European Journal of Endocrinology 10.1530/EJE-17-0243 3 de ,, 1 Juan Jose Reina Beatriz González Astorga between MKIsissuggested in thyroidcancer, highlighting theimportanceofprospectivesequentialclinicalstudies. thyroid cancerregardlessofhistologyasfirst-linetherapy. To ourknowledge,thisisthefirsttimethatcross-resistance Conclusion mucositis (29.8%);grade3/4AEsincludedanorexia(6.4%), diarrhoea(4.3%)andcardiactoxicity(4.3%). dose reductionto3 PFS of13.6 monthscomparedwith16.7%and10.6 months assecond-linetreatment.Twelve (25.5%)patientsrequired 9.4 months (95%CI:4.8–13.9)).Betteroutcomeswerereported withfirst-lineaxitinib,anORRof53%andamedian 29.4% andMTC:23.1%)medianPFSwas8.1 months (95% CI:4.1–12.2)(DTC:7.4 months3.1–11.8)andMTC: as third/fourth-linein12patients(25.5%).Withamedian follow-upof11.5 months(0–24.3),ORRwas27.7%(DTC: Results Regulatory authoritiesvalidatedtheCUP, and allpatientssignedinformedconsentform. In SolidTumors (RECIST)v1.1.Progression-free survival(PFS)andadverseevents(AEs)weresecondaryobjectives. 5 (DTC, Subjects andMethods programme (CUP)inSpain(October2012–November2014). Background Abstract Department, UniversityofBarcelona,HospitalClínicSpain d’Hebron UniversityHospital,UniversitatAutònomadeBarcelona,Spain,and Creu iSantPau,Barcelona,Spain, University HospitalRamónyCajal,,Spain, 16 Reina Sofía,Córdoba,Spain, 13 Hospital VirgendelasNieves,,Spain, Endocrine SurgeryDepartment,UniversityHospitalReyJuanCarlos,Madrid,Spain, , Spain, Hospital ClínicofBarcelona,Spain, Barcelona, Spain, Hospital ofMóstoles,Madrid,Spain, Institute (ICO-),UniversityHospitalGermansTrias yPujol,Barcelona,Spain, Carles Zafón Llopis Jaume Capdevila refractory medullarythyroid cancer(MTC) differentiated (DTC)and Axitinib treatment inadvancedRAI-resistant Endocrinology Department,UniversityHospitalPuertadeHierro,Madrid,Spain, Medical OncologyDepartment,GastrointestinalandEndocrineTumor Unit,Vall d’HebronUniversityHospital,UniversitatAutònoma Endocrinology Department,UniversityHospitalPuertadeHierro,Madrid,Spain, Medical OncologyDepartment,HospitalVirgendelaSalud,Toledo, Spain, DOI: 10.1530/EJE-17-0243 www.eje-online.orgwww.eje- Clinical Study n : Axitinibwasadministeredasfirst-linetherapyin17patients (36.2%),assecond-linein18patients(38.3%)and

= online.org 34) ormedullarythyroidcancer(MTC, mg b.i.d.Theprimaryefficacy endpointwasobjectiveresponserate(ORR)byResponseEvaluationCriteria : Axitinibhadatolerablesafetyprofileandclinicallymeaningful activityinrefractoryandprogressive : Axitinib,anantiangiogenicmultikinaseinhibitor(MKI),wasevaluatedinthecompassionateuse 7 9 Medical OncologyDepartment,Translational GenomicsandTargeted TherapeuticsinSolidTumors (IDIBAPS),

Medical OncologyDepartment,UniversityHospitalofSantaCreuiSantPau,Barcelona,Spain, 15 1 , Nuria Palacios , José Manuel Trigo mg b.i.d.All-gradeAEsincludedasthenia(53.2%),diarrhoea (36.2%),hypertension(31.9%)and 6 , Òscar Reig : 47patientswithadvancedradioactiveiodine(RAI)-refractorydifferentiated thyroidcancer 15 Medical OncologyDepartment,UniversityHospitalVirgenMacarena,Sevilla,Spain, 2 Medical OncologyDepartment,UniversityHospitalVirgendelaVictoria,Málaga,Spain, 19 11 Medical OncologyDepartment,GastrointestinalandEndocrineTumor Unit,Vall , Ana López-Alfonso © 2017EuropeanSociety ofEndocrinology J Capdevilaandothers 7 , Uriel Bohn 16 8 12 6 Medical OncologyDepartment,UniversityHospitalofGranCanariaDoctorNegrín, , Enrique Grande Endocrinology andNutritionDepartment,Vall d’HebronUniversityHospital, Medical OncologyDepartment,UniversityHospitalInfantaLeonor, Madrid,Spain, 18 2 Medical OncologyDepartment,UniversityHospitalofSanta , Javier Aller Printed inGreatBritain 8 n , Teresa Ramón y Cajal

