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    Clinical Trial Results:
    A Phase 3 Randomized Open-label Study of Brigatinib (ALUNBRIG®) Versus Alectinib (ALECENSA®) in Advanced Anaplastic Lymphoma Kinase-Positive Non–Small-Cell Lung Cancer Patients Who Have Progressed on Crizotinib (XALKORI®)

    Summary
    EudraCT number
    		 2018-001957-29
    Trial protocol
    		 FR   SE   ES   DE   AT   GR   HR   IT   RO  
    Global end of trial date
    18 Sep 2024

    Results information
    Results version number
    		 v2(current)
    This version publication date
    18 Jun 2025
    First version publication date
    14 Feb 2025
    Other versions
    		 v1
    Version creation reason

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    Brigatinib-3001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03596866
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Takeda
    Sponsor organisation address
    95 Hayden Avenue, Lexington, MA, United States, 02421
    Public contact
    Study Director, Takeda, TrialDisclosures@takeda.com
    Scientific contact
    Study Director, Takeda, TrialDisclosures@takeda.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    18 Sep 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Sep 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the trial was to compare the efficacy of Brigatinib to that of Alectinib in participants with anaplastic lymphoma kinase-positive (ALK+) locally advanced or metastatic non–small-cell lung cancer (NSCLC) who have progressed on Crizotinib as evidenced by PFS as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
    Protection of trial subjects
    Each participant signed an informed consent form (ICF) before participating in the study.
    Background therapy
    		 NA
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 Apr 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 2
    Country: Number of subjects enrolled
    Canada: 4
    Country: Number of subjects enrolled
    Chile: 17
    Country: Number of subjects enrolled
    France: 6
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Greece: 3
    Country: Number of subjects enrolled
    Hong Kong: 11
    Country: Number of subjects enrolled
    Italy: 4
    Country: Number of subjects enrolled
    Korea, Republic of: 24
    Country: Number of subjects enrolled
    Mexico: 1
    Country: Number of subjects enrolled
    Romania: 7
    Country: Number of subjects enrolled
    Russian Federation: 54
    Country: Number of subjects enrolled
    Spain: 7
    Country: Number of subjects enrolled
    Sweden: 1
    Country: Number of subjects enrolled
    Taiwan: 9
    Country: Number of subjects enrolled
    United States: 3
    Country: Number of subjects enrolled
    China: 93
    Worldwide total number of subjects
    248
    EEA total number of subjects
    30
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    205
    From 65 to 84 years
    43
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants took part in the study at various investigative sites globally from 19 April 2019 to 18 September 2024.

    Pre-assignment
    Screening details
    		 Participants with anaplastic lymphoma kinase positive (ALK+) non-small-cell lung cancer (NSCLC) who had progressed on crizotinib were administered either brigatinib or alectinib in this study.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Brigatinib
    Arm description
    		 Participants were administered brigatinib 90 mg, tablets, orally, QD for 7 days, followed by brigatinib 180 mg, tablets, orally, QD until objective disease progression per RECIST v1.1, as assessed by the investigator, or intolerable toxicity, or up to 63.47 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Brigatinib
    Investigational medicinal product code
    AP26113
    Other name
    Alunbrig
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Brigatinib 90 mg, tablets, orally, QD for 7 days was administered to participants followed by brigatinib 180 mg, tablets, orally, QD until objective disease progression per RECIST v1.1, as assessed by the investigator, or intolerable toxicity, or up to 33.8 months.

    Arm title
    		 Alectinib
    Arm description
    		 Participants were administered alectinib 600 mg, capsules, orally, BID until objective disease progression per RECIST v1.1, as assessed by the investigator, or intolerable toxicity, or up to 59.83 months.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Alectinib
    Investigational medicinal product code
    RO5424802/F03
    Other name
    Alecensa
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Alectinib 600 mg, capsules, orally was administered to participants BID until objective disease progression per RECIST version 1.1, as assessed by the investigator, or intolerable toxicity, or up to 33.8 months.

    Number of subjects in period 1
    		Brigatinib Alectinib
    Started
    125
    123
    Completed
    3
    6
    Not completed
    122
    117
         Adverse event, serious fatal
    37
    24
         Consent withdrawn by subject
    4
    6
         Reason Not Specified
    14
    13
         Lost to follow-up
    2
    3
         Site terminated by Sponsor
    64
    65
         Missing
    -
    6
         Protocol deviation
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Brigatinib
    Reporting group description
    		 Participants were administered brigatinib 90 mg, tablets, orally, QD for 7 days, followed by brigatinib 180 mg, tablets, orally, QD until objective disease progression per RECIST v1.1, as assessed by the investigator, or intolerable toxicity, or up to 63.47 months.

