswith95%confidenceintervals(CIs)basedonthe binomialexactmethod.Secondaryefficacyendpointswere evaluated using the Kaplan-Meier method to estimate summarystatistics,includingmedians.Datacutoffdatefor theseanalyseswasSeptember26,2018.

3. Results

3.1. Baselinepatientcharacteristics

Medianfollow-upforalltrialpatientswas11.4mo(range, 0.1–41.2mo).Of370patients,302(82%)wereaged65yr,

179(48%)wereaged75yr,119(32%) wereaged65yr withECOGPS2,and78(21%)wereaged75yrwithECOG PS2.Baselinepatientcharacteristicsweregenerally compa-rableacrossgroups(Table1).

3.2. Efficacy

ORRswere29%,27%,29%,and31%forthe65yr,75yr, 65yr+ECOG PS2, and 75 yr+ECOG PS2 subgroups, respectively(Table2).ThebestresponseofCRwasachieved by 9%, 5%, 6%, and 6%, respectively, and that of PR was achieved by 20%, 22%, 23%, and 24%, respectively. A supportive analysis of responses inpatients aged85 yr (n=40)yieldedanORRof28%(11PRs).TheORRsamong patientswithatumorCPSof10were52%(32/62),50%(17/ 34), 52%(17/33),and55%(12/22)for the65yr,75yr, 65yr+ECOG PS2, and 75 yr+ECOG PS2 subgroups, respectively(Fig.1).For patientswhowere<65yrofage (n=68)andthosewhowere<65yrofagewithECOGPS2 (n=37),ORRswere29%and19%,respectively.

Median time to response was similar among all subgroups (median, 2.1 mo overall). Median DOR was 30.1 mo for both the 65yrand the 65yr+ECOG PS2 subgroup,12.5moforthe75yrsubgroup,and11.8mofor the75yr+ECOGPS2subgroup(Table2).Proportionsof patients whomaintainedresponse for24mowere 53% and51%forthe65yrand65yr+ECOGPS2subgroups, respectively,and35%and45%forthe75yrand75yr +ECOGPS2 subgroups,respectively.Findingsfor patients with CPS10 were similar (median time to response, 2.1mooverall;medianDORwasnotreachedforallbutthe 75 yr+ECOG PS2 subgroup, in which it was 13 mo; SupplementaryTable1).Forresponderswhowere<65yrof age(n=20)andthosewhowere<65yrofagewithECOGPS 2(n=7),median(range)DORwas18.1(1.4+to31.9+),which was not reached (5.6 to 26.3+), respectively. Similar proportions of patients in each subgroup experienced a reductionintumorsize frombaseline:59%ofthe65yr, 58%ofthe75yr,60%ofthe65yr+ECOGPS2,and57%of the75yr+ECOGPS2subgroup(Fig.2).

Median PFS was 2.3 mo for the 65yrsubgroup and 2.1mofortheotherthreesubgroups(Table3).PFSratesat 6mointhe65yr,75yr,65yr+ECOGPS2,and75yr +ECOG PS2 subgroups were 34%, 31%, 33%, and 31%, respectively.Forpatientswhowere<65yrofage(n=68) andwere <65yrof agewithECOGPS 2(n=37),median (95% CI) PFS was 2.2 (2.0–31.9+) and 2.1 (1.9–3.6) mo, respectively. Median(95% CI) OS was11.0 (9.5–12.5), 9.7 (7.8–11.5),8.7(5.2–10.6),and8.2(4.4–10.8)mo, respective-ly, andOS ratesat 24 mo were 29%,21%, 24%, and23%, respectively. In patients with CPS10, median OS was 16.6mo(95%CI,11.5–27.6)in65yr,13.6mo(95%CI,10.0– 27.6)in65yr+ECOGPS2, 11.5mo(95%CI,5.8–17.1)in75 yr, and 10.6mo (95% CI, 4.4–27.0) in 75yr+ECOG PS2 patients.ThesamepatternwasobservedfortheOSratesat 24 mo (Supplementary Table 1). For patients who were <65yrofage(n=68)andthosewhowere <65yrofage withECOGPS2(n=37),median(95%CI)OSwas15.7(6.9– 24.2)and14.1(5.2–24.2),respectively.