= 12 13) withdocumenteddiseaseprogressionweretreated , Javier Medina Martínez 3 17 , José Luís Manzano , Elena Cillán 14 Medical OncologyDepartment,UniversityHospital cancer Axitinib inrefractorythyroid Published byBioscientifica Ltd. 4 Medical OncologyDepartment,Catalan 17 11 Medical OncologyDepartment, 5 Medical OncologyDepartment,University Medical OncologyDepartment,University 20 Medical Oncology 18 , Ignacio Matos 9 , Manuel Duran-Poveda 4 , Silvia García Adrián 13 , Ignacio Porras Downloaded fromBioscientifica.com at10/02/202109:35:03AM 10 19 General and and (2017) Endocrinology European Journal of [email protected] Email to JCapdevila should beaddressed Correspondence Juan Jose Grau 177 14 10 177 : , 4 5 177 , , :4 , 309–317

309 20 –317 via freeaccess European Journal of Endocrinology targeting the VEGF pathway have shown significant efficacy targeting theVEGFpathwayhaveshownsignificantefficacy processes ( endothelial growthfactor(VEGF)andincreasedangiogenic the mostfrequent. and anaplasticthyroidcarcinoma (ATC), withDTCbeing carcinoma thyroidcarcinoma (DTC), medullary (MTC) thyroid carcinoma byhistology aredifferentiatedthyroid of thyroid cancer with 7500 deaths. The main types of deaths in2012( individuals worldwideandresultedinabout40000 Thyroid cancer was diagnosed in approximately 298,000 Introduction • • • objectives: Learning prospective sequentialclinicalstudies( in thyroidcancerandhighlightingtheimportanceof treatment, suggestingcross-resistancebetweenMKIs reported whenaxitinibwasadministeredasafirst-line tumour histology(DTCorMTC).Betteroutcomeswere and progressive thyroid cancer regardless of refractory and providedpromisingclinicalefficacytopatientswith therapies. Axitinib, an antiangiogenic MKI, was tolerable orlocoregional tostandardsurgery cancer (MTC)refractory thyroid differentiated thyroidcancer(DTC)ormedullary frequently used to treat radioactive iodine (RAI)-refractory Antiangiogenic multikinaseinhibitors(MKIs)are Implications forpractice www.eje-online.org Antiangiogenic multikinaseinhibitors(MKI)are Current practice Table 1 • • • approved forthetreatmentof thyroidcancer treatment ofrenalcellcarcinoma, hasnotbeen antiangiogenic MKIcurrentlyapproved forthe managed withsurgeryorlocal therapies.Axitinib,an medullary thyroidcancer(MTC) thatcannotbe refractory differentiated thyroidcancer(DTC)or frequently usedtotreatradioactiveiodine(RAI)- Clinical Study MKIs inthyroidcancer. Understand thepossibilityofcross-resistancebetween first-line MKIaxitinib. thyroidcancerreceive when patientswithrefractory Recognize thepotentialforimprovedclinicaloutcomes thyroidcancer.axitinib inpatientswithrefractory Delineate the efficacy andsafety profile ofthe MKI Thyroid tumours have elevated levels of vascular Thyroid tumourshaveelevatedlevelsofvascular Implications oftheuseantiangiogenicmultikinaseinhibitors inthetreatmentofDTCandMTC. 2 ). Several multikinase inhibitors (MKIs) ). Severalmultikinaseinhibitors(MKIs) 1 ). InEuropetherewere63000cases J Capdevilaandothers Table 1 ). Axitinib haspromisingclinical Best practice in thesepatients considered forfurtherresearch (DTC orMTC)andmightbe regardless oftumourhistology progressive thyroidcancer of patientswithrefractoryand efficacy asfirst-linetreatment and safety of axitinib in patients with advanced thyroid and safetyofaxitinibinpatientswithadvancedthyroid cancer ( in hepatocellularcarcinoma andnon-smallcelllung cytokine) andalsohasbeentestedassecond-linetherapy (RCC) afterfailureofpriorsystemictherapy(sunitinibor approved forthetreatmentofadvancedrenalcellcarcinoma receptors (VEGFRs)1,2and3.Thisdrugiscurrently unresectable metastaticMTC( toRAItherapyandlocallyrecurrentor DTC refractory MKIs forthetreatmentofpatientswithmetastatic Current treatmentguidelinesrecommendantiangiogenic DTC. forradioactiveiodine(RAI)-refractory or symptomaticunresectableMTC,andsorafenib include cabozantinibandvandetanibforprogressive strategy inthesetumours.Approvedtherapeuticagents that targetingangiogenesisisanappropriatetherapeutic thyroidcancer,in advancedandrefractory corroborating included in the Spanish CUP of axitinib for metastatic This wasaretrospectivelongitudinalstudyofpatients Design andpatientpopulation Subjects andmethods (GETHI, Spanish Task Force forOrphanandInfrequentTumours (CUP) ofaxitinib.Thestudywasconductedwithinthe treated inSpainwithinacompassionateuseprogramme DTCandlocallyadvancedormetastaticMTC refractory being themostfrequentlyreportedadverseevents(AEs). hypertension, weightdecreaseandhand-footsyndrome axitinib wasmanageable,withdiarrhoea,fatigue,nausea, ( PFS of15.0–18.1 months overall response rate (ORR) of 30%–38% and a median active, welltoleratedandreportedaninvestigator-assessed antiangiogenic agents,previouslyshowedthataxitinibwas cancer, whohadnotpreviouslyreceivedtreatmentwith cancer Axitinib inrefractorythyroid Axitinib is an oral, potent and selective MKI of VEGF Axitinib isanoral,potentandselectiveMKIofVEGF We reporttheanalysisofpatientswithadvanced RAI- 6 Grupo EspañoldeTumoresGrupo eInfrecuentes Huérfanos , 7 , 8 ). Two phaseIIstudiesevaluatingtheefficacy Better outcomeswerereportedwhen The resulting gap tial clinicalstudies importance ofprospectivesequen thyroid cancerandhighlighting the cross-resistance betweenMKIs in first-line treatment,suggesting axitinib wasadministeredasa Downloaded fromBioscientifica.com at10/02/202109:35:03AM 9 , 10 3 , , 4 11 , 5 ). The safety profile of ). Thesafetyprofileof ). 177 :4