    Reporting group title
    Alectinib
    Reporting group description
    		 Participants were administered alectinib 600 mg, capsules, orally, BID until objective disease progression per RECIST v1.1, as assessed by the investigator, or intolerable toxicity, or up to 59.83 months.

    Reporting group values
    		 Brigatinib Alectinib Total
    Number of subjects
    		 125 123
    Age Categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 53.0 ( 12.17 ) 52.9 ( 13.53 ) -
    Gender categorical
    Units: Subjects
        Female
    		 67 68 135
        Male
    		 58 55 113
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 7 14 21
        Not Hispanic or Latino
    		 116 106 222
        Unknown or Not Reported
    		 2 3 5
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 74 66 140
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 0 2 2
        White
    		 50 52 102
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 1 3 4

    End points

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    End points reporting groups
    Reporting group title
    Brigatinib
    Reporting group description
    		 Participants were administered brigatinib 90 mg, tablets, orally, QD for 7 days, followed by brigatinib 180 mg, tablets, orally, QD until objective disease progression per RECIST v1.1, as assessed by the investigator, or intolerable toxicity, or up to 63.47 months.

    Reporting group title
    Alectinib
    Reporting group description
    		 Participants were administered alectinib 600 mg, capsules, orally, BID until objective disease progression per RECIST v1.1, as assessed by the investigator, or intolerable toxicity, or up to 59.83 months.

    Primary: Progression-free Survival (PFS) as Assessed by Blinded Independent Review Committee (BIRC) per RECIST v1.1

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    End point title
    		 Progression-free Survival (PFS) as Assessed by Blinded Independent Review Committee (BIRC) per RECIST v1.1
    End point description
    PFS is defined as the time interval from the date of randomization until the first date at which disease progression is objectively documented via RECIST v1.1 by BIRC, or death due to any cause, whichever occurs first, in the full analysis set. PFS was censored for participants without documented disease progression or death at the last valid tumor response assessment. FAS included all participants randomized to each regimen regardless of whether they were ALK+ by an FDA approved test (Vysis ALK Break Apart FISH Probe Kit, Ventana ALK (D5F3) CDx Assay, Foundation Medicine’s FoundationOne CDx) or a local test other than FISH and immunohistochemistry, or whether they received study drug or adhered to the assigned dose. 99999 indicates the upper limit of 95% confidence interval (CI) was not estimable due to censoring.
    End point type
    Primary
    End point timeframe
    Up to 33.8 months
    End point values
    		 Brigatinib Alectinib
    Number of subjects analysed
    125
    123
    Units: months
        median (confidence interval 95%)
    19.253 (15.671 to 99999)
    19.187 (12.879 to 99999)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Alectinib v Brigatinib
    Number of subjects included in analysis
    248
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8672 [1]
    Method
    		 2-sided Stratified Log-rank Test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.968
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.658
         upper limit
    		 1.424
    Notes
    [1] - P-value from a 2-sided stratified log-rank test using the stratification factors: presence of intracranial central nervous system (CNS) metastases at baseline, and best prior response to crizotinib therapy as assessed by the investigator.

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS is defined as the time interval from the date of randomization until death due to any cause in the full analysis set. OS was censored on the date of last contact for those participants who are alive. FAS included all participants randomized to each regimen regardless of whether they are ALK+ by an FDA approved test (Vysis ALK Break Apart FISH Probe Kit, Ventana ALK (D5F3) CDx Assay, Foundation Medicine’s FoundationOne CDx) or a local test other than FISH and immunohistochemistry, or whether they receive study drug or adhere to the assigned dose. 9999 indicates the median was not estimable due to low number of participants with events and 99999 indicates 95% CI was not estimable due to low number of participants with events.
    End point type
    Secondary
    End point timeframe
    Up to 64 months
    End point values
    		 Brigatinib Alectinib
    Number of subjects analysed
    125
    123
    Units: months
        median (confidence interval 95%)
    9999 (38.472 to 99999)
    9999 (9999 to 99999)
    Statistical analysis title
    		 Overall Survival (OS)
    Comparison groups
    Brigatinib v Alectinib
    Number of subjects included in analysis
    248
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0713 [2]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.592
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.956
         upper limit
    		 2.652
    Notes
    [2] - P-value was based on a 2-sided stratified log-rank test using the stratification factors: presence of intracranial CNS metastases at baseline and best prior response to crizotinib therapy as assessed by the investigator.

