Ensartinib published phase 3 global trial results in the journal of JAMA Oncology Ensartinib vs Crizotinib for Patients With Anaplastic Lymphoma Kinase−Positive Non–Small Cell Lung Cancer A Randomized Clinical Trial

Ensartinib vs Crizotinib for Patients With Anaplastic Lymphoma Kinase−Positive Non–Small Cell Lung Cancer ARandomizedClinicalTrial LeoraHorn,MD,MS;ZipingWang,MD;GangWu,MD;ElenaPoddubskaya,MD;TonyMok,MD;MartinReck,MD;HeatherWakelee,MD; AlbertoA.Chiappori,MD;DaeHoLee,MD,PhD;ValeriyBreder,MD,PhD;SergeyOrlov,MD;IrfanCicin,MD;YingCheng,MD;YunpengLiu,MD; YunFan,MD;JenniferG.Whisenant,PhD;YiZhou,PhD;VanceOertel,MS;KimHarrow,MBA;ChrisLiang,PhD;LiMao,MD; GiovanniSelvaggi,MD;Yi-LongWu,MD IMPORTANCE Ensartinib,anoraltyrosinekinaseinhibitorofanaplasticlymphomakinase (ALK),hasshownsystemicandcentralnervoussystemefficacyforpatientswith ALK-positive non–smallcelllungcancer(NSCLC). OBJECTIVETocompareensartinibwithcrizotinibamongpatientswithadvanced ALK-positive NSCLCwhohadnotreceivedpriortreatmentwithanALKinhibitor. DESIGN, SETTING, AND PARTICIPANTSThisopen-label,multicenter,randomized,phase3trial conductedin120centersin21countriesenrolled290patientsbetweenJuly25,2016,and November12,2018.Eligiblepatientswere18yearsofageorolderandhadadvanced, recurrent,ormetastatic ALK-positiveNSCLC. INTERVENTIONSPatientswererandomized(1:1)toensartinib,225mgoncedaily,orcrizotinib, 250mgtwicedaily. MAIN OUTCOMES AND MEASURES Theprimaryendpointwasblindedindependentreview committee–assessedprogression-freesurvival(PFS).Secondaryendpointsincluded systemicandintracranialresponse,timetocentralnervoussystemprogression,andoverall survival.Efficacywasevaluatedintheintent-to-treat(ITT)populationaswellasa prespecifiedmodifiedITT(mITT)populationconsistingofpatientswithcentral laboratory–confirmed ALK-positiveNSCLC. RESULTSAtotalof290patients(149men[51.4%];medianage,54years[range,25-90 years])wererandomized.IntheITTpopulation,themedianPFSwassignificantlylongerwith ensartinibthanwithcrizotinib(25.8[range,0.03-44.0months]vs12.7months[range, 0.03-38.6months];hazardratio,0.51[95%CI,0.35-0.72];log-rank P < .001),withamedian follow-upof23.8months(range,0-44months)fortheensartinibgroupand20.2months (range,0-38months)forthecrizotinibgroup.InthemITTpopulation,themedianPFSinthe ensartinibgroupwasnotreached,andthemedianPFSinthecrizotinibgroupwas12.7 months(95%CI,8.9-16.6months;hazardratio,0.45;95%CI,0.30-0.66;log-rank P < .001). Theintracranialresponserateconfirmedbyablindedindependentreviewcommitteewas 63.6%(7of11)withensartinibvs21.1%(4of19)withcrizotinibforpatientswithtargetbrain metastasesatbaseline.Progression-freesurvivalforpatientswithoutbrainmetastaseswas notreachedwithensartinibvs16.6monthswithcrizotinibasaresultofalowercentral nervoussystemprogressionrate(at12months:4.2%withensartinibvs23.9%with crizotinib;cause-specifichazardratio,0.32;95%CI,0.16-0.63; P = .001).Frequenciesof treatment-relatedseriousadverseevents(ensartinib:11[7.7%]vscrizotinib:9[6.1%]),dose reductions(ensartinib:34of143[2 3.8%]vs crizotinib:29of146[19.9%]),ordrug discontinuations(ensartinib:13of143[9.1%]vscrizotinib:10of146[6.8%])weresimilar, withoutanynewsafetysignals. CONCLUSIONS AND RELEVANCEInthisrandomizedclinicaltrial,ensartinibshowedsuperior efficacytocrizotinibinbothsystemicandintracranialdisease.Ensartinibrepresentsanew first-lineoptionforpatientswith ALK-positiveNSCLC. TRIAL REGISTRATIONClinicalTrials.govIdentifier: NCT02767804 JAMA Oncol.doi:10.1001/jamaoncol.2021.3523 PublishedonlineSeptember2,2021. Visual Abstract Editorial Supplemental content Author Affiliations:Author affiliationsarelistedattheendofthis article. Corresponding Authors:LeoraHorn, MD,MS,Vanderbilt-IngramCancer Center,Nashville,TN( leorahorn@ gmail.com);Yi-LongWu,MD, GuangdongLungCancerInstitute, GuangdongProvincialPeople’s HospitalandGuangdongAcademyof MedicalSciences,Guangzhou,China ([email protected]). Research JAMA Oncology | Original Investigation (Reprinted) E1 Downloaded From: https://jamanetwork.com/ on 09/02/2021 C hromosomalrearrangementsinvolvingtheanaplastic lymphomakinase(ALK)gene(OMIM 105590)havebeen detected in 3% to 11% of non–small cell lung cancers (NSCLCs).1-5TheresultantALKfusionproteinisavalidatedtar- getinNSCLC,andtestingforthefusionproteinisstandardof careglobally.6,7Sincethe2011approvalofcrizotinibasafirst- linetreatment,8 ALKtyrosinekinaseinhibitorshavebecome standardofcareforpatientswith ALK-positiveNSCLC.9-11Sec- ond-generation(ceritinib,alectinib,andbrigatinib)andthird- generation(lorlatinib)ALKtyrosinekinaseinhibitorswerede- veloped to overcome crizotinib resistance and its poor brain penetration,12-15 and recent randomized clinical trials have shownthatalectinib,brigatinib,andlorlatinibhadsuperioref- ficacy compared with crizotinib for treatment-naive patients.16-18 Ensartinibisasecond-generationsmallmoleculethatpo- tentlyandselectivelyinhibitsALK. 19Inthephase1tophase2 eXalt2trial,ensartinib,225mgoncedaily,therecommended phase 2 dose, was associated with high systemic and central nervous system (CNS) response rates in both ALK inhibitor- −naivepatientsandthosewhoreceivedpriorcrizotiniband/or a second-generation ALK inhibitor. 20 In addition, ensar- tinib’ssafetyprofileisfavorable,withrashandtransaminitis asthemostfrequentanddistinctivetoxiceffects,althoughthey weremostlylowgradeandmanageable. 20 The eXalt3 study was designed to compare ensartinib vs crizotinibamongpatientswith ALK-positiveNSCLCwhohad not received prior treatment with an ALK inhibitor. Here we reporttheresultsoftheinterimanalysis. Methods Patients Eligiblepatientswere18yearsofageorolder,hadadvancedor recurrent(stageIIIBnotamenableformultimodalitytreatment) or metastatic (stage IV) NSCLC that wasALKpositive as deter- minedbylocaltesting,andhadmeasurablediseaseperResponse EvaluationCriteriainSolidTumours(RECIST),version1.1. 