Efficacy and Safety of Brigatinib Compared With Crizotinib in Asian vs. Non-Asian Patients With Locally Advanced or Metastatic ALK–Inhibitor-Naive ALK+ Non–Small Cell Lung Cancer: Final Results From the Phase III ALTA-1L Study

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Efficacy and Safety of Brigatinib Compared With Crizotinib in Asian vs. Non-Asian Patients With

Locally Advanced or Metastatic

ALK–Inhibitor-Naive ALK + Non–Small Cell Lung Cancer: Final Results From the Phase III

ALTA-1L Study

Myung J. Ahn,

¹

Hye R. Kim,

²

James C.H. Yang,

³

Ji-Yu Han,

⁴

Jacky Yu-Chung. Li,

⁵

Maximilian J. Hochmair,

⁶

Gee-Chen Chang,

⁷

Angelo Delmonte,

⁸

Ki H. Lee,

⁹

Rosario G. Campelo,

¹⁰

Cesare Gridelli,

¹¹

Alexander I. Spira,

¹²

Raffaele Califano,

¹³

Frank Griesinger,

¹⁴

Sharmistha Ghosh,

¹⁵

Enriqueta Felip,

¹⁶

Dong-Wan Kim,

¹⁷

Yuyin Liu,

¹⁸

Pingkuan Zhang,

¹⁹

Sanjay Popat,

²⁰

D. Ross Camidge

²¹

Abstract

WeevaluatedbrigatinibefﬁcacyandsafetycomparedwithcrizotinibinananalysisofAsian(n=108)andnon- Asian(n=167)subgroupsfromthephaseIIIALTA-1Lstudy.BrigatinibshowedbetterBIRC-assessedPFSover crizotinibinAsiansandnon-Asians(HR[95%CI],log-rank:Asians,0.35[0.20-0.59],P=.0001;non-Asians,0.56 [0.38-0.84],P=.0041).Overallsafetywassimilarbetweengroups.

Background:Brigatinibisanext-generationanaplasticlymphomakinase(ALK)inhibitorwithdemonstratedefﬁcacy inlocallyadvancedandmetastaticnon–smallcelllungcancer(NSCLC)incrizotinib-refractoryandALKinhibitor-naive

Abbreviations:AE,adverseevent;ALK,anaplasticlymphomakinase;ALK+,anaplas- ticlymphomakinaserearrangement–positive;ALT,alanineaminotransferase;ALTA- 1L,ALKinLungCancerTrialofbrigAtinibin1stLine;AST,aspartateaminotransferase;BIRC,blindedindependentreviewcommittee;BMI,bodymassindex;CI, confidenceinterval;CNS,centralnervoussystem;CPK,creatinephosphokinase;CR, completeresponse;DOR,durationofresponse;ECOG,EasternCooperativeOncol- ogyGroup;FDA,USFoodandDrugAdministration;HR,hazardratio;iPFS,intracra- nialprogression-freesurvival;NE,notevaluable;NR,notreached;NSCLC,non–small celllungcancer;OR,oddsratio;ORR,objectiveresponserate;OS,overallsurvival;

PFS,progression-freesurvival;PK,pharmacokinetic;PR,partialresponse;RECIST, ResponseEvaluationCriteriainSolidTumors;TEAE,treatment-emergentadverse event;TKI,tyrosinekinaseinhibitor.

1DivisionofHematology-Oncology,SamsungMedicalCenter,Sungkyunkwan UniversitySchoolofMedicine,Seoul,SouthKorea

2DivisionofMedicalOncology,DepartmentofInternalMedicine,YonseiCancer Center,YonseiUniversityCollegeofMedicine,Seoul,SouthKorea

3DepartmentofMedicalOncology,NationalTaiwanUniversityCancerCenter, Taipei,Taiwan,andDepartmentofOncology,NationalTaiwanUniversityHospital, Taipei,Taiwan

4CenterforLungCancer,NationalCancerCenter,Goyang,SouthKorea

5DepartmentofClinicalOncology,HongKongUnitedOncologyCentre,Kowloon, HongKong

6DepartmentofRespiratoryandCriticalCareMedicine,KarlLandsteinerInstituteof LungResearchandPulmonaryOncology,KlinikFloridsdorf,Vienna,Austria

7SchoolofMedicine,andInstituteofMedicine,ChungShanMedicalUniversity, DivisionofPulmonaryMedicine,DepartmentofInternalMedicine,ChungShan MedicalUniversityHospital,andDivisionofChestMedicine,DepartmentofInternal Medicine,TaichungVeteransGeneralHospital,Taichung,Taiwan

8MedicalOncology,IstitutoRomagnoloperloStudiodeiTumori"DinoAmadori"

(IRST),IRCCS,Meldola,Italy

9DepartmentofInternalMedicine,ChungbukNationalUniversityHospital, ChungbukNationalUniversityCollegeofMedicine,Cheongju,SouthKorea

10MedicalOncologyDepartment,ThoracicTumorsUnit,ComplejoHospitalario UniversitarioACoruña,ACoruña,Spain

11DivisionofMedicalOncology,A.O.S.G.Moscati,Avellino,Italy

12MedicalOncology,VirginiaCancerSpecialistsandUSOncologyResearch,Fairfax, VA

13DepartmentofMedicalOncology,TheChristieNHSFoundationTrust,and DivisionofCancerSciences,TheUniversityofManchester,Manchester,England,UK

14UniversityDepartmentofInternalMedicine-Oncology,Pius-HospitalOldenburg, UniversityofOldenburg,Oldenburg,Germany

15DepartmentofMedicalOncology,Guy’sandStThomas’NHSFoundationTrust, London,England,UK

16MedicalOncologyDepartment,Valld’HebronUniversityHospital,Barcelona, Spain

17DepartmentofInternalMedicine,SeoulNationalUniversityCollegeofMedicine andSeoulNationalUniversityHospital,Seoul,RepublicofKorea