3.3. Safety

Treatment-relatedAEs(TRAEs)ofanygradewerereported by210(70%), 125(71%),72(61%),and50(64%)ofthe65yr, 75 yr, 65yr+ECOG PS2, and 75 yr+ECOG PS2

subgroups,respectively(Table4).Ratesofgrade3–5TRAEs were 22%, 20%, 19%, and 17%, respectively. The most commonTRAEsweresimilarbetweenthesubgroups,with bothfatigueandpruritusoccurringin10%ofpatientsin anysubgroup.OtherTRAEsoccurringin10%ofpatients Table 2 _–Best confirmed objective response and response duration based on RECIST v1.1 per central imaging.

Age subgroups Age/ECOG PS2 subgroups Age65yr (n = 302) Age75yr (n = 179) Age65yr+ECOGPS2 (n = 119) Age75yr+ECOGPS2 (n = 78)

Objectiveresponserate,n(%) 86(29) 48(27) 34(29) 24(31)

Completeresponse 27(9) 9(5) 7(6) 5(6) Partialresponse 59(20) 39(22) 27(23) 19(24) Stabledisease 56(19) 32(18) 17(14) 10(13) Progressivedisease 125(41) 78(44) 48(40) 34(44) Notevaluable 9(3) 6(3) 5(4) 4(5) Noassessment 26(9) 15(8) 15(13) 6(8)

Timetoresponse(mo)a

,median(range) 2.1(1.3–9.0) 2.1(1.3–4.7) 2.1(1.3–5.0) 2.1(1.3–4.7)

Durationofresponse(mo)a,b

,median(range) 30.1(1.6+to35.9+) 12.5(1.6+to33.4+) 30.1(1.6+to34.3+) 11.8(1.6+to33.4+)

Proportionofpatientswithresponseslasting24mo(%)a,b

53 35 51 45

ECOGPS2=EasternCooperativeOncologyGroupperformancestatus2;RECISTv1.1=ResponseEvaluationCriteriainSolidTumorsversion1.1.

a

Inpatientsachievingcompleteorpartialresponsesonly.

b

BasedontheKaplan-Meiermethod.

Table 1 –Patient baseline characteristics and study disposition.

Characteristic Agesubgroups Age/ECOGPS2subgroups

Age 65yr (n = 302) Age 75yr (n = 179) Age 65yr + ECOG PS2 (n = 119) Age 75yr + ECOG PS2 (n = 78) Baselinecharacteristics

Age(yr),median(range) 76(65–94) 81(75–94) 78(65–91) 81(75–91)

Sex(men),n(%) 230(76) 137(77) 93(78) 57(73)

ECOGPS,n(%)

0or1 183(61) 101(56) 0 0

2 119(39) 78(44) 119(100) 78(100)

3 0 0 0 0

Uppertractprimarytumora

,n(%) 57(19) 27(15) 23(19) 14(18)

Metastasislocationb_,n(%)

Visceraldisease 257(85) 154(86) 98(82) 64(82)

Lymphnodediseaseonly 41(14) 21(12) 19(16) 12(15)

Livermetastases,n(%) 65(22) 43(24) 30(25) 22(28)

Hemoglobin<10g/dl,n(%) 31(10) 21(12) 15(13) 11(14)

Priorchemotherapy,n(%) 54(18) 27(15) 22(19) 10(13)

Reasonsforcisplatinineligibility,n(%)

Renaldysfunction 154(51) 90(50) 9(8) 7(9)

ECOGPS2 87(29) 54(30) 81(68) 49(63)

ECOGPS2+renaldysfunction 31(10) 22(12) 27(23) 20(26)

Otherc 30(10) 13(7) 2(2) 2(3) Studydisposition Completed,n(%) 34(11) 8(5) 12(10) 5(6) Discontinued,n(%) 268(89) 171(96) 107(90) 73(94) Adverseevent 50(17) 34(19) 22(19) 15(19) Clinicalprogression 36(12) 22(12) 15(13) 9(12) Completeresponse 11(4) 7(4) 5(4) 4(5) Physiciandecision 10(3) 8(5) 5(4) 4(5) Progressivedisease 142(47) 89(50) 51(43) 36(46) Withdrawalbypatient 18(6) 11(6) 8(7) 5(6)

