Trial Outcomes & Findings for ALTA-1L Study: A Study of Brigatinib Versus Crizotinib in Anaplastic Lymphoma Kinase Positive (ALK+) Advanced Non-small Cell Lung Cancer (NSCLC) Participants (NCT NCT02737501)

Last Updated: 2021-08-20

Results Overview

PFS as assessed by Blinded Independent Review Committee (BIRC), per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, was defined as the time interval from the date of randomization until the date of the first documented PD event. The data was censored for participants without a PFS event.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

275 participants

Primary outcome timeframe

Up to end of study (Up to 56 months)

Results posted on

2021-08-20

Participant Flow

Participants took part in the study at 92 investigative sites in Australia, Hong Kong, Singapore, South Korea, Taiwan, Austria, Denmark, France, Germany, Italy, Luxembourg, Netherlands, Norway, Spain, Sweden, Switzerland, United Kingdom, Canada, and the United States of America from 26 May 2016 to 29 January 2021.

Participants with anaplastic lymphoma kinase and non-small-cell lung cancer (ALK+ NSCLC) who had not previously received an ALK-targeted tyrosine kinase inhibitor (TKI) were enrolled in 1:1 ratio to receive brigatinib 90 mg for 7 days followed by 180 mg or crizotinib 250 mg. Participants from crizotinib arm who experienced progressive disease (PD) or received radiotherapy to the brain in Randomized Phase were crossed over to receive brigatinib 90 mg/180 mg in the Crossover Phase.

Participant milestones

Participant milestones
Measure	Randomized Phase: Brigatinib 90 mg QD/180 QD Brigatinib 90 mg, tablets, orally, once daily (QD) for first 7 days followed by 180 mg, orally, QD, in each 28-day cycle until disease progression (PD), intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 34.86 months).	Randomized Phase: Crizotinib 250 mg BID Crizotinib 250 mg, tablets, twice daily (BID) in each 28-day cycle until disease progression, intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 9.26 months).	Crossover Phase: Brigatinib 90 mg QD/180 mg QD Participants who experienced PD as assessed by the blinded Independent Review Committee (BIRC) or received radiotherapy to the brain while on 'Crizotinib 250 mg BID' therapy in Randomized Phase were crossed over. Following 10-day washout period, crossover participants received brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, tablets, orally, QD in each 28-day cycle up to end of the study (The median duration of exposure was 17.25 months).
Randomized Phase STARTED	137	138	0
Randomized Phase Safety Analysis Set	136	137	0
Randomized Phase COMPLETED	20	84	0
Randomized Phase NOT COMPLETED	117	54	0
Crossover Phase STARTED	0	0	65
Crossover Phase COMPLETED	0	0	10
Crossover Phase NOT COMPLETED	0	0	55

Reasons for withdrawal

Reasons for withdrawal
Measure	Randomized Phase: Brigatinib 90 mg QD/180 QD Brigatinib 90 mg, tablets, orally, once daily (QD) for first 7 days followed by 180 mg, orally, QD, in each 28-day cycle until disease progression (PD), intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 34.86 months).	Randomized Phase: Crizotinib 250 mg BID Crizotinib 250 mg, tablets, twice daily (BID) in each 28-day cycle until disease progression, intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 9.26 months).	Crossover Phase: Brigatinib 90 mg QD/180 mg QD Participants who experienced PD as assessed by the blinded Independent Review Committee (BIRC) or received radiotherapy to the brain while on 'Crizotinib 250 mg BID' therapy in Randomized Phase were crossed over. Following 10-day washout period, crossover participants received brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, tablets, orally, QD in each 28-day cycle up to end of the study (The median duration of exposure was 17.25 months).
Randomized Phase Died	41	29	0
Randomized Phase Withdrawal by Subject	16	6	0
Randomized Phase Lost to Follow-up	0	1	0
Randomized Phase Site Terminated by Sponsor	58	16	0
Randomized Phase Reason not Specified	1	1	0
Randomized Phase Never Treated	1	1	0
Crossover Phase Died	0	0	22
Crossover Phase Withdrew Consent	0	0	9
Crossover Phase Physician Decision	0	0	1
Crossover Phase Site Terminated by Sponsor	0	0	23