310 via freeaccess - ). European Journal of Endocrinology disease progressionasdetermined bytheinvestigatoror the timefrominclusioninto theCUPuntilaneventof (PFS)definedfrom safety profile,progression-free survival included intheCUP. endpointsincluded Thesecondary to-treat (ITT)population,whichincludedallpatients The efficacyanalyseswereperformedontheintent- Evaluation CriteriaInSolidTumors (RECIST)v1.1( and complete responses obtained according to Response of theobjectiveresponserate(ORR)thatincludedpartial endpointwas determination (CTCAE) v4.0.Theprimary the Common Terminology Criteria for Adverse Events patients withthyroidcancerwasdefinedaccording to cancer centresinSpain.Thesafetyprofileofaxitinib in who receivedaxitinibaspartoftheCUP in 16referral with radiologicallydocumenteddiseaseprogression, DTC,orunresectablemetastaticMTC refractory clinical outcomeofpatientswithadvancedRAI- We soughttodefinetheefficacy, toxicityprofile and Objectives 8–12 weeks. (CEA) wereperformedevery thyroglobulin, calcitoninandcarcinoembryonic antigen imaging techniqueused.Tumour markerevaluationsof define responseorprogressiondiseaseregardlessofthe weeks.RECISTv1.1hasbeenusedto 8–12 PET every radiologically by CT scan, MRI or fluorodeoxyglucose month and following routine clinical practice every informed consentdocument.Patientswereevaluated authorities,andallpatientssigned and localregulatory the study. Theprogrammewasapprovedbynational months oftreatmentwithotherMKIswereincludedin in thisstudy, orfollowingdiseaseprogressionwithin6 allowed tobetreatedwithaxitinibasfirst-linetherapy offollow-up.Patientswere progression within6 months cancer subtypeswithradiologicallydocumenteddisease Patients withpapillary, thyroid follicularandmedullary was reducedto3 b.i.d. Whendosereductionwasnecessary, axitinibdose 7 dose increasedto7 ≤ b.i.d. withnoadversereactionsandbloodpressure permitted as perthe SmPC. Patients tolerating 5 Doseescalationwas disease progressionwasobserved. clinical benefit,untilunacceptabletoxicityoccurredor treated withaxitinib5 between October2012andNovember2014.Patientswere thyroid carcinoma. PatientswereincludedintheCUP 150/90 mg b.i.d.couldalsohavetheirdoseincreasedto10 Clinical Study mmHg for two consecutive weeks could have their mg b.i.d.andfurtherto2 mg. Subsequently, patientstolerating mg b.i.d.aslongitprovided J Capdevilaandothers mg b.i.d. 12 mg mg ). ). responders ( purposes ofcalculatingORRtheywereconsiderednon- were considered‘Notevaluable/missing’,andforthe response. Patientswithunavailableresponseassessments was assessedonthebasisofinvestigator-assessedtumour statisticsarepresentedforallvariables.Efficacy Summary Statistical analysis that hadbiomarkerinformationavailable. biomarker analyseswerecarriedoutinthepopulation at least30% from thebaselinelevelsof biomarker. The be aresponderbybiomarkersiftherewasreductionof calcitonin andCEAforMTC.Apatientwasconsideredto tumour markerlevels:thyroglobulinforDTC,and calcitonin, and their correlation between efficacy and analyses werecarriedoutforthyroglobulin,CEAand from inclusionintotheCUPuntildeath.Biomarker (OS)definedfromthetime death, andoverallsurvival are shownin baseline patientcharacteristics andprevioustreatments compared withpatients MTC(23%); significantly more frequent in patients withDTC (74%) metastases) andbones.Lungmetastaticdiseasewas lymphadenopathies intheneckanddistantlymphnode metastasis werelungs,lymphnodes(bothunresectable had MTC histology ( one patientaxitinibwasstoppedduetoaGrade4AE. discontinued treatmentduetodiseaseprogressionand in are continuingtreatmentwithaxitinib,34patients was 4.7(range:0–32.5) years. AsofMay2015,12patients between diagnosisandstartingtreatmentwithaxitinib when startingtreatmentwithaxitinib.Themediantime analysis. Themeanageofthepatientswas62 axitinib viatheCUPandwereincludedinthisretrospective Forty-seven patientsfrom16centresinSpainreceived Patient population Results or higher. undertaken withthestatisticalsoftwareSPSSversion17.0 was establishedat markers and efficacy. The levelof statistical significance distribution usedforthecorrelationbetweentumour and OS,withcorresponding2-sided95%CIs estimates wasusedtoobtainofmedianPFS cancer Axitinib inrefractorythyroid Thirty-four (72%)patientshadDTCand13(28%) 12 Table 2 ). Log rank of Kaplan–Meier survival ). LogrankofKaplan–Meiersurvival . Table 2 P