Noncompliancewithstudydrug 1(<1) 0 1(1) 0

Treatmentongoing,n(%) 0 0 0 0

ECOGPS=EasternCooperativeOncologyGroupperformancestatus.

a

Unknownforonepatient.

b _{Unknownforfourpatients.}

c

weredecreasedappetite,hypothyroidism,andrashinthe 65yrgroupanddecreasedappetiteinthe75yrgroup. Treatment-relatedSAEsrangedfrom 9%to12%acrossthe foursubgroups.Ratesofstudydiscontinuationsattributable toaTRAEoratreatment-relatedSAEwerealsoconsistent among subgroups (8–10% and 3–5%, respectively). Four grade 4 treatment-related AEs (myocarditis, asthenia, decreased appetite, and hypercalcemia) occurred in two patientswhowere 75yrold butdidnothaveECOGPS

2. Only one death was considered attributable to pem-brolizumab(myositisinapatientaged75yrbutnotwith ECOGPS2).Onlythreeimmune-mediatedAEsoccurredin >2% of patients (across subgroups): hyperthyroidism, hypothyroidism,andpneumonitis(Table4).Hepatitisand prurituswerealsoobservedin>2%ofpatientsinthe75yr and75yr+ECOGPS2subgroups,respectively. Hypothy-roidismoccurredin11%ofthe65yr,7%ofthe75yr,5%of the65yr+ECOG PS2,and8%ofthe75yr+ECOGPS2

Fig.2–BestpercentagechangefrombaselineinthesumofthelongestdiametersoftargetlesionsasperRECISTv1.1byacentralimagingreviewin

thesubgroupsofpatientsaged65yr(n=270),75yr(n=158),65yrwithECOGPS2(n=102),and75yrwithECOGPS2(n=70).Dottedlines

correspondtopatientswitha20%increaseintumorburdenanda30%decreaseintumorburden.ECOGPS2=EasternCooperativeOncologyGroup

performancestatus2;RECISTv1.1=ResponseEvaluationCriteriainSolidTumorsversion1.1.

Fig.1–ObjectiveresponserateasperRECISTv1.1bycentralimagingreviewinpatientswithCPS10(validationset)foreachofthepatient

subgroups.ThestripedbarrepresentsCR,whilethesolidbarrepresentsPR.CI=confidenceinterval;CPS=combinedpositivescore;CR=complete

response;ECOGPS2=EasternCooperativeOncologyGroupperformancestatus2;ORR=objectiveresponserate;PR=partialresponse;RECISTv1.1=

subgroups.Therateofpneumonitis—at5%,6%,7%,and6%, respectively—wassimilaracrossthefoursubgroups. 4. Discussion

PatientswithadvancedUCwhoareineligiblefor cisplatin-basedtherapyand,inparticular,thosewhoareolderand/or havepoor performancestatus represent apopulation for whom systemic chemotherapy may be challenging and palliativecareisoftenrecommendedinstead[3,4].Inthis population, chemotherapeutic alternatives to cisplatin-based chemotherapy tend to be associated with higher levels of toxicity, lower response rates, and inferior outcomes [10,20,21]. In the first-line setting, median OS was7–10mowith GCa,13 mowith paclitaxel+ gemcita-bine,and8mowithsingle-agentgemcitabine;toxicitywas particularlyproblematicwithcombinationtherapies,such asGCaandgemcitabine+paclitaxel[4,7,20].

This exploratory post hoc analysis of KEYNOTE-052 demonstrated that pembrolizumab displays meaningful antitumor activity in the subset of cisplatin-ineligible patientswithlocallyadvanced(unresectable)ormetastatic UC who are considered senior (aged 65 or 75 yr), includingthosewithpoorfunctionalstatus(ie,ECOGPS2). Overall,neitheragenorpoorperformancestatusappeared tohavehadanimpactontheefficacyofpembrolizumabin thispatientpopulation;thislackofimpactofageorpoor performancestatus isalso clinicallyrelevantfor patients whocannottolerateanychemotherapy. ORRwas27–31% acrossthefour subgroups, with 5–9%and20–24%of the subgroups achieving CR and PR,respectively; inpatients 85 yr (n = 40), the ORR was 28%. The data in these subgroups were comparable with those of the overall population[18];inaddition,giventhatmostpatientswere aged65yr(82%),thesepatientsappearedtobedrivingthe results inthe overall population.Percentagesof patients witharesponseat24morangedfrom35%to53%across the four subgroups, whereas median DOR, PFS, OS, and overallefficacywerecomparablewiththoseintheoriginal analysisoftheentirepopulation[18].