    Secondary: PFS as Assessed by Investigator per RECIST v1.1

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    End point title
    		 PFS as Assessed by Investigator per RECIST v1.1
    End point description
    PFS is defined as the time interval from the date of randomization until the first date at which disease progression is objectively documented via RECIST v1.1 by investigator, or death due to any cause, whichever occurs first, in the full analysis set. PFS was censored for participants without documented disease progression or death at the last valid tumor response assessment. FAS included all participants randomized to each regimen regardless of whether they are ALK+ by an FDA approved test (Vysis ALK Break Apart FISH Probe Kit, Ventana ALK (D5F3) CDx Assay, Foundation Medicine’s FoundationOne CDx) or a local test other than FISH and immunohistochemistry, or whether they receive study drug or adhere to the assigned dose.
    End point type
    Secondary
    End point timeframe
    Up to 33.8 months
    End point values
    		 Brigatinib Alectinib
    Number of subjects analysed
    125
    123
    Units: months
        median (confidence interval 95%)
    16.789 (10.940 to 19.417)
    16.591 (13.602 to 27.565)
    Statistical analysis title
    		 PFS as Assessed by Investigator per RECIST v1.1
    Comparison groups
    Brigatinib v Alectinib
    Number of subjects included in analysis
    248
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2501 [3]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.232
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.862
         upper limit
    		 1.761
    Notes
    [3] - P-value was based on a 2-sided stratified log-rank test using the stratification factors: presence of intracranial CNS metastases at baseline and best prior response to crizotinib therapy as assessed by the investigator.

    Secondary: Objective Response Rate (ORR) as Assessed by BIRC and Investigator per RECIST v1.1

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    End point title
    		 Objective Response Rate (ORR) as Assessed by BIRC and Investigator per RECIST v1.1
    End point description
    ORR is defined as the percentage of the participants who are confirmed to have achieved complete response (CR) or partial response (PR), using RECIST v1.1 after the initiation of study treatment. Percentages were rounded off to the nearest single decimal place. FAS included all participants randomized to each regimen regardless of whether they are ALK+ by an FDA approved test (Vysis ALK Break Apart FISH Probe Kit, Ventana ALK (D5F3) CDx Assay, Foundation Medicine’s FoundationOne CDx) or a local test other than FISH and immunohistochemistry, or whether they receive study drug or adhere to the assigned dose.
    End point type
    Secondary
    End point timeframe
    Up to 33.8 months
    End point values
    		 Brigatinib Alectinib
    Number of subjects analysed
    125
    123
    Units: percentage of participants
    number (confidence interval 95%)
        BIRC Assessed
    52.0 (42.9 to 61.0)
    61.0 (51.8 to 69.6)
        Investigator Assessed
    40.8 (32.1 to 49.9)
    56.1 (46.9 to 65.0)
    Statistical analysis title
    		 ORR: BIRC Assessed
    Statistical analysis description
    BIRC Assessed
    Comparison groups
    Brigatinib v Alectinib
    Number of subjects included in analysis
    248
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1555 [4]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.42
         upper limit
    		 1.15
    Notes
    [4] - P-value was from a Cochran-Mantel-Haenszel test stratified by the stratification factors: presence of intracranial CNS metastases at baseline and best prior response to crizotinib therapy as assessed by the investigator.
    Statistical analysis title
    		 ORR: Investigator Assessed
    Statistical analysis description
    Investigator Assessed
    Comparison groups
    Brigatinib v Alectinib
    Number of subjects included in analysis
    248
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0169 [5]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.33
         upper limit
    		 0.9
    Notes
    [5] - P-value was from a Cochran-Mantel-Haenszel test stratified by the stratification factors: presence of intracranial CNS metastases at baseline and best prior response to crizotinib therapy as assessed by the investigator.

    Secondary: Duration of Response (DOR) as Assessed by BIRC and Investigator Per RECIST v1.1

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    End point title
    		 Duration of Response (DOR) as Assessed by BIRC and Investigator Per RECIST v1.1
    End point description
    DOR is defined as the time interval from the time that the measurement criteria are first met for CR or PR(whichever is first recorded) until the first date that the progressive disease(PD) is objectively documented or death,as assessed by the investigator and BIRC,using RECIST v1.1.Participants who did not progress or died,were censored at the last tumor assessment date prior to receiving subsequent anticancer therapy.FAS=all participants randomized to each regimen regardless of whether they are ALK+ by an FDA approved test (Vysis ALK Break Apart FISH Probe Kit,Ventana ALK(D5F3) CDx Assay,Foundation Medicine’s FoundationOne CDx) or a local test other than FISH and immunohistochemistry,or whether they receive study drug or adhere to the assigned dose.Subjects analyzed(N)=number of participants with data available for analysis.n=number of participants with data available for analysis at specified categories.99999 indicates the data was not estimable due to low number of participants.
    End point type
    Secondary
    End point timeframe
    Up to 33.8 months
    End point values
    		 Brigatinib Alectinib
    Number of subjects analysed
    78
    88
    Units: months
    median (confidence interval 95%)
        BIRC Assessed (n=65,75)
    17.544 (14.784 to 99999)
    20.205 (12.649 to 99999)
        Investigator Assessed (n=51,69)
    17.511 (11.335 to 23.031)
    19.614 (14.226 to 99999)
    No statistical analyses for this end point

