Atezolizumab in Patients with Metastatic Urothelial Carcinoma Who Have Progressed After First-line Chemotherapy: Results of Real-life Experiences

Bladder

Cancer

Atezolizumab

in

Patients

with

Metastatic

Urothelial

Carcinoma

Who

Have

Progressed

After

First-line

Chemotherapy:

Results

of

Real-life

Experiences

Deniz

Tural

*

,

O¨mer

Fatih

O¨lmez

,

Ahmet

Taner

Su¨mbu¨l

,

Mehmet

Artac¸

,

Nail

O¨zhan

,

Emre

Akar

,

Burcu

C¸

akar

,

Osman

Ko¨stek

,

Meltem

Ekenel

,

Mustafa

Erman

,

Hasan

Şenol

Co

şkun

,

Fatih

Selc¸

ukbiricik

,

O¨zge

Keskin

,

Fatma

Paksoy

Tu¨rko¨z

,

Kerem

Oruc¸

,

Selami

Bayram

,

U
gur

Y

ǵlmaz

, _Irem

Bilgetekin

,

Birol

Y

ǵldǵz

,

Mehmet

Ali

Nahit

Şendur

,

Nail

Paksoy

,

Ahmet

Dirican

,

Dilek

Erdem

,

Meltem

Selam

,

O¨zgu¨r

Tanr

ǵverdi

,

Semra

Payda

ş

,

Zuhat

Urakc¸

ǵ

,

Elif

Ata

g

,

Sabri

Gu¨ncan

,

Yu¨ksel

U¨ru¨n

,

Ali

Alkan

,

Ali

Osman

Kaya

,

Deniz

Tataro

glu

O¨zyu¨kseler

,

Halil

Ta

_şkaynatan

,

Mustafa

Y

_ǵldǵrǵm

,

Mu¨ge

So¨nmez

,

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kap

a_{BakirköyDr.SadiKonukTrainingandResearchHospital,Istanbul,Turkey;}b_{MedipolUniversityHospital,Istanbul,Turkey;}c_{MedicalFaculty,BaskentUniversity,}

Adana,Turkey;d_{MedicalFaculty,NecmettinErbakanUniversityMeram,Konya,Turkey;}e_{MedicalFaculty,PamukkaleUniversity,Denizli,Turkey;}f_{MedicalFaculty,Ege}

University,Izmir,Turkey;g_{MedicalFaculty,TrakyaUniversity,Edirne,Turkey;}h_{IstanbulUniversityInstituteofOncology,Istanbul,Turkey;}i_{MedicalFaculty,Hacettepe}

University,Ankara,Turkey;j_{MedicalFaculty,AkdenizUniversity,Antalya,Turkey;}k_{MedicalFaculty,KocUniversity,Istanbul,Turkey;}l_{MedicalFaculty,Selcuk}

University,Konya,Turkey;m_{MedicalParkGoztepeHospital,Istanbul,Turkey;}n_{MedicalFaculty,IstanbulUniversity-Cerrahpasa,Istanbul,Turkey;}o_{AntalyaTraining}

andResearchHospital,Antalya,Turkey;p_{MedicalParkIzmirHospital,Izmir,Turkey;}q_{Dr.AbdurrahmanYurtaslanAnkaraOncologyTrainingandResearchHospital,}

Ankara,Turkey;r_{GulhaneTrainingandResearchHospital,Ankara,Turkey;}s_{AnkaraYǵldǵrǵmBeyazǵtUniversity,FacultyofMedicine,Ankara,Turkey;}t_Medical

Faculty,CelalBayarUniversity,Manisa,Turkey;u_{MedicalParkSamsunHospital,Samsun,Turkey;}v_{LivHospital,Istanbul,Turkey;}w_{MedicalFaculty,SitkiKocman}

University,Mugla,Turkey;x_{MedicalFaculty,CukurovaUniversity,Adana,Turkey;}y_{MedicalFaculty,DicleUniversity,Diyarbakir,Turkey;}z_{MedicalFaculty,DokuzEylul}