Baseline Characteristics

Number analyzed is number of participants with data available for global health status/QoL at Baseline.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Randomized Phase: Brigatinib 90 mg QD/180 QD n=137 Participants Brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, orally, QD, in each 28-day cycle until PD, intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 34.86 months).	Randomized Phase: Crizotinib 250 mg BID n=138 Participants Crizotinib 250 mg, tablets, BID in each 28-day cycle until disease progression, intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 9.26 months).	Total n=275 Participants Total of all reporting groups
Age, Continuous	57.9 years STANDARD_DEVIATION 13.46 • n=137 Participants	58.6 years STANDARD_DEVIATION 11.42 • n=138 Participants	58.2 years STANDARD_DEVIATION 12.46 • n=275 Participants
Sex: Female, Male Female	69 Participants n=137 Participants	81 Participants n=138 Participants	150 Participants n=275 Participants
Sex: Female, Male Male	68 Participants n=137 Participants	57 Participants n=138 Participants	125 Participants n=275 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=137 Participants	0 Participants n=138 Participants	0 Participants n=275 Participants
Race (NIH/OMB) Asian	59 Participants n=137 Participants	49 Participants n=138 Participants	108 Participants n=275 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=137 Participants	0 Participants n=138 Participants	0 Participants n=275 Participants
Race (NIH/OMB) Black or African American	0 Participants n=137 Participants	2 Participants n=138 Participants	2 Participants n=275 Participants
Race (NIH/OMB) White	76 Participants n=137 Participants	86 Participants n=138 Participants	162 Participants n=275 Participants
Race (NIH/OMB) More than one race	0 Participants n=137 Participants	0 Participants n=138 Participants	0 Participants n=275 Participants
Race (NIH/OMB) Unknown or Not Reported	2 Participants n=137 Participants	1 Participants n=138 Participants	3 Participants n=275 Participants
Race/Ethnicity, Customized Hispanic, Latino or Spanish	6 Participants n=137 Participants	10 Participants n=138 Participants	16 Participants n=275 Participants
Race/Ethnicity, Customized Not Hispanic, Latino or Spanish	131 Participants n=137 Participants	128 Participants n=138 Participants	259 Participants n=275 Participants
Region of Enrollment Australia	2 Participants n=137 Participants	5 Participants n=138 Participants	7 Participants n=275 Participants
Region of Enrollment Hong Kong	10 Participants n=137 Participants	6 Participants n=138 Participants	16 Participants n=275 Participants
Region of Enrollment Singapore	5 Participants n=137 Participants	1 Participants n=138 Participants	6 Participants n=275 Participants
Region of Enrollment Korea, Republic Of	29 Participants n=137 Participants	28 Participants n=138 Participants	57 Participants n=275 Participants
Region of Enrollment Taiwan, Province Of China	12 Participants n=137 Participants	9 Participants n=138 Participants	21 Participants n=275 Participants
Region of Enrollment Austria	5 Participants n=137 Participants	4 Participants n=138 Participants	9 Participants n=275 Participants
Region of Enrollment Denmark	2 Participants n=137 Participants	1 Participants n=138 Participants	3 Participants n=275 Participants
Region of Enrollment France	7 Participants n=137 Participants	4 Participants n=138 Participants	11 Participants n=275 Participants
Region of Enrollment Germany	6 Participants n=137 Participants	11 Participants n=138 Participants	17 Participants n=275 Participants
Region of Enrollment Italy	19 Participants n=137 Participants	19 Participants n=138 Participants	38 Participants n=275 Participants
Region of Enrollment Luxembourg	1 Participants n=137 Participants	0 Participants n=138 Participants	1 Participants n=275 Participants
Region of Enrollment Netherlands	5 Participants n=137 Participants	6 Participants n=138 Participants	11 Participants n=275 Participants
Region of Enrollment Norway	0 Participants n=137 Participants	2 Participants n=138 Participants	2 Participants n=275 Participants
Region of Enrollment Spain	14 Participants n=137 Participants	17 Participants n=138 Participants	31 Participants n=275 Participants
Region of Enrollment Sweden	0 Participants n=137 Participants	1 Participants n=138 Participants	1 Participants n=275 Participants
Region of Enrollment Switzerland	0 Participants n=137 Participants	1 Participants n=138 Participants	1 Participants n=275 Participants
Region of Enrollment United Kingdom	10 Participants n=137 Participants	8 Participants n=138 Participants	18 Participants n=275 Participants
Region of Enrollment Canada	0 Participants n=137 Participants	2 Participants n=138 Participants	2 Participants n=275 Participants
Region of Enrollment United States	10 Participants n=137 Participants	13 Participants n=138 Participants	23 Participants n=275 Participants
Global Health Status/Quality of Life (QoL)	60.432 score on a scale n=131 Participants • Number analyzed is number of participants with data available for global health status/QoL at Baseline.	59.160 score on a scale n=131 Participants • Number analyzed is number of participants with data available for global health status/QoL at Baseline.	59.796 score on a scale n=262 Participants • Number analyzed is number of participants with data available for global health status/QoL at Baseline.