Under-representation and under-reporting of older patients in clinical trials render direct comparison with other studies problematic; the National Cancer Institute, along with several agencies and organizations, strongly recommendsequalaccesstoclinicaltrialsregardlessofage

[5].Pembrolizumab(indirectly)compareswellwith histor-icaldatawithchemotherapyintheaged,poorlyfunctioning populationwithadvancedUC.MedianOSwas11.3mowith pembrolizumab (KEYNOTE-052 trial) and 9.3 mo with carboplatin/gemcitabine in the overall population in an earliertrial[10],butresponsedurationappearedhigherina phase2international studyofgemcitabineandpaclitaxel (time to disease progression, 7.6 mo) [20]. However, comparisons among trials should always be interpreted withgreatcaution becauseofselection,confounding,and otherpossiblebiases.

AlthoughbothGCaand methotrexate/carboplatin/vinblas-tine (M-CAVI) conferred antitumor activity in cisplatin-ineligiblepatientswithadvancedUC(N=238),severetoxicity (definedastreatment-relateddeath,grade4 thrombocytope-nia with bleeding, grade3 or4 renal toxicity,neutropenic fever, and mucositis) was experienced by 9.3% of patients receiving GCaand21.2% receivingM-CAVI[10].Thecurrent analysisdemonstratesthatpembrolizumabappearstobewell tolerated, and its safety profile in these patient subsets, includingmoreseniorpatientswithpoorperformancestatus, wassimilartothatofthetotaltrialpopulation[18].Thedata corroboratefindingsfromtheKEYNOTE045trialthatshowed higher tolerabilityandfavorablepatient-reported outcomes with pembrolizumab over cytotoxic chemotherapy in the platinum-refractorysetting[22,23].Additionalinformationin thispopulationwillbeavailablefromtheongoing KEYNOTE-361trialinwhichpembrolizumab,withorwithout platinum-based chemotherapy, is compared with platinum-based chemotherapy for advanced UC in the first-line setting (NCT02853305).

Studylimitationsincludetheexploratorynatureofthe subset analyses, open-label study design, and lack of a comparator arm (single-arm phase 2). The similarity in outcomes between the overall study population and the Table 3 _–Summary of PFS and OS according to age and age/ECOG PS2 subgroups.

Survival Age subgroups Age/ECOG PS2 subgroups

Age65yr (n = 302) Age75yr (n = 179) Age65yr+ECOGPS2 (n = 119) Age75yr+ECOGPS2 (n = 78) PFSa ,mo(95%CI) Median 2.3(2.1–3.4) 2.1(2.0–3.4) 2.1(2.0–3.5) 2.1(2.0–4.7) PFSrateat6mo 33.6(28.3–39.0) 31.3(24.6–38.1) 32.8(24.5–41.2) 30.8(20.9–41.1) PFSrateat12mo 22.2(17.7–27.1) 17.7(12.5–23.6) 20.0(13.3–27.6) 18.9(11.1–28.3) OSa ,mo(95%CI) Median 11.0(9.5–12.5) 9.7(7.8–11.5) 8.7(5.2–10.6) 8.2(4.4–10.8) OSrateat12mo 45.6(39.9–51.1) 39.1(32.0–46.2) 36.6(28.0–45.2) 35.9(25.5–46.4) OSrateat18mo 34.9(29.6–40.3) 25.7(19.6–32.3) 27.2(19.6–35.5) 26.9(17.7–37.0) OSrateat24mo 28.9(23.9–34.1) 21.2(15.5–27.4) 23.8(16.6–31.8) 23.0(14.4–32.8)

CI=confidenceinterval;ECOGPS2=EasternCooperativeOncologyGroupperformancestatus2;OS=overallsurvival;PFS=progression-freesurvival.

elderlysubgroupwaspredictable,giventhatthemajorityof patientsenrolledinthisstudywereaged65yr(n=302, 82%).Thesecaveatscanbeaddressedfurtherintheongoing KEYNOTE-361(NCT02853305)trial.