University,Izmir,Turkey;aa_{MedicalFaculty,MersinUniversity,Mersin,Turkey;}bb_{MedicalFaculty,AnkaraUniversity,Ankara,Turkey;}cc_{OsmaniyeStateHospital,}

Osmaniye,Turkey;dd_{MedicanaHospital,Istanbul,Turkey;}ee_{IstanbulKartalDr.LutfiKirdarTrainingandResearchHospital,Istanbul,Turkey;}ff_{KatipCelebiUniversity}

AtatürkTrainingandResearchHospital,Izmir,Turkey;gg_{MedicalParkGaziantepHospital,Gaziantep,Turkey;}hh_{OrduStateHospital,Ordu,Turkey;}ii_{MedicalFaculty,}

MarmaraUniversity,Istanbul,Turkey;jj_{AntalyaMemorialHospital,Antalya,Turkey;}kk_{HacettepeUniversityInstituteofOncology,Ankara,Turkey}

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 : w w w . e u r o p e an u r o l o g y . c o m / e u f o c u s

Articleinfo Articlehistory:

AcceptedSeptember18,2020 AssociateEditor:PeterBlack

Keywords: Atezolizumab Urothelialcarcinoma Bladdercancer Immunotherapy Abstract

Background: Atezolizumab(ATZ)hasdemonstratedantitumoractivityandmanageable safetyinprevious studiesinpatientswithlocally advancedormetastatic platinum-resistanturothelialcarcinoma.

Objective: Tocomparethereal-lifeexperienceanddataofclinicaltrialsonATZ treat-mentinmetastaticurothelialcarcinoma.

Design,setting,andparticipants: PatientswithurothelialcancertreatedwithATZafter progressiononfirst-linechemotherapyfromanexpandedaccessprogramwere retro-spectivelystudied.Dataofpatientswereobtainedfromtheirfilesandhospitalrecords. SafetywasevaluatedforpatientstreatedwithatleastonecycleofATZ.

Outcomemeasurementsandstatisticalanalysis: Theprimaryendpointwasobjective responserate(ORR).Thesecondaryendpointsareoverallsurvival(OS),progression-free

*Correspondingauthor.DepartmentofMedicalOncology,BakirkoyDr.SadiKonukTraining,and

ResearchHospital,TevfikSaglamSt.No:11,Bakirkoy,ZuhuratbabaDistrict,Istanbul,Turkey.

Tel.+902124147171;Fax:+902124147172.

E-mailaddress:deniztural@gmail.com(D.Tural).

https://doi.org/10.1016/j.euf.2020.09.010

1. Introduction

Urothelial carcinoma, which is the ninth most common tumor worldwide,is anaggressive malignancywith a 5-yrsurvivalrateofabout5%inthemetastaticsetting[1,2]. Thestandardfirst-linetreatmentformetastatic urothe-lial carcinoma is cisplatin-based chemotherapy, and the median overall survival (OS) ranges from 14 to 15.2 mo

[3].Patientswhorelapsedaftercisplatin-based chemother-apyhaveapoorprognosis,with medianOS rangingfrom 5to7mo[4].

In thepast fewyears, effectiveantitumor activity has beenreported,withseveralimmunecheckpointinhibitors targeting the programmed cell–death protein-1 (PD-1) receptoranditsligand, programmeddeathligand-1 (PD-L1), in metastatic urothelial carcinoma in the first- or second-linesetting[5].

Recently,second-linetreatment optionsfor metastatic urothelial carcinoma have improved with advances in immunotherapy. Pembrolizumab demonstrated improved OS rates: median OS of 10.3 compared with 7.4 mo in metastaticurothelialcarcinomapatientstreatedwith che-motherapy [6]. The single-arm, open-label CheckMate 275studyofnivolumabinpatientswithmetastatic urothe-lial cancer who received prior therapy demonstrated medianOSof8.74mo[7].Atezolizumab(ATZ)has demon-strateditsantitumoractivityandefficacywithmanageable safetyinpreviousstudiesconductedinpatientswithlocally advancedormetastaticplatinum-resistanturothelial carci-noma[8–10].ATZ wasexaminedincisplatin-ineligibleor metastatic platinum-resistant urothelial carcinoma patients in theIMvigor210 phaseII trial, and medianOS of7.9mowasreported[8].

