Precision and Future Medicine 2019;3(2):77-84 ORIGINAL https://doi.org/10.23838/pfm.2019.00016 ARTICLE pISSN: 2508-7940 · eISSN: 2508-7959 Olaratumab and doxorubicin for the treatment of metastatic soft tissue sarcoma: a retrospective case series 1 1 1,2 Joon Young Hur , Se Hoon Park , Su Jin Lee 1 DivisionofHematologyandOncology,DepartmentofMedicine,SamsungMedicalCenter,SungkyunkwanUniversitySchoolof Medicine,Seoul,Korea 2 DivisionofHematologyandOncology,DepartmentofInternalMedicine,EwhaWomansUniversitySchoolofMedicine,Seoul, Korea Received: March 8, 2019 Revised: April 1, 2019 Accepted: April 18, 2019 ABSTRACT Purpose: Softtissuesarcomas(STS)arearareandheterogeneoustumorgroupwith Corresponding author: Su Jin Lee limitedtreatmentoptions.Thisstudyaimedtoevaluatetheanti-tumorefficacyof Division of Hematology and olaratumabanddoxorubicininpatientswithadvancedSTSinfront-lineandsalvage Oncology, Department of setting. Medicine, Samsung Medical Methods: PatientswithSTSwhoreceivedolaratumabanddoxorubicinbetweenOcto- Center, Sungkyunkwan ber2017andAugust2018wereretrospectivelyreviewed.Responserate,progres- University School of Medicine, sion-freesurvival(PFS),andoverallsurvival(OS)wereanalyzedaccordingtohistologic 81 Irwon-ro, Gangnam-gu, subtype,EasternCooperativeOncologyGroupperformancestatus,andnumberofprior Seoul 06351, Korea chemotherapyregimens. Tel: +82-2-3410-3459 Results: Atotalof26patientswereincludedintheanalysis.Thecommonhistologic E-mail: [email protected] subtypesincludedundifferentiated/unclassifiedsarcoma(n=8),leiomyosarcoma (n= 7),liposarcoma(n= 3),andsolitaryfibroustumor(n= 2).Of26patients,10patients (38.4%)receivedmorethantwochemotherapyregimensbeforeolaratumabanddoxo- rubicin.Atthetimeofanalysis,152cyclesofolaratumabhadbeenadministered(medi- an,fivecycles),andtherewasnotreatment-relatedmortality.Thediseasecontrolrate was61.5%(n= 16),andtheoverallresponseratewas15.3%(partialresponse,n= 4; completeresponse,n= 0).Partialresponseswereachievedinonepatientwithsolitary fibroustumor,onewithdedifferentiatedliposarcoma,onewithleiomyosarcoma,and onewithpleomorphicrhabdomyosarcoma,allinsalvagesetting.Withamedianfol- low-updurationof11.1months(95%confidenceinterval[CI],11.1to13.1months),the medianPFSwas4.1months(95%CI,2.1to6.1months),andthemedianOSwasnot reached. Conclusion: Olaratumabanddoxorubicindemonstratedacceptableanti-tumoractivity inAsianpatientswithsarcoma. This is an Open Access article distributed under the terms of the Creative Commons Attribution Keywords: Doxorubicin;Olaratumab;Sarcoma Non-Commercial License (http:// creativecommons.org/licenses/ by-nc/4.0/). Copyright © 2019 Sungkyunkwan University School of Medicine 77 Olaratumabanddoxorubicininsofttissuesarcoma INTRODUCTION follows:(1)histologicallyconfirmeddiagnosisofadvanced unresectableormetastaticSTSnotamenabletocurative Softtissuesarcomas(STS)accountfor6%ofchildhoodcan- treatmentwithsurgeryorradiotherapyand(2)availabilityof cersand1%ofalladultmalignancies[1,2].Amongmorethan completeclinicalinformationincludingpatientdemograph- 100subtypesofSTS,themostcommonhistologicsubtypes