18OncologyStatistics,TakedaDevelopmentCenterAmericas,Inc.,Lexington,MA

19ClinicalScience,TakedaDevelopmentCenterAmericas,Inc.,Lexington,MA

20LungUnit,TheRoyalMarsdenHospitalandTheInstituteofCancerResearch, London,England,UK

21DepartmentofMedicine,DivisionofMedicalOncology,UniversityofColorado CancerCenter,Aurora,CO

Submitted:May25,2022;Revised:Jul8,2022;Accepted:Jul16,2022;Epub:21July 2022

Addressforcorrespondence:Myung-JuAhn,MD,DivisionofHematology-Oncology, SamsungMedicalCenter,SungkyunkwanUniversitySchoolofMedicine,81Irwonro Gangnamgu,06531,Seoul,Korea

E-mailcontact:[email protected]

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settings.ThisanalysisassessedbrigatinibinAsianvs.non-Asianpatientsfromthefirst-lineALTA-1Ltrial.Patientsand Methods:ThiswasasubgroupanalysisfromthephaseIIIALTA-1Ltrialofbrigatinibvs.crizotinibinALKinhibitor–naive ALK+NSCLC.Theprimaryendpointwasprogression-freesurvival(PFS)asassessedbyblindedindependentreview committee(BIRC).Secondaryendpointsincludedconfirmedobjectiveresponserate(ORR)andoverallsurvival(OS)in theoverallpopulationandBIRC-assessedintracranialORRandPFSinpatientswithbrainmetastases.Results:Ofthe 275randomizedpatients,108wereAsian.BrigatinibshowedconsistentsuperiorityinBIRC-assessedPFSvs.crizotinib inAsian(hazardratio[HR]:0.35[95%CI:0.20-0.59];log-rankP=.0001;median24.0vs.11.1months)andnon-Asian (HR:0.56 [95%CI:0.38-0.84];log-rank P= .0041;median24.7 vs.9.4months)patients.Resultswereconsistent withinvestigator-assessedPFSandBIRC-assessedintracranialPFS.Brigatinibwaswelltolerated.Toxicityprofilesand dosemodificationratesweresimilarbetweenAsianandnon-Asianpatients.Conclusion:Efficacywithbrigatinibwas consistentlybetterthanwithcrizotinibinAsianandnon-AsianpatientswithlocallyadvancedormetastaticALKinhibitor- naiveALK-+NSCLC.TherewerenoclinicallynotabledifferencesinoverallsafetyinAsianvs.non-Asianpatients.

Keywords:ALKTKI-naive,Anaplasticlymphomakinase,Clinicaltrial,Firstline,Tyrosinekinaseinhibitor

Introduction

Anaplastic lymphoma kinase (ALK) receptor tyrosine kinase rearrangements occur in approximately 3% to 5% of patients with non–small cell lung cancer (NSCLC)and occur atsimilar rates among Asian and non-Asian populations.^1-4 A number of ALK inhibitors, including crizotinib, alectinib, ceritinib, brigatinib,andlorlatinib,havereportedefficacyintreatmentofpatients withALKTKI-naiveanaplasticlymphomakinase–positive(ALK+) NSCLC.^5-12Crizotinib,thefirstapprovedALKinhibitor,demon- stratedefficacysuperiortopemetrexedplusplatinumchemotherapy inpreviouslyuntreatedpatients.⁶ Studiesoftheefficacyandsafety of crizotiniband of alectinib have demonstrated similar efficacy betweenAsianandnon-Asianpatients.⁴^,⁸^,^13-16

Brigatinib(ARIAD Pharmaceuticals, Inc.,Cambridge, MA)is a next-generation ALK inhibitor that targets a broad range of ALKresistancemutations.^17-19ThephaseIIIALKinLungCancer Trial of brigAtinib in 1st Line (ALTA-1L; NCT02737501) trial compared the efficacy and safety of brigatinib and crizotinib in ALK inhibitor-naive advanced ALK+ NSCLC.^9-11 The primary endpoint,blindedindependentreviewcommittee(BIRC)-assessed progression-freesurvival(PFS),wasmetatthefirstinterimanalysis andconfirmedatthesecondinterimanalysis.⁹^,¹⁰Atthefinalanaly- sis,withmedianfollow-upforbrigatinibof40.4months,brigatinib maintainedsuperiorityinBIRC-assessedPFS(hazard ratio[HR]:

0.48[95%CI:0.35-0.66];P<.0001),withmedianPFSof24.0 monthsvs.11.0months,respectively.¹¹

At the first interim analysis of ALTA-1L, a subgroup analysis in Asian and non-Asian patients reported longer BIRC-assessed PFSwithbrigatinibcomparedwithcrizotinibinbothpopulations (HRfordiseaseprogressionordeath,Asian:0.41[95%CI:0.20- 0.86]; non-Asian: 0.54 [95% CI: 0.33-0.90]).⁹ Here, we report finalefficacyandsafetyresultsofALTA-1LinAsianandnon-Asian patients.

Patients and Methods

ALTA-1L is an open-label, randomized, international, phase IIItrial. The trialwasconducted in accordancewith the ethical standards of the Declaration of Helsinki and the International

Councilfor Harmonizationguideline forGood ClinicalPractice andwasapprovedbylocalinstitutionalreviewboards.Allpatients providedwritteninformedconsent.Thedetailedmethodsforthis studyhavebeenpreviouslypublished.⁹

Briefly,eligiblepatientswereadults≥18yearsofagewhohad locallyadvancedormetastaticNSCLCwithatleast1measurable lesionaccordingtoResponseEvaluationCriteriainSolidTumors (RECIST)v1.1²⁰ and had not previouslyreceived ALK-targeted therapy.PatientsmusthavebeenALK+basedonlocallydetermined testing. Asymptomatic or stable central nervous system (CNS) metastaseswerepermitted.Patientswhohadreceivedmorethan1 priorsystemicanticancerregimen, orradiationtherapywithin14 daysbeforethefirstdoseoftrialdrug,wereexcluded.