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European Journal of Endocrinology www.eje-online.org MKI, multikinase inhibitor;MTC,medullarythyroidcancer. DTC, differentiated thyroid cancer;EBRT, externalbeamradiotherapy;ECOGPS,EasternCooperativeGroupOncologyPerformanceStatus; c a response, butall47patients wereincludedintheITT Overall, 38ofthe47patients haddataonradiologic Efficacy radiological responseandno additionalsideeffects. was increased from 5 had DTC and 5 had MTC). Only in one patient the dose 5 patients whohadadosereductionofaxitinibfromthe line treatmentfor2(4%)patients.Therewere12(25.5%) third-line treatmentfor10(21%)patientsandfourth- patients, second-linetreatmentfor18(38%) Overall, axitinibwasfirst-linetreatmentfor17(36%) in patients with MTC it was 6.9 (range: 0–24.3) months. and treatment durationwas8.1(range:0–22.4) months, months. In patients with DTC the median 0–24.3) Median treatment with axitinib was 7.1 (range: Treatment MKI Surgery Previous treatments, CNS Liver Bone Lung Location ofmetastases, Hürtle Follicular Papillary Histology (%) 2 1 0 ECOG PS Age atstartoftreatment,years Female Male Sex, Characteristic Table 2 Histology subgroup onlyforDTC. One patientwithDTCwasmissingECOGPS; mg b.i.d.startingdoseto3 No priorpharmacologicaltreatment Adjuvant Adjuvant EBRT Radioactive iodine Thyroid (localunresectabledisease) Lymph nodes Poorly differentiated Median (range) Clinical Study 3 priorMKI 2 priorMKI 1 priorMKI n (%) b a (%) Patient demographics,diseasecharacteristicsandpriortreatmentregimens. n (%) n mg b.i.d. to 7 (%) mg b.i.d(7ofthesepatients J Capdevilaandothers b Prior MKIsincludedsorafenib,lenvatinib,vandetanib,,sunitinibandlucitanib; mg b.i.d., with no Patients withDTC 13 (38.2) 14 (41.2) 21 (61.8) 34 (100) 32 (94.1) 11 (32.4) 25 (73.5) 24 (70.6) 10 (29.4) 15 (44.1) 17 (51.5) 10 (30.3) 64 (26–82) 18 (52.9) 16 (47.1) 1 (2.9) 1 (2.9) 9 (26.5) 3 (8.9) 6 (17.6) 6 (18.2) 1 (2.9) 6 (17.6) 2 (5.9) 4 (11.8)