ics,primarytumorsite,stage,andtreatmentrecord.Thefol- areundifferentiatedunclassifiedsarcoma,liposarcoma,leio- lowingclinicopathologicvariableswerecollected:age,sex, myosarcoma,synovialsarcomaandmalignantperipheral histologictype,extentofmetastasis,EasternCooperative nervesheathtumors[3].Surgicalresectionwithappropriate- OncologyGroup(ECOG)performancestatus,andtreatment lynegativemarginsisthestandardprimarytreatmentforre- history.ThestudywasreviewedandapprovedbytheInstitu- sectableSTS,andpatientswithextremitySTSarecommonly tionalReviewBoardofSMC(IRBNo.2018-08-107),andin- treatedwithlimbpreservationsurgeryincombinationwith formedconsentwaswaived. adjuvantradiotherapy[4].Chemotherapywithsingleagents (e.g.,dacarbazine,doxorubicin,epirubicin,ifosfamide,pazo- Treatment panib,trabectedin,oreribulin)oranthracycline-basedcom- Patientsreceiveolaratumab(15mg/kg)intravenouslyon binationregimens(doxorubicinorepirubicinwithifosfamide days1and8plusdoxorubicin(75mg/m²)onday1ofeach and/ordacarbazine)hasbeenwidelyusedforpatientswith 21-daycycle.Aftereightcycles,patientswereallowedtore- advanced,unresectable,ormetastaticdisease[5-8]. ceiveolaratumabmonotherapyuntildiseaseprogression Olaratumab(Lartruvo,EliLillyandCompany,Indianapolis, providedthattheyhavenodiseaseprogressionorunaccept- IN,USA)isafullyhumanimmunoglobulinG1monoclonal abletoxicities.Duringcycles5to8,dexrazoxanewasallowed antibodythatselectivelybindstheexternaldomainofhu- onday1ofeachcycletoreducethepotentialfordoxorubi- manplatelet-derivedgrowthfactorreceptor-α(PDGFR)with cin-relatedcardiotoxicity.Cardiacechographywasdonefor highaffinityandblocksligandbinding[2].InOctober2016, monitoringcardiacfunctionduringtreatment.Treatment theU.S.FoodandDrugAdministrationgrantedaccelerated wascontinueduntildiseaseprogression,unacceptabletoxic- approvaltoolaratumabincombinationwithdoxorubicin ity,orpatientrefusal.Tumorresponsewasevaluatedevery6 (olaratumab+doxorubicin)forthetreatmentofadultpatients or9weeksusingcomputedtomographyscansormagnetic withSTSwithahistologicsubtypeforwhichananthracy- resonanceimaging.Responseswereassessedaccordingto cline-containingregimenisappropriateandnotamenableto theResponseEvaluationCriteriainSolidTumors(RECIST), curativetreatmentwithradiotherapyorsurgery[9]. version1.1.AdverseeventsweregradedaccordingtotheNa- However,studiesontheefficacyandtolerabilityofolara- tionalCancerInstituteCommonTerminologyCriteriaforAd- tumabanddoxorubicininAsianpatientswithsarcomaare verseEventsversion4.0. limited.Inaddition,clinicaloutcomeandtolerabilityofthe regimeninheavilypre-treatedpatientsarescarcelyreported. Statistical analysis Hence,theefficacyandtolerabilityofolaratumabanddoxo- Standarddescriptiveandanalyticalmethodswereusedto rubicininAsianpatientsisyettobeestablishedandshould describethepatientpopulationandtheirbaselinecharacter- beevaluated.Therefore,thisretrospectivestudyaimedto istics.Overallsurvival(OS)wasdefinedasthetimefromthe evaluatetheanti-tumorefficacyofolaratumabanddoxoru- initiationofolaratumabanddoxorubicintreatmenttothe bicininSTSpatientsinAsia.Particularly,wefocusedoneval- dateofdeathorlastfollow-up.Progression-freesurvival uatingthetolerabilityandanti-tumorefficacyinheavily (PFS)wasdefinedasthetimefrominitiationofolaratumab