Patientswererandomized1:1toreceiveoralbrigatinib180mg once daily (with7 dayslead-in period at 90 mg once daily) or oralcrizotinib 250 mg twice daily in 28 days cycles; they were further stratified according to the presence or absence of brain metastasesatbaseline and thecompletion of atleast1full cycle ofchemotherapyforlocallyadvancedormetastaticdisease(Yesvs.

No).Treatmentwascontinueduntildiseaseprogression,asassessed byBIRC,unacceptable toxicity, orother discontinuation criteria weremet.TheintracranialBIRCreviewerswereindependentfrom the systemic BIRC reviewers. Crossoverfrom the crizotinibarm tothebrigatinibarmwaspermittedfollowingdiseaseprogression, aftera10-daywashoutperiod.Brigatinibcouldbecontinuedafter diseaseprogressionattheinvestigator’s discretion.Doseinterrup- tionsor reductions were permitted for treatment-relatedadverse events(TEAEs).

The primary endpoint was PFS according to RECIST v1.1 as assessed by the BIRC. Secondary endpoints included the confirmed objective responserate (ORR),confirmed intracranial ORR,intracranialPFS,overallsurvival(OS),durationofresponse, and safety. Disease assessments were performed every 8 weeks throughcycle14 andthenevery12weeksuntiltheendoftreat- ment.Responseswereconfirmedatleast4weeks aftertheinitial response.Adverseevents(AEs)werecategorizedusingtheNational CancerInstituteCommonTerminologyCriteriaforAdverseEvents, v4.03.

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Table1 DemographicsandBaselineCharacteristics

Asian Non-Asian

Brigatinib (n=59)

Crizotinib (n=49)

Brigatinib (n=78)

Crizotinib (n=89)

Medianage,years(range) 55(32-80) 56(30-89) 60(27-86) 60(29-83)

Female,n(%) 31(53) 26(53) 38(49) 55(62)

Medianweight,kg(range)^a 60(43-96) 60(40-85) 70(46-111) 70(46-117)

MedianBMI,kg/m²(range)^b 23(16-31) 23(16-32) 26(18-41) 26(18-44)

ECOGperformancestatus,n(%)

0 18(31) 13(27) 36(46) 40(45)

1 39(66) 33(67) 37(47) 45(51)

2 2(3) 3(6) 5(6) 4(4)

Diseasestageatstudyentry

IIIB 2(3) 5(10) 6(8) 7(8)

IV 57(97) 44(90) 72(92) 82(92)

ALKstatusassessedbylocallyFDA-approvedtest,n(%)^c 54(92) 41(84) 69(88) 71(80)

Baselinebrainmetastases,n(%)^d 21(36) 16(33) 19(24) 25(28)

Priorradiotherapytothebrain,n(%) 7(12) 8(16) 11(14) 11(12)

Priorchemotherapyinthelocallyadvancedormetastaticsetting,n(%)^e 19(32) 12(24) 17(22) 25(28)

ALK=anaplasticlymphomakinase;BMI=bodymassindex;ECOG=EasternCooperativeOncologyGroup;FDA=FoodandDrugAdministration;;FISH,ﬂuorescenceinsituhybridization;IHC, immunohistochemistry

aAsiancrizotinibarm,n=48.Non-Asianarms:brigatinib,n=77;crizotinib,n=87

bAsiancrizotinibarm,n=48.Non-Asianarms:brigatinib,n=71;crizotinib,n=82

cPatientswhoseALK+statuswastestedlocallybyVysisFISHorVentanaIHC

dAsassessedbyinvestigator

ePriorchemotherapydeﬁnedascompletionof≥1fullcycleofchemotherapyinthelocallyadvancedormetastaticsetting

Thefinalanalysiswasconducted followingthelastpatientlast visit inJanuary, 2020, approximately 3.5 years after last patient first enrollment.Thisprespecified subgroupanalysis of outcomes inAsianvs.non-Asianpatientswasconductedfollowingthefinal analysis.Asianpatientsincluded allpatientswhoseracewasself- reportedasnative Asian.Efficacywasevaluated inthe intention- to-treatpopulation,inAsianandnon-Asianpatientsseparately.PFS wascomparedbetweenthe2armsusinga2-sidedstratifiedlog-rank test(stratificationfactors:presenceofintracranialCNSmetastasesat baseline[Yesvs.No],andpriorchemotherapyforlocallyadvanced or metastaticdisease [Yesvs.No]);ethnicitywasnotastratifica- tionparameter.Mediantimetoefficacyeventsand95%CIswere estimatedforeachtreatmentarmusingtheKaplan-Meiermethod.

Thesafetypopulationincludedallpatientswhoreceivedatleast1 doseofstudydrug.StatisticalanalyseswereperformedusingBase 9.4SAS/STAT13.1software(SASInstitute,Cary,NC).Dataare reportedasofthedatacutoff dateforthefinalanalysisofJanuary 29,2021.¹¹

Results

Patients

A total of 275 patients were randomized, with 108 (39%) Asian patients and 167 (61%) non-Asian patients. The median age, weight,and bodymassindexofAsianpatientswereslightly lessthanthoseofnon-Asianpatients(Table1).Numericallymore Asian patientshadEasternCooperative Oncology Groupperfor- mancestatus1comparedwiththenon-Asianpopulation(Table1).

There wereno other substantial differences betweenpopulations

or between brigatinib- and crizotinib-treated patients. At study completion, no patient in either arm remained on treatment.

Median follow-up wassimilar betweenthe Asianand non-Asian cohorts;40.7months(range0.7-49.9months)and 39.8months (range0-52.4months)inthebrigatinibarm,respectively,and13.6 months(range0.1-47.0months)and15.5months(range0.3-51.7 months),respectively,inthecrizotinibarm.