    Secondary: Time to Response as Assessed by Investigator and BIRC Per RECIST v1.1

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    End point title
    		 Time to Response as Assessed by Investigator and BIRC Per RECIST v1.1
    End point description
    Time to response is defined as the time interval from randomization until the initial observation of CR or PR, as assessed by the investigator and BIRC, using RECIST v1.1. Time to response will be summarized using descriptive statistics in participants with confirmed objective response. FAS=all participants randomized to each regimen regardless of whether they are ALK+ by an FDA approved test (Vysis ALK Break Apart FISH Probe Kit, Ventana ALK (D5F3) CDx Assay, Foundation Medicine’s FoundationOne CDx) or a local test other than FISH and immunohistochemistry, or whether they receive study drug or adhere to the assigned dose. Subjects analysed (N)=number of participants with data available for analysis. n=number of participants with data available for analysis at specified categories.
    End point type
    Secondary
    End point timeframe
    Up to 33.8 months
    End point values
    		 Brigatinib Alectinib
    Number of subjects analysed
    78
    88
    Units: months
    median (confidence interval 95%)
        BIRC Assessed (n=65,75)
    1.873 (1.64 to 16.49)
    1.840 (1.41 to 16.56)
        Investigator Assessed (n=51,69)
    1.873 (1.61 to 14.00)
    1.873 (1.41 to 10.87)
    No statistical analyses for this end point

    Secondary: Confirmed Intracranial Objective Response Rate (iORR) as Assessed by BIRC per Modified RECIST v1.1

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    End point title
    		 Confirmed Intracranial Objective Response Rate (iORR) as Assessed by BIRC per Modified RECIST v1.1
    End point description
    Confirmed iORR, as assessed by the BIRC, is defined as the percentage of the participants who have achieved CR or PR in the central nervous system (CNS) per a modification RECIST v1.1 after the initiation of study treatment in participants with CNS metastases at baseline. Percentages were rounded off to the nearest single decimal place. Measurable iCNS disease population included all participants in the full analysis population determined by the BIRC to have had at least 1 measurable iCNS tumor lesion.
    End point type
    Secondary
    End point timeframe
    Up to 33.8 months
    End point values
    		 Brigatinib Alectinib
    Number of subjects analysed
    30
    31
    Units: percentage of participants
    number (confidence interval 95%)
        Measurable
    73.3 (54.1 to 87.7)
    67.7 (48.6 to 83.3)
    Statistical analysis title
    		 Measurable iORR
    Comparison groups
    Brigatinib v Alectinib
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6246 [6]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.44
         upper limit
    		 3.84
    Notes
    [6] - P-value was from a Cochran-Mantel-Haenszel test stratified by best prior response to crizotinib therapy as assessed by the investigator at randomization per IXRS.

    Secondary: Intracranial Duration of Response (iDOR) as Assessed by the BIRC per Modified RECIST v1.1

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    End point title
    		 Intracranial Duration of Response (iDOR) as Assessed by the BIRC per Modified RECIST v1.1
    End point description
    iDOR, as assessed by the BIRC per modified RECIST v1.1, is defined as the time interval from the time that the measurement criteria are first met for CR or PR in the CNS (whichever is first recorded) until the first date that the PD in the CNS is objectively documented or death. Participants who did not progress or died, were censored at the last iCNS tumor assessment date prior to receiving subsequent anticancer therapy. Measurable iCNS disease population included all participants in the full analysis population determined by the BIRC to have had at least 1 measurable iCNS tumor lesion. Subjects analysed is the number of participants with data available for analysis. 9999 indicates median was not estimable due to low number of participants with events and 99999 indicates upper limit of 95% CI was not estimable due to low number of participants with events.
    End point type
    Secondary
    End point timeframe
    Up to 33.8 months
    End point values
    		 Brigatinib Alectinib
    Number of subjects analysed
    22
    21
    Units: months
    median (confidence interval 95%)
        Measurable
    17.413 (7.425 to 99999)
    9999 (5.552 to 99999)
    No statistical analyses for this end point

    Secondary: Time to Intracranial Disease Progression (iPD) as Assessed by BIRC per Modified RECIST v1.1