21Af- teraprotocolamendment, ALKtestingwasalsoperformedata centrallaboratoryusingtheUSFoodandDrugAdministration– approvedVysisfluorescenceinsituhybridizationassay(Abbott Laboratories).Patientswithasymptomaticbrainmetastaseswere allowedtoenroll.Patientsmayhavereceivedupto1priorche- motherapyregimenformetastaticdisease.Patientswereexcluded iftheyhadreceivedcancertherapywithin4weeksorradiotherapy within14daysofstudyentry.Patientscouldnothavereceived priorALKtyrosinekinaseinhibitorsorprogrammeddeath1orpro- grammeddeathligand1therapy.Patientswerenotrequiredto haveprogressivediseasewhilereceivingpriorchemotherapy.This studywasconductedinaccordancewiththeethicalstandardsof theDeclarationofHelsinki22andtheInternationalConferenceon HarmonisationGuidelineforGoodClinicalPractice.23Allpatients providedwritteninformedconsentpriortoundergoinganyre- searchprocedures,andtheprotocolandinformedconsentdocu- ments were approved by the governing ethical review boards. Completeinclusionandexclusioncriteriaareprovidedinthetrial protocol(Supplement1). Trial Design eXalt3 is a global, open-label, multicenter, randomized (1:1), phase 3 study conducted at 120 centers in 21 countries (NCT02767804 ). Patients were stratified by prior chemotherapy, Eastern Cooperative Oncology Group performance status (0 or 1 vs 2), CNS metastases at baseline, and geographic region (Asia vs rest of the world) and then randomized(centrallyviaaninteractivevoiceresponsesystem using a permuted block randomization) to receive oral ensartinib,225mgoncedaily,orcrizotinib,250mgtwicedaily. Patients were permitted to continue treatment until disease progression, unacceptable toxic effects, or withdrawal of consent. Crossover was not permitted. Disease assessments includedimagingofthechest,abdomen,pelvis,head,andbone (ifapplicable)every8weeksforupto19monthsandthenevery 12weeks.Responseswereconfirmedatleast4weeksafterthe initialresponse.Patientswhodiscontinuedtreatmentwithout radiographicprogressionperRECIST,version1.1werefollowed up until radiographic progression or new anticancer therapy wasstarted.Treatmentbeyondprogressionwasallowedatthe physician’s discretion. All adverse events (AEs) were graded using the National Cancer Institute’s Common Terminology CriteriaforAdverseEvents,version4.03. 24 Outcomes Theprimaryendpointforthestudywasprogression-freesur- vival(PFS)intheintent-to-treat(ITT)populationasassessed byablindedindependentreviewcommitteeaccordingtoRE- CIST, version 1.1. Key secondary end points included overall survival, CNS response rate, and CNS time to progression, as assessedbytheblindedindependentreviewcommittee. Statistical Analysis An O’Brien-Fleming Lan-DeMets25 alpha spending function wasusedtocontroltheoverallαlevelat.05(2-sided).Assum- ingamedianPFS(mPFS)of10monthsinthecrizotinibgroup 26 (basedontheassumptionthatapproximatelytwo-thirdsofthe patientswillbechemotherapynaive)withanimprovementto 16 months in the ensartinib group, a sample size of 266 pa- tientswasdeterminedtoallowfordetectionofa6-monthim- provement in PFS with a hazard ratio (HR) of 0.625 and 90% Key Points Question Isensartinibsuperiortocrizotinibforpatientswith advancedanaplasticlymphomakinase( ALK)–positivenon–small celllungcancer(NSCLC)whohavenotbeentreatedpreviously withanALKinhibitor? Findings Thisrandomizedclinicalphase3trialincluding290 patientsmettheprimaryendpoint;themedianprogression-free survivalwasstatisticallysignificantlylongerwithensartinibthan withcrizotinib(25.8vs12.7months),andtheconfirmed intracranialresponseratewas64%withensartinibvs21%with crizotinibforpatientswithbrainmetastasesatbaseline.Ensartinib hadafavorablesafetyprofile. Meaning Ensartinibrepresentsanewfirst-linetreatmentoption forpatientswith ALK-positiveNSCLC. Research Original Investigation EnsartinibvsCrizotinibforPatientsWith ALK-PositiveNSCLC E2 JAMA Oncology PublishedonlineSeptember 2,2021 (Reprinted) jamaoncology.com Downloaded From: https://jamanetwork.com/ on 09/02/2021 power.Thefinalanalysesweretobeperformedafter190events of either progression or death. One interim analysis was planned at approximately 75% (143 events) of all 190 ex- pected events (2-sided α of .019). Of the key secondary end points,onlyoverallsurvivalwastestedformallyatanαlevel of.05(2-sided). EfficacywasevaluatedintheITTpopulationaswellasin themodifiedITT(mITT)population.LocalALKtestingwasal- lowed prior to protocol amendment 2.0, but ALK testing, as confirmedbycentrallaboratoryanalysisusingtheVysisfluo- rescenceinsituhybridizationtest(AbbottLaboratories),was requiredafterprotocolamendment2.0.Allpatientsenrolled intheITTpopulationtestedpositivefor ALKthroughlocaltest- ingpriortoprotocolamendment2.0.ThemITTpopulationin- cludedpatientswhowererandomizedintothetrialbasedon positive local test results with additional central confirma- tion or positive central testing. Central testing was support- iveoftherequiredcompaniondiagnosticdevelopment. Theprimaryendpointwascomparedbetweentheensar- tinibandcrizotinibgroupsbyusinga2-sidedlog-ranktestac- cordingtothefactorsusedforrandomization.Foralltime-to- eventefficacyanalyses,medianvalueswereestimatedusing Kaplan-Meiermethods.Hazardratioswereestimatedbyusing theCoxproportionalhazardsregressionmodel.Theprimary end point of PFS was also analyzed in subgroups based on stratificationvariablesaswellasdemographicandbaselinepa- tient characteristics. These results were considered explor- atorybecauseofthemultiplicityissueandthesmallersample sizesthatcouldnotbeprespecified.Thesafetypopulationin- cluded patients who received at least 1 dose of either study drug. EfficacyandsafetydatawerereportedasofJuly1,2020. StatisticalanalyseswereperformedwithSAS,version9.4(SAS InstituteInc).Statisticalmethodsaredescribedfurtherinthe statisticalanalysisplanincludedin Supplement1. Results Patients BetweenJuly25,2016,andNovember12,2018,396patients werescreened;290patients(149men[51.4%];medianage,54 years [range, 25-90 years]) were randomized (ITT; ensar- tinib,143patients;crizotinib,147patients; Figure1).Thebase- linecharacteristicswerebalanced( Table);47patients(32.9%) intheensartinibgroupand57(38.8%)inthecrizotinibgroup