Efficacy

Systemic Progression-freeSurvival. Consistentwith results from the overall population, brigatinib demonstrated better BIRC- assessedPFSovercrizotinibinbothAsianandnon-Asianpatients.

InAsianpatients,theHRforPFSwas0.35[95%CI:0.20-0.59];

P=.0001bylog-ranktest;Figure1A).Innon-Asianpatients,the HRwas0.56[95% CI:0.38-0.84];P = .0041bylog-ranktest;

Figure 1B). Investigator-assessedPFS supports BIRC assessment, continuingtoshowimprovementswithbrigatinibinAsianandin non-Asianpatientsvs.crizotinib(Figure1C,D).

Systemic ResponseRateandDurationofResponse. AmongAsian patients,the BIRC-assessedconfirmed ORR(n/N;95%CI)was 80%(47/59;67%-89%) inthe brigatinibarm and71%(35/49;

57%-83%)inthecrizotinibarm(Table2).Innon-Asianpatients, confirmedORRwas71%(55/78;59%-80%)withbrigatiniband 57%(51/89;46%-68%)withcrizotinib.Diseasecontrolrateswere similaracross treatment groupsinAsianand non-Asianpatients.

Thedurationofresponseamongconfirmedresponderswaslonger withbrigatinibtreatment,withamediandurationof22.2months

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Figure1 EfficacyofbrigatinibandcrizotinibinAsianandnon-AsianpatientswithTKI-naiveALK-+NSCLC.

Kaplan-Meier–estimatedBIRC-assessedPFSfor(A)Asianand(B)non-Asianpatientsintheintention-to-treat population;Kaplan-Meier–estimatedinvestigator-assessedPFSfor(C)Asianand(D)non-Asianpatientsinthe intention-to-treatpopulation;overallsurvivalfor(E)Asianand(F)non-Asianpatientsintheintention-to-treat population.

ALK=anaplasticlymphomakinasegene;BIRC=blindedindependentreviewcommittee;CI=conﬁdenceinterval;HR=hazardratio;NR=notreached;

NSCLC=non–smallcelllungcancer;OS=overallsurvival;PFS=progression-freesurvival;TKI=tyrosinekinaseinhibitor.

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Figure1 Continued

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Table2 BIRC-AssessedObjectiveResponseRate(Intent-to-treatPopulation)

Brigatinib Crizotinib OR(95%CI)^a Brigatinib Crizotinib OR(95%CI)^a Intention-to-treatpopulation

No.ofpatients 59 49 78 89

ConﬁrmedORR,n(%) (95%CI)

47(80) (67-89)

35(71) (57-83)

1.70 (0.69-4.18);

P=.2546

55(71) (59-80)

51(57) (46-68)

1.77 (0.93-3.36);

P=.0783 Diseasecontrolrate,n

(%)(95%CI)

53(90) (79-96)

45(92) (80-98)

64(82) (72-90)

74(83) (74-90) MedianDORin

conﬁrmedresponders, months(95%CI)

22.2 (16.6-NE)

11.0 (9.1-19.3)

41.4 (22.2-NE)

19.4 (11.1-35.8)

Probabilityofmaintainingresponse,%(95%CI)

1year 76

(61-86)

46 (28-63)

79 (66-88)

63 (47-75)

2years 48

(33-62)

25 (11-41)

60 (45-72)

42 (27-56)

3years 46

(31-60)

14 (4-29)

52 (37-64)

33 (19-48) Patientswithanybrainmetastasesatbaseline(asassessedbytheBIRC^b)

No.ofpatients 21 18 26 31

Conﬁrmedintracranial ORR,%(95%CI)

13(62) (38-82)

6(33) (13-59)

7.24 (1.22-42.87);

P=.0212

18(69) (48-86)

1(3) (0-17)

71 (6.86-734.32);

P<.0001

IntracranialCR,n(%) 11(52) 0 10(38) 1(3)

IntracranialPR,n(%) 2(10) 6(33) 8(31) 0

BIRC=blindedindependentreviewcommittee;CI=conﬁdenceinterval;CR=completeresponse;DOR=durationofresponse;NE=notevaluable;NR=notreached;OR=oddsratio;ORR= objectiveresponserate;PR=partialresponse

aORs(brigatinibvs.crizotinib)andPvaluesarefromaCochran-Mantel-Haenszelteststratiﬁedbypresenceofbrainmetastasesatbaselineandpriorchemotherapyforlocallyadvancedormetastatic disease

bIntracranialreviewerswereindependentfromsystemicreviewers

and 11.0 months among Asian patients treated with brigatinib andcrizotinib,respectively.Mediandurationofresponsewas41.4 monthsforbrigatinibcomparedwith19.4monthsinthecrizotinib groupinthenon-Asiangroup(Table2).

Overall Survival. A total of 92 patients died as of the data cutoff date(January29,2021).In boththeAsianand non-Asian subgroups,morepatientsdiedinthecrizotinibarm(Asianpatients:

brigatinib, 13 [22%]; crizotinib, 14 [29%]; non-Asian patients:

brigatinib,28 [36%];crizotinib,37[42%]). OStrendedinfavor of brigatinib inboth the Asianand non-Asianpopulations (HR forOS,Asianpatients:0.71[95%CI:0.33-1.53];P= .4063by log-ranktest(Figure1E);non-Asianpatients:0.89[95%CI:0.54- 1.46];P=.6800bylog-ranktest(Figure1F).

EfficacyinPatientsWithBrainMetastases. Atotalof96patients hadbaselinebrainmetastasesasassessedbyBIRC(Asianpatients:

brigatinib, 21, crizotinib,18; non-Asianpatients: brigatinib, 26, crizotinib,31).TherewasabetterintracranialORRinbothAsian andnon-Asianpatientstreatedwithbrigatinibthanwithcrizotinib.