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    End point title
    		 Time to Intracranial Disease Progression (iPD) as Assessed by BIRC per Modified RECIST v1.1
    End point description
    Time to iPD, as assessed by the BIRC, is defined as the time interval from the date of randomization until the first date at which iPD is objectively documented via a modification of RECIST v1.1. Time to iPD was analyzed descriptively using Kaplan-Meier estimate method and was censored for participants without documented iPD at the last valid intracranial tumor response assessment. FAS included all participants randomized to each regimen regardless of whether they are ALK+ by an FDA approved test (Vysis ALK Break Apart FISH Probe Kit, Ventana ALK (D5F3) CDx Assay, Foundation Medicine’s FoundationOne CDx) or a local test other than FISH and immunohistochemistry, or whether they receive study drug or adhere to the assigned dose. n=number of participants with data available for analyses at the specified time points.
    End point type
    Secondary
    End point timeframe
    Up to 33.8 months
    End point values
    		 Brigatinib Alectinib
    Number of subjects analysed
    125
    123
    Units: months
    median (confidence interval 95%)
        6 months (n=83,86)
    0.873 (0.792 to 0.925)
    0.916 (0.845 to 0.956)
        12 months (n=45,48)
    0.747 (0.640 to 0.826)
    0.795 (0.695 to 0.865)
        18 months (n=23,27)
    0.628 (0.498 to 0.733)
    0.735 (0.617 to 0.822)
        24 months (n=9,13)
    0.502 (0.351 to 0.636)
    0.665 (0.516 to 0.777)
    Statistical analysis title
    		 Time to iPD as Assessed by BIRC
    Comparison groups
    Brigatinib v Alectinib
    Number of subjects included in analysis
    248
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1423 [7]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.483
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.872
         upper limit
    		 2.52
    Notes
    [7] - P-value was based on a 2-sided stratified log-rank test using the stratification factors: presence of intracranial CNS metastases at baseline and best prior response to crizotinib therapy as assessed by the investigator.

    Secondary: Health-Related Quality of Life (HRQOL) from European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30 v3.0) Score

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    End point title
    		 Health-Related Quality of Life (HRQOL) from European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30 v3.0) Score
    End point description
    EORTC QLQ-C30 incorporates 5 functional scales(physical functioning,role functioning,emotional functioning,cognitive functioning,and social functioning),1 global health status scale,3 symptom scales(fatigue,nausea and vomiting,and pain), and 6 single items(dyspnea,insomnia,appetite loss,constipation,diarrhea,and financial difficulties).EORTC QLQ-C30 contains 28 questions(4-point scale where 1=Not at all [best] to 4=Very Much [worst]) and 2 questions(7-point scale where 1=Very poor [worst] to 7= Excellent [best]).Raw scores are converted into scale scores ranging from 0 to 100.For the functional scales and the global health status scale,higher scores represent better quality of life(QOL);for the symptom scales,lower scores represent better QOL.The patient-reported outcome(PRO) analysis set included all participants with baseline and at least 1 post-baseline PRO measurement in the full analysis set.Subjects analysed is the number of participants with data available for analysis.
    End point type
    Secondary
    End point timeframe
    Up to 33.8 months
    End point values
    		 Brigatinib Alectinib
    Number of subjects analysed
    37
    41
    Units: score on a scale
    median (full range (min-max))
        End of Treatment
    86.15 (35.9 to 100.0)
    84.74 (36.6 to 100.0)
    No statistical analyses for this end point