PRIMARY outcome

Timeframe: Up to end of study (Up to 56 months)

Population: ITT Population included all participants randomized to each regimen regardless of whether they tested ALK+, or whether they received study drug or adhered to the assigned dose.

Outcome measures

Outcome measures
Measure	Randomized Phase: Brigatinib 90 mg QD/180 QD n=137 Participants Brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, orally, QD, in each 28-day cycle until PD, intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 34.86 months).	Randomized Phase: Crizotinib 250 mg BID n=138 Participants Crizotinib 250 mg, tablets, BID in each 28-day cycle until disease progression, intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 9.26 months).	Crossover Phase: Brigatinib 90 mg QD/180 mg QD n=65 Participants Participants who experienced PD as assessed by the BIRC or received radiotherapy to the brain while on 'Crizotinib 250 mg BID' therapy in Randomized Phase were crossed over. Following 10-day washout period, crossover participants received brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, tablets, orally, QD in each 28-day cycle up to end of the study (The median duration of exposure was 17.25 months).
Progression-free Survival (PFS)	24.016 months Interval 18.46 to 43.2	11.072 months Interval 9.13 to 13.01	16.821 months Interval 10.12 to 23.85

SECONDARY outcome

Timeframe: Baseline up to end of treatment (Up to 36 months)

Population: ITT Population included all participants randomized to each regimen regardless of whether they tested ALK+, or whether they received study drug or adhered to the assigned dose.

ORR was defined as percentage of participants who achieved Complete response (CR) or Partial responses (PR) using Response Evaluation Criteria in Solid Tumors (RECIST) version (v). 1.1 criteria. CR is defined as disappearance of all extranodal target and non-target lesions. All pathological lymph nodes must have decreased to less than (\<) 10 mm in short axis for target lesions and all lymph nodes must be non-pathological in size (\<10 mm short axis), normalization of tumor marker level for non-target lesions. PR is at least a 30% decrease in SLD of target lesions, taking as reference baseline sum diameters.

Outcome measures

Outcome measures
Measure	Randomized Phase: Brigatinib 90 mg QD/180 QD n=137 Participants Brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, orally, QD, in each 28-day cycle until PD, intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 34.86 months).	Randomized Phase: Crizotinib 250 mg BID n=138 Participants Crizotinib 250 mg, tablets, BID in each 28-day cycle until disease progression, intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 9.26 months).	Crossover Phase: Brigatinib 90 mg QD/180 mg QD n=65 Participants Participants who experienced PD as assessed by the BIRC or received radiotherapy to the brain while on 'Crizotinib 250 mg BID' therapy in Randomized Phase were crossed over. Following 10-day washout period, crossover participants received brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, tablets, orally, QD in each 28-day cycle up to end of the study (The median duration of exposure was 17.25 months).
Confirmed Objective Response Rate (ORR)	74.5 percentage of participants Interval 66.3 to 81.52	62.3 percentage of participants Interval 53.68 to 70.42	56.9 percentage of participants Interval 44.04 to 69.15

SECONDARY outcome

Timeframe: Baseline up to end of treatment (Up to 36 months)

Population: ITT Population included all participants randomized to each regimen regardless of whether they tested ALK+, or whether they received study drug or adhered to the assigned dose. Overall number of participants analyzed are the participants with data available for analyses.

ORR was defined as percentage of participants who achieved CR or PR in the central nervous system (CNS) in randomized participants with intracranial CNS metastasis at baseline. CR is defined as disappearance of all extranodal target and non-target lesions. All pathological lymph nodes must have decreased to \<10 mm in short axis for target lesions and all lymph nodes must be non-pathological in size (\<10 mm short axis), normalization of tumor marker level for non-target lesions. PR is at least a 30% decrease in the SLD of target lesions, taking as reference the baseline sum diameters.