ConfirmedintracranialORR(n/N;95%CI)inAsianpatientswas 62%(13/21;38%-82%)forbrigatiniband33%(6/18;13%-59%) forcrizotinib (oddsratio[OR] forbrigatinibvs.crizotinib, 7.24

[95%CI:1.22-42.87];P=.0212;Table2).Innon-Asianpatients, confirmedintracranialORRwas69%(18/26;48%-86%)forbriga- tiniband3%(1/31;0%-17%)forcrizotinib(OR:71.00[95%CI:

6.86-734.32];P<.0001).Amongallpatients,regardlessofwhether brainmetastaseswerepresent atbaseline, BIRC-assessedintracra- nialPFSwasbetterinpatientstreatedwithbrigatinibvs.crizotinib (Figure2A,2B).

Safety

Brigatinib was well tolerated in both Asian and non-Asian populations (Table 3). The most common (> 25% of patients overall) any-grade TEAEs were gastrointestinal events, increased bloodcreatinephosphokinase,cough,increasedaminotransferases, and peripheral edema. There were no remarkable differences in AE profiles between the Asian and non-Asian populations.

The incidence of increased aspartate aminotransferase (31% vs.

22%), increased alanine aminotransferase (31% vs. 17%), and constipation (25% vs. 16%) was numerically higher in Asian patients treated with brigatinib than in non-Asian patients.

Diarrhea(64%vs.51%), nausea (40%vs.24%), andperipheral edema(13% vs.5%) weremore frequentin non-Asianpatients treatedwith brigatinibthaninAsianpatientstreatedwithbriga-

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Figure2 Intracranialefficacyofbrigatinibandcrizotinibin(A)Asianand(B)non-AsianpatientswithTKI-naiveALK-+NSCLC regardlessofbrainmetastasesatbaseline.Kaplan-Meier–estimatedBIRC-assessedPFSfortheintention-to-treat population.Intracranialreviewerswereindependentfromsystemicreviewers.¹¹

ALK=anaplasticlymphomakinasegene;BIRC=blindedindependentreviewcommittee;CI=conﬁdenceinterval;HR=hazardratio;iPFS=intracranial progression-freesurvival;NR=notreached;NSCLC=non–smallcelllungcancer;PFS=progression-freesurvival;TKI=tyrosinekinaseinhibitor.

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Table3 Safety Overview and Treatment-Emergent Adverse Events^a of Any Grade Reported in ≥ 25% of All Patients (SafetyPopulation^b)

Brigatinib(n=59) Crizotinib(n=48) Brigatinib(n=77) Crizotinib(n=89) Any Grade≥3 Any Grade≥3 Any Grade≥3 Any Grade≥3 Overviewofadverseevents,n(%)

Anyadverseevent 59(100) 42(71) 48(100) 25(52) 77(100) 53(69) 89(100) 52(58)

Adverseeventleadingtodosereduction 27(46) – 9(19) – 33(43) – 25(28) –

Adverseeventleadingtotreatmentinterruption 43(73) – 21(44) – 55(71) – 44(49) –

Adverseeventleadingtotreatmentdiscontinuation 5(8) – 3(6) – 13(17) – 9(10) –

Adverseeventsreportedin≥25%ofallpatients,n(%)

Diarrhea 30(51) 1(2) 23(48) 0 49(64) 2(3) 54(61) 4(4)

IncreasedbloodCPK 30(51) 20(34) 7(15) 1(2) 38(49) 16(21) 16(18) 1(1)

Cough 22(37) 0 6(13) 0 27(35) 0 23(26) 0

IncreasedAST 18(31) 4(7) 17(35) 1(2) 17(22) 2(3) 19(21) 8(9)

IncreasedALT 18(31) 4(7) 21(44) 3(6) 13(17) 2(3) 28(31) 11(12)

Constipation 15(25) 0 16(33) 0 12(16) 1(1) 41(46) 0

Nausea 14(24) 0 27(56) 2(4) 31(40) 3(4) 54(61) 2(2)

Vomiting 11(19) 0 20(42) 1(2) 19(25) 2(3) 41(46) 2(2)

Peripheraledema 3(5) 0 19(40) 0 10(13) 1(1) 44(49) 1(1)

AE=adverseevent;ALT=alanineaminotransferase;AST=aspartateaminotransferase;CPK=creatinephosphokinase

aAEsstartingorworseningonoraftertheﬁrstdoseofstudytreatmentandnolaterthantheearliestof(1)30daysafterthelastdoseoftreatmenttowhichthepatientwasassigned,or(2)thedaybefore thestartofbrigatinibtherapyinpatientswhocrossedover

bPatientstreatedwith≥1doseofstudymedication

tinib. It is notable that this trend of slight differences in AE frequency was also generally observed in patients treated with crizotinib.

Grade≥3TEAEsoccurredatsimilarratesinAsian(71%)vs.

non-Asianpatients(69%)treatedwithbrigatinib.MoreAsianthan non-Asianpatientstreatedwithbrigatinibexperiencedgrade≥3 increasesincreatininephosphokinase(34%vs.21%).Inthisstudy, diseaseprogressionwasrequiredtobereportedasanAEunlessitwas asymptomaticradiologicalprogressionalone.Twenty-twopatients hadAEsleadingtodeath,mostattributedtolungcancerprogres- sion.Noneweredeemedrelatedtostudytreatmentbytheinvesti- gator.AmongAsianpatients,interstitiallungdisease/pneumonitis atany time occurred in7% of patients(4/59) inthe brigatinib arm and no patients in the crizotinib arm, with grade 3 or 4 interstitiallungdiseaseoccurringin3%ofpatients(2/59)treated with brigatinib. Any-grade interstitial lung disease/pneumonitis with early onset (defined as within 14 days of treatment initia- tion)wasobservedin3%ofpatients(2/59)inthebrigatinibarm.