5. Conclusions

Results from this subgroup analysis of older cisplatin-ineligiblepatientswithadvancedUCwithorwithoutpoor performancestatussuggestthatfirst-linepembrolizumab elicitsclinicallymeaningfulanddurableresponses

consis-tent with those of the overall study population.No new safetysignalswereidentified,consistentwithpriorreports. Pembrolizumabrepresentsanestablishedtreatmentoption for patientswith advancedUCwhomay nottolerateany platinum-basedchemotherapyandareusuallytreatedwith bestsupportivecareonly.

Author contributions: All authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.Study concept and design: Bellmunt, de Wit, Hahn,Powles.

Table 4 –Summary of TRAEs and list of TRAEs at any grade occurring in 5%of patients.

Agesubgroups Age/ECOGPS2subgroups

Age 65yr (n = 302) Age 75yr (n = 179) Age 65yr + ECOG PS2 (n = 119) Age 75yr + ECOG PS2 (n = 78) AEsummary,n(%)

TRAE,anygrade 210(70) 125(70) 72(61) 50(64)

TRAE,grades3–5 66(22) 36(20) 23(19) 13(17)

SeriousTRAEs 34(11) 21(12) 13(11) 7(9)

Immune-mediatedAEa _{78(26) 39(22) 23(19) 18(23)}

DiscontinuationsbecauseofaTRAE 28(9) 17(10) 10(8) 6(8)

DiscontinuationsbecauseofaseriousTRAE 12(4) 9(5) 4(3) 2(3)

DeathsbecauseofaTRAE 1(<1) 1(<1) 0 0

TRAEs(anygrade)occurringin5%ofpatientsinanysubgroup,n(%)

Fatigue 57(19) 32(18) 12(10) 8(10) Pruritus 56(19) 33(18) 15(13) 12(15) Rash 35(12) 16(9) 9(8) 6(8) Decreasedappetite 35(12) 23(13) 9(8) 7(9) Hypothyroidism 30(10) 11(6) 6(5) 6(8) Diarrhea 28(9) 13(7) 11(9) 6(8) Nausea 25(8) 11(6) 8(7) 3(4) Asthenia 14(5) 9(5) 8(7) 5(6)

ALTlevelincreased 13(4) 9(5) 3(3) 3(4)

ASTlevelincreased 14(5) 11(6) 4(3) 4(5)

Pneumonitis 14(5) 9(5) 7(6) 4(5)

Pyrexia 11(4) 6(3) 6(5) 3(4)

Dysgeusia 11(4) 7(4) 4(3) 4(5)

TRAEs(grades3–5)occurringin2patientsinanysubgroup,n(%)

All 66(22) 36(20) 23(19) 13(17) Myocarditis 2(1) 2(1) 1(1) 1(1) Colitis 4(1) 1(1) 0 0 Diarrhea 3(1) 1(1) 2(2) 1(1) Asthenia 3(1) 2(1) 2(2) 1(1) Fatigue 8(3) 6(3) 2(2) 1(1) Autoimmunehepatitis 2(1) 1(1) 1(1) 1(1) Hepatitis 5(2) 4(2) 1(1) 1(1)

ALTlevelincreased 2(1) 2(1) 0 0

ASTlevelincreased 4(1) 4(2) 1(1) 1(1)

ALPlevelincreased 6(2) 3(2) 2(2) 1(1)

Decreasedappetite 2(1) 2(1) 1(1) 1(1)

Dehydration 2(1) 0 1(1) 0

Hyperglycemia 2(1) 1(1) 0 0

Type1diabetesmellitus 2(1) 1(1) 0 0

Muscularweakness 4(1) 3(2) 1(1) 1(1)

Pneumonitis 4(1) 2(1) 3(3) 1(1)

