Metastatic Renal Cell Carcinoma Rapidly Progressive to Sunitinib: What to Do Next?

Metastatic

Renal

Cell

Carcinoma

Rapidly

Progressive

to

Sunitinib:

What

to

Do

Next?

Melissa

Bersanelli

*

,

Roberto

Iacovelli

,

Sebastiano

Buti

,

Nadine

Houede

,

Brigitte

Laguerre

,

Giuseppe

Procopio

,

Ste´phanie

Lheureux

,

R.

Fischer

,

Sylvie

Negrier

,

Alain

Ravaud

,

Ste´phane

Oudard

,

Bernard

Escudier

,

Laurence

Albiges

,

Camillo

Porta

a_{MedicalOncologyUnit,UniversityHospitalofParma,Parma,Italy;}b_{DepartmentofMedicineandSurgery,UniversityofParma,Parma,Italy;}c_{MedicalOncology}

Department,InstitutGustaveRoussy,Villejuif,France;d_{OncologyUnitB,SapienzaUniversityofRome,Rome,Italy;}e_{MedicalOncologyDepartment,Institut}

Bergonie,Bordeaux,France;f_{MedicalOncologyDepartment,CentreEugèneMarquis,Rennes,France;}g_{IRCCSIstitutoNazionaleTumori,Milano,Italy;}h_Medical

OncologyDepartment,CentreFrançoisBaclesse,Caen,France;i_{MedicalOncologyDepartment,TheRoyalMarsdenHospital,London,UK;}j_{MedicalOncology}

Department,UniversityofLyon,CentreLéonBérard,Lyon,France;k_{MedicalOncologyDepartment,BordeauxUniversityHospital,Saint-AndréHospital,Bordeaux,}

France;l_{MedicalOncologyDepartment,HopitalEuropeenGeorgesPompidou,Paris,France;}m_{MedicalOncology,IRCCSPoliclinicoSanMatteo,Pavia,Italy}

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: AcceptedJune19,2019 AssociateEditor: PaulNguyen Keywords: Primaryrefractory Primaryresistance Rapidlyprogressive Renalcellcarcinoma Sunitinib

Tyrosinekinaseinhibitors

Abstract

Background: From10% to26%of patientswithmetastaticrenal cellcarcinoma(mRCC) experiencerapidlyprogressivedisease(PD)ontreatmentwithsunitinib.

Objective: Toinvestigatethebenefitofsubsequenttreatmentwithanothertyrosinekinase inhibitor (TKI) or a mammalian target of rapamycin (mTOR) inhibitor in such primary refractorypatients.

Design,setting,andparticipants: Atotalof150mRCCpatientswithrapidlyPDon first-linesunitinib(withintwocycles,n=93,orfourcycles,n=57)wereidenti_fied:medianage 59yr;nephrectomy86%;histologicalsubtypes:clearcell(77.8%),papillary(14%),and sarco-matoidfeatures(18%);accordingtotheMemorialSloan-KetteringCancerCenterandFrench classifications:goodrisk(11%and7%,respectively),intermediate(68%and63%,respectively), andpoor(21%and29%,respectively).

Outcomemeasurementsandstatisticalanalysis: Datawereretrospectivelycollectedby aquestionnairefrom19EuropeanoncologycentersbetweenMarch2005andMarch2011. Pro-gression-freesurvival(PFS)andoverallsurvival(OS)werecalculated(Kaplan-Meiermethod). Results and limitations: MedianOS fromthestartof first-linetreatmentwas 7.4mo. Second-linetreatmentwasadministeredto86(57%)patients(44mTORinhibitors:23 ever-olimusand21temsirolimus;39TKIsaloneorincombination;threechemotherapy). Second-linePFSwasnotsignificantlydifferentbetweenTKIsandmTORinhibitors(2.0vs0.9mo; p=0.536).MedianOSfromthestartofsecond-linetreatmentwas5.0moformTORinhibitors and6.6moforTKIs(p=0.15).