had brain metastases at baseline, with similar rates of prior brain radiotherapy (ensartinib, 7 patients [4.9%]; crizotinib, 7patients[4.8%]).Therewereimbalancesinthebaselinechar- acteristicsbetweenAsianandnon-Asianpatients(non-Asian patientsincludedWhite[ensartinib,63(44.1%);crizotinib,57 (38.8%)], Black or African American [ensartinib, 1 (0.7%); cr- izotinib,3(2.0%)],andother[ensartinib,3(2.1%);crizotinib, 4(2.7%)]);Asianpatientshadmorebrainmetastases(64of157 [40.8%] vs 40 of 133 [30.1%]) and were younger, with fewer patients older than 65 years (19 of 157 [12.1%] vs 28 of 133 [21.1%]). Of 76 patients who had received prior chemo- therapy, 55.3% (42; 22 in the ensartinib group and 20 in the crizotinibgroup)showedevidenceofprogressivediseasedur- ingorafterchemotherapy. ThemITTpopulationincluded247patientsrandomlyas- signedtothetrialbasedonpositiveresultsoflocaltestingfor ALK with subsequent central confirmation (n = 112) or posi- tivecentraltestingfor ALK(n = 135),asshownineFigure1in Supplement 2. Of the patients who were randomly assigned priortoprotocolamendment2.0,43wereexcludedfromthe mITTpopulationbecausetheyhadinsufficientsamplesavail- able (n = 27), uninterpretable findings (n = 7), or had nega- tivetestresultsoncentralconfirmationofalocalpositive ALK test(n = 9).ThemITTpopulationultimatelyincluded121pa- tientsintheensartinibgroupand126inthecrizotinibgroup. As of July 1, 2020, 64 patients (44.8%) in the ensartinib groupand25(17.0%)inthecrizotinibgroupstillreceivedtreat- ment, with a median follow-up of 23.8 months (range, 0-44 months)intheensartinibgroupand20.2months(range,0-38 months)inthecrizotinibgroup. Efficacy ITT Population AsofJuly1,2020,139PFSevents(73.2%of190expectedtotal PFSevents)fortheprimaryendpointhadoccurredintheITT population. The mPFS in the ensartinib group was statisti- cally superior to that in the crizotinib group (25.8 months Figure 1. Screening, Enrollment, Randomization, and Follow-up 396 Patients were screened 106 Failed screening 143 Were assigned to receive ensartinib, 225 mg once daily 143 Received assigned treatment 79 Discontinued treatment 49 Had disease progression 12 4 Had adverse events Withdrew consent 4 Died 4 Were withdrawn from trial by physician 6 Had other reasons 45 Were no longer in the trial at date of data cutoff 37 Died 4 Withdrew consent 4 Had other reasons 147 Were assigned to receive crizotinib, 250 mg twice daily 146 Received assigned treatment 122 Discontinued treatment 100 Had disease progression 9 4 Had adverse events Withdrew consent 1 Died 2 Were withdrawn from trial by physician 6 Had other reasons 47 Were no longer in the trial at date of data cutoff 34 Died 5 Withdrew consent 1 Was lost to follow-up 7 Had other reasons 1 Did not receive assigned treatment 290 Had ALK-positive disease and underwent randomization (ITT) Datareportedasofthecutoffforthefirstinterimanalysis(July1,2020)are shown.Intheensartinibgroup,49patientshaddocumenteddisease progressionaccordingtotheResponseEvaluationCriteriainSolidTumours (RECIST),version1.1.Inthecrizotinibgroup,100patientshaddocumented diseaseprogressionaccordingtoRECIST,version1.1. ALKindicatesanaplastic lymphomakinasegene;ITT,intenttotreat. EnsartinibvsCrizotinibforPatientsWith ALK-PositiveNSCLC Original Investigation Research jamaoncology.com (Reprinted) JAMA Oncology PublishedonlineSeptember 2,2021 E3 Downloaded From: https://jamanetwork.com/ on 09/02/2021 [range,0.03-44.0months]vs12.7monthsmonths[range, 0.03- 38.6months];HR,0.51;95%CI,0.35-0.72;log-rank P < .001) (Figure2). Theconfirmedobjectiveresponseratewas74%(95%CI, 66%-81%) in the ensartinib group and 67% (95% CI, 58%- 74%) in the crizotinib group (eTable 1 inSupplement 2). The median duration of response among patients with complete or partial response was not reached (95% CI, 22.0 months to notreached)intheensartinibgroupandwas27.3months(95% CI,12.9monthstonotreached)inthecrizotinibgroup. mITT Population ThemITTpopulationwasusedtodescribetheefficacyamong patientswithcentrallaboratory–confirmed ALK-positivesta- tus.ThebaselinecharacteristicsofthemITTpopulationwere similar to those of the ITT population and were balanced by group. In the mITT population, 119 PFS events for the pri- maryendpointhadoccurredasofJuly1,2020(62.6%ofthe 190 expected PFS events). The mPFS in the ensartinib group was not reached, with 54.2% (95% CI, 43.4%-63.7%) of PFS probabilityat24months,comparedwith36.4%(95%CI,27.1%- 45.9%)ofPFSprobabilityat24monthsinthecrizotinibgroup (Figure 3A). The median PFS in the ensartinib group was not reached (95% CI, 20.2 months to not reached), and the me- dianPFSinthecrizotinibgroupwas12.7months(95CI%,8.9- 16.6months;HR,0.45;95%CI,0.30-0.66;log-rank P < .001). Subgroup analyses (Figure 3B) were not powered to pro- vide significant comparisons because of small sample sizes. However,severaldifferenceswereobserved,includinganon- significantly greater benefit for Asian patients. Among pa- tientswithoutpriorchemotherapy,themPFSwasnotreached (95%CI,20.2monthstonotreached)intheensartinibgroup and was 11.1 months (95% CI, 7.8-16.6 months) in the crizo- tinib group. Among patients who had received prior chemo- therapy, the mPFS was 22.0 months (95% CI, 10.9 months to notreached)intheensartinibgroupand12.8months(95%CI, 5.5 months to not reached) in the crizotinib group. The best systemic change from baseline in target lesions is shown in eFigure2in Supplement2.Theconfirmedobjectiveresponse rateinthemITTpopulationwas75%(95%CI,66.5%-82.6%) intheensartinibgroupand68%(95%CI,58.5%-75.5%)inthe crizotinib group. Complete response rates were more than 2-foldhigherwithensartinib(14%[95%CI,8.4%-21.5%])com- paredwithcrizotinib(6%[95%CI,2.3%-11.1%]).Themedian durationofresponseinthispopulationwasnotreachedinthe ensartinibgroup,with59%(95%CI,45%-70%)ofpatientshav- ingdurableresponseslasting36monthsormore. Eleven patients receiving ensartinib and 19 patients re- ceiving crizotinib