pre-treatedrefractorysarcomapatients. anddoxorubicintreatmenttothedateofdocumenteddis- easeprogressionordeathfromanycause.Kaplan-Meier METHODS curveswereusedtoanalyzetime-to-eventvariables,and 95%confidenceintervals(CIs)werecomputedfortime-to- Study design eventmedians.Survivalcomparisonswereperformedusing Weretrospectivelyreviewedthemedicalrecordsofpatients univariatelog-ranktests.Allstatisticalanalyseswereper- withadvancedSTSwhoweretreatedwitholaratumaband formedusingRversion3.4.4(RFoundationforStatistical doxorubicinbetweenOctober2017andAugust2018atSam- Computing,Vienna,Austria),andtwo-tailedP-valuesofless sungMedicalCenter(SMC),Korea.Inclusioncriteriawereas than0.05wereconsideredstatisticallysignificant. 78 http://pfmjournal.org JoonYoungHur,etal. Table 1. Patient demographics and clinical characteristics RESULTS Characteristic Value Patient characteristics BetweenOctober2017andAugust2018,26STSpatientsre- Total 26(100) ceivedolaratumabanddoxorubicin.Baselinepatientcharac- Age(yr) 53(25–73) teristicsatthestartofolaratumabanddoxorubicintreat- Sex Male 15(57.6) mentaresummarizedinTable1.Themedianagewas53 Female 11(42.3) years(range,25to73years),and57.6%ofpatientswere ECOGPS male.Mostpatients(92.3%)hadagoodECOGperformance 1 24(92.3) status(0–1).Thedistributionofhistologicsubtypeswasas 2 2(7.6) follows:eightpatientshadundifferentiated/unclassifiedsar- Histology coma;seven,leiomyosarcoma;three,liposarcoma;three, Undifferentiated/unclassifiedsarcoma 8(30.7) pleomorphicsarcoma;two,solitaryfibroustumor.French Leiomyosarcoma 7(26.9) FédérationNationaledesCentresdeLutteContreleCancer Liposarcoma 3(11.5) gradeswereavailableforeightpatients(30.6%);sixofthese Solitaryfibroustumor 2(7.6) Pleomorphicrhabdomyosarcoma 1(3.8) patients(23.0%)hadgrade3sarcoma.Theprimarytumor Endometrialstromalsarcoma 1(3.8) sitewasthetrunkorretroperitoneumin19patients(73.0%) Epithelioidsarcoma 1(3.8) andtheextremitiesinfivepatients(19.2%).Themostcom- Carcinosarcoma 1(3.8) monmetastasissiteswerethelung(n=14,53.8%),liver Clearcellsarcoma 1(3.8) (n= 7,26.9%),andbone(n= 4,15.3%). MPNST 1(3.8) Atotalof13patients(50%)ofpatientspreviouslyhadat FNCLCCgrade leastonechemotherapyregimenbeforeolaratumaband 1 0 doxorubicintreatment,whiletheother13patientswereche- 2 2(7.6) 3 6(23.0) mo-naïve.Tenpatients(38.4%)wereheavilypre-treatedwith Unknown 18(69.2) twoormorelinesofchemotherapy. Primarysite Atotalofnine(34.6%),eight(30.7%),seven(26.9%),and Trunkorretroperitoneum 19(73.0) twopatients(7.6%)hadreceivedpriorpazopanibchemo- Extremity 5(19.2) therapy;docetaxelandgemcitabinechemotherapy;etopo- Headandneck 2(7.6) side,ifosfamide,andcisplatinchemotherapy,andpembroli- Organinvolvement zumabchemotherapy,respectively. Lung 14(53.8) Atotalof152cyclesofolaratumabanddoxorubicinthera- Liver 7(26.9) Bone 4(15.3) pywereadministered,withamedianoffivecyclesperpa- tient(range,1to16cycles).Atthetimeofanalysis,threepa- No.ofpriorchemotherapyregimenschemotherapies 0 13(50.0) tientswerestillreceivingolaratumabanddoxorubicintreat- 1 3(11.5) ≥ ment,andtheremaining23patientshadstoppedtreatment 2 10(38.4) becauseofprogression(n= 21),patientrefusal(n= 1),oroth- Agentsusedinpriorregimen(s) erreasons(n= 1). Pazopanib 9(34.6) Docetaxel/gemcitabine 8(30.7)