Tothebestofourknowledge,verylimitedreal-lifedata areavailableonpatientstreatedwithATZafter platinum-basedchemotherapy. Inthisstudy,we presenteda retro-spective analysis of patients with metastatic urothelial

cancerwhoweretreatedwithATZafterprogressionwith first-linechemotherapyregistered from35oncology cen-tersinTurkeytoanexpandedaccessprogram(EAP).

2. Patientsandmethods

Weevaluatedtheretrospectivedataof140 patientswith metastatic

urothelialcarcinoma,registeredtotheEAPfrom35oncologycentersin

TurkeybetweenJuly25,2016,andJuly31,2017.Thecutoffdatefordata

analysiswasSeptember21,2019.

Fourteenpatientsdidnotreceiveanytreatmentand126patients

receivedatleastonecycleofATZtreatment.Dataof11patientswerenot

available.Consequently,115patientswhoreceivedatleastonecycleof

ATZ treatment after progressionwith first-line chemotherapy were

finally eligiblefor thestudy.The decisiontoincludethepatientsin

theEAPwastakenbytheattendingphysicianonanindividual

case-to-casebasis.Dataofpatientswereobtainedfromtheirrespectivefilesand

hospitalrecords.Demographic,clinicopathological,laboratory,and

clin-icaloutcomedatawerecollected.

UndertheEAP,thepatientsweretreatedwithATZ,1200mg,

intra-venouslyevery3wkintheoutpatientsettinguntiloccurrenceofdeath

from anycause,unacceptabletoxicity,withdrawalofconsent,orthe

primaryphysician’sdecision.Thestudywasapprovedbythelocalethics

committee(approvalno:2019-291).

Theprimaryendpointwastheobjectiveresponserate(ORR).

Sec-ondaryendpointsincludedOS,progression-freesurvival(PFS),duration

oftreatmentresponse,andsafety.

TheBellmuntmodeldemonstratedthatthreeriskfactorspredictOS

inpatientswiththeplatinum-refractorydiseaseonsecond-line

chemo-therapy.TheseareEasternCooperativeOncologyGroup(ECOG)

perfor-mancestatus(PS)>0,hemoglobinlevel<10g/dl,andthepresenceof

livermetastasis[11].Thepatientswereriskstratifiedaccordingtothe

criteriade_finedinthisclassi_fication.

The medianfollow-up durationwascalculatedusingthe

Kaplan-Meier method and log-rank test for comparison between different

subgroups.Responseswereassessedbycomputedtomographyevery

12 wk according to Response Evaluation Criteria in Solid Tumors

(RECIST),version1.1.Treatmentresponsewasdeterminedbythedata

collectoronthebasisofradiographicstudiesandclinicnotes.

survival (PFS), duration of response, and safety profile of patients. Kaplan-Meier methodswereusedtocalculatemedianfollow-upandestimatePFSandOS.

Resultsand limitations: Data of 115enrolled patients were analyzed. Most of the patients (92.3%, n = 106) had received chemotherapy regimen only once prior to ATZ.Themedianfollow-updurationwas23.5mo.Thecompleteresponserate,partial responserate,andORRwere8.7%(n=10),20.0%(n=23),and28.7%(n=33),respectively. Themediandurationofresponsewas20.4mo(95%confidenceinterval[CI],6.47–28.8). Ofthe33patientswhorespondedtotreatment,60%(n=20)hadanongoingresponseat thetimeoftheanalysis.PFSandOSwithATZwere3.8mo(95%CI,2.25–5.49)and9.8mo (95%CI,6.7–12.9),respectively.All-causeandany-gradeadverseeventswereobserved in113(98%)patients. Ofthepatients, 64%experienceda treatment-relatedadverse eventofanygradeand24(21.2%)hadagrade3–4treatment-relatedadverseevent. Limitationsofthestudyincludeditsretrospectivedesign,anddeterminationof treat-mentresponsebasedonclinicalnotesandlocalradiographicstudies.