Pruritus 2(1) 2(1) 2(2) 2(3)

Immune-mediatedAEs(anygrade)occurringin2%ofpatientsinanysubgroup,n(%)

Hypothyroidism 34(11) 13(7) 6(5) 6(8)

Pneumonitis 15(5) 10(6) 8(7) 5(6)

Hyperthyroidism 10(3) 7(4) 3(3) 3(4)

Pruritus 2(1) 2(1) 2(2) 2(3)

Hepatitis 5(2) 4(2) 1(1) 1(1)

AE=adverseevent;ECOGPS=EasternCooperativeOncologyGroupperformancestatus;TRAE=treatment-relatedadverseevent.

Acquisition of data: Plimack, O’Donnell,Bellmunt, Hahn, Frenkl. Analysis and interpretation of data: Grivas, Plimack, Balar, Bellmunt, Bajorin,Castellano,deWit,Hahn,Ellison,Frenkl,Godwin,Vuky. Draftingofthemanuscript:Hahn,Plimack,Bajorin,Powles,Ellison,Frenkl. Critical revision of the manuscript for important intellectual content: Grivas, Plimack, Balar, O_’Donnell,Bellmunt, Castellano, de Wit, Bajorin, Hahn, Ellison, Frenkl, Godwin, Vuky.

Statistical analysis: Ellison. Obtainingfunding:None.

Administrative,technical,ormaterialsupport:None. Supervision: None.

Other: Provision of study materials: Plimack, Balar, O_’Donnell,Bellmunt, Castellano, de Wit, Hahn, Bajorin.

Financial disclosures: Petros Grivas certi_fiesthat all con_flictsof interest, including specificfinancialinterests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg,employment/affiliation,grantsorfunding,consultancies,honoraria, stockownershiporoptions,experttestimony,royalties,orpatentsfiled, received, orpending), are the following: Petros Grivas: consultant/ advisory role_—Merck,Bristol-Myers Squibb, AstraZeneca, Clovis Oncol-ogy, EMD Serono, Seattle Genetics, Foundation Medicine, Driver, Pfizer, QED Therapeutics, Heron, Janssen, Bayer, Genzyme, Mirati Therapeutics, Exelixis, Roche, and GlaxoSmithKline; research funding (institution)— Pfizer,ClovisOncology,BavarianNordic,Immunomedics,Bristol-Myers Squibb, and Debiopharm Group. Elizabeth R. Plimack: consultant— AstraZeneca, Bristol-Myers Squibb, Genentech/Roche, Merck, Novartis, P_fizer, Eli Lilly, Inc., Inovio, Clovis, Horizon Pharma, Exelixis, Incyte, Seattle Genetics, Janssen, and Flatiron Health; research funding (to institution)—AstraZeneca,Bristol-Myers Squibb, Merck, Peloton, and Pfizer;developmentofeducationalpresentations—Bristol-MyersSquibb, Merck,Roche,Novartis,andAstellas;USpatents14/588,503and15/ 226,474. Arjun V. Balar: research funding and personal fees from Roche/ Genentech, Merck, Seattle Genetics, and AstraZeneca; research funding from Bristol-Myers Squibb. Daniel Castellano: consultant/advisory role— Pfizer,Astellas, Janssen, Roche, Merck, Ipsen, Novartis, and Pierre Fabre. Peter H. O’Donnell: honoraria—Genetech/Roche, Novartis, Merck, AstraZeneca, AstellasPharma, Seattle Genetics, Inovio, andParexel; research funding_{—Boehringer} Ingelheim, Merck, Genentech/Roche, AstraZeneca/Medimmune, Acerta Pharma, and Janssen. Joaquim Bell-munt: consultant/advisory role—Genentech,Merck & Co., Inc., Pfizer, Bristol-Myers Squibb, Pierre Fabre, and Janssen; honoraria—Genentech, Merck & Co., Inc., Pfizer,Bristol-Myers Squibb, Pierre Fabre, and Janssen; research funding—Takeda and Pfizer. Thomas Powles: honoraria— AstraZeneca, Bristol-Myers Squibb, Merck & Co., Inc., Roche, P_fizer, and Seattle Genetics; research funding_{—AstraZeneca}and Roche. Noah M. Hahn: consultant/advisory role_{—AstraZeneca,} Bristol-Myers Squibb, Champions Oncology, Ciclomed, Ferring Pharmaceuticals, Genentech Inc., Health Advances, Inovio Pharmaceuticals, Incyte Corporation, JanssenPharmaceuticalsInc.,Merck&Co.,Inc.,PierisPharmaceuticals, PrincipiaBiopharmaInc.,RexahnPharmaceuticalsInc.,SeattleGenetics, TARIS BioMedical Inc., and TransMed; grant/research support from Astex Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, Genentech Inc., Incyte Corporation, Merck & Co., Inc., Pieris Pharmaceuticals, Principia Biopharma Inc., and Seattle Genetics; honorarium from Bladder Cancer Academy.RonalddeWit:advisoryandspeakerfeeswithinthesubmitted workforMerck;advisoryandspeakerfeesoutsidethesubmittedwork for Sano_fi, Roche, Janssen, and Clovis. Dean F. Bajorin: supported by Memorial Sloan Kettering Cancer Center (P30 CA008748); personal fees and other from Merck Sharp and Dome, Genentech, Bristol-Myers Squibb, Fidia Farmaceutici, Pfizer,AstraZeneca, and Eli Lilly, and grants andotherfromMerckandNovartis,duringtheconductofthestudy. MisooC.Ellison:employeeofMerckSharp&DohmeCorp.,asubsidiary