Among non-Asian patients, interstitial lung disease/pneumonitis atany timewasreported in5%of patients(4/77) inthe brigatinib arm,similar to thatinAsian patients,and 3%of patients (3/89)inthecrizotinibarm.Grade3or4pneumonitisoccurredin 3%ofpatients(2/77)treatedwithbrigatiniband1%ofpatients (1/89) treated with crizotinib. Any-grade early-onset pneumoni- tiswasreportedin3%ofpatients(2/77)treatedwithbrigatinib;

noearly-onsetinterstitiallung diseasewasreported innon-Asian patients.

Thedosemodificationratewassimilarbetweenbothpopulations treatedwithbrigatinib(Table3).Medianbrigatinibdoseintensity

was150.0mg/dforAsianpatientsand165.6mg/dfornon-Asian patients.Inthecrizotinibarm,themediandoseintensitywas496.9 mg/dand494.5mg/dayforAsianandnon-Asianpatients,respectively.DosereductionduetoAEswasmandatedbyinvestigatoror protocolin46%and19%ofAsianpatientsinthebrigatiniband crizotinibarms,respectively,and in43%and28%of non-Asian patients,respectively.FewerAsianpatients(brigatinib,8%; crizotinib, 6%) than non-Asianpatients (brigatinib, 17%; crizotinib, 10%)discontinuedtreatmentduetoTEAEs.Therewasnoremark- abledifferenceintheprofileofAEsthatledtodrugdiscontinuation inAsianvs.non-Asianpatients.

Discussion

ResultsfromaphaseIethnobridgingstudy(dataonfile)demon- stratedalackofraceeffectsonthepharmacokinetic(PK)profileof brigatinibinhealthyAsianandwhitevolunteers.Theseresultswere supportedbyapopulationPKmodel–basedanalysisofpatientsin ALTA-1Lthatshowedconsistentbrigatinibsystemicexposuresin Asianandnon-Asianpatients.²¹

In this ALTA-1L final analysis, brigatinib showed sustained improvementinsystemicand intracranialefficacycomparedwith crizotinib in both Asian and non-Asian patients with ALK inhibitor–naive ALK+ NSCLC, consistent with the analyses of theoverallpopulation^9-11^,²²andwiththereportbasedonthefirst interimanalysis.⁹ AsianpatientsshowatrendofbetterPFSwith brigatinib over crizotinib than non-Asian patients; however, the HRshad overlapping95%CIsand the medianPFS wassimilar forbothtreatmentarmsinAsianandNon-Asianpopulations.One limitationofour analysisisthatthe Coxproportionalregression

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analysisdidnotaccountforcovariatesotherthanthe2stratification factors,whichhaveslightly,butnotsignificantly,differentdistribu- tionsintheAsianandnon-Asianpopulations.Toavoidanypoten- tialimpactfromthese2randomizationfactors,theywereincluded intheregressionmodelforadjustment.ThemedianPFSisapoint estimateofsurvival,whileHRdescribestheoveralldistribution.The Kaplan-MeiercurvesshowthattheseparationinBIRC-assessedPFS betweenbrigatinibandcrizotinibismoreobviousinAsiansthanin non-Asianswithoutconsideringtheimpactofanycovariateandcan explainthelowerHRintheAsianpopulation.

PreviousstudieshavedemonstratedsimilarefficacybetweenAsian andnon-Asianpatientstreatedwithcrizotinibandalectinib.⁴^,⁸^,^13-15 Inananalysisofpreviouslytreated(1priorplatinum-basedregimen) anduntreatedpatientsfromPROFILE1007and1014,comparable benefitswereobservedinAsianandnon-Asianpatients.⁴ InAsian patients,theHRforPFSwas0.53(95%CI:0.36-0.76;P<.001;

medianPFS:crizotinib8.1months,chemotherapy2.8months);in non-Asianpatients,theHRforPFSwas0.45(95%CI:0.30-0.66;

P<.001;medianPFS:crizotinib7.1monthsvs.chemotherapy3.2 months).⁴ Inthe ALEXstudycomparingalectiniband crizotinib inpatientswithTKI-naiveNSCLC,PFSsubgroupanalysesshowed similarbenefitinAsian(HR:0.46[95%CI:0.280-0.75])andnon- Asian(HR:0.49[95%CI:0.32-00.75])patients.⁸^,¹⁵Withlonger follow-upofALTA-1L,thisstudystrengthenstheobservationthat second-generationALKTKIsimprovePFSandintracranialefficacy comparedwithcrizotinibinpatientswithadvancedALK+NSCLC, regardlessofethnicity.

InALTA-1L,Asianpatientshad atrendtowardbettersurvival in both arms compared with non-Asian patients, with numerically higher 3-year OS rates for both brigatinib and crizotinib.

In subgroup analyses of Asian and non-Asian patients from the PROFILE1014trialofcrizotinibvs.chemotherapy,theHR(95%

CI)forOSwas0.93(0.58-1.49)inAsianpatientsand0.72(0.47- 1.11)innon-Asians.¹⁶IntheALEXtrialofalectinibvs.crizotinib, theHRforOSwas0.74(0.40-1.36)forAsiansand0.69(0.43-1.10) fornon-Asians.¹⁵

ThesafetyprofileofbrigatinibinAsianandnon-Asianpatients wasconsistentwiththeestablishedsafetyprofileofbrigatinibfrom multiplestudies.¹¹^,¹⁹^,²³BrigatinibwaswelltoleratedinbothAsian and non-Asianpatients,reflectedbysimilarratesof dosemodifi- cations betweenthe 2subpopulations.Certain toxicities, suchas nauseaandvomiting,weremorefrequentinthenon-Asianpopula- tion inboth treatment arms. A similarfinding was observedfor alectinibinasubgroupanalysisoftheALEXstudy.²⁴ Theunder- lyingreason isunknownandmaybe relatedtodietaryhabits or reporting bias. With longerfollow-up, the pneumonitisrate did notsignificantlydifferinAsianvs.non-Asianpatientswhoreceived brigatinib.