Conclusions: TreatmentwithfurtherTKIsormTORinhibitorsformRCCpatientsprimarily refractorytofirst-linesunitinibintheobservedtimeperiodachievedveryminimalbenefit, suggestingavoidingTKIrechallengeandpossiblypreferringalternativestrategies,suchas immunecheckpointinhibitors,afterPDtoatreatmentlineincludingaTKIinthissetting. Patientsummary: Thepresentworkcollecteddataabout150patientsaffectedby meta-staticrenalcellcarcinoma,whoreceivedoneofthecurrentstandard ofcareasfirst-line treatment,namely,theantiangiogenicdrugsunitinib,andexperiencedrapidworseningofthe disease.Weinvestigatedanddescribedthesubsequentoutcomeofsuchpatientstreatedwith twodifferenttypesofdrug,administeredassecond-linetherapy,tobetterunderstandthebest strategytoadoptforpatientswhogotnobenefitfromsunitinibandtodescribethecurrent therapeuticapproachinsuchcases.

©2019EuropeanAssociationofUrology.PublishedbyElsevierB.V.Allrightsreserved. *Correspondingauthor.MedicalOncology,UniversityHospitalofParma,ViaGramsci14,Parma 43126,Italy.Tel.+390521702316,+393313581097;Fax:+390521702660.

E-mailaddress:bersamel@libero.it (M.Bersanelli).

https://doi.org/10.1016/j.euo.2019.06.018

1. Introduction

Targetedtherapywithtyrosinekinaseinhibitors(TKIs)has increasedoverallsurvival (OS)ofpatientswithmetastatic renal carcinoma (mRCC) [1,2]. However, a subgroup of patientstreatedwithsuchagentsneverexperiencestumor shrinkage, and can be identified as harboring a “primary refractorydisease”orarapidlyprogressivedisease(PD)to TKI therapy[3].Despitethecurrentavailabilityofnewtreatment options,suchasimmunecheckpoint inhibitors(CKIs),the sequentialuseoforaldrugsandtherechallengeoffurther TKIs are still currently indispensable for patients with a longer course of disease, while no data have yet been providedforCKIrechallenge.Inthislight,itwouldbeusefulto understandwhichtypeofsubsequentmechanismofaction (MOA)couldbeexploitedforprimaryTKI-refractorypatients. Primaryrefractory disease has no standarddefinition, andthismaypartlyaccountforthefewstudiesavailableon patients with rapidly PD [3–5]. The terms are both commonly used to refer to patients in whom the best responseisdiseaseprogressionaccordingtotheResponse Criteria in Solid Tumors (RECIST). Two series have been reportedtodatefocusingonthispopulation:Hengetal.[4]

identified272primaryrefractorycasesamongacohortof 1056 patients receiving TKI (incidence rate, 26%); Busch etal.[5]reported35caseswithintrinsicresistancetoTKIs amongacohortof189patients(18.5%).

In large randomized studies reported with vascular-endothelial growth factor receptor (VEGFR) inhibition as first-linetreatment,theincidenceofPDasthebestresponse was10.3–12%forsorafenib[6,7],18%forpazopanib[8],20% forbevacizumabplusinterferon-

a

Owingtoofthefeelingthatprimaryresistancetosunitinib willapplytootherTKIs,themostcommontreatmentstrategy forpatientswithrapidlyPDinthepre-CKIerawastheuseof mammaliantargetofrapamycin(mTOR)inhibitors,despite thelackofevidencefortheefficacyofsuchswitchinthis setting.GiventhepossibilitytochoosetheCKInivolumabas next-linetherapy,theissuewouldnowbesimple,ifitwere not for the current availability of a new multitarget TKI, namely,cabozantinib,whichgivesthechancetoovercome thepriorTKIresistance(throughMETandAXLinhibition), demonstratinglowerratesofprimaryrefractorycaseswhen indirectlycomparedwithnivolumabassecond-linetherapy (12%vs35%)[12–14].