    Secondary: HRQOL from EORTC QLQ- Lung Cancer (LC) 13

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    End point title
    		 HRQOL from EORTC QLQ- Lung Cancer (LC) 13
    End point description
    HRQOL scores were assessed with European Organization for Research and Treatment (EORTC), its lung cancer module QLQ-LC13. QLQ-LC13 contains 13 questions assessing lung cancer-associated symptoms (cough, hemoptysis, dyspnea, and site-specific pain), treatment-related side effects (sore mouth, dysphagia, peripheral neuropathy, and alopecia), and use of pain medication. Scale score range: 0 to 100. Higher symptom score = greater degree of symptom severity. The PRO analysis set included all participants with baseline and at least 1 post-baseline PRO measurement in the full analysis set. Subjects analysed is the number of participants with data available for analysis of this outcome measure at end of treatment visit.
    End point type
    Secondary
    End point timeframe
    Up to 33.8 months
    End point values
    		 Brigatinib Alectinib
    Number of subjects analysed
    37
    40
    Units: score on a scale
    median (full range (min-max))
        End of Treatment: Dyspnoea
    22.22 (0.0 to 88.9)
    11.11 (0.0 to 88.9)
        End of Treatment: Coughing
    33.33 (0.0 to 100.0)
    33.33 (0.0 to 66.7)
        End of Treatment: Haemoptysis
    0.00 (0.0 to 33.3)
    0.00 (0.0 to 66.7)
        End of Treatment: Sore mouth
    0.00 (0.0 to 100.0)
    0.00 (0.0 to 66.7)
        End of Treatment: Dysphagia
    0.00 (0.0 to 100.0)
    0.00 (0.0 to 66.7)
        End of Treatment: Peripheral neuropathy
    0.00 (0.0 to 66.7)
    0.00 (0.0 to 100.0)
        End of Treatment: Alopecia
    0.00 (0.0 to 33.3)
    0.00 (0.0 to 100.0)
        End of Treatment: Pain in chest
    0.00 (0.0 to 66.7)
    0.00 (0.0 to 100.0)
        End of Treatment: Pain in arm or shoulder
    0.00 (0.0 to 66.7)
    0.00 (0.0 to 100.0)
        End of Treatment: Pain in other parts
    0.00 (0.0 to 66.7)
    0.00 (0.0 to 100.0)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to approximately 5 years 4 months
    Adverse event reporting additional description
    Safety Analysis Set included all participants who received at least 1 dose of study drug. As per planned analysis, data for adverse events was collected per treatment groups (brigatinib and alectinib) irrespective of the dosing regimen and is presented accordingly.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.0
    Reporting groups
    Reporting group title
    Brigatinib
    Reporting group description
    		 Participants were administered brigatinib 90 mg, tablets, orally, QD for 7 days, followed by brigatinib 180 mg, tablets, orally, QD until objective disease progression per RECIST v1.1, as assessed by the investigator, or intolerable toxicity, or up to 63.47 months.

    Reporting group title
    Alectinib
    Reporting group description
    		 Participants were administered alectinib 600 mg, capsules, orally, BID until objective disease progression per RECIST version 1.1, as assessed by the investigator, or intolerable toxicity, or up to 59.83 months.