( n =34) (95% CI:4.1–12.2)( line treatment. line treatment and in 50% of patients receiving second- DCR wasreportedin82% ofpatientsreceivingfirst- after progressiontoapreviousMKI( patients whoreceivedaxitinibassecond-linetreatment treatment, with an ORR of 53% compared with a 17% in inpatientswhoreceivedaxitinib asfirst-line observed according to the line of treatment, a better outcome was patient populations.Whenresponseratewasanalysed The resultswerecomparableinboththeDTCandMTC by RECISTv1.1criteria)were28%and55%respectively. response (26%). The ORRand disease control rate (DCR in 13(28%)patientsandprogressivedisease12 response wasreported in 11 (23%) patients, stable disease best radiologic response totreatment( analyses. Two (4%)patientshadacompleteresponseas cancer Axitinib inrefractorythyroid Median PFS of the ITT population was 8.1

+ partial response Patients withMTC 66 (37–79) 10 (76.9) 3 (23.1) 2 (15.4) 2 (15.4) 3 (23.1) 4 (30.8) 2 (15.4) 6 (46.2) 5 (38.5) 6 (46.2) 7 (53.8) 4 (30.8) 1 (7.7) 4 (30.8) 4 (30.8) 9 (69.2) 1 (7.7) 2 (15.4) 0 (0) 0

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( + n ), witha7.4 =13) stable diseaseasbestresponse 177 al 4 Table Table 3 All patients :4 month (95%CI: 11 (23.4) 13 (27.7) 28 (59.6) 28 (59.6) 23 (50.0) 15 (32.6) 64 (26–82) 23 (48.9) 24 (51.1) 17 (36.2) 10 (21.3) 18 (38.3) 30 (63.8) 34 (72) 42 (89.4) 1 (2.1) 4 (8.5) 8 (17.4) 2 (4.3) 3 (6.4) 6 (12.8)

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European Journal of Endocrinology Best tumourresponse(%) Table 4 (68%). Thyroglobulinwasincludedintheanalysiswhen patients withDTC,aresponsein15 Thyroglobulin levelswereavailablein22ofthe34 Biomarker analyses third-line treatment(6.4 months). median OShadonlybeen reached inpatients receiving patients withfewerlinesofprevioustreatment;indeed in significantly improvedmedianOSwasalsoobserved (95%CI:18.4–19.4))populations.A MTC (18.9 months months(95%CI:16.5–24.9))and in theDTC(20.7 16.6–22.8) intheoverallpopulationandwascomparable treatment benefitinfunctionofline( regardinghistologyand differences wereobserved 2.0–5.2) in third-line treatment. No statistically significant months(95%CI: 6.8–14.3) insecond-lineand3.6 (95%CI: who receivedaxitinibasfirst-line,10.6 months (95%CI:8.5–18.6)inpatients the PFSwas13.6 months who hadreceivedfewerpriorlinesoftreatment.Therefore Similarly, medianPFSwassignificantlybetterinpatients months(95%CI:4.8–13.9)inpatientswithMTC. 9.4 3.1–11.8) median PFS in patients with DTC and Overall responserate(%) Besut tumourresponse(%) Table 3 DTC, differentiated thyroidcancer;MTC,medullary cancer. progressive disease. There were2patientswhoreceived axitinibas4 Disease controlrate(%) Overall responserate(%) DTC, differentiated thyroidcancer;MTC,medullarycancer. lung andlymphnodemetastasesupto2–3 followed byCTscansandmaintainedcompleteresponseatthetimeofdataanalysis.Inbothcases,tumourburdencanbeconsideredlow-medium,with *The twocompleteresponseswereobservedinpatientswithpapillarythyroidcancerlungandlymphnodemetastases.Both Disease controlrate(%) Clinical Study Not evaluable/missing Progressive disease Stable disease Partial response Complete response* Not evaluable/missing Progressive disease Stable disease Partial response Complete response h einO a 97 months(95%CI: The medianOSwas19.7 Best responseratetoaxitinibinpatientswithadvancedthyroid canceraccordingtothelineoftreatment. Best responseratetoaxitinibinpatientswithadvancedthyroidcancer.