of Merck & Co., Inc., Kenilworth, NJ, USA. Tara L. Frenkl: former employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth,NJ,USA,atthetimeoftheanalysis;iscurrentlyanemployee of GlaxoSmithKline. James L. Godwin: employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Jacqueline Vuky: consultant/advisory role_—Puma,BioTheranostics, and Agendia; research funding (institution)—Pfizer,Merck, Roche/Genen-tech, Celldex, and Eli-Lily.

Funding/Support role of the sponsor: Funding for this research was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Representatives and academic advisors for Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, designed the study.

Acknowledgments:Theauthorsthankthepatientsandtheirfamilies andallinvestigatorsandsitepersonnel.TheauthorsalsothankMarkus Pulhmann, Jill Lindia, Steve Keefe, and Xiao Fang (employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA) for their contributions to the development of the manuscript. Medical writing and/or editorial assistance was provided by Matthew Grzywacz,PhD,oftheApotheCompembrolizumabteam(Yardley,PA, USA). Thisassistancewasfunded byMerckSharp&Dohme Corp.,a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA_’sdata sharing policy, including restrictions, is available at http://engagezone. msd.com/ds_documentation.php. Requests for access to the clinical studydatacanbesubmittedthroughtheEngageZonesiteorviaemailto dataaccess@merck.com.

CRediTauthorshipcontributionstatement

Petros Grivas: Investigation, Writing - original draft, Writing-review&editing.ElizabethR.Plimack: Investi-gation,Resources,Writing-originaldraft,Writing-review &editing.ArjunV.Balar:Investigation,Resources,Writing -review & editing. Daniel Castellano: Investigation, Resources,Writing-review&editing.PeterH.O’Donnell: Investigation, Resources, Writing - review & editing. Joaquim Bellmunt: Conceptualization, Investigation, Resources, Writing - review & editing. Thomas Powles: Conceptualization, Investigation, Writing - original draft, Writing-review&editing.NoahM.Hahn: Conceptualiza-tion, Investigation, Resources, Writing - original draft, Writing-review&editing.RonalddeWit: Conceptualiza-tion, Investigation,Resources,Writing- review&editing. DeanF.Bajorin:Investigation,Resources,Writing-original draft,Writing-review&editing.MisooC.Ellison:Formal analysis, Data curation, Investigation, Writing - original draft,Writing-review&editing.TaraL.Frenkl: Investiga-tion, Writing- originaldraft, Writing- review& editing. JamesL.Godwin:Investigation,Writing-review&editing. JacquelineVuky:Investigation,Writing-review&editing.

AppendixA. Supplementarydata

Supplementary material related to this article can be found,intheonlineversion,atdoi:https://doi.org/10.1016/j. euo.2020.02.009.

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