    Serious adverse events
    		 Brigatinib Alectinib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    38 / 125 (30.40%)
    24 / 122 (19.67%)
         number of deaths (all causes)
    37
    25
         number of deaths resulting from adverse events
    12
    3
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Brain neoplasm
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervix carcinoma
    Additional description: Number of participants at risk in each arm is based on the male population in this study.
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervix carcinoma recurrent
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibroadenoma of breast
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatocellular carcinoma
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal adenocarcinoma
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Non-small cell lung cancer
         subjects affected / exposed
    3 / 125 (2.40%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    Metastases to ovary
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperpyrexia
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nodule
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pelvic mass
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Swelling face
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Dyspnoea
         subjects affected / exposed
    5 / 125 (4.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    5 / 125 (4.00%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    3 / 125 (2.40%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Pleural effusion
         subjects affected / exposed
    2 / 125 (1.60%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Cardiovascular somatic symptom disorder
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    1 / 125 (0.80%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchoscopy
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Radiation necrosis
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pericardial effusion
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Brain oedema
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    1 / 125 (0.80%)
    2 / 122 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 125 (0.80%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain lower
         subjects affected / exposed
    1 / 125 (0.80%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis erosive
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    2 / 125 (1.60%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    0 / 125 (0.00%)
    2 / 122 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia
         subjects affected / exposed
    2 / 125 (1.60%)
    3 / 122 (2.46%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypophagia
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Brigatinib Alectinib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    122 / 125 (97.60%)
    118 / 122 (96.72%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    59 / 125 (47.20%)
    47 / 122 (38.52%)
         occurrences all number
    112
    103
    Aspartate aminotransferase increased
         subjects affected / exposed
    71 / 125 (56.80%)
    51 / 122 (41.80%)
         occurrences all number
    177
    127
    Amylase increased
         subjects affected / exposed
    26 / 125 (20.80%)
    14 / 122 (11.48%)
         occurrences all number
    62
    36
    Alpha hydroxybutyrate dehydrogenase increased
         subjects affected / exposed
    8 / 125 (6.40%)
    0 / 122 (0.00%)
         occurrences all number
    18
    0
    Bilirubin conjugated increased
         subjects affected / exposed
    2 / 125 (1.60%)
    10 / 122 (8.20%)
         occurrences all number
    3
    21
    Blood creatine phosphokinase MB increased
         subjects affected / exposed
    7 / 125 (5.60%)
    3 / 122 (2.46%)
         occurrences all number
    22
    3
    Blood creatinine increased
         subjects affected / exposed
    16 / 125 (12.80%)
    21 / 122 (17.21%)
         occurrences all number
    42
    68
    Blood creatine phosphokinase increased
         subjects affected / exposed
    92 / 125 (73.60%)
    39 / 122 (31.97%)
         occurrences all number
    279
    102
    Blood cholesterol increased
         subjects affected / exposed
    8 / 125 (6.40%)
    3 / 122 (2.46%)
         occurrences all number
    14
    4
    Blood bilirubin unconjugated increased
         subjects affected / exposed
    2 / 125 (1.60%)
    7 / 122 (5.74%)
         occurrences all number
    3
    18
    Blood glucose increased
         subjects affected / exposed
    9 / 125 (7.20%)
    3 / 122 (2.46%)
         occurrences all number
    17
    6
    Blood alkaline phosphatase increased
         subjects affected / exposed
    16 / 125 (12.80%)
    25 / 122 (20.49%)
         occurrences all number
    26
    49
    Blood bilirubin increased
         subjects affected / exposed
    7 / 125 (5.60%)
    39 / 122 (31.97%)
         occurrences all number
    9
    121
    Blood insulin increased
         subjects affected / exposed
    14 / 125 (11.20%)
    9 / 122 (7.38%)
         occurrences all number
    35
    12
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    25 / 125 (20.00%)
    13 / 122 (10.66%)
         occurrences all number
    46
    43
    Weight decreased
         subjects affected / exposed
    11 / 125 (8.80%)
    3 / 122 (2.46%)
         occurrences all number
    22
    7
    Neutrophil count decreased
         subjects affected / exposed
    3 / 125 (2.40%)
    7 / 122 (5.74%)
         occurrences all number
    4
    17
    Lipase increased
         subjects affected / exposed
    29 / 125 (23.20%)
    23 / 122 (18.85%)
         occurrences all number
    78
    66
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    8 / 125 (6.40%)
    2 / 122 (1.64%)
         occurrences all number
    17
    2
    Blood urea increased
         subjects affected / exposed
    1 / 125 (0.80%)
    9 / 122 (7.38%)
         occurrences all number
    1
    15
    White blood cell count decreased
         subjects affected / exposed
    1 / 125 (0.80%)
    7 / 122 (5.74%)
         occurrences all number
    3
    14
    Weight increased
         subjects affected / exposed
    6 / 125 (4.80%)
    12 / 122 (9.84%)
         occurrences all number
    6
    18
    Vascular disorders
    Hypertension
         subjects affected / exposed
    38 / 125 (30.40%)
    5 / 122 (4.10%)
         occurrences all number
    63
    7
    Nervous system disorders
    Headache
         subjects affected / exposed
    23 / 125 (18.40%)
    21 / 122 (17.21%)
         occurrences all number
    38
    29
    Dizziness
         subjects affected / exposed
    10 / 125 (8.00%)
    8 / 122 (6.56%)
         occurrences all number
    11
    8
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    27 / 125 (21.60%)
    45 / 122 (36.89%)
         occurrences all number
    58
    136
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    15 / 125 (12.00%)
    8 / 122 (6.56%)
         occurrences all number
    19
    10
    Fatigue
         subjects affected / exposed
    11 / 125 (8.80%)
    19 / 122 (15.57%)
         occurrences all number
    16
    26
    Oedema peripheral
         subjects affected / exposed
    4 / 125 (3.20%)
    23 / 122 (18.85%)
         occurrences all number
    5
    27
    Influenza like illness
         subjects affected / exposed
    9 / 125 (7.20%)
    9 / 122 (7.38%)
         occurrences all number
    12
    12
    Pyrexia
         subjects affected / exposed
    4 / 125 (3.20%)
    7 / 122 (5.74%)
         occurrences all number
    8
    13
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    6 / 125 (4.80%)
    7 / 122 (5.74%)
         occurrences all number
    7
    8
    Constipation
         subjects affected / exposed
    14 / 125 (11.20%)
    35 / 122 (28.69%)
         occurrences all number
    17
    52
    Diarrhoea
         subjects affected / exposed
    16 / 125 (12.80%)
    21 / 122 (17.21%)
         occurrences all number
    19
    32
    Dyspepsia
         subjects affected / exposed
    7 / 125 (5.60%)
    2 / 122 (1.64%)
         occurrences all number
    11
    3
    Nausea
         subjects affected / exposed
    18 / 125 (14.40%)
    11 / 122 (9.02%)
         occurrences all number
    29
    38
    Vomiting
         subjects affected / exposed
    13 / 125 (10.40%)
    12 / 122 (9.84%)
         occurrences all number
    115
    17
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    16 / 125 (12.80%)
    26 / 122 (21.31%)
         occurrences all number
    18
    33
    Dyspnoea
         subjects affected / exposed
    15 / 125 (12.00%)
    12 / 122 (9.84%)
         occurrences all number
    18
    13
    Productive cough
         subjects affected / exposed
    3 / 125 (2.40%)
    8 / 122 (6.56%)
         occurrences all number
    3
    11
    Skin and subcutaneous tissue disorders
    Photosensitivity reaction
         subjects affected / exposed
    8 / 125 (6.40%)
    2 / 122 (1.64%)
         occurrences all number
    18
    4
    Pruritus
         subjects affected / exposed
    9 / 125 (7.20%)
    11 / 122 (9.02%)
         occurrences all number
    11
    12
    Rash
         subjects affected / exposed
    19 / 125 (15.20%)
    12 / 122 (9.84%)
         occurrences all number
    31
    15
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    7 / 125 (5.60%)
    6 / 122 (4.92%)
         occurrences all number
    7
    7
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    15 / 125 (12.00%)
    19 / 122 (15.57%)
         occurrences all number
    25
    31
    Back pain
         subjects affected / exposed
    13 / 125 (10.40%)
    16 / 122 (13.11%)
         occurrences all number
    17
    20
    Muscle spasms
         subjects affected / exposed
    7 / 125 (5.60%)
    3 / 122 (2.46%)
         occurrences all number
    10
    3
    Pain in extremity
         subjects affected / exposed
    8 / 125 (6.40%)
    6 / 122 (4.92%)
         occurrences all number
    11
    7
    Myalgia
         subjects affected / exposed
    8 / 125 (6.40%)
    20 / 122 (16.39%)
         occurrences all number
    14
    27
    Infections and infestations
    COVID-19
         subjects affected / exposed
    13 / 125 (10.40%)
    13 / 122 (10.66%)
         occurrences all number
    15
    13
    Nasopharyngitis
         subjects affected / exposed
    3 / 125 (2.40%)
    7 / 122 (5.74%)
         occurrences all number
    4
    7
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 125 (3.20%)
    8 / 122 (6.56%)
         occurrences all number
    6
    11
    Metabolism and nutrition disorders
    Hypercholesterolaemia
         subjects affected / exposed
    8 / 125 (6.40%)
    2 / 122 (1.64%)
         occurrences all number
    13
    4
    Decreased appetite
         subjects affected / exposed
    16 / 125 (12.80%)
    5 / 122 (4.10%)
         occurrences all number
    17
    9
    Hypokalaemia
         subjects affected / exposed
    8 / 125 (6.40%)
    12 / 122 (9.84%)
         occurrences all number
    22
    16
    Hyponatraemia
         subjects affected / exposed
    10 / 125 (8.00%)
    8 / 122 (6.56%)
         occurrences all number
    22
    18
    Hypoalbuminaemia
         subjects affected / exposed
    7 / 125 (5.60%)
    7 / 122 (5.74%)
         occurrences all number
    11
    13
    Hyperuricaemia
         subjects affected / exposed
    12 / 125 (9.60%)
    17 / 122 (13.93%)
         occurrences all number
    31
    56
    Hyperglycaemia
         subjects affected / exposed
    13 / 125 (10.40%)
    11 / 122 (9.02%)
         occurrences all number
    22
    28
    Hypertriglyceridaemia
         subjects affected / exposed
    9 / 125 (7.20%)
    5 / 122 (4.10%)
         occurrences all number
    20
    12