Outcome measures

Outcome measures
Measure	Randomized Phase: Brigatinib 90 mg QD/180 QD n=47 Participants Brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, orally, QD, in each 28-day cycle until PD, intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 34.86 months).	Randomized Phase: Crizotinib 250 mg BID n=49 Participants Crizotinib 250 mg, tablets, BID in each 28-day cycle until disease progression, intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 9.26 months).	Crossover Phase: Brigatinib 90 mg QD/180 mg QD n=42 Participants Participants who experienced PD as assessed by the BIRC or received radiotherapy to the brain while on 'Crizotinib 250 mg BID' therapy in Randomized Phase were crossed over. Following 10-day washout period, crossover participants received brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, tablets, orally, QD in each 28-day cycle up to end of the study (The median duration of exposure was 17.25 months).
Confirmed Intracranial ORR (iORR)	66.0 percentage of participants Interval 50.69 to 79.14	14.3 percentage of participants Interval 5.94 to 27.24	35.7 percentage of participants Interval 21.55 to 51.97

SECONDARY outcome

Timeframe: Baseline up to end of study (Up to 56 months)

Intracranial PFS as assessed by BIRC, is defined as the time from randomization until first CNS PD is documented, or death due to any cause. PD is SLD increased by at least 20% from the smallest value on study (including baseline, if that is the smallest), the SLD must also demonstrate an absolute increase of at least 5 mm, and unequivocal progression of existing non-target lesions.

Outcome measures

Outcome measures
Measure	Randomized Phase: Brigatinib 90 mg QD/180 QD n=47 Participants Brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, orally, QD, in each 28-day cycle until PD, intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 34.86 months).	Randomized Phase: Crizotinib 250 mg BID n=49 Participants Crizotinib 250 mg, tablets, BID in each 28-day cycle until disease progression, intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 9.26 months).	Crossover Phase: Brigatinib 90 mg QD/180 mg QD n=42 Participants Participants who experienced PD as assessed by the BIRC or received radiotherapy to the brain while on 'Crizotinib 250 mg BID' therapy in Randomized Phase were crossed over. Following 10-day washout period, crossover participants received brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, tablets, orally, QD in each 28-day cycle up to end of the study (The median duration of exposure was 17.25 months).
Intracranial Progression Free Survival	23.951 months Interval 12.91 to 30.78	5.520 months Interval 3.71 to 7.52	24.542 months Interval 12.58 to Upper limit of 95% confidence interval (CI) was not estimable due to low number of participants with events.

SECONDARY outcome

Timeframe: Baseline up to end of study (Up to 56 months)

Population: ITT Population included all participants randomized to each regimen regardless of whether they tested ALK+, or whether they received study drug or adhered to the assigned dose.

Overall survival is defined as the time from randomization until death due to any cause.

Outcome measures

Outcome measures
Measure	Randomized Phase: Brigatinib 90 mg QD/180 QD n=137 Participants Brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, orally, QD, in each 28-day cycle until PD, intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 34.86 months).	Randomized Phase: Crizotinib 250 mg BID n=138 Participants Crizotinib 250 mg, tablets, BID in each 28-day cycle until disease progression, intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 9.26 months).	Crossover Phase: Brigatinib 90 mg QD/180 mg QD n=65 Participants Participants who experienced PD as assessed by the BIRC or received radiotherapy to the brain while on 'Crizotinib 250 mg BID' therapy in Randomized Phase were crossed over. Following 10-day washout period, crossover participants received brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, tablets, orally, QD in each 28-day cycle up to end of the study (The median duration of exposure was 17.25 months).
Overall Survival (OS)	NA months Median and 95% CI was not estimable due to fewer number of participants with events.	NA months Median and 95% CI was not estimable due to fewer number of participants with events.	35.023 months Interval 30.42 to Upper limit of 95% CI was not estimable due to fewer number of participants with events.

SECONDARY outcome

Timeframe: Baseline up to end of study (Up to 56 months)

Population: ITT Population included all participants randomized to each regimen regardless of whether they tested ALK+, or whether they received study drug or adhered to the assigned dose. Only responders were reported for this outcome measure.

Duration of response as assessed by BIRC, is defined as the time interval from the date that the criteria are first met for CR/PR (whichever is first recorded) until the first date that progressive disease (PD) is objectively documented. CR is defined as disappearance of all extranodal target and non-target lesions. All pathological lymph nodes must have decreased to \<10 mm in short axis for target lesions and all lymph nodes must be non-pathological in size (\<10 mm short axis), normalization of tumor marker level for non-target lesions. PR is at least a 30 % decrease in the SLD of target lesions, taking as reference the baseline sum diameters. PD is SLD increased by at least 20% from the smallest value on study (including baseline, if that is the smallest), the SLD must also demonstrate an absolute increase of at least 5 mm, and for non-target lesions, unequivocal progression of existing non-target lesions.