Conclusions: Inthesereal-lifedata,ATZwaseffectiveandwelltoleratedinpatientswith metastaticurothelialcarcinomawhohaveprogressedwithplatinum-basedfirst-line chemotherapy.ATZis an effectiveand tolerabletreatmentfor patientswithlocally advancedormetastaticplatinum-resistanturothelialcarcinomainourstudy,similarto previouslyreportedtrials.

Patientsummary: Atezolizumabiseffectiveandwell-toleratedinpatientswith meta-staticurothelialcancerwhoprogressedwithfirst-linechemotherapy,consistentwith theoutcomesofthepreviousclinicaltrialsinthissetting.

OSandPFSweredefinedasthedurationfromthefirstdoseofATZto

deathfromanycauseandthedurationfromthefirstdoseuntildisease

progressionordeathfromanycause,whicheveroccurredfirst,

respec-tively.BothOSandPFSwerecensoredatthedateoflastinformationand

wereestimatedusingtheKaplan-Meiermethod.Exact95%con_fidence

intervals(CIs)wereused.ORRwasde_finedasthebestresponse,either

confirmedcompleteresponseorpartialresponse.Durationofresponse

ratewasdefinedas thetimefromthefirstdocumentedresponseto

diseaseprogressionordeathfromanycause,whicheverwasearlier.All

statisticalanalyseswereperformedusingSPSSStatistics,version23.0

(IBMCorporation,USA).Thesafetyandtolerabilitywereassessedbefore

initiatingeachATZcycleaccordingtoguidelinesenumeratedbythe

NationalCancer InstituteCommonTerminology Criteriafor Adverse

Events,version4.0.

3. Results

Dataof115eligiblepatientswere analyzed,andpatients’ characteristicsareshowninTable1.

Themedianfollow-updurationwas23.5mo.Ofallthe patients,100(87%) weremaleand15(13%)were female. Themedianagewas65.3yr(range,37–86yr).Themajority ofpatients(96.5%;n=111)hadECOGPSscoresof0–1.Ofthe

patients, 87 (77.7%) hada historyof smoking. The most common primary localization occurred in the bladderin 85.2%ofpatients(n=98).Atthetimeofdiagnosis,41.7%of the patients had undergone cystectomy and 40.9% pre-sentedwithmetastaticurothelialcarcinoma.The frequen-ciesofvisceralmetastasisandlymphnode–onlymetastasis beforeATZwere76.5%and15.7%,respectively.Thirty-two patients (27.8%) hadahemoglobin levelof<10g/dl. The breakupoftheprognosticgroupaccordingtothecriteriaof Bellmuntetal[11]inourstudyisdocumentedasfollows:of the patients,18.3% had no riskfactors, 53% hadone risk factor,23.5%hadtworiskfactors,and5.2%hadthreerisk factors.

Most of the patients (92.3%) received chemotherapy regimen only once before ATZ. Priorsystemic treatment includedcisplatin-based chemotherapyin50.4% (n= 58), carboplatin-based chemotherapy in 35.7% (n = 41), and otherchemotherapyregimensin3.6%(n=4),and chemo-therapyregimendatawerenotavailablein10.3%(n=12)of thepatients.

Themedianfollow-upwas23.5mo.Completeresponse rate,partialresponserate,andORRwere8.7%(n=10),20.0% (n = 23), and 28.7% (n = 33), respectively. The median duration ofresponsewas20.4mo(95% CI,6.47–28.8).Of the33patientswhorespondedtotreatment,20(60%)had anongoingresponseatthetimeoftheanalysis(Fig.1).The medianPFSandOS withATZwere 3.8mo(95%CI,2.25– 5.49) and9.8 mo(95%CI,6.7–12.9),respectively.The 12-and 24-mo PFS rates were foundto be 22.3% and 16.9%, respectively.The12-and24-moOSrateswere42.2%and 3.5%,respectively(Fig.2).