ConsideringthecurrentlyongoingshiftofCKIsinthe first-linesettingofmRCCtreatment[15,16]and,ontheotherhand, thepossibleapplicabilityofcabozantinibasfirst-lineoption incertainsubgroups(poor/intermediate-riskpatients)[11], whattodoinsecondorsubsequenttreatmentlinesaftera priorTKIstillremainsanactuarialissue.

Theaimofthepresentstudywasthereforetoanalyzethe outcome of second-line treatment of patients rapidly progressing(within24wk)onfirst-linesunitinibtherapy, representingthegoldstandardformRCCprimarytreatment atthetimeofthestudyplanning,todeterminewhetherthe TKI rechallenge strategy, or the mTOR-inhibition switch, stillhasanyclinicalrationale.

2. Patientsandmethods 2.1. Patients

WeperformedaretrospectiveanalysisofdataonpatientswithmRCC whoexperiencedrapidlyPDon_first-linesunitinibtreatment,de_finedas PDwithin24wk(fourcycles)fromstartingtherapyandwithouttumor shrinkageaftertwocyclesofsunitinib.Datawerecollectedbysendinga questionnaire tocontactoncologists from theFrench KidneyCancer Group,ItalianNephro-OncologyGroup,andRoyalMarsdenHospital(UK) for distribution to their members. Members had to complete the questionnaire for all patientswith mRCC ful_filling all the following criteria:(1)patientswithhistologicallyprovenmRCC;(2)patientswho had beentreated withfirst-line sunitinibbetween March 2005and March2011,accordingtostandardschedule(4wkon,2wkoffcycle); (3)patientswhohadprogressedwithin24wk(fourcycles)fromstarting therapyandwithouttumorshrinkageaftertwocyclesofsunitinib;and (4) patients with documentedbaseline characteristics andadequate follow-up.Inallcases,informedconsentmusthavebeenobtainedfor therapyadministration.

Dataregardingpatientsandtheirtumorswereretrospectivelycollected. PatientswereclassifiedaccordingtotheMemorialSloan-KetteringCancer Center(MSKCC)modifiedcriteria[17]andalsoaccordingtotheFrench prognostic criteria [18,19] (performance status [PS] _>0, number of metastaticsites_>1,intervalbetweeninitialdiagnosisofmRCCandsystemic treatment<1yr,andpresenceoflivermetastases).Theprinciplesoutlined intheDeclarationofHelsinkihavebeenfollowedforthepresentwork.

2.2. Statisticalanalysis

OSwascalculatedfromthestartofsunitinibtodeathorthelast follow-up. For patientswho received a second-line treatment, second-line survivalwasalsocalculatedfromthestartofsecondlinetodeathorthe lastfollow-up.Inaddition,progression-freesurvival(PFS)forsecond linewasde_finedastheintervalfromthestartofsecond-linetherapyto thefirstdocumentationofdiseaseprogressionordeathfromanycause, whicheveroccurredfirst.

Allvalueswereexaminedasbinaryvariables.Multivariateanalysiswas performed using the Cox proportional hazardmodel, and a stepwise selectionalgorithmthatusedatypeIerror of0.05 formodelentry and 0.10for elimination. Additional elimination was applied to identify signi_ficant variablesatthelevelofp<0.05.Thechi-squaretestwasusedtoassessthe differences.WeusedPredictiveAnalyticsSoftWare(PASW,v18;IBMSPSS).

3. Results

Overall,150patients(meanage,58yr[range22–83])from 19majorEuropeanoncologycenterswereincludedinthis analysis. Their baseline characteristics are presented in

Table 1.The mean time fromsurgeryto the diagnosisof

metastaticdiseasewas11mo,including78patients(52%) withsynchronousmetastaticdiseaseatdiagnosis.