had measurable brain metastases at base- lineandapostbaselineCNSevaluation.Ifthetargetlesionhad disappeared,themeasurementwasrecordedas0mm.Thebest changefrombaselineintargetbrainlesionswas63.6%inthe ensartinibgroup(n = 7)vs21.1%inthecrizotinibgroup(n = 4). Theintracranialbestchangefrombaselineforthesepatients is shown in eFigure 3 inSupplement 2. Progression-free sur- vival for patients without brain metastases was not reached Table. Baseline Characteristics of Patients in the ITT Population Characteristic Patients, No. (%) Ensartinib (n = 143) Crizotinib (n = 147) Age, median (range), y 54 (25-86) 53 (26-90) >65 y 24 (16.8) 23 (15.6) Sex Male 72 (50.3) 77 (52.4) Female 71 (49.7) 70 (47.6) Race and ethnicity Non-Asiana 66 (46.2) 63 (42.9) Asian 77 (53.8) 84 (57.1) ECOG performance status 0 or 1 136 (95.1) 139/146 (95.2) 2 7 (4.9) 7/146 (4.8) History of tobacco use Never smoked 85 (59.4) 94 (63.9) Current or former smoker 58 (40.6) 53 (36.1) Stage of disease IIIB 13 (9.1) 10 (6.8) IV 130 (90.9) 137 (93.2) ALK status assessed centrallyb 121 (84.6) 126 (85.7) Brain metastases at baselinec 47 (32.9) 57 (38.8) Previous radiotherapy to brain 7 (4.9) 7 (4.8) Previous chemotherapy 34 (23.8) 42 (28.6) Abbreviations: ALK,anaplasticlymphomakinasegene;ECOG,Eastern CooperativeOncologyGroup;ITT,intent-to-treat. a Non-AsianpatientsincludedWhite(ensartinib,63[44.1%];crizotinib,57 [38.8%]),BlackorAfricanAmerican(ensartinib,1[0.7%];crizotinib,3[2.0%]), andother(ensartinib,3[2.1%];crizotinib,4[2.7%]). b ALKpositivityassessedbytheAbbottfluorescenceinsituhybridizationassay. c Thepresenceofbrainmetastaseswasassessedbyablindedindependent reviewcommittee. Figure 2. Efficacy of Ensartinib and Crizotinib Among Patients With Non–Small Cell Lung Cancer 0 No. at risk 0 69 30 33 3615 24 2712 18 21 100 80 Progression-free survival, % Time, mo 60 40 20 3 Ensartinib Crizotinib Ensartinib (n = 143) mPFS (95% CI), mo 25.8 (21.8-NR) 12.7 (9.2-16.6) Hazard ratio (95% CI) 0.51 (0.35-0.72) Crizotinib (n = 147) P value (log-rank test) <.001 143 106 98 10 5 178 30 2186 72 54125 147 94 75 2 1 143 10 656 32 23124 Ensartinib Crizotinib Kaplan-Meierestimatesofprogression-freesurvivalbyblindedindependent reviewcommitteeamongpatientsintheintent-to-treatpopulation.Tickmarks indicatecensoreddata.mPFSindicatesmedianprogression-freesurvival;NR, notreached. Research Original Investigation EnsartinibvsCrizotinibforPatientsWith ALK-PositiveNSCLC E4 JAMA Oncology PublishedonlineSeptember 2,2021 (Reprinted) jamaoncology.com Downloaded From: https://jamanetwork.com/ on 09/02/2021 Figure 3. Efficacy of Ensartinib and Crizotinib Among Patients With Centrally Confirmed Anaplastic Lymphoma Kinase−Positive Non–Small Cell Lung Cancer 0 No. at risk 0 69 30 33 3615 24 2712 18 21 100 80 Progression-free survival, % Time, mo 60 40 20 3 Ensartinib Crizotinib PFS in the mITT populationA Ensartinib (n = 121) mPFS (95% CI), mo NR (20.2-NR) 12.7 (8.9-16.6) Hazard ratio (95% CI) 0.45 (0.30-0.66) Crizotinib (n = 126) P value (log-rank test) <.001 121 90 84 6 4 167 24 1675 61 45107 126 82 66 2 1 138 9 650 28 20109 0 2.01.0 1.5 Hazard ratio (95% CI) 0.5 Favors ensartinib Favors crizotinibSubgroup No. of patients ensartinib/ crizotinib Hazard ratio (95% CI) ≥65 17/21 NA Age, y Overall 121/126 0.45 (0.30-0.66) <65 104/105 0.42 (0.27-0.64) Sex Female 60/62 0.45 (0.25-0.81) Race and ethnicity Smoking status Asian 73/78 0.32 (0.19-0.55) Never used 74/83 0.39 (0.23-0.65) Male 61/64 0.44 (0.25-0.77) Non-Asian 48/48 0.61 (0.34-1.11) No 81/76 0.40 (0.23-0.70) Brain metastases at baseline Yes 40/50 0.55 (0.30-1.01) Prior chemotherapy None 95/90 0.43 (0.27-0.68) Region Asia-Pacific region 73/74 0.32 (0.19-0.55) 1 Prior regimen 26/36 0.59 (0.27-1.27) Rest of world 48/52 0.70 (0.39-1.25) Past use 41/41 0.78 (0.39-1.57) ECOG performance status 0 or 1 115/119 0.44 (0.29-0.65) Currently uses 6/2 NA 2 6/7 NA Hazard ratios for disease progression or deathB Ensartinib Crizotinib 0 No. at risk 0 69 30 33 3615 24 2712 18 21 100 80 Progression-free survival, % Time, mo 60 40 20 3 Ensartinib Crizotinib PFS in the mITT population without brain metastasesC Ensartinib (n = 81) mPFS (95% CI), mo NR (25.8-NR) 16.6 (12.7-29.5) Hazard ratio (95% CI) 0.46 (0.27-0.77) Crizotinib (n = 76) P value (log-rank test) .003 81 67 64 6 4 153 21 1560 48 3576 76 56 47 2 1 131 9 641 23 1872 Ensartinib Crizotinib 0 No. at risk 0 69 30 33 3615 24 2712 18 21 100 80 Overall survival, % Time, mo 60 40 20 3 Ensartinib Crizotinib Overall survival in the mITT populationD Ensartinib (n = 121) mOS (95% CI), mo NR (NR-NR) NR (NR-NR) Hazard ratio (95% CI) 0.91 (0.54-1.54) Crizotinib (n = 126) P value (log-rank test) .73 121 114 111 12 8 298 63 38104 93 85117 126 120 114 12 7 4105 60 34112 100 85121 Crizotinib Ensartinib A,Kaplan-Meierestimatesofprogression-freesurvival(PFS)byblindedindepen- dentreviewcommitteeinthemodifiedintent-to-treat(mITT)population.B,The presenceofbrainmetastasesatbaselinewasassessedbytheinvestigator.C, Kaplan-MeierestimatesofPFSbyblindedindependentreviewcommittee.D,Over- allsurvivalinthemITTpopulation.ECOGindicatesEasternCooperativeOncology Group;mITT,modifiedintent-to-treat;mOS,medianoverallsurvival;mPFS,median progression-freesurvival;NA,notapplicable;andNR,notreached. EnsartinibvsCrizotinibforPatientsWith ALK-PositiveNSCLC Original Investigation Research jamaoncology.com (Reprinted) JAMA Oncology PublishedonlineSeptember 2,2021 E5 Downloaded From: https://jamanetwork.com/ on 09/02/2021 with ensartinib vs 16.6 months with crizotinib. A signifi- cantlylowerpercentageofpatientswithoutbrainmetastases atbaselineintheensartinibgroupvsthecrizotinibgroupde- velopedbrainmetastasesat12months(4.2%vs23.9%;cause- specific HR, 0.32; 95% CI, 0.16-0.63;P = .001) (eFigure 4 in Supplement 2). The mPFS among patients without baseline brain metastases receiving ensartinib was not reached (Figure3C),with61%ofpatientsdiseasefreeat36monthsvs 