In subgroup analyses, the median OS was 2.3 mo in patients with liver metastases, 8.11 mo in patients with ECOGPSscore1,3.35moinpatientswithhemoglobinlevels below 10 mg/dl, 3.08 moin patients with twoBellmunt criteria,1.38moin patientswith three Bellmuntcriteria, and4.56moinpatientswithbaselinecreatinineclearance <60 ml/min.OSresultswithATZinallclinicalsubgroups aredemonstratedinTable2.

All-causeandany-gradeadverseeventswerereportedin 113(98%)of115patients.Ofthepatients,64%experienced one treatment-relatedadverseeventofanygrade,and24 (21.2%) patients hadgrade 3–4 treatment-relatedadverse events.Themostfrequentlyreportedadverseeventswere fatigue (in 53.3% of patients) and decreased appetite (in 41.2%ofpatients).Themostfrequentlyreportedgrade3–4 adverse event wasfatigue (in8% of thepatients; n= 9). Treatmentwasdiscontinuedin7%ofpatients(n=8)dueto treatment-related side effects. Adverse events that war-ranted systemic steroid usewere reportedin onlyseven patients(6.1%).Fourpatients(3.5%)dieddueto treatment-relatedcauses:threebecauseofpneumonitisandonedue tosepsis(Table3).

4. Discussion

The treatment paradigm of metastatic bladder cancer continues to change dynamically due to the use of

Table1–Patientcharacteristics

Characteristics n %

Age(median,yr):65.3(37–86)

Malesex 100 87

Siteofprimarytumor

Bladder 98 85.2 Renalpelvis 11 9.6 Ureter 4 3.5 Urethra 2 1.7 ECOGPS 0 31 27 1 80 69.6 2 4 3.5

Baselinecreatinineclearance<60ml/min 43 37.1

Baselinehemoglobinconcentration<10g/dl 32 27.8

Tobaccouse

Current 29 25

Previous 61 53

Never 25 22

Metastaticsiteatbaseline

Visceral 88 76.5

Liver 19 16.5

Lymphnodeonly 18 15.7

NumberofBellmuntriskfactors

0 21 18.3

1 61 53

2 27 23.5

3 6 5.2

Metastaticatthetimeofdiagnosis 47 40.9

Neoadjuvantchemotherapy 23 20 Cystectomy 48 41.7 Palliative/curativeradiotherapy 37 32.2 Previouschemotherapy Cisplatinbased 59 51.3 Carboplatinbased 42 36.6

Otherandmisseddata 14 12.1

Numberofprevioussystemic

chemotherapyinthemetastaticsetting

1 96 83.5

2 8 7

Unknown 11 9.6

recentlyapprovedcheckpoint monoclonalantibodies as perfindingsinseveralstudies[6–8,12–14].Themajority of clinical trials do not broadly represent real-world populationoutcomes.Manyoftherandomizedcontrolled trialsarehighly selective,that is, patientshave alower riskprofilethan real-worldpopulations[15].To address this problem, this studyaimed toassess the character-isticsandtreatmentpatternsofpatientswithmetastatic bladdercancerwho receivedATZafterfirst-line chemo-therapyoutsideofaclinicaltrial.In reviewingthe liter-ature,limitedreal-lifedatawerefoundtobeavailableon patientswhoweretreatedwithATZafterplatinum-based chemotherapy[16,17].

Inthesecurrentexpandedaccessdata,ATZwas admin-istered to 115patients with urothelial cancerafterbeing treatedwith first-linechemotherapy.Clinicalactivityand safetyobservedfromthecurrentreal-lifedatawere consis-tentwiththeoutcomesofthepreviousstudiesonATZin thissetting[8–10,16–18].