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Jun 2019
    The following changes were made as per Amendment 2: 1. Updated title to reflect Brigatinib (Alunbrig®) registration. 2. Updated the date that participant enrolment began. 3. Updated the guidance regarding female contraception. 4. Updated Excluded Medications to include moderate cytochrome P450 (CYP)3A inhibitors and to provide further guidance to investigators. 5. Updated inclusion criteria.
    09 Mar 2020
    The following changes were made as per Amendment 3: 1. Updated sponsor information from ARIAD Pharmaceuticals, Inc to Takeda Development Center Americas, Inc. 2. Removed “time to iPD” from the key secondary endpoints and revised the order of other secondary endpoints. 3. Added new exclusion criterion 7 (other primary malignancies other than NSCLC) and renumbered subsequent criteria. 4. Added requirement for acknowledgment of receipt when reporting adverse events (AEs) and serious adverse events (SAEs) by facsimile. 5. Revised the secondary endpoint analyses to reflect that iPD will no longer be a key secondary endpoint and was removed from hierarchical testing.
    08 Mar 2021
    The following changes were made as per Amendment 4: 1. Updated the creatine phosphokinase (CPK) dose modification guidance. 2. Updated the storage condition of Brigatinib to “Store at controlled room temperature of 20°C to 25°C with excursions permitted between 15°C to 30°C.” 3. Added the description of direct-to-patient (DTP) drug delivery during the coronavirus disease 2019 (COVID-19) pandemic. 4. Added criteria to terminate BIRC assessment if the primary endpoint is met at the interim analysis (IA) or primary analysis, or not met at the primary analysis. 5. Added description of remote source document verification during the COVID-19 pandemic.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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