3.1. Responsetofirst-linetreatmentwithsunitinib

All150patientsreceivedsunitinibasfirst-linetherapy;133 (89%)receivedastandarddoseof50mg4wkonfollowed by2wkoff.Eleven percentofpatients startedatalower doseof37.5(n=13,8.7%)or25mg/d(n=4;2.7%).

Two-thirds of the patients (n=93, 62.2%) stopped treatment withinthefirsttwocycles oftreatmentforPD (12wk),andthe remainder (n=57,37.8%)received upto

fourcycles(Fig. 1).Assessmentofthese57patientsaftertwo cycles identified 29 patients with PD who received two furthercyclesdespitePDonevaluationand28withstable disease (SD)according tothe RECISTcriteriabutwithout anytumorshrinkage,consistentwiththeinclusioncriteria. MedianOSintheoverallpopulationwas7.4mo(6.6–8.2;

Fig. 2). OS was significantly shorter in the group that receivedtwocyclesthaninthegroupreceivingfourcycles (6.0[5.2–6.8]vs9.3[7.4–11.3]mo;p=0.008).

3.2. Responsetosecond-linetreatments

Of the 150 patients, 86 (57.3%) received second-line treatment.Thereasonsfornotreatmentfortheremaining 64 (42.7%)were apoor PS relatedtodisease progression (n=55), diagnosis of brain metastases (n=3), surgery (n=1), patient refusal (n=1), unaffordable treatment (n=1), and unknown (n=3). Second-line response rates were0%forcompleteresponse, 10%forpartialresponse,and 27%forSD.Only22patients(25.5%)experiencedaclinical benefitlastingfor>3mo.

At the time of analysis, 23/150 patients (15.3%) were alive.Mediansecond-linePFSandsecond-linesurvivalwere 1.6 (0.5–2.7) and 5.9 (4.3–7.4) mo, respectively (Fig. 3). MedianOSwassignificantlylongerinpatientswhoreceived second-linetreatmentthaninthosewhodidnot(10.5[8.0– 13.1]vs4.1[2.8–5.5]mo;log-ranktest,p<0.0001).

Amongthe86patientsreceivingsecond-linetreatment, 44 received an mTOR inhibitor (21 everolimus and 23 temsirolimus), 39 received a TKI either alone or in combination(35sorafenib,twoaxitinib,andtwosunitinib plusbevacizumab),andthreepatientsreceived chemother-apy. The groups receiving mTOR and TKI as second-line targeted therapy had similar baseline characteristics

(Table 2). Median second-line survival (6.6 vs 5.0mo;

p=0.157)andsecond-linePFS(2.0vs0.9mo;log-ranktest, p=0.536)werenotsignificantlydifferentbetweenTKIand mTORinhibitors(Table3andFig.4).

3.3. Prognosticvariables

Variables,includingKarnofskyperformancestatus(KPS)of <80,absenceofnephrectomy,increasedbaselinevaluefor lactate dehydrogenase (LDH), MSKCC poor-risk group, number of metastatic sites >1, absence of second-line treatment, and number of cycles (2 vs 4 cycles), were associated with worse OS in univariate analyses. In a multivariateanalysis,aKPSof<80,highbaselinevaluesfor LDH,andcorrectedcalciumwerefoundtobeindependent prognosticfactors.

3.4. Exploratoryanalysis

Among the 150 patients, 122 exhibited PD at two-cycle computedtomographyscan,while28werenonprogressive patientswithnotumorshrinkageaccordingtotheinclusion criteria (Fig. 5A). Patients who had PD at two-cycle evaluationhadmedianOS of6.6mo,whilepatients with SDattwocycleshadmedianOSof9.3mo(p=0.12;Fig.5B). Among the 122 patients with PD at cycle 2, 93 stopped sunitinib withmedianOS of5.9moand29 patientswho received twofurther cycles of sunitinib had 10.0-mo OS (p=0.043; Fig. 5C). It is noteworthy that patients who receivedasecond-linetreatmentafterdiscontinuationdue toprogressionhadOSof5.2versus5.1moforpatientswho stayed on sunitinib despite PD at two cycles (p=0.9;

Fig.5D).