ORRs observed in this study were similar to those reported in previousphase I ATZ, IMvigor210, and IMvi-gor211clinicaltrialsofATZinmetastaticplatinum-resistant urothelialcarcinoma,whichhadsimilarpatientpopulations tothisstudy[8,9,18].

Inourcurrentexpandedaccessdata,themedian dura-tionofresponsewas20.4moatthetimeoftheanalyses.In

Fig.1–SwimmerplotoftimeontreatmentforpatientswhoreceivedmorethanonedoseofATZ.ATZ=atezolizumab;CR=completeresponse;PR=

partialresponse.

longer-termfollow-upofthephaseIATZtrial,themedian durationofresponsewas22.1moinallpatientsatthetime oftheanalyses[18].Thus,thephaseIATZstudysupports our results. In theIMvigor210 and IMvigor211 trials, the mediandurationofresponsewasnotreachedatthetimeof publication[8,9].Inthisstudy,themedianfollow-up dura-tionwaslongerthanthatreportedintheIMvigor210and IMvigor211trials, andthushere we canwitnessa better long-termeffectofATZ[8,9].

In this study, the median PFS and median OS were 3.8 and 9.8 mo, respectively. OS data from this analysis wereconsistent with those in prior ATZ studies

[8–10,16–18]. However, in our current expanded access

data,PFSwaslongerthanthatobservedintheIMvigor210 andIMvigor211studies.

Inourcurrentexpandedaccessdata,wealsoevaluated subgroupsurvivaloutcomes.

Thisstudydemonstratedthatlivermetastasis,poorECOG PS(score1),creatinineclearance<60ml/min,and hemo-globinlevelsbelow10mg/dlwerenegativeprognosticfactors for survival outcomes in patients with urothelial cancer treated with ATZ. These findings are consistent with the previousstudiesthatconductedsubgroupanalyses[8,10,19]. The frequency oftreatment-related adverse events was generally similar to those reported previously [8– 10,17,18].Thetreatment-relatedfatiguewasreportedatthe highestfrequencyatanygrade,andnonewsafetysignalswere identifiedinthstudyincontrasttopreviouslyreportedstudies in patients who received ATZ [8–10,17,18]. In our current expandedaccessdata,weobservedmoredeathsassociated withATZthanthoseintheIMvigor210andIMvigor211trials

[8,9].Thisvariationinoutcomemaybeattributedtoreal-life patients,notbeingselectedbasedonspecificcriteriaasthey wereinclinicaltrials[8,9].Ourobservationsonthetolerability and safety of ATZ in patients with urothelial cancerafter progressionbythefirst-linechemotherapywereinagreement withthepreviousstudiesonATZinthissetting[8–10,17,18].In ourstudy,long-termfollow-upshowedthatgoodtolerability wasmaintainedwithadurableclinicalbenefit.

The mainlimitationsofourstudyareitsretrospective natureandthepresenceofpotentialconfounders.Owingto the retrospective study design, treatment response was determined by the data collector on the basis of radio-graphic and clinical evaluations,and itdid not includea centralevaluationbyablindedradiologistaccordingtothe guidelinesofRECIST,version1.1.

WedemonstratedinthisretrospectivestudythatATZis an effective and tolerable treatment for patients with urothelial cancer treated with ATZ after progression by the first-linechemotherapy. In ourdata,a broaderrange

Table2–Medianoverallsurvivalresultsofthesubgroupsof

115ATZpatients

Subgroups Months 95%CI pvalue

Allpatients 9.8 6.76–12.87 NA Age(yr) 65 8.83 4.43–13.24 0.575 >65 9.82 5.60–14.04 Smoking Yes 10.28 6.98–13.58 0.969 No 7.72 1.88–13.55 Tumorlocalization Uppertract 5.12 2.38–7.86 0.077 Bladder 10.28 7.11–14.45 ECOGPS 0 18.66 9.20–28.12 <0.001 1 8.11 4.85–11.37 2 1.01 0.91–1.12

Baselinecreatinineclearance(ml/min)

<60 4.56 1.33–7.80 0.007

60 14.55 8.04–21.06

Baselinehemoglobinconcentration(g/dl)