25%ofpatientswhoreceivedcrizotinib.ThemPFSamongpa- tientswithbrainmetastasesatbaselinewas11.8months(95% CI,5.5monthstonotreached)intheensartinibgroupand7.5 months(95%CI,5.5-9.3months)inthecriz otinibgroup(HR, 0.55;95%CI,0.30-1.01; P = .05)(eFigure5in Supplement2). In the ensartinib and crizotinib groups, 21 of 47 (44.7%) and 35of57(61.4%)PFSevents,respectively,involvedtheCNS. Sixty-twopatientsinthemITTpopulationdied(30of121 [24.8%] in the ensartinib group and 32 of 126 [25.4%] in the crizotinib group [HR, 0.91; 95% CI, 0.54-1.54]) with a 2-year overall survival rate of 78% (95% CI, 69%-84%) in the ensar- tinibgroupand78%(95%CI,70%-85%)inthecrizotinibgroup. The median overall survival was not reached in either group (Figure3D). Safety The most common (≥10% of patients) ensartinib-related AEs wererash(67.8%[97of143]),elevatedtransaminaselevels(as- partate aminotransferase, 37.8% [54 of 143]; alanine amino- transferase, 48.3% [69 of 143]), pruritus (26.6% [38 of 143]), nausea (22.4% [32 of 143]), constipation (20.3% [29 of 143]), edema (21.0% [30 of 143]), anemia (14.0% [20 of 143]), vom- iting (11.9% [17 of 143]), blood alkaline phosphatase increase (13.3%[19of143]),bloodcreatinineincrease(14.0%[20of143]), γ-glutamyltransferase increase (13.3% [19 of 143]), and de- creasedappetite(11.2%[16of143]),mostofwhichweregrade 2orless( Figure4).Grade3rashwasreportedin11.2%ofpa- tients(16of143)andwasmanagedbywithholdingandreduc- ingthedose;themediandurationofgrade3rashwas18days. The treatment-emergent AEs occurring with both ensartinib andcrizotinibarelistedineTable2in Supplement2. Only 3 grade 4 AEs associated with ensartinib were ob- served(increasedbilirubinlevel,increasedcreatinephospho- kinase level, and hyponatremia). The most frequent AEs as- sociatedwithcrizotinibwerelivertoxiceffects,nausea,edema, and constipation. The frequency of treatment-related seri- ous AEs (ensartinib, 11 patients [7.7%]; crizotinib, 9 patients [6.1%]) was low and, for ensartinib, consisted mainly of rash (n = 3)andlivertoxiceffects(n = 3).Thetreatment-relatedAEs associatedwithdosereduction(ensartinib,34of143[23.8%]; crizotinib, 29 of 146 [19.9%]) and dose discontinuation (ens- artinib,13of143[9.1%];crizotinib,10of146[6.8%])weresimi- lar. Adverse effects associated with treatment discontinua- tion of ensartinib included increased liver enzymes (n = 12), pneumonitis(n = 2),chestpain(n = 1),pyrexia(n = 1),abnor- malhepaticfunction(n = 1),vomiting(n = 1),dryskin(n = 1), hyponatremia(n = 1),cerebralinfarction(n = 1),interstitiallung disease (n = 1), and rash (n = 1), whereas most dose reduc- tionswereassociatedwithfatigue,rash,transaminaseeleva- tion, constipation, edema, and sinus bradycardia. No treat- ment-relateddeathswerereportedineithergroup. Discussion IntheeXalt3study,ensartinibshowedsuperiorefficacycom- pared with crizotinib against both systemic and intracranial diseaseamongpatientswith ALK-positiveNSCLCwhohadnot receivedanypriorALKinhibitor.Attheplanned75%interim analysis,theprespecifiedthresholdforsignificanceforthepri- maryendpointofmPFSasassessedbytheblindedindepen- dentreviewcommitteewasmet.Withamedianfollow-upof 23.8 months in the ensartinib group and 20.2 months in the crizotinibgroup,ensartinibwasassociatedwitha49%lower Figure 4. Treatment-Related Adverse Events Reported in 10% or More of All Patients 10 3020 40 50 60 7010 3020 40 50 60 700 Relative frequency, % Ensartinib (n = 143) ALT increase AST increase Pruritus (all) Nausea Edema (all) Constipation Anemia Blood creatinine increase Alkaline phosphatase increase γ-GT increase Vomiting Decreased appetite 0 Relative frequency, % Crizotinib (n = 146) Rash (all) ALT increase AST increase Pruritus (all) Nausea Edema (all) Constipation Anemia Blood creatinine increase Alkaline phosphatase increase γ-GT increase Vomiting Decreased appetite 2 3 1 Grade Rash (all) ALTindicatesalanineaminotransferase;AST,aspartateaminotransferase;andγ-GT,γ-glutamyltransferase. Research Original Investigation EnsartinibvsCrizotinibforPatientsWith ALK-PositiveNSCLC E6 JAMA Oncology PublishedonlineSeptember 2,2021 (Reprinted) jamaoncology.com Downloaded From: https://jamanetwork.com/ on 09/02/2021 risk of disease progression or death (HR, 0.51; log-rank P < .001). In addition, the blinded independent review com- mittee–assessedmPFSwithensartinibwas25.8months,which isconsistentwiththeALTA-1L27(24.0months)andALEX17(25.7 months)studies,whichexploredbrigatinibvscrizotiniband alectinibvscrizotinib,respectively,alsointhesamefirst-line setting with an open-label design and independent radio- logicassessment.(IntheCROWNstudy, 18PFSwasnotreached with lorlatinib.) Cross-trial comparisons should be inter- pretedwithcautionowingtodifferencesinenrolledpopula- tionsanddifferentperformancesofthecontrolgroups. The prespecified, centrally tested ALK mITT population isuniquetothisstudybecausepreviousphase3studieseither mandatedcentraltestingfromthestudystart(ALEX 17)orac- cepted local testing (CROWN18 and ALTA-1L27). In the mITT population,themPFSwithensartinibwasnotreachedandwas potentially trending toward longer PFS with further fol- low-upofongoingpatientsandananticipatedrateoflessthan 1eventpermonthintheexperimentalgroup.Thisdatapoint seemscomparabletotheonerecentlyreportedintheCROWN study,18 although the median follow-up time was 6 months shorterforlorlatinibthanensartinibandthepopulationsdif- fered owing to prior chemotherapy not being allowed. A no- tableearlierseparationofthePFScurves(atapproximately3 vs 6 months) than seen in other second-generation ALK in- hibitorstudieswithalectinibandbrigatinib17,28suggestshigher efficacywithensartinibforpatientswithprimaryresistance, despite differences in study populations, and warrants fur- therinvestigationtoidentifythemolecularbasisbehindsuch primaryresistance.Primaryandacquiredresistancepatterns to first-line ALK inhibitors will be the determinants to select anagentofchoiceandthesequencingofnext-generationALK inhibitors.Reportsofexploratorybiomarkerdatafromall4re- centphase3studiesshouldexpandourunderstandingofthe dynamicevolutionofresistancepatternsandmayleadtothe choiceofanoptimalfirst-linestrategy. 