Conclusion

ResultsfromthefinalanalysisoftheALTA-1Ltrialdemonstrate brigatinib tobebetter intermsof efficacy compared withcrizo- tinibinbothAsianandnon-Asianpatients.Brigatinibiswelltoler- atedandrepresentsa once-daily,single-tablet,promisingfirst-line treatmentoptioninbothAsianandnon-AsianpatientswithALK inhibitor-naivelocallyadvancedormetastaticALK+NSCLC.

ClinicalPracticePoints

• Brigatinibisasecond-generationALKTKIapprovedfortreat- mentofadvancedALK+NSCLC.InthephaseIIIALTA-1Ltrial, brigatinibdemonstratedsuperiorefficacyvs.crizotinibinpatients withALKTKI-naiveALK+NSCLCandwaswelltolerated.We conductedaplannedanalysisinAsianandnon-Asiansubgroups fromALTA-1Ltodeterminetheeffectsof ethnicityonefficacy andtolerabilityofbrigatinib.

• Consistent with overall ALTA-1L results, brigatinib demonstrated consistently better BIRC-assessed PFS compared with crizotinib in both Asian and non-Asian patients (HR, Asian:

0.35[95% CI: 0.20-0.59], P = .0001; HR,non-Asian: 0.56 [0.38-0.84], P = .0041). Patients in the brigatinib arm also had numerically better overall ORR (OR [Asian/non-Asian]:

1.70/1.77), intracranial ORR (OR: 7.24/71.00),and trendto longerOS (HR: 0.71/0.89)vs. crizotinib. Brigatinib waswell toleratedinbothgroups.Higherpercentagesofincreasedcreati- ninephosphokinase, aspartateaminotransferase,alanineaminotransferase,andconstipationreportedinAsianpatientswerenot clinicallymeaningful, and dose modificationrates weresimilar betweenAsianandnon-Asianpatients.

• TheseresultsaresupportedbyaphaseIPKstudyinhealthyAsian andwhitevolunteersthatdemonstratedalackofraceeffectson thebrigatinibPKprofile(dataonfile).ApopulationPKmodel- basedanalysis of patientsinALTA-1Lalsoshowedcomparable systemicexposurestobrigatinibinAsianandnon-Asianpatients.

• Thissubgroupanalysis fromlong-termfollow-updemonstrates the consistent efficacy and tolerability of brigatinib in Asian and non-Asianpatients. Brigatinib represents a first-line treat- mentoptioninAsianpatientswithALKinhibitor-naiveadvanced ALK+NSCLC.

Author Contributions

Conceptualization: M.J. Ahn, M.J. Hochmair, P. Zhang, S.

Popat,D.R.Camidge

Data curation (Management activities to annotate [produce metadata],scrubdataandmaintainresearchdata[includingsoftware code, whereitisnecessary forinterpretingthe dataitself]forinitial useandlaterreuse):G.C.Chang,A.I.Spira,F.Griesinger,Y.Liu,P.

Zhang,S.Popat

Formalanalysis:M.J.Hochmair,A.I.Spira,F.Griesinger,Y.Liu, P.Zhang

Fundingacquisition:A.I.Spira,P.Zhang

Investigation:M.J.Ahn,H.R.Kim,J.C.H.Yang,J.Y.Han,J.Y.C.

Li, M.J.Hochmair,G.C.Chang, A.Delmonte, K.H.Lee,M.R.

GarcíaCampelo,C.Gridelli,A.I.Spira,R.Califano,F.Griesinger, S.Ghosh,E.Felip,D.W.Kim,P.Zhang,S.Popat,D.R.Camidge

Methodology: M.J.Hochmair,A.I.Spira,Y.Liu, P.Zhang, S.

Popat,D.R.Camidge

Projectadministration(Managementandcoordinationresponsibil- ityfortheresearchactivityplanningandexecution):M.J.Hochmair, G.C. Chang, A.I. Spira, R. Califano, P. Zhang, S. Popat, D.R.

Camidge

Resources(Provisionofstudymaterials,reagents,materials,patients, laboratory samples, animals, instrumentation, computing resources, or other analysis tools): M.J. Ahn, H.R. Kim, J.C.H. Yang, J.Y.

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Han,J.Y.C.Li,M.J.Hochmair,G.C.Chang,A.Delmonte,K.H.

Lee, M.R.GarcíaCampelo,C.Gridelli,A.Spira,R.Califano,F.

Griesinger,S.Ghosh,E.Felip,D.W.Kim,P.Zhang,S.Popat,D.R.

Camidge

Software(Programming,softwaredevelopment;designingcomputer programs; implementation of the computer code and supporting algorithms;testingofexistingcodecomponents):M.J.Hochmair

Supervision(Oversightandleadershipresponsibilityfortheresearch activityplanningandexecution,includingmentorshipexternaltothe core team): A.I. Spira, F. Griesinger, P. Zhang, S. Popat, D.R.

Camidge

Validation(Verification,whetherasapartoftheactivityorseparate, oftheoverallreplication/reproducibilityofresults/experimentsandother research outputs): M.J. Ahn,M.J. Hochmair,G.C. Chang, M.R.

GarcíaCampelo,A.I.Spira,R.Califano,F.Griesinger,E.Felip,Y.

Liu,P.Zhang,S.Popat,D.R.Camidge

Visualization (Preparation, creation and/or presentation of the publishedwork,specificallyvisualization/datapresentation):M.J.Ahn, M.J. Hochmair,M.R. García Campelo, A.I.Spira, P. Zhang, S.

Popat,D.R.Camidge

Writing-review&editing:Allauthors

Data Sharing Statement

Thedata sets,including the redactedstudy protocol,redacted statisticalanalysisplan,andindividualparticipantdatasupporting theresultsreportedinthisarticle,willbemadeavailablewithin3 monthsfrominitialrequest,toresearcherswhoprovideamethod- ologically sound proposal. The data will be provided after de- identification, in compliance with applicable privacy laws, data protection,andrequirementsforconsentandanonymization.