J Capdevilaandothers cm ofmaximumdiameter. 1st lineaxitinib th Patients withDTC linemultikinaseinhibitor. Onepatient reportedapartialresponseandonepatienthad 14 (82.4) 0 9 (52.9) 3 (17.6) 5 (29.4) 8 (47.1) 1 (5.9) 18 (52.9) 10 (29.4) 8 (23.5) 8 (23.5) 8 (23.5) 8 (23.5) 2 (5.9)

P

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(50%) andacalcitoninbiomarkerresponsein7patients MTC; therewasaCEAbiomarkerresponsein5patients calcitonin expressionwereavailablein10patientswith was performedduetothelownumberofcases.CEAand analysis of variations in anti-thyroglobulin antibodies anti-thyroglobulin antibodieswerenotpresent.No ( The mostfrequentlyreportedAEswereasthenia(53% Safety radiological andbiologicalresponse. between statistically significantcorrelationwasobserved CEA andcalcitonininpatientswithMTC.Thereforeno for thyroglobulininpatientswithDTC,0.14/0.05 > between (70%). TheKappaindexcorrelationobserved with DTC.Thecardiactoxicitywasanacutemyocardial only 1Grade4AEreported,acardiactoxicityinpatient of Grade1or2,withfew Grade 3AEs reported. There was MTC populations.ThemajorityoftheAEsreportedwere frequency andtypeofAEwerecomparableintheDTC ( cancer Axitinib inrefractorythyroid n n 30% biomarkerreductionandORR/DCRwas0.05/0.68

= = 2nd lineaxitinib 15)) andmucositis(30%( 25)), diarrhoea(36%(

9 (50.0) 3 (16.7) 5 (27.8) 4 (22.2) 6 (33.3) 2 (11.1) 1 (5.6) Patients withMTC 0 1 (7.7) 4 (30.8) 5 (38.5) 3 (23.1) 8 (61.5) 3 (23.1)

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( n ). The =47) 313 via freeaccess European Journal of Endocrinology www.eje-online.org trials withaxitinib.Two phase IIstudieshaveevaluated CUP werecomparabletowhat hasbeenreportedinclinical axitinib outsidethetrialsetting. may provideinformationon theefficacyandtoxicityof made in a CUP is difficult but cancer with observations safety profile. Comparing clinical trialresults in thyroid a promisingORR,DCRandPFS,aswellmanageable a CUP and showed that first-line axitinib has activity with thyroid cancerofDTCorMTChistologyinthesetting of treatment-naive orMKI-pretreatedpatientswithadvanced We have evaluated the clinical use of axitinib either in Discussion after specifictherapyanddrugdiscontinuation. infarction andventricular systolicdysfunction,recovered permission fromKINOME Technology, Inc.( Kinome analysisofaxitinib(A),lenvatinib(B),(C)andvandetanib(D).IllustrationreproducedcourtesyCellSig naling Figure 1 Clinical Study The overallefficacyresults obtained inthesettingofa www.ce llsignal.com scan , adivisionofDiscoveRxCorporation,DISCOVERXCORPORATION 2010. J Capdevilaandothers ). Adaptedfrom( 25 ) andimagegeneratedusingTREE 9%C:1.–01 months), with a greater axitinib (95% CI: 14.6–40.1 months months) andmedianOSof27.2 CI: 14.6–21.8 months(95% (95% CI:22–49%),amedian PFSof16.1 DTC or MTC resulted in an ORR of 35% RAI-refractory patients withmetastaticorunresectable, locallyadvanced 5 ( respectively and35 months PFS andOSwere15 months months, median an estimatedmedianfollow-upof34 outcomes reportedanORRof38%andDCR68%.After 18.1 months (95%CI:12.1tonotestimable)( ORR of30%(95%CI:18.9–43.2%)andmedianPFS of axitinib 5 control thediseaseorwasnotappropriatetherapy, of advancedthyroidcancerinwhichiodine-131failed to phase IIstudyin60patientswithallhistologicalsubtypes axitinib inpatientswithadvanced DTC orMTC.Inone cancer Axitinib inrefractorythyroid 8 mg b.i.d. for a median duration of 12.9 months in52 mg b.i.d.foramediandurationof12.9 months ). InasecondphaseIIstudy, axitinibadministration of mg b.i.d. showed an investigator-assessed spot Downloaded fromBioscientifica.com at10/02/202109:35:03AM SoftwareTool andreprintedwith 177 :4 7 ). Long-term 314 via freeaccess