29,30 Consistentwithpreviousresults, 20 ensartinibcontinued to demonstrate efficacy in controlling intracranial disease. In the small group of 11 patients treated with ensartinib who had measurable brain metastases at baseline and a valid postbaseline assessment, the confirmed objective response rate was 64%, with a disease control rate of 100%. Such activity against brain metastases mirrors what has been observed in previous reports of ensartinib in phase 1 and 2 data sets that showed consistent waterfall plots of very high disease control rates of target brain metastases.20,31 The cohorts of patients with target brain lesions in the other 3 available randomized clinical trials16-18 with ALK inhibitor vscrizotinibconsistof17to21patientsandarethereforetoo small to draw relevant comparisons, especially considering other factors, such as prior therapies (eg, brain radiotherapy or chemotherapy) that could also account for differences across studies. However, allthese agents represent a step toward controlling intracranial disease in the brain com- pared with first-generation ALK inhibitors. More impor- tantly, on the clinical management side, the incidence of intracranial failure with ensartinib was significantly lower than that with crizotinib (4.2% vs 23.9% at 12 months) among patients without brain metastases, the larger propor- tion of patients with newly diagnosedALK-positive NSCLC; consequently, the mPFS among patients without brain metastasesatbaselinewasnotreachedwithensartinib,sug- gesting durable protection against disease spreading to the brain. Overall survival data for this trial are currently too immature to draw definitive conclusions. Thesafetyprofilesofensartinibandcrizotinibwerecon- sistentwiththoseinpreviousstudies. 20,26Thenumberofdose reductionsordiscontinuationsowingtotreatment-relatedAEs wassimilarbetweentreatmentgroups,aswasthefrequency of serious AEs. Consistent with findings from the eXalt2 study,32 rash and other skin toxic effects (eg, pruritus) con- tinue to be the most frequently observed AEs with ensar- tinib, together with transaminitis and edema, which were mostlylowgradeandasymptomatic.Ofpatientswhoexperi- encedgrade3rash(11.2%),allinstancesweresuccessfullyman- agedbywithholdingorreducingthedose.Gastrointestinal(eg, diarrheaandvomiting),ocular,andcardiactoxiceffectswere lessfrequentwithensartinib;thus,itcomparesfavorablywith othersecond-generationALKinhibitors,suchasalectinib 17or brigatinib,28intermsofoverallsafetyprofile.Thedistinctsafety profile of this class of agents possibly stems from a different pattern of off-target effects resulting from their kinase profiles. Limitations This interim analysis has some limitations. The overall sur- vival data are immature and potentially confounded by sub- sequent use of otherALK tyrosine kinase inhibitors at pro- gression in both study groups outside the current protocol. With further follow-up, data in both groups will mature and help to better contextualize the role of ensartinib compared with other next-generationALK inhibitors. Another limita- tionisthatthestudyincludedpatientswhose ALKstatuswas notcentrallyconfirmed,thuspossiblyimpactingefficacyout- comesintheITTpopulation. Conclusions Ensartinibrepresentsanewfirst-linetreatmentoptionforpa- tients withALK-positive NSCLC. In this randomized clinical trial,ensartinibshowedsuperiorsystemicandintracranialef- ficacycomparedwithcrizotinibandanoverallfavorablesafety profilethatisdistinctfromthatofotheragentsinthisclass.A more precise understanding of primary and acquired resis- tance mechanisms is warranted to establish the optimal se- quence of ensartinib and other available second- and third- generation ALKinhibitorsinthefirst-linesetting. ARTICLE INFORMATION Accepted for Publication:May27,2021. Published Online:September2,2021. doi:10.1001/jamaoncol.2021.3523 Open Access:Thisisanopenaccessarticle distributedunderthetermsofthe CC-BY-NC-ND License.©2021HornLetal. JAMA Oncology. EnsartinibvsCrizotinibforPatientsWith ALK-PositiveNSCLC Original Investigation Research jamaoncology.com (Reprinted) JAMA Oncology PublishedonlineSeptember 2,2021 E7 Downloaded From: https://jamanetwork.com/ on 09/02/2021 Author Affiliations:DivisionofHematologyand Oncology,DepartmentofMedicine, Vanderbilt-IngramCancerCenter,Nashville, Tennessee(Horn,Whisenant);NowwithGlobal ClinicalHeadforLungCancerandLungCancer Strategy,AstraZeneca,Nashville,Tennessee(Horn); DepartmentofThoracicMedicalOncology,Peking UniversityCancerHospitalandInstitute,Beijing, China(Wang);CancerCenter,UnionHospital, TongjiMedicalCollege,HuazhongUniversityof ScienceandTechnology,Wuhan,China(G.Wu); ClinicalCenterforOncology,I.M.SechenovFirst MoscowStateMedicalUniversity(Sechenov University),Moscow,Russia(Poddubskaya);Clinical CenterVitaMed,Moscow,Russia(Poddubskaya); DepartmentofClinicalOncology,StateKey LaboratoryofTranslationalOncology,TheChinese UniversityofHongKong,HongKong,China(Mok); LungClinic,AirwayResearchCenterNorth,German CenterforLungResearch,Grosshansdorf,Germany (Reck);DepartmentofMedicine,Divisionof OncologyandStanfordCancerInstitute,Stanford University,Stanford,California(Wakelee);Thoracic OncologyProgram,MoffittCancerCenter,Tampa, Florida(Chiappori);DepartmentofOncology, UniversityofUlsanCollegeofMedicine,Asan MedicalCenter,Seoul,SouthKorea(Lee); DepartmentofChemotherapyNo.17,N.N.Blokhin RussianCancerResearchCenter,Moscow,Russia (Breder);DepartmentofBiochemistry,PavlovFirst SaintPetersburgStateMedicalUniversity,St Petersburg,Russia(Orlov);DepartmentofMedical Oncology,FacultyofMedicine,TrakyaUniversity, Edirne,Turkey(Cicin);DepartmentofThoracic Oncology,JilinCancerHospital,Changchun,China (Cheng);DepartmentofMedicalOncology,The FirstHospitalofChinaMedicalUniversity, Shenyang,Liaoning,China(Liu);ThoracicTumor Center,ZhejiangCancerHospital,Hangzhou,China (Fan);Biometrics,XcoveryHoldingsInc,Palm BeachGardens,Florida(Zhou);ClinicalOperations, XcoveryHoldingsInc,PalmBeachGardens,Florida (Oertel,Harrow);NowwithEQRx,Cambridge, Massachusetts(Harrow);ClinicalScience,Xcovery HoldingsInc,PalmBeachGardens,Florida(Liang); ClinicalDevelopment,XcoveryHoldingsInc,Palm BeachGardens,Florida(Mao,Selvaggi);Nowwith SinoBiopharmaceuticalLtd,Beijing,China(Mao); GuangdongLungCancerInstitute,Guangdong ProvincialPeople’sHospitalandGuangdong AcademyofMedicalSciences,Guangzhou,China (Y.