Outcome measures

Outcome measures
Measure	Randomized Phase: Brigatinib 90 mg QD/180 QD n=102 Participants Brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, orally, QD, in each 28-day cycle until PD, intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 34.86 months).	Randomized Phase: Crizotinib 250 mg BID n=86 Participants Crizotinib 250 mg, tablets, BID in each 28-day cycle until disease progression, intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 9.26 months).	Crossover Phase: Brigatinib 90 mg QD/180 mg QD n=37 Participants Participants who experienced PD as assessed by the BIRC or received radiotherapy to the brain while on 'Crizotinib 250 mg BID' therapy in Randomized Phase were crossed over. Following 10-day washout period, crossover participants received brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, tablets, orally, QD in each 28-day cycle up to end of the study (The median duration of exposure was 17.25 months).
Duration of Response (DOR)	33.150 months Interval 1.84 to 50.6	13.832 months Interval 1.45 to 49.81	19.154 months Interval 1.97 to 33.15

SECONDARY outcome

Timeframe: Baseline up to end of treatment (Up to 36 months)

Population: ITT Population included all participants randomized to each regimen regardless of whether they tested ALK+, or whether they received study drug or adhered to the assigned dose. Only responders were reported for this outcome measure.

Time to response as assessed by BIRC, assessment and is defined as the time interval from the date of randomization until the initial observation of CR or PR. CR is defined as disappearance of all extranodal target and non-target lesions. All pathological lymph nodes must have decreased to \<10 mm in short axis for target lesions and all lymph nodes must be non-pathological in size (\<10 mm short axis), normalization of tumor marker level for non-target lesions. PR is at least a 30% decrease in the SLD of target lesions, taking as reference the baseline sum diameters.

Outcome measures

Outcome measures
Measure	Randomized Phase: Brigatinib 90 mg QD/180 QD n=137 Participants Brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, orally, QD, in each 28-day cycle until PD, intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 34.86 months).	Randomized Phase: Crizotinib 250 mg BID n=138 Participants Crizotinib 250 mg, tablets, BID in each 28-day cycle until disease progression, intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 9.26 months).	Crossover Phase: Brigatinib 90 mg QD/180 mg QD n=65 Participants Participants who experienced PD as assessed by the BIRC or received radiotherapy to the brain while on 'Crizotinib 250 mg BID' therapy in Randomized Phase were crossed over. Following 10-day washout period, crossover participants received brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, tablets, orally, QD in each 28-day cycle up to end of the study (The median duration of exposure was 17.25 months).
Time to Response (TTR)	1.840 months Interval 1.02 to 29.47	1.873 months Interval 0.79 to 7.43	1.873 months Interval 0.2 to 18.33

SECONDARY outcome

Timeframe: Baseline up to end of treatment (Up to 36 months)

Population: ITT Population included all participants randomized to each regimen regardless of whether they tested ALK+, or whether they received study drug or adhered to the assigned dose.

Disease control as assessed by BIRC, defined as percentage of randomized participants who have achieved CR, PR, or stable disease (SD) after randomization. CR defined as disappearance of all extranodal target and non-target lesions. All pathological lymph nodes must have decreased to \<10 mm in short axis for target lesions and all lymph nodes must be non-pathological in size (\<10 mm short axis), normalization of tumor marker level for non-target lesions. PR: at least a 30% decrease in SLD of target lesions, taking as reference baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. PD: SLD increased by at least 20% from the smallest value on study, SLD must also demonstrate an absolute increase of at least 5 mm, and unequivocal progression of existing non-target lesions.

Outcome measures

Outcome measures
Measure	Randomized Phase: Brigatinib 90 mg QD/180 QD n=137 Participants Brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, orally, QD, in each 28-day cycle until PD, intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 34.86 months).	Randomized Phase: Crizotinib 250 mg BID n=138 Participants Crizotinib 250 mg, tablets, BID in each 28-day cycle until disease progression, intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 9.26 months).	Crossover Phase: Brigatinib 90 mg QD/180 mg QD n=65 Participants Participants who experienced PD as assessed by the BIRC or received radiotherapy to the brain while on 'Crizotinib 250 mg BID' therapy in Randomized Phase were crossed over. Following 10-day washout period, crossover participants received brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, tablets, orally, QD in each 28-day cycle up to end of the study (The median duration of exposure was 17.25 months).
Disease Control Rate (DCR)	85.4 percentage of participants Interval 78.36 to 90.85	86.2 percentage of participants Interval 79.34 to 91.5	73.8 percentage of participants Interval 61.46 to 83.97

SECONDARY outcome

Timeframe: From first dose up to 30 days after last dose of study drug (Up to approximately 37 months)

Population: Treated Population included all participant who received at least 1 dose of study drug and served as basis of safety analysis.