European Journal of Endocrinology as thetranslocationofrearranged duringtransfection inhibition of interestingtargetsin thyroid cancer, such nanomolar level.However axitinibhasnoadditional IC best VEGFRinhibitorsinclinical developmentregarding different treatmentlines( MKI activitycouldexplainhowthesedrugsareactive in progression tocytokines( comparedwiththosewhoreceivedaxitinibafter in thosepatientstreatedwithaxitinibafterprogression to in the subgroup analyses that PFS was significantly shorter the pivotal phase III study ofaxitinib in RCC also showed 14 not beenreportedwithotherMKIsinclinicaltrials( advanced thyroid cancer is suggested. This hypothesis has resistance to sequential antiangiogenic MKI therapy in prior MKIs.To ourknowledgethisisthefirsttimethat CUP significantlydecreasedwhenpatientshadreceived CUP vs18.1 months). Efficacyoutcomesofaxitinibinthe DCR 68%),albeitalowermedianPFS(13.6 months inthe compared withthephaseIIclinicalstudies(ORR38%and the ORR(53%)andDCR(82%)werehigherinCUP patients whoreceivedaxitinibasfirst-linetreatment, symptoms wasreported. in symptomsorinterferencedailylifecausedby treatment withaxitinibandnosignificantdeterioration Importantly, qualityoflifewasmaintainedduring exposure correlatingwithalongermedianPFS( Mucositis Hypertension Diarrhoea Table 5 Cardiac toxicity Anaemia Vomiting Nausea Weight loss Abdominal pain Anorexia Rash Hand-foot syndrome Asthenia DTC, differentiated thyroid cancer;MTC,medullarythyroidcancer. Other toxicities Cough Hyperglycaemia Hypercholesterolaemia Peripheral oedema Headache Clinical Study 50 , 15 valuesofinhibitionVEGFR1–3, evenatabelow Interestingly, whenconsideringonlytheresultsfrom , 16 Safety profileofaxitinibinpatientswithadvancedthyroidcancer. , 17 ) or in clinical practice ( Fig. 2 20 ). Thedifferentspectrumof 12 (35.3) 11 (32.4) 12 (35.3) 15 (44.1) All grades 1 (2.9) 2 (5.9) 1 (2.9) 1 (2.9) 2 (5.9) 5 (14.7) 5 (14.7) 3 (8.8) 5 (14.7) 3 (8.8) 1 (2.9) 1 (2.9) ) ( 0 0 0 J Capdevilaandothers 3 ). Axitinibisoneofthe Patients withDTC 18 , 19 ). Furthermore,

( n Grade =34) 0 0 0 0 0 0 0 0 0 0 0 0 1 (2.9) 2 (5.9) 1 (2.9) 1 (2.9) 1 (2.9) 3 (8.8) 1 (2.9) 13 9 ). ≥ , 3 The approved MKIs for refractory thyroidcancerhave The approvedMKIsforrefractory (EGFR) orfibroblastgrowthfactorreceptors(FGFR1–4). (RET/PTC), BRAF, c-MET, epidermal receptor thyroidcancer tyrosine kinasereceptorinpapillary to lineoftreatment. of axitinibinpatientswithadvanced thyroidcanceraccording Kaplan–Meier curvesindicating progression-freesurvival(PFS) Figure 2 cancer Axitinib inrefractorythyroid 10 (76.9) All grades Patients withMTC 0 0 0 2 (15.4) 4 (30.8) 5 (38.5) 1 (7.7) 2 (15.4) 2 (15.4) 2 (15.4) 1 (7.7) 1 (7.7) 4 (30.8) 4 (30.8) 1 (7.7) 1 (7.7) 1 (7.7) 1 (7.7)