ToinvestigatetheimpactofPDtiming,thepopulationof patients whoreceivedfourcyclesofsunitinibbut experi-encedPDwithtwocycles(n=29)wascomparedwiththose whoexperiencedPDwithinfourcycleswhilenon-PDafter twocycles(n=28).TherewasnodifferenceinOSbetween thesetwopopulations(9.3vs10mo;p=0.9).

4. Discussion

Despiterecentadvancesinthetreatmentofpatientswith mRCC,patientswithrapidlyPDonTKItreatmentrepresent arelativelysubstantialsubsetofpatientswithaverypoor prognosis.Therateofprimaryresistance,definedasPDas Table1–Patientcharacteristics

Characteristics Patients Male/female 115/35 Age(yr) 58(22–83) Diseasecharacteristics(%) T1 6 T2 14 T3 58 T4 8.7 NA 13.3 N0 26.7 N1 10.7 N2 21.3 NA 41.3 Histology(%) Clearcell 77 Papillary 13.5 Puresarcomatoid 5.4 Sarcomatoidcomponent 13 Others 4 Metastaticatdiagnosis(%) 49

Numberofmetastaticsites(%)

1 19 2 33 3 48 Sitesofmetastasis(%) Lung 70 Lymphnode 59 Bone 31 Liver 25 Brain 11 Renalbed 9 MSKCCclassification(%) Good 10.7 Intermediate 63.7 Poor 18.9 NA 6.7 Frenchclassification(%) Good 7.7 Intermediate 62 Poor 28.3 NA 2

thebestresponse,was21%inthepivotalphaseIIItrialof sunitinib[2],anditwasconfirmedinthetworetrospective studiesfocusingonthissubpopulationbyHengetal.[4]and Buschetal.[5](ratesof26%and18.5%,respectively).Since in clinical practice about one patient out of five do not benefit from treatment, the issue of the prognosis and decisionoffurthertreatmentmustbeenlightened.

Inthepresentstudy,whichused24wkasatimelimitto definerefractorydisease,medianOSoftheentirecohortof 150 patients was 7.4mo. These data are consistent with those from Heng et al.’s [4] cohort (6.8mo). Regarding second-linetreatment options,Hengetal. [4] reporteda 40%rateofsecond-linetreatment,whilewereporta57%

rate.Inourexperience,therewasnodifferencein second-linePFSorOSregardlessofthechoiceofaTKIoranmTOR inhibitor,inlinewithHengetal.’s[4]findings.Itmustbe underlined that we provide the most homogeneous comparison between the type of second-line treatments regarding the number of patients (39 vs 44) as well as prognosischaracteristics(Table4).

In our cohort, the overall benefit of a second-line treatment, regardlessofitsnature, ishighlyquestionable withsecond-linePFSof1.6moandsecond-linesurvivalof 5.9mo,consistentwiththosepreviouslyreported[4].

Furthermore, it is still not possible to predictively identifypatientsrefractorytosunitinib.Inourpopulation, the only prognostic element isolated in multivariate analysis was the MSKCC score, with the limitations due to the retrospectivedesignof thisstudyusing data from questionnaires.

Ofnote,theselectionofprogressivepatientswithinfour cyclesoftreatmentprovidesuswithinformationonthree moreaspectsregardingthissubpopulation:

The comparisonamongpatientswithPDattwocycles betweenthosewhobenefitfromanalternativesecondline (n=49)andthose whostayedon sunitinib fortwomore cycles despite progression (n=29) stated no statistical differenceinfavorofatherapeuticchangetoanalternative second line (Fig. 5D). It is therefore highly questionable whetherswitchingtoanotherdrugratherthanstayingon sunitinib despite PD is useful. Nevertheless, this finding could be partially related to a selection bias in favor of patients staying on sunitinib therapy, probablyidentified by the clinicians as individuals with a clinical benefit despitePD.