-L.Wu). Author Contributions:DrsHornandY.-L.Wuhad fullaccesstoallthedatainthestudyandtake responsibilityfortheintegrityofthedataandthe accuracyofthedataanalysis. Concept and design:Horn,Mok,Wakelee,Cicin, Fan,Harrow,Liang,Mao,Selvaggi,Y.-L.Wu. Acquisition, analysis, or interpretation of data:Horn, Wang,G.Wu,Poddubskaya,Mok,Reck,Wakelee, Chiappori,Lee,Breder,Orlov,Cicin,Cheng,Liu,Fan, Whisenant,Zhou,Oertel,Harrow,Mao,Selvaggi, Y.-L.Wu. Drafting of the manuscript:G.Wu,Poddubskaya, Mok,Reck,Lee,Orlov,Cicin,Fan,Whisenant,Zhou, Oertel,Selvaggi. Critical revision of the manuscript for important intellectual content:Horn,Wang,Mok,Reck, Wakelee,Chiappori,Lee,Breder,Orlov,Cicin, Cheng,Liu,Fan,Zhou,Harrow,Liang,Mao, Selvaggi,Y.-L.Wu. Statistical analysis:Mok,Lee,Fan,Zhou. Obtained funding:Orlov,Mao,Selvaggi. Administrative, technical, or material support:Horn, G.Wu,Reck,Chiappori,Liu,Fan,Whisenant, Oertel,Mao. Supervision:Horn,Reck,Liu,Harrow,Liang,Mao. Conflict of Interest Disclosures:DrHornreported receivinggrantsand/orpersonalfeesfromXcovery HoldingsInc,Amgen,AstraZeneca,Merck,Bristol MyersSquibb,Incyte,EMDSerono,Pfizer,and AbbVie,whileaffiliatedwithVanderbiltUniversity; currentlyanemployeeofAstraZeneca.DrMok reportedreceivingpersonalfees,grants,orother feesfromAbbVie,ACEAPharma,AlphaBiopharma CoLtd,Amgen,AmoyDiagnosticsCoLtd, AstraZeneca,BeiGene,BoehringerIngelheim, BristolMyersSquibb,BlueprintMedicines Corporation,CStonePharmaceuticals,Daiichi Sankyo,Eisai,FishawackFacilitateLtd, geneDecode,GritstoneOncologyInc,Guardant Health,HengruiTherapeutics,IgnytaInc,IQVIA, IncyteCorporation,InMedMedicalCommunication, Janssen,Lilly, Loxo-Oncology,LunitInc,MDHealth (Brazil),Medscape/WebMD,MerckSerono,Merck Sharp&Dohme,MiratiTherapeuticsInc,MORE Health,Novartis,OrigiMed,PeerVoice,Physicians’ EducationResource,PermanyerSL,PfizerInc, PrIMEOncology,PumaTechnologyInc,Researchto Practice,Roche,Sanofi-AventisR&D,Takeda,Touch MedicalMedia,VirtusMedicalGroup,Yuhan Corporation,AstraZenecaPLC,HutchisonChi-Med, SanomicsLtd,ClovisOncology,SFJ Pharmaceuticals,Xcovery,CurioScience,Inivata, BerryOncology,G1TherapeuticsInc,andAurora.Dr Reckreportedreceivingpersonalorotherfeesfrom Amgen,AstraZeneca,BristolMyersSquibb, BoehringerIngelheim,Lilly,Merck,MSD,Novartis, Pfizer,andRoche.DrWakeleereportedreceiving feesfromadvisoryboards,grants,orotherfees fromACEABiosciences,ArrysTherapeutics, AstraZeneca/Medimmune,BlueprintOncology, BristolMyersSquibb,Celgene,Clovis,Daiichi Sankyo,Exelixis,Genentech/Roche,Gilead,Helsinn, Janssen,Merck,Mirati,Novartis,Pharmacyclics, SeattleGenetics,andXcoveryHoldingsInc.Dr Chiapporireportedreceivingfeesforspeakers bureausand/oradvisoryboardsfromGenentech, Takeda,Merck,Celgene,Novartis,AstraZeneca, Pfizer,Jazz,Amgen,AbbVie,andBristolMyers Squibb.DrLeereportsreceivingpersonalfeesfrom AbbVie,AstraZeneca,BoehringerIngelheim, Takeda,BristolMyersSquibb,ChongKunDang,CJ Healthcare,EliLilly,Janssen,Merck,MSD, Mundipharma,Novartis,Ono,Pfizer,Roche, SamyangBiopharm,STCube,GreenCross,and Genexine.DrBrederreportsreceivingpersonalfees ornonfinancialsupportfromAstraZeneca,Bristol MyersSquibb,BoehringerIngelheim,Lilly,MSD, Takeda,Roche,andIpsen.DrWhisenantreported havingapatentwithAnasysInstrumentswith royaltiespaid.DrZhoureportedbeinganemployee ofXcoveryHoldingsInc.MrOertelreportedbeing anemployeeofXcoveryHoldingsInc.MsHarrow reportedreceivingpersonalfeesfromXcovery HoldingsIncduringtheconductofthestudy;and currentlybeinganemployeeofEQRx.DrLiang reportedbeinganemployeeandshareholderof XcoveryHoldingsInc.DrMaoreportedbeinga formeremployeeandshareholderofXcovery HoldingsInc;andcurrentlyanemployeeofSino BiopharmaceuticalLimited.DrSelvaggireported beinganemployeeandshareholderofXcovery HoldingsInc.DrY.-L.Wureportedreceivinggrants and/orpersonalfeesfromAstraZeneca,Bristol MyersSquibb,BoehringerIngelheim,EliLilly, Hengrui,MSD,Pfizer,Roche,andSanofi.Noother disclosureswerereported. Funding/Support:Financialsupportforthisstudy wasprovidedbyXcoveryHoldingsInc,which manufacturesandintendstomarketensartinib afterapprovalbyregulatoryauthorities.Xcovery HoldingsIncprovidedfinancialsupportforthis article,includingeditorialandmedicalwriting assistancebyAlexLoeb,PhD,CMPP,Chrysalis MedicalCommunications. Role of the Funder/Sponsor:Thestudyprotocol wasdevelopedbyXcoveryHoldingsIncin collaborationwiththestudysteeringcommittee. XcoveryHoldingsIncwasalsoinvolvedindata collection,management,analysis,and interpretationofthedata;preparation,review,or approvalofthemanuscript;anddecisiontosubmit themanuscriptforpublication.Statisticalanalyses wereperformedbystatisticiansatXcovery HoldingsInc. Data Sharing Statement:SeeSupplement3. Additional Contributions:Weespeciallythankthe patientsandtheirfamiliesforparticipatinginthis research.Wealsothanktheclinicalinvestigators (seeeTable3in Supplement2)andassociated clinicaloperationsstafffortheircontributionsto thiswork. REFERENCES 1. SodaM,ChoiYL,EnomotoM,etal.Identification ofthetransforming EML4-ALKfusiongenein non-small-celllungcancer. Nature.2007;448 (7153):561-566.doi:10.1038/nature05945 2. KoivunenJP,MermelC,ZejnullahuK,etal. EML4-ALKfusiongeneandefficacyofanALK kinaseinhibitorinlungcancer. Clin Cancer Res. 2008;14(13):4275-4283.doi:10.1158/1078-0432.CCR- 08-0168 3. KrisMG,JohnsonBE,BerryLD,etal.Using multiplexedassaysofoncogenicdriversinlung cancerstoselecttargeteddrugs. JAMA.2014;311 (19):1998-2006.doi:10.1001/jama.2014.3741 4. TakeuchiK,ChoiYL,TogashiY,etal.KIF5B-ALK, anovelfusiononcokinaseidentifiedbyan immunohistochemistry-baseddiagnosticsystem forALK-positivelungcancer. Clin Cancer Res.2009; 15(9):3143-3149. doi: 10.1158/1078-0432.CCR-08- 3248 5. LinE,LiL,GuanY,etal.Exonarrayprofiling detects EML4-ALKfusioninbreast,colorectal,and non-smallcelllungcancers. Mol Cancer Res.2009;7 (9):1466-1476.doi:10.1158/1541-7786.MCR-08-0522 6. ChuangJC,NealJW.Crizotinibasfirstline therapyforadvanced ALK-positivenon-smallcell lungcancers. Transl Lung Cancer Res.2015;4(5): 639-641. 