An AE is any untoward medical occurrence in a participant. An AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product whether or not considered related to the medicinal product. Any worsening of a preexisting condition which is temporally associated with the use of the study drug (i.e., occurs after the first dose of study drug) is also an AE. TEAEs are defined as AEs starting/worsening on or after the first dose of study treatment and no later than the earliest of 30 days after the last dose of the treatment to which the participant was assigned, or the day before start of brigatinib therapy in crossover participant.

Outcome measures

Outcome measures
Measure	Randomized Phase: Brigatinib 90 mg QD/180 QD n=136 Participants Brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, orally, QD, in each 28-day cycle until PD, intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 34.86 months).	Randomized Phase: Crizotinib 250 mg BID n=137 Participants Crizotinib 250 mg, tablets, BID in each 28-day cycle until disease progression, intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 9.26 months).	Crossover Phase: Brigatinib 90 mg QD/180 mg QD n=65 Participants Participants who experienced PD as assessed by the BIRC or received radiotherapy to the brain while on 'Crizotinib 250 mg BID' therapy in Randomized Phase were crossed over. Following 10-day washout period, crossover participants received brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, tablets, orally, QD in each 28-day cycle up to end of the study (The median duration of exposure was 17.25 months).
Percentage of Participants With Treatment-emergent Adverse Events (TEAEs)	100 percentage of participants	100 percentage of participants	98.5 percentage of participants

SECONDARY outcome

Timeframe: Baseline and Month 36

HRQoL: perceived quality of participant's life, includes self-reported multidimensional measures of physical and mental health. Patient-reported symptoms (PROs) and HRQoL will be collected by administering the european organisation for research and treatment of cancer (EORTC) quality of life (QLQ)-C30 questionnaire. EORTC-QLQ-C30 contains 30 items across 5 functional scales (physical, role, cognitive, emotional, and social), 9 symptom scales (fatigue, nausea and vomiting, pain, dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial difficulties) and a global health status/QOL scale. The 30 items have 4 response levels (not at all, a little, quite a bit, and very much), with 2 questions relying on a 7-point numeric rating scale. Raw scores are converted into overall score ranging from 0 to 100, where lower scores indicate better QOL. A negative change from Baseline indicates improvement.

Outcome measures

Outcome measures
Measure	Randomized Phase: Brigatinib 90 mg QD/180 QD n=104 Participants Brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, orally, QD, in each 28-day cycle until PD, intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 34.86 months).	Randomized Phase: Crizotinib 250 mg BID n=53 Participants Crizotinib 250 mg, tablets, BID in each 28-day cycle until disease progression, intolerable toxicity, consent withdrawal, or death (The median duration of exposure was 9.26 months).	Crossover Phase: Brigatinib 90 mg QD/180 mg QD Participants who experienced PD as assessed by the BIRC or received radiotherapy to the brain while on 'Crizotinib 250 mg BID' therapy in Randomized Phase were crossed over. Following 10-day washout period, crossover participants received brigatinib 90 mg, tablets, orally, QD for first 7 days followed by 180 mg, tablets, orally, QD in each 28-day cycle up to end of the study (The median duration of exposure was 17.25 months).
Change From Baseline in Global Health Status/Quality of Life as Assessed by EORTC QLQ-C30 (Version 3.0)	4.007 score on a scale Standard Deviation 25.7563	-4.088 score on a scale Standard Deviation 27.4748	—

Adverse Events

Randomized Phase: Brigatinib 90 mg QD/180 QD

Serious events: 56 serious events

Other events: 132 other events

Deaths: 41 deaths

Randomized Phase: Crizotinib 250 mg BID

Serious events: 53 serious events

Other events: 135 other events

Deaths: 29 deaths

Crossover Phase: Brigatinib 90 mg QD/180 mg QD

Serious events: 24 serious events

Other events: 63 other events

Deaths: 22 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

Takeda

Phone: +1-877-825-3327

Email: [email protected]

Results disclosure agreements

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