Fig.1–Populationflowchart.BSC=bestsupportivecare;mRCC=metastaticrenalcellcarcinoma;mTOR=mammaliantargetofrapamycin; PD=progressivedisease;SD=stabledisease;VEGFR=vascular-endothelialgrowthfactorreceptor;4wkON-2wkOFF=4wkon,2wkoffcycle.

Continuingtreatment for twoextra cycles whenPD is diagnosed at firstevaluation, we identified that patients receivingfourcyclesofsunitinibdespitealackofresponse after two cycles (n=29) had better OS than those who experienced PD and stopped sunitinib (n=93; 10.1 vs 5.9mo, p=0.049). This comparison is allowed as the percentageofpatientswhowerereferredtobestsupportive care(47.8% vs 41.8%) is similar in both groups (Fig. 5C).

Therefore,wehypothesizedthatthedifferenceinOSmay indeedberelatedtothelongerexposuretosunitinib.

ThetrendinOSbetweenpatientswhoexhibitPDwithin twocycles(n=122)versusthosewhoexhibitedSDatfirst evaluation(withnotumorshrinkage;6.6vs9.3mo)wasnot significant (p=0.12; Fig. 5B). About the meaning of developing PD after two or four cycles, there was no differenceinOSbetweenpatientsdevelopingPDatthese

Fig.3–Second-linePFSandOS(calculatedfromthestartofsecondline).Cum=cumulative;PFS=progression-freesurvival;OS=overallsurvival.

Table2–Comparisonbetweenbestsupportivecare(BSC)andsecond-linetreatment

Characteristics BSC (n=64) 2ndline (n=86) Chi-squaretest (pvalue) Males(%) 73.4 67.4 0.4 Age(yr) 59(28–83) 57(23–76) 0.4 Diseasecharacteristics Histology(%) 0.6 Cellulesclear 79.0 75.6 Otherhistologies 21.0 23.4 Sarcomatoidfeatures(%) 16.1 19.8 0.6

Numberofmetastaticsites(%) 0.3

1 21.9 17.4 2 29.7 36.0 3 48.4 46.6 Sitesofmetastasis(%) Lung 75.0 66.3 0.2 Abdominalnodes 25.0 47.7 0.005 Liver 26.6 24.4 0.8 Bone 31.3 31.4 0.9 Prognosticfactors(%) Intervaldiagnosis—sunitinib<1yr 67.2 77.9 0.1 KarnofskyPS<80% 26.9 7.1 0.001 Cacorrect>UNR 11.9 4.8 0.1 Hemoglobin<LNR 61.9 38.1 0.004 LDH1.5UNR 21.1 13.4 0.2 MSKCCclassification(%) 0.08 Good 10.2 12.2 Intermediate 59.3 74.4 Poor 30.5 13.4 Frenchclassification(%) 0.4 Good 7.9 7.1 Intermediate 55.6 69.1 Poor 36.5 23.8

twodifferenttimepointsofafour-cycletreatment(9.3vs 10mo;p=0.9),raisingthehypothesisthatwhetherthePD wasoccurringearlierorlaterwithinthefirst6modidnot impact OS. Furthermore, this observation is in favor of definingprimaryresistancenotonlyinPDoccurringwithin 3mobutalsoextendingthedefinitiontothefirst6moof sunitinibtreatment.

Thefirsttwohighlightedpointsdidnotcollidewiththe evidence that the currently available alternative TKI cabozantinibcanachieveabenefitirrespectiveofprimary

resistancetofirst-lineTKI:infact,itisuncertainwhether theinhibitionofMET,RET,orAXLdrivesthemajorclinical activityofcabozantiniborwhetherthebenefitissimplydue toaVEGFRinhibitoryeffect[20].Interestingly,cabozantinib efficacy seems tobeindependent of METexpressionand by its typical “VEGF inhibition–related” toxicity profile. These previous data, together with our current findings, suggest that maintaining “VEGF pressure” can still slowdisease progression irrespectiveof theprimary sensitivitytoTKI[21].