7. NationalComprehensiveCancerNetwork.NCCN Clinicalpracticeguidelinesinoncology:non-small celllungcancer.AccessedOctober5,2020. https:// www.nccn.org/professionals/physician_gls/pdf/ nscl.pdf 8. Xalkori(crizotinib).Prescribinginformation. Pfizer;2011.AccessedOctober5,2020. http:// labeling.pfizer.com/showlabeling.aspx?id=676 9. McCuskerMG,RussoA,ScillaKA,MehraR,Rolfo C.HowItreatALK-positivenon-smallcelllung cancer. ESMO Open.2019;4(suppl2):e000524. doi:10.1136/esmoopen-2019-000524 Research Original Investigation EnsartinibvsCrizotinibforPatientsWith ALK-PositiveNSCLC E8 JAMA Oncology PublishedonlineSeptember 2,2021 (Reprinted) jamaoncology.com Downloaded From: https://jamanetwork.com/ on 09/02/2021 10. CostaDB,ShawAT,OuSH,etal.Clinical experiencewithcrizotinibinpatientswith advanced ALK-rearrangednon-small-celllung cancerandbrainmetastases. J Clin Oncol.2015;33 (17):1881-1888.doi:10.1200/JCO.2014.59.0539 11. CostaDB,KobayashiS,PandyaSS,etal.CSF concentrationoftheanaplasticlymphomakinase inhibitorcrizotinib. J Clin Oncol.2011;29(15):e443- e445.doi:10.1200/JCO.2010.34.1313 12. RothensteinJM,ChoobackN.ALKinhibitors, resistancedevelopment,clinicaltrials. Curr Oncol. 2018;25(suppl1):S59-S67.doi:10.3747/co.25.3760 13. GainorJF,DardaeiL,YodaS,etal.Molecular mechanismsofresistancetofirst-and second-generationALKinhibitorsin ALK-rearrangedlungcancer. Cancer Discov.2016;6 (10):1118-1133.doi:10.1158/2159-8290.CD-16-0596 14. ShawAT,SolomonBJ,BesseB,etal. ALK resistancemutationsandefficacyoflorlatinibin advancedanaplasticlymphomakinase-positive non-small-celllungcancer. J Clin Oncol.2019;37 (16):1370-1379.doi:10.1200/JCO.18.02236 15. ShawAT,SolomonBJ,ChiariR,etal.Lorlatinib inadvanced ROS1-positivenon-small-celllung cancer:amulticentre,open-label,single-arm,phase 1-2trial. Lancet Oncol.2019;20(12):1691-1701.doi: 10.1016/S1470-2045(19)30655-2 16. CamidgeDR,KimHR,AhnMJ,etal.Brigatinib versuscrizotinibinadvancedALKinhibitor-naive ALK-positivenon-smallcelllungcancer:second interimanalysisofthephaseIIIALTA-1Ltrial. J Clin Oncol. 2020;38(31):3592-3603. doi:10.1200/JCO. 20.00505 17. PetersS,CamidgeDR,ShawAT,etal;ALEXTrial Investigators.Alectinibversuscrizotinibin untreated ALK-positivenon–small-celllungcancer. N Engl J Med . 2017;377(9):829-838. doi:10.1056/ NEJMoa1704795 18. ShawAT,BauerTM,deMarinisF,etal;CROWN TrialInvestigators.First-linelorlatiniborcrizotinibin advanced ALK-positivelungcancer. N Engl J Med. 2020;383(21):2018-2029.doi:10.1056/ NEJMoa2027187 19. LovlyCM,HeuckmannJM,deStanchinaE,etal. InsightsintoALK-drivencancersrevealedthrough developmentofnovelALKtyrosinekinase inhibitors. Cancer Res.2011;71(14):4920-4931. doi:10.1158/0008-5472.CAN-10-3879 20. HornL,InfanteJR,ReckampKL,etal. Ensartinib(X-396)inALK-positivenon–smallcell lungcancer:resultsfromafirst-in-humanphaseI/II, multicenterstudy. Clin Cancer Res.2018;24(12): 2771-2779.doi:10.1158/1078-0432.CCR-17-2398 21. EisenhauerEA,TherasseP,BogaertsJ,etal. Newresponseevaluationcriteriainsolidtumours: revisedRECISTguideline(version1.1). Eur J Cancer. 2009;45(2):228-247.doi:10.1016/j.ejca.2008.10.026 22. WorldMedicalAssociation.WorldMedical AssociationDeclarationofHelsinki:ethical principlesformedicalresearchinvolvinghuman subjects. JAMA.2013;310(20):2191-2194.doi: 10. 1001/jama.2013.281053 23. DixonJRJr.TheInternationalConferenceon HarmonizationGoodClinicalPracticeguideline. Qual Assur.1998;6(2):65-74.doi: 10.1080/ 105294199277860 24. NationalCancerInstitute.Common terminologycriteriaforadverseevents:version 4.03.AccessedJuly29,2021. https://ctep.cancer. gov/protocoldevelopment/electronic_applications/ docs/CTCAE_4.03.xlsx 25. DeMetsDL,LanKK.Interimanalysis:thealpha spendingfunctionapproach. Stat Med.1994;13 (13-14):1341-1352.doi:10.1002/sim.4780131308 26. SolomonBJ,MokT,KimDW,etal;PROFILE 1014Investigators.First-linecrizotinibversus chemotherapyin ALK-positivelungcancer. N Engl J Med.2014;371(23):2167-2177.doi: 10.1056/ NEJMoa1408440 27. CamidgeDR,KimH,AhnM,etal.Brigatinibvs crizotinibinpatientswithALKinhibitor–naive advancedALK+NSCLC:updatedresultsfromthe phaseIIIALTA-1Ltrial. Ann Oncol.2019;30(suppl9): ix195-ix196. 28. CamidgeDR,KimHR,AhnMJ,etal.Brigatinib versuscrizotinibin ALK-positivenon–small-celllung cancer. N Engl J Med.2018;379(21):2027-2039. doi:10.1056/NEJMoa1810171 29. LinJJ,ZhuVW,YodaS,etal.Impactof EML4-ALKvariantonresistancemechanismsand clinicaloutcomesin ALK-positivelungcancer. J Clin Oncol.2018;36(12):1199-1206.doi: 10.1200/JCO. 2017.76.2294 30. OuS-HI,AhnJS,DePetrisL,etal.Alectinibin crizotinib-refractory ALK-rearrangednon–small-cell lungcancer:aphaseIIglobalstudy. J Clin Oncol. 2016;34(7):661-668.doi:10.1200/JCO.2015.63.9443 31. YangY,ZhouJ,ZhouJ,etal.Efficacy,safety,and biomarkeranalysisofensartinibin crizotinib-resistant,ALK-positivenon-small-cell lungcancer:amulticentre,phase2trial. Lancet Respir Med.2020;8(1):45-53.doi: 10.1016/S2213- 2600(19)30252-8 32. WakeleeH,ReckampK,LealT,etal.Rashand efficacyinanaplasticlymphomakinasepositive (ALK+)non-smallcelllungcancerpatientstreated withensartinib. J Thoracic Oncol.2019;14(10S):S566. AbstractP1.14-32.doi:10.1016/j.jtho.2019.08.1183 EnsartinibvsCrizotinibforPatientsWith ALK-PositiveNSCLC Original Investigation Research jamaoncology.com (Reprinted) JAMA Oncology PublishedonlineSeptember 2,2021 E9 Downloaded From: https://jamanetwork.com/ on 09/02/2021

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