<10 3.35 1.59–5.10 <0.001

10 13.56 8.35–18.78

Metastaticatthetimeofdiagnosis

Yes 8.54 5.18–11.89 0.286

No 10.28 5.27–15.29

Lymphnode–onlymetastasis

Yes 17.80 7.11–28.49 0.393 No 8.54 6.05–11.02 Visceralmetastasis Yes 8.70 5.36–12.05 0.705 No 11.89 6.15–17.63 Livermetastasis Yes 2.10 0.61–3.59 <0.001 No 11.89 8.41–15.36

NumberofBellmuntriskfactors

0 20.05 16.28–23.82 <0.001 1 13.07 7.11–19.03 2 3.08 1.69–4.48 3 1.38 0.77–2.68 Cystectomy Yes 10.64 4.26–17.02 0.326 No 9.69 7.29–12.08 Neoadjuvantchemotherapy Yes 9.82 3.02–16.61 0.531 No 9.69 6.36–13.01 Radiotherapy(palliative/curative) Yes 13.37 4.03–22.70 0.167 No 8.21 5.80–10.62

ATZ = atezolizumab; CI = confidence interval; ECOG PS = Eastern

CooperativeOncologyGroupperformancestatus;NA=notapplicable.

Table3–Treatment-relatedadverseeventsofATZ

Adverseevents Anygrade Grade3–4

n % n %

Anyadverseevent 74 64.3 24 21.2

Fatigue 60 52.2 9 7.9 Nausea 13 11.3 0 – Decreasedappetite 42 36.4 2 1.7 Pruritus 16 13.9 0 – Pyrexia 6 5.2 1 0.9 Diarrhea 4 3.5 0 – Rash 7 6.1 0 – Arthralgia 6 5.2 0 – Dyspnea 7 6.1 4 3.5 Anemia 32 27.8 3 2.6

Elevatedaspartateaminotransferase 10 8.7 0 –

Pneumonitis 6 5.2 4 3.5

Hypotension 4 3.5 1 0.9

Colitis 3 2.6 1 0.9

Other 5 4.3 1 0.9

of patients were represented, compared with prior ATZ trials[8–10,18].Furthermore,agreaternumberofpatients who previouslyreceived carboplatin as a first-line treat-ment for metastatic urothelial cancer and patients with ECOG PS 2 were included in this study compared with the patients included in phase1–3 ATZ trials. Thus, this studydemonstratedthatATZwasalsoeffectiveinabroad rangeofurothelialcancerpatientsafterprogressionbythe first-linechemotherapy.

5. Conclusions

ATZhasshownpositiveoutcomesinpatients with meta-staticurothelialcarcinomaafterprogressionfromfirst-line chemotherapy.Larger,wider,prospectivestudiesmightbe beneficialtofurtherconfirmthefindingsofourstudy.

Authorcontributions:DenizTuralhadfullaccesstoallthedatainthe

studyandtakes responsibilityfor the integrityof the dataandthe

accuracyofthedataanalysis.

Studyconceptanddesign:Allauthors.

Acquisitionofdata:Allauthors.

Analysisandinterpretationofdata:Allauthors.

Draftingofthemanuscript:Allauthors.

Criticalrevisionofthemanuscriptforimportantintellectualcontent:All

authors.

Statisticalanalysis:Allauthors.

Obtainingfunding:Allauthors.

Administrative,technical,ormaterialsupport:Allauthors.

Supervision:Allauthors.

Other:None.

Financialdisclosures:DenizTuralcerti_fiesthatallcon_flictsofinterest,

includingspeci_{ficfinancial}interestsandrelationshipsandaf_filiations

relevanttothesubjectmatterormaterialsdiscussedinthemanuscript

(eg,employment/affiliation,grantsorfunding,consultancies,honoraria,

stockownershiporoptions,experttestimony,royalties,orpatentsfiled,

received,orpending),arethefollowing:None.

Funding/Supportandroleofthesponsor:None.

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