Table3–Second-lineprogression-freesurvival(PFS)andsecond-linesurvival(OS)

Classofsecondline n 2nd-linesurvival n 2nd-linePFS

Valuea _{95%CI Value}a _95%CI

TKI 39 6.6 4.8–8.5 22 2.0 0.3–3.6

mTOR 44 5.0 3.0–7.0 36 0.9 0.1–1.9

Global 83 5.9 4.4–7.4 58 1.6 0.3–2.9

CI=confidenceinterval;mTOR=mammaliantargetofrapamycin;OS=overallsurvival;TKI=tyrosinekinaseinhibitor.

a

ValuelimitedtothemaximaltimeofOS,ifcensored.

Fig.4–Second-linePFSandsecond-lineOSaccordingtothenatureoftreatment.Cum=cumulative;inhib.=inhibitor;mTOR=mammaliantargetof rapamycin;PFS=progression-freesurvival;OS=overallsurvival;TKI=tyrosinekinaseinhibitor;VEGFR=vascular-endothelialgrowthfactorreceptor.

Fig.5–Exploratoryanalysis.(A)Overallpopulation.(B)PrognosisofpatientswithSDversusPDwithintwofirstcyclesofsunitiniba

SDwithnotumor shrinkage.(C)PrognosisofpatientswithPDattwocycles:differencebetweensunitinibarrestandsunitinibcontinuation.(D)PatientswithPDattwo cycles:similarprognosisofpatientswithsecond-linetreatmentversussunitinibcontinuation.BSC=bestsupportivecare;OS=overallsurvival; PD=progressivedisease;pts=patients;SD=stabledisease.a

Finally,weprovidedinformativeobservationson patho-logicalcharacterization:ourpopulationincludedarelatively highproportionoftumorswithsarcomatoidfeatures(18%) compared withhistorical cohorts [22,23], underlining the interest fordifferent therapeutic strategiesin these poor-prognosissubtypes,which maybenefitfrom conventional chemotherapy[24]andpossiblyfromtheuseofCKIs[25].

The designof ourstudy hasseveral caveats.First, the studycohortisoutdated,referringtoyears2005–2011and lacking cases treated with second-line nivolumab or cabozantinib; thus, it is limited to providing data about classicaltherapeuticoptions(suchas"old"TKIsandmTOR inhibitors), beyond the obvious possibility to treat TKI-refractorypatientswith thenewimmunotherapy,incase theyhavenot receiveditpreviously.Then, thestudywas retrospective, relied on the analysis of data from ques-tionnaires,andthenumberofpatientsdidnotexceed150, althoughthepatientswerefrommanyoncologycentersin three countries. Our study nevertheless has several strengths. Weused areproducibledefinitionfor primary refractory disease (progression within four cycles of treatment); the numbers of patients receiving TKIs or mTOR inhibitors as second-line treatment were well balanced; we applied two different classifications for prognosis;detailswereavailableontumorhistology. 5. Conclusions

RapidlyprogressivemRCCpatientscanbeconsideredhaving asimilardismalprognosistopoor-prognosispatients.The TKI or mTOR switch strategy might not be superior to continuedtreatmentwith sunitinibinthissetting. Never-theless, given the current rapidly changing treatment landscape for first-line approach in mRCC, the setting representedinthisstudyisgoingtobeoutdated.Moreover, thepresentstudyonlyreporteddataaboutsunitinib,withno clearapplicabilityforpazopanib,anddoesnotprovidedata aboutthenewmultitarget TKIcabozantinib. Actually, our findingscanstillbeusefultosuggestonlyachangeofthe MOA, considering immunotherapy as possibly the best managementoptionforprimaryrefractorypatientstoTKI, inviewoftheirpoorprognosisandthelackofefficacyof“old” second-linetreatments.