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European Journal of Endocrinology www.eje-online.org einPSws1. monthsinthesorafenibarm median PFSwas10.8 MTC. In patients with DTC, the ORR was 12.2% and the vandetanib armintheZETA trial( the EXAMtrial( monthsinthecabozantinibarm was 28%and11.2 approval PFS in the phase III studies leading to regulatory DTC.TheORR and median lenvatinib forRAI-refractory approved forunresectableMTC,andsorafenib sequential clinicaltrials. treatment lines,conditioningthedesignoffuture line therapythatprogressivelydecreasedinsuccessive clinical benefitwhenadministratingaxitinibinfirst- randomized clinicaltrials.Therewasanencouraging further supportforevaluationofaxitinibinprospective, metastatic thyroid cancer; however our results provide conclusions ontheactivity of axitinibinpatientswith trials. Furthermore,itisimpossibletodrawdefinitive for aCUPcomparedwiththoseincluded in clinical and theworseperformancestatusofpatientswhoqualify characteristics, the local investigator-assessed efficacy, such astheheterogeneityinpatientsanddisease the characteristiclimitationsderivedfromaCUP weaknesses, consideringtheretrospectivedesignand other agentsintheclass( study dataconfirmatoxicityprofilecomparabletothatof reported inpatientswithmetastaticRCC,andclinical this studyisconsistentwithwhathadbeenpreviously discontinuation. Theoverallsafetyprofilereportedin and fourtreatment-relatedAEsledtopermanentaxitinib thyroid cancer, 40%ofthepatientshadadosereduction Grade 4 cardiac toxicity. In a phase II study of axitinib in one patientrequiredtreatmentdiscontinuationduetoa adosereductiontomanagetoxicity,underwent and reductions. Approximatelyone-quarterofthepatients are manageablewithsymptomatictreatmentanddose decreased appetiteandhand-footsyndrome( diarrhoea, hypertension,fatigue,dysphonia,nausea, axitinib weremildtomoderateinseverity. Theyincluded from previousclinicaltrials.MostcommonAEsof with asafetyprofileaccordingtowhatwasexpected other MKIsinthyroidcancer. with axitinib after progression to resistance observed The lackoftheseadditionaleffectscouldbebehindthe cabozantinib andlenvatinibintheirphaseIIIstudies. work afterprogressiontoapriorMKI,clearlyshownfor the resistancetoantiangiogenesisinhibitionandcould this additionalactivitytoothertargetsthatcouldrevert Clinical Study As notedearlier, cabozantinibandvandetanibare We acknowledge that our study has important In ouranalysis,axitinibwasgenerallywelltolerated 15 n 5 n 05 monthsinthe ) and45%30.5 21 ). J Capdevilaandothers 22 ) inpatientswith 6 ). MostAEs

help definethesuccessfulsequentialtreatmentschedules agents ( as monotherapyandincombinationwithothertargeted DTC and vandetanib and cabozantinib for MTC), both drugs in both histologies (sorafenib and lenvatinib for efficacy ofdifferentMKIsafterprogressiontoapproved cancer. Currently, manyclinicaltrialsareassessingthe steps in the treatment of patients with advanced thyroid warrantscarefulconsiderationofthenext observation resistance inthyroidcancersetting.Ourclinical MKIs raisingthehypothesisofanti-angiogenic cross- lines afterprogressiontopriorsystemictherapywith axitinib significantlydecreasesinsecondandsuccessive with DTCandMTChistologies.Howevertheefficacyof and safetyprofileinfirst-linetreatmentbothpatients and 18.7 months inpatientsreceivingfirst-linelenvatinib. the lenvatinibarminSELECTtrial( the DECISION trial ( References logistical support. (online database),forhelppromotingtheCUP, andforproviding acknowledgement isgiventoGETHIforsupportduringdatacollection who providedmedicalwritingservices,onbehalfofPfizer, Spain.Special and theirfamiliescaregivers.TheauthorsalsothankAuroraO’Brate The authorswishtothankallthepatientswhoparticipatedinstudy Acknowledgements The CUPofaxitinibwasfundedbyPfizer, Spain. Funding A, ALJMM,IP, JR,NP, EC,IMandJGhavenoconflicts ofinterests. consulting feesbyBayerandEisai.JT, JLM,SGA,CZ,OR,UB,MDP, BG Pfizer. TRC hasreceivedlecturing feesbyPfizerand AstraZeneca, and Bayer, AstraZeneca,PfizerandEisai,hasreceivedresearchgrantfrom Pfizer andEisai.EGhasreceivedhonorariaasspeakeroradvisoryroleby J CandAhavereceivedhonorariaasspeakeroradvisoryrolebyBayer, Declaration ofinterest significantly reduced. drugs inmoreadvanced stages wherelifeexpectancy is for thesepatientsandminimizetheexposuretoinactive cancer Axitinib inrefractorythyroid 2 1 growth factorgeneandprotein:strong expressioninthyroiditis Weryha G,DuprezA,LeclèreJ 20 April 2015. on Cancer, 2013.(Available at:http://globocan.iarc.fr). Accessedon No. 11(Internet).Lyon, :InternationalAgencyforResearch v1.0, cancerincidenceandmortalityworldwide:IARCCancerBase Rebelo M,ParkinDM,FormanD,BrayF Klein M,PicardE,Vignaud JM,MarieB,BreslerL,Toussaint B, M,DikshitR,EserS,MathersC, Ferlay J,SoerjomataramI,Ervik In conclusion,axitinibshowedpromisingefficacy 24 ). Thecorrectdesignoftheseclinicaltrialswill 23 ) and 64.8% and 18.3 months in ) and 64.8% and 18.3 months Downloaded fromBioscientifica.com at10/02/202109:35:03AM et al . Vascular endothelial et al 177 . GLOBOCAN2012 :4 17 ), with65.6%

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