ClinicalTrials.gov registration

NCT02737501

Acknowledgments

Theauthorswouldliketothankthepatients,theirfamilies,and theircaregivers;theALTA-1Linvestigatorsandtheirteammembers ateachstudysite;and colleaguesfromMillenniumPharmaceuti- cals, Inc.,Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. Professional medical writing assistancewasprovided byLaurenGallagher,RPh, PhD, of PelotonAdvantage,LLC, an OPEN Healthcompany,Parsip- pany,NJ,USA,andfundedbyMillenniumPharmaceuticals,Inc.

TeodorG.Paunescu,PhD(TakedaPharmaceuticalsU.S.A.,Inc.)is acknowledgedforeditorialassistance.

This study was supported by ARIAD Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. The sponsor designed and conducted the study and collected the data together with the authors.Thesponsor managedand analyzedthe data.Datawere interpretedbytheauthorsandthesponsor.Thesponsortogether withtheauthorsprepared,reviewed,andapprovedthemanuscript andmadethedecisiontosubmitthemanuscriptforpublication.

Disclosure

M.J.Ahn:Honoraria (AstraZeneca,MerckSharp &Dohme, Roche,BristolMyersSquibb,MerckKGaA,AlphaPharmaceuticals)

outsideofthesubmittedwork.H.R.Kim:Honoraria(BristolMyers Squibb,AstraZeneca,MerckSharp&Dohme,Takeda)outsideof the submitted work.J. C. H. Yang: Honoraria or advisory role (BoehringerIngelheim,EliLilly,Bayer,Roche/Genentech/Chugai, Astellas,MerckSharp&Dohme,MerckSerono,Pfizer,Novartis, Celgene,Merrimack,YuhanPharmaceuticals,BMS,OnoPharma- ceutical,DaiichiSankyo, Takeda, AstraZeneca, Hansoh Pharma- ceuticals). J. Y.Han: Researchgrants (Hoffmann-La RocheLtd, Ono,Pfizer,Takeda);consulting/advisorfees(AstraZeneca,Bristol Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Novartis, Pfizer,Takeda, MedPacto,Abion, Ono);honoraria (AstraZeneca, Bristol Myers Squibb, Hoffmann-La Roche Ltd., Merck Sharp

& Dohme, Takeda). M. J. Hochmair: Honoraria (AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Merck Sharp &

Dohme, Pfizer, Takeda, Roche); consulting or advisory role (Boehringer Ingelheim, Merck Sharp & Dohme, Pfizer, Novar- tis, Takeda, Roche). G. C. Chang: Honoraria (F. Hoffmann–

La Roche, Ltd, Eli Lilly and Company Oncology, AstraZeneca, Novartis, Pfizer, Boehringer Ingelheim, Bristol Myers Squibb, MerckSharp&Dohme). A.Delmonte: Consulting/advisoryrole (AstraZeneca, Boehringer Ingelheim). K. H. Lee: Support of clinical research (Merck), honoraria for advisory board participation (AstraZeneca, Bristol Myers Squibb, Lilly, Merck Sharp

& Dohme, Pfizer, Yu-han). M. R. García Campelo: Consult- ing/advisoryrole(MerckSharp&Dohme,BristolMyersSquibb, Roche,BoehringerIngelheim,Pfizer,Novartis,AstraZeneca,Lilly, Takeda, Bayer, Sanofi, Janssen); speakers bureau (Merck Sharp

&Dohme, Bristol Myers Squibb, Roche,Boehringer Ingelheim, Pfizer,Novartis,AstraZeneca, Lilly,Takeda, Janssen). C.Gridelli:

Honorariaasadvisoryboard memberorspeaker bureaumember (AstraZeneca, Roche, Pfizer, Eli Lilly, Merck Sharp & Dohme, BristolMyersSquibb,Novartis);honorariaasconsultant(Menarini, Roche).A.Spira:Consulting/advisoryrole(ARIAD,AstraZeneca, Clovis Oncology, Roche, Amgen, Mirati, Bristol Myers Squibb, Merck). R. Califano: Honoraria and consulting or advisory role (AstraZeneca, Bristol Myers Squibb, Roche, Merck Sharp &

Dohme, BoehringerIngelheim, Takeda, Novartis). F. Griesinger:

Supportofscientificresearch(AstraZeneca,BoehringerIngelheim, Bristol Myers Squibb, Celgene, Lilly, Merck Sharp & Dohme, Novartis, Pfizer,Roche,Takeda, Siemens,Amgen,GlaxoSmithK- line,Janssen);honorariaforpresentations(AstraZeneca,Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Lilly, Merck Sharp

& Dohme, Novartis, Pfizer, Roche, Takeda, ARIAD, AbbVie, Siemens, Amgen, GlaxoSmithKline, Janssen, Sanofi); advisory board participation (AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Lilly, Merck Sharp & Dohme, Novar- tis, Pfizer, Roche, Takeda, ARIAD, AbbVie, Siemens, Glaxo- SmithKline, Janssen, Sanofi). E. Felip: Personal fees (AbbVie, Amgen, AstraZeneca, Bayer, BeiGene, Blue Print Medicines, Boehringer Ingelheim, Bristol Myers Squibb, CME Outfitters, Eli Lilly, GlaxoSmithKline, Janssen, Medical Trends, Medscape, MerckKGaA,MerckSharp&Dohme,Novartis,PeerVoice,Pepto- myc, Pfizer, Prime Oncology, Puma Biotechnology, Regeneron, Roche,Sanofi Genzyme,Springer,Takeda,TouchMedical);grants (GrantforOncologyInnovation[GOI],FundaciónMerckSalud);

advisoryboard(SyneosHealth);independentmemberoftheboard