Authorcontributions:MelissaBersanellihadfullaccesstoallthedatain thestudyandtakesresponsibilityfortheintegrityofthedataandthe accuracyofthedataanalysis.

Studyconceptanddesign:Albiges,Iacovelli,Porta,Escudier.

Acquisitionofdata:Albiges,Iacovelli,Porta,Houede,Laguerre,Procopio, Lheureux,Fischer,Negrier,Ravaud,Oudard,Escudier.

Analysis and interpretationof data: Albiges, Iacovelli, Porta, Houede, Laguerre,Procopio,Lheureux,Fischer,Negrier,Ravaud,Bersanelli,Buti, Oudard,Escudier.

Draftingofthemanuscript:Albiges,Porta,Bersanelli,Buti,Escudier. Critical revision of the manuscript for important intellectual content: Albiges,Iacovelli,Porta,Houede,Laguerre,Procopio,Lheureux,Fischer, Negrier,Ravaud,Bersanelli,Buti,Oudard,Escudier.

Statisticalanalysis:Iacovelli,Houede,Laguerre,Lheureux,Fischer. Obtainingfunding:None.

Administrative,technical,ormaterialsupport:None. Supervision:Albiges,Porta,Escudier.

Other:None.

Financialdisclosures:MelissaBersanellicerti_fiesthatall con_flictsof interest, includingspeci_{fic financial}interests andrelationships and affiliationsrelevanttothesubjectmatterormaterialsdiscussedinthe manuscript(eg,employment/affiliation,grantsorfunding, consultan-cies,honoraria,stockownershiporoptions,experttestimony,royalties, orpatentsfiled,received,orpending),arethefollowing:L.Albigesand R.Iacovelli:none.C.Portastatedtohavereceivedresearchgrantsfrom BayerScheringPharmaandNovartisPharma,aswellashonorariafrom BayerScheringPharma,PfizerOncology,HoffmanLaRoche,GSKand NovartisPharma.N.Houede,B.Laguerre,G.Procopio,S.Lheureux,and R.Fischer:none.S.NegrierstatedhonorariumfromPfizer,GSK,Roche, andNovartis.A.RavaudstatedtobeamemberofglobalEuropeanand Frenchadvisoryboardsonurologicaltumorsandmedicaltreatments for Novartis,P_fizer,BayerSchering,GSK,Roche,andDendreon;and receivedinstitutionalgrantsfromNovartisandRoche.S.Butireceived honorariaas aspeakeratscientificeventsandforadvisory roleby Brystol-Myers Squibb (BMS), Pfizer, MSD, Ipsen, Roche, Eli-Lilly, AstraZeneca,andNovartis;andalsoreceivedresearchfundingfrom Novartis. M.Bersanellireceivedhonorariaas aspeakeratscientific eventsbyBrystol-MyersSquibb(BMS)andP_fizer;asaconsultantfor advisoryrolebyNovartis,Mundipharma,BMSandP_fizer;asamedical writer by Mundipharma;and also received research fundingfrom Seqirus,Pfizer,Novartis,andBMS,andtravelexpensesforscientific eventsfromBMS,Pfizer,MSD,Ipsen,Roche,Eli-Lilly,andNovartis.S. Oudard:none.B.EscudierstatedhonorariafromBayer,Roche,Pfizer, Wyeth,andNovartis.

Funding/Supportandroleofthesponsor:None. Table4–Second-linecharacteristicsbetweenmTORgroupandVEGFRinhibitorgroup

Characteristics VEGFRinhibitor

(n=39) mTORinhibitor (n=44) Chi-squaretest (pvalue) Males(%) 89.7 70.5 0.03 Age(yr) 57(31–83) 56(28–78) 0.5 Histology(%) 0.8 Cellulesclear 76.9 75.0 Otherhistologies 23.1 25.0 Sarcomatoidfeatures(%) 15.4 20.5 0.5

Numberofsunitinibcycles(%) 0.9

2 54.4